Synthesis of new 1,2,4-triazolines and 1,3,4-thiadiazolines from bithioureas

2,4-Disubstituted thiosemicarbazides 1 react with acyl isothiocyanates to give bithioureas 2 , which by the action of sodium ethanolate cyclize to 1,2,4-triazoline-3-thiones 3 and 5 , respectively. Treatment of 2 with methyl iodide yields 1,3,4-thiadiazoline-2-imines 8 isomeric with 3 . Compound 8d undergoes a thermal induced DIMROTH rearrangement to give 3d in good yield.     

Reaction of 5-methyl-1,3,4-thiadiazoline-2-thione with molecular iodine

Russian Chemical Bulletin - The formation of the n-σ* complex of 5-methyl-1,3,4-thiadiazoline-2-thione with molecular iodine of the composition C3H4N2S2·I2 in dilute chloroform solutions...     

The Route of Alkylation of 5-Substituted 1,3,4-Thiadiazoline-2-thiones

The reaction of 5-anilino(toluidino-, morpholino)-1,3,4-thiadiazoline-2-thiones at 80°C with allyl bromide and benzyl chloride in alcohol, acetonitrile or DMF in the presence of KOH and also with phenoxymethyloxirane in alcohol in the absence of base gives the corresponding novel allyl-, benzyl-, and 2-hydroxy-3-phenoxypropyl products substituted at the exocyclic S atom. Alkylation of the indicated thiones with benzyl chloride at 150-153°C in DMF in the presence of KOH occurs similarly. Under these conditions, allyl bromide forms alkylation products at the endocyclic N(3) atom as a result of an SN thio-Claisen rearrangement of the initially formed product which is allyl substituted at the exocyclic S atom.     

Syntheses of substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles

Starting from readily available ethyl-4-nitropyrrole-2-carboxylate ( 1 ), substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles were prepared. The reaction of 1 with diazomethane gave ethyl 1-methyl-4-nitropyrrole-2-carboxylate ( 2 ). Reaction of compound 2 with hydrazine hydrate afforded the corresponding hydrazide 3 . The reaction of 3 with formic acid yielded 1-(1-methyl-4-nitropyrrole-2-carboxyl)-2-(formyl)hydrazine ( 7 ). Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 6 in 40% yield. Reaction of compound 7 with phosphorus pentoxide afforded compound 9 . Reaction of compound 3 with 1,1′-carboxyldiimidazole in the presence of triethylamine yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-oxadiazoline-4(H)-5-one ( 11 ). Refluxing compound 3 with cyanogen bromide in methanol gave compound 12 . Compound 13 could be obtained through the reaction of compound 3 with carbon disulfide in basic medium. Alkylation of compound 13 afforded the correspanding alkylthio derivative 14 . Reaction of 1-methyl-4-nitropyrrole-2-carboxylic acid ( 15 ) with thiosemicarbazide and phosphorus oxychloride gave 2-amino-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 16 ). Sandmeyer reaction of compound 16 yielded 2-chloro-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 17 ). Refluxing of the latter with thiourea afforded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazoline-4(H)-5-thione ( 18 ). Alkylation of compound 18 gave the corresponding alkylthio derivative 19 . Oxidation of the latter with hydrogen peroxide in acetic acid yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-5-methylsulfonyl-1,3,4-thiadiazole ( 20 ).     

Synthesis of aromatic polythioamide-oxothioxoquinazolines from bis(1,3,4-thiadiazoline-5-thione) and aromatic bis-o-amino esters

Aromatic polythioamide-oxothioxoquinazolines were synthesized by the polycondensation of 2,2′-(m-phenylene)bis-1,3,4-thiadiazoline-5-thione with aromatic bis-o-amino esters. The polymerizations were carried out at 160°C in acidic media such as m-cresol, sulfolane, and polyphosphoric acid to produce polymers with reduced viscosities up to 0.5 dL/g. These polymers were soluble in polar aprotic solvents like N-methyl-2-pyrrolidone and some acidic media including m-cresol. The polythioamide-oxothioxoquinazolines showed relatively good thermal stability with 10% weight loss at 344–394°C in air.     

