Hydrazone Intermediates Research Articles

Regioselective synthesis of novel nitroso-pyrazolylquinoxalines via HOAc-mediated cyclocondensation of 2-hydroxyimino-1,3-diketones with hydrazinylquinoxalines.

This article describes the regioselective synthesis of novel nitroso-pyrazolylquinoxalines via cyclocondensation of 2-hydroxyimino-1,3-diketones with hydrazinylquinoxalines. Of note, this is the first time that 2-hydroxyimino-1,3-diketones are used as electrophilic reagents to cyclocondensation with hetarylhydrazines. The cyclocondensation proceeded through a hydrazone intermediates formation. A series of novel nitroso-substituted pyrazolylquinoxalines were synthesized by both "one-pot" and "two-step" procedures in up to 86% yields. Importantly, a gram-scale synthesis of nitroso-pyrazolylquinoxalines, their oxidation and reduction were successfully accomplished.

Selective primary aniline synthesis through supported Pd-catalyzed acceptorless dehydrogenative aromatization by utilizing hydrazine.

By utilizing hydrazine (N2H4) as the nitrogen source in the presence of a hydroxyapatite-supported Pd nanoparticle catalyst (Pd/HAP), various primary anilines can be selectively synthesized from cyclohexanones via acceptorless dehydrogenative aromatization. The strong nucleophilicity of N2H4 and the stability of the hydrazone intermediates can effectively suppress the formation of the undesired secondary aniline byproducts.

Design and synthesis of novel quinoline derivatives bearing oxadiazole, isoxazoline, triazolothiadiazole, triazolothiadiazine, and piperazine moieties

AbstractA new series of 2,3‐disubstituted quinoline derivatives were synthesized from 2‐chloroquinoline‐3‐carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2‐chloroquinoline‐3‐carbaldehyde 1, which was transformed to 2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐carbaldehyde 2 by reaction with 4‐phenylpiperazine in DMF‐containing anhydrous K2CO3; then, compound 2 was oxidized by iodine in methanol, and methyl 2‐(4‐phenylpiperazin‐1‐yl)quinoline‐3‐carboxylate 3 was synthesized. The key intermediate 4, 4‐amino‐5‐[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]‐4H‐1,2,4‐triazole‐3‐thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazoles 5a‐c and 1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines 6a‐c, respectively. Moreover, compound 2 condensed with o‐phenylenediamine to give 2‐[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]‐1H‐benzimidazole 7. Interaction of 7 and 2‐chloromethyl‐5‐aryl‐1,3,4‐oxadiazoles in the presence of K2CO3 led to the title compounds 8a‐c. Furthermore, 4,5‐dihydroisoxazoline derivatives 9a‐c were obtained by the reaction of readily accessible starting materials including 2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐carbaldehyde 2, 1‐phenyl‐2‐(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et3N. The hydrazone intermediates 10a‐c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3‐acetyl‐5‐aryl‐2‐[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]‐2,3‐dihydro‐1,3,4‐oxadiazoles 11a‐c. Structures of these compounds were established by their elemental analysis, IR, 1H NMR, and mass spectral data.

Copper(II)-Catalyzed C-H Nitrogenation/Annulation Cascade of Ketene N,S-Acetals with Aryldiazonium Salts: A Direct Access to N2-Substituted Triazole and Triazine Derivatives.

Direct synthesis of N2-substituted triazole and triazine derivatives has been a challenge in N-heterocyclic chemistry. Under copper(II) catalysis ketene N,S-acetals, that is, alkylthio-substituted enaminones, efficiently reacted with aryldiazonium salts to allow the regioselective generation of functionally diverse N2-substituted 1,2,3-triazoles and 2,3-dihydro-1,2,4-triazines. The oxidant and base-dependent reaction yielded the five- and six-membered N-heterocyclic products, respectively. The synthetic protocol features broad substrate scopes and good functional group tolerance under mild conditions. The mechanistic studies have revealed that the reaction proceeds via alkenyl azo/imino hydrazone intermediates.

Nickel-catalyzed alkyl-alkyl cross-coupling reactions of non-activated secondary alkyl bromides with aldehydes as alkyl carbanion equivalents.

A novel nickel-catalyzed alkyl-alkyl cross coupling of non-activated secondary alkyl bromides with aldehydes via hydrazone intermediates has been developed. Aldehydes as alkyl carbanion equivalents replace traditional organometallic reagents. This coupling occurs on the carbon of the hydrazone rather than the nitrogen. In addition, non-activated primary and tertiary alkyl bromides also undergo the cross-coupling reaction to form new C(sp3)-C(sp3) bonds in moderate yields.

