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

A concise and efficient cross-coupling synthetic strategy has been developed to construct 2-aryl-4H-thiochromen-4-one derivatives from 2-sulfinyl-thiochromones and arylboronic acids. This reaction proceeds via a catalyst system of Lewis acid and palladium(II) combined with XPhos as an optimal ligand in moderate to good yields. Besides, this flexible methodology provides a wide scope for the synthesis of different functionally substituted thiochromone scaffolds and can be further exploited to construct diverse thioflavone libraries for pharmaceutical research.


■ INTRODUCTION
Thioflavones are an important class of sulfur-containing heterocycles in medicinal chemistry due to their structural similarity to flavones, and this scaffold exhibits various biological and pharmacological properties, 1 including antibacterial, 2,3 anticancer, 4−6 and anti-HIV activities. 7 However, the synthetic methods for thioflavones via cross-coupling reaction are rarely reported. The major common synthetic routes include synthesizing from benzoylthiosalicylic acid via intramolecular Wittig cyclization (Scheme 1, method A) 8 or coupling of thiophenols with β-keto ester in the presence of polyphosphoric acid (Scheme 1, method B). 3,9 Recent synthetic methods of thioflavone mainly rely on the cyclization of various 2-substituted β-vinyl-aromatic ketones (Scheme 1, methods C and D) or intermolecular Michael addition of βethynyl-aromatic ketones (Scheme 1, methods E and F). 10−19 However, the preparation of various starting materials for current methods limits the rapid synthesis of large libraries of valuable thioflavone precursors for pharmaceutical studies. To the best of our knowledge, there are no reports of the construction of thioflavones via cross-coupling reactions using sulfinyls as coupling partners.
Organoboron-mediated cross-coupling is a useful C−C bond-forming reaction. The commercial availability of boron reagents, broad functional group tolerance, and general applicability of the reaction make it suitable for derivative expansion. Flavones can be synthesized by organoboron crosscoupling; 20,21 especially, the synthesis of flavones via transition metal-catalyzed cross-coupling reactions has particularly attracted our attention. 22,23 Recently, our group has developed an efficient method to synthesize 2-amino-4H-benzothiopyran-4-ones from 2-sulfinylthiochromones via conjugated addition−elimination in which the sulfinyl group worked well as a leaving group (Scheme 2). 24 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. 25,26 Herein, we report a Lewis acid and Pd(II)-catalyzed cross-coupling method for synthesizing 2-aryl-4H-thiochromen-4-one derivatives from 2sulfinyl-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.

