5-[(E)-丙-1-烯基]苯并[1,3]二氧杂环戊烯 | 4043-71-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 中文名称: 5-[(E)-丙-1-烯基]苯并[1,3]二氧杂环戊烯
• 英文名称: isosafrole
• 英文别名: (E)-5-(prop-1-en-1-yl)benzo[d][1,3]dioxole；(E)-isosafrole；trans-isosafrole；isosafrol；5-(prop-1-en-1-yl)-1,3-benzodioxole；5-[(E) 1-propenyl]-1,3-benzodioxol；5-[(E)-prop-1-enyl]-1,3-benzodioxole
• CAS: 4043-71-4
• 化学式: C₁₀H₁₀O₂
• mdl: MFCD00005838
• 分子量: 162.188
• InChiKey: VHVOLFRBFDOUSH-NSCUHMNNSA-N

物化性质

• 熔点：
  6.8°C
• 沸点：
  253°C (estimate)
• 密度：
  1.1224
• 物理描述：
  Isosafrole is a colorless fragrant liquid with odor of anise. Used in small quantities in root beer and sarsaparilla flavors.
• 颜色/状态：
  Colorless liquid
• 气味：
  Fragrant
• 溶解度：
  In water, 144 mg/L at 25 °C (est)
• 蒸汽压力：
  2.32X10-2 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 分解：
  Hazardous decomposition products formed under fire conditions. - Carbon oxides
• 折光率：
  Index of refraction: 1.576 at 20 °C
• 碰撞截面：
  138.4 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 保留指数：
  1296;1296;1357;1360;1355;1298

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  18.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

甲氧基苯（MDBs）和结构相关的烯基苯被比较了它们在预防四氯化碳（CCl4）引起的小鼠肝脏坏死的有效性。用异黄樟素、黄樟素、二氢黄樟素和苯并二氧杂环戊烷在剂量低至10 mg/kg的情况下预处理，显著预防了血浆转氨酶水平的升高和与CCl4诱导的肝脏坏死相关的组织化学变化，而胡椒基丁氧化物（PBO）、丁香酚、异丁香酚、芝麻酚和姜黄素即使在200 mg/kg的剂量下也不能预防CCl4的肝毒性。然而，如果毒物给药后10分钟内给予异黄樟素，其仅部分具有肝保护作用。在异黄樟素给药后1小时分离的肝脏微粒体中CYP2E1活性显著降低，而PBO给药后则没有。异黄樟素、黄樟素、二氢黄樟素和苯并二氧杂环戊烷在体外也比丁香酚和异丁香酚更有效地抑制CYP2E1依赖的代谢，而PBO并不抑制CYP2E1活性。因此，异黄樟素、黄樟素和苯并二氧杂环戊烷的保护作用主要归因于它们能够使CYP2E1失活，CYP2E1是参与CCl4生物活化的主要同工酶。在CYP2E1诱导的小鼠中，CCl4肝毒性的显著增强也被异黄樟素而非PBO预处理完全预防，支持异黄樟素通过抑制CYP2E1对其对CCl4的肝保护作用有所贡献的假设。异黄樟素和黄樟素还预防了溴三氯甲烷（BrCCl3）诱导的肝细胞毒性，而PBO则无效。

Methylenedioxybenzenes (MDBs) and structurally related alkenylbenzenes were compared for their effectiveness in preventing carbon tetrachloride (CCl4)-induced liver necrosis in mice. Pretreatment with isosafrole, safrole, dihydrosafrole, and benzodioxole at dosages as low as 10 mg/kg significantly prevented the increase in plasma transaminase levels and histochemical changes associated with CCl4-induced liver necrosis, whereas piperonyl butoxide (PBO), eugenol, isoeugenol, sesamol, and curcumin did not prevent CCl4 hepatotoxicity even at 200 mg/kg. However, isosafrole was only partly hepatoprotective if administered 10 min after the toxicant. Liver microsomes isolated 1 hr after isosafrole but not after PBO administration had a markedly decreased CYP2E1 activity. Isosafrole, safrole, dihydrosafrole, and benzodioxole in vitro also inhibited CYP2E1-dependent metabolism more effectively than eugenol and isoeugenol, whereas PBO did not inhibit CYP2E1 activity. The protective effects of isosafrole, safrole, and benzodioxole were therefore predominantly attributed to their ability to inactivate CYP2E1, the major isozyme involved in CCl4 bioactivation. The marked potentiation of CCl4 hepatotoxicity in CYP2E1-induced mice was also completely prevented by isosafrole but not PBO pretreatment, supporting the hypothesis that CYP2E1 inhibition by isosafrole contributes to its hepatoprotective effect against CCl4. Isosafrole and safrole also prevented bromotrichloromethane (BrCCl3)-induced hepatocyte cytotoxicity, whereas PBO was ineffective.

