Azine Derivatives Research Articles

Novel and selective synthesis of unsymmetrical azine derivatives via a mild reaction

A new, convenient, benign procedure for the one-step synthesis of unsymmetrical azines by reaction of aromatic aldehyde derivatives and hydrazine sulfate in triethylamine and absolute ethanol solution is presented. This methodology is more useful than the well-known two-step variant (involving preparation of a hydrazone and subsequent reaction with an aldehyde), because it enables the formation of unsymmetrical azines in a one-pot and rapid method without formation of any by-product or without requirement to separate the hydrazone intermediate. The mildness, selectivity, short reaction time, easy work-up, and applicability for large-scale reactions are the main advantages of this protocol for the synthesis of unsymmetrical azine derivatives. Structures of all new compounds were elucidated by 1H and 13C NMR, IR, MS, and CHN measurements.

Convenient Synthesis and Antibacterial Activity of Tricyclic Azine Derivatives

1,4-Phenylenediamine reacted readily with 2 mol of ethyl acetoacetate to give diethyl ( 2Z,2′Z)-3,3′-[(1,4-phenylene)-bisimino]dibut-2-enoate, which reacted with dimethylformamide dimethylacetal, activated methylene nitriles, ylidenemalononitriles and phenyl and benzoyl isothiocyanate to give, respectively, a 4,7-phenanthroline-2,9-dicarb-oxylate-1,10-diol, and tricyclic bispyridine and bispyrimidine derivatives. Two compounds showed strong antibacterial activity against several microorganisms, while six others showed high to moderate activity.

Sequential amination of heteroaromatic halides with aminopyridine 1 - oxides and their N-protected derivatives based on novel aza-Smiles rearrangement

Abstract The SNAr and Pd-catalyzed amination of chloro derivatives of azines, diazines, and triazines with 2-aminopyridine 1-oxides and their N-protected derivatives was described.

An Efficient Protocol for the Green and Solvent-Free Synthesis of Azine Derivatives at Room Temperature Using BiCl3-Loaded Montmorillonite K10 as a New Recyclable Heterogeneous Catalyst

A new BiCl3-loaded montmorillonite K10 catalyst has been prepared by solid dispersion method and was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), and cyclic voltammetry (CV) measurements. BiCl3 loaded K10 (BiCl3-K10) has been used as solid acid catalyst for the synthesis of azine derivatives from benzophenone hydrazone and ketones/aldehydes by simple physical grinding. This BiCl3-K10 gives an excellent yield with short reaction time and is an inexpensive, easily recyclable catalyst for this reaction.

Electronic Spectra of Cycl[3.3.2]azine and Related Compounds: Solvent Effect on Vibronic Couplings

Quantitative ab initio calculations are presented for the ultraviolet-visible peaks of cycl[3.2.2]azine and its mono- and dibenzannulated polycyclic compounds at the multistate CASPT2 (MS-CASPT2) level of theory, with 11 nm deviation from the experimental S0 → S1 absorption. The electrophilic substitution reactions of cycl[3.2.2]azine, benzo[a]/[g]annulated cycl[3.2.2]azines, and 6-dimethylamino[2.2.3]cyclazine-1-carboxylates with 3-cyano-4-methylthiomaleimide gave the corresponding functionalized cycl[3.2.2]azine derivatives, which exhibited the absorption maxima around 510-630 nm. The first intense peaks were investigated by means of time-dependent density functional theory (TD-DFT). These peaks were systematically underevaluated by ∼50 nm, within the acceptable accuracies of TD-DFT. Furthermore, we calculated vibronic coupling constants of the electronic excited states of cycl[3.2.2]azine and simulated absorption spectra both in vacuo and in ethanol. The solvent effect is found to enhance oscillator strengths and vibronic couplings. This is because the solvent effect gives rise to changes in the electron density difference on the phenyl ring, and in turn, the intensified overlap between the electron density difference and the potential derivative in the phenyl ring leads to enhanced vibronic couplings in ethanol.

ChemInform Abstract: Novel Access to 1,4‐Benzodiazepin‐2‐ones via the Buchwald Reaction and Application to the Synthesis of Novel Heterocyclics.

AbstractA two‐step sequence is presented for the synthesis of biologically interesting title compounds via Buchwald reaction of benzophenone or benzoyl azine derivatives with amides followed by cyclocondensation.

Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis and Antimicrobial Activity of Some New Azole and Azine Derivatives

Reactions of 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano(2,3-c)pyrazole-5-carbonitrile (1) with a va- riety of reagents leads to the synthesis of pyrano(2,3-c)pyrazole derivatives has been investigated with the aim to explore the use of this exceptionally reactive nitrile in heterocyclic synthesis. Keywords Dihydropyrano(2,3-c)pyrazole, Enaminonitriles, Azoles, Pyrimidines, Pyridines

The Reaction of Cyanoacetylhydrazine with Chloroacetone: Synthesis of 1,2,4-Triazine, 1,3,4-Oxadiazine and Their Fused Derivatives with Antitumor Activities

The reaction of cyanoacetylhydrazine with chloroacetone gave the N-(1-chloropropan-2-ylidene)-2-cyanoacetohy- drazide. This compound reacted with either hydrazine hydrate or phenylhydrazine to give the corresponding 1,2,4-tri- azine derivatives. On the other hand, its reaction with either benzenediazonium chloride or benzaldehyde gave in each case the 1,3,4-oxadiazine derivatives. Moreover, the reaction of the cyanoacetylhydrazine with 2-boromocyclohexa- none gave the corresponding hydrazine-hydrozon derivative. The antitumor evaluation of the newly synthesized prod- ucts against three cancer cell lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) was recorded. Some of the tested compounds showed activities which was higher than the reference doxorubicin.

Synthesis of some mono-Mannich bases and corresponding azine derivatives and evaluation of their anticonvulsant activity.

Mono-Mannich bases, 3-amino-1-aryl-1-propanone hydrochlorides (Ig1-Ig4), and their corresponding azine derivatives, N,N'-bis(3- amino-1-aryl-propylidene) hydrazine dihydrochlorides (D1-D4), were synthesized and their anticonvulsant activities were evaluated. Alterations in biological activity depending on modifications in chemical structure were also followed. The aryl part was phenyl in Ig1, D1, Ig2, D2, Ig3, D3, or p-hydroxyphenyl in Ig4, and D4. The amine part was dimethylamine in Ig1, D1, Ig4, and D4, piperidine in Ig2, D2 or morpholine in Ig3, D3. Compounds D2, D3, and D4 are new. The anticonvulsant activity was determined by maximal electroshock (MES) and subcutaneous metrazole (pentetrazol; scMet) tests. The rotorod toxicity test was used for determining neurological deficits. While the compounds were not effective in scMet, they were found to exert protective effect in MES. The results of MES are as follows: Compound [dose level (mg/kg), time (h)]: Ig1 [30 (0.5 h), 100 (0.5 h)]; Ig2 [30 (0.5 h, 4 h)]; Ig3 [30 (0.5 h), 100 (0.5 h), 300 (0.5 h, 4 h)]; Ig4 [300 (0.5 h, 4 h), 100 (4 h)]; D1 [30 (0.5 h)]; D3 [100 (0.5 h,4 h), 300 (0.5 h), 30 (4 h)]]; D4 [300 (0.5 h, 4 h)]. D2 did not show any anticonvulsant activity in both tests. Ig1, Ig2, D1, D2, and D3 exhibited neurotoxicity. Compounds Ig2, D1, and D2 were neurotoxic at 100 mg/kg dose level at 0.5 h. Ig1 was neurotoxic at 300 mg at 0.5 h, D3 was neurotoxic at 300 mg at 4 h. Conversion of mono-Mannich bases to their corresponding azine derivatives generally decreased the anticonvulsant activity. Ig3, Ig4 and D4 seem to be promising candidates to develop new anticonvulsant compounds for grand mal epilepsy for further synthesis and in vivo studies, since they were effective in MES screening and no neurotoxicity was observed with them.

