Synthesis of Indoles and Benzisoxazolines from Baylis-Hillman Adducts of 2-Nitrobenzaldehydes

Abstract

Recently a variety of interesting chemical transformations involving the use of Baylis-Hillman adducts have been reported. Among them the use of Baylis-Hillman adducts of 2-nitrobenzaldehydes have been investigated extensively for the synthesis of quinoline-N-oxides, quinolines, quinolones, benzisoxazolines, and indoles. Although there have been reported numerous methods for the synthesis of indole derivatives, a development of new synthetic method of indole scaffold is required due to their biological importance and usefulness as synthetic intermediates. A few years ago we reported the synthesis of 3-alkoxymethyl 2(1H)-quinolones from the SnCl2-mediated reduction of the Baylis-Hillman adducts 1a in alcohol solvent (Scheme 1). In the reaction, the nitro group of 1a was reduced to amino group and we obtained 3-alkoxymethyl 2(1H)-quinolones as the major products. In some cases we obtained benzisoxazoline compounds (5-10%) like 3a as the side products, which might be formed via the hydroxylamine intermediate. At that time we also observed the formation of trace amounts of indole derivatives in some cases, especially when we used alcohols having high boiling point. Encouraged by recent publications on the synthesis of indoles from Baylis-Hillman adducts, we reinvestigated the SnCl2-mediated reduction of 1a in order to obtain the benzisoxazoline or indole derivatives in improved yields. To our delight, we found an efficient condition for the formation of 3-substituted indoles and benzisoxazolines and wish to report herein the results (Scheme 1). As shown in Scheme 1, the reaction of Baylis-Hillman adduct 1a of 2-nitrobenzaldehyde and SnCl2 in 1,4-dioxane at refluxing temperature gave the indole 2a and benzisoxazoline 3a in moderate yields. As described above the formation of benzisoxazoline compound was already reported in part in our previous paper and the reaction mechanism could be regarded involving the hydroxylamine intermediate (I) and the cyclized intermediate (II) as in Scheme 2. Although the reaction mechanism for the formation of indole 2a was not clear at this stage we could tentatively propose a plausible mechanism as shown in Scheme 2: (i) formation of nitroso intermediate (III), (ii) Michael addition to form (IV), (iii) reversible retro-aldol type ring-opening to form (V), (iv) cyclization to (VI), (v) water-assisted elimination of formic acid to give indoline derivative (VII), (vi) dehydration to (VIII) and the final isomerization to indole 2a. Based on the experimental results and the proposed mechanism there must be formed hydroxylamine intermediate (I) and nitroso intermediate (III) under SnCl2/dioxane conditions in a variable ratios. In order for the selective formation of either (I) or (III), we examined the reaction conditions including solvent, temperature, the equivalents of SnCl2, but all failed to improve the yields or selectivity. The nitro group is readily converted to a series of functions of various degrees of reduction: very exceptionally to a nitroso group, more often to a hydroxylamino group and most frequently to the amino group. Nitroso compounds are usually not obtained directly but rather by reoxidation of hydroxylamino compounds, which can be prepared from nitro compounds by SnCl2. Moreover there have been few instances in