Baran Group Meeting
Radicals & Transition Metals: The Kochi Legacy
Introduction
Jay K. Kochi: Physical organic chemist
Erik Werner
Radicals in Transition Metal Catalysis
Early Years - Kharasch and Sosnovsky
Born 1927 - Los Angeles
Of Japanese descent - Family confined to camps during WWII
B.S.: 1949 UCLA
Ph.D.: 1952 Iowa State university
Lectureship at Harvard
Faculty position at Case Institute of Technology 1962
Moved to Indiana University in 1969
Moved to University of Houston in 1984
Died 2008
O
H2O2
HO
O
HO
OOH
HO
FeII
O
O
O
HO
OH
8
Kharasch, M. J. Org. Chem. 1958, 23, 1322 - above reaction via intermediate dimers
Early Years - Kochi Radical Oxidation
O
FeII
H2O2, MeOH
O
+ CuII
O
MeO
- CuIX
MeO
George Hammond and Jay Kochi
>570 papers - Significant impact on organic, and inorganic chemistry
Early years - Fundamental physical organic chemistry: JACS, 1953, 75, 3445
Depending on solvent
and electronic nature of
radical
R
X
or
R
Nu
or
R
via ligand
transfer
Transition metal oxidations of organic radicals
Fundamentals of transition metal catalysis
Recently - Organic redox couples: JACS, 2008, 130, 1944
O
O
CuII
O
+ CuI
Comprehensive review of radicals in transition metal catalyzed reactions:
Jahn, U. Top. Curr. Chem. 2012, 320, 121
Outline: Kochi contributions in Ag, Cu, Fe catalysis - Brief Ni
Kochi, J. JACS, 1961, 83, 2013 - Olefins or alcohols depending on radical structure
Kochi, J. JACS, 1962, 84, 774, 1572 - Allyl/crotyl esters arising from butene radicals
Kochi, J. JACS, 1962, 84, 2785 - tBu ether products arising from conjugated olefins
Kochi, J. JACS, 1962, 84, 3946 - Summary
Radicals & Transition Metals: The Kochi Legacy
Baran Group Meeting
Early Years - Radical Oxidation
A day in the Kochi Lab:
O
FeSO4
H2O2, MeOH;
butadiene
CuSO4
~ 20 g
Radical Based Cross-Coupling
Silver Catalysis - Kochi
O
O
+
MeO
O
+
OMe
MeO
6%
R
O
+
MeO
Initial studies stoichiometric, found NO3 oxidizes Ag
Net Reaction: Catalytic
2%
O
OMe
MeO
Br
+
tBu
O
+
R'
AgNO3
MgBr
R-R + R-R' + R'-R'
Kinetics: Rate independent of Grignard reagent
16%
45%
O
Erik Werner
Br
: iPr
Br
: nPr
Br
relative rates: 20:3:1
Simplified by the use of CuSO4
HO
R arising from R-Br can be intercepted
8%
Kochi, J. JACS, 1962, 84, 3946
ie:
Early Years - Kochi cross coupling - Practical outcomes
Et
Et-Br + Ag
various
products
Et
Silver
Et
AgBr
MgBr +
Br
Pr
Et-Et + Et-Pr +
Pr-Pr
Proposed mechanism:
Kochi, J. JACS, 1971, 93, 1483
Copper
Et-CuI
+
C2H4 + C2H6 + C3H6 + C3H8
Pr-CuI
R'
Ago
+
Ago
+
R
Br
R
MgBr + AgI-Br
slow
AgI-Br
+
R
AgI-R
AgI-R' + MgBr2
Kochi, J. JACS, 1971, 93, 1485
AgI-R' +
AgI-R
Iron
MgBr +
nHex
Br
FeCl3
nHex
83%
Kochi, J. JACS, 1971, 93, 1487
Kochi, J. JACS, 1971, 93, 1483
R-R + R-R' + R'-R' + 2 Ag0
Baran Group Meeting
Radicals & Transition Metals: The Kochi Legacy
Radical Based Cross-Coupling
Erik Werner
Silver Catalysis - More Synthetic Utility
Silver Catalysis - More Synthetic Utility
20 and 30 alkyl bromides with different catalysts:
But understood?
