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Oxidations on Carbamothioates. 16 [1]; Electrochemical Oxidations. 2 [2]: Electrochemical Oxidations of Carbamodithioates, Analytical Evaluation of Peak Potentials It is possible to oxidize carbamodithioates of type I to the related carbamothioates of type II by electrochemical anodic oxidation. As analytical methods have been applied direct current voltammetry, differential pulse polarography and cyclic voltammetry. Each of these methods could be applied to the carbamodithioates 1-11 resulting in values for well defined oxidation-potentials.

Structural Variations by Reactions of the Thiocarbonyl GroupThe 2,3-dihydrothiazol-2-thiones 1a—c have been methylated to the 2-methylsulfanylthiazolium iodides 2a—c, which could be reacted with double activated CH-acidic compounds like 4-nitrophenylacetonitrile (3) to yield 5 and 6a,b, with malonic acid derivatives 7a—c to yield the push pull substituted ketene-S,N-acetales 8a—c or with 3-aminorhoda-nine derivatives to yield 12a,b. Vinylogous CH-acidic compounds like 9a—d reacted with 2b to the push-pull substituted butadienes 10a—d. With p-phenethidine 2b formed depending on the reaction conditions either the rare structure of an ortho-dithiocarbonic diester diamide (14) or the isothiourea 15. With hydrazino compounds, 16a—c with hydrazono partial structure resulted. Efforts to acylate the unsubstituted nitrogen of 17 with carbonic acid ester derivatives always yielded the S-acylated products 18 and 20a,b.

Reaction of isothiocyanates 1 with γ-thiobutyrolactone (2) in alkaline medium yielded 4-thiocarbamoylthiobutyric acids 3 after acidification, which could be cyclized to the 2-thioxo-1,3-thiazepan-4-ones 6. Additional reactions were observed with the formation of 6t from p-phenylenediisothiocyanate (1s) and with the formation of 6w from benzyl isothiocyanate (1t). 3-Acetylamino-γ-thiobutyrolactone (7) could also be used in this reaction yielding the butyric acid derivatives 3u-3w. Cyclization yielded the 1,3-thiazepane derivatives 6x, y which rearranged under ring contraction to the 1,3-thiazinanes 8a, b.

3-Benzyl-2-memyltmo-4,5-dmydrothiazolium iodide (1), 5-metlyl-2-methylthio-3-phenethylthiazolium iodide (4) and 3-methyl and 3-benzyl-2-methylthio-5,6-dihydro-1,3-thiazinium iodides 7a, b were reacted with the vinylogous doubly activated CH-acidic compounds 2a-d and the phenylogous doubly activated components 8, 11, 16, 19 and 21 to yield new types of S, N-heterocycles 3, 5, 6, 9, 10, 12, 13, 14, 15 with the partial structure of push-pull substituted butadienes and 17, 18, 20, 22, 23 and 24 with the character of push-pull substituted phenyl ketene S, N-acetals.

The title compounds 1a-c and 2 werre reacted with several doubly activated methylene components to yield the cyclic ketene S,N-acetals 3-10.

N-Boc-protected 2-methylthio-1,3-thiazinium 3 and 2-methylthiothiazolium salts 4,7 obtained from the corresponding 1,3-thiazine-2-thiones and thiazolidine-2-thiones by the action of methyl iodide or trimethyloxonium tetrafluoroborate were reacted with vinylogous CH-acidic compounds forming ketene N,S-acetals 5,6,8,9. The protection group was removed with trifluoroacetic acid whereupon the desired cyclisation to pyrido[2,1-b]-1,3-thiazines 10 and thiazolo[3,2-b]pyridines 11,12 took place.

N-Boc-protected 2-memylthio-1,3-thiazinium 1 and 2-methylthiothiazolium iodides 2, 3 obtained from the corresponding 3,4,5,6-tetrahydro-2H-1,3-thiazine-2-thiones and thiazolidine-2-thiones by the action of methyl iodide were reacted with 3-armno-2-cyano-3-arylacrylonitriles forming the cyclic isothioureas 5–7. The protection group was removed with trifluoroacetic acid whereupon the desired cyclisation to 3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazines 8a-c, 8a′-c′ and thiazolo[3,2-b]pyrimidines 9a,b, 9a′,b′, 10a,b took place.

