Catalytic Conjugate Addition

I 70 Mechonlimi of Cofjfjer-medloted Addition ond tAbitittAtion Reactions 

Syntlietic cliemists can now work witli tlitee-dlmensional pictures of tlie conjugate addition available on a website [80]. In tlie absence of steric hindrance i5-nietliylcydobexenone, for example), an axial attack tlitougb a balf-diait conformation is favored, while in tlie corLisone syntliesis an equatorial attack tliroLigli a half-boat conformation is favored because of tlie constraint imposed by tlie bicydic tings [83]. 

There are a large number of reports on copper(I)-catalyzed conjugate additions, yet there is only scant information available about their reaction mechanisms. Recently, the conjugate addition of organozinc compounds to enones was found by Kitamura, Noyori, et al. to be catalyzed by N-benzylbenzenesulfonamide and CuCN, and the mechanism was scrutinized (Fig. 10.1). The kinetic rate was found to be first order in the concentrations of the catalyst that exist in equilibrium with R2Zn and enone [77]. 

In the enantioselective copper(I)-catalyzed conjugate addition of a cyclic enone with a chiral ligand, the observed nonlinear effects indicate that Cu(I) aggregates participate in the reaction [78]. 

---

Scheme 7.1. Catalytic conjugate addition and tandem conjugate addition.

Scheme 10.13. MeaSiCI- and BFa-accelerated catalytic conjugate addition and a cortisone synthesis.

Fig. 7 Proposed catalytic cycle for the amino catalytic conjugate addition enamine trapping sequence...

The use of organosilanes for rhodium-catalyzed conjugate addition is also feasible. In 2001, Mori reported that the catalytic conjugate addition of aryl(ethyl)silanediols to a,f -unsaturated carbonyl compounds takes place in the presence of [Rh(OH)(COD)]2 in a... 

Wittig reaction to give the desired Michael acceptor. A second catalytic conjugate addition using Josiphos or its enantiomer affords with excellent diastereoselectivities the syn- or awf/-l,3-dimethyl derivative. 

Since the previous review in this comprehensive book [1], the asymmetric catalytic conjugate additions of stabilized carbanions have made considerable advances. Publications between 1996 and early 2002 are summarized in this supplementary according to the same categorization as before. Several reviews have also appeared on this subject [2-4]. 

Suppl. to Chapter 31.2 Catalytic Conjugate Addition of Stabilized Carbanions... 

Multiple-component difunctionalization reactions of a,/ -unsaturated carbonyl systems have been achieved by catalytic conjugate addition/aldol sequences. As Scheme 8.13 illustrates, an efficient method reported by Montgomery [46] allows regioselective addition of an aryl iodide to the /i-position of an unsaturated ester under nickel catalysis and subsequent trapping with an aldehyde to give / -hydroxyesters (e.g. 33). Significantly, premature termination of the sequence by the /Miydride elimination process that is usually observed in Pd-catalyzed Heck reactions does not occur here. 

Highly enantioselective catalytic conjugate addition of A-heterocycles, namely purines, benztriazole, benzimidazole, and 5-phenyltetrazole, to a,ft-unsaturated ketones and imides has been attained with chiral, salen-type (Jacobsen) aluminium complexes as catalysts.142... 

Enantioselective catalytic conjugate addition of diethylzinc to chalcone using DBNE (Structure 1) as a chiral ligand27... 

The simply obtainable thiourea compounds 142-145 were the first organo-catalysts for the catalytic conjugate addition of indoles with nitroalkenes to yield optically active 2-indolyl-l-nitro derivative as 2.R-50 in fairly good yields and enantioselectivity. The simple thiourea-based organo catalyst 145 could be easily accessed in both enantiomeric forms from the commercially available materials. At the same time, the extremely simple methodology has proved the new approach useful for the synthesis of optically active target... 

In this area, Krische and co-workers have developed a family of catalytic transformations based on the use of enones as latent enolates. Nucleophilic activation of the enone is induced via carbometallation, nucleophilic organocatalysis or hydrometallation. The following examples illustrate some aspects of these new catalytic conjugate addition/electrophilic trapping reactions. 

SCHEME 40. Enantioselective catalytic conjugate addition of a thiophenolate on an enone with diastereocontrolled protonation of the intermediate enolate (Ar = o-TMS-C6H4)181... 

SCHEME 41. Enantioselective catalytic conjugate addition of a lithium peroxide on chalcone184... 

Myers MC, Bharadwaj AR, Milgram BC, Scheidt KA (2005) Catalytic conjugate additions of carbonyl anions under neutral aqueous conditions. I Am Chem Soc 127 14675-14680... 

High levels of enantioselectivity (94-98% ee) and good chemical yield (72-95%) were observed in the catalytic conjugate addition of dialkylzinc reagents to numerous cyclic enones (eq 1) using a catalyst prepared in situ from Cu(OTf)2 and this chiral phosphoramidite ligand. Here the steric properties of the substrate and the reagent appear to be unimportant. 

Catalytic Enantioselective Conjugate Addition of Dialkylzincs to Enones. A chiral nickel complex modified with DBNE and an achiral ligand such as 2,2 -bipyridyl in acetonitrile/toluene is an highly enantioselective catalyst for the addition of dialkylzincs to enones. p-Substituted ketones with up to 90% ee are obtained (eq 23). The method is the first highly enantioselective catalytic conjugate addition of an oiganometallic reagent to an enone. 

A highly enantioselective catalytic conjugate addition of iV-heterocycles including purines 76 to a,P-unsatured ketones and amides 77 has been developed to give 6,9-disubstituted purines 78 <05AG(E)2393>... 

Conjugate addition reactions are some of the most fundamental C-C bondforming reactions in organic synthesis, and their asymmetric versions have been studied extensively [ 1 ]. Treated in this chapter is the catalytic conjugate addition of stabihzed carbanions, especially enolate derivatives, for which the term Michael addition and/or reaction is used. The asymmetric Michael reactions can be categorized into two groups (Fig. 1) ... 

---