The Lewis acid-catalyzed [3+1+1] cycloaddition of azomethine ylides with isocyanides
Graphical abstract
Introduction
The pyrrolidines and their derivatives are nitrogen-containing five-membered heterocycles that represent important intermediates in the production of pharmaceuticals and natural alkaloids and also serve as effective organocatalysts in organic synthesis.1 There are many approaches to the synthesis of pyrrolidine derivatives, but one of the most versatile involves the use of aziridines as three-atom precursors, a method, which is also applicable to the synthesis of many nitrogen-containing biologically active molecules.2 The behavior of aziridines is largely based on the reactivity of the C–N bond, since these molecules are highly strained cyclic amines. As an example, an N-tosylaziridine will undergo formal [3+2] cycloaddition as a masked 1,3-dipole via C–N bond cleavage when reacting with alkenes,3 alkynes,4 and aldehydes.5 The nucleophilic ring opening reactions of aziridines will also take place in the presence of catalytic amounts of a Lewis acid.6 In addition, aziridines are known to transform into the corresponding azomethine ylides by opening at the C–C bond, a process that can be promoted by a Lewis acid,7 radiation8 or heat.9 The resulting azomethine ylides commonly serve as 1,3-dipoles, allowing the ready preparation of five-membered nitrogen heterocycles.10 A Lewis acid strategy is one of the most useful means of achieving the C–C bond cleavage of N-aryl aziridines with the aim of generating metal-coordinated azomethine ylides, an approach pioneered by Carrie11 and Johnson.12 More recently, Zhang, Lu, and Wang have demonstrated that N-tosylaziridine dicarboxylate will readily undergo C–C bond cleavage in the presence of a Lewis acid as the result of the strongly electron-withdrawing tosyl group. Based on this process, Zhang et al. reported the 1,3-dipolar cycloaddition of azomethine ylides, generated from N-tosylaziridine dicarboxylate in the presence of catalytic amounts of a Lewis acid, with aldehydes, alkenes, and alkynes to afford the corresponding nitrogen-containing heterocycles in reasonable yields.13 Only a few examples of the reaction of azomethine ylides with isocyanides have been reported to date, giving the corresponding imino azetidines via [3+1] cycloaddition.14 Herein, we describe the first instance of the novel [3+1+1] cycloaddition of azomethine ylides, based on the nucleophilic addition of an isocyanide in a so-called Ugi-type reaction, to form highly functionalized nitrogen-containing heterocycles.15 This cycloaddition reaction is very unique in that it involves the trapping of a nitrilium intermediate by a carbanion.16, 17
The Passerini and Ugi reactions18 generally require a carboxylic acid, which activates an aldehyde or imine and traps a nitrilium ion to form an acyloxylated intermediate. Subsequent acyl transfer leads to the corresponding α-acyloxy amide or α-amino amide. In our previous studies, silanol or borinic acid acted in place of the carboxylic acid in a Passerini-type reaction (Eq. 1).19 In addition, we have expanded this concept to the intramolecular trapping of the nitrilium intermediate in a Ugi-type reaction. Thus, if a molecule contains both an electrophile (CN) and a potential nucleophilic group (Nu−), intramolecular trapping of the nitrilium intermediate can be readily achieved in the same manner as occurs in the intermolecular version. Based on this hypothesis, we have already developed the [5+1] cycloaddition between C,N-cyclic N′-acyl azomethine imines and isocyanides to afford the corresponding imin-1,3,4-oxadiazin-6-one derivatives through trapping the nitrilium intermediate with nucleophilic oxygen (Eq. 2).20, 21 In the present study, we chose azomethine ylides generated from N-tosylaziridine dicarboxylate to act as masked 1,3-dipoles via C–C bond cleavage. We initially examined whether the N-tosylaziridine dicarboxylate could act as an imine analogue, capable of trapping an isocyanide as a C1 source to afford the corresponding heterocycles (Eq. 3). In the reaction of N-acyl azomethine imines, either the acyl carbon or acyl oxygen could act as a nucleophilic center.
Section snippets
Results and discussions
Our initial attempts involved using the well-known N-tosylaziridine dicarboxylate 1a as a masked azomethine ylide precursor together with tert-butyl isocyanide (2a) in the presence of a commercially available Lewis acid in dichloromethane (CH2Cl2). We were surprised to see that when 1.0 equiv of 1a and 2.0 equiv of 2a were combined with a 20 mol % solution of Sc(OTf)3 in CH2Cl2 at room temperature, the reaction yielded not the expected azetidine derivative but rather a mixture of 3aa and its
Conclusion
We have developed the Lewis acid-catalyzed [3+1+1] cycloaddition reaction between azomethine ylides and aliphatic isocyanides, leading to pyrrolidine derivatives. Azetidine derivatives were also obtained by the use of aromatic isocyanides. These reactions proceed efficiently under mild conditions. The selective syntheses of five- or four-membered heterocycles, representing pyrrolidines or azetidines, have been achieved by appropriate choice of isocyanides, including aliphatic or aromatic
General
1H NMR was recorded on a JEOL ECS 400 (400 MHz) NMR spectrometer. Chemical shifts δ are reported in parts per million (ppm) using TMS as an internal standard. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constant (J) and integration. 13C NMR spectra were recorded on JEOL ECS 400 (100 MHz) NMR spectrometer. The chemical shifts were determined in the δ-scale relative to CDCl3 (δ=77.0 ppm). The IR spectra were
Acknowledgements
This work was partially supported by a Grant-in-Aid for Young Scientists (B) (24750037) and a Grant-in-Aid for Scientific Research (B) (24350022) from the Japan Society for the Promotion of Science.
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