Download - Mechanistic Studies in Copper Catalysis
Mechanistic Studies in Copper Catalysis
Jen AllevaMay 1st 2013
Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Glaser, C. Ann. D. Chemie U. Pharm, 1869, 2, 137–171
1869
Glaser
first cross-couplings
General Historical Overview
Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Ullman, F. Ber. 1903, 36, 2382–2384Goldberg, I. Ber. 1906, 39, 1691–1692
1869
Glaser
first cross-couplings
General Historical Overview
Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem, 1952, 17, 1630–1634
1923 1952
Reich Gilman
synthesis of first copperorganometallic reagents
1869
Glaser
first cross-couplings
General Historical Overview
Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Huisgen, R. Proc. Chem Soc., 1961, 357–396
1923 1952
Reich Gilman
synthesis of first copperorganometallic reagents
1869
Glaser
first cross-couplings
Huisgen
1961
2001
Sharpless
"Click" Chemistry
General Historical Overview
Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Huisgen, R. Proc. Chem Soc., 1961, 357–396
1923 1952
Reich Gilman
synthesis of first copperorganometallic reagents
1869
Glaser
first cross-couplings
Huisgen
1961
2001
Sharpless
"Click" Chemistry
General Historical Overview
1998
Chan-Evans-LamCu C–N couplings
Copper in Cross-Coupling Reactions
Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
■ forms shorter bonds than Pd
■ harder Lewis acidity than Pd
■ higher affinity for O, N ligands
■ smaller coordination shell can notaccomodate large ancillary ligands
Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808
NNH N
H
R
CuIII
Br
Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
■ forms shorter bonds than Pd
■ harder Lewis acidity than Pd
■ higher affinity for O, N ligands
■ smaller coordination shell can notaccomodate large ancillary ligands
■ highly electrophilic and unstable
■ potent oxidizer
■ requires highly stabilizing ligands
Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808
Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
■ forms shorter bonds than Pd
■ harder Lewis acidity than Pd
■ higher affinity for O, N ligands
■ smaller coordination shell can notaccomodate large ancillary ligands
■ highly electrophilic and unstable
■ potent oxidizer
■ requires highly stabilizing ligands
■ unstable towards the reversereductive elimination
■ can not take part in ligand exchange
■ requires the nucleophile to be in thecoordination sphere prior to oxidativeaddition
Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808
Cross-Coupling Classifications
R1 XR2
HN
R3B ML X
R2N
R3BH
organic N–Hnucleophile
base
regular cross-coupling: transition metal mediated nucleophilic substitution
electrophile
R1
Cross-Coupling Classifications
R1 XR2
HN
R3B ML X
R2N
R3BH
organic N–Hnucleophile
base
regular cross-coupling: transition metal mediated nucleophilic substitution
electrophile
R1
Pd0/PdII
Pd0
PdIIR1 X
R1 X R2
HN
R3
B
PdIIR1 N R3
R2
R2N
R3
R1
BH
Cross-Coupling Classifications
R1 XR2
HN
R3B ML X
R2N
R3BH
organic N–Hnucleophile
base
regular cross-coupling: transition metal mediated nucleophilic substitution
electrophile
R1
Pd0/PdII CuI/CuIII
Pd0
PdIIR1 X
R1 X R2
HN
R3
B
PdIIR1 N R3
R2
R2N
R3
R1
BH
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
