1

Co2(CO)8 MediatedPauson–Khand Reaction (PKR)

Nathan BennettMay 11, 2009

R1 R2

R5

R6R4

R3+

Co2(CO)8

Promoter / SolventCO atmosphere

O

R1

R2

R6R5

R3

R4

Xn

R

R'

(n = 1-3)X = O, NR'', CR''2

Co2(CO)8

Promoter / SolventCO atmosphere

Xn

R

O

R'

Pauson-Khand Reaction (PKR) General Information

R1 R2

R5

R6R4

R3+

TransitionMetal Complex

Promoter / Solvent(CO atmosphere)

O

R1

R2

R6R5

R3

R4

Xn

R

R'

(n = 1-3)X = O, NR'', CR''2

TransitionMetal Complex

Promoter / Solvent(CO atmosphere)

Xn

R

O

R'

Kürti and Czakó. Pauson Khand Reaction, In Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Amsterdam and Boston : 2005, pp 334–335.

Schore, Chem. Rev. 1988, 88, 1081–1119. (PKR 1085–1091)

Transition Metals = Co, Rh, Ti, Ru, Mo, W, Fe, Ni, Zr, Ir, Pd

Promoters = NaBH4, Amines, Nitriles (CH3CN), Amine N-Oxides (NMO, TMAO), Thioureas, Phophines, Phosphites, Sulfoxides (DMSO), Sulfides, Thioacetals, Silica Gel

Solvent = Benzene, Toluene, DCM, Acetonitrile, DMSO, Methanol, Hexanes, Ethyl Acetate, etc.

Completely compatible with ethers, alcohols, 3° amines, thioethers, ketones, ketals, esters, 3° amides, aromatic rings (benzene furan, thiophene)

Partial tolerance to alkyl/aryl halides, vinyl ethers and esters, ordinary alkene and alkynes in presence of more reactive unsaturation

2

PKR General Information

R1 R2

O

R1

R2

R6R5

R3

R4

Kürti and Czakó. Pauson Khand Reaction, In Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Amsterdam and Boston : 2005, pp 334–335.

Schreiber, J. Am. Chem. Soc. 1986, 108, 3128–3130.

(CO)3Co Co(CO)3

R1 R2

Co2(CO)8

Promoter / SolventCO atmosphere

R1 R2

Co2(CO)6

R5

R6R4

R3

Co(CO)3

Co(CO)3

R2

MeO HMe

Lewis AcidCo(CO)3

Co(CO)3

R2

HMe

Geometry Changes

Isolable

NucleophileCo(CO)3

Co(CO)3

R2

Nuc HMe

Electronic Changes – Nicholas Reaction

CoCoCoCoR2O

R1 Co

R1R2O

COH

R2O

H

Co

R1

O

R2O

H

O

CoCo

R1R2O

H

O

R1

Magnus, Tetrahedron Lett. 1985, 26, 4851–4854.Magnus, Tetrahedron 1985, 41, 5861–5869.

Δ

Isolable

PKR MechanismMagnus Mechanism

3

Co

Co

Co

CoH

HOC

COCO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

H OC

OCCO

CO

COCO

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.

–CO +alkene

+CO –alkene

Ligand Substitution CobaltacycleFormation

+CO

CO Insertion

+COOH

H

OC CO

OC COCO

PKR MechanismGeneral Mechanism

ReductiveElimination

–Co2(CO)8O

H

H

Co

CoH

HOC

COCO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

COCo

CoH

H OC

OCCO

CO

CO

Co

CoH

H OC

OCCO

CO

COCO

0.0

+33.5

+12.0

+28.5

+14.1

–14.1

(33.5) (16.5)

Ligand Substitution Cobaltacycle Formation

Rate DeterminingStep

Stereochemical DeterminingStep

PKR MechanismDFT Calculations

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.

A

B

C D

E

F

4

PKR Early Work

Khand and Pauson, J. Chem. Soc. Chem. Comm. 1971, 1, 36.Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 975–977.Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1976, 1, 30–32.

Origin

J. Chem. Soc., Perkin Trans. 1 1973, 9, 975–977 and 977–981 Originally reported by Peter L. Pauson in 1973 First Author: lhsan U. Khand Two Other Authors: Graham R. Knox and William E. Watts Department of Pure and Applied Chemistry University of Strathclyde in Glasgow, Scotland Pauson refers to as "Khand Reaction"

Peter L. PausonFour Main Papers

First Example in Literature

Adam Hoye, (Jun 2007) http://ccc.chem.pitt.edu/wipf/Frontiers/Adam.pdf, (Accessed May 2, 2009).Connection with Ferrocene: Hoffmann, Angew. Chem., Int. Ed. 2000, 39, 123–124.

Khand and Pauson, J. Chem. Soc. Chem. Comm. 1971, 1, 36.Khand and Pauson, J. Chem. Soc., Perkin Trans. 1, 1973, 9, 975–977.

R1= H, Ph

R2 = H, Ph+

CoOC CO

Co

Co

Co

Co

O O

OCOC

COCO

O

OC CO

R2

(CO)3Co Co(CO)3

HR1

+

PKR Early WorkFirst Publications

Co

Co

Co

Co

O O

OCOC

COCO

O

OC CO

R3

+

HH

O

R1

R2

+(CO)3Co Co(CO)3

R2R1

R3 = H, Ph

R2

R3

5

R1

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.

+(CO)3Co Co(CO)3 H

HO

R1

R2

HH

O

R1

R2

HH

O

HH

O

R1

R2

HH

OR1R2 R2

R1R2R1

PhH or PhMe+

A B C

PKR Early WorkPublication Main Results

entry BA CR2

% Yield

1 2943 4H H

2 1733 4.4H Me

3 1345 n/aH Ph

4 n/a28 n/aPh Ph

5 n/a23 n/aEt Et

+

CoOC CO

Co Co(CO)3

O

O

OCCo Co

O

O

OC CO

+

Co

CoR1

R2OC

COCO

OCCO

CO

Co

CoR1

R2OC

OCCO

CO

COCO

Magnus, Tetrahedron Lett. 1985, 40, 4851–4854.Magnus, Tetrahedron 1985, 24, 5861–5869.

