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Chris Prier
MacMillan Group Meeting
March 23, 2011
Interaction of Organic Radicals with Transition Metals
IrICOPPh3Cl
Ph3P R•IrII
COPPh3Cl
Ph3PR
IrIIICOPPh3Cl
Ph3PRRX
X
R•
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
R• MnXm
addition to the metalR Mn+1Xm
ligand transferR X Mn-1Xm-1
electron transferR± Mn±1Xm
! What are the mechanisms by which an alkyl radical can interact with a transition metal?
Kochi, J. K. Science. 1967, 27, 415-424.
Transition Metals and Organic Radicals
! Different CuII sources show divergent reactivity with respect to ethyl radical
CH3CH2•CuCl2CuSO4
CH3CH2• H2C=CH2 CH3CH2Cl
! Oxidation by CuSO4 is an electron transfer processes (outer-sphere)
Kochi, J. K. Science. 1967, 27, 415-424.
Oxidation of Alkyl Radicals by CuII
CH3CH2•+CuII CH3CH2+CuI +
Cu(OAc)2exclusive product
Cu(OAc)2
t-BuO Me
O
80% 20%
Me Cu(OAc)2 Me
20%
MeOAc
80%
CuII
55% 23% 22%thermodynamic distribution at 30 ºC: 2% 75% 20%
! Stabilities of the oxidation products do not control the selectivity of oxidative elimination
H2C=CH2 + H+
! Radicals which would give more stabilized carbocations give more substitution product
! Oxidation by CuCl2 is a ligand transfer processes (inner-sphere)
Kochi, J. K. Science. 1967, 27, 415-424.
Oxidation of Alkyl Radicals by CuII
CH3CH2•+CuII CH3CH2Cl
! Product ratios match those obtained with atom transfer reagents
CuICl Cl Cl
CuCl2Cl
Cu(OAc)2
! Oxidation of neopentyl radical gives no rearranged products with CuCl2
OAc
exclusive productcarbocation rearrangement products
ClCl
CuCl2:t-BuOCl:
70%70%
30%30%
! Analogy with Taube inorganic ligand transfer process
[CrII(H2O)5]2+
[CoIII(NH3)5Cl]2+[(H2O)5CrII–Cl–CoIII(NH3)5]4+
[CrIII(H2O)5Cl]2+
[CoII(NH3)5]2+
CuIICl ClH3CH2C
! Metal-alkyl bonds are characteristically weak, correlate with degree of steric crowding
Metal-Alkyl Bond Strengths
bond dissociation energy (kcal/mol)2
25201822241917
3741412121
53
SALOPH = N,N'-disalicylidene-o-phenylenediamine, (DH)2 = dimethylglyoxime
(py)(SALOPH)Co–CH2CH2CH3(py)(SALOPH)Co–CH(CH3)2(py)(SALOPH)Co–CH2C(CH3)3(py)(SALOPH)Co–CH2C6H5(PMe2Ph)(DH)2Co–CH(CH3)C6H5(PEtPh2)(DH)2Co–CH(CH3)C6H5(PPh3)(DH)2Co–CH(CH3)C6H5
(CO)5Mn–CH3(CO)5Mn–CF3(CO)5Mn–C6H5(CO)5Mn–CH2C6H5(CO)5Mn–COC6H5
(CO)5Re–CH3
Halpern, J. Inorg. Chim. Acta. 1985, 100, 41-48.Brown, D. L. S.; Connor, J. A.; Skinner, H. A. J. Organomet. Chem. 1974, 81, 403-409.
Connor, J. A. et al. Organometallics. 1982, 1, 1166-1174.
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
! Concerted pathway: cis insertion via a three-center, two-electron bond
Hegedus, L. S. Transition Metals in the Synthesis of Complex Molecules. 1999, 2nd ed.
