CN112194559A - 一种手性及非手性2,2’-二卤代联芳基化合物的合成方法 - Google Patents
一种手性及非手性2,2’-二卤代联芳基化合物的合成方法 Download PDFInfo
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- -1 biaryl compounds Chemical class 0.000 title claims abstract description 51
- 238000001308 synthesis method Methods 0.000 title description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000001879 copper Chemical class 0.000 claims abstract description 9
- 238000010189 synthetic method Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000292 calcium oxide Substances 0.000 claims description 7
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- JTNVCJCSECAMLD-ROUUACIJSA-N (4r)-4-phenyl-2-[2-[(4r)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]propan-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound C1([C@H]2N=C(OC2)C(C)(C)C=2OC[C@H](N=2)C=2C=CC=CC=2)=CC=CC=C1 JTNVCJCSECAMLD-ROUUACIJSA-N 0.000 claims description 5
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- HWUPLUNLNUHIQZ-UHFFFAOYSA-N copper;trifluoromethanesulfonic acid Chemical compound [Cu].OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F HWUPLUNLNUHIQZ-UHFFFAOYSA-N 0.000 claims 1
- 238000010626 work up procedure Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000006555 catalytic reaction Methods 0.000 abstract description 5
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- 125000005841 biaryl group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- ULAQISQDFQAUCH-UHFFFAOYSA-N trifluoromethanesulfonic acid hydroiodide Chemical compound I.OS(=O)(=O)C(F)(F)F ULAQISQDFQAUCH-UHFFFAOYSA-N 0.000 description 8
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000000297 Sandmeyer reaction Methods 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- ABMKWMASVFVTMD-UHFFFAOYSA-N 1-methyl-2-(2-methylphenyl)benzene Chemical compound CC1=CC=CC=C1C1=CC=CC=C1C ABMKWMASVFVTMD-UHFFFAOYSA-N 0.000 description 1
- JUHIIKHSYNKSET-UHFFFAOYSA-N CC(C=CC=C1)=C1C1=C(C)C=CC=C1.I Chemical compound CC(C=CC=C1)=C1C1=C(C)C=CC=C1.I JUHIIKHSYNKSET-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001500 aryl chlorides Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229940108928 copper Drugs 0.000 description 1
