General and synthetic methods: A review of the literature published during 1984, Volume 9

General and Synthetic Methods ~ Volume 9 A Specialist Periodical Report General and Synthetic Methods Volume 9 A R...

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General and Synthetic Methods ~

Volume 9

A Specialist Periodical Report

General and Synthetic Methods Volume 9

A Review of the Literature Pubtished in 19Wq*:+, I

'/

f >

"~

~

-.:y.

. ...

:;k''Phph

Me

+

S'

Me

0

Reagents: i, ZLDA;

ii, NH4CI; iii. LDA, Me1

Scheme 59

+ Me+ Me

34

General and Synthetic Methods

spontaneously to the formation of cyclized products (Scheme 60). Protonation at low temperature, to give the intermediate ( 8 1 ) , followed by separate treatment with LDA gives higher yields. However, application of this two-step procedure to the unsubstituted ester (82) yields differently substituted cyclopentenones (Scheme 61). Finally in this section, several new metnods for the synthesis of alkylidene lactones and butenolides have been reported. Scheme 62 illustrates a new route to a-methylene-y-butyrolactones developed by Otera et al.’O1 The key step in this sequence is t h e high-yielding thioallylic rearrangement of a-methoxyallyl sulphides which occurs on heating in refluxing hexane in the presence of silica gel. Radical cyclization also appears t o be a useful approach to the synthesis of compounds of this type. Thus, cyclization of radicals derived from the appropriately substituted bromo-acetals (83) or (84) occurs stereoselectively t o give the corresponding tetrahydrofurans (85) and (86), which are then easily converted into a- and B - m e t h y l e n e - y - b u t y r o l a c t o n e s , respectively (Scheme 63).Io2 Bromo-acetals of type (83) are readily prepared by the reaction of butoxyallene with an excess of allylic alcohol in the presence of N-bromosuccinimide. A one-pot procedure for the (E)-selective preparation of spiro-a-ethylidene-y-butyrolactones (87), which involves treatment of the dianion of methyl tiglamide with cycloalkariones, has been reported by Ladlow and Pattenden (Scheme 64).ID3 In another report, sodium salts derived from a formyl-lactones have been shown to react with aldehydes to give mixtures of ( E ) - and (L)-a-alkylidene-y- and 6-lactones in good yield. O4 Utimoto and his co-workers have examined the palladium(I1)catalysed cyclization of 3-, 4 - , and 5-alkynoic acids to but-3-en4-olides1 pent-4-en-4-olides1 and hex-5-en-5-olides1 respectively. I o 5 Similar results have also been obtained in an independent study using yellow mercury(I1) oxide. Io6 The reaction of dianions derived from N-substituted-3-(phenylsulphonyl)propanamides with aldehydes and ketones constitutes a short and versatile approach to 5-alkyl-2(5H)-furanones. I o 7 The application of this method to the synthesis of optically active products using chiral amides further enhances its importance (Scheme 65). Finally, Tanis and Head have made use of the silylfurans ( 8 8 ) and ( 8 9 ) as butenolide anion equivalents. lo’ The derived Grignard reagents couple with alkyl halides to give the corresponding 3 - and

35

1: Saturated and Unsaturated Hydrocarbons

zlCO,,. '

Reagents:

i. m ) z C u L i ; ii, LDA

Scheme 60

0

(82)

Reagents: i, Pr'MgCI, C u l ; ii, LDA

Scheme 61

SPh But Me,Si

6

OMe

Rv

...

111,

iv

t

& + -s R p h '

0

Rcogcnts: i, SiOz, hexanc,

A ; ii. 30% H2SO4 ; iii. CrOg , H#Q, Schema 62

OH acetone;

iv, DBU


36

Br Bu0

Reagents: i, ButgSnH, AIBN; ii, Jones oxidation

Scheme 63

.

Reagents: i, 2 BusLi; ii,

.

; iii, H + , A

Scheme 64

j i, ii

PhSOZ

H

‘IY7fiNx PhS@

Reagents: i, 2 BuLi; ii, C8H17CHO; iii, H+

Scheme 65

H

Ph


37

4-alkylsilylfurans (9. Scheme 66). Subsequent oxidation with peracetic acid then effectively unmasks the latent butenolides, thus providing a general route to 3- and 4-alkyl-2(5H)-furanones.

3 Conjugated 1,3-Dienes The research groups of bill up^'^^ and Staley' l o have independently reported the synthesis of methylenecyclopropene ( 9 0 1 , the simplest cross-conjugated cyclic hydrocarbon (Scheme 67). Characterization of this novel compound both spectroscopically and by means of chemical trapping experiments is possible only at low temperatures. As part of an approach to polycyclic compounds via sequential Diels-Alder reactions, Minami and co-workers have devised a new synthesis of 1,2-bisylidenecyclobutanes, which proceeds in good yield. Thus, treatment of benzaldehyde with the ylide (91 ) , generated in,situ from the phosphonium salt (92) and diethyl lithiophosphonate, leads to the formation of diene (93) in 70% yield (Scheme 68). Cinnamaldehyde reacts in a similar manner (43%). l,l-Diphenyl-4,4-bis(trifluoromethyl)butatriene undergoes a concerted thermal [ n2s + x2s] cycloaddition reaction with 1 , l dimethoxyethylene at 100-110 OC to produce the structurally related 1,2-bismethylenecyclobutane (95). Enamines such as (96 ) react in the same way even at temperatures as low as 20-100 O C (Scheme 69). The reaction of aromatic five-membered heterocycles with Grignard reagents, in the presence of nickel catalysts such as 1,3bis-(dipheny1phosphino)propanenickel dichloride, has proved to be a Although (z,Z)-buta- 1 ,3-dienes tend useful route to 1,3-dienes. to be formed preferentially the stereochemical outcome of the reaction is sometimes dependent on the nature of the Grignard reagent (3. Scheme 70). The allyltitanium species (97), prepared by sequential treatment of t-butyl-3-trimethylsilylprop-I-enyl sulphide (98) with t-butyllithium and titanium tetra-isopropoxide, undergoes condensation with aldehydes at -78 OC. l 5 Subsequent substitution of the t-butyl sulphide group takes place on treatment with Grignard reagents in the presence of a nickel catalyst to afford (E,Z)dienes, as illustrated in the synthesis of spilanthol (99), an insecticidal natural product isolated from Spilanthes oleranceae (Scheme 71). The development of several new synthons for terminal 1,3-dienes

'

38


Reagents: i, Mg,THF;

ii,;'B -r

iii, MeC03H

Scheme 66

Reagents: i, K0But, ChromosorbW, RT, 20-30 mtorr; ii, KOBut,THF, -40

OC,

0.50 torr

Scheme 67

0

(91)

(92) 0 II Reagents: i, (EtO+PLi;

ii, PhCHO

Scheme 6%

Ph

">

RZ

- YC Ph

A

(94) R' = R 2 = OMe (96) R' = R Z = NMe, Scheme 69

\

R'

RZ

(95)


39

Bun

Ph Reagents: i, Bun MgBr. 1 , 3 -bis(diphenylphosphino)propanenickel dichloride;

ii, PhMgBr, bis(tripheny1phosphino) nickel dichloride

Scheme 70

ButS,p,SiMel

ButMe2Si0 ~

X

SBU'

(98) X = H

ii - v

(97) X = Ti(OR)3

\

CONHBu'

( 99)

ii. MeMg1, Ni(cat.1; iii, B g 4 N F ; iv, (COC1)2, DMSO, Et3N;

Reagents: i, ButMe2SiO-CHO; V,

PhjP=CHCONHBu'

Scheme 71 ..

..

II,III

Ph

%S -

i Me3

+

SiMe, /

OSiMe3

Reagents: i ,

P h w M g C I ; ii, H2, Lindlar; iii, SnC14;

iv,

(5 (102)

Scheme 72

Ph

/ -

40


has been reported this year. Clive and Angoh, for example, have examined the vinylogous counterpart of the well known fragmentation of 8-hydroxysilanes (Scheme 72). l 6 Thus, the aldehyde ( 100), readily prepared from propargylsilane, reacts with Grignard reagents such as (101) or silyl enol ethers (102) to give the corresponding propargyl alcohols. Subsequent semi-hydrogenation over Lindlar catalyst, followed by treatment with SnCl,,, leads stereospecifically to (E)-1,3-dienes in good yields. An alternative approach to compounds of this type is provided by the work of Shechter and Hsiao, who have used (E)- and benzenesulphonyl-4-trimethylsilylbut-2-ene as a general (El-l-buta1,3-dienyl synthon.’I7 The application o f this method to a highly stereoselective synthesis of (E)-dodeca-9,11-dien-l-y1 acetate (103), a sex pheromone of the red bollworm moth, is illustrated in Scheme 73. Regiospecific alkylation at the 2-position of 2,5dihydro-3-methylthiophene 1,l-dioxide (104), followed by Lhermal extrusion of sulphur dioxide, forms the basis of a useful method for stereoselective introduction of a terminal isoprene unit (Scheme 74). l8 Similarly , 3-acetyl-2,5-dihydrothiophene 1 , I dioxide (105) has been shown to be a stable precursor of 2acetylbuta-l13-diene (106), a useful synthetic building block (Scheme 75). 119 In a continuation of their work on the synthesis of 1,3-dienes via the vinylogous Rambert-Backlund reaction of a,@-unsaturated bromomethylsulphones, Block and co-workers have observed good regioselectivity in the y-deprotonation of unsymmetrical substrates (Scheme 76). In the case of the (L)-isomer ( 1 0 7 ) , the regioselectivity may be reversed on changing the base from potassium to lithium t-butoxide, possibly as a result of Mild complexation of the lithium cation by the sulphonyl group conditions for the synthesis of 1,3-dienes via the palladiumcatalysed coupling o f enol triflates with a variety of functionalized olefins have been reported by Ortar et al. (Scheme 77). 12’ Similar methodology involving the coupling of enol triflates with organostannanes in the presence of [Pd(PPh ) 1 and 3 4 lithium chloride has been applied to a short stereospecific synthesis of pleraplysillin-I ( 108) (Scheme 78). 122 The palladium(0)-catalysed reaction of vinyl halides with allenes in the presence of sodium ethyl malonate leads to functionalized dienes, such as (log), in good yields (Scheme 79). 123 Aryl halides react similarly to afford styrenes. In

(z)-l-


41

M

e

3

/

SO2Ph

S

i

Br

3

S02Ph

Reagents: i, Br(CH2)8Br, HMPA, BuLi; ii, Bun4NF, 0 O C ;

iii, NaOAc, DMF, 120 “c

Scheme 73

Reagents: i, LiN(SiMeg)z,THF; i i ,

wB , r , A. ”‘ 111

Scheme 74

(106 1

(105) Scheme 75 S02CH2Br i. ____)

R

R

6 BrcH2sh II

R

R

(107 1

Reagents.

I,

KOBU’, ii, LiOBut

Scheme 76

42


Reagents; i, P C O z M e , Pd(OAc12, W h 3 , Et3N

Scheme 77

i=/'"""'

LiCy

Reagents: i,

'''Q

, [Pd(PPh3I4], LiCl

Scheme 78

Scheme 79

TT -

Et02C

C02Et

Reagents: i, [RhCI(PPh3)3];

Et:x2E EtoP l i

ii, [Pd(PPh3)4]

Scheme 80


43

certain cases, stereoselectivity can be high. Smooth deoxygenation of 1,4-endoperoxides to 1,3-dienes occurs readily on treatment with low-valent titanium at room temperature. 124 Under the influence of palladium o r rhodium catalysts, 2-bromo1,6-dienes cyclize to give mixtures of conjugated five-membered bis-exocyclic dienes and six-membered mono-exocyclic dienes. 125 In contrast, 2-bromo-1,7-dienes cyclize regiospecifically to give sixmembered rings only. The selectivity appears to be strongly dependent on reaction conditions. Thus, in the case of diene (IIO), 5-exo-trig cyclization predominates when the reaction is carried out in the presence of [RhCl(PPh ) 1 , whereas [Pd(PPh3)4] 3 3 favours the formation of the 6-endo-trig product (Scheme 80). Diynes of type ( 1 1 1 ) undergo a unique stereoselective cyclization at -20 O C on treatment with d i c y c l o p e n t a d i e n y l t i t a n i u m dichloridem e t h y l d i p h e n y l p h o s p h i n e - s o d i u m amalgam (molar ratio 1:1:2) to afford on hydrolysis (E,E)-exocyclic dienes (112) in good yields (Scheme 81).126 The reaction works well for five-, six- and sevenmembered rings, but fails for eight-membered rings and for substrates containing terminal acetylene functions. Both 2,3-bis(trimethylstannyl)buta-l,3-diene (113) and the bis(trimethylstanny1)acetylene (114) have proved to be useful as synthetic equivalents of the 2,3-dianion of buta- 1 ,3-diene. 27 Thus, step-wise lithiation of (113) followed by reaction with electrophiles, o r electrophilic substitution of (114), permits the synthesis of a wide range of both symmetrical and unsymmetrical 2,3-disubstituted buta-1,3-dienes (Scheme 82). Sternbach's group has studied the reaction of fulvenes with various nucleophiles as a means of preparing substituted cyclopentadienes required as intramolecular Diels-Alder precursors (Scheme 83). 128 2-Fluorodienes can be readily prepared from 2-fluoroalk-2-enals using standard Wittig methodology. 12' Although product isomer ratios are similar to those observed with the corresponding nonfluorinated substrates, the observed reaction rates appear to be significantly retarded. An alternative entry to compounds of this type involves the concerted fragmentation of I-chloro-I-fluoro-2(trimethylsilyl)methylcyclopropanes. This reaction occurs smoothly on heating to 130-140 OC in diethylene glycol dimethyl ether in the presence of tetrabutylammonium fluoride o r chloride (Scheme 84). 30 B-Alk-l-enyl-9-borabicyclo~3.3.llnonanes undergo a highly stereoselective conjugate addition-elimination sequence on treatment with 4-methoxybut-3-en-2-one (115) at room temperature to

44


Reagents: i , [CpzTiCIz], MePPhZ, Na/Hg

Scheme 01 SnMe:, Me3Sn

X

Me3Sn

Y

Ill

(113 1

'%Me3

(114) Scheme 82

Reagents: i,

0 I

EtZNH; ii, DIGAL, iii, LiAlHL

Scheme 83

ie

SiMe,

CI

I

Me

Reagents: i, Bu"~NF, 130

OC

Scheme 84

M

p

O A (115)

~

Scheme 85

45


furnish the corresponding (E,E)-dienes in quantitative yield. The preparation of (E1E)-trideca-3,5-dien-2-one (116) is illustrative (Scheme 8 5 ) . 1 3 ’ The availability of both enantiomers of the tricarbonyliron complex (117) in optically active form permits the synthesis of various functionalized (E1E)-1,4-diene complexes of known absolute configuration and with high optical purity ( > 9 5 % e.e). 1327133 Final decomplexation to unmask the free dienes is simply carried out by treatment with ceric ammonium nitrate in methanol at -15 O C . The palladium-catalysed amination of the phosphonate (118) followed by condensation with aldehydes and ketones affords a general route to the 5-aminopenta-Il3-diene moiety, a structural feature present in several naturally occurring compounds (Scheme 86).134 Although overall yields are good, mixtures of 2 2 0 nm) of both (169) and (170) leads to the formation of anti-tricyclo-octadiene (171), possibly suggesting the


62

,

R e a g e n t s : i , BuLi ; ii , Z n C I Z iii I C H = CHCI,[ Pd(PPh3)4]( cat.); iv, NaNH2 ,NH3; v, E

Scheme 117

Scheme 118

(172) Reagents:i,LiAIH4;

ii,MsCl;iii L i B r ; i v , A 1 2 0 3 j v , B u L i ; v i , C I P O ( O E t ) 2 ; v i i , L i , N H ~

S c h e m e 119

+

63

1: Saturated and Unsaturated Hydrocarbons i n t e r m e d i a c y of ( 1 6 9 ) i n t h e p h o t o c h e m i s t r y of ( 1 7 0 ) . Scheme 119 shows t h e f i n a l s t a g e s i n t h e s y n t h e s i s o f 1 1 , 1 2 -

dimethylbicyclo[5.3.2ldodeca-I

,6, 1l-triene

( 1 7 2 ) (m.p.

36-38

OC),

a

f a s c i n a t i n g m o l e c u l e i n which t h e c o n j u g a t e d d o u b l e b o n d s a r e

E.

90' t o e a c h o t h e r . 183 D e s p i t e e a r l i e r p r e d i c t i o n s r e g a r d i n g t h e t h e r m a l s t a b i l i t y of t h e h i g h l y permanently f i x e d a t

u n s a t u r a t e d p r o p e l l a n e s ( 1 7 3 ) a n d ( 1 7 4 ) , t h e s e m o l e c u l e s h a v e now b e e n s y n t h e s i z e d by PaqLlette e t a l . a n d shown t o be r e m a r k a b l y s t a b l e . 184

I n d e e d , on h e a t i n g ( 1 7 4 ) a t 160

evidence f o r retro-Diels-Alder

OC

f o r 90 h , no

f r a g m e n t a t i o n was f o u n d .

p e n t a e n e ( 1 7 3 ) , h o w e v e r , p r o v e d t o b e more r e a c t i v e , s m o o t h l y a t 95

The

fragmenting

OC.

The s y n t h e s i s by Corey a n d E c k r i c h o f 5 , 6 - d e h y d r o a r a c h i d o n i c a c i d ( 1 7 5 ) , o u t l i n e d i n Scheme 1 2 0 , s e r v e s t o i l l u s t r a t e a new, s t e r e o s p e c i f i c r o u t e t o complex p o l y u n s a t u r a t e d f a t t y a c i d s o f t h i s The i m p o r t a n t f e a t u r e s o f t h i s method w o r t h n o t i n g a r e

-

t y p e 185

t h e c i s - c a r b o s t a n n y l a t i o n of a l k y n e s u s i n g t r i b u t y l t i n t r i f l a t e and t h e s u b s e q u e n t i t e r a t i v e c o u p l i n g b a s e d on t h e d i f u n c t i o n a l intermediate (176).

The key s t e p i n a v e r s a t i l e s y n t h e s i s o f

e n y n e s , d i y n e s , a n d p o l y e n e s d e v e l o p e d by O t e r a ' s r e s e a r c h g r o u p i s t h e f o r m a t i o n o f a c e t y l e n i c o r p o l y e n i c b o n d s w h i c h o c c u r s on t r e a t m e n t of u n s a t u r a t e d 6 - a c e t o x y - s u l p h o n e s

(or t h e corresponding

THP e t h e r s ) w i t h p o t a s s i u m t - b u t o x i d e . 186

The method h a s b e e n a p p l i e d , f o r e x a m p l e , t o t h e f o r m a l t o t a l s y n t h e s i s o f (&)muscone,

p a r t of w h i c h i s shown i n Scheme 121.

Thermolysis (200

OC,

sealed

t u b e ) of t h e divinylcyclopropane (177) l e a d s smoothly t o t h e f o r m a t i o n o f t h e two p r o d u c t s ( 1 7 8 ) a n d ( 1 7 9 ) ( r a t i o 4 : l ) i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d (Scheme 1 2 2 ) . 187

Subsequent c o n t r o l l e d h y d r o g e n a t i o n ( L i n d l a r c a t a l y s t ) f o l l o w e d by m i l d

alkaline hydrolysis furnishes both arachidonic acids.

cis- a n d

trans-7,13-bridged

I-Chloro-(~,~)-l74-dienes of t y p e ( 1 8 1 1 , which

a r e r e a d i l y a v a i l a b l e by t h e t r e a t m e n t o f ( E ) - a l k e n y l a l a n e s ( 1 8 0 ) react with terminal alkynes i n t h e p r e s e n c e o f [ P d ( P P h 3 ) 4 ] ( 5 mol%)>,c o p p e r i o d i d e ( 1 5 mol%), a n d b u t y l a m i n e t o g i v e t h e d i e n y n e s ( 1 8 2 ) i n 80-90% y i e l d (Scheme 1 2 3 ) 188 T r i p l y u n s a t u r a t e d h y d r o c a r b o n s s u c h as ( 1 8 4 ) a n d ( 1 8 5 ) r e s u l t from t h e s t e r e o s p e c i f i c c r o s s - c o u p l i n g o f with (E)-dichloroethylene,

-

e n y n y l d i a l k y l b o r a n e s ( 1 8 3 ) w i t h a l l y 1 b r o m i d e s or l-bromo-la l k y n e s , r e s p e c t i v e l y (Scheme 1 2 4 )

.

89

Finally, the ylide derived

bromide f r o m l-(trans-2,3-dichloroprop-2-enyl)triphenylphosphonium r e a c t s w i t h a v a r i e t y o f a l d e h y d e s , k e t o n e s , a n d e n o n e s a t -30 OC


64

(174 1

(173)

I. , I .I

9o010

'

Bu3Sn \_/C5Hll

1, .1 .1 ,

iv

bu35n

i i i , iv 184°/o

-COzH ... Ill

e

c

Reagents: i , ( C 5 H l l ) Z C u L i

5

H

1

1

j i i , Bu3SnOTfi i i i , B u L i

v

,VI

84'1.

i v , Bu3Sn/?

C02E t

c02et

0 R e a g e n t s : i, B u t C l , ZnC12; ii, MeOH, HCL;

111,

t)H R 1 R 2 C 0 , ZnC12; iv, cyclohexenone, ZnC12

Scheme 36

R CH 2C 0,H

iii, , Me2N=CH ZLiNPr’2 +

NMe2

‘02

+

‘p OSiMe,

R

_t

R&

0

R&

C02Et

I

C02Et

SiMe, (1 63)

(16 4 )

(1 6 5 )

(166)


162 a r e a l w a y s l e s s t h a n 60%. R3=H)

However, c l e a v a g e o f c y c l o p r o p a n e s ( 1 6 0 ;

w i t h bromine g i v e s t h e c o r r e s p o n d i n g a - b r o m o - d e r i v a t i v e s o f

keto-esters

( 1 6 1 ) w h i c h c a n s o m e t i m e s be i s o l a t e d .

Subsequent

e l i m i n a t i o n of H B r t h e n l e a d s t o t h e u n s a t u r a t e d homologues ( 1 6 2 ) . 56

S i m i l a r l y , TiC14-catalysed

r i n g opening of cyclopropanes

( 1 6 0 ) i n t h e p r e s e n c e of p h e n y l s e l e n e n y l c h l o r i d e o r

0-

nitrophenylsulphenyl chloride gives the potentially useful a-seleno

o r u - s u l p h e n y l d e r i v a t i v e s ( 1 6 1 ; R 4 = PhSe o r g-N02C6H4S).157 r i n g - c l e a v a g e r e a c t i o n a l s o c o n s t i t u t e s a key s t e p i n t h e

A

' r e d u c t i v e s u c c i n o y l a t i o n ' approach t o 6 - s u b s t i t u t e d y-keto-esters. T h u s , t h e t r a p p e d a c y l o i n ( 1 6 4 ) , d e r i v e d from d i e t h y l s u c c i n a t e , undergoes SnC14-catalysed a l d o l - t y p e

condensations with a c e t a l s

(163) leading d i r e c t l y t o the ring-cleavage useful, semi-protected y-keto-esters i n t o y-keto-esters

products (165).

These

c a n be i s o l a t e d o r c o n v e r t e d

( 1 6 6 ) d u r i n g work-up. 1 5 8 Yet a n o t h e r r o u t e t o

y - k e t o - e s t e r s which r e l i e s upon L e w i s a c i d - c a t a l y s e d r i n g c l e a v a g e o f a s i l y l o x y - c y c l o p r o p a n e i n v o l v e s an i n i t i a l r e a c t i o n between t h e mixed a c e t a l ( 1 6 7 ) o f c y c l o p r o p a n o n e a n d z i n c c h l o r i d e , w h i c h p r o d u c e s t h e z i n c h o m o e n o l a t e s ( 1 6 8 ) . 235 S u b s e q u e n t c o u p l i n g w i t h a n a c i d c h l o r i d e i n t h e p r e s e n c e of c u p r o u s i o d i d e a n d HMPA l e a d s t o simple

y

-keto-esters

( 169) i n high y i e l d .

Homoenolates ( 168)

a l s o add i n a Michael f a s h i o n t o e n o n e s , b u t o n l y i n t h e p r e s e n c e o f t h e Me S i c 1 f o r m e d d u r i n g t h e i r g e n e r a t i o n , t o g i v e t h e E - k e t o 3 ester d e r i v a t i v e s (170) i n high y i e l d s . I s o x a z o l i n e s ( 1 7 1 1 , o b t a i n e d by [ 1 , 3 ] - d i p o l a r c y c l o a d d i t i o n s between n i t r i l e o x i d e s and a c r o l e i n d i e t h y l a c e t a l , undergo t h e e x p e c t e d N-0 bond c l e a v a g e on r e d u c t i o n w i t h R a n e y - n i c k e l , l e a d i n g t o t h e useful hydroxy-acetals (172). However, on t r e a t m e n t w i t h HC1-EtOH, t h e s e undergo rearrangement w i t h s u r p r i s i n g f a c i l i t y t o g i v e t h e y-keto-esters (169; R 1 = E t ) i n very high yields.16' High e n a n t i o m e r i c e n r i c h m e n t s h a v e b e e n o b t a i n e d i n a l k y l a t i o n s o f b i c y c l i c l a c t a m s d e r i v e d from 3 - b e n z o y l p r o p i o n i c a c i d a n d valinol, leading t o

ci

,a-disubstituted

keto-esters

(L)-

( 173). 16'

U n f o r t u n a t e l y , t h e method i s n o t s u i t a b l e f o r t h e s y n t h e s i s o f t h e c o r r e s p o n d i n g mono-alkyl

d e r i v a t i v e s ( 173; R2=H)

owing t o e x t e n s i v e

r a c e m i z a t i o n d u r i n g t h e f i n a l a c i d h y d r o l y s i s of t h e lactams. Novel v e r s i o n s o f t h e M i c h a e l r e a c t i o n c o n t i n u e t o p r o v i d e new r o u t e s t o b o t h y - and 6 - k e t o - e s t e r s . N i t r o - o l e f i n s ( 1 7 4 ) a c t as e x c e l l e n t Michael a c c e p t o r s i n r e a c t i o n s w i t h k e t e n e s i l y l a c e t a l s ( 1 7 5 ) u n d e r t h e now f a m i l i a r c o n d i t i o n s c o n s i s t i n g o f T i C 1 4 - C H 2 C 1 2 a t -78

OC,

a l t h o u g h i n some c a s e s t h e f u r t h e r a d d i t i o n o f T i ( O P r 1 ) 4

3: Carboxylic Acids and Derivatives

163

i s b e n e f i c i a l . 162 H y d r o l y s i s of t h e r e s u l t i n g n i t r o - e s t e r s t o k e t o - e s t e r s (176) i s b e s t c a r r i e d o u t i n s i t u by a d d i n g DME-H20. A z o - a n i o n s (177) d e r i v e d from a l d e h y d e t - b u t y l h y d r a z o n e s u n d e r g o M i c h a e l r e a c t i o n s w i t h m e t h y l c r o t o n a t e t o g i v e a z o - e s t e r s (178; R 2 = M e ) ; s u b s e q u e n t i s o m e r i z a t i o n (TFA) a n d h y d r o l y s i s ( o x a l i c a c i d ) l e a d s t o t h e 7 - k e t o - e s t e r s (179) i n 50-60% o v e r a l l y i e l d s . 163 A l t e r n a t i v e l y , a z o - e s t e r s (178; R 2 = H ) c a n be o b t a i n e d d i r e c t l y f r o m t h e r m a l ene r e a c t i o n s between t h e t - b u t y l h y d r a z o n e s and methyl Similar e n e r e a c t i o n s of p h e n y l h y d r a z o n e s and m e t h y l acrylate. a c r y l a t e a l s o g i v e a z o - e s t e r s [cf.(178)1 w h i c h c a n be s u c c e s s f u l l y r e d u c e d u s i n g Adam's c a t a l y s t a n d h y d r o c h l o r i c a c i d t o h y d r o c h l o r i d e s a l t s of 7 - a m i n o - a c i d s . L e w i s acid-catalysed Michael a d d i t i o n s o f k e t e n e s i l y l a c e t a l s (175) t o e n o n e s (180), l e a d i n g t o & k e t o - e s t e r s , h a v e b e e n known f o r some time. A m o d i f i c a t i o n t o t h i s is t o c a t a l y s e t h e r e a c t i o n s with tris(dimethylamino1s u l p h o n i u m difluorotrimethylsiliconate (TASF), 1 6 4 w h i c h i s n o t o n l y

a good s o u r c e o f c o m p l e t e l y a n h y d r o u s f l u o r i d e b u t a l s o a l l o w s f o r t h e e a s y i s o l a t i o n o f t h e i n i t i a l s i l y l e n o l e t h e r s (181). I n some unhindered examples, such Michael a d d i t i o n s can be simply c a r r i e d o u t a t room t e m p e r a t u r e by u s i n g n i t r o m e t h a n e a s s o l v e n t i n t h e a b s e n c e of f l u o r i d e . (A previously reported fluoride-free alternative involves heating the reactants i n acetonitrile.) An e x c e p t i o n t o t h e u s u a l o b s e r v a t i o n t h a t l i t h i u m e n o l a t e s add mainly [1,2] t o e n o n e s i s t h e f i n d i n g t h a t m e t h y l l i t h i o t r i m e t h y l s i l y l a c e t a t e a d d s t o c y c l o p e n t e n o n e t o g i v e t h e M i c h a e l a d d u c t [cf.(l81; R=SiMe ) ] i n 85% y i e l d . 165 A s i m i l a r r e a c t i o n w i t h c y c l o h e x e n o n e 3 g i v e s m a i n l y t h e [ 1 , 2 ] a d d u c t . Howzver, s i m p l e l i t h i u m e n o l a t e s d e r i v e d from e s t e r s w i l l add i n a Michael f a s h i o n t o v e r y r e a c t i v e enones; such is t h e c a s e with t h e e x o c y c l i c a ' - e t h y l i d e n e c y c l o p e n t e n o n e (182). 166 A l k y l a t i o n o f t h e i n t e r m e d i a t e e n o l a t e s w i t h r e a c t i v e e l e c t r o p h i l e s ( E + > p r o v i d e s t h e homologues ( 183). L i t t l e or no a t t a c k a t t h e endo-enone f u n c t i o n i s o b s e r v e d . B a s e d on some p r e v i o u s r e p o r t s s c a t t e r e d t h r o u g h o u t t h e l i t e r a t u r e , C o a t e s a n d Hobbs h a v e d e v e l o p e d a g e n e r a l method f o r t h e i n t r o d u c t i o n o f a n a - a l k o x y a l l y l g r o u p i n t o 0 - d i c a r b o n y l compounds a n d r e l a t e d r e a d i l y e n o l i z a b l e s u b s t r a t e s . 167 The r e a c t i o n s s i m p l y i n v o l v e h e a t i n g t h e s u b s t r a t e and an a c e t a l of an a , B - e n a l , t o g e t h e r w i t h a t r a c e o f [ N i ( a c a c ) , l i n t h e case o f a 0 - k e t o - e s t e r . The p r o d u c t s [e.g. (184)l amount t o f o r m a l M i c h a e l a d d u c t s b u t may arise v i a 0 - a l k y l a t i o n and s u b s e q u e n t C l a i s e n rearrangement.


164

-

R

OEt

R&

(177)

0

(169)

Ph

OH

(178)

(179)

+

C02Me

ii, 5"L NaOH

COZEt

C0,Me


165

Unsaturated Esters.- A full account has been given of the alkylation and subsequent base-induced ring cleavage of the 4oxothiolane anion ( 185) leading to acrylates ( 186). 1 6 8 The anion ( 1 8 5 ) can thus be regarded as the equivalent of the vinyl carbanion ( 187). A tandem Michael addition-Peterson olefinationlgO sequence starting with the a-silylacrylate ( 1 8 8 ) can be used to obtain highly substituted acrylates (189) in a 'one-pot' reaction. So far, the method has been found to be successful with PhMgBr, 2 lithiobutadiene, and lithio(methylsulphiny1)methyl sulphide but not with alkyl Grignard reagents. The useful skipped dienes (191) can be readily obtained by coupling bromomethyl methacrylate (190) with a terminal acetylene using zinc-zinc bromide in THF under ultrasonic agitation. I7O Sensitive functionalities such as trimethylsilyl ethers and diethyl acetals are tolerated. Carbon radicals, R', generated from an acid chloride, R C O C 1 , and Ehydroxy-2-thiopyridone as mentioned earlier,56 157 add to the methacrylate derivative (192) to give homologues (193) in 56-74% yield l7 O f particular significance is the finding that tertiary radicals react as efficiently as less substituted species. The synthesis of chiral a-(hydroxyalky1)acrylates (195) of 75% e.e. has been achieved, albeit in poor yield, by sequential condensation betweer, the magnesium enolate of chiral sulphoxide ( 194) and an aldehyde, followed by thermolysis. 172 The related threo-y-alkoxy homologues (196) have been prepared by highly diastereoselective condensations between esters of 0-alanine and C I alkoxy-aldehydes. 17' A Wadsworth-Emmons approach to substituted acrylates (193) consists simply of treating a-substituted phosphonates (197) with potassium carbonate and 30% aqueous formaldehyde. 174 An alternative method for the preparation of these useful phosphonates is by Wolff rearrangement of a-diazo-0-ketophosphonates, available f r o m esters following reaction with a lithiomethylphosphonate and diazo-group transfer using TsN 175 These latter authors use LDA3' THF at -15 OC followed by anhydrous formaldehyde to effect the Wadsworth-Emmons reaction leading to (193). Modified recipes also continue to be developed for Wadsworth-Emmons approaches to a , B unsaturated esters in general. Condensations of phosphonates (197; R = H ) with aldehydes can be effected using solid potassium carbonate in d i o ~ a n e 'o~r ~ lithium chloride and an amine such as DBU or diisopropylethylamine. 177 Both methods result in high ( E l selectivity; the latter method is especially designed for use with

166


C0,Me

CO, Me

(188)

CO, B u t

(189)

(196)

(198)

CHO

(199) n = 0,1, or 2

P h S e w

(200)

(1 91 1

(190)

(197)

SCO),, A r

C02But

(2011

----

OMe R

Ho&cozBut

(202)

167

3: Carboxylic Acids and Derivatives base-sensitive

substrates.

When B u n L i i s u s e d a s b a s e , e n o l a t e s o f

p h o s p h o n a t e s (197; R=Me) c o n d e n s e w i t h a - b r a n c h e d a l d e h y d e s a t l o w t e m p e r a t u r e s t o g i v e s e l e c t i v e l y t h e ( Z ) - i s o m e r s o f e s t e r s ( 198; R ’

= Me). 178 P h o s p h i n e o x i d e s c o r r e s p o n d i n g t o (197; R=Me) by c o n t r a s t l e a d t o t h e ( E ) - i s o m e r s (198; R 1 = M e ) . Knoevenagel r e a c t i o n s between a l d e h y d e s and t h e s u l p h u r s u b s t i t u t e d a c e t a t e s (199) c a n b e c a t a l y s e d b y p i p e r i d i n e a n d i n g e n e r a l l e a d t o t h e (El-isomers acceptors.

(200) of t h e s e u s e f u l Michael

An u n u s u a l r o u t e t o u , B - u n s a t u r a t e d

esters (202) (201) w i t h

c o n s i s t s of s e q u e n t i a l treatment of t h e 8-selenenyl-enal

a l i t h i u m e n o l a t e of an ester, t p c h l o r o p e r b e n z o i c a c i d , and LiOHThe m e c h a n i s m i n v o l v e s t h e i n t e r m e d i a c y o f a 3 - m e t h o x y o x e t a n e a n d r e l i e s on t h e a b i l i t y o f a s e l e n o n y l g r o u p t o a c t b o t h as a n a c t i v a t o r o f d o u b l e bonds t o M i c h a e l a d d i t i o n s a n d as a good

MeOH. I8O

leaving group.

A nitro-group

is a l s o u s e f u l i n t h e l a t t e r r e s p e c t .

T h i s h a s b e e n e x p l o i t e d i n a new a p p r o a c h t o u n s a t u r a t e d e s t e r s c(204); n

0 and

a,B-

a s w e l l as

y,b-

2 r e s p e c t i v e l y ] by r e a c t i o n s

between t h e a l l y l i c nitro-compounds ( 2 0 3 ) and l i t h i u m d i a l k y l c u p r a t e s . 18’

Although only t r i e d with r a t h e r simple

s u b s t r a t e s , t h e method l o o k s t o h a v e a f a i r l y g e n e r a l a p p l i c a t i o n and l e a d s l a r g e l y t o t h e ( E ) - i s o m e r s .

Lewis acid-catalysed

a d d i t i o n s of a l l y l i c sulphides t o methyl p r o p i o l a t e g i v e t h e u s e f u l v i n y l s u l p h i d e s ( 2 0 5 ) whose s t e r e o c h e m i s t r y i s d e t e r m i n e d by t h e n a t u r e o f t h e L e w i s a c i d u s e d ; ZnC12 g i v e s v i r t u a l l y p u r e ( Z ) isomers while A1C13 g r e a t l y favours formation of t h e ( E ) isomers.

182

A m i l d and n o n - b a s i c method f o r t h e c o n s t r u c t i o n o f ( E ) - u , B -

u n s a t u r a t e d e s t e r s ( 198 ; R =H) p r o c e e d i n g

via

a r a d i c a l coupling(206) a n d a n a l k y l b r o m i d e , i n i t i a t e d by h e x a b u t y l d i t i n t h e r m o l y s i s , h a s b e e n e l i m i n a t i o n sequence involving e t h y l 8-stannylacrylate

e x e m p l i f i e d i n a s y n t h e s i s o f a c y c l o p e c t a n o i d i s o c y a n i d e .I 83 A l l y l i c h a l i d e s i n g e n e r a l undergo very e f f i c i e n t couplings with v i n y l t i n In these s p e c i e s [ e . g . (206)l u s i n g p a l l a d i u m c a t a l y s t s . 18‘ e x a m p l e s , t h e s t e r e o c h e m i c a l i n t e g r i t y o f t h e v i r , y l t i n d o u b l e bond

-

i s r e t a i n e d [ e . g . (207) (20811. O t h e r v a l u a b l e f e a t u r e s o f t h i s w i d e - r a n g i n g t e c h n i q u e a r e t h e t o l e r a n c e of a n u m b e r o f f w c t i o n a l g r o u p s ( e . g . O H , C N , C02R, a n d C H O ) w h i c h c a n b e p r e s e n t i n e i t h e r r e a c t a n t and t h e c o m p l e t e i n v e r s i o n of s t e r e o c h e m i s t r y w h i c h o c c u r s a t t h e h a l i d e carbon c(207) (20811. When c a r r i e d o u t i n t h e

-

p r e s e n c e o f c a r b o n m o n o x i d e , k e t o n e s a r e f o r m e d by i n s e r t i o n o f CO i n t o t h e n e w l y f o r m e d C-C b o n d . B e n z e n e a n d f u r a n s car, b e d i r e c t l y


168

0

II

b

C02Me

(Et0)2PO

-

M e p Li

OCONHPh (218)

(219 1

(220)

169


c o u p l e d t o a c r y l a t e s t o g i v e u n s a t u r a t e d e s t e r s ( 2 0 9 ; A r = Ph or 2f u r y l ) u s i n g p a l l a d i u m s a l t s i n t h e p r e s e n c e of t - b u t y l p e r b e n z o a t e . 185 S i m i l a r r e a c t i o n s w i t h some m o n o s u b s t i t u t e d b e n z e n e s ( C 6 H 5 C 1 and C 6 H 5 C H 3 ) w e r e u n f o r t u n a t e l y nonregioselective.

P a l l a d i u m - c a t a l y s e d a l k y l a * - + i o n s of s i m p l e e n o l a t e s

by a l l y l i c a c e t a t e s a r e u s u a l l y u n s a t i s f a c t o r y owing t o t h e s l o w n e s s o f t h e r e a c t i o n , which t e n d s t o l e a d t o p o l y a l k y l a t i o n . However, by u s i n g e n o l s t a n n a n e s , g e n e r a t e d from l i t h i u m e n o l a t e s using t r i m e t h y l t i n t r i f l u o r o a c e t a t e , high-yielding mono-alkylations c a n be a c h i e v e d i n t h e c a s e o f a c e t a t e ( 2 1 0 ) , w h i c h r e a c t s u s u a l l y b u t n o t a l w a y s r e g i o s p e c i f i c a l l y a t t h e c a r b o n a- t o s i l i c o n , l e a d i n g t o u n s a t u r a t e d k e t o - e s t e r s ( 2 1 1 ) . 86 O r g a n o m e r c u r y compounds a r e o f t e n u s e f u l s u b s t r a t e s i n p a l l a d i u m - c a t a l y s e d p r o c e s s e s ; a good e x a m p l e of t h i s i s t h e p r e p a r a t i o n o f u n s a t u r a t e d

esters (198; R1

H ) by P d - c a t a l y s e d

c a r b o n y l a t i o n of v i n y l

m e r c u r i a l s o b t a i n e d f r o m t e r m i n a l a c e t y l e n e s by s e q u e n t i a l h y d r o b o r a t i o n and boron-mercury

exchange.

The l a c k of

(E)-

s t e r e o s e l e c t i v i t y which is sometimes o b s e r v e d , e s p e c i a l l y w i t h h i g h e r m o l e c u l a r w e i g h t a c e t y l e n e s , h a s now b e e n l a r g e l y o v e r c o m e by o p t i m i z a t i o n of t h e c o n d i t i o n s f o r B-Hg e x c h a n g e . 187 The v a l u a b l e method f o r c o n v e r t i n g 8 - k e t o - e s t e r s

(212) i n t o

via

sequence

unsaturated esters (214)

an a d d i t i o n - e l i m i n a t i o n

involving t h e corresponding enol-phosphates d e s c r i b e d i n f u l l . 188

( 2 1 3 ) h a s been

I n some a c y c l i c e x a m p l e s , m i x t u r e s o f MeMgCl

and MeCu h a v e been f o u n d t o g i v e h i g h e r s t e r e o s e l e c t i v i t i e s t h a n Me2CuLi i n t h e s e c o n d s t e p . 1 8 9 A l t h o u g h many e x a m p l e s of t h e u s e o f t h e P e t e r s o n r e a c t i o n ” ’

in

& , @ - u n s a t u r a t e d e s t e r s y n t h e s i s h a v e b e e n r e p o r t e d , t h e method a p p e a r s n o t t o have been extegded t o a - s u b s t i t u t e d homologues ( 2 1 6 ) until recently. lgl

The d i p h e n y l m e t h y l s i l y l e s t e r s ( 2 1 5 ) a r e u s e d

m a i n l y b e c a u s e t h e y c a n be o b t a i n e d by d i r e c t 5 - s i l y l a t i o n of t h e c o r r e s p o n d i n g e s t e r l i t h i u m e n o l a t e s ; t h e r e a c t i o n s show m o d e r a t e t o good ( Z ) - s e l e ~ t i v i t y land ~ ~ i n c o n t r a s t t o some o f t h e a n a l o g o u s W i t t i g - t y p e a p p r o a c h e s a r e a p p l i c a b l e t o b o t h a l d e h y d e s and ketones. The a v a i l a b i l i t y o f a , @ - u n s a t u r a t e d e s t e r s by a p l e t h o r a of m e t h o d s , some e x e m p l i f i e d a b o v e , means t h a t d e c o n j u g a t i o n t o t h e c o r r e s p o n d i n g B , y - u n s a t u r a t e d e s t e r s c a n be a n a t t r a c t i v e method f o r t h e p r e p a r a t i o n o f t h i s l a t t e r c l a s s o f compound.

However,

s t e r e o s e l e c t i v i t y i s a problem w i t h long-chain e s t e r s ; t h i s can be overcome by u s i n g crowded e s t e r s d e r i v e d f r o m 2 , 4 - d i m e t h y l p e n t a n - 3 -

170


In the case of such an ester derived 01 and KN(SiMe3)2 as base. l g 3 from (El-dodecanoic acid, selectivity in favour of the (L)-isomer (217) can be as high as 97:3. Likewise, deconjugation of methyl (2E,4E)-dienoates, using LDA as base, leads to the (3E,5Z) deconjugated dienoates (218) with 72-80% stereochemical purities whereas similar treatment of the corresponding (2E,4Z)-dienoates gives the (3E,5E)-isomers of (218) with stereoselectivities of 8198%.194 Possibly these could be improved by using the foregoing methodology. An unprecedented ‘decarboxylative reduction’ of unsaturated carbamates [e.g. (219)l occurs on reaction with a lithium dialkylcuprate leading to 0,y-unsaturated esters [e.g. (22011 in excellent yields.lg5 The method can also be applied by acyclic analogues of (219) and to cyclic carbamates. A full account has been given of the palladium-catalysed decarboxylationcarbonylation process whereby allylic carbonates (221) can be converted into unsaturated esters (222). Yields are generally around 70% but much lower in examples where a secondary carbonate is used. Details have also been given of ar, appropriate precedure for the homologation of nerol o r geraniol into the homologous esters “223) and (E)-(223) respectively], without migration o r isomerization of the sensitive olefinic bond, by conversion into the corresponding sulphones, followed by carboxylation and desulphurization. y-Seleno-esters (224) can be obtained by Wadsworth-Emmons reactions using a-selenoaldehydes and, after oxidation to the corresponding selenoxides, undergo [2,3]sigmatropic rearrangements to provide a novel route to a-hydroxyB,y-unsaturated esters (225). y,b-Unsaturated (a-ally1)-esters (226) can be obtained in 64-91% yields by palladium-catalysed reactions between ketene silyl When such reactions are acetals and allylic carbonates (221 ) . lg9 carried out using a phosphine-free palladium catalyst [e.g. P~(OAC)~], unsubstituted a,b-unsaturated esters derived from the ketene acetal are produced; this could prove to be a useful twostep dehydrogenation procedure for esters. Yields are 70%. aNitro-derivatives (227) of esters (226) can be similarly obtained by palladium-catalysed couplings of a-nitroacetates to allyl carbonates (221) o r allyl phenyl esters.200 A full discussion has been given regarding vinylogous Wolff rearrangements of f3,y-unsaturated diazoketon-es (228) which wher, catalysed by copper salts in the presence of an alcohol, R30H, lead to the rearranged esters (229) accompanied by little or none of the

=.


171

R'

R2

R'

R2

NOq

(227)

(229 1

(228)

dR3 C02Me

CO,E t

( 2 31)

(230)

@CO2Me

R2

(232)

172


simple Wolf f rearrangement products. 2o For use in planning syntheses, this process can be regarded overall as an alternative to ortho-ester or Ireland-type Claisen rearrangements. The former version of the Claisen rearrangement is somewhat limited because of the requirement of an acid catalyst, usually EtC02H, to trigger transetherification between the allylic alcohol and ortho-ester components. It has now been shown that this can be done using a palladium catalyst; hence such Claisen rearrangements can be effected under neutral conditions .202 In ger,eral, ketene silyl acetals derived from esters can only be successfully mono-alkylated under Lewis acid conditions by halides which can form a stabilized carbonium ion, such as secondary benzylic halides leading to, in the latter case, esters (230). 203 This methodology thus neatly complements the various anionic approaches to ester homologues which would almost certainly fail with secor,dary allylic or befizylic halides. An additional example of this principle is the preparation of the gem-dichloro-enoates (231; R1=R2iH) from ketene silyl acetals and secondary or tertiary

1,1,3-trihalogenopropene derivatives. This approach car, also be used to obtain 4-alkynoates from secondary propargyl chlorides .204 Efficient monoalkylations of methyl phenylacetates can be carried out using a base, generated by cathodic reduction of 2pyrrolidoce, to give homologues (232; R 1 Me, E t , or Pri) in 8 1 99% yield. 205 More conventional bases generally lead to mono- and dialkylated products. PheFylacetates (232; R1=H), as well as ber,zoates and crotonates, can be readily obtained in excellent yields by rhodium o r in some cases rhodium-palladium assisted carbonylations ( 1 atm C O , 75 OC) of benzylic, aryl, or styryl bromides respectively in the presence In many cases, it seems reasonable to of ar, aluminium alkoxide.2"6 expect that this method will supersede Grignard-based homologation procedures using carbon dioxide or chloroformates as electrophiles. Similar carbonylations (6.8 atm C O , 75 'C) of various heteroaromatic bromides using palladium catalysts have also been effected in usually excellent yields.207 Some rather unusual reactions have been reported in aromatic ester chemistry this year. For example, treatment of nitrobenzenes with enolates of chloroacetates yields p-nitrophenylacetates (233; R 1 = H , C 1 , F o r OPh) .208 Presumably a Meisenheimer complex is involved, but further than this the mecharism is m c l e a r . This w o r k is closely related to earlier results reported by Makosze

173


et al., who have now found that the same type of transformation can also be effected using a-phenylthioacetates 209 Perhaps surprisingly, the orselliniate anion (234) can be generated at -78 OC using LDA as base. Presumably reaction of (234) with the parent ester is suppressed because of steric hindrance. Anion (234) reacts efficiently with a number of simple electrophiles; with aldehydes dihydroisocoumarins are formed directly.210 A full account has been given of the remarkable modification of the Birch reduction in which benzoic acid esters can be successfully reduced to the dihydro-esters (235) by adding water 1.5 equiv.) before the metal; some mechanistic rationales are given. 21 1 Ethyl lithiopropynoate (236) is known to condense well with aldehydes and ketones at low temperatures. The useful intermediates (237) thus produced can serve as precursors to the ( 2 ) - (238) and (E)-unsaturated esters (239) after protection of the alcohol group (R2=THP, MEM or TBDMS); as yet direct reduction to the (E)-isomers is rather inefficient .21 However, in general the acetylide (236) does not afford good yields with other electrophiles owing to the typically low reactivity associated with acetylides, which necessitates the use of higher temperatures at which (236) tends to polymerize. This problem is overcome by making use of the analogous ortho-ester (240) which is formed from the corresponding TMS-acetylene using BunLi at 0 OC .21 Subsequent reactions with a range of electrophiles proceed unexceptionally at 0-20 OC; the ester group can be revealed simply by reaction with aqueous oxalic acid. Condensations between ester enolates and various polyhalogeno-olefins have been examined, resulting in the . )

(z.

development of routes to a number of useful acetylenic esters [e.g. (241; R = C l 1 Ph, SPh, or H)l.214 A detailed description of the preparation of allenic esters [e.g. (24211 from an acid chloride and a phosphorane has been given.215 Conjugated dienoates and trienoates (243; ;=I or 2) can be obtained in variable yields by palladium-catalysed coupling between acrylates and enol triflatesl2I6 in reactions which are closely similar to those with vinyl bromides. The regioselectivity of Reformatsky reactions between ethyl 4bromocrotonate and ketones or aldehydes has been found to be critically dependent on the nature of the zinc used and on the solvent. Thus the 'a-adducts' (244) are usually produced exclusively using a zinc-copper couple in ether while 7-adducts (245) are mainly formed using pure zinc in hydrocarbon solvents or


174

i n THF.217 I s o l a t i o n o f t h e s e s e n s i t i v e p r o d u c t s i s o f t e n b e s t a c h i e v e d by i n s i t u a c e t y l a t i o n , w h i l e d e h y d r a t i o n l e a d s t o t h e i s o m e r i c d i e n o a t e s (246) and (247) r e s p e c t i v e l y .

Bromo-crotonates

c a n a l s o be d i m e r i z e d r e g i o s e l e c t i v e l y u s i n g z i n c i n DMSO t o g i v e t h e a l l - ( E-) - 2 , 6 - d i e n o a t e s

(248).2 1 8 I n c o r , t r a s t t o t h e u s u a l

R e f o r m a t s k y r e a g e n t s d e r i v e d from m e t h y l o r e t h y l b r o m o a c e t a t e s , which have a n e n o l a t e - t y p e s t r u c t u r e , t h o s e d e r i v e d from t - b u t y l ab r o m o - e s t e r s h a v e b e e n f o u n d t o b e 2 - m e t a l l a t e d . 219 T h e s e i n t e r m e d i a t e s c a n be e f f i c i e n t l y a l k y l a t e d by a l l y l i c b r o m i d e s (SN2') or a l k y l i o d i d e s i n c l u d i n g primary y-bromocrotonates, Meerwein's r e a g e n t , Me30+BF4-,

leading t o d i e s t e r s (249).

c a t a l y s e s t h e coupling of a l l y 1 s i l a n e s t o y - v i n y l b u t y r o l a c t o n e s , r e s u l t i n g i n a g e n e r a l approach t o (E)-nona-4,8-dienoates (250; = H o r Me). 220 The c o r r e s p o n d i n g ( Z ) - i s o m e r s c a n b e o b t a i n e d i n t h e same way, b u t u s i n g

(z)- h e ~ - Q - e n o l i d e ~a s~ s t a r t i n g

material.

Thioesters.-

Homologation o f a l d e h y d e s o r k e t o n e s u s i n g t h e r e a g e n t

(251) g i v e s g e n e r a l l y e x c e l l e n t y i e l d s of k e t e n e - g , S - a c e t a l s

(252).

T h e s e c a n be c o n v e r t e d i n t o t h e t h i o e s t e r s by d e m e t h y l a t i o n e i t h e r d i r e c t l y u s i n g LiSMe o r i n d i r e c t l y

via

the 2-silyl,

2-acetals using

Me S i I f o l l o w e d by a l u m i n a o r f l u o r i d e ; t h e l a t t e r p r o c e s s , i n 3 p r i n c i p l e , should a l l o w a n o t h e r s u b s t i t u e n t t o be i n c o r p o r a t e d i n t h e a - p o s i t i o n by a l k y l a t i o n o f t h e i n t e r m e d i a t e e n o l a t e .221 Nitro-olefins

( 2 5 4 ) a r e e a s i l y p r e p a r e d by a l d o l c o n d e n s a t i o n s

b e t w e e n a l d e h y d e s a n d p h e n y l t h i o n i t r o m e t h a n e , PhSCH NO

*

2; good M i c h a e l a c c e p t o r s w i t h a number of n u c l e o p h i l e s ( R

a n d act as

=

a l k o x i d e s , amide a n i o n s , s u l p h i n a t e s , o r m a l o n a t e ) t o p r o v i d e n i t r o n a t e s a l t s w h i c h on o z o n o l y s i s , i n s i t u , g i v e t h e t h i o e s t e r s

(255).222

The method c a n a l s o b e a d a p t e d t o p r o v i d e a - h y d r o x y A d d i t i o n o f o r g a n o m e t a l l i c s , RM ( M = M g X

t h i o e s t e r s ( 2 5 5 ; R2=OH).

o r L i ) , or h y d r i d e s ( R = H ) t o a - 0 x 0 - k e t e n e

thioacetals (256)

f o l l o w e d by d e g r a d a t i o n u s i n g HBF4 a n d / o r m e r c u r y s a l t s g i v e s t h e u n s a t u r a t e d t h i o e s t e r s (257).223 A s t h e s t a r t i n g m a t e r i a l s a r e p r e p a r e d f r o m t h e c o r r e s p o n d i n g k e t o n e e n o l a t e s a n d CS2-MeI,

this

sequence i s , overall, a [1,3]-carbonyl t r a n s p o s i t i o n . A f u r t h e r e x a m p l e o f t h e a b i l i t y of p y r i d i n i u m c h l o r o c h r o m a t e a n d r e l a t e d o x i d a n t s t o c l e a v e f u r a n r i n g s i s i n r e a c t i o n s w i t h 2a l k y l t h i o f u r a n s (258) which g i v e u n s a t u r a t e d t h i o e s t e r s ( 2 5 9 ) i n i t i a l l y a s t h e ( Z ) - i s o m e r s w h i c h t h e n i s o m e r i z e t o t h e (E)-form on p r o l o n g e d r e a c t i o n . 224 A l d o l c o n d e n s a t i o n s o f b o r o n e n o l a t e s


(236)

175

(237)

(238)

(239)

CO,Me

R5 R 4 R2 T,.co2BUt

.

R (248)

SPh

(254)

(249)

w R6

C R3

O

2

R' (250)

M

e


176

d e r i v e d from p h e n y l t h i o p r o p i o n a t e w i t h a l d e h y d e s g i v e a l m o s t p u r e

syn-O-hydroxy-thioesters ( 2 6 0 ) , r e g a r d l e s s of t h e e n o l a t e g e o m e t r y . 225 C o n d e n s a t i o n s w i t h c h i r a l a - s u b s t i t u t e d a l d e h y d e s give variable relative stereoselectivities.

0 - A l k y l t h i o e s t e r s ( 2 6 1 ) 2 2 6 c a n be e a s i l y o b t a i n e d f r o m t h e c o r r e s p o n d i n g e s t e r s by 2 - s i l y l a t i o n

(LDA; TMSC1) f o l l o w e d by

t r e a t m e n t w i t h h y d r o g e n s u l p h i d e .227 The d i r e c t c o n v e r s i o n o f

e s t e r s , a c i d s , and a c i d c h l o r i d e s i n t o d i t h i o e s t e r s u s i n g L a w e s s o n ‘ s r e a g e n t 2 2 8 h a s b e e n amply d o c u m e n t e d i n r e c e n t y e a r s . However, r a t h e r h i g h t e m p e r a t u r e s a r e r e q u i r e d , w h i c h h a s l e d t o t h e d e v e l o p m e n t o f a number o f a n a l o g u e s of t h e o r i g i n a l r e a g e n t which are e f f e c t i v e a t lower t e m p e r a t u r e s , 2 2 9 and which can a l s o be u s e d t o p r e p a r e t h i o a m i d e s from a m i d e s a n d t h i o a m i d e b o n d s i n

pep tide^.^^'

A l t h o u g h a g e n e r a l r o u t e t o d i t h i o e s t e r s i s by

c o n d e n s a t i o n of o r g a n o m e t a l l i c s w i t h c a r b o n d i s u l p h i d e , 23 lithium species, RC(O)Li,

acyl-

g e n e r a t e d from R L i and carbon monoxide,

c o n d e n s e w i t h CS2 t o g i v e 2 - m e t h y l t h i o e s t e r s a f t e r m e t h y l a t i o n w i t h M e I ; 2 3 2 t h e r e a c t i o n s may i n v o l v e t h e i n t e r m e d i a c y o f a n a d i t h i o l a c t o n e s p e c i e s (see a l s o ref. 381).

[%.

N-Phenylthioimidoesters

( 2 6 2 1 1 , r e a d i l y o b t a i n e d from t h e a p p r o p r i a t e G r i g n a r d

r e a g e n t and p h e n y l i s o t h i o c y a n a t e , c a n be a l k y l a t e d e f f i c i e n t l y a t t h e a - p o s i t i o n u s i n g LDA-RX. sulphide gives dithioesters

Subsequent t r e a t m e n t w i t h hydrogen

[s. (263)l

whereas a c i d h y d r o l y s i s

l e a d s t o t h e c o r r e s p o n d i n g t h i o e s t e r s . 233

S i m i l a r a l k y l a t i o n s of

t h i o i m i n o e s t e r s i n which t h e r e a c t i n g c a r b a n i o n i s n o t a l l y l i c as i n (262) r e s u l t i n N-alkylation; using diar.ionic intermediates. hydroxy-dithioesters

t h i s l i m i t a t i o n c a n be o v e r c o m e by A probably g e n e r a l r o u t e t o B-

(264) i n v o l v e s c o n d e n s a t i o n s between methyl

d i t h i o a c e t a t e a n d a l d e h y d e s o r k e t o n e s , u s i n g NaH-THF a t - 2 0 o C . 2 3 4 T h i s i s somewhat more c o n v e n i e n t t h a n a p r e v i o u s l y r e p o r t e d method u s i n g LDA as b a s e , a n d d e l i v e r s t h e h y d r o x y - e s t e r s isolated yields.

(264) i n

E.

60%

C o n d i t i o n s have a l s o been e s t a b l i s h e d f o r t h e

dehydration o f esters (264) t o t h e corresponding a , B - u n s a t u r a t e d a n a l o g u e s , w h i c h a r e u s e f u l b o t h as d i e n e s a n d d i e n o p h i l e s i n Diels-Alder

r e a c t i o n s ; i n d e e d s u c h compounds r a p i d l y d i m e r i z e v i a a

[ 4 + 2 1 c y c l o a d d i t i o n when d e r i v e d f r o m e s t e r s (264) i n w h i c h R2 i s hydrogen.

R’Y


177

R’

0

R1

H H

R2

(2721

( 2 731

(274)

(275)

Generul and Synthetic Methods

178

3 Lactones Butyro1actones.- A versatile approach to butyrolactones is by condensations between h o m ~ e n o l a t e sand ~ ~ ~aldehydes or ketones. The first reported example of a syn-diastereoselective versior. of such a reaction is the condensation of butenyl carbamates (265) with aldehydes which leads largely to the (E)-=-isomers (266), following metallation (BunLi) and cation exchange (Bui2AlS03Me) .236 Conversion into the cis-disubstituted butyrolactones (267) proceeds with retention of configuration using known methodology. In related work, a highly enantioselective approach to 11- and 4,4disubstituted butyrolactones has been developed involving condensations of the cyclic urea (268) readily derived from (-)-ephedrine, with aldehydes or methyl ketones; subsequent degradation leads to optically pure butyrolactones ( 2 6 9 ; R2=H or Me) .237 Very high ( 3 9 3 % ) diastereoselectivity has beer, found in reactions between allenic zinc reagents and aldehydes, leading to the homopropargylic alcohols (270) . 2 3 8 Conversion to the translactones (271) is then achieved by silylation, hydroboration, ar.d oxidation of the acetylene function.6 The asymmetric reduction of propargyl ketones using Alpine-borane O8 leading to chiral propargyl alcohols (272) has been discussed at length.239 These valuable intermediates can serve as precursors to chiral a- ar,d 8-substituted butyrolactones as well as to butenolides or valerolactones, and can also be obtained by reductior,s of propargylic ketones using LiAlH,, modified by the addition of chiral binaphth01~~' or ephedrine derivatives. 24 Chiral dianionic species (273; R=H or Me) car, be obtained from readily available ' 12' subsequent carboxylation gives the chiral PHB; butyrolactones (274; R=H or Me). 242 Presumably this method could be exter,ded to more interesting products. The 'quercus' or 'oak' lactones C(275) and the corresponding trans-isomer] have beer. obtained by diastereoselective condensations between suitable allylic boronates and pentanal; this approach should be applicable to many homologues of (275) .243 Further examples of Lewis acid-catalysed ring closures of terpenoid acids to give annulated butyrolactones include alternative syntheses of the pheromones (+)-anastrephin (2'76) and epianastrephin (isomeric at C-4)244 and of the tobacco constituer:t (277) , directly from (5,E) -homofarnesic acid .245 The related butyrolactone (279) has been obtained using a novel oxidative

179


c l e a v a g e o f a n o l e f i n (278) u s i n g PCC o r , b e t t e r , ( b i p y H 2 ) A l t h o u g h c l e a r l y l i m i t e d t o t e r t i a r y a l c o h o l s a n d monoo l e f i n s , t h i s method s h o u l d f i n d o t h e r a p p l i c a t i o n s . Treatment of

CrOC15 . 2 4 6

cyclopropanecarboxylates

[e.g.(280)l

( M e 3 S i ) 2 S 0 4 l e a d s t o t h e *-fused

with the Lewis acid

b u t y r o l a c t o n e s (2811 .247

S i m i l a r l y , a-ethoxycarbonyl l a c t o n e s

[e.g.(28211

can be o b t a i n e d

f r o m vinylcyclopropane-1,l-dicarboxylates a n d f u s e d l a c t o n e s (283) f r o m bicyclo[3.1.01-butyrolactones. t h u s a p p e a r s t o be c o n s i d e r a b l e .

The p o t e n t i a l o f t h i s m e t h o d Further e x p l o r a t i o n s of

c y c l o a l k a d i e n y l t r a n s i t i o n metal c o m p l e x e s h a v e r e s u l t e d i r : s t e r e o s e l e c t i v e r o u t e s t o t h e u s e f u l s y n t h e t i c i n t e r m e d i a t e s (284; R

a-

or B - C 0 2 M e or H)248 a n d ( 2 8 ~ ) ; ~t h~e’ l a t t e r a i e o f

p a r t i c u l a r i n t e r e s t as t h e c o n t r o l of stereochemistry around a cycloheptane r i n g is something of a black a r t .

During s t u d i e s

aimed a t Q u a s s i n o i d t o t a l s y n t h e s i s , c a e s i u m f l u o r i d e h a s been u s e d t o e f f e c t i n t r a m o l e c u l a r M i c h a e l a d d i t i o n i n t h e e n o n e (286), I n t r a m o l e c u l a r Die 1s - A l d e r l e a d i n g t o t h e b u t y r o l a c t o n e (287).25 r e a c t i o n s u s i n g b u t e n o l i d e s as d i e n o p h i l e s h a v e been shown t o r e p r e s e n t v i a b l e and s t e r e o s p e c i f i c r o u t e s t o b u t y r o l a c t o n e d e r i v a t i v e s s u c h as (288).25 D e h y d r a t i o n o f k e t o - d i a c i d d e r i v a t i v e s (289), w h i c h a r e r e a d i l y a v a i l a b l e by a l k y l a t i o n s o f 8 - k e t o - e s t e r s

w i t h a-bromo-acids

(R2CHBrC02H), l e a d s t o t h e u n s a t u r a t e d l a c t o n e s ( 2 9 0 ) w h e r e a s r e a c t i o n w i t h a l l y l z i n c b r o m i d e g i v e s b u t y r o l a c t o n e s (291) .252 I t seems l i k e l y t h a t o t h e r t y p e s of b u t y r o l a c t o n e c o u l d b e o b t a i n e d from t h e s e p r e c u r s o r s . An i n c r e a s i n g i n t e r e s t h a s b e e n shown i n t h e s y n t h e s i s o f butyrolactones related t o carbohydrates.

A g e n e r a l b u t non-

s t e r e o s e l e c t i v e r o u t e t o h y d r o x y - b u t y r o l a c t o n e s (292) c o n s i s t s of L e w i s acid-mediated c y c l o a d d i t i o n s of u,b-epoxy-aldehydes or -ketones t o t h e ketene dimethyl acetal of propionic a c i d , followed by a c i d h y d r o l y s i s o f t h e r e s u l t i n g o ~ e t a n e . A~ n~u m ~ber o f r o u t e s t o a - a m i n o - b u t y r o l a c t o n e s C-. (29311, r e l a t i v e s o f a m i n o - s u g a r s , h a v e a l s o b e e n r e p o r t e d , many b a s e d on n u c l e o p h i l i c a d d i t i o n s t o t h e a c e t o n i d e o f ( L ) - g l y c e r a l d e h y d e . 254 T h e h o m o l o g o u s (5s)b e n z y l o x y m e t h y l d e r i v a t i v e o f g l y c e r a l d e h y d e , a p r o t e c t e d form of ( L ) - t h r e o s e , d e r i v e d from d i e t h y l ( R , R ) - t a r t r a t e , a t o t a l s y n t h e s i s of ( + ) - D e l e s s e r i n e

h a s been used i n

(294), t h e v i t a l s t e p b e i n g a

non-stereoselective condensation with a phenyl-lactic acid derivative.255 The compound e x i s t s i n s o l u t i o n a s a m i x t u r e o f (294) a n d t h e c o r r e s p o n d i n g b i c y c l i c h e m i a c e t a l . An e n t i r e l y


180

Me II

( 2 84)


181

different approach to a-amino-butyrolactones, (2961, which is also applicable to a-amino-valerolactones, is by thermal ene reactions of N-sulphonylimines, [%. (295)1, generated in situ from the corresponding aldehydes and t o l u e n e - f l - s u l p h o n a m i d e . Such stereoselective ene reactions can also be carried out intermolecularly, leading to unsaturated a-amino-acid derivatives which can be iodolactonized to give annulated a-aminobutyrolactones [e.g.(297)1. 256 The utility of enzymes in enantiospecific syntheses has been amply demonstrated by results discussed in the diacid and 8hydroxy-ester sections of this chapter. Further examples of this are to be found in another report of the ability of horse liver alcohol d e h y d r ~ g e n a s e ~ to ~ ' catalyse oxidations of meso-diols to optically pure butyrolactones such as (298) .257 Various enzyme systems have also been found which can mono-hydrolyse prochiral meso-diacetates to chiral intermediates (299) ,258 ( 300) , 259 and (301 ) .259 As the two alcohol groups are now chemically distinguishable, standard methods can be used to prepare both enantiomers of many compounds from these single isomers. This is exemplified in the cases of the Corey lactone (302),258 the biotin precursor (303),259 and the precursor (304 )259 to the microbial autoregulator 'A-factor'. Both the related '(L)-L-factor' (305) and its (5S)-diastereoisomer have been synthesized from (D)-ribose employing Wittig reactions to introduce the required substituent chains. 260 Controlled base-induced epimerization at an appropriate stage was used to gain access to the (5S)-derivative. L-Factor (305) has also been prepared from 2,3,6-tri-2-acetyl-D-glucan; introduction of the alkyl side chain was achieved in this case by the coupling of a tosylate derivative with lithium di-nbutylcuprate, an example of a generally useful procedure for this A number of reports262 have emphasized type of homologation.26 the potential of cheap, commercially available D-ribonolactone ( 3 0 6 ) in the elaboration of chiral butyrolactones such as the 8 hydroxy-derivatives (307) and various naturally occurring a ylidenelactones ( 3 0 8 ) . When chiral sulphoxides are used in the previously reported route to butyrolactones from vinyl sulphoxides and chloroketenes, asymmetric induction is complete leading to optically pure a halogeno-butyrolactones [-. (30911; hopefully other examples will be forthcoming.263 Chiral sulphoxides also feature in an enantioselective approach to lignans (312) by asymmetric Michael

182


(295)

(296)

( 2 98)

(297)

0 AcO & O H OAc

HO-

I

\

‘OAc

(301 1

(300)

(299)

I

I

I

I

II

I

3

4

9

0 BzN

H

N6z

H

HO

(304)

(303)

(302)

H

HO

n-C5Hll

(305)

(306)

(307)

(308)


183

addition of a benzylic Grignard to the butenolide (310) followed by Raney nickel desulphurization to give lactones (311). Subsequent trans-acylation then gives (312) of 95% optical purity in the one example quoted. 264 This method will very likely be applicable to many other related derivatives. Lignans belonging to the dioxabicyclo[3.3.0loctane family have been obtained diastereoselectively by using a novel intramolecular aldol reaction C(313) (314)l.265 Although yields are not spectacular, this brief approach is clearly ripe for further development. An alternative type of asymmetric Michael addition has been used to prepare a prostaglandin analogue [from (316)l by addition of a sulphonylcarbanion to chiral butenolide ( 3 1 5 ) , readily derived from oxide. Subsequent in situ trapping can be effected (S)-propylene using a propargyl iodide but unfortunately fails with other electrophiles such as allylic or alkyl halides. 26 6 Under suitable conditions, y16-unsaturated amides o r thioamides (317; X 0 o r S ) have been found to undergo highly stereoselective halogenolactonizations to give trans-disubstituted butyrolactones (318), in contrast to such reactions of the corresponding acids which usually show some *-selectivity. 2,3,4-Trisubstituted analogues can also be obtained stereoselectively in some cases .267 An alternative and high-yielding method for carrying out halogenolactonizations consists of brief treatment of the usual substrates with m-chloroperbenzoic acid, an excess of sodium iodide ( o r bromide), and catalytic amounts of 18-crown-6.268 As the peracid is rapidly consumed, possibly by formation of an acyl hypohalite, non-participating double bonds are not epoxidized; the method can also be used to prepare tetrahydrofurans and pyrans. A synthesis of (+)-blastmycinone (319)269 makes use of an asymmetric enolate Claisen rearrangement33 ' 34 while a further preparation of the racemic compound proceeds 2 nitrile oxide addition to an olefin followed by stereoselective alkylation of the resulting isoxazoline .270 Radical-mediated cyclizations have once again been featured in a number of novel approaches to butyrolactones. Cobalt(1)-initiated cyclizations of the vinyl ethers (320; R'=H or Me) lead to high yields of the ring-fused lactones (321), after oxidation using Jones reagent, presumably 2 [1,2]-elimination of C o - H from an intermediate cyclohexyl-cobalt complex. 27 Analogous cyclizations initiated by Bu"SnH give the corresponding saturated homologues . The ability of tin to participate in radical reactions has further

-


184

R'

Ph--

0

R2

c

0

OSiMe,

(317 1

(320)

(319)

(318)

(321)

(322)

(323) H

OH

OH

185


been exploited in a general route to butyrolactones (323) by 1 stereorandom cycloadditions of stannyl a-iodo-esters (322; R =H or Me) to 0 1 e f i n s . ~ ~The ~ cyclization of alkynoic acids to ylidenebutyrolactones using mercury salts has been known for some time; such reactions can also be carried out efficiently using a palladium(I1) catalyst. 273 Stoicheiometric amounts of Pd(OAcI2 are required to effect a new alkoxycarbonylation-lactonization sequence [(324) (325)l which will be of use in the synthesis of various naphthoquinone antibiotics containing this type of fused pyran-7The reaction proceeds with stereoselectivities lactone system.274

-

z.

of 5 : l in favour of the *-fused isomer. Another type of double annelation is by treatment of B-keto-acids 1%. (326; X=CH2 or O ) ] with Mn30(0AcI7. 275 This method has considerable utility, being also applicable to cyclopentene derivatives and to acyclic precursors. As is usual in such cyclizations, all-*-products

[e.g. (32711 are produced. a-Methylenebutyro1actones.- There have been relatively few developments in this area recently. A rather lengthy approach to

-

lactones (330) involves a thioallylic rearrangement C(328) (329)l which is brought about using silica gel. The starting materials (328) are obtained by Peterson olefination of the corresponding ketones which are available from B-hydroxy-amides or -esters and PhSCH(Li)OMe. Completion of the sequence is carried out by acid hydrolysis (30% H 2 S 0 4 ) , Jones oxidation, and elimination of the elements of PhS02H using DBU. A chiral centre in the original B hydroxy-ester can be carried through unmolested. 276 Lactones (330; R2=H) have also been obtained by Bun3SnH-induced cyclizations of vinyl bromides (331)277 along similar lines to the route discussed in the foregoing section.271 The method is also applicable to the synthesis of B-methylenebutyrolactones. a-Alkylidenelactones (333) can be readily obtained by heating aldehydes with the sodium salt (332), obtained from butyrolactone itself and ethyl formate. 278 The final elimination step finds precedent in the conversion of a-acetyl-lactones into the corresponding a-methylene derivatives by condensation with formaldehyde. Spiro-(E)-ethylidene-lactones [e.g. (335)l are obtained in 40-55% yields in a 'one-pot' sequence beginning with condensations of the amide dianion (334) with cycloalkanones, followed by acid hydrolysis and lactonization. (pH 3, A , 14 h).279 Acrylate derivatives (336) react with dienes in the presence of

186


(328)

(329)

(336)

R3 R 2 Q R 4 - ; y

(337)

R3

(330)

(338)

(339)

K4 R3

95% yield of the isolatable enol esters (400) using the 'push-pull' acetylene (399) .333 Cyclization is effected in greater than 80% yield by the slow addition of these adducts to hot toluene containing a trace of camphorsulphonic acid o r magnesium bromideetherate; presumably the mechanism is related to other 'doubleactivation' methods (see ref. 348). Two additional features of this particular method are the absence of racemization at a chiral centre u- to the alcohol group and the relatively high concentrations at which it can be carried out (final dilution: E. 1 mmol per 20 ml of solvent). Two other new methods, using either active esters derived from a 1 , 2 - b e n z i ~ o t h i a z o l eor ~ ~the ~ bistrimethylsilyl derivatives of w-hydroxy-acids and Pr2BOTf ,335 although efficient will only be of interest to those with small amounts of substrate to lactonize as very high dilutions are required ( 1 mmol in 750 ml or 450 ml respectively). An unusual intramolecular Diels-Alder reaction C(402) (40311 occurs in 58% yield at 170 O C in dilute solution in xylene (1.6 x M) .336 As well as providing a useful entry into the anthracyclins, this suggests that other macrolide systems could perhaps be obtained in this way. A conceptually related approach to naphthoquinones (405) proceeds the cobalt complex (404), readily obtained from the corresponding benzocyclobutenedione, and has been used in a total synthesis of the natural quinone (?INanaomycin. 337

-

196


0 n

Y

“Me2

(399)

...-.

”

(4011

(400)

O(CH2)60COCH=CH2

co-

CI

0-0

I

‘PPh3

0

0

197


Alternative types of ring expansion continue to be developed for the synthesis of macrolides. The cyclo-octanone derivative (406) has been converted into a 14-membered lactone (409) via a two-stage 'zip reaction, first to the undecanolide (407) using Bun4NF followed by reductive cleavage of the pendant olefin function to the corresponding alcohol (408) and a final acid-catalysed expansion. 338 Presumably, this method could be applied to other systems although the subtle balance between the various driving forces in these steps makes definite predictions difficult. A rather more general four-atom ring expansion method also begins with 2-nitrocycloalkanones which are first converted into the aldehydes (410). Subsequent reaction with [MeTi(OPri) 3 occurs 3 regioselectively at the aldehyde group leading to the cyclic hemiacetals (411), Grob-type fragmentation of which affords the expanded products (412).339 The unusual [3,3]-sigmatropic rearrangement which occurs when ally1 sulphides are treated with dichloroketene has been adapted to a general approach to large thiolactones by a four-carbon expansion and subsequently to macrolides (415) by a 'zip' reaction. Thus, treatment of a suitable vinylthiane (413) with dichloroketene leads smoothly to the thiolactones (414) which, after dechlorination and deprotection, undergo facile S 0 acyl transfer when treated with acid. 340 A number of natural macrolides have been the subject of synthetic work during 1984; however, lack of space dictates that neither their structures nor a discussion of the procedures can be given. Therefore there follows a listing of these compounds together with the key lactonization methods used. In some cases, the yields from these steps are at best moderate and extremely high dilution conditions are often required and therefore consultation of these papers is recommended for those planning such work. Lactonization of w-hydroxy-acids has been used to prepare the following: ( 3 2 , 6~)-ll-methylundecadienolide and the 12- and 13-membered homologues [2-chloro-l-methylpyridinium iodide (Mukaiyama's reagent )I, 341 the 16-membered Protomycinolide [mixed anhydride with 2,4,6-trichlorobenzoic acid (TCBAI-DMAP] , 342 (+)-Colletodiol [DEAD, Ph P ( M i t s ~ n o b u )or~ ~TCBA-DMAP], ~ 344 3 (+)-Conglobatin [TCBA-4-pyrrolidinopyridine], 345 ( - 1-Brefeldin A [Mukaiyama's reagent], 346 ( + 1-Brefeldin A [pyridinethiol ester347 o r the push-pull acetylene method33393481, (-)-Hybridalactone [bis (4-t-butyl-~-isopropylimidazol-2-yl)disulphide-Ph PI. 349

-

3

198


(406 1

63

OR

(4131

(4071

(408)

Q!

