Imidazo pyridines, ring synthesis

There has been one report of the synthesis of the imidazo[l,2-a]pyridine ring system (336) by the closure of both rings by the reaction of (334) and (335), but closure of the pyridine ring probably occurs first (73ZOR2006). 

The first report of the synthesis of an imidazo[4,S-6]pyridin-S--one by closure of a pyridine ring is a base-catalysed cyclization of the amino-malonylidene diester. Complementary to this method is that in which a monoester mononitrile of malonic acid is heated in acetic acid to give a high yield of the fused pyridinone. Me... 

The traditional ring synthesis of imidazo[l,2-a]pyridines is based on the Chichibabin route to indolizines... 

Since the publication of the first edition of this work numerous reactions resulting in the formation of the imidazo[l,2-fl]pyridine ring system have been reported. Nevertheless the method of choice for the synthesis of most imidazo[l,2-a]pyridines remains the condensation of a 2-aminopyridine and an a-halocarbonyl compound, usually a ketone or aldehyde. 

The ring synthesis of imidazo[l,2-a]pyridines is based on the Chichibabin route to indolizines (Section 25.1.2), but using 2-aminopyridines instead of 2-alkylpyridines. The initial reaction with the halo-ketone is regioselective for the ring nitrogen, so isomerically pure products are obtained. 2-Oxoimidazo[l,2-a]pyridines are the products when an o-bromo-ester is used instead of a ketone. 

Among other condensed thiazole ring systems, imidazo[2,l-6]thiazoles (tetramisole is a member of this class), thiazolo-pyrimidines, and thiazolo-pyridines continue to attract the most interest. Attention is concentrated on synthesis and biological activity. Unexpectedly, dihydrothiazolo[3,2-a]pyridinium bromide is readily brominated when the pyridine ring has a 3-nitro-substituent but not when it has a 3-amino-substituent. 

This reaction procedure has also been used for the synthesis of oxazolo[3,2-fl]pyridine and imidazo[l,2-fl]pyridine derivatives, and the numerous variations studied, allowing changes of the substituent pattern and the number and position of the nitrogen atoms in the six-membered ring, are described in Chapters 4.10 and 4.29. 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

Irnidazo[ 1,2-tf ]py ridines were covered in CHEC(1984) <1984CHEC(6)613> along with others imidazoles fused to six-membered rings and they were reviewed together with imidazo[l,5- ]pyridines in CHEC-II(1996) <1996CHEC-II(8)249>. The chemical literature on this heterocycle is very abundant, due to its easy synthesis (most of the preparations use readily available 2-aminopyridines) and to the very broad spectrum of bioactivities displayed by many derivatives. A simple Beilstein search on the fully conjugated heterocycle (free sites everywhere) disclosed ca. 3000 hits for the past decade. Therefore, this chapter cannot be exhaustive in view of space limitations, but will mainly focus on the original synthetic methods that have appeared in the last decade. 

Interaction of substituted dienediamines with ethylenediamine yields im-idazo[3,2-n]pyridine derivatives (95JHC477). 3-Arylaminoindoles, with distinct enamine properties, are the starting materials for the synthesis of indolo[3,2-b]quinoline derivatives [96KFZ(7)42]. a-Carboline derivatives can be obtained from enamine-based 3-dimethylamino-2-indolinones [96KFZ(9)35, 96KFZ(10)32], The synthesis and transformation of enamines based on the pyrido[l,2-n]pyrazine ring system into imidazo[l,2-n]pyridine and imidazo[l,2-a]pyrimidine derivatives have been reported... 

A number of other five-membered ring nitrogen heterocycles have been prepared by cyclative cleavage. The illustrative examples (Fig. 4) depict the synthesis of pyrazolones,12 succinimides and phthalimides,13 pyrrolo[3,4-h] pyridines,14 2-aminoimidazolones,15 imidazo[4,5-fr]pyridin-2-ones,16 and l,2,4-triazoline-3,5-diones.17... 

Starting with 4-aminopyridine (337), a total synthesis of the parent ring imidazo[4,5-c]pyridine (338) has been reported <86T1511) in a 41 % overall yield (Scheme 35). 

In a recent article by Beifuss and co-workers [126], the synthesis of pyrido [2, l 2,3]imidazo[4,5-c]isoquinolin-5(6//)-ones 90 has been described in good yields by means of a microwave-assisted three-component reaction of a 2-amino-pyridine, an isocyanide and a 2-carboxybenzaldehyde under acidic conditions. The reactions are easy to perform, robust, and highly efficient. This process allows the formation of two heterocyclic rings and four new bonds in a single synthetic operation (Scheme 67) ... 

Imidazo[4,5-c]pyridine (408 R = R = H) and a number of its 2-substituted and 1,2-disubstituted derivatives have been prepared in moderate to good yields by the reaction of the 3,4-diaminopyridines (407) with aliphatic, aromatic and heteroaromatic aldehydes in aqueous alcohol solution in the presence of excess copper(II) acetate in a sealed tube at 130-150 °C (38CB2347, 42CB1936). The Schiff bases (409) are formed primarily in this synthesis, and in many cases it is preferable to isolate the base (409) and effect the subsequent oxidation in a separate operation in alcohol solution. Ring closure of 5-substituted, 6-substituted and 2,6-disubstituted 3,4-diaminopyridines (410) to 7-substituted, 6-substituted... 

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