Alternative Catalyst Sources and Applications in Synthesis of the

Pauson-Khand Reaction

Jill MorrisFebruary 16, 2005

Introduction

• Formally a [2 + 2 + 1] cyclization of an alkene, an alkyne and CO to produce a cyclopenteone

• Typical conditions: Co2(CO)8, solvent, CO (3-40 atm), 80-150° C

Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977-981.

Co catalyst OC O

History in the making…• First Reported in 1971a

• By 1973, was believed that complex (III) was actually (IV) below based on spectral datab

(OC)3Co Co(CO)3

R H

+PhHor

PhMe Co

OC CO

+Co

Co

CoCo

CO

COCO

CO

CO

CO

O

OO

H/Me

(II)(III)

(a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. Chem. Comm. 1971, 36(b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977-981.

O H

H

R

H

(IV)

Mechanism

RC CR' + Co2(CO)8

(OC)3Co Co(CO)3

R R'

(OC)3Co Co(CO)2

R R'

(OC)3Co Co(CO)3

R R'

CO

(OC)3Co Co

R R'

O(CO)2

O(OC)3Co

(OC)2Co

De Bruin, T. J. M.; MIlet, A.; Robert, F.; Gimbert, Y.; Greene, A. E. J. Am. Chem. Soc. 2001, 123, 7184-7185

Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2001, 123, 1703-1708

Limitations of Co2(CO)8

• Stoichiometric amount of catalyst

• Purification before each use

• High temperature (> 100 °C)

• High pressure (~10-40 atm)

• Formation of Co4(CO)12

• Air sensitive and pyrophoric when highly pure

Krafft, M. E.; Boñaga, L. V. R.; Hirosawa, C. J. Org. Chem. 2001, 66, 3004-3020; Comely, A. C.; Gibson, S. E.; Stevenazzi, A.; Hales, N. J. Tetrahedron Lett. 2001, 42, 1183-1185

Catalytic PKR with Cobalt• First example in 1973, modern protocol developing since 1990

• Parameters affecting the PKR

• Concentration of alkyne (low suppress side reactions)

• CO pressure (high promotes PKR)

• Alkene pressure (ethene used, high pressures needed)

• Temperature (high temperature needed)

• Results

• Best result using heptyne and ethene at 47-49 %

Rautenstrauch, V.; Mégard, P.; Conesa, J.; Küster, W. Angew. Chem. Int. Ed. Engl. 1990, 29, 1413-1416

Mechanism of Catalytic PKR

Co

Co

R

Co

Co

R

Co

Co

R

Co

Co

R

O

OR

Co Co

[Co2(CO)8]

CO

CO CO

CO

2 COCO

RO

R

Rautenstrauch, V.; Mégard, P.; Conesa, J.; Küster, W. Angew. Chem. Int. Ed. Engl. 1990, 29, 1413-1416

Modern Catalytic Conditions• Livinghouse

• Additives (amine N-oxides, DMSO)

• Purity of Co2(CO)8

• Solvent (1,2-DME, ethyl acetate, some hydrocarbons)

• Lower CO pressure (1 atm)

• Lower temperatures (50-55 °C with hν; 60-70 °C without)

• Purification requirements for the cobalt catalyst pushed the development of variations to the octacarbonyl dicobalt complex including

• Non-CO ligands on the cobalt metal

• Different metal sources using numerous ligand systems

Pagenkopf, B. L.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118, 2285-2286; Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7637-7640

Alternative Catalytic Ligands• PPh3/P(OPh)3 with Co2(CO)8

a

• Et3SiH with Co2(CO)6-alkyneb

81 %

EtO2C

EtO2C

OAc

Co2(CO)6

HHO

Et3SiH (5 mol%), 30% thiophene, 65°C, 1,2-DME

(10 mol%)EtO2C

EtO2CO

OAc

(a) Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc. 1994, 116, 3159-3160 (b) Belanger, D. B.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7641-7644

81 %

O

Ph

EtO2C

EtO2C

Co2(CO)8 (3 mol%), P(OPh)3 (10 mol%)CO (3atm), DME, 120°C

EtO2C

EtO2C

O Ph

O

Alternative Ligands cont.

