CO O

The Pauson-Khand Reaction: The inter- or intramolecular cobalt-catalyzed synthesis of cyclopentenones via coupling of an alkyne, an alkene, and carbon monoxide.

Co2CO8 cat. CO atmC

O O

Co

Co

R1COOC

COCOOC

OCΔΔ

Stoichiometric Catalytic

R

R1 R1R1

R2R2 R2R2

•Alkyne-hexacarbonyldicobalt complexes are kinetically competent intermediates. The complexes are verystable and often utilized as alkyne protecting groups

Co CoOC

OCCOCO

COOC

CODissociativeSubstitution Co CoOC

COCO

COOC

R

R

Co CoCOCO

CO

R

COOC

InsertionCo CoCOCO

CO

R

COOCO

CO

R

ReductiveElimination

O

R

Mechanism: The currently accepted mechanism was originally proposed by Magnus in the context of intramolecular Pauson-Khand reactions: Magnus, P.; Principe, M.; Tet. Lett. 1985, 26, 4851-4854.

•Typically requires elevated temperatures (>60 °C) and long reaction times•The intermolecular variant is mostly limited to reactive alkenes such as norbornene•The carbon monoxide pressure is dependent on the reaction conditions and may vary from 0-40 atm•Pregenerated alkyne-hexacarbonyldicobalt complexes are used for stoichiometric processes

AlkeneInsertion

CO atm

Co2CO8

2 CO

Regioselectivity: Formation of2-substituted cyclopentenones is favored when terminal alkynesare utilized

Diastereoselectivity for internal alkynes

O

R2

H3CH3C

R1O

H

O

R2

H3CH3C

HR1Syn

CO

R2

Co CoOC

OCOC

COCO

CO

R

DMEor

Isooctane

CoOC COCoOC

OCCo

R2

Co COCO

CoOC CO

C CO O

Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. Chem. Comm. 1971, 36

"In addition to the above products, the reaction of norbornadiene with complexes (I) yields hydrocarbon and ketonic products derived from norbornadiene, acetylene, and carbon monoxide."

(I)R = H, Ph

The History of the Pauson-Khand Reaction: An investigation of the chemistry between alkyne Co2CO6 complexes and norbornadiene led to the formation of interesting cobalt complexes and an interesting observation.....

Co CoOC

OCOC

COCO

CO

a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc. Perk. Trans. 1 1973, 975-977. b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M.I. J. Chem. Soc. Perk. Trans. 1 1973, 977-981.

9.4 mol% Co2CO8Iso-octane

C2H2:CO (1:1)

60-70 °C74% yield

•A catalytic reaction was also reported where increased yields relative to the stoichiometric process were observed.

52% yield

Cyclopentenone synthesis: Co2CO6 complexes of ethyne, propyne, phenylacetylene, diphenylacetylene and hex-3-yne

•The above work is often referenced as the first report of the Pauson-Khand reaction even though the ketone containing products were unidentified at the time.

O H

H

O H

H

The Intramolecular Pauson-Khand: Schore's report on the first intramolecular Pauson-Khand reaction rekindled interest in the transformation and served as basis for the intense research activity that followed.

O O

1.0 equiv Co2CO81 atm CO

CO purgedtrimethylpentane

95 °C, 4 d31% yield

1.0 equiv Co2CO81 atm CO

CO purgedtrimethylpentane

95 °C, 4 d60% yield

Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436-5438

O

H3C CH3Co2CO6

adsorbed on silica gel

O2

45 °C, 30 minO O

75% yield

H3C CH3

Simonian, S. O.; Smit, W. A.; Gybin, A. S.; Shashkov, A. S.; Mikaelian, G. S.; Tarasov, V. A.; Ibragimov, I. I.; Caple, R.; Froen, D. E. Tet. Lett. 1986, 27, 1245-1248.

C5H11 Co2CO6

•Rate acceleration observed only for ether containingsubstrates

•The authors speculate that a more reactive conformation is induced by interation with the silica gel surface

•Hydrogen bonding between the silica gel Si-OH andether oxygen may cause bond angle compression(i.e. Thorpe-Ingold effect).

