Mohamed Hilmy Elnagdi

Efficient synthesis of 3-aroylcinnolines from aryl methyl ketones

Abstract An efficient synthesis of 3-aroylcinnolines starting from the appropriate aryl methyl ketones is described. The latter were converted in two steps to the corresponding 3-oxo-3-aryl-2-arylhydrazonopropanals, which upon acid catalyzed cyclization in conc. sulfuric acid or polyphosphoric acid (PPA) led to the corresponding 3-aroylcinnolines.

2-Aminothiophenes as building blocks in heterocyclic synthesis: Synthesis and antimicrobial evaluation of a new class of pyrido[1,2-a]thieno[3,2-e]pyrimidine, quinoline and pyridin-2-one derivatives

Multisubstituted 2-aminothiophenes 1a-c can be readily cyanoacylated via reaction with cyanoacetic acid in presence of acetic anhydride under a microwave irradiation to form the corresponding cyanoacetamides 2a-c, which condensed with DMF-DMA to form the corresponding enamines 4 that reacted with hydrazine hydrate to yield the aminopyrazoles 5. Moreover the cyanoacetamides 2a-c reacted with a variety of arylidenmalononitrile to afford a novel pyrido[1,2-a]thieno[3,2-e]pyrimidine derivatives 12a-o. In addition the enamines 4a,b reacted with malononitrile to afford the pyrido[1,2-a]thieno[3,2-e]pyrimidine derivatives 19a,b. The cyanoacetamides 2a,b reacted also with salicylaldehyde to afford the quinoline derivatives 24a,b. Moreover the cyanoacetamides 2a,b reacted with the enaminones 25a-c to form the corresponding Pyridin-2-one derivatives 29a-c. Reactions of 2a,c with bezenediazonium chloride afford the arylhydrazones 30a,b that reacted with chloroacetonitrile to form the acyclic product 31 which could not be further cyclized to the corresponding 4-aminopyrazole. The X-ray crystallographic analyses of seven products could be obtained thus establishing with certainty the proposed structures in this work. Most of the synthesized compounds in this investigation were tested and evaluated as antimicrobial agents.

Utility of cyanoacetamides as precursors to pyrazolo〔3,4-d〕pyrimidin-4-ones,2-aryl-6-substituted 1,2,3-triazolo〔4,5-d〕pyrimidines and pyrazolo〔1,5-a〕pyrimidine-3-carboxamides

Cyanoacetamides (7a-c) were prepared via reacting cyanoacetic acid (5) with amines in the presence of acetic anhydride. Compounds (7a-c) coupled with benzenediazonium chloride to yield the phenylhydrazones (8a-c). These reacted with chloroacetonitrile to yield aminopyrazolecarboxamides (lla-c). Reaction of (8a,b) with hydroxylamine hydrochloride in DMF in presence of anhydrous sodium acetate afforded the amino-l,2,3-triazolecarboxamides (36a,b). Also compounds (7a-c) reacted with dimethylformamide dimethylacetal (DMFDMA) to yield the enamines (9a-c) which react with hydrazine hydrate to afford the aminopyrazoles (16a-c). Compounds (16) and (36) reacted with DMFDMA to yield the title heterocyclic derivatives.

Chapter 1 Recent Developments in Pyridazine and Condensed Pyridazine Synthesis

Publisher Summary This chapter discusses recent developments in pyridazine and condensed pyridazine synthesis. Today, the pyridazine nucleus and its 3-oxo derivatives have been recognized as versatile pharmacophores. This key subunit is constituted in many biologically active substances with a broad range of biological and pharmaceutical activities including inhibitors of PED III, IV, a 1 - and a 2 - adrenoceptors, antibacterial and antifungal activities, 5-lipoxygenase inhibitors and inhibitors of interleukin, b-production. This chapter surveys recent reported synthetic approaches to pyridazines and highlights new methodologies. It discusses synthesis of pyridazine by two bond formation (via 3+3 atom and 4+2 atom), by combining alkylpyridazinylcarbonitrile with a,b-unsaturated nitriles, and by coupling aromatic diazonium salts with carbon nucleophilic 4 atom fragments. It also discusses the synthesis of condensed pyridazine via one bond formation (5+1 combination) and by utilizing functionally substituted arylhydrazones precursors via one bond formation.

Pyrolysis of aminonitriles, cyanohydrazones, and cyanoacetamides. Part I. Elimination reaction of 1-arylmethyleneamino-1,2-dihydro-4,6-dimethyl-2-oxopyridine-3-carbonitriles and substituted benzaldehyde cyanoacetylhydrazones

Pyrolysis of the Schiff bases of 1-arylmethyleneamino-1,2-dihydro-4,6-dimethyl-2-oxopyridine-3-carbonitriles (1–5) has been studied. These compounds eliminate via a six-membered transition state to produce substituted benzonitriles and 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile. These eliminations are unimolecular first-order reactions. The kinetic data gave a good correlation with σ0 values of the substituents on the aryl group with ρ = 0.83 at 520 K. Utilization of the pyrolytic reaction in synthesis of various benzonitriles is considered, and mechanistic information has been obtained by comparing the kinetic data and product analysis of the Schiff bases with their open-chain substituted benzaldehyde cyanoacetylhydrazones (6–9) analogues.