OR 0 C l

(414)

(409)

(415)


199

( + )-3-Deoxyrosaranolide, 350 Baccharin B5, 35 and Roridin E35 were obtained by alternative macro-cyclizations using Horner-Emmons reactior,s. Interest in the synthesis of the related verrucarins continues to be intense. Approaches to model 18-membered lactones have included examples of the Mitsunobu procedure as well as lactone bond formation from w-hydroxy-thioesters using either NBS or Hg(02CCF ) 352 This work also features the use of a 3 2' cyclobutene function fused to the triolide ring which is open by

thermolysis to provide ring-expanded (E,L)-triolides corresponding to the natural products. The final macrolide linkage in Verrucarins B353 and J354 has been formed using a mixed-anhydride method. New routes to precursors of these compcunds, V e r r u c a r 0 1 ~ ~ ~ and Verrucarinic acid,356 will also be of interest to workers in this area. Two new lactonization procedures have been developed during total syntheses of examples of macrocyclic pyrrolizidine alkaloids. During a synthesis of the 12-membered (')-Integerriminel the final lactone bond was formed from the (methylsulphonyl) methyl ester (416 )357 whereas syntheses of ( + )-Fulvine and ( + )-Crispatine , both Il-membered pyrrolizidine dilactones, relied upon cyclizations of B-trimethylsilylethyl ester mesylates (417) .358 Both methods may well find other applications. 4 Amides Synthesis.- The useful dianion (418) can be readily derived from and can be alkylated or acylated to provide homologous amides or 6-keto-amides respectively in E. 50% isolated yield.359 An attraction of this reagent is the simple removal of the silyl protecting group on acidic work-up. Claisen rearrangements of enamines formed from propargyl alcohols (419) and amide acetals (420) can be readily carried out by uncatalysed reactions between the two starting materials in refluxing benzene, and lead to the allenic amides (421 ) in 54-88% yields.360

N-(trimethylsilyl)acetamide,

Furthermore, treatment of these initial products with alumina in hot benzene gives largely the (2E,4L)-dienamides (422), thus complementing the known base-catalysed isomerization (KOBut) of allenes (421), which affords the corresponding all-(:)-isomers. In an extension of previous studies, it has been found that vinyl boranes (424), obtained from terminal acetylenes (423) and boron tribromide, react with phenyl isocyanate to give unsaturated amides


200

6r

Br

0 (423)

(424)

(426)

( 4 2 7)

0 H

(430)

-

(422 1

(425 )

( 4 2 8 ) n =1 o r 2

R2R3NH

(429)

0

___)

RANR2R3 (431)

20 1

3: Carboxylic Acids and Derivatives ( 4 2 5 ) i n 65-80% y i e l d s ; 3 6 1 isomer r a t i o s a r e d e p e n d e n t b o t h o n s u b s t i t u e n t s i z e a n d on r e a c t i o n t e m p e r a t u r e , a n d a r e u s u a l l y better than 4:l

i n f a v o u r of one isomer.

L a c t o n e s ( 4 2 6 ) c a n be

(z.

c o n v e r t e d i n t o u n s a t u r a t e d a m i d e s ( 4 2 7 ) s i m p l y by t h e r m o l y s i s 180 O C ) i n HMPA; y i e l d s , h o w e v e r , a r e r a t h e r v a r i a b l e . 3 6 2 Readily a v a i l a b l e 2 - o x a z o l i n e and 2 - o x a z i n e

d e r i v a t i v e s (428) can be r i n g -

o p e n e d i n h i g h y i e l d t o p r o v i d e s e c o n d a r y c a r b o x a m i d e s ( 4 2 9 1 , by t r e a t m e n t w i t h Me S i x w h e r e X C1, N 3 , S P h , o r S e P h . 3 6 3 The 3 r e a c t i o n s a r e u s u a l l y b e s t p e r f o r m e d i n r e f l u x i n g m e t h a n o l , when t h e r e a c t i n g s p e c i e s is p r o b a b l y ' H X ' ,

and w i l l be u s e f u l f o r t h e

s y n t h e s i s o f a w i d e v a r i e t y of a m i d e s c o n t a i n i n g s e n s i t i v e functionality. A u s e f u l m e t h o d f o r t h e e x c h a n g e of a m i d e g r o u p s , w h i c h d o e s n o t

r e q u i r e h y d r o l y s i s t o t h e c o r r e s p o n d i n g a c i d s , i s by N - n i t r o s a t i o n

o r !-nitration o f a s e c o n d a r y a m i d e ( 4 3 0 ) f o l l o w e d by d i s p l a c e m e n t o f t h e a c t i v a t e d a m i d e g r o u p by ammonia o r a s e c o n d a r y a m i n e t o ~ ~ of t h e reaction g i v e p r i m a r y o r t e r t i a r y a m i d e s ( 4 3 1 ) . ~ Most c o n d i t i o n s a p p e a r m i l d e n o u g h t o p e r m i t t h e i n c l u s i o n o f many t y p e s of functionality i n t h e substrates.

Two known r e a c t i o n s h a v e b e e n

combined t o p r o v i d e f o r t h e s y n t h e s i s o f t h e t e r m i n a l l y functionalized g-alkylamides

(434) from u n s u b s t i t u t e d amides (432)

However, t h i s method i s and a m o n o s u b s t i t u t e d o l e f i n (433).365 p r o b a b l y l i m i t e d t o mono- a n d s y m m e t r i c a l c y c l i c o l e f i n s a n d a m i d e s which do n o t c o n t a i n o t h e r o l e f i n i c f u n c t i o n s . Complete asymmetric i n d u c t i o n h a s been o b s e r v e d i n a l k y l a t i o n s (LDA; R3X) o f t h e c h i r a l p y r r o l i d i n e s ( 4 3 5 ) . 3 6 6

The i n i t i a l

p r o d u c t s c a n be h y d r o l y s e d t o t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d s u s i n g 1M-HC1 w i t h no r a c e m i z a t i o n .

Such p y r r o l i d i n e s u b s t i t u e n t s

s i m i l a r l y d i r e c t a c y l a t i o n s t o p r o v i d e c h i r a l B-keto-amides R'

(436; = R4CO) w h i c h on z i n c b o r o h y d r i d e r e d u c t i o n a r e c o n v e r t e d i n t o

t h e c h i r a l B-hydroxy-amides o p t i c a l y i e l d s . 367

(437) i n e s s e n t i a l l y q u a n t i t a t i v e

An a l t e r n a t i v e a p p r o a c h t o c h i r a l B - h y d r o x y -

a m i d e s i s by c o n d e n s a t i o n s b e t w e e n t h e m a g n e s i u m e n o l a t e s o f c h i r a l a - s u l p h i n y l a c e t a m i d e s and a l d e h y d e s ; a f t e r d e s u l p h u r i z a t i o n , t h e e n a n t i o m e r i c e x c e s s e s o f t h e hydroxy-amides s i m p l e c a s e s . 368

Lewis acid-catalysed

d e r i v e d from ( S ) - p r o l i n e

a r e >95% i n t h r e e

a l l y l a t i o n s of a-keto-amides

have been used t o p r e p a r e c h i r a l a - a l l y l -

a - h y d r o x y - a r n i d e ~ ~a ~n d~ s i m p l e c h i r a l a - h y d r o x y - a m i d e s

have been

o b t a i n e d by h y d r o g e n a t i o n o f c h i r a l p y r u v a m i d e s d e r i v e d f r o m (21-am e t h y l b e n z a m i d e o r s i m i l a r a m i n e s ; 370 i n b o t h c a s e s e i t h e r t h e chemical or o p t i c a l y i e l d s are n o t s p e c t a c u l a r .

202


An extensive and useful review of a-amidoalkylation at carbon by Mannich-type reactions has been published .371 Under the usual allylic bromination conditions, g-bromosuccinimide reacts with N,Ndimethylamides to give the succinimido-derivatives (438) generally in excellent yields; as expected, the corresponding IJ-bromomethylN-Bromo-amides (439 ) can be N-methylamides are intermediates. 3 7 2 obtained in generally excellent yields from the parent primary amides using aqueous sodium bromite in acetic acid.373 A generally applicable method for the homologation of amide N-alkyl g r o u p s is by metallation of the latter a- to nitrogen [cf. (44011. This type of reaction has been thoroughly reviewed374 and is perhaps more relevant to the section on amine synthesis as clearly the amide cannot contain protons a- to the carbonyl group. The development of novel metallated intermediates has also contributed significantly to benzamide chemistry, particularly in the work of Snieckus and co-workers. Two severe restrictions on the utility of ortho-lithiated tertiary benzarnides (441) is their failure to condense cleanly with allylic halides and aldehydes. These problems can be largely solved by transmetallation to the corresponding magnesium species thus allowing a general access to dihydroisocoumarins (442) and phthalides (443). 375 3-Aryl-3,4dihydroisocoumarins can also be prepared by condensations of the homologous toluamide anion (444) with aromatic aldehydes followed by base hydrolysis.376 The use of trimethylsilyl groups to block the more reactive site in these types of ortho-metallations has been extended to examples where removal of the silicon group generates a further useful anionic species. For example, treatment of the 2-silyl-benzamide (445) with C s F in DMF in the presence of an aromatic aldehyde (ArCHO), followed by acid hydrolysis, leads to the 3-arylphthalides (446),377 which are useful as precursors to anthraquinones following a known hydrogenolysis-cyclizationoxidation sequence. The silyl group in amides (445) can also be replaced by bromine ( B r 2 , CC14, 25 OC), thus providing an alternative and somewhat milder route to the phthalides (446) after rapid halogen-metal exchange using BunLi , and condensation with ArCHO. Amide metallation chemistry also provides a simple route to the 3-triflyl-benzamide ( 4 4 7 ) which is converted into the benzyne (448) on treatment with Bun4NF in acetonitrile at room temperature. 378 The benzyne (448) undergoes typical Diels-Alder reactions and regioselective attack by nucleophiles at the 3 position. Silyl g r o u p s are also effective in protecting an ortho-


203

/OMEM

LOR2 (435)

0

o.... .L i

0

RA N N 0

"9

RA N H B r

$NJ

1 R

0

(4401

(439)

(438 1

& aCON Et 2

HCI

\

(442)

(4411

4oK;Et2 Me0

R (443)

SiMe3

Me0

(444)

CONEt 2

(445) Me3Siv

SiMe 3

(446)

.

OTf

(447)

(448)

(449)

(450)

o

204


methyl substitutent against metailation. Thus, double metallation and silylation of p-methoxy-2-toluamide gives the derivative ( 4 4 9 ) , which then undergoes metallation at the ortho-position; subsequent condensation with an aromatic aldehyde, desilylation (CSF-DMF-H O), and acid-catalysed cyclization also leads to phthalides (450). 3?9 Thioamides.- Enolates generated from unsaturated thioamides (451) by Michael addition of R 2 M condense stereoselectively with aldehydes to give largely or exclusively the threo-adducts (452), thereby providing a good alternative to direct condensations of thioamide enolates with aldehydes which tend to lead to erythroisomers or to mixtures of products, depending on the substituents present. 380 The acyl-lithium species RC(C0)Li mentioned earlier232 reacts cleanly with alkyl (but not phenyl) isothiocyanates to give Similarly , reactions with good yields of u-keto-thioamides. 38 isocyanates give the corresponding a-keto-amides. Condensations between methyl or phenyl isothiocyanate and the carbanion of EtP(0)(OEt)2 afford the Wittig-Horner substrates (453) which, after deprotonation using sodium hydride, react with aromatic aldehydes (or cinnamaldehyde) to give the unsaturated thioamides (4541, probably with the ( E ) - c ~ n f i g u r a t i o n . ~This ~~ first example of a successful Wittig-Horner reaction with a B-thioxo-phosphonate unfortunately fails with aliphatic aldehydes, although this is not too serious as aliphatic amides (454; ' A r ' = alkyl) can be prepared in other ways. (&)-S-Silylketene S,N-acetals (455) react with enones such as benzylidine acetophenone (PhCH:CHCOPh) in the presence of TiC1(OPr1)3 to give the [1,2]-adducts (456) with little o r no stereoselectivity in 47-84% yields.383 In some cases, [ I , 4 1 addition products are formed when titanium(1V) isopropoxide is used in place of TiC1(OPri) 3' Amide (Peptide) Bond Formation.- Some further modifications a n d extensions of existing coupling reagents have been reported this year. An improved preparation of the benzotriazolyl coupling reagent (457) has been reported .384 This method seems particularly attractive combining as it does the features of rapidity, efficiency, and mildness with an absence of racemization. The direct use of N-tritylamino-acid l-benzotriazolyl esters has been successfully applied to peptides such as leucine-enkephalin. 385 Similarly, related 3-acyl-1,3-thiazolidine-2-thiones undergo very efficient aminolysis with unprotected a-amino-acids in aqueous THF to give peptides in which no significant racemization h a s occurred


205

(451)

SSiMe, "&NMe2

(453)

-

(455)

+

HO

R2 NMe2

(456)

/ N+

n i 04-c'

(457)

(454)

(458)

I

oYNtP-C' 0 (459)

206

General and Synthetic Methods Furthermore, it is n o t n e c e s s a r y t o

i n e i t h e r component.386

p r o t e c t hydroxyl o r t h i o l groups i n t h e s e coupling r e a c t i o n s ; t h e r e f o r e t h i s m e t h o d c o u l d be e s p e c i a l l y u s e f u l i n some c a s e s , a s some awkward p r o t e c t i o n p r o b l e m s c a n b e a v o i d e d . 2-Acyl-lm e t h y l i m i d a z o l e s c a n a l s o be u t i l i z e d i n a m i d e s y n t h e s i s f o l l o w i n g conversion i n t o the corresponding 2 - s i l y l cyanohydrin, q u a t e r n i z a t i o n ( M e 2 S 0 4 , 70

OC)

of t h e r e m a i n i n g u n s u b s t i t u t e d

n i t r o g e n , and f i n a l l y r e a c t i o n w i t h an amine.

This sequence looks

t o be u n s u i t a b l e f o r p e p t i d e s y n t h e s i s , b u t i s u s e f u l f o r t h e p r e p a r a t i o n o f o t h e r a m i d e s as w e l l a s e s t e r s a n d t h i o e s t e r s a n d f o r the C-acylation

o f B - k e t o - e ~ t e r s . ~ A~ ~f u r t h e r a n a l o g u e o f

- c a r b o n y l d i - i m i d a i o l e , b a s e d on 2( 35)- b e n z o x a z o l e t h i o n e , h a s been r e p o r t e d ; t h e enhanced s t a b i l i t y o f t h e r e a g e n t t o m o i s t u r e

N

may b e a n a d v a n t a g e i n c e r t a i n c i r c u m s t a n c e s . 388 Amj.de,. a r e e f f i c i e n t l y o b t a i n e d f r o m e q u i m o l a r a m o u n t s o f a c a r b o x y l i c a c i d , a n a l k y l o r a r y l a z i d e , a n d t r i p h e n y l p h o s p h i n e , on h e a t i n g i n benzene.389

It is p e r h a p s s u r p r i s i n g t h a t t h i s

a p p l i c a t i o n of t h e S t a u d i n g e r r e a c t i o n h a s n o t been p r e v i o u s l y r e p o r t e d when s o many o t h e r p h o s p h o r u s - b a s e d m e t h o d s h a v e b e e n u s e d i n a m i d e bond f o r m a t i o n . One s u c h p h o s p h o r u s r e a g e n t , w h i c h h a s b e e n u s e d f o r r a c e m i z a t i o n - f r e e p e p t i d e s y n t h e s i s as w e l l a s i n a w i d e v a r i e t y o f o t h e r a p p l i c a t i o n s ( s e e , f o r e x a m p l e , r e f . 8) i s diphenyl phosphorazidate,

(Ph0),P(O)N3;

a d e t a i l e d procedure f o r The p h o s p h i n i c c h l o r i d e

i t s p r e p a r a t i o n h a s now b e e n p u b l i s h e d . 390

f u n c t i o n , R2P(0)C1, h a s p r o v e n t o be o f c o n s i d e r a b l e u t i l i t y i n p e p t i d e s y n t h e s i s by p r i o r f o r m a t i o n o f a m i x e d p h o s p h i n i c c a r b o x y l i c a n h y d r i d e f o l l o w e d by a m i n o l y s i s .

During a study of

v a r i o u s t y p e s o f p h o s p h i n i c c h l o r i d e , l-oxo-l-chlorophospholane

( 4 5 8 ) (CptC1) h a s b e e n f o u n d t o b e p a r t i c u l a r l y good i n t h i s r e s p e c t e s p e c i a l l y as t h e by-product phosphinic a c i d is r e a d i l y removed by a n a q u e o u s w a s h . 3 9 1 An i m p r o v e d r e c i p e h a s b e e n f o u n d f o r a m i d e bond f o r m a t i o n u s i n g t h e p h o s p h o r d i a m i d i c

chloride (459)

which a v o i d s premature r e a c t i o n w i t h t h e amine component, l e a d i n g t o u n r e a c t i v e p h o s p h ~ r o t r i a m i d e s . ~A~ ~f u l l a c c o u n t h a s b e e n g i v e n of t h e u t i l i t y of t h e s t r a i n e d s u l t o n e (460) i n p e p t i d e s y n t h e s i s . 3 9 3 The r e a c t i o n s p r o c e e d via a m i x e d a n h y d r i d e w h i c h r e a r r a n g e s t o t h e a c t i v a t e d e s t e r s (461) and c o u l d be p a r t i c u l a r l y u s e f u l f o r t h e s e l e c t i v e a c y l a t i o n of p r i m a r y a m i n e s i n t h e p r e s e n c e of u n p r o t e c t e d s e c o n d a r y amines. The u s e of D C C i n p e p t i d e bond f o r m a t i o n i s o f t e n a c c o m p a n i e d by e x t e n s i v e r a c e m i z a t i o n a l t h o u g h t h i s c a n b e m i n i m i z e d by v a r i o u s

207

3: Carboxylic Acids and Derivatives a d d i t i v e s s u c h as l - h y d r o x y b e n z o t r i a z o l e

(HOBt).

I t h a s now b e e n

f o u n d t h a t c o p p e r ( I 1 ) c h l o r i d e is a l s o v e r y e f f e c t i v e i n t h i s r e s p e c t . 394

The a d d i t i o n o f a 4 - d i a l k y l a m i n o p y r i d i n e

is v e r y

e f f e c t i v e i n t h e p r o m o t i o n o f DCC c o u p l i n g r e a c t i o n s b u t t h i s c a n a l s o r e s u l t i n some o r c o m p l e t e r a c e m i z a t i o n o f , f o r e x a m p l e , a c y l a m i n o - a c i d c o m p o n e n t s . 395 However , v a r i o u s u r e t h a n e

g-

derivatives survive rather better. V a r i o u s new p o l y s t y r e n e s u p p o r t e d 4 - a m i n o p y r i d i n e s h a v e b e e n d e s c r i b e d , some o f w h i c h d i s p l a y a g o o d c a t a l y t i c a c t i v i t y i n a m i d e bond f o r m a t i o n ; r a c e m i z a t i o n p r o b l e m s w e r e n o t e x a m i n e d . 396

F u r t h e r s t u d i e s have

b e e n r e p o r t e d on t h e u s e o f a D C C a n a l o g u e f o r t h e f o r m a t i o n o f s y m m e t r i c a l a n h y d r i d e s f r o m !-protected by-product

amino-acids,

i n which t h e

u r e a s c a n b e removed b y a n a q u e o u s a c i d wash l e a v i n g t h e

a n h y d r i d e s i n t a c t . 397 The s l u g g i s h c o u p l i n g r e a c t i o n s b e t w e e n Z - a m i n o - a c i d 1 - h y d r o x y s u c c i n i m i d a t e e s t e r s a n d galkoxycarbonylmethylamino-esters i s g r e a t l y a c c e l e r a t e d by t h e

la-

a p p l i c a t i o n of high p r e s s u r e (10 k b a r ) ; y i e l d s of t h e coupled p r o d u c t s ( 4 6 2 ) a r e s t i l l g e n e r a l l y p o o r b u t a g r e a t i m p r o v e m e n t on t h e r e a c t i o n s a t a t m o s p h e r i c p r e s s u r e which g i v e abysmal N-Hydroxysuccinimide esters have a l s o been used as key r e t u r n s . 398 i n t e r m e d i a t e s i n t h e s y n t h e s i s of p e p t i d e s c o n t a i n i n g l-hydroxyg r o u p s .399 E x c e l l e n t y i e l d s o f some d i p e p t i d e s h a v e b e e n o b t a i n e d o n a p r e p a r a t i v e s c a l e by u s i n g t h e e n z y m e s t h e r m o l y ~ i na n~ d~ ~Q chymotrypsin. 400140

The m i l d n e s s o f t h e p r o c e d u r e s a n d t h e h i g h

o p t i c a l p u r i t y of t h e p r o d u c t s s u g g e s t t h a t many f u r t h e r developments w i l l be forthcoming i n t h i s a r e a . The e x t r e m e l a b i l i t y o f 9 - f l u o r e n y l m e t h y l

protecting groups i n

t h e p r e s e n c e of s e c o n d a r y a m i n e s , which h a s found c o n s i d e r a b l e a p p l i c a t i o n i n p e p t i d e e l a b o r a t i o n , h a s been used i n t h e d e s i g n o f

a new v e r s a t i l e a n c h o r i n g g r o u p f o r s o l i d - s t a t e p e p t i d e P r o t e c t e d p e p t i d e s c a n a l s o be r e m o v e d f r o m 2-[4s y n t h e s i s . ‘02 (hydroxymethyl)phenylacetoxy]propionyl r e s i n s u s i n g s i m i l a r conditions, the best reagents being the hindered non-nucleophilic b a s e s t e t r a m e t h y l g u a n i d i n e and DBU. 403 Bromoacetamide g r o u p s a r e s u i t a b l e f o r a t t a c h i n g t h e f i r s t amino-acid t o a p o l y a c r y l i c r e s i n v i a a n e s t e r l i n k a g e which c a n be c l e a v e d q u a n t i t a t i v e l y w i t h o u t Various r a c e m i z a t i o n u s i n g b o i l i n g 1N-sodium c a r b o n a t e . ‘04 b i f u n c t i o n a l compounds s u c h as 2 - ( 4 - c a r b o x y p h e n y l s u I p h o n y l ) e t h a n o l a r e v e r y u s e f u l f o r t h e a t t a c h m e n t of g r o w i n g p e p t i d e c h a i n s t o s u p p o r t s , b e i n g s u i t a b l y r o b u s t a n d c l e a v a b l e by a m i l d , b a s e -

208


.

catalysed 8-elimination ‘05 Diphenylphosphinic mixed anhydrides have been shown to be very suitable for solid-state syntheses of pept ides in general. 406

5 Amino-acids General Synthesis .- A further development407 in the phase-transfer alkylations of Schiff bases (463) derived from a-amino-esters is the discovery that potassium carbonate is a sufficiently strong base for such reactions when carried out in refluxing acetonitrile, thus avoiding nucleophilic bases such as NaOH, the use of which can result in the occurrence of side reactions in some examples. Yields of the alkylated amino-acids (464) are usually in the order of 75% after deprotection; simple n-alkyl bromides as well as more reactive benzylic or allylic halides can be used as electrophiles. The diphenylmethylene Schiff base derived from aminoacetonitrile can be doubly alkylated, under PTC conditions using sodium hydroxide as base, by u,w-dibromides. In the cases of 1,2dibromoethane or 1,4-dibromobutane, the cyclic products (465; p. = 1 or 3 ) are formed in excellent yields; while other ring sizes or more substituted products have not been obtained by this method, the use of two equivalents of the Schiff base results in good yields of diaminodicarboxylic acids (466 1 , after hydrolysis. ‘08 Both stereoisomers of the chlorocyclopropanecarboxylic acids (467) have also been prepared but using diazomethane addition to a 4(chloromethylene )-oxazolone to form the three-membered ring. 409 Not surprisingly the major developments in this area, however, have been in the diastereoselective and enantioselective synthesis of amino-acids. Anions of Schiff bases derived from glycine can be converted into optically active alanine by methylation using a chiral methyl sulphate derived from (D)-glucose; the highest optical yields (up to 71%) were observed when the substituents at nitrogen were very large andlor were electron donating pExcellent enantiomeric enrichments have been Me2NC6H4). ‘lo observed in the transaminations of some u-keto-acids into a-aminoacids (alanine, nor-valine, tryptophan) using a pyridoxal co-enzyme model.411 Serine analogues (469) have been prepared by an extension of the ‘self-reproduction of chirality’ principle following condensations between the oxazolidine enolate (468) and a variety of electrophiles. As is pointed out in this paper, the products (469) are versatile intermediates for syntheses of the

(x.


Ar

(463 )

-

209

+ R3

NH3

R1 xco;

(464)

NH2 ( F C 0 2 H

(465)

Ho2c NH,

NH2

(466)

CHO

(4671

(468)

Scheme 2

(469)


210

o p p o s i t e e n a n t i o m e r s or of o t h e r a-amino-acids. This principle has b e e n a m p l y d e m o n s t r a t e d by R a p o p o r t a n d c o - w o r k e r s 4 ’ who h a v e d e v e l o p e d r o u t e s t o a number o f D - a - a m i n o - a c i d s i n e x p e n s i v e 2-(phenylsulphony1)-L-serine;

starting with

the first s t e p is d i r e c t

conversion i n t o t h e corresponding p r o t e c t e d a-amino-ketones

by t h e

a d d i t i o n o f a n o r g a n o l i t h i u m o r G r i g n a r d r e a g e n t w h i c h is t h e n f o l l o w e d by v a r i o u s , r e l a t i v e l y s t r a i g h t f o r w a r d , t r a n s f o r m a t i o n s (Scheme 2 ) .

An a l t e r n a t i v e ‘ s e l f - r e p r o d u c t i o n ’ m e t h o d i n v o l v e s

a l k y l a t i o n of t h e r e a d i l y a v a i l a b l e o x a z o l i d i n o n e s ( 4 7 0 ) i n which t h e e l e c t r o p h i l e a p p r o a c h e s f r o m t h e o p p o s i t e f a c e of t h e b u l k y a r y l s u b s t i t u e n t t o g i v e t h e o p t i c a l l y p u r e homologues ( 4 7 1 ) a f t e r h y d r ~ l y s i s . ~ ’The ~ oxazin-2-ones (E)-(2-furyl)glycine

( 4 7 2 ) , r e a d i l y prepared from

and a c h i r a l a - h y d r o x y - a c i d ,

can be s i m i l a r l y

a l k y l a t e d s t e r e o s p e c i f i c a l l y on t h e l e s s h i n d e r e d f a c e , l e a d i n g t o PhCH2 o r Me). t h e furyl-glycine analogues (473; R The r e l a t e d b i s - l a c t i m e t h e r method h a s been f u r t h e r e x t e n d e d t o a n a s y m m e t r i c s y n t h e s i s of a - a l k y l - l e u c i n e s . 416 An i m p r o v e d p r o c e d u r e h a s b e e n developed417 f o r t h e p r e p a r a t i o n of t h e amino-dioxan

( 4 7 4 ) , which

h a s b e e n u s e d i n a s y m m e t r i c S t r e c k e r - t y p e s y n t h e s e s o f c h i r a l aa m i n o - and a - m e t h y l - a - a m i n o - a c i d s . h a s as t h e key s t e p a [3,31-

A novel r o u t e t o a-amino-acids

sigmatropic (acetimidate) rearrangement.

Thus, condensation of a n

a l l y l i c alcohol with trichloroacetonitrile leads t o the a c e t i m i d a t e s ( 4 7 5 ) which r e a r r a n g e t o t h e a l l y l i c amines ( 4 7 6 ) i n refluxing xylene.

S u b s e q u e n t o x i d a t i v e c l e a v a g e (RuC13; N a I 0 4 ) and

h y d r o l y s i s a f f o r d s t h e amino-acids yields418

(cf. r e f .

445).

( 4 7 7 ) i n 50-75% o v e r a l l

A r e v i e w of v a r i o u s a s p e c t s o f

electrochemistry i n s y n t h e s i s i n c l u d e s a d i s c u s s i o n of t h e c o n v e r s i o n of a-methoxycarbamates

i n t o a-amino-acid

derivatives.

The p o s s i b i l i t y o f o b s e r v i n g e n h a n c e d b i o l o g i c a l a c t i v i t i e s i n p e p t i d e s by i n t r o d u c i n g n o n - n a t r u a l

amino-acid

residues has

r e s u l t e d i n t h e development of an e x p e d i t i o u s s y n t h e s i s of t h e b i c y c l i c a n a l o g u e ( 4 7 8 ) o f p r o l i n e by c o u p l i n g a n e n a m i n e o f c y c l o p e n t a n o n e w i t h a p r o t e c t e d d e h y d r o a l a n i n e f o l l o w e d by c y c l i z a t i o n and f i n a l l y h y d r o g e n a t i o n . 420 n a t u r a l 2-carboxymethyl-amino-acids d e v e l o p e d . 42 1

threo-B-Hydroxy-a-amino-acids

F u r t h e r r o u t e s t o non-

(479) have a l s o been

(480) c a n b e o b t a i n e d by s o d i u m

b o r o h y d r i d e r e d u c t i o n o f t h e c o r r e s p o n d i n g f u l l y p r o t e c t e d B-ketoc o m p o u n d s . 4 2 2 D i a s t e r e o s e l e c t i v i t i e s a r e v e r y h i g h a n d much b e t t e r t h a n t h o s e o b t a i n e d i n d i r e c t a l d o l - t y p e a p p r o a c h e s t o a c i d s (480).


Ph'

21 1

,

NH;

NHCOCCl

I

CCI,

NH2

(474 1

(475)

(476)

(477)

OH

C0,Me

cVNH "1

OH

(4791

(478)

R2°2H

H,N L

(4801

(4821

+

(Me3SiI2NCH20Me 5 CH2NH2

R4

(483)

(484)

(485)

H H

(486)

(4871

(488) I

OH H

CO, H

H 2N

Ph*O2H

OH

(4901

(489)


212

A s t e r e o c o n t r o l l e d a p p r o a c h t o c y c l i c y-hydroxy-a-amino-esters

( 4 8 1 ) h a s as t h e key s t e p an i n t r a m o l e c u l a r c y c l o a d d i t i o n o f a n an i t r o n e e s t e r t o a d i s t a l o l e f i n i c bond.423 A number o f u s e f u l p r o c e d u r e s f o r t h e r e s o l u t i o n o r a n a l y s i s o f

a-amino-acid

d e r i v a t i v e s have been r e p o r t e d t h i s y e a r .

o f a number o f r a c e m i c 5-acetyl-[a-'H]-a-amino-acids k i d n e y a c y l a s e g i v e s g e n e r a l l y e x c e l l e n t y i e l d s of

D-a-Amino-acids

a m i n o - a c i d s . 424

Treatment

with porcine

( L )- [ a - 2 H ] - a -

containing an aliphatic side-chain

(e.g. V a l , L e u , I l e ) c a n b e s e p a r a t e d f r o m r a c e m i c m i x t u r e s s i m p l y by t r e a t m e n t w i t h L - p h e n y l a l a n i n e A g e n e r a l method f o r a m i n o - a c i d

r e s o l u t i o n i s by c o n v e r s i o n o f a

r a c e m i c m i x t u r e of a - a m i n o - e s t e r s

(R,R,R)-

i n aqueous sodium h y d r o x i d e . 425 into the Schiff bases using

or (S,S,S)-2-hydroxypinan-2-one f o l l o w e d by c o l u m n

c h r o m a t o g r a p h y and h y d r o l y s i s .

O v e r a l l y i e l d s of o p t i c a l l y pure

p r o d u c t s a r e e x c e l l e n t , and f u r t h e r m o r e t h e method looks t o be v e r y g e n e r a l l y a p p l i c a b l e t o b o t h n a t u r a l and n o n - n a t u r a l a c i d s . 426

a-amino-

Another c h i r a l s t a t i o n a r y phase h a s been developed for d e r i v a t i v e s as w e l l a s amino-

t h e d i r e c t r e s o l u t i o n of a-amino-acid a l c o h o l s , a m i n e s , a n d a l c o h o l s . 427

T . 1. c .

a n a l y s i s of d a n s y l a m i n o - a c i d s c a n b e c a r r i e d o u t on r e v e r s e - p h a s e p l a t e s , p r e t r e a t e d w i t h a c o p p e r ( I 1 ) c o m p l e x o f N,N-di-n-propyl-4-alanine. 4 2 8 Enantiomers of a l l t h e n a t u r a l amino-acid w i t h t h e e x c e p t i o n of d a n s y l - p r o l i n e .

d e r i v a t i v e s are r e s o l v e d

Oxazolidine-2,5-dione

d e r i v a t i v e s , r e a d i l y o b t a i n e d from N-methyl-a-amino-acids

and

p h o s g e n e , c a n be r e s o l v e d by gas c h r o m a t o g r a p h y u s i n g a c h i r a l s t a t i o n a r y p h a s e ; t h i s m e t h o d l o o k s t o be p a r t i c u l a r l y u s e f u l f o r

small-scale,

q u a n t i t a t i v e work.429

Isoxazolidin-5-ones

( 4 8 2 ) c a n b e o b t a i n e d i n t w o s t e p s by

c o n j u g a t e a d d i t i o n s of N - s u b s t i t u t e d

hydroxylamines t o a,B-

u n s a t u r a t e d e s t e r s f o l l o w e d by c y c l i z a t i o n u s i n g L i N ( S i M e 3 I 2 ( o t h e r b a s e s w e r e i n e f f e c t i v e ) ; s u b s e q u e n t h y d r o g e n o l y s i s of ( 4 8 2 ; R 1 = 4 (483).430 The R g r o u p c a n

Bz) l e a d s d i r e c t l y t o B - a m i n o - a c i d s

a l s o be a d d e d l a t e r by a l k y l a t i o n o f t h e i n i t i a l a d d u c t s ( 4 8 2 ; R4=H); u n f o r t u n a t e l y ,

i n c o r p o r a t i o n of a c h i r a l s u b s t i t u e n t a t

n i t r o g e n d o e s n o t l e a d t o good c h i r a l i n d u c t i o n i n t h i s o t h e r w i s e r a t h e r g e n e r a l a p p r o a c h t o t3-amino-acids. 'disconnection'

An a l t e r n a t i v e

f o r t h e s y n t h e s i s of B-amino-acids

of t h e 2 , 3 - b o n d s ;

i s by c l e a v a g e

t h e f o r w a r d r e a c t i o n would t h e n i n v o l v e

a l k y l a t i o n of a n e s t e r e n o l a t e , or e q u i v a l e n t , w i t h a 'CH2NH2 s y n t h o n ( 4 8 5 ) . T h i s h a s b e e n a c h i e v e d by c o n d e n s i n g 2 - s i l y l e n o l a t e s w i t h t h e a m i n e ( 4 8 4 ) i n t h e p r e s e n c e of TMSOTf.431

ester Yields


213

a r e g e n e r a l l y b e t t e r t h a n 80% a n d t h e r e a c t i n g s p e c i e s i s p r o b a b l y a n i m i n i u m s a l t , (TMSI2fi:CH2, r e l a t e d t o E s c h e n m o s e r ' s s a l t . aM e t h o x y c a r b a m a t e s c a n be u s e d i n p l a c e o f r e a g e n t ( 4 8 4 ) i n s i m i l a r r e a c t i o n s w i t h 2 - s i l y l e s t e r e n o l a t e s . 4 3 2 A n o t h e r way t o f o r m t h e C ( 2 ) - C ( 3 ) bond i n B - a m i n o - a c i d s i s t o c o n d e n s e l i t h i u m e n o l a t e s o f e s t e r s w i t h t h e t i t a n i u m a l k o x i d e r e a g e n t s ( 4 8 6 ) ; 4 3 3 t h e method is a l s o u s e f u l f o r t h e p r e p a r a t i o n o f B-amino-ketones. The B-aminoa c i d ( 4 8 9 ) , a p r e c u r s o r of B e s t a t i n , h a s b e e n p r e p a r e d u s i n g a s t e r e o c o n t r o l l e d iodocyclocarbamation of t h e a l l y l a m i n e (4871, w h i c h g i v e s l a r g e l y t h e t r a n s - i s o m e r ( 4 8 8 ) .434 T h i s a p p r o a c h a p p e a r s t o have c o n s i d e r a b l e p o t e n t i a l f o r t h e e l a b o r a t i o n of a wide v a r i e t y of r e l a t e d s t r u c t u r e s . The a s y m m e t r i c S h a r p l e s s e p o x i d a t i o n of a l l y l i c a l c o h o l s h a s been extended t o h o m o a l l y l i c a l c o h o l s although o p t i c a l y i e l d s are u n f o r t u n a t e l y rather lower (23-55% .435 U s i n g t h i s m e t h o d , ( - )-y-amino-B-(R)-hydroxybutanoic a c i d (GABOB) ( 4 9 0 ) h a s b e e n s y n t h e s i z e d i n t h r e e s t e p s f r o m b u t - 3 e n - 1 - 0 1 ; t h e f i n a l p r o d u c t h a d a n e n a n t i o m e r i c e n r i c h m e n t of 49%. U n s a t u r a t e d Amino-acids.- F u l l d e t a i l s have been g i v e n o f t h e p r e p a r a t i o n of t h e p h o s p h o n a t e s ( 4 9 1 ) and t h e i r s u b s e q u e n t u s e i n t h e s y n t h e s i s o f d e h y d r o a m i n o - a c i d d e r i v a t i v e s ( 4 9 2 ) .436 I n g e n e r a l , such r e a c t i o n s are l i m i t e d t o non-conjugated a l i p h a t i c or a r o m a t i c a l d e h y d e s , a l t h o u g h i n t h e s e cases y i e l d s are e x c e l l e n t ( 7 0 - 9 0 % ) a n d , a l t h o u g h a v a r i e t y o f bases c a n b e e m p l o y e d , t h e r e a g e n t of c h o i c e is p o t a s s i u m t - b u t o x i d e i n d i c h l o r o m e t h a n e a t -70 O C , t h e u s e o f w h i c h u s u a l l y l e a d s t o a p r e d o m i n a n c e of t h e The u n s a t u r a t e d a m i n o - a c i d (L)-isomers i n t h e products (492). d e r i v a t i v e s ( 4 9 2 ) c a n a l s o be o b t a i n e d by c o n d e n s a t i o n s b e t w e e n a z l a c t o n e s d e r i v e d from N-acetyl- or N-benzoyl-glycine and a n a l d e h y d e , f o l l o w e d by a l c o h o l y s i s . 437- A l t h o u g h o n l y a r o m a t i c a l d e h y d e s a n d c i n n a m a l d e h y d e were u s e d , i m p l y i n g t h a t t h e m e t h o d may n o t be s u c c e s s f u l w i t h a l i p h a t i c a l d e h y d e s , t h i s a p p r o a c h d o e s work w i t h c y c l o h e x a n o n e 1 - p h e n y l i m i n e and c o u l d t h u s p e r h a p s be a p p l i e d t o o t h e r k e t o n e s , t h e r e b y p r o v i d i n g a way a r o u n d o n e o f t h e l i m i t a t i o n s o f t h e f o r e g o i n g Wadsworth-Emmons m e t h o d o l o g y . 436 Readily a v a i l a b l e a-azido-esters (493) can a l s o s e r v e as precursors t o d e h y d r o a m i n o - e s t e r s (492; R 1 = A c ) , f o l l o w i n g t r e a t m e n t w i t h a c e t i c a n h y d r i d e a n d a c a t a l y t i c a m o u n t of r h e n i u m h e p t a s u l p h i d e , Re2S7. 438 S i m i l a r l y , a , 8-unsaturated-a-azido-esters c a n b e t r a n s f o r m e d i n t o esters (492) u s i n g e i t h e r t h i s method or c a t h o d i c r e d u c t i o n . 439


214

A d e r i v a t i v e (494) of t h e parent dehydroamino-acid,

d e h y d r o a l a n i n e , h a s b e e n s i m p l y o b t a i n e d by d e h y d r a t i o n o f t h e c o r r e s p o n d i n g S c h i f f b a s e of s e r i n e methyl e s t e r u s i n g 1 , l ' carbonyldi-imidazole. 440

I n c o n t r a s t t o other such N-arylidene

d e r i v a t i v e s , t h i s p a r t i c u l a r analogue is a r e l a t i v e l y s t a b l e s o l i d which s h o u l d prove t o be a u s e f u l s y n t h e t i c i n t e r m e d i a t e as it u n d e r g o e s f a c i l e M i c h a e l a d d i t i o n s and a l s o c o n t a i n s an e a s i l y removable 1-protecting group. acid derivatives

A n o v e l approach t o dehydroamino-

[e.g.( 4 9 6 ) l c o n s i s t s o f a d d i t i o n o f

p h o t o c h e m i c a l l y g e n e r a t e d s i n g l e t o x y g e n , i n t h e p r e s e n c e of t h e b a s e DBU,

t o t h e corresponding imidazoles (4951, i n a Diels-Alder

l i k e p r o c e s s w h i c h i s f o l l o w e d by b a s e - c a t a l y s e d

isomerization.

44 1

A s t h e i n i t i a l products (496) can be subsequently hydrogenated t o d e r i v a t i v e s o f 88-96% e . e .

g i v e c h i r a l amino-acid

u s i n g a rhodium

c a t a l y s t w i t h (E,R)-DIPAMP a s l i g a n d , t h i s a p p r o a c h c o u l d r e p r e s e n t a n e x c e l l e n t method f o r f u l l y p r o t e c t i n g a n a m i n o - a c i d

residue

during peptide synthesis. A b r o a d l y a p p l i c a b l e a n d e n a n t i o s e l e c t i v e r o u t e t o B,runsaturated-a-amino-acids ( 4 9 7 ) f e a t u r e s a n e x t e n s i o n o f S c h d l l k o p f ' s b i s - l a c t i m e t h e r methodology i n which t h e l a t t e r are condensed e i t h e r with an u-silyl-aldehyde or a thioketone; o p t i c a l y i e l d s a r e u s u a l l y h i g h . 442 Racemic a m i n o - a c i d s ( 4 9 7 ; R 3 = H ) c a n b e s i m p l y o b t a i n e d u s i n g a o n e - p o t s e q u e n c e b a s e d on t h e S t r e c k e r

r e a c t i o n , t h e key s t e p b e i n g t h e a d d i t i o n of t r i m e t h y l s i l y l c y a n i d e t o i m i n e s d e r i v e d f r o m a ,@ - u n s a t u r a t e d a l d e h y d e s .443 member o f t h i s g r o u p o f a m i n o - a c i d s ,

L-vinylglycine

R3 = H), can be r e a d i l y o b t a i n e d from L-glutamic

The s i m p l e s t

( 4 9 7 ; R 1 = R2 =

a c i d i n an

o p t i c a l l y p u r e s t a t e by e l i m i n a t i o n o f t h e e l e m e n t s o f f o r m i c a c i d from t h e p r o p i o n i c a c i d s i d e - c h a i n Cu ( OAc ) 2. 444

o f t h e l a t t e r u s i n g Pb(OAc)4-

Racemic v i n y l g l y c i n e h a s b e e n p r e p a r e d f r o m ( L ) - b u t -

2-ene-I , Q - d i o l , 445 t h e key s t e p b e i n g a [ 3 , 3 ] - s i g m a t r o p i c r e a r r a n g e m e n t of t h e t y p e m e n t i o n e d a b o v e i n a n o v e l s y n t h e s i s o f a-amino-acids

[(475)

-

(476)].418

T h e u t i l i t y of t h e r e l a t e d

Claisen rearrangement i n t h e s y n t h e s i s of a-allenyl-a-amino-acid d e r i v a t i v e s was d e s c r i b e d some n i n e y e a r s a g o b y S t e g l i c h a n d c o workers.

However,

t h e v a l u e of

t h i s m e t h o d was s e v e r e l y l i a i t e d

b y p r o b l e m s a t t h e f i n a l d e p r o t e c t i o n s t e p s ; t h e s e h a v e now b e e n o v e r c o m e , 4 4 6 a l l o w i n g t h e m e t h o d t o b e u s e d for t h e p r e p a r a t i o n of t h e free amino-acids

(498).

Homologous a l l e n i c a c i d s , s u c h as t h e

n a t u r a l l y o c c u r r i n g c o m p o u n d (S)-2-aminohexa-4,5-dienoic a c i d (500), c a n be o b t a i n e d i n good y i e l d s (55-60%) w i t h n o r a c e m i z a t i o n


215

0 ( MeO), FycozMe

R~CHO ~

R 2 y c o z M e

NHR'

NHR'

( 4 9 1 ) R'= Boc,Ac or CHO

(492)

YCoZMe

- RzYo N3

( 4 93 1

Bz

b

N

Ph (494)

(497)

(495 )

(496)

(498)

C02Et %NHTs Ar

(503)

H2NLC02H (504)

216


[s.

by radical coupling reactions between an alkyl iodide (499)l and triphenylprop-2-ynylstannane, followed by deprotection. 447 A straightforward synthesis of 2-methylidene-2-aminopropanoates ( 5 0 3 ) is based on previous observations and simply involves heating ethyl acrylate (501) with an 1-tosylbenzaldimine (502) in the presence of DABCO. 448 Two new routes to y-allenic GABA (504) have been reported, both of which have 5-allenyl-2-pyrrolidinone as the penultimate compound, prepared either by BF3-catalysed coupling of propargy 1t r imethy Isi lane and 5-ethoxy-2 -pyr r o lid i n ~ n e or ~ ~by a novel example of an aza-Cope rearrangement. '5' Asymmetric Hydrogenation.- Useful discussions have been published on the design and efficiency of a variety of chiral rhodiumphosphine complexes in asymmetric hydrogenations of both !acyldehydro-u-amino-acids and dehydropeptides. 45 I A new addition to the ever-growing list of chiral ligands is (&,&)-g-benzoyl-3,4bis(dipheny1phosphino)pyrrolidine derived in eight steps from (+Itartaric acid. 4 5 2 This stable and rigid ligand, designated 'benzoylpyrphos', in combination with [ R h ( ~ o d ) ~ l B Fproduces ~ the which catalyses the novel complex [Rh(cod)(benzoylpyrphos)]BF4, hydrogenation of a-(acety1amino)cinnamic acid to give (S)-g-acetylphenylalanine with 99% e.e. More significantly, some preliminary experiments have revealed that re-usable catalysts derived from this complex and either Merrifield resin or silica gel can effect the same hydrogenation with >95% e.e., a selectivity which has not previously been achieved in heterogeneous catalysis. Some homogeneous rhodium(1) catalysts containing chiral diphosphine ligands based on 1,l'-binaphthyls have been found to give optical yields of up to 100% in hydrogenations of various a-(acy1amino)acrylic and -cinnamic acids. 453 Modifications of DIOP ligands by the introduction of aryl groups onto the dioxolane ring or by replacing one of the PPh2 groups by PAr2 can result in slightly higher optical yields when compared with the parent ligand, especially in hydrogenations of some dehydropeptides 454 A new diphosphinite ligand, ( 1 ~ , 3 ~ ) - b i s ( d i p h e n y l p h o s p h i n o x y ) 1,3-diphenylpropane, has been reported which, in conjunction with rhodium(I), effects asymmetric hydrogenations of some (Z-)-a(acy1amino)cinnamic acids in 79-84% optical yields.455 However, in general, currently available diphosphinite ligands are only useful in the asymmetric hydrogenation o f certain dehydrodipeptides .456 Optical yields of between 43 and 93% have been observed in

.

217


h e t e r o g e n e o u s h y d r o g e n a t i o n s of d e h y d r o a l a n i n e r e s i d u e s i n c h i r a l t r i p e p t i d e s c o n t a i n i n g a t e r m i n a l p r o l i n e r e s i d u e , u s i n g 5% Pd-C a s c a t a l y s t ; 4 5 7 p o s s i b l y t h i s i d e a c o u l d be e x t e n d e d t o o t h e r , r a t h e r rigid substrates. Amino-acid

Protection.-

An e s t a b l i s h e d t h r e e - s t e p

e s t e r i f i c a t i o n of a-amino-acids

method f o r t h e

c o n s i s t s of p r o t e c t i o n o f t h e amino

f u n c t i o n by e n a m i n e f o r m a t i o n u s i n g e t h y l a c e t o a c e t a t e f o l l o w e d by a l k y l a t i o n of t h e p o t a s s i u m s a l t of t h e c a r b o x y l i c a c i d g r o u p and finally acid hydrolysis.

T h i s o v e r a l l conversion can be performed

much more r a p i d l y a n d i n o n e p o t when a m i x t u r e o f d i m e t h y l Y i e l d s of esters are

s u l p h o x i d e and b e n z e n e is u s e d a s s o l v e n t . 4 5 8

i n t h e r a n g e 67-89% when a d i a l k y l s u l p h a t e o r b e n z y l i c h a l i d e i s u s e d as t h e a l k y l a t i n g r e a g e n t , a n d f u r t h e r m o r e t h e method i s v i r t u a l l y f r e e from r a c e m i z a t i o n drawbacks.

N-Protected

a-amino-

a c i d s can be simply converted i n t o t h e corresponding diphenylmethyl (Dpm) e s t e r s by d i r e c t r e a c t i o n w i t h Dpm d i p h e n y l p h o s p h a t e . 459 No r a c e m i z a t i o n o c c u r s and g i v e n a c h o i c e t h e r e a g e n t w i l l r e a c t p r e f e r e n t i a l l y w i t h t h e a l c o h o l g r o u p of a hydroxy-acid f o r e x a m p l e , t h e p r e p a r a t i o n o f lf-L-serine-g-Dpm pyridy1)ethoxycarbonyl

ether.

allowing, The 2-(2-

(2-Pyoc) f u n c t i o n h a s r e c e n t l y been

e s t a b l i s h e d as an i m p o r t a n t v a r i a n t o f e x i s t i n g m e t h o d s f o r aminogroup protection.

Perhaps predictably,

t h i s f u n c t i o n h a s a l s o been

f o u n d t o b e u s e f u l for t h e p r o t e c t i o n o f c a r b o x y l i c a c i d g r o u p s during peptide synthesis.460 formed u s i n g 2 - p y r i d y l e t h a n o l ,

The s o - c a l l e d DCC,

Pet-esters

(505) are

a n d e i t h e r H O B t o r DMAP a n d a r e

s t a b l e t o a c i d h y d r o l y s i s ( d e p r o t e c t i o n of t-butyl-based functions), t o hydrogenolysis

(removal of benzyl g r o u p s ) , and t o

a m i n e s ( r e m o v a l of Fmoc o r F M - e s t e r s ) . i n much t h e same way a s If-Pyoc

Pet-esters

can be c l e a v e d

g r o u p s by q u a t e r n i z a t i o n u s i n g

m e t h y l i o d i d e f o l l o w e d by t r e a t m e n t w i t h d i e t h y l a m i n e ; t h e r e f o r e t h i s t y p e o f p r o t e c t i n g g r o u p is n o t u s u a l l y c o m p a t i b l e w i t h e i t h e r h i s t i d i n e or methionine residues.

Both t h e p r o t e c t i o n and

d e p r o t e c t i o n s t e p s a r e e s s e n t i a l l y f r e e of r a c e m i z a t i o n .

The

r e l a t e d 2-(diphenylphosphino)ethyl ( D p p e ) g r o u p h a s s i m i l a r l y b e e n u s e d t o p r o t e c t c a r b o x y l i c a c i d f u n c t i o n s a n d o f f e r s much t h e same a d v a n t a g e s as P e t - g r o u p s . 4 6 1

An a l t e r n a t i v e t o t h e e x i s t i n g

(506) u s i n g mild r e d u c i n g a g e n t s i s e l e c t r o c h e m i c a l r e d u c t i o n u s i n g DMF a s s o l v e n t . 4 6 2 T h i s methods f o r t h e c l e a v a g e of (Maql-esters

f u n c t i o n is a l s o u s e f u l f o r N"-protection. a - A m i n o - e s t e r s c a n b e N - m e t h y l a t e d by p r i o r c o n v e r s i o n i n t o t h e

218


S c h i f f b a s e or p r e f e r a b l y t h e a m i d i n e d e r i v a t i v e s ( 5 0 7 ) f o l l o w e d b y m e t h y l a t i o n u s i n g d i m e t h y l s u l p h a t e or MeOTf usual base-alkyl

,

and h y d r o l y s i s .463

reactions provide a useful a l t e r n a t i v e t o t h e

These Decker-type

h a l i d e m e t h o d a n d p r o c e e d i n 41-75% y i e l d s w i t h

l i t t l e o r no r a c e m i z a t i o n i f t h e c o n d i t i o n s a r e c a r e f u l l y controlled.

Free a-amino-acids

(508) can be d i r e c t l y alkylated

without racernization t o give only mono-alkylated

p r o d u c t s ( 5 0 9 ) by 464

t r e a t m e n t w i t h a n a l d e h y d e o r k e t o n e a n d NaBH CN i n m e t h a n o l .

3

T h i s r e d u c t i v e a l k y l a t i o n method, previously a p p l i e d t o t h e

is v e r y e f f i c i e n t and i t s g e n e r a l i t y a p p e a r s

s y n t h e s i s of t-amines,

t o b e l i m i t e d m a i n l y by t h e n e c e s s i t y t o a v o i d t h e p r e s e n c e o f o t h e r f u n c t i o n s which react w i t h cyanoborohydride.

Yet a n o t h e r s t a b l e , c r y s t a l l i n e r e a g e n t f o r t h e i n t r o d u c t i o n o f

Na-Boc g r o u p s i s t - b u t y l 2 - p y r i d y l c a r b o n a t e . 4 6 5 hydroxypyridine,

phosgene, and t - b u t y l

w i t h a-amino-acids

a t 20

OC

P r e p a r e d f r o m 2-

alcohol, t h e reagent reacts

i n 50% a q u e o u s DMF c o n t a i n i n g E t N t o

3

g i v e 8 5 - 9 9 % o f t h e NQ-Boc d e r i v a t i v e s w i t h o u t r a c e m i z a t i o n . d e s c r i p t i o n of t h e u t i l i t y o f t h e d i p h e n y l p h o s p h i n y l i n amino-group

p r o t e c t i o n h a s been g i v e n . 466

( 5 1 0 ) a r e o b t a i n e d from a - a m i n o - e s t e r s

f o l l o w e d by e s t e r h y d r o l y s i s .

A full

(Dpp) f u n c t i o n

NQ-Dpp-amino-acids

by t r e a t m e n t w i t h D p p C l

The f u n c t i o n i s s t a b l e t o b a s e a n d

h y d r o g e n o l y s i s b u t is e a s i l y removed u n d e r a v a r i e t y o f a c i d i c c o n d i t i o n s , t h e b e s t o f t e n b e i n g s i x e q u i v a l e n t s of h y d r o g e n c h l o r i d e i n methanol.

A s m e n t i o n e d a b o v e , 4 6 0 t h e 2-(2-

pyridy1)ethoxycarbonyl

(2-Pyoc) group is a l s o v a l u a b l e f o r t h e

p r o t e c t i o n of amino f u n c t i o n s ; t h e 4 - p y r i d y l a p p e a r t o o f f e r similar a d v a n t a g e s . 467

isomer (4-Pyoc) would

A disadvantage a s s o c i a t e d w i t h t h e use of p r o t e c t i n g groups which c a n be v e r y s e l e c t i v e l y c l e a v e d is t h a t t h e y are o f t e n r a t h e r b u l k y (3. Fmoc g r o u p s ) .

A f u n c t i o n a l i t y which does n o t s u f f e r

from t h i s p o t e n t i a l drawback i s t h e a l l y l o x y c a r b o n y l

(Aloe) group

w h i c h c a n b e r e a d i l y r e m o v e d by a l l y 1 t r a n s f e r t o dirnedone u s i n g [Pd(PPh )

same

1

a s c a t a l y s t . 468

A l l y 1 esters c a n be c l e a v e d i n t h e

t h e one obvious d i s a d v a n t a g e of t h e s e groups is t h e i r

i n c o m p a t i b i l i t y w i t h t h e h y d r o g e n o l y s i s c o n d i t i o n s u s e d t o remove benzyl-based protecting groups.

T h e m o r e c o m p l e x Ea-DB-t-Boc

f u n c t i o n [see ( 5 1 1 ) l is r e m a r k a b l y s t a b l e t o a c i d i c h y d r o l y s i s b u t c a n b e r e m o v e d s i m p l y b y w a r m i n g i n m e t h a n o l or e t h a n o l , 4 7 0 a n d h e n c e c o u l d p r o v e o f g r e a t u t i l i t y i n some c a s e s .

e s t e r i-NOPY-Gly-OSu

The a c t i v a t e d

( 5 1 2 ) i s u s e f u l for t h e i n t r o d u c t i o n o f

g l y c i n e r e s i d u e s i n t o p r o t e i n s or p o l y p e p t i d e s u n d e r a q u e o u s


219

3

R1$

0

NHR NHR~

0 (506 1

(505)

-

RYco2Me "Yo'"

R~COR

NH2

(508)

(507)

I HNPPh,

(510)

""y0x:: I

(511 1

(509)


220

c o n d i t i o n s a n d f e a t u r e s t h e u s e of t h e i-NOPY a m i n o - p r o t e c t i n g g r o u p ( t h e N - c y c l o h e x y l homologue h a s b e e n r e p o r t e d p r e v i o u s l y ) w h i c h i s r e a d i l y r e m o v e d upon e x p o s u r e t o ammonium h y d r o x i d e . 4 7 1 Some new p r o c e d u r e s f o r t h e r e m o v a l o f known N " - p r o t e c t i n g g r o u p s have been developed. "Q-Z(OMe

)I

N-4-Methoxybenzyloxycarbonyl g r o u p s

c a n be removed u s i n g t o l u e n e - p - s u l p h o n i c

acid i n

a c e t o n i t r i l e ; t h e s o l v e n t a p p e a r s t o a c t as a s c a v e n g e r o f t h e b e n z y l i c c a t i o n s p r o d u c e d d u r i n g d e g r a d a t i o n . 472 A q u e o u s h y d r a z i n e a t pH 7-9 h a s b e e n shown t o b e v e r y e f f e c t i v e f o r t h e r e m o v a l o f (TNP) f u n c t i o n s . 4 7 3 H y d r a z i n e i s a l s o

Na-2,4,6-trinitrophenyl

o f t e n t h e r e a g e n t of c h o i c e f o r t h e c l e a v a g e of p h t h a l i m i d o g r o u p s u s i n g t h e Ing-Manske

procedure.

Racemization can be a drawback

w i t h t h i s method and so an e s s e n t i a l l y r a c e m i z a t i o n - f r e e

m e t h o d ,474

c o n s i s t i n g o f s e q u e n t i a l t r e a t m e n t of t h e p h t h a l i m i d e w i t h s o d i u m b o r o h y d r i d e i n propan-2-01

f o l l o w e d by a c e t i c a c i d , c o u l d l e a d t o

g r e a t e r u s e b e i n g made o f t h i s p r o t e c t i n g g r o u p i n p e p t i d e synthesis.

The r e c e n t l y i n t r o d u c e d c y c l o h e x a d i e n y l - b a s e d

p r o t e c t i n g g r o u p , N"-PChd,

amino

c a n be r e m o v e d by c a t h o d i c r e d u c t i o n i n

a c i d i c m e t h a n o l , a g a i n w i t h o u t r a c e m i z a t i o n . 475 A number o f r e a g e n t s h a v e b e e n i n t r o d u c e d f o r d e b l o c k i n g v a r i o u s

t y p e s of t h i o l p r o t e c t i n g g r o u p s i n c y s t i n e r e s i d u e s .

2-4-

(MBZL) g r o u p s a r e u s u a l l y c l e a v e d u s i n g s o d i u m i n A useful l i q u i d ammonia476 o r h y d r o g e n f l u o r i d e - a n i s o l e

Methoxybenzyl

.

a l t e r n a t i v e i s t o u s e t h e homogeneous e l e c t r o n t r a n s f e r r e a g e n t ,

tris(4-bromophenyl)ammoniumyl w h i c h p r o v i d e s t h e c o r r e s p o n d i n g c y s t i n e d i s u l p h i d e s i n E. 90% y i e l d s . 477 The Boc a n d Z g r o u p s a r e n o t a f f e c t e d by t h i s r e a g e n t .

2-Mpt

(dimethylphosphinothioyl)

p r o t e c t i n g g r o u p s c a n b e r e m o v e d u s i n g p o t a s s i u m f l u o r i d e a n d 18crown-6

i n a c e t ~ n i t r i l e - m e t h a n o lw~h~e~r e a s d i a c e t o x y p h e n y l i o d i n e

,

PhI(OAc)2, is c a p a b l e of o x i d a t i v e l y c l e a v i n g 2-triphenylrnethyl ( T r t ) , 2-diphenylmethyl

(Dpm), a n d 2 - a c e t a m i d o m e t h y l

(Acm)

f u n c t i o n s , i n e a c h case g i v i n g t h e o p t i c a l l y p u r e c y s t i n e i n 65-97% y i e l d s , a n d l e a v i n g N"-Boc a n d Z g r o u p s i n t a c t . 4 7 9 A new m e t h o d f o r m a s k i n g t h e i n d o l i c n i t r o g e n i n t r y p t o p h a n i s by c o n v e r s i o n t o t h e Nin-Boc d e r i v a t i v e by t r e a t m e n t w i t h Boc20-DMAP. 480 C a r e f u l a c i d i c c l e a v a g e i s p o s s i b l e i n t h e p r e s e n c e o f o t h e r Na-Boc g r o u p s . F i n a l l y , t h e t-butoxymethyl

group h a s been found t o be eminently 48 1

s u i t a b l e f o r b l o c k i n g t h e i m i d a z o l e NH f u n c t i o n i n h i s t i d i n e .

221

3: Carboxylic Acids and Derivatives References 1 2

3 4 5

6

7 8 9 10

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1811. 11

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u,

12 13 14 15

16 17 18

19 20

21 22

23 24 25 26 27

28 29 30

31 32 33 34

u.,

.

w.,

222 35 36 37 38 39

General and Synthetic Methods T-Fujisawa, K.Umezu, and M.Kawashima, Chem. Lett., 1984, 1795. A.I.Meyers and P.D.Panegrau, Tetrahedron Lett., 1984, 25, 2941. G.A.Artamkina, A.A.Grinfel'd, and I.P.Beletskaya, Tetrahedron Lett., 1984, 25, 4989. G.Silvestri, S.Gambino, G.Filardo, and A.Gulotta, Angew. Chem., Int. Ed. Engl., 1984, 23, 979. C.Giordano, G.Castaldi, and F.Uggeri, Angew. Chem., Int. Ed. Engl,, 1984, 23, 413. T.Wollmann and B.Franck, Angew. Chem., Int. Ed. Engl., 1984, 23, 226. S.Uemura, S.Fukuzawa, T.Yamauchi, K.Hattori, S.Mizutaki, and K.Tamaki, J. Chem. SOC., Chem. Commun., 1984, 426. Y.Tamura, Y.Shirouchi, and J.Haruta, Synthesis, 1984, 231. E.C.Taylor, R.A.Conley, A.H.Katz, and A.McKillop, op, J. Org. Chem., Chz., 1984, 3840. R.P.Kopinski, J.T.Pinhey, and B.A.Rowe, Aust. J. Chem., 1984, 37, 1245. For a review of the use of diaryliodonium salts in this transformation, see A.Varvoglis, Synthesis, 1984, 709. C.Riichardt, H.Gartner, and U.Salz, Angew. Chem., Int. Ed. Engl., 1984, 23, 162; U.Salz and C.Ruchardt, Chem. Ber., 1984, 3,3457. G.Schmitt, N.D.An, J.-P. Poupelin, J.Vebre1, and B. Laude, Synthesis, 1984, 758. F.Bigi, G.Casiraghi, G.Casnati, and G.Sartori, J. Chem. S O C . , Perkin Trans. 1 , 1984, 2655. R.Grigg and H.Q.N.Gunaratne, J. Chem. SOC. , Chem. Commun., 1984, 661. C.D.Buttery, D.W.Knight, and A.P.Nott, J. Chem. SOC., Perkin Trans. 1 , 1984, 2839. D.P.Stack and R.M.Coates, Synthesis, 1984, 434. For a review, see 0.DeLucchi and G.Modena, Tetrahedron, 1984, 5, 2585. Y.Kita, S.Akai, M.Yoshigi, Y-Nakajima, H.Yasuda, and Y.Tamura, Tetrahedron Lett., 1984, 6027. B.Giese and G.Kretzschmar, Chem. Ber., 1984, 117,3175. O.Toussaint, P.Capdevielle, and M.Maumy, Tetrahedron, 1984, 40, 3229; Tetrahedron Lett., 1984, 25, 3819. B.H.R.Barton, D.Bridon, and S.Z.Zard, Tetrahedron Lett., 1984, 25, 5777. D.H.R.Barton, D.Crich, and W.B.Motherwel1, J. Chem. SOC., Chem. Commun., 1984, 242. D.H.R.Barton, Y.Herv6, P.Potier, and J.Thierry, J. Chem. SOC., Chem. Commun., 1984, 1298. S.Itoh, N.Kato, Y.Ohshiro, and T.Agawa, Tetrahedron Lett., 1984, 25, 4753. R.Pellicciari, B.Natalini, S.Cecchitti, and S.Santucci, Tetrahedron Lett., 1984, 2, 3103. D.Hermeling and H.J.Schafer, Angew. Chem., Int. Ed. Engl., 1984, 23, 233; M.Huhtasaari , H. J.Schafer , and L.Becking, g . , p .980. For a review of the Kolbe reaction, see M.M.Baizer, Tetrahedron, 1984, 40, 935. Chem 1984, 9, 1732. N-Rabjohn, W.L.Cranor, and C.M.Schofield J Or T.L.Capson and C.D.Poulter, Tetrahedron t e e & : 3515. S.Kajigaeshi, T.Nakagawa, S.Fujisaki, A.Nishida, and M.Noguchi, Chem. Lett., 1984, 713. G.M.Loudon, A.S.Radhakrishna, M.R.Almond, J.K.Blodgett, and R.H.Boutin, J. Org. Chem., 1984, 4272; R.H.Boutin and G.M.Loudon, g., p.4277. M.J.Cohen and E.McNelis, J. Org. Chem., 1984, 5, 515. 983. C-Blankenship and L.A.Paquette, Synth. Commun., 1984, L.N.Pridgen, S.C.Shilcrat, and I.Lantos, Tetrahedron Lett., 1984, 25, 2835. M.Kimura, S.Matsubara, and Y.Sawaki, J. Chem. SOC., Chem. Commun., 1984, 1619. H-Mastalerz. J. Ora. Chem.., 1984. 49. 4092. E.W.Logusch; Tetrahedron Lett ., i984; 25, 4195. S.Kim, J.I.Lee, and Y.K.Ko, Tetrahedron Lett., 1984, 25, 4943. M.Ballester-Rodes and A.L.Palomo-Coll, Synth. Commun., 1984 9 14, 51 5. S.Murata, Bull. Chem. SOC. Jpn., 1984, 57, 3597. See also O X i t sun0bu , A.Takemasa, and R.Endo, Chem. Lett., 1984, 855. -'

40 41 42 43 44

45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69

70 71 72 73

74

c,

s,

2,

14,

,

223

3: Carboxylic Acids and Derivatives 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101

102 103 104 105 106 107

F.E.Carlon and R.W.Draper, Synth. Commun., 1984, 14, 725. E.Binderup and E.T.Hansen, Synth. Commun., 1984, 857. S.Kim and J.I.Lee, J. Org. Chem., 1984, 1712. S.Hashimoto, M.Hayashi, and R.Noyori, Bull. Chem. SOC. Jpn., 1984, 57, 1431. S.E.Fry and N.J.Pienta, J. Org. Chem., 1984, 2, 4877. J:M.Renga and P.-C.Wang, Synth. Commun., 1984, 11(, 77. E.J.Corey and B-Samuelsson, J. Org. Chem., 1984, 4735. See also Y.Masuyama, M.Takahashi, and Y.Kurusu, Tetrahedron Lett., 1984, 25, 4417. 1.Reichelt and H.-U.Reissig, Liebigs Ann. Chem., B. A.Feit , R .Elser, Y .Melamed , and I.Golc and L.K.Sydnes and S.Skare, Can. J. Chem., 1984, 62, i C.Gluchowski, T.Tiner-Harding, J.K.Smith, D.E.Berbreiter, and M.Newcomb, J. Org. Chem., 1984, 9, 2650. S.De Lombaert and L.Ghosez, Tetrahedron Lett., 1984, 25, 3475. A.Zapata and C.Acuna, Synth. Commun., 1984, 5, 27. K.Hofmann and G.Simchen, Liebigs Ann. Chem., 1984, 39. V.Fiandanese, F.Naso, and A.Scilimati, Tetrahedron Lett., 1984, 25, 1187. N.Ono, A.Kmimura, and A.Kaji, Synthesis, 1984, 226. 1.Fleming and T.W.Newton, J. Chem. S O C . , Perkin Trans. 1 , 1984, 1805; 1.Fleming and D.Waterson, p . 1809. B.H.Lipshutz, R.S.Wilhelm, and J.A.Kozlowski, Tetrahedron, 1984, 40, 5005 See also S.H.Bertz and G.Dabbagh, J. Org. Chem., 1984, 9, 1119. R.D.Pergola and P.DiBattista, Synth. Commun., 1984, 121. A-ABel-Magid, I.Lantos, and L.N.Pridgen, Tetrahedron Lett., 1984, 25, 327 3. K.E.Hashem, J.B.Woel1, and H.Alper, Tetrahedron Lett., 1984, 25, 4879; J.B.Woel1 and H.Alper, p.3791. G.C.Tustin and R.T.Hembre, J. Org. Chem., 1984, 49, 1761. J.Kang, W.Cho, and W.K.Lee, J. Org. Chem., 1984,-2, 1840. B.M.Trost and M.-H.Hung, J. Am. Chem. SOC., 1984, 106,6837. B.M.Trost and A.Brandi, J. Org. Chem., 1984, 9, 4811. D.Ferroud, J.P.Genet, and J.Muzart, Tetrahedron Lett., 1984, 25, 4379. D.Djahanbini, B.Cazes, and J.Gore, Tetrahedron Lett., 1984, 25, 203. M.Ahmar, B.Cazes, and J.Gore, Tetrahedron Lett., 1984, 25, 4505. T.Hayashi, M.Konishi, and M.Kumada, J. Chem. SOC., Chem. Commun., 1984, 1 07. K.Hiroi, R.Kitayama, and S.Sato, Chem. Lett., 1984, 929. B.R.Chhabra, M.L.Bolte, and W.D.Crow, Aust. J. Chem., 1984, 37, 1795. C.-C.Chan and X.Huang, Synthesis, 1984, 224. M.Yamaguchi, M.Tsukamoto, S.Tanaka, and I.Hirao, Tetrahedron Lett., 1984, 25, 5661; M.Yamaguchi, M.Tsukamoto, and I.Hirao, Chem. Lett., 1984, 375. J.K.Gawronski, Tetrahedron Lett., 1984, 25, 2605. F.A.Davis, L.C.Vishwakarma, J.M.Billmers, and J. Finn, J. Org. Chem., 1984 , 49. 3241. H.C.Brown, G.G.Pai, and P.K.Jadhav, J. Am. Chem. SOC., 1984, 1531. M.Larchev&que and Y.Petit, Tetrahedron Lett., 1984, 25, 3705. O.Piccolo, L.Filippini, L.Tinucci, E.Valoti, and A.Citterio, Helv. Chim. Acta, 1984, 9, 739; A.Citterio, M.Gandolfi, O.Piccolo, L-Filipptni, L.Tinucci, and E.Valoti, Synthesis, 1984, 760. M.T.Reetz, Angew. Chem., Int. Ed. Engl., 1984, 23, 556. T.Oishi and T.Nakata, Acc. Chem. Res., 1984, 17,338. C.J.Sih and C.-S.Chen, Angew. Chem., Int. Ed. Engl., 1984, 23, 570. T.Fujisawa, T.Itoh, and T.Sato, Tetrahedron Lett. , 1984, 25, 5083. K.Nakmura, K.Ushio, S.Oka, A.Ohno, and S.Yasui, Tetrahedron Lett., 1984, 25, 3979. R.W.Hoffmann, W.Ladner, and W.Helbig, Liebigs Ann. Chem., 1984, 1170. D.W.Brooks, N.Castro de Lee, and R.Peevey, Tetrahedron Lett., 1984, 25, 4623. D.Seebach , P. Renaud , W. B. Schweizer , M. F .Z&ger, and M.- J.Brienne , Helv. Chim. Acta, 1984, 9, 1843. D.Seebach, M.F.Ziiger, F.Giovannini, B.Sonnleitner, and A-Fiechter, Angew. Chem., Int. Ed. Engl., 1984, 23, 151.

2,

2,

u.,

111,

u.,

,~

108 109 110 111 112

113 114 115 116 117 118 119

E,

5,


224 120

121 122 123 124 125

126 127

128 129

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s,

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130

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138 139 140 141 142 143 144

145 146 147 148 149 150 151 152 153 154

155

106,

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2,

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160 161 162

106,

106,

106,

106,

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167 168

9,

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169 170 171 172 173 174 175 176

177 178 179 180 181 182 183 184 185

186 187 188 189

190 191 192 193 194 195 196 197 198 199 200 20 1 202 203 204 205

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226 206 20 7 20 8 20 9 21 0 21 1 21 2 21 3 21 4 21 5 21 6 21 7 21 8 21 9 220 221 222 223 224 225 226 227 228 229

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c,

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252 253 254

255 256 257 258 259 260 26 1 262

263 264

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2,

I

31 3 314 315 316

-

,

229

3: Carboxylic Acids and Derivatives 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 36 1 362 363 364 365

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u.,

106,

9, 9,

106,

106,

5,

67,

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230


366 367 368

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z,

1984, 38 1 382 38 3 38 4 38 5 386 387 38 8 389 390 39 1 392 39 3 39 4

2,

2,

106,3876.

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g,

2,

3: Carboxylic Acids and Derivatives 41 0 41 1 41 2

41 3 41 4 41 5 41 6 41 7 41 8 41 9 420 42 1 42 2 423 424 42 5 42 6 427 42 8 42 9 430 43 1 432 43 3 43 4 43 5 436 43 7 438 439 4 40 441 4 42 443 444 445 446 447 448 449 450

23 1

z, u.,

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u.,

2,

9,

c

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45 1

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452 453 454 45 5 456 457 458 459 460

46 1 462 46 3 464 46 5 46 6 46 7 468 469 470 47 1 472 47 3 47 4 47 5 476 47 7 478 479 480 48 1

c,

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Alcohols, Halogeno-compounds, and Ethers BY L. M. HARWOOD

Reactions are listed according to the type of compound prepared wherever possible. For example ROH RC1 reactions are classified

-

as halide preparations and not alcohol reactions. Exceptions are those reactions which are considered to be protection or deprotection procedures. Within each class preparations are discussed before reactions. Cross-referencing to earlier Reports follows the established style. 1 Alcohols

Preparation.- By Addition to Alkenes. The hydroboration characteristics of lithium borohydride-ethyl acetate, sodium borohydride-titanium( 111) chloride, and the complex between sodium borohydride and dicyclopentadienyltitanium dichloride3 have been investigated. Aromatic olefins are reductively oxygenated to benzyl alcohols in good yield by molecular oxygen and tetraethylammonium borohydride in the presence of a cobalt(I1) catalyst. Hydroxyalkylation of olef ins has been achieved in moderate yield by heating olefins neat with hydroxyperoxydiazenes (care, explosive) in a sealed tube.5 Procedures for %-I ,2hydroxylation of alkenes have been reported using cetyltrimethylammonium permanganate in dichloromethane at room temperature, and mercury( 11) oxide-f luoroboric acid in water at 70 0C.7 Further work has been published regarding empirical rules to predict the stereochemistry of osmylation of allylic alcohols. a

By Reduction of Carbonyl Compounds. Sodium (dimethy1arnino)bor-ohydride and sodium(t-buty1amino)borohydride have been shown to be more powerful reducing agents than sodium borohydride, reducing esters to alcohols.' Reduction of ketones with borohydride has been found to be accelerated by carrying out the reaction in an emulsion. I " The alloy LaNi5 readily absorbs hydrogen and has been applied to the reduction of ketones; yields are high and the 233

For References s e e page 277.

234


r e a c t i o n i s c a r r i e d o u t i n m e t h a n o l a t low t e m p e r a t u r e . ”

A

combination of l i t h i u m borohydride-Grignard reagent provides a c o n v e n i e n t means o f c o n v e r t i n g e s t e r s i n t o s e c o n d a r y a l c o h o l s i n y i e l d s t h a t compare w i t h s t a n d a r d m u l t i s t e p p r o c e d u r e s (Scheme I ) . ’ *

The s u c c e s s o f t h e p r o c e d u r e r e s u l t s f r o m t h e

r e d u c t i o n o f t h e i n i t i a l l y formed k e t o n e o c c u r r i n g a t a g r e a t e r r a t e than a d d i t i o n o f a second equivalent of t h e Grignard reagent. Chemoselective Carbonyl Reductions. S e l e c t i v e reduction of aldehydes i n t h e presence of s a t u r a t e d ketones h a s been demonstrated u s i n g sodium b o r o h y d r i d e i n d i m e t h y 1 , s u l p h o x i d e i n t h e p r e s e n c e of e i t h e r c e r i u m ( 111) c h l o r i d e o r c o b a l t ( 11) c h l o r i d e h y d r a t e s . system a l s o reduces a , ~ - u n s a t u r a t e d ketones.

This

Some s e l e c t i v i t y f o r

aldehyde over k e t o n e r e d u c t i o n h a s a l s o been found w i t h t i n f o r m a t e s i n d i g y l m e a t 160 oC.14a

The same a u t h o r s h a v e s h o w n t h a t

t h e y i e l d s a n d s e l e c t i v i t y a r e i m p r o v e d by t h e a d d i t i o n o f n - b u t a n o l , when r e a c t i o n o c c u r r e d a t 1 1 5 t i n r e a g e n t . 14b

OC

a n d was c a t a l y t i c i n

F o r e x p e d i e n c y h o w e v e r , o n e o r two e q u i v a l e n t s o f

t h e s t a n n a n e a r e recommended, t h e mechanism b e i n g t h a t o f t h e Merwein-Pondorf-Verley

couple under t h e s e conditions.

Borohydride

e x c h a n g e r e s i n i n m e t h a n o l a t room t e m p e r a t u r e s e l e c t i v e l y r e d u c e s a,B-unsaturated

c a r b o n y l compounds t o a l l y l i c a l c o h o l s w i t h o u t

a f f e c t i n g t h e d o u b l e bond.15

T h i s r e a g e n t i s more e f f i c i e n t t h a n

o t h e r s , a n d c a n b e r e m o v e d by f i l t r a t i o n a t t h e e n d o f t h e S e l e c t i v e r e d u c t i o n of e s t e r s i s p o s s i b l e u s i n g l i t h i u m b o r o h y d r i d e c a t a l y s e d by ~-methoxy-9-borabicyclo[3.3.llnonane, 1 6

reaction.

a n d a l s o s o d i u m b o r o h y d r i d e i n r e f l u x i n g t e t r a h y d r o f u r a n or t - b u t y l a l c o h o l t o which methanol i s s l o w l y added.”

