Synthesis and activity of four (N,N‐dimethylamino)benzamide nonsteroidal anti‐inflammatory drugs based on thiazole and thiazoline

Four compounds derived from 2‐aminothiazole and 2‐amino‐2‐thiazoline were prepared by coupling the respective bases with the acid chlorides of either 3‐ or 4‐(N,N‐dimethylamino)benzoic acid. Products were identified using infrared spectroscopy, ¹H NMR spectroscopy and electrospray mass spectroscopy and in two cases by single‐crystal X‐ray diffraction. Of the four, N‐(thiazol‐2‐yl)‐3‐(N,N‐dimethylamino)‐benzamide (1), N‐(thiazolin‐2‐yl)‐4‐(N,N‐dimethylamino)benzamide (2), N‐(thiazolin‐2‐yl)‐3‐(N,N‐dimethylamino) benzamide (3) and N‐(thiazolin‐2‐yl)‐4‐(N,N‐dimethylamino)benzamide (4), the hydrochloride salts of compounds 3 and 4 showed anti‐inflammatory activity across a concentration range of 10^?2?5 × 10^?4 M while 3 (at a concentration of 10^?5 M) was found to have no adverse effect on myocardial function. The X‐ray crystal structure of 2 and the 1:1 adduct structure of 3 with 3‐(N,N‐dimethylamino)benzoic acid are reported.     

Two new polymorphs of 4‐(N,N‐dimethyl­amino)­benzoic acid

Two new polymorphs of 4‐(N,N‐dimethyl­amino)­benzoic acid, C₉H₁₁NO₂, resulting from the attempted cocrystallization in ethanol of 4‐(N,N‐dimethyl­amino)­benzoic acid and a mixture of 3‐(N,N‐dimethyl­amino)­benzoic acid and 3‐(3‐pyrid­yl)‐2‐pyridone producing one polymorph, and a mixture of 3‐(N,N‐dimethyl­amino)­benzoic acid and 5‐meth­oxy‐3,3′‐bipyridine producing the second polymorph, have been crystallographically characterized. The primary inter­molecular O—H⋯O hydrogen bonds generate a dimeric acid–acid motif that is present in all three polymorphs.     

Kinetics and simulations of reaction between safranine‐O and acidic bromate and role of bromide therein

Safranine‐O, a dye of the phenazinium class, was found to exhibit intricate kinetics during its reaction with bromate at low pH conditions. Under conditions of excess concentrations of acid and bromate, safranine‐O (SA⁺) initially depleted very slowly (k = (3.9 ± 0.3) × 10^?4 M^?3 s^?1) but after an induction time, the reaction occurred swiftly. Bromide exhibited a dual role in the reaction mechanism, both as an autocatalyst and as an inhibitor. The added bromide increased the initial rate of depletion of SA⁺, but delayed the transition to rapid reaction. The overall stiochiometric reaction was found to be 6SA⁺ + 4 BrO₃ ^? = 6SP + 3N₂O + 3H₂O + 6H⁺ + 4Br^?, where SP is 3‐amino‐7‐oxo‐2,8‐dimethyl‐5‐phenylphenazine. The fast kinetics of the reaction between aqueous bromine and safranine‐O (k = (2.2 ± 0.1) × 10³ M^?1 s^?1) are also reported in this paper A 17‐step mechanism, consistent with the overall reaction dynamics and supported by simulations, is proposed and the role of various bromo and oxybromo species is also discussed. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 542–549, 2002     

Novel Synthesis and Antimicrobial Activity of 3‐Substituted 5‐bromo‐7‐methyl‐1,2,4‐triazolo‐[3,4‐b]‐benzothiazoles

