Heterocyclic Aldehydes Research Articles

A Facile, Efficient and Solvent-Free Titanium (IV) Ethoxide Catalysed Knoevenagel Condensation of Aldehydes and Active Methylenes

: Titanium ethoxide has been employed as a novel and efficient reagent for the Knoevenagel condensation of aldehydes with active methylenes such as diethyl malonate and ethyl cyanoacetate under solvent free conditions to afford substituted olefins in high to excellent yields. The reaction is suitable for a variety of aromatic, aliphatic and heteroaromatic aldehydes with various active methylenes. Parallel to this, microwave irradiation has been utilized to achieve improved reaction rates and enhanced yields. Herein, we illustrated a convenient method for the preparation of α,β-unsaturated compounds using both conventional and microwave irradiation methods. An efficient and solvent free Knoevenagel condensation between aldehydes and active methylenes was developed using titanium ethoxide. The procedure proved to be successful with a wide range of substrates such as aromatic, aliphatic and heterocyclic aldehydes and various active methylenes to afford substituted olefins. The reaction was also carried out under microwave irradiation to accomplish the corresponding olefins with improved reaction rates, yields and cleaner reaction profiles.We have developed an efficient and novel methodology for the synthesis of olefinic compounds by Knoevenagel condensation under solvent-free conditions using titanium ethoxide, for the first time, as a reagent as well as a solvent. This method is appropriate for the synthesis of a variety of aromatic aldehydes containing various electron-donating and withdrawing groups, aliphatic and heteroaromatic aldehydes. The significant advantages offered by this methodology could be applied to various active methylenes in order to offer the corresponding Knoevenagel products. Thus, we believe that this method delivers high conversions, cleaner reaction profiles under solvent-free reaction conditions and shorter reaction times, all of which make it a very useful and attractive approach for the preparation of a wide range of substituted olefins.

Synthesis and antioxidant activity of derivatives of 8Н -[1,2,4]triazolo[4,3-в][1,2,4]triazin-7-ones

Oxidative stress is usually connected with many severe diseases, such as atherosclerosis, hypertension, Alzheimer’s disease etc. Therefore, the search for new antioxidants is a very important pharmacological task. The aim of the study – to synthesize new derivatives of 8-(41-hydroxy-3R-benzylidenamino)-6-tertbutyl-8Н-[1,2,4]triazolo[4,3-b][1,2,4]triazine-7-ones and to evaluate their antioxidant properties in screening test in vitro as compared with ionol and ascorbic acid. By interaction of equimolar amounts of 8-amino-6-tert-butyl-8H-[1,2,4]triazolo[4,3-b][1,2,4]triazin7-one with the corresponding aromatic and heterocyclic aldehydes in ethanol, a series of Schiff bases with the key fragment 8H-[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-one were synthesized. The structure and purity of all the substances obtained were confirmed by 1H NMR spectroscopy. Screening of compound’s antioxidant activity (AOA) was studied in vitro by their ability to inhibit lipoperoxide formation, induced by FeSO4 in yolk lipoproteins emulsion. It is shown, that, depending on the structure, the test substances exhibit both antioxidant and prooxidant properties. The regularities of the chemical structure – pharmacological action are established. It is shown that the introduction of electron-withdrawing substituents (F, Cl, Br and COOMe) into the benzene ring leads to a decrease in the antioxidant properties as to the base molecule 6-tert-butyl-8(benzylideneamino)-8Н-[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-оne 8 а without substitutes. The most active were derivatives of 8-(benzylideneamino)-6-~{tert}-butyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin7-ones, which had a hydroxyl group and an additional oxyalkyl fragment in the third position of the benzene ring (8 l, 8 o). The data obtained substantiate the feasibility of further studying the most active derivatives of 6-tertbutyl-8-(benzylideneamino)-8Н-[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-оnes as potential antioxidant agents.

