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Radziszewski Reaction
A. GENERAL DESCRIPTION OF THE REACTION This reaction was rst reported by Debus in 1858,1 fully developed by Radziszewski beginning in 1882,2 and further modied by Weidenhagen in 1935.3 It is the synthesis of an imidazole derivative by the condensation of an -dicarbonyl compound (e.g., glyoxal), an aldehyde and two equivalents of dry ammonia in alcohol. Therefore, this reaction is generally known as the Radziszewski reaction.4 Occasionally, it is also called the Radziszewski synthesis,5 Weidenhagen Synthesis,5 or Debus-Radziszewski imidazole synthesis.6 As a result, imidazole is also referred to as glyoxaline because of this reaction.7 Other names that have been designated for imidazoles include iminazole7 and 1,3-diazole,7 which have been rarely used in recent literature; whereas the term imidazole was originally chosen as the name for such molecules by Hantzsch8 and was given ofcial recognition.9 In this reaction, a variety of -dicarbonyl compoundsincluding glyoxal,4b pyruvaldehyde,5b porphyrin-2,3-diones,10 and benzil2a have been successfully used to the synthesis of corresponding imidazole derivatives. It is interesting that the replacement of one equivalent ammonia with a primary amine results in the formation of 1-substituted imidazoles.11 Although this reaction in general gives poor yields of imidazoles5b,12 and suffers from some side reactions (e.g., the reverse Aldol Condensation and oxazole formation)12a the condensation of benzil with benzaldehyde and ammonia in alcohol gives nearly a quantitative yield of 2,3,5-triphenylimidazole (lophine).2a,13 This reaction is useful for the preparation of imidazoles with a substituent at position 2 from adjacent di-carbonyl compounds.5a In fact, this reaction is the only reaction of industrial importance for the production of imidazole derivatives.

Comprehensive Organic Name Reactions and Reagents, 3V Set, by Zerong Wang Copyright 2009 John Wiley & Sons, Inc.

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RADZISZEWSKI REACTION

B. GENERAL REACTION SCHEME

C. PROPOSED MECHANISMS Although there is no general mechanism for this reaction in the cited literature, it is plausible that ammonia (or primary amine) reacts with an -dicarbonyl compound to form -diimine, which then condenses with an aldehyde, as displayed here. In the meantime, it is also possible to form an oxazole by-product from this multicomponent condensation.

D. MODIFICATION This reaction has been extended by Weidenhagen through the condensation of -acetoacetone, cupric acetate, and aqueous ammonia to afford imidazoles in yields up to 60%.3,14 This method is thus known as the Weidenhagen modication4b,15 or Weidenhagen Synthesis.5a In addition, the Radziszewski reaction has been further modied to proceed in acetic acid by the use of ammonium acetate or ammonium carbonate as the source of ammonia to give imidazoles of markedly improved yields,16 and this protocol has been recently carried out under microwave irradiation.12a Furthermore, it has been reported that the reaction of an amidine with an -halo ketone also readily yields imidazoles.12b

CITED EXPERIMENTAL EXAMPLES

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E. APPLICATIONS This reaction is very useful for the preparation of imidazole derivatives.

F. RELATED REACTIONS N/A

G. CITED EXPERIMENTAL EXAMPLES

HO HN t-Bu

CHO NaOAc + NH3/H2O/MeOH 32.1% O HN t-Bu HO O

H N N

Reference 4b. A mixture of 10 g 4-[3-(tert-butylamino)-2-hydroxypropoxy]-benzaldehyde (0.04 mol), 31 g 40% glyoxal (0.22 mol), 26 g NaOAc3H2 O (0.19 mol), 100 mL concentrated ammonium hydroxide (NH4 OH), and 250 mL MeOH was stirred overnight at room temperature. After removal of MeOH under reduced pressure, the aqueous layer was treated with 100 mL saturated Na2 CO3 solution and extracted with CHCl3 (3 200 mL). The combined organic layers were dried, ltered, and concentrated. The residue was chromatographed on silica gel using 30% MeOH-CHCl3 as the eluent, and 3.7 g 2-[4-[3-(tert-butylamino)-2hydroxypropoxy]-phenyl]imidazole was obtained after nal crystallization from CH3 CN, in a yield of 32.1%.
F O F CHO + O NH4Ac AcOH, 180C microwave 97% N H N

Reference 12a. To a 2-mL SmithsynthesizerTM reaction vial containing a magnetic stir bar were added 1.0 mL acetic acid, 42 mg benzil (0.2 mmol), 25 mg 4-uorobenzaldehyde (0.2 mmol), and 154 mg ammonium acetate (2.0 mmol). The reaction vessel was heated in the Smithsynthesizer reactor cavity for 5 min at 180 C, after which the vessel was rapidly cooled to 40 C by the unit. The reaction mixture was added dropwise to a concentrated NH4 OH solution cooled to 0 C and immediately formed a white precipitate, which was collected by ltration and washed with H2 O. The solid was dried in a vacuum oven for 18 h at 50 C to

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afford 61 mg 2-(4-uorophenyl)-4,5-diphenylimidazole as a bright white solid, in a yield of 97%. Other references related to the Radziszewski reaction are cited in the literature.17