Reactions with hydrazonoyl halides XXVIII*: Synthesis of some 2‐thiazolylimino‐2,3‐dihydro‐1,3,4‐thiadiazoles

Hydrazonoyl halides have been caused to react with each of methyl 5‐ethoxycarbonyl‐4‐methylthiazole‐2‐aminothiocarbamate, benzyl 5‐ethoxycarbonyl‐4‐methylthiazole‐2‐aminothiocarbamate, and 5‐ethoxycarbonyl‐4‐methylthiazol‐2‐ylphenylthiourea in the presence of triethylamine to give 2‐imino‐(5‐ethoxycarbonyl‐4‐methyl)thiazolyl‐2,3‐dihydro‐1,3,4‐thiadiazoles in good yields. Structures of the new compounds were elucidated on the basis of elemental analyses, spectral data, and alternative methods of synthesis whenever possible. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:213–217, 2000     

The reaction of 2-indolecarbohydrazones with ethoxycarbonyl chloride. New synthesis of 2,3-dihydro-2-oxo-1,3,4-oxadiazoles and 1,2,3,4-tetrahydro-4-oxo-5H-pyridazino[4,5-b]indoles

The synthesis of 2,3-dihydro-2-oxo-1,3,4-oxadiazole ( 4 ) and 5H-pyridazino[4,5-b]indole ( 7 ), are described. Compounds 4 were obtained by reduction of O-ethoxycarbonylcarbohydrazones 3 with sodium borohydride. Compounds 7 were obtained by cyclization of compounds with ethanol/hydrochloric acid and removing the ethoxycarbonyl group with hydrazine. Compounds 3 were obtained by reaction of 2-indolecarbohydrazones 1 with ethoxycarbonyl chloride.     

Reaction of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acyl isothiocyanates

The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acetyl, benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-substituted aminomethylphosphonic acids.     

Nucleosides. Part LI The 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) and 2-(2,4-dinitrophenyl)ethoxycarbonyl (dnpeoc) groups for protection of hydroxy functions in ribonucleosides and 2′ -deoxyribonucleosides

The Common 2′ -deoxypyrimidine and -purine nucleosides, thymidine ( 4 ), O⁴-[2-(4-nitrophenyl)ethyl]-thymidine ( 17 ), 2′-deoxy-N⁴-[2-(4-nitrophenyl)ethoxycarbonyl]cytidine ( 26 ), 2′-deoxy-N⁶-[2-(4-nitrophenyl)-ethoxycarbonyl]adenosine- 39 , and 2′-deoxy-N²-[2-(4-nitrophenyl)(ethoxycarbonyl]-O⁶-[2–4-nitrophenyl)ethyl]-guanosine ( 52 ) were further protected by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) and the 2-(2,4-dinitrophenyl)ethoxycarbonyl (dnpeoc) group at the OH functions of the sugar moiety to form new partially and fully blocked intermediates for nucleoside and nucleotide syntheses. The corresponding 5′-O-monomethoxytrityl derivatives 5 , 18 , 30 , 40 , and 56 were also used as starting material to synthesize some other intermediates which were not obtained by direct acylations. In the ribonucleoside series, the 5′ -O-monomethoxytrityl derivatives 14 , 36 , 49 , and 63 reacted with 2-(4-nitrophenyl) ethyl chloroformate ( 1 ) to the corresponding 2′,3′-bis-carbonates 15 , 37 , 50 , and 64 which were either detriylated to 16 , 38 , 51 , and 65 , respectively, or converted by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) treatment to the 2′,3′-cyclic carbonates 66 – 69 . The newly synthesized compounds were characterized by elemental analyses and UV and ¹H-NMR spectra.     

Reactions with cyclic amidines II. The behaviour of cyclic amidines toward ethoxycarbonyl and aroyl isothiocyanates

The behaviour of the aminopyrazole derivatives 1a-c, 2-amino-4-phenylthiazole (2) and 2-amino-5-phenyl-1,3,4-thiadiazole (3) toward the action of ethoxycarbonyl and benzoyl iso-thiocyanate is reported. The data clearly demonstrates the dependence of the nature of the products obtained from the reaction of isothiocyanates with cyclic amidines on the nature of the substituents on the heterocyclic ring.     