3-Aminorhodanine 2 was reacted with cyclic anhydrides yielding 3-(2,5-dioxopyrrolidin-1-yl), 3-(2,6-dioxopiperidin-1-yl), and 3-(1,3-dioxoisoindolin-2-yl)rhodanine 6-8, which in turn were condensated in 5 position with several aldehydes yielding the new rhodanine derivatives 9-11.

A number of 5-condensated 3-acylaminorhodanines 3 was prepared as potential inhibitors of the aldose reductase by acylation of the amino group of 3-aminorhodanine 1 and subsequent condensation of the 5-methylene function with appropriate aldehydes. Some of these compounds displayed interesting activity.

Treatment of methyl 4,6-O-benzylidene-2-(dicyanomethylene)-2,3-dideoxy-α-D-erythro-hexopyranoside (2) with 3-benzyl-2-methylthio-2-thiazolinium iodide (3), 4,5-dihydro-3-methyl-2-methylthio-1,3-thiazinium iodide (5) and 3-benzyl-4,5-dihydro-2-methylthio-1,3-thiazinium iodide (6), respectively, gave methyl 4,6-O-benzylidene-3-[(2Z)-3-benzyl-2-thiazolidinylidene, 3-methyl-1,3-thiazinan-2-ylidene and 3-benzyl-1,3-thiazinan-2-ylidene]-2-(dicyanomethylene)-2,3-dideoxy-α-D-erythro-hexopyranoside (4), (7), (8), respectively.

Cyclische Salze des Dithiokohlensaure-diester-imidium Typs (3, 5) wurden mit NH2-Nucleophilen zu den cyclischen Isothioharnstoffen 6–8 umgesetzt. Einige dieser Verbindungen konnten zu cyclischen Isothioharnstoff-S,S-dioxiden (9, 10) oxidiert werden. Iminium Carbonic Acid Derivative Salts VII, Part I: Electrophilic Reactions of 2-Methylthio-5,6-dihydro-4H-1,3-thiazinium Iodides, 2-Methylthio-4,5-dihydrothiazolium Iodides, and 2-Methylthio-5-methylthiazolium Iodides with N-Nucleophiles Cyclic salts of the dithiocarbonic acid diester imidium type (3, 5) react with NH2-nucleophiles to the cyclic isothioureas 6–8. Some of these compounds were oxidized to cyclic isothiourea-S,S-dioxides (9, 10).

Selective Synthesis of ortho-Disubstituted Tetrahydroanthracenes with Retinoid Structure A synthesis of analogues of Temarotene (Ro 15-0778) (1) is described. This synthesis achieves the selective substitution in ortho-positions of a tetrahydroanthracene system using palladium-catalyzed coupling techniques.

Two pentacyclic analogues of the retinoid temarotene (1) have been prepared. We describe the first palladium-catalyzed coupling of a stannylated pyridine with an aromatic triflate and a novel way for the preparation of the benzo-[c]-1,8-naphthyridine skeleton.

Synthesis of Retinoids with Aryltetrahydroanthracene Structure We describe the synthesis of analogues of the retinoid Temarotene (Ro 15-0778) (1a), which shows due to its lack of a polar end group no signs of hypervitaminosis A. A variety of substituted tetrahydroanthracenes 6, 8, 11, 13 is prepared starting from 2-methoxynaphthalene (5b) using palladiumcatalyzed coupling techniques.

Numerous novel N,N-disubstituted 5-alkyliden- or 5-aralkyliden-3-aminorhodanines 2 have been prepared by condensation of carbonyl compounds with 1. The effectiveness of some derivatives in an "akanthose test" with hairless mice was shown.

Allopurinol, Nitroindazole und 5-Nitrobenzotriazole reagieren mit cyclischen Ethern bei Oxidation mittels Nitrosyltetrafluorborat oder 2,3-Dichlor-5,6-dicyanbenzochinon zu C-N-Verknupfungsprodukten. Nitrosation of Derivatives of Hydrazines, VIII: Novel Oxidative C-N-Coupling of Indazoles and Benzotriazoles with Cyclic Ethers Allopurinol, nitroindazoles and 5-nitrobenzotriazoles react with cyclic ethers under oxidation with nitrosyl-tetrafluoroborate or 2,3-dichloro-5,6-dicyanobenzoquinone yielding C-N-coupled products.

