Preparation of 4,4a,9,9a-tetrahydrocarbazoles and 1,3a,4,8b-tetra-hydrocyclopenta[b]indoles

Halocyclization of mesylates or tosylates of 2-(cycloalk-2-en-1-yl)anilines gives N-methanesulfonyl-or N-toluenesulfonyl-1-halo-1,2,3,4,4a,9a-hexahydrocarbazoles, heating of which in DMF at 160°C or in piperidine at 110°C leads to 4,4a,9,9a-tetrahydro-3H-carbazoles. Heating N-methanesulfonyl-1-iodo-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole in DMF at 180—200°C gives 1,3a,4,9b-tetrahydrocyclopenta[b]indole, while in the presence of an ortho-methyl substituent the dehydroiodination reaction proceeds in piperidine at 110°C in high yield. The effect of the nature of the ortho substituent of N-methyl-1-iodo-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole on the conformational equilibrium of the cyclopentane ring has been established by ¹H NMR spectroscopy. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1184–1190, August, 2006.     

Synthesis of 7-bromo, 7-phenylethynyl, 7-azido,and 7-nitro derivatives of N-acetyl-1,3a,4,8b-tetrahydrocyclopenta[b]indole

7-Bromo-, 7-phenylethynyl-, 7-azido-, 7-nitro-, and 5,7-dinitro-substituted N-acetyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles have been synthesized starting from anilines and 3-chlorocyclopentene. The NMR spectra of N-acetyl-7-nitro-1,3a,4,8b-tetrahydrocyclopenta[b]indoles displayed no signal doubling typical of the other 7-substituted derivatives.     

Reactions of N- and C-alkenylanilines: IX. Synthesis, oxidation, and nitration of some 7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles

Heating of 4-acyl-3-iodo-7-methyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indoles in piperidine gave 4-acyl-7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles which were oxidized with KMnO4 to obtain the corresponding 4-acyl-7-methyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole-1,2-diols. Oxidation of 4-acyl-7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles at the olefinic double bond with hydrogen peroxide in acetonitrile in the presence of formic acid afforded stereoisomeric epoxides with cis and trans orientation of the nitrogen-containing and oxirane rings. Nitration with a mixture of ammonium nitrate and trifluoroacetic anhydride produced 5-nitro derivatives. The structure of 1-{(1aR*,1bR*,6bS*,7aS*)-5-methyl-1a,1b,2,6b,7,7ahexahydrooxireno[4,5]cyclopenta[1,2-b]indol-2-yl}ethanone was determined by X-ray analysis.     

Synthesis of N-acetyl-3,3a,4,8b- and -1,3a,4,8b-tetrahydrocyclopenta[b]indoles from N- and 2-(cyclopent-2-en-1-yl)anilines

Reactions of 2-bromo-N-(cyclopent-2-en-1-yl)-4-methylaniline and N-(cyclopent-2-en-1-yl)-2-iodo-4,6-dimethylaniline with acetyl bromide in the presence of potassium carbonate gave mixtures of syn and anti atropisomers of the corresponding N-acetyl derivatives at ratios of 1: 1 and 3: 2 respectively. Heating of these mixtures in toluene in the presence of Pd(OAc)₂, PPh₃, Et₃N, and K₂CO₃ (KOAc) afforded mixtures of isomeric N-acetyl-7-methyl-3,3a,4,8b- and -1,3a,4,8b-tetrahydrocyclopenta[b]indoles at a ratio of 3: 1 or N-acetyl-5,7-dimethyl-3,3a,4,8b- and -1,3a,4,8b-tetrahydrocyclopenta[b]indoles at a ratio of 2: 3. N-Acetyl-3,3a,4,8b-tetrahydrocyclopenta[b]indole was found to undergo thermal isomerization into N-acetyl-1,3a,4,8btetrahydrocyclopenta[b]indole.     

