Thiols Michael addition

Michael addition Thiol and a, 3-unsaturated carbonyl group pH 6—8, reaction time <30 min No catalyst required Reversible Cell encapsulation, controlled cargo deliveiy ... 

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. 

HSCH2CH2SH, Zn(OTf)2 or Mg(OTf)2, CICH2CH2CI, heat, 16 h, 85-99% yield.o ,l3-Unsaturated ketones such as carvone are not cleanly converted to ketals because of Michael addition of the thiol. ... 

A thiol, usually under basic catalysis, can undergo Michael addition to an activated double bond, resulting in protection of the sulfhydryl group as a substituted 5-ethyl derivative. 

The starting material was thiol (27) whose synthesis appears on page 25, Michael addition to... 

In a similar way, lipases catalyze Michael addition of amines, thiols [110], and even 1,3-dicarbonyl derivatives [111, 112] to a,/ -unsaturated carbonyl compounds (Scheme 5.21). 

By using 10 mol% of 51, MS4A, and t-BuSH, the desired product 52 was obtained in up to 98% ee in 80% yield. A complementary role by two metals (Ga and Li) in activating and positioning both of the substrates has been proposed. The MS4A (sodium aluminosilicate) accelerated the reaction however, the actual role of this additive was not clearly defined, although the possibilty that MS4A delivers Na ions was pointed out. Tomioka et al. reported the asymmetric Michael addition of an aromatic thiol to a,P-unsaturated esters in the presence of 8 mol% of 53 to provide 54 in up to 97% ee in 99% yield (Eq. 7.40) [47]. 

By using LaNa3-tris(binaphthoxide) (LSB) 55, catalytic asymmetric Michael addition of thiols to cycloalkenones took place to provide the adduct 56 with high ees in good yields (Eq. 7.41) [48]. 

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. 

Synthesis of thiopheno[3,4-c]isoxazoline is shown in Eq. 4.4, in which the Michael addition of allyl thiol to 3-nitro enones and subsequent nitrile oxide cyclization are involved.7... 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

Barrett and coworkers have explored hetero-substituted nitroalkenes in organic synthesis. The Michael addition of nucleophiles to 1-alkoxynitroalkenes or 1-phenylthionitroalkenes followed by oxidative Nef reaction (Section 6.1) using ozone gives a-substituted esters or thiol esters, respectively.41 As an alternative to nucleophilic addition to l-(phenylthio)-nitroalkenes, Jackson and coworkers have used the reaction of nucleophiles with the corresponding epoxides (Scheme 4.4).42 Because the requisite nitroalkenes are readily prepared by the Henry reaction (Chapter 3) of aldehydes with phenylthionitromethane, this process provides a convenient tool for the conversion of aldehydes into ot-substituted esters or thiol esters. 

Furthermore, a neighboring group participation of a phenylthio function is observed in the Lewis acid-catalyzed nucleophilic substitution reaction of various P-nitrosulfides. Because the P-nitrosulfides are readily available, by the Michael addition of thiols to nitroalkenes (see Michael addition Chapter 4), this reaction is very useful. The P-nitrosulfides are prepared stereoselectively, and the reaction proceeds in a stereo-specific way (retention of configuration) as shown in Eqs. 31-34.35... 

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. 

A series of 3-oxothiophene derivatives has been prepared by intramolecular thia-anti-Michael addition of a thiol anion to an enone functionality, resulting for instance in preparation of the target 20 by treatment of the precursor 21 with an amine <06JOC8006>. 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

E Emori, T. Arai, H. Sasai, M Shibasaki, A Catalytic Michael Addition of Thiols to a, -Unsaturated Carbonyl Compounds Asymmetric Protonations, J. Am Chem Soc 1998,120, 4043-4044. 

