Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation

Abstract

Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.

Studies on the diastereoselective reductive alkylation of (R)-phenylglycinol derived phthalimide: observation of stereoelectronic effects

“…1,3,[5][6][7][8][9][10][11][12][13] Among them, the most flexible and straightforward ones are those where the alkyl groups at the C-3 position are introduced directly. This has been achieved either by the reaction of 3-metalated isoindolin-1-ones with electrophiles (Scheme 1, path a); 9 by the reaction of an N-acyliminium equivalent with nucleophiles (path b); 10 by the reaction of methyl o-lithiobenzoate to imines (path c); 11 or by organometallic reagents addition to phthalimide followed by reductive deoxygenation (path d). 12,13 However, few flexible methods are available for the asymmetric synthesis of simple 3-alkyl-isoindolin-1-ones in high enantiomeric excess.…”

Total Syntheses of Taliscanine, Velutinam, and Enterocarpam II

“…Syntheses of phthalimidine (2,3-dihydro-1 H -isoindol-1-one) derivatives have been widely investigated, but the applications of traditional methods are quite limited and unsatisfactory because of severe reaction conditions, difficulties in purification, and above all, limitations in substituents . To obviate these problems a direct annulation approach based on a four-component condensation involving phenyllithium, an imine, diversely substituted o -iodobenzoates, and BF 3 −Et 2 O has been recently proposed, but the isoindolinones were invariably aryl- or alkylated at the 3-position of the heterocyclic nucleus …”

Main Group Metal‐Mediated Transformations of Imines

“…Al ater report by Campbell and co-workers in 1996 expanded on the cyclisation pathways extendingt oN-methylbenzamides and 2-methyl-iodobenzoate as precursors (Scheme 21). [65] These routes overcome some of the challenges presented by Bradsher's study employing the unstable isopro-pyl ortho-lithiobenzoate. An improvement in yields and scope were noted, including imines with hydrogens a to the imine carbon.S tartingf rom ab enzamide derivative at wo-step process occurs, firstly ad ianionic intermediate is formed, which then undergoes nucleophilic addition of the imine, followed by heatinga t1 30 8Cf or 30 min results in the cyclised product.…”

“…A later report by Campbell and co‐workers in 1996 expanded on the cyclisation pathways extending to N ‐methyl‐ benzamides and 2‐methyl‐iodobenzoate as precursors (Scheme 21). [65] These routes overcome some of the challenges presented by Bradsher's study employing the unstable isopropyl ortho ‐lithiobenzoate. An improvement in yields and scope were noted, including imines with hydrogens α to the imine carbon.…”