An Expeditious Synthesis of N-Functionalized Isoindolinones. Application to the Synthesis of Biologically Active Compounds

The isoindolinone ring system has featured in recent years as a desirable synthetic target since it represents the core unit of a wide range of synthetic and naturally occurring bioactive molecules [1]. Within this family of 6,5-fused heterobicyclic compounds, model compounds functionalized on the lactam nitrogen occupy a place of choice as witnessed by a great number of recent patents emphasizing the biological potential of the piperidinyl derivatives 1 (psychoses treatment) [2], 2 (sigma receptor ligand) [3],


Introduction
The isoindolinone ring system has featured in recent years as a desirable synthetic target since it represents the core unit of a wide range of synthetic and naturally occurring bioactive molecules [1].Within this family of 6,5-fused heterobicyclic compounds, model compounds functionalized on the lactam nitrogen occupy a place of choice as witnessed by a great number of recent patents emphasizing the biological potential of the piperidinyl derivatives 1 (psychoses treatment) [2], 2 (sigma receptor ligand) [ 3 (microsomal triglyceride transfer protein inhibitor) [4],and of the anilinoethyl derivative 4 (inflammation and allergy inhibitor) [5].Organic chemists have at their disposal a great number of synthetic methods for the preparation of substituted isoindolinones but their applicability is quite insufficient because of restrictions in the choice of substituants namely in their nature, their number and above all their position [6].They are notably plagued by difficulties associated with the presence of diverse functional groups connected to the lactam nitrogen.

Results and Discussion
Herein we wish to delineate a tactically and conceptually new synthetic approach to a variety of diversely N-functionalized isoindolinones.Our strategy is based upon the exploitation of the Parham cyclization process that hinges upon aromatic lithiation and subsequent reaction of the so formed aryllithiated species with an internal electrophile [7].Application of this concept to the elaboration of five-membered lactams are scarce [8] and furthermore utilization of carbamates as internal electrophiles has been confined thus far to acyclic systems [8a, 9].

Retrosynthetic analysis
We reasoned that interception of the aryl lithiated species derived from compounds 6 by an oxazolidinone or an oxazinone, a thiazolidinone or an imidazolidinone ring system would provide the potential for direct access to isoindolinones 5 with the concomitant connection of the hydroxyl, thio or aminoalkyl chain respectively on the lactam nitrogen.(Retrosynthetic Scheme).

Application to the synthesis of two pharmacologically active compounds
The versatility and the potentiality of the process have been emphasized by the synthesis of two highly functionalized compounds endowed with pharmacological properties.
The 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-2,3-dihydro-1H-isoindol-1-one ( 9) has been shown to display very high in vitro binding affinity for 5-HT 1A receptors [10].This compound has been readily assembled by coupling the piperazine derivative 10 with the N-chloroalkylisoindolinone 11 which was easily obtainable from the corresponding hydroxyl derivative 5a synthesized according to the precedently reported procedure.isoindol-1-one (AQ-A 39) (12) has been reported to induce cardiovascular actions which might be of benefit in the treatment of ischemic heat disease [11].This compound was synthesized via a reductive amination process involving a suitably substituted secondary benzylamine 13 with an isoindolinone 14 equipped with a carboxyalkyl chain.This compound is the product of the Swern oxidation reaction of the corresponding hydroxypropyl derivative 5e which has been prepared by a metalation/anionic cyclization sequence applied to the oxazinone derivative 6e.

X
= O, S, NR Y = Br, I