O R3 Co R4 R Co2(CO)8 Mediated Pauson–Khand …stoltz2.caltech.edu/seminars/2009_Bennett.pdf2 PKR...
Transcript of O R3 Co R4 R Co2(CO)8 Mediated Pauson–Khand …stoltz2.caltech.edu/seminars/2009_Bennett.pdf2 PKR...
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