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.

CobaltacycleFormation

+CO

PKR MechanismDetermining Stereochemistry

CO

Co

CoR1

R2OC CO

OCCO

CO Co

R1

OCCO

Co

CO

R2

a

b OR

B (Favored)A (Unfavored)

(CO)3Co

Co

CO Insertion

+COOR2

R1

OC CO

ReductiveElimination

–Co2(CO)8

R2 > R1

HH

R2

R1

O

LigandSubstitution

Worse Sterics

6

Pauson and Khand, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.Billington and Pauson, J. Organomet. Chem. 1988, 354, 233–242.

"Moreover when the samples of the mixture from the condensation reactionwere withdrawn at intervals and examined by g.l.c. it was found that theendo-isomer was barely detectable after 1 h but increased steadily withreaction time. Thus, endo-isomer arises by catalysed isomerisation of theexo-isomer formed in the initial reaction.

This isomerisation is irreversible: a sample of pure endo-ketone was heated inthe presence of octacarbonyldicobalt for 18 h showed no trace of the exo-isomer . . .

The isomerisation, unlike the condensation reaction must require the seconddouble bond since no endo-isomer of ketone (A) was found.

Moreover it is strongly hindered by substitution: we do not detect peaks attributable to endo-isomers in the ketones from substituted acetylenes . . . "

PKR Early WorkExo–Endo Isomerization

+(CO)3Co Co(CO)3 H

HO

R1

R2R2R1

PhH or PhMe1 h

HH

O

TimeR1

R2

Co2(CO)8

18 h

A

Pauson and Khand, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.Billington and Pauson, J. Organomet. Chem. 1988, 354, 233–242.

PKR Early WorkExo–Endo Isomerization

On working with rate enhancing procedures:

"This conflicted with the earlier conclusion that the endo–compound results from isomerisation of the exo form. Indeed, when a sample of pure exo–ketone was keptat 70 °C in the presence of octacarbonyldicobalt for 24 h no such isomerisation occurred but less than 50% of the ketone was recovered. We concluded that the previously noted change in isomer ratio of a mixed sample must have resulted from differential rate of loss of the two stereoisomers and not from isomerisation."

∆, Time

Degradation

+(CO)3Co Co(CO)3 H

HO

R1

R2R2R1

PhH or PhMe1 h

HH

O

TimeR1

R2

Co2(CO)8

18 h

A

7

H

R1

+(CO)3Co Co(CO)3

R2R1

PhH or PhMe

PKR Early WorkOther Substrates

entry % YieldR2

1 23H H

2 38H Me

3 31H Ph

4 28Ph Ph

O

R2R1

HCO2Me

CO2Me

CO2Me

CO2Me

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.

+H

HO

Co2(CO)8iso-octane, 60–70 °C

1)

2) CO: (1:1) 60–70 °C

Norbornene Product

g mmol g mmol g % Yield

1.0 3 3 32 3.54 74

.52 1.5 6.05 64.25 5.8 61.5

mol %

9.4

2.3

PKR Early WorkFirst Catalytic Example

Co2(CO)8

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.

8

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.

+(CO)3Co Co(CO)3 H

HO

R1

R2

HH

O

R1

R2

HH

O

HH

O

R1

R2

HH

OR1R2 R2

R1R2R1

PhH or PhMe+

A B B

PKR Early WorkPublication Summary

Bulkier alkyne substituent located at C–2 position Exo-isomer major product Bis–functionalized product possible Dicobalt mono– and bis–norbornadiene carbonyl complexes not part of mechanism Endo and Exo-isomers degrade (no isomerization) Impact of substitution and electronics of alkene First catalytic example

+

R1entry BA CR2

% Yield

1 2943 4H H

2 1733 4.4H Me

3 1345 n/aH Ph

4 n/a28 n/aPh Ph

5 n/a23 n/aEt Et

R1

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1976, 1, 30–32.

+(CO)3Co Co(CO)3 H

HO

R1

R2R2R1

PhH or PhMe

PKR Early WorkExpanding Reaction Scope

entry % YieldR2

1 43H H

2 33H Me

3 45H Ph

4 28Ph Ph

5 23Et Et

R1entry % YieldR2

6 65Me Ph

7 38Me SiMe3

8 aMe CH2C≡CMe

9 aMe CH2CH=CHMe

a Unpublished results.

9

H

R1

+(CO)3Co Co(CO)3

R2R1

PhH or PhMe

PKR Early WorkExpanding Reaction Scope

entrya % YieldR2

1 23H H

2 38H Me

3 31H Ph

4 28Ph Ph

5 80H H

n n

O

R2R1

HCO2Me

CO2Me

CO2Me

CO2Me

n

1

1

1

1

2

6 36H Me2

7 85H Ph2

1. Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1973, 9, 977–981.2. Khand and Pauson, J. Chem. Res., Synop. 1978, 346–347.

a Entries 1-4, see Ref 1. Entries 5-7, see Ref 2.

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1976, 1, 30–32.

+(CO)3Co Co(CO)3 H

HO

R1

R2R2R1

PhH or PhMe

PKR Early WorkImpact of Distant Sterics

R1entry BAR2

% Yield

1 825H H

2 953H Me

3 1444H Ph

4 1428Me Ph

+

CO2Me

CO2Me

HH

R1

OR2

CO2Me

CO2Me

A BCO2Me

CO2Me

10

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1976, 1, 30–32.

