Preparation of Acrylophenones and 2-Alkyl Indanones Utilizing Hexamethylenetetramine as an Inexpensive Mannich Reagent.

Abstract

Hexamethylenetetramine/acetic anhydride-promoted α-methylenation of aryl alkyl ketones followed by acid-catalyzed cyclization of the resulting acrylophenones produce 2-alkyl indanones in excellent yields.

Notes

(e) Cost of ([CH₃)₂N]₂CH₂) is $264/Kg for 100 Kg lots available from TCI America.

Hexamethylenetetramine, readily obtainable from ammonia and formaldehyde, is a stable reagent with an adamantane-like structure. Hexamethylenetetramine has been widely used for the introduction of the formyl group and amino group (Sommelet reaction and Duff reaction) in aromatic compounds. (For review, see Synthesis. 1979, 161).

Cost 40oS / Ib for commercial quantities (Chemical Marketing Reporter, May 1, 1995).

The HMTA/Ac₂O-mediated methylenation is limited to the preparation of 2-alkyl indanones. Thus simple acetophenone fails to undergo methylenation under the reaction conditions presumably due to lack of enolization of the substrate.

Electron poor aryl alkyl ketones, although undergoes facile methylenation, fails to cyclize under acidic conditions to the indanones due to deactivation of the aromatic ring e.g.

(a) A mixture (60:40) of the two regioisomeric cyclized products (6-bromo and the 4-bromo) was obtained; the ratio was verified by C-H correlation and quantitative 13C NMR experiments.

A finite concentration of the enolate anion would be present by the action of HMTA on the aryl alkyl ketone.

The olefination which was performed neat without any solvent is also environmentally attractive.