Interaction of Organic Radicals with Transition Metals
Ph3P
Cl
IrI
CO
PPh3
R•
R
Ph3P
Cl
IrII
CO
PPh3
Chris Prier
MacMillan Group Meeting
March 23, 2011
RX
R
Ph3P
Cl
IrIII
X
CO
PPh3
R•
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Transition Metals and Organic Radicals
! What are the mechanisms by which an alkyl radical can interact with a transition metal?
addition to the metal
R Mn+1Xm
ligand transfer
R•
MnXm
R X
Mn-1Xm-1
R±
Mn±1Xm
electron transfer
! Different CuII sources show divergent reactivity with respect to ethyl radical
CuSO4
CH3CH2•
CuCl2
H2C=CH2
CH3CH2•
CH3CH2Cl
Kochi, J. K. Science. 1967, 27, 415-424.
Oxidation of Alkyl Radicals by CuII
! Oxidation by CuSO4 is an electron transfer processes (outer-sphere)
CuII
+
CuI
CH3CH2•
+
CH3CH2+
+
H2C=CH2
H+
! Radicals which would give more stabilized carbocations give more substitution product
Cu(OAc)2
exclusive product
Cu(OAc)2
O
t-BuO
80%
Me
20%
OAc
Me
Cu(OAc)2
Me
Me
20%
80%
! Stabilities of the oxidation products do not control the selectivity of oxidative elimination
CuII
thermodynamic distribution at 30 ºC:
55%
23%
22%
2%
75%
20%
Kochi, J. K. Science. 1967, 27, 415-424.
Oxidation of Alkyl Radicals by CuII
! Oxidation by CuCl2 is a ligand transfer processes (inner-sphere)
Cl
CuII Cl
+
CH3CH2•
H3CH2C
Cl
CH3CH2Cl
CuII Cl
Cl
CuI
! Oxidation of neopentyl radical gives no rearranged products with CuCl2
Cu(OAc)2
CuCl2
Cl
OAc
carbocation rearrangement products
exclusive product
! Product ratios match those obtained with atom transfer reagents
Cl
Cl
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+
Kochi, J. K. Science. 1967, 27, 415-424.
Metal-Alkyl Bond Strengths
! Metal-alkyl bonds are characteristically weak, correlate with degree of steric crowding
bond dissociation energy (kcal/mol)
2
(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
25
20
18
22
24
19
17
(CO)5Mn–CH3
(CO)5Mn–CF3
(CO)5Mn–C6H5
(CO)5Mn–CH2C6H5
(CO)5Mn–COC6H5
37
41
41
21
21
(CO)5Re–CH3
53
SALOPH = N,N'-disalicylidene-o-phenylenediamine, (DH)2 = dimethylglyoxime
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
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Two-Electron Mechanisms of Oxidative Addition
! Concerted pathway: cis insertion via a three-center, two-electron bond
Br
Ph
Br
L2Pd
L2Pd0
Br
L2PdII
H
H
Ph
Ph
! SN2-type substitution: highly nucleophilic metal complexes attack primary or secondary halides
Ph3P
Cl
IrI
CO
PPh3
CH3Br
+
CH3
Ph3P
CO
Ir
Cl
PPh3
Br–
Ph3P
Cl
CH3
CO
IrIII
PPh3
Br
Hegedus, L. S. Transition Metals in the Synthesis of Complex Molecules. 1999, 2nd ed.
One-Electron Mechanisms of Oxidative Addition
! Radical pathway (two inner sphere one-electron processes)
initiation:
propagation:
Ph3P
Cl
Ph3P
Cl
IrI
IrI
In•
CO
Ph3P
PPh3
Cl
R•
CO
PPh3
RX
In
IrII
CO
Cl
IrII
Cl
PPh3
R
Ph3P
In
Ph3P
CO
IrIII
X
CO
R•
PPh3
R
RX
Ph3P
Cl
PPh3
IrIII
X
CO
R•
PPh3
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
! Electron-transfer mechanism (outer sphere one-electron process, then inner sphere one-electron process)
+
X
Mn+2
X
Mn
Mn+1
X–
Mn+1
X
X–
Mn+2
Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319-6332.