+(CO)3Co Co(CO)3 H

ArO

HH

PhH or PhMe

PKR Early WorkFirst Substituted Alkene Examples

HH

Ar = ferrocene (65% yield)Ar = Ph (60% yield)

+(CO)3Co Co(CO)3 H

ArO

HH

PhH or PhMeAr

Ar = ferrocene (18% yield)

ArH

H

Alkene Selectivity Using Co2(CO)8

O

R Ph

Ar HAr

O

O

O

O

Khand and Pauson, J. Chem. Soc., Perkin Trans. 1 1976, 30.Khand and Pauson, Ann. N.Y. Acad. Sci. 1977, 295, 2–14.Schore, J. Org. Chem. 1981, 46, 5357–5363.

O

PhRMe

O

Ph

RMe

Me

R

O

Ph

R

Pauson, Organometallics 1982, 1, 1560–1561.Pauson, Tetrahedron 1985, 41, 5855–5860.Krafft, J. Am. Chem. Soc. 1988, 110, 968–970.

Ar = Ferrocene 100:0

HAr

OH

HArH

H

ArH

O

entry Alkene 2,5–Product 2,4–Product 2,5 : 2,4

ArH

OH

H

Ar = FerroceneAr = Ph

O

O

100:0100:0

100:0

R = (CH2)2NMe2R = CH2OTHP

24:1Mix

R = CpR = MeR = C6H13

100:01:15:6

R

O

PhRO

O

Ph

RO

RO

Alkyne

Ph

Ph

Ph R = OMeR = t-Bu

1:11:1

1

23

89

456

1011

7

11

Diene Reactivity

HH

O

RR

SO2

PhPh

4Ph

R

PhPh

4

Khand and Pauson, Ann. N.Y. Acad. Sci. 1977, 295, 2–14.Khand and Pauson, J. Chem. Res., Synop. 1978, 346–347.Khand and Pauson, J. Chem. Res., Synop. 1978, 348–349.

Pauson, Tetrahedron 1985, 41, 5855–5860.

R = HR = MeR = Ph

NotReported

NotReported

OR2

R2

R1

R2R2

R1R1 = H, R2 = PhR1 = Me, R2 = PhR1 = Ph, R2 = Me

151523

O

RR R = Me

R = Ph5560

Alkyneentry Alkyne Product % Yield

1

678

910

2 Ph

203865

345

Khand and Pauson, Chem. Commun. 1974, 379.Pauson, Tetrahedron 1985, 41, 5855–5860.

Electronic Effects1,3–Diene Products

+(CO)3Co Co(CO)3

Ph H

CO2EtPh

CO2Et

CN

CO2Et

(45% yield)

Ph+

+(CO)3Co Co(CO)3

Ph HPh

CN

3.5 : 1

12

CoCoCoCo

(OC)3

(CO)3

R Co

R(CO)3

(CO)3 Co

R

O

(CO)3

(CO)2O

RΔ

EnoneProduct

Khand and Pauson, Chem. Commun. 1974, 379.Pauson, Tetrahedron 1985, 41, 5855–5860.

Electronic Effects1,3–Diene Mechanism

+(CO)3Co Co(CO)3

Ph H

CO2EtPh

CO2Et

CN

CO2Et

(45% yield)

Ph+

+(CO)3Co Co(CO)3

Ph HPh

CN

3.5 : 1

EWG EWG EWGEWGH

COInsertion

CoCoCoCo

(OC)3

(CO)3

R Co

R(CO)3

(CO)3 Co

R

O

(CO)3

(CO)2O

RΔ

Co

Co

R(CO)3

(CO)3

H

Co(CO)3

Co(CO)3

RH

CHR

DieneProduct

EnoneProduct

Khand and Pauson, Chem. Commun. 1974, 379.Pauson, Tetrahedron 1985, 41, 5855–5860.

Electronic Effects1,3–Diene Mechanism

+(CO)3Co Co(CO)3

Ph H

CO2EtPh

CO2Et

CN

CO2Et

(45% yield)

Ph+

+(CO)3Co Co(CO)3

Ph HPh

CN

3.5 : 1

EWG EWG

EWG EWGEWG

EWGEWGH

β–HydrideElim

ReductiveElim

ReductiveElim

COInsertion

13

Khand and Pauson, Chem. Commun. 1974, 379.Pauson, Tetrahedron 1985, 41, 5855–5860.

Khand and Pauson, J. Chem. Res., Synop. 1977, 9.

Ph+(CO)3Co Co(CO)3

Ph HPhHC C

HCH

CHPh +O

Ph Ph

3 : 1

Electronic Effects1,3–Diene Products

+(CO)3Co Co(CO)3

Ph H

CO2EtPh

CO2Et

CN

CO2Et

(45% yield)

Ph+

+(CO)3Co Co(CO)3

Ph HPh

CN

3.5 : 1

Khand and Pauson, J. Chem. Res., Synop. 1978, 350–351.

+(CO)3Co Co(CO)3

Ph HPhHC C

HCH

CHAr +O

Ph Ar

Electronic EffectsSubstituted Styrene

R

Rentry EnoneDiene

% Yield

1 13264–Me

2 3504–F

3 884–Cl

4 4162–Cl

5 27424–MeO

14

Khand and Pauson, J. Chem. Res., Synop. 1978, 348–349.Khand and Pauson, J. Chem. Res., Synop. 1978, 350–351.

+(CO)3Co Co(CO)3

R1 HR1HC C

HCH

CHR2 +O

R1 R2

Electronic EffectsAromatic Alkenes

Alkeneentry EnoneDiene

% Yield

1 0trans, trans: 15

2

3 150

4 250

Fe

Ph

Ph

MeO

O

trans, trans: 49 trace

O R1

Ph

Ph

Ph

Ph

R1

O

PhPh

O

Ph Ph

Me

Alkeneentry EnoneDiene

% Yield

5

67

Ph: 38Me: 35

Ph

PhMe

R1

trans, trans: 3cis, trans: 2 25

O

PhAr

Ph: 4Me: 0

OR1

89

H: 31Me: 41

HMe

H: 0Me: 0

OR1

101112

H: 24Me: 26Ph: 38

HMePh

H: 0Me: 0Ph: 0

Alkene

Khand and Pauson, J. Chem. Res., Synop. 1978, 352–353.