Two-Electron Mechanisms of Oxidative Addition
! SN2-type substitution: highly nucleophilic metal complexes attack primary or secondary halides
L2Pd0
PhBr
L2PdBr
H
PhH
L2PdIIBr
Ph
IrICOPPh3Cl
Ph3PCH3Br
IrCOPPh3Cl
Ph3PCH3
+
Br– IrIII COPPh3Cl
Ph3PCH3
Br
! Radical pathway (two inner sphere one-electron processes)
Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319-6332.
One-Electron Mechanisms of Oxidative Addition
IrI COPPh3Cl
Ph3PIn•
IrII COPPh3Cl
Ph3PIn
IrIIICOPPh3Cl
Ph3PInRX
X
R•
X
Mn
X
Mn+1 Mn+1X–
Mn+2+
X– Mn+2
X
! Electron-transfer mechanism (outer sphere one-electron process, then inner sphere one-electron process)
IrI COPPh3Cl
Ph3P R•IrII CO
PPh3ClPh3P
R
IrIIICOPPh3Cl
Ph3PRRX
X
R•
initiation:
propagation:
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
! Concerted pathway: requires retention of configuration
Stereochemical Consequence of Oxidative Addition Pathways
! SN2-type substitution: requires inversion of configuration
! Radical pathways: likely to proceed with loss of stereochemistry
Mn BrR1
R3
M Br
R1
R2 R3
‡
Mn+2R1
R2R3
+
Br– Mn+2R1
R2R3Br
MnBr
R1R2
R3
BrM
R1 R2
R3 Mn+2
Br
R1
R2R3
R2
Mn R1R2
R3
Mn+1
R1 R2
R3Mn+1
R1R2
R3
Br
R1R2
R3
Mn+2
R1 R2
R3Mn+2
R1R2
R3
Br
Br
‡
! Oxidative addition of alkyl halides to an IrI complex proceeds with loss of stereochemistry
Stereochemical Consequence of Oxidative Addition Pathways
IrICOPMe3Cl
Me3PIrI CO
PMe3ClMe3P
1:1 mixture
DPh
Br
FD
PhBr
F
Labinger, J. A.; Osborn, J. A. Inorg. Chem. 1980, 19, 3230-3236.
IrI COPMe3Cl
Me3P
Br
F
PhD
IrI COPMe3Cl
Me3P
Br
F
PhD
! Cross-coupling of endo- and exo-2-norbornane leads to the same exo product
González-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 5360-5361.
Br
Br
Ph
Ph
6% NiI26% trans-2-aminocyclohexanol
84%
91%NaHMDS (2 equiv.)isopropanol, 60 ºC
! Cis- and trans-1,2-dichloroethylene give the same isomeric mixture of oxidative addition product
Fitton, P.; McKeon, J. E. Chem. Commun. 1968, 4-6.
! Complete retention of configuration is observed in the oxidative addition to Pd(PPh3)4
Evidence for Radical Chain Process
Cl
Cl
Cl Cl
IrI COPMe3Cl
Me3P
IrIIICOPMe3Cl
Me3P
Cl
Cl
40:60 cis:trans
IrIIICOPMe3Cl
Me3P
Cl
Clor
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
Pd(PPh3)4
Cl
Cl
Pd(PPh3)4
Cl Cl
PdIIPPh3Cl
Ph3P
Cl
PdIIPPh3Cl
Ph3P
Cl
! Radical initiators promote the oxidative addition of alkyl halides to IrI complexes
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
! Radical inhibitors depress the oxidative addition of alkyl halides to IrI complexes
Evidence for Radical Chain Process
IrI COPMe3Cl
Me3PPh
Br
IrIIICOPMe3Cl
Me3P
Br
Phinitiator
5
noneAIBN
benzoyl peroxide
conversion (%)
after 100 min5
1134
after 46 h5
36100100
F
F
65 ºC
IrI COPR3Cl
R3P
PhBr
IrIIICOPR3Cl
R3P
Br
Ph inhibitor555
noneduroquinone
galvinoxyl
conversion (%)after 5 min
5
421419
F
FCO2Et EtO2C
r.t.
