Cs2CO3-Mediated Regio- and Stereoselective Sulfonylation of 1,1-Dibromo-1-alkenes with Sodium Sulfinates

Abstract A highly selective synthesis of (Z)-1-bromo-1-sulfonyl alkenes via Cs2CO3-promoted sulfonylation of 1,1-dibromo-1-alkenes with sodium sulfinates is described. Notably, using excess amounts of Cs2CO3 and sodium sulfinate in such a reaction regenerated the parent aldehyde. Interestingly, the reaction of 1-(2,2-dibromovinyl)-2-nitrobenzene in the presence of sulfinates and Cs2CO3 produced isatin. The Sonogashira cross coupling of synthesized (Z)-1-bromo-1-sulfonyl alkenes with phenylacetylene gave selectively the corresponding sulfonylalkynyl alkenes.

This paper is dedicated to Professor Majid M. Heravi on the occasion of his 68 th birthday. Organosulfur compounds, particularly vinyl sulfone derivatives, have attracted considerable research interest because they are abundantly found in useful synthetic products and naturally occurring substances. 1 In addition, the vinyl sulfonyl group is extensively used as a synthetic intermediate in organic synthesis. 2 Usually, vinyl sulfones are prepared using sulfone agents such as sodium sulfinates, sulfonyl hydrazides, sulfinic acids, and tosyl methyl isocyanide (TosMIC), and alkene resources. 3 Among the sulfone agents, sodium sulfinates are readily available and stable; therefore, they are widely applied in organic transformations. 4 Furthermore, 1,1-dibromo-1-alkenes have been extensively used as an efficient alkene and alkyne resource for generating complex alkene and alkyne derivatives. 5 They can easily be derived from aldehydes or ketones using CBr 4 /PPh 3 . 6 One common and practical method for synthe-sizing terminal alkynes (Corey-Fuchs reaction) and bromoacetylenes is the treatment of 1,1-dibromo-1-alkenes with a base. 7 Although gem-dibromoalkenes are widely used in organic transformations, the occurrence of the selective reaction that produces 1,1-difunctional alkenes by the remaining one Br atom is rare. For instance, the monoalkenylation, 8 selenation, 9 alkynylation, 10 arylation, 11 etherification, 12 and borylation 13 of germinal dibromoalkenes have been reported. Chen et al. established the synthesis of 2-arylbenzofurans(thiophenes) via the tandem reaction of 2-(gem-dibromovinyl)phenols(thiophenols) and sodium arylsulfinates in the presence of the TBAF-PdCl 2 -Cu(OAc) 2 -NEt 3 system. 14 A stereoselective synthesis of vinyl triflones starting from gem-dibromovinyl derivatives has been achieved via triflyl migration reactions. 15 Although the synthesis of vinyl sulfones has been widely and intensively studied, the synthesis of 1-bromo-1-sulfonylalkenes has been shown only in few reports. For instance, sulfonylation of activated alkynes with sodium sulfinates, 16 as well as sulfinic acids 17 in water as the reaction medium have been developed. In both cases, ethyl 3-bromopropiolate reacted with sodium toluenesulfinate or toluenesulfinic acid to yield ethyl 3-bromo-3-tosylacrylate (Scheme 1, eq. 1). Fisher et al. have prepared -bromovinylsulfone for their study in four steps starting from propylene oxide (Scheme 1, eq. 2). 18 In the first step, ring opening of the epoxide took place with a sulfinate salt producing an alcohol that was converted to the corresponding vinyl sulfones via treatment with methanesulfonyl chloride and base. The vinyl sulfone was dibrominated with Br 2 under radical conditions and subsequent dehydrobromination mediated by DBU afforded -bromovinylsulfone. Condensation of bromomethyl sulfone and aldehyde generated the corresponding vinyl bromide. 19 Also diethyl bromo(phenyl-M. Shiri et al.

Scheme 1 Synthesis of -bromovinyl sulfones
From the perspective of diversity-oriented synthesis, the incorporation of bromine and sulfone functional groups onto the terminal carbon atom of an alkene may be a significant achievement as it produces novel and more complex molecules. Inspired by the aforementioned results and based on our continued interest in exploring the application of gem-dibromoalkenes, 21 we envisioned that the selective debromosulfonation of 1,1-dibromo-1-alkenes can be performed. Herein, we report a practical protocol for the highly regioselective synthesis of (Z)-1-bromo-1-sulfonylalkenes 3 using sodium sulfinates and 1,1-dibromoalkenes in a basic medium (Scheme 1, Eq. 4).
Under the established optimal conditions, the scope of this reaction with a variety of aromatic and heteroaromatic dibromoalkanes with aliphatic and aromatic sodium sulfinates was examined. As shown in Scheme 2, the tandem reaction of ,-dibromostyrenes containing Br, Cl, NO 2 , OMe, Me, or CF 3 substituents in para-, meta-, or ortho-position with sodium phenyl, methyl, or tolyl sulfinate produced the corresponding -bromo--sulfonylstyrenes 3a-k in 65-91% yields.
Next, we focused on the reaction of sodium phenylsulfinate with 2-chloro-3-(gem-dibromovinyl)quinoline because it bears an active C-Cl bond in the 2 position of quinoline. Interestingly, debromosulfonation occurred in the same way as described in the previous results and the C-Cl bond remained intact to yield 3l. When the other vinylquinolines were employed, the selectivity was identical for the aliphatic and aromatic sodium sulfinates to afford the corresponding products 3m-r in good to excellent  M. Shiri et al.
To test the efficiency of this method in gram-scale synthesis, gem-dibromoalkene 1c (1.22 g) was chosen to react with sodium phenylsulfinate (0.778 g) in the presence of Cs 2 CO 3 (4 mmol) in DMSO (20 mL), which gave 3c in 71% yield after 10 hours (Scheme 3).

