Ringerweiterung von sechs- zu neungliedrigen Heterocyclen: Umsetzung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin mit 3,4-Dihydro-2H-1,2,4-benzothiadiazin-3-on-1,1-dioxiden

Ring Enlargement of Six- to Nine-Membered Heterocycles: Reaction of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine with 3,4-Dihydro-2H-1,2,4-benzothiadiazin-3-one 1,1-Dioxides Reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) and N-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazin-3-one 1,1-dioxides ( 4 ) in CHCl₃ yields 3-(dimethylamino)-4,5,6,7-tetrahydro-1,2,5,7-benzothiatriazonin-6-one 1,1-dioxides 5 , a novel nine-membered heterocyclic system, by ring enlargement (Schemes 2 and 4). In refluxing MeOH, the heterocycle 5a rearranges to give the N-[1-methyl-1-(1,1-dioxo-4H-1,2,4-benzothiadiazin-3-yl)ethyl]-N′, N′-dimethylurea 10 . The three isomeric 2-(methylamino)benzenesufonamides 8,9 , and 11 (Scheme 3) are obtained by naBH₄ reduction of 5a and 10 , respectively. Mechanisms for the thermal isomerization 5a → 10 and the NaBH₄ reduction of 5a are proposed in Schemes 5 and 6.     

2H-1,2,4-benzothiadiazine 1,1-dioxides 2. A condensation of 2-aminobenzenesulfonamide with chloroalkyl isothiocyanates

A reaction of 2-aminobenzenesulfonamide ( 1 ) with 2-chloroethyl or 3-chloropropyl isothiocyanate in isopropanol afforded 2-(2′-chloroethylthioureido)- and 2-(3′-chloropropylthioureido)benzenesulfonamides ( 2a,b ) in 67% and 55% yield respectively. Treatment of 2a,b with triethylamine in methanol at room temperature furnished 3-(2′-aminoethylthio)- and 3-(3′-aminopropylthio)-2H-1,2,4-benzothiadiazine 1,1-dioxides ( 9a,b ) in quantitative yield. Heating 2b to reflux in methanol under neutral conditions gave 9b but in the form of the hydrochloride 8b which could be converted into the free base 9b by treating with ammonia water. When compounds 2a,b were treated with triethylamine in methanol at elevated temperature, 3-(2′-mercaptoethylamino)- and 3-(3′-mercaptopropylamino)-2H-1,2,4-benzothiadiazine 1,1-dioxides ( 10a,b ) were obtained in good yield. Alternatively, 10a,b could also be prepared from 9a,b in 95% and 77% yield respectively.     

An anomalous acylation of an aminobenzenesulfonamide

Acylation of 2-amino-4-chlorobenzenesulfonamide by 2-acetoxyisobutyryl chloride under acidic conditions unexpectedly gave 6-chloro-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide and 8-ehloro-2,2,3a-trimethyl-3a,4-dihydrooxazolo[2,3-b] [1,2,4]benzothiadiazin-1-one 5,5-dioxide, the skeletons of which incorporate the carbon atom of the acetoxyl carbonyl group of the acid chloride.     

Synthesis of 4-β-D-arabinofuranosyl-5,6-dihydro-2H-1,2,4-thiadiazin-3-one 1,1-dioxide and x-ray diffraction analysis of its 2′,3-anhydro precursor

Reaction of 2-amino-3′,5′-bis(O-tert-butyldimethylsilyl)-β- D -arabinofuran[1′,2′:4,5]-2-oxazoline with 2-chloroethylsulfonyl chloride in the presence of sodium bicarbonate followed by removal of the protecting groups gave 2′,3-anhydro-4-β- D -arabinofuranosyl-5,6-dihydro-2H-1,2,4-thiadiazin-3-one 1,1-dioxide ( 5 ), which by treatment with ammonia was converted to 4-β- D -arabinofuranosyl-5,6-dihydro-2H-1,2,4-thiadiazin-3-one 1,1-dioxide ( 6 ). The structure of compound 5 was unequivocally established by means of an x-ray diffraction analysis. The compound crystallized in the space group P2₁2₁2₁ with unit cell dimensions a = 5.883(3), b = 9.352(2), c = 18.769(7) Å, Z = 4. Its structure was established by direct multisolution techniques and refined by the full matrix least squares method to a final R value of 0.058 for the 1515 reflections observed.     

