Microwave-assisted synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252): a new potentiator of Nerve Growth Factor (NGF)-induced neurite outgrowth

The synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252) using an MW-assisted nucleophilic aromatic substitution (S_NAr) reaction will be discussed. Utilization of this method allowed for the rapid generation of B-355252 heteroaryl ether core structure in the presence of cesium carbonate in dimethylformamide or tripotassium phosphate in N-methyl-2-pyrrolidone in 94% yield. Evaluation of B-355252 enhancement of nerve growth factor’s ability to stimulate neurite outgrowths was determined using NS-1 cells.     

Synthesis and some transformations of 2-(2-thienyl)-1H-acenaphtho[1,2-d]imidazole

Three-component reaction of acenaphthenequinone, 9,10-thiophene-2-carbaldehyde and ammonium acetate in glacial acetic acid afforded 2-(2-thienyl)-1H-acenaphtho[1,2-d]imidazole. Its N-methylated product undergoes electrophilic substitution reactions (nitration, bromination, sulfonation, formylation, acylation) in KOH-1-methyl-2-pyrrolidone mixture. Depending on the reaction conditions electrophilic attack occurred at both thiophene ring and acenaphthene fragment.     

Nitropyrazoles: XII. Transformations of the 4-Methyl Group in 1,4-Dimethyl-3,5-dinitropyrazole and Cyclization of the Transformation Products

A preparative procedure for the synthesis of 1,4-dimethyl-3,5-dinitropyrazole by nitration of 1,4-dimethylpyrazole was developed. The reaction of 1,4-dimethyl-3,5-dinitropyrazole with dimethoxymethyl- (dimethyl)amine (N,N-dimethylformamide dimethyl acetal) gave (E)-N,N-dimethyl-2-(1-methyl-3,5-dinitropyrazol- 4-yl)ethenylamine. Acid hydrolysis of the latter afforded (1-methyl-3,5-dinitropyrazol-4-yl)acetaldehyde, and the reaction with sodium nitrite in hydrochloric acid led to formation of 2-hydroxymino-2-(1-methyl- 3,5-dinitropyrazol-4-yl)acetaldehyde. The corresponding O-methyloxime and phenylhydrazone reacted with K₂CO₃ to give 6-methyl-4-nitropyrazolo[4,3-d]isoxazole-3-carbaldehyde O-methyloxime and 1-methyl-3-nitro-4-(2-phenyl-2H-1,2,3-triazol-4-yl)pyrazol-5-ol, respectively. Treatment of (1-methyl-3,5-dinitropyrazol-4-yl)-acetaldehyde with benzenediazonium chloride gave (1-methyl-3,5-dinitropyrazol-4-yl)acetaldehyde phenylhydrazone which underwent intramolecular cyclization with replacement of the 5-nitro group by the action of K₂CO₃ in acetonitrile; in the reaction with K₂CO₃ in ethanol, the 5-nitro group was replaced by ethoxy.     

Formation of O(3P) atoms and epoxides from the gas- phase reaction of O3 with isoprene

The formation yields of 1,2-epoxy-2-methyl-3-butene and 1,2-epoxy-3-methyl-3-butene have been measured from the reaction of O₃ with isoprene at room temperature and one atmosphere total pressure of N₂ and air diluents, with and without cyclohexane to scavenge the OH radicals formed in this reaction system. In addition, a relative rate method was used to determine a rate constant for the gas-phase reaction of O₃ with 1,2-epoxy-2-methyl-3-butene of (2.5 ± 0.7) x 10^-18 cm³ molecules^-1 s^-1 at 296 ± 2 K. Our data show that the epoxide yields in N₂ and air diluents are the same, with formation yields of 1,2-epoxy-2-methyl-3-butene of 0.028 ± 0.007 and of 1,2-epoxy-3-methyl-3-butene of 0.011 ± 0.004. These data further show that the epoxides arise from the primary O₃ reaction with isoprene, and not via the formation of O(³P) atoms from the O₃ - isoprene reaction followed by reaction of these O(³P) atoms with isoprene.     

Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 2₁/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF₄. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6_, monoclinic, space group P 2₁/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 2₁/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.     

Lactam and acid amide acetals. 63. Reaction of amide acetals with enaminodicarbonyl compounds

Corresponding dienediaminodicarbonyl compounds were synthesized by the reactions of a series of dimethylaminomethylenedicarbonyl compounds with N,N-dimethylacetamide and N-methylcaprolactam diethylacetals. In the reaction of N-methylvalerolactam diethylacetal, the process is accompanied by a rearrangement with the formation of a 3-methylenepiperidon-2-one derivative. It was found that the introduction of a substituted amino group into the meso-position of the intermediate -alkoxyenamine (in the preparation of dienediaminodicarbonyl compounds) takes place intermolecularly, and a general scheme of the unusual reaction studied has been proposed.For communication 62, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 218–223, February, 1991.     

Skeletal transformations of perfluoro-1-ethyl-1-phenylbenzocyclobutene in the reaction with antimony pentafluoride

Interaction of perfluoro-1-ethyl-1-phenylbenzocyclobutene with SbF₅ at room temperature gives, after treatment of the reaction mixture with H₂O, perfluoro-4-[1-(2-methylphenyl)propylidene]cyclohexa-2,5-dienone as a main product. The reaction at 90-95 °C leads, after treatment with H₂O, to a mixture of perfluorinated 9-ethyl-9-methyl-1,2,3,4-tetrahydro-9H-fluorene, 9-ethyl-4a-methyl-4,4a-dihydrofluoren-1-one, 3-ethyl-3-phenylphthalide, 1-hydroxy-2-methyl-1-phenylindan, 3-methyl-2-phenylindenone and small amounts of other products.     

Lactam and acid amide acetals 57. Synthesis,protonation, and acid-base properties of condensed derivatives of 4-oxo-1,4-dihydro-1,8-naphthyridine

A number of 4-oxo-1,4-dihydro-1,8-naphthyridine derivatives that differ with respect to the sizes of the azaand carbocycles were synthesized by the reaction of 3-amino-4-ethoxycarbonyl-5,6-dihydro-7H-pyrindine and 3-amino-4-ethoxycarbonyl-5,6,7,8-tetrahydroisoquinoline with N,N-dimethylacetamide diethylacetal and N-methylbutyrolactam, N-methylvalerolactam, and N-methylcaprolactam diethylacetals and subsequent cyclization of the intermediate amidines. It was established by UV and ¹H and ¹³C NMR spectroscopy that the protonation of these compounds takes place at the exocyclic oxygen atom. The dependence of the ionization constants of the compounds obtained in 70% DMFA on the size of the saturated cyclic fragments of the molecules was established.See [1] for Communication 56.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 643–651, May, 1990.     

Preparation and properties of new ortho-linked polyamide-imides bearing ether, sulfur, and trifluoromethyl linkages

A CF₃-containing diamine, 2,2′-thiobis-[4-methyl(2-trifluoromethyl)4-aminophenoxy) phenyl ether] (DA), was successfully synthesized from 2-2′-sulfide-bis-(4-methyl phenol) and 2-chloro-5-nitrobenzotrifluoride. The sulfur containing diimide-diacid (DIDA) was prepared by condensation reaction of diamine DA and trimellitic anhydride. A series of novel organic-soluble polyamide-imides (PAIs) bearing flexible ether and sulfide links, electron-withdrawing trifluoromethyl groups and ortho-phenylene units were synthesized from DIDA, by direct polycondensation with various aromatic diamines in N-methyl-2-pyrrolidone using triphenyl phosphite and pyridine as a condensing agent in the presence of dehydrating agent (LiCl). The polyamide-imides were obtained in high yields and possessed inherent viscosities in the range of 0.42-0.95 dL g⁻¹. All of the polymers were amorphous in nature, showed outstanding solubility and could be easily dissolved in amide-type polar aprotic solvents (e.g., N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and N,N-dimethylformamide) and even dissolved in less polar solvents (e.g., pyridine and tetrahydrofuran). They showed good thermal stability with glass transition temperatures between 195-245 °C, 10% weight loss temperatures in excess of 485 °C, and char yields more than 50% at 700 °C in nitrogen atmosphere. Moreover, these PAIs possessed low refractive indexes (n = 1.57-1.59) and low birefringence (Δ ≈ 0.02) due to the trifluoromethyl pendent groups and thioether bridged ortho-catenated aromatic rings that interrupt chain packing and increase free volume.     