Search for new luminophores with predetermined physicochemical and chemical properties. XIV.N-Arylmethylene- and N-hetarylmethylene derivatives of poly (3‒aminopropene)

The possibility of creating polymers with fluorescence, derivatives of poly (3-aminopropene) (PAP) by alkylation of amino groups with aromatic or heterocyclic aldehydes by Leykart-Wallach reaction with own fluorescence was investigated. Synthesis of N-alkylated PAP derivatives was performed by sequential conversion: acrylamide → PAA (Mν = 100 kDa) → PAP → alkylated PAP. Due to the impossibility of using LiAlH4 to reduce the amide groups of polyacrylamide to amine due to the low solubility of PAA in the non-aqueous (diethyl ether, tetrahydrofuran, etc.) solvents, the reduction of PAA by other reducing agents was optimized. It was found that the best conditions for the reduction of amide groups of PAA to amine - acetic acid - dioxane as a solvent and NaBH4 (suspended in anhydrous 1,4-dioxane) as a reducing agent. According to IR spectroscopy, the products obtained are copolymers of 3-aminopropene (the main amount of elementary units), acrylamide and acrylic acid. To modify the structure of the obtained polymer, the Leuckart-Wallach reaction was used, where the following aldehydes having luminescence were selected: pyrene-3-aldehyde, 2-hydroxy-1-naphthaldehyde, anthracene-9-carbaldehyde, and 3.5 phenyl-1-(4-formylphenyl)-2-pyrazoline. To obtain N-Ar/Het-methylene derivatives, a mixture of PAP, aldehyde and 98% formic acid was heated under harsh conditions (6 hours, glycerol bath), isolated and purified. The obtained modified samples of polymers are intensely fluorescent both in the solid state and in the form of solutions, which indicates the successful passage of the Leykart-Wallach reaction. Spectral characteristics were obtained for solutions in a mixed solvent – ethyl acetate – formic acid (9 : 1). For both the original aldehydes and the copolymers in the mixed solvent used, the spectral fluorescence curves lose their oscillatory structure, probably due to the specific effect of the mixed solvent on the phosphor molecules (for the original aldehydes) and the side methylamino-N-arylmethylene - […СН2-СН(СН2-NH-CH2-Ar)- …] and methylamino-N-getarylmethylene […-СН2-СН(СН2-NH-CH2-Het)-…] groups both in the ground and in the excited state, and for polymers of inhomogeneity of the medium with local polarity zones.

A Facile Microwave and SnCl2 Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones

An elegantly simple, facile, and robust approach to a scaffold of biological importance, 2,3-dihydroquinazolin-4(1H)-ones, is reported. A catalytic 1% SnCl2/microwave-mediated approach afforded access to pure material, collected by cooling and filtration after 20-min microwave irradiation at 120°C. A total of 41 analogues were prepared in isolated yields of 17–99%. This process was highly tolerant of aliphatic, aromatic, heterocyclic, and acyclic aldehydes, but furan, pyrrole, and thiophene aldehyde reactivity correlated with propensity towards electrophilic addition and/or Diels–Alder addition. As a result, thiophene afforded high yields (80%) whereas pyrrole carboxaldehyde failed to react. With simple cinnamaldehydes, and in the SbCl3-mediated reaction, and with α,β-unsaturated aldehydes the equivalent quinazolin-4(3H)-ones, and not the 2,3-dihydroquinazolin-4(1H)-ones, was favoured.

Anti-proliferate Activity and 5α-reductase Inhibitors of Chiral Macrocyclic (Nα-di-nicotinoyl)[L-phenylalaninyl-L-leucinyl]Pentapeptide Candidates Against LNCaP and PC-3 Prostate Cancer Cell Lines

A series of macrocyclic derivatives 2-6 were prepared using N α -dinicotinoyl-bis[L-phenylalaninyl-L-leucyl]hydrazide 1 and cyclo pentapeptide hydrazide 2 as starting materials. The hydrazide 1 was cyclized with diaminoalkanes to macrocyclic hezaazahexaamide derivatives 3a-c , respectively. Finally, compound 2 was condensed with 3,5-diacetylpyridine gave the corresponding macrocyclic Schiff base 4 . Finally, condensation of 2 with substituted aromatic or heterocyclic aldehyde derivatives gave the corresponding Schiff base derivatives 5a-f and 6a-c , respectively. The synthesized compounds were screened as 5α-reductase inhibitors and anti-proliferative activity against prostate cancer cell lines.