4‐Methyl acetanilide ( 1 ) on treatment with bromine in acetic acid, followed by hydrolysis with dilute HCl/NaOH solution, yielded 2‐bromo‐4‐methyl aniline ( 2 ), which on treatment with sodium thiocyanate in acetic acid afforded 2‐amino‐4‐bromo‐6‐methyl benzothiazole ( 3 ). Compound 3 in ethylene glycol was heated at 150°C with 80% hydrazine hydrate to get 4‐bromo‐2‐hydrazino‐6‐methyl benzothiazole ( 4 ). This hydrazino compound 4 on heating with formic acid for 3 h yielded 4‐bromo‐2‐hydrazinoformyl‐6‐methyl benzothiazole ( 5 ). Same compound 4 when heated independently with formic acid for 6 h/urea for 3 h/carbon disulfide in alkali afforded 5‐bromo‐7‐methyl ( 6 )/5‐bromo‐3‐hydroxy‐7‐methyl ( 7 )/5‐bromo‐3‐mercapto‐7‐methyl ( 8 )‐1,2,4‐triazolo‐[3,4‐b]‐benzothiazoles, respectively. Compound 4 on heating with acetic acid/acetic anhydride gave acetyl benzothiazolyl derivative 9 , which on cyclization with orthophosphoric acid yielded 5‐bromo‐3,7‐dimethyl‐1,2,4‐triazolo‐[3,4‐b]‐benzothiazole ( 10 ). All these newly synthesized compounds were screened for antimicrobial activity against Escherichia coli (Gram ?ve), Bacillus subtilis (Gram +ve), Erwinia carotovora, and Xanthomonas citri using ampicillin, streptomycin, and penicillin as a standard for comparison.     

Unusual tosyl transfer solvolysis reaction to 3‐n‐butyl‐4‐methyl‐5,5‐di‐p‐toluenesulfonyl‐ 3 ‐pyrrolin‐2‐one

The title compound ( 1 ) was isolated in 20‐30% recovery following solvolysis of a mixture of 5‐bromo‐3‐n‐butyl‐4‐methyl‐2‐p‐toluenesulfonylpyrrole ( 4b ) and 5‐bromo‐4‐n‐butyl‐3‐methyl‐2‐p‐toluenesulfonyl‐pyrrole ( 4a ) in trifluoroacetic acid and water, a reaction designed to produce 5‐p‐toluenesulfonyl‐3‐pyrrolin‐2‐ones, e.g., 5a and 5b .     

Synthesis, Structure and Biological Activities of S-[α-（ 4-Methoxyphenylcarbonyl ）-2-（1,2,4-triazole-l-yl） ethyl-N, N-dime-thyldithiocarbamate

The title compound was prepared by reaction of N, N‐dimethyldithiocarbamate sodium with l‐bromo‐l‐(4‐methoxyphenylcarbonyl)‐2‐(1, 2, 4‐triazole‐l‐yl) ethane. Its crystal structure has been determined by X‐ray diffraction analysis. The crystal belongs to triclinic with space group Pī, a = 0.7339(2) nm, b = 1.1032(2) nm, c = 1.1203(2) nm, a = 90.27(3)°, β = 102.03(3)°, γ = 104.91(3)°, Z=2, V = 0.8556(3) nm³, D_c = 1.360 g/cm³, μ =0.325 mm^?1, F(000)=368, final R₁ =0.0475. The planes of 4‐methoxybenzyl group and triazole ring are nearly perpendicular to each other. The dihedral angle is 83.97°. There is an obvious π‐π stacking interaction between the molecules in the crystal lattice. The results of biological test show that the title compound has fungicidal and plant growth regulating activities.     

An Efficient Synthesis of 3′‐Amino‐3′‐deoxyguanosine from Guanosine

3′‐Amino‐3′‐deoxyguanosine was synthesized from guanosine in eight steps and 58% overall yield. The 2′,3′‐diol of 5′‐O‐[(tert‐butyl)diphenylsilyl]‐2‐N‐[(dimethylamino)methylidene]guanosine was reacted with α‐acetoxyisobutyryl bromide and treated with 0.5n NH₃ in MeOH to yield 9‐{2′‐O‐acetyl‐3′‐bromo‐5′‐O‐[(tert‐butyl)diphenylsilyl]‐3′‐deoxy‐β‐D ‐xylofuranosyl]‐2‐N‐[(dimethylamino)methylidene]guanine, which was reacted with benzyl isocyanate, NaH, and then 3.0n NaOH, and finally with Pd/C (10%) and HCO₂NH₄ in EtOH/AcOH to afford 3′‐amino‐3′‐deoxyguanosine.     

