Organic Reaction in Water . Part 31 : Diastereoselectivity in Michael Additions of Thiophenol to Nitro Olefins in Aqueous Media

Tiofenóis reagem com nitro olefinas em meio aquoso dando os correspondentes nitro-sulfetos em 58 95 % de rendimento. Este processo leva à formação, predominante, de produtos anti. Para o caso da nitro olefina cíclica 1-nitro-ciclo-hexeno é observada unicamente a formação de cis-1nitro-2-(tio-fenil)-ciclo-hexano. Esta metodologia é interessante porque utiliza-se água como solvente levando à minimização do custo, diminuindo os problemas de toxidez e poluição ambiental


Introduction
Two of the most characteristic features of thiols are the relatively high acidity and the facility with which they undergo nucleophilic reactions 2 .Thiols are, therefore, good substrates for Michael addition reactions, which are conventionally promoted in the presence of catalytic amounts of sodium methoxide or triethylamine 3 .Procedures using Triton B 4 and quaternary ammonium fluoride 5 as catalysts have been previously published.
Modern methods mediated by resins and heterogeneous catalysts have also been employed.The Dowex MAS-1 impregnated with fluoride 6 and BER 7 give good results.Ranu and Bhar 8 developed an interesting procedure for Michael addition on the surface of alumina.Transition metal complexes have many applications as catalysts for this kind of reaction, particularly for the asymmetric variant 9 .
Recently, we showed that Michael addition of dicarbonyl compounds, nitroalkanes and thiols to the 2-cyclohexen-1-one can be accomplished in water without phase transfer agents.We also observed that the reaction is extremely sensitive to the pH of the reaction media, and depending on the nucleophile, the optimized pH is different 1 .This work has importance for the study of organic reactions in aqueous media.This field of study has grown steadily since Breslow demonstrated, in 1980, the use of the hydrophobic effect to promote Diels-Alder reactions 10 .Examples of reactions performed in aqueous media in the sub- 11 and super-heated 12 states can be found in the literature.
Apart from the physical chemistry aspects which stimulate academic interest and can be useful in organic synthesis, the use of water as a reaction medium to substitute organic solvents is important for human and economic reasons as it minimizes environmental impact, reduces the cost and presents smaller operational hazards.
In this work, we have studied the Michael addition of thiophenol to nitro olefins in aqueous media to form nitrosulfides (Scheme 1).An anti diastereoselectivity was observed that is quite different from that encountered using the traditional method with triethylamine as base and acetronitrile as solvent (Scheme 2, method A), whilst the diastereoselectivity is similar to that observed by Kamimura where the addition of thiolates is followed by protonation with acetic acid at -78 o C in THF as solvent (Scheme 2, method B).

Results and Discussion
The reaction of (E)-1-methyl-1-nitro-styrene (1a) with thiophenol was studied under three different conditions, with the main variant being the pH of the reaction media.The reaction was catalysed with NaOH (pH 14), Na 2 CO 3 (pH 10) or NaHCO 3 (pH 7-10) 16 .
Using the above conditions, diastereoselectivity was observed and a 70:30 (anti:syn) mixture of nitro-olefins (2a) was obtained 14 .However, at pH 14 the substrate was not totally consumed.
When the mixture of isomers 2a (73:27, anti: syn) was treated with an aqueous solution of NaOH (pH 14), the formation of nitro olefin 1a and thiophenol was observed, after 30 min.Thus, we conclude that at pH 14 the product can suffer a retro-Michael reaction.
Having found that the reaction proceeds in good yields and under mild conditions in aqueous NaHCO 3 , we decided to further investigate the use of this media.
On the other hand, when a bulky substituent such as isopropyl in 1c is present, the stereoselectivity is markedly decreased, leading to a 38:62 mixture of the anti:syn products, as also verified by Kamimura 3 .It was further noted that the reaction was slowed down and that the substrate was not totally consumed.
We also verified, that this method was useful for the stereoselective preparation of cis-1-nitro-(phenylthio) cyclohexane (2d) 17 by the reaction of 1-nitro-cyclohexene (1d) with thiophenol (Scheme 3).Kamimura and coworkers 3 observed anti selectivity for the addition of several metal thiolates to nitro-olefins in THF, followed by acetic acid treatment at -78 o C (Scheme 2, method B).They attributed this selectivity to the protonation stage of the nitronate anion and theorized that this may occur in the perpendicular conformation shown in Figure 1.Thus, the R 3 S group covers one face of the nitronate group explaining the diastereoselectivity.In order to ascertain the preferred structure of the intermediates, Kamimura and coworkers 3 also carried out ab initio molecular orbital (MO) calculations which provided support for the proposed conformation.The proposed intermediate (Figure 1) also explains the observed selectivity in water, but it is important to point out that in water the process occurs at room temperature (25-30 o C).

Conclusions
Thus, we concluded that thiophenol reacts with nitroolefins 1a and 1b in aqueous media leading to the corresponding β-nitro-sulfides in good yields and with anti selectivity.However, when 3-methyl-2-nitro-3-pentene (1c) was used the selectivity was inverted and markedly decreased.The anti selectivity is not pH dependent but the yield of the reaction decreases at high pH values because the products can suffer a retro-Michael reaction.This methodology is of interest due to the use of water as the solvent, thus minimizing the cost as well as operational hazards and environmental pollution.
Fundação José Bonifácio for additional financial support of this work and A. M. Sanseverino for the good ideas in the synthesis of the necessary nitro olefins for this study.
Reaction of nitro olefin with thiophenol in water.