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