Synthesis and reduction of some 1H-2,1,3-benzothiadiazin-4(3H) one 2,2-dioxides

Several 2,1,3-benzothiadiazin-4(3H) one 2,2-dioxides were synthesized as possible sweetening agents by reacting sulfamoyl chloride with various anthranilic acid derivatives. The isolation of 1-methyl-4-methoxy-2,1,3-benzothiadiazine 2,2-dioxide and preparation of 3,4-dihydro-2,1,3-benzothiadiazine 2,2-dioxide is also reported.     

The mass spectrometic fragmentation patterns of some biologically active derivatives of 2H-1,2,4-benzothiadiazine 1,1-dioxides

The mass spectra of some twenty-six derivatives of 2H-1,2,4-benzothiadiazine 1,1-dioxide are discussed. All compounds studied follow relatively simple fragmentation routes; as a consequence the fragmentation pattern gives a clear guide to the structure of the compound under investigation.     

Acetylenic chemistry. Part 17 Acetylenic amides as precursors for the synthesis of 3-propynylquinazolinones

Cyclocondensation of acetylenic amides with triethylorthoformate and triethylorthoacetate in boiling glacial acetic acid under nitrogen gave 3-propynylquinazolinones. 2-Ethoxy-2-methyl-3[1,1-dimethylpropynyl]quinazolin-4(1H,3H)-one ( 3b ) and 2-ethoxy-2-methyl-3-[1-cyclohexylpropynyl]quinazolin-4(1H,3H)-one ( 3c ) in refluxing ethanolic sodium hydroxide afforded the corresponding oxazoloquinazolinones.     

Synthesis of 4-substituted 3-hydroxy-and 3-amino-6H-1,2,6-thiadiazine 1,1-dioxides

Reaction of sulfamide with ethoxymethylene derivatives yielded 4-ethoxycarbonyl-, 4-cyano-, and 4-nitro-2H,6H-1,2,6-thiadiazine 1,1-dioxide. In some cases, the corresponding open chain sulfamidomethylene derivatives were isolated. Preparation of 4-amino- and 4-amino-5-methyl-2H,6H-1,2,6-thiadiazin-3-one 1,1-dioxide is also described. Reaction of sulfamide with ethyl 3,3-ethoxypropionate afforded 3,7-bis(etlioxycarbonylmethyl)perhydro-1,5,2,4,6,8-dithiatetra-zocine 1,1,5,5-tetroxide.     

Über neue tetracyclische Ringsysteme, 1. Mitt.: Synthese und Derivate des 11-Oxo-11H-isoindolo[1,2-c] (1,2,4)-benzothiadiazin-5,5-dioxids

Zusammenfassung Es wurden neue tetracyclische 1,2,4-Benzothiadiazin-Derivate dargestellt und deren Konstitution wahrscheinlich gemacht. Durch Kondensation von Phthalsäure mit o-Aminobenzolsulfonamid wurde das 11-Oxo-11H-isoindolo[1,2-c] (1,2,4)-benzothiadiazin-5,5-dioxid erhalten, das durch Reduktion mit NaBH₄ und anschließende Acetylierung in sein 6,6a-Dihydro- bzw. 6,6a-Dihydro-6-acetyl-Derivat übergeführt wurde. Durch Verwendung eines entsprechend substituierten o-Amino-benzolsulfon-amids wurde das 2-Chlor-3-sulfamyl-Derivat des neuen Ring-systems erhalten, das als potentielles Diureticum von Interesse ist.

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New tetracyclic 1,2,4-benzothiadiazine derivatives were produced and their constitution postulated. Condensation of phthalic acid with o-amino-benzenesulphonic acid amide yielded 11-oxo-11H-isoindolo[1,2-c](1,2,4)-benzothiadiazine-5,5-dioxide which, upon reduction with NaBH₄ and subsequent acetylation was converted to its 6,6a-dihydro- and 6,6a-dihydro-6-acetyl derivative respectively. By utilizing a suitably substituted o-aminobenzenesulphonic acid amide the 2-chloro-3-sulfamyl derivative of the new ring system was obtained which is of interest as a potential diuretic.

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Herrn Prof. Dr.H. Bretschneider zum 60. Geburtstag gewidmet.     

