CN114456022A - 氮杂环卡宾催化不饱和醛与α-芳基草酸酯反应合成轴手性化合物的制备方法 - Google Patents
氮杂环卡宾催化不饱和醛与α-芳基草酸酯反应合成轴手性化合物的制备方法 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 19
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 title claims abstract description 16
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title abstract description 7
- -1 obtains an alpha Chemical class 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002274 desiccant Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- GQIGHOCYKUBBOE-UHFFFAOYSA-N 2,6-ditert-butyl-4-(3,5-ditert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)cyclohexa-2,5-dien-1-one Chemical group C1=C(C(C)(C)C)C(=O)C(C(C)(C)C)=CC1=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1 GQIGHOCYKUBBOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 4
- 125000005504 styryl group Chemical group 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 5
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 125000001072 heteroaryl 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 86
- 238000001228 spectrum Methods 0.000 description 35
- 238000004896 high resolution mass spectrometry Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 150000004705 aldimines Chemical class 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
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- 238000010168 coupling process Methods 0.000 description 1
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- 238000007876 drug discovery Methods 0.000 description 1
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- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
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Abstract
本发明公开了氮杂环卡宾催化不饱和醛与α‑芳基草酸酯反应合成轴手性化合物的制备方法,属于化学合成领域。本发明在温和的反应条件下,使用手性氮杂环卡宾催化剂催化活化不饱和醛,在氧化的条件下获得α,β‑不饱和酰基唑阳离子中间体,可以与α芳基草酸酯发生阻转选择性环合,进一步杂芳香化可以获得轴手性5‑芳基‑2吡喃酮化合物;本发明方法中获得的5‑芳基‑2吡喃酮化合物可以与芳基炔在温和的条件下进行反应转化为轴手性联芳基化合物。本发明方法条件温和,反应高效,具有很好的底物普适性,所报道的利用催化获得的α,β‑不饱和酰基唑阳离子中间体发生阻转环化/杂芳构化串联的路径为制备轴手性化合物为提供了重要的方法,有应用于工业生产的潜力。
Description
技术领域
本发明属于化学合成领域,特别涉及一种氮杂环卡宾催化不饱和醛与α-芳基草酸酯反应合成轴手性化合物的方法。
背景技术