(Ph)2P

P(Ph)2

Co(CO)3

Co(CO)3

O

O

R

R'

MeO

OMe

R=alkyneR'=alkene

• Polymer-supporteda

• Bulky propargylic C2-symmetric acetalb

• Vinyl sulfoxidec SR

O

(a) Comely, A. C.; Gibson, S. E.; Hales, N. J. Chem. Comm. 2000, 305-306 (b) Krafft, M. E.; Boñaga, L. V.; Felts, A. S.; Hirosawa, C.; Kerrigan S. J. Org. Chem. 2003, 68, 6039-6042 (c) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc. 2003, 125, 14992-14993

Alternative Ligands cont.

EtO2C

EtO2C

(PPh3)Co2(CO)7 (5 mol%)

1,2-DME, CO (1.05 atm), 75°C O

EtO2C

EtO2C

Ph3P Co Co

N

NOC CO

OC

CO

OC CO

• (PPh3)Co2(CO)7a

• N-Heterocyclic carbene dicobalt complexesb

• Chiral biaryl phosphitesc

(a) Gibson, S. E.; Johnstone, C.; Stevenazzi, A. Tetrahedron 2002, 58, 4937-4942 (b) Gibson, S. E.; Johnstone, C.; Loch, J. A.; Steed, J. W.; Stevenazzi, A. Organometallics2003, 22, 5374-5377 (c) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 2002, 67, 3398-3403

O

OP

O

O

P

O

O

80 %

Alternative Ligands cont.• Chiral phosphine ligands

• Effective route to optically active 2-cyclopentenone derivatives

• Using Co4(CO)12 (3.75 mol%) with ligand (7.5 mol%) also afforded

product; axially chiral diphospanes react with the phosphine free

cobalt centerb

Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron: Asymmetry 2000, 11, 797-808 (b) Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.; Tozer, M.J. Organometallics 2003, 22, 5382-5384

RX

R'

Co2(CO)8 (0.2 equiv.), (S)-BINAP (0.2 equiv.)

CO (atm), DME, reflux

XO

R'

R

Alternative Ligands cont.• Proposed Mechanism

Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.; Tozer, M.J. Organometallics 2003, 22, 5382-5384

OC

Co CoCO

COCO

OCPP

OC

Co CoCO

COCO

OCPP

CO

-CO

OC

Co CoCO

CO

OCPP

OC

Co CoCO

COCO

OCPP O

CCo Co

CO

CO

OCPP

OC

Co CoCO

COCO

OCPP

-CO

+CO

OCO

+CO

O

Alternative Ligands cont.• Chiral bidentate (P, S) ligands

• PuPHOS/CyPuPHOS• Asymmetric

intermolecularcyclization usingnorbornadiene + TMSalkyne

Verdaguer, X.; Moyano, A.; Pericàs, M. A.; Riera, A.; Maestro, M. A.; Mahía, J. J. Org. Chem. 2004, 69, 8053-8061

S

O

CH3

P

R

RH3C

H3C

BH3

R=Ph (PuPHOS)R= Cy (CyPuPHOS)

Summary• Ligands

• Most ligands have limited application exceptions include PPh3,P(OPh)3, chiral diphosphanes and phosphane sulfides

• Additives often still used to promote reaction, sometimes needed• All complexes are easier to utilize than Co2(CO)8• First asymmetric intermolecular PKR

Alternative Metal Sources• Co on charcoal

• Reusable-10 cycles without lose of activity

• Additive needed: 1.26 mmol TsH3CC6H4SO2

EtO2C

EtO2C

0.1g Co/C (Co 12 w%)