Synthesis of 3-substituted cyclopenta[b]indoles

When reacting with I₂, 2-(cyclopent-2-enyl)anilines undergo cyclization into 3-iodo-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indoles in high yields. The minor reaction products were 3,5- or 3,7-diiodoindolines. Ammonolysis of 3-iodo-5-methyl-1,2,3,3a,4,8b-hexahydro-cyclopenta[b]indole or itsN-chloroacetyl derivative results in 3-amino-5-methyl-1,2,3,3a,48b-hexahydro- and 5-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles. Published inIzvestiya Akademii Nauk. Seriya Khimischeskaya, No. 10, pp. 1789–1793, October, 2000.     

Reaction of α,α-, α,α′-dihalothiones with 8-mercaptoquinolinium halides as a route to tetrahydro-1,4-thiazinoquinolinium halides

The reaction of 8-mercaptoquinolinium bromide with 1,3-dibromopropane-2-thione or 3,3-dibromobutane-2-thione in methanol gave the 2-bromomethyl-2-mercaptotetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium and 3-bromo-2-mercapto-2,3-dimethyltetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium bromides which readily exchanged the Br⁻ anion for ClO ₄ ⁻ upon treatment with sodium perchlorate in methanol. Oxidation of the 3-bromo-2-mercapto-2,3-dimethyltetrahydro-1,4-thiazino[2,3,3,4-i,j]-quinolinium bromide by selenium dioxide gave 2,2-dithiobis(3-bromo-2,3-dimethyltetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium) bromide. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1720–1723, November, 2006.     

Reactions of N - and C -alkenylanilines: VIII. Synthesis of functionalized cycloalka[ b ]indoles from o -(cycloalk-2-en-1-yl)anilines

N-Acyl-2-(cyclohex-2-en-1-yl)anilines react with molecular iodine to give the corresponding N-acyl-1-iodo-1,2,3,4,4a,9a-hexahydrocarbazoles which undergo isomerization into 1-R-2a,3,4,5,5a,10a-hexahydro[1,3]oxazolo[5,4,3-j,k]carbazol-10-ium iodides; no isomerization occurs with N-acetyl-3-iodo1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole. The reaction of N-p-tolylsulfonyl-3,4,4a,9a-tetrahydrocarbazoles with hydrogen peroxide leads to the formation of a single 1,2-epoxy derivative with trans orientation of the nitrogen-and oxygen-containing rings. N-p-Tolylsulfonyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles give rise to the corresponding 2,3-epoxy derivatives with both trans and cis orientation of the dihydropyrrole and oxirane fragments. The resulting epoxides undergo trans-opening with formation of N-p-tolylsulfonyl-1-hydroxy-2-methoxy-1,2,3,4,4a,9a-hexahydrocarbazoles and N-p-tolylsulfonyl-3-hydroxy-2-methoxy-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indoles on heating in methanol in the presence of KU-2 cation exchanger. Mutual orientation of the oxirane and nitrogen-containing rings in the epoxides derived from cyclopenta[b]-indoles was proved by X-ray analysis. Original Russian Text ? R.R. Gataullin, N.A. Likhacheva, K.Yu. Suponitskii, I.B. Abdrakhmanov, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 9, pp. 1316–1326. For communication VII, see [1].     

Interaction of benzimidazole-2-thione with propargyl bromide and 1,3-dibromopropyne

Interaction of benzimidazole-2-thione with propargyl bromide under found conditions permitted the direct synthesis of 2-(2-propynylsulfanyl)-3H-1,3-benzimidazolium bromide, the base 2-(2-propynylsulfanyl)-1H-1,3-benzimidazole, stable crystalline 2-(1,2-propadienylsulfanyl)-1H-1,3-benzimidazole, and 3-methyl[1,3]thiazolo[3,2-a][1,3]benzimidazole. The reaction of benzimidazole-2-thione with 1,3-dibromopropyne in chloroform or absolute methanol gave 2-(3-bromo-2-propynylsulfanyl)-3H-1,3-benzimidazolium bromide, and in absolute methanole in the presence of a twofold excess of sodium methoxide the reaction proceeded stereo-and regioselectively to give 3-[(Z)-bromomethylidene][1,3]thiazolo[3,2-a][1,3]benzimidazole. Presented to Academician B. A. Trofimov on his 70^th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1399–1405, September, 2008.     

