WO2016197580A1 - Method of synthesizing α-amino acid derivative with α-alkyl side chain substitution - Google Patents

Method of synthesizing α-amino acid derivative with α-alkyl side chain substitution Download PDF

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WO2016197580A1
WO2016197580A1 PCT/CN2015/098519 CN2015098519W WO2016197580A1 WO 2016197580 A1 WO2016197580 A1 WO 2016197580A1 CN 2015098519 W CN2015098519 W CN 2015098519W WO 2016197580 A1 WO2016197580 A1 WO 2016197580A1
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amino acid
acid derivative
synthesizing
formula
imine
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PCT/CN2015/098519
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曾伟
肖新生
卢晓霞
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华南理工大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/24—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing ⁇ -alkyl branched-chain substituted ⁇ -amino acid derivatives.
  • Amino acids are not only the basic building blocks of proteins, but their derivatives are also important structural units of many natural products and drug molecules. Amino acids and their derivatives have important applications in the field of biomedicine. Amino acids are also precursors for the synthesis of many catalysts. Therefore, the synthesis methods of ⁇ -amino acid derivatives have been widely recognized.
  • the synthesis methods of the currently reported ⁇ -amino acid derivatives mainly include: first, hydrogenation of the imine under certain conditions by a reducing reagent to obtain a target product.
  • a reducing reagent for example, (1) H 2 is used as a reducing reagent; (2) Hantzsch ester is used as a reducing reagent; and (3) other reagents are used as a reducing agent.
  • the second is the target product obtained by adding an imine under certain conditions by an organometallic reagent.
  • organometallic reagent such as: (1) organoaluminum reagent; (2) organozinc reagent; (3) organoboron reagent.
  • the object of the present invention is to provide a simple and efficient method for synthesizing ⁇ -alkyl branched-chain substituted ⁇ -amino acid derivatives, and the raw materials used in the method are cheap and easy to obtain and have no Poison, the whole process is simple and easy.
  • a method for synthesizing an ⁇ -alkyl branched-substituted ⁇ -amino acid derivative comprising the steps of:
  • the product is separated and purified by column chromatography; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
  • the structure of the imine is as shown in the formula A
  • the structure of the olefin is as shown in the formula B
  • the structure of the 9-bbn is as shown in the formula C
  • the structure of the ⁇ -amino acid derivative is as shown in the formula D.
  • R 1 is 4-MeOC 6 H 4 , 2-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC 6 One of H 4 , 4-NO 2 C 6 H 4 , Ph, 4-COOEtC 6 H 4 or 1-naphthyl;
  • R 2 is n-butyl, cyclohexyl, Ph, 4-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC One of 6 H 4 , 4- t BuC 6 H 4 , 1-naphthyl or 2-thienyl;
  • the molar ratio of the olefin to 9-bbn is 1:1;
  • the molar ratio of the olefin to the imine is (1-3): 1, preferably 1.5: 1.
  • the transition metal salt is palladium dichloride, palladium acetate, palladium trifluoroacetate, palladium dichlorodiacetonitrile, palladium dichloroditriphenylphosphine, copper acetate, copper chloride, copper bromide, trifluoromethanesulfonate.
  • One of copper acid, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide or copper perchlorate, preferably cuprous cyanide has a high yield.
  • the base is one of Cs 2 CO 3 , NaOMe, NaO t Bu, LiOMe, Li 2 CO 3 , Na 2 CO 3 , NaOEt, K 2 CO 3 , LiO t Bu or KOEt, preferably Cs 2 CO 3
  • the yield is higher.
  • the organic solvent is toluene or 1,2-dichloroethane.
  • the method of the invention is simple and efficient, and the raw materials used are simple and easy to obtain and non-toxic.
  • the preparation method is not sensitive to water and air during the reaction.
  • the whole operation process is simple and easy, the steps are simple, and the product is easy to be purified.
  • an olefin and 9-bbn are used to form an alkyl boron reagent in situ, and the reaction conditions are mild, and a wide variety of olefins are available.
  • the existing synthesis methods all require strict anhydrous and anaerobic conditions, the reaction operation is complicated, the reaction needs to be carried out at a low temperature, and the refrigeration cost is high. While the present invention does not require anhydrous anaerobic conditions, the reaction can be carried out at room temperature or at a slightly higher temperature.
  • Figure 1 is a hydrogen spectrum of Compound 1.
  • Figure 3 is a hydrogen spectrum of Compound 2.
  • Figure 5 is a hydrogen spectrum of Compound 3.
  • Figure 6 is a carbon spectrum of Compound 3.
  • Figure 7 is a hydrogen spectrum of Compound 4.
  • Figure 8 is a carbon spectrum of Compound 4.
  • Figure 9 is a hydrogen spectrum of Compound 5.
  • Figure 10 is a carbon spectrum of Compound 5.