! Rate of reactivity of alkyl halides is consistent with radical process, inconsistent with SN2
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
! Trapping of radical intermediates with acrylonitrile
Evidence for Radical Chain Process
IrI COPMe3Cl
Me3PIrIIICO
PMe3ClMe3P
R
X
RX relative reactivity2
1.0 (defined)5.46.8
RX2
n-BuBrs-BuBrt-BuBr
CN
IrICOPMe3Cl
Me3PCN
n
IrIIICOPMe3Cl
Me3Pi-Pr
I
i-PrI
10 equiv.
CN
IrICOPMe3Cl
Me3PCN
n
IrIIICOPMe3Cl
Me3PMe
I
MeI
not observed
! Alkyl iodides bearing tethered alkenes undergo radical cyclization concomitant with oxidative addition
Phapale, V. B.; Buñuel, E.; García-Iglesias, M.; Cárdenas, D. J. Angew. Chem. Int. Ed. 2007, 46, 8790-8795.
Radical Cyclizations in Oxidative Addition
O O
I
BrZn O
O
OO
H
H
O
O
79%
[Ni(py)4Cl2] (10%)(S)-(s-Bu)-Pybox (10%)
THF, 23 ºC
O O O O
H
H
NiII
NiIII I
NiIO O
I
R
R =O
O
L*
NiI*L I
O O
CH2
O O
H
H
NiII
R
L*
O O
H
H
NiIII
R
L*I
! Isopropyl iodide accelerates the Kumada cross-coupling of aryl Grignard reagents
Manolikakes, G.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 205-209.
Alkyl Iodide Accelerated Kumada Couplings
MgCl
Br OMe
rate enhancementdue to presence
of i-PrI
conversion after 15 min
8%82%
OMe
L Pd0 L PdI I
Ar1 Br
L PdII IBr
Ar1•
L PdIII IBr
Ar1L PdIII X
Ar2
Ar1
Ar2MgX
Ar1 Ar2 L PdI X
Me Me
! Rate acceleration arises from initiation of radical pathway by isopropyl iodide
PEPPSI (2 mol%)
THF, 0 ºC
Grignard prepared from PhCl and Mg/LiClGrignard prepared from PhI and i-PrMgCl•LiCl
I
MeMe
! Aryl halides bearing an alkene tether undergo radical cyclization
Manolikakes, G.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 205-209.
Radical Cyclizations in the Accelerated Kumada Coupling
MgCl
OMe
Br
OMeOMe
additive
nonei-PrI (1.1 equiv.)
80%34%
7%50%
time
60 min5 min
MgCl
Br
OMe
OMe
78%
PEPPSI (2 mol%)
THF, 25 ºC
! No cyclized products are observed when the alkene tether is on the Grignard reagent
PEPPSI (2 mol%)
THF, 25 ºC, 5 minI
i-PrMgCl•LiCl
THF, -20 ºC, 1h
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
! Synthesis of !-lactones by reaction of Mn(OAc)3 with olefins
Oxidative Reactions with Manganese(III) Acetate
inner-sphereoxidation
MnIII OMnII
MnIII O
OCH2
Mn(OAc)3•2H2O (2 equiv.) O
O
PhHOAc, KOAc135 ºC, 1 h
proposed intermediate:
" "O
CH2HO
Heiba, E. I.; Dessau, R. M.; Koehl, W.J. J. Am. Chem. Soc. 1968, 90, 5905-5906.Heiba, E. I.; Dessau, R. M.; Rodewald, P. G. J. Am. Chem. Soc. 1974, 96, 7977-7981.
60%
MnIII OMnIII
OO
MnIII O
O
OO
Me
Me
Me MnIII OMnII
MnIII O
OR
! Key mechanistic question: Is the species that adds to the olefin a free or metal-complexed radical?