Naphthalene-ring containing diamine and resulting thermally stable polyamides

A new naphthalene-ring containing diamine, bis-[4-(5-amino-naphthalene-1-yloxy)-phenyl]-methanone was prepared from reaction of 5-amino-1-naphthol with 4,4′-dichlorobenzophenone in the presence of K₂CO₃. A series of novel polyamides were prepared by direct polycondensation of the diamine with various commercially available diacid chlorides including terephthaloyl chloride, isophthaloyl chloride, adipoyl chloride, and sebacoyl chloride. All the synthesized polyamides showed good solubility in amide type solvents such as N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and N,N-dimethylformamide and they exhibited inherent viscosities in the range of 0.44-0.52 dL/g. According to the DMTA analysis, the glass transition temperatures of the polyamides were found to be 131-187 °C. Thermogravimetric analysis indicated that the polymers were stable up to 190 °C and the 10% weight loss temperatures were recorded in the range of 350-418 °C in air atmosphere.     

Photochemistry of alkenyl- and acetal-substituted pyridines

Ethyl 3-(2-pyridyl)propionate formation results from irradiation of 3-(2-pyridyl)propanal diethylacetal in acetonitrile. This photoreaction is unique to the heteroaromatic pyridine and only occurs in acetonitrile. A minor product, 1-aza-2-methyl-3-(2-ethanal diethylacetal)-4-ethoxycycloocta-1,3,5,7-tetraene, is also obtained. The irradiation of 2-methyl-6-(2-pyridyl)-2-pentene in the presence of various sensitizers results in addition to the alkene side-chain to produce oxetanes.     

Highly efficient one-pot synthesis of 1-substituted-1,2,3,4-tetrahydropyrazino[1,2-a]indoles

A practical and general one-pot synthesis of 1-substituted-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indoles is described. The approach uses 2-(3-methyl-1H-indol-1-yl) ethylamine, benzotriazole and aldehydes in the presence of catalytic amount of acid catalysts (AlCl₃, ZnCl₂, ZnBr₂, p-TsOH, CH₃SO₃H) and proceeds in high yields via iminium cation intramolecular cyclization. The mechanism of the observed intramolecular cyclization reaction has been investigated theoretically by means of PM3 semiempirical method and results were consistent with the experimental results.     

Acetals of lactams and acid amides. 49. Reaction of N-methyl-2-pyrrolidone and N-methyl-2-piperidone acetals with enamino diketones

It was established that acetals of lactams react with enamino diketones to give cyclic dienediamines. The dienediamines obtained in the reaction of N-methyl-2-pyrrolidone diethylacetal with 2-aminomethylenedimedone and 2-N,N-dimethyl-aminomethylenedimedone are converted to 3-(-methylamino)ethyl-6,6-dimethyl-5,6, 7,8-tetrahydro-5-coumarinone hydrochloride when they are heated in dilute hydrochloric acid.See [1] for Communication 48.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1477–1482, November, 1987.     