CO (20atm), 130° C, THF O

EtO2C

EtO2C

98 %

Son, S. U.; Lee, S. I.; Chung, Y. K. Angew. Chem. Int. Ed. 2000, 39, 4158-4160

Metal Sources cont.• Co nanoparticles on charcoal

• Tandem Hydrogenation-PKR

• Reusable-5 cycles without leaching

• Air stable for several months

MeO2C

MeO2C

H2 (5 atm), CO (5 atm)

Co/C, THF, 130° C, 18h O

MeO2C

MeO2C

92 %

H

H

Son, S. U.; Park, K. H.; Chung, Y. K. Org. Lett. 2002, 4, 3983-3986

Metal Sources cont.• Co on Silica

• Air Stable

• Reusable-4 cycles with small amount of leaching

EtO2C

EtO2C

0.1g Co/Silica (Co 9-10 w%)

CO (20atm), 130° C, THF O

EtO2C

EtO2C

95 %

Kim, S. W.; Son, S. U.; Lee, S. I.; Hyeon, T.; Chung, Y. K. J. Am. Chem. Soc. 2000, 122, 1550-1551

Metal sources cont.• Co/Pd on Silica

• More active than Co/silica and Co/C

• Bleeding occurs after 3 cycles (Pd)

MeO2C

MeO2C

OAc

PCNS (0.1g), CO (10 atm)

THF, NaH, 130° C, 18hO

MeO2C

MeO2C

73 %

+

Park, K. H.; Son, S. U.; Chung, Y. K. Org. Lett. 2002, 4, 4361-4363

Metal sources cont.

MeO2C

MeO2C

trans-[RhCl(CO)(dppp)]2 (2.5 mol%)

CO (1 atm), 110° C, PhCH3 O

MeO2C

MeO2C

96 %

• Rhodium

• Milder conditions

• Metallocycle Intermediates

MLn

R

R'

Jeong, N. Organometallics 1998, 17, 3642-3644

Metal sources cont.• Rh under reduced CO

• Rate acceleration

• Lower temperature

• Low CO pressure

MeO2C

MeO2C

[RhCl(CO)2]2 (5 mol%)CO (0.1 atm) + Ar (0.9 atm)

60° C, PhCH3, 12h O

MeO2C

MeO2C

90 %

EtEt

Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73-87

Metal sources cont.• Rh with BINAP

• Rate faster then with dppp ligand due to decreased Lewisacidity with a phosphine

X

[RhCl(CO)2]2 (3 mol%)(S)-BINAP (6 mol%)

AgOTf (12 mol%), THF 1 atm @ 90° C, 2-3 atm @ 130° C

XO

R

R

H

CO

X= CE2, O, N-TsR= Me, Ph, Bu 40-96 %

Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122, 6771-6772

Metal Source cont.• Tandem allylic alkylation/PKR using Rh

• Control regioselectivity with C-2 center

Np

OCO2Me

CH2NLiTs

TsNO

HNp

[RhCl(CO)(dppp)]2

MeCN, 30° 80° C

82 %Z:E 43:1

Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609-4610

Mechanism using Catalytic Rhodium Complexes

Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609-4610

X

R'R

X

R'

R

MLn XR'

MLnH

R

X

R

R'

MLn

H

X

R'

R

MLn X

R'

O

HR

X

R'

O

HR

H

H

Metal Source cont.