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:

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Abstract

The present invention discloses a method of synthesizing an α-amino acid derivative with α-alkyl side chain substitution. The method comprises: reacting an alkene with 9-bbn at 0-80˚C for 0.5-12 h, and then adding an imine to react at 0-90˚C for 12-48 h with the presence of a transition metal salt, a base and an organic solvent to generate an α-amino acid derivative. In the present invention, an alkene is employed to in-situ generate an alkyl boron reagent, wherein the reaction condition is mild and the alkaline can be selected from a wide range. For the existing synthesis methods, a strict anhydrous and anaerobic condition is required, complex reaction operations are involved, and a low temperate is needed for the reaction to occur, thus causing a high cooling cost. On the contrary, the present invention does not require an anhydrous and anaerobic condition, and the reaction can occur at the room temperature or a slightly higher temperature.

Description

α-烷基支链取代的α-氨基酸衍生物的合成方法Method for synthesizing α-alkyl branched-chain substituted α-amino acid derivatives 技术领域Technical field
本发明属于有机合成领域，具体涉及α-烷基支链取代的α-氨基酸衍生物的合成方法。The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing α-alkyl branched-chain substituted α-amino acid derivatives.
背景技术Background technique
氨基酸不仅是蛋白质的基本构成单位，其衍生物还是很多天然产物和药物分子的重要结构单元。氨基酸及其衍生物在生物医药领域有着重要用途，氨基酸还是许多催化剂的合成前体，因此α-氨基酸衍生物的合成方法一直得到广泛的重视。Amino acids are not only the basic building blocks of proteins, but their derivatives are also important structural units of many natural products and drug molecules. Amino acids and their derivatives have important applications in the field of biomedicine. Amino acids are also precursors for the synthesis of many catalysts. Therefore, the synthesis methods of α-amino acid derivatives have been widely recognized.
目前报道的α-氨基酸衍生物的合成方法主要有：一是通过还原试剂，在一定条件下对亚胺进行氢化作用得到目标产物。如：(1)以H2作为还原试剂；(2)以Hantzsch酯作为还原试剂；(3)以其他试剂作为还原剂。The synthesis methods of the currently reported α-amino acid derivatives mainly include: first, hydrogenation of the imine under certain conditions by a reducing reagent to obtain a target product. For example, (1) H 2 is used as a reducing reagent; (2) Hantzsch ester is used as a reducing reagent; and (3) other reagents are used as a reducing agent.
二是通过有机金属试剂，在一定条件下对亚胺进行加成从而得到的目标产物。如：(1)有机铝试剂；(2)有机锌试剂；(3)有机硼试剂。The second is the target product obtained by adding an imine under certain conditions by an organometallic reagent. Such as: (1) organoaluminum reagent; (2) organozinc reagent; (3) organoboron reagent.
上述试剂制备难度高，保存条件苛刻，可选种类少。The above reagents are difficult to prepare, have strict storage conditions, and have few options.
发明内容Summary of the invention
为了克服现有技术的缺点与不足，本发明的目的在于提供一种简便、高效的α-烷基支链取代的α-氨基酸衍生物的合成方法，该方法所用到的原料廉价易得且无毒，整个操作过程简单易行。In order to overcome the shortcomings and deficiencies of the prior art, the object of the present invention is to provide a simple and efficient method for synthesizing α-alkyl branched-chain substituted α-amino acid derivatives, and the raw materials used in the method are cheap and easy to obtain and have no Poison, the whole process is simple and easy.
本发明的目的通过下述技术方案实现：The object of the invention is achieved by the following technical solution:
α-烷基支链取代的α-氨基酸衍生物的合成方法，包括以下步骤：A method for synthesizing an α-alkyl branched-substituted α-amino acid derivative, comprising the steps of:
(1)取烯烃与9-硼双环(3,3,1)-壬烷(简称9-bbn)在0-80℃(优选60℃)下反应0.5-12h，然后加入亚胺，在过渡金属盐、碱和有机溶剂存在的情况下，于0-90℃(优选70℃)下反应12-48h，生成α-氨基酸衍生物； (1) taking an olefin and reacting 9-boron bicyclo(3,3,1)-nonane (abbreviated as 9-bbn) at 0-80 ° C (preferably 60 ° C) for 0.5-12 h, then adding an imine in the transition metal In the presence of a salt, a base and an organic solvent, the reaction is carried out at 0-90 ° C (preferably 70 ° C) for 12-48 h to form an α-amino acid derivative;
(2)反应结束后，采用柱层析将产物分离纯化；所述柱层析的洗脱液为石油醚和乙酸乙酯的混合溶剂。(2) After the end of the reaction, the product is separated and purified by column chromatography; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
所述亚胺的结构如式A所示，烯烃的结构如式B所示，9-bbn结构如式C所示，α-氨基酸衍生物的结构如式D所示。The structure of the imine is as shown in the formula A, the structure of the olefin is as shown in the formula B, the structure of the 9-bbn is as shown in the formula C, and the structure of the α-amino acid derivative is as shown in the formula D.
