Synthesis of Indole Derivatives by [2 + 2] Photocycloaddition of Indoline-2-thiones with alkenes and photodesulfurization of indoline-2-thiones

The photochemical synthesis of indole derivatives starting from the indoline-2-thiones 1 is described. Irradiation of indoline-2-thiones 1 in the presence of alkenes 3 gave 2-alkyl-3H-indoles 4 – 7 or 2-alkylindoles 8 – 22 through the ring cleavage of the intermediates, spirocyclic amino-thietanes, initially derived by [2 + 2] cycloaddition of the C?S bond of 1 and the C?C bond of 3 . Irradiation of 1 in the presence of trialkylamines 26 gave desulfurization products 27 – 32 and unexpected 3-alkylindoles 33 – 40 . N-Acylindoline-2-thiones 11 - p yielded the deacylated products, indoline-2-thiones 1a - b , and ethyl esters 43 through γ-H abstraction by the excited thioamide S-atom when irradiated in CDC1₃/EtOH or benzene/EtOH. Oxygen analogues 2a - d also underwent intramolecular H abstraction to give the indolin-2-ones 2e – f and ethyl esters 43 in a similar way.     

Unprecedented Multicomponent Reaction of Indoles,CS2 and Nitroarenes: Stereoselective Synthesis of (Z)-3-((Arylamino)methylene)indoline-2-thiones

An efficient method for the stereoselective synthesis of (Z)-3-((arylamino)methylene)indoline-2-thiones have been developed via a novel multicomponent reaction of indoles, CS₂ and nitroarenes. A range of functionalized indoline-2-thiones were prepared in moderate to good yields from easily available starting materials. The indoline-2-thione products can be easily derivatized to give biologically active thieno[2,3-b]indole and thiopyrano[2,3-b]indole skeletons in high yields.     

Copper-catalyzed synthesis of 2-sulfenylindoles from indoline-2-thiones and aryl iodides

A novel and efficient method for synthesis of 2-sulfenylindole via copper-catalyzed coupling reaction of indoline-2-thiones with aryl iodides has been developed. A series of N-substituted and N-free 2-sulfenylindole were obtained in high yields. Furthermore, the method was employed to synthesis of benzothieno[2,3-b]indoles from indoline-2-thiones with 1,2-diiodobenzene in the presence of CuI and Pd(OAc)₂ as catalysts.     

BF3 etherate-mediated microwave-assisted facile synthesis of thiopyrano[2,3-b]indol-2-one

A facile synthesis of indole annulated 2H-thiopyran-2-ones has been developed by condensation of indoline-2-thiones with acetoacetic esters in the presence of borontrifluoride etherate (BF₃ etherate) using microwave irradiation. This one-step operationally simple methodology leads to thiopyrano[2,3-b]indol-2-ones in good yields.     

Homogeneous and heterogeneous asymmetric reactions. Part 5. Diastereoselective and enantioselective hydrogenation of cyclic β-keto esters on modified Raney-nickel catalysts

The hydrogenations of methyl 2-oxoeyclopentanecarboxylate ( 1 ), ethyl 2-oxocyelohexanecarboxylate ( 3 ), and 2-methylcyclohexanone ( 5 ) on unmodified Raney-Ni catalyst lead predominately to the formation of the cis-hydroxy diastereoisomers of 2 , 4 , and 6 , respectively (Scheme 2). In the asymmetric hydrogenations on catalysts modified with chiral tartaric acid ((R, R )-C₄H₆O₆/Raney-Ni and (R, R)-C₄H₆O₆/NaBr/Raney-Ni), the predominance of the cis-isomer increases significantly. The hydrogenations of β-keto esters 1 and 3 proceed with an enantioselectivity of 10–15% on the modified catalysts, while the similar hydrogenation of 5 yields optically inactive 6 . The (1S,2R)-enantiomers of the cis-isomers of 2 and 4 are formed in larger quantity, whereas the (lR,2R)-enantiomers of the corresponding trans-isomers predominate (Scheme 1). The enantioselective formation of trans- 2 and trans- 4 can be interpreted mainly in terms of the asymmetric hydrogenation of cyclic β-keto esters through the keto form, while that of the corresponding cis-hydroxy esters proceeds through the enol form.     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Composés sulfurés hétérocycliques. CII. Action de l'hydroxylamine sur les dihydro-1,2 benzothiazine-3,1 thiones-4

