Synthesis and biological activity of new 1,3,4-thiadiazole derivatives

The aminothiadiazole (II) on treatment with aromatic aldehydes yielded Schiff bases, which cyclized to thiazolidinone derivatives by reaction with thioglycolic acid. Reaction of II with phenyl isocyanate and phenyl isothiocyanate afforded the carbamide and carbothiamide derivatives, respectively, which on reaction with malonic acid in acetyl chloride gave barbituric and thiobarbituric acid derivatives. However, reaction of carbon disulfide and methyl iodide with II gave dithiocarbamidate derivative which on treatment with ethylenediamine or o-phenylenediamine gave the condensed N-imidazolylthiadiazolylamine derivatives.     

Chemistry of sulfonyl isocyanates and sulfonyl isothiocyanates. X. Possible routes to substituted imidazolidinethiones and hexahydropyrimidinethiones

4-Toluenesulfonyl isocyanate (I) reacted with 2-aminoethanol and 3-amino-l-propanol to give 2:1 isocyanate/amino alcohol addition products. 1-Amino-2-propanol and I gave 1:1 and 2:1 adducts while 2-amino-2-methyl-l-propanol afforded only a 1:1 adduct. 4-Toluenesulfonyl isothio-cyanate (III) gave 1:1 adducts with 2-aminoethanol, l-amino-2-propanol and 3-amino-l-propanol, the first two of which were cyclized by concentrated sulfuric acid to 1-(4-toluenesulfonyl)-imidazoline-2-thiones and the third to 1-(4-toluenesulfonyl)hexahydropyrimidine-2-thione. A 1:2 adduct was obtained from III and 2-amino-2-methyl-l-propanol. Amino acids reacted with I and with 4-chlorobenzenesulfonyl isocyanate (II) to give N-(arylsulfonyl)-N¹-(carboxylic acid)-ureas. N-(4-Toluenesulfonyl)-N¹-(acetic acid)-urea (XVI) was converted to the methyl ester (XIX) by concentrated sulfuric acid and methanol and to water-soluble unrecoverable products by sulfuric acid alone. Glycine and III gave N-(4-toluenesulfonyl)-N¹-(acetic acid)-thiourea (XX) which was converted to the methyl ester (XXII) by concentrated sulfuric acid/methanol and to the cyclic 1-(4-toluenesulfonyl)imidazolin-5-one-2-thione (XXI) by sulfuric acid alone.     

Studies on chemotherapeutics III. Synthesis and cyclisation of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarbonyl-semicarbazide and- thiosemicarbazide

1,4-Disubstituted-semicarbazide and thiosemicarbazide derivatives were synthetized from 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarbohydrazides and cyclized to 3-mercapto-4H-1,2,4-triazoles. The obtained compounds could be S-methylated with methyl iodide in methanol. The new compounds were tested for antibacterial and antifungal activities.     

Reactions of Heterocumulenes with Organometallic Reagents: VIII. Reactions of Carbanions Derived from Alkoxy- and Alkylsulfanylethenes with Isothiocyanates-A Convenient Route to 2-Propenethioamides, 1-Methylsulfanyl-2-propen-1-imines,and Benzothiazoles

>Metalated alkoxy- and alkylsulfanylethenes readily add to isothiocyanates; the subsequent hydrolysis or alkylation of the adducts leads to formation of 2-propenethioamides or 1-methylsulfanyl-2-propen-1-imines (as mixtures of synand antiisomers) in 74-100% yield. The reaction of metalated alkoxyethenes with 2-fluorophenyl isothiocyanate opens the way to new benzothiazole derivatives. Hydrolysis of the latter provides a simple method for the preparation of 2-benzothiazolyl ketones.     

Reactions with Carbo(heterylhydrazonoyl) Halides. I. Chemistry of Carbo(3-phenylpyrazol-5-yl-hydrazonoyl) Chlorides

The Carbo(3-phenylpyrazol-5-yl-hydrazonoyl) halides 1a , b react with active methylene compounds to yield the 1-(3-phenylpyrazol-5-yl)-pyrazole derivatives 2a – k (Scheme 1). The acyclic intermediates 3a , b could be isolated from reaction of 1a , b with acetylacetone, thus establishing the substitution mechanism for these reactions. Compounds 1a , b reacted with carbon disulfide, phenyl isothiocyanate, methyl cyanide, and with p-chlorobenzaldehyde to yield the corresponding heterocyclic derivatives 5 – 8 , respectively (Scheme 2). The behaviour of compounds 2 with hydrazine hydrate is reported.     