+ O O

O

H

HToluene

100 °C, 24 h

Standard conditions, 47% yieldUltrasonic Irradiation, 52% yield73 mol% Bu3PO, 64 % yield

5.9 equivBillington, D. C.; Helps, I. M.; Pauson, P. L.; Thomson, W.; Willison, D. J. Organomet. Chem. 1988, 354, 233-242

Milder Conditions and Expanded Substrate Scope

Silica Gel Adsorbtion:

Sonication and Phosphine Oxide Additives

Amine-N-Oxide Promoters: The Schreiber N-methylmorpholine-N-oxide modification of the Pauson-Khand reactionallows the process to be effected at room temperature with a wide variety of substrates resulting in excellent yields and high diastereoselectivity.

Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tet. Lett. 1990, 31, 5289-5292

O

OSi(CH3)3

6.0 equiv NMO

CH2Cl2, rt8-16 h

4O

OSi(CH3)3

4

O

H

O6.0 equiv NMO

CH2Cl2, rt8-16 h

Co2CO6

70% yield4:1 dr

O O

H HH

98% yield>25:1 dr

H3C

TBSOO

H

TBSO

H3CH3CH3C

6.0 equiv NMO

CH2Cl2, rt8-16 h

87% yield5:1 dr

•Interestingly, in their 1988 report, Billington and Pauson stated that trimethylamine-N-oxide gave erratic results.

Co CoCOCOOC

OC

OCCo CoOC

OC

OC OO

CO

Co CoOCOC

OC OO

CO

R3N + CO2

Co CoCOCOOC

OC

OC

OR3N

R R

COCO

R3N R3N

R

COR

Amine-N-Oxides Oxidize CO to CO2 and Create Vacant Sites on Cobalt:

Schreiber Concludes his Paper with an Interesting Statement: "However, it is unclear whether or not the N-oxide or the tertiary amine produced during the reaction, can also act as ligands for one of the cobalt-containing intermediates, thereby diverting the steric and electronic course of the reaction away from that ofthe classical, thermal Pauson-Khand."

HO

H3C CH3Co2CO6 +

6.0 equivBrucine-N-oxide

THF, –70 °C, 5 d

O

HO

H3C CH3

76% yield (BORSM)44% ee

N

O

N

O

H

H

H

H

O

H3CO

H3CO

Brucine-N-oxideKerr, W. J.; Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085-1086

Ph

CH3

Co2CO6 3.5 equivcyclohexylamine

DCE, 83 °C, 10 min89% yield

Ph

O

CH3H

The Following Results may be an Indication that Amines do in Fact Bind to Cobalt:

Asymmetric stoichiometric Pauson-Khand reaction with a chiral amine-N-oxide

Cyclohexylamine and ammonia afford large rate accelerations in the stoichiometric Pauson-Khand reaction

O

Ph

Co2CO6

1,4-dioxane 2M NH4OH(aq)

100 °C, 45 min75% yield

O

Ph

O

H H H

Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C. Angew. Chem. Int. Ed. 1997, 36, 2801-2804

H

H

Lewis Basic Promoters: Sulfur as Part of the Side Chain

TsN Co2CO6

3.5 equivcyclohexylamine

1,2-Dichloroethane83 °C, 30 min

HNTs

15% yield

3.5 equivn-BuSCH3

1,2-Dichloroethane83 °C, 30 min

TsN O

79% yield

+Ph

Co2CO6

O

Ph

H

H

Toluene

reflux, 3 d23% yield2.0 equiv

4.0 equivn-BuSCH3

1,2-Dichloroethane83 °C, 30 min

85% yield

6.0 equiv NMO

CH2Cl2, 23 °C, 10 min

Co2CO6

SC2H5Toluene

71 °C, 0.15 h74% yield

O

SC2H5

10 equiv NMO•H2O

CH2Cl2, rt, 0.13 h39% yield

10 equivNMO•H2O

CH2Cl2, rt79% yield

Co Co

H3CS

OCOCOC

COCO

COCo Co

COCO

CO

COOCS

H3C

Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelmann, S.; Van Pelt, C. E. J. Am. Chem Soc. 1993, 115, 7199-7207

10 equiv NMO•H2O

CH2Cl2, rt, 5 d35% yield

O

SCH3•Rate accelerations were observed with heteroatom containing side chains (sulfur being optimal)•Certain chain lengths allowed for stable, isolable complexes to be formed