Minimization of the auxiliary reagent loading for direct arylation polymerization (DArP) of 2‐bromo‐3‐hexylthiophene

In this work, we present a powerful set of synthetic strategies aimed at minimization of auxiliary reagent loading for direct arylation polymerization (DArP) of 2‐bromo‐3‐hexylthiophene. As such, we report efficient lowering of Pd(OAc)₂ catalyst loading as well as loading of other auxiliary reagents, such as neodecanoic acid and N,N‐dimethylacetamide. Unprecedented low loadings of catalyst down to 0.0313% (313 ppm) were achieved, while producing polymer in high yield (91% after Soxhlet extraction), with a high molecular weight (24.2 kDa) and carefully controlled chemical structure thus making the optimized DArP protocol significantly more cost‐effective, convenient, sustainable, and environmentally friendly. The resulting polymer samples were thoroughly investigated in terms of their chemical structure as well as optical, thermal, chain ordering and electronic properties using GPC analysis, ¹H NMR, MALDI, UV–vis, GIXRD spectroscopy, DSC, and SCLC hole mobility measurements. The results demonstrate that the reagent lowering strategies increase the polymer regioregularity from 94.6 to 96.5% as evidenced by ¹H NMR spectra and corroborated by GIXRD, DSC, and UV–vis measurements. Additionally, polymer samples obtained at low reagent loading are more uniformly proton‐terminated as evidenced by ¹H NMR and MALDI end‐group analysis. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1492–1499     

Synthesis and Heterocyclization of 1‐Aryl‐2‐methyl‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylates

A series of novel isoxazole, dihydropyrazolone, and tetrahydropyridine derivatives were synthesized by the reaction of corresponding ethyl 1‐substituted aryl‐2‐methyl‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylates with different hydrazines and hydroxylamine. Reaction of tetrahydropyridone with N ,N‐dimethylformamide dimethyl acetal provided 1‐(5‐chloro‐2‐methylphenyl)‐2‐[2‐(dimethylamino)ethenyl]‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylate, which was cyclized into a bicyclic compound on treatment with ammonium acetate. The structures of all synthesized compounds were confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopy data. The structure of 5‐(5‐chloro‐2‐methylphenyl)‐4‐methyl‐2‐phenyl‐2,5,6,7‐tetrahydro‐3H‐pyrazolo[4,3‐c]pyridin‐3‐one was unambiguously assigned by means of X‐ray analysis data.     

Synthesis of N‐amino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone

2‐[(Disubstituted‐methylene)‐hydrazino] benzoic acid phenacylesters 2a‐2d , prepared from anthranilic acid phenacylester 1 , were unsuccesfully tried as starting materials for the synthesis of N‐amino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone 8 . The desired compound 8 was prepared by cyclization of N‐acetyl as well as N‐benzoyl‐hydrazinobenzoic acid phenacylester 6a or 6b in polyphosphoric acid to afford N‐acylamino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone 7a or 7b , respectively. Surprisingly, the acyl group was resistant to attack by both hydrochloric acid as well as sodium hydroxide solution. It could be removed by boiling the compounds 7a or 7b respectively in 50% sulphuric acid to afford the the target compound 8 .     

Synthesis of benzo[c][1,8]phenanthrolin‐6‐one through cyclization of N‐(isoquinol‐5‐yl)‐2‐bromo‐benzamide derivatives

In the course of our search for compounds with potential antitumor properties we have undertaken the synthesis of benzo[c][1,8]phenanthroline derivatives. Our project required the preparation of 8,9‐dimethoxy benzo[c][1,8]phenanthrolin‐6‐ones. This was first attempted by the lithiumdiisopropylamide cyclization of N‐(isoquinol‐5‐yl)‐2‐bromo‐4,5‐dimethoxybenzamide. The reaction led to 40% of the unexpected internal Diels‐Alder adduct 3,4‐dimethoxy‐6H‐pyrido[2,3‐i]6,8a‐ethenoindolo[cd]isoquinoline‐2(1H)‐one, which arose from a benzyne intermediate. In a second and more successful approach, the internal biaryl palladium diacetate‐assisted coupling reaction of properly N‐protected N‐(isoquinol‐5‐yl)‐2‐bromo‐4,5‐dimethoxybenzamide was studied. The optimisation of the protecting group necessary for this procedure led to a 64% yield of the target compound starting from N,N‐(isoquinol‐5‐yl)‐bis‐(2‐bromo‐4,5‐dimethoxybenzamide).     