C-5-monosubstituierte Rhodaninderivate reagieren unter nitrosierenden oder nitrierenden Bedingungen zu 5-Nitro-rhodanin-Derivaten. Nitrosations of Hydrazine Derivatives, XI: 5-Nitrorhodanines from 5-Monosubstituted Rhodanine Derivatives Under Nitrosating Conditions C-5-monosubstituted rhodanine derivatives react to 5-nitrorhodanines under nitrosating or nitrating conditions.

C-5-unsubstituierte 3-Aminorhodanine 1 werden durch NaNO2/HCl, Nitrosyl- und Nitroniumtetrafluoroborat in 5-Hydroximinorhodanine 2 uberfuhrt, durch HNO3 in 5-Hydroximinothiazolidin-2,4-dione 3. 5-Aralkyliden-3-aminorhodanine 7 werden durch HNO2 unter drastischen Bedingungen in 2-Stellung oxidativ desulfuriert. Nitrosations of Hydrazine Derivatives, X; Oxidations of Carbamothioates, XI: Reactions of 3-Aminorhodanines under Nitrosating Conditions C-5-unsubstituted 3-aminorhodanines 1 are converted to 5-hydroximinorhodanines 2 with NaNO2/HCl, nitrosyl- and nitronium-tetrafluoroborate. With HNO3 5-hydroximinothiazolidine-2,4-diones 3 arise. Under drastic conditions 5-aralkyliden-3-aminorhodanines 7 are desulfurized oxidatively in 2-position by HNO2.

Indazole und Benzotriazole reagieren unter Einwirkung von 2,3-Dichlor-5,6-dicyanbenzochinon (DDQ) mit Verbindungen, die zur Bildung stabilisierter Carbeniumionen neigen, wie Cycloheptatrien, Di- und Triphenylmethan, Fluoren, Xanthen und Thioxanthen zu C-N-verknupften Produkten. Nitrosation of Derivatives of Hydrazines, IX: Novel Oxidative C-N-Coupling of Indazoles and Benzotriazoles with Cyclohepatriene, Di- and Triphenylmethane Derivatives In the presence of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) indazoles and benzotriazoles react with compounds forming stabilized carbenium ions like cycloheptatriene, di- and triphenylmethane, fluorene, xanthene and thioxanthene, yielding C-N-coupled products.

Two pentacyclic analogues of the retinoid temarotene (1) have been prepared. We describe the first palladium-catalyzed coupling of a stannylated pyridine with an aromatic triflate and a novel way for the preparation of the benzo-[c]-1,8-naphthyridine skeleton.

2,3-Dihydropyrazolo[5,1-b]thiazoles 3 are the first representatives of a heterocyclic system, which are conveniently prepared by heating 3-aminorhodanines 1 with ethyl 2-bromo-3,3-diethoxypropionate (2), via a tandem condensation-sulfur extrusion reaction.

α-Bromoacetylaminorhodanines (1) were reacted with NH 4 SCN yielding 3-(thiazolidin-3-yl)rhodanines (4), a novel type of rhodanine deri- vatives bearing a uncommon N-N ring-connection

A number of 5-condensated 3-acylaminorhodanines 3 was prepared as potential inhibitors of the aldose reductase by acylation of the amino group of 3-aminorhodanine 1 and subsequent condensation of the 5-methylene function with appropriate aldehydes. Some of these compounds displayed interesting activity.

Treatment of methyl 4,6-O-benzylidene-2-(dicyanomethylene)-2,3-dideoxy-α-D-erythro-hexopyranoside (2) with 3-benzyl-2-methylthio-2-thiazolinium iodide (3), 4,5-dihydro-3-methyl-2-methylthio-1,3-thiazinium iodide (5) and 3-benzyl-4,5-dihydro-2-methylthio-1,3-thiazinium iodide (6), respectively, gave methyl 4,6-O-benzylidene-3-[(2Z)-3-benzyl-2-thiazolidinylidene, 3-methyl-1,3-thiazinan-2-ylidene and 3-benzyl-1,3-thiazinan-2-ylidene]-2-(dicyanomethylene)-2,3-dideoxy-α-D-erythro-hexopyranoside (4), (7), (8), respectively.

