Reaction of alkyl 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylates with zinc enolates prepared from zinc and 1-arul-2-bromo-2-phenylethanones, 2 bromoindanone, and 2-bromo-6-methyltetralone

Alkyl 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylates react with zinc enolates prepared from 1-aryl-2-bromo-2-phenylethanones, 2-bromo indanone, 2-bromo-6-methyltetralone and zinc with formation of ethyl 4-(2-aryl-2-oxo-1-phenyl-ethyl)-5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylates, alkyl 5,5-dimethyl-2-oxo-4-(1-oxoindan-2-yl)tetrahydrofuran-3-carboxylates, and ethyl 5,5-dimethyl-4-(6-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-oxotetrahydrofuran-3-carboxylates respectively, mainly as single diastereomers.     

High functionalization of 5-nitro-1H-imidazole derivatives: the TDAE approach

We report herein the synthesis of substituted 2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-arylethanols, ethyl 3-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)-phenyl]-2-hydroxypropanoate and 2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)benzyl]-2-hydroxy-acenaphthylen-1(2H)-one from the reactions of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole with various aromatic carbonyl and a-carbonyl ester derivatives using tetrakis(dimethylamino)ethylene (TDAE) methodology.     

Synthesis,characterisation and structural aspects of some symmetrical organotellurium halides based on Bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride

Bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride (2) has been synthesised in good yield by reacting 1-(2-chloroethyl)-3,5-dimethylpyrazole with in situ prepared sodium telluride, Na₂Te in an aqueous solution. A number of new organotellurium halides from bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride have been synthesised by using different halogenating reagents. Reaction of 2 with bromine gave bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride dibromide (5a) in addition to unexpected product bis(2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride dibromide (5b). All compounds were characterized by different spectroscopic techniques viz., ¹H, ¹³C, ¹²⁵Te NMR, Mass spectroscopy, IR and CHN analysis. EDXRF studies have also been employed to confirm the identity of 5a and 5b. Thermal gravimetric analysis of bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride (IV) chloride (4) and bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)telluride (IV) iodide (5c) reveals the thermal stability of these molecules above 100°C. The X-ray studies of 5c shows trigonal bipyramidal geometry around tellurium atom and intermolecular secondary interaction viz., C-H π stacking between H23A and C22 showing a supramolecular packing between two molecules.     

Reaction of 1-hydrazino-3,3-dimethyl-3,4-dihydroisoquinoline with ethyl acetoacetate. The crystal structure and IR spectra of ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidenehydrazono)-2-oxobutanoate

The reaction of 1-hydrazino-3,3-dimethyl-3,4-dihydroisoquinoline with ethyl acetoacetate afforded ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidenehydrazono)-2-oxobutanoate. The crystal structure of the title compound was established by X-ray diffraction analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 966–970, May, 1999.     

Studies on hypotensive agents. Synthesis of 1-substituted 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H,3H)-quinazoline diones.

3-(2-Chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H,3H)-quinazoline dione was newly prepared. 1-Hydrogen atoms of the compound were variously substituted in order to test for their hypotensive activities on relaxing effects of the blood vessels. The compounds with 2-(1-pyrrolidinyl) ethyl, 2-(1-piperidinyl)ethyl, 3-(dimethylamino)propyl, and 3-(N-benzyl-N-methylamino)propyl moieties showed significant activity. The 2-(1-piperidinyl)ethyl compound possessed activity approximately 23 times more potent than papaverine, however, it was less potent than cinnarizine.     

Synthesis and Crystal Structure of Diethyl-2,6- dimethyl-3,5- diyl- （ 1- （2- chlorob enzoyl）- 1H- pyrazole-3-diethyl-carboxylate）-pyridine

The reaction of hydrazine hydrate with a new α,γ-diketone ester 3, derived from the reaction of 2,6-dimethyl-3,5-diacetyl-pyridine 2 with diethyl oxalate in the presence of sodium ethoxide, afforded the pyrazole derivative 4. Treatment of 4 with 2-chlorobenzoyl chloride gave diethyl 2,6-dimethyl-3,5-diyl-（1-2（chlorobenzoyl）-1H-pyrazole-3-diethyl-carboxylate） pyridine 5. Fine crystal of 5 suitable for XRD analysis was obtained form recrystalization in ethyl acetate. The crystal belongs to the triclinic system, space group P1^-, with a = 1.0342（11）, b = 1.2211（12）, c = 1.5013（15） nm, α = 82.5190（10）,β = 85.7960（10）,γ = 85.3150（10）°, V= 1.8697（3） nm^3, Dc= 1.173 g/cm^3, μ = 0.219 mm^-1, F（000） = 684, Z = 2, the final R = 0.0720 and wR = 0.2211.     

