Presented by: Anna Vlassova
Literature Meeting, March 14, 2012
OUTLINE
• NUCLEOPHILIC ORGANOCOPPER REAGENTS
• HISTORIC BACKGROUND
• STRUCTURES OF ORGANOCOPPER COMPOUNDS
 Cu(I)-Complexes
 Cu(I)-Aggregates
 Cu(III)-Complexes
• FUNDAMENTAL REACTIVITY OF ORGANOCOPPER COMPOUNDS
 Homocuprate Molecular Orbital Geometry
 Frontier Molecular Orbitals of Heterocuprates
 Frontier Molecular Orbital Interaction of Homocuprates with Electrophiles
2
OUTLINE
• REACTION MECHANISMS
 General Mechanism for RCu(I)-Mediated C-C Bond Formations
 Addition Reactions
 Carbocupration
 Conjugate addition
 Substitution Reactions
 Allylic substitution
 SN2
• CONCLUSION
3
Nucleophilic Organocopper(I) Reagents
• Delivery of carbanions to electrophilic substrates via:
 Conjugate addition
 Carbocupration
 Alkylation, Allylation, Alkenylation and Acylation
4
Historic Background
5
1940 – 1960
• 1941 – Kharasch and Tawney observe a conjugate addition reaction of a
Grignard with catalytic Cu(I) salt
Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308.
• 1952 – Gilman et al. report the synthesis of Me2CuLi – “Gilman Cuprate”
Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630.
• 1966 – Costa et al. perfect the formation and characterize PhCu(I)
Costa, G.; Camus, A.; Gatti, L.; Marsich, N. J. Organomet. Chem. 1966, 5, 568.
6
1960 – 1970
• 1966 – Whitesides et al. report a conjugate addition of Gilman cuprate to an
enone
 Gilman cuprate is the proposed reactive species
House, H. O.; Respess, W, L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128.
• 1967 – 1968 – Corey and Posner discover the coupling reaction of alkyl,
alkenyl, allyl and aryl halides with various organocuprates
Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911.
Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5302.
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1960 – 1980
• 1967 – Whitesides reports oxidative homocoupling of Gilman cuprates with O2
as the oxidant
Whitesides, G. M.; San Filippo, J., Jr.; Casey, C. P.; Panek, E. J. J. Am. Chem. Soc. 1967, 89, 5302.
• Mid 1970’s – further development of substitution reactions of alkyl, aryl
halides, alkyl tosylates, epoxides, allyl, propargyl and acyl electrophiles
• Addition reactions to electron-deficient and unactivated alkynes also achieved
• Synthesis of a mixed organocuprate R1R2CuLi, which allows selective
delivery of R1
• Isolation of a highly reactive cyano-Gilman cuprate R2CuLi * LiCN
Yoshikai, N,; Nakamura, E. Chem. Rev. DOI:10.1021/cr200241f
8
C-C Bond Formation with Directing Groups
via
Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett. 1997, 38, 8299 - 8302.
9
Development of Enantioselective Allylic Substitutions
and Conjugate Additions
Alexakis, A.; Backvall, J.-E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796.
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Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-756.
Development of Enantioselective Reductions via
CuH species
Preparation of Stryker’s Reagent
Catalytic Enantioselective 1,4 Reduction
Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916.
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Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273 - 1275.
Development of Enantioselective Reductions via
CuH species
Tandem Conjugate Reduction – Cyclization
Enantioselective 1,2 Reduction
Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743 - 5746.
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Mostefai, N.; Sirol, S.; Courmarcel, J.; Riant, O. Synthesis 2007, 1265 - 1271.