nucleophile plays the role of ancillary ligand in CuI/CuIII
Cross-Coupling Classifications
R1 MR2
HN
R3
ML MR2
NR3
M
organic N–Hnucleophile
oxidative cross-coupling: transition metal mediated coupling of two nucleophiles
nucleophile
R1
–2e–
Cross-Coupling Classifications
R1 MR2
HN
R3
ML MR2
NR3
M
organic N–Hnucleophile
oxidative cross-coupling: transition metal mediated coupling of two nucleophiles
nucleophile
R1
PdII/PdIV
PdIIR1 M
R1 M R2
HN
R3
PdIIR1 N R3
R2
R2N
R3
R1
–2e–
PdII
PdIVR1 N R3
R2
O2
Cross-Coupling Classifications
R1 MR2
HN
R3
ML MR2
NR3
M
organic N–Hnucleophile
oxidative cross-coupling: transition metal mediated coupling of two nucleophiles
nucleophile
R1
PdII/PdIV CuI/CuII/CuIII
PdIIR1 M
R1 M R2
HN
R3
PdIIR1 N R3
R2
R2N
R3
R1
CuII
R2
HN
R3
CuIINR3
R2
R1 X
CuIINR3
R2
R1
R2N
R3
R1
–2e–
PdII
CuI
CuII
CuIIINR3
R2
R1
O2
PdIVR1 N R3
R2
O2
Cross-Coupling Classifications
R1 XR2
NR3
MLLG
R2N
R3
organic N–Helectrophile
inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution
nucleophile
R1LG
nucleofugal leavinggroup
Cross-Coupling Classifications
R1 XR2
NR3
MLLG
R2N
R3
organic N–Helectrophile
inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution
nucleophile
R1
Pd0/PdII
Pd0
PdIIN LG
R1 X
PdIIR1 N R3
R2
R2N
R3
R1
LG
R2N
R3
LG R3
R2
nucleofugal leavinggroup
Cross-Coupling Classifications
R1 XR2
NR3
MLLG
R2N
R3
organic N–Helectrophile
inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution
nucleophile
R1
Pd0/PdII CuI/CuIII
Pd0
PdIIN LG
R1 X
PdIIR1 N R3
R2
R2N
R3
R1
CuI
CuIR1 X
CuIIINR3
R2
R1
R2N
R3
R1
LG
R2N
R3
LG R3
R2
nucleofugal leavinggroup
R2N
R3
LGR1 X
Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
Mechanistic Studies in Copper Catalysis
Shannon Stahl Xavi Ribas Ted Cohen
Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
Chan-Evans-Lam Couplingoxidative cross-coupling
OH
Me
BHO OH
2 equiv. Cu(OAc)2
4Å mol sieves, O2EtOAc
O
Me
heteroatom boronic acid diaryl ether
Chan D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933.Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. T., Combs, A. Tetrahedron Lett. 1998, 39, 2941.
nucleophile
Chan-Evans-Lam Couplingoxidative cross-coupling
OH
Me
BHO OH
2 equiv. Cu(OAc)2
4Å mol sieves, O2EtOAc
O
Me
heteroatom boronic acid diaryl ethernucleophile
CuI/CuII/CuIIICuII
R2
HN
R3
CuIINR3
R2
R1 X
CuIINR3
R2
R1
R2N
R3
R1
CuI
CuII
CuIIINR3
R2
R1
O2
CEL is stoichiometric in CuII
can be made catalytic with anadded oxidant
Chan-Evans-Lam Couplingselect catalytic methods
BHO OH
N
HN 20 mol% [Cu(OH)•TMEDA]2Cl2
CH2Cl2, O2, r.t.
NN 72%
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236
Chan-Evans-Lam Couplingselect catalytic methods
NNH2
O
Si(OMe)31.1 equiv Cu(OAc)2
TBAF, DMF, O2, r.t.N
HN
O
61%
Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429
BHO OH
N
HN 20 mol% [Cu(OH)•TMEDA]2Cl2
CH2Cl2, O2, r.t.
NN 72%
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236
Chan-Evans-Lam Couplingselect catalytic methods
NNH2
O
Si(OMe)31.1 equiv Cu(OAc)2
TBAF, DMF, O2, r.t.N
HN
O
61%
Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429
BHO OH
N
HN 20 mol% [Cu(OH)•TMEDA]2Cl2
CH2Cl2, O2, r.t.
NN 72%
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236
5 mol% Cu(OAc)2
2,6-lutidine, PhMe, r.t.