Stereochemical Consequence of Oxidative Addition Pathways
! Concerted pathway: requires retention of configuration
Mn
R1
‡
Br
Br
M
Br
R3
R3
R2
R3
Mn+2
R2
R1
2
R1 R
! SN2-type substitution: requires inversion of configuration
Mn
Br
R2
‡
R1
R1
M
R3
R1
Mn+2
Br
+
R3
R1
Br–
Br
Mn+2
R2
R2 R3
! Radical pathways: likely to proceed with loss of stereochemistry
Br
Mn
R1
R3
R2
R1
Mn+1
R2
R3
Mn+1
R1
R3
R2
R1
R3
R2
R3
R2
R1
R2
R3
Mn+2
Br
Br
Mn+2
R1
R3
R2
Stereochemical Consequence of Oxidative Addition Pathways
! Oxidative addition of alkyl halides to an IrI complex proceeds with loss of stereochemistry
F
F
D
Br
Me3P
Cl
IrI
D
Ph
F
D
CO
Me3P
PMe3
Cl
IrI
Br
Ph
F
CO
Ph
Br
D
Me3P
PMe3
Cl
IrI
Br
CO
Me3P
Ph
Cl
IrI
CO
PMe3
PMe3
1:1 mixture
Labinger, J. A.; Osborn, J. A. Inorg. Chem. 1980, 19, 3230-3236.
! Cross-coupling of endo- and exo-2-norbornane leads to the same exo product
Br
Br
Ph
84%
Ph
91%
6% NiI2
6% trans-2-aminocyclohexanol
NaHMDS (2 equiv.)
isopropanol, 60 ºC
González-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 5360-5361.
Evidence for Radical Chain Process
! Cis- and trans-1,2-dichloroethylene give the same isomeric mixture of oxidative addition product
Cl
or
Me3P
Cl
IrI
Cl
CO
Cl
Cl
Cl
Me3P
PMe3
Cl
IrIII
Cl
Cl
Me3P
CO
Cl
PMe3
IrIII
Cl
CO
PMe3
40:60 cis:trans
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
! Complete retention of configuration is observed in the oxidative addition to Pd(PPh3)4
Cl
Cl
Cl
Pd(PPh3)4
Ph3P
Cl
PdII
Cl
Pd(PPh3)4
PPh3
Cl
Cl
Ph3P
Cl
PdII
PPh3
Fitton, P.; McKeon, J. E. Chem. Commun. 1968, 4-6.
Evidence for Radical Chain Process
! Radical initiators promote the oxidative addition of alkyl halides to IrI complexes
conversion (%)
F
Me3P
Cl
IrI
CO
Ph
Br
Ph
F
Me3P
PMe3
65 ºC
Cl
IrIII
CO
PMe3
Br
initiator
after 100 min
after 46 h
5
5
5
none
AIBN
benzoyl peroxide
11
34
36
100
100
! Radical inhibitors depress the oxidative addition of alkyl halides to IrI complexes
F
Br
Ph
R3P
Cl
IrI
CO
PR3
inhibitor
Ph
CO2Et
EtO2C
R3P
r.t.
Cl
555
F
IrIII
CO
PR3
none
duroquinone
galvinoxyl
conversion (%)
after 5 min
5
42
14
19
Br
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
Evidence for Radical Chain Process
! Rate of reactivity of alkyl halides is consistent with radical process, inconsistent with SN2
RX
Me3P
Cl
IrI
CO
Me3P
PMe3
Cl
relative reactivity
RX
R
IrIII
2
2
CO
1.0 (defined)
5.4
6.8
n-BuBr
s-BuBr
t-BuBr
PMe3
X
! Trapping of radical intermediates with acrylonitrile
Me3P
Cl
IrI
CO
i-PrI
Me3P
PMe3
Cl
CN
i-Pr
CO
IrIII
PMe3
I
CN
n
10 equiv.
MeI
Me3P
Cl
IrI
CO
PMe3
Cl
CN
CN
Me
Me3P
IrIII
I
CO
PMe3
n
not observed
Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236-3243.
Radical Cyclizations in Oxidative Addition
! Alkyl iodides bearing tethered alkenes undergo radical cyclization concomitant with oxidative addition
O
I
O
[Ni(py)4Cl2] (10%)
(S)-(s-Bu)-Pybox (10%)
O
H
O
BrZn
O
O
THF, 23 ºC
O
O
H
NiII
O
R=
*L
O
NiIII I
H
O
NiI I
I
L*
O
79%
O
CH2
O
H
R
NiI L*
H
O
O
L*
O
NiII
NiIII I
H
R
O
O
H
R
O
H
O
O
Phapale, V. B.; Buñuel, E.; García-Iglesias, M.; Cárdenas, D. J. Angew. Chem. Int. Ed. 2007, 46, 8790-8795.
