Enantioselective Hydroalkenylation of Olefins with Enol Sulfonates Enabled by Dual Copper Hydride and Palladium Catalysis

Abstract

The catalytic enantioselective synthesis of α-chiral olefins represents a valuable strategy for rapid generation of structural diversity in divergent syntheses of complex targets. Herein, we report a protocol for the dual CuH-and Pd-catalyzed asymmetric Markovnikov hydroalkenylation of vinyl arenes and the anti-Markovnikov hydroalkenylation of unactivated olefins, in which readily available enol triflates can be utilized as alkenyl coupling partners. This method allowed for the synthesis of diverse αchiral olefins, including tri-and tetrasubstituted olefin products, which are challenging to prepare by existing approaches.

A Dual CuH- and Pd-Catalyzed Stereoselective Synthesis of Highly Substituted 1,3-Dienes

“…[42][43] Hydrocupration of an olefinic precursor results in a catalytically generated Cu(I) species (I) that can engage in bond-forming reactions with a range of electrophiles, including carbonyls, 44 heterocycles, [45][46] and LPd(II)-complexes. [47][48][49][50] However, the equivalent transformations employing alkyne pronucleophiles have been underexplored. [51][52][53][54][55][56][57][58][59][60] Recently, we developed a dual CuH-and Pd-catalyzed hydroalkenylation of olefins (Figure 1C), employing widely available enol sulfonates to synthesize highly substituted α-chiral olefins.…”

“…[51][52][53][54][55][56][57][58][59][60] Recently, we developed a dual CuH-and Pd-catalyzed hydroalkenylation of olefins (Figure 1C), employing widely available enol sulfonates to synthesize highly substituted α-chiral olefins. 50 We reasoned that an analogous approach to generate the otherwise elusive Z,E-and Z,Z-1,3-dienes could be realized by exploiting the syn-selective hydrocupration of alkynes and the rapid transmetalation of a vinyl-Cu(I) species (II) with an LPd(II)alkenyl complex. 60 We anticipated several specific challenges for the dual-catalytic alkyne hydroalkenylation (Figure 1D).…”

“…We reasoned that tuning the rates of the two catalytic cycles (e.g., hydrocupration, oxidative addition, transmetalation) would be crucial to suppress off-cycle reactivity and enable construction of the C-C bond at the resulting diene 2-position. 50 We focused on developing a set of dual-catalytic conditions for the stereoselective alkyne hydroalkenylation, using 1-phenyl-1hexyne (1a) as a model substrate and 1-cyclohexenyl trifluoromethanesulfonate (2a) as the alkenyl coupling partner (Table 1). 61 Utilizing our previously described reaction conditions for olefin hydroalkenylation, 50 we observed the Z-diene (3a) in moderate yield (entry 1, 33% yield, as determined by 1 H NMR).…”

“…50 We focused on developing a set of dual-catalytic conditions for the stereoselective alkyne hydroalkenylation, using 1-phenyl-1hexyne (1a) as a model substrate and 1-cyclohexenyl trifluoromethanesulfonate (2a) as the alkenyl coupling partner (Table 1). 61 Utilizing our previously described reaction conditions for olefin hydroalkenylation, 50 we observed the Z-diene (3a) in moderate yield (entry 1, 33% yield, as determined by 1 H NMR). Contrary to our olefin hydroalkenylation process, which was ineffective at room temperature, 50 we found that conducting the alkyne hydroalkenylation at room temperature resulted in moderate yield of 3a (entry 3).…”

Recent Advances in Mono‐ and Difunctionalization of Unactivated Olefins

“…An interesting dual CuHÀ and Pd catalyzed asymmetric Markovnikov hydro alkenylation protocol for the enantioselective synthesis of α-chiral olefins 152 from vinyl arenes and olefins was described by Buchwald et al (Scheme 61). [57] In this protocol, enol triflates were used as alkenyl coupling partners. This methodology successfully afforded various α-chiral olefins, including tri-and tetra substituted olefin products.…”