Ylide compounds Michael additions

A second common reaction of sulphonium ylides is Michael addition to ajS-unsaturated carbonyl compounds, giving cyclopropanes. This reaction forms the basis of a cyclopentene synthesis starting from sulphonium allylide (14). Other recent examples include the preparation of spiro[cyclopropane-l,4-A -pyrazolin]-5 -one derivatives (15) and cyclopropyl-ulose (16). Un-... 

Triphenylphosphine gives Michael additions to the activated triple bond of acetylene dicarboxylic esters in presence of acidic compounds HY (Scheme 1). The reactions take place easily at room temperature, even at -10°C [1], through formation of intermediate activated vinylic phosphonium salts, which undergo a subsequent Michael addition of HY. The reactions afford various stabilized ylides which can be isolated in high yields or undergo possibly evolution, for example by intramolecular Wittig reaction [2]. 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

Unstabilized sulfonium ylides and stabilized sulfoxonium ylides show different reactions with a,P-unsaturated carbonyl compounds the former give epoxides and the latter give cyclopropanes. The epoxide formation (i.e. 1,2-addition) is kinetically favourable while cyclopropane formation (i.e. 1,4-addition, Michael addition) is energetically favourable. 

The Michael addition represents an extremely efficient synthetic method for achieving chain elongation by adding a three (or more) carbon fragment electrophile to a nucleophilic moiety. Notice that the typical Michael electrophiles (e.g. 90) are products of condensation of carbonyl compounds and can be easily formed via the aldol-like condensation, the Wittig reaction (with ylides like 81), the Perkin reaction, or the Mannich reaction (see below). 

Ylides can cyclopropanate unsaturated systems which are susceptible to Michael additions, i.e. a,jS-unsaturated ketones, esters, amides, nitriles, sulfones, sulfonamides, and nitro compounds. Enhancement of electron withdrawal from the carbon-carbon double bond facilitates the reaction. The reaction is non-stereospecific. The intermediacy of zwitterions has generally been accepted, and hence the stereochemistry of the product may be predictable on the basis of the stepwise mechanism. Namely, the Michael addition of the ylide will occur predominantly from the less hindered side of the double bond in a given molecule and the subsequent cyclization will take place in the conformation which minimizes the non-bonded repulsions. 

This reaction was first reported by Krohnke et al. in 1961. It is the synthesis of 2,4,6-trisubstituted pyridine derivatives involving the formation of pyridinium ylide from pyridine and a-bromoketone, which undergoes the 1,4-Michael addition to an a, -unsaturaled compound to form 1,5-dicarbonyl compounds and cyclizes with ammonium acetate. Therefore, it is generally known as the Krohnke pyridine synthesis or Krohnke reaction. In this reaction, the intermediate 1,5-dicarbonyl compounds do not need to be isolated from reaction mixture. Because three different substituents can be introduced into pyridine ring, this reaction becomes the ideal model for combinatorial synthesis, and a library pool containing pyridine from 9 to over 200 has been generated by this reaction. 

A broad range of enantiomericaUy pure 4,5-dihydrobenzo[r [l,3]diox-epines 177 have been prepared via a four-component Mannich reaction and subsequent intramolecular oxo-Michael reaction (14CC2196). The reactions proceeded with both high enantio- and diasteroselectivity, utilizing a dual catalytic system of Rh2(OAc)4 and a chiral phosphoric acid 178. The rhodium catalyst forms the protic oxonium ylide 174 from a diazo compound 171 and this subsequently adds to imine 175, formed in situ. The resulting enantiomericaUy enriched intermediate 176 then undergoes an intramolecular and diastereoselective oxo-Michael addition to form the final product 177. 

Later on, the same group developed another three-component reaction of diazo compounds with anilines and 4-oxo-enolates based on their previous work [44], By controlling the addition sequence of the substrates, this three-component reaction could proceed through an aza-Michael addition/ylide generation/intramolecular aldol... 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

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