C a ta lytic R e d u ctive C o u p lin g R e a ctio n s€¦ · without PPh3 alkylative coupling...

Catalytic Reductive Coupling Reactions

Erin VogelMichigan State University

3:00 p.m.28 September 2005

Reductive Hydrogenation

Wilkinson’s Complex

Jardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.

RhCl

Ph3PPPh3PPh3

Rh PPh3ClHPh3P

H

Rh PPh3ClHPh3P

H

Rh PPh3ClPPh3Ph3P

Rh

PPh3

Cl

PPh3

H

R

RhClPPh3PPh3

H2PPh3

R

R

RH

H H

PPh3

fast

Reductive Hydrogenation

Wilkinson’s Complex

Jardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.

RhCl

Ph3PPPh3PPh3

X

R' HR'

X

R

HH

?

Rh PPh3ClHPh3P

H

Rh PPh3ClHPh3P

H

Rh PPh3ClPPh3Ph3P

Rh

PPh3

Cl

PPh3

H

R

RhClPPh3PPh3

H2PPh3

R

R

RH

H H

PPh3

fast

Outline

• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant

• Mechanistic Considerations• Conclusions

Outline

• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant

• Mechanistic Considerations• Conclusions

Cyclopentane Natural Products

Trost, B. Chem. Soc. Rev. 1982, 11, 141—170.

O

OOH

OHH

H

O

Coriolin

HO

HOH

OH

H

Capnellane Isocomene

OO

CO2H

O

Pentalenolactone

Cedrene

CO2H

Retigeranic Acid

OH

OHO2C

H

H

Hirsutic Acid

OCO2H

C5H11HO

Prostaglandins

Alder-Ene Reaction

O N SY:X , , , , , etc.

H

XY

XY

H

HYX

HYX

Choong, N.; Sammes, P.; Smith, G.; Ward, R. Chem. Comm. 2001, 2062—2063.

NPh3C NPh3C140 oC

xylene, 4 dH

H

Pd(0)-Catalyzed Allylic Alkylations

Trost, B. Acc. Chem. Res. 1980, 13, 385—393.

E

OAc

E

EE85%

(Ph3P)4Pd (3-5 mol%)NaH, THF, reflux

E

E

E

OAc

E

OAcPdL

L

E

PdLL

OAc

Nu

E

NuPdL

L

E

Nu Pd(PPh3)4

Trost-Tsuji Reaction

Pd(0)-Catalyzed Couplings

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

allyl acetate (Ph3P)4Pd (3-5 mol%)NaH, THF, reflux enyne

E

E

E

OAc

OAc

OAc

OAc

E

EE

E E

E

E

E

E

entry allyl acetate enyne yield

1

2

3

4

85%

87%

87%

71%

Alder-Ene Cyclization

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.Trost, B.; Lautens, M.; Chan, C.; Jebartham, D; Mueller, T. J. Am. Chem. Soc. 1991, 113, 636—644.

E EE

OAc

H H

E E

E

EE

HE(Ph3P)4Pd

85%

FVT550oC80%

E E

(Ph3P)4Pd87%

E

E FVT78%

EE

Discovery of Reductive Cyclization

Trost, B. Acc. Chem. Res. 1980, 13, 385—393.Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.Trost, B.; Lautens, M.; Chan, C.; Jebartham, D; Mueller, T. J. Am. Chem. Soc. 1991, 113, 636—644.

1 2 3

E

OAc

E

E

E

E

E

(Ph3P)4Pd24 hr, 65 oC

35% H

HE

E

E

650 oC No Reaction

675 oC Decomposition

E

OAc

E

E

E

E

E

(Ph3P)4Pd24 hr, 65 oC

85%

E

OAc

E

E

E

E

E

(Ph3P)4Pd24 hr, 65 oC

85%

Discovery of Reductive Cyclization

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.Trost, B.; Lautens, M.; Chan, C.; Jebartham, D; Mueller, T. J. Am. Chem. Soc. 1991,113, 636—644.