+(CO)3Co Co(CO)3

Ph HO

Ph

Electronic EffectsCoordinated Substituted Styrene

R

Rentry EnoneDiene

% Yield

1 3732H

2 39294–Me

3 0294–Cl

4 29444–F

5 38354–MeO

Co(CO)3

R

Co(CO)3

Ph R

Co(CO)3

R

Co(CO)3

Co2(CO)6 +R

15

Selectivity Summary1,3–Diene Summary

Alkynes • Bulkier substituent located at C2 position of cylcopentenone • Swich functionality to C3 through use of silyl protecting groups

Alkenes • Aryl alkenes favor 2,5–products • Alkyl alkenes are generally mixtures of 2,5– and 2,4–products • Bidentate ligands can improve selectivity

1,3–Diene Products • EWG favor 1,3–diene • Styrenes have intermediate reactivity producing both 1,3–dienes and enones • Other aromatics have mixed reactivity greatly dependent on substrate • Co2(CO)8 does not offer the best path to diene products

Co

CoH

HOC

COCO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

COCo

CoH

H OC

OCCO

CO

CO

Co

CoH

H OC

OCCO

CO

COCO

0.0

+33.5

+12.0

+28.5

+14.1

–14.1

(33.5) (16.5)

Ligand Substitution Cobaltacycle Formation

Rate DeterminingStep

Stereochemical DeterminingStep

PKR MechanismDFT Calculations

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.

A

B

C D

E

F

16

PKR MechanismInfluence of Alkene Strain on Reaction

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.Milet and Gimber, J. Org. Chem. 2004, 69, 1075–1080.Gibson, Angew. Chem., Int. Ed. 2005, 44, 3022–3037.

Cobaltacycle Formation

Stereochemical DeterminingStep

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

COCo

CoH

H OC

OCCO

CO

CO

Co

CoH

H OC

OCCO

CO

COCO

+12.0

+28.5

+14.1

–14.1

(16.5)

C D

E

F

Strain Impact on Ea

Alkene strain impacts energy of 2nd step Intermediate D releaves alkene strain ⇒ ↓ Ea Co back donation ≈ Cobaltcycle barrier • Looking for lower LUMO of Alkene • ∠alkene ≈ LUMOalkene Less strained alkenes proceed at higher T

PKR MechanismInfluence of Alkene Strain on Reaction

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.Milet and Gimber, J. Org. Chem. 2004, 69, 1075–1080.Gibson, Angew. Chem., Int. Ed. 2005, 44, 3022–3037.

Cobaltacycle Formation

Stereochemical DeterminingStep

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

COCo

CoH

H OC

OCCO

CO

CO

Co

CoH

H OC

OCCO

CO

COCO

+12.0

+28.5

+14.1

–14.1

(16.5)

C D

E

FAlkene ΔH°f (kcal/mol)

–32.0

–31.3

–32.5

–27.8

–21.7

–21.6

–47.3

Alkene ΔH°f (kcal/mol)

Strain Impact on Ea

Alkene strain impacts energy of 2nd step Intermediate D releaves alkene strain ⇒ ↓ Ea Co back donation ≈ Cobaltcycle barrier • Looking for lower LUMO of Alkene • ∠alkene ≈ LUMOalkene Less strained alkenes proceed at higher T

17

PKR MechanismInfluence of Alkene Strain on Reaction

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.Milet and Gimber, J. Org. Chem. 2004, 69, 1075–1080.Gibson, Angew. Chem., Int. Ed. 2005, 44, 3022–3037.

Alkene ΔH°f (kcal/mol)

–32.0

–31.3

–32.5

–27.8

–21.7

–21.6

–47.3

Alkene ΔH°f (kcal/mol)

Strain Impact on Ea

Alkene strain impacts energy of 2nd step Intermediate D releaves alkene strain ⇒ ↓ Ea Co back donation ≈ Cobaltcycle barrier • Looking for lower LUMO of Alkene • ∠alkene ≈ LUMOalkene Less strained alkenes proceed at higher T

(CO)3Co Co(CO)3

R H 1. NMO, DCM, -35 °C

2. , DCM, -35 °C

O

R

entry % YieldR

1 tBu 93

2 Ph 50

3 51

4 Ph3Si 82

HO

6 62C6H13

5 45Ph

HO

H

OTMS

H

HH

HH

HOTMS

O

R2 R1

O

R2 R1

(CO)3Co Co(CO)3

R1 R2

(CO)3Co Co(CO)3

R1 R2

Khand and Pauson, J. Chem. Res., Synop. 1977, 8.

a. R1 = R2 = Hb. R1 = H, R2 = Mec. R1 = H, R2 = Phd. R1 = Me, R2 = Phe. R1 = R2 = Etf. R1 = R2 = Ph

Alkene ReactivityAlkene Strain Impact

"Only strained alkenes (e.g. norbornene) are reactive under mild conditions (60–80 °C), whilesimple alkenes participate only at much higher temperatures (e.g. 140–150 °C) and usuallyproduce very low yields of cyclopentenones."

Schore, J. Org. Chem. 1981, 46, 5436–5438.