Synthesis of 1- and 5-Aryl-2,4-benzothiazepines. 25th Communication on Seven-membered Heterocycles

α-Aryl-o-xylyl dibromides 1 reacted with thioureas to give the mono-isothiouronium salts 2 , bis-isothiouronium salts 4 being formed as by-products in some cases. Compounds 2 , which readily reacted with water or alcohols to form 3 , were cyclized with Na₂CO₃ in anhydrous acetone to yield 5-aryl-2,4-benzothiazepines 5, 6 and 7 , but the 2′-chlorophenyl-derivative 21 exceptionally cyclized to the cyclobutene 20 . The 1-aryl-2,4-benzothiazepines 14, 15 and 16 were prepared unequivocally by acid-catalysed cyclizations of thioureas 13 and 19 .     

Synthesis and Antiradical Activity of 5-Acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic Acid Nitriles

The alkylation of 3-cyano-1,4-dihydropyridine-2(3H)-thiones or the condensation of an aromatic aldehyde, cyanothioacetamide, acetylacetone, and methyl iodide in the presence of piperidine has given a series of novel 5-acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic acid nitriles. A compound was obtained from 3,5-di(tert-butyl)-4-hydroxybenzaldehyde in the molecule of which were combined the active part of the antioxidant ionol and a 1,4-dihydropyridine ring. It was found that, among the compounds synthesized, the highest antiradical activity occurred in a compound having two hydroxyl groups in the 4-phenyl substituent.     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.     

Studies of the reactions between indole-2,3-diones (isatins) and 2-aminobenzylamine

Reflux of equimolecular amounts 2-aminobenzylamine and isatins in acetic acid produced indolo[3,2-c]quinolin-6-ones in good yields. A proposed mechanism involving initial formation of a spiro compound is given. This isolable intermediate subsequently rearranges via a sequential isocyanate ring opening and a cyclisation process to a urea derivative which finally cyclized to the indolo[3,2-c]quinolin-6-ones. The urea derivative could be prepared separately and cyclized selectively to indolo[3,2-c]quinolin-6-one. Reaction of N-acetylisatin with 2-aminobenzylamine at room temperature yielded the 1,4-benzodiazepinone 3-(2-acetamidophenyl)-1,5-dihydro-1,4-benzodiazepin-2-one whereas its isomer 2(2-acetamidophenyl)-4,5-dihydro-1,4-benzodiazepin-3-one was obtained from 2-(2-acetylaminophenyl)-N-(2-aminobenzyl)-2-oxoacetamide in acetic acid at room temperature.The previously unknown linear isomer of indolo[3,2-c]quinolin-6-one, i.e. indolo[2,3-b]quinolin-11-one, has been prepared by thermal (260°C) cyclization of methyl 2-phenylamino indole-3-carboxylate, which in turn was prepared in two steps from methyl indole-3-carboxylate.     

Synthesis and Evaluation of 2-{[(2-Oxo-1H-quinolin-8-yl)oxy]methyl}-Substituted α-Methylidene-γ-butyrolactones

O-Alkylation of 8-hydroxy-1H-quinolin-2-one ( 1 ) afforded 8-(2-oxopropoxy)-1H-quinolin-2-one ( 2 ) which was immediately cyclized to form the tricyclic 2,3-dihydro-3-hydroxy-3-methyl-5H-pyrido[1,2,3-de][1,4]benzoxazine,-5-one ( 3). The Reformatsky-type condensation of 3 furnished antiplatelet 8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)melhoxy]-1H-quinolin-2-one ( 4 ). Its counterparts 7a – f , Ph-substituted at C(2) of the furan ring, were obtained from 1 via alkylation and the Reformatsky-type condensation. Although compound 4 was less active against platelet aggregation than 7a – f , it was the only compound which exhibited significant inhibitory activity on high-K⁺ medium, Ca²⁺-induced vasoconstriction and was more active than most of its Ph-substituted counterparts against norepinephrine-induced vasoconstrictions.     