Pyrimidine derivatives XII. A convenient preparation of 6-formylpyrimidinedione and 2- and 3-formylpyridine derivatives from corresponding nitrooxymethyl derivatives

The convenient preparation of 6-fomylpyrimidinedione derivatives and 2- and 3-formylpyridine are described. Thus, 5-bromo-1,3-dimethyl- ( 1a ), 5-bromo-3-methyl-1-(2-nitrooxyethyl)- ( 1b ), and 5-bromo-3-methyl-1-(3-nitrooxypropyl)-2,4(1H,3H)-pyrimidine-dione ( 1c ) were converted to the corresponding 6-formyl compounds 2a, 2b , and 2c , respectively, in excellent yields by the reaction with triethylamine and 1,4-diazabicyclo[2.2.2]octane. These 6-formylpyrimidinedione derivatives are key intermediates for the preparation of 6-carbon-carbon substituted compounds, which are expected to be potential antitumor and antiviral agents. Similarly, 2-(and 3-)formylpyridine ( 9a (and 9b )) were obtained by the reaction of 2-(and 3)nitrooxymethylpyridine ( 8a (and 8b )) with 1,4-diazabicyclo[2.2.2]octane.     

Synthesis and molecular structure of substituted 2-hydroxyperhydro-[1,3,2]dioxaborinino[5,4-<Emphasis Type="Italic">c</Emphasis>]pyridines,perhydro[1,3]dioxano[5,4-<Emphasis Type="Italic">c</Emphasis>]pyridine,and their precursor-4-hydroxy-3-(α-hydroxybenzyl)-1-methyl-4-phenylpiperidine

4,8a-Diphenyl-substituted 2-(2-propoxy)perhydro[1,3,2]dioxaborinino[5.4-c]pyridine was obtained by the condensation of 4-hydroxy-3-(α-hydroxybenzyl)-1-methyl-4-phenylpiperidine with triisopropyl borate, and its 2-hydroxysubstituted analog in the presence of water. 1-Methyl-4,8a-diphenyl-perhidro[1,3]dioxano[5,4-c]pyridine was synthesized by the reaction of the same piperidol with formaldehyde. A comparative study of the molecular structures of the three products was carried out by X-ray crystallography. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1726–1735, November, 2008.     

Study of Nitrogen- and Sulfur-Containing Heterocycles. 57. Synthesis and Conversion of 4′-Substituted 5-(5-Amino-6-Pyrimidylthio)-2,2-Dimethyl-4,6-Dioxo-1,3-Dioxanes

By reaction of 4-substituted 5-amino-6-mercaptopyrimidines with 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, we have obtained 4′-substituted 5-(5-amino-6-pyrimidylthio)-2,2-dimethyl-4,6-dioxo-1,3-dioxanes. We have studied diazotization of these compounds by isoamyl nitrite. In the case of 4′-methoxy- and 4′-dimethylamino-substituted derivatives, we have obtained derivatives of novel heterocyclic systems: pyrimido[5,4-e][1,3,4]thiadiazine and pyrimido[5,4-e][1,3,4]thiadiazine-7-spiro-5′-1,3-dioxane, and in the case of the 4′-isopropylamino-substituted derivative we obtained 4-isopropyl-7-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1,2,3-triazolo[5,4-d]pyrimidin-7-ylidene.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 613–623, April, 2005.     

Michael addition of N-isobutylidene-t-butylamine to dimethyl methoxymethylenemalonate and a new synthesis of some fused pyrazole derivatives from the adduct

N-Isobutylidenemethylamine reacted with dimethyl methoxymethylenemalonate to afford the N-alkylation product 3a exclusively. Exchanging the N-substituent of the Schiff's base from methyl to t-butyl altered the course of the reaction, allowing Michael addition to take place predominantly. The Michael adduct 4c on reaction with hydrazinoalkanols 6a,b, 6c,d and 6e gave tetrahydropyrazolo[5,1-b]oxazoles 9a,b , tetrahydro-pyrazolo[5,1-b][1,3]oxazines 9c,d and hexahydropyrazolo[5,1-b][1,3]oxazepine 9e , respectively.     

