Michael acceptors enones

With respect to the substrate scope, ketones are the most efficient nucleophiles although the intermolecular reaction works also well for esters, amides and Weinreb amides (Fig. 2.7). Regarding the Michael acceptor, enones are the best electrophiles with a wide range of substituents tolerated (alkyl, aryl and heteroaryl ketones). a,p-Unsaturated esters, in the case of the intermolecular cyclopropanation, and a,p-unsaturated diimides for the intramolecular reaction, extends the substrate scope of the process (Fig. 2.7). A transition state model for the intramolecular cyclopropanation reaction has been proposed as depicted in Scheme 2.38 for catalyst 65 [106d]. In this model the ammonium salt adopts a conformation that gives the Z-enolate of the nucleophile on deprotonation with the base. The intramolecular conjugate addition of the enolate then takes place through a boat-type transition state. 

The area of asymmetric Michael reaction of 1,3-dicarbonyl to enone can be simply divided into three types (Scheme 9.2). In type I, the Michael acceptor (enone) reacts with the prochiral Michael donor to induce a chiral center on the Michael donor side. In type II, the prochiral Michael acceptor reacts with the Michael donor to give an asymmetric center on the Michael acceptor side. For type III, the prochiral Michael acceptor reacts with the prochiral Michael donor to afford adjacent chiral centers on both sides in one step. Because (3-substituted enone is often used as a Michael acceptor in both type II and type III, the catalytic asymmetric Michael addition is generally divided into two classes 1) Michael addition of vinyl ketone and 2) Michael addition of (3-substituted enone. In the asymmetric Michael addition of class I, vinyl ketone is often employed as a Michael acceptor to react with (3-keto ester for... 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

Ye and co-workers have shown that NHC 67 can catalyse the aza-Morita-Bay-lis-Hillman reaction of enones 66 and N-tosyl imines 63, presumably via initial NHC conjugate addition to the enone to generate an azolium enolate 68 [18]. A related conjugate addition approach has been exploited by Fu and co-workers, with tautomerisation of the initial enolate 72 derived from NHC conjugate addition to 70 giving 73, with subsequent cyclisation resulting in the umpolung of Michael acceptors (Scheme 12.13) [19]. 

Conjugate addition [2] to Michael acceptors is the most important and useful reaction in organocopper chemistry, and the reaction is often used as the key step in the synthesis of numerous natural and unnatural products. Perhaps one of the most efficient methods for the synthesis of quaternary carbon centers is organo-copper-mediated conjugate addition to /I, yS-disubstituted enones. 

When cyclic enones were used as Michael acceptors, both malonates and acetoacetates gave impressive yields and enantioselectivities of the desired Michael addition products (Scheme 5.2Q) NMR spectra and single-crystal X-ray data supported the following ruthenium intermediate (Scheme 5.21) and transition state (Figure 5.8). 

E+ = RX RCHO R2CO RCOC1 enone a, -unsaturated esters Michael acceptors R3SiCl R... 

Conjugate additions of carbamates to a, P-unsaturated enones require - apart from metal halide - TMSC1 as a stoichiometric additive [96]. The addition of ethyl carbamate to cyclohexenone (41h) requires only 50mol% TMSC1, which was an exceptionally low amount compared with other Michael acceptors. With 10 mol% of the catalyst, the yield of 3-aminocyclohexenone derivative 66 was good (93%) [97], Aza-Michael reactions also proceed in aqueous media with good results if Co(II),... 

Enones with a pendant aldehyde, RC(=0)-CH=CH-(CH2)2-CH0, have been cyclized via an intramolecular MBH reaction in a study of the influence of Michael acceptor stereochemistry on yield.164 Using triphenylphosphine as catalyst, the Z-isomer consistently gave 2.5-8.5 times higher yield of the product (55), using reaction times of 1-3 days. It is unclear whether this is due to the relative accessibility of the /3-positions of the isomers to the nucleophilic catalyst, or differential stability in the enolate intermediates. 

A study of the effect of the Michael acceptor configuration on the efficiency of intramolecular Morita-Baylis-Hillman reactions has been performed. Enones containing a pendant aldehyde moiety attached at the -position of the alkene group were employed as substrates and the reactions were catalysed by a phosphine. In all cases examined, with Ph3P as the catalyst, cyclization of (Z)-alkene (117) gave 2.5-8.5 times higher yield than with the E-isomer (115) under identical reaction conditions, both affording the same product (116). Steric effects are believed to be the source of this difference in reactivity.172... 

This raises the regioselectivity question of whether the enolate will add in a conjugate (or Michael) fashion 5 or directly to the carbonyl group. We need to consider which types of enol(ate) and which types of enone (Michael acceptors) are good at conjugate rather than direct addition. 

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