Studies on the chemistry of 5‐propynyloxy‐ and 5‐propynylthiopyrimidines: New syntheses of furo‐ and thieno[3,2‐<i>d</i>]pyrimidines

Abstract

Abstract The utility of certain 5‐alkynyloxy‐, 5‐alkynylthio, and 5‐alkynylsulfinyl‐pyrimidines as precursors of 7‐substituted furo[3,2‐ d ]‐ and thieno[3,2‐ d ]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3‐dimethyl‐5‐(2‐propynyloxy)uracil ( 6 ) cyclizes to afford 1,3,7‐tri‐methylfuro[3,2‐ d ]pyrimidine‐2,4‐(1 H ,3 H )‐dione ( 12 ) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5‐(2‐butynyloxy)pyrimidine ( 7 ), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8‐methylpyrano[3,2‐ d ]pyrimidine 8 in methyl sulfoxide and the 6,7‐dimethylfuro[3,2‐ d ]pyrimidme 11 in dimethylformamide. The 5‐(2‐propynylthio)pyrimidine 15 affords the allene 19 and the 1‐propyne 22 when treated with various bases, but none of the 7‐methylthieno[3,2‐ d ]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio‐Claisen rearrangement process to afford the 6‐methylthieno[3,2‐ d ]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7‐thiomethoxymethyl substituent derived from the solvent. Heating the 5‐(2‐propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3‐dimethyl‐7‐formylthieno[3,2‐ d ]pyrimidine‐2,4‐(1 H ,3 H )‐dione ( 29 ) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′‐proton of 23 . This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma‐tropic rearrangements, and the intermediacy of a dihydrothieno[3,2‐ d ]pyrimidine such as compound 30.