5th Winter Conference on Medicinal and
Bioorganic Chemistry (WCMBC)
Steamboat Springs, Colorado
January 26 – 31, 2003
C-H Activation: The New
Generation
Victor Snieckus, Christopher Jones, Bert Nolte and VS Group
Queen’s University
Kingston, ON Canada
Email: snieckus@chem.queensu.ca
Victor Snieckus, Queen’s University, Session Chair
C-H Activation: An Overview
Professor Robert Bergman, University of California, Berkeley
C-H Activation: the Last Generation Tries to Keep Up with the
Next Generation
Professor John Hartwig, Yale University
Catalytic Regioselective Functionalization of Alkanes and Arenes
with Borane Reagents
Professor Howard Alper, University of Ottawa
Metal Catalyzed Reactions of Pharmaceutical Value
?
Professor Shinji Murai, Osaka University
Manipulation of usually unreactive C-H bonds for organic synthesis
Holy Grails of Chemistry
Grail (Holy): cup or platter used (according to legend)
by Christ at the Last Supper, and in which Joseph of
Arimathea received Christ’s blood at the Cross; this as
object of prolonged quest (by medieval knights, or fig.)
[ME, OF groal etc. f. med. L. gradalis dish, of unkn.
orig.]
The Concise Oxford Dictionary
7th Ed. Clarendon Press, 1987.
Reference works define a Holy Grail (“usually
capitalized”) as an “eminently desirable and ultimate
object of extended effort”, a “knightly quest”. … Holy
Grails are also said to be “achievable only by those
chaste in thought, word, and deed”; we leave
judgment in this regard to our readers.
Bard, A.J., Whitesides, G.M.; Zare, R.N.; McLaffertv,
F.W. Acct. Chem. Res. 1995, 28, 91.
Holy Grails of Chemistry
One “Holy Grail” of C-H activation research, therefore,
is not simply t o find new C-H activation reactions but
to obtain an understanding of them that will allow the
development of reagents capable of selective
transformations of C-H bonds into more reactive
functionalized molecules.
Arndtsen, B.A.; Bergman, R.G.; Mobley, T.A.; and
Peterson, T.H. Acc. Chem. Res. 1995, 28, 154.
Holy Grails of Chemistry
I am pleased that you should write to me about the
series of articles "Holy Grails." I do not have any
interest in any of the Holy Grails mentioned in your
letter.
I have been interested in several efforts to find the
Holy Grail, that is, to find the answer to some question
that I had formulated.
Linus Pauling, Acct. Chem. Res. 1995, 28, 93
Reaching for the Holy Grail: Activation of
Traditionally Unreactive Bonds
•
•
•
•
Efficient, economic, clean (green) methods to bulk commodity chemicals
Synthesize new raw materials for industry, medicine, research
Overcome traditional dependence on C-X (X = heteroatom) SMs
C – H Activation: inexpensive, available sources of functionalized carbon
from hydrocarbon feedstocks - oil, petroleum (50% methane), natural gas
•
C – X (X = Cl, F, OR) Activation: destruction of man-made environmental
toxic compounds
•
C – C Activation: application in synthesis
•
Si – Si Activation: materials
•
N triple bond N Activation: discover an environmentally friendly Haber
process – production of ammonia
Murai, S. Ed. Activation of Unreactive Bonds and Organic Synthesis, Springer:
Berlin, 1999. (Book review: Snieckus, V. Advanced Synthesis & Catalysis,
2001, 3, 139)
Herrmann,W.A.; Cornils, B. Angew. Chem. Int. Ed. 1999, 36, 1048.
C-H Activation: The New Generation. Reviews
•
Jones, W.D. In Murai, S. Ed. Activation of Unreactive Bonds and Organic
Synthesis, Springer: Berlin, 1999, p 9. See also Jones, W.D.et al
Organometallics 2002, 21, 5320 (mechanism).
•
Kakiuchi, F.; Murai, S. In Murai, S. Ed. Activation of Unreactive Bonds and
Organic Synthesis, Springer: Berlin, 1999, p 47.
Reviews:
•
Thermal Activation of Hydrocarbon C-H Bonds by Cp*M(NO) Complexes of
Molybdenum and Tungsten, Pamplin, C.B.; Legzdins, P. Acc. Chem. Res.
2003,
Web Release Date: 09-Jan-2003; (Article) DOI: 10.1021/ar0202215
•
Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
•
Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
•
Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
•
Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999, 1047.
•
Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1699.
•
Stahl, S.S.; Labinger, J.A.;Bercaw, J.E. Angew. Chem. Int. Ed. 1998, 37,
2181.
