CN115872820A - 仿生催化不对称氢化合成手性2-官能团化四氢喹啉的方法 - Google Patents
仿生催化不对称氢化合成手性2-官能团化四氢喹啉的方法 Download PDFInfo
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- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 15
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- 230000003197 catalytic effect Effects 0.000 title claims abstract description 13
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 84
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 19
- -1 (4-isopropyl toluene) ruthenium iodide dimer Chemical group 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
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- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
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- MHSVUSZEHNVFKW-UHFFFAOYSA-N bis-4-nitrophenyl phosphate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1OP(=O)(O)OC1=CC=C([N+]([O-])=O)C=C1 MHSVUSZEHNVFKW-UHFFFAOYSA-N 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000003278 mimic effect Effects 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- LJZVDOUZSMHXJH-UHFFFAOYSA-K ruthenium(3+);triiodide Chemical class [Ru+3].[I-].[I-].[I-] LJZVDOUZSMHXJH-UHFFFAOYSA-K 0.000 claims 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 229910052707 ruthenium Inorganic materials 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 84
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 230000014759 maintenance of location Effects 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 9
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 7
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
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- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- 238000004296 chiral HPLC Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
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- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- CILJSZLWPHTUIP-UHFFFAOYSA-N methyl quinoline-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)OC)=CC=C21 CILJSZLWPHTUIP-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
