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Lipshutz, B. H. Organocopper Chemistry, in Organometallics in Synthesis: A Manual, 2nd Ed; Schlosser, M., Ed.; Wiley: New York, 2002, pp 665–815.
Organocopper Chemistry
Have a great historical importance, but still remain highly useful reactions. If not the first organometallic reactions developed they are among the first.
Most often used in conjugate addition reactions and couplings with sp2 carbons, but are also quite useful in epoxide openings, SN2 and SN2' reactions, and alkyne addtions.
While there are a few generaliteis that can be made, this area is still quite empirical and experimentation is critical. Finding a close example in the literature is recommended.
We will discuss mechanism a bit, but the details are still debated and are not well understood.
Most reactions are still run with stoichiometric amounts of Cu, but catalytic methods are becoming more important.
Organocopper Chemistry – Initial Observations
Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308–2316.O
MeMeMe
MeMeMe
HO MeMeMgBr
Et2O5–12 ºC
91% 1,2-additionno 1,4-addition
MeMeMe
1 mol% CuClMeMgBr
Et2O5–12 ºC
O
Me83% 1,4-addition7% 1,2-addition
CuCl was unique, no other metal halide additive gave higher than ~5% 1,4-addition.
R1 MgX
Gilman, H.; Straley, J. M. Recl. Trav. Chim. Pays-Bas Belg. 1936, 55, 821–834.Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630–1634.
+ CuI R1 CuR2COCl
R2 R1
Olow to moderate
yieldsinsoluble1 equiv 1 equiv
Me Li + CuI
soluble2 equiv 1 equivMe2CuLi
Et2O
Et2O
Has since become known asthe Gilman reagent
Organocopper Chemistry – Key Rectivity Papers
Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911–3912.
House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128–3141.
Me2CuLiO
R
R
R
O
R
R
RMe
M
M = Li, MgBr, or Cu
O
R
R
RMe
OAc
R
R
RMe
Ac2Ohigh yields, with >99% 1,4-additionquick reaction times (<1 hr)
R IMe2CuLi
Et2OR Me
I
75%
Me
Br
75%
Me
89%Br Me
81%
Br Me
Lower Order Gilman Cuprates – R2CuLiSoluble, thermally unstable; typically generate in situ; often the "recipe" used to make the regent and/or react with substrate is critical to success; often discovered emperically
Because of low basicity, diorganocuprates undergo alkylation reactions with a variety of organic electrophiles; generally with high levels of inversion and little elimination; typically reacts in SN2' manner if available
primary > secondary > > tertiraryorder of reactivity
iodide > bromide > chloridealkenyl halides and triflates work as well, with retention of configuration (cis, trans)RCOCl > aldehydes > tosylates ~ epoxides > iodides > ketones > esters > nitriles
Some examples:
Can utilize and transfer virtually any sp2 or sp3 hybridized carbon
Me
OAc
Me
Me
Me2CuLi
J. Am. Chem. Soc. 1976, 98, 7854
Me OTrCl Cl
Me
Me OTr
Et Et Me
Me2CuLi
J. Am. Chem. Soc. 1970, 92, 737
Lower Order Gilman Cuprates – R2CuLiUndergoes conjugate addition reactions with α,β-unsaturated electrophiles; the intermediate enolate can be trapped with a variety of electrophiles
Ketones – most reactive, only slightly diminished rates with substitution at α or β positionEsters – less reactive than ketones, dramtically lower rates with substitution at α or β position
Sulfones are competent substrates; carboxylic acids do not react; amides and anhydrides have seen limited work; aldehydes see competing 1,2-addition
Esters – less reactive than ketones, dramtically lower rates with substitution at α or β position
Addition of phosphine lignads can often speed up troublesome reactions
Some examples:O
O
O
Bu3PCu (CH2)4CH3
OTBS
(CH2)3CO2MeI
O
O
O
(CH2)3CO2Me
(CH2)4CH3
TBSOJ. Am. Chem. Soc. 1988, 110, 4726
O
Me
H
OAc
O
Me
H
OAcMe2CuLi
Me
J. Org. Chem. 1971, 36, 877
Lower Order Mixed Cuprates – RtRrCuLiA major problem associated with Gilman-type organocuprate reagents is that they require two alkyl groups, but only transfer one. This is particularly problematic when wanting to transfer "precious" alkyl groups. Also can be quite unstable, so excess reagent often needed.
