presented by: anna vlassova literature meeting, march 14, 2012
TRANSCRIPT
Presented by: Anna Vlassova
Literature Meeting, March 14, 2012
2
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
3
OUTLINE
• REACTION MECHANISMS General Mechanism for RCu(I)-Mediated C-C Bond Formations Addition Reactions
Carbocupration Conjugate addition
Substitution Reactions Allylic substitution SN2
• CONCLUSION
Nucleophilic Organocopper(I) Reagents
CuI RMX+(excess)
M= Mg+2, Zn+2, Li+X= halide, heteroatom anion, CN
RCu/R2Cu- or R2CuM or RCu(X)M
R = alkyl, alkenyl, aryl simple organocopper
species
metal organocuprates
homocuprate heterocuprate
• 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
• 1952 – Gilman et al. report the synthesis of Me2CuLi – “Gilman Cuprate”
• 1966 – Costa et al. perfect the formation and characterize PhCu(I)
O
MeMgBr
CuCl (cat.)
O
Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308.
2MeLi 2CuCl2+ Cu2Cl2 + 2LiCl
Ethane
2MeLi 2CuCl2+ 2[MeCu] + 2LiCl
Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630.
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
O
+ Me2CuLi
OO LiH2O
NH4Cl
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
Br(nBu)2CuLi
80%
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.
7
1960 – 1980
• 1967 – Whitesides reports oxidative homocoupling of Gilman cuprates with O2
as the oxidant
• 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
2PhLi + [ICuPBu3]4THF, -78oC
Ph2CuLiO2, -78oC
75%
Whitesides, G. M.; San Filippo, J., Jr.; Casey, C. P.; Panek, E. J. J. Am. Chem. Soc. 1967, 89, 5302.
Yoshikai, N,; Nakamura, E. Chem. Rev. DOI:10.1021/cr200241f8
C-C Bond Formation with Directing Groups
O
TBSO
A= nBuCu(CN)Li
B= (nBu)2Cu(CN)Li2
O
TBSO nBu
+
O
TBSO nBuEt2O, -78oC
1>99 :
>99:2
A or B
92%
via
RO
A
[CuRLn]
O
cis
RO
B
trans
[CuRLn]
O
Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett. 1997, 38, 8299 - 8302. 9
Development of Enantioselective Allylic Substitutions and Conjugate Additions
Ph
CO2MeMeO2C
S
OTMS
tBu
[Cu]*
Ph
CO2MeMeO2C
S
O
tBu
*
OAcBuMgI
[Cu]*Bu
*
Alexakis, A.; Backvall, J.-E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796.
O1) Me2Zn, CuX (1 mol %)
Ligand 2 (2 mol %)
2) I (10 equiv.)HMPA (10 equiv.)
O O
O
Clavularin B80%, 97% ee
Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-756.10
PPh2
N
HN
O
MeMe
NHBu
O
Ph
Ligand 2
Development of Enantioselective Reductions via CuH species
Preparation of Stryker’s Reagent
CuX + MHLigand (L)
(L)CuH + MX
X= Cl, OAcM= H, SiR3, SnL = Phospine, NHC
Catalytic Enantioselective 1,4 Reduction
Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916.Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273 -
1275.
O
O
O
O
PAr2
PAr2
Ar = 3,5-tBu2-4-MeOC5H2
[(R)-DTBM-SEGPHOS]
Ligand A
OCuCl (1 mol %)
Ligand A (0.1 - 0.5 mol %)
NaOtBu (1 mol %)PMHS (2 equiv.)PhMe, -35oC, 3d
O
88%, 98.5% ee
11
Enantioselective 1,2 Reduction
F
O CuF(PPh3)3* 2MeOH (0.05 mol %)Ligand C (0.05 mol %)
PhSiH3 (1.2 equiv.)PhMe, -60oC, air F
OH
95%, 93% ee
PAr2
PAr2MeO
MeO
Ar= 3,5-tBu2-4-MeOC5H2
[(S)-Xyl-MeO-BIPHEP]
Ligand C
Tandem Conjugate Reduction – Cyclization
O O
OPhCu(OAc)2*H2O (5 mol %)
Ligand B (5 mol %)
TMDS (1 equiv.), THF
69%, 70% ee
O
O
HO
Ph
PAr2
PAr2MeO
MeO
Ar= 3,5-Me2C6H3
[(R)-Xyl-MeO-BIPHEP]
Ligand B
Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743 - 5746.Mostefai, N.; Sirol, S.; Courmarcel, J.; Riant, O. Synthesis 2007, 1265 - 1271.