不对称催化是制备手性化合物最重要的方法。氮杂环卡宾作为一类重要的有机小分子催化剂,近年来在催化合成手性分子领域发挥了重要的作用,获得了较快的发展。但是已经报道的反应类型大多基于氮杂环卡宾催化制备中心手性化合物,而催化制备带有手性轴的化合物则鲜有报道,四取代轴手性化合物的不对称催化制备更是一个挑战。而α,β-不饱和醛和α-芳基草酸酯作为重要且易于获得的原料,利用其制备具有结构新颖的轴手性功能化有机分子具有重要意义,所发展的氮杂环卡宾催化阻转选择性环化/氧化串联反应为制备轴手性化合物提供了新的机遇,合成的结构新颖的轴手性功能化有机分子将为药物发现和筛选提供新的可能。
发明内容
本发明公开了一种如式III-A或III-B所示的轴手性化合物的制备方法,氮杂环卡宾催化不饱和醛与α芳基草酸酯反应合成如式III-A或III-B所示的轴手性化合物
其中:R1为卤素原子Cl,Br,I硫苄基SBn,N,N-二苄基N(Bn)2,三氟甲基或二氟甲基;R3为甲基,乙基,异丙基,叔丁基,环戊基,环己基,苯基或苄基;R4和R5为氢,F,Cl或Br;
R2为苯基,4-甲基苯基,4-氟苯基,4-氯苯基,4-溴苯基,4-三氟甲基苯基,4- 甲氧酰基苯基,4-氰基苯基,3-氟苯基,3-甲基苯基,3-三氟甲基苯基,3-氯苯基, 3-甲基苯基,3,5-二三氟甲基苯基,2-氟苯基,2-氯苯基,2-萘基,2-吡啶,2- 噻吩或2-呋喃,苯乙烯基或丙烯基;
所使用的催化剂如下:
Ar为取代的苯基;X为取代的芳香基,硝基,或卤素原子;Y为Cl原子或四氟硼酸基团BF4;
所使用的碱为下列中的一种:碳酸钾,碳酸铯,1,8-二氮杂二环十一碳-7-烯,三乙胺,磷酸钾,叔丁醇钾或N,N-二异丙基乙胺;
所使用的溶剂为下列中的一种:四氢呋喃,1,4-二氧六环,二氯甲烷,甲苯,1,3,5-均三甲苯,三氯甲烷,四氯化碳,甲基叔丁基醚或三氟甲基苯;
所述氧化剂为3,3′,5,5′-四叔丁基-4,4′-联苯醌(DQ)或二氧化锰。
优选所述的催化剂结构如下:
优选所述的如式I-A所示的结构如下:
优选所述的如式I-B所示的结构如下:
优选所述的如式II所示的结构如下:
优选使用结构式I的α芳基草酸酯和结构式为II的不饱和醛衍生物为原料,在 NHCA作为催化剂,3,3′,5,5′-四叔丁基-4,4′-联苯醌DQ作为氧化剂,DBU作为碱,四氢呋喃作溶剂及MS作为干燥剂的条件下于-20℃,20-48小时至反应完成,反应液经硅胶柱纯化得到结构式为III的目标产物;
其中:R1为卤素原子Cl,Br,I,硫苄基SBn,N,N-二苄基N(Bn)2,三氟甲基或二氟甲基。R2为各种取代的芳香环,具体为苯基,4-甲基苯基,4-氟苯基,4-氯苯基, 4-溴苯基,4-三氟甲基苯基,4-甲氧酰基苯基,4-氰基苯基,3-氟苯基,3-甲基苯基,3-三氟甲基苯基,3-氯苯基,3-甲基苯基,3,5-二三氟甲基苯基,2-氟苯基, 2-氯苯基,2-萘基,2-吡啶,2-噻吩或2-呋喃;苯乙烯基或丙烯基;R3为甲基,乙基,异丙基,叔丁基,环戊基,环己基或苄基;R4和R5为卤素原子F,Cl或Br。优选所述氮杂环卡宾催化剂NHC A的用量是式I化合物用量的15mol%;所述式I化合物和式II化合物的摩尔比是1∶1.8;所述式I化合物与氧化剂用量的摩尔比是1∶2.2;所述碱DBU的用量是式I化合物用量的150mol%;,所述干燥剂 MS的用量是1000mg/mmol,反应浓度相对于式I化合物为0.1M。
所述化合物III-A和III-B的结构式如下:
有益效果:本发明公开了一种氮杂环卡宾催化不饱和醛与α-芳基草酸酯反应合成轴手性化合物的方法。本发明在温和的反应条件下,使用手性氮杂环卡宾催化剂催化活化不饱和醛,在氧化的条件下获得α,β-不饱和酰基唑阳离子中间体,进一步与α-芳基草酸酯发生阻转选择性环合反应,生成结构新颖的带有手性轴的 5-芳基-2-吡喃酮化合物;这种创新的手性催化合成轴手性化合物的合成方案,降低手性化合物的合成成本;本发明方法条件温和,反应高效,具有很好的底物普适性,所报道的氮杂环卡宾催化不饱和醛发生阻转环化/氧化串联反应的策略为合成多种多样的功能轴手性化合物提供了重要的方法,有应用于工业生产的潜力。
附图说明
图1是化合物IIIa的氢谱;图2是化合物IIIa的碳谱;图3是化合物IIId 的氢谱;图4是化合物IIId的碳谱;图5是化合物IIIr的氢谱;图6是化合物 IIIr的碳谱;图7是化合物IIIh的氢谱;图8是化合物IIIh的碳谱;图9是化合物IIIi的氢谱;图10是化合物IIIi的碳谱;图11是化合物IIIj的氢谱;图12 是化合物IIIj的氟谱;图13是化合物IIIj的碳谱;图14是化合物IIIk的氢谱;图15是化合物IIIk的碳谱;图16是化合物IIII的氢谱;图17是化合物IIII的碳谱;图18是化合物IIIm的氢谱;图19是化合物IIIm的氟谱;图20是化合物IIIm的碳谱;图21是化合物IIIo的氢谱;图22是化合物IIIo的氟谱;图23 是化合物IIIa的碳谱;图24是化合物IIIp的氢谱;图25是化合物IIIp的碳谱;图26是化合物IIIaf的氢谱;图27是化合物IIIaf的碳谱;图28是化合物IIIag 的氢谱;图29是化合物IIIag的碳谱;图30是化合物IIIah的氢谱;图31是化合物IIIah的碳谱;图32是化合物IIIai的氢谱;图33是化合物IIIai的碳谱;图34是化合物IIIaj的氢谱;图35是化合物IIIaj的碳谱。