18

H

Alkene Reactivity

OTMS

H

HH

HH

HOTMS

O

R2 R1

O

R2 R1

(CO)3Co Co(CO)3

R1 R2

(CO)3Co Co(CO)3

R1 R2

Khand and Pauson, J. Chem. Res., Synop. 1977, 8.Khand and Pauson, J. Chem. Res., Synop. 1977, 9.

n n

O

n = 1–4

R2

R1

(CO)3Co Co(CO)3

R1 R2

R2 > R1

Cycloalkenes possible at higher temp (60 – 120 °C) 5 and 7 rings work best 6 ring is "sluggish"

a. R1 = R2 = Hb. R1 = H, R2 = Mec. R1 = H, R2 = Phd. R1 = Me, R2 = Phe. R1 = R2 = Etf. R1 = R2 = Ph

Alkene Strain Impact

Khand and Pauson, J. Chem. Res., Synop. 1977, 9.Pauson, Tetrahedron Lett. 1985, 41, 5885–5860.

Alkene ReactivityEthylene and Equivalents

H

HH

HO

C5H11

Me

O

Me

C5H11

(CO)3Co Co(CO)3

Me C5H11

12.5 : 1

+

H

HH

H

O

Me

Co2(CO)8

Et+

Et

H

HH

H Br BrOR OR(CO)3Co Co(CO)3

R1 R2

R2 > R1

O

R2

R1

R

R = H, Me

19

Pauson, J. Chem. Res., Synop. 1980, 277.

Alkene ReactivityExamples En Route to Prostoglandins

H

HH

H(CO)3Co Co(CO)3

R H

Autoclave, 160 °C

O

R

H

O

CO2Me

O

CO2Me

O

CO2Me

entry R

C6H12CO2Me

CH2CH=C3H6CO2Me

1

2

3 C6H12CO2Me

Product % Yield

46

57

33

OR

H

H

Intramolecular PKRFirst Publications

Schore, Chem. Rev. 1988, 88, 1081–1119.

Neil E. Schore

J. Org. Chem. 1981, 46, 5357–5363.J. Org. Chem. 1981, 46, 5436–5438.Chem. Rev. 1988, 88, 1081–1119.

J. Org. Chem. 1981, 46, 5357–5363 and 5436–5438

Articles

First Intramolecular PKR

Originally reported by Neil E. Schore in 1981 University of California, Davis 1st Paper Focus: Synthesis of Vinyl Ether and Ester Enynes 2nd Paper Focus: Intramolecular PKR"Unfortunately, unstrained alkenes are considerably less reactive in this cyclization process, thus severely limiting its generality: simple olefins react only under forcing conditions, and the yields of cyclopentenones obtained vary greatly. We suspected, however, that the intramolecular disposition of the functional groups in a,w–enynes might enhance the desired mode of reactivity."

20

Intramolecular PKRFirst Publications

Schore, J. Org. Chem. 1981, 46, 5357–5363 and 5436–5438.

Co2(CO)8, CO

2,2,4-trimethylpentane95 °C, 4 d

O

(35–40% yield)

O

Co2(CO)8, CO

isoocatne95 °C O

O Challengingto isolate

OCo2(CO)8, CO

2,2,4-trimethylpentane95 °C

(31% yield)

Co2(CO)8

2,2,4-trimethylpentane95 °C

R3Mixture of

TrimerizationProducts

Intramolecular PKRThorpe–Ingold Precursors

Magnus, Tetrahedron 1985, 41, 5861–5869.Magnus, J. Am. Chem. Soc. 1987, 28, 5465–5468.

OR3

R2R1

R5

R1

H

R5

R2

R3O

R1

H

R5

R2

R3

+

“While yield of the cyclopentenones, whether formed inter– or intramolecularly, are relatively modest, we felt that this could be easily improved by choice of appropriate substituents connecting alkyne and alkene.

Undoubtedly, the Co2(CO)8 mediated conversion . . . should greatly benefit from the gem–methyl group (Thorpe–Ingold effect) . . .” [bold added]

Co2(CO)8

R4 R4 R4

21

Intramolecular PKRInfluence of Substituents

Magnus, Tetrahedron 1985, 41, 5861–5869.Magnus, J. Am. Chem. Soc. 1987, 28, 5465–5468.

Schore, Chem. Rev. 1988, 88, 1081–1119.

OCo2(CO)8, CO

heptane95 °C, 20 h

TBSOR

(31% yield)

EtO2C

TMS Co2(CO)8, CO

heptane95 °C, 20 h

TBSO

H

R

O

TBSO

H

R

+

R = TMSR = Me

79 %50 %

3 %15 %

(26:1)(3:1)

O

H

R

EtO2CO

H

R

EtO2C

(55:45)

OCo2(CO)8, CO

TMS

H

TMS

O

H

TMS

R = TBS OR H (80 °C, 48 h)R = MOM (125 °C, 36 h)R = (CH2)2OMOM (115 °C, 36 h)

RO R R

+

+

(25% yield)(20 % yield)(78 % yield)

(55:45)(2.6:1)(100:0)

Co

CoCoCoR2

R1 Co

R1R2

COH

R2

H

Co

R1

O

R2

H

O

CoCo

R1R2

H

O

R1

Magnus, Tetrahedron Lett. 1985, 26, 4851–4854.

Δ

Intramolecular PKRInfluence of α–Substituent

Co

Co

R1R2

COH

+

Co

CoCoCo

R1 Co

R1

COH

H

Co

R1

OH

O

CoCo

R1

H

O

R1

Δ Co

Co

R1

COH

+

R2 R2

R2 R2 R2

R2

Sterics AcrossRing

22

Intramolecular PKRInfluence of α–Substituents

Magnus, J. Org. Chem. 1987, 52, 1483–1486.Magnus, J. Am. Chem. Soc. 1987, 28, 5465–5468.

Co2(CO)8, CO,(n-Bu)3P=O

(1 equiv)

heptane86 °C, 30 h

TMS

O

H

TMS

O

O

(45% yield)

O

O

HO2C

OH

6a-carboprostaglandin I2(carbacyclin)

OH

modelstudy

toward

HH

Single Isomer

R1entry 1 2R2

% Yield

1 90 14H H

2 86 29Me H

3 69 29Me Me

4 87 41H H

5 92 41H H

Co(CO)3(CO)3Co

R3

PKR IntramolecularOther Substrates

R3

H

H

H

Me

(CH2)2OTHP

O

R2R1Co2(CO)8

pet ether25 °C, 2–4 hR3

O

R2R1

O O

R3

CO

isooctane60 °C, 24 h

1 2

Billington, Tetrahedron Lett. 1984, 25, 4041–4044.

