2-甲基-1,5-苯并硫氮杂的基态和激发态反应的研究 II:2-甲基-1,5-苯并硫氮杂的光异构化和Fries重排

2-甲基-1,5-苯并硫氮杂(2a-2d)在苯溶液中光照生成相应的2,4-异构化产物3a-3d,其中2a和2d同时还生成双键位移产物4a和4d.4a经碱性醇解生成一对2, 4-异构体2b和3b.2-甲基-4-芳酰氧基-1,5-苯并硫氮杂(2e-2g)在苯中光照主要经Fries重排生成2-甲基-3-芳酰基-1,5-苯并硫氮杂-4(5H)-酮(5e-5g).同时还生成少量2,4-异构化产物2-芳酰氧基-4-甲基-1,5-苯并硫氮杂(3e-3g).但2-甲基-4-烷基酰氧基-1,5-苯并硫氮杂(2i,2j)在相同条件下光照只生成2,4-异构化产物-2-烷基酰氧基-4-甲基-1,5-苯并硫氮杂(3i,3j).2-甲基-4-对硝基苯甲酰氧基-1,5-苯并硫氮杂(2h)可发生热Fries重排,生成2-甲基-3-对硝基苯甲酰基-1,5-苯并硫氮杂-4(5H)-酮(5h).化学和光谱数据证明5e-5h和6e-6h为互变异构体.     

2-甲基-1,5-苯并硫氮杂的基态和激发态反应的研究 Ⅰ.2-甲基-1,5-苯并硫氮杂-4 (5H)-酮的卤化和亲核取代反应

2-甲基-1,5-苯并硫氮杂草-4(5H)-酮(1a)与不同的氯化试剂——五氯化磷、三氯氧磷和氯化砜在不同的条件下氯化,可分别生成:2-甲基-4-氯-1,5-苯并硫氮杂草(2a)、2-氯-4-甲基-1,5-苯并硫氮杂草(3a)、2-二氯甲基苯并噻唑(5)、2-三氯甲基苯并噻唑(6)和2-甲基-1,5-苯并硫氮杂草-4(5H)-酮盐酸盐(4)。2-甲基4-氯-1,5-苯并硫氮杂草与醇钠反应生成相应的2-甲基-4-烷氧基-1,5-苯并硫氮杂草外,还可以分离到它的2,4-异构体,2-烷氧基-4-甲基-1,5-苯并硫氮杂??。产物的结构均经元素分析、红外光谱、~1H和~(13)C核磁共振谱和质谱鉴定.     

2-甲基-1,5-苯并硫氮杂的基态和激发态反应的研究III:2-甲基-1,5-苯并硫氮杂4-(5H)-酮与-4-甲基-1,5-苯并硫氮杂-2(3H)-酮间的互变异构

用化学反应和光谱分析证实了2-甲基(1,5)苯并硫氮杂环庚三烯-4(5H)-酮和4-甲基(1,5)苯并硫氮杂环庚三烯-2(3H)-酮是作为互变异构混合物存在的.     

2-甲基-1,5-苯并硫氮杂的基态和激发态反应的研究 Ⅱ.2-甲基-1,5-苯并硫氮杂的光异构化和Fries重排

2-甲基-1,5-苯并硫氮杂草(2a-2d)在苯溶液中光照生成相应的2,4-异构化产物3a-3d,其中2a和2d同时还生成双键位移产物4a和4d.4a经碱性醇解生成一对2,4-异构体2b和3b。2-甲基-4-芳酰氧基-1,5-苯并硫氮杂草(2e-2g)在苯中光照主要经Fries重排生成2-甲基-3-芳酰基-1,5-苯并硫氮杂草-4(5H)-酮(5e-5g),同时还生成少量2,4-异构化产物2-芳酰氧基-4-甲基-1,5-苯并硫氮杂草(3e-3g)。但2-甲基-4-烷基酰氧基-1,5-苯并硫氮杂草(2i,2j)在相同条件下光照只生成2,4-异构化产物2-烷基酰氧基-4-甲基-1,5-苯并硫氮杂草(3i,3j)。2-甲基-4-对硝基苯甲酰氧基-1,5-苯并硫氮杂草(2h)可发生热Fries重排,生成2-甲基-3-对硝基苯甲酰基-1,5-苯并硫氮杂草-4(5H)-酮(5h)。化学和光谱数据证明5e-5h和6e-6h为互变异构体。     

2-甲基-1,5-苯并硫氮杂(艹卓)的基态和激发态反应的研究 Ⅲ.2-甲基-1,5-苯并硫氮杂(艹卓)-4(5H)-酮与4-甲基-1,5-苯并硫氮杂(艹卓)-2(3H)-酮间的互变异构

Ried和Marx曾报道邻氨基硫代苯酚与乙酰乙酸乙酯或二烯酮反应分别合成了2-甲基-1,5-苯并硫氮杂(艹卓)-4(5H)-酮(la)和4-甲基-1,5-苯并硫氮杂(艹卓)-2(3H)-酮(lb)。但有关这两个化合物的结构鉴定除可查到la的红外光谱数据外,它们的~1HNMR和~13CNMR数据均未见报道     

3-碘-5-甲基-1,5-苯并硫氮杂(艹卓)-4(5H)-酮的合成

以2-甲基硫代苯胺为原料,通过酰化反应、碘环化反应合成了3-碘-5-甲基-1,5-苯并硫氮杂(艹卓)-4(5H)-酮,总收率86.3%,其结构经NMR,IR和MS表征.     

