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Lewis acid-promoted cascade reaction for the synthesis of Michael acceptors and its application in a dimerization reaction.

An efficient Lewis acid-promoted cascade reaction with dimethyl sulfoxide as a methylene source for the synthesis of Michael acceptors is reported. The key to developing this procedure is the selection of a mild base to modulate the equilibrium of various intermediates in order to drive the reaction forward to the formation of Michael acceptor and dimeric compound products. Extensive studies were performed to gain insight into a possible reaction mechanism.


Introduction
Molecules containing various Michael acceptor scaffolds are common in pharmaceuticals, agrochemicals and natural products and have attracted considerable attention from organic chemists and medicinal chemists. 1 Michael acceptors have been found to have various different biological activities, such as antibacterial, anticancer and antiviral activities. 2 For example, the crystal structure of HCoV-NL63 M Pro complexed with a Michael acceptor inhibitor was obtained, providing insight into the rational development of wide spectrum antiviral therapeutics to treat infections caused by human coronaviruses. 3 Two Michael acceptors used as cysteine protease inhibitors, K-777 (CRA-3316) and rupintrivir (AG7088), and developed to treat Chagas disease and as an antirhinoviral agent, respectively, are already in clinical trials. 4 On the other hand, as basic building blocks Michael acceptors have been extensively employed in the area of organic chemistry, such as in multicomponent cascade or Domino reactions, 5 transition-metal catalyzed reactions, 6 enantioselective organocatalysis 7 and complex natural product synthesis. 8 In the textbook of graduate students, dimethyl sulfoxide (DMSO) is described as a high-boiling, protic and low-toxicity solvent, and a widely used oxidant 9 in several named reactions, such as the Swern oxidation 10 and Pftizner-Moffatt oxidation. 11 In the past few decades, the nature of DMSO has been further exploited as a reagent that can act as an oxygen source, a carbon source and a sulfur source. 12 However, the reaction scope of DMSO is still limited and needs to be expanded. To date, a cascade reaction with DMSO as both a solvent and one-carbon source for the preparation of Michael acceptors has not been reported.
Herein, we report a Lewis acid-promoted cascade reaction for the synthesis of a,b-unsaturated amides. The proper choice of base in the reaction results in the production of dimeric compounds. The Pummerer rearrangement with DMSO as a methylene source is believed to be an initial step for the reaction based on mechanistic studies.

Results and discussion
We are focused on C(sp 3 )ÀH bond functionalization reactions. 13 In this project, the C(sp 3 )ÀH bond functionalization in amide substrate 1a was tested under the following reaction conditions: CoCl 2 (1.5 equiv), KOAc (2.0 equiv) and AgOAc (2.0 equiv) dissolved in DMSO (2.0 mL) in a microwave and heated at 150 C for 2 h. To our delight, functionalization at the benzylic position occurred as expected, affording a, b-unsaturated carboxylamide 2a in a 23% yield ( Table 1, entry 1). Control experiments showed that this reaction proceeded with similar results in the absence of AgOAc, while the reaction did not occur without KOAc (Table 1, entries 2e4). Then, various Lewis acids were screened in this reaction ( Table 1, entries 5e9). When one equivalent of PbCl 2 was used as the Lewis acid, the yield of product 2a increased to 55% along with some amount of sulfide product 3a (Table 1, entry 9). The effect of the base on the reaction was screened with various bases. The results of this screening indicated that potassium acetate and sodium acetate are the most favorable bases for this reaction ( Table 1, entries 9e11 and details in supporting information). When the reaction was carried out in air or under O 2 atmosphere, the yield of product decreased (Table 1, entries 12e13). In contrast, under N 2 , the reaction afforded product 2a in a 65% yield ( Table 1,entries 14). This indicated that the oxidizing reagents hindered the reaction from proceeding. The effect of temperature on the reaction was subsequently investigated, which showed that temperatures either above 160 C or below 150 C were not suitable for this reaction ( Table 1, entries 14e17). Finally, optimized reaction conditions of PbCl 2 (1.5 equiv) and KOAc (1.5 equiv) in DMSO at 156 C in a sealed tube under N 2 for 13 h gave the product 2a in 77% yield and 3a in 12% yields, respectively (Table 1, entry 17). Interestingly, when Ac 2 O was used instead of PbCl 2 , sulfide product 3a was obtained in 50% yield (Table 1, entry 18). The combination of Ac 2 O/AcOH, or Ac 2 O/ TsOH, or TFAA/TFA in DMSO, commonly used in the Pummerer rearrangement reaction, did not afford any product.
The coexistence of products 2a and 3a throughout the process of optimizing the reaction conditions stimulated us to investigate the mechanism of this reaction. Several experiments concerning the study of the mechanism were conducted (eqs. (1)e (4)). Isolated sulfide 3a was subjected to the standard reaction conditions, affording product 2a in 75% yield with 22% recovery of 3a (eq. (1)). When purified 2a was put back under the standard conditions, it gave 17% yield of 3a with 74% recovery of 2a. These results indicated that there is an equilibrium between 2a and 3a in the reaction mixture. When the reaction was carried out in DMSO-d 6 , it provided the corresponding deuterated products (d 2 -2a and d 5 -3a) in 73% and 9% yields, respectively, which provided precise evidence for the methylene group originating from the solvent dimethylsulfoxide (eq. (3)). When six equivalents of TMPO was added to a reaction run under the reaction conditions, 53% of 2a and 5% of 3a were still obtained, which suggested that this reaction probably did not involve any radical species (eq. (4)). Moreover, two control experiments showed that both Lewis acid PbCl 2 and KOAc are necessary for the reaction to occur (see the supporting information).
Based on these preliminary results and some leading references on the Pummerer rearrangement 14 reaction, a rational mechanism for this reaction is proposed in Scheme 1. A sulfur-substituted carbocation is obtained through promotion by both the Lewis acid (PbCl 2 ) and base (KOAc), and it then reacts with a carbon nucleophile to afford a-substituted sulfide 3a. There is an equilibrium between 3a and 2a in the reaction mixture. Michael acceptor Table 1 Optimization of reaction conditions. a,b