Evaluation of the Cytotoxicity of Some Mono-Mannich Bases and Their Corresponding Azine Derivatives against Androgen-independent Prostate Cancer Cells

Mono-Mannich bases derived from acetophenones, 1-aryl-3-amino- 1 -propanone hydrochlorides (Igl-Ig4), and their corresponding azine derivatives, N, N'-bis(3-amino-l-aryl-propylidene) hydrazine dihydrochlorides (DI-D4), were designed and synthesized as cellular thiol alkylating agents. The aryl portion was replaced by a phenyl group in Ig1, Ig2, Ig3, D1, D2, and D3, and by a p-hydroxyphenyl group in Ig4 and D4. The amine side chain was replaced by a dimethylamine group in Igl, D1, Ig4 and D4, by a piperidine group in Ig2 and D2, and by a morpholine group in Ig3 and D3. The cytotoxic activity of the compounds was tested against the androgen-independent prostate cancer cell line PC-3. The relationship between cytotoxicity and pKa value of the amine group and partition coefficients of the compounds was also investigated. Azine derivative D4 was found to be the most potent among all the compounds tested and the cytotoxicity increased 1.73 fold compared with the mono-Mannich base Ig4 in PC-3 cells. On the other hand, conversion of mono-Mannich bases Igl-Ig3 to their corresponding azine derivatives DI-D3 decreased the cytotoxicity considerably. Substitution of the hydroxyl group at the para position of the aromatic ring in azine derivative D4 increased the cytotoxicity, and a rational explanation in this regard is described in length. The results emerged from this investigation guide the future expansion of these series of compounds.

Synthesis of decahydropyrrolo[2,1,5-cd]indolizine derivatives through RuCl3/AgOTf induced alkene–alkene and alkene–arene double cycloisomerizations

In the presence of RuCl3/AgOTf, pyrrolizidine derivative with styrenyl substituents at the 3,5-positions undergo a 6-exo-trig cyclization and subsequent intramolecular Friedel–Crafts reactions to form decahydropyrrolo[2,1,5-cd]indolizine or decahydrocycl[3.2.2]azine derivatives. The cycloisomerization is highly stereoselective. Presence of electron donating groups on the styrenyl substituents inhibits the double cycloisomerization process and results in a trans to cis epimerization instead. No reaction takes place when electron withdrawing groups are present on the styrenyl substituents. Possible mechanisms are proposed for the observed reactions.

Azoalkanes—novel flame retardants and their structure–property relationship

AbstractA number of symmetrical and unsymmetrical azoalkanes of the general formula R′−N = N−R and related azoxy, hydrazone as well as azine derivatives have been synthesized in order to assess their potential as novel flame retardants for polypropylene alone or in combination with commercially available flame retardants such as alumina trihydrate (ATH), decabromodiphenyl ether (DecaBDE) and tris(3‐bromo‐2,2‐bis(bromomethyl)‐propyl)phosphate (TBBPP). The experimental results show that in the series of different sized azocycloalkanes the flame retardant efficacy decreased in the following order: R = cyclohexyl > cyclopentyl > cyclobutyl > cyclooctanyl >> cyclododecanyl. Whereas in the series of aliphatic azoalkanes compounds the efficacy decreased in the following order: R = n‐alkyl > tert‐butyl > tert‐octyl. In addition, also some of the prepared azoxy, azine, and hydrazone derivatives provide flame retardancy to polypropylene films at already very low concentrations (0.25–1 wt%). Noteworthy is that in contrast to other halogen‐free radical generators, the azoalkanes are also very effective as flame retardants in polypropylene thick moldings. Interestingly, it was found that 4,4′‐bis(cyclohexylazocyclohexyl)‐methane) shows a strong synergistic effect with ATH. Thus, in the presence of 0.5 wt% of azoalkane the ATH loading could be reduced from 60 to 25 wt% and still UL94 V‐2 rating could be reached. Furthermore, the fire testing data reveal that azoalkanes show a synergistic effect with DecaBDE and when used in conjunction with very low loadings of TBBPP. Copyright © 2010 John Wiley & Sons, Ltd.

An expeditious and solvent free synthesis of azine derivatives using sulfated anatase–titania as a novel solid acid catalyst

Solid acid catalyst sulfated anatase–titania (TiO2–SO42−) has been used for the synthesis of azine derivatives from benzophenone hydrazone and ketones/aldehydes by simple physical grinding. This sulfated titania gives an excellent yield with short reaction time and is an inexpensive, easily recyclable catalyst for this reaction.

Transition-Metal-Catalyzed C-H Functionalization for the Synthesis of Substituted Pyridines

The direct functionalization of pyridine and related azine derivatives through carbon-carbon bond-forming reactions is reviewed. Various transformations that use a variety of transition-metal catalysts are covered, including alkylation, alkenylation, arylation, and acylation. In addition to the conventionally observed C2-selectivity for these transformations, recent developments involve selective introduction of newly formed carbon-carbon bonds to the C3- and C4-positions of pyridine and azine nuclei. The reaction scope and a proposed mechanism for each transformation are briefly summarized.

