Copper-Catalyzed Allylic Substitution Reactions

Knochel, P. Duebner, F. Copper-Catalyzed Enantioselective Allylic Substitution Reactions, PCT Int. Appl. 2000. 

Geurts K, Fletcher SP, van Zijl AW, Minnaaid AJ, Feiinga BL (2008) Copper catalyzed asymmetric allylic substitution reactions with organozinc and Grignaid reagents. Pure Appl Chem 80 1025-1037... 

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. 

In the 1952 paper mentioned above [3], Gilman reported on the formation of lithium dimethylcuprate from polymeric methylcopper and methyllithium. These so-called Gilman cuprates were later used for substitution reactions on both saturated [6] and unsaturated [7, 8, 9] substrates. The first example of a cuprate substitution on an allylic acetate (allylic ester) was reported in 1969 [8], while Schlosser reported the corresponding copper-catalyzed reaction between an allylic acetate and a Grignard reagent (Eq. 2) a few years later [10]. 

A copper-catalyzed reaction between the propargylamine 313 and the vinyl sulfone 314 provided the pyrrolidine 315 (Equation 93). Extension of this procedure with a palladium-catalyzed allylic substitution with phenols afforded a series of 4-(phenoxymethyl)-3-pyrrolines or their isomers <2002EJ01493>. 

AUylic substitution catalyzed by copper is a transformation that is related to ally-lie substitutions catalyzed by other transition metals discussed previously in this chapter, but several features of copper-catalyzed allylations make them worth differentiating. First, copper-catalyzed allylic substitutions are conducted with different types of nucleophiles tiian most allylic substitutions catalyzed by other metals. Second, the regioselectivity of the copper-catalyzed reactions is typically different from that of reactions catalyzed by complexes of other metals, particularly of reactions catalyzed by complexes of palladium. Thus, this last section of tiie chapter describes studies on allylic substitution catalyzed by copper, witii an emphasis on enantioselective examples. 

It may be concluded from die different examples sliown here tiiat die enantio-selective copper-catalyzed allylic substitution reaction needs ftirdier improvemetiL High enantioselectivities can be obtained if diirality is present in tiie leaving group of die substrate, but widi external diiral ligands, enantioselectivities in excess of 9096 ee have only been obtained in one system, limited to die introduction of die sterically hindered neopeatyl group. 

The method was later extended to the synthesis of a number of meroter-penoids from epoxygeranyl carbonates or acetates in a two-step approach combining titanocene catalysis with Stifle reactions (carbonates) [108,109] or copper-catalyzed allylic substitutions (acetates) [110-112], The cyclizations... 

The chloroacetoxylation reaction is synthetically useful since the chloride can be substituted with either retention [Pd(0)-catalyzed reaction] or inversion (Sjv2 reaction) by a number of nucleophiles. In this way both the cis and trans isomers are accessible and have been prepared from a number of allylic acetates (Schemes 5 and 6). In a subsequent reaction the allylic acetate can be substituted by employing a copper- or palladium-catalyzed reaction. The latter reactions are stereo specific. 

The moderate ees obtained with the copper arenethiolate ligands discussed above prompted a search for new chiral ligands for use in asymmetric allylic substitution reactions. The binaphthol-derived phosphoramidite ligand 32, used successfully by Feringa et al. in copper-catalyzed 1,4-addition reactions [37], was accordingly tested in the reaction between 21 and n-BuMgl. 

Allylic substitutions with nonstabilized C-nucleophiles are an important domain of organocopper chemistry [51]. However, on close inspection of the literature, it becomes apparent that regioselectivity in favor of the branched allylic alkylation products is only obtained with alkyl copper compounds, while aryl copper compounds mainly give the linear alkylation products. This observation was an incentive for Alexakis et al. [52] to probe the reactions of aryl zinc hahdes in the Ir-catalyzed allylic substitution (Scheme 9.18). 

Propargylic mesylates such as fluorine-substituted derivative 265 react with PhZnCl in the presence of Pd(PPh3)4 (5 mol%) in THF at 0°C within 2 h to provide the anti-Si 2 product in excellent yield and complete transfer of the stereochemistry leading to the allene 266 (Scheme 78). Copper(I) catalyzed allylic substitutions with functionalized diorganozincs proceed with high 8 2 selectivity. Thus, the reaction of the chiral allylic phosphate 267 with 3-carbethoxypropylzinc iodide in the presence of CuCN 2LiCl (2 equivalents) furnishes the awf/-Sjv2 substitution product 268 in 68% yield. By the addition of w-BuLi (1.2 equivalents) and TMSCl (1.5 equivalents), the bicyclic enone 269 is obtained in 75% yield and 93% ee (Scheme 79) . 

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