Antileishmanial activity and cytotoxicity of ent-beyerene diterpenoids.

We describe the in vitro activity of two natural isomeric ent-beyerene diterpenes, several derivatives and synthetic intermediates. Beyerenols 1 and 2 showed EC50 of 4.6 ± 9.4 and 5.3 ± 9.4 μg/mL against amastigotes of L. (V) brazilensis, with SI of 5.1 and 7.7, respectively. Beyerenol 1 was synthesized from stevioside. In vivo experiments with bereyenols showed cure in 50% of hamsters infected with L. (V) brazilensis topically applied as Cream I (beyerenol 1, 0.81%, w/w) and Cream III (beyerenol 2, 1.96%, w/w). These results suggest that beyerenols are potential candidates for cutaneous leishmaniasis chemotherapy by topical application. In vitro assays of amastigotes of L. (V) brazilensis showed EC50 of 1.1 ± 0.1 and 1.3 ± 0.04 μg/mL, with SI of 3.1 and 3.5 for hydrazone intermediates 10 and 11, respectively.

Nickel-catalyzed cross-coupling of aldehydes with aryl halides via hydrazone intermediates.

Traditional cross-couplings require stoichiometric organometallic reagents. A novel nickel-catalyzed cross-coupling reaction between aldehydes and aryl halides via hydrazone intermediates has been developed, merging the Wolff-Kishner reduction and the classical cross-coupling reactions. Aromatic aldehydes, aryl iodides and aryl bromides are especially effective in this new cross-coupling chemistry.

Microwave-assisted stereoselective approach to novel steroidal ring D-fused 2-pyrazolines and an evaluation of their cell-growth inhibitory effects in vitro

Novel ring D-condensed 2-pyrazolines in the Δ5-androstene series were efficiently synthesized from 16-dehydropregnenolone or its acetate with different arylhydrazines or methylhydrazine, respectively, under microwave irradiation. The reactions are assumed to occur via hydrazone intermediates, followed by intramolecular 1,4-addition leading to the fused heteroring stereoselectively with a 16α,17α-cis ring junction. The synthesized compounds were subjected to in vitro pharmacological studies of their antiproliferative activities against four human breast (MCF7, T47D, MDA-MB-231 and MDA-MB-361) and three cervical (HeLa, C33A and SiHA) malignant cell lines. Flow cytometry revealed that the most potent agent elicited a cell cycle disturbance.

ChemInform Abstract: Facile One Pot Synthesis of 8‐Chloro‐[1,2,4]triazolo[4,3‐a]pyrazines via Oxidative Cyclization Using Chloramine T.

AbstractThe reaction of 3‐hydrazinylpyrazines with aldehydes and subsequent chloramine T promoted cyclization of the resulting hydrazone intermediates provides the title compounds.

Synthesis, docking study, and DNA photocleavage activity of some pyrimidinyl hydrazones and 3-(quinolin-3-yl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine derivatives

In the present study, synthesis of a series of some novel 3-(Quinolin-3-yl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine derivatives (4a–e) has been achieved by oxidative cyclization of new pyrimidinyl hydrazone intermediates (3a–e) using hypervalent iodine reagent(III) under mild conditions. The structures of all synthesized compounds were established on the basis of IR, NMR (1H and 13C), mass spectral data, and elemental analysis. All compounds were evaluated for their DNA photocleavage activity. Compounds 4a, 4b, 4d and 3a–e were found to possess good activity at 40 μg/μl concentration and were mainly responsible for the conversion of supercoiled form of DNA into open circular form. Further, docking study was carried out using Molegro Virtual Docker version 2010.4.2.0 using PDB (1AB4) in support of the results obtained.

Zinc Halide Mediated Synthesis of 3-Amidoindoles

Reported is the zinc halide mediated synthesis of 3-amidoindoles through a domino alkyne amination-Fischer indole sequence. The majority of the substrate scope was performed using N-acyl propargylamine, but examples using other N-substituted propargylamines were shown to perform well under a subtle change of conditions. For each example two sets of conditions are shown. It is not clear whether more conditions were examined or if there was a rationale behind choosing these conditions. In contrast to the known instability of many 3-aminoindole products, the obtained compounds are reported to be crystalline stable materials which are easily handled. This process constitutes a complementary route to the synthesis of hydrazone intermediates for the Fischer indole reaction and, in view of the ready availability of alkynes, promises to find broader utility.

