Reactions of 4-substituted 5H-1,2,3-dithiazoles with primary and secondary amines: fast and convenient synthesis of 1,2,5-thiadiazoles, 2-iminothioacetamides and 2-oxoacetamides

The treatment of 5H-1,2,3-dithiazole-5-thiones 1 in chloroform under reflux and 5H-1,2,3-dithiazol-5-ones 2 in THF at room temperature with primary aliphatic amines and benzylamine afforded 1,2,5-thiadiazole-3(2H)-thiones 3 and 1,2,5-thiadiazol-3(2H)-ones 6, respectively. The structure of dithiazolone 3f was confirmed by X-ray diffraction analysis. The reaction of dithiazolone 2e bearing an electron-donating methyl group in the 4-position gave 2-oxoacetamide 7e in high yield. The reaction of thiones 1 with secondary aliphatic amines in DMSO yielded 2-iminothioacetamides 8 in moderate yields together with elemental sulfur. Interestingly, the treatment of dithiazolones 2 with secondary amines under the same conditions afforded 2-oxoacetamides 9—the products of the hydrolysis of corresponding imino derivatives 10, which was isolated as 10b. A general mechanism was proposed for the formation of the products.     

The degradation of 4,5-dichloro-1,2,3-dithiazolium chloride in wet solvents

4,5-Dichloro-1,2,3-dithiazolium chloride 1 (Appel salt) reacts in wet DCM, THF or MeCN to give elemental sulfur, dithiazole-5-thione 4, dithiazol-5-one 5 and thiazol-5-one 6. Furthermore the reaction of 2-phenylthiazol-5(4H)-one 12 with Appel salt 1 at ca. 20 °C gives 4-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-phenylthiazol-5(4H)-one 13 (26%) while at ca. 82 °C a new product 2,2′-diphenyl-4,4′-bithiazol-ylidene-5,5′-dione 14 (36%) is additionally isolated. Finally, 4,4′-bithiazolylidene-5,5′-dione 14 is prepared directly by treating 2-phenylthiazol-5(4H)-one 12 with N-chlorosuccinimide. All new compounds are fully characterised and rational mechanisms are proposed for the formation of all key compounds.     

The preparation of dicyano-1,3,4-thiadiazole and tricyanothiazole via 1,2,3-dithiazole chemistry

Treatment of 1,2-bis(4-chloro-5H-1,2,3-dithiazol-5-ylidene)hydrazine 4 with benzyltriethylammonium iodide (1 equiv) affords dicyano-1,3,4-thiadiazole 3 and 5-cyano-1,3,4-thiadiazole-2-carboxamide 5 in 79 and 21% yields, respectively. By using polymer bound triphenylphosphine instead of benzyltriethylammonium iodide the dicyano-1,3,4-thiadiazole 3 can be isolated in 70% yield without chromatography. The reaction of DAMN with Appel salt 8 gave 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile 7 (14%), 2,3-bis-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)fumaronitrile 10 (14%), and 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)maleonitrile 11 (24%) together with other products. The maleonitrile 11 isomerizes into the fumaronitrile 10 on irradiation at 365 nm. Reaction of aminoacetonitrile with Appel salt 8 gives the (dithiazolylidene)acetonitrile 7 in 33% yield. Treatment of (dithiazolylidene)acetonitrile 7 with polymer bound triphenylphosphine gives tricyanothiazole 6 in 76% yield. A rational general mechanism for the transformation of bisdithiazoles to percyanoheteroles is proposed.     

The reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with dimethylsulfonium dicyanomethylide: an improved synthesis of (4-chloro-1,2,3-dithiazolylidene)malononitrile

4,5-Dichloro-1,2,3-dithiazolium chloride 6 (Appel salt) reacts with dimethylsulfonium dicyanomethylide 11 to give 5-(4-chloro-1,2,3-dithiazolylidene)malononitrile 1 and a mixture of E/Z isomers of 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-3-chloro-2-(methylthio)acrylonitrile 13. The reaction of 4-chloro-5H-1,2,3-dithiazole-5-thione 10 with dimethylsulfonium dicyanomethylide 11 gives (dithiazolylidene)malononitrile 1 in 92% yield. All new compounds are fully characterised and rational mechanisms are proposed for the formation of all key compounds.     