- 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 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/361—Preparation of halogenated hydrocarbons by reactions involving a decrease in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/38—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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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
本发明提供了一种手性及非手性2,2’‑二卤代联芳基化合物(III)的合成方法,本合成方法以二芳基环状碘鎓盐和廉价的卤盐为原料,在铜盐的催化下一步通过开环反应生成2,2’‑二卤代联芳基化产物;本发明原料来源丰富,成本低廉,操作简捷,收率高,并且合成的产物结构多样、新颖,具有广泛的应用性;
Description
技术领域
本发明涉及一种手性及非手性2,2’-二卤代联芳基化合物的合成方法。
背景技术
联芳基骨架是一类在天然产物、药物分子、生物活性分子、精细化学品、材料分子和手性分子中广泛存在的重要组成部分,因此该类化合物的高效合成方法一直是有机合成化学界一个热门研究方向。联芳基卤化物(芳基碘,芳基溴,芳基氯)是一类易于进行多样性转化的合成起始原料,例如,在过渡金属的催化下,芳基卤可以经Suzuki偶联反应通过构建碳碳键转化成芳基,经Buchwald偶联反应通过构建碳氮键转化成芳基胺,经铜催化可以构建碳氧,碳硫键等有实用价值的含杂原子芳基化合物。在使用具有轴手性的联芳基卤化物作为反应原料时,可经相应反应合成结构类型丰富的联芳基轴手性化合物,这些手性化合物在钯、钌、铑等多种金属催化的不对称反应中具有重要的应用价值。
目前,2,2’-二卤代联芳基化合物的合成方法单一,最为常用的合成方法是通过桑德迈尔反应(Sandmeyer reaction),在铜盐的催化下将芳基胺经重氮化后转化成相应的芳基卤。而轴手性2,2’-二卤代联芳基化合物常需要以轴手性联芳基二胺为原料,或者通过手性拆分的方法得到。通过这些合成方法得到的2,2’-二卤代联芳基化合物结构类型单一,不利于从2,2’-二卤代联芳基化合物出发合成结构类型更为丰富,附加值更高的联芳基化合物。
本合成方法以二芳基环状碘鎓盐和廉价的卤盐为原料,在铜盐的催化下一步通过开环反应生成2,2’-二卤代联芳基化产物。无论是从原料来源的丰富性,经济性,反应的原子经济性,合成方法的简捷性还是从所合成产物的结构多样性、新颖性和广泛的应用性上来讲,都是对以往合成方法的一个比较大的突破。因此,具有一定的实际应用价值。
发明内容
本发明通过二芳基环状碘鎓盐类化合物与卤盐反应,高效的合成手性及非手性2,2’-二卤代联芳基化合物。该反应可在空气下进行,反应步骤简单,后处理方便。本发明解决了以往合成2,2’-二卤代联芳基化合物需要复杂的合成原料或者合成方法效率低下的问题。
本发明的技术方案如下:
一种手性及非手性2,2’-二卤代联芳基化合物(III)的合成方法,所述的合成方法为:
当合成非手性产物时:将二芳基环状碘鎓盐类化合物(I)、卤盐、铜盐与溶剂二氯甲烷混合均匀,在20~30℃下搅拌反应6~20h,之后反应液经后处理,得到产物2,2’-二卤代联芳基化合物(III);
所述二芳基环状碘鎓盐类化合物(I)、卤盐、铜盐的物质的量之比为1:1~1.5:0.005~0.05;
所述溶剂二氯甲烷的体积用量以二芳基环状碘鎓盐的物质的量计为10~30mL/mmol;
所述铜盐选自:碘化亚铜、溴化亚铜、溴化铜、氯化亚铜、氯化铜或三氟甲磺酸铜等;
所述卤盐选自:碘化钠、碘化钾、四丁基碘化氨、溴化钠、溴化钾、溴化锂、四丁基溴化氨、氯化钠、氯化钾、氯化锂或四丁基氯化氨等;
所述后处理的方法为:反应结束后,将反应液浓缩,进行柱层析,以石油醚与乙酸乙酯体积比200~10:1的混合液作为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到产物(III);
当合成手性产物时:投料时还需加入手性配体、氧化钙,其余操作与上述相同;所述二芳基环状碘鎓盐类化合物(I)与手性配体、氧化钙的物质的量之比为1:0.01~0.1:2~4;
所述手性配体为手性噁唑啉类配体,具体例如:(R,R)-2,2'-异亚丙基双(4-苯基-2-噁唑啉);
式(I)或(III)中,
R1、R2为所在苯环上的一个或多个取代基,所述取代基各自独立选自:C5~C10芳基、取代C5~C10芳基、C1~C6直链烷基、C3~C6支链烷基、C3~C8环状烷基、含杂C2~C6烷基、不饱和C2~C6烷基、硝基、三氟甲基、羟基、酯基或卤素,优选例如:甲基、乙基、丙基、氯或氟;
X为:氯、溴或碘。
本发明具有以下优点:反应体系简单,反应条件温和,原料特别是卤盐容易得到,底物无需多步制备,后处理简单,总收率较高。
本发明的创新点在于,在空气中于一定温度下使用卤盐和二芳基环状碘鎓盐一步就能得到2,2’-二卤代联芳基化合物。本发明所得非手性2,2’-二卤代联芳基化合物收率最高为99%;所得手性2,2’-二卤代联芳基化合物收率最高为99%,ee值最高为98%。