The first 1,6-addition reactions of thiolates to steroid dienones were examined well before the discovery of the antiestrogenic properties of 7o -substituted steroids. Ralls and coworkers129 and Djerassi and coworkers130 studied thiol additions to A3,5-steroids for example, the reaction of 3,5-cholestadien-7-one with ethanethiol was reported to proceed with high 1,6-regioselectivity and -stereoselectivity (equation 47)129. In a series of papers, Brueggemeier and coworkers131-137 described the synthesis and biochemical evaluation of numerous 7at-sul fur-substituted steroids which were prepared by Michael addition to steroid dienones. Thus, 4,6-androsta-3,17-dienone was treated with various... 

Asymmetric induction of the Michael addition of thiols to electron-deficient alkenes (4.6.1) has been achieved in high overall conversion using both free [e.g. 12-20] and polymer-supported [e.g. 21, 22] cinchona alkaloids and their salts [23-25], but with varying degrees of optical purity. The corresponding asymmetric Michael addition of selenophenols to cyclohex-2-enones is promoted by cinchoni-dine to give a chiral product (43% ee) [26],... 

A bicyclic urea (123) was an unexpected product of the reaction between pyrrolidine and the phenyl ester of 2-cyano-l,4,5,6-tetrahydro-l-pyridinecarboxylic acid (124 R = Ph) the corresponding methyl ester (124 R = Me) reacted, as expected, to give the product of Michael addition (125). ° The better leaving ability of phenoxide vs methoxide presumably tilted the reaction towards the substitution rather than the addition product, although thiols (e.g. PhSH) underwent only the addition reaction. 

An efficient asymmetric Michael addition of thiols to cycloalkenones (103) (56-90% ee) and an effective asymmetric protonation in Michael additions of thiols to non-cyclic enones (104) (75-90% ee), catalysed by LaNas tris(binaphthoxide) (105) and SmNas-tris(binaphthoxide) (106) complexes, respectively, has been reported. ... 

Shi, B. Greaney, M. F. Reversible Michael addition of thiols as a new tool for dynamic combinatorial chemistry. Chem. Commun. 2005, 886-888. 

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

Scheme 22. Michael addition of thiols onto chlorocyclopropylideneacetates 1-Me, 2 [7l, 9,15b, 22 b, 27]...

It is not surprising that chloro esters 1, 2 readily add thiols, catalyzed by sodium thiolates or triethylamine, to give the corresponding 2-(r-organylthiocy-clopropyl)-2-chloroacetates 85,86 (Scheme 22) [15 b, 22b, 27]. This reaction with thiophenol has been used to quantify the Michael reactivity of 1-Me, 2-Me, 3-X in comparison to simple acrylates (see above). With an excess of PhSH, the nucleophilic substitution of the chlorine in 85 a (but not in 85h) proceeded to give the corresponding bis(phenylthio) derivative in 63% yield [15bj. Alkali thiolates (e.g. NaSMe, NaSBn) add smoothly onto 1-Me, 2c-Me and 2p-Me at - 78 °C, because at this temperature subsequent nucleophilic substitution of the chlorine is much slower [7l, 9]. The Michael additions of sodium phenylselenide and sodium arylsulfenates onto 1-Me and their synthetic utility have been discussed above (see Table 1). 

Chiral pyrrolo[d]thiepine 166 can be obtained efficiently in 63% yield starting from N-alkylated maleimide 164. Successive Michael addition of phenethyl thiol and regioselective reduction are followed by spontaneous loss of hydrogen by N-acyliminium intermediates 165 and 7r-aromatic intermolecular a-amidoalkylation... 

Various 2-functionalized-l,3-oxathianes have been prepared from 1,3-thioalcohols by a combined SNV/Michael addition sequence using (Z)-l,2-bis-phenylsulfonylethylene (BPSE) as Michael acceptor. The yields were in the range of 72-90% for aliphatic 1,3-thioalcohols and somewhat lower for 2-hydroxymethyl-substituted aromatic thiols (33%) (Equation 90) <2003TL5723>. 

The principal disadvantage of the intramolecular cyclization approach using Michael addition of a cysteine-based thiol to dehydroalanine is its nonstereoselectivity. Similarly, even when using 3-bromoalanine derivatives in a halide-based substitution reaction with cysteine-... 

---