3,6,6-trimethyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole in Schmidt reaction and Beckmann rearrangement conditions for the 4-hydroxyimino derivative

Treatment of 3,6,6-trimethyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with sodium azide in acids gives 3,7,7-trimethyl-5-oxo-1-(2-pyridyl)-5,6,7,8-tetrahydro(4H)pyrazolo[4,3-b]azepine. Heating 1-(2-pyridyl)-3,6,6-trimethyl- and 1-phenyl-6,6-dimethyl-4-hydroxyimino-4,5,6,7-tetrahydroindazoles in polyphosphoric acid gives 1-phenyl-5,6-dimethyl- and 1-(2-pyridyl)-3,5,6-trimethyl-4-aminoindazole respectively: The reactions of the latter with 4-dimethylaminobenzaldehyde gave the 4-(4-dimethylaminobenzalamino) derivative and with 2-formyldimedone the 4-(4,4-dimethyl-2,6-dioxocyclohexylidenemethylamino) derivative.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 830–834, June, 2000.     

Synthesis and Photochemistry of Novel 3,5-Diacetyl-1,4-dihydropyridines

Summary.  Some novel 3,5-diacetyl-1,4-dihydropyridine derivatives were synthesized; their photochemical behaviour was studied under oxygen or argon atmosphere. Irradiation of these compounds resulted in the aromatization of the ring and formation of 3,5-diacetylpyridine derivatives. The presence of oxygen plays an important role in the type, rate, or failure of oxidation. Irradiation of these compounds with of 2-furyl or 5-methyl-2-furyl substituents in position 4 under argon resulted in the formation of a pyridine ring with retention of these substituents, whereas loss of these substituents and ring aromatization was observed upon irradiation under oxygen. Received September 4, 2001. Accepted September 17, 2001     

Heterocyclization of Oximes of 3,5-Dimethyl(1,3,5-trimethyl)-2,6-diphenylpiperid-4-ones and N-Benzylpyrrolid-3-ones with Acetylene in a Superbasic Medium

It has been established that on heterocyclization of 3,5-dimethyl-2,6-diphenylpiperid-4-one oxime with acetylene in a superbasic medium migration of the 3a-CH₃ group to the anionic nitrogen atom occurs, leading to the formation of 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine. The formation of the N-anion causes aromatization of the tetrahydropyridine ring. Tetrahydropyrrolo[1,2-c]pyrimidines are formed in the Trofimov reaction as a result of decomposition of the intermediate 3H-pyrrole in a retro-Mannich reaction.     

One-pot four-component synthesis of 4-hydrazinothiazoles: novel scaffolds for drug discovery

One pot ring synthesis of novel 4-hydrazinothiazoles through sequential four-component route employing carbonyl compounds, aminoguanidine, isothiocyanates, and α-haloketones was accomplished under mild reaction conditions. Base-assisted eliminative aromatization in the [4+1] ring synthesis shed light on interesting leaving group propensities of amine versus hydrazine resulting in the exclusive formation of the title compounds with immense potential as scaffolds for drug discovery. Hydrazone deprotection was effected by acylation which subsequently provided a new set of diacylated molecular systems with a wider scope as chemical handles in the design of thiazolyl drug candidates.     

Studies on 1, 2, 4-Benzothiadiazine 1, 1-Dioxide IX.1 Synthesis and Pharmacological Evaluation of 1, 2, 4-Benzothiadiazine 1, 1-Dioxide Biphenyl Tetrazoles as Angiotensin II Antagonists

In the course of our investigations on the development of cardiovascular agents, 3-butyl-2-[2′-(2H-tetrazol-5-yl)bipheny]-4-yl]methyl-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide ( 2 ) was considered as a potential angiotensin II antagonist on the basis of bioisosteric replacement of the quinazoline ring of compound 1 with a 1, 2, 4-benzothiadiazine 1, 1-dioxide ring system. Alkylation of 6 with 4 afforded 7 and 8 in 24% and 28% yields, respectively. An attempt to remove the trityl group of compounds 7 and 8 under acidic condition gave the ring opened products 9 and 11 in 28% and 36% yields, respectively. However, compounds 2 and 10 were obtained in 46% and 85% yields when compounds 7 and 8 were refluxed in methanol. Preliminary assays of compounds 9 and 11 against angiotensin II receptors revealed weak activity with IC₅₀ values of 3.6 μM and 5.4 μM, respectively. Compound 10 (IC₅₀ = 87 nM) exhibited stronger binding affinity than compound 2 (IC₅₀ = 750 nM).     

Anomalous Beckmann Reaction in a Series of Oximes of 4-Aryl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines in Polyphosphoric Acid. 2. Unexpected Synthesis of 3'-Ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'-tetrahydrospiro(cyclohexa-2,5-diene-1,2'-pyrrolo[4,3,2-d,e]quinolines)

Oximes of 3-ethoxycarbonyl-4-halo(methoxy)phenyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines are converted in polyphosphoric acid (PPA) into 3'-ethoxycarbonyl-4',7',7'-trimethyl-4-oxo-2',6',7',8'-tetrahydrospiro(cyclohexa-2,5-diene-1,2'-pyrrolo[4,3,2-d,e]quinoline). An X-ray structural analysis has been carried out on one of the synthesized compounds.     

