A Versatile and One-Pot Strategy to Synthesize α-Amino Ketones from Benzylic Secondary Alcohols Using N-Bromosuccinimide

Abstract

A metal-free one-pot strategy has been developed for the first time to synthesize pharmaceutically important α-amino ketones from readily available benzylic secondary alcohols and amines using N-bromosuccinimide. This new reaction proceeds via three consecutive steps involving oxidation of alcohols, α-bromination of ketones, and nucleophilic substitution of α-bromo ketones to give α-amino ketones. Importantly, this novel one-pot greener reaction avoids direct usage of toxic and corrosive bromine. This methodology has been employed efficiently to synthesize pharmaceutically important amfepramone and pyrovalerone in a single step.

N-Halosuccinimides as Precatalysts for C-, N-, O-, and X-Nucleophilic Substitution Reactions of Alcohols under Mild Reaction Conditions

“…The assumption that NXSs are actually precatalysts producing HOX, X 2 , and protons during the process while these species could catalyze nucleophilic substitutions seems to be reasonable [37]. The discrimination between the oxidation process observed in the case of the use of molar excess of NXSs (1.3 to 2 equivalent excess) [26][27][28] was achieved using substoichiometric amounts of NIS and by the selection of alcohols, which could after realizing hydroxyl group form, through resonance or strong inductive effect, stabilize carbocation intermediates which readily collapse with present nucleophile sources. Alkyl alcohols or some primary benzyl alcohols were inactive under our reaction conditions.…”

“…A group of organic compounds bearing an active N-halogen bond, N-halosuccinimides (NXSs) (chloro, bromo, and iodo), are an inexpensive, commercially available, easy-to-handle, and metal-free compounds, employed for oxidation, hydroxyhalogenation or halogenation reactions [19,20]. NXSs have attracted significant interest as mediators for comprehensive organic transformations [21][22][23][24][25][26][27][28]. However, the use of NXSs as the mediator for the direct transformation of alcohols forming C-C or C-heteroatom bonds has not been discovered so far.…”

Dual Role of N‐Bromosuccinimide as Oxidant and Succinimide Surrogate in Domino One‐Pot Oxidative Amination of Benzyl Alcohols for the Synthesis of α–Imido Ketones

“…Traditionally, α‐amino ketones can be synthesized from ketone and amine using molecular bromine . In addition to this, recent developments have been made for the synthesis of α‐amino ketones by using both transition‐metal and transition metal‐free conditions . For example, MacMillan et al developed a Cu‐catalyzed α‐amination of ketones .…”

A Straightforward Synthesis of α‐Amino Diaryl Ketones from (Hetero)Arylacetonitriles Promoted by N‐Bromosuccinimide

“…Very recently, Sudalai, and Sekar groups have also developed new synthetic protocols for accessing alkyl substituted α ‐amino ketones under metal‐free conditions utilizing alkenes and benzylic secondary alcohols as a key starting material (Scheme ). Despite this significant progress, a major limitation of the aforementioned strategies lies in the choice of substrates (essentially require elaborate‐to‐access starting materials, which eventually increases the cost of the reaction), and mostly afforded sterically less hindered alkyl substituted α ‐amino ketones.…”