• Aldehyde as CO source with Rha,b

• CO transferc

• No CO gas (poisonous, handle in fume hood)

X

Rh(dppp)2Cl (5 mol%)Ar (atm), 120° C

orRhCl(cod)2/dpppN2 (atm), 130° C

XO

RR

R' H

O

+

(a) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806-3807 (b) Shibata, T.; Tashida, N.; Takagi, K. Org. Lett. 2002, 4, 1619-1621 (c) Shibata, T.; Tashida, N.; Takagi, K. J. Org. Chem. 2002, 67, 7446-7450

Metal Sources cont.• Co/Rh nanoparticles with aldehyde as CO source

• R1, R2 = H, Me, Ph; R3 = Ph, TMS

• Yields: 50-77 %

R1 H

O

R2 R3

O

R3

R2

R1

Co2Rh2

130° C, 18h+

Park, K. H.; Jung, I. G.; Chung, Y. K. Org. Lett. 2004, 6, 1183-1186

Metal Sources cont.• Rh using alkynyl allenes

• Form 5-7 bicyclics

• Form 6-7 bicyclics without dppp ligand

SO2Ph

CZ1 Z1

Z2 Z2R

[RhCl(CO)2]2or

[RhCl(CO)(dppp)]2

toluene, CO (1 atm)

SO2Ph

O

Z2

Z2

Z1

Z1

a: Z1=Z2=H, b: Z1=H, Z2=CO2Me, c: Z1=CO2Me, Z2=H

Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett. 2002, 4, 1755-1758; Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.; Richards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931-1934

Metal Sources cont.

R3

C

R1

R2A

B R2R1

O

R3

R3

O

R1R2

• Mo using alkynyl allenes

• Conditions: Mo(CO)6 (1.2 equiv)DMSO (10 equiv)toluene, 100° C, Ar atm

• Mono and 1,3-sub allenes follow path A

• 3,3-sub allenes follow path B

Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63, 6535-6545

R1 = H, Ph, C7H15, TMSR2 = C4H9, MeR3 = TMS, H

Metal Sources cont.

• Cp2Ti(CO)2a

• (S,S)(EBTH)Ti(CO)2b

• Similar yields, 50-96%ee

• (S,S)(EBTH)Ti(Me)2c

• Slightly reduced yields and %ee

X

Cp2Ti(CO)2 (5-20 mol%)CO (18 psi)

toluene, 90° CX

O

RR

X= CE2, O, N-TsR= Me, Ph, Bu

83-92 %

(a) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.Soc. 1999, 121, 5881-5898 (b) Hicks, F. A.; Buchwald, S. L. J. Am. Chem.Soc. 1999, 121, 7026-7033 (c) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 1999, 64, 5547-5550

Titanium Mechanism

LTi(CO)

LTiX

R

OC

LTiX

R

LTiX

R

LTiX

R

CO

XR

LTiX

R

O

LTi(CO)2

± COCO

CO

X

R

O

Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.Soc. 1999, 121, 5881-5898

Metal Sources cont.• Iridium

• Conditions:[Ir(COD)Cl]2 + 2 (S)-tolBINAP(10 mol%)toluene, CO (1 atm), reflux

• X = O, NTs, CE2R = Ph, Me, p-OMePh

OC

Ir

P

P

Cl

[Ir(COD)Cl]2

tolBINAPunder CO

X

R

IrCl

P

P

XIr

R

Cl

P

P

X

Ir

R

O

P

PCl

CO

CO

enyne

CO

cyclopentenone

Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852-9853

Metal Sources cont.• Ruthenium

• Conditions: Ru3(CO)12 (2 mol%), DMAc or dioxane, 140° C, CO(15 atm)

• Yield were fair to good

• Enynes were varied, best yields with oxygen and N-Ts tethers

• No asymmetric version and high temperature and pressures

Kondo, T.; Suzuki, N.; Okada, T. Mitsudo, T. J. Am. Chem. Soc. 1997, 119, 6187-6188; Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem. 1997, 62, 3762-3763

Summary• Metals

• Metal variations show increased yields and enantioselectivity at times but no single complex stands out

• Heterogeneous catalysts allow easy separation from solution andpossess high turnover

