Thio-Michael reaction

The reaction has heen expanded to an asymmetric thio-Michael reaction by the addition of aiylmethyl mercaptans to cyclohex-2-enone in the presence of 10 mol% of triphenylmethyl-L-cysteine (9 examples, 44-86%, ee 8-58%). Maleimides undergo Michael addition with a,a-disubstituted aldehydes (Scheme 12.10). Several catalytic systems have been tested to promote the reaction, including a- or p-amino acids, potassium salts of amino acids... 

The Michael addition is one of the most important carbon-carbon bond-forming reactions in organic synthesis [46]. Recently, Yoshida et al. [47] examined several primary amino acids in the Michael addition of benzyl thiols to 2best catalyst for this thio-Michael reaction (Scheme 3.13). 

Scheme 33.37 Thio-Michael reaction reported by Singh and Deng.

TEA (trifluoroacetic add) 65, 538, 580 TFAA (trifluoroacetic anhydride) 879 TFE (trifluoroethanol) 593 TFPB (tetrakis[3,5-bis(trifluoromethyl) phenyljborate) 434 Theonella cf. swinhoei 1352 thermal effect 581, 593 thiazolium salts 498 thio-Michael addition 52 thio-Michael reaction 1005 a-thio-substituted furanones 178 thioamides 109... 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

Scheme 6.130 Proposed mechanism of the 121-catalyzed enantioselective thio-Michael-aldol tandem reaction of 2-mercaptobenzaldehydes with a,P-unsaturated oxazolidinones bifunctional activation through thiourea 121.

Scheme 6.131 Typical thiochromanes obtained from the 121-catalyzed asymmetric thio-Michael-aldol tandem reaction between various 2-mercaptobenzaldehydes and a, 3-unsaturated oxazolidinones.

Figure 6.61 Bifunctional hydrogen-bonding pyrrolidine-(thio)ureas utilized for Michael reactions of ketones with nitroalkenes.

The Michael reaction was shown to proceed rapidly to produce a dihydrobenzo[6]thio-phene-3-acetic acid derivative (81) in excellent yield when the cinnamic acid (80) was treated with dry sodium methoxide in methanol (50JA2209). 

Hydroxyalkyl derivatives of seleno- and thio- chromones can be formed by the reaction of aldehydes with appropriate propynones in which an intramolecular Michael reaction is followed by an aldol condensation (Scheme 9) <02TL7039>. 

Chan JW, Zhou H, Wei H, Hoyle C. (2008) Mechanism of the primary and secondary amine catalyzed thio-Michael addition reaction with (meth)acrylates. Abstracts of Papers, 235th ACS National Meeting, New Orleans, LA, United States, April 6-10,2008 168 pp. 

Wang and coworkers found that the quinine-derived thiourea catalyst 81b (1 mol%) was also highly reactive and enantioselective for the tandem thio-Michael-aldol reaction of various 2-mercaptobenzaldehydes (103) with a,P-unsaturated oxazolidi-nones (104), furnishing benzothiopyranes (105) with three stereogenic centers in... 

The stereoselective, one-step synthesis of (l,4)-5-thiodisaccharides (7-2) is a classical example (Scheme 2) of exploiting the excellent functionality of levoglucosenone as Michael reaction acceptor. The methodology of functionalization of C-2 either via conventional and stereoselective reduction, or oximation and then stereoselective reduction of the oximino functionality is unique in providing both classes of 5-thio-disaccharides. Moreover, the C-2 amino functionalized nonhydrolyzable 5-thio-disaccharide, after deprotection of C-2 acetamido function represents a convenient molecular scaffold for the generation of diverse libraries of peptidomimetics as a selected class of glycoconjugates. 

C-methylation reaction is the methylation of the C-5 position of cytosine in DNA. In this case, the carbon C-5 of cytosine cannot directly act as a nucleophile. The electron withdrawal by N-3 and the carbonyl, however, makes the C-5—C-6 double bond electron deficient and prone to attack by nucleophiles in a reaction that is similar to a Michael reaction. In DNA methyltransferases (DNMTs), this nucleophile is the thio-late from a Cys residue. The addition product is nucleophilic and reacts with SAM via an Si,j2-like mechanism to capture the methyl group. The resulting intermediate then eliminates the Cys of DNMT to give the methylated cytosine product (Figure 1.9). The methylation of C-5 of cytosine is an example of converting an electron-deficient methyl acceptor to a nucleophile for the methyl-transfer reaction by addition of an active site Cys thiolate. 

Recently an expansion of the electrophile scope of the conjugate addition of sulfur nucleophiles has been reported by different groups. As depicted in Fig. 2.29 for selected examples, Cinchona-denwed catalysts 203 and 205 promote highly enantioselective additions to nitrooleflns [387] and a,p-unsaturated V-acylated oxazolidin-2-ones [388] through non-covalent catalysis. Especially interesting results the Michael reaction to P-substituted nitroacrylates catalyzed by chiral thio-... 

In expanding the number Michael/aldol domino processes, chiral N-sulfinimines 27 could be subjected to a magnesium thiolate in the presence of an acrylate 26 to undergo an asymmetric thio-Michael/nucleophilic addition reaction (Scheme 7.4)... 

Scheme 7.4 Asymmetric thio-Michael/nucleophilic addition domino reaction.

The sulfa-Michael reaction to a (3,(3-disubstituted Michael acceptor, affording adducts with a new quaternary stereocenter, is usually challenging, mainly due to the low reactivity and reversibility of the process. Xiao and co-workers [41] reported that thiourea 12 promoted the highly enantioselective conjugate addition of arenethiols and substituted benzyl thiols to a-substituted (3-nitroacrylates. The enantioenriched adducts could be easily transformed into a-thio-(P -amino acids, valuable building blocks for the synthesis of p- or mixed p/a-peptides (Scheme 14.12). 

J.-B. Gualtierotti, X. Schumacher, P. Fontaine, G. Masson, Q. Wang, J. Zhu, Chem. Eur. J. 2012, 18, 14812-14819. Amidation of aldehydes and alcohols through a-iminonitriles and a sequential oxidative three-component Strecker reaction/ thio-Michael addition/alumina-promoted hydrolysis process to access P-mercaptoamides iiom aldehydes, amines, and thiols. 

Keywords Ninhydrin, malononitrile, aryl isothiocyanates, primary aliphatic amines, ethanol, triethylamine, room temperature, one-pot multicomponent synthesis, thio-Michael and Knoevenagel reactions, sulfur-nitrogen heterocycles, oxathiaaza[3.3.3]-propellanes, che-moselectivity, regioselectivity... 

Stereoselective thio-Michael-aldol tandem reaction has been reported, using a mixture of PhSLi, O -unsaturated ester (148), and aldehyde (149) in CH2CI2 (Scheme 21). The adducts, j0-hydroxy-a-(l-phenylthioalkyl) esters (150), were obtained in moderate... 

Kamimura, A., Okawa, H., Morisaki, Y., Ishikawa, S., Uno, H. (2007). Asymmetric thio-Michael/nucleophilic addition domino reaction with chiral A-sulfinimines. Journal of Organic Chemistry, 72, 3569-3572. 

---