Efficient synthesis of 1,2,4-dithiazolidine-3,5-diones [dithiasuccinoyl-amines] from bis(chlorocarbonyl)disulfane plus bis(trimethylsilyl)amines

The 1,2,4-dithiazolidine-3,5-dione heterocycle, also referred to as a dithiasuccinoyl (Dts)-amine, serves as a readily removable amino protecting group for building blocks used in syntheses of peptides, glycopeptides, and PNA; it is also useful as a masked isocyanate and (inversely) as a sulfurization reagent for trivalent phosphorus. Bis(chlorocarbonyl)disulfane, the two-sulfur analogue of succinyl chloride, has been envisioned as a reagent for facile single-step elaboration of the heterocycle. However, reactions of bis(chlorocarbonyl)disulfane directly with primary amines fail to yield Dts-amines for reasons that are discussed. Inspired by several precedents from the organosilicon chemistry literature that a trimethylsilyl group may serve as a "large proton," a successful, high-yield preparation of Dts-amines through reactions of bis(chlorocarbonyl)disulfane with bis(trimethylsilyl)amines has been developed. Studies aimed at elucidating mechanistic reasons for these observations are also presented.     

Synthetic and structural studies on 1,2,4-dithiazolidine-3,5-dione derivatives

Methods have been developed for the N-alkylation of 1,2,4-dithiazolidine-3,5-dione 2 and the subsequent conversion of the N-alkylated derivatives into isocyanates 5. An extension of this methodology onto a solid-support is also reported. X-ray crystallographic analysis has been carried out on potassium 1,2,4-dithiazolidine-3,5-dione 3 for structural comparison with the parent heterocycle 2.     

Efficient synthesis of 1,2,4-dithiazolidine-3,5-diones (dithiasuccinoyl-amines) and observations on formation of 1,2,4-thiadiazolidine-3,5-diones by related chemistry

An efficient synthesis of 1,2,4-dithiazolidine-3,5-diones ( 1 ) from chlorocarbonylsulfenyl chloride ( 3 ) plus O-dimethylaminoethyl-N-alkyl or aryl thiocarbamates ( 4 ) has been worked out. In this synthesis, 1,2,4-thiadiazolidine-3,5-diones ( 5 ) have been shown to arise as low-level by-products, and experiments were conducted to elucidate the mechanism of the side reaction. N,N′-Dimethyl-1,2,4-thiadiazolidine-3,5-dione ( 5a ) was prepared in one step from N,N′-dimethylurea plus 3 , or from 4a plus one equivalent of sulfuryl chloride. A general route to 5 involved reaction of equimolar amounts of isocyanates ( 6 ), isothiocyanates ( 7 ) and sulfuryl chloride followed by hydrolysis of intermediate 9 . Heterocycles reported have been characterized by nmr, ir, uv, ms, and hplc.     

Multiple reactivity of freund's “methyl isothiocyanate sulfide” in cycloaddition-elimination reactions

4-Methyl-5-methylimino-1,2,4-dithiazolidine-3-thione ( l )and 2,4-dimethyl-1,2,4-thiadiazolidine-3,5-dithione ( 2 ) are interconvertible in acetone at 50°. They react with ketenes and electrophilic acetylenes to give the thiazole derivatives 6 and 7 after elimination of methyl isothiocyanate or carbon disulfide. Electrophilic isothiocyanates and phenylsulfonyl isocyanate transform the C = S function of 1 in an imine function ( 8 ), and a similar transformation of the thiourea C = S function of 2 is observed on reaction with phenylsulfonyl isocyanate, giving 9 .     

Reactions of 3,5-dibromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with NH-azoles

Reactions of 3,5-dibromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with 3,5-dimethylpyrazole, 1,3-dimethyl-3,7-dihydropurine-2,6-dione, 3,5-dibromo-1,2,4-triazole, 2,4,5-tribromoimidazole, and 2-chlorobenzimidazole lead to the formation of 5-azolylmethyl-2-bromo-5,6-dihydrothiazolo[3,2-b]-1,2,4-triazoles. In the case of 8-bromo-1,3-dimethyl-3,7-dihydropurine-2,6-dione the intermediate thiolate anion undergoes cyclization into 7-[(3,5-dibromo-1,2,4-triazol-1-yl)methyl]-1,3-dimethyl-6,7-dihydrothiazolo[2,3-f]purine-2,4(1H,3H)-dione. The structure of reaction products depends on the relative rate of substitution of leaving groups in the reagents.     