STUDIES WITH 2-BENZIMIDAZOLYLACETONITRILE, SYNTHESIS OF NEW BENZIMIDAZO-2-YLTHIOPHENES ANDBENZO[g]IMIDAZO[1,2-a]PYRIDINES

Abstract The synthesis of new benzimidazo-2-ylthiophenes, and benzo[g]imidazo[1,2-a]pyridines utilizing 2-benz-imidazolylacetonitrile (1) as starting component is reported.

Recent developments in utility of green multi-component reactions for the efficient synthesis of polysubstituted pyrans, thiopyrans, pyridines, and pyrazoles

Developments made since 2010 in the utilization of multi-component reactions as green efficient methodologies for the synthesis of polysubstituted pyrans, thiopyrans, pyridines, and pyrazoles are reviewed and the mechanisms of these processes are discussed. Reference is made to classical older synthetic methods developed earlier in our laboratories.Graphical Abstract

Approaches towards the synthesis of a novel class of 2-amino-5-arylazonicotinate, pyridazinone and pyrido[2,3-d]pyrimidine derivatives as potent antimicrobial agents

BackgroundDespite significant progresses in antimicrobial therapy, infectious diseases caused by bacteria and fungi remain a major worldwide health problem because of the rapid development of resistance to existing antimicrobial drugs. Therefore, there is a constant need for new antimicrobial agents. There are a large number of heterocyclic derivatives containing nitrogen atoms that possess a broad spectrum of biological activities including pyridine and pyridazine, which are two of the most important heterocycles in medicinal chemistry.ResultsThe reaction of 3-oxo-2-arylhydrazonopropanals 2 with ethyl cyanoacetate and malononitrile 3a,b has led to the formation of 2-amino-5-arylazo-6-aryl substituted nicotinates 8a-k as sole isolable products when the aryl group in the arylazo moiety was substituted with an electron-withdrawing group like Cl, Br, NO2. The pyridazinones 10 were formed from the same reaction when the arylazo moiety was phenyl or phenyl substituted with an electron-donating group. The 2-aminoazonicotinates 8 were condensed with DMF-DMA to afford the amidines 13a,b, which then were cyclized to afford the targeted pyrido[2,3-d]pyrimidine derivatives 15a,b, respectively. The structures of all new substances prepared in this investigation were determined by using X-ray crystallographic analysis and spectroscopic methods. Most of the synthesized compounds were tested and evaluated as antimicrobial agents and the results indicated that many of the obtained compounds exhibited high antimicrobial activity comparable to ampicillin, which was used as the reference compound.ConclusionA general rule for the synthesis of 2-amino-5-arylazo-6-aryl substituted nicotinic acid and pyridazinone was established using 3-oxo-2-arylhydrazonopropanal as a precursor. Moreover, a novel route to pyrido[2,3-d]pyrimidine was achieved. Most of the synthesized compounds were found to exhibit strong inhibitory effects on the growth of Gram-positive bacteria especially Bacillus subtilis. Compounds 1a, 8a-h, 10a-c, 15b and 16 showed a broad spectrum of antimicrobial activity against B. subtilis.

Green methodologies in organic synthesis: recent developments in our laboratories

The results of the studies carried out in our laboratories during the last 15 years, aimed at developing green methodologies for the synthesis of polyfunctionalized heteroaromatic substances, are surveyed. The results of the investigations demonstrate that green methodologies are not only less hazard than classical preparative methods but they also are more efficient and economical. For example, short reaction times and higher yields are observed for reactions in which conventional heating is replaced by microwave or ultrasound irradiation. The implementation of multicomponent reactions in green preparative routes also reduces the cost of carrying out the reactions because multiple separation and crystallization steps are avoided. In general, by employing the new green methodologies we have been able to produce a large number of polyfunctional aromatic substances in a highly efficient manner.

Green synthetic approaches: solventless synthesis of polyfunctionally substituted aromatics as potential versatile building blocks in organic synthesis utilizing enaminones and enaminonitriles as precursors

Abstract A variety of 1,3,5-trisubstituted benzenes could be obtained upon heating enaminones in absence of solvent over montmorillonite-K-10. Heating mixtures of two different enaminones 2a–d have also afforded 1,3,5-trisubstituted benzenes 7b–d and 8b–d resulting from self-condensation of one enaminone with two molecules of the other enaminone. Heating enaminone 2b with ethyl propiolate afforded a mixture of triaroylbenzene 3b in addition to diaroylbenzoic acid esters 11 and 1,3,5-aroylbenzene dicarboxylate 12. On the other hand, reaction of enaminone derivative 2b with dimethyl acetylenedicarboxylate has afforded 2-oxopyran-4-carboxylic acid derivative 15. 2-Aminoprop-1-ene-1,1,3-tricarbonitrile 16 was reacted with enaminones to yield polysubstituted benzenes 19a–c. Likewise the reaction of 2-aminoprop-1-ene-1,1,3-tricarbonitrile 16 with benzylidenemalononitrile has afforded polysubstituted benzenes 24.