ChemInform Abstract: Preparation of New Nitrogen‐Bridged Heterocycles. Part 71. A New Synthetic Approach to Some Functionalized Cycl[3.2.2]azine Derivatives.

AbstractFunctionalized cyclazine derivatives (VI) are obtained by dehydrogenation of dihydrothiazinoindolizine derivatives (III) and (IV) in low to moderate yields.

ChemInform Abstract: Highly Efficient Practical Procedure for the Synthesis of Azine Derivatives under Solvent‐Free Conditions.

A general and useful method for the synthesis of azines of aromatic aldehydes and ketones in good yields was elaborated. This reaction is carried out under solvent-free con- ditions and in the absence of catalyst to afford good yields of the relevant azines. The reac- tion is also environmentally friendly without the inconvenience of undesired by-products and has advantages over the previously reported methods. Products were characterized by the usual procedures (infrared, 1 H NMR, and 13 C NMR).

Organic Crystalline Solids Response to Piezo/thermo Stimulus: Donor–Acceptor (D–A) Attached Salicylaldehyde Azine Derivatives

A salicylaldehyde azine-based derivative, which exhibited switchable solid-state fluorescence in response to external thermal and mechanical grinding stimulus, was reported in this study. Diffuse reflectance solid-state spectroscopy, fluorescence spectroscopy, solid-state 13C and 1H NMR spectroscopy, single crystal XRD analyses, powder X-ray diffractometry, and differential scanning calorimetry were used for investigating the changes of molecular packing modes. The multistimuli fluorescence originated from two distinctive crystalline lattices via different π–π interactions. The local dipole coupling among molecules with donor–planar–acceptor structure was evidenced to be the essential factor for the effective solid luminescence-switching properties.

Thermolysis and photolysis of N-benzoylhydrazone derivatives

Two selected N-benzoylhydrazones were subjected to thermolysis by refluxing at 200 °C. Benzil, benzoic acid, biphenyl, benzanilide together with the corresponding ketones, nitriles, substituted methanes, and imines were isolated. Similar treatment of a third hydrazone at 250 °C afforded, in addition to the previous products, toluene, bibenzyl, stilbene, and 2-phenylindole. Photolysis of the same hydrazones in acetonitrile gave the previously reported products but in different ratios along with azine derivatives and substituted methanes. A free radical mechanism involving homolysis of the N–N and C–N bonds is suggested, substantiated by trapping of the phenyl radical with isoquinoline, to account for the formation of the identified products.

Highly selective and sensitive fluorescence reporter for toxic Hg(II) ion by a synthetic symmetrical azine derivative

A symmetrical azine derivative, N,N′-Bis(imidazo[1,2-a]pyridine-2-ylmethylene hydrazine (sensor L) has been synthesized and its fluorescence sensing potential towards metal ions has been demonstrated using simple fluorometric technique. The sensor shows high fluorescence selectivity and high sensitivity towards Hg 2+ ion in aqueous-methanol media. Only Hg 2+ ion is found to effectively enhance fluorescence quantum yield of the nearly non-fluorescent sensor. The sensor can effectively distinguish Hg 2+ from Cd 2+ or Zn 2+ ion within the same group via different mechanistic pathway i.e. chelation enhanced fluorescence (CHEF) effect for Hg 2+ ion and charge transfer (CT) mechanism for Cd 2+ or Zn 2+ ion. Experimental spectral properties have been correlated with theoretical calculation based on Density Functional Theory method.

Synthesis of Decahydropyrrolo[2,1,5-cd]indolizine through Consecutive [2 + 3] Cycloadditions and 6-Exo-Trig Cyclization

Azomethine ylide formed from glycine methyl ester and cinnamaldehyde adds to N-phenylmaleimide to form pyrrolidine derivative, further treatment of which with cinnamaldehyde and N-phenylmaleimide affords the second [2 + 3] cycloaddition adduct, a pyrrolizine derivative with two styrenyl groups at the 3,5-positions. Addition of ICl to the pyrrolizine derivative results in the 6-exo-trig cyclization of the styrenyl groups to form a cycl[3.2.2]azine derivative. The reactions are highly stereoselective affording 11 chiral carbons in three steps. The structure of the cycl[3.2.2]azine derivative was determined by single-crystal X-ray analysis.