具体实施方式
下面通过具体实施例对本发明作进一步的说明,但本发明的保护范围并不仅限于此。
实施例1化合物IIIa的合成
将四丁基碘化氨(88.6mg,0.24mmol),2,2'-二甲基-[1,1'-联苯]-环状三氟甲磺酸碘鎓盐(91.2mg,0.2mmol),碘化亚铜(1.9mg,5mol%)溶解在2mL二氯甲烷中,该溶液在室温下搅拌反应12h。浓缩,经硅胶柱层析,石油醚/乙酸乙酯=200:1洗脱,浓缩得到产物85.9mg,收率为99%。
1H NMR(500MHz,CDCl3)δ=7.85–7.81(m,2H),7.30(dt,J=7.6,0.9Hz,2H),7.03(t,J=7.7Hz,2H),2.04(s,6H)ppm.13C NMR(126MHz,CDCl3)δ=147.4,137.6,136.8,130.0,129.4,100.7,21.4ppm.产物结构式为:
实施例2光学纯化合物(R)-IIIa的合成
将碘化钠(36.0mg,0.24mmol),2,2'-二甲基-[1,1'-联苯]-环状三氟甲磺酸碘鎓盐(91.2mg,0.2mmol),碘化亚铜(1.9mg,5mol%),(R,R)-2,2'-异亚丙基双(4-苯基-2-噁唑啉)(5.0mg,7.5mol%),氧化钙(22.4mg,0.4mmol),溶解在2mL二氯甲烷中,该溶液在室温下搅拌反应20h。浓缩,经硅胶柱层析,石油醚/乙酸乙酯=200:1洗脱,浓缩得到产物85.9mg,收率为99%。
1H NMR(500MHz,CDCl3)δ=7.85–7.81(m,2H),7.30(dt,J=7.6,0.9Hz,2H),7.03(t,J=7.7Hz,2H),2.04(s,6H)ppm.13C NMR(126MHz,CDCl3)δ=147.4,137.5,136.8,130.0,129.4,100.6,21.4ppm.ee值使用手性IC柱经HPLC测定(正己烷:异丙醇=99.5:0.5,0.4mL/min,254nm,98%ee);tr=8.52min(S),tr=9.03min(R).产物结构式为:
实施例3化合物IIIc的合成
按实施例1所述的方法,不同的是所用碘鎓盐底物为1,2,8,9-四甲基二苯并[b,d]三氟甲磺酸碘鎓盐(96.8mg,0.2mmol),得到产物89.6mg,收率为97%。
1H NMR(500MHz,CDCl3)δ=7.71(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,2H),2.31(s,6H),1.93(s,6H)ppm.13C NMR(126MHz,CDCl3)δ=147.9,137.1,136.3,136.1,130.8,97.6,20.3,17.8ppm.产物结构式为:
实施例4光学纯化合物(R)-IIIc的合成
按实施例2所述的方法,不同的是所用碘鎓盐底物为1,2,8,9-四甲基二苯并[b,d]三氟甲磺酸碘鎓盐(96.8mg,0.2mmol),得到产物86.8mg,收率为94%。
1H NMR(500MHz,CDCl3)δ=7.71(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,2H),2.31(s,6H),1.93(s,6H)ppm.13C NMR(126MHz,CDCl3)δ=147.9,137.1,136.3,136.1,130.8,97.6,20.3,17.8ppm。ee值使用手性IC柱经HPLC测定(正己烷:异丙醇=99.5:0.5,0.4mL/min,254nm,97%ee);t r=9.60min(S),tr=10.61min(R).产物结构式为:
实施例5化合物IIId的合成
按实施例1所述的方法,不同的是所用碘鎓盐底物为4-氯-1,9-二甲基二苯并[b,d]三氟甲磺酸碘鎓盐(98.0mg,0.2mmol),得到产物89.8mg,收率为96%。
1H NMR(500MHz,CDCl3)δ=7.83(d,J=7.9Hz,1H),7.41(d,J=8.1Hz,1H),7.32–7.28(m,1H),7.26–7.22(m,1H),7.03(t,J=7.7Hz,1H),2.01(s,3H),2.00(s,3H)ppm.13CNMR(126MHz,CDCl3)δ=150.0,147.9,137.3,136.9,136.8,135.4,131.2,130.2,129.6,128.3,104.8,100.2,21.3,21.0ppm.产物结构式为:
实施例6化合物IIIe的合成
按实施例1所述的方法,不同的是所用碘鎓盐底物为1-氯-9-甲基二苯并[b,d]三氟甲磺酸碘鎓盐(95.2mg,0.2mmol),得到产物86.2mg,收率为95%。
1H NMR(500MHz,CDCl3)δ=7.90(dd,J=7.9,1.1Hz,1H),7.82(d,J=7.9Hz,1H),7.52(dd,J=8.0,1.1Hz,1H),7.30(d,J=7.6Hz,1H),7.06(td,J=7.9,3.9Hz,2H),2.08(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=146.3,146.3,137.8,137.8,136.7,133.4,130.4,129.9,129.9,129.6,100.9,100.0,21.2ppm.产物结构式为:
