CN110041355B - 一种合成硼取代的手性二苯并-1,4-氮杂*类化合物的方法 - Google Patents
一种合成硼取代的手性二苯并-1,4-氮杂*类化合物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 230000002194 synthesizing effect Effects 0.000 title description 3
- -1 cyclic imine Chemical class 0.000 claims abstract description 61
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 150000001361 allenes Chemical class 0.000 claims abstract description 25
- 239000003446 ligand Substances 0.000 claims abstract description 20
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052796 boron Inorganic materials 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000002184 metal Substances 0.000 claims abstract description 5
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 150000001879 copper Chemical class 0.000 claims description 7
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 239000012429 reaction media Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 37
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000001228 spectrum Methods 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Chemical group 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 150000002466 imines Chemical class 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 241001559589 Cullen Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005256 alkoxyacyl group Chemical group 0.000 description 1
- 238000005905 alkynylation reaction Methods 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 125000005620 boronic acid group Chemical group 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 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
- 229960003280 cupric chloride Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- GMDGXJQUWIQOLE-UHFFFAOYSA-N prop-2-enylborane Chemical compound BCC=C GMDGXJQUWIQOLE-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
技术领域
背景技术
二苯并-1,4-氮杂类是一种重要的药效基团,这种结构存在于众多天然化合物中,因此在制药工业和药物化学中引起了广泛关注。许多抗抑郁药物,抗组织胺类药物,孕酮受体激动剂等药物均含有该药效基团[(a)J.M.Klunder,K.D.Hargrave,M.West,E.Cullen,K.Pal,M.L.Behnke,S.R.Kapadia,D.W.McNeil,J.C.Wu,G.C.Chow and J.Adams,J.Med.Chem.,1992,35,1887;(b)A.Hadou,A.Hamid,H.Mathouet,M.-F.and A.Heterocycles 2008,76,1017.(c)P.P.M.A.Dols,B.J.B.Folmer,H.Hamersma,C.W.Kuil,H.Lucas,L.Ollero,J.B.M.Rewinkel and P.H.H.Hermkens,Bioorg.Med.Chem.Lett.,2008,18,1461.]。而有机硼化物的获取方法已成为现代合成有机化学的核心课题,其碳硼键可用于形成碳碳键以及引入羟基等高转换价值的官能团。因此,在化合物中引入含硼官能团对于该化合物的进一步改造具有重要的意义。[(a)Miyaura,N.;Suzuki,A.Chem.Rev.1995,95,2457.(b)Miyaura,N.Top.Curr.Chem.2002,219,11.(c)Molander,G.A.;Ellis,N.Acc.Chem.Res.2007,40,275.(d)Boronic Acids;Hall,D.G.,Ed.;Wiley-VCH:Weinheim,2011.]
尽管硼取代的手性二苯并-1,4-氮杂类化合物非常重要,但制备手性的二苯并-1,4-氮杂类化合物的方法较少,并且硼取代的手性二苯并-1,4-氮杂类化合物至今仍未被合成[(a)Y.-Q.Wang and Y.-Y.Ren,Chinese J.Catal.2015,36,93;(b)Y.-Y.Ren,Y.-Q.Wang and S.Liu,J.Org.Chem.2014,79,11759.]。到目前为止,与该化合物相关的的合成仅仅报道两例第一例是在醋酸银和手性磷酸的催化下,把二苯并-1,4-氮杂和炔发生不对称的炔基化第二例是铱催化下的二苯并-1,4-氮杂的不对称氢化[(a)Y.-Y.Ren,Y.-Q.Wang and S.Liu,J.Org.Chem.2014,79,11759.(b)K.Gao,C.-Bi.Yu,Y.-G.Zhou andX.Zhang,Chem.Commun.2011,47,7845;]。因此,发展高效的合成硼取代的手性二苯并-1,4-氮杂类化合物的方法将提高此类药物活性结构的多样性,对药物发现、合成起到推动作用,具有重要的科学和社会价值。