具体实施方式
以下所用化学试剂均购自商业化产品。溶剂为购自商业化的超干溶剂。薄层色谱分析(TLC)使用60F254硅胶板,在254nm的UV光下显色。1H NMR和13C NMR使用Bruker 400M核磁共振仪表征,溶剂为氘代氯仿。耦合常数的单位是 Hz.。旋光度用Jasco P-1030polarimeter旋光仪测量。对映体过量用Shimadzu LC-20AD HPLC测定.高分辨质谱(HRMS)使用Waters Q-TOF Permier Spectrometer测定。
通过以下实施例有助于进一步理解本发明,但并不限制本发明的内容。
实施例1
采用以下的制备方法进行制备IIIa:
向干燥的试管中加入醛亚胺I(0.1mmol),NHC A(7.5mg,15mol%),K3PO4 (31.8mg,0.15mmol),DQ(90.0mg,0.22mmol),MS(100mg),然后向混合物中加入1mL THF作溶剂,将体系冷却到-20℃,继续向体系中加入1.8倍量的α,β- 不饱和醛和1.5倍量的DBU。反应体系在-20℃搅拌24小时,TLC监测反应完全后,反应混合物使用硅胶柱分离纯化,洗脱剂为乙酸乙酯/石油醚=1∶8,产物为白色固体。
5-(2-氯-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-甲酸乙酯:82%yield,94.5:5.5er. HPLC condition:Chiralpak IA(Hex/iPrOH=90/10,1.0mL/min,tR(major)=15.9min,tR(minor)=14.5min).[α]D 25(c 1.0,CHCl3)=+29.33
1H NMR(400MHz,CDCl3)δ7.93(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.40 (t,J=8.0Hz,1H),7.23-7.27(m,1H),7.17(d,J=8.0Hz,2H),7.08-7.10(m,2H), 6.59(s,1H),4.17(q,J=7.2Hz,2H),1.18(t,J=8.0Hz,3H);13C NMR(100MHz, CDCl3)δ159.30,159.23,157.38,149.40,145.02,136.11,134.96,134.47,130.15, 129.63,129.10,128.36,127.58,123.29,120.56,119.16,62.79,13.85.HRMS(ESI) Calcd for C20H15ClNO6 +[M+H]+400.0582;Found:400.0584.
实施例2
可采用以下的制备方法进行制备IIIa:
向干燥的试管中加入醛亚胺I(0.1mmol),NHC B(7.0mg,15mol%),K3PO4 (31.8mg,0.15mmol),DQ(90.0mg,0.22mmol),MS(100mg),然后向混合物中加入1mL THF作溶剂,将体系冷却到-20℃,继续向体系中加入1.8倍量的α,β- 不饱和醛和1.5倍量的DBU。反应体系在-20℃搅拌24小时,TLC监测反应完全后,反应混合物使用硅胶柱分离纯化,洗脱剂为乙酸乙酯/石油醚=1∶8,产物为白色固体。
5-(2-氯-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-甲酸乙酯:75%yield,89:11er. HPLC condition:Chiralpak IA(Hex/iPrOH=90/10,1.0mL/min,tR(major)=15.9min,tR(minor)=14.5min).[α]D 25(c 1.0,CHCl3)=+29.33
1H NMR(400MHz,CDCl3)δ7.93(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.40 (t,J=8.0Hz,1H),7.23-7.27(m,1H),7.17(d,J=8.0Hz,2H),7.08-7.10(m,2H), 6.59(s,1H),4.17(q,J=7.2Hz,2H),1.18(t,J=8.0Hz,3H);13C NMR(100MHz, CDCl3)δ159.30,159.23,157.38,149.40,145.02,136.11,134.96,134.47,130.15, 129.63,129.10,128.36,127.58,123.29,120.56,119.16,62.79,13.85.HRMS(ESI) Calcd for C20H15ClNO6 +[M+H]+400.0582;Found:400.0584.
