A Versatile Method for the Elaboration of Diversely Substituted N-Alkylated and Free-NH Isoindolinones . Application to the Asymmetric Synthesis of the C 3-Substituted Models

Isoindolinones and their derivatives of generic structure 1, 2 have gained considerable attention due to their diverse physiological and chemotherapeutic activities [1] and for their importance as key intermediates for the construction of various drugs, biologically active compounds [2] and naturally occurring alkaloids [3].


Introduction
Isoindolinones and their derivatives of generic structure 1, 2 have gained considerable attention due to their diverse physiological and chemotherapeutic activities [1] and for their importance as key intermediates for the construction of various drugs, biologically active compounds [2] and naturally occurring alkaloids [3].

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The most common synthetic routes to these benzolactams are portrayed in Scheme 1.They are generally of procedural simplicity and proceed in satisfactory yields but the reported methods suffer from several drawbacks and particularly from restrictions in the choice of substituents in their nature, their number and their specific position on the basic aromatic nucleus.Furthermore the elaboration of free-NH models 2 requires an additional and somewhat erratic deprotection step [4].

Results and Discussion
A new synthetic approach to these bicyclic lactams 1, 2 that is based on the Parham cyclization protocol [15], i.e. creation of an aryllithiated species by halogen/metal exchange and subsequent trapping by an internal electrophile, has then been developed.

Synthesis of the N-alkylated isoindolin-1-ones (1)
For the assembly of the N-substituted models 1 a variety of poly and diversely substituted N-alkyl-halobenzylcarbamates 3a-g were initially synthesized and subsequently exposed to tBuLi at -90 °C followed by gentle warming to rt.Th is technique ensured the optimal formation of the transient aryllithiated species 4 (Scheme 2).With the carbamate function acting as the internal electrophile the targeted annulated compounds 1a-f were solely obtained with very satisfactory yields (Table 1).The method tolerates the presence of fluorinated substituents that survive the halogen/metal interconversion reaction (Table 1, entries 5,6).This process can also be applied to model compound where the carbamate function is embedded in an oxazolinone ring system, e.g.3g, as exemplified by the assembling of the benzolactam 1g equipped with an hydroxyalkyl chain which may serve as a handle for further synthetic development (Table 1, entry 7).

Synthesis of the free-NH isoindolin-1-ones (2)
Since an alkoxide species was released upon the anionic cyclization of carbamate 3a-g (see Scheme 2) we reasoned that incorporation in the annulated compounds 1 of a temporary protecting group R 5 highly sensitive to nucleophile attacks would conceivably deliver the free-NH models 2 (R 5 = H) in a straightforward manner.The choice of the alkoxycarbonyl group (R 5 = COOMe) originated from the following premises: (i) the carbamate group is endowed with a remarkable propensity to react with basic and nucleophilic reagents, in particular with alkoxy moieties, inter and intramolecularly [21] and (ii) the presence of a symmetrical N-diacyl functionality in the parent models 5 should not alter the annulation process leading to the fused benzolactams 2.
A range of iodinated benzyldicarbamates 5a-e which are liable to favor halogen/metal interconversion upon treatment with organolithiated reagents while sparing the diacyl functionality were initially assembled by a Mitsonobu reaction between the benzylic alcohols 6a-e and dimethyl iminodicarboxylate (Scheme 3).They were subsequently exposed to nBuLi at -90 °C followed by warming to rt and reflux ing for a short period.This protocol delivered a variety of free-NH annulated products 2a-e (Table 2) upon acidic workup following the anticipated mechanistic pathway depicted in Scheme 3.

Application to the asymmetric synthesis of the C3-substituted isoindolin-1ones (7a-c)
The key step of the synthetic approach is based upon the construction of the C3substituted isoindolinone template by the Parham type cyclization of chiral haloarylcarbamates 8a-c as depicted in Scheme 4 (Table 3).Noteworthy the alkoxy groups on the basic benzene nucleus were prone to force and facilitate the regioselective bromination of the opened carbamate 9a-c and installation of the bromine atom at the in between site could be readily secured under standard conditions.