•
Shilov, A.E.; Shul’pin, G.B. Chem. Rev. 1997, 97, 2879.
•
Arndtsen, B.A.; Bergman, R.G.; Mobley, T.A.; and Peterson, T.H. Acc.
Chem. Res. 1995, 28, 154.
•
Crabtree, R.H. Chem. Rev. 1995, 95, 2599.
Direct C-H Activation. Consequences
C
C
C
C
C
O
C
H
CH4: Sen, A. 91 JACS 700
Hermann, W. A. 02 ACIE 1745
rev: Fujiwara, Y. 01 ACR 633
C
B
?
C
N
Alk: Hartwig, J. F. 2000;
Ar: Smith, M. R. 2000;
Hartwig, 2001;
Miyaura & Hartwig 2002.
C
Si
Murai, S. 2001
rev: 02 ACR 826
Murai, S.; Alper, H. Activation of Unreactive Bonds and Organic Synthesis, Springer, 1999.
Enantioselective Synthesis of β-Amino Acids
H
O
Rh
O
Rh
O
N
Csp3-H
C-C Bond
Ar = p-C12H25C6H4
[Rh2(S-DOSP)4]
SO2Ar
Ph
Ph
N
PG
CO2Me
N2
[Rh2(S-DOSP)4]
2,2-dimethylbutane
23°C
77 % yield, 93% ee
PG = Cbz,
Fmoc, Teoc, Boc
Ph
N
PG
Ph
CO2Me
H2N
Ph
CO2H
This work 02 ACIE 2197; see also 02 TL 9981. Rev: 02 ACR 644; 95 ACR 154
Immobilized di-Rh Complex for
Asymmetric C-H Activation
Rh2(S-DOSP)4: Ar = p-C12H25C6H4
Rh2(S-TBSP)4: Ar = p-tBuC6H4
effective cats
H O Rh
N
O Rh
CO2Ar
4
O
N
O
Z
Csp3-H
C-C Bond
1. Rh2(S-DOSP)4
tol / rt / 2 h
Z Rh2(S-DOSP)4
2. tol wash (5 x)
loading
0.17 mmol/g
Rh-pyridine coord
This work: Davies, H. M. L. OL 03 (via DOI: 10.1021/ol0273506). Related work: 02
JOC 6582 (lactams) Rev: Davies, H.M.L. J. Mol. Catal. A. Chem. 2002, 189, 125;
J. Organometalic. Chem. 2001, 617-618, 47; Doyle, M.P. 02 TL 4131.
Immobilized di-Rh Complex for
Asymmetric C-H Activation
Ph
Z Rh2(S-DOSP)4
(0.5 mol %)
N2
Ph
Csp3-H
C-C Bond
CO2Me
CO2Me
tol / rt
80 % yield
84-87 % ee
10 cycles possible
O
S
O
Cl
S
N
O
(+)-cetledil
This work: Davies, H. M. L. 03 OL (via DOI: 10.1021/ol0273506) Related work: 02
JOC 6582 (lactams) Rev: Davies, H. M. L. J. Mol. Catal. A. Chem. 2002, 189, 125;
01 JOMC 617; Doyle, M. P. 02 TL 4131.
Catalytic Arylation, Alkenylation of Unactivated C-H Bonds
Csp3-H
C-C Bond
Si
N
N
S
Me
Pd(OAc)2 (cat)
2 eq Cu(OAc)2
DMF 100 °C
Me
N
N
Pd S
AcO Pd S
Ph
S
Me
Sames, D. 02 JACS 13372
Ph
Me
Ar, HetAr C-H Activation. Addition to Olefins
Ar
H
HetAr
H
Csp2
C
H
C
Csp2-H
C-C Bond
OH
Ph
Ph
N
O
[CpZr+ ]
[Rh]
Yamazaki, H. 1978
[Ru]
Lewis, L.N.;
Smith, J.F. 1986
Jordan, R.F. 1989
R1
NMe 2
O
CO2R
Ar
Het Ar
FG
R2
[Pd] / [Cu]
Miura, M. 1997
[Ru]
Pfeffer, M. 2000
[Rh]
Bergman R.G.;
Ellman, J. A. 2002
Ar, HetAr C-H Activation. Addition to Olefins
HetFG
O
HetFG =
R
=
RuH2(CO)(PPh3)3
tol / 2 h
135°C
reflux
CN
NtBu
=
H
O
=
HetFG
N
Si(OEt)3
[Ru]
Murai,S.1993
Rev: 02 ACR 826
=
N
R = Alkyl
= OAlkyl
Csp2-H
C-C Bond
Ar-H Act
C-CBond Form
Competitive Heck Intramolecular
C-H Activation
