Transcript Nickel-Catalyzed Reductive Conjugate Addition to Enones

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
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1Taylor,
R. J. K., Synthesis, 1985, 364.
Y.; Nakamura, E.; Kuwajima, I., J. Org. Chem., 1986, 51, 4323.
2Horiguchi,
Conjugate Addition of Aryl & Vinyl Nucleophiles
• Trapping with chlorosilanes for subsequent regioselective
reactions
• α-hydroxylation1
• α-amination1
• α-arylation2
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1Smith,
2Su,
A. M. R.; Hii, K. K., Chem Rev, 2011, 111, 1637.
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
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1Fagnou,
K.; Lautens, M., Chem. Rev., 2003, 103, 169.
2Miyaura, N., Synlett, 2009, 2039.
• No trapping demonstrated
• Good functional group compatibility
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
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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.
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Conjugate Addition with Electrophilic Aryl Reagants (Reductive
Heck Reaction)
• Strengths:
• No preformed organometallic reagants
• Enantioselectivity has been shown with Pd catalyst
• Weaknesses
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Goal & Inspiration
• Combine the mildness of the reductive Heck reaction with the
ability to form silyl enol ether products
• Precedent with allylnickel (II) reagants1
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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
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Shrestha, R.; Weix, D. , J. Org. Chem., 2011, 13, 2766.
This work
• Includes aryl and vinyl halides
• Wide substrate scope
• Mechanistic study
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Optimization
• Ligands
• Bidentate ligands show
best results
• Substitution is important
• Electronics only play a
small role
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Optimization
• Silane reagant
• Trimethylsilyl = low
yield
• Large silicon groups
(TIPS & TBDPS) = low
yield
• TESCl, nPr3SiCl &
TBSCl show best
results
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Enone Scope
• 5- to 7- membered ring
enones
• Acyclic enones products
are formed with modest E:Z
Ratio (2:1 to 3:1)
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Arene Scope: electronic effects
• Electron-rich & electronpoor 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
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Arene Scope: functional group compatibility
• Bpin is tolerated under these
Conditions
• Compatible with high
oxidation-state sulfur
Compounds
• Compatible with hydrolyzable
groups (aryl ester & trifluoroacetamide)
• limitations found: Nitroarene &
heteroarenes (pyridine &
thiophene)
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Mechanistic Study
• The possible
pathways
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Mechanistic Study
• Monitoring MLCT band
• rapid coordination to TESCl & enone with TESCl
• slow coordination to iodobenzene and enone
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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.
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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
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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
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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
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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
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