Literature Meeting Mylène de Léséleuc September 18, 2013 Nickel-Catalyzed Reductive Conjugate Addition to Enones via Allylnickel Intermediates Shrestha, R; Dorn, S. C. M.; Weix, D. J., J. Am. Chem. Soc., 2013, 135, 751-762 Literature Meeting Mylène de Léséleuc September 18, 2013

Conjugate Addition of Aryl & Vinyl Nucleophiles Importance in synthesis Can be used in the synthesis of prostaglandins1 Can be used in the synthesis of steroids2 1Taylor, R. J. K., Synthesis, 1985, 364. 2Horiguchi, Y.; Nakamura, E.; Kuwajima, I., J. Org. Chem., 1986, 51, 4323.

Conjugate Addition of Aryl & Vinyl Nucleophiles Trapping with chlorosilanes for subsequent regioselective reactions α-hydroxylation1 α-amination1 α-arylation2 1Smith, A. M. R.; Hii, K. K., Chem Rev, 2011, 111, 1637. 2Su, W.; Raders, S.; Verkade, J. G.; Liao, K.; Hartwig, J. F., Angew. Chem., Int. Ed., 2006, 45, 5852.

Conjugate Addition with Nucleophilic Aryl Reagants Examples Rh catalyzed1 Pd catalyzed2 No trapping demonstrated Good functional group compatibility 1Fagnou, K.; Lautens, M., Chem. Rev., 2003, 103, 169. 2Miyaura, N., Synlett, 2009, 2039.

Conjugate Addition with Nucleophilic Aryl Reagants Strengths of this method Good enantioselectivity Enolate trapping is possible when Cu or Ni catalysts are used Good functional group compatibility when Rh or Pd catalysts are used Weaknesses of this method Need to preform the organometallic reagants = extra synthetic steps Enolate trapping has not been demonstrated with the presence of Rh or Pd catalysts

Conjugate Addition with Electrophilic Aryl Reagants (Reductive Heck Reaction) Examples Pd catalyzed1 Co catalyzed2 Pd: electron-rich aryls only Co: no β-substitution on enone 1MInatti, A.; Zheng, X.; Buckwald S. L., J. Org. Chem., 2007, 72, 9253. 2Amatore, M.; Gosmini, C., Synlett, 2009, 1073.

Conjugate Addition with Electrophilic Aryl Reagants (Reductive Heck Reaction) Strengths: No preformed organometallic reagants Enantioselectivity has been shown with Pd catalyst Weaknesses

Goal & Inspiration Combine the mildness of the reductive Heck reaction with the ability to form silyl enol ether products Precedent with allylnickel (II) reagants1 1 Johnson, J. R.; Tully, P. S.; Mackenzie, P. B.; Sabat, M., J. Am. Chem. Soc., 1991, 113, 6172.

Previous Work Limited to unactivated alkyl halides Tridentate ligand Functional group tolerance limited to esters and nitriles Mechanism remains nebulous Shrestha, R.; Weix, D. , J. Org. Chem., 2011, 13, 2766.

This work Includes aryl and vinyl halides Wide substrate scope Mechanistic study

Optimization Ligands Bidentate ligands show best results Substitution is important Electronics only play a small role

Optimization Silane reagant Trimethylsilyl = low yield Large silicon groups (TIPS & TBDPS) = low TESCl, nPr3SiCl & TBSCl show best results

Enone Scope 5- to 7- membered ring enones Acyclic enones products are formed with modest E:Z Ratio (2:1 to 3:1)

Arene Scope: electronic effects Electron-rich & electron- poor arenes = good yield This method is complementary to the reductive Heck reaction which is limited to electron-rich aryl halides Ortho-substituted aryls give lower yields, but could be tuned by ligand

Arene Scope: functional group compatibility Bpin is tolerated under these Conditions Compatible with high oxidation-state sulfur Compounds Compatible with hydrolyzable groups (aryl ester & trifluoro- acetamide) limitations found: Nitroarene & heteroarenes (pyridine & thiophene)

Mechanistic Study The possible pathways

Mechanistic Study Monitoring MLCT band rapid coordination to TESCl & enone with TESCl slow coordination to iodobenzene and enone

Mechanistic Study Preparation of two possible intermediates and their viability Both solutions are stable for at least 10 minutes. Corresponding dimer products were observed beyond this time.

Mechanistic Study Reactions with Intermediate IA No desired product obtained with the addition of stochiometric amounts of enone and TESCl When excess amount of reagants are added, with a reductant: 1st turnover gives biaryl products, subsequent turnovers give desired product and enone dimer

Mechanistic Study Reactions with Intermediate IIA Low yield when PhI is added (stoich.) Increased yield when Mn is added Product obtained when TDAE is used instead of Mn Reaction with IA and IIA

Proposed Catalytic Cycle allylnickel intermediates are formed faster than arylnickel and alkylnickel species Only the allylnickel intermediates react to form the desired product Mechanism by which the allylnickel intermediates reacts with the phenylhalide is unknown

Conclusion New reductive conjugate addition of aryl halides, vinyl halides and alkyl halide to α,β-unsaturated ketones Superior functional group compatibility than previous methods Mechanism is not yet fully understood, but strong evidence for an ‘’enone-first’’ first step