R2R1

23

PKR IntramolecularOther Substrates

Co2(CO)8

PhH80 °C, 4 d

Schore, J. Org. Chem. 1984, 49, 5025–5026.Schore, J. Org. Chem. 1987, 52, 569–580.

Schore, J. Am. Chem. Soc. 1988, 110, 5224–5225.Sarratosa, Tetrahedron Lett. 1985, 26, 2475–2476.

R

RR

O

R

35%< 1%

R = HR = Me

Co2(CO)8

PhH80 °C, 18–22 h

O

30%0%

R = HR = TMS

MOMO

R

Two or ThreeStereoisomers

Co2(CO)8

heptane110 °C

sealed tube

O

3%45%

H

O

H+

Co2(CO)8, CO

isooctane160 °C

O

MOMO

R

R

TBSO

RTBSO R

TBSO

TBSO

low yields76%

R = HR = TMS

O

O

O

perhydrotriquinacene9 steps

Co

CoH

HOC

COCO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

COCo

CoH

H OC

OCCO

CO

CO

Co

CoH

H OC

OCCO

CO

COCO

0.0

+33.5

+12.0

+28.5

+14.1

–14.1

(33.5) (16.5)

Ligand Substitution Cobaltacycle Formation

Rate DeterminingStep

Stereochemical DeterminingStep

PKR MechanismDFT Calculations

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.

A

B

C D

E

F

24

PKR MechanismLowering Ea

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.

Increasing Reaction Rate

Substrate assisted dissociation Increase rate of CO removal • Oxidize CO → CO2 • Ligand Substitution • Induce CO Dissociation Stabilize intermediates

Additives

Increase rate of CO removal • Irradition, microwave • Tertiary Amine N-Oxides (TMO, NMO) • Phosphine Oxides, Phosphines, Sulfoxides, Sulfides, Thioacetals, Nitriles, Amines, Thioureas Stabilize intermediates • SiO2, Al2O3 • Molecular Sieves

Co

CoH

HOC

COCO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

0.0

+33.5

+12.0

(33.5)

Ligand Substitution

Rate DeterminingStep

A

B

C

Pericàs, Pure Appl. Chem. 2002, 74, 167–174.Pericàs, J. Org. Chem. 2000, 65, 7291–7302.

Electronic EffectsSubstrate Assisted Dissociation

Co(CO)2

Co(CO)3X

HCO

X = NR2, OR, SR,

Co(CO)2

Co(CO)3X

HCO

Co(CO)3(OC)3Co

R2N H

Extremely reactive Stored in freezer under CO

25

AdditivesPhotoinduced CO Dissociation

OCo2(CO)8, CO (1 atm)

1,2–DMEConditionsa

MeO2C

MeO2C

MeO2C

MeO2C

0.1 M

entry %Yield

1c 50–554 955.0 Q Beamd

2 50–5512 300.5 Q Beamd

3 0 or 1712 no rxn5.0 Q Beamd

4 5012 6412.5 Vitalite

Co2(CO)8b

mol %hν

SourceTime(h)

Temp(°C)

Livinghouse, J. Am. Chem. Soc. 1996, 118, 2285–2286.

a 30 min equilibration then 4 h Irradition. b Purity important.c EtOAc – 80% yield. d Q Beam Max Million by Brinkmann, Inc.

AdditivesPhotoinduced CO Dissociation

OEtO2C

EtO2C

EtO2C

EtO2C

Livinghouse, J. Am. Chem. Soc. 1996, 118, 2285–2286.

TsNTsN O

R R

TsN TsN O

OEtO2C

EtO2C

EtO2C

EtO2COAc OAc

OEtO2C

CO2Et

EtO2C

EtO2C

OEtO2C

EtO2C

EtO2C

EtO2C

O

MeO

MeO

MeO

MeO

OH

OH

O

MeO

MeO

MeO

MeO

Oallyl

Oallyl

O O O

entry %Yield

95

90

67

74

1b

4

5c

6

Enynea Product

8175

R = HR = Ph

23

entry %Yield

91

67

norxn

7

9d

10

Enynea Product

808

a Standard conditions: 5 mol% Co2(CO)8, 0.1 M in 1,2–DME, 12 h irradiation, 50–55 °C except where stated.b 4 h irradtion. c 10 mol% Co2(CO)8. d 12.5 mol% Co2(CO)8.

26

AdditivesTertiary Amine N–Oxides

First suggested by Pauson in 1988 ("erratic results")

Details

J. Organomet. Chem. 1988, 354, 233–242

". . . encountered some limitations because of its intrinsicproblems in reaction conditions such as requiring hightemperature (usually 60–120 °C) and long reaction time(6h – 4 days).

. . . we envisioned that these reagents [tertiary amine N–oxides] could serve as promoters to generate vacancy forincoming olefins and accelerate the overall reaction."

NR3 removable by evaporation

Further development by Nakcheol Jeong

Jeong, Synlett 1991, 204–206

Indications of Decarboxylation with N–Oxides

Shvo, Chem. Commun. 1974, 336–337.Shi and Baslow, Organometallics 1987, 6, 1528–1531.Shi and Baslow, Organometallics 1989, 8, 2144–2147.

(CO)nFeL L + NR3 + CO2 + "Iron Compounds

Co

CoH

HOC

COCO

OCCO

CO

Co

CoH

HOC CO

OCCO

CO

A

B

AdditivesTertiary Amine N–Oxides

Jeong, Synlett 1991, 204–206.