■ RESULTS AND DISCUSSION
Initially, 2-(methylsulfinyl)-4H-thiochromen-4-one (1a), which was synthesized according to the reported method, 24 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 1, entry 1). Considering that the ligand strongly affects the efficiency of transition-metal catalyzed C−C cross-coupling reactions, 27 we screened several ligands generally used in Pd(II)-catalyzed cross-coupling reactions. First, monodentate phosphine ligands, such as PPh 3 (triphenylphosphine) and TFP (tri(2furyl)phosphine), were investigated, but they showed unsatisfactory yields of 34 and 25%, respectively (  8−10). Although the reaction in THF proceeded well (yield 56%, entry 11), difficult-to-remove yellow impurities were mixed with the target product 3a. Therefore, DMF was confirmed as the optimal solvent. In addition, we also tried to replace Pd(OAc) 2 with Pd(PPh 3 ) 4 , but it only gave a low yield of 25% (Table 1, entry 12). The aforementioned results provided the proof of concept of using Pd(OAc) 2 -catalyzed cross-coupling to synthesize thioflavones from 2-sulfinyl-thiochromones.
Based on the reported catalytic effect of Lewis acids in the Pd(II)-catalyzed coupling reaction of arylboronic acids with chromones to form flavanones, 28 subsequently, a variety of Lewis acids were screened to further optimize the reaction condition to construct thioflavones ( Table 2). We initially investigated SbCl 3 , which worked well in the Pd(II)-catalyzed coupling of arylboronic acids with α,β-unsaturated ketones; 29 however, it did not improve the present reaction and gave a yield of 42% only (Table 2, entry 1). We then tested various triflate (OTf)-based Lewis acids. 28 The results displayed that TMSOTf (trimethylsilyl triflate) and Cu(OTf) 2 decreased the yields (39−50%) ( Table 2, entries 2 and 3), whereas Fe(OTf) 3 gave a yield of 59%, which was similar to the yield without using Lewis acid (  3 and Zn(OTf) 2 increased the yields to 64 and 67%, respectively (Table 2, entries 5 and 6). Considering the cost and availability, Zn(OTf) 2 was chosen as the Lewis acid for this protocol. We further investigated the solvent impact by replacing DMF with THF under the use of Lewis acid, which resulted in a lower yield ( Table 2, entries 6 vs 7). 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 2) versus entry 1 (trace product, Table 1), 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 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). Given the potential irreversible poisoning of transition-metal catalyst by sulfur compounds, 12,30 the amount of Pd(OAc) 2 was increased from 0.1 to 0.2 or 0.4 equiv; however, the yields of product 3a were not significantly improved ( Table 2, entries 11 and 12). In a summary, we selected 2-(methylsulfinyl)-4Hthiochromen-4-one as the substrate, XPhos (0.1 equiv) as the ligand, Pd(OAc) 2 (0.1 equiv) as the catalyst, and Zn(OTf) 2 (0.2 equiv) as the Lewis acid in DMF to further investigate the scope and applications of our approach.
With the optimal conditions in hand, the reactions of various substituted phenylboronic acids with 1a were tested to explore the functional group compatibility of our method. As summarized in Table 3, the approach tolerated well with a variety of phenylboronic acids substituted by various functional groups, including electron-donating groups (3b−f, 3j, methyl, methoxy, benzyloxy, and hydroxyl, yields 50−67%) and electron-withdrawing groups (3g−i, 3k, 3l, halogen, nitro, trifluoromethyl, and methoxycarbonyl, yields 38−65%). Therefore, the compatibility of the reactions with bromine, nitro, hydroxyl, and benzyloxy groups facilitates subsequent structural expansion.
Next, we explored the efficiency of the approach on the scope of the substituted 2-sulfinyl-thiochromones (1). As shown in Table 4, most 2-sulfinyl-thiochromones (1) could be readily transformed into the corresponding thioflavones in moderate to good yields (41−66%), with the electrondonating (3m−o) or electron-withdrawing substituents (3p− u) on the thiochromone phenyl group. The results indicated that the electronic effect and position of the substituents had less impact on the reactivity. The reaction was also tolerant to nitro and halogen groups, which is convenient for subsequent derivatization.
A plausible mechanism as outlined in Scheme 3 was proposed based on our experimental observations and previously reported literature. 26,28 Lewis acid Zn(OTf) 2 may coordinate with the oxygens of carbonyl and sulfinyl, which activates the electrophilicity at C-2 position of the thiochromone (5). The oxidative insertion of 5 by Pd(0) which is pre-activated by XPhos from Pd(II) generates thiochromone palladium species 6. Subsequently, the transmetalation of 6 with arylboronic acid followed by the reductive elimination affords the final product 2-aryl thiochromone 8.

■ CONCLUSIONS
In conclusion, we developed a concise and efficient approach to synthesizing 2-aryl-4H-thiochromen-4-ones from 2-sulfinylthiochromones and arylboronic acids via a Lewis acid and Pd(II)-catalyzed cross-coupling reaction. To the best of our knowledge, this is the first use of sulfinyls as coupling partners to construct thioflavones through an organoboron crosscoupling reaction. The reaction exhibits good substituent compatibility and substrate adaptability. Furthermore, our method was extended to the synthesis of 2-heteroaryl thioflavone analogues, exploiting the good availability of heteroarylboronic acids. This strategy provides an effective complementary approach to the existing synthetic methods for thioflavone derivatives, which are used to construct diverse thioflavone libraries for pharmaceutical research.
apparatus. Substrates 1 were prepared according to the reported procedures. 24 General Procedure for the Synthesis of Thioflavones 3a−z and 2-Heteroaryl Thioflavone Analogues 4a−d.