Synthesis of 1,2,3-thiadiazoles

Several methods were explored for preparing certain 4,5-disubstituted-1,2,3-thiadiazoles. The reaction of phenoxyacetyl chlorides with diazoacetylamides yielded α-diazo-β-ketoacetamides which were cyclized, with hydrogen sulfide and ammonium hydroxide, to 4-carboxamido-5-phenoxymethyl-1,2,3-thiadiazoles. However, treatment of α-diazo-α-benzoylacetamides with hydrogen sulfide and ammonium hydroxide yielded hydrazones rather than thiadiazoles. The reaction of α-[(ethoxycarbonyl)hydrazono]benzenepropanoic acid ( 25 ) with thionyl chloride yielded 5-phenyl-1,2,3-thiadiazole-4-carbocylic acid (26a) , the corresponding acid chloride 26b , and 5-(phenylmethyl)-2H-1,3,4-oxadiazine-2,6(3H)dione ( 27 ). The yields of 26a, 26b , and 27 were dependent on the reaction conditions employed. Oxadiazine 27 could also be converted to acid chloride 26b with thionyl chloride. Reduction of 1-([5-(4-chlorophenoxy)methyl-1,2,3-thiadiazol-4-yl]-carbonyl)piperidine ( 10b ) with diborane yielded a boron complex which produced 1-([5-((4-chlorophenoxy)methyl)-1,2,3-thiadiazol-4-yl]methyl)piperidine ( 31 ) upon recrystallization from ethanol.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

Synthesis of phosphonyl 1,2,3‐thiadiazoles

In accord with the Hurd‐Mori reaction conditions, 1‐ or 2‐phosphonyl hydrazones reacted with thionyl chloride to afford 4‐ or 5‐phosphonyl 1,2,3‐thiadiazoles in good yields and purity. A synthesis of 1‐ or 2‐phosphonyl hydrazones using two methods is described. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 16:413–416, 2000     

Selenium heterocycles XLIV. Syntheses of 8,9‐dihydro‐1,2,3‐thiadiazolo[4,5‐a]‐4,7‐dihydroxynaphthalene and 1,2,3‐selenadiazolo[4,5‐a]‐4,7‐dimethoxynaphthalene

The reaction of thionyl chloride with the semicarbazone 2 gave 4,5‐dihydro‐6,9‐dihydroxynaphtho‐[1,2‐d][1,2,3]thiadiazole ( 3 ) instead of 4,5‐dihydro‐6,9‐dimethyoxynaphtho[1,2‐d][1,2,3]thiadiazole ( 4 ). Selenium dioxide oxidation of compound 2 gave 4,5‐dihydro‐6,9‐dimethyoxynaphtho[1,2‐d][1,2,3]selenadiazole ( 5 ). Oxidation of compound 5 with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone afforded 6,9‐dimethyoxynaphtho[1,2‐d][1,2,3]selenadiazole ( 6 ).     

Synthèse et structure d'oxo-2 benzo-5,6 dihydro-3,4 oxathiazines-1,2,3

Reaction of thionyl chloride with various 1,3-aminophenols gives two series of cyclic sulfinamates. The structure of these 3,4-dihydro-2H-benzo[2][1,2,3]oxathiazines is shown by nmr and also for the 3 series by equilibration of the diastereoisomers.     

Selenium heterocycles. XLI . Syntheses of substituted thiazolo,selenazolo, 1,2,3-thiadiazolo and 1,2,3-selenadiazoloquinolines

The reaction of thionyl chloride with the semicarbazone 2 gave 4,5-dihydro[1,2,3]thiadiazolo[4,5-f]quinoline. Selenium dioxide oxidaion of compound 2 gave 4,5-dihydro[1,2,3]selenadiazolo[4,5-f]quinoline ( 4 ) and the aromatic analog 5 . Thermolysis of compound 5 yielded [1,4]diselenino[2,3-f:5,6-f′]diquinoline ( 6 ). Reaction of selenourea with α-bromoketone 7 gave 2-amino-4,5-dihydroselenazolo[4,5-f]quinoline ( 8 ). Compounds 9 and 10 were prepared from the reaction of selenobenzamide and thiobenzamide with compound 7 .     

An Efficient Synthesis of Pyrazolyl‐1,2,3‐thiadiazoles via Hurd–Mori Reaction

An efficient synthetic strategy has been developed for the synthesis of pyrazolyl‐1,2,3‐thiadiazoles via Hurd–Mori cyclization reaction. The reaction of various pyrazolyl‐phenylethanones with semicarbazide hydrochloride in the presence of sodium acetate/methanol gave the corresponding semicarbazones ( 3a – i ). These semicarbazones were further reacted with thionyl chloride via the Hurd–Mori cyclization conditions to accomplish the title products ( 4a – i ). The present protocol favored for the formation of both pyrazolyl semicarbazone derivatives and pyrazolyl‐1,2,3‐thiadiazole derivatives by forming C─S, N─S, and C═N bonds in excellent yields with variety of substrates. The final compounds were characterized by analytical and spectral studies.     