1 mol% AgNO3
Et2O, 3 h
+
C8H17
Br
BrMg
C6H13
C8H17
R
1.3 equiv
R
Si
Ph
alkylR
alkylR-AgI
+
KF proposed to dissociate AgBr aggregates
Silver Catalysis
2 Ag0 + PhCH2CH2Ph
alkylR-Br
+ AgBr
alkylR
+ Ag0
alkylR-AgI
+ AgCH2Ph
PhCH2-alkylR
Background - Booker-Milburn cleavage of cylopropyloxy radicals
R
O
O
Cu, Fe, Mn
+ Ag0
Authors not sure why cross-coupling predominates
Success due to slow formation of
Oshima,K. Org. Lett. 2008, 10, 969
62%
-10 oC
Radical Oxidation
Silver Catalysis - Oshima's Mechanism
Ag0
Ph
C6H13
20 and 30alkyl bromides with alkyl Zincs: Oshima, Chem. Asian J. 2010, 1487
with benzyl- or fluorenyllithiums: Oshima, Tetrahedron. 2010, 66, 5993
via cyclization of
intermediate radical
2 PhCH2-MgBr + 2 AgNO3
CH2Cl2/Et2O
O
low yield
I
Ph
Oshima, Tet. Lett. 2009, 50, 3270
2.5 mol% AgNO3
1.5 equiv PhCH2Br
Si
+ BrMg
55-87%
Secondary alkyl bromides also work well
Primary give low yields
O
Br
10 mol% AgBr
10 mol% KF
?
de Boer, Tet. Lett. 1973, 14, 827 - Cu/simple substrates
Kwon, J. Org. Chem. 1992, 57, 2399 -Cu/more complex
Booker-Milburn, Tet. 1998, 54, 15321 Fe
O
Radicals & Transition Metals: The Kochi Legacy
Baran Group Meeting
Radical Based Cross-Coupling
Radical Oxidation - β−keto radicals
Wanted to get away from excess Mn
OTBS
OH +
Ph
Copper Catalysis - Kochi
10 mol% AgNO3
pyridine, DMF
O
O
Ph 1.5 equiv (NH4)2S2O8 Ph
Et
Ph
81%
Silver Catalysis - Mechanism
O
Ph
Butane + MgBr2
Ph
Evidence for tBu radical
via trapping with styrene
Ph
Subsequent Cu-catalyzed cross coupling focused on 2 electron chemistry
R2
R2
Cu
Br
OTBS
R1
R1
R2
Et
Br
Via 2 electron chemistry - 1o alkylcuprates not intercepted by alkene
OTBS
O
AgI
CuI or CuII
MgBr
Largely in agreement with Whitesides - JACS, 1966, 88, 4541
Narasaka, K. Chem. Lett. 2006, 35, 18
R1 OH
Erik Werner
Kochi, J. J. Am. Chem. Soc. 1971, 93, 1485
AgI
Radical Oxidation
(NH4)2S2O8
AgI
Ag0
O
+
OTBS
R1
Kharasch-Sosnovsky
O
Ph
R2
R
R
Silver Catalysis - Application
H
O
OH
O
H
O
H
OHC CO2H
O
CuBr
O
H
TBSO
O
R
Works with CuII
But much slower
R
Kharasch, JACS, 1958, 80, 756
OMe
OH
O
OR'
R
O
O
R''
CuI
R'
R'
O
R''
O
Sordarin
R
AgI-catalyzed
radical
cyclization
OH
But CuII?
OTBS
Narasaka, K. J. Am. Chem. Soc. 2006, 128, 6931
O
CuI
+
O
R
O
R
O
R''
R''
Beckwith, Zavitsas, JACS, 1986, 108, 8230
CuIII
OCuII
Radicals & Transition Metals: The Kochi Legacy
Baran Group Meeting
Erik Werner
Copper Catalyzed Radical Oxidation
Copper Catalyzed Transformations - Ligand Transfer
Kharasch-Sosnovsky; Kochi Contribution
How does CuII work? Kinetic studies, detailed analysis of products...
Kochi Precedent
O
O
R
thermal decomp
O
O
O
R'
R'
+
O
Br
O
R
O
- H+
R
+
CuI
CuII
R
O
Kharasch-Sosnovsky like reaction; Application
N
H
N
HN
NHPh
O
CO2Et
53%
O
MeO2C
Me
Cl
DCE, µwave
84%
- 2 HCl
Cl
N
N
CuICl
CO2Et
N
HN
Can also be done with base, then heat 2-pot procedure
N
NHPh
Cl
N
N
Cl
O2CCl2
NHC Ligand
Cl
- CO2
Chloride
isol. at
80 oC
Ligand-transfer
O
O
Cl
CuCl2;
Cl
CuCl
Ligand-transfer
Quayle, ACIEE, 2007, 46, 1869
O
O
Cl CuCl2
O
Cl
Arcadi, Tet. Lett. 1997, 38, 2329
Cl
5 mol% CuCl
5 mol% NHC ligand
CCl3
O
Mechanism?