Alkyl Iodide Accelerated Kumada Couplings
! Isopropyl iodide accelerates the Kumada cross-coupling of aryl Grignard reagents
Br
MgCl
OMe
PEPPSI (2 mol%)
OMe
THF, 0 ºC
rate enhancement
due to presence
of i-PrI
conversion after 15 min
Grignard prepared from PhCl and Mg/LiCl
Grignard prepared from PhI and i-PrMgCl•LiCl
8%
82%
! Rate acceleration arises from initiation of radical pathway by isopropyl iodide
Ar1 Br
I
L
Pd0
Me
Me
Me
Me
L
PdI
Br
I
Ar2MgX
Ar2
Ar1
Ar2
L
PdI X
L
PdIII X
Ar1
L
PdII I
Ar1•
Br
L
PdIII I
Ar1
Manolikakes, G.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 205-209.
Radical Cyclizations in the Accelerated Kumada Coupling
! Aryl halides bearing an alkene tether undergo radical cyclization
OMe
OMe
MgCl
Br
PEPPSI (2 mol%)
THF, 25 ºC
OMe
additive
none
i-PrI (1.1 equiv.)
time
80%
34%
7%
50%
60 min
5 min
! No cyclized products are observed when the alkene tether is on the Grignard reagent
Br
I
i-PrMgCl•LiCl
PEPPSI (2 mol%)
THF, -20 ºC, 1h
THF, 25 ºC, 5 min
MgCl
OMe
OMe
78%
Manolikakes, G.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 205-209.
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Oxidative Reactions with Manganese(III) Acetate
! Synthesis of !-lactones by reaction of Mn(OAc)3 with olefins
O
Mn(OAc)3•2H2O (2 equiv.)
proposed intermediate:
O
HOAc, KOAc
135 ºC, 1 h
"
"
O
Ph
HO
60%
CH2
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.
! Key mechanistic question: Is the species that adds to the olefin a free or metal-complexed radical?
outer-sphere
oxidation
Me
O
O
MnIII
MnIII
O
O
MnIII
O
Me
HO
O
Me
O
inner-sphere
oxidation
styrene
O
styrene
MnIII O
MnII
CH2
O
Ph
HO
CH2
MnIII O
O
MnIII O
MnIII O
MnII
R
O
Evidence Against Intermediacy of Discrete Radicals
! No polymerization of styrene observed
Mn(OAc)3•2H2O
no polymerization observed
HOAc, Ac2O
reflux
Bush, J. B., Jr.; Finkbeiner, H. J. J. Am. Chem. Soc. 1968, 90, 5903-5905.
! Acetate esters add to olefins upon initiation with (Ot-Bu)2, but not Mn(OAc)3•2H2O
Mn(OAc)3•2H2O
no rxn
HOAc, Ac2O
reflux
ClH2C
O
(Ot-Bu)2
O
OEt
C6H13
C6H13
155 ºC
OEt
Cl
73%
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.
! No dimerization of acetic acid radicals observed
H3C
O
Mn(OAc)3•2H2O
O
OH
Ac2O, reflux
no alkene
OH
HO
succinic acid not observed
O
Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Tetrahedron. 1986, 42, 3429-3442.
Evidence for Metal-Complexed Radical
! H/D exchange experiments show no rate dependence on the metal
O
A: 0.25 M Mn(OAc)3•2H2O
B: no metal
O
O
rateA = rateB
+
H3C
OH
D3C
OD
KOAc, reflux
DH2C
OD
HOAc-d2
! !-lactone formation exceeds total solution H/D exchange
! Results are only consistent with rate-determining enolization of complexed acetate
Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Tetrahedron. 1986, 42, 3429-3442.
Consensus Mechanism of Manganese(III) Acetate Oxidation
! Rate-determining enolization followed by single-electron oxidation generates metal-bound radical
Me
O
O
MnIII
MnIII
O
O
MnIII
-H+
O
MnIII O
MnIII
Me
O
inner-sphere
oxidation
O
MnII
enolization
CH2
MnIII O
MnIII
O
MnII
O
CH2
O
O
Me
styrene
O
MnII
O
MnIII O
oxidative lactonization
MnIII O
MnIII O
Ph
MnII O
MnII
Ph
Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Tetrahedron. 1986, 42, 3429-3442.