发明内容
在惰性气体保护下,将铜盐与手性配体,碱添加剂,在反应介质中搅拌,后在惰性气体保护下加入含硼化合物搅拌,最后再在惰性气体保护下加入七元环状亚胺和联烯进行反应。反应完毕,减压旋蒸,柱分离,得到手性的硼取代二苯并-1,4-氮杂类化合物。
所述铜盐与七元环状亚胺的摩尔比为0.01:1-10:1。
所述手性配体与七元环状亚胺的摩尔比为0.01:1-10:1。
所述碱添加剂与七元环状亚胺的摩尔比为0.1:1-10:1。
所述联烯与七元环状亚胺的摩尔比为1:1-10:1。
所述含硼化合物与七元环状亚胺的摩尔比为1:1-10:1。
所述的反应介质至少为四氢呋喃,乙醚,甲苯,1,4-二氧六环,三氟甲苯,1,2-二氯乙烷中的一种。优选反应介质为三氟甲苯。
I和II互为对映异构体,式中:R1、R2、R3、R4、R5、R6、R7为C1-C40的烷基,C3-C12的环烷基,带有取代基的C3-C12环烷基,苯基或取代苯基,苄基或取代苄基,含一个或二个以上氧、硫、氮原子的五元或六元杂环芳香基团,C1-C10的烷基并环结构;X为氧、硫或碳。R8为吸电子基团,如烷氧酰基、氨酰基、氰基、三氟甲基等。
所述的联烯至少具有以下结构:
R1、R2、R3、R4与I、II中的R1、R2、R3、R4相同;
所述的七元环状亚胺至少具有以下结构:
R5、R6、X、R8与I、II中的R5、R6、X、R8相同;
所述的含硼化合物至少具有以下结构:
R7与I、II中的R7相同
所述铜盐为无水醋酸铜、无水硫酸铜、三氟甲磺酸铜、氯化铜、醋酸亚铜、氯化亚铜、碘化亚铜、高氯酸亚铜、三氟甲磺酸亚铜、Cu(CH3CN)4BF4、Cu(CH3CN)4ClO4中的一种。
所述手性配体至少具有以下结构之一:
R9为C1-C10内的烷基,C3-C8内的环烷基,苯基及取代苯基,或苄基及取代苄基;R10、R11为C1-C10内的烷基、烷氧基,C3-C8内的环烷基,取代或非取代的芳香基团;R12为含有手性结构的下列基团:C1-C10内的烷基,C3-C8内的环烷基,苯基或取代的苯基,苄基或取代苄基。
所述碱添加剂为各种无机碱或有机碱,如三乙胺、DBU、K3PO4、K2CO3、Cs2C03、Na2CO3、t-BuONa、t-BuOLi以及t-BuOK。优选为t-BuOK。
所述的反应温度为:-80~200℃;优选为25℃。
反应时间为:5min~100h;优选为12小时。
本发明的方程式为:
1、原料、手性催化剂廉价易得,反应操作简单,可以有效节省人力、物理成本,且操作简单可有效减少后处理废物的产生。
2、反应活性好、立体选择性高。铜盐与手性P,N-(或P,P-、卡宾)配体原位生成的金属络合物与联二硼酸酯、联烯生成手性有机金属中间体,其可有效控制最后一步对七元环状亚胺亲核加成反应的立体选择性,从而高立体选择性的得到目标产物(最高达到>20:1的非对映选择性(I:II)以及96%ee值的对映选择性(I))。
附图说明
图1是实施例1制备的(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1的核磁共振氢谱;
图2是实施例1制备的(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1的核磁共振碳谱;
图3是实施例11制备的(S)-11-((R)-1-(4-溴苯基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-2的核磁共振氢谱;
图4是实施例11制备的(S)-11-((R)-1-(4-溴苯基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-2的核磁共振碳谱;
图5是实施例12制备的(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-(对甲苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-3的核磁共振氢谱;
图6是实施例12制备的(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-(对甲苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-3的核磁共振碳谱;
图7是实施例13制备的(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1-(4-(三氟甲基)苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-4的核磁共振氢谱;
图8是实施例13制备的(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1-(4-(三氟甲基)苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-4的核磁共振碳谱;
图9是实施例14制备的((S)-7-氯-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-5的核磁共振氢谱;
图10是实施例14制备的((S)-7-氯-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-5的核磁共振碳谱;
图11是实施例15制备的(S)-7-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-6的核磁共振氢谱;
图12是实施例15制备的(S)-7-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-6的核磁共振碳谱;
图13是实施例16制备的((S)-8-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-7的核磁共振氢谱;
图14是实施例16制备的((S)-8-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-7的核磁共振氢谱。
具体实施方式
