1. 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,
Literature Meeting
Mylène de Léséleuc
September 18, 2013

2. 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.

3. 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.

4. 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.

5. 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

6. 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.

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

8. 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.

9. 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.

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

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

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

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

14. 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

15. 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)

16. Mechanistic Study
The possible
pathways

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

18. 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.

19. 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

20. 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

21. 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

22. 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