Scheme 3 Gram-scale synthesis of 3c
The debromosulfonylation reaction proceeded regioselectively and stereoselectively to produce the corresponding Z-brominated alkenyl sulfone 3 in good yields, and no E-isomer was observed. Although the reason for this high selectivity is not clear, the formation of an intramolecular hydrogen bond between C2-H and Br atom may be a factor.
The structure of compound 3c was confirmed via X-ray crystallographic analysis (Figure 1). 22 Further, 1-(2,2-dibromovinyl)-2-nitrobenzene (1l) was converted to isatin (5) in the presence of sodium phenylsulfinate and Cs 2 CO 3 in 90% yield (Scheme 4). The same results were obtained when sodium tolylsulfinate was used as the sulfone source. Considering the removal of two oxygens of the nitro group and the appearance of oxygen on positions 2 and 3 of isatin, we propose the mechanism outlined in Scheme 4. The reaction commences from the base-promoted HBr elimination of 1l to generate bromoacetylene A. 5b,7b To approve this step, 1l was treated to Cs 2 CO 3 in DMSO, which yielded A. Subsequently, the -addition of ArSO 2 − to intermediate A formed B. 16,23 Intermediate B was subjected to intramolecular oxa-Michael addition to yield C. 24 The ring opening of C followed by base promoted the intramolecular hydroalkylation of nitroso group to afford E. 25 Final-Scheme 2 Scope of various 1,1-dibromo-1-alkenes and sodium sulfinates

Paper Synthesis
ly, HBr elimination via oxaziridine formation led to the ring opening of F assisted by the removal of sulfonyl, eventually affording 5 (Scheme 4).

Scheme 4 Plausible mechanism for the formation of isatin (5) from 1l
Furthermore, the feasibility of using 3 to obtain more complex molecules was investigated. In this regard, the Sonogashira cross coupling of 3a and 3c with phenylacetylene resulted in the corresponding alkynylated products 6a and 6b in 91% and 88% yield, respectively (Scheme 5).

Scheme 5 Synthetic utility of (Z)--bromovinyl sulfones
In summary, we have developed a robust transitionmetal-free synthetic method for the highly regioselective and stereoselective debromosulfonylation of 1,1-dibromo-1-alkenes using sodium sulfinates. The Cs 2 CO 3 -mediated reaction of a wide range of aromatic, and heteroaromatic substrates has wide applicability with good functional-group compatibility. From the reaction of 1-(2,2-dibromovinyl)-2nitrobenzene with sodium phenyl-and tolylsulfinate, isatin was isolated as the sole product. As an example of the synthetic potential of 3, the selective palladium-catalyzed alkynylation of these compounds with phenyl acetylene was demonstrated.
The solvents and chemicals were purchased from Merck and Aldrich chemical companies. Unless otherwise mentioned they were used without further purification. The 1,1-dibromoalkenes were prepared according to the reported procedures. 26 Melting points are taken on an Electrothermal 9100 apparatus and are uncorrected. FT-IR spectra were recorded on a Shimadzu Infra-Red Spectroscopy IR-435. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AVANCE Spectrometer 400 MHz for 1 H,100 MHz for 13 C) in DMSO-d 6 as solvent. Mass spectra recorded on Agilent Technology (HP) 5973 Network Mass Selective Detector operating at an ionization potential of 70 eV and a Leco CHNS, model 932 was used for elemental analysis.

Cs 2 CO 3 -Promoted Sulfonylation of 1,1-Dibromo-1-alkenes with Sodium Sulfinates; General Procedure
To a mixture of respective gem-dibromoalkene 1 (1.0 mmol) and Cs 2 -CO 3 (326 mg, 1.0 mmol) in DMSO (5.0 mL) was added the corresponding sodium sulfinate (1.2 mmol). The mixture was stirred at 100 °C for 5 h. Upon completion of the reaction, H 2 O (20 mL) was added and the whole was extracted with CH 2 Cl 2 (20 mL). The organic layer was washed with brine and dried (MgSO 4 ). The solvent was removed and the residue was purified by column chromatography using n-hexane/EtOAc (9:1) to obtain 3 in pure form.

Funding Information
We are thankful to Alzahra University and the Iran National Science