Macroexpansion methodology : Medium ring synthesis based on an eight unit ring expansion process

Treatment of 1,2-(E,E)-di(1-buta-1,3-dienyl)cyclohexanol (21) with potassium hydride in tetrahydrofuran at room temperature resulted in the facile formation of a 14-membered ring dienolate which on kinetic protonation provided cyclotetradeca-3,5,7-trien-1-one. This novel rearrangement which provides the basis for an efficient, eight unit ring expansion method was also observed when 5,8-dimethyl-5-hydroxy-1,3,7,9-decapentaene (28), the acyclic analogue of 21, was treated with potassium hydride in tetrahydrofuran. Methodology for the preparation of 21 and 28 including the preparation of 1-lithio-1,3-butadiene is also described.     

Synthesis and ring transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-ones

Heating 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolinium chloride in the presence of hydrazine bishydrate produces regioselectively the five-membered heterocycle 1-amino-1,2,3,9a-tetrahydro-9,9,9a-trimethylimidazo[1,2-a]indol-2(9H)-one. The assignment of the structure is based on extensive ¹H, ¹³C and ¹⁵N NMR spectroscopic studies. No ring-chain tautomerism of the 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one was observed to open-chain hydrazides or the corresponding six-membered 1,2,10,10a-tetrahydro[1,2,4]triazino[4,3-a]indol-3(4H)-one. Further transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one were performed by treatment with aromatic aldehydes, acid chlorides and isocyanates giving access to 40 novel hydrazones, N,N′-diacylhydrazines, N-acyl-N′-carbamoylhydrazines and 1,3,4-oxadiazoles.     

Alkylation of 1,2,3-benzotriazole with iodomethyl ketones

Solvent-free reactions of 1,2,3-benzotriazole with 1-iodopropan-2-one and 1,3-diiodopropan-2-one in the absence of a catalyst involved alkylation of the heteroring at the N¹ atom and subsequent quaternization at the N³ atom with formation of 1,3-bis(2-oxopropyl)-1H-1,2,3-benzotriazolium triiodide which is a new conducting ionic liquid. The reaction of 1,2,3-benzotriazole with 1,3-diiodopropan-2-one was accompanied by reductive deiodination of the iodomethyl groups in the initial ketone with hydrogen iodide liberated by N¹-alkylation. Triiodide ion readily exchanges for nitrate ion by the action of AgNO₃ to produce 1,3-bis(2-oxopropyl)-1H-1,2,3-benzotriazolium nitrate. The reaction of 1,2,3-benzotriazole with 2-iodo-1-phenylethan-1-one in melt resulted in the formation of 1,3-bis(2-oxo-2-phenylethyl)-1H-1,2,3-benzotriazolium triiodide.     

Verbenone in the synthesis of o-menth-1-en-3-one and 5,7,7-trimethylazabicyclo[4.1.1]octane derivatives

At treatment with sulfuric acid in acetonitrile solution the verbenone (4,6,6-trimethylbicyclo[3,1.1]hept-3-en-2-one) suffers an opening of the four-membered ring with the rupture of the C¹-C⁶ bond of the pinane skeleton and transforms into o-menthene derivatives, o-mentha-1,6-dien-3-one and 8-acetamido-o-menth-1-en-3-one, whose ratio depends on the reaction conditions. E-and Z-isomers of verbenone oxime under the same conditions undergo the Beckmann rearrangement leading to the formation of 5,7,7-trimethyl-3-azabicyclo[4.1.1]oct-4-en-2-one and 5,7,7-trimethyl-2-azabicyclo[4.1.1]oct-4-en-3-one, respectively.     

Formation of pyridin-4(1H)-one versus 1H-azepin-4(7H)-one by treatment of 4-tert-butyldimethylsilyloxy-2-amino-1-aza-bicyclo[4.1.0]hept-3-enes with tetrabutylammonium fluoride

Cycloadducts 3 and 4 were treated with tetrabutylammonium fluoride and rapidly suffer cleavage on the three-membered ring to form either pyridin-4(1H)-one or 1H-azepin-4(7H)-one. When R¹ is an oxycarbonyl or a 2-pyridyl group and R² is a negative charge-stabilizing group (cases 3a,b and 4f) the C-C bond cleaves forming products 5. However, when R²=H (case 3c) the ring expands to seven members. When R¹ is an acyl group the pyridin-4(1H)-one formation includes an unexpected shift of the carbonyl group.     