Development of Enantioselective Reductions via CuH species
12
Materials Application
C60
1) PhMgBrCuBr*Me2SPhMe/THF-78oC -> rt
2) NH4Cl/H2OPh2CuMgBr1,4-bisaddition
Ph
Ph
Ph
PhPh
Ph
Ph
PhPh
Ph
Ph
CuPh
Ph
PhPh
Ph
Ph
H
NH4Cl/H2O
Sawamura, M.; Iikura, H.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 12850.
• 5-fold addition of an organocopper reagent vs monoaddition of a Grignard or organolitium reagents
13
Structures of Organocopper Compounds
14
Organocopper(I)ate Complexes (R2CuM)
Contact Ion Pair (CIP)
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
R2CuLi*LiX
CuI RR
Li Li
R RCuI
SS
R
CuI
R
Li*Sn
R RCuILi Li
X SS
15
Coordination of X to Lewis Acidic Countercation (RXCuM)
RCu
X
M
favoured
RCu
XM
less favoured
X = halide, NR2, SRR = alkyl, aryl
RCu
CX
X = N, CR
MR
CuC
M
X
favoured less favoured
R = alkyl, aryl
• 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+)
• Non-transferable anions (X) facilitate the formation of aggregates by bridging the Cu-atom with the main-group metal
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121,
8941.
16
Li
S
S
S
S
Cu RR
Cu RR
Li Li
R RCu
SS
SS
Cu RR
Li Li
R RCu
SS
SS
Cu RR
Li Li
R RCu
SS
THF Et2O
n-1
Xie, X.; Auel, C.; Henze, W.; Gschwind, R. M. J. Am. Chem. Soc. 2003, 125, 1595.
• THF induces aggregate dissociation while Et2O allows higher aggregation• Steric hindrance affects aggregate formation• LiCN as a salt will lead to higher aggregation
Cu RR
Li Li
R RCu
XS
SS
Cu RR
Li Li
R RCu
SXLi
S
SLi
SX
n-1
Cu RR
Li Li
R RCu
XX
SS
Cu RR
Li Li
R RCu
XX
Li
Li
Li
Li
S S
SS S
SS SS
S S Sn-1
X = I, CN
• Homodimer aggregates proposed as the most reactive species
Organocopper(I)ate Complexes: Higher Aggregates
17
• 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)
Effect of Aggregates on Reactivity
O
Me
Me2CuLi
O
Me
Me-50oC -> -78oCEt2O
90%with 12-crown-4 0%
Ouannes, C.; Dressaire, G.; Langlois, Y. Tetrahedron Lett. 1977, 815.
2 [R-Cu-R1]
CuI RR1
L L
R R1CuI
k1
k-1 k2
O
R
O
Bertz, S. H.; Chopra, A.; Eriksson, M.; Ogle, C. A.; Seagle, P. Chem. – Eur. J. 1999, 5, 2680.
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
18
Effect of Solvent on Aggregate Dissociation
Cu RR
Li Li
R RCu
IS
SS
LiS
S
addition of THFLi
S
I
S
S
Cu CH3H3C
Li Li
CH3 CH3Cu
SS
SS
Cu RR
Li Li
R RCu
NN
SN
Cu RR
Li Li
R RCu
NS
CLi
S
S S
C
C
Li
Li
S S S
SSS
CLi
S SS
Cu RR
Li Li
R RCu
NS
CLi
S SS
S
Saddition of THF
• 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/cr200241f19
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
CuIIIF3C
F3C
S
SNEt2 CuIII
CF3
F3C
CF3
CF3
-
CuIII
CF2H
HF2C
CF2H
CF2H
-
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. Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem. 1996, 519, 7.
NN
N
N N N
NCuIII
2+
2 ClO4-
Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899.
