Synthesis and alkylation of new functionally substituted 4,4-dimethylpiperidin-2-ones

The reaction of ethyl isopropylidenecyanoacetate with ethyl 3-amino-3-thioxopropanoate gave rise to ethyl 4,4-dimethyl-6-oxo-2-thioxo-5-cyanopiperidine-3-carboxylate whose alkylation provided ethyl 2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate, ethyl 5-benzyl-2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate, and ethyl 7,7-dimethyl-5-oxo-6-cyano-3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]pyridine-8-carboxylate.     

Reaction of Zinc Enolates Derived from Substituted 2,2-Dibromobutyrophenones with Ethyl 5,5-Dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate

Zinc enolates derived from substituted 2,2-dibromobutyrophenones react with ethyl 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate to give ethyl 6-aroyl-6-ethyl-4,4-dimethyl-2-oxo-3-oxabicyclo[3.1.0]-hexane-1-carboxylates mostly as a single geometric isomer.     

Synthesis and selected reactions of ethyl 5-(1-chloroethyl)-2-methylfuran-3-carboxylate

Ethyl 2-methylfuran-3-carboxylate is smoothly chloroethylated at 0°C in the 5 position of the ring. The resulting halide alkylates secondary amines but eliminates HCl with sodium diethyl phosphite under the Michaelis-Becker reaction conditions and with trimethyl phosphite under the Arbuzov reaction conditions. In the reaction with sodium diethyl phosphite, small amounts of 5-[1-(diethoxyphosphoryl)ethyl]furan-3-carboxylate and 5-ethylfuran-3-carboxylate are formed. In the Arbuzov reaction at a 1: 1.22 furan: trimethyl phosphite molar ratio, methyl 2,4-dimethyl-1-methoxy-1-oxo-1λ⁵-1,2-dihydrophospheto[3,2-b]furan-5-carboxylate was isolated.     

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 hydrazinolysis of β-(1,3,4-oxadiazol-2-yl)pyridines

Cyclization of the hydrazide of 5-ethoxycarbonyl-2,6-dimethylpyridine-3-carboxylic acid by acylation with aromatic or aliphatic acid chlorides with subsequent boiling in POCl₃ or heating in orthoformic acid gave the corresponding ethyl 2,6-dimethyl-5-(5-R-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate. The cyclization of the reaction products with hydrazine hydrate has been studied. Cyclization of the dihydrazide of 2,6-dimethyl-3,5-pyridinedicarboxylic acid under analogous conditions gave only 3,5-bis-(5-R-1,3,4-oxadiazol-2-yl)-2,6-dimethylpyridines, containing R = 2-FC₆H₄, H.     

Synthesis of 2-aminoethyl-5-carbethoxythiazoles utilizing a Michael-like addition strategy

Ethyl 4-(trifluoromethyl)-2-vinylthiazole-5-carboxylate was utilized as a precursor to ethyl 4-(trifluoromethyl)-2-(aminoethyl)thiazole-5-carboxylate analogs via Michael-like addition of various secondary amines. Reactions employed 1.2 equiv of amine, and the products were isolated by solvent removal and acid/base extraction. Use of primary amines was also investigated.     

Synthesis of 5,8-Diamino-Substituted Pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]pyrimidines and Pyrimido[4′,5′:4,5]thieno[2,3-<Emphasis Type="Italic">c</Emphasis>]isoquinolines

Ethyl 1-amino-8,8-dimethyl-5-(piperidin-1-yl)-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carboxylate and ethyl 1-amino-5-(piperidin-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxylate reacted with benzoyl isothiocyanate to give the corresponding 1-thioureido derivatives which underwent cyclization to 2,2-dimethyl-5-(piperidin-1-yl)-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4″,3″:4′,5′]pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidin-8(9H)-one and 5-(piperidin-1-yl)-10-thioxo-1,2,3,4,10,11-hexahydropyrimido-[4′,5′:4,5]thieno[2,3-c]isoquinolin-8(9H)-one. The cyclization products were converted into 8-chloro derivatives, and the chlorine atom therein was replaced by various amines.     

Synthesis and properties of 5-(p-carbomethoxyphenyl)- 15-(p-dimethylaminophenyl)porphyrin

An unsymmetrically substituted 5,15-diarylporphyrin 1 , with p-dimethylamino and p-carbomethoxy substituents, was synthesized via a MacDonald condensation of aryldipyrromethane precursors 6 and 12 , which were prepared in good yield by three or four step procedures starting from ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate ( 2 ).     