Hypothesis:Pd(0) O2 Pd(2+)

E

EE

H

HE

E

E

Pd (2+)solvent, rt

E

OAc

E

EPd(0) 65 oC

E

EE

H

HEE

E

Pd(2+)rt

Screening Pd(2+) Catalysts

entry catalyst solvent temperature time (h) yield (%)

1 (Ph3P)4Pd THF reflux 12 0

2 Pd(OAc)2 THF room temp. not reported 50

3 (Ph3P)2Pd(OAc)2 THF 64 °C 1.5 70

4 (Ph3P)2Pd(OAc)2 C6D6 60 °C 1.5 85

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

catalystsolvent

E

EE

H

HE

E

E

Catalytic Reductive Cyclization

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

enyne (Ph3P)2Pd(OAc)2 (5 mol%)Ph3P (5 mol%), C6D6, product

E

OAc

OAc

OAc

OAc

E

EE

E E

E

E

E

E

entry allyl acetate enyne yield

1

2

3

4

85%

87%

87%

71%

product yield

H

HE

E

E

E

E

EE

E

E

85%

68%

64%

75%

Catalytic Reductive Cyclization

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

enyne (Ph3P)2Pd(OAc)2 (5 mol%)Ph3P (5 mol%), C6D6, product

E

OAc

OAc

OAc

OAc

E

EE

E E

E

E

E

E

entry allyl acetate enyne yield

1

2

3

4

85%

87%

87%

71%

product yield

H

HE

E

E

E

E

EE

E

E

85%

68%

64%

75%

1,3-Diene vs. 1,4-Diene Formation

Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

Pd(+4)E

E

RHa

E

E

Pd(+4)

R R'

Ha

R'

β−H eliminationαβ

E

E

R'

RL2PdX2

Pd(+4)E

E

RHa

L

L

XX

path aR' and/or R = H

path bR' or R = H

E

E

Pd(+4)

R R'

Ha

E

E

Pd(+4)

HaR

Hb

Hb

R'

R'

Hb

E

E

HaR R'

Hb

E

E

R R'Hb

Ha

E

E

R'

R

E

E

R R'

E

E

R R'

Pd-Catalyzed Cycloisomerizations

Trost, B.; Lautens, M.; Chan, D.; Jebaratnam, D.; Muller, T. J. Am. Chem. Soc. 1994, 116, 4255—4267.

n

n

(+2) Pd

n(+4) Pd

n or

HbR'

(+4) PdHa n

(+4) PdHb

HbR'

n

Hb

R'

Ha

Hb

n(+2) Pd

HaR

HaRR R'

HaR

R R'

R'

R

R'

R

Outline

• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant

• Mechanistic Considerations• Conclusions

Nickel Catalyzed Coupling Reactions

entry ligand R1 yield (%a) yield (%b)1 - H 51 112 - Ph 68 83 PPh3 H 0 924 PPh3 Ph 19 475 PPh3 Bu 16 58

Montgomery, J.; Savchenko, A. J. Am. Chem. Soc. 1996, 118, 2099—2100.

Ph

O

R1

Ph

OR1

Bu

Ph

OR1

H

a

b

Ni R1LL

Ph

O

Ni(COD)2 5 mol%

Bu2Zn/BuZnCl

PPh325 mol %

Proposed Coupling Mechanism

Montgomery, J.; Oblinger, E.; Savchenko, A. J. Am. Chem. Soc. 1997, 119, 4911—4920.Montgomery, J. Acc. Chem. Res. 2000, 33, 467—473.

1

R1

O R2

LnNiR2

BuZnO

R1

HH

Ni R2LL

R1

O

Bu

R2

LnNiR2

BuZnO

R1

H

Ni(COD)2

ZnBu2(transmetallation)

without PPh3

alkylative coupling

with PPh3

reductive coupling

reductive eliminationL = THF or 1

β-hydride eliminationL = PPh3

R1

OH

R2

R1

O

Ni R2LL

R1

O

Stereoselective Preparation of Allylic Alcohols

Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065—9066.

O

HPh H

Ph

Ph Ph

OH BuZnBu2 Ni(COD)2

71%

H

O Ph HOEt

PhZnEt2Ni(COD)2

67%

H

O Ph HOH

PhZnEt2Ni(COD)2 : PBu3

1 : 462%

O

HPh H

Ph

Ph Ph

OH BuZnBu2

Ni(COD)2PBu3

Reductive Coupling of Alkynes and Aldehydes

entry phosphine yield (%) regioselectivity

1 Cy3P 76 77 : 23

2 Et3P 46 91 : 9

3 (n-Bu)3P 77 92 : 8

Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065—9066. Huang, W.; Chan, J.; Jamison, T. Org. Lett. 2000, 26, 4221—4223.

