Substitution at C-4 in 3,5-disubstituted 4H-1,2,6-thiadiazin-4-ones

3,5-Diaryl-4H-1,2,6-thiadiazin-4-ones react with NaBH₄ to give the 3,5-diaryl-4H-1,2,6-thiadiazin-4-ols and with MeLi to give 4-methyl-3,5-diaryl-4H-1,2,6-thiadiazin-4-ols. The latter dehydrate with p-toluenesulfonic acid to give (3,5-diarylthiadiazin-4-ylidene)methanes. (3,5-Diphenyl-4H-1,2,6-thiadiazin-4-ylidene)methane 15 suffers mono bromination with NBS to give bromo(3,5-diphenyl-4H-1,2,6-thiadiazin-4-ylidene)methane 17. Dichloro- and dibromo(3,5-diphenyl-4H-1,2,6-thiadiazin-4-ylidene)methanes 18 and 19 are formed directly from the 3,5-diphenylthiadiazin-4-one 9 via the Appel reaction using Ph₃P and CCl₄ or CBr₄, respectively. 3,5-Diarylthiadiazin-4-ones treated with P₂S₅ give 3,5-diarylthiadiazine-4-thiones that react with tetracyanoethylene oxide to give the (thiadiazin-4-ylidene)malononitriles. Finally, the 3,5-diphenylthiadiazine-4-thione 20 reacts with ethyl diazoacetate to give ethyl 2-(3,5-diphenyl-4H-1,2,6-thiadiazin-4-ylidene)acetate 26. The above reactions show that a variety of substitutions at C-4 of 3,5-diaryl substituted 1,2,6-thiadiazin-4-ones can be achieved, which extends the potential applications of this heterocycle. All compounds are fully characterized and a brief comparison of their spectroscopic properties is given.     

Synthesis of 2-(4H-1,2,6-thiadiazin-4-ylidene)malononitriles

The base-free TiCl₄-mediated condensation of 3,5-disubstituted-4H-1,2,6-thiadiazin-4-ones 8 with malononitrile affords 20 difficult to access (3,5-disubstituted-4H-1,2,6-thiadiazin-4-ylidene)malononitriles 7. The reaction tolerates 3,5-diaryl, diphenoxy, dimethoxy and diphenylthio substituted thiadiazinones, but not diamino, monohydroxy or dihalo substituents. Nevertheless, asymmetrically substituted 3-halo-5-phenyl- and 3-chloro-5-methoxy-4H-1,2,6-thiadiazin-4-ones convert into the corresponding ylidenemalononitriles in good yield. Furthermore, the condensation works well with ethyl cyanoacetate and diethyl malonate, but not with Meldrum's acid, dimedone or nitromethane. Finally, 2-(3-chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (7q) reacts with aniline to give 4,7-diphenyl-6-(phenylimino)-6,7-dihydropyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitrile (12) in moderate yield demonstrating the potential use of these ylidenes to prepare novel 6–5 fused 4H-1,2,6-thiadiazines.     

Synthesis of asymmetric 3,5-diaryl-4H-1,2,6-thiadiazin-4-ones via Suzuki–Miyaura and Stille coupling reactions

Asymmetric 3,5-diaryl substituted 4H-1,2,6-thiadiazin-4-ones can be prepared from 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1) via a multi-step protocol: selective nucleophilic mono-chloro substitution gives either the mono-methoxy or benzyloxy substituted mono-chlorothiadiazinones that can be phenylated via Suzuki–Miyaura coupling. Subsequent BBr₃ mediated dealkylation gives 3-hydroxy-5-phenyl-4H-1,2,6-thiadiazin-4-one (9) that can be activated by a modified Finkelstein halodehydroxylation via the triflate, enabling further arylation reactions using Suzuki–Miyaura or Stille coupling chemistry.     

Selective Stille coupling reactions of 3-chloro-5-halo(pseudohalo)-4H-1,2,6-thiadiazin-4-ones

A series of 3-chloro-5-halo(pseudohalo)-4H-1,2,6-thiadiazin-4-ones (halo/pseudohalo = Br, I, OTf) are prepared from 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (3) in good yields. Of these the triflate reacts with tributyltin arenes (Stille couplings) chemoselectively to give only the 5-aryl-3-chloro-4H-1,2,6-thiadiazin-4-ones in high yields. This allowed the preparation of a series of unsymmetrical biaryl thiadiazines and ultimately a series of oligomers. Furthermore, treatment of 3-chloro-5-iodo-4H-1,2,6-thiadiazin-4-one (10) with Bu(3)SnH and Pd(OAc)(2) gave the bithiadiazinone which can also be further arylated via the Stille reaction to give bisthien-2-yl and bis(N-methylpyrrol-2-yl) analogs.     

Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors

A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.     

