The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

ISOQUINOLINES This is a part ofthe thirty-eighth volume in the series THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS THE CH...

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ISOQUINOLINES

This is a part ofthe thirty-eighth volume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A

SERIES OF MONOGRAPHS

EDWARD C. TAYLOR, Editor ARNOLD WEISSBERGER, Founding Editor

ISOQLJINOLINES Part 3

Edited by

Gary M. Coppola and Herbert F. Schuster

AN INTERSCIENCE@PUBLICATION

JOHN WILEY & SONS, INC.

-

NEW YORK * CHICHESTER * BRISBANE * TORONTO SINGAPORE

This text is printed on acid-free paper. Copyright 3;: 1995 by John Wiley & Sons. Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or furthei information should be addressed to the Permissions Department, John Wiley & Sons, Inc.. 605 Third Avenue, New York, NY 10 f 58-0012. Library of Congress Cataloging in Publication Data:

Isoquinolines. (The chemistry of heterocyolic compounds, 0069-31M: V. 38.) Pt. 2 edited by F.G. Kathawala. Gary M.Coppola, Herbert F. Schuster; pt. 3 edited by Gary M.Coppola and Herbert F. Schuster. "An Interscience-publication." Includes bibliographical references and indexes. 1. Isoquinoline. 2. Isoquinolines. I. Grethe. Guenter. QD401.183 54T.596 80-1 1510 ISBN 0-471-37481-4 (v. I ) ISBN 0-471-62855-7 (v. 3)

10987654321

To Clare and Perer -G. M. C. To my wife, Maro:

my daughter; Kristianu; my son. SteJan

-H. F. S.

Contributors

Hiroshi Hara Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan Osarnu Hoshino Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan F. G. Kathawala Sandoz Research Institute East Hanover, New Jersey

Herbert F. Schuster Sandoz Research Institute East Hanover, New Jersey Bunsuke Urnezawa Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan

The Chemistry of Heterocyclic Compounds Introduction to the Series The chemistry of heterocyclic compounds constitutes one of the broadest and most complex branches of chemistry. The diversity of synthetic methods utilized in this field, coupled with the immense physiological and industrial significance of heterocycles, combine to make the general heterocyclic arena of central importance to organic chemistry. The Chemistry of Heterocyclic Compounds, published since 1950 under the initial editorship of Arnold Weissberger, and later, until Dr. Weissberger’s death in 1984, under our joint editorship, has attempted to make the extraordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has dealt with syntheses, reactions, properties, structure, physical chemistry, and utility of compounds belonging to a specific ring system or class (e.g., pyridines, thiophenes, pyrimidines, threemembered ring systems).This series has become the basic reference collection for information on heterocyclic compounds. Many broader aspects of heterocyclic chemistry are recognized as disciplines of general significance which impinge on almost all aspects of modem organic and medicinal chemistry, and for this reason we initiated several years ago a parallel series entitled General Heterocyclic Chemistry, which treated such topics as nuclear magnetic resonance, mass spectra, and photochemistry of heterocyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cycloaddition reactions. These volumes are of interest to all organic and medicinal chemists, as well as to those whose particular concern is heterocyclic chemistry. It has become increasingly clear that this arbitrary distinction created as many problems as it solved, and we have therefore elected to discontinue the more recently initiated series General Heterocyclic Chemistry and to publish all forthcoming volumes in the general area of heterocyclic chemistry in The Chemistry of Heterocyclic Compounds series. EDWARD C. TAYLOR Department of Chemistry Princeton Uniuersiry Princeton, New Jersey

ix

Preface

The isoquinoline skeleton is found in a wide variety of natural and pharmaceutically interesting compounds. Because the field of isoquinolines is so large, four volumes were planned for the presentation of this material. However, unforeseen circumstances and author delays forced a reorganization of the orginally proposed chapters that were outlined in Isoquinolines: Part One. This final volume of the Isoquinoline series examines the chemistry surrounding two classes of isoquinolines, those containing basic functionalitiesin the side chain and those possessing hydroxyl or thiol substituents. The authors have kindly updated their original manuscripts, and we thank them for their efforts. It is our hope that this volume will serve as a useful reference to those actively involved in isoquinolineresearch and to those whose interests will lead them into the rich field of isoquinolines.

GARY M. COPPOLA HERBERT F. SCHUSTER East Hanorer. New Jersey July 1994

xi

Contents

I.

ISOQUINOLINES BEARING BASIC SIDE CHAINS H.F. SCHUSTERAND F.G. KATHAWALA

II. ISOQUINOLINES AND THEIR HYDROGENATED

1

DERIVATIVES 0. HOSHIYO, H.H A R4~~ , R. U W L A I V A

225

INDEX

545

ISOQUINOLINES

This is a part of the thirty-eighth volume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

Chemistry of Heterocyclic Compounds, Volume38 Edited by Gary M. Coppola, Herbert F. Schuster Copyright 0 1995 by John Wiley & Sons, Ltd.

Isoquinolines Bearing Basic Side Chains H.F. Schuster and F. Kathawala I. Introduction 11. Isoquinolines Having Basic-Containing Substituents at C1 A. l-(Aminoalkyl)isoquinolines B. l-(Aminoalkoxy)is~uinolines C. Isoquinolines Containing Aminophenyl Substituents 1. 1-Anilinoisoquinolines (n = 0) 2. I-(Aminobenzyl)isoquinolines(n= 1) 3. 1-(Aminophenethyl)isoquinolines( n = 2) D. Isoquinolines Bearing Basic Heterocyclic Substituents at Cl I. Five-Membered Heterocycles 2. Six-Membered Heterocycles Isoquinolines a. Substituted I -(Pyridyl)isoquinolines b. Substituted I-(Piperidyl)isoquinolines c. Conclusion E. Bis-isoquinolines F. Emetine 111. Isoquinolines Having Basic-Containing Substituents at C2 A. 2-(Aminoalkyl)isoquinolines

B. Substituted 2-(Aminophenyl)isoquinolines C. 2-Heterocyclic Substituted Isoquinolines IV. Isoquinolines Having Basic-Containing Substituents at C3 V. Isoquinolines Containing Basic Substituents at C4 VI. Miscellaneous Isoquinolines Having Basic Substituents References

1

2 2 27 35 36 53 65 70 70 14

14

88 89 89 114 133 133

161

I 69

183 204 212 214

1. INTRODUCTION This chapter discusses the preparation and reactions of side-chain isoquinoline and hydrogenated isoquinoline compounds bearing basic-containing functionalities not directly attached to the isoquinoline nucleus (see Chapter 111 by I. W. Mathison and W. E. Solomons in Isoquinolines. Part Two, F. G. Kathawala, G. M. Coppola, and H. F. Schuster, eds., John Wiley & Sons, New York, 1990). The pharmacological importance of many of these compounds has been the motivation for the syntheses of the numerous variations found in this class of compounds. 1

Isoquinolines Bearing Basic Side Chains

2

11. ISOQUINOLINES HAVING BASIC-CONTAINING SUBSTITUENTS AT C1

A. l-(Aminoalkyl)isoquinoliaes The search for isoquinolines possessing biological activity has provided a variety of synthesis for 1-(aminoalkyl)isquinolines,which have also been further elaborated into more complex heterocyclic systems. A general method for the preparation of unsubstituted aminoalkylisoquinolines involves the reduction of an appropriate nitrile to an amine. The reaction of l-methyl-3,4-dihydroisoquinoline(1) with acrylonitrile followed by the lithium aluminum hydride reduction of 2 furnishes a modest yield of l-(4-aminobutyl)3,4-dihydroisoquinoline(3)' (Equation 1).

qN-qN-'

N Q

CH 2 CH 2 CH2 CN

CHI 1

~ H ~ ( c H ~ ) ~ N H ~

2

3

(1) l-(Alkylha1ide)isoquinolines can undergo an SN2 reaction with amines to furnish unsubstituted or substituted 1-(aminoalky1)isoquinolines.The reaction of l-(chloromethyl)-3,4-dihydroisoquinoline(6), easily prepared in two steps from the appropriately substituted phenethylamine 4, with monosubstituted amines provides 1-(substituted aminomethyl)-3,4-dihydroisoquinolines (7), which can be catalytically reduced to their corresponding 1,2,3,4-tetrahydroisoquinolines 8'-* (Scheme 1).

8

7

Scbemcl

11. Isoquinolines Having Basic-Containing Substituents at C1

3

Derivatives of 8 were converted into a variety of substituted imidazoC5,la]isoquinoIines 9 and pyrazino[2,1-~]isquinoIines 14 by Archer and his Sterling group4-* (Scheme 2).

R'

8

9

I

10

R' 11

I

14

R'

An alternative pathway that has been extensively employed for the preparation of 1-(aminoaIkyl)isoquinolinesinvolves the use of acyl phenethylamines 15 wherein the nitrogen atom of the basic side chain is suitably protected with either a succinoyl or phthaIoy1 group. Subjecting 15 to the BischlerNapieralski cyclization reaction affords 16 which can be hydrolyzed to 17.

4


Catalytic reduction of 17 leads to the 1.2,3,4-tetrahydroisoquinoline 1810.19.22,24.3 1.40.41.43 (&heme 3).

POCI, or

PPA

0

0

15

16 OH

In their attempt at preparing aza-steroids having hypotensive properties, Burchhalter et al." have reacted 1-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolines 19 with the iminoether 20 to produce 21 (Equation 2).

R

dHNH ~ ~ z C H 2 mC O z *C t

O-SOC

CHjO

CI

-

19

R=H b R=OCH,

8

Shiotani and M i t s u h a ~ h i ~ ~refluxed * ~ ~ * ~ ~@-(m-methoxypheny1)-Nphthalimidoacetyl alanine methyl ester (22) for 2 hr with phosphorous oxychloride and phosphorous pentoxide to afford 1-phthalimidomethyl-3-carboethoxy6-methoxy-3,4-dihydroisoquinoline(23) which on catalytic reduction with hydrogen over platinum oxide yields the corresponding 1,2,3,4-tetrahydroisoquin-


5

oline 24. Treatment of 24 with hydrazine hydrate generates 8-methoxy-1,2,5,6tetrahydro-l,5-iminobenz[dlazocino-4(3H)-one (25) in excellent yield (Scheme 4).

23

22

H ‘

“

3

\ 0

y

p

y

H

25

The double cyclization of 26 provides in reasonable yield 4-phenyl-9,10dimethoxy-6,7-dihydro-2tl-pyrimido[4,3-uJisoquinoline (28)24(Equation 3). PZ 01

CHCI,

26

ij

-

cHJo CHJO

H NCPh

II

27

0

cH’Olq.. CH3O

6


Either 4,Sdimethoxy- or 5,6-dimethoxy-l-phthalirnidomethyl-1,2,3,4-tetrahydroisoquinoline 29a or 29b reacts with p-methylbenzenesulfonyl chloride in pyridine to provide 30 which on refluxing with hydrazine hydrate yields 31. Heating 31 with 37% aqueous formaldehyde for 2 hr resulted in the ring closure at C7 to furnish the 2,3,7,8,9,9a-hexahydro-lH-benzo[d,e][ 1,7]naphthyridines 3% and 32bZ2(Scheme 5). R py rid, n e

0

0

2!3 a R=4,SdiMeO b R=5,6diMe0

1

32

N I H ~' HzO

31

scbeme 5

The Reissert compound 33 on basic hydrolysis affords isoquinoline- 1carboxamide (34)which can be reduced with hydrogen over platinum oxide to the 1,2,3,4-tetrahydroisoquinoline35. Subsequent reduction with lithium alumi(Scheme 6). num hydride provides XZ5

35

36 seb#nc6

11. lsoquinolines Having Basic-Containing Substituents at Cl

7

The reduction of the Reissert compound 37 with “Basler” nickel catalyst at 90‘C and 70 atm pressure for 24 hr affords 38 which under acidic hydrolysis yields X3*(Equation 4).

Catalytic reduction of I-cyanoisoquinoline (39) leads to 1-(aminomethy1)isoquinoline(40)which after acylation with an appropriate acid chloride can be cyclized with phosphorous oxychloride to the imidazoC5,fa]isoquinoline (41) in very good yield4’ (Equation 5).

0

II

I RCCl

CN

40

NH2

41

(5)

A series of 1-(a-aminoalky1benzyl)isoquinolines44 were prepared in reasonable yields by the benzylic oxidation of 1-benzylisoquinoline 42 with selenium 6). dioxide followed by a reductive ~ x i m a t i o n(Equation ~~

Because of the medicinal interest in papavarine-like compounds, a large number of aminoalcohols 46 were prepared by reacting papaveraldine 45 with the appropriate Grignard reagents containing a variety of amino functionality12 (Equation 7).

8

Isoquinolines Bearing Basic Side Chains CH30 CH30

go -

CH30

OCH3

45

46

a R = N(CH& b R = morpholino c R = piperidyl

Isoquinoline analogs 48 of the antihistamine Decapryn were prepared by reacting either methylphenyl(14soquinolyl)carbinol (47a) or diphenyl(1isoquinoly1)carbinol (4%) with b-dimethylaminoethyl chloride and sodium in toluene at 60°C followed by refluxing for 15 hrJ5(Equation 8).

dH

I . CICH,CH,N(CH,), Naltol uenc/t4J°C

2. 1 1 0 ~ C l l S h

47

48

a R=CH3 b R=CIHs

I

(9)

1. H,O'

2. NaBH,

I

H

CHzCHCH2N' C ~ H P

I

OH 51


9

The acidic character of the methyl group of 1-methylisoquinoline (49) was exploited by Meyer et a1.j’ for the preparation of a-[(t-buty1amino)methyl-1isoquinoline]ethanol (51). Treating 49 with n-butyllithium and reacting the lithio derivative with t-butylacetonitrile affords 1-[2-amino-3-(~butylamino)propenyl]isoquinoline (50) which after hydrolysis and reduction with sodium borohydride provides the amino alcohol 51 (Equation 9). The synthesis of potential antitumor agents such as 5-(N-ethyl-Nalky1amino)- (53), 5-(N-monoalkylamino)- (54), and 5-(N-alkylacetamido)-lformylisoquinoline thiosemicarbazone (55) from 49 is depicted in Scheme 7.” R, I . B,H6

2. sco, 3. H,NNHCNHl I1

____,

i?

CCH3

49

@ \

R,

CH,

tH3

52

I . SCO

A

2. H,NNCNH,

II

S

,CHzCH2

N I

0 N

,H

10


The isoquinoline alkaloid amphibine I (%), isolated from crude alkaline extracts of Ziziphus arnphibid5, possesses chiral centers at C1 and C9 and a third due to the presence of natural (S)-valine.

CHjO

H

CHqO CHqO 2 NaBH,CN

0

0

n

58

0

1

I . HCHOIHCOOH 2. N ~ H I

- 2. H 2 I Pd - c

3. Separation of isomers

59 56 Scbeme 8


11

In order to correctly assign the absolute configuration of 56, a total synthesis was undertaken. The condensation of N-phthaloyl-L-alaninewith 3,4dimethoxyphenethylamine affords 57. A Bischler-Napieralski ring closure followed by reduction to the 1,2,3,4-tetrahydroisoquinoline58 occurs with total racemization of the alanine. Considerable racemization could be avoided when a rapid reduction and work up was employed immediately after ring closure. Alkylation and deprotection of 58 affords 59, which after acylation with (S)-Cbzvalylglycine and separation of the resulting mixture yielded 56. By varying the chirality of the amino acids used, all possible diastereomers were prepared and characterized. From this information it was determined that 56 possesses the Cl-(S),C9-(R),syn absolute c~nfiguration~~ (Scheme 8). TABLE 1. BIOLOGICAL ACTIVITY Structure

R

l

q

N

Biological Activity

, NN

Rd.

CNS (central nervous system)

67

CNS depressant, sedative, and

4.V

Antibacterial

22

An tispasmodic

16

tranquilizer

I

R'

anticonvulsant

I

R'

I

P'

12


TABLE 1. (Continued) Structure

Biological Activity

Ref.

29

H

Antihistaminic

35

8-Adrenergic blocker

30

Antipasmodic hypotensive. antipsychotic, analgesic, anticonvulsant

12

Antifertility

11.32

CHzfHCHZN'

CH30 C

H

3

0

CH2CHZN 7

' k2 R'

OCH3 OCH3

CH3

13

11. Isoquinolines Having Basic-Containing Substituents at C1 TABLE 1 . (Continued) Structure

Biological Activity

R'

HN(CH z ) n N

/

Ref.

Antimalarial

20.34

Antitussive, antifibrillatory

23

Iontotropic

42

Coronary circulatory activity

37

Sedative, tranquilizcr. hyptmsivc, and cardiovascular

3

\

RZ

R'

HN(CH 2 )n N

/

\

RZ

CHiO

CH2--N /N-R3

W 32

TABLE 2. 1-(AMIN0METHYL)ISOQUINOLINES

n

5

%

0'

X

z n

X

X

14

x x x

N

r,

r,

u"

u"

I

x

I

z

X

x

2"

I

I

X

X

2

0

0

0

Ym

1s

0

' I rn

Rl

3-CH3

H

R'

H

H

TABLE 2. (Continued)

R3

31 225-228 1N6°4

CZOHZ

31

Ref.

230-232

MP ("C)

C21H13N604

Formula

R’ -NH, -NHCH2C6H5 --O(CHz),N(CHdz --O(CHdzN(CH3)z --(CH,),N(CH,),

R

6,7 diMeO 6.7-diMe0 H H

6.7diMeO

3.4-diMe0

C6H5

OH

R3

3.4diMeO 3.4diMeO H H

H H CH3

X

TABLE 3. l-(AMINOBENZYL)ISOQUlNOLlNES

C25H32N205

C26H28N20

c21 H24N20

C.?7H2BN204

C20H22N204

Formula

(CH3I) 127-130

104-106

165-167 126-127 ( H a ) 226-228 99-99.7 ( H a ) 197.6-198.4

MP CC)

12

12 12 35 35

Ref.

R’

-(CHI)

-(CH,),N

-(CH,)3N

-NH, -NH, -NH2

6,7-diMe0

6.7-diMe0

5.7-diMe0 6,7-diMe0 5,7-diOEt

3

3

\p

3N

/7

-(CH,),NCH,

6’7-diMe0

6,7diMe0

R


H H H

OH

OH

OH

OH

2.3-diMe0 H H

3.4-diMe0

3.4-diMe0

3.4-diMe0

3.4-diMe0

CZOH,*N2O2

I B H 1BNZ04

C20H22N204

C27H34N20S

CZ*H,,N,O,

C27H34N204

C27H36N203

120-150 155-160(d~) 130 (dec)

109-1 10 (CHSI) 135-136

154-155

(CHJ) 158

129- 130 (CH3I) 144-145

93-94 (CHSI) 115-1 16

44 44 44

I2

I2

12

12


19

TABLE 4. I-(AMINOALKYL)-3,4-DlHYDROlSOQUlNOLlNES

R'

~-

R'

R2

6-OMe 6.7-diOMe

H H

H

3-Me 3-COzEt -C

Formula

--CH,CH,NH, -CH,CH,NH,

ClzH16N20 Ci3Hi,NzOz

3

H zCH2 N

233 (dcc) 277 (dW (diHCl) 146-147

Ref. 10

1424

CzOHz8N,O, (dipicrate) 172

17 23

H

H

--CH,CH,N(Et),

Cl5H2,N2

H

H

-CH2CH2N(Et),

C16Hz,N,

H 6.7diOMe 6-OMe 6-OMe 6-CHj 6.7-diOMe 7x1 6.7-Methylenedioxy

H H H 3-Me 4-Me H H H

CH3 --CH,CH,N(Me), --CH,CH,N(Me), --CH,CH,N(Me), ---CH ,CH2N(Me), -CH ,CH ,"Me), --CH,CH,N(Et), -CH,CH,N(Et), --CH,CH,N(Et),

6,7-diOMe

H

I

MP ("C)

(diHC1) 232-235.(dec) (diHI) 223-250 (fumarate ) 172

23

(fumarate) 160-162 (diHCI) 170 (diHCI) 124- 126 104-106 (dipicrate) 137-139 (diHI) 255 (diHCl) 206-207 184-186 (diH1) > 160

23 49 48.49 49 49 23 23 23

131.8-137.6

3

f

00 I-"

5

x-

u'

r" z I

I

N

w

n

X

2 u

X

X

X

X

X

X

ez X

X

X

x

-d

N

-

H

H

6,7-diM&

6.7-Mcthylenedioxy 8-OMe

CH3

Ms 1

1

1

Ts

H

6,7diMe0

I

5,MiMeO

H

Ts

H

6-OMe 6,7-diMe0 6,7-diMe0

3 3 I

H

6,7-diMe0

I

H

H

6.7-diMe0

CH,C,H,

H

H

6.7-diMe0

I

H

H

6.7-diMe0

H

H H

H

6.7-diMe0

2

H

6.7-diMe0

CH3

H

6.7-diMe0

I

H

CHj

-NH,

N

-NHz

-NHz

-NH,

-NH,

-NH, -NHz -NH,

-NHCHC

-

-NHC,H,

--NHC,H,

C

H 2 CH j

e

l

233 277 145-150/0.03 mm (diHC1) 265 sulfate-2H20 274-275 178-180 (HCI) 235-238 138-139 (HCI) 255-256 158-160 ( H a ) 250 183

(diHBr) 267

(diHCI) 193-196

102-106 (diHCI) 212-214

79.5-82.5 (HCI) 186-192

78-79

(diHCI) 202-230

28

22

22

22

10 10 43 19

9

9

8

8

n

8

8

Do

N

N 00

c( 00

N 00

N 00

N 00

3 T

P

2

* m

c

2

? !

i ' x

I

I-

ro

$

8

EII

O+

X

z

z

I

3

I

3

i V

u

r"

d

I:

2

X

u X

3:

X

2:

Do

N 00

N P

N

N X

N m

z

N Do

8

N

z

N

9 u I II z

I

I

k$ X

c1

I

z

I

I

X

23

I

X

m 12

m

s

VI

P) m

I

09 m P) m

A

E

s u

2u

X

X

X

5

z

X

7 0 12

*24

u

W

3

Q 2

0

u, X u E

5 2 d 0

-Lo -N

-N

H

H

H

6,7-diM&

6.7-Methy lmdioxy

47diOH

\p

n

n \p

-N

n \p n

R'

H

R'

6,7-diOH

R

2

2

2

1

n

+

C,,H22N20, 2HBr

CI6H22NIO3-2HCI

C,,H,,N,03.2HCI-H2Q

CIIHZONIOJ -2HBr

Formula

TABLE 6. IdALKY LHETEROCYCLE)-I,2.3.4-TETRAHY DROISOQUINOLINES

283-284 (dw)

259 (dcc)

25&252 (dtc)

278 (dec)

Mp or Bp ("C)

so

Ref.

OI

N

H H H

6,7-diOH

6,7-diOH

6,7-diOH

H

6,7,8-ttiOH

H

CH,

6.7diOH

6.7-diOH

R'

R


n

W0

n

W0

n

\p

A

42

2

2

3

2

2

n

-

n2 LN

--NIC,H

-"W0

-N

-N

--N

R'

C,,H,,N,02 -2HBr

CI,H,,N,0,-2HBr

C16HZ4NJOZ-2HBr

Cl,H,,N,0,-2HBr.

CI$H22N104* 2HBr

C,bH22N,O,*ZWBr

Formula

260-262 (dec)

224-226 (dec)

262-263 (dec)

260-261 (dec)

266 (dec)

286 (dec)

Mp or Bp {"C)

Ref.


27

B. l-(Aminoalkoxy)isoquinolines Because of their potential use as therapeutic agents, l-(aminoa1koxy)isoquinolines have received considerable attention. The synthesis of these compounds employs an aromatic nucleophibc substitution reaction of a labile C1 functionality, such as a chloride. Easily generated from the corresponding isoquinoline 60, the 1-chloro 61 undergoes facile substitution with substituted aminoalkoxy sodium salts to afford 62, which have interesting local anaesthetic a~tivity~’-’~’ 61-64 (Equation 10). R

W

R

‘

R

-

v

R’

\

0

CI

60

/

NaOICHzlnR’R’

R’

/N

R 62

q

61

(10)

/R’

O(CHz)n N \

R?

Modifications of 62 in which an afkyl ether occupies C4 can be prepared in the same manner by starting from the 4-keto derivative 63.These types of structural changes were carried out for the purpose of enhancing the local anaesthetic activitys9 (Equation 11). 0

ORZ

I . POCI,

R

W

0R

‘

2. KzCO, RzX

Cl 63

64

b(CH2h NR3R4 65

28


The displacement of the chloride with the hydroxymethyloxazolidines 67 provides 68. The hydrolysis of 68 with aqueous acid affords the 2-hydroxy derivative 69, which acts as an adrenaline antagonist in guinea pigs6' (Equation 12). R'

66

68

& H ~ C H C HN ~HR~

I

OH

68

In an effort to develop a nonsteroidal antifertility agent based on the finding that racemic l-phenyl-2-phenethyl-l,~3,4-tetrahydroisoquinolinehydrochloride is active as a female antifertility agent in the rat, a series of analogs in which the 1-phenyl was replaced with a I-phenolic group wherein the 4'-hydroxy functionality is alkylated with a variety of alkylamines were prepared. The starting compound 70 can be prepared either from the Pictet-Spengler reaction or the Bischler-Napieralski reaction depending on the degree of electron enrichment provided by the substituents. Acylation and diborane reduction provides the 2-N-alkylisoquinolines 71, which is demethylated with hydrobromic acid and then alkylated with a variety of chloroalkylamines to afford 72'* (Scheme 9). Treating 73 with hydrogen sulfide in pyridine generates 74, which readily reacts in an SN2fashion with chloroalkylamines to provide the aminoalkylthio derivatives 7!P9 (Equation 13).

@ , -@ N

\

/N

pyridine H1S

OH 73

SH 74

CI(CH2hNR2RJ,

@ \

/ N

(13)

S(CHZ)~NR* R3 75


kH2CH2NRZR3 72

29


30

A variety of antitussive and defibrillatory agents 77 were prepared by reacting 76 with an assortment of aminoalkylarniness6 (Equation 14). R'

HN(CH~),NR'R'

R

q

N

-

R

q

R'-N(CH?X,

SCH3

n

76

(14)

N NR2R3

TABLE 7. l-(AMINOALKOXY)ISOQUrNOLI"S

R

R'

RZ

Molecular Formula

H

C13H16N20

C2H5

C13H16N20

CH3

Cl'H18N2O

C2H5

I5

20NZ0

C2H5

C15H20N20

CZH5

C16H2ZN202

CH3 n-C3H7

C16H22N20

CH3

c I ,H 22N20 C17H22N20

C2H5

C17H24N20

C2H5

Cl7H22N2O2

n-C,H9

C17H24N20

iso-C,H9

C17H24N20

C2H5

C,8H24N20

n-C5H1

1

C18H26N20

C6H5

C19H20N20

C2H5

C19H2.9N20

n-C6H

I3

H CH2C6H5 C2H5

n-C,H9

C19H28N20 C19H28N20

C2oH2zNzO CzoHz2NzO hydrochloride C20H2BN20

Fp (Flash point) or Bp ("C)

133-134 (2 mm) 177-178 (0.5 mm) 132-134 (I mm) 158- 164 (4 mm) 153-156 (2 mm) 169-172 (0.3 mm) 153-154 (1-2 mm) 150-152 (2 mm) 175-178 (1 mm) 154-157 (1 mm) 170-172 (0.3 mm) 155-157 (3 IUIII) 140-141 175-178 162-164 198-200 172-175 175-176 172-173 188-189 154-155

(0.4 mm) ( 1 mm) (1 IUIII)

(1 mm) (2 mm) (0.4mm) (2 mm) (0.4 IUIII)

189-191 (1 mm)

Ref. 6263 52.61 52.61 52.6 I 52.61 52.6 1 62,63 62.63 62,63 6263 52,61 52-54, 61-63 52.61 62,63 5261 516 1 52.6 1 52.61 62,63 52.61 62,63 52,61


31

TABLE 7. (Conrinued)

Molecular Formula

R’

R

R’

C2H5

-CH-(CHI)

CZH, n-C4H,

n-C,HP n-C3H,

C*H5 C,H,

H

CH 3

CH3

I

I

II-C~HP n-C,H,

5261

188-190 (2 mm) 177-178 (2 mm)

52.61 52,61

207-208 (0.3 mm) 220-225 (0.5 mm)

5x61 52,61

C22H32N20

186- 189 (0.4 mm)

52.6 1

C24H36N20

201-203 (0.4 mm)

5261

Fp or Bp (“C)

Ref.

cZl

H32N,0

C21H32N.70

-cH246H4~cH2)2-

CZZHZ4N20

3,4-Dimethoxy- CzzH,,N203 benzyl CH3

CH3

-CH-CH

Z-CH-CH

I

I

C2H5

Ref.

176-1 77 (0.4 mm)

C2oHzLlNzO

J-CH-

Fp (Flash point) or Bp (”C)

(CH3)2 2-C-

I

C6HlJ

I

‘ZH5

-CH-(CH,)-

TABLE 8. I-(AMINOALKOXY)ISOQUlNOLINES

R

X

Formula


32

TABLE 8. (Continued) R CzH5

Formula

X

--O--CH,-CH2--CH,-N(Et)2

-0-LH

A-CH31Hz

n-C,H,

- 0 0 - C H 3

I

I CH 2-CH- CH 2

166- 169 (4 mm)

52,61

C19H24N20

177-178 (1 mm)

52,61

154-156 (0.3mm) 168-170 (0.3mm)

5261 5861

C20H30N20

177-179 (0.5 mm)

52,61

cZ 1 H24N20

179-180 (0.05 mm)

55

c, ,H,*N20

189-190 (0.4m)

57,61

cl I H30N20

174-176 (1mm)

57,61

ClPHlBN20 C,9HZ9N3

H

-0-C

I

H- CHz-N( El),

Ref.

C18H26N2O

CHZ-CHCZHS

Fp or Bp (“C)

C6H5

CHZ--CH-CHz n-C,H,

-0-CH

I I

I I

N-Me

CH*--CH-CHz

n-C4H,

I

-O-

0

\\

0

A

R?

Formula

TABLE 47. SUBSTITUTED 142-PYRl~YL)-1,2,3.4-TETRAHYDROlSOQUlNOLlNES

101

2HBr. H20: 155-1 57 153

110-132

81-82 HC1:252-253 HBr: 249-250 150- 15 1

104-106

107

135-140 (0.1 mm) ZHCI: 1968

121 HCI:204

FP ("C)

216

203 203 203

203

210

210 204-2 10

204-210

204-210

Ref.

7-a

7-cI

%Me

H H

H

H

H H H

H H H

Me

H H

H

H H

H

H

H H H

H

H

H H

H H H H H H H H

H

H

H H

H H H H H H H H

H H

H

H H H H H

H

H H H

R2

H H H H H H H H

H

H

H

H

TABLE 48. SUBSTITUTED l-(4-PYRIDYL)-3,4-DIHYDROISOQUINOLINES~a4~ 210

2HCI: 198-200 65-67 2HCI : 236-238 91.5-92 110-1 12 63-64 110-1 12 91-92 2HCI: 235-240

60-61

171-172 95-96

H

H

H

H

H

H H €4

6-CI

6-OMe

6.7-diOMe

H

7-a

H

H

H

6-Me

H

H

H

H H

H

H

H H

H

H

H

H

H

H

H

H

R5

H

H

H H

R4

R3’

Me Me +CHz)d-Me Me

H

H

H

H

R’

R2

R’

H H H

H

H

H

H

H

R6

H H H

H

H

H

H

H

R’

R?

C16H16Nz C1,HlBNZ Cl,HIICIN,

C16HlbNLQI

C1,HI*NZO

CI,H,ICIN2

CIJH14Nz

C,,HI2N2

Formula

TABLE 49. SUBSTITUTED 143-PYRIDYL)-3,4-DIHYDROISOQUINOLINES

95-97 2HCI: 182-184 2HCI :228-230

122-123

dipicrate 186-187 bp 1 mm. 185-188

98-99 bp 1 m% 183-185

161-163 dipicrate: 192 bp 2 m m 179-184 HCl: 233-4 bp lmm, 170-173

FP K)

2w-210

204-210 204-210

21 1

21 I

21 1

21 I

21 I

Ref.

5 N

% u X

X X X X X

X

X X X X X

X

x z r r e

S

X

0

X

u s x x x

u 3 v r“ 2s: u u

X 0

X

2

106

X

x s u s x


107

TABLE 51. SUBSTITUTED I-(2-PYRlDYL)-3,4-ISOQUINOLINES199~z00

R’ H H H H H

H H

Rz H H

C H H H H H

R3

R4

R5

R6

R’

H H , H H CH, CH, CH,

H H H H H CH, H

H H H H H H H

H H

H H CH3 H CH3 H H

H CH,

H H CH3

Formula

FP (“C)

Picrate (“0

74.5-75.3 75.6-76.3 165“/0.35mm

167.2-168 177- 177.6 156- 156.5 161-161.5 1 70- 170.5 170- 171 162-162.5

55.5-55.8

7I .5-72 142/0.15mm 75-15.6

The Ullmann reaction of I-bromoisoquinoline (253)in the presence of copper powder at 200 “Cprovides a poor yield of l,l’-bis-isoquinoline (254), which gives a negative ferroin r e a ~ t i o n ~ (Equation ~ ~ ’ ~ ~ ’63).

Bischler-Napieralski cyclization of the two corresponding amides in 256, prepared by the reaction of homoveratrylamine (255) with diethyl oxalate at 160- 170 “C, affords 6,6’,7,7’-tetramethoxy-3,3’,4,4‘-tetrahydroI,l’-bisisoquinoline (257)254(Equation 64).


108

0

0

II If

ErOC-COEI

cC HH3 03 0 m N H 2

160-1 70'

CH30

w 256

1

POCI,

CHJO

Alternatively, 257 can be prepared from the reaction of I-carboethoxy-6,7dihydroisoquinoline (258)with 255 followed by the Bischler-Napieralski cyclization of 259 to provide 25725*(Equation 65).

The reduction of bis(tripheny1phosphine)nickel(I1) bromide with zinc in the presence of tetraethylammonium iodide produces a reactive nickel catalyst that effects the coupling of I-chloroisoquinoline (260)to afford in 37% yield 2!%255 (Equation 66). Bridging is easily introduced by a Bischler-Napieralski cyclization of the appropriate diamide. Thus, the cyclization of malondi-fl-phenethylamide(261) affords 1,1'-methylene-bis(3,4ihydroisoquinoline) (262) which can be reduced to the bis-l,2,3,4-tetrahydroisoquinoline 263256(Equation 67).


W N

NiBr ,(PPh,),

Zn/THF Et,NI

254

CH 2

I

toluene

261

109

262

The alkylation of the Reissert compound 37 with 2-dimethylaminoethyl chloride followed by the alkaline hydrolysis provides in addition to the major product 264 the minor product 1.241'-isoquinoly1)ehtane(265)257(Equation 68).

37

264

Generally, the alkylation reaction of Reissert compound 37 with a variety of bifunctional halides allows for the preparation of a large number of interestingly functionalized bis-isoquinolines 266a-d258(Equation 69). The Bischler-Napieralski cyclization of diamide 267 with phosphorous pentoxide in refluxing xylene affords N,N-bis-(3,4-dihydro-l-isoquinolylmethyl)-~phenethylamine (268)259(Equation 70). The reaction of 269 with primary amines results in the double alkylation of the m i n e to provide a large variety of tertiary amines 270259-261 (Equation 71).

110


2.67

268

VCH’ = WCH3 kH2Cl

269

CH 2

I

N-R

I

CHz

I

no

11. lsoquinolines Having Basic-Containing Substituents at C1

111

The double Bischler-Napieralski cyclization of 271 followed by a catalytic reduction provides racemic 272 which failed to exhibit amoebicidal activity226 (Equation 72).

271

1 . P:OI

1

2. [ H I

(72)

m In an effort to improve on the fibrinolytic activity of 273, Buchanan and

coworker^^^^.^^^ have developed two methods for the preparation of the N-

monosubstituted derivatives 276 and 278. Monoprotection of 273 affords 274 in moderate yields. Direct alkylation followed by deprotection provides 276, whereas acylation of 274 followed by a subsequent deprotection and amide reduction yields the homologated 278 (Scheme 19). Alternatively, a synthetic route involving sequential derivatization of each individual isoquinoline was developed to prepare 281, which is readily converted to either 276 or 278 (Equation 73). Bis-isoquinolines 283 bearing a variety of aromatic bridges can also be readily prepared by way of the double Bischler-Napieralski ~yclization’~’ (Equation 74). N-Acylisoquinolinium salts 284 react with pyrroles to afford 2,5-bis(2-acyl1,2-dihydorisoquinolyl)pyrroles285 in good yields266(Equation 75). The reaction of piperazine with 269 in the presence of potassium carbonate 1’)methylpiperazine(286) results in the formation of 1,4-di-(3’-methylisoquinolylin rather poor yields267(Equation 76).

w

& 8 -)$ d

c

h N

c

h N

X

X

-2-

0,

w

0,

u

X

X

W

x

0, X

0, X

V

0

0,

0, X

V

c

h

u

X

z V

0, X u

s u

P N

0,

0, = u

.2

3 N

0, X u

0, X u

w-3 N

0,

0, X u

u X

0, X

0, r

u

u

112

w

11. lsoquinolines Having Basic-Containing Substituents at C1 0 I.

c H 3 0 p N H 2 CH3O

II

0

II

CIC(CH2),COMc

2. 4. 3. B [Hi POCI3 aN,

113

cH30 CH3O

(CHz),

279

I

COzMe 280

mi BircMer-Na pierilrk I

.aH A I

282

0 ;

25-WoC

X284

AI

(74)

283

HNa

(75)

285

qcH3 qcH3 ‘H Isoquinolines Bearing Basic Side Chains

114

H

iNI

L NJ K,CO, H

n

CHzCI

CH*----NWN-cHz

269

F. Emetine Emetine (ma),the principal alkaloid of ipecac obtained from the ground roots of Uragoga ipecucuanha (Brot.)Baill. Rubiaceae, is a potent a n t i a m e b i ~ ~ ~ ~ . CH30

CH3O

H 287

a R=H b R=Ac

The total synthesis of emetine as well as the synthesis of related compounds A.R. Battersby represents the efforts of three groups: the Glaxo and coworkers2s4and A. Brossi and coworkers at Hoffmann-LaRoche.2s6-2ss Published works of groups that do not take into consideration the stereochemistry of synthesized intermediates related to emetine are not reviewed in this s e c t i ~ n .l .~ ~ ~ - ~ ~ Establishing the correct absolute configuration at C1 of the isoquinoline nucleus of emetine involved a series of Hoffman degradative steps of Nacetylemetine (28713) that resulted in the isolation of the chiral acetic acid 288. This acid was shown to have the same negative rotation as the acid derived from the synthesized chiral ester 289 (Equation 77).

CH~O’

-

A

2a8

11. Jsoquinolines Having Basic-Containing Substituents at C1

115

TABLE 52. BIS-ISOQUINOLINES

R

Q

H H

-CH- CHZCHZ-

CHj -CHzN

n /N-CH2-

Formula

MP("C)

Ref.

C,PH,,Nz CZ0Hl6N2

(Dipicrate) 228-229 bp 160-163/ 1 mm (picrate) 159-161

274 251

CZ6HZON,

160-162 (4 picrate) 210-21 1 (4HCI) 216-217

256


116

TABLE 53. N,N-BIs(l-ISOQUINOLYL-3-METHY L)ALKYLAMINES

CH2-N-

I

R

R

ck, MP (“C)

Formula

C6H 11

c6H5cH2-

C~H~CHZCHZCeHsHZCH-

I

Rd

(2HCl) 228-231 (2HCl) 272-273 (2HC1) 176 (2HCI) 102

261 261 261 26 I

118-1 19

275

130-13 1

275

146-147

275

188- 189

275

181

260

123-124

260

198

260

200-202

260

CH,


117

TABLE 54. I,l'-BIS(3,4-DIHYDROISOQUINOLINES)

R' R'

R2

Formula

H

H

C,,H,,NZ

5.6-diMe0

H

C,,H20N20z

5,6-diMe0 5.6diMeO

S'b'-Methyienedioxy S'b'diMeO

Cz,H10N104 C,,HZIN204

MP ("C) 76" dipicrate 144-146 (monopicrate)220-221 (2HCI) I 1 7 (dipicrate) 225 (Ha) 197-199 (dipicrate) 159-161 CHJ 139-140

Ref. 254 254 254 254


118

TABLE 55. BIS(3,4-DIHYDROISOQUINOLINES)SEPARATED BY 2

R

q

Q

/N

R2

R'

R2

Q.

Formula

MP VC)

274

H 5,ddiMeO

Ref.

5',6'-diMe0

5,GdiMeO

-43-

265 265

265

5,6diMe0

5,GdiMeO

5',6'-diMeO

5.6-diMeO

5',6'-diMeO

265

-0-

265

5,dMethylenedioxy

265

5.6-diMe0

5,6'-diMeO

-CH2CHCH2-

5,6-diM@

Et 5',6'-diMc0 CH2-CHCH2-

I

I

a 2 a 2 C H 3

CZ7H34N204 (2HBr) 168-170 (2CH3I) 175-176

262

CIBH3gN204

262

125.5-126.5 (2HCl) 185-187 (dec) (2HBr) 184-185 (dec) (2CH3I) 156-158


119

TABLE 56. Sly 1.2-DIHYDROISOQUINOLINES)

R'

RZ

Q

Formula

Mp("C)

Ref.

C,,H,,N,O,

197-198

276

C,,H,,N,O,

170-171

274

n N W

3

I

I

QQ B 2

eW

h

h

aa

120

aa

ow


TABLE 58. C H3

121

OCH 3

N.

R' ''R

R'

R'

R3

H CH3 H

H H H

CH3

CH3

C'H, CZH, n-C3H7CZH,

Cz7H3,N,0, CZBHSaNzO, C,,H3aNz0, C29HMN20,

CH3 CH,

H CH3

tK3H7 n-C3H7

CZQH'0Nz04 C3,H,zN,O,

Formula

MP ("C)

(Dioxalate) 185-187" (2HI) 212-214 (dioxalate) 181-183 (2HI) 240-241 (2HBr) 265-266 ( d e ) (2813215-216 (2HI) 235-237 (dm)

Ref. 262 262 262 262 262 262

Correlating the absolute configuration of 288 with the amine 291 derived from (+)-calycotomine (290), whose absolute configuration was clearly establ i ~ h e dconfirmed , ~ ~ ~ the geometry of 287) (Equation 78).

2w

Brossi and coworkers prepared ( +)-Zdehydroemetine (293) from the Bischler-Napieralski cyclization of the benzo[a]quinolizine 292 followed by a reduction and resolution of the racemic mixture with tartaric acidz8" (Equation 79). Catalytic reduction of 292 affords a separable mixture of diastereomeric benzo[a]quinolines from which 294 is cyclized under Bischler-Napieralski conditions to 2%. Catalytic reduction provides dl-emetine (Equation 80). Chapman and coworkers284provided an elegant total synthesis of emetine in which the key step of the synthesis involved the condensation of acetone dicarboxylic acid with 3,4-dihydro-6,7dimethoxyisoquinoline(296)to provide the two diastereomeric ketones 297 and 2!M. By the appropriate choice of reaction conditions it was possible to obtain 298 in 60% yield (Equation 81).


122

I . POCl3 2. NaBH,

CH30

3. resolution

CH3O

$H

2

HmOCH3

3

292

292

I.

H2

2. Sepsrruon

CZHS CH2

1

295


123

Hh Hot,

OCH,

297

+

?kXocH OCH 3

Alternatively,292the reaction of the pseudobase 299 with the keto acid 300 provided a separable mixture of the diastereomeric ketones 301 and 302 which after debenzylation afforded 297 and 298 (Equation 82). By means of a series of synthetic transformations, 301 is used to prepare racemic isoemetine while 302 provides racemic emetine292*293 (Scheme 20).

124

Isoquinolines Bearing Basic Side Chains CH30 CH3O HO

299

~H~CCH,COOH

II

0


tI =0

303

3a2

I . LiINH, 2.HS-SH 3. RaNi

304

305

scheme 20

125

126


TABLE 59A. BISISOQUINOLINES RELATED TO EMETINE-LIKE COMPOUNDS AND EMETINE TOTAL SYNTHESIS

R

R

Nm0c

I

I

CH2

OCH,

R

Formula

Fp("C)

13 1-4 36 105-110

A

J-j

295

295

H3

P

B

190-196 173.5-175

Ref.

C27H33N204

hydroiodide* H,O

295 193-195

Racemate A: C27H36N204

dihydroiodide Racemate B dihydroiodide

247-249 210-220

295

127

11. lsoquinolines Having Basic-Containing Substituents at C1 TABLE 59B. BIS-ISOQUINOLINES FOR TOTAL SYNTHESIS OF EMETINEzs4*2 9 ' . 2 9 3

Series A

Series B (leads to f emetine)

R'

R

Series

Formula

A

H

H

B

H

H

A A B

-COCH3 --COCH,CHZCH, -COCH,CH2CH3

-COCH3 --COCH,CH,CH, -COCH2CH2CH,

C33H44N207 C33H,4N207

-CH,--C,H5

C32H38N205

4H2--C6H5

C32H38N205

A

H

B

H

C25H32N205

dihydrochloride C25H32N205

sulfate. 3 H 2 0 C19H36N207

dihydrochloride * 2 H 2 0 dihydrobromide

FP VC) 143-144 204-205 144-145 140-142 (dec)

20-202 173.5-175 161.5- 163 150-152 152- 155

-CH,CH,COCH,

-CH,CH,COCH,

A H ZCH ZCOCH,

xHaCH2COCH3

4 H J C HSCOCHj

A

B

A

B --CHIC6HS

XH2CbHj

IH,SO, 3. HCI

340

NH


151

TABLE 66. INTERMEDIATES FOR SYNTHESIS OF 1.2.3.4-TETRAHYDROISO-

QUINOLINE-2-CARBOXAMIDINES

R’

R2

A

Formula

Fp(”C)

Ref.

H

H

-C

,SCZH~ *NH.HBr

C,,H, ,N,S * HBr

157-160

321

6.7-diOMe

CH,

-C,

4

C13H18N202S

138-140

321

6-OH,7-OCH,

CH,

-C,

C,,H,,N,O,S.HBr

157-159

321

6.7-diOCH3

H

-C,

C,,H,,N,O,S*HBr

142-144

321

6,7-diOCH3

CH,

-Cs

C,,H,,N,O,S-HBr

-

32 1

NH 2

4NH.HBr SCzH: +NH.HBr SC2Hs NH-HBr SCzHj

152


TABLE 67A. SUBSTITUTED 1,2,3,4-TETRAHYDROISOQUINOLINE-2-CARBOXAMIDINES

R1

R2

R3

67-diOMe

H

H

H

6.7-diOMe

H

6.7-diOMe

H

&OH, 7-OMe

CH3 -CH2-CH2-0

6,7-diOMe

H

-CH2CH2-N

-CHz-CH

2-

\p

C18H28N403

hydrobromide

hydrobromide

C19N23N302

hydrobromide

-CH2CH2-0

c2 IH27N204

hydrobromide

C22H29N304

hydrobromide

154-156

321

147-49

321

160-62

321

188-190

321

147-50

321

213-215

321

210-211

321

-CH2-CH2

6,7-diOMe

CH, -CH2CH2-O

C22H29N304

hydrobromide

111. lsoquinolines Having Basic-Containing Substitoents at C2

153

TABLE 67B.

-

Rgp+:-&NH

“H-R3

R’ R’ H

R2

H

R3 H

or

R’

R’

Formula

H

CIOH13N3 H2C03

hydrochloride nitrate hydrobromide monosulfate 6,7-diOMe

H

H

H

H

0

Cl,H17N,O, monosulfate

Fp(”C)

Ref.

60-63 179-181 146-148 175-176 274-276 261-262

312,313 312,313 312,313 312,313 312,313 312,313 312.313

m

353


154

TABLE 68. SUBSTITUTED 3,4-DIHY DRO-2(1H)ISOQUINOLINE CARBOXAMIDOXIM ES

R’ H 6.7diOH 5-OH 5-CH3 &Me 7-Me 8-Me H H 6.7diOH 5NHAc H H H H

H

5-CH3 &Me 7-Me 8-Me

H

H 6.7diOMe 6.7diOMe

Formula

R2

H H H H H

H

H I-CH, 3-CH3 I-CH,

H

1--C2H, 3-CZHS 1,I di(CH,) 3.3-di(CH3) 4,4diCH, 1-CH,

1-CH, 1-CH, I-CH, 1,3,3-triMe 1,4,4-triMe I-Me 3-Me

C,,H 13N30p-toluenesulfonate C,,H,,N,O, hydrochloride CloHI3N302 hydrochloride cl 1H1,N30

C , lHl,N,O hydrochloride 1‘

lH1sNJ0

C11H1,N30 1 ‘

lHllN30

cl

I

1S N 3 0

CllH,,N,03 hydrochloride C12Hl,N,O, C, ,HI ,NjO hydrochloride Cl *H ,N,O hydrochloride C12Hl T N 3 0 C12Hl

7N30

C12H17N30

C,,H I ,N,O hydrochloride C12H17N30 C12H17N30

Cl,H17N,0 hydrochloride C13H19N30 1 ‘

9N30

c13H19N303

C, ,H 19N,0, hydrochloride

FP (“C) 144-145 198-200 212-21 3 142-144 152-154 141-145 145-149 170- 172 I 20- 122 195-197 164-166 183-184 135-142 161-162 122-123 117-1 19 193-194 156-1 58 151-1 54 210-21 3 161-1 63 134- 135 149- I50 178-181

Ref. 314,315 314,315 314,315 314,315 314,315 314,315 314.315 314,315 314,315 314,315 314,315 314,315 314,315 314,315 314.315 314,315 314,315 314,315 314,315 314,315 314,315 314,315 314,315 314,315


155

TABLE 69. SUBSTITUTED 2-(GUANIDINOALKYL)-l,2,3,4-TETRAHYDROISOQUINOLINES ' m - C H * - ( C H 2 ) , , n

R'

-Y

Formula

Y

Fp("C)

Ref. ~

H

I

-NH--C(

H H H H Ring totally reduced H

1

-NH-C( = St-NHCH, -NH--C( = S)--NHCH, -NH--C(=StNHEt -NH--C( =S)NH(cyclohexyl) -NH--C( = NH)NH,

2 2 2 I

=NH)--NH,

C12HtllN4

disulfate*~H,O c I ,H IPN3S ',,HZ

INSS

C15H23N3S

C,,H,,N,S 12

~~

204-207

3 l6,3I7

316,317 316.317 180-181 316,317 135.5-136 316,317 195-199 318

-

84-85

TABLE 70. 2-(BIGUANID)-l,2,3,4-TETRAHYDROISOQUlNOLINES

Formula

Y

--C( =NH)--NH--C( -C( =NHF-NH-C(

= NH)NH,

=NH)NHCH,

C,,H,,N, hydrochloride C,2H,,N, hydrochloride

Ref.

FP ("C)

226-228 196-198

319,320 319,320

TABLE 71.

Y

-S-C( -S O

4. Swcrn oaidalion

CH30

0 355

356

(99% ee) SekmeM

B. Substituted 2-(Amiaopbenyl)isoquinlines As a potential antineoplastic agent, l-{p-[bis(2-chloroethyl)amino]benzyl} isoquinolinium p-toluenesulfonate (362) is prepared by the reaction of isoquinoline with pbis(2-chloroethyl)amino]benzyl alcohol (361) in the presence of p-toluenesulfonyl chloride335(Equation 93). The reaction of 6-methylisatoic anhydride (363) with 6,7-dimethoxy-1,2,3,4tetrahydroiosquinoline (357) under basic conditions affords 364, which is reduced with lithium aluminum hydride (LAH) to N-(2-amino-S-rnethylbenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiosquinoline (365), a compound possessing minor tranquilizer properties336(Equation 94).

162


I

pTs0

CHZOH

362

361

357

/

LiAl H4

cC H 330 0 m N C H 2 @ c H 3 N H ~

366

The alkylation of 1,2,3,4-tetrahydroiosquinoline with methyl 2-chloropropionate heated with potassium carbonate in a sealed tube provides 366,which after aminolysis with aniline and lithium aluminum hydride reduction affords 2-(a-methyl-~-aminophenethyl)-1~3,4-tetrahydroisoquinoline (367), which has potential local anesthetic activityJ3' (Equation 95). l-Methyl-3,4,-dihydroisoquinoline(368)reacts smoothly with 2-chloro-Nphenylbenzamide to provide after treatment with potassium iodide the quaternary iodide 369,which is reduced first with sodium borohydride and then with lithium aluminum hydride to yield 370, a compound possessing antiprotozoal activity3'* (Equation 96). Under basic conditions, substituted isoquinolines 371 react with p-nitrostyrene epoxide (372) at the less hindered carbon to afford 373, which can be


163

CHI

I

CICHC0,Me

m

N

H

N-CHC02Me

K~COI

3m

369

(96)

reduced catalytically to 374. Depending on the nature of the substituents, these compounds have been useful as sedatives, hypotensives, analgetics, and 97). a n t i t u s s i v e ~(Equation ~~~

[

373 X=NOZ

371

IHI

34

X=NHZ

(97)

Isoquinoline Bearing Basic Side Chains

164

The alkylation of 1-phenyl-6,7,-disubstituted-1,2,3,4-tetrahydroisoquinolines 375 with 1,3-dibromopropaneso as to allow only one bromo group to react with the secondary amino group of 375 affords in good yields 376, which can be reacted with different anilino derivatives to provide either 377a or 377). These compounds have been found to be potential t u b e r c u l ~ s t a t (Equation s~~~ 98).

