Module 3
Organometallic Reagents
Lecture 23
3.3 Organocopper Reagents
Keywords: Nucleophile, Transmettalation, Addition, Carbonyl Compounds, C-C
Bond Formation, Heterocyclic Compounds
Organocopper reagents are prepared by transmetallating the organomagnesium, organolithium or
organozinc reagent with copper(I) salts (Scheme 1).
There are two major reactions with
organocuprates: (1) reaction with alkyl halides and (2) conjugate addition with -unsaturated
carbonyl compounds. The substitution reactions are promoted by the use of THF or ether-HMPA
solvent, while the conjugate addition is facile when ether is employed as a solvent. The general
reactivity of organocuprates with electrophiles follows the order:
RCOCl > R-CHO > R-OTs > R-I > R-Br > R-Cl > RCOR > R-CO2R' R-CN > RCH=CH2
R = alkyl, aryl or heteroaryl and can have remote functionaliyt such as ethers, aetal or ketals
RMgX
2RLi
2RMgX
CuI
RCu + MgXI
Transmetallation
CuI
R2CuLi + LiI (Gilman Cuprates)
CuI
R2CuMgX + MgXI (Normant Cuprates)
CuCN
RCu(CN)ZnX (Knochel Cuprates)
2RZnX
LiCl
Scheme 1
3.3.1 Reactions with Dialkylcuprates (Gilman Reagent)
3.3.1.1 Coupling Reactions
Organocuprates can replace halide ion from primary and secondary alkyl halides to give crosscoupled products (Scheme 2). This method provides effective route for the construction C-C
1
Module 3
Organometallic Reagents
bond between two different alkyl halides, which is not possible by the well known Wurtz
coupling reaction, in which a number of products are formed.
(Me)2CuLi
I
CuLi
2
Br
Me
CuLi
2
Br
Me
Me
CuLi
2
O
Br
O
Scheme 2
Similar results are obtained from the reactions of aryl halides and organocuprates (Scheme 4).
Me
I (Me) CuLi
2
Ph
I
Ph2CuLi
OMe
I
OMe
OMe
n-BuLi, CuI
OMe
Cu
I
pyridine, heat
(-LiI)
OMe
OMe OMe
OMe
OMe OMe
2
Module 3
Organometallic Reagents
Scheme 4
Examples:
OMe
O
OMe
t-BuLi, Li2CuCl4, THF
Br
OTBDMS
O
OTBDMS
OMe
Br
784%
OMe
M. Bogenstatter, A. Lmberg, L. E. Overman, A. L. Tomasi, J. Am. Chem. Soc. 1999, 121, 12206.
OMe
Me
Br
Cu
Me
+
Me
OMe
n-BuLi, THF
OTHP -105 oC
Me
CuLi
Me
Me
OTHP
Cl
N(Me)CO2Me
MeO
I
Cl
N(Me)CO2Me
MeO
Me
OTHP
E. J. Corey, H. F. Wetter, A. P. Kozikowski, A. V. R. Rao, Tetrahedron Lett. 1977, 777.
3.3.1.2 Reactions with Acid Chlorides
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Module 3
Organometallic Reagents
The reaction of a dialkyl cuprate and acid chloride is a preferred method to synthesize ketones
(Scheme 5). Unlike in the case of Grignard reagents, the ketones formed do not react with
organocopper reagent.
O
CuLi
2
O
MeO
Cl
O
O
MeO
O
COCl
(Me)2CuLi
NO2
NO2
O
O
Me
Me
Cl
Me
Me
O
t-BuS
O
Me
Et2CuLi
Me
O
-78 oC
t-BuS
O
O
O
Me
Me
Scheme 5
3.3.1.3 Conjugate Addition
Conjugate addition is among the basic carbon-carbon bond forming reactions. Traditionally,
organocopper reagents were choice to undergo this synthetic transformation. The organocopper
reagents are softer than Grignard reagents (because copper is less electropositive than
magnesium), and add in conjugate fashion to the softer C=C double bond.
The mechanism of the transfer of the alkyl group from the organocuprates to the β-position of the
carbonyl compounds is uncertain. It is believed that initially a d-π* complex between the
organocopper(I) species and the enone is formed followed by the formation of a Cu(III)
intermediate which may undergo reductive elimination to form the product (Scheme 6).
4
Module 3
Organometallic Reagents
O
(R2CuLi)2 +
R
Cu
Me
R
OLi.R2CuLi
OLi.R2CuLi
R
Li
Me
Me
Cu
Me
Li R
OH
R
CuR2
Me
R
O
Scheme 6
In the case of enones, consecutive addition of the organocopper reagent and alkyl halides, two
different alkyl groups can be introduced in one operation (Scheme 7).