O
CH2HO
O
HO
styrene
Ph
outer-sphereoxidation
styrene
! No polymerization of styrene observed
Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Tetrahedron. 1986, 42, 3429-3442.
Evidence Against Intermediacy of Discrete Radicals
no polymerization observed
O
OEtClH2Cno rxn OEt
O
Cl
C6H13C6H13
73%
(Ot-Bu)2
155 ºC
Mn(OAc)3•2H2O
HOAc, Ac2Oreflux
Mn(OAc)3•2H2O
HOAc, Ac2Oreflux
Bush, J. B., Jr.; Finkbeiner, H. J. J. Am. Chem. Soc. 1968, 90, 5903-5905.Allen, J. C.; Cadogan, J. I. G.; Hey, D. H. J. Chem. Soc. 1965, 1918-1932.
! Acetate esters add to olefins upon initiation with (Ot-Bu)2, but not Mn(OAc)3•2H2O
! No dimerization of acetic acid radicals observed
H3C OH
O Mn(OAc)3•2H2O
Ac2O, refluxno alkene
HO
OOH
O
succinic acid not observed
Bush, J. B., Jr.; Finkbeiner, H. J. J. Am. Chem. Soc. 1968, 90, 5903-5905.
! H/D exchange experiments show no rate dependence on the metal
Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Tetrahedron. 1986, 42, 3429-3442.
Evidence for Metal-Complexed Radical
H3C
O
OH+
D3C
O
OD DH2C
O
OD
! !-lactone formation exceeds total solution H/D exchange
! Results are only consistent with rate-determining enolization of complexed acetate
rateA = rateB
KOAc, reflux
A: 0.25 M Mn(OAc)3•2H2OB: no metal
HOAc-d2
! Rate-determining enolization followed by single-electron oxidation generates metal-bound radical
Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Tetrahedron. 1986, 42, 3429-3442.
Consensus Mechanism of Manganese(III) Acetate Oxidation
inner-sphereoxidation
MnIII OMnII
MnIII O
OCH2MnIII O
MnIIIO
O
MnIII O
O
OO
Me
Me
Me
MnIII OMnII
MnIII O
OPh
styrene
-H+
enolizationMnIII O
MnII
MnIII O
OCH2
oxidative lactonization
MnIII OMnII
MnIIO
O
Ph
! Mn(OAc)3 initiates radical cyclizations of !-keto esters and 1,3-diketones
Kates, S. A.; Dombroski, M. A.; Snider, B. B. J. Org. Chem. 1990, 55, 2427-2436.
Oxidative Cyclization of !-Dicarbonyls
O
OMe
O
Me
Mn(OAc)3•2H2O (2 equiv.)Cu(OAc)2•H2O (1 equiv.)
HOAc, 50 ºC, 1 h
O
OMe
OO
OMe
O
Cu(OAc)2
! Cu(OAc)2 is used to oxidize the alkyl radical to the alkene
O
OMe
O!-hydride
elimination O
OMe
O
Cu(OAc)
O
OMe
O
Me
71% (mixture of tautomers)
Me
OO
Mn(OAc)3•2H2O (2 equiv.)Cu(OAc)2•H2O (1 equiv.)
HOAc, 25 ºCO
O
Me
48%
O O
OMeMe
O O
OMeMe
Me
OCO2Me
Me
OCO2Me
Me
OCO2Me
(OAc)2CuMe
OCO2Me !-hydride
elimination
! Mn(OAc)3 can initiate radical cascade cyclizations
Zoretic, P. A.; Shen, Z.; Wang, M.; Riberio, A. A. Tetrahedron Lett. 1995, 36, 2925-2928.
Oxidative Radical Cascade Cyclizations
86%
(14% without Cu(OAc)2)
MnIIMn(OAc)3•2H2O (2 equiv.)Cu(OAc)2•H2O (1 equiv.)