Application of axially dissymmetric ligand recoverable with fluorous solvent as a chiral auxiliary

(Ra)-(R)₂-2,2′-Bis(1-hydroxy-1H-perfluorooctyl)biphenyl ((Ra)-(R)₂-1c), which is an axially dissymmetric ligand with two chiral centers, works as a good chiral auxiliary for asymmetric aldol reaction. Thus, the reaction of monopropanoyl ester of 1c (2) with benzaldehyde in the presence of triethylamine and titanium(IV) chloride gave (2R),(3S)- and (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoic acid esters (3a) in an approximate ratio of 4:1 in a total high yield. This result shows that stereoselectivity at 2-position is quite high, while that at 3-position is moderate. Both isomers were easily separated by column chromatography. Methanolysis of the separated isomers gave nearly quantitative recovery of 1c by extraction with a fluorous solvent without any loss of ee, while methyl (2R),(3S)- or (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoates were obtained by CH₂Cl₂ extraction quantitatively in >99% ee. Aldol reaction of 2 with various aldehydes gave similar results.     

The dramatic effect of thiophenol on the reaction pathway of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with thiophenolates: ring expansion versus nucleophilic substitution

Ethyl 4-methyl-2-oxo-7-phenylthio-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylate and/or ethyl 6-methyl-2-oxo-4-(phenylthiomethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate were obtained in the reaction of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with PhSNa or PhSK with or without PhSH, depending on the reagent ratio, reaction time, or temperature, as a result of ring expansion and/or nucleophilic substitution. The reaction pathway was affected strongly by the basicity-nucleophilicity of the reaction media. The results obtained were confirmed by reactions of 4-mesyloxymethyl-6-methyl-5-tosyltetrahydropyrimidin-2-one with PhSNa/PhSH and ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with NaCN/HCN or NaCH(COOEt)₂/CH₂(COOEt)₂.     

Synthesis and luminescent properties of neutral Eu(III) and Gd(III) complexes with 1-(1,5-dimethyl-1h-pyrazol-4-yl)-4,4,4-trifluoro-1,3-butanedione and 4,4,5,5,6,6,6-heptafluoro-1-(1-methyl-1H-pyrazol-4-yl)-1,3-hexanedione

Neutral [EuL₃Phen] complexes were synthesized by the reaction of EuCl₃ with heterocyclic diketones-1-(1,5-dimethyl-1H-pyrazol-4-yl)-4,4,4-trifluoro-1,3-butanedione and 4,4,5,5,6,6,6-heptafluoro-1-(1-methyl-1H-pyrazol-4-yl)-1,3-hexanedione—and 1,10-phenanthroline (Phen) in an aqueous alcohol solution in the presence of NaOH. The reaction of GdCl₃ with the same diketones under analogous conditions, but without adding 1,10-phenanthroline, yielded [GdL₃(H₂O)₂] complexes. The composition of the complexes was determined by elemental analysis, and their optical and luminescent properties were examined.     

Syntheses and structures of iron carbonyl complexes derived from N-(5-methyl-2-thienylmethylidene)-2-thiolethylamine and N-(6-methyl-2-pyridylmethylidene)-2-thiolethylamine

