CN113816818A - 一种铜催化不对称烯丙基烷基化反应方法及手性化合物 - Google Patents
一种铜催化不对称烯丙基烷基化反应方法及手性化合物 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000005804 alkylation reaction Methods 0.000 title claims abstract description 17
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 title claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- 150000001879 copper Chemical class 0.000 claims abstract description 39
- 239000000758 substrate Substances 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 24
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 21
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 19
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 20
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 13
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 10
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001979 organolithium group Chemical group 0.000 claims description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- 229940045803 cuprous chloride Drugs 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 claims description 4
- JJNUJWMGIWJSLT-UHFFFAOYSA-N lithium trimethylsilanide Chemical compound [Li+].C[Si-](C)C JJNUJWMGIWJSLT-UHFFFAOYSA-N 0.000 claims description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 4
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 claims description 3
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 3
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 3
- WZZMHOBVLAEJOD-UHFFFAOYSA-N methylsulfanylmethane;hydrobromide Chemical compound [Br-].C[SH+]C WZZMHOBVLAEJOD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000012434 nucleophilic reagent Substances 0.000 abstract description 10
- 229910052802 copper Inorganic materials 0.000 description 17
- 239000010949 copper Substances 0.000 description 17
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 7
- 239000012038 nucleophile Substances 0.000 description 7