BHO OHNH2
10 mol% myristic acid
HN
91%
Antilla, J. C.; Buchwald, S. L. Org Lett, 2001, 3, 2077–2079
Chan-Evans-Lam Couplingdetermining reaction stoichiometry
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Chan-Evans-Lam Couplingdetermining reaction stoichiometry
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Cu and O2 stoichiometry determined from anaerobic single-turnover experiment
CuII/product ratio is 2:1
Chan-Evans-Lam Couplingdetermining reaction stoichiometry
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Cu and O2 stoichiometry determined from anaerobic single-turnover experiment
CuII/product ratio is 2:1 CuI/O2 ratio is 4:1
result consistent withCu oxidase mechanism
Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Initial rates experiment: suggest transmetalation as turnover-limiting
Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Initial rates experiment: suggest transmetalation as turnover-limiting
■ 1st order dependence on Cu(OAc)2
■ saturation dependence on boronic ester
Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Initial rates experiment: suggest transmetalation as turnover-limiting
■ 1st order dependence on Cu(OAc)2
■ saturation dependence on boronic ester
■ 0 order dependence on O2
CuI oxidation is relativelyfast compared totransmetalation
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
ground state
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
gobs: empirical value from spectrum
ge: energy of free electron (2.00023)
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
gobs: empirical value from spectrum
ge: energy of free electron (2.00023)
x: modification factor of the free electron based on orbital mixing
Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
gobs: empirical value from spectrum
ge: energy of free electron (2.00023)
x: modification factor of the free electron based on orbital mixing
λ: spin orbit coupling constant
ΔE: energy between two orbitals
Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
EPR spectroscopy shows catalyst resting state as CuII
no strong field aryl ligand evidentconsistent with transmetalation being as
turnover-limiting
reaction progress correlated withEPR spectra
Chan-Evans-Lam Couplingequilibrium prior to transmetalation
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
Chan-Evans-Lam Couplingequilibrium prior to transmetalation
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
deviation from standard conditions effect on efficiency
added acetate
added acetic acid
Cu(ClO4)2 instead of Cu(OAc)2
inhibition
inhibition
no reactivity
Chan-Evans-Lam Couplingequilibrium prior to transmetalation
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
deviation from standard conditions effect on efficiency
added acetate
added acetic acid
Cu(ClO4)2 instead of Cu(OAc)2
Cu(ClO4)2 + 1 equiv NaOAc
Cu(ClO4)2 + 1 equiv NaOMe
inhibition
inhibition
no reactivity
rate acceleration
rate acceleration
Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signals appears after addition of boronic ester
Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signals appears after addition of boronic esterexhibits a saturation depedence on
concentration of ester
Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
acetic acid additive sodium acetate additive
both display an inhibitory effect on EPR signalsuggesting that paddlewheel structure is stabilized
Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signal obtained immediately after mixingCu(OAc)2 and boronic ester displays two species
Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signal obtained immediately after mixingCu(OAc)2 and boronic ester displays two species
relative concentrations of the two species are alteredby the addition of additives
Chan-Evans-Lam Couplingmechanism of transmetalation
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
BMeO OMe
1/2[Cu(OAc)2]2Me
O
O
CuII(OAc)
BOMe
OMeMe
O
O
CuII
BOMe
OMe
–OAc
inhibitory effect of addedacetate
Chan-Evans-Lam Couplingmechanism of transmetalation
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
BMeO OMe
1/2[Cu(OAc)2]2Me
O
O
CuII(OAc)
BOMe
OMeMe
O
O
CuII
BOMe
OMe
–OAc
MeO
O
CuII
BOMe
OMe MeOH OB
CuII
MeOMe
OMe
–HOAc
inhibitory effect of addedacetic acid
Chan-Evans-Lam Couplingmechanism of transmetalation
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
BMeO OMe
1/2[Cu(OAc)2]2Me
O
O
CuII(OAc)
BOMe
OMeMe
O
O
CuII
BOMe
OMe
–OAc
MeO
O
CuII
BOMe
OMe MeOH OB
CuII
MeOMe
OMe
–HOAc
inhibitory effect of addedacetic acid
BOMe
OMe
MeO
irreversibletransmetalation
aryl Cu(II)
CuII
Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OH
Me
Cu(II)
OCu(II)
Menucleophile coordination
Copper Oxidasemechanism
lowersCuII/CuIII redox potential
Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
O Cu(II)
Me
Me
nucleophile coordination
transmetalation
Copper Oxidasemechanism
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
Cu(II)
Cu(I)
O Cu(II)
Me
Me
O Cu(III)
Me
nucleophile coordination
transmetalation
Copper Oxidasemechanism
Oxidation to Cu(III)
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
stoichiometry determinedfrom single turnover
experiment
Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
Cu(II)
Cu(I)
O Cu(II)
Me
Me
O Cu(III)
Me
O
Me
Cu(I)
nucleophile coordination
transmetalation
Copper Oxidasemechanism
reductive eliminationOxidation to Cu(III)
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
stoichiometry determinedfrom single turnover
experiment
Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
Cu(II)
Cu(I)
O Cu(II)
Me
Me
O Cu(III)
Me
O
Me
Cu(I)
O2
H2O
nucleophile coordination
transmetalation
Copper Oxidasemechanism
reductive eliminationOxidation to Cu(III)
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
stoichiometry determinedfrom single turnover
experiment
stoichiometry determinedfrom single turnover
experiment
Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
Ullmann-Goldberg Reaction
Classic Ullmann-Goldberg reaction
cross-coupling reaction mediated by CuI/CuIII redox cycle
X
X = Br, Cl, I2 equiv.
