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

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

How Canadians Save on Toothpaste !

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 Howard AlperUniversity of Ottawa

Metal Catalyzed Reactions of Pharmaceutical Value

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)

Professor Shinji MuraiOsaka University

Manipulation of usually unreactive C-H bonds for organic synthesis

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