Cu-catalyzed conjugate addition

Simple acyclic a,/ -unsaturated esters are not reactive in the conjugate addition of dialkylzincs. In contrast, nitro-substituted unsaturated esters68 and malonates69 are applicable for this reaction. Using peptide-based chiral phosphine 66, Hird and Hoveyda realized the Cu-catalyzed conjugate addition of Et2Zn to iV-acyloxazolidinones with excellent enantioselectivity (Scheme 21).70... 

Alexakis et al. showed that under optimized experimental conditions, the enantioselectivity of the Cu-catalyzed conjugate addition of dialkylzinc to cyclic nitroolefin was improved to 95% with both (A,A)-55 and (R,S,S)-29.79,79a Biphenol-based phosphoramidite ligand (S,S)-55 also provided acyclic nitroalkenes adducts with 95-96% ee.42... 

An initial stndy demonstrated that Josiphos and its inverted analogue 11 were very effective in promoting the Cu-catalyzed conjugate addition of EtMgBr to unsaturated crotonates (Scheme 5). It is noteworthy that the use of sterically hindered esters, which nsnally helps to avoid nndesired 1,2-additions, or alternatives for esters such as an oxa-zolidinone, are not reqnired. Indeed, the highest conversions and stereoselectivities are obtained with methyl crotonate. ... 

Where possible, it may be most economical to effect a chiral transformation on a pre-formed, pro-chiral ring. Ben Feringa of the University of Groningen prepared (Chem Commun. 2005, 1711) the enone 2 from 4-methoxypyridine 1. Cu -catalyzed conjugate addition of dialkyl zincs to 2 proceeded in up 96% . Pd-mediated allylation of the intermediate zinc enolate led to 3, with the two alkyl subsituents exclusively trans to each other. 

Table 8 Cu-Catalyzed conjugate addition reaction with ligand L6 (6-12mol%) with ZnR2. Products were obtained with good to excellent diastereoselectivity favoring the anti diastereomer...

Pyridine amide, derived from (5)-desmethyl-MAP, induces high enantioselectivity in Cu-catalyzed conjugate addition of Et2Zn to enones (eq 10). ... 

Problem 6.11. Propose a mechanism for the following Cu-catalyzed conjugate addition. 

The synthesis was begun, as shown in Scheme 4.19, by the Cu -catalyzed conjugate addition of allyl Grignard reagent to (4- )-pulegone (86) (88%). Base-catalyzed equilibration afforded a mixture of diasteromers (85 15 trans cis) from which the major isomer 87 could be separated chromatographically. Stereospecific bishydroxylation from the si face of the allyl group then led to a 76% yield of hemiketal 88. 

Representative procedure for NHC-Cu-catalyzed conjugate addition of silyl substituted vinylaluminum reagents to unsaturated enones ... 

Scheme 11.1 Chiral Cu-catalyzed conjugate addition/electrophilic trapping sequence.

Organocatalytic asymmetric carbon-halogen bond-forming reactions have been combined with other catalytic asymmetric reactions in a single flask to effect cascade reactions. Quintard and Alexakis [78] developed a cascade reaction in which a Cu-catalyzed conjugate addition to an a,p-unsaturated aldehyde was followed by an enamine-catalyzed a-fluorination or chlorination. 

To extend the scope of the carbometallative aldol cycloreduction, the feasibility of Cu-catalyzed conjugate addition-aldol cyclization process was examined. Cu-catalyzed addition of organozinc compounds to o ,jS-unsaturated carbonyl compounds has been well established (169-171,187-189). Trapping of the Zn-enolates using aldehydes (169,188,190) and acetals/ketals (191) has been reported however, the use of ketones as electrophiles to trap Zn-enolates failed in the absence of strong Lewis acids (191). Rrische and co-workers reported the first successful example of Cu-catalyzed tandem conjugate addition-aldol cyclization with ketones, esters, and nitriles as electrophiles (Scheme 107) (192). In this cyclization process, enone-ketones 237 and 239 afforded products in good to excellent... 

Figure 5.24 Various types of chiral ligands used for the Cu-catalyzed conjugate addition of PhMgBr to enone substrates [104-107].

Though Cu-catalyzed addition of alkynes to electrophilic substrates such as imines has received considerable attention in the past decade, enantioselective methods for Cu-catalyzed conjugate addition of alkynes remain scarce. To this end, Carreira and co workers have developed an outstanding method for enantioselective... 

The bromination is directed into the -position in contrast to a with X = H and the Cu-catalyzed conjugate addition of benzyhnagnesium chloride takes place mainly with the para-position to give rise to 662. 

Stable precursors, such as boranes and silanes, were also shown to display good reactivity in NHC-Cu-catalyzed conjugated additions. The groups of Ohmiya and Sawamura reported the copper-catalyzed 1,4-addition of alkyl-boranes to enones, respectively in a racemic and enantioselective version. Organosilanes, te. RSiFj or RSi(OR )3, can also be used with NHC-Cu catalysts in conjugate addition to enones and allylic epoxides. ... 

The NHC-Cu-catalyzed conjugated addition of [B(pin)]2 on a,p-unsaturated carbonyl species has also been investigated. Perez and Fernandez initially reported the p-borylation of conjugated enals. Enantioselective versions of this transformation started to emerge afterwards, but the first methods that were developed exhibited only moderate ee s. Hoveyda and McQuade in 2010, and Song and Ma in 2015 reported a series of new NHC precursors that performed the same reaction on acrylates with high efficiency and selectivity (Scheme 11.6). Similar chiral NHCs were also used by Hoveyda and McQuade in the development of copper-catalyzed enantioselective allylic substitution using [B(pin)]2 as a formal pronucleophile. 

The Cu-catalyzed conjugate addition of organomanganese reagents to a,/3-ethyle-nic aldehydes gives similar results than those obtained via lithium organocuprates in the presence of trimethylchlorosilane (Scheme 13.41) [36]. However, the reaction is easier to carry out since the aldehyde is obtained in one step instead of the two steps required with an organocuprate. It is important since the partial aldoli-... 

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