An improved method for the reaction of 2,4-dichlorothiazole-5-carbaldehyde (2) with secondary amines was established using potassium carbonate in acetonitrile at room temperature instead of deprotonation with butyllithium in tetrahydrofuran at −78°. The method is convenient and the yields of 3 even higher. Compound 2 could also be reacted by this method with thiophenols to yield 4-chloro-2-phenylthiothiazole-5-carbaldehydes 4.

Oxidations of Thiourethanes, 10. — Synthesis, Crystal Structure, Oxidation and Photochemistry of Thione S-Oxides of Cyclic Dithiourethanes and Dithiocarbazates Several cyclic dithiocarbamates and dithiocarbazates (2–4) have been oxidised with mCPBA to give the corresponding thione S-oxides 5–7. The sulfine structure was confirmed by oxidation to the corresponding oxo derivatives and X-ray crystal structure analysis. Photolysis of the sulfines gave the corresponding oxo as well as the thioxo derivatives. The isolation of both the oxo and the thioxo derivatives is reported here for the first time, it provides an other evidence for the postulated thioxirane intermediate in the photolysis of sulfines.

Carbazoylchloride reagieren mit 2-Thioxo-tetrahydro-1,3-thiazinen 6 und 7 zu N-Carbazoyl-thiazinderivaten 9 und 11. Thiocarbazoylchloride greifen kinetisch kontrolliert am 2-Thioxoschwefel an zu S-Substitutionsprodukten 10 und 12, die thermisch intramolekular zu den stabileren N-Substitutionsprodukten 9 und 11 umgelagert werden konnen. Investigations on 1,3-Thlazines, XLII1): Carbazoylations and Thiocarbazoylations of 2-Thioxo-tetrahydro-1,3-thiazine Derivatives+) Carbazic acid chlorides react with 2-thioxo-tetrahydro-1,3-thiazines 6 and 7 yielding N-Carbazoyl-thiazine derivatives 9 and 11. Thiocarbazic acid chlorides attack under kinetic control at the 2-thioxo sulfur yielding S-substitution products 10 and 12, which can thermally be rearranged intramolecularly to the more stable N-substituted products 9 and 11.

Via virtual screening we identified a thioglycolic amide as an arginine methyltransferase (PRMT) inhibitor and tested it and related compounds against the fungal PRMT RmtA and human PRMT1. Compound RM65 was the most potent druglike inhibitor (IC(50)-PRMT1: 55.4 microM) and showed histone hypomethylation in HepG2 cells. Docking studies proposed binding at the substrate and SAM cofactor binding pocket. It may serve as a lead for further PRMT inhibitors useful for the treatment for hormone dependent cancers.

An improved method for the reaction of 2,4-dichlorothiazole-5-carbaldehyde (2) with secondary amines was established using potassium carbonate in acetonitrile at room temperature instead of deprotonation with butyllithium in tetrahydrofuran at −78°. The method is convenient and the yields of 3 even higher. Compound 2 could also be reacted by this method with thiophenols to yield 4-chloro-2-phenylthiothiazole-5-carbaldehydes 4.

Cyclische Dithiocarbamate und -carbazate wurden im Zweiphasensystem mittels H2O2 mit und ohne Zusatz von Na2WO4 zu den entsprechenden 2-Oxo-Analogen desulfuriert. Oxidation of Thiourethanes, XII: Oxidative Desulfuration of Cyclic Dithiocarbamates and -carbazates Using Hydrogenperoxide or Hydrogenperoxide/Sodium Tungstate in a Two-Phase-System Cyclic Dithiocarbamates and Dithiocarbazates were desulfurized to the corresponding 2-oxo-analogues using H2O2 with or without addition of Na2WO4 in a two-phase-system.