Under t h e l a t t e r

c o n d i t i o n s c h l o r i d e s , c y a n i d e s , amides, and n i t r o and c a r b o x y l a t e groups are s t a b l e , t h e a d d i t i o n of methanol being t h e e s s e n t i a l 13-Keto-esters are c o n v e r t e d i n t o l , 3 - d i o l s f e a t u r e of t h e p r o c e s s . i n h i g h y i e l d u s i n g t h i s s y s t e m . 1 8 E s t e r s p o s s e s s i n g a n cr-hydroxygroup are s e l e c t i v e l y reduced with diborane-dimethyl

sulphide i n

t h e p r e s e n c e o f s o d i u m b o r o h y d r i d e c a t a l y s t ( e . g . Scheme 2 1 . S t e r e o s e l e c t i v e Carbonyl Reductions. Zinc borohydride i n e t h e r a t O C s e l e c t i v e l y r e d u c e s a-methyl-B-hydroxy-ketone d e r i v a t i v e s t o

0

g i v e a m i x t u r e i n which t h e e r y t h r o - p r o d u c t dominates.20 T h i s r e s u l t i s s u g g e s t e d t o b e t h e c o n s e q u e n c e of a c y c l i c c h e l a t e d t r a n s i t i o n s t a t e ( S c h e m e 3 ) . T h e same g r o u p h a s u s e d t h i s r e a g e n t t o reduce a-methyl-8-keto-esters w i t h t h e same s t e r e o c h e m i c a l

4: Alcohols, Halogeno-compounds, and Ethers

23 5

OH R1C02Et

-b

R1 A

R

2

Reagent: i; Lif3H4, R 2 MgCl ( 0 . 5 : 2.01, THF, -20-0

OC,

24 h

Scheme 1

Reagent : i, BH3Me2S, NaBH4 cat., THF, r . t , 1 h

Scheme 2

"'AH

i R

0

I

A

H

+

R1+H

OR2

HO

OR2

crythro major

Reagent : i , Zn(BH4I2, Et20,

o

O c

R2

possibly via :

/

H

Scheme 3

HO

OR2

236


outcome in the synthesis of structures related to subunits in polyether antibiotics.21a 0-Hydroxy-ketones with a-substituents are similarly converted largely into the erythro configurated products by initial treatment with tri-n-butylphosphine followed by sodium borohydride at -100 OC (Scheme 4).22 In contrast, L-Selectride has been shown to convert a-methyl-u,B-unsaturated ketones into the threo-homoallylic alcohols, generally with 99% stereoselectivity (Scheme 5) . 2 3 L-Selectride has also been found to reduce ketones with an a-thioether substituent to largely the *-products whereas the same substrates frequently gave antiproducts when zinc borohydride was used (Scheme 6)?4 Lithium aluminium hydride reduces B,B-dimethylthio-a,~-unsaturatedketones to the a n t i - a l c ~ h o l s . ~The ~ stereospecific reduction of the double bond is explained by formation of a cyclic intermediate (Scheme 7). Other reducing agents which have been investigated include sodium hydrogen telluride (prepared in situ from tellurium-sodium borohydride) which chemoselectively reduces ~1 ,f3-epoxy-ketones to 8-hydroxy-ketones . 2 6 Potassium 9-thexyloxy-9boratabicyclo[3.3.1]nonane ( 1 ) has been shown to possess similar selectivity to L-selectride, and to be stable for long periods when stored under nitrogen in tetrahydrofuran. 27 A combination of sodium borohydride-tartaric acid has been shown to reduce cyclic In this instance the ketones mainly to the equatorial alcohols.28 reducing species is presumed to be an in situ generated acyloxyborohy&ide . Asymmetric Carbonyl Reductions. Enantioselective reducing agents in which a chiral moiety is combined with a reducing species continue to attract much attention. For borane-base reducing agents the chiral adducts have ranged from (2)-(-)-2-amino-3methyl- 1 , I -diphenylbutan-I -01 (2) ,29 polymer-bound 2-proline ( 3 ) , 30 and isopinocamphenylborane derivatives , 3 1 a 7 b but optical yields using these reagents rarely reach useful levels. Borane-ammonia complexes with chiral ethers are restricted in their application to aromatic ketones and again the optical yields are generally only moderate. 32 Conversely , optical yields approaching 100% are frequently obtained using B-(3-pinanyl)-9borabicyclo[3.3.l]nonane (cf.2 , 115; 2 , 156) with u-keto-t-butyl esters33 or propargylic ketones. 34 Reductions with this reagent are accelerated and the optical yields may be increased by application of high pressure (6 kbar) to the reaction.35 Changing

231


major Reagents : i * Bun3B, air, THF, r t , 2 h ; i i , NaBH4, -100

Scheme

OC,

6h

4

threo major usually about 99 : 1 Reagent: i. L-selectride, THF, -78

OC

Scheme 5

anti 5 ii, R3= Me

minor

R e a g e n t s : i, L - s e l e c t r i d e , THF; ii. Z n ( B H 4 I 2 , T H F

Scheme 6

major


238

RJy

HO

H

i ,

SMe

Regents : i , LiALH4, THF, 0

C'

-

H

reflux

Scheme 7

q

H ONH2 H

& o c H * + @

I

Me

/x

(410;X = - B

c

b ; X =-AlCl;!

(3)

SMe


239

from 8-(~-lO-pinanyl)-9-boratobicyclo~3.3.1]nonane (4a) to the corresponding aluminium derivative ( 4 b ) permits a change in reductive Bnantioselectivity .36 Use of the aluminium reagent (4b), prepared in four steps from (-)-B-pinene, generally results in optical yields of about 80%.37 Several research groups continue to investigate the enantioselectivity of aluminium hydrides combined with 2,2'd i h y d r ~ x y b i p h e n y l s ~(5a) ~ and the related binaphthy13' (cf. 2, 143; 6 , 16 1 ) (5b) and biphenanthry14' ( 5 c ) derivatives. These reagents generally only show good enantioface selectivity with aromatic ketones. Other chiral partially decomposed lithium aluminium hydride reagents investigated included the protected a-Dglucofuranose complex ( 6 ) , which results in only moderate enantiomeric excesses of (S)-alcohols. A q in situ prepared reagent from lithium aluminium hydride/(lf172S)-(-)-E-methylephedrine/ 2-alkylaminopyridine (1:1:2) has been applied to the reduction of cyclic ketones with some success.42 Sharpless has developed a readily available chiral sulphamide for use as a chiral ligand in lithium aluminium hydride reductions ,43 and a reducing agent derived from di-isobutylaluminium hydride, tin(I1) chloride, and a proline-derived diamine has also been applied to ketone reductions with moderate optical yields. " N-Benzolycysteine has been used similarly as a chiral ligand with lithium borohydride, frequently giving high optical yields in the reduction of aromatic ketones.45 Microbial enantioselective reduction of ketones is growing in importance particularly as the extremely high optical yields are frequently being complemented by good chemical conversions. A review of the strategies of using intact cells or isolated enzymes has appeared during 1984.46 Ready availability is undoubtedly a feature in the popularity of Baker's yeast (Saccharomyces cerevisiae). Substrates have included a-sulphenyl-B-keto-esters (Scheme 8a) ,47 aryl ketones (Scheme 8b) ,48 and 4-thiacyclohexanone carboxylic esters (Scheme 8c) .49 A l l substrates gave good chemical and usually excellent yields. Reduction has been shown to occur on the re face of the prochiral ketones.47 Baker's yeast has been successfully used in cyclohexane-1,3-dione reductions to synthesize a zoapatanol precursor50 and in the preparation of chiral anthracyclinone intermediates. Other microbial systems used for enantioselective reductions of 8-keto-esters include Saccharomyces fermentati,52 Aspergillus niger , Geotrichum candidum,53 and the thermophilic bacterium


240

OR (5)

c;

L =

qH

+02 R’

R3

i

-

I

,j l / c o z

- iii R

R3

SR2 R e a g e n t s : i , Yeast, a q glucose, I I , ~ - C L C ~ H ~ C O iii, ~ HAI/Hg ,

I

d

Reagent

: i , Yeast, a q . glucose

Reagent : i , Y e a s t , aq. sucrose, 30

Scheme

OC,

8

MeOH, 2 - 3 d a y s

a


The rmoanaerobium br ock ii

24 1

.

By Nucleophilic Additions. Investigations into stereoselective aldol condensations continue to be pursued vigorously and the by Reetz on the subject has been reviewed by H e a t h ~ o c k . ~Work ~ titanium(1V)-catalysed aldol addition to chiral a- and B-alkoxyaldehydes has been shown to yield mainly 'chelationlsyn' adducts (Scheme 9 ) . 5 6 This result, somewhat in conflict with earlier work of Heathcock, is considered to be due to initial precomplexation of the alkoxy-aldehyde at -78 OC as temperatures higher than -50 OC have been found to cause decomposition of the complex.57 Indeed Reetz has demonstrated the reversal of stereoselectivity with this system if boron trifluoride is used as the Lewis catalyst,58 although selectivities are lower than in the chelation-controlled titanium(1V) chloride process (Scheme 1 0 ) - Temperature-dependent stereoselectivity has also been noted in the aldol reaction of organotin reagents with aldehydes when threo-alcohols predominate at -78 OC and erythro at +45 0C.59 High erythro selectivity is observed using enolates obtained by generation with phenyldichloroborane and Hoenig ' s base,6 o and chiral boroazaenolates (7) derived from oxazolines have also been demonstrated to show stereoselectivity . a-Trimethylsilanes undergo regioselective aldol condensations depending on whether the enolate is generated with base or by using a Lewis acid (Scheme 1 1 ) .62 a-Methylene-8-hydroxy-esters may be stereoselectively prepared by reaction of the enolate of 8-dimethylaminopropanoates with aldehydes followed by quaternization and elimination (Scheme 1 2 ) . 6 3 The iron complexaluminium enolate (8) has been shown to undergo stereoselective condensation with aldehydes to give complexes which yield erythro8-hydroxy-acids upon further alkylation and oxidative decomplexation. 64 Chiral a-halogenoimidates have been utilized in a chiral aldol procedure favouring syn-adducts which in some cases, where the halide was bromide, could be converted into epoxides to constitute a chiral Darzens condensation (Scheme 1 3 ) .65 A wide range of metals has been investigated in the search for a means of allylating carbonyl compounds in a regio- and diastereo-selective manner. The Lewis acid-mediated reactions of crotyl-stannanes has been shown to occur at the y-position of the allylic unit to yield predominantly erythro-B-methyl-homoallyl alcohols regardless of initial crotyl stereochemistry 66 Allyl-stannanes likewise add to

.


242

-

-

7

JC ! RO"

1,

"0

ii, iii

Ph

RO

RO

non-chelation/unti Reagents

i. T i C t 4 , - 7 8

RO chelation /anti

non -chelation/syn

OCj

, -78

ii,

Scheme

Reagents : i, BF3 gas, CHZCIz,

- 95

OC,

RO

OC;

c helation /syn

iii,H30+

9

5 min; ii.

,

4 0 T M S B "t

Scheme 10

- 95

OC,

1h

243


0

R’

R+’R2

i,ii

~

R3+ R2 OH

SiMe3

0

iii, i i 4

Reagents : i . BF3.Et20, SnC14 or TiCl,+, CH2Cl , - 7 8 O C , 1 h; ii, R3CHOi iii, L D A , THF,

- 78

OC,

15 min

Scheme 11

c

R2## H

R’O i

R’0

H

- iii R2

CHO

N

H

-co2R3 OH

co,

R~

+

R2 HO’

major

Me, N

Reagents : i , LDA , THF; ii, MeI, MeOH,

- 15 OC; i i i , DBU,

Scheme 12

a c e t o n e , r.t.

H


244

Y

GR + yy R

I

i

X

i, ii, iii 4

0 Y

X = Br or C I Y =

L f-i

V R

+

X

syn (favoured)

iii,

RCHO,

- 20

iu anti

O K0" Reagents : i , L D A , E t 2 0 , THF; ii, Bu"2BOTf;

Y

OC

Scheme 13

[ dBR

R

245

4: Alcohols, Halogeno-compounds, and Ethers a-silyloxy-aldehydes erythro-Cram

under Lewis a c i d c a t a l y s i s t o g i v e l a r g e l y

p r o d u c t s . 67

Use o f

0:

-benzyloxy-aldehydes

similar c o n d i t i o n s f u r n i s h e s t h e threo-anti-Cram

stereoselectivity. y-position.68ay

under

products with high

C r o t y l d e r i v a t i v e s once a g a i n a t t a c k

via

the

A l l y l - s t a n n a n e s g e n e r a t e d i n s i t u from t h e

r e q u i s i t e b r o m i d e s a n d t i n powder a d d i n h i g h y i e l d t o c a r b o n y l c o m p o u n d s , 6 9 a n d s u c h a p r o c e s s h a s b e e n made c a t a l y t i c i n t i n by e l e c t r o c h e m i c a l l y r e g e n e r a t i n g t h e a l l y l - s t a n n a n e .70 Acetylenic a l c o h o l s h a v e a l s o b e e n p r e p a r e d by g e n e r a t i n g b i s a l l e n y l s t a n n y l d i b r o m i d e f r o m p r o p a r g y l b r o m i d e a n d t i n metal a n d r e a c t i n g t h i s with carbonyl

compound^.^'

y-(Alky1thio)allylboronates a d d t o t o give B-thioalkyl-homoallylic a l c o h o l s w i t h h i g h d i a s t e r e o s e l e c t i v i t y d e p e n d e n t upon t h e i n i t i a l

aldehydes a t t h e y-position

s t e r e o c h e m i s t r y of t h e a l l y l u n i t .72

Extremely high

e n a n t i o s e l e c t i v i t y i n t h e a l k y l a t i o n of aldehydes h a s been achieved u s i n g t h e a l l y l a t e d di-isopinocamphenylboranes ( 9 a ) a n d ( 9 b ) 7 3 a n d

B-allyldi-isocaranylborane

(

(cf.3 , 1 4 4 ; 5 ,

164;

6,

169).

T i t a n i u m r e a g e n t s d e r i v e d from a l l y l t h i o e s t e r s r e a c t w i t h aldehydes with high a - s e l e c t i v i t y due t o t h e t h i o e t h e r s u b s t i t u e n t .75

The d i a s t e r e o s e l e c t i v i t y f o r t h e

y

-adducts obtained

from t h e r e a c t i o n of c r o t y l t i t a n i u m r e a g e n t s t o a l d e h y d e s h a s been shown t o b e d e p e n d e n t upon L e w i s a c i d p r o m o t i o n . 7 6

I n the absence

of boron t r i f l u o r i d e t h e e r y t h r o - p r o d u c t s a r e favoured whereas t h e i n v e r s e r e s u l t i s o b t a i n e d i n t h e p r e s e n c e of boron t r i f l u o r i d e (Scheme 1 4 ) .

B i s a l l e n y l z i n c c h l o r i d e , g e n e r a t e d from a l l e n y l -

l i t h i u m , r e a c t s with aldehydes t o f u r n i s h homopropargylic alcohols77 similarly t o the allenyl-stannanes. at the y-position

Alkylation occurs

and, i n t h e case of y-alkylallenyl reagents,

t h r e o s e l e c t i v i t y is observed. Allyl-cerium r e a g e n t s add c l e a n l y t o c a r b o n y l g r o u p s a n d t h i s c o n v e r s i o n c a n b e s i m p l y c a r r i e d o u t by r e a c t i n g a l l y l i o d i d e w i t h c e r i u m amalgam i n t h e p r e s e n c e o f t h e k e t o n e .78

High a - r e g i o s e l e c t i v i t y

for t h e a l l y l n u c l e o p h i l i c

m o i e t y c a n be o b t a i n e d u s i n g t h e a l u m i n i u m o r b o r o n ' a t e ' c o m p l e x e s ( 1 1 ) . 7 9 A l l y l - s i l a n e s h a v e b e e n shown t o r e a c t w i t h h i g h d i a s t e r e o f a c i a l s e l e c t i v i t y w i t h c h i r a l a- a n d B - b e n z y l o x y aldehydes under L e w i s a c i d c a t a l y s i s . 8 0 c o n t r o l l e d and u-benzyloxyaldehydes

The r e a c t i o n i s c h e l a t i o n

lead t o threo-diol

derivatives

w i t h h i g h s e l e c t i v i t y (Scheme 1 5 ) . P r o p a r g y l i c s i l a n e s r e a c t w i t h c a r b o n y l compounds i n t h e p r e s e n c e of t e t r a b u t y l a m m o n i u m f l u o r i d e w i t h r e a r r a n g e m e n t t o produce a l l e n i c a l c o h o l s , u s u a l l y i n moderate y i e l d s . 8 1

Grignard


246

r X = Cl, Br or I

\

Favoured

threo ii

~

erythro Favoured

R e a g e n t s : i, RCHO; ii, RCHO, BF3.Et20

Scheme 14.

threo 45

R e a g e n t : i , SnC14, CH2C12, - 78

OC

Scheme 15

erythro 1


247

reagents are reported to undergo stereoselective Cram-type addition to 2-alkyl-3-trimethylsilyl-3-unsaturated aldehydes in good yield These substrates react similarly with ketone and (Scheme 16) ester enolates.83 (1sopropoxydimethylsilyl)methylmagnesium chloride has been developed as a synthon for the hydroxymethyl anion.84 The advantage of this reagent over the similar di-isopropoxymethylsilyl derivative is that it will undergo conjugate additions as well as simple additions to carbonyl compounds. Another means of hydroxymethylating ketones involves the samarium iodide-mediated addition of chloromethylbenzyl ether followed by hydrogenolysis. 85 This method may also be applied to aldehydes although with these substrates pinacol coupling is frequently troublesome. a-Alkoxysilanes similarly add to carbonyl compounds in the presence of an equivalent o f caesium fluoride in dimethylformamide to furnish 1 , 2 diols after removal of the alcohol masking group.66 1,3-Diols may be prepared f r o m ally1 alcohols silylmethyl radical cyclization and oxidative cleavage of the cyclic silyl ether thus produced (Scheme 17).87 The anion generated from chlorome.thy1 phenyl sulphone has been shown to add to ketones to produce a,8-epoxy-sulphones, which on base treatment furnish a-hydroxy-aldehydes, resulting in homologation of ketones to a-hydroxy-aldehydes .88 Similar homologation may be achieved by nucleophilic addition of the anion derived from cyclic 1,3-oxathianes to aldehydes. The adduct may be converted directly into the homologated product or oxidized and realkylated by Cram addition of alkyl Grignard reagents (Scheme 18).89 This sequence has lent itself to the efficient asymmetric synthesis of various a-hydroxylated compounds using 1,3-oxathiane Alkylation of ketones with a-nitroderived from (+)-pulegone .” anions is usually inefficient when both the ketone and nitrocompound are sterically encumbered. However, it has been demonstrated that in some cases use of tetrabutylammonium fluoride and high pressure (9 kbar) renders such condensations efficient .” Nucleophilic cleavage of acetals continues to be developed as a means of generating chiral alcohols (Scheme 19). Combinations of Grignard reagents with titanium(1V) or organotitanium reagentsg3 are commonly used, but organoaluminium cleavageg4 and boron trif luoride-promoted cleavage with organocupratesg5 have also been reported. The readiness of epoxides to undergo nucleophilic cleavage has


248

-

S iMe,

SiMe, OH

R'M~X

R'+cHo

R2

R1+

Scheme 16

SO" --L-0 I

-Lq h SiMe,

j iii

HO

6 r CH2SiMe2 Reagents : i, Me2SiCl(CH2Br), Et3N,CH2Cl2, r.t C6H6,

A ; iii, H202

;

OH

ii, Bun3SnH, AIBN (cat.)

or peracid, DMF, KF or KHFZ

Scheme 17

1 Reagents: i, BuLi; ii, R CHO; iii, OMSO,(CF,CO),O, VI

Et3N; iv, R2MgI;

V.

H20;

, N- chlorosuccinimide, AgN03

Scheme 18

y -L

R2

ii, iii

-> , OH

R' O X H0

Reagents: i, R2 Metal, Lewis acid; ii, Oxidation; iii, Base

Scheme 19

Rlx;


249

received further attention. Dilithium tetrabromonickelate(I1) has been used as a source of soft nucleophilic bromide to convert epoxid,es into b r ~ m o h y d r i n s . ~The ~ reaction is very sensitive to steric factors and hindered epoxides are unreactive. Opening of epoxides with lithium acetylides promoted by boron trifluoride is high-yielding and is regioselective with attack occurring at the least hindered carbon. 97 Alternatively a catalytic quantity of trimethylgallium has been shown to increase the yield of this r e a ~ t i o n . ’ ~ A trimethylsilyl cyanide-zinc iodide combination will cleave chiral a,B-epoxy-alcohols obtained by the Sharpless procedure to establish three contiguous chiral centres and furnish 3-substituted 1,2-diols.99 13 ,y-Epoxy-halides are cleanly converted into allylic alcohols using butyl-lithium o r sodium iodide-zinc An electrochemical epoxide cleavage procedure dust (Scheme 20). l o o has been developed,”’ and the chiral amide base (12) derived from (S)-2-(pyrrolidinomethyl)pyrrolidine has been used to obtain (S)-2cyclohexen-1-01 in 92% e.e. from cyclohexene epoxide. 102 Nucleophilic substitution of oxetanes, although less facile than that of epoxides, occurs readily with lithium alkyllo3 and acetylidelo4 reagents. The use of aminosilanes o r aminostannanes provides a two-step procedure for regiospecifically converting oxetanes into 3-amino-alcohols (Scheme 21). O 5 An intramolecular nucleophilic substitution of the oxetane system has been carried out by in situ generated benzyl anion (Scheme 22). 106 Regioselective ring opening of unsymmetrical cyclic ethers has been demonstrated using aluminium chloride-sodium iodide in acetonitrile. The yields are good and in all instances the alcohol with the highest degree of a-substitution is the major product.lo7 Miscellaneous Methods. Wittig [2,3]-sigmatropic rearrangements have been widely utilized to generate B-substituted homoallylic alcohols with a high degree of stereoselectivity, both relative and absolute. g-Crotyl ethers yield threo-alcohols O 8 and Z-crotyl ethers form erythro-products (Scheme 23). ’ 0 9 ’ ’lo 1,4-Chirality transfer has been demonstrated using chiral allylic propargyl ethers, chiral bisallylic ethers, and ethers in which the migrating terminus constitutes a chiral azaenolate ( 13). Organoaluminium-promoted aliphatic Claisen rearrangements have been used to prepare homoallylic alcohols via initial rearrangement of ally1 vinyl ethers followed by transfer of an alkyl group from the aluminium reagent to the aldehyde thus formed.

250


i

HO"

R

SO"

X = Br, I or CL Reagents : i, Sharpless epoxidation procedure; ii BunLi, THF, I

or

Z n , NaI, MeOH, reflux

Scheme 2 0

- 23

OC


25 1

Ph

n = 1 , 2 , 3 or 4 Reagents: i, BunLi, HMPA, THF, - 7 8 to 0 OC

Scheme 2 2

I I

I

erythro

threo

Scheme 23

252


a-Acyloxyacetates are rearranged in the presence of potassium carbonate into 2-hydroxy-3-keto-esters. a-Hydroxylation of this ketones has been demonstrated using 2-iodosylbenzoic acid ;I procedure is facilitated by the base solubility in alkali of the 2-iodobenzoic acid produced. The phenyldimethylsilyl group may be converted into a hydroxy-group via the fluorodimethylsilyl species by sequential treatment with fluoroboric acid and peracid. 177 a,8-Unsaturated aldehydes are precursors to a-functionalized a-hydroxyallenes a-phenylseleno-enals (Scheme 24). 118 Cohalogenation of olefins has been applied to the synthesis of allylic alcohols in which the double bond has undergone a 1,2transposition (Scheme 25). 119

Protection and Deprotection.- Various bases have been shown to be advantageous in the preparation of t-butyldimethylsilyl ethers. 1,1,3,3-Tetramethylguanidine (0.2 equvalents) has been shown to be more effective than triethylamine for primary and secondary alcohols’2o and di-isopropylamine in dichloromethane or DMF also In DMF permits protection of tertiary and hindered alcohols. 12’ the silylation of primary alcohols is exothermic using this reagent. t-Butylmethoxyphenylsilyl bromide has been developed as a less sterically demanding, acid-stable protecting group for primary, secondary, and tertiary alcohols when used in DMF with triethylamine. 122 Use of dichloromethane as solvent in the absence of base permits selective protection of primary alcohols and the ethers formed are more easily cleaved with fluoride than t-butyldimethylsilyl ethers. Japanese workers have developed the related 2-benzyloxyprop1 -ene123 and 2-benzyloxy-3-fluoroprop-I -enel 24 to protect alcohols

as acetals under neutral conditions with palladium catalysis. Deprotection is carried out by hydrogenolysis and the acetals derived from the fluoro-reagent are resistant to acid hydrolysis. 3,4-Dimethoxybenzyl ethers may be oxidatively cleaved more readily than the 4-methoxybenzyl ethers previously used. 125 Both of these ethers are more resistant to hydrogenolysis than benzyl ethers, permitting selective removal of the latter. 126 Benzyl ethers may be cleaved with triethylsilane, palladium(I1) chloride, and triethylamine at elevated temperatures if the presence of sensitive functionalities within the molecule renders catalytic or Birch reduction impossible. 127 Methoxymethyl ethers may be cleaved with trimethylsilyl bromide

253


R’

R1

\

i . ii

\

0

\\

qh

R’

Fc‘ R ’ R2

R2

HO

Reagents : i, Morpholinobenzeneselenamide, hexane r . t ; ii, S i 0 2 ; iii, RZCH=PPhg ~

THF, -30

OC;

iv, H202, CHZCl2, 20

OC;

V.

Et3N, THF, H20, A

Scheme 24

Reagents

;

i, NBS, R20H (RZ=PhCH2 or Me 1; ii,ButOK, 18 - c r o w n - 6, C6H6, r e f l u x

iii, N a , NH3 (R2=PhCH2), NaI, ButCOCl, K2CO3

(R2= Me)

Scheme 25

Reagents: i, E l e c t r o l y s i s , AcOH, AcONa; ii, K2CO3; aq. MeOH

Scheme 26

I

PhO

I

k O ] M e , I

I

I

I

Figure 1

i


254

i n d i c h l o r o m e t h a n e a t 0 OC when e s t e r s a n d b e n z y l a n d t-butyldimethylsilyl

e t h e r s a r e s t a b l e . 28

Similarly,

m e t h o x y e t h o x y m e t h y l e t h e r s a r e d e p r o t e c t e d w i t h a c o m b i n a t i o n of t r i m e t h y l s i l y l c h l o r i d e - s o d i u m i o d i d e a t low t e m p e r a t u r e w i t h o u t a f f e c t i n g l a c t o n e s or e s t e r s .

C h l o r o m e t h y l m e t h y l e t h e r , now

d i f f i c u l t t o o b t a i n c o m m e r i c a l l y o w i n g t o i t s t o x i c i t y , may b e c o n v e n i e n t l y p r e p a r e d by a p r o c e d u r e i n w h i c h m e t h o x y a c e t i c a c i d i s

(cf.2 ,

refluxed with thionyl chloride

153) .I3'

Methyl thiomethyl

e t h e r s a r e c o n v e r t e d i n t o a c e t o x y m e t h y l e t h e r s by e l e c t r o l y s i s i n a c e t i c a c i d , a c e t a l s and t e t r a h y d r o p y r a n y l e t h e r s r e m a i n i n g i n t a c t under t h e s e c o n d i t i o n s .

The a c e t o x y i n t e r m e d i a t e s may b e

d e p r o t e c t e d w i t h o u t t h e n e c e s s i t y f o r i s o l a t i o n (Scheme 2 6 ) . T r i s ( m e t h y 1 t h i o ) m e t h y l e t h e r s h a v e b e e n shown t o b e c l e a v e d w i t h mercury(I1) a c e t a t e i n aqueous a c e t o n i t r i l e . P e r f l u o r o a r y l e t h e r s may b e c l e a v e d u s i n g s o d i u m m e t h o x i d e i n DMF.

" Under t h e s e c o n d i t i o n s p h e n o l e t h e r s a r e s e l e c t i v e l y

deprotected over a l i p h a t i c ethers.

Boron t r i c h l o r i d e s e l e c t i v e l y

c l e a v e s h i n d e r e d a r y l m e t h y l e t h e r s . 34

This f e a t u r e is

r a t i o n a l i z e d as c o m p l e x a t i o n o f t h e b o r o n w i t h t h e e t h e r , which h a s been deformed o u t o f t h e p l a n e of t h e a r o m a t i c r i n g , h a v i n g i t s oxygen l o n e p a i r s more a v a i l a b l e .

The d e f i n i t i v e p a p e r o f e a r l i e r

work o n t h e u s e o f d i m e t h y l b o r o n b r o m i d e a n d d i p h e n y l b o r o n b r o m i d e

for m i l d e t h e r c l e a v a g e h a s a p p e a r e d d u r i n g I 9 8 4 . 35

Aluminium

i o d i d e h a s b e e n f o u n d t o show n o v e l c l e a v a g e b e h a v i o u r c o m p a r e d w i t h boron and s i l i c o n h a l i d e s ,

over a l k y l ethers (Figure 1)

.

selectively cleaving aryl ethers

36

Dimethylaluminium c h l o r i d e h a s

been found u s e f u l i n t h e s e l e c t i v e c l e a v a g e of t e t r a h y d r o p y r a n y l e t h e r s i n t h e p r e s e n c e o f t - b u t y l d i m e t h y l s i l y l e t h e r s . 37 P r o t e c t i o n g r o u p i n t e r c o n v e r s i o n h a s been r e p o r t e d whereby m e t h o x y m e t h y l e t h e r s may b e c o n v e r t e d i n t o t h i o e t h e r s w i t h d i ( i s o p r o p y 1 t h i o ) b o r o n b r o m i d e i n t h e p r e s e n c e of 2 e q u i v a l e n t s of 4-dimethylaminopyridine

a t -95

p y r i d i n e t h e a l c o h o l is obtained.

I n the absence of t h e Conversion i n t o t h e cyanomethyl

e t h e r may b e a c h i e v e d w i t h a n e x c e s s o f d i e t h y l a l u m i n i u m c y a n i d e i n toluene near reflux. Reactions.- Oxidation. O x i d a t i o n s of p r i m a r y a n d s e c o n d a r y a l c o h o l s t o aldehydes and k e t o n e s r e s p e c t i v e l y have been d e m o n s t r a t e d u s i n g bis(2,2'-pyridyl)copper(II)

p e r m a n g a n a t e . 139

P h o t o - o x i d a t i o n , c a t a l y s e d by p l a t i n i z e d t i t a n i u m ( I 1 ) o x i d e , h a s b e e n d e v e l o p e d a s a c o n v e n i e n t m e a n s of p r e p a r i n g a l d e h y d e s

255


a l t h o u g h o x i d a t i o n of s e c o n d a r y a l i p h a t i c a l c o h o l s i s l o w e r y i e l d i n g . I4O Crown e t h e r s h a v e b e e n a p p l i e d t o t h e h e t e r o g e n e o u s o x i d a t i o n o f secondary a l c o h o l s , a c c e l e r a t i n g and improving t h e y i e l d of chromium t r i o x i d e o x i d a t i o n s i n d i c h l o r o m e t h a n e . O x i d a t i o n of s e c o n d a r y a l c o h o l s h a s a l s o b e e n c a r r i e d o u t u n d e r n e u t r a l c o n d i t i o n s via t h e i r c a r b o n a t e s u n d e r p a l l a d i u m catalysis. Phase t r a n s f e r - c a t a l y s e d o x i d a t i o n o f 2-hydroxynitroalkanes yield

h a s been demonstrated t o occur i n high

and a-hydroxy-esters

and - n i t r i l e s

catalysed oxidation with t-butyl r e s p e c t i v e keto-products. 144

undergo ruthenium-

hydroperoxide t o furnish t h e

S p e c i f i c o x i d a t i o n s of b e n z y l i c and a l l y l i c a l c o h o l s h a v e been c a r r i e d o u t u s i n g a suspension o f barium r u t h e n a t e i n dichloromethane

a n d a l s o r u t h e n i u m d i o x i d e i n 1 ,2 - d i c h l o r o e t h a n e

under a n oxygen atmosphere.

A v a r i a t i o n of t h i s system u s e s

RuVI1 s p e c i e s , g e n e r a t e d by o x i d a t i o n o f r u t h e n i u m ( 111) c h l o r i d e w i t h p o t a s s i u m p e r s u l p h a t e ; i n t h i s case p r i m a r y a l c o h o l s a r e o x i d i z e d t o c a r b o x y l i c a c i d s . 146 A n o t h e r r e a g e n t s y s t e m w h i c h o x i d i z e s b e n z y l i c and a l l y l i c a l c o h o l s s e l e c t i v e l y is t e t r a k i s ( p y r i d i n e ) s i l v e r d i c h r o m a t e ' 47 a n d a t m o s p h e r i c o x y g e n , m e d i a t e d by c o p p e r ( I 1 ) a n d n i t r o s o n i u m i o n . 148 N o v e l r e a g e n t s f o r t h e highly s e l e c t i v e oxidation of benzylic alcohols include cetyltrimethylammonium permanganate, trihydroxyhydroperoxide chromate'

ceric

i n benzene, I5O b i s [ t r i n i t r a t o c e r i u m ( IV) I

and d i m e t h y l s e l e n o x i d e - p o t a s s i u m b e n z e n e s e l e n i t e . 152

Various r e a g e n t s have been developed t o c a r r y o u t s e l e c t i v e o x i d a t i o n s of s e c o n d a r y i n t h e p r e s e n c e o f primary a l c o h o l s . s t e p procedures have u t i l i z e d polymer-supported cerium( IV) r e a g e n t s molydbdate-hydrogen

,

One-

c h r o m i u m ( I I 1 ) or

r e g e n e r a t e d w i t h s o d i u m p e r b o r a t e , 15'

ammonium

p e r o x i d e , 154 a n d b e n z y l t r i m e t h y l a m m o n i u m

tetrabromo-oxomolybdate. 1 5 5

A three-step

procedure proceeds

s e l e c t i v e s i l y l a t i o n o f p r i m a r y a l c o h o l s f o l l o w e d by o x i d a t i o n o f secondary hydroxy-groups with pyridinium f l u o r o c h r o m a t e , which does n o t r e m o v e a c i d - l a b i l e s i l y l g r o u p s ( S c h e m e 27).156 A m e a n s o f c a r r y i n g o u t t h e a l t e r n a t i v e c o n v e r s i o n , G. primary i n p r e f e r e n c e t o s e c o n d a r y a l c o h o l o x i d a t i o n , i n v o l v e s t h e u s e of a n e q u i v a l e n t

o f osmium t e t r a o x i d e i n e t h e r - a c e t i c

a c i d a t room t e m p e r a t u r e . 157

I n t h e absence of primary hydroxy-groups, hydroxy-groups can be c l e a n l y o x i d i z e d .

however, secondary

O x i d a t i v e c l e a v a g e of b e n z y l i c d i o l s have been demonstrated u s i n g tris[trinitratocerium(IV)I

p a r a p e r i o d a t e . 158

256


Deoxygenation. A review has been published which covers the preparation of olefins via deoxygenation of vicinal diols.159 A radical chain reaction deoxygenation procedure for tertiary alcohols has been developed based on the decomposition of the mixed oxalate ester with N-hydroxy-2-thiopyridine (Scheme 28). 160 Tertiary hydroxy-groups have also been reductively removed from &,@-unsaturated 6-hydroxy-ketones using a chlorotrimethylsilanesodium iodide combination as an alternative to zinc-acetic acid reductions16 (cf. 6, 179). Iodotrimethylsilane (presumably the active species in the previous case) has been used to effect selective removal of the tertiary hydroxy-group at C-17 of the dihydroxyacetone moiety of steroids. 16* Miscellaneous Reactions. The conversions of alcohols nucleophilic attack on oxyphosphonium intermediates have been reviewed. 163 Benzoyl triflate has been introduced as a reagent f o r benzoylating sterically hindered secondary and tertiary alcohols. 1 6 4 Alcohols may be converted into triflates and tosylates under neutral conditions using the sulphonyl pyridiniurn Tertiary, benzylic, and allylic alcohols may be reagents (14). converted into dialkyl selenides by reacting with the requisite alkyl selenides in refluxing 1,2-dichloromethane in the presence of zinc chloride. Alkanesulphuric acids have been prepared from alcohols via the 2-alkylthiobenzothiazoles in good overall yield (Scheme 29). Under Lewis acid catalysis, benzylic and tertiary alcohols have been converted into azides with hydrazoic acid. Quantitative dehydration of tertiary and benzylic cycloalkanols has been shown to be possible using 4h or 5A molecular sieves in benzene at room temperature, 69 and threo- 1 ,2-diols may be stereospecifically converted into Z-01-efins with phosphonium iodide followed by treatment with base. 17' An efficient method for inverting secondary alcohols uses an excess of caesium acetate in refluxing toluene together Kith 18crown-6. 17' In the absence of crown ether some olefinic products are also formed. Allylic alcohols have been found to undergo stereoselective y e - m e t a l l a t i o n with n-butyl-lithium in the presence of TMEDA. 172 The bisanionic products react with a wide variety of electrophiles (for long-chain alkyl halides a Cox' catalyst is required) with retention of configuration. Stereospecific migration of the alkenyl group of allylic alcohol derivatives via triethylaluminium-


257

Reagents : i, ButMeZSiCl, Et3N; ii, pyridinium fluorochromate, CHzCIZ, 2 5

iii, 6 u 4 N + F - , THF, 2 5

OC

OC

Scheme 27

o$- -+ 0

R&H

R3 0.

f Reagents:

i, ( C O C I ) ~ ; ii,& ((

I

OH

S Scheme 20

/-\

(14)

R =

or

CF3,

X = BFq-


258

c a t a l y s e d p i n a c o l rearrangement h a s been developed t o p r o v i d e

a c c e s s t o o p t i c a l l y p u r e ( e . e . >99%) a-methyl-B,y-unsaturated k e t o n e s (Scheme 3 0 ) . 173 a ,B - U n s a t u r a t e d a l d e h y d e s are p r o d u c e d from p r o p a r g y l i c a l c o h o l s

via

a d d i t i o n of t h i o p h e n o l t o t h e

a c e t y l e n i c m o i e t y f o l l o w e d by h y d r o l y s i s o f t h e i n t e r m e d i a t e a d d u c t ( S c h e m e 31 ) . 17'

h a v e b e e n c o n v e r t e d i n t o B ,y -

Hex-5-en- I - y n - 3 - 0 1 s

u n s a t u r a t e d k e t o n e s by s i l v e r t r i f l a t e - c a t a l y s e d oxy-Cope r e a r r a n g e m e n t (Scheme 3 2 ) . 175

A one-step

h o m o a l l y l i c a l c o h o l s t o six-membered which u t i l i z e s r u t h e n i u m - c a t a l y s e d

homomologation o f

l a c t o n e s h a s been r e p o r t e d

hydroformylation under an

a t m o s p h e r e o f c a r b o n m o n o x i d e a n d h y d r o g e n a t 350 p . s. i . 76 2 - A c e t o x y b e n z o y l b r o m i d e , p r e p a r e d by t h e a c t i o n o f b r o m o s u c c i n i m i d e on 2 - a c e t o x y b e n z a l d e h y d e 1

E-

is a convenient reagent

f o r converting 1 , 2 - d i o l s i n t o epoxides i n a two-stage

procedure

via

t h e c o r r e s p o n d i n g a c e t y l a t e d b r o m o h y d r i n s w h i c h c o l l a p s e on b a s e t r e a t m e n t . 177 2

Halogeno-compounds

Preparation.-

From A l c o h o l s .

Various phosphine-derived

reagent

s y s t e m s h a v e b e e n shown t o c o n v e r t a l c o h o l s i n t o h a l i d e s .

Zinc azodicarboxylate-triphenylphosphine i n a n h y d r o u s THF c a u s e s m i l d SN2 r e a c t i o n and i s p a r t i c u l a r l y u s e f u l f o r o b t a i n i n g u n r e a r r a n g e d h a l i d e s from a l l y l i c a l c o h o l s . 178 O t h e r s y s t e m s developed include triphenylphosphine-methyl halide-4-methyl-Il2,4t r i a z o l i n e - 3 ,5 - d i o n e , triphenylphosphine-carbon t e t r a c h l o r i d e i m i d a z o l e , I8O and a p o l y m e r - s u p p o r t e d v a r i a n t . 18' Sterically h i n d e r e d c y c l o p r o p y l c a r b i n o l s may b e c o n v e r t e d i n t o t h e corresponding h a l i d e s , without formation of homoallylic cleavage p r o d u c t s , by t r e a t m e n t w i t h t r i p h e n y l p h o s p h i n e i n DMF f o l l o w e d by b r o m i n e o r by i n v e r s e a d d i t i o n t o a s t i r r e d s l u r r y o f 182 triphenylphosphine i n hexachloroacetone. D i r e c t conversions of a l c o h o l s i n t o c h l o r i d e s have been a c c o m p l i s h e d via a c l e a n S N 2 p r o c e s s u s i n g t h e i m i n i u m c h l o r i d e ( 1 5 ) . 1 8 3 C h l o r i d e s may a l s o b e o b t a i n e d u s i n g t o l u e n e - 2 - s u l p h o n y l The y i e l d s o f c h l o r i d e a r e chloride-dimethylaminopyridine. 18' g e n e r a l l y h i g h a n d s e n s i t i v e g r o u p s s u c h a s a c e t a l s , THP e t h e r s , and epoxides a r e u n a f f e c t e d . Regio- and s t e r e o - s e l e c t i v e c o n v e r s i o n of a l l y l i c a l c o h o l s i n t o h a l i d e s h a s b e e n a c h i e v e d t r e a t m e n t of t h e c o r r e s p o n d i n g a l l y l i c p h o s p h a t e s w i t h l i t h i u m h a l i d e s i n DMF a t room t e m p e r a t u r e . 185 The c o n d i t i o n s a r e m i l d

halide-diethyl

259


Reagents: i,

(ayF%,Bu3P, THF, ii. K M 4 . aq.AcOH; iii, NaBH4, MeOH Scheme 29

Reagents : i, €$A[,

CH2C12, -42

OC

Scheme 30

R‘

P OH

R2J&s,ph i’ii

*

iii

~

R2L

C

H

O

OH predominantly E

Reagents:

i, PhSH (0.25 q u i v added in 3 portions), 0 “c; i i , Recovery of excess alcohol, iii, H3O+

Scheme 31

Reagents

i, F3CS03Ag, og.THF, 20-60 C ‘,

1-48 h

Scheme 32

260


Ph'

(15)

f

I I

SePh

iii, iv

+ ,Ph CL

Reagents :

i, PhSeCl , MeCN ; ii, CL2,CCl4 ; iii, Bun4NfCI-;

iv, H202

Scheme 33

Reagents : i, ( 4 8 ;

ii, MeOH;

iii, 12 ,NaOH, THF

3

Scheme 34

iii. i v

R 9

Reagents: i, NaOH a q . 5N; ii, I*, Etfl; iii, Br2,CH2CLZ, -25

Scheme 35

OC

; iv, N a m e , MeOH

261


enough t o c a u s e l i t t l e m i g r a t i o n a n d no g e o m e t r i c a l i s o m e r i z a t i o n

of t h e d o u b l e bond. By A d d i t i o n t o U n s a t u r a t e d S u b s t r a t e s .

A s a r e s u l t of a c o n v e n i e n t

method f o r i n s i t u g e n e r a t i o n o f D C 1 , u - d e u t e r i o - c h l o r i d e s o b t a i n e d r e a d i l y f r o m o l e f i n s . 186

may b e

The r e a g e n t i s g e n e r a t e d by

a d d i t i o n o f t i t a n i u m ( 1 V ) c h l o r i d e t o MeOD or D20 a t 5 OC. 1 , 2 - D i c h l o r i d e s h a v e b e e n p r e p a r e d by t h e a c t i o n o f m a n g a n e s e ( I I 1 ) c h l o r i d e s p e c i e s u p o n o l e f i n s . 187

Manganese(II1) a c e t a t e is

t r e a t e d w i t h e i t h e r c a l c i u m c h l o r i d e or a c e t y l c h l o r i d e i n r e f l u x i n g a c e t i c a c i d i n t h e presence of t h e o l e f i n . s o m e t i m e s r e s u l t s i n low y i e l d s f o r t h i s p r o c e s s . c h l o r i d e h a s been used i n a f o u r - s t e p

Elimination

Phenylselenyl

procedure f o r o v e r a l l

a d d i t i o n o f c h l o r i n e t o o l e f i n s , 1 8 8 a n d 4-(dimethylamino)pyridinium bromide perbromide i n a c e t i c a c i d r e a d i l y c o n v e r t s o l e f i n s i n t o 1,2-dibromides

(Scheme 3 3 ) .

B-Iodo-9BBN

i n r e f l u x i n g hexane has

b e e n shown t o r e a c t w i t h t e r m i n a l a l l e n e s t o g e n e r a t e 2 - i o d o - l a l k e n e s ; l g o B-bromo-9BBN procedure.

i s t o o u n r e a c t i v e t o be u s e d i n t h i s

l-Iodopenta-l,4-dienes

i o d i n a t i o n of penta-1,4-dienylboron

a r e t h e p r o d u c t s o b t a i n e d by derivatives,

themselves derived

from t r i a l l y l b o r a n e and t e r m i n a l a c e t y l e n e s (Scheme 3 4 ) .

Ene-

t y p e c h l o r i n a t i o n of t r i s u b s t i t u t e d o l e f i n s h a s b e e n d e m o n s t r a t e d t o occur with dichlorine oxide, furnishing t h e rearranged a l l y l i c chloride.

Both c h l o r i n e atoms of t h e r e a g e n t are u t i l i z e d and

t h e y i e l d s and r e g i o s e l e c t i v i t y are r e p o r t e d t o be h i g h . Interhalide Conversions.

Primary a l k y l c h l o r i d e s have been

c o n v e r t e d i n t o t h e i r c o r r e s p o n d i n g bromides w i t h sodium bromide i n DMF-methylene

bromide

” a n d a l s o via a p h a s e - t r a n s f e r v a r i a n t o f

t h e F i n k e l s t e i n r e a c t i o n using calcium bromide-tetra-nbutylammonium b r o m i d e .

94

I n t e r c o n v e r s i o n of primary a l k y l

b r o m i d e s a n d c h l o r i d e s i n t h e p r e s e n c e o f a q u a t e r n a r y ammonium

s a l t i s p o s s i b l e by r e f l u x i n g i n 1 , 2 - d i c h l o r o e t h a n e ( R B r R C 1 ) or R B r ) .Ig5 A l k y l f l u r o i d e s may b e o b t a i n e d by

p r o p y l bromide ( R C 1

-

--t

t h e a c t i o n o f q u a t e r n a r y ammonium f l u o r i d e s u p o n a l k y l h a l i d e s . T h i s p r o c e s s i s m o s t e f f i c i e n t when a n h y d r o u s t e t r a - n - b u t y l a m m o n i u m f l u o r i d e ( o b t a i n e d by h e a t i n g t h e c o m m e r c i a l l y a v a i l a b l e h y d r a t e t o 40 OC u n d e r h i g h v a c u u m ) i s u s e d a t room t e m p e r a t u r e i n t h e a b s e n c e of solvent.

262


Miscellaneous Methods. Iodine in the presence of a mixture of copper(1) and copper(I1) chlorides will directly iodinate carboxylic acids at the a-position. Hexabromocyclopentadiene will readily brominate activated sites such as a-keto and benzylic positi~ns.’’~ Benzyl halides may be obtained from the corresponding aldehydes by treatment with an inorganic halide in the presence of chlorotrimethylsilane-I , I , 3,3-tetramethylsiloxane. This combination of reagents has been used to carry out reductive halogenation of terminal epoxides to give 2-halogenoalkanes . Procedures have been published f o r the synthesis of E-vinyl bromides and Z-vinyl iodides from ?-vinyl boronic esters (Scheme 3 5 ) .201 Aromatic compounds may be directly iodinated in the presence of mercury(I1) oxide-fluoroboric acid supported on silica. 202

”’

Reactions.- The use of polyvalent iodine compounds in organic synthesis has been the subject of a review.203 Monohalogenomethyllithium reagents, of potential synthetic utility, have been shown to be stabilized by the presence of an equivalent of lithium bromide and may thus be generated by the addition of s-butyllithium to the methylene dihalide-lithium bromide mixture at -110 0c.204 Reductive dehalogenation of 1,2-dibromides to olefins has been performed using titanium catalysts,2 0 5 sodium sulphide under phasetransfer conditions,206 potassium-graphite intercalate,*07 tin( 11) chloride-di-isobutylaluminium hydride ,208 and sodium dithionite under phase-transfer conditions. 209 In the latter instance threodibromides are shown to be converted selectively into E-olefins whereas erythro-dibromides gave mixtures. Monodebromination of 1,l-dibromides has been shown to be possible using sodium hydrogen A telluride whereas sodium borohydride was ineffective .20 procedure has been developed in which a,w-dibromides are converted into w-bromo-I-alkenes by adding HMPA slowly to the hot dibromide and allowing the product to distil out.211 The order of addition is crucial for avoiding bis-elimination. Reductive dehalogenation of ortho- and para-halogenophenols with excess aluminium chlorideethanethiol has been the subject of further investigation . 2 1 2 Carbonylation of unactivated bromides to esters has been carried out using trialkyl borates with carbon monoxide at atmospheric pressure with palladium(0) or rhodium(1) catalysis.213 The same research group has demonstrated that the use of aluminium alkoxides

263


i n s t e a d of b o r a t e e s t e r s u n d e r s i m i l a r c o n d i t i o n s c o n v e r t s b e n z y l and a r y l bromides i n t o t h e c o r r e s p o n d i n g c a r b o x y l i c e s t e r s .214 I n t h i s case hexa-1,5-dienylrhodium(I) c h l o r i d e d i m e r i s t h e p r e f e r r e d catalyst.

Cyanomethylation of a r y l bromides h a s been d e m o n s t r a t e d

t o o c c u r by p a l l a d i u m - c a t a l y s e d

reaction with

cyanomethyltributyltin. Palladium-catalysed cross-coupling of a l l y 1 h a l i d e s w i t h organostannanes r e s u l t s i n h i g h l y r e g i o - and s t e r e o - s e l e c t i v e r e a c t i o n . 216 I n a c o n t i n u a t i o n of t h i s work, v i n y l i o d i d e s have been found t o c o u p l e w i t h v i n y l t i n r e a g e n t s u n d e r CO a t m o s p h e r e a n d p a l l a d i u m ( I 1 ) c a t a l y s i s t o f u r n i s h u n s y m m e t r i c a l d i v i n y l k e t o n e s i n good y i e l d s u n d e r n e u t r a l a n d m i l d conditions.217

R e d u c t i o n o f n i c k e l h a l i d e s by l i t h i u m i n g l y m e

w i t h n a p h t h a l e n e as a n e l e c t r o n c a r r i e r f o r m s h i g h l y r e a c t i v e m e t a l l i c n i c k e l , Lihich w i l l c a u s e c o u p l i n g o f b e n z y l i c h a l i d e s . 2 1 8 S i l v e r n i t r a t e s u p p o r t e d on a l u m i n a c a u s e s t h e c o n v e r s i o n o f 5-halogenopent-2-enes 3 6 ) .‘I9

i n t o I-cyclopropyl

F o r t h e iodo-compound

e t h y l n i t r a t e (Scheme

simple percolation through t h e

r e a g e n t i s s u f f i c i e n t w h e r e a s t h e b r o m i d e r e q u i r e s s t i r r i n g a t room t e m p e r a t u r e and t h e c h l o r i d e is u n r e a c t i v e .

I n a similar p r o c e s s ,

s i l v e r acetate treatment of homoallylic i o d i d e s e f f i c i e n t l y y i e l d s c y c l o p r o p y l c a r b i n y l a c e t a t e s . 220 t o E-methylene-cycloakanes

w-Alkynyl

h a l i d e s may b e c y c l i z e d

Cr’I-induced

radical cyclization

i n a q u e o u s D M F - e t h y l e n e d i a m i n e , 221 when i o d i d e s g i v e b e t t e r y i e l d s than bromides.

In a four-step

s e q u e n c e (Scheme 3 7 ) 1 , l - d i b r o m o a l k -

I - e n e s may b e r e a c t e d w i t h a l d e h y d e s t o p r e p a r e a l l e n e s . 2 2 2 T e r t i a r y a l k y l e s t e r s a n d e t h e r s a r e t h e p r o d u c t s f o r m e d by r e a c t i n g t h e z i n c s a l t s o f c a r b o x y l i c a c i d s , p h e n o l s , or a l c o h o l s i n non-polar

s o l v e n t s and i n t h e p r e s e n c e o f b a s e w i t h t e r t i a r y

alkyl halides.223

The u s e of u l t r a s o u n d p e r m i t s t h e s y n t h e s i s o f

a z i d e s f r o m p r i m a r y h a l i d e s u s i n g a q u e o u s s o d i u m a z i d e . 224 3

Ethers

The r e d u c t i o n o f Preparation (see a l s o Alcohols - Protection).t h i o c a r b o x y l i c a c i d g-esters t o e t h e r s h a s b e e n r e v i e w e d . 225 A s t r a i g h t f o r w a r d m e a n s o f p r e p a r i n g a l i p h a t i c e t h e r s by t h e s t a n d a r d means o f r e a c t i n g a l k y l h a l i d e s w i t h a l k o x i d e s u s e s KOH-aliquat

336

i n t h e a b s e n c e of s o l v e n t t o g e n e r a t e t h e n u c l e o p h i l i c s p e c i e s ; 2 2 6 y i e l d s a r e e x c e l l e n t with primary a l c o h o l s .

Diphenylmethyl e t h e r s

may b e p r e p a r e d u s i n g d i p h e n y l m e t h y l d i p h e n y l p h o s p h a t e a s t h e a l k y l a t i n g a g e n t . 227 A l t h o u g h t h i s r e a g e n t a l s o c o n v e r t s a c i d s


264

Y

R2=H, X = I , Y =NO2 b ; R1 = Me, R2 = H , X = B r , Y = NO2 C ; X = I, Y = OAc a ; R'=Me,

Reagents: i a, 30% AgN03/ At203 column , pentane eluant; i b, 30% ASfJO3/ A1203 suspended in neat halide, r. t . ;

ic,

AgOAc , C&,

r . t . , dark

Scheme 36

bc4

R'

R'

Reagent:

i, BunLi, THE

Br

-

R'

i -iv

-105 "C; ii, RZCHO, r.t. ; iii, (MeaSi)zNH, Me3SiC1, KOH, pyridine;

iv. ButLi

Scheme 37

Reagent:

i, SOSiMq(2 equiv.), Me351 (10 ml.*/.), CHzC12;

Scheme 38

ii, -SiMe3


265

into diphenylmethyl esters it reacts faster with alcohols and permits some degree of selectivity. Aryl bromides may be methoxymethylated using methoxymethyltributyltin in the presence of a palladium(I1) catalyst in HMPA.228 A salt-free synthesis of aryl ethers utilizes methyl trichloroacetate to act as a 'sponge' for the acid produced, liberating chloroform, carbon dioxide, and the methyl halide.229 The procedure is carried out at 150 OC and requires catalytic quantities of 18-crown-6. Carbonyl compounds can be converted into homoallyl ethers in a one-pot procedure via the reaction of the acetals with allyl-silane (Scheme 38).230 The use of sugar 7-lactones has been described as a convenient means of synthesis of chiral tetrahydrofurans. 23 Pentaethoxyphosphorane in dichloromethane at 0 O C has been found to cyclodehydrate butane-l,4-diols. Increasing the degree of 1,4substitution slows the reaction but yields are generally high. 232 In a stereocontrolled synthesis of trans-2,5-disubstituted tetrahydrofurans from 5-hydroxyalk-l-enes (Scheme 39) cyclization to the 3-bromotetrahydropyrans is followed by solvolysis using silver fluoroborate in aqueous acetone to furnish the desired products. 233 Tetrahydrofurans have also been obtained from benzylidene acetal derivatives of pentane-l,3,5-triols on treatment with N-bromosuccinimide in chloroform (Scheme 40). 234 Intramolecular alkoxypalladation-carbonylation of alk-l-en-6-01s has been shown to result in formation of 2,5-disubstituted tetrahydropyrans ,235 in which the =-products are favoured. Silver nitrate cyclization of allenic alcohols to tetrahydropyran derivatives has been independently reported by two groups.2367237 In the case of secondary alcohols the *-2,5disubstituted tetrahydropyrans are the major products. 237 Reactions (see also Alcohols - Deprotection).- Oxidative cleavage of primary alkyl ethers with p-nitroperbenzoic acid is reported to yield carboxylic acids,238 although, if one of the alkyl groups is secondary, a Baeyer-Villiger-type oxidation occurs. Tetrahydrofuran may be cleaved with sodium iodide-chloroglyoxalate esters in methyl cyanide to form 4-iodobutylglyoxalates .239 The reactivity of allylic ethers towards cleavage by alkyl-copper reagents has been shown to be markedly enhanced by the addition of boron t r i f l ~ o r i d e ~ ~ (see ' also cleavage of acetalsg5). Similarly, boron trifluoride etherate-assisted cleavage of oxetanes by alithiated esters and amides has been used in a synthesis of 6-


266

I*.

%L+-++

Br

major

lii Reagents: i, 2,4,4,6-tetrabrornocyclohexo-2,5-dienone,

C H ~ C L Z ; ii, AgBFb, aq. acetone

Scheme 39

. ..

1

Reagents: i, N - Brornosuccinimide, CHC13, r. t .

Scheme 40

1

267


lactones. Superacid-catalysed oxygenation of a l i p h a t i c e t h e r s w i t h o z o n e r e s u l t s i n g o o d y i e l d s of o x o a l k y l e t h e r s by e l e c t r o p h i l i c i n s e r t i o n of p r o t o n a t e d ozone i n t o t e r t i a r y or secondary centres at the 6-position o x y g e n . 24 2

4

or f u r t h e r from t h e e t h e r

Thiols

S e l e c t i v e r e d u c t i o n o f d i s u l p h i d e s t o t h i o l s h a s b e e n shown t o b e po s s i b 1e w i t h p o t a s s i um t r i - i s o p r o p o x y b o r ohy d r i d e polystyryldiphenylphosphine

.2 4 4

a three-step

primary amines i n t o t h i o l s o v e r a l l y i e l d (Scheme 4 1 ) .

and

2-Mercaptobenzothiazole

converts

p r o c e s s i n u s u a l l y good

N-Sulphinylbenzenesulphonamide

u n d e r g o e s e n e r e a c t i o n s w i t h o l e f i n i c s u b s t r a t e s a t 0 OC t o y i e l d a d d u c t s w h i c h may b e r e d u c e d t o t h i 0 1 s . ~ ' ~ T h i s p r o c e d u r e h a s b e e n a p p l i e d t o t h e s e p a r a t i o n of o p t i c a l l y a c t i v e t h i o l s from t e r p e n e p r e c u r s o r s (Scheme 4 2 ) .

M e t h y l a r y l t h i o e t h e r s may b e c o n v e r t e d

i n t o the aromatic thiols

via

a m i l d one-pot p r o c e d u r e based upon

Pummerer r e a r r a n g e m e n t o f t h e i n t e r m e d i a t e s u l p h o x i d e s ( S c h e m e O v e r a l l y i e l d s f o r t h e p r o c e s s are h i g h and r e a c t i o n

43).24-6

c o n d i t i o n s a r e c o m p a t i b l e w i t h a w i d e v a r i e t y of f u n c t i o n a l i t i e s . Oxidation r e a g e n t s f o r t h i o l s t h a t have been r e p o r t e d d u r i n g t h e year include potassium superoxide f o r the conversion of aromatic t h i o l s i n t o d i s u l p h i d e s ,246 and b i s [ t r i n t r a t o c e r i u m ( I V )

1

c h r o m a t e . 247 An e f f i c i e n t s y n t h e s i s o f u n s y m m e t r i c a l d i s u l p h i d e s h a s b e e n r e p o r t e d which u t i l i z e s t h e r e a c t i o n of

alkylthiotriphenylphosphonium p e r c h l o r a t e s w i t h t h i o l s . 248 T h e phosphonium r e a g e n t s are p r e p a r e d e l e c t r o c h e m i c a l l y from t h e d i s u l p h i d e s and t r i p h e n y l p h o s p h i n e .

P y r i d y l e t h y l a t i o n has been

developed as a n o v e l t h i o l p r o t e c t i o n sequence .249

Michael

a d d i t i o n o f t h i o l s w i t h 2- o r 4 - v i n y l p y r i d i n e y i e l d s t h e a d d u c t s w h i c h may b e d e p r o t e c t e d by q u a t e r n i z a t i o n o f t h e p y r i d i n e a n d treatment of t h e i s o l a b l e methiodides w i t h potassium carbonate. Aryl v i n y l sulphones have been used t o p r o t e c t t h i o l s

via

a similar

M i c h a e l a d d i t i o n - b a s e e l i m i n a t i o n s e q u e n c e . 250 5

Thioethers

S u l p h i l i m i n e s and sulphoximines have been found t o be c o n v e r t e d i n t o t h i o e t h e r s by a q u e o u s p o t a s s i u m h y d r o x i d e - c h l o r o f o r m u n d e r

268


-

R2

\cHs,-?’n tHNH2 4

R2

\

R

Reagents: i, ButONO,

R2

S

ii, iii

‘CHSH

~

/

R

a>>SH,

r.t.; it, Me2S04, 90 “C;

R’

iii, NH2NH2, EtOH

Scheme 41

Reagents: i, EtZO, 0 “c; ii.LiAIH4

Scheme 42

0Reagents: i, m-ClC6H4CO$,

CHCl3, 0°C;

\OTFA ti, Ca(OH)2 ;

Scheme 43

iii, (CF$O)20,

40

OC;

iv, Et3N, MeOH


269

phase-transfer conditions. 251 The same research group has demonstrated the reduction of sulphoxides and sulphilimines to thioethers by sodium borohydride in the presence of a catalytic quantity of meso-tetraphenylporphyrin metal complexes. 2 5 2 Deoxygenation of sulphoxides has been demonstrated using a series of boron bromide reagents at low temperature (Me2BBr, g B B N - B r , BBr3). 253 Decomposition of S-alkylthiouronium salts under anhydrous basic conditions provides a convenient way of generating the thiolates which can be reacted with alkyl halides to generate unsymmetrical thioethers. 254 Reduction of dithioacetals with pyridine-borane complex in trifluoroacetic acid provides an efficient means of preparing thioethers from carbonyl compounds .255 Excellent yields of phenyl vinyl sulphides are obtained from benzyne-induced ring opening of thiiranes ; 256 nickel (11 -catalysed coupling of 3-methoxy-I-phenylthioprop-I-ene with Grignard reagents provides an alternative approach. 257 In a stereoselective construction of allylic thioethers, divinylcuprates have been coupled with a-halogenothioethers in good yields .258 Aromatic di-, tri-, or tetra-halides under phase-transfer conditions react with thiolates .259 In unsymmetrical substrates substitution occurs predominantly at the halogen lacking para-substitution. Phenols undergo ortho-alkylthiolation on sequential treatment with aluminium powder followed by the requisite disulphide at elevated temperature. 260 Aromatic amines may be converted into thioethers by reaction of the diazonium salts with methythiocopper at 4 0C.261 In this procedure yields are usually good and the technique is reported to involve less risk of explosion than other methods. S-Alkyl-4-methylbenzenethiosulphonates have been shown to be useful reagents for the a-thiolation of cyclic ketones and hence introduction of unsaturation. 2 6 2 Thioacetylenes may be prepared by pyrolytic elimination of a - a c y l - a - t h i o p h o s p h o r a n e s ( 16) at 230 OC and reduced pressure. 2 6 3 The phosphoranes are obtained by reaction of alkylthiomethylenetriphenyl phosphorane with acyl halides at room temperature. The oxidation of sulphides has continued to attract much attention. Heterogeneous permanganate oxidation of thioethers using either potassium permanganate-copper(I1) sulphate or copper(I1) permanganate in refluxing hexane produces sulphones without attacking any double bonds in the substrate. 264 Work-up simply involves filtration from the reagent and evaporation of the solvent. Reagents used for converting thioethers into sulphoxides


270

include a-azohydroperoxides in base,265 and hexamethylphosphoramidochromium(V1) oxide diperoxide. 266 Diarylbut not dialkyl-thioethers may be oxidized to sulphoxides by a twophase system of 20% aqueous sulphuric and nitric acids with nitromethane at room temperature. 267 Further application of the use of gold(II1) oxidation under phase-transfer catalysis is described by the same group in the selective mono-oxidation of dithia-alkanes to sulphoxides. 268 Selectivity for mono-oxidation decreases with increasing separation of the two thioether groups. Modifications of the Sharpless system for sulphoxidation include the substitution of vanadium and molybdenum catalysts for titanium( IV) i s o p r o p ~ x i d eand ~ ~ ~addition of water to the reaction mixture. 270 In general the enantiomeric excesses obtained are inferior to those obtained with the original reagent combination. Cyclodextrin-mediated chiral sulphoxidations similarly give disappointing ( 0 - 3 4 % ) enantiomeric excesses ,27 but microbial oxidation with Corynebacterium equi has been found frequently to result in high enantiomeric excess with conversions ranging from 7 to 1 0 0 ” / . 2 7 2 Allylic sulphides have been shown to add to propiolic esters under Lewis acid the El2 ratio of products being dependent upon the thioether and the Lewis acid used (Scheme 44). Vinyl sulphides may be reduced in good yield with triethylsilane promoted by titanium( IV) chloride. 2 7 4 Treatment of phenyl thioethers with a mixture of copper metal, copper(I1) acetate, and lithium acetate in acetic acid-acetic anhydride leads to substitution of the phenylthio-group to form acetates.275 A copper(1) species is believed to be operative.

6

Crown Ethers, Thia-Crown Ethers, and Related Structures

Owing to the large number of reports concerning cr-own ethers which have appeared during this year it is not possible to detail those prepared by standard methods but only those structures having a degree of novelty. The synthesis of a series of lithium-selective acyclic polyethers ( 1 7 ) has been described.276 Phase-transfer catalysis has been profitably applied to the construction of crown ethers containing benzoin subunits277 and aza-crown ethers. 278 The first syntheses of ‘ostrich molecules’ , a r e n e d i a ~ o n i u m ~’ 280 ~ ’ ( 18 and anilinium280 lariat crown ethers ( 1 9 ) , have been reported together with evidence for intramolecular sidearm-macrocycle interaction.

27 1


R = Ph R = cyclohexyl

Lewis acid = ZnCI;!: Lewis acid = AICI, :

3 90

:

97

:

10

92% 80°h

Reagents: i, HC3CC02Me, Lewis acid. CH2C12, r.t.

Scheme 44

+

-I-

272


Other lariat crown ethers include those possessing an epoxy-group in the side chain281 and 'double armed' crown Polymer-supported crown ethers (20) have been prepared and have found use as phase-transfer catalysts for nucleophilic displacement reactions284 (cf. 2 , 137; 2 , 1 5 9 ) . Crown ethers containing novel subunits include tetraester dipyrazole crowns (21) , 2 8 5 lipophilic crown diacids (22),286 and a flavin crown ether mimic.287 Crowned morphine and isosmorphine analogues (23) have also been prepared. 288 Further examples of chiral crown ethers incorporating carb~hydrate~~ '290 ' (cf.2 , 1 4 0 ) and tartaric acid derived subunits291 have been reported, and name 'pagiand' (Greek n a y l a trap) being proposed for the latter. Optically active biphenanthryl crowns (24) have also been further i n ~ e s t i g a t e d ~ ' ~ and a related class of crown ethers in which a steric restraint is imposed by a three-blade propeller substituent ( 2 5 ) has been reported. 293 Novel photoresponsive crown ethers have been synthesized which consist of a polyether chain possessing two anthracene subunits which undergo cycloaddition to generate the crown ether (Scheme 45). 294 Further examples of photoresponsive azobenzene crown ether systems have been reported , 2 9 5 '296 of which an interesting variant generates an 'ostrich' crown ether on irradiation (Scheme 46) .297 The same research group has published further work on redox-switched crown ethers in which the macrocycle is constructed by disulphide formation (Scheme 47) .298 Additional reports of the synthesis of oxa-crown ethers containing a ferrocene nucleus299 ' 300 have been accompanied by a synthesis of the thiaand the ruthenocene thia-oxa-crown (26).302 crown analogues3' Chiral macrocyclic polysulphides (27) have been developed as ligands for nickel(I1)-catalysed C - C bond formation although the enantiomeric excesses in the products are The macrobicyclic polyethers ( 2 8 ) 304 and other bicyclic systems ( 2 9 ) 305 and (30I3O6 have been reported. The latter compounds act as V-shaped hosts for cis-diamine-transition metal complexes. Further spherand analogues have been reported (cf.i, T O ) , including structures (31) possessing additional functionality on the outer periphery307 and extended hemispherands (32) .308


273

274


Y

Scheme 45

Scheme 46

275


qsH 9- p S-

sJQ

SH

ox

A

Red

Scheme 47

?

Ru

W ( 2 6 ) n = 2 , 3 , or 4

(28 1 n = lor2 n =Oorl

(27)

(29)

276


x

= 0,

Q -0

-0

or -0

n 0-' 0-

0-

Me

X

(31)

R = Me or H

p

0

Me

(32) X = S , SO2, or

0 -t-

277

4: Alcohols, Halogeno-compounds, and Ethers References 1 2

3 4 5

6 7

8 9 10 11

12 13 14 15 16 17

18 19 20

21 22 23 24

9,

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.

.

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.

Y

v

I

I

I

,

*

2,

14,

-

~

I

2,

2,

~

282


238 23 9 240 24 1 24 2

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2,

14,

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4538.

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2679

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1111.

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Lett -

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"0,

3935. 28 1 28 2 28 3 28 4

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4: Alcohols, Halogeno-compounds, and Ethers 285 286 287 28 8 289 290 29 1 29 2 29 3 29 4 29 5 29 6 297 29 8 29 9 30 0 30 1 302 30 3 304 30 5 30 6

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2,

v ,

~

307 30 8

283

~-

r .

1

~

I

- - I

-

Amines, Nitriles, and Other Nitrogen-containing Functional Groups BY S.

G. LISTER

1 Amines

Reductive methods are s t i l l amongst t h e most

P r i m a r y Amines.-

popular f o r t h e preparations of amines.

I n p a r t i c u l a r t h e ease o f

n i t r a t i o n o f many a r o m a t i c s y s t e m s a n d t h e g e n e r a l s y n t h e t i c v e r s a t i l i t y of a r y l nitro-compounds has continued to f a c i l i t a t e a n i l i n e f o r m a t i o n by a n i t r a t i o n - r e d u c t i o n

sequence.

Although well

d o c u m e n t e d , b o t h s t a g e s s t i l l r e c e i v e much a t t e n t i o n , w i t h t h e s e a r c h f o r s e l e c t i v e r e a g e n t s c a p a b l e of e f f e c t i n g t h e l a t t e r s t e p i n t h e presence of o t h e r f u n c t i o n a l i t y being of prime importance. R e d u c t i o n of n i t r o a r e n e s h a s b e e n a c h i e v e d w i t h s o d i u m borohydride - copper(1) chloride under conditions t h a t t o l e r a t e d an electron-donating

substituent i n the ortho-

relatively simple substrates.

SnC12.2H20

a n d p a r a - p o s i t i o n s of ( i n ethanol or ethyl

acetate) and t h e a n h y d r o u s s a l t ( i n e t h a n o l ) proved t o be e f f i c i e n t reductants for a wide v a r i e t y of n i t r o a r e n e s c o n t a i n i n g s e n s i t i v e s u b s t i t u e n t s.2

Y i e l d s , w h i c h were c o n s i s t e n t l y s u p e r i o r t o t h o s e

previously r e p o r t e d , appeared t o be independent o f both t h e n a t u r e and p o s i t i o n of t h e a r y l s u b s t i t u e n t s . More e s o t e r i c r e a g e n t s e f f e c t i n g n i t r o a r e n e r e d u c t i o n h a v e included the rare-earth

i n t e r m e t a l l i c a l l o y LaNi5 ( a s L a N i 5 H 6 )

although t h i s r e a g e n t w i l l be o f l i m i t e d u t i l i t y s i n c e it a l s o r e a d i l y reduces a l k e n e s , a l k y n e s , aldehydes, and ketones.

Castor

soap (derived from c a s t o r o i l and aqueous sodium hydroxide) a l s o s e r v e d i n t h e p r e p a r a t i o n of a n i l i n e s , b u t e x a m p l e s were l i m i t e d t o simple substrates

.4 B e n z e n e t e l l u r o l i n e t h a n o l - b e n z e n e - w a t e r

has

a l s o b e e n i d e n t i f i e d a s a n e f f i c i e n t r e a g e n t f o r t h e c o n v e r s i o n of n i t r o a r o m a t i c s i n t o a n i l i n e s (Scheme 1 ) .5 C a t a l y t i c systems f o r n i t r o a r e n e r e d u c t i o n s have been extensively studied.

Use of P d / C w i t h ammonium f o r m a t e a s a

c a t a l y t i c hydrogen-transfer

agent has l e d to t h e synthesis of both 6 i n m o d e r a t e t o good y i e l d s ,

primary a l k y l - and aryl-amines

e l e c t r o c a t a l y t i c reductions employing Devarda-copper e l e c t r o d e s i n For References see page 386.

284

285

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

PhTeSiMe3-f MeOH r(PhTeTcPh

+ H,PO,

%

Y PhTeTePh + NaBH4

L-

I

+PhTtTePh i-ArNH,

1

- - - ------ J

- _ - _ -

Reagents : i, C C I 4

I-ArNO,

[PhTeH]

r . t . , A r ; i i , THF

I

H 2 0 ; i i i , C6H6

, H20

,EtOH

Scheme 1

fyR X

G

N

0

2

-k

3

X

e

N

H

2

+

(YR

3 5-5

SH

SH

LAm

DHLAm

R = (CH2I4CONH 2 R e a g e n t : F e r r o u s a m m o n i u m s u l p h a t e , Na2C03

Scheme

,

NaHC03

2

OMe

OR

OR

OMe

R = CH2Ph, S02Ph , o r Me R e a g e n t : FeS04.7H20

OMe

OMe

R = M e or S0,Ph

, NH40H/H20 Scheme

3

286


b a s i c media have allowed m i l d e r ( ' l o w e r a p p l i e d p o t e n t i a l s ' )

and

more s e l e c t i v e ( t h a n w i t h c o n v e n t i o n a l e l e c t r o d e s ) r e d u c t i o n s o f nitro-groups;

and a polymer-bound

s y s t e m8

a n t h r a n i l i c acid-PdC12

are a l l noteworthy amongst r e c e n t r e p o r t s . Homogeneous r e d u c t i o n o f n i t r o a r e n e s by t w o a z o b e n z e n e - P d " c a t a l y s t s i n DMF a l s o p r o v e d effective,

although m-dinitrobenzene

and p - n i t r o p h e n o l

be reduced t o t h e corresponding hydroxylamines.

could only

Presumably t h e s e

i n t e r m e d i a t e s were n o t r e d u c e d f u r t h e r o w i n g t o t h e i r p o o r a b i l i t y t o co-ordinate t h e metallic c e n t r e . Formic a c i d and t r i e t h y l a m i n e i n t h e p r e s e n c e of c a t a l y t i c a m o u n t s o f dichlorotris(triphenylphosphine)ruthenium(II) s u c c e s s f u l l y employed i n r e d u c t i o n o f c h l o r o - , methoxy-substituted

nitroaromatics. lo

methyl-,

have been and

Reactions proceeded even i n

t h e a b s e n c e o f s o l v e n t , b u t r a t e s were a c c e l e r a t e d w i t h e t h a n o l a s

s o l v e n t , w i t h b e n z e n e g i v i n g o p t i m u m r e d u c t i o n s i n t e r m s of r a t e and s e l e c t i v i t y .

However, u s i n g t h i s p r o c e d u r e 4 - n i t r o a c e t o p h e n o n e

yielded only the corresponding ethanol derivative.

Dihydrolipoamide-iron(I1) i n b u f f e r e d e t h a n o l p r o v e d t o b e a n o t h e r v e r s a t i l e s y s t e m g i v i n g good y i e l d s o f a n i l i n e s i n smallscale reductions.

''

Both o r t h o - and p a r a - e l e c t r o n - d o n a t i n g - w i t h d r a w i n g s u b s t i t u e n t s were t o l e r a t e d ( S c h e m e 2 ) .

and

Another i r o n ( I 1 ) s a l t (FeS04.7H20) h a s been u s e d t o p e r f o r m r e d u c t i o n s of 2 - n i t r o - t o 2-amino-cinnamic a c i d s i n a h i g h - y i e l d m o d i f i c a t i o n o f t h e P s c h o r r p h e n a t h r a c e n e s y n t h e s i s (Scheme 3 ) . l 2 M e t a l l i c i r o n i n a c e t i c a c i d h a s b e e n u s e d t o p r e p a r e 3-bromo-2-

v i n y l a n i l i n e from t h e c o r r e s p o n d i n g nitro-compound

as p a r t of a

s y n t h e t i c approach t o Ergot a l k a l o i d s . l 3 Another approach t o t h e s e compounds i n v o l v e d a t r i f l u o r o a c e t i c a c i d - m e d i a t e d a z a - C l a i s e n rearrangement of meta-substituted

a n i l i n e s t h a t afforded 2-allyl-3-

s u b s t i t u t e d a n i l i n e s c a p a b l e of f u r t h e r t r a n s f o r m a t i o n t o t h e p r e v i o u s l y d e s c r i b e d U h l e ' s k e t o n e ( 1 ) (Scheme 4 ) . l4 Although r e d u c t i o n s of nitro-compounds have been s t u d i e d i n d e t a i l , i t h a s o n l y r e c e n t l y b e e n shown t h a t s u c h r e d u c t i o n s c o u l d be c a r r i e d out i n t h e presence of an a l k y l n i t r i l e group.15 Thus, on a small s c a l e , t h e e x o t h e r m i c r e d u c t i o n o f a n i t r o - g r o u p achieved i n e x c e l l e n t y i e l d w i t h h y d r a z i n e and Raney-nickel

can be a t or

b e l o w room t e m p e r a t u r e . Nitrile r e d u c t i o n o n l y o c c u r s w i t h a large e x c e s s of h y d r a z i n e a t h i g h e r r e a c t i o n t e m p e r a t u r e s . I t was a l s o d i s c l o s e d t h a t on a l a r g e r s c a l e u s e o f p a l l a d i u m - o n - c a r b o n prevented over-reduction problems t h a t a r o s e from poor c o n t r o l of r e a c t i o n t e m p e r a t u r e i n t h e f i r s t s t e p (Scheme 5 ) .

287


CEN

E N

d-0

gn

NH

I

I

H

R

g0

I

I

H

H (1

1 U h l e ' s ketone

-?

R = COZEt CHo

iv,v

R e a g e n t s : i , CF3COZH (1.5 e q u i v . ) ; i i , N a B H 4 , E t O H ; i i i, O 3 iv

, Ag20 , MeOH , H20 ; v ,

EtOH

, CHzClz , - 7 8

, HCI

Scheme 4

X = N or CH Reagents:

i , N2H4.H20, R a - n i c k e l ; ii, N H .H 0, P d / C ; 2 4 2

Scheme 5

iii, N H H 0 2 4' 2

OC ;

288

Generul and Synthetic Methods

-ortho-Substituted aminoaphthalenes have been synthesized in reasonable yields from the parent nitro-compounds by conjugate additions of suitable Grignard reagents followed by treatment of the adducts with phosphorus trichloride in THF. l 6 Conjugate reductions of nitro-olefins have also led to the synthesis of primary amines, l 7 the reductions being achieved with borane-THF plus a small amount of sodium borohydride. Electrochemical reductions of tertiary nitroalkanes have also been studied. 1 8 As well as the aforementioned report of nitrile reduction, the use of Raney-nickel-hydrogen in basic ethanol in a high-pressure conversion of dinitriles and aminonitriles into diamines and polyamines has been reported, as has been the selective reduction of acyl cyanides to a-amino-ketones with zinc and excess acetic anhydride in acetic acid.20 In the latter reduction, yields of amines from aryl and a,B-unsaturated nitriles were poor. Similarly, hydrogenolysis of nitriles to primary amines has found an application in the synthesis of N-methylputrescine and related homologues. 21 Azides are an extremely useful source of arnines, particularly in the carbohydrate area where nucleophilic azide anion can be introduced SN 2-type displacement of an active ester or sulphonate ester, or alternatively at an epoxide centre (see below 1 . Organotellurium reagents have featured prominently in the preparation of primary amines from nitro-compounds, and likewise sodium hydrogen telluride has found application in their preparation from azides.22 The reduction is also compatible with other sensitive functionality. Another report described reduction of the azido-aminoester (2) to the diamino-acid ( 3 ) with hydrogen sulphide in aqueous pyridine .23 Oximes, too, are a valuable source of amines by reduction. Lithium aluminium hydride reduction of substituted benzaldehyde oximes afforded benzylamines , 2 4 which were evaluated as antimycobacterial agents. Attempted hydrosilylation of oximes with diphenylsilane catalysed by either chlorotris(tripheny1phosphine)rhodium(1) or [Rh(COD)C1I2 in the presence of the chiral phosphine (-)-diop gave moderate yields of primary amines after acidic deprotection of the product diphenylsilylamines. However, product enantiomeric excesses were poor, with 14.4% the best figure obtained. 25


289

Treatment of aromatic and aliphatic ketone oximes with lithium aluminium h y d r i d e - 3 - ~ - c y c l o h e x y l m e t h y l - l 7 2 - ~ - c y c l o h e x y l i d i n e - 4 - a - D glucofuranose complex afforded 2-amines of up to 5 2 % optical 26 purity. Reduction of oximes has also been realized with sodium borohydride in the presence of transition-metal salts .27 Sodium borohydride-NiC12.6H20 effected reductions of unsaturated oximes to their saturated amine counterparts, whereas the use of Moo3 allowed reductions with preservation of the double bond. Differences in the stereochemistry of the two reductions were also noted. A method of in situ conversion of oximes into imines (by tributylphosphine-diphenyl disulphide), which can be trapped as amines (with sodium cyanoborohydride) o r as a-aminonitriles (with sodium cyanide-acetic acid) , has been reported. 28 Diphenyl disulphide appears to act catalytically in this process which can represent an overall reductive animation of ketones that works well even in cases of severe steric hindrance. A study concerned with the synthesis of analogues of anhydrotetracycline utilized a reduction of the 2-quinone monooxime 9-nitrosoanhydrotetracycline ( 5 ) by sodium dithionite in order to bring about specific 9-amination of anhydrotetracycline (4); the tetracycline (4) was prepared using standard methods.29 7 Aminoanhydrotetracycline ( 7 ) was also prepared, by coupling of (4) with diazotized sulphanilic acid and reduction of the so-formed azo dye with sodium dithionite. 2-Amino-4,6-dimethoxyindane has been prepared from 5 , 7 dimethoxyindan-2-one via hydrogenation of the a-oximino-ketone ( 8 ) . 3 0 Ketones are normally encountered as by-products in oximeto-amine transformations but it has recently been disclosed that inclusion of slight modifications of reaction conditions boric acid and excess acetone in the reaction mixture) lead to formation of ketones exclusively.' Related reductive aminations of ketones constitute another useful method for the preparation of amines. A recent development here has allowed enantioselective syntheses of $-substituted amines via metallation and alkylation of SAMP-hydrazones derived from the corresponding aldehydes (Scheme 6). 32 The amines were liberated from the product hydrazines by hydrogenolysis, the by-product of which, (S)-2-methoxymethylpyrrolidine, may be recycled by nitrosation and reduction. Asymmetric syntheses of 2-substituted cyclohexanamines from

(e.