The conversion of 2-(4-chloro-5H-1,2,3-dithiazolylideneamino)benzonitriles into 3-aminoindole-2-carbonitriles using triphenylphosphine

2-(4-Chloro-5H-1,2,3-dithiazolylideneamino)benzonitrile 1a reacts with triphenylphosphine (4 equiv) in the presence of water (2 equiv) to afford anthranilonitrile 2a, 3-aminoindole-2-carbonitrile 3a and (2-cyanoindol-3-yl)iminotriphenylphosphorane 4a, together with triphenylphosphine sulfide and oxide. The use of polymer bound triphenylphosphine provides cleaner reaction mixtures. 2-(4-Chloro-5H-1,2,3-dithiazolylideneamino)-4,5-dimethoxybenzonitrile 1h does not give the corresponding indole on treatment with triphenylphosphine but gives 6,7-dimethoxyquinazoline-2-carbonitrile 5 (15%) and 2-cyano-4,5-dimethoxy cyanothioformanilide 6 (36%). A total of seven new 3-aminoindole-2-carbonitriles 3a-g are prepared and fully characterised.     

The first entry to pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones

Wittig olefination of 3-aminoquinoline-2,4(1H,3H)-diones 1 with ethyl (triphenylphosphoranylidene)acetate (Ph₃PCHCO₂Et) afforded (E)-3-amino-4-ethoxycarbonylmethylene-1,2,3,4-tetrahydro-2-quinolones (E)-2 and pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3. An alternative approach for the synthesis of 3 via 3-bromoacetamidoquinoline-2,4(1H,3H)-diones 7, their corresponding triphenylphosphonium salts 8, and ylides A that undergo intramolecular Wittig reaction, was investigated. Under the applied reaction conditions, the phosphonium salts 8 and ylides A are so unstable that they partly decompose to 3-acetamidoquinoline-2,4(1H,3H)-diones 9 during the synthesis of 3.     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

A facile approach for the synthesis of novel substituted 4H-chromenes and condensation reactions of 4H-chromenes leading to chromenopyrrolones and triazolylchromenopyrrolones

A facile method has been developed for the synthesis of 4H-chromene-3-carboxylates 3a–d by the nucleophilic substitution reaction of 2-hydroxy-2H-chromene-3-carboxylates 2a–d with triethylsilane in the presence of BF₃·O(C₂H₅)₂. Cyclocondensation of 4H-chromene-3-carboxylates 3a–d with benzylamines 4a–d afforded a series of 2,3-dihydrochromenopyrrolones 5a–p and with propargylamine afforded 2-propynyl-2,3-dihydrochromenopyrrolones 6a–d. Click reaction of 6a–d with benzyl azides 7a–d provided a series of 1H-1,2,3-triazolylmethyl-2,3-dihydrochromenopyrrolones 8a–p. Thus synthesized compounds 3a–d, 5a–p, 6a–d, and 8a–p are novel heterocyclic compounds and being reported for the first time.     

Reaction of (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile with N-arylisoindolines

In a multistep reaction, 3,3′-(2-aryl-2H-isoindol-1,3-ylene)-di-(1,4-naphthoquinone-2-carbonitriles) 13a-f have been formed in 25-61% yield from a series of N-arylisoindolines 8a-f with (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile (1) in aerated pyridine. The structure of one of these products (13f) has been unambiguously confirmed by a single crystal X-ray structure analysis. Under otherwise the same conditions, 2-(3-methoxyphenyl)-isoindoline (8g) and 1 gave 38% of [4-(2,3-dihydro-1H-isoindol-2-yl)-2-methoxyphenyl]-1,3-dioxoindan-2-ylidene)acetonitrile (15). Rationales for these conversions involving the known rearrangement of the radical anion of 1 into the radical anion of 1,4-naphthoquinone-2,3-dicarbonitrile (3) are presented.     

Synthesis and tautomeric structure of 2-[N-aryl-2-oxo-2-arylethanehydrazonoyl]-6-methyl-4(3H)-pyrimidinones

Two series of 2-(N-aryl-2-oxo-2-arylethanehydrazonoyl)-6-methyl-4(3H)-pyrimidinones 11 (12) were prepared by coupling of diazotized anilines with 2-(aroylmethylene)-1,2-dihydro-6-methyl-4(3H)-pyrimidinones 2 (3). The spectral data of such compounds together with their 3-methyl analogs 13 (14) indicated that they exist predominantly in the hydrazone tautomeric form.     

