Regioselective 1,3-Dipolar Cycloaddition Reactions of Unsymmetrical Münchnones (1,3-Oxazolium-5-olates) with 2- and 3-Nitroindoles. A New Synthesis of Pyrrolo[3,4-b]indoles

The unsymmetrical mesoionic münchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenylsulfonyl)indole), and 17 (ethyl 3-nitroindole-1-carboxylate) in refluxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles 15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 18 (2-benzyl-1-methyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole). In several cases the regiochemistry, which is opposite to that predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6+13→19 in 74% yield.     

Synthesis of 1H-thieno[3,4-c]pyrazoles,thieno[3,4-b]furans,selenolo[3,4-b]furans and pyrrolo[3,4-d]thiazoles

Starting from the readily available aryl 2-methyl-5-phenyl-3-furyl ketones, 5-methyl-1H-1-phenylpyrazole-4-yl ketones and 4-methyl-2-phenyl-5-thiazolylcarboxaldehyde, a series of 2-phenyl-4-arylthieno[3,4-b]-furan, 2-phenyl-4-(p-methoxyphenyl)selenolo[3,4-b]furan, 4-aryl-1H-1-phenylthieno[3,4-c]pyrazole and 5-benzyl-2-phenylpyrrolo[3,4-d]thiazole were prepared in high yield.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VI. Synthesis of ethyl or methyl 1,5-disubstituted 1H-pyrazole-4-carboxylates

Reaction of ethyl or methyl 3-oxoalkanoates with N,N-dimethylformamide dimethyl acetal gave, generally in excellent yields, a series of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates II which reacted with phenylhydrazine to afford the esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids III in high yields. Esters III were hydrolyzed to the relative 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles in excellent yields. Reaction of II with methylhydrazine afforded in general a mixture of 3- and 5-substituted ethyl 1-methyl-1H-pyrazole-4-carboxylates with the exception of IIg , which gave in high yield methyl 5-benzyl-1-methyl-1H-pyrazole-4-carboxylate, which was hydrolyzed to the relative pyrazolecarboxylic acid. This afforded by heating 5-benzyl-1-methyl-1H-pyrazole in quantitative yield.     

Synthesis of 4H-pyrazolo- and 4H-pyrrolophenothiazin-4-one derivatives

5-Methyl- and 6-methyl-2-phenyl-2H-indazole-4,7-diones were condensed with 2-aminobenzenethiol or 6-substituted-3-aminopyridine-2(1H)thiones 4 to produce a new type of 5-methyl-2-phenyl-4H-pyrazolophenothiazin-4-ones or 8-substituted-7-aza-5-methyl-2-phenyl-4H-pyrazolophenothiazin-4-one derivatives. From 6-bromo-2,5-dimethyl-1,3-diphenyl-2H-isoindole-4,7-dione and 4 8-substituted-7-aza-2,5-dimethyl-1,3-diphenyl-4H-pyrrolophenothiazin-4-one derivatives were also prepared.     

Bildung von 5,6-Dihydro-1,3(4H)-thiazin-4-carbonsäure-estern aus 4-Allyl-1,3-thiazol-5(4H)-onen

Formation of Methyl 5,6-Dihydro-l, 3(4H)-thiazine-4-carboxyiates from 4-Allyl-l, 3-thiazol-5(4H)-ones . The reaction of N-[1-(N, N-dimethylthiocarbamoyl)-1-methyl-3-butenyl]benzamid ( 1 ) with HCl or TsOH in MeCN or toluene yields a mixture of 4-allyl-4-methyl-2-phenyl-1,3-thiazol-5(4H)-one ( 5a ) and allyl 4-methyl-2-phenyl-1,3-thiazol-2-yl sulfide ( 11 ; Scheme 3). Most probably, the corresponding 1,3-oxazol-5(4H)-thiones B are intermediates in this reaction. With HCl in MeOH, 1 is transformed into methyl 5,6-dihydro-4,6-dimethyl-2-phenyl-1,3(4H)-thiazine-4-carboxylate ( 12a ). The same product 12a is formed on treatment of the 1,3-thiazol-5(4H)-one 5a with HCl in MeOH (Scheme 4). It is shown that the latter reaction type is common for 4-allyl-substituted 1,3-thiazol-5(4H)-ones.     