Five related N′‐(2,2,2‐trichloroethanimidoyl)benzene‐1‐carboximidamides

In the solid state, 4‐methoxy‐N′‐(2,2,2‐trichloroethanimidoyl)benzene‐1‐carboximidamide, C₁₀H₁₀Cl₃N₃O, (I), N′‐(2,2,2‐trichloroethanimidoyl)benzene‐1‐carboximidamide, C₉H₈Cl₃N₃, (II), 4‐chloro‐N′‐(2,2,2‐trichloroethanimidoyl)benzene‐1‐carboximidamide, C₉H₇Cl₄N₃, (III), 4‐bromo‐N′‐(2,2,2‐trichloroethanimidoyl)benzene‐1‐carboximidamide, C₉H₇BrCl₃N₃, (IV), and 4‐trifluoromethyl‐N′‐(2,2,2‐trichloroethanimidoyl)benzene‐1‐carboximidamide, C₁₀H₇Cl₃F₃N₃, (V), display strong intramolecular N—H...N hydrogen bonding across the chelate ring and also intramolecular N—H...Cl contacts. Additional intermolecular hydrogen bonds link the molecules into chains, double chains or sheets in all cases except for compound (V). For compound (II), there are three independent molecules per asymmetric unit.     

Three Arene‐Ru(II) compounds of 2‐halogen‐5‐aminopyridine: Synthesis,characterization, and cytotoxicity

Three novel compounds, (η⁶‐p‐cymene)RuCl₂(2‐fluoro‐5‐aminopyridine) (compound 1), (η⁶‐p‐cymene)RuCl₂(5‐amino‐2‐chlorpyridine) (compound 2) and (η⁶‐p‐cymene)RuCl₂(2‐bromo‐ 5‐aminopyridine) (compound 3), were synthesized and characterized. The compound 1 and 3 were determined by X‐ray diffraction, showing a distorted piano‐stool type of geometry with similar bond lengths and angles around the ruthenium. Compound 2 exhibited moderate in vitro activity against A549 and MCF‐7 human cancer cells, the other two lower activities. The UV–vis and fluorescent absorption titrations showed that three compounds binded with CT‐DNA in a minor groove. The intrinsic binding constants (Kb) were calculated to be 2.13(±0.03) × 10⁵ M^?1, 2.89(±0.03) × 10⁵ M^?1 and 2.45(±0.03) × 10⁵ M^?1 for compound 1, 2 and 3, respectively, by using UV–vis absorption titrations data. Among the three compound, the highest value of intrinsic binding constant of compound 2 was consistent with its highest cytoxicity against A549 and MCF‐7 human cancer cells in vitro.     

Synthesis of 3‐thiocyanato‐1H,3H‐quinoline‐2,4‐diones

4‐Hydroxy‐1H‐quinolin‐2‐ones ( 1 ) react with thiocyanogen in acetic acid to the corresponding 3‐thiocyanato‐1H,3H‐quinoline‐2,4‐diones ( 2 ) in good yields. In some cases, 3‐bromo‐1H,3H‐quinoline‐2,4‐diones ( 4 ) were isolated as minor reaction products. Compounds 2 are very reactive towards nucleophiles and easily hydrolyze to the corresponding 4‐hydroxy‐1H‐quinoline‐2‐ones ( 1 ).     

Solvent‐ and Temperature‐Controlled In Situ Ligand Reactions Mediated by CuII and 3′‐[(E)‐{[(1S,2S)‐2‐Aminocyclohexyl]imino}methyl]‐4′‐hydroxy‐4‐biphenylcarboxlic Acid

Three new compounds, CuL, CuL′, and Cu₂O₂L′′₂ (H₂L=3′‐[(E)‐{[(1S,2S)‐2‐aminocyclohexyl]imino}methyl]‐4′‐hydroxy‐4‐biphenylcarboxlic acid, H₂L′=3′‐[(E)‐{[(1S,2S)‐2‐aminocyclohexyl]imino}methyl]‐4′‐hydroxy‐5′‐nitro‐4‐biphenylcarboxlic acid, H₂L′′=3′‐(N,N‐dimethylamino methyl)‐4′‐hydroxy‐4‐biphenylcarboxlic acid), were selectively synthesized through a controlled in situ ligand reaction system mediated by copper(II) nitrate and H₂L. Selective nitration was achieved by using different solvent mixtures under relatively mild conditions, and an interesting and economical reductive amination system in DMF/EtOH/H₂O was also found. All crystal structures were determined by single‐crystal X‐ray diffraction analysis. Both CuL and CuL′ display chiral 1D chain structures, whereas Cu₂O₂L′′₂ possesses a structure with 13×16 Å channels and a free volume of 41.4 %. The possible mechanisms involved in this in situ ligand‐controlled reaction system are discussed in detail.     