Highly stereoselective synthesis of para-substituted (E)-N-styrylcarbazoles via sequential silylative coupling-Hiyama coupling reaction

A series of new para-substituted (E)-(N)-styrylcarbazoles, i.e., eight (E)-9-[2-(aryl)ethenyl]-9H-carbazoles (5-12) and 1,4-bis[(E)-2-(9H-carbazol-9-yl)vinyl]benzene (13), have been synthesized in high yield and stereoselectively by a sequential silylative coupling-Hiyama coupling reaction, i.e., coupling of commercially available 9-vinylcarbazole with vinyltriethoxysilane or divinyltetramethyldisiloxane in the presence of [RuHCl(CO)(PCy₃)₂] (I), followed by Pd (II) catalyzed cross-coupling with para-substituted iodobenzenes.The tandem procedure has facilitated the synthesis of 13. X-ray structures of the intermediate silylvinylcarbazole (4), as well as products 12 and 13 have been obtained.     

l-Proline catalyzed one-step synthesis of 4,5-diaryl-2H-1,2,3-triazoles from heteroaryl cyanostilbenes via [3+2]cycloaddition of azide

Use of a novel reagent has been established for the synthesis of a series of 4,5-diaryl-2H-1,2,3-triazoles (6a–i and 9a–e) from cyanostilbene analogs of benzo[b]thiophene, benzo[b]furan, and indole, catalyzed by l-proline via Lewis base-catalyzed one-step [3+2]cycloaddition of azide. This method provides an efficient, simple, and environmentally benign procedure that affords good yields and relatively short reaction times.     

Syntheses of rac/meso-{PhP(3-t-Bu-C5H3)2}-Zr{RN(CH2)3NR}, structural analyses of rac-{PhP(3-t-Bu-C5H3)2}Zr{RN(CH2)3NR} (where R is SiMe3 or Ph), and meso to rac isomerization

Syntheses of rac/meso-{PhP(3-t-Bu-C₅H₃)₂}Zr{Me₃SiN(CH₂)₃NSiMe₃} (rac-3/meso-3) and rac/meso-{PhP(3-t-Bu-C₅H₃)₂}Zr{PhN(CH₂)₃NPh} (rac-4/meso-4) were achieved by metallation of K₂[PhP(3-t-Bu-C₅H₃)₂] · 1.3 THF (2) with Zr{RN(CH₂)₃NR}Cl₂(THF)₂ (where R = SiMe₃ or Ph, respectively) using ethereal solvent. These isomeric pairs were characterized by ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectroscopy; rac-3 and rac-4 were also examined via single crystal X-ray crystallography. The structures of rac-3 and rac-4 are notable in the tendency of the cyclopentadienyl rings towards η³ coordination. While isolated samples of rac-3/meso-3 and rac-4/meso-4 slowly isomerize in tetrahydrofuran-d₈ to equilibrium ratios, the isomerization rate for 3 is more than 15-fold greater than that for 4. In addition, equilibrium ratios are rapidly reached when isolated samples of rac-3/meso-3 and rac-4/meso-4 are exposed to tetrabutylammonium chloride in tetrahydrofuran-d₈ solvent. We propose that a nucleophile (either chloride or the phosphine interannular linker) brings about dissociation of one cyclopentadienyl ring, thus promoting the rac/meso isomerization mechanism.     

Endoplasmic reticulum (ER) stress protecting compounds from the mushroom Mycoleptodonoides aitchisonii

Two novel compounds, 3-(hydroxymethyl)-4-methylfuran-2(5H)-one (1) and (3R,4S,1′R)-3-(1′-hydroxyethyl)-4-methyldihydrofuran-2(3H)-one (2), were isolated along with two known ones (3 and 4) from an edible mushroom Mycoleptodonoides aitchisonii. The structures of 1-4 were determined by the interpretation of spectroscopic data. Compounds 1-4 showed protective activity against endoplasmic reticulum (ER) stress-dependent cell death.     

