CN104945233A - 一种苄基溴化的方法 - Google Patents
一种苄基溴化的方法 Download PDFInfo
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- CN104945233A CN104945233A CN201510340576.7A CN201510340576A CN104945233A CN 104945233 A CN104945233 A CN 104945233A CN 201510340576 A CN201510340576 A CN 201510340576A CN 104945233 A CN104945233 A CN 104945233A
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- benzyl
- methyl
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- benzylphosphonium bromide
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title abstract description 7
- 230000031709 bromination Effects 0.000 title abstract description 5
- 238000005893 bromination reaction Methods 0.000 title abstract description 5
- FOBHBDUEDTWUIL-UHFFFAOYSA-N benzylphosphane;hydrobromide Chemical compound [Br-].[PH3+]CC1=CC=CC=C1 FOBHBDUEDTWUIL-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- IBRFADOGWACKHH-UHFFFAOYSA-N acetaldehyde;toluene Chemical class CC=O.CC1=CC=CC=C1 IBRFADOGWACKHH-UHFFFAOYSA-N 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000376 reactant Substances 0.000 abstract description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052794 bromium Inorganic materials 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000005286 illumination Methods 0.000 abstract description 3
- YXWWHNCQZBVZPV-UHFFFAOYSA-N 2'-methylacetophenone Chemical class CC(=O)C1=CC=CC=C1C YXWWHNCQZBVZPV-UHFFFAOYSA-N 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 238000006734 Wohl-Ziegler bromination reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种苄基溴化的方法，将邻甲基苯乙酮衍生物邻位甲基溴化，产率最高达到81%。本发明提供一个温和的苄基溴化方法，无需用溴、四氯化碳等毒性大污染大试剂，无需光照，并且在反应物中出现多个苄基时，可以选择性溴化其中一个，本发明适合工业化应用。
Description
技术领域
本发明涉及一种苄基溴化的方法，涉及有机化学领域。
背景技术
溴化苄是一类重要的有机合成原料1，苄基溴化的经典方法，是Wohl-Ziegler溴化，用NBS(N-溴代丁二酰亚胺)、过氧化物在四氯化碳溶剂中和反应物一起回流2，但四氯化碳破坏臭氧层，蒙特利尔议定书(Montreal Protocol)禁止工业化应用。所以后来出现了一些新的苄基溴化方法，但这些方法存在如下缺点：所用试剂溴毒性大或者腐蚀性大3，对环境污染大；光照的方法工业化不方便，存在操作困难4。如果反应物中出现多个苄基，如何选择性溴化其中一个，目前文献方法没有解决这个问题。
参考文献：
(1)Larock,R.C.Comprehensive Organic Transformations:A Guide to Functional Group Preparations,2nd ed.；Wiley-VCH:New York,1999.
(2)(a)Wohl,A.Ber.Dtsch.Chem.Ges.1919,52,51-63.(b)Ziegler,
K.；Spath,A.；Schaaf,E.；Schumann,W.；Winkelmann,E.Justus Liebigs Ann.Chem.1942,551,80-119.
(3)(a)Jiang,X.；Shen,M.；Tang,Y.；Li,C.TetrahedronLett.2005,46,487-489.(b)Nishina,Y.；Morita,J.；Ohtani,B.RSC Adv.2013,3,2158–2162.
(4)(a)Nishina,Y.；Ohtani,B.；Kikushima,K.BeilsteinJ.Org.Chem.2013,9,1663–1667.(b)Cantillo,D.；Frutos,O.；Rincon,J.A.；Mateos,C.；Kappe,C.O.J.Org.Chem.2014,79,223-229.