Studies on 1, 2, 4-Benzothiadiazine 1, 1-Dioxide IX.1 Synthesis and Pharmacological Evaluation of 1, 2, 4-Benzothiadiazine 1, 1-Dioxide Biphenyl Tetrazoles as Angiotensin II Antagonists

In the course of our investigations on the development of cardiovascular agents, 3-butyl-2-[2′-(2H-tetrazol-5-yl)bipheny]-4-yl]methyl-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide ( 2 ) was considered as a potential angiotensin II antagonist on the basis of bioisosteric replacement of the quinazoline ring of compound 1 with a 1, 2, 4-benzothiadiazine 1, 1-dioxide ring system. Alkylation of 6 with 4 afforded 7 and 8 in 24% and 28% yields, respectively. An attempt to remove the trityl group of compounds 7 and 8 under acidic condition gave the ring opened products 9 and 11 in 28% and 36% yields, respectively. However, compounds 2 and 10 were obtained in 46% and 85% yields when compounds 7 and 8 were refluxed in methanol. Preliminary assays of compounds 9 and 11 against angiotensin II receptors revealed weak activity with IC₅₀ values of 3.6 μM and 5.4 μM, respectively. Compound 10 (IC₅₀ = 87 nM) exhibited stronger binding affinity than compound 2 (IC₅₀ = 750 nM).     

A Ring Enlargement from Seven- to Ten-Membered-Ring sulfonamide derivatives

The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1a ) with 4,5-dihydro-7,8-dimethoxy-1,2-benzothiazepin-3-one 1,1-dioxide ( 4 ) in dioxane at room temperature gave the correspondingly substituted 4H-1,2,5-benzothiadiazecin-6-one 1,1-dioxide 5a in 64% yield (Scheme 2). The structure of this novel ten-membered ring-enlargement product was established by X-ray crystallography (Fig.). Under more vigorous conditions (refluxing dichloroethane), 5a was formed together with the isomeric 6a , both in low yield. The 3-(dimethylamino)-2H-azirines 1b and 1c reacted sluggishly to give the two isomeric ring-enlargement products of type 5 and 6 in yields of 24–29% and 2–4%, respectively (Table 1). Even less reactive is 2,2-dimethyl-3-(N-methyl-N-phenylamino)-2H-azirine ( 1d ), which reacted with 4 in MeCN only at 65°. Under these conditions, besides numerous decomposition products, only traces of 5d and 6d were formed. No ring enlargement was observed with the sterically crowded 1e , which bears an isopropyl group at C(2).     

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.     

AN UNUSUAL ADDITION AND RING-CLOSURE REACTION OF 1-(2-BROMOETHYL)-2,3-DIHYDRO- 3-PROPYL-1,3,2-BENZO-DIAZAPHOSPHORIN-4(1H)-ONE 2-OXIDE WITH CARBON DISULFIDE FOR A NEW AND CONVENIENT SYNTHESIS OF THE FUSED PHOSPHORUS HETEROCYCLIC COMPOUND

ABSTRACT

The reaction of 1-(2-bromoethyl)-2,3-dihydro-3-propyl-1,3,2-benzodiazaphosphorin-4(1H)-one 2-oxide with carbon disulfide takes an alternative pathway in the use of different bases. The sodium hydride mediated reaction leads to the formation of the tricyclic fused 1,2,3,4,4a,4b,5,6-octahydro-6-oxo-5-propyl-4-thia-3,4b,4a-thiazphosphaphenanthridine 4a-oxide via addition of H-P bond across the double bond of carbon disulfide followed by intramolecular cyclization. In the presence of triethylamine, refluxing a mixture of 1-(2-bromoethyl)-2,3-dihydro-3-propyl-1,3,2-benzodiazaphosphorin-4(1H)-one 2-oxide with carbon disulfide in benzene takes an unusual course with formation in excellent yield of the first example of fused phosphorus heterocyclic 4-[1′-(β-bromoethyl)-4′-oxo- 3′-propyl-1′,2′,3′,4′-tetrahydro-1,3,2-benzodiazaphosphorin-2′- sulfide]-1,2,3,4,4a,4b,5,6-octahydro-6-oxo-5-propyl-3,4b, 4a-thiazphosphaphenanthridine 4a,2′-dioxide, which was confirmed by spectroscopic methods, microanalyses and single crystal X-ray structure determination.     

Synthesis and chemical properties of cyclic β-keto sulfones (review)

Published data on the synthesis and chemical properties of dihydrothiophen-3(2H)-one 1,1-dioxide, dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide, 1-benzothiophen-3(2H)-one 1,1-dioxide, and 1H-isothio-chromen-4(3H)-one 2,2-dioxide are reviewed. The choice of subjects was based on the presence of identical structural fragments, carbonyl, active methylene, and sulfonyl groups.     