实施例3
可采用以下的制备方法进行制备IIIa:
向干燥的试管中加入醛亚胺I(0.1mmol),NHC C(6.3mg,15mol%),K3PO4 (31.8mg,0.15mmol),DQ(90.0mg,0.22mmol),MS(100mg),然后向混合物中加入1mL THF作溶剂,将体系冷却到-20℃,继续向体系中加入1.8倍量的α,β- 不饱和醛和1.5倍量的DBU。反应体系在-20℃搅拌24小时,TLC监测反应完全后,反应混合物使用硅胶柱分离纯化,洗脱剂为乙酸乙酯/石油醚=1∶8,产物为白色固体。
5-(2-氯-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-甲酸乙酯:80%yield,93:7er. HPLC condition:Chiralpak IA(Hex/iPrOH=90/10,1.0mL/min,tR(major)=15.9min,tR(minor)=14.5min).[α]D 25(c 1.0,CHCl3)=+29.33
1H NMR(400MHz,CDCl3)δ7.93(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.40 (t,J=8.0Hz,1H),7.23-7.27(m,1H),7.17(d,J=8.0Hz,2H),7.08-7.10(m,2H), 6.59(s,1H),4.17(q,J=7.2Hz,2H),1.18(t,J=8.0Hz,3H);13C NMR(100MHz, CDCl3)δ159.30,159.23,157.38,149.40,145.02,136.11,134.96,134.47,130.15, 129.63,129.10,128.36,127.58,123.29,120.56,119.16,62.79,13.85.HRMS(ESI) Calcd for C20H15ClNO6 +[M+H]+400.0582;Found:400.0584.
实施例4
采用与实施例1相同的制备方法进行制备IIIb,产物为白色固体:
5-(2-氯-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸甲酯,80%yield,94:6er.HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=30.4min,tR (minor)=26.6min).[α]D 25(c 1.0,CHCl3)=+26.89
1H NMR(400MHz,CDCl3)δ7.95(d,J=8.4Hz,1H),7.60(d,J=8.4Hz,1H),7.41 (t,J=8.0Hz,1H),7.24-7.28(m,1H),7.16-7.20(m,2H),7.08-7.11(m,2H),6.61(s, 1H),3.77(s,3H);13C NMR(100MHz,CDCl3)δ159.87,159.07,157.34,149.34, 144.58,136.08,134.90,134.52,130.17,129.66,128.92,128.38,127.58,123.34, 120.99,119.36,53.34;HRMS(ESI)Calcd for C19H13ClNO6 +[M+H]+386.0426; Found:386.0427.
实施例5
采用与实施例1相同的制备方法进行制备IIId,产物为白色固体:
5-(2-氯-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,90%yield,97.5:2.5er. HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(maior)=22.4min, tR(minor)=20.6min).[α]D 25(c 1.0,CHCl3)=+99.73
1H NMR(400MHz,CDCl3)δ7.88(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.38 (t,J=8.0Hz,1H),7.23(t,J=8.0Hz,1H),7.15(t,J=8.0Hz,2H),7.04-7.06(m,2H), 6.53(s,1H),1.27(s,9H);13C NMR(100MHz,CDCl3)δ159.46,158.06,157.42, 149.42,146.54,136.31,135.12,134.30,130.03,129.53,129.49,128.30,127.54, 123.29,118.83,118.57,84.46,27.59.HRMS(ESI)Calcd for C22H19ClNO6 +[M+H]+ 428.0895;Found:428.0901.
实施例6
采用与实施例1相同的制备方法进行制备IIIh,产物为白色固体:
5-(2-溴-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,87%yield,99:1er. HPLC condition:Chiralpak ODH(Hex/iPrOH=90/10,1.0mL/min,tR(major)=20.2min,tR(minor)=18.1min).[α]D 25(c 0.3,CHCl3)=+11.78
1H NMR(400MHz,CDCl3)δ7.93(d,J=8.4Hz,1H),7.80(d,J=8.0Hz,1H),7.32 (t,J=8.0Hz,1H),7.22-7.26(m,1H),7.14-7.18(m,2H),7.07-7.09(m,2H),6.55(s, 1H),1.28(s,9H);13C NMR(100MHz,CDCl3)δ159.47,158.00,157.30,149.49, 146.49,137.56,135.07,131.22,130.32,129.50,128.28,127.71,126.91,123.89,120.86,118.66,84.44,27.58.HRMS(ESI)Calcd for C22H19BrNO6 +[M+H]+472.0390; Found:472.0390.