Figure PCTCN2015098519-appb-000001
Figure PCTCN2015098519-appb-000001
在式A和式D中，R1为4-MeOC6H4、2-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-NO2C6H4、Ph、4-COOEtC6H4或1-萘基中的一种；In Formula A and Formula D, R 1 is 4-MeOC 6 H 4 , 2-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC 6 One of H 4 , 4-NO 2 C 6 H 4 , Ph, 4-COOEtC 6 H 4 or 1-naphthyl;
在式B和D中，R2为正丁基、环己基、Ph、4-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-tBuC6H4、1-萘基或2-噻吩基中的一种；In formulae B and D, R 2 is n-butyl, cyclohexyl, Ph, 4-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC One of 6 H 4 , 4- t BuC 6 H 4 , 1-naphthyl or 2-thienyl;
所述亚胺式A已有文献报道(Borrione,E.；Prato,M.；Scorrano,G.；Stivanello,M.Synthesis and cycloaddition reaction of ethyl glyoxylate imines.Synthesis of substituted furo-[3,2-c]quinolines and 7H-indeno[2,1-c]quinolines[J].J.Heterocycl.Chem.1988,25,1831)。The imine formula A has been reported in the literature (Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M. Synthesis and cycloaddition reaction of ethyl glyoxylate imines. Synthesis of substituted furo-[3, 2-c Quinolines and 7H-indeno [2, 1-c] quinolines [J]. J. Heterocycl. Chem. 1988, 25, 1831).
所述烯烃与9-bbn的摩尔比为1:1；The molar ratio of the olefin to 9-bbn is 1:1;
所述烯烃与亚胺的摩尔比为(1-3):1，优选1.5:1。The molar ratio of the olefin to the imine is (1-3): 1, preferably 1.5: 1.
所述的过渡金属盐为二氯化钯、醋酸钯、三氟醋酸钯、二氯二乙腈钯、二氯二三苯基膦钯、醋酸铜、氯化铜、溴化铜、三氟甲磺酸铜、氯化亚铜、溴化亚铜、碘化亚铜、氰化亚铜或高氯酸铜中的一种，优选氰化亚铜，其产率较高。The transition metal salt is palladium dichloride, palladium acetate, palladium trifluoroacetate, palladium dichlorodiacetonitrile, palladium dichloroditriphenylphosphine, copper acetate, copper chloride, copper bromide, trifluoromethanesulfonate. One of copper acid, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide or copper perchlorate, preferably cuprous cyanide, has a high yield.
所述的碱为Cs2CO3、NaOMe、NaOtBu、LiOMe、Li2CO3、Na2CO3、NaOEt、K2CO3、LiOtBu或KOEt中的一种，优选Cs2CO3，其产率较高。The base is one of Cs 2 CO 3 , NaOMe, NaO t Bu, LiOMe, Li 2 CO 3 , Na 2 CO 3 , NaOEt, K 2 CO 3 , LiO t Bu or KOEt, preferably Cs 2 CO 3 The yield is higher.
所述的有机溶剂为甲苯或1,2-二氯乙烷。The organic solvent is toluene or 1,2-dichloroethane.
上述过程中发生的化学反应如下式所示： The chemical reactions that occur during the above process are as follows:
Figure PCTCN2015098519-appb-000002
Figure PCTCN2015098519-appb-000002
本发明相对于现有技术具有如下的优点及效果：The present invention has the following advantages and effects over the prior art:
本发明的方法简便、高效，所用到的原料简单易得且无毒，本制备方法在反应过程中对水和空气都不敏感。另外整个操作过程简单易行，步骤简便，产物易纯化。The method of the invention is simple and efficient, and the raw materials used are simple and easy to obtain and non-toxic. The preparation method is not sensitive to water and air during the reaction. In addition, the whole operation process is simple and easy, the steps are simple, and the product is easy to be purified.
本发明中采用烯烃与9-bbn原位生成烷基硼试剂，反应条件温和，烯烃可选种类多。同时现有合成方法都需要严格无水无氧条件，反应操作复杂，反应需要在低温下进行，制冷成本高。而本发明不需无水无氧条件，同时反应可以在室温或稍高一些的温度下进行。In the present invention, an olefin and 9-bbn are used to form an alkyl boron reagent in situ, and the reaction conditions are mild, and a wide variety of olefins are available. At the same time, the existing synthesis methods all require strict anhydrous and anaerobic conditions, the reaction operation is complicated, the reaction needs to be carried out at a low temperature, and the refrigeration cost is high. While the present invention does not require anhydrous anaerobic conditions, the reaction can be carried out at room temperature or at a slightly higher temperature.
