降压药物的合成研究 Ⅱ.若干氮七环基和氮八环基化合物的合成

1-邻氯苄基氮七环和1-邻氯苄基氮八环与碘乙烷、邻氯苄基溴或对甲苯磺酸甲酯分别反应,生成相应的季铵盐(Ⅲa,b,c,e);N,N-环六亚甲基-N',N'-环七亚甲基-1,2-乙二胺与邻氯苄基溴反应,得到双季铵盐(Ⅲd).1-β-氯乙基氮七环和1-β-氯乙基氮八环与过量的水合肼或氮八环作用,各自得β-取代氨基乙肼(Ⅳa,b)和1,2-乙二胺化合物(Ⅳf). 水合肼与1-氮七环基乙醛缩合,生成的连氮化合物用氢化铝锂还原得N,N'-双-(β-1-氮七环基乙基)肼(Ⅳc).由1,2-二溴乙烷与氮七环或氮八环反应,得对称乙二胺衍生物(Ⅳd,e).借1-β-氯乙基氮七环双分子环合季铵化和1,2-乙二胺衍生物与二溴代烷的反应,得螺环双季铵盐(Ⅳ).     

O-乙基O-芳基N-异丙基硫代磷酰胺脂结构与活性定量关系中芳基邻位取代效应的影响

利用π、Σσ、F、Verloop的STERIMOL参数及邻位取代基形成氢键的指示变量、定量地分析了39个O-乙基O-芳基N-异丙胺基硫代磷酰胺酯类化合物结构与除草活性的关系,进一步讨论了芳基邻位取代基团对分子除草活性的贡献。     

邻位和间位取代苯胺与丙烯腈的单氰乙基化反应

对于邻位、间位取代苯胺与丙烯腈发生单氰乙基反应生成相应的N-氰乙基邻位取代苯胺和N-氰乙基间位取代苯胺的过程,AlCl3具有高的催化活性。在芳香胺/丙烯腈/AlCl3=1/1.10/(0.05～0.10)(摩尔比)、反应温度60～80℃,反应时间6～10h的条件下,反应的收率达87%～90%。用毛细管气相色谱法分析了单氰乙基化反应中各组份的含量;所合成的7种N-氰乙基邻位取代苯胺和N-氰乙基间位取代苯胺用DTA-TG、UV、IR、1HNMR和EA进行了物性和结构表征。     

2-氰基-3,4-二氢喹唑啉衍生物的合成

邻硝基苯甲醛与取代苯胺(1)或取代苄胺(2)进行还原氨化反应得N-(2-硝基苄基)取代苯胺(3)或N-(2-硝基苄基)取代苄胺(4);将3或4的硝基还原为氨基生成关键中间体N-(2-氨基苄基)取代苯胺(5)或N-(2-氨基苄基)取代苄胺(6);5或6分别与4,5-二氯-1,2,3-二噻唑氯化物进行缩合反应,合成了一系列新的2-氰基-3,4-二氢喹唑啉类衍生物,收率36%~72%,其结构经1H NMR和HR-MS确证。     

有机磷化合物的研究 ⅩⅤ.合成α-氨基取代苄基膦酸的新方法

在三氟化硼催化下,二乙基磷酰胺、取代苯甲醛和亚磷酸三苯酯反应生成α-二乙基磷酰氨基取代苄基膦酸二苯酯(1),再经溴化氢的乙酸溶液处理,能选择性除去氨基上的保护基,得到相应的α-氨基取代苄基膦酸二苯酯溴化氢盐(2).2可视为合成膦酸肽的中间体.继续酸性水解可得α-氨基取代苄基膦酸(3).这个新的合成方法具有操作简便和产物纯度及得率均较高的特点.     

4-[4’-(二乙基氨基)苯乙烯基]-N-(4″-乙氧基苯基)-N-(4-氨基苯基)苯胺的合成

对硝基苯胺和对碘苯乙醚经取代反应制得4’-硝基-(4-乙氧基苯)苯胺(3);3与对氟苯甲醛经取代反应制得含乙氧基的脂溶性中间体4-[(4’-乙氧基苯基)(4″-硝基苯基)氨基]苯甲醛(5);5与4-N,N-二乙基胺基苄基三苯基鏻盐经Witting成烯反应后经Pd/C催化、水合肼还原合成了新化合物4-[4’-(二乙基氨基)苯乙烯基]-N-(4″-乙氧基苯基)-N-(4-氨基苯基)苯胺,其结构经1H NMR,IR,MS和元素分析表征。     