Reactions of 4-phenyl-1,2,4-triazoline-3,5-dione with 2-pyrazolines

4-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) acts as an efficient Michael acceptor in reactions with 1-unsubstituted 2-pyrazolines, giving substituted (3,5-dioxo-4-phenyl-1,2,4-triazol-idin-1-yl)-1-pyrazolines in quantitative yields. Through elimination of molecular nitrogen, the latter are easily transformed into the corresponding cyclopropanes. A reaction of methyl 5-methyl-2-pyrazoline-5-carboxylate with a twofold excess of PTAD leads to an intermediate bisadduct, which undergoes dediazotization to form a 1,3,5-triazabicyclo[3.3.0]octane-2,4-dione derivative. 1-Substituted 2-pyrazolines also add to PTAD with the exception that the 2-pyrazoline structure is retained in the product because of the migration of the C(3)H proton to PTAD.     

Synthesis of 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one. Derivatives and their ring transformation into 5-benzamido-1,2,4-triazolidine-3,5-dione derivatives

Some 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one derivatives 6 and 9 have been synthesized in two ways. The expected thermal ring transformation into 2,5-disubstituted 1,3,4-oxadiazoles did not occur but, by acid hydrolysis of 5-aryl-3-[3-benzylidene-2-methyl(or phenyl)carbazoyl]-1,3,4-oxadiazol-2(3H)-ones 6 , a new ring transformation took place and the corresponding 4-benzamido-1-methyl(or phenyl)-1,2,4-triazolidine-3,5-dione derivatives 11 were formed. The 4-amino-1-phenyl-1,2,4-triazolidine-3,5-dione ( 19 ) has been prepared and its structure was confirmed by some reactions.     

Reaktionen vonN-Sulfinylverbindungen mit dem 1,2,4-Trithia-3,5-diborolan-Ringsystem und Substitutionsreaktionen am 1,2,4-Trithia-3,5-diborolan und 1,2-Dithia-4-aza-3,5-diborolidin

The reaction of trimethylsilyl- and pentafluorophenyl-N-sulfinylamine respectively with 3,5-dihalogeno-1,2,4-trithia-3,5-diborolanes yields the 1,2-dithia-4-aza-3,5-diborolidines1-3.Tert-butyl-N-sulfinylamine and 3,5-dimethyl-1,2,4-trithia-3,5-diborolane react analogous. OtherN-sulfinylamines however split the disulfane bridge in 3,5-dimethyl-1,2,4-trithia-3,5-diborolane and the 1,4-dithia-2-aza-3,5-diborolidines5A-7(A) are formed. Besides of boroxines, cyclo-2,4,6-trimethyl-1,3-dioxa-5-aza-2,4,6-triboranes and cyclo-2,4,6-trimethyl-1-oxa-3,5-diaza-2,4,6-triboranes are formed as byproducts,8–10 have been isolated. In 1,2,4-trithia-3,5-diborolanes and 1,2-dithia-4-aza-3,5-diborolidines the bromo-atoms can be substituted by alkyl (13, 14), by amino (15–20) and by isothiocyanato groups. The compounds were characterised analytically and spectroscopically (MS; NMR:¹H,¹¹B,¹⁹F,²⁹Si; IR).

     

Unusual reactivity of N-acyl imides: N-aroyl-1,2,4-dithiazolidine-3,5-diones as acyl isocyanate equivalents

Crystalline samples of three N-aroyl-1,2,4-dithiazolidine-3,5-diones have been prepared as the first examples of a novel class of compound that displays the reactivity of an acyl isocyanate when treated with nucleophiles.     

Biomimetic oxidation of metribuzin with hydrogen peroxide catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides

The biomimetic oxidation of metribuzin, a pre- and post-emergence herbicide with hydrogen peroxide catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides [TAPFe(III)Cl], has been studied yielding 6-t-butyl-3-methylthio-1,2,4-triazine-5(4H)-one, 4-amino-6-t-butyl-3,5(2H,4H)-dione and 6-t-butyl-1,2,4-triazin-3,5(2H,4H)-dione under various reaction conditions.     