Entry
Lewis acid Base Additive (equiv) product 2a is afforded by an elimination reaction of 3a affected by the base (KOAc). Meanwhile, 2a undergoes a Michael addition reaction to afford 3a. Furthermore, another Michael addition reaction proceeds with 2a through the attack of a carbon nucleophile to afford 4a.
With the optimized conditions in hand, we next explored the effect on the reaction of substitution on the phenyl ring. The results are summarized in Table 2. Generally, electron-donating groups on the phenyl ring under our standard conditions led to good to excellent combined yields of products 2a-o and 3a-o (Table 2). This reaction tolerated mono-, di-or even tri-substituted patterns on the phenyl ring. Interestingly, a substrate with a heterocycle instead of a phenyl ring, such as thiofuran, afforded the corresponding product (2o) in a synthetically useful yield (Table 2). When substrates with electron-withdrawing groups on the phenyl rings were subjected to the standard reaction conditions, they gave low yields of the corresponding products. After an exploration of the types and amounts of bases, it was found that decreasing the amount of KOAc to 0.6 equivalent led to good yields of 2p-x and 3p-x with the concomitant production of dimeric compounds 4p-v ( Table 3). The reaction tolerated many electron-withdrawing groups on the phenyl rings, such as F, Cl, Br, I, OCF 3 and SCF 3 .
The substrate scope with different phenyl amine groups was subsequently investigated (Table 4). In general, electronwithdrawing groups on the phenyl amine rings promoted the reaction, probably due to the easy formation of a carbon anion at the benzylic position of these substrates in the reaction mixture. In the case of substrates bearing alkylamines being used as the amide component, the reaction did not work at all.
After an extensive screening of many different bases, KHCO 3 was identified to be the optimal one for producing a set of dimeric products (4a, 4l-m, 4o-x) in synthetically useful yields, probably because the mild basicity of KHCO 3 modulates the equilibrium between the intermediates, such as the sulfur-substituted carbocation, carbon nucleophile, a-substituted sulfide 3a and Michael acceptor 2a, all of which exist in the reaction mixture, to directly push the reaction forward to the formation of dimeric compounds (Table 5). Unfortunately, in the case of substrates with electron-donating groups on the phenyl ring, the reaction was unable to afford any of the corresponding dimeric products, regardless of the kind of base used.

Conclusion
In conclusion, we have studied a Lewis acid-promoted cascade reaction with dimethyl sulfoxide as a methylene source for the synthesis of a,b-unsaturated amides. The reaction proceeds with a wide substrate scope under mild conditions and with inexpensive reagents. The identity of both the Lewis acid and base were found to be critical for this reaction to proceed well. Extensive studies provide insight into a possible mechanism, leading to the belief that the Pummerer rearrangement with dimethyl sulfoxide as a methylene source is an initial step.

General techniques
All melting points are uncorrected. Preparative chromatographic separations were performed on silica gel (300e400 mesh). Reactions were followed by TLC analysis using silica plates with a fluorescent indicator (254 nm) and visualized with a UV lamp. 1 H and 13 C NMR spectra were recorded in Fourier transform mode at the field strength specified on a 400, or 600 MHz spectrometer. Spectra were obtained on CDCl 3 solution in 5 mm diameter tubes, and chemical shifts in ppm (part per million) are quoted relative to the residual signals of chloroform (d H 7.26 ppm, or d C 77.00 ppm). J values are given in hertz. IR spectra were measured for samples as Table 2 Substrate scope with the electron-donating groups on the phenyl ring. a KBr pellets in a FT-IR spectrophotometer. High resolution mass spectra (HRMS) were measured at 70 eV using a double focusing magnetic sector mass analyzer with an EI source or ESI source. 2-Phenyl-N-[2-(trifluoromethoxy) phenyl]acetamides (1a-1x, 1aa- Table 3 Substrate scope with the electron-withdrawing groups on the phenyl ring. a Table 4 The effect on the reaction of substituents on the phenyl amine ring. a 1ae and 1ba-1bc) were prepared according to the literature procedure. 13a Among them, substrates 1aa, 15 1ad 16 and 1ae 17 were known.