- AJKDUJRRWLQXHM-UHFFFAOYSA-N 3-bromocyclohexene Chemical compound BrC1CCCC=C1 AJKDUJRRWLQXHM-UHFFFAOYSA-N 0.000 description 4
- 238000006717 asymmetric allylation reaction Methods 0.000 description 4
- CPPXYWFRJQKLIC-UHFFFAOYSA-N (6-bromocyclohexen-1-yl)benzene Chemical compound BrC1CCCC=C1C1=CC=CC=C1 CPPXYWFRJQKLIC-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- ZKGXAEJNBLJUQF-UHFFFAOYSA-N 3-bromocycloheptene Chemical compound BrC1CCCCC=C1 ZKGXAEJNBLJUQF-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- UZPWKTCMUADILM-UHFFFAOYSA-N 3-methylcyclohexene Chemical compound CC1CCCC=C1 UZPWKTCMUADILM-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- -1 copper salt Chemical class 0.000 description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- BAGSBIKCNLYDJO-UHFFFAOYSA-N 3-ethylcyclohexene Chemical compound CCC1CCCC=C1 BAGSBIKCNLYDJO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000003775 Density Functional Theory Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IIDVGIFOWJJSIJ-UHFFFAOYSA-M lithium;2-methylpropanoate Chemical group [Li+].CC(C)C([O-])=O IIDVGIFOWJJSIJ-UHFFFAOYSA-M 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
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Abstract
本发明提供了一种铜催化不对称烯丙基烷基化反应方法及制备的手性化合物,所述反应方法包括:在‑78℃‑0℃条件下,以铜盐和手性配体作为催化剂,在溶剂中使有机锂试剂与环状底物进行烷基化反应,其中,所述环状底物、所述铜盐和所述手性配体的摩尔比为1:0.05:(0.055‑0.06)。本发明以有机锂试剂作为不对称烯丙基烷基化反应的亲核试剂,不仅能够实现良好的反应收率及对映选择性,且所用催化剂用量较低。
Description
技术领域
本发明涉及化工技术领域,具体而言,涉及一种铜催化不对称烯丙基烷基化反应方法及手性化合物。
背景技术
手性是指分子可以像人的左右手一样,互为镜像,但是却不能互相重合,具有这样性质的分子为手性分子,一对互为镜像关系的手性分子互为对映异构体,不同构型的手性分子具有不同的功能。不对称烯丙基烷基化(简称AAA)反应是一种有效的构筑手性化合物的方法,烯丙基烷基化反应是一种碳-碳键形成的反应,反应历程为亲核取代反应,因此反应过程中需用到亲核试剂,现有技术中通常使用格氏试剂作为亲核试剂,但所得产物的对映选择性较差、产率较低。
发明内容
本发明解决的问题是现有技术中以格氏试剂为亲核试剂进行的不对称烯丙基烷基化反应的产率较低、产物的对映选择性较差。
为解决上述问题,本发明提供一种铜催化不对称烯丙基烷基化反应方法,包括:
在-78℃-0℃条件下,以铜盐和手性配体作为催化剂,在溶剂中使有机锂试剂与环状底物进行烷基化反应,其中,所述环状底物、所述铜盐和所述手性配体的摩尔比为1:0.05:(0.055-0.06)。
较佳地,所述环状底物、所述铜盐和所述手性配体的摩尔比为1:0.05:0.06。
较佳地,所述有机锂试剂包括甲基锂、乙基锂、丁基锂、异丁基锂、三甲基硅甲基锂、叔丁基锂和正己基锂中的一种。
