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Transcript of 5 th Winter Conference on Medicinal and Bioorganic Chemistry (WCMBC) Steamboat Springs, Colorado...
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: [email protected]
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
Victor Snieckus, Queen’s University, Session Chair
C-H Activation: An Overview
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 Dictionary7th 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 H
C OC C
C B C SiC N
CH4: Sen, A. 91 JACS 700Hermann, W. A. 02 ACIE 1745 rev: Fujiwara, Y. 01 ACR 633
Murai, S. 2001 rev: 02 ACR 826
Alk: Hartwig, J. F. 2000;Ar: Smith, M. R. 2000;Hartwig, 2001; Miyaura & Hartwig 2002.
Murai, S.; Alper, H. Activation of Unreactive Bonds and Organic Synthesis, Springer, 1999.
?
Enantioselective Synthesis of β-Amino Acids Csp3-HC-C Bond
N
O
O
O
Rh
Rh
H
SO2Ar
Ar = p-C12H25C6H4[Rh2(S-DOSP)4]
Ph N
PG
Ph CO2Me
N2
Ph N
PG
Ph
CO2Me
2,2-dimethylbutane23°C
77 % yield, 93% eePG = Cbz, Fmoc, Teoc, Boc
CO2H
PhH2N
[Rh2(S-DOSP)4]
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
Csp3-HC-C Bond
N
CO2Ar
O
O
Rh
Rh
H
4
Rh2(S-DOSP)4: Ar = p-C12H25C6H4
Rh2(S-TBSP)4: Ar = p-tBuC6H4
effective cats
O
ON
1. Rh2(S-DOSP)4 tol / rt / 2 h
2. tol wash (5 x) loading 0.17 mmol/g
Rh2(S-DOSP)4
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.
Z
Z
Immobilized di-Rh Complex for Asymmetric C-H Activation
Csp3-HC-C Bond
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.
Ph CO2Me
N2 (0.5 mol %)
tol / rt
Ph CO2Me
OCl
S
ON
S O
(+)-cetledil
80 % yield84-87 % ee10 cycles possible
Rh2(S-DOSP)4Z
Catalytic Arylation, Alkenylation of Unactivated C-H Bonds
Csp3-HC-C Bond
N
S
Me
Si
Pd(OAc)2 (cat)2 eq Cu(OAc)2DMF 100 °C
N
S
Me
N
S
Me
Pd
Ph
AcO
N
S
Me
Pd
Ph
Sames, D. 02 JACS 13372
Ar, HetAr C-H Activation. Addition to Olefins Csp2-H
C-C BondCsp H C C
Ph
Ph
O
N
OH
[Rh] [CpZr+ ] [Ru]
Yamazaki, H. 1978 Jordan, R.F. 1989 Lewis, L.N.; Smith, J.F. 1986
R1
R2
OCO2R
[Pd] / [Cu]Miura, M. 1997
NMe2
[Ru]Pfeffer, M. 2000
FG
ArHet Ar
[Rh] Bergman R.G.;
Ellman, J. A. 2002
Ar H
HetAr H
2
Ar, HetAr C-H Activation. Addition to Olefins Csp2-H
C-C Bond
HetFG
Si(OEt)3
[Ru]Murai,S.1993
Rev: 02 ACR 826
HetFG
O
R
CN
NtBu
H
O
N
N
=
=
=
=
=
HetFG
RuH2(CO)(PPh3)3tol / 2 h135°C reflux
R = Alkyl= OAlkyl
Gallegher, T. 02 OL 3115; see also Larock, R.C. 02 JACS 14326Review: Dyker, G. 99 ACIEE 1699; Fujiwara, Y. O1 ACR 633 (via -complexes)
Competitive Heck Intramolecular C-H Activation