0 377a R’= 3 C 2H5(68%) 37?b R = 3,4diMe(70%)

377

Ethyl 2-(2-aminobenzyl)- or 2-(2-aminophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate(379) or (380)were utilized as key intermediates for the synthesis of the interesting tetracyclic compounds 381 which depending on the nature of the substituents were examined as potential sedatives, analgesics, tranquilizers, diuretics, and hypoten~ives’~~ (Equation 99).

m

R’

COzEt

R2

mz

R1 2. RaNi or

P i 0 ,I

378

*

CO2Et

RZ

H

R&NH2

381

R3

(99)

111. Isoquinolines Having Basic-Containing Substituents at C2 TABLE 77. ISOQUINOLINIUM SALTS WITH AMINOPHENYL GROUP IN 2 POSITION

165

QI QI

L

H

H

CH, CH, N(C0Et) CH2 CH(0H)

CH, CH(0H)

CH,CH(OH) CH, CH(0H)

H 6.7-U-CHIO

6.7-diOMe

6,740Me CH,CH(OH) 6.7,s-triOMe QNH, 3-NH2

4-NH,

I-Me H

1-CH,

I-CH3

CH, CH, NH

H

1-CH,

CHzCONH

H H

R2

l-CbH5

CHzCH[OCH2CH,N(CHzCH,),]H H

~~

C O W , H, C O W , H, COOC2H5 l-C,H,

H H

H

H

P-OCH2 CH, W H , CHdI

H

2-Amino-S- Me H H 2-NH2 2NH,, 4-CI 2NHz H

R1

CH,CH,

CH, CH(NH,)-CH,

Y

H

H

6.7diOMe H H H H H H

R1

R3

-~

dihydrochlonde

O3 c 2 0 HZ6 N2 0 4

cZO H26 ‘2

hydrochloride

c19 H24 N2, O3

N, 0 3 dihydrochloride

c,, H,,

H20 NZ.o

hydrochloride CI8 Hz2 MZ, hydrochlonde C,lHZ,NZO

clB

H34 N Z

dihydrochloride

cZY

cZ9 H34 N.2°

dihydrochloride * 25H,O

dihydrochloride * 5C2H,0H

c Z 4 H Z 6 HZ

c 1 9

clB

CIN2O4S Hzz N, 0, c,, H2, N, dihydrochloride * 25H20

c J B H20 H2°4S

-

C,Y H24 N, 0, CIS H2o N2O Cl8 H22 N,

-

Formula

TABLE 78. SUBSTITUTED 1,2,3,4-TETRAHYDROISOQUINOLINES WITH AMINOPHENYL GROUP IN 2 POSITION

239-240

121-122

180 164-165 220

-

235-237

184- 187

97-143

2 10.5-2 18.5

231-239

2 10.5-21 8.5

84-85

101 218(1 mm) 142- 149 147-148

-

FP (“C)

339

339

339

339

338

338

338

314

314

374

336 337 337 34 1 341 341 374

Ref.

Ill. Isoquinolines Having Basic-Containing Substituents at C2

I67

TABLE 79. SUBSTITUTED 3-(AMINOPHENYL)-l,2-DIOXO-1,2,3,4-TETRAHYDROISOQUINOLINES

Re

&

R

-

2

HO R ’

R

R2

R’

Br

pBr--€,H4 C6H5

Fp (“C)

Formula

N(CH3),

C23H,, BrN203

203-204

N(CH3)2

c24 H7.2 N 2 0 3

146

c 2 5 H14 N 2

O.3

165 153

‘29

NZ

110

CH3 OCH3

C6H5

N(CHdz

CzhHzzN204

C2H5

C6H5

N(CH3)2

H

C6Hr-’%H,

N(CH3)2

R‘w

Ref. 375 376 374 375 375

TABLE 80. Z-(PIPERAZINYLALKYL) ISOQUINOLIN-1,3-DIONES”’

0

R’ R’

R2 CI

0

R3

N-(CH2),

R4 H

-N

A

WN-R’

n

c23 HZ6 C1N3

hydrochloride

H

H

H

H

F

H

FP CC)

Formula

OZ

C23HZ6C1N302

hydrochloride

228

H26 C1N3 O2 dih ydrochloride

135

c23

c23 H26 FN3 O2

dih ydrochloride

H

H

H

H

231-232

c,?J H27 N3 O2

dihydrochloride ‘23

HZ8 N4°2

dihydrochloride H

H

H

H

c24 H,?9 N 3 O2

H

3-Me

c24 H29 N3

c24 H26 F3 N 3 O2

hydrochloride hydrochloride

OZ

hydrochloride

200-203 193-205 (dm) 176- 178

230 235-238 1%


168 TABLE 80. (Continued)

Rl H

H

FP W)

R3

R4

n

C6H4(2Me)

H

2

c24 H29 N 3 O2

2

c24 H29 N 3

R2

Formula hydrochloride

247

O3 hydrochloride

215-218

H

043%

C6HS

H

H

H

C6H4(2)CH3)

H

2

Cz4 Hm N3 0

H

H

C6H4(mH3)

H

2

cZ4

H

H

&Me-2-Pyridyl

H

3

c24 H30 N4 O2

wH3

2-Pyridyl

H

3 3

H H

H

C&(XF,)

H

H

H

C6H3(2,6diMe)

H

2 2

H

H

C6H4(2Et)

H

H

H

C6H4(20Me)

H

3

C6H4(20Me)

H

2

H

C6H3(3,4-diOMe)

H

2

H

O(3.b

CMe-2-Pyrodyl

H

3

OCH, OCH,

OCH3 OCH,

C,H4(20Me) C6H4(20Me)

H

2 3

H H

H

3

dihydrochloride H Z 9 N3

O3

dihydrochloride hydrochloride c24 H30 N4

O3

dihydrochloride c2S H28 F3 N3 O2

hydrochloride CZ5H31N302

hydrochloride c25 H31 N3 0 2 dihydrochloride c*5H31 N3 0 3 hydrochloride C25H31N304

dihydrochloride C25H31N304

dihydrochloride

2 15-21 7

228 88(d%C) 193-196 215-220 230 (d YoC) 188-192 235-237 211-213 158

c25 H32 N4

O.3

c26 H33 N3

OS

172-1 76 264-265

hydrochloride

198-Nx)

dihydrochloride

cz, H3, N, 0,


169

TABLE 81. SUBSTITUTED 24ETHYLAMINOALKYL)-I.3-ISOQUINOLINDIONES377

~~

R’

R2

R’

Formula

n

H

H

3.4-diOMe

C23H28N204

H

OCH,

4-OMe

C23H7.BN204

H

a

3.4-diOMe

H

H

3,4-diOMe

C24H30N204

H

OCH,

3.4-diOMe

C24H30N205

H

OCH,

2Me, 3,4-diOCH3

1

H

OCH,

3,UiOMe

2

H

SCH,.

3.4-diOMe

cZ$

H

OCH,

3.4.5-triOM~

C26H34N206

w H 3

OCH,

3.4-diOMe

C26H34N206

(33%

OCH,

2-Me, 3,UiOMc

C2’1H36NZ06

hydrochloride

Cz4 Hz, ClNz 0

hydrochloride

175- 176 4

hydrochloride

hydrochloride C,, H,, N, 0, hydrochloride CZIH32NtOI hydrochloride H32 NZ

~~~

148-151

hydrochloride

2

FP W)

O4S

hydrochloride hydrochloride hydrochloride

hydrochloride

222-226 162- 165 263-265 138-140 191- 193 133-135 157-159 98-101 167-168

C. %HeterocyclicSubstituted Isoquiaolines

The syntheses of 2-heterocyclic substituted isoquinolines generally involves the nucleophilic displacement of an appropriately substituted heterocyclic halide with the basic nitrogen of an appropriately substituted isoquinoline. Isoquinoline and o-bromopicoline (382) react in boiling benzene to give a red solid quaternary bromide 383, which when brominated and subsequently treated with pyridine provides 5-bromopyridino[ 1”: 2”-3:4]isoquinolino [2’: 1 :2)glyoxalinium bromide monohydrate (384)342(Equation 100).

170


382 C6Hb

383

The reaction of 1,2,3,4-tetrahydroisoquinolinewith 2-chloromethylpyridine (385) in cold acetonitrile affords 2-(2-pyridylmethyl)-1,2,3,4-tetrahydroisoquinoline (386),which can be cyclized to the quaternary spiro salt 387 by boiling 386 with I J - d i b r ~ m o e t h a n e (Equation ~~~ 101)

The Michael addition of isoquinolines to an appropriately substituted vinyl pyridine 388 is a very effective method for the preparation of the 242pyridylethyl) derivative 389.343-346. These compounds have been examined for as well as fungicidal activity344(Equation 102). hypertensive

R

388

The reaction of variously substituted 1,2,3,4-tetrahydr0-2-isoquinoline ethanols 390 with nicotinoyl chloride hydrochloride in methyl propionate provides 2-(2-nicotinoyloxyethyl)-l,2,3,4-tetrahydrois~uinolines 391, which have been found useful as peripheral vasodilator^^^' (Equation 103).

171


390

Ether derivatives 393 which are potent vasodilators and blood-pressurereducing (antihypertensive; i.e., hypotensive) agents, can be conveniently prepared by the reaction of substituted 2-(/3-chloroethyl)-l,2,3,4tetrahydroisoquinolines 392 with 3-pyridol under basic conditionsJ4* (Equation 104).

Ra)/-VC' @

OH

'

r

n

N

-

4

SOH

toluene

392

393

(104)

Morpholine adds in a Michael-like fashion to 5-ethyl-2-vinylpyridine 388 (R=ethyl) to provide S-ethyl-2-(P-rnorpholinoethyl)pyridine394. Catalytic re-

duction of 394 with platinum oxide in acetic acid followed by N-alkylation of the basic nitrogen with formaldehyde affords a suitable intermediate for a nucleophilic substitution reaction with substituted 1,2,3,4tetrahydroisoquinolines to yield 5-ethyl- 1-methyl-2-[ B-( I ,2,3,4-tetrahydroisoquinoline)ethyl]piperdine (3%). The bis-quaternary salts of 395 have been investigated for their antihypertensive properties 3 4 5 * 3 5 4 (Equation 105).

388

'.W R

3% H

/

2. I .C PH t O, O IIHl

172


When 1-(l-piperidyl)-l-[a~l,2,3,4-tetrahydro-2-isoquinolyl)benzylJacetone (3%) is treated in benzene with four equivalents (4 eq) of methylmagnesium iodide, the a,B-diamino tertiary carbinol 2-methyl4phenyl-3-(1 -piperidyl)-4(1,2,3,4-tetrahydro-2-isoquinolyl)-2-butanol (397) is obtained in 14% yield349 (Equation 106).

Substituted 6-aminomethylguanamines 398, prepared for their possible filaricidal activity, can be prepared in two steps by the reaction of 337 first with ethyl chloroacetate under basic conditions and second with a suitably substituted arnine3s073s1(Equation 107). 0

II

I . CICHICOEt NaOCH,

2. HNR'R'

NH

337

NH

NH 2

Isoquinolinium pyrimidine salts 400 have been prepared by treating 2-alkyl4-amino-5-(brornoethyl)pyrirnidine (399) with isoquinoline in a c e t ~ n i t r i l e ~ ~ ~ (Equation 108).

Under basic conditions a-acetyl-y-butyrolactone 401 reacts with 332 to afford

241,2,3,Q-tetrahydroisoquinolino)-4-methyl-5-(2-hydroxyethyl)py~midine (402),

which when treated with phosphorous oxychloride undergoes a dehydrative ring closure to S,ddihydrofuro[2,3-d]pyrimidine (403)3s3 (Equation 109).


173

WNYNH* G

o

401

NIOEI

NH

332

/

402

4a3

(109)

A series of substituted 2-(2-piperidinoethyl)-1,2,3,4-tetrahydroisoquinolines 405 were prepared from the reaction of 2-(2-~hloroethyl)pipeeridine404 with substituted 1,2,3,4-tetrahydroisoquinolines in the presence of magnesium

oxide3ss. These were examined for various pharmacologic activities356 (Equation 110).

W .' 'a!" MgO 404

A

' m N 3 4M

(1 10)

Refluxing 1,2,3,4-tetrahydroisoquinolinehydrochloride with paraformaldehyde in acetone containing absolute ethanol affords in 59% yield 4-(1,2,3,4 tetrahydroisoquinoline)-2-butanone hydrochloride (406).The photochemical bromination of 406 generates the a-bromo derivative 407, which undergoes a cyclization with thiourea in an acidic aqueous solution to afford 2-amino-4-[2(1,2,3,4-tetrahydroisoquinolino)ethyl]thiazole (Equation 1 I 1). Because of their promising activity against certain cancers, a variety of quaternary ammonium salts 410 were prepared by reacting substituted isoquine ~ ~ ~ 1 12). olines with 2-amino-4-(chloroethyI)thiazole(409)in p ~ r i d i n (Equation Refluxing 41 1 with substituted 1,2,3,4-tetrahydroisoquinolinein benzene affords in 52-84% yields 3-phenyl-5-[~-(substituted-1,2,3,4-tetrahydro-2isoquinolyl]-l,2,4-oxadiazolehydrochlorides (412), which were useful agents as analgesics, antiphlogistics, antispasmodics, and local anaesthetics359 (Equation 113).

174

lsoquinolines Bearing Basic Side Chains

406

I

HB r 407

f HCH O), acetone

409

411

R' 4u


175

Isocarbostyril(413) reacts with methyl vinyl ketone under basic conditions to provide 2-(3-oxobutyI)-2(1H)-isoquinolone (414) in 72% yield. Treatment of 414 with ammonium carbonate and sodium cyanide in 50% ethanol affords the hydantoin 415 which can be ring-opened to racemic 2-amino-2-methyl-4-(1oxo-2(2H)-isoquinolyi)butyricacid (416) with barium hydroxide360(Scheme 27).

413

414

416

415

Scbeme 27 TABLE 82. 3-PHENYL-5-~-(I,2.3,4-TETRAHYDRO-2-ISOQUINOLY L)ETHY L3- 1.2.4-OXADIAZOLE HYDROCHLORIDES359

R

R1

H H H H H OCH3 OCH,

H CH3 CH3CH, C,H, H H CH3

R’ H H H H CH3 H H

Formula

MP CC)

C21H23N30

207 178 I56

C22H2SN30

140

C,9H

C20H21N30

C20H21N30 c2 I H23N,03

C22H2.5N303

175 196 184

L

8

t-

t

x

a z

2

z

ri

n)

ri

ri

X

X

X

I

X

X

176

3

VI v, m

VI

m

E E

m

v,

m

-

xN

L

b

I-

8

Y

t, T

6

A

N

5

2, L,

N

X

N

N

N

I

2

T

X

T

T

N

I77

w

' I ) lr)

m

cE

::

P

r!

I

r-

vlm

Q) N

- N

G X

N

X

178

ri

N

m

X

3:

X

X

X

X

zm

4 m

?

m

0.

01

m 01

2

-

a. c/

N

X

X

X

r

179


180

TABLE 84. HETEROSUBSTITUTED N-I,2,3&TETRAHYDROISOQUINOLINOAMINOMETHYLGUANAMINES'so

Hetero

I

0

0

Formula

Mp or Bp ("C)

155-157

I

A -"W0

A

159-160

171-172

-"WN -co Et

137-139

-"wN-

152- 153

A

A

-NWN-' /N

A

m

137- 139

166-168

126-1 27


181

TABLE 85.

R

R'

Ref.

H

288

378

3CH,

247

378

3CH,

253

318

H

256

378

244-245 (dec)

358

H

H

Herero

Formula

Mp or Bp ("C)

n

C,3H,2N,CI

343 342

~~

~

t t 9z L Z 'H93'H30-L "H30-9 O N H 3 t t 82 t2 Ol3!PL'9 O N H 3 t t sz t z WW!PL'9 O N H 3 9 t S Z CZ @NUl-8'L69 O N H 3 t t 92 CZ 013!P-L'9 O N H 3 t t 92 C2 gaW!PL'9 O N H 3 t t 9 2 CC WW!P-L'9 O N H 3 t t 9 2 C2 OaW!PL9 O N H 3 sO ?Nt 2 H zz 3 OW!JI-8'L'9 5 t tz rz WWPl-8'L'9 O N H 3 5 t tz I 2 OWIPL'9 O N H 3 5 t 5 z zz WW!PL'9 O N H 3 0t NtzH L Z 3 0tN C Z H"3 t t

0tN ZZH"3

t

tOtN2ZH

I

z3

t

O t NE l H 0 23 tOtNOZHOz3

t t 81 0 N HoZ3

rO*N02"023

t t 02 0 2 O N H 3 f t oz 02 O N H 3 O 5 N L I H 6 13 t

OW!PL'9 OaN!W?'L'9 OaW!PL'9 WW!PL'9 Xxo!paualbqlaW-L'g OW!P-L'9 OaW!PL'9 OWIP-L '9 OaW!PL'9

gaW!PL'9

gaM!PLP

WM!P-L'9 OWL ' O W 9 WUO-L '01W9 gaW!Jl-L'9'S WW!P-LL 013!P-L'9 Jd!OL ' O W 9

C ~ ~ 2 ~ 'ow-9 3 Z ~ 3 0 OW!P8'L OW!PL'9 @WUl-8'L'9 OaWyUl-L'9'S

gaW-L 'Ow9 OaN-L WN!P8'L OaW!W'S gaW!PL'9 HO-8 'O%I-L ~xo!pua~bqlq.q-~'9

H0-9 ' W W - L

H O L '01W-9 OaW-L

20n-1

IV. Isoquinolines Having Basic-Containing Substituents at C3

183

TABLE 87. BIS-I-CYANO-(I.2,3,4-TETRAHYDROISOQUINOLINES)38'

IV. ISOQUINOLINES HAVING BASIC-CONTAINING SUBSTITUENTS AT C3 A variety of 3-(aminoalkyl)- and 3-(aminoaryl)isoquinolines have been synthesized either as a part of a general synthetic effort or as a specific goal toward the discovery of biologically interesting compounds. Ethylenediamine derivatives 418 with potential antiarrhythmicantifibrillatory activity have been prepared from the reaction of ethyl 1,2,3,4tetrahydroisoquinoline-3-carboxylate(417) with a wide assortment of substituted e t h y l e n e d i a m i n e ~ ~ '(Equation ~ - ~ ~ ~ 114).

417

418

(1 14)

Primary amines react with ethyl 2-benzyl-l,2,3,4-tetrahydroisoquinoline-3carboxylates 419 to provide the amides 420, which when reduced with lithium aluminium hydride afforded substituted 1,2,3,4-tetrahydro-3-aminomethylisoquinolines 421. Depending on the nature of the substituents, these have been used as antiarrhythmic agentsje5 as well as agents for treating mental depresion^'^ (Equation 115).

Isoquinolincs Bearing Basic Side Chains

184

R

w

N

H

R

‘

TABLE 88. SUBSTITUTED 1,2,3,4TETRAHYDROISOQUINOLINE-3-CARBOXAMIDES(408)382*314

0

R

RL

R’

Formula

BP (“C)

H H H

CH3 H CZH,

CH, iC,H, CZH,

C,,HzI N 3 0 C,,H,,N,O C,,HZ,N,O

192- 195/0.1 Torr 198-200/0.5 Tom 205-210/0.I TOIT

The carefully regulated reduction of methyl 2-methyl-3,4-dihydrocarbostyril3-carboxylate (422) with lithium aluminum hydride provides 3-hydroxymethyl2-methyl-3,4-dihydroarbostyril (423), 3-hydroxymethyl-2-methyl-1,2,3,4tetrahydroisoquinoline (424) and 8-aza-6-oxa-8-methyl-3,4-dihydrobicycloC3.2. lloctane (425), all of which can be separately isolated. Further treatment of either 423 or 425 with lithium aluminum hydride yields only 424 which is converted in three steps to 3-(2-aminoethyl)-2-methyl-1,2,3,4tetrahydroisoquinoline (427). Alternatively 423 can first be converted to the chloride 426, which is transformed in three steps to 427387(Scheme 28). Ethyl isoquinoline-3-carboxylate(429), prepared from 1,2,3,4-tetrahydro-3isoquinoline carboxylic acid (428), undergoes a Claisen reaction with ethyl 341’benzoyl-4‘-piperidy1)propionate(430) to afford after hydrolysis and decarboxyl-


185

TABLE 89. SUBSTITUTED 1,2,3.+TETRAHY DROISOQUINOLINE-3-AMINOMETHYL DERIVATIVES385.386

Formula

R'

R H

H

H 6.7-diMc0

CH3 H

H H

iC,H,

C17H26N2

Mp or Bp (%) 155/1.0 Torr 51-52 (2HBr) 204-206 150/0.1 Torr

213-214/0.1 Torr (2HCI) 180-182 (2HCI.)HzO) 148-150 71.5-73

C6H5

22210.25 Torr

--CH

H

-

225/0.1 Torr

2C6H 5

2a O) 0

239m.85 Torr (2HC1) 160-162 (dec)

ation 2-(4-piperidylethyl)-3-isoquinolylketone (431). Treatment of 431 with sodium hypobromite followed by a cyclization reaction with sodium ethoxide generates the 3-isoquinolyl 2-quinuclidyl ketone 432, which was tested for antimalarial p o t e n t i a l i t i e ~ ~(Scheme " ~ . ~ ~ ~29). The condensation of 429 with piperidine provides 3-piperidinocarbonylisoquinoline (433), which on reduction with lithium aluminum hydride yields 3piperidinomethylisoquinoline (434)390*393 (Equation 1 16). 3-Isoquinolinecarboxaldehyde(435) is easily converted to 3-cyanoisoquinoline (436),'91 which has been used as a common intermediate for the synthesis of either 3-(4-substitutedthiaole)isoquinolines437391or 3-isoquinolinecarboximidic acid hydrazide (438), which can be further reacted with vicinyl diketones to provide the triazines 439, 440,441392(Scheme 30). l-Chloro-3-chloromethyl-4-methylsubstitutedisoquinolines 442 contain two reactive chloride moieties that have been exploited for the preparation of antitussive isoquinoline derivative^.^^^-'^^ Using only a two-to three-fold excess of a primary amine heated for 4-6 hr at 140°C results in the nucleophilic

186


423

422

425

424

I SOCI,

2.

c,n,

I PBr, 3 RaNi

429

428

4

CH,CH,CO,Et

KOE I

O ~ C . H 5

430

43 2

431

Se&m29

IV. lsoquinolines Having Basic-Containing Substituents at C3

COzEt

187

N

H

dphenyloaidc

433

429

434 TABLE 90. 3-HETEROCYCLICCARBONYL ISOQUINOLINES

~~

R

-.3 A

-NwN-

Formula CI,H,,NzO

C,SH,,N,O

-

~~~

Mp or Bp ("C) 210-215/3-4 Torr

Ref.

94-95 (picrate) 174-175

390

140/0.001 TOKT

393

388,389

-CH2CH*CNH

C,,HzoNzO

93-94

388,389

substitution of the chloromethyl chloride to provide 443, which under reductive conditions is converted to 444. Using a large excess of a primary amine and allowing the reaction to undergo complete halide substitution yields 445 (Scheme 31).

Isoquinolints Bearing Basic Side Chains

188

I . HONH,’HCI, 2. Ac,O

43s

pcN NH,

HIS RCOCHzX

I

437

(R = H,CH,,or C ~ H S ) NH,NH,

ethand

438

A number of aliphatic and alicyciic mono- and diamino derivatives 448 of 1-substituted-3-bromomethyl-3-methyl-3,4-dihydroisoquinoline 447 were prepared by reacting methallylbenzene (446) with the appropriate nitrile in the presence of aluminum chloride and brominejg’ (also known as the Ritter reaction) (Equation 117).

189

IV. Isoquinolines Having Basic-Containing Substituents at C3 TABLE 91. 3-HETEROCYCLIC ISOQUINOLINES

R’

R

Formula

H

MP CC)

Ref.

CiiHnNiS

116-117

39 1

CI3HloN2Spicrate

150-151 184.5-185

391

173.5- 174 191.5- 192

391

C, BH ,N,S picrate

H

CinHiiN2

151.5-152

39 1

H

C22H14N6

221-222

392

H

C24H16N4

198-199

392

344-352

392

176-177

392

H

H

qND N

’

C16H1,N3

190


TABLE 9 I . (Continued)

R

R'

Formula ~~

MP ("C)

Ref.

H

C19H12N4

235-236

392

H

C15H10N4

278-279

392

H

C22H15N3

189-190

392

C17H16N2

Oil

394

1 53- 154

394

C6H5

C,H,

C20H14N2

(HCI)


443

191

445

444

RCN

AICI, Br,

u

446

447

R=CHIC,H, b R=CH, c R=C6H, 8

/WN" NR'R*

R 448

(1 17)


192

TABLE 92. 1 -CHLORO-3-METHY LA M I N 0 4 M ETH Y L (ISOQUINOLINES)(434)396

~~

~

R

R

Formula

Mp or Bp (“C) 159-160

n

65-66

-NWo

79-80

5

106-108

N

A

NwN-cH3

173- 175

67- 59

n NWN-coZEr -N

W

-OH

O

H

127- 128

110-1 12

02 I

n O W N -

z

901-WI

V

WI-SPI

O? N?Z H 613

n

-

13-L

'ON-S

HO wN 2

*ON5

CN-

O w N -

O ?N nzH 1 23

H

PSZ-ZSZ

PLI -ZL I 26-06

OC N 5 2 H 613

? s cc 22 O N H 3

l3

H

H

n -

H

I 11-601 -

H 13H

zOs N scHrz3

n H

HO-NwN

n

13H

8EZ 111-011 6EZ

sN I f H12 3

fH3-NWN-

ENCN-

13H. rNszH613 c

111

N 6z Hi t 3

H H

H


194

The reactive methylene at C3 of 4-hydroxyisoquinoline (449)was subjected to the Mannich reaction for the preparation of either 3-(aminoalkyl)-4hydroxyisoquinoline 450 or 451 398399 (Equation 118).

449

450

TABLE 94. 1-SUBSTITUTED-3-METHYL-3-METHYLAMINOSUBSTITUTED-

3,4-DIHYDROISOQUINOLINES (438)397

R C6H5CH2

C6HSCH2

C6H&H2

R2

-NMe2

n

-NWo

-.3

C6H5CH2

C6H5CH2

--HN-OH

Formula

MP ec,

C20H24N2* 2HBr

225-227

C22H26N20. 2HBr

231-232

C2,H2,N2 * 2HBr

212.5-213.5

CZ2HZ6N2 *2HBr

195-197

C20H26N20

Oil

1V. lsoquinolines Having Basic-Containing Substituents a t C3

195

TABLE 94.(Continued)

R

R'

OH

n

-N

W0

-.3

Formula C, 5H3 N, 3H Br

239.5-240

CZ5H3,N,O-3HBr

228-230

C,,H,,N,

231

*

2HBr

C,,H,,N,O

C,,H,,N,

C,,H,,Nz C,,H,,N, dipicrate

8 0 "

MP C'C)

2HBr

-2HBr * H 2 0

- 2HBr - 3HBr

238 (dcc)

232-233 186- 187 119- 122

Oil

C14H22N20 C,,H,,N,

219.5-220

- 3HBr

207-209 114-1 I9

' y N ( E r ) 2

, ,,N 3 0 3HBr

C ,H

*

185-195

OH

Ph

NMe,

A "WO

164-166 and 212-214 (dec) C,,H,,N,

-2HBr

241-242

250-255 (dw) C,,H,,N,~ 2HBr

C26H3SN3

tripicrate

152-155 and 208-210 (dm)

Oil 197.5-199


196 TABLE 94. (Continued)

R

R’

Formula

C,,H,,N,

g-N(Et),

*

3HBr

131-136 (dw)

The preparation of 3-@-dimethylaminostyryl)isoquinoline methyl iodide (453) and isoquinoline 3-aldehyde-p-dimethylamjnoanilmethyl iodide (454) utilizes the reactive character of the 3-methyl substituent in 3-methylisoquinoline methyl iodide (452)400(Equation 119)

$/

’ N ‘

453

452 dine

NO

I

I‘ 454

The ring expansion of substituted 3-hydroxy-1-0x0-2-isoindolineacetic acid ethyl ester 456 was utilized for the preparation of a number of substituted 3-(2-irnidazoline-2-yl)isoquinoline-l(2H)-ones 458, which were examined for their CNS depressant activity4” (Scheme 32).

197

IV. Isoquinolines Having Basic-ContainingSubstituents at C3

FHzcozE‘

R%l

R%oH

Npiperidinc HI.HCI

NCHZCOZ Et

R

R’ 455

456

&heme 32

451

The exploitation of the tetrahydroberberine 459 as a starting material allows for the preparation of the CNS agent 3-(2-diethylaminoethyl)-4,5methylenedioxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoIine (460)402 (Equation 120).

& do O

CHJO

3. 2I N E ai ,ONHH CNBr

CHjO

CH3O

1

CHzCHZNEtz

CH30 459

460

(120)

Compounds structurally related to 2.2’-bipyridyl have high antimycoplasmal activity. The synthesis of a series of 3-(2-pyridyl)isoquinolines 463 with ortho substituents in its 2,2’-bipyridyl moiety proceeds from 2-phenylacetylpyridine 461. Bischler-Napieralski cyclization of the amide 462 and deprotection with triphenylphosphine in dimethylformamide provides 463. It was found that alkyl

198


substituents have an enhanced activity over the unsubstituted series, which may be due to variations in lipophilic, steric and electronic properties of these s u b s t i t u e n t ~(Equation ~ ~ ~ * ~ ~121). ~

@2'.. ZnIRCOOH NHzoH

3 . CH,I

46 1

&IO 7 N H

1 WCI,

CHI

R

2.p7 462

R

463

Treating the 3-chloroisoquinolines 464 with an assortment of primary or secondary arnines in refluxing toluene yields the isoquinoline-4carboxaldehydes 465 which then can be reduced to the alcohols 466.Converting these alcohols to the corresponding methyl chlorides with phosphorous pentachloride followed by treatment with primary or secondary amines provides the CNS derivatives 467405(Equation 122).

466

@

R'

467

IV. lsoquinolines Having Basic-Containing Substituents at C3 TABLE 95. I-SUBSTITUTED PHENYL-3-DIMETHYLAMINOALKY L-3,4-DIHYDRO-SUBSTITUTED ISOQUINOLINES*04

R H H 7-CI 7-F 7-CI 7-CH3 H 5-c1

H H H H H H H

R' H 2-F 2- F H H H

n

1 1

1

ClBH*ONZ C1aH19FNz C1aHiBCIFN2 CIBH19FN2

1

C18HlSCINZ

H

2

Cl9H22N2

4- F

2

C19H2,FNZ

C19H22N2

H

C19H21C1N2

4-a

&Me0 4-CH, 4-NOI

H

2-F

MP ("C)

Formula

CX9H21aN2

2

CZoH2,N20

2 3

C2,H2lN,O2 CzoH24N2

C20H23N2

C20H23FNZ

68

(Oxalate) 200 (2HCI) 150 98 100

90 (2HCI-H20)228 (2HCI) 200 (2HCI*H20)194 (2HCI) 210 (ZHCI) 200 (2HCI-H20)220 (2HCI) 185 (Dioxalate) 163 (Dioxalate) 138

199

Isoquinoiines Bearing Basic Side Chains

200

TABLE 96. 1-SUBSTITUTED PHENYL-3-AMINOSUBSTITUTEDISOQUINOLINE4 CARBOXALDEHYDES (4SS)405

R3

R'

R4

MP W )

Formula

n

-"wNH

H

H

147-148 ( H a ) 218

n

-NwNCH n

Z4-diCl

H

166-168 (HCI) 231

4-CI

H

182- 184 (HCI) 230

-NwN-cH n

H

6.7-diMeO

158-160 ( H a ) 214

H

6-CI

Oil (HCl) 212

H

H

( H a ) 270

H

H

(2HCI) >270

4-Cl

H

( H a ) 210

NwN-cH3 -N

n W0

H -NCHzCH,N

A

\p

CzH5 / H -NCHzCHzN,

C2H5

Oil

mi

IV. lsoquinolines Having Basic-Containing Substituents at C3 TABLE 96. (Continued)

a

I

-NCH

3 2

Formula

CH 3

/

CH 2 N,

'R

R3

R' H

H

CH i

A

-NwNcH3 A

H

6-CI

2-F

H

-2CH3

H

C20H23N30

C21H7. t a N 3 0

MP K) Oil (HCI) 195 185-187

( H a ) 240

-NwN-CH3 A

-"WN A

C22H23N30

166-168

H

H

C28HZ7N30

(Ha) 188

H

H

C22H2SN30

73-14

-NwN-CH-c6H5 /C2HS H -NCHZCH2 N, CzHs

143-146 (HCI) 235


202

TABLE 97. I-SUBSTITUTED PHENYL-3-AMINOSUBSTiTUTED ISOQUINOLINE4METHY L ALCOHOLS (456)*05

R'

R*

R3

Formula

MP ("C)

H

H

179- 181

2.4-diCI

H

109-116 ( H a ) 238

n

4C1

H

169- I72 (HCI) 238

n

H

6.7-diMe0

164-170 (HCI) 230

A

H

6-CI

202-205 (HCl) 254

A

H

2-F

140-430 (HCI) 229

H

H

102-104

H

H

109-110

CPyridyl

H

210-215

-"wN-

-NwN-cH

-NwN-cH -NwN-cH3 A

-NWN-c4 N -HCH2

C2HS

/

CH2N

\

CzHS

n

-NwN-cH

203

IV. Isoquinolines Having Basic-Containing Substituents at C3 TABLE 98. I-SUBSTITUTED PHENY L-3-AMINO-SUBSTITUTED.CSUBSTITUTED AMINOMETHY LISOQUINOLINES (457)405

R'

RZ

-NHCbH, A -NWNCHr

A

-"wNH n

-"wN'

n

CHI

-HNC H CH 2C H N/\ 2

2

R'

H

H

C2sH,,N,

Oil (dimakate) 167

H

H

C,,H,,N,

Oil (3HC1) 166

H

H

C ~ ~ H ~ S N 74-76 , (trimaleate) 158

2-F

H

C2,H3,FN,

H

6-CI

CZ6H3,C1N, Oil (trimaleate) 173

2-CH,

H

C27H37N5

Formula

CHI

H --NCH:CH?CH2N

/CHI \

CHI

H -NCH

-NWN-cH'

/CHI

,CH CH N

\

H -NCH,CH?CHzN

-NWN-cH'

MP C'C)

95-96 (trimaleate) 143

CHI

H /CH' A - N C H I C H I C H ~ N\ -NWN-cH ' CHI

n

R'

/CHI

\

CH3

Oil (trioxalate) 145

204

Isoquinolincs Bearing Basic Side Chains

V. ISOQUINOLINES CONTAINING BASIC SUBSTITUENTS AT C4 Isoquinolines bearing basic substituents in the C4 position are usually prepared from the appropriately substituted uncyclized precursors. Cyclization results in the introduction into the C4 position of the desired chemical moiety, which lends itself to a variety of functional-group manipulations for the purpose of creating the desired heterocyclic variant. Heating ethyl 3-amino-2-(3,4-dimethoxyphenyl)propionate(468)with formaldehyde and formic acid affords a good yield of 4-ethoxycarbonyl-6,7dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(469).Reduction of 469 with lithium aluminum hydride followed by heating with thionyl chloride yields the chloride hydrochloride 470, which can be heated with a variety of amines to provide 4-(substituted-aminomethyl)-2-alkyl-1,2,3,4-tetrahydroisoquinolines 471. Depending on the substitution, these derivatives have found use as analgesic, antiinflammatory, and gastric-juice-secretion-stimulating agents406 (Scheme 33). 4-(Benzylaminomethyl~I,2,3,4-tetrahydroisoquinoline(478) is the key intermediate in the synthesis of the azabenzomorphan 4-benzyl-3,4,5,6-tetrahydrolH-2,6-methanobenzo[e][ 1,3]diazocine (479). The first synthesis involves C02Et

CO2Et

I

I

ri,:

ri2

468

469

1

H2NR4R5

_R"H

R' &R !3

I . LIAIH, 2. SOCI,

R 1 J $ ! N R 3

R2

R2

471

470

R 1 = R 2 = O C H 3 or H ; R ' = C H ,

CHzCl

V. lsoquinolines Containing Basic Substitucnts at C4

205

heating a mixture of isoquinoline-4-carboxylicacid (472) with benzylamine at 160 “C, followed by treatment with phosphorous oxychloride to generate in good yield 4-benzylcarbamoylisoquinoline(473). Catalytic reduction of 473 followed by a metal hydride reduction of the amide affords 478. The second synthesis involves the benzoylation of 4-aminomethylisoquinoline (474), derived from 476, to provide 475, which is sequentially reduced to 478. Finally, the reduction4” of 4-cyanoisoquinoline (476) followed by a reductive amination of the resulting amine with benzaldehyde yields 478. When a mixture of 478, paraformaldehydeand benzene is refluxed for 40 min, a good yield of 479 is obtained4” (Scheme 34).

COOH

I

472

473

0

CHzNHz

I

0

\

I . PiOz/Hz 2. LLAIH,

HI1 CHzNCCbH5

I

w

C,H,CCI

474

H

CH~NCH~C~HS

I

2 LiAIH,

475

478

dN 476

479


206

Heating 480 with N,N-dimethylaniline in the presence of copper powder at 180-200°C affords a mixture of products from which 481 can be isolated. Subsequent decarboxylation and Bischler-Napieralski cyclization with phosphorous oxychloride yields l-phenyl-3,4dihydro-4-(dimethylaminophenyl)-6,7dimethoxyisoquinoline (48Z)408 (Equation 123).

' N '

CH3O cu 2. pyrrdine

480

CH30

@

481 POCI,,

Q cH30)Ql$ ' N '

J

I

CH30

482

As series of novel 3-amino-4-substituted aryl isoquinolines 485 and 3-amino4-substituted benzylisoquinolines 486 were prepared and evaluated for CNS depressant a c t i ~ i t y . ~The ~ ~ alkylation *~'~ of a-cyano-o-tolunitrile (483) with nitrophenyl halides or nitrobenzyl halides in the presence of potassium hydroxide in pyridine followed by a cyclization and rearomatkition yields 485 or 486 (Equation 124). Isoquinolines, such as 487, undergo alkylation at C4 with a variety of alkylaminoalkyl halides to provide 1,2,3,4-tetrahydro-3-isoquinolines488, which have been found useful as antispasmodic agents. Their quaternary salts are also valuable as germicides and disinfectants4' (Equation 125).

'

V. Isoquinolines Containing Basic Substituents at C4

LdN

483

207

eN

b

QNH2

R = NO:

R

x

485

I . base

2. RX

FN

484

X

487 n

488

R', R2

Formula

Mp or Bp ("C)

CZ,H,,NzO

(HZSO.) 241-242 (CH,I) 229-230

Cz2Hz,NzO,

136.5-138

CZ,H,,N,O ClzHz,NzO

Bp 187-199/0.03 Ton Bp 216-221/2.5 Torr

u

n \p

2

-N

2 2

Me CZH,


208

TABLE 99. 3-AMINO-e(AMINO-SUBSTITUTED ARY L)ISOQUINOLINES'09~410

x X

Y

n

H H H H Br H Br H

4-NHz 4-NHAc 4-NHEt 2-NHZ CNHZ 2-NH2 4-NH2 4NHt

0

MP ("C)

Formula

153-154.5 235-237 141-143 142- 143

0 0 0

175 (dec) 135.5- 137 > 170 (dec)

0 1 1 1

153-155

Basic substituted 1,4-dihydro-2H-isoquinolinederivatives 491 exhibiting anticonvulsant activity were prepared by the cyclization of either 489 or 490 with an appropriate aldehyde followed by an arninolysi~~'~ (Equation 126).

R4&(7 R3qx I . RCHO/P20, PPA

R4

RI

R*

R

489 ( X = C N ) 490 (X=COOH)

HOy

C

HO OH 492

0

O

NnOCl H

(126)

R'

"-")$ 49 1

H HO

O

HO

0 OH 493

T

u 494

HO OH 495

(127)

V. Isoquinolines Containing Basic Substituents at C4

209

Macrostomine (501), the main alkaloid of Papauer macrosromum Boiss et Huet,*14 contains a pyrrolidine ring at the C4 position of the isoquinoline The nucleus. A model for the biosynthesis of such alkaloids was de~eloped.4'~ oxidative decarboxylation of 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid 492 with sodium hypochlorite provided 493, which on condensation with N-methyl-A'-pyrrolidinium acetate (494) and subsequent aerial oxidation yielded 44 1-methyl-2-pyrrolidinyl)isoquinoline4% (Equation 127). A complete synthesis of macrostomine (501) has been developed in which both sides of the isoquinoline nucleus are attached by high-yield carbon-carbon bond formation with lithiated n i t r ~ s a m i n e s . The ~ ~ ~ 4-hydroxy-1,2,3,4tetrahydroisoquinoline 496, obtained in 63% overall yield from the Pomeranz-Fritsch reaction of veratryl aldehyde with a-aminoacetaldehyde acetal, is quantitatively nitrosated with sodium nitrite, doubly deprotonated, alkylated with 3,4-methylenedioxybenzyl bromide, and in situ denitrosated to provide, in 80% yield, a diastereomeric mixture of alcohols 497. N-Benzoylation followed by sodium hypochlorite oxidation affords the ketone 498, which adds lithionitrosopyrrolidine to give in 62% yield a diastereomeric mixture of 499. Denitrosation with Raney nickel provides 500, which after some nontrivial manipulations affords 501 (Scheme 35).

TABLE 100. I-ARYL4SlJBSTITUTEDl.4-DIHYDRO-2H-ISOQUINOLINES41z

X

R

X C6H5

H

H H H H H H H 6.7-diOMe C6H5 CNOzC6H4 6.7-diOMe 6,7-diOMe CPyridyl QNHZC6H4 6.7-diOMe C6H5

2ClC6H4 4diC1C6H3 4-N02C6H4 4-diC1C6H3 CCHSC6Ha 4-NHZCeH4

R' H H H H H H H H H H H H

-

R2

-CH?CH?N

3

Formula

MP CC)

CzIHZ4NzO

(HCI) 224-227 (HCI) 176-179 (HCI) 100-103 150-152 138- 139 133-137 113-115 245-248 169 212-21 3 171-173 (HCI) 183

210


I NaNO,

CH30

3

496 4 denitrosation

0 497 (80%)

I C6H,COCIIEt,N 2 NaOCl

CH30 CH,O

498

il

several steps

H C c30*NH 3 0

501

Sebcme 35

V. lsoquinolines Containing Basic Substituents at C4

21 1

TABLE 101. 1-(4-CH LOR0 PH E N Y L)-4&DISUBSTITUTED 1,4-D1HY DRO-2HISOQUINOLINES4*z

R

R

R2

R’

H

Q

Formula

MP (“c) 251-255

H

(HCI) 165-166

H

(HCI) 148-150

3

H

-CH>CH>N

H

-CHlCH2N

H H H H

-CH,CH,CH,N (Me), -CH,CH,CH,N (Me), -CHzCHzN (CZH,) --CH,CH,CHzN (Me),

H

-CH

3

2 CH 2-N

3

(HCI) 240-242

(HCl) 172-175 157-158 156-1 59 120 170-172 138-143

H

193- 196

H H H H 7-diOMe

112-114 227-229 (HCI) 202-205 119-122

212



R

R2

R'

A

H

H

&

Cz 1Hz,NzCIO,

-cH2CHzNWo A

H

H

Formula

-CH ZCH 2 N-N-CH

0 HI1

CH 2 CH 2 NC4

3

C,,H,,N,CIO

MP ("c) 239-245 (Oxalatc)

201-250

NT TTTT \ NY Hi

CH2 CH 2NC4

502

L POCI,

A

/-

504

RaNi

503

-

505

I PdlC 2HCI.

506

VI. Miscelkdneous Isoquinolines Having Basic Substituents

213

VI. MISCELLANEOUS ISOQUINOLINES HAVING BASIC SUBSTITUENTS Substitution of the 5, 6, 7, or 8 positions of isoquinolines with basic heteroatomic moities has been realized through diverse synthetic routes. Heating 1,3-bis(2-benzamidoethyl)benzene (502) with phosphorous oxychloride at 120- 130 "C for 4 hr affords 1-phenyl-6-(2-benzamidoethyl)-3,4-dihydroisoquinoline (503) without formation of the corresponding C8 isomer. Refluxing 503 with concentrated hydrochloric acid provides the free amine 504. Reduction with Raney nickel in ethanol yields 505, while further oxidation with palladium/charcoal and subsequent debenzylation generates S4" (Scheme 36). The Mannich reaction of 5-hydroxyisoquinoline (507) with 3-azabicyclo[3.2.2]nonane (508)in 37% aqueous formaldehyde yields 5-hydroxy-6-(3azabicycloC3.2.2Jnonanemethy1)isoquinoline (W),a compound examined for its potential antibacterial properties4'* (Equation 128).

507

508

The Mannich reaction of 7-hydroxyisoquinoline (510) with piperidine in formaldehyde and methanol generated 7-hydroxy-8-(1-piperdylmethyl)isoquinoline (511)419(Equation 129). H

HO 510

HCHO MeOH

HO

511

214


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Isoquinolinols and Their Hydrogenated Derivatives Osamu Hosbino, Hiroshi Ham, and Bunsuke Umezawa*

1. lsoquinolinols and Their Derivalives

A. Isoquinolinols and Their Ethers 1. Preparation a. By Ring Closure b. By Dehydrogenation c. By 0-Dealkylation d. By Substitution e. By 0-Alkylation and 0-Arylation f. By Miscellaneous Reaclions g. By 0-Acylation 2. Reactions a. The Reissert Reaction b. Reduction c. Oxidation d. Electrophilic Substitution e. Nucleophilic Substitution f. Miscellaneous Reactions 3. Properties a. General b. Clsoquinolinol c. 4.8-isoquinolinediol d. Dissociation Constants and Ultraviolet Absorption Bands of lsoquinolinols B. Quaternary Salts of Isoquinolinols and Their Derivatives 1. Preparation a. By Reaction with Alkyl Halides, Dimethyl Sulfate, and Alkyl pToluenesulfonata b. By Anion Exchange c. By Oxidation d. By 0-Dealkylation e. By 0-Alkylation and 0.N-Dialkylation f. By Miscellaneous Reactions

'Deceased May 24. 1988.

225

229 229 229 229 233 234 234 238 240 24 1 242 242 243 244 244 247 248 248 248 249 250 25 I 25 I 251 25 I 252 252 255 255 255

226

Isoquinolinois and Their Hydrogenated Derivatives

2 Reactions a. Reduction b. Oxidation c. Nucleophilic Substitution d. N-Dealkylation e. Miscellaneous Reactions 3. Properties a. pK, Values 11. Dihydroisoquinolinols and Their Derivatives A. 3,QDihydroisoquinolinolsand Their Ethers 1. Preparation a. By Ring Closure b. By Dehydrogenation (Oxidation) c. By 0-Dealkylation d. By Miscellaneous Reactions 2. Reactions a. Reduction b. Oxidation c. Nucleophilic Substitution d. Miscellaneous Reactions B. Quaternary Salts of 3,4-Dihydroisoquinolinolsand Their Derivatives 1. Preparation a. By Reaction with Alkyl Halides and Sulfonates b. By Anion Exchange c. By Ring Closure d. By Oxidation e. By 0-Dealkylation f. By Miscellaneous Reactions 2. Reactions a. Nucleophilic Substitution b. Cleavage of C=N+ Bond c. Reduction d. Oxidation Including the Cannizzaro Reaction e. N-Dealkylation 1. Miscellaneous Reactions C. l,2-,1.4, and 7,8-Dihydroisoquinolinolsand Their Ethers 1. Preparation a. By Ring Closure b. By Miscellaneous Reactions 2. Reactions a. Substitution b. Reduction D. 1,2-Dihydro-2-(p-tosyl)isoquinolinols and Their Ethers 1. Preparation a. By Ring Closure 2. Reactions a. Oxidation 111. Phenol Betaines A. Preparation 1. By Oxidation 2. By Base B. Reactions 1. 1.3-Dipolar Cycloaddition 2. Reduction 3. Cleavage of Dimeric Phenol Betaine

258 258 260 261 264 265 265 265 266 266 266 266 267 268 269 270 270 210 271 272 274 274 274 274 274 275 277 277 280 280

284 285 285 287 287 287 287 287 287 289 289 289 290 290 290 290 290 290 290 290 290 293 293

294 294

Isoquinolinols and Their Hydrogenated Derivatives IV. Tetrahydroisoquinolinolsand Their Derivatives A. I,2,3,4-Tetrahydroisoquinolinols and Their Ethers and Esters 1. Preparation a. By Ring Closure b. By Reduction c. By 0-Dealkylation d. By 0-Alkylation and 0-Arylation e. By Miscellaneous Reactions 2. Reactions a. N-Alkylation and N-Arylation b. Oxidation c. C-Alkylation B. 2-Acyl (Aroylk and 2-Arene (Alkane)sulfonyl-l2.3,4-tetrahydroisoquinolinols and Their Ethers 1. Preparation a. By Ring Closure b. By the Schotten-Baurnann Type Reactions c. By 0-Alkylation d. By Miscellaneous Reactions 2. Reactions a. Reduction b. Oxidation c. Condensation d. Nucleophilic Substitution C. 5,6,7,8-Tetrahydroisquinolinols and Their Ethers 1. Preparation a. By Reduction b. By Substitution 2. Reactions V. Octahydro- and Decahydroisoquinolinols A. Preparation I. By Ring Closure 2. By Reduction B. Reactions I . N-Alkylation 2. Oxidation VI. lsoquinolinethiols and Their Hydrogenated Derivatives A. lsoquinolinethiols and Their Ethers I . Preparation a. By Ring Closure b. By Substitution c. By S-Alkylation d. By 0-Alkylation and 0-Acylation 2. Reactions a. Reduction b. Substitution c. Miscellaneous Reactions B. I-Methylthioisoquinoliniurn Iodide I . Preparation a. By Methyl Iodide C. 3,4-Dihydroisoquinolinethiols and Their Ethers 1. Preparation a. By Ring Closure b. By Alkylation

221

295 295 295 295 297 300 301 302 304 305 305 306 307 307 307 308 309 309 310 310 310 31 I 312 312 312 312 313 313 314 314 314 314 317 317 318 318 318 318 318 318 319 320 320 320 32I 321 323 323 323 324 324 324 324

228

VII. VIII.

IX.

X. XI.

Isoquinolinols and Their Hydrogenated Derivatives 2. Reactions a. Nucleophilic Substitution D. 1,2-Dihydro-2-(ptosyI)isoquinolines I. Preparation a. By Ring Closure b. By Miscellaneous Reactions E. 1,2,3,4-Tetrahydro-2-sulfenyl-and 1,~3,4-Tetrahydro-2-sulfonylisoquinolines 1. Preparation a. By Sulfenylation b. By Ring Closure 2. Reactions F. Sulfoxides and Sulfones in Isoquinolines 1. Preparation a. By Oxidation 2. Reactions a. Nucleophilic Substitution Natural Products Pharmacology A. Quaternary Salts of Isoquinolinols and Their Esters B. Quaternary Salts of Alkoxyisoquinolines C. I-Alkoxy- and I-Aryloxyisoquinohes Carrying Basic Functions D. Alkoxy-3,4dihydroi~0quinolinesand Their Quaternary Salts and Their Ethers E. 1,2,3,~Tetrahydroisoquinolinols Analysis and Spectroscopy A. Analysis 1. Polarographic Analysis 2. Fluorirnetric Analysis 3. Chromatographic Analysis a. Paper Chromatography b. Thin-Layer Chromatography c. Gas-Liquid Chromatography d. High-Performance Liquid Chromatography B. Spectroscopy I. Mass Spectrometry 2. Infrared Spectroscopy 3. Ultraviolet Spectroscopy 4. Nuclear Magnetic Resonance Spectroscopy Tables of Isoquinolinols and Their Hydrogenated Derivatives Tabks of Isoquinolinethiols and Their Hydrogenated Derivatives References

324 324 325 325 325 325 326 326 326 327 328 329 329 329 329 329 330 331 33 1 332 333 334 336 339 339 339 339 340 340 341 341 341 341 341 347 360 372 400 504 514

1. lsoquinolinols and Their Derivatives

229

I. ISOQUINOLINOLS AND THEIR DERIVATIVES A.

lsoquinolinols and Their Ethers

I.