实施例7
采用与实施例1相同的制备方法进行制备IIIi,产物为白色固体:
5-(2-碘代-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,86%yield,99:1er. HPLC condition:Chiralpak IA(Hex/iPrOH=97/3,1.0mL/min,tR(major)=36.9min, tR(minor)=34.4min).[α]D 25(c 1.0,CHCl3)=-30.53
1H NMR(400MHz,CDCl3)δ8.04(d,J=8.0Hz,1H),7.96(d,J=8.4Hz,1H), 7.21-7.26(m,1H),7.13-7.17(m,3H),7.07-7.09(m,2H),6.55(s,1H),1.26(s,9H);13C NMR(100MHz,CDCl3)δ159.45,157.89,157.06,148.98,146.47,143.98,134.98,134.53,130.56,129.50,128.23,128.03,124.65,124.37,118.93,103.95,84.42,27.62. HRMS(ESI)Calcd for C22H19INO6 +[M+H]+520.0252;Found:520.0252.
实施例8
采用与实施例1相同的制备方法进行制备IIIj,产物为白色固体:
5-(2-硝基-6-(三氟甲基)苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,51%yield, 93:7er.
HPLC condition:Chiralpak IA(Hex/iPrOH=97/3,1.0mL/min,tR(major)=23.5min, tR(minor)=25.1min).[α]D 25(c0.5,CHCl3)=+39.40
1H NMR(400MHz,CDCl3)δ8.16(d,J=8.0Hz,1H),7.93(d,J=7.6Hz,1H),7.63 (t,J=8.0Hz,1H),7.21-7.26(m,1H),7.14(d,J=8.0Hz,2H),6.96-6.98(m,2H), 6.52(s,1H),1.27(s,9H);19F NMR(376MHz,CDCl3)δ-57.9;13C NMR(100MHz, CDCl3)δ159.32,158.01,157.55,149.39,145.98,134.93,131.37(q,J=5.1Hz), 130.90(q,J=30.0Hz),130.01,129.52,129.20,128.42,128.23,127.91,122.81(q,J= 273.5Hz),118.37,117.46,84.57,27.56.HRMS(ESI)Calcd for C23H19F3NO6 + [M+H]+462.1159;Found:462.1159.
实施例9
采用与实施例1相同的制备方法进行制备IIIk,产物为白色固体:
5-(2-(二苄基氨基)-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,51%yield, 93:7er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=20.7min,tR(minor)=14.1min).[α]D 25(c 0.3,CHCl3)=+96.33
1H NMR(400MHz,CDCl3)δ7.82(d,J=8.0Hz,1H),7.21-7.30(m,7H),7.12(t,J =7.6Hz,1H),7.05-7.07(m,2H),6.94-6.98(m,2H),6.85-6.88(m,4H),6.73(s,1H), 6.56(d,J=8.0Hz,1H),3.83(d,J=14.4Hz,2H),3.38(d,J=14.4Hz,2H),1.41(s, 9H);13C NMR(100MHz,CDCl3)δ160.12,159.26,158.66,151.16,150.76,145.64, 135.44,134.96,130.10,129.35,129.21,128.84,128.33,127.92,127.85,127.58, 126.33,120.51,120.24,118.64,84.79,54.04,27.84.HRMS(ESI)Calcd for C36H33N2O6 +[M+H]+589.2333;Found:589.2334.
实施例10
采用与实施例1相同的制备方法进行制备IIII,产物为白色固体:
5-(2-(苄硫基)-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,78%yield,92:8 er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=36.5min,tR(minor)=30.6min).[α]D 25(c 1.0,CHCl3)=+90.00
1H NMR(400MHz,CDCl3)δ7.73(dd,J=2.4,6.8Hz,1H),7.21-7.36(m,8H), 7.06-7.13(m,4H),6.53(s,1H),3.98-4.08(m,2H),1.25(s,9H);13C NMR(100MHz, CDCl3)δ159.69,158.17,157.80,149.00,146.57,141.41,135.31,135.16,130.46, 129.49,129.38,128.97,128.86,128.07,128.00,127.90,127.86,121.16,118.96, 118.68,84.17,37.62,27.59.HRMS(ESI)Calcd for C29H26NO6S+[M+H]+516.1475; Found:516.1473.