Preparation of tetrahydrocyclopenta[b]indoloquinones

The nitration of N-acyl-7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indole with a mixture NH₄NO₃-(CF₃CO)₂O afforded 5-nitro derivatives whose reduction with Fe(OH)₂ in H₂O led to the formation of 5-amino derivatives. The oxidation of the 5-amino derivatives with Fremy’s salt gave the corresponding indoloquinones.     

Reaction of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with electrophilic reagents: Bromine and nitric acid

Reactions of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with bromine and nitric acid lead to the electrophilic substitution of the hydrogen atom in the meta-position with respect to the nitro group. At thebromination the primarily formed 4-bromo-6-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide when kept in the solution loses an oxygen atom forming 4-bromo-6-nitrospiro[benzimidazole-2,1′-cyclohexane] 1-oxide and an isomerization product, 8-bromo-6-nitrospiro[3H-[2,1,4]benzoxadiazine-3,1′-cyclohexane] 4-oxide. The latter exposed to light turns into 4-bromo-6-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide. The reaction of the initial 1,3-dioxide with nitric acid afforded 4,6-dinitrospiro[benzimidazole-2,1′-cyclohexan]-7-ol 1-oxide whose heating in o-dichlorobenzene resulted in 3,5-dinitro-1,8-diazatricyclo[7.5.0.0^2,7] tetradeca-2(7),3,5,8-tetraen-6-ol.     

Di-6R,7R1-4(3H)-Oxo-2-quinazolinyl-substituted Cyclobutanes from Pinic and sym-Homopinic Acids

The corresponding diamides were obtained from reaction of cis-3-carboxy-2,2-dimethylcyclobutylacetic acid (pinic acid) and of cis/trans-3-(carboxymethyl)-2,2-dimethylcyclobutylacetic acid (homopinic acid) dichlorides with two equivalents of 5-bromo-, 4-chloro-, and 4,5-dimethoxyanthranilic acids. Treatment of them with formamide leads to the formation of the corresponding 2,2-dimethyl-3-[4(3H)-oxo-2-quinazolinyl]methyl-1-[4(3H)-oxo-2-quinazolinyl]cyclobutanes and 2,2-dimethyl-1,3-di[4(3H)-oxo-2-quinazolinylmethyl]cyclobutanes.     

Octahydropyrrolo[4,3,2-m,n]acridine derivatives. I. Synthesis and molecular structure of derivatives of 2,3,4,5,7,8,9,10-octahydropyrrolo[4,3,2-m,n]acridin-10-one,a new heterocyclic system

Heating 1,1-bis(5,5-dimethyl-1,3-cyclohexanedion-2-yl)acetone with ammonia gave a new heterocyclic compound, namely, 1,4,4,8,8-pentamethyl-2,3,4,5,7,8,9,10-octahydropyrrolo[4,3,2-m,n]acridin-10-one. Analogously, 3,6-dimethyl-9-benzoyl-1,2,3,4,5,6,7,8-octahydroxanthene-1,8-dione gave 4,8-dimethyl-1-phenyl-2,3,4,-5,7,8,9,10-octahydropyrrolo[4,3,2-m,n]acridin-10-one. The structures of these products were demonstrated by PMR and IR spectroscopy and x-ray diffraction analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 107–112, January, 1987.     

Synthesis of Functionalized Tetrahydro‐4‐oxoindeno[1,2‐b]pyrroles from Ninhydrin,Acetylenedicarboxylates, and Primary Amines

A one‐pot synthesis of dialkyl 1,3a,4,8b‐tetrahydro‐3a,8b‐dihydroxy‐1‐alkyl‐4‐oxoindeno[1,2‐b]pyrrole‐2,3‐dicarboxylates via three‐component reaction from indan‐1,2,3‐trione hydrate (ninhydrin), primary amines, and dialkyl acetylenedicarboxylates is described.     