Synthesis of 3-carboethoxy-4,11-dihydro-11-alkyl/phenyl-4-oxopyrimido[1,2-b][1,2,4]benzothiadiazine 6,6-dioxides. A novel heterocyclic ring system

The synthesis of some novel 3-carboethoxy-4,11-dihydro-11-alkyl/phenyl-4-oxopyrimido[1,2-b][1,2,4]benzo-thiadiazine 6,6-dioxides ( IVa-c ) from 3-amino-4-alkyl/phenyl-4H-1,2,4-benzothiadiazine 1,1-dioxides ( 1a-c ) and diethyl ethoxymethylenemalonate ( II ) is described. The compounds have been screened for their antibacterial activity.     

Synthesis of certain 1,2,4-triazole nucleoside derivatives

The syntheses of 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and its 2′-deoxy analog 8b as well as 5-amino-2-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-3-one ( 12 ) have been accomplished. Compounds 8a and 8b were synthesized via glycosylation of 3-bromo-5-nitro-1,2,4-triazole which was followed by replacement in three steps of the 3-bromo function to yield 3-nitro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 4a ) and its 2′-deoxy analog 4b . Compounds 4a and 4b were methylated at N², hydrogenated and deblocked to give 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and the 2′-deoxy analog 8b . Compound 12 was synthesized by glycosylation of 3-amino-1-methyl-1,2,4-triazolin-5(2H)-one ( 10 ). The structures of 8b and 12 were confirmed by single crystal X-ray diffraction analysis.     

Synthesis of 2H-1,4-thiazin-3(4H)-one 1-oxide and 2H-1,4-thiazin-3-(4H)-one 1,1-dioxide,structural analogs of uracil

The synthesis of 1,4-thiazine 1-oxide and 1,1-dioxide analogs of the antibiotic emimycin is described. Reaction of methylthioglycolate with 1-bromo-2,2-diethoxyethane gave methyl (2,2-diethoxyethylthio)acetate ( 2 ). Treatment of 2 with methanolic ammonia followed by cyclization furnished 2H-1,4-thiazin-3(4H)-one ( 5 ). Oxidation of 5 with m-chloroperoxybenzoic acid converted it to 2H-1,4-thiazin-3(4H)-one 1-oxide ( 6 ). Oxidation of 2 with potassium permanganate, followed by treatment with methanolic ammonia, and cyclization gave 2H-1,4-thiazin-3(4H)-one 1,1-dioxide.     

1,2,4-Triazines. 8. Reduction of 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride. Regioselective preparation of dihydro-1,2,4-triazin-5(4H)-ones

Reduction of 3-methylthio-1,2,4-triazin-5(4H)-one ( 1a ) with sodium borohydride afforded 3-methylthio-1,6-dihydrotriazin-5(4H)-one ( 2b ) selectively. 3-Methylthio-6-t-butyl-1,2,4-triazin-5(4H)-one ( 1d ) reacted with sodium borohydride to give mainly 6-t-butyl-2,3-dihydro-1,2,4-triazin-5(4H)-one ( 3d ). The reaction of various 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride and the influence of bulkiness and electronic effect of the substituents at the 3- and 6-positions upon the product ratio, are also discussed.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Pyrrole-Annulated Heterocyclic Systems. Synthesis of 2H-Pyrrolo[3,4-b][1,5]benzothiazepine 4,4-Dioxide Derivatives

Condensation of 2-nitrothiophenol with ethyl propiolate afforded 3-(2-nitrophenylthio)propenoate. Oxidation of sulfur atom to sulfone group gave ethyl 3-(2-nitrophenylsulfonyl)propenoate, which underwent condensation with tosyl methylisocyanide (TosMIC) to yield ethyl 4-(2-nitrophenylsulfonyl)pyrrole-3-carboxylate. Reduction of nitro group afforded ethyl 4-(2-aminophenylsulfonyl)-1H-pyrrole-3-carboxylate, which was cyclized to 2H-pyrrolo[3,4-b][1,5] benzothiazepin-10(9H)-one 4,4-dioxide. Similar procedure was used for the synthesis of 9,10-dihydro-10-methyl-2H-pyrrolo[3,4-b][1,5]benzothiazepine 4,4-dioxide.