实施例11
采用与实施例1相同的制备方法进行制备IIIm,产物为白色固体:
5-(2-(二氟甲基)-6-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,83%yield, 95:5er.
HPLC condition:Chiralpak IA(Hex/iPrOH=85/15,1.0mL/min,tR(major)=14.2 min,tR(minor)=45.7min).[α]D 25(c 0.5,CHCl3)=-6.80
1H NMR(400MHz,CDCl3)δ8.10(d,J=8.0Hz,1H),7.86(d,J=8.0Hz,1H),7.60 (t,J=8.0Hz,1H),7.14-7.26(m,3H),6.96-6.98(m,2H),6.56(s,1H),6.52(t,J= 54.4Hz,1H),1.24(s,9H);19F NMR(376MHz,CDCl3)δ-108.81(dd,J=56.4, 307.94Hz),-112.71(dd,J=56.00,307.94Hz);13C NMR(100MHz,CDCl3)δ159.14, 157.94,157.09,148.74,146.62,134.82(t,J=22.6Hz),134.75,130.92(t,J=5.7Hz), 130.20,129.70,128.56,127.74,127.01,118.57,116.72,111.92(t,J=239.3Hz), 84.89,27.54.HRMS(ESI)Calcd forC23H20F2NO6 +[M+H]+444.1253;Found: 444.1253.
实施例12
采用与实施例1相同的制备方法进行制备IIIn,产物为白色固体:
5-(6-溴-3-氟-2-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,81%yield,>99:1 er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=19.6min). [α]D 25(c 1.0CHCl3)=+29.20
1H NMR(400MHz,CDCl3)δ7.60(dd,J=4.8,9.2Hz,1H),7.29-7.33(m,1H), 7.20-7.24(m,4H),7.13(t,J=8.8Hz,1H),6.52(s,1H),1.36(s,9H);19F NMR(376 MHz,CDCl3)δ-121.61;13C NMR(100MHz,CDCl3)δ158.98,157.53,157.04, 153.41(d,J=260.0Hz),147.96,136.06(d,J=8.0Hz),134.74,131.44,129.79, 128.35,128.04,120.34(d,J=3.7Hz),118.78(d,J=20.7Hz),118.80,117.94,84.95, 27.61.HRMS(ESI)Calcd forC22H18BrFNO6 +[M+H]+490.0296;Found:490.0298.
实施例13
采用与实施例1相同的制备方法进行制备IIIo,产物为白色固体:
5-(4,6-二溴-3-氟-2-硝基苯基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,85%yield.>99:1er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=12.0min).[α]D 25(c 0.3CHCl3)=+33.30
1H NMR(400MHz,CDCl3)δ7.83(d,J=6.0Hz,1H),7.33-7.37(m,1H),7.25-7.29 (m,2H),7.20-7.22(m,2H),6.52(s,1H),1.40(s,9H);19F NMR(376MHz,CDCl3)δ -114.47;13CNMR(100MHz,CDCl3)δ158.80,157.54,156.74,150.74(d,J=258.6 Hz),148.19,138.56,134.59,130.48,129.99,128.53,128.01,120.57,118.89,117.39, 111.70(d,J=21.1Hz),85.29,27.67.HRMS(ESI)Calcd for C22H17Br2FNO6 + [M+H]+567.9401;Found:567.9402.
实施例14
采用与IIIa相同的制备方法进行制备IIIp,产物为白色固体:
5-(3-溴-5-硝基吡啶-4-基)-2-氧代-4-苯基-2H-吡喃-6-羧酸叔丁酯,75%yield,96:4 er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=14.5min, tR(minor)=13.3min).[α]D 25(c 1.0CHCl3)=-4.60
1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.85(s,1H),7.25-7.29(m,1H),7.16-7.20(m,2H),7.02-7.04(m,2H),6.55(s,1H),1.33(s,9H);13C NMR(100MHz,CDCl3)δ 158.90,157.75,156.01,155.74,146.40,144.77,144.34,139.91,134.36,129.95, 128.61,127.46,124.23,119.04,118.86,85.35,27.63.HRMS(ESI)Calcd for C21H18BrN2O6 +[M+H]+473.0343;Found:473.0343.
实施例15
采用与IIIa相同的制备方法进行制备IIIaf,产物为白色固体:
5-(2-碘代-6-硝基苯基)-2-氧代-4-(吡啶-2-基)-2H-吡喃-6-羧酸叔丁酯,83%yield, 99:1er.