Benzomorphan related compounds. IV. The stevens rearrangement of a trimethoxybenzyl-1,2,5,6-tetrahydropyridinium salt

The potassium hydroxide-induced (Stevens) rearrangement of 1,3,4-trimethyl-1-(3,4,5-trimethoxybenzyl)-1,2,5,6-tetrahydropyridinium chloride (I) gives the desired 1,3,4-trimethyl-2-(3,4,5-trimethoxybenzyl)-1,2,5,6-tetrahydropyridine (III) and the Hofmann elimination product, N-methyl-N-(3,4,5-trimethoxybenzyl)-2,3-dimethyl-2,4-pentadienamine (II). In the presence of ethereal phenyllithium, the salt I undergoes rearrangement giving the expected tetrahydropyridine III in about 17% yield and four other products, N-(3,4,5-trimethoxybenzyl)methylamine (VI), 1,3,4-trimethyl-2-(6-methyl-2,3,4-trimethoxyphenyl)-1,2,5,6-tetrahydropyridine (IV), 1,3,3-trirnethyl-2-(3,4,5-trimethoxyphenyl)-4-rnethylenepiperidine (V) and 1,3,4-trimethyl-4-(3,4,5-trimethoxybenzyl)-1,4,5,6-tetrahydropyridine (VII), the latter being the 1,4-Stevens rearrangement product which cyclizes easily to β-2′,3′,4′-trimethoxy-2,5,9-trimethyl-7,8-benzomorphan (VIII). Their structures have been proved both by analytical and spectral data. A possible route for VIII and its stereochemical aspects are discussed.     

Nucleotides. Part XLVI. The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology

The application of the improved phosphoramidite strategy for the synthese of oligonucleotides using β-eliminating protecting groups to phospholipid chemistry offers the possibility to synthesize phospholipid conjugates of AZT ( 6 ) and cordycepin. The synthesis of 3′-azido-3′-deoxythymidine ( 6 ) was achieved by a new isolation procedure without chromatographic purification steps in an overall yield of 50%. Protected cordycepin ( = 3′-de-oxyadenosine) derivatives, the N⁶,2′-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin ( 12 ) and the N⁶,5′-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin ( 13 ) wre prepared by known methods and direct acylation of N⁶-[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin ( 9 ), respectively. These protected nucleosides and the 3′-azido-3′-de-oxythymidine ( 6 ) reacted with newly synthesized and properly characterized lipid-phosphoramidites 21–25 , catalyzed by 1H-tetrazole, to the corresponding nucleoside-phospholipid conjugates 26–38 in high yield. The deprotection was accomplished via β-elimination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in aprotic solvents to give analytically pure nucleoside-phospholipid diesters 39–51 as triethylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and UV and ¹H-NMR spectra.     

Novel regioselective synthesis of 3′H,4H‐spiro[chromene‐3,2′‐[1,3,4]thiadiazol]‐4‐one containing compounds

A variety of 3″,5″‐diaryl‐3″H,4′H‐dispiro[cyclohexane‐1,2′‐chromene‐3′,2″‐[1,3,4]thiadiazol]‐4′‐ones 3a‐c were synthesized regioselectively through the reaction of 4′H,5H‐trispiro[cyclohexane‐1,2′‐chromene‐3′,2″‐[1,3,4]oxadithiino[5,6‐c]chromene‐5″,1″′‐cyclohexan]‐4′‐one ( 1 ) with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a‐c ) in refluxing dry toluene. Single crystal X‐ray diffraction studies of 3a,b add support for the established structure. Similarly, 3′,5′‐diaryl‐2,2‐dimethyl‐3′H,4H‐spiro[chromene‐3,2′‐[1,3,4]thiadiazol]‐4‐ones 5a‐c were obtained in a regioselective manner through the reaction of 2,2,5′,5′‐tetramethyl‐4H,5′H‐spiro[chromene‐3,2′‐[1,3,4]oxadithiino[5,6‐c]chromen]‐4‐one ( 4a ) with nitrilimines under similar reaction conditions. On the other hand, reaction of 2,5′‐diethyl‐2,5′‐dimethyl‐4H,5′H‐spiro[chromene‐3,2′‐[1,3,4]oxadithiino‐[5,6‐c]chromen]‐4‐one ( 4b ) with nitrilimines in refluxing dry toluene afforded the corresponding 3′,5′‐diaryl‐2‐ethyl‐2‐methyl‐3′H,4H‐spiro[chromene‐3,2′‐[1,3,4]thiadiazol]‐4‐ones 5d‐f as two unisolable diastereoisomeric forms.     