HOAc, r.t., 26 h
OCO2Et
Me
MeMe
H
HO
43%
Me MeMn(OAc)3•2H2O (2 equiv.)Cu(OAc)2•H2O (1 equiv.)
HOAc, r.t., 24 hCO2EtH
Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc. 1990, 112, 2759-2767.
! Baran's Cu(II)-mediated indole-carbonyl coupling
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem. Int. Ed. 2005, 44, 609-612.
Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857-12869.
Indole Coupling via !-Carbonyl Radicals
O
NH
ONH
2 equiv.
ONH
43%
O
N
O
OMe
NH
Bn
54%, 5:1 d.r.
OH NH
Me
53%, single diastereomer(5 equiv. indole: 77%)
Me
Ph
O
Me
NH
30%
O
O Me
NH
51%
THF-78 ºC to r.t.
LHMDS (3.3 equiv.)Cu(II)2-ethylhexanoate (1.5 equiv.)
! Oxidation of enolate to !-ketoradical enables coupling with copper-coordinated indole
Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857-12869.
Proposed Mechanism of Indole-Carbonyl Coupling
O
NH
OCuII
N
OCuI
NOCuI
N
Cu0
O NH
THF-78 ºC to r.t.
LHMDS (3.3 equiv.)Cu(II)2-ethylhexanoate (1.5 equiv.)
! Free N-H is required for reactivity under copper conditions
Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857-12869.
Evidence for Electron Transfer via Copper Enolate
! Reaction proceeds with a known outer-sphere oxidant
no reaction
Fe+
discrete !-carbonyl radical
Me Me
N
SO O
O
N
Me Me
N
SO O
O
N
implicates inner-sphere oxidation via indole-bound copper enolate:
LHMDSCu(II)2-ethylhexanoate
-78 ºC to r.t.
PF6-
LHMDS, NEt3
Me Me
N
SO O
O
N
Me Me
N
SO O
O
N
11%, 4.5:1 d.r.(after benzoylation)
OCuI
NOCuII
N
! Enables the synthesis of 1,4-dicarbonyl compounds via !-carbonyl radicals
Oxidative Enolate Coupling
! Reaction does not proceed via formation of the !-bromoester
O
t-BuOOt-Bu
O
Rathke, M. W.; Lindert, A. J. J. Am. Chem. Soc. 1971, 93, 4605-4606.
t-BuO
OBr
t-BuO
OLi
t-BuO
O
Me
85%
O
t-BuOOt-Bu
O10%
! Proposed to proceed via single-electron oxidation of enolate to !-carbonyl radical
lithium amide baseCuBr2 (2 equiv.)
t-BuO
O
Me t-BuO
OCuII
t-BuO
OCuI
! Heterocoupling can be achieved in the coupling of imides or amides with ketones or esters
Oxidative Enolate Coupling
R1
O
R2 R3
R4
O
R1
O
R2 O
R4
R3
O
O N
O
PhBn
Me
O
Ph
Fe(III): 57%, 1.8:1 d.r.Cu(II): 55%, 1:1.6 d.r.
Fe(acac)3 (2.0 equiv.) orCu(2-ethylhexanoate)2 (2.0 equiv.)
LDA (2.1 equiv.)
THF, -78 ºC to r.t.
O
O N
O
PhBn
O
O
Fe(III): 60%, 2.6:1 d.r.
NMOM
O
1 equiv. 1 equiv.
Me
Me
OO
Fe(III): 73%, 2:1 d.r.
