The Photochemical Mediated Ring Contraction of 4-1,2,6-Thiadiazines To Afford 1,2,5-Thiadiazol-3(2)-one 1-Oxides.

1,2,6-Thiadiazines treated with visible light and O under ambient conditions are converted into difficult-to-access 1,2,5-thiadiazole 1-oxides (35 examples, yields of 39-100%). Experimental and theoretical studies reveal that 1,2,6-thiadiazines act as triplet photosensitizers that produce O and then undergo a chemoselective [3 + 2] cycloaddition to give an endoperoxide that ring contracts with selective carbon atom excision and complete atom economy. The reaction was optimized under both batch and continuous-flow conditions and is also efficient in green solvents.

The Synthesis and Biological Applications of the 1,2,3-Dithiazole Scaffold.

The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a potential wealth of opportunities within these activities and further afield. The 1,2,3-dithiazole scaffold has already been reported as an antifungal, herbicide, antibacterial, anticancer agent, antiviral, antifibrotic, and is a melanin and Arabidopsis gibberellin 2-oxidase inhibitor.

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

A focused series of substituted 4-1,2,6-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.

Synthesis and Chemistry of Benzo[][1,2,6]thiadiazino[3,4-][1,4]diazepin-10(11)-ones and Related Ring Transformations.

2-[(3,5-Dichloro-4-1,2,6-thiadiazin-4-ylidene)amino]benzamides are cyclized to benzo[][1,2,6]thiadiazino[3,4-][1,4]diazepin-10(11)-ones via (i) treatment with NaH and via (ii) Pd-catalyzed C-N coupling. The behavior of the latter toward nucleophiles and thermal, oxidative, and reductive conditions revealed unexpected transformations to 3,5-dioxo-4,5-dihydro-3-benzo[][1,4]diazepine-2-carbonitrile and 2-(4-substituted-1,2,5-thiadiazol-3-yl)quinazolin-4(3)-ones.

The Conversion of 5,5'-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-]isothiazoles.

Thermolysis of 4,4'-dichloro-, 4,4'-diaryl-, and 4,4'-di(thien-2-yl)-5,5'-bi(1,2,3-dithiazol-ylidenes) affords the respective 3,6-dichloro-, 3,6-diaryl- and 3,6-di(thien-2-yl)isothiazolo[5,4-]-isothiazoles in low to high yields. The transformation of the 4,4'-diaryl- and 4,4'-di(thien-2-yl)-5,5'-bi(1,2,3-dithiazolylidenes) occurs at lower temperatures in the presence of the thiophiles triphenylphosphine or tetraethylammonium iodide. Optimized reaction conditions and a mechanistic rationale for the thiophile-mediated ring transformation are presented.

1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.

We demonstrate for the first time that 4-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.

Evaluation of PVP/Au Nanocomposite Fibers as Heterogeneous Catalysts in Indole Synthesis.

Electrospun nanocomposite fibers consisting of crosslinked polyvinylpyrrolidone (PVP) chains and gold nanoparticles (Au NPs) were fabricated, starting from highly stable PVP/Au NP colloidal solutions with different NP loadings, followed by thermal treatment. Information on the morphological characteristics of the fibers and of the embedded Au NPs was obtained by electron microscopy. Cylindrical, bead-free fibers were visualized by Scanning Electron Microscopy (SEM) while Transmission Electron Microscopy (TEM) and Energy Diffraction X-ray (EDX) analysis supported the presence of Au NPs within the fibers and gave information on their morphologies and average diameters.

The Acid and/or Thermal Mediated Ring Contraction of 4H-1,2,6-Thiadiazines To Afford 1,2,5-Thiadiazoles.

A near-quantitative acid and/or thermal mediated ring contraction of 3',5'-diarylspiro(benzo[d][1,3]dioxole-2,4'-[1,2,6]thiadiazines) affords 3-aryl-4-(2-arylbenzo[d][1,3]dioxol-2-yl)-1,2,5-thiadiazoles. The reaction scope was studied providing 11 examples of this ring contraction. A double Wagner-Meerwein reaction mechanism is proposed.

A Qualitative Comparison of the Reactivities of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine and 4,5-Dichloro-1,2,3-dithiazolium Chloride.

The high yielding transformations of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine into 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (up to 85%) and 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (up to 83%) have been investigated and compared to the analogous transformations of the closely-related 4,5-dichloro-1,2,3-dithiazolium chloride (Appel's salt) into 4-chloro-5H-1,2,3-dithiazol-5-one and 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile. Furthermore, cyclocondensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with 2-aminophenol and 1,2-benzenediamines gave fused 4H-1,2,6-thiadiazines in 68%-85% yields.

Synthesis of N-Aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines from 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine.

Condensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with a range of anilines gave 22 N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines in 43-96% yields. The scope and limitations of this condensation are briefly investigated. Furthermore, mono- and bis-substitution of the C-3 and C-5 chlorines of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-imine by amine and alkoxide nucleophiles is explored.

Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step.

Piperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r-3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product.

Stereoselective synthesis of densely functionalized pyrrolidin-2-ones by a conjugate addition/nitro-Mannich/lactamization reaction.

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield).

The reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with sulfimides: a new synthesis of N-aryl-1,2,3-dithiazolimines.

N-Aryl-S,S-dimethylsulfimides 3(Ar = 4-NO(2)C(6)H(4)), 4 (Ar = Ph) and 5 (Ar = 4-Tol)react with Appel salt 1 to give the corresponding N-aryl-(4-chloro-5H-1,2,3-dithiazolylidene)benzenamines 8 (Ar = 4-NO(2)C(6)H(4)), 9 (Ar = Ph) and 10 (Ar = 4-Tol) in 84, 94 and 87% yields, respectively. The reaction proceeds in the absence of base and a proposed reaction mechanism is given.