HETEROCYCLES

Communication | Regular issue | Vol. 78, No. 5, 2009, pp. 1177-1181
Received, 8th December, 2008, Accepted, 23rd January, 2009, Published online, 27th January, 2009.
DOI: 10.3987/COM-08-11621

■ Facile Synthesis of 1-Aryl-2,3-dihydro-1H-isoindoles by Cyclization of N-Formyliminium Ion via Geometrically Disfavored 5-Endo-trig Process

Michikazu Kitabatake, Toshiaki Saitoh, Takehiro Sano, and Yoshie Horiguchi*

Showa College of Pharmaceutical Sciences, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

Synthesis of 1-aryl-2,3-dihydro-1H-isoindoles (isoindolines) (10) was achieved in a highly effective manner via acid catalyzed cyclization of N-formyliminium ion (8) obtained from 2,3-dimethoxybenzylamine and carbonyl compounds with acetic-formic anhydride under a one pot procedure. This Pictet-Spengler type reaction provides a convenient method for preparing 1-arylisoindolines.

Compounds containing 2,3-dihydro-1H-isoindoles (isoindoline) (1) such as 1-methyl-1-phenyl-(3) and 1-phenyl-derivative (4) are known to be a non-competitive NMDA antagonist1, 2 and a phencyclidine agonist3 respectively. However, isoindoline derivatives are very rare in spite of biological interest, when

compared to 1,2,3,4-tetrahydroisoquinoline (2) derivatives that constitute the fundamental ring system of various medicines. Although there are several syntheses of isoindoline in the literature,4-10 only one paper which deals with a general methodology leading to the isoindoline ring system is reported.10
In this paper we report the synthesis of 1-aryl-2,3-dihydro-1H-isoindole (10) utilizing a simple and convenient method via a Pictet-Spengler type reaction, that is, the intramolecular cyclization of N-formyliminium ion (8). We have recently developed this methodology for the synthesis of tetrahydroisoquinoline (2) producing not only 1-substituted but also 1,1-disubstituted derivatives.11
The N-formyliminium ions (8a~e), substrates of the reaction, were readily prepared by formylation of imines (7a~e) with acetic-formic anhydride. The imines (7a~e) were obtained by heating a mixture of 3,4-dimethoxybenzylamine (5) and arylaldehydes (6a~d) or acetophenone (6e). The procedures are shown in Table 1.
The intramolecular cyclization of N-formyliminium ions (8) leading to the isoindoline ring system via 5-endo-trig process was anticipated to be difficult to achieve when compared with the Pictet-Spengler reaction to 1,2,3,4-tetrahydroisoquinoline via 6-endo-trig; according to the Baldwin rule12 the former reaction of 5-endo-trig process is geometrically disfavored while the latter 6-endo-trig one is favored. This disadvantage was overcome by finding reaction conditions using a large excess of trifluoroacetic acid (TFA) described in Table 1. However, when the process of removing acetic-formic anhydride from the reaction mixture was omitted or inadequate, the cyclization did not occur in a practical sense. This fact revealed that the acidity of the reaction solution is critically important to produce this intramolecular cyclization. Thus, the 1-aryl-2,3-dihydro-2-formyl-1H-isoindoles (9) were obtained in fairly good yields, as shown in Table 1.13 Hydrolysis of 9 with hydrochloric acid yielded the corresponding 1-aryl-2,3-dihydro-1H-isoindoles (10) in a quantitative yield.13 The direct cyclization of the imine (7) to the isoindoline (10) did not occur at all even when treated with TFA even under more forced conditions, indicating that the cyclization is the reaction of N-formyliminium ions (8) activated by N-formyl group. These experiments clearly demonstrated that the cyclization of the N-formyliminium ion to isoindoline

occurs through the geometrically disfavored 5-endo trigonal process. It is especially noteworthy that the N-formyliminium ion (8e), in spite of having the congested tetra-substituted C=N+ system, readily caused the cyclization to give 9e in 86% yield.
The occurrence of this cyclization may be explained in terms of mesomeric effect. The C=N+ bond is conjugated to the benzene ring. Therefore, the energy of the transition state should be lowered by the contribution of mesomeric enamino-structure 8B featuring 5-exo trigonal cyclization. Thus, the 5-endo trig process of the imino-structure 8A to 9, although geometrically disfavored, will be facilitated by the contribution of 8B that is geometrically favored. The relatively low yield of isoindoline 9d probably is attributable to the instability of the cation of 8B which is induced by the electron attractive meta OMe group (R2) .

Thus, the Pictet-Spengler type reaction of N-formyliminium ions obtained from 3,4-dimethoxybenzylamine and carbonyl compounds under a one pot procedure provides a convenient method for preparing 1-arylisoindolines. Investigation concerning the scope and limitation of this methodology is underway.

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