+Ph

Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett 1999, 771-773

•Sugihara's system effects intermolecular Pauson-Khand reactions with cyclic alkenes such as cyclohexene and cycloheptene as well as terminal alkenes. Intermolecular Pauson-Khand reactions are problematic with N-oxide promoted systems sincealkyne-Co2CO6 complexes undergo rapid decomplexation when treated with N-oxides in the absence of alkenes

Lewis Basic Promoters: Sulfur Containing Additives

N

OO

H

CH3

Co2CO6

N

O

O

O

HH

H3C

(CH3)3NO

93% yieldNTs

OTMS

HH

H3C

H

OMOMNH

CO2H

CO2HH

(–)-α-Kainic acidYoo, S.-E.; Lee, S. H. J. Org. Chem. 1994, 59, 6968-6972

Si(CH3)3

CH3

OOH

Co2CO6 + Δ

86% yield

CH3

OOHO

(H3C)3Si

H

H

sole product

CH3

H

H

H3C HH3C

H

H3C CH3

(13Z)-Spata-13(15),17-dieneDauben, W. G.; Kowalczyk, B. A. Tet. Lett. 1990, 31, 635-638

Hexane, 42 °C, 12 h

55% yield5-6:1 dr

H3CH3C

Co2CO6

O

Ph

CH3

H3CH3C O

CH3

ORH3CH3C

H HH

H3CH

(+)-Hirsutene

Total Synthesis of (–)-α-Kainic acid Via an Intramolecular Pauson-Khand Reaction

A Highly Regioslective Intermolecular Pauson-Khand Reaction: Synthesis of (13Z)-Spata-13(15),17-diene

Chiral Auxiliary-Based Intramolecular Pauson-Khand Reaction: Formal Synthesis of (+)-Hirsutene

Castro, J.; Sorensen, H.; Riera, A.; Morin, C.; Moyano, A.; Pericas, M. A.; Greene, A. E. J. Am. Chem. Soc. 1990, 112, 93889389

O

N CH3

H

H H

CH3H3CO

(–)-DendrobineCH3H3C

CH3N CH3

OAc

1)Co2CO82) NMO•H2O

CH3CN

3) Pd/C, H251% yield

N CH3

H

H H

CH3H3C

O

OAc

Cassayre, J.; Zard, S. Z. J. Am. Chem. Soc. 1999, 121, 6072-6073

Co Co

O

H3C CH3SCH3

COCO

COOCOC

OC

+ Δ

82% yield24:1 dr

OO

RO

H

H H

HH

CH3

OTBS

O

H

CH3

OTBS

CO2C4H9HO

H

HO

O

CH3

(+)-Brefeldin A

Bernardes, V.; Kann, N.; Riera, A.; Moyano, A.; Pericas, M. A.; Greene, A. E. J. Org. Chem. 1995, 60, 6670-6671

N CH3

H

H H

CH3H3C

OAcNC

The Intramolecular Pauson-Khand Reaction in the Total Synthesis of (–)-Dendrobine

Chiral Auxiliary Approach for Intermolecular Pauson-Khand Reactions: Total Synthesis of (+)-Brefeldin A

Co

H

H

H3C

Si(CH3)3

O

O CH3CH3

CH3

H

1:1 mixture of diastereomers

H

H

H3C

Si(CH3)3

O

OCo2CO6 CH3

CH3

CH3

HCo2CO8 (C2H5)2AlCl

CH2Cl2, –78 °C82% yield (2 steps)

> 20:1 dr

H3C H

H

CoOC CO

COCO

COCO

O

H3CH3C

NMOCH2Cl2

rt

70% yield11:1 dr

H3C H

HO CH3

CH3H

O

H

H3C H

HO CH3

CH3H

H

NCH3CO

H

H3C H

HO CH3

CH3H

H

H3C

H

Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1994, 116, 5505-5506Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353-4363

Tandem Nicholas/Pauson-Khand Reaction in the Total Synthesis of (+)-Epoxydictymene

(+)-Epoxydictymene

CH3

100 atm CO, 40 atm C2H40.22 mol% Co2CO8

Toluene, 150 °C, 16 h47-49% yield

OCH3

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

The Catalytic Pauson-Khand Reaction: Even though Pauson and Khand reported a catalytic variant of the reaction in their initial publication, the next catalytic Pauson-Khand reaction appeared only 17 years later.