or polymerization
Modern Application
Kochi, J. Tetrahedron 1968, 24, 5099
MeO2C
Br
MeO
Kochi, J. JACS, 1962, 84, 3946
Once CuI is formed, oxidation of alkenes becomes very rapid
tBuOOCOPh
CuBr, Cu(OAc)2
CuCl2
O
- CO2
R
Br
MeO
MeO
Cl
O
Cl
Cl
Baran Group Meeting
Radicals & Transition Metals: The Kochi Legacy
Copper Catalyzed Transformations - Heterocycle oxidations
Iron Catalysis - Alkyl Halides
5 mol% [Cu(PPh3)Cl]4
THF, reflux
Et
42%
>95% ee
Me
O N
Ph
Me
N
Ph
CuI
MgBr
+ Et
Br
FeII or FeIII
Ethane, Ethylene, very little butane
Like Ag - Rate independent of [Grignard]
Like Cu - See disproportionation rather than cross coupling - alkyl-Br
H
Et
-CuI
-MeCHO
[O] of oxaziridines known since 50's
Emmons, JACS, 1957, 79, 5739
Erik Werner
MgBr
+ tBu
Br
FeII or FeIII
But styrene prevents formation of butane-derived products
Conclusion (by larger community) - alkyl bromides incompatible
overcome later
Me
CuIIO
Kochi, J. JACS, 1971, 93, 1487
N
N
CuIIO
Ph
Iron Catalysis - Vinyl Halides
Br
Br
Me
CuIIO
CuIIO
N
N
Me
FeII or FeIII
Me
+ MeMgBr
+ MeMgBr
High yielding
stereoselective
FeII or FeIII
Me
Odd proposal
Kochi, J. JACS, 1971, 93, 1487
Ph
Iron Catalysis - Vinyl Halides
Aube, JACS, 1992, 114, 5466
Later proposed
THF oxidation
R
10 mol% CuBr
TBHP, THF, air, 60 oC
O
R
FeIII
O
49-67%
Zhang, Org Lett. 2009, 11, 2908
FeI
Br
MeMgBr
FeIII
Me
Kochi, J. JOC, 1975, 40, 599
Kochi, J. JOC. 1976, 41, 502
FeIII
FeIII
Me
Me
Baran Group Meeting
Radicals & Transition Metals: The Kochi Legacy
Erik Werner
Radical Based Cross-Coupling
The mechanism - Decipherable version
Iron Catalysis - The mechanism
FenX +
Ar-Fen
XAr-Fen+1
Ar-M
Fen-Ar
rapid TM to generate active catalyst
ArXFen+1 + R
X-R
+R
SET to form alkyl radical
Ar
R Fen+2X
R-Ar + XFen
Recombination and reductive elimination OR
Ar
R-Ar + XFen
Fen+1X + R
Direct radical coupling with the aryl group
FenX +
Ar-M
Fen-Ar
Catalyst regeneration
Upshot: 1) If you can get to Ar-Fe, successful catalysis should ensue
2) Transmetallation appears to be facile in all cases studied so 1) is readily attainable
3) Catalysts can switch between oxidation states via TM-TM-RE
4) Therefore, multiple cycles may be operative in a given pot
5) 2 electron pathways can not be ruled out in all cases
Kochi, J. and
Bogdonovic, ACIEE, 2000, 39, 4610
Bedford, JOC, 2006, 71, 1104
Nagashima, JACS, 2009, 131, 6078
Makamura, Chem. Comm. 2010, 46, 6054
and many others
Jahn, Top. Curr. Chem. 2012, 320, 191.
