WEIDENHAGEN Imidazole Synthesis

WEERMAN Degradation 405 WEIDENHAGEN Imidazole synthesis 406 WEINREB Ketone synthesis 407 WEISS Annulation 408 WENCKER AZsidsie synthesis 409 WENZL-IMAMOTO Reduction 4t0... 

WEIDENHAGEN Imidazole Synthesis Imidazole synthesis from a-ketols, formaldehyde and ammonia (see 1st edition). 

Reactions of this type include the major early methods used by Debus,22 Radziszewski,23 Weidenhagen,24 and Maquenne.25 All these suffer from deficiencies such as difficulty of synthesis of starting materials, low yields, and, more often than not, from the formation of mixtures of products which require tedious separation. Among recent modifications26 27 of the Maquenne method is the preparation of dialkyl 4,5-imidazole dicarboxylates in yields of 45-65 % by treatment of a dialkyltartrate dinitrate with either an aliphatic aldehyde or a formaldehyde precursor, in the presence of ammonium ions at pH 3.5-6.5. 

It is convenient to combine these two synthetic approaches because they are formally similar. Both condense an a-functionalized ketone or aldehyde (C-4-C-5 synthon) with an amine or ammonia (N-1, N-3) and an aldehyde (C-2). "Die alternative Bredereck modification uses formamide as the source of the C-2-N-3 bond and of N-1. The older (Radziszewski or Weidenhagen) methods give 4-mono-, 4,5-di- and 2,4,5-trialkyl or -triaryl imidazoles the Bredereck formamide synthesis is largely restricted to the preparation of imidazoles with no 2 substituent. 

The first syntheses of IcP, also including unsubstituted 2, 86, 61 and 62 were carried out with 3,4-DAPs 29 and 48 and aliphatic or aromatic aldehydes. A specific feature of a procedure described by Weidenhagen et al. was the application of an oxidant, copper(II) acetate (38CB2347), to complete imidazole ring formation. This reaction was later extended to the synthesis of other IPs derivatives (42CB1936). 

This reaction has been extended by Weidenhagen through the condensation of Qf-acetoacetone, cupric acetate, and aqueous ammonia to afford imidazoles in yields up to 60%. " This method is thus known as the Weidenhagen modification or Weidenhagen Synthesis. In addition, the Radziszewski reaction has been further modified 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,and this protocol has been recently carried out under microwave irradiation. Furthermore, it has been reported that the reaction of an amidine with an of-halo ketone also readily yields imidazoles. 

Weidenhagen Synthesis The Weidenhagen synthesis of imidazoles is a modification of the Radziszewski reaction [65] and was first pubhshed in 1935 [66]. In this... 

SCHEME 12.10 Synthesis of 2-phenyl-4(5)-(2 -hetaryl)imidazoles 38 by Weidenhagen reaction. 

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