Polymer-supported 1,3-oxazolium-5-olates: synthesis of 1,2,4-triazoles

A traceless synthesis of 3,5-disubstituted 1,2,4-triazoles has been developed on polymeric supports. The synthetic process utilizes immobilized mesoionic 1,3-oxazolium-5-olates (munchnones) as key intermediates in the 1,3-dipolar cycloaddition reaction. The initial step in the synthesis involves reductive alkylation of phenylglycine methyl esters with Ameba resin. The resulting immobilized amino acid esters were subsequently acylated with a variety of carboxylic acid chlorides and subjected to hydrolysis with 15% KOH to yield the polymer-bound carboxylic acids. Finally, the cycloaddition between diethyl diazocarboxylate or 4-phenyl-4H-1,2,4-triazoline-3,5-dione and the polymer-bound munchnones generated from the corresponding carboxylic acids afforded the polymer-bound 3,5-disubstituted 1,2,4-triazoles. Cleavage from the polymeric support using trifluoroacetic acid gave the desired 3,5-disubstituted 1,2,4-triazoles with excellent yield and high purity.     

Trapping of benzene oxide-oxepin and methyl-substituted derivatives with 4-phenyl- and 4-pentafluorophenyl-1,2,4-triazoline-3,5-dione

4-Phenyl-1,2,4-triazoline-3,5-dione and its pentafluoro analogue are efficient reagents for trapping arene oxides, e.g. benzene oxide-oxepin, affording crystalline adducts that can be quantitatively analysed by HPLC and MS techniques.     

Synthetic Approach to 6-Benzoyl-2H-[1,2,4]triazine-3,5-dione and 6-Benzyl-5-thioxo-3,4-dihydro-2H-[1,2,4]triazin-3-one and Studies on Their Transformation to Fused[1,2,4]triazine Systems

Reaction of phenylpyruvic acid with semicarbazide afforded 6-benzyl-2H-[1,2,4]triazine-3,5-dione ( 1 ) which upon oxidation with potassium dichromate furnished 6-benzoyl-2H-[1,2,4]triazine-3,5-dione ( 2 ) in good yield. Constructing pyrazolo[3,4-e][1,2,4]triazine system ( 4 ) was achieved by reacting 2 with arylhydrazines in ethanolic solution. However treatment of 2 with the less reactive heteroarylhydrazines gave only the corresponding hydrazones ( 3 ). Attempt for constructing 1,2,4,5,10-pentaaza-dibenzo[a,d]cyclohept-3-one ( 7 ) from 2 was failed and (benzoimidazol-2-yl) [1,2,4] triazine derivative ( 6 ) was the only product. Reaction of 1 with phosphorus pentasulphide afforded compounds 8 and 9 . Compound 8 was transformed to the hydrazino compound 14 , which led to the construction of triazolo[4,3-d] [1,2,4]triazine system. Thus compounds 15 and 16 were obtained by reacting 14 with carbon disulfide or acetic anhydride respectively. Attempt to couple 8 with chloroacetic acid failed, while it's known isomer 10 led to the formation of thiazolo [2,3-c] [1,2,4]triazine derivative ( 13 ). Simple theoretical calculation using AM1 and PM3 semiempirical Hamitonian provided rational ways to correlate the reactivity with structure proposed.     

Pressure,temperature, and solvent effects on the rates of reactions of 3,4-dihydro-2H-pyran with tetracyanoethylene and 4-phenyl-1,2,4-triazoline-3,5-dione

Russian Chemical Bulletin - The effects of high hydrostatic pressure, temperature, and solvent on the rates of reactions of tetracyanoethylene (1) and 4-phenyl-1,2,4-triazoline-3,5-dione (2) with...     

Studies on the syntheses of azole derivatives. Part IX. Formation of 2,4-disubstituted δ2 -1,3,4-oxadiazolin-5-one and 4-substituted 1,2,4-triazolidin-3,5-dione derivatives by thermal reaetion of N-aryl-N-benzylearbamoyl azides

The structure of the novel produets, 2,4-ltis-(N-benzy1-4-nitroanilino)-Δ²-1,3,4-oxadiazolin-5-one (VII), 2-benzy1-1-(N-benzy1-4-chloroanilino)-4-(4-chlorophenyl)-1,2,4-triazolidin-3,5-dione (XIVa), and 2-benzy1-1-(N-benzylanilino)-4-pheny1-1,2,4-triazolidin-3,5-dione (XIVb), obtained upon thermal reaction of N-bcnzyl-N-(4-nitrophenyl)carbamoyl azide (la), N-benzyl-N-(4-chloro-phenyl)carbamoyl azide (Ib) and N-benzyl-N-phcnylcarbamoyl azide (le), respectively, were determined.     