O

HPh H

Ph

Ph Ph

OH BuZnBu2

Ni(COD)2PBu3

O

Hn-Hept H

Ph

n-Hept Ph

OH H

45%

Ni(COD)2 (10 mol%)(n-Bu)3P (20 mol%)

Et3B (200 mol%)toluene, 0 oC, 18 h

MePhO

PhH Ph PhMe

OHNi(COD)2 (10 mol%)phosphine (20 mol%)

Et3B (200 mol%)THF, 23 oC, 18 h100 mol% 100 mol%

Reductive Couplings of Allenes and Aldehydes

Ng, S-S.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 7320—7321.

N N

i-Pri-Pr

i-Pr i-Pr

NHC-iPr (1)

H

R2

HR1

O

H Ar R3SiHcat. Ni(COD)2NHC-iPr (1)

THFR1 Ar

OSiR3

R2

H

n-Pr

Hn-Pr

entry allene product allylic:homoallyic

yield (allylic)Z / E

siteselectivity

ee(%)

1 n-Pr

OSiEt3

n-Pr

94 : 6 80%>95:5 NA 95

2OSiEt3

Me

93 : 7 76%>95:5 >95:5 98

H

Me

HCy

Proposed Coupling Scheme

Ng, S-S.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 7320—7321.

NiO

Ni

Cy H

Me

H L

OHPh

HCy

Me

H

LPh

H

Ni HL

Cy HPh

OR

MeH

H

MeHH

H ROHCy

Ph

Et3SiH

H

Me

HCy

O

H Ph

cat. Ni(COD)2NHC-iPr (1)

THF

NiCy H

Me

H L

R = SiEt3

H

Me

HCy

O

H Phcat. Ni(COD)2NHC-iPr (1)

THFCy Ph

OSiEt3

Me

Et3SiH

Ni-Catalyzed Reductive Couplings of Epoxides

entry X yield (%) regioselectivity(endo:exo)

1 CH2 45 >95:5

2 NBn 65 >95:5

3 C(CO2Me)2 88 >95:5

Molinaro, C.; Jamison, T. J. Am. Chem. Soc. 2003, 125, 8076—8077.

PhX

O

X

OHPh

Ni(COD)2 (10 mol%)Bu3P (20 mol%)Et3B (200 mol %)

ether, 3hendoexo

Mechanism for Ni-Catalyzed Reductive Coupling

Molinaro, C.; Jamison, T. J. Am. Chem. Soc. 2003, 125, 8076—8077

PhX

O

X

OHPh

Ni(COD)2 (10 mol%)Bu3P (20 mol%)Et3B (200 mol%)

ether, 3h

R OHR Ni O

Bu3P

ONiR

Bu3P

OBEt2Ni

R

PBu3Et

OBEt2Ni

R

PBu3HOH

H

R

LnNi-PBu3

Et3B

6-exo-digcyclization

Total Synthesis of Amphidinolide T1 and T4

Colby, E. O’Brien, K.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 4297—4307.

O N

O

MeMe

Me

O

TBSOPhMe

O

Me

TBSOMe

Me OHPh

PhMe

TMS

Me

Ph

TMSMe

OH

Ni(COD)2 (10 mol%)Bu3P (20 mol%)Et3B,

81% yield>99% dr

40-44% yield>95:5 dr

♦

nickel-catalyzed alkyne-aldehydereductive coupling (intramolecular)

nickel-catalyzed alkyne-epoxidereductive coupling (intermolecular)

*O

O

Me

CH2

OMe

Me

O

HOMe

amphidinolide T1

♦

* *♦

O

O

Me

CH2

OMe

Me

MeO

HO

amphidinolide T4

Total Synthesis of Amphidinolide T1 and T4

Colby, E. O’Brien, K.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 4297—4307.