一种仿生催化不对称氢化合成手性2‑官能团化四氢喹啉的方法，其用到的催化体系是钌、基于平面手性环蕃环的可再生NAD(P)H模拟物以及布朗斯特酸。反应能在下列条件内进行，温度：25‑100℃；溶剂：乙酸乙酯；压力：20‑80个大气压；底物和催化剂的比例是200/l；催化剂为(4‑异丙基甲苯)碘化钌二聚体和布朗斯特酸。通过对2‑官能团化的喹啉的不对称氢化得到相应的手性2‑官能团化四氢喹啉的方法，其对映体过量可达到99％。本发明操作简便实用，原料易得，对映选择性高，产率好，且反应具有绿色原子经济性，对环境友好等优点。
Description
技术领域
本发明涉及一种应用仿生催化体系高对映选择性氢化2-官能团化的喹啉合成手性2-官能团化四氢喹啉的方法。
技术背景
手性四氢喹啉是合成许多天然产物，药物和复杂化学分子的重要合成子，并通常具有广谱的生理活性和药理活性，如：抗菌和消炎等特性。同时也被广泛地应用于配体的合成。特别是一些具有官能团化的手性四氢喹啉，是许多药物活性分子的核心骨架。因此对该类化合物的合成和生物活性研究引起了有机化学家和药学界的广泛重视。下面式1的就具有生物活性分子的含官能团化的手性四氢喹啉的结构单元：
鉴于四氢喹啉及其衍生物在药物和合成化学领域中的重要性，化学家们已经发展了一些方法来合成该类化合物，特别是采用环境友好且效率高的不对称氢化的方法来构建手性四氢喹啉，但是目前不对称氢化方法主要局限在是对2位或2,3位是烷基或芳基取代的喹啉能取得较大的成功。然而通过不对称还原的方法来构建2位是官能团化的四氢喹啉，目前成功的例子并不多。2013年，Maj小组通过铱和双膦配体体系实现2-官能化喹啉的不对称氢化，最高可以96％的ee值得到2-官能化的四氢喹啉。(文献1:Maj,A.M.；Suisse,I.；Hardouin,C.；Agbossou-Niedercorn,F.Synthesis of New Chiral 2-Functionalized-1,2,3,4-tetrahydroquinoline Derivatives via Asymmetric Hydrogenation ofSubstituted Quinolines.Tetrahedron 2013,69,9322-9328.)。随后在2019年，Tsantrizos小组报道了一例用汉栖酯作氢源，手性布朗斯特酸为催化剂的喹啉不对称氢化，其中有一个2-官能团化的底物，但仅有30％的ee值。(文献2:Yuan,M.；Mbaezue,I.I.；Zhou,Z.；Topic,F.；Tsantrizos,Y.S.P-Chiral,N-phosphoryl Sulfonamide
Acids with An Intramo-lecular Hydrogen Bond Interaction that Modulates Organatalysis.Org.Biomol.Chem.2019,17,8690-8694)。
从上述例子中，目前通过不对称还原的方法来高对映选择性地合成手性2-官能团化四氢喹啉的成功例子并不多。因此，发展一种高产率、高立体选择性的方法合成2-官能团化四氢喹啉化合物仍然是目前研究的难点和热点。
发明内容
本发明的目的是提供一种仿生催化不对称氢化合成2-官能团化四氢喹啉化合物的方法，本发明操作简便实用，原料易得，对映选择性高，产率好，且反应具有绿色原子经济性，环境友好等优点。
为实现上述目的，本发明的技术方案如下：
仿生催化不对称氢化合成手性2-官能团化四氢喹啉的方法，其催化体系为(4-异丙基甲苯)碘化钌二聚体和布朗斯特酸以及基于平面手性环蕃环的可再生NAD(P)H模拟物，反应式和条件如下：
式中：
温度：25-100℃；
溶剂：二氯甲烷、甲苯、四氢呋喃、乙酸乙酯、1,4-二氧六环、氯仿、乙腈中的一种或二种以上的混合溶剂；
氢气压力：20-80个大气压；
时间：46-72小时；
催化剂：(4-异丙基甲苯)碘化钌二聚体和布朗斯特酸；
氢源：为基于平面手性环蕃环的可再生NAD(P)H模拟物
所述R为苯基或含取代基的苯基(其中苯基上的取代基为-CF3、Me、MeO、Ph以及Cl中的一种取代基或二种取代基或三种取代基或四种取代基，取代基的个数为1-5个)以及为C1-C20的烷基,甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、叔丁氧基，C1-C10的伯胺或四元至六元的环状仲胺或非环状仲胺；
所述Ar为苯基或含取代基的苯基，苯基上的取代基为-CF3、Me、MeO、Ph以及F中的一种取代基或二种取代基或三种取代基或四种取代基，取代基的个数为1-5个；
所述布朗斯特酸为対甲苯磺酸，苯甲酸，乙酸，三氟乙酸，磷酸二苯酯,双(对硝基苯基)磷酸酯等中的一种；
进一步地，在上述技术方案中，优选地，将(4-异丙基甲苯)碘化钌二聚体和布朗斯特酸，平面手性环蕃环骨架的NAD(P)H模拟物和底物1加入溶剂中在室温搅拌2-5分钟；然后充入氢气20-80个大气压，在25-100℃下搅拌反应46-72h后，柱层析得目标产物。
进一步地，在上述技术方案中，优选地，所述仿生氢源是基于手性环蕃环骨架的NAD(P)H模拟物，反应中氢源的使用量和底物的摩尔比0.01:1到0.1:1。
进一步地，在上述技术方案中，优选地，所述布朗斯特酸是反应所需的活化剂，反应中使用量和底物的摩尔比为0.005:1～0.05:1。