Oxidative Cyclization of !-Dicarbonyls
! Mn(OAc)3 initiates radical cyclizations of !-keto esters and 1,3-diketones
O
O
O
Mn(OAc)3•2H2O (2 equiv.)
Cu(OAc)2•H2O (1 equiv.)
OMe
O
OMe
Me
HOAc, 50 ºC, 1 h
71% (mixture of tautomers)
Me
Me
O
O
Mn(OAc)3•2H2O (2 equiv.)
Cu(OAc)2•H2O (1 equiv.)
O
Me
HOAc, 25 ºC
48%
O
! Cu(OAc)2 is used to oxidize the alkyl radical to the alkene
O
O
O
O
O
OMe
OMe
O
OMe
!-hydride
elimination
O
O
OMe
Cu(OAc)2
Cu(OAc)
Kates, S. A.; Dombroski, M. A.; Snider, B. B. J. Org. Chem. 1990, 55, 2427-2436.
Oxidative Radical Cascade Cyclizations
! Mn(OAc)3 can initiate radical cascade cyclizations
O
O
Mn(OAc)3•2H2O (2 equiv.)
Cu(OAc)2•H2O (1 equiv.)
OMe
O
MnII
O
CO2Me
O
OMe
Me
HOAc, r.t., 26 h
Me
Me
O
86%
O
CO2Me
!-hydride
elimination
O
CO2Me
CO2Me
(14% without Cu(OAc)2)
Me
Me
Me
(OAc)2Cu
Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc. 1990, 112, 2759-2767.
Me
Me
Mn(OAc)3•2H2O (2 equiv.)
Cu(OAc)2•H2O (1 equiv.)
Me
Me
H
HOAc, r.t., 24 h
O
CO2Et
Me
O
H
43%
H
CO2Et
Zoretic, P. A.; Shen, Z.; Wang, M.; Riberio, A. A. Tetrahedron Lett. 1995, 36, 2925-2928.
Indole Coupling via !-Carbonyl Radicals
! Baran's Cu(II)-mediated indole-carbonyl coupling
LHMDS (3.3 equiv.)
Cu(II)2-ethylhexanoate (1.5 equiv.)
O
NH
N
H
THF
-78 ºC to r.t.
2 equiv.
O
O
NH
O
Me
43%
30%
O
O
NH
Ph
O
O
O
NH
NH
O
Me
H
NH
N
Me
Me
Me
Bn
51%
54%, 5:1 d.r.
53%, single diastereomer
(5 equiv. indole: 77%)
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.
Proposed Mechanism of Indole-Carbonyl Coupling
! Oxidation of enolate to !-ketoradical enables coupling with copper-coordinated indole
LHMDS (3.3 equiv.)
Cu(II)2-ethylhexanoate (1.5 equiv.)
O
N
H
O
CuII
N
THF
-78 ºC to r.t.
Cu0
O
NH
O
CuI
CuI
N
O
N
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
! Free N-H is required for reactivity under copper conditions
Me
Me
LHMDS
Cu(II)2-ethylhexanoate
O
no reaction
N
-78 ºC to r.t.
N
S
O
O
! Reaction proceeds with a known outer-sphere oxidant
Me
Me
Me
O
Me
O
O
N
N
S
Me
O
Fe+ PF6-
N
O
Me
N
S
O
LHMDS, NEt3
N
S
O
O
discrete !-carbonyl radical
implicates inner-sphere oxidation
via indole-bound copper enolate:
O
CuII
N
O
11%, 4.5:1 d.r.
(after benzoylation)
CuI
N
O
N
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.
Oxidative Enolate Coupling
! Enables the synthesis of 1,4-dicarbonyl compounds via !-carbonyl radicals
lithium amide base
CuBr2 (2 equiv.)
O
O
Me
t-BuO
Ot-Bu
t-BuO
O
85%
! Reaction does not proceed via formation of the !-bromoester
O
Br
t-BuO
O
OLi
Ot-Bu
t-BuO
t-BuO
O
10%
! Proposed to proceed via single-electron oxidation of enolate to !-carbonyl radical
O
t-BuO
O
Me
t-BuO
CuII
O
CuI
t-BuO
Rathke, M. W.; Lindert, A. J. J. Am. Chem. Soc. 1971, 93, 4605-4606.
Oxidative Enolate Coupling
! Heterocoupling can be achieved in the coupling of imides or amides with ketones or esters
O
O
R1
Fe(acac)3 (2.0 equiv.) or
Cu(2-ethylhexanoate)2 (2.0 equiv.)
