1,ω‐Bis(4‐amino‐1,2,4‐triazole‐5(1H)‐thion‐3‐ylsulfanyl)alkanes: Versatile precursors for novel bis(S‐triazolo[3,4‐b][1,3,4]thiadiazines) as well as novel bis(macrocyclic schiff bases)

Two synthetic routes were attempted for the synthesis of the novel bis(5,6‐dihydro‐S‐triazolo[3,4‐b]thiadiazines) 12a,b and 14 . In the first route the bis(aminotriazoles) 4a,b were reacted with the appropriate α‐haloketones or α‐haloesters to give the corresponding bis(S‐triazolo[3,4‐b]thiadiazines) 11a‐d followed by reduction with NaBH₄. In the second route, the bis(Schiff bases) 13d were reacted with the appropriate α‐haloesters in refluxing DMF containing TEA to give the target compound 14 . Cyclocondensation of 4a,b with the appropriate bis(carbonyl) ethers 15a,b in refluxing acetic acid under high dilution conditions afforded the corresponding macrocyclic Schiff bases 16a‐c . The latter underwent alkylation with the appropriate halo compounds to give the corresponding alkylated derivatives 17a‐d .     

Bis(α‐bromo ketones): Versatile Precursors for Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) and Bis(as‐triazino[3,4‐b][1,3,4]thiadiazines)

A synthesis of bis(α‐bromo ketones) 5a‐c and 6b,c was accomplished by the reaction of bis(acetophenones) 3a‐c and 4b,c with N‐bromosuccinimide in the presence of p‐toluenesulfonic acid (p‐TsOH). Treatment of 5a‐c and 6b,c with each of 4‐amino‐3‐mercapto‐1,2,4‐triazoles 9a,b and 4‐amino‐6‐phenyl‐3‐mercapto‐1,2,4‐triazin‐5(4H)‐ones 13 in refluxing ethanol afforded the novel bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 10a‐d and 11a‐c as well as bis(as‐triazino[3,4‐b][1,3,4]thiadiazines) 14a‐c and 15 , respectively, in good yields. Compounds 11b and 11c underwent NaBH₄ reduction in methanol to give the target 1,ω‐bis{4‐(6,7‐dihydro‐3‐substituted‐5H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)phenoxy}butanes 12a and 12b in 42 and 46% yields, respectively.     

Microwave‐assisted Synthesis of 6‐{(5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)methyl}‐6H‐indolo[2,3‐b]quinoxalines

An efficient and convenient synthesis of a new series of 2‐{(6H‐indolo[2,3‐b]quinoxalin‐6‐yl)methyl}‐5‐aryl‐1,3,4‐oxadiazoles from readily available 1,2‐diaminobenzene and isatins under microwave irradiation conditions was disclosed. The 6‐{(5‐aryl‐1,3,4‐oxadiazol‐2‐yl)methyl}‐6H‐indolo[2,3‐b]quinoxalines were also prepared by the thermal cyclo‐condensation reaction of 2‐(6H‐indolo[2,3‐b]quinoxalin‐6‐yl)acetohydrazides with carboxylic acids in refluxing POCl₃. The microwave‐assisted synthesis was rapid and resulted in higher yield of the products at lower operating temperature with reduced waste generation in comparison with the thermal reaction protocol.     

Synthesis of 1,3,4‐Oxadiazole Acyclo C‐Nucleosides Bearing 5‐Methylthio{7‐substituted‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}moieties

Oxidative cyclization of the sugar hydrazones ( 3_a‐f ) derived from {7H‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐ylsulfanyl}acetic acid hydrazide ( 1 ) and aldopentoses 2_a‐c or aldohexoses 2_d‐f with bromine in acetic acid in the presence of anhydrous sodium acetate, followed by acetylation with acetic anhydride gave the corresponding 2‐(per‐O‐acetyl‐alditol‐l‐yl)‐5‐methylthio{7H‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}‐1,3,4‐oxadiazoles ( 5_a‐f ). Condensative cyclization of the sugar hydrazones ( 3_a‐f ) by heating with acetic anhydride gave the corresponding 3‐acetyl‐2‐(per‐O‐acetyl‐alditol‐1‐yl)‐2,3‐dihydro‐5‐methylthio{7‐acetyl‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}‐1,3,4‐oxadiazoles ( 11_a‐f ). De‐O‐acetylation of the acyclo C‐nucleoside peracetates ( 5 and 11 ) with methanolic ammonia afforded the hydrazono lactones ( 7 ) and the acyclo C‐nucleosides ( 12 ), respectively. The structures of new oxadiazole derivatives were confirmed by analytical and spectral data.     

