Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylmetal Nucleophiles: Negishi Reactions of Racemic Benzylic

We have developed a nickel-catalyzed method for the asymmetric cross-coupling of secondary electrophiles with secondary nucleophiles, specifically, stereoconvergent Negishi reactions of racemic benzylic bromides with achiral cycloalkylzinc reagents. In contrast to most previous studies of enantioselective Negishi cross-couplings, tridentate pybox ligands are ineffective in this process; however, a new, readily available bidentate isoquinoline-oxazoline ligand furnishes excellent ee's and good yields. The use of acyclic alkylzinc reagents as coupling partners led to the discovery of a highly unusual isomerization that generates a significant quantity of a branched cross-coupling product from an unbranched nucleophile. In recent years, substantial progress has been made in the development of metal-catalyzed cross-couplings of alkyl electrophiles (generally primary or secondary) with alkyl nucleophiles (nearly all primary, with a limited number of secondary and tertiary).1,2 Furthermore, enantioselective variants of some alkyl–alkyl coupling processes have been described,3,4,5 although the success to date has been limited, with one exception,6 to reactions with primary alkyl nucleophiles. Expanding the scope of asymmetric processes to encompass secondary–secondary couplings is one of the key remaining objectives in this field. Herein, we report an advance toward that goal, specifically, enantioselective Negishi reactions of racemic secondary benzylic bromides with achiral secondary cycloalkylzinc reagents (eq 1). As indicated above, even non-asymmetric cross-couplings between two secondary partners are relatively uncommon;2 nevertheless, we decided to pursue the possibility of developing an enantioselective process. Due to the ready availability and the functional-group compatibility of organozinc reagents, we viewed them as particularly attractive coupling partners.7 Several years ago, we reported that a nickel/pybox catalyst can couple 1bromoindanes with primary alkylzinc reagents with good ee (eq 2);8 on the other hand, other benzylic bromides, including acyclic electrophiles, cross-couple with more modest Correspondence to: Gregory C. Fu. Corresponding [email protected]. Supporting Information. Experimental procedures and compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. The authors declare no competing financial interest. NIH Public Access Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2013 October 17. Published in final edited form as: J Am Chem Soc. 2012 October 17; 134(41): 17003–17006. doi:10.1021/ja308460z. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript enantioselectivity (<80% ee). Perhaps not surprisingly, an attempt to apply this method to the Negishi reaction of an acyclic benzylic bromide with a secondary alkyl-zinc reagent provided a disappointing result (eq 3).