一种新型Hsp90抑制剂的合成及其抑制活性

对氨基苯甲酸经重氮化后再与2-氯乙酰乙酸乙酯反应制得(Z)-4-[2-(1-氯-2-乙氧基-2-羰亚甲基)肼基]苯甲酸(1);1与二甲基环己二酮成环后再与对羟基环己胺完成酰胺化反应合成了一种新型Hsp90抑制剂——N-(4-羟基环己基)-4-[1-(6,6-二甲基-4-氧-3-乙酰氧基-4,5,6,7-四氢吲唑)]苯甲酰胺(3),其结构经1HNMR表征。荧光偏振法研究结果表明3对Hsp90α具有明显的抑制活性。     

Synthesis and crystal structure of optically active 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate (NZ-105).

(S)-2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate ((S)-NZ-105) and R isomer were synthesized through the fractional crystallization of (S)-2-Methoxy-2-phenylethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate. Calcium antagonism activity was found to reside in the S isomer from single crystal X-ray diffraction analysis.     

1-(2-Quinoxalyl)-, 1-[3,5-Di(trifluoromethyl)phenyl]-, 1-(2-Carboxyphenyl)-, and 1-Ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydroindazoles

The corresponding 1-(2-quinoxalyl)-, 1-[3,5-di(trifluoromethyl)phenyl]-, and 1-ethoxycarbonyl-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles have been obtained from reactions of 2-acetyl-1,3-cyclohexanedione, its 5,5-dimethyl and 5-(2-furyl) derivatives, with 2-hydrazinoquinoxaline, 3,5-di(trifluoromethyl)phenylhydrazine, and ethoxycarbonylhydrazine. On interaction with ethoxycarbonylhydrazine the intermediate 2-[1-(-ethoxycarbonyl)hydrazino]ethylidene-1,3-cyclohexanediones were also isolated. From the potassium salt of 2-formyldimedone and 2-carboxyphenylhydrazine hydrochloride, 2-(2-carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione was obtained, the cyclization of which in ethanol in the presence of HCl led to 1-(2-carboxyphenyl)- and 1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole.     

Synthesis and Bioactivity of Novel Aminomethyl-2-（1, 2,4-triazol）-4, 4-dimethyl-3-pentanone （ol）

3, 3-Dimethyl-1-(1,2,4-triazol)-2-butanone was treated with aqueous formaldehyde to give an additional product, and subsequent elimination by acetic anhydride yielded 4,4-dimethyl-2-(1,2,4-triazol)-1-penten-3-one. Further addition with substituted amines provideda series of (1,2,4-triazol)-4,4-dimethyl-3-pentanone, which were then reduced by KBH4 to obtaina series of (1,2,4-triazol)-4,4-dimethyl-3-pentanol. Their structures were confirmed by ^1HNMR and elemental analysis. The results of bioassay showed that the title products possess good fungicidal activities.     

Stereoselective synthesis of 2-substituted 6-[1-(2,6-difluorophenyl)ethyl]-5-methylpyrimidin-4(3<Emphasis Type="Italic">H</Emphasis>)-ones

A procedure has been proposed for the synthesis of 2-(cyclopentylsulfanyl)-6-[(1R)-1-(2,6-difluorophenyl) ethyl]-5-methylpyrimidin-4(3H)-one through intermediate (3R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl (2R)-2-(2,6-difluorophenyl)propanoate which was obtained from prochiral 2-(2,6-difluorophenyl)prop-1-en-1-one generated in situ. The proposed procedure may be regarded as stereoselective route to 6-[(1R)-1-(2,6- difluorophenyl)ethyl]-5-methylpyrimidin-4(3H)-one derivatives.     