To address this problem modified reagents have been developed with one "transferable" group and one "residual" group. These are often stable at higher temps (–20 ºC and 0 ºC). Often the reactivity is altered (for better or worse) relative to Gilman-type reagents. Best to compare with known systems.
CuOt-BuRLi
RCu(Ot-Bu)LiCuSPhRLi
RCu(SPh)Li
lithium t-butoxy(alkyl)cupratelithium phenylthio(alkyl)cuprate
Can also have mixed "alkyl"cuprates with spectator ligands (these are most popular):
R C CLiCuI
R C C CuRLi
R C C Cu(R)Lilithium acetylide(alkyl)cuprate
CuI RLi
lithium 2-thienyl(alkyl)cuprate
S Li
2-thienyl lithium
S Cu S Cu(R)Li
Lower Order Mixed Cuprates – RtRrCuLi
Can also use P- and N-based ligands; these are especially stable (still reactive after 24 hrs @ rt)
Cy2NLiCuI
Cy2NCu RCu(NCy2)LiRLi
Cy2PLiCuI
Cy2PCu RCu(PCy2)LiRLi
J. Am. Chem. Soc. 1982, 104, 5824J. Org. Chem. 1984, 49, 1119
lower oder cyanocuprates, ease of preparation (start from CuCN), but less reactive than other mixed cuprates, but are quite useful in epoxide openings
CuCNRLi
RCu(CN)Li
"Higher order cyanocuprates" can be made by addition of two equivalents of RLi to CuCN; Brings reactivity mor ein line with Gilman reagents, but are still more stable
CuCN R2Cu(CN)Li2
RLi(2 equiv)
OTMS
O
R
OTMS
R
MeCu(CN)Li
OH
Me
J. Org. Chem. 1979, 44, 4467
Me
Additives – BF3•Et2OIf the cuprate of choice is unreactive at low temperature and especially unstable at higher temperatures, the use of BF3•Et2O or Me3SiCl may improve reactivity.
Me
O Me O Me
Me MeLiMe2CuBF3•Et2O
Et2O, –78 ºC71% yield, 2x
[R2CuLi]2 + 2 BF3 R3Cu2Li + +RLi•BF3 BF3
J. Am. Chem. Soc. 1989, 111, 1351
J. Org. Chem. 1982, 47, 1845
OO
H
MeMe
Me
HOO
H
MeMe
Hex
(Hex)2CuLiBF3•Et2O
Et2O, –78 to –55 ºC89% yield, 1 diastereomer
Tetrahedron Lett. 1984, 25, 3083
Additives – BF3•Et2O
R2Cu(CN)Li2 + RCu(CN)Li + RLi•BF3
J. Am. Chem. Soc. 1988, 110, 4834
with cyanocuprates the effect is more complex and likely involves coordination of the BF3 to the nitrile at some point.
BF3 R2Cu(CN–BF3)Li2
OPh2Cu(CN)Li2
BF3•Et2O
THF, –78 to –50 ºC>95% yield
O
Ph
Tetrahedron Lett. 1984, 25, 5959
CO2MeOTBS
OTs
CO2MeOTBSMe2Cu(CN)Li2
BF3•Et2O
MeJ. Am. Chem. Soc. 1986, 108, 7420
Additives – Me3SiClExactly how Me3SiCl modifies the Gilman reagents is debated; Me3SiBr can also be used and may give improved benefit
CHO
Bu2CuLiMe3SiCl, HMPA
THF, –70 ºC80% yield, 98:2 E:Z
Bu OTMS
Tetrahedron 1989, 45, 349
O
Me3Ge Cu(CN)Li
Me3SiBr, THF, –78 to –48 ºC83% yield
(34% yield with TMSCl) O
Me3Ge
Mechanistic StudiesThe question of how cuprates undergo 1,4-addition has been greatly depated over the years.
CuMe Me(I)
CuMe Me+(I)
O O.A.