Preparation

a. By Ring Closure The Pomeranz-Fritsch reaction of the Schiff bases, derived from benzaldehydes and aminoacetals, is performed by use of acidic reagents such as concentrated sulfuric 73-82% sulfuric phosphoryl chloride/polyphosphoric acid,".' polyphosphoric acid,' boron trifluoride/trichloroacetic,14 trifluor~acetic'~ anhydride, and chlorosulfonic acidl6*" to give the following compounds: 7-2*4*6*'8 and 7 - m e t h o ~ y - 8 - ' ~isoquinolinols; ~'~ and 7-methoxy-,1.3.4.7.8.17.19 7-eth0xy-,'*~ 7-butoxy-,15 6,7-1nethylenedioxy-,~*~ 6,7-dimetho~y-,'~*~~~~~-'~ 7,8-methylenedioxy-,9 and 7,8-dirnetho~y-~*'~-'~ isoquinolines. Another type of Schifl base (I), derived from a benzylamine and glyoxal hemiacetal, also goes into the reaction with 76% sulfuric acid affording 7methoxyisoquinoline (2).3

'

'

2

1 srbcme I

The direction of cyclization is generally to the para position of an activating group. However, cyclization ortho to a hydroxyl group is observed giving a low yield of 5-isoq~inolinol.~ A further exceptional cyclization occurs meta to a methoxyl group leading to 6,8-dimethoxyisoquinoline.20 The secondary amine derived from Schiff base of the common type undergoes cyclization to initially form the 1,2-dihydroisoquinoline,(see this Chapter, Section 1I.C.1.a) which is so unstable in the acidic conditions (concentrated sulfuric acid or 6N hydrochloric acid) that oxidation or disproportionation an isoquinotakes place concomitantly, yielding 6-methoxy-7-isoq~inolinol,~~ line dimer, and 1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol.2 6,7-Dimethoxy i ~ o q u i n o l i n e ~is~ the * ~ 'sole product when the same cyclization is conducted in the presence of an oxidant, arsenic acid.

230

Isoquinolinols and Their Hydrogenated Derivatives CH3 0

752 HISOL 0’

CH30

- r.t. -~

-

C H 3 0 ~ ~ N 0 c z H 25 ) conc.

HC1

or conc. HISOL

CH30

CH,O

arsenic acid

looo

CH3O

Scheme 2

Sulfonamides of similar secondary amines undergo a Pomeranz-Fritsch reaction and successive elimination of p-toluenesulfinic acid when heated with 6N hydrochloric acid in dioxane or treated with potassium tert-butoxide in tert5,8-dimethbutanol yielding 7-methoxy-8-isoquinolinol,245,7-dimetho~y-.~~ OXY-,5 ~ ,~6 , 7 - t r i m e t h o ~ y , ~6,7,8-trimetho~y-,~~ ~-~~ 7 - m e t h o ~ y - , ’ ~7,8-dim.~~-~~ 5 , 7 - d i b e n ~ y l o x y - , ~ 7,8-di~-~~ e t h o ~ y - , ~8-benzylo~y-7-methoxy-,~~~~’-~~ ~.~~ isoquinolines. b e n z y l ~ x y - , and ~ ~ *6-methoxy-7-(8’-isoquinolyloxy)34 ~~

1

bN HC1 dioxane b

1,2-Dihydro-2-(p-tosyl)isoquinolines[see Section 1I.D.La), the initial products of the reaction, are isolable by quenching at proper stages. As another modification of the Pomeranz-Fritsch reaction a Schiff base reacts with ethyl chloroformate followed by trimethyl phosphite to give the intermediate carbamate phosphites (3), which are treated with titanium tetra-


23 1

TiCL CHClj

scheme 4

chloride in boiling methylene chloride to form isoquinolines. Thus, 6-, 7-, and 8methoxy-, 6,7-dimethoxy-, and 6.7-methylenedio~yisoquinolines~~ are obtained. 6-Methoxy-7-isoquinolinol is also produced without any protection of the phenolic hydroxyl group.” The modified Pictet-Gams variation of the Bischler-Napieralski reaction (5)36from Nmakes it possible to prepare 6-benzyloxy-7-methoxyisoquinoline [2-(3‘-benzyloxy-4’-methoxyphenyl)-2-methoxyethyl]formamidine (4).

POCl,

toluene A

CH3O

3

4 sfhelw 5

The Cope reaction is applied to cotarnine oxime (6), phenylhydrazone, semicarbazone, t hiosemicarbazone, and benzoylhydrazone. Thus, on refluxing, with 46-50% potassium hydroxide in the presence of potassium cyanide, they are transformed to 8-methoxy-6,7-methylenedioxyisoquinoline(7).37*38

{Ip CHZNOH

6

CaHsOH KOH-KCN

A

scheme 6

-r

(OWN 0

CH30

7

Isoquinolinols and Their Hydrogenated Derivatives

232

By similar treatment of symmetric cotamazine (8). compound (9) or (lo), 8methoxy-6,7-methylenedioxyisoquinoline(7) and norcotarnine (11)38 are produced.

7

CH3b 50% KOH aq.

0

CH3O

0

KCN n-CcHeOH Ha0

*

+

h

CH3b

11

scbeme 7

Cyclopalladated imines (12) give rise to 7- and 6,7-dimetho~yisoquinolin~.~~ In this case, no 6- or 8-methoxyisoquinoline is formed.

12


233

b. By Dehydrogenation 3,4-Dihydroisoquinolyl ethers and 3,4-dihydroisoquinolinolsundergo dehydrogenation with 5%40.41 and 1 * 4 2 * 4 3 palladium on carbon, palladium b l a ~ k , 33% ~ ~ .palladium ~ ~ asbe~tos,~'or Raney nickel and napthalene.46*47 Similarly, with 10-30% palladium on arbo on^^*^^.^^-^^ or Raney nickel and na~hthalene,~ dehydrogenation of 1,2,3,4-tetrahydroisoquinolinesis achieved. A 1-(2'-picolyl)-3,4-dihydroisoquinolylether is dehydrogenated when heated with palladium on carbon in a sealed tube." Thus, the following isoquinolines are yielded: 6-metho~y-7-~ and 7-meth0xy-8-~~isoquiniolinols; 5,6-dimethoxy-,4O 5,6,7-trimetho~y-,~~ 5,8-dimetho~y-,~'6-rnetho~y-?~*~' 6,7-di6,8-dimetho~y-,~~ and 7,8methoxy-,lO*' 1-45.47 6,7-methylenedio~y-,~~~~~ d i m e t h ~ x y isoquinolines. -~~ l q 4

CH30

10% Pd-C, Pd-black. or Raney Ni-naphthalene

-

CH3O

Dehydrogenation of 1,2,3,4-tetrahydro-4-isoqunionolinol(l3) with palladium black proceeds to yield 4-isoquinolinol (14),53 whereas a rlhydroxyl group in most 1,2,3,4-tetrahydroisoquinolylethers tends to be removed when dehydrogenated with palladium on carbon. Thus, 5,6,7-trimetho~y-'~ and 7,8-dimethO X Y - isoquinolines ~ ~ are produced. Dehydrogenation with gaseous formaldehyde in a dried protein layer of 1,2,3,4-tetrahydro-4,6,7-isoquinolinetriol yields 3,4-dihydro-4,6,7isoquinolinetriol, which is dehydrated to 6,7-isoqunilinediol with warm dilute hydrochloric acid55 (see Section IX.A.2). OH

-

OH

Pd-black

13 CH3 OH CH3O cH30&NH

102 Pd-C

p-cymene

0

14

C H . ; S N CH,O

234


1,2,3,4-Tetrahydro-7,8-dimethoxy-4-isoquinolinol(15) undergoes dehydrogenation with N-bromosuccinimide to presumably furnish 3,4-dihydro-7,8dirnethoxy-4-isoquinolino1,which is readily transformed to 7,8-dimethoxyisoquinoline (16)56on treatment with 6N hydrochloric acid. In contrast, dehydrogenation of 6,7-dimethoxy-2,3-dihydro-4( 1 H)-isoquinolinone (17) with 5% palladium on carbon yields 6,7-dimethoxy-4-isoquinolinol ( 18).s7

CH3Oe CH3

N

15

H

1.

N-bromosuccinimide

2.

6N HC1

CHCl,

CH3O CH3O

16

-

cH301&H

5X Pd-C

CH30

toluene A

17

18 scheme 11

Oxidative or photochemical dehydrogenation of 1,2,3,4-tetrahydroisoquinoline and its derivatives with 5% potassium permanganate in acetone4’ or ultraviolet irradiations8 gives 7,8- or 6,7-dimethoxyisoquinoline. c. By 0-Dealkylation 0-Demethylation of phenolic methoxyl groups is accomplished by heating with 48% hydrobromic a ~ i d ~ ~or *57% ~ ’ hydroiodic20 * ~ ~ acid. 6-Isoquinolare produced in this way. 44pino148.59 and 6,8-isoq~inolinediol~~*~ Tosy1oxy)isoquinoline(19) is converted to 4-isoquinolinol( 14)60*6’through the agency of 38% sulfuric acid or caustic alkali. An unusual 0-demethylation is known. Specifically, heating 4-methoxyisoquinoline (20) with sodium methoxide in methanol leads to 4-isoquinolinol (14)62 as its sodium salt.

’

d. By Substitution

Electron-withdrawing groups at the 1 position of isoquinolines greatly en1-~b -r ~~ ~m o - , ~ ~ hance the electrophilic reactivity of the site. Thus, l - ~ h l o r o - , ~ 1-nitro-,78 l - ~ u l f i n y l - and , ~ ~ l - s ~ l f o n y i -isoquinolines ~ ~ ~ ~ ~ react with sodium or potassium alkoxides to produce 1- a l l y l ~ x y - ,l~ ~- m e t h o ~ y - , ~ ~ * ~ ~ * l - e t h o ~ y - , ~l -~i s.o~p~r ~ p o x y - , 1-(2’-dimethyIaminoetho~y)-,~~*~~ ~~ 1-[2’(di-nbuty1amino)ethoxy]-,63*6s*661-(3’-pyridyIo~y)-,~ 1-( 3’-quinoIylo~y)-,~ 6,7dimethoxy-l-(2’-dimethylaminoethoxy)-,64 6,7-dimethoxy-l-(4-N-methyl-

'""mN -

1. Isoquinolinois and Their Derivatives

235

48% HBr

n

19

202 alkali

OH

14 n

20

OA r

Ar=

-@

"2'

ZH 5

Q

Scheme 13

piperidyl~xy)-,~~ 1,4-diethox~-,~~ and 1 -(2'-dialkylaminoethoxy)-4-alkoxy-7 isoquinolines and l-(3'-alkylamino-2'-hydroxypropoxy)isoquinolyl ether^.'^ The fact that 1 -chloroisoquinoline is less reactive than 1-bromoisoquinoline is well reflected in their reaction with phenols. Consequently, reaction of the

236


former" requires Ullmann reaction conditions (cuprous oxide and potassium carbonate), whereas the latter" does not. Since 3-chloroisoquinoline is envisaged as a vinylog of 1-chloroisoquinoline, it enters into reaction with sodium methoxide or ethoxide to yield 3-rneth0xy-'~ or 3-eth0xy-,'~ isoquinoline. Analogously, 3-(4-carbethoxyphenoxy)isoquinoline8'is produced. In this case, however, cupric oxide is needed as a catalyst.

Scheme 14

On the contrary, 4-bromo- and 5-bromo- or 5-iodo-isoquinolines exhibit significantly reduced reactivity compared to benzene analogs toward nucleophilic attack by sodium alkoxide, hydroxide, or phenoxide. The presence of catalysts such as copper,8s cupric copper bronze-cupric sulfate,86 azoxybenzene, nitrobenzene, dinitrobiphenyl, and l,l-diphenylethylene62is indispensable to ensure the reaction. This method has been used to produce 4-isoquinolinol (14),864-methoxy (20)-.6' and 4- and 5-(0-methoxyphenoxy)-~~ isoquinolines. An unusual reaction of 1-bromoisoquinoline with quinoline 1-oxide is reported to give 1-(3'-quinolyloxy)isoquinoline.82'B7~88 Alkali fusion of isoquinolinesulfonic acids proceeds normally. In this way, 5-,6790-98 7-,94 and 8-59*90isoquinolinols are obtained. 4,8-isoq~inolinedioI,~~ 5-Aminoisoquinoline is transformed to 5-isoquinolinol by three routes: diazotization followed by hydrolysis with hydrochloric acid92.99or with concentrated sulfuric acid,"' hydrolysis with concentrated hydrochloric acid in a , ~ ~ the sealed tubeg2 or 85% phosphoric acid at an elevated t e m p e r a t ~ r eand Bucherer reaction with 20% sodium bisulfitelO1(see Section I.A.2.e). 5,8-Isoq~inolinediol''~is accessible by nitrosation of either 5- or 8-isoquinolinol followed by reduction of the nitroso function with iron and concentrated hydrochloric acid. Alternatively, oxidation of 5-amino-8- or 8-amino-5-

237

1. Isoquinolinols and Their Derivatives OCH3

NaOCHt CuCla

in a sealed tube b

20

@N

Br

scheme 15

OH

mN

1. NaNOL, d i l . HC1 2. Felconc. H C l

HO

OH

A

5 or 8

Scbeme 16

isoquinolinol with ferric chloride produces these compounds via the p-quinone rnonoxime or rnonoirnine. A chloro group at the 1 and 3 positions is reducible to hydrogen by catalytic or with reduction with palladium on carbon and potassium Raney nickel and sodium e t h ~ x i d e ' ~or ' triethylamine106 or by heating

cH30wN 10% Pd-CIHa

CH3O

CH

CI

KOH, &OH or

NaH.*HzO,

30w OCH,

c H 3 0 m CH3O

b

5% Pd-C/Hz KOH-CzH,OH

A

Scbeme 17

cH30QQ OCH3

238


with hydrazine hydrate.47 An iodo group at the 5 position is hydrogenolyzed with Raney nicke1.lo7 Thus, 8-isoquin0linol~~~ and l - p h e n ~ x y - , '3,6-di~~ methoxy-,lo4 3,7-dirnetho~y-,'~~ 4-ethoxy-,'06 6,7dimetho~y-,4'*'~~ 6,8-dimethoxy-," and 7,8-dirnetho~y-"~isoquinolines are obtained. 3-Acetoxyisoquinoline (22)'08 is derived from 3-aminosioquinoline (21) on reaction with isoamyl nitrite in acetic acid. I-CSHIIONO CHsCOaH

OCOCH

c

22

21 Scbme 18

e. By 0-Alkylation and 0-Arylation 0-Alkylation of 1(2H)-isoquinolinoneis accomplished with alkyl halides with to lead to l-methoxythe aid of a silver saltlog or potassium Io9 or l-[3"(l"-morpholinyl)propoxy]-1'0~''1 isoquinoline. The silver salt (23) enters into reaction with a-acetylbromoglucose (a-ABG) by boiling for a short time in anhydrous toluene giving 1-/?-(tetraacetylglucosyloxy)isoquinoline (25),'12 which is convertible to the a-anomer on prolonged treatment with mercuric bromide. 1-Ethoxyisoquinoline(24)behaves similarly, although its reactivity is much lower than that of the silver salt (23).Thus, the fl-anomer

W N-

/ 0-ABC

toluene

OAg

25

reflux. 10 min

no solvent,

50". 2 days

24 sfbeme 19

28 H

R-COCH,

OR HgBr, toluene

A

1.

Isoquinolinols and Their Derivatives

239

(25) is produced in 2 days by fusion of the two components under pressure, while the z-anomer (26) requires 4 days of heating in toluene.'13 Similarly, 0-

allyllation of 3(2H)-isoquinolinone with ally1 bromide is performed in the presence of silver arb on ate.'^ AgaCO,

W

H

O

W O C H 1 ( H a C H z

CH2=CHCH.Br DUF r.t.

Scheme 20

0-Alkylation of isoquinolinols in general is effected with diazomethl9 or phenyltriane,2 1.54.97.114- 1 18 an alkyl bromide or iodide and base,50*92*1 methylammonium methoxide120.'21 to yield 3-methoxy-,' l 6 4-methoxy-,' l 8 5 - m e t h o ~ y - , ~l 4~ "5-eth0xy-,~' 7-[Z-(carbomethoxy) ethoxy-,' 7-carbethoxymethoxy-.' l 9 6,7-dimetho~y-,~'.' l7 8-rnethoxy-," 5*1203121 8-benzyloxy-7m e t h o ~ y - and . ~ ~ 4,5,6,7-tetrametho~y-~~ isoquinolines.

Scheme 21

0-Silylation occurs also with N-trimethylsilyltrifluoroacetamide to give 5- or 8-trimethylsilyloxyisoquinoline.1z2 The Ullmann reactionlZ3 with aryl bromides under forced conditions or reaction with diaryliodonium bromides' 23 is used for 0-arylation. Thus

scheme 22

240


5-(7'-isoquinolyloxy)-, S-(p-formy1phenoxy)-, 5-(ptolyIoxy)-, 5-(p-methoxy)-, 7-(m-formylphenoxy)-, 7-(p-formylphenoxy)-, 'I-(ptolyloxy)-, 7-(p-hydroxy6-methoxy-7-(p-tolyloxy)-, and 6-methoxy-7-(pmethy1phenoxy)-, methoxyphenoxy)-isoquinolines'23 are produced.

f. By Miscellaneous Reactions Both alkali of papaveraldine (27) and lithium aluminum hydride treatment 12' of 1 1-benzoyl-1,2,5,6-tetrahydro-2,6-imino-8,9-dimethoxy-3benzazocin-4-(3H)-one (28)are reported to produce 6,7-dimethoxyisoquinoline.

cH30wN CH3O

t7 CH 3O cH30@@

28

Isoquinoline, on treatment successively with lithium aluminum hydride and oxygen, is transformed to 4-isoquinolinol (14).'

W N

1. LiAlH,, e t h e r

2. 01, CHC1,

-

mN OH

+

other products

14

On thermolysis of methoxyazabullvalene (29), 1- and 3-methoxyisoq ~ i n o l i n e s ' ~30~ as * ' well as azabicyclo C4.2.21 decatetraene (30)are produced. Hydrogenolytic debenzylation of 2-benzyl-4-hydroxyisoquinolinium chlorides over 10% palladium on carbon proceeds well to yield the isoquin~Iinols.'~'-''~

I. Isoquinolinols and Their Derivatives

Q

+

/

@Q

4

24 1

+

OCH,

woc

ao

20

Boiling a 1 -(2'-benzothiazolyl)-1,2,3,4-tetrahydro-6,7-dihydroisoquinoline-3carboxylic acid with 2N hydrochloric acid causes fission accompanied by partial dehydrogenation to produce 6,7-isoquinolinediol and 3,4-dihydro-6,7isoquinolinediol.' '' The formation of isoquinolines by acid treatment of 1,3-diazabiphenylene (31)'34 or by hetero-Diels- Alder reaction of disilylated iminoether (32)'35 with p-quinone is reported to give 1,3-dimethoxy-'34 or 3,5,8-tria~toxy-"~ isoquinoline.

[&CF3C0.H

CH30H r.t.

cH30Q@

31

(CH, ),C(CH,),SiO (CH,)

YCH2 1.

kH ,C(CH,),Si 0

2.

'0' cR3co@

(CH.CO)IO CHJCOIH A

OCti,

0COCH-j OCOCH,

Isoquinoline 2-oxide reacts with p-tosyl c h l ~ r i d e ' ~ ~to* yield ' ~ ~ 4-(ptosyloxy)isoquinoline, while reaction with acetic anhydride' 37 followed by hydrolysis yields 4-isoquinolinol(l4) and 1(2H)-isoquinolinone.Similarly, reaction of isoquinoline 2-oxide with ethyl benzoylacetate and acetic anhydride gives 4-acetoxyisoquinoline'3* and a 1 -alkylated isoquinoline. g.

By 0-Acylation

3-Acetoxyisoquinoline (22)'08.' 39 is derived from 3(2H)-isoquinolinone on acylation with acetic anhydride in 1N sodium hydroxide or boiling acetic


242

OCOCH,

(CH3CO)rO 1N NaOH

hN- WN OCOC6H!j

C.HsCOC1

OCOC6H,

OH

Scheme 27

anhydride, respectively. Similarly, 8 - b e n z o y l o ~ y -5,8-dibenzoyIo~y-'~~ ~~ isoquinolines are produced.

2. Reactions a. The Reissert Reaction Reaction of isoquinolyl ethers with benzoyl chloride and potassium cyanide10~11~25~L6~29~30-32.54.'40~' or aroyl chlorides such as p-methoxybenzoyl and cinnamoyl chloride and liquid hydrogen cyanide" gives rise to socalled Reissert compounds. 2-Furoy1, 2-thien0y1,'~' or p - t o ~ y l chloride '~~ and ethyl chioroformate' s3 also react. Additionally, isoquinolinols are liable to be 0-benzoylated under these reaction conditions. 5 4

CH30

CH3O CN

p- CH ~ O C ~COCl HQ

CH30

+

OH

Scheme 28

I. lsoquinolinols and Their Derivatives

243

b. Reduction Catalytic hydrogenation' O0 of 4-(p-tosyloxy)isoquinoline (19) over palladium on carbon causes detosyloxylation, while reduction of 4-isoquinolinol(l4) over Adams catalyst yields 5,6,7,8-tetrahydro-4-isoquinolinol.'00

-

OSOzCbH4CH3-

P

20% Pd-C/H.

&N

CaH,OH

19 Scheme 29

A high-pressure hydrogenation [3000 psi (lblin.')] of 5-isoquinilinol over in the presence of sodium hydroxide in ethanol9* is known to Raney nickel (W7) give 2-ethyl-decahydro-5-isoquinolinol(33).

OH

OH C,H,OH, Raney N i /NaOH Ha

A.

c

mN 100-fold) than the former.

94% DaSO.

1 4 5 ' , 15 min

14

/ D$$$D

hr

45 hr

D

D Scheme 42

NMR peaks in the medium are recorded as 6: 8.36 (s, C-I), 8.31 (complex, C-8), 7.82 (s, C-3), 7.87 (complex, C-5), 7.63 (complex, C-'), 7.55 (complex, C-6).

250

Isoquinolinols and Their Hydrogenated Derivatives OH

OH

OH 1N NaOD

-

145". 5 min

220 rnin

D

I4 scheme 43

It is notable that hitherto known electrophilic substitution reactions such as bromination,"O iodination,"' diazo coupling,16' and the Mannich reaction 167 as well as deuterium labeling take place most preferentially at the 3 position of 4-isoquinolinol(l4). Obvious reaction entities in these neutral (14), and anionic reactions are classified into three species: cationic (M), (36),depending on the reaction media employed. Furthermore, in neutraI medium, 70% of the isoquinolinol is believed to exist in a dipolar form (35) on the basis of tautomerization constant (K,[NH form]/[OH form] = 2.39)177,'82 measured by ultraviolet spectroscopic means; the constant is 3.76 in another report. 83

cationic Corm

34

neutral form

d i p o l a r form

35

14 %beme 44

b a s i c form

36

Thus, a calculation performed on the four possible forms by use of the highest molecular orbital (HMO) r n e t h ~ d ~ ~ ~ . approximately '~~.'~' parallels the chemical data displaying that n-electron density is in the decreasing order of C-3 > C-1 >C-8,7,6,5 in all cases and higher in basic than in acidic medium. A NMRlE4study also confirms the point. c. 4,8-1soquinolinediol Similarly, a deuterium labeling experiment of 4,8-isoquinolinediol in 1N sodium hydroxide-d indicates that the benzene ring possesses a somewhat enhanced reactivity that the pyridine ring; the deuterium exchange rate constants are in the order of K 7 > K3>KS>K1.179*180 This is consistent with the common belief that pyridine relative to benzene is inactive toward electrophiles. The deuterium content at the 1 position of the isoquinolinediol amounts up to 90% on 52-hr heating in the medium.

1. Isoquinolinols and Their Derivatives

@& I N NaOD

1 4 5 ' , 10 min

OH

13-52 hr

D OH

D

D

D

25 1

OH

I

-THF 2-3”

-

CH ’ 0 CH30

~

98 Scherne 101

N

~

&

3

Isoquinolinolsand Their Hydrogenated Derivatives

280

Sodium in liquid ammonia in the presence of ethanol cleaves the methylenedioxy group of cotarnine chloride with concomitant removal of one hydroxyl group to produce 3,4-dihydro-6-hydroxy-7-methoxyisoquinolinium salt.369

Heating of 3,4-dihydro-l -diphenylhydroxymethylisoquinolineZZ6with methyl iodide under pressure and an undetailed treatment of a l-benzyl-3,4-dihydro-2rnethylisoquinolinium salt203yield 3,4-dihydro-2-methylisoquinolinium salts.

2. Reactions a. Nucleophilic Substitution Since the electrophilic character of the carbon at the 1 position of 3,4-dihydroisoquinolinium salts is greatly reinforced by the positive charge on the nitrogen, pseudocyanides (e.g., 99) and pseudobases (e.g., 88 or 100)

are

readily

produced

on

treatment

of

the

salts with

potassium sodium

C y a n ~ ~ e 2 8 4 , 2 8 0 , 2 9 7 , 3 O 3 , 3 l 7 . 3 4 6 . 3 S 3 , 3 6 4 , 3 6 8 , 3 9 3 . 3 9 7 , 4 O S . 4 O 9 , 4 l ~ , 4 2 7 - 4 3 Oand

or potassium hydroxide212.254.3 10.3 13.~14,368.37S.307.391-393.397.407.408,412.416. 420*43 -433 or t~iethylamine,'~respectively. Cotarnine chloride is transformed to a pseudosulfide or hydr~sulfide.~'

cH30qN 1 CH3O

I

NaOH-Ha0

Scheme 103

The phenomenon that the pseudobase (101) turns yellow in polar solvents is due to the appearance of the quaternary ammonium species (102). Thus, the establishment of an between the carbinolamine (101) and the

28 1

11. Dihydroisoquinolinols and Their Derivatives

quaternary ammonium hydroxide (102) is widely accepted mainly on the basis of ~ ~ ~ -the ~ * 'measurement of electrical the ultraviolet s p e c t r o s c ~ p i c ~ ~ ~ -and cond~ctivity.*~~**~~ The former method also confirms that the pseudosalts derived from a pseudobase by the action of sodium hydrogen sulfide or sulfurous acid change into the true salts on dissolution in water.441Likewise, a pseudocyanide that is by no means e l e c t r o l y t i ~turns ~ ~ ~partly * ~ ~ to ~ a true cyanide on dissolution in

The polarographically active form442-444of cotarnine (86) and related substances is believed to be the ammonium cation even in strongly alkaline solution. A quantitative analysis of narcotine (39) in poppy capsules, opium, and its pharmaceutical preparations involves preoxidation of the alkaloid to cotarnine (86)and its polarographic estimation.445 Cotarnine chloride in slightly acidic to neutral aqueous solutions is extractable with various solvents;446isoamyl alcohol, l,Zdichloroethane, benzene or chloroform, and ether at pH 6.0-7.5, 5.5-6.5, 5.0-6.5, and 5.0-6.0, respectively. Moreover, the chloride in aqueous solutions, on reaction with diazosulfanilic acid, is photometrically determinable down to 50 pg.446 Polarography of the ~ h l o r i d e ' ~ *has . ~ also ~ ~ been determined. Hydrastine (40)when exposed to ultraviolet light for a short time is oxidized to hydroastinine (101). which displays blue fluoroescence"' by UV light. The whole operation is conveniently conducted on a filter paper. In a formal sense, the salt is regarded as a cyclic Mannich component. Thus, on the activated carbon, attack at the 1 position of various nucleophiles, including the Grignard reagents,1 20.2 20.248.262.2 6 5 . 2 86.40 2 -404.406.449 - 4 5 1 active methyls,147.356.357.359.366.368.397.4 12.414.452-464 and active methylene,274.289.317.323.465 organomelithium ~ o m p o ~ n d s , ~ ~ani~ , ~ ~ ~ . line:' 6*4 and r e s o r ~ i n o l .Reformatsky-type ~~~ reactionz89s32 1,469-47 or electroreductive a l k y l a t i ~ -n4 7~4~of~ alkoxy-3,4-dihydroisoquinoliniumsalts is also known. Intramolecular reactions of this type take place more readily. Thus, the Michael reaction of a 3,4-dihydroisoquinolyl ether hydrochloride with methyl vinyl ketone421first forms the 3,4-dihydroisoquinolinium salt (103) as an active intermediate, which then undergoes cyclization on treatment with sodium carbonate to yield the 1 1bH-benzo[a]quinolizidine (104).

'


282

CH,MgI

barium hydroxide >sodium hydroxide > potassium hydroxide on the basis of the determination of rates.430 e. N-DeaIkylation N-Dealkylation of 3,4-dihydro-Z-methylisoquinolinium methylsulfates occur with 7.5% potassium hydroxide,252although the results are unreliable.

f. Miscellaneous Reactions Hydrolysis of the acetoxyl group in the side chain of a 3,4-dihydroisoquinolinium iodide with hydrochloric acid followed by chlorination with thionyl chloride399proceeds normally.

CH3O

Scheme 116

Reaction of a 3,4-dihydroisoquinolinium salt with diazomethane produces an aziridinium salt, which is reductively cleaved with Raney nikel (W2) to give a ben~azepine.~'~ C.

1,2-, l,4, and 7,&Dihydroisoquinolino~ and Their Ethers

1.

Preparation

a. By Ring Closure The Schiff base generated from a benzaldehyde and diethyl aminoacetal, when reduced to the secondary amine, and cyclized with concentrated hydrochloric acid, produces dihydroisoq~inolines."~~ However, 1,2-dihydroisoquinolinols and their ethers undergo further reactions21*199*496-498 because of general instability (see Section 1.A.I .a). b. By Miscellaneous Reactions Reaction of 1,4-dihydro-3(2H)-isoquinolinonewith triethyloxonium tetrafluoroborate yields 3-ethoxy-1,4-dihydroisoquinoline (1W).499*500

lsoquinolinols and Their Hydrogenated Derivatives

288

cone. HCI

I

Scheme 117

109

Scheme 118

Ketalization of 7,8-dihydro-6(5H)-isoquinolinone (110) with ethyleneglycol in the presence of excess p-toluenesulfonic acid gives 7,8-dihydro-6-(/Ihydroxyethoxy) isoquinoline (1 1 as a by-product. The dihydroiso1)5013502

p" P-CH,C.H.SOsH benzene A

+

110

Scheme 119

N& '

11. Dihydroisoquinolinols and Their Derivatives

289

quinoline usually forms a methiodide, which is also obtained on quaternization with methyl iodide of 7,8-dihydro-6(5H)-isoquinolinoneethylene acetal (1 12) although not mainly.501~502

2. Reactions a. Substitution Aldehydes can be coupled to the 4 position of 1,2-dihydroisoquinoline,which is a typical cyclic enamine."j Thus, a 1,2-dihydroisoquinolyl ether reacts with 89 yielding a 4-benzyl- or phenacylb e n ~ a l d e h y d e or ~ ~phenylglyoxal,' ~*~~~ isoquinoline. 3-Ethoxy- 1,4-dihydroisoquinoline (109) is comparable to the 1 -ethoxy-3,4dihydro analog in its reactivity (see Section II.A.2.c). Thus, the former undergoes nucleophilic substitution with c y ~ l o p r o p y l a m i n eor ~ ~p-diethylarnino~ ethylamine.500

benzaldehyde

c HO H 3 C1- 0 m conc. H C 1 . A ! H HO 2

m" OCzHs

c1-

cyclopropylamine i-CaH70H. A

scheme 120

b. Reduction Sodium borohydride reductions01~s02 of 7,8-dihydro-6-(p-hydroxyethoxy)isoquinolinium methiodide yields octahydro-2-methyl-6(5H)-isoquinolinone ethylene acetal.

290


D. 1,2-Dihydro-%(ptosyl)isoquinolinols and Their Ethers

1 . Prepuration a. By Ring Closure Stability of 1,2-dihydroisoquinolinesis greatly enhanced by fixing the lonepair electrons of the nitrogen atom. As a result, a Pomeranz-Fritsch reaction of N-benzyl-N-tosylaminoacetaldehyde dimethyl acetals with 6N hydrochloric acid in boiling dioxane under nitrogen yields, 1,2-dihydr0-7-rneth-,’~~’~ 1,2-dihydr0-8,7-dimethoxy-,’~ 1,2-dihydr0-5,6,7-trimethoxy-,~~ 1,2dihyro6,7,8-trimetho~y-,’~ 1,2-dihydr0-6,7-methylenedioxy-,’~1,2-dihydro-7,8-dimeth~xy-.’~ 1,2-dihydr0-6,7-dimethoxy-,’~ 1,2-dihydro-7,8-dimetho~y-,~~ 8-benzyloxy-1,2-dihydro-7-methoxy,’4~’7*’9 and 7,8-diben~yloxy~’*~’ 24ptosyl)isoquinolines, which are spectroscopically well characterized (see Section I.A.1.a). Among others, the last six are sufficiently stable to allow recrystallization.

2. Reac I ions a. Oxidation The title compounds are readily oxidized to isoquinolines (see Section LA. 1.a).

111. PHENOL BETAINES A.

I.

Preparation

By Oxidation

Narcotoline (113), on oxidation with mercuric acetate in the presence of the disodium salt of ethylenediamine tetraacetate, yields a phenol betaine, tarconine (114).’14

2. By Base Tarconine (I 14) is also formed by heating 0-methyltarconine hydroxide (derived from its chloride on treatment with silver oxide) withSo4or without barium hydroxide216. A phenol betaine, cotarnoline (1IS), is produced when narcotoline (113)243*506*507 narcotolinediol (116), narcotolic acid (117), and narcotosoline (118)’14 are treated with ammonia or when 115 is hydrolyzed with 0.01N

Ill. Phenol Betaines

I

sot"*-,

g0

U

113

dCH 3

Hg(OCOCH,)

I

EDTA (disodlum s a l t ) 1% CH,CO.H

<w+ 29 1

'CH3

0-

114

CHaOH

NHs-H.0,

4

& r n 0N : c " 3

115 scheme 122

( ' y ' HC HOH 3

'OH

116 R 5 C H 2 0 H 117 R = CO,H

sodium hydroxide.214The structure of the phenol betaine is deduced by the fact that no reaction occurs with diazomethane or nitromeconine and that the values of its pK, (13.0) and p K , (9.15)closely resemble those (>13 and 9.58) of tarconine (114), apparently differing from those (- and 3.42) of O-methyltarconine hydro~ide.''~ 4-Hydroxy-2-[(E)-p-chlorocinnamoyl]isoquinolinium chloride also produces a phenol betaine,203 when treated with triethylamine. Treatment of 4-hydroxy-2-methylisoquinolinium iodide (119) with Amberlite IRA-401 gives rise to another phenol betaine, 2-methyl-4-oxidoisoquinolinium ( 1 2 0 ) . ~ ~ * The third phenol betaine is derived from 3,4-dihydro-6,7-dihydroxy-2methylisoquinolinium chloride with a calculated quantity of sodium hydroxide, excess sodium carbonate, or

292


&+ N Y H3

Amberlfte IRA-401 Ha0

CH3

I-

118

140 scheme 124

scheme 125

Since methylation of the phenol betaine with methyl iodide or benzylation with benzyl iodide411 takes place mainly at the 6 position, the structure is most probably 7-hydroxy-2-methyl-6-oxidoisoquinolinium, On oral administration of 1-(a-diazo)methylhydrocotarnines (121-I=), 3,4dihydro-7,8-dimethoxy-2-methyl-6-oxidoisoquinolinium (124), along with cotarnoline (115), is excreted as a major metabolite in the urine of male Wistar ratS.509,510

115

Scheme 126

I l l . Phenol Betaines

293

Moreover, treatment of a 3,4-dihydro-7-hydroxy-2-methylisoquinolinium salt with ammonium hydroxide410or potassium carbonate4’ * leads to the dimeric phenol betaine (125). HO

cH30

conc. SH.OH

HO

0 N.

c H i i W N < c H 3

CH3

c1-

125

c1Sebeme 127

B. Reactions 1. 1.3-Dipolar Cycloaddition 2-Methyl-4-oxidoisoquinolinium (120) enters into a 1,3dipolar cycloaddition r ea~t ion”~ with acrylonitrile and methyl acrylate yielding the endo-cycloadduct (126) or a mixture consisting of the exo- and endo- cycloadducts (127 and l a ) , respectively. CHl*CHCN

/---

THF, reflux

120

THF. r e f l u x

CN

128

294


Similarly, 4-hydroxy-2-(2’,4-dinitrophenyl)isoquinoliniumchloride leads to the regioisomeric cycloadducts [(129:130)] (1 : l), when boiled with phenylacetylene in acetonitrile in the presence of triethylamine.206 Other dipolarophiles that can be employed in these reactions are dimethyl acetylenedicarboxylate, diethyl azodicarboxylate, N-phenylmaleinimide, styrene, and acrylonitrile.

149

+ ITS ISOMER

130

Scheme 129

2. Reduction Cotarnoline (115) is reduced to the 1,2,3,4-tetrahydroisoquino~ine (131) by use of sodium amalgam and water.*I4

115

131

3. Cleavage of Dimeric Phenol Betaine The dimeric phenol betaine (132) is severed to its components when treated with an equivalent amount of hydroiodic acid408or methyl i~dide.~’’

IV. Tetrahydroisoquinolinols and Their Derivatives

295

I-

+

Scheme 131

IV. TETRAHYDROISOQUINOLINOLSAND THEIR DERIVATIVES A. 1,2,3,4Tetrahydroisoquinolinolsand Thew Ethers and Esters

I.

Preparation

a. By Ring Closure The Pictet-Spengler reaction allows easy access to these systems and uses methyla15' -521 and formalin as one carbon unit and generally aqueous hydrochloric acid of varying concentrations. The following compounds and 1,2,3,4tetraare prepared in this way: 1,2,3,4-tetrahydrod-metho~y-~~~ hydr0-6,8-dirnethoxy-~~~ 7-isoquinolinols; 1,2,3,4-tetrahydro-6,7-dimethoxy8-isoquinolinol(anhalamine~ 133);52 1,2,3,4-tetrahydro-6,7-isoquinolinedio1;519*5241,2,3,4-tetrahydro-4,6,7-isoquinolinetri0~;~~~~~~~~~~~ 1,2,3,4-tetrahydr0-4,8,7-isoquinolinetriol;~ and 1,2,3,4-tetrahydr0-5,6-dimethoxy-,~~~ Set hox y- 1,2,3,4-tetrahydr0-6-methoxy-,~ 1,2,3,4-tetrahydr0-6-methoxy-,~ 26* 528 - 530 -6-ethoxy-1,2,3,4-tetrahydr0-,~~~ 1,2,3,4-tetrahydro-6,7-methoxylenedioxy-,5 1 1 - 513.526.51 3 - 533 1,2,3,4-tetrahydro-6,7-dimethoxy-,5'7.5zo~526~53~~ 534-538 7-ethoxy-l,2,3,4-tetrahydro-6-methoxy-,s27 7-benzyloxy-l,2,3,4 tetrahydr0-6-methoxy-,~~'1,2,3,4-tetrahydr0-6,7,8-trimethoxy-,~~* and 6ethoxy-l,2,3,4-tetrahydro-7-metho~y-~~~ isoquinolines. A t times addition of acid is unnecessary. Consequently, heating of 4-alkoxy-3hydroxyphenethylamine hydrochlorides with formalin is enough to ensure the 542 and 7-ethoxy-1,2,3,4reaction leading to 1,2,3,4-tetrahydr0-7-methoxy-~~Ot e t r a h y d r ~ - ~ 6-isoquinolinols. ~'.~~~ Moreover, 3,4-dihydroxyphenethylamine

'

i

296


hydrobromide enters into reaction with formalin in ethanol at room temperature and, after a prolonged time, yields 1,2,3,4-tetrahydro-6,7i s o q ~ i n o l i n e d i o l7-3H-( . ~ ~ ~ +)-Norepinephrine reacts with formalin at pH 6 (1M A sodium acetate buffer) yielding 1,2,3,4-tetrahydro-4.,6,7-isoquinolinetriol.544 condensing agent is not necessarily required. Thus, 3,4-dimethoxy- and 3,4dihydroxy-phenethylaminesreact with 40% formalin at an elevated temperature or with gaseous formaldehyde yielding 1,2,3,4-tetrahydro-6,7dimethoxyis~quinoline~' and 1,2,3,4-tetrahydro-6,7-dihydroxyisoquinoline,sz4 respectively. Preferential cyclization occurs at the para position to an activating 0-function and the directing power of methoxyl group is likely to be stronger than that of h y d r o ~ y l , ~although ~' not conclusive. Whereas the benzyloxy group is deben~ y l a t e d ~ ' ~in. ~ the' ~reaction, ethoxycarbonyloxy remains intact.523

133 scbrme 132

A phenethylamine with an a-hydroxyl group is converted to the tetrahydroisoquinoline with no loss of the group. Thus, 1,2,3,4-tetrahydro-4,6,7isoquinolinetriols'8~szo~5zs~s4s~s46 is obtained along with a trace of the regioisomeric 4,7,8-tri01.~'~ Contrary to the general directing effect, two e ~ a m p l e s ~ ' ~where -~*~ the cyclization takes place at the meta position to an 0-function are reported, for l 6 and 1,2,3,4-tetrahydr0-7-~~~ isexample, 1,2,3,4-tetrahydro-5-metho~y-4-~'~*~ oquinolinols (134 and 135).

134

sebcme 133


297

A logical intermediate in the Pomeranz-Fritsch reaction, a 1,2,3,4tetrahydro-rtisoquinolinol,is virtually isolable by use of 6 N hydrochloric acid at room temperature or below. The following compounds are prepared in this way; 1,2,3,4-tetrahydr0-5,6,7-trirnethoxy-,’~1,2,3,4-tetrahydro-5,7,8-trimethO X Y - , ’ ~ ~ 1,2,3,4-tetrahydr0-5-methoxy-7,8-methylenedioxy-,~~~ 1,2,3,4-tetrahydro-6,7-rnethylenedio~y-,’~~~~~~ 1,2,3,4-tetrahydr0-6,7dimethoxy-,~~*~~~ and 1,2,3,4-tetrahydr0-7,8-dimethoxy-~~*~~*’~~ 4-isoquinolinols; 1,2,3,4tetrahydr0-7-methoxy-4,6-,~~~ 1,2,3,4-tetrahydro-6-methoxy-4,7-,s4s~550 and 1,2,3,4-tetrahydro-7-methoxy-4,8-54s-isoquinolinediols, and 1,2,3,4-tetrahydroand 1,2,3,4-tetrahydro-4,7,8iso4,5,8-,s48 1,2,3,4-tetrahydro-4,6,7,s46~sso*ss1 quinolinetriols. Hydrogenolysis of the tetrahydro-4-isoquinolinolsover 5- 10% palladium on carbon yields tetrahydroisoquinolines. For example 1,2,3,4-tetrahydro-7and 1,2,3,4m e t h o ~ y - 6 - , ~ ’ *1,2,3,4-tetrahydro-6-methoxy-7-,21*400~498 ~~~ tetrahydro-7-methoxy-8-z1~400~498 isoquinolinols and 1,2,3,4-tetrahydro-5,6,7t r i m e t h o ~ y - , ” * ~1,2,3,4-tetrahydr0-6,7-dimethoxy-,~’ ~~ 1,2,3,4-tetrahydro-7isoquinolines are m e t h ~ x y - , ~ ’ . and ~ ~ ’ 1,2,3,4-tetrahydr0-7,8-dimetho~y-~~ produced. Application of the Mannich reaction to the synthesis of 1,2,3,4-tetrahydro-78-isoquinolinolsis of synmethoxysS3and 1,2,3,4-tetrahydr0-6,7-dirnethoxy-’~~ thetic value. For instance, a mixture consisting of guiacol, formalin, and dimethylaminoacetal is first treated with 6N hydrochloric acid to effect the cyclization and subsequently subjected to direct hydrogenolysis over 5% palladium carbon, to produce the desired product.

HO

+ CHZO + NHzCHzCH(OCH,),

’.

6N”C1

2 . 5% Pd-C/Ha

,s c HO H

3

0

m

N

~

scheme 134

b. By Reduction

3,4-Dihydroisoquinolines are readily hydrogenated to the tetrahydoisoquinolines by catalytic (palladium on carbonz53or Adams c a t a l y ~ t , ’ ~ ’ ~metallic ~~~), (tin and concentrated hydrochloric a ~ i d ~of sodium ~ * ~amalgams32), ~ ~ , ~or ~ ~ reduction. Thus, the following compounds sodium borohydridez63~300~ss5*ss6 are produced: 1,2,3,4-tetrahydr0-6.’~~ 1,2,3,4-tetrahydr0-8-methoxy-6-,~~~ 1,2,3,4-tetrahydr0-5-methoxy-7-,~~~ 1,2,3,4,-tetrahydr0-6-methoxy-7-,~~~ and 1,2,3,4-tetrahydr0-7-methoxy-8-~~~ isoquinolinols and 1,2,3,4-tetrahydro-6,71,2,3,4-tetrahydro-6.7-methylenedio~y-,~~~~~~~~~~~ 7-ethoxydimetho~y-,~ ~.~~~ 1,2,3,4-tetrahydro-6-methoxy-,253 8-benzyloxy-l,2,3,4-tetrahydro-6,7-dimethO X Y - , ~ ’ ~ 1,2,3,4-tetrahydro-8-methoxyd,7-methylenedioxy-,z84and 6benzyloxy- 1,2,3,4-tetrahydr0-7,8-dimet hoxy 56 isoquinolines.

’


298

Since hydrogenation is nucleophlic in nature, hydrogen first adds to the pyridine ring of isoquinoline. Likewise, isoquinolines carrying electron-donating group(s) in the benzene ring are hydrogenated to the tetrahydroisoquinolines by catalytic (usually under pressure: palladium on carbonzfi7 or Adams 5s9) or metallic (tin and hydrochloric a ~ i d , ' ~ * ~ ' zinc * ' ' and hydrochloric acid,7 sodium and absolute ethanol? or sodium in liquid ammonia and methano1114)reduction.

O 'm N iBr@!Ni

C1-

NaBHL H.0,

C.C.

PtO,/H,(50

psi)

CaH,OH, r.t.

RO

WNH RO

R-H,

CH3 Scbcme 135

Thus, the following compounds are prepared: 1,2,3,4-tetrahydr0-5-,97.~~*~~~ 1,2,3,4-tetrahydr0-7-,"~ and 1,2,3,4-tetrahydro-8-l2'isoquinolinols and 1,2,3,4tetrahydr0-5-methoxy-."~ 1,2,3,4-tetrahydr0-6-methoxy-,~~~ 1,2,3,4tetrahydr0-6,7-dimethoxy-,'~~~~ 1,2,3,4-tetrahydr0-6,8-,~"~ 1,2,3,4-tetrahydro-71,2,3,4-tetrahydr0-8-rnethoxy-,~~~ and 1,2,3,4-tetrahydro-8methoxy-$3' metho~y-6,7-methylenedioxy-~~ isoquinolines. Chemical behavior of the hydroxyl or carbonyl group at the 4 position toward the catalytic hydrogenation over palladium on carbon is dependent on the reaction conditions. Whereas the hydroxyl group readily undergoes hydrogenolysis over 5% palladium on carbon in hydrochloric acid,s48 the 2-benzyl-2,3-dihydro-4(1 H)isoquinolinone (136) is reduced to a 1,2,3,4-tetrahydro-4-isoquinolinol over 5-10% Pd-C/H,

CHICO zH

CH3O

136 5% Pd-C/H,

CHJO

6N HCl. r.t.

Sebeme 136

CH3Od

N

H

HowNH

CH3O


299

5- 10% palladium on carbon in acetic Similarly, the propionate group at the 4 position undergoes no hydrogenolysis under the latter conditions.1

32.1 33

2-Benzyl-2,3-dihydro-6-hydroxy-7-met hoxy-4(1H)-isoquinolinone ethylenethioacetal undergoes both desulfurization and debenzylation to lead to 1,2,3,4tetrahydro-7-methoxy-6-isoquinolinol 32 when hydrogenated over Raney nickel. As is well known, palladium on carbon is an effective catalyst for Ndebenzylation. Accordingly, a 2-benzyl-1,2,3,4-tetrahydro-4-propionoyloxyisoquinolyl ether is hydrogenated over the catalyst in acetic acid to yield a 1,2,3,4tetrahydro-4-propionoyloxyisoquinolyl ether132-133or by high-pressure (33-80 atm) hydrogenation of 2-benzyl-tetrahydroisoquinolines'33*560- 562 over 10% palladium on carbon.

CH 3O

HO

w,

10% P d - C A i 2 . A

under pressure

scheme 137

- PNH CH3O

1,2,3,4-Tetrahydro-7,8-dimethoxy-4-isoquino~in0l~~~~~~~ is produced from the 2,3-dihydro-2-(p-tosyI)-4(lH)-isoquinolinone(137) on reduction with sodium bis(2-methoxyethoxy)aluminum hydride. Reductive hydrolysis of 2sulfonyltetrahydroisoquinolylether with the same reagent is also known to give 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, s65 The lactam carbonyl group of 3,4-dihydro- 1(2H)-isoquinolinones is reducible to a methylene group by use of sodium and absolute ethanol256 or lithium aluminum hydride.37.364,386,557 The following compounds are produced in and 1,2,3,4this way: 1,2,3,4-tetrahydro-6,7-dimethoxy-8-isoquinolinol264 1,2,3,4-tetrahydro-7-meth ~ x y -5,7~ 1,2,3,4tetrahydro-6-met h ~ x y - ,'~ OH

137 LiAlH,

dioxane

CH3O

0

60"

scheme 138

=, CH3b

300


tetrahydr0-8-methoxy-,~~~ 1,2,3,4-tetrahydr0-6,7-methylenedioxy-,~~~ 1,2,3,4tetrahydro-6,7-methylenedioxy-8-methoxy-,37 and 8-benzyloxy-l,2,3,4tetrahydr0-6,7-dimethoxy-~~~ isoquinolines. Optically active (-)-2-acetyl1,2,3,4-tetrahydro-4-isoquinolinol is formed from 2-acetyl-1,2,3,4-tetrahydro-4isoquinolinone by reduction with chiral bis(2,2’-naphthyloxyethoxy)aluminum h~dride.’~~ Although details are unknown, the treatment of 8-methoxyisoquinoline hydrochloride with sodium methoxide in methanol gives rise to 1,2,3,4tetrahydro-8-methox yisoquinoline. 2o c. By 0-Dealkylation 0-Dealkylation is achieved with concentrated hydrochloric acid under or by 36%s68 and 48%s19vs67 hydro20% hydrochloric 1,2,3,4-tetrahydr0-7-,”~ and bromic acid. Thus, 1,2,3,4-tetrahydr0-6-,~~~~~~~ 1,2,3,4-tetrahydro-8isoquinolinols and 1,2,3,4-tetrahydro-5,6-, 1,2,3,4tetrahydr0-6,7-,~26*567 1,l -dideuterio-1,2,3,4-tetrahydr0-6,7-,~’~and 1,2,3,4tetrahydr0-7,8-’~~.’~~ isoquinolinediols are prepared.

s c k

t39

Partial 0-demethylation is performed by 20% hydrochloric529 or 36% hydrobromicS6*acid under strictly controlled conditions and the fact that the steric factor (see Section 1I.A.l.c) plays in the reaction a decisive role is well reflected in the following transformations. The reaction of 1,2,3,4-tetrahydro6,7,8-trimethoxyisoquinolinol(anhalinine) (138) with 20% hydrochloric acid (139),569while yields mainly 1,2,3,4-tetrahydro-6,8-dimethoxy-7-isoquinolinoI

cH30mH 202 t l C l

A

CH30

CH36

138

CH30@!H

CH30

20%A ttclH N m ”

CHO IW HO N,

CH30

36% HBr 115’

*

“ “ HO

,:”

139

HO CH30QQH

HO

133


301

that of both the latter and 1,2,3,4-tetrahydro-6,7-dimethoxy-8-isoquinolinol proceeds smoothly to yield 1,2,3,4-tetrahydro-6-methoxy-7,8isoquinolinediol ( In accordance with the generality, 1,2,3,4tetrahydro7-metho~y-8-isoquinolinol~~~ is largely produced when 1,2,3,4-tetrahydro-7,8dimethoxyisoquinoline reacts with 36% hydrobromic acid. Hydrogenolytic 0-debenzylation with palladium on carbon is of some synthetic utility and 1,2,3,4-tetrahydr0-7,8-dimethoxy-6-~~~ and 1,2,3,4-tetrahydro6 , 7 - d i m e t h o ~ y - 8 - isoquinolinols ~ ~ ~ * ~ ~ ~ are prepared in this manner. (133)

O W N H

CH3O

Pd/Ha

F

CH30

CH30 Scbemc 141

d. By 0-Alkylation and 0-Arylation O-Methylation of the phenolic tetrahydroisoquinolinols with diazomethane proceeds normally, and 1,2,3,4-tetrahydr0-5-methoxy-,9~ and 1,2,3,4tetrahydro-6,7,8-trimetho~y-~~~~~~~ isoquinolines are produced. undergoes selecInterestingly, 1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol tive 0-acylation with 3,4,5-trimethoxybenzoic acid in polyphosphoric acid to produce 1,2,3,4-tetrahydro-6-methoxy-7-(3',4,5'-trimethoxybenzoyloxy)isoquinoline. 52 C HHO3 0 @ 3 N H

ArCOaH PPA, h

Ar

=

@:lHC CH30

Scbeme 142

A mixture consisting of 6-methoxy-7 and 7-methoxy-6-isoquinolinols (0.62 : is formed on methylation of 1,2,3,4tetrahydro-6,7-isoquinolinediol with catechol 0-methyltransferase. Likewise, 1,2,3,4-tetrahydro-4,6,7-isoquinolinetriolundergoes selective 0methylation to lead to 1,2,3,4-tetrahydro-6-methoxy-4,7-isoquinolinediol544 when incubated with brain or liver homogenate. Biologically, the 6-0-methyl and 7-0-methyl isomers are distributed in the three brain regions (striaturn, hypothalamus, and hippocampus) of the rat in a ratio of about 55:45.'"