R
R
R
R
CO2Et
Pd(OAc)2,
(o-Tol)3P/ NEt3
R
CO2Et
Br MeCN
125 °C/ 20 h
CO2Et
L
L
PdII
PdII Br
N
N
N
direct Heck
X
D
R
direct
Heck
Br
C
Z D:C
NO 2 3 : 1
H
2:1
OMe 3 : 1
Conds
C
N
R = NO2 (56%)
= OMe (61%)
N
(70%)
(90%)
(94%)
Z
CO2Et
N
crossover Heck
R = NO2
3:1
R=H
7:1
R = OMe 10 : 1
I
D:C
yld / %
NBu4NCl 100 : 0 100
Cspiv
54 : 46 93
D
N
(85 - 90%)
L
L
N
Gallegher, T. 02 OL 3115; see also Larock, R.C. 02 JACS 14326
Review: Dyker, G. 99 ACIEE 1699; Fujiwara, Y. O1 ACR 633 (via s-complexes)
Cross Metathesis (CM) as Conceptual
Equivalent for Vinyl Substitution and Allylic
Oxidation
H
N
H
N
H
R
Cl
H
Ph
H
Cl
PCy3
+
H
X
H
X
R
Ru
Csp2-H
C-C Bond
+
H
olefin CM
H
H
H
use excess of more
available partner
if one olefin forms
homo dimer at slower
k than all other rxns
(steric or electronic),
ethylene removed, then
only cross product
H
non selective
via H-B
O
B
AcO
3
O
+
Bpin
+
P(O)(OEt)2
R'
(64%)
P(O)(OEt)2
R
(88-97%)
AcO
R = alkyl, aryl
CHO
3
(all-E, 97%)
R
CHO
+
R
O
R
C
O
H Activation. Hydroacylation of Olefins
O
C
H
O
C
C
C
R
O
O
O
*
R
[Rh]
[Rh]
70 bar / PhH / 100 OC
TOF 4 h -1
CHCl3 / rt
69% (with ethylene)
Marder, T.B. 1988
Miller, R.G. 1980
[Rh]
CH2Cl2 / rt
BINAP / Me - Diphos
>95%, >99% ee
James, B.R. 1983
Sakai, K. 1991
Bosnich, B. 1994, 1997
H
Act
Catalyzed Hydroacylation Reactions. Imines
N
R
Act
H
N
+
CH3
3 mol%
Ru3(CO)12
NH
tol / 6 h
130°C
1
R
2
R
N
CH3
CH3
N
N
(77-93%)
R
R
Ph
Cl
1
2
C-C Bond
Rh
(Cy3P)2 H
Me
O
Me
O
H
n
H
N
NH
RhI (cat)
Ph (n = 0,1,2)
N
N
Rh
n
H
These works: Jun, C.-H. et al., 99 OL 2161; ibid. 02 ACIE 3031; ibid. 00 ACIE 3440;
Related work: Kurosawa, H., 02 Organometallics 5464 (Pt activation)
Csp3-H
C-N Bond
Enantioselective Synthesis of Alkaloids
OH
Me
H2
OH
1. ClSO2NCO, HCO2H
CO2Et Rh [(S,S)-EtDUPHOS)(cod)]OTf
OTBDPS
OTBDPS
S
O
O
NH 2
CO2Et
OTBDPS
HN
PhI(OAc)2/ MgO
CH2Cl2
(85%)
Br
HN
N
O
O
O
2 mol %
Rh2(OAc)4
(87%)
(3:1 C6 epimers)
N
H
2. separation of
isomers
> 95:5
O
Me
CO2Et
Me HO2C
R'O
Me
O
S
HN
O
CO2Et
HO
N
Me
Manzacidin A
(marine alkaloid)
 - adreonoreceptor blocker
serotonin antagonist
actomyosin
ATPase activator
Du Bois 02 JACS 124, 12950; see also: Hashimoto, H. 02 TL 9561 (general
enantioselective activation)
CO2H
O
O
H2N S
H
O
R'O
Me
CO2Et
Activation of Traditionally Unreactive
Bonds: Some Categories
Transition Met
C
Enzymatic
C
H
30 yrs in progress
Bergman, P. C. 1982
Graham, W. G. 1982
Crabtree, R. H. 1979
C
H
C
review: Holland, H. L.
Current Opinion Chem. Biol.
1999, 3, 22
cf Lipscomb, J. D. 00 BBA 47
Lippard, S. J. 02JACS 14608
C
unstrained
Milstein, D. 1993
Whittlesey, M. K.