Hydroxylamine reacts with 1-alkyl-1,2-dihydro-3,1-benzothiazine-4thiones ( 1 ), giving 1-alky1-3-hydroxy-2,3-dihydro-1H-quinazoline-4-thiones ( 2 ). The same reagent, in neutral medium, converts 1-aryl-1,2-dihydro-3,1-benzothiazine-4-thiones ( 3 ) into 1-aryl-4-hydroxyimino-1,4-dihydro-2H-3,1-benzothiazines ( 4 ). In acidic medium, the same starting materials lead to 1-aryl-3-hydroxy-2-3-dihydro-1H-quinazoline-4-thiones ( 5 ). genrally with some quantity of the isomer 4 . Thiones 2 and 5 , as well as oximes 4 , heated at 200°, decomopose, yielding, in varying proportions, 1H-quinazoline-4-thiones ( 6 or 7 ), 1H-quinazoline-4-ones ( 9 ) and 2,3-dihydro-1H-quinazoline-4-thiones ( 11 ). Reacting with methyliodide, 1H-quinazoline-4-thiones ( 7 ) give 4-methylthioquinazolin-1-ium iodidies ( 12 ) which can be hydrolysed into 1H-quinazolin-4-ones ( 9 ). The latter are also obtained by reacting benzonitrile N-oxide with the corresponding thiones. 1-Aryl-1 H-quinazoline-4-thiones ( 7 ) react readily with nitrogen nucleophiles XNH₂ to give 1-aryl-4-imino-1,4-dihydro-quinazolines diversely substituted on the imino group. While thiones 7 are S- methylated by methyl iodide, the corresponding 1-aryl-1H-quinazolin-4-ones (9), with the same reagent, ungergo a N-methylation, yielding 1-aryl-3-methyl-4-oxo-3,4-dihydroquinazolin-l-ium iodides ( 18 ). Structure have been confirmed by uv, ir and nmr spectra.     

Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8-nitropyrido[2",3":4,5]thieno[2,3-b]pyridin-2(1H)-ones.     

β-Funktionalisierte Hydrazine aus N-Phthalimidoaziridinen und ihre hydrogenolytische N,N-Spaltung zu Aminen

β-Functionalized Hydrazines from N-Phthalimidoaziridines and their Hydrogenolytic N,N-Cleavage to Amines The three N-phthalimido-aziridines 1–3 were reacted with phenol, thiophenol, aniline, p-toluenesulfonic acid, and H₂O in selected combinations. These nucleophiles opened the 3-membered ring to yield the N-phthalimidoamines 4a–d, 5a–d, 6a–c , and 6e ; all these products (except the carbinol 6e ) carry an aryl-substituted functional group on the C-atom vicinal to the N-substituent. Hydrazinolysis of 4, 5, 6a–c , and 6e afforded the β-functionalized hydrazines 7, 8, 9a–c , and 9e . The reducing medium Raney-Ni/N₂H₄ transformed 4, 5, 6a–c , and 6e to the β-functionalized amines 10, 11, 12a–c , and 12e . By a study with the hydrazide 6a and the hydrazine 9a , it was shown that the N,N-cleavage is a catalytic hydrogenolysis by H₂ generated from N₂H₄ with Raney-Ni and that it does not take place on the hydrazide 6 , but rather on the hydrazine 9 , generated as intermediate from 6 with N₂H₄. Spectroscopic data confirmed that the conversions of 1–3 to 4–6 occurred exclusively with inversion and that the resulting configurations remained fully intact during the transformations of 4, 5 , and 6 (via 7, 8 , and 9 ) to 10, 11 , and 12 , respectively.     

Electron ionization mass spectra of some 4β-phenyl-substituted cycloalkane-cis-fused 1,3-oxazin-2(3H)-ones, -2(3H)-thiones and 1,4-oxazepin-3(4H)-ones

The 70 eV mass spectra of 4β-phenyl-substituted cyclopentane- and cyclohexane cis-fused 1,3-oxazin-2(3H)-ones, the two related 2-thiones, 6,7-cis-trimethylene-5β-phenyl-1,4-oxazepin-3(4H)-one and its 2β-methyl derivative were recorded and their fragmentations examined by means of metastable ion analysis, collision induced dissociation technique and exact mass measurement. The fragmentation patterns of the 1,3-oxazin-2(3H)-ones were relatively simple: the favored formation of cycloalkene ions implied that a considerable proportion of the molecular ions might possess an enol structure. Changes in the size of the fused cycloalkane ring had little or no effect on the fragmentations. Instead, small changes in the heterocyclic part of the molecule caused remarkable effects on the fragmentation behavior. Compared to 1,3-oxazin-2(3H)-ones studied, both 1,3-oxazine-2(3H)-thiones and 1,4-oxazepin-3(4H)-ones showed much more complicated fragmentation patterns.     