进一步地，在上述技术方案中，优选地，以(4-异丙基甲苯)碘化钌二聚体计，所述配合物摩尔量为氢化底物摩尔量的0.01％～0.05％。
进一步地，在上述技术方案中，优选地，所述溶剂用量为每0.25毫摩尔氢化底物1用2～4毫升。
进一步地，在上述技术方案中，优选地，所述反应式为对2-官能团化的喹啉通过仿生催化不对称氢化得到相应的手性2-官能团化四氢喹啉，钌金属前体为(4-异丙基甲苯)碘化钌二聚体，仿生氢源为基于手性环蕃环骨架的NAD(P)H(10mol％)，布朗斯特酸为双(对硝基苯基)磷酸酯，溶剂为乙酸乙酯，温度为60度，氢气压力为33个大气压，所述结果最佳，对映体过量可达到99％。
本发明具有以下优点
1.反应活性和对映选择性高，反应完全，生成产物专一，分离方便，能获得高的对映体过量纯品。
2.能得到各种类型的手性2-官能团化四氢喹啉化合物。
3.催化剂制备方便，反应操作简便实用。
4.氢化反应条件温和，后处理简单。
5.比较传统合成方法，此方法采用少量的手性催化剂就可得到大量手性2-官能团化四氢喹啉化合物，实现手性增值，而且还可以通过改变手性氢源的构型而获得不同构型的手性手性2-官能团化四氢喹啉化合物，同时底物范围较广泛。
具体实施方式
下面通过实施例详述本发明；但本发明并不限于下述的实施例。
所用原料和催化体系中物质为商业化产品。
实施例1-14：条件的优化
往安培瓶中加入称量好的(4-异丙基甲苯)碘化钌二聚体(0.0005毫摩尔,0.5毫克)和布朗斯特酸(0.005毫摩尔)，手性氢源(0.01毫摩尔)，喹啉-2-羧酸甲酯(0.1毫摩尔)，溶剂2.0毫升，搅拌2-5分钟。然后将安培瓶放入一个不锈钢的高压釜中，通入氢气33个大气压，反应温度、反应时间见表1。慢慢释放氢气，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂：石油醚和乙酸乙酯的体积比为10:1)分离得到纯的产物，反应式及配体如下：
表1.溶剂、布朗斯特酸和手性氢源的筛选
aConditions(序号1-9):1a(0.10mmol),[Ru(p-cymene)I2]2(0.5mol％),NAD(P)Hmodels(10mol％),Transfer catalysts(5.0mol％),Solvent(2.0mL),H2(33个大气压),50℃,24h.b Measured by analysis of1H NMR.c Determined by chiral HPLC.d 48h.f 60℃.
产率为分离收率，产物的对映体过量用手性液相色谱测定，见表1。
实施例15-36：仿生催化不对称氢化合成手性2-官能团化四氢喹啉
往安培瓶中加入称量好的(4-异丙基甲苯)碘化钌二聚体(0.00075毫摩尔,0.7毫克)和双(对硝基苯基)磷酸酯(0.0075毫摩尔，2.6毫克)，手性氢源H4(0.015毫摩尔,4.6毫克)，2-官能团化喹啉(0.15毫摩尔)，乙酸乙酯2.0毫升，搅拌2-5分钟。然后将安培瓶放入一个不锈钢的高压釜中，通入氢气33个大气压，60度下反应72小时。慢慢释放氢气，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂石油醚和乙酸乙酯的体积比为10:1)分离得到纯的产物；反应式如下：
(R)-Methyl 1,2,3,4-tetrahydroquinoline-2-carboxylate(2a)：28mg,98％yield,pale yellow oil,Rf＝0.60(hexanes/ethyl acetate 10/1),97％ee,[α]20 D＝-31.33(c 0.45,CHCl3).1H NMR(400MHz,
127.1,120.6,117.7,114.6,53.9,52.4,25.8,24.7.HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 14.9min(major)and19.1min.
(R)-Ethyl 1,2,3,4-tetrahydroquinoline-2-carboxylate(2b)：30mg,97％yield,pale yellow oil,Rf＝0.50(hexanes/ethyl acetate 20/1),98％ee,[α]20 D＝-38.00(c 0.40,CHCl3).1H NMR(400MHz,CDCl3)δ6.96-6.85(m,2H),6.60-6.50(m,2H),4.23-4.09(m,2H),3.98-3.90(m,1H),3.76(brs,1H),2.80-2.62(m,2H),2.26-2.17(m,1H),1.97-1.86(m,1H),1.22(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ173.2,142.9,129.1,127.1,120.7,117.8,114.7,61.3,54.0,25.9,24.8,14.2.HPLC:Chiralcel OJ-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 11.8min(major)and17.9min.