Cu
R
RR
• Addition of a ligand provides a more stable square-planar complex
20
• Trialkylcopper(III) species relevant to synthesis have been detected by RI-NMR
OTMS
CuIII
Me
CN
Me
Li+
CuIII
Me
Et
Me
X
Li+
X = I, CN, SCN, SPh, Me
CuIII
Me Me
CuIIIMe
X
MeLi+
X = CN, Me
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.
Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A. J. Am. Chem. Soc. 2008, 130, 11244.
Organocopper(III) Complexes
21
FUNDAMENTAL REACTIVITY OF ORGANOCOPPER COMPOUNDS
22
Homocuprate Molecular Orbital Geometry
23
H3C Cu CH3
H3CCu
CH3
FMO of Heterocuprates
• In R(X)Cu- complexes, ligand X acts as a non-transferable dummy ligand
Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941. Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697.
• Lower σ-donor ability of X, decreases the overall nucleophilicity of the complex and causes desymmetrization of the HOMO
24
FMO Interaction of Homocuprates with Electrophiles: Carbocupration
CuIIIR R
HH
H
RRCuI
H
HOMO
Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805.Mori, S.; Nakamura, E. J. Mol. Struct. (THEOCHEM) 1999, 461, 167.
25
HH
H
R
H
CuIR
R2CuM
• A bent geometry of the nucleophile is needed for optimal orbital in-phase interaction with the electrophile
• A cuprio-cyclopropane intermediate is formed
CuIIIR R
Me
R Me RCuI+
HOMO
Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805.Mori, S.; Nakamura, E. J. Mol. Struct. (THEOCHEM) 1999, 461, 167.
26
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
Xorbital
alignment
ineraction withnucleophile
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
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
28
REACTION MECHANISMS
General Mechanism of RCu(I)-Mediated C-C Bond Formation
Yoshikai, N,; Nakamura, E. Chem. Rev. DOI:10.1021/cr200241f
CuIXR-M
[RCuI(X)]-M+ [R2CuI]-M+
transmetalation
R-M
transmetalation
E+ oxidativeaddition
E+ oxidativeaddition
RCuIII(X)E R2CuIIIE
reductiveelimination
reductiveeliminationCuIRCuIX
R-E R-E
Gilman Cuprate
• Transmetalation and CuI/CuIII redox sequence is common to stoichiometric and catalytic organocopper reactions
• Stoichiometry of R-M will determine the organocopper reactive species
29
Addition Reactions
30
Carbocupration of Acetylene with a Lithium Organocuprate Cluster
Me MeCuILi Li
X
HH+
donation/back-donation CuIII
Me Me
HH
HH
LiMeCuIII
Me
Li LiX
CuIII
HH
Li
MeX
LiMe
cuprio(III)cyclopropene transient Cu(III) intermediate
X
Li
HH
LiCuI
Me
X
Li
Me
red. elim. TS transientMeCu + alkenyllithium
HHLi
CuIMe
X
LiMe
reductiveelimination transmetalation
alkenylcuprate(I)
Nakamura, E.; Mori, S.; Nakamura, M.; Morokuma, K. J. Am. Chem. Soc. 1997, 119, 4887.
31
• Carbocupration – addition of organocuprate across a C-C double or triple bond• This reaction provides a reactive cis-alkenylcopper(I) species
Carbocupration of Acetylenic Carbonyl Compounds: Acetylenic Ester (Ynoate)
O
MeO
R2CuLiRLiRCu
OMeO
H+
low. temp.
RH
OMeO
high
RMeO
LiO+
RCu
R
LiRCu
OMeO H+ R
H
OMeO
ex: 0oCtemp.
(ex: -78oC)
• 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, 2051.32
Carbocupration of Acetylenic Carbonyl Compounds: Acetylenic Ketone (Ynone)
O
Me
R2CuLi RMe
LiHO+
RCu
H+ R
H
OMe
Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N. Chem. - Eur. J. 1998, 4, 2051.
