Organocatalytic Synthesis of Benzazetidines by Trapping Hemiaminals with Protecting Groups

Abstract

Benzazetidines are highly strained and inherently unstable heterocycles. There are only few methodologies for assembling these compounds. Here, a protocol is presented to trap an elusive cyclic, 4-membered hemiaminal structure. This method affords several benzazetidine in moderate to good yields (up to 81%), it uses inexpensive materials and does not require catalysts based on transition metals. The high ring strain energy of these benzazetidine systems was estimated by DFT calculations to be about 32 kcal mol-1. This synthesis can be applied also on gram scale with reaction yield essentially unchanged.

Benzazetidines and Related Compounds: Synthesis and Potential

“…However, on the basis of mono‐ and bidimensional NMR spectra, together with IR experiments, the structure 2 r can be assigned to all the synthesized compounds, as consisting of the four‐membered benzo‐fused system . Furthermore, on the basis of 15 N NMR spectroscopy, UV/Vis spectra, and GIAO DFT calculations of 13 C chemical shifts, the formation of the alternative six‐membered cyclic acetal structure 55 could be ruled out …”

“…In 2019, Bella, Salvio, and their co‐workers, in the course of their studies about enantioselective organocatalysis, reported an organocatalytic synthesis of benzazetidines starting from inexpensive materials, which does not require any additive based on transition metals, unlike the procedure recently reported and illustrated above . The starting materials of this preparation are isatin and its derivatives.…”

“…The starting materials of this preparation are isatin and its derivatives. These compounds can be promptly turned in their corresponding N‐protected derivatives with Boc 2 O . The protection induces a higher reactivity in the carbonyl in position 2, at variance with unprotected isatins 49 .…”

Preparation of chiral DMAP derivatives and investigation on their enantioselective catalytic activity in benzazetidine synthesis and kinetic resolutions of alcohols

“…In this work, in the context of a growing interest of our group for organocatalysis-related issues and DMAPpromoted reactions [36][37][38][39], we present the synthesis and the study of the catalytic activity of two chiral DMAP derivatives. These compounds were selected because of their straightforward synthesis and the cheapness of the reagents used in the procedures.…”

“…These compounds were selected because of their straightforward synthesis and the cheapness of the reagents used in the procedures. Their catalytic activity was tested in t-butoxycarbonyl transfer reactions such as the kinetic resolution of alcohols and the enantioselective preparation of benzazetidines [39,40] showing, in some cases, good yields and fair enantiomeric ratios.…”