Solvent-controlled dehydration and diastereoselective formation of indenone-fused thiazolo[3,2-a]pyridines via a one-pot four-component reaction

A solvent-controlled four-component reaction has been described for the preparation of either hydroxy-tetrahydro-thiaza-cyclopenta[c]fluoren-6-one or dihydro-thiaza-cyclopenta[c]fluoren-6-one from nitroketene dithioacetals, cysteamine hydrochloride, 1,3-indandione and aromatic aldehydes starting materials by changing solvent systems. These reactions proceed under catalyst-free conditions affording a range of two types of skeletally distinct thiazolo[3,2-a]pyridines-based heterocycles. Hydroxy-tetrahydro-thiaza-cyclopenta[c]fluoren-6-one was obtained in H₂O/EtOH (3:1, v/v) in high yield and diastereoselectivity but in contrast dihydro-thiaza-cyclopenta[c]fluoren-6-one was synthesised in EtOH in moderate to good yields and in the longer reaction time. The structural diversities have been confirmed spectroscopically, by IR ¹H and ¹³C NMR, and EI-MS spectra, which agree with the proposed structures.     

Samarium dienolate mediated stereoselective synthesis of anti-1,3-diol monoesters via aldol-Tishchenko reaction

The reaction of an (E)-samarium dienolate, generated by the regioselective reductive cleavage of a phenylsulfonyl activated cyclopropyl ketone with samarium(II) iodide, with aliphatic and aromatic aldehydes gives the 2-substituted anti-1,3-diol monoester derivatives, stereoselectively, in good to excellent yields. The results represent the first report of a dienolate in the aldol-Tishchenko reaction and also provide an optically active polyol with (R)-glyceraldehyde.     

Arylation of geminally activated nitroethenes

3-Aryl-2-nitroprop-2-enenitriles and 1,3-diphenyl-2-nitroprop-2-en-1-one reacted with N,N-dimethylaniline to give the corresponding arylation products, 3-aryl-3-(4-dimethylaminophenyl)-2-nitropropanenitriles and 3-(4-dimethylaminophenyl)-1,3-diphenyl-2-nitropropan-1-one, whose structure was confirmed by IR and ¹H and ¹³C-{¹H} spectroscopy with the use of ¹H-¹³C HMQC and HMBC heteronuclear correlation techniques.     

Alkylation of C- and N-aminotriazoles with α-iodoketones

C- and N-Amino-1,2,4-triazoles react with 1-iodopropan-2-one in the absence of bases and phasetransfer catalysts (40°C, 9-12 h) to furnish 3-amino-1,4-bis(2-oxo-propyl)-4H-1,2,4-triazolium triiodide and 4-amino-1-(2-oxopropyl)-4H-1,2,4-triazolium iodide. The alkylation of 1,2,4-triazol-4-amine with 1-iodopropan-2-one and 1,3-diiodopropan-2-one in the presence of elemental iodine led to the formation of 4-amino-1-(2-oxopropyl)-4H-1,2,4-triazolium triiodide and 2-oxopropane-1,3-diylbis(4-amino-4H-1,2,4-triazolium) bis(triiodide). Triiodides are oily fluids possessing electric conductivity of 1.1 × 10^?3 Ω m^?1 opening the route to new types of electroconducting ionic liquids.     

Synthesis,characterization and study of antibacterial activity of enaminone complexes of zinc and iron

Complexes of enaminones; 4-N,N-diethylamine-pent-3-ene-2-one [HL¹], 4-N,N-di n-propylamine-pent-3-ene-2-one [HL²] and 4-N,N-dicyclohexylamine-pent-3-ene-2-one [HL³] with Fe(II) and Zn(II) ions were prepared by reacting the equimolar ethanolic solutions of the ligands (HL¹, HL² and HL³) with ethanolic metal solutions. The complexes formed, were characterized by infrared, ultraviolet and atomic absorption spectroscopy. Ligands and their metal complexes were tested against Escherichia coli and Staphylococcus aureus bacteria to assess their antibacterial action using disc diffusion method. Ligands were completely inactive against bacteria whereas the complex Zn (HL¹) has significant action on both bacteria, indicating that it has a good potential as bactericide. Other complexes have normal antiseptic character.     

Incorporation of carbon dioxide into molecules of acetylene hydrocarbons on heterogeneous Ag-containing catalysts

The reaction between 2-(2-phenylethynyl)aniline and carbon dioxide on heterogeneous Ag-containing catalysts can lead either to benzoxazine-2-one or to 4-hydroxyquinoline-2(1Н)-one, depending on the reaction conditions (nature of the base, CO₂ pressure). The structures of the products were confirmed by ¹Н and ¹³С NMR spectroscopy. The maximum yield of the products (60 and 30% for benzoxazine-2-one and 4-hydroxyquinolin-2(1Н)-one, respectively) is achieved on the catalyst Ag(1%)/γ-Al₂O₃(F). According to the results of physicochemical studies, the high activity of the catalysts in the reactions proceeding via triple bond activation results from the combination of three factors. First, the catalyst contains metallic silver particles with the size >2 nm; second, metallic silver particles coexist with silver cations; and third, strong acid sites are present on the support surface.     