6-氨基-2-取代吲哚-3-羧酸乙酯及其衍生物的合成与生物活性评价

以2,4-二硝基氯苯和乙酰乙酸乙酯为原料, 经过亲核置换、还原-环化协同反应, 合成了6-氨基-2-甲基吲哚-3-羧酸乙酯, 而后在催化剂作用下, 与乙酰乙酸乙酯反应生成烯胺, 环化合成9-羟基-2,7-二甲基吡咯(2,3-f)喹啉-3-羧酸乙酯; 类似地, 合成了6-氨基-2-苯基吲哚-3-羧酸乙酯和6-氨基-2-(呋喃-2'-基)吲哚-3-羧酸乙酯. 其结构均由¹H NMR, IR以及MS波谱数据表征. 所得化合物具有抑制肺癌A549细胞生长的活性, 其抑制效果具有浓度依赖性.     

Five-membered 2,3-dioxoheterocycles: LXXIX. Three-component condensation of 1<Emphasis Type="Italic">H</Emphasis>-pyrrol-2,3-diones with acetonitriles and dimedone. Crystal and molecular structure of substituted spiro[chromene-4,3′-pyrrole]

5-Phenyl-4-ethoxycarbonyl-1H-pyrrole-2,3-diones react with acetonitriles and dimedone to form ethyl 2-amino-7,7-dimethyl-2′,5-dioxo-5′-phenyl-1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-pyrrole]-4′-carboxylates. The crystal and molecular structure of ethyl 2-amino-1′-benzyl-7,7-dimethyl-2′,5-dioxo-5′-phenyl-3-cyano-1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-pyrrole]-4′-carboxylate was proved by XRD analysis.     

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.     

Three-step synthesis of ethyl canthinone-3-carboxylates from ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate via a Pd-catalyzed Suzuki-Miyaura coupling and a Cu-catalyzed amidation reaction

Ethyl canthin-6-one-1-carboxylate (1b) and nine analogues 1c-k were prepared from readily prepared ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (2b) via a three-step non-classical approach that focused on construction of the central pyrrole (ring B) using Pd-catalyzed Suzuki-Miyaura coupling followed by Cu-catalyzed C-N coupling. Furthermore, treatment of the ethyl canthinone-1-carboxylate 1b with NaOH in DCM/MeOH (9:1) gave the canthin-6-one-1-carboxylic acid (6) in high yield. All compounds are fully characterized.     

Synthesis,Reactions, and Structure of 5-Cyano-4-ethoxy-1-ethoxycarbonyl-2-methylazuleno[1,8-b,c]pyran

Bicyclic azulene compounds, ethyl 4-(cyanoethoxycarbonylmethyl)-2-methylazulene-1-carboxylate (2) and ethyl 4-(cyanoethoxycarbonylmethyl)azulene-1-carboxylate (3) were prepared from ethyl 4-chloro-2-methylazulene-1-carboxylate (7) and ethyl 4-ethoxyazulene-1-carboxylate (8), respectively. Oxidation of 2 with DDQ gave the title compound, 5-cyano-4-ethoxy-1-ethoxycarbonyl-2-methylazuleno[1,8-b,c]pyran (1) and a minor compound, ethyl 4-cyanomethyl-2-methylazulene-1-carboxylate (9). Oxidation of 3 by DDQ produced only ethyl 4-cyanomethylazulene-1-carboxylate (10), Reaction of 1 with 100% H₃PO₄ at room temperature and 100 °C gave 5-cyano-4-ethoxy-2-methylazuleno[1,8-b,c]pyran (11) and 2-methyl-4,5-dihydrozuleno[1,8-b,c]pyran-4-one (12), respectively. All the new compounds were characterized by IR, UV-vis, NMR and Mass spectra, and the structure of 1 was determined by X-ray crystallography. Crystal data for 1; space group P2₁/n, a = 7.391(1), b = 9.660(5), c = 22.859(1) Å, B = 97.01(1)°, V = 1620.0(3) ų, Z = 4, with final residuals R = 0.047 and Rw = 0.055.     

