Imidazo pyridines, reactions with

Imidazo[4,5-c]pyridine-2(3f7)-thione, 1-methyl-reactions with acrylonitrile, 5, 620 Imidazo[l,2-a]pyridine-2(3H)-thiones synthesis, 5, 632... 

Mercaptoacetic acid could be used as a versatile synthon for the synthesis of 17/,3//-thiazolo[3,4-tf]benzimidazole-type compounds <1996FA279, 1997FA673>. For instance, 2,3-diaminopyridine and 2-mercaptoacetic acid were reacted in a three-component reaction with a suitable carbonyl compound and provided the 17/,3//-thiazolo[3,4- ]-imidazo[4,5- ]pyridines 451 (Equation 212) <1994FA345>. 

Only a few of such reactions of these rings have been reported since CHEC-II(1996). However, Weaver and Tennant <1999TL8157, 2000TL9319> have demonstrated that imidazo[4,5-f]isoxazoles such as 19 undergo thermally driven reactions with acetylenic diesters (such as 22) to yield, rather than the expected bridged bicyclic compound 20 or the pyridine Woxide 21, the 2-pyrrol-2-ylimidazole 24 which the authors suggest proceeds via loss of a methyl oxalate unit. The proposed pathway is outlined in Scheme 1. 

Reactions with methylphenylcyclopropenone (154) provided an opportunity to compare the reactivities of the two different C—CO bonds. The reaction of 2-aminopyridines with methylphenylcyclopropenone (154) proceeded more slowly than with the diphenyl analog (153). In ether, formation of the ds-2-oxopyrido[l,2-a]pyrimidines (158 R1 = Me) and/or the imidazo[l,2-c<]pyridines (162) was observed, indicating that the cycloaddition proceeds via cleavage of the PhC—CO bond. The methyl-substituted trans-2-oxopyrido[l,2-a]pyrimidine (160 R1 = Me) was only detected in the reaction mixture of 2-amino-3-methylpyridine, where the H NMR spectrum exhibited signals assigned to 160 (R1 = Me, R = 9-Me). The compound was not isolated. The imidazo[l,2-a]pyridines (162) readily hydrolyzed to the acids (163), work-up therefore leading mainly to isolation of the acids. 

The reaction with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

This reaction appears to be similar to the imidazo-pyridine formation mentioned above, most likely via a [5+1] insertion reaction of the isocyanide into the corresponding hydrazone. This reaction mechanism seems likely since only electron-rich aromatic hydrazines yielded cinnolines. The Ugi 4-CR reaction with phe-nylhydrazine is known and has been reported to give the expected Ugi-type 4-CR product. 

Substituted imidazo[4,5-c]pyridin-2-ones such as compound (149) upon reaction with iodo-methane gave intractable mixtures rather than the desired product (150). To prepare compound (150) one must first /V-alkylate the imidazole (151) and subsequently annulate <93JMC1341>. 

The condensation of the 2,3-diaminopyridine (286) with 3,3-dimethylglutaric anhydride (287) in refluxing acetic acid afforded the 2-substituted imidazo[4,5-6]pyridine (288) in good yield (Scheme 28) (94JHC73). Compound (288) may also be prepared by the initial condensation of the pyridine (286) with the aldehyde (289) in the presence of acid to produce an intermediate Schiff base which on oxidation with iodine in 1,2-dimethoxyethane gives compound (290) which was hydrolyzed to the acid (288) <93JMC1175>. The yield in this reaction sequence was less than that from the condensation using the anhydride (287). 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reaction with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reaction, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rationale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

The synthesis of the same nucleus (imidazo[l,2-a]pyridines) 17 has been described by Rousseau and co-workers [68] applying zinc chloride. In a domestic microwave oven, in one-pot fashion, a number of imidazo[l,2-a]pyridines has been synthesized in reasonable yields and with short reaction times. The reaction with nicotinaldehyde did not proceed to completion, as zinc chloride form a stable complex with the imine. However, when Montmorillonite clay KIO was used as catalyst, the desired product was obtained in good yield (Scheme 16). 

Dipyrido[l,2-a 3, 3 -containing aluminum chloride (78CPB2924). 

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