附图说明DRAWINGS
图1是化合物1的氢谱图。Figure 1 is a hydrogen spectrum of Compound 1.
图2是化合物1的碳谱图。2 is a carbon spectrum of Compound 1.
图3是化合物2的氢谱图。Figure 3 is a hydrogen spectrum of Compound 2.
图4是化合物2的碳谱图。4 is a carbon spectrum of Compound 2.
图5是化合物3的氢谱图。Figure 5 is a hydrogen spectrum of Compound 3.
图6是化合物3的碳谱图。Figure 6 is a carbon spectrum of Compound 3.
图7是化合物4的氢谱图。Figure 7 is a hydrogen spectrum of Compound 4.
图8是化合物4的碳谱图。Figure 8 is a carbon spectrum of Compound 4.
图9是化合物5的氢谱图。Figure 9 is a hydrogen spectrum of Compound 5.
图10是化合物5的碳谱图。Figure 10 is a carbon spectrum of Compound 5.
具体实施方式detailed description
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。The present invention will be further described in detail below with reference to the embodiments and drawings, but the embodiments of the present invention are not limited thereto.
实施例1Example 1
α-氨基酸衍生物的合成方法，包括以下步骤： A method for synthesizing an α-amino acid derivative, comprising the steps of:
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯(10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。(1) In a sealed tube, p-methoxyaniline (12.3 mg, 0.1 mmol), ethyl glyoxylate (10.2 mg, 0.1 mmol), anhydrous sodium sulfate (71 mg, 0.5 mmol), dichloromethane ( 2 mL), the mixture was stirred at room temperature for 0.5 h. Then, sodium sulfate was filtered off, and the residue was washed with dichloromethane, and the solvent was evaporated to dichloromethane to yield 0.1 mmol of imamine.
Figure PCTCN2015098519-appb-000003
Figure PCTCN2015098519-appb-000003
(2)在已抽真空充氮气的密封管中加苯乙烯(15.1mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在60℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入碳酸铯(5mg，0.015mmol)、氰化亚铜(0.9mg，0.01mmol)，步骤(1)的亚胺，密封后在70℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品23.5mg，产率为：75％。(2) Add styrene (15.1 mg, 0.15 mmol), 9-bbn (0.3 mL, 0.15 mmol, 9-bbn in 0.5 mol/L THF solution) to a sealed tube which has been vacuum-filled with nitrogen, and anhydrous toluene. After 1 mL of the mixture was stirred at 60 ° C for 1 h, the heating was stopped and cooled to room temperature. Then, cesium carbonate (5 mg, 0.015 mmol) and cuprous cyanide (0.9 mg, 0.01 mmol) were successively added, and the imine of the step (1) was sealed and reacted at 70 ° C for 24 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered, spun dry, and further separated and purified by column chromatography to give the product 23.5 mg, yield: 75%.
本实施例所得产品的结构表征数据如下：The structural characterization data of the products obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.28(t,J＝7.3Hz,2H),7.18(d,J＝7.2Hz,3H),6.75(d,J＝7.9Hz,2H),6.56(d,J＝7.8Hz,2H),4.14(q,J＝7.1Hz,2H),3.97(s,1H),3.91(s,1H),3.71(s,3H),2.77(t,J＝7.7Hz,2H),2.06(ddd,J＝27.9,13.5,6.9Hz,2H),1.22(t,J＝7.1Hz,3H).氢谱图见图1。 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (t, J = 7.3 Hz, 2H), 7.18 (d, J = 7.2 Hz, 3H), 6.75 (d, J = 7.9 Hz, 2H), 6.56 (d) , J = 7.8 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 3.91 (s, 1H), 3.71 (s, 3H), 2.77 (t, J = 7.7 Hz) , 2H), 2.06 (ddd, J = 27.9, 13.5, 6.9 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). The hydrogen spectrum is shown in Figure 1.
13C NMR(101MHz,CDCl3)δ174.35,152.83,141.07,128.58,128.53,126.18,115.30,114.92,61.05,57.38,55.72,34.81,31.93,14.31.碳谱图见图2。 13 C NMR (101 MHz, CDCl 3 ) δ 174.35, 152.33, 141.07, 128.58, 128.53, 126.18, 115.30, 114.92, 61.05, 57.38, 55.72, 34.81, 31.93, 14.31. The carbon spectrum is shown in Fig. 2.
High Resolution MS：计算值C19H23NO3[M+H]+:314.1751,发现:314.1749。High Resolution MS: Calculated for C 19 H 23 NO 3 [M + H] +: 314.1751, found: 314.1749.