螺二邻二亚甲基噻吩和环二邻二亚甲基噻吩的合成

Errede等曾利用氢氧化邻甲基苄基三甲基铵的热解制得螺二邻二亚甲基苯、环二邻二亚甲基苯和聚邻二亚甲基苯。Winberg等人对噻吩的季铵碱的热解有所研究,但未能触及活泼的中间体2,3-二亚甲基-2,3-二氢化噻吩Ⅷ及其二聚体螺环化合物和环状化合物。     

保护的几丁寡糖及结构类似物的合成：复杂氨基寡糖合成的通用方法

建立了逐步合成具有重要生物活性的2-脱氧-2-氨基葡萄糖寡糖链的通用方法。采用邻苯二甲酰基保护氨基、硫代苯基为还原末端的离去基团,以氨基葡萄糖为起始原料,几种保护的几丁寡糖及结构类似物被合成：3-O-乙酰基-4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基-b-D-吡喃葡萄糖-（1→4）-（3-O-乙酰基-6-O-苄基-2-脱氧-2-邻苯二甲酰亚氨基）-b-D-吡喃葡萄糖甲苷（4）、3-O-乙酰基-4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基-b-D-吡喃葡萄糖-（1→4）-（3-O-乙酰基-6-O-苄基-2-脱氧-2-邻苯二甲酰亚氨基-b-D-吡喃葡萄糖）-（1→4）-（3-O-乙酰基-6-O-苄基-2-脱氧-2-邻苯二甲酰亚氨基）-b-D-吡喃葡萄糖甲苷（6）、3-O-乙酰基-4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基-b-D-吡喃葡萄糖-（1→3）-（4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基）-b-D-吡喃葡萄糖甲苷（8）、3-O-乙酰基-4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基-b-D-吡喃葡萄糖-（1→3）-（4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基-b-D-吡喃葡萄糖）- （1→3）-（4,6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基）- b-D-吡喃葡萄糖甲苷（10）。所合成化合物通过核磁共振和质谱分析确证了其化学结构。     

新型含咪唑啉2,4-二酮的(硫代)磷酸酯类化合物的合成和生物活性测定

以对羟基苯基和对羟基苄基咪唑啉2,4-二酮羧酸酯类化合物为二次先导结构,根据Hydantocidin在植物体内的作用形式是Hydantocidin 5’-Phosphate的特点,将3种对羟基苯(苄基)-2,4-咪唑啉二酮中间体与(硫代)磷酰氯反应合成得到了38个结构新颖的含有2,4-咪唑啉二酮的(硫代)磷酸酯类化合物,其结构通过IR,1H NMR,31P NMR和元素分析表征.初步生物测定结果表明O-乙基-O-苯基-5-(4-羟基苯基)-2,4-咪唑啉二酮硫代磷酸酯(B14)和O,O-二苯基-5-(4-羟基苄基)-2-硫代-4-咪唑啉二酮硫代磷酸酯(B25)在100μg/mL浓度下对油菜的抑制率为53.1%和62.7%,化合物O,O-二(邻甲氧基苯基)-5-(4-羟基苯基)-2,4-咪唑啉二酮硫代磷酸酯(B7),B14和O,O-二(对甲基苯基)-5-(4-羟基苄基)-2,4-咪唑啉二酮硫代磷酸酯(B17)对蚜虫表现了一定的杀虫活性,在300μg/mL浓度下24 h的校正死亡率分别为52%,51%和69%.     

氨基硫醚及氨基砜化合物的制备

苄基β-氯乙基硫醚、苯基β-溴乙基硫醚、苄基β-氯乙基砜、苯基β-溴乙基砜分别与各种仲胺作用,制成一系列氨基上有各种不同取代基的β-氨基硫醚及β-氨基砜.有的β-氨基砜则由相应硫醚以过氧化氢氧化制成. 二苯甲磺酰乙酸与苯甲醛及醋酸铵共热,除获得预期产物二苯甲基β-氨基-β-苯基乙基砜外,并得副产品二苯甲基β-苯乙烯基砜及二苯甲基甲基砜.苄磺酰乙酸反应时也生成类似产物.二苯甲硫醇与甲醛及仲胺进行Mannich反应,生成预期的氨甲基化产物.     

