Hydroacylation

Hydroacylation is a type of organic reaction in which an electron-rich¹ unsaturated hydrocarbon inserts into a formyl C-H bond. With alkenes, the product is a ketone:

RCHO + CH₂=CHR' → RC(O)CH₂CH₂R'

With an alkyne instead, the reaction produces an α,β-unsaturated ketone.²

The reaction requires a metal catalyst or a radical initiator.¹ Even so, the reaction is difficult to engineer, as oxidizing aldehydes to acyl radicals occurs only at high electrochemical potential.³ It is almost invariably practiced as an intramolecular reaction using homogeneous catalysts, often based on rhodium phosphines.

Hydroacylation first appeared in 1949, part of Kharasch's studies on peroxide effects.³ Because chain transfer occurs very slowly,^{45: 21–22} the radical reaction required a very large excess of aldehyde and, with dicarbonyl substrates, decarbonylation byproducts appeared in large quantity.³

In the 1970s, metal-catalyzed hydroacylation was discovered for the synthesis of certain prostanoids.⁶ The reaction required tin tetrachloride and a stoichiometric amount of Wilkinson's catalyst:

An equal amount of a cyclopropane was formed as the result of decarbonylation.

The first catalytic application involved cyclization of 4-pentenal to cyclopentanone using (again) Wilkinson's catalyst.⁷ In this reaction the solvent was saturated with ethylene.

CH₂=CHCH₂CH₂CHO → (CH₂)₄CO

As of 2019, metal-catalyzed reactions continued to require rhodium catalysis.³

In the 1990s, studies on acyl radicals revealed that thiols or N-hydroxyphthalimide could catalyze rapid chain transfer, mostly removing the drawbacks of Kharasch's original radical reaction.^{435: 21–22} However, substrate scope remained limited. Modern work focuses on photoredox catalysis, and has produced mediocre-yielding catalysts that handle arbitrary substrates.³

In the presence of a metal catalyst, hydroacylation begins with two oxidative additions: of the alkene and into the aldehydic carbon-hydrogen bond. The relative order of these two coordinations is unclear. The product is an acyl-metal hydride alkene complex. Then the alkene ligand undergoes migratory insertion into either the metal-acyl or the metal-hydride bonds. Finally, the resulting alkyl-acyl or beta-ketoalkyl-hydride complex undergoes reductive elimination.²⁵

A competing side-reaction is decarbonylation of the intermediate acyl-metal hydride to give an alkane and a metal carbonyl:⁵

R"C(O)-ML_n-H → R"-M(CO)L_n-H → R"-H + M(CO)L_n

Hydroacylation as an asymmetric reaction was demonstrated in the form of a kinetic resolution.⁸⁹ A true asymmetric synthesis was also described.¹⁰¹¹ Both conversions employed rhodium catalysts and a chiral diphosphine ligand. In one application the ligand is Me-DuPhos:¹²