HPLC condition:Chiralpak ODH(Hex/iPrOH=90/10,1.0mL/min,tR(major)=26.7 min,tR(minor)=31.7min).[α]D 25(c 1.0CHCl3)=-190.73
1H NMR(400MHz,CDCl3)δ8.21(d,J=6.4Hz,1H),8.05(d,J=7.6Hz,1H),7.98 (d,J=8.0Hz,1H),7.61-7.65(m,1H),7.42(d,J=7.6Hz,1H),7.11-7.17(m,2H), 6.74(s,1H),1.27(s,9H);13C NMR(100MHz,CDCl3)δ159.62,157.87,154.22,153.19,149.63,148.75,147.53,143.39,136.90,134.80,130.06,124.06,123.89, 123.53,118.69,103.57,84.28,27.63.HRMS(ESI)Calcd for C21H18IN2O6 +[M+H]+ 521.0204;Found:521.0206.
实施例16
采用与实施例1相同的制备方法进行制备IIIag,产物为白色固体:
5-(2-碘代-6-硝基苯基)-2-氧代-4-(噻吩-2-基)-2H-吡喃-6-羧酸叔丁酯,83%yield, 99:1er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=42.1min,tR(minor)=37.3min).[α]D 25(c 1.0CHCl3)=+19.50
1H NMR(400MHz,CDCl3)δ8.13(d,J=7.6Hz,1H),8.07(d,J=8.4Hz,1H), 7.30-7.34(m,2H),6.88-6.93(m,2H),6.77(s,1H),1.27(s,9H);13C NMR(100MHz, CDCl3)δ159.37,157.92,150.08,149.45,146.75,143.99,135.74,133.98,131.31, 130.31,129.95,127.71,124.68,122.98,116.38,104.21,84.63,27.62;HRMS(ESI) Calcd forC20H17INO6S+[M+H]+525.9816;Found:525.9817.
实施例17
采用与实施例1相同的制备方法进行制备IIIah,产物为白色固体:
4-(呋喃-2-基)-5-(2-碘代-6-硝基苯基)-2-氧代-2H-吡喃-6-羧酸叔丁酯,83%yield, 97.5:2.5er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=44.6min,tR(minor)=38.6min).[α]D 25(c 0.5CHCl3)=+43.27
1H NMR(400MHz,CDCl3)δ8.23(d,J=8.0Hz,1H),8.16(d,J=8.4Hz,1H),7.45 (d,J=1.6Hz,1H),7.41(tJ=8.0Hz,1H),7.02(s,1H),6.26(dd,J=1.6,3.6Hz,1H), 5.37(d,J=3.6Hz,1H),1.29(s,9H);13C NMR(100MHz,CDCl3)δ159.82, 157.96,149.62,147.17,145.63,144.05,143.12,134.40,131.26,124.74,120.72,114.44,112.88,112.19,103.56,84.58,27.63.HRMS(ESI)Calcd for C20H17INO7 + [M+H]+510.0044;Found:510.0047.
实施例18
采用与实施例1相同的制备方法进行制备IIIaf,产物为白色固体:
(E)-5-(2-碘代-6-硝基苯基)-2-氧代-4-苯乙烯基-2H-吡喃-6-羧酸叔丁酯,77%yield, 96:4er.
HPLC condition:Chiralpak IA(Hex/iPrOH=95/5,1.0mL/min,tR(major)=43.4min, tR(minor)=37.6min).[α]D 25(c 0.5CHCl3)=+180.89
1H NMR(400MHz,CDCl3)δ8.23(d,J=8.0Hz,1H),8.12(d,J=8.4Hz,1H),7.37 (t,J=8.0Hz,1H),7.29-7.31(m,3H),7.20-7.25(m,3H),6.81(s,1H),6.12(d,J= 16.4Hz,1H),1.27(s,9H);13C NMR(100MHz,CDCl3)δ159.95,157.85,152.57, 149.53,146.08,143.99,138.37,135.24,133.87,130.99,129.88,128.99,127.67, 124.58,123.78,120.73,112.65,102.87,84.39,27.63.HRMS(ESI)Calcd for C24H21INO6 +[M+H]+546.0408;Found:546.0408.