下面结合附图和实施例对本发明的进行详细的描述,但并不因此而限制本发明。核磁共振是通过300M核磁共振仪测定,高效液相色谱(HPLC)是通过Agilent1100系列高效液相色谱测定。
实施例1
CuCl和L-1-1作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
首先,把史莱克管中抽换气三次后,加入CuCl(0.02mmol,10mol%),配体L-1-1(0.024mmol,12mol%),t-BuOK(0.2mmol,1eq.)和三氟甲苯(1ml),常温下搅拌1h。再在氩气保护下把双联频哪醇硼酸酯V-1(0.22mmol,1.1eq.)溶于三氟甲苯(0.5ml)中,加入上述反应体系,继续常温搅拌半小时。最后再在氩气保护下把亚胺IV-1(0.2mmol,1eq.)和联烯III-1(0.3mmol,1.5eq.)溶于0.5ml三氟甲苯中,加入上述反应体系,25℃反应12h。反应完毕,减压旋蒸至约0.5毫升,硅胶柱分离(石油醚/乙酸乙酯=10:1),减压浓缩,真空干燥,得到化合物I-1,白色固体,75%收率,88%的ee值;
(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1的核磁共振氢谱,核磁共振碳谱分别如图1、图2所示:
1H NMR(300MHz,CDCl3)δ 7.23–7.17(m,2H),7.18–7.10(m,5H),7.07(d,J=7.0Hz,1H),6.90–6.78(m,1H),6.82–6.72(m,2H),6.67(td,J=7.6,1.6Hz,1H),6.49(dd,J=7.9,1.6Hz,1H),5.93(d,J=3.0Hz,1H),5.79(d,J=3.0Hz,1H),5.04(d,J=11.3Hz,1H),4.62–4.48(m,2H),1.34(d,J=4.3Hz,12H).13C NMR(75MHz,CDCl3)δ 156.6,143.1,142.7,137.1,132.4(d,J=4.3Hz),129.0,128.2,127.8(d,J=5.7Hz),125.7,123.8,123.2,121.2,120.5,118.0(d,J=6.2Hz),83.4,60.6,57.6,24.5。HPLC(DAICEL CHIRALPAK IA,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=6.5min,tR(minor)=7.5min.
L-1-1,III-1,IV-1,V-1的结构式如下:
实施例2
L-1-2作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
将实施例1中的配体L-1-1用配体L-1-2替代,其余同实施例1。反应得到化合物I-1,95%收率,72%ee值。
L-1-2,I-1的结构式如下:
实施例3
L-3-1作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
将实施例1中的配体L-1-1用配体L-3-1替代,其余同实施例1。反应得到化合物I-1,55%收率,96%ee值。
L-3-1,I-1的结构式如下:
实施例4
L-4-1作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
将实施例1中的配体L-1-1用配体L-4-1替代,其余同实施例1。反应得到化合物I-1,60%收率,66%ee值。
L-4-1,I-1的结构式如下:
实施例5
L-5-1作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
将实施例1中的配体L-1-1用配体L-5-1替代,其余同实施例1。反应得到化合物I-1,80%收率,15%ee值。
L-5-1,I-1的结构式如下:
实施例6
用六氟磷酸四乙腈亚铜和L-1-1作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
将实施例1中的CuCl用六氟磷酸四乙腈亚铜替代,其余同实施例1。反应得到化合物I-1,71%收率,82%ee值。
实施例7
用三氟甲磺酸亚铜和L-1-1作为催化剂催化反应,生成产物(S)-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-1。
将实施例1中的CuCl用六氟磷酸四乙腈亚铜替代,其余同实施例1。反应得到化合物I-1,65%收率,80%ee值。
实施例8
将实施例1中的t-BuOK用t-BuONa替代,其余同实施例1。反应得到化合物I-1,57%收率,87%ee值。
实施例9
将实施例1中的t-BuOK用KOMe替代,其余同实施例1。反应得到化合物I-1,59%收率,86%ee值。
实施例10
将实施例1中的反应温度改为-10摄氏度,其余同实施例1。反应得到化合物I-1,52%收率,88%ee值。
实施例11
用联烯III-2作为底物制备(S)-11-((R)-1-(4-溴苯基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-2。
将实施例1中的联烯III-1用联烯III-2替代,其余同实施例1。反应得到化合物I-2,76%收率,88%ee值。
(S)-11-((R)-1-(4-溴苯基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-2的核磁共振氢谱,核磁共振碳谱分别如图3、图4所示:
1H NMR(300MHz,CDCl3)δ 7.32–7.21(m,2H),7.16–7.00(m,5H),6.90–6.77(m,2H),6.77–6.71(m,1H),6.67(dd,J=7.6,1.6Hz,1H),6.47(dd,J=7.9,1.6Hz,1H),5.92(d,J=2.9Hz,1H),5.76(d,J=2.9Hz,1H),4.95(d,J=11.3Hz,1H),4.53(d,J=11.2Hz,1H),4.45(s,1H),1.31(d,J=2.6Hz,12H).13C NMR(75MHz,CDCl3)δ 156.6,143.0,141.8,136.8,132.8,132.0,130.8,129.5,128.9,128.4,123.9,123.4,121.2,120.6,119.5,118.1,118.0,83.5,60.5,57.0,24.4.HPLC(DAICEL CHIRALPAK IE.,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=6.9min,tR(minor)=7.3min.
