Alkylative cyclization, carbon-nitrogen

Formation of the amino-acrylate of aminopyrimidine intermediates was reported. In the absence of base, alkylation occurred on the carbon and not the nitrogen, followed by cyclization to give 125. In the presence of base (EtONa), condensation occurred on the nitrogen. Cyclization under thermal conditions afforded 128. °... 

The aniline nitrogen is then converted to the para-toluenesulfonamide (4-3). Reaction of this intermediate with ethyl co-chlorobutyrate in the presence of potassium carbonate then gives the alkylation product (4-4). Potassium tert-butoxide-catalyzed Claisen condensation of this diester leads to azepinone (4-5) as a mixture of methyl and ethyl esters resulting from alternate cyclization routes. A strong acid leads to the transient keto-acid, which then decarboxylates the toluensulfonyl group is lost under reaction conditions as well as affording the benzazepinone (4-6). This last intermediate is then acylated with the benzoyl chloride (4-7) to afford amide (4-8). 

In the latter example, cyclization occurs exclusively to the carbonyl carbon rather than with nucleophilic displacement of chloride at the a-carbon. Intramolecular alkylation of nitrogen does occur in other systems the 3-chloropropylsulfonylhydrazide (194), for example, ring closes to give the 1,2,3-thiadiazine dioxide (195) on treatment with base (62JPR(19)56). 

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