Synthesis of 7-oxindolylidene-3a,9a-diphenylimidazothiazolo[2,3-c][1,2,4]triazines by skeletal rearrangement of their [3,2-b]-fused isomers

Previously unavailable 7-oxindolylidene-1,3-dimethyl-3a,9adiphenylimidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazines were obtained in 63–90% yields by skeletal amidine rearrangement of the thiazolo-triazine system in the corresponding imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazines on treatment with sodium methoxide.     

Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo[4,5-d][1,2,3]triazines

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedländer reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.     

Synthesis and Biological Evaluation of New Fused Thiazolo[4,5-d] Pyridazine Derivatives

The synthesis of thiazolo[4,5-d]pyridazines and the unknown ring systems, thiazolo[4,5-d]-1,2,4-triazolo- and tetrazolo[4,3-b]pyridazines as well as thiazolo(4,5-d]pyridazino[2,3-c]2H triazines, has been achieved according to different pathways. Biological testing of the new tricyclic heterocycles revealed that some of these compounds possess remarkable antibacterial activity.     

Cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]thiazole with oxalic acid derivatives

Refluxing 3-amino-2-iminonaphtho[1,2-d]thiazole ( 1 ) with diethyl oxalate ( 2a ) in a 2:1 molar ratio in dry pyridine provided 2,2′-binaphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 3 ). On the other hand, when 1 was treated with excess amount of 2a in dimethylformamide, it afforded ethyl naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole-2-carboxylate ( 4a ) on heating and ethyl N-(2-iminonaphtho[1,2-d]thiazol-3-yl)oxamate ( 5 ) by stirring at room temperature. Cyclization of 5 upon fusion led to the formation of 3-hydroxy-2H-naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazin-2-one ( 6 ). Compound 6 could also be prepared directly from 1 by refluxing either with 2a neatly, in glacial acetic acid or with oxalic acid ( 2b ) in the same medium. The acid form of 4a might be obtained from 1 and 2b on heating in dimethylformamide, but it was decarboxylated to naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 4b ) during the reaction.     

Regioselectivity of cyclization of 3-allyl(propargyl)sulfanyl-5<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indoles

The interaction of 3-allylsulfanyl-5H-[1,2,4]triazino[5,6-b]indole with iodine led to 1-iodomethyl-1,2-dihydro[1,3]thiazolo[2',3':3,4][1,2,4]triazino[5,6-b]indol-11-ium pentaiodide with an angular structure, on the basis of which 1-iodomethyl-1,2-dihydro[1,3]thiazolo-, 1-methylidene-1,2-di-hydro[1,3]thiazolo, and 1-methyl[1,3]thiazolo derivatives were obtained. The intramolecular cyclization of 3-propargyl(allyl)sulfanyl-5H-[1,2,4]triazino[5,6-b]indoles under the influence of concentrated sulfuric acid led to linear annelated products:3-methyl[1,3]thiazolo[3',2':2,3][1,2,4]tri-azino[5,6-b]indole or its 2,3-dihydro derivative.     

Synthesis and Diels-Alder reactions of the benzo[4,5]thieno [2,3-c]pyrrole ring system

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system and its derivatives, as well as their Diels-Alder reactions with DMAD and N-phenylmaleimide are reported. A new synthesis of the benzo[4,5]thieno[2,3-d]pyridazine ring system is also described.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 9. Phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline,benzo[f]phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline,and benzo[h]-phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline

The synthesis of three novel polycyclic heterocyclic ring systems are reported via photocyclization. The specific final products in these ring systems are: phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline ( 13 ), benzo[h]-phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline ( 14 ), and benzo[f]phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline ( 15 ).     

[1,3]Thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines – A New Heterocyclic System Accessed via Bromocyclization

A facile access to novel condensed system of [1,3]thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5‐a]pyrimidine is presented. This protocol consists of bromine‐assisted direct electrophilic heterocyclization of 3‐N‐allylamine‐5,6‐dihydro[1,3]thiazolo[2,3‐c][1,2,4]triazole. The bromination took place in acetic acid and gave a good yield of the target product, which was dehydrobrominated by sodium acetate action.     

Polyazasteroids II.. 1,2,4-Triazolol[3′,4′:2,3]pyrimido[4,5-c]quinolin- 11(12H)ones,imidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3] pyrimido[4,5-c]quinolin-11(12H)ones

Starting with 2-substituted quinoline-3,4-dicarboxylic acids, a series of substituted 1,2,3,4-tetrahydropyrimido[4,5-c]quinolinone-3-thiones were obtained. The latter compounds were converted to the three novel polyazasteroid series: 1,2,4-Triazolo[3′,4′:2,3]pyrimido[4,5-c]-quinolin-11(12H)ones, imidazo[2′,1′:2,3]pyrimido[4,5c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones. The intermediate 3-hydrazino-1,2-dihydropyrimido[4,5-c]quinolinones and nitrous acid gave the 3-azido derivatives rather than the tetrazolo compounds.     