Nitrogen–Carbon Bond Formation by Reactions of a Titanium–Potassium Dinitrogen Complex with Carbon Dioxide,tert-Butyl Isocyanate,and Phenylallene

Nitrogen–carbon bond-forming reactions at coordinated dinitrogen in a bifunctional titanium–potassium system are reported. A titanium atrane complex with a tris(aryloxide)methyl ligand ( 1 ) was treated with two equivalents of potassium naphthalenide under N₂ atmosphere to generate a bifunctional complex ( 2 ) in which N₂ binds end-on to two titanium centers and side-on to three potassium cations. Dinitrogen complex 2 reacted with carbon dioxide, tert-butyl isocyanate, and phenylallene, forming nitrogen–carbon bonds and affording diverse N-functionalized products. The reaction of 2 with CO₂ followed by addition of Me₃SiCl resulted in the formation of the starting complex 1 with concomitant release of silylated carboxyl hydrazines while the reaction with two equivalents of tert-butyl isocyanate proceeded by insertion into the Ti−N bonds. Treatment of 2 with phenylallene afforded vinyl-substituted hydrazido complexes.     

Synthesis of 1-alkyl-2-methylazetidin-3-ones and 1-alkyl-2-methylazetidin-3-ols

Several 1-alkyl-2-methylazetidin-3-ones were prepared in good yield by the hydride-induced cyclization of the corresponding β-bromo-α,α-dimethoxyketimines, the resulting 3,3-dimethoxyazetidines being hydrolyzed by acid. Imination of these 1,2-disubstituted azetidin-3-ones, followed by alkylation under kinetic control conditions resulted in regioisomeric mixtures of 2,4- and 2,2-dialkylated compounds. Analytical samples of the major 2,4-disubstituted derivatives were obtained after extensive chromatographic separation. The cis stereochemistry of the major 2,4-dialkylated isomer was demonstrated on the basis of NMR data.     

Nitrogen–Carbon Bond Formation by Reactions of a Titanium–Potassium Dinitrogen Complex with Carbon Dioxide,tert‐Butyl Isocyanate,and Phenylallene

Nitrogen–carbon bond‐forming reactions at coordinated dinitrogen in a bifunctional titanium–potassium system are reported. A titanium atrane complex with a tris(aryloxide)methyl ligand ( 1 ) was treated with two equivalents of potassium naphthalenide under N₂ atmosphere to generate a bifunctional complex ( 2 ) in which N₂ binds end‐on to two titanium centers and side‐on to three potassium cations. Dinitrogen complex 2 reacted with carbon dioxide, tert ‐butyl isocyanate, and phenylallene, forming nitrogen–carbon bonds and affording diverse N‐functionalized products. The reaction of 2 with CO₂ followed by addition of Me₃SiCl resulted in the formation of the starting complex 1 with concomitant release of silylated carboxyl hydrazines while the reaction with two equivalents of tert ‐butyl isocyanate proceeded by insertion into the Ti−N bonds. Treatment of 2 with phenylallene afforded vinyl‐substituted hydrazido complexes.     

Simple syntheses of benzothiazol‐2‐ylazoles

Syntheses of the title ring systems are described starting with benzothiazol‐2‐ylacetohydrazide (1). Thus, 1 was reacted with carbon disulfide to afford the 2‐methyl heteroaryl derivative 2, which on reaction with hydrazine hydrate yielded the corresponding triazole compound 3. Also, 1 can undergo a reaction with an isothiocyanate to give the N‐thiocarbonyl adduct 4 that can then be cyclized to produce a 2‐methyl heteroaryl analog 5 or 6. Compounds 8 or 9 could be obtained by the reaction of 1 with an aryl aldehyde followed by malononitrile or via its self‐cyclization, respectively. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 177–182, 1999     

Bond-switch rearrangement of 3-oxo-Δ4-1,2,4-thiadiazolin-5-yl ureas

5-Amino-3-oxo-Δ⁴-1,2,4-thiadiazolines 5a,b react with isocyanates to yield 1,2,4-thiadiazolidine derivatives 9a-d via bond switching of the corresponding isomers 7 . The same type of products 9e-m was obtained by treatment of 5-amino-1,2,3,4-thiatriazoles 6a-d with two equivalents of isocyanate.     

