Thio-Michael addition

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. 

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 Acetphenones, aromatic aldehydes, thiols, BuOK, BuOH, room temperature, P-aryl-p-mercapto ketones, one-pot multicomponent synthesis, thio-Michael addition... 

Figure 8 Synthesis of hyperbranched polymers by CCTP and subsequent functionalization by phosphine-mediated thio-Michael addition.

A first literature precedent describes the reaction of y-thiobutyrolactone with propiolic acid under basic hydrolysis conditions, generating the corresponding acrylic acid 4 (Scheme 3a) [113]. As an alternative to this sequential hydrolysis and conjugate addition (thio-Michael addition), the lysis of thiolactones under basic conditions is often carried out in the presence of an alkylating agent. Because of the high nucleophilic character of the liberated thiol, 5-alkylated compounds are the final products of these reactions [108]. Methanolysis of homocysteine-y-thiolactone hydrochloride l.HCI and subsequent alkylation by treatment with an alkyl halide in a one-pot fashion has been reported as a simple method for the synthesis of S-alkylhomocysteines 5 (Scheme 3b) [114, 115]. 

Scheme 3.13 Thio-Michael addition promoted by a primary amino acid.

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... 

Purines, N-alkyl-N-phenyl-synthesis, 5, 576 Purines, alkylthio-hydrolysis, 5, 560 Mannich reaction, 5, 536 Michael addition reactions, 5, 536 Purines, S-alkylthio-hydrolysis, 5, 560 Purines, amino-alkylation, 5, 530, 551 IR spectra, 5, 518 reactions, 5, 551-553 with diazonium ions, 5, 538 reduction, 5, 541 UV spectra, 5, 517 Purines, N-amino-synthesis, 5, 595 Purines, aminohydroxy-hydrogenation, 5, 555 reactions, 5, 555 Purines, aminooxo-reactions, 5, 557 thiation, 5, 557 Purines, bromo-synthesis, 5, 557 Purines, chloro-synthesis, 5, 573 Purines, cyano-reactions, 5, 550 Purines, dialkoxy-rearrangement, 5, 558 Purines, diazoreactions, 5, 96 Purines, dioxo-alkylation, 5, 532 Purines, N-glycosyl-, 5, 536 Purines, halo-N-alkylation, 5, 529 hydrogenolysis, 5, 562 reactions, 5, 561-562, 564 with alkoxides, 5, 563 synthesis, 5, 556 Purines, hydrazino-reactions, 5, 553 Purines, hydroxyamino-reactions, 5, 556 Purines, 8-lithiotrimethylsilyl-nucleosides alkylation, 5, 537 Purines, N-methyl-magnetic circular dichroism, 5, 523 Purines, methylthio-bromination, 5, 559 Purines, nitro-reactions, 5, 550, 551 Purines, oxo-alkylation, 5, 532 amination, 5, 557 dipole moments, 5, 522 H NMR, 5, 512 pJfa, 5, 524 reactions, 5, 556-557 with diazonium ions, 5, 538 reduction, 5, 541 thiation, 5, 557 Purines, oxohydro-IR spectra, 5, 518 Purines, selenoxo-synthesis, 5, 597 Purines, thio-acylation, 5, 559 alkylation, 5, 559 Purines, thioxo-acetylation, 5, 559... 

High enantioselectivities may be reached using the kinetic controlled Michael addition of achiral tin enolates, prepared in situ, to a,/i-unsaturated carbonyl compounds catalyzed by a chiral amine. The presence of trimethylsilyl trifluoromethanesulfonate as an activator is required in these reactions236. Some typical results, using stoichiometric amounts of chiral amine and various enolates are given below. In the case of the l-(melhylthio)-l-[(trimethylsilyl)thio]ethene it is proposed that metal exchange between the tin(II) trifluoromethanesulfonate and the ketene acetal occurs prior to the 1,4-addition237,395. 

A thio-substituted, quaternary ammonium salt can be synthesized by the Michael addition of an alkyl thiol to acrylamide in the presence of benzyl trimethyl ammonium hydroxide as a catalyst [793-795]. The reaction leads to the crystallization of the adducts in essentially quantitative yield. Reduction of the amides by lithium aluminum hydride in tetrahydrofuran solution produces the desired amines, which are converted to desired halide by reaction of the methyl iodide with the amines. The inhibitor is useful in controlling corrosion such as that caused by CO2 and H2S. 

The final example of a domino process under high pressure, to be discussed in this chapter, is a combination of a Horner-Wittig-Emmons (HWE) reaction with a Michael addition developed by Reiser and coworkers [5]. Hence, reaction of a mixture of an aldehyde such as 10-18, a phosphonate 10-19 and a nucleophile 10-20 in the presence of triethylamine at 8 kbar led to 10-21. By this method, (3-amino esters, 3-thio esters and 3-thio nitriles can be prepared in high yield (Scheme 10.4). Many of these transformations do not occur under standard conditions, thereby underlining the importance of high pressure in organic chemistry. 

A Michael addition-Nef reaction sequence was used in a synthesis of disaccharides. Addition of the sodium salt of 1-thio-D-glucose to sugar nitroolefin 112 gave a mixture of isomers 113. The subsequent deacetylation, followed by a Nef reaction, afforded the S -disaccharides 114 and 115 (Scheme 35).82... 

Figure 6.40 (Thio)urea catalysts derived from dihydroquinine and dihydroquinidine screening results obtained from the asymmetric Michael addition of dimethyl malonate to frans-p-nitrostyrene.

Asymmetric Michael addition.1 The highest optical yield for addition of thio-phenol to maleates is obtained with diisopropyl maleate catalyzed by cinchonine (equation I). The succinate obtained in this way was used for synthesis of (R)-( + )-3,4-epoxy-l-butanol. 

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). 

Lewis acid-catalyzed tandem Michael imino-aldol reactions enable the one-pot synthesis of 7-acyl-(5-lactams from a, j6-unsaturated thio-esters, silyl enolates and imines [15]. For the initial Michael addition, the combination of SbClj with Sn(OTf>3 (5 mol %) proved to be efficient. However, after the addition of the imino compound the iminoaldol product was isolated in moderate yield. For the enhancement of turnover and yield, Sc(OTf)3, once again proved to be the Lewis acid of choice (Scheme 4, 15 16 = 81 19, 94%). 

Figure 8 Irreversible inhibitors of proteases. Serine and cysteine proteases can be acylated by aza-peptides, which release an alcohol, but cannot be deacylated due to the relative unreactivity of the (thio) acyl-enzyme intermediate. Reactive carbons, such as the epoxide of E64, can alkylate the thiol of cysteine proteases. Phosphonate inhibitors form covalent bonds with the active site serine of serine proteases. Phosphonates are specific for serine proteases as a result of the rigid and well-defined oxyanion hole of the protease, which can stabilize the resulting negative charge. Mechanism-based inhibitors make two covalent bonds with their target protease. The cephalosporin above inhibits elastase [23]. After an initial acylation event that opens the p-lactam ring, there are a number of isomerization steps that eventually lead to a Michael addition to His57. Therefore, even if the serine is deacylated, the enzyme is completely inactive.

Other saccharide electrophiles utilized have been an a, 8-unsaturated keto derivative and ethylated thiolevoglucosan. The former yielded in a Michael addition with tetra-O-acetyl-l-thio-/3-D-glucop)Tanose the (1— 4)-linked disaccharide in an excellent yield (O Scheme 59) [183,184]. The latter, when reacted with the sodium salt of the above glucose thiol, gave the (1 6)-linked disaccharide as its thioethyl glycoside (O Scheme 60) [185]. 

---