TfOH-catalyzed formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles: Synthesis of tetrafunctionalized 2-imidazolines

Highlights

• TfOH-catalyzed cycloaddition of N-tosylaziridine dicarboxylates and nitriles gave tetrafunctionalized 2-imidazolines.

• The method features mild conditions and wide scope of substrates.

• First example of C–N bond cleavage of N-tosylaziridine dicarboxylates catalyzed by Brønsted acid.

• A S_N2 process.

Abstract

We developed an efficient method for synthesis of tetrafunctionalized 2-imidazolines using TfOH-catalyzed formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles. This is the first report of C–N bond cleavage of N-tosylaziridine dicarboxylates catalyzed by Brønsted acid and the reaction worked well over wide scope of substrates in good to excellent yields under mild conditions. The method has the potential to be applied to pharmaceutical design and synthesis of tetrafunctionalized 2-imidazolines.

Introduction

The synthesis of tetrafunctionalized 2-imidazolines has received considerable attention due to their common use as bioactive molecules [1], [2], [3], [4], [5], [6], [7], organocatalysts [8] and ligands for asymmetric synthesis [9], [10] (Fig. 1). For example, Nutlin-3, which is based on a tetrasubstituted 2-imidazoline scaffold, efficiently disrupted the interaction between p53-MDM2 for cancer treatment [5], [6]. Several approaches are known to synthesize tetrafunctionalized 2-imidazolines, involving multistep cyclization of 1,2-diamines [11], [12], [13], [7], [14] or β-amino alcohols [15], the metal-catalyzed or metal-free protocols for multicomponent reactions [16], [17], [18], [19], [20], [21], [22], [23], [24] or formal [3+2] annulation [25], [26], [27], [28], [29], and the transformations of the protected α, β-diamino esters [30], unsymmetrical imidazolines [31], [32] or imidoyl chlorides with aziridines [33].

However, there still remain challenges in this field such as difficult availability of precursors and the use of complex reagents including transition metal salts. Hence, a novel and efficient synthesis approach to the potentially bioactive heterocycles is still valuable.

The formal [3+2] annulations of N-tosylaziridine dicarboxylates (donor–acceptor aziridines) with diverse nucleophiles has emerged as a potentially powerful approach for convenient access to structurally complex five-membered azaheterocycles via Lewis acid-catalyzed/mediated C–C bond cleavage of donor–acceptor (DA) aziridines (Scheme 1A) [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47]. Although most nitriles are known to be poor dipolarophiles for [3+2] cycloaddition reactions, the groups of Zhong & Zeng [48] and Wang [49] have independently demonstrated that TfOH-catalyzed cycloaddition of oxiranes dicarboxylates or donor-acceptor cyclopropane and nitriles successfully via C–C bond cleavage of oxiranes or cyclopropanes (Scheme 1B).

Inspired by the above achievements and based on our interest in developing antitumor heterocycles and potentially bioactive azaheterocycles, we envisioned that the formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles to provide tetrafunctionalized 2-imidazolines. Herein, we describe the first example of the development of a remarkably mild TfOH-catalyzed formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles, providing a facile and step-economical access to tetrafunctionalized 2-imidazolines bearing ester functional groups, which serve as key building blocks in the potent NF-κB inhibitor TCH-013 (Scheme 1C) [50], [51]. Of particular note is the fact that Brønsted acid have been not exploited in annulation reaction of DA aziridines with diverse nucleophiles or electron-rich reaction groups, though the similar catalytic process has been reported to prepare trifunctionalized 1H-imidazoles using nitriles and common aziridines in the presence of TfOH via Ritter reaction [52], where the electronic nature of common aziridines were different from DA aziridines. In this light, DA aziridines inherently favour C–C bond cleavage, which was supported by density functional theory (DFT) studies [53] and the experimental results showed that Lewis acids catalyzed C–C bond heterolysis of DA aziridines.