Supramolecular nanostructured assemblies of different types of porphyrins with fullerene using TiO2 nanoparticles for light energy conversion

TiO₂ nanoparticles were modified with porphyrin derivatives, 5-[4-benzoic acid]-10,15,20-tris[3,5-di-tert-butylphenyl]-21H,23H-porphyrin (Ar-H₂P-COOH), 5-[4-benzoic acid]-10,20-tris[3,5-di-tert-butylphenyl]-21H,23H-porphyrin (H-H₂P-COOH), and 5,10,15,20-tetra[4-benzoic acid]-21H,23H-porphyrin (H₂P-4COOH). The porphyrin-modified TiO₂ nanoparticles were deposited on nanostructured OTE/SnO₂ electrode together with nanoclusters of fullerene (C₆₀) in acetonitrile-toluene (3/1, v/v) using an electrophoretic deposition technique to afford the porphyrin-modified TiO₂ composite electrode denoted as OTE/SnO₂/(porphyrin-modified TiO₂ nanoparticle+C₆₀)_n. The porphyrin-modified TiO₂ composite electrodes have efficient light absorbing properties in the visible region, exhibiting the photoactive response under visible light excitation using redox couple. The incident photon-to-photocurrent efficiency (IPCE) values of supramolecular nanostructured electrodes of porphyrin-modified TiO₂ nanoparticles with fullerene [OTE/SnO₂/(Ar-H₂P-COO-TiO₂+C₆₀)_n, OTE/SnO₂/(H-H₂P-COO-TiO₂+C₆₀)_n, and OTE/SnO₂/(H₂P-4COO-TiO₂+C₆₀)_n] are much larger than those of the reference systems of porphyrin-modified TiO₂ nanoparticles without C₆₀ [OTE/SnO₂/(Ar-H₂P-COO-TiO₂)_n, OTE/SnO₂/(H-H₂P-COO-TiO₂)_n, and OTE/SnO₂/(H₂P-4COO-TiO₂)_n]. In particular, the maximum IPCE value (41%) is obtained for OTE/SnO₂/(H-H₂P-COO-TiO₂+C₆₀)_n under the bias potential of 0.2 V versus SCE. This indicates that the formation of supramolecular complexes between porphyrins and fullerene on TiO₂ nanoparticles plays an important role in improvement of the light energy conversion properties.     

Synthesis of new triazole substituted pyroaminoadipic and pipecolic acid derivatives

Racemic 5-(4,5-substituted-1H-1,2,3-triazol-1yl)-pyroaminoadipic and pipecolic acid derivatives were synthesized from meso dimethyl-α,α′-dibromoadipate 1 in good yields using mild reaction conditions. The key step of this reaction sequence was the 1,3-dipolar cycloaddition of an acetylenic compound on α-azido-α′-bromoadipate 2. A reactive α-(substituted-1H-1,2,3-triazol-1-yl)-α′- bromoadipate derivative 3a-d was generated and reacted with sodium azide followed by Pd/C-catalyzed hydrogenation to provide lactams 5a-d. The chemoselective reduction of the amide carbonyl group of 5a-d with BH₃ followed by acid hydrolysis provided 5-(4,5-substituted-1H-1,2,3-triazol-1-yl) pipecolic acids in racemic form.     

2(H)-1,4-Oxazin-2-ones as ambident azadienes

3,5-Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 4, 5-chloro-6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one 5 and 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7, are ambident azadienes reacting efficiently and selectively with both electron rich and electron poor dienophiles.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

Control of electron demand in the cycloadditions of 2(H)-1,4-oxazin-2-ones

3-Methoxy-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one 4, 3-methoxy-5-chloro-6-phenyl-2(H)-1,4-oxazin-2-one 5, 3-phenylsulfenyl-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one 6, and 3-phenylsulfenyl-5-chloro-6-phenyl-2(H)-1,4-oxazin-2-one 7, are ambident dienes and undergo Diels-Alder cycloadditions with electron neutral, rich and deficient dienophiles.     

Efficient synthesis of new 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones

The synthesis of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones 5, 6a-d from 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d is reported. The 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d were obtained from regiospecific bromination of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 1, 2a-d with molecular bromine. The NMR and X-ray diffraction data showed that 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones were brominated at 4-position in the pyrrolidin-2-one ring.