2,6-Dithiodecahydro-1H,5H-Diimidazo[4,5,-b:4′,5′-e]Pyrazine and related dioxo- and diimino-decahydrodiimidazopyrazines

Thiourea condensed with 1,4-diformyl-2,3,5,6-tetrahydroxypiperazine 2 in the presence of hydrochloric acid to give 2,6-dithiodecahydro-1 H,5H-diimidazo[4,5,-b:4′,5′-e]pyrazine 5 isolated as the dihydrochloride salt. The salt 5 . 2HCl was converted to the free base 5 by lithium hydroxide, to the dinitrate salt 5 . 2HNO₃ by silver nitrate, degraded to 2-thio-2,3,4,7-tetrahydro-1 H-imidazo[4,5-b]pyrazine 6 in a reaction with tert-butyl amine, and converted to 4,8-dihydro-4,8-dinitro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine-2,6- disulfonic acid 9 by nitric acid (100%) at −40°C. Denitration of the dinitramine 9 to give 4,8-dihydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 11 was brought about by methanolic hydrogen chloride in ether. In one run nitration without oxidation converted the salt 5 · 2HCl to the dinitrate salt of the 4,8-dinitro derivative 10 ; treatment with triethyl amine liberated the free base 10 from the salt. Degradation of 2,6-dioxo-1,3,4,5,7,8-hexanitrodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 12 to 2-oxo-2,3-dihydro-1,3-dinitro-1H-imidazo[4,5-b] pyrazine 13 was brought about by hydrochloric acid. Treatment with lithium hydroxide also liberated 2,6-dioxodecahydro-1H,5H-diimidazo [4,5-b:4′,5′-e]pyrazine 3 from its dihydrochloride salt. Attempts to liberate 2,6-diiminodecahydro-1H, 5H-diimidazo[4,5-b:4′,5′-e]pyrazine 4 from its tetrahydrochloride salt led instead to intractable mixtures. The tetrahydrochloride salt 4 · 4HCl was converted to the dihydrochloride salt 4 · 2HCl in a reaction with tert-butyl amine.     

Electrocyclic rearrangement of pentamethylcyclooctapyrimidine-2,4-diones: reaction pathway into a 9,11-diazapentacyclo-[6.4.0.0(1,3).0(2,5).0(4,8)]dodecane system and a 9,11-diazapentacyclo [6.4.0.0(1,3).0(2,6).0(4,8)]dodecane system

Photolysis of 6-chloro-1,3-dimethyluracil and mesitylene in the presence of trifluoroacetic acid (TFA) at low temperature gave 1,3,5,7,9- and 1,3,6,8,10-pentamethylcyclooctapyrimidine-2,4-diones (1b, 1c). Sequential photoreaction of the former (1b) resulted in the formation of 9,11-diazapentacyclo[6.4.0.0(1,3).0(2,5).0(4,8)]dodecane-2,4-dione (2b) by way of 9-exo-methylene derivative (7b) and cyclobutaquinazoline (8b). On the other hand, UV-irradiation of 1c led to the bond shift isomer (5c) whose photolysis in the presence of TFA gave rise to the formation of the [6.4.0.0(1,3).0(2,6).0(4,8)]dodecane isomer (3c).     

Synthesis and properties of derivatives of 7-aroylalkylxanthinyl-8-thioacetic acid

When 7-aroylalkyl-8-bromo-3-methyl- and 1,3-dimethylxanthines are boiled with an excess of thioglycolic acid, a reductive dehalogenation takes place, while reaction with an equimolar amount of thioglycolic acid in DMFA leads to 7-aroylalkyl-3-methyl- and 1,3-dimethylxanthinyl-8-thioacetic acids. Cyclization of the latter with acetic anhydride in the presence of anhydrous sodium acetate results in the formation of 3-aryl-1,4-dihydro-9-methyl- and-7,9-dimethylthiazino[3,2-f]xanthine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 967–970, July, 1990.