O
OLi
Me
CuLi
O
Br
THF
Scheme 7
In case of conjugated esters, greater reactivity observed when RCu∙BF3 is as the organocopper
reagent.
Examples:
Me
Me
Me
Me2CuLi, ether
Me
Me
0 oC
Me
Me
O
O
G. H. Posner, Organic. React. 1972,19.
BnO
CO2Et
O
Me
CuLi
Me
2
CO2Et
BnO
-40 oC
O
O
O
K. C. Nicolaou, M. R. Pavia, S. P. Seitz, J. Am. Chem. Soc. 1982, 104, 2027.
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Module 3
Organometallic Reagents
3.3.1.4 Reactions with Aldehydes and Ketones
Organocuprates react with aldehydes to give alcohols in high yield (Scheme 8). In the presence
of chlorotrimethylsilane, the corresponding siliylenol ethers can be obtained.
Me
O
Me
CHO
O
Me
Me2CuLi
Me
OH
O
-70 oC
O
Me
anti:syn 30:1
Me
CHO
Ph
n-Bu2CuLi
OTMS
Ph
+
Me
Me
Me3SiCl
-70 oC
OTMS
64:1
THF
Scheme 8
The reaction of ketones with organocuprates is very sluggish. However, the reaction takes place
conveniently in the presence of chlorotrimethylsilane (Scheme 9).
O
Me
2 n-Bu2CuLi, THF Me
OTMS
Me3SiCl, -70 oC
Scheme 9
3.3.1.5 Reactions with Epoxides
The epoxide is attacked by organocopper reagents at the least substituted carbon atom giving the
corresponding alcohol (Scheme 10).
6
Module 3
Organometallic Reagents
Me2CuLi
O
H+
OH
major product
Scheme 10
3.3.2 Higher Order Mixed Cuprates
Cuprates are useful but there are a few problems associated with them. To overcome these
limitations, Lipshutz developed higher order mixed cuprates, R2Cu(CN)Li2, by the reaction of
organolithium reagent with cuprous cyanide (Scheme 11).
R2Cu(CN)Li2
2 R-Li + CuCN
Scheme 11
Higher order cuprates show greater reactivity compared Gilman reagents with alkyl halides, even
secondary halides. For example, (S)-2-bromooctane reacts with EtMeCu(CN)Li at 0 oC to give
(R)-3-methylnonane in 72% yield (Scheme 12).
H
Br
EtMeCu(CN)Li2
Et
H
THF, 0 oC
Scheme 12
Opening of epoxides ring is more efficient with the higher order cuprate than with Gilman
reagents, and attack takes place at the less sterically hindered carbon (Scheme 13).
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Module 3
Organometallic Reagents
Cu(CN)Li2
CuLi
OH
O
2
OH
2
ether, 0 oC, 16 h
THF, 0 oC, 6 h
30%
86%
Scheme 13
Higher order cuprates react with -unsaturated carbonyl compounds as Gilman reagent to
afford the addition product in excellent yield (Scheme 14).
O
H
O
H
t-BuO2C H
[MeC(=CH2)]2CuCNLi2
S
S
ether, -78 oC
t-BuO2C H
S
90%
Scheme 14
Examples:
8
S
Module 3
Organometallic Reagents
Me
Br
+
Br
Me2CuLi
Me
Me
Me
OH
Me
+
Me2CuLi
OH
Me
Me
I
Me
Me
HOH2C
O
OCH2Ph +
Me
HOH2C
Me2CuLi
OCH2Ph
OH
1,4-addition
C7H15
CO2Me
+
C7H15
Me2CuLi
CO2Me
Me
Me
OAc
+
Me
Me2CuLi
Reactions involving in situ genarated organocopper species
Me
Me
+
Br
Me
SN2' displacement
OTf
MeO2C
Li
CuI,THF
MeMgBr
CO2Me
CO2Et
MeO2C
+
BuMgCl
cat Li2CuCl4
THF,NMP
Problems
Predict the products of the following reactions
9
Bu
C7H15
CO2Me
CO2Et
CO2Me
Module 3
Organometallic Reagents
CuI
COOMe
A
LDA
B
MeI
MgBr
O
Ph2CuLi, TMSCl
Et
C
+
H /H2O
O
O
2CuLi
OMe
D
Me
2CuLi
I
Me
O
Me2CuLi
Me
E
F
Text Book
J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University Press,
2001.
10