Based-Catalyzed Stereoselective Thiosulfonylation of Ynones

The first catalytic vicinal thiosulfonylation of ynones has been developed. Under the catalysis of 1-10 mol% Cs2CO3, various thiosulfonates underwent Michael addition/nucleophilic substitution tandem reaction with different ynones to form C-SO2 and C-S bonds simultaneously and produce multifunctional vinyl sulfones in high yields and excellent E-selectivity.


Introduction
Organosulfur compounds are widely used in medicinal and biochemistry, organic synthesis and material science. 1 Thus, the development of efficient method for the construction of C-S bond and the installation of sulfurcontaining functional groups into organic molecules are topics of continuous interest. Among different sulfur-containing compounds, vinyl sulfones often serve as the critical structural motifs in numerous pharmaceuticals and biologically active compounds. 2 Given the great significance, considerable efforts have been exerted to develop efficient methods for the synthesis of these important frameworks. 3 Except for the classic Knoevenagel condensation reaction, 4 Horner-Wadsworth-Emmons olefination 5 and vinyl sulfides oxidation reactions, 6 atom transfer radical addition (ATRA) 7 has emerged as a powerful strategy for the synthesis of vinylsulfone derivatives. A number of difunctionalization of alkynes, including halosulfonylation, 8 selenosulfonylation, 9 aminosulfonylation, 10 disulfonylation, 11 thiocyanatosulfonylation, 12 carbosulfonylation 13 and carboxysulfonylation, 14 have been developed through ATRA reactions. In sharp contrast, thiosulfonylation of alkynes has only rarely investigated, which allows concomitant formation of C-SO 2 and C-S bond in one step.
Recently, Xu and coworkers 15 reported an elegant dual gold/photoredoxcocatalyzed ATRA to alkynes, which provides a novel protocel for the synthesis of thio-functionalized vinylsulfones. Interestingly, using Eosin Y as photocatalyst, Jia and coworkers 16 realized a similar thiosulfonylation of alkynes under metal-free conditions, but with reversed regioselectivity.
Very recently, Reddy and coworkers 17 reported that the same products can also be obtained through a new radical-involved vicinal thiosulfonylation of 1,1-dibromo-1-alkynes. However, these aforementioned radical reactions are not suitable for thiosulfonylation of ynones due to the dramatically reduced stability of α-ketone alkenyl radical intermediate as compared to alkenyl radical.

Scheme 1 α-ketone alkenyl radical and alkenyl radical
To the best of our knowledge, there is no method for vicinal thiosulfonylation of ynones has been disclosed to date. Therefore, the development of novel and mechanically different method for vicinal thiosulfonylation of ynones is highly desirable. As part of our continuous research on C-S bond formation reactions, 18 we envisaged that a base can catalyze the Michael-addition/nucleophilic substitution tandem reaction of ynones and thiosulfonates to produce multifunctional vinylsulfones through a novel non-radical process. Herein, we would like to report this result.

Results and discussion
At outset, we commenced our study with ynone 1a and thiosulfonate 2a as the model substrates. To our delight, in the presence of 10 mol% DBU, the vicinal thiosulfonylation reaction proceeded smoothly in THF at room temperature to produce the desired product 3a in 87% yield ( With the optimal reaction conditions in hand, we first examined the substrate scope of ynones, with the results summarized in Table 2. A variety of ynones with substituents on the aromatic rings underwent the thiosulfonylation efficiently to give the desired vinyl sulfones in high yield and excellent regio-and stereoselectivity (3a-3q). In addition, different positions and electronic properties have no apparent impact on the reaction yield and selectivity (3r-3x). The bulky naphthyl derived ynones 1y and 1z participated in the reaction to afford the corresponding products 3y and 3z in 98% and 88% yields, respectively. Heteroaryl substituted ynones were proven to be very good reactants for the reaction, furnishing the corresponding produces in excellent yield (3aa-3ac). Gratifyingly, different alkyl-substituted ynones also performed very well, giving the desired products in high yield and excellent E-selectivity (3ad-3ai). isolated yield, ratio of E/Z isomers was determined by 1 H NMR analysis of the crude products; b Cs 2 CO 3 (1 mol%); c Cs 2 CO 3 (2 mol%); d Cs 2 CO 3 (10 mol%); e Cs 2 CO 3 (20 mol%).
To gain insight into the reaction mechanism, several control experiments were performed (Scheme 2). The addition of a radical scavenger TEMPO to the reaction has no influence on the formation of the product (eq. 1).
Phenylacetylene is a very good reactant in photoredox-catalyzed thiosulfonylation reaction. But under our standard conditions, phenylacetylene cannot react with ynone to give the vicinal thiosulfonylation product (eq. 2). Under that catalysis of DBU, thiosulfonate underwent multicomponent reaction with ynone and H 2 O to give vinylsulfone 5a in 97% yield (eq. 3). When D 2 O was used instead of H 2 O, deuterated product 5b was achieved in 85% yield with 99% Dincorporation. These results indicate that the reaction do not proceed through a radical process.

Scheme 2 Control experiments
Based on the results presented above, a plausible mechanism was proposed in Scheme 3. Base attacks thiosulfonate to generate sulfonyl anion I and species II. Sulfonyl anion I undergoes Michael addition with ynone to give allenoate III, which subsequently attacks the sulfur atom of species II to produce the final product with release of catalyst. In order to minimize the steric repulsion, the adjacent sulfonyl group and the thio group prefer to adopt a trans-conformation, which leads to the formation of E-isomer as the major product.

Conclusions
In summary, a base-catalyzed difunctionalization of ynones has been described. The metal-free conditions, broad substrate scope, high atomeconomy, excellent reaction yield and stereoselectivity provide a novel method for the synthesis of multifunctionalized vinylsulfones. Further studies on a broader substrate scope and the applications of this method are ongoing in our laboratory.

Conflicts of interest
There are no conflicts to declare.