N
RCO2Et
N
Z
Br
D
C
D : C
N
X C
I
D
D : C yld / %
R = NO2 (56%) = OMe (61%)
direct Heck
ZNO2HOMe
3 : 12 : 13 : 1
(85 - 90%)
NBu4NClCspiv
100 : 0 54 : 46
100 93
Conds
N
R
PdIIBr
L
L
N
R
PdII
L
LN
R
Br
N
R
N
R
CO2Et
Pd(OAc)2,(o-Tol)3P/ NEt3
R = NO2R = HR = OMe
3 : 1 7 : 110 : 1
(70%)(90%)(94%)
direct Heck crossover Heck
MeCN 125 °C/ 20 h
CO2Et
CO2Et
Ar-H ActC-CBond Form
Cross Metathesis (CM) as Conceptual Equivalent for Vinyl Substitution and Allylic Oxidation
Csp2-HC-C Bond
R
H
H
H
R
H
X
H
H
H
X
H
H
H
H
H
Ru
PCy3
N N
olefin CM
+ +
Cl
Cl
Ph
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
AcOB
3 O
O
(64%)
Bpin+
via
R' R
H-B
RP(O)(OEt)2
(88-97%)R P(O)(OEt)2+
R = alkyl, aryl
AcOCHO
3
(all-E, 97%)
CHO+
non selective
Activation. Hydroacylation of OlefinsR C H
O
O
HCCCC
O
R
O
70 bar / PhH / 100 OCTOF 4 h -1
Marder, T.B. 1988
[Rh]
O
[Rh]
CHCl3 / rt69% (with ethylene)
Miller, R.G. 1980
O
[Rh]
CH2Cl2 / rtBINAP / Me - Diphos>95%, >99% ee
R*
James, B.R. 1983Sakai, K. 1991Bosnich, B. 1994, 1997
O
HAct
Catalyzed Hydroacylation Reactions. Imines N
HAct
C-C Bond
R
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)
N
CH3
Rh(Cy3P)2 H
ClN
CH3
NH
R1+
R2
N
CH3
N
R1R2
3 mol%Ru3(CO)12
tol / 6 h 130°C
(77-93%)
O
H H N
Me
NH
Ph
O
n
RhI (cat)(n = 0,1,2)
N
Rh
N
Me
Hn
Ph
Enantioselective Synthesis of AlkaloidsCsp3-HC-N Bond
OH
CO2Et
OTBDPS
H2
Rh [(S,S)-Et-DUPHOS)(cod)]OTf
OH
CO2Et
OTBDPS
Me
> 95:5
1. ClSO2NCO, HCO2H
(87%) (3:1 C6 epimers)
O
CO2Et
OTBDPS
MeS
OO
NH22 mol %Rh2(OAc)4
PhI(OAc)2/ MgOCH2Cl2 CO2Et
R'O
OS
HN
OO
MeCO2H
HO
NHN
Me
HO2C
O
NHN
MeO
NH
Br
Du Bois 02 JACS 124, 12950; see also: Hashimoto, H. 02 TL 9561 (general enantioselective activation)
2. separation of isomers
(85%)
Manzacidin A(marine alkaloid) - adreonoreceptor blockerserotonin antagonistactomyosin ATPase activator
CO2Et
R'O
O
S
H
OO
Me
H2N
Activation of Traditionally Unreactive Bonds: Some Categories
C C
C H C X
C Si
Transition Met
30 yrs in progressBergman, P. C. 1982Graham, W. G. 1982Crabtree, R. H. 1979
C H
Enzymatic
review: Holland, H. L.Current Opinion Chem. Biol. 1999, 3, 22cf Lipscomb, J. D. 00 BBA 47Lippard, S. J. 02JACS 14608
McQuillin, F. 1973Alper, H.; Grushin V. V. 1993
C O
without3 complexYamamoto, A. 1975
unstrainedMilstein, D. 1993Whittlesey, M. K.02 JACS 4944PhCH2-H [Ru I Mes]
Tilley, T. D. 01 JACS 10526 Ar-Si [Sm]
Si H
Kubas, G. J.00 Organometallics4193 [Pt]
Si Si
Schubert, C. 1994Ito, Y. 1998
X = Cl (ArCl)
X = F
Milstein, D. 1995cf Jones, W. D. 01JACS 10973Perutz, R. N. 99 JCS Dalton 2039