III-2,I-2的结构为:
实施例12
用联烯III-3作为底物制备(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-(对甲苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-3。
将实施例1中的联烯III-1用联烯III-3替代,其余同实施例1。反应得到化合物I-3,57%收率,88%ee值。
(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-(对甲苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-3的核磁共振氢谱,核磁共振碳谱分别如图5、图6所示:
1H NMR(300MHz,CDCl3)δ 7.16–7.04(m,5H),6.94(d,J=7.9Hz,2H),6.85–6.75(m,3H),6.65(td,J=7.6,1.6Hz,1H),6.47(dd,J=7.9,1.6Hz,1H),5.88(d,J=3.0Hz,1H),5.75(d,J=3.0Hz,1H),5.04(d,J=11.3Hz,1H),4.66–4.42(m,2H),2.22(s,3H),1.32(d,J=3.9Hz,12H).13C NMR(75MHz,CDCl3)δ 156.6,143.1,139.7,137.1,135.1,132.5,132.2,128.9,128.5,128.1,127.5,123.8,123.2,121.1,120.5,118.0,117.8,83.3,60.4,57.2,24.4,20.6.HPLC(DAICEL CHIRALPAK IE,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=5.4min,tR(minor)=7.0min.
III-3,I-3的结构为:
实施例13
用联烯III-4作为底物制备(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1-(4-(三氟甲基)苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-4。
将实施例1中的联烯III-1用联烯III-4替代,其余同实施例1。反应得到化合物I-4,65%收率,83%ee值。
(S)-11-((R)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1-(4-(三氟甲基)苯基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-4的核磁共振氢谱,核磁共振碳谱分别如图7、图8所示:
1H NMR(300MHz,CDCl3)δ 7.38(d,J=8.2Hz,2H),7.30(d,J=8.3Hz,2H),7.12(dd,J=4.9,1.3Hz,3H),6.92–6.74(m,2H),6.74–6.62(m,2H),6.48(dd,J=7.9,1.6Hz,1H),5.95(d,J=2.9Hz,1H),5.79(d,J=2.9Hz,1H),4.98(d,J=11.2Hz,1H),4.65(d,J=11.2Hz,1H),4.48(s,1H),1.32(d,J=3.2Hz,12H).13C NMR(75MHz,CDCl3)δ 156.6,146.8,143.0,136.7,133.3,131.8,128.9,128.5,128.0,124.7(d,J=3.9Hz),124.0,123.4,121.3,120.7,118.1,118.0,83.5,60.6,57.5,29.4,24.4.HPLC(DAICEL CHIRALPAK IE,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=5.9min,tR(minor)=7.4min.
III-4,I-4的结构为:
实施例14
用亚胺IV-2作为底物制备(S)-7-氯-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-5。
将实施例1中的亚胺IV-1用联烯IV-2替代,其余同实施例1。反应得到化合物I-5,68%收率,80%ee值。
((S)-7-氯-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-5的核磁共振氢谱,核磁共振碳谱分别如图9、图10所示:
1H NMR(300MHz,CDCl3)δ 7.20–7.03(m,8H),6.92–6.66(m,3H),6.39(d,J=8.5Hz,1H),5.92(d,J=3.0Hz,1H),5.78(d,J=3.0Hz,1H),5.01(d,J=11.3Hz,1H),4.70–4.33(m,2H),1.33(d,J=5.0Hz,12H).13C NMR(75MHz,CDCl3)δ 156.1,143.1,142.4,135.9,132.5,132.1,129.0,128.3,127.9,127.7,125.8,123.7,123.5,121.6,121.3,120.5,118.6,83.4,60.5,57.6,24.4.HPLC(DAICEL CHIRALPAK IE,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=7.3min,tR(minor)=9.0min.
