Elsevier

Tetrahedron

Volume 75, Issue 33, 16 August 2019, Pages 4626-4631
Tetrahedron

Diastereoselective synthesis of multisubstituted isoindolines via Sequential Ugi and aza-Michael addition reaction

https://doi.org/10.1016/j.tet.2019.07.006Get rights and content

Abstract

A new efficient and diastereoselective synthesis of multisubstituted isoindolines with two stereogenic centers via sequential Ugi/aza-Michael addition reaction was developed. Ugi-3CR of aldehydes 1, amines 2 and isocyanates 3 in the presence of catalytic amount of H3PO4 produced intermediates 4, which were then transformed to isoindolines 5 with good 1,3-trans diastereoselectivity in the presence of K2CO3 by intramolecular aza-Michael addition. Sequential Ugi-azide and aza-Michael addition reaction of aldehydes 1, amines 2 and trimethylsilyl azide 6 also produced 4-tetrazolyl substituted isoindolines 8 with good 1,3-trans diastereoselectivity in the presence of potassium carbonate.

Introduction

Multisubstituted isoindoline derivatives are active structural unit of some synthetic drugs and have an extensive application in pharmaceutical and chemical industry. Compounds containing isoindoline structural motif has been approbated to exhibit a wide range of biological activities, including antitumor [1], anti-inflammatory [2], and anticancer activities [3]. Other isoindoline derivatives have been used as platelet aggregation inhibitors [4], selective and potent DPP8 inhibitors [5], mitochondrial respiration activators [6], and fluorescent probes [7]. Various methods had been reported for the synthesis of isoindoline derivatives [[8], [9], [10], [11], [12], [13], [14], [15]], including palladium-catalyzed intramolecular oxidative aminoarylation of alkenes [8], chlorination/cyclodehydration of amino alcohols [9], and microwave-assisted cyclization from primary amines and dihalides [10]. However, these reported procedures have the limitations of the utilization of the precious transition-metal catalysts, inaccessible starting materials and troublesome operation. Therefore, the development of new simple and convenient method for the synthesis of isoindoline is of great significant.

Isocyanide based multicomponent reactions (IMCRs), especially Ugi four-component reactions (Ugi-4CR), have been extensively applied for the construction of many heterocyclic compounds with high atom economy [16]. The catalytic three-component Ugi Reactions (Ugi-3CR) have also been utilized in synthesis of 2-amino acetamides starting from aldehydes, amines and isocyanides in the presence of an acid catalyst [17]. Michael addition reactions, including oxo-, aza-, and sulfa-Michael addition reactions, have provided a powerful method for construction of C–C, C–O, C–N and C–S bonds in an operationally simple and atom economical procedure [[18], [19], [20]]. Recently the sequence of Ugi-4CR/Michael addition reactions has been utilized in synthesis of a series of biologically useful heterocycles [[21], [22], [23], [24], [25], [26], [27]], such as 2,5-diketopiperazines, 1H-pyrrol-2(5H)-ones, chromeno[3,4-c]pyrrole-3,4-diones, and β-lactams. However, there is no report on the sequential Ugi-3CR/Michael addition or Ugi-azide/Michael addition reaction for construction of structurally diverse complex molecules. Continuing our interests in the synthesis of various heterocycles via multicomponent reactions [28], herein we wish to report a new diastereoselective synthesis of multisubstituted isoindolines via sequential Ugi-3CR/aza-Michael and Ugi-azide/aza-Michael addition reactions.

Section snippets

Results and discussion

We initiated our one-pot experiment by the Ugi three-component reaction of aldehyde 1a, amine 2a, and isocyanide 3a. The Ugi product 4a was produced successfully in the presence of 20 mol% phosphoric acid in methanol at room temperature (Table 1), detected by TLC. Afterward potassium carbonate was added directly to the mixture to both neutralize the solution and catalyze the intramolecular aza-Michael addition reaction of 4a to 5a. The isoindoline 5a was finally obtained in 45% yield and the

Conclusion

In summary, we have developed an efficient and diastereoselective synthesis of multisubstituted isoindolines via sequential Ugi-3CR/aza-Michael and Ugi-azide/aza-Michael addition reactions, starting from three or four-component starting materials. The new synthetic approaching had the advantages of mild reaction condition, easily accessible starting materials, facile one-pot operation and relatively good diastereoselectivity.

General

Melting points were determined using a X-4 model apparatus and were uncorrected. NMR were recorded in CDCl3 or [D6] DMSO on a Varian Mercury 600 spectrometer and resonances relative to TMS. HRMS was measured on an Agilent 6224 TOF LC/MS spectrometer. Aldehydes 1 were prepared by Heck reaction of 2-bromobenzaldehyde with methyl or ethyl acrylate according to literature report [30].

Methyl 2-(3-(tert-butylcarbamoyl)-2-(4-chlorophenyl) isoindolin-1-yl) acetate (5a)

To a solution of aldehyde 1 (R1 = H, R2 = CH3, 0.570 g, 3.0 mmol) in methanol (15 mL) was added amine 2 (R3 = Cl,

Acknowledgment

We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (No. 21572075) and the 111 Project B17019.

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