LDA (2.1 equiv.)
R4
R2
1 equiv.
R3
O
R4
R1
R3
1 equiv.
R2
THF, -78 ºC to r.t.
O
OBn
O
O
O
Me
O
Ph
N
Ph
O
O
O
O
N
Bn
Me
O
Fe(III): 60%, 2.6:1 d.r.
O
O
O
Me
O
N
O
Ph
Bn
Fe(III): 57%, 1.8:1 d.r.
Cu(II): 55%, 1:1.6 d.r.
O
N
MOM
Fe(III): 73%, 2:1 d.r.
i-Pr
CO2t-Bu
Ph
Cu(II): 62%, 1.2:1 d.r.
(1.75 equiv. ester)
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.
Proposed Mechanism of Oxidative Enolate Coupling
! Formation of ketone-iron enolate followed by single-electron oxidation furnishes !-carbonyl radical
O
O
O
O
O
N
Ph
Bn
Li
O
Ph
N
LDA
Fe(III)
O
Bn
O
O
O
Me
FeIII
Li
O
Ph
Ph
Bn
O
Me
N
FeII
FeII
O
O
O
Me
Ph
N
Ph
O
Bn
Ph
Ph
Me
O
Me
FeIII
Ph
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.
Mechanism of Oxidative Enolate Coupling
! Fe(III) and Cu(II) show divergent reactivity in cyclopropane radical clock studies
O
O
Fe(III) or Cu(II)
LDA (2.1 equiv.)
O
O
N
O
O
O
N
Ph
Ph
Bn
THF, -78 ºC to r.t.
Me
Bn
Ph
Ph
Ph
Fe(III): trace
Cu(II): 20% (mixture
of ring-opened products)
O
O
O
O
Ph
Ph
N
Ph
Bn
O
Fe(III) or Cu(II)
LDA (2.1 equiv.)
Ph
Ph
THF, -78 ºC to r.t.
Ph
Ph
Fe(III): trace
Cu(II): 14%
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
Mechanism of Oxidative Enolate Coupling
! Fe(III) and Cu(II) promote cyclization with tethered olefins
O
O
O
Me
Fe(III) or Cu(II)
LDA (2.1 equiv.)
Me
O
N
O
O
Me
Me
N
THF, -78 ºC to r.t.
Bn
Bn
Fe(III): 27%
Cu(II): 28%
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
! Extent to which metal enolate behaves like an !-carbonyl radical depends on the identity of the metal
Mn
•R
O
O
R
X
X
Y
Y
Mn-1
O
•R
O
R
X
X
Y
Y
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546-11560.
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Asymmetric Negishi Coupling of !-Bromoamides
! Racemic starting material is converted to single enantiomer product via radical intermediate
10% NiCl2•glyme
13% (R)-(i-Pr)-Pybox
O
Bn
Et
N
Ph
n-Hex
Br
O
Bn
ZnBr
DMI/THF (7:1)
0 ºC, 12 h
1.3 equiv.
Et
N
Ph
n-Hex
90%, 95% ee
racemic !-bromoamide
NiII
NiIII Br
O
O
Bn
N
X
Et
Ph
NiI
Bn
O
Et
N
Ph
NiII
X
Bn
O
Et
N
Ph
NiIII X
X
n-Hex
ZnBr
Bn
Et
N
Ph
NiIII n-Hex
X
achiral radical intermediate
Fischer, C. F.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-4595.
Asymmetric Cross Coupling of Alkyl Halides
! Wide range of asymmetric cross couplings of racemic secondary alkyl halides has been developed
O
n-Hex
O
Me
Ph
Et
BHTO
Ph
Me
Ph
81%, 92%
80%, 99% ee
89%, 96% ee
!-bromoketones
!-bromoesters
secondary benzylic halides
Angew. Chem. Int. Ed. 2009, 48, 154-156.
