Palladium-Catalyzed Oxidative C(alkenyl)–H Activation and Asymmetric Alkene Hydrocarbonation Mingyu Liu , 1 Sri Krishna Nimmagadda, 1 Malkanthi K. Karunananda, 1 Pusu Yang, 1 Yanyan Wang, 2 De-Wei Gao, 1 Omar Apolinar, 1 Jason S. Chen, 1 Peng Liu, 2* Keary M. Engle 1* 1 Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037 USA 2 Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260 USA Oxidative C(alkenyl)–H Activation Background • A rare dimeric alkenyl palladium complex bridged by ϖ-coordination was characterized, featuring a short distance between the two vinyl carbons (1.55 Å, very close to a C–C single bond length 1.47 Å). Asymmetric Hydrocarbonation Background • Enantioselective directed alkene (di)functionalization methods using alkene-facial differentiation have been developed in recent years. 3,4 • Herein, enantiocontrol with prochiral nucleophiles is achieved by merging transition metal catalysis and asymmetric organocatalysis in a synergistic manner. 5 1. Shang, X.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42, 3253–3260. 2. Liu, M.; Yang, P.; Karunananda, M. K.; Wang, Y.; Liu, P.; Engle, K. M. J. Am. Chem. Soc. 2018, 140, 5805–5813. 3. Wang, H.; Bai, Z.; Jiao, T.; Deng, Z.; Tong, H.; He, G.; Peng, Q.; Chen, G. J. Am. Chem. Soc. 2018, 140, 3542–3546. 4. Liu, Z.; Li, X.; Tian, Z.; Engle, K. M. ACS Catal. 2019, 9, 3260–3265. 5. Nimmagadda, S. K.; Liu, M.; Karunananda, M. K.; Gao, D.-W.; Apolinar, O.; Chen, J. S.; Liu, P.; Engle, K. M. Angew. Chem. Int. Ed. 2019, 58, 3923–3927. 6. Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984–12986. 7. Zaitev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155. Representative Substrate Scope Dimeric Vinyl Palladium Complex Energy Profile of the C–H Activation Step Representative Substrate Scope • Sensitive to steric bulk on the alkene backbone. 5 • Allylation product (1,4-diene) was obtained using allyl acetate as coupling partner. • E/Z isomers were obtained at the acrylonitrile moiety (E:Z = 2.3:1). • No β-hydride elimination was observed when using vinyl ketone as coupling partners. As such, oxidant is not required. • The C–H activation step is rate-determining. 2 • Although the five-membered palladacycle (a) is the most thermodynamically stable, the formation of the six-membered palladacycle (b) is more kinetically favored. Product Transformations 6,7 Non-Linear Effect Financial Support References • C(alkenyl)–H activation was successful with “activated” alkenes, i.e. conjugated alkenes, enamines/enamides etc. and isolated alkenes with atypical carbon skeletons. 1 Tandem Alkene Isomerization and C–H Activation • In the cases where E alkene was used as starting material, lower temperature (50 °C) is required. • Acid additive is another major factor that affects the E/Z ratio of the product. 2-Naphthoic acid instead of pivalic acid is necessary to reach high stereoselectivity with E alkene substrate. Catalytic Cycle Nucleophile Substituent Optimization • The combination of C3-substituted CPA and C2-substituted azlactone provides the opportunity to tune the yield and enantioselectivity of the reaction. • 4-Methoxyphenoxyphenyl (PPMP) group at C2 position of azlactone offers the best yield and enantioselectivity. π-Stacking between azlactone and CPA is speculated to be involved. The Origin of Enantioselectivity by DFT Calculation • No erosion of ee was observed when the product was resubjected to reaction conditions. • Lack of non-linear effect suggests one CPA is bound during enantiodetermining step.