较佳地,所述铜盐包括溴化亚铜二甲硫醚、噻吩-2-甲酸铜(I)、氯化亚铜、溴化亚铜、碘化亚铜、氰化亚铜以及三氟甲烷磺酸铜(Ⅱ)中的一种。
较佳地,所述手性配体包括(R,R)-L1配体、(S,S,S)-L2配体、(S,S,S)-L3配体及(S,R,R)-L4配体中的一种;
其中,所述(R,R)-L1配体的结构式为:
所述(S,S,S)-L2配体的结构式为:
所述(S,S,S)-L3配体的结构式为:
所述(S,R,R)-L4配体的结构式为:
较佳地,所述铜盐为溴化亚铜二甲硫醚,所述溴化亚铜二甲硫醚的用量为5mol%,所述手性配体为(S,S,S)-L2配体,所述(S,S,S)-L2配体的用量为6mol%。
较佳地,所述环状底物包括:
较佳地,铜催化不对称烯丙基烷基化反应方法的步骤如下:
将所述铜盐和所述手性配体溶于无水二氯甲烷中,室温搅拌,得到反应液;
将所述环状底物滴加至所述反应液中,加入内标物质,在设定温度下冷却设定时间;
将所述有机锂试剂稀释后,在2h内逐滴滴加至所述反应液中,滴加完成后,继续反应1-2h。
较佳地,铜催化不对称烯丙基烷基化反应方法的步骤如下:
在干燥的管中,加入干燥的磁子,称取当量的所述铜盐和所述手性配体,抽气换气多次,用氮气保护,向其中加入无水二氯甲烷溶剂,在室温下搅拌10-20min,使所述手性配体与所述铜盐充分配位,得到反应液;
然后取所述环状底物滴加到所述反应液中,加入1当量内标物质,将其转移到-78℃的低温循环搅拌器中,冷却10-15min,将1.5当量的所述有机锂试剂稀释后,在2小时内,逐滴滴加到所示反应液中,滴加完成后,继续反应1小时,反应结束后用1M稀盐酸缓慢滴加淬灭,测量分离产率和对映选择性。
本发明还提供一种手性化合物,采用如上所述的铜催化不对称烯丙基烷基化反应方法制备而成。
本发明相较于现有技术具有的有益效果如下:
本发明以有机锂试剂作为不对称烯丙基烷基化反应的亲核试剂,不仅能够实现良好的反应收率及对映选择性,且所用昂贵的手性配体催化剂用量较低。
附图说明
图1为本发明实施例中铜催化不对称烯丙基烷基化反应流程图;
图2为本发明实施例中铜催化不对称烯丙基烷基化模板反应示意图;
图3为本发明实施例中铜催化不对称烯丙基烷基化反应过程示意图。
具体实施方式
现有技术中,通过使用格氏试剂作为亲核试剂在-78℃条件下进行外消旋环状底物的不对称烯丙基烷基化反应,经DFT计算表明,该反应是一种直接的对映体收敛转化,即外消旋底物中的两个对映体经过不同的反应路径生成同一种构型的产物。但采用此种方法所得产物的对映选择性及产率均存在较大的提升空间。
为使本发明的上述目的、特征和优点能够更为明显易懂,下面结合附图对本发明的具体实施例做详细的说明。
本发明实施例提供一种铜催化不对称烯丙基烷基化反应方法,包括:
在-78℃-0℃条件下,以铜盐和手性配体作为催化剂,在溶剂中使有机锂试剂与环状底物进行烷基化反应,其中,环状底物、铜盐和手性配体的摩尔比为1:0.05:(0.055-0.06),优选为1:0.05:0.06,此时铜盐与手性配体的摩尔比为1:1.2,即本实施例中,铜盐与手性配体的摩尔比为1:(1.1-1.2)。
本实施例以有机锂试剂作为不对称烯丙基烷基化(简称AAA)反应的亲核试剂,与铜催化剂共同催化实现环状底物的不对称烯丙基烷基化反应,本实施例所用方法不仅能够实现良好的反应收率及对映选择性,且所用催化剂用量较低。
如图1所示,本实施例的具体步骤如下:
将铜盐和手性配体溶于无水二氯甲烷中,室温搅拌,得到反应液;其中,搅拌时间优选为10-20min;
将环状底物滴加至反应液中,加入内标物质,在设定温度下冷却设定时间;其中,设定温度为-78℃-0℃,设定时间优选为10-15min;
将有机锂试剂稀释后,在2h内逐滴滴加至反应液中,滴加完成后,继续反应1-2h。
具体地,按照本发明,首先,选择合适的模板反应,以3-溴环己烯作为模板底物,甲基锂作为亲核试剂,进行模板反应(如图2所示)实验条件的优化,包括对手性配体、铜盐、温度、催化剂载量的筛选和优化,试验结果如表1所示。其中,铜盐包括溴化亚铜二甲硫醚(CuBr·SMe2)、噻吩-2-甲酸铜(I)(CuTc)、氯化亚铜(CuCl)、溴化亚铜、碘化亚铜(CuI)、氰化亚铜以及三氟甲烷磺酸铜(Ⅱ)中的一种。
图2中虚线左侧表示模板反应的反应过程,反应物为3-溴环己烯,在甲基锂、铜催化剂、手性配体(以L*表示)及溶剂的作用下,在-78℃下进行不对称烯丙基烷基化反应,得到3-甲基环己烯产物的反应过程示意图,虚线右侧表示手性配体L*包括四种配体,分别为(R,R)-L1配体、(S,S,S)-L2配体、(S,S,S)-L3配体及(S,R,R)-L4配体(分别简称为L1、L2、L3及L4);其中,各配体的结构式如下所示:
