A novel acid-catalyzed rearrangement of 2-substituted-3-(2-nitrophenyl)oxiranes for the synthesis of di- and mono-oxalamides

Abstract

A new acid-catalyzed rearrangement of oxiranes for the syntheses of biologically important pharmaceutical molecules with anthranilic acid and oxalamide moieties has been discovered.

Synthesis and Mechanistic Insights of the Formation of 3-Hydroxyquinolin-2-ones including Viridicatin from 2-Chloro-N,3-diaryloxirane-2-carboxamides under Acid-Catalyzed Rearrangements

“…Compounds 1a – i were prepared by the modification of a literature procedure from dichloroacetyl chloride and N -methyl-, N -benzyl-, N -(4-methoxybenzyl)­anilines, , N -benzyl-4-methylaniline, N -(4-chlorobenzyl)-4-methylaniline, N -(4-bromobenzyl)-4-methylaniline, N -(4-methoxybenzyl)-3,5-dimethylaniline, and N -(4-methoxybenzyl)-3-methylaniline. N -Methyl- and N -benzylanilines are commercially available and were used without further purification, and other anilines were prepared in two steps according to a literature procedure. , All aromatic aldehydes were commercially available and were used without purification.…”

“…According to our previous experience with anilides of arylglycidic acids ( N ,3-diaryl-3-oxirine-2-carboxamides), the direction of acid-catalyzed rearrangements and the structure of the resulting products are sensitive to small changes in the structures of these compounds. For example, the acid-catalyzed rearrangement of N ,3-diaryloxrine-2-carboxamides, which do not contain ortho -nitro groups in the aryl fragment of the epoxy ring, proceeds with the formation of the corresponding 3-arylquinoline-2­(1 H )-ones regardless of the nature of the substituents in the aryl fragments, , and the rearrangement of 3-(2-nitrophenyl)­oxirane-2-carboxamides ( N ,3-diaryloxirane-2-carboxamides with an ortho -nitro group in the aryl fragment at the epoxy ring) proceeds with the formation of N -(2-carboxyphenyl)­oxalamides. , …”

Acid‐Catalyzed Rearrangements of 3‐Aryloxirane‐2‐Carboxamides: Novel DFT Mechanistic Insights

“…Interestingly, when trans ‐3‐(2‐nitrophenyl)‐ N ‐phenyl‐oxirane‐2‐carboxamide ( 1 c ) instead of 1 b was used as the substrate for which competitive rearrangements to both 3‐(2‐nitrophenyl)quinolin‐2(1 H )‐one ( 2 c ) and N ‐(2‐carboxyphenyl)‐ N ‐phenyl‐oxalamide ( 3 c ) become possible, only the oxalamide product 3 c was formed exclusively . Fully consistent with such experimental results, the DFT‐computed overall barriers for the catalytic rearrangements of very similar substrates 1 a and 1 c to the quinoline‐2‐one 2 a and the oxalamide 3 b are 21.9 and 18.6 kcal/mol, respectively, with the oxalamide product channel being kinetically 3 kcal/mol more favourable.…”

“…Such idea is further supported by our test DFT calculations showing that similar nucleophilic oxirane opening reactions can also be induced by simple NO, CHO and CH=CH 2 groups at the ortho ‐site of the proximal phenyl group (see ESI). Interestingly, it was experimentally known that the replacement of the amide NH 2 of 1 b with a phenyl group can lead to the same H 2 SO 4 ‐catalyzed rearrangement into 2‐(2‐oxo‐2‐phenylacetamido)benzoic acid, though an additional O 2 ‐elimination channel to form 2‐phenyl‐3‐hydroxyquinolin‐4‐one was also found very recently …”

“…Alternatively, functional groups can be introduced as substituent to the oxirane ring to realize novel conversions via either synergetic or sequential rearrangements . Recently, very interesting sulfuric acid (H 2 SO 4 ) catalyzed rearrangements of 3‐aryloxirane‐2‐amides in acetic acid (CH 3 COOH) solution were achieved for very efficient one‐pot synthesis of 3‐arylquinolin‐2(1 H )‐ones and N ‐(2‐carboxyaryl)‐oxalamides (Scheme ), tentatively assumed to be initialized by the classical Meinwald rearrangement (forming neutral carbonyl intermediates), and followed by intramolecular electrophilic Friedel‐Crafts alkylation of the amide N ‐aryl or nucleophilic addition to the nitro group . Quinolin‐2‐ones and oxalamides are omnipresent in naturally occurring and synthetic compounds displaying a broad range of pharmacological activities and practical applications .…”