α – OSiR3 Insertion: Phosphonocyclopentenones
OMe
O
R1
R2
OTBDMS
1. LiCH2PO(OMe)2
2. TsN3 / K2CO3 / MeCN
O
R1
R2
OTBDMS
N2
PO(OMe)2
(50-60%)
PO(OMe)2
OR1
R2
Rh2(OAc)4
PhMe / reflux
(67-74%)
Doutheau, A. et al. 02 TL 4131
Csp3 HC-C Bond Form
α – OSiR3 Insertion: Phosphonocyclopentenones
TBDMSO N2 PO(OMe)2
O
OTBDMS
Rh2(OAc)4
PhMe / refluxO OTBDMS
PO(OMe)2
OTBDMS
(72%)
PO(OMe)2
O
O O
PO(OMe)2
(62%)
Doutheau, A. et al. 02 TL 4131
TBDMSO N2 PO(OMe)2
O
(9%)
Rh2(OAc)4
PhMe / reflux +
Csp3 HC-C Bond Form
H CC
CO2Et
CO2EtNCEtO2C
O
PrOi
O
Me
O
[Ru]
72% (97:3)
Murahashi S.-I., 1989
NC
[Rh]
99%, 86% ee
Ito, Y. 1999
Ph
OOMe
HO
CNCN
Yamamoto, Y. 1994
3sp
100%
C
[Pd]
Csp3HAcidic C-H Activation. Addition to
and Aldehydes
H CC
CO2Et
CO2EtNCEtO2C
O
PrOi
O
Me
O
[Ru]
72% (97:3)
Murahashi, S.-I. 1989
NC
[Rh]
99%, 86% ee
Ito, Y. 1999
Ph
OOMe
HO
CNCN
Yamamoto, Y. 1994
3sp
100%
C
[Pd]
EWG Ar-H ActC-CBond Form
Csp3-HC-C Bond
Enantioselective Synthesis of β-Amino Acids
Ph N
PG
Ph
CO2Me
LiOHH2O / THF Ph N
PG
Ph
CO2H
NH
Ph
CO2Me
O
Ph
NH
Ph
H2NPh
MeO2C
1.
EDC / HOBt / CH2Cl22. 30% HBr in AcOH
.
(67% overall)
This work 02 ACIE 2197; see also 02 TL 9981. Rev: 02 ACR 644; 95 ACR 154
Csp3-HC-C Bond
Catalytic Arylation, Alkenylation of Unactivated C-H Bonds
Sames, D. 02 JACS 13372
N
S
Me
N
S
Me
R
R = Ph (73%)R = PhCH=CH (63%)
Ph2Si(OH)Me or
PhSi(OH)Me2
R
O
N
O
N
R = Ph (78%)R = PhCH=CH (63%)
Ph
OMe
N Ar
OMe
N ArPh
no arylation
arylation
Pd II / CuII
Chelation-Assisted β-Alkylation of Unsaturated Ketones Csp2-H
C-C Bond
O
Ph
R
O
Ph
R
O
Ph
R
RhCl(PPh3)3 (5 mol%)PhCO2H (10 mol%)
sec-amine (50 mol%)PhMe
+
+
R2N
Ph
[Rh] H
This work: Jun, C.-H. et al. 02 TL 4233; Related work: Trost 95 JACS 5371; Murai 95 CL 679; Rev : 00 CEJ 1519
R = H, n-C4H9, Cy, t-Bu, TMSamine = Et2NH, (i-Pr)2NH, Cy2NH
Vinyl C-H Activation. Addition to Olefins
H
H
O
Alk
Si(OEt)3
Murai, S. 1995Trost, B. M. 1995
2Csp C C
Csp3 HC-C Bond Form
Ar C-H Activation. Coupling with Olefins. Addition to Acetylenes
Ar H
Ph
CO2Et
5 equiv Benzene[Pd] / t-BuOOH (20 mol %)56%, TON = 280Fujiwara, Y. 1999Review: 01 ACR 633
Csp2 H C C
+ olefin
+ acetylenePr
Pr
O
[Ru](72 - 83%) [Ru]
(71 - 96%)
Murai, S.1995, 2002 O
R'
R
O
O
TMS
Ph
O
[Ru](83%)
X O
R2
R1
[Pd]X = O, NH, S(50-91%)
Fujiwara, Y. 2000Murai, S.1995, 2002
Murai, S.1995, 2002
Ar C – H Activation. Coupling with CO and Olefins
C CAr HCO
O
HO OHOPR3
RhCl
R3P
H
[Rh] / h / 1 bar / rt benzene = solvent / TON = 74 rev: Pfeffer, M. 02 CR 1731