'

290


NHZ

NH Z

( 2 )

(3)

Me

R2

R’ HO

HO

( 4 )R’= R 2 = H

(5)

( 6 ) R ’ = NH, , R 2 = H ( 7 ) R’= H , R,=NH,

NOH

M eO

( 8 )

R2 e . e . 3 95’1.

;roMe + -v , V-I -

( R e c y c Iing)

SAM P

N”

R1J

( -N IL O M I ( S)

QOMe

H\”N

eMO‘

R1yJ

(S)

I

I V

2 2 yii” R2

,h

OMe

R d . e . 3 95*10 Reagents:

I,

LDA,

11,

R2X ;

III,

catecholborane;

Scheme

IV,

6

R a - N i , HI ; V , R O N O ; v i , LiALH4

29 1


r a c e m i c c y c l o h e x a m o n e s by m e a n s o f a t h r e e - s t e p r e d u c t i v e a m i n a t i o n Condensation of k e t o n e s w i t h

s e q u e n c e h a v e a l s o b e e n r e p o r t e d . 33

c h i r a l a u x i l i a r y a m i n e s g a v e i m i n e s w h i c h were h y d r o g e n a t e d w i t h Raney-nickel.

P r i m a r y a m i n e s w e r e s u b s e q u e n t l y o b t a i n e d by

c a t a l y t i c hydrogenolysis of t h e r e d u c t i o n products u s i n g palladiumon-charcoal

(Scheme 7 ) .

The p r o c e s s g a v e h i g h c h e m i c a l y i e l d s

under complete d i a s t e r e o m e r i c and very h i g h e n a n t i o m e r i c c o n t r o l . Enantiomeric excesses (determined using d i a s t e r e o m e r i c a c y l a t e d a m i n e s ) o f b e t w e e n 9 2 a n d 99% were c l a i m e d . R e d u c t i o n o f p,~'-dimethoxybenzhydryl i m i n e s o f s u b s t i t u t e d cyclohexanones with l i t h i u m t r i a l k y l b o r o h y d r i d e s a f f o r d e d p r o t e c t e d p r i m a r y a m i n e s w i t h a h i g h d e g r e e of s t e r e o s e l e c t i v i t y f o r a x i a l l y s u b s t i t u t e d p r o d u c t s . 34 P r i m a r y a m i n e s were o b t a i n e d a f t e r standard deprotection with formic acid. T r a n s f o r m a t i o n s o f h e t e r o c y c l i c k e t o n e s t o a m i n e s , w h i c h may f o r m a l l y be regarded as r e d u c t i v e a m i n a t i o n s , have a l s o been documented.

The m o s t n o t a b l e e x a m p l e s i n c l u d e a r e p o r t o f

s y n t h e s i s o f 4-aminoquinoline-2-carboxylates f r o m t h e c o r r e s p o n d i n g 4-0x0-derivatives

w i t h p-chlorophenoxysulphonyl i s o c y a n a t e

( S c h e m e 8 ) , 3 5 a n d o n e c o n c e r n i n g a g e n e r a l r o u t e t o 5- a n d 6s u b s t i t u t e d 4-amino-2-pyridones

f r o m 4-hydroxy-2-oxo-1,2-

d i h y d r o p y r i d i n e s e f f e c t e d by r e f l u x i n g i n b e n z y l a m i n e a n d s u b s e q u e n t h y d r o g e n o l y t i c d e b e n z y l a t i o n ( S c h e m e 8 ) . 36 The C u r t i u s r e a r r a n g e m e n t i s a c l a s s i c a l method u s e d t o o b t a i n amines from c a r b o x y l i c a c i d s .

A new v a r i a n t d e s c r i b e s t r a p p i n g t h e

i s o c y a n a t e formed i n t h e r e a c t i o n w i t h 2 - t r i m e t h y l s i l y l e t h a n o l

with

t h e a m i n e s l i b e r a t e d a f t e r d e s i l y l a t i o n by t e t r a b u t y l a m m o n i u m f l u o r i d e . 37

S i m i l a r l y , Hofmann d e g r a d a t i o n o f a m i d e s i s a l o n g -

e s t a b l i s h e d method o f amine p r e p a r a t i o n .

R e a s o n a b l e y i e l d s of

p r i m a r y amines c a n be o b t a i n e d u s i n g sodium b r o m i t e i n aqueous s o d i u m h y d r o x i d e t o b r i n g a b o u t t h e r e a r r a n g e m e r ~ t . ~I~t h a s a l s o b e e n d e m o n s t r a t e d t h a t L,I-bis(trif1uoroacetoxy)iodobenzene c a n a c h i e v e t h e same t r a n s f o r m a t i o n ( S c h e m e 9 ) .

The s c o p e of t h e

r e a c t i o n , 39 i n e f f e c t a n a c i d i c Hofmann r e a r r a n g e m e n t , k i n e t i c s a n d mechanism4'

and its

have been s t u d i e d .

E l e c t r o p h i l i c a m i n a t i o n o f o r g a n o m e t a l l i c r e a g e n t s i s a more recent general strategy. T o s y l a z i d e h a s p r e v i o u s l y been r e p o r t e d

a s a v i a b l e +NH2 s y n t h o n and h a s been f u r t h e r u t i l i z e d i n a s y n t h e s i s of anthramycin (11).

Key s t e p s of t h e s y n t h e s i s i n v o l v e d

p r e p a r a t i o n o f ( 1 0 ) by l i t h i a t i o n o f ( 9 ) f o l l o w e d by a d d i t i o n of t o s y l a z i d e , borohydride r e d u c t i o n , and p r o t e c t i o n , t h e s e s t e p s

292


qR%p

H

QR

-k H2N-C-Ph I*

QR%

I

R

Me

0

N

NH.HC1

2 Me-CLH I Ph

Reagents:

I,

Ra-Ni,H2 ;ii,HCI,EtOH;

III,

I* Me-CI

NH,.H CI

H

Ph

H 2 , P d / C , EtOH

Scheme 7

.x

\

N H

I

k'

Reagents:

I,

C0,Me

x = c i a o - so,-

4-CLC6H40SO2NCO;

II

,HCL , E t O H ;

I I I , ~ ,N2;

iv,H2(1atm),Pd/C

Scheme 8

0

II

RCNH,

0

+

H,O

+

II

PhI(OCCF3),

MrCN

0

RNH;

p H 1-3

Scheme

9

+

PhI

II + CO, + ZC5CO + H'


293

being achieved in 72% overall yield (Scheme 1 0 ) . 4 1 An interesting report details conversion of a primary halide into a homologated primary amine via formation of a Grignard reagent and its reaction with a ~,IJ-bis(trimethylsilyl)aminomethyl ether obtained from sodium bis(trimethylsily1)amide and chloromethyl methyl ethers (Scheme 1 1 ) . 4 2 A similar study specified N-,~-bis(trimethylsilyl)methoxymethylamine, prepared from lithium hexamethyldisilazide and chloromethyl methyl ether, as the reagent of choice (Scheme 11).43 The mechanism of a related amination of organolithiums by alkoxyamines has also been studied in more detail. 44 An interesting and more novel example of amination of organometallics described use of the oxime tosylate derived from tetraphenylcyclopentadienone as the electrophilic species. lr5 After displacement of toluenesulphonate by the nucleophile the amine was liberated by exchange with hydroxylamine, thus establishing a 'catalytic ' cycle. The classical method for preparing primary amines from the corresponding alkyl halides without polyalkylation is the Gabriel synthesis. A new method of similar applicability facilitates alkylation of halides and sulphonates with the sodium salt of trifluoroacetamide and thus allows a much easier deprotection reaction.46 Primary amines are thus formed essentially free of secondary amines although some competing dehydrohalogenations were observed in the alkylations. In a similar vein, a one-pot, twostage deprotection of phthalimides leading to isolation of primary amines (and also amino-acids) in good yield has also been described. 47 As well as their utility in the synthesis of homologated amines from alkyl halides as described above, the potential of N,Nbis(trimethylsily1)amines (formed from sodium hexamethyldisilazide and alkyl halides or tosylates) to yield non-homologated primary amines directly by acidic hydrolysis was recognized and naturally exploited. 48 As well as by simple reductive methods nitriles can serve as a source of primary amino functionality in cyclizations where a nucleophilic centre can close onto a suitably disposed cyano-group. Such reactivity has been commonly employed in heterocyclic syntheses, e.g. Scheme 1 2 . 49-52 Michael additions to acrylonitriles also constitute a versatile method for amino-substituted heterocycles, with 5-aryl-3-amino-2-


294

0

(11 1

T

-

0-0’

i- iv

Me&

Multistep

0-0’

Me&NH

C02But

7 2 ‘10

R e a g e n t s : i , ButLi ; i i , T s N 3

j

iii, NaBHq ; i v

,( B U ~ O ) ~ C O

S c h e m e 10

N a N ( S i Me3l 2

R2-0

- CH,-N(SiMe,),

4- R’MgBr

bR’-CH2-NN(SiMe3)z

ii i

R1CH2NH..$I

L

R = M e or C,H,3

[RMI RH

vi

RCH,N( S i Me3),

v ii

*

RCH2NH2

Y MzLi

or MgX

R e a g e n t s : I , R 2 0 C H 2 C l , HN(SiMe3I2 ; i i , E t z O , r . t . ,

Et20; v , L i , Mg8r2;

VI

12h ;

III

,HCI,H20,Et20;iv,Mg,

, ( M e 3 S ~ ) 2 N C H 2 0 M e ,t h e n aq. KOH;

or S i 0 2

S c h e m e 11

VII,

MeOH,p-TSA


Reagent : AlCL3

,P h C l S c h e m e 12

S c h e m e 13

L

(12)

R e a g e n t s : NHZOH.HCL

~

NaOH ; i i ) NH20H.HCL, N o

S c h e m e 14

295

296


alkoxycarbonylthiophenes and 5-aryl-aminopyrazoles resulting from treatment of 8-chlorocinnamonitriles with esters of a mercaptoacetic (Scheme 13). Addition of has led to the cyclization of

acid53 and hydrazine hydrate5'

respectively , e.g.

hydroxylamine hydrochloride to 2-halogenonitriles synthesis of 3-amino-2,l-benzisoxazoles ( 1 3 ) upon the initial adducts (Scheme 14).55 Rearrangements of preformed heterocycles have also led to amino

substitution; for example the reduction of 4-cyanoisoxazoles afforded 5-amino-oxazoles ,56 whose preparation from 1 - a c y l - a aminonitriles has also been studied , 57 whilst base-induced rearrangement of (2-oxo-2-anilinoethyl)-Il2,4-oxadiazoles has afforded 3-(acylamino)-l-aryl-2-pyrazolin-5-ones, which can be easily deacylated to yield the corresponding primary amino derivatives .58 5-Amino-7(6H)-furazano[3 , 4-dlpyrimidinone can be obtained from a wide variety of 5 - a m i n o f u r a z a n o [ 3 , 4 - d l p y r i m i d i n e s after either basic or acidic ring cleavage, esterification, and recyclizat ion - 5 9 Addition-eliminations between malononitrile and heterocycles has served in the preparation of amino-cyano-substituted compounds. Thus, 2-amino-3-cyanopyridines have been made from 2(1Ij)pyrimidinones6' and 2-amino-3-cyan0-4-pyrones were synthesized from 1 , 3-oxazin-4-one-2-thiones .61 Hydrazine hydrate effected a novel amination of 6-aryl-3(25)pyridazinones in the 4-position. 6 2

Studies concerning the high-pressure liquid chromatographic separation of enantiomeric amines has revealed that primary amines could be separated using (~)-~-(3,5-dinitrobenzoyl)phenylglycine covalently bound to y -aminopropylsilanized silica.63 As well as a range of primary amines that included substituted cyclohexylamines, amino-alcohols and amino-acid derivatives could be separated. Another chiral stationary phase based on a-(6,7-dimethyl-lnaphthyl )isobutylamine was also developed . 6 4 E- ( 3 , 5 Dinitrobenzoy1)amines were resolved reasonably well (as were aminoalcohols, amides and amino-acids). The same report revealed that another stationary phase derived f r o m a-(l-naphthy1)ethylamine performed better for some amines, but generally less well for amino-acids. Secondary Amines.- Monoalkylation of primary amines is a key functional group transformation in organic synthesis and perhaps


297

the most obvious approach to the synthesis of secondary amines. However, there has been a long history of problems with overalkylation associated with the method which is, therefore, still investigated thoroughly. Ruthenium-catalysed 1-alkylations and N-benzylations of aminoarenes with alcohols have been reported, with excellent yields of secondary amines obtained when equimolar mixtures of amines and alcohols were employed with dichlorotris(tripheny1phosphine)ruthenium(I1) as the catalyst precursor.65 It was noted that use of an excess of alcohol gave predominant tertiary amine formation. Although monomethylation of primary arylamines via treatment of N-(alkoxymethy1)-N-arylamines with sodium borohydride (to reduce presumed arylmethyleneamine intermediates) in refluxing ethanol has been reported (Scheme 15) ,66 similar treatment of N-(alkoxymethy1)N-alkylamines failed to give monomethylated alkylamines. This problem was circumvented by effecting the reduction with lithium aluminium hydride in ether at -60 O C , under which conditions monomethylated amines were obtained essentially free of primary or N,N-dimethylated amines. In a subsequent paper, the same authors reported that ~-alkyl-~-(alkylthiomethyl)ammoniumchlorides afforded monomeric N-methylenealkylamines (stable at -60 OC) which could then be trapped with organometallic reagents, thus providing unsymmetrical secondary amines (Scheme 15 .67 A similar reaction of organolithiurn o r organomagnesium reagents with N-(cyanomethyl)or 1-(aminomethyl)-amine derivatives led to unsymmetrical secondary amine formation presumably via addition of the organometallic nucleophile to methyleneamine intermediates. 68 The selective methylation of primary amines has also been achieved, in a few examples, using methyltrialkoxyphosphonium tetrafluoroborates as the alkylating species.69 In another report, metathesis of primary amines to secondary amines was accomplished with d i c h l o r o b i s ( t r i p h e n y I p h o s p h o s p h i n e ) p l a t i n u m ( I I ) , but only in the presence of SnC12. 2H20. 7 0 Yields were variable, and particularly so for primary diamines. In bio-organic chemistry the study of polyamines has traditionally been an important area, and selective alkylations and acylations of the ubiquitous polyamines putrescine, spermidine, and spermine are thus of crucial importance. From the many strategies employed to achieve these goals a selective monoprotection (that would enable monoalkylation) occurred with benzyloxycarbonyl chloride provided that the reagent was added to the diamine with

298


careful control of P H . ~ ’ A pH of between 3.5 and 4.5 is essential if diacylated products (formed at pH > 5 . 0 ) are to be avoided (Scheme 1 6 ) . Another approach leading to the synthesis of Emethylputrescine and its homologues involved alkylation of 4bromobutyronitrile with alkylbenzylamines followed by a hydrogenolysis to effect both reduction of the nitrile to primary amine as well its .debenzylation to yield the secondary amino function (Scheme 16).21 A third strategy utilized ltrifluoroacetyl-protected amino-acids which were converted through acyl halides to amides. This followed by alkylation and deprotection of the trifluoroacetamide moiety allowed the target compounds to be isolated after borane-dimethyl sulphide reduction of the amide as the final step (Scheme 16).72 Selective ~4-monoacylation of spermidine with hydroxycinnamoyl groups has been achieved from either 7-aminobutyric acid (Scheme 1 6 ) , 7 3 o r from , N 4 ,N8 -tri-t-butoxycarbonylspermidine via a known (see Volume 8, p.262) preferential 4 -deprotection with methyl-lithium andlor n-butyl-lithium in THF at -20 0C.73 A complementary approach to secondary amines is the dealkylation of tertiary amines. This more difficult transformation has been achieved N-oxides by formation of silyloxyammonium salts upon reaction with trialkyltrifluoromethanesulphonates. In the presence of a strong base these rearrange to a-silyloxyamines which react further with suitable electrophiles. Thus in the presence of an acyl halide acylated secondary amines can be isolated.74 Since Eoxide formation is nearly quantitative, overall yields for the process are high. A novel system employing a , B , y tetraphenylporphynatoiron(III), molecular oxygen, and sodium dithionite in which the iron(II1) species acts catalytically has been ~ t u d i e d . ’ ~ In the case of dealkylation of g-ethyl-gmethylaniline by this reaction both possible dealkylated products were obtained with the N-demethylated product predominating. A further dealkylative method required treatment of tertiary amines with a-chloroethyl chloroformate ( ACE-C1) in 1,2-dichloroethane . 7 6 The quaternized intermediate was not isolated, and the resultant acylated secondary amine was deprotected merely by heating in methanol. The method was applied to the development of improved syntheses of naltrexone and nalbuphine. As with primary amines, secondary amines may be prepared by reduction of imines. One example of reduction by an inter-metallic rare-earth alloy La5Ni6 (see above) was reported.

M1

x

299


R e a g e n t s : i I (CH20),

, NaOMe;

11,

NaBH4, then

1M-KOH ; i i i , ( a ) (CH20),

,(~)HcI

( 3 e q u I v . 1 , a n h y d r o u s E t 2 0 , ( c ) R2SH; i v , R 3 M ( 3 e q u i v . ) , E t 2 0 ; v , l M - K O H

S c h e m e 15

0

0 HzN(CH2),NH2

II

II

+ PhCH20-C-Cl

--LPhCHzO-C - NH(CH,),NH,

n =2-7 iii

I1

PhCH2NHR 4- B r C HZCHzCHzCN -b PhCHZNRCH2C3CH2CN+RNHCH2C3CH2CHzNH2.2HCl

-

R=Me,Et,Prn,

0 TFANH(CH,),CCI

It

iv

o r Bun

0

I

TFANH(CH,),CNR’R~ VI

0

R3

II

II

TFAN(CH,),,CNR’R~

,vi i

0

II

VI, V I I

R3iH,(CH2!,,+,iH

R1R2 2 Y-

R3NH(CHz),CNR’R2

a

0

H (CH&l

Boc NH (CH,),CON

-%B o c NH(C H,),CON

H (CH 2)3N

0 XI1

BocNH(CHZI4NH ( C H ~ ) ~ N H B O CaBocNH(CH,)3CONH(CH2)3NHBOC ( C H2)3NHBoc

CHSHCON xlll.l \/

R2+

YH2

)3NH3

CHXHCON \

- J $R

( C Hz 14NHBOC

R Reagents-

XlV,XV)

R

+

+

( C H&+NH3

2 CF3COO-

I , MeS03H, b r o m o c r e s o l g r e e n : ii,KZC03(1 e q u i v ) , K I (0.1equiv 1; vii,HCL; viii,K2C03; I V , R1R 2NH,py;R3XJK2CO3,MeZCO;vi,BH3.Me25;

111,

IX,

H,,Pd,C; NaH,

p h t h a l i r n i d e , N a I ; x , N2H4.H20;x~,(But0CO)Z0,NaZC03; XII, Na(CF3COZ)6H3;X I I I , 3-R’-4-

R2- 5 -R3C6HZCH=CHCOCI,CHZClZ ; X I v, MeOH, NH3 ; xv ,CF3C02H

S c h e m e 16


3 00

Asymmetric r e d u c t i o n s w i t h l i t h i u m aluminium h y d r i d e complexes d e r i v e d f r o m 3-~-benzyl-l12-~-cyclohexylidine-~-D-g1ucofuranose g a v e r i s e t o o p t i c a l l y a c t i v e s e c o n d a r y amines a l b e i t i n low enantiomeric excess.”

The mechanism o f i m i n e r e d u c t i o n s , and i n

p a r t i c u l a r t h e case of 3 ,N-diphenylbutan-2-irninet

78 h a s b e e n

studied. R e d u c t i v e a m i n a t i o n o f c a r b o n y l c o m p o u n d s w i t h o u t i s o l a t i o n of i m i n e s is becoming a f r e q u e n t l y used s y n t h e t i c a l t e r n a t i v e t o t h e above methods.

Sodium hydrogen t e l l u r i d e e f f e c t s t h e

t r a n s f o r m a t i o n i n m o d e r a t e t o good y i e l d s

,79 w h i l s t b o r a n e - p y r i d i n e

h a s been proposed a s a v e r s a t i l e and c h e a p r e a g e n t f o r t h i s purpose, with t h e additional advantage t h a t t h e severe t o x i c i t y problems a s s o c i a t e d w i t h t h e popular r e a g e n t sodium c y a n o b o r o h y d r i d e a r e a v o i d e d . 8o

Borane-THF

h a s been s i m i l a r l y used

not only f o r t h e synthesis of simple a l i p h a t i c amines but a l s o f o r see-amino-alcohols

81

and sec-amino-phenols.

Imines have proven t o be e x c e l l e n t s u b s t r a t e s t o which o r g a n o m e t a l l i c n u c l e o p h i l e s may b e a d d e d .

They u n d e r g o t h r e o -

s e l e c t i v e a d d i t i o n of a l l e n y l s i l a n e s 8 2 a n d C r a m - s e l e c t i v e o f allyl-9-BBN

83 ( s e e S e c t i o n 3).

a-Hydrogen-containing

additions imines

a f f o r d e d good y i e l d s o f s e c o n d a r y a m i n e s a f t e r t r e a t m e n t w i t h b o r o n trifluoride-complexed Alkynyl-boranes

a l k y l c o p p e r r e a g e n t s (Scheme 1 7 ) .

84

( a n d -berates) a n a l o g o u s l y p r e p a r e d i n s i t u f r o m

l i t h i u m a c e t y l i d e a n d BF3.Et20 a l s o a d d w e l l t o a l d i m i n e s , y i e l d i n g R-aminoalkynes

( s e e S e c t i o n 3 ) .85

The r o l e o f o r g a n o b o r o n c h e m i s t r y i n t h e p r e p a r a t i o n o f s e c o n d a r y a m i n e s h a s been f u r t h e r e x t e n d e d by a r e p o r t t h a t reaction of trialkylboranes with N-chloroalkylamines can be u t i l i z e d t o synthesize a v a r i e t y of functionally s u b s t i t u t e d d i a l k y l a m i n e s i r , g r e a t e r t h a n 60% y i e l d

( S c h e m e 1 8 ) .86

Thus a n

o v e r a l l o l e f i n t o a m i n e t r a n s f o r m a t i o n was r e a l i z e d . Sulphonamidomercuration of o l e f i n s and subsequent r e d u c t i v e demercuration leading t o N-alkylsulphonamides

h a s b e e n s t u d i e d . 87

The r e a c t i o n of n i t r o g e n n u c l e o p h i l e s w i t h n - o l e f i n p a l l a d i u m ( I 1 ) c o m p l e x e s h a s been c o v e r e d a s p a r t of a l a r g e r r e v i e w d e a l i n g w i t h t h e t o p i c of p a l l a d i u m ( I 1 ) - a s s i s t e d r e a c t i o n s of mono-olefins.

88

Reductive aminations of ethynylpyridines with primary amines and s o d i u m c y a n o b o r o h y d r i d e h a v e a l s o b e e n d e m o n s t r a t e d .89 m e t h o d o l o g y was a l s o a p p l i e d t o t h e s y n t h e s i s o f some

The

B-(N,N-

dialky1amino)pyridines i n analogous r e a c t i o n s employing secondary amines.


301

S c h e m e 17

R’

+ R ~ ~ B - NI+-

~’p + CINHR’~ Reagents :

I,

I H

THF, NaHC03 ; 1 1 ~ 1 ‘100 HCL ;

III

, 3N-

~2

% R’R~NH

NaOH

S c h e m e 18

OTs

0=

H0’

‘

H

/J

HO

I

H I

____)

-

I

H

H

I1

1

-

8

I1

R’

R

4-

IJ H

R e a g e n t s : i ,(Me3SiI2NH ; i i , L e w i s a c i d , R’NHR‘

S c h e m e 19

Me2SiOH


3 02 In a synthesis of aphidicolin

(15) a key s t e p r e q u i r e d

i n t r a m o l e c u l a r a l k y l a t i o n o f a n e n o l a t e d e r i v e d from ( 1 4 ) .

The

d e s i r e d d e p r o t o n a t i o n ( a t c a r b o n a ) was o n l y a c h i e v e d e f f e c t i v e l y when l i t h i u m d i - t - b u t y l a m i d e

was u s e d a s b a s e .

However, t h e amine

was o n l y p r e p a r e d w i t h d i f f i c u l t y a n d t h i s p r o m p t e d d e v e l o p m e n t of a g e n e r a l s y n t h e s i s of d i - t - a l k y l a m i n e ~ . ~ ~T h e s t a g e s of t h e

preparation are:

( i > oxidation of t-alkylamine

with peracetic acid

i n e t h y l a c e t a t e , ( i i ) conversion of t h e so-formed t - a l k y l n i t r o s o compound i n t o t h e c o r r e s p o n d i n g tri-t-alkylhydroxylamine by s u c c e s s i v e t r a p p i n g o f t w o t - a l k y l r a d i c a l s , a n d ( i i i ) r e d u c t i o n of t h e l a t t e r compound m e d i a t e d by s o d i u m n a p h t h a l i d e . The s y n t h e s i s o f u n s y m m e t r i c a l l y s u b s t i t u t e d l , 4 - d i a l k y l a m i n o s u b s t i t u t e d a r o m a t i c s y s t e m s h a s b e e n p r o m i n e n t i n t h e s e a r c h for antineoplastic agents. Photochemical methods have been used w i t h increasing success i n t h i s direction. I n one i n s t a n c e 1,4-

dimethoxyanthracene-9,lO-dione u n d e r w e n t p h o t o c h e m i c a l m o n o s u b s t i t u t i o n i n 30-51% y i e l d i n t h e p r e s e n c e of a p r i m a r y a m i n e , w i t h a s e c o n d a m i n e m o i e t y s u b s e q u e n t l y i n t r o d u c e d (28-92% y i e l d ) i n a thermal s u b ~ t i t u t i o n . ~ ’ Another e f f o r t developed a s u c c e s s f u l photochemical p r e p a r a t i o n o f 8-alkylamino-5-amino-3-

butylamino-2-cyano-l,4-naphthoquinones f r o m t h e p a r e n t 8u n s u b s t i t u t e d compound, and p r i m a r y a m i n e s . 9 2

Providing reactions

were c a r r i e d o u t under a n i n e r t atmosphere ( n i t r o g e n ) a h i g h l y r e g i o s e l e c t i v e s y n t h e s i s o f t h e d e s i r e d compounds, a v o i d i n g t h e c o m p l e x p r o d u c t m i x t u r e s a n d l o w y i e l d s e n c o u n t e r e d when r e a c t i o n s took p l a c e i n t h e p r e s e n c e of oxygen, could be accomplished.

A

f u r t h e r report noted displacements of alkoxy s u b s t i t u e n t s para- t o a n i t r o - g r o u p by p r i m a r y a m i n e s i n t h e a b s e n c e o f o t h e r

reagent^.'^

I n t h e c a s e s s t u d i e d , r e p l a c e m e n t o f a p r i m a r y by a s e c o n d a r y a m i n e l e d t o t h e f o r m a t i o n o f p h e n o l s by d e a l k y l a t i o n . C o v a l e n t a m i n a t i o n o f l - a l k y l - a n d l-aryl-3-carbamoylpyridinium c h l o r i d e s w i t h l i q u i d ammonia h a s b e e n s t u d i e d , a n d t h e p o s i t i o n of s u b s t i t u t i o n f o u n d t o b e d e p e n d e n t on t h e n a t u r e of t h e n i t r o g e n s u b s t i t u e n t .g4

1- n - A l k y l

whereas l-branched

groups led t o exclusive 6-substitution,

a l k y l g r o u p s d i r e c t e d s u b s t i t u t i o n t o t h e C-4

a n d C-6 p o s i t i o n s w i t h p r o d u c t r a t i o s s h o w i n g d e p e n d e n c y o n t h e s i z e of t h e n i t r o g e n s u b s t i t u e n t . l - A r y l d e r i v a t i v e s were s u b s t i t u t e d o n l y a t C-2 a n d C-6, t h e r a t i o s of p r o d u c t s i n t h e s e cases b e i n g t e m p e r a t u r e dependent. I n t h e f i e l d of h e t e r o c y c l i c c h e m i s t r y a n e f f i c i e n t m e t h o d f o r a m i n a t i o n of h y d r o x y - N - h e t e r o c y c l e s h a s b e e n d e v e l o p e d . 9 5 The

303

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups method i n v o l v e s a o n e - s t e p ,

one-pot

silylation-amination

The a d d i t i o n - e l i m i n a t i o n o f a m i n e s t o 2 - s i l y l a t e d

procedure.

heterocycles with

l i b e r a t i o n of t r i m e t h y l s i l a n o l is L e w i s acid-catalysed

and a

p a r t i c u l a r l y e f f i c i e n t procedure i n t h e presence of excess h e x a m e t h y l d i s i l a n e which c o n v e r t s t h e s i l a n o l t h u s formed i n t o hexamethyldisiloxane. The m e t h o d w o r k s e q u a l l y w e l l u s i n g ammonia

o r a s e c o n d a r y a m i n e i n p l a c e of t h e p r i m a r y a m i n e (Scheme 1 9 ) . I n g e n e r a l , d i s p l a c e m e n t o f a l e a v i n g g r o u p by a p r i m a r y a m i n e is a s t r a t e g y t h a t works w e l l f o r t h e s y n t h e s i s of a h e t e r o c y c l i c secondary (and a l s o t e r t i a r y ) amines. T h i s p o i n t may b e e x e m p l i f i e d by t h e s y n t h e s i s o f 4 - a l k y l a m i n o f u r a n o n e s , 96 a n d t h e p r e p a r a t i o n o f 2-aminopyrazine l-oxides.97

from 4-alkoxy-2(5K)from 2-halogeno-

I t was a l s o f o u n d t h a t t r e a t m e n t o f 5-

a c e t y l o x a z o l e s w i t h p r i m a r y a m i n e s l e d t o t h e i s o l a t i o n o f I!-2-s-

alkylamino-5-acetylimidazoles a s t h e major p r o d u c t s a l o n g w i t h s m a l l a m o u n t s o f 2 - a l k y l a m i n o - 4 - m e t hy 1 - 5 - h y d r o x y p y r i m i d i n e s . The u s e o f c o v a l e n t l y bound (g)-l-(3,5-dinitrobenzoyl)p h e n y l g l y c i n e a s a c h i r a l s t a t i o n a r y p h a s e for t h e s e p a r a t i o n o f e n a n t i o m e r i c amines h a s been extended t o i n c l u d e g-a-naphthoyl d e r i v a t i v e s o f c y c l i c s e c o n d a r y a m i n e s ,9 9 w h o s e e n a n t i o s e l e c t i v e s y n t h e s i s by a l k y l a t i o n s o f 1,2,3,4-tetrahydroisoquinolines h a s b e e n t h e s u b j e c t o f c o n t i n u e d s t u d y . 1oo-102 S t u d i e s o f r e l a t e d p y r r o l i d i n e , 1 0 3 ’ 1 0 4 p i p e r i d i n e , ’03-’05 a n d t e t r a h y d r o - g c a r b o l i n e l o 6 m e t a l l a t i o n s have been published. T e r t i a r y Amines.-

Reductive a l k y l a t i o n s of b o t h primary and

s e c o n d a r y amines c o n s t i t u t e f a c i l e r o u t e s t o t e r t i a r y amino derivatives.

The f o r m e r m e t h o d c a n b e i l l u s t r a t e d by t h e

d i m e t h y l a t i o n o f (6) a n d ( 7 ) w i t h f o r m a l d e h y d e a n d s o d i u m c y a n o b o r o h y d r i d e ,29 w h i l s t s o d i u m d i h y d r o g e n p h o s p h a t e i n c o n j u n c t i o n w i t h formaldehyde proved t o be a u s e f u l a l t e r n a t i v e r e a g e n t f o r N,X-dimethylation o f p r i m a r y and N-methylation o f secondary amines. Io7 The a l k y l a t i o n o f d i a r y 1 a n d a r o m a t i c secondary amines under phase-transfer

conditions with polyethylene

g l y c o l m e t h y l e t h e r i n p l a c e o f 18-crown-6 b e e n r e p o r t e d . 108

as c a t a l y s t h a s a l s o

An i n t e r e s t i n g r o u t e t o 1 - a l k y l - g - a r y l a n i l i n e s

b a s e d on

r e d u c t i v e a l k y l a t i o n o f a m i n e s w i t h c a r b o n y l compounds h a s b e e n d e v e l o p e d a f t e r h i g h y i e l d s o f t h e s e c o m p o u n d s were u n e x p e c t e d l y o b t a i n e d on c o n d e n s a t i o n o f c y c l o h e x a n e - 1 , 4 - d i o n e s and N,N-diaryl-amines

respectively

( S c h e m e 2 0 1. l o g

with 1-aralkyl-


304

The n u m e r o u s t y p e s o f a - m e t a l l o a m i n e s y n t h o n s h a v e b e e n comprehensively reviewed and l i s t e d a c c o r d i n g t o t h e t y p e of activating substituent present. 'lo t e r t i a r y a l i p h a t i c N-methylamines a c t i v a t i o n , u s i n g Bu'Li-KOBut

,

It h a s a l s o been r e p o r t e d t h a t can be d e p r o t o n a t e d w i t h o u t

Formation o f t e r t i a r y amine g - o x i d e s fruitful.

'

and s u b s e q u e n t l y a l k y l a t e d . h a s also p r o v e d m o s t

a - S i l o x y a m i n e s d e r i v e d f r o m t h e m , by r e a c t i o n w i t h

t r i a l k y l s i l y l trifluoromethanesulphonates a n d r e a r r a n g e m e n t o f t h e r e s u l t a n t siloxyammonium s a l t s w i t h s t r o n g b a s e , n o t o n l y a f f o r d s e c o n d a r y a m i n e s by d e a l k y l a t i ~ nb~u t~ may a l s o b e s u b s t i t u t e d i n the a-position

by r e a c t i o n w i t h G r i g n a r d r e a g e n t s o r

t r i a l k y l a l u m i n i u m s i n m o d e r a t e t o good y i e l d s (Scheme 2 1 ) . ' I 2 In a d d i t i o n treatment of a-siloxyamines w i t h a l k y l h a l i d e s g i v e rise t o a-siloxyammonium

s a l t s capable of f l u o r i d e ion-induced

d e s i l y l a t i o n thereby a f f o r d i n g t r a n s a l k y l a t e d t e r t i a r y amines ( S c h e m e 21 1. 1 1 3 A l t h o u g h i t h a d b e e n p r e v i o u s l y shown t h a t q u a t e r n a r y p y r i d i n i u m salts could undergo r i n g f u s i o n , transamination,

and r e c y c l i z a t i o n

t o g i v e a r o m a t i c a m i n e s , t h e r e a c t i o n was p r o n e t o c o m p l i c a t i n g side reactions.

I t h a s now b e e n d e m o n s t r a t e d t h a t a b u l k y

E-

s u b s t i t u e n t f a v o u r s t r a n s a m i n a t i o n o f t h e a c y c l i c i n t e r m e d i a t e . l l' U s e f u l y i e l d s ( g r e a t e r t h a n 50% i n a l l c a s e s ) o f t e r t i a r y a m i n e s were o b t a i n e d by p r o l o n g e d ( 4 0 - 4 5 h ) h e a t i n g ( 1 8 0 - 2 0 0 O C ) o f 1 i s o p r o p y l p i c o l i n i u m i o d i d e w i t h a n amine and i t s s u l p h i t e s a l t i n One e x a m p l e o f s e c o n d a r y aqueous s o l u t i o n i n a s e a l e d ampoule. amine formation u s i n g t h i s t e c h n i q u e is c i t e d . A Lewis acid-mediated p r e n y l a t i o n of s e c o n d a r y amines u s i n g p r e n y l d i - i s o p r o p y l p h o s p h a t e may f i n d a p p l i c a t i o n i n c a s e s w h e r e s e l e c t i v i t y i s i m p o r t a n t . W i t h BF3.0Et2 o t h e r a m i n e s f a i l e d t o react, secondary amines g i v i n g reasonable y i e l d s of N-prenylated products. Diarylamines gave s i g n i f i c a n t l y higher y i e l d s than arylalkylamines, nitrogen-containing heterocycles affording n u c l e u s - p r e n y l a t e d p r o d u c t s . 115 Aminomethylations of a d e n i n e , c y t o s i n e , and guanine have been d e s c r i b e d . l 6 M o n o a l k y l a t e d p r o d u c t s were o n l y o b s e r v e d i n r e a c t i o n s of a d e n i n e w i t h aminomethylating a g e n t s d e r i v e d from r e l a t i v e l y non-basic amines used i n equimolar q u a n t i t i e s . Bisa l k y l a t e d p r o d u c t s were o b t a i n e d on r e a c t i o n s o f a d e n i n e w i t h a m i n o m e t h y l a t i n g a g e n t s d e r i v e d f r o m b a s i c a m i n e s , a n d were f o r m e d e x c l u s i v e l y i n r e a c t i o n s of c y t o s i n e and g u a n i n e r e g a r d l e s s o f b o t h

305


Scheme 2 0

R’

0-

\h/

R’2

R2HN\CH2R3

‘CH2R3

R’

RI +/

OSiMe2Buf

I

v

/ O S i Me2Buf

\

N-CH

R2/

‘R3

t

Me2Bu

,OSi

-0Tf

0F R’,

R’

CH(R3)-&-SiMe26u

L2 /‘id\R

x-

R

R’

\

ii

+

iv

2/

N-R

R

R4 N-CHC

N-E

R2/

R2’

R3

E = COR ( C 0 2 R J NO, or H 1 R e a g e n t s : i, B u t M e 2 S i O T f ; ii

MeLi ; iii

R X ; iv,Bun4NF; v , R4MgBr or R 2 I ; v i , R C O C I

S c h e m e 21

General and Synthetic Methods amine b a s i c i t y and r e a g e n t s t o i c h e i o m e t r y . Diamines.-

The s y n t h e s i s o f f o r m a m i n a l s on r e a c t i o n o f s e c o n d a r y

amines with formaldehyde is a l o n g - e s t a b l i s h e d

procedure.

Somewhat

s u r p r i s i n g l y , secondary amines reacted with bis(chloromethy1) e t h e r t o y i e l d methylenebisamines.

A mechanism i n v o l v i n g Grob

fragmentation t o dialkylaminomethyl chloromethyl e t h e r i n t e r m e d i a t e s was p r o p o s e d t o e x p l a i n t h e s e o b s e r v a t i o n s . F o r m a m i n a l s were a l s o p r e p a r e d f r o m s e c o n d a r y a m i n e s a n d d i c h l o r o m e t h a n e i n m e t h a n o l by c o n s e c u t i v e h i g h - p r e s s u r e Mensc h u t k i n r e a c t i o n s .

I n a d d i t i o n , a m i n a l s were o b t a i n e d f r o m

aminocarbenes, generated from phenylbromodiazirine, amines.

and s e c o n d a r y

'9

Hetero-Diels-Alder

r e a c t i o n s have played a n important p a r t i n

t h e synthesis of unsaturated v i c i n a l diamines.

Thus, bis(imides1

o f s u l p h u r d i o x i d e a c t e d as d i e n o p h i l e s i n r e a c t i o n s w i t h b o t h

(E,E)- a n d ( E , L ) - h e x a - 2 , 4 - d i e n e s . For e a c h p a i r o f 1 - a m i n o - 3 , 6 dihydro-2E-ll2-thiazines s o f o r m e d , s e p a r a t i o n o f S , C 6 - c i s - a n d S,C - t r a n s - i s o m e r s was a c h i e v e d c h r o m a t o g r a p h i c a l l y . Both isomers 6d e r i v e d from t h e ( E , g ) - d i e n e

c o u l d be c o n v e r t e d i n t o threo-N-

protected-3-ethylene-I,2-diaminesl w h e r e a s t h o s e a d d u c t s of t h e ( E , L ) - d i e n e were c o n v e r t e d i n t o t h e e r y t h r o - i s o m e r s . I 2 O These transformations required treatment of t h e S,C6-trans-isomers

with

p h e n y l m a g n e s i u m b r o m i d e f o l l o w e d by a d d i t i o n o f t r i m e t h y l p h o s p h i t e and r e a r r a n g e m e n t of t h e S , C 6 - c i s - i s o m e r s

t o Il2,5-thiadiazolidines

i n r e f l u x i n g b e n z e n e f o l l o w e d by t h e i r r e d u c t i o n w i t h s o d i u m b o r o h y d r i d e (Scheme 2 2 ) . Vicinal di-t-amines

have been p r e p a r e d i n up t o

54% y i e l d by a n

a m i n a t i v e r e d u c t i v e c o u p l i n g o f a r o m a t i c a l d e h y d e s i n d u c e d by

tris(dialkylamino)methylvanadium(IV).

T h e v a n a d i u m s p e c i e s was

p r e p a r e d i n s i t u e i t h e r b y t r e a t m e n t of chlorotris(dialky1amino)vanadium(1V) w i t h m e t h y l - l i t h i u m

or by s e q u e n t i a l a d d i t i o n s o f

l i t h i u m d i a l k y l a m i d e s ( 3 e q u i v a l e n t s ) and m e t h y l - l i t h i u m s o l u t i o n of vanadium t e t r a c h l o r i d e i n e t h e r - p e n t a n e . method f a c i l i t a t e s a one-pot

procedure s i n c e t h e aldehyde can be

added d i r e c t l y t o t h e r e a c t i o n m i x t u r e . m e c h a n i s m was p r o p o s e d

to a

The l a t t e r

A radical coupling

(Scheme 2 3 ) .

A p r e v i o u s l y r e p o r t e d m e t h o d o f v i c i n a l d i a m i n a t i o n of o l e f i n s

u s i n g cyanamide and N-bromosuccinimide been improved. 122 B-bromoalkylisourea

( s e e Volume 8 , p . 2 5 3 )

has

A k e y s t e p i n t h e s y n t h e s i s was c y c l i z a t i o n o f a

t o a n a z i r i d i n e [Scheme 2 4 ; ( 1 7 ) - ( 1 9 ) ] .

I t was


Me

307

Rfl-s,

YH R

H

NHR

Me

Me

RN-S Me R*

I

YHR Me

&

M

H Me

iii,(MeO$P;

V

e

NHR

I

R e a g e n t s : i, C 6 H 6 ; i i , P h M g B r ;

e

iv,PhH,A;v,NaBH4

Scheme 22


308

[,,hANEt2] Me

,1

MeMlY(NEt,), -MeMw(NEt,), PhCHO

-I- O=M ( N E t 2 I 2

I NEt,

1l 2 PhF

P

h

NEt, Scheme 2 3

J

'tt'

I

Qc-c'2 H2N/

f

\NH2

(17) R = OEt (18) R : H

HNYN

R=H I"

R

R = O E t or H Reagents :

I ,

N H 2 C N , NBS ;

ii,

H2

, lo/,

Pd / C ;

III

, NaOMe

Scheme 2 4

f--

N

I

HNGCNR (IS)R=OEt or

H

; I V , 0 . 2 5 M - N a O H ; v , 5 0 " l o a q KOH


309

p o s t u l a t e d t h a t m i l d e r c o n d i t i o n s f o r t h e c y c l i z a t i o n and h y d r o l y s i s s t e p s would l e a d t o a more e f f i c i e n t p r o c e s s o v e r a l l . The f o r m a m i d i n e ( 1 8 ) was f o u n d t o b e a s u p e r i o r i n t e r m e d i a t e a n d was p r e p a r e d by t r e a t m e n t o f t h e b r o m o c y a n a m i d e ( 1 6 ) w i t h 1 % P d / C i n methanol-acetic acid. Sodium m e t h o x i d e t r e a t m e n t o f ( 1 8 ) a f f o r d e d t h e i m i d a z o l i n e which c o u l d t h e n be h y d r o l y s e d w i t h a q u e o u s b a s e ( S c h e m e 24).

I t was a l s o f o u n d t h a t h y d r o g e n a t i o n i n

t h e absence of acetic a c i d l e d t o t h e formation of t h e d e b r o m o f o r m a m i d i n e ( 2 0 ) which a f f o r d e d t h e r e l a t e d monoamines on t r e a t m e n t w i t h b a s e (Scheme 2 4 ) . Acid-catalysed

r i n g f r a g m e n t a t i o n s o f 2 - o x a z o l i n e s were f o u n d t o

y i e l d N-(2-aminoethyl)carboxamides

i n good t o e x c e l l e n t y i e l d s

p r o v i d i n g s e c o n d a r y o r h i n d e r e d p r i m a r y n u c l e o p h i l e s were employed.123

These amides were e a s i l y h y d r o l y s e d i n b a s i c or

a c i d i c m e d i a t o c o m p l e t e a s i m p l e s e l e c t i v e s y n t h e s i s of unsymmetrically substituted ethylenediamines.

cis-N,N,~',Nf-Tetramethyl-l,2-diaminocyclopentanewas

obtained

by r e d u c t i v e a m i n a t i o n o f 2-(dimethylamino)cyclopentanone

with

s o d i u m b o r o h y d r i d e . 12' P r o t e c t e d 1,3- and 1,4-diamines

r e s u l t e d from r e d u c t i o n s of

b i c y c l i c h y d r a z i n e s (Scheme 25). 125 B o t h a l i p h a t i c a n d o x y g e n a t e d c y c l i c d i a m i n e s were e l a b o r a t e d . 1,3-Diamines r e l e v a n t t o t h e s y n t h e s i s of c h l o r p r o m a z i n e a n a l o g u e s have been s y n t h e s i z e d i n a s o l i d - l i q u i d

(dimethy1amino)propylation o f s e c o n d a r y a m i n e s . 1 2 6

t w o - p h a s e N,NThe m e t h o d

u t i l i z e d sodium h y d r o x i d e / p o t a s s i u m c a r b o n a t e i n b e n z e n e w i t h 10 mol% o f t e t r a - n - b u t y l a m m o n i u m b i s u l p h a t e a s t h e c a t a l y s t . An a l t e r n a t i v e a p p r o a c h t o t h e s y n t h e s i s o f s u b s t i t u t e d putrescines

(cf. a b o v e )

u t i l i z e d degradation of 2-alkylpyrroles

w h i c h a f f o r d e d b i s - o x i m e s when t r e a t e d w i t h h y d r o x y l a m i n e h y d r o c h l o r i d e and sodium b i c a r b o n a t e i n e t h a n o l .

These were t h e n

r e d u c e d t o t h e d i a m i n e s by s o d i u m i n r e f l u x i n g e t h a n o l . a l k y l p y r r o l e s were u l t i m a t e l y d e r i v e d from p y r r o l e s

The 2Vilsmeier-

Haak a c y l a t i o n u s i n g I , I - d i m e t h y l a c y l a m i n e s (from s e c o n d a r y a m i n e s a n d a c y l h a l i d e s ) a n d s u b s e q u e n t r e d u c t i o n o f t h e r e s u l t a n t 2a c y l p y r r o l e s w i t h h y d r a z i n e and p o t a s s i u m h y d r o x i d e i n h o t e t h y l e n e g l y c o l . 27 A l k y n y l d i a m i n e s h a v e b e e n p r e p a r e d by a m i n o m e t h y l a t i o n o f 3128

arylaminobut-l-ynes.


310

NHCO, E t

4

LNHC0,Et

c ) ) y

R2 &yC02E

COZE

NC0,Et

t

NC0,Et

- R'::

R2 z O H

-

R': O H , R ~ = H NHC02Et

N H CO, Et It

O = O

II

A HC0,Et

NHC0,Et

+R ' = R 2 =OH 2

1

R =OH,R = H e Reagents: i

, H2 ,P t 0 2 ;

i i , Na ,NH3

Scheme 25

0 II

O H II I

%Ph2P-C

Ph2P-CH,-Nn0

W

1

I

O -N

R-C-OLi

A

-

0

II

Ill

H

+Ph2P-C R'-

I

-NnO

I

C-OH ' 2

&Y

R e a g e n t s : i , Bu"Li ; i i ) R'R'CO;

iii, NH CL ; i v , K 0 6 u t 4

S c h e m e 26

R

-

311

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 2 Enamines

A l t h o u g h m e t h o d s o f e n a m i n e s y n t h e s i s a r e l o n g e s t a b l i s h e d many of t h e more t r a d i t i o n a l p r e p a r a t i o n s a r e l i m i t e d i n t h a t t h e y are o n l y a p p l i c a b l e t o u n f u n c t i o n a l i z e d s y s t e m s , and also i n t h a t prolonged and o f t e n v i g o r o u s r e a c t i o n c o n d i t i o n s a r e r e q u i r e d .

Thus t h e

s e a r c h f o r new m e t h o d s f a c i l i t a t i n g p r e p a r a t i o n of f u n c t i o n a l i z e d enamines under mild c o n d i t i o n s continues. W i t t i g - t y p e methodology h a s proven v a l u a b l e i n a c h i e v i n g such

aims. M o r p h o l i n o - s u b s t i t u t e d H o r n e r - W i t t i g r e a g e n t s h a v e b e e n f o u n d t o r e a c t , i n good t o e x c e l l e n t y i e l d s , w i t h a r y l , a l i p h a t i c , and a , B - u n s a t u r a t e d a l d e h y d e s t o g i v e e n a m i n e s o f t h e c o r r e s p o n d i n g h o m o l o g a t e d a l d e h y d e s (Scheme 2 6 ) . 29 A n a l o g o u s l y , a- (N-

methylani1ino)methyldiphenylphosphine

o x i d e was f o u n d t o r e a c t w e l l

w i t h t h e s e s u b s t r a t e s and i n a d d i t i o n w i t h c y c l i c a n d a c y c l i c ketones.

Four d i f f e r i n g but complementary methods f o r p r e p a r i n g

t h e s e r e a g e n t s and t h e i r a - s u b s t i t u t e d

c o u n t e r p a r t s were

p r e s e n t e d ; 30 t h e s e w e r e b a s e d u p o n A r b u z o v r e a c t i o n s , M a n n i c h t y p e c o n d e n s a t i o n s o f d i p h e n y l p h o s p h i n e o x i d e w i t h formaldehyde and s e c o n d a r y a m i n e s , a d d i t i o n of d i p h e n y l p h o s p h i n e o x i d e t o e n a m i n e s , and f i n a l l y quenching of c a r b a n i o n s d e r i v e d from a - u n s u b s t i t u t e d

aminomethyldiphenylphosphine o x i d e s w i t h s u i t a b l e e l e c t r o p h i l e s . The a - s u b s t i t u t e d

reagents reacted w e l l with aromatic, aliphatic,

a n d a ,8 - u n s a t u r a t e d

a l d e h y d e s . 31 S i n c e t h e p r o d u c t h o m o l o g a t e d enamines can be converted i n t o t h e c o r r e s p o n d i n g c a r b o n y l d e r i v a t i v e s , t h e a p p l i c a t i o n of t h e a-unsubstituted

a n d a-

s u b s t i t u t e d d i p h e n y l p h o s p h i n e o x i d e s r e s p e c t i v e l y a s new f o r m y l a n d acyl-anion

equivalents is a l s o described.

I n r e c e n t y e a r s t i t a n i u m t e t r a c h l o r i d e h a s been used i n c r e a s i n g l y as a d e h y d r a t i n g a g e n t i n enamine s y n t h e s e s .

A

m o d i f i c a t i o n of t h e s t a n d a r d p r o c e d u r e , u s e of a p r e f o r m e d a m i n e T i C l 4 c o m p l e x , h a s b e e n r e p o r t e d as a g e n e r a l l y a p p l i c a b l e

( a l d e h y d e s , c y c l i c and a c y c l i c a l i p h a t i c k e t o n e s , and a r y l a l k y l k e t o n e s a l l b e i n g good s u b s t r a t e s ) m e t h o d , c l a i m e d t o b e t h e most Yields r a p i d m e t h o d of e n a m i n e s y n t h e s i s d e s c r i b e d t o d a t e . 1 3 2 were g e n e r a l l y v e r y g o o d , a l t h o u g h s t e r i c a l l y h i n d e r e d k e t o n e s r e q u i r e d l a r g e r a m o u n t s of t h e c o m p l e x a n d e x t e n d e d r e a c t i o n times (though s t i l l s h o r t e r than i n conventional procedures) f o r complete conversion.

The s c o p e of t h e m e t h o d was e x t e n d e d t o i n c l u d e

p r e p a r a t i o n o f e n a m i n e s from f u n c t i o n a l i z e d c a r b o n y l compounds. A r e l a t e d r e p o r t g i v e s d e t a i l s of i n v e s t i g a t i o n s of enamine

’’


312

syntheses utilizing Lewis acids i n conjunction with various solid supports.134 The s u c c e s s of t h e r e a c t i o n was f o u n d t o b e h i g h l y d e p e n d e n t on r e a c t i o n t e m p e r a t u r e , t i m e , a n d t h e r a t i o s of t h e amine used t o t h e s o l v e n t , L e w i s a c i d , and s u p p o r t .

Best r e s u l t s

were o b t a i n e d f o r prolonged r e a c t i o n between bulky k e t o n e s and a l a r g e e x c e s s o f t h e a m i n e w i t h T i C 1 4 i n t h e p r e s e n c e of n e u t r a l o r a c i d i c alumina i n r e f l u x i n g hexane.

Y i e l d s were c o n s i s t e n t l y

higher i n t h e presence of t h e s u p p o r t , but evidence t o support t h e o c c u r r e n c e o f s i m u l t a n e o u s r e a c t i o n s on t h e s u p p o r t and i n s o l u t i o n

is presented. A h i g h l y e n a n t i o s e l e c t i v e i s o m e r i z a t i o n of p r o c h i r a l t e r t i a r y a l l y l a m i n e s c a t a l y s e d by c h i r a l d i p h o s p h i n e - r h o d i u m ( 1 ) h a s b e e n p u b l i s h e d . 135

complexes

Secondary a l l y l i c amines rearranged t o

imines under t h e r e a c t i o n c o n d i t i o n s .

A number of c a t a l y s t s ,

i n c l u d i n g a c h i r a l o n e s , were e x a m i n e d i n o r d e r t o d e t e r m i n e t h e e f f e c t o f t h e p h o s p h i n e l i g a n d s on t h e c o u r s e o f t h e r e a c t i o n . I t h a s a l s o been f o u n d t h a t s i m p l e e n a m i n e s c a n be g e n e r a t e d s i t u by o x i d a t i o n o f t r i a l k y l a m i n e s by i o d i n e . 1 3 6 i n t e r c e p t e d by c a t i o n s ;

in

T h e s e c o u l d be

t h e p r e s e n c e of a second e q u i v a l e n t ( o r

a n e x c e s s ) of I 2 t h e p r o d u c t s s o f o r m e d w e r e t r a n s f o r m e d i n t o iminium d y e s which c o u l d t h e n be h y d r o l y s e d back t o c a r b o n y l compounds.

A m e c h a n i s m was p r o p o s e d t o r a t i o n a l i z e t h e g e n e r a t i o n

of t h e e n a m i n e s (Scheme 2 7 ) . The s y n t h e s i s o f I - a c y l a t e d

and I - c a r b o x y l a t e d

enamine

d e r i v a t i v e s h a s c o n t i n u e d t o r e c e i v e much a t t e n t i o n . R e p r e s e n t a t i v e e x a m p l e s i n c l u d e t h e s y n t h e s i s o f a-amino-a,Bu n s a t u r a t e d k e t o n e s from c h l o r o m e t h y l k e t o n e s d e r i v e d from p r o t e c t e d a m i n o - a c i d ~ l a~n ~ d t h e p r e p a r a t i o n o f 2-acylamino-2a l k e n o i c a c i d s f r o m m i x e d a n h y d r i d e s o f e i t h e r g - a c e t y l - o r Eb e n z o y l - g l y c i n e . l 38 The l a t t e r p r e p a r a t i o n i n v o l v e d c y c l i z a t i o n of t h e m i x e d a n h y d r i d e s t o 5-oxo-4,5-dihydro-l,3-oxazoles f o l l o w e d by condensation of t h e heterocycles with ketones or ketimines. H y d r o l y s i s o f t h e u n s a t u r a t e d a z l a c t o n e s t h u s formed a f f o r d e d t h e d e s i r e d compounds. A n o v e l d e s i l y l a t i o n - r i n g f r a g m e n t a t i o n o f 1(trimethylsilylmethy1)aziridines c o n t a i n i n g a t l e a s t o n e a n i o n s t a b i l i z i n g c e n t r e , l e a d i n g t o t h e f o r m a t i o n of a-acylaminoe n a m i n e s , u s i n g CsF i n H20-HMPA h a s b e e n r e p o r t e d . 13’ The r e a c t i o n was f a c i l i t a t e d by c o n v e r s i o n o f a n o n - s t a b i l i z e d i n t o a s t a b i l i z e d a n i o n a n d t h e c o u r s e of t h e r e a c t i o n was d e p e n d e n t b o t h o n t h e number o f a n i o n - s t a b i l i z i n g g r o u p s a n d on t h e n a t u r e of t h e

3 13

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups quenching reagents. I n c o n t r a s t t o t h e n o r m a l mode o f a d d i t i o n o f n u c l e o p h i l e s ,

k.

a t t a c k a t t h e carbonyl centre with displacement of cyanide anion, t o b e n z o y l cyanide,bis(pentanedionato)nickel

was f o u n d t o d i r e c t

a t t a c k o f t h e C-2 c e n t r e o f 8 - d i c a r b o n y l c o m p o u n d s t o t h e c y a n o moiety.

S i m i l a r l y , t h e c o r r e s p o n d i n g z i n c (11) c o m p l e x

[Zn(acac),]

c a t a l y s e d a d d i t i o n o f C-2 i n v a r i o u s 8 - d i c a r b o n y l 141 systems t o cyanogen. D e s u l p h u r i z a t i o n o f 5 - a l k y l - q u a t e r n a r y c y a n i d e s h a s a f f o r d e d new s y n t h e s e s of l-cyanoenamines

i n moderate yields. 142

The method

i n v o l v e s s i m p l e t r e a t m e n t w i t h a n e x c e s s of m e t h y l i o d i d e f o l l o w e d (Scheme 2 8 ) .

by b a s i c work-up

Rhenium h e p t a s u l p h i d e h a s b e e n f o u n d t o c a t a l y s e c o n v e r s i o n s o f a-azidocarboxylic a c i d esters t o N-acetyl- and N,g-diacetyl-a,@-

e s t e r s via N 2 e l i m i n a t i o n . didehydro-a-amino-acid Good y i e l d s were a c h i e v e d t h r o u g h o u t a n d a d d i t i o n o f water b e f o r e w o r k - u p allowed e x c l u s i v e i s o l a t i o n of t h e monoacylated p r o d u c t s . R e d u c t i v e s i l y l a t i o n of a - s i l o x y - n i t r i l e s w i t h c h l o r o t r i m e t h y l s i l a n e a n d l i t h i u m i n THF a t 0 O C h a s b e e n e x a m i n e d a s a p o t e n t i a l r o u t e t o 1 N N-tris(trimethylsily1)enamines ( e n a m i n e s o f a c y l s i l a n e s )'-'" . Although t h e t r a n s f o r m a t i o n could be a c h i e v e d , y i e l d s w e r e p o o r owing t o a c o m p e t i n g r e a c t i o n l e a d i n g t o a-siloxysilane formation. D e p r o t o n a t i o n o f l - p h o s p h o r y l e n a m i n e s f o l l o w e d by s i l y l a t i o n o r a l k y l a t i o n h a s been found t o y i e l d homologous ( g ) - l phosphorylenamines capable of f u r t h e r h y d r o l y s i s t o C-3-alkylated carboxylic acids. always occurred

D e p r o t o n a t i o n s of compounds o f t h e t y p e ( 2 1 )

cis t o

t h e phosphoryl moiety with t h e r e s u l t a n t

a n i o n i s o m e r i z i n g r a p i d l y a b o u t t h e C-1-C-2

bond.

These h i g h l y

r e g i o - and s t e r e o - s e l e c t i v e d e p r o t o n a t i o n s a l l o w e d i n t r o d u c t i o n o f up t o t h r e e d i f f e r e n t a l k y l groups i n t o t h e molecule. M e t a l l a t e d y n a m i n e s were shown t o r e a c t n o r m a l l y w i t h m e t h y l e n e m a l o n o n i t r i l e and similar s y s t e m s t o g i v e 2-metallo-3aminobuta-1,3-diene (Scheme 29 )

.

2-Acylated

derivatives (metallated l-vinylenamines)

46 enamines t o o have been important s y n t h e t i c

i n t e r m e d i a t e s and a o n e - s t e p a l t e r n a t i v e t o a p r e v i o u s l y d e s c r i b e d improved two-step reported.

Blaise r e a c t i o n

( s e e Volume 8 , p . 2 6 6 ) h a s b e e n

The m e t h o d i n v o l v e s t r e a t m e n t o f e p o x i d e s d e r i v e d

f r o m (E)-ethylhex-3-enedioate c h l o r i d e i n aqueous e t h a n o l .

w i t h s o d i u m a z i d e a n d ammonium The r e s u l t a n t c y c l i c ( & ) - e n a m i n o -


314

Et,N

+

+ I,

Et,NI

=

+

NEt3

NEt3

MeCH=NEt2 =CHFCHNEt2

1-

1-

Scheme 27

'

CN PhCH2-

CN

=*

C -N -0

PhCH=LNAo

U

1 -

SMe Scheme 2 8

M R3,

I

Ill I N R1/

R4

+

R5

Ill I

Ac c"Acc'

N

Rl/ \ R 2

\ 2

R

MeCN( 0

OC

3. _9

Acc'

N ' R'

Scheme

29

'

Acc' Acc'


315

e s t e r c a n b e i s o l a t e d p u r e i n 67% y i e l d by f r a c t i o n a l c r y s t a l l i z a t i o n f r o m t h e ( Z ) - i s o m e r and t h e n s u b s e q u e n t l y a l k y l a t e d on n i t r o g e n .

4-Dialkylaminobut-3-en-2-ones a r e r e c o g n i z e d a s i m p o r t a n t i n t e r m e d i a t e s i n h e t e r o c y c l i c s y n t h e s e s , and a f a c i l e , highy i e l d i n g p r e p a r a t i o n of t h e s e d e r i v a t i v e s by t r e a t m e n t o f 4,4dimethoxybutan-2-one p u b l i s h e d . 14'

with secondary amines i n methanol h a s been

A s an a l t e r n a t i v e , a d d i t i o n s of secondary (and

p r i m a r y ) a m i n e s t o B-alkoxy- a, B - e t h y l e n e - k e t o n e s A more i n t e r e s t i n g v a r i a n t ,

were d e s c r i b e d . 14'

h o w e v e r , i s t h e c o n v e r s i o n o f B-amino-

k e t o n e s t o t h e d e s i r e d enaminones u s i n g b i s ( a c e t o n i t r i 1 e ) d i c h l o r o p a l l a d i u m ( I 1 ) and t r i e t h y l a m i n e (Scheme 3 0 ) . I 5 O

This

p r o c e d u r e i s a t t r a c t i v e s i n c e t h e s t a r t i n g materials a r e e a s i l y a v a i l a b l e f r o m b o t h c a r b o n y l c o m p o u n d s by M a n n i c h r e a c t i o n s a n d t h e i r a,B-unsaturated

c o u n t e r p a r t s by M i c h a e l a d d i t i o n s .

However,

one d i s a d v a n t a g e i s t h a t t h e u s e of a s t o i c h e i o m e t r i c amount o f t h e complex i s r e q u i r e d . It h a s been d i s c o v e r e d t h a t n i t r i l i u m i o n s r e a c t w i t h enamines t o a f f o r d m i x t u r e s o f enamino-ketones and enaminimines i n good S i n c e t h e l a t t e r compounds a r e h y d r o l y s e d t o t h e f o r m e r

yield.15'

i n d i l u t e a c i d t h e p r o c e d u r e may w e l l f i n . d f u r t h e r a p p l i c a t i o n s . y-Amino-enamines

were a l i t t l e known c l a s s o f f u n c t i o n a l i z e d

e n a m i n e s u n t i l a r e c e n t d e s c r i p t i o n o f a f a c i l e s y n t h e s i s of t h e s e c o m p o u n d s by a d d i t i o n o f a t w o - f o l d e x c e s s o f trimethylsilyldialkylamines t o a - u n s u b s t i t u t e d t e m p e r a t u r e . 152 slowly.

In contrast a-substituted

a l d e h y d e s a t room

aldehydes reacted very

However, e l e v a t i o n o f r e a c t i o n t e m p e r a t u r e and a d d i t i o n of

c a t a l y t i c amounts of toluene-p-sulphonic y i e l d s i n r e a s o n a b l e r e a c t i o n times.

a c i d l e d t o improved

A f u r t h e r s t u d y showed t h a t

u s e o f o n l y o n e e q u i v a l e n t o f t h e s i l y l a t e d a m i n e s a f f o r d e d Ba m i n o t r i m e t h y l s i l y l e n o l e t h e r s , s i l y l e t h e r s o f B-aminok e t o n e s . 153

Aminomethylations of e n a m i n o - e s t e r s have a l s o been r e c o r d e d , t h e s e o c c u r r i n g a t t h e 2 - p o s i t i o n of primary and

s e c o n d a r y a m i n e - d e r i v e d 3 - a m i n o b u t - 2 - e n o a t e s . 15' 3-N,Ndialkylaminobut-2-enoates d i d n o t r e a c t a n a l o g o u s l y w i t h a l d e h y d e s a n d a m i n e s b u t were a m i n o m e t h y l a t e d a t C-4 w i t h N,Ndimethylmethyleneiminium c h l o r i d e i n a n h y d r o u s a c e t o n i t r i l e . In a r e l a t e d s t u d y , a l l t h r e e t y p e s o f 3-aminobut-2-enenitriles were f o u n d t o u n d e r g o a m i n o m e t h y l a t i o n a t C-2 u n d e r t h e s t a n d a r d c o n d i t i o n s . 155 (Dimethy1amino)allene h a s been s u c c e s s f u l l y r e a c t e d w i t h

316


CI

R1

i-

[PdHCIL2]

'

L

L '

N

R

2

,

S c h e m e 30

CI

-

PO(OEt l2

ii

*

c

o

w

I iii

+ R'

I V

,v

PO(OEt),

R2N

R = M e or CH,Ph


317

aliphatic secondary amines, and the initial adducts rearranged with water or ammonium chloride or acidic alumina to give 3aminoenamines. 56 3-Alkoxy- and 3-Alkylthio-enamines were similarly obtained. 2-Alkylthio- and 2-alkoxy-enamines were synthesized from propargyl thioethers and ethers respectively following aminomercuration-demercuration sequences. 57 A previously reported preparation of enamino-sulphones had been restricted to the synthesis of N-unsubstituted examples. However, it was subsequently demonstrated that transaminations were possible, 158 and the conditions also applied to the synthesis of Ealkyl- and N-aryl-enamino-nitriles from 3-amino-2-ethylenenitrile derivatives. 2-Alkyl-3-aminoprop-2-enenitriles were prepared by a two-stage hydrogenolysis of 1,l-dicyanocyclopropanes which underwent the expected C-I-C-3 bond fission. 159 2-Alkylbenzothiazoles have been shown to undergo Claisen-type self-condensations to yield 2-(2-benzothiazolyl)enamines, on treatment with Grignard reagents. 160 0-(Enamino)-a,B-ethylene aldehydes have been obtained from gasphase pyrolyses of 5-(aminomethylene)-l,3-dioxane-4,6-diones. 161 Recent advances in the chemistry of conjugated enamines have been reviewed, 162 and two notable methods for their synthesis have appeared. The first reported details of 5-E,g-dialkylaminopental,+diene preparations in Wittig-like reactions utilizing l-amino4-phosphonobut-2-enes (as potassium rather than lithium salts) and aldehydes. 163 The organophosphorus reagents were prepared from 1,3-dienes by a three-step sequence involving palladium(I1) acetate-catalysed chloroacetoxylation, Arbuzov reaction, and tetrakis(tripheny1phosphine)palladium-catalysed allylic amination of the resultant l-acetoxy-~-phosphonobut-2-ene (Scheme 31). The second method was concerned with the synthesis of conjugated enamino-ketones 2 reaction of aralkyl ketone enolates with 1,5diazapentadienium (vinamidinium) salts, and in particular (22) (Scheme 32). 16' Ene-1,2-diamines have been produced on reaction of 1,2-di-imines with alkyl-lithiums, Grignard reagents, and trialkylaluminiums. 165 The use of higher reaction temperatures and non-polar solvents was found to favour formation of 2-alkylated products.

318


I

I

Me

Me

i or

ii

n = 1 , 2 or 3 Reagents: i , NaH, N E t 3 ; ii, L D A , NEt3

Scheme 32

H\ R1/

c=c

/

R2 /Me CH2- N \ CHO

0 Reagents

I , E t 2 0 , -50 t o - 2 5

OC

;

[ I ,

HCONMe( CHIC\)

Scheme 33

;III,

N-chloromethylphthalimlde

3 19

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 3 A l l y l a m i n e s , Homoallylamines, and Alkynylamines Organocopper r e a g e n t s have proven h i g h l y v a l u a b l e i n t h e p r e p a r a t i o n of a l l y l i c amines, p a r t i c u l a r l y t e r t i a r y a l l y l a m i n e s . C a r b o c u p r a t i o n of a l k y n e s t o a f f o r d a l k e n y l - c u p r a t e

and -copper

r e a g e n t s is a f r e q u e n t l y u t i l i z e d s y n t h e t i c o p e r a t i o n ; however, r e a c t i o n s of t h e s e n u c l e o p h i l i c s p e c i e s w i t h 1 - c h l o r o m e t h y l - 1 methylformamide and E - c h l o r o p h t h a l i m i d e

were u n r e c o r d e d .

These

r e a c t i o n s have r e c e n t l y been d e s c r i b e d , r e s u l t i n g i n good y i e l d s o f p r o t e c t e d primary and secondary a l l y l a m i n e s .

S i n c e t h e free amines

may b e l i b e r a t e d e a s i l y by s t a n d a r d d e p r o t e c t i o n t e c h n i q u e s a u s e f u l s y n t h e t i c p r o c e d u r e h a s e m e r g e d ( S c h e m e 3 3 ) . 1 6 6 The same a u t h o r s d i s c o v e r e d t h a t ( L ) - a l k e n y l c u p r a t e s and (El-alkenylaluminium r e a g e n t s added t o b o t h a m i n o - e t h e r s and a m i n o t h i o - e t h e r s t o yield

(L)-

or ( E l - t e r t i a r y a l l y l a m i n e s r e s p e c t i v e l y ;

these

p r e p a r a t i o n s gave good y i e l d s of amines w i t h 99.5-99.9% stereoisomeric purity. Organoselenium chemistry h a s f e a t u r e d prominently i n strategies f o r r e g i o - and s t e r e o - c o n t r o l l e d

f o r m a t i o n o f C-N

bonds, and h a s

t h u s found a p p l i c a t i o n s i n t h e f i e l d of a l l y l a m i n e s y n t h e s i s .

The

discovery t h a t anhydrous chloramine-T i n methanol e f f i c i e n t l y c o n v e r t s a l l y l i c phenyl s e l e n i d e s i n t o 1-allyl-toluene-

p - s u l p h o n a m i d e s h a s l e d t o t h e p r e p a r a t i o n o f a number o f allylamines.

The r e a c t i o n was a s s u m e d t o o c c u r

via

[2,3]-

sigmatropic rearrangement of an a l l y l i c selenimide i n t e r m e d i a t e , t h i s being c o n s i s t e n t w i t h t h e observed predominance of (L)-trisubstituted

(El-

over

a l l y l a m i n e s i n t h e cases s t u d i e d (Scheme 3 4 ) .

Use o f t h e a n h y d r o u s r e a g e n t i s e s s e n t i a l f o r t h e s u c c e s s o f t h e ' p r o c e s s and t h u s t h e h a z a r d s a s s o c i a t e d w i t h h a n d l i n g t h e r e a g e n t a n d a l s o t h e l i m i t e d number o f m i l d s u l p h o n a m i d e d e p r o t e c t i o n Subsequent s t u d i e s methods a v a i l a b l e l e f t s c o p e f o r improvement. d e m o n s t r a t e d t h a t t - b u t y l - a n d benzyl-N-chloro-1-sodiocarbamates c o u l d b e u s e d t o p r e p a r e t h e m o r e v e r s a t i l e t-Bocp r o t e c t e d a l l y l a m i n e s . 16'

a n d Cbz-

However, t h i s m o d i f i c a t i o n s u f f e r s i n

t h a t t h e r e a g e n t s are p o t e n t i a l l y u n s t a b l e .

Thus a f u r t h e r

r e f i n e m e n t was m a d e , a n d t h e p a r e n t c a r b a m a t e s , H u n i g ' s b a s e p l u s

N-chlorosuccinimide,

were a d d e d t o a m e t h a n o l i c s o l u t i o n o f t h e

appropriate selenide i n order to achieve the desired transformation (Scheme 3 4 ) . I 7 O The a b i l i t y of p a l l a d i u m c o m p l e x e s t o f u n c t i o n a l i z e a l l y l i c s u b s t r a t e s , i n c l u d i n g a l l y 1 nitro-compounds, is well recognized.


320

+

[PhSeZ]

R

P = B o c or Cbz Reagents : i, anhydrous chloramine T (TsNClNa) ; ii, ButOCONCI-Na’;

iii, Bu~OCONHZ(2.5 equiv. )

P r ‘ NEt2, NCS

Scheme 3 4

ON 2 -

R

1

R

^-1 b

type c

RZN

‘

R= R’=R‘+H

Scheme 3 5

H

32 1

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups However, a l l y l i c n i t r o - d e r i v a t i v e s a r e s y n t h e t i c a l l y r a t h e r elusive. T h i s a p p a r e n t i n c o m p a t i b i l i t y , however, h a s been circumvented with t h e observation t h a t a d d i t i o n o f amines t o t h e

more r e a d i l y a v a i l a b l e n i t r o a l k e n e s i n t h e p r e s e n c e o f z e r o - v a l e n t palladium l e a d s t o t h e i s o l a t i o n of ( E ) - a l l y l i c amines r a t h e r t h a n t h e expected Michael adducts.

The f a c t s t h a t r e a c t i o n r a t e s showed

marked s o l v e n t d e p e n d e n c y and t h a t c e r t a i n a l l y l a m i n e s c o u l d b e d e r i v e d from more t h a n o n e r e g i o i s o m e r i c n i t r o a l k e n e s u g g e s t e d t h a t t h e n i t r o a l k e n e s were i s o m e r i z e d t o t h e a l l y l i s o m e r s by t h e a m i n e s b e f o r e a d d i t i o n , t h i s b e i n g f a v o u r e d by p o l a r s o l v e n t s . f o r m a t i o n o f common n - a l l y l - p a l l a d i u m

Thus t h e

intermediates before

n u c l e o p h i l i c a t t a c k by t h e a m i n e was u s e d t o e x p l a i n t h e o b s e r v e d r e g i o - and s t e r e o - s e l e c t i v e s u b s t i t u t i o n s . r e a c t i v i t y were i d e n t i f i e d ( S c h e m e 3 5 ) . 1 7 1 The s y n t h e s i s o f 2 - p h e n y l by p a l l a d i u m - p h o s p h i n e

T h r e e d i s t i n c t modes o f

or 2-alkenyl-substituted

complex-catalysed

allylamines

f u n c t i o n a l i z a t i o n of 1 , 2 -

d i e n e s h a s a l s o b e e n r e p o r t e d (Scheme 3 6 ) . 1 7 2 A z i r i d i n e f r a g m e n t a t i o n s a f f o r d i n g enamines have been d i s c u s s e d a b o v e . 39

D e t a i l s o f N-ethoxycarbonylaziridine t h e r m o l y s e s

y i e l d i n g a l l y l carbamates have a l s o appeared, 173 w i t h primary a l l y l a m i n e s o b t a i n e d f r o m t h e l a t t e r compounds f o l l o w i n g s t a n d a r d deprotections. One e x a m p l e of a n e n z y m i c c o n v e r s i o n o f a n a l l y l i c a m i n o - a c i d i n t o a n a l l y l a m i n e h a s a p p e a r e d . 17'

The t r a n s f o r m a t i o n of ( 2 4 )

i n t o ( 2 5 ) was e f f e c t e d by a r o m a t i c L - a m i n o - a c i d ( 2 4 ) p r e p a r e d from ( 2 3 )

via

decarboxylase with

a s t r a i g h t f o r w a r d d i s p l a c e m e n t (Scheme

37). The a d d i t i o n o f o r g a n o m e t a l l i c n u c l e o p h i l e s t o i m i n e s h a s b e e n a l l u d e d t o i n S e c t i o n 1, S e c o n d a r y Amines. i s o l a t e d a f t e r a d d i t i o n s of allyl-9-BBN

H o m o a l l y l a m i n e s c a n be

t o imines.

Very h i g h 1 , 2 -

a s y m m e t r i c i n d u c t i o n was o b s e r v e d i n some c a s e s a n d a s t e r e o e l e c t r o n i c e f f e c t was i n v o k e d t o e x p l a i n t h e e n h a n c e m e n t o f C r a m s e l e c t i v i t y ( S c h e m e 3 8 ) .82 , 8 3 A l l e n i c o r g a n o s i l a n e r e a g e n t s were f o u n d t o add t o i m i n e s w i t h t h r e o - s e l e c t i v i t y (Scheme 3 8 ) . 8 2 The p r o d u c t s i l y l a t e d h o m o a l k y n y l a m i n e s were e l a b o r a t e d i n t o h o m o a l l y l a m i n e s by d e s i l y l a t i o n a n d r e d u c t i o n .

N-Diallylalkyl-2-aminophenols

were o b t a i n e d u p o n t r e a t m e n t o f

b e n z o x a z o l e s w i t h a l l y l i c G r i g n a r d r e a g e n t s . 175 A s i m i l a r r e a c t i o n of benzothiazoles t o y i e l d disulphide-bridged bis(dihomoally1amine) d e r i v a t i v e s was a l s o r e p o r t e d . S y n t h e s i s o f a l l e n i c a m i n e s h a s become a n i m p o r t a n t a r e a o w i n g


322

R2 R2X

A

[R'PdX]

___) ii

R32NCH2C( R )=CH R'

[A$]

+

j

2i R 32X

H

Pd(OACl2- L n

R32NCH2CR=CHR1 2 R3$ H 2 i R2PdX L n

p-

CH~=C=CHR'

3

2 R,NH

s.

2

*PldXLn

Reagents : i , P d ( O A ~ ) ~ ( 0 . 0 2equiv.),dppe(O.O5equiv.) 5 ; ii ,CH=C=CHd; 2

iii,R3 NH(2 equiv.) 2

S c h e m e 36

Reagents : i

L D A ; ii, NH3 DMSO; i i i , aq. H e r , propylene o x i d e ; i v , h o g

kidney AADC

0.1M- p h o s p h a t e b u f f e r , p y r i d o x a l p h o s p h a t e , HOCH2CH2SH, pH 7.2 I 37 O C

S c h e m e 37

323


erythro

threo

i i.J.iv

I

v

- ++

NHR PhX C O H

+mM

II 0

M= L i , Mg , 8 ,

Ph

P

h bH

OH

-2:l

Si ....