Synthesis of pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates via the Hurd-Mori reaction. Investigating the effect of the N-protecting group on the cyclization

A route to methyl pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates as potential plant activators and inducers of systemic acquired resistance (SAR) is reported. A synthetic strategy based on cyclization of the thiadiazole ring system utilizing thionyl chloride via the Hurd-Mori protocol as key step was developed. Success of the ring closure reaction turned out to be highly dependent on the nature of the N-protecting group of the pyrrolidine precursor. While electron donors such as alkyl gave only poor conversion to the required 1,2,3-thiadiazoles, an electron withdrawing substituent such as methyl carbamate gave superior yields.     

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

A 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.     

Syntheses of [1,2,3]selenadiazolo[4,5‐e]benzofuran or benzothiophene, [1,2,3]thiadiazolo[4,5‐e]benzofuran or benzothiophene,and 2‐benzofuranyl‐1,3,4‐oxodiazole derivatives

Dehydrogenation of ethyl 3‐methyl‐4‐oxo‐4,5,6,7‐tetrahydrobenzofuran‐2‐carboxylate 1 with 2,2′‐azobi‐sisobutyronitrile and N‐bromosuccinimide gave ethyl 4‐hydroxy‐3‐methylbenzofuran‐2‐carboxylate 3 . Reaction of compounds 3–4 with hydrazine hydrate afforded the corresponding hydrazides 5a‐b . The reaction of 5a‐b with aldehydes yielded substituted hydrazones 6a‐l . Compounds 7a‐d were prepared from compounds 6a‐d and bromine in acetic acid. Lead tetraacetate oxidation of compounds 6e‐l afforded substituted oxadiazoles 8e‐l . Selenium dioxide oxidation of 4‐oxo‐4,5,6,7‐tetrahydrobenzofuran semicarbazones 9, 14a and 4‐oxo‐4,5,6,7‐tetrahydrobenzothiophene 14b gave the tricyclic 1,2,3‐selenadiazoles 10, 15a and 15b respectively. Reaction of semicarbazones 9, 14a and 14b with thionyl chloride afforded the corresponding 1,2,3‐thiadiazoles 12, 16a and 16b respectively.     

Investigation of the products of the reaction of epichlorohydrin with aromatic amines

The action of hydrogen halides on 7a,8-dihydro-7H-azirino[1,2-]benz[g]indole gives 2-halomethyl-2,3-dihydro-1H-benz[g]indoles and 3-halo-1,2,3,4-tetrahydrobenzo[h]quinolines, which were converted to the corresponding N-nitroso derivatives and then to the isonitroso derivatives. 2-(Benzoxymethyl)-2,3-dihydro-1H-benz[g]indole hydrohalides were obtained by heating 1-benzoyl-2-halomethyl-2,3-dihydro-1H-benz[g]indoles. The reaction of 3-halo-1,2,3,4-tetrahydrobenzo[h]quinolines with thionyl chloride at room temperature gives 3-halo-6-chloro-1,2,3,4-tetrahydrobenzo[h]quinolines, while refluxing with thionyl chloride gives 6-chlorobenzo[h]quinoline.See [1] for communication XVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 342–346, March, 1973.     

1,2,3-thiadiazoles. I. Synthesis of sodium (or potassium) 1,2,3-thiadiazole-4-thiolates via thiocarbazonate esters and N-acylthiohydrazonate esters

A general synthesis of 1,2,3-thiadiazole-4-thiolates 1 and their derivatives 2–3 by an extension of the Hurd-Mori 1,2,3-thiadiazole synthesis is described. Treatment of methyl (or ethyl) [1-(alkylthio)alkylidene]hydrazinocarboxylates 11 (thiocarbazonate esters) or other N-acylthiohydrazonate esters [Y = ureido ( 12 ) or arenesulfonyl ( 13 )] with thionyl chloride affords 2–3 efficiently. Intermediates 11–13 are readily obtained from the N²-thioacylcarbazates 8 , N³-thioacylsemicarbazides 9 , or N²-thioacyl-N¹-(p-toluenesulfonyl)hydrazides 10 , respectively, by S-alkylation. Physicochemical properties of the 1,2,3-thiadiazoles 1–3 and N-acylthiohydrazonate esters 11–13 are also described.     

A novel serotonin antagonist 2,2′-bis[3-(2-N,N-dimethylaminoethyl)indolyl]sulfide (BDIS)

A novel serotonin antagonist, 2,2′-bis[3-(2-N,N-dimethylaminoethyl)indolyl]sulfide (BDIS) was synthesized in one step from the reaction of N,N-dimethyltryptamine with thionyl chloride.     