Stereochemical studies. 81. Saturated heterocycles. 69 . Preparation of methylene-bridged 3,1-benzoxazines, 3,1-benzoxazin-2-ones and 3,1-benzoxazine-2-thiones

3-exo-Aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid and ethyl 3-endo-aminobicyclo[2.2.1]heptane-2-endo-carboxylate ( 6 ) were reduced with lithium aluminum hydride to the corresponding bicyclic aminoalcohols 3 and 4 . These and the saturated endo-endo and exo-exo N-methylaminoalcohols 16 and 22 , respectively, were converted to methylene-bridged tetrahydro- ( 11 ) and hexahydro-3,1-benzoxazin-2-ones 12, 17, 23 and 3,1-benzoxazin-2-thiones 13, 14, 18, 24 . The exo-exo 3 and endo-endo 4 aminoalcohols were cyclized by means of ethyl arylimidates to tricyclic dihydro-1,3-oxazines 7a-d, 8a-d . The structures were confirmed by ir, ¹H and ¹³C nmr spectroscopy.     

Synthesis of indeno[2,1-b][1,4]benzothiazine derivatives from 2-bromoinden-1-ones

2-Bromoinden-1-ones 2 were condensed with 6-substituted 3-aminopyridine-2(1H)-thiones to produce a new type of 4-azaindeno[2,1-b][1,4]benzothiazine derivatives 3 . Substituted 6-phenylindeno[2,1-b][1,4]benzothiazines 4 were also prepared by reacting 2-bromo-5-methoxy- and 2,6-dibromo-5-methoxyinden-1-ones with o-aminobenzenethiol.     

Heterocyclic compounds from 3,3-dimercapto-1-aryl-2-propen-1-ones. Note 1. 4-Ary1-1,3-dihydro-2H-1,5-benzodiazepine-2-thiones

A series of new 4-aryl-1,3-dihydro-2H-1,5-benzodiazepine-2-thiones ( 3 ) has been synthesized by condensing the 3,3-dimercapto-1-aryl-2-propen-1-ones with o-phenylenediamine. The structure was established by the results of acid cleavage and by nmr spectra. The alkylation of compounds 3 gave 2-alkylthio-4-aryl-3H-1,5 benzodiazepines ( 10 ).     

Reaction of acetylenedicarboxylic acids esters with 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-1-carbothioamides and 3,4,5,6-tetrahydro-2<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazepine-3-thiones

The reactions of dimethyl acetylenecarboxylate with 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones and 4,5-dihydro-1H-pyrazole-1-carbothioamides are convenient methods for the synthesis of 7,8-dihydrothiazolo[3,2-b][1,2,4]triazepin-3-ones derivatives and methyl esters of (2Z)-[2-(4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acids, respectively. The reaction of methyl propynoates with 4,5-dihydro-1H-pyrazole-1-carbothioamides or with 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione gives 2-(4,5-dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones.     

Synthesis of some new spiroindoline derivatives incorporated with pyrazoloheterocycles

Indole-2,3-dione ( 1 ) was treated with malonic acid ( 2 ) in a mixture of ethanol/pyridine to afford 1-[3-(2-oxoindolinylidene)]acetic acid ( 3 ). Compound 3 reacted with thionyl chloride to give the corresponding acid chloride ( 4 ). The acid chloride 4 reacted with arenes in the presence of AlCl₃ to yield 3-(2-oxoindolinylidene)acetophenones 5a–c . Compounds 5a–c reacted with 3-methylpyrazolin-5-one derivatives 6a , b to give 3-aracyl-3-[4′-(3′-methylpyrazolin-5-onyl)]-indoline-2-one derivatives 7a–f . Compounds 7a–f were treated with phosphorus pentoxide in phosphoric acid, with ammonium acetate or methanolic methylamine and with phosphorus pentasulfide to give spiro[indoline-3,4′-(pyrazolo[4,5-b]pyran)]-2-ones 8a–f , spiro[indoline-3,4′-(pyrazolo[4,5-b]-dihydropyridine)]-2-ones 9a–f , 10a–f and spiro[indoline-3,4′-(pyrazolo[4,5-b]thiopyran)]-2-ones 10a–f , respectively. All of the synthesized spiroheterocycle derivatives were identified by conventional spectroscopic methods (IR, ¹H NMR) and elemental analyses. © John Wiley & Sons, Inc.     