PhA c / H

+

m

B

a

L

P

k

i

i -I-h P

NH

AH

R'

R'

R'

up to

1oo:o

Reagents : i , ButLi (1.1 equiv.); ii,CITi(OPri)g or B(OMe)30r A I E t 3 ; iii, NaOMe,MeOH;iv,H2,

PdlBaSOq;v, PhCH20COCI,Na2C03; v i , T H F , -78OC,N2

c""'-yz

Scheme 3 8 +]sR14N,R2

RCECH RCEC-BF3Li

H

Ill

I

R R e a g e n t s : i , 6unLi (1 e q u i v . ) , THF, - 7 8 i i i , R'CHZCH=NR2, - 7 8

OC,

OC,

3 0 min

, Ar

; ii, BF3.0Et2, Et20,10 min,

l h t h e n r . t . , l h ; 1 0 ° / ~a q . NaOH

S c h e m e 39

i

324


t o t h e p o t e n t i a l o f t h e s e compounds t o i n h i b i t p y r i d o x a l p h o s p h a t e d e p e n d e n t enzymes i r r e v e r s i b l y . attention.

T h u s t h e s u b j e c t h a s r e c e i v e d much

It h a s been found t h a t a l l e n y l a m i n e s c a n be s y n t h e s i z e d

f r o m a - e t h y n y l a m i n e s . 177 T h e l a t t e r c o m p o u n d s were t r e a t e d w i t h di-isopropylamine-formaldehyde p l u s c u p r o u s b r o m i d e i n d i o x a n e t o y i e l d t h e d e s i r e d compounds. N-t-Butoxycarbonyl esters of t h e corresponding a-allenyl-a-amino-acids

c o u l d a l s o be p r e p a r e d i n

t h i s w a y , b u t t h e a l l e n y l m o i e t y was f o u n d t o b e i n c o m p a t i b l e w i t h the deprotection conditions required.

An a l t e r n a t i v e p r o c e d u r e

esters o f a m i n o - a c i d s a f f o r d e d b e n z a m i d e s w h i c h were m o r e e a s i l y deprotected t o g i v e t h e desired a-allenyl amino-acids. Racemic b a s e d on t h e C l a i s e n r e a r r a n g e m e n t of N - b e n z o y l p r o p a r g y l i c

a l l e n y l d e r i v a t i v e s o f GABA, p u t r e s c i n e , and p h e n y l a l a n i n e t h u s f o r m e d were f o u n d t o b e i r r e v e r s i b l e t i m e - d e p e n d e n t

inhibitors of

m a m m a l i a n 4-aminobutyrate-2-oxoglutarate a m i n o t r a n s f e r a s e (GABA-TI, b a c t e r i a l o r n i t h i n e d e c a r b o x y l a s e , and b a c t e r i a l L-aromatic-aamino-acid

decarboxylase respectively.

Two s y n t h e s e s of a - a l l e n i c - G A B A , r e a r r a n g e m e n t , 17'

the other

via

one i n v o l v i n g a n o v e l aza-Cope

h y d r o l y s i s of 5 - a l l e n y l - 2 -

p y r r o l i d i n o n e p r e p a r e d by r e a c t i o n o f propargyltrimethylsilane w i t h

a y-ethoxylactam

i n t h e p r e s e n c e of a L e w i s a c i d (BF3.0Et,),

179

have a l s o appeared. A l k y n y l a m i n e s h a v e r e s u l t e d n o t o n l y f r o m t h e r e a c t i o n of a l l e n y l s i l a n e s with imines above, but a l s o from t h e a d d i t i o n of alkynyl-boranes

( a n d -berates) t o a l d i m i n e s c o n t a i n i n g a - h y d r o g e n s

( S c h e m e 39 1. 85

A s i m p l e p r o c e d u r e f o r t h e p r e p a r a t i o n o f l i t h i u m IJ,gbis(trimethylsilylaminornethy1)acetylide a n d t h e r e a c t i o n s o f t h i s compound w i t h v a r i o u s e l e c t r o p h i l e s h a v e b e e n described. I 8 O S i m i l a r l y , n o v e l s u b s t i t u t i o n s of s t a n n y l a t e d ynamines have been reported.

T h e r e a c t i o n s o f e i t h e r (3,4,4-trichlorobut-3-en-I-

y n y 1 ) a m i n e s o r (pentachlorobuta-l,3-dienyl)amines w i t h t w o or t h r e e e q u i v a l e n t s of n-butyl-lithium

t o a f f o r d l i t h i u m 4-aminobuta-1,3-

d i y n i d e s and t h e i r s u b s e q u e n t a d d i t i o n s t o e l e c t r o p h i l e s have been r e p o r t e d as a s y n t h e s i s of alka-I , 3 - d i y n y l ) a m i n e s . 4 Amino-alcohols The i m p o r t a n c e o f a m i n o d e o x y - s u g a r s

and h y d r o x y l a t e d amino-acids i n

n a t u r a l p r o d u c t c h e m i s t r y h a s e n s u r e d t h a t t h e s y n t h e s i s of c o m p o u n d s w i t h a m i n o - a l c o h o l f u n c t i o n a l i t y h a s r e m a i n e d a n a r e a of

325

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups competitive research.

S y n t h e t i c s t r a t e g i e s l e a d i n g t o amino-

a l c o h o l formation can be broadly c l a s s i f i e d i n t o t h o s e i n v o l v i n g SN2-like displacements

e.g. r e a c t i o n s

o f amino- o r a z i d e -

nucleophiles with sulphonates, halides, or epoxides, those i n v o l v i n g r e d u c t i v e m e t h o d s , and t h o s e i n v o l v i n g f r a g m e n t a t i o n o f N,O-heterocycles

w h i c h may b e f o r m e d a f t e r c y c l o a d d i t i o n s o r by

f u n c t i o n a l i z a t i o n o f b o t h a c y c l i c and c y c l i c a l l y 1 a l c o h o l s o r allylamines.

Trifluoromethanesulphonates h a v e p r o v e n p a r t i c u l a r l y u s e f u l i n t h e s y n t h e s i s of a m i n o d e o x y - s u g a r s s i n c e t h e y u n d e r g o s m o o t h S N 2 d i s p l a c e m e n t w i t h ammonia183 a n d a z i d e a n i o n . 1 8 4 R e d u c t i o n s o f a z i d e s f o r m e d i n t h i s way h a v e b e e n u t i l i z e d i n s y n t h e s e s of

u-

m a n n o s i d a s e i n h i b i t o r s t y p i f i e d by 1,4-dideoxy-I,4-imino-D-mannitol ( 2 6 ) 185 a n d 1,5-dideoxy-l,5-imino-D-mannitol ( 2 7 ) . 186 S y n t h e s e s o f D-ossamine

(28) and D-tolyposamine

( 2 9 ) were l i k e w i s e f a c i l i t a t e d

by r e d u c t i o n s of a z i d e s w h i c h were i n t r o d u c e d by d i s p l a c e m e n t s o f a n a l l y l i c s u l p h o n a t e and an a l l y l i c i o d i d e r e s p e c t i v e l y . 187 S i m i l a r l y , a d i s p l a c e m e n t of a s e c o n d a r y m e s y l a t e by a n a z i d e , a n d i t s s u b s e q u e n t r e d u c t i o n , formed key s t e p s i n a s y n t h e s i s of 188 swainsonine (30). A s t r a t e g y d i r e c t e d t o w a r d s t h e t o t a l s y n t h e s i s of (+Ic a s t a n o s p e r m i n e ( 3 1 ) a n d ( + ) - d e o x y n o j o r i m y c i n ( 3 2 ) was b a s e d on t h e 89 The a m i n o f u n c t i o n was

c y c l i z a t i o n of an amino-epoxide. introduced

via

t h e formation of a glycosylamine from a r e d u c i n g

s u g a r a n d b e n z y l a m i n e f o l l o w e d by r e d u c t i o n ( S c h e m e 40). Allylamino-,

anilino-,

a n d morpholino-glycosylamines h a v e b e e n

p r e p a r e d from g l y c o s y l f l u o r i d e s and t h e a p p r o p r i a t e amines under t h e i n f l u e n c e of a Lewis a c i d . ” ’

The a m i n e c o u l d a l s o b e r e p l a c e d

by a z i d e t o g i v e a p r e p a r a t i o n o f t h e c o r r e s p o n d i n g g l y c o s y l azides. R e d u c t i o n s of a m i n o c a r b o n y l c o m p o u n d s a n d t h e i r d e r i v a t i v e s h a v e c o n t i n u e d t o be o f i m p o r t a n c e i n a m i n o - a l c o h o l

syntheses.

E n a n t i o m e r s o f e t i l e f r i n e were p r o d u c e d by e n a n t i o s e l e c t i v e h y d r o g e n a t i o n s of an a-amino-ketone. u-Amino-ketones were a l s o demonstrated t o undergo d i a s t e r e o c o n t r o l l e d

reductions with

hydrosilanes, with excellent selectivities for erythro-like products observed.lg2

I t was f o u n d t h a t r e d u c t i o n o f s y n - 0 -

hydroxy-ketone-g-benzyloximes w i t h l i t h i u m a l u m i n i u m h y d r i d e p r o c e e d e d w i t h h i g h s e l e c t i v i t y for ~ - 1 , 3 - a m i n o - a l c o h o l s w h i l s t o n l y m o d e r a t e s t e r e o s e l e c t i o n was o b s e r v e d i n r e d u c t i o n s o f t h e anti-oxime isomers.

C o n d i t i o n s were modified i n o r d e r t o


326

R =COCF3 or H

&/

R

CH,OH

&*oY OR

R=BnZlx R=H

+Hoe

Of3n

?H

R = CH(OH)CH,CO R = CO,H

H0 ' .

R: CHO

xiii

xi

R = CH(OH)CH~CO~B"~

"1

OH

OH

xvc H H0 '

O

~

H0 ' .

0

Reagents :

I,

BnNH2(10 e q u i v 1 ;

11,

LIALH~ ;

III

(CF3CO),O;

IV,

v , M s C I , p y , v i , Bun4NF; v 1 1 , N a O M e ; v i i i , N a B H 4 , H2

I

Pd I C ; X I , D M S O , o x a l y l c h l o r i d e , N E t 3 ; X I I ,

ix,chromatography,x, C H T C ( O L I ) O B U ~; XIII,

c h r o m a t o g r a p h y a n d h y d r o g e n o l y s i s (XI; xiv,TFA

Scheme 40

TBDMSCI, r m i d a z o l e ,

HZO,60 OCJ3h;xv,Dlbal-H

H


327

circumvent t h e need t o s e p a r a t e t h e oximes b e f o r e t h e i r r e d u c t i o n , a n d i t was f o u n d t h a t i n t h e p r e s e n c e o f s o d i u m m e t h o x i d e a n t i o x i r n e s were r e d u c e d t o syn-1 , 3 - a m i n o - a l c o h o l s a t -78 O C ( a s o p p o s e d t o 0 OC i n r e a c t i o n s w i t h l i t h i u m a l u m i n i u m h y d r i d e a l o n e ) w i t h 95.5% s e l e c t i v i t y , 2 a n a s s u m e d s i x - m e m b e r e d t r a n s i t i o n s t a t e i n w h i c h t h e s o d i u m c a t i o n was c h e l a t e d . l g 4 S i n c e t h e s y n - o x i m e s c o u l d n o t c h e l a t e Na+ n o r a t e e n h a n c e m e n t was o b s e r v e d a n d r e d u c t i o n s o c c u r r e d ( w i t h 95.5% s e l e c t i v i t y ) a t 0 OC e i t h e r i n t h e p r e s e n c e o r a b s e n c e o f sodium m e t h o x i d e (Scheme 4 1 ) . S t e r e o s e l e c t i v e c a t a l y t i c h y d r o g e n a t i o n s of a - h y d r o x y - k e t o x i m e s w i t h Pd/C w e r e o b s e r v e d t o g i v e e r y t h r o - l i k e a m i n o - a l c o h o l s i n a p p r o x i m a t e l y 80% d i a s t e r e o m e r i c e x c e s s i r r e s p e c t i v e of w h e t h e r t h e E- o r 2 - o x i m e was r e d u c e d . l g 5 The s y n / a n t i i s o m e r i z a t i o n o f t h e o x i m e s i n t h e p r e s e n c e o f t h e c a t a l y s t was t h e r e f o r e s t u d i e d i n connection with t h e observed s t e r e o s e l e c t i v i t i e s .

N-Protected amino-acid esters have i n t h e p a s t been reduced t o t h e c o r r e s p o n d i n g a m i n o - a l c o h o l s by s o d i u m b o r o h y d r i d e . An improved p r o c e d u r e f o r t h i s t r a n s f o r m a t i o n h a s been p u b l i s h e d which i n v o l v e s s l o w a d d i t i o n o f m e t h a n o l t o t h e r e a c t i o n m i x t u r e . 196 T h i s enabled t h e r e d u c t i o n t o be performed i n t h e p r e s e n c e o f o n l y a small e x c e s s of t h e h y d r i d e t r a n s f e r r e a g e n t . A l t h o u g h r e a c t i o n o f a - a m i n o - c a r b a n i o n s w i t h c a r b o n y l compounds would a p p e a r t o be a f e a s i b l e a p p r o a c h t o a m i n o - a l c o h o l s , i t s u s e h a s b e e n somewhat r e s t r i c t e d i n t h e p a s t . However t h e a l k a l o i d s macromerine ( 3 3 ) and s t o v a i n e ( 3 4 ) have r e c e n t l y been prepared from c a r b o n y l compounds and a - d i m e t h y l a m i n o m e t h y l - l i t h i u m , g e n e r a t e d by t r a n s m e t a l l a t i o n of t h e c o r r e s p o n d i n g t r i - n - b u t y l s t a n n a n e . S t a n n a n e s o f t h i s t y p e were p r e p a r e d by t r e a t m e n t o f ad i a l k y l a r n i n o r n e t h y l e t h e r s w i t h tri-n-butylstannylmagnesium c h l o r i d e i n e t h e r , t h e l a t t e r r e a g e n t s b e i n g p r e p a r e d by t h e a c t i o n o f i s o p r o p y l m a g n e s i u m c h l o r i d e on t r i - n - b u t y l s t a n n a n e , a g a i n i n d i e t h y l ether.

F r a g m e n t a t i o n s o f N , O - h e t e r o c y c l e s h a v e p r o v i d e d many a m i n o a l c o h o l d e r i v a t i v e s , and t h e s y n t h e s i s o f a - a m i n o - a l c o h o l s f r o m i s o x a z o l i n e s c o n s t i t u t e s p a r t of a larger t r e a t i s e of t h e u s e o f isoxazolines as intermediates i n n a t u r a l product syntheses. The u s e of i n t r a m o l e c u l a r n i t r i l e o x i d e c y c l o a d d i t i o n s h a s been a p p l i e d I n t h e case t o t h e s y n t h e s i s o f e r g o t a l k a l o i d s via i s o x a z o l i n e s . of p a l i c l a v i n e (35) t h e o l e f i n a l s o bore an a l l y l i c asymmetric c e n t r e which, disappointingly, gave only marginal d i a s t e r e o f a c i a l s e l e c t i o n i n t h e c y c l i z a t i o n s t e p (Scheme 4 2 ) .

328


\

Y

Li+

+

AlH3 O B n I /

BUn

/OBn Na

BnO

b

+

L i A l H30Me

Reagents :

I ,

LiAIHL

, NaOMe ; i i I

\

N

LiAIH,OMe

aq. N a 2 S 0 4

S c h e m e 41

MeO

!- II Me

0- C

MeO&-!:-CHz-NMe2

(33)

Et

(34)

CH,-

NMe,

5: Am in es, Nitriles, and Other Nitrogen - conta ining Functiona1 Groups

R e a g e n t s : i , HZC=CHNOZ > C 6 H 6 ; i i , P h N C O , c a t . N E t 3

Scheme 4 2

329


330

I s o x a z o l i n e s were a l s o e m p l o y e d i n t h e s y n t h e s i s o f a m i n o s u g a r s , w i t h 2-amin0-2~3-dideoxy-ribo-hexoses b e i n g p r e p a r e d f r o m 200 4-vinyl-l,3-dioxolanes and n i t r o a c e t a l d e h y d e a c e t a l s . AL-Isoxazolines have been proposed a s i n t e r m e d i a t e s i n a n a p p r o a c h t o Lankacidin s y n t h e s i s and a one-pot

C-4-carboxylation-

m e t h y l a t i o n p r o c e d u r e h a s been d e v e l o p e d f o r t h i s p u r p o s e . 201 Reductive fragmentations of i s o x a z o l i d i n e s ,

t o o , have played a

r o l e i n t h e s y n t h e s i s of compounds c o n t a i n i n g a m i n o - a l c o h o l m o i e t i e s , and e x a m p l e s o f s u c h r e a c t i o n s c a n b e f o u n d i n s y n t h e s e s of p t i l o c a u l i n (36Ir2O2 h i r s u t e n e

(38)

( 3 7 ) ( t h e amino f u n c t i o n

o f w h i c h was removed i n a s u b s e q u e n t Cope e l i m i n a t i o n ) , 2 0 3 a n d a204 hydroxy-a-amino-esters b a s e d on a l i c y c l i c s y s t e m s . A somewhat d i f f e r e n t u s e o f o x a z o l i d i n e s was t h e

E-

d e r i v a t i z a t i o n (primary t o secondary amine) o f amino-alcohols d e r i v e d from a - a m i n o - a c i d s . Reactions of t h e amino-alcohols w i t h a l d e h y d e s l e d t o t h e f o r m a t i o n of c h i r a l o x a z o l i d i n e s which were \ t h e n t r e a t e d w i t h benzylmagnesium c h l o r i d e t o a f f o r d h y d r o x y a l k y l a t e d p h e n y l e t h y l a m i n e h y d r o c h l o r i d e s ( s e e Volume 8 , p . 2 5 4 ) . 20 5 D e r i v a t i v e s o f t h e o x a z o l e r i n g system have a l s o been e x t e n s i v e l y used t o provide a c c e s s t o amino-alcohol

derivatives.

The o x a z o l e ( 3 9 ) was t r a n s f o r m e d t o t h e l a c t o n e ( 4 0 ) w h i c h a f t e r The 2-amino-3p r o t e c t i o n and h y d r o g e n a t i o n a f f o r d e d ( 4 1 ) .206

E-

was t h e n e l a b o r a t e d i n t o L - d a u n o s a m i n e ( 4 2 ) a n d d e r i v a t i v e ( 4 3 ) (Scheme 4 3 ) .207 2-0xazoline-4-phosphonates, p r e p a r e d f r o m diethylisocyanomethanephosphonates a n d c a r b o n y l c o m p o u n d s i n t h e p r e s e n c e of c u p r o u s o x i d e , w e r e f o u n d t o be h y d r o l y s e d t o l - a m i n o 2-hydroxyalkanephosphonic a c i d s ( m o l e c u l e s o f p o t e n t i a l b i o l o g i c a l i m p o r t a n c e ) or i n c e r t a i n c a s e s u n d e r m i l d e r c o n d i t i o n s t o d i e t h y l 1 -formylamino-2-hydroxyalkanephosphonates ( S c h e m e 4 4 ) . 2 0 8 hydroxy-lactone

a l s o i n t o a p r o t e c t e d L-vancosamine

H y d r o l y s i s of (411,5E)-4-buta-l,

3 - d i e n y l )-5-methyl-2-phenyl-AL-

o x a z o l i n e , u l t i m a t e l y d e r i v e d from L - t h r e o n i n e , benzoylated amino-alcohol

afforded an

0-

which formed an i n t e r m e d i a t e i n t h e

s y n t h e s i s of a c t i n o b o l i n .209 I o d o c y c l i z a t i o n s of a l l y l i c t r i c h l o r o a c e t a m i d a t e s h a v e b e e n d e v e l o p e d i n t o a v e r s a t i l e s t r a t e g y for t h e s y n t h e s i s o f a m i n o -

*

a l c o h o l d e r i v a t i v e s ( s e e Volume 8 , p . 2 7 0 ) . Cyclizations n i t r o g e n l e a d t o 4-iodoalkyl-2-trichloromethyloxazolines w h i c h may be hydrolysed t o iodoamino-alcohols and t h e n d e i o d o n a t e d . Such m e t h o d o l o g y w i t h t h e c y c l i z a t i o n r e a c t i o n i n i t i a t e d by E-

331


M e - - R O

-ko Me, , e MeOCH,O

HO

O d N

1

2

(431R-Me0, R = H 1 2 R = H , R = Me

ii

NH,.HCI

HO

(41)

NHBoc

(42)

R e a g e n t s : i t 10°/o H C I I M e O H ; i i , ( B o c ) 2 0 , N a H C 0 3 ; i i i , H 2 , R h / A 1 2 0 3 , A c O E t

Scheme 1 3

0

NC

I O,IEt R ~ - C H - P\

+ 0E t

R2

R3'

\c=o

i ,

OEt

ii, iii

HO NH2

I I +R --C-C-PO,Hz 2

13 1 1

R R

R1=Hor Ph

0 HO

HN-CHO

I

I

Ph-CH-CH-P,,

,OEt

11

0

9

OEt

R2 R H

NH-CHO

0

Reagents: i , Cu20,C6Hg, KOBU~

A;

qMe,

ii, H C I , H * O ; ~ ~ ~ ,

H Schtme 44

EtOH; A

;

iv,H20,MeOH,b; v ,

332


i o d o s u c c i n i m i d e , h a s been a p p l i e d t o t h e s y n t h e s i s of methyl-a-l21 0

daunosaminide hydrochloride.

I t was a l s o d e m o n s t r a t e d t h a t t h e n o r m a l mode o f c y c l i z a t i o n o f a l l y l i c and h o m o a l l y l i c 2 - c a r b a m a t e s

( t o give d i o l s following

h y d r o l y s i s o f t h e h e t e r o c y c l e s ) c a n b e r e v e r s e d s i m p l y by u s i n g a n

N-sulphonylcarbamate, although t h e n a t u r e of t h e sulphonyl group d i d not appear t o a l t e r t h e d i a s t e r e o s e l e c t i v i t y

or t h e c h e m i c a l

y i e l d o f t h e c y c l i z a t i o n s . 21 A p r e v i o u s l y e s t a b l i s h e d p r o c e d u r e for t h e s y n t h e s i s o f

( s e e Volume 8 , p . 2 7 0 ) b a s e d on 'allylic-functionalization' m e t h o d s h a s b e e n o p t i m i z e d , a n d

protected aminocyclohexanediols cyclohex-2-en-1-01

converted i n t o f i v e protected derivatives

(44)-

( 4 8 ) o f t h e s e v e n p o s s i b l e 1 ,2 , 3 - a m i n o c y c l o h e x a n e d i o l s . 2 1 I o d o c y c l i z a t i o n s of c a r b o n i m i d a t e s , and t h e i r r e a r r a n g e m e n t s and s u b s e q u e n t c y c l i z a t i o n s of t h e r e s u l t a n t c a r b o n i m i d a t e s , b o t h l e a d i n g t o o x a z o l i d i n o n e f o r m a t i o n , c o n s t i t u t e d t h e two major

s t r a t e g i c o p e r a t i o n s (Scheme 4 5 ) . The l a t t e r s t r a t e g y o u t l i n e d a b o v e i n v o l v e d c y c l i z a t i o n of a d e r i v a t i z e d a l l y l i c amine t o an o x a z o l i d i n e .

Hydroxylations of

h e t e r o c y c l e f o r m a t i o n a n d h y d r o l y s i s a l s o seem t o

allylamines

form a g e n e r a l l y a p p l i c a b l e approach t o s t e r e o c o n t r o l l e d s y n t h e s i s of amino-alcohols.

cis-Hydroxyamino-sugars

have again provided an

a r r a y of a t t r a c t i v e t a r g e t s , and L-garosamine h a s been s y n t h e s i z e d v i a b o t h o x a z o l i n e and o x a z o l i d i n o n e i n t e r m e d i a t e s formed i n iodonium d i c o l l i d i n e p e r c h l o r a t e - i n d u c e d

cyclizations.

The

n i t r o g e n f u n c t i o n a l i t y was d e r i v e d f r o m a s u b s t i t u t i o n o f a n a l l y l i c e p o x i d e by a n a m i n e . * I 3

T h e l a t t e r r o u t e was f o u n d t o b e

more c o n v e n i e n t s i n c e N - m e t h y l a t i o n and r e d u c t i o n s t e p s , r e q u i r e d i n t h e f o r m e r r o u t e , were n o t n e e d e d , a n d t h u s a s y n t h e s i s o f e t h y l 214

h o l o c o s a m i n i d e was a c h i e v e d ( S c h e m e 4 6 ) . a-Acylamino-alcohols

h a v e b e e n made f r o m u n s a t u r a t e d a z l a c t o n e s

upon h y d r o g e n a t i o n . 215 [4+2]-Cycloadditions

have been u t i l i z e d e x t e n s i v e l y t o prepare

h e t e r o c y c l i c i n t e r m e d i a t e s from w h i c h a m i n o - a l c o h o l s obtained.

can be

The s y n t h e s e s o f t h r e o - and e r y t h r o - s p h i n g o s i n e s h a v e

been f u r t h e r described2'

and t h e g - s u l p h i n y l - t y p e

dienophiles

used i n t h e i r s y n t h e s e s have a l s o been employed i n a s y n t h e s i s o f 218 5-epi-desosamine (Scheme 4 7 ) . Acyl nitroso-compounds

have been u t i l i z e d as d i e n o p h i l e s i n

syntheses culminating i n t h e formation of amino-alcohol derivatives.

The s y n t h e s i s o f t a b t o x i n ( 5 0 )

via

(49)was a notable


333

N - Cycli z a t i on

SMe

( 4 4 ) R = H or Ac

liv

111c

o +

I

CH2Ph (46) Reagents :

I,

I

I

CHZPh

CH2Ph

(471

R = H or Ac

PhCHZNCS, N a H , Me1 ; 1 1 , 1 2 ;1 1 1 , Ag0COCF3

L-SeLectrlde;

vi,PhCH2N=C(OMe)CL,

I

MeN02 ;

IV,

PCC, CH2CLZ; v ,

KH; vii ,PhMe,n, v i i i , 0 ~ 0 ~ , N M M N O

Scheme 45

334


1

2

R=R=H 3 R =H

EE

CH(0Et)Me

ix I

\

Me

AEE

OR

v, v i

X - I, R :EE X=H,R=EE l x i X-R=H 4 xii

V

i

OMe

OMe

+ ...

Me

; OH Me

Me

R:H

.. .

Xlll

ko.

MeNX

OEt

'=

Me

ry

rO T s

XVlll

+

Y

l x i v

X = C02Et 4

o . I

xvii Reagents:

I,

X = Y = I

L O MeN P O R 2 / OR' X

OE t

OEt

or EE

x= X =

X=Y=H

NH3 ; i i , PhCOCl , NaHC03 ; iii , EVE ,PPTS ; I V , i o d o n i u m dicollidineperchlorate

(1.Oequiv.); v , Bun3SnH; v i , Me1 , MeN02 ; v i i , NaBH4 ; v i i i , MeOH , HCI; ix,iodinium d i c o l l i d i n e p e r c h l o r a t e (1.0equiv.l; x , H 2

,1 0 O l 0

P d I C ; xi , PPTS,EtOH; xii,15"/0

a q . K O H ; x i i i , MeNH2 ,DMSO;xiv, ClC02Et, N E t 3 ; xv, iodonium dicollidine perchlorate (1.5 e q u i v . ) , d i o x a n e ; x v i , NaI,Me2CO; xvii,Bun3SnH,cat.(PhC0 1 ;xviii,5"/oaq.KOH; 22

xix,Ac20

Scheme 46

335


?H

M

e

2

N

Me

Me+

h

Me

6H

Me2N

OH OH Me riii

i, i i + H

Me

$OR Me

O ' 0k

Me

Me

\

R = H or CONH,

I

R e a g e n t s : i , P h M g E r ; i i , p i p e r i d i n e , E t O H ; iii,(HCHO),

,cat.p-TSA;iv,LiAIH4;

v i ,03,s i l i c a g e l

Scheme 4 7

CO CH2CI

I

NH

'

H02C H02Ce

0

0

v,TFA;


336 e x a m p l e ( s e e Volume 8 , p . 2 7 6 ) .

A more d e t a i l e d a c c o u n t o f t h e

s y n t h e s i s h a s been p u b l i s h e d 1 2 1 gand i n a d d i t i o n r a c e m i c diaminodideoxy-lyxopyranoses have been p r e p a r e d a l o n g similar

lines.

220,

a-Chloronitroso-compounds h a v e a l s o b e e n e x a m i n e d a s d i e n o p h i l e s i n hetero-Diels-Alder

r e a c t i o n s and isomers o f diaminodideoxykonduritols p l u s a n a l o g u e s o f s t r e p t a m i n e h a v e b e e n s y n t h e s i z e d 2 t h e i r c y c l i z a t i o n s w i t h trans-6-azido-cyclohexaI l 3 - d i e n - 5 - o l . 221 The p o t e n t i a l f o r u t i l i z i n g a - c h l o r o n i t r o s o compounds c o n t a i n i n g c h i r a l a u x i l i a r i e s i n a s y m m e t r i c h e t e r o - D i e l s Alder r e a c t i o n s l e a d i n g t o t h e s y n t h e s i s of e n a n t i o m e r i c a l l y pure a m i n o c y c l o h e x e n o l s h a s a l s o b e e n e v a l u a t e d 2 2 2 , 223 i n some d e t a i l . The u s e o f a - a m i n o - a c i d s a s c h i r a l e d u c t s f o r t h e s y n t h e s i s o f h y d r o x y l a t e d D-a-amino a c i d s via a m i n o - a l c o h o l i n t e r m e d i a t e s h a s b e e n d e s c r i b e d . 224 Lithium e n o l a t e s of N,N-dibenzylglycinate

have f e a t u r e d i n t h e

s y n t h e s i s o f a-amino-B-hydroxy-acids. 225 T h e e n o l a t e c o u l d b e a c y l a t e d w i t h a c y l h a l i d e s a t low t e m p e r a t u r e s o r r e a c t e d w i t h However, t h e l a t t e r r e a c t i o n s were n o t p a r t i c u l a r l y d i a s t e r e o s e l e c t i v e , a n d r e d u c t i o n s of t h e a m i n o d i c a r b o n y l compounds r e s u l t i n g f r o m t h e a c y l a t i o n s w i t h e x c e s s

aldehydes i n a l d o l condensations.

N a B H 4 i n a q u e o u s e t h a n o l b u f f e r e d by ammonium c h l o r i d e ( w i t h o u t w h i c h t h e r e d u c t i o n s d i d n o t o c c u r ) f o l l o w e d by d e p r o t e c t i o n s l e d t o t h e d e s i r e d hydroxylated amino-acids threo:erythr-o

w i t h much b e t t e r

s e l e c t i v i t i e s ( r a t i o s i n t h e r a n g e 89:ll t o 9 9 : l w e r e

cited). A three-step

s y n t h e s i s o f (-1-a-amino-B-hydroxybutyric a c i d

(GABOB) i n 6 6 % o v e r a l l y i e l d a n d i n 49% e n a n t i o m e r i c e x c e s s h a s b e e n d i s c l o s e d . 226 The s e q u e n c e i n v o l v e d a s y m m e t r i c e p o x i d a t i o n o f a homoallylic a l c o h o l , o x i d a t i o n of t h e epoxy-alcohol t o t h e c o r r e s p o n d i n g epoxy-acid, and f i n a l l y o p e n i n g o f t h e e p o x i d e w i t h a n e x c e s s o f c o n c e n t r a t e d ammonium h y d r o x i d e . R e a c t i o n o f (2gl2S-)-2,3-(cyclohexylidenedioxy)butanenitri1e [prepared from e i t h e r L - ( + ) - t a r t r a t e o r ( S ) - l a c t a t e ] w i t h t h e magnesium e n o l a t e o f t - b u t y l a c e t a t e g a v e a ( L ) - B - a m i n o a c r y l a t e a d d u c t , w h i c h was u l t i m a t e l y c o n v e r t e d i n t o N - b e n z o y l - L - d a u n o s a m i n e by c o n s e q u e n t i v e a c e t y l a t i o n , s t e r e o s e l e c t i v e h y d r o g e n a t i o n , a c i d i c h y d r o l y s i s , p r o t e c t i o n , l a c t o n i z a t i o n , and dibal-H reduction.227 R e v e r s i b l e o x y a m i n o p a l l a d a t i o n s o f a l k e n e s 2 2 8 and a d d i t i o n s o f b e n z e n e s u l p h e n e a n i l i d e s t o olef i n s 2 2 9 have a l s o been s t u d i e d .


337

5 Amino-carbonyl Compounds

Syntheses of a-amino-aldehydes in electrocyclic rearrangements have been reported. Propargyl allyl ethers may be aminomercurateddemercurated to yield 8-allyloxy-enamines, Claisen rearrangement of which occurs almost quantitatively to afford 2-aminopent-4-enals (Scheme 48).230 When the allyl moiety formed part of an aromatic system, however, products were found to arise from [1,3]-(as opposed to [3,31-)sigmatropic rearrangements. Amino-ketones have been prepared in a number of ways. gTrifluoroacetyl-a-amino-acid chlorides have been employed in Friedel-Crafts acylations of arenes (reduction of the products to aralkylamines was also reported ,231 and high-pressure Mannich reactions have effected dimethylaminomethylation of ketones with bis (dimethylamino )methane. 232 Ketone t-butyldimethylsilyl enolates have been successfully added to Eschenmoser's salt, dimethyl(methy1ene)ammonium iodide,with retention of the protecting group to give silyl enol ethers of Mannich bases.233 Diastereoselective syntheses of novel examples of this type of compound have been achieved through the use of organotitanium reagents. Thus titanates of g,g-hemiacetals (trichlorotitanium dialkylamino-alkoxides) were used to convert lithium enolates into 8-dialkylamino-ketones and -esters. 234 The organotitanium species were generated either from lithium alkoxides and titanium tetrachloride o r from addition of trichlorodialkylamino-titanium to aldehydes (Scheme 49). Novel 2-amino-3-cyanophenyl ketones were obtained from cycloaddition-eliminations of vinyl ketones and 2-amino-3cyanofurans (Scheme 5 0 ) . 235 These compounds were employed as precursors to potential anticonvulsant quinazolines and 1,4benzodiazepines that had previously been synthetically inaccessible. 2 - A l k y l a m i n o b e n z o p h e n o n e s have been prepared from both 3-aryl2,I-benzisoxazolinium salts236 and the parent 3-aryl-2,l2b e n ~ i s o x a z o l i n e sthrough ~~~ the agency of iodotrimethylsilane Amino-3-acetyl-4-phenylpyridines have been prepared from 4-amino-lazabutadienes via reaction with diketene and rearrangement of the resultant dihydropyrimidines 238 Amino-esters have been isolated from thermal inter- and intramolecular E-sulphonylimine ene reactions, which favoured formation of products from endo transition states in most cases,239 in couplings of ethyl acrylate to N-(toluene-E-sulphonyl)imines catalysed by 1,4-diazabicycl0[2.2.2loctane,~~~and in dye-

.

.


338

h2 I

R2 S c h e m e 40

Scheme 4 9

Scheme 50

339

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 24 1 s e n s i t i z e d photo-oxygenations of 4(1H)-quinolones. B-Amino-acid e s t e r s c a n be p r e p a r e d by a m i n o m e t h y l a t i o n s o f s i 1y 1k e t e n e a c e t a 1s w i t h a-me

a n d E, EThe l a t t e r p r i m a r y

t h o x y c a r bama t e s 2 4

b i s ( t r i m e t h y l s i l y l )methoxymethylamine. 243

a m i n o m e t h y l a t i n g a g e n t was a l s o f o u n d t o r e a c t w i t h s i l y l - s u l p h i d e s and - p h o s p h i t e s t o g i v e aminomethyl-sulphides 24 4 respectively.

and -phosphonates

6 Amides a n d T h i o a m i d e s F o r m a m i d e s h a v e b e e n p r e p a r e d f r o m s e c o n d a r y a m i n e s on a t t e m p t e d silylation with t-butyldimethylsilyl

chloride-triethylamine-N,N-4-

d i m e t h y l a m i n o p y r i d i n e i n DMF, 2 4 5 a n d by d i e t h y l z i n c - c a t a l y s e d c a r b o n y l a t i o n of a m i n e s . 2 4 6 proceed

via

The f o r m e r r e a c t i o n was p r e s u m e d t o

t h e Vilsmeier-type

reagent (51).

be used as a m i d o a l k y l a t i o n r e a g e n t s , and

Formamides c a n a l s o

n o t a b l y I-formyl-5-

methoxyproline methyl ester, generated e l e c t r o c h e m i c a l l y from t h e d e s m e t h o x y d e r i v a t i v e , was f u n c t i o n a l i z e d i n t h e 5 - p o s i t i o n by N-Arylarylcarboxamides r e a c t i o n w i t h n u c l e o p h i l e s .247 -

and amides

o f weak c a r b o x y l i c a c i d s h a v e t r a d i t i o n a l l y b e e n r e g a r d e d a s d i f f i c u l t t o p r e p a r e , and as a r e s u l t numerous n o v e l r e a g e n t systems, e s p e c i a l l y methods f o r carboxy-group d e v i s e d i n o r d e r t o circumvent t h e problem. such systems are still a c t i v e l y sought.

a c t i v a t i o n , have been However, v a r i a n t s o f

Many o f t h e s e r e a g e n t s a r e

b a s e d on some a s p e c t o f o r g a n o p h o s p h o r u s c h e m i s t r y .

and i t h a s been

shown t h a t a m i d e s c a n b e made f r o m e q u i m o l a r q u a n t i t i e s o f c a r b o x y l i c a c i d s , a z i d e s , and t r i p h e n y l p h o s p h i n e i n r e f l u x i n g benzene.

The r e a c t i o n o c c u r s t h r o u g h p r o t o n a t i o n o f t h e i n i t i a l l y

formed phosphazenes ( S t a u d i n g e r r e a c t i o n between t h e a z i d e and p h o s p h i n e ) by t h e a c i d f o l l o w e d by a d d i t i o n of c a r b o x y l a t e a n i o n t o t h e phosphonium s p e c i e s and r e a r r a n g e m e n t w i t h e l i m i n a t i o n o f t r i p h e n y l p h o s p h i n e o x i d e (Scheme 5 1 ) . 2 4 8

N,N-Carbonyldi-imidazole i s a commonly u s e d r e a g e n t f o r a c t i v a t i o n of c a r b o x y - g r o u p s t o w a r d s n u c l e o p h i l i c a t t a c k a n d i t s u s e h a s b e e n a p p l i e d t o t h e s e l e c t i v e a c y l a t i o n of p r i m a r y a m i n o g r o u p s i n s p e r m i d i n e and o t h e r l i n e a r t r i a m i n e s . 249

N ,ECarbonyldi[2(3~)-benzoxazolethionel h a s b e e n d e v e l o p e d a s a r e a g e n t w i t h similar a p p l i c a b i l i t y , namely s y n t h e s i s o f a m i d e s , e s t e r s , p e p t i d e s , and polyamides. 250

N - M e t h y l a t i o n of trimethylsilyl-cyanohydrins o f 2 - a c y l - l K i m i d a z o l e s h a s a f f o r d e d i n t e r m e d i a t e s from which amides c a n be

340


o b t a i n e d i n good y i e l d .

Thus s e q u e n t i a l t r e a t m e n t of t h e

acylimidazole with trimethylsilyl cyanide, n-butyl-lithium, d i m e t h y l s u l p h a t e , a n d a n a m i n e a f f o r d e d a m i d e ~ . ~ ~An’ a c y l n i t r i l e was t e n t a t i v e l y p r o p o s e d a s t h e r e a c t i v e i n t e r m e d i a t e o f t h e p r o c e s s (Scheme 5 2 ) . S e l e c t i v e one-pot

a c y l a t i o n s of benzylic amines i n t h e presence

of a n i l i n e s were made p o s s i b l e by u t i l i z a t i o n o f 3 , 6 - d i e t h y l - 2 h y d r o x y p y r a z i n e as a n a c y l t r a n s f e r r e a g e n t ( S c h e m e 5 3 ) .252 I n g e n e r a l t h e o r d e r f o r e a s e o f a c y l a t i o n was p r i m a r y > s e c o n d a r y a l i p h a t i c amine = primary > s e c o n d a r y a r y l amine. Amides c a n b e p r e p a r e d f r o m a v a r i e t y o f o t h e r n i t r o g e n -

For i n s t a n c e , a m i d e s w e r e p r e p a r e d

containing functional groups.

f r o m n i t r i l e s by r e a c t i o n w i t h c y c l i c h y d r o x y l a m i n e s t y p i f i e d by 4-

benzyloxy-l-hydroxy-2,2,6,6-tetramethylpiperidine, 253 f r o m k e t o x i m e s u s i n g !,I-carbonyldi-imidazole

i n c o n j u n c t i o n w i t h a l l y 1 bromide o r

o t h e r a c t i v e h a l i d e s , 254 f r o m a 2-amino-3-phenylcarbamoylazirene on r e a c t i o n w i t h a c y l h a l i d e s 255 i n p l a t i n u m - p h o s p h i n e c a t a l y s e d , Lewis acid-mediated

c o m p o u n d s , 256 a n d by r e a c t i o n o f N - n i t r o s o a l k y l a m i d e s w i t h a m i n e s .257

complex-

reductive Ij-acylations

of n i t r o -

a n d Ij-nitro-!-

In the last reaction arylamines

reacted poorly with the N-nitrosocarboxamides,

whereas t h e N-nitro-

compounds r e a c t e d w e l l . The a d d i t i o n o f a m i n e s t o p h o t o c h e m i c a l l y g e n e r a t e d k e t e n e s h a s a l s o b e e n e x a m i n e d .258

N-Bromoamides

have been i s o l a t e d a f t e r t r e a t m e n t w i t h aqueous

sodium b r o m i t e i n a c e t i c t h e p r e p a r a t i o n o f a m i n e s . 35

as w e l l a s b e i n g i n t e r m e d i a t e s i n o r t h o - A l k y l a t i o n of a c e t a n i l i d e s w i t h

a l k y l h a l i d e s and p a l l a d i u m acetate has a l s o been a c h i e v e d .260 H e t e r o c y c l e s h a v e a l s o b e e n u s e d a s s o u r c e s of a m i d e s . a-Aminoa c i d a m i d e s h a v e b e e n o b t a i n e d f r o m a c i d i c h y d r o l y s e s o f 4i m i d a z o l i d i n o n e s a n d f r o m 4 - i m i n o - o x a z e t i d i n e s . 261 P h o t o o x y g e n a t i o n o f 1 , 2 , 4 - t r i s u b s t i t u t e d i m i d a z o l e s w i t h s i n g l e t oxygen i n t h e p r e s e n c e o f DBU and a s e n s i t i z e r l e d t o t h e f o r m a t i o n o f i m i n e - d i a m i d e s i s o l a t e d a f t e r p u r i f i c a t i o n by c h r o m a t o g r a p h y , w h i c h f o l l o w i n g i s o m e r i z a t i o n t o enamine-diamides afforded a-acetylamino-acid w e r e o b t a i n e d f r o m !-protected

a m i d e s . 26

a-

amino-acids

and h y d r o g e n a t i o n

Acy l a m i n o - a c i d amid e s by s e q u e n t i a l t r e a t m e n t

with Ij-methylmorpholine, i s o b u t y l c h l o r o f o r m a t e , and c o n c e n t r a t e d a q u e o u s a m ~ n i a . a~- A~m i~n o - a c i d a m i d e s a l s o r e s u l t e d f r o m r e a c t i o n s o f s e c o n d a r y a m i n e s w i t h t r i c h l o r o e t h y l e n e e f f e c t e d by aqueous sodium h y d r o x i d e and s m a l l amounts of b e n z y l t r i e t h y l a m m o n i u m c h l o r i d e a t 70 0C.264


RCO L.H N,R'

Ph,P J

341

i

+) *Ph,P=NR1

J. J. + Ph,PO

(+ N,)

S c h e m e 51

-

Me

Reagents :

Me

I ,

-

T M S C N , c a t . BunLi ; M e 2 S 0 4 , 70 " C ; i i i ,

Scheme 5 2

Scheme 53

Me

Me SOL

R'NH,

0

OC

1

RCONHR'


342

Amides o f u n s a t u r a t e d a c i d s h a v e a l s o b e e n much s o u g h t a f t e r , and b e n z y l i c a c r y l o y l a m i n a t i o n s have been a c h i e v e d u t i l i z i n g f e r r i c p e r c h l o r a t e n o n a h y d r a t e and a c e t i c a c i d t o c o n v e r t a r e n e s and a c r y l o n i t r i l e i n t o a r y l a c r y l a m i d e s i n moderate y i e l d s . 265

3-

Dimethylphosphonoacetyl-l,~-thiazolidine-2-thione(DMPATT) was u s e d t o prepare a,B-unsaturated

amides i n moderate t o good y i e l d s

r e a c t i o n w i t h a m i n e s f o l l o w e d by W i t t i g - H o r n e r a l d e h y d e s a n d k e t o n e s ( S c h e m e 5 4 ) . 266

via

coupling with

I n t h e f o r m a t i o n of

a l i p h a t i c amides t h e coupling s t e p favoured formation of 5 - o l e f i n s . a m i d e s h a v e b e e n o b t a i n e d a f t e r r e a c t i o n s of

a,13,7,6-Unsaturated

p r o p a r g y l a l c o h o l s and acetals of l - a c e t y l - p y r r o l i d i n e -piperidine.

and

I s o m e r i z a t i o n of t h e r e s u l t a n t 8 - a l l e n y l a m i d e s

2 ( E ) , 4 ( & ) - d i e n a m i d e s was p r o m o t e d by t h e 2 (E ) , 4 ( E-) - i s o m e r s

to

t h e formation of

with potassium-t-butoxide

having a l r e a d y been

e s t a b l i s h e d (Scheme 5 5 ) . A number o f dihydropyran-5-carboxamides r e s u l t e d from t r e a t m e n t of d i h y d r o p y r a n s w i t h t o s y l i s o c y a n a t e i n THF. 2 6 8 Olefin-substituted several instances.

enamides have a l s o been s y n t h e s i z e d i n

N-Acetyl-

and N,N-diacetyl-a,B-didehydro-a-

a m i n o - a c i d a m i d e s r e s u l t e d f r o m t r e a t m e n t of a - a z i d o c a r b o x a m i d e s w i t h rhenium c a t a l y s t s i n a c e t i c a n h y d r i d e ,269 and l-phenyl-8a m i d e s were o b t a i n e d

bromo-a,B-unsaturated

via

bromoboration of

t e r m i n a l a l k y n e s f o l l o w e d by t r e a t m e n t o f t h e r e s u l t a n t 8bromoalkenyl-boranes

with phenyl isocyanate.

The

E:L r a t i o s

of

p r o d u c t s d e r i v e d from a l i p h a t i c a l k y n e s appeared t o be dependent upon t h e t e m p e r a t u r e a t w h i c h t h e p h e n y l i s o c y a n a t e was a d d e d . Temperatures of 23

OC

a n d -78

Z-B-bromo-a,B-unsaturated

OC

f a v o u r e d t h e f o r m a t i o n of

E-

and

a m i d e s r e s p e c t i v e l y ( S c h e m e 5 6 ) .270

Alkyl-3-arylazo-2-halogenobut-3-enamides were f o r m e d by r i n g o p e n i n g s of l-aryl-4,4-dihalogeno-3-methylpyrazoline-5-ones w i t h a m i n e s a n d ammonia. 27 y,b-Unsaturated

*

a m i d e s h a v e r e s u l t e d f r o m c y c l i z a t i o n s of t h e

c o r r e s p o n d i n g epoxy-amide

e n o l a t e s f o l l o w e d by d e h y d r a t i o n , t h i s

sequence being exemplified with p r e p a r a t i o n s of p y r e t h r o i d a m i d e s , 2 7 2 and i n moderate y i e l d s f o l l o w i n g t r e a t m e n t of

l,N-

dimethylamino-4-alkanoic a c i d l a c t o n e s w i t h HMPA a t h i g h temperatures.273

S i m i l a r r i n g o p e n i n g s o f 6- and E - l a c t o n e s

were

noted i n the latter report. Ynamines h a v e b e e n f o u n d t o r e a c t w i t h s i l y l a l d o k e t e n e s i n t h e n o r m a l [2+21 s e n s e t o g i v e y - s i l y l a t e d a l l e n e c a r b o x a m i d e s , w h i c h c a n t h e n b e t r a n s f o r m e d i n t o y - s i l y l y n a m i d e s . 274


343

’ yellow ’

‘colourless ’ Reagents:

i, DCC- D M A P ; ii, R’R’NH;

iii , N A H , T H F ; i v , R 3 R 4 C 0

Scheme 5 4

OH

\ii

iii/

-

R e a g e n t s : i , MeC(OEt)2NdCH2),

; i i , ALZ03 ; iii , KOBut

Scheme 55

-

Br RCECH

R e a g e n t s : i , BBr3 ; ii

\ RIC =c\

, PhNCO

ii,iii

H

/CONHPh 7=c\ +

Br

\ R

; iii, H20

Scheme 5 6

H

H

Br\

/

R

‘CONHPh


344

Michael a d d i t i o n s t o a ,B-unsaturated amides have s e r v e d t o 2-Carbamylethylphosphonous e x t e n d t h e s c o p e of amide s y n t h e s i s . a c i d was p r e p a r e d b y a d d i t i o n o f h y p o p h o s p h o r o u s a c i d t o a c r y l a m i d e ( m e t h a c r y l a m i d e a n d c r o t o n y l a m i d e r e a c t e d p o o r l y ) , 275 N - p r o t e c t e d 2-carbalkoxyaminothioethers were f o r m e d i n m o d e r a t e t o g o o d y i e l d s by a d d i t i o n s t o l - B o c - p r o t e c t e d d e h y d r o - a - a m i n o - a c i d s , 276 a d d i t i o n o f sodium b e n z e n e s u l p h i n a t e

t o N,N-diethylacrylamide

afforded the

s u l p h o n e a m i d e ( 5 2 1 , w h i c h was a l s o c o n v e r t e d i n t o t h e c o r r e s p o n d i n g t h i o a m i d e ( 5 3 ) w i t h P 4 S , 0 ,277 a n d ( L ) - B - a r y l s e l e n o a,B-ethylene

c a r b o x a m i d e s were o b t a i n e d i n g o o d y i e l d s u p o n

a d d i t i o n s o f s e l e n o l s t o a l k y n a m i d e s . 278 The s y n t h e s i s o f o x y g e n a t e d a m i d e s m u s t a l s o b e c o n s i d e r e d t o b e a n i m p o r t a n t area.

a-Oxoamides

have been s y n t h e s i z e d i n good

y i e l d s by t r e a t m e n t o f a l k y l - l i t h i u m s w i t h c a r b o n m o n o x i d e i n t h e p r e s e n c e o f i s o c y a n a t e . 279

a - O x o t h i o a m i d e s were s i m i l a r l y p r e p a r e d i n t h e analogous reactions with isothiocyanates. Addition of

Grignard r e a g e n t s t o e t h y l oxamate a l s o a f f o r d e d a-0x0-amides. I n t e r m e d i a t e s i n t h i s p r e p a r a t i o n c o u l d a l s o b e c o n v e r t e d i n t o ah y d r o x y - a m i d e s by h e a t i n g i n t o l u e n e ( S c h e m e 5 7 ) .280 Asymmetric s y n t h e s i s o f B - h y d r o x y a c e t a m i d e s

h a s b e e n r e a l i z e d by

a l d o l c o n d e n s a t i o n s b e t w e e n e n a n t i o m e r i c a l l y p u r e as u l p h i n y l a c e t a m i d e s a n d a l d e h y d e s f o l l o w e d by r e d u c t i v e E n a n t i o m e r i c e x c e s s e s of u p t o

d e s u l p h u r i z a t i o n o f t h e a d d u c t s . 281

47% were o b t a i n e d .

B-Keto-carboxamides

have been o b t a i n e d i n

m o d e r a t e y i e l d s by a d d i n g t h e d i a n i o n d e r i v e d f r o m

l-

(trimethylsily1)acetamide t o e s t e r s a n d 1-methoxy-N-methylbenzamide ( a l k y l a t i o n s w i t h a l k y l h a l i d e s and h y d r o x y a l k y l a t i o n s w i t h a l d e h y d e s were a l s o d e m o n s t r a t e d ) , 2 8 2 a n d f r o m t h e r m a l r e a c t i o n s o f

2,2-dimethyl-2~,4~-1,3-dioxin-4-ones with amines, these occurring i n t e r m e d i a c y of a l ~ y l k e t e n e s . ~ ~ ~ The a d d i t i o n s o f N-halogeno-N-alkylamides a n d N-halogeno-!-

via the

acylamides (N-halogenoimides) t o o l e f i n i c s u b s t r a t e s under 284 photochemical c o n d i t i o n s have been s t u d i e d and compared. Amidomercuation-demercurations o f o l e f i n s h a v e b e e n d o c u m e n t e d ( s e e Volume 8 , p . 2 8 2 ) a n d a n e x t e n s i o n t o t h e p r o c e d u r e h a s b e e n made by performing t h e demercuration of t h e a-amidomercurial

in the

presence of an e l e c t r o n - d e f i c i e n t o l e f i n . T h i s l e a d s t o 1,4d i f u n c t i o n a l i z e d p r o d u c t s i n r e a s o n a b l e y i e l d s ( S c h e m e 58). 2 8 5 Recent advances i n a-amidoalkylation

reactions at carbon centres

h a v e b e e n r e v i e w e d , 286’287 a n d a new a m i d o a l k y l a t i o n r e a c t i o n h a s b e e n a c c o m p l i s h e d by c o n d e n s a t i o n of c a r b a n i o n s w i t h c y c l o - 1 , 3 -


345

X

II

0 (52) X = O

(53) x = s

OMget NHMgBr

EtO

RMg8r

-% R

R

50 f

0

Jiii OMgBr

“ . ,

NHMg8r

R

IK

&

NH,

R

0

0

R = C,alkyl ; n = 2 , 4 , 6 - 1 0 R e a g e n t s : i , EtOCOCONH,;

i i , H20 ; iii, PhMe

Scheme 57

R’

0 1

4-

R-CH=CH-R2 Reagents : i

~

R3-C-NH,

Hg(NO3I2 ; i i , H,C=CHX

-*

I

, II

R

3

11

- C-

NH-

RZ

I I CH-CH-CH,CH,X

NaBH4

Scheme 5 8

S

S

S R-P’

ii s \s’H

(55) X = H ( 5 6 ) X=OMe

(54) R :MeOC6H4-p (57)R= MeS ( 5 8) R = Ph SC6H4-p

\P-R

s (59)R = MeOC6H,.-p (60)R = PhOC,H,-p


346 o x o i m m i n i u m s a l t s . 288

High-yielding

p r e p a r a t i o n s o f new

3-(

1-

acylaminobenzyl)-2-oxo-2~-1 - b e n z o p y r a n s were a l s o d i s c l o s e d . 2 8 9 S y n t h e s i s of amido m o i e t i e s w i t h i n h e t e r o c y c l i c n u c l e i h a v e been a c h i e v e d by a d i v e r s i t y o f m e t h o d s . Representative examples i n c l u d e s y n t h e s e s of 4-carbamyl-1,2,3-triazoles b y r e c y c l i z a t i o n o f 5 - h y d r o x y - 1 ,2,3-triazole-4-aldimines,290 p r e p a r a t i o n s o f (Ns u b s t i t u t e d carboxamido)methylene d e r i v a t i v e s of 1,2,5-oxathiazole a n d 1 , 2 , 3 - t h i a d i a z o l e b y t r e a t m e n t o f 2-substituted-5-aryl-3(2H)i s o t h i a z o l o n e s w i t h hydroxylamine and a r y l h y d r a z i n e s r e s p e c t i v e l y , 291 p l u s p r e p a r a t i o n s o f s y m m e t r i c a l and mixed

imidazole-4,5-dicarboxamides f r o m t h e p a r e n t d i a c i d . 2 9 2 Some t h i o f o r m a m i d e s h a v e b e e n made b y t r e a t m e n t o f f o r m a m i d i n e s w i t h h y d r o g e n s u l p h i d e i n DMF b e l o w 0 0C.293 T h i o n a t i o n of a m i d e s c o n s t i t u t e s a v e r y p o p u l a r m e t h o d f o r t h e p r e p a r a t i o n of t h i o a m i d e s .

A number of improved v a r i a n t s of

Lawesson's r e a g e n t ( 5 4 ) have been r e p o r t e d .

( 5 5 ) a n d ( 5 6 ) were

shown t o c o n v e r t a m i d e s i n t o t h i o a m i d e s a t room t e m p e r a t u r e i n

THF,294 a n d ( 5 8 ) - ( 6 0 ) were f o u n d t o e f f e c t s i m i l a r t r a n s f o r m a t i o n s w i t h e x t r e m e l y s h o r t ( l e s s t h a n f i v e m i n u t e s ) r e a c t i o n t i m e s . 295 a,b-Unsaturated

t h i o a m i d e s h a v e b e e n p r e p a r e d by W i t t i g - H o r n e r

c o u p l i n g o f p h o s p h o n a t e a n i o n s , a r i s i n g from d e p r o t o n a t i o n of ( 6 1 1 , w i t h a l d e h y d e s (Scheme 5 9 ) .296 S y n t h e s e s o f a-alkyl-B-hydroxyalkyl-thioamides achieved via threo-selective

have been

a l d o l c o n d e n s a t i o n s of t h i o a m i d e

e n o l a t e s , d e r i v e d b y M i c h a e l a d d i t i o n s o f o r g a n o l i t h i u m or organomagnesium r e a g e n t s t o c r o t o n o t h i o a m i d e , s o r b o t h i o a m i d e , c i n n a m o t h i o a m i d e , w i t h a l d e h y d e s .297 7 2 9 8

and

Michael a d d i t i o n s of

9BBN a n d d i b a l - H were a l s o a c c o m p l i s h e d b u t t h e y l e d t o condensations t h a t proceeded with poorer e r y t h r o - s e l e c t i v i t y . A new s y n t h e s i s of m o n o t h i o d i a c y l a m i n e s h a s b e e n d e s c r i b e d , 299

a n d N-thioacylthionocarbamic a c i d e s t e r s h a v e b e e n s y n t h e s i z e d from b o t h i m i n o c h l o r i d e s a n d potassium-2-alkylxanthates a n d s u l p h e n y l h a l i d e s a n d t h i o n o c a r b a m i c a c i d e s t e r s . 300

7 Nitriles and Isocyanides S y n t h e s i s o f n i t r i l e s by d e h y d r a t i o n o f c a r b o x y l i c a c i d d e r i v a t i v e s

i s commonplace.

C a r b o x a m i d e s h a v e b e e n d e h y d r a t e d by s u p p o r t e d

p h o s p h o r u s p e n t o x i d e , 30

a n d by m i x t u r e s o f c a r b o n y l d i - i m i d a z o l e

conjunction with an excess of an a c t i v e halide.254 Thioamides and a l d e h y d e s c a n a l s o f u r n i s h n i t r i l e s i n m o d i f i e d

in


0

0

Et02P,

’

(Et012P,-

,CH2 Me

Me

’.

CH

-

347

0 ( E t 0 l 2 P ~ S -

-

Me

NR

J

iii

J

Reagents : i, 6u”Li ; ii, RNCS(0.5equiv.); iiiI H30+; i v , N a H ; v , R’CHO

Scheme 5 9

-2e

t

B r - 4 Br+’; N a + +

MeONa

+ 1’zH2

RCH2NHzARCH2NHBr-1’,RCH=NH

,

Indirect Electro- oxidation

-!+ RCH=NBr !!+

a::;Reagents : i ‘ B r ”

I

b a s e ; ii, b a s e

Scheme 60

RC=N


348 Willgerodt-Kindler

r e a c t i o n s u s i n g e l e m e n t a l s u l p h u r , sodium

n i t r i t e , a n d l i q u i d ammonia.302 A l d o x i m e s may be d e h y d r a t e d t o n i t r i l e s a n d s u c h r e a c t i o n s h a v e b e e n n o t e d on t h e i r t r e a t m e n t w i t h t r i - n - b u t y l p h o s p h i n e - d i p h e n y l d i s u l p h i d e , 28 a n d w i t h d i m e t h y l ( s u c c i n i m i d y 1 ) s u l p h o n i u m c h l o r i d e t r i e t h y l a m i n e . 303 N i t r i l e s h a v e been o b s e r v e d as p r o d u c t s a r i s i n g from f l a s h p y r o l y s e s o f i s o c y a n i d e s , 304 a n d h a v e b e e n o b t a i n e d ion-mediated

electro-oxidation

halonium

o f a m i n e s ( S c h e m e 6 0 ) . 305

Acyclic

d i n i t r i l e s w e r e p r o d u c e d by f r a g m e n t a t i o n o f c y c l i c ? , 2 - d i a m i n e s using the l a t t e r procedure. A novel s y n t h e s i s of a l k y l n i t r i l e s from t e r m i n a l a l k e n e s

r e s u l t e d f r o m f o r m a t i o n o f t r i a l k y l b o r a n e s f o l l o w e d by a d d i t i o n o f a l a r g e e x c e s s o f sodium c y a n i d e p l u s s t o i c h e i o m e t r i c q u a n t i t i e s of l e a d t e t r a - a c e t a t e . 306 Y i e l d s were p o o r i n c a s e s s t u d i e d i n i t i a l l y , a l t h o u g h c o n s i d e r a b l e improvements r e s u l t e d from u s e of

9-BBN a s t h e h y d r o b o r a t i n g a g e n t . The e f f i c i e n c y o f d i p h e n y l a l k y l s u l p h o n i u m s a l t s i n a l k y l a t i o n s o f c y a n i d e a n i o n and p h e n y l a c e t o n i t r i l e

h a s b e e n e v a l u a t e d . 307

P r i m a r y n i t r i l e s w e r e p r o d u c e d i n good y i e l d s , and m o n o a l k y l a t i o n s of phenylacetonitrile

were achieved i n h i g h y i e l d s w i t h o n l y t r a c e s

of contaminating dialkylated products detected. E l e c t r o p h i l i c t h a l l a t i o n o f a r e n e s f o l l o w e d by n u c l e o p h i l i c d i s p l a c e m e n t o f t h e t h a l l i u m m o i e t y h a s a l l o w e d a number of f l e x i b l e a r e n e f u n c t i o n a l i z a t i o n methods t o be developed.

Cuprous

cyanide treatment of a r y l t h a l l i u m b i s ( t r i f 1 u o r o a c e t a t e s ) r e s u l t e d i n t h e f o r m a t i o n o f a r y l n i t r i l e s i n good y i e l d s . 3 0 8 The r e a c t i o n i s a n a l o g o u s t o t h e Rosenmund-von B r a u n r e a c t i o n o f h a l o g e n o a r e n e s w i t h Cu'CN

a n d t h e p r o c e s s was f a c i l i t a t e d by u s e o f t h e

e l e c t r o n e g a t i v e t r i f l u o r o a c e t a t e l i g a n d s which i n c r e a s e d t h e o x i d a t i o n p o t e n t i a l o f t h e metal.

Both e l e c t r o n - r i c h

and e l e c t r o n -

d e f i c i e n t a r e n e s could be converted i n t o t h e c o r r e s p o n d i n g n i t r i l e s , and t h e u s e of a c e t o n i t r i l e a s s o l v e n t a i d e d r e g e n e r a t i o n o f Cu'

by s t a b i l i z i n g i t t h r o u g h c o m p l e x a t i o n .

An e l e g a n t s y n t h e s i s o f 2 - a l k y l - 3 - c y a n o - b e n z o i c a c i d s or -benzaldehydes involved a d d i t i o n of a-metallated a l k y l n i t r i l e s t o t h e b e n z y n e d e r i v e d f r o m 2-(~-chlorophenyl)-4,4-dimetyl-1,3o x a z o l i n e . 309 C h e l a t i o n of t h e l i t h i u m c a t i o n promoted a d d i t i o n t o the ortho-position,

and t h e s e i n i t i a l a d d u c t s t h e n c y c l i z e d t o

benzocyclobutenimines which s u b s e q u e n t l y fragmented t o g i v e b e n z y l i c a n i o n s o f t y p e ( 6 2 ) (Scheme 6 1 ) . T h e s e c o u l d t h e n be

349

5: Arnines, Nitriles, and Other Nitrogen-containing Functional Groups

1

X

0x2

0x2

I

Li

&R CN

CN

CN

(6 2)

X=COtMe or CHO

1

iii

X

R'

0x2

X=CO,Me or CHO Reagents i , RCH(Li)CN; i i , E t O H ; i i i , R ' X

S c h e m e 61 MeSCN

iJ.

Bu3P(CN)SMe

Bu,P+SMe

Ar CHOW-

I

CN

it

CN I

pFiHAr

p\

@--tAr 4

Bu,P=O Reagents

'

I)

Bu3P ;

11,

Bu3Pf0CHAr

I

c-

ArCHO

CN

"

SMe

S Me

+ ArCH2CN + ArCOSMe Scheme 62

-

R1

350


a l k y l a t e d , o r p r o t o n a t e d , p r i o r t o d e p r o t e c t i o n o f t h e o x a z o l i n e by either hydrolysis or reduction. A r o m a t i c a l d e h y d e s may a l s o be t r a n s f o r m e d i n t o a r y l n i t r i l e s following treatment with t r i m e t h y l s i l y l a z i d e i n t h e presence of

via collapse

z i n c c h l o r i d e ,310’ 31

of t h e t r i m e t h y l s i l y l

azidohydrin to a benzylic nitrenium ion. The s y n t h e s i s o f a r y l a c e t o n i t r i l e s i s a n a r e a w h i c h h a s n o r m a l l y received considerable attention.

Palladium-catalysed

reactions of

c y a n o m e t h y l t r i b u t y l t i n with a r y l bromides a f f o r d e d moderate y i e l d s of a r y l a c e t o n i t r i l e s , e x c e p t i n c a s e s o f a r y l b r o m i d e s w h i c h c o n t a i n e d s t r o n g l y e l e c t r o n - w i t h d r a w i n g s u b s t i t u e n t s . 312 A r y l a c e t o n i t r i l e s have a l s o been o b t a i n e d from k e t o n e s f o r m a t i o n o f c y a n o p h o s p h a t e s f o l l o w e d by h y d r o g e n a t i o n , 31 t r e a t m e n t of a r y l a l d e h y d e s w i t h t r i - n - b u t y l p h o s p h i n e

a n d by

and methyl

thiocyanate i n a novel disproportionation reaction t h a t also afforded S-methylthiobenzoates

(Scheme 6 2 ) . 3 1

A r y l m a l o n o n i t r i l e s were f o r m e d i n p a l l a d i u m - c a t a l y s e d

couplings

o f t h e sodium s a l t of m a l o n o n i t r i l e t o a r y l h a l i d e s . 3 1 5

E-a

,B-Unsaturated

n i t r i l e s have been s y n t h e s i z e d w i t h h i g h

s t e r e o s e l e c t i v i t y using Wittig-Horner

r e a c t i o n s employing

diphenyl(cyanomethy1 Iphosphine oxides.316 cited.

a,B-Unsaturated

E:L

r a t i o s o f > 9 5 : 5 were

n i t r i l e s were a l s o o b t a i n e d i n r e a c t i o n s

u t i l i z i n g d i e t h y l p h o s p h o r o c y a n i d a t e i n t h e p r e s e n c e of l i t h i u m cyanide3’ alk-2-ene

( i n t e r m e d i a t e cyanophosphates were c o n v e r t e d i n t o 2-aryln i t r i l e s by b o r o n t r i f l u o r i d e e t h e r a t e ) , f r o m

trisubstituted olefins

via

ene-type

c h l o r i n a t i o n s , 318 a n d i n

h e t e r o g e n e o u s Knoevenagel c o n d e n s a t i o n s o f b o t h a l d e h y d e s and k e t o n e s w i t h m a l o n o n i t r i l e o r e t h y l c y a n o a c e t a t e c a t a l y s e d by T y p e I a n d Type I V c y a n o l i p i d s b o t h c o n t a i n A1P04-A1203.319 a l l y l i c n i t r i l e m o i e t i e s a n d t h e s e c o m p o u n d s were p r e p a r e d f r o m t h e c o r r e s p o n d i n g a , B - u n s a t u r a t e d a l d e h y d e s by t r e a t m e n t w i t h p o t a s s i u m c y a n i d e , a c y l h a l i d e s , a n d 18-crown-6 Palladium-catalysed

i n t o l u e n e (Scheme 6 3 1.320

a l k y l a t i o n s of a l l y 1 a c e t a t e s w i t h e t h y l

c y a n o a c e t a t e h a v e a l s o b e e n s t u d i e d , a n d m i x t u r e s o f mono- a n d d i h o m o a l l y l n i t r i l e s p r o d u c e d .321

The g e n e r a l u t i l i t y o f n i t r i l e s i n

n a t u r a l p r o d u c t s y n t h e s i s was a p t l y d e m o n s t r a t e d by t h e s y n t h e s i s of b o n g k r e k i c a c i d ( 6 7 ) i n w h c i h t h e a - c y a n o - k e t o n e ( 6 3 ) was c o n v e r t e d i n t o t h e a l k y n y l n i t r i l e ( 6 5 ) by way of t h e e n o l t r i f l a t e (64) and t h e n c e i n t o t h e L-a,B-unsaturated

n i t r i l e ( 6 6 ) upon

a d d i t i o n of d i m e t h y l c o p p e r l i t h i u m a t l o w t e m p e r a t u r e i n THF ( S c h e m e 6 4 ) 322

.


k C H 0

&

,xo2cR -

R = 2 Me(CH,),CH=CH(CH,),

2 - Mc(CH2),CH=CH(CHz)l,,

CN

c17H33co2 ~

351

,

,C,H3,C,HB9 or C5H,,

0 2 c c 1 7 H 3 3

CN Reagents: i, RCOCI,KCN,18-crown-6; ii, P B r 3 ( 0 . 5 e q u i v . ) ; iii, C1fLJ02Na(2

equiv.),Bu*NBT

4

(0.1equiv.),ultrasound,iv,Mn02,C6H14v,C H COCI,KCN, 18-crown-6 17 33

Scheme 63

I

iii

+ ’ OMe

c

;

c

Me /

=

TIPS’

Me

COZH (66)

(67) Reagents: i , NaH, T f 2 0 ( 1 . 5 e q u i v . ) ;

11,

N a H , DMSO ; iii, MeZCuL I

Scheme 64

CN

352


I t was shown t h a t t h e r e a c t i v e i n t e r m e d i a t e h e x y n y l c y a n o k e t e n e c o u l d b e g e n e r a t e d by p y r o l y s i s o f 2,5-diazido-3,6-dihexynyl-l,4-

b e n z o q u i n o n e i n b e n z e n e , a n d t h a t i n t h e p r e s e n c e of a n e x c e s s o f a l c o h o l s a l k y l 8-alkoxy-a-cyano-a,B-ethylenecarboxylates

were

formed.323

R e a c t i o n s of t h e k e t e n e w i t h imines gave cyanos u b s t i t u t e d 8 - o r y - l a c t a m s d e p e n d i n g on t h e s t r u c t u r e of t h e imine. The c h e m i s t r y of o x y g e n a t e d n i t r i l e s i s a l s o a n i m p o r t a n t a r e a ,

a n d t h e c h e m i s t r y o f 3 - o x o a l k a n e n i t r i l e s h a s b e e n r e v i e w e d 324

Methoxy-2-(benzenesulphonyl)propenenitriles

r e a c t i o n s of o r t h o e s t e r s with benzenesulphonyl from c a r b o x y l i c a c i d c h l o r i d e s

3-

h a v e b e e n s y n t h e s i z e d by a c e t o n i t r i l e and

a-cyano-B-keto-sulphones.

325

W i t h i n t h i s a r e a t h e s y n t h e s i s of h y d r o x y a l k y l a t e d n i t r i l e s i s a more s p e c i a l i z e d i n t e r e s t .

2-(l-Hydroxyalkyl)acrylonitriles

were

s y n t h e s i z e d from s a t u r a t e d a l i p h a t i c a l d e h y d e s and a c r y l o n i t r i l e i n a r e a c t i o n c o c a t a l y s e d by t r i - n - b u t y l p h o s p h i n e t r i e t h y l a l u m i n i u m ( S c h e m e 65). 326 r e s u l t e d from base-mediated

and

7-Hydroxyalkene n i t r i l e s

r e a c t i o n s of a-(phenylsulphiny1)-

a c e t o n i t r i l e w i t h a l d e h y d e s a n d k e t o n e s . 327 The s u l p h o n e - t h i o a m i d e

( 5 3 ) was m e t h y l a t e d w i t h d i m e t h y l

s u l p h a t e and t h e n t r e a t e d w i t h p o t a s s i u m c y a n i d e t o a f f o r d t h e a -

cyano-y-phenylsulphonylenamine (68) . 3 2 8 A d d i t i o n s o f sodium s a l t s o f a r y l a c e t o n i t r i l e s t o 1 , l bis(methylthio)-2-phenylsulphonylethene g a v e r e a s o n a b l e y i e l d s of E-3-(methylthio)vinyl n i t r i l e s with near t o t a l s t e r e o s e l e c t i v i t y .329 The a c t i o n of c y a n o t r i m e t h y l a m m o n i u m m e t h y l i d e on d i a l k y l t r i t h i o c a r b o n a t e s a f f o r d e d 3,3bis(alky1thio)acrylonitriles by e l i m i n a t i o n of s u l p h u r f r o m 2,2d i t h i o a l k y l - 3 - c y a n o - e p i s u l p h i d e i n t e r m e d i a t e s .330 6 - K e t o - a c y l c y a n i d e s r e s u l t e d from r e a c t i o n s b e t w e e n e n o x y s i l a n e s a n d a , @ - u n s a t u r a t e d a c y l c y a n i d e s , 331 t h e f o r m e r compounds t h e n b e i n g c o n v e r t e d i n t o 6 - k e t o - c a r b o x y l i c a c i d s . S u b s t a n t i a l i n t e r e s t h a s b e e n shown i n t h e s y n t h e s i s o f af u n c t i o n a l i z e d n i t r i l e s and a v a r i e t y of s u c h d e r i v a t i v e s h a v e been A f a c i l e s y n t h e s i s o f a - a m i n o - n i t r i l e s was d e v e l o p e d , synthesized. w i t h t r e a t m e n t of s i l y l a t e d c y a n o h y d r i n s by a m i n e s o r ammonia g i v i n g g o o d t o e x c e l l e n t y i e l d s of t h e d e s i r e d compounds?32 A s y m m e t r i c s y n t h e s i s of t h e s e c o m p o u n d s i n h i g h o p t i c a l p u r i t y was a l s o p o s s i b l e when c h i r a l a m i n e s were e m p l o y e d , a l t h o u g h c h e m i c a l y i e l d s were somewhat d e c r e a s e d i n t h e s e i n s t a n c e s . 333 A p a r t f r o m t h e a p p l i c a t i o n o f t h e s e compounds t o t h e s y n t h e s i s of a-amino-


Y3P

Et3AI BU&H,CHCN

( Y = Bu,

+ CH2=CHZ

Y36CH2eHZ

+

Eu3PCH2CHCN --j Bu,bCH2CCN

I

I

RCH-0-

Z = CN)

+ CHFCCN I

RCH-OH

Scheme 65

HC

NCN

Ph

‘N=C< Ph

E E O Hy M e

-

EEOYc;

CHO

HO

(70)

(71)

TMS

TMS

#k%

Me

3 53

C02Mc

0 Me

0

RCH-OH

+

ByP


3 54

a c i d s , c h i r a l a m i n o - n i t r i l e s d e r i v e d from a l d e h y d e s c a n b e m e t a l l a t e d and added t o a l d e h y d e s t o y i e l d , a f t e r d e p r o t e c t i o n , hydroxy-ketones

i n u p t o 9 7 % e n a n t i o m e r i c e x c e s s . 334

Q-

Reaction of

N,g-dimethylaminoacetonitrile w i t h l - b r o m o m e t h y l - 3 , 3 dim,ethylcyclohexene

a l k y l a t i o n and r e a r r a n g e m e n t f a c i l i t a t e d

t h e synthesis of y-cyclocitral nitrate-induced

i n w h i c h t h e l a s t s t e p was a s i l v e r

deprotection i n water-diethyl

e t h e r - T H F . 335

a ,B-

were p r e p a r e d from t h e a p p r o p r i a t e

Unsaturated a-amino-nitriles

a l d e h y d e s by t r e a t m e n t o f t h e i r i m i n e s w i t h t r i m e t h y l s i l y l c y a n i d e . 336

F u r t h e r h y d r o l y s i s a f f o r d e d a ,8 - u n s a t u r a t e d

amino-

acids. Acylated y-amino-nitriles

were o b t a i n e d f r o m a - a m i d o e t h y l a t i o n s

o f s i m p l e n i t r i l e s w i t h 1 - a c y l a z i r i d i n e s . 337 Cyclic a-imino-nitriles

c a n b e o b t a i n e d by r e a c t i o n o f ( 6 9 ) w i t h

1 ,G-dibromoalkanes under phase-transfer

c o n d i t i o n s . 338

@-Nitro-

n i t r i l e s , p r e p a r e d by r e a c t i o n o f n i t r o a l k a n e c a r b a n i o n s w i t h potassium cyanide i n t h e presence of t r i p o t a s s i u m h e x a c y a n o f e r r a t e ( I I I ) , were f o u n d t o r e a c t r e a d i l y w i t h a n i o n s o f o t h e r nitro-compounds

t o yield the corresponding B-nitro-nitriles

i n g o o d t o e x c e l l e n t y i e l d s . 339 The p r e p a r a t i o n o f c y a n o h y d r i n s a n d f u n c t i o n a l i z e d d e r i v a t i v e s t h e r e o f i s a n o t h e r area which r e c e i v e s c o n s i d e r a b l e a t t e n t i o n .

The

c y a n o h y d r i n ( 7 1 ) was p r e p a r e d f r o m a l d e h y d e ( 7 0 ) by a n e x c h a n g e r e a c t i o n w i t h a c e t o n e c y a n o h y d r i n , i n a s y n t h e s i s of g-benzoyl-Lacosamine from e t h y l ( S ) - l a ~ t a t e , T ~ h~e ~r o l e o f t h e c h o i c e o f c a t a l y s t i n r e a c t i o n s of c y a n o t r i m e t h y l s i l a n e h a s a l r e a d y been n o t e d ( s e e Volume 8 , S e c t i o n 7 ) a n d t h i s p o i n t h a s b e e n f u r t h e r e x e m p l i f i e d by t h e p r e p a r a t i o n o f b o t h ( 7 2 ) a n d

(73) f r o m m e t h y l

2,4-dioxopentanoate using, respectively, cyanotrimethylsilane alone and c y a n o t r i m e t h y l s i l a n e p l u s z i n c i o d i d e . New examples of t h e cyanation-cleavage

34’ of c h i r a l acetals have

been r e p o r t e d , 3 4 2 o n e s u c h r e a c t i o n l e a d i n g t o an i n t e r m e d i a t e f o r t h e s y n t h e s i s o f p y r e t h r o i d i n s e c t i c i d e s (Scheme 6 6 ) . o-Methoxy-nitriles

h a v e b e e n p r e p a r e d f r o m d i m e t h y l a c e t a l s by

t r e a t m e n t w i t h b o t h c y a n o t r i m e t h y l s i l a n e i n t h e p r e s e n c e of

e l e c t r o g e n e r a t e d a c i d , 3 4 3 a n d t- b u t y l i s o c y a n i d e - t i t a n i u m t e t r a c h l o r i d e , 344 w h i l s t a - a l k y l - t h i o n i t r i l e s were p r e p a r e d by c y a n a t i o n of d i t h i o a c e t a l s w i t h c y a n o t r i m e t h y l s i l a n e a n d t i n t e t r a c h l o r i d e i n d i c h l o r o m e t h a n e (Scheme 6 7 ) .345

The l a t t e r c l a s s

o f compounds have a l s o been p r e p a r e d from a r y l a l d e h y d e s and a r y l t h i o c y a n a t e s u s i n g t r i b u t y l p h o s p h i n e ( S c h e m e 6 7 ) , 346 a n d h a v e f o u n d

355


R

X

Nu

p - elimination

.