•Although low catalyst loadings areutilized, prohibitively high pressures ofcarbon monoxide and ethene are required as well as elevated temperatures

A trans-dihydrojasmonate precursor (important to the perfume industry)

2 Co2CO8 Co4CO12 + 4 CO

2-Pentylcyclopent-2-en-1-one Via a Catalytic Pauson-Khand Reaction:

Co4CO12-Catalyzed Inter- and Intramolecular Pauson-Khand Reactions:

•At 50 °C, Co2CO8 is converted to Co4CO12 which is inactive towards alkynes•The equilibrium shifts to the left under high CO pressures

+

0.5 mol% Co4CO1210 atm CO

CH2Cl2, 150 °C, 6 h75% yield O

TsN

0.5 mol% Co4CO1210 atm CO

CH2Cl2, 150 °C, 6 h75% yield

TsN O

•The intermolecular Pauson-Khand reactionsare limited to norbornene and norbornadiene.

Kim, J. W.; Chung, Y. K. Synthesis, 1998, 142-144

Cobalt-Catalyzed Intramolecular Pauson-Khand Reactions: A Very Narrow Thermal Window

TsN7.5 mol% Co2CO8

1 atm CO

DME

TsN O

80 °C, 41%, 3 h60 °C, 86%, 12 h

5 mol% Co2CO81 atm CO

DME

O

50 °C, 50%, 24 h60 °C, 83%, 12 h

EtO2CEtO2C

C2H5O2CC2H5O2C

Only substrate

•Catalytic Pauson-Khand reactions may be performed under one atmosphere of CO with high purity Co2CO8 at 60-65 °CBelanger, D. B.; O'Mahony, D. J. R.; Livinghouse, T. Tet. Lett. 1998, 39, 7637-7640

Alternative Cobalt Catalysts in the Pauson-Khand Reaction: Attempts to replace the toxic and pyrophoric Co2CO8

Co

(1,5-cyclooctadiene)(Indenyl)Cobalt(I)-Catalyzed Pauson-Khand Reactions:

HO +

1.0 mol% 115 atm CO

DME, 100 °C, 40 h96% yield O

HOH

H

(COD)(Indenyl)Co(I)

1

•Negligible reactivity was observed with CpCo(CO)2 and CpCo(COD)•Less reactive and/or strained alkenes such as ethene, cyclopentene, allyl alcohol, and methyl acrylate are not viable substrates

Lee, B. Y.; Chung, Y. K. J. Am. Chem. Soc. 1994, 116, 8793-8794

•Complex 1 is moderately stable and can bestored in the freezer for a prolonged period of time

TsN TsN O

2.0 mol% 115 atm CO

DME, 100 °C, 40 h94% yield

Co2CO8 + Ph3P

THFrt, 30 min65% yield

Co CoPh3P COOC

CO

OC CO

COOC

•Purified by silica gel chromatography!

A Stable Heptacarbonyl(triphenylphosphine)dicobalt(0) Catalyst:5 mol% (Ph3P)Co2(CO)7

1.05 atm CO

DME, 75 °C, 4 h85% yield

H3CO2CH3CO2C CH3 OH3CO2C

H3CO2C

CH3

Ph +

O

Ph

H

H5 mol% (Ph3P)Co2(CO)71.05 atm CO

DME, 75 °C, 4 h96% yield

-CO

•Norbornadiene was the only alkene utilized for intermolecular reactions•The system allows both intra- and intermolecular Pauson-Khand reactions under mild conditions

Gibson, S. E.; Johnstone, C.; Stevenazzi, A. Tetrahedron 2002, 58, 4937-4942

•Identical results are obtained with a catalyst stored at 4 °C for 18 months under an atmosphere of air

Catalytic Asymmetric Pauson-Khand Reaction: A first!

