Pauson–Khand reaction

In it, an alkyne, an alkene, and carbon monoxide combine into a α,β-cyclopentenone in the presence of a metal-carbonyl catalyst[1] [2] Ihsan Ullah Khand (1935–1980) discovered the reaction around 1970, while working as a postdoctoral associate with Peter Ludwig Pauson (1925–2013) at the University of Strathclyde in Glasgow.

[6] The traditional reaction requires a stoichiometric amounts of dicobalt octacarbonyl, stabilized by a carbon monoxide atmosphere.

[8][9][10][11] While the mechanism has not yet been fully elucidated, Magnus' 1985 explanation[12] is widely accepted for both mono- and dinuclear catalysts, and was corroborated by computational studies published by Nakamura and Yamanaka in 2001.

Typical Pauson-Khand conditions are elevated temperatures and pressures in aromatic hydrocarbon (benzene, toluene) or ethereal (tetrahydrofuran, 1,2-dichloroethane) solvents.

Adsorbing the metallic complex onto silica or alumina can enhance the rate of decarbonylative ligand exchange as exhibited in the image below.

[clarification needed] Additionally using a solid support restricts conformational movement (rotamer effect).

[20] Sulfur compounds are typically hard to handle and smelly, but n-dodecyl methyl sulfide[21] and tetramethylthiourea[22] do not suffer from those problems and can improve reaction performance.

It is believed that these additives remove carbon monoxide ligands via nucleophilic attack of the N-oxide onto the CO carbonyl, oxidizing the CO into CO2, and generating an unsaturated organometallic complex.

Density functional investigations show the variation arises from different transition state metal geometries.

[41] Heteroatoms are also acceptable: Mukai et al's total synthesis of physostigmine applied the Pauson–Khand reaction to a carbodiimide.

In addition to using a rhodium catalyst, this synthesis features an intramolecular cyclization that results in the normal 5-membered α,β-cyclopentenone as well as 7-membered ring.

1:
Alkyne coordination , insertion and ligand dissociation to form an 18-electron complex ;
2:
Ligand dissociation to form a 16-electron complex;
3:
Alkene coordination to form an 18-electron complex;
4:
Alkene insertion and ligand association ( synperiplanar , still 18 electrons);
5:
CO migratory insertion;
6, 7:
Reductive elimination of metal (loss of [Co 2 (CO) 6 ]);
8:
CO association, to regenerate the active organometallic complex. [ 14 ]
The PK reaction has poor regioselectivity with monosubstituted alkenes. Phenylacetylene and 1-octene produce at least 4 isomeric products. ("tol" = toluene )
An electron-withdrawing group (ethyl benzoatyl) prefers the C 3 position. ("Tol" = toluene )
An intramolecular Pauson-Khand reaction
An intramolecular Pauson-Khand reaction produces a bicycle with 97% syn to the bridgehead and 3% anti.
Pauson-Khand in DME (dimethoxyethane? dimethyl ether?) at 120°C
Original reaction: 24 hours at 60°C with 30% yield. Dry reaction: silica, oxygen, 45°C for 0.5 hours for 75% yield.
Adding silica improved this reaction rate by a factor of ≈50.
Reaction in cyclohexanamine fails to proceed, but with neo-butyl methyl sulfide it runs to 79% yield.
NMO = N ‑methylmorpholine N ‑oxide , DCM = dichloromethane
(NMO = N ‑methylmorpholine N ‑oxide , DCM = dichloromethane ) A step in the total synthesis of epoxydictymene: temperature and ultrasound failed to improve the d.r. for the desired diastereomer (the red hydrogen). But the N -oxide additive, while lower yielding, gave a d.r. of 11:1. [ 28 ]
The key step in Takayama et al 's asymmetric total synthesis of the Lycopodium alkaloid huperzine-Q : Co 2 (CO) 8 catalyzes an enyne cyclization. [ 33 ] The siloxane ring ensures [ 34 ] that only a single product enantiomer forms. [ 33 ]
PK reaction with Wilkinson's catalyst
PK reaction with Wilkinson's catalyst
PK reaction with molybdenum hexacarbonyl
Molybdenum catalyzes a Pauson-Khand reaction at an allene's internal double bond. Rhodium would catalyze a reaction at this substrate's terminal double-bond instead.
Pauson Khand reaction Seigal 2005
Pauson Khand reaction Seigal 2005