3-碘-5-甲基-1,5-苯并硫氮杂-4(5H)-酮的合成

以2-甲基硫代苯胺为原料,通过酰化反应、碘环化反应合成了3-碘-5-甲基-1,5-苯并硫氮杂-4(5H)-酮,总收率86.3%,其结构经NMR,IR和MS表征。     

2-酯基-1,5-苯并氧氮杂的合成及反应副产物的研究

以取代苯、丁烯二酸酐、邻氨基(对氯邻氨基)苯酚为原料,合成了一系列2-酯基-1,5-苯并氧氮杂衍生物,其结构通过IR,1H NMR,MS(HRMS)及元素分析进行表征.同时,确定了一个主要副产物2-苯甲酰甲基-2H-1,4-苯并噁嗪-3(4H)-酮(6h’)的结构,提出了其可能的生成机理.研究还表明,中间体4-芳基-4-氧代-2-丁烯酸酯(4)在对甲基苯磺酸为催化剂、DMF作溶剂、回流温度下反应时主要生成目标产物2-酯基-1,5-苯并氧氮杂6,而在冰醋酸为催化剂、甲醇作溶剂、回流温度下反应时则主要生成副产物6h’.     

C(2)-酰胺基-4-芳基-1,5-苯并硫氮杂的合成及抑菌活性的研究

设计合成了三类C(2)酰胺基取代的1,5-苯并硫氮杂衍生物:2-酰胺基(N-芳基)-4-芳基-1,5-苯并硫氮杂、2-酰胺基(N-烷基)-4-芳基-1,5-苯并硫氮杂和2-酰胺基(N,N-二烷基)-4-芳基-1,5-苯并硫氮杂,其结构用元素分析,IR,MS及1H NMR确证.测定了目标化合物的抑真菌活性,结果表明部分化合物对新生隐球菌具有中等强度的抑真菌活性.还研究了2-酰胺基-4-芳基-1,5-苯并硫氮杂的合成反应条件.     

新型含2-苯基-1,2,3-三唑基的1,5-苯并硫氮杂革及其β-内酰胺衍生物的合成

α,β-不饱和酮(1a～1e)与邻氨基苯硫酚反应,得到含2-苯基-1,2,3-三唑基的1,5-苯并硫氮杂革(2a～2e),然后以其为原料与烯酮"现场"进行[2+2]环加成,合成出一系列含2-苯基-1,2,3-三唑基的β-内酰胺并合的1,5-苯并硫氮杂革衍生物(3a～3j).产物经1H NMR,IR,元素分析及MS加以确证.     

Synthesis and Antimicrobial Evaluation of Some New 1,5-Benzothiazepine Derivatives and Their Ribofuranosides

( - )- cis -2(4-Methoxyphenyl)-3-hydroxy/methoxy-6,8-dichloro/6-chloro-2,3-dihydro-1,5-benzothiazepin-4[5H/5-chloroacetyl/5-(4'-methylpiperazino-1')acetyl]-ones have been synthesized by the condensation of 2-amino-3,5-dichloro/3-chloro benzenethiol with methyl-( - )- trans -3(4-methoxyphenyl)glycidate in xylene. Ribofuranosides viz ( - )- cis -2(4-methoxyphenyl)-3-methoxy-6,8-dichloro/6-chloro-2,3-dihydro-1,5-benzothiazepine-4-[5-(2',3',5'-tri- O -benzoyl- g -D-ribofuranosyl)-ones have been synthesized by the treatment of 3-methoxy derivatives of 1,5-benzothiazepines with sugar viz g -D-ribofuranose-1-acetate-2,3,5-tribenzoate in toluene at vacuo. Synthesized compounds have been characterized by elemental analysis, IR, 1 H NMR spectral studies and screened for their antimicrobial activity.     

Chlorination of 4-methyl-8-methoxy-2,3-dihydro-1H,1,5-benzodiazepin-2-one

The results of the chlorination of 4-methyl-8-methoxy-2,3-dihydro-1H,1,5-benzodiazepin-2-ones are compared with the results of quantum-chemical calculations of 4-methyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones with various substituents in the benzene ring in the case of homolytic halogenation. The chlorination of 4-methyl-8-methoxy-2,3-dihydro-1H-1,5-benzodiazepin-2-one (I) with N-chlorosuccinimide leads to 3-chloro- and 3,3-dichloro-4-methyl-8-methoxy-2,3-dihydro-1H-1,5-benzodiazepin-2-ones, whereas chlorination with sulfuryl chloride leads to 4-chloromethyl and 3,3-dichloro-4-methyl derivatives. The IR, PMR, and mass spectra of the synthesized compounds are presented.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1272–1274, September, 1981.     