02 JACS 4944
PhCH2-H [Ru I Mes]
C
Si
Tilley, T. D. 01 JACS
10526 Ar-Si [Sm]
X
X = Cl (ArCl)
McQuillin, F. 1973
Alper, H.;
Grushin V. V. 1993
C
O
without 3 complex
Yamamoto, A. 1975
X=F
Milstein, D. 1995
cf Jones, W. D. 01JACS 10973
Perutz, R. N. 99 JCS Dalton 2039
Si
H
Kubas, G. J.
00 Organometallics
4193 [Pt]
Si
Si
Schubert, C. 1994
Ito, Y. 1998
α – OSiR3 Insertion: Phosphonocyclopentenones
O
O
R1
Csp3 H
C-C Bond
Form
OMe
1. LiCH2PO(OMe)2
2. TsN3 / K2CO3 /
MeCN
R2
OTBDMS
R1
R2
PO(OMe)2
N2
OTBDMS
(50-60%)
O
Rh2(OAc)4
PhMe / reflux
(67-74%)
Doutheau, A. et al. 02 TL 4131
R1
PO(OMe)2
R2
α – OSiR3 Insertion: Phosphonocyclopentenones
OTBDMS
OTBDMS
O
TBDMSO
N2
PO(OMe)2
Rh2(OAc)4
PO(OMe)2
PhMe / reflux
O
OTBDMS
(72%)
O
PO(OMe)2
O
(62%)
Rh2(OAc)4
TBDMSO
N2
PO(OMe)2
PhMe / reflux
+
PO(OMe)2
O
Doutheau, A. et al. 02 TL 4131
(9%)
O
Csp3 H
C-C Bond
Form
Acidic C-H Activation. Addition to
and Aldehydes
Csp3
EWG
H
C
Ar-H Act Csp3 H
C-CBond Form
C
O
HO
O
CO2Et
EtO2C
NC
CO2Et
[Ru]
72% (97:3)
Murahashi S.-I.,
Murahashi,
S.-I. 1989
CN
CN
O
Ph
PrOi
NC
Me
Me
O
[Rh]
[Pd]
99%, 86% ee
100%
Ito, Y. 1999
O
Yamamoto, Y. 1994
Enantioselective Synthesis of β-Amino Acids
Ph
Ph
N
PG
. O / THF
LiOHH
2
Ph
N
PG
CO2Me
1. H2N
Ph
MeO2C
EDC / HOBt / CH2Cl2
2. 30% HBr in AcOH
Csp3-H
C-C Bond
Ph
CO2H
O
Ph
N
H
N
H
Ph
Ph
CO2Me
(67% overall)
This work 02 ACIE 2197; see also 02 TL 9981. Rev: 02 ACR 644; 95 ACR 154
Catalytic Arylation, Alkenylation of Unactivated C-H Bonds
Csp3-H
C-C Bond
OMe
N
N
N
S
Ph
O
Me
no
arylation
Pd II / CuII
Ph2Si(OH)Me
or
Si(OH) Me2
Ph
OMe
Ph
N
R
Ar
R
N
Ar
N
S
O
Me
R = Ph (73%)
R = PhCH=CH (63%)
Sames, D. 02 JACS 13372
R = Ph (78%)
R = PhCH=CH (63%)
arylation
Chelation-Assisted β-Alkylation
of Unsaturated Ketones
Csp2-H
C-C Bond
R
O
O
Ph
+
RhCl(PPh3)3 (5 mol%)
PhCO2H (10 mol%)
Ph
sec-amine (50 mol%)
PhMe
R
= H, n-C4H9, Cy, t-Bu, TMS
R
amine = Et2NH, (i-Pr)2NH, Cy2NH
+
R
R2 N
[Rh]
H
Ph
O
Ph
This work: Jun, C.-H. et al. 02 TL 4233; Related work: Trost 95 JACS 5371; Murai
95 CL 679; Rev : 00 CEJ 1519
Vinyl C-H Activation. Addition to Olefins
Csp2
H
C C
Si(OEt)3
H
Alk
O
Murai, S. 1995
Trost, B. M. 1995
Csp3 H
C-C Bond
Form
Ar C-H Activation. Coupling with Olefins.
Addition to Acetylenes
Csp2
C
H
Ph
Ar
H
+ olefin
C
5 equiv Benzene
[Pd] / t-BuOOH (20 mol %)
CO2Et
56%, TON = 280
Fujiwara, Y. 1999
Review: 01 ACR 633
Pr
Pr
R
+ acetylene
O
R'
Murai, S.