根据以上数据推断所得产品的结构如下所示：Based on the above data, the structure of the resulting product is as follows:
Figure PCTCN2015098519-appb-000004
Figure PCTCN2015098519-appb-000004
化合物1 Compound 1
实施例2Example 2
α-氨基酸衍生物的合成方法，包括以下步骤：A method for synthesizing an α-amino acid derivative, comprising the steps of:
(1)在密封管中，加入对氯苯胺(12.7mg，0.1mmol)，乙醛酸乙酯(10.2mg， 0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。(1) In a sealed tube, p-chloroaniline (12.7 mg, 0.1 mmol) and ethyl glyoxylate (10.2 mg, 0.1 mmol), anhydrous sodium sulfate (71 mg, 0.5 mmol), dichloromethane (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, sodium sulfate was filtered off, and the residue was washed with dichloromethane, and the solvent was evaporated to dichloromethane to yield 0.1 mmol of imamine.
Figure PCTCN2015098519-appb-000005
Figure PCTCN2015098519-appb-000005
(2)在已抽真空充氮气的密封管中加苯乙烯(15.1mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在0℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入碳酸钠(1.6mg，0.015mmol)、碘化亚铜(1.9mg，0.01mmol)，步骤(1)的亚胺，密封后在90℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品19mg，产率为：60％。(2) Add styrene (15.1 mg, 0.15 mmol), 9-bbn (0.3 mL, 0.15 mmol, 9-bbn in 0.5 mol/L THF solution) to a sealed tube which has been vacuum-filled with nitrogen, and anhydrous toluene. After 1 mL of the mixture was stirred at 0 ° C for 1 h, the heating was stopped and cooled to room temperature. Then, sodium carbonate (1.6 mg, 0.015 mmol) and cuprous iodide (1.9 mg, 0.01 mmol) were successively added, and the imine of the step (1) was sealed and reacted at 90 ° C for 24 hours. After the completion of the reaction, the reaction system was cooled to room temperature, filtered, dried, and further purified by column chromatography to give the product 19 mg (yield: 60%).
本实施例所得产品的结构表征数据如下：The structural characterization data of the products obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.29(t,J＝7.3Hz,2H),7.20(dd,J＝16.3,7.2Hz,3H),7.10(d,J＝8.3Hz,2H),6.49(d,J＝8.3Hz,2H),4.16(dt,J＝11.7,5.9Hz,3H),4.04–3.97(m,1H),2.75(t,J＝7.8Hz,2H),2.21–2.12(m,1H),2.04(dd,J＝13.7,7.0Hz,1H),1.26(d,J＝6.6Hz,3H).氢谱图见图3。 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (t, J = 7.3 Hz, 2H), 7.20 (dd, J = 16.3, 7.2 Hz, 3H), 7.10 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 8.3 Hz, 2H), 4.16 (dt, J = 11.7, 5.9 Hz, 3H), 4.04 - 3.97 (m, 1H), 2.75 (t, J = 7.8 Hz, 2H), 2.21 - 2.12 ( m, 1H), 2.04 (dd, J = 13.7, 7.0 Hz, 1H), 1.26 (d, J = 6.6 Hz, 3H). The hydrogen spectrum is shown in Fig. 3.
13C NMR(101MHz,CDCl3)δ173.66,145.42,140.71,129.15,128.53,128.50,126.24,123.01,114.69,61.26,56.19,34.43,31.73,14.25.碳谱图见图4。 13 C NMR (101 MHz, CDCl 3 ) δ 173.66, 145.42, 140.71, 129.15, 128.53, 128.50, 126.24, 123.01, 114.69, 61.26, 56.19, 34.43, 31.73, 14.25. The carbon spectrum is shown in Fig. 4.
High Resolution MS：计算值C18H20ClNO2[M+H]+:318.1255,发现:318.1254.High Resolution MS: calcd for C 18 H 20 ClNO 2 [M+H] + : 318.1255, found: 318.1254.
根据以上数据推断所得产品的结构如下所示：Based on the above data, the structure of the resulting product is as follows:
Figure PCTCN2015098519-appb-000006
Figure PCTCN2015098519-appb-000006
化合物2Compound 2
实施例3Example 3
α-氨基酸衍生物的合成方法，包括以下步骤：A method for synthesizing an α-amino acid derivative, comprising the steps of:
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯 (10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。(1) In a sealed tube, p-methoxyaniline (12.3 mg, 0.1 mmol), ethyl glyoxylate was added. (10.2 mg, 0.1 mmol), anhydrous sodium sulfate (71 mg, 0.5 mmol), dichloromethane (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, sodium sulfate was filtered off, and the residue was washed with dichloromethane, and the solvent was evaporated to dichloromethane to yield 0.1 mmol of imamine.
