Bromination of Enamines from Tertiary Amides Using the Petasis Reagent: A Convenient One-Pot Regioselective Route to Bromomethyl Ketones

Abstract

An original one-pot synthesis of bromomethyl ketones is achived using the Petasis reagent (dimethyltitanocene) as a key for enamine generation. Several amides were used to test the limits of the procedure by changing either the alkyl chain R or the amino portion of the starting materials. The enamines generated in situ were allowed to react with bromine at low temperature followed by hydrolysis to yield bromomethyl ketones in excellent yields (85 to 95%). Mechanistic details and optimum conditions for the reaction are briefly discussed. The present approach offers several advantages such as regioselectivity in enamine formation, good yields, mild reaction conditions, and ease of experimentation.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource: Full experimental and spectral details.]

GRAPHICAL ABSTRACT

Keywords:

• Bromination
• bromomethyl ketones
• enamines
• Petasis reagent
• tertiary amides

ACKNOWLEDGMENTS

We are grateful for financial support from the Lebanese University and the Centre National de la Recherche Scientifique Libanaise. We also thank Dr. Mahmoud K. Faraj for useful discussions.

Notes

^a Petasis reagent in situ, introduction of the amide, evaporation of solvent, introduction of the solvent of bromination, addition of this mixture drop by drop to a solution of Br₂ at −78 °C. All tested amides have an N,N,-dimethyl amino portion. Amides 1a–i: Experiments conducted in methylene chloride as solvent of bromination. Amides 1a–i*: Experiments conducted in toluene as solvent of bromination.

^b Percentage yields of bromethyl ketones 2a–i calculated after purification.

^c Percentages of side products 4a–i and 5a–i determined from ¹H NMR spectra before purification.

^a Petasis reagent in situ, introduction of the amide, evaporation of solvent, introduction of the solvent of bromination, addition of this mixture drop by drop to a solution of Br₂ at −78 °C. All tested amides have an ethyl R portion. 2j–n: Experiments conducted in methylene chloride as solvent of bromination. 2j–n*: Experiments conducted in toluene as solvent of bromination.

^b Percentage yields of bromethyl ketones 2j–n and 2j–n* calculated after purification.

^c Percentages of side products, determined from ¹H NMR spectra, before purification.