O
O N
O
CO2t-Bu
Phi-Pr
Cu(II): 62%, 1.2:1 d.r.(1.75 equiv. ester)
OBn
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083-7086.DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
! Formation of ketone-iron enolate followed by single-electron oxidation furnishes !-carbonyl radical
Proposed Mechanism of Oxidative Enolate Coupling
O
O N
O
BnPh
MePh
O
O
O N
O
Bn
Ph
Ph
O
Li
LDAFe(III)
Me
FeIII
Ph
OMe
FeII
O
O N
O
Bn
Li
Ph
Me
O
Ph
O
O N
O
BnPh
Me
O
Ph
FeIII FeII
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083-7086.DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
! Fe(III) and Cu(II) show divergent reactivity in cyclopropane radical clock studies
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
Mechanism of Oxidative Enolate Coupling
O
O N
O
Bn PhPh
MePh
OFe(III) or Cu(II)
LDA (2.1 equiv.)
THF, -78 ºC to r.t.
O
O N
O
Bn
PhPh
Fe(III): traceCu(II): 20% (mixture
of ring-opened products)
O
O N
O
BnPh
Ph
O
Ph
Ph
Fe(III) or Cu(II)LDA (2.1 equiv.)
THF, -78 ºC to r.t.
O
Ph
Ph Ph
Fe(III): traceCu(II): 14%
O
O N
O
Bn
MeMe Fe(III) or Cu(II)LDA (2.1 equiv.)
THF, -78 ºC to r.t.
O
O N
O
Bn
MeMe
Fe(III): 27%Cu(II): 28%
! Fe(III) and Cu(II) promote cyclization with tethered olefins
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
Mechanism of Oxidative Enolate Coupling
! Extent to which metal enolate behaves like an !-carbonyl radical depends on the identity of the metal
X
O
Y
Mn
X
O
Y
Mn-1•R
•R
X
O
Y
R
X
O
Y
R
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
! Racemic starting material is converted to single enantiomer product via radical intermediate
Asymmetric Negishi Coupling of !-Bromoamides
O
Br
EtN
Bn
Ph
n-Hex ZnBr
O
n-Hex
EtN
Bn
Ph
90%, 95% eeracemic !-bromoamide
OEt
NBn
Ph
achiral radical intermediate
Fischer, C. F.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-4595.
NiIO
EtN
Bn
Ph NiII
OEt
NBn
Ph NiIII
X
10% NiCl2•glyme13% (R)-(i-Pr)-Pybox
DMI/THF (7:1)0 ºC, 12 h
X
XX
OEt
NBn
Ph NiIII
Xn-Hex
n-Hex ZnBr
1.3 equiv.
NiII
NiIII Br
! Wide range of asymmetric cross couplings of racemic secondary alkyl halides has been developed
Asymmetric Cross Coupling of Alkyl Halides
Ph
O
Ph
Me
!-bromoketones
J. Am. Chem. Soc. 2005, 127, 10482-10483.
n-HexMe
89%, 96% ee81%, 92%
Angew. Chem. Int. Ed. 2009, 48, 154-156.J. Am. Chem. Soc. 2010, 132, 1264-1266.
Phn-Bu
Ph
84%, 94% ee
homobenzylic halides
J. Am. Chem. Soc. 2008, 130, 6694-6695.
secondary allylic chlorides
Me Me
n-Hex
95%, 87% ee
J. Am. Chem. Soc. 2008, 130, 2756-2757.
OMe
n-Hex
acylated halohydrins
N
OBn
Ph
80%, 94% ee
J. Am. Chem. Soc. 2010, 132, 11908-11909.
BHTO
OEt
Ph
!-bromoesters
80%, 99% ee
J. Am. Chem. Soc. 2008, 130, 3302-3303.
secondary benzylic halides
! A copper/chiral diamine catalyst controls the dimerization of 2-naphthol derivatives
Enantioselective Oxidative Biaryl Coupling
OH
CO2Me
N
N HCuIOMeO
O
N
N HCuIOMeO
O
OMe
OOH
H
OH
CO2Me
OH
CO2MeN
N HH
10 mol%
CuI (10 mol%), O2MeCN, 48 h, 40 ºC
enolization and catalyst release
HH
85%, 93% ee
N
N H
H
CuIIHO I
Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137-1140.Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 12232-12233.