Synthesiss of novel 3‐(2‐thienyl)‐1,2‐diazepino[3,4‐b]quinoxalines with algicidal activity

The reaction of the quinoxaline N‐oxide 1 with thiophene‐2‐carbaldehyde gave 6‐chloro‐2‐[1‐methyl‐2‐(2‐thienylmethylene)hydrazino]quinoxaline 4‐oxide 5 , whose reaction with 2‐chloroacrylonitrile afforded 8‐chloro‐2,3‐dihydro‐4‐hydroxy‐1‐methyl‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]quinoxaline‐5‐carbonitrile 6 . The reaction of compound 6 with various alcohols in the presence of a base effected alcoholysis to provide the 5‐alkoxy‐8‐chloro‐2,3,4,6‐tetrahydro‐1‐methyl‐4‐oxo‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]‐quinoxalines 7a‐d . The reaction of compounds 7a and 7b with diethyl azodicarboxylate effected dehydrogenation to give the 5‐alkoxy‐8‐chloro‐4,6‐dihydro‐1‐methyl‐4‐oxo‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]‐quinoxalines 8a and 8b , respectively. Compounds 8a and 8b were found to show good algicidal activities against Selenastrum capricornutum and Nitzchia closterium.     

Synthesis of Functionalized Polynorbornanes Employing 2,5‐Bis(trifluoromethyl)‐1,3,4‐oxadiazole

Cycloaddition reaction of 2,5‐bis(trifluoromethyl)‐1,3,4‐oxadiazole with strained olefinic bonds of norbornenes was used to synthetize functionalized polynorbornanes. This simple, one step procedure was more effective when reaction was carried out by classical heating, in comparison to microwave‐assisted reactions. Various functional groups were stable in the reaction conditions (ester, imide, phthalimide, piperidyl, and carboxylic acid), whereas anhydride, N‐Boc, or TMS functionalities do not withstand reaction conditions.     

Reduction of 3‐Aminoquinoline‐2,4(1H,3H)‐diones and Deamination of the Reaction Products

3‐Aminoquinoline‐2,4‐diones were stereoselectively reduced with NaBH₄ to give cis‐3‐amino‐3,4‐dihydro‐4‐hydroxyquinolin‐2(1H)‐ones. Using triphosgene (=bis(trichloromethyl) carbonate), these compounds were converted to 3,3a‐dihydrooxazolo[4,5‐c]quinoline‐2,4(5H,9bH)‐diones. The deamination of the reduction products using HNO₂ afforded mixtures of several compounds, from which 3‐alkyl/aryl‐2,3‐dihydro‐1H‐indol‐2‐ones and their 3‐hydroxy and 3‐nitro derivatives were isolated as the products of the molecular rearrangement.     

2,2‐Bis(methoxy‐NNO‐azoxy)ethyl Derivatives of 4,8‐Dihydro‐bis‐furazano[3,4‐b:3′4′‐e]pyrazine: The Synthesis and X‐ray Investigation

The first synthesis of 4,8‐dihydro‐bis‐furazano[3,4‐b:3′4′‐e]pyrazine bearing 2,2‐bis(methoxy‐NNO‐azoxy)ethyl groups has been developed. These compounds are obtained by aza‐Michael reaction of 1,1‐bis(methoxy‐NNO‐azoxy)ethene or its equivalents, such as 2,2‐bis(methoxy‐NNO‐azoxy)ethanol derivatives, with 4,8‐dihydro‐bis‐furazano[3,4‐b:3′4′‐e]pyrazine.     

Synthesis of dihydrofuro[2,3‐b]pyridines by the reaction of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles with α,β‐unsaturated carbonyl compounds

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles 1a‐d with α,β‐unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a‐d , 3a‐d and 4a‐d. Compounds 2a‐d and 3a‐c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a‐alkoxyhexahydrofuro[2,3‐b]pyridines 5a‐d, 6a‐d, 7a‐c and 8a‐c . Treatment of 5a‐d, 6a‐d, 7a‐c and 8a‐c with potassium tert‐butoxide produced the corresponding dihydrofuro[2,3‐b]pyridines 9a‐d and 10a‐c . The reaction of 4a‐c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro‐furo[2,3‐b]pyridines 11a‐c .     

Quinolone analogues 8 [1‐6]. Synthesis of 3‐aminopyridazino‐[3,4‐b]quinoxalin‐4(lH)‐one

The 3‐amino‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐one 6 and N‐(1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxalin‐3‐yl)carbamates 17a,b were synthesized from the 1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxa‐line‐3‐carboxylate 1b via the 1,5‐dihydro‐4‐hydroxy‐1‐methylpyridazino[3,4‐b]quinoxaline‐3‐carbohydrazide 13b and then 1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxaline‐3‐carboxazide 8 . Heating of compound 13b and arylalde‐hydes afforded the 1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxaline‐3‐carbo(2‐arylmethylene)hydrazides 14a‐d.     