Synthesis of glutarimide antibiotics and their analogs through 1,3-cycloaddition of 3-glutarimidylacetonitrile oxide to 2-cyclohexenones

A mixture of 4,4-dimethyl-9-(3-methylglutarlmidyl)-2-oxo-7-oxa-8-azabicyclo[4.3.0] non-8-ene and 3-(3-methylglutarimidyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenz-[d]isoxazole was obtained by in situ 1,3-dipolar cycloaddition of 3-glutarimidyl-acetonitrile oxide to 5,5-dimethylcyclohex-2-en-1-one. Reductive cleavage of these compounds by catalytic hydrogenation over Pd catalysts gives 3-[2-amino-2,2-(4,4-dimethyl-2-oxocyclohexylene)ethyl]glutarimide and the known 3-[2-amino-2,2-(4,4-dimethyl-2,6-dioxocyclohexylene)ethyl]glutarimide, respectively, in quantitative yield. Hydrolysis of the latter leads to 3-[2-oxo-2-(4,4-dimethyl-2,6-dioxocyclo-hexyl)ethyl]glutarimide. The ketones obtained are analogs of glutarimide antibiotics and polyfunctional intermediates in their synthesis.See [1] for a preliminary communication.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 230–234, February, 1979.     

Structure elucidation of two new unusual monoterpene glycosides from Euphorbia decipiens, by 1D and 2D NMR experiments

Two new unusual monoterpene glycosides, (Z)-3,6-dimethyl-3-(β-D-O-glucosylmethylene)cyclohept-4-ene-1-one (1) and 3,6-dimethyl-3-(β-D-O-glucosylmethylene)cycloheptanone (2) have been isolated along with five known compounds, 3-hydroxy-4-methoxybenzoic acid, 6,7-dihydroxycoumarin, luteolin, apigenin 5-O-αl-L-rhamnoside, and pinocembrin-7-O-rutinoside from ethyl acetate extract of Euphorbia decipiens. The structures of the isolated compounds were elucidated by extensive 1D- and 2D-NMR, and mass spectroscopic analyses.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101).

Six optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101, 1.2HCl.2H2O), a potent calcium antagonist, were successfully prepared by using optically active (2R,4R)-(-)- and (2S,4S)-(+)-2,4-pentanediols, and cis-2,4-pentanediol and optically active (S)-(+)-2-methoxy-2-phenylethanol. Their proton nuclear magnetic resonance investigations demonstrate that the 1,3,2-dioxaphosphorinane group is conformationally constrained around the C-P bond. Calcium-antagonistic and hypotensive activities of the optical isomers were examined and found to depend mainly on the absolute configuration at a stereogenic center in the 1,4-dihydropyridine ring rather than the configuration of the 1,3,2-dioxaphosphorinane moiety.     

Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]-ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate hydrochloride

Optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [(S)-(+)-1 and (R)-(-)-1] hydrochlorides were synthesized with high optical purities from (R)-(-)- and (S)-(+)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)- 3-pyridinecarboxylic acids [(R)-(-)-6 and (S)-(+)-6], which are available from (+/-)-6 by optical resolution using quinidine and cinchonidine, respectively. From pharmacological investigations of (S)-(+)-1 and (R)-(-)-1 such as the antihypertensive effect on spontaneously hypertensive rats and inhibition of [3H]nimodipine binding to rat cardiac membrane homogenate, the active form of 1 was defined to be the (4S)-(+)-enantiomer of 1.     

Synthesis and reactions of 3-(3-ethoxycarbonyl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)propenic acid

The reaction of ethyl 4-formyl-1-phenyl-1H-pyrazole-3-carboxylate with the malonic acid led to the formation (2E)-3-(3-ethoxycarbonyl-1-phenyl-1H-pyrazol-4-yl)propenic acid. In reactions of this acid chloride with 4-amino-5-aryl(hetaryl)-4H-1,2,4-triazole-3-thiols were obtained ethyl 4-[(E)-2-{3-aryl(hetaryl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl}ethenyl]-1-phenyl-1H-pyrazoe-3-carboxylates, with 5-aryltetrazoles, ethyl 4-[(E)-2-(5-aryl-1,3,4-oxadiazol-2-yl)-ethenyl]-1-phenyl-1H-pyrazole-3-carboxylates, with 1-(2-hydroxy-3,5-dimethylphenyl) followed by the Baker-Venkataraman rearrangement and the cyclization, ethyl 4-[(E)-2-(6,8-dimethyl-4-oxo-4Hchromen-2-yl)ethenyl]-1-phenyl-1H-pyrazole-3-carboxylate.     