! Iron(salan)-catalyzed process enables oxidative biaryl heterocoupling
Egami, H.; Matsumoto, K.; Oguma, T.; Kunisu, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 13633-13635.
Enantioselective Oxidative Biaryl Coupling
(salan)FeIII
HO
FeIII(salan)OH
HO
O(salan)FeIII
O2
O2•–
O(salan)FeIV
+
O(salan)FeIII
HO+
HO
HOHO
X = H, Y = Br: 52%, 89% eeX = Ph, Y = CO2Me: 70%, 90%eeX = Ph, Y = Ac: 65%, 88%ee
X
X
X
X
Y
Y Y
HO
XO2
•–
H2O2
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R
! Homolysis of cobalt-carbon bond generates carbon-centered radical capable of performing catalysis
Buckel, W.; Golding, B. T. Annu. Rev. Microbiol. 2006, 60, 27-49.
Coenzyme Vitamin B12 is a Source of Radicals
N N
NN
Me
Co
Me
H2NO
H
MeMe
H2N
O
H
H2N
OH
NH
O
OP
OOO
MeO
N
N
Me
Me
H
OHHH
Me
HOH
MeNH2
OH
NH2
O
O
NH2
H
MeMe
O
OH
OH
N
N
N
N
NH2
CoIII
CH2R
CoII
CH2R
BDE = 30 kcal/mol
5'-deoxyadenosyl radical
"latent radical reservoir"
! Glutamate mutase converts (S)-glutamate to (2S,3S)-3-methylaspartate
Buckel, W.; Golding, B. T. Annu. Rev. Microbiol. 2006, 60, 27-49.
Catalysis by Coenzyme Vitamin B12
CO2--O2C
NH4+
CO2-
-O2C
NH4+
CH2
CoIII
CH2
Ado
CoII
CH2
Ado
CH3
AdoCO2
--O2C
NH4+
CO2-
-O2C
NH4+
CH3
-O2C
NH3+
CO2-
glycyl radical
(S)-glutamate(2S,3S)-3-methylaspartate
! Methylmalonyl CoA mutase converts L-methylmalonyl CoA to succinyl CoA
Banerjee, R.; Ragsdale, S. W. Annu. Rev. Biochem. 2003, 72, 209-247.
Catalysis by Coenzyme Vitamin B12
CoIII
CH2
Ado
CoII
S
OCoA
O
O
HHH
S
OCoA
O
O
H H
O
OS
OCoA
O
OS
OCoA
succinyl CoAL-methylmalonyl CoA
CH2
Ado
CH3
Ado
O
O O
SCoA
! D-ornithine aminomutase converts D-ornithine to (2R,4S)-2,4-diaminopentanoic acid
Catalysis by Coenzyme Vitamin B12
CoIII
CH2
Ado
CoII
2,4-diaminopentanoic acidD-ornithine
CH2
Ado
CH3
Ado
CO2-
NH2
NCO2
-
NH2
Me
N
CO2-
NH2
N
R
CO2-
NH2N
R
R = pyridoxal phosphate
CO2-
NH2
H2C
N
R
R
R
Banerjee, R.; Ragsdale, S. W. Annu. Rev. Biochem. 2003, 72, 209-247.Chen, H.-P.; Wu, S.-H.; Lin, Y.-L.; Chen, C.-M. J. Biol. Chem. 2001, 276, 44744-44750.
Interaction of Organic Radicals with Transition Metals
oxidation of alkyl radicals
CH3CH2•H2C=CH2
CH3CH2X
CuII
radical mechanism ofoxidative addition !-carbonyl radicals
metal-radical interactionsin asymmetric catalysis coenzyme vitamin B12
L PdII IBr
Ar1•
L PdIII IBr
Ar1 Ph
OMe
FeII
O
Br
EtN
Bn
Ph
O
n-Hex
EtN
Bn
PhCoII
CH2R