N-Nitroimines: I. Synthesis,Structure, and Properties of 3,5-Diamino-1-nitroamidino-1,2,4-triazole

The reaction of 3,5-diamino-1,2,4-triazole with 2-methyl-1-nitroisothiourea gives 3,5-diamino-1-nitroamidino-1,2,4-triazole instead of the expected 1-[5(3)-amino-1,2,4-triazol-3(5)-yl]-2-nitroguanidine. Almost planar structure of the molecule of 3,5-diamino-1-nitroamidino-1,2,4-triazole gives rise for direct polar conjugation which is responsible for the low basicity of the amino groups.     

Synthesis,characterization and antitumour activities of some synthetic curcuminoid analogues and their copper complexes

The cytotoxic and antitumour activities of four curcuminoid analogues, namely 1,7-diphenyl-1,6-heptadiene-3,5-dione (HL¹), 1,7-bis(4-methoxyphenyl)-1,6-heptadiene-3,5-dione (HL²), 1,7-bis(3,4-dimethoxyphenyl)-1,6-heptadiene-3,5-dione (HL³), 1,7-bis(3,4-dihydroxyphenyl)-1,6-heptadiene-3,5-dione (HL⁴) and their Cu^II complexes were investigated.The Cu complexes were found to be more active as antitumour agents compared to the free curcuminoids, in both in vitro studies and in increasing the life span of tumour bearing mice. The synthesis and characterization of the curcuminoid analogues and their Cu^II chelates employing u.v., i.r., ¹ H-n.m.r., e.s.r. and mass spectral studies are also included in this report.     

Low-temperature photosensitized oxidation of a guanosine derivative and formation of an imidazole ring-opened product

An organic-soluble guanosine derivative, 2',3',5'-O-(tert-butyldimethylsilyl)guanosine (1), was prepared and its photosensitized oxidation was carried out in several solvents at various temperatures. Singlet oxygen is the reactive oxidizing agent responsible for this reaction. Neither an endoperoxide nor a dioxetane intermediate was detected by low-temperature NMR even at -78 degrees C. A product (A) with an oxidized imidazole ring was the only major product detected at room temperature; this compound could be isolated by low-temperature column chromatography and was characterized by (1)H and (13)C and mass spectroscopy. CO(2) was the other major product. A small amount of the corresponding 8-oxo-7,8-dihydroguanosine derivative B was detected during the initial stage of the photooxidation and was shown to be intermediate in the formation of two products of extensive degradation, C and D. Reaction of 1 with the singlet oxygen analogues 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) gave products consistent with a proposed mechanism involving the rearrangement of an initially formed endoperoxide to give A and B from reaction of 1 with singlet oxygen.     

Nouvelles synthèses de systèmes bicycliques hétéroaromatiques. I. Cycloaddition [4 + 2]π de la diméthyl-2,7 diméthylthio-3,5 triazépine-1,2,4

The cycloaddition of 3,5-dimethylthio-1,2,4-triazepine (1) to various dienophiles has been studied. 4-Phenyl-1,2,4-triazoline-3,5-dione, dimethyl acetylene dicarboxylate and meleic anhydride react with I to give the [4+2]π cycloadduct. The heterocyclic products were found to be formed via 1,3-sigmatropic rearrangement of this cycloadduct.     

Synthesis of a digermane-containing tricylic nonadecadienedione incorporating an equivalent of ring-opened THF

The combination of 2 equiv of bis[bis(trimethylsilyl)amide]germylene (5) with 2 equiv of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) in tetrahydrofuran (THF) results in the ring-opening of 1 equiv of THF to form 2,2,8,8-tetrakis(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-5,16-diphenyl-7,9,14-trioxa-1,3,5,16,18,19-hexaaza-2,8-digerma-tricyclo[13.2.1.13,6]nonadeca-6(19),15(18)-diene-4,17-dione (6). This fast and nearly quantitative reaction builds a 15-membered ring from five different molecules. The new ring, structurally assigned by X-ray crystallography, contains a flexible methylene chain that moves rapidly on the NMR time scale.