来源:Hazardous Substances Data Bank (HSDB)

代谢

产量为3,4-亚甲基二氧苯甲醛，可能是在苍蝇中。/来自表格/

Yields 3,4-methylenedioxybenzaldehyde probably in fly. /From table/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在氧化异香豆素的过程中，最初会生成一个烯丙醇和另一个未识别的共轭醇，它们进一步氧化分别变成烯酮和胡椒醛。然后，烯酮与胺的缩合将导致三级胺基甲二氧基丙酸苯酮的形成。

On oxidn isosafrole gives rise initially to an allyl alcohol & another unidentified conjugated alcohol which are further oxidized to the vinyl ketone & piperonyl acrolein, respectively. Condensation of vinyl ketone with amine would then lead to formation of tertiary aminomethylenedioxypropiophenones.

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 生成 3'-羟基异补骨脂酚。

... Yields 3'-hydroxyisosafrole.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：异黄樟素是一种无色液体。异黄樟素存在顺式-(Z)-异构体（阿尔法-异黄樟素）和反式-(E)-异构体（贝塔-异黄樟素）。异黄樟素用于香精中，但在美国已不再用于食品中。黄樟素和异黄樟素可以用作3,4-亚甲二氧基甲基苯丙胺（MDMA）的前体。人体研究：在8%的凡士林中测试时，在人类受试者上进行48小时封闭贴片试验后未产生刺激性。对25名志愿者进行了最大程度测试，未产生致敏反应。一名19岁的男子在摄入异黄樟素后出现了类似精神分裂症的精神病。他使用安非他命和LSD没有产生类似的综合征。动物研究：将异黄樟素原液涂抹在完整或磨伤的兔皮肤上，24小时封闭使用后，产生中等程度的刺激性。异黄樟素是一种微弱的啮齿类动物肝脏致癌物，致癌性可能是由非遗传毒性机制介导的。异黄樟素代谢物在小鼠肝脏DNA上可能只产生非常低的结合。在异黄樟素处理的小鼠中观察到了肝细胞瘤和肺肿瘤。异黄樟素处理的小鼠中，雄性的肝细胞瘤发生率倾向于高于雌性。异黄樟素（19.7%顺式/78.2%反式异构体）在未代谢激活或代谢激活的情况下，没有诱导鼠伤寒沙门氏菌TA 98、TA 100、TA 1535、TA 1537、TA 1538或大肠杆菌WP 2 uvr A的基因突变。

IDENTIFICATION AND USE: Isosafrole is a colorless liquid. Isosafrole exists as a trans-(E-)isomer (beta-isosafrole) and as a cis-(Z-)isomer (alfa-isosafrole). Isosafrole is used in fragnances, but it is no longer used in foods in the United States. Safrole and isosafrole can be used as precursors for 3,4-methylenedioxymethylamphetamine (MDMA). HUMAN STUDIES: When tested at 8% in petrolatum, it produced no irritation after a 48-hr closed-patch test on human subjects. A maximization test was carried out on 25 volunteers and produced no sensitization reactions. A 19-year-old man developed a schizophrenia-like psychosis after ingesting isosafrole. His use of amphetamines and LSD failed to produce a similar syndrome. ANIMAL STUDIES: Isosafrole applied full strength to intact or abraded rabbit skin for 24 hr under occlusion was moderately irritating. Isosafrole is a weak rodent hepatocarcinogen, the carcinogenicity is probably mediated by a nongenotoxic mechanism. Isosafrole metabolites may give rise to only very low binding to liver DNA in mice. Hepatomas and pulmonary tumors were observed in isosafrole-treated mice. Hepatoma incidence tended to be higher in males than females with isosafrole. Isosafrole (19,7% cis/78.2% trans isomer) did not induce gene mutations in Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, TA 1538 or in Escherichia coli WP 2 uvr A with or without metabolic activation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

美国环保局健康与环境评估办公室的人类健康评估小组对异莎佛勒进行了致癌性评估。根据他们的分析，异莎佛勒的致癌证据权重为B2组，这是基于动物实验中的充分证据。目前没有关于人类的数据。作为B2组化学物质，异莎佛勒被认为可能对人类具有致癌性。