Synthesis of 5-(1H-benzimidazol-2-yl)-1H-pyrazolo-[3,4-<Emphasis Type="Italic">b</Emphasis>]pyridines by the <Emphasis Type="Italic">p</Emphasis>-(dimethylamino)benzaldehyde modification of Hantzsch reaction

The reactions of p-(dimethylamino)benzaldehyde with 5-amino-3-methyl-1-phenylpyrazole and 2-RCOCH₂-1H-benzimidazoles have produced 5-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines. The transformation includes the formation of compounds in accordance with a Hantzsch reaction containing a 1,4-dihydropyridine ring, and is completed by the aromatization either by the splitting off of N,N-dimethylanyline or oxidation. The splitting is produced by acetic acid and the oxidation by a nitrocompound. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 578–584, April 2007.     

Molecular and crystal structure of 4,6,6-trimethyl-2-oxo-5,6-dihydro-2H-pyran-3-carbonitrile and 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

Single crystals of 4,6,6-trimethyl-2-oxo-5,6-dihydro-2H-pyran-3-carbonitrile and 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile were prepared and submitted to X-ray diffraction analysis. Both compounds have a molecular structure belonging to the C₁ symmetry group. The heterocyclic rings are in a distorted envelope conformation. The crystals belong to the monoclinic system and each contain four molecules in the unit cell. In the crystal the pyridine derivative exists in the form of centrosymmetric dimers stabilized by intermolecular hydrogen bonds between the oxygen atoms of the carbonyl group and the hydrogen atom at the nitrogen atom of the ring. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1620–1624, November, 2007.     

Synthesis and Photochemistry of Novel 3,5-Diacetyl-1,4-dihydropyridines

 Some novel 3,5-diacetyl-1,4-dihydropyridine derivatives were synthesized; their photochemical behaviour was studied under oxygen or argon atmosphere. Irradiation of these compounds resulted in the aromatization of the ring and formation of 3,5-diacetylpyridine derivatives. The presence of oxygen plays an important role in the type, rate, or failure of oxidation. Irradiation of these compounds with of 2-furyl or 5-methyl-2-furyl substituents in position 4 under argon resulted in the formation of a pyridine ring with retention of these substituents, whereas loss of these substituents and ring aromatization was observed upon irradiation under oxygen.     

A novel synthetic approach to 4-acetamido-1-arylindazoles via Semmler–Wolff rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime

A simple and efficient procedure for the syntheses of 4-acetamido-1-arylindazoles from corresponding 1-aryl-6,7-dihydro-5H-indazol-4-one oximes by Semmler–Wolff aromatization using acetic anhydride and sodium iodide is reported.     

Oxidizing Reactions of Azines. 7. Imination of 4-Aryl-1,2,3,6-tetrahydropyridines by Arylamines in the Presence of Potassium Permanganate. Molecular Structure of 1-Methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine

On treating 4-aryl substituted 1-methyl-1,2,3,6-tetrahydropyridines with potassium permanganate in the presence of arylamines a previously unknown intermolecular oxidative imination reaction occurs leading to the formation of 2-(arylimino)-1,2,5,6-tetrahydropyridines. The molecular structure of 1-methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine was studied by X-ray analysis and it was shown that the hydropyridine ring of the molecule has a sofa conformation and its amidine fragment is in the E-configuration.     

TiCl(4)-promoted Baylis-Hillman reactions of substituted 5-isoxazolecarboxaldehydes with cycloalkenones)

The Baylis-Hillman (BH) reaction of substituted 5-isoxazolecarboxaldehydes with cyclohexenone in the presence of TiCl(4) invariably lead to the formation of hemiacetals beside the BH adducts. A similar reaction in the presence of DABCO, DBU, or 3-HQN yielded minor quantities of phenols in addition to the usual BH adducts. Similar to 5-isoxazolecarboxaldehydes, the TiCl(4)-mediated BH reaction of cyclohexenone with various benzaldehydes also furnishes hemiacetals in considerable yields. The reaction mechanism involving the formation of alpha-chloromethyl enone as an intermediate has been proposed. The synthesis of hemiacetals 5 and 14 from compound 4 in the presence of cyclohexenone and cyclopentenone, respectively, under acidic conditions indicates that enolization and aromatization of the cyclohexene ring are the key steps in the reaction mechanism.     

An efficient approach to isoindolo[2,1-b][2]benzazepines via intramolecular [4+2] cycloaddition of maleic anhydride to 4-α-furyl-4-N-benzylaminobut-1-enes

Acylation of 4-α-furyl-4-N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid via amide formation followed by intramolecular Diels-Alder reaction of furan (IMDAF). The cycloaddition proceeded under mild reaction conditions (25 °C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave isoindolo[2,1-b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acids were further transformed into useful synthetic intermediates.     