发明内容
本发明的目的在于提供一种苄基溴化的方法，该方法解决了上述所述的问题。
本发明是这样实现的，其特征在于：方法步骤为在氮气环境下，反应瓶中加入0.3mmol邻甲基苯乙酮衍生物，2equiv CuBr2，2mLAcOH，反应混合物在搅拌下加热至100℃，反应24小时，停止加热后，反应混合物加5mL水，乙酸乙酯萃取三次，萃取液干燥，浓缩，柱层析提纯得到苄基溴化产物。
其方程式为：
本发明的技术效果是：本发明用溴化铜作为溴化试剂，将邻甲基苯乙酮衍生物邻位甲基溴化。本发明提供一个温和的苄基溴化方法，无需用溴、四氯化碳等毒性大污染大试剂，无需光照，并且在反应物中出现多个苄基时，可以选择性溴化其中一个，本发明适合工业化应用。
具体实施方式
本发明是这样实现的，其特征在于：方法步骤为在氮气环境下，反应瓶中加入0.3mmol邻甲基苯乙酮衍生物，2equiv CuBr2，2mLAcOH，反应混合物在搅拌下加热至100℃，反应24小时，停止加热后，反应混合物加5mL水，乙酸乙酯萃取三次，萃取液干燥，浓缩，柱层析提纯得到苄基溴化产物。
实施例1：1-【(2-溴甲基-4-甲基)-苯基】乙酮的制备：产物是无色液体，产率79％。1H NMR(400MHz,CDCl3)7.54(d,J＝7.7Hz,1H),7.02(d,J＝8.2Hz,2H),4.14(s,2H),2.44(s,3H),2.29(s,3H).
实施例2：1-【(2-溴甲基-5-甲基)-苯基】乙酮的制备：产物是无色液体，产率81％。1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.24(d,J＝7.7Hz,1H),7.17(d,J＝7.7Hz,1H),4.13(s,2H),2.47(s,3H),2.37(s,3H).
实施例3：1-(2-溴甲基-苯基)乙酮的制备：产物是无色液体，产率77％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.6Hz,1H),7.43(t,J＝7.2Hz,1H),7.29(d,J＝6.1Hz,2H),4.13(s,2H),2.53(s,3H).
实施例4：1-【(2-溴甲基-4，5-二甲基)-苯基】乙酮的制备：产物是无色液体，产率73％。1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.05(s,1H),4.12(s,2H),2.47(s,3H),2.27(s,6H).
实施例5：1-【(2-溴甲基-4-氟)-苯基】乙酮的制备：产物是无色液体，产率73％。1H NMR(400MHz,CDCl3)δ7.83–7.68(m,1H),6.98(t,J＝9.0Hz,2H),4.19(s,2H),2.55(s,3H).
Claims (1)
1.一种苄基溴化的方法，其特征在于：方法步骤为在氮气环境下，反应瓶中加入0.3mmol邻甲基苯乙酮衍生物，2equiv CuBr2，2mL AcOH，反应混合物在搅拌下加热至100℃，反应24小时，停止加热后，反应混合物加5mL水，乙酸乙酯萃取三次，萃取液干燥，浓缩，柱层析提纯得到苄基溴化产物。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1526696A (zh) * | 1994-10-27 | 2004-09-08 | 住友化学工业株式会社 | N-[1-(2，4-二氯苯基)乙基]-2-氰基-3，3-二甲基丁烷酰胺的制造方法 |
| CN101486635A (zh) * | 2009-02-27 | 2009-07-22 | 上海医药工业研究院 | α-环丙基羰基-2-氟苄基卤素的制备方法 |
| CN104326923A (zh) * | 2014-09-05 | 2015-02-04 | 南京华威医药科技开发有限公司 | 一种琥珀酸去甲文拉法辛的合成方法 |
-
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- 2015-06-18 CN CN201510340576.7A patent/CN104945233A/zh not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1526696A (zh) * | 1994-10-27 | 2004-09-08 | 住友化学工业株式会社 | N-[1-(2，4-二氯苯基)乙基]-2-氰基-3，3-二甲基丁烷酰胺的制造方法 |
| CN101486635A (zh) * | 2009-02-27 | 2009-07-22 | 上海医药工业研究院 | α-环丙基羰基-2-氟苄基卤素的制备方法 |
| CN104326923A (zh) * | 2014-09-05 | 2015-02-04 | 南京华威医药科技开发有限公司 | 一种琥珀酸去甲文拉法辛的合成方法 |
Non-Patent Citations (1)
| Title |
|---|
| BHASKER RADARAM 等: "A green bromination method for the synthesis of benzylic dibromides", 《TETRAHEDRON LETTERS》 * |
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