Practicable Synthesis of 1-(1-Phenylethyl)-1H-pyrido[2,3-b][1,4]oxazine

Abstract

The benzo[1,4]-oxazine ring system executing an important template has attracted considerable interest in the search for novel pharmaceutical compounds, but their pyridine derivatives were rarely mentioned in the literature. Only very few like synthesis of 2H-pyrido[3,2-b][1,4]oxazine, pyrido[4,3-b][1,4]oxazine and 4-acetyl-3(R)and 3(S)(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b]oxazine were reported. On the other hand most of the compounds reported in the literatures possess [1,4]-oxazinone moieties. Thus the reported methods demonstrated the synthesis of pyrido[3,2-b][1,4]-oxazine derivatives but there is no synthetic approach valuable for the synthesis of its isomer pyrido[2,3-b][1,4]-oxazine series having the nitrogen of pyridine and N of oxazine in trans fashion. It is known that 2-amino-3-pyridol is liable to O-alkylation rendering the formation of pyrido [3,2-b][1,4]oxazine. The selection of 2hydroxy pyridine is less liable and more problematic for the O-alkylation to obtain [1,4]-oxazine. We have earlier reported the reaction of 2-chloro-3-pyridol with chloroacetamides could undergo Smiles rearrangement to afford pyrido[2,3b][1,4]oxazinones. In this paper we outline the approach to synthesize pyrido[2,3-b][1,4]oxazine as potential scaffold for bioactive compounds. Endlessly, benzo[1,4]oxazines and pyrido[3,2-b][1,4]oxazines are prepared by direct cyclization of 2-haloacetyl halides or alkyl 2-halopropionates with 2-aminophenol or 2amino-3-hydroxypyridine. A similar approach, however, is not directly applicable to the pyrido[2,3-b][1,4]oxazine ring system. Nevertheless it was felt that the Smiles rearrangement could be exploited to circumvent this limitation. Since the Smiles rearrangement necessitates an electron-deficient center to proceed at a reasonable rate, we selected 2haloacetamide and 2-halo-3-hydroxypyridine as the reaction partners. The reduction of the lactam function with metal hydrides was found to be promising but it was found that sodium borohydride was better reagent for reduction of pyrido[2,3-b][1,4]oxazinone. In order to form the oxazine the hydroxy group was replaced with mesyl group by reacting with mesyl chloride and the mesyl ester thus obtained was removed with sodium methoxide to afford pyrido[2,3b][1,4]-oxazines. The use of three-step reaction condition in converting the oxazine by reduction of lactam, converting to O-Ms and the removal of O-Ms by base afforded pyridooxazines. Moreover the regioselective formation of pyrido[3,2-b][1,4]oxazine could be understood by this and it can be applied for the synthesis of large number of heterocycles by Diels-Alder or Aza Diels-Alder reactions to synthesize a various kinds of scaffold for new drug development. In an demonstrative experiment, reaction of 2-chloro-3hydroxy pyridine with (S)-2-chloro-N-(1-phenylethyl) acetamide 2 in the presence of potassium carbonate furnished (S)-2-(2-chloropyridin-3-yloxy)-N-(1-phenylethyl) acetamide 3 as the major product in 96% yield (Scheme 1). The 2-chloro-N-(1-phenylethyl) acetamide 2 was prepared by known procedures using chloroacetyl chloride with (S)(−)-α-methyl benzylamine 1 in the presence of potassium carbonate (95% yield). The subsequent exposure of 3 with cesium carbonate afforded cyclized product, (S)-1-(1-