OLi
CuMeMe(III)
R.E. O
MeCuMe(I)
+
Me2CuLi +
O
electrontransfer O
Me2Cu + Li+
O
Mechanism A
Mechanism B
π-complexes and Cu(III) intermediates have been observed by NMR, see:J. Am. Chem. Soc. 2002, 124, 13650J. Am. Chem. Soc. 2007, 129, 7208J. Am. Chem. Soc. 2007, 129, 11362
Mechanistic Studies – Evidence for Radical Pathway
Isomerization without conjugate addition
t-BuCO2t-Bu
<1 equivMe2CuLi
CO2t-But-Bu
t-Bu OLi
Ot-Buvia
Radical clocks
O
O
Me2CuLi
Me2CuLi
O
O
Me
Me
55%
43%
O
O
39%
49%
+
+
Et
1.3 x 108 s-1
Tetrahedron Lett. 1971, 2875.
Mechanistic Studies – Evidence for Radical Pathway
Radical clocks, cont'd
COt-Bu
Me Me2CuLi
COt-Bu
Me
Me
radical anion intermediate is very rapidly trapped by cuprate reagent, or mechanism change is occuring
Trapping of radical anion
O
OTs
Me2CuLi
O
Tetrahedron Lett. 1975, 187
no conjugate addition observed
Mechanistic Studies – Evidence for Radical Pathway
Reduction potentials
Me2CuLi Me2CuLi + e– Eox = –2.35 V
Ph Me
O
J. Am. Chem. Soc. 1972, 94, 5495
–1.63 V t-Bu
Me
O
–2.12 V
Substrates that react (78–98% yield) and their Ered
–2.20 VO
OMe Me OMe
O
–2.33 V
Substrates that don't react (>90% recovery) and their Ered
–2.43 V
OBu
Ot-Bu
OEt
O
–2.45 Vt-Bu
–2.50 V
CO2Me
Orbital PictureBoth conjugate additions and SN2' reactions can be explained by d→π* interactions
Tetrahedron Lett. 1984, 25, 3063
anti-SN2' in allylic systems
some SN2 character
cross-couplingreactions
addition to alkynes conjugate additions
electron repulsion in highly occupied d orbitals of Cu make them quite diffuse and sterically accessible
Transmetallation Onto Copper
"Functionalized" cuprates can be prepared through transmetallation routes
FG R XZn
FG R ZnX FG R Cu(R)ZnICuX
organozinc halide• compatible with many
different functional groups reactions
copper sources: CuCN•2LiCl, Cu(OTf)2, CuBr•SMe2compatibility of zinc species allows catalytic copper to be used in many cases
Transmetallation from other organometals (M=Sn, Zr, Al, Te) possible as well, many times Me2CuLi is used and Me serves as a spectator ligand
Bu3Sn Me2CuLi Li(Me)Cu
O
O
StereoselectionDiastereoselectivity can generally be predicted with existing models and chair-like transition states
3,4-selectivityO
R
R'2CuLi
O
RR'
O
RR'
+
major minor
OR
H
axial additionH
H
R O
Major
Minor
3,5-selectivityO
R'2CuLi
O
R'
O
R'+
major minorR R R
OR
O
H
R H
axial addition blockedboth conformations
approximately equal, but only one is reactive
H
StereoselectionFused rings
N
O
HN
O
H
Me2CuLiMe
O
Me
O
MeMe2CuLi
Me
OTHP OTHP
LiO
consider the radical anion intermediate
"Equitorial" approach favored by large nucleophiles (cuprates), but slowed by 1,2-torsional interactions Me
H
H
"Axial" approach disfavored by large nucleophiles due to 1,3-diaxial interactions
H
Stereoselectionexocyclic olefins
t-BuO
Me2CuLi
t-BuO
Me
EWG
H
t-Bu
HH
H preferred by large nucleophiles (cuprates)
acyclic electrophiles
Me CO2Et
NBn2
Me CO2Et
NBn2
R
>95:5
Bn
NBn2
H
CO2EtH
HBn
NBn2
H CO2EtH
H
Favored
R2CuLi
TMSClAngew. Chem. Int. Ed. Engl.
1989, 28, 1706
A1,2