The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated isosafrole for carcinogenicity. According to their analysis, the weight-of-evidence for isosafrole is group B2, which is based on sufficient evidence in animals. No data are available in humans. As a group B2 chemical, isosafrole is considered probably carcinogenic to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

没有关于人类的数据。动物致癌性的证据有限。总体评估：第3组：该物质对人类致癌性无法分类。

No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌物：异黄樟素

IARC Carcinogenic Agent:Isosafrole

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：第3组：对其对人类的致癌性无法分类

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans

来源:International Agency for Research on Cancer (IARC)

反应信息

• 作为反应物：
  描述：

  5-[(E)-丙-1-烯基]苯并[1,3]二氧杂环戊烯 在 臭氧 、 溶剂黄146 、 锌 作用下， 反应 2.0h， 以77%的产率得到胡椒醛
  参考文献：
  名称：

  Thienylhydrazon with digitalis-like properties (positive inotropic effects)

  摘要：

  该发明揭示了一种具有以下式（I）的化合物，其中R1选自氢、1至6个碳原子的烷基、未取代苯基和取代苯基的群；R2选自H、烯烃、未取代酚和取代苯基的群；以及其药学上可接受的盐，具有类似毛地黄的特性。该发明进一步揭示了一种合成3,4-亚甲二氧基苯甲酰-2-硫代肼（LASSBio-294）的新方法。LASSBio-294对心脏和骨骼肌产生正性肌力作用。该发明可用于治疗充血性心力衰竭和肌肉疲劳。它不具有毛地黄苷类药物中所见的毒性效应。

  公开号：

  US07091238B1
• 作为产物：
  描述：

  胡椒酸 在 sodium tetrahydroborate 、 正丁基锂 、 硫酸 、 sodium hydride 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.5h， 生成 5-[(E)-丙-1-烯基]苯并[1,3]二氧杂环戊烯
  参考文献：
  名称：

  Buss, Antony D.; Warren, Stuart, Journal of the Chemical Society. Perkin transactions I, 1985, p. 2307 - 2326

  摘要：

  DOI：

文献信息

• Copper(I)-Catalyzed Allylic Substitutions with a Hydride Nucleophile
  作者：T. N. Thanh Nguyen、Niklas O. Thiel、Felix Pape、Johannes F. Teichert

  DOI：10.1021/acs.orglett.6b00941

  日期：2016.5.20

  easily accessible copper(I)/N-heterocyclic carbene (NHC) complex enables a regioselective hydride transfer to allylic bromides, an allylic reduction. The resulting aryl- and alkyl-substituted branched α-olefins, which are valuable building blocks for synthesis, are obtained in good yields and regioselectivity. A commercially available silane, (TMSO)2Si(Me)H, is employed as hydride source. This protocol

  容易获得的铜（I）/ N-杂环卡宾（NHC）络合物能够将区域选择性氢化物转移至烯丙基溴，从而实现烯丙基还原。得到的芳基和烷基取代的支链α-烯烃，是合成的重要组成部分，可以高收率和区域选择性地获得。使用可商购的硅烷（TMSO）2 Si（Me）H作为氢化物源。该协议为建立的碳催化亲核试剂催化的金属烯丙基取代提供了统一的替代方法，因为不需要使催化剂适应亲核试剂的性质。
• Nickel-Catalyzed Allylic C(sp²)-H Activation: Stereoselective Allyl Isomerization and Regiospecific Allyl Arylation of Allylarenes
  作者：Qiang Wu、Lanlan Wang、Rizhe Jin、Chuanqing Kang、Zheng Bian、Zhijun Du、Xiaoye Ma、Haiquan Guo、Lianxun Gao

  DOI：10.1002/ejoc.201600955

  日期：2016.11

  allylarenes with excess Grignard reagent. It occurs regiospecifically at the position of C(sp2)–H activation and represents a new method for the synthesis of 1,1-disubstituted olefins. The results of deuterium labeling experiments reveal an alkenyl/alkyl mechanism involving allylic internal C(sp2)–H activation and multiple intermolecular 1,2-, 1,3-, and 2,3-hydride shifts. These methods represent new