One-pot synthesis of 2-isopropyl-3-benzyl-1,3-thiazolidin-4-ones and 2-phenyl-3-isobutyl-1,3-thiazolidin-4-ones from valine, arenealdehydes and mercaptoacetic acid

A three-component one-pot synthesis of 2-isopropyl-3-benzyl-1,3-thiazolidin-4-ones and 2-phenyl-3-isobutyl-1,3-thiazolidin-4-ones from valine, arenealdehydes and mercaptoacetic acid with good yields is reported. Characterization of products was generally achieved by NMR techniques and specifically for 2-isopropyl-3-(4-nitrobenzyl)-1,3-thiazolidin-4-one by X-ray crystallography.     

Reaction of 2-isobutyl-5-methyl-4-phenyl-1,3,2-dioxaborinane with acetonitrile

Reaction of 2-isobutyl-5-methyl-4-phenyl-1,3,2-dioxaborinane (a mixture ofcis- andtrans-isomers in a 81 : 19 ratio) with acetonitrile yielded 2,5-dimethyl-4-phenyl-5,6-dihydro1, 3-oxazine as a mixture ofcis- andtrans-forms in a 50 : 50 ratio. The possible mechanism of this transformation is discussed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1297–1298, May, 1996.     

Synthesis of Some New Thiazoles and Pyrazolo[1,5-a]pyrimidines Containing an Antipyrine Moiety

Ethyl 2-{2-[4-(2,3-dimethyl-5-oxo-1-phenyl-3-(pyrazolin-4-yl)]-2-cyano-1-(phenylamino)vinylthio}-acetate, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl-(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]2-(4-oxo-3-phenyl-(1,3-thiazoilidin-2-ylidene))ethanenitrile, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]-2-(4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))ethanenitrile, 2-(5-acetyl-4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))-2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]ethanenitrile, and ethyl 2-(cyano(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)methylene)-2,3-dihydro-4-methyl-3-phenylthiazole-5-carboxylate were synthesized by treatment of 2-(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-mercapto-3-(phenylamino)-acrylonitrile with appropriate halo ketones or halo esters. Also, 4-{2-[5,7-dimethyl-2-(phenylamino)(7a-hydropyrazolo[1,5-a]pyrimidin-3-yl](1,-thiazol-4-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one derivatives were synthesized via reaction of 4-{2-[5-amino-3-(phenylamino)pyrazolin-4-yl](1,3-thiazol-2-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with β-diketone or β-keto ester. All synthesized compound were established by elemental analysis, spectral data, and alternative synthesis whenever possible.     

Synthesis and crystal structure of ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate

Reaction of 5-phenyl-2,3-dihydro-2,3-furandione with ethyl 3-benzylamino-2-butenoate, resulting in ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate and benzylamide ofN-benzoylpyruvic acid, was studied. The structure of the pyrrole derivative was confirmed by X-ray analysis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1552–1555, August, 1995.     

Oxidation of 1,3-Dioxacycloalkanes with Complexes of Potassium Chlorochromate and Chlorodiperoxochromate with 15-Crown-5, Catalyzed with 2,2,5,5-Tetramethyl- 4-phenyl-3-oxo-3λ5-imidazolin-1-yloxyl

2,2,5,5-Tetramethyl-4-phenyl-3-oxo-3⁵-imidazolin-1-yloxyl catalyzes oxidation of 2-isopropyl-1,3-dioxolane, 2-phenyl-1,3-dioxolane, 2-phenyl-4-chloromethyl-1,3-dioxolane, and 2-phenyl-1,3-dioxane with 15-crown-5 complexes of potassium chlorodiperoxochromate (KCrO₅Cl·2C₁₀H₂₀O₅) and potassium chlorochromate (KCrO₃Cl·2C₁₀H₂₀O₅). 2-Isopropyl-1,3-dioxolane is oxidized to the corresponding monoester in quantitative yield, and the 2-phenyl derivatives yield benzaldehyde. The spiro ketal, 2,2-pentamethylene-4-methyl-1,3-dioxane, is decomposed to cyclohexanone.     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

Novel four-component route to the synthesis of spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives

An effective route to spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives is described. This involves reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, and benzylamine derivatives or aliphatic amines in the presence of alkyl acetoacetate (1,3-dicarbonyl compounds) in dry methanol under reflux conditions. The reactive 1:1 enaminone, which is obtained from the addition of the amine to 1,3-dicarbonyl compound, adds to the α,β-unsaturated ketone, which is formed from the reaction of isatin and 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, to produce the alkyl 1′-benzyl-2′-methyl-2-oxo-6′-phenyl-1′H-spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives in excellent yields.     

Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (emivirine)

Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7- hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4- dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4- dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated emivirine analogues 7-(3,5-dimethylphenyl)-1- ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline- 2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locaTed analogues of emivirine. However, the compounds 4 6 showed lower activities against HIV-1 than emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.     

Formation of pyrrole derivatives through aminolysis of 2-azetidinone derivatives

A mixture of 3-(α,β-epoxyisopropyl)-1-phenyl-2-azetidinone and benzylamine was heated in a sealed tube at 120–130° yielding 4-anilinomethyl-1-benzyl-3-hydroxy-3-methyl-2-pyrrolidinone as a mixture of diastereoisomers. By this method, 4-anilinomethyl-3-hydroxy-3-methyl-1-phenyl-2-pyrrolidinone and 4-anilinomethyl-3-hydroxy-3-methyl-1-(3,4-dimethoxyphenethyl)-2-pyrrolidinone were obtained by using aniline and 3,4-dimethoxyphenethylamine, respectively, instead of benzylamine. The reaction of 4-formyl-1-phenyl-2-azetidinone with 3,4-dimethoxyphenethylamine afforded 4-anilino-1-(3,4-dimethoxyphenethyl)-2,3-dihydro-2-oxopyrrole. In a similar fashion, the 1-n-butyl and 1-isobutyl analogues were obtained by the use of n-butylamine and isobutylamine, respectively, instead of 3,4-dimethoxyphenethylamine.     

Alternative Synthesis and Crystal Structures of Titanocene(III)-β-Diketonate Complexes

Abstract

Reaction of titanocene prepared from Cp₂TiCl₂ and 2n-BuLi with β-diketones (β-diketone = 1-phenyl-1,3-butanedione, 1,3-diphenyl-1,3-propanedione, 3-methyl-2,4-pentanedione or 3-ethyl-2,4-pentanedione) afforded the titanocene(III) β-diketonate complex. The compounds [Ti(η⁵-Cp)₂(1-phenyl-1,3-butanedionate)] and [Ti(η⁵?Cp)₂(1,3-diphenyl-1,3-propanedionate)] have been characterized by X-ray crystallography.     

Synthesis and structure determination of isomeric 7- and 8-chloro-1,5-benzodiazepine derivatives

Reaction of 4-chloro-1,2-benzenediamine with 3,3-dimercapto-1-phenyl-2-propen-1-one afforded, as expected, a mixture of 7-chloro and 8-chloro-1,3-dihydro-4-phenyl-2H-1,5-benzodiazepine-2-thione. After separation of the two components and further reaction, their structure was established by chemical degradation of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine to 5-chloro-1,3-dihydro-1-methyl-2H-benzimidazol-2-one. The structure was also confirmed by single X-ray analysis of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine.     

Crystal structure of diethyl-1-isobutyl-9-hydroxy-9-methyl-7-phenyl-1,4-diazaspiro[4,5] decane-6,8-dicarboxylate C25H38N2O5

The reaction of diethyl-4-hydroxy-4-methyl-2-phenyl-6-oxocyclohexane-1,3-dicarboxylate with Nisobutylethylenediamine is performed and the crystal structure of this reaction product (diethyl-1-isobutyl-9-hydroxy-9-methyl-7-phenyl-1,4-diazaspiro[4,5]decane-6,8-dicarboxylate) is determined by X-ray crystallography.     

