Pyridine, halo, carbonylation

Table 14 Synthesis of imidazo[1,2-a]pyridines through cyclocondensation of 2-aminopyridine and a-halo carbonyls 2-Aminopyridine a-Halo carbonyl Conditions Product Yield (%) Reference...

This synthesis, originally devised by Tschitschibabin,8 is still the most widely used because it can easily be modified to yield substituted indolizines. The synthesis involves the quaternization of a 2-substituted pyridine, normally using an a-halo carbonyl compound, followed by intramolecular cyclization of the quaternary salt with a mild base, usually aqueous sodium bicarbonate (Scheme 1). 

COOH — —CHO. This conversion can be effected in one flask by treatment of the carboxylic acid with N,N dimethylchloromethyleniminium chloride (prepared from DMF and oxalyl chloride) and pyridine to form a betaine, which is then reduced to the aldehyde by the hydride in the presence of a catalytic amount of Cul at — 78° The reaction is applicable to aliphatic and aromatic acids, and can tolerate halo, cyano, ester, and even carbonyl groups. Yields are usually —65-80%. 

In 1965, Murdoch described the synthesis of a series of halo-bridged allyl carbonyl complexes of the type [NEt4][M2(/a-X)3(CO)4(17 -03115)2] (5), which are prepared by reaction of [NEt4][MX(CO)5] with C3H5X. A year later, Murdoch and Henzi described the bridge-splitting reactions of (5) (M = Mo, X = Cl) with nitrogen donors such as pyridine or bipy to yield complexes of the type 6. 

Nitrosobenzene, CjHsNO, which is obtained by the oxidation of phenylhydroxylamine, and p>nitrosodimethylaniline, p-(CH3)2NCjH4NO, which is easily prepared by the nitrosation of dimethylaniline, are fairly specific oxidizing agents for the preparation of aromatic aldehydes from benzyl halides or tosylates and of a-dicarbonyl compounds from from a-halo ketones [984, 985]. Also, a methylene group flanked by two carbonyls can be oxidized to a carbonyl group by nitrosodimethylaniline [986]. Pyridine is frequently used to form quaternary pyridinium salts from reactive halides prior to their oxidation to aromatic aldehydes, a-ketoaldehydes, or a-diketones [984] (equations 22 and 23). 

The traditional route to indolizines is the Chichibabin synthesis, " which involves quatemisation of a 2-aUcyl-pyridine with an a-halo-ketone, followed by base-catalysed cyclisation via deprotonation of the pyridinium a-methyl, rendered easy by the quatemisation, then intramolecular attack on the carbonyl group. ... 

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