The synthesis of novel polycyclic heterocyclic ring system via photocyclization. 18. Benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c]quinoline and benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c] [1,2,4]triazolo[4,3-a]quinoline

The synthesis of two previously unknown polycyclic ring systems, benzo[h]naphtho[1′2′:4,5]-thieno[2,3-c]quinoline ( 1 ) and benzo[h]naphtho[1′,2′:4,5]thieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline ( 2 ), was achieved via oxidative photocyclization of 1-chloro-N-(1-naphthyl)naphtho[2,1-b]thiophene-2-carboxamide ( 5 ). The total assignment of their ¹H and ¹³C nmr spectra was determined by the concerted use of two-dimensional nmr methods.     

Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides inspired by marine topsentines and nortopsentines

We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.     

Fused 1,2,4-triazole heterocycles. IV. Synthesis of four new heterocyclic ring systems of [1,2,4]triazolo[1,3]thiazinoquinolines

Syntheses of 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,4-c]quinolines 8, 5H-[1,2,4]triazolo[3′,4′:2)3][1,3]thiazino[5,4-c]quinolines 9, 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,6-c]quinolines 14 and 5H-[1,2,4]triazolo[3′,4′:2,3][1,3]thiazino[5,6-c]quinolines 15 are described starting from 4-chloro-3-chloromethylquinaldine (4) and 1,2,4-triazole-5-thiols 5 taking advantage of different reactivity of the chlorine atoms of 4 under different reaction conditions. The structures of products 8, 9, 14 and 15 and the intermediates leading to them were confirmed by desulfurization, unequivocal syntheses and nmr spectroscopy as well.     

Ionic Liquid-Mediated Facile Synthesis and Antimicrobial Study of Thiazolo [2,3-b]Benzo[h]Quinazolines and Thiazino[2,3-b] Benzo-[h]Quinazolines

Abstract

8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione, obtained by the condensation of 2-benzylidene-6-methoxy-3,4-dihydronapthalene-1(2H)-one with thiourea, on reaction with chloroacetic acid and 3-chloropropanoic acid in the presence of the ionic liquid N-methylpyridinium tosylate furnishes 3-methoxy-7-phenyl-7,10-dihydro-5H- benzo[h]thiazolo[2,3-b]quinazoline-9(6H)-one and 3-methoxy-7-phenyl-5,6,10,11-tetrahydro- benzo[h][1,3]thiazino[2,3-b]quinazoline-9(7H)-one. Further, condensation of the thione with 1,2-dibromoethane and 1,3-dibromopropane yields 3-methoxy-7-phenyl-6,7,9,10-tetrahydro-5 H-benzo[h]thiazolo[2,3-b]quinazoline and 3-methoxy-7-phenyl-5,6,7,9,10,11-hexahydrobenzo [h][1,3]thiazino[2,3-b]quinazoline respectively. Arylidene derivatives have been obtained by two routes. The structures of the cyclized compounds have been established on the basis of elemental analysis and spectroscopic data. The synthesized compounds were screened for antimicrobial activity. Some of the compounds showed promising antimicrobial activities.     

Synthesis of pyrido[3,2-e]pyrrolo[2,1-c][1,2,4]triazines from pyrido[3,2-e][1,2,4]triazine derivatives

In carrying on our interest in heteropolycyclic structures with biological activities, we projected the preparation of compounds containing the pyrido[3,2-e][1,2,4]triazine or pyrido[2,3-b][1,4]triazepine systems. The established synthetic approach for the preparation of latter system led to the triazine derivatives 5a-f while a new bicyclic triazepine structure 6 is accomplished with difficulty. In expanding the pyridotriazine structure, we obtained derivatives of a new tricyclic structure, 5-substituted-6a-ethyloxycarbonyl-5,6,6a,7-tetrahydropyrido[2,3-e]pyrrolo[2,1-c][1,2,4]triazin-9(8H)-ones 8 in which the triazine ring is fused with a pyrrole nucleus. Compounds 5a-f and 8a,b will be tested as potential CNS depressant, antiinflammatory, analgesic and antibacterial agents.     

Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones using Mn(OAc)3

2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-aminothiazole, respectively. A new class of compounds, 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent (92%) inhibitory potential, comparable with the standard drug Donapezil®.     