302


e. By Miscellaneous Reactions

1,2,3,4-Tetrahydro-5-isoquinolinol9 7 * 5 5 7 and 1,2,3,4-tetrahydro-Smeth-

OX^-,^^*''^ and 6-benzyloxy-1,2,3,4-tetrahydro-7-methoxy-,’ ”*’ 5 6 isoquinolines

are produced on hydrolysis of their 2-formyl, 2-acetyl, or 2-carbethoxy derivatives with 3N and concentrated hydrochloric acids or sodium hydroxide.

conc. HCl

b

N

Y

H

O

ref lux

*

Scheme 143

N-Oxides of 1,2,3,4-tetrahydro-2-phenethylisoquinolines7’ and N-fl-( 1,2,3,4tetrahydroisoquinoly1)propionic acidS7l and its ethyl e ~ t e r ’ ~ ’ . undergo ’~~ a Cope rearrangement yielding 1,2,3,4-tetrahydro-2-hydroxyisoquinoline.’71 - 573 In the case of the latter two, aqueous sodium hydroxide is necessary to bring about the reaction. Formation of the 2-hydroxyisoquinoline is also confirmed when 1,2,3,4-tetrahydroisoquinolinereacts with acetone and 1.5% hydroperoxide.572Additional evidence concerning the structure is ofTered by oxidation of the tetrahydroisoquinoline to a cyclic nitrone (see Section IVA.2.b). The borohydride adduct of 3,4-dihydro-6,7-dimethoxyisoquinoline(see Section 1I.B.1.f) is transformed to 1,2,3,4-tetrahydr0-6,7-dimethoxyisoq u i n ~ l i n ewhen ~ ~ ~boiled with concentrated hydrochloric acid in ethanol. conc. HC1 CIHSOH,

reflux

*

H I 3=’NH

CH3O

scheme 144

A methoxyl group flanked by two others in the benzene moiety of the tetrahydroisoquinolines is displaced by hydrogen on treatment with sodium in liquid ammonia. Thus, 1,2,3,4-tetrahydro-5,7- and 6,8-dimethoxyisoquinoli n e P 7 are yielded from 1,2,3,4-tetrahydro-5,6,7-and 1,2,3,4-tetrahydro-6,7,8trimethoxyisoquinolines, respectively.

Na/liq.NH,

CH30 cH30&NH

CH3O

Meme 145

1V. Tetrahydroisoquinolinols and Their Derivatives

303

Catalytic hydrogenation of the tetrahydroisoquinolines containing nitrogen substituents at the 1 Dosition over palladium on carbon in hydrochloric acid 1,2,3,4-tetrahydr0-6,7-dimethoxy-~~~ and 1,2,3,4-tetrahydro-6,7yields methylenedioxy-8-methoxy-405 isoquinolines.

cH30mv

CH30 102 Pd-CIH.

80% CHJOH

conc. HC1

c H 3 0 ~ N ~ ~ C H 2 ~ 2 C O C H ~ CH30

OCH3 schemc 146

The formers74 is also produced on photolysis of 1,2,3,4-tetrahydro-6,7dimethoxy-Z(p-tosy1)isoquinoline in the presence of sodium borohydnde and sodium carbonate.

Scheme 147

1,2,3,4-Tetrahydro-4-isoquinolinols3*s7s is produced on reductive cyclization of 2-(r-hydroxy-/?-nitroethyl)benzaldehydelactol with Adams catalyst. Deprotection of a 7-ethoxycarbonyloxy-1,2,3,4-tetrahydrois~uinoline with sodium hydroxide produces 1,2,3,4-tetrahydro-6,8-dimethoxy-7isoq~inolinol.'~~ Interestingly, bicyclic phenethylamine (141) reacts with N-methylmaleimide to give 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.s76 ( +)-2-Benzoyl- 1,2,3,4tetrahydro-4-isoquinolinol is shown to be produced by an enzymatic reaction of 2-benzoyl- 1,2,3,4-tetrahydroisoq~inoline.~~'

304

cH30m


6 W H 3

CH3O

+

0

_______c Ha0 50'

CH3O

2. Reactions Being a typical secondary amine, 1,2,3,4-tetrahydroisoquinolines undergo Nalkylation, N-nitrosation," ' 3 3 * 5 7 8 N-cyanat ion,' 78 N-formamidation,' 79*'80 and the M a n n i ~ h ~-m3 ~ ~ .or ' ~ the ~ M i ~ h a e 1 ~ reaction ~ ~ * ~without ~ ~ - ~ ~ ~ difficulty. Sn/HCl

N 7, F,, 450 nm, Em,, 370 nm), the presumed fluorescent entity of which is a phenol betaine, 2-methyl-6-oxoisoquinolinium.223 t-Methoxyisoquinoline in 95% ethanol also displays fluorescence (Fmaa 347 nm, Em,, 321.5 nm).742

OH 3. HC1-He0

c1-

CH3

scheme 218

3. Chromatographic Analysis a. Paper Chromatography

’

3,4-Dihydr0-6,7-isoquinolinediol,~ ’3’ 3.4-di hydro-6,7-dimethoxyisoquinoline, and hydr~chloride’~~ and alkyl iodides743of 3,4-dihydroisoquinolyl ethers can be chromatographically analyzed on paper. In a systematic R , values of the alkyl iodides show no linear correlation with number of carbon atoms in the alkyl group but increase with that of the solvent (butanol, 1pentanol, etc.) saturated with water.

IX. Analysis a n d Spectroscopy

341

b. Thin-Layer Chromatography Determination of 1,2,3,4-tettahydro- and 3,4-dihydr0-6-isoquinolinols~~~ (= (see Section IX.A.2), anhalamine (133) and anhalinine (138)668*67’*672 Section VII), and 1,2,3,4-tetrahydro-6,7-isoquinolinedio1606~744 on thin-layer plates is documented. Dopamine hydrochloride yields the diol on incubation with rat brain homogenate in the presence of 5-methyltetrahydrofolicacid.606 Retardation factor (Rf) values728of hydrochlorides of 6,7-dimethoxyisoquinoline and its hydrogenated bases or 1,2,3,4-tetrahydro-7-methoxy-6i s o q u i n ~ l i n o are l ~ ~recorded. ~ c. Gas-Liquid Chromatography Gas-liquid chromatography has been used for the detection of peyote663 and a n h a l ~ n i u m alkaloids ~~~ (see Section VII), 1,2,3,4-tetrahydro-6,7isoquinolinediolas an in vitro metabolite597(see Section IX.A.3.b), and tetrahydroisoquinoline alkaloids formed in the nervous tissues by the condensation of norephinephrine with alcohol metabolite^.^^^*^^^ d. High-Performance Liquid Chromatography This type of chromatography is useful for determination of alkaloids. Conare rapidly detersequently, hydrochlorides and tetrahydroi~oquinolinols~~~ mined by use of ion-pairing reverse chromatography in conjuction with electrochemical detection. Retention time (Rt) values of 6,7-dimethoxyisoquinolineand its hydrogenated bases have been determined.728

B. Spectroscopy 1.

Mass Spectrometry

Mass spectrometry of isoquinolinols, isoquinolinethiols, and their hydrogenated derivatives has not been studied systematically. This restricts its application only to detect molecular ions. Gas-liquid chromatography-mass spectrometry was discussed elsewhere (see Section VII).

h,

Cl- * 1.5H20

c1-

II-

1I11-

' Doubly char@ ions with m/z.

m/z (Relative Intensity)

188(M')b(l kO),173(M' -15)(14+7), 159(Mi-29){6&1). 156(5+2), 142(100*0) M2(M 'y( 1 20). l87(M '- I5)(9rl: 3). 170(4f 3h 159(M -43)( I 2 rl: 2). 142(100+01, I88lM 'T(l1 k I). 173(M - 15)(35k 3), 159IM - 29)(65f8), 156(69* 7), 142(92f 1I) 202(Mt)b(16+2), 187(M'-l5)(18kl), 170(22*3), 159(M+-43)(84* 12). 142(100~0) 202(M ?(2 & 1 ) , I 73{M - 29)(100 f 0). 156(88f9) 216(MtT(2f), 173(M+-43)(100*0), 170(46* 11) B 5 t M ' + 1)(7).2M(M t)(C,~H140z)b(10), l89{100).188(62) 326(M++1)(44). 325(Mt)(C,,H,,NO,)b(55X 320(M'- 15)(24),319(M+-1 -15) 122). 279(Mt - l5-31)(21), 204(21). 190(100~188(23), 176(8.8), 147 (5.9),162'(8), 161SC(60),155'(3), 154'(3)

145(M+p(89), 118(17). 1 17(loo), 1 16(1I), 104(28),103(1l), %(SO), 89(42) 159(M'P(94), 158(100),130(53),129(63), 116(26), 102(29), 89(M), 63(26) 217(Mf)"(72),202(lOO) 217(M+)'(62), 202(100) 272(M'Y(100),271(Mt -1)(16),245(7).244(17), 243(17), 128(9), 116(10), lOl(12) 251(M'Pt100), 252(M'+ 1)(17),250(15).234(8),222(18),145(37),129(17), 116 (19),106(22),101(14),89(119),79(24),77(14) 189(M')"(100), 174(Mi - 15)(14),147(70) 189(M'P(i00), 174(M'- IS)( 15). 146(M -43) 174(M' - 15),158(29),145(44), 129(38), 116(22),103(19), 95(45),89(10).75(10). 63(9),51(6) 207(82), 206(97),191(31),178(100), 163(25) 203(tCQ), 188(47),160(2),158(75),130(2),102(31)

The alkyl isoquinolinium ions without associated iodide.

' Parent peaks.

2-C,H,,6-CH,O, 2-C3H7,6-CH,O 2-CZH3.7-CHJO 2-C3H7,7-CH,O 2-C2HS36,7-(OCH20) 2+C3H7,6.7-(OCH10) 2-CH3, 6,7-(CH@), 2-CH3. 6.7-(CH30)z, 8-(p-HOCHZC,H,)

(b) Quaternary Salts of Alkoxyisoquimlines

7,8-(CH,O), 6,7-(OCHzO), 8-CH30

3-HO 3-CH3O 4-(CH 3),Si0 5-(CH3)3Si0 5-(7-isoquinolyloxy) ~~PHW H~C~H ~O )