Synthesis and structure of benzimidazo[1,2-c][1,2,3]thiadiazoles: first examples of a novel ring system

(1-Amino-1H-benzimidazol-2-yl)methanol 1 with thionyl chloride at reflux afforded 3-chlorobenzimidazo[1,2-c][1,2,3]thiadiazole 4, which reacted with various nucleophiles to give different products depending on the nature of the solvent. The structures of 4 and di(benzimidazo[1,2-c][1,2,3]thiadiazol-3-yl)sulfide 8 were confirmed by single-crystal X-ray analysis.     

Alkali metal 2-(1-adamantyl)ethynethiolates: Synthesis and reactions with electrophilic reagents

Treatment of ethyl 2-[1-(1-admantyl)ethylidene]hydrazine-1-carboxylate with thionyl chloride gave 4-(1-adamantyl)-1,2,3-thiadiazole which readily underwent decomposition by the action of strong bases with formation of alkali metal 2-(1-adamantyl)ethynethiolates. The latter were brought into reactions with proton donors and benzyl halides.     

A facile synthesis of novel 1-aryl-1H-pyrazolo[3,4-b]quinoxalines

The reactions of 3-methyl-2-oxo-1,2-dihydroquinoxaline 3 with chlorophenyl diazonium salts afforded the hydrazones 4a-c , whose chlorinations with phosphoryl chloride gave the dichlorides 5a-c . Refluxing of the dichlorides 5a-c and base in N,N-dimethylformamide provided the 1-aryl-1H-pyrazolo[3,4-b]quinoxalines 6a-c .     

Investigation of the regioselectivity of the Hurd-Mori reaction for the formation of bicyclic 1,2,3-thiadiazoles

A series of new pyrrolo[d][1,2,3]thiadiazole carboxylates and 5,6-dihydro-4H-cyclopenta[d][1,2,3]thiadiazoles has been synthesized via the Hurd-Mori reaction. The regioselectivity of the cyclization has been studied and trends were established to predict the cyclization direction to afford bicyclic 1,2,3-thiadiazoles. Effects promoting and disfavoring the reaction have also been investigated to guide the synthesis of scaffolds of this type.     

A study of the products of the reaction of epichlorohydrin with aromatic amines

The halogenation of 1,2,3,4-tetrahydrobenzo[h]quinoline and of 3-hydroxy-1,2,3,4-tetrahydrobenzo[h]quinoline and its O-benzoyl and N,O-dibenzoyl derivatives has been studied. The action of thionyl chloride or bromide on 1,2,3,4-tetrahydrobenzo[h]quinoline at room temperature gives 6-chloro-1,2,3,4-tetrahydrobenzo[h]quinoline and 6-bromo-1,2,3,4-tetrahydrobenzo[h]quinoline. When 6-chloro-3-hydroxy-1,2,3,4-tetrahydrobenzo[h]quinoline is heated with thionyl chloride, aromatization of the tetrahydropyridine ring takes place, and when 6-bromo-3-hydroxy-1,2,3,4-tetrahydrobenzo[h]quinoline is heated with thionyl chloride, in addition to the aromatization of the tetrahydropyridine ring the bromine atom is replaced by a chlorine atom with the formation of 6-chlorobenzo[h]quinoline. 6-Bromobenzo[h]quinolme has been obtained by heating 3-hydroxy-1,2,3,4-tetrahydrobenzo[h]quinoline with thionyl bromide.For Communication IV, see [6].Translated from Khimiya Geterotsiklicheskikh Soedinenii.Vol. 6,No.7, pp. 969–973, July, 1970.     

Intramolecular 1,3-cycloadditions of nitrile ylides bearing an acetylenic function

Treatment of amides 1a,b with thionyl chloride followed by reaction with triethylamine gave 1,4-dihydro[1]benzopyrano[4,3-b]pyrrole derivatives ( 4a,b ) arising from intramolecular 1,3-cycloaddition of intermediate nitrile ylides ( 3a,b ).     

Versatile, convenient synthesis of pyrimido[1,2,3-cd]purinediones

The alkylation of 3-substituted cycloalkylcarboxamido-6-aminouracil derivatives with 3-bromo-1-propanol followed by ring closure yields 1,3,8-trisubstituted xanthine derivatives bearing a polar hydroxyl group. Use of the more reactive 1,3-dibromopropane or homologous dibromoalkanes for the alkylation reaction results in simultaneous alkylation at N1 and the exocyclic amino group (N⁶) yielding imidazo-, pyrimido- and diazepino-pyrimidine derivatives. The pyrimidopyrimidine derivatives can subsequently be cyclised using hexamethyldisilazane at high temperature affording an easy, convenient and general access to tricyclic pyrimido[1,2,3-cd]purinediones. Alternatively, 3-substituted 6-amino-5-benzylideneaminouracil derivatives can be reacted with 1,3-dibromopropane followed by an oxidative cyclisation using thionyl chloride to obtain the desired tricyclic pyrimido[1,2,3-cd]purinediones, which are sterically fixed analogues of pharmacologically active purine derivatives.