Figure PCTCN2015098519-appb-000007
Figure PCTCN2015098519-appb-000007
(2)在已抽真空充氮气的密封管中加对溴苯乙烯(27mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在80℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入NaOtBu(1.5mg，0.015mmol)、醋酸钯(2.4mg，0.01mmol)，步骤(1)的亚胺，密封后在0℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品22.3mg，产率为：57％。(2) Add p-bromostyrene (27 mg, 0.15 mmol), 9-bbn (0.3 mL, 0.15 mmol, 9-bbn in 0.5 mol/L THF solution) to a sealed tube which has been vacuum-filled with nitrogen. 1 mL of toluene was stirred at 80 ° C for 1 h, and the heating was stopped and cooled to room temperature. Then, NaO t Bu (1.5 mg, 0.015 mmol) and palladium acetate (2.4 mg, 0.01 mmol) were added in this order, and the imine of the step (1) was sealed and reacted at 0 ° C for 24 h. After completion of the reaction, the reaction system was cooled to room temperature, filtered, dried, and further purified by column chromatography to give the product 22.3 mg, yield: 57%.
本实施例所得产品的结构表征数据如下：The structural characterization data of the products obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.8Hz,1H),7.06(d,J＝7.8Hz,1H),6.76(d,J＝8.2Hz,1H),6.57(d,J＝8.3Hz,1H),4.15(q,J＝7.1Hz,1H),3.93(t,J＝6.3Hz,1H),3.86(s,1H),3.74(s,1H),2.73(t,J＝7.7Hz,1H),2.05(ddd,J＝21.1,13.7,7.0Hz,1H),1.23(t,J＝7.1Hz,2H).氢谱图见图5。 1 H NMR (400MHz, CDCl 3 ) δ7.40 (d, J = 7.8Hz, 1H), 7.06 (d, J = 7.8Hz, 1H), 6.76 (d, J = 8.2Hz, 1H), 6.57 (d , J = 8.3 Hz, 1H), 4.15 (q, J = 7.1 Hz, 1H), 3.93 (t, J = 6.3 Hz, 1H), 3.86 (s, 1H), 3.74 (s, 1H), 2.73 (t , J = 7.7 Hz, 1H), 2.05 (ddd, J = 21.1, 13.7, 7.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 2H). The hydrogen spectrum is shown in Fig. 5.
13C NMR(101MHz,CDCl3)δ174.17,152.90,140.87,139.95,131.54,130.30,119.92,115.33,114.91,61.10,57.17,55.71,34.54,31.25,14.25.碳谱图见图6。 13 C NMR (101 MHz, CDCl 3 ) δ 174.17, 152.90, 140.87, 139.95, 131.54, 130.30, 119.92, 115.33, 114.91, 61.10, 57.17, 55.71, 34.54, 31.25, 14.25. The carbon spectrum is shown in Fig. 6.
High Resolution MS：C19H22BrNO3计算值[M+H]+:392.0856,发现:392.0848.High Resolution MS: C 19 H 22 BrNO 3 calc. [M+H] + : 392.0856, found: 392.0848.
根据以上数据推断所得产品的结构如下所示：Based on the above data, the structure of the resulting product is as follows:
Figure PCTCN2015098519-appb-000008
Figure PCTCN2015098519-appb-000008
化合物3Compound 3
实施例4Example 4
α-氨基酸衍生物的合成方法，包括以下步骤： A method for synthesizing an α-amino acid derivative, comprising the steps of:
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯(10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。(1) In a sealed tube, p-methoxyaniline (12.3 mg, 0.1 mmol), ethyl glyoxylate (10.2 mg, 0.1 mmol), anhydrous sodium sulfate (71 mg, 0.5 mmol), dichloromethane ( 2 mL), the mixture was stirred at room temperature for 0.5 h. Then, sodium sulfate was filtered off, and the residue was washed with dichloromethane, and the solvent was evaporated to dichloromethane to yield 0.1 mmol of imamine.
Figure PCTCN2015098519-appb-000009
Figure PCTCN2015098519-appb-000009
(2)在已抽真空充氮气的密封管中加1-己烯(12.6mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在60℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入NaOMe(0.8mg，0.015mmol)、溴化亚铜(1.4mg，0.01mmol)，步骤(1)的亚胺，密封后在70℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品21.1mg，产率为：72％。(2) Add 1-hexene (12.6 mg, 0.15 mmol), 9-bbn (0.3 mL, 0.15 mmol, 9-bbn in 0.5 mol/L THF solution) to a sealed tube filled with nitrogen and nitrogen. 1 mL of water toluene was stirred at 60 ° C for 1 h, and the heating was stopped and cooled to room temperature. Then, NaOMe (0.8 mg, 0.015 mmol) and cuprous bromide (1.4 mg, 0.01 mmol) were successively added, and the imine of the step (1) was sealed and reacted at 70 ° C for 24 h. After completion of the reaction, the reaction system was cooled to room temperature, filtered, dried, and further purified by column chromatography to give the product 21.1 mg, yield: 72%.