The Use of Pinner Type Reaction for the Synthesis of New Indeno[2,1‐c]pyridine‐4‐carbonitrile Derivatives

An efficient and convenient route was developed for the synthesis of new pyridinecarbonitrile derivatives by using the Pinner type of reaction. The 2‐((E)‐2‐((dimethylamino)methylene)‐1,2‐dihydro‐5,6‐dimethoxyinden‐3‐ylidene) malononitrile 2 was reacted in the presence of dry HCl gas to yield 3‐chloro‐6,7‐dimethoxy‐9H‐indeno[2,1‐c]pyridine‐4‐carbonitrile ( 3 ) in good yield. The S_NAr reaction on compound 3 with various nucleophiles yielded 3‐substituted pyridinecarbonitriles 4 , 5 , 6 , 7 , 8 , 9 in moderate to good yield.     

Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides

As part of the structure‐activity relationship of the dopamine D₂ and serotonin 5‐HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5‐HT₃ receptors binding affinity of (R)‐5‐bromo‐N‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and (R)‐5‐bromo‐N‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐(p‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[N‐(tert‐butoxycarbonyl)‐N‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of (R)‐3‐[N‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐N‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D₂ receptors than 1 .     

Synthesis,crystal structure,spectral characterization,and DFT studies on 4‐((1‐phenyl‐1H‐tetrazol‐5‐ylthio)methyl)benzoic acid

A new thiotetrazole compound, 4‐((1‐phenyl‐1H‐tetrazol‐5‐ylthio)methyl) benzoic acid ( 1 ), has been synthesized and characterized by elemental analysis, ¹H and ¹³C NMR, ESI‐MS, FT‐IR, UV–vis, fluorescence spectra, and single‐crystal X‐ray diffraction analysis. The structural analysis reveals that compound 1 adopts a nonplanar geometric structure and exhibits an extensive but not uniform π delocalization with all members of the tetrazolyl ring and the exocyclic sulfur atom. A density functional theory (DFT) calculation at B3LYP/6‐31G** level of theory was performed to elucidate the structure of this thiotetrazole system. And the time‐dependent DFT (TD‐DFT) calculations of absorption spectra reveal two electron‐transition bands derived from the contribution of π → π* transitions, which are in agreement with experimental results. Moreover, compound 1 exhibits a blue‐light emission (λ_em = 441 nm) in the solid state at room temperature. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:435–443, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21034     

Synthesis and Characterization of Novel N‐Alkylamine‐ and N‐Cycloalkylamine‐Derived 2‐Benzoyl‐N‐aminohydrazinecarbothioamides, 1,3,4‐Thiadiazoles and 1,2,4‐Triazole‐5(4H)thiones

4‐Aminomorpholine, 1‐aminopiperidine, and 1,1‐dimethylhydrazine were carried out in the corresponding methyl dithiocarbamates and those in turn in aminohydrazinethioamides, which under the influence of acid chlorides (benzoyl, 4‐chlorobenzoyl, 4‐fluorobenzoyl, 4‐methoxybenzoyl and 2‐furoyl) gave arylcarbonyl derivatives. Those compounds were cyclized in concentrated H₂SO₄ to 2‐(N‐cycloalkylamino‐ and N‐dimethylamino)‐amino‐5‐phenyl‐1,3,4‐thiadiazole derivatives and in 10% NaOH aqueous solution to 4‐cycloalkylamino‐ and 4‐dimethylamino‐3‐phenyl‐1,2,4‐triazole‐5(4H)‐thiones.     

Nickel‐Catalyzed Conversion of Enol Triflates into Alkenyl Halides

A Ni‐catalyzed halogenation of enol triflates was developed and it enables the synthesis of a broad range of alkenyl iodides, bromides, and chlorides under mild reaction conditions. The reaction utilizes inexpensive, bench‐stable Ni(OAc)₂?4 H₂O as a precatalyst and proceeds at room temperature in the presence of sub‐stoichiometric Zn and either 1,5‐cyclooctadiene or 4‐(N,N‐dimethylamino)pyridine.