♦

nickel-catalyzed alkyne-aldehydereductive coupling (intramolecular)

nickel-catalyzed alkyne-epoxidereductive coupling (intermolecular)

*O

O

Me

CH2

OMe

Me

O

HOMe

amphidinolide T1

♦

* *♦

O

O

Me

CH2

OMe

Me

MeO

HO

amphidinolide T4

1. Ni(cod)2 (20 mol%)PBu3 (40 mol%)

Et3B, toluene, 60oC

HO

O

OMe

MeO

PhMe Ph

Me

3O

O

Me

OMe

Me

HOMe

Ph

Ph

OPh

OMe

OH

Me

O

HO

Ph Me

O

O

Me

O

OMe

Me

MeO

TBSO

amphidinolide T1

amphidinolide T42. TBSCl, imid.3. O3; Me2S

3

44%, >10:1 dr

70%

31%>10:1 dr

74%

Outline

• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant

• Mechanistic Considerations• Conclusions

Rh-Catalyzed Intramolecular Alder-Ene Reactions

entry R1 R2 catalyst ligand product yield (%) ee (%)

1 Ph Et [Rh(COD)Cl]2 ---- 2a < 5 ----

2 Ph Me [Rh(COD)Cl]2 dppb 2b 84 ----

3 Ph Et [Rh(COD)Cl]2 (R)-BINAP (-)-2c 96 > 99.5

4 Ph OAc [Rh(COD)Cl]2 (S)-BINAP (+)-2d 96 99.7

Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490—6491Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem. Int. Ed. 2002, 41, 3457—3460.

R1

O

R2

O

*R2

R1

1 2

CataystAgSbF6

ClCH2CH2ClO O

5 Ph Et [Rh(COD)Cl]2 (S)-BINAP (+)-2e 93 > 99

6 Ph OAc [Rh(COD)Cl]2 (R)-BINAP (-)-2f 96 >99

P P

dppb =1,4-Bis(diphenylphosphino)butane (S)-BINAP

PPh2Ph2P

Mechanism via Oxidative Cyclometallation

Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.

O

MX

R

O

O

R

O

X

R

O O

X

R

O O

X[RhI]+

O

R

O

M HX

M = [RhIII]+

[RhI]+

x = alkyl, OH, OAc, OBz, H

a

b

c

H

H

H

H

O

Cl

O

Intramolecular Halogen Shift

Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 6370—6371.

O OO O

Cl

10 mol% RhCl(PPh3)3DCE/ reflux

Cl

73% Yield

O

Cl

O

10 mol% RhCl(PPh3)3DCE/ reflux

OO

Cl

92% Yield

Mechanism via Oxidative Cyclometallation

Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organometallics 2001, 20, 3724—3728.

PdX3

Y

PdX4

YPdX4

Y-trans-elimination

2-3-2-X-

-X-

Rates of heteroatom (Y) elimination:

β−halide > β−OAc > β−OR > β−OH ~ β−H

M = [RhIII]+

O

MX

R

O

O

R

O

M HX

O

R

O

M X

X = OAc, OBz

X = Cl, Br

H

H

Mechanism via Oxidative Cyclometallation

Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109—1112.

O

MCl

R

O

O

R

O

H

R

O O

Cl

R

O O

Cl[RhI]+

O

R

O

M ClH

M = [RhIII]+

[RhI]+

a

b

c

H

H

H

Cl

OO

Cl

Reaction Mechanism via π-Allyl Rhodium Species

Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.

R

O O

ClRhI

O

M

O

R

Cl

R

O O

MCl

RhI

M = LnRhIII

O

R

O

R

O O

Cl

Cl

Total Synthesis of (+)-Blastmycinone

OO

C3H7

OO

C3H7O

O

OH

O

C3H7

O

O

O

C3H7O

(-)-Blastmycinolactol

(+)-Blastmycinone(+)-Antimycin

O

OOn-Bu

i-BuO2C

O

O OH HNCHO

C5H11

O O OO

C5H11

C5H11

O O

[Rh(COD)Cl]2(R)-BINAP

AgSbF695%

47%, >99% ee 48%, >99% ee(±)

H, M.; Lei, A.; Zhang, X. Tetrahedron Lett. 2005, 46, 1823—1826.

Outline

• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant

• Mechanistic Considerations• Conclusions

C-C Bond Formation with H2 as Terminal Reductant

Breit, B. Acc. Chem. Res. 2003, 36, 264—275.Evans, D.; Osborn, J.; Wilkinson, G. J. Chem. Soc. A 1968, 3133—3142.

