An Easy Approach for the Synthesis of N-Substituted Isoindolin-1-ones

Abstract

A practical and efficient two-step synthesis of N-substituted isoindolin-1-ones was developed. The one-pot reaction of 2-formylbenzoic acid with amines and dimethyl phosphite proceeds in short time either with conventional heating or microwave irradiation under catalyst-free conditions to afford the corresponding Nsubstituted dimethyl 3-oxoisoindolin-1-ylphosphonates in good yield which, by means of a dephosphonylation reaction with lithium aluminum hydride, give the target N-substituted isoindolin-1-ones in moderate to good yield.Isoindolin-1-ones (2,3-dihydro-1H-isoindol-1-ones) have gained considerable attention recently due to their fascinating properties and potential applications in many fields, especially in biology and medicinal science. 1 The interest in these heterocyclic compounds stems mainly from their diverse biological activities. For example, isoindolin-1-ones 1-3 ( Figure 1) have been tested as antimicrobial agents, 2 while indoprofen (4) has been shown to have anti-inflammatory activity 3,4 and deoxythalidomide (5) is an inhibitor of tumor necrosis factor production. 5 Additionally, the isoindolin-1-one skeleton is a key intermediate for the synthesis of many naturally occurring bioactive compounds. 6 Figure 1Consequently, the chemistry of isoindolinones has attracted much attention, and a number of synthetic strategies have been developed over the past few years including the reduction of phthalimides, 7 the condensation of anilines with o-phthalaldehydes, 8 amination and lactamization of 2-carbomethoxybenzaldehyde, 6h,9 palladium(0)-catalyzed carbonylation-amination, 10 synthesis from isocyanates 11 and base-induced aryne-mediated cyclization of o-halo-N-(phosphinylmethyl)benzamide derivatives; 12,13 however, despite their potential utility, these procedures typically suffer from one or more disadvantages, such as the use of harsh conditions or tedious multisteps which are necessary for these syntheses. Thus, there is still a need to develop versatile and flexible methods for the synthesis of isoindolin-1-ones. In this context, herein we describe an efficient method for the synthesis of N-substituted isoindolin-1-ones. Our synthetic strategy is based upon a onepot reaction of 2-formylbenzoic acid with alkyl-or arylamines and dimethyl phosphite using conventional heating or microwave irradiation under catalyst-free conditions, 14 followed by a dephosphonylation reaction.We have recently developed 15 an efficient and highly diastereoselective method for the synthesis of 3-oxoisoindolin-1-ylphosphonate 7a by a three-component, one-pot reaction of 2-formylbenzoic acid (6), (S)-a-methylbenzylamine and dimethyl phosphite under catalyst-and solvent-free conditions (Table 1, entry 1). To establish the generality of this three-component, one-pot process we carried out the reaction of 2-formylbenzoic acid (6) with either alkyl-or arylamines and dimethyl phosphite. Thus, the reaction of 2-formylbenzoic acid (6) with tert-butylamine or benzhydrylamine and dimethyl phosphite at 80°C under catalyst-and sol...

First practical synthesis of novel 1‐phosphonylated pyrrolo[1,2‐a]pyrazine derivatives

“…However, when we carried out the reaction of the cyclic α‐aminophosphonate 9a with LiAlH 4 in anhydrous THF at reflux, the C ‐dephosphonation also occurred, giving the 2‐benzyl‐1,2,3,4‐tetrahydropyrrolo[1,2‐ a ]pyrazine 11 in 65% yield (Scheme ). These results are in agreement with the results obtained for us, when the isoindolin‐1‐one‐3‐phosphonates were reacted under similar reaction conditions.…”

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

“…The same research group found a useful method for the synthesis of isoindolin-1-one-3-phosphonates from aromatic amines [ 41 ]. The one-pot reaction of aniline 59 with formylbenzoic acid ( 55 ) and dimethyl phosphonate ( 31 ) under the above-mentioned conditions at 90 °C afforded the desired isoindolin-1-one-3-phosphonates 60 in only 14% yields after five days.…”

Microwave-assisted synthesis of α-aminophosphonates with sterically demanding α-aryl substituents

“…Up to now, only three cases were reported for the Kabachnik-Fields-type syntheses of a-aryl-a-aminophosphonates containing an N-benzhydryl group. [22][23][24] In one case the condensation of benzhydrylamine, 1-naphthaldehyde and diethyl phosphite was carried out in the presence of montmorillonite KSF catalyst in a kitchen MW oven. [22] A scandium tris(dodecylsulfate)-catalyzed synthesis of a-aryl-a-aminophosphonates was also described, where triethyl phosphite was applied as the P-component.…”

“…[23] Benzhydrylamine was also reacted with formylbenzoic acid and dimethyl phosphite, where 3-oxoisoindolin-1-ylphosphonate was synthesized in a moderate yield. [24] In most cases, these derivatives were synthesized by the Pudovik reaction of a-aryl imines with dialkyl phosphites, [25,26] also providing new information on the peculiar proximity H atoms. [26] In this paper, the synthesis of a-aryl-a-aminophosphonates by the solvent-and catalyst-free Kabachnik-Fields condensation of benzhydrylamine, aromatic aldehydes and dialkyl phosphites was revisited under MW irradiation.…”