Synthesis and antiemetic activity of 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives

5-HT₃ receptor antagonists, such as Ondansetron, are used for anti-emesis after chemotherapy, radiotherapy and operations. Some Ondansetron analogs possessing piperazine ring as side chains were synthesized in our lab. Thus, one of the two carbonyl groups of starting material 1,3-cyclohexandione (1) was condensed with phenylhydrazine hydrochloride to form monophenylhydrazone (2). 1,2,3,9-Tetrahydro-4H-carbazol-4-one (3) was prepared from 2 via cyclization and rearranged in the presence of ZnCl₂. Through a methylation reaction, compound 3 was converted to 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (4). 3-Dimethylaminomethyl substituted compound (5) was synthesized from 4 by a Mannich reaction in glacial acetic acid. Nine novel 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives (6a–6i) were synthesized through nucleophilic substitution reaction of 5 with piperazines. The structures of all the target compounds were determined by elemental analysis, IR, MS, ¹H NMR and ¹³C NMR spectra. The results of preliminary pharmacological test show that part of the novel compounds have antiemetic activity comparable to that of the control Ondansetron. __________ Translated from Chinese Journal of Organic Chemistry, 2008, 28(2) (in Chinese)     

2-Trif luoromethyl-4H-thiochromen-4-one and 2-trif luoromethyl-4H-thiochromene-4-thione: Synthesis and reactivities

2-Trifluoromethyl-4H-thiochromene-4-thione obtained from 2-trifluoromethyl-4H-thiochromen-4-one and P₂S₅ reacts with aromatic amines, hydrazine hydrate, phenylhydrazine, and hydroxylamine at the C(4) atom of the chromene ring to give the corresponding anils, azine, hydrazones, and oxime of thiochromone. 2-Trifluoromethyl-4H-thiochromen-4-one is oxidized by hydrogen peroxide in AcOH into 4-oxo-2-trifluoromethyl-4H-thiochromene 1,1-dioxide and reduced by NaBH₄ to 2-trifluoromethyl-4H-thiochromen-4-ol or cis-2-(trifluoromethyl)thiochroman-4-ol. When treated with hydrazine hydrate, thiochromen-4-one gives 3(5)-(2-mercaptophenyl)-5(3)-trifluoromethylpyrazole. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 504–509, March, 2006.     

Synthetic exploitation of the ring-opening of 3,4-dinitrothiophene. Part 4. Synthesis of 1,4-disubstituted 3-hydroximino-2-nitro-1-butenes and their cyclization to 4-nitroisoxazoles

The reduction of a single nitrovinyl moiety in 1,4-dialkyl- and 1,4-diaryl-2,3-dinitro-1,3-butadienes 1 with stannous chloride dihydrate in ethyl acetate furnishes the corresponding 3-hydroximino-2-nitro-l-butenes 4 in satisfactory yields. The oxidative cyclization of the latter compounds gives variable yields of 3,5-disubsti-tuted 4-nitroisoxazoles 5 , most likely arising from aromatization of the corresponding 4,5-dihydroisoxazoles, formed through an intramolecular Michael addition of the hydroximino group in 4 to the nitroalkene functionality. In the case of the l-naphthyl derivative 4d such oxidative cyclization mainly leads to the competitive formation of 3-[(l-naphthyl)methyl]-2-nitrobenzo[f]quinoline N-oxide 7.     

Photocycloaddition of Quinoxaline-2(1H)-thiones to Alkenes

A synthetically useful C? C bond formation involving the photochemical addition of quinoxaline-2(1H)-thiones to alkenes is described. Irradiation of the quinoxaline-2(1H)-thiones 1–4 in the presence of the alkenes 7 gave the 2-(2′-mercaptoalkyl)quinoxalines 8–11 in moderate-to-good yields via ring cleavage of an intermediate aminothietane with aromatization of the quinoxaline ring. The latter was formed by [2+2] photocycloaddition of the C?S bond of the quinoxaline-2(1H)-thione and the C?C bond of the alkene.     

Polymerization systems driven by aromatization energy: Anionic polymerization of 4-allylidene-2,6-dimethyl-2,5-cyclohexadien-1-one and spiro[2,5]octadienone derivatives

To investigate the polymerization systems driven by aromatization energy, 4-allylidene-2,6-dimethyl-2,5-cyclohexadien-1-one ( Ia ), 5,7-dimethyl-1-vinylspiro[2,5]octa-4,7-dien-6-one ( Ib ), 4,7-dimethyl-1-vinylspiro[2,5]octa-4,7-dien-6-one [ Ic ], 2-vinyl-2′-methylspiro[cyclopropane-1,4′-(1′-naphthalenone)] ( Id ), and 2-phenyl-2′-methylspiro[cyclopropane-1,4′-(1′-naphthalenone)] ( Ie ) were prepared and polymerized with sodium cyanide in N,N-dimethylformamide. Monomer Ia was highly polymerizable even at ?65°C. Monomers Ib–Ie also polymerized well, giving powdery polymers that were soluble in common solvents. All the polymerizations took place through the aromatization of the cyclohexadienone ring, suggesting that the aromatization energy is the driving force for the polymerization of these monomers.