Materials Application
• 5-fold addition of an organocopper reagent vs monoaddition of a
Grignard or organolitium reagents
Sawamura, M.; Iikura, H.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 12850. 13
Structures of Organocopper Compounds
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Organocopper(I)ate Complexes (R2CuM)
Contact Ion Pair
(CIP)
•
•
•
•
•
R2CuLi*LiX
Solvent-Separated
Ion Pair (SSIP)
In a CIP, C-Cu bond is covalent, C-Li bond is largely ionic
In a SSIP, solvated Li-cation is separated from diorganocuprate cation
CIP is dominant in a weakly coordinating solvent – ex: Et2O
R2CuLi*LiX preferred in a more coordinating solvent ex: THF
Unreactive SSIP is observed in the presence of a Lewis base ex: crown ether
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Coordination of X to Lewis Acidic Countercation
(RXCuM)
• Non-transferable anions (X) facilitate the formation of aggregates by
bridging the Cu-atom with the main-group metal
• Halides and heteroatom anions possess lone pairs which can coordinate to
the cationic metal
• Cyanide and acetylide ligands have π-electrons available for interaction
with the metal (M+)
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.
16
Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941.
Organocopper(I)ate Complexes: Higher Aggregates
• THF induces aggregate dissociation while Et2O allows higher aggregation
• Steric hindrance affects aggregate formation
• LiCN as a salt will lead to higher aggregation
• Homodimer aggregates proposed as the most reactive species
Xie, X.; Auel, C.; Henze, W.; Gschwind, R. M. J. Am. Chem. Soc. 2003, 125, 1595. 17
Effect of Aggregates on Reactivity
• Crown ether, highly coordinating Lewis base, inhibits the formation of aggregates
• Mostly unreactive SSIPs present in solution
• Faster reaction in Et2O due to a more dominant presence of CIPs than in THF (a
more coordinating solvent)
Et2O: k1 = 1000 s-1, k-1= 10 s-1, k2 = 3.4 L mol-1 s-1
THF: k1 = 10 s-1, k-1= 1000 s-1, k2 = 3.4 L mol-1 s-1
Ouannes, C.; Dressaire, G.; Langlois, Y. Tetrahedron Lett. 1977, 815.
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Bertz, S. H.; Chopra, A.; Eriksson, M.; Ogle, C. A.; Seagle, P. Chem. – Eur. J. 1999, 5, 2680.
Effect of Solvent on Aggregate Dissociation
• Reaction rate increases with a small addition of THF to a solution of Et2O when
R2CuLi*LiI is the cuprate
• Reactivity decreases with addition of THF to Me2CuLi*LiCN in Et2O solvent
• Organocuprate reactivity correlates directly to the aggregate structures in solution
Yoshikai, N,; Nakamura, E. Chem. Rev. DOI:10.1021/cr200241f
19
Organocopper(III) Complexes
• Cu(III) species have been proposed as transient intermediates
• Neutral triorgano-Cu(III) complexes have a T-shaped
geometry and are kinetically unstable
• Addition of a ligand provides a more stable square-planar
complex
Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899.
Willertporada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc., Chem. Commun. 1989, 1633.
Naumann, D.; Roy, T.; Tebbe, K. F.; Crump, W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1482.
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Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem. 1996, 519, 7.
Organocopper(III) Complexes
• Trialkylcopper(III) species relevant to synthesis have been detected by RI-NMR
A
B
C
D
• A – Cu(III)-intermediate for conjugate addition to cyclohexenone
• B - Cu(III)-intermediate for substitution reactions
• C, D – π–allyl and σ-allyl Cu(III)-intermediates for allylic SN2 and SN2’
reactions
Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor, B. J. J. Am. Chem. Soc. 2007, 129, 7208.
Bertz, S. H.; Cope, S.; Dorton, D.; Murphy, M.; Ogle, C. A. Angew. Chem., Int. Ed. 2007, 46, 7082.
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Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A. J. Am. Chem. Soc. 2008, 130, 11244.
FUNDAMENTAL REACTIVITY OF ORGANOCOPPER
COMPOUNDS
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Homocuprate Molecular Orbital Geometry
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FMO of Heterocuprates
• In R(X)Cu- complexes, ligand X acts as a non-transferable dummy ligand
• Lower σ-donor ability of X, decreases the overall nucleophilicity of the
complex and causes desymmetrization of the HOMO
Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941.
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Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697.
