2,2,2-Trichloroethyl Aryldiazoacetates as Robust Reagents for the Enantioselective C-H Functionalization of Methyl Ethers David M. Guptill and Huw M. L. Davies* Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States * S Supporting Information ABSTRACT: A new class of reagents is described for C- H functionalization by means of C-H insertion using donor/acceptor-substituted rhodium(II) carbene inter- mediates. The 2,2,2-trichloroethyl aryl and heteroaryl diazoacetates, together with the dirhodium triarylcyclo- propane carboxylate catalyst Rh 2 (R-BPCP) 4 , enabled the enantioselective intermolecular C-H functionalization of a range of methyl ethers with high levels of site selectivity and enantioselectivity. C-H Functionalization is rapidly becoming a powerful tool for the construction and modification of complex molecules. 1 Among the most challenging aspects of developing robust C- H functionalization methodologies is identifying catalyst and reagent combinations capable of site-selective as well as diastereo- and enantioselective reactions. 2 The rhodium- catalyzed reactions of donor/acceptor carbenes is an effective approach for site-selective sp 3 C-H functionalization, controlled by competing steric and electronic influences. 3,4 Since the reaction is initiated by a hydride transfer-type event, tertiary sites are electronically favored, but this is offset by the steric demands of the rhodium carbene complex. With the most widely used catalyst, Rh 2 (DOSP) 4 (Figure 1), the site selectivity typically favors secondary C-H bonds. 3d We are currently developing a toolbox of reagents/catalysts to expand the scope of reagent control in the site selectivity of C-H functionalization reactions. Recently, we reported a new family of sterically crowded catalysts, 5 including Rh 2 (BPCP) 4 and Rh 2 (BTPCP) 4 (Figure 1), that favors functionalization at primary benzylic C-H bonds over secondary and tertiary sites. 6 Despite these advances, numerous challenges remain (Scheme 1). 6 First, when the system was expanded to a methyl ether, the enantioselectivity dropped considerably. Second, an electron- withdrawing group on the benzene ring of the substrate causes it to be less reactive and resulted in a low yield of the C-H functionalization product. Third, when the substrate contained two benzylic C-H bonds with similar steric environments (such as in 4-ethyltoluene), a mixture of products was formed. For the C-H functionalization chemistry to become more broadly useful, these limitations need to be addressed. Herein, we report the discovery of the 2,2,2-trichloroethyl (TCE) aryldiazoacetates as a robust new class of reagents for carbene C-H functionalization. In order to demonstrate the synthetic potential of TCE aryldiazoacetates, we examined the intermolecular C-H functionalization of methyl ethers. Such a reaction can be considered, strategically, as a surrogate to an asymmetric aldol reaction with formaldehyde (an often challenging reaction), 7 followed by trapping with an alkyl halide (Scheme 2). Even though a few examples of inter- and intramolecular insertion of methyl ethers are known, 8,9 only two examples of enantiose- lective intermolecular reactions have been reported prior to our most recent work 6 and in those cases the substrates (tert-butyl methyl ether and dimethoxyethane) were used as solvent in the reaction. 10 The advantages of using TCE aryldiazoacetates were discovered during attempts to improve the site selectivity of C-H functionalization of tolyl derivatives by using larger ester groups. Simply using larger alkyl ester groups is not a viable strategy when attempting to conduct challenging intermolecular C-H insertion reactions because intramolecular C-H insertions into the ester group would become a competing trans- Received: October 19, 2014 Published: December 4, 2014 Figure 1. Dirhodium(II) tetracarboxylate catalysts. Scheme 1. Influence of Ester Group Scheme 2. Aldol/Alkylation Reaction Surrogate Communication pubs.acs.org/JACS © 2014 American Chemical Society 17718 dx.doi.org/10.1021/ja5107404 | J. Am. Chem. Soc. 2014, 136, 17718-17721