IV-2,I-5的结构为:
实施例15
用亚胺IV-3作为底物制备(S)-7-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-6。
将实施例1中的亚胺IV-1用联烯IV-3替代,其余同实施例1。反应得到化合物I-6,42%收率,85%ee值。
(S)-7-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-6的核磁共振氢谱,核磁共振碳谱分别如图11、图12所示:
1H NMR(300MHz,CDCl3)δ 7.21–7.16(m,2H),7.16–7.01(m,5H),6.95(d,J=1.9Hz,1H),6.85–6.71(m,2H),6.64(dd,J=8.0,2.0Hz,1H),6.39(d,J=8.0Hz,1H),5.90(d,J=3.0Hz,1H),5.76(d,J=3.0Hz,1H),5.00(d,J=11.3Hz,1H),4.52(d,J=11.3Hz,1H),4.39(s,1H),2.24(s,3H),1.32(d,J=4.3Hz,12H).13C NMR(75MHz,CDCl3)δ 156.6,142.9,142.7,134.2,132.3,129.0,128.1,127.7,125.6,124.3,123.1,121.5,120.5,118.2,83.3,60.7,57.4,24.4,19.9.HPLC(DAICEL CHIRALPAK IE,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=6.5min,tR(minor)=8.4min.
IV-3,I-6的结构为:
实施例16
用亚胺IV-4作为底物制备(S)-8-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-7。
将实施例1中的亚胺IV-1用联烯IV-4替代,其余同实施例1。反应得到化合物I-7,58%收率,83%ee值。
((S)-8-甲基-11-((R)-1-苯基-2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烯丙基)-10,11-二氢二苯并[b,f][1,4]氧氮杂I-7的核磁共振氢谱,核磁共振碳谱分别如图13、图14所示:
1H NMR(300MHz,CDCl3)δ 7.23–7.15(m,2H),7.15–6.93(m,6H),6.79–6.71(m,2H),6.45(dd,J=8.3,2.0Hz,1H),6.29(d,J=2.0Hz,1H),5.93(d,J=3.0Hz,1H),5.80(d,J=3.0Hz,1H),5.02(d,J=11.3Hz,1H),4.56(d,J=11.3Hz,1H),4.46–4.39(m,1H),2.18(s,3H),1.32(d,J=4.2Hz,12H).13C NMR(75MHz,CDCl3)δ 156.8,142.7,141.1,136.6,133.3,132.3,132.2,128.9,128.1,127.7,125.6,123.2,120.9,120.4,118.5,118.2,83.3,60.4,57.5,24.4,20.3.HPLC(DAICEL CHIRALPAK IE,isopropanol/hexane=1/99,1.0ml/min,detector 254nm),tR(major)=6.4min,tR(minor)=8.1min.
IV-4,I-7的结构为:
Claims (1)
所述金属盐为氯化亚铜;
所述手性配体为L-3-1或L-4-1,结构式如下:
所述联烯具有以下结构式:
所述七元环状亚胺具有以下结构式:
所述含硼化合物具有以下结构式:
所述目标产物I具有以下结构式:
具体步骤为:
在惰性气体保护下,将铜盐与手性配体,碱添加剂,在反应介质中搅拌,然后在惰性气体保护下加入含硼化合物搅拌,最后再在惰性气体保护下加入七元环状亚胺和联烯进行反应;反应完毕,减压旋蒸,柱分离,得到手性的硼取代二苯并-1,4-氮杂类化合物;反应温度为:25℃,反应时间为:5min~100h;
所述铜盐与七元环状亚胺的摩尔比为0.01:1-10:1;
所述手性配体与七元环状亚胺的摩尔比为0.01:1-10:1;
所述碱添加剂与七元环状亚胺的摩尔比为0.1:1-10:1;
所述联烯与七元环状亚胺的摩尔比为1:1-10:1;
所述含硼化合物与七元环状亚胺的摩尔比为1:1-10:1;
所述的反应介质为四氢呋喃,乙醚,甲苯,1,4-二氧六环,三氟甲苯,1,2-二氯乙烷中的一种。
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