An Efficient and Waste-Minimized One-Pot Procedure for the Preparation of N-Boc-γ-amino Alcohols Starting from α,β-Unsaturated Ketones in Flow

Abstract

We report herein a clean multistep flow process that starting from α,β-unsaturated ketones 1 allows the preparation of N-Boc-γ-amino alcohols 3 in high yields. The final products have been isolated in pure form without any additional purification step. The cleanness and the environmental efficiency achieved by using our protocol is proven by the calculation of green metrics such as E-factors.

Approaches for Performing Reductions under Continuous-Flow Conditions

“…Vaccaro and co-workers recently reported on their development of a flow-based route to access N-Boc-γ-amino alcohols through the simultaneous reduction of an azide and ketone functionality and Boc protection of the resulting amine (Scheme 7). 12 The transformation was achieved through the use of CoCl 2 •6H 2 O as a catalyst in the presence of tetramethylammonium borohydride and Boc-anhydride. The group prepared the β-azido ketones under flow conditions using TMSN 3 as the azide source, the azide was then mixed with Boc-anhydride in a reservoir (a column reactor was used as the reservoir) prior to passage through a packed-bed reactor housing CoCl 2 •6H 2 O, and simultaneously (CH 3 ) 4 NBH 4 was pumped from a separate reservoir into the packed-bed reactor.…”

Definition of green synthetic tools based on safer reaction media, heterogeneous catalysis, and flow technology

“…The activation of Si-N bond of TMS-N 3 nucleophile by Amberlyst fluoride has allowed the preparation of β-azido ketones and carboxylic acid in water and allowed to achieve multistep flow procedure in SolFC for the preparation of β-azido and N-Boc-β-amino ketones or N-Boc-γ-amino alcohols with high efficiency and very low E-factor [97][98][99].…”

Recent Applications of Solid-Supported Ammonium Fluorides in Organic Synthesis

“…In general, its use under water-free conditions is possible by drying the commercial product under reduced pressure. [11][12][13][14]…”

“…Amb-F has been recently used to set up a new one-pot procedure for the synthesis in flow of N-Boc-β-amino ketones 16 or N-Boc-γ-amino alcohols 19 starting from α,βunsaturated ketones. [11][12][13] The optimization of this procedure is potentially of great interest in synthesis, since βamino ketones are very labile compounds that often decompose during workup; thus, they require an in situ protection of the amine functionality.…”

“…As an extension of previous work, Vaccaro and co-workers set up a novel flow system to synthesize N-Boc-γ-amino alcohols starting from α,β-unsaturated ketones in three high-yielding consecutive steps (Scheme 8). 13 After a careful screening of the catalysts and the experimental conditions, the first step (i.e., azidation of the substrate 14) was performed, as already described, using 1.1 equivalents of TMSN 3 and pumping the mixture through a glass column filled with Amb-F at 30 °C for 5 hours under solvent-free conditions. After that time, the reaction mixture, containing mainly the intermediate azido compound 15, was again collected in the reservoir and melted Boc 2 O was added.…”