+

(a) Isoquinolinols and Alkoxyisoquinolines

+

Anion

+

Substituent

+

TABLE 1. ISOQUINOLINES

+

762 762 762 762 762 762 763 763

292 41 41 510 510

760 83 76 1 76 I I23 I23

Ref.

~~~-~

pcaks without hydrochloride. Metastable ions. Parent peaks. AIkyl isoquinolinium ions without associated anions.

' Parent

(b) 5,6-DihydroisoquinolInc 5P75a1HO),

1-

2-CH,,7,8-(CH30), 2-CHa. 7-CH3O. 8-C,H,0

I-

I-

CI -

2-CH5,6,8-(CH,O),

(a)

3.4-Dihydroisoquinolinesand Their Quaternary Salts 5,6-(CH,O)2 H C1

Salf or Anion

r( r(

28 1

191(M 'P(l00). 190[14, 189.01(rnt)b], 176(79, l62.I8(1n*)~J. 16118, I47.28(m*)*], 149(8), 146(9),133(1I) ZOS(M')"(100). 190[26, 176.10(m*)b],177[11, 158.52(m*)b]. l76( 13). 162148. 148,27(m*).b138.1 3(m*)b] 191(M * 100). 176fM - 1S){SS). 164(61. 134(10) I9 1 (M 100L 176(27). 163(8) 297(M 'r(20). 284(4), 206(12), 167(10),120(15),91(100) I94(7), 193(M')d(60),192(M' - 1)(66). 191(6), 190(12), 177 ( 1 6). 151(12). I50(CqH,o02 )(100) W ( M - lY(23). 19L(M - 1 - 15)(l I). I l4( 16). 71(14), 69(!4). 59( 18). 58(27), 57(27), 55( 17). 43( IOO), 42( 1 I), 41 ( I 6) 191(M+-CH31)(]OD), 142(52), 127(57),77(23) 282(M+Y(2),230(7). 229(5). 218(24), 192(25), 191(1W), 190W).189(m*).b167(17), 143(3), 129.4(m8y 307(Mfr(31), 147(43),75(45). 73(100)

761

400

290

764

765 750

764

292

272

Ref.

mi: (Relative Intensity)

+

Subslituenf

+

TABLE 2. DIHYDROISOQUINOLINES

+

+

' Relative intensity is not described.

4-Oxido-2-(p-anisyl)isoquinolinium 6-Oxido-3,4-dihydro-7,8-dimethoxy2-methyliquinolinium &Oxido-3,edihydro-6,7-rnethylene dioxy-2-methylisoquinolinium (cotarnoline]

COxido-2-phenylisquinoliniurn 4-Oxido-2-(p-nitropheny1)isoquinoliniurn

Structure

TABLE 3. PHENOL BETAINES (Relative Intensity)

22i(lCO), 220(40), 193(26), 192(14), 165(19) 256(100),238(33), 220(12), 208(10), 192(27) 251 (71).250(29), 223(23), 222(13),2oS(IOO~ 221(36). 206(100), 192(4), 190(23), 180(5), 178(18) 211.'206(100) 205(100), 176(10), 164(81), 147(16)

m/z

767 510

510

766 766

766

Ref.

Salt

2-(CH,),CCO.6,7-IOCH~O~ 6.71CH30)zb 2*C,H5CO, 6,7-(CH,0)2 2-(CH,),CCO. 5.7-(CA30)2‘ 6974CH30)Z

2-CHjCO,4-HO 2-(CH313Si,4-(CH, ),SiO 4.6-(HO), 4,WHO)z 6.7-(HO)zb 4.6.7-(HO), 4.6.84HO), 4.7,8-(HO)3 6-HO. 7-CH3O 2-C2H,C0. 6-C2H,CO,,7-CH30 4-HO. 5,84CH,O), 2-CH3CO. 4-HO, 5,8-(CH,O), 4-HO, 484C,H,01, I-CHjO, 2-CeHSCHICO 7-CH30

HCIe HCI’ HCI

HCI‘

HCI

HCI HCI HCI

HCI HCI

m/z (Relative Intensity)

179(M’r(70). 178(67),163(24),lH)(100), 135(35),107(31),91(9) 471(9). 352(7). 32W1). 309(26), 308(33),297(14),296(100),277(7). 264(5), 253(6), 205(6) 209(M+)?d I%O(K@) 251(M+),’*d 190(100) 361(M’)”(4),360(2),341(4),332(7),270(tO),269(5),lS1(8),91(100) 281.45(M r(0.5) 163(M*):.d l34( 100) 163(M+p(60), 162(331, l35(17), 134(100), 119(8), I04(8),91(17) 261(M’r(100). 246.204.176,161, 148,57 194(M’ + 1)(28),193(M+r(100), 265(M +)(32),236(100) 277(Mtr(100),262,220, 192,177,176,164,57 193(M+y(90),l92(57). 178(9), 165(17),164(100), 149/34), 121(16) 193(M+)”(61.5),192(60), 176(11.5). 165(18), 164(100), 149(17). 121(19) 193(Mt)”(63),192(59), 176(14), 165(19.5), 164(100), 149(19),121(20)

331(2Mt +1)(4),330(2Mt)(5), 166(M++1)(90). 165(M‘r(100), 164(Mt -1)(19), 181(M’)”(13),164(67),162(75). 152(58), 151(65), 136(100) 181(M’)’(25), 180(9). 162(13),lSZ(l(M).123(48) 181(M+)”(19),164(42),162(77), 152(82),151(100),136(50)

173(86),148(9),IM(1001, 119(75),91(43) 203(46).202(45), 192I80).177(100).147(19),73(86) 165(M’)”(17),164(5), 146(39), 136(95),135(66),I07(100).77(60) 1651M*Y(23),164(4). 146(41),136(100), 135(96), 107(69),77(88)

(a) 1.2,3.4-7etrahydroisoquinoIinolsand Their Derivatives

Substituent

TABLE 4. TETRAHY DROISOQUINOLINES

+

773 52 I 52 1

745 745 771 77 I 768 788 771 773 757 769 772 757

525.769

768 768 769 769 768

566

566

Ref.

HCI' HCI' HCIh

7MCH 3 0 1 2 5d,74CH,O), 5,6,7&(CH 30)4 2-(p-tosyl) 221,206,192,178, 164, 150, 137, 121, I09,91,77,65,53 222,207, 193, 179,165. 151, 138, 122. 110,92,78,66, 53

193(M+)"(IOD), 192(46), 164(82), 178(14), 149(45), 121(11) 223(M+P(80),222(48), 194(65), 192(100), 179(39), 156(58) 267(M'Y(90), 266(96),236(100),224(96).209(93), 181(17) 287(M *f(9.8), 286(9), 223(0.6),222(3), 155(3.5), 139(0.9),132(100),131I33.1)

m/r (Relative Intensity)

Parent peaks without hydrochloride. Measured by field desorption mass spectrometry. Parent peaks. Relative intensities are not described. Measurement by chemical ionization mass spectrometry gives m j i 164 (M + H)+. Natural product. Measurement by chemical ionization mass spectrometry gives m/r 244 (h4+ HI'. Measurement by chemical ionization mass spectromctry gives miz 268 (M + H)'.

(b) 5.6.7.8-Tetrahydroisoquinolines 1.34C2H50),d 1,3-(C2H50),, 4-Dd

Salt

Substituent

TABLE 4. ( C o n r i n d )

622 622

773 773 773 775

Ref.

1X. Analysis and Spectroscopy

347

2. Infrared Spectroscopy Assignment of the carbon-nitrogen or the carbon-quaternary nitrogen double bond of isoquinolines and 3,4-dihydroisoquinolinesor their quaternary salts in spectroscopy is uncertain because of the complex vibrational interaction between the carbon-carbon and the carbon-nitrogen or the carbon-quaternary nitrogen double bond. In addition, no characteristic absorption bands are available in the case of 1,2,3,4-tetrahydroisoquinolines. TABLE 5. ISOQUINOLINOLS AND THEIR DERIVATIVES Substituent

Anion

(a) lsoquinolinols and Their Derivatives 4-HO HCI 8-HO 5-HO 4-CH3C0, 6-HO 7-HO 4-HO, 7-CH3O 6.8iHO)z 637iHO)z 3-CH,O 3-CZH50 3-n-C3H,O 3-i-C3H,0 3-n-CaHqO 4-Ce H $0 CCH,SO,O 4-C,H,SOZ0 4-CsH$OzO qp-losyloxy) I-CHJSO,. QCH3SOZO 5-(7-isoquinolyloxy) 6,74CH30)2

HCI

HCI HCI

HCI HCI

Sample Handling K Br KBr K Br KBr K Br K Br KBr KBr KBr. Nujol Film Film-CHCI CHCI, CHCl, CHCI, CHCI, CHCI, Film KBr KBr K Br KBr K Br K Br K Br Nujol Nujol Nujol Film Film

,

v (an-')

Ref.

1620, I580 1626,1582 1645, 1615, 1595 1621. 1557 1623, 1588 1625,1585 1625,1614 1628,1589 1620, 1600 1625, 1575, 1545 1630 1632,1595 1640.1600 1150 I170 I160 I160 1635, 1625. 1220 1335, 1178 1370,1172 1370, I 1 9 0 1372,1190 1368,1288,1150,1132

137 776 131 776 776 137 776 776 131 20 426 83 116 777 777 777 777 778 576 576 576 576 576 123 300 351 20 56

1580

1632, 1614,1570 1644 1635,1575 1630.1590, 1565 3250,2060 3000.2400.2100. 1620.I460,l I65

30

719

348


TABLE 5. (Continued) Substit uen t

Anion

Sample Handling

v

7 N C7 H7 0 ) ~ 6,7-(CH30),, 8-CTH70

HCI HCI

Film KBr

I625 1655, I595

30 286

1647 1660,1611 2940,1590,1385, 1165 3275 3400,1605 Moo,2960,1630,1610 1630,1610,1570 1630,1600,1560

I21 83 239 780 78 I 93 352 56

(b) Quaternary Salts of lsoquinolinols and Their Derivatives 2-CH3.8-HO 1K Br 2-CH3, 3-CHsO INujol 2-C7H,,4-@-tOsylOxy) BrKBr 2-NH2.7-CH30 CH3SO; KBr 2-C7H,, 5,7-(C7H-@), Br- -C,H,OH' Nujol 2-CH3,6.7-(CH3O), IK Br 2-(3-lndolylethyl),6,7-(CH30), Br KBr 2-(3,4-Methyleaedioxyphenethyl), INujol 7,84CH30)2 2-(3.4-Dimethoxyphenethyl), 7.84CH@)2 2-CH3,6,7-(OCH,O), 8-HqCH 3 0 )

(an

I)

Ref.

I-

Nujol

1635.1610, 1570

56

CI -

K Br

16401630,1600

214

TABLE 6. DIHYDROISOQUINOLINOLS AND THEIR DERIVATIVES Substituent

Salt or Anion

Sample Handling

v

KBr CHCI, KBr K Br Nujol CHCI, KBr Nujol KBr KBr KBr CHCI, KBr

1635 1625 1599,1510 1625,1580,1490 1624 1630,1605.1580 1632,1614,1570 1644 1630 1800,1650 I629 1625,1605,1580 1645

(an-')

Ref. 266 264

300 290 351 292 300 351 782 782 355 764 765

IX. Analysis and Spectroscopy

349

TABLE 6. (Continued) Substituent

Salt o r Anion

Sample Handling

(b) Quaternary Salts of 3.4-Dihydroisoquinolinolsand Their Derivatives CHCI, 2-H,6,7-(CH30)2,8-0-0 -b 2-CH3,6-0-,7,84CH30), -' Nujol 2-CH3.6,74CH30),. 8 - 0 2-CH3.6-CH30.7-HO CI b KBr HSO; 2-CH3.4-H0,6,74CH30), BrKBr 2-CH3.6,7-(OCH20) CIKBr 2-BH3.6.74CH3O)Z KBr 2-CH3.6,74CH,O)2 INujol 2-HO(CH2)2,6.7-(CH30), BrKBr 2-HO(CH2)3.6,74CH,O), BrKBr BrKBr 2-C2H,OOC, 6,7-(CH3 0 ) 2 BrKBr ~-CH,COZ(CH~),.~,~~CH~O)Z CIKBr 244-N0,C,H,CH2) 6,74CH,O), BrCHCI, 242-CzH ,O,CC,H,CH2 ). 6.74CH3O)Z Br CHCI,

Y

(cm- ')

Ref.

1695 1610 1645-1595 1655 164O,l6l0,1580 1660.1600,1575 1672 I646 1659 1647 1645 1661 2900,1740,1620 1656 1643,1606 1650.1610

680 510 680 20 1 783 783 432 426 351 353 353 353 365,784 353 360 360

1655, 1570 1660,1582.1498 1665,1605,1580 1661,1618 1655,1600 1655

476 290 403 785 286 286

2-

674CH3O)z 2-CH3,6,74CH30)2 2-CH3.7-CH30. E-CTHTO 2-CH3,6,7-(OCH,O), 8-CH30 2-CH3,6,74CH3O),. 8-C7H,O 2-C7H7,6.7-(CH30)2.8-C7H70 Phenol betaina. No description. Borane complex.

CI ICIO;

CIBrBr-

KBr KBr KBr CHCI, KBr KBr

Salt

(a) 1,2,3,4-Tetrahydroisoquinolinolsand Their Ethers nci 4-HO HCI 5-HO 2-CH3OOC, 5-HO 2-CH3OOC. S-CH,OOCO 6-HO 7-HO 8-HO 2-C7H,OOC, &HO,7-CHaO 2-C,H,OOC, 6-CH3O. 7-HO 4HO,6,8-(CH,O), HCI I-CH,O, 2-C,H,CH,CO HCI +CH30 2-CH3OOC. S-CH,O 6-CH30 7-CHJO HCl 8*CH,O 2-(CH,),CCO. 6,7-(0CH,O) 24CH3)3CCO7&7-(CH30), 6-CH30, 7-~-D-Glucopyranosyloxy 2-C7H,00C, 6-CH30, 7-/?-DGlucopyranosyloxy

Substituent

K Br Film Fitrn Film KBr Film K Br KBr KBr KBr

-

-0

Film K Br KBr K Br KBr KBr

-a

KBr KBr

Sample Handling

TABLE 7. TETRAHYDROISOQUINOLINOLS AND THEIR ETHERS

(m-')

3290,2950,2786 3326,2980,2853. 1601 3326.1674 3005,2957.1765,1705, I469 3290,3120,2945.2845,2735,2670,1580 3340,2996,2860,2705,2680,2500,1618,1517 3225,3119,3036,2926,2824,2654,1597 3 m , 1480 3420,1700 3375,1610, I160 1650,1450 3289,2950,2786 3036,2984,1701, 1589, 3300.3040,2960,2870.1612 1504 3350,309S.2974,2875,1617,1567 2910,2830,2784l. ISM, 1240 3268,3038,2934.1603,1588 2980,2%40,1630,1480 2980,2950,1615.1515 3400,3250,2900,2700-2400,1680,1610 3350,1700, ,1690

V

788 786 557 557 557 773 557 757 757 787 787

768

786 557 557 557 557 557 557 787 787

Ref.

W

z!

No description

(b) 5.6.7.8-Tetrahydroiosoquinolinols and Their Ethers 5-HO I-CZHSO, 3-CHaO 1,34CzH,O),

5,6.7.H-(CH,O),

7,WCHaO)Z 5,6,7-(CH rO), 5-CH,0,7,8-(0CH,O) 5,7.8-(CH JO)3

2-C,H ,OOC, 6-Tetra-0-acetyl-p-Dglucopyranosyloxy. 7-CH ,O

2-C7H,OOC, h-P-n-Glucopyrdnouylony. 7-CH 3 0

HCI HCI

HCI HCI

HCI

nci 0

Nujol Nujol Nujol

K Br

K Br K Br

....

K Br K Br

CHCI, K Br

79 1 622 622

773 773 547 547 173 79 I 772

3035,2720,2600, 1580. 1495 2920.2770.1585,1480,1 I 15 2770-2470 2770-2470 2900,2750, 1610. 1510 2950,2780.2720.25M. 1470, t420 2830.2540. 1415 . 1 3 6 0

3210 1605. I570 1610,1580

7x7 787

7H7 717

7H7

1695 1720. 1710. 1260-1205

3250-3500.1610 3320, 1705. 1680

K Br

6-/~-D-Glucopyranouyloxy.7-CH,O

K Br

1720. 1710.1695,12RO-1205

K Br

awtyI-8-D-glucopyranosylaxy

2-C,H700C. 6-CH30. 7-Tetra-O-

352


TABLE 8. ISOQUINOLINETHIOLS AND THEIR DERIVATIVES Substituent

Salt

(a) Isoquinolinethiols and Their Derivatives I-HS I-CHaS I-CHZ =CHCHz I-CH,SOz I-CzH,SOz I-C,H,SOz I-@-Tosyl) 3-CH3SOZ 3-CzH,SOz 3-(p-T0~yl) 4-CzH,S0 C@-Tosyl)

Sample Handling

v(cm-')

Ref.

KBr CHCI, KBr Neat K Br KBr K Br KBr K Br KBr KBr CHCI, CHCI3

1630 1627 I551 1642 1300, 1138 1295,l I24 1305,1140 1290,1138 1290.1 I25 1290.1132 1308,l I48 1130 1320.1140

792 792 792 641 576 576 576 576 576 576 576 793 777

1620 3230,1630 1620 3300,1627,1100 1680 1120-1040 3250 3350.1 120-I020

794 794 794 794 795 795 795 795

CHCI, CHCI, CHCI, CHCI, CHCI, CHCI, CHCI, CHCI,

1350,1160 1350, I160 1350,1170 l350,1150 l350,1170 1350, 1I70 1360.1 I70 1340,l I35

7% 7% 796 796 796 796 796 797

CHCI, CHCI,

1360,1160 134O.1140

796 797

(b) Alkylthio-3,4-dihydroisoquinolinesand Their Derivatives I-CH,S

I -CzH I-CHz=CHCHz 1-(2-Cyclohexenylrhio)

HS03F HBF, HBr HCIO, H Br HCIO,

Film Nujol Film Nujol CHCI, CHCI, CHCI, CHCI,

(c) Sulfonamides of 1.2,3,4-TetrahydroisoquinoIine and Its Ether

2-CH3SOZ ~~PNO&.H~SOZ) 24pTosyl) 2-(d-Camphorsulfonyl) 2-(pTosyl),6-CH30 2-(pTosyl),8-CH30 2-@-Tosyl),6,7-(OCHzO) 2-[CH,OOC(CHz)zSOZ], 6.74CH3O)z 24pTosylh 6974CH3O)z 2-(3',4'-CI,C,H,CHzSO~), 6.74CH3O)z

5-HO

4-HO

3-HO

(a) Isoquinolinols and Their Ethers

Substit uen t

HCI

salt or Anion

.

E 95%E pH 6.92 O . i N HCI-M 0.01N HCI-M Conc. HClO, 0.I MHCIO, pH 7.0 0.01 N NaOH-M 0.1 NaOH-M

E E M

E E

pH 6.74 IN KQH IP E

E 25%E IN HCI

E

E

E

-

Solvent

TABLE 9. ISOQUINOLINOLS AND THElR DERIVATIVES

4o(y

I^__--

248(4.27Lb334(3.85)b 248(4.28), M(3.81)

223(4.60).233(s)(4.5 I 345(3.26) 234(2.25), 295I3.67)-320I3.73). 330(3.76) 230(4.2I), 295(3.60), 330(3.69) 234(4.21), 295(3.63), 318(3.68). 330(3.71) 230(4-24),294(3.65), 315(3.67),329(3.72) 209(4.66),230(4.22). 295(3.54),319(3.62), 331(3.65) 209(4.53), 232(s)(4.05), 261 (s)(3.62),330(3.59). 355(3.71) 222(s)(4.49).229(4.53),284(3.45), 295(3.43). 331(s)(3.86), 342U.93) 240(s or infl.) (3.94).3Mts or infl.) (3.63). 359(3.88) 223(4.091. 248(4.09). 323(3)(3.75),345(3.83) 233(4.40), 286(3.51), 298(3.52), 33 1-332(3.88)*342-243(3.87) 218(4.77),265(3.58), 272(3.64), 283(3.56). 308(3.44), 321 (3.54) 218(4.75), ZM(3.68). 273(3.72), 284(3.58), 308(3.46),321 (3.55) 260(s)(3.703' 273(3.76)? 283(3.65).bm(3.55): 32006 I 265(3.70)? 274(3.76)? 284(3.65)! 308(3.5)! 322(3.60? 2 l8(4.8 I), 265(3.70), 274(3.74),285(3.62). Ms(3.5 I), 322(3.61) 234(4.45),303(3.65), 328(3.70) 235(4.49), 302(3.72). 326(3.72) 235(4.41lb286(3.63): 326(3.65? 230(4.36), 296(3.55). 330(3.64).4oo(s or infl.)(2.13) 251(4.47), 318(3.63),3.67(3.70) 248(4.45Xb3 12(3.45Lb360(3.65p 446' 359'

L: (nm)(log E )

800 189,798

800 801 801 801

800 I82 189

I82 799 131 576 576 loo 160 576 189 183,798

76 I 798 183 53 76 I 799 799 799

Ref.

(Continued)

8-HO

7-HO

6-HO

Substituent

TABLE 9.

na

Salt or Anion

IP

O.iN NaOH-M

0.1NHCI-M

pH 7.03

IF

__a

M E

E 95%E P -_ pH 7.29 0.01N HCI 0.1N HCI-M 0.01N NaOH 0.1N NaOH-M

M M

pH 7.50 0.1N HCI-M 0.1N NaOH-M

CH

183 800 76 1 183 800 189,798 800 189,798 189 183,798 762 107 183,798 189 189 107

189,798 761 183 183 189,798 189.798 802 189,798

229(4.65), 266(3.62), 286(3.65),300(3.63) 228(4.78), 290(3.77) 225(4.41),280(3.33), 319(2.84) 229(4.64) 263(4.24). 353(3.91) 228(4.55), 247(4.51).321(3.84) 241(4.46),253(4.40),276(s)(3.20), 308(3.87). 332(3.65) 224(4.55), 260(3.59), 268(3.59), 273(3.42), 333(3.58) 224(4.55). 260(3.59). 268(3.59),273(3.42). 301(s)(3.3 I), 333(3.54) 225(4.72),259(3.74), 338(3.54) 265(3.74): 332(3.48),’ 345(3.53y 224(4.74), 257(3.77), 267(3.78), 338(3.56) 221(4.69), 257(3.82),338(3.49), W(2.04) 235(4.70): 272(3.65Lb 344(s)(3.52); 360(3.54)b 241(4.64), 278(3.65). 3 18(s) (3,16).362(3.63) 236(4.60Lb 282(3.91): 366(3.53? 238(4.64), 282(3.85), 289(3.88), 360(3.51) 233(4.47X M(3.57). 334(3.79) 233(4.45), 333t3.61). 380(3.27) ZZ(4.49). 334(3.39) 233(4-38).294(5)(3.48),332(3.72) 247(s or infl.)(4.19), 328(3.64). 430(3.43) 245(4.47), 3 10I3.39). 378(3.72) 247(4.281,328(3.66),370(3.78) 244(4.31), 310(3.36), 335(s)(3.301 379(3.55)

M

-*

Ref.

Solvent

v,

v,

7-CH30

4-CbH SO WH,O

3-CH30

I-CH3O

(b) Alkoxyisoquinolines

4-HO, 7-CHsO

HCL

HCI

E

M

M

IP 0.1N HCI

E 0.lN HCI-M 0.lH NaOH-M

M

0 . l N HCI-M 0.1N NaOH-M

E

Abs0.E

E

pH 0.2

pH 6.0

1P E E

E

E

E

IP

237.W.72). 255(3.73), 300(3.68),3 lO(3.67). 36512.56)

233(4.31), 261 (QI3.27).285(s)(3.49), BFj(3.531,316f3.72) 243(4.36), 279(s)(3.0),306(3.19), 368(3.77) 288I3.41). 300(3.40), 320(3.40) 258(3.81), 352(3.54), 362(3.56)

(3.32), 309(3.52). 320(3.50) 220(4.60), 227(s)(4.56),234(s)(4.36).225(3.59), 264 (3.57). 274(3.43). 304(5)(3.46), 3 18(3.71). 330(3.69) 224f4.9I), 265(3.67). 337(3.68} 339(3.56) 208(3.26), 274(2.97), 284(2.86), 31 lJ(2.61). 323.5(2.60) 230(4.49),247(4.45).31 t(3.76) 231(4.65),266(3.40). 280(3.49), tW(3.50) 256(3.763.264(3.73). 326(3.46),337(3.43) 225(4.70),257(3.74), 264(3.71). 327(3.52),339(3.59) 241 (4.58). 268(3.58), 275(3.61), 354(3.46) 233(4.67). 255(3.69),263(3.66), 326(3.32), 337(3.33)

262(s ar infl.}(3.651,270(3.78). 281 (3.71), 29H(s)

239(4.46),291 (3.36).298(3.36).335(3.20). 334I3.39) 239t4.46). 265(3.6).278(3.65).287(s)(3.62),3 I7(3.52),329f3.53) 239(4.63). 268(3.67),280(3.621,291(3.57),315(3.45),327(3.46) 253(4.68), 3I7(3.89).340- 341 (3.81) 248(4.53). 287(3.77).298(3.74),330(3.74).343(3.77) 24W4.42). 3233.491

235(4.55). 253(4.26), 261 (4.23).281-282(3.60), 291 (3.54). 347 -348(3.74),358 --359(3.72)

803

I21 104 104

121

a3 I 16.798 77x I 89,798 189.798 17 24 189,798 I89.798 802

74,798

74,798

20

54

24 1 39 139 131

131

(Continued)

Substituent

TABLE 9.

HCI

HCIO,

Salt or Anion

E

M

W E

E M E E M

E E E

E

2N HCI-E

M E E E ME D 1M HCI

E E

Solvent

246(4.61). 285(3.87),325(3.79), 338(3.83)

244(4.11), 318(3.71), 341(3.76), 234(4.49), 278(3.40), 289(3.33), 313(3.22), 327(3.33) 268(4.55), 310(3.61), 322(3.69) 23614.79). 275(3.55), 287(3.50), 310(3.42), 323(3.45) 235(4.81), 265(3.65),270(~)(3.62),285.5(~)(3.51),310(3.41), 323(3.46) 235(3.68),265(3.56), 275(s)(3.56), 2%0(infl.)(3.54),31 1 (3.53), 324(3.54) 312(3.78) 242(4.30), 262(s)(3.7 I), 273(3.62). 309(3.45),322(3.52) 228(s)(4.30), 248(4.78), m(3.94) 252(4.87), 310(4.12) 238t4.71) 306(3.72), 319(3.691 206(4.25), 236(4.73), 265(3.69), 312(3.46), 324(3.50) 236(4.63), 276(3.65), 284(3.68), 329(3.45), 347(3.55) 236(4.33), 252(4.35), 29O(s)(3.493 360(3.28) 234(4.69), 277(3.66),286(3.59), WS(3.65) aZ(3.48). 290(3.43), 336(3.45), 342(3.46) 240(4.73),320(3.72)335(s)(3.66) 240(4.70),279(3.46), 290(3.37), 323(3.34), 334(3.35) 243’ 218(4.03), 255(4.04), 336(4.16) 239(4.99), 286(3.79). 323(3.61), 334(3.49) 235(4.92), 284(3.81)

L G (m) (log €1

54

34

802 24

510

24

104 54

24

56

20 36 24

43

803

803

43

292

w>

24 24 17 24

Rd

2-C,H7, 4-HO. 6.7-(CH30), 2-CH 1, 6.7-(OCH20), 8-HO

2-Y, 8-HO 2-C7H7,4-HO, 7-CH,O

2-Y, 5-HO 2-CH3.6-HO 2-CH3.7-HO

,so;

CI-

aaa-

III-

11CI-

c1-' CI -

CH

CHjSO;

I-

1-

of Isoquinolinols 2-CH3.4-HO CI 2-C,H,,4-HO a2-(pNOzC,H,), 4-HO cl2-(pCH30C,H,), 4-HO c12-CH3. 5-HO a-

(c) Quaternary Salts

M

IP

O.IN KOH

IP

.

0.1N HCI-M 0.IN NaOH-M -

IP

pH 10

pH 10 pH 10 0.1N HCI-M 0.1N NaOH-M

-a

E pH 10 0.IN HCI-M 0.1N NaOH-M Conc. HCIO, pH 7.0

E E

pH 8.5

ZSS(3.W). 320(s or infl.)(3.56),364(3.98) 227(4.32), 243(4.31).258(4.28), 338(4.53) 247(3.89), 283(4.21), 352(4.01) 235(4.70), 293(4.27), 339(4.19) 233(4.23), 269(4.32).349(3.79),408(3.57) 255(4.51), 322(3.46), 368(3.66) 245(s)(4.22).274(4.26).362(3.871.430(3.52) 446c 401 254(4.38) 230(4.54),267(4.36), 358I4.09) 261(4.70),298(3.91X 408I3.47) 217(4.48), 243(4.71). 280(3.72), 3.67(3.54) 217(4.39), 265(4.641 MS(3.86). 424(3.38) 257(4.30), 334(3.69).q 3 . 1 6 ) 2m4.48). 314(3.30),38 I(3.72) 217(4.48), 250I4.31)/315(3.22), 378(3.68) 263(4.21), 347(3.59).460(3.69) 254(4.40) 239-240(4.61), 262-263I4.34). 284-286(3.76), 364-365(3.72) 231-232(4.58), 278(4.22),308-3W43.47). 378(3.96) 256(4.74), 323[4.08), M(3.94) 264( 1.99); 314(0,3L' 365(0.2y

189 122 131 131 131 214

39 189

183

189

1 89

183

801 122 183

8q1

189 189

183 231 231 231 183

w VI w

~

Salt or Anion

M

I-

1-

CIOi

Cl0;

CI0;

ao;

1-

I-

i-

E

I

-

M

M M M

E 0.03M HCI-E 1M HCI

iP

c1-

I-

M M

E

W

Solvent

ao; c10;

I-

(d) Quaternary Salts of AlkoxyisoquinoEnese CI0;

-

Substiluent


258(4.74), 285(3.763,318(4.11)

272(s)(3.45),280(3.47), 334(3.60) 270(3.63), 278(3.58). 360(3.84) 231(4.51), 251 (4.49),315(3.97) 244(4.69),277(3.68),358(3.45) 249(4.44), 280(3.32),W(3.22). 341(3.77) 253(4.91), 3 lO(3.95) 220(4.45),254(4.77), 314(4.01) 310(3.97) 227(4.47), 25 1(4.74), 310(3.97) 25414.87). 314t4.12) 255(4.76), 314(4.03) 254(4.74), 3 I4(4.02) 256(4.82), 3 16(4.I 1) 280(4.29), 310(4.20)

L.,: (nm) (1% E)

36

8W 803 433 803 805 238 238 238 199

215 215 121

207 83

Ref.

u l

*

w

CI -

2-CHp 6.7-(OCH,Q), 8-CHsO

KOH-E

M E

E

E

E

. ..I

-1

262( 1.96): 3 16(0.6).b357(0.3?

258(4.49),2874s) (3.74)

255(4.59).290f3.70). 385(3.60) 258(4.56),293(3.83)

The solvent is not described. Wavelengths (h)and molecular extinction coefficients (c) are obtained from figures in the original literaturc. ' Mulecuhr extinction coefficients (E) are not described. ' E- values. ' Since the spectral data of 6.7-methylenedioxy- and 8-methoxy-6,7-methylenedioxy-2-methylisoquinolinium salts (Rel. 213) are obtained on the maction mixtures. no tabulation is attempted. f Wavenumben ( l / h3370, l / h 3150) are described. Wavenumber ( l / h3380) is described.

II'

1-

7.84CH,0I2

II-

6-C,H-,O, 7-CHsO 2-CH3, 7,8-(CH,O), 3.4-IOCHzOfCeH &CHz)2. 7.84CI-130), 3.4-(CH,OI,C,H,(CHz)z.

217

214 217

56

803 56

360


3. Ultraviolet Spectroscopy For simplicity and clarity, the spectroscopic data randomly scattered in the cited literature are tabulated according to the following principles. All of the largest molecular extinction coefficients ( E ) are converted to the logarithmic values (log E). 2. Abbreviations used here are as follows: E, ethanol; M. methanol; W, water; IP, isopropanol; C, chloroform; D, dioxane; CH, cyclohexane; ME, methoxyethane; s, shoulder; infl., inflexion. 3. The original data presented as figures are as far as possible described in terms of absorption maxima (Amx) and log E on the reviwers’ own responsibility or indicated in the form of a reference number. 1.

The relationship between the spectra and the molecular orbital method has been described briefly elsewhere (see Section I.A.3.d).

2

w

7-Ha. K H j O

7-HO,S-CH,O

GHO, 8-CH30

HCI, H l r HCI, HBr HCI, HBr H k

HCI, HBr H a H3r HCI, HBr HBr

HBr H k HBr H 3r

HBr

HBr

HCI

(a) 3, QDihydroisoquinolinols' 5-HO, 6-CHJO

5-HO, 8-CH,O GHQ,7-CH10

Salt or Anion

Substituent

E

0.01N HCI-E 0.01N NaOH-E

E

0.01 N HCI-E 0.01N NaOH-E

E E

0.01 N HCI-E 0.01 N NaOH-E E 0.01 N HCI-E 0.01N NaOH-E

E

0.01 N HCI-E 0.01N NaOH-E E 0.01 N HCI-E 0.01 N NaOH E E 0.1N KOH

E E E

Solvent

TABLE 10. DIHYDROISOQUINOLINOLS AND THEIR DERIVATIVES

213(4.22), 243(3.75). 275(infl.)(3.57),324(4.06) 23 l(3.90). 263(3.85). 342(3.64) 269(3.98), 316(3.58). 402(4.32) 248(4.19), 307(3.96). 362(3.92) 245(4.126), 332(4.14) 248(4.18), 397(3.%), 362(3.96) 249(4.19), 307(3.97), 361(3.%) 246(4.18), 333(4.16) 238(3.98), 320(infl.) (4.02). 351 (4.18). 380(3.80) 223(4.26). 261(3.62). 303(3.80). 385(3.08) 237(4.37),273(3.69), 350(3.38) 238(4.36). 270(3.823,310(3.82) 247(4.27), 303(4.00). 360(3.90) 245I4.48). 278(s) (3.74),347(3.73) 246(4.32). 302(4.06). 360(3.%) 246{4.32), 303(4.06), 358(3.96) 245(4.56), 275(s) (3.88), MS(3.84) 217(4.13), 235(infl.)(3.90).307(4.09), 398(3.53) 224(3.98), 270(3.94). 310(3.57), W(4.32) 245(4.21), 305(3.95), 353(4.02) 245(4.08).331(4.26) 246(4.17), 305(3.91), 355(4.00) 24514.20). 304(3.94), 354(4.02) 245(4.1 I), 332(4.26) 213(4.10), 240(3.85), 312(4.14). 410(3.48)

L, (nm) (log el

300 300 267 300 300 300 300 300 300 267

3w 300 300 267 267 267 300 300 300 300

300

267 267 300 300

Ref.

5,64CH,O),

a-

CI-

3H3

HQ

Ha

na

HCI HCI

Ha

HCI HCI HCI

(c) Alkoxy-3,4dihydroisoquinolines

2-CH,, 7-HO, 6-CHJO

@) Quaternary Salts 3,4-DihydroisoquinolinoIs


E

E

90% E E

0.01N NaOH-E 0.1M NaOH-E

Ha-E

0.011%’HCI-E

E E E

1M HCI 1 M HCI IN HCI

E

0.1 M NaOH-E

E HCI-E

HCI-E O.1M NaOH-E

E

NHj-M 210(4.19),238(3.76),279(s)(3.74),327(4.13) 2 15(4.18),262(4.14) 223(4.20), 306(3.91), 385(3.23) 215(4.26). 235(s)(3.93),298(4.08),408(3.78) 225(s) (4.16). 263(3.98). 333(3.72) 215(4.10), 240(Infl.)(3.73). 298(3.90),W(3.56) 248(4.26), 305(3.76), 363(3.88) 248(4.24), 305(3.793,363(3.88) 248(4.27), 303(3.80),362(3.88) 225(s) (4.15), 276(3.98), 325I3.89) 230(4.39), 278(3.85), 310(3.85) 230(3.64), 278(3.58), 309(3.57) 226(4.36), 273(3.88), 306(3.84) 243(4.29), 301(3.97), 350(3.96) 244(4.25), 306(4.00), 355(3.93) 225(4.46), 269(3.93), 306(3.86) 230(4.21), 272(3.98), 303(3.91) 242(4.31), 290(s)(3.91), 299(3.98). 332(4.01) 245(4.15), 308(3.88), 360(3.80) 237(4.07), 245(405), 308(3.84), 360(3.70) 310: 36ob

251(4.24). 312(4.00),370(3.86) 265,b 325*

300 300 807 300 807 426 810 352 270

808 803 809 272 352 29 2

267

807

807 807 267 807

806 750

NiiOH-E E 0.01N HCI-E 0.01N NaOH-E

HCI

HCI HBr H Br HBr H Br

HCI

HCI

HCI

W

nci

0.1N HCI 0.1N KOH

IP

HCI IM HCI IN H C I

1M

HCI-E

IM H C I

E

E IM HCI

0.1 M NaOW-E

HCI-E

0.1M HCI-M

M

E

HCI-E E

NaOH-E

HCI-E

E

NaOH-E E

HCI

HCI

HCI

1 M HCI-W

1M HCI

HCI 244(4.26), 306(4.00). 356(3.%) 244(4.25), 306(4.00), 355(3.93) 230: 270: 310) 230(4.34). 277(3.79), 308(3.73) 243(4.23). 302(3.94). 352(3.9 1 ) 246I4.45). 308(1.44), 361(4.09) 237(4.25), 301(3.95). 3333.94) 223(4.42). 269(3.90), 305(3.83) 23 1(4.40), 269(3.90), 308(3.78) 246(4.34), 307(3.%), 353(3.88) 230(4.41). 278(3.86). 308(3.76) 223(4.20), 306(3.91). 385(3.23) 210(4.14), 237(4.16), 3M(inA.) (4.07). WS(4.14) 209(4.29), 232(4.42). 280(3.91), 313(3.85) 227(4.42). 262(3.92), 320(3.34) 218(s) (4.17). 23f(s)(4.10),297(4.04), 375(3.41) 237 (4.06). 293(3.98), 374(3.34) 224(4.38), 260(3.87), 322(3.32) 224(4.23), 268(3.67), 298(3.83). 380(3.04) 237(4.06), 293i3.98). 374(3.34) 234 (4.271 ZSS(3.85). 3 12(3.79) 246(3.921 307(3.671353(3.6 1) 237(4.06). 293(3.98). 374(3.34) 252(4.09), 330(4.14), 370(3.61) 252(4.09), 330(4.14). 370(s), (3.61) 252(4.08), 330I4.12) 216(4.15). 252(4.10). 318(4.15) 241(4.16). 330(4.15) 24q4.15). 323(4.13) 232(4.32), 279(3.96) 36 290 290 807 807 267 803 782 782 807 807 803 812 809 286 286 286

807 247

270 270 270

81 1 803 2m 810 300 307 300 300

Subtituent


Salt or Anion

1M HCI INHCI

E E

NaOH-E W

-t

E 1M HCI

E

NaOH-E

W E

0.1M NaOH-E IM HCI 0.03M H a - E HCI-E 0.1MNaOH-E

HCI-E

0.03M H a - E

-

W

-c

Solvent

355 784 814 815

245.7(4.33), 309.2(4.07), 359.6I4.04) 2I2(3.90), 253(3.93), 320(3.78), 380(3.75) 210(3.71), 285(2.85) 247(4.28), 311(4.04), 364(4.02) 249(4.26), 310(4.05), 363(4.02)

353

270

401

m3

35 1

810 810 270

807 803 432 807 807 217

807

433

2w

210(s)(4.37),247t4.31). 308(4.MA 360(4.06) 282(3.60) 310; 36ob 248(4.33), 308(4.05), 360(4.05) 244(4.35), 308(4.03), 358(4.00) 247(4.47), 310(4.13), 361(4.09)

-

250(4.25), 306(3.84), 371(3.98) 365I3.95) 244(4.25), 306(4.00), 355t3.95) 234(3.66), 293(3.67) 250(4.27), M7(3.81). 365(3.94) 358(4.03) 244(4.35), 308(4.03), 358(4.00) 222(4.26), 285(3.54)

272 813 36h

247.5(4.06),304.8(3.85). 366.7(3.94)

Ref.

216(4.52),331(4.32)

Lx(nm) (lot3 €1

248(4.4), 314(4.21), 379(4.22) 247(4.54), 311(4.33), 367(4.31) 24J3(4.64), 310(4.4), 364(4.41) 246(4.56). W(4.31). 361 (4.28) 246(4.60), M7(4.34), 359(4.32)

2Br2Br-

W W W

W

W

2Br

2Br2Br

282(3.75)

NaOH-E

1-

313(4.08),350(4.37),365(4.05)

2W3.92) 250(4.39.314(4.12).368(4.09)

2w

310) 3 W 250(4.30),312(4.08). 365(4.08) 282(3.62) 209(4.20). 254(4.19). 317(3.891. 373t3.115) 248(4.34), 3I2(4.07), 367(4.07) 310: 36ob 248(4.34),312(4.08), 3.67(4.08) 284(3.94)

E

M

NaOH-E NaOH-E NaOH-E

E

E

M E

NaOH-E

E

E

I-

1Br-

I'

1-

II-

1-

Br-

1I' 1-

815 817 817 817 81s

810

810

360

8 10 270 816

2 70 810

816

360

270 810 810

E

1.-

rp O.1H HC1

BrBr-

2-C7HT,6,7-(CH30)1,8-C,H,O

IP 0.1N HCI

-c

BrBr-

W W 0.03M HCI-E 1 M HCI HCI-E 0.lM NaOH-E 7.8 x 10-4N KOH O X N NaOH 025N KOH-E

E

E

0.03M HCI-E I M HCI 0.1 M NaOH-E IP

M HCI-E

c1-’

c1-

a-

-4 CI -

-4

CI CI -4

CI -

c10; CI CI -

1-4

1

-1

E

HCI-E NaOH-E

Solvent

2-CH3,6,7-(CH,O),, 8-C7H7O

2-CH3,7-CH,O, 8-CTHTO 2-CH,,6,7-(OCH,O). 8-CH3O

2-CH3, 7,8-(CH30),

CICI CI -

2-@-C,H,OC,H,CH,). 7-C,H,0

6-CH30,

Salt or Anion

Substituent


25O(4.37), 3 I 3(4.08 ), 365(4.05) 250(4.37), 313(4.07), 365(4.03) 282(3.75) 218(4.06), 297(3.77), 375(3.03) 219(4.43), 244(s)(4.03),300(4.03),380(3.38) 380(3.38) 2 19(4.43), 244(4.03). 300(4.03) 223(4.32), 254(3.43), 287(3.43) 239(4.12), 301(4.07), 379(3.43) 254(0.65),f 334(0.89) 255(4),”338(8)s 254.8(4.14), 332.6(4.24) 251(0.74),’ 331(0.87)f 338(4.16) 252(3.98), 334(4.08), 375(s)(3.56) 252(3.98), 334(4.08), 3751s) (3.56) 219(4.22), 2301s) (3.86), 287(3.28) 283(0.15)f 279(0.14),’ 325(0.08),’ 377I0.03)’ 249(0.33),’ 337(0.39)’ 255(4.09). 335(4.23) 248(4.17). 333(4.19), 26W) (3.89) 247(4.19),326(4.16) 248(4.1 I), 341(4.31) 246(4.12). 335(4.28)

270 270 270 290 807 433 803 807 402,403 43 1 808 813 43 I 433 803 807 807 43 I 43 I 43 1 401 286 286 286 286

Ref.

'

W

Since the spectral data of 3.4-dihydro-disoquinolinol (Ref. 263) and 3,4-dihydrcc6,7-isoquInolinol(Ref. 5 5 ) in the reaction mixtures are presented as figures, no tabulation is atiempted. Molecular extension coefiients (E) are not described. The solvent is not described. Anions are not described. ' The spectrum measured with an old instrument is presented as figure. Wavelengths (I)and E values are obtained from figures in the original literature. Values described in the original literature.

226I4.64).295I4.39) 225(4.56),295I3.97) 230; 289 229(4.40).313(3.73) 232(4.25),293I3.95) 227: 291' 228: 2Mb 229,b 2 w

24 24 24 24 24 24 24 24

368


TABLE 11. PHENOL BETAINES structure

2-Methyl4oxidoisoquinolinium 2-Methyl-6,7-methylenedioxy-8oxidoisoquinolinium 3,4-Dihydro-6,7-dimethoxy-8oxidoisoquinolinium

Solvent -e

680

1% HCI-E

28ob 276' 336: 422' 335.5' 290: 346' 219,' 268.6 395'

M

232: 257,' 352: 428'

510

345.5: 4 w

680 680

C D E

C D E

0.1N NaOH-E

' Molecular extention coefficients

Ref. 1028 214

1% HCI-E

' The solvent is not described.

(nm) (log E )

367' 285( 1.8r

M

0.1N NaOH-E 3,4-Dihydro-7,8-dimethoxy-2-methyl- M

6-oxidoisoquinolinium 3,4-Dihydro-6,7-met hylenedioxy-2methyl-8-oxidoisoquinolinium (cotarnoline) 3,4-Dihydro-6.7-dimethoxy-2-methyl8-oxidoisoquinolinium

,A

340?448' 341(4.26), 425(3.90) 337b 340; 4206

( E ) are not described. Wavelengths (1)and E values are obtained from figure in the original literature.

680

680 680 680 510

680 55 1 55 1

3

(a)

HCI

0.1N KOH

0.1N

IP

0

1,2.3.4,-Te~rahydroisoqunolinols and Their Derivatives 8-HO IP HCI IP HCt O.1N KOH 4-OH. 7-CH3O HCI 1P 5.HO. 7-CH,O E E HBt HBr 6-HO, 8-CH30 E 7-HO. S-CH3O H Br E 7-HO, 6-CH3O E 0.01N HCI-E 0.01 N NaOH-E HCt E HCl 0.01N HCI-E 0.01N NaOH-E HCI 7-HO, 8-CH30 Hcl Ha 0.1N KOH 8-HO. 7-CH3O HCI E HCI 0.1 N KOH 2-CHO, 8-HO,7-CH,O rp 0.1N KOH 6-HO 7,8-(CH30), IP 0.1N HCI 0.1N KOH HBr IP HBr 0.1N HCI HBr 0.1N KOH

TABLE 12. TETRAHYDROISOQUINOLINOLS AND THEIR DERIVATIVES

220(s)(3.88). 274(3.26), 281 (3.26) 216(3.84), 275f3.38). 281 (3.37) 242(3.96),288(3.53) 227(4.01), 277-278(3.24). 284(3.22) 225(infl.)(4.03), 280(infl.) (3.32). 286(3.33) 227(inff.)(3.96). 280(infl.)(3.40). 286(3.41) 224I3.891, 281(3.32) 225(3.89),282(3.43) 223(s)(3.85), 284(3.59) 224(3.83), 283.5(3.59) 243.5(3.94), m(3.76) 225(3.75). 285(3.60) 225(3.83), 285(3.60) 245I3.88). 302(3.71) 28 1-283I3.3 1) 239-240(3.911,295-296(3.48) 230(s)(3.76), 280(3.34) 245(3.87). 290(3.63) 2306) (3,83), 280(3.36) 240(3.86),292(3.65) 23U(s)(3.90), 273(s) (3.20). 282(3.26) 233(s)(3.92), 273(s)(3.11). 279(3.15) 240(9)(3.89), 295(3.56) 23W) (3.90),275(s)(3.18), 281(3.20) 225(s)(3.90),27S(s) (3.14). 279(3.15) 24O{s] (3.89),295(3.56) 227(s) (3.98). 272(2.90), 280(s) (2.84) 225(s)(3.92), 270(2.88), 280(s) (2.70) 240(s)(3.90),285(3.38)

568 561 403 403 262 262 262 262 262 262 286 286 286

568

300 568

Mo

3M)

300 300

300

562 562 267 267

510

121 121 121

(b) 5.6,7,8-Tetrahydroisoquinolinol 4-HO

The solvent is not described. Molecular extinction coefficients ( E ) are not described

HCI

5$,7,84CH10),

HCI HCf HCI HCI

HCI

IP

W

0.1N HCI 01N KOH

IP

M

W

W

E

W

E

W

IP

HCI

IP

E

a

10% HCI

E

E -

HCI H a

HCI

-a

HCI

E

0.1N HCI O.1N KOH

M IP

Solvents

nci

HCI HCI HCI

Salt

HCI HCI HCI HC1

Substituent

TABLE 12. (Continued) (nm) (log 4

233(3.44), 282-283i3.81)

270(2.93),340(1.98) 227(s)(3.98),272(2.93),280(s) (2.83) 222(s)(3.93), 270(2.88), BO(2.72) 240(s)(3.91). 284(3.39) 290(2.95) 284(3.31) 206(4.59), 227(infl.)(3.85), 271(2.96), 280 (infl.) (2.86) 283b 271(3.14) 271(3.17) 28ob 281,' 2 8 9 225-226(3.94), 280(3.42),287(3.40) 200(4.4), 214(3.83,280(3.4),288(3.4) 2 18(3.87),272(3.24), 278(3.26) 226(3.94),283(3.40) 203I4.5). 220U.83, 284(3.6),288(s) (3.6) 226(3.82),276(s)(3.23), 282(3.25) 201(4.5),223(s) (3.9), 278(3.4),286(3.4), 293(s) (3.3) 203(4.4), 223(s) (3.7), 281 (3.2), 290(s)(3.0) 240: 279: 284b 225(s) (4.1 I),2591s)(2.83),265(s)(2.93), 275 (3.04). 2800.05) 280(3.08) 280(3.21) 205I4.0). 223(s)(3.5),282(2.9),292(s)(2.8)

,L

131

267 773 131 773 773 510 286 286 286 773

122

819 286 286 286 54 568 569 525 114 1 I4 525 7 131 173

Ref.

2

W

salt

HCIO,

HCIO,

HC10,

HCIO,

CH

E

E

E E

E pH 1.0 pn 9.4

E

E

E pH -3.2 pH 6.0

95% E E

pH 9.0 95% E

pH -2.0 pH 6.0

E pH -3.6

Sol ven I

' Molecular extinction coefficients ( E ) are not dexribed.

14CH2=CHCH,S) 1+2-Cyclohexenylthio)

(b) Alkylthio-3,4-dihydroi~oquinolines

3-CH3SQ, 3-C,H,SO, 3-C,H,S02

I -CH,SO,

1 -(2-Oxocyclohexylthio)

1 -HO(CHz)zS

l-CH,S

I-CH,SO2.4-CH,SO,

(a) lsoquinolinethiols and Their Derivatives

Substitucnt

TABLE 13. ISOQUlNOLlNETHlOLS AND THEIR DERIVATIVES

28V 240." 275'

2234.553. 28 1 (3.54). 292(3.53). 3 14( 3.5 I ), 3264 3.57) 225(4.46),23q4.44). 2W(s)(3.81), 278(4.02). 28Q3.94). 348(3.9%), 361(3.98) 237(4.571.279(3.58 ).305(s)(3.32). 34S-34q 3.78) 222(4.63), 26f(s)( 3.49). 277(3.55), 287(sH3.481, 315(sW3.5111.325(3.65) 245(~)(3.82). 2W3.75). 296(3.79), 330(3.79), 3*5)(3.76) 226,' 2 4 5 q ~ )2747s). , 283.' 294,' 310-3W (broad hump) 237'(s), 286'(s).297.' 325,'336" 21Y4.74b 245(sH3.88), 2Wsn3.73). 278(3.76),297(3.78). 324(sM 3.73),334(3.74) 234," 284,' 3 W . 3.70" 243(4.63). 283(s or infl.)(3.22).293(3.27), 308(3.13), 3533.61 1 227(4.58),281(3.4S), 32q3.63) 223(4.53). 277(3.53), 312(sM3.51),32q3.57) 22q4.493. 267(sH3.48), 27q3.521, 32y3.54) 225(4.39),275(3.47),323(3.45) 233(4.19),2534.42). 285(3.84), 373(3.53) 24644.34L 269(s)(3.89),28q3.97). 290(3.91), 342(3.25) 225(4.86). 272(3.60), 303(3.32). 3W3.25). 317I3.43) 226(4.55), 272 (3.37). 303(3.09), 309(3.02), 317I3.20) 222(4.31), 24oI4.27), 265@)(3.66),305(3.15), 310(3.06), 31q3.23)

A,,.* (nm)(loed

795 795

643 74.820 74,820 576 576 576 684,820 684,820 576 576 576

641 78

6114.820 641

79.820 79.820

576 684,820

Ref.

372


4. Nuclear Magnetic Resonance Spectroscopy To be useful for the reader, the table of the ‘H-NMR spectroscopic data originally reported in a variety of ways is listed according to the following principles. However, the tables of I3C-NMR spectroscopic data are excluded because of few l i t e r a t ~ r e . ” ~-~7 5~5 ~citations. * 1. All chemical shifts are given in b values. Values originally in 7 are converted

to those of b. 2. A part of the assignment of chemical shifts, to which the original authors make no remarks, is added when it is self-evident. Most of the chemical shifts including signal shapes, however, are tabulated as given by the original authors. 3. Abbreviations used here are as follows: s, singlet; bs, broad singlet; b, broad; d, doublet; dd, double doublet; t, triplet; asym. t, asymmetric triplet; rough t, rough triplet; q, quartet; AB, AB quartet; bq, broad quartet; AA BB, A A BB system; ABXm, ABX multiplet; m, multiplet; bm, broad multiplet; c, complex; Wt, half-band width; TFA, trifluoroacetic acid; AcOH-d4, tetradeuterioacetic acid; DMSO-d,, hexadeuteriodimethylsulfoxide; DMSO, dimethylsulfoxide.

W

4

W

Salt

l-CH,O, N-oxide I-CZHSO

HCI

AcOHd, CM3 AcOH-d,-CDCI,

8-HO, 7-CHJO

CW3 cM313

DMSO-d6

DMSO-d6 1N NaOD

CDCI,

CDCls

CDCl,

AcOH-d4

AcOH-d,

CDc4

CXI,

CDCI,

cm3

Solvent

8-C6H,C02

(a) Isoquinolinols and Their Ethers CCH,SO,O 4-C2H,S0,0

Substituent

TABLE 14. ISOQUINOLINIOLS AND THElR DERIVATIVES

2.34(s,3H,OZCCH3),6.04(~,ZH,OCH,0)."6.99. 7.13,7.22(~,3H,4-,5,8-H), 8.74(~,1H. I-H) 1.35(s,3H,O,CCH3). 3.98(&6H,2xOCH,), 7.02,7.17, 7.28(~,3H,4-,S-,8-H). 8.854%1 H. 1-H) 4.01,4.03(~.6H.2xOCH,), 7.52(5,1H), 7.qs,lH), 8.16(S, I-H,l-H), 8.79(~,I H , E H ) 3.98,4.05(~,6H,2xOCHJ, 7.53,7.78,8.03,9.12(~,4H,8-,5-,3-,I-H) 6.60(dd,lH,J=l.8,7.5 H~,7-fl),7.21ym,lHJ=0.8,8.5,1.8Hz,S-H), 7.42(q,lH,J=8.5,7.5Hs6-H), 7.57(~,1H,3-H),8.61(d,lH,J=O.S Hz,I-H) 6.88b(q,2H,J= 2 k5-.7-H),8.05,' 8.3SC(q,2H,J= 6 HG 4.3-H), 9.40(~,1H,l-H) 8.0yd.J = 6.5 H2.3-H) 7.08(~,4-H),7.9Ys.3-H)

8.6yd,lH,3-H),9.7y~,lH,l-H)

3.26(~,3H,CH,), 7.40-8.14(m411). 8.4S(b~.3-H),9.10(bs, I-H) 1.62(t,3H.CH3), 3.48(q,2H,0CH1). 7.48-8.24(m,4H), 8.51(s.3-H), 9. Iqs, I-H) 7.28-8,M(m,9H), 8. l q r 3 - H 9.13s 1 -H) 2.44(s,3H.ArCH3), 7.20-8.30(m.9H), 9.17(bs.I-H) 7.30,7.54(q,2H,J=2.5,8H~S-or~-H),7.94(1,1H,J=8Hz6-H), 8.lYd,IH,J=6HZ,4-H),8.SO(d,lH,J=6 Hz,~-H),~.~~(s.IH,I-H) 7.4-7.9(m.7H,arom. H),ca-8.36(m.2H,arom.H'). 8.84(d.lH.J=6 k t ~ 3 - H ) . 9.53s. 1H.I-H) 4.05(s, 3H. OCH,), 7.Hl(rn. 4H. arom. H), 9.66(s, IH, I-H) 3.97(s,0CH3), 7.37(m,4-.5-,6-H), R.M(d,J = 5 Hs3-H), 9.53(1H) 3.95(s,3H,ArOCH3),4.07(+3H,7-OCH3), 7-8.4(rn.7H,arorn. H),

6 Wpm)

822 823

20

190

131

82 1

139

I39

so

24

so

50

50

576 516

576

5'16

R d.

2

W

~-wC~H~O 3-i-C3H,0 3-n-C4H,0 4-CH30 4-CH30, N-oxide CCZHSO 5-(7-lsoquinolyloxy) 7-CH30

3-CHjO

Substi tuent


~

Salt

CDCI,

CDCI,

CDCI,

CDCl, CDCI, CDCI, CDCI,

CDCI, CDCI, CDCI, CCI,

cm,

CDCI,

CDClJ

Solvent 4.03(S90CH,), 6.98(~,4H),8.95(~, I-H) 4.OYs,OCH3),7.OD(s,lH),7.2-8.qm,4H, 8.8(s,lH) 3.90(s.3H.0CH3),6.78(s,IH), 7.36(m,4H), 8.7(s,lH) 6.9qs.4-H), 8.88(~,I-H) 4.O3(s,3H,OCW3),7.00Is,IH,4-H), 7.68,7.88(d,2H, J = 8 H~,5-,8-)1).8.9Ys,lH,I-H) 7.l(~,4-H),8.854s.l-H) I-H) 6.69(~,4-H),8.w~ 6.95(~,4-H),~ . Wl-H) S, 6.94(~,4-H).8.88(~,I-HI 6.9ys,4-H), 8.88(~,I-H) 7.00(~,4-H),8.96(~,1-H) 4.Ol(s.3H), 7.40-8.10(m5H), 8.22-9.3qbr, IH) 7.7(d.J=2 HL 3-H).8.3S(d.J=2 Hz. I-H) 8.q43-H). 8.81(~,1-H) 7.24-8.06(88), 8.6q2H). 9.1qlH). 9.40(1H) 3.95(s,0CH3).7.5qrn,5-.6-,8-H), 7.53(d,J =6 Hz,QH1, 8.4yd.J = 6 H&3-H),9 . m 1-H) 1.28(t,3H.J=7 Hz),4.3flIq,2H,J=7 Hz),4.77(s,2H), 7.2qd.lH.J = 3 Hz), 7.4ydd.lH.J = 3.9 Hz), 7 . q d . l H . J = 6 Hz), 7.80(d,1H.J = 9 Hz), 8.47(d,I H,J = 6 Hz). 9.18(s, 1H) 22o(t,2H,J=7 Hz),3.63(~,3H),4.q1,2H,J=7Hz), 7.20(d, 1H,J = 3 Hz), 7.43dd. I H,J = 3,9 Hz), 7.62(d,l H,J =6 Hz), 7.78(d, IH,d,J =9 Hz), 8.Wd. 1H.J = 6 Hz). 9.154,lH) 1.2-2.3(m,lOH), 3.9(m,2H), 3.65(s,3H), 7.15(d,IH), 7.401d,lH,J=3.9 Hz),7.60(d,lH.J=6 Hz), 7.8qd,IH, J = 9 Hz).8.45(d,IH,J=6 Hz), 9.2qs.IH)

119

1 I9

119

822 777 823 777 777 717 62 822 823 123 24

83 116 I30 777 824

Ref.

____

HCI

CDCI,

HCIO,

TFA

CDCI,

CDCI,

CDCI,

CDCI,

CDCI,

CDCI,

9.77( b,1H,1-H)

49

24

20

I5

749

43

815

43

24

7.46(d,IH.J=6HzQH),8.38(d,lH,J=6 H2.3-H), 9.02(s,IH, I-H), 3.97(~,2x OCH,). 6.98(~,8*H).7.14(~,5-H),7,45(d.J= 6 Hq4-H), 8.4qd.J=6 Hz.3-H), 9.02(1-H) 3.97(~.2~OCH3).6.97.7.12(~,5-.8-H).7.42.8.30(d,J=5.8 H%4-,3-H), 8.95(~.I-H) 3.99.4.02(s,6H,2xOCH3),7.06.7.1~arom. H).7.54.8.15 (d,2HJ=6 H2,4-,3-H). 8 . 9 4 IH.1-H) ~~ 4.00,4.04(2~OCH3).7.55,7.6Y5-,&H),8.10.8.27(d.J=6 H&4,3-H), 9.2qs. 1-H) 3.80(&3H,OCH3), 5.O2(s,2H.OCH2C,H,), 6.76.6.9qs.2H. 5 - 3 - or 8-3-H), 7.00-7.28(m.6H,arom.H],8.07(d,lH.J=6 Hz.3-H), 8.66(s,IH,I-H) 0.95-2.1 [m,7H. (CH,)z,CH3],4.15(s- 3H,0CH3), 4.20-4.35 (t,2H.0CHz), 7.35--8.4~arom.H),9.6#s,IH,I-H) 6.5D"(q,2H.J=2 H~.5-,7-H17.39.' 8.3Y(d,2H,J=6 Hz, 4.3-H). 9.44(~.1H,I-H) 3.92,4.00(s,2xOCH3). 7.40(~,5-,6-H17.44(d.J=7Hz,4H), 8.3qd.127 H2,3-H).9.5qI-H) 4.24,4.36(~,6H.2 x OCH,), 8.16,8.38(bs,4H,3-,4,5-,6-H),

CDCI,

M

779

24

~.~~(S.~H~~OCH~),~.O~(S.~H,S-H).~.I~(~.IH,~-H).

3.94,3.96(~.2x OCH3). 6.63dJ = 3 Hz,6-H), 6.8qd.J = 3 HKS-H), 7.91(d.J=6 Hs4-H), 8.4qdJ-6 H~.3-H),9.14((I-H) 4.0(6H),7.1(1H),7.311H),8.4(2H19.4(1H) 5.16(s.4H.2xOCH,C,H,).6.82,6.88(d,2H,J=2.5 Hz.6-.8-H). 7.2--7.6(m.IOH.2 x C,H,).7.95.11.40(AB.ZH.J=6 Hz.4.3-H),9.07(s,lH,I-H) 3.92,3.94(~.2x OCH,). 6.68(d,J = 6 Hz.~-H),6.8qd,J = 6 Hz, 6-H), 7.90(d.J=6 H~.4-HJ.8.54(d,J=6 H~,3-H).9.54( I-H) 6.05(s.OCH,O). 7.02(s.&H1.7.12(~,5-H),7.43(d.J = 7 Hz, 4-H), 1(.32(d.J=7 HZ,3-H), 8.94(1-H) 6.l4(s.2H,OCH2O). 7.08.7.15(arom. H), 7.53.8.18(d.ZH.J = 6 Hz4-,3-HJ, 8.92(~,I I f . I -H)

CDC13

CDCI,

CDCI,

CDCI,

DMSO-d, CDCI,

BH 3

HCI

CDCI,

Salt

~~

CDCI,

CDCI,

CDCI, cDC1,

CDCI,

AcOHd,

CDCI,

CDCl,

TFA

Solvent

DSOi

AcOD

SO%DZSO,-

(b) Quaternary Salts of Isoquinolinols and Their Ethers 2-CH3, I-DO DSO; IO%D2SO,AcOD

Substituent


4.18(N'CH,), 7.81(4-H), 7.88(3-H),8.58(8-H)

4.00(NiCH,), 7.45(4-H),7.75(3-H), 8.538-HI

8.45(d,J=5 Hz3-H) 9.131-H) 3.95,3.96,4.10(~.3x OCH,), 6.82(~,5-H],7.41145 = 6 H&4-H) 8.37(d,J = 6 H&3-H),9.34(1-H) 3.93,4.05,4.18(~,9H.3x OCH,),6.98, 7.10, 7,24(~,3H,5-,5'-,8'-H), 7.38-7.68(m,2H,4-,4-H), 8.20-8.59(m2H, 3-,3'-H), 8.83,9.29(~,2H,1-, 1'-H) 3.9qs,3H,OCH,). 3.98(~6H,2x OCH3).4.038,3H,OCH,), 7.02(~,1H,8-H), 7.97,8.68(~,2H.3-,I-H)

827

827

54

34

24

24

4.00,4-05(~,3~OCH3),7.07(~,8-H),7.84(d,J=5H~,4-H),

8.43(d, 1H.J = 6 Hr3-H). 9.1qs.lH. 1-H)

821 54

30

50

29

24

828

46

3.98,4.01,4.03(s,9H,3xOCH3),7.17(s,1H~7.4~~1H),8.77(s,lH) 3.97,3.99,4.03(~.9H,3x OCH,), 7.07(~, 1H,8-H),7.85(d91H,J~6 Hs4-H),

4.2,4.3(sV6H,2x OCH,), 8.1(b~,2H,5-,6-H),8.4(k2H33-,4-H), 9.8(d,IH,J=7 H r l - H ) 1.47(t,3H.J = 7 HrCHzCH,), 3.94(~,3H,OCHa),4.24(qJH, J = 7 H&OCH,CH,), 7.24-7.%(m,3H,arom.H), 8.28(diKused d,lH, 5 = 7 Hs3-H),9.38(bs,IH,I-H) 3.8S(s,0CH3),5.82(s,0CHIAr), 7.38(m,4-,5-,6-H),7.40(m,C6H,), 8.38(d,J = 6 Hz,~-H),~.S(I-H) 3.88(OCH3), 5.19(OCH2Ar).7.15-7.6(8H.arorn. H),8.38(d,J= 6 Hz, 3-H), 9.y I-H) 3.87(s,3H,0CH3),5.28(s,2H,0CHzAr),6.43(d, lH,arom.H), 7.00-7.44(m,8H,arom.H). 9.37(s.lH,l-H) 5.23(~,4H,2x OCH&H,X 7.1-7.6 (m,13HX 8.31(d,J=6 Hz,~-H), 9.41(~,1H,I-H)

Rd.

-I

4

W

2-C7H 7,4-HO, 6.7-(CH3O), 2-CH3,6.74HO),

2-Y, 8-HO

CD,OD D&CD,OD

CDCI,-TTFA

1-

ao;

TFA

a-

a-

CD3OD CDCI,

DMSO-d,

DMSO-d,

CH,SO; Br-:C,H,OH

CI -

DMSO-d,

DMSO-d,

2-CH 3. h-HO

Pictate

DMSO-d,

CD,OD

CH ,so,

2-Y, 5-HO

2-CH3, 5-HO

DMSO-db

CD,OD CD3OD CD,OD

Br

a-

CI -

CI -

3.3(q,2HX 3.7ysq3H),s.I(d,lH). 5.5(q,2H), 5.6Yq.lH), 6.7(~,1H),7.lys.2H), 7.531, lH), 7.8(d,2H), 8.3d.lHh 9.l(d,lH),9.5(d,lH), 10.09(s,IH) 4.03,4.1qs,bH,2 x OCH 3). 5.93(~,2H,N'CHlAr). 7.3-7.8(~.7H.C,H,, 5-,8-H), 8.35,9.5(~,2H,2-.3-H) 4.37,(~,3H,N+CH,j,7.73, 7.8Ys.2H.5-.8-H),8.23.8.53(ddJ=7HZ. 4-3-H), 9.86(~,1H.1-H) 3.90(s,3H,OCH3), 7.4-8.3(m.SH.3-,4-. arom. H), 9.28(s,lH,I-H) 1.21(1,H,J =7 HzCH,CH,OH), 3.70(q,2HJ= 7 H&CH,CH,OH), 5.21(~,4H.2 x OCH,C,H,), ~.~~(S.~H,N+CH,C,H,), 7.0-7.9(m, 17H). 8.33,8.73(AB,2H,J-7 H14-,3-H), 10.97(s,lH,I-H) 4.27,4.30(~,6H,2x OCH,), 4.57(q3H.NiCH,), 7.60(s,lH,5-H), 7.7ys,lH,8-H), 8.22(b~,2H,3-,4-H),9.30(9.1H,l-H) 4.07,4.12(~,2x OCH,),4.43(s,N+CH,), 7.64,7.71(~,5-,8-H),8.20, 8.3YABq.J = 7 H&2-.3-H), 9.38(~,1-H) 4.10,4.1~2xOCH3).4.47(N+CH,),7.&, 7.74(5-,8-H),8.23, 8.3yJ-6.8 H&4-,3-H),9.3q1-H)

9.7q1H3 I-H)

6.7(s,IH). 7.2(s,2H),7.6(t,lH). 7.83d,2H), 8.5Yd.IH). 9.1yd. lH), t0.09(s,lH) 4.40(N+CHJ),8.52QH.arom. af picratc), 7.5-8.5(5H.nrom.H),

3.3~q.2H),3.7~s.3H),5.1(ld,lH),5.5(q,2H),5.6~q,IH),

7.7(5H,C,H,),8.0-8.7(5H,3-.5-,6,7-,8-H), 9.3 lH, 1-H) 7.2-7.8(4H,C,H,). 8.0-8.7(5H,3-,5-,6-,7-,8-H), 9.3IH, 1-HI 3.97(3H,OCH3). 7.1 -7.7(4H.C,HA), 7.9-8.7(5H.3-,5-,6-.7;8-H), 9.q lH.1-H) 2.46(s,3H,ArCH3), 6.17(s,2H, N'CH,C,H,), 7.30-8.90(m. I3H.arom.H). 8.98(~, 1H,3-H), 10.72(~,lH,I-H) 3.66(OCH3).4.40(N'CH3), 7.33(dd,8-H),7.67(m,ZH,6-.7-H), 8.29, 8.35(d,l=6.8 HZ..4-,3-H),9.61(S.l-H)

805

43

804

433

780 781

230

131

I22

230

I22

210

710

23 1 23 I 23 1

QI

w 4

salt

&tho protons

CDIOD

TFA

I-

Cl-: 1.5 H,O

TFA

Solvent

I-

of benzoyloxy group. Measured at the center of an AB system. Part of an AB system. ' The spoctral data (Ref. 127) are presented as figure. Aromatic protons of a phenethyl group.

a

2-CH3, 6,74CH3O)Z3 8+-HOCHlC,H,0)

2-E3,4-(CH,O),C,H,COCH,I, 6.74CH30)Z 2-[3,e(OCH,O)C,H,(CH*),]. 7,8-CH,0),

~-CL~-(CH~~)~C~H~CH CIZ- ] . 674CH3O)Z

Substitucnt


3.3Yt.2H,N +CH,CH,Ar), 4.20(s,6H,2 x OCH,), 5.qt,2H,N+CH2CH,Ar), 5.95(s.2H,0CH20),6.5,6.8(m,3H,arom. He).8.08(s,2H,5-,6-H), 8.25(~,2H,3-,4-H), 9.2S(s,IH, I-H) 3.76,4.17(7-,4-OCH,), 4.41(N*CH,). 4.57(28), 6.97, 7.33d.4H. J = 8 Hz),7.67(S-H),8.29(d,lH,J=6 Hq4-H). 8.44(qd,IH,J=2,6 l 4 ~ 3 - H ) . 9.44(bs,I-H)

3.82.3.94,4.08,4.15(s, IZH, 4 x OCH,, 6.10(s, 2H, NtCHzAr), 6.92-7.58(m.4H.arom H), 7.98(s, lH, arom. H), 8.14, 8.48(ABq.2H,J=7.5 Hz, 4.3-H), 10.72(s,lH,l-H) 7.25(s,2H,N +CH,Ar), 8.9(bs,2H,3-,4-H), 9.25(s IH,I-H)

8 (PPm)

763

56

199

826

Ref.

\o

4

W

Salt or Anion

DMSO-d, DZO DMSO-db CDCI, DMSO-d, DMSO,-db

CDCI,

H Br

HBr

HBr

HCI

Hcl

HCI

6.7-(HO),

7,8iHO), 6 C H ,O, N-oxide

5.7-(CH30),

5.84CH3O)Z

5-C2H,0, 6-CH30

D2O

CDCI, CDCI,

DMSO-d,

DMSO-d,

DMSO-d,

DMSO-d,

Solvent

8-HO, 7-CHJO

HCI

HBr

7-HO, 5-CHJO

7-HO, 6-CH30

H Br

HCI

b-HO, 8-CHJO

5-HO. 8-CHJO

5-HO. 6-CH,O

(a) 3,4-Dihydroisoquinolinulsand Their Ethers

Substituent

TABLE 15. DIHYDROISOQUINOLINES AND THEIR DERIVATIVES Ref.

3.03. 3.86(4H.4-,3-H), 4.00(3H,OCH,). 7.15,7.53(2H,7-,8-H). 267 8-931 H.1 -HL9.M 1H.OH) 2.50.3.60(4H,4-,3-H). 3.80(3H,OCH,). 6.86,6.90(2H.6-,7-H), 267 8.43 1H, I-H) 3.03,3.R0(4H,4~,3~H),3.92(3H,OCH~).6.49(2H,5-.7~~), 8.8Q1H.1-H). 267 1 i.B(2H,OH.N+H) 21q2H.4-H). 3.8q 3M,OCH3). 3.85(2H.3-H), 6.89.6.9S(2H.b.,I(-H 1, 267 9.16( IH.1-H), I0.1(2H,OH.N+H) 3.93(sa3H.0CH3). 6.69,6.90(~,2H,5-.8-H) 266 3.93(OCH,).6.67,6.88(arom. H).8.21(t,IH,J=2.3 HzI-H) 336 2.30(1.2H,4-H), 3.16(s,3H,OCH3). 3.19(t,2H,>H).6.14.6.27 300 (S.ZH.~-.&H). 7.8%~,IH, I-H) 2.95, 3.85(3H,4-,3-H), 3.89(3H,OCH,).6.80,7.34(2H,5-,6-H), 267 9.0 I( 1H . I-H) 300 222(t.ZH.4-H), 3.131t.2H.3-H). 5.93, 6.28(s,2H.arom. H), 7.79( S, 1H,1-H ) 2.93. 3.83(4H,4-,3-H), 6.66.7.79(2H,5-,6-H).9.01H,I-H) 67 I 3.12(t, 1 H , J = 7 Hz),,3.82(~,3H).4.OY1.2H,J=7 Ht),6.80(4 IH, 729 J = 2 Hz),6.82(dd,IH.J=2,8 Hz), 7.12(d,lH.J=8 H~).7.77(s,lH) 267 2.93,3.88(4H,4-,3-H), 3.85,3.88(6H,2 x OCHA), 7.03,7.19(2H.&,S-H), 9.1S( 1H, I-H) 2.94,3.86(4H.4,3-H), 3.78,386(6H,2 x OCHII. 7.10,7.S2(2H,C, 267 7-H), ,8.W( IH, I -H) 1.38(t.3H,I=7 H&CH3). 2.74(t,2H,J=2H HGQH). I47 3 . 7 q t d , m , ~=a,z HG 3-14),3 . 8 9 ( s . 3 ~ , 0 ~ ~ , ~ 4.02(qV2H,J= 7 Hit,OCH,), 6.80,7.03(AB,2H, J = S Hgar0rn.H). 8.24(t,IH,J=2 H s l - H )

(PPm)

CDCI,

CDCI,

DMSO-d,

CDCl,

DMSO-I,

2-CH3 7-HO, K H 3 O

c1D20

(b) Quaternary Salts of 3,4Dihydroisoquinolinolr and Their Ethers

6-CqHT0, 7,8-(CH,O)z

HCI

HC)

CDCI,

CDCI,

6CH30,7-C7H,O

cm3

CDCI,

Solvent

CDCI,

Salt or Anion

6,74CH30),, N-oxide

Substbuent


6.8qs,IH,arom.

H),7.37(~,5H,C,H,),8.17(s,lH,I-H)

3.W%3H,N+CH3),3.78(s,3H,0CH3),6.74,6.89(%2H,arom.H), 8.5O(S, lH, I-H)

2.61(1,2H.J=8 Hz,~-H),3.70(m2N.J=2,8 H2.3-H), 4.88(s,3H,0CH3), 5.1O(s,2H,OCH2Ar),6.65. 6.79(~,2H,8-,5-H),8.1 1(t, 1H J = 2 HG I-H) 3.03,3.81(4H,4-,3-H), 3.97(6H,2 x OCH,), 6.65(2H,5-,7-H), 8.78( IH, I-H) 2.54(P,4H.J=8 H2,3-,4H), 3.89,3.93(~,6H,7-,8-OCH,), 6.90(~,2H,5;6-H).8.7(bS, 1-H) 3.05,3.91(4H,4-,3-H), 3.91,4.00(68.2~OCH,),7.17, 7.56(2H,5-,6-H), 9.i2(1H, 1-H) 2.58-3.Wm,4H.4-,3-H). 3.87.3.!W(s,6H,2 x OCH,). 5.1Ys 2H.0CH2ArX 6.48(s, 1H . 5-H), 7.40(m, SH,C,H,), E.Sl(t,lH,J =2.5 Hz, 1-H) 260-3.7qm,4H,4-,3-H), 3.87,3.9S(~,6H,2 x OCH,), 5.15(s,2H, OCH,Arh 7.4i(m,5H,C6H,), 8.58,(1,IHJ =2.5 H a I-H)

3.7’(2H,3-H), 82(t,lHJ=2 Hal-H), 2.63(bq,2H,J = 8 Hz). 3.74(m,2H).3.87(s,6H), 6.65(s,lHX 678(s,IHX 8.2qbs.lH) 3.13(1,2Hb=8 Hz),3.90,3.93(~,6H),4.08(l,ZH, J = 8 Hz). 6.70,6.80,7.70(~.3H) 2.63(1,2H.J =8 Hz.4-H). 3.71(rn,2H,3-H), 3.87(s,3H,OCH,), 5.11(q2H, OCH,ArX 6.68(s,lH,amm. H).

6 (PPm)

20 1

265

265

671

189

267

355

270

729

292

503

Rel.

Bc -

Br-

D20

I-

CD,OD

CDCI,

cm3

3.16(t,2ZHJ=7.5 H~4-l-l).3.8-4.0(rn.2H.3-H), 3.88,3.94.3.96. 4.Ws, 12H,4 x OCH,), 5.4&2H,N +CH,Ar). 6.94-7.34(m.4H.arorn. H), 7.74(s,lH,arorn. Ff), 10.46(s.1H,!-HJ 3.0-4.qm,4H,4-,3-Hb 3.8Ysq6H,2x OCH,), 3.86, 3.93(s.6H,2 xOCH,), 5.10(s,2H,NSCH,Ar), 7.03,7.08, 7.43(s.3H,arorn. H).9.01(s. lH,I-H) 3.20(t.J=7.5 H e e H ) , 3.8-4.0(m.3-H), 3.77,3.82(~,6H,2xOCH,). 3.8qa6H.2 x OCH,).5.4ys.N +CHzAr),6.ms.5-H). 6.95-7.2qm. arom.H), 7.69(s,8-H), lO.I~s,I-H)

to.oys,IH.l-H)

CDCI,

1-

CDCl, CDCI,

TFA

c1-

362

826

8 26

826

830 360

275

2.88.3.2qt,J=8 H2,4-.3-H), 3.76(~.3H,N'CH3), 3.88. 3.96(~.6H, 2xOCH3),7.OB(s,1H.arom. H),8.72(s,IH.arorn. H) 3.91,4.00(2 x OCH,). 6.83. 7.7qarom. H),lO.l3$s,l-H) 3.21 (bm,4H.4;3-Hb 3.90,3.99(~,6H.2Y OCH,), 5.78(s.2H.CH,ArX 6.88(s, 1 H,S-H), 7.62-83 (m, SH.arom. H), 10.25(s, 1 H,1-H1 3.0-3.7(m,4H.4-.3-H), 3.88- 3.95(s,6H.2 x OCH,). 5.38 (&2H,N CH,Arh 5.9Ys2H.0CtlzO), 6.7-7.2(m.4H,arorn. H), 7.68(s,IH,arorn. H),

TFA

c1-

8.0S(brs. I-H)

1.!wt,3H,J = 7 HsCH,), 3.10-3.55(m,4H.4-,3-H). 272 3.74s.3H.N +CH,), 4.WS.3H.OCH3b 4.03(q,2H.J = 7 HIOCHZ), 7.28,7.69(A3.2H,J=8 Hz.ar0rn.H). 9.17(bs.lH,I-H) 3.29. 3.89(tL4H,J= 7 Hq4-,3-H), 3.80 s,3H,N 'CH,). 433 6.17(~.2H,OCH,0), 6.94(~,lH,S-H), 7.14(~,IH,B-HI, 8.52L~,Iff.!-H) 3.37,4.W1,4H,J=7 Hq4-,3-H). 3.87(~,38,N'CH,I4.07,4.12(s6H, 433 2 x OCH,), 7 . I q s I H.5-H). 7.43[5,1H,&H). 8.7%~.IH. I-H) 2.56,3.6!(t,J =7.8 H54-,3-H), 3.80(2 x OCH,),6.51,6.73(~,5-,8-H). 43

DMSO-d,

1-

Suhtit uent

Table IS. (Conrinued)

CDCl, CDCI, CW,

3r-

%I-

1-

I-

CI-

I-

CD,OD

CD,OD

CDCi,

Br-

%r-

CD,OD

Solvent

a-

8r-

Salt or Anion

830

360

826

362

Rd.

-

830 6.82,7.45(~,2H,5-,8-H),9 . 8 % ~I-H) 3.40,4.031n,4H,C,3-H), 393(~.3H,N+CH3), 400 4.03(~,3H.OCH3),6.94.7.73 (~,2H,5-,8-H), S.2qs,2ff,0CH2Ar), 7.40(m,SH,C 6Hs), 8.78(s, Iff, I-H) 3.05,3.8qt,4N.J = 8 Hz4-.3-H), 5.07,5.18(s,4ff.2x OCH,Ar), 364 5.39(s,2H,N+CHz,Ar),6.90,7.78(~,2H.arom.H), 7.0-7.7(111,15H, 3 xC ~ H , ) ,10.31(~,lff,l-H) 3.0-3.20(111,2H,4-H), 3.92,3.95@,6H,2 x OCH3), 3.6-4.l(m,2H,3-H), 764 6.60(b6.2H,5-,7-H), $.92(bs,lH, I-H) 433 3.27,4.10(1,4H,J=7 H2,4-,3-H), 3.w~,3H.N+CH3),4.00, 4.20(~,6H.2x OCH,), 7.14,7.32(d,2H,J=8.5 HsS-,6-H), 9.12(~,1H,I-H) 3.39(te,4H,J=8 Hz),3.86(~,3H,N+CH3),3.95,4.I0(&6H,7-, 290 8-OCH3). 7.15, 7.52(d.lH,J=& HZ,S-,CHX9.27(bs,IH,I-H)

4.05,4.10,4.20(3xOCH3),6.18(s,2H.N+CHzCO),

3.20(tJ=7.5 Hs4-H), 3.8-4.0(rn,3-H).3.92,3.9@,2 x OCH3), 5.46(s,N+CH2Ar.).5.9qs,%HzO), 6.75(4J=8.5 HGarom. H), 6.82(s,S-H], 7.0-7.2(m,arorn. H), 10.24(s,lH) 2.9-3.S(m,4H,4-,3-H), 3.81,3.83, 3.85, 3.95(s,12H,4 x OCH,), 5.Ws,2H,N+CH2Ar), 6.8-7.2(rn,4H,arom. H), 7 4 s , I H , arorn.H), 9.01(s,IH,l-H) 1.37(t33H,J= 7 Hz,CH,CH~),3.28(bm4H,4-,3-H), 3.94(d.6H,2 x OCH,), 4.36(q.2H,J= 7 H G O C H ~CH~) , 5.70(s,2H,CH2Ar),6.99-8.0(rn,6H,arom. H) 4.00(6H,2 x OCH,), 6.41,6.83~,2H,5-.8-H),lO.OO(s.1-H)

6 (PPd

00

W

6,7-(OCH,O)

(c) Alkoxy- 1.2-dihydro-2-(p-losyl)isoquinolines 7-CH 3 0

c1o;

CDCI,

CDCI,

CDCI,

CDCI,

DMSO-I,

D,o

TFA

CDClj

DMSO-I,

-

2.38(~,ArCH,),3.76($OCH,), 4.56( I-H), 5.82(d.J = 7 Ha 4-H), 6.78(d.J = 7 Hz.3-H). 6.80(m,5-,6-H), 7.28, 7 . 7 3 6 5 = 8 Hrarom. H ) 2.45(s.ArCH,), 4.231-HA 5.95(s,0CH20). 6.47{d,J= 7 H2.4-H), 6.69(~,5*,8-H), 6.83(d,J = 7 HZ.3-H), 7.35.7.75 ( d J - 8 Hz,arom. H) 2.37(s.ArCH,). 3.72(~,2x OCH,). 4.60(1-H). 6.11(d,J=8 Hg 4-H), 6.61IS,6*,7-H8),6.7Yd.J = 8 Hz3-H), 7.27, 7.7qd.J = 8 Hz,arom. H ) 2.31(s,ArCH3), 3.76(s.2 x OCH,), 4.52( I-H), 5.77(d,J=8 H r 4-H), 6.49(5-H). 6.56(8-H),6,68(d,J=8 HZ.3-H), 7.24. 7.72(d,J = 8 H i a r o m . H )

-

3.07.(t.2H.J=8 H14-H). 3.76(s.3H,N+CH3), 3.93~,3H.oCH,), 3.9'(t.ZH.J=8 Hr3-H), 5.22(~,2H,OCHzAr). 7.13. 7.47(AB 2W.J = 8 Hr,5-,6-H), 7.43(~,5H,C,H,) 3.16,3.98( t,4H,4-,3-H). 3.8qs. 3H, N 'CH J), 3.89(OCH,). 7.28(6.5-,6-H), 5.30(OCH,Ar), 7.35(C,H 5), 8.73 I-H) 3.I8,3.95(~,4H.J = 7 Hr4-.3-H), 3.75(s,3H,N*CHS). 4.27is.38. OCH,), 6.12(s,2H,OCH,O), 6.58(~,1N.5-H),8.72(~,1H.t.H) 3.88(3H.N 'CH,). 3.97,4.10,4.18(~,9H,3x OCH,], 7 . 0 w 1 H,5-H). 9.09(~.1H, I-H) 3.08(t,ZH,4-H),- 3.80(rn,2H,3-H), 3.80. 3.98(s.6#.2 x OCH,), 5.33(m.4H.OCH,Ar.NfCH,A~), 7.1 I(s.IH.5-H), -7.SQ111.10tf. 2 x C ~ H , ) , ~ . ~ I ( S . I H , I - H )

24

24

24

24

286

406

433

4M)

403

z CDCI, CJXI,

5,6.74CH,O),

6,7,84CH,O),

'

a

Half of an A2X, triplet. further spilitting (J=2 Hz) into six lines. Closely overtapping triplet. Closely overlapping poorly diffused triplet. Patially hidden by the N+CH3and OCH, signals. ' In the original literature these assignments are described as 5 and 8 positions

CDCI

7&(C,H,O)2

,

CDCI,

CDC13

7-CH30, 8-C,H,O

~

Solvent CDCI,

~~~

!&It or Anion

7,8-(CH3011

~~

Substituent


2.32(s,ArCH,). 3.7qs.2 xOCH,), 4.62(1-H), 5.72(d.J=8 Hz, 4-H). 6.61(~,5-,6-H),6.62(d,J=8 Hs3-H), 7.20.7.66(d J = 8 Hzarom. H) 2.29(s,ArCH3),3.76(qOCH3),4.37( I-H).4.90(s,0CH2Ar), 5.61(d,J = 8 HzCH), 6.55(m,3-,5-,6-H,arom.H), 7.36(m,arom. H) 2.29(qArCH3),3.76(s,0CH1,),4.37( I-H), 4.90(s,0CH2Ar), H), 5.61(d,J = 8 H~3-H).6.40-6.71(3H.arom. 7.07-7.63(9H,arom. H) 2.35(st3H.ArCH,h 4.50(~,2H,I-H), 4.95, 5.05(~,4H2x OCH,Ar). 5.7qd. 1H,J = 7.9 Hz,Q-HX 6.57,6.74(AB,2H,J = 8.5 Hz,S;~-H), 6.624d,IH,J=7.9 Hz3-H), 7.15(AB,2H,J=8.3 Hz,.arom. Hh7.30. 7.33(s.IOH,C6H,). 7.6qAB,2H,J=8.3 Hzarom. H) 2.39(rArCH3),3.72(m), 3.83(s,3 x OCH,), 4.5ql-H), 6.09(d,J = 6 Hz4-H). 6.33(~,8-H),6.67(d,J=6 Hz,3-H), 7.22,7.69(d,J = 8 HLarom. H) 244(s,ArCH,), 3.85(m,3 x OCH& 4.33(1-H) 6.69(d,J=6 WLCH), 6.80(~,S-H), 7.06(d.J=6 Hs3-HA 7.36,7.70(d,J = 8 Hzarom. H)

6 (PPm)

24

24

30

29

24

24

Ref.

W

v,

~~

' Overlapped with a proton at 8 position.

8-oxidoiscquIndinIum

3,4-Dihydro-6.7-dimethoxy-2-methyl-

6-oxidoisoquinoliniurn 3,4-Di hydro-6,7-methylenedioxyS-oxidoisoquinolinium (cotarnoline) 3,4-Dihydro-6,7dimethoxy8-oxidoisoquinolinium

3,4-Dihydro-7,8dimethoxy-2-methyl-

2-Methyl-6-oxidoisoquinolinium

Struaure

TABLE 16. PHENOL BETAINES

DMSO

DMSO

ACCIOW-~~

DMSO-Ib-TFA Acetone-d,

DMSO-I6

Solvent -

6( P W ) ~

~~

3.92(N'CH,). 6.32(dgJ=2Hz, 5-H),6.77(q.J=9 Hz. 7-H), 7.13(d, J = 7 HG 4-H). 7 . W ( d , 3-H), 7.62(d, 8-H). 8.50(1-H) 4.d0(N'CH3), 9.67(1H, I-H) 2.80(1,4.H), 3.40(N*CH,), 3.55(t, 3-H), 3.76. 3.92(7-.8-OCH,), 5.85(1-H). 7.80(5-H) 2.82(t. 4-H), 3.49(N+CH,), 3.60(t, 3-H), 5.67(OCH20), 5.72(1-H), 8.20(5-H) 2.75(m,4ff), 3.82(3H), 3,88(s. 3 H ) . 6.20(s, I f f ) , 8.33(bs, 1H) 2.85(m, 4H), 3.4% 3H). 3.60(s, 3H),3.824%3H), 6 1O(s. 1H).8.40(1 H)

~

680

680

510

230 510

230

Ref.

o\

00

W

Salt Solvent

DMSO-d,

DMW, DMSOd6

D M Sod6 DMSO-d, DMSO-d,

HCI

HCI

HBr

HCI

HCI HBr

640

7-HO

CDCI,

2-CH,OzC, 5-CH,COz

CDCI,

W l S DMSOd,

l-Dz, 3-D,, 4-HO 5-HO

2-CH,OzC, 5-HO

CDCI,

4-HO

HCI

CCI,

2-HO

(a) 1,2,3,4-Tetrahydmisoquinolinolsand Their Derivatives

Substituent

6( P P 4 2.94(b~,4H, 3-,4-H), 3.94(b~,2H, 1-H), 6.99(b, 4H, 5-,6-,7-,8-H). 7.67(b, 1 H,OH) 2,47(bs. 2H. 3-H), 3.7(b~,4H, I-H. NH, OH), 4.43(t. 1H,4-H), 7.16(m, 4H. arorn. HI 2.7(bs, 2H,OH, NH),4.52(s, 1H,4-H), 6.95-7.5(m, 4H) 2.79(t, 2H.4-H), 3.27(t, ?H.3-H), 4.11(~.2H, I-H), 6.59(d, IH, J = 7 Hz, 6-H), 6.80(d, lH, J ~ 7 . Hz, 5 8-H). 7.00(t, IH, 7-H). 9.71(bs, OH, N'H,) 2.94(t,J=5.9 H z , ~ - H )3.85(t. , J = 6 Hz, 3-H), 3.91(s,OCH,), 4.63(s, I-H), 6.73-7.18(m, arom. H, OH) 2.73(t, J-5.9 Hr4-H), 3.68(t,J=6.1 Hz, 3-H), 3.73. 3.88, 4.63(s. 1-H), 6.87-7.27(rn, arorn. H) 3.24(t, 2H,3-H), 4.06(~,2H, 1-H), 6.60(bs. IH, S-H), 2.89(t, 2H,4-H), 6.64ldd. 1H,J=2.5,8Hz,7-H),6.97(d,tH,J=8Hz,8-H), 9.48(s, 1H.OI-l).9.67(b,N+HL) 2.89(t, 4-H), 3.24(t, 3-H) 2.92(t, J=6.5 Hz, 4-H), 3.33(t, J z 5 . 8 Hz, 3-H), 4.15(~,1-H), 6.61 (s, 5-H), 6.69(d, J = 1.95 Hz, 7-H), 7.02(d, J = 8.3 HZ 8-H), 9.44(0H, N+Hz) 2.87(1,2H, 4-H). 3.25(t, 2H.3-H), 4.10(~,2H, 1-H), 6.60(b~.lH, 8-H), 6.68(dd, lH, J=2.5,8 Hz, 6-H), 6.96(d, 1 H , J = 8 Hz, 5-H), 9.61(b, OH, N+H,) 2.87(t, 4-H), 3.25(t, 3-H) 2.88(t,J=5.48 Hz, 4H), 3.33(t.J=5.37 Hz, 3-H), 4.18(~,l-H), 6.61(~,8-H). 6.70(d,l=8.31 Hz, 6-H), 7.00(d, J-8.31 Hz, 5-Hh 9.42-9.18(OH, N+tI,)

TABLE 17. TETRAHYDROISOQUINOLINES AND THEIR DERIVATIVES

789 757

121

789 757

121

757

757

831 I21

786

571

Ref.