• Carbocupration of an ynone provides an E/Z mixture of product• This observation also supports a Li-allenolate intermediate
33
A Unified Mechanism Based on Computational Predictions
CuI RR
Y Li
Y = Li-Cl, Li-RCuR
CuIII
H
X
O
R RLi
Y
CuIII
H
X
O
RLi
Y
R
CuI
HX
O
R
Li
Y
R
alkenylcuprateH
RO
X
LiY R
CuIslow (X = alkoxy)
f ast (X = alkyl)
lithium allenolate
Mori, S.; Nakamura, E.; Morokuma, K. Organometallics 2004, 23, 1081.
• The alkenylcuprate product is more stable in the ynoate carbocupration
• In the ynone reaction, the alkenylcuprate and allenolate have the same stability
34
HOMO
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
Cu
O
+ Me2CuLi*LiI
(excess)
Et2O
-69oC ~ -58oC
OLi
Me
O Li
R
R
OLi
CuR2
slow
Canisius, J.; Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644.35
Conjugate Addition: General Mechanism
R
CuI
R
Li*Sn
CuI RR1
L L
R R1CuI
O
O H
H
CuIIIRR
LiRCu
RLi
r.d.s.O
HH
CuIII
R
LiRCu
RLi
R OH
H
CuIR
LiRCu
RLi
R
oxidativeaddition
reductiveelimination
Yamanaka, M, Nakamura, E. Organometallics 2001, 20, 5675.
β-cuprio(III)enolate
36
37
Conjugate Addition: FMOsR CuI R
O
oxidativeaddition
reductive elimination
ROCu
R
• 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
Conjugate Addition: Reductive Elimination
38
Colour Legend:Green – CopperOrange – LithiumDark Gray – CarbonLight Gray – HydrogenRed - Oxygen
Remote Conjugate Addition
39
R R
OR'2CuM
R R
O
R R
OR' R'
+
• Several possible reactive positions lead to a low and unpredictable regioselectivity
Exceptional Case
O
OEt
R n = 1, 2, 3
n1) Me2CuLi
2) H
O
OEt
n = 1, 2, 3
n
R
Me
• 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.
40
Proposed Mechanism Established by Theoretical Studies
CuIIIR1
O n
R2CuLiR1
LiO n
R R
migration of CuIII
R1
LiO n
CuIIIR
R
reductiveelimination
R1
LiO nR
oxidativeaddition
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.
Substitution Reactions
41
Allylic Substitution Reactions
42
Me
OAc 0oC
Me
Me
+
Me
Me
MeCu(CN)LiMe2CuLi
450 :
: 9650
• 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
Goering, H. L.; Singleton, V. D. J. Org. Chem. 1983, 48, 1531.
• 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
43
Non-Regioselective Mechanism for Allyl Acetate Substitution Based on Theoretical Studies
CuI RR1
Li Li
R R1CuI
OAc
+
CuIR
LiR
R
OMe
O
CuI
RLi
CuIR
LiR
R
OMe
O
CuI
RLi
R2CuLiLiOAc
CuIIIR R
R
R
oxidativeaddition
reductiveelimination
π-complex ox. add. TS
π-allylcopper(III)
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.
44
The Reductive Elimination Step
CuIIIR R
CuIIIR
R
CuIIIR R
L
RCuIR
CuIII
R
RL CuIII
R
RL
L+ L-
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
π-allylcopper(III)
45
Reductive Elimination – MOs
Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697.
CuIIIR R
CuIIIR
R1
231
2
3
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
46
Allylic Substitution with Heterocuprates
CuIIIR CN
CuIIIR CN
R CNCuI
OAc
+
OAc
CuIIINC R
OAc
OAc
OAc
CuIIINC R
R
R
• Two diastereomeric pathways are possible for the oxidative addition of a heterocuprate to an allyl acetate
Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862.
favoured disfavoured
SN2 Alkylation Reactions
47
LGR2CuLi
R
R2CuLi + R1 X R R1
• 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.
48
SN2 Alkylation Reactions: Proposed Mechanism
Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, 7294-7307.
R RCuILi Li
X R1 X
R RCuILi
XLi X
R1
R RCuILi
XLi
X
R1
R RCuIII
L
R1
R RCuIII
L
R1
R R1 R CuI L+
oxidativeaddition
reductiveelimination
HOMO
• 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.
49
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