Bis(α‐bromo ketones): Versatile Precursors for Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) and Bis(thiazoles)

A synthesis of novel bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 4 , 5 , 6 in which the triazolothiadiazine is linked to the benzene core through the thiadiazine ring via phenoxymethyl spacers was reported. First attempt to synthesize 4 , 5 , 6 by the reaction of the appropriate bis(acetophenones) with 4‐amino‐3‐mercapto‐1,2,4‐triazole derivatives using an acidified acetic acid method were unsuccessful. On the other hand, reaction of the corresponding bis(α‐bromoketones) with 4‐amino‐3‐mercapto‐1,2,4‐triazole derivatives afforded 4 , 5 , 6 in good yields. The reaction pathway is assumed to involve S‐alkylation to give bis(aminotriazole) intermediates, followed by intramolecular cyclocondensation to give 4 , 5 , 6 . The successful isolation of the corresponding bis(aminotriazole) intermediates provides strong evidence for the proposed mechanism. The novel bis(thiazoles) 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , linked to alkyl or aryl spacers can also be synthesized by reaction of the appropriate bis(bromoacetyl) compounds 12a , 12b , 12c and 14 , 15 , 16 , 17 , 18 , 19 with the corresponding thioamide derivatives 20 , 21 , 22 .     

Synthesis of dihydrothieno[2,3‐b]pyridines based on titanium(IV) chloride‐mediated michael reactions of 2‐amino‐4,5‐dihydro‐3‐thiophenecarbonitriles with α,β‐unsaturated ketones

2‐Arnino‐4,5‐dihydro‐3‐thiophenecarbonitriles 1a‐c reacted with α,β‐unsaturated ketones (e.g. methyl vinyl ketone 2 and benzalacetone 3 ) in the presence of titanium(IV) chloride to give the corresponding Michael adducts 4a‐c and 5a‐c. Thermal treatment of compounds 4a‐c and 5a‐c with titanium(IV) chloride caused intramolecular cyclocondensation to yield the corresponding tetrahydrothieno[2,3‐b]pyridines 6a‐c and 7a‐c. Aromatization of 6a‐c and 7a‐c with potassium tert‐butoxide in refluxing tert‐butyl alcohol pro ceeded smoothly to afford the corresponding dihydrothieno[2,3‐b]pyridines 8a‐c and 9a‐c.     

Efficient Routes for the Synthesis of Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines)

Bis(triazolo[3,4‐b]thiadiazine) 4 in which the fused system is linked directly to the benzene core can be synthesized in 75% yield by, firstly, preparation of bis(s‐triazole) 2 followed by reaction with phenacyl bromide 3 in refluxing EtOH/DMF mixture containing piperidine. Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 8 and 11 in which the triazolothiadiazines are linked to benzene core via alkyl or ether linkage were synthesized in 70 and 72% yields, respectively, starting from dicarboxylic acids 5 and 9 upon treatment with two moles of thiocarbohydrazide 6 to give the corresponding bis(4‐amino‐5‐mercapto‐s‐triazolo‐3‐y1) derivatives 7 and 10 and subsequent reaction with two equivalents of phenacyl bromide. Bis(6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines) 15a , 15b , 15c , 15d , 15e , 15f , which are linked to arene cores via sulfanylmethylene spacers, were prepared by the reaction of 4‐amino‐4H‐1,2,4‐triazole‐3,5‐dithiol 12 with the appropriate bis(bromomethyl)benzenes 13a , 13b , 13c , 13d , 13e , 13f to give bis(4‐amino‐5‐mercapto‐4H‐3‐sulfanylmethyl)arenes 14a , 14b , 14c , 14d , 14e , 14f and subsequent reaction with phenacyl bromide. Compounds 15a , 15b , 15c , 15d , 15e , 15f were alternatively obtained in 60–70% yields by twofold substitution of 13a , 13b , 13c , 13d , 13e , 13f with two equivalents of 6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine‐3‐thiol 16 in refluxing EtOH/DMF mixture containing KOH. Bis(triazolothiadiazine) 22 attached to the benzene core through the thiadiazine ring via an amine linkage was prepared in 70% yield starting from p‐phenylenediamine 19 by, firstly, acylation with chloroacetyl chloride 18 followed by bis‐alkylation with 1,2,4‐triazole 20 and subsequent intramolecular ring closure upon treatment with phosphorus oxychloride.     