FMO Interaction of Homocuprates with Electrophiles:
Carbocupration
• A bent geometry of the nucleophile is
needed for optimal orbital in-phase
interaction with the electrophile
• A cuprio-cyclopropane intermediate is
formed
Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805.
Mori, S.; Nakamura, E. J. Mol. Struct. (THEOCHEM) 1999, 461, 167.
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FMO Interaction of Homocuprates with Electrophiles:
SN2 Alkylation
• The ground state linear geometry of
organocuprate is required for an optimal
orbital interaction
• T-shaped Cu(III)-intermediate is formed
Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805.
Mori, S.; Nakamura, E. J. Mol. Struct. (THEOCHEM) 1999, 461, 167.
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FMO Interaction of Homocuprates with Electrophiles:
Allylic Substitution
• A new LUMO is created due to
C=C π* and C-X σ* mixing when
aligned
• In-phase mixing occurs between
Cu dxz HOMO and the electrophile
LUMO
• FMO interaction is the major
driving force for C-X bond
cleavage and reorganization of
the π-bond
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.
Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 12264.27
REACTION MECHANISMS
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General Mechanism of RCu(I)-Mediated C-C Bond
Formation
• Transmetalation and CuI/CuIII redox sequence is common to stoichiometric
and catalytic organocopper reactions
• Stoichiometry of R-M will determine the organocopper reactive species
Yoshikai, N,; Nakamura, E. Chem. Rev. DOI:10.1021/cr200241f
29
Addition Reactions
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Carbocupration of Acetylene with a Lithium
Organocuprate Cluster
• Carbocupration – addition of organocuprate across a C-C double or triple bond
• This reaction provides a reactive cis-alkenylcopper(I) species
Nakamura, E.; Mori, S.; Nakamura, M.; Morokuma, K. J. Am. Chem. Soc. 1997, 119, 4887.31
Carbocupration of Acetylenic Carbonyl Compounds:
Acetylenic Ester (Ynoate)
• Syn-carbocupration at low temperature provides the cis-product
• Non-stereoselective conjugate addition observed at higher temperatures and
in Et2O which affords the cis/trans product
Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N. Chem. - Eur. J. 1998, 4, 2051.
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Carbocupration of Acetylenic Carbonyl Compounds:
Acetylenic Ketone (Ynone)
• Carbocupration of an ynone provides an E/Z mixture of product
• This observation also supports a Li-allenolate intermediate
Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N. Chem. - Eur. J. 1998, 4, 2051.
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A Unified Mechanism Based on Computational
Predictions
• The alkenylcuprate product is more stable in the ynoate carbocupration
• In the ynone reaction, the alkenylcuprate and allenolate have the same stability
Mori, S.; Nakamura, E.; Morokuma, K. Organometallics 2004, 23, 1081.
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Conjugate Addition
• In the presence of an excess of cuprate, reaction was 1st order (cuprate
concentration had no effect)
• An intramolecular rate determining step was proposed
• Based on further KIE studies, it was determined that the C-C bond-forming
reductive elimination is the RDS
Canisius, J.; Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644. 35
Conjugate Addition: General Mechanism
β-cuprio(III)enolate
Yamanaka, M, Nakamura, E. Organometallics 2001, 20, 5675.
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Conjugate Addition: FMOs
• Cu(I) prefers to form a π-complex with a C=C bond rather than a C=O
• For reductive elimination, the Cu(III) has to recover its d-electrons from
the β-C bond
• This generates a vacant orbital on the β-C, which accepts the R ligand
Yoshikai, N,; Nakamura, E. Chem. Rev. DOI:10.1021/cr200241f
37
Conjugate Addition: Reductive Elimination
Colour Legend:
Green – Copper
Orange – Lithium
Dark Gray – Carbon
Light Gray – Hydrogen
Red - Oxygen
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Remote Conjugate Addition
• Several possible reactive positions lead to a low and unpredictable
regioselectivity
Exceptional Case
• In the case of polyenynyl compounds, conjugate addition occurs
exclusively at the terminal carbon
Marshall, J. A.; Ruden, R. A.; Hirsch, L. K.; Phillippe, M. Tetrahedron Lett. 1971, 3975.
Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019.
Wild, H.; Born, L. Angew. Chem., Int. Ed. Engl. 1991, 30, 1685.
Handke, G.; Krause, N. Tetrahedron Lett. 1993, 34, 6037.
Haubrich, A.; Vanklaveren, M.; Vankoten, G.; Handke, G.; Krause\, N. J. Org. Chem. 1993, 58, 5849.
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Proposed Mechanism Established by Theoretical
Studies
β-cuprio(III)enolate
σ/π-allenylcopper(III)
• Post oxidative addition the β-cuprio(III)enolate undergoes sequential
Cu(III)–migrations until the terminal alkyne
• The σ/π-allenylcopper(III) complex is kinetically unstable and rapidly
undergoes reductive elimination
Mori, S.; Uerdingen, M.; Krause, N.; Morokuma, K. Angew. Chem., Int. Ed. 2005, 44, 4715.
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Substitution Reactions
41
Allylic Substitution Reactions
• Several products are possible due to variable regioselectivity for the α or
the γ- position and the stereoselectivity, anti or syn to the leaving group
• The homocuprate provides no regioselectivity and anti-stereoselectivity
• The heterocuprate yields γ-regioselectivity and anti-stereoselectivity
General Trends
•Anti-selectivity is generally observed, however syn-SN2’ –selectivity can be
achieved when LG can chelate to Cu
•Regioselectivity and SN2’-selectivity depend on reagents and reaction
conditions
Goering, H. L.; Singleton, V. D. J. Org. Chem. 1983, 48, 1531.
42
Non-Regioselective Mechanism for Allyl Acetate
Substitution Based on Theoretical Studies
π-complex
ox. add. TS
π-allylcopper(III)
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.
43
The Reductive Elimination Step
π-allylcopper(III)
σ-allylcopper(III)
• For unsubstituted allylic electrophiles, reductive elimination has no
regioselectivity
• For substituted electrophiles, reductive elimination will preferentially occur at
the unsubstituted position and its rate will increase with an electron-donating
substituent
44
Reductive Elimination – MOs
donation
back-donation
desymmetrization
• Bonding interaction: allyl to Cu donation and Cu to allyl back-donation
• A desymmetrization to an enyl [σ+π]-type structure occurs in the TS
45
Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697.
Allylic Substitution with Heterocuprates
• Two diastereomeric pathways are possible for the oxidative addition of a
heterocuprate to an allyl acetate
favoured
disfavoured
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.
46
SN2 Alkylation Reactions
• SN2 alkylations will usually occur with inversion of configuration at the
electrophilic carbon center (except for secondary alkyl iodides)
• Exclusive formation of a cross-coupling product has been observed
• Lewis acidity of Li+ is important as reaction is slower in the presence
of crown ether
Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1998, 120, 8273.
47
SN2 Alkylation Reactions: Proposed Mechanism
• Presence of Li+ assists the R1-X bond cleavage
• The trans-relationship of the R-ligands of the cuprate is retained during ox. add.
• Cu(III)-complex features a cis-orientation of the R and R1 ligands which results in
exclusive formation of the cross-coupling product (R-R1) post red. elim.
Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, 7294-7307.
48
CONCLUSION
• Nucleophilic organocopper reagents have been in development since the
1940’s
• Structure of organocopper(I) and (III) species have been synthesized and
characterized, which provided support for proposed mechanisms and
helped determine the reactive species
• Aggregation plays an important role and may be influenced by solvent and
the chemical composition of the organocuprate
• Fundamental reactivity of organocuprates can be explained by molecular
orbital (MO) interactions between the nucleophile and the electrophile, as
well as the geometry of the Cu(I)-species
• Extended mechanistic studies led to the elucidation of the mechanisms for
several synthetically important reactions : carbocupration, conjugate
addition, allylic substitution and SN2 alkylations
49