Palladium-Catalyzed Oxidative C(alkenyl)–H Activation and Asymmetric Alkene HydrocarbonationMingyu 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. Engle1*

1 Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037 USA2 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–Csingle bond length 1.47 Å).

Asymmetric Hydrocarbonation Background

• Enantioselective directed alkene (di)functionalization methods using alkene-facialdifferentiation have been developed in recent years.3,4

• Herein, enantiocontrol with prochiral nucleophiles is achieved by mergingtransition 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 thermodynamicallystable, the formation of the six-membered palladacycle (b) is more kineticallyfavored.

Product Transformations6,7

Non-Linear Effect

Financial Support

References

• C(alkenyl)–H activation was successful with “activated” alkenes, i.e. conjugatedalkenes, 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-Naphthoicacid instead of pivalic acid is necessary to reach high stereoselectivity with E alkenesubstrate.

Catalytic Cycle

Nucleophile Substituent Optimization

• The combination of C3-substituted CPA and C2-substituted azlactone provides theopportunity to tune the yield and enantioselectivity of the reaction.

• 4-Methoxyphenoxyphenyl (PPMP) group at C2 position of azlactone offers the bestyield and enantioselectivity. π-Stacking between azlactone and CPA is speculatedto 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.