实施例19
采用与实施例1相同的制备方法进行制备IIIaj,产物为白色固体:
(E)-5-(2-碘代-6-硝基苯基)-2-氧代-4-(丙-1-烯-1-基)-2H-吡喃-6-羧酸叔丁酯,48% yield,93:7er.
HPLC condition:Chiralpak IA(Hex/iPrOH=90/10,1.0mL/min,tR(major)=15.3 min,tR(minor)=14.0min).[α]D 25(c 0.5CHCl3)=+119.00
1H NMR(400MHz,CDCl3)δ8.21(dd,J=1.2,8.0Hz,1H),8.09(dd,J=1.2,8.0Hz,1H),7.35(t,J=8.0Hz,1H),6.62(s,1H),6.41-6.50(m,1H),5.45-5.51(m,1H),1.73 (dd,J=1.6,6.8Hz,3H),1.25(s,9H);13C NMR(100MHz,CDCl3)δ160.08,157.87, 152.87,149.39,145.96,143.95,137.41,133.96,130.85,124.55,124.22,123.67, 112.52,102.84,84.26,27.61,19.17;HRMS(ESI)Calcd for C19H19INO6 +[M+H]+ 484.0252;Found:484.0248。
Claims (7)
1.一种如式III-A或III-B所示的轴手性化合物的制备方法,其特征在于:氮杂环卡宾催化不饱和醛与α芳基草酸酯反应合成如式III-A或III-B所示的轴手性化合物
其中:R1为卤素原子Cl,Br,I硫苄基SBn,N,N-二苄基N(Bn)2,三氟甲基或二氟甲基;R3为甲基,乙基,异丙基,叔丁基,环戊基,环己基,苯基或苄基;R4和R5为氢,F,Cl或Br;
R2为苯基,4-甲基苯基,4-氟苯基,4-氯苯基,4-溴苯基,4-三氟甲基苯基,4-甲氧酰基苯基,4-氰基苯基,3-氟苯基,3-甲基苯基,3-三氟甲基苯基,3-氯苯基,3-甲基苯基,3,5-二三氟甲基苯基,2-氟苯基,2-氯苯基,2-萘基,2-吡啶,2-噻吩或2-呋喃,苯乙烯基或丙烯基;
所使用的催化剂如下:
Ar为取代的苯基;X为取代的芳香基,硝基,或卤素原子;Y为Cl原子或四氟硼酸基团BF4;
所使用的碱为下列中的一种:碳酸钾,碳酸铯,1,8-二氮杂二环十一碳-7-烯,三乙胺,磷酸钾,叔丁醇钾或N,N-二异丙基乙胺;
所使用的溶剂为下列中的一种:四氢呋喃,1,4-二氧六环,二氯甲烷,甲苯,1,3,5-均三甲苯,三氯甲烷,四氯化碳,甲基叔丁基醚或三氟甲基苯;
所述氧化剂为3,3′,5,5′-四叔丁基-4,4′-联苯醌或二氧化锰。
6.根据权利要求1所述的制备方法,其特征在于:使用结构式I的α芳基草酸酯和结构式为II的不饱和醛衍生物为原料,在NHC A作为催化剂,3,3′,5,5′-四叔丁基-4,4′-联苯醌DQ作为氧化剂,DBU作为碱,四氢呋喃作溶剂及MS作为干燥剂的条件下于-20℃,20-48小时至反应完成,反应液经硅胶柱纯化得到结构式为III的目标产物;
其中:R1为卤素原子Cl,Br,I,硫苄基SBn,N,N-二苄基N(Bn)2,三氟甲基或二氟甲基。R2为各种取代的芳香环,具体为苯基,4-甲基苯基,4-氟苯基,4-氯苯基,4-溴苯基,4-三氟甲基苯基,4-甲氧酰基苯基,4-氰基苯基,3-氟苯基,3-甲基苯基,3-三氟甲基苯基,3-氯苯基,3-甲基苯基,3,5-二三氟甲基苯基,2-氟苯基,2-氯苯基,2-萘基,2-吡啶,2-噻吩或2-呋喃;苯乙烯基或丙烯基;R3为甲基,乙基,异丙基,叔丁基,环戊基,环己基或苄基;R4和R5为卤素原子F,Cl或Br。
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CN115850336A (zh) * | 2022-12-05 | 2023-03-28 | 四川大学 | 一种芳基-吡唑轴手性化合物及其制备方法和应用 |
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