Chemoselective Synthesis of Amines from Ammonium Hydroxide and Hydroxylamine in Continuous Flow

Abstract

The chemoselective amination of alkyl bromides and chlorides with aqueous ammonia and hydroxylamine was achieved in continuous flow to produce primary ammonium salts and hydroxylamines in high yields. An in-line workup was designed to isolate the corresponding primary amine, which was also telescoped in further reactions, such as acylation and Paal–Knorr pyrrole synthesis. Monosubstituted epoxides are also compatible with the reaction conditions.

Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides

“…With the alkyl mesylate substrates in hand, the synthesis of N -methyl secondary amines using aqueous methylamine in continuous flow was investigated. At the outset, a 0.1 M solution of mesylate 1 in methanol was used on the basis of the reaction conditions previously developed with ammonia . The commercially available aqueous methylamine solution has a concentration of 12.8 M and was applied neat in the process (Table ).…”

“…In 2018, our group reported a novel procedure capitalizing on a continuous flow process for the amination of halides using aqueous ammonia and hydroxylamine to produce primary ammonium salts and alkylated hydroxylamines in high yields (Scheme ). The process was extended to ring openings of epoxides . The absence of headspace in the continuous flow microreactor combined with the use of an aqueous solution of the amine appeared as key elements to avoid polyalkylation reactions.…”

A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis

“…Thus, we focused our efforts on adapting the batch process to flow utilizing BPRs in standard flow reactors at elevated temperatures. Surprisingly, the use of aqueous NH 4 OH in flow organic synthesis has not been frequently reported; we identified only one prior example in the literature . The use of ammonia surrogates was also investigated, but we found these to be unsuitable for flow operation .…”

“…Surprisingly, the use of aqueous NH 4 OH in flow organic synthesis has not been frequently reported; we identified only one prior example in the literature. 27 The use of ammonia surrogates was also investigated, but we found these to be unsuitable for flow operation. 28 The use of gaseous ammonia in flow was considered but not explored because of development timelines.…”