Total synthesis of the sesquiterpene (±)-hirsutene using an organoselenium-mediated cyclization reaction

Cyclization of 2-carbomethoxy-3-(4',4'-dimethylcyclopent-2-enylmethyl)cyclopentanone (4) with N-phenylselenophthalimide and tin(IV) chloride affords cis-syn-cis-1β-carbomethoxy-4,4-dimethyl-3β-phenylselenotricyclo [6.3.0.0^2,6]undecan-11-one (8) and cis-anti-cis-1β-carbomethoxy-4,4-dimethyl-3α-phenylselenotricyclo [6.3.0.0^2,6]undecan-11-one (9). Both of these selenides can be elaborated to cis-anti-cis-4,4-dimethyl-1β-methyltricyclo [6.3.0.0^2,6]undecan-11-one (13) which upon treatment with CH₂Br₂/ TiCl₄/Zn affords the sesquiterpene (±)-hirsutene (1) in 20% overall yield.     

Reactive species from aromatics and oxa-di-π-methane rearrangement: a stereoselective synthesis of (±)-hirsutene from salicyl alcohol

A total synthesis of hirsutene, a triquinane sesquiterpene, from salicyl alcohol is reported. Oxidation of salicyl alcohol in the presence of cyclopentadiene gave 9-spiroepoxy-endo-tricyclo[5.2.2.0^2,6]undeca-4,10-dien-8-one which was elaborated to the 3-hydroxy-2-methyl-endo-tricyclo[5.2.2.0^2,6]undeca-10-en-8-one containing major structural and functional features of hirsutene. Photochemical sigmatropic 1,2-acyl shift in 3-hydroxy-2-methyl-endo-tricyclo[5.2.2.0^2,6]undeca-10-en-8-one followed by radical induced cleavage of peripheral cyclopropane bond, olefination and Simmon-Smith reaction furnished 11-hydroxy-1-methyl-4-spirocyclopropanetricyclo[6.3.0.0^2,6]undecane that upon treatment with hydrogen on PtO₂ and PCC oxidation gave 1,4,4-trimethyltricyclo[6.3.0.0^2,6]undecan-11-one, a known precursor. Wittig methylenation on this precursor gave hirsutene.     

Unusual reaction of chloroacetyl chloride with 1,2-dichloroethene. Synthesis and properties of 2-chlorovinyl dichloromethyl ketone

The reaction of chloroacetyl chloride with 1,2-dichloroethene in the presence of AlCl₃ unexpectedly led to the formation of (E)-1,1,4-trichlorobut-3-en-2-one whose structure was proved by ¹H and ¹³C NMR, IR, and mass spectra and independent synthesis. A probable reaction scheme was proposed, which involves transformation of initially formed 1,2,4-trichloro-3-oxobutan-2-yl cation by the action of AlCl₃. The high reactivity of the vinylic halogen atom in (E)-1,1,4-trichlorobut-3-en-2-one was demonstrated by its reactions with nitrogen-centered nucleophiles (triethylamine, aniline, 3,5-dimethyl-1H-pyrazole) and sodium sulfide. These reactions involved only the C-Cl bond in the vinyl fragment and afforded (4,4-dichloro-3-oxobut-2-en-1-yl)triethylammonium chloride, 1,1-dichloro-4-phenylaminobut-3-en-2-one, 1-(4,4-dichloro-3-oxobut-2-en-1-yl)-3,5-dimethyl-1H-pyrazole, and 4,4′-thiobis(1,1-dichlorobut-3-en-2-one), respectively. The reaction of 1,1,4-trichlorobut-3-en-2-one with benzylhydrazine gave a mixture of 1,3- and 1,5-disubstituted pyrazoles.     

Diastereoselective synthesis of 5-benzylthio- and 5-mercaptohexahydropyrimidin-2-ones

A three-stage diastereoselective synthesis of (4R^∗,5R^∗,6S^∗)-5-mercapto-4-methyl-6-phenylhexahydropyrimidin-2-one has been developed. The first stage involves the formation of 4-hydroxy-5-(4-methoxybenzylthio)-4-methyl-6-phenylhexahydropyrimidin-2-one by the reaction of N-[(phenyl)(tosyl)methyl]urea with the sodium enolate of 1-(4-methoxybenzylthio)propan-2-one. Reduction of the obtained compound by NaBH₄-CF₃COOH and removal of the p-methoxybenzyl protecting group results in the target compound.     

