Imidazoles and benzimidazoles

Grimmett. Imidazoles and Benzimidazoles.htm −1− Introduction When faced with the challenge of writing a monograph on the synthesis of imidazoles and benzimidazoles, one is immediately aware that although there are general methods available for the bicyclic compounds, the contrary is true for imidazoles themselves. Indeed, it is necessary to consider a number of widely divergent processes each time a synthesis is contemplated. For this reason I have divided the synthetic approaches arbitrarily into methods which make specific bonds in the imidazole product, those which transform another heterocycle, and those which start with the preformed imidazole ring. With such a myriad of methods it has not been possible to check many of the actual syntheses included, although an endeavour has been made to cross check among different publications, and our experiences in the laboratory at Otago University have been drawn on extensively in assessing methods included. I have provided an index which should help lead research workers to specifically substituted products, so that comparisons can be made of the possible approaches. In addition, care has been taken to ensure that the referencing is sufficiently detailed. Benzimidazole synthesis has been reviewed in detail in Preston's volumes [7] which contain a wealth of tabular material. Other review material has been less heavily oriented towards synthesis [1−6, 8−15]. When making use of the synthetic details included one needs to be aware of modern safety considerations. In consequence, it may be advisable to seek alternatives to solvents such as benzene, chloroform, carbon tetrachloride and hexane used in the methods described. Some earlier examples quoted could profitably be unproved by the use of more modem separation and purification techniques. Yields quoted are those from the original publications; in our experience these have sometimes been shown to be optimistic. My thanks are due to the University of Otago who granted me a short period of study leave, part of which was devoted to this work, and to the staff of the Chemistry Department at the Open University, Milton Keynes, UK, where I was able to work with few distractions in a friendly environment. I also owe much to Julie Leith, Andrea Krause and Diane Watson who so expertly did most of the word processing and preparation of diagrams at the University of Otago. 1. INTRODUCTION REFERENCES 1. Ê. Hofmann, in The Chemistry of Heterocyclic Compounds. Imidazole and its Derivatives, Part 1 (ed. A. Weissburger). Interscience, New York, 1953. 2. E. S. Schipper and A. R. Day, in Heterocyclic Compounds (ed. R. C. Elderfield). Wiley, New York, 1957, Vol. 5. 3. P. N. Preston, Chem. Rev. 74, 279 (1974). 4. P. N. Preston and G. Tennant, Chem. Rev. 72, 627 (1972). 5. M. R. Grimmett, Adv. Heterocyd. Chem. 12, 103 (1970). 6. M. R. Grimmett, Adv. Heterocyd. Chem. 27, 242 (1980).

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Grimmett. Imidazoles and Benzimidazoles.htm 7. P. N. Preston, in Benzimidazoles and Congeneric Tricyclic Compounds (ed. P. N. Preston). Interscience−Wiley, New York, 1981. 8. M. R. Grimmett, in Comprehensive Heterocyclic Chemistry (ed. A. R. Katritzky and C. W. Rees). Pergamon Press, Oxford, 1984, Vol. 4.08 (ed. Ê. Ò. Potts), p. 457. 9. M. R. Grimmett, in Comprehensive Heterocyclic Chemistry. Elsevier, (ed. A. R. Katritzky and C. W. Rees) Oxford, Vol. 3.02 (ed. I. Shinkai) 1996, p. 77. 10. A. F. Pozharskii, A. D. Gamovskii and A. M. Simonov, Russ. Chem. Rev. (Engl. Transl.) 35, 122 (1966). 11. J. B. Wright, Chem. Rev. 48, 397 (1951). 12. G. V. Nikitina and M. S. Pevzner, Chem. Heterocycl. Compd. USSR (Engl. Transl.) 29, 127 (1993). 13. L. B. Townsend and G. R. Revankar, Chem. Rev. 70, 389 (1970). 14. A. R. Katritzky and J. M. Lagowski, Chemistry of Heterocyclic N−Oxides. Academic Press, New York, 1971. 15. V. I. Kelarev and V. N. Koshelev, Russ. Chem. Rev. (Engl. Transl.), 64, 317 (1995). −2− Ring Synthesis by Formation of One Bond 2.1 FORMATION OF THE 1,2 (OR 2,3) BOND C−N ñ, Ü NR NR C−N c. ,c NR Synthetic procedures which fall under this heading apply to both imidazoles and benzimidazoles, and some are closely related to those methods which involve formation of both the 1,2 and 2,3 bonds. This section should therefore be read closely with Section 3.1.2, particularly with regard to benzimidazole synthesis. 2.1.1 Imidazoles The earliest method of this type was the old Wallach synthesis, which formed the imidazole ring by cycli/ation of an AW−disubstituted oxamide with phosphorus pentachloride; the usual product was a 1−substituted 5−chloroimidazole (1) (Scheme 2.1.1) [1−4]. Although initially thought to be rather limited in 2

Grimmett. Imidazoles and Benzimidazoles.htm its application, the method was later extended to cyclization of higher symmetrical and unsymmetrical oxamides, and now provides access to a variety of 5−chloroimidazoles [5−8]. (CONHR), a NR (D Scheme 2.1.1 Symmetrically substituted oxamides can be made in 84−94% yields from diethyl oxalate and primary amines [5], whereas the unsymmetrical W−alkyl−N'−arylmethyloxarnides are available in high yields by initial treatment of an ethanolic solution of diethyl oxalate with a benzylamine at 0°C, followed by 2. RING SYNTHESIS BY FORMATION OF ONE BOND TABLE 2.1.1 5−Chloroimidazoles (2) prepared from N.TV'−disubstituted oxamides or from W−formylglycine amides R1 Et nPr nBu iBu CH3(CH2)4 CH2Ph Me Me Me (CH2)OMe Me Me Et iPr nBu iBu Ph PhCH2

R2 Me Et nPr iPr nBu Ph ð−\^Ë — Ñ−6−Ã14