Hydroacylation

Hydroacylation is a type of organic reaction in which an electron-rich ^[1] 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.

History

Hydroacylation first appeared in 1949, part of Kharasch's studies on peroxide effects. ^[3] Because chain transfer occurs very slowly, ^{[4] [5] : 21–22} the radical reaction required a very large excess of aldehyde and decarbonylation byproducts appeared in large quantity with dicarbonyl substrates. ^[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. ^{[4] [3] [5] : 21–22} However, substrate scope remained limited. Modern work focuses on photoredox catalysis, and has produced mediocre-yielding catalysts that handle arbitrary substrates. ^[3]

Reaction mechanism

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. ^{[2] [5]}

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

Asymmetric hydroacylation

Hydroacylation as an asymmetric reaction was demonstrated in the form of a kinetic resolution. ^{[8] [9]} A true asymmetric synthesis was also described. ^{[10] [11]} Both conversions employed rhodium catalysts and a chiral diphosphine ligand. In one application the ligand is Me-DuPhos: ^[12]

References

1. Smith (2020), March's Organic Chemistry, 8th ed. Rxn. 15-30.
2. Michael C. Willis (2009). "Transition Metal Catalyzed Alkene and Alkyne Hydroacylation". Chem. Rev. 110 (2): 725–748. doi:10.1021/cr900096x. PMID   19873977.
3. Voutyritsa, Errika; Kokotos, Christoforos G. (2019). "Green metal-free photochemical hydroacylation of unactivated olefins". Angewandte Chemie. 58 (4) (International ed.). Wiley: 1735–1741. doi:10.1002/anie.201912214. PMID   31736186 – via academia.com.
4. Chatgilialoglu, Chryssostomos; Crich, David; Komatsu Mitsuo; Ryu Il-Hyong (Aug 1999) [17 Nov 1998]. "Chemistry of acyl radicals". Chemical Reviews. 99 (8). American Chemical Society: 2001. doi:10.1021/cr9601425.
5. Ahern, Jenna Marie (Oct 2010). Radical Hydroacylation of C-C and N-N Double Bonds in Air (PDF) (PhD dissertation). University College London. pp. 12–13.
6. K. Sakai; J. Ide; O. Oda; N. Nakamura (1972). "Synthetic studies on prostanoids 1 synthesis of methyl 9-oxoprostanoate". Tetrahedron Letters . 13 (13): 1287–1290. doi:10.1016/S0040-4039(01)84569-X.
7. Transition-Metal-Promoted Aldehyde-Alkene Addition Reactions Charles F. Lochow, Roy G. Miller J. Am. Chem. Soc., 1976, 98 (5), pp 1281–1283 doi : 10.1021/ja00421a050
8. The Asymmetric cyclisation of substituted pent-4-enals by a chiral rhodium phosphine catalyst Brian R. James and Charles G. Young J. Chem. Soc., Chem. Commun., 1983, 1215 - 1216, doi : 10.1039/C39830001215
9. Catalytic decarbonylation, hydroacylation, and resolution of racemic pent-4-enals using chiral bis(di-tertiary-phosphine) complexes of rhodium(I) Brian R. James, and Charles G. Young Journal of Organometallic Chemistry Volume 285, 1985, Pages 321-332 doi : 10.1016/0022-328X(85)87377-0
10. Asymmetric cyclization reactions by Rh(I) with chiral ligands Yukari Tauraa, Masakazu Tanakaa, Kazuhisa Funakoshia and Kiyoshi Sakai. Tetrahedron Letters . Volume 30, Issue 46, 1989, Pages 6349-6352 doi : 10.1016/S0040-4039(01)93891-2
11. Asymmetric cyclization reactions. Cyclization of substituted 4-pentenals into cyclopentanone derivatives by rhodium(I) with chiral ligands Yukari Taura, Masakazu Tanaka, Xiao-Ming Wu, Kazuhisa Funakoshi and Kiyoshi Sakai. Tetrahedron . Volume 47, Issue 27, 1991, Pages 4879-4888 doi : 10.1016/S0040-4020(01)80954-6
12. Synthesis of D- and L-Carbocyclic Nucleosides via Rhodium-Catalyzed Asymmetric Hydroacylation as the Key Step Patricia Marce, Yolanda Dıaz, M. Isabel Matheu, Sergio Castillon Org. Lett., 2008, 10 (21), pp 4735–4738 doi : 10.1021/ol801791g