334 TABLE OF CONTENTS PREVIOUS REACTION NEXT REACTION SEARCH TEXT

PAUSON-KHAND REACTION
(References are on page 647)
Importance:
1 2-31 32-35 36-47
[Seminal Publication ; Reviews ; Modifications & Improvements ; Theoretical Studies ]

In 1973, I.U. Khand and P.L. Pauson reported that various acetylenehexacarbonyl dicobalt complexes reacted with
1
alkenes in hydrocarbon or ether solvents to give cyclopentenones in good yield. The scope and limitation of this
reaction was determined by the research group of P.L. Pauson in the 1970s. The transition metal (cobalt) catalyzed
formal [2+2+1] cycloaddition of alkynes, alkenes, and carbon-monoxide to form substituted cyclopentenones is
referred to as the Pauson-Khand reaction. The general features of this process are: 1) the reaction is feasible both
inter- and intramolecularly; 2) acetylene and terminal as well as internal alkynes are all substrates for the reaction.
However, derivatives of propynoic acid do not react; 3) the required alkyne-cobalt complexes are easily prepared by
reacting alkynes with dicobalt octacarbonyl; 4) internal alkynes tend to give lower yields of the product than terminal
alkynes; 5) a wide range of alkenes are feasible reaction partners and, generally, strained cyclic alkenes react the
fastest; 6) the order of reactivity is significantly influenced by the substitution pattern of the alkene substrate: strained
cyclic alkene > terminal alkene > disubstituted alkene >> trisubstituted alkene, and tetrasubstituted alkenes do not
react; 7) alkenes with strongly electron-withdrawing groups give poor or no reaction; 8) the reaction is highly
1
regioselective: the larger alkyne substituent (R ) ends up next to the carbonyl group in the product, but the
regioselectivity with respect to the alkene is less predictable in intermolecular reactions; 9) with cyclic alkenes the
reaction is highly stereoselective and the exo product is formed preferentially; 10) intramolecular reactions proceed
with excellent regio- and stereoselectivity; 11) with the use of chiral auxiliaries the reaction conditions are compatible
with a large number of different functional groups. However there are certain functionalities that are only partially
tolerated: alkyl and aryl halides, vinyl ethers, and vinyl esters; 12) the reaction can be accelerated by the addition of
various promoters (such as tertiary amine oxides, high-intensity light, etc.), which help to open a coordination site at
one of the cobalt atoms for the alkene to coordinate; 13) it is possible to run the cyclization catalytically but only in the
presence of a high pressure atmosphere of CO; and 14) besides Co2(CO)8, other transition metal complexes also
efficiently catalyze the cyclization (e.g. Fe(CO)5, Ru2(CO)12, etc.)

Pauson & Khand (1973): O

R 3
R 5 C R6
Co2(CO)8 (1 equiv) R1
R1 R2 + R5
R4 R6 solvent / heat
R4
terminal or internal mono-, di- or R1 > R 2 R2 R3
alkyne trisubstituted alkene Substituted cyclopentenone

Modified P-K reaction: Intramolecular variant:

transition metal R1
O Co2(CO)8 R1
1 2 complex
R R C R6 ∗ ∗
(≤1 equiv) R1 (≤1 equiv)
+ R 5 X C O
promoter / solvent X promoter / solvent
R3 R5 R 4 2
CO atmosphere R X = CH2, CHR,
R2 R3 R2
4 6
CR2, O, NHR, S
R R

R1-6 = H, alkyl, aryl, substituted alkyl and aryl; transition metal complex: Co2(CO)8, Fe(CO)5, Ru2(CO)12, Cp2TiR2, Ni(COD)2,
W(CO)6, Mo(CO)6, [RhCl(CO)2]2; promoter: NMO, TMAO, RSCH3, high-intensity light/photolysis, "hard" Lewis base

48-62
Mechanism:

The mechanism of the Pauson-Khand reaction has not been fully elucidated. However, based on the regio- and
stereochemical outcome in a large number of examples, a reasonable hypothesis has been inferred.

