Preparation of Arylpropynamides and Their Reaction with Malonyl Acid Derivatives

Abstract

Synthesis of arylpropynamides and their reactions with different malonic acid derivatives is described. Treatment of arylpropynamides with unsubstituted malonyl chloride furnished N-(3-arylprop-2-ynoyl)-6-chloro-4-hydroxy-2-oxo-2H-pyran-3-carboxamides; monosubstituted malonyl chlorides or their derivatives, (chlorocarbonyl)ethylketenes, reacted with arylpropynamides to give 4-hydroxy-2-(phenylethynyl)-6H-1,3-oxazin-6-ones; and the reaction of arylpropynamides with disubstituted malonyl chlorides furnished open-chain arylpropenamides exclusively.In medicinal chemistry the alkyne group deserves particular interest because of its bioisosteric relationship to an aromatic system. In addition, the alkyne group can affect the pharmacological and pharmacokinetic properties of a drug molecule. 1 As an example, the acetylenic pharmacophore has been realized within steroids, 2 the antimycotic Terbinafin, 3 the non-nucleoside reverse transcriptase inhibitor Evafirenz and its derivatives, 4 and the MAO-inhibitors Selegeline and Rasagiline. 5 Furthermore, naturally occurring (poly)acetylenes were found to display interesting biological activity. 6 In recent years enediyne antibiotics, characterized by either nineand ten-membered rings containing two triple bonds separated by a double bond, have attracted considerable interest as novel antitumor agents. 7 The present work is aimed at the synthesis of novel and potentially bioactive alkyne-substituted 1,3-oxazines by the reaction of arylpropynamides 1 with malonyl chlorides or (chlorocarbonyl)ketenes. Cyclization of carboxamides with malonyl chlorides or (chlorocarbonyl)ketenes to 4-hydroxy-6H-1,3-oxazin-6-ones with different substituents at the 2-and 5-positions is a well-known reaction. 8 A single 4-hydroxy-5-phenyl-2-(phenylethynyl)-6H-1,3-oxazin-6-one (8e) was prepared by Komarov et al. from 3-phenylprop-2-ynamide and phenylmalonyl chloride in refluxing 1,2-dichloroethane. 8cHerein we describe the results from our studies directed to the reaction of arylpropynamides 1 with unsubstituted malonyl chloride, monosubstituted malonyl chlorides or (chlorocarbonyl)ketenes, and a disubstituted malonyl chloride.3-Phenylprop-2-ynamide (1a) was prepared in high yield according to literature procedures by the reaction of 3-phenylprop-2-ynoic acid ester with aqueous ammonia solution. 9 Following this procedure, the corresponding arylpropynamides 1b-e were obtained in good yields by ammonolysis of the crude arylpropynoic ethyl esters, which in turn resulted from esterification of the corresponding arylpropynoic acids with ethanol (Table 1). Unexpectedly, treatment of 1a-d with unsubstituted malonyl chloride 2 in diethyl ether or tetrahydrofuran under ice cooling did not deliver 4-hydroxy-2-(phenylethynyl)-6H-1,3-oxazin-6-ones of type 8 but N-(3-arylprop-2-ynoyl)-6-chloro-4-hydroxy-2-oxo-2H-pyran-3-carboxamides 5a-d, the formation of which can be explained according to Scheme 1: elimination of hydrogen chloride from malonyl chloride affords (chlorocarbonyl)ketene 3 that undergoes [4+2] cyc...

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“…Yield: 62% (0.47 g) (Variant A); colourless crystals; mp: 202-203 C; 1 H NMR (400 MHz, DMSO-d 6 , 25 C): d 12.76 (br s, 1H, OH), 7.70 (m, 2H, o-CH-Ar), 7.61 (m, 1H, p-CH-Ar), 7.52 (m, 2H, m-CH-Ar), 3.01 (sept, 3 J HH = 7.00 Hz, 1H, CH), 1.17 (d, 3 J HH = 7.00 Hz, 6H, CH 3 ) ppm. 13 16), no other peaks >10%; analysis (calcd., found for C 15 H 13 NO 3 ): C (70.58, 70.38), H (5.13, 5.32), N (5.49, 5.43) (Petina et al, 2013). .…”

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