Orale Antidiabetica vom Sulfonylsemicarbazid-Typ wie Tolazamid (1) und Glisoxepid (2) wurden unter milden nitrosierenden Bedingungen, auch annahernd physiologischen in vitro Bedingungen, nach einem neuartigen Reaktionsverlauf in Sulfonyltriazene 3a, b umgewandelt. Modellverbindungen mit N4-Acyl-semicarbazidstruktur 4 zeigen abweichendes Reaktionsverhalten, wobei Saureamide 5 neben Nitrosaminen 6 gebildet werden. Nitrosations with Hydrazine Derivatives, VI: Novel Reaction of Oral Antidiabetics of the Sulfonylsemicarbazide Type under Nitrosating Conditions Oral antidiabetics of the sulfonylsemicarbazide type like Tolazamide (1) and Glisoxepide (2) were transformed under mild nitrosating conditions, even nearly physiological in vitro conditions, to sulfonyl triazenes 3a, b by a novel reaction pathway. Model compounds with N4-Acyl-semicarbazide structure 4 showed different reaction behaviour yielding carbonamides 5 and nitrosamines 6.

Umsetzungen von Thiazolidin-2-thion (1) mit Carbazoyl- und Thiocarbazoylchloriden 5 fuhren zu S-Substitutionsprodukten 6, von denen nur die S-Carbazoylderivate thermisch in die N-Carbazoylderivate 7 umgelagert werden konnen. Aus 5 und 5-Methylen-thiazolidin-2-thion (8) werden nicht umlagerungsfahige heteroaromatische Thiazolderivate 9 erhalten. Thiazolidin-2,4-dion (10) gibt nur N-Substitutionsprodukte 11. Carbazoylations and Thiocarbazoylations of 2-Thioxo-thiazolidines1) Reactions of thiazolidine-2-thione (1) with carbazic and thiocarbazic acid chlorides 5 lead to S-substitution products 6 which only in case of the carb-azoic derivatives can be thermally rearranged to N-carbazoyl derivatives 7. Not rearrangeable heteroaromatic thiazoles 9 are obtained from 5 and 5-methylen-thiazolidine-2-thione (8). Thiazolidine-2,4-dione (10) only yields N-substitution products 11.

Investigations of 1,3-Thiazines, 44. – Novel Rearrangement of 3,3′-Carbonylbis(tetrahydro-2H-1,3-thiazine-2-thiozine) and 3,3′-Carbonylbis(2-thiazolidinethione)2) 2-Thioxo-1,3-thiazine and -thiazolidine derivatives react with phosgen yielding N,N′-carbonylbis(heterocycles) 3, 9, 11, 12. With excess of phosgen 3 and 9 gave a novel rearrangement to the 3,5-bis(ω-chloroalkyl)-2,6-dithioxo-perhydro-1,3,5-thiadiazin-4-ones 8 and 10.

Investigations on 1,3-Thiazines, 43. – Newman-Kwart Rearrangement in the Course of Thiocarbazoylation of Tetrahydro-2H-1,3-thiazin-2-one and Thiazolidin-2-one Thiocarbazoylation of tetrahydro-2H-1,3-thiazin-2-one (1) with thiocarbazic acid chlorides leads to N-thiocarbazoyl derivatives 5 and N-carbazoyl-tetrahydro-2H-1,3-thiazin-2-thiones 8, which are interpreted as products of an O-thiocarbazoylation to 6, subsequent Newman-Kwart rearrangement to 7 and final SN transcarbazoylation. Thiocarbazoylation of thiazolidin-2-one (9) yields an isolable Newman-Kwart rearrangement product 12 and its product 13 of SN transcarbazoylation.

Die stark elektrophilen N-substituierten 2-Chlor-5,6-dihydro-4H-1,3-thiaziniumsalze 1 reagieren in einer Vilsmeier-artigen Reaktion mit Pyrrolderivaten und Indol zu den uberraschend stabilen Salzen 2–4. Investigations on 1,3-Thiazines, XLI1); Iminium Carbonic Acid Derivative Salts, V1): Vilsmeier-Type Reactions with N-Substituted 2-Chloro-5,6-dihydro-4H-1,3-thiazinium Salts The strongly electrophilic N-substituted 2-chloro-5,6-dihydro-4H-1,3-thiazinium salts 1 react in a Vilsmeier-type reaction with pyrrol derivatives and indol to yield the surprisingly stable salts 2–4.