0 21

W

DMSO-d6

HBr

H Br

5-HO. 7-CHJW

6-HO. S-CH,O

HCI

D*O

HCI

DMSO-d,

CDCI,

D,O

HCI

7-HO. 6-CH,O

2-CH0, 7-HO. MHaO

DMSO-dh

DMSO-I,

DMSO-dh

2-CHO, 7-HO, 5-CH3O.

7-HO, 5-CHSO

HBr

DMSO-dh

H Br

2-CH0, 6-HO, S-CHJO

CDCI, DMSO-I,

HCI

2-CH 3CO. 7-CH 3C0, 8-HO

DMSO-I,

CDCI,

2-CHJCO. 7-HO 2.18(COCH,), 4.54, 4.68(~.2H, I-H). 6.76(8-H), 8.72. 7.01(d, 1 H, arom. H) 2.16(s, 3H. NCOCH,), 2.28(s. 3H,OCOCH,), 4.59. 4.70(s, 2H. I-H) 2.94(m. 2H. 4-H). 3.27(m. 2H. 3-H). 4.00(s, 2H. I-H), 6.72(d, I H , J = 7 HL 7-H). 6.7R(d. 1 H. J = 7.5 Hz, 5-HI, 7.M(1. 1H.6-H). 9.72(b. N'H,). 9.96(b,OH) 2.94(1, J = 6 . 3 H z 4 - H ) , 3.34(1.J=5.6Hz9 3-H). 4.05(~,I-H). 6+66(d.J-7.8 HZ 7-H), 6.75(d. J =8.4 Hz, S-H), 7.08(t, J ~ 7 . H8 L 6-H), 9.13(bs. NH), 9.87(bs. OH) 2.82(1.2H, J = 6 HG 4-H). 3.45(1. 2H, I =6 HL 3-H), 3.67(~,3H. OCHJ), 4.16(~,2H. 1-H), 6.25td. I H , 5 = 2 Hz. 6-H), 6.36(d. I H , J = 2 Hz.8-H). 9.03(s,ZH. N'H,), 9.65(~.IH,OH) 2.87, 3.30(4H. 4-,3-H). 3.76(3H. OCH,)), 3.98(2H, I-HI. 6.23, 6.33(2ff. S.7-H). 9.25(3H. OH, N'H,) 2*73,3.60(4H. 4-. 3-H). 3.75(3H. OCHJ, 4.21(2H. I-HI. 6.17, 6.27(2H, 5-,7-H), 8.13. 8.20(1H.NCHO). 9.23(1H.OH) 2.68, 3.29(4H,4-,3-H), 3.71(3H,0CH3),4.11(2H, I-H), 6.18, 6.33(2H, 6-.8-H), 9.27(3H, OH, N'H,) 2.50, 3.57(4H. 4-.3-H), 3.70(3H, OCH,). 4.41(2H, I-H), 6.17, 6.24(2H,6-.8-H). 8.12, 8.16(IH,NCHO), 9.26(1H,OH) 3.3, 3.6(48,4-,3-H), 3.94(3H, OCH,), 4.25(2H, I-H), 6.99, 7.06(2H, 5-,8-H) 3.10(t, 2H. 4-H), 3.57(t, 2H, 3-H), 3.88(~,3H, OCH,), 4.30(s. 2H. I-H). 6.72. 6.87(s. 2H.worn. fl) 2.78(t. 2H,4-H), 3.5-3.8(rn. 2H. 3-H), 3.8% 3H, OCI-I,), 4.42, 4.56(2H, I-H). 6.18(1H,OH), 6.60, 6.66(2H, 5-,8-H), 8.16, 8.20(1H, NCHO) 2.83(t. 2 H , J = 6 Hz.4-H). 3.21(t, 2H, J = 6 HC 3-H), 3.74(s, 3H.OCH3),4.09(s. 2H, I-H), 6.71, 5.82(AB, 2H. J = 8 . 5 Hz, 5-,6-H), 9.30-10.10(b, 3H. OH, N*H,)

568

400

300

400

267

267

267

267

562

757

121

77 I

771

00

00

W

4.S*(HO)2, 7-CH3O 4,6+(HO)2.7-CH,O 4,7-(Ho),, 6-CH30

7,8-(HO)*

GHO, 7,8-(CH30)2

CHO, 6,7-(OCH,O) CHO,7,8-(CH30),

4HO,5,8-(CH30)2 2-CHaCO. &HO, 5,8-(CH30)2

Substituent


HCI

HCI HC1

Ha

HCI

HCI

Mt

DZO

DMSO-d,

CDCI,

CDCI, CDCI,

DMSGd,

CDCI3-TFA CDCI,

DMSO-d,

Solvent

561

L52(t, 2H,J=5.5Hg4-H), 280(t,2H,J=5.5&3-H), 3.67(~.5H. I-H, OCH,), 5.2(b, 2H. OH, NH), 6.38, 6.63(AB, 2H. J = 8 HC S.6-H) 3.04, 3.47(t, 4H, 4-,3-H), 3.86(~,3H. OCH,), 4.28(~,2H, I-H), 6.78, 6.98(d, 2H, 5-.6-H) 6.7, 4.8(d, J=8.5 Hz, 5-,6-H) 2.6-2.85(rn, 2H, CH), 3.4-3.8(m, 2H,3-H), 3.79(s, 3H, OCH3), 4.44, 4.58(2H, 1-H), 5.85(bs, IH,OH). 6.5-6.7(m, 2H. 5-,6-H), 8.12, 8.19(1H, NCHO) 2.82Irough t, 2 H , J = 6 Hz,4-H), 3.63, 3.78(1,2H,I=6 Hz, 3-H), 3.88(~,3H,OCH3). 4.55. 4.68(~,2H. 1-H). 5.72(~,lH, OH), 6.7ob(AB. 2H,5-,6-H), 8.22, 8.28(s, lH, NHCO) 3.70, 3.78(s, 6H, 2xOCH3), 4 . W . lH,4-H),6.68(~,2H,arom. H) I.I5(COCH,), 3.78, 3.83(~.6H, ZXOCH~), 4.95(bt, lH,&H). 6.70(bs, 2H, arorn. H) 3.3-3.7(q, 3-H), 4.8-5.l(asyrn. t,4-H),4.2-4.4(9, I-H) .2.98(m,2H. 3-H), 3.24(bs, 3H,2xOCH3), 3.8-4.6(m, 2H, 4-H, NH), 6.89, 7.12(d, 2 H , J = 8 Hz, 5-,6-H) -2.68(m 2H, 4-H), -3.07(m. 2H. 3-H), 3.80, 3.85(s. 6H, 2xOCH3). -3.90(rn,2H, I-H), 6.42(s, lH, 5-H) 2.92, 3.22(AABB’. 4H. 5 = 6 HZ, C,3-H), 4.07(~,2H, 1-H), 6.51, 6.75(AB, 2H,J=8.5 Hz, 5*,4H) 3.3-3.7(q, 3-H), 4.8-5.l(asym. 1, 4-H),4.3b(AB, I- 13 Hg 1-H) 3.3-3.7(t, 3-H), 4.8-5.l(asym. t, 4-H),4.2-4.4(~,I-H) 2.50(t, 2H, 3-H), 3.93% 3H, OCHI), 4.33(~,2H, 1-H), 5.05(1,2H, 4-H, OH), 6.75, 7.10(s, arom. H)

548 548 548

%a

262

49

548

832 832

403

400

399

400

Rd.

6 bpml

2

W

CDCI,

DMSO-d6

DMSO-d,

CDCI,

5-CHjO

HCI

CDCI,

4CH30

I-CH,O, 2-(C6H,CHzCO)

(b) Alkoxy-I,2,3,4-tctrahydroisoquinolinesand Their Derivatives

3.B. 3.29(s, 3H, OCH,). 25-4.0(m,4H,4-,3-H), 5.82, 6.55(s.0.71/0.29H, I-H), 7.32(m.9H. arom.H) 2.95(& 2H. 3-H). 3.75[~,6H. 1-H, OCH,, NH (exchangeable with D,O)], 4.44(1, IH, QH), 7.15(m, 4H. arom. H) 2.07(~, NH), 2.63(t, J 5.86 Hz,4-H), 3.10(t.J = 5.86 Hz., 3-H). 3.79(OCH3). 3.95(s. IH), 6.61(d, I = 7.92 H g atom. H), 6.65(d, J = 8.3 Hz,arom. H). 7.08(t, J = 7.71 Hz, 7-H) 2.81(t, 2H.4-H), 3.25(t. 2H, 3-H), 4.14(~,2H, I-H), 3.76(~,3H,OCH3),6.76(d,lH,J-8H~CH),6.84(d,lH, J = 8 HG 8-H), 7.18(t, IH, 7-H), 9.86(d, W , N'H,) 2.59, 3.60(4H, 4-,3-H), 3.76(3H, OCHJ, 4.52(2)1, 1-H), 6.50-6.90. 7.03(38.6-.7-,8-H), 8.14,8.19(1H,NCHO) 2.66(t, J = 5.9 Hz, 4-H), 3.57(t. 6.1 Hz,3-H), 3.63, 3.70(2 x OCH,), 4.46(s.I-H), 6.43-7.12(m, arom. H)

2.88, 3,25(111,4H, 4.3-H), 3.77(~.3H. OCHS).4.00(~.2H.1-H), 6.32(~.1H.5-H). 8.53. 8.88(b,2H. 2xOH). 9.H)(b,2H, N'HZ) 3.3-3.7(q. 3-H), rl.l-S.l(asym. 1.4-H), 4.3*(AB. J = 13 Hz, I-H) 3.3-3.8(mr, 2H.3-H), 4.3(s, 2H. I-H). 4.9{rnd,4-H), 6.7,6.95(~.2H. S.8-H) 3.60(t, 2H. 3-H), 4.33(~,ZH, I-H), S.OO(t, IH,&H). 6.78. 7.00(s. 2H.arom. H) 3.55(m. 2H), 4.26(s. 2H), 4.95(t. IH, J = 3 Hz), 6.68, 6.91(s, 2H)

757

267

121

757

786

788

525

550

546

US

545

s

0

2*CH&O. 7-CH 3 8-CH30

7-CHaO

6-CH 3

Substituent

0


HCI

HCI

HCI

salt

CXl,

CDCI,

CDCI,

DMSO-db

CWI,

cm,

CDCI,

DMSO-db

CDCI,

Solvent

7%

121

757

Rd

77 I 833

173

121

~.~~(s,NH~,~.~~(~,J=~.SHZ,CH),~.O~(~,J=S.~H~ 757 3-H), 3.75(OCHJ, 3.90(5, I-H), 6.61(d, J = 8.1 Hz, 7-H), 6.67(d,J=7.2 WZ,5-H), 7.07(t,J=7.8 Hz,6-H)

2.90(1, 2H. 4-H), 3.24(t. 2H, 3-H), 3.69(~,3H. OCH3), 6.77(d, IH,J=Z.SHz.S-H), 6.78(dd, 1H,J=2.5, 9 Hz, 6-H), 7.07(d, lH, J = 9 HL 5-H), 9.84{d.2H,N+H2) 3.0, 3.5(1,4H, 4.3-H), 3.8(s, 3H,OCH,), 6.8(unresolved t, 6H), 6.9(d,IH,J=2.6H~,8-H),7.2(d,IH,J=8.6HZ,5-H) 2.07(s. 3H, NCOCH,). 3.68(s, 3H, OCHJ 1.58(s, IH), 2.75, 3.OD(d.4H.J=5 Hz),3.73(s. 3H), 3,90(9,2H). 6.61(m. 2H), 7.031~ IH)

6.67(dd,lH,J=3,9H~.7-H),6.92(d,lH,J=9H~,8-H).7.27. 7.67(AB, 4H. J =8 Hz, arom. H) 2.40(~,NH),2.68(t,J=5.8 Hz,4-H), 3.07(t,J=5.8 Hz, 3-H), 757 3.75(0CH3), 3.88(~,1-HI, 6.94(6J = 7.8 Hz, 5-H) 3.65(~,3H,OCH,), 4.55(~,2H,1-H) 77 1

1.64(S, NH), 2.75(1 J ~ 6 . H 2 s 4-H), 3.03(t. J = 5 Hz,3-H), 3.73(OCH3), 3.88(bs, l-H), 6.57(h 5-H), 6.68(d, J=7.7 Hz, &H), 6.86(d.I = 7.7 H& 8-H) 2.96(t. 2H,4H),3.24(1.2H, 3-H). 3.70(~,3H, OCH,), 4.0!3(~,2H, 1-H), 6 . 7 3 h lH, 5-H), 6.77(dd,J=2.5. 9 Hz. 7-Hh 7.09(d. IH,J =9 HG 8-H), 9.84(b,2H, N'HZ) 2.41(~,3H. ArCH,). 2.87(1,5=6 Hz, 4-H), 3.32It. 2H. J = 6 Hz, 3-H), 3.73(s, 3H. OCH,), 4.16(s, 2H, 1-H), 6.55(d, I f f , 5-H),

6 bpm)

2-CHO,5-CH,O, 74 1-Phcnyltetrazolyl-5-oxy) 2-[(CH,),CCO]. 6,7-(OCH,O)

2-CHO, 8-CH30

HCI

HCI

HCI

CD,OD

D,O

CDCI,

CDCI,

DMSO-d,

DMSO-d,

CDCI,

CDCI,

CDCI,

DMSO-rlh

DMSO-J, 2.96(1, ZH, 4-HI. 3.24(t, 2H. 3-H). 3.78(~,3H. OCH,). 4.00(~,2H. I-H), 6.77(d. IH. J = 3 HZ 7-H), 6,84(d. I H , J = 8 HLS-H). 7.21(t. IH,6-H), 9.85(b. 2H, N'H,) 2.95. 3.6W4H. 4-,3-H). 3.79(3H. OC'H,). 4.40(2ff, I-H)% 6.60-6.91. 7.15(3H, 5-,6-.7-H). 8.1 I . 1.20(111, NCHO) 1 . 2 8 [ ~9H. C(CH,),]. 2.80(bt. 2H. 4-H), 3.8(s, 3H. OCH,), 3.5-4.0(m. 2II. 3-H). 4.65(s, 2H. 1-H), 6.5 -7.4(m. 3H. arom. H) 2.811. ZH. 4-H). 3 . 7 ( ~5H. , OCH,, I-H), 4.6(bs, 2H. 3-H), 6.5-7.3(m, 3H, worn. €4). 7.4{s. 5H,C,H,) 2.41(~,3H, ArCH,), 2.89, 3.32(1. 4H. 5 = 6 Hr,4-,3-H), 3.76(~.3H. OC'H,). 4.16(~.2H. I-H). 6.63(d. 2H. 1 = 9 Hz.5-,7-H). 7.07(t,lH.J=9Hz.6-H). 7.27. 7 . 7 1 ( d , 4 H . J = 8 H ~ a r o m .H) 1.331s. 9H. C(CH,),J. 2.83(bt* 2H. 4-H), 3.73s. 3H. OCH,). 3.5 4.0(m. 2H.3-H), 4.67(bs, ZH,I-H), 6.5-7.2(rn, 3H. arorn. H). 7.37(s. 4H, C6H4) 2.8(1,2H. J - 6 Hz 4-H). 3.73(s, 3H, OCH,), 3.5-4.0(m. 2H. 3-H), 4.6S(bs 2H, 1-H), 6.5-7.7(m. IZH, arom. H) 2.85, 3.32(4H,4-.3-H), 3.76, 3.81(~,6H. 2 xOCH,). 4.15(2H. 1-H). 6.40, 6.48(2H, 6-.8-H), 9.62{2H, "HI) 2.66. 3.65(4H. 4-,3-H). 3.75(3H, OCH,], 4.54(2H, 1 -H), 6.95, 7.05(2H, 6-,8-H), 7.50-8.00(5H, C,H,), 8.16. 8.21(IH, NCHO) 1 C(CH,),]. 2.76. 3.78(t. 5 = 6 Hz. 4-.3-H), 4.63(s, 1-H) 5.88(s, OCH,O), 6.56(s, arom. H) 4.15(s, 2H, I-H), 6.52, 6.47(~,2H, 5-,8-H) Z.IO(NH), 3.77(2 x OCH,),6.47, 6.63(s, arom. H) 3.0(1,2H, +H), 3.5(t, 2H, 3-H), 3.8(~.6H,2 x OCH,), 4.3(s 2H, I-H), 6.0, 6.8(s, 2H. arom. H) 3.80(s, 6H. 2 x OCH,), 4.27(5,2H. I-Hj. 6.78. 6.80(s, 2H, arorn. H) 521

796 712 773

757

26 7

267

833

833

796

833

x33

267

121

2-CH SCO, 6,7-(CH 3 0 ) 2 2-C,H,O,C, 6,7*(CH,O),

Substitucnt


Salt

CDCI,

CDCI,

CDCI,

CDCI, CDC1,

Solvent

-

2.93, 3.68(t, 4-,3-H), 4.38(1-H), 6.66, 6.67(5-,8-H), 7.37(CH-N), 7.66, 8.14(AB, arom. H) 1.99, 2.03(~12H,4 x COCHJ, 2.75, 3.7C(t, 4H, 4.3-H). 3.78(s, 3H, WHd, 4.24(m,2H, sugar CH,), 4.55(s, 2H, 1-H), 4.85-5.35(m, 4H. sugar CH), 5.18(s, 2H, OCH,C6H,), 6.68, 6.90(~,2H, S-,8-H), 7.38(~,5H. C,HJ 3.43. 3.85(4H, 43-H), 4.08, 4.10(2 x OCHJ, 4.47(2H, 1-H), 6.75(231, S.7-H) 3.0, 3.4(n 4H, 4-,3-H), 3.8, 3.9(5 6H, 2 x OCH,), 4 . 4 ( ~ , 2 HI-H), , 7.l(~,ZH, 5-,6-H)

4.469 4.55[~,lH( 3 : 2r,I-H)] 1.37(1, CH,), 3.90(~,2 x OCHj), 4.62(~,2H, I-H), 6.63, 6.67(s, arom. H) 3.83(2 X OCH,), 4.62(bS, CHZCCI,). 4.73(~,I-H), 6.57.6.60(s, arom.H) 1.30[s, C(CH3)J, 2.78(1, J -8 Hz,4-H), 3.76-3.88(m, 2 x OCH,, 3-H), 4.66(s, I-H). 6.58(s, ZH,arom. H) 1.20(t, CH,), 2.62-3.05(m, 4H, 4-H, CH,CO). 3.26(t, 2H, SCH,), 3.53(t,3-H), 3.80(~,6H. 2 x OCH,), 4.36(~,1-HI, 6.51, 6.57(~,5-J-H) 287, 3.59(t,4,3-H), 4.36(~,I-H). 6.71, 6.72(~,5-,8-H), 7.61. 8.M(AB. arom. H) 2.72(4 4-W 3 W t . 3-H). 3.83(6H, 2 x OCH,), 4.13(~,ZH, SCH,), 4.26(s, 1-H).6.42-6.57(5-,8-H). 7.00-7.67(m, arom. H) 4.18( 1 -H), 6.51, 6.55(5-J-H)

6 (PPm)

773

267

787

835

7%

565

835

565

757

772

834 772

Ref.

2-CHO. 7-CHl0, 8-( 1-Phenyl-tetrazolyl-5-oxy)

HCI

HCI

HCI

HCI

TFA

HCI

J

CDCI,

J

TFA

HCI

CDCl

CDCI

HCI

DMSO-d6

CDCI, 2.6-2.9(m,2H,4-H), 3.4-3.8(m.ZH,J-H). 3.M. 3.86(3H.0CH3). 4.26, 4.60(2H, I-H), 5.07(2H, OCH,Ar), 6.80(2H, 5-.6-H), 7.34(5H.C6H,), 7.96, 8.13(1H. NCHO) 2.03, 2.08(s. 12H,4xC0CH3), 2.75, 3.71(1,4H,4-,3-H), 3.78(s. 3 H , OCH,), 4.2S(m, 2H.sugar CH,). 4.6(s, 2H, I-H). 5.20(s 2H. C,H,CH,O), 5.35(m,4H. sugar CH). 6.64. 6.90(~.2H, 5-,8-H), 7.40(~,SH,C*H,) 2.90, 3.73(4H. 4-.3-H), 3.90(3H, OCH,), 4.45(2H, 1-H). 7.00, 7.15(2H, S.7-H). 7.60-8.03{5H, C6H5),8.24, 8.34(IH, NCHO) 3.85, 3.88(~,3 x OCHJ). 2.97(t, 2H, 4H), 3.5(1,2H, 3-H), 4.3(~.2H, I-H), 6.7(~,IH. 8-H) 3.10(1. ZH, J = 6 HG 4-H), 3.55-3.85(111, 2H. 3-H). 3.92(~,3H. OCH,), 4.48(bt, ZH, I = 5 HG 1-H). 5.99(s, 2H, OCH,O). 6.66(s. IH, 6-H), 7.66(bs, N'H,) 3.07(t,2H.J=6Hz,4-H). 3.5&3.80(m.2H.3-H), 3.93(s. 3H, OCH,), 3.9(s. 3 H , OCH,),3.96(46H, 2 x OCH,), 4.58(b1,2H,J=5 HG I-H), 6.70(~,1H. 6-H), 7.65(bs, 2H. N'H,) 2.53-2.65, 289-3.02(m, 4H, 4-,3-H), 3.70, 3.78(~.12H. 4 Y OCHS), 3.80(bs,2H. I-H) 2.92-3.12. 3.35-3.4S(m. 4H. 4.3-H). 3.75. 3.78, 3.81. 3.84(S, 12H. 4 x OCH,).4.16(b~,2H, I-H), 9.82(bs, 2H, NH,HCI) 3.2(mV4H.4-,3-H),3.83, 3.86, 3.88, 3.9(s, 12H, 4 xOCH,), 4.2(bs. 2H, I-H) 3.64.21m: 2H. 3-H), 4.35-5.1(m, ZH, I-H), 5.2(s, OH), 5.1-5.8(m:' 1H,4H), 7.35(s, ZH,5-,6-H) 3.5l(m, 2H), 4.33(ABq, 2H). 4.99(t, IH, J = 3 Hz),6.95(s, 2H)

525

546

773

790

790

547

547

773

267

787

400

'

H Br

Salt

~~

D2O

DMSad,

solvent

CDCI,

'

Measured at the center of an AB system. AB Part of an ABX system. X Part of an ABX system. ' Coalesces to a single line at 80°C.

' J Values are not described in the original literature (Ref. 267).

&%

CDCI,

1-C2HS0,3-CH30

1J-(C,H

CDCls

5-HO

(c) 5.6.7.8-Tetrahydroisoqurnolinols and Their Ethers

6,7-(HO),

8-HO. 6,7-(CH,O),

Substituent


~~

2.0(m,4H, 2 x CHI), 2.7(m, ZH, CHI), 4.7(m, IH, 5-H), 6.1 (s. I H, OH), 7.4(d, IH, J = 5 Hq 4-H), 8.2 (m. 2H,1-,3-H) 1.34(t, 3H, I = 7 HG CHjCH,), 1.5-1.87, 2.3-2.74(111,8H), 3.75(~,3H. OCH,), 4.34(q. 2H, 5 = 7 HG CHICH,), 5.94(s, 1H) 1.28, 1.32(t,6H.J=7 Hz,2xCHZCHa). 1.76-1.9, 2.35-2.7(rn, 8H), 4.22,4.3(q, 4H, 5 = 7 Hz, 2 xCH,CH,), 5.89(s,lH)

2.86(m, 4H, 4-,3-H), 3.75/3.66[(5/3)s, (I-H, 2 x OCH,)],

S.OO(b, 2H. OH, NH), 6.21(s, IH, 5-H) 3.09(m2H), 3.60(m,2H), 4.90,6.84(m, 2H)

2.55,

-- -

d(PP4

622

622

79 I

543

286

Ref.

IX. Analysis and Spectroscopy

395

TABLE 18. DECAHY DROlSOQUINOLINOLS Structure ( f)-4,4a-cis-4a.&-1rons-Decahydro-

Solvent

CDCI, 4-isoquinolinol (kt4,4a-rr(ms-448a-rra~-Decahydro- CDCI, 4isoquinolinol ( )-4,4a-cis-4a,8a-cis-DecahydroCDCI, 4-isoquinolinol ( f)-4,4a-rrans-4a,&-cis-DecahydroCDC1, Cisoquinolinol

6 (ppm)

Ref.

3.53 (b, 1H. W/2= 6 Hz,4-H)

630

3.33 (b. lH, W/2= 22 Hz, 4-H)

630

3.68 (b, IH, W / 2 = 17 Hz.4-H)

118

3.61 (b, I f f , W / 2 = 14 H z , ~ - H )

118

Anion Solvent

CDCI,

I-CH,&HCH,S

I-[(E)-CHjCH=CHSJ

CDCI, CKI3

DCI-D,O

l-CIH,S 1-CzH,SO,

I-CHpCHS

I-CH3S02

1-CH,SO

CDCI, DCI-D,O or DzSO,-DzO CDCI, CDCI,

CDCI3 DCI-DZO CDCI,

I-CH3S

I-CICHZS

CDCl,

I-CH,SOz, CCH,SO,O

8 (PPm)

3.55(CH3), 7.92(4-8), 7.95(5-,6-.7-H), 8.58(3-H), 9.09(8-H) 3.43(s, 3 H , CW,), 7.40-7.9O(m, 4H, arorn. H), 8.32(d, 1 H , J = 6 Hr3-H), 8.84(m, lH, 8-H) 3.92(CH,), 8.6(5-,6;7-H), 9.1(3-&H), 9.2(8-H) 5.17-5.46(m,2H. vinylic H),6.83(d, IH, vinylic H). 7.45-9.00(m, 6H.arom. H) 7.18(4 l H , J = d H t 4 - H ) , 8.20(d, 1H.J=6H2.3-H) 1.52(t, 3H,5=8 %CH,CH,). 3.78(q,2H. J = 8 Hz,CH,CH,), 7.44-8.24(rn, 4H, arorn. H). 8.51(d, IH,J=~Hz,~-H),~.O~(~,IH,~-H) 4.02(d, 2H. J ='I HI, CH,), 4.95-5.75(ABXm 3H, CH-CH,), 7.21(d, lH, J = 6 Hr4-H), 8.21(d, lH, J = 6 H&3-H), 7.3-7.7, 8.0-8.15jrn, 4H,arom. H) 1.85(dd. 3H, J = 1.5.6 H z C H X H C H &, 5.72-6.06(rn, lH,vinylic H), 7.17(d, IH, J = 6 & vinylic H), 7.33-8.27(m, 6H, arom. H)

3.35(~,3H .OSOICHJ, 3.51(~,3H, SOZCH,), 7.5&8.40(111, 3H), 8.56(s,3-H), 9.02(m,8-H) 2.75(CH,), 7.45(4-H), 7.?5(5-,6.7-H), 8.34(8-H). 8.47{3-H) 2.93(CHj), 7.78(4-H), 8.00(5-,&-.7-,8-H). 8.05(3-H) 5.38(s, ZH, SCH,CI), 7.27-7.72(m, 4H). 7.85-8.07(m, 1H). 8.27(d, 1H , J = 6 Hz,3-H) 2.99(CHj), 7.5-7.8(5;6,7-H), 8.65(3H), 8.80(S-H) 3.33(CH3), 8.92(3-H), 8.3-8.5(5-,&,7-,8-H), 8.79(4-H)

(a) Alkylthioisoquinolinesand 1-Methylsulfinyl- and CUkyl(aryl)sulfonyl-isoquinolines

Substitucnts

TABLE 19. ISOQUINOLINETHIOLS AND THEIR DERIVATIVES

83?

641

576

793

74 751

576

74

79

19

74 835

74

576

Rel.

CWI, DCCI,

CDCI,

1- ( PTOSYI)

3-CH sS0,

3-CZH5SOZ

1-DS, 2-CH3

DSOi DSO;

(b) Quaternary Salts of Isoquinoline-l(2H)-thione

cDc1,

I-CeH $0,

50% DZSO4-AcOD

10% DZSO4-AcOD

DMSO-db

DMSO-d,

CDCI,

CDCI,

1-(2-Oxocyclohexylthio)

4.64(N+CH3). 300 (dec)'

-

207 207-208

-

23 1-233

Mp or Bp ('C)

90

1073 197

98 6 98 98 684

6 3,91,92,94.97, 107,114,122, 123,154.17 I , 177.183.185189,195,204. 2052 10.224. 225,234,235, 557,756,76 1, 785,798,800, 801,847-854, 856-858, 1073,1074 92 131 687 92 92

Rd.

2n oz n

2

2

I

X

I

2

0

2

I

2

X

X

I

I

X

I

I

I

z

I

T

I

403

H

H

H

H

n

H

H

H

H

HO

H

4 "

H

HO

H H

H

H

H

H

H

H

H

R'

H

R'


R3

H 0-CHI-0

H

CHJO

HO

H H

H

R4

CHSO

CH30

HO

C,HgO

H CH,O

H

R'

pCEI,OC,H*CO, H

HO

H

H

C6HSCOI H

HO

R'

HCI

Picric acid Ficric acid

Picric acid Styphnic acid

HCI HCI

Picric acid

H*Ptfl,

HCI

HCI

HCI

Salts with

218-220 220-225 M4-206 270-272'

-

249-250 159-163 181-1 83 183-184

252-254

-

182-183

279-280 206 179 l8&181.5

285 76-77

I

-

244

240-242

-

MP or BP ("c)

139

50

24

50

14 13

50

59 50 866.867 131-133 15 35 868 21 201,503 21 21 24

90

177,183, 185-189,236, 785,798,858. 861,863,1075 107 59 236

Ref.

H HO

H H

H

H

H H

H

HO

CH,C02

CHjO H HO C,H,CO, H H

H

H H H H H H

H

H H HO HO

H

CH,O CH,O

CH,O CH,O CH,O CH,O

0-CHI-0

0-CHa-0

' Browned BI 215'C. ' Labelled with tnO. ' Sublimed at lsO°C/9 x lo-' mm and measured in a sealed tube. ' Blackened at 20°C. ' Water of crystallization. The salt contains two bases. Dried at 50-60 'C. ' Darkened at > 260 "C.

CH,COl

ti H H H H

H H HO

H

H

H

NaO CH,CO, HO NaO CH,CO, H

H

CHSO CH,O H H H HO H

CH,O CH,O CH,O CH,O

CHIC02

HO

HO C.SH5COI H

HO

HO H

H H H H

H

H

HBr:H,O'

HCI

HCI HCI

HCI

:H,O'

-

220 (dec) 253-257 (dw) 250 (dec)

162- 163 -

-L

-

96-98.5 243-245 242-244 (dec) 264-265 196-197 (dw) 116-117

-

..

> 360 134- I36

51 135

m

54 89,l 79.1 80 I02 102 55.117 51

232

I39 I39 I39 I39 I 39 821 220 57 131,133

n-CdH90

CH, =CHCH20

i-C3H70

C2H50

C2H50

CH,O

CH,O

R

TABLE 23. ALKOXYISOQUINOLINES A. I-ALKOXYISOQUINOLINESAND THEIR DERIVATIVES

R

Picric acid

Picric acid

Picric acid

N-wxide HsCIz Picric acid Picric acid Picric acid Picric acid

Salh with

-

-

156 156-1 57 12813 rnm 170 102-104/1.5 mrn

156 160-162 161-162 163.5-165.5 (dw] 1 69 170- 17 1 102-102.5/3.5 mm 7210.3 mm -

s4ss

Il6-119/8-9mm 119p rnm 135-136/21 rnm 138-14/25 rnm 240 -

Mp or Bp ("C)

80 74,79 69 76 113,163,823, 838,869 69 838 69 69 73 213

70

109 129,130 78

822

70 742 68 74 109 129,130,172 176,754,798,822

Ref.

3-Quinol yloxy

2-H ydroxy-3-neopentylaminopropoxy 2-H ydroxy-H 1',I 'dimethylpropyny1amino)propony

2-Hydroxy-3-(2-methyl-3'-butylarnino)propoxy 3-Cydopentylamino-2-hydroxypropoxy

'.

3-( 1'-Morphoriny1)propoxy 2- Hydroxy-3-( I I'-dimethyl-2-propenylamino)propoxy 2-Hydroxy-3-( l',l'-dimethyl-2'-propynylamino)propoxy

2-Hydroxy-3-isopropylaminopropoxy 3-Cyclopropylamino-2-hydrox ypropoxy 2-H ydroxy-3-isobut ylaminopropoxy 3-t-3ut ytamino-2-hydroxypropoxy 2-nydr~wy-3-(2-hydroxy-I '.I '-dimethylethylaminu~propoxy

HCI

Fumaric acid

Picric acid

Fumaric acid Furnaric acid Maleic acid Maleic acid Maleic acid

Maleic acid Furnaric acid Maleic acid Maleic acid Naphthalene-l.5disulfonic acid

Picric acid

75

6355.66 75 75 75

.-

172- 173/2 m m 121-123

77.87.88 81 75

82

110.1 1 I 75 75 75 75 75 75 77.87.88

75

75 75

81 75 75

105

63.65 77.82 77.82 870

282-284' 98 148-1496

-

I 7 6 1 71b 176- 177' 178- l 8 P 115-117' 151- 153" 75-76

195-196/2 mrn

178- 180" 180' 168- 171

166-167" -b

._.

133- 134/2 mrn 40.5-42 195.5 - 196 68-69 69

3-(2’-Phenethyl)-2-phenyl-5-oxazolidinylmethoxy 3-[ 2‘-(p-Chlorophenyl)ethyl)]-2-phcnyl-5~x~lidinylmethoxy 3-[2’-(p-Tolyl)ethyl)]-2-phenyl-5-oxazolidInylmethoxy 3-~2’~3’.4-Dimethoxyphenyl)ethyl]-2-phenyl-5-oxazolidinylmethoxy 34 1‘-Adamantyl)-2-phenyI-5-oxazolidinylmet hoxy

D-a-Tetraacetylglucosyl 3-( I’,I’-Dimethyl-2’-propenyl)-2-phenyl-5-oxazolidinylmethoxy 34 1‘.I ‘-Dimethyl-2’-propynyl)-2-phenyl-S-oxazolidinylmethoxy 34 I ‘.I ’-Dimethyl-3’-butyny~)-2-phenyl-5-0x~lidinylmethoxy 3-Cyclopentyl-2-phenyl-5-oxazolidin~Imet hoxy 3-Neopent yl-2-phcnyl-5-oxazolidinylrnet hoxy 34 ]’,I ‘-Dimethylpropyl)-2-phenyl-5-mazolidinylmethoxy 3-( 1’. I‘-Diethyl-2’-propyny1)-2-phenyl-5-oxazolidinylmethoxy 34 I’-Methylcyclohexyl)-2-phenyl-59xazolidinylmethoxy 3-D-N-Methylmorphinyloxy

2-Hydroxy-3-[2’~3’,4‘-dimethoxy-phenyl)xy ZHydroxy-34I ‘-adamanty1amino)propolry 3-lsopropyl-2-phenyl-5-oxazolidinylme~ hoxy 3-Cyclopropyl-2-phenyl-5-oxazolidinylmethoxy 3-lsobutyl-2-phenyl-5-oxazolidinylmethoxy 3-(2’-Hydroxy-I ’,1 ’-dimethylethyl)-2-pheny~-5-oxazolidinylmethoxy D-fi-Tetraacetylglucosyl

R

TABLE 23. (Continued) Fumaric acid Maleic acid

Salts with

104-107 -_

132- 134 134- 135

-

168-169 166-167*

M P or BP(aC) i5

75

75

15

75

75

81

75 75

15

15

IS

75

75

75

75 75 75 75 75 113 112 112,113

Ref.

III- m I-Ip

t

0

X

c n

f

J,

E

E E

E

2

O

H

0-CH,OC, H 4 0 PCH,W*H40 p-CHOC,H40 7-Isoquinolyloxy

H

H

H

C,H,O PCH JC6H40

(CH,),SiO

C2H50

CH,O

H

R'

H H H H

H

e HH

H H H

H H H

R2 H

(Continued)

H

R'

TABLE 23B.

Picric acid HCI Picric acid

Picric acid

Ficric acid

Picric acid

HCI HCI HCI

Picric acid

Salts with

21 5-2 I6 192-195 %/o.15 mm' 206 207-210 205-206 152-153

.-

130-140/0.06 m d 223 120/5mm

122/1 mm 170 191-194 186-187 164-167 66-67

Mp or Bp ("C)

97,115.856.872 I14 92 122 149 864 I23 85 85 123 123 I23

I14

823,869 106 87 1 871 871 778 85 85

106

Ref.

m

00 Q

I Q -

0

I Q -

0

PQ

0

PQ

2

0

m

N Q

f

X

I

I

I

X

X

I

r

I

2

I

2

41 1

P

N

c

H

CHJO

R'

CH,O

H

R2

H

H

H

H

8'

R'

TABLE 23C. 6-,7-, or 8-ALKOXYISOQUINOLINES AND THEIR DERIVATIVES

Picric acid Picric acid Picric acid

HCl

Salts with

48 48-48.5 49 49-49.5

167

.-

214-216 216 223 225

132-135/5 m m -

Mp or Bp ("C) 859

24

26 4,802

19

874

48 202

46

48.115,164,165,189, 202,245,762798, 872,873 859 46 35

Ref.

H H

HCI H,P1C16 H 2 P1CI6 H ,504 HzCrz07 Oxalic acid Tartaric acid Picric acid F’icric acid Picric acid Picric acid Picric acid Picric acid Picric acid

202

-

245b 24rb(dec)

-

223

-

202-204 7-9 182-183/27mrn 199150 m m

I98 IW-MO (dec)

193-194 193-195 194-195 194- 196

-.

180-182

-

4 1.4

1

2,3 4 4 4

1 4

14 4

7

35

8 3.4 24

1

4 4 7 4

1

762,780.798.875

4 4

22I 235-236 ( ~ c c ) ’ 235-236b

I__

14 8 14 17 1,802 4 39,170,189.245.559,

49-50 I I1/3 m m 118-120/7mm 146-14715 m m 182-186/34mm 194-195/50mm

0

0

' E 'C

s,X.s.s"

x x z z x x x x

20, 2 2

u u

x x

X

x x

X

H

H

H

H

H H CH,O H H H

CHAO H H

RS

H CH,O H H H H CH,O H H H

H

H

H H H H

H

H

H

H

H

H

n

H

H

H

R4

H

R'

R'

R'

H H H

H

CH,O H H

R'

H H 2-H ydroxy-3-isopropylaminopropoxy H 3-r-Butylamino-2-h ydroxy propox y H 3-t-But ylamino-2-hydroxy propox y H 3-Isopropyl-2-phenyl-5-oxazolidinylmethoxy H 3-lsopropyl-2-phenyl-5-oxazolidinylmetho~y H 3-Isopropyl-2-phenyl-5-oxazolidinylmethoxy H 3-t-Butyl-2-phenyl-5-oxazolidinylmethoxy H 3-r-Butyl-2-phenyl-5-oxazolidinylmethoxy H

2-Hydroxy-3-isopropylilminopropoxy 2-H ydraxy-3-isopropylaminopropxy

R'

R4

TABLE 23D. lJ(4.5.6. or 7)-DIALKoXYISOC)UlNOLlNES AND THEIR DERlVATlVES

CH,O

n

H H CH,O

cn,o

H

cn,o

H

H

H

H

H

H H H H

H

H

Rh

Maleic acid

Mdeic acid

Maleic acid

HBr

HBr

HCI

HCI

HCI HCI

Salts wilh

__

-

-

134- I46 190-192"

158.-160' 95-97 144-146'

144

I33 43

56

I75 I42 180 109 148- 150

56

55

Mp or Bp ("C)

75 75 75 75 75 75 75

75

71 71 75 75

t34 72 72 71 71 71 71 71 71 71

ReC.

"WR'

R2

H

H

CH,O

CH3O

CH,O

C,H,O

R'

CH,O

CH,O

H

H

H

H

H

C,H,O

H

CH,O

H

H

H

H

CH,O

H

H

H

H CH,O

RS

R'

R'

CH,O

H

CH,O

R3

R4

R2

HCI HCI

Picric acid Picric acid

HCI Picric acid

Picric acid

Salts with

217-218 Id=) 219-220 Id=)

-

2 10 (dec) 210-212 113-li5

192-193 227 57-58 58 -

-_

211 75-76

-

40

8 0 / W 3 TorP

58

80/10- Tomn

78

Mp or Bp ("C)

TABLE 23E. 3.6(7)- or 5,6(7 or S)-DIALKOXYISOQUINOLINESAND THEIR DERIVATIVES

30

30

40 803 40 24 779,876,871 779 24 24 40 159 40 24 30-32 78I

104 104 I04 104

Ref.

21

e

CH,O

0-CHZ-0

R'

CH,O

R=

H

n

R'

HCI HlPtCI, HZPtCl6 Picric acid Picric acid Picric acid Picric acid Picric acid

Salts with

R'

66 88 89 88-90 91 90-91

250 (dec) 243 (dcc)' r26Sb 204-206 206 235 (dec) 240-241' -

-

.-

I 18 119-120 I22 122- I23 124 127-128 170/1 mm 214-216/50mm

Mp or Bp ("C)

TABLE 23F. 6.7-, 63-, or 7.8-DIALKOXYISOQUINOLlNESAND THEIR DERIVATIVES

52 2 44 4 I17 IS 3s 579 878 24.26

2 24

4

4

44 44 43.143,146.762.825.877

z4

25

52 24 35

Ref,

R'

R2

TABLE 23F. (Continued 1

R'

HQ

HCI HCI:3H,O' HCI HCI HCI

Salts with

208-210 (dK) 216-218 (dec) 219 220 221 (corr)

336

-

93-94.5 94.5 80-100/0.01 mm' 130- 150/0.2 m m 13210.5 m m 132/0.05 m m 140-150/0.1 mmf 152- I58/0.8-0.9 m m 160/1 mm 198-200/10 mrn

93-94

91-92 92-93 92 93 (corr.)

Mp or Bp ("C)

15 22 47 837 45 23

1078

10 44 I92 3,16,36,39,41,58,133, l4O,145,147,151, 155- 1 57,174,194, 196,352,368,426,497, 6'75,752,803,825,826, 872,873,875,877, 880-885,882,1077,

45

I5

22.44,4 7 1 26 125 126 43 42

23

126 17,879 43,192

Ref.

B9 3

I N

r

419

X

x

x

z

X

R'

R2

TABLE 23F. (Continued)

H

H

H

H

H

H

H

H H

H

H H

R3

HCI

HCI

Picric acid

HCI

HCI

HCI

HCI

HCI

191

87

115/0.01 m m 206

112

89 13Spl.05m m 21 1 96 195 89 138/0,01m m 209 127-128 250 (dec)

225

111

66 145/0.01m m I58

-

-

192-195 73 169 150-153

Picric acid

HCI

Mp or Bp ("C)

Salts with

749,887

15

15 15 15

15

36

36

15 IS IS 15 15 IS I5

15

IS

1s

15

IS

15

34

123 15 I5 749

Ref.

H

H

n

H

H H

CiH4

CH,O CH,O

0-CH 2 -0 CH,O CH30

ClHl0

CJ,O

C,H,O

CH30 CH,O

H H CH,O

H

Picric acid Picric acid

HCIO4 Picric acid Picric acid Picric acid Picric acid Picric acid

Picric acid

HCI HCI HCI

172- 175 189-191 70-71

-

205-216 55-60 185- 188 188

197- I93 200-201 204 -

166- 167

-

(I 34/0.5 mrn) 140/1mnl

107-309~.15m m I2%/0.5mm

90

124-125 125- 126 loO/al mm' 230 (dec)

121

68 186 205 200

30

24,29 50

29 59 28 24,27,144,150,890, 1079

888 3,5,9,12,24,41,49.56, 141.l42675.877.888 56 24,26 103 14 5 828

13

9 14

51 20 20 51 51

15

IS

15 IS

H H

H H

2-Hydroxy-3H isopropylarninopropoxy 3-I~0~0pyl-2-ph~yl-S-H oxazolidinylmet hoxy CHAO H CH30 CH,O

H CH,O

H

CH30

CH,O

H

H

CH,O

H

H

CH,O

CH30

CH,O

R’

H

R‘

H

H

H

I-M~thyl-4-pi~ridyl0~y H

(CH,)zN(CHM

H

R’

H

RZ

H

R’

H H

H

CH30 CH,O CH30

H

H

H

H

CH,O

CH,O

CH,O

CH,O

R6

TABLE 23G. TRI- OR TETRAALKOXYISOQUINOLINES AND THEIR DERIVATIVES R‘ R’

It’

HCI Picric acid Picric acid Picric acid

Picric acid

Salts with

180-181 180-182

179

179- I80

-

100/10- Torte 166-167 160/0.5mm

114

98-100

181-182/1 mm 200-201‘ -

Mp or Bp (‘C)

25 24 26

54

821 888 24,25,54.132, 148,675,877, 888,891

104 104

75

67 75

64 64

Rd.

&

w

N

H

' '

H

H

CH30

Labeled with a deuterium at I position. Bath temperature. Sublimation. In vacuum. Water of crystallization.

' Isolated as hydrogen fumarate.

' Isolated as monopicrate.

* The salt contains two bases.

' Isolated as hydrogen maltate.

H

H

H H

H

H

H

H

H H

H H

H H

CH,O

CH,O

H

H

CH,O H

CHJO

CH,O

CH,O CH,O

CH,O

CH,O

CH,O

CH,O

CH ,O

H 0-CHI-0

CHaO

H

C,H,O

CH,O

CH,O CH,O

HCI

Picric acid

H,PtCI, Picnc acid

HCI HCI:fH,O

HCI

HCI

-

148-150

96

179- 180

I65/0.5mm

228

b

192 224

141- 143 142-144 143-144

I59

54 54 675

216 216 37 888 24,888 24 3

I99

37

no2

38 38 37.38 510

R'

HO HO pTosyloxy pTosyloxy pTosyIoxy

HO

HO

HO

HO

HO

R2

TABLE 24. QUATERNARY SALTS OF ISOQUINOLINOLS A. 4- OR 5-ISOQUINOLINOLS AND THEIR DERIVATIVES

R'

H

H

H

H

H H

H H

H

H

R'

R2

X-

aa-

Br-

CI1-:1/2i-I*@

CI-

CI -

c1-

a-

CI 3rBr1IPicrate Picrate Picrate CI -

~-~

185

253 222 213-215 191-192 151 (dcc] 170-173 184-185

208 185-186

224-23V 233 144-145 (dec) 222-226 224-228' 227

-

MP.( 'C)

60

239 100

100

203

206

231 231

203

841,991 222 222 222 23 1

508

222 222

183

Ref.

H

HO HO

HO

H

H

HO

H

I-:2H,0b pTosylate Br OH -:2H,0b C1-:2H20b

Br-

Cr CH,SO; CH,SO; CH3SO; CH$O; pTosylate pTosylate OH-:2H,0b OHBr-:2H2@ Br-

NO;

IIII-

I-

a-

CI-

OHCI CI-:3/2H,Ob

117J

110

212-213

275

-

200 209.4-210.6

7w

I72 100 (dxr 140 270-275 (dec) 280 ( d a y 184-187 -

234-235 235-237 239 239 (dx) 246-247

-

1M(daC) 256-258 259 259-251 (dx)

92 92

1074

92 205

686,687

234235

96 204 92 234.235 92

801

92

90

97 189 92.200 90 225 92 92 210

90 I83

92 90 92

CZH,

2-(3',4',5'-Trimethoxybe1uoyloxy)ethyl 2-(3',4,5'-Trimet hoxybenzoyloxy)propyI 3-(3'.4'.5'-Trimet hoxybenzoy1oxy)propyI

H H H

H

H

H

H H

H

6-(3',4',5'-Trimethoxy bemoy1oxy)hexyl

too-

H

(Continued)

2-(3',4,5'-Trimethoxy benzoy1oxy)ethyl

R'

TABLE 24A. R'

HO

no

HO

%3

Br -

BrCI -

Br-

Picrate BrBrBr-

I-

1'"

BrIBr -

228

1353

203 212 212-213

-

-

195 I95

195

684 685 197 686 687 686 195

122

i95 195 195

-4

N P

CH 3

CH,

R'

HO HO HO

H H

H

R'

H

HO

R'

R4

H

H H

H

H

R4

TABLE 248. 6-, 7-, OR 8-ISOQUINOLINOLS AND THEIR DERIVATIVES

ICI-

r-

I-

CI-

Picratc

BrITartrate

a-

OHC1-:H 'Ob CI - :H,Ob

X-

-

273-274

__

21 8-220

225

2 16-2 I9 202-204 185 (dcc)

-

I26 208

90

122

183 189 18,237 237 874

230 230

m2

202

230 223 230 183

s 0

s

X

X

X

2

z

CI

Q

V

P V

0

428

X. Tables of Isoquinolinols and Their Hydrogenated Derivatives

429

TABLE 24C. ALKOXYISOQUINOLINOLS AND ISOQUINOLINEDIOLS

R’

RZ

R’

R4

R’

HO

H

CH,O

H

H

CH,O

HO

H

H CH,O

CH,O CH,O

HO H

H

HO H

HO

0-CHZ-0

HO

H

0-CHZ-0

H

CH,O

CH,O

HO

H

HO

HO

H

X-

CI -

c1a-

IICI CI CI CI CI CI-:H,Ob HS04:3H,0b SO:- :6H,0b

so:-

Picrate CI ICI -

’ In an evacuated capillary tube.

’ Water of crystallization.

‘ The salt contains two bases.

‘ Decomposition starts at -270°C. ’

The anhydrous product decomposes at 160°C. The anhydrous product melts at 202°C after drying at 1 0 0 - 1 10°C. Over a range starting at 135°C. Dried at 72% in vacuum. Dried at I20 ”C and the anhydrous product is hygroscopic.

MP ( “C)

Ref.

251-253

131,132 133

-

I

217-218 196-197 229-234 23a-239 . ~

-

241-243 (dec) -1

174- 175 188 (dec) 270-275

201 201

13J4 221 131,I 32 133 214 216 504 216 216 216 214 232 232 230

CH,O

R'

CHJO CH,O

H

H

H

R3

R'

CHSO H

H

R2

R'

TABLE 25. QUATERNARY SALTS OF ALKOXYISOQUINOLINES A. QUATERNARY SALTS OF 3-, 4, OR 5-ALKOXYISOQUINOLINES

H

H H

H

R*

a0;

BrBrI-

200-203 227-228 170-173

173-175 (dec)

130-131 (deer

171-173

I-

CI -

139-140 154-155 -

._

104

101-102

MP ('C)

CH,SO; p-Tosylate Picrate

c10; c10; ao;

X-

83 196 196 196 196 196

209 207 892 208 209 209 I081

Ref.

M

30 OI

-u I

9 2,

3u

T

X

b

X

TI:

T

I

X I

I

43 1

R' R1

H

H

H

H H

H

H

H

H H

H

H H H H H

H

H

H H H

H

H H H H

H

H H H

I-

H

H

CI -:CH,OHd BrBrC1-:3/2H,(Y BrBrIBr-:HzW HSO; :H# IIBrBr1-

a-:3/2H,(r

Br-

Cr0,-

X-

'R

R'

TABLE 25B. QUATERNAY SALTS OF 6-,7-. OR 8-ALKOXYISOQUINOLINES

80-83 208-210 182-186 188-189 130-133 63 160-161.5 125-127 115-116 238-240 (da) 121-123

21 1

133- 134 155-158

57

232-234 210-211 140-142

MP ('C)

245 202 202 762 762 202 202 202

202 245

115 202 202 202

202 215 202 202

Ref.

H

CH,O

H H H CH,O

H

H H

H

H

H

H

H H H

H

H H H

H H

H

H

H H H

H H

H

H

n

I(30;

Br-:H,(Y pTosyla te Br-:H20‘ Br-:H,CT BrBrBrI1II-

Br-:H,O‘

CI-:H,OC

H

CI-:H,CT

Br -:H2@ Picrate BrBrBrBr-:H,@ ICI -

1-

1-

H H H H

H

H H H

H

H H

H

188-189

-

137 129 233-235 149-152 173- I76 194-196 207 (dcc) 112-1 1 s 206-208 125- 128 64-65 83-85 83-85 77 144- 146 178-180 105-107 210-213 223-225 165-169 189-191 195-196 196197 196-198

215

4 3 249,894

8 21 1

202 202 202 202 202 202 202

202 202

202 202

202 202 202 202 202 202 202 m2 202

R'

TABLE 25B. (Continued)

H H

H

R2

H H H

CH,O

H

H

CHaO CH,O CH,O CH,O

R4

R3

I-

11IIICI -

c10;

Br1-

IBr -

I-

X-

175-210

I22

-

120

4

4 I23 120.12 I 120 115

4 762 762 895 245 245 245

Ref.