[1] Benzofuro[2,3-d] pyridazines. VI. Etude des reactions de scission des acyltetrahydrobenzofuropyridazones

The cleavage of the pyridazine ring of the acyltetrahydro [1] benzofuro [2,3-d] pyridazones was carried out by hydrolysis, alcoholysis or aminolysis reactions and they affect the lactam 3,4-bond. They lead chiefly to benzofuran derivatives with acid, ester, amide or hydrazide groups in the 2-position and eventually an acylated methylhydrazine group in the 3-position. The cyclization reactions of 3-hydrazinomethylbenzofuran-2-carboxylic acid and its derivatives or ethyl 3-bromome thylbenzofuran-2-carboxylate affords tetrahydrobenzofuropyridazones. The nmr spectra were studied.     

Synthesis,characterization and assignment of the absolute configuration of 4,4-dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid and its esters: a combined experimental and theoretical investigation

The synthesis of a new, optically active, paraconic-acid derivative 4,4-dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid and its methyl and ethyl esters was accomplished by a procedure involving the kinetic enzymatic resolution of the racemic ethyl ester. Thus, ethyl (+)-4,4-dimethyl-5-oxo-tetrahydrofuran-3-carboxylate, derived from a ring fission, was isolated at low conversion values, with 94% ee using HLAP as the enzymatic source. The corresponding enantiomerically pure acid was also obtained.The absolute configuration of the products was determined based on the results of an extensive computational study of the specific rotation of the acid and methyl ester. Four different wavelengths were considered and comparisons with the sign and magnitude of the corresponding experimental observations were carried out. Solvent effects on both the conformational space and the specific rotation were included in the computations using the Polarizable Continuum Model.The assigned absolute configuration of the title compounds is (R)-(+), which is in agreement with a tentative experimental assignment based on an analysis of the circular dichroism curves.     

Functional Derivatives of Ethyl 4-(Chloromethyl)-2,6-dimethylpyridine-3-carboxylate

The condensation of ethyl 4-(chloromethyl)-2,6-dimethylpyridine-3-carboxylate with substituted phenols in ethanol in the presence of potassium carbonate afforded the corresponding aryl pyridin-4-ylmethyl ethers. Analogous condensation with substituted anilines gave 2-aryl-4,6-dimethyl-1,2-dihydropyrrolo[3,4-c]- pyridin-3-ones. Esters containing 1,2-azole fragments were synthesized by acylation of hydroxymethylsubstituted ethers with 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carbonyl chlorides.     

REACTIONS OF HYDRAZONOYL HALIDES 371: SYNTHESIS OF TRIAZOLO[4,3-a]PYRIMIDINES, 1,3,4-THIADIAZOLES AND 1,3,4-SELENADIAZOLES

1,2,4-Triazolo[4,3-a]pyrimidines, thiadiazolines and selenadiazolines synthesized via reactions of hydrazonoyl halides with each of ethyl 4-(3,4-dimethoxyphenyl)-6-methyl-2-methylthio-3,4-dihydropyrimidine-5-carboxylate (or ethyl 6-(3,4-dimethylphenyl)-4-methyl-2-thio1,3,6-trihydropyrimidine-5-carboxylate), ethyl 4-(2,3-dimethoxyphenyl)- 6-methyl-2-methylthio-3,4-dihydropyrimidine-5-carboxylate, potassium thiocyanate, potassium selenocyanate, and carbodithioates respectively.     

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。     

Double rearrangement in the pyrrolidine-1,2-oxide system leading to pentasubstituted pyrroles.

Acid catalyzed double rearrangement of the ethyl 6-oxa-2,2, 4,4-tetramethyl-1-azabicyclo[3,1,0]hexane-3-carboxylate leading to ethyl 1,2,4,5-tetramethyl-pyrrole-3-carboxylate is proposed on the basis of identification of the intermediate ethyl 5-hydroxy-1,2,4,4-tetramethylpyrroline-3-carboxylate.     

5-(4-叔丁氧基羰基哌嗪基)苯并呋喃-2-甲酸乙酯的合成

5-溴苯并呋喃-2-甲酸乙酯与4-叔丁氧基羰基哌嗪进行Buchwald-Hartwig偶联反应,若催化剂是Pd(OAc)2/BINAP,碱是Cs2CO3,则产物主要是5-(4-叔丁氧基羰基哌嗪基)苯并呋喃-2-甲酸乙酯,转化率达70%;若催化剂是Pd(dba)2/P(t-Bu)3,碱是叔丁醇钾,则产物中几乎没有5-(4-叔丁氧基羰基哌嗪基)苯并呋喃-2-甲酸乙酯.文中讨论了影响这个Buchwald-Hartwig偶联反应的因素.