interaction of organic radicals with transition metals of organic radicals with transition metals...
TRANSCRIPT
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