C-dimethylated Chalcones:Towards Possible Dual Acting Agents-Against Tuberculosis and cancer(A549) and an SAR study

A series of seventeen C-dimethyl chalcones on ring ‘A’ were synthesized by using a known condensation method. The chalcones include the utilization of heterocyclic aldehydes such as N,N-dimethyl benzaldehyde, furfural-2-aldehyde, and N-methyl indole aldehyde. All the compounds were found to possess moderate to potent anticancer activity on human lung adenocarcinoma cell line “A549” in the MTT cell proliferation method. The dimethyl chalcone 9f with furfural ring was found to possess potent anti-cancer activity followed by 9m with o-chloro substitution on ring ‘B’ with IC50values of 1.0 and 1.2 μg/mL respectively. Similarly compounds 9n, 9j, 9g, 9k, 9p, 9d, 9b,and 9ealso showed good anti-cancer activity (IC50values from 6.5 to 9.8μg/mL). Further, the compounds were also compared with the known anti-TB activities in order to ascertain their properties towards dual acting agents against tuberculosis and cancer for more beneficiaries.

N-Heterocyclic Carbene-Catalyzed Formal [6+2] Annulation Reaction via Cross-Conjugated Aza-Trienolate Intermediates.

The diverse reactivity of N-heterocyclic carbenes (NHCs) in organocatalysis is due to the possibility of different modes of action. Although NHC-bound enolates and dienolates are known, the related NHC-bound cross-conjugated aza-trienolates remain elusive. Herein, we demonstrate the NHC-catalyzed formal [6+2] annulation of nitrogen-containing heterocyclic aldehydes with α,α,α-trifluoroacetophenones leading to the formation of versatile pyrrolooxazolones (29 examples). The catalytically generated cross-conjugated aza-trienolates (aza-fulvene type) underwent smooth [6+2] annulation with electrophilic ketones to afford the product in moderate to good yields under mild conditions. Preliminary DFT studies on the mechanism are also provided.

SYNTHESIS AND BIOLOGICAL EVALUATION OF SPIRO (INDOLE-THIAZOLIDINE) DERIVATIVES AS ANTIMICROBIAL AGENTS

Objective: The present study aims to synthesize and biological evaluation of Spiro-[Indole-Thiazolidine] derivatives as antimicrobial agents.
 Methods: The reaction sequence involves microwave-induced preparation of N-(2-oxo-1,2-dihydro-3’H-indol-3-ylidene)pyridine-4-carbohydrazide [3] from isoniazid [1] and isatin [2] followed by the cyclo condensation of [3] and mercaptoacetic acid under microwave condition to achieve the synthesis of spiro-[indole-thiazolidine] derivatives [4]. The resulting compounds were then allowed to react with various aromatic and heterocyclic aromatic aldehydes to afford arylidene derivatives [5a-l].
 Result: Isoniazid (1) on condensation with isatin (2) in the presence of catalytic amount of glacial acetic acid furnished N-(2-oxo-1,2-dihydro-3’H-indol-3-ylidene) pyridine-4-carbohydrazide (3), which showed characteristic IR, absorption bands. Compound (3) underwent Spiro cyclization upon its reaction with mercaptoacetic acid in the presence of anhydrous ZnCl2 to form spiro-[indole-thiazolidine] compound (4). Compound (4) was then condensed with aromatic aldehydes to give arylidene derivatives (5a-l), which were characterized by IR and 1H NMR spectral data.
 Conclusion: All the synthesized compounds were screened for antimicrobial activity by the cup plate method. Most of the derivatives showed good antimicrobial activity against Gram-Positive and Gram-negative bacteria.

One-Pot Assembly for Synthesis of 1,4-Dihydropyridine Scaffold and Their Biological Applications

A one-pot procedure for the preparation of functionalized 1,4-dihydropyridines by three-component reaction using substituted heterocyclic aldehydes, ammonium acetate, and substituted β-ketoesters catalyzed by L-proline was described. Present protocol offers excellent yield up to 92%, flexibility with different substitution, convenient operation, and eco-friendliness. The synthesized products were confirmed by 1H-NMR, 13C-APT, and IR spectroscopy. Herein, final confirmation of the targeted motif was made by X-ray single-crystal analysis of representative compounds (4f, 4j, 4k, 4l, and 4o). The chemically synthesized compounds were evaluated for the antiproliferative activity by cell viability (MTT) assay and dual AO/EB (acridine orange/ethidium bromide)-staining method against human A549 lung cancer cell lines. The viability of the treated cell was evaluated adopting MTT assay. According to associated changes in cell membranes during the process of apoptosis, a clear difference was observed between normal cells, early and late apoptotic cells, and necrotic cells. All compounds were found effective against Saccharomyces cerevisiae which was confirmed by increased reactive oxygen species production and DNA damage as compared to untreated yeast cell culture. Altogether, these compounds showed promising hope for application in pharmaceutical aid against yeast infections.