21G215 193- 194 122- 123 219-222 231 -232 204-209.5 196

.....

178- 179 178.5-179.5 114-1 17 -

MP ("C)


435

TABLE 25C. QUATERNARY SALTS OF DI- OR TRIALKOXYISOQUINOLINE R?

RJ

R'

R'

R'

R4

X-

BrBrBrBr-:CzH,OH C1-:3/2Hz0 I-:2HzO

2,4-(N02)zC,H, C7H7

C7H7O C,H70

CH'O H

H CiHiO

CH3 CH3

CH30 CHJO

CH30 CH'O

p-HOCH2C,H,0 p-IHgCH&,HdO

Mp("C)

115-120 102-110 196 240

TABLE 25D. QUATERNAY SALTS OF 6.7-METHYLENEDlOXY ISOQUINOLINE

R

X-

MP ("C)

Ref.

113 119

244 __ b

169- I70 230-232 138-141

4 119,241 I19 119 1 I9 1 I9 213 762 762 244,890

Ref. 895 246,896 78 1 78 1 763 763

436


TABLE 25E. QUATERNARY SALTS OF 6,7-DIMETHOXYISOQUINOLINE

xMP ("c)

X-

R CI CI 111-

II1-

I-

11-

CIO; c10;

na: -

185.5- 186.5 182 223-224 (dw) 234 (dec) 236-237 237 (dec) 238 (dec) 253-254 -256 (dec) (corr.) 295-298

HSO; CHaSO; Picrate Picrate

-b 257-259 202-203 209 221-223

a0;

228-230 244-245

-

clo;

aBrBr -

Picrate

c1-

c1CI Br-

aBr-:H,O

CIO;

c1Br I-

195- I96 160-165 123-125

254 154-155 109-112 115-1 17 168 177-187 114' 204-205

-

Ref. 804 228,897 42 41 226 24 1 191 43 21 23 247,433,803, 894 805 229 221 227 227 241 226 898 238 238 464 198 88I 881 240 126 240,243 244 826 899 238 227 368 368


437

TABLE 25E. (Conrinued) R

~,-WCH~O)ZC~HJCHZ 3NCH ,O)zC6H,CHz

1;

3,YCH,OhCJ+KHz),

CI BrI-

Br1-

I-

2-(3’-Indolyl)cthyl 2-(3’-lndolyl)ethyl

BrBr-:fCH,OH’ I-

I-

C~HSCOCH~ 3,4-(CH,O)zC,H,COCHz

MP (“C)

X-

Picrate BrI-

159-160 137-138 203-204 -

-

209-210 (dm) 210-21 1 215-218 (dm)’ 219(dec) 246-247 (dm) 247-248 (dm) 180

121- 122.5

189-190

Ref. 368 397 397 36 245 36 56 352 194 194 I96 194 1% 199

P

w

W

R’

R2 R3

R4

R4

T A B L E 25F. QUATERNARY SALTS OF 6.7; OR 7.8-DIALKOXYISOQUINOLINES

X-

198-200 181-182 162- 163 164-165 182.5-184

166-1 70 (d=)L 175- 178 174-176 178 182-183 (dK)

208-210 206-207 250

MP (“C)

56 56 50 901

56

12 14 141 13,14 49 803 9

900

9

123

36

Ref.

X. Tables of lsoquinolinols and Their Hydrogenated Derivatives TABLE 2%. QUATERNARY SALTS OF 8-METHOXY-6.7METHY LENEDlOXYlSOQUlNOLlNE

R

XOH C1- :3/2HzO' III1; 1; 1; 1; a04 SCNHgCl; HgCl; HgIi AuCI; AuCI;

ptc1:PtcI: BiBr;

-

M P ("C)

205-208 (dm) -

192 205

I51 - 1 52 160

161 67-70 234-236 __

225

I51

-

220-22Sb -. b

BiI;

SbBr; SbBr; SbI; HSO; Picraie Br Br Br Br Br Br CI -

I 80 225-227 200 195-198 214-215 190

225-227 218-220

Ref. 2 12,2I 6,504 218 212,214,216 504 233 37 198,212,2 16 2 17,248 212 216 218 212 215 212 218 212 212 218 212 218 2 12,216 212 212 212 212 212 233 213.218 198 198

198 198 198 198 198

439

440


TABLE 25H. BIS-QUATERNARY SALTS OF ISOQUINOLINOLS AND THEIR DERIVATIVES

R R'z&N+

xR'

R2

2

HO CH,SO, CH,SO, (CHdzNCOz (CH&NCOz

H H H H H

CHZOCH, CHZOCH, (CH2)IO CH2OCH2 (CH,), (n=3-7) (n=8) (n=9)

%bR R'

'Z'

X'

MP ec,

X-

(n = 10)

II-

237 219

Picrate

I18

IBrBr Br-

221

-

121-125

__

NO;

HSO;

-

c10; (CH&NC02 (CzH,0)2PO2

H H

(CHz)m(n=ll-16) CHZOCH,

H

CH,O (CH,),o

-

257-258

200 684 684 685 1073 1073 1073 1073 1073 1073 1073 1073 1073 197

(C$AB HOZCCOOBrPicrate

-

II-

208-210 (dm) 191 190

-

TABLE 251. BIS-QUATERNARY SALTS OF BISISOQUINOLYL ETHERS

I-

Ref.

123

X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 25J. TRIS-QUATERNARYSALTS OF 4-METHOXYISOQUINOLINE

MP ("C)

X-

aa

225 (dec)

Ref.

192,193

Decomposed on attempted recrystallization.

' The salt contains two bases. Water of crystallization. ' Methanol of crystallization. f

No description.

Softened at 109°C.

' Sintered at 21 1 "C.

The salt decomposes at 166-170°C when heated slowly, but when inserted into a preheated bath at 170"C.it does not decompose until 193°C.

441

S X

x x

X Z T

x x

0,

0

X X X U

x x

x x x

T X

X X X

XI

0

0

0 0

x x

x x

x x

f

d

N

w

A

m

L 442

x x

m N I-. I N N

E

m

s

r 0

I S

x x

PP 0, X

x u

0 0 X

T T E

00

P

zzs

x

0

I

r x 0

0

I I

X X X

I

r r

x x

S

x

X I

I

X

443

H

H

H

H

H

n

H

C , W

R'

RZ

H H

H

H

R'

CH,O

H

R'

H

H

R5

H

H

R6 Salts with

-

156-168

-

I I 1-1 12/10 m m 129-131/16 m m 100-110/0.1 Torr I 55/16 mm -

Mp or Bp ( "C)

TABLE 27. ALKOXY-3.4-DIHYDROISOQUINOLINES A. 1-, 6,OR 8-ALKOXY- A N D 1,4(6)- OR 5,6(7 OR 8)-DIALKOXY-3,4DIHYDROISOQUINOLINES A N D THEIR DERIVATIVES

308

909

324,909

258

254 829,843,872, 912-9 15 916 917

263

910,911

905

Ret

H

H

H H

H

H

H

H

H H H

H

H

CH,O

H H H H CH,O CH30

H H CH,O

H

CH,O H H

H

H H

H

H

H

H

H CH,O H

H H H

CH,O

H H CH,O

H H H

H CH,O

H

HCI Picric acid

HCI HCI HCIO, Picric acid Picric acid HCI HCI

HCI

HCI HCI

267

I60

185-187

-

225-227

203'

293

267

40

460 267

272 267

40 185 186-188

236,833 120,236 308 308 252807 28 1 803

-

-

193'

-

175- 175.5

-

904 322

446

Isoquinolinols and Their Hydrogenated Derivatives TABLE 27B. 3.4-DIHYDRO-6.7-METHYLENEDIOXYISOQUINOLINE A N D ITS DERIVATIVES

0 MP (“C)

Salts with

Ref.

257,276-278 44 44 44 250.256,283,291, 346.36 1,392,532, 554,909,913.91 8-924 276,808.809 321,803.9O9,925 44 276 218 276

90-91 92-94 95-86 170/1mmb

192

HCI

HCI

-~

Picric acid Picric acid Picricacid

H2PtCI,

230-232’ 237-238 238 240 (dec)’

TABLE 27C. 3.4-DIHYDRO-6.7-METHYLENEDIOXY-ISOQUINOLINE A N D ITS DERIVATIVES CH c 3H0 3 Salts with

0

m

MP ( “C)

39-40 53-54.5 132/0.4mm 132/0.6m m 146-14812 m m 150/0.01Tomb lSO/O.STOK 150-156/2-3mm 155-160/1 m m 159-160/1 m m 159-16111 m m 169-170/9mm 205-208/24m m

N Ref.

268,269 417 268,269 42 351 292 555 259 44 358 260 41 297


447

TABLE 27C. (Conrinued)

MP ( 'C)

Salts with -

Ref. 11,19,41,43,45,54.55,117.174J63,273,275,282, 287-289,291-297,300,302-305,307,3 10-3 17, 3 19-324323-339.34 1-345,349,354,360-363,365, 366,4 1 7.429,452,464.468,469,476,477,483-489, 491,492,494,503,555,675,745,750,752,753,784,807, 8 10,826,829,843,880,902-904,907,909,913,918-920, 922-924,926-959,1083 677 677

HCI HCl HCI HCI HCI

194-196 195-196 201-205 (dec) 208 (dec) -

HCI:3HZO' HCI:3H20' HCI:3H20c HCl:3:H20'

72-75 75-76' 72-75

81 1

HCI:3;H,Or

-

HBr HBr H Br HBr

186- 188 196- 198 230 231

412 288 307 300 301 743 165 917 582

-

-

HI

-

HCIO,

194-196 185-187

HZSO, Naphthalene-2sulfonic acid BH3 BH 3 Picric acid Picric acid Picric acid Picric acid Picric acid Picric acid Picric acid Rcric acid Picric acid Picric acid

174- 1 7 9

144.5-145.5 199-200 201-202 20 1-203 201-206 202-203 203 204-206 206-208 207-208 __

35 I

297 275,295,303.3 1 5 3 18,319,321,354,423,425, 478,492,690,728,732,803,8 10,925,961,962 297 305 424,425

426 926 260 351 44 298 47 42 280 297 10 303


448

TABLE 27D. 3,CDIHYDRODIALKOXY- OR TRIALKOXYISOQUINOLINES AND THEIR DERIVATIVES

R4 R'

R2

R3

R*

R' Salts with

H

Mp or Bp ("C) 84-85 86-87

279 253

202 (dec) 202 (dec)' 206

253 253 219 32 1 270 300 355 255 347,354,359,468, 908,923,959 300 354,355,459 764 807 764 267 219 280,347 318 279 782 312,184,835,909. 963,964 782 312 322904,909,922, 925,965 318 341,852,966 300 36

-

H H

HCI HXRCI, Picric acid HCI

CH,O HCI H HCI Picric acid H

H

191-191.5

~-

58-60

HCI

H H

-.

95-96 91-98 101-101.5 183 -

HCI HCI

Ref.

-

20 1-203 m3-204 12 -

-

195 46-47 -

HCI HCI HCI

223-224 250

HCI

-

HCI HCl HCI HCI Oxalic acid Picric acid

103-104 105 192-193

__

-

184 (dec) 188- 189

-

347

300

967 366 36 364


449

TABLE 27D. [Conrinued) R'

H

R2

H 0-CHZ-0 CH,O

H

R3

R*

CH,O

CH j 0

CH,O

H H

Salts with

HCI HCI

143-145 _.

-

HBF,

CH,O

GCHZ-0

M p or Bp ("C)

175-177 89-90 9 1-92 _.

H

CH,O

CH,O

H

CH,O CH,O

CH ,O CH,O

H

H H H

HCI HCI H Br HI H,PtCI, Picric acid Picric acid

182-183 (dec) -4

HCI HCI 2HzO' HCIO, Salicylic acid

152- 153 140-142 167-1 69 122- 123

CH,O

CH,O

CH,O

CH,O

CH,O

181-182 182- 184 91-92 215-217 138-140/0.5 m m

-

44-46 120- 122/0.I m m

C2H50

C2H50

187

__ HCI HCIO, Picric acid

148-150 142-144 172- 174

Ref.

41,290,675,807 267 803 308 308,968 969 38 284 285,423427,429. 492,803,807 284,809,8 12 250 288 250 219 284 250,251 191 306 191 264,274,354 26 1 262,265.27 1,286. 290,970 286 265 265 27 1 264 191 191 232,262,265,27 1 265 265 232


450

TABLE 27E. 3,CDIHYDROTRIALKOXY- OR TETRAALKOXYISOQUINOLINES AND THEIR DERlVATIVES

R'

N* 2R R'

R4 R'

R'

R3

R4

CH30 C,H,O

CH,O CH,O

CH30 CH,O

H

CH,O

CH,O

CH,O

H

CH,O

Salts with

HCI

Acetone/ether. Bath temperature. ' In an evacuated capillary tube. ' The salt contains two bases. Water of crystallization. I Decomposed at 198-201 "C. Double melting points are observed at 170-171 "C and 174-175°C.

MP ("C)

Rd.

-

765 765 675

114

-

o, X u

X

s X

2 0

u

45 1

-t: -8

E

9 s m

v)

ZI

L

s o

v x x

z

02 x x x

452

2

e

W

,

'

HO HO HO HO H

H H HO

HO

H

HO If0 HO

HO

H

HO

HO

HO

H

H

H H H H H

HO

HO

HO HO HO HO HQ

HO

HO

HO HO HO HO HO

SO;-.:

CI 1CI IBr -

CI ICI I-

I

CI -

~

2H2W

CI CF,COO

Water of crystallization. Sintered from 140°C. Sintered from I55 "C. Dried at 100°C. A methoxyl group and a hydroxyl group are located at 6 or 7 and 7 or 6 positions, respectively. The salt contains two bases.

j3-(3',4-Dihydroxyphenyl)ethyl H CHJOO' HO CHICOOH HO CH, H

H

H

n-C,H,

I-C,H,

H

i-C,H,

n-C,H,

CH,COOCHICOOH CHJOCO C,H,OCO --

265-270 (dcc)'

175- 176

203 (corr.) -

173.5 (corr.) -

190.5 (corr.)

-

-

2325 (corr.)

-

741 409

739

372

350 350 350 350 3% 350 350 350

3M

350

975

232 (corr.)

739,913 74 1 974

CH3 H H H

H

H

H CH30 CH30

CH30

H

2-Chlorobenzyl

CH30

H

H

R’

R’

R’

CH30 H H

H H

H

H

H

H

R4

I

1II1-

aa-

1; CI CI III-

1;

i-

r-

a-

X-

CI -

R‘

TABLE 29. QUATERNARY SALTS OF ALKOXY-3,4-DIHYDROISOQUINOLINES A. QUATERNARY SALTS OF 6- OR 8- ALKOXY- AND 5.6-DIALKOXY-3,4DIHYDROtSOQUINOLINES

174-175 165

182-182.5

64 (soft) (corr.) 76 (flow)(corr.) -

82 (dec) 82 (dcc) 156- I58 (dtc) 150 (corr.)’

199 (dcc)

137 (c0rr.P

350 254 254 218,350 254 254 917 350 258,350 258 258 350 350 258.350 120,236 252 272

912

-

-

Ref.

m p rc)

X. Tables of lsoquinolinols and Their Hydrogenated Derivatives

455

TABLE 29B. QUATERNARY SALTS OF 3,4-DIHYDR0-6,7-METHYLENEDlOXYlSOQUJNOLINE

CH,SO; CI CI CI -

aI1-

II-

I1; 1;

-

232-237 233-234 234 238

-

132-134

-

-

HSO;

216 216 (dec)

HSO; HSO; CH,SOi Cr,O+Cr,O:Cr,O:-

cr,o;

HCr,O;

pta: PtcI: Picrate Picrate Picrate Picrate

ClH 5SO;

-

-

117-119 1 74b 175b.' l7Sb

-b

175 (dec) 247 (dec)b __ b

172-173 173 175

-

-

CI -

222 195-197 I75 215

CI BrPicrate CIO;

187-188 230 184-185 186-188

IHPtCI, Picrate Br-

2,3-Methylenedioxy-6(trimethylsilylmethyl~ phenylmethyl

210 212 212 (dec)

c10;

c10;

2,4-(NOz)zC,H, 3.4-Methylenedioxyphenylmethyl

.__

-.

976 375 398,691,977 370 282,374,392,401, 41 1,432,433,437, 450,692,803,813 921 379,977 277,392 356 I91,278,357,367. 398,467,471,978, 979 413 398 387 392 691 370 408 278,392 4 407 691 387 370 4 370,386,387 25 1 388,392,401,414 278 386 392 392 251 251,392 392 470,471 492 340 346 361

456


TABLE 29C. QUATERNARY SALTS OF 3,4-DIHYDRO-6,7-DIMETHOXYISOQUINOLlNE

CHjO

CH3O

X-

R

H CH3

R

CH3SO;

TsO CI CI- 34H20’

clCI -

acl-

MP (“C)

-

61-62 61-62 (corr.) 186 (dec) (c0rr.Y 186 188 (corr.)’

-

OH -

-

CHJSO;

-

CH,SOi

Br Br BrBr1-

II-

II-

1-

IIII1-

1-

I-

1-

I-

2H,O‘

157

87-90‘ 195 (c0rr.Y 212 87-90 (corr.) 18C182 187-I93 189-196 198-200 194 (dec) 191 (dec) 199 199 (dec) 199-201 201 (dec) 201-202 202

203-205 (dw) 218

-

X-

-

BF;

-

ao;

AuCI;

185-187 169 (corr.)

Ref.

783,976

901

291 393 315 375.693 350 217,280, 295-2974 10, 438,810,926 980 366 473 291 393 783 393 459 275 275 955 226 43 555

401

351 47 259 280 288 268,269 23,147,270,289,321. 349,350,363,371, 456,458,467, 471-473,475,493, 743,752,774,803. 901,921,950,953. 976,978,919, 981-983 299,395,474 807,898,984 371 938,985 393

X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 29C. (Conrinued)

NHACHA N+H,(CH,), .Br NH,COCH, n-C3H,

Picrate Picrate Picrate Cl- : 2H,0d CI CI BrIIAuCI; Picrate BrBrBrBrBr- : H,O' CI CI- :2H,O CI Br11-

Picrate I(CH,), Ally1 3.3-Ethylenediox ypropyl

i-C,H, C,H@CO CH,OCOCH, C,H,OCOCH,

169 169-170 (corr.) 170 91-92 (corr.) * 190 (dec) (COIT.). 192 (dec) (corr.) 188-189 186.5 .-

138-139 (corr.) 139-140 (COIT.) 170-171 171

-

226 189 225 (dec) 78-79 (corr.) 177 (dec) (corr.)" 182-183 158 -

148-149 (COIT.)'

1-

-

BrBr-

-

c1-

IICF,COOBrBrBrBrIBrCI-:H,O' Br-:H,O' BrBrBrCI CI II-

161-163

183 (dec) (corr.) 201 (Pas) ._

-

170-172

-

138-139

-

148-149 I92 188 199

205 (dec) I96

-

147-150 169 (dec) (corr.). 152

-

375 393 389,401 295 295 350 463 348 350,743,981 295 295 480 353 273 429 429 429 295 350 288 348 350,981 295 471 830 369 350 348 350,743 975 472 471,481 472 784 939 353 422 429 429 434 986 353 350 348 350,743,981

451


458

TABLE 29C.

(Cunrinued)

R

n-C5H1

MP

X-

1

ICI - :2H,O' CI- :2HzO' CI CI CI I1CI 1-

II-

a-

-

142-143 148-149 197-198 143 (corr.) I23 165 (dec) (corr.)' 134.5 .-

__

I

CI-:H,O" CI -

a-

CI -

189-190 ( d e ) 193-194 (dec) I89 -

BrBrBrBrBr-

181- 183 191 191-192 192-195 ( d e ) 198-200 -

BrBr-

aa-

C,H,CO o-FC,H,CH,

IPicrate CI CI CI- :+H,O' a-:tH,@ Cl-:+H,O' CI-:iH,O' CI- :H20' :H,O' CI - :fH,@

a-

pCIC,H,CHz 2,4-CI,C,jH3CH 2

113-1 I5

-

HSO; CI CI a-:fH,O'

__

157-159 (dec) 80- 120 196-198 (dec) 2049 24lY 225s 2@ 165s 24oL 196-197 194- I96 227-229 182-184 183-184 138'

Ref. 47 1 424,425 423 423 303 350 348 350 350 348 350 47 I 412,478 365 365 412,814.81 5 425 424,425 405 405 492 412 917 452 268,269 309 310.31 3,314 269,362,364. 466,470,471 270,8 10 309 492 917 269.358 358 269,358 358 269.358 358 268,269 917 917 917 268,269 269


459

TABLE 29C. (Conrinued)

R

c1-

3,4-CI,C,H,CH, p-N0,C6H4CH, p-N0,C6H4C0 2.3-Methylenedioxyphenylmethyl 3,QMet hylenedioxyphenylmethyl /?-Acetyl-pisobutylethyl 2,3-Dimethoxyphenylmethyl

BrCI BrCI CI BrBr-

199-202 215' 208-209 187-189 195-197 202-205 200

c111;

CI -

c1-

.-

52-56 123-127 153-154 153-154' __

I1; BrBr - :fH,O' BrBrI-

184-185 160 187-188 187- 188' 186- 188 192-193

Br-

CI Br-

165 154-155 192 196-199 202-203 (dw) 193-195 (dm) 181-183 (dw) -

CI- :H,@

179- 180 189-190

CI Br-

Br-

BrI-

o-CH,C,H,CH, PCHIC~H~CHZ 2-BrCH2C,H4CH2 C~HSCO(CH,)~ C6HlCH =CHCO(CH,), ~-Acctyl-~-benzylethyl 2,2,4,4-Tetraethoxycarbonylbutyl C,H, NHCOCH (C,H,) 3,4,5-TrirnethoxyphenyImethylphenylmethyl

190-192 90-110 164-166

-

ao;

p-CH30C6H4COCH2 pBK~H~COCHI 6-Ethyl-3.4-methylenedioxyphenylmethyl 0-C, H sOCOC6H4CH 1 /3-(3',4'-Dimethoxyphenyi)ethyl

1 W

1-

CI CI CI -

8-(3',4'-Met hy1eneioxyphenyl)ethyl

1W -

CI -

BrBr-

3,QDimethoxyphenylmethyl

MP ("C)

X-

a-

a-

._

c1-

-

CI CI CI -

136137 I72 187-189 (dw) -

ao;

Ref.

269 453 269 360 492 826 362 269 270,810,816 324,325 826 362 826 368 368 397 826 268 269 354 826 397 397 950 349,494 830 830 816 360.489 372 349,494,950 479 495 372 917 917 473 353 303 412 317 42 1 917 985

460


TABLE 29C. (Continued)

R

MP (“C)

X-

6-(Brornomethyl)-3,4-methylenedioxyphenylernthyl 6-(Bromomethyl)-3,4imethoxyphenylmethyl 6-(Trirncthylsilyl)-3,4-dirnethoxyphenylmethyl

X-

Br-

ao;

._

176- 178

X-

__

CI -

-

Ref. 810 472 361 982

476

0 CH,O

c H 3%.CH

c1- :4H@

137

416

C ~ H S OOCzH5 CF3SO;

a-

468.959 303

m

w

VI

I?

N

.r

VI-

IZI?

X

X

I

i

u

461

T

Z

I

%; h)

6-(Trimethylsilylmethyl)-3,4dimethoxyphenylmethyl CH,

~-(3',4'-Dimethoxyphenyl)ethyl 3.43-Trimcthoxyphenylmethyl P C ~ H ~ ~ ~ H ~ C H Z

R'

TABLE 29D. (Continued)

CH30

H

H CH30

CH,O

CH,O CZHSO

H

CH,O

H

H H H

ClHlO

CiHiO ClHlO CiH70

R3

CH,O

CH,O CH,O CH30

R2

R4

1-

a-

II-

a-

CI - :2H,0d Br- :H,Od BrIAuCI; Picrate Br -

c1-

180 (dec)(corr.)" -

-

95 100 164 131-132 155-156 190-191 187'-189,

__

-

145-146 176-178

CI CI IX-

170-172

-

MP ("C)

Br-:H20d

a-

X-

347 350 350

280 280

39 1 391 39 1 764 39 1 39 1 417

354 354 270 354 354 810 373

Ref.

CH,O

CH,O

CH,O CH,O CH,O C7HiO

C7H70

H

H

H

H

CH,O

H

6-Hydroxymethyl-3,4 met hylenedioxyphcnoxy 6-Chloromethyl-3,4methylenedioxyphenoxy 6-Acetoxymcthyl-3,4methylenedioxyphenoxy

C7H7O

H

-.

ICFSSO;

-

._

CI -

__

235 (dec) I-

c10;

c10;

I-

Cl0;

~

-

142-144 176- I77 194-195 165-166 > I 0 0 (dcc) 165-166

-

222-225

135-136 181-182.5 I81 - I83

X-

II-

Br I-

1-

CH,SO; Picrate

ao;

Ic10;

468,959

399

399

374 41 I 314 3% 41 I 41 I 364 764 290 803 807 400 400 402-404 220 399


464

TABLE 29E. QUATERNARY SALTS OF 3.4-DIHYDRO-&METHOXY4,7-METHYLENEDJOXYISOQUINOLINE

R

c1-

X-

CI CI CI- :2H# CI -

Br IIII-

15

I; :H,@ OHXCNNO; HSO;

so:-

H a , AuCI; AuCl; Pta: Ptct: CH,SO; Picrate Picrate Picrate Picrate Phthalate Hydrogen Phthalate:H20' Hydrogen Phthalate

MP ( "C) 190 (dec) 192 197 197 (dec)

Ref.

143-144 102-105 113-1 I5

375 792 818 390,987 29,212,251,283, 369,374,4Oo,401, 409,414,415,419, 427,428,431-433, 436,439,441,446, 441,449,465,490, 692,803,813,988 288 288 284.419 250351 233,248,289,321, 420,471,979 212 396 767 807 449 989 408 409 419 218 390,987 419 219,409 25I 251 390 218,284,401, 987,990 414 987 987

140

987

-

197-198 179 180 184-186

-

142 144

-_

-b

180 136 136-137 212

_.

129-130" 143" 143

X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 29E. (Conrinued)

R

X-

MP ( "C)

Ref.

I-

163-164

284

Br-

209 (dec)

429

a-

182 (dec) 120-122 169- I70 153 201

429 284 284 353 429

193 (dec) 77

429 284 41 2,424,425 418 416 405 416 405 405 416 284 416 492 424

Br1BrBrBrBrc1BrCI BrBrBr' BrBrBrBrc1c1-

-

178- I80 (dm) 151 184-185 (dec) 232 179- 184 (dec) 188-189 (dm) 164 I62 I58 187-188 208-209

465

CH,O CH,O C,H,O H

H

CHI

R'

CH3 CH3 CH, CA,

Ri R'

CH,O

CHSO

R'

CH,O

0 -CH,-O H CHJO CH,O H CH,O CH,O H CH,O 0 --CH,-O

R3

R2

BrIIX-

XCI-: lfH,O" AuCl; Picrate

XX-

X-

TABLE 29F. QlJATERNARY SALTS OF TRIALKOXY-3.4-DIHYDROISOQUINOLINES

-

185 (dec) 127 (dec) 1W 184 179-180 (dec) -

-

MpI'CI

3w 406,411,979 474

191

406

984 984 984 390 390

Ref.

& 4

C',H,O C,H,O

H

H

C,H7

CH,

CZHSO

H

CH 3

CH30

H

C-H,

CH3O CH,O UH,O CH,O

CHaO CHJO

H

H

H

n

H H

CH,

CH 3

CHI CH,

CIH, 3.4,s-Trimethrrryphenylmerhyl

CH,O

CH,O

CZHSO

CH,O

CHJO CH,O

C,H,O CH,O

CHJO

CH,O

CH,O

CH,O

C2HSO

C,H,O

p-HOC,H C,H,O

C,H@

CH,O

CH3O CH 3O

3 0

1-

Br-

I-

Br-

1-

Br "

Br-

Br -

IOH BrBr-

1-

C1~

203 (dec) 170-172

150-151

145-146.5 147- 148

-

163-164 178- 180.5

155-157 (dw)

191 265 232 262

2 18,262

286

22045 I

265 286

980

264 26 I

191

354


468

TABLE 29G. BIS-QUATERNARY SALTS OF 3.4DIHYDRO-6,7-DIMETHOXYISOQUINOLINE

n

X-

2

BrBrCI BrBr-

3 4 5 6 7

8 10

clBrBrBrBrBrBrBrBrI-

I' Dried at

YBrBrBr Br Br Br Br Br Br Br Br BrBr Br iI-

2H2@ 2H,@

2H,@

MP ("C)

Ref.

197-199 197-199 165 181-182 181-182 1% 232-233 232-233 217 203-204 205-207 210 180-181

815 430 430 817 430 430 817 436 430,817 430 430 430.81 5 430 289 32 1 694

-

168-170 -

100°C.

The salt contains two bases.

' Sintered.

' Water of crystallization. ' In a sealed tube.

Sintered at 146°C. Measured on a Buchi apparatus. Measured on a Kofler hot plate. ' Effervesces at 142°C after drying at 80°C in vacuum. Sintered at 125°C. The anhydrous product melts at 135-138°C after drying at 80°C in vacuum. I Solvent of crystallization. Then solidifies on cooling and melts sharply at 143"C. " Sintered at 130°C. Sintered at 90°C. 1

*

'

X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 30. 1,4-, 5 . 6 , AND 7,8-DIHYDROISOQUINOLINOLSAND THEIR ETHERS

R

Salts with

MP ("C)

GHsO

HCI

107

Ref. 499.500

R'

R

R

OH

OH

-

Salts with

Mp("C)

Ref.

-

761

~~

R'

R'

HO(CH,)@

H

H

OH

Salts with

MP ("C)

Picric acid

127-128 155.5-156

Ref. 501,502

501.502 756

TABLE 31. QUATERNARY SALTS OF 7.8-DIHYDRO-6(8HYDROXYETHOXY) ISOQUINOLINE

R 2 m N ; R' xR' CH3

R2 HO (CHzhO

X-

Mp("C)

II-

138-139 139-140

Rd. 502 501,502

469

470


TABLE 32. ALKOXY-1,2-DIHYDRO-2-@-TOSY L) ISOQUINOLINES

R'

R4 R'

R2

R'

R4

H

H

CHJO

H

Mp("C)

Ref.

112-113

26 24 24 24 24 24 24 24,29 27,28 33 30 24 24

-

CH,O CH30 H H H H

H H

CH,O

H

O--CH,-0 CH,O CH30 H CH30 H CHAO

__

H CH,O H H CH,O

-

C7H7O

99.5-100.5

144-145 107-108 10 I - 102 _.

H

103-106 104-106

CH,O H

CH,O CH,O

H CH30

CH,O CH30

TABLE 33. PHENOL BETAINES A. PHENOL BETAINES OF ISOQUINOLINOLS

R'

R'

R' R' CH3 C6H5 C1H7

PNOzC6H4 pCH,0C6H4 CH,

R3

R4

0-

H

H

0000-

H H H H MH2

R2

H

R' ~

H H H H -0

Mp("C)

Ref.