2 equiv. CuIL
symmetric biaryl bond
Ullmann-Goldberg Reaction
X
H NuCuIL
Nu
X H
Classic Ullmann-Goldberg reaction
Ullmann-type coupling
cross-coupling reaction mediated by CuI/CuIII redox cycle
X
X = Br, Cl, I
X = Br, Cl, I2 equiv.
2 equiv. CuIL
symmetric biaryl bond
C–heteroatom bond
Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
CuI
nucleophile coordination/deprotonation
CuI
R1
HN
R2
NR2
R1
proposedmechanism
Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
CuI
nucleophile coordination/deprotonation
CuI
R1
HN
R2
NR2
R1
X
NCuIIIR1
R2
oxidative additionreversible
proposedmechanism
Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
CuI
nucleophile coordination/deprotonation
CuI
R1
HN
R2
NR2
R1
X
NCuIIIR1
R2
oxidative addition
reductive elimination
NR2
R1
reversible
proposedmechanism
Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
NCuIIIR1
R2
putative aryl CuIII
■ CuIII has been widely proposed as an intermediate
■ oxidative addition product has never been observed
■ oxidative addition to Cu has no precedent
Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
NCuIIIR1
R2
putative aryl CuIII
NNH N
H
R
X
utilization of constrainingmacrocyclic ligands
UV-Vis spectroscopy (NMR, CV, X-ray) kinetics
Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition
NO2
Br
CuOTf, aq. NH3
acetone
NO2
O2N
NO2
Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753
Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition
NO2
Br
CuOTf, aq. NH3
acetone
NO2
O2N
NO2
Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753
formation of 2, 2'-dinitro-biphenyl:
NO2
BrCuOTf
2nd order dependence 1st order
formation of nitrobenzene:
NO2
BrCuOTf
1st order1st order
Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition
NO2
Br
CuOTf, aq. NH3
acetone
NO2
O2N
NO2
Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753
NO2
Br
Cu OTf CuIIIBr
NO2k1
k–1
CuIIIBr
NO2NO2
Br
k2
NO2
O2N
Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H
Ribas and Stahl's strategy:
X Cu X NNH N
H
R
CuIII
x
X CuI
highly constrained and stabilizedaryl CuIII species
macrocyclic ligand shown toundergo C–H insertion with Cu
Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H
Ribas and Stahl's strategy:
X Cu X NNH N
H
R
CuIII
x
X CuI
highly constrained and stabilizedaryl CuIII species
macrocyclic ligand shown toundergo C–H insertion with Cu
■ allows for characterization by 1H NMR, CV and UV-Vis
■ allows for study of reductive elmination
Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
X
Ribas and Stahl's strategy:
NNH N
H
R
CuIII
xX CuI
NH
O
Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
X
Ribas and Stahl's strategy:
NNH N
H
R
CuIII
xX CuI
■ allows for study of oxidative addition
■ allows for study of mechanism of C–N bond formation
NH
O
Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
electronic spectra (LMCT): agrees with ligand field strengths of the halides
369 and 521 nm 399 and 550 nm 422 and 635 nm
Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
cyclic voltammetry: values for CuIII/CuII redox couple
–330mV –310mV –300mV
Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xN
NH N
H
R
Cl
CuCl2 HOTf (1.5-10 equiv)
MeCN, 298K<1hr
quantitative
Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xN
NH N
H
R
Cl
CuCl2 HOTf (1.5-10 equiv)
MeCN, 298K<1hr
quantitative
Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xN
NH N
H
R
Cl
CuCl2 HOTf (1.5-10 equiv)
MeCN, 298K<1hr
quantitative
NNH N
H
R
CuIII
x
complexX R E1/2 (mV) kobs(S–1) (298K)
Cl
Br
Cl
H
H
Me
–330
–300
–400
7.12(6)x10-2
4.08(5)x10-4
5.05(5)x10-3
rate of reductive elimination controlled by C–halogen bond strength
C–X reductive elimination rates do not correlate with E1/2 values
Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
BrNNH N
H
R
CuIII
Br
NNH N
H
R
N-pyr
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
CuI/CuIII
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
CuI/CuIII
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
■ macrocyclic ligand lowers barrier to oxidative addition