The synthesis of pyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitriles from (4H-1,2,6-thiadiazin-4-ylidene)malononitriles

[3,5-Bis(dialkylamino)-4H-1,2,6-thiadiazin-4-ylidene]propanedinitriles 6a-c, react with sodium methoxide or ethoxide to give the corresponding 6-alkoxy-4-dialkylamino substituted pyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitriles 7a-f in variable yields. These new compounds are fully characterised and two rational mechanisms are proposed for their formation.     

Palladium catalyzed C-C coupling reactions of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one

Palladium catalyzed Suzuki-Miyaura, Stille, and Sonogashira coupling reactions are reported for the electron-deficient heterocyclic scaffold 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1). Furthermore, 3,5-di(thien-2-yl)-4H-1,2,6-thiadiazin-4-one (7m) is further elaborated to afford the tetrathienyl 3,5-bis[(2,2'-bithien)-5-yl]-4H-1,2,6-thiadiazin-4-one (9). All compounds are fully characterized.     

Synthesis of isomeric N-substituted 5-methyl-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides from sulfamides and diketene

The reaction of N-n-butyl and N-benzylsulfamides with diketene in acetic acid solution in the presence of mercuric cyanide as a catalyst, afforded the corresponding 5-methyl-2-substituted-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides. The reaction of the above mentioned sulfamides with diketene in an aqueous alkaline medium resulted in the isolation of the corresponding N-aceto-acetyl-N' -substituted-sulfamides, which were then converted into 5-methyl-6-substituted-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides. Catalytic hydrogenation of the 5-methyl-2- and 6-n-butyl-2H-1,2,6-thiadiazin-3(6H)one 1,1-dioxides furnished the corresponding dihydro-derivatives. The structures of the isomeric 1,2,6-thiadiazine 1,1-dioxide derivatives obtained were assigned on the basis of nmr spectroscopic studies.     

Tetrahydro-2-thioxo-2H-1,3,5-thiadiazin-4-ones and their derivatives representing a novel heterocyclic ring system

The cyclization reaction between N-substituted dithiocarbamates ( 1 ) and N-substituted N-chloromethylcarbamoyl chlorides ( 2 ) gives 3,5-disubstituted tetrahydro-2-thioxo-2H-1,3,5-thiadiazin-4-ones ( 3 ). In order to decide among the theoretically possible structures 3-5 , the compounds 6a,b , containing a thioxo group instead of an oxo group as in 3a,b , as well as the S-oxide derivative of 3a was also established by X-ray structure determination.     

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.     

Synthesis of purine-like ring systems derived from 1,2,6-thiadiazine 1,1-dioxide

7-Amino-1H,4H-imidazo[2,3-c][1,2,6]thiadiazine 5,5-dioxide was prepared by a multi-step reaction sequence form 3,5-diamino-4H-1,2,6-thiadiazine 1,1-dioxide. 7-Amino-4H-furazano-[3,4-c][1,2,6]thiadiazine 5,5-dioxide was obtained by lead tetraacetate oxidation of 3,5-diamino-4-hydroxyimino-4H-1,2,6-thiadiazine 1,1-dioxide.     

4-bromo-5-methyl-(2H)-1,2,6-thiadiazin-3(6H)one 1,1-dioxides

The title compounds, bearing an alkyl and/or bromine substituent on nitrogen, were synthesized. Unlike 5-bromo-6-methyluracil, 4-bromo-5-methyl-(2H)-1,2,6-thiadiazin-3-(6H)one 1,1-dioxides have the ability to act as a bromonium ion source.     

Synthesis of 7-amirio-2H, 4H-vic-triazolo[4,5-c]-[1,2,6]thiadiazine 5,5-dioxides

7-Amino-2H,4H-vic-triazolo[4,5-c][1,2,6]thiadiazine 5,5-dioxide was prepared by two different ways from 3,4,5-triamirio-1,2,6-lhiadiazine 1, 1-dioxide and 3,5-diamino-4H-1,2,6-thia-diazine 1, 1-dioxide respectively. 7-A:nino-2-phenyl-4H-vic-triazolo[4,5-c] [1,2,6]thiadiazine 5,5-dioxide was obtained by lead telraacetate oxidation of 3,5-diamino-4-phenylazo-1, 2, 6-thiadiazine 1, 1-dioxide.     

Syntheses of pyrimidine and purine analogs derived from 1,2,6-thiadiazine 1,1-dioxide

5-Amino-3-oxo-2H, 4H-1,2,6-thiadiazine 1,1-dioxide and the monopotassium salt of 3,5-dioxo-2H, 4H,6H-1,2,6-thiadiazine 1,1-dioxide was obtained by condensation of sulfamide and ethyl cyanacetate and diethyl malonate, respectively. 7-Oxo-1H,4H,6H-imidazo[2,3-c]-1,2,6-thia-diazine 5,5-dioxide was prepared by a multi-step reaction sequence from 5-amino-3-oxo-2H, 4H-1,2,6-thiadiazine 1,1-dioxide.     