Synthesis of Bis{(S‐methyl)azolespoly(ethylene oxide)} from 3,6‐dioxa‐1,8‐octanedithiol

Bis(1,3,4‐oxadiazoles) 4 , 5 and bis(1,2,4‐triazoles) 6a , 6b have been prepared from 3,6‐dioxa‐1,8‐octanedithiol 1 through a multistep reaction sequence. Compound 4 reacted with the appropriate alkyl halide in the presence of potassium carbonate in refluxing acetone to give the corresponding bis(S‐alkylated‐1,3,4‐oxadiazoles) 7a , 7b . The title compound 8 was prepared by condensing 4 with benzoyl bromide in the presence of triethylamine. Further, 6,9‐dioxa‐3,12‐dithiotetradecanedihydrazide 3 was converted to bis{N′‐(phenylaminocarbonyl) hydrazides} and bis{N′‐(phenylaminocarbonothioyl)hydrazides} 9a , 9b using phenylisocyanate and phenylthioisocyanate, respectively, which underwent cyclization in alkaline medium to produce 6,9‐dioxa‐3,12‐dithiotetradecane bis(4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one) and their 3‐thio analogs 10a , 10b . The new compounds 4 , 5 , 6 , 7 , 8 , 9 , 10 were characterized by their IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analyses.     

Synthesis of 2,3,3a,9a‐Tetrahydro‐1H‐cyclopenta[b]quinoxaline‐1,3,4,9‐tetracarboxylate by Cyclization of 1,5‐Bis[(trimethylsilyl)oxy]penta‐1,4‐dienes with Quinoxalines

The cyclization of 1,5‐bis[(trimethylsilyl)oxy]penta‐1,4‐dienes with quinoxalines and chloroformates afforded 2,3,3a,9a‐tetrahydro‐1H‐cyclopenta[b]quinoxaline‐1,3,4,9‐tetracarboxylate.     

Synthesis of spiro‐pyrazole‐3,3′‐thiopyrano[2,3‐b]pyridines and azolo[a]pyrido[2′,3′:5,6]thiopyrano[3,4‐d]pyrimidines as new ring systems with antifungal and antibacterial activities

Reactions of 2,3‐dihydro‐4‐oxo‐thiopyrano[2,3‐b]pyridine with aldehydes and with DMF‐DMA furnished the 3‐benzylidene and 3‐(N,N‐dimethylamino)‐methylene derivatives. The latter products afforded spiro‐pyrazolo‐3,3′‐thiopyrano[2,3‐b]pyridines and new tetra‐ and penta‐heterocyclic ring systems when treated with nitrilimines and aminoazoles, respectively. A number of the products showed high antifungal and antibacterial activities.     

Heterocyclization reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines under appel's conditions

The reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines 12 with triphenylphosphine, carbon tetra‐chloride, and triethylamine (Appel's conditions) led to the corresponding carbodiimides 13 , which underwent intramolecular cycloaddition reaction with aziridine under the reaction conditions to give the pyridine‐fused heterocycles, 2,3‐dihydro‐1H‐imidazo[2′,3′:2,3]imidazo[4,5‐b]pyridines 16 and 12,13‐dihydro‐5H‐1,3 ‐benzodiazepino [2′,3′:2,3] imidazo[4,5‐b]pyridines 17 .     

Polycyclic N‐Heterocyclic Compounds,Part 69: Synthesis of 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridines and their transformations to related compounds

Reaction of 3‐(3‐cyanopropoxy)[1]benzofuran‐2‐carbonitriles with potassium tert‐butoxide gave 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridines and 5‐amino‐2,3‐dihydro[1]benzofuro[3,2‐b]oxepin‐4‐carbonitriles as new ring systems. Reactions of the 5‐chloro derivative, obtained from 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridine, produced a dihydrofuran ring‐opened compound and 5‐substituted compounds. J. Heterocyclic Chem.,(2011).     

Bis(enaminones) as Versatile Precursors for Novel Bis([1,2,4]triazolo[1,5‐a]pyrimidines) and Bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones)

Novel bis([1,2,4]triazolo[1,5‐a]pyrimidines) and bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones) were prepared utilizing bis(enaminones) as precursors. The structures of the prepared compounds were elucidated by several spectral tools as well as elemental analyses.     

Photoaddition of thiocarboxylic acids to 2,3‐diallyltetraazathiapentalenes

Photoirradiation of acetone solutions of 2,3‐diallyl‐6,7‐dihydro‐5H‐2a‐thia(2a‐S^IV)‐2,3,4a, 7a‐tetraazacyclopent[cd]indene‐ 1,4(2H,3H)‐dithione ( 1 ) in the presence of excess thioacetic acid and thiobenzoic acid afforded addition products, 2,3‐bis(3‐acetylthiopropyl)‐ and 2,3‐bis(3‐benzoylthiopropyl)‐6,7‐dihydro‐5H‐2a‐thia(2a‐S^IV)2,3,4a, 7a‐tetraazacyclopent[cd]indene‐1,4(2H,3H)‐dithiones, respectively, in good yields. These photoaddition reactions were facilitated by the addition of oxygen.