97-

PhO

I

0

&cN PhO

acidic or method

ii

HO

basic) HO

PhO &CN

~

;0

H' OR

--LA

I

H

iii6"

iv

R =H

,

R =

Reagents : i , TMSCN, T i C I G ; ii, PCCJCH2CL2 ; iii

, p-TSA.H20

H20 ; i v , R C O C l

Scheme 66

R2 1

R2

1

R -C - 0 M e

I

+

1

Me3SiCN

1

4-

R -C-CN

I

OMe

Me3SiOMe

OMe

Ri/oMe + * R
a 1k a n - 1 - 0 1 s .364

-

357

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups G l y c o s y l c y a n i d e s have r e s u l t e d from r e a c t i o n s of g l y c o s y l f l u o r i d e s w i t h cyanotrimethylsilane-boron t r i f l u o r i d e - d i e t h y l e t h e r a t e 365 d i m e t h y l a l u m i n i u m c y a n i d e , 365 a n d f r o m a d d i t i o n o f diethylaluminium cyanide t o 3-2-acylated

g l y c a l s . 366

Cyano-

c o n t a i n i n g C - g l y c o s i d e s were s i m i l a r l y p r e p a r e d from g l y c o s y l f l u o r i d e s u s i n g e i t h e r trimethylsilylacetonitrile-boron

trifluoride-

d i e t h y l e t h e r a t e o r a c r y l o n i t r i l e p l u s magnesium b r o m i d e - d i e t h y l e t h e r a t e , t r i - n - b u t y l s t a n n a n e , a n d A I B N . 365 T h e s e m e t h o d s a r e i l l u s t r a t e d i n Scheme 6 8 . S y n t h e s e s o f t- b u t y l d i m e t h y l s i l y l c y a n i d e 3 6

and t h e

c o r r e s p o n d i n g i s o c y a n i d e , 368 t r i f l u o r o a c e t o n i t r i l e o x i d e , 369 c h l o r o c y a n o k e t e n e , 370 a n d

l-( c y a n o m e t h y l me than amid ate^^^

have a l l

appeared. On r e a c t i o n o f (74) w i t h e x c e s s c y a n o t r i m e t h y l s i l a n e a n d z i n c iodide i n refluxing dichloromethane,

t h e corresponding 1 , 2 - ~ - 2 , 3 -

anti-1,2-bistrimethylsilyloxy-~-isocyano-compound ( 7 5 )

was

o b t a i n e d , and t h e n c o n v e r t e d i n t o (1~*,2~*,3~*)-3-aminocyclohexane1 ,2 - d i o l

( S c h e m e 6 9 1 . 372 K e t o n e s may be c o n v e r t e d i n t o I-isocyano-I-tosyl-I-alkenes by

t h e a c t i o n of t o s y l m e t h y l i s o c y a n i d e , and t h e n t o t h e c o r r e s p o n d i n g

3-isocyano-3-tosyl-I-alkenes by t r e a t m e n t w i t h p o t a s s i u m t - b u t o x i d e a n d a n a l k y l a t i n g a g e n t . 373 into a,b-unsaturated

C o n v e r s i o n o f t h e l a t t e r compounds

k e t o n e s was a l s o d e s c r i b e d .

L i t h i a t e d 4-

methyloxazoles can be converted i n t o e i t h e r t h e 8trimethylsilyloxy-

or t h e B - a c e t o x y - a c e t o n i t r i l e s

( 7 6 ) . 374

*

f r a g m e n t a t i o n o f t h e o x a z o l i n e ( 7 7 ) l e d t o t h e f o r m a t i o n of t h e 8 -

hydroxyformamido-derivative

( 7 8 ) w h i c h was t o s y l a t e d a n d t r e a t e d

w i t h D B U t o g i v e t h e u n s a t u r a t e d i s o c y a n i d e ( 7 9 ) by i s o m e r i z a t i o n of t h e d i e n e . The i s o c y a n i d e ( 7 9 ) was t h e n e l a b o r a t e d i n t o t h e f u n g a l i s o c y a n i d e a n t i b i o t i c ( 8 0 ) ( S c h e m e 7 0 ) .375 2 , 3 - E p o x y - 2 i s o c y a n o a l k a n o a t e s w e r e s y n t h e s i z e d by t r e a t m e n t o f m e t h y l ai s o c y a n o a c r y l a t e s w i t h e i t h e r H202 i n a q u e o u s s o d i u m h y d r o x i d e or

m-CPBA

a n d s o d i u m m e t h o x i d e i n m e t h a n o l .376

P r e p a r a t i o n of

( a r y l s u l p h o n a m i d o ) m e t h y l i s o c y a n i d e s h a s a l s o b e e n r e p o r t e d . 377 8 N i t r o - and Nitroso-compounds The i m p o r t a n c e o f n i t r o - c o m p o u n d s

as s y n t h e t i c intermediates is

r e f l e c t e d b o t h i n t h e d i v e r s i t y o f s u c h compounds p r e p a r e d , and i n t h e v a r i e t y o f a p p l i c a t i o n s of t h e s e d e r i v a t i v e s h a v e f o u n d . The n i t r a t i o n o f a r e n e s i s a c l a s s i c a l p r o c e d u r e w h i c h s t i l l f i n d s much


3 58

2oT i or ii (R=CN) or

iii ( R = c H ~ c Nor ) iv* O C H , ~ ~( R2CH2CH2CN)

PhCH PhCHzO'

OCH2Ph

R2

R'

R3

OCH,Ph

R4

H M e OAc H (3cc-OAc) H Me H OAc ( 3 a - O A c ) CHzOAc H H OAc ( 3 p - O A c ) H H H OAC ( 3 a - o ~ ~ ) Reagents

I,

Me2AICN(1 Z e q u i v ) ,

11

I

M e 3 S i C N ( 2 0 e q u t v ) , B ~ . 0 E t 2 ( 0 . 2 e q u l v),iii,Me3S~C

YN

( 2 . 0 e q u i v 1, EF O E t (0.2 e q u i v 1, i v , H,C=CHCN ( 1 0 e q u l v ) , M g B r . O E t i S e q u i v 1, 3' 2 B u n 3 S n H ( 2 . O e q u i v ) , A I B N ( 0 . l e q u t v 1, PhMe,v, EtALCN ( 1 5 - 3 0 e q u l v )

Scheme 68

(75)

Reagents.

I,

T M S C N ( 4 e q u i v 1 , 1 5 mol 'lo a n h y d r o u s Z n 1 2 ;

MeOH

Scheme 69

11,

K F ( 5 e q u i v );

111,

HCI,


359

(76) R': R 2 = Ph R'= Me, R2- H P : Ac or TMS

C02Et

SnBu3

+

NHCHO

(77)

COZEt

JNC&

iiii

LC

C02Et

03SC6H4Me-p

CO 2 Et

&OH

C02Et

NHCHO

$;"

dNCdNC v ii

+

(79)

Reagents

I

, N B S (1.0 equi v 1 ; IiJBun3SnSnBun3 (0.03 e q u IV.

NMe3(5- 1 0 e q u i v ) ; v , D R U ( 1 . 5 - 1 0 e q u i v VII

~

NC

(80)

); iii,T

HF, H20 ; I v, TsCL ( 2.2 equiv 1,

) ; v i , [ * H 6 ] b e n z e n e J 12(0.3 m o \ ' L ) ;

1M- L i O H

S c h e m e 70


360

use. Nitronium t e t r a f l u o r o b o r a t e is an e s t a b l i s h e d a g e n t f o r t h e n i t r a t i o n o f a r e n e s a n d a new m e t h o d o f g e n e r a t i n g t h e r e a g e n t e l e c t r o c h e m i c a l l y i n s i t u i n a c e t o n i t r i l e h a s r e c e n t l y been p u b l i s h e d .378

In addition t o t h e preparation of nitro-aromatics

yields superior t o those previously obtained,

a-nitro-ketones

produced from e n o l s i l y l e t h e r s , v i c i n a l n i t r o - a m i d e s

in

were

prepared from

o l e f i n s , and m i x t u r e s o f 1 , 2 - and 1 , Q - n i t r o a c e t a m i d e s p r e p a r e d f r o m 1,3-dienes

(Scheme 7 1 ) . Rates o f n i t r a t i o n o f p o l y c y c l i c a r o m a t i c h y d r o c a r b o n s u s i n g n i t r o g e n d i o x i d e i n s o l u t i o n have been measured and e v i d e n c e s u p p o r t i n g an e l e c t r o n - t r a n s f e r n i t r a t i o n mechanism h a s been d i s c u s s e d . 379 N i t r a t i o n o f p h e n o l s by u s e o f c l a y - s u p p o r t e d f e r r i c n i t r a t e h a s b e e n s t u d i e d , 3 8 0 a n d t h e u s e of c e r i c ammonium n i t r a t e t o e f f e c t n i t r a t i o n of n a p h t h y l e s t e r s w i t h o u t h y d r o l y s i s h a s been reported.381

Good y i e l d s o f 2- a n d 5 - n i t r o - I - n a p h t h y l

nitro-2-naphthyl

a c e t a t e plus I-nitro-2-naphthyl

acetates

8-

b e n z o a t e were

obtained with t h e latter procedure. A range of unsymmetrically s u b s t i t u t e d b i p h e n y l s h a s b e e n s y n t h e s i z e d i n v e r y h i g h y i e l d by a n i n t e r e s t i n g c o u p l i n g of a r y l b o r o n i c a c i d s w i t h a r y l bromides, c a t a l y s e d by z e r o v a l e n t p a l l a d i u m c o m p l e x e s . 382

The n i t r o

s u b s t i t u e n t was t o l e r a t e d i n b o t h s u b s t r a t e s i n a r e a c t i o n w h o s e y i e l d s were i n s e n s i t i v e t o s t e r i c c o n s t r a i n t s (Scheme 7 2 ) . Nitro-substituted

a r y l h y d r o x y l a m i n e s and a l k o x y a m i n e s h a v e been

o z o n i z e d t o y i e l d p o l y n i t r o b e n z e n e s . 383

The h y d r o x y l a m i n e s w e r e

prepared from t h e c o r r e s p o n d i n g b r o m o n i t r o a r e n e s .

In addition,

p o l y n i t r o a n i l i n e s were o x i d i z e d t o t h e f u l l y n i t r a t e d d e r i v a t i v e s by p e r o x y d i s u l p h u r i c a c i d g e n e r a t e d i n s i t u f r o m s u l p h u r t r i o x i d e and o z o n e .

The r a t e o f n u c l e o p h i l i c a r o m a t i c s u b s t i t u t i o n o f

a c t i v a t e d a r e n e s by NO2-

( a n d a l s o o t h e r n u c l e o p h i l e s ) was f o u n d t o

be a c c e l e r a t e d i n t h e p r e s e n c e o f c e r t a i n m a c r o c y c l i c p o l y a m i n e s . 384

The a p p l i c a t i o n o f i p s o - n i t r a t i o n

t o the

p r e p a r a t i o n o f nitrocyclohexa-2,4-dienones h a s c o n t i n u e d t o b e s t u d i e d . 385 386 F u n c t i o n a l i z a t i o n of n i t r o a r e n e s h a s s e r v e d t o w i d e n t h e r a n g e o f t h e s e compounds p r e p a r e d . Additions of Grignard r e a g e n t s t o a r e n e s f o l l o w e d by o x i d a t i o n o f a r y l n i t r o n a t e a d d u c t s b a c k t o nitroarenes (along with preparations of t h e corresponding a r y l nitroso-compounds

by t r e a t m e n t o f t h e a d d u c t s w i t h a c i d ) h a v e b e e n

t h e s u b j e c t of a review.387 A s e r i e s of r e l a t e d p a p e r s c o n c e r n i n g v a r i o u s n u c l e o p h i l i c s u b s t i t u t i o n s of hydrogen p a r a t o a n i t r o - g r o u p i n a r e n e s has been

-


NHCOMe

361

NHCOMe

R e a g e n t : i , NOZBF4

, L i BF4 , P t , 50

mA

-2

cm

Scheme 71

Scheme 72

X = leaving g r o u p

, Y-carbanion

s t a b i l i z i n g group

a

, S P h , M e , P r ' Ph , CI f r o m : SPh , C I , S R , Me,NCS,, MeS , P h O , F , Br , I Y f r o m : SPh , S0,Ph S R , C N , C02Me, CO,Bu* ,morpholino R from: H

X

S c h e m e 73

R = substituent


362

published. Reactions of chloromethyl phenyl sulphone w i t h nitrocyclohexadienonitronate a n i o n s , 38a p l u s a d d i t i o n s o f a n i o n s d e r i v e d f r o m a l d e h y d e d i t h i o a c e t a l s , 389 a n i o n s o f a - s u b s t i t u t e d n i t r i l e s and e s t e r s 3 ” ( l e a d i n g t o d i r e c t a - c y a n o a l k y l a t i o n a n d aalkoxycarbonylalkylation), a-halogenoalkyl phenyl sulphone a n i o n , 391 ’ 392 a n d t h e a n i o n of p h e n y l t r i t h i o o r t h ~ f o r m a t e ~ ~ ~ ( l e a d i n g t o n u c l e o p h i l i c f o r m y l a t i o n ) w e r e a l l r e p o r t e d (Scheme

73). A m u l t i s t e p r o u t e t o nitro-compounds

f r o m e i t h e r p r i m a r y or

secondary h a l i d e s o r s u l p h o n a t e s h a s been developed i n c o n n e c t i o n with a s y n t h e s i s of tunicamycin.

The m e t h o d i n v o l v e d S N 2

d i s p l a c e m e n t by a z i d e , a n d f o r m a t i o n o f a p h o s p h i n e - i m i n e

followed

by o z o n o l y s i s ( r e q u i r i n g t h r e e e q u i v a l e n t s o f o z o n e ) a t l o w t e m p e r a t u r e . 394

The f o r m a t i o n o f c a r b o n y l c o m p o u n d s a s s i d e

p r o d u c t s i s f a v o u r e d by t h e p r e s e n c e o f a n a - p h e n y l

substituent i n

t h e a z i d e (Scheme 7 4 ) . Reduction of a,b-unsaturated

nitro-compounds

a l s o s e r v e s as an

e f f e c t i v e method f o r t h e p r e p a r a t i o n o f n i t r o a l k a n e d e r i v a t i v e s . B-Phenyl-substituted n i t r o e t h a n e s h a v e b e e n p r e p a r e d by n i t r o olefin reductions using trialkylborohydrides o f n i t r o n a t e s a l t s on s i l i c a

f o l l o w e d by h y d r o l y s i s

by u s e o f sodum b o r o h y d r i d e i n

m e t h a n o l , 396 a n d w i t h 3 , 5 - d i e t h o x y c a r b o n y l - 2

6-dimethyl-I ,4-

d i h y d r o p y r i d i n e - s i l i c a g e l . 397 The C - a l k y l a t i o n o f n i t r o a l k a n e c a r b a n i o n s w i t h I - a l k y l - 2 - t butyl-4-phenyl-(and

2,4-diphenyl-)5,6-dihydrobenzo-[~]-quinoliniurn

c a t i o n s h a s b e e n r e p o r t e d .398

More s p e c i a l i z e d s t u d i e s h a v e

i n c l u d e d s y n t h e s i s o f 1 , 4 - d i n i t r o c u b a n e , 399 p l u s a n e x a m i n a t i o n o f t h e e f f e c t s of sodium n i t r i t e - a c e t i c

a c i d on b o t h a- a n d 8 -

- 400

pinene The p r e p a r a t i o n o f a , b - u n s a t u r a t e d r e p o r t e d on s e v e r a l o c c a s i o n s .

nitro-compounds

h a s been

D i r e c t n i t r a t i o n s of o l e f i n s have

b e e n a c h i e v e d i n t e r a l i a by u s e o f n i t r i c a c i d - a c e t i c ( l e a d i n g t o n i t r a t i o n of an enol-lactone

anhydride

i n t e r m e d i a t e i n an

C/D r i n g s y n t h o n s ) 1401 a n d w i t h cisbis(acetonitri1e)dinitro-(or chloronitro-)palladium(II) u n d e r s t r i c t l y anhydrous c o n d i t i o n s . 4 0 2 N i t r o - o l e f i n s have a l s o r e s u l t e d f r o m t h e c o n d e n s a t i o n o f n i t r o m e t h a n e w i t h some s a l i c y l a l d e h y d e s i n t h e p r e s e n c e of d i m e t h y l a m m o n i u m c h l o r i d e a n d p o t a s s i u m f l u o r i d e i n The a d d i t i o n o f a c e t y l n i t r a t e t o c y c l i c relfuxing toluene.396 o l e f i n s was a l s o i n v e s t i g a t e d . H o w e v e r , 1 , 2 - a d d i t i o n was f o u n d t o be a m i n o r pathway w i t h 1 , 3 - and l y 4 - a d d i t i o n p r o d u c t s

approach t o 1 I-keto-steroid


R’N3

+R P

+ R’NO,

dN=PR;%

3 63

+

R;P=O

+ N2

/O

R*CH~N’ ‘0-

J. +R33p0 R’CH=N-OOH

-

RZCH~N=O

+ 2 0, R’CHO

fog+ 0

OC HZC C 1,

-To

K)(= N, X=

‘ I

i’

NO2

R e a g e n t s : i , CHZC12, 3 5 O C ; i i , 0 3 ( 3 . 3 - 4 e q u i v . )

Scheme 74

yx

Y

RX

+

0

NaCo(CO14

Y

4, (CO

II + CO -+ RC-CoKO),

=

KO),

0

R

J.

B-

A4yR 0

Scheme 75


364

p r e d o m i n a t i n g . 403 H o m o a l l y l i c n i t r o - d e r i v a t i v e s w e r e o b t a i n e d on s u b s t i t u t i o n o f a l l y l p h e n y l e t h e r s and a l l y l c a r b o n a t e s w i t h n i t r o a c e t a t e s c a t a l y s e d by p a l l a d i u m c o m p l e x e s , p a r t i c u l a r l y [Pd ( d d p e ),I

, 404

and

w e r e a l s o o b t a i n e d f r o m a l l y l a c e t a t e s u s i n g [ P d ( d b a ) 2 1 - P h P and 3 [Pd ( d p p e ) , I , 323 a l t h o u g h i n t h e l a t t e r r e p o r t a - d i a l l y l a t e d n i t r o a c e t a t e s were sometimes o b s e r v e d . The s y n t h e t i c u t i l i t y o f n i t r o e t h e n e s a s M i c h a e l a c c e p t o r s i s w e l l known a n d h a s b e e n e x e m p l i f i e d

i n t h e s y n t h e s i s o f 6-oxo-PGE1,

a n d 6 - 0 x o - P G F 2 , , ~ ~ a~n d a l s o i n a n o v e l c y c l o p e n t e n o n e a n n u l a t i o n . 406 2 ' - N i t r o p r o p - 2 I - e n y l - 2 , 2 - d i m e t h y l p r o p a n o a t e r e p o r t e d t o b e a v e r s a t i l e n i t r o a l l y l a t i n g r e a g e n t . '07

was

The Henry r e a c t i o n was a l l u d e d t o a b o v e i n c o n n e c t i o n w i t h t h e s y n t h e s i s of n i t r o a l k e n e s

nitroaldol products. This useful r e a c t i o n h a s b e e n a c c o m p l i s h e d u n d e r h i g h - p r e s s u r e c o n d i t i o n s , 408 a n d a l s o u n d e r s o l v e n t - f r e e c o n d i t i o n s on s i l i c a g e l . 4 0 9

Products

of t h e l a t t e r method w e r e o x i d i z e d t o l i n e a r a - n i t r o - k e t o n e s

chromium r e a g e n t s u n d e r p h a s e - t r a n s f e r

using

c o n d i o n s .409

E-Nitro-B,y-enones have been s y n t h e s i z e d , i n moderate y i e l d s from 1 , 3 - d i e n e s and a l k y l n i t r o n a t e s under t h e i n f l u e n c e of ( n - a l l y l ) c o b a l t complexes.410

T h i s r e a c t i o n was f o u n d t o b e h i g h l y

sensitive t o s t e r i c constraints with severely hindered substrates g i v i n g r i s e t o p r o d u c t s a r i s i n g from competing dienone f o r m a t i o n (Scheme 7 5 ) .

A l l e n e s were found t o undergo similar r e a c t i o n

a f f o r d i n g 2-[1-(2-nitroethyl)len-2-ones.

2-(2-Nitroethyl)-1,3-dioxolane

was r e p o r t e d t o b e a u s e f u l 3-

oxopropyl a n i o n synthon i n t h e s y n t h e s i s of jasmonoid and p r o s t a n o i d compounds i n t e r m e d i a t e s . 41 1

via

nitro-alcohol

and n i t r o - k e t o n e

I n a similar v e i n t o t h e hydrogen s u b s t i t u t i o n s noted above, s i l y l e n o l e t h e r s a n d s i l y l k e t e n e a c e t a l s were f o u n d t o r e a c t w i t h n i t r o a r e n e s i n the presence of a f l u o r i d e i o n s o u r c e , f o r example

tris(dimethy1amino)sulphonium

difluorotrimethylsiliconate, t o g i v e

a - n i t r o a r y l c a r b o n y l c o m p o u n d s on o x i d a t i o n o f t h e i n t e r m e d i a t e a d d u c t s w i t h b r o m i n e ,41 w h i l s t 2 - c h l o r o p r o p i o n a t e s w e r e shown t o g i v e good y i e l d s o f 2-(4-nitroaryl)-propionates i n t h e p r e s e n c e o f b a s e . 413 The s y n t h e s i s o f n i t r o - s u b s t i t u t e d c5.4.0. O2

.O3? l o .05'91undecane-8

,1 l - d i o n e s

pentacyclowas r e p o r t e d . 4 1 4

a - N i t r o - c a r b o x y l a t e s w e r e p r e p a r e d f r o m t h e c o r r e s p o n d i n g achloro-a-nitro-compounds by t r e a t m e n t w i t h t r i p h e n y l p h o s p h i n e . 4 1 5 S i m i l a r l y , t h e =,a-dichloro-a-nitro-derivatives c o u l d b e

365

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups s e l e c t i v e l y dehalogenated t o g i v e t h e a-chloro-a-nitro-esters. l-Nitro-3-ethylene-l,1,5-trichlorides w e r e o b t a i n e d u p o n c u p r o u s chloride-assisted d i e n e s . 416

a d d i t i o n s of trichloronitromethane a c r o s s 1,3-

A number o f o t h e r h e t e r o a t o m - s u b s t i t u t e d

been r e p o r t e d .

nitro-compounds

have

A d d i t i o n s of t h i o p h e n o l and formaldehyde t o n i t r o -

o l e f i n s w e r e f o u n d t o be c a t a l y s e d by t e t r a m e t h y l g u a n i d i n e ,

and

f o l l o w i n g a c y l a t i o n I-acyloxymethyl-I-nitro-2-phenylthioalkanes were o b t a i n e d .417

T h e s e s u b s t r a t e s were u t i l i z e d i n s y n t h e s e s o f

a l l y l i c actates since tri-n-butyltin

hydride reduction led t o

r e g i o s e l e c t i v e d e n i t r a t i o n and d e s u l p h u r i z a t i o n .

1-Nitroalkane

p h o s p h o n a t e s w e r e o b t a i n e d upon o x i d a t i o n o f t h e c o r r e s p o n d i n g p h o p h o n o x i m e s w i t h F-CPBA

i n d i c h l o r o m e t h a n e . ‘I8

A Henry-type

r e a c t i o n o f p h e n y l t h i o m e t h a n e w i t h some a l d e h y d e s a f f o r d e d a l d o l p r o d u c t s w h i c h g a v e r i s e t o I-nitro-I-phenylthioalkenes o n t r e a t m e n t w i t h m e t h a n e s u l p h o n y l c h l o r i d e . ‘Ig

T h e s e p r o v e d t o be

e x c e l l e n t s u b s t r a t e s f o r Michael s u b s t i t u t i o n s w i t h n u c l e o p h i l e s , t h e s e r e a c t i o n s l e a d i n g u l t i m a t e l y t o t h e f o r m a t i o n of a -

substituted-2-phenyl-thioesters.

I-Aryl

(and a l k y l ) - l - e t h y l t h i o - 2 -

n i t r o - o l e f i n s c a n be p r e p a r e d from a - n i t r o - k e t o n e s the c o r r e s p o n d i n g d i e t h y l t h i o a c e t a l s by t r e a t m e n t w i t h e t h a n e t h i o l i n t h e p r e s e n c e of e i t h e r z i n c c h l o r i d e o r boron t r i f l u o r i d e d i e t h y l e t h e r a t e . 420

A d d i t i o n of b e n z e n e s e l e n y l bromide t o v i n y l s i l a n e s i n

t h e p r e s e n c e of H g C 1 2 i n THF a t -78

OC

f o l l o w e d by a d d i t i o n o f

s i l v e r n i t r a t e i n a c e t o n i t r i l e l e d t o t h e i s o l a t i o n o f 1-

selenophenyl-I-trimethylsilyl-2-nitroalkanes.

O x i d a t i o n of

s e l e n i u m a n d s y n - e l i m i n a t i o n o f t h e s e l e n o x i d e f u r n i s h e d 2n i t r o v i n y l s i l a n e s w h i c h were s t u d i e d f u r t h e r i n r e l a t i o n t o t h e i r p o t e n t i a l as D i e l s - A l d e r d i e n o p h i l e s . 42 1 The i n t r o d u c t i o n o f a n i t r o - g r o u p i n t o h e t e r o c y c l i c n u c l e i c o n t i n u e s t o be a matter o f i n t e r e s t .

was p r e p a r e d f r o m 2 - a m i n o - 4 - n i t r o a n i l i n e

The n i t r o b e n z i m i d a z o l e ( 8 1 ) by r e a c t i o n w i t h

N,l-

dimethylchloroformiminium c h l o r i d e i n t o l u e n e , 4 2 2 w i t h r e l a t e d , n i t r o i n d a z o l e s b e i n g p r e p a r e d f r o m t h e c o r r e s p o n d i n g 2a l k y l n i t r o d i a z o n i u m s a l t s , p o t a s s i u m a c e t a t e a n d 18-crown-6 i n c h l o r o f o r m . 423 I n g e n e r a l i n d a z o l e s b e a r i n g e l e c t r o n - d o n a t i n g o r - w i t h d r a w i n g s u b s t i t u e n t s c o u l d b e p r e p a r e d by t h i s m e t h o d . A n u m b e r of 2 - n i t r o b e n z o f u r a n s

have been s y n t h e s i z e d .

One r o u t e

t o t h e s e compounds i n v o l v e d m e t a l l a t i o n of 3 - a l k y l - I - b e n z o f u r a n s

at

with t-butyl-lithium, transmetallation with trimethylchlorotin, 424 and s u b s e q u e n t r e a c t i o n w i t h t e t r a n i t r o m e t h a n e (Scheme 7 6 ) , C-2


3 66

+ R3

BrCH,NO,

i v or 7

3

R4

R4

R e a g e n t s : i, 6utLi (1.lequiv.);

NO2

R

OH

ii,Me3SnCL,(1.1equiv.);

K Z C 0 3 ( 2 . 3 e q u i v . ) , Me2C0, 2 5 O C

iii, C ( N O 2 ) 4 , D M S O ; iv,

; v, K2C03(2.5 e q u i v . ) , OMSO

Scheme 76

5: Amines, Nirriles, and Other Nitrogen-containing Functional Groups

367

while another l e a d i n g t o a wider range of 3-unsubstituted-2nitrobenzo[b]furans required only treatment of t h e appropriate s a l i c y l a d e h y d e d e r i v a t i v e s w i t h p o t a s s i u m c a r b o n a t e i n DMSO (Scheme 7 6 1. 425 The n i t r a t i o n of m e t h y l 2 - f u r o a t e w i t h a c e t y l n i t r a t e h a s b e e n s t u d i e d i n d e t a i l and t h e s t r u c t u r e s of s i x i s o l a t e d i n t e r m e d i a t e a d d u c t s w e r e c h a r a c t e r i z e d .426

N i t r a t i o n i n t h e c a r b o z o l e series

h a s a l s o b e e n s t u d i e d . 427 Novel n i t r o p y r a z i n e s were s y n t h e s i z e d as hypoxic c e l l r a d i o s e n s i t i z e r s ,428 a n d 3 - n i t r o - 5 - a c y l p y r i d i n e s p r e p a r e d by c o n d e n s a t i o n o f n i t r o m a l o n a l d e h y d e w i t h e n a m i n o n e s . 429 The l a t t e r r e p o r t a l s o p r e s e n t e d e v i d e n c e f o r t h e i n t e r m e d i a c y of 3 - c h l o r o - 2 nitroacrolein i n the preparation.

A one-pot

u n s u b s t i t u t e d 3-nitro-2H-chromenes

involving refluxing

s y n t h e s i s of 2-

s a l i c y l a l d e h y d e s w i t h n i t r o e t h a n o l and di-n-butylammonium i n i s o p e n t y l a c e t a t e h a s been d e s c r i b e d (Scheme 7 7 ) . 4 3 0

chloride 6- and 7-

Methoxy-2-aryl-3-nitro-2H-chromenes (3-nitroflavenes) have a l s o been r e p o r t e d , being s y n t h e s i z e d from t h e a p p r o p r i a t e m e t h o x y s a l i c y l a l d e h y d e s and w - n i t r o s t y r e n e s i n t h e p r e s e n c e o f t r i e t h y l a m i n e , 431 t h i s forming p a r t of a n o v e l methoxyflavonol synthesis.

N i t r o g e n d i o x i d e h a s been observed t o n i t r a t e

m e t a l l o p o r p h y r i n s i r r e v e r s i b l y , a n d t h e s i t e of n i t r a t i o n f o u n d t o b e d e p e n d e n t on t h e c o - o r d i n a t e d

Copper ( 1 1 1 , n i c k e l ( I I ) ,

a n d p a l l a d i u m ( I 1 ) c o m p l e x e s were n i t r a t e d a t t h e p o r p h y r i n B p y r r o l i c p o s i t i o n w h e r e a s m i x t u r e s o f p r o d u c t s , i n w h i c h t h e meson i t r a t e d compounds p r e d o m i n a t e d ,

were o b t a i n e d f r o m t h e

m a g n e s i u m ( I I ) , z i n c ( I I ) , c o b a l t ( I I ) , and c h l o r o i r o n ( I I 1 ) porphyrins. The g e n e r a l u t i l i t y o f d e o x y n i t r o - s u g a r s b e on t h e i n c r e a s e .

i n synthesis appears t o

The p r e p a r a t i o n o f I - C - n i t r o g l y c o s y l

chlorides

f r o m p a r t i a l l y p r o t e c t e d 4- o r 5 - h y d r o x y - s u g a r NaOCl under p h a s e - t r a n s f e r

oximes w i t h aqueous c o n d i t i o n s h a s b e e n d e s c r i b e d , 433 a l o n g

w i t h d e t a i l s c o n c e r n i n g s u b s t i t u t i o n s o f t h e s e c o m p o u n d s by w e a k l y b a s i c c a r b a n i o n s . 434 C h a i n e l o n g a t i o n o f t h e d e o x y - n i t r o r i b o s e d e r i v a t i v e ( 8 2 ) by M i c h a e l a d d i t i o n t o t h e v i n y l p h o s p h o n a t e ( 8 3 ) l e d u l t i m a t e l y t o a s y n t h e s i s o f d i e t h y l phosphashikimate ( 8 4 ) . 435 An a t t e m p t e d s y n t h e s i s of ( 8 4 ) 2 p r e p a r a t i o n o f ( 8 5 1 , h o w e v e r , f a i l e d s i n c e t h e l a t t e r compound c o u l d n o t b e p r e p a r e d . However, p r e p a r a t i o n of a s i m i l a r a - n i t r o - a - b u t y r o l a c t o n e

was d e s c r i b e d . 436 N-Nitro-compounds

d e r i v a t i v e (86)

h a v e been p r e p a r e d on a number o f o c c a s i o n s .


368

NO2 CH=O

I

'

CH2 f3un22NCH2 Cl-

+ I

CH2

R3

R4

OH

'W"

R3

I

R4

OH

S c h e m e 77

T r O g N o 2

a

HyPOIEtl

HO'

O

x

0

(83)

OH OH

(841

(82)

-.$

H 02C

NO2

(86)

O2NR

0

4 (85 1

369


a - A c e t o x y n i t r a m i n e s h a v e b e e n s y n t h e s i z e d , 437 a n d r e l a t e d l - a c o x y c o n v e r t e d i n t o 1 - a l k o x y - I - n i t r a m i n e s .438 N i t r a t i o n o f

N-nitramines

-N-alkyl-2-benzolyhydroxylamines d e r i v a t i v e s . 439

a f f o r d e d t h e c o r r e s p o n d i n g !-nitro-

The s y n t h e s i s o f c y c l i c 1 , 3 - d i n i t r a m i n e s h a s a l s o

b e e n r e p o r t e d . 440 Treatment of N - c h l o r o d i a l k y l a m i n e s w i t h sodium n i t r a t e a f f o r d e d i n o v e r 90% y i e l d , 4 4 1 a n d , f u r t h e r m o r e , i t was

N-nitrosamines

d i s c o v e r e d t h a t s e c o n d a r y a m i n e s c o u l d be c l e a n l y c o n v e r t e d i n t o n i t r o s a m i n e s i n high y i e l d under phase-transfer s o d i u m n i t r i t e a n d N - c h l o r o s u c c i n i m i d e . 442

E-

conditions using

I n a d d i t i o n , sodium

n i t r i t e was u s e d t o c o n v e r t N , N - d i a l k y l s u l p h a m o y l c h l o r i d e s i n t o t h e c o r r e s p o n d i n $ 1 - n i t r o s a m i n e s i n n e a r q u a n t i t a t i v e y i e l d s . 443 The s y n t h e s i s o f p h e n o l i c a l k y l b e n z y l n i t r o s a m i n e s h a s b e e n reported.

444

Reaction of n i t r o s y l c h l o r i d e with imines afforded N-alkyl-I-

chloro-N-nitrosoalkylamines w h i c h c o u l d b e s u b s t i t u t e d by c a r b o x y l a t e a n i o n s . 445 a-Chloroketoximes nitrosoalkenes,

were e v a l u a t e d as p r e c u r s o r s o f

s i n c e t h e s e compounds h a v e been p o s t u l a t e d a s d i e n e

"'

Ncomponents of i n t r a m o l e c u l a r Diels-Alder-type r e a c t i o n . N i t r o s o - d i p e p t i d e s h a v e b e e n s y n t h e s i z e d , 447 a n d l a r g e - s c a l e preparations of t h e carcinogens E-nitrosodiethanolamine

a n d a-

ureidodimethylnitrosamine h a v e b e e n r e p o r t e d . 448 Thionitroso-compounds were r e p o r t e d t o a r i s e from t r e a t m e n t of some s t e r i c a l l y h i n d e r e d E - n i t r o s a m i d e s and f r o m b e n z i s o t h i a z o l e r i n g

w i t h L a w e s s o n ' s r e a g e n t , 449

fragmentation^.^^'

Thiophene

y l i d e s w e r e shown t o r e a c t r e a d i l y w i t h e l e c t r o n - r i c h t o y i e l d a d d u c t s f o r m e d by e x t r u s i o n o f a c y l thionitroso-compounds

S,g-

dienophiles

and s u l p h o n y l -

which were r e a d i l y t r a p p e d as t h e i r

corresponding Diels-Alder

or e n e - r e a c t i o n a d d u c t s .45

N i t r o s y l s a l t s have been g e n e r a t e d i n anhydrous c h l o r i n a t e d hydrocarbons

via

c l e a v a g e of a l k y l n i t r i t e s w i t h t r i m e t h y l s i l y l

h a l i d e s2. 5 - 2

9 Hydrazines and Hydrazones H y d r a z i n e s h a v e b e e n p r e p a r e d from azo-compounds

by t h e a c t i o n of

p h e n y l t e l l u r o l ( g e n e r a t e d i n s i t u from phenyl-lithium

and m e t a l l i c . t e l l u r i u m i n THF) i n t h e p r e s e n c e o f t r i f l u o r o a c e t i c a c i d . 4 5 3 (Amines c o u l d a l s o b e p r e p a r e d from n i t r o - c o m p o u n d s u s i n g t h e r e a g e n t , and t h e r e a g e n t s p e c i f i c i t y compared w i t h t h a t o f h y d r o g e n


370

N i t r o s a m i n e s w e r e c o n v e r t e d i n t o h y d r a z i n e s on

telluride.)

r e a c t i o n i n a q u e o u s s o l u t i o n w i t h t i t a n i u m t r i c h l o r i d e , f o l l o w e d by t r e a t m e n t w i t h p o t a s s i u m h y d r o x i d e . 454

P r e p a r a t i o n s of c a r b o x y l i c

a c i d h y d r a z i d e s have a l s o been r e p o r t e d .455 Cupric chloride-catalysed

a d d i t i o n s of a r y l a m i n e s t o

a r y l a z o a l k e n e s l e d t o t h e f o r m a t i o n of some 2a r y l a m i n o h y d r a z o n e s . 456

An i n d e p e n d e n t

s y n - and a n t i - p h e n y l h y d r a z o n e s d e p e n d e n t . 457

s t u d y showed t h a t r a t i o s o f

o b t a i n e d i n t h i s manner were s o l v e n t

Improved c o n d i t i o n s f o r t h e p r e p a r a t i o n and

r e d u c t i v e c l e a v a g e o f s t e r o i d a l k e t o n e t o s y l h y d r a z o n e s , by s i m p l e m o d i f i c a t i o n s of l i t e r a t u r e m e t h o d s , were r e p o r t e d . 458 S y n t h e s e s of t h i o a c y l h y d r a z ~ n e s a~n~d ~ s y m m e t r i c a l h y d r a z o n y l ~ u l p h i d e s ~ h~a 'v e b e e n p u b l i s h e d . A s y m m e t r i c s y n t h e s e s i n v o l v i n g m e t a l l a t i o n of c h i r a l h y d r a z o n e s h a v e been mentioned above;32 t h e u s e of s u c h r e a c t i o n s i n enantioselective a-alkylations 46 1

of a c y c l i c k e t o n e s h a s been f u r t h e r

described.

10 H y d r o x y l a m i n e s a n d H y d r o x a m i c

Acids

Hydroxylamines have been o b t a i n e d from a c y l nitro-compounds

by

t r e a t m e n t w i t h e x c e s s h y d r a z i n e h y d r a t e and s m a l l amounts o f Raney N i c k e l W-4

i n ethanol-dichloromethane

(1:l)

at 0

OC.

462

Unstable

hydroxylamines were c o n v e r t e d i n s i t u i n t o t h e i r r e s p e c t i v e benzoylhydroxamic a c i d s . P h e n o x y a m i n e s w e r e p r e p a r e d by t h e a c t i o n of s o d i u m h y d r i d e a n d on p h e n o l s i n a n e x c h a n g e r e a c t i o n . 4 6 3

2,4-dinitrophenoxyamine

Y i e l d s w e r e s e n s i t i v e t o t h e pKa of t h e p h e n o l i n a m a n n e r consistent with a competitive bimolecular decomposition involving the reagent.

2,4-Dinitro-

a n d 2,4,6-trinitro-chlorobenzenes were

shown t o r e a c t w i t h a l k o x y a m i n e h y d r o c h l o r i d e s , or f r e e 464 t r i t y l o x y a m i n e , t o y i e l d 2-alkyl-PJ-arylhydroxylamines.

0-Benzoylhydroxylamines have been i s o l a t e d f o l l o w i n g t r e a t m e n t of p r i m a r y a m i n e s a l t s w i t h p o t a s s i u m c a r b o n a t e and d i b e n z o y l p e r o x i d e . 465

The p r e p a r a t i o n of h y d r o x a m i c e s t e r - c h l o r i d e s

h a s been r e p o r t e d

a n d t h e r e a c t i o n s of t h e s e s p e c i e s w i t h v a r i o u s n u c l e o p h i l e s h a v e b e e n e x a m i n e d . 466

The s y n t h e s i s of t h i o h y d r o x a m i c a c i d s h a s

evolved i n t o an i m p o r t a n t area owing t o t h e i r a b i l i t y t o c h e l a t e m e t a l i o n s a n d t h e d i v e r s i t y of r e a c t i o n s w h i c h t h e y u n d e r g o . Conversion of hydroxamic a c i d s i n t o t h e i r 2 - a c e t a t e s ,

f o l l o w e d by


37 1

OH C-CI

R e a g e n t s : i , NaHC03 L a w e s s o n 's

+

CHZCLZ or

I

HN-R-

CHCL3 ; ii, A c C I , NaHC03

reagent ; i v , NaOH

Scheme 7 8

I

4 Arnolecular sieves;iii,

372


t h i a t i o n w i t h Lawesson's r e a g e n t and d e a c e t y l a t i o n , allowed d e v e l o p m e n t of a c o n v e n i e n t s y n t h e t i c m e t h o d f o r t h e s e c o m p o u n d s (Scheme 7 8 ) . 4 6 7 11 Imines,

I m i n i u m S a l t s , a n d R e l a t e d Compounds

D i r e c t l i t h i a t i o n of i m i n e s i n t h e p r e s e n c e o f p h e n a n t h r e n e a s a h y d r o g e n a c c e p t o r h a s been d e m o n s t r a t e d , 468 and a l k y l a t i o n s o f t h e r e s u l t a n t a n i o n s have been d e s c r i b e d . P e r h a p s t h e most i m p o r t a n t r o u t e s t o i m i n e s a r e t h e i r p r e p a r a t i o n s f r o m c a r b o n y l compounds a n d t h e i r d e r i v a t i v e s .

An

&

s i t u oxime t o i m i n e r e d u c t i o n u s i n g t r i - n - b u t y l p h o s p h i n e - d i p h e n y l d i s u l p h i d e h a s b e e n a l l u d e d t o a b o v e 2 8 a n d t h e same r e a g e n t s w e r e f o u n d t o r e d u c e n i t r o a l k a n e s t o i m i n e s some o f w h i c h c o u l d b e t r a p p e d i n t r a m o l e c u l a r l y t o y i e l d p y r r o l e s . 469 4 , 5 - D i h y d r o - 2 -

methyl-5-methyleneaminofuran-3-carboxylates were s y n t h e s i z e d f r o m a c e t o a c e t a t e s and n i t r o - o l e f i n s

(Michael a d d i t i o n ) p l u s a c t i v e

m e t h y l e n e c o m p o u n d s .470 An i n t e r e s t i n g m u l t i s t e p c o n v e r s i o n o f h i n d e r e d k e t o n e s i n t o imines h a s been d i s c l o s e d .

Formation of t h e ketoxime from t h e

c a r b o n y l compounds was f o l l o w e d by t r e a t m e n t w i t h n i t r o s y l c h l o r i d e The l a t t e r compound c o u l d

t o yield t h e corresponding N-nitrimine.

b e t r e a t e d w i t h ammonia t o y i e l d t h e i m i n e ( S c h e m e 7 9 ) . 4 7 1 Imines r e s u l t e d from r e a c t i o n s of carbodi-imides

and t u n g s t e n -

c a r b e n e complexes i n a m e t a t h e s i s r e a c t i o n i n v o l v i n g four-membered r i n g i n t e r m e d i a t e s .472 The i m p o r t a n c e o f p h o s p h i n e - i m i n e s

h a s b e e n i n c r e a s e d by t h e i r

u s e i n t h e a f o r e m e n t i o n e d s y n t h e s i s of n i t r o - c o m p o n d s . 394 s y n t h e s i s of phosphine t o s y l i m i n e s h a s been s t u d i e d .

The

Thus f o r

e x a m p l e t r i p h e n y l p h o s p h i n e was a d d e d t o a s o l u t i o n of t e t r a b u t y l a m m o n i u m 1-chlorotoluene-p-sulphonamide ( p r e p a r e d from chloramine-T t r i h y d r a t e and tetrabutylammonium c h l o r i d e ) i n methylene c h l o r i d e t o g i v e (N-toluene-p-sulphonyl-P,P,Pt r i p h e n y l p h o s p h i n e i m i d e . 473-

Related methods l e a d i n g t o

t o s y l i m i n o p h o s p h o r i c a c i d esters and t o s y l s u l p h i n i l i m i n e s (from t h i o e t h e r s ) were a l s o d e s c r i b e d .

[(Trimethylsilyl)methylliminotriphenylphosphorane, p r e p a r e d i n s i t u f r o m [(trimethylsilyl)methyl]azide and t r i p h e n y l p h o s p h i n e , g a v e r i s e t o ( t r i m e t h y l s i l y 1 ) m e t h y l i m i n e s on r e a c t i o n w i t h c a r b o n y l c o m p o u n d s i n a one-pot

procedure.474

lithio-species

Copper(1) a l d i m i n e s g e n e r a t e d from t h e

( p r e p a r e d by a d d i t i o n o f

an

alkyl-lithium

t o an


R\ C=N

R\

O ,H

C=N

R’

R’

+ / 0N ‘O

-

373

R’

\0

H,N-NO,

R\ ,C=NH

-k

&--

R Reagents : i , N O C l , T H F ; ii, NH,

R\

N,O,

C=N R’

,T H F Schema 79

/

Ph

Ph

+ A?-CH=N-A?

Ph C HZr;Et3Cc

I

Ar2-NH-CH-CH-N=C,

PhCHZ-N=ch I, S c h e m e 80

Br2 , C s F

R\

RCZN

-t CSBr,

,C=N

F

‘or

S c h e m e 81

ph

0

Ph

374


i s o c y a n i d e ) added c o n j u g a t i v e l y t o ~ , B - u n s a t u r a t e d c a r b o n y l compounds t o g i v e 4 - i m i n o - k e t o n e s .475 T h e s e c o u l d be f u r t h e r elaborated i n t o 1,4-diketones.

1 - I m i n o a l k y l i m i d a z o l e s were

obtained i n a novel r e a c t i o n of cuprous imidazolide with n i t r i l e s and a l k y l h a l i d e s .476 Reactions of phenyl g l y o x a l with primary amines has allowed t h e s y n t h e s i s o f some m o n o i m i n e s . 4 7 7

N-Cyanamines a n d N-,N'-dicyanoquinone

d i - i m i n e s have been

r e p o r t e d , 478 a s h a v e g - c y a n ~ r n e t h y l m e t h a n i m i d a t e a~n~d~ r e l a t e d F a c i l e s y n t h e s e s of s u b s t i t u t e d N-methylenecarboxanides

and

alkyl-N-methylenecarbamates h a v e b e e n a c h i e v e d by r e a c t i o n o f t r i m e t h y l s i l y l i m i n e s w i t h t h e a p p r o p r i a t e a c y l c h l o r i d e s or chloroformates.

N-

480

A d d i t i o n s o f N-diphenylmethylenebenzylamine t o S c h i f f b a s e s l e d t o f o r m a t i o n o f 1,2-diarylethane-1,2-diamine d e r i v a t i v e s ( S c h e m e

8 0 ) .481 A new i m i n a t i o n p r o c e d u r e f o r g - a l k y l - p y r i d i n i u m a n d -quinolinium salts h a s been p r e s e n t e d , t h i s i n v o l v i n g o x i d a t i o n o f t h e a p p r o p r i a t e s u b s t r a t e s with potassium permanganate i n l i q u i d ammonia. 482 R e p o r t s c o n c e r n i n g a n u m b e r o f o t h e r h e t e r o a t o m s u b s t i t u t e d imines have appeared. B e n z i m i d o y l c h l o r i d e s and d i a l k y l phosphites afforded benzimidoyl phosphites i n t h e presence of t r i e t h y l a m i n e h y d r o c h l o r i d e . On h e a t i n g i n v a c u o t h e s e compounds r e a r r a n g e d t o t h e c o r r e s p o n d i n g b e n z i m i d o y l a n d - s u l p h o x i d e s were p h o s p h o n a t e s . 483 a - I m i n o - s u l p h e n a t e s o b t a i n e d via e l e c t r o p h i l i c a l k y l a t i o n o f t h i o a m i d e - 2 - o x i d e s ( a m i n o s u l p h i n e s ) . 484 An e f f i c i e n t s y n t h e s i s o f N - b r o m o p e r h a l o g e n o I-alkanimines h a s been d e s c r i b e d . The m e t h o d i n v o l v e d a d d i t i o n o f p e r f l u o r o a l k y l n i t r i l e s and bromine t o a c t i v a t e d caesium f l u o r i d e (Scheme 81 ) .485 The b r o m o i m i n e s c o u l d b e p h o t o l y s e d t o y i e l d perfluoroalkyl azines. Sulphenimines ( t h i o - o x i m e s ) have been s y n t h e s i z e d e l e c t r o c h e m i c a l l y i n a m a g n e s i u m b r o m i d e - p r o m o t e d r e a c t i o n o f aa m i n o - a l k a n o a t e s w i t h d i a l k y l o r d i a r y 1 s u l p h i d e s . 486 (2Silyloxyalky1)dialkylphosphine s i l y l i m i n e s w e r e p r e p a r e d f r o m o x i r a n e s and N , N - d i s i l y l p h o s p h i n o u s a c i d a m i d e s i n t h e p r e s e n c e o f N - S u b s t i t u t e d and N - u n s u b s t i t u t e d s u l p h o x i m e s z i n c bromide. were o b t a i n e d on t r e a t m e n t o f s u l p h i l i m i n e s w i t h p o t a s s i u m s u p e r o x i d e a n d 18-crown-6 i n d i c h l o r o m e t h a n e . 4 8 8 I t h a s b e e n shown t h a t , u n d e r c e r t a i n c o n d i t i o n s , c h i r a l 1 , 2 -

"'

375

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups d i m i n e s ( d i a z a d i e n e s ) d e r i v e d from amines w i t h s e c o n d a r y or t e r t i a r y a - c a r b o n s c a n b e s y n t h e s i z e d .489 S y n t h e s i s o f 1 , 3 d i c h l o r o - 1 ,5-diazapenta-l , 4 - d i e n e s , 4 g 0 1 , 2 - h y d r o x y i m i n o i m i n e s ( o b t a i n e d by d i r e c t n i t r o s a t i o n o f B-thio-8-amino-a,B-unsaturated k e t o n e s w i t h n i t r o s y l c h l o r i d e ) ,49

and N,"-bis(2-

h y d r o x y b e n z y l i d e n e ) a r y l m e t h a n e d i a m i r ~ e sh~a ~ v e~ a l l b e e n r e p o r t e d . B e t a i n e s r e s u l t e d f r o m a l k y l a t i o n s o f i m i n e s b e a r i n g a n ahydroxy-group with a l k y l or a l l y 1 i o d i d e s . 493 12 Oximes

The f o r m a t i o n o f a n o x i m e i s a c l a s s i c a l m e a n s o f d e r i v a t i z i n g a c a r b o n y l compound.

I t h a s r e c e n t l y b e e n shown t h a t m e t h o d s f o r

s u c h t r a n s f o r m a t i o n c a n be a p p l i e d t o a - k e t o - c a r b o x y l a t e An e x a m p l e was t h e s y n t h e s i s o f a - a l k o x i m i n o - c a r b o x y l i c moderate y i e l d s from a - k e t o - t h i o l i c alkoxyamines. 4g4

systems. acids in

a c i d e s t e r s and

The method was a p p l i e d t o t h e s y n t h e s i s of

a m i n o p y r i d i n e - c o n t a i n i n g B-lactams. C a t a l y t i c n i t r o s a t i o n o f s t y r e n e d e r i v a t i v e s may become a u s e f u l m e t h o d for t h e s y n t h e s i s of o x i m e s a f t e r t h e r e p o r t t h a t t h e c a t a l y s t [ C O ( D M G H ) ~ ( ~ ~ p) rCo ~ m ]o t e d r e g i o s e l e c t i v e h y d r o n i t r o s a t i o n o f s t y r e n e i t s e l f t o g i v e a c e t o p h e n o n e ~ x i m e . ~ 'O~x i m e s h a v e a l s o b e e n o b t a i n e d i n g o o d y i e l d s from a c t i v e m e t h y l e n e c o m p o u n d s by t r e a t m e n t with. s i l v e r n i t r a t e - t h i o n y l

c h l o r i d e ( S c h e m e 8 2 1. 4 9 6

M e t a l l a t i o n s o f o x i m e s , and i n p a r t i c u l a r a l d o x i m e s , h a v e b e e n t h e s u b j e c t of s e v e r a l s t u d i e s , a n d i t was d i s c l o s e d t h a t d e p r o t o n a t i o n o f a l d o x i m e s c a n be a c h i e v e d and t h e r e s u l t i n g a n i o n s a l k y l a t e d i n h i g h y i e l d .497

Anions g e n e r a t e d from t r i a l k y l s i l y l

e t h e r s of methyl ketoximes were found t o undergo r e a r r a n g e m e n t w i t h 1,4-migration

of t h e s i l y l m o i e t y , t h i s b e i n g r e v e r s e d i n a t h e r m a l

1 , Q - m i g r a t i o n of s i l i c o n from c a r b o n t o oxygen

.498

I n t h e s t e r o i d s e r i e s , 6 - n i t r o - o l e f i n d e r i v a t i v e s underwent f a c i l e r e a c t i o n s w i t h ammonia, m e t h a n o l , and z i n c t o a f f o r d e x c l u s i v e l y t h e o x i m e s o f t h e c o r r e s p o n d i n g 6 - k e t o - s t e r o i d s .499

It

was a l r e a d y known t h a t c o n j u g a t e a d d i t i o n o f G r i g n a r d r e a g e n t s t o

nitroarenes afforded I-alkylnitronates into alkylated nitro16).

t h a t c o u l d be t r a n s f o r m e d

and n i t r o s o - a r e n e s

( s e e , f o r example, r e f .

T r e a t m e n t o f s u c h n i t r o n a t e a d d u c t s d e r i v e d f r o m l-methoxy-4-

nitronaphthalene with hexamethylphosphoric t r i a m i d e l e d t o t h e i s o l a t i o n of 2 - a l k y l - 4 - m e t h o x y - l - ( 2 H ) - n a p h t h a l e n o n e ammonium c h l o r i d e work-up

oximes w i t h an

a n d f o r m a t i o n o f l-alkyl-2,3-dihydro-l,4-

376


Et02CCH2C02Et

-h E tO,CCH(

PhCH20COCH2C02CHfh

NO,)CO,Et

NOH PhCH,OCOCCO,CH II ,Ph

R e a g e n t s : i 1 CF SO C L ( l . O e q u i v . 1 , A g N 0 3 ( 1 . 1 e q u i v . ) , K O B u t (1.0 e q u i v . ) ;

3

2

ii,SOClz

( l . O e q u i v . ) , AgN03 (1.1 e q u i v . )

Scheme 82

OMe

4- RMgX

-b

OMe

OMc

N

/OH

0 Reagents : i , THF; i i , P ( N M e 3 ) 3

Scheme 8 3

377

5: Am in es, Nitriles, and 0t her Nitrogen -conta ining Fun ctiona1 Groups naphthoquinone-I-oximes

i f a work-up

c h l o r i d e was u s e d ( S c h e m e 8 3 ) .

with methanolic hydrogen

16

P y r r o l e d e r i v a t i v e s r e a c t e d with benzenesulphonyl c a r b o n i t r i l e o x i d e g e n e r a t e d i n s i t u t o g i v e 2- a n d 3 - s u l p h o n y l o x i m e s

without

i s o l a b l e oxazoline i n t e r m e d i a t e s , whereas f u r a n r e a c t e d t o g i v e an o x a z o l i n e from w h i c h t h e c o r r e s p o n d i n g 2 - s u l p h o n y l o x i m e was obtained after a ~ i d i f i c a t i o n . ~ " 3-Substituted indoles afforded t h e corresponding 2-sulphonyloximes,

w h i l s t 3-sulphonyl

o x i m e s were

obtained otherwise.

N-Aroyl-N-t-butylhydroxylamines a f f o r d e d 0chlorosulphonylbenzohydroximoyl c h l o r i d e s on t r e a t m e n t w i t h t h i o n y l chloride.

F u r t h e r t r e a t m e n t with e t h a n o l a f f o r d e d benzohydroximoyl

chlorides.501

I-Imidazoyl(hydroximino)acetate was u n e x p e c t e d l y

i s o l a t e d as t h e major p r o d u c t of a r e a c t i o n between 3-ethoxy-2-

.

n i t r o p r o p e n o a t e and i m i d a z o l e 502 G l y o x i m e s were o b t a i n e d f r o m 4 - a c y l - n 2 - o x a z o l - 5 - o n e s

acyl-4-halogeno-A2-oxazol-5-ones

via

4-

by s e q u e n t i a l t r e a t m e n t o f t h e

f o r m e r compounds w i t h s u l p h u r y l c h l o r i d e , h y d r o g e n c h l o r i d e i n

acetic a c i d , sodium b i c a r b o n a t e , and f i n a l l y hydroxylamine h y d r o c h l o r i d e . 503 a - C h l o r o s i l y l k e t o x i m e s h a v e b e e n u s e d a s n i t r o s o a l k e n e p r e c u r s o r s .504 13 Carbodi-imides M i x t u r e s of t w o c a r b o d i - i m i d e s a f f o r d e d u n s y m m e t r i c a l d i - i m i d e s by a m e t a t h e s i s i n v o l v i n g t h e c a r b e n e complex p e n t a c a r b o n y l ( i s o p r o p y 1 i s 0 c y a n i d e ) t u n g s t e n (Scheme 8 4 ) . 4 7 2 The r e a c t i o n o f [(trimethylsilyl)methyl]iminotriphenylphosphorane with e i t h e r i s o c y a n a t e s o r i s o t h i o c y a n a t e s y i e l d e d t h e (Scheme c o r r e s p o n d i n g N'-[(trimethylsilyl)methyl]carbodi-imides 85).474 14 A z i d e s and Diazo-compounds The a b i l i t y o f a z i d e a n i o n t o a c t as a n u c l e o p h i l e i n d i s p l a c e m e n t r e a c t i o n s o f e p o x i d e s , s u l p h o n a t e s , and o t h e r a c t i v a t e d e s t e r s h a s ensured t h a t its use i n t h e s y n t h e s i s of amino-sugars a l c o h o l s h a s been prominent ( s e e a b o v e ) .

and amino-

That a z i d e anion i s

p a r t i c u l a r l y s u i t a b l e f o r displacement of secondary t r i f l a t e s i n b o t h f u r a n o i d a n d p y r a n o i d s u g a r s was e x e m p l i f i e d by s y n t h e s e s o f l-~-methyl-3-azido-2,3-dideoxy-b-ribofuranose, 5 0 5 a n d 1 , 6 - a n h y d r o -


378

4- C,H,,N=C

(CO &W=C =NPr

(

=NC 6Hll

I c 0 I5W-coNPr

I

I

//C-N, ‘6”llN

C6Hll

ti

-I- C6H,,N=C= N P r ’

(CO)5W=C=NC6Hl,

ti

+ Pr I N = C =

hN ‘6*11 (CO,,W-C’ I I 4C-N Pr ‘N ‘Pr i

N Pr’

1.r (CO15W=C =N Pr ’

+

C6H,,N=C=NPr1

Scheme 84

Me3SiCH, N, -tPh,P

+Me3SiCH2N=PP h,

-

Me3Si CH,N=C=N

R

R = Ph, c y c l o h e x y l , or E t Reagents : i , R N C O ; i i , R N C S

g$8& Scheme 85

y&EzMe \

N CO2Et

(87)

‘

N

‘ C02Et

(88)

N

\

H

N

H

(major 1 Clavicipitic a c i d (minor)


379

2-azido-2-deoxy- B-D-glucopyranose derivatives. 506

Use of tosylazide as the ‘+NH2I synthon for the electrophilic amination of arenes and organometallics has been mentioned , 4 1 and treatment of the substituted malonate derivative (87) with sodium hydride and tosylazide in sequence led to the azide ( 8 8 ) , this being a key intermediate in an approach to clavicipitic acids.507 An overall synthesis of primary azides from terminal alkenes resulted from treatment of trialkylboranes with lead tetra-acetate and azidotrimethylsilane (cf. ref. 306) .508 Although hydrazoic acid is normally considered to be unreactive towards alkenes, it has been demonstrated that Lewis acids, particularly titanium tetrachloride, promote addition of the acid to phenylethylenes or 1,1-disubstituted ethylenes but not to monosubstituted 01efins.~” Under these new conditions enoxysilanes gave I-silyloxyazides. It was also found that tertiary ally1 and benzyl alcohols also afforded azides in the presence of titanium tetrachloride, whilst primary alcohols did not. Treatment of a-hydroxyacetophenone dimethyl acetals with azidotrimethylsilane and tin tetrachloride has led to the isolation of both 1-alkoxy-2-silyloxyazides and tetrazoles (&. isolation of intermediate azides was not achieved), the product obtained being dependent on the nature of the aryl substituent (Scheme 86).510 Clay-supported ferric nitrate has been used to convert hydrazines to azides , the latter compounds also being elaborated into iminophosphoranes . 5 1 2 A good deal of research has been directed towards the synthesis of unsaturated azides. Propargylic azides have been synthesized from the corresponding bromides 2 direct displacement with azide anion, and also by addition of the anion to the unsubstituted terminus of allenyl iodide .51 Ultrasonication has facilitated synthesis of propargyl azide, azidoacetonitrile, and primary allylic azides from the corresponding activated halides and aqueous sodium a ~ i d e . ~ ’ These ~ conditions were applied to the synthesis of azido-butadienes via displacement of propargylic bromides with azide anion followed by migration of azides to the vinylic position via an allylic rearrangement (Scheme 87). 5 1 5 Bimolecular nucleophilic substitution of halogenonitroarenes by azide anion was shown to be catalysed by a macrocyclic ammonium salt (cf. ref. 384) .516 2- and 4-Azido-4H-2-chromenes were prepared by addition of excess sodium azide to benzopyrylium salts.517 Ferrier-type


380

OMe

I

X=H x-CI

OMt

I

C

- CH,OH

X X=Me or OMe TMSN3- S n C I 4

,":N

1

CH ,OH

X

Scheme 8 6

BrCH,-CEC-

CH, B r

4' [ N3CH2-

4N~CH,-C~C-CH,N,

C,C-CH,Brl

Reagents : i , NaN,

, EtOH

; ii,

C6H6 ; i i i , NaN3 MeOH; i v , TMGN, Scheme 87

sulpholane


381

carbocyclization of azido hex-5-enopyranosides of D-arabino configuration led to chiral cyclohexane precursors of a m i n o ~ y c l i t o l s . ~In ~ ~ a second study of such reactions, attempted carbocyclization of 3-azido-4-~-benzoyl-2,4,6-trideoxy-B-D-erythrohex-5-enopyranoside led to a cyclohexenone (89) elimination of the elements of hydrazoic acid .51 The a-D-threo-isomer reacted without such elimination (Scheme 88). Addition of p-tosyl azide and various other aryl azides to nbutyl-lithium-treated THF at low temperature was found to result in the formation of diazomethane. The enolate of acetaldehyde (resulting from cycloreversion of THF in the presence of n-butyllithium) was identified as the agent responsible for initiation of the azide decomposition. 520 2,2,2-Trifluorodiazoethane was prepared and used as a protecting reagent for sulphonic acids since, unlike other diazo-compounds, it did not react with carboxylic acids to form esters.521 The reagent was prepared by direct nitrosation of 2,2,2-trifluoroethylamine followed by washing the ethereal solution of the reagent with aqueous citric acid to remove unreacted started amine. 7-Substituted l-diazo-2-norbornanones were synthesized on chromatography of the monotosylhydrazones, derived from the corresponding a-diketones, on basic alumina. 522 The discovery that a-diazoacetates can be transformed into the corresponding silylenol ethers on reaction with trialkylsilyl trifluoromethanesulphonates facilitated an approach to chiral thienamycin analogue precursors (Scheme 89 .523 Efficient preparations of a-diazo-0-ketophosphonates and adiazophosphonoacetates have been described,524 and their intramolecular cyclopropanation reactions studied. The former compounds also underwent photo-induced Wolff rearrangements to yield substituted phosphonoacetates 525 Electrophilic diazolalkane substitution of (diazomethyllphosphoryl compounds with pyrylium tetrafluoroborate afforded 4diazo(phosphony1 )methyl-4g-pyrans. 526 Thermolysis of 3,3diazidotetrahydroquinoline-2,4-diones afforded 3diazidotetrahydroquinoline-2,4-diones 527 Alkyl nitrites and tralkylsilyl halides can be used to generate nitrosyl halides which can react with N,N-bis(trimethylsilyl)amines to generate diazonium salts with the exclusion of a nucleophile from the reaction mixture (since the by-product of the reaction is hexamethyldisiloxane). This method was termed

.

.


382

elimination

OH

OH

RO--Q--OMe Ok

-&

N, R = PhCO or

+

P h C H zRO O..o

Bz 0

PhC HzOO

OAc N3

R e a g e n t s . I , Me3SiS02CF3, E t 3 N ;

1 1 )

PhCHzo.:Q RO, X

PhCH20’

Scheme 89

N3

X=H,R=H

Bu~M~~SIO E tT3 ~ N ;, i i i , ZnC12,

OAc

IV,

1N-NaOH

5: Amines, Nitriles, and Other Nitrogen-containing Functiona 1 Groups

383

'azodesilylation I . 528 15 Azo- and Azoxy-compounds Azo-compounds were reported to result from oxidations of arylamines with bis(2,2'-bipyridyl )copper(II) ~ermanganate.~~' Both 2- and pdiaminobenzenes and 0- and p-aminophenols were oxidized by potassium superoxide to yield diaminoazobenzenes and dihydroxyazobenzenes respectively. 530 Hydrazines may also be converted into azo-compounds. Alkyl- and aryl-hydrazines were oxidized with 2-(trifluoromethy1)benzenesulphonyl peroxide and then treated with base to afford azocompounds which yield products typical of the expected degradation pathways.531 Ethylenediamine has been examined as a potential agent for the reduction of nitroarenes to azo-compounds. At 150 OC meta- and para-substituted nitroarenes afforded symmetrical azo-compounds in good yield, although the corresponding ortho-isomers were inert. 5 32 On the other hand 0- and p-nitroanilines were not reduced whereas the meta-isomer was, affording a mixture of 3,3'-diaminoazobenzene and 1,3-diaminobenzene. 2- and p-Halogenonitrobenzenes were substituted by the reagent. Nitrobenzene was reduced with hexamethyldisilane and a catalytic quantity of tetrabutylammonium fluoride in THF to give azobenzene in 84% yield.533 In an analogous reaction azoxybenzene gave azobenzene in 95% yield. ortho-Substituted nitrobenzenes gave the corresponding azoxycompounds under these conditions, with the exception of 0nitrobenzaldehyde, bulky ortho-substituents preventing further reduction of the azoxy- to azo-compounds. 4-Nitropyridine !-oxide afforded the azoxy-compound (90) which precipitated from the reaction solvent ~,~-dimethylimidazoline-2-one,in 52% yield, plus the azo-compounds (91) and (92) which were recovered in 26% and 12% yields respectively from the mother liquors. Reduction of 4nitropyridines to azo-compounds (or to amines) by lithium aluminium hydride was also described.534 The reaction products that were obtained were dependent on the nature of the pyridine substituents. Substituted 21-hydroxyacetophenone-4-bromophenylhydrazones were readily oxygenated in the presence of Co(Sa1pr) in ethanol to give good yields of 2- (4-bromophenylazo )-I , 3-benzodioxoles. 535 A mechanistic rationale was offered in explanation of the formation of azo-compounds in sodium hydride-induced decompositions of ethyl-


384

N- (2-azidoaryl )carbonates. 536 16 Isocyanates, Thiocyanates, Isothiocyanates, and Selenocyanates Isocyanates have been obtained from perfluoroaklyl hydroxamic acids of I-silyloxy-I-silyloximes derived from the former compounds by treatment with hexamethyldisilazane in acetonitrile .537 Hindered aryl isocyanates may be prepared in exchange reactions between hindered anilines and phenyl isocyanate. 538 a-Arylazo-isocyanates and -isothiocyanates were obtained after the respective oxidations of 2,5,5-trisubstituted 1,2,4-triazolidin-3-ones and -3-thiones with potassium permanganate .539

via pyrolysis -

Reactions of (93) with alkyl halides in the presence of potassium carbonate afforded alkyl thiocyanates. 540 Benzylic thiocyanates were obtained on reaction of the corresponding nitrates with potassium thiocyanate. 54 The benzylic nitrates were formed by the action of ceric ammonium nitrate on methyl benzenes, followed by neutralization of excess nitric acid with potassium carbonate. Hydroxide, cyano, azide, and piperidine nucleophiles were used in place of thiocyanate to afford a useful method for benzylic functionalization. As a reagent system isothiocyanatotributyltin-iodine was found to be superior to potassium thiocyanate-iodine f o r the preparation of v&-iodothiocyanates from olefins .542 The tin reagent was prepared from chlorotributylstannane and potassium thiocyanate. An aryl silane was substituted with thiocyanate by means of thiocyanogen and aluminium chloride. 543 Thiocyanate-subst itur;ed pyridines and pyridinopyrimidines have also been reported .544 As well as hindered isocyanates, hindered aryl isothiocyanates have been prepared in a metathesis between hindered amines and aryl isothiocyanates .545 Glycosyl isothiocyanates have been prepared from anomeric halides and potassium thiocyanate in a polar aprotic solvent in the presence of a tetralkylammonium salt .546 The reaction of cycloalkanones with silicon tetraisothiocyanate in the presence of zinc isothiocyanate or bis(trimethylsilyl!sulphate/tri-n-butyltin fluoride afforded I-cycloalkenyl isothiocyanates in good yield under mild conditions.547 Chloro(pheny1thio)methyltrimethylsilane reacted with lead

385

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups t h i o c y a n a t e t o a f f o r d phenylthio(trimethylsily1)methyl

i s o t h i o c y a n a t e w h i c h was u s e d t o p r e p a r e o x a z o l e s on r e a c t i o n w i t h a r y l aldehydes i n t h e presence of f l u o r i d e ion.54g

3-(3- a n d 4-Methylselenopheny1)alanines were p r e p a r e d by a d d i t i o n o f m e t h y l G r i g n a r d t o acetamido(cyanoselenobenzy1)m a l o n a t e s f o l l o w e d by h y d r o l y s i s .549

The l a t t e r c o m p o u n d s were

f o r m e d by d i a z o t i z a t i o n o f t h e a p p r o p r i a t e a r o m a t i c a m i n e s f o l l o w e d by d e c o m p o s i t i o n o f t h e i n t e r m e d i a t e s i n t h e p r e s e n c e o f a q u e o u s selenocyanate salts.

17 N i t r o n e s N i t r o n e s h a v e b e e n o b t a i n e d from s e c o n d a r y a m i n e s i n o n e s t e p by s o d i u m t u n g s t a t e o x i d a t i o n w i t h h y d r o g e n p e r o x i d e .5501551 ZN i t r o n e s w e r e s y n t h e s i z e d u n d e r m i l d c o n d i t i o n s by a d d i t i o n o f alkoxyamines t o aldehydes i n t h e p r e s e n c e of sodium b i c a r b o n a t e and

C-Aryl-N-( I - c a r b o x y a l k y l ) - n i t r o n e s were o r by c o n d e n s a t i o n o f a - h y d r o x y i m i n o - c a r b o x y l i c a c i d s w i t h a r o m a t i c a l d e h y d e s .553 N-

calcium c h l o r i d e . 552

p r e p a r e d by a l k y l a t i o n of a r o m a t i c 2 - a l d o x i m e s

Carbamoyl-nitrones

w e r e p r e p a r e d by l o w - t e m p e r a t u r e

addition of

i s o c y a n a t e s t o a l d o x i m e s . 554 The r e a r r a n g e m e n t s of 2-chloro-2-nitrosofenchane a n d 2 - c h l o r o - 2 nitrosocamphane t o c h l o r o n i t r o n e s have been r e c o r d e d , 555 and r e c e n t s y n t h e t i c a p p l i c a t i o n s of n i t r o n e s have been reviewed.556

18 N i t r a t e s a n d N i t r i t e s A s w e l l a s t h e a f o r e m e n t i o n e d r e p o r t o f b e n z y l i c n i t r a t i o n by c e r i c

ammonium n i t r a t e , 54

photochemical r e a c t i o n of t o l u e n e s with ceric

ammonium n i t r a t e i n a c e t o n i t r i l e h a s b e e n r e p o r t e d t o e f f e c t t h e same t r a n s f o r m a t i o n i n g o o d y i e l d s u n d e r m i l d c o n d i t i o n s . 557 Both t h i o n y l c h l o r i d e - n i t r a t e

a n d t h i o n y l n i t r a t e were e f f e c t i v e

r e a g e n t s f o r t h e n i t r a t i o n of p h e n o l s and a l c o h o l s .

The f i r s t

r e a g e n t proved s u i t a b l e f o r n i t r a t i o n of primary a l c o h o l s i n c a r b o h y d r a t e m o l e c u l e s , w h e r e a s t h e s e c o n d r e a g e n t was s u f f i c i e n t l y r e a c t i v e t o n i t r a t e secondary hydroxy-groups primary.

i n addition t o

T h u s s e l e c t i v e n i t r a t i o n s o f r i b o n u c l e o s i d e s were

f a c i l i t a t e d .496 A c h r o m a t o g r a p h i c medium c o n s i s t i n g of 30% s i l v e r n i t r a t e -

n e u t r a l a l u m i n a p r o v e d a means f o r c o n v e r t i n g 5 - h a l o g e n o p e n t - 2 - e n e s i n t o 1 - c y c l o p r o p y l e t h y l n i t r a t e . 558

3 86

General and Synthetic Methods References

1

2 3 4 5

6

7 8 9 I0

11

12 13 14 15

16

17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

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9,

9,

2, 2,

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-

.

106,

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92

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2, 9,

5,

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2,

.

-


388 93 94

95 96 97 98 99 100 101 102

103

104 105 106 107 108 109 110 111

112 113 114 115

116

117 118 119 120 121 122 123 124 125 126 127

128 129 130 131 132 133 134 135 136 137 138

14,

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5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 139 140 141 142 143 144 145 146 147 148 149

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150 151 152 153

389

,

16,

.

fi,

-

-


390

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-

c,

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 232 23 3 234 235 236 237 238 23 9 240 24 1 242 243 24 4 24 5 24 6 24 7 248 249 250 25 1 252 25 3 254 25 5 256 257 258 259 260 26 1 26 2 26 3 264 26 5 26 6 267 268 269 270 27 1 27 2 27 3 274 27 5 276 27 7 278 279 280 28 1 28 2

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c,

67,

2,

~

14,

~

s,

396


465 46 6

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500 50 1 502 503 50 4 50 5 50 6

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2,

2,

fi,

2,

1

-

z - z

2,

s,

3,

54 5 546 547 548 549 5 50 551 5 52 5 53 554 555 5 56 5 57 5 58

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16,

Organometallics in Synthesis BY J. BLAGG, S. G. DAVIES, AND P. F. GORDON

The Transition Elements by J. Blagg and S. G. Davies

PART I: 1

Introduction

The format of this report is similar to that of previous years, and as last year the section covering carbon-carbon bond-forming reactions has been subdivided. A book highlighting some practical aspects of the spplications of transition metals for organic synthesis has appeared, as have several useful reviews covering various aspects of the applications of transition metals to organic synthesis. Topics which have been reviewed include the oxidation of olefins to ketones catalysed by palladium, transition-metal-catalysed Cope and Claisen rearrangements, palladium-assisted reactions of mono-olef ins,4 carbene complexes in organic synthesis, copper-assisted coupling and substitution reactions, and cobalt-mediated [2+2+21 'cycloadditions .7 2

Reduction

Further examples of the use of cationic rhodium and iridium catalysts to achieve hydroxyl directed hydrogenations of allylic, homoallylic, and bis-homoallylic alcohols have been reported. Hydrogenation of 3-methylenecyclohexanol ( 0 . 1 M ) at 1 atm H2 pressure with [ (Ph2P (CH2)4PPh2)Rh(norbornadiene) I+BPh4- as catalyst (2 mol%) has been shown to give trans-3-methylcyclohexanol with Very little greater than 98% stereoselectivity (Scheme 1 ) stereocontrol was observed on similar reductions of 2-methylenecyclohexanol and 2-methylenecyclohexanemethanol. The use of the BPh4 salt suppresses competing isomerization 1" eact ions Some optimization of the conditions for these stereoselective hydrogenations and a comparison between the catalysts

.*

For References see page 433.

398

399

6: Organometallics in Synthesis

OH

OH

>> 9 8

OH OIO

90%

trans 1

OMe

R=Ph,Me3Si,Bun, or Me Reagents : i,EtC =CEt

,45OC, 2 4 h i i i , F e m ; iii,Ce=,H20;

iv,CeH,MeOHiv,BuLii

[Cr(CO)6]i vii, NMe4Br; viii, MeS03F , i x , Me3SiOh;x, xi,450Ci xii,Fem,xiii , R C E C H ; x i v , 02

xl;",

Me3SiCl;

/ \

Scheme 59

Scheme 6 0

Scheme 61

$ $ NaNH2 Me I

0

>90

OIO

Scheme 6 2

vi,

0

56 *lo


I32

ii

RCHO

R

y;"o

Reagents: i , [(CO)5MnSiMegl, CO; ii, [(C0)5MnH]

Scheme 63 ,OSiE tpMe 88 '10

i

O @

c

100 %

Reagents: i .HSiEtzMe, CO(50atm),[Co2(C0)~l,PPh3

Scheme 6 4

0 48 - 89 ' l o R$)R'

[(MeCN j2 PdCl 1 B

&

Scheme 65

89%

433

6: Organometallics in Synthesis References

1

2 3 4 5 6 7 8 9 10 11

12 13 14

15 16 17 18 19 20 21 22 23 24

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9,

z, 2,

1593.

36 37

.

1984, 38 39 40 41

42 43

.

.

.

.

.

K Tan i , T Yamagat a , S Akut ag awa , H Kumobay a s h i , T Taket omi , H Takay a , A . M i y a s h i t a , R.Noyori, and S . O t u k a , J . Am. Chem. S O C . , 1984, 5208. E.Curzon, B.T.Golding, C . P i e r p o i n t , and B.W.Waters, J . Organomet. Chem.,

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71

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H . M a s t a l e r z , J . Org. Chem., 19' N.K.Capps, G.M.Davies, and D.W. Young, T e t r a h e d r o n L e t t . , 1984, 2 5 , 4157. S.Achab, J . P . C o s s o n , and B.C.Das, J . Chem. SOC., Chem. Commun., 1984, 10140. R.Noyori and M.Suzuki, Angew. Chem., I n t . Ed. E n g l . , 1984, 23, 847.


