Polyhalonitrobutadienes as Versatile Building Blocks for the Biotargeted Synthesis of Substituted N-Heterocyclic Compounds

Abstract

Substituted nitrogen heterocycles are structural key units in many important pharmaceuticals. A new synthetic approach towards heterocyclic compounds displaying antibacterial activity against Staphylococcus aureus or cytotoxic activity has been developed. The selective synthesis of a series of 64 new N-heterocycles from the three nitrobutadienes 2-nitroperchloro-1,3-butadiene, 4-bromotetrachloro-2-nitro-1,3-butadiene and (Z)-1,1,4-trichloro-2,4-dinitrobuta-1,3-diene proved feasible. Their reactions with N-, O- and S-nucleophiles provide rapid access to push-pull substituted benzoxazolines, benzimidazolines, imidazolidines, thiazolidinones, pyrazoles, pyrimidines, pyridopyrimidines, benzoquinolines, isothiazoles, dihydroisoxazoles, and thiophenes with unique substitution patterns. Antibacterial activities of 64 synthesized compounds were examined. Additionally, seven compounds (thiazolidinone, nitropyrimidine, indole, pyridopyrimidine, and thiophene derivatives) exhibited a significant cytotoxicity with IC50-values from 1.05 to 20.1 µM. In conclusion, it was demonstrated that polyhalonitrobutadienes have an interesting potential as structural backbones for a variety of highly functionalized, pharmaceutically active heterocycles.

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

“…The next step of our investigation was the two-step synthesis of persubstituted aminopyrazoles 5 upon reaction of the benzotriazolyl derivative 2c with primary, secondary, aliphatic, or (het)aromatic amines (first step) and successive reaction of the obtained dienes 4 with 7-chloro-4-hydrazinylquinoline. Thus, the reaction of compound 2c with methylamine, 1,2,3,4-tetrahydroisoquinoline, 1-methyl-1,2,3,4-tetrahydroisoquinoline, (2-fluorophenyl)methylamine, and 5-methylisoxazolyl-3-amine proceeded smoothly under mild conditions (methanol, 0 °C to rt), similarly to the previously obtained dienes 4b – e [ 14 ], 4f [ 9 ], 4i [ 14 ], 4j [ 9 ], 4k [ 26 ], and 4m , n [ 27 ], and led to dienes 4a , 4g , 4h , 4l , and 4o , respectively, in yields of 52–85%. The subsequent treatment of the butadienes 4 with 2.20 equivalents of 7-chloro-4-hydrazinylquinoline in methanol or ethanol led to the formation of pyrazoles 5 in strongly varying yields (5–72%) and dual orientation (either 3,5- or 5,3-positions) of an amino and dichloromethyl unit in the pyrazole ( Scheme 3 ).…”

New Ketene Dithioacetals Generated from 2‐Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities

“…Since the yield of compound 2 was low, the study was continued with compound 3 ( Scheme 1). The main function of the nitro group (EWG) is to guide the initial nucleophilic attack onto C4 because of LUMO located at the dihalonitrovinyl fragment in 2‐nitroperchlorobutadiene 1 [1–5] . The one of S,S‐nucleophile in 1,2‐etandithiole can initially replace a chlorine atom firstly on the terminal carbon (C4) of the nitrovinyl moiety.…”

“…In addition, it is known that introduction of chlorine atoms and nitro group generally enhances the biological effect and activities of chemical compounds [1,2] . Due to their graded reactivity in substitution reactions, perhalonitrobutadienes have proven to be precious synthetic precursors for a variety of four‐ to six‐membered, often pharmaceutically and biologically active heterocycles [3–5] …”

A New Way to 2,3,4-Trisubstituted Benzo[h]quinolines: Synthesis, Consecutive Reactions and Cellular Activities

“…Previous articles in the field of polyhalogenated nitrobutadienes have already demonstrated the enormous potential of pentachloro-2-nitro-1,3-butadiene (1) as a precursor for the "click synthesis" of highly functionalized (hetero)cyclic as well as acyclic compounds [1,2]. The corresponding syntheses that we have developed up to now always start with the attack of an appropriate nucleophile at the activated terminal carbon atom of the nitrodichlorovinyl group within 1 to undergo a vinylic substitution reaction.…”