H. REFERENCES
1. Debus, H., Ann., 1858, 107, 204. 2. (a) Radziszewski, B., Ber., 1882, 15, 1493. (b) Radziszewski, B., Ber., 1882, 15, 2706. (c) Radziszewski, B., Ber., 1883, 16, 487. (d) Radziszewski, B., Ber., 1883, 16, 747. 3. (a) Weidenhagen, E., Ber., 1935, 68, 1953. (b) Weidenhagen, E., Ber., 1937, 70, 570. 4. (a) Breslin, H. J.; Miskowski, T. A.; Rafferty, B. M.; Coutinho, S. V.; Palmer, J. M.; Wallace, N. H.; Schneider, C. R.; Kimball, E. S.; Zhang, S.-P.; Li, J.; Colburn, R. W.; Stone, D. J.; Martinez, R. P. and He, W., J. Med. Chem., 2004, 47, 5009. (b) Baldwin, J. J.; Engelhardt, E. L.; Hirschmann, R.; Lundell, G. F.; Ponticello, G. S.; Ludden, C. T.; Sweet, C. S.; Scriabine, A.; Share, N. N. and Hall, R., J. Med. Chem., 1979, 22, 687. (c) James, D. S. and Fanta, P. E., J. Org. Chem., 1962, 28, 390. 5. (a) Curtis, N. J. and Brown, R. S., J. Org. Chem., 1980, 45, 4038. (b) Oliver, J. E. and Sonnet, P. E., J. Org. Chem., 1973, 38, 1437. 6. Tymoshenko, D. O., ARKIVOC, 2005, (viii), 1. 7. (a) Townsend, L. B., Chem. Rev., 1967, 67, 533. (b) Fox, S. W., Chem. Rev., 1943, 32, 47. 8. Hantzsch, A., Ann., 1888, 249, 2. 9. Patterson, A. M. and Capell, L. T., The Ring Index, Reinhold Publishing, New York, 1940, p. 42. 10. Crossley, M. J. and McDonald, J. A., J. Chem. Soc., Perkin Trans. I, 1999, 2429. 11. Hofmann, K., Imidazole and Its Derivatives, Part I, Interscience Publishers, New York, 1953. 12. (a) Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z. J. and Lindsley, C. W., Org. Lett., 2004, 6, 1453. (b) Baldwin, J. J.; Christy, M. E.; Denny, G. H.; Habecker, C. N.; Freedman, M. B.; Lyle, P. A.; Ponticello, G. S.; Varga, S. L.; Gross, D. M. and Sweet, C. S., J. Med. Chem., 1986, 29, 1065. 13. Wiley, R. H., Chem. Rev., 1945, 37, 401. 14. (a) Weidenhagen, R. and Rienacker, H., Ber., 1939, 72, 57. (b) Weidenhagen, R. and Wegner, H., Ber., 1938, 71, 2124. (c) Weidenhagen, R. and Weeden, U., Ber., 1938, 71, 2347. (d) Weidenhagen, R. and Wegner, H., Ber., 1937, 70, 2309. (e) Weidenhagen, R., Ber., 1936, 69, 2263. (f) Weidenhagen, R. and Herrmann, R., Ber., 1935, 68, 2205. (g) Weidenhagen, R. and Herrmann, R., Angew. Chem., 1935, 48, 596. 15. Baldwin, J. J.; Lumma, P. K.; Novello, F. C.; Ponticello, G. S.; Sprague, J. M. and Duggan, D. E., J. Med. Chem., 1977, 20, 1189. 16. (a) Steck, E. A. and Day, A. R., J. Am. Chem. Soc., 1943, 65, 452. (b) Davidson, D.; Weiss, M. and Jelling, M., J. Org. Chem., 1937, 2, 319. 17. (a) Acke, D. R. J.; Orru, R. V. A. and Stevens, C. V., QSAR & Combinatorial Sci., 2006, 25, 474. (b) Wr blewska, A.; Huta, O. M.; Midyanyj, S. V.; Patsay, I. O.; Rak, J. and Blazejowski, o J., J. Org. Chem., 2004, 69, 1607. (c) McKenna, J. M.; Halley, F.; Souness, J. E.; Mclay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K. and Ahmed, I., J. Med. Chem., 2002, 45, 2173. (d) Zhou, Y. H.; Baker, W. E.; Kazmaier, P. M. and Buncel, E., Can. J. Chem., 1998, 76, 884. (e) Ross, M. G., Imidazole and Benzimidazole Synthesis, Academic Press: San Diego, CA, 1997. (f) Ling, Y.-z.; Li, J.-S.; Liu, Y.; Kato, K.; Klus, G. T. and Brodie, A., J. Med. Chem., 1997, 40, 3297. (g) Sarchar, S.; Siev, D. and Mjalli, A. M. M., Tetrahedron Lett., 1996, 37, 835. (h) Baldwin, J. J.;

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Denny, G. H.; Hirschmann, R.; Freedman, M. B.; Ponticello, G. S.; Gross, D. M. and Sweet, C. S., J. Med. Chem., 1983, 26, 950. (i) Tsuda, T.; Yoshimoto, K. and Nishikawa, T., Chem. Pharm. Bull., 1981, 29, 3593. (j) Shibamoto, T. and Bernhard, R. A., J. Agri. Food Chem., 1978, 26, 183. (k) Wolff, J. and Covelli, I., Eur. J. Biochem., 1969, 9, 371. (l) Pozharskii, A. F.; Garnovskii, A. D. and Simonov, A. M., Russ. Chem. Rev., 1966, 35, 122. (m) White, E. H. and Harding, M. J. C., J. Am. Chem. Soc., 1964, 86, 5686. (n) Kyrides, L. P.; Zienty, F. B.; Steahly, G. W. and Morrill, H. L., J. Org. Chem., 1947, 12, 577.