Saturated heterocycles,part 161 [1]. Synthesis of 2-hydroxycycloalkyl-substituted 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles

A number of 2-hydroxycycloalkyl-substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives were prepared by different methods from cis- and trans-2-hydroxy-1-cycloalkanecarbohydrazides and their isocyanate or isothiocyanate adducts. In contrast with the related ring-closure reactions of 2-aminobenzoylhydrazides, no condensed skeleton heterocycles were formed in this case.     

Synthesis of novel fused tricyclic quinolones: 4a,5‐Dihydro‐1H‐[1;2,4]triazino[1,6‐a]quinoline‐2,4,6(3H)‐triones

A versatile methodology to build the 1H‐[1,2,4]triazino[1,6‐a]quinoline‐2,4,6(3H)‐trione structure from methyl 6‐fluoro4‐oxo‐1,4‐dihydro‐2‐quinolinecarboxylate was developed. The method involves an N‐ami‐nation followed by condensation of an aroyl isocyanate to form an alpha semicarbazidocarboxylate that readily cyclizes to the fused [1,2,4]triazino ring under ammonia/ethanol condition. Also, the reactivity of the [1,2,4]triazino ring thus obtained was studied.     

Ring closure reactions of methyl N-(haloacetyl)anthranilates with ammonia

In the presence of ammonia, methyl N-(bromoacetyl)anthranilate ( 4 ) is cyclized into 3H-1,4-benzodiaze-pine-2,5(1H,4H)-dione ( 1 ). However, when 4 is replaced with methyl N-(chloroacetyl)anthranilate ( 6 ), the only heterocyclic product formed in the reaction is 2-(chloromethyl)quinazoline-4(3H)-one ( 7 ). Under analogous conditions, 3-haloacetamidocrotonates (9, 10) do not yield any heterocyclic products and no 1,4-diazepines can be obtained.     

Fixation of carbon dioxide and related small molecules by a bifunctional frustrated pyrazolylborane Lewis pair

The bifunctional frustrated Lewis pair 1-[bis(pentafluorophenyl)boryl]-3,5-di-tert-butyl-1H-pyrazole (1) was employed for small molecule fixation by reaction with carbon dioxide, paraformaldehyde, tert-butyl isocyanate, tert-butyl isothiocyanate, methyl isothiocyanate and benzonitrile, affording the adducts 3-8 as zwitterionic, bicyclic boraheterocycles. Treatment of 1 with tert-butyl isocyanide gave the isocyanide-borane complex 9, whereas the zwitterionic alkynylborate 10 was formed by C-H bond activation of phenylacetylene. The molecular structures of all products 3-10 were established by X-ray diffraction analyses. DFT calculations at the M06-2X/6-311++G(d,p) level of theory revealed that CO(2) fixation by 1 and formation of the adduct 3 is strongly exothermic and proceeds with a low energy barrier of approximately 7.3 kcal mol(-1) via an intermediate van der Waals complex.     

Dihydrobenzoxazines and tetrahydroquinoxalines by a tandem reduction‐reductive amination reaction

A tandem reduction‐reductive amination reaction has been applied to the synthesis of 3,4‐dihydro‐2H‐1,4‐benzoxazines and 1‐acetyl‐1,2,3,4‐tetrahydroquinoxalines. The nitroketones required for the benzoxazine ring closures were prepared by (A) alkylation of the anion derived from 2‐nitrophenol with an allylic halide or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2‐nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palladium‐on‐carbon in methanol then gave the target heterocycles by a reduction‐reductive amination sequence. The N‐methyl derivatives for both ring systems were easily prepared by adding 5‐10 equivalents of aqueous formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purification by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed differentiated functionality on the two nitrogens.