有机锂试剂包括甲基锂、乙基锂、丁基锂、异丁基锂、三甲基硅甲基锂、叔丁基锂和正己基锂中的一种。
环状底物包括不同碳原子数的环状底物如六元环、七元环等以及带有修饰基团的环状底物,如七元环的3-溴环庚烯和邻位有苯基取代的6-溴-1-苯基环己烯。示例性地,几种环状底物的结构式如下所示:
另外,图2中还示出了各反应物的用量情况,其中,甲基锂用量为1.5当量,铜催化剂(铜盐)的用量用X表示,单位为mol%,手性配体L*的用量为1.1X,单位为mol%,即手性配体的用量为铜催化剂用量的1.1倍,或者说铜盐与手性配体的摩尔比为1:1.1,下文中仅限定了铜盐的用量,应当知晓,模板反应中,手性配体的用量为铜盐用量的1.1倍。
其中表1的表头中,entry表示每组试验的条目号;L代表手性配体,包括L1、L2、L3及L4;Cu salt表示铜盐;X表示铜催化剂的用量,即铜盐的用量,mol%表示摩尔百分比;Temp表示温度,单位为℃;yielda表示核磁产率,单位为%;eeb表示对映选择性,单位为%,其中的b表示对映选择性由气相手性柱直接测得。
首先用L3配体对铜盐进行筛选,分别选用CuTc、CuCl、CuI、CuBr·SMe2作为铜盐,进行条目1-条目4号的实验,其中,这四组实验中,铜催化剂用量均为5mol%,反应温度均控制在-78℃。结果表明不同种类的铜盐对反应的影响非常大,其中表现最好的是铜盐为溴化亚铜二甲硫醚的络合物,当铜催化剂的用量为5mol%时,在-78℃下的反应对映选择性可以达到91%,如表1中的条目4所示。
选定溴化亚铜二甲硫醚的络合物作为铜催化剂,筛选适合该反应的不同的手性配体,对L1、L2、L3、L4四种配体分别进行实验,如表1中条目4-7所示。结果表明八氢萘酚手性单磷配体L2表现最好,相同实验条件下可以达到98%的ee值和99%的产率,如表1其中条目6所示。
在此基础上对反应温度进行优化,与表1中条目6所示的其它实验条件相同(包括所用手性配体、铜盐种类、铜催化剂用量等),仅是改变反应温度,设计条目9和条目10两组实验。实验表明当反应温度升高时,反应的对映选择性下降明显,当温度提高至-40℃(表1,条目9)和0℃(表1,条目10)时,ee值分别为77%和70%。
对铜催化剂的当量进行优化,与表1中条目6所示的其它试验条件相同(包括所用手性配体、铜盐种类、反应温度等),仅是改变铜催化剂当量,设计条目8实验。实验表明,当降低铜催化剂当量至1mol%时,该铜盐和配体的催化组合仍然表现了较高的活性,反应ee值可达93%,如表1中条目8所示。
表1筛选不同配体、铜盐、温度、催化剂当量
a核磁产率,二溴甲烷作内标;b由气相手性柱直接测得
反应机理如图3所示,以溴化亚铜二甲硫醚的络合物(CuBr·SMe2)为铜催化剂,与手性配体(以L表示)共同作为该反应的催化剂,以甲基锂(MeLi)为亲核试剂,以3-溴环己烯为环状底物,包括R型和S型,图3中分别以(R)-1a和(S)-1a表示。在催化剂的作用下,(R)-1a经过反式的SN2’(anti-SN2’)氧化加成形成Int-1a中间体,(S)-1a经过反式的SN2(anti-SN2)氧化加成形成Int-1a中间体,然后Int-1a中间体经过快速的还原消除生成单一构型的目标产物(R)-2a。
经过上述条件优化实验,得到有机锂参与的外消旋环状底物AAA反应的最优实验条件为:在-78℃的条件下,用5mol%的溴化亚铜二甲硫醚络合物作为铜盐催化剂,以6mol%(S,S,S)-L2八氢手性联萘酚作为手性配体,以无水二氯甲烷作溶剂,使用有机锂作为亲核试剂,与外消旋的溴代环状底物进行不对称烯丙基烷基化反应,反应时间为1h,就可获得高产率和对映选择性的手性化合物。
示例性地,具体的反应过程如下:在一个干燥的10ml的史莱克管中,加入干燥的磁子,称取当量的铜盐和配体,抽气换气三次,用氮气保护,向其中加入无水二氯甲烷溶剂2ml,在室温下搅拌10-20min,优选为15min,使配体与铜盐充分配位,然后用微升针取0.5mmol的溴代环状底物滴加到反应液中,加入1当量内标物质(二溴甲烷),将其转移到-78℃的低温循环搅拌器中,冷却10-15min,将1.5当量的甲基锂试剂用无水甲苯(其它有机锂试剂用正己烷稀释)稀释至1ml,在2小时内,逐滴滴加到反应液中,滴加完成后,继续反应1小时,反应结束后用1M稀盐酸缓慢滴加淬灭,测得分离产率和ee值。
