Thia-Michael addition

A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with A,A-dimethyl-4-A ,A -bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-A,A-bis(trimethylsilyl)aminobut-2-ynoate 31b, respectively <06TL8661>. Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. 

The synthesis of pent-4-en-l-yn-3-ones from alkynes involves their deprotonation and condensation with ot,(3-unsaturated aldehydes and subsequent oxidation of the allylic alcohol. A double thia-Michael addition occurs when the enynone is treated with sulfide which leads to 2,3-dihydrothiopyran-4-ones bearing different substituents at the 2- and 6-positions (Scheme 217) <2006TL5095>. 

SSA is an efficient catalyst for thia-Michael addition to electron-deficient and sterically unhindered conjugated enones under solvent-free and mild conditions [95]. The reactions of thiols with enones such as cyclohexenone, cyclopentenone and ethyl vinyl ketone afforded the corresponding adducts in excellent yields. However, when chalcones were used as an enone, the corresponding adducts were obtained in very poor yields (Scheme 5.16). 

Scheme 5.16 thia-Michael addition to conjugated enones under solvent-free, mild conditions. 

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

Recently, Alexakis and Quintard [93] reported an interesting example in the acyclic series exploiting the reactivity of vinyl sulfones in an enamine/iminium activated three-component oxa-Michael/Michael cascade in the presence of enals and oximes, leading to highly optically enriched products (Scheme 16.44). The reaction can also be initiated by an aza-Michael or a thia-Michael addition. 

Another significant application of the ADMET polymerisation relates to the preparation of star-shaped polymers, which are branched macromolecules in which several linear polymer chains are attached to a unique branching point or core [48]. Montero de Espinosa, Winkler and Meier [49] described an ADMET approach to obtain those architectures (three- and four-arm) using small tri-acrylates and tetra-acrylates. More recently, Unverferth and Meier [50] reported the synthesis of well-defined star-shaped polymers via a head-to-tail ADMET polymerisation whereby di(trimethylolpropane)tetra-acrylate (four-arm) and dipentaerythritol hexa-acrylate (six-arm) served as core units, and fatty acid-derived 10-undecenyl acrylate as asymmetric a,(0-diene monomers. In this case, star-shaped polymers containing arms of 10 or 20 monomer units with an a,(0-unsaturated ester backbone and their subsequent post-polymerisation via a base-catalysed Thia-Michael addition were prepared. 

Pore et al. (2006) documented the thia-Michael addition involving the conjugate addition of thiols to a,p-unsaturated ketones in the presence of SSA as a heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 5.53). The catalytic activity was comparatively studied with potassium phosphate. Studies revealed that SSA is suitable for electron-deficient a,P-unsaturated compounds, whereas K3PO4 catalyzed the reactions of both electron-deficient as well as electron-rich enones. SSA catalyzes a rapid, green, and chemoselective aza-Michael addition of amines and thiols... 

Jprgensen and coworkers exploited an approach in 2005 by designing a three-component reaction involving iminium/enamine activation (Scheme 2.23). They demonstrated that thiols 84 can initiate the sequence by a thia-Michael addition to... 

Alternatively, Wang and coworkers reported a highly enantioselective domino thia-Michael/aldol sequence using bifunctional thiourea-tertiary amine catalysts to afford spirocyclic compound 76 [43]. ( )-Benzylidene chromanone derivatives 74 reacted with 2-mercaptobenzaldehydes 75 in the presence of a bifunctional tertiary amine-thiourea catalyst XVIII. The thia-Michael addition to the benzylidene was followed by an intramolecular aldol reaction between the resulting enolate and the aldehyde moiety. As shown in Scheme 10.26, the reaction afforded the highly functionalized spirocycles in excellent yields and stereoselectivities. 

The addition of sulfur nucleophiles to activated alkenes is a popular and valuable approach to the synthesis of sulfur-carbon(sp ) bonds. Due to the importance of the products, a vast array of catalysts and conditions have been developed to promote this reaction. One of the most direct approaches to these thia-Michael additions entailed simply stirring a thiol with the activated alkene in water (Scheme 5.4) [4]. This remarkably straightforward approach was also fast, and outstanding yields of a range of sulfides were obtained in less than 15 min. It should be noted that water was critical for the success of this reaction. Removing the water and performing the reaction under neat conditions was less successful. 

In addition to the chemistry described previously, a variety of enantioselective thia-Michael reactions have been developed [5]. An example of one of these approaches involved the addition of allyhc thiols to highly activated ketones using a thiourea organocatalyst (Scheme 5.5) [6]. This thia-Michael addition was carried out in a cascade process with another Michael addition to generate trisubstituted tetrahydrothiophenes under mild conditions. The reaction was highly enantioselective and high yielding. In related work. 

SCHEME 5.7 Organocatalyzed asymmetric thia-Michael addition reactions [8],... 

In addition to the thia-Michael chemistry described previously that was successful in water, a range of metal-catalyzed approaches were devised that used organic solvents. These approaches are important if the substrate undergoes secondary reactions in the presence of water. One of the metal-catalyzed approaches used an NHC-supported iron catalyst to promote a thia-Michael addition (Schane 5.9) [10]. The organic solvent played a critical role in... 

SCHEME 5.9 Iron-catalyzed thia-Michael additions [10]. 

SCHEME 5.10 Carbene-promoted thia-Michael addition reactions [11]. 

Need a thia-Michael addition that can tolerate air (oxygen)... 

Starting from a vinyl lactam and need Markovnikov selectivity Need an inexpensive metal to promote a thia-Michael addition reaction Need to make several sulfones, and it would be convenient to start from carboxylic acids... 

The iron-catalyzed thia-Michael addition to enones has been reported [10]. 

The second strategy to achieve the asymmetric protonation of double bonds through a conjugate addition is based on the use of a chiral proton source. This last strategy mainly focuses on the use of organocatalysts. This concept introduced by Pracejus et al. in 1977 in the course of thia-Michael addition to acceptor 98, mainly uses protic nucleophiles with low pKa such as thiol, a-ketoester, a-cyanoester, or secondary phosphine oxyde. ... 

Early in the 1990s, Kumar and co-workers described an asymmetric synthesis of (5)-naproxen by means of a thia-Michael addition of thiophenol to acrylate 115 (Scheme 31.39). Desulfurization followed by acid cleavage... 

Chen C, Lin Y, Liu C. Catal3dic carbon-sulfur bond formation by amphoteric vanadyl trifiate exploring with thia-Michael addition, thioacetalization, and transacetalization reactions. Tetrahedron 2009 65 10470-10476. 

Firouzabadi H, Iranpoor N, Abbasi M. A facile generation of C—S bonds via one-pot, odorless and efficient thia-Michael addition reactions using alkyl, aryl or aUyl halides, thiourea and electron-deficient alkenes in wet polyethylene glycol (PEG 200) under mild reaction conditions. Tetrahedron 2009 65 5293-5301. 

Scheme 3.29 Cinchona alkaloids catalyzed enantioselective thia-Michael addition of thiols to methyl 2-phthalimidoacrylate...

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