The synthesis of 5,6-dihydro-6-methylthiazolo-[2,3-b] [1,3] benzodiazepines, 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5] thiazolo[2,3-b] [1,3] benzodiazepine,and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b] [1,3]-benzodiazepine via 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione

Catalytic reductive scission of 4-methylcinnoline (V) with Raney nickel afforded o-amino-β-methylphenethylamine (IV) in 57% yield. Treatment of IV with carbon disulfide followed by thermal cyclization of the product furnished 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione (III). Reaction of III with ethyl chloroacetate, ethyl 2-bromohexanoate, ethyl 2-chloroacetoacetate, 2-bromo-2′-methoxyacetophenone, and 2-bromoacetophenone provided a series of substituted 5,6-dihydro-6-methylthiazolo[2,3-b][1,3]benzodiazepines. Condensation of III with 2-chlorocyclopentanone and 2-chlorocyclohexanone gave 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5]thiazolo[2,3-b][1,3]benzodiazepine and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b][1,3]benzodiazepine, respectively. Structure assignments are discussed. None of the compounds possessed appreciable biological activity.     

Synthesis of representative 10-aryl-, 10-aralkyl- and 10-heteraryl-9H-naphtho[1′,2′:4,5]thiazolo[3,2-b]- [1,2,4]triazin-9-ones as potential anti-HIV agents

To prepare the title compounds, cyclocondensation of 1-amino-2-iminonaphtho[1,2-d]thiazole ( 2 ) with some representative glyoxylic acid derivatives was investigated. Heating 2 with methyl phenylglyoxylate ( 3a ) in methanol afforded only the open chain intermediates 4a,b . However, when this reaction was performed in re-fluxing glacial acetic acid, the expected compound, 10-phenyl-9H-naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]- triazin-9-one ( 5a ) was produced in 27% yield. Similar treatment of 2 with benzyl-, 2-furyl- and 2-thienylgly-oxylic acids 3b-d gave the corresponding 10-benzyl-, 10-(2-furyl)- and 10-(2-thienyl)-9H-naphtho[1′,2′:4,5]thi-azolo[3,2-b][1,2,4]triazin-9-ones 5b-d in 48–67% yields. As by-products, 9-benzoyl- and 9-(2-thenoyl)naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazoles 6a,d were also isolated. Compound 5a was selected for in vitro anti-HIV evaluation but found to be inactive.     

Regioselective synthesis of new imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazines via reaction of imidazo[4,5-e][1,2,4]triazinethiones with ethyl phenylpropiolate

A method for the regioselective synthesis of imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazine derivatives has been developed by the reaction of imidazotriazinethiones with ethyl phenylpropiolate upon treatment with potassium carbonate or sodium methoxide in methanol. The synthesis was accomplished by Michael-type addition of the imidazotriazinethiones to the triple bond of ethyl phenylpropiolate followed by subsequent intramolecular cyclization.     

Reaction of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with benzyltriethylammonium chloride

3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine was reacted with BnEt₃NCl (10?mol%) to give perchloro-9-thia-1,5,8,10-tetraazaspiro[5.5]undeca-1,4,7,10-tetraene (up to 18% yield), 4,5,6-trichloropyrimidine-2-carbonitrile (up to 44% yield) and four minor side products: 2,7-dichlorothiazolo[5,4-d]pyrimidine-5-carbonitrile, 2-(4-chloro-6H-thiazolo[5,4-c][1,2,6]thia-diazin-6-ylidene)malononitrile, 4,8-dichloropyrrolo[2′,1′:2,3]imidazo[4,5-c][1,2,6]thiadiazine-6,7-dicarbonitrile and 4,7-dichloro-[1,2,6]thiadiazino[3,4-b]thiazolo[5,4-e][1,4]diazepin-9(10H)-one. Single crystal X-ray studies support the structures of the minor products. Tentative rationale for the formation of these minor products and the synthesis of 8-bromo-4-chloropyrrolo[2′,1′:2,3]imidazo[4,5-c][1,2,6]thiadiazine-6,7-dicarbonitrile are presented.     

A convenient synthesis of 1,2,4-triazolo[4,3,2-o,p]-[1,3]diazocino[4,5-b]quinoxalines via a 1,3-dipolar cycloaddition reaction and a ring transformation

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 5 with triethyl orthoformate gave 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 5-oxide 6. The reaction of compound 6 with phenyl isocyanate afforded 7-chloro-4-phenylamino-1,2,4-triazolo[4,3-a]quinoxaline 7 , while the reaction of compound 6 with phenyl isothiocyanate resulted in deoxygenation to provide 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 8. However, the reaction of compound 6 with allyl isothiocyanate effected the 1,3-dipolar cycloaddition reaction, but not deoxygenation, to furnish 9-chloro-4,5-dihydroisoxazolo[2,3-a][1,2,4]triazolo[3,4-c]quinoxalin-5-ylmethylisothiocyanate 9. Moreover, the reduction of compound 9 with iron/acetic acid resulted in ring transformation to give 11 -chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2- o,p][1,3]diazocino[4,5-b]quinoxaline 10 , whose acetylation afforded 5-acetyl-11-chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2-o,p][1,3]diazocino[4,5-b]quinoxaline 11.