实施例7化合物IIIf的合成
按实施例1所述的方法,不同的是所用碘鎓盐底物为3,7-二氟-1,9-二甲基二苯并[b,d]三氟甲磺酸碘鎓盐(98.4mg,0.2mmol),得到产物90.2mg,收率为96%。
1H NMR(500MHz,CDCl3)δ=7.55(dd,J=7.8,2.5Hz,2H),7.09–6.98(m,2H),2.02(s,6H)ppm.13C NMR(126MHz,CDCl3)δ=161.5(d,JC-F=152.2Hz),142.7(d,JC-F=3.4Hz),139.3(d,JC-F=8.1Hz),123.8(d,JC-F=23.4Hz),117.2(d,JC-F=21.2Hz),100.4(d,JC-F=8.9Hz),21.7(d,JC-F=1.6Hz)ppm.产物结构式为:
实施例8化合物IIIg的合成
将四丁基溴化氨(77.4mg,0.24mmol),1,3,7,9-四甲基二苯并[b,d]三氟甲磺酸碘鎓盐(96.8mg,0.2mmol),溴化亚铜(1.4mg,5mol%)溶解在2mL二氯甲烷中,该溶液在室温下搅拌反应12h。浓缩,经硅胶柱层析,石油醚/乙酸乙酯=200:1洗脱,浓缩得到产物78.7mg,收率为95%。
1H NMR(500MHz,CDCl3)δ=7.42–7.36(m,1H),7.17(d,J=1.2Hz,2H),7.08(dt,J=1.7,0.8Hz,1H),2.51(s,3H),2.38(s,3H),2.00(s,3H),1.95(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=145.1,141.9,139.8,139.0,137.7,134.7,130.7,130.1,129.6,128.7,123.7,107.6,29.4,21.0,21.0,20.6ppm.产物结构式为:
实施例9光学纯化合物(R)-IIIg的合成
将溴化锂(20.8mg,0.24mmol),1,3,7,9-四甲基二苯并[b,d]三氟甲磺酸碘鎓盐(96.8mg,0.2mmol),溴化亚铜(1.4mg,5mol%),(R,R)-2,2'-异亚丙基双(4-苯基-2-噁唑啉)(5.0mg,7.5mol%),氧化钙(22.4mg,0.4mmol),溶解在2mL二氯甲烷中,该溶液在室温下搅拌反应20h。浓缩,经硅胶柱层析,石油醚/乙酸乙酯=200:1洗脱,浓缩得到产物78.7mg,收率为95%。
1H NMR(500MHz,CDCl3)δ=7.42–7.36(m,1H),7.17(d,J=1.2Hz,2H),7.08(dt,J=1.7,0.8Hz,1H),2.51(s,3H),2.38(s,3H),2.00(s,3H),1.95(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=145.1,141.9,139.8,139.0,137.7,134.7,130.7,130.1,129.6,128.7,123.7,107.6,29.4,21.0,21.0,20.6ppm.ee值使用手性IC柱经HPLC测定(正己烷:异丙醇=99.5:0.5,0.4mL/min,254nm,97%ee);t r=9.94min(S),tr=10.98min(R).产物结构式为:
实施例10化合物IIIh的合成
按实施例9所述的方法,不同的是所用碘鎓盐底物为3,7-二氟-1,9-二甲基二苯并[b,d]三氟甲磺酸碘鎓盐(98.4mg,0.2mmol),得到产物79.3mg,收率为94%。
1H NMR(500MHz,CDCl3)δ=7.54(dd,J=7.8,2.6Hz,1H),7.31(dd,J=8.1,2.6Hz,1H),7.07–7.00(m,2H),2.03(s,3H),2.00(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=162.6(d,JC-F=37.6Hz),160.6(d,JC-F=38.8Hz),140.2(d,JC-F=7.6Hz),139.8(d,JC-F=3.2Hz),139.4(d,JC-F=7.4Hz),139.0(d,JC-F=3.2Hz),124.4(d,JC-F=10.4Hz),123.7(d,JC-F=22.5Hz),117.6(d,JC-F=24.2Hz),117.1(d,JC-F=21.1Hz),116.4(d,JC-F=20.8Hz),100.1(t,JC-F=7.8Hz),21.5,20.9ppm.产物结构式为:
实施例11化合物IIIi的合成
将四丁基氯化氨(66.7mg,0.24mmol),1,3,7,9-四甲基二苯并[b,d]三氟甲磺酸碘鎓盐(96.8mg,0.2mmol),氯化亚铜(1.0mg,5mol%)溶解在2mL二氯甲烷中,该溶液在室温下搅拌反应12h。浓缩,经硅胶柱层析,石油醚/乙酸乙酯=200:1洗脱,浓缩得到产物71.0mg,收率为96%。
