Synthesis of phenyl and substituted phenyl 3-ethyl-2,3,5,9b-tetrahydro[1,3]oxazolo[2,3-a]isoindol-5-ones

Abstract

Oxazolo [2,3-a]isoindol-5-one derivatives exhibit anticonvulsant and anti-inflammatory activities. 1 The chemistry and reactivity of isoindolinone ring system is an area of interest because of its biological activity. 2 Recently Allin and coworkers 3 have reported a new synthesis of non-racemic isoindolinone targets through application of oxazolo-[2,3-a]isoindolinones as N-acyl iminium ion precursors in reactions with carbon and hydride nucleophiles. We had earlier reported the formation of a novel 10 membered chiral ring system 4 while attempting to synthesise oxazolo-[2,3-a]isoindol-5(9bH)-one using (R) or (S)-2-amino-1butanol via Meyers methodology 5 involving reduction of the imide and cyclisation using trifluoro acetic acid. The phenyl group was introduced by the addition of phenyl magnesium bromide (c) to (R) or (S)-2-(1-hydroxy)phthalimides 3a or 3b. These were derived from phthalic anhydride 1 and (R)-(-)-2amino-1-butanol 2a or (S)-(+)-2-amino-1-butanol 2b. The resulting dihydroxy compounds 4a or 4b were not isolated, but were directly subjected to acid-catalysed cyclisation to furnish the 9b-phenyl substituted oxazolo[2,3a] isoindolinones 10a or 10b in 40-50% yields. In a similar fashion the addition of p-fluoro(d), p-chloro(e), p-methoxy(f) and p-methyl(g) substituted phenyl magnesium bromides furnished the corresponding 9b-substituted-phenyl substituted oxazolo[2,3a] isoindolinones 11a-14a or 11b-14b respectively (Scheme 1).Compound 10b was subjected to a single crystal X-ray diffraction analysis 6 and its structure was solved and refined by SHELX 97 program 7 (Fig. 1). The absolute configuration of the phenyl substituted oxazolo[2,3-a]isoindolin-5-one was found to be (3S, 9bR).

Acyclic Twisted Amides

“… ,− As expected, comparatively fewer examples of structurally characterized N-pyramidalized amides embedded in six-membered rings have been reported; however, these amides feature significant N-pyramidalization (average χ N of 46.1°), while twist is much lower (average τ of 11.2°). These values compare well with the five-membered fused ring lactams (χ N , 45.9°; τ, 11.7°), − ,− …”

“…Similar to β-lactams, the amide bond geometry of structurally characterized amides embedded in a fused five-membered ring system (Figures –) − ,− can be characterized as N-pyramidalized (average χ N of 45.9°) with minimal twist (average τ of 11.7°). As expected, the average values of N-pyramidalization and twist are slightly lower as compared to β-lactams ...…”

“…Most common in this class (Figures –) − ,− is ring fusion to six-membered rings in a [ 3 .4.0] scaffold, including piperazine, such as 4.120 , and hexahydropyrimidine, such as 4.121 , and much more common [ 3 .3.0] ring system with the ring fusion to five-membered rings, including pyrrolidine, such as 4.122 , thiazolidine, such as 4.123 ,…”

“…This class also includes benzo-fused lactams, such as 4.140 , 4.146 , and 4.173 , and tricyclic fused ring systems, such as 4.138 , 4.171 , 4.172 , and 4.181 . In general, increased substitution at the α-position to the nitrogen atom and additional constraints of the five-membered ring, such as unsaturation, conformationally rigid ring systems, and steric effects, lead to higher N-pyramidalization. − ,− …”