Radicals & Transition Metals: The Kochi Legacy
Baran Group Meeting
Erik Werner
Radical Based Cross-Coupling
Unconventional R-X
Iron Catalysis
N
Mes
Fe
Br
N
Mes
OPiv
Ar-Hexenyl + No cyclization
CO2Et +
corresponding L2FeArBr much slower (bromooctene)
nHexyl-MgBr
1 mol% FeCl2
6 equiv LiCl
THF, 0 oC
nHexyl
CO2Et
2 equiv
94%
Br
N
Mes
Fe
N
+
Mes
Ar
17%
Conclusion
Ar2FeIIL2
R
Little mechanistic discussion
Ar
Reaction inhibited by TEMPO
55%
Br
Shi, Z. J. JACS, 2009, 131, 14656
Ar2FeIIIL2Br
Ar-R
R
Radical with
Short Lifetime
Radical Transfer
N
Nagashima, H. JACS, 2009, 131, 6078
Unconventional R-X
MeO
OTs
MeO
1 mol% FeCl3
N
tBuOMe, ArMgX
I
1.2 equiv ZnI2(tmeda)
2.4 equiv PhMgBr , THF;
2.5-5 mol% Fe(acac)2
Ar
Yields 54-91%
Ph
ArMgX
XFen-Ar
- FenX
87%
Compatible with esters, nitriles
thiophenes, alkynes
Via in situ preparation of R-I
in situ preparation of Ar-ZnX
N
atom
abstraction
Nakamura, M. Org. Lett, 2009, 11, 4306
H
+ Ar-Fen+1
Unconventional R-X: Avoiding Grignard reagents
5 mol% FeCl3
1.2 equiv TMEDA
Br +
Br
Ph
1.2 equiv
N
1.2 equiv Mg
THF, 0 o
ArFen+2
Ar2Zn also an effective transmetallating agent
Ph
52%
Deuterium labeling supports intramolecular hydrogen transfer
Potential for enantioselective desymmeterizing reaction?
Via in situ preparation of alkyl Grignard
von Wangelin, A. J. ACIEE, 2009, 48, 607
N
Nakamura, E. JACS, 2010,132, 5568
Radicals & Transition Metals: The Kochi Legacy
Baran Group Meeting
Fe-Catalysis: Iron-II
O
Fe-Catalysis: C-H Cross Coupling
5 mol% [Li(tmeda)2Fe(C2H4]4
PhMgBr, THF, - 20 oC
85%
O
Erik Werner
O
O
O
Ph
I
Tertiary radicals may form, but don't cross couple - Compare to Ag
O
O
"
O
O
Ph
O
+
Ph
O
O
Ph
OMe
Ph
solvent
O
Other compatible solvents:
Et
O
H
Allylic rearrangement faster than cyclization
75%
OMe
77%
I
10 mol% Fe2(CO)9
DTBP, 100 oC
O
82%
O
Et
H
73%
S
Ph
98%
N
H
53%
"
Ph
Li, Z. ACIEE, 2008, 47, 7497
84%
Br
Fe-Catalysis: C-H Cross Coupling via Hydrogen Transfer
15 mol% FeCl3
DCE, 65 oC
Furstner, A. ACIEE, 2004, 43, 3955
Fe-Catalysis: C-H Cross Coupling
Ph
O
20 mol% FeCl2
2 equiv DTBP
12 equiv
MeO
MeOCOCH2CO-pClC6H4Cl
80%
OH
O
p-C6H4Cl
+
Ph
1.5 equiv
62%
O
tBuO
Malonate
Indene
R
R'
R''
Li, Z. ACIEE, 2007, 46, 6505
H
OH
R''
+
FeIV
R
R'
+
Product + FeII
Ph
- FeIII
H
HO FeIII
R
O
Ph
FeIII
R''
FeIII
OH
R'
R'''
Zhang, Y. Q. ACIEE, 2009, 48, 8761
OH R
R''
R'
+
H
FeIV
Baran Group Meeting
Radicals & Transition Metals: The Kochi Legacy
Nickel Cross Coupling
Asymmetric Suzuki cross couplings to deliver challenging products
Many groups have investigated mechanism
Corey: JACS, 1967, 89, 2755
Hegedus: JACS, 1975, 97, 459
Phillips: JOC, 2008, 73, 3680
Eschavarren: JACS, 1994, 13, 2262
Vicic: JACS, 2006, 128, 13175
Kochi, JACS, 1979, 101, 6319
Erik Werner
O
Ph
10 mol% NiII
Et + R-(9-BBN)
N
Ph
Ph
X
MeHN
O
Ph
Ph
NHMe
N
Ph
Et
R
45-80% yield
79-91% ee
racemic
Review: Jahn, Top. Curr. Chem. 2012, 320, 323
R = 1o or 2o alkyl, Ar
Mechanism depends on R-X (Carbon hybridization), ligand, solvent, halide, etc
Gregory Fu
R-(9-BBN)
LnNiI-X
Ln
NiI-R
X
alkyl
SET
R
LnNiII
X
alkyl
Enantiodetermining
SET
R-alkyl
R
- LnNiI-X
LnNiIII
alkyl
X
Conclusion: Kochi an incredibly meticulous physical organic chemist
Invaluable contributions to cross coupling and radical [O]
chemistry
Many of his contributions are not covered
More info on radical/TM chem: Jahn, Top. Curr. Chem. 2012,
320, 121
Fu, G. JACS, 2011, 133, 15362