On the Synthesis of 2-Acetyl-4-aryl-6H-1,3,4-thiadiazin-5-ones by Reaction of Nitrilimines with α-Mercapto Alkanoic Acids

Summary.  N′-Arylacetonitrilimines were generated from acetohydrazonyl chlorides and reacted with mercaptoalkanoic acids forming 4-aryl-5-oxo-3-thiahexanoic acids. These were cyclized by reaction with dicyclohexyl carbodiimide yielding 2-acetyl-4-aryl-6H-1,3,4-thiadiazin-5-ones. Received November 13, 2001. Accepted January 9, 2002     

Two-step conversion of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine into 4,5,6-trichloropyrimidine-2-carbonitrile

Tin reduction of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine afforded perchloro-9-thia-1,5,8,10-tetraazaspiro[5.5]undeca-1,4,7,10-tetraene (10%) and 3,5-dichloro-4H-1,2,6-thiadiazine-4-thione (27%), the structures of which were supported by single crystal X-ray crystallography. Treating the tetrachlorothiadiazine with Ph₃P (1 equiv.) afforded the corresponding spirocycle in a useful 66% yield, the degradation of which with BnEt₃NCl (0.5 equiv.) afforded densely functionalized 4,5,6-trichloropyrimidine-2-carbonitrile in 81% yield. Rational mechanisms for the formation of products are proposed.     

The preparation of 3,5-disubstituted tetrahydro-4H-1,3,5-oxadiazine-4-thiones,tetrahydro-4H-1,3,5-thiadiazin-4-ones,and tetrahydro-4H-1,3,5-thiadiazine-4-thiones

The reaction of 1,3-disubstituted thioureas with formaldehyde under acidic conditions with removal of water yielded 3,5-disubstituted tetrahydro-4H-1,3,5-oxadiazine-4-thiones. When hydrogen sulfide was bubbled through the reaction mixture, the corresponding tetrahydro-4H-1,3,5-thiadiazine-4-thiones were formed. Similarly, starting from 1,3-disubstituted ureas, a number of tetrahydro-4H-1,3,5-thiadiazine-4-ones were prepared. The latter compounds were also oxidized to the corresponding sulfoxides and sulfones.     

Reductive coupling of hydantoins with benzophenones by low-valent titanium: Synthesis of 4-substituted 1H-imidazol-2(3H)-ones and unusual two-to-two coupled products

The reductive coupling of 1,3-dimethyhydantoin with benzophenones by TiCl₄-Zn in THF gave 4-diarylmethyl-1H-imidazol-2(3H)-ones as four-electron reduced one-to-one coupled products and their dimers as two-to-two coupled products predominantly by controlling the reaction conditions. The reductive coupling of 5-alkyl-1,3-dimethyhydantoins with benzophenones produced 5-alkyl-4-diarylmethyl-1H-imidazol-2(3H)-ones as the sole products irrespective to the reaction conditions. On the other hand, the reductive coupling of 1,3-dimethyhydantoin with cyclic benzophenones selectively 4-arylhydroxymethyl-1H-imidazol-2(3H)-ones as two-electron reduced one-to-one coupled products and they were further reduced to 4-diarylmethyl-1H-imidazol-2(3H)-ones.     

Synthesis and biotests of 2-aryl-5-arylmethylidene-substituted 1,3-oxazol-5(4<Emphasis Type="Italic">H</Emphasis>)-ones and <Emphasis Type="Italic">N</Emphasis>-methyl-3,5-dihydro-4<Emphasis Type="Italic">H</Emphasis>-imidazol-4-ones as combretastatin A-4 analogs

A series of 2-aryl-5-arylmethylidene-1,3-oxazol-5(4H)-ones and 2-aryl-5-arylmethylidene-N-methyl-3,5-dihydro-4H-imidazol-4-ones was synthesized as structural analogs of combret- astatin A-4 (a compound possessing antitumor activity). (5Z)-5-[(4-Methoxyphenyl)methyl-idene]-3-methyl-2-(4-methylphenyl)-3,5-dihydro-4H-imidazol-4-one was found to exhibit the highest cytotoxicity against cells of human A549 lung carcinoma line (EC₅₀ = 6±0.8 μmol L^?1).     

Synthesis 5-(pyrazolin-3-ylmethylidene)-2-thiohydantoins and 2-alkylsulfanyl-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro-4<Emphasis Type="Italic">H</Emphasis>-imidazol-4-ones

A reaction of 3-allyl- and 3-phenylthiohydantoins with 1,5-diphenyl- and 1-phenyl-substituted 3-formyl-2-pyrazolines was used to obtain a series of 5-(pyrazolin-3-ylmethylidene)-2-thioxotetrahydro-4H-imidazol-4-ones, the subsequent alkylation of which with methyl iodide or ethyl chloroacetate gave the corresponding 2-alkylthio-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro-4H-imidazol-4-ones in the yields from 30 to 77%. The oxidation of (5Z)-3-phenyl-5-[(1,5-diphenylpyrazolin-3-yl)methylidene]-2-methylsulfanyl-4,5-dihydroimidazol-4-one with lead tetraacetate led to the corresponding pyrazole in 48% yield.