X

20 mol% Co2CO820 mol% (S)-BINAP

1.0 atm CO

DME, reflux, 24 h

PPh2PPh2

(S)-BINAP

X O

53% yield90% ee

31% yield63% ee

R1R2

R1

R2

H3CO2CH3CO2C O

H H3CO2CH3CO2C O

H

CH3

H3CO2CH3CO2C O

CH3

CH3

90% yield0% ee

60% yield93% ee

13% yield62% ee

•Limited substrate scope

•Enantioselectivity varies fromexcellent to non existentdepending on the substituents

TsN O

H

TsN O

CH3

36% yield82% ee

TsN O

CH3

a) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tet. Lett. 2000, 41, 891-895. b) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tet. As. 2000, 11, 797-808

Catalytic Pauson-Khand Type Reactions: Ruthenium Carbonyl

2.0 mol% Ru3(CO)1215 atm CO

DMAC, 140 °C, 8 h

R

C2H5O2CC2H5O2C

H3CO2CH3CO2C O

R

R = CH3, C2H5, C3H7, C4H9, Si(CH3)3 78-89% yield

•High Temperatures and CO pressures are required•Ruthenium carbonyl is an inexpensive, innocuous ruthenium complex1,1- and 1,2-disubstituted olefins are somewhat challenging substrates

H3CO2CH3CO2C O

C2H5

CH341% yield5.6:1 dr

H3CO2CH3CO2C O

C2H5

CH373% yield

Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T-. A. J. Am. Chem Soc. 1997, 119, 6187-6188For another ruthenium carbonyl-based system see: Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem. 1997, 62, 3762-3765

Pauson-Khand Type Reactions: Titanocene-Catalyzed Cyclocarbonylation of Enynes

XR 5-20 mol% Cp2Ti(CO)2

18 psig CO

Toluene, 90 °C, 12-48 hX O

R

C4H9

BnO

O

C4H9

BnO H

C4H9

7.5 mol% cat.

92% yield3.5:1 dr

(i-Pr)3SiO

O

C4H9

H

(i-Pr)3SiO10 mol% cat.

92% yield8:1 dr

C4H9 10 mol% cat.

86% yield O

C4H9

CH3

t-BuO2Ct-BuO2C

CH35 mol% cat.

94% yieldO

CH3

t-BuO2Ct-BuO2C

CH3

a) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 9450-9451. b) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5881-5898. c)Buchwald,S. L.; Hicks,F. A. in Comprehensive Asymmetric Catalysis; Jacobsen E. N., Pfaltz, A., Yamamoto,H., Eds; Springer: Berlin, 1999; Vol. II, p 491

Cp2Ti(CO)2X

R

Cp2Ti

R

X

CO

OC

COCp2Ti

R

XXCp2Ti

R

COOCCO

XCp2Ti

O

ROC

CO

Cp2Ti

OR

COX

XCp2Ti

O

OC

R

Cp2Ti

O R

X CO

First proposed mechanism

Second proposed mechanism

COXO

R

•Lower loadings of a commercially available catalyst provide higher yields than previous titanium-based systems developed by Buchwald

•Excellent functional group compatibility: ethers, amines, esters, nitriles, and ketones are tolerated

•1,1- and 1,2-disubstituted olefins are viable substrates but terminal alkynes require 20 mol% catalyst in order for high yields to be obtained

•The mechanism of the reaction is unclear, however, discrepencieshave been observed between a previous system which relied on the extremely unstable Cp2Ti(P(CH3)3)2 as catalyst

Catalytic Asymmetric Pauson-Khand Type Reaction: (S,S)(EBTHI)Ti(CO)2

TiOC CO

(S,S)(EBTHI)Ti(CO)2

XR1

R2

(S,S)(EBTHI)Ti(CO)2 cat.2.0 atm CO

Toluene, 90 °C, 12 hX O

R1

R2

O O

Ph

H20 mol% cat.

85% yield, 96% ee

O

Ph

H20 mol% cat.

70% yield, 87% ee

O

Ph

HC2H5O2CC2H5O2C

7.5 mol% cat.92% yield, 94% ee

O

C3H7

HC2H5O2CC2H5O2C

5.0 mol% cat.94% yield, 89% ee

O

C3H7

HC2H5O2CC2H5O2C

5.0 mol% cat.94% yield, 89% ee

O

CH3

HC2H5O2CC2H5O2C

5.0 mol% cat.90% yield, 87% ee

BnN O

CH3

H15 mol% cat.

