In this paper we describe the phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of azomethine imines and allenoates. These processes mark the first use of azomethine imines in nucleophilic phosphine catalysis, producing dinitrogen-fused heterocycles, including tetrahydropyrazolo-pyrazolones, -pyridazinones, -diazepinones, and -diazocinones. Counting the two different reaction modes in the [3 + 3] cyclizations, there are five distinct reaction pathways—the choice of which depends on the structure and chemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions, affording a broad range of 1,2-dinitrogen–containing heterocycles in moderate to excellent yields. A zwitterionic intermediate formed from a phosphine and two molecules of ethyl 2,3-butadienoate acted as a 1,5-dipole in the annulations of azomethine imines, leading to the [3 + 2 + 3] tetrahydropyrazolodiazocinone products. The incorporation of two molecules of an allenoate into an eight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis. The salient features of this protocol—the facile access to a diverse range of nitrogen-containing heterocycles and the simple preparation of azomethine imine substrates—suggest that it might find extensive applications in heterocycle synthesis.

The first metal-catalyzed [6 + 3] cycloaddition of tropone with azomethine ylides has been developed. With the use of a chiral ferrocenylphosphine-copper(I) complex as the catalyst, the asymmetric variant of the [6 + 3] cycloaddition has also been successfully achieved. The reactions proceeded smoothly under mild conditions, affording piperidine-fused bicyclic heterocycles in moderate to high yields with good to excellent diastereo- and enantioselectivies. The procedures are operationally simple and the catalysts are cheap and readily accessible, thus providing a practical approach to piperidine-fused bicyclic heterocycles.

Phosphine-catalyzed [3+2] and [4+3]annulation reactions of C,N-cyclic azomethine imines with allenoates have been developed to give a variety of pharmaceutically attractive tetrahydroisoquinoline derivatives in moderate to excellent yields. The two distinct reaction pathways, [3+2] and [4+3]cyclization, depend on the nature of the nucleophilic phosphine and the allenoate. Generally, for α-alkylallenoates, the reactions always proceed with [3 +2]cyclization as the major pathway no matter what phosphine was used; for α-ArCH2-substituted allenoates, the reaction pathway was controlled by the phosphine catalyst used.

The reaction pathways can be triggered by choice of the allenoate and the phosphine catalyst.

Abstract:The thermal [3+2] cycloadditions of two classes of aromatic azomethine imines with allenoates have been investigated. The reactions are operationally simple and proceed smoothly under mild reaction conditions to provide a variety of dinitrogen-fused heterocycles in moderate to excellent yields.Key words: cycloaddition, azomethine imine, allenoate, quinoline, isoquinoline Quinoline, isoquinoline and structurally related heterocycles occur widely in nature and some have a broad range of clinical applications, exhibiting a wide range of biological activities such as antitumor, anti-HIV, antibiotic, antifungal, antivirus, anti-inflammatory, anticoagulation, and bronchodilation, and can also act on the central nervous system. The tetrahydroquinoline derivative II shows activity against antibacterial targets such as DNA gyrase. 6 Accordingly, the synthesis of quinoline and isoquinoline derivatives has attracted much attention. 7 However, although many synthetic methods have been developed, 7 new procedures for their synthesis would still be highly desirable.Azomethine imines have emerged as a versatile 1,3-dipole for various thermal, metal-catalyzed, and organocatalytic 1,3-dipolar cycloaddition reactions and have been extensively applied in organic synthesis because of their easy accessibility, stability and the potential applications of the corresponding cycloadducts. 8,9The range of azomethine imines available for the cycloaddition reactions has been expanded to include various imines such as 3-oxopyrazolidin-1-ium-2-ide derivatives and benzoyl(3,4-dihydroisoquinolin-2-ium-2-yl)amides, but research on aromatic azomethine imines is somewhat limited. As part of our continuing efforts to develop the annulation reaction of azomethine imines, 11 we recently investigated the reactions of aromatic azomethine imines with allenoates. Herein, we present our results on the thermal [3+2] cycloaddition of aromatic azomethine imines with allenoates to furnish functionalized dinitrogen-fused tricyclic heterocycles. Figure 1 Pharmaceutically active quinoline and isoquinoline-related derivativesThe azomethine imines 1, 8 and 13 were easily prepared according to reported procedures. 13In initial attempts, azomethine imine 1 was treated with the allenoate 2a in dichloromethane at room temperature for 96 hours (Scheme 1). The reaction worked sluggishly, and two new products were isolated in total 20% yield. When the reaction was carried out in toluene at room temperature for 96 hours, the same two products were obtained in poor yield (5%) due to the poor solubility of azomethine imine 1 in toluene. To increase the yield, the reaction was carried out in refluxing toluene. Under these conditions the azomethine imine was completely converted in 72 hours to give the product in 70% yield. However, several side-