[Pd] / K2S2O8 TFA / rt
+ CO +
N
NR
OO N Me
NtBu
OH
RuHetFG
[Ru] (65%)Murai, S. 2002
[Ru]pyridine = solventMoore, E. J. 1992
[Ru] Murai, S. 2002
Summary for sp2and sp3C-H bond activation and to heterocyclic N: 02 JOC 7557
rev: Fujiwara, Y. 01 ACR 633
+ CO
Catalyzed Hydroacylation Reactions. Aldehydes O
HAct
C-C Bond
H
O
R
5,6
O
R
5,6
20 mol%Rh(dppe) ClO4
CH2Cl2 / 65°C ethylene(54-65%)
R1 H
O
+ H R2R1
O
R25 mol%[Rh(PPh3)3] Cl
tol / 2 h(63-96%)
Rh
O
LX
L
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)
R1 = Ar, HetAr
R2 = Alkyl, benzyl
Robert Bergman and Group
2002 - PresentGerald E.K. Branch Distinguished ProfessorUniversity of California, Berekeley
1977ProfessorUniversity of California, Berkeley
1969Assistant ProfessorCalifornia Institute of Technology
1966Ph.D.University of Wisconsin(Prof. Berson)
1963B.A.Carleton College
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
Professor Robert BergmanUniversity of California, Berkeley
C-H Activation: the Last Generation Tries to Keep Up with the Next Generation
1992-PresentProfessorYale University
1990-1992Post Doctoral FellowMassachusetts Institute of Technology(Prof. Stephen Lippard)
1986-1990Ph.D.University of California, Berkeley(Prof. Robert Bergman)
1982-1986B.A.Princeton University
John Hartwig and Group
Selected Awards and Honours:
1997 Camille Dreyfus Teacher-Scholar Award
1997 Arthur C. Cope Scholar
1996 Alfred P. Sloan Research Fellow
Professor John HartwigYale University
Catalytic Regioselective Functionalization of Alkanes and Arenes with Borane Reagents
Howard Alper
1963B.ScSir George Williams University
1967Ph.D.McGill University
1967-1968Post DoctoralPrinceton University
1968-1971Assistant ProfessorState University of New York at Binghamton
1971-1974Associate ProfessorState University of New York at Binghamton
1975-1978Associate ProfessorUniversity of Ottawa
1978ProfessorUniversity of Ottawa
1997-PresentVice-Rector, ResearchUniversity of Ottawa
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
1996Associate Vice-Rector, ResearchUniversity of Ottawa
Professor Murai and Group
1999-PresentDean, Faculty Of EngineeringOsaka University
1961-1963M. Eng.Osaka University
1963-1966D. Eng.Osaka University
1966-1973Assistant ProfessorOsaka University
1973-1987Associate ProfessorOsaka University
1987-1999ProfessorOsaka University
Selected Awards and Honours:
1998 The Chemical Society of Japan Award
1985 Divisional Award of the Chemical Society of Japan (Organic Chemistry)