53-54

508 7 7 8 9I 766 766 766 766 214 504

~~~

H H H H

H

-

.-

-. H 0238-240 2H20" 244

X Tables of Isoquinolinols and Their Hydrogenated Derivatives

47 1

TABLE 33B. PHENOL BETAINES OF 3,4-DIHYDROISOQUINOLlNOLS

R?

R'

R' R4

R'

R2

R'

R4

CH,O CH30 CH,O

0H CH30 0-

~

CH,O 00O---CHz-O

CH,O CH30 HO (0-) O-(HO)

0H

0-(NaO)

H

NaO(O-)

HO (0-) 0 - ( H O )

159-165

95- 104

HzO" 4HZW 6Hz04 HZO'

H

~~

680 760

222 (dec) (corr.)

-

235 (dec) (corr.)

509,510,912 214,505,506 509,510 680 410 374 410 410 410

TABLE 33C. EXTERNAL PHENOL BETAINES OF 3,4-DIHYDROISOQUINOLlNOLS

R2

R'

R3

R'

CH,O ( O w ) 0-(CH,O)

HO

HO

CH3O (HO) C,H,O

HO (CH30) CH,O (0-1 0-(CH,O) HO C4,O 0-

Water of crystallization.

XCI- H,O' ICI- 34Hz(T 1-

MP ( "C)

Ref. ~~

186-187 (corr.) 410 181-182 (con.) 410 135 (dec) (corr.) 410 196- 198 41 I

w N

X

2

X

X

X

X

X

X

d

ez

2

ez

0 X

X

X

3:

X

472

W

2

CzH5NHC0 (C~H,)ZNCO C,H,NHCO C,H,NHCS H

CHO

CH,CO

CH,OCO C,H,CO

H

H

H H

CHO C,H,CO C,H,CH,CO NH,(NH)C

H H H H

H H H H H

CH,CO

H

H H

HO HO

HO

HO

H

H

H H H H HO

H H H H

H

HO HO HO HO H

HO HO HO HO

HO

H H

H

H H H

H

H H H H H

H H H H

H

H

H

H

H

H

H

H

H

H H H

H H H H

H

HCI HCI HCl

HCI HCI HCI ( + )-Mandelic acid ( - )-Mandelic acid

105.6-106.7 178-180

-

171-172 172- 174

254 257.6-259.7 275-277 171-172 -

-

185 156 273

__

153 264-266

-J

101-102

201-202 203 (dec) 155- 156" 155-1 56b 108b-r 97-98 -

992 52,575 786.993 566 566 566 566 41 5,548,551, 579.786 786 994 786 786 580 669,83 1 786 786 786 786 96 995 96 557 120 96 615 96 97 995 557 995

H H H H H H

:

H H H H H H

R’

CHO CH,CO pCIC,H,CO NH,(NH)C CH3CO H

NHz(NH)C CH,CO CH30C0 CH3CO C,H,CO H

RZ


H H H H H H

H H H H H H

R3

H H H H H H

HO CH,COZ CH,OCO, C,H,CO, C,H,CO, H

R4

HO HO HO HO CH,CO, H

H H H H H HO

RS

H H H H HO

H

H H H H H H

R6

H H H H H H

R’

HCl HCI HBr Picric acid Picric acid

HCI HCI HCI HCI HBr HBr

Salts with

129-1 30 210-220/18 m m 254-255 210.3-211.4 195 (dcc) 198-201

185.5-186 135-136 170 -

-

196.7-197.8

-

190.5 222-224 233

-

128-130 113-115 192-193

-

-

Mp or Bp (“C)

699 995 557 995 995 263 589,874,902, 987,996 121 263 526 789,696-698 557 615,874,997 615,616 a74 874 699 874 874 599 558,592,600,998 121 514,599,789 557 514 599

Ref.

W

E!

& X

0

0, o x T u x

P

X b X

I X I

x

III

x

x x x

x x x

x

1 x 2

x z x

r

2 x 2

% o x

x x

X X X X

0, X u x

X T T X

z

6

0

0

PP

X T 475

0 0 0

%

x

u x x x

x

X T X X

T

H H

H

H

H

H ? i H 9* H H H

H H

R'

R2

CHO H CHO H

H

H

CZHSCO C,H,OCO CH,CO CZFICO

CHO CH3CO

-


H H H

H

H

H CH30 CH30 H

H

H

cn,o

HO H H

HO HO CH3COZ CZFSCO, HO HO

H H H

H H H H H

H

HO HO

R5

H H

R4

H H

R3

HO HO

HO

H

CJ,O H

CH,O

CH,O CH,O CH,O

CH30 CH,O

R6

H

H

CH,O €I

CH,O

H

H

H

H

H

H

H

R'

HBr

HBr

HCI HCI HCl H Br Picric acid

Salts with

-

264-265 196- 198 198-2W' 234-235 167- 169 272-274 158-160 197-199 214-217 216-21 7 220-22 1

-

-

116-118 102-103

-

259-260 260-263 238-240 172.5-174 149-150

MP of BP ('0

503,570,583.596, 597,601,looOA

300

745 541,542 267 267 267 267 267 267 522 491 21

601

548 21.497 616,747,781 615 21,497 615,616 601 616 615.616 787

Ref.

2

H

H

H

H

H H H

HO

H

CH,O

benzoyl

CHO CH,O 3,4,5-Trimethoxy-

CH,CO CH,CO ClF5C0 o-CICH,C,H,CO H CHJO H

H

H

CHO

H

H

H H

B

HO

HO

H HO

H H

H

H

H

H H H

H

H CH,O CH,O

H

H H

H

CH,O

CH,O CH,O CHSO

H H O--CH1-0

CH,O

H

H

H

H

CH,C02

HO

HO

HO

H

H

CH,O

CH,O CH ,o CH,O

CH,O

H

H

H H

CH,O CH ,O H

H

C1F5C01

HO CH ,COl

HO

HC1 Picric acid

HCI HCI HCI

picric acid

HQ HCI HCI HCI HCI HCI Ha HCI HCI HCI HCI

122 187-190 254-256 256-258 266-267 22 1-223 145-147 159-160 176- 179

169

-.

-

-

160-161

177- 179

246-248 280 280-282 28 1-282.5 281 -283 282-283 282-284 283 283-284 283-286 204-206 177- I78

601

522

601

400

21.497

21.497 300

400

21 568 497 561 267 402,404 2 1.50.497 400 402-404 601 601 745 913 832 832 548

400 550

522 3 9 548

P 0,

2 0

o x

X

0,

o x x u

X

u z

o,o,

on X

X X

X

x x u u

u

x x

X

X X

0 X

X X

0 X X

X

X X

X

478

X X

H

H

H H

H

H

H H

H

H

H

H

H H

H

H

CH ,O CH ,O

CH 3O

HO

C,H,O,CO CH ,O

HO

CH,O

CH,O HO

CH,O

CH,O

HCI HC1 HCI HCI HCI HCI

HCI :2H2@

HCI

HCl HCI

Salicylic acid

HCI HCI H Br H Br

.-

256-258' 256-258" 257 257-258 258" 274-275 277-278

185.5 186" 186- I88 187-188" 188-1 89" 189- I9 1"

213-215 214.5-215.5 155-1 57 166- I67

214-216

172-174 173- I75

lo05

556 264,553 523,1006 819 286 262,265,539,607, 666,68471 t 1009,1011,1012

262 265 1003 1003 262,556 556.672 262 262 523 104 569 523 607 665 286 523,1005 666 672, looh 289.406.569. 583.593,598. 667-67 I m. 1004.1007-101 I 523

0

P 00

CHO CHaCO C6H,C0 m-NO,C,H,CO

m-NO,C,H,CO

H H

H H

H

HO H

H H

R2

H H H H

R'


HO HO

H HO

H

H H H H

R'

CH,O H H

CHJO CH,O

CH,O

H

O-CH,-O CH,O

CR,O

CH,O CH,O CH ,o

CH,O

R5

H

H

H H H

R4

O--CH,--O CH,O

CH,O

CH,O CH,O CH30 CH,O

R6

CH,O

c6H SCo2

HO HO HO HO

R'

234-236 234-236'

HCl:H,Ok HCI:2H2@ H,FtCI,' HIS04' Picric acid Picnc acid Picric acid Picric acid Picric acid Salicyclic acid

138- 139 -

-

167.5" 173- 175 173-175' 175-176 128-129" 129"

-

237-24@ 249-2449.5' 222-223.5

235-237"

MP or BP VC)

Salts with

547

541

539 522 54 996,1013

607 607 607 607,1005 523 1005 523 1006 286 262 670,672,674 670,672,674 607,1005 523 523 539 607,1005 1006

Ref.

H

H

H

H

H

H

H

H

H

H

HO

H

H

HO

H

H

H

H

HO

HO

HO

H

HU

I4

H HO

H

H

HO

HO

H

H

H

)I

HO

260 (dec)

H Br HBr HBr HBr H Br

-r

260-262*

260-262

255-258 262 265

265-267

__

246

219-220 229-232 (dw)

207-209 (dm) 208-210

HCI HCI HCI:H,@ HCI

HCI

HCI HCI HCI HCI HCI

HCI

HCI

537 519 1016 705,7 12,713, 717-7 19,721, 731,738,739

543

586 748,7 68. 1014.1060 768 1014 768,996,I014 1014 768 748 526 696-698 1015 548 5 19,524,570. 609,699-704, 707-716.738, 744,769,902. 999, IOOO, 1016- I022 567 526 55 696-698,704. 706,724,747, 1023,1024

@ @ cj T X

x

ggg

0

x xxx

2 so

2

0 0

u u x

z x x

x x x

225:

0 X

nxnx

X

482

W

P 00

H

H

H

H HO

H

H

+ 8.7"(c = 1.2, C,H,OH).

H

[ZJD

+3.53".

-7.2" (c=0.78. C,H,OH).

The salt contains two btlscs. Sublimed at 140°C in high vacuum. Dried at 100 "C/70mm. After sublimation. Water of crystallization. h c r i b e d in the footnote of the original Literature. Dried at 55 'C in vacuum. " Natural product. In a scaled tube. In vacuum. Labclcd with two deutcriums at I position. ' LabeIed with tritium. * Dried at 64°C in vacuum.

*

'

4R-Isomer.

' 4S-Isomer.

HO

H

H

HO

HO

' [%In- 14.4" ( ~ = 0 . 1 8CZHSOH). .

4R-1mmer.

4S-Ismcr.

H

H

HO

HO

HO

HO

HO

H

HCI

HCI HCI

HC1:+HI@

-

-

168- 172 (dK) 196-198

225-227.5

-

1 W

720

546

748 768 525.996 551

E

e

3

I

= I 3 I I I I I I I I l l 1

uX

X

9 5

2

x

X

3:

v,

P eo

CHO

CHO

CHSCO

cno

p.NO,C,H,CO

CH,CO

O CH30C0

a

H

R'

0 (CHJ,CHNHCH,CHIOHKH1O (CH&CNHCHzCH(OH)CHZO

0

CH,O CHJO CH,O CHSO C02-C,HFH,0 0 CH2C,H,a,O

CH 3

RZ

Ref.

615

615

H €I

H

615,997

615

97,267 557 97 91

114551 1 I4

H

157

-

__

I 15p.05m m

-

97

233 233-234 234.9-236 21 5-216 (dec)

1 I4

I14

114

105-10715 m m 228-230

lo(r126

Mp or Bp ("0

H

HCI HCI HCI HCI Picric acid

f H P

Salts with

H

H

RS

H

H

R'

H

H H H H

H

R3

R'

TABLE 358. ALKOXY-1~,3,4-TETRAHYDROlSOQUlNOtlNESAND THEIR DERIVATIVES

rn

00 P

H

H

R’

H

H H

H

Picric acid

H,PtCl,$

HCI HCI HCI HCI HCI HCI

198 173- 174 (doc)

-

233-234 236 238-239 242.6-244.1 244-2455’

143-34436 mrn -

Maleic acid’ 178- I80

235-240

Ref.

528 40.46,47,530, 535,559.584, 589,590.619, 678,729,859. 872,874,1027 528,529,58I 526 121 557 679 6 18,696-698, 708,726,874 528 528

871

1076

HCI‘

61 5

H

Mp or Bp (“C)

615

Salts with

H

R5

H

R4 H

R3

H

\N--(CH2fzo CH,O

A

(CH3)ZCHNHCHzCH(0H)CHzO (CH,),CNHCH,CH(OH)CH,O

(Continued)

(PF CBH&CH(CH z ) 3 - ~

CH3C0

CH,CO

R’

TABLE 358.

& 4

H

H

H

H

CH,CO

CHO

Cf,CO

CA,CO

H

H

CHO

CbH,CO

H

CH,CO

0

CHI-CHCHZO

H

CHO H

H H H H H

Y

Y

(CH3)aCNHCHZCH(0H)CHlO

(CH,),CNHCW,CH(0H)CH ,O

H

H

H

H

(CH3)ZCHNHCHz- H CH(OH)CH,O

CH,-CHCH,O H \ I 0 (CHA)ICHNHCH,- H CH(0H)CH ,O

\ I

CH,O CH,O CHaO CH,O C,H@

H H H H H

KSO,O(CH,),SO, pTosyl CTHL,CO pFC,H,CO(CH,),CO H

H

H

H

H

H

H

H

H

HCI

HCI

HCI HCI

?4-75

~~

173- 174.5

1Htl21

-

147-148 75-76

-

56.5-58

-

69-70

78-79

-

25 I

135

147-148

874 874

615

615 616

615 616 616

615 616 616

616

615.616 997

619 796 872 590 527 696-698 615,616

R'

H H H H H

H H H

H

H

H

H

H H


R2

Y H

Y

Y

Y

Y

Y Y Y Y Y Y Y Y

R3

H H H H H H CH,O

N

H H H H H H

R*

H H H H H H

H

H H

H

H H H H

R'

HCI HCl HCI HCI HCI

HCI

HCI

Salts with

228 228-229 23 1-232 231.5-232 232-233 233 233-234

146/11 mn 184-186/50 MBI

Mp or Bp ("C) 814

21

557 173

874 874 814 814 814 814 814 549 4 21,535,597, 675,618,710, 132,171,773 773 4,549 121 131

814

874

an

814

814

Rd

CI,CHCO CH,CO

H

C6H3SQ2

CIICHCO

CH,CO

H H H

H H

H H H H

H

H H

H

H H

H

H

H H

H

H

H

)I

H

H H

H H

H H

H H

H H H H

H H H H

Y Y Y Y

Y

Y Y

Y

Y Y

Y

Y Y

Y

CZH5 0 (CH,),CN HCHZCH(0H)CHZO

CIH@

CH,O CH,O

cn,o

H

H H H H H H H H H H

H H

H H

H

H H

H H HCI H,PICI,#

H2PtC16’ Picric acid Picric acid

Ha

Ha

135-137 194-195/50 m m 256 218

202 207-208 215-216

235-236

874 a14 874 814 a74 a74 a74 874 a74 874 a74 a74 874 874

615

605 4 4 4 1048

loQs

7 21 997

552 713 4

’

CHO (CH,),CCH,CO C6H,co (CH,),C,H,CO PGHSC6H4CO pTosyl CH,CO

H

CPiColinoyl

8’

H

H


R2

H H

R’

Y=

Y H

R4

,CI

CH,-CHCH,O \ / 0

CH,O CH,O CH,O CHJO CH,U CH,O

CH30

H

R5

HCI HCI HCI HCI

Salts with

259.1-261.2 260.5-263 261-262 (dec) 261-262.5 14-16 19-80 133-135 111-113 171-173 136

-

38-39 13-16/65 pm

Mp or Bp (“C)

814 833 833 120,236 551 120,236 a33 121 267 833 833 833 833 1% 991

Ref.

X. Tables of lsoquinolinols and Their Hydrogenated Derivatives

491

TABLE 3SC. I.2,3,4-TETRAHYDRO-6.7-DIMETHOXYISOQUI”LlNE AND ITS DERIVATIVES

R

Salts with

Mp or Bp (“C)

80- I3P 84-85 86 126-121 116-117/1 m m 175/10m m

H

-

HCI HCI HCI HCI HCI H CI HCI HCI HCI HCI HCI HCI HCI HCI HCI HCI HCI HCI

Hf-0, Oxalic acid Oxalic acid Pi& acid

240-242‘ 243 248 248-251 2w. 252 253 254-255 254-256 255 255-256+2 (dec) 255-256 256-251 262 (corr.) 263 264-266 261

-

-

213-215 ( d e ) 214-21 5 197-199

Ref.

23 21 517,585 538 772 587 41,43,58,287,291, 293,303,321,522, 534,535,537,555, 578,586,588,591, 592,591,602, 608-610,675,676. 129,752,169,710, 173,835,855,884,916, 934,970,975,1000, 1019,1028-1041 519 676 773.1042 521 521 173 526 536 930 1029 538 531 426,517,585 23 581 534 16

1 17,287,292,303, 405,574,578,582,588, 617,690,696-698, 705,728,731-733, 960,975.1O44- 1046 287 49 531 565

492


TABLE 35C. (Continued) ~

R

NO CHO CH,CO CICH,CO CI,CHCO CICH(CH,)CO NH2CS C,H50C0

Picric acid Rcric acid Picric acid Rcric acid Picric acid

198-200.5 199-200 202-203 (con.) 2osrns

-

125- 126

-

104-105

-

115-116 122-123 __

171-172 70-72

-

114 129 123- 124 123- 126 85-86 106-106.5 I10 220 172-173 141-143 144-145 110-111 76-78 200/10-2.5 127.5- 129.5

574 538 22 21 303 960,1068

531 155,156,1032 534 834 1043 1043 1043 578 975 712 772 604 757 855 655 603 419 617 565 298 7% 1044

119-120

608,620 610 581 730.1044 609

141.5-143

587

-

X

X

X

T

x z

X

X

X

X

x x

e

0,

5

0,

o_

U

u

X

B 0

X

X

493

u, E vx v

x

H

CHSO

CH,O

H

H H H H

H H

H

H H H

CHJO

H H

1

OCHj

CHiO CH,O

CH,O CHIO CH,U CHiO

H

b'

5-yloxy

n-C,H,O 2-4.1idyl0~y

n-C,H,O i-C,H,O CH2=CHCH20 CH2-CHCH20

H

H

1-Phenyl- IH-tetrazol-

H

CH,O

CHO

'R H

R3

CHJO

H

R2

(CH3)JCNHCH2CH(OH)CH,O CH,O

(Continued)

CHJCO

R'

TABLE 35D.

597

597

597

H

253 656698 597 597

253

1048

737

597

H

Ref.

267 734,735,1047

615

997

-

266-267

1 15-1 32'

-

145-147 258-259 189-190

-

Mp or Bp ("C)

H

HCl HCI

HCI

Salts with

n

H

n

H

CH 3O

H CH30

H

R'

vi n

2 s " '0 * * w ro

"'0

P P X

w w

P I-

moo I-r-

d VI

c

E E oo

0,

h

I S

2

X

2 2 2

I

X

X

I

a X

a X 0

a 2

a X u

a a a aa 2 2 x X I v

u u

O V

X

X

X

T

2

X

2 2 2

V

2

x z

X

V

495

I

T X

vx

CH30

CHI-CHCH20

‘ 0 ’ CICH2CH(OHjCH,0 CH30 (CHJ2CHNHCHZ- CH,O CH(OH)CH,O

ClHSCQ

CH3C0 CHO

b’

CH30

CHZ-CHCHZO

CHO

cn,co

/ ; \

R3

CH~O

R2

CH -CHCH,O

H

H

C,H,OCO

C,H70C0

R’

TABLE 35D.(Continued) R*

R’

HCI HCI HCI HCI HCI HCI HCI

HCI

HCI

HCI

HCI

Salts with

-

291,5l0,522.

-

59 1,597 512 533 532 533 548 526 568,690.73 1,732

616

255-257 274-275 274-276 275 276278 >315

615

110-111

61 5616

-

6768

1.1I-! 12

121-121.5

-

268

-

282 -

615,6316,997

787 597,835 527 696-698 591 527 696-698 615,616

161-162

-

781

Ref.

137-138

MP or BP m

i3

x

x x x

P

989 ddd

0, u X

x u

?L4

z

p u

000, x x u u

X X

x x

x x

P

x u 497

R2

o-CICH,C,H,CO o-CICH,C,H,CO C,H5C0

C,H ,CO H

H H H

H

R'

CH,O C2H50 H

H H

H H H

H

H

H

H

H H H MH2-O

CH ,O

H

CH,O CHjO CH,O CH ,o CH,O

R'

CHSO CH,O H

H

CH,O

H

H H H

R"

C2H50

H H CH,O

R3

R6

R3

CH,O

CHI0 MH,-0

CH,O CHJO CH ,o CH ,O CH ,O

R4

CH 3o

CHIO

CHjO

H H H H H

R1

WBr HBr

HBr

NCI

HCI

HCI HCI HCI Picric acid HCI HCI

HCI

Salts with

238-240 240 240 (dec) 61-63'

-

175-177

230-233 279-284 63 244-245

260 268 268-269 213-215

-

115-1 16 120-122 122-123 132-133 71-72

Mp or Bp ("C)

TABLE 35E. TRIALKOXY-OR TETRAALKOXY-I.2,3,4-TETRAHYDROISOQUiNOLINES AND THEIR DERIVATIVES

666.612,6?3, 1005,1006,

541 284 405 288 31 37 284

541

113 21 261 21

615.678.773 113

913 913 603 603 21 25,594,595.597,

Ref.

H

H

H

H

H

H

H

H

Dimaleate. Natural product. The salts contain two bases.

' Dichloridc.

Syn : mi-geometric isomer ratio is 71 : 29. Sun : anti-geometric isomer ratio is 35 : 65. ' Water of crystallization.

H

CHO C1,CHCO m-N0,C6H,C0 H

H

$p

H H H

CH,O

H

H H H H

' '

CH ,O

CH ,o

204-307 164-165 172-173

HCI HCI

-

188-190

207-209" HCI

HCI HCI

147- 14%

139-140' 139-140 207-208 (dw) 184-185

-

242-243' 24f-251y 248-250

Readily takes up CO, from the air. Dried at 8O"C in vacuum. Sintered at 107°C. Bath temperature. In a sealed tube. Double melting points are observed at 180-190°C and 207-209°C.

CH,O

CH,O

CH ,O

CH30

C7Hl0

CH ,O CH ,O CHjO C,HlO

CH,O

CH,O CH ,O

CH,O CH,O CH,O CH,O

HCI HCI HCI HCI HAuCI, HAuCI, H,PtCI, Picric acid

539 226.286,556 265 286 262,265 265 615,113,790 1042 773 790

1043

670,672614

673,1005 267,406,553. 559.567-569, 593.597.671 1006 539 553 569.666.1014 1006 539 539 539.1006


500

TABLE 36. 5,6,7,8-TETRAHYDROiSOQUINOLINOLS AND THEIR ETHERS R4 R'

d -

H

R'

R'

R2

H

HO

Rs

R4 H

Salts with

H

Mp or Bp("C)

Ref.

192-193 194-196

60,101,621 118

HCI H H

p-Tosyloxy H

H HO

H H

C2Hs0 H

H

H

H

H

CH,O

H

H

H

H H

H

H

CZHSO CH,O C2Hs0 C,H,O

H

H

C,H,O

H H

H H

H H

Picric acid HCI Picric acid

191-192 114 89.5-91 130-132/0.5m m

-

137 104-105/4mm 132-136/11 mm 195-197 156-157

-

51 38

61

131 61 791 791 621 621 118

I18 118 118 423 217 217

X. Tables of Isoquinolinols and Their Hydrogenated Derivatives TABLE 37. OCTAHYDRO- O R DECAHYDROISOQUINOLINOLS AND THEIR DERIVATIVES A. OCTAHYDROISOQUlNOLINOLS

R

H CH,CO

Ref.

Mp or Bp ("C) ~~

85/0.06 Toma -

85p.66Tom'

626 627 626

B. ALKOXYOCTAHYDROISOQUINOLINE

OH

R

Mp or Bp ("C)

Ref.

C*H,

-

1053

501

a

0

m

zz

Q Q Q X

x x

2 x 2

x x

X X 2 Z

x x

x x x x

x x

0 X Z Z T

& &

2 z x

QiQiQiX

6

0 0

5 5u

a

x x 502

u,

O F

Z 2 2 X

E!

v1

H H

H

H

C,H &O H

CHJO

H

.

H

. .....

H

CH,SO, H H H

H H H H

~

H H H

H H HO CH,SO, HO

Z-HO a-HO H H H

H

H HO HO H

H H

H

H

HO

H

H

HO

H

HCI HCI

' 90%

optically pure compound [4a(S),8a(R)].

' Diastereomeric mixlure.

' Stereochemistryof a hydroxyl group at the 4 position is not presented in the original literature.

' Unless otherwise noted, the prefixes a and ) are arbitrary, expressing only thc relative configuration.

Stereochernisiry is not described.

H

H H H

~

H H

H H H H C,H,CO

CH,CO

H

CH,CO

558 624 ti2 5 624 625 624

117" 119-119.5 243" 248-250 (dec) I lo*

98 98 1054 628 628 632,to27 632 632 633 632 8

--

108-1 15/3 mm'

-d

4

-1

._d

258-259 208-209.5 -d

163- 166/0.2-0.25 mmd 189-193/2 mmd -

H

H

CH3CH=CHS

H H H

H

H H H H

H

H H

H

H H

H H

C6HsCOS H

RZ

CNCH,S CHI = CHS HOzCCHzS CH, =CHCH,S

H CH3S

R' R3

H

H H H H

H

H

H

H H

R4

R'

TABLE 38. ISOQUINOLINETHIOLS A. ISOQUINOLINETHIOLS AND THEIR ALKYL (ARYL) THIOETHERS R4 R'

H

H

H H H

H

H H

H H

R'

HCIO,

HCIO,

HCI04

HCIO,

HCIO,

Salts with

107-109 -

95.5 122 98

142-145

128-132/1 m m

641,648,649 641 648,649 751,837

75 I 640

640

641,US, 541

793

649 648 836

82

-

684 74,79,80,646, 649,776,820, 836,1055

Ref. 139 -

Mp or Bp ("C)

XI. TABLES OF ISOQUINOLINETHIOLS AND THEIR HYDROGENATED DERIVATIVES

H H

H

H

H

H

H

H

H

H

H H CH,S

H CH,S H

H

H

H H H H H H

H

H

CH,COCH,S 2-Hydroxypropylthio ICH,j,CS CH,CO(CH )2S C,H,S(CH,),S N-Succinylmcthylthio

CH3S H

H H H

H

H H H H H H

CH,S

H

H H

H

H H

H

H

H

H

H

H

H

H

H H

HCI

HCI

HCIO,

HCIO,

44-47

177- I79 -

214-216 136.-140 156-1 58 143-145 60-62

_.

t 38- 140 197- 199" 66-67

108-109 115-1 I6 144

loo-101

88-92

59-6I)

85-87/0.05 m m I 20- I 2 I 80 101 I72 -. I 73 57.5-59 5n-60

642 642 646 637 650 637 793 637 637 637 636 637 634,637 634,637

644 644 838 HO 78 643 639 641 642 642

641 641 635 642 63X

SO6


qR2

TABLE 38B. ALKYLTHIOISOQUINOLINOLS AND THEIR ETHERS

R'

R'

R'

Mp ("C)

Ref.

CH,COz CH3CO2 H

63 64 258

647 647 72

H CH,O

99.5-101.5

1057 647 647 647 647 72 72 72 71.72 12 71,72

R2

R'

Salts with

57 70 66 95 55 138 143 196(dec) I35 190 I38 138 (dec) I28 128 (dec) 200 (dec)b

C2H50

n-C,H,O C,H,O H H H H H H H

2-Diethyaminopropylthio and Z-diethylamino-I-methylethylthio 1-(4'-Methoxyisoquino1yl)thio 1-(4'-Ethoxyisoquinoly1)thio After sublimation.

H

HCI HCI HCI HCI HCI HCI HCI

71

72 71 72 71

H

205-206

72

H

146

72

A mixture of two isomers.

TABLE 39. 1-METHYLTHIOISOQUINOLINIUMIODIDE MP ("C)

Structuk

Ref. ~ _ _ _

q N + ,CH3 r SCH,

' Dried at 100°C.

134 (dec)

65 1

143-146'

1055

XI. Tables of Isoquinolinethiols and Their Hydrogenated Derivatives TABLE 40. 3.4-DIHYDROlSOQUlNOLlNETHlOLS A. I-ALKY LTHIO-3.4-DIHYDROISOQUlNOLlNES AND THEIR DERIVATIVES

R

Salts with

Mp or Bp (“C)

80-84/0.05m m 82-82fl.05mm 98-100/0.7m m

CHjS

-

HBF, HI Picric acid

188 195-198 136 89-90/0.5m m 89-9510.1 100-102/0.2m m 109-1 11/0.7m m

__

HBF, Picric acid CH, = CHS CH, =CHCH,S

.-

-

HCIO, HBr n-C,H,S

Picric acid HzSO, HCIO, H Br C6H5S

125 130

Picric acid

Picric acid

104-105 129-1 30 120/1m m

117 -

163-164

-

118-120 129-130 79-80 I78 (dec) 83 79 167 I42

Picric acid

I19 168

Ref.

794 794 652 653,655, 656,911, 1058-1060 794 1061

652 652 653 794 654,794 656,657,1059 794 652 75I 795 795 795 652 655 652 638 655 795 795 195 652 652 652 638 652 652 652 652

507

508

Isoquinolinols and Their Hydrogenated Derivatives TABLE 40B. 6-METHY LTHIO-3.4-DIHYDROISOQUINOLINE Structure

Salts with

Oxalic acid

Mp ('C)

Ref.

-

1062 637

147- I5 1'

TABLE 4 K . ALKOXY-1-ALKYLTHIO-3.4-DIHYDROISOQUINOLINES AND THEIR DERIVATIVES

R'

R3

R4

RS

Salts with

Mp or Bp ("C)

CH,O H

H CH,O

H H

HFSO, H BF, HFSO,

106-1 19 208-209.5

R2

H

CH,S CH,S

H

C2H$ CH,S CH,S

H H CH,O

H

CH,O O--CH, 0 H H

H H CH,O

CH,S

H

CH,O

H

CH,O

HI Picric acid

HI C2H8

CH,O

CH,O

H

C2H8

CH ,O

H

H

CH,O

n-C,H,S

CH,O

H

H

CH,O

258-260 57-58 143-144/0.6 m m 155

94-96

HCI HCI HI H

-

HBF, Picric acid Picric acid

Ref. 969 969 969 654 655 652 652 652 653,654. 794 645,10631065

190-192 (dec) 190-192 1%

653 794 655

-

645

142-145/0.25 m m 174- 176 140/0.4 mm 160 38 170-171/1 mm 141

794 794 652 652 652 652 652

XI. Tables of Isoquinolinethiols and Their Hydrogenated Derivatives TABLE JOD. 1.2-DIHYDRO-I-METHYLTHIOISOQUINOLINE Structure

M P (‘C)

Ref.

Hemioxalate.

TABLE 41. I,2-DlHYDRO-2-(pTOSYL)ISOQUINOLINES

R

H

p-CH,C,H,S pCH,C,H,SO P-TOSYI

M P (‘C)

Ref.

121-122 129- I30 142.5 143.5 167- 168

658 658 658 658

509


510

TABLE 42. 1,2,3,4-TETRAHYDROISOQUlNOLINETHlOLS A. 1~3,4-TETRAHYDROISOQUlNOLlNETHlOLS AND THEIR ALKYLTHIOETHERS

R4

R‘

R2

R’

R4

H

H

HS

H

CHSCO H H

H H CH’S

HS H

H HS H

H CH&O H CH3C0 H

H H H H H

CH’S CHIS CF,S CF,S C13CS

H H H H H

CH,CO H H H

H H

a3cs

H CH,S

H

H H H

H

H

Salts with

Mp(”C)

Ref.

HCI

-

1066 1066 1066 1066 1062 634 1066 1066 1066 1066 1066 1066 1066 1066 1066

HCI HCI HCI

HCI Maleic acid

-

230-235 247-248

-

190-191

-

218-220 159-160

-

-

CFSS

CI’CS

1066

1066

TABLE 42B. METHYLTHIO-l,2,3.4-TETRAHYDROISOQUINOLIN40LS

R’

R*

CHSS

H

H

CH,S

Salts with

MP CC)

R d

138-140

634 1062 643 1062

-

I02

-

XI. Tables of lsoquinolinethiols and Their Hydrogenated Derivatives

51 1

TABLE 43. SULFOXIDES AND SULFONES OF ISOQUINOLINES

R'

R'

CH,SO, H CH3SO

H P-TOSYI H

CH,SO, HO H

175- 175.5 179-180 65-66 -

CH,SO,

H

H

152 153-1 54

C,H,SO, C,H,S02

H

H

83-84

H

H

C,H,CH,SO,

H CH3S0,

H H

C,H,SO* CeHsCHzSO, H H

H H

140.5-141.5 142-143 177- 177.5 94-95 78-79

H H H H H

CzH5SO C,HsCH,SOi

182-183

191-193

576 1067 79 820 80 74,576 79,820 576 576 80

576 576 576 576 793 777


512

TABLE 44. SULFOXIDES AND SULFONES OF 1,2,3.4-TETRAHYDROISOQUINOLINES

R4

R' H H

H H

CF,CO

H

CH3CO CF,CO CH,CO CH,CO

H CH3CO H CH3CO CH3CO

R'

R3

H H H H H H H H

CF,SO CF3SOZ CF,SO, FSO, FSO, NHzSOz CISO, CISO, CF,SO CF,SO, CH3S0 CH,SO CH3S0, CH,SO, CI,CSO H H H H H H H

H H H H H

H

H

H H H

H

H H H

H CH3C0 H H H

H H

R4

H H H

H H H

Salts with H CI HCI

Fumaric acid HCl

H

H H H CH,SO CH,S02 CISO, CF3S0 CF,SO,

Ref.

205-206

1066 1066 1066 1066 1066 1047 1066 1066 1066 1066 1066 1066

__

199-200 230-232 99-103

__

H H

H H H

Mp ("C)

108-109 _.

HCI

200-202 -

HCI

258-260 -

__

I _

__

c1,cso

-

CI,CSO,

-

1066 1066 1066 1066 1066 1066 1066 1066 1066 1066

XI. Tables of Isoquinolinethiols and Their Hydrogenated Derivatives TABLE 45. SULFENAMIDES AND SULFONAMIDES OF 1.2.3.4TETRAHYDROISOQUINOLlNE

R 2,4-(NO,),C6H,S CH,SO, C,H,SO,

p-NH,C,H,SO, p-NO,C,H,SOZ p-Tosyl

d-Camphorsulfonyl pCH,CONHC,H,SO, p-( I ,2,3.4-Tet rah ydroisoquinol2-yl)benzenesulfon yl

MP ("C) 157.5-159.5 129- 130 I52 153-1 54 154 155-1 56 174' 177-178 179- 180.5 161 179 138- 141 142 142- I43 143 I45 145- 146 147 -

Ref. 659 7% 660 128 661 605

175-176b 181.5-183 I4 1 - 142'

970 663 613 612 796 613 612 663 61 I 614 42 1,614,662 664 796 775 796 663 612 663

142-144' 149* 153-154' 153-156' 157-1579

663 663 663 663 663

160

With softening at 172 'C. Heated at 100°C in vacuum. An opaque liquid. ' Softened at 140 'C after drying in vacuum for I week. ' Softened at 144 "C(from benzene-cyclohexane). I n vacuum for 3 weeks. Recrystallization from ethanol-acetone. ' Softened at 153 "C (from CCI,).

51 3

514


Acknowledgments The authors are grateful to Dr. Hiroshi Mishima for his valuable suggestion on this manuscript and to Mr. Toshiaki Ishida and Dr. Hiromichi Ogasawara for their help in preparing the manuscript.

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Index 3-Acetoxyisoquinoline. 238.24 I 4-Acetoxyisoquinoline. from isoquinoline 2-oxide. 241 5-Acetoxyisoquinoline. oxidation of. 244 3-Acetoxy- I -methylthioisoquinoline.320 a-Acetyl-y-butyrolactone. 172 N-Acylisoquinolium salts. reaction with pyrroles. I 1 I Adams catalyst. 243.259.297.298.3 12.3 14 in reductive cyclization. 303 Adiantifoline. 56 Adlumidine. 275 hydrastinine salts from. 275 Aldol reaction. retro. 269 2-Al kyl-4-ami no-5-(bromoethyl)pyrim id ine. reaction with isoquinoline. 172 I-(Alkylha1ide)isoquinolines.reaction with amines. 2 I-Allyloxyisoquinoline. Claisen rearrangement of. 248 Amberlite IRA-401. 291 I-(Aminoa1koxy)isoquinolines.27 Ida-AminoalkylbenzyI)isoquinolines.7 3-(Aminoalkyl)4hydroxyisoquinoline.194 I-(Aminoal kyl)isoquinolines. 2 2-(Aminoalkyl)isoquinolines. 133 3-(Am inoal ky1)isoqui nolines. I83 N.(Aminoal ky1)- I .2,3.4-tetrahydro-2isoquinoline carboxamide. 138 4-Aminoal ky1-30.4.5.9h-tetra hydroisoxazole~5.4-c~isoquinolines. 124 3-(Aminoaryl)isoquinolines. 1x3 2-(p-Aminohenzenesulfonyl)-l.2.3.4tetrahydroisoquinoline. 328 I -(4-Aminobenzyl)-7-hydroxy-bmethoxy1.2.3.4-retrahydroisoquinoline. 5X

I-(Aminohenzy1)isoquinolines.53 I-(4-Aminohenzyl)isoquinoline.54 I-(4-Aminobutyl~3.4-dih~droisoquinolin~. 2 I-Amino-4-(chloroethyl)thiazoIe. reaction with 1.2.3..btetrahydroisoquinolines. 173 N-(’-Aminoeth~I)isoquinolinium bromide hydrohromide. reduction with lithium aluminum hydride. 133 3-i\minoisoquinoline. diazotiration of. uith i ~ o i ~ nnitrite. ~ q l 138

5-Aminoisoquinoline. diazotization of. 236 5-Amino-8-isoquinolinol. oxidation of. with ferric chloride. 236 8-Amino-5-isoquinolinol. oxidation of, with ferric chloride. 236 N-(2-Amino-S-methyl benzyl)-6.7-dimethoxy1.2.3.4-tetrahydroisoquinoline.161 6-Aminomethylguanamines. 172 I-(Aminomcthyl)isoquinoline.7 4-Aminomet hylisoquinoline. benzoylation of. 205 34 2-Aminomethyl)-2-methyl1.2.3.4tetrahydroisoquinoline. 184 2-Amino-2-methyl-l-( I -oxo-Z(ZH)isoquinoly1)butyric acid. 175

I-(Aminophenethyl)isoquinolines. 65 I-( 2-Aminophenyl)-6.7-dimethoxy1-3,4d i h yd roisoq u i no1i ne. 4 1 I-(2-Aminophenyl)-3.3-dimethyl-3.4dihydroisoquinoline. 40 I -(4-Aminophenyl )isoquinoline. 4 I

2-(Aminophenyl)isoquinolines.I61 N-( 3-Aminopropy1)- I .2.3.4tetrahydroisoquinoline. 134 N-(Aminopropyl)isoquinoliniumbromide hydrobromide. reduction with lithium aluminum hydride. 133 Aminoprotoberberines. 57 3-Amino-4-substituted arylisoquinolines. 206 2-Amino-4-[2-( I .2,3.4-tetra hydroisoquino1ino)ethyljthiazole. 173 Amphibine 1. 10 Anhalamine. 295.330.331 alkylation of. 305 hydrochloride of. 339 Schottcn-Baumann reaction of. 308 thin layer chromatography of. 341 Anhalinine. 300.330 quaternization of. 305 thin laycr chromatography of. 341 I-Anilinoisoquinolines. 36 Anthranilonitrile. acid catalyzed reaction of. 40 Apaverdldine. 240 Armepavine: hiomimetic oxidation of. 275 electrolysis of. 275

ti45

546

Index

Azahicyclo~4.2.2jdecatetraene. 2.10 3-ALabicyclo13.2.2)nonane.2 12 X-ALa-6-oxa-8-methyl-3.4-di hydrohicyclol3.2. Iltxtane. I84 Azastcroids. 4. 73

Brnzamidaro[2.1-alisoquinoline,262

(S)-Benzoquinolizine. 158 Benzolujquinolizidine derivatives. from 3.4-dihydmisoquinolyl ethers. 27 1 Benro[alquinolizine. 121 4-(Brnzylaminomethyl)- 1.2.3.4-tetra hydroisoquinoline. 204 4-Benzylcarhamoylisoquinolinr. synthcsis of. 205 2-Benzyl-2.3-di hydro-q I H)-isoquinolinoncb. oxidation of. 254 7-Benzyloxy-3.4-dihydro-6.8-diniethox~ isoquinolinr. 266 8-Benz y loxy-3.44 ih ydm-6.7-d imet hoxyisoquinoline. 266 7-Benzyloxy-3.44 hydro-6-met hoxyisoquinolinr. 266 6-Benzyloxy-7-mrthoxyisoquinoline. 23 1 8-Benz yloxy-7-mrthoxyisoquinoline. 239 6-Benzyloxy- 1.2.3.4-tetra hydro-7.8dimethoxyisoquinoline. 297 2-Benzyl- 1.2.3.4-tetrahydroisoquinoline-3carboxylates. 183 4-Benzyl-3.4.5.6-tetrahydro- I ti-2.hmethanobenzo[el( I .3ldiazocine. 204 2-Benzyl-l.2.3.4-tetra hydro-4-oxoisoquinoline. 258 Riguanidincs. 149 2.5-Ris(2-acyl- 1.2-dihydroisoquino1yl)pyrroles. 1 1 I 1.3-Bis(2-henzamidorthyl)henrene.reaction with phosphorous oxychloridr. 2 12 p-(Bis(2-chlora.thyl)amino(henzyl alcohol. reaction with isoquinoline. 161 I-{p-~Ris(2-chloroethyl)aminolhenzyl~isoquinolinium p-toluenesulfonatc. 161 Bischltrr-Napieralski reaction. 3. 11. 28. 36. 37. 53.66. 70. 72-74. 86. 88. 107. 100. 1 11. 121. 197.2oh.266.274.3Ix Pictet-Gams variation of. 23 I tandem. 286 N.N-Bis-(3.4-dihydro- I-isoquinolylmethyl)-Bphenethylamine. 100 His-isoquinolines. 89 1.1 '-derivatives. 107

N'-Bispad-N.N-dimethylformamidine. 158 Bis-1.2.3.4-telrahydroisoquinoline. I08 I -Bromoisoquinoline. I07 suhstitution of. 234

4-Bromoisoquinolinr. reaction with sodium phenylmercaptide. 318 (+ )-(.S)-6'-Bromolaudanosine. 56 w-Bromopicoline. I69 5-Bromopyridinoll" :2"-3 :4lisoquinolino12': I :2)glyoxalinium bromide. I69 Bucherer reaction. 236.248 I-(I-Butylthio)isoquinoline. 3 18 I+)-Calycotomine. I21 Cannizzaro reaction. 286 Capnoidins. 275 1-Chloro-3i.hloromethyl4methyl substitutedisoquinolines. 185 2-('-Chloroethyl)piperidine. reaction with I 2.3.4-tetra hydroisoquinolines. I73 N-( 2-Chloroet h yl)- I .2.3.+telrahydroisoquinoline. reaction with sodium dicthyl chloromalonate. 149 2-(PChloroethyl)-1.2.3.4-tetrahydroisoquinoline. reaction with 3-pyridol. 171 I-Chloroisoquinolinr. 55 hydrogenolysis of, 237 reaction with 1-butylmcrcaptide. 3 I X 3-Chloroisoquinoline. I98 substitution of. 236 4-Chloroisoquinoline. from 4-isoquinolinol. 245 I-(Chlorc~methyl)-3.4-Jihydr~~isoquinoline. 2 2-C'hloromethyl-6-niethylpyridine. 84 2-C'hloromethylpyridine. reaction with I .2.3A-tetrahydroisoquinoline. 170 Cope reaction. 23 I rearrangement. 302 Corypalline. catalytic oxygenation oC 253 Cotarine. peroxide derived from. 278 Cotarnazine. 232 Cotarnine. 281.334 chloride: clciivage of. 280 conversion t o hydrosulfide. 280 extraction of. 281 oxime. 23 I polarographic activity of. 281 reaction with methyl iodide. 278 Cotarnoline: formation of. 290 reduction of. 295 urine metabolite. 292 Cotarnone. 267 l - C y ~ ~ n o i s o ~ u i n o lI85 in~. 4-Cyanoisoquinolinc. reduction of. 105 I-Cyanomethylthioisoquinoline.reaction with henzoyl chloride. 321 a-Cyano-rr-tolunitrilr. alkylation of. 206

Index

547

formation ol. 266 0-Dea I h! I u tion. w i t h concs n tra ted H Cl. 3 M ) thsrnio1)sis of. 283 0-Dehenr! lation. h) drogenol! tic. 301 7.X-Dihydro-6(SN)-isoquinolinone. f)ec.ah!dro-5-isoquinolinol. 259 ketalization of. 2x8 Decah!Jroisoquinolin[)ls. 3 I4 X.9-Dihydro- I3hH-isoquinolinol2. I-+ (+)-'-Deh!droenietine. 121 quinamlines. 41 13eh)drogenation. 24 I 1.2-Dihydro-h.7-methylencdioxy-2~pwith .\'-hroniosuccin iniide. 234 tosyl )isoquinolinc. 2YO with palladium hlack. 234 3.4-Dihydro-5-nirrht,xy-7-isoquinolinol. 269 with piillatlium (in carhon. 233 .~.4-DihSdro-h-mcthox)'-S-isoquinolinoI.266 with ptitawiuni perniangiiniite. 234 3.4-Dihydro-h-mrthoxy-7-isoquinolinol. 266 photochemical. 234 nitration of. 26Y Demethoh~-O-nieth)l a n h ~ d r t ~ ) n i h i n e66. ?.4-I~ihydro-7-methoxy-~isoquinolinoI. 269 0-Denieth) lation. 234 3.4-Di hydro-X-methoxy-5-isoquinolinol. 269 Dihenzolu.Klquinoliridine. 158 1.2-Di hydro-2-(p-tosyl)isoquinolinrs. 230 7.X-Dihenr~los~-2-(p-tos~l)isoquinol1ne. 2%) 3.4-Di hydrtrh.7.X-trimethoxyisoquinoline. 6.7-Dic hloroi\oquinolin-5.X-dione. 247 266 Dic!andianiine. reiic~ionnith 1.2..?.4-tetr;i1.2-Di hyJro-Z.h.7-rrimcthoxy-2-(ph! droisoquinol ine. I49 tosy1)isoquinoline. 3 0 Diels-Alder reaction. hetero. 241 1.2-Di hytIro-6.7.X-trimrthoxy-~-(p3-( 2-Dieth! laminoeth! I )-4.5-nieth>lenetosy1)isoquinoline. 290 dioxyphen) I-7.X-Jiniethos! - I .2.3.4-tetra(2.S-Di-iaoquinoline)pyrrole.7 1 h! d roisoq u i noli ne. I 97 6.7-Diiiiethoxy-2.3-dihydro-4(I I { ) ?.J-Dih!Jro-s.h-Jimethos! iwquinoline. 266 isoquinolinone. dehydrogenation of. 3.CDih! dro-6.7-tlimethoa> isoquinoline. I2 I . with palladium o n carhon. 233 266.269 1.3-Dimethox) isoquinoline. 241 from O-nieth!lation rsiiction. 269 3.h-Dinierhox) isoquinoline. 238 from .\'-norarmspa\ ine. 267 3.7-Dinicthox)isoquinoline. 238 paper chromatograph! ol.340 ?.4-Dih~dro-h.X-dimsthos~-7-isoquiiiolinol. 6.7-Dimethox) isoquinoline. 229. 234. 238. 139.240 269 I'roni Pomcranr-Fritsch reaction. 23 I 1.2-Dih!dro-?.X-dinicthos! - 2 - ( p t o s ! I ) i w quinoline. 2W pcrmanganate oxidation of. 244 5.6-Dih!drofuro(2.3-~/lp)riniidinr. 172 reaction with allyltriniethyltin. 248 h.X-Ditiiclhox!,isoclinoline.E Y . 2.18 I .2-Dih)Jroisoquinoline: coupling of a1deh)des to. 28Y 7.X-Dimcthoa!, isoquinolins. 233.234.238 reaction with phen>lgl)oxals. 257 S.h-Dimethox! isoquinolinol. 233 I .4-Di h>dro-'l/-isty uinolincs. S.X-Dimethoxvisoquinolino1.233 anticon\ulsant ctctivit?. 208 h.7-Dimethoxyisoquinolinol. 233 3.J-Dih> dro- I (2H)-isoquinol inones. reaction 6.7-Dimcthox> -4-isoqu inolinol. 234 with trieth! losonium 1etr;iIluorohorate. 6.8-I)imethoxyisoquinolinol. 233 269 7.X-1)iniethosyisoquiiiolinol. 233 3.4-Di h) d ro- I (2H)- isoq u i no1inone. red uct ion 6.7-Dinicthox>- I .2..;.4-tetra hydroisoquiiiolinc: reaction with ,V '-hispad-,V.Nof lacrani group. 2YY ?.4-Dih>droisoquinolines. from 1.2.3.4dinieth~lformamidine.I Z X tctrah!droisoyuinolinrs. 267 reaction with 6-niethqlisatoic anh)dride. ?.4-l)ih!dro-h.7-isoquinolinedi~~l.24 I I61 piper chromatograph) of. 340 2-( 3-Diniet h y lani inopropy l)isoquinoliniu in 3.4-Dihgdroisoquinc)Iiniuni salts: chloride hydrochloride. 133 3-(~~-Dinirthvlsmiiiosh.ryl)isoquinoline 2-alk>l.reduction of. 2x5 0-dealk)lation of. 277 methyl iodide. 196 oxidation of. 2x5 I.CDi-(3'-niethylisoquinolyl-l ')methyl3.4-Dih!droisoquiriolinols. quaternan siilts piperazine. I 1 I of: 274 Diphenyl( I-isoquinoly1)carbinol. X 3 . 4 D i h ~ J r o i s o q u i n o1I ethers: ~ .~.3-Disuhstitutrd-?.4-Jihydroisoquinolines. dehydrogenation 01.233 from pyridylnitriles. 83

Index

548 &Domesticine. 55

Emetine. I14 (-)-enantionier. 158 cll-Epidicentrine. 55 4-Ethoxyca~onyl-6.7-dimethoxy-2-mef hql1.2.3.4-tetrahydroisoquinoline.204 I-Ethoxy-3.4-dihydroisoquinoline. 269 3-Ethoxy- 1.4-dihydroisoquinoline.288.289 ~Ethoxy-3.4-dihydr~~isoquinolinc. 266 I-Ethoxyiscyuinoline. 238 ether cleavage of. 248 nitration of. 245 3-Ethoxyisoquinoline. 236 4-Ethoxyisoquinoline. 238 animation of. 247 5-Ethoxyisoquinoline. 239 7-Ethoxy- 12.3.4-tetrahydro-6-isoquinolinol. 295

Ethyl 2-(2-aminobenzyl)-12.3.4-tetrahydroisoquinoline-3-carhoxylate.164 Ethyl 3-amino-2-(3.4-dimethoxyphenyl)propionate. reaction with formaldehyde. 204 Ethyl 3-( I'-henzoyl-4'-piperdyl)propionate. I84 2-Ethyl-5-hydroxyisoquinoliniumhydroxide. hydrogenation of. 259 Ethyl isoquinoline-3-carboxylate.Claisen reaction of. 184 5-Ethyl- I -methyl-2-Jf3-(1.2.3.4-tetrahydroisoquino1ine)ethyl)piperidine. I7 I S-Ethyl-2-(P-morpholinoethyl)pyridine.I7 I Ethyl I.2.3.4-tetrahydroisoquinoline-3carhoxylate. 183 I -Ethylthioisoquinoline. 320 5-Ethyl-2-vinylpyridine. addition o f morpholine to. 171 Formamidines. metallation of. 158 2-Formyl-1.2.3.4-tetrahydro-5-isoquinolinol. 243 2-Form yl- I .2.3.4-tetrahydro-6-benzyloxy-7methoxyisoquinoline. 243 Friedel-Crafts acylation. 72 Glaziovine. 58 Graf-Ritter conditions. 83 Heliamine. 330 2-Heterocyclic substituted isoquinolines. 169 2.3.7.8.9.9a-Hexahydro- I HhenzoldeJ I I .7 J naph th yridines. 6 I .2,3.4.5.10.10a-Hexa hydroimidazoI12-hlisoquinoline. 133

1.2.2.5.6. IM-Hexahydroimidazo-

[2.lwlisoquinolines. 137 I J.4.6.7. I Ib-Hexahydro-2H-pyrimido12.1wlisoquinoline. 134. 137 2.3.4.6.1 1.1 lo-Hexahydro-l H-pyrimido[ 1.2-hlisoquinoline. 133 Hoffmann elimination. 285 Homoveratrylamine. reaction with diethyl oxalate. 107

Hydrastine: oxidation of. with iodine. 253 oxidation to hydroastinine. 281 Hydrastinine chloroplatinate. 275 7-Hydro-8-( I-pipridylmethy1)isoquinoline. 212 Hydroastinine. from hydrastine. 181 Hydrogenation. 259 exhaustive. 314 high pressure. 316 5-Hydroxy-6(3-azahicyclo(3.2.2]nonamethy1)isoquinoline. 212 I-( B-HydroxyethyI)-2-rnethyl12.3.4tetrahydroisoquinolines. 85 N-Hydroxygua nidines. I 4 4 4-Hydroxyisoquinoline. in the Mannich reaction. 194 S-Hydroxyisoquinolinr. Mannich reaction of. 212 7-Hydroxyisoquinoline. Mannich reaction or. 212 S-H ydroxyisoyuinoline-2-oxide. from 5-acctoxyis~uinoline.244 4-Hydroxy-2-rnethylisoquinolinium iodide. 29 I 3-Hydroxymethyl-2-methyl-3.4dihydrwarhostyril. 184 Hydroxy-2-methylisoquinoliniumhalides. pK, values of. 265 3-Hydroxymethyl-2-methyl-1.2.3.4tetrahydroisoquinoline. 184 3-Hydroxy- I-0x0-2-isoindoline acetic acid ethyl ester. ring expansion of. 196 2-Hydroxy-1-(4-pyridyl)isoquinolines. 86 4-Hydroxy- 1.2.3.4-tetra hydroisoquinoline.

-'OH

Imidazol5. I -a lisoquinoline. 3.7 3-(2-lmidazoline-2-yl)isoquinolineI(2H)ones. 1% Indenoisoquinoline. 57 lsatoic anhydrides. 3 10 Isoanhalamine. 331 Isocarhostyril. reaction with methyl vinyl ketone. 175

Index Isoquinoline: catalytic hydrogenation of. 3 I2 hydrogenation of the pyridine ring. 298 oxidation of. 240 reaction with tosyl chloride. 325 lsoquinoline 3-aldeh~de-p-dimethylanil methyl iodide. 196 Isoquinoline-4-carhoxaldehydes.198 3-lsoquinolinecarboxaldehyde. 185 Isoquinoline- I-carboxamide. 6 3-lsoquinolinecarhoximidicacid hydrazide. reaction with vicinyl diketones. 185 lsoquinoline-4-carboxylicacid. reaction with benzylamine. 205 4.8-lsoquinolinediol. 236 deuterium labeling of. 250 S.X-lsoquinolinediol. 236 6.7-lsoquinolinediol. 24 I Isoquinoline-5.8-dione. 244 1(2H)-Isoquinoline oxime. 248 lsoquinolinium pyrimidine salts. from 2-alkyl-4-amino-S-(bromoethyl)pyrimidine. 172 lsoquinolinium salts: dealkylation of. 264 reaction with Grignard reagents. 263 reduction of. with lithium aluminum hydride. 258 4lsoquinolinol. 233.234 coupling of. 246 deuterium labeling of. 249 from demethylation of 4methoxyisoquinoline. 234 hydrogenation of. 314 from isoquinoline. 240 from isoquinoline ?-oxide. 241 nitration of. 244 reaction with phosphoryl chloride. 245 reduction of. with Adams catalyst. 243 5-lsoquinolinol. 236 from S-aminoisoquinoline. 236 nitration of. 247 nitrosation of. 236 7-lsoquinolinol. 236 Mannich reaction of. 247 nitration of. 247 8-lsoquinolinol. 236.238 nitrosation of. 236 Isoquinolinols. 0-alkylation of. 239 1(2H)-lsoquinolinone. 248 0-alkylation of. 238 3(2H)-lsoqu inoli none. 248 0-allylation of. 239 2 4 I-Isoquinolyl)[email protected])pyrrole. 84

549

14 I -Isoquinolyl)-3-cyano-5-phenylpyrrole. 72 l 2 - ( 1'-lsoquinolyl)ethane. 109 I -( 1 -Isoquinolyl)-2-(pyridyl)ethylenes. 87 3-lsoquinolyl-2-quinuclidylketone, 185

Jones oxidation. 3 18 Kreysigine. 67 Laudanosine. oxidative debenzylation of. 275 Lemaireocereine. 330 Lithiated nitrosamines. in carbon-carbon bond formation. 209 Lodal. 334 Longimammatine. 330 Macrostomine. 209 Malon-di-p-phenethylamide. cyclization of. I08 Mannich reaction. 57.212.250.297 of 4-hydroxyisoquinoline. 194 of 7-isoquinolinol. 247 of 1.2.3.4-tetrahydroisoquinolines, 304 Mercaptopyridine-N-oxide.85 Methallylbenzene. 188 I-Methanesulfonylisoquinoline.reaction with nucleophiles. 329 Methoxyazabullvalene. thermolysis of. 240 I-Methoxyisoquinoline. 240 fluorescence of. 340 hydrolysis of. 248 methyl migration of. 248 3-Methoxyisoquinoline. 236.239.240 4-Methoxyisoquinoline. 239 5-Methoxyisoquinoline. 239 6-Methoxyisoquinoline: from Pomeranz-Fritsch reaction. 231 nitration of. 245 7-Methoxyisoquinoline: from Pomeranz-Fritsch reaction. 231 nitration of. 247 8-Methoxyisoquinoline. 239 from Pomeranz-Fritsch reaction. 23 1 6Methoxyisoquinolinol. 233 6Methoxy-7-isoquinolinol. 229.233 7-Methoxy-8-isoquinolinol. 230.233

8-Methoxy-6.7-methylenedioxyisoquinoline.

23 1 7-Methoxy-8-nitroisoquinoline. 247 8-Methoxy- 1.2.3,4-tetrahydro- I .5iminobenzldlazocino-rl(3H)-one. 5 24a-Methyl-&aminophenethyl)-1.2.3.4tetrahydroisoquinoline. 162 0-Methylandrocymbine. 67

550

Index

N-Methylcoclaurine. oxidation of. 275 I-Methyl-3.4-dihydroisoquinoline. 2.69. I62

I. I '-Methylene-bis(3.4-dihydroisoquinoline). 108 6.7-Meth ylenedioxyisoquinoline. from Pomeranz-Fritsch reaction. 231 6,7-Methylenedioxyisoquinolinol.233

bMethylisatoic anhydride. 161 I-Methylisoquinoline. 9.87 3-Methylisoquinoline methyl iodide. 196 2-Methyl-I(2H)-isoquinoline.248 2-Methylisoquinolinium salts. oxidation of. with potassium ferricyanide. 260 2-Methyl-3(2H)-isoquinolinonr.265 Methyl l-methyl-3.4-dihydrocarhostyril-3carboxylate. reaction with lithium aluminum hydride. 184 a-Methylpapaverinol. fission of. 256 Methylphenyl(1-isoquinoly1)carbinol. X 2-Methyl-J-phenyl-3-( I -piperdyl)-4-( I .2.3.4tetrahydro-2-isoquinolyl~2-hutanol.172 I-Methyl-3-phenyl-5.6.7.8-tetra hydroisochromylium perchlorate. 65 N-Methyl-AI -pyrrolidinium acetate. 209 4-(I-Methyl-2-py~olidinyl)isoquinoline. 209 S-Methylpseudothiourea. I49 reaction with 12.3.4-tctrahydroisoquinoline. 144

0-Methylpscudourea. reaction with 1.2.3.4tetrahydroisoquinoline. 144 0-Methyltarconine: alkyl halides of. 332 chloride. bromination of. 265 iodide. reaction with phenylmagncsium bromide. 263 6Methylthio-3.4-dihydroisoquinoline.3 1 X I-Methylthio-3(4H)-isoquinoline. alkylation of. 320 4-Methylthioisoquinoline.amination of. 32 I 5-Methylthioisoquinoline. 3 18 7-Methylthioisoquinoline.3 18 bMethylthio- 1.2.3.4-tetra hydroisoquinoline. 318 7-Methylth io- 1.2.3.4-tetra h yd ro-4isoquinolinol. 3 I8 Michael reaction. 279 of isoquinolines. 170 of 1.2.3.4-tetrahydroisoquinolines. 30 retro. 269 (+)-Morphinans. 158 Narcotine. 262 oxidative degradation of. 275 quantitative analysis of. 281

Narcotolic acid. reaction with ammonia. 290 Narco~oline.reaction with ammonia. 2% Narcotolinediol. reaction with ammonia. 2% Nicotinoyl chloride hydrochloride. 170 2-(2-Nicotinoyloxyethyl)-1.2.3.4-terra hydroisoquinolines. 170 8-Nitro-3.4-dihydroisoquinolinol.272 I-Nitroisoquinoline, substitution of. 234 5-Nitro-6-mcthoxyisoquinoline. 245 p-Nitrostyrene epoxide. I62 N-Norarmepavinc. electrolysis of. 267 Norcotarnine. 232 hromination of. 272 formation of. 2h6 from i t Cope-typc cyclization o f cotarnone. 267 Nortehuanine. 330

(S)-( + Mkoteine. I58

1.2.3.4.5.6.7.8-Octahydroisoquinoline. 158 ~tahydroisoquinolinols.3 14 I-Oxoaporphine. 57 2-(3-Oxobutyl)-2( IH)-isoquinolone. 175 2-OxohydrobenzolaIquinolizidine.rctroaldol of. 269 I-Phenoxyisoquinolinc. 23X I-Phenyl~-(2-henzamidoethyl)-3.4-dihydroisoquinoline. 212 I-Phcnyl-3.4-dihydro-4-(dimeihylaminophenyl)-6.7-dimethoxyisoquinoline. 206 4-Phenyl-9. I0-dirnethoxy-6.7-dihydrc-2Hpyrimido[4.3-a]isoquinolinc.5 I-Phenyl-h.7-disubstituted- 12.3.4-tetrahydroisoquinolines. alkylation with l.3dihromopropane. I 6 4 3-Phenyl-5-1~-~suhstituied)-1.2.3.4-tctra hydro2-isoquinolyll- I .2.4-oxidiazole hydrochloride. 173 4-Phenylthioisoquinoline. 3 18 Phosphorous pentachloride. 198 Pictet-Spengler reaction. 28.74.82. 83.295. 314.318 modified. 307 3-Piperidinocarbonylisoquinoline.reduction with lithium aluminum hydride. 185 2-(2-Piperidinoethyl)- 1.2.3.4-tetrahydroisoquinolines. 173

3-Piperidinomethylisoquinoline.185 2-(4-Pi~ridylethyl)-3-isoquinolylketone.

reaction with sodium hypobromite. 185

I-(Piperidyl)isoquinolines. 88 I-( I-Piperidyl)- I-[a-(I .2.3A-tetrahydro-2isoquinolyl)~enzyl]acetone.172

isolation of intermediates. 3 7 mtdilication of. 230 of sulfonamidcs. 230 N-Propargyl- 1.2.3.4-tetra hydroisoquinoline. 138 Protoberberincs. 2x3 Pschorr reaction. 55. 56. 57.67 Pyrazinol2. I w I isoquinolines. 3 3-Pyridol. 17 1 2-(4-Pyridyl)-3-(p-anisyl)pyrrolo I2.t-alisoquinoline. 84 I-(Pyridyl)isoquinolincs.74 3-(-1-PyridqI)isoquinolines.197 (3-Pyridyl p 1-isoquinol yl ether. X7 2-(2-Pyridyl methyl )- 1.2.3.4-let ra h yd roisoquinoline. 170 1-~~-(2-~ridyl-~Y-oxide)mercaptoethyij-2methyl- 1.2.3.4-tetra hydroisoquinoline.

n5

4-Pyridyl onime. 86 I 42-PyrroI)- I .2-di h ydroisoquinolines. 7 I I-(1-Pyrrolyl)isoquinolines.from Reissert compounds. 71 Quarternar) spiro salt. of I .2.3.4-tetrahqdroisoquinolinc. 170 Raney nickel. 137.312.314 dehydrogenation catalyst. 233 Reissen compound. 6. 7.52. 71. 84.274 alkaline hydrolysis of. 109 alkylation of. 109 Reissert reaction. 142 Ritter reaction. 188 )-Salutaridine. 158 Schottrn-Baumann reaction. 308 Spirolindan-I. 1'-isoquinolinesl. 67 Styrylisoquinolines. 65 4-(Substituted-aminomethyl)-2-alkyl1.2.3.4tetrahydroisoquinolines.104 I-Substi?uted-3-hromomerhyl-3-methyl-3.~di h) droisoquinoline. 1x8 ?-(rl-Suhstituted thiarole)isoquinolincs. 185 I-Sulrrnylisoquinoline. 234 I-Sulfonylisoquinolinc. substitution of. 234 (-

Tarconine. 290 from 0-methy Itarconinc hydroxide. 290 1.2.3.4-Terra hydro-3-aminoniethylisoquinolines. 183 Tetrahydroherberine. 197 Tetrahydroll.l-dl1 1.4)-henzodiazepine~.37

202 I .2.3.4-Tetrahydro-6.7-dimethoxyisoquinoline. 302 1.2.3.4-Tetrahydro-7.8~imethoxyisoquinolinc. reaction with 36% HBr. 301 1.23.4-Tetrahydro-6.7-dimet hoxy-4isoquinolinol. 297 1.2.3.4-Tetrahydro-7.8-dimet h o x y 4 isoquinolinol, -197.299 I .2.3.4-Tetrahydro-6.7-dimethoxy-8isoquinolinol. 297.299.300 1.2.3.4-Tetrahydro-7.8-dimethoxy4 isoquinolinol. dehydrogenation of. with N-bromosuccinimide. 234 1.2.3.4-Tetrahydro-6.11-dimethoxy-7isoquinolinol. 295 from anhalinine. 300 1.2.3.4-Tetra hydro-2-hydroxyisoquinoline. oxidation of. with mercuric oxide. 305 1.2.3.4-Tetra hydroisoquinolines: acylation of. with isatoic anhydrides. 310

2-alkyl. 185 1%'-alkylation of. 304 N-Boc derivative. alkylation at the I-position. 399 I-carboxymethyl. 272 from catalytic hydrogenation of. 3.4di hydroisoquinolines. 297 M-cyanation of. 304 dehydrogenation of. photochemical. 234 N-formamidation of. 304 N-formylation of. 309 Mannich reaction of. 304 Michael reaction of. 304 N-nitrosation of. 304 oxidation of. 267 photolysis of. 268 quaternary spiro salt of. 170 N-sulfonation of. 300 4-(1.2.3.4-Tetrahydroisoquinoline)-2-hutanone hydrochloride. 173 I 2.3 &Tetra hyd roisoq ui no1ine-2-a rboxam ide hydrohromide. I44 1.2.3.4-Tetra hydro-3-isoquinoline carboxylic acid. 184 I .2.3.4-Tetrahydroisoquinoline-3-carboxylic acid. oxidative decarhoxylation of. 209 1.2.3.4-Tetra hydro-5.8-isoquinolinediol.hlood pressure lowering of. 336 I .2.3.4-Tetra hydro-6.7-isoquinolinediol. 326 2-124 1.2.3.4-Tetra hydroisoquinoline))ethylguanidine sulfate. 149

552

Index

123.4-Tetrahydroisoquinoline hydrochloride.

reaction with paraformaldehyde. I73 2 4 1.23.4-Tetra hydroisoquinoline- I-ylkthylamine. reaction with S-methylpseudothiourea. 149 1,2,3.4-Tetrahydro-4.6.7-isoquinolinetriol. 2% dehydrogenation of, 233 effects on endogenous catecholamine. 337 1.2.3.4-Tetra hydro-2-isoquinolinothanols. reaction with nicotinoyl chloride hydrochloride. 170 Tetrahydroisoquinolinols.0-methylation of. with diazomethane. 301 1.23.4-Tetrahydroisoquinolinols. 2-acctyl. hydrogenation of. 3 16 I.23.4-Tetrahydro-4-isoquinolinol.303 dehydrogenation of. with palladium black. 233 i.2.3.4-Tetrahydro-5-isoquinoIinol.302 1.2.3.4-Tetrahydro-6-isoquinolinol.300 1.2.3.4-Tetrahydro-7-isoquinolinol.300 5.6.7.8-Tetrahydro-Q-isoquinolinol. 243 2-( I .2.3.4-Tetra hydroisoquinolino)-4-rnethyl5-(2-hydroxyethyl)pyrimidine. 172 d./.y-N-( 12.3.4-Tetra hydroisoquinolyl)-ahydrazinobutyric acid, 149

I .2,3.4-Tetrahydro-S-methoxyisoquinoline. 298 1.2.3.4-Tetrahydro-6-methoxyisoquinoline.

29Y 1.2.3.4-Tetrahydro-7-met hoxyisoquinoline. 298.299 1.2.3.4-Tetra hydro-8-me1hoxyisoquinoline. 298.300 1.2.3.4-Tetrahydro-6rnethoxy-7-isoquinolinol. 229.295 1.2.3.4-Tetrahydro-7-methoxy-6-isoquinolinol. 295 12.3.4-Tetrahydro-7-methoxy-8-isoquinolinol.

297.301 I .2.3.4-Tetrahydro-6.7-me~hylenedioxyisoquinoline. 300 1.2.3.4-Tetra hydro-6.7-methylenedioxy4 isoquinolinol. 297

12.3.4-Tetrahydro-6.7-methylenedioxy-8rnethoxyisoquinoline, 300 1.3.4.1 16-Tetrahydro-2H-pyrimido12.1w]isoquinoline. 134 1.2.3.4-Tetra hydro-6.7.8-trimethoxyisoquinoline. 330 partial demethylation of. 300 I.2.3.4-Tetra hydro-5.6.7-trimethoxy-4isoquinolinol. 297 I.2.3,4-Tetrahydro-S.6.8-trimethoxy-4isoquinolinol. 297 (+ )-(S)-l2.3.4-Tetramethoxy-9hydroxyaporphine. 56 4.S.6.7-Tetrarnethoxyisoquinoline. 239 6.6‘.7.7’-Tetramethoxy-3,3’,4.4‘-tetrahydroI. I’bisisoquinoline. I07 1-(2-ThienyI)isoquinolines.72 1(2H)-Thioisoquinolines.methylation on sulfur. 324 bThiomethyl-8.9-dihydro-I3hHisoquinolino~2.1-c]quinazoline. 41 qp-Tosy1oxy)isoquinoline.hydrogenation or. 243 3.5.8-Triacetoxyisoquinoline.241 Triazines. 185 5.6.7-Trimethoxyisoquinoline.233 5.6.7-Trimethoxyisoquinolinol.233 dl-Tuduramine. 55 Ullmann reaction. 37.56. 107.239 Valine dimethylformamidine. 158 4Vinylpyridine. 84 Weheridine. 330

The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

Isoquinolines, Part 1 (The Chemistry of Heterocyclic Compounds, Volume 38)

The Chemistry of Heterocyclic Compounds, The Chemistry of 1,2,3-Thiadiazoles (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 62)

The Chemistry of Heterocyclic Compounds, Supplement I (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 58)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Indoles. Part 1 (Chemistry of Heterocyclic Compounds, Volume 25a)

The Chemistry of Heterocyclic Compounds, The Naphthyridines

The Chemistry of Heterocyclic Compounds, Acridines

Chemistry of Heterocyclic Compounds The Pyrazines 2C

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

Indoles. Part 3 (Chemistry of Heterocyclic Compounds, Volume 25c)

The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 60)

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

Quinazolines, Supplement I (The Chemistry of Heterocyclic Compounds, Volume 55)

Triazoles: 1,2,3 (The Chemistry of Heterocyclic Compounds, Volume 39)

Aza-Crown Macrocycles (The Chemistry of Heterocyclic Compounds, Volume 51)

Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

The Chemistry of Heterocyclic Compounds, Thiazole and Its Derivatives

Handbook of Heterocyclic Chemistry

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II

Aromaticity in heterocyclic compounds

Advances in Heterocyclic Chemistry, Volume 38

Heterocyclic Chemistry (v. 1)

Heterocyclic chemistry

Heterocyclic Chemistry

Heterocyclic chemistry

Heterocyclic Chemistry

The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

Isoquinolines, Part 1 (The Chemistry of Heterocyclic Compounds, Volume 38)

The Chemistry of Heterocyclic Compounds, The Chemistry of 1,2,3-Thiadiazoles (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 62)

The Chemistry of Heterocyclic Compounds, Supplement I (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 58)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Indoles. Part 1 (Chemistry of Heterocyclic Compounds, Volume 25a)

The Chemistry of Heterocyclic Compounds, The Naphthyridines

The Chemistry of Heterocyclic Compounds, Acridines

Chemistry of Heterocyclic Compounds The Pyrazines 2C

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

Indoles. Part 3 (Chemistry of Heterocyclic Compounds, Volume 25c)

The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 60)

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

Quinazolines, Supplement I (The Chemistry of Heterocyclic Compounds, Volume 55)

Triazoles: 1,2,3 (The Chemistry of Heterocyclic Compounds, Volume 39)

Aza-Crown Macrocycles (The Chemistry of Heterocyclic Compounds, Volume 51)

Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

The Chemistry of Heterocyclic Compounds, Thiazole and Its Derivatives

Handbook of Heterocyclic Chemistry

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II

Aromaticity in heterocyclic compounds

Advances in Heterocyclic Chemistry, Volume 38

Heterocyclic Chemistry (v. 1)

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