• Aldehydes can be used as carbonyl source with rhodium metal

Synthetic Applications

R

R

O n

1. Co2(CO)8

2. NMOn = 1, 2

R

R

O

O

n

R

R

O

O

n

O

and/or

R = Me, t-BuA B

R = Me; A: 0%, B: 42%R = t-Bu; A: 18%, B: 36%

• Bridged medium sized rings

• MechanismCo

Co

O

R

R

O

R

R

CoCo

R

R

O

O

Lovely, C. J.; Seshadri, H.; Wayland, B. R.; Cordes, A. W. Org. Lett. 2001, 3, 2607-2610

Synthesis cont.• Alkyne + cyclopropene

• R = t-Bu, Ph, Hexyl, Ph3Si, PhCH3C(OH), (CH3)2C(OH)

• Yield: 45-93 % in 5 minutes

R H

1. Co2(CO)8

2. NMO, CH2Cl2-35° C,

R

H

O

H

H

Marchueta, I.; Verdaguer, X.; Moyano, A.; Pericàs, M. A.; Riera, A. Org. Lett. 2001, 3, 3193-3196

Synthesis cont.

R H

1. Co2(CO)8

2. NMO, CH2Cl2

3. h , CHCl3ν

R

OH

• Ortho-substituted phenols

• R = t-Bu, Ph, Hexyl, Ph3Si, PhCH3C(OH), (CH3)2C(OH)

• Goes through a diradical species

Marchueta, I.; Olivella, S.; Solà, L.; Moyano, A.; Pericàs, M. A.; Riera, A. Org. Lett. 2001, 3, 3197-3200

H

H

O

H

H

H

H

O

H

H

H

H

H

H

O

H

H

H

OH

H

H

H

HH

H

H H

Synthesis cont.

OH

H

MeA B

C

OH

H

Br

OTBS

H

O

TBSO

Nitiol

• A-Ring of Nitiol

• Retrosynthesis

• PKROTBS

Co2(CO)8 (10 mol%)

CO (atm), DME, C6H11NH2

H

O

OTBS

H

O

OTBS

+

84 %, Z/E: 5.7:1

Wilson, M. S.; Dake, G. R. Org. Lett. 2001, 3, 2041-2044

Synthesis cont.• Cyclopenta[c]proline derivatives

• Fused bicyclic amino acids, core structure for wide variety of naturalproducts; chiral azabicycles which are believed to form from cyclopenta[c]prolines

NBn

Ph CO2Me Co2(CO)8 (10 mol%)Bu3PS (60 mol%)CO (1 atm)

benzene, 70° C, 4hNBn

H

O

Ph CO2Me

67 %

Jiang, B.; Xu, M. Org. Lett. 2002, 4, 4077-4080

Synthesis cont.

R

R

R

R

O

O

TIPS

TIPS

O

O

PhOMeH

• Dicyclopenta[a, e]pentalene

• Retrosynthesis

• PKR

TIPS

TIPS

O

O

PhOMeH

Mo(CO)6 (10 mol%)DMSO ( 20 equiv)

toluene, Ar, 53-55° C, 48h

TIPS

TIPS

O

OO

O

HPhOMe

65-70 %

Cao, H.; Flippen-Anderson, J.; Cook, J. M. J. Am. Chem. Soc. 2003, 125, 3230-3231

Synthesis cont.

OHCOH

AcO

O

Guanacastepene A

O

OTBS

OTBS

OTBS

OTBS

DPS

• Carbon skeleton of Guanacastepene A

• Retrosynthesis

• PKR

Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491-3494

OTBS

OTBS

DPS

[Rh(CO)2Cl]2 (10 mol%)

tolueneCO (1 atm)

80 °C

O

OTBS

OTBS

DPS

65 %

Conclusion• Catalytic PKR can be affected in high yield and high

enantioselectivity

• Ligand and metal variations in the original Co2(CO)8 catalystpromote these increases with no real outstanding complex

• Lower pressure and lower temperature increases the facility of these reactions

• Utility in organic synthesis is varied and widespread

Acknowledgements• Dr. Babak Borhan

• Family and Friends