PMDTA-catalyzed multicomponent synthesis and biological activity of 2-amino-4H-chromenes containing a phosphonate or phosphine oxide moiety.

László G Puskás,Javad Iskanderov,László Hackler,Ádám Tajti,Erika Bálint,Kármen Emőke Szabó,Nóra Popovics-Tóth,Beáta Kari,Franc Perdih

doi:10.1039/d1ob01204e

Abstract

A new approach for the preparation of (2-amino-3-cyano-4H-chromen-4-yl)phosphonate derivatives is described. The multicomponent reaction of salicylaldehydes, malononitrile and dialkyl phosphites catalyzed by pentamethyldiethylenetriamine (PMDTA) provided the bicyclic derivatives in high yields. The method developed did not require chromatographic separation, since the products could be recovered from the reaction mixture by simple filtration. Our approach made also possible condensation with secondary phosphine oxides, and this reaction has not been previously reported in the literature. The crystal structures of five derivatives were studied by single-crystal XRD analysis. The in vitro cytotoxicity on different cell lines and the antibacterial activity of the (2-amino-4H-chromen-4-yl)phosphonates synthesized were also explored. According to the IC50 values determined, several derivatives showed moderate or promising activity against mouse fibroblast (NIH/3T3) and human promyelocytic leukemia (HL-60) cells. Furthermore, three (2-amino-3-cyano-4H-chromen-4-yl)phosphine oxides were active against selected Gram-positive bacteria.

Highlights

Phosphorus-substituted heterocycles represent an important group within organophosphorus compounds
Based on the above considerations, in this paper, we report on a fast, cheap and efficient PMDTA-catalyzed solvent-free process for the synthesis of novel (2-amino-3-cyano-4Hchromen-4-yl)phosphonates by the domino Knoevenagel– phospha-Michael reaction of salicylaldehydes, malononitrile and dialkyl phosphites
In a few literature examples, salicylaldehyde and malononitrile were reacted with triethyl phosphite (TEP) instead of DEP as the P-reagent, according to our experience only 2-(2-hydroxybenzylidene)malononitrile (1) was formed, and no product 2a in the reaction mixture was obtained at 60 °C for 30 min in the absence of any solvent (Table 1, entry 11)

Summary

Introduction

Phosphorus-substituted heterocycles represent an important group within organophosphorus compounds. Based on the above considerations, in this paper, we report on a fast, cheap and efficient PMDTA-catalyzed solvent-free process for the synthesis of novel (2-amino-3-cyano-4Hchromen-4-yl)phosphonates by the domino Knoevenagel– phospha-Michael reaction of salicylaldehydes, malononitrile and dialkyl phosphites. Using dipropylamine (DPA) in the absence of any solvent, the conversion was complete, and the reaction mixture contained 65% of 2-(2-hydroxybenzylidene)malononitrile (1) ([M + H]+ = 171.1) as an intermediate formed by the Knoevenagel condensation of salicylaldehyde with malononitrile and 35% of diethyl (2-amino-3-cyano-4H-chromen-4-yl) phosphonate (2a) (Table 1, entry 1).

Results

Conclusion