The reaction of 4-amino-2-oxazolines with isocyanates and isothiocyanates. Synthesis and X-ray structures of polysubstituted 2-imidazolidinones, 1,3-oxazolidines and 1,3-thiazolidines

Reactions of 4-alkylamino-2-phenyl-2-oxazolines 1 with isocyanates and isothiocyanates provide unprecedented efficient and regioselective heterocycle-heterocycle transformations. Compounds 1 reacted rapidly with tosyl isocyanate yielding directly 3-alkyl-4-benzamido-1-tosyl-2-imidazolidinones 4 in almost quantitative yields. The corresponding ureido intermediates 2 were not isolable species. However, the reactions with non-sulfonylated isocyanates or isothiocyanates were slower, leading to the expected ureido and thioureido derivatives 5, which were easily and efficiently transformed to either polysubstituted 2-imino-1,3-oxazolidine or 2-imino-1,3-thiazolidine hydrochlorides 7, respectively, by treatment with hydrochloric acid. The possible reasons for this disparity in chemical behaviour are discussed. X-ray crystallographic structures for 4-benzamido-3-methyl-1-tosyl-2-imidazolidinone 4b, 4-[1-isopropyl-3-(4-nitrophenyl)ureido]-2-phenyl-2-oxazoline 5e, (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-oxazolidine hydrochloride 7a and (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-thiazolidine hydrochloride 7b have been determined.     

Ringschlussreaktionen mit 2-(β-Styryl)benzylaminen 5-Phenyl-1H-2-benzazepine. 23. Mitteilung über siebengliedrige Heterocyclen

Cyclization reactions with 2-(β-styryl)benzylamines 5-Phenyl-1H-2-benzazepines Cyclization of the urea derivative 3 with POCl₃ to give 2-(4-methyl-1-piperazinyl)-4-phenylquinoline ( 4 ) was carried out in analogy to the quinoline synthesis of Foulds & Robinson. This reaction was used for the preparation of 2-benzazepines. The trisubstituted ureas 6 and 8 , derived from the 2-(β-styryl)-benzylamines 5 , were cyclized with POCl₃ to yield the 3-amino-5-phenyl-1H-2-benzazepines 7 and 9 , respectively. Similarly, cyclization of the corresponding acetyl-derivatives 10 gave the 3-methyl-5-phenyl-1H-2-benzazepines 12 . On the other hand, the disubstituted urea 15 , cyclized under the same conditions to the 1-methyl-1-phenylisoindoline derivative 16 , and 2-(β-styryl)benzylamine ( 5a ) on treatment with phosgene gave the isoindoline 17 in an analogous manner.     

Conformational preferences of Si–Ph,H and Si–Ph,Me silacyclohexanes and 1,3-thiasilacyclohexanes. Additivity of conformational energies in 1,1-disubstituted heterocyclohexanes

The conformational equilibria of 1-phenyl-1-silacyclohexane 1, 3-phenyl-1,3-thiasilacyclohexane 2, 1-methyl-1-phenyl-1-silacyclohexane 3, and 3-methyl-3-phenyl-1,3-thiasilacyclohexane 4 have been studied for the first time by low temperature ¹³C NMR spectroscopy at 103 K. Predominance of the equatorial conformer of compound 1 (Ph_eq/Ph_ax=78%:22%) is much less than in its carbon analog, phenylcyclohexane (nearly 100% of Ph_eq). And in contrast to 1-methyl-1-phenylcyclohexane, the conformers with the equatorial Ph group are predominant for compounds 3 and 4: at 103 K, Ph_eq/Ph_ax ratios are 63%:37% (3) and 68%:32% (4). As the Si–C bonds are elongated with respect to C–C bonds, the barriers to ring inversion are only between 5.2–6.0 (ax→eq) and 5.4–6.0 (eq→ax) kcal mol^?1. Parallel calculations at the DFT and MP2 level of theory (as well as the G2 calculations for compound 1) show qualitative agreement with the experiment. The additivity/nonadditivity of conformational energies of substituents on cyclohexane and silacyclohexane derivatives is analyzed. The geminally disubstituted cyclohexanes containing a phenyl group show large deviations from additivity, whereas in 1-methyl-1-phenyl-1-silacyclohexane and 3-methyl-3-phenyl-1,3-thiasilacyclohexane the effects of the methyl and phenyl groups are almost additive. The reasons for the different conformational preferences in carbocyclic and heterocyclic compounds are analyzed using the homodesmotic reactions approach.