Methyl groups with anils

The reaction sequence described herein enables the preparation of heteroaromatic stilbenes by direct condensation of methyl or methylene groups with anils derived from aromatic aldehydes, in the presence of strong base, and in certain dipolar aprotic solvents. 

This volume contains two articles which bring up to date older reviews in the Series. Progress in the chemistry of the 1,3-oxazines since they were covered by Eckstein and Urbanski in Volume 2 (1963) is described by the same authors. Acheson and Elmore review reactions of acetylenecarboxylic esters with nitrogen heterocycles, which have been the subject of much concentrated research in the years since Acheson s article in Volume 1. The review on indolizines (Swinboume, Hunt, and Klinkert) also concentrates on the advances of the last IS years and up-dates reviews published elsewhere. Anastassiou and Kasmai provide a critical account of the V-excessive heteroannulenes, and Fletcher and Siegrist deal authoritatively with the olefin-forming condensations of anils with methyl groups, the Anil Synthesis. ... 

Formation of the oxazole ring is not always the last step in synthesis of the brightener. Unsymmetrical compounds that contain both a benzoxazole group and an ethene linkage can be prepared by the anil synthesis [51], in which a compound possessing an activated methyl group reacts with a Schiff base. The preparation of brightener 11.31 is an illustration of this method (Scheme 11.12). 

For less reactive methyl groups, condensation with the aldehyde anils, rather than the aldehydes themselves, can be more effective <78AHC(23)l7l). 

Methyl groups in position 7 of triazolopyridines of type 2 are sufficiently reactive to condense with anils, giving diarylakenes such as compound 299 27o,27i Methyi groups in positions 6 and 8 are not reactive in condensation, but a bis adduct (300) has been obtained by using a reactive 2-tolyl group. A methyl group in position 3 of system 3 is also sufficiently active to condense... 

Diphenylfuran, 2-phenylbenzo [ ]furan, and dibenzofuran have been found to be stable under the conditions of the Anil Synthesis. Hence, their methyl derivatives have been reacted with anils at higher temperatures, with the result that more than one methyl group within the same molecule is brought to react. 

As previously mentioned, the methyl group of 2-(p-tolyl)-s-triazolo-[l,5-a]pyridine is inert under the conditions of the Anil Synthesis. However, introduction of a chlorine atom in ortho position to this methyl group enables reaction to be carried out at 20°-30°C (Section II,E,3). Thus, for example, from 2-(3-chloro-4-methylphenyl)-j-triazolo[l,5-a]pyridine (19) and Schiff s base 171, the stilbene 172 is formed. In the case of 2-phenyl-7-methyl-j-triazolo[l,5-a]pyridine (173), however, reaction with 171 gives the styryl derivative 174, without additional activation of the methyl group.19... 

The methyl group in nitrotoluenes reacts with benzaldehyde much more readily than that of toluene itself, giving the corresponding derivatives of stilbene. Mono-, di- and tri-nitrotoluenes also react with p- nitrosodimethylaniline to form the corresponding anils. Such a product is not obtained in the case of toluene (Sachs and Kempf [34]). The methyl group of 2,4-dinitrotoluene also reacts with pyridine N-oxide in the presence of iodine to yield 2,4-dinitrobenzaldehyde [155], Poray-Koshits and Chizhevskaya [35] found that di- and trinitrotoluenes react with phthalic anhydride to form nitro derivatives of benzylidenephthalide ... 

The methyl group in nitrotoluene is activated by the nitro group and can react, for example, with p- nitrosodimethylaniline to form an anil ... 

An alternative approach to the synthesis of benzodiazepines involves the reaction of /3-chlorovinyl carbonyl compounds with o-phenylenedi-amine. In the first example methyl /3-chlorovinyl ketone was used to obtain 5-methylbenzodiazepinium chloride.31 An extensive investigation has been made of the use of /3-chlorovinylaldehydes for the preparation of 2,3-substituted benzodiazepines.3233 The preferred conditions for reaction were in alcoholic hydrogen chloride. By this means a variety of 2-aryl-, 2,3-cycloalkeno-, and 2,3-diarylbenzodiazepines was prepared. If no acid is present an uncyclized anil results, formed by condensation of one amino group with the aldehyde. Since the /3-chlorovinylaldehydes are themselves readily obtained by reaction of a-methylene ketones with phosphoryl chloride and N, JV-dimethylformamide or jV-methylformani-lide,34 this provides an attractive route to 2,3-disubstituted benzodiazepines. 

When o-phenylenediamine is allowed to react with alloxan in aqueous solution, the quinoxaline ureide 19 is produced.The structure of the product formed in this reaction has been the subject of controversy. It was at first suggested to be the anil 20 since a superficially similar product, now known to be the spiro compound 22, is obtained by reaction of o-aminodimethylaniline and alloxan in aqueous ethanol. Compound 22 is believed to be formed via the intermediate anil 21, which undergoes a unique cyclization in which an N-methyl group is involved. 

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