82% yield, 92% ee

O

CH3

CH3

t-BuO2Ct-BuO2C

20 mol% cat.90% yield, 72% ee

O

H

Ht-BuO2Ct-BuO2C

20 mol% cat.87% yield, 50% ee

CH3

OC2H5O2CC2H5O2C

20 mol% cat.77% yield, 47% ee

•Low ees are observed with terminal alkynes and 1,7-enynes

•3- or 5-substituted enynes are poor substrates

•Failure to cyclize sterically demanding substrates likely arises from unfavorable steric interactions between the ligand and the substrates

R

C2H5O2CC2H5O2C

R = i-Pr, C5H9, SiH(CH3)2

Substrates wich cannot be cyclized:

Ph

H3CH3C

BnOC4H9

TIPSO C4H9

BnO

Ph

C2H5O2CC2H5O2C

CH3

R

C2H5O2CC2H5O2C

R = CH3, Ph O

Ph CH3

t-BuO2Ct-BuO2C

a) Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 11688-11689. 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

Catalytic Asymmetric Pauson-Khand Type Reactions: Rhodium

3 mol% [(CO)2RhCl]29 mol% (S)-BINAP

12 mol% AgOTf

0.5-3 atm COTHF, 90-130 °C, 3-20 h

XR

X O

R

H

PPh2PPh2

(S)-BINAP

O

CH3

HC2H5O2CC2H5O2C

93% yield71% ee

O

CH3

Hi-PrO2Ci-PrO2C

40% yield90% ee

O

Ph

HC2H5O2CC2H5O2C

67% yield61% ee

O

Ph

H61% yield51% ee

O O

CH3

H40% yield96% ee

O O

Ph

H88% yield81% ee

O O

C4H9

H60% yield65% ee

TsN O

CH3

H80% yield84% ee

TsN O

Ph

H93% yield74% ee

Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122, 6771-6772. b) Jeong, N.; Lee, S.; Sung, B. K. 1998, 17, 3642-3644For other rhodium-catalyzed systems see: Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73-87

[(CO)2RhCl]2

2 (S)-BINAP2 AgOTf

2 AgCl

RhCO

COP

P

RhCO

XR

Rh

XR

HCO

PP

PP

CO

RhPP

XO

CO

H

X O

R

H

Plausible Mechanism

•Limited to unsubstituted alkenes•Enantioselectivity and yields range from modest to excellent

CO

CO

XR

CO

CO

Catalytic Asymmetric Pauson-Khand Type Reactions: Iridium

5.0 mol% [(COD)IrCl]210 mol% (S)-tolBINAP

1 atm COToluene, reflux, 20-72 h

XR

X O

R PAr2PAr2

(S)-tolBINAP

[(COD)IrCl]2

2 (S)-tolBINAP

2 COD

IrCO

ClP

P

IrCl

XR

Ir X

R

Cl

PP

PP

IrPP

XO

Cl

XR

X O

R

Plausible Mechanism

Ar = 4-tolyl

O

O

H3CO80% yield96% ee

O O

CH3

75% yield97% ee

O

O

54% yield90% ee

Ph

TsN O

Ph

85% yield95% ee

O

Ph

74% yield84% ee

C2H5O2CC2H5O2C

O O

Ph

30% yield88% ee

CH3

+ CO

OC

Ph

CH3+

5.0 mol% [(COD)IrCl]210 mol% (S)-tolBINAP

1 atm COToluene, reflux, 20-72 h

32% yield, 93% ee

O

Ph

CH3

•Low CO Pressure yet lengthy reaction times and high catalyst loadings of an expensive iridium complex are required

•May be performed intermolecularly with excellent ee albeit at the expense of yield

•1,1-disubstituted olefins are sluggish but product is obtained with good ee

•No examples of 1,2-disubstituted olefins

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

CO

COCO

Expanding the Scope of the Pauson-Khand Reaction:

CH3

O 10 mol% Cp2Ti(PMe)218 psig CO

Toluene, 105 °C, 15-18 h98% yield

O OH3C

H

γ-Butyrolactones from Enones

H3C

O

CO2C2H5

1.1 equiv Cp2Ti(PMe)215 psig CO

70 °C90% yield

OO

H3C CO2C2H5

Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L.; J. A. Chem. Soc. 1996, 118, 5818-5819

H3CO2CH3CO2C CH3 1.0 mol% (Ph3P)2RhCl(CO)

1.0 mol% AgSBF6

DCE, rt, 24 h96% yield

O

CH3

H3CO2CH3CO2C

The Dienyl Pauson-Khand Reaction

Wender, P. A.; Deschamps, N. M.; Gamber, G. G. Angew. Chem. Int. Ed. 2003, 42, 1853-1857