J. Am. Chem. Soc. 2010, 132, 1264-1266.
J. Am. Chem. Soc. 2008, 130, 3302-3303.
J. Am. Chem. Soc. 2005, 127, 10482-10483.
n-Hex
Me
Ph
O
n-Bu
Bn
Me
Ph
N
Ph
Me
O
n-Hex
95%, 87% ee
84%, 94% ee
80%, 94% ee
secondary allylic chlorides
homobenzylic halides
acylated halohydrins
J. Am. Chem. Soc. 2008, 130, 2756-2757.
J. Am. Chem. Soc. 2008, 130, 6694-6695.
J. Am. Chem. Soc. 2010, 132, 11908-11909.
Enantioselective Oxidative Biaryl Coupling
! A copper/chiral diamine catalyst controls the dimerization of 2-naphthol derivatives
N
H
CO2Me
CO2Me
N
H
10 mol%
OH
OH
OH
H
85%, 93% ee
CO2Me
N
N
HO
CuI (10 mol%), O2
MeCN, 48 h, 40 ºC
H
enolization and catalyst release
CuII
I
H
MeO
H
N
O
CuI
MeO
N
N
N
O CuI
H
H
O
O
H
H
O
O
OMe
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.
Enantioselective Oxidative Biaryl Coupling
! Iron(salan)-catalyzed process enables oxidative biaryl heterocoupling
X = H, Y = Br: 52%, 89% ee
X = Ph, Y = CO2Me: 70%, 90%ee
X = Ph, Y = Ac: 65%, 88%ee
H
O
(salan)FeIII
FeIII(salan)
O
H
X
X
H2O2
HO
HO
HO
O2
Y
(salan)FeIII
X
O
O2•–
O2•–
HO
+
X
X
(salan)FeIV
O
(salan)FeIII
HO
O
HO
+
Y
Y
Egami, H.; Matsumoto, K.; Oguma, T.; Kunisu, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 13633-13635.
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Interaction of Organic Radicals with Transition Metals
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12
Coenzyme Vitamin B12 is a Source of Radicals
! Homolysis of cobalt-carbon bond generates carbon-centered radical capable of performing catalysis
NH2
N
N
N
N
O
5'-deoxyadenosyl radical
OH
O
H2N
H Me
Me
H2N
H
O
Me
N
Me
H2N
CH2
CoII
NH2
O
N
H
Me
R
CH2
CoIII
N
N
O
Me
H
BDE = 30 kcal/mol
Me
Me O
Me
O
NH2
"latent radical reservoir"
N
NH
Me
HO
Me
O
Co
H
R
OH NH2
N
H
O H
O P
O
O
O
H
H
OH
Buckel, W.; Golding, B. T. Annu. Rev. Microbiol. 2006, 60, 27-49.
Catalysis by Coenzyme Vitamin B12
! Glutamate mutase converts (S)-glutamate to (2S,3S)-3-methylaspartate
Ado
CH2
CoIII
CoII
NH4+
-O C
2
Ado
NH4+
CH2
CO2-
CO2-
-O C
2
CH3
(S)-glutamate
(2S,3S)-3-methylaspartate
NH4+
NH4+
Ado
-O C
2
CO2
-
-O C
2
CH3
CO2CH2
NH3+
-O C
2
CO2-
glycyl radical
Buckel, W.; Golding, B. T. Annu. Rev. Microbiol. 2006, 60, 27-49.
Catalysis by Coenzyme Vitamin B12
! Methylmalonyl CoA mutase converts L-methylmalonyl CoA to succinyl CoA
Ado
CH2
CoIII
O
O
S
O
H
CoII
H
O
Ado
CoA
CH2
H
succinyl CoA
O
O
S
O
H
CoA
O
L-methylmalonyl CoA
O
S
O
Ado
CoA
S
O
CH3
CoA
O
H
O
O
O
S
CoA
Banerjee, R.; Ragsdale, S. W. Annu. Rev. Biochem. 2003, 72, 209-247.
Catalysis by Coenzyme Vitamin B12
!
D-ornithine aminomutase converts D-ornithine to (2R,4S)-2,4-diaminopentanoic acid
Ado
CH2
CoIII
CoII
NH2
R
N
R = pyridoxal
phosphate
Me
Ado
NH2
CH2
CO2-
CO2N
D-ornithine
R
2,4-diaminopentanoic acid
R
NH2
NH2
N
H2C
Ado
CO2-
CH3
N
R
N
CO2-
R
NH2
CO2Banerjee, 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
CuII
Ar1•
H2C=CH2
Br
CH3CH2•
L
PdII I
CH3CH2X
Br
L
PdIII I
Et
Ph
Br
Bn
N
Ph
metal-radical interactions
in asymmetric catalysis
CH2
Et
n-Hex
FeII
Ph
!-carbonyl radicals
R
O
O
N
Me
Ar1
radical mechanism of
oxidative addition
oxidation of alkyl radicals
Bn
O
CoII
coenzyme vitamin B12