Solution-phase parallel synthesis of 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones

Practical and efficient parallel methods have been developed for the synthesis of 7,8-disubstituted 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones and 3,7,8-trisubstituted 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones. This benzothiazepin-4(5H)-one skeleton possesses three or four diversity points. Furthermore, three novel tricycles integrating a benzothiazepin-4(5H)-one scaffold with other privileged structures, such as benzimidazole, benzimidazolone, and thio-benzimidazole, were also developed. The synthetic strategy provides an efficient way to access the benzothiazepinone core, starting from commercially available 1,5-difluoro-2,4-dinitrobenzene (DFDNB), and also allows further derivation of the strategically anchored functionalities.     

A step forward in the field of drug design: 1,5-benzothiazepines and their nucleosides

(±)cis-2-(4-methoxyphenyl)-3-hydroxy/methoxy-6-methoxy/8-methoxy-2,3-dihydro-1,5-benzothiazepin-4-[5H/5-chloroacetyl/5-(4′-methylpiperazino-1′)acetyl]-ones and nucleosides viz; (±)cis-2-(4-methoxyphenyl)-3,6-dimethoxy-2,3-dihydro-1,5-benzothiazepin-4-[5-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)]-one and (±)cis-2-(4-methoxyphenyl)-3,8-dimethoxy-2,3-dihydro-1,5-benzothiazepin-4-[5-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)]-one have been synthesized by the condensation of substituted-2-aminobenzenethiols with methyl (±)trans-3-(4-methoxyphenyl)glycidate in xylene and by stirring the 3-methoxy derivative of 1,5-benzothiazepin-4(5H)-ones with sugar namely β-D-ribofuranosyl-1-acetate-2,3,5-tribenzoate at 155–160 °C in vacuo for 10 hours, respectively. The synthesized compounds have been characterized by the elemental analyses and spectral data and screened for their antimicrobial activity.     

Structural assignment of regioisomeric 3-[2- or 5-anilino-2-(alkylamino)phenyl]propanoic acids, 2H-1,4-benzothiazin-3(4H)-ones and 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones by 1D NOE and gHMBC NMR techniques

The 1H and 13C NMR spectra of compounds 1-11 and 16-22 in CDCl3 and DMSO-d6 solutions allowed structural assignment to regioisomers 1/5 and 2/6 and their regioselective cyclization products 16-18 utilizing one- and two-dimensional NMR techniques (APT, DEPT, NOE difference, COSY, NOESY, HETCOR and gHMQC, gHMBC). Temperature-dependent 1H NMR spectra of 8-anilino-5-(4-methyl-2-pentyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (18) indicated a free energy of activation (deltaG++) of ca 17 kcal mol(-1) for interconversion between rotamers. The 1H and 13C NMR spectra of 20 and 22 containing two chiral centers exhibit duplication of several signals, indicating the existence of two diastereomeric forms. The structure of 4 was unambiguously confirmed by x-ray crystallography.     

Synthesis and structure determination of isomeric 7- and 8-chloro-1,5-benzodiazepine derivatives

Reaction of 4-chloro-1,2-benzenediamine with 3,3-dimercapto-1-phenyl-2-propen-1-one afforded, as expected, a mixture of 7-chloro and 8-chloro-1,3-dihydro-4-phenyl-2H-1,5-benzodiazepine-2-thione. After separation of the two components and further reaction, their structure was established by chemical degradation of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine to 5-chloro-1,3-dihydro-1-methyl-2H-benzimidazol-2-one. The structure was also confirmed by single X-ray analysis of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine.     

Electron impact mass spectral fragmentation of 2a,4-disubstituted 2-chloro/2,2-dichloro-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothia zepin-1-ones

The mass spectrometric behaviour of nine 2a,4-disubstituted 2-chloro/2,2-dichloro-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]b enzothiazepin-1-ones has been studied with the aid of mass-analysed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization. All compounds show a tendency to eliminate a neutral chlorine atom, or a chloroketene, or neutral propene, or styrene or substituted styrene molecule, plus Cl and/or H (or Cl) atom(s), to yield [M-Cl]+ ions, 2,3-dihydro-1,5-benzothiazepine derivative ions, 4,5-dihydro-5H-1,5-benzothiazepin-4-one ions which can further lose CO to give 1,4-benzothiazine ions. Both molecular ions and [M-Cl]+ ions show a tendency to eliminate an ethyl or benzyl/substituted benzyl radical to produce 2,2a-dihydro-1H-azeto[2,1-c][1,4]benzothiazin-1-one ions. The [M-Cl]+ ions could undergo rearrangement to yield 2,2a-dihydro-1H-azeto[2,1-d][1,5]benzothiazepin-1-one ions, 2,2a,3,4-tetrahydro-1H-azeto[1,2-a]quinoline ions or 1,1a,2,3-tetrahydro-azirino[2,1-d][1,5]benzothiazepine ions by loss of an ethane or a benzene/substituted benzene, a SH radical or a CO molecule. The molecular ions could also undergo rearrangement reactions to form other small fragment ions.