■ macrocyclic ligand stabilizes CuIII
*effectively inverts the relative rates of both redoxsteps
Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
CuI/CuIII
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
■ macrocyclic ligand lowers barrier to oxidative addition
■ macrocyclic ligand stabilizes CuIII
*effectively inverts the relative rates of both redoxsteps
■ mechanism of Ullmann-Goldberg can vary
*use of less coordinating nucleophiles or higher coordinateligands can affect key redox steps
Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835
RR2
HN
Z
Cu
O2R N
Z
R2
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
CuII
R RCuIII CuI
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
Glaser-Hay Type Couplingsoxidative cross-coupling
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
2 equiv. CuX2
AcOH MeO
O Me
O
OMeOMe
Glaser-Hay Type Couplingsoxidative cross-coupling
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
2 equiv. CuX2
AcOH MeO
O Me
O
OMeOMe
Cu(OAc)2
Cu(OTf)2
Cu(ClO4)2
CuF2
CuCl2CuBr2
X
Glaser-Hay Type Couplingsoxidative cross-coupling
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
2 equiv. CuX2
AcOH MeO
O Me
O
OMeOMe
MeO
OMe
MeO
OMe
Cl Cl
Cl
70% 7%Cu(OAc)2
Cu(OTf)2
Cu(ClO4)2
CuF2
CuCl2
CuBr2
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
25 mol% CuBr2
AcOH, 60°C
OMe
MeO
OMeBr
LiBr
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
25 mol% CuBr2
AcOH, 60°C
OMe
MeO
OMeBr
MeO
25 mol% CuCl2
AcOH, 100°C
OMe
MeO
OMeCl
LiBr
LiCl
6 equiv.
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
25 mol% CuBr2
AcOH, 60°C
OMe
MeO
OMeBr
LiBr
CuBr2 2 CuBr Br2
Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448
Δ
regioselectivity follows that of electrophilic aromatic bromination
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
CuBr2 2 CuBr Br2
Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448
Δ
regioselectivity follows that of electrophilic aromatic bromination
OMe
OMe
Br
20 mol% NaNO2
1.3 equiv HBr
Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
CuBr2 2 CuBr Br2
Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448
Δ
regioselectivity follows that of electrophilic aromatic bromination
25 mol% CuBr2
Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866
Br
BrAcOH, O2, LiBr
75%
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H
Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H NNH N
H
R
CuIII
Br
CuBr2
–HBr
MeCNN
NH N
H
R
CuI
Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H NNH N
H
R
CuIII
Br
CuBr2
–HBr
MeCNN
NH N
H
R
CuI
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H NNH N
H
R
CuIII
Br
CuBr2
–HBr
MeCNN
NH N
H
R
CuI
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
NNH N
H
R
CuIII
Br
MeCNN
NH N
H
R
NpyrHN
O
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
kinetics determined by O2 consumption
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
arene ligand (mM) CuII (mM) pO2 (torr)
1st order dependence 1st order dependence 0 order dependence
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
arene ligand (mM) CuII (mM) pO2 (torr)
1st order dependence 1st order dependence 0 order dependence
catalytic steps involving O2 are comparatively fastCu reoxidation is not rate-determining
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
1H NMR complicated due to paramagnetic line broadeningindicates that CuII is formed during reaction
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
CuIII
CuII
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
CuIII
CuII
Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
NNH N
H
R
CuIII
Br
NNH N
H
R
CuI
Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
MeOH
NNH N
H
R
CuIII
Br
CuI
NNH N
H
R
OMe
NNH N
H
R
CuI
O2
H2O
Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
MeOH
NNH N
H
R
CuIII
Br
CuI
NNH N
H
R
OMe
NNH N
H
R
CuI
O2
H2O
accounts for apparentbuild-up of CuII during
reaction
Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
Copper in Cross-Coupling Reactions