芳汞基芳基硫化合物的合成与波谱性质研究

芳汞基氯化汞和苯硫酚或对甲基硫酚在乙醇中反应合成了两个系列共32种芳汞基芳基硫化合物,其中22种为新化合物。 研究了这些化合物的紫外吸光谱和核磁共针氢谱,所得结果表明,对此两个系列的标题化合物,在△γ~MAX~与Hammett取代基常数 ~P之间有良好的线性关系,但共轭作用未完全通过硫原子贯穿到整个分子。也对取代基~1H NMR的影响进行了研究。     

N,N-Coupled heterobicycles from cyclic hydrazine derivatives. Part 6 . Electron ionization mass spectrometry of some substituted 1-thiocarbamoyl and 1-carbamoylpyrazolidines

The electron ionization mass spectra of six substituted 1-thiocarbamoyl and four substituted 1-carbamoyl-pyrazolidines were measured and carefully analyzed. The fragmentation pathways were elucidated by metastable ion analysis and exact mass measurement. The principal fragmentations were the same for all the compounds studied. The related importance of different decomposition channels, however, varied according to the structure of the compounds. Some substituents also prompted fragmentations unique to them. The most important reaction was the loss of the thiocarbamoyl or carbamoyl substituent with simultaneous hydrogen atom migration from the (thio)carbamoyl nitrogen to the ring nitrogen giving rise to ionized pyrazolidine at m/z 72. In this process for 1-(N-arylthiocarbamoyl)pyrazolidines the charge tended to remain with the substituent part of the molecule. Moreover for all the compounds studied [M-2H]^+. ion peaks formed by dehydrogenization of the original compounds were observed.     

Synthesis of Nonracemic 9-(1-Methoxycarbonylethyl)-1,2,3,4-tetrahydrocarbazole

A new approach has been proposed to the synthesis of indole derivatives containing a chiral substituent at the nitrogen atom, comprizing Fischer indolization of phenylhydrazines with a chiral substituent at the -nitrogen atom. The initial hydrazines were obtained by the alkylation (Mitsunobu reaction applying optically active esters of lactic acid) of anilines containing an electron-accepting substituent at the amino group. Subsequent removal of the activating acceptor grouping was realized by nitrosation of the chiral secondary aniline followed by reduction of the corresponding N-nitroso compound.     

New insight into the reaction of singlet oxygen with sulfur-containing cyclic alkenes: dye-sensitized photooxygenation of 5,6-dihydro-1,4-dithiins

The reaction of 3-methyl-5,6-dihydro-1,4-dithiins with singlet oxygen affords dicarbonyl compounds and/or ring-contracted ketosulfoxides, the latter regio- and stereoselectively, depending on the nature of the substituent at C-2 and on the reaction conditions. In competition with normal fragmentation, the intermediate dioxetanes, derived from [2 + 2] cycloaddition of singlet oxygen to the double bond, undergo an intramolecular oxygen transfer to the sulfur-1 atom, leading to labile epoxide intermediates. The latter convert to cis- and trans-ketosulfoxides through a non-concerted S-4 migration. This pathway is promoted by the electron-withdrawing group at C-2 and, for monosubstituted amide, by the solvent basicity. S-Oxidation of dithiins is insignificant, except for the monosubstituted amide derivative or in the presence of protic species, and occurs selectively at the S-1 atom.     

Influence of the aryl substituent identity in 4-arylamino-3-nitrocoumarins on their thermal behavior

Thermal behavior of structurally similar 4-arylamino-3-nitrocoumarin derivatives substituted with different electron-donor and electron-acceptor substituents on the aryl side group was investigated. The thermal stability of these compounds was studied by non-isothermal thermo-gravimetric analysis, differential thermo-gravimetry, differential thermal analysis, and pyrolysis–gas chromatography–mass spectrometry. The thermal degradation of the three synthesized 4-arylamino-3-nitrocoumarins, possessing an iodine atom, a nitro or a methyl group, proceeds in three steps. The thermal stability of the coumarin derivative with the electron-donating methyl substituent is lower than that of the compounds with the electron-accepting nitro group or iodine atom. This least stable compound (4-[(4-methylphenyl)amino]-3-nitro-2H-chromen-2-one) was also characterized with the greatest loss in mass that accompanied the degradation, and all of the three degradation steps of this compound began at the lowest temperature in comparison to the other two.     

Synthesis, cytotoxic effect, and structure-activity relationship of Pd(II) complexes with coumarin derivatives

We report the influence of the substituent at the N atom of the ligands on the synthesis, biological activity, and stability of Pd(II) complexes of the general formula PdL(2). The compounds adopt a cis or trans configuration with respect to the substituent at the nitrogen atom. Sterically hindered substituents promote the formation of trans isomers, whereas when the nitrogen atom is unsubstituted, cis isomers are formed. The compounds were characterized by elemental analysis, infrared and 1H NMR spectroscopies, and electrospray mass spectrometry. The complexes were also studied using X-ray diffraction and computational DFT methods. Both complexes cis-3a and trans-3c exhibit square-planar geometries around the Pd(II) atom. The cytotoxic effects of these complexes were examined on two human leukemia cell lines, HL-60 and NALM-6. Pd complex cis-3a showed significant cytotoxic activity. The effects exhibited by this complex were comparable to those reported for carboplatin. Loigand 2a was not cytotoxic. Computational analysis carried out at the PB/B3LYP/LACVP**//mPW1PW91/LanL2DZ level showed excellent correlation between the energy difference of the cis and trans isomers and the cytotoxic activity, rendering computations a useful predictive tool for the design of new drugs.     