OEtO2C

EtO2C

EtO2C

EtO2C

Co2(CO)8

23 °CConditions

Conditionsentry SMProduct

% Yield

1 090TMANO (3 equiv), O2, DCM, 3 h

2 4532CAN (3 equiv), DCM, 16 h

3 800CAN (3 equiv), acetone, 3h

4 087NMO (3 equiv), DCM, 8 h

+ SM + NR3

27

Tertiary Amine N–OxidesIntermolecular

Jeong, Synlett 1991, 204–206.

1

2

3

entry Alkene Product

80(83:17 = exo:endo)

45(exo only)

Alkyne

Ph

(CH2)3OH

Ph

O

Catalyzed Uncatalyzed% Yield

O

O

80 74Inseparable

93(88:12 = exo:endo)

69(exo only)Ph

O

R

1. Co2(CO)8 DCM, 30 min, 23 °C

2. Alkene, TMO (3 equiv) O2, DCM, –78→23 °C

O

R

64 (2:1)30 (3:1)

NotProvidedPh4

5OR

O

Ph ORR = HR = THP

O

Ph

OR

Tertiary Amine N–OxidesIntramolecular

Schreiber, Tetrahedron Lett. 1990, 21, 5289–5292.Jeong, Synlett 1991, 204–206.

3

entry ProductAlkyne % Yield

70 (5:1)

R

Alkene, NMO

DCM, 23 °C O

R

836

Co2(CO)6

OO O

R2

R1R1

R1R1

R2

85 (14a)92 (29a)

12

R1 = R2 = HR1 = Me, R2 = H

Co2(CO)6

O

RR

H

HO

H

H

OTBSOTBSO

H

OTBSO

H

86 (5:1)68 (11:1)

45

R = HR = Me

TBSO OEt

OEt

CH2(OEt)2TBSO

a Uncatalyzed yields.

O

RR

28

AdditivesTertiary Amine N–Oxides

Jeong, Synlett 1991, 204–206.Jeong, Tetrahedron Lett. 1991, 32, 2137–2140.

Krafft, J. Org. Chem. 1992, 57, 204–206.Takno, Chem. Commun. 1992, 169–170.

Kerr, Synlett 1995, 457–458.Kerr, Synlett 1995, 1083–1084.Kerr, Synlett 1995, 1085–1086.

Chung, Organometallics 1995, 14, 3104–3107.Greene, J. Org. Chem. 1995, 60, 6670–6671.Kerr, Organometallics 1995, 14, 4986–4988.

Kerr, Tetrahedron 1996, 52, 7391–7420.Krafft, J. Am. Chem. Soc. 1996, 118, 6080–6081.

Kerr, Synlett 2000, 1573–1576.

Articles

Chung, Coordination Chemistry Reviews 1999, 188, 297–341.

Review Articles

entry L2 % YieldL1

1 24CO 36CO2a 5CO 8PPh3

3b 36CO 45PBu3

4b 8CO 14P(OPh)3

5b 16CO 6P(OMe)3

6b 40 5

Time(h)

PPh2Ph2P

(CO)2Co Co(CO)2

Ph H

L1 L2

7c 36CO 69 (36d)Bu3PO

PhMe, Reflux

Conditions+

O O

Ph

O

a Reflux in PhH. b Based on > 10% recovery.c Reflux in hexane. d Uncatalyzed yield.

AdditivesPhosphorous Compounds

Billington and Pauson, J. Organomet. Chem. 1988, 233–242.

29

AdditivesAmines

Sugihara and Yamaguchi, Angew. Chem., Int. Ed. 1997, 36, 2801–2804.

OCo2(CO)8

23 °CConditions

entry % YieldSolvent

1 3 d 0n-hexane

2 3 d 0PhMe

3 3 d 01,2–dichloroethane

4 3 d 01,4–dioxane

5 3 d 0EtOH

6 3 d 0

Time

7 3 d 46Et2NH

35

35

35

35

35

35

Temp(°C)

35

8 5 min 52n-PrNH2 35

Et3N

9 5 min 68

10 5 min 72CyNH2

35

35

11 3 d 54t-BuNH2 35

i-PrNH2

Amines act as hard ligands to: • Displace CO • Activate Alkynes Primary amines work best Also investigated NH4OH • 1,4–dioxane/NH4OH sol (1:3 v/v) works best • High yields and fast rxn time

Amine Impact

AdditivesAmines

Sugihara and Yamaguchi, Angew. Chem., Int. Ed. 1997, 36, 2801–2804.

OCo2(CO)8

23 °CConditions

entry % YieldSolvent

1 3 d 0n-hexane

2 3 d 0PhMe

3 3 d 01,2–dichloroethane

4 3 d 01,4–dioxane

5 3 d 0EtOH

6 3 d 0

Time

7 3 d 46Et2NH

35

35

35

35

35

35

Temp(°C)

35

8 5 min 52n-PrNH2 35

Et3N

CyNH2(equiv)

9 5 min 68

10 5 min 72CyNH2

35

35

11 3 d 54t-BuNH2 35

i-PrNH2

entry % Yield

1 10 d 46

2 5 min 99

3 5 min 99

4 15 min 99

5 90 min 94

6 10 h 62

Time

25

83

83

83

83

83

Temp(°C)

10

6

3.5

3

1

0

OCo2(CO)8

1,2–dichloroethane23 °C

Conditions

30

AdditivesSiO2 and Al2O3 (DSAC)

O

Co2(CO)3

Si SiOH HO Non-polar repulsion

with silica surface bringsalkene and alkyne closer

together ⇒ ↓ ΔS

First reported by W. A. Smit in 1986 Dry State Adsorption Conditions (DSAC) SiO2 (mostly used) and Al2O3 (pH independent) 10–20% H2O Optimal; 5–30% H2O Inactive Substrate must have polar groups Procedure • Add silica gel • Evaporate solvent • Heat under appropriate gas • Reaction finished when silica turns gray Increase reaction rate • Interaction of polar groups with silica surface limits molecular movement (↓ ΔS), bringing the alkyne and alkene closer together • Surface displace carbonyl ligands

First Silica Gel Example

Tetrahedron Lett. 1986, 27, 1241–1244

Schore, Chem. Rev. 1988, 88, 1081–1119.Marco–Contelles, Organic Preparations and Procedures Int. 1998, 30, 121–143.