Synthesis of New Derivatives Benzo[4′,5′]imidazo[2′,1′:6,1]pyrido[2,3-d]pyrimidine

The reactions of 4-methyl- and (RS)-4,6-dimethyl-2-phenyl-5,6-dihydrobenzo[4′,5′]imidazo-[2′,1′:6,1]pyrido[2,3-d]pyrimidines and 4-methyl-5,6-dihydrobenzo[4′,5′]imidazo[2′,1:6,l]pyrido[2,3-d]pyrimi-din-2-ol with aromatic and heterocyclic aldehydes under various experimental conditions were studied. It was shown that the reaction with aldehydes upon boiling in acetic anhydride involves exclusively the 6-methylene group in the a-position to the benzimidazole fragment of the tetracycle and is accompanied by a 1,3-prototropic shift, which results in the formation of 6-aryl(hetaryl)methyl-4-methyl derivatives. The 4-methyl group in the substituted 2-phenyl(hydroxy)derivatives of 5,6-dihydrobenzo[4′,5′]imidazo[2′,1′:6,1]pyrido[2,3-d]pyrimidines reacts with aldehydes only under fusion conditions in the presence of ZnCl2. The structure of the synthesized compounds was confirmed by one- and two-dimensional (NOESY) 1H NMR spectroscopy and XRD analysis.

Synthesis of Macrocyclic Ttipeptidopyridine Schiff Base Candidates

In the current study, a series of macrocyclic tripeptide Schiff bases 2–6 were synthesized by using macrocyclic tripeptide hydrazide 1 as starting material. Treatment of hydrazide 1 with active carbonyl cycloalkanones gave cycloalkanone hydrazines 2a–2d. Also, condensation of 1 with aromatic and heterocyclic aldehydes, or aromatic and heterocyclic acetyl derivatives afforded the corresponding Schiff base candidates 3a–3e, 4a–4c, 5a–5c, and 6a–6c, respectively.

Substituted 2-(2-Arylethenyl)quinazolines. Synthesis and Structure

The reaction of 2-methyl-4H-3,1-benzoxazin-4-one and its 6-iodo derivatives with a number of amines in polyphosphoric acid afforded 3- and 3,6-substituted 2-methylquinazolin-4(3H)-ones. The latter reacted with aromatic and heterocyclic aldehydes under solvent-free conditions to give 2-[(E)-2-arylethenyl]-quinazolin-4(3H)-ones. The structure of the synthesized compounds was confirmed by two-dimensional 1H–1H NOESY data and X-ray analysis.

Bis-styrylquinazolinones Connected by Flexible Linkers

3,3′-(Ethane-1,2-diyl)-, 3,3′-(butane-1,4-diyl)-, 3,3′-hexane-1,6-diyl-, and 3,3′-[azanediylbis(ethane-2,1-diyl)]bis(2-methylquinazolin-4(3H)-ones) were synthesized by reactions of 2-methyl-4H-3,1-benzoxazin-4-one with ethane-1,2-diamine, butane-1,4-diamine, hexane-1,6-diamine, and N-(2-aminoethyl)ethane-1,2-di-amine, respectively, and their condensation with aromatic and heterocyclic aldehydes in acetic anhydride under reflux afforded the corresponding bis[2-[(E)-2-arylethenyl]quinazolin-4(3H)-ones].