434 44 45 46 47 48 49 50

51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72

73 74 75 76 77

K . S a k a i , Y.Ishigut-o, K.Funakoshi, K.Ueno, and H.Suemune, T e t r a h e d r o n L e t t ., 1984, 25, 961. C.Lambert, K.Utimoto, and H.Nozaki, T e t r a h e d r o n L e t t . , 1984, 25, 5323. P . M a r t i n , Helv. Chim. Acta, 1984, 1647. A . C a p r i t a , F . B o n a c c o r s i , and R.Rossi, T e t r a h e d r o n L e t t . , 1984, 2 5 , 5193. 5157. J . T s u j i , I.Minami, and I . S h i m i z u , T e t r a h e d r o n L e t t . , 1984, J . T s u j i , K.Takahashi, I.Minami, and I . S h i m i z u , T e t r a h e d r o n L e t t . , 1984, 4783. J.P.Genet and D.Ferroud, T e t r a h e d r o n L e t t . , 1984, 2, 3579; D.Ferroud, J . P . G e n e t , and J . M u z a r t , p.4379. T . T a k a h a s h i , A.Ootake, and J . T s u j i , T e t r a h e d r o n Lett., 1984, 25, 1921. 2246, S.A.Godleski and E . B . V i l l h a u e r , J . Org. Chem., 1984, 6835. B.M.Trost and J.W.Herndon, J . Am. Chem. S O C . , 1984, R.Tamura, K.Hayashi, Y.Kai, and D.Oda, T e t r a h e d r o n L e t t . , 1984, 2 5 , 4437. F62. R.C.Larock, L.W.Harrison, and M.H.Hsu, J . Org. Chem., 1984, 1872 ; T e t r a h e d r o n A.J.Pearson and M.N.I.Khan, J . Am. Chem. SOC., 1984, 1984, 25, - 3507. A . J . P e a r s o n , P.Bruhn, and I . C . R i c h a r d s , T e t r a h e d r o n L e t t . , 1984, 387 B.M.R.Bandara, A.J.Birch, a n d L . F . K e l l y , J . Org. Chem., 1984, 2496. M.Uemura, T.Minami, and Y.Hayashi, J . Chem. SOC., Chem. Commun., 1984, 1 193. E.J.Corey and M. Kang, J . Am. Chem. SOC., 1984, 5384. G . F r i o u r , G . C a h i e z , and J . F.Normant , S y n t h e s i s , 1984, 37. M.Wada, Y.Sakurai, and K.Akiba, T e t r a h e d r o n L e t t . , 1984, 25, 1079. T.Imamoto, Y . S u g i u r a , and N.Takiyama, T e t r a h e d r o n L e t t . , 1984, 25, 4233. A . G h r i b i , A - A l e x a k i s , and J.F.Normant, T e t r a h e d r o n L e t t . , 1984, 3075 A . G h r i b i , A - A l e x a k i s , and J.F.Normant, T e t r a h e d r o n L e t t . , 1984, 3083 A.E.Greene, J.P.Lansard, J.-L.Luche, and C . P e t r i e r , J . Org. Chem., 1984, 931. J . B e r l a n , Y.Besace, D . P r a t , and G . P o u r c e l o t , J . Organomet. Chem., 1984, 399. N.Aktogu, H . F e l k i n , G . J . B a i r d , S . G . D a v i e s , and 0-Wat ts , J . Organomet. Chem., 49. 1984, S.G.Davies, I.M.Dordor, and P.Warner, J . Chem. SOC., Chem. Commun., 1984, 956. L . S . L i e b e s k i n d and M.E.Welker, T e t r a h e d r o n L e t t . , 1984, 25, 4341. S.G.Davies, I.M.Dordor, J. C.Walker, and P.Warner , T e t r a h e d r o n L e t t . , 1984, 2 5 , 2709. 1743; K.Broadley and S.G.Davies, T e t r a h e d r o n L e t t . , 1984, L . S . L i e b e s k i n d , M.E.Welker, and V.Goedken, J . Am. Chem. SOC., 1984, 441. G . J . B a i r d , S.G.Davies, R.H.Jones, K . P r o u t , and P.Warner, J . Chem. SOC* , Chem. Commun., 1984, 745. P . J . C u r t i s and S.G.Davies, J. Chem. S O C . , Chem. Commun., 1984, 747. S.G.Davies and J . I . S e e m a n , T e t r a h e d r i3n L e t t . , 1984, 25, 1845. S.M.Clift and J . S c h w a r t z , J . Am. Chem. SOC., 1984, 106, 8300. L.S. Hegedus, M. A. McGuire, L .M. S c h u l t !ze. C.Yi.iun. . and 0.P.Anderson , J . Am. Chem. SOC.. 1984. 106. 2680. W.J.Scott, G.T.Crisp, and J . K . S t i l l e , J . Am. Chem. SOC., 1984, %, 4630. 2271. S . C a c c h i , E.Morera, and G-Ortar, T e t r a h e d r o n L e t t . , 1984, M.Kosugi, T.Sumiya, T.Ogata, H.Sano, and T . M i g i t a , Chem. L e t t . , 1984, 1225. K.C.Eapen, S.S.Dua, and C.Tamborski, J . Org. Chem., 1984, 4 9 , 478. H.Suzuki, S.V.Thiruvikraman, and A.Osuka, S y n t h e s i s , 1 9 8 4 , 7 1 6 . M.Kosugi, I.Hagiwara, T . S m i y a , and T . M i g i t a , B u l l . Chem. S O C . , J p n . , 1984, 5 7 , 242. E . N e g i s h i , N-Okukado, S . F . L o v i c h , and F.T.Luo, J . Org. Chem., 1984, 2629. 2657. P . J . H a r r i n g t o n and L.S.Hegedus, J . Org. Chem., 1984, E.R.F.Gesing, U.Groth, and K.P. C - V o l l h a r d t , S y n t h e s i s , 1984, 351. R.E.Geiger , M.Lalonde, H . S t o l l e r , and K . S c h l e i c h , Helv. Chim. A c t a , 1984, 6 7 , 1274. 4181. M.S.South and L . S . L i e b e s k i n d , J . Am. Chem. SOC., 1984,

3,

25,

w.,

9, 106,

78 80 81 82 83 84

85 86

87 88

106,

g.,

2,

25,

2,

106,

25, 25,

264,

262,

-

25,

106, -

,

I

79

2,

-

- 7

25,

-

9,

9,

-

106,


43 5

M.E.Wright , J. F.Hoover , G.O.Nelson, C.P.Scott, and R.S.Gfass, J. Org. Chem., 1984, 2, 3059; R.S.Glass and W.W.McConnel1, Organometallics. 1984, 3, 1630. -. 90 W.D.Wulff, K.-S.Chan, and P.-C.Tang, J. Org. Chem., 1981+,49, 229 3. . 1984, 106, 4 3 4 7 W.D.Wulff and P.-C.Tang, J. Am. Chem. SOC.. 91 W.D.Wulff and D.C.Yang, J. Am. C-hem. SOC., 1984, 106,7565. 92 P.-C.Tang and W.D.WUlff, J. Am. Chem. SOC., 1984, 106, 1132. 93 D.C.Billington and D-Willison, T'etrahedron Lett ., 1984, 25, 4041. 94 M.J.Knudsen and N.E.Schore, J. Org. Chem. - 198-4, 5 0 2 c 95 L .Daalman , R. F. Newton, P. L .Pauson, R.,G.Taylor, and A.Wadsworth, 3 . Chem. 96 Res. ( S ), 1984, 344 ; L.Daalman, R.F.Newton, P.L .Pauson, and A-Wadsworth, ib_ i_d- .-. n.246.- P.Eilbracht, E.Balss, and M.Acker, Tetrahedron Lett., 1984, 25, 1131. 97 K.C.Brinkman and J. A-Gladysz, Organometallics, 1984, 3, 147: 98 N.Chatani, H-Furukawa, T.Kato, S.Murai, and N.Smoda, J. Am. Chem. SOC., 99 1984, 106,430. 100 V.Rautenstrauch, J. Org. Chem., 1984, 2, 950. 89

2,

-

I

r - +


436 PART 11:

Main Group E l e m e n t s by P. F . Gordon 1

Group I

S e l e c t i v e L i t h i a t i o n s . - S n i e c k u s and h i s co-workers have c o n t i n u e d t h e i r a c t i v e r e s e a r c h on s p e c i f i c o r t h o - l i t h i a t i o n r e a c t i o n s i n b e n z e n e compounds. Much o f t h i s work i s now t a r g e t t e d t o w a r d s p r e p a r i n g n a t u r a l p r o d u c t s , and t h i s y e a r h a s s e e n e x t e n s i v e u s e made o f t h e a m i d e g r o u p (CONEt2) a n d t o a l e s s e r e x t e n t t h e carbamate and e t h e r g r o u p s t o p r o v i d e t h e n e c e s s a r y d i r e c t i n g i n f l u e n c e . For example t h e benzamides ( l a , b ) a r e c o n v e r t e d i n t o t h e s i l y l protected 2-toluamides (2a,b) i n a sequence t h a t involves t h r e e separate l i t h i a t i o n reactions; t h e first is an orthol i t h i a t i o n and t h e second and t h i r d are used t o i n t r o d u c e t h e protecting s i l y l groups. ortho-Lithiation of t h e toluamides (2a,b) and r e a c t i o n w i t h t h e c o r r e s p o n d i n g a r y l a l d e h y d e t h e n l e a d s t o p h t h a l i d e s ( 3 ) , f r o m w h i c h t h e a n t h r a q u i n o n e s (4) a n d ( 5 ) c a n b e o b t a i n e d by c o n v e n t i o n a l f u n c t i o n a l g r o u p t r a n s f o r m a t i o n s . '2 A similar s e q u e n c e l e a d s from t h e benzamide ( 6 ) t o e r y t h r o l a c c i n t e t r a m e t h y l e t h e r ( 7 ) . 'b P a r t i c u l a r l y n o t e w o r t h y i n t h i s l a t t e r

case is t h a t r e a c t i o n w i t h t h e a r y l a l d e h y d e a c t u a l l y o c c u r s w i t h t h e i n t e r m e d i a t e g e n e r a t e d by f l u o r i d e - i n d u c e d d e s i l y l a t i o n o f t h e benzamide ( 8 ) r a t h e r t h a n d i r e c t l y from t h e o r t h o - l i t h i a t e d b e n z a m i d e , as was t h e c a s e f o r (4) a n d ( 5 ) . L i k e w i s e , t h e t r i s u b s t i t u t e d benzamide ( 9 ) is o b t a i n e d a f t e r o r t h o - l i t h i a t i o n and a l k y l a t i o n , and is f u r t h e r l i t h i a t e d and r e a c t e d w i t h a r y l a l d e h y d e s t o p r o v i d e isocoumarins ( 1 0 1 , p r e c u r s o r s t o h y d r a g e n o l and p h y l l o d u l c i n . '2 An e l e g a n t s y n t h e s i s of a n t h r a m y c i n p r e c u r s o r ( 1 1 ) u s e s t h e methylmethoxy e t h e r and carbamate g r o u p s i n c o n s e c u t i v e o p e r a t i o n s . T h u s , t h e e t h e r - c a r b a m a t e ( 1 2 ; R = NHC02But) i s p r o d u c e d f r o m t h e e t h e r (12; R = H ) , and t h e carbamate so i n t r o d u c e d i s t h e n used t o d i r e c t t h e n e x t ortho-lithiation/trapping r e a c t i o n s t o g i v e t h e t e t r a s u b s t i t u t e d benzene ( I ? , ) , which is c o n v e r t e d e a s i l y i n t o

(ll).ld Another popular o r t h o - d i r e c t i n g group is t h e o x a z o l i n e r i n g s y s t e m . Scheme 1 i l l u s t r a t e s i t s a p p l i c a t i o n t o t h e s y n t h e s i s o f 3-cyano-2-alkyl-benzoic acids (and a l d e h y d e s ) and i n v o l v e s a tandem a d d i t i o n rearrangement. Y i e l d s are u s u a l l y good a n d s u b s t i t u e n t s I R a n d R may b e v a r i e d b e t w e e n h y d r o g e n , a l k y l , a n d a r o m a t i c groups. For References see page 485,

437


8 pE:3 CONEt,

CONEt,

R

R &o AT

R

( 2 ) a; R = H

(1) a; R = H

b;R =OMe

(3)

b;R=OMe

R

0 (4)R = H

0 (5) R=OMe

OMe (6)

General and Synthetic Method:

43 8

Asymmetric s y n t h e s i s i n v o l v i n g l i t h i u m r e a g e n t s c o n t i n u e s t o b e a p o p u l a r and i m p o r t a n t t o p i c f o r r e s e a r c h . I n t h i s c o n t e x t , c h i r a l sulphoxide groups have achieved prominence as c h i r a l a u x i l i a r i e s and t h i s y e a r h a s s e e n s e v e r a l more e x a m p l e s o f t h e i r use.

I n t h e s y n t h e s i s of o p t i c a l l y p u r e f u r a n o n e s ( 1 4 a , b ) t h e

l i t h i a t e d s u l p h o x i d e ( 1 5 ) a c t s as a c h i r a l homoenolate a n i o n e q u i v a l e n t by a d d i n g t o a l d e h y d e s t o g i v e d i a s t e r e o i s o m e r i c

B-sulphoxide-y-lactones,which c a n b e s e p a r a t e d a n d p y r o l y s e d t o A t r u e asymmetric induction is observed w i t h c h i r a l l i t h i a t e d s u l p h o x i d e s (16), w h i c h y i e l d B - h y d r o x y k e t o n e s ( 1 7 ) and ( 1 8 ) upon r e a c t i o n w i t h a l k y l a t i n g a g e n t s and give the furanones.3

a l d e h y d e s , r e s p e c t i v e l y , and a f t e r r e d u c t i v e unmasking.

429b

A point worth n o t i n g f o r workers i n t h i s g e n e r a l f i e l d is t h a t i n

t h e a d d i t i o n o f l i t h i a t e d a r y l m e t h y l s u l p h o x i d e s (ArSOCH2Li) t o c a r b o n y l c o m p o u n d s t h e u s e of a n o r t h o - p y r i d y l s u b s t i t u t e d s u l p h o x i d e g r o u p d r a m a t i c a l l y i n c r e a s e s t h e l e v e l of a s y m m e t r i c i n d u c t i o n o v e r t h a t found w i t h t h e more u s u a l p - t o l y l group.

substituted

T h i s i n t e r e s t i n g r e s u l t may w e l l h a v e w i d e r a p p l i c a t i o n s .

P y r r o l i d i n e s , e.g.

( 1 9 ) and (201, a l s o prove t o be e x c e l l e n t

c h i r a l a u x i l i a r i e s i n t h e asymmetric a - a l k y l a t i o n and - a c e t y l a t i o n of l i t h i a t e d carboxamides ( 2 1 ) where e n a n t i o m e r i c e x c e s s e s ( e . e . ' s ) g r e a t e r t h a n 95% h a v e b e e n a c h i e v e d . 6 *

Furthermore, t h e acylated

d e r i v a t i v e s can be reduced s t e r e o s e l e c t i v e l y w i t h z i n c b o r o h y d r i d e t o g i v e t h e corresponding c h i r a l 8-hydroxy-ketone;

the overall

s e q u e n c e is t h e r e f o r e a u s e f u l a l t e r n a t i v e t o t h e a l d o l r e a c t i o n . L i k e w i s e , l i t h i a t e d c h i r a l i m i d a t e esters ( 2 2 ) are a l k y l a t e d a t t h e a-position

t o yield a,B-disubstituted

c a r b o x y l i c a c i d s w i t h good

t o e x c e l l e n t e . e , ' ~ . ~I n c o n t r a s t , i n

the a-alkylation of the

i m i n e of g l y c i n e ( 2 3 ) t h e c h i r a l g r o u p r e s i d e s i n t h e a l k y l a t i n g agents (RX*). However, t h e s t r u c t u r e o f t h e i m i n e p l a y s a n i m p o r t a n t r o l e s i n c e a m a r k e d i n c r e a s e i n t h e l e v e l of a s y m m e t r i c i n d u c t i o n is o b s e r v e d where R 1 i s p - d i m e t h y l a m i n o p h e n y l and R2 h a s 8 adamantyl. C h i r a l o x a z o l i n e s a r e y e t a n o t h e r e f f i c i e n t c h i r a l a u x i l i a r y and

a high steric requirement,

x.

h a v e b e e n u s e d t h i s y e a r by M e y e r s e t a l . i n c o n v e r t i n g 1 - a n d 2 - n a p h t h y l o x a z o l i n e s i n t o 1 , 1 , 2 - t r i s u b s t i t u t e d and 1 , 2 , 2 t r i s u b s t i t u t e d 1,2-dihydronaphthalenes, ( 2 4 ) a n d ( 2 5 ) , The o v e r a l l respectively, with high enantioselectivity

.-

p r o c e s s i n v o l v e s t h e n u c l e o p h i l i c a d d i t i o n of v a r i o u s o r g a n o l i t h i u m r e a g e n t s ( R L i ) t o a c h i r a l n a p h t h y l o x a z o l i n e f o l l o w e d by a t r a p p i n g o f t h e i n t e r m e d i a t e a z a - e n o l a t e w i t h e l e c t r o p h i l e s (E'). A mild


439

0x2

R’

X

R’

X = CHO or C 0 2 E t Reagents : i , RCH(CN)Li; ii, E t O H ; iii , H’or

[HI ; i v ,

RIX

Scheme 1

(17) R4 = Ar,

R5 = H

(18) R4 = a l k y i , R 5 = OH

(19) R = Me

(20)R = MOM


440

h i g h - y i e l d i n g procedure f o r unmasking t h e o x a z o l i n e moiety t o g i v e a n a l d e h y d e i s r e p o r t e d i n t h e same p a p e r . A s j u s t seen, c h i r a l a u x i l i a r i e s a r e extremely important agents i n m e d i a t i n g a s y m m e t r i c i n d u c t i o n , s o new o r i m p r o v e d r o u t e s t o them a r e a l w a y s welcome. I n t h i s context c h i r a l binaphthyls (26; X , Y = B r , I ) c a n be mono- o r d i - l i t h i a t e d t o g i v e ( 2 6 ; X Li, Y = B r , I ) and ( 2 6 ; X = Y = L i ) , r e s p e c t i v e l y ; b o t h s p e c i e s are c o n f i g u r a t i o n a l l y s t a b l e b e l o w -44 O C a n d h a v e b e e n r e a c t e d f u r t h e r t o g i v e b i d e n t a t e l i g a n d s u s e f u l i n a s y m m e t r i c s y n t h e s e s , s u c h as 10 hydrogenations, V a l i n e and t h e c y c l i c u r e a ( 2 7 ; R H ) ) have a l s o been used as c h i r a l a u x i l i a r i e s . V a l i n e reacts t o form t h e i s o q u i n o l i n e ( 2 8 ) , which can be l i t h i a t e d and t h e n a l k y l a t e d t o y i e l d , a f t e r

e.

deprotection, isoquinolines (291, with enantiomeric excesses g r e a t e r t h a n 9374.’’ This r e a c t i o n has obvious a p p l i c a t i o n s i n a l k a l o i d s y n t h e s e s . On t h e o t h e r h a n d , t h e u r e a ( 2 7 ; R = H ) , p r e p a r e d f r o m e p h e d r i n i u m c h l o r i d e a n d u r e a , p r o v i d e s access t o o p t i c a l l y p u r e y - l a c t o n e s ( 3 0 ) via t h e s e q u e n c e : a l l y l a t i o n t o ( 2 7 ; R = CH2CH=CH2),

m e t a l l a t i o n and quenching w i t h e l e c t r o p h i l e s t o f o r m a l c o h o l s ( 2 7 ; R = CH=CHC(OH)R1R2), a n d f i n a l l y h y d r o l y s i s a n d o x i d a t i o n t o ( 3 0 ) . l 2 The u r e a i s p r o p o s e d t o f u n c t i o n a s a d i r e c t i n g g r o u p by s e l e c t i v e l y c o - o r d i n a t i n g w i t h t h e metal p r i o r t o q u e n c h i n g w i t h t h e e l e c t r o p h i l e . An u n p r e c e d e n t e d l y h i g h s t e r e o s e l e c t i v i t y i s o b s e r v e d d u r i n g t h e a l d o l - t y p e c o n d e n s a t i o n o f B-dimethylaminopropionates (R1R2CO)

(Me2NCH2CH2C02R) w i t h o r - a l k o x y - a l d e h y d e s , y i e l d i n g a n t i - o r methylene-8-hydroxy-y-alkoxy-esters ( 3 1 ) l 3 Best s e l e c t i v i t i e s ( 2 4 : l ) a r e f o u n d w i t h e t h e r a s s o l v e n t a n d when t h e r e a c t i o n i s c a r r i e d out under e q u i l i b r a t i n g c o n d i t i o n s .

.

S y n t h e t i c Equivalents.- 3-Alkoxyallenyl-lithium r e a g e n t s , 3. ( 3 2 1 , f u n c t i o n as B - a c y l v i n y l a n i o n e q u i v a l e n t s , r e a c t i n g w i t h e l e c t r o p h i l e s (RX, C 0 2 , Me S i C 1 , Me2S2) t o f o r m t h e o r , B - u n s a t u r a t e d 3 d e r i v a t i v e s ( 3 3 ) . 1 4 T h i s u s e f u l r e a c t i o n h a s been used i n a s h o r t s y n t h e s i s of t h e m a c r o l i d e a n t i b i o t i c p y r e n o p h o r i n . The a c y l a n i o n e q u i v a l e n t ( 3 4 ; R 1 = R 2 = H ) c a n be e a s i l y c o n v e r t e d i n t o t h e d i a l k y l a t e d compound ( 3 4 ; R 1 , R 2 = a l k y l ) f r o m w h i c h k e t o n e s (R1R2CO) c a n be o b t a i n e d a f t e r r e d u c t i o n a n d a s i l a A l t e r n a t i v e l y , ( 3 4 ; R2 = H ) c a n be Pummerer r e a r r a n g e m e n t . 1 5 l i t h i a t e d and r e a c t e d w i t h k e t o n e s (R3R4CO) t o g i v e t h e s y n t h e t i c a l l y u s e f u l v i n y l s u l p h o n e s ( 3 5 ) . Y i e l d s are i n t h e r a n g e

441


R

R

w;; H

(27)

(30)

(29)

Me0

E’

“+C02ROH

R’ R2 Ph02S X S i M e )

R Ph02S

Li

>=

-

R ~ R ~ C O

R2

OH

R2

547

8: Saturated Heterocyclic Ring Synthesis

(40)

(41) E+= H+, Br+, I+, or PhSe'

R2

i. Bu"Li _____)

ii,NH4Cl aq.

Bu'02S

Buto2sT!+ (44)

(45)

_____) Amberlyst 15

X

\

R2 OH

(46)

toluene, 80 "C

.-O/'$RZ

548


Michael s e n s e t o t h e v i n y l sulphone moiety t o g i v e t h e dihydrobenzofurans (45).

2,2-Dialkyldihydrobenzofurans, most commonly p r e p a r e d by t h e C l a i s e n r e a r r a n g e m e n t , a r e much more r e a d i l y s y n t h e s i z e d by t h e a c i d - c a t a l y s e d d e h y d r a t i o n o f t h e h y d r o x y b e n z y l a l c o h o l s ( 4 6 ) . 34 A m b e r l y s t 15 i s t h e a c i d c a t a l y s t u s e d a n d y i e l d s a r e e x c e l l e n t

Six-membered R i n g s . - T e t r a h y d r o p y r a n s . The c y c l i z a t i o n o f s i m p l e a l l e n i c a l c o h o l s t o g i v e monosubstituted t e t r a h y d r o p y r a n s has been e x t e n d e d t o t h e s y n t h e s i s o f more complex t e t r a h y d r o p y r a n s by two r e s e a r c h g r o u p s . 35 36 e i t h e r s i l v e r or mercury salts and, i n a d d i t i o n t o t h e high r e g i o s p e c i f i c i t y , h i g h s t e r e o s p e c i f i c i t y i s o b s e r v e d i n many c a s e s . Thus, t h e secondary a l l e n i c a l c o h o l s ( 4 7 ) c y c l i z e t o g i v e predominantly =-2,6-disubstituted p r o d u c t s ( 4 8 ) , and s u b s t i t u t e d a l l e n e s (49) g i v e t h e E - o l e f i n i c tetrahydropyrans (50) a s t h e major isomers. U . V . i r r a d i a t i o n o f y - a l l y l o x y - c a r b o n y l compounds a f f o r d s t h e t e t r a h y d r o p y r a n s ( 5 1 ) via i n t r a m o l e c u l a r € - h y d r o g e n a b s t r a c t i o n a n d r a d i c a l c o m b i n a t i o n . It is e s s e n t i a l f o r t h e s u c c e s s of t h e r e a c t i o n t o have a f u l l y s u b s t i t u t e d y - p o s i t i o n o t h e r w i s e N o r r i s h Type I1 r e a c t i o n becomes t h e m a j o r pathway.37

D i h y d r o p y r a n s . A f u l l p a p e r on t h e p r e p a r a t i o n of d i h y d r o p y r a n s a n n e l a t e d t o c y c l o p e n t a d i e n e s h a s now b e e n p u b l i s h e d , e x t e n d i n g t h e scope and d e m o n s t r a t i n g t h e i r u s e i n t h e s y n t h e s i s of i r i d o i d s and seco-iridoids. Danishefsky’s continued i n t e r e s t i n t h e hetero-Diels-Alder r e a c t i o n has r e s u l t e d i n t h e p u b l i c a t i o n of s e v e r a l p a p e r s d e t a i l i n g f u r t h e r advances i n t h e f i e l d . Thus, formaldehyde itself h a s b e e n shown t o b e a n e f f e c t i v e d i e n o p h i l e g i v i n g m o d e r a t e y i e l d s o f t h e d i h y d r o p y r o n e s ( 5 2 ) , w h i c h i n c l u d e s t h e p r e v i o u s l y unknown p a r e n t member ( 5 2 ; R ’ = R 2 = H) .39 f u n c t i o n a l i t y h a s a l s o been i n v e s t i g a t e d d e m o n s t r a t i n g t h a t , w i t h a 3-trimethylsilyloxy-group i n t h e d i e n e , t h e c y c l o c o n d e n s a t i o n i s successful with 1-silyloxy-I-alkyl, I - a l k y l , and 1 , l - d i m e t h o x y s u b s t i t u e n t s ( s e e Scheme 6 ) . 4 0 t h a t l,l-dimethoxy-3-trimethylsilyloxydiene i s a s u i t a b l e p a r t n e r i n t h e hetero-Diels-Alder r e a c t i o n . The d e g r e e o f s t e r e o c o n t r o l i n t h e c y c l o a d d i t i o n h a s a l s o b e e n


549

(48)

(47)

I

(49)

“y

OMe

+

Me3Si0

/s H

(50)

ZnCL2

H R’

R’

(52)

Me,SiO t

R

2

+ R4CH0

-oG [Eu(fod)31

R4

R3

R3

Scheme 6

R’ = OMe or a1kyl R 2 = OMe or OSiMe, R3= Me or H R4=Ph or hexyl

550


a d d r e s s e d by D a n i s h e f s k y ' s g r o u p . They h a v e f o u n d t h a t magnesium b r o m i d e d i r e c t s t h e r e a c t i o n by c h e l a t i o n c o n t r o l g i v i n g e x c l u s i v e l y t r a n s - d i h y d r o p y r o n e s w i t h a-alkoxy-aldehydes and 8 - a l k o x y - a l d e h y d e s ( s e e Scheme 7 ) . 4 2 t i t a n i u m t e t r a c h l o r i d e g i v e s t h e c i s - d i h y d r o p y r o n e s via a n a l d o l process. L e w i s a c i d c a t a l y s i s h a s a l s o proved u s e f u l i n t h e i n v e r s e hetero-Diels-Alder r e a c t i o n such t h a t s u b s t i t u t e d a c r o l e i n s react with enol e t h e r s t o f u r n i s h t h e dihydropyrans (53) i n moderate y i e l d s (30-80%) .43 h a s been a p p l i e d i n an i n t r a m o l e c u l a r s e n s e t o g i v e t h e D/E r i n g system (54) of t h e heteroyohimbine a l k o l o i d s . I n an approach broadly similar t o t h a t published p r e v i o u s l y , b u t w i t h an extended s c o p e , a c e t a l s d e r i v e d from e t h y l v i n y l e t h e r ,

l-chloromethoxy-2-methoxymethane,and 3 , 4 - d i h y d r o p y r a n w i t h y-unsaturated a l c o h o l s c y c l i z e under t i t a n i u m t e t r a c h l o r i d e c a t a l y s i s t o g i v e d i h y d r o p y r a n s i n g e n e r a l l y h i g h y i e l d ( 6 5 - 9 8 % ) as o u t l i n e d i n Scheme 8 . The e n o l a t e C l a i s e n r e a r r a n g e m e n t h a s b e e n u s e d e x t e n s i v e l y i n t h e s y n t h e s i s o f s t e r e o c h e m i c a l l y d e f i n e d s y s t e m s and t h i s y e a r a n i n t e r e s t i n g u s e of t h e rearrangement i n t h e s y n t h e s i s of dihydropyrans has been published. Thus t h e d i o x a n p r e c u r s o r s ( 5 5 ) a r e t r a n s f o r m e d t o t h e d i h y d r o p y r a n s ( 5 6 ) i n good y i e l d ( > 5 2 % ) w i t h high stereospecificity. The d i h y d r o p y r o n e s ( 5 7 ) a r e s y n t h e s i z e d from c y c l o h e x a n e d i o n e s by i n i t i a l e n o l i c 2 - a c y l a t i o n f o l l o w e d by F r i e s r e a r r a n g e m e n t u s i n g t i t a n i u m t e t r a c h l o r i d e as t h e c a t a l y s t . 47 The p r o d u c t s a r e e a s i l y c o n v e r t e d i n t o t h e b e n z o p y r o n e s ( 5 8 ) , n o t e a s i l y p r e p a r e d by o t h e r m e t h o d s . Benzo-3-pyrones ( 6 0 ) a r e u s u a l l y p r e p a r e d f r o m o r t h o d i s u b s t i t u t e d benzene d e r i v a t i v e s , which t h e m s e l v e s are o f t e n d i f f i c u l t t o p r e p a r e . Saba h a s a p p l i e d t h e i n t r a m o l e c u l a r k e t o c a r b e n e a d d i t i o n t o p r e p a r e t h e b e n z o p y r o n e s ( 6 0 ) f r o m t h e much more a c c e s s i b l e a c i d c h l o r i d e s ( 5 9 ) i n h i g h y i e l d ( > 7 3 % ) . A l t h o u g h t h e M i t s u n o b u r e a c t i o n i s known t o work w e l l f o r t h e c o u p l i n g o f p h e n o l s and a l c o h o l s , t h e i n t r a m o l e c u l a r v a r i a n t h a s o n l y j u s t been p u b l i s h e d and p r o v i d e s a f a s t and e f f i c i e n t s y n t h e s i s of b o t h b e n z o d i h y d r o f u r a n s a n d b e n z o d i h y d r o p y r a n s ( s e e Scheme 9 ) .lr9 The b e n z o d i h y d r o p y r a n a - t o c o p h e r o l h a s b e e n synthesized enantiospecifically using the c h i r a l sulphoxide (61) t o s e t up t h e a s y m m e t r i c c e n t r e a n d t h e method s h o u l d b e a p p l i c a b l e t o a w i d e r a n g e o f b e n z o p y r a n s 50

.


TkH

0

OCH2Ph- Hi, i i

551

OCHZPh iii, iv

.J$H

0& K H 2

R

Ph

R

/ v,vi

Q"

A=

$Me;

B=

OCH2Ph

0

Et

Me3Si0

lM

Me3Si0

Reagents :i,A,MgBr2; ii ,AcOH; i i i , MgBr2, B,THF; iv, Et3N, MeOH; v, A,TiC14, CHZC12; v, TFA

Scheme 7

q0 +

H R'

R2

(&. (--$ f Ph

CPh

A

H

0

(541

552


R2

R2

R3 OSiMe3]

# /

co, Me

(59)

(60)

Phg P,DEAD

OH Scheme 9

553

8: Saturated Heterocyclic Ring Synthesis G e n e r a l methods f o r t h e s y n t h e s e s of benzopyrans and 3 - n i t r o b e n z o p y r a n s have a l s o been p u b l i s h e d , f e a t u r i n g i n t h e f o r m e r case c y c l i z a t i o n o f s u b s t i t u t e d p h e n o l s w i t h t h e halogenopropionaldehyde a c e t a l ( 6 2 ) , 5 1 and c y c l i z a t i o n o f

o-hydroxybenzaldehydes ( 6 3 ) w i t h 2 - n i t r o e t h a n o l case.52

2-H-Pyrans,

i n the latter

w h i c h a r e a much l e s s w e l l known c l a s s o f

compounds, a r e r e a d i l y s y n t h e s i z e d by t h e r e a c t i o n o f

alkylthiodiphenylcyclopropenium s a l t s a n d 1 , 3 - d i k e t o n e s , g i v i n g products (64) with 2-alkylthio s u b ~ t i t u e n t s . ~ ~ [ 5 , n l S p i r o a c e t a l s . The i n t e r e s t i n s p i r o a c e t a l s y n t h e s i s h a s c o n t i n u e d u n a b a t e d a n d t h u s o n l y a few o f t h e many p u b l i c a t i o n s i n t h i s f i e l d h a v e b e e n r e v i e w e d , f e a t u r i n g m e t h o d s o f a more g e n e r a l nature. F u l l d e t a i l s of t h e organoselenium-mediated

s y n t h e s i s of

s p i r o a c e t a l s d e v e l o p e d by Ley e t a l . h a v e b e e n p u b l i s h e d 5 4 a n d t h e i n t r a m o l e c u l a r Michael a d d i t i o n of an hydroxy-group t o an u n s a t u r a t e d s u l p h o x i d e g r o u p h a s b e e n shown t o g i v e s p i r o a c e t a l s with a high degree of stereocontrol, providing t h e

2-

or E-isomers

r e s p e c t i v e l y f r o m t h e s u l p h o x i d e s ( 6 5 ) a n d ( 6 6 ) .55 The g e n e r a l i t y o f t h e a d d i t i o n o f d i h y d r o p y r a n - c u p r a t e s t o e p o x i d e s and s u b s e q u e n t c y c l i z a t i o n t o g i v e s p i r o a c e t a l s h a s b e e n f u r t h e r d e m o n s t r a t e d by K o c i e n s k i ' s g r o u p i n a s y n t h e s i s o f T a l a r o m y c i n B ( s e e Scheme 1 0 ) , 5 6 a n d Amouroux h a s shown t h a t t h e corresponding lithio-dihydropyran protected iodo-alcohols

i s e f f i c i e n t l y a l k y l a t e d by t h e

( 6 7 ) t o g i v e d i h y d r o p y r a n a l c o h o l s which

then c y c l i z e under a c i d i c c o n d i t i o n s t o g i v e t h e

.

s p i r o a c e t a l s ( 6 8 ) 57 Another p o t e n t i a l l y very g e n e r a l s y n t h e s i s of s p i r o a c e t a l s i s b a s e d on t h e H o r n e r - W i t t i g r e a c t i o n . 58

The d i p h e n y l p h o s p h i n o x y

c y c l i c e t h e r s ( 6 9 ) , p r e p a r e d from t h e c o r r e s p o n d i n g c y c l i c e n o l e t h e r s , c o u p l e w i t h a l d e h y d e s or l a c t o l s t o g i v e a m i x t u r e o f i s o m e r i c p r o d u c t s which c y c l i z e under a c i d c a t a l y s i s t o g i v e t h e spiroacetals (70) i n generally high yield. F i n a l l y , on t h e a s p e c t o f new g e n e r a l m e t h o d s K o c i e n s k i a n d S t r e e t h a v e e x t e n d e d t h e i n t r a m o l e c u l a r Mukaiyama r e a c t i o n t o t h e s y n t h e s i s of s p i r o a c e t a l s , i n v o l v i n g t h e a d d i t i o n o f a n e n o l e t h e r t o a d i o x o n i u m i o n w h i c h i s g e n e r a t e d by t h e r e a c t i o n o f a spirocyclic ortholactone with a Lewis acid.59

The method h a s b e e n

e x e m p l i f i e d by t h e s y n t h e s i s of t h e s p i r o a c e t a l p o r t i o n ( 7 1 ) of Milbemycin 8 3 .


554

I

i ,B U " ~ N F

ii, NaOMe. MeOH

0

Y'

R2xYoH i, KH, THF

ii. Bun4NI, (62)

R3

pTs-OH

R'

R~

R3

\


555

Ph

\

I

i, p-TsOH, MeOH

i, p-TsOH,MeOH

ii, KH, THF

ii, KH, THF

PhS ,O

PhSO

556


+ 0

OH

.1

aq. HCl

4

H0

Scheme 10

Q

L

i

+

557


Me,SiO

ll OH

(72)

(74)

(73)

R'

DCA, hu _____)

02,MeCN

R*

* ' Y O H

R e a g e n t s : i , m-CLC6H4CO3H;

H+

i i , H+, HC(OMeI3, Me2CO; iii, KOH, DMSO

Scheme 11

(75)

General and Synthetic Method5

558

The v a s t m a j o r i t y o f p u b l i c a t i o n s on s p i r o a c e t a l s y n t h e s i s h a v e u t i l i z e d k e t o - d i o l c y c l i z a t i o n s as t h e k e y r i n g - f o r m i n g s t e p a n d consequently have n o t been covered.

H o w e v e r , m e n t i o n m u s t b e made

o f M o r i ' s g r o u p who h a v e made a n o t a b l e c o n t r i b u t i o n t o s p i r o a c e t a l c h e m i s t r y i n t h e i r s y n t h e s e s o f all t h e i s o m e r s o f t h e i n s e c t pheromones ( 7 2 ) , ( 7 3 1 , ( 7 4 ) , and ( 7 5 ) i n o p t i c a l l y p u r e form. S i x - m e m b e r e d R i n g s C o n t a i n i n g More t h a n One O x y g e n . o b s e r v a t i o n t h a t DCA-sensitized o f I,l=di-(p-anisyl)ethylene R1 = R2

p-MeOC6H4)

electron-transfer

g i v e s t h e 1,2-dioxane

60-62

The i s o l a t e d

photo-oxygenation

(76;

h a s now b e e n e x t e n d e d t o a g e n e r a l

s y n t h e s i s of s y m m e t r i c a l 1 , 2 - d i o x a n e s .

The y i e l d s a r e g e n e r a l l y

v e r y h i g h ( > 7 5 % e x c e p t when R 1 = R2 = P h ) , a n d t h e f o r m a t i o n o f s i d e products is negligible.63 Acid-catalysed

d i m e r i z a t i o n of a - h y d r o x y - d i m e t h y l a c e t a l s ,

on t h e

o t h e r hand, a f f o r d s 1 , 4 - d i o x a n e s ( 7 7 ) i n h i g h y i e l d and h i g h p u r i t y where t h e r e q u i r e d d i o x a n e c r y s t a l l i z e s d i r e c t l y from t h e r e a c t i o n medium.64

F u l l d e t a i l s on t h e s y n t h e s i s o f 1 , 4 - d i o x a n e

analogues

of zoapatanol, previously only published i n t h e patent l i t e r a t u r e , h a v e now a p p e a r e d w h e r e b y y , b - u n s a t u r a t e d and c y c l i z e

via

ketones a r e epoxidized

t e t r a h y d r o f u r a n s as shown i n Scheme 1 1 . 6 5

J e f f o r d ' s g r o u p h a s c o n t i n u e d work o n t h e s y n t h e s i s o f 1 , 2 , 4 trioxanes.

The g e n e r a l m e t h o d o l o g y u s e d by t h e g r o u p i n v o l v e s t h e

t r a p p i n g of 8-hydroperoxy

c a t i o n s or z w i t t e r i o n i c p e r o x i d e s w i t h

a l d e h y d e s , and s e v e r a l e x t e n s i o n s t o t h e method h a v e b e e n p u b l i s h e d t h i s year.

Thus, t h e dye-sensitized

photo-oxygenation

of t h e

i n d o l e ( 7 8 ) i n t h e p r e s e n c e of a l d e h y d e s g i v e s t h e t r i o x a n e s ( 7 9 ) as t h e major p r o d u c t s , 6 6 t h e y i e l d s of t r i o x a n e s from t h e r e a c t i o n o f e n d o p e r o x i d e s ( 8 0 ) w i t h a l d e h y d e s a r e much i m p r o v e d i f

t r i m e t h y l s i l y l trifluoromethanesulphonate i s u s e d a s t h e a c i d c a t a l y s t , 6 7 a n d t h e c y c l i c a l l y l i c h y d r o p e r o x i d e (81 ) r e a c t s w i t h a l d e h y d e s t o g i v e t r i o x a n e s . 68 Both symmetrical and unsymmetrical s p i r o o r t h o c a r b o n a t e s a r e r e a d i l y p r e p a r e d from t e t r a m e t h y l o r t h o c a r b o n a t e by r e a c t i o n w i t h two e q u i v a l e n t s of d i o l s t o g i v e t h e s y m m e t r i c a l o r t h o c a r b o n a t e s ( 8 2 ) , o r by r e a c t i o n w i t h p r o p a n e - 1 , 3 - d i o l t o g i v e t h e 1 , 3 - d i o x a n e ( 8 3 ) which t h e n a f f o r d s t h e u n s y m m e t r i c a l o r t h o c a r b o n a t e s ( 8 4 ) on r e a c t i o n w i t h a l k a n e d i o l s .69 S e v e n - a n d E i g h t - m e m b e r e d R i n g s . - T h e r e h a v e b e e n v e r y few new c o n t r i b u t i o n s i n t h i s area. C a r l e s s and Fekarurhobo, i n an


559

Me

’

02

R’R’CO

*

I

Me

Me Me OOH

H

Me (79

(78)

@

QI..p

____, RCHO

R2


560

a p p r o a c h t o a n a n a l o g u e o f t h e e l u s i v e t h r o m b o x a n e A 2 , h a v e shown t h a t v i n y l o x y c a r b o n y l compounds u n d e r g o i n t r a m o l e c u l a r photocycloaddition t o the 2,7-dioxabicylo[4.1.1 ]octanes (85)

which

s u b s e q u e n t l y r i n g - o p e n i n t h e p r e s e n c e of a c i d i c m e t h a n o l t o g i v e

.

t h e seven-membered r i n g s ( 8 6 ) 7 0 I n a n a p p r o a c h t o t h e s y n t h e s i s of l a u r e n c i n , a m a r i n e n a t u r a l p r o d u c t , S c h r e i b e r and K e l l y h a v e d e v e l o p e d a g e n e r a l method whereby, under c e r t a i n c o n d i t i o n s , a l k y n y l - l i t h i u m s add t o 6 - l a c t o n e s t o g i v e t h e eight-membered r i n g s ( 8 7 ) . 7 1

The s u c c e s s of

t h e r e a c t i o n g r e a t l y d e p e n d s b o t h on t h e n a t u r e o f t h e a l k y n y l l i t h i u m a n d t h e s u b s t i t u t i o n p a t t e r n of t h e l a c t o n e . 2 Sulphur-containing Heterocycles

Ring e x p a n s i o n s and r e a r r a n g e m e n t s h a v e f e a t u r e d h e a v i l y i n s u l p h u r h e t e r o c y c l e s y n t h e s i s t h i s y e a r , and so i t is f i t t i n g t h a t a p r i m e e x p o n e n t i n t h i s area o f c h e m i s t r y , V e d e j s , h a s p u b l i s h e d a r e v i e w on s u l p h u r - m e d i a t e d r i n g e x p a n s i o n s i n t o t a l s y n t h e s i s . 72 The a l l e n e e p i s u l p h i d e ( 8 8 ) r e a c t s w i t h v a r i o u s e l e c t r o p h i l e s t o 2-Lithio-

g i v e a r a n g e of s u l p h u r h e t e r o c y c l e s ( s e e S c h e m e 1 2 ) . 7 3

1 , 3 - d i t h i a n e s h a v e b e e n u s e d e x t e n s i v e l y a s Umpolung r e a g e n t s i n t h e l i t e r a t u r e , but t h e deprotonation of 2 , 2 - d i s u b s t i t u t e d dithianes has received l i t t l e attention.

1,3-

I k e h i r a and Tanimoto have

shown t h a t t h e d i t h i a n e s ( 8 9 ) u n d e r g o W i t t i g r e a r r a n g e m e n t on t r e a t m e n t w i t h LDA t o g i v e t h e 2 , 2 - d i s u b s t i t u t e d tetrahydrothiophene-3-thiols ( 9 0 ) . 7 4 1,3-Dithianes (91; n = 3 ) rearrange i n a d i f f e r e n t s e n s e , under t h e influence of phenyl selenenyl c h l o r i d e t o g i v e dihydro-l,4d i t h i e p i n e s , and t h e r e a c t i o n a l s o works f o r 1 , 3 - d i t h i o l a n e s ( 9 1 ; n 2 ) t o g i v e d i h y d r o - I , Q - d i t h i i n ~ . ~R i~n g e x p a n s i o n o f t h e v i n y l d i t h i o a c e t a l s ( 9 2 1 , i n i t i a t e d by c a r b e n e a d d i t i o n t o s u l p h u r , provides t h e first e n t r y t o t h e betweenanenes (93)

alkoxycarbonyl-stabilized

via

y l i d e s . 76

The s c o p e o f t h e r e a c t i o n o f t h e m e r c a p t o c a p r o a t e ( 9 4 ) w i t h o l e f i n s a n d a c e t y l e n e s h a s now b e e n c l a r i f i e d i n a p u b l i c a t i o n f r o m Anklam a n d M a r g a r e t h a .

T h u s i r r a d i a t i o n of ( 9 4 ) i n t h e p r e s e n c e o f

o l e f i n s or a c e t y l e n e s l e a d s t o t h i o l a n e s (95) or dihydrothiophenes ( 9 6 ) r e s p e c t i v e l y i n v a r i a b l e y i e l d . 77 Most o f t h e r e m a i n i n g m e t h o d s have u s e d v a r i a t i o n s on t h e theme of cycloaddition chemistry i n t h e c o n s t r u c t i o n of sulphur heterocycles. Y o s h i d a ' s g r o u p h a s shown t h a t

561


-

hu

McOH, H+

w CgH6

R’

R’

R’

0

+ R O2

R ’ = H, Me, or SMe;

R = H or Me

R2= H, CH,OMe, or CH(OEt12

+

/4

R’

R2

Scheme 12

-

nR


562

R3X

4 2 s R1

R2

(89)

k 2 S R 3 R’

R2

(90)

I

ROH hu

HS

[2,3] shift

AcozR (94)

563

8: Saturated Heterocvclic Ring Synthesis

N-methyldithiophthalimide

is an e x c e l l e n t d i e n o p h i l e g i v i n g

h i g h y i e l d s of d i h y d r o t h i o p y r a n s w i t h h i g h r e g i o s e l e c t i v i t y and m o d e r a t e s t e r e o s e l e c t i v i t y ( s e e Scheme 1 3 1 , 78 a n d t h e h e t e r o - D i e l s A l d e r r e a c t i o n o f a , @ - u n s a t u r a t e d d i t h i o e s t e r s , a s t h e 41[ component, w i t h d i e n o p h i l e s g i v e s t h e a d d u c t s ( 9 7 ) i n v a r i a b l e y i e l d (20-100%) .79 The i n t r a m o l e c u l a r D i e l s - A l d e r

r e a c t i o n of t h e d i e n y l

a - m e t h a c r y l t h i o i m i d a t e s h a s been s t u d i e d under a v a r i e t y of c o n d i t i o n s g i v i n g t h e b i c y c l i c r i n g system ( 9 8 ) and ( 9 9 ) i n generally high yield.

The r e a c t i o n s p r o c e e d r a p i d l y w h e r e n = 0 ,

more s l o w l y w h e r e n = 1 , and n o t a t a l l w h e r e n = 2 , a n d t h e exop r o d u c t s a r e f o r m e d i n s l i g h t p r e f e r e n c e o v e r t h e e n d o - a d d u c t 7s .

0

Hantke and G o t t h a r d t have d i s c l o s e d t h e s y n t h e s i s of t h e

dithiabicyclo~4.2.1~nonenones( 1 0 1 ) v i a a 1 , 3 - d i p o l a r c y c l o a d d i t i o n of t h e m e s o i o n i c compounds ( 1 0 0 ) w i t h 1 , 3 - d i e n e s .

This is the

f i r s t r e p o r t o f s u c h a r e a c t i o n a n d t h e y i e l d s a r e m o d e r a t e t o good 81 (34-8 1 % ) . F i n a l l y i n t h i s s e c t i o n , G r o s s e r t e t a l . h a v e shown t h a t i n t r a m o l e c u l a r a l k y l a t i o n of t h e keto-sulphone

halide (102) leads

t o t h e c y c l i c s u l p h o n e ( 1 0 3 ) a n d t h a t t h e method s h o u l d b e w i d e l y a p p l i c a b l e . 82 3 R i n g s w i t h More t h a n One H e t e r o a t o m NitrogenRings.

and Oxygen-containing Rings.-

T h r e e - a n d Four-membered

C h i r a l s u l p h a m y l o x a z i r i d i n e s h a v e b e e n s y n t h e s i z e d by t h e

o x i d a t i o n of t h e o p t i c a l l y a c t i v e s u l p h a m i d e s ( 1 0 4 ) w i t h MCPBA and t h e y have been used as e n a n t i o s e l e c t i v e s u l p h i d e o x i d a t i o n reagents.83

The o x i d a t i o n o f t h e a z a d i e n e s (105) w i t h MCPBA l e a d s

t o t h e v i n y l o x a z i r i d i n e s ( 1 0 6 ) w h i c h a r e good b u i l d i n g b l o c k s f o r t h e s y n t h e s i s o f v a r i o u s h e t e r o c y c l e s , a s o u t l i n e d i n Scheme 14. 8 4

1,3,4-Dioxazine-2,5-diones a r e known t o u n d e r g o e x p u l s i o n o f C 0 2 a n d G e f f k e n h a s p u b l i s h e d a new e n t r y

t o give 1,2-oxazetidinones,

i n t o t h e p r e c u r s o r s by t r e a t m e n t o f t h e g l y c o l o h y d r o x a m i c a c i d s with carbonyl diimidazole.

The d i o x a z i n e d i o n e s ( 1 0 7 ) t h e n r e a r r a n g e

e i t h e r i n s i t u or after i s o l a t i o n , t o g i v e t h e oxazetidinones (108) i n h i g h y i e l d (86-97%). 85

F i v e membered R i n g s . The u s e o f n i t r i l e o x i d e s a n d n i t r o n e s i n t h e 1,3-dipolar cycloaddition r e a c t i o n t o g i v e i s o x a z o l i n e s or i s o x a z o l e s h a s b e e n e v e r p o p u l a r , a n d s e v e r a l new m e t h o d s f o r t h e

5 64

General and Synthetic Methods R’

+

@ M :e

R’

S R2

Scheme 13

POCI3.pyridine

R2

S

R3

R4

R’ R2

(97)

i-iii

Ph

Reagents;

i, NaH, THF; ii, Bu”Li; hi, Br(CH2)3CI; iv, NaI, Me2C0


565

major product

PhCH2COCI

R’

phN/

R’

\y/R2

phNro Scheme 14

566


g e n e r a t i o n of t h e r e a c t i v e i n t e r m e d i a t e s h a v e b e e n p u b l i s h e d . F o r example, c h l o r i n a t i o n of aldoximes with N-chlorosuccinimide r a t h e r t h a n c h l o r i n e f o l l o w e d by t r e a t m e n t w i t h t r i e t h y l a m i n e l e a d s t o n i t r i l e o x i d e s c l e a n l y a n d r a p i d l y , 86 a n d p r i m a r y n i t r o - c o m p o u n d s a r e c o n v e r t e d i n t o n i t r i l e o x i d e s by d e h y d r a t i o n w i t h a c a t a l y t i c amount o f t o l u e n e - p - s u l p h o n i c a c i d . 8 7 The o x a z i r i d i n e ( 1 0 9 )

r e a r r a n g e s i n t h e p r e s e n c e of s i l i c a t o g i v e t h e n i t r o n e ( 1 1 0 ) which u n d e r g o e s t h e n o r m a l c y c l o a d d i t i o n r e a c t i o n s . 88 Kozikowski’s group has i n v e s t i g a t e d t h e d i a s t e r e o s e l e c t i v i t y of n i t r o n e c y c l o a d d i t i o n when t h e o l e f i n i s c h i r a l , a n d h a s shown t h a t t h e --product p r e d o m i n a t e s , p r e s u m a b l y by t h e d i r e c t i n g e f f e c t o f t h e o x y g e n . 8 9 The h i g h e s t s e l e c t i v i t i e s a r e s e e n w i t h t h e i s o p r o p y l i d e n e a c e t a l ( 1 1 1 ) (Scheme 1 5 ) . T e t r a h y d r o p y r a n y l n i t r o n e ( 1 1 2 ) i s r e a d i l y g e n e r a t e d from t h e oxime o f 5 - h y d r o x y p e n t e n a l a n d paraformaldehyde and p r o v i d e s a u s e f u l e n t r y i n t o t h e tetrahydropyranyl-protected i s o x a z o l i d i n e s ( 1 1 3 ) N i t r o n a t e s undergo c y c l o a d d i t i o n r e a c t i o n s w i t h o l e f i n s t o g i v e n i t r i l e o x i d e a d d u c t s ( 1 1 4 ) ,’I a n d t h e n i t r i l e o x i d e s ( 1 1 5 ) h a v e b e e n shown t o add t o a z o m e t h i n e s t o g i v e t h e o x a d i a z o l e s ( 1 1 6 ) i n

.”

m o d e r a t e y i e l d (35-60%) . 9 2 P o l y c y c l e f o r m a t i o n h a s been u s e d many t i m e s f o r t h e s y n t h e s i s of c o m p l e x n a t u r a l p r o d u c t s , e m p l o y i n g v a r i o u s methodologies. Kozikowski e t a l . have demonstrated t h a t t h e d i e n e nitro-compound ( 1 1 7 ) i s a u s e f u l p o l y c y c l e r e a g e n t i n v o l v i n g t h e intermediacy of a n i t r i l e o x i d e s p e c i e s (see Scheme 1 6 ) 93 The f a t e o f a l d e h y d e a n d k e t o n e o x i m e s i n c y c l o a d d i t i o n r e a c t i o n s h a s n o t b e e n e x t e n s i v e l y s t u d i e d up u n t i l now, b u t G r i g g

.

h a s d o n e a s y s t e m a t i c s t u d y of t h i s r e a c t i o n and h a s m o d i f i e d a n d e x t e n d e d t h e r e s u l t s of p r e v i o u s i s o l a t e d p u b l i c a t i o n s . 9 4 H i s g r o u p h a s f o u n d t h a t a l l p o s s i b l e r e g i o - a n d s t e r e o - i s o m e r s of t h e 2 : l a d u c t s (118) are formed. I n c o n t r a s t t o t h e c y c l o a d d i t i o n approach t o five-membered n i t r o g e n - and o x y g e n - c o n t a i n i n g r i n g f o r m a t i o n t h e r e h a v e b e e n muck fewer a l t e r n a t i v e s t r a t e g i e s published t h i s y e a r . A o n e - p o t c o n v e r s i o n of k e t o n e s i n t o t h e o x a z o l i n o n e s ( 1 1 9 ) has b e e n r e p o r t e d a n d i s a c c o m p l i s h e d by t h e a d d i t i o n of a r y l t h i o l s t c e t h y l c y a n o f o r m a t e i n t h e p r e s e n c e o f TiC14 a n d t r i e t h y l a m i n e , f o l l o w e d by a d d i t i o n o f t h e k e t o n e s . Although t h e y i e l d s are n o t

h i g h (15-40%) t h e s i m p l i c i t y of t h e method makes it an a t t r a c t i v e o n e . 95 A l l y l i c a l c o h o l s are r e a d i l y c o n v e r t e d i n t o a c y l a m i n o e t h y l ethei


567

-/i.a - -$I silica gel

PhNCO

0-

(1091

(110)

C02Me

CO 2 Me

major

Scheme 15

Qb4HOI-i

I

0-

minor


568

-

R2 -R3

+

RCH =N02R'

x3

R

(114)

R = PhS02, COZEt, PhCO, or MeCO

+

, ; ' -hP

0-

AJ-N-A,~

---+

EtOH, 0

OC

Ar

'Ar

CI

\

N%cN H

Y H

H

Scheme 16

-

X I

-

xI

X


NCic"

ArSH ______)

OEt

EtZNH, Tic14

569

ArskO R~R~CO

HN

BF3' E t 2 0

OEt

R'

R2

( 119)

Hop R

E

____)

0 (122)

R

R ' y f

AYE air

E = electrophile

R1+

0

HN R3

570


derivatives (120) and cyclization to oxazolidines is known to proceed with halogen electrophiles, usually giving predominantly cis-oxazolidines. Harding et al. have shown that a mercuric ioninitiated cyclization gives the trans-oxazolidines (121) as the major products.96 In a similar vein cyclization of propargyl amine derivatives (122) with electrophiles gives selectively the dihydrooxazoles (123) rather than the corresponding six-membered ring (124) .97 During an investigation into the reactions of diketones with amines directed toward pyridine synthesis, Tashiro et al. observed the unusual oxidative cyclization of the enamines (125) to the dioxotetrahydrofuro[3,2-b]pyrroles (126) albeit in modest yield (3-60%) .98 Six-membered and Larger Rings. Nitroso-compounds are useful intermediates for the synthesis of heterocycles Diels-Alder reaction, and several new facets of this reaction type have emerged this year. Thus, the enantiomerically pure a-chloronitrosocompounds (127) and (129) react with cyclohexadiene to give the adducts (128) and (130) in 69% chemical yield and >95% optical yield. 99 ’ l o o Regiochemistry rather than stereochemistry has been investigated in a publication from Boger and Patel. They have shown that acyl nitroso-compounds give predominantly the paraadducts (l3l), in contrast to aryl nitroso-compounds. 10 1 Nitrosoalkenes participate in the intermolecular Diels-Alder reaction as the 4n component, but there are severe restrictions to the applications of the reaction. However the intramolecular variant of the reaction proceeds in much better yield and with high stereoselectivity. For example, the nitrosoalkene (133), generated in situ from the chloro-oxime (132) by slow release of fluoride ion, gives the adduct (134) as the predominant (5:1 ) isomer. lo* The Diels-Alder reaction of triethyl azomethinetricarboxylate with electron-rich dienophiles such as enol ethers or styrenes gives dihydro-I ,3-oxazines (135) in good yields (61-98%), Io3 whereas dihydro-l,4-benzoxazines (136) are prepared in a one-pot procedure from ortho-amino-phenols and chloroacetyl chloride. O4 The opening of epoxides with 1-hydroxycarbamate gives the corresponding methoxycarbonylaminoxy-alcohols which can then be transformed into either 1,4,2-tetrahydrodioxazine-3-ones (137) o r 2-methoxycarbonyl-I ,4,2-tetrahydrodioxazines ( 1381, I o 5 and the previously unknown 1,2,4-oxadiazin-6-ones (139) are readily


(129)

571

(130 1

(131)

+

+Si- I


572

EtOzC,

C02Et

,CO2Et

EtO

R

G

o

+

H

- Ra:&

cl(),c'

TEBA NaHC03,CHC13

NH2

H

R'

R2 R1~o,~KO".

0

aR2 HON H

+

J

R2

R'+O

0

HO

I

R3

)=o H

-

+

Y N"2

H'OMe

4 R2

0,N/C02Me

(138)

+

OMe

R' x ~ A ~ 3

O Y0 N H

Ar-C=N-O

R3

or

Co2E'

0

573

8: Saturated Heterocyclic Ring Synthesis s y n t h e s i z e d by t h e n u c l e o p h i l i c a d d i t i o n of a - a m i n o - a c i d s n i t r i l e o x i d e s . 106

to

T h e dihydro-1,3,4-oxadiazepine h e t e r o c y c l i c r i n g s y s t e m i s s i m i l a r l y r a r e , a n d now a n e a s y a n d g e n e r a l s y n t h e s i s h a s b e e n published.

The m e t h o d e n t a i l s t h e a d d i t i o n o f h y d r a z i n e a n d

carboxylic a c i d s t o e i t h e r t h e propenones (140) or t h e d e r i v a t i v e s ( 1 4 1 ) or ( 1 4 2 ) g i v i n g t h e p r o d u c t s ( 1 4 3 ) i n m o d e r a t e y i e l d (30-72%) and i n a s i n g l e s t e p . Io7 The e i g h t - m e m b e r e d r i n g ( 1 4 5 1 , a dihydro-1,2,6-oxadiazocine, h a s b e e n p r e p a r e d by t r e a t m e n t o f t h e (chloroacety1amino)propiophenone o x i m e s ( 1 4 4 ; R = CH2Ph) w i t h s o d i u m h y d r o x i d e , w h e r e a s t h e corresponding desbenzyl derivatives dimerize t o give the sixteenmembered r i n g c o m p o u n d s ( 1 4 6 ) u n d e r t h e same r e a c t i o n 108 conditions. Oxygen a n d S u l p h u r - , a n d N i t r o g e n a n d S u l p h u r - c o n t a i n i n g R i n g s . Bromomethanesulphonyl bromide, r e c e n t l y developed f o r t h e s y n t h e s i s of d i e n e s , h a s now b e e n u s e d f o r t h e p r e p a r a t i o n o f 1 , 3 - o x a t h i o l e 3 , 3 - d i o x i d e s (147) from t r i m e t h y l s i l y l e n o l e t h e r s i n t h e p r e s e n c e o f e t h y l e n e o x i d e f o l l o w e d by t r e a t m e n t w i t h D B N . 109 K o s k i m i e s h a s r e p o r t e d on t h e s y n t h e s i s o f 1 , 4 - o x a t h i a n - 2 - o n e s by a v a r i e t y of m e t h o d s ( s e e Scheme 1 7 ) , a n d h a s a l s o i n v e s t i g a t e d t h e i r s t a b i l i t y demonstrating t h a t t h e oxathianones are less s t a b l e than t h e corresponding v a l e r o l a c t o n e s . l o I n an extension t o a p r e v i o u s s t u d y Abramovitch e t a l . h a v e s y n t h e s i z e d seven-membered sultams using t h e s o l u t i o n p y r o l y s i s of arylpropanesulphonyl azides.”’

The b e s t y i e l d s a r e o b t a i n e d u s i n g t h e r a t h e r e x o t i c

s o l v e n t F r e o n 113. T h i s y e a r h a s s e e n a n i n c r e a s e i n t h e n u m b e r of p u b l i c a t i o n s on t h e s y n t h e s i s o f s u l p h u r - and n i t r o g e n - c o n t a i n i n g r i n g s and t h e methods can be c l a s s i f i e d i n t o s e v e r a l g e n e r a l themes. V a r i a t i o n s on i n t r a m o l e c u l a r d i s p l a c e m e n t r e a c t i o n s h a v e b e e n t h e m o s t common m e t h o d r e p o r t e d ; f o r e x a m p l e , t h e t r e a t m e n t o f t h e i s o t h i o c y a n a t o a l l y l c h l o r i d e s (149) w i t h e i t h e r a l c o h o l s or amines g i v e s t h e 1 , 3 - t h i a z i n e s ( 1 5 0 ) o r ( 1 4 8 ) by i n i t i a l a d d i t i o n t o t h e i s o t h i o c y a n a t e f o l l o w e d by d i s p l a c e m e n t o f c h l o r i n e . T h e arylazomethylenephosphoranes ( 1 5 1 ) r e a c t w i t h c a r b o n disulphi.de t o g i v e t h i a d i a z o l i n e t h i o n e s i n g e n e r a l l y high y i e l d ( > 7 0 % ) , via t h e i n t e r m e d i a t e ( 1 5 2 ) w h i c h t h e n d i s p l a c e s triphenylphosphine. dihydro-oxothiadiazine

A p r e v i o u s r e p o r t of t h e s y n t h e s i s of t h e

( 1 5 3 ) h a s now b e e n shown t o b e i n c o r r e c t ,

5 74

General and Synthetic Methoc:

0 (140)

‘b R1woH R1woco NHz NH2

*

R*CO*H

ij (141 1

(143)

0

(142)

NaOH c

R1

(144)

R

0

R1%N

=

CH2Ph

-


>-;

OSiMe

R’

R2

+

BrCH2S02Br

“\s\

575

o ~ ~ c H 2 BDBNr

A

A (147)

Br

Scheme 17

576


L

(152 1

N-N

ArNHN-

7 rs

N-N

I

Ar

C02H

(153)

(155)

(154)

R’

I

PhCH2 S-CH(CH 2)n- NX

I (Olm

I

(156)

rn=

Oor2

n =

Oorl Scheme 18

PhCHzSCH(CH2InN =CHPh

I

R’ (157

LDA

Ph

H

__j

KC

(153

577


t h e a c t u a l p r o d u c t s b e i n g t h e t h i a z o l i d i n o n e s ( 1 5 4 ) . The t h i a d i a z i n e s ( 1 5 3 ) c a n , h o w e v e r , b e p r e p a r e d by t h e i n t r a m o l e c u l a r c o u p l i n g of t h e a c i d s ( 1 5 5 ) w i t h DCC.

Intramolecular

s u b s t i t u t i o n o f a v a r i e t y of d e r i v a t i v e s o f ( 1 5 6 ) w i t h LDA g i v e s t h e c o r r e s p o n d i n g t h i a z o l i d i n e s , t h i o m o r p h o l i n e s , and d i h y d r o b e n z o t h i a z i n e s i n v a r i a b l e y i e l d (24-100%) a s d e s c r i b e d i n Scheme I 8 . ’ l 5

The r e a c t i o n i s a l s o s u c c e s s f u l f o r t h e

i n t r a m o l e c u l a r a d d i t i o n t o t h e enamine ( 1 5 7 ) . Intramolecular a d d i t i o n a l s o f e a t u r e s i n t h r e e o t h e r methods reported t h i s year. Thus, t h e r e a c t i o n of amines with carbon d i s u l p h i d e and p r o p a r g y l bromide a f f o r d s t h e a d d u c t s (158),, which t h e n c y c l i z e t o g i v e 3,6-dihydro-1,3-thiazine-2-thiones ( 1 5 9 ) , whereas t h e propargylamines (160) r e a c t with carbon d i s u l p h i d e i n t h e p r e s e n c e of b a s e t o g i v e t h e 3,4-dihydro-1,3-thiazine-2116 thiones. The a c e t y l e n i c d e r i v a t i v e s ( 1 6 1 ) r e a c t w i t h h e t e r o c y c l e s t o g i v e t h e fused h e t e r o c y c l i c r i n g systems (162) containing an exocyclic methylene i n poor t o moderate y i e l d t h e a c e t y l e n i c moiety.

l7

via

i n t r a m o l e c u l a r a m i n a t i o n of

F u r t h e r s t u d i e s on t h e r a d i c a l

h e t e r o c y c l i z a t i o n of N - a l l y l - 2 - a m i n o t h i o l s

t o g i v e m i x t u r e s of

t h i o m o r p h o l i n e s a n d t h i a z o l i d i n e s h a v e shown t h a t t h e m o r e s u b s t i t u t e d t h e d o u b l e bond t h e h i g h e r t h e r a t i o o f t h i o m o r p h o l i n e 118

t o t h i a z o l i d i n e (Scheme 1 9 ) .

The 2 , 3 - s i g m a t r o p i c r e a r r a n g e m e n t of N - y l i d e s , N - i m i d e s ,

and i s well p r e c e d e n t e d , b u t i n c o n t r a s t 2-imide r e a r r a n g e m e n t s had n o t been r e p o r t e d . S a s h i d a and Tsuchiya have

S-ylides

f i l l e d t h a t g a p w i t h t h e r i n g e x p a n s i o n of t h e 2 - v i n y l t h i a c y c l o a l k e n e N-imides

(163) t o give 1,2-thiazocycles i n

The a n i l i n e d e r i v a t i v e s ( 1 6 4 ) u n d e r g o a n i n t r i g u i n g v a r i a n t of t h e 2,3-sigmatropic rearrangement involving

60-70% y i e l d .

f o r m a t i o n o f t h e a z a - s u l p h o n i u m i n t e r m e d i a t e s ( 1 6 5 ) g e n e r a t e d by t r e a t m e n t of ( 1 6 4 ) w i t h N - c h l o r o s u c c i n i m i d e . I 2 O On a t t e m p t i n g t o p r e p a r e a d i - i m i d e

from t h e t h i o u r e a ( 1 6 6 a )

B e r n a u e r e t a l . i s o l a t e d t h e r e a r r a n g e m e n t p r o d u c t ( 1 6 7 a ) . 12’ F u r t h e r i n v e s t i g a t i o n l e d t o t h e d i s c o v e r y of t h e g e n e r a l r e a c t i o n where t h e t h i o u r e a s ( 1 6 6 ) and ( 1 6 8 ) r e a r r a n g e t o g i v e t h e

cis- a n d

trans-dihydrothiazolothiazoles ( 1 6 7 ) a n d ( 1 6 9 ) w h e r e t h e r a t i o s A s i m p l e s y n t h e s i s of t h e depend on t h e c o n d i t i o n s used. 2,3-dihydrobenzisothiazoles ( 1 7 0 ) , r e l a t i v e s of t h e s a c c h a r i n r i n g s y s t e m , i s a c c o m p l i s h e d by t h e r e a r r a n g e m e n t o f b e n z o t h i e t e s i n t h e p r e s e n c e of a m i n e i n r e f l u x i n g t o l u e n e . 1 2 2

It is e s s e n t i a l t o have

578


R e a g e n t s : i, NaOH; ii, piperidine, or

Triton B, or HgS04, H2S04

i, Et3N

RNH7 + csz

ii, HCL, H20

N

* S

Y = Br Or OTS

R3

I

RadiCQ I

Scheme 19


579

0 S-N

Ts n =4 140 OC

+ S

-

+

I

(168) Me

H

;I (169)


580

a n e x c e s s of t h e a m i n e , o t h e r w i s e s i d e p r o d u c t s a r e p r o d u c e d i n significant quantities. W e i n r e b ' s g r o u p h a s p u b l i s h e d f u r t h e r work on t h e D i e l s - A l d e r r e a t i o n s o f s u l p h u r d i o x i d e b l s i m i d e s w i t h d i e n e s , 1 2 3 12'

and t h e

i r r a d i a t i o n o f t h e e n a m i d e s ( 1 7 1 ) i n h e x a n e f u r n i s h e s good y i e l d s (75-80%) of t h e 5 , 5 - d i s u b s t i t u t e d

t h i a z o l i n e s ( 1 7 2 ) .125

4 Nitrogen-containing Heterocycles Three-membered

Rings.-

Two d e h y d r a t i v e p r o c e d u r e s f o r t h e s y n t h e s i s

o f a z i r i d i n e s from 2 - a m i n o - a l c o h o l s h a v e b e e n r e p o r t e d , u s i n g e i t h e r d i p h o s p h o r u s t e t r a i o d i d e 1 2 6 o r triphenylphosphine-diethyl a z o d i c a r b o x y l a t e (Scheme 2 0 ) . 1 2 7

C y c l i z a t i o n occurs under mild

c o n d i t i o n s and y i e l d s a r e g e n e r a l l y g o o d , a l t h o u g h t h e l a t t e r method o n l y w o r k s w e l l i f t h e r e i s a t l e a s t o n e s u b s t i t u e n t a t t a c h e d t o e i t h e r o f t h e two c a r b o n a t o m s b e t w e e n oxygen and n i t r o g e n i n t h e precursor amino-alcohols.

2-Phenylsulphinylaziridines ( 1 7 5 ) h a v e b e e n p r e p a r e d by t h e a d d i t i o n of a-halogenosulphinyl c a r b a n i o n s ( 1 7 3 ) t o i m i n e s ( 1 7 4 ) . 128

The same r e s e a r c h g r o u p h a s a l s o d e s c r i b e d t h e

p r e p a r a t i o n o f 2-phenylsulphonylaziridines ( 1 7 6 ) by a n a n a l o g o u s p r o c e d u r e . 12' Two r e l a t e d m e t h o d s f o r t h e p r e p a r a t i o n of a z i r i d i n e s by r i n g c l o s u r e of a - c h l o r o - E - l i t h i o s p e c i e s h a v e a l s o a p p e a r e d : Mauz4 h a s r e p o r t e d t h e s y n t h e s i s of aza-I-bicyclobutanes

( 1 7 9 ) by r e a c t i o n o f

a z i r i n e s ( 1 7 7 ) w i t h gem-chloro-(alky1)allyl-lithium r e a g e n t s ( 1 7 8 ) , '30 a n d De Kimpe e t a l . h a v e p r e p a r e d a z i r i d i n e s ( 1 8 1 ) by a d d i t i o n o f m e t h y l - l i t h i u m t o a - c h l o r o i m i n e s

(1801,

a l t h o u g h t h e homologated i m i n e s ( 1 8 2 ) are a l s o produced i n t h i s r e a c t i o n by a c o m p e t i n g h y d r i d e s h i f t o r 1 , 2 - e l i m i n a t i o n mechanism.

'

2- and 5-N,N,N-trimethylhydrazonium i o d i d e s ( 1 8 3 ) h a v e been reduced t o s a t u r a t e d or a,B-unsaturated

a z i r i d i n e s ( 1 8 4 ) and ( 1 8 5 )

r e s p e c t i v e l y by sodium bisC2-methoxyethoxylaluminium h y d r i d e : ( 1 8 4 )

o r ( 1 8 5 ) c a n be p r o d u c e d s e l e c t i v e l y d e p e n d i n g upon r e a c t i o n c o n d i t i o n s , a n d y i e l d s a r e g e n e r a l l y h i g h e r t h a n t h o s e o b t a i n e d by r e d u c t i o n of t h e c o r r e s p o n d i n g o x i m e s . 3 2 E t h o x y c a r b o n y l n i t r e n e , w h i c h i s g e n e r a t e d by a - e l i m i n a t i o n f r o m

4-nitrobenzenesulphonyloxyurethane (NBSU), a d d s t o a l l y 1 e t h e r s ( 1 8 6 ) t o p r o d u c e a z i r i d i n e s ( 1 8 7 ) i n good y i e l d b e f o r e c h r o m a t o g r a p h y : no C-H i n s e r t i o n p r o d u c t s w e r e d e t e c t e d . 33

581


Ar

AyR H

(172)

(171 1

R1

R1

,COZEt N

1

II

1

, Ph3P

& /R -3

D

45

R4

R2, R3, R4 not all H

- 75 *I*

-

59 90 Scheme 20

0

11

N

1

Ar2

(0)"

II

-

(175) 42 100%

+

PhsYLi x (173)

R2

*b SOZPh

N 1

Ar

(176) 72

- 100

'/a

582


H

-

Ph

H -90

2

OC

.-*THF

+ (R-CCFCH-CH,)Li (178) (177)

-

J

i, -90 'C, -40

Ph

OC

i i , H20

H 2*

R1

CH=CH,

(179) 10

R1 '$2R

H

-

- 46

O/o

R1

I

R1

MeLi

Ether

R2fN\ Me

+ Me

R2JMe

Me

Me C I

(180)

I-

(181) 40 - 7 5 'I0

(182) 25

- 50 '10

+

P 4 e 3 N

H Na (MeOCH2 C H2 0 I 2 A l H2 >

"

h

H R

3

R2

(183)

R'

(184) 2

4-

z

d

R3

- 95

"10

R

3 R3

(185) 0

- 98.10

583


Four-membered R i n g s . - N e w p r o c e d u r e s f o r t h e c y c l i z a t i o n of 3 - a m i n o p r o p a n o l s t o a z e t i d i n e s h a v e b e e n r e p o r t e d , b a s e d upon t h e M i t s u n o b u r e a c t i o n ; 134 N - b e n z y l a z e t i d i n e

( 1 9 0 ) , f o r e x a m p l e , c a n be

p r e p a r e d from a c i d s a l t s of t h e a m i n o - a l c o h o l

(188) i n good y i e l d .

Under t h e same c o n d i t i o n s t h e f r e e b a s e ( 1 8 8 ) r e a c t s t o g i v e o n l y t h e hydrazide (189). The N - t o l y l a z e t i d i n e

(192) h a s been p r e p a r e d from p - t o l u i d i n e

( 1 9 1 ) i n e x c e l l e n t y i e l d by a s i m p l e a l k y l a t i o n p r o c e d u r e w h i c h may h a v e g e n e r a l a p p l i c a t i o n . 135

Five-membered

Rings.-

Two r e v i e w s r e l e v a n t t o t h e s y n t h e s i s o f

five-membered n i t r o g e n h e t e r o c y c l e s have appeared t h i s y e a r : r i n g f o r m a t i o n by r e a c t i o n o f n i t r o g e n n u c l e o p h i l e s w i t h x - o l e f i n palladium complexes h a s been d e s c r i b e d i n a r e v i e w of p a l l a d i u m ( 1 1 ) - a s s i s t e d r e a c t i o n s o f mono-olef i n s ,

" and

a review

of' s y n t h e t i c a p p l i c a t i o n s of t h e i n t r a m o l e c u l a r D i e l s - A l d e r

r e a c t i o n i n c l u d e s r e f e r e n c e t o t h e s y n t h e s i s of f i v e - and s i x membered N - h e t e r o c y c l i c s y s t e m s . 37

'

The f o r m a t i o n o f s u b s t i t u t e d p y r r o l i d i n e s by 1 , 3 - d i p o l a r c y c l o a d d i t i o n of azomethine y l i d e s t o o l e f i n s c o n t i n u e s t o be a very popular a r e a f o r study.

Grigg e t a l . have published f u r t h e r

d e t a i l s , a n d some b a c k g r o u n d d i s c u s s i o n , on t h e g e n e r a t i o n o f s t a b i l i z e d 1 , 3 - d i p o l a r s p e c i e s f r o m i m i n e s o f a m i n o - a c i d e s t e r s by a 1,2-H s h i f t and s u b s e q u e n t t r a p p i n g w i t h o l e f i n s . 138 promoted c y c l o a d d i t i o n o f !-(phenylthiomethy1)amino-acid

A new b a s e -

esters

( 1 9 3 ) and o l e f i n s ( 1 9 4 ) t o p r o d u c e p y r r o l i d i n e s ( 1 9 5 ) h a s b e e n d e s c r i b e d by Imai e t a l . I 3 '

The r e a c t i o n p r e s u m a b l y p r o c e e d s

via

t h e i n t e r m e d i a c y of a 1 , 3 - d i p o l e a l t h o u g h r e g i o - and s t e r e o s e l e c t i v i t y a r e g e n e r a l l y low.

The same g r o u p h a s a l s o d e s c r i b e d

t h e p r e p a r a t i o n of 2 , 2 , 4 - s u b s t i t u t e d

pyrrolidines with high

r e g i o s e l e c t i v i t y by two c o m p l e m e n t a r y 1 , 3 - c y c l o a d d i t i o n p r o c e d u r e s , s t a r t i n g f r o m t h e trimethylsilylmethyLamine d e r i v a t i v e ( 1 9 6 ) (Scheme 2 1 ) . I 4 O S e v e r a l new m e t h o d s f o r t h e g e n e r a t i o n and t r a p p i n g of nons t a b i l i z e d a z o m e t h i n e y l i d e s b a s e d upon a l k y l a t i o n - d e s i l y l a t i o n sequences have been d e s c r i b e d .

N-(Trimethylsilylmethyl)aminomethyl

e t h e r s ( 1 9 7 ) a r e e a s i l y p r e p a r e d and f u n c t i o n a s e x c e l l e n t azomethine y l i d e p r e c u r s o r s t o produce, a f t e r t r a p p i n g w i t h electron-deficient

olefins (198), the substituted pyrrolidines

( 1 9 9 ) s t e r e o s p e c i f i c a l l y and i n h i g h y i e l d . I n two u s e f u l e x t e n s i o n s o f known m e t h o d o l o g y , 1 , 3 - d i p o l a r s p e c i e s h a v e a l s o b e e n


584

X' hPii , + - l 4? - - ) HO

HO

I N t i

Ph

Ph

v

v

X-

X=BFL, 51 ' l o X =Br, 40 'lo

(189)

(190 1

Reagents: i, Et02CN=NC02Et,

M

e

o

N

H

Ph3P; i i , HX

Z + Et

CHzCL2

+

Si

-rNCs) / \

(229)

0

II

+ Ph2PCL

'lo

-

R

i, EtOH,HCL

HN

ii, NaBH4 iii, H +

( 2 3 0 ) 48 -71%

R'

I

Ph,PCH,N(CH,),Cl

R10N-O

R2

( 2 2 8 ) R2=H,R3=PhCH2, 9 2 "lo

4 -70 OC THF

A' (231) 80

- 90%

( 2 3 2 ) 5 7 -87%

n = l or 2

(233)

( 2 3 4 ) 32 - 90 '10 overall


594

HAL BU '2 -70 OC 4 r . t .

.1

NaF, H 2 0

(237) n = 1 or 2

54 - 8 6 '1.