(R)-Propyl 1,2,3,4-tetrahydroquinoline-2-carboxylate(2c)：32mg,97％yield,pale yellow oil,Rf＝0.60(hexanes/ethyl acetate 20/1),98％ee,[α]20 D＝-12.68(c 0.56,CHCl3).1H NMR(400MHz,CDCl3)δ6.95-6.85(m,2H),6.60-6.47(m,2H),4.26(brs,1H),4.12-4.00(m,2H),3.95(dd,J＝8.9,3.8
(R)-Butyl 1,2,3,4-tetrahydroquinoline-2-carboxylate(2d):35mg,95％yield,pale yellow oil,Rf＝0.65(hexanes/ethyl acetate 20/1),98％ee,[α]20 D＝-15.78(c 0.64,CHCl3).1H NMR(400MHz,CDCl3)
114.6,65.2,54.0,30.6,25.9,24.8,19.1,13.7.HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 8.4min(major)and 11.2min.
(R)-Methyl 6-methoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate(2f):32mg,96％yield,pale yellow oil,Rf＝0.35(hexanes/ethyl acetate 5/1).98％ee,[α]20 D＝+9.69(c 0.64,CHCl3).1H NMR(400
121.9,115.9,114.4,113.2,55.8,54.2,52.3,26.0,24.9.HPLC:Chiralpak AD-H column,254nm,30℃,detector:254nm,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time11.8min(minor)and 12.8min(major).
(R)-Methyl 8-methoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate(2g):30mg,90％yield,pale yellow oil,Rf＝0.40(hexanes/ethyl acetate 10/1).70％ee,[α]20 D＝-15.17(c 0.60,CHCl3).1H NMR
55.4,53.6,52.3,25.4,24.6.HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 15.6min and 17.3min(major).
(R)-Methyl 6-fluoro-1,2,3,4-tetrahydroquinoline-2-carboxylate(2h):29mg,92％yield,pale yellow oil,Rf＝0.30(hexanes/ethyl acetate 10/1),97％ee,[α]20 D＝-23.45(c 0.58,CHCl3).1H NMR
(400MHz,CDCl3)δ6.68-6.57(m,2H),6.44(dd,J＝8.7,4.8Hz,1H),4.17(brs,1H),3.93(dd,J＝8.6,3.8Hz,1H),3.69(s,3H),2.77-2.58(m,2H),2.25-2.12(m,1H),1.97-1.86(m,1H).13C NMR(100MHz,CDCl3)δ173.7,155.8(d,1JF-C＝234.0Hz),139.1(d,4JF-C＝1.8Hz),121.9(d,3JF-C＝6.9Hz),115.4(d,4JF-C＝1.8Hz),115.3(d,2JF-C＝27.5Hz),113.6(d,2JF-C＝22.3Hz),54.0,52.4,25.8,24.4.19F NMR(376MHz,CDCl3)δ-127.6.HPLC:Chiralcel OJ-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time9.8min and 12.2min(major).
(R)-Methyl 6-chloro-1,2,3,4-tetrahydroquinoline-2-carboxylate(2i):32mg,95％yield,pale yellow solid,Rf＝0.30(hexanes/ethyl acetate 10/1).97％ee,[α]20 D＝-44.68(c 0.64,CHCl3).1H NMR(400
115.6,53.8,52.5,25.6,24.3.HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 10.6min and 11.8min(major).
(R)-Methyl 6-bromo-1,2,3,4-tetrahydroquinoline-2-carboxylate(2j):34mg,84％yield,white solid,
53.7,52.5,25.5,24.2.HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 11.3min(minor)and 12.1min(major).
(R)-Methyl 7-chloro-1,2,3,4-tetrahydroquinoline-2-carboxylate(2k):31mg,92％yield,white solid,Rf＝0.30(hexanes/ethyl acetate 10/1),96％ee,[α]20 D＝-18.59(c 0.64,CHCl3).1H NMR(400MHz,
118.8,117.4,114.0,53.6,52.5,25.3,24.4.HPLC:Chiralcel OJ-H,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 13.6min(major)and 15.2min(minor).