CeCl3⋅7H2O-catalysed hydrophosphonylation of aldehydes and ketones: An expeditious route to α-hydroxyphosphonates under solvent-free conditions

A cerium(III) chloride-catalysed expeditious synthesis of α-hydroxyphosphonates via a modified Abramov synthetic protocol has been developed. The scope of the current protocol is broad, with a range of aromatic, α,β-unsaturated and heterocyclic aldehydes being efficiently converted to the anticipated products in very good to excellent yields (89–96%) in 15 min using low catalytic loading. The protocol was efficiently extended to hitherto unactivated cyclic ketones such as cyclopentanone and cyclohexanone to afford the required products in excellent yields. However, the reaction with cyclohexenone delivered a Michael product instead of the anticipated α-hydroxyphosphonates. The solvent-free conditions, low catalytic loadings, avoidance of toxic reagents and good to excellent yields are significant advantages of this protocol.

A Straightforward Synthesis of Tribromomethyl Carbinols from Aldehydes and Bromoform with Potassium Hydroxide as the Catalyst

AbstractKOH was used as the catalyst for an efficient synthesis of tribromoethyl carbinols from aldehydes and bromoform. The new synthesis method has many advantages, such as the low price of the raw materials and catalyst, the wide range of substrates such as, aromatic, aliphatic and heterocyclic aldehydes. It's worth mentioning that the reaction could be scaled up to grams in excellent yield (99%), in the presence of 10 mol% KOH.

Highly efficient synthesis of pyrazolylphosphonate derivatives in biocompatible deep eutectic solvent

A straightforward and highly efficient one-pot preparation of biologically interesting pyrazolylphosphonate derivatives via a three-component reaction between pyrazolone or phenylpyrazolone, various aromatic, fused aromatic, heterocyclic, and aliphatic aldehydes, and triethyl or trimethyl phosphite in presence of an ammonium-based deep eutectic solvent (DES) at 25 °C has been developed. The ammonium-based DES was easily prepared from choline chloride and urea (1:2) at 80 °C for 2 h. It is biodegradable, fairly inexpensive, easily separated from the reaction mixture using water, and can be reused at least four times without loss of its catalytic activity. The most important features of this method are its eco-friendliness, high yields, high atom economy, and the fact that it does not require column chromatographic purification for isolation of the products. Thus, it represents an alternative method for the synthesis of a wide range of pyrazolylphosphonates with shorter reaction times.

Catalyst-free three-component synthesis of new pyrrolidine derivatives via 1,3-dipolar cycloaddition

Differently substituted pyrrolidine derivatives have been prepared by a three-component reaction of heterocyclic aldehydes, amino acid methyl or ethyl esters, and trans -1,2-dibenzoylethylene in toluene under catalyst-free conditions. This simple one-step procedure allows to obtain the desired 3,4-dibenzoyl-5-hetarylpyrrolidines in high yields ensuring high diastereoselectivity. Given the fact that the fundamental stage of the proposed reaction mechanism is based on 1,3-dipolar cycloaddition, DFT and TDDFT quantum-chemical calculations have been used for better understanding and characterization of geometry and electronic structure of the reaction intermediates and products.

Promiscuous enzyme-catalyzed cascade reaction in water: Synthesis of dicoumarol derivatives

Lipase RMIM was firstly used as a promiscuous biocatalyst to catalyze the Knoevenagel-Michael cascade reactions of 4-hydroxycoumarin with aromatic, heterocyclic or aliphatic aldehydes to synthesize dicoumarol derivatives in water. Results showed that the adopted methodology could offer many advantages, such as mild reaction conditions, pure aqueous reaction system, wide substrate applicability, recyclable catalyst, excellent yields (81–98%), operational simplicity, and environmentally friendly reactions.

Hydroxyl alkyl ammonium ionic liquid assisted green and one-pot regioselective access to functionalized pyrazolodihydropyridine core and their pharmacological evaluation

Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two CC and one CN bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.

A Convenient One‐pot Synthesis of N‐Fused 1,2,4‐Triazoles via Oxidative Cyclization Using Trichloroisocyanuric Acid

A facile one‐pot synthesis of N‐fused 1,2,4‐triazoles from heterocyclic hydrazines and aldehydes is reported. The reaction is efficiently promoted by trichloroisocyanuric acid to afford the desired products mostly in high yields and in relatively short time. The mild nature of the synthesis and short reaction time are notable advantages of the developed protocol. This protocol is effective toward various substrates having different functionalities.