其中,ee值的测量除了3-甲基-1-环己烯、3-乙基-1-环己烯用气相手性柱直接测量以及6-溴-1-苯基环己烯用液相手性柱直接测量外,其余产物均在纯化后通过环氧衍生化之后用气相手性柱进行ee值的测试,示例性地,通过柱层析分离提纯,然后用磷酸氢二钠和氧化剂间氯过氧苯甲酸(m-CPBA)将双键氧化为环氧,通过气相手性柱测ee值。
本发明另一实施例提供一种手性化合物,采用如上的铜催化不对称烯丙基烷基化反应方法制备而成。
实施例1
使用5mol%溴化亚铜二甲硫醚铜盐和6mol%手性配体L2作为催化剂,溶剂为二氯甲烷(DCM),在-78℃的温度条件下,催化甲基锂与3-溴环己烯进行不对称烯丙基烷基化反应。
本实施例中,反应的对映选择性为97%,核磁产率为99%。
实施例2
与实施例1不同之处在于,亲核试剂为乙基锂,产物为
本实施例中,反应的对映选择性为94%,核磁产率为99%。
实施例3
与实施例1不同之处在于,亲核试剂为丁基锂,产物为
本实施例中,反应的对映选择性为90%,分离产率为82%。
实施例4
与实施例1不同之处在于,亲核试剂为异丁基锂,产物为
本实施例中,反应的对映选择性为70%,分离产率为74%。
实施例5
与实施例1不同之处在于,亲核试剂为三甲基硅甲基锂,产物为
本实施例中,反应的对映选择性为80%,分离产率为60%。
实施例6
与实施例1不同之处在于,亲核试剂为叔丁基锂,产物为
本实施例中,反应的对映选择性为50%,分离产率为76%。
实施例7
与实施例1不同之处在于,亲核试剂为己基锂,产物为
本实施例中,反应的对映选择性为80%,分离产率为99%。
实施例8
与实施例1不同之处在于,外消旋底物为3-溴环庚烯,产物为
本实施例中,反应的对映选择性为62%,分离产率为92%。
实施例9
与实施例1不同之处在于,外消旋底物为6-溴-1-苯基环己烯,产物为
本实施例中,反应的对映选择性为80%,产率为98%。
需要说明的是,上述实施例中,亲核试剂为含甲基和乙基的有机锂试剂时,由于产物具有剧烈易挥发性,没有得到分离产率,而以核磁定产率,其余有机锂试剂情况下的产物皆为分离产率。
虽然本公开披露如上,但本公开的保护范围并非仅限于此。本领域技术人员在不脱离本公开的精神和范围的前提下,可进行各种变更与修改,这些变更与修改均将落入本发明的保护范围。
Claims (10)
1.一种铜催化不对称烯丙基烷基化反应方法,其特征在于,包括:
在-78℃-0℃条件下,以铜盐和手性配体作为催化剂,在溶剂中使有机锂试剂与环状底物进行烷基化反应,其中,所述环状底物、所述铜盐和所述手性配体的摩尔比为1:0.05:(0.055-0.06)。
2.根据权利要求1所述的铜催化不对称烯丙基烷基化反应方法,其特征在于,所述环状底物、所述铜盐和所述手性配体的摩尔比为1:0.05:0.06。
3.根据权利要求1所述的铜催化不对称烯丙基烷基化反应方法,其特征在于,所述有机锂试剂包括甲基锂、乙基锂、丁基锂、异丁基锂、三甲基硅甲基锂、叔丁基锂和正己基锂中的一种。
4.根据权利要求1所述的铜催化不对称烯丙基烷基化反应方法,其特征在于,所述铜盐包括溴化亚铜二甲硫醚、噻吩-2-甲酸铜(I)、氯化亚铜、溴化亚铜、碘化亚铜、氰化亚铜以及三氟甲烷磺酸铜(Ⅱ)中的一种。
6.根据权利要求1所述的铜催化不对称烯丙基烷基化反应方法,其特征在于,所述铜盐为溴化亚铜二甲硫醚,所述溴化亚铜二甲硫醚的用量为5mol%,所述手性配体为(S,S,S)-L2配体,所述(S,S,S)-L2配体的用量为6mol%。
8.根据权利要求1所述的铜催化不对称烯丙基烷基化反应方法,其特征在于,步骤如下:
将所述铜盐和所述手性配体溶于无水二氯甲烷中,室温搅拌,得到反应液;
将所述环状底物滴加至所述反应液中,加入内标物质,在设定温度下冷却设定时间;
将所述有机锂试剂稀释后,在2h内逐滴滴加至所述反应液中,滴加完成后,继续反应1-2h。
9.根据权利要求1所述的铜催化不对称烯丙基烷基化反应方法,其特征在于,步骤如下:
在干燥的管中,加入干燥的磁子,称取当量的所述铜盐和所述手性配体,抽气换气多次,用氮气保护,向其中加入无水二氯甲烷溶剂,在室温下搅拌10-20min,使所述手性配体与所述铜盐充分配位,得到反应液;
然后取所述环状底物滴加到所述反应液中,加入1当量内标物质,将其转移到-78℃的低温循环搅拌器中,冷却10-15min,将1.5当量的所述有机锂试剂稀释后,在2小时内,逐滴滴加到所述反应液中,滴加完成后,继续反应1小时,反应结束后用1M稀盐酸缓慢滴加淬灭,测量分离产率和对映选择性。
10.一种手性化合物,其特征在于,采用如权利要求1-9任一项所述的铜催化不对称烯丙基烷基化反应方法制备而成。
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