Reaction with hydrazonoyl halides. Part 32 [1]: Reaction of C‐acyl‐N‐(3‐phenyl‐5‐pyrazolyl)hydrazonoyl chlorides with potassium thiocyanate and synthesis of some new 2,3‐dihydro‐1,3,4‐thiadiazoles and slenadiazoles

C‐acyl‐N‐(3‐phenyl‐5‐pyrazolyl)hydrazonoyl chlorides 1a,b react with potassium thiocyanate and potassium selenocyanate to give 5‐acyl‐2,3‐dihydro‐2‐imino‐3‐(3′‐phenyl)pyrazol‐5′‐yl)‐1,3,4‐thiadiazoles 2a,b and 5‐acetyl‐2,3‐dihydro;‐2‐imino‐3‐(3′‐phenyl)pyrazol‐5′‐yl)‐1,3,4‐selenadiazole 10a,b . Also, 2‐[mercapto‐(methylthio)methylene]indan‐1,3‐dione 16 reacts with hydrazonoyl halides 15 and 22–25 to afford 2,3‐dihydro‐1,3,4‐thiadiazoles 19 and 26–29 , respectively. Structures of the newly synthesized compounds are elucidated on the basis of spectral data, chemical transformations, and alternative synthesis methods. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:468–474, 2001     

Synthesis and characterization of some nitrogen heterocycles from d-galactose derivatives

The tetrazoles 5-(6′-acetamido-6′-deoxy-1′,2′:3′,4′-di-O-isopropylidene-D-glycero-α-D-galactohexopyranos-6′-yl)tetrazole ( 1 ) and 5-(6′-acetamido-6′-deoxy-1′,2′:3′,4′–di-O-isopropylidene-L-glycero-α-D-galacto-hexopyranos-6′-yl)-tetrazole ( 2 ) were synthesized by the 1,3-dipolar cycloaddition reaction of the epimeric α-acetamidonitriles 5 and 6 , respectively, with sodium azide. Reaction of tetrazole 1 with acetic anhydride in the presence of pyridine afforded the N-acetyl-1,3,4-oxadiazole derivative 3 and the N-acetylacetamido-1,3,4-oxadiazole derivative 7 . The N-acetylacetamido-1,3,4-oxadiazole derivative ( 8 ) was isolated when the tetrazole 2 was allowed to react under the same conditions. The physical and spectroscopic data of the five new compounds 1, 2, 3, 7 and 8 are presented.     

Chemistry of biureas—I: Cyclisation of ethoxycarbonyl derivatives of thiobiureas and bithioureas

The interaction of ethoxycarbonyl isothiocyanate with semicarbazides or thiosemicarbazides produces 1-ethoxycarbonyl-2-thiobiureas or bithioureas, respectively. The former are cyclisable to 2-ethoxycarbonamido-5-hydroxy-l,3,4-thiadiazole in acid, or to 2(H)-carbamoyl-3-hydroxy-5-alkylthio-1,2,4-triazoles, and thence to 3-hydroxy-5-mercapto-1,2,4-triazole in alkaline media. The ring-closure of the 1-ethoxycarbonylbithioureas proceeds similarly affording, under the influence of acids, 5-amino (or mercapto)-2-ethoxycarbonamido-1,3,4-thiadiazoles. The action of alkali produces compounds derived from 3-hydroxy-5-mercapto-1,2,4-triazole; the isolation, in a selected example, of the 2(H)-phenylthiocarbamoyl-derivative, elucidates the course of this reaction. Hydrazinolysis of 1-ethoxycarbonylbithiourea yields 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole.     

