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

Abstract

A Pd-catalyzed/Cu-mediated oxidative dehydrosulfurative carbon–oxygen cross-coupling reaction of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with aryl alcohols is described. Due to the ready availability of diverse DHPMs and aryl alcohols, the reaction method offers facile access to biologically and pharmacologically valuable 2-aryloxypyrimidine derivatives with rapid diversification.

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

“…This result supports that the oxidative dehydrogenation (aromatization) proceeds via a radical intermediate as described in the literatures published by others 15 and us. 11,13 The reaction of 2-mercaptopyrimidine 7 with phenol provided the phenoxypyrimidine 8 (Scheme 4B), which can agree with the proposition that the C-S single bond generated aer deprotonation participates in the coupling of DHPM. We found that the reaction of dihydropyrimidinyl thioether 9 with PhOH yielded pyrimidinyl thioether 10 as the major product along with a trace amount of 3a, which indicates that the oxidative dehydrogenation could proceed prior to the C-O coupling.…”

“…With respect to base, Ag 2 CO 3 , which gave the desired product in 91% yield, was superior to other bases examined in the studies, such as Cs 2 CO 3 , K 2 CO 3 , t-BuOK, CsF, and Na 2 CO 3 (entries 8-12). Toluene was better than other solvents, such as o-xylene, 1,4-dioxane, N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or dimethylsulfoxide (DMSO) for the reaction (entries [13][14][15][16][17]. With respect to the amount of Cu(OAc) 2 , it was shown that 1.5 equivalents of Cu(OAc) 2 was as effective as 2 equivalents of Cu(OAc) 2 in the production of the desired product (entry 18).…”

“…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. The large amount of metals required for these reactions led us to pursue an alternative method that reduce the amount of Cu source and can be used for both aromatic and aliphatic alcohols.…”

Palladium-catalyzed/copper-mediated carbon–carbon cross-coupling reaction for synthesis of 6-unsubstituted 2-aryldihydropyrimidines

“… 21 As a result, we realized the Pd-catalyzed/Cu-mediated 2-arylation reaction of 1-Boc 2-methylthio-DPs with arylstannane reagents. 22 The Boc group significantly increases reactivity of DPs. This protocol enables the synthesis of 6-unsubstituted 2-aryl-DPs using various substituents at the 2- and 4-positions; to the best of our knowledge, the general formula of the 2-aryl-DPs has not been reported.…”

Copper-promoted dehydrosulfurative carbon–nitrogen cross-coupling with concomitant aromatization for synthesis of 2-aminopyrimidines

“…To our knowledge, no reports describing Cu-promoted direct C–N cross-coupling of thiono substrate with amine have been published. 18–20…”