Oxidative Dehydrosulfurative Cross-Coupling of 3,4-Dihydropyrimidine-2-thiones with Alkynes for Access to 2-Alkynylpyrimidines

Abstract

A reaction method is described for the one-step synthesis of 2-alkynylpyrimidines from 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative Sonogashira cross-coupling with concomitant oxidative dehydrogenation using a Pd/Cu catalytic system. Together with the ready availability of DHPMs possessing various substituents at the C4–C6 positions, this transformation offers rapid and general access to diverse 2-alkynylpyrimidine derivatives.

Oxidative Dehydrosulfurative Carbon–Oxygen Cross-Coupling of 3,4-Dihydropyrimidine-2-thiones with Aryl Alcohols

“…To Biginelli three-component reaction, 14 as a surrogate for the C2-(pseudo)halopyrimidine. DHPMs with diverse substituents at the C4−C6 positions were demonstrated to be suitable substrates for Pd-catalyzed/ Cu-mediated dehydrosulfurative C−C or C−N cross-coupling with concomitant oxidative dehydrogenation (aromatization) to yield C2-arylated (azolated), 15 -alkynylated, 16 and -aminated pyrimidines 17 in a single step. 18,19 Recently, we reported a Cu-mediated oxidative dehydrosulfurative C−O crosscoupling of DHPMs with primary, secondary, and tertiary trialkylborates (boric esters) to yield the corresponding 2alkoxypyrimidines, in moderate-to-good yields (Scheme 1B).…”

“…A functionalized aryl group, such as 4-fluorophenyl at C6, also yielded the desired product Our previous oxidative dehydrosulfurative C−C, C−N, or C−O cross-coupling of DHPM possessing the t-butyl group at the C4 position provided the debutylated pyrimidine as the major product. [15][16][17]20 Similarly, the reaction of the DHPM 4 bearing the C4 t-butyl group with phenol also resulted in the debutylated product 5 26 as the major product (eq 1, Scheme 3). The results support that the aromatization of the dihydropyrimidine proceeds via the generation of a radical intermediate presumably due to the Cu species present in the reaction, as described in the oxidative dehydrogenation of 2alkylthiodihydropyrimidines.…”

“…DHPMs with diverse substituents at the C4–C6 positions were demonstrated to be suitable substrates for Pd-catalyzed/Cu-mediated dehydrosulfurative C–C or C–N cross-coupling with concomitant oxidative dehydrogenation (aromatization) to yield C2-arylated (azolated), -alkynylated, and -aminated pyrimidines in a single step. , Recently, we reported a Cu-mediated oxidative dehydrosulfurative C–O cross-coupling of DHPMs with primary, secondary, and tertiary trialkylborates (boric esters) to yield the corresponding 2-alkoxypyrimidines, in moderate-to-good yields (Scheme B) . In the course of these studies, we found that triphenylborate was also compatible with this method for producing the 2-phenoxypyrimidine derivative (R 1 = Ph, R 2 = CO 2 Et, and R 3 = Me).…”

“…Previously, we found that the oxidative dehydrogenation (aromatization) occurred under an argon atmosphere in both the Pd-catalyzed/Cu-mediated and Cu-mediated reactions of DHPMs, in which Cu species presumably served as oxidants. − , Thus, our initial studies were accomplished under an argon atmosphere with the reaction of DHPM 1a and phenol. The reaction in the presence of palladium­(II) acetate (Pd­(OAc) 2 ) (20 mol %), Cu­(I)-thiophene-2-carboxylate (CuTC, 3.0 equiv), and K 2 CO 3 (3.0 equiv) in toluene at 100 °C for 18 h provided the desired 2-phenoxypyrimidine 3aa in 47% yield.…”

Aerobic copper-promoted oxidative dehydrosulfurative carbon–oxygen cross-coupling of 3,4-dihydropyrimidine-1H-2-thiones with alcohols

“… 11 The reaction method with triarylborates was also found to be applicable to the synthesis of 2-aryloxypyrimidines, but not practical due to non-commercial availability and non-trivial preparation of most of the triarylborates. We subsequently developed Libeskind–Srogle-type 12 Pd-catalyzed/Cu-mediated oxidative dehydrosulfurative C–O cross-coupling of DHPMs with readily available aryl alcohols for the synthesis of 2-aryloxypyrimidines ( Scheme 1B2 ). 13 Although both reaction methods offered the desired 2-alkoxypyrimidine products in moderate to good yields, their reaction conditions require large amounts of metals – 4.5 equivalents of Cu for borates and the mixture of 0.2 equivalents of Pd and 3 equivalents of Cu for aryl alcohols.…”