Nucleotides. Part XXXI. Modified Oligomeric 2′–5′ A Analogues: Synthesis of 2′–5′ oligonucleotides with 9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine and 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)adenine as modified nucleosides

A series of new 2′–5′ oligonucleotides carrying the 9-(3′-azido-3′deoxy-β-D-xylofuranosyl)adenine moiety as a building block has been synthesized via the phosphotriester method. The use of the 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) blocking groups for phosphate, amino, and hydroxy protection guaranteed straightforward syntheses in high yields and easy deblocking lo form the 2′–5′ trimers 21 , 22 , and 25 and the tetramer 23 . Catalytic reduction of the azido groups in [9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine]2′-yl-[2′-(O^p-ammonio)→ 5′]-[9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenin]-2′-yl-[2′-(O^p-ammonio)→ 5′]-9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine ( 21 ) led to the corresponding 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)-adenine 2′–5′ trimer 26 in which the two internucleotidic linkages are formally neutralized by intramolecular betaine formation.     

Microwave‐Assisted Expeditious Synthesis of Novel Carbazole‐Based 1,3,4‐Oxadiazoles

A microwave‐assisted expeditious synthetic route to novel carbazole‐based 1,3,4‐oxadiazoles is described. The reactions of 9‐ethylcarbazol‐3‐carbaldehyde with aroylhydrazines under microwave irradiation first gave intermediates, l‐aroyl‐2‐(9′‐ethylcarbazol‐3′‐yl‐methylidene)hydrazines, which were further treated with potassium permanganate in DMF under microwave irradiation to rapidly afford a series of 2‐aryl‐5‐(9′‐ethylcarbazol‐3′‐yl)‐1,3,4‐oxadiazoles in excellent yield.     

A regioselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-chromene thiadiazole derivatives

A variety of 4′-(4-R-phenyl)-4-(methylthio)-2′-phenyl-2′H-spiro[chromene-2,5′-[1,2,3]thiadiazole] 5a–d and 5′-(4-R-phenyl)-4-(methylthio)-3′-phenyl-3′H-spiro[chromene-2,2′-[1,3,4]thiadiazole] 6a–d were synthesized regioselectively through the reaction of 4-(methylthio)-2H-chromene-2-thione 2 with diarylnitrilimines under refluxing dry chloroform. Whilst the reaction of 4-(allylthio)-2H-chromene-2-thione 3 with diarylnitrilimines under similar reaction conditions afforded the corresponding 4-(allylthio)-5′-(4-R-phenyl)-3′-phenyl-3′H-spiro[chromene-2,2′-[1,3,4]thiadiazole] 7a–d and 5-(4-R-phenyl)-2′-methyl-3-phenyl-2′,3′-dihydro-3H-spiro[[1,3,4]thiadiazole-2,4′-thieno[3,2-c]chromene] 9a–d as two unisolable diastereoisomeric forms. The structures of the obtained spiro cycloadduct thiadiazoles have been assigned by means of spectroscopic measurements.     

Chemistry of amidrazones—IV : Addition-cyclisation of amidrazones with isocyanate esters and ethoxycarbonyl isothiocyanate

The interaction of amidrazones and isocyanate esters in dimethylformamide produces good yields of 4-substituted -1-imidoylsemicarbazides. They are unaffected by acids, but are cyclised to 3-alkyl (or aryl)-1,2,4-triazol-3-ones or their 4-substituted analogues in alkaline media. Analogous linear adducts arising in good yields from amidrazones and ethoxycarbonyl isothiocyanates are cyclised to 3-substituted 5-ethoxycarbonamido-1,3,4-thiadiazoles by acids, but are cleaved into small fragments by alkalis.