本实施例所得产品的结构表征数据如下：The structural characterization data of the products obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ6.76(d,J＝8.7Hz,2H),6.59(d,J＝8.6Hz,2H),4.16(q,J＝7.1Hz,2H),3.94(t,J＝6.4Hz,1H),3.81(d,J＝4.0Hz,1H),3.73(s,3H),1.82–1.70(m,2H),1.42(s,2H),1.33–1.26(m,6H),1.23(t,J＝7.1Hz,3H),0.88(t,J＝6.4Hz,3H).氢谱图见图7。 1 H NMR (400 MHz, CDCl 3 ) δ 6.76 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.94 (t , J = 6.4 Hz, 1H), 3.81 (d, J = 4.0 Hz, 1H), 3.73 (s, 3H), 1.82 - 1.70 (m, 2H), 1.42 (s, 2H), 1.33 - 1.26 (m, 6H), 1.23 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H). The hydrogen spectrum is shown in Fig. 7.
13C NMR(101MHz,CDCl3)δ174.62,152.69,141.16,115.12,114.88,60.86,57.92,55.72,33.26,31.62,29.02,25.60,22.54,14.25,14.03.碳谱图见图8。 13 C NMR (101 MHz, CDCl 3 ) δ 174.62, 152.69, 141.16, 115.12, 114.88, 60.86, 57.92, 55.72, 33.26, 31.62, 29.02, 25.60, 22.54, 14.25, 14.03. The carbon spectrum is shown in Fig. 8.
High Resolution MS：C17H27NO3计算值[M+H]+:294.2064,发现:294.2063.High Resolution MS: C 17 H 27 NO 3 calcd [M+H] + : 294.2064, found: 294.2063.
根据以上数据推断所得产品的结构如下所示：Based on the above data, the structure of the resulting product is as follows:
Figure PCTCN2015098519-appb-000010
Figure PCTCN2015098519-appb-000010
化合物4Compound 4
实施例5Example 5
α-氨基酸衍生物的合成方法，包括以下步骤：A method for synthesizing an α-amino acid derivative, comprising the steps of:
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯 (10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。(1) In a sealed tube, p-methoxyaniline (12.3 mg, 0.1 mmol), ethyl glyoxylate was added. (10.2 mg, 0.1 mmol), anhydrous sodium sulfate (71 mg, 0.5 mmol), dichloromethane (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, sodium sulfate was filtered off, and the residue was washed with dichloromethane, and the solvent was evaporated to dichloromethane to yield 0.1 mmol of imamine.
Figure PCTCN2015098519-appb-000011
Figure PCTCN2015098519-appb-000011
(2)在已抽真空充氮气的密封管中加环己烯(12.3mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在60℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入碳酸锂(1mg，0.015mmol)、二氯化钯(1.8mg，0.01mmol)，步骤(1)的亚胺，密封后在70℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品21mg，产率为：72％。(2) Add cyclohexene (12.3 mg, 0.15 mmol), 9-bbn (0.3 mL, 0.15 mmol, 9-bbn in 0.5 mol/L THF solution) to a sealed tube which has been vacuum-filled with nitrogen. 1 mL of toluene was stirred at 60 ° C for 1 h, and the heating was stopped and cooled to room temperature. Then, lithium carbonate (1 mg, 0.015 mmol) and palladium dichloride (1.8 mg, 0.01 mmol) were successively added, and the imine of the step (1) was sealed and reacted at 70 ° C for 24 hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered, dried, and further purified by column chromatography to give the product 21 mg (yield: 72%).
本实施例所得产品的结构表征数据如下：The structural characterization data of the products obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ6.75(d,J＝8.3Hz,2H),6.60(d,J＝8.4Hz,2H),4.15(q,J＝7.1Hz,2H),3.85(s,1H),3.75(d,J＝6.0Hz,1H),3.73(s,3H),1.86(d,J＝12.1Hz,1H),1.77(d,J＝11.5Hz,2H),1.67(d,J＝11.6Hz,3H),1.27–1.12(m,8H).氢谱图见图9。 1 H NMR (400MHz, CDCl 3 ) δ6.75 (d, J = 8.3Hz, 2H), 6.60 (d, J = 8.4Hz, 2H), 4.15 (q, J = 7.1Hz, 2H), 3.85 (s , 1H), 3.75 (d, J = 6.0 Hz, 1H), 3.73 (s, 3H), 1.86 (d, J = 12.1 Hz, 1H), 1.77 (d, J = 11.5 Hz, 2H), 1.67 (d , J = 11.6 Hz, 3H), 1.27 - 1.12 (m, 8H). The hydrogen spectrum is shown in Figure 9.
13C NMR(101MHz,CDCl3)δ174.02,152.64,141.68,115.22,114.87,63.41,60.69,55.74,41.33,29.68,29.23,26.23,26.11,26.09,14.30.碳谱图见图10。 13 C NMR (101 MHz, CDCl 3 ) δ 174.02, 152.64, 141.68, 115.22, 114.87, 63.41, 60.69, 55.74, 41.33, 29.68, 29.23, 26.23, 26.11, 26.09, 14.30. The carbon spectrum is shown in FIG.