A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones and Facile Extension to 5,7(6H,8H) Isomers

A new route to substituted pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones is outlined. The synthesis proceeds via pre-formed hydrazone intermediates, which are then condensed with an activated chlorouracil to build up the entire molecular framework, followed by a reductive ring closure to provide the parent series. The route has been extended to the isomeric pyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-dione class via the use of methylhydrazine as hydrazine surrogate, followed by regiospecific alkylation of the N(8)-H pyrimidotriazinediones with a range of alkyl and alkaryl substituents. This new methodology permits the generation of a wide range of compounds with variable substitution at the N(1), C(3), and N(8) positions for a heterocyclic scaffold with demonstrated pharmacological activity.

Site selectivity in reaction of hydrazonoyl halides with 2-(aroylmethyl)-6-methylpyrimidin-4(3H)-ones

Reaction of hydrazonoyl halides 1 with 2-(aroylmethyl)-6-methylpyrimidin-4(3H)-ones 3 proved to be site selective and gave 2-(3-acetyl-1,5-diarylpyrazol-4-yl)-6-methylpyrimidin-4(3H)-ones 5 via dehydrative cyclisation of the hydrazone intermediates 4. The structures of both 4 and 5 were elucidated by spectral data and alternative synthesis. The mechanism of the reaction was discussed.

Synthesis of Condensed and Uncondensed Tetrazolo[1,5-b][1,2,4]triazines as Potential Antimicrobial Agents

Reactions of two cyclic amidrazones, the 6-methyl and 6-phenyl derivatives of 7-hydrazinotetrazolo[1,5-b][1,2,4]triazines with mono- and dicarbonyl compounds afforded various heterocyclic systems. Thus, acetic acid, benzoyl chloride, or ethyl chloroformate reacted with the former cyclic amidrazones to yield the corresponding [1,2,4]triazolo[4,3-d]tetrazolo[1,5-b][1,2,4]triazines. With pyruvic acid or ethyl pyruvate the corresponding hydrazone derivatives were obtained, which then cyclized to tetrazolo[1′,5′:2,3][1,2,4]triazino[5,4-c][1,2,4]triazines. The 9,10-dioxotetrazolo-triazinotriazine structures were synthesized by condensative cyclization of the cyclic amidrazones with diethyl oxalate, whereas the reaction of these amidrazones with acetylacetone or ethyl acetoacetate furnished pyrazolyltetrazolo[1,5-b][1,2,4]triazines through the isolable hydrazone intermediates. Some of the representative members of the prepared compounds were screened for antimicrobial activity.

New Synthesis of Fischer Indole Hydrazone Intermediates

A one-pot domino reaction sequence for the synthesis of tryptophols (3-hy­droxyethylindole) and its homologues is reported. The key step is a titanium-catalyzed hydroamination of alkynes by aryl hydrazines to give azatitanacycles with excellent Markovnikov regioselectivity. Following rearrangement and removal of titanium, hydrazones are produced which, when subjected to Lewis acid-mediated Fischer indole cyclization, give substituted tryptophols in up to 95% yield.

An Efficient Synthesis of Substituted Hydrazides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Efficient Synthesis of Substituted Hydrazides

Routes for the selective synthesis of 1-, or 2-substituted hydrazides, and 1,2-disubstituted hydrazides are reported. These routes proceed via cyanoborohydride reduction of stable acyl hydrazone intermediates.

Oxidative metabolism of some hydrazine derivatives by rat liver and lung tissue fractions.

The enzyme systems in rat liver and lung responsible for the oxidative metabolism of hydrazine derivatives were studied to determine whether these enzymes, cytochrome P-450 and monoamine oxidase, were responsible for metabolically activating hydrazines to carcinogenic/toxic metabolites. Cytochrome P-450 preferentially oxidized the nitrogen to nitrogen bond of 1,2-disubstituted hydrazines and hydrazides, while monoamine oxidase oxidized the nitrogen to nitrogen bond of all the classes of hydrazine derivatives that were tested. Oxidation of the nitrogen to nitrogen bond led to the formation of stable azo intermediates in the case of 1,2-disubstituted hydrazines and to unstable monoazo (diazene) metabolites in the case of monosubstituted hydrazines and hydrazides. In addition, cytochrome P-450 preferentially oxidized the carbon to nitrogen bond of monoalkylhydrazines; this reaction resulted in the formation of aldehyde metabolites (via hydrazone intermediates). Monosubstituted hydrazines were shown to be potent, irreversible inhibitors of mitochondrial monoamine oxidase. In contrast, the 1,2-disubstituted hydrazines appeared to be good substrates for the monoamine oxidase and served as competitive inhibitors at high concentrations. There did not appear to be any monoamine oxidase isozyme (form A or B) specificity in the metabolism of either the 1,2-disubstituted hydrazines or the monoalkylhydrazines, ethyl- and n-propylhydrazine.