(Z)-1-[2-(三苯基锡基)乙烯基]-1-茚满醇及其酯和卤代物的合成与表征

在氮气保护下,1-乙炔茚满醇与三苯基氢化锡进行游离基加成反应,获得加成物(Z)-1-[2-(三苯基锡基)乙烯基]-1-茚满醇(1);将加成物(1)与苯酐反应,得到新型邻苯二甲酸单酯有机锡衍生物(2);衍生物(2)分别与二丁基氧化锡和三苯基氧化锡进行脱水反应,分别获得两个新型邻苯二甲酸酯的有机锡衍生物(3)和(4).将加成物(1)与卤素反应后,与锡原子直接相连的苯基被取代,得到一卤代和二卤代物(5～10).通过元素分析、¹HNMR和IR等手段对化合物1～10进行了结构表征,确定了该类邻苯二甲酸单酯和邻苯二甲酸酯的有机锡衍生物的结构.并测定了加成物(1)和一溴代物(6)的晶体结构,在加成物(1)中,由于分子内存在较弱的O→Sn[0.2778(8)nm]配位作用,锡原子呈扭曲三角双锥构型.在一溴代物(6)分子中,存在分子内O→Sn[0.2364(2)nm]配位键,锡原子呈扭曲的三角双锥构型.该系列化合物分子内的O→Sn配位能力和Lewis酸性强弱的顺序为:二卤化物>一卤化物>加成物;氯代物>溴代物>碘代物>加成物.     

Competitive formation of cis and trans derivatives in the nucleophilic substitution reactions of cyclophosphazenes having a mono-spiro P-NHR group

Nucleophilic substitution reactions of N(3)P(3)Cl(4)[NH(CH(2))(3)NMe] (1) and N(3)P(3)Cl(4)[NH(CH(2))(3)O] (2) with mono-functional alcohols (methanol, 2,2,2-trifluoroethanol, phenol) and a secondary amine (pyrrolidine) were used to investigate the relationship between the incoming nucleophile and the proportions of products with substituents that are cis or trans to the spiro NH moiety. The reaction products were characterized by elemental analysis, mass spectrometry, (1)H and (31)P NMR spectroscopy and the configurational isomers by X-ray crystallography. Six products have been characterised with the substituent cis to the spiro NH group for the alcohol (methanol, phenol) and pyrrolidine derivatives of both compounds 1 and 2, compared to just one derivative with the substituent trans to the spiro NH group, that for the pyrrolidine derivative of compound 2. For each reaction the relative proportions of cis and trans isomers were determined by (31)P NMR measurements of the reaction mixtures. It was found that the reactions of compound 1 with all three alcohols and of compound 2 with methanol lead to exclusive formation of isomers with the substituent cis to the NH moiety, whereas all other reactions lead to mixtures of cis and trans isomers in different ratios under standard reaction conditions. However, when crown ether is included in the reaction medium for the reactions of compound 2 with both 2,2,2-trifluoroethanol and phenol, it is found that only cis isomers are formed. All these results are rationalised in terms of the competition between at least two effects; the cis-directing effect by hydrogen bonding of the incoming nucleophile to the spiro N-H group already present on the cyclophophazene ring and the cis-directing effect of the sodium cation coordinating to the oxygen lone pairs of the P-O moiety of the spiro ring.     

4-Azidotetronic Acids: A New Class of Azido Derivatives

4-Azidotetronic derivatives bearing different substituent groups on the carbon atom in position 3 were easily obtained by reaction of the corresponding 4-bromotetronic compounds with sodium azide in methanol at room temperature.     

Highly diastereoselective intramolecular Diels-Alder reaction of chiral silatrienes

New Si-chiral 2-silahexa-3,5-dienyl acrylates were prepared in six steps from dichloro(chloromethyl)methylsilane. The EtAlCl₂ catalysed intramolecular Diels-Alder reaction of these compounds gave chiral 4-sila-4a,7,8,8a-tetrahydroisochroman-1-ones in good yield. Very good diastereoselectivity was observed for a silatriene bearing a methyl and a 2-methoxyphenyl substituent on the chiral silicon atom.