1H NMR(500MHz,CDCl3)δ=7.18–7.16(m,1H),7.15(s,2H),7.04–7.01(m,1H),2.49(s,3H),2.37(s,3H),1.98(s,3H),1.91(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=143.6,140.1,139.8,138.7,137.6,134.8,132.9,129.6,129.5,128.7,127.5,107.6,29.4,21.1,20.9,20.1ppm.产物结构式为:
实施例12光学纯化合物(R)-IIIi的合成
将氯化锂(10.2mg,0.24mmol),1,3,7,9-四甲基二苯并[b,d]三氟甲磺酸碘鎓盐(96.8mg,0.2mmol),氯化亚铜(1.0mg,5mol%),(R,R)-2,2'-异亚丙基双(4-苯基-2-噁唑啉)(5.0mg,7.5mol%),氧化钙(22.4mg,0.4mmol),溶解在2mL二氯甲烷中,该溶液在室温下搅拌反应20h。浓缩,经硅胶柱层析,石油醚/乙酸乙酯=200:1洗脱,浓缩得到产物70.3mg,收率为95%。
1H NMR(500MHz,CDCl3)δ=7.18–7.16(m,1H),7.15(s,2H),7.04–7.01(m,1H),2.49(s,3H),2.37(s,3H),1.98(s,3H),1.91(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=143.6,140.1,139.8,138.7,137.6,134.8,132.9,129.6,129.5,128.7,127.5,107.6,29.4,21.1,20.9,20.1ppm.ee值使用手性IC柱经HPLC测定(正己烷:异丙醇=99.5:0.5,0.4mL/min,254nm,95%ee);tr=8.93min(S),tr=9.44min(R).产物结构式为:
实施例13化合物IIIj的合成
按实施例12所述的方法,不同的是所用碘鎓盐底物为3,7-二氟-1,9-二甲基二苯并[b,d]三氟甲磺酸碘鎓盐(98.4mg,0.2mmol),得到产物74.1mg,收率为98%。
1H NMR(500MHz,CDCl3)δ=7.54(dd,J=7.7,2.9Hz,1H),7.12(dt,J=5.7,2.8Hz,1H),7.08–7.01(m,1H),6.97(dt,J=5.8,2.9Hz,1H),2.03(s,3H),1.98(s,3H)ppm.13C NMR(126MHz,CDCl3)δ=162.7(d,JC-F=44.3Hz),160.5(d,JC-F=45.2Hz),140.1(d,JC-F=8.6Hz),139.6(d,JC-F=8.2Hz),138.2(d,JC-F=4.2Hz),137.2(d,JC-F=3.6Hz),134.4(d,JC-F=6.9Hz),123.8(d,JC-F=23.3Hz),117.1(d,JC-F=20.7Hz),115.8(d,JC-F=21.4Hz),114.5(d,JC-F=24.6Hz),100.0,21.4,20.4ppm.产物结构式为:
Claims (4)
1.一种手性及非手性2,2’-二卤代联芳基化合物(III)的合成方法,其特征在于,所述的合成方法为:
当合成非手性产物时:将二芳基环状碘鎓盐类化合物(I)、卤盐、铜盐与溶剂二氯甲烷混合均匀,在20~30℃下搅拌反应6~20h,之后反应液经后处理,得到产物2,2’-二卤代联芳基化合物(III);
所述二芳基环状碘鎓盐类化合物(I)、卤盐、铜盐的物质的量之比为1:1~1.5:0.005~0.05;
所述铜盐选自:碘化亚铜、溴化亚铜、溴化铜、氯化亚铜、氯化铜或三氟甲磺酸铜;
所述卤盐选自:碘化钠、碘化钾、四丁基碘化氨、溴化钠、溴化钾、溴化锂、四丁基溴化氨、氯化钠、氯化钾、氯化锂或四丁基氯化氨;
当合成手性产物时:投料时还需加入手性配体、氧化钙,所述二芳基环状碘鎓盐类化合物(I)与手性配体、氧化钙的物质的量之比为1:0.01~0.1:2~4;所述手性配体为手性噁唑啉类配体;
式(I)或(III)中,
R1、R2为所在苯环上的一个或多个取代基,所述取代基各自独立选自:C5~C10芳基、取代C5~C10芳基、C1~C6直链烷基、C3~C6支链烷基、C3~C8环状烷基、含杂C2~C6烷基、不饱和C2~C6烷基、硝基、三氟甲基、羟基、酯基或卤素;
X为:氯、溴或碘。
2.如权利要求1所述手性及非手性2,2’-二卤代联芳基化合物(III)的合成方法,其特征在于,所述溶剂二氯甲烷的体积用量以二芳基环状碘鎓盐的物质的量计为10~30mL/mmol。
3.如权利要求1所述手性及非手性2,2’-二卤代联芳基化合物(III)的合成方法,其特征在于,所述后处理的方法为:反应结束后,将反应液浓缩,进行柱层析,以石油醚与乙酸乙酯体积比200~10:1的混合液作为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到产物(III)。
4.如权利要求1所述手性及非手性2,2’-二卤代联芳基化合物(III)的合成方法,其特征在于,所述手性配体为(R,R)-2,2'-异亚丙基双(4-苯基-2-噁唑啉)。
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