H

(238)

(240)27-68 ' l o

t

t

0

11

R3\ ,C-OEt CH

i

n

I

R, T - - - M O ( C O ) ~

R2

H

595


C T I I

Ph

0-25OC

r N \ 0 C O 2 Et

Ph (241) n = 1-3,5, or 9

Me,Al .-

6I "lo

PhJj OH

(243)

R = E t or Me

(244)22% diastereomeric excess

J CF' 4

0-q ROzC

C02R

Scheme 25

CO2R

596


(245) has been described, based upon the rearrangement sequence shown in Scheme 25,175 and the A3-pyrrolines (247) and (248), useful precursors for 4-amino-4-deoxy-D,L-ribose derivatives, have been prepared by base-catalysed ring contraction of tetrahydropyridazine (246). 176 Tseng et al. have reported the preparation of 2-pyrrolidinones (250) by the cyclization of N-allylhalogenoacetamides (249) in the presence of ferrous salts, presumably via a free-radical mechanism, 177 and hart and co-workers have published full details of their studies of the generation and intramolecular addition of a-acylamino radicals to olefins and allenes to give pyrrolizidinones and indolizidinones. 178 The same group has a l s o published two syntheses of isoretronecanol (214) using this methodology. 17’ 3-Pyrrol-2-ones (254) and (255) are formed by reaction of N,Ndialkylpyruvamides (251) with diethyl (diazomethy1)phosphonate (2521, via the alkylidene carbene (253). 8o Although combined yields of (254) and (255) are acceptable, these products are always accompanied by significant amounts of the but-2-ynamides (256) and the reaction is probably only useful synthetically in cases where the pyruvamide is symmetrically substituted. Five-membered Rings Containing More than One Nitrogen.- Further details have appeared of the synthesis of the imidazo[1,2-a]indolespirolactone ring system of the tryptoquivalines by oxidative double cyclization, 18’ with specific application to the total synthesis of (+)-tryptoquivaline. 182 Pyrazoline derivatives (259) have been prepared in good yield by reaction of the dianion of acetophenone N-ethoxycarbonylhydrazone (257) with a-chloroketones (258), 183 and tetrahydropyrazolo[l ,5-a]pyridine derivatives (261) have been produced in generally good yields by cycloaddition of I-aminopyridinium salts (260) with electron-deficient olefins in the presence of base. 184 Two novel heterocyclic systems containing five-membered rings with three nitrogens have been reported. Huth et al. have prepared the triazolo[1,2-al-triazole-l,3-diones (264) by reaction of substituted oxazoles (262) with PTAD (263), 185 and several derivatives of the tetrahydro-l~-pyrrolo[1,2-b]~1,2,4]triazole2(3H)-thione ring system (268) have been prepared in low yield by a double cyclization reaction of thiosemicarbazides (265) with 186 y-chlorobutyrophenones (266), 2 the thiosemicarbazone (267).

597


“C

_____) THF, LDA, -45 2 . 2 eq.

+

@r02Et

tE2;$(

NHC02Et

NHCO2Et

(2461

.UX

Y

I

Fe C Lz

R2-C-X CH=CH, o A N / C H ZI

____)

0

diglyme, A

I

R1

(250) 30 - 83.10 R’ = allyl,Ph or 3 -CF,C,H4

x

= C l or Br Y = CL,Br or H R * = H or ci

(249)

0.

0

II

MeC-fi-NyRZ

(EtOZPCHN2

(R1

(252)

O

,y“’

Me $R’

0

+

+ MR ? I$e‘

0

R3

43 - 6 3 “lo

R


598

EtO2CNH

CO2Et

\

i, 2

Bu”Li, -78

ii, R’COCHCLR’

Ph A M e

N-N’

*C, THF

>

(258)

Ph

iii,H+

( 2 5 9 ) 39 - 6 2 O l 0

(257)

MeCN, H20

Ph

Ph

I

R2

NH* H

B F ~

(261) R1= H or C02Et

(260)

R2=CN or C02Et

-

30 92 ‘lo

4

N

Ar dioxane ____)

0

R

(263)

( 2 6 4 ) 20

R’

R2

O

- 60 ‘lo R2

R’

I

I PA

+ A

H~NNCSNHR’

+ A t CO (CH,),CL

(266)

(267)

-

( 2 6 8 ) 10 46 ‘lo

599

8: Saturated Heterocyclic Ring Synthesis R e a c t i o n o f n i t r i l i u m s a l t s ( 2 6 9 ) w i t h a z i d e s ( 2 7 0 ) g i v e s good y i e l d s of (271).

1,4,5-alkyl-

or -aryl-substituted

tetrazolium salts

R e d u c t i o n o r a l k y l a t i o n of t h e s e s a l t s l e a d s t o f o r m a t i o n

of t h e c o r r e s p o n d i n g t r i - o r t e t r a - s u b s t i t u t e d

tetrazolines

(272) Six-membered

R i n g s C o n t a i n i n g One N i t r o g e n . -

R e v i e w s on t h e

s y n t h e s i s and p r o p e r t i e s of h i n d e r e d ( 2 , 2 , 6 , 6 - t e t r a a l k y l ) p i p e r i d i n e s 88 a n d s y n t h e t i c a p p l i c a t i o n s o f t h e m o d i f i e d P o l o n o v s k i r e a c t i o n as an approach t o s u b s t i t u t e d p i p e r i d i n e s h a v e a p p e a r e d t h i s y e a r . The s y n t h e s i s o f t e t r a h y d r o p y r i d i n i u m

s a l t s and t h e i r a p p l i c a t i o n t o a l k a l o i d s y n t h e s e s h a s a l s o been reviewed. Several novel cycloaddition or electrocyclization routes t o sixmembered n i t r o g e n h e t e r o c y c l e s h a v e b e e n r e p o r t e d .

Ihara et al.

have d e s c r i b e d a novel s y n t h e s i s of b e n z o [ a ] q u i n o l i z i d i n e s an intramolecular Diels-Alder u n s a t u r a t e d amides ( 2 7 3 ) .

'''

( 2 7 4 ) by

r e a c t i o n , s t a r t i n g from t h e a,@-

stereoisomers i n moderate y i e l d s , p o s s i b l y

a transition state

i n v o l v i n g z i n c c h e l a t i o n w i t h t h e e s t e r and amide oxygens. Indole[a]quinolizidines

c a n a l s o b e p r e p a r e d by a s i m i l a r r e a c t i o n

sequence. T e t r a h y d r o q u i n o l i n e d e r i v a t i v e s (278) and ( 2 7 9 ) have been p r e p a r e d i n low y i e l d by a L e w i s a c i d - c a t a l y s e d

[4+21 c y c l o a d d i t i o n

r e a c t i o n of o l e f i n s ( 2 7 5 ) o r ( 2 7 6 ) w i t h i m i n e ( 2 7 7 ) , I g 2 a n d W e i n r e b and co-workers have p u b l i s h e d a t o t a l s y n t h e s i s of t h e s p e r m i d i n e a l k a l o i d a n h y d r o c a n n a b i s a t i v e n e by a p p l i c a t i o n o f t h e i r i n t r a m o l e c u l a r imino-Diels-Alder

methodology.

1 , 2 - D i h y d r o i s o q u i n o l i n e ( 2 8 1 ) h a s b e e n p r e p a r e d by a n o v e l procedure involving an intramolecular c y c l o a d d i t i o n of a z i d e (280) f o l l o w e d by a r h o d i u m - c a t a l y s e d

carbene insertion-ring

expansion

s t e p . 'g4 A new a p p r o a c h t o t h e s y n t h e s i s of N-acyl-1,2-dihydropyridines ( 2 8 4 ) h a s b e e n r e p o r t e d by Wyle a n d F o w l e r , b a s e d upon e l e c t r o c y c l i z a t i o n of I - a z a t r i e n e s ( 2 8 3 ) , which are formed i n s i t u by f l a s h vacuum p y r o l y s i s o f h y d r o x a m i c a c i d d e r i v a t i v e s ( 2 8 2 ) . 195 A new r o u t e t o t h e a l k a l o i d d e r i v a t i v e N - b e n z o y l m e r o q u i n e n e m e t h y l

e s t e r ( 2 8 7 ) h a s a l s o b e e n d e s c r i b e d , u s i n g as t h e k e y s t e p a s t e r e o s p e c i f i c C l a i s e n rearrangement of t h e E - s i l y l k e t e n e acetal d e r i v e d from a z a l a c t o n e ( 2 8 5 ) t o c o n s t r u c t t h e d e s i r e d d i s u b s t i t u t e d p i p e r i d i n e r i n g system (286).

cis-


600

R1Cd-R2

R3N3 (270)

R’

R’

A

R2-N

\

N-N

A’

NaBH4 ( R 4 = H )

N-R3

R4MgX or R4Li

I

(R~*H)

A(271 1

(269)

R4

’ RLN\N=N N-R3 i

(272) 40- 90 ‘/o

Me0 Me0

(273) NEt3

Me0

Me0

Me0

Me0

J Me0 N ,=

M e 0W

Et 0 2 C

y

O

?/\

R’

I? ( 2 7 4 ) 41-5Z0/o

BF3.Et20

&0r2 /

R1o + PhCH=NPh

*-

A

R20

(277)

\

‘

Me

Ph

H A

(278) R 1 , R 2 = Me, 30%

(279) R1+R2= CH2, 16 ‘1.


601

CO Et +tN-

r

CO, Et

(281)

53%

-

OCO, Me

L?K"

A

0

R

(282)

(2841 3 2 -58 '/o

-

r

63

1

H% O Y R

7

1

RAO

LDA.1.2 eq.

But MqSiCl, 1.2 eq. T H E - 7 0 C'

*

PhAO (285)

Q

4

L

Ph

(286) 93"h

(287)

602


Cyclization of N-acyliminium ions as a route to six-membered nitrogen heterocycles continues to be explored by several groups. Thus, Kano et al. have prepared the tetrahydropyrimidoisoquinoline derivative (289) and related compounds from ureas (288) in good yieldIg7 and Liao et al. have applied similar procedures to the synthesis of annelated hydantoins and 2-imidazolidinones. 198' A convenient entry into the quinolizidine and benzoquinolizidine ring systems h a s also been described, based upon anodic a methoxylation of the N-heterocycle precursors and subsequent 200 intramolecular Lewis acid-catalysed cyclization. Overman and his group have published a full report of the enantioselective total synthesis of pumiliotoxins B and 251D via stereospecif ic iminium ion-vinylsilane cyclizations ,20 and the indole alkaloid (-)-hobartine (291) has been prepared in good yield via a stereoselective biomimetic cyclization of imine (290) .202 Three useful modifications to existing procedures for the synthesis of tetrahydroisoquinolines and related heterocycles by electrophilic cyclization onto an aromatic system have been reported. The methylthio-group has been found to be a useful activating group for six different cyclization routes to the isoquinoline ring system and has the advantage over the methoxygroup that it can be readily removed after cyclization by nickel boride-induced desulphurization. Tetrahydroisoquinolines (292) and (293), for example, can be prepared in moderate yield under conditions where reaction does not occur in the absence of activating groups. 2 0 3 Pictet-Spengler condensation using activated alkynes has been shown to be a useful alternative to the standard reaction using carbonyl compounds: the 1,2,3,4-tetrahydro-~-carbolines (296) are produced in excellent yield from reaction of tryptamines (294) with electron-deficient alkynes (295) .204 The use of carbonyl partners in the reaction gave poor and irreproducible yields. Some simple tetrahydroisoquinolines have also been prepared in good yield by the reaction of arylethylamines with paraformaldehyde and formic acid at 40 O C , conditions which are milder than those normally employed in Pictet-Spengler cyclizations. 205 1,2-Dihydro-B-carbolin-4(3~)-ones (298) have been produced in good yield an acid-catalysed rearrangement of aminonitriles (297) .206 Carruthers et al. have synthesized 2,6-dialkylpiperidines (302) by intramolecular amidomercuration of carbamate (299), followed by


603

0

I1

RCH,CH, NHCNH

Et02C

(288)

R Me0

(289) 63%

(290)

M

e

s

p

N

f'

R

CF3C02H or HCL

(291)

64'/0

Mesq - qN R

R

(292) R=Ph, 75% ( 2 9 3 ) R = H, 51 "/o


604

R4

I

R5 L

(295)

A

R’

(296) 76 -99.5’10

H2S04

~

O ‘c, 15 min ‘R2

I

A1

(298) 41-88’10

t NH

I

R’

H’,

H20


605

reductive trapping of the intermediate organomercurial (300) with electron-deficient olefins (301). 207 Yields are variable, however, and the products are formed as mixtures of‘ diastereomers. The trans-5-hydroxy-2-propylpiperidine (?)-pseudoconhydrine (303) has also been synthesized by an intramolecular amidomercuration procedure, followed by a ring-expansion sequence (Scheme 26) .208 Mercuric chloride-catalysed reaction of the propargyl ethers (304) with N-methylaniline (305) leads to formation of 1,4-dihydroquinolines (306), possibly via the mechanism shown. 209 An example of the formation of a nitrogen heterocycle by platinum-mediated ortho-functionalization of benzylamine has been described: 165 reaction of the platinum complex (307) with ethyl iodoacetate gives 3-0X0-1,2,3,4-tetrahydroisoquinoline (308) as the major product. Abe et al. have reported that cis-6-alkyl-2-methylpiperidines (310) can be prepared simply and in high yield by reductive aminocyclization of alkane-2,6-diones (309). 210 The products are formed as single isomers in all cases, making this a very useful synthetic method for compounds of this type. Marsden and MacLean have reported full details of the synthesis of the protoberberine ring system by condensation of cyclic imines with phthalide anions2’’ and have applied the same methodology to the synthesis of thiaprotoberberines.212 Meyers and his group have described procedures for the enantioselective alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquinolinesto produce I-alkyl-I ,2,3,4-tetrahydroisoq~inolines.~~~ The intramolecular version of this reaction leads to an enantioselective synthesis of benzoquinolizine (311) in good yield and extends the group’s other published work on the synthesis of fused six-membered nitrogen heterocycles by the same general intramolecular alkylative procedure. 16’ ’ 70 A convenient synthesis of 3,4-dihydrocarbostyrils (313) has been reported, based upon reduction-cyclization of the readily available o-nitrocinnamates (312) ,214 and 3,4-dihydropyridinones (315) have been prepared by the reaction of l-azabuta-1,3-dienes (314) with ethyl bromoacetate under Reformatsky reaction conditions. No products derived from 1,2-addition to the azadiene were detected. 215 Finally, two natural product syntheses involving formation of six-membered N-heterocyclic systems have been reported. Holmes


606

C02Me (299)

COz Me ( 300)

(302) X =CN,COZEt, or COC7H15 25 -75.1,

(303) 56.1. overall

Scheme 26


+

ROCH2CECH

607

PhNHMe

(304)

(305)

(306 1 4 6 - 89%

Ph\ N / M e

I

R0CHz-- C -CH2-C-Me

II

N+ \Ph

’

Me

I

11 Ph\+/Me NH

ROCHz-C=CH

I

Me

N N , ~

t

CHzOR

I

-C-Me

I

- PhNHMe ____)

j

G$20R I

CH20R

CHrOR

Me

1

i, HCI ii, NazC03

608


et al. have prepared the spiro-amino-ketone (316) as an intermediate in their formal synthesis of (')-perhydrohistrionicotoxin,216 and the 1 6 ~ -and 1613- epimers of (~)-3-hydroxy-16,17-butanomorphinan (317) have been prepared by a novel route involving the intramolecular alkylation-ring expansion sequence shown in Scheme 27. 217 Six-membered Rings Containing More than One Nitrogen.- Two research groups have described new routes to the tetrahydropyridazine ring system by [4+2] cycloaddition reactions. Two papers by Hunig and co-workers describe Diels-Alder reactions with inverse electron demand, where the protonated azines (318) serve as electrondeficient dienes and react with electron-rich olefins (319) to give heterocycles of general type ( 320 ) . ' For example , reaction of the trimer of dihydropyridazine (321) with cyclopentadiene gives the adduct (322) in good yield. Nelson et al. have invsstigated the potential of protonated azo-compounds (323) in the Diels-Alder reaction and found that these species can be trapped with dienes to yield stable adducts (324) in good yield. 220 Under the same conditions the unprotonated diazenes fail to react with cyclohexadiene. The hexahydropyrrole[l,2-~]quinazoline derivative (326) has been prepared by Reinhoudt and co-workers by thermal isomerization of imine (325). 221 A similar process also afforded a tetrahydropyrrolo[l,2-a]benzothiazine derivative by cyclization of the thiocarbonyl analogue of imine (325). Reaction of 6-sulphinyl or f3-sulphenyl enones (327) with di-imines (328) provides a simple route to Il2-dihydropyrimidine derivatives (329), albeit in only moderate yield.222 A one-step, biomimetic synthesis of the dihydropyrimidinone unit of syncarpurez (332) has been accomplished from syncarpic acid (330) and the l-carboxamido- A'-pyrrolinium ion (331 1 , formed in situ from citrulline by treatment with N-bromosuccinimide .223 The 2,3,8-triazabicyclo[3,3,llnon-3-ene (335), a new heterocyclic system, has been synthesized in good yield by basecatalysed isomerization of tetrahydropyridine (333) to the enamine (334) and subsequent intramolecular cyclization of the hydrazone derivative. 224 An interesting synthetic route to novel annelated 1,2,4triazines has been reported. Reaction of 2-(l-hydroxyalkyl)indole derivatives (336) with the Mitsunobu reagent DEAD-


609 H

NaBbCN, NH4Br MeCOCH2CH2CHzCOR

MeOH, r . t .

(3091

(310) 71-91'ir

Ph

H

S-(311) 70°/090'1.

e.e.

R'mcHo

R2

NO2

+ Ph,P =C

A

__j

Ph H

/ R3

(312 1

'C02Et

PhCH=CH-CH=NAr

(314)

+

BrCHZCqEt

(313) 45- 94% overall

- &* Zn dust, PhH

A

1

Ar

(315) 16-90%


610

2

Z = PhCH20CO

(316)

H

iv

M eO

1,

Meo+

v, v i

HO

Reagents: i( (CF3CO)zO; ii, m-CIC&C03H,

iii, NaBH4 ; iv, PBr3; v, H 2 , PtOZ

Scheme 27

:

v i , BBr3

61I


I

BF4-

H

( 3 2 3 ) n = 1 or 2

C=NAr Me

(324) n = 2 , 97O1,

-118OC q Sdays TM e

H

I

H

CF3 (32 5)

0 R'

0

II -CCH=

II

C( R2 ) SR3

or

CF3

( 3 2 6 ) 66%

H N

R1

h;% phP R4

Ph ( 328)

*

PhH, 130 "c, 12 h,

Ph+Ph

sealed take

A4

(327)

( 3 2 9 ) 23

- 48'10


612

0 (330)

Me

I

(331)

Me

KO H

(334)

a

Ph

H'

I

(335)

6770

613

8: Saturated Heterocyclic Ring Synthesis triphenylphosphine results in cyclization to give the 1,2-dihydro[1,2,4]triazino[4,5-a~indole-2-carboxylates

(337). 225

These can be converted into the corresponding 4-0x0-derivatives (338) by acid treatment. Pyrrolo[1,2-d][1,2,4]-triazines can also be prepared in the same way. Medium-ring Nitrogen Heterocycles.- Rings Containing One Nitrogen. 3,4,5,6-Tetrahydroazepino[4,5-b]indoles (341) have been prepared via a novel thermolysis route from vinyl azides (339). A possible mechanism is shown in Scheme 28: in some cases the intermediate enamines (340) could be isolated and shown to cyclize to azepinoindoles (341). 226 Preliminary results indicate that this cyclization is only successful if R~ = H. A convenient one-step synthesis of benzazepines (343) by anodic cyclization of enaminones (342) has been described ,227 and Ssnchez et al. have reported a total synthesis of lycoramine which features a further application of their modified Tscherniac-Einhorn amidoalkylation procedure to form the requisite tetrahydrobenzazepine

-

Two interesting ring expansion reactions have been used in the synthesis of medium-ring azaheterocycles. The 0x0-lactams (345) have been prepared by an iron(I1)-catalysed radical cleavage of oxaziridines (344),229 and photolysis of pyrrolo[2,1-a]isoquinolinium salt derivatives (346) gave the hexahydrobenzazonine derivatives (347) in moderate yield .230 A biomimetic synthesis of the dibenz[d,f]azonine alkaloids neodihydrothebaine (349) and bractazonine (350) from thebaine (348) has also been reported.231 Rings Containing Two Nitrogens. Dihydrodiazepines (353) have been prepared in excellent yield by cycloaddition of diazoalkanes (352) to diazobicyclohexene (351) followed by nitrogen elimination and thermal ring expansion .232 A ring-expansion sequence has also been used to prepare tetrahydro-1,2-diazepine derivatives (355) by treatment of isoxazoloC3,4-dlpyridazin-7(6~)-ones (354) with base.233 Kellog and co-workers have applied their caesium carbonate-DMF macrocyclization procedure to the synthesis of a range of azamacrocycles of general structure (357) from bis-tosylamide derivatives (356) .234 High-dilution conditions are not required, and the tosyl groups are readily removed with sodium amalgam.

614

General and Synthetic Method:

DMF

A

( 339)

R' =

(3411

CH20Me

R 3 = H, 60'1.

R2= H

R 3 = Me, 5'10

R3 = H or Me

(340 1

It

COZEt [1 61H

b

Q-+==f3

Scheme 28

MeOH, NaC104

elec tro I ysis

Me0

( 3 4 3 ) X = CH2, 4Oo/e X=-CH2CMe2 -, 43'1'

OH

0

OH

(345)

=3-6 30 - 42 '10 n

615

8: Saturated Heterocyclic Ring Synthesis Me

i

i , h W 2 5 0 nm), R20H ii, basification

Me0

Me0

( 3 4 6 ) R = H, D, or Me R = H or Me

Meoq -0

1

reduct ion

Me0

1

reduction

M eO

HO

Me0 OMe

(350)

(349)

616


a”Eo+,y R

R( 3Z5C2N)Z ,

N E ‘

‘E =H, Me, or Ph

(351) R E =COzMe

N

E‘

cl

(353) 80 - 95’10 Ph

-

(355 1 50 72.18

TsNH (chain lo NHTs

i , CszCO3, DMF

11,

Br(chan)b&

Ts

I

(chain la

(chain)b

(356

1 Ts

(357) a = 5 or 10 b = 4- 6,10, or 16 2 5 - 95’10


617

Reaction of diphenyl-l,2,4,5-tetrazine (358) with the enolate or enamine derived from cyclobutanone provides a simple route t o 1,2diazocines (359) via a cycloaddition-ring expansion mechanism. 235

5 B-Lactams, Penicillins, Cephalosporins, and Related Compounds

A review on the stereospecific construction of chiral B-lactams has appeared .236 The 8-lactam (364) has been prepared via a novel route involving stereoselective formation of the B-amino-acyl complex (363) from the enolate (361) of iron acetyl complex (360) and imine (362). Addition occurs from the least hindered face of (361) to give (363) with >98% stereoselectivity. 237 Ley and co-workers have continued their studies of the use of n-allyltricarbonyliron lactone complexes in 8-lactam synthesis by applying the method to a formal total synthesis of ( + ) - t h i e n a m ~ c i n . ~Full ~ ~ details have also appeared of the synthesis of 8-lactams by reaction of chromium carbene complexes with imines. 239 A novel high-yielding synthesis of thietane-fused 8-lactams (366) has been reported via a photochemical intramolecular [2+21 cycloaddition of N-(thiobenzoy1)methacrylamides (365). 240 Standard desulphurization and oxidation chemistry can be carried out on products (366) to give B-lactams (367) and (368), respectively. Kaneko and co-workers have described a useful route to monocyclic 24 1 substituted 8-lactams by photoisomerization of pyridones (369). Although this method is well known, cleavage of bicyclic B-lactams (370) generally involves ozonolytic cleavage of the C-5=C-6 double bond. 4-(2'-Hydroxyethyl)azetidinones (372) have now been prepared by an alternative cleavage procedure involving reduction of (370) followed by a retro-aldol reaction. A procedure for isolating (371 ) ( R 1 ,R2,R3 = H) has also been described.242 Padwa et al. have published full details of the synthesis of B-lactams by photochemical o r thermal ring contraction of isoxazolidines. 243 Optically pure B-lactams (375) have been obtained by a highpressure [2+21 cycloaddition reaction of toluene-4-sulphonyl isocyanate (374) with glycals (373). 244 This reaction has been investigated by several groups in the past but is relatively unsuccessful at normal pressure. In this case, the reaction is


618

Ph

' Ph

Ph (359)

(358)

X =OH, 40'1. X = NEt,,SO'/r Reagents: i , MeO',

MeOH, A; ii, HNEt2,

A

H

Q '.!/ I o c q y o PPh3 (360)

(361)

I

I '

orCAN CuCl2

Ei;r$NHPh

'Ph (364)

H

Ph

619


Me

Me ( 3 6 6 ) 55-96’1.

(365)

m -CIkH4C03H R = CH2Ph

Me

(368)

(369)

( 3 7 2 ) 6 4 - 8 0 % overall

L

(371 1

R3

J&+

R3

R* 10 k b a r

+

__i,

r . t . ether

R’

(373)

R’ Q-Ts 0

(374) ( 37 5 )

60 -77 *la

620


r e g i o - and s t e r e o - s p e c i f i c : t h e C-3 a c e t o x y - g r o u p ,

t h e isocyanate always adds t r a n s - t o

and y i e l d s a r e g o o d .

S e v e r a l p o t e n t i a l l y u s e f u l v a r i a t i o n s of t h e s t a n d a r d a c i d c h l o r i d e - i m i n e r o u t e t o B-lactams have been r e p o r t e d t h i s y e a r . P h e n y l p h o s p h o r o d i c h l o r i d a t e h a s b e e n shown t o b e a n e f f i c i e n t c a r b o x y l g r o u p a c t i v a t o r i n t h e s y n t h e s i s of m e t h o x y c a r b o n y l v i n y l amino-8-lactams

f r o m Dane s a l t s a n d i m i n e ~ a n d~ i~n ~a s i m i l a r w a y ,

p h e n y l (N-me thyl-N-pheny l p h o s p h o r a m i d o c h l o r i d a t e ,2 4

s a c c h a r i n , 247

and N ,N-dimethylchlorosulphitemethaniminium c h l o r i d e 2 4 8 h a v e b e e n used i n mild one-pot s y n t h e s e s of s u b s t i t u t e d B-lactams. C a r d e l l i n i e t a l . have confirmed t h a t 4-alkoxy-B-lactams

can be

p r e p a r e d from i m i d a t e s and a c i d c h l o r i d e s , i n t h e p r e s e n c e o f t r i e t h ~ l a m i n e , ~ a~n’d a f u l l r e p o r t h a s a p p e a r e d of t h e s y n t h e s i s o f s u b s t i t u t e d B-lactams by r e a c t i o n o f c h i r a l i m i n e s w i t h ac h l o r o i m i n i u m c h l o r i d e s . 250 Bose e t a l . h a v e p u b l i s h e d f u l l d e t a i l s o f t h e i r s t u d i e s o f t h e s y n t h e s i s o f 8 - l a c t a m s from a - a m i n o - 8 - h y d r o x y - a c i d derivatives 2 a n i n t r a m o l e c u l a r M i t s u n o b u - t y p e r e a c t i o n , 2 5 1 a n d t h e Merck g r o u p h a s u s e d t h e same c y c l i z a t i o n method i n t h e s y n t h e s i s o f

N-( tetrazol-5-y1)azetidinone d e r i v a t i v e s . 2 5 2 ’ 253

F u r t h e r examples

o f t h i s l a t t e r c l a s s o f compounds h a v e a l s o b e e n p r e p a r e d by t h e a d d i t i o n o f g l y c i n e e n o l a t e s t o N-(tetrazol-5-yl)imines, f o l l o w e d by ~ y c l i z a t i o n . ~ ~ ~ S u b s t i t u t e d monocyclic 8-lactams have been p r e p a r e d from 8-amino-acids

i n good y i e l d by u s i n g 2-chloro-l-methylpyridinium

i o d i d e a s t h e c o n d e n s i n g r e a g e n t 2 5 5 a n d Shono e t a l . h a v e r e p o r t e d

a g e n e r a l s y n t h e s i s o f B - l a c t a m s ( 3 7 8 ) by r e a c t i o n o f u-methoxylated

carbamates (376) with ketene methyl t r i m e t h y l s i l y l

a c e t a l s ( 3 7 7 ) . 256 A l d o l - t y p e r e a c t i o n s h a v e b e e n u t i l i z e d i n s e v e r a l B-lactam syntheses t h i s year.

Reaction of ketene bis(trimethylsily1)

a c e t a l s ( 3 7 9 ) w i t h i m i n e s ( 3 8 0 ) g a v e p r o d u c t s ( 3 8 1 ) i n good y i e l d and under mild c o n d i t i o n s , w i t h no f o r m a t i o n of t h e c o r r e s p o n d i n g B - a m i n o - a c i d s . 257

T h r e e g r o u p s h a v e r e p o r t e d on t h e u s e o f

d i a n i o n s of 3-hydroxybutyrates produce B-lactams of N - t r i m e t h y l s i l y l co-workers

(Scheme 2 9 ) .

i n the reaction with imines t o A s p a r t o f a s t u d y of t h e r e a c t i o n

i m i n e s w i t h a r a n g e o f e s t e r e n o l a t e s , Hart a n d

f o u n d t h a t B-lactams c o u l d b e p r o d u c e d by r e a c t i o n o f

t h e d i e n o l a t e ( 3 8 2 ) w i t h t h e i m i n e ( 3 8 3 ) b u t w i t h low s t e r e o c o n t r o l : p r o d u c t s ( 3 8 4 ) - ( 3 8 7 ) a r e formed as a p a r t i a l l y s e p a r a b l e m i x t u r e , a l t h o u g h *-isomer ( 3 8 4 ) i s formed a s t h e major

62 1


Me0 (376 1

i, HBr,AcOH TiCl4

+

R'

CH2C12, -70 'C*r.t.

R5 R%siMe3

ii RMgBr

(378) 11-69% overal

OMe

R'xos Me3 OSiMe,

R2

+

R3CH=NR4 (380)

(379)

xR4

R3 Tic14 CHzCI2, r.t.

'

R'

R2

(381)

Me S i C

OLi

0k N \ R 2

-

60

- 75'10

C C H=NSi M e 3

OLi

(382 1

HMPA( ph-\ 1.5 eta.) THF, -20

OC

+r.t.,

6h

43 *lo; trans

(388 1 Scheme 29

s*

95%


622

p r o d u c t . 258 The s a m e r e a c t i o n h a s b e e n c a r r i e d o u t by C h i b a e t a l . I n c o n t r a s t , reaction of w i t h e s s e n t i a l l y t h e same r e s u l t . 2 5 9 d i e n o l a t e ( 3 8 2 ) w i t h b e n z y l i d e n e a n i l i n e u n d e r t h e c o n d i t i o n s shown gives trans-azetidinone

.

( 3 8 8 ) w i t h 95% d i a s t e r e o s e l e c t i v i t y 2 6 0

In

a s i m i l a r t y p e of r e a c t i o n , u l t r a s o u n d h a s b e e n f o u n d t o p r o m o t e

the reaction of ethyl bromoacetate with imines (389) t o give

B-lactams

( 3 9 0 ) i n e x c e l l e n t y i e l d . 26

The spiro-epoxy-azetidinones ( 3 9 2 ) h a v e b e e n p r e p a r e d i n g o o d y i e l d from b i s ( chloromethy1)propionamides

(39 1 ) ,262 and crown

e t h e r s h a v e b e e n shown t o b e e x c e l l e n t p h a s e - t r a n s f e r t h e s y n t h e s i s of (3-lactams

catalysts for

f r o m N-aryl-B-bromopropionamides . 2 6 3

Two n o v e l s y n t h e s e s of t h e c a r b a p e n a m s k e l e t o n h a v e a p p e a r e d . P r o d u c t s ( 3 9 5 ) a n d ( 3 9 6 ) a r e p r o d u c e d i n l o w y i e l d by a new b a s e c a t a l y s e d c y c l o a d d i t i o n r e a c t i o n of t h e i o d o m e t h y l a z e t i d i n o n e s (393) with 2-thiosubstituted

dimethyl fumarate d e r i v a t i v e s (394)

a n d Wasserman h a s a p p l i e d a new p h o t o - o x i d a t i v e

264

c l e a v a g e method o f

g e n e r a t i n g v i c i n a l t r i c a r b o n y l systems t o s y n t h e s e s of t h e carbapenam ( 3 9 7 ) and t h e carbacepham ( 3 9 8 ) (Scheme 3 0 ) . 265,266 The Merck g r o u p h a s r e p o r t e d t h e s y n t h e s i s o f 3-methylphosphonylthienamycin a n d r e l a t e d 3-phosphonyl-carbapenems v i a a r h o d i u m - c a t a l y s e d i n s e r t i o n r e a c t i o n of t h e a p p r o p r i a t e a - d i a z o p h o s p h o n a t e p r e c u r s o r s , 267 a n d F a r m i t a l i a w o r k e r s h a v e p r e p a r e d c a r b a p e n e m ( 4 0 0 ) a n d p e n e m s ( 4 0 2 ) by r e d u c t i v e c o u p l i n g o f t h e monocyclic d i c a r b o n y l - a z e t i d i n o n e s (399) and ( 4 0 1 ) , r e s p e c t i v e l y . 268-270 The l - p h o s p h a c e p h a l o s p o r i n r i n g s y s t e m h a s b e e n s y n t h e s i z e d f o r t h e f i r s t t i m e by a r o u t e i n v o l v i n g t h e i n t r a m o l e c u l a r W i t t i g r e a c t i o n shown i n Scheme 31. F i n a l p r o d u c t s ( 4 0 3 ) a n d ( 4 0 4 ) were T h e same g r o u p h a s a l s o d e v o i d of a n t i b a c t e r i a l a c t i v i t y . 2 7 1 d e s c r i b e d t h e s y n t h e s i s of o p t i c a l l y a c t i v e 7 - s u b s t i t u t e d 1- p h o s p h a c e p h a l o s p o r i n s by s i m i l a r p r o c e d u r e s . 2 7 2 T h i o p e n a m d e r i v a t i v e s ( 4 0 7 ) a n d ( 4 0 8 ) h a v e b e e n p r e p a r e d by r e a c t i o n of alkynyl s i l y l s u l p h i d e (405) with d i h y d r o t h i a z o l e s ( 4 0 6 ) a~n d~ ~a f u l l r e p o r t o f t h e s y n t h e s i s of y-lactam a n a l o g u e s 274

of p e n i c i l l a n i c a n d c a r b a p e n i c i l l a n i c a c i d s h a s a p p e a r e d .

623


Br-CH2

KArl

+

I

N

COtEt

sonication Zn, 1121 dioxane, 25 "C

0

'A?

CH2CI

I

R2C02-

KOH

C-CONHR'

___)

O

THF

CHzCI 1

(391)

(392 )

SR2

Me02C

(394)

i (R2=Ph) or ii (R2=Me)

C02Me

R' = H ,

(396)

27'10 OSiMe2Bu'

, 15*/.

Reagents : i, KH, 10-crown-6,

70 - 80%

/4c02Me

+

(395)

Y N\R1

THF; ii , PhZCHK, 18-crown-6, THF


624

R’.H/-

H

H

I

i,HF, Py

ii, 3

A molecular sieves

..R’

TMSl

0

0

Cop R2

CO ZR

(397) n = 1 , R’ = E t , R‘ = PNB, 120/~overall (398) n = 2 , R ’ = H, R 2 = B u t , Scheme 30

But Me2Si 0

But M e2Si 0 P(OEt13,A

CO2 PNB

cO2 PNB


625

CO2R

C02R

+ C02R

1

i, AIC13, anisole ii, NaHC03

i ii

tE$+J

$ J b . -

0

0 C02Na

C02 Na

(403)

(404)

Scheme 31

Bu' - CEC-S-SiMe3

+

[ n$:;] But

(405) 2 OC, 7 days without solvent ~

yut

sonic,"'io~L>*dPR*

SSiMea

1

R'

(406)

R2

R'

(407)R' ,R = H, 80% ( 4 0 8 ) R' = COiMe, R 2 = Me, 55%

General and Synthetic Methodr

626 References 1.

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5,

2.

25,

3.

4. 5. 6. 7

9,

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38 39. 40.

-

41. 42. 43. 44. 45. 46.

5,

106,

-

5,

25,

.

9,

25,

25,

.

106,

.

..

25,

5,

.

9,

3,

~

2,

2,

8: Saturated Heterocyclic Ring Synthesis 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87.

88. 89. 90. 91.

621

A.Arnoldi, Synthesis, 1984, 856. A.Saba, Synthesis, 1984, 268. P.A.Aristoff, A.W.Harrison, and A.M.Huber, Tetrahedron Lett., 1984, 25, 3955. G.Solladie and S.Moine, J. Am. Chem. SOC., 1984, 106,6097. P.F.Shuda and J.L.Phillips, J. Heterocycl. Chem., 1984, 21, 669. D.Dauzonne and R.Royer, Synthesis, 1984, 348. H.Yoshida, M.Nakajima, T.Ogata, and K.Matsumoto, Bull. Chem. SOC. Jpn., 1984, 57, 734. A.M.Doherty, S.V.Ley, B.Lygo, and D.J.Williams, J. Chem. SOC., Perkin Trans. 1 , 1984, 1371. C.Iwata, K.Hattori, S.Uchida, and T.Imanishi, Tetrahedron Lett., 1984, 5, 2995. P.Kocienski and C.Yeates, J. Chem. SOC., Chem. Commun., 1984, 151. R.Amouroux, Heterocycles, 1984, 22, 1489. S.V.Ley and B.Lygo, Tetrahedron Lett ., 1984, 25, 113. P.Kocienski and S.D.A.Street, J. Chem. SOC., Chem. Commun., 1984, 571. K.Mori and H.Watanabe, Tetrahedron Lett., 1984, 25, 6025. K.Mori, T.Uematsu, H.Watanabe, K.Yanagi, and M.Minobe, Tetrahedron Lett., 1984, 25, 3875. K.Mori and M.Ikunaka, Tetrahedron, 1984, 110, 3471. K.Gollnick and A.Schnatterer, Tetrahedron Lett., 1984, 25, 2735. 4581. R.M.Moriarty and K.-C.Hou, J. Org. Chem., 1984, 9, Z.G.Hajos, M.P.Wachter, H.M.Werblood, and R.E.Adams, J. Org. Chem., 1984, 49, 2600. C.W. Jefford, D.Jaggi , J. Boukouvalas, S.Kohmoto, and G .Bernardinelli, Helv. Chim. Acta, 1984, 67,1104. C.W. Jefford, J.Boukouvalas, and S.Kohmoto, J. Chem. SOC , Chem. Commun., 1984, 523. C.W.Jefford, D.Jaggi, S.Kohmoto, J.Boukouvalas, and G.Bernardinelli, Helv. Chim. Acta, 1984, 67,2254. T.Endo and M.Okawara, Synthesis, 1984, 837. H.A.J.Carless and G.K.Fekarurhobo, J. Chem. SOC., Chem. Commun., 1984, 667. S.L.Schreiber and S.E.Kelly, Tetrahedron Lett., 1984, 25, 1757. E.Vedejs, Acc. Chem. Res., 1984, 17,358. W.Ando, T.Furuhata, Y.Hanyu, and T.Takata, Tetrahedron Lett., 1984, 25, 401 1. H.Ikehira and S.Tanimoto, Bull. Chem. SOC. Jpn., 1984, 57, 2474. C.G.Francisco, R-Freire, R-Hernandez, J.A.Salazar, and E.Suarez, Tetrahedron Lett., 1984, 2, 1621. A.Nickon, A.Rodriguez, V.Shirhatti, and R.Ganguly, Tetrahedron Lett., 1984, 25, 3555. E-Anklam and P.Margaretha, Helv. Chim. Acta, 1984, 2, 2198. Y-Tamaru, H.Satomi, O.Kitao, and Z-Yoshida, Tetrahedron Lett., 1984, 25, 2561. K.R.Lawson, A.Singleton, and G.H.Whitham, J. Chem. SOC., Perkin Trans. 1 , 1984, 859. Y.Tamaru, 0-Ishige, S.Kawamura, and Z.Yoshida, Tetrahedron Lett., 1984, 25, 3583 K.Hantke and H.Gotthardt, J. Chem. SOC., Chem. Commun., 1984, 1682. J.S.Grossert, J.Hoyle, and D.L.Hooper, Tetrahedron, 1984, 40, 1135. F.A.Davis, J.P.AcAuley,Jr., and M.E.Haraka1, J. Org. Chem., 1984, 2,1465. Y.Ohshir-o, M.Komatsu, M. Uesaka, and T.Agawa, Heterocycles, 1984, 22, 549. D.Geffken, Liebigs Ann. Chem., 1984, 894. K.E.Larsen and K.B.G.Torssel1, Tetrahedron, 1984, 40, 2985. T.Schimizu, Y.Hayashi, and K.Teramura, Bull. Chem. SOC., Jpn., 7984, 57, 2531. S.P.Ashburn and R.M.Coates, J. Org. Chem., 1984, 2, 3127. A.P.Kozikowski and A.K.Ghosh, J. Org. Chem., 1984, 2, 2762. S.Mzengeza and R.A.Whitney, J. Chem. SOC., Chem. Commun., 1984, 606. P.A.Wade, N.V.Amin, H.-K.Yen, D.T.Price, and G.F.Huhn, J. Org. Chem., 1984, 49, 4595.

.

-

-

628 92. 93.

94. 95.

96. 97. 98.

99. 100. 101.

102. 103. 104. 105.

106.

107. 108. 109. 110. 111.

112.

113. 114. 115.

116. 117. 118. 119. 120. 121.

122. 123.


14,

K.K.Singa1, Synth. Commun., 1984, 1047. A.P .Kozikowski, K.Hiraga, J. P.Springer , B. C.Wang, and Z.-B.Xu, J. Am. Chem. SOC., 1984, 106,1845. R.Grigg, M. Jordan, A. Tangthongkum, F .W .B.Einstein, and T.Jones, J. Chem. SOC., Perkin Trans. 1 , 1984, 47. P.Wipf and H.Heimgartner, Tetrahedron Lett., 1984, 25, 5127. K.E.Harding, R.Stephens, and D.R.Hollingsworth, Tetrahedron Lett., 1984, 2 4631. C.Capozzi, C.Caristi, and M.Gattuso, J. Chem. SOC., Perkin Trans. 1 , 1984, 255. S.Mataka, K.Uehara, K.Takahishi, and M.Tashiro, Synthesis, 1984, 663. M.Sabuni, G.Kresze, and H.Braun, Tetrahedron Lett ., 1984, 3,5377. H.Felber, G.Kresze, H.Braun, and A-Vasella, Tetrahedron Lett., 1984, 25, 5381. 4098. D.L.Boger and M.Pate1, J. Org. Chem., 1984, S.E.Denmark, M.S.Dappen, and J.A.Sternberg, J. Org. Chem., 1984, 9, 4741. H.K.Hal1, Jr. and D.L.Miniutti, Tetrahedron Lett., 1984, 25, 943. X.Huang and C.-C.Chan, Synthesis, 1984, 851. A.Fruchier , V. Moragues, C.Petrus, and F.Petrus, Bull. SOC Chim. Fr , Part 2, 1984, 173. A.Q.Hussein, M.M. El- Abadelah, and W.S.Sabri, J. Heterocycl. Chem., 1984, 21 455. G.Cignarella and D.Barlocco, Synthesis, 1984, 342. H.Cnichte1, J.-U.Wahner, and K.Hirte, Liebigs Ann. Chem., 1984, 1696. E.Block, M.Aslam, R.Iyer, and J.Hutchinsin, J. Org. Chem. , 1984, 9, 3664 J.K.Koskimies, Acta Chem. Scand., Ser. B, 1984, 2,101. R.A.Abramovitch, A.O.Kress, S.P .McManus, and M. R.Smith, J Org. Chem., 1984, 9, 3114. K.Schulze, C.Richter, F.Richter, E.Mrozek, R.Weisheit, and F.Anchenbac J. Prakt. Chem., 1984, 326, 101. A. Alemagna, P. D.Buttero, E. Licandro, S-Maiorana, and R .Trave, Tetrahedron, 1984, 5, 971. Y.Matsubara, S.Yamada, M.Yoshihara, and T-Maeshima, Chem. Pharm. Bull ., 1984, 32, 1590. Y.Ishikawa, Y.Terao, K.Suzuki, N.Shikano, and M.Sekiya, Chem. Pharm. Bull. 1984, 32, 438. W.Hanefeld, Arch. Pharm. (Weinheim, Ger.), 1984, 317, 297. T.Sasaki and I.Shimizu, Heterocycles, 1984, 22, 1225. M.P.Crozet, M.Kaafarani, and J.-M.Surzur, Bull. SOC. Chim. F r . , Part 2, 1984, 390. H.Tashida and T.Tsuchiya, Heterocycles, 1984, 22, 1303. S.Sato, K.Tomita, H.Fujita, and Y.Sato, Heterocycles, 1984, 22, 1045. J.Borgulya, J.J.Daly, P.Schonholzer, and K.Bernauer, Helv. Chim. Acta, 1983, 3, 1827. K.Kanakarajan and H.Meier, Angew. Chem., Int. Ed. Engl., 1984, 3,244. H.Natsugari, R.R.Whittle, and S.M.Weinreb, J. Am. Chem. SOC., 1984, 106,

9,

.

.

.

-

7867. R.S.Garigipati, A.J.Freyer, R.R.Whittle, and M.Weinreb, J. Am. Chem. SOC., 1984, 106,7861. 125. A.Couture, R.Dubiez, and A.Lablache-Combier, J. Org. Chem., 1984, 714. 126. H.Suzuki and H.Tani, Chem. Lett., 1984, 2129. 127. J.R.Pfister, Synthesis, 1984, 969. 128. C.Mahido1, V.Reutraku1, V.Prapansiri, and C.Panyachotipun, Chem. Lett., 1984, 969. 129. V.Reutraku1, V.Prapansiri, and C.Panyachotipun, Tetrahedron Lett., 1984, 25. 1949. -_ - 130. B.Mauzk, Tetrahedron Lett., 1984, 25, 843. 131. N.DeKimpe, B.DeCorte, R.Verhe, L.DeBuyck, and N.Schamp, Tetrahedron Lett., 1984, 25, 1095. 132. Y.Girazt, M.Decouzon, and M.Azzaro, Tetrahedron Lett., 1984, 25, 2763. 133. M.A.Loreto, L.Pellacani, P.A.Tardella, and E.Toniato, Tetrahedron Lett., 1984, 25, 4271. 124.

2,

I

~

8: Saturated Heterocyclic Ring Synthesis 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147.

148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177.

629

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.

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I

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5,

2,

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63 1

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x,

9,

2,

.

2,

9,

632 273. 274.

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Highlights in Total Synthesis of Natural Products BY K. E. B. PARKES AND G. PATTENDEN

1 Introduction This Report is similar in selectivity and subjectivity to the previous chapters in the series.

2 Terpenes The pentalenane family of angularly fused triquinane antibiotic metabolites produced by Streptomycetes has attracted the attentions of a number of synthetic chemists over the past few years. During 1984, the authors' research group outlined a stereocontrolled synthesis of (?I-pentalenene (6) which was based on an intramolecular photocycloaddition-cyclobutane fragmentation, 2. (1) ( 2 ) ; (3) (4), to set up the central bicycloC6.3.01undecadiene intermediate ( 5 ) for transannulation to (6) in the presence of boron trifluoride. A second new synthesis of ( ? ) pentalenene (6) featured a recently developed methylenecyclopentane

-

-

'

annulation process, from ( 7 ) , and using 4-chloro-2-trimethylstannyl2 but-l-ene, to provide the tricyclic intermediate ( 8 ) (Scheme 1 ) . The scope for the intramolecular photocycloaddition-cyclobutane fragmentation approach to ring synthesis, mentioned above, has also been exemplified in a new synthesis of (t)-pentalenic acid ( 1 1 ) (Scheme 2 ) , where the key step involved reductive cleavage of the tricyclic adduct (10) produced from irradiation of the dienone ( 9 ) . 3 Shirahama and Matsumoto's research group4 has extended their elegant investigations of the biomimetic in vitro conversions of humulene ( 1 2 ) to provide neat syntheses of a number of natural pentalenolactones, 3.(13b), and Cane et a1.5 have highlighted the use of an intramolecular carbene insertion sequence to elaborate the 6-lactone ring in their synthesis of ( 2 ) pentalenolactones E (14) and F (13a). An interesting synthesis of (+)-modhephene ( 1 7 1 , the first carbocyclic [3.3.3]propellane isolated from Nature, has employed a For References see page 676.

633


634

; ii,

0 3 ; iii, Me02CCH=PPh3;

Scheme 2

i v , h v , 366nm; v, L i , N H 3

9: Highlights in Total Synthesis of Natural Products

635

(13) a; R = H b; R = OH

(12)

a

& H?

___) MeNHOH E tONa

H

H

H

H

(18) steps

$

OH

H

636


chelation-controlled r e g i o s e l e c t i v e epoxide-carbonyl

i.e. (15)

-

(16),

rearrangement,

as a key s t e p . 6

A l t h o u g h a n u m b e r of s y n t h e s e s o f t h e l i n e a r - f u s e d

triquinanes

h i r s u t e n e ( 2 0 ) a n d c o r i o l i n ( 1 9 ) h a v e now b e e n p u b l i s h e d ,7 a n i n t e r e s t i n g new a p p r o a c h t o h i r s u t e n e h a s e m p l o y e d a n a t t r a c t i v e intramolecular nitrone-olefin

cycloaddition reaction using the

easily accessible ketone (18).

8

P a q u e t t e and S t e v e n s have p u b l i s h e d f u l l d e t a i l s of t h e i r s y n t h e s i s of t h e m a r i n e m e t a b o l i t e c a p n e l l e n e ( 2 3 ) , which f e a t u r e s

a Nazarov c y c l i z a t i o n ,

G. (21)

-

( 2 2 ) , 9 and two a l t e r n a t i v e

s y n t h e s e s of t h i s i n t e r e s t i n g m e t a b o l i t e , b o t h h i g h l i g h t i n g some u s e f u l stannane chemistry, have been d e s c r i b e d - l o

The n o v e l a n d

u n u s u a l f u s e d 5-8 r i n g h y d r o c a r b o n p r e c a p n e l l a d i e n e ( 2 5 ) i s believed t o be t h e b i o g e n e t i c precursor of capnellene ( 2 3 ) i n marine c o r a l .

F i r s t s y n t h e s i z e d i n 1 9 8 0 , t h i s r i n g s y s t e m h a s now

b e e n e l a b o r a t e d by t h e r e s e a r c h g r o u p s o f M e h t a ” Paquette. l2

and of

Whereas Mehta and Murty have u s e d t h e t r i q u i n a n e ( 2 4

as a c e n t r a l i n t e r m e d i a t e i n t h e i r s y n t h e s i s , P a q u e t t e e t a l . employed t h e C l a i s e n r e a r r a n g e m e n t of (27) t o precapnelladiene. Cope r e a r r a n g m e n t ,

(26) t o produce t h e precursor

Another rearrangement,

t h a t is t h e oxy-

h a s been used i n an i n t e r e s t i n g manner t o

p r o d u c e t h e 5-8 r i n g f u s e d s y s t e m ( 2 9 ) from ( 2 8 ) i n a t o t a l s y n t h e s i s of ( 2 ) - p o i t e d i o l

( 3 0 ) found i n r e d seaweed L a u r e n c i a

p o i t e i . ’3 The e n g a g i n g s e s q u i t e r p e n e q u a d r o n e ( 3 5 ) h a s now b e e n synthesized i n c h i r a l non-racemic acid-catalysed

form u s i n g a s t r a t e g y b a s e d on

rearrangement of t h e propellane (34 )

.

The

p r o p e l l a n e ( 3 4 ) i s e a s i l y a v a i l a b l e from t h e b i c y c l i c e n o n e ( 3 1 ) following photocycloaddition of isobutene, t o ( 3 2 ) , reduction t o ( 3 3 1 , m e s y l a t i o n , and l a c t o n i z a t i o n .

(+)-Quadrone, the enantiomer

o f t h e n a t u r a l p r o d u c t , was p r o d u c e d f r o m a r e s o l v e d s a m p l e o f ( 3 3 ) using S-(+)-g-acetylmandelic

acid.

Additional work, i n c l u d i n g t h e

f u l l d e t a i l s of B u r k e ‘ s s y n t h e s i s , on a p p r o a c h e s t o w a r d s q u a d r o n e and r e l a t i v e s , h a s a l s o been p u b l i s h e d . l5 T h e b i t t e r p r i n c i p l e s o f q u a s s i a wood Q u a s s i a a m a r a , known as quassinoids,

possess potent cytotoxic properties.

With t h e i r high11

oxygenated t e t r a c y c l i c c a r b o n s k e l e t o n s and d e n s e s t e r e o c h e m i c a l d e t a i l , t h e s e f e a t u r e s h a v e c o m b i n e d t o make t h e q u a s s i n o i d s p a r t i c u l a r l y challenging molecules f o r synthesis.

During 1984,

Grieco e t a1.I6 d e s c r i b e d a t o t a l s y n t h e s i s of q u a s s i n ( 3 8 ) , t h e m a j o r c o n s t i t u e n t o f q u a s s i a wood, w h i c h f e a t u r e d t h e L e w i s a c i d -


637

steps

H (22)

(21)

H

Ru02

+ Na104 '

(23)

@ steps

0

H

(25)

(24)

200

*c

steps

+

(25)

I

(2 6)

(27)

50 *C ___)

' A

G

O

H

4 h

steps

.OH


638

I

I

C02Me

J

(31)

NaBH4

C0,Me

(32)

=-!

C0,Et

(36)

/

Scheme 3

(37)

OMe


c a t a l y s e d i n t e r m o l e c u l a r Diels-Alder

639 r e a c t i o n between t h e

d i e n o p h i l e ( 3 6 ) and e t h y l E-4-methylhexa

- 3,5-dienoate

( 3 7 ) (Scheme

3). G i b b e r e l l i c a c i d ( 3 9 1 , t h e phytohormone which p l a y s a c e n t r a l r o l e i n t h e r e g u l a t i o n o f p l a n t g r o w t h , f i r s t succumbed t o t o t a l

s y n t h e s i s i n 1978. T h i s c h a l l e n g i n g t a r g e t , however, s t i l l a t t r a c t s a t t e n t i o n from s y n t h e t i c c h e m i s t s throughout t h e world. D u r i n g 1 9 8 4 , Mander a n d h i s g r o u p ” u n d e r p i n n e d t h e i r n o v e l a n d o u t s t a n d i n g c o n t r i b u t i o n s i n t h i s area with an a d d i t i o n a l s y n t h e s i s o f g i b b e r e l l i c a c i d which h i g h l i g h t e d t h e i m p o r t a n c e o f ( a ) i n t r a m o l e c u l a r a l k y l a t i o n o f r - s y s t e m s by p r o t o n a t e d d i a z o m e t h y l k e t o n e s , and ( b ) r e d u c t i v e a l k y l a t i o n of a r o m a t i c s u b s t r a t e s , i n g e n e r a l s y n t h e s i s (Scheme 4 ) . The b i c y c l i c h y d r o c a r b o n t r i c h o d i e n e ( 4 2 1 , b i o g e n e t i c p r e c u r s o r t o t h e biologically a c t i v e trichothecanes, is a deceptively simple s y n t h e t i c t a r g e t , c o n t a i n i n g a s i t d o e s two a d j a c e n t c h i r a l quaternary centres. Two e f f e c t i v e s o l u t i o n s t o t h i s p r o b l e m h a v e now b e e n d e s c r i b e d . T h e s e s o l u t i o n s a r e b a s e d on f r a g m e n t a t i o n o f t h e p o t a s s i u m s a l t d e r i v e d from ( 4 0 ) , 1 8 a n d on Beckmann

f r a g m e n t a t i o n f r o m t h e oxime of t h e k e t o n e ( 4 1 ) p r o d u c e d by a Nazarov r e a c t i o n (Scheme 5 ) . A n e a t s y n t h e s i s of p e r i p l a n o n e B ( 4 5 ) , t h e p o t e n t s e x a t t r a c t a n t and s e x e x c i t a n t pheromone of t h e American c o c k r o a c h P e r i p l a n e t a a m e r i c a n a , h a s b e e n a c h i e v e d by S c h r e i b e r a n d S a n t a n i (Scheme 6 ) . 2 0 I n t h i s r o u t e t h e 10-membered r i n g i n t h e p h e r o m o n e was e l a b o r a t e d a n a n i o n - a c c e l e r a t e d oxy-Cope r e a r r a n g e m e n t , i . e . (43) ( 4 4 ) , f o l l o w e d by e l e c t r o c y c l i c r i n g o p e n i n g o f t h e resulting cyclobutene. The t a x a n e f a m i l y o f b i o l o g i c a l l y a c t i v e m e t a b o l i t e s , f i r s t i s o l a t e d f r o m t h e common Yew t r e e , i n c o r p o r a t e a n o v e l a n d u n u s u a l f u s e d 6 , 8 , 6 - r i n g s y s t e m [ s e e ( 4 8 ) l . H o l t o n 2 ’ h a s now shown t h a t +

t r e a t m e n t of t h e epoxide ( 4 6 ) , d e r i v e d i n f o u r s t e p s from commercial p a t c h o u l i a l c o h o l , w i t h dimethyl s u l p h i d e r e s u l t s i n s m o o t h f r a g m e n t a t i o n t o t h e f u s e d 6 , 8 - r i n g p o r t i o n of t h e t a x a n e s i n essentially quantitative yield. E l a b o r a t i o n of ( 4 7 ) t o t h e c o m p l e t e t a x a n e r i n g s y s t e m ( 4 8 ) was t h e n a c c o m p l i s h e d by a l k y l a t i o n f o l l o w e d by a l d o l i z a t i o n ( S c h e m e 7 ) .


540

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3 Steroids S t e r n b e r g and V o l l h a r d t h a v e p u b l i s h e d f u l l d e t a i l s o f t h e i r e l e g a n t work on t h e s y n t h e s i s of s t e r o i d s b a s e d on c o b a l t - m e d i a t e d

[2+2+21 c y c l o a d d i t i o n r e a c t i o n s . 2 2 ( 4 9 ) t o e x c e s s [CpCo(CO),]

T h u s , e x p o s u r e of t h e e n e d i y n e

i n boiling iso-octane gave the red

c r y s t a l l i n e c o b a l t c o m p l e x ( 5 0 ) i n 65% y i e l d . d e m e t a l l a t i o n of

Oxidative

( 5 0 ) t h e n p r o v i d e d t h e a r y l d i e n e ( 5 1 ) w h i c h was

c o n v e r t e d i n t o t h e known k e t o n e ( 5 2 ) u s e d e a r l i e r i n a s y n t h e s i s o f oestrone. I n a f u r t h e r a p p l i c a t i o n of t h e p o l y e n e c y c l i z a t i o n a p p r o a c h t o s t e r o i d s y n t h e s i s , i t h a s b e e n shown t h a t a n e n o l a c e t a t e c a n f u n c t i o n as a u s e f u l t e r m i n a t o r ;

t h u s , treatment of t h e epoxy-enol

a c e t a t e ( 5 3 ) w i t h a L e w i s a c i d , f o l l o w e d by m a n i p u l a t i o n o f t h e i n t e r m e d i a t e ( 5 4 ) , produced t h e androst-4-en-3

-one - 1 , 1 7 - c a r b o x y l i c

a c i d ( 5 5 1 i n 11% y i e l d .23 4 Anthracyclinones S n i e c k u s and h i s c o l l e a g u e s have c o n t i n u e d t h e i r development o f t h e arylamide ortho-lithiation

s t r a t e g y with s y n t h e s e s of e r y t h r o l a c c i n

t e t r a m e t h y l e t h e r ( 6 0 a ) , 2 4 and d e s o x y e r y t h r o l a c c i n t r i m e t h y l e t h e r I n b o t h of t h e s e s y n t h e s e s , t h e r e a d y b e n z y l i c l i t h i a t i o n

(60b).25

o f t h e A-ring

a r y l m e t h y l had t o b e p r e v e n t e d s o a s t o a l l o w t h e

r e q u i r e d a r y l l i t h i a t i o n f o r p h t h a l i d e f o r m a t i o n by c o n d e n s a t i o n w i t h 3,5-dimethoxybenzaldehyde, (59b).

e. (56a)

-

( 5 9 a ) and (56b)

-

Two s t r a t e g i e s f o r o v e r c o m i n g t h i s d i f f i c u l t y were

developed.

I n t h e former s y n t h e s i s extremely r a p i d halogen-metal

e x c h a n g e o f ( 5 7 ) , o b t a i n e d by s i l y l a t i o n , m e t h y l a t i o n , a n d b r o m o d e s i l y t i o n of t h e b e n z a m i d e lithium.

I n t h e s y n t h e s i s of

b l o c k e d by b i s - s i l y l a t i o n

(56a) gave t h e r e q u i r e d a r y l -

( 6 0 b ) , b e n z y l i c l i t h i a t i o n was

as (581, w i t h t h e b l o c k i n g groups b e i n g

r e m o v e d by t r e a t m e n t w i t h c a e s i u m f l u o r i d e . The e n o r m o u s p o w e r o f t h e D i e l s - A l d e r

r e a c t i o n is w e l l

i l l u s t r a t e d t h i s y e a r w i t h a s y n t h e s i s o f v i n e o m y c i n B2 a g l y c o n e methyl e t h e r (61).26

I n t h i s s y n t h e s i s , both of t h e phenol r i n g s

a n d t h e p y r a n c o m p o n e n t o f t h e n a t u r a l p r o d u c t were c o n s t r u c t e d by Diels-Alder

r e a c t i o n s (Scheme 8 ) .

The n a p h t h o q u i n o n e a n t i b i o t i c

(*)-nanaomycin

A ( 6 6 ) h a s been

prepared using the i n t e r e s t i n g intramolecular phthaloylcobalt acetylene insertion-reductive elimination sequence ( 6 2 ) ( 6 3 ) .27

-

643

9: Hightights in Total Synthesis of Natural Products

n

(50)

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9: Highlights in Total Synthesis of Natural Products Z i n c r e d u c t i o n of ( 6 3 ) t h e n g a v e t h e p r e s u m e d i n t e r m e d i a t e (64) a 6 - e n d o t r i g c y c l i z a t i o n , a n d o x i d a t i v e work-up l e d t o t h e p y r a n o n a p h t h o q u i n o n e ( 6 5 ) w h i c h was c o n v e r t e d i n t o t h e n a t u r a l product (66). T h i s y e a r , 1 9 8 4 , a l s o saw t h e p u b l i c a t i o n of a T e t r a h e d r o n Symposium-in-Print

on ' R e c e n t A s p e c t s o f A n t h r a c y c l i n o n e

which g a v e a v a l u a b l e and d e t a i l e d p i c t u r e of t h e s t a t e 28 of contemporary anthracyclinone chemistry.

Chemistry',

5 Alkaloids Cycloaddition reactions, p a r t i c u l a r l y those involving 1,3-dipoles, h a v e been u s e d e x t e n s i v e l y i n a l k a l o i d s y n t h e s i s i n 1984. E s p e c i a l l y a t t r a c t i v e was a o n e - p o t s y n t h e s i s of t h e i s o - i n d o l e ( T O ) , an a n t i m i c r o b i a l m e t a b o l i t e i s o l a t e d f r o m a Mexican s p o n g e . I n t h i s s y n t h e s i s t r e a t m e n t of t h e amine ( 6 7 ) w i t h s i l v e r f l u o r i d e formed a n azo-methine y l i d e i n t e r m e d i a t e ( 6 8 ) , which underwent [ 3 + 2 ] c y c l o a d d i t i o n w i t h 2-methoxy-3-methylbenzoquinone t o g i v e (69).

The q u i n o n e ( 6 9 ) was t h e n o x i d i z e d i n s i t u t o t h e n a t u r a l

p r o d u c t by e x c e s s s i l v e r f l u o r i d e

.*'

Confalone's r e s e a r c h group has reported t h e i r a p p l i c a t i o n o f an i n t r a m o l e c u l a r iminium y l i d e - o l e f i n s y n t h e s i s of ( + I - a - l y c o r a n e

( 7 4 ) .30

[3+21 c y c l o a d d i t i o n f o r t h e In this synthesis the ylide

( 7 2 ) , w h i c h was g e n e r a t e d by h e a t i n g t h e a l d e h y d e ( 7 1 ) w i t h

g-

b e n z y l g l y c i n o i n t h e p r e s e n c e of b a s e , u n d e r w e n t c y c l i z a t i o n d i r e c t l y t o y i e l d ( 7 3 ) w h i c h was t h e n c o n v e r t e d i n t o ( + ) - a - l y c o r a n e ( 7 4 ) by d e p r o t e c t i o n a n d P i c t e t - S p e n g l e r

cyclization.

T h e same

r e s e a r c h g r o u p h a s a l s o used t h i s methodology f o r t h e s y n t h e s i s o f t h e Sceletium a l k a l o i d A4 (76)

via

the aldehyde (75).31

Rebek e t a l . h a v e now p u b l i s h e d t h e f u l l d e t a i l s o f t h e i r s y n t h e s i s o f m i t o s e n e ( 8 0 ) , i n which a key s t e p i n v o l v e d t h e u s e of iminium y l i d e s i n a Huisgen p y r r o l e s y n t h e s i s t o form t h e p y r r o l i z i d i n e r i n g system of t h e n a t u r a l product,

-

G. (77)

-

(78)

(79).32 I n t e r e s t i n g u s e h a s b e e n made d u r i n g 1984 o f o t h e r [ 3 + 2 1

c y c l o a d d i t i o n s , such as those o f n i t r o n e s i n a s y n t h e s i s of inatoxin-a

(861, t h e ' v e r y f a s t d e a t h f a c t o r ' i s o l a t e d f r o m t h e

blue-green

a l g a e A n a b a e n a f l o s - a q u a e . 33

In t h i s synthesis the

a d d u c t ( 8 3 ) o f t h e n i t r o n e ( 8 1 ) w i t h t h e d i e n o l ( 8 2 ) was, a f t e r o x i d a t i o n of t h e a l c o h o l , t r e a t e d w i t h m - c h l o r o p e r b e n z o i c a c i d t o g e n e r a t e a new n i t r o n e (84), w h i c h u n d e r w e n t a n i n t r a m o l e c u l a r

648


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(71)

(72)

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(73)

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c y c l o a d d i t i o n t o form ( 8 5 1 , c o n t a i n i n g t h e r i n g system of t h e alkaloid. The s y n t h e s i s was f i n i s h e d i n f o u r f u r t h e r s t e p s . N i t r o n e s have a l s o played a key r o l e i n a remarkably g e n e r a l approach t o t h e p h e n a n t h r o i n d o l i z i d i n e and p h e n a n t h r o q u i n o l i z i d i n e alkaloids.34

The a p p r o a c h i s t y p i f i e d by t h e s y n t h e s e s o f

j u l a n d i n e ( 8 9 ) and ( ' ) - c r y p t o p l e u r i n e quinolizidine

( 9 0 ) c o u l d be p r e p a r e d

(92).

(2)-

Thus, t h e d i a r y 1

by a l d o l c y c l i z a t i o n o f t h e

acylated piperidine

( 8 8 ) d e r i v e d from t h e n i t r o n e c y c l o - a d d u c t

(87).

(90) then gave ( f ) - j u l a n d i n e ( 8 9 ) , o r

Reduction of

a l t e r n a t i v e l y , p h o t o l y s i s i n t h e p r e s e n c e of i o d i n e g a v e t h e a r y l coupling product (91)

which c o u l d be r e d u c e d t o t h e a n t i - t u m o u r

agent (5)-cryptopleurine

(92).

The s a m e r e s e a r c h g r o u p h a s a l s o

used n i t r o n e s i n a n e a t s y n t h e s i s of ( + ) - l a s u b i n e I ( 9 5 ) . 3 5

Here

t h e a d d i t i o n of hydrogen c h l o r i d e t o t h e n i t r o n e adduct (931, f o l l o w e d d i r e c t l y by r e d u c t i v e c l e a v a g e o f t h e n i t r o g e n o x y g e n bond leads

(94) t o t h e natural product.

An a p p r o a c h t o c l a v i c i p i t i c a c i d (99), a n e r g o t a l k a l o i d d e r a i l m e n t p r o d u c t , i s a l s o b e l i e v e d t o p r o c e e d by a [ 3 + 2 1 c y c l o a d d i t i o n r e a c t i o n . 36

o-dichlorobenzene

a t I90

Thus, t h e r m o l y s i s of t h e a z i d e ( 9 6 ) i n OC

g a v e (97) c o n t a i n i n g t h e r e q u i r e d

via ( 9 8 ) a s p r e s u m e d i n t e r m e d i a t e . via a n i t r e n e was d i s c o u n t e d on t h e b a s i :

natural product r i n g system, The a l t e r n a t i v e m e c h a n i s m

o f t h e s o l v e n t e f f e c t s o b s e r v e d , and a l s o t h e l a c k o f b y - p r o d u c t s . Amongst c y c l o a d d i t i o n r e a c t i o n s , t h e D i e l s - A l d e r

reaction has

l o n g been a f a v o u r e d s t r a t e g y , and t h i s y e a r t h e r e a c t i o n h a s p r o v i d e d a s h o r t s y n t h e s i s o f e l l i p t i c e n e ( 1 0 2 ) by t h e r e a c t i o n o f p y r i d y n e w i t h t h e i n d o l o p y r a n o n e ( 1 0 0 ) .37

Unfortunately

,

no

r e g i o s e l e c t i v i t y was o b s e r v e d , a n d t h e p r o d u c t h a d t o b e s e p a r a t e d from an e q u a l q u a n t i t y of i s o - e l l i p t i c e n e ( 1 0 1 ) . A n o t h e r , l o n g e r s y n t h e s i s b a s e d on a c l o s e l y r e l a t e d d i s c o n n e c t i o n h a s a l s o b e e n p u b l i s h e d , b u t a g a i n no r e g i o s e l e c t i v i t y was o b s e r v e d . 38 A hetero-diene

Diels-Alder

r e a c t i o n h a s been used i n an

i n t e r e s t i n g s y n t h e s i s o f t h e known p r e c u r s o r ( 1 0 5 ) o f t h e heteroyohombine a l k a l o i d s t e t r a h y d r o a l s t o n i n e (106b).39

( 1 0 6 a ) and akummiginf

Thus, t h e r m o l y s i s of t h e e n a l (103) i n r e f l u x i n g x y l e n e

g a v e t h e d i h y d r o p y r a n ( 1 0 4 ) i n 73% y i e l d . Friedel-Crafts

R e d u c t i o n , f o l l o w e d by

t y p e m e t h o x y c a r b o n y l a t i o n and d e b e n z y l a t i o n , t h e n

g a v e t h e known i n t e r m e d i a t e ( 1 0 5 ) . W e i n r e b e t a l . h a v e now a p p l i e d t h e i r i m i n o Diels-Alder

reactior

t o t h e c o n s t r u c t i o n of t h e t e t r a h y d r o p y r i d i n e m o i e t y o f t h e s p e r m i d i n e a l k a l o i d (f)-anhydrocannabisativine ( 1 1 0 ) . 4 0 T h u s ,

65 1


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cop (96)

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I

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I

H

+

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(108)

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a c e t y l a t i o n of t h e c r u d e p r o d u c t f r o m t h e r e a c t i o n of m e t h y l g l y o x y l a t e w i t h t h e c a r b a m a t e ( 1 0 7 ) g a v e ( 1 0 8 ) , w h i c h on h e a t i n g i n t h e p r e s e n c e o f H u n i g ' s b a s e a t 215 a c i d and underwent a Diels-Alder

OC

f o r 3 h both l o s t a c e t i c

reaction t o (109).

Hydrolysis of

t h e c a r b a m a t e , a n d e l a b o r a t i o n o f t h e m a c r o l i d e , w h i c h was c l o s e d a t t h e amine n i t r o g e n , completed t h e s y n t h e s i s .

Use h a s b e e n made o f a n a s y m m e t r i c [ 2 , 3 1 s i g m a t r o p i c r e a r r a n g e m e n t o f a n ammonium y l i d e i n a s y n t h e s i s o f t h e m i l l i p e d e In t h i s synthesis the i n s e c t r e p e l l a n t (+)-polyzonimine ( 1 14).41 t e r t i a r y a m i n e ( I l l ) , d e r i v e d f r o m L - b e n z y l p r o l i n o l , was f i r s t c o n v e r t e d i n t o t h e ammonium s a l t ( 1 1 2 ) by t r e a t m e n t w i t h cyanomethyl benzenesulphonate. potassium t-butoxide,

Formation of t h e y l i d e w i t h

rearrangement, and i n s i t u h y d r o l y s i s of t h e

r e s u l t i n g cyano-amine w i t h c o p p e r ( I 1 ) c a t a l y s i s t h e n g a v e t h e c h i r a l a l d e h y d e ( l l 3 ) , w h i c h was c o n v e r t e d i n t o ( + ) - p o l y z o n i m i n e . The p r o d u c t was f o u n d t o h a v e t h e same s e n s e of r o t a t i o n a s t h e n a t u r a l p r o d u c t , a l t h o u g h t h e a b s o l u t e c o n f i g u r a t i o n i s n o t known. ortho-Lithiation

methodology h a s proved a powerful r o u t e t o

d e n s e l y f u n c t i o n a l i z e d aromatic and hetero-aromatic

systems.

S n i e c k u s e t al.42 h a v e now f o u n d t h a t t h e m e t h o x y m e t h y l e t h e r ( 1 1 5 ) may b e a m i n a t e d

via

e q u i v a l e n t TsN3.

the lithio-derivative

by u s i n g t h e fiH2

The p r o d u c t w a s t h e n c o n v e r t e d i n t o t h e c a r b a m a t e

( 1 1 6 ) , which c o u l d i t s e l f be l i t h i a t e d a n d l e d t o t h e a c i d ( 1 1 7 ) after treatment with carbon dioxide. This acid then provided a p i v o t a l i n t e r m e d i a t e i n t h e i r s y n t h e s i s o f ( 1 1 8 ) , a known p r e c u r s o r o f t h e anti-tumoural a l k a l o i d anthramycin (119). L i t h i a t i o n h a s a l s o b e e n u s e d i n a s y n t h e s i s o f b e r n i n m y c i n i c a c i d ( 1 2 3 ) ~T ~ h u ~s , t r e a t m e n t of t h e p y r i d i n e d e r i v a t i v e ( 1 2 0 ) w i t h e x c e s s b u t y l l i t h i u m f o l l o w e d by MeOCH2NCS g a v e ( 1 2 1 ) , t h e r e b y s i m u l t a n e o u s l y f u n c t i o n a l i z i n g t h e p y r i d i n e n u c l e u s and i n t r o d u c i n g an amide p r o t e c t i n g group.

Treatment of (121) w i t h e t h y l bromopyruvate t h e n g a v e t h e b i s t h i a z o l e ( 1 2 2 ) , w h i c h was c a r r i e d on t o b e r n i n m y c i n i c a c i d (123) i n a f u r t h e r t h r e e s t e p s . The p y r r o l i d i n e a l k a l o i d s c o n t i n u e t o b e a n a r e a o f c o n s i d e r a b l e a c t i v i t y , a l t h o u g h much o f t h e work i s a l o n g w e l l t r o d d e n p a t h s . H o w e v e r , a s y n t h e s i s o f ( + ) - i s o r e t r o n e c a n o l ( 1 2 6 ) ,44 by a f r e e r a d i c a l cyclization of the succinimide-derived

s u l p h i d e ( 1 2 4 ) by

t r e a t m e n t w i t h t r i b u t y l t i n h y d r i d e i n i t i a t e d by A I B N , i s noteworthy.

The c y c l i z a t i o n g i v e s ( 1 2 5 ) a s t h e m a j o r p r o d u c t

i s o m e r , w i t h o n l y small q u a n t i t i e s o f t h e d i a s t e r e o m e r a n d p r o d u c t s of r e d u c t i o n a n d e n d o - c y c l i z a t i o n b e i n g f o u n d .


654

0 (118)

(119)

HN

NHBU'

0 (1 20 1

0 (121)

C02 E t /

0

OH

0

(123)

(122)

OAc

OAc

b

HO

steps

0

(124)

(125)

(126)


655

Holmes a n d c o - w o r k e r s h a v e p u b l i s h e d a n e a t s y n t h e s i s o f t h e known perhydrohistrionicotoxin p r e c u r s o r ( 130 ) 4 5 f r o m t h e a d d u c t of nitrosyl chloride with octalin (127). of t h e Boc-protected

I n t h e key s t e p , o z o n o l y s i s

a m i n e ( 1 2 8 1 , f o l l o w e d by r e d u c t i v e w o r k - u p

with methyl s u l p h i d e , gave t h e n a t u r a l product r i n g system as t h e enamine ( 1 2 9 ) .

The b e n z y l d e r i v a t i v e ( 1 3 0 ) was t h e n o b t a i n e d i n A general entry t o another group of f r o g

s i x further steps.

t o x i n s , t h e p u m i l i o t o x i n s h a s a l s o been p u b l i s h e d .46 T h i s s y n t h e s i s h i n g e s on a s t e r e o s p e c i f i c i m i n i u m i o n - v i n y l s i l a n e cyclization,

(131)

(132).

+

The s i d e c h a i n was t h e n e l a b o r a t e d

u s i n g Wittig methodology l e a d i n g t o p u m i l i o t o x i n B ( 1 3 3 ) . A r e g i o s e l e c t i v e Polonovski rearrangement has provided

s t e p i n a s y n t h e s i s of ( - 1 - c h e r y l l i n e

t h e key

( 1 3 7 ) . ~ T~ h u s , t r e a t m e n t o f

t h e c h i r a l a m i n e o x i d e ( 1 3 5 1 , d e r i v e d by c y c l i z a t i o n , r e s o l u t i o n , and o x i d a t i o n of t h e d i b e n z y l amine ( 1 3 4 ) , w i t h p o t a s s i u m tb u t o x i d e and q u e n c h i n g w i t h e t h y l c h l o r o f o r m a t e g a v e ( 1 3 6 ) i n a n 8 : l m i x t u r e w i t h t h e product of c l e a v a g e o f t h e a l t e r n a t i v e b e n z y l i c C-N

bond.

Deformylation, carbamate r e d u c t i o n , and

d e p r o t e c t i o n then gave (-1-cherylline

( 1 3 7 ) i n 46% o v e r a l l y i e l d .

The n o v e l b i c y c l i c s t r u c t u r e o f t h e now c o m m e r c i a l l y c u l t u r e d a n t i b i o t i c bicyclomycin

(140) continues t o a t t r a c t a t t e n t i o n .

In

o n e i n t e r e s t i n g r o u t e t h e e t h e r b r i d g e was i n t r o d u c e d by nucleophilic attack a t electrophilic centres i n a dioxopiperazine r i n g g e n e r a t e d by t r e a t m e n t o f t h e p y r i d i n e t h i o l d e r i v a t i v e s ( 1 3 8 ) 48

and ( 1 3 9 ) w i t h s i l v e r t r i f l a t e .

L a s t l y , i n t h i s s e c t i o n , Inoue's group has r e p o r t e d an i m p r e s s i v e s y n t h e s i s of ( f ) - s u r u g a t o x i n

(141 ) .4g

6 Prostanoids The i s o l a t i o n o f t h e e n d o p e r o x i d e s P G G 2 a n d P G H 2 ,

some t e n y e a r s

ago, has given support t o the idea t h a t t h e prostaglandins are b i o s y n t h e s i z e d f r o m C 2 0 - p o l y u n s a t u r a t e d f a t t y a c i d s by a f r e e r a d i c a l process involving i n t e r m e d i a t e s of t h e t y p e (1421, ( 1 4 3 ) , and ( 1 4 4 ) .

Now C o r e y a n d h i s c o - w o r k e r s

h a v e mimicked t h i s

s e q u e n c e i n t h e l a b o r a t o r y t o p r o v i d e a new, s u b t l e r o u t e t o t h e s y n t h e s i s o f PGs. 50

Thus, t r e a t m e n t of t h e h y d r o p e r o x i d e ( 145)

w i t h m e r c u r y ( I 1 ) c h l o r o a c e t a t e l e d t o t h e endo-peroxide ( 1 4 6 ) which c o u l d b e c o n v e r t e d i n t o a m i x t u r e o f t h e a d v a n c e d PG p r e c u r s o r s (147) and (1481, f o l l o w i n g r e d u c t i o n w i t h t r i p h e n y l p h o s p h i n e and transacetalization i n t h e presence of pyridine tosylate.

656


(131) Ph

A

(132)

,

HO

Me (133) Me0

OMe

H

-0 Ph

Ph

Ph (135)

(134)

CHO

&ph

-

6 I

Me0

3 steps

,OC'

Et

HO E

N

Ph (1 36)

(1 37)

,

Me


657

(138)

(139)

42

HO

H

0

H o e M e

OH

Br

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