The reaction of N-(5-methyl-2-thienylmethylidene)-2-thiolethylamine (1) with Fe₂(CO)₉ in refluxing acetonitrile yielded di-(μ₃-thia)nonacarbonyltriiron (2), μ-[N-(5-methyl-2-thienylmethyl)-η¹:η¹(N);η¹:η¹(S)-2-thiolatoethylamido]hexacarbonyldiiron (3), and N-(5-methyl-2-thienylmethylidene)amine (4). If the reaction was carried out at 45 °C, di-μ-[N-(5-methyl-2-thienylmethylidene)-η¹(N);η¹(S)-2-thiolethylamino]-μ-carbonyl-tetracarbonyldiiron (5) and trace amount of 4 were obtained. Stirring 5 in refluxing acetonitrile led to the thermal decomposition of 5, and ligand 1 was recovered quantitatively. However, in the presence of excess amount of Fe₂(CO)₉ in refluxing acetonitrile, complex 5 was converted into 2-4. On the other hand, the reaction of N-(6-methyl-2-pyridylmethylidene)-2-thiolethylamine (6) with Fe₂(CO)₉ in refluxing acetonitrile produced 2, μ-[N-(6-methyl-2-pyridylmethyl)-η¹ (N_py);η¹:η¹(N); η¹:η¹(S)-2-thiolatoethylamido]pentacarbonyldiiron (7), and μ-[N-(6-methyl-2-pyridylmethylidene)-η²(C,N);η¹:η¹(S)-2- thiolethylamino]hexacarbonyldiiron (8). Reactions of both complex 7 and 8 with NOBF₄ gave μ-[(6-methyl-2-pyridylmethyl)-η¹(N_py);η¹:η¹(N);η¹:η¹(S)-2-thiolatoethylamido](acetonitrile)tricarbonylnitrosyldiiron (9). These reaction products were well characterized spectrally. The molecular structures of complexes 3, 7-9 have been determined by means of X-ray diffraction. Intramolecular 1,5-hydrogen shift from the thiol to the methine carbon was observed in complexes 3, 7, and 9.     

Synthesis of the dibenzo[f,h]phthalazine and dibenzo[f,h]cinnoline skeleton via a ‘Suzuki-Pd-catalyzed intramolecular arylation’ and a ‘Suzuki-Pschorr’ approach

Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2H)-one yielded hitherto unknown 2-benzyldibenzo[f,h]phthalazin-1(2H)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl)-4-phenylpyridazin-3(2H)-one via a Pschorr type reaction was also investigated. Similarly, the construction of 2-methyldibenzo[f,h]cinnolin-3(2H)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(2H)-one and 2-methyl-5-(2-aminophenyl)-6-phenylpyridazin-3(2H)-one is also reported. Removal of the N-benzyl protective group of 2-benzyl-dibenzo[f,h]phthalazin-1(2H)-one with AlCl₃ yielded unsubstituted dibenzo[f,h]phthalazin-1(2H)-one.     

Synthesis of thieno[3,4-b]pyrrole derivatives based on the reaction of 1-methyl-2-nitromethylenepyrrolidine with isothiocyanates

The reaction of 1-methyl-2-nitromethylenepyrrolidine with arylisothiocyanates in the presence of a base was found to proceed at the 3-СН₂ group of the nitroenamine followed by further cyclization to afford 4-R-imino-1-methyl-1,2,3,4-tetrahydro-6H-thieno[3,4-b]pyrrol-6-one oximes. Under analogous conditions, alkylisothiocyanates add to 1-methyl-2-nitromethylenepyrrolidine giving 1-methyl-2-nitromethylenepyrrolidine-3-carbothioic acid amides, and no cyclization was observed. A tentative mechanism for the formation of thieno[3,4-b]pyrrolе derivatives is proposed.     

Effect of the solvent on the properties of solutions of polysulfone-polyethersulfone blends

The effect of the solvent on the properties of concentrated solutions of polysulfone-polyethersulfone blends, which can be used to produce film and fibrous materials, is studied. It is found that equiconcentrated solutions of polysulfone-polyethersulfone blends, at the same ratio of polymers in N,N-dimethylacetamide and N-methyl-2-pyrrolidone, significantly differ in structure and rheological and optical properties. Solutions in N,N-dimethylacetamide are polydisperse emulsions, while solutions in N-methyl-2-pyrrolidone are systems composed of closely sized interpenetrating fields of polysulfone and polyethersulfone solutions, in which the dispersed phase and the dispersion medium cannot be detected. The turbidity-spectrum method is used to show that, after the introduction of the second (incompatible) polymer, the average size of supramolecular particles significantly increases in N,N-dimethylacetamide and hardly changes in N-methyl-2-pyrrolidone relative to the particle sizes in solutions of the individual polymers. It is determined that these differences results from the different thermodynamic qualities of N,N-dimethylacetamide and N-methyl-2-pyrrolidone with respect to polysulfone.