Synthesis of substituted tetrahydron-1H-carbazol-1-one and analogs via PhI(OCOCF3)2-mediated oxidative C–C bond formation

A variety of tetrahydro-1H-carbazol-1-ones and analogs were conveniently synthesized from the reaction of the corresponding 2-(phenylamino)cyclohex-2-enone with hypervalent iodine reagent PhI(OCOCF₃)₂ (PIFA), through a direct intramolecular oxidative C(sp²)–C(sp²) bond formation. This approach realized the construction of the biologically important tetrahydro-1H-carbazol-1-one and tetrahydrocyclohepta[b]indol-6(5H)-one skeletons. The mechanism of the process was proposed and briefly discussed.     

1,3-Heterazolidines-2-heterounsaturated compounds derived from ephedrines

Herein, a direct and easy method for preparing 2-oxo-, 2-thione- or 2-imine-1,3-heterazolidines derived from ephedrines and norephedrines are reported. The method is based on solvent free heating of ephedrines with oxocyanate or thiocyanate salts (180–200 °C). In the reactions with potassium oxocyanate in refluxing ethanol, it was possible to isolate ureidic derivatives. The structure and stereochemistry of the compounds were determined by ¹H, ¹³C NMR, IR spectroscopies and mass spectrometry. Ureidic derivatives, cis-1,5-dimethyl-4-phenyl-imidazolidine-2-thione and trans-4-methyl-5-phenyl-thiazolidine-2-one are new compounds. Ephedrineurea, cis-1,5-dimethyl-4-phenyl-imidazolidine-2-thione and trans-4-methyl-5-phenyl-thiazolidine-2-one were also studied by X-ray diffraction.     

Microwave synthesis,characterization and antimicrobial study of new pyrazolyl-oxopropyl-quinazolin-4(3H)-one derivatives

Heterocyclic compounds containing pyrazolyl-oxopropyl-quinazolin-4(3H)-one are reported to possess significant biological activity. Syntheses of 6-bromo-2-(3-chloro-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 2 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl)quinazolin-4(3H)-one 3 and 6-bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 5a–j using microwave irradiation have been described. These compounds have been characterized on the basis of the UV, IR, ¹H NMR, ¹³C NMR, Mass and elemental analysis. Compounds have been evaluated for their antimicrobial activity.     

The dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat: asymmetric synthesis of α-vinyl-β-hydroxycarboxylic acid derivatives and conversion to α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products)

The synthesis of α-vinyl-β-hydroxyesters and α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) via the dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat is described. High levels of syn-diastereoselectivity (up to >98% de) are observed for the dienolate aldol reaction with boron enolates, generated either directly with Bu₂BOTf or by transmetalation of the potassium enolate with B-bromocatecholborane. Cleavage of the resultant syn-aldol products from the auxiliary gives α-vinyl-β-hydroxyesters in >98% de and >98% ee. Subsequent isomerisation of the double bond into conjugation provides α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) in high diastereo- and enantiopurity (≥91:9 [(E):(Z)] and >98% ee).     

One-pot synthesis of polycyclic heterocyclic compounds by condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts with pyridine-2, 3, and 4- and quinoline-4-carboxaldehydes

A one-pot synthesis of new polycyclic heterocyclic compounds was carried out via the condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with pyridine- and quinolinecarboxaldehydes. The heating of the aforementioned 3H-indolium salts with 1 eq. of pyridine-2, 3, and 4- or quinoline-4-carboxaldehyde in ethanol in the presence of piperidine as a catalyst provided 9a-[2-(pyridyl)ethenyl]- or 9a-[2-(quinolyl)ethenyl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one derivatives as the main products. However, reaction outcome was dramatically different for the analogous reactions in acetic acid. In this case, the heating of the chloride with 2 eq. of pyridine-2-carboxaldehyde afforded derivatives of 9a-[3-(pyridin-2-yl)indolizin-2-yl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one as the major product, while the use of 2 eq. of pyridine-3 and 4- or quinoline-4-carboxaldehyde led to the formation 2-heteroaryl-1-heteroarylmethyl-9H-pyrrolo[1,2-a]indole-3-carboxamides. Plausible pathways for the cyclization reactions are discussed. The structural assignments were based on ¹H, ¹³C and ¹⁵N NMR spectroscopy, HRMS and single-crystal X-ray diffraction data.