Hydroformylation

O

O

O

Me

Ac

O

O

Me

Me

Ac

Ac

1 mol% [Rh(CO)2acac]CO/H2 (1:1), 80oC

80% yield

anti78%

syn22%

RhH

COPPh3

Ph3PPh3P

RhHPh3P

Ph3P CO

R

RhCO

PPh3Ph3P

RhCO

PPh3Ph3P

RhH

CO

Ph3P

Ph3P

H

RhH

CO

PPh3Ph3P

R

H2

R

O

CO

R

O

O

R

R

HH

H

H

RhCO

COPh3PPh3P

R

H

-PPh3

H

Intramolecular Reductive Aldolization

entry catalyst ligand additive yield aldol (syn:anti) yield 1,4-reduction

1 Rh(PPh3)3Cl --- --- 1% (99:1) 95%

2 Rh(COD)2OTf PPh3 --- 21% (99:1) 25%

3 Rh(COD)2OTf PPh3 KOAc 59% (58:1) 21%

4 Rh(COD)2OTf (p-CF3Ph)3P --- 57% (14:1) 22%

5 Rh(COD)2OTf (p-CF3Ph)3P KOAc 89% (10:1) 0.1%

Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2002, 124, 15156—15157.

Ph

O Catalyst (10 mol%)Ligand (24 mol%)

H2 (1 atm), Addditive (30 mol%)DCE, 25 oC

Ph

OOHO

Ph H

OO

H

Reductive Hydrogenation

Wilkinson’s Complex

Jardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.

RhCl

Ph3PPPh3PPh3

Rh PPh3ClHPh3P

H

Rh PPh3ClHPh3P

H

Rh PPh3ClPPh3Ph3P

Rh

PPh3

Cl

PPh3

H

R

RhClPPh3PPH3

H2PPh3

R

R

RH

H H

PPh3

X

R' HR'

X

R

HH

?

Homolytic HydrogenActivation

Heterolytic Hydrogen Activation

Brothers, P. Prog. Inorg. Chem. 1981, 28, 1—62.

LnRh X

H2

LnRhH

XH

(Base)

LnRh H HX (Base)

RhPh3PPh3P

PPh3

ClRh

Ph3PPh3P

ClH

H

RhPh3PPh3P

PPh3

H

HCl BH+ Cl-B

RhPh3PPh3P

PPh3

H

R

RhPh3PPh3P

PPh3

R

RhPh3PPh3P

PPh3

R

H2

R

B

H

HO H

R'

H2

O

HR'

R' R

OH H

PPh3

Addition of Aldehyde Enolates to Ketones

Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.

OH

CH3O

OH OH

CH3

OH

O O

OHHO

CH3

OHHO

CH3O

1b, 72%, 2:1(16%)

2b, 73%, 10:1(21%)

3b, 63%, 5:1(30%)

4b, 59%, 4:1(29%)

1a, n = 1, m = 1

2a, n = 2, m = 1

3a, n = 1, m = 2

4a, n = 2, m = 2

1b-4b, Yield %, syn:anti,

(Yield % 1,4 Reduction)

O CH3

H

OOH

CH3O

OH

m

Rh(COD)2OTf (10 mol%)(2-furyl)3P (24 mol%)

H2 (1 atm)K2CO3 (100 mol%)

THF, 40 oC

O

nn

m

Proposed Catalytic Mechanism

Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.

H3C

O

O

O

LnRhIHLnRhIII(H2)X-HX (Base)

HX

OH

CH3O

OH

O CH3

H

OO

LnRhI

O

CH3O

OH

LnRhI

O

CH3O

OH

Ln(H)2RhIII

-HX (Base)

H2

Mono-HydrideCatalytic Cycle

Conjugate ReductionManifold Disabled

H

H

H

H

O CH3

H

OO

O CH3

H

OO

O CH3

H

OO

LnRhIX

H2

ConjugateReduction

Di-HydrideCatalytic Cycle

LnRhIIIHX

H

HH

Catalytic Cycloreduction Employing Deuterium

Huddleston, R.; Krische, M. Org. Lett. 2003, 5, 1143—1146.

