An efficient and concise access to 2-amino-4H-benzothiopyran-4-one derivatives

Abstract

A highly efficient and convenient protocol was developed to access 2-amino-4H-benzothiopyran-4-ones through a process of conjugated addition–elimination. The sulfinyl group was proved to be the optimum leaving group by thorough investigations on the elimination of sulfide, sulfinyl, and sulfonyl groups at the 2-position of benzothiopyranone. Most 2-aminobenzothiopyranones were obtained in good to excellent yields under refluxing in isopropanol within 36 h. This method is base-free and the substrate scope in terms of electronic properties of the substituents of the benzothiopyranone is broad. The ten grams scale-up synthesis of the representative compounds 4a and 4d was implemented to show the practical application of this reaction, which afforded the corresponding compounds in good yields and excellent chemical purity without requiring column chromatographical purification.

Synthesis of 2-Aryl-4H-thiochromen-4-one Derivatives via a Cross-Coupling Reaction

“…Comparing with the reaction without Lewis acid in the absence of the ligand XPhos, Zn­(OTf) 2 improved the reaction yield significantly, exemplified by entry 8 (yield 18%, Table ) versus entry 1 (trace product, Table ), which demonstrated the catalytic effects of Lewis acid. In our previously published work, we compared the difference in the reactivity of sulfide, sulfinyl, and sulfonyl groups in the conjugated addition–elimination reaction using 2-sulfinyl-thiochromones to construct 2-amino-4 H -benzothiopyran-4-ones . Thus, in this present work, we continuously investigated the effect of different substrates on C–C formation via the cross-coupling reaction.…”

“…Initially, 2-(methylsulfinyl)-4 H -thiochromen-4-one ( 1a ), which was synthesized according to the reported method, and phenylboronic acid ( 2a ) were chosen as the test substrates for the reaction in the presence of Pd­(OAc) 2 to investigate the feasibility of our method. However, the reaction only offered a trace amount of the desired product 3a (Table , entry 1).…”

“…In our previously published work, we compared the difference in the reactivity of sulfide, sulfinyl, and sulfonyl groups in the conjugated addition− elimination reaction using 2-sulfinyl-thiochromones to con- a 1a (0.5 mmol, 1 equiv), 2a (2 equiv), catalyst (0.1 equiv), and ligand (0.1 equiv) in solvent (3.0 mL) were stirred at 80 °C for 6 h. struct 2-amino-4H-benzothiopyran-4-ones. 24 Thus, in this present work, we continuously investigated the effect of different substrates on C−C formation via the cross-coupling reaction. Under the same reaction conditions, the sulfinyl as a leaving group still performed the best with the yield of 67% compared to the sulfide and sulfonyl groups with yields of 34 and 12%, respectively (Table 2, entries 6 vs 9 and 10).…”

“…Melting points were determined on a Yanaco MP-J3 microscope melting point apparatus. Substrates 1 were prepared according to the reported procedures …”

“…Recently, our group has developed an efficient method to synthesize 2-amino-4 H -benzothiopyran-4-ones from 2-sulfinyl-thiochromones via conjugated addition–elimination in which the sulfinyl group worked well as a leaving group (Scheme ). The use of sulfinyl and sulfonyl groups in Suzuki–Miyaura cross-coupling encouraged us to consider the potential of 2-sulfinyl-thiochromones as substrates for synthesizing thioflavone analogues. , Herein, we report a Lewis acid and Pd­(II)-catalyzed cross-coupling method for synthesizing 2-aryl-4 H -thiochromen-4-one derivatives from 2-sulfinyl-thiochromones in order to expand libraries for biological screening and investigate 2-sulfinyl-thiochromones as important building blocks. This protocol delivers a reliable and concise method for producing thioflavones.…”