Synthesis of 3,3-Disubstituted Isoindolin-1-ones via Iodoamination of α-Substituted Secondary 2-Vinylbenzamides

Abstract

A new and simple method for the preparation of 3,3-disubstituted isoindolin-1-ones from a-substituted 2-bromostyrenes is described. Construction of the isoindolin-1-one skeleton was accomplished by treating a-substituted secondary 2-vinylbenzamides, easily obtainable from the reaction of a-substituted 2-lithiostyrenes with isocyanates, with iodine to afford 3-substituted 3-iodomethylisoindolin-1-ones.A number of synthetic methods for 3-substituted isoindolin-1-ones have been reported, 1 mainly on account of their biological interest. 2 For example, the alkylation of 2-substituted 3-lithioisoindolin-1-ones, first reported by Couture et al., 1b is one of the most efficient methods for preparing this class of compounds. However, there have been few reports on the synthesis of 3,3-disubstituted derivatives in literature. 3 In this paper we wish to demonstrate that the intramolecular iodoamination 4 of asubstituted secondary 2-vinylbenzamides provides a simple and convenient method for the synthesis of 3,3-disubstituted isoindolin-1-one derivatives. 5 Our synthesis of 3,3-disubstituted isoindolin-1-one derivatives was conducted as outlined in Scheme 1. Thus, the bromine-lithium exchange between readily available asubstituted 2-bromostyrenes 1 and butyllithium in diethyl ether at 0 °C for one hour generated the corresponding asubstituted 2-lithiostyrenes. Almost complete generation of 1-(2-lithiophenyl)-1-phenylethene from 1a was confirmed by obtaining 1,1-diphenylethene almost quantitatively after quenching with aqueous ammonium chloride. Then, these lithium products were allowed to react with isocyanates to give the a-substituted secondary 2-vinylbenzamides 2 in the yields summarized in Table 1. It indicates that aliphatic isocyanates (entries 3 and 4) gave poorer results than aromatic isocyanates (entries 1, 2, 5, and 6). The moderate yields of 2 may be ascribed to the liability of isocyanates to oligomerization.The regioselective intramolecular iodoamination of these amides 2 proceeded smoothly on treatment with iodine in the presence of sodium hydrogen carbonate in acetonitrile at 0 °C to give the 3-iodomethylisoindolin-1-one derivatives 3 in fair to good yields. Reduction of the iodo moiety of 3 with tributyltin hydride smoothly proceeded in benzene at room temperature to afford the 3-methylisoindolin-1-one derivatives 4 in fair to good yields. These results are also summarized in Table 1.We attempted the nucleophilic substitution reactions of 3a with sodium thiolates; however, this resulted in the formation of intractable mixtures of products.In conclusion, we have shown that 3,3-disubstituted isoindolin-1-ones can be synthesized in two steps from readily available a-substituted 2-bromostyrenes and under milder reaction conditions. This method may find some value in synthesis because of its simplicity.The melting points were determined on a Laboratory Devices MEL-TEMP II melting-point apparatus and are uncorrected. The IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer. The 1 H NMR spectra were deter...

Hydriodic Acid‐Mediated Cyclization of α‐Substituted Secondary 2‐Ethenylbenzamides: Synthesis of 2‐Substituted 2,3‐Dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones and 3,3‐Disubstituted (E)‐1‐(Arylimino)‐1,3‐dihydroisobenzofurans

“…The reaction was complete at 08 in 1 h, and the precipitated product was collected. However, we found that the spectroscopic data (IR and 1 H-NMR) of this product were not identical to those of previously prepared 2,3-dihydro-3-methyl-2,3-diphenyl-1H-isoindol-1-one [1]. We determined the structure of this product to be (E)-1,3-dihydro-3-methyl-3-phenyl-1-(phenylimino)isobenzofuran (6a) on the basis of its spectroscopic data and elemental analysis (see Exper.…”

“…of HI in MeCN at room temperature to yield the desired 2,3-dihydro-3,3-dimethyl-2-phenyl-1H-isoindol-1-one (3a) in fair yield. The IR and 1 H-NMR spectra were identical to those reported in [1]. The use of less than 2 mol-equiv.…”

“…from the 2-bromostyrenes 1 as described in [1]. Thus, Li/Br exchange between 1 and BuLi in Et 2 O at 08 generated the corresponding 2-lithiostyrene derivatives.…”

“…-We previously reported a synthesis of 3,3-disubstituted-2,3-dihydro-1H-isoindol-1-ones based on iodoamination of a-substituted secondary 2-ethenylbenzamides, which could be prepared by the reaction of a-substituted 2-lithiostyrenes with isocyanates [1]. As an extension of this work, we herein describe the results of our study on HI-mediated cyclization of a-substituted secondary 2-ethenylbenzamides, which provide concise and efficient synthetic routes to 2-substituted 2,3-dihydro-3,3-dimethyl-1H-isoindol-1-ones and 3,3-disubstituted (E)-1-(arylimino)-1,3-dihydroisobenzofurans depending on the a-substituents of a-substituted secondary 2-ethenylbenzamides.…”

“…These compounds were prepared by reacting asubstituted 2-lithiostyrenes, generated by the Br/Li exchange between 1 and BuLi, with isocyanates under the conditions previously reported by us [1]. 2,3-Dihydro-3,3-dimethyl-2-phenyl-1H-isoindol-1-one (3a).…”