H3C

O

O

O

O

HO CH3Rh(COD)2OTf (10 mol%)Ph3P (24 mol%)

D2 (1 atm)K2CO3 (80 mol%)

DCE, 80oC83% isolated yieldNo 1,4 Reduction

D

O

Reductive Condensation Continued

Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.

BIPHEPPPh2

Ph2P

No Basic Additives Needed--Heterolytic Hydrogen Activation??

Ph OR

O

R

Ph

OH

OLnRh(I) (5 mol%)Phosphine

DCE (0.1 M), 25 oCH2 (1 atm)

200 mol% 100 mol% 1b-4b

Ph

Ph

OH

O

2-Nap

Ph

OH

O Ph

OH

OS

Ph

OH

OO

1b86%

2b89%

3b78%

4b70%

Proposed Catalytic Mechanism

Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.

LnRhIHLnRhIII(H2)X-HX (Base)

HX

Ph

Ph

OH

O

Ph OPh

O OH

CH3O

OH

O CH3

H

OO

LnRhI

O

CH3O

OH

LnRhI

O

CH3O

OH

Ln(H)2RhIII

-HX (Base)

H2

Mono-HydrideCatalytic Cycle

Conjugate ReductionManifold Disabled

H

H

H

H

O CH3

H

OO

O CH3

H

OO

O CH3

H

OO

LnRhIX

H2

ConjugateReduction

Di-HydrideCatalytic Cycle

LnRhIIIHX

H

HH

Reductive Condensation Continued

Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.

Ph

D OHPh

O

Ph

Ph

OH

O

Ph OPh

O

Predicted

Experimental

Ph OPh

O Rh(COD)2OTf (5 mol%)BIPHEP (5 mol%)

DCE (0.1 M), 25 oCD2 (1 atm)

No Basic Additives Needed--Heterolytic Hydrogen Activation??

Possible Mechanisms for Reductive Coupling

Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.

RhILn

Ph

D

Ph

D OPh

O

RhILn

Ph

D OPh

O

RhIII(D)2Ln

LnRhIX LnRhIDD2

-DX

Ph

O

O

Ph

D2Ph

D ODPh

O

Hydrometallative Mechanism

Heterolytic H2Activation

Ph

D OPh

O

RhIII(D)2Ln

LnRhIX LnRhIDD2

-DX

Ph

O

O

Ph

D2Ph

D ODPh

O

OxidativeCoupling

MechanismHeterolytic H2

Activation

RhIIILnD

Ph

Ph

LnRhIII OPh

O

D

LnRhIX LnRhIIIX(D)2D2

-DX

Ph

O

O

Ph

Ph

D ODPh

O

Hydrometallative Mechanism

Homolytic H2Activation

RhIIIX(D)Ln

Ph

D

Ph

D OPh

O

RhIIIX(D)Ln

D2

Ph

D OPh

O

RhIIIDLn

LnRhIX

Ph

O

O

Ph

D2Ph

D ODPh

O

OxidativeCoupling

MechanismHomolytic H2

Activation

RhIIILnX

Ph

Ph

LnRhIII OPh

O

X

X

Reductive Cyclization of Diynes

Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.

Ph

Ph

H3CO2C

H3CO2C

Ph

Ph

O

Ph

Ph1b, 85% 2b, 78% 3b, 89%

TsN

CH3

CH3

4b, 62%

E

E

Ph

Ph

Rh(COD)2OTf (5 mol%)BIPHEP (5 mol%)DCE (0.1 M), 25oC

D2 (1 atm)

E

E

Ph

D

Ph

D

XR1

R2

Rh(COD)2OTf (3 mol%)rac-BINAP or BIPHEP (3 mol%)

DCE (0.1M), 25 oCH2 (1 atm)

X

R1

R2

Hydrometallative Catalytic MechanismRegio-Determining C-D Bond Formation Precedes C-C Bond Formation

Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.

E

E

Ph

PhE

E

E

E

Ph

D

Ph

Rh(I)Ln

E

E

Ph

D

Ph

E

E

Ph

D

Ph

D

Rh(I)Ln OTf Rh(I)Ln DD2

-DOTf

D2

Rh(I)Ln

DPh

Ph

Rh(III)(D)2Ln

Oxidative Cyclization Catalytic MechanismRegio-Determining C-C Bond Formation Precedes C-D Bond Formation

Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.