The Course of the Catalytic Hydrogenation/Isomerization Reaction of Steroidal Ring B Olefins in the 13β- and 13α-Series

The course of the catalytic hydrogenation and isomerization (H₂/Raney-Ni/dioxane or H₂/Pd/C/EtOH) of Δ^5.7-, Δ⁷-, Δ⁸-, and Δ⁸⁽¹⁴⁾-steroid olefins was shown to depend strongly on the configuration at C(13). The known hydrogenation/isomerization of reactions of Δ^5.7-dienes in the 13β-series to Δ⁷-(H₂/Raney-Ni/dioxane) and Δ⁸⁽¹⁴⁾-olefins (H₂/Pd/C/EtOH) were also confirmed in the 3β, 19-epoxy-13β- and 3-Oxo-19-acetoxy-13β-steroid series (e.g. 32 → 35 → 37 , Scheme 3). On the other hand, in the corresponding 13α-steroid series the same reactions afforded the Δ⁷-. and the Δ⁸-olefins (mixture of products with H₂/Raney-Ni/dioxane; quantitatively the Δ⁸-compounds with H₂/Pd/C/EtOH; s. e.g. Scheme 3). A similar dependence on the C(13) configuration was observed in the allylic oxidation of these olefins with SeO₂ (Fieser's test, see Table), and in the acid catalyzed opening of the 7α, 8α-epoxides (e.g. 60 → 62 + 63 in the 13β-series, and 56 → 64 + 65 in the 13α-series, Scheme 8).     

Reactions of alkyl 2-benzylidene-2-polyfluoroacylacetates with N,N-dinucleophiles

Alkyl 2-benzylidene-2-polyfluoroacylacetates react with urea and thiourea to yield 5-ethoxycarbonyl-4-fluoroalkyl-4-hydroxy-6-phenylhexahydropyrimidin-2-ones and -2-thiones and with guanidine sulfate to form 2-amino-5-ethoxycarbonyl-4-fluoroalkyl-6-phenyl-1,6-dihydropyrimidines and 3,6-diethoxycarbonyl-2,7-difluoroalkyl-4,5-diphenyl-4,5-dihydro-1H-pyrido[1,2-a]pyrimidines, and they react with phenylhydrazine to afford 4-alkoxycarbonyl-3-fluoroalkyl-3-hydroxy-1,5-diphenylpyrazolidines. Hydrazine hydrate catalyzes the formation of 3,5-diethoxycarbonyl-2,6-difluoroalkyl-2,6-dihydroxy-4-phenyltetrahydropyrans. When treated with anhydrous hydrazine and o-phenylenediamine, these esters cleave to form the products of condensation of fluoroacyl ester and benzaldehyde with diamines.     

Reaction of piperidine and morpholine with 2H-pyran-2-ones, 2H-thiopyran-2-ones, 2H-pyran-2-thiones,and 2H-thiopyran-2-thiones. A novel route to thiophene derivatives

The reaction of piperidine or morpholine with 2H-pyran-2-ones was found to give open chain δ-oxoamides, while with 2H-thiopyran-2-ones, thiophene derivatives were formed. For 2H-pyran-2-thiones, either open chain δ-oxothioamides or thiophene derivatives were obtained. From the ¹ H nmr data of the pyran derivatives, the effect of the replacement of ring and carbonyl oxygens with sulphur on the chemical shift of the H-3 proton could be studied.     

Transition-Metal Free Catalytic Synthesis of Trifluoromethyl Indolines by [4+1] Cycloaddition of Trifluoromethyl Benzoxazinones with Sulfur Ylides

Stereoselective catalytic synthesis of 3-trifluoromethyl indolines through the [4+1] cycloaddition of benzoxazinones and sulfur ylides in a transition-metal-free manner was developed. In the presence of a catalytic amount of sodium hydride, aza-ortho-quinone methide intermediates were formed from trifluoromethyl benzoxazinones through decarboxylation after the first nucleophilic attack of sulfur ylides, which progressed to a second nucleophilic attack of sulfur ylides, resulting in the [4+1] cycloaddition. The key for this catalytic transformation is the dual attack of sulfur ylides on substrates. This unique transition-metal-free protocol is applicable to the synthesis of non-fluorinated vinyl-, ethynyl- or methyl-substituted indolines. The synthesis of 3-trifluoromethyl indoles was also achieved described under stoichiometric conditions.