  研究了烯丙基与包含镍 (II) 和芳基格氏试剂的催化体系的立体选择性烯丙基异构化和区域特异性烯丙基芳基化反应。这两个反应都是由原位形成的 Ni0 激活烯丙基内部 C(sp2)-H 触发的，Ni0 被插入到烯丙基部分的 2 位的 C-H 键中，没有导向基团。烯丙基芳烃异构化为 1-丙烯基芳烃有利于 E 异构体并进行定量转化。芳基化通过烯丙基芳烃与过量格氏试剂的氧化交叉偶联发生。它区域特异性地发生在 C(sp2)–H 活化的位置，代表了一种合成 1,1-二取代烯烃的新方法。氘标记实验的结果揭示了烯基/烷基机制，涉及烯丙基内部 C(sp2)–H 活化和多个分子间 1,2-、1,3- 和 2,3- 氢化物位移。这些方法代表了烯烃官能化的新方法，机理研究有助于发现和设计烯烃官能化的新策略。
• Cationic [5+2] cycloaddition reactions promoted by trimethylsilyl triflate in highly polar media
  作者：Jon L. Collins、Paul A. Grieco、John K. Walker

  DOI：10.1016/s0040-4039(97)00030-0

  日期：1997.2

  Trimethylsilyl triflate is an effective reagent in 3.0 M lithium perchlorate-ethyl acetate for promoting cationic [5+2] cycloaddition reactions.

  三氟甲磺酸三甲基甲硅烷基酯是3.0 M高氯酸锂-乙酸乙酯中用于促进阳离子[5 + 2]环加成反应的有效试剂。
• Iron Catalyzed Double Bond Isomerization: Evidence for an Fe ^I /Fe ^III Catalytic Cycle
  作者：Callum R. Woof、Derek J. Durand、Natalie Fey、Emma Richards、Ruth L. Webster

  DOI：10.1002/chem.202004980

  日期：2021.4

  Density Functional Theory (DFT) and Electron Paramagnetic Resonance (EPR) spectroscopy. The data obtained support a pre‐catalyst activation step that gives access to an η2‐coordinated alkene FeI complex, followed by oxidative addition of the alkene to give an FeIII intermediate, which then undergoes reductive elimination to allow release of the isomerization product.

  据报道，铁催化的烯烃异构化使用铁(II) β-二酮亚胺预催化剂。该反应在催化量的氢化物源（例如频哪醇硼烷（HBpin）或氨硼烷（H 3 N·BH 3））下进行。已研究了与烯丙基芳烃和脂肪族烯烃的反应性。通过多种手段研究了催化机理，包括氘化研究、密度泛函理论（DFT）和电子顺磁共振（EPR）光谱。获得的数据支持预催化剂活化步骤，该步骤提供了 η 2配位烯烃 Fe I络合物，然后通过氧化加成烯烃得到 Fe III中间体，然后进行还原消除以释放异构化产物。
• Proazaphosphatrane P(RNCH2CH2)3N (R=Me,i-Pr)-Catalyzed Isomerization of Allylaromatics, Allyl Phenyl Sulfide, Allyl Phenyl Sulfone, andbis-Allylmethylene Double Bond-Containing Compounds
  作者：Zhengkun Yu、Shenggang Yan、Guangtao Zhang、Wei He、Liandi Wang、Yu Li、Fanlong Zeng

  DOI：10.1002/adsc.200505224

  日期：2006.1

  Using a proazaphosphatrane catalyst, P(RNCH2CH2)3N (R=Me, i-Pr), allylaromatics and allyl phenyl sulfide were selectively isomerized to the corresponding vinyl isomers in yields up to >99% in CH3CN at 40 °C. Efficient transformation of allyl phenyl sulfone at ambient temperature afforded an isomerization/dimerization product in >95% yield. Conjugation of bis-allylmethylene double bond-containing compounds

  使用原氮杂磷杂环戊烷催化剂，将P（RNCH 2 CH 2）3 N（R = Me，i- Pr），烯丙基芳烃和烯丙基苯硫醚选择性异构化为相应的乙烯基异构体，在40° C的CH 3 CN中收率最高> 99％℃。在环境温度下烯丙基苯基砜的有效转化以> 95％的收率得到异构化/二聚产物。含双烯丙基亚甲基双键的化合物的共轭可得到相应的顺式，顺式-9,12-十八碳烯醇及其甲基醚的共轭异构体，收率最高可达97％，并且三甲基甲硅烷基的催化反应可制得甲硅烷基化/共轭产物。的以太顺式，顺式-9，12-十八碳烯基醇。基于在反应条件下在CD 3 CN或CH 3 CN中的1 H和31 P NMR监测的反应，讨论了反应机理。

表征谱图