Synthesis of Pyridyl- β -ketophosphonates

Abstract

Abstract. In this paper we report a three-stage synthesis of alkyl ethyl 2-oxo-2-(pyridin-2-, -3-and -4-yl)ethylphosphonates (2a-e, 3a-e, 4a-e) starting from commercially-available triethyl phosphite. Triethyl phosphite was first transesterified with alcohols in the presence of sodium catalyst to give the alkyl diethyl phosphites (1b-e) in low to moderate yields. The Claisen condensation between 2-lithioalkylphosphonates and ethyl pyridine-2-,-3-and -4-carboxylate, followed by an Arbusov reaction with methyl iodide, gave the final products in moderate yields. The structures of the products were confirmed by 1H-NMR, 13C-NMR, and 31P-NMR. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). , and the reaction of phosphite with epoxysulfones [8] or with silyl enol ethers using a hypervalent iodine compound [9]. Cyclic β-ketophosphonates can also be prepared in good yields by the reaction of a dialkyl phosphite anion and α -nitro epoxides [10]. The present paper, reports a simple method for the synthesis of 2-oxo-2-(pyridin-2-, -3-and -4-yl)ethylphosphonates (2a-e, 3a-e and 4a-e) starting from triethyl phosphite. ResultsAs shown in Scheme 1, the alkyl ethyl 2-oxo-2-(pyridin-2-, -3-and -4-yl)ethylphosphonates (2a-e, 3a-e, 4a-e) can be prepared using a three-stage procedure starting from commercially-available triethyl phosphite. In the first stage, alkyl diethyl phosphites (1b-e) are prepared by reaction of alcohols (butan-1-ol, hexan-1-ol, octan-1-ol and 2-ethylhexan-1-ol) with triethyl phosphite in the presence of Na as catalyst [11]. Then, the Arbusov rearrangement of alkyl diethyl phosphites was used to prepare alkyl ethyl methylphosphonates [12]. According to this procedure ethyl pyridine-2-, -3-or-4-carboxylate is transformed into the corresponding β-ketophosphonate by treatment with 1.2 equivalents of the lithium anion of diethyl methylphosphonate (11a) or alkyl ethyl methylphosphonate (11b-e) in THF at −78 ℃, in good yields. The results are shown in Table