Increasing Rate

O

Si SiOH HO

Co

Co(CO)3

CO(CO)2

Lower Ea reactionbarrier

AdditivesSilica Gel (DSAC)

Smit, Tetrahedron Lett. 1986, 27, 1241–1244.Smit, Tetrahedron Lett. 1986, 27, 1245–1248.

SiO2

60 °C, 4 dO

(74% yield)MeHO

MeO Co2(CO)6 MeO

OHMe

MeH

SiO2

60 °C, 4 dO

(40% yield)MeHO

MeO Co2(CO)6 MeO

OHMe

MeH

O O O

Co2(CO)6SiO2, O2

45 °C, 30 min(75% yield)

O O O

Co2(CO)6SiO2, Ar

45 °C, 90 min

15% 40%

O+HO

31

AdditivesSilica Gel (DSAC)

Smit, Tetrahedron Lett. 1986, 27, 1245–1248.

O O

O O

OHO

O O

O O

O O

RH

O O

H

O O

O O

O O

Temp(°C)

45

60

60

50

50

5060

R = HR = Me

Temp(min)

120

45

45

45

20

21090

%Yield

92

64

50

80

58

5846

Temp(°C)

60

60

50

45

Temp(min)

90

60

120

150

%Yield

46

48

60

60

entry

1

2

3

4

5

67

entry

8

9

10

11

Product Product

AdditivesDSAC References

Schore, Chem. Rev. 1988, 88, 1081–1119.Marco–Contelles, Organic Preparations and Procedures Int. 1998, 30, 121–143.

Review Articles

Smit, Tetrahedron Lett. 1986, 27, 1241–1244.Smit, Tetrahedron Lett. 1986, 27, 1245–1248.

Smit, Synthesis 1989, 472–476.Smit, Tetrahedron Lett. 1989, 30, 4021–4024.Smit, Tetrahedron Lett. 1991, 32, 2105–2108.Smit, Tetrahedron Lett. 1991, 32, 2109–2112.

Smit, J. Am. Chem. Soc. 1992, 114, 5555–5556.Becker, Tetrahedron Lett. 1993, 34, 2087–2090.Becker, Tetrahedron Lett. 1993, 49, 5047–5050.

Articles

32

PKR Review References

Pauson and Khand. Uses of Cobalt–Carbonyl Acetylene Complexes in Organic Synthesis. Ann. N.Y. Acad. Sci. 1977, 295, 2–14.Schore. Transition metal-mediated cycloaddition reactions of alkynes in organic synthesis. Chem. Rev. 1988, 88, 1081–1119.Geis and Schmalz. New developments in the Pauson-Khand reaction. Angew. Chem., Int. Ed. 1998, 37, 911–914.Marco-Contelles et al. The asymmetric Pauson-Khand reaction. A review. Organic Preparations Procedures Int. 1998, 30, 121–143.Chung. Transition metal alkyne complexes: the Pauson-Khand reaction. Coordination Chemistry Review 1999, 188, 297‚Äì341.Adrio and Carretero. The tert-Butylsulfinyl Group as a Highly Efficient Chiral Auxiliary in Asymmetric Pauson‚àíKhand Reactions. J. Am. Chem. Soc. 1999, 121, 7411–7412.Brummond and Kent. Recent advances in the Pauson-Khand reaction and related [2+2+1] cycloadditions. Tetrahedron 2000, 56, 3263–3283.Fletcher and Christie. Cobalt mediated cyclisations. J. Chem. Soc., Perkin Trans. 1 2000, 11, 1657–1668.Sugihara et al. Advances in the Pauson-Khand reaction: development of reactive cobalt complexes. Chem.–Eur. J. 2001, 7, 1589–1595.Rivero et al. Pauson–Khand reactions of electron-deficient alkenes. Eur. J. Org. Chem. 2002, 17, 2881–2889.Rivero and Carretero. Intramolecular Pauson-Khand reactions of alpha,beta-unsaturated esters and related electron-deficient olefins. J. Org. Chem. 2003, 68, 2975–2978.Gibson (Née Thomas) and Stevenazzi. The Pauson–Khand Reaction: the Catalytic Age Is Here! Angew. Chem., Int. Ed. 2003, 42, 1800–1810.Bonaga and Krafft. When the Pauson-Khand and Pauson-Khand type reactions go awry: a plethora of unexpected results. Tetrahedron 2004, 60, 9795–9833.Blanco-Urgoiti et al. The Pauson-Khand reaction, a powerful synthetic tool for the synthesis of complex molecules. Chemical Society Reviews 2004, 33, 32‚Äì42.Alcaide and Almendros. The Allenic Pauson‚àíKhand Reaction in Synthesis. Eur. J. Org. Chem. 2004, 18, 3377–3383.Laschat et al. Regioselectivity, Stereoselectivity and Catalysis in Intermolecular Pauson-Khand Reactions: Teaching an Old Dog New Tricks. Synlett 2005, 2547–2570.Gibson (Née Thomas) and Mainolfi. The Intermolecular Pauson-Khand Reaction. Angew. Chem., Int. Ed. 2005, 44, 3022–3037.Pérez-Castells and Müller. Cascade Reactions Involving Pauson–Khand and Related Processes. Topics in Organometallic Chemistry 2006, 19, 207–257.Shibata. Recent Advances in the Catalytic Pauson–Khand-Type Reaction. Adv. Synth. Catal. 2006, 348, 2328–2336.

Review Articles