Thiol-Michael addition reaction

The thiol Michael addition reaction rate increases with pH, connected to the increase of thiolate anion concentration (Rizzi and Hubbell, 2005). The reaction on the polymeric system is shown in Fig. 14.9. 

Apart from base catalysis, Michael addition of thiols can also be performed using nucleophUic catalysis. Primary and secondary amines and certain phosphines are the most commonly used catalysts. Nucleophile mediated thiol-Michael addition reactions have extensively been studied. The nucleophiles attack the Michael acceptors to generate a carbanion, which abstracts protons from thiols to generate thiolate anions, which in turn propagate the reaction (Scheme 1.16) [56]. NucleophUicity of the catalyst plays a crucial role in the kinetics of the nucleophile-based thiol-Michael addition reactions, as stronger the nucleophile, more easily the thiolate anion will be generated. 

Owing to the low p/C values of thiols, thiol—Michael addition reactions can be performed under ambient conditions in water or other protic solvents. However, both base- and nucleophile-catalyzed thiol-Michael addition reaction are affected to some extent by the presence of external protic species, especially the nucleophUe-mediated pathway is more affected due to low catalytic concentration of nucleophiles compared to bases in these reactions. 

The Michael addition reaction of amines and thiols with bismaleimides or functionalized monomaleimides is a versatile tool ia the synthesis of chain-extended maleimide-terroinated prepolymers. These prepolymers generally are soluble ia organic solvents from which they can be processed to prepreg and molded to high quaUty, void-free laminates. 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

Consequently, the Michael addition reaction of sugar thiol proceeds smoothly with the formation of P- (l-2)-2,3-dideoxy-2-C-nitromethyl-thio-disacharides in 63-70 % yield (scheme 6). 

Scheme 2 Michael addition reaction of acrylates, vinylsulfones, and maleimides with thiol...

As electron-rich olefins are more reactive, vinyl-sulfones are the most reactive species and are capable of reacting with thiols, amines, and even with small nucleophilic alcohol groups. Less reactive are acrylamides and acrylates, which are reactive towards amines and thiols. Maleimides are the least reactive of the mentioned species and allow selective addition of thiols in the presence of amines in the pH range 6.5-7.5. However, hydrolysis of the imide, especially at elevated pH values [35], may be a concern for certain applications. The mentioned Michael addition reactions do not require organic solvents and can be carried out at physiological temperature and pH [36], In acidic conditions, the reaction is either very slow or does not proceed because protonation removes the nucleophilic form in the case of amines, and the thiolate anion is usually the active species in Michael additions involving thiols [25],... 

Several heteroatom nucleophiles, for example, amines, alcohols, thiols, carboxylates, and dialkylphosphines, undergo Michael addition reactions with alkene- and alkyne-substituted carbene complexes. Reaction of alkyne-substituted chromium carbenes with urea affords products derived from Michael... 

Enantioselective Michael addition of thiols to enones is a useful reaction for the synthesis of sex pheromones [26] and terpenes [27]. For example, enantioselective Michael additions of thiols to 2-cyclohexenone (64) and maleic acid esters in the presence of chiral bases such as cinchona alkaloids [28, 29] and optically active amino alcohols [30, 31] have been reported. It has also been found that the enantioselective Michael addition reaction proceeds efficiently in an inclusion crystal... 

In order to provide additional evidence In support of the proposed Michael addition reaction, a sediment study was also performed. Acrylic acid was added directly to slurries of reducing sediments from Blscayne Bay and the formation of 3-mercaptopropionate In the porewater, relative to unsplked controls, was monltered by HPLC. The concentration of added acrylic acid was 0.1 mmol per liter slurry ( 0,2 mM In the porewater) and the slurries were Incubated under argon at 37 C for 2 hours prior to thiol analysis. Figure 6 clearly shows that addition of acrylic acid to reducing sediment gives rise to 3-mercaptopropionate, the main product expected from the Michael addition of HS to acrylic acid. 

Scheme 6.10 Aza- or thia-Michael addition reactions of amines or thiols...

For a carbohydrate microarray, a glass slide is modified by the thiol group as solid support. Carbohydrates in the form of glycosylamines are converted into maleimide via a hydrocarbon tether chain and covalently bound to the glass surface by hetero-Michael addition reaction (Park and Shin, 2(X)2) between the thiol group and the maleimide moiety of the glycosyl derivative (Fignre 14.4C). 

Shafizadeh s laboratory (31-34) reported the first successful studies of thiol addition. Our recent studies (35-37) and others (38) on the Michael addition reaction of reactive thiols to levoglucosenone and its isomer isolevoglucosenone (39) clearly indicate the complete stereoselectivity of the addition and its general synthetic approach to 1,4- and 1,2-thiodisaccharides (40). 

Baker, L. M., P. R. Baker, F. Golin-BiseUo et al. 2007. Nitro-fatty acid reaction with glutathione and cysteine. Kinetic analysis of thiol alkylation by a Michael addition reaction. J Biol Ghent 282 (42) 31085-93. 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

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