1995, 2002
[Ru]
(72 - 83%)
R1
TMS
[Ru]
(83%)
O
Murai, S.
1995, 2002
[Ru]
(71 - 96%)
Ph
O
O
O
X
Murai, S.
1995, 2002
O
Fujiwara, Y. 2000
R2
[Pd]
X = O, NH, S
(50-91%)
Ar C – H Activation. Coupling with CO and Olefins
O
Ar
H
C
C
CO
O
O
H
OH
PR3
+ CO
Cl
Rh
H
R 3P
[Rh] / h / 1 bar / rt
benzene = solvent / TON = 74
rev: Pfeffer, M. 02 CR 1731
[Pd] / K2S2O8
TFA / rt
rev: Fujiwara, Y.
01 ACR 633
+ CO +
NtBu
N
N
R
O
[Ru]
pyridine = solvent
Moore, E. J. 1992
O N
[Ru] (65%)
Murai, S. 2002
Me
O
H
Ru
HetFG
[Ru]
Murai, S. 2002
Summary for sp2and sp3C-H bond activation and to heterocyclic N: 02 JOC 7557
O
Catalyzed Hydroacylation Reactions. Aldehydes
Act
H
C-C Bond
O
O
20 mol%
Rh(dppe) ClO4
H
5,6
R
CH2Cl2 / 65°C
ethylene
(54-65%)
O
R
1
H
+
H
R1 = Ar, HetAr
R
2
O
X
Rh
5,6
L
L
R
5 mol%
[Rh(PPh3)3] Cl
O
R1
R2
tol / 2 h
(63-96%)
R2 = Alkyl, benzyl
These works: Shair, M. D. et al. 00 JACS 12610; Jun, C.-H. et al. 02 ACIE 2146;
Original work: Sakai, K. et al., 72 TL 1287 (5-rings); Benz, G. A. 91 TL 3473 (6-rings)
How Canadians Save on Toothpaste !
Robert Bergman and Group
2002 - Present
Gerald E.K. Branch Distinguished
Professor
University of California, Berekeley
1977
Professor
University of
California, Berkeley
1969
Assistant Professor
California Institute of
Technology
1966
Ph.D.
University of Wisconsin
(Prof. Berson)
Selected Awards and Honours
2003 ACS James Flack Norris Award in Physical Organic Chemistry
1999 American Institute of Chemists Chemical Pioneer Award
1996 American Chemical Society Arthur C. Cope Award
1963
B.A.
Carleton College
Professor Robert Bergman
University of California, Berkeley
C-H Activation: the Last Generation Tries
to Keep Up with the Next Generation
John Hartwig and Group
1992-Present
Professor
Yale University
1982-1986
B.A.
Princeton University
1986-1990
Ph.D.
University of California,
Berkeley
(Prof. Robert Bergman)
Selected Awards and Honours:
1997 Camille Dreyfus Teacher-Scholar Award
1997 Arthur C. Cope Scholar
1996 Alfred P. Sloan Research Fellow
1990-1992
Post Doctoral Fellow
Massachusetts Institute of
Technology
(Prof. Stephen Lippard)
Professor John Hartwig
Yale University
Catalytic Regioselective Functionalization of
Alkanes and Arenes with Borane Reagents
Howard Alper
1996
Associate Vice-Rector,
Research
University of Ottawa
1971-1974
Associate Professor
State University of New
York at Binghamton
1963
B.Sc
Sir George Williams
University
1997-Present
Vice-Rector, Research
University of Ottawa
1975-1978
Associate Professor
University of Ottawa
1967
Ph.D.
McGill University
1978
Professor
University of Ottawa
1967-1968
Post Doctoral
Princeton University
Selected Awards and Honours:
2000 Gerhard Herzberg Canada Gold Medal for Science and Engineering
1999 Officer of the Order of Canada, 1999
1986 Killam Research Fellow
1968-1971
Assistant Professor
State University of New
York at Binghamton
Professor Howard Alper
University of Ottawa
Metal Catalyzed Reactions of
Pharmaceutical Value
Professor Murai and Group
1999-Present
Dean, Faculty Of
Engineering
Osaka University
1973-1987
Associate Professor
Osaka University
1961-1963
M. Eng.
Osaka University
1987-1999
Professor
Osaka University
1963-1966
D. Eng.
Osaka University
1966-1973
Assistant Professor
Osaka University
Selected Awards and Honours:
1998 The Chemical Society of Japan Award
1985 Divisional Award of the Chemical Society of Japan (Organic Chemistry)
Professor Shinji Murai
Osaka University
?
Manipulation of usually unreactive C-H
bonds for organic synthesis