High Resolution MS：C17H25NO3计算值[M+H]+:292.1907,发现:292.1906。 High Resolution MS: C 17 H 25 NO 3 calcd [M + H] +: 292.1907 , found: 292.1906.
根据以上数据推断所得产品的结构如下所示：Based on the above data, the structure of the resulting product is as follows:
Figure PCTCN2015098519-appb-000012
Figure PCTCN2015098519-appb-000012
化合物5Compound 5
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。 The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and combinations thereof may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims (7)

  1. α-烷基支链取代的α-氨基酸衍生物的合成方法，其特征在于包括以下步骤：A method for synthesizing an α-alkyl branched-chain substituted α-amino acid derivative, which comprises the steps of:
    取烯烃与9-硼双环(3,3,1)-壬烷在0-80℃下反应0.5-12h，然后加入亚胺，在过渡金属盐、碱和有机溶剂存在的情况下，于0-90℃下反应12-48h，生成α-氨基酸衍生物；The olefin is reacted with 9-boron bicyclo(3,3,1)-nonane at 0-80 ° C for 0.5-12 h, then the imine is added, in the presence of a transition metal salt, a base and an organic solvent, at 0- The reaction is carried out at 90 ° C for 12-48 h to form an α-amino acid derivative;
    所述亚胺的结构如式A所示，烯烃的结构如式B所示，9-bbn结构如式C所示，α-氨基酸衍生物的结构如式D所示：The structure of the imine is as shown in Formula A, the structure of the olefin is as shown in Formula B, the structure of 9-bbn is as shown in Formula C, and the structure of the α-Amino acid derivative is as shown in Formula D:
    Figure PCTCN2015098519-appb-100001
    Figure PCTCN2015098519-appb-100001
    在式A和式D中，R1为4-MeOC6H4、2-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-NO2C6H4、Ph、4-COOEtC6H4或1-萘基中的一种；In Formula A and Formula D, R 1 is 4-MeOC 6 H 4 , 2-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC 6 One of H 4 , 4-NO 2 C 6 H 4 , Ph, 4-COOEtC 6 H 4 or 1-naphthyl;
    在式B和D中，R2为正丁基、环己基、Ph、4-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-tBuC6H4、1-萘基或2-噻吩基中的一种；In formulae B and D, R 2 is n-butyl, cyclohexyl, Ph, 4-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC One of 6 H 4 , 4- t BuC 6 H 4 , 1-naphthyl or 2-thienyl;
    所述烯烃与亚胺的摩尔比为(1-3):1；The molar ratio of the olefin to the imine is (1-3): 1;
    所述的碱为Cs2CO3、NaOMe、NaOtBu、LiOMe、Li2CO3、Na2CO3、NaOEt、K2CO3、LiOtBu或KOEt中的一种。The base is one of Cs 2 CO 3 , NaOMe, NaO t Bu, LiOMe, Li 2 CO 3 , Na 2 CO 3 , NaOEt, K 2 CO 3 , LiO t Bu or KOEt.
  2. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述烯烃与9-硼双环(3,3,1)-壬烷的摩尔比为1:1。The method for synthesizing an α-amino acid derivative according to claim 1, wherein a molar ratio of said olefin to 9-borobicyclo(3,3,1)-nonane is 1:1.
  3. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述烯烃与亚胺的摩尔比为1.5:1。The method for synthesizing an α-amino acid derivative according to claim 1, wherein the molar ratio of the olefin to the imine is 1.5:1.
  4. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述的过渡金属盐为二氯化钯、醋酸钯、三氟醋酸钯、二氯二乙腈钯、二氯二三苯基膦钯、醋酸铜、氯化铜、溴化铜、三氟甲磺酸铜、氯化亚铜、溴化亚铜、碘化亚铜、氰化亚铜或高氯酸铜中的一种。The method for synthesizing an α-amino acid derivative according to claim 1, wherein the transition metal salt is palladium dichloride, palladium acetate, palladium trifluoroacetate, palladium dichlorodiacetonitrile or dichlorotriene. Phenylphosphine palladium, copper acetate, copper chloride, copper bromide, copper triflate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide or copper perchlorate Kind.
  5. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述 的过渡金属盐为氰化亚铜。The method for synthesizing an α-amino acid derivative according to claim 1, wherein: The transition metal salt is cuprous cyanide.
  6. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述的碱为Cs2CO3。The method for synthesizing an α-amino acid derivative according to claim 1, wherein the base is Cs 2 CO 3 .
  7. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述的有机溶剂为甲苯或1,2-二氯乙烷。 The method for synthesizing an α-amino acid derivative according to claim 1, wherein the organic solvent is toluene or 1,2-dichloroethane.
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