Zinc-Catalyzed Regioselective Addition of Alkyl Thiols to Alkenes via Anion or Radical Reactions

Zn-catalyzed reactions of alkenes with alkyl thiols could afford alkyl sulfides regioselectively. When the ZnI 2 - catalyzed hydrothiolation of alkenes was achieved using alkyl thiols at 100 º C, Markovnikov-type alkyl sulfides were obtained in excellent yields without the formation of linear products. To the contrary, Zn(OAc) 2 - catalyzed reaction gave rise only to anti -Markovnikov-type products regioselectively. The reaction proceeded via a radical process


Introduction
][8][9][10][11][12] The reaction usually produces two regioisomers.Development of regioselective reactions is greatly to be desired.As a general rule, arenethiols readily generate thiyl radicals in the presence of oxygen or light; however their formation from alkyl thiols is very slow (Figure 1). 13To generate alkyl thiyl radicals, irradiation using UV or blue light in the presence of metal catalysts is required.5][16] For example, the Ru-catalyzed reaction performed under irradiation with blue light affords anti-Markovnikov-type products in excellent yields. 14,158][19][20][21][22] For instance, In-or Mont K10-catalyzed reactions of alkenes with alkyl thiols afford Markovnikov-type products regioselectively (Scheme 1). 17,22ecently, it was reported that the ZnI2-catalyzed reactions of aryl alkenes with thiols produces Markovnikovtype sulfides regioselectively in the presence of 4-toluenesulfonic acid. 23This method cannot afford radical reaction products, whereas zinc salts have the ability to promote radical reactions 24,25 thus, various zinc salts were screened.Fortunately, on one hand, it was found that ZnI2-catalyzed reactions using alkyl thiols afforded Markovnikov-type products in the absence of 4-toluenesulfonic acid.On the other hand, Zn(OAc)2-catalyzed reactions produced anti-Markovnikov-type sulfides.In this paper, these methods are described.To establish the hydrothiolation of alkenes using alkyl thiols, various conditions were investigated.As shown in Table 1, when the ZnI2-catalyzed reaction of styrene with 1-butanethiol was performed in dichloromethane or toluene at room temperature, the expected sulfide 2 was not obtained (Entries 1-2).Also the reaction did not proceed in acetic acid at 100 °C did not proceed (Entry 3).However, when the solvent was changed to toluene, the corresponding branched sulfide 3 was obtained in a 79% yield without the formation of other products (Entry 4).Similarly, the reaction using ZnBr2 produced the same result (Entry 5).Notably, the reactions using ZnF2 or Zn(OAc)2 catalysts afforded linear sulfide 3 in 38% or 49% yields, regioselectively (Entry 7).Furthermore, when the Zn(OAc)2-catalyzed reaction was performed for 36 h, the production of 3 increased to 87% yield (Entry 9).The reactivity of other metal catalysts were examined similarly, but these led to unsatisfactory results (Entries 10-14).Sequentially, the Zn(OAc)2-catalyzed reactions were also surveyed for the preparation of anti-Markovnikovtype sulfides (Table 3).When a mixture of alkene with alkyl thiol was heated at 100 °C for 36 h, the expected products 3 were regioselectively obtained in excellent yields (Entries 1-5).Similarly, the procedure worked with various styrene derivatives (Entries 6-9).Regrettably, using internal or terminal alkyl alkenes produced lower yields (Entries 10-12).
On the basis of developed procedure, numerous substrates were next investigated (Table 2).When styrene was reacted with different alkyl thiols, the expected products were obtained in excellent yields without the formation of linear sulfides (Entries 1-6).Numerous styrene derivatives were suitable substrates for the procedure (Entries 7-13).Furthermore, cyclic alkenes afforded 2 in excellent yields, regioselectively (Entries 14-16).A using vinyl pyrrolidine gave only the expected sulfide 2 with an 81% yield (Entry 17).On the other hand, the reaction of methyl acrylate produced linear products in a 90% yield (Entry 18).Regrettably, other internal alkenes or terminal alkyl alkenes did not undergo the reaction satisfactorily (Entries 19-20).To clarify these reaction mechanisms, several experiments were then carried out.Initially, the reactions were performed in the presence of 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger (Scheme 2).
Although the ZnI2-catalyzed reactions gave the corresponding product in an 80% yield, Zn(OAc)2 did not promote the reaction.These results indicate that the reaction using Zn(OAc)2 as catalyst might involve a radical process.Furthermore, reactions in the absence of oxygen were also examined.When a mixture of styrene with 1-butanethiol was treated by ZnI2 under an argon atmosphere, the corresponding sulfide 2a was obtained in a 77% yield.However, again, Zn(OAc)2 catalysis did not occur (Scheme 3).It is conceivable that the thiyl radicals are generated in the presence of oxygen.From these results, a plausible reaction mechanism is considered to be as follows (Figure 2). 11In the ZnI2catalyzed reaction, after the reaction of ZnI2 with the alkyl thiol produces an alkylS-ZnI complex, 9 Markovnikov-type products are produced by the addition of the complex to the alkene.Alternatively, in reactions using a Zn(OAc)2 catalyst in oxygen, thiyl radicals are efficiently produced.Ultimately, anti-Markovnikov-type products are obtained.

Conclusions
In conclusion, the ZnI2-catalyzed hydrothiolation of alkenes using alkyl thiols was achieved at 100 °C.The procedure regioselectively affords excellent yields of Markovnikov-type products.However, Zn(OAc)2catalyzed hydrothiolation regioselectively produces anti-Markovnikov-type products via a radical process.Thus, regioselective additions of alkyl thiols to alkenes were achieved using different zinc catalysts.

Experimental Section
General Procedure and Chemicals.All reactions were carried out in air. 1 H and 13 C NMR spectra were recorded on a JEOL EX-270 spectrometer (270 MHz for 1 H, 67.8 MHz for 13 C).Chemical shifts are reported in  ppm referenced to an internal tetramethylsilane standard for 1 H NMR and chloroform-d ( 77.0) for 13 C NMR. IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrometer.

Table 1 .
Investigation of suitable conditions a a Reaction conditions: A mixture of 1 (0.3 mmol), n-BuSH (0.33 mmol) and cat.M (10 mol%) in solvent (0.3 mL).b Determined by 1 H NMR. c Isolated yield after silica gel chromatography.dThereaction was performed for 36 h.