R1
O R1 R1
C loss of R 3 Co(CO)3
(OC)3Co Co(CO)3 R1 R2 Co(CO)3 CO Co(CO)3
2 R2
C R R2 Co CO
loss of 2 CO Co Co alkene
O CO
(CO)3 (CO)2 coordination
18 e- complex R 1 > R2 18 e- complex 16 e- complex R3
-
18 e complex
R1 R1
(CO)3Co(CO)3Co
R1 loss of R1
R2 Co(CO)3 R2 R2 [Co2(CO)6]
+ CO + CO Co(CO)3 R2
C O
alkene Co(CO)3 CO Co(CO)3 C O
insertion insertion
R3 R3
R3 O R3
18 e- complex 18 e- complex
 TABLE OF CONTENTS PREVIOUS REACTION NEXT REACTION SEARCH TEXT 335

PAUSON-KHAND REACTION

Synthetic Applications:

The total synthesis of the sesquiterpene (+)-taylorione was achieved in the laboratory of J.G. Donkervoort who used
the modified Pauson-Khand reaction to prepare the five-membered ring of the natural product.63 The preformed
alkyne-cobalt complex was exposed to excess triethylamine-N-oxide, which oxidized off two CO ligands to free up a
coordination site for the ethylene. The optimum pressure of the ethylene gas had to be at 25 atm, and the reaction
was conducted in an autoclave.

H O
25 atm
O O O O C
H2C CH2 steps
(OC)6Co2 C
H 2C H H
H H toluene/autoclave O H H
TMANO·2H2O (6 equiv)
40 °C, 24h; 81% (+)-Taylorione

During the synthetic studies toward the natural product kalmanol, L.A. Paquette and co-workers prepared the CD
diquinane substructure by using an intramolecular Pauson-Khand reaction.64 The use of an N-oxide promoter for the
cyclization resulted in very mild conditions and afforded the desired triquinane in good yield and as a single
diastereomer.

O
Me MeO2C H Me
OTBDPS
TMANO (anhydrous)
(6 equiv) steps
Co2(CO)6 O C
CH2Cl2, -78 °C to r.t.
85% H H H TBSO H
Me Me
OTBDPS CD diquinane
triquinane substructure of kalmanol

In the laboratory of S.L. Schreiber, the total synthesis of (+)-epoxydictymene was accomplished by the tandem use of
cobalt-mediated reactions as key steps.65 The eight-membered carbocycle was formed via a Nicholas reaction, while
the five-membered ring was annulated by the Pauson-Khand reaction. Several P.-K. conditions were explored and
the best diastereoselectivity was observed when NMO was used as a promoter. The annulated product was isolated
as an 11:1 mixture of diastereomers.

(CO)3 O H2
Co C C
Me H Me H Me H Me
Co(CO)3 NMO (0.6 equiv) 12 H H
CH2Cl2, r.t., 12h Me steps Me
H
O 70% O Me O Me
H H H H H H

dr = 11:1 at C12 (+)-Epoxydictymene

The key bicyclo[4.3.0]nonenone intermediate in the total synthesis of (±)-13-deoxyserratine was prepared by a highly
diastereoselective intramolecular Pauson-Khand reaction of a functionalized enyne-cobalt complex in the laboratory
66
of S.Z. Zard. The reactive conformation of this complex is one in which the OTBS group occupies the
pseudoequatorial position. The observed diastereoselectivity was high as the alternative conformer was significantly
higher in energy. The concave shape of the bicyclic product was exploited in controlling the introduction of the
remaining three stereocenters.

Me OTBS Me OH
Me OR

OTHP NMO·H2O
Me H
CH2Cl2, THF steps H
OR 89% THPO
(OC)6Co2 R =TBS C C
(OC)6Co2 N
O O
THPO dr = 93:7
13-Deoxyserratine