E

E

Ph

PhE

ERh(III)LnD

Ph

Ph

E

E

Ph

Rh(I)Ln

Ph

D

E

E

Ph

Rh(III)(D)2Ln

Ph

E

E

Ph

D

Ph

D

Rh(I)Ln OTf Rh(I)Ln DD2

-DOTf

D2

H-D Cross-Over Experiments

Jang, H.; Hughes, F.; Gong, H.; Zhang, J.; Brodbelt, J.; Krische, M. J. Am. Chem. Soc. 2005, 127, 6174—6175.

Hydrometallative Intermediate

Oxidative CyclizationIntermediate

H

Rh(COD)2OTfrac-BINAP

DCE, 25 oC, 2-3 hr

PhX

Et

XRhIIILnD

Ph

D

CH3

X RhIIILn

Ph

CH3

TsN

Ph

H

CH3D2

5 mol% Catalyst LoadingX = NTs, 52% Yield

(42% Alkyne Reduction)X = O, 60% Yield

100 mol% Catalyst LoadingX = NTs, 45% Yield

(8% Alkyne Reduction)X = O, 71% Yield

Cycloisomerization Without Deuterium

Incorporation

A B

PhTsN TsN

H

Ph

HTsN

D

Ph

DTsN

H

Ph

DTsN

D

Ph

H

H2/D2, 95% Yield 1 : 2 : 3 & 480.1 : 19.5 : 0.4

DH, 88% Yield 1 : 2 : 3 & 43.0 : 0.5 : 96.5

1 2 3 4

Rh(COD)2OTfrac-BINAP

DCE, 25 oC, 2-3 hrH2 and D2

or DH

TsNH

Ph

H

TsND

Ph

D

TsNH

Ph

D

TsND

Ph

H

1

2

3

4

TsN Rh(III)LnD

Ph

TsN

Ph

Rh(III)(D)2LnX

TsN

Ph

DD

D2

PhTsN

D

PhTsNRh(III)LnD

LnRh(I)X LnRh(I)DD2-DX

Oxidative Cyclization with Heterolytic H2 ActivationH2/D2, 95% Yield 1 : 2 : 3 & 480.1 : 19.5 : 0.4

DH, 88% Yield 1 : 2 : 3 & 43.0 : 0.5 : 96.5

Oxidative Cyclization with Homolytic H2 Activation

TsN Rh(III)LnX

Ph

TsN

Ph

Rh(III)DLnX

TsN

Ph

DD

D2

PhTsN

D

PhTsNRh(III)LnX

LnRh(I)X

TsNH

Ph

H

TsND

Ph

D

TsNH

Ph

D

TsND

Ph

H

1

2

3

4

H2/D2, 95% Yield 1 : 2 : 3 & 480.1 : 19.5 : 0.4

DH, 88% Yield 1 : 2 : 3 & 43.0 : 0.5 : 96.5

Hydrogen-Mediated C-C Bond Formation

Jang, H.; Krische, M. Acc. Chem. Res. 2004, 37, 653—661.

R1

R2

R1 MLnH

R2 X

H

R1 MLnH

R2

R1 HH

R2

R1

H

R2

X

R3

H MLn(H-X, base)

C-H reductive elimination

LnM X

X

H R3

H2

Homolytic activation of H2

Heterolytic activation of H2

Conventional reduction

C-C bondformation

H2 (1atm)M X (cat)

MLn

R1

R2

X

H R3LnM X

R3

R2R1

R1

H

R2

X

R3

H

H2

H MLn

MLn

MLn

MLnH

HX

Homolytic activation of H2

Conclusions

• Transition-metal catalysis allows access to typically synthetically challenging reactions

• Choice of terminal reductant offers opportunity for reaction modification

• Reductive hydrogenation has been transformed into an effective C-C bond forming reaction

• Understanding reaction mechanisms can help expand the scope of transition metal catalyzed reductive couplings

Acknowledgments

• Dr. Baker• Dr. Smith• Dr. Odom• Dr. Wagner• Group Members: Bao, DJ, Feng, Jon,

Leslie, Ping, Qin, Sampa, Xuwei, and Ying

• Nicki