Synthesis of (R)-(+)-tanikolide through stereospecific C-H insertion reaction of dichlorocarbene with optically active secondary alcohol derivatives

Stereospecific alpha C-H insertion reaction of protected chiral 1,2-glycols, (S)-1,2-isopropylidenedioxytridecane (3) and ethyl (S)-4,5-isopropylidenedioxy-pentanoate (4), prepared from (R)-glyceraldehyde acetonide (2), with dichlorocarbene generated from CHCl(3)/50% NaOH/cetyltrimethylammonium chloride (as ptc.) took place with complete retention of configuration to provide (S)-4-dichloromethyl-2,2-dimethyl-4-undecyl-1,3-dioxolane (5) and ethyl (S)-3-(4-dichloromethyl-2,2-dimethyl-1,3-dioxolan-4-yl)-propanoate (8), respectively. The ester (8) was transformed to 5 by elongation of the side chain. The glycol derivative (5) was converted into O-TBDPS-protected (S)-2-hydroxymethyl-2-undecyloxirane (16). Reaction of 16 with a cuprate reagent containing homoallylic carbon chain followed by oxidative manipulation of the terminal olefin afforded (R)-(+)-tanikolide (1).     

(Z)-3,3-二甲基-1-(1H-1,2,4-三唑-1-基)-2-丁酮肟(5-芳基-1,3,4-噁二唑-2-基)甲基醚的合成和抑菌活性

以3,3-二甲基-1-（1H-1,2,4-三唑基）-2-丁酮肟为原料,经醚化、肼解及腙化3步反应得到（E）-N'-（取代苯亚甲基）-2-[（Z）-3,3-二甲基-1-（1H-1,2,4-三唑-1-基）丁基-2-亚甲氨氧基]乙酰肼（3a~3u）,化合物3与二乙酸碘苯（IBD）反应,合成了21个（Z）-3,3-二甲基-1-（1H-1,2,4-三唑-1-基）-2-丁酮肟-（5-芳基-1,3,4-噁二唑-2-基）甲基醚（4a~4u）,化合物4的化学结构经核磁共振谱、高分辨质谱和元素分析确证.采用单晶X射线衍射仪测定了化合物4c的晶体结构.抑菌活性测试结果表明,在500 mg/L浓度下,化合物4k,4f,4j和4n对纹枯病菌的防效率分别为70.9%,60.2%,60.0%和60.6%;在25 mg/L浓度下,化合物4b,4c,4d和4e对菌核病菌的抑制率为71.8%~76.9%.     

Asymmetric cycloaddition reactions of diazoesters with 2-alkenoic acid derivatives catalyzed by binaphthyldiimine-Ni(II) complexes

The catalytic activity of chiral binaphthyldiimine (BINIM)-Ni(II) complexes for asymmetric enantioselective diazoalkane cycloadditions of ethyl diazoacetate with 3-acryloyl-2-oxazolidinone and 2-(2-alkenoyl)-3-pyrazolidinone derivatives was evaluated. The cycloadditions of 3-acryloyl-2-oxazolidinone and its 5,5-dimethyl derivative, in the presence of the BINIM-Ni(II) complex (10 mol %; prepared from (R)-BINIM-4Ph-2QN (ligand C) and Ni(ClO(4))(2)·6H(2)O) afforded 2-pyrazolines having a methine carbon substituted with an oxazolidinonyl group in moderate ratios (70:30 to 72:28), along with high enantioselectivities (90-92% ee) via 1,3-proton migration. On the basis of the investigations on the counteranions of the Ni(II) complex, the N-substituent of pyrazolidinone, and reaction temperatures, the optimal enantioselectivity (97% ee) and ratio (85:15) of 2-pyrazoline were obtained for the reaction of 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-Ni(II) ((R)-C/Ni(II)) complex prepared using Ni(BF(4))(2)·6H(2)O. In the cases of 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone, 1-benzyl-2-(2-butenoyl)-5,5-dimethyl-3-pyrazolidinone, and 1-benzyl-5,5-dimethyl-2-(3-ethoxycarbonyl)propenoyl-3-pyrazolidinone, the use of the (R)-BINIM-2QN-Ni(II) ((R)-A/Ni(II)) complex gave good to high enantioselectivities (85-93% ee) with the sole formation of the 2-pyrazoline having a methine carbon substituted with a pyrazolidinonyl group. Relatively good enantioselectivity (77% ee) was observed for the reaction between 2-acryloyl-5,5-dimethyl-1-naphthylmethyl-3-pyrazolidinone and an α-substituted diazo ester, ethyl 2-diazo-3-phenylpropanoate, which has yet to be employed as a diazo substrate in asymmetric cycloaddition reactions catalyzed by a chiral Lewis acid.