(2R,3S)-Methyl 3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate(2l-cis):23mg,75％yield,pale yellow oil,Rf＝0.75(hexanes/ethyl acetate 10/1),81％ee,[α]20 D＝-6.50(c 0.40,CHCl3).1H NMR
142.3,129.9,127.0,118.8,117.6,114.1,57.6,52.2,34.1,28.0,14.3.HPLC:Chiralcel OD-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time7.4min and 11.6min(major).
(2R,3R)-Methyl 3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate(2l-trans):7mg,22％yield,pale yellow oil,Rf＝0.50(hexanes/ethyl acetate 10/1),99％ee,[α]20 D＝-51.11(c 0.18,CHCl3).1H
CDCl3)δ174.0,141.9,129.4,127.0,120.1,118.2,114.6,60.0,52.2,32.7,28.8,18.7.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.7mL/min,retention time 8.9min(major)and 11.9min.
(R)-Piperidin-1-yl(1,2,3,4-tetrahydroquinolin-2-yl)methanone(2m):35mg,96％yield,pale yellow oil,new compound,Rf＝0.30(hexanes/ethyl acetate 3/1).99％ee,[α]20 D＝-56.00(c 0.70,CHCl3),1H
127.0,121.2,117.7,116.1,52.5,46.3,43.5,27.0,26.6,25.6,25.1,24.5.HPLC:Chiralcel OJ-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time11.3min(major)and 13.6min.HRMS Calculated for C15H21N2O[M+H]+245.1648,found:245.1652.
(R)-Pyrrolidin-1-yl(1,2,3,4-tetrahydroquinolin-2-yl)methanone(2n):33mg,96％yield,pale yellow oil,Rf＝0.40(hexanes/ethyl acetate 3/1),98％ee,[α]20 D＝-20.47(c 0.64,CHCl3),1H NMR
143.2,129.0,127.0,121.3,117.8,116.1,54.2,46.5,46.1,27.0,26.3,24.4,24.0.HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 12.7min(major)and 16.5min.
(R)-N,N-Diethyl-1,2,3,4-tetrahydroquinoline-2-carboxamide(2o):33mg,95％yield,pale yellow oil,Rf＝0.55(hexanes/ethyl acetate 1/1),99％ee,[α]20 D＝-45.55(c 0.72,CHCl3),1H NMR(400MHz,
121.3,117.8,116.2,52.7,41.4,40.5,27.0,25.4,14.6,13.0.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝1.0mL/min,retention time 9.7min and12.7min(major).
(R)-N-Butyl-1,2,3,4-tetrahydroquinoline-2-carboxamide(2p):32mg,92％yield,pale yellow oil,new compound,Rf＝0.30(hexanes/ethyl acetate 1/1),69％ee,[α]20 D＝68.07(c 0.52,CHCl3),1H NMR
2.29-2.18(m,1H),1.90-1.78(m,1H),1.46-1.32(m,2H),1.29-1.17(m,2H),0.82(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ173.5,141.5,129.3,127.1,122.6,118.8,115.2,55.5,39.1,31.7,24.8,24.4,20.1,13.7.HPLC:Chiralcel OJ-H column,Detector 254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.7mL/min,retention time 7.1min(major)and7.8min.HRMS Calculated for C14H21N2O[M+H]+233.1648,found:233.1647.
(R)-1-(1,2,3,4-Tetrahydroquinolin-2-yl)ethan-1-one(2q):19mg,73％yield,pale yellow oil,new compound,Rf＝0.20(hexanes/ethyl acetate 10/1),92％ee,[α]20 D＝-31.31(c 0.38,CHCl3),1H NMR
117.4,114.5,61.3,26.9,26.1,24.8.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 10.1min and 11.4min(major).HRMSCalculated for C11H14NO[M+H]+176.1070,found:176.1069.
(R)-Phenyl(1,2,3,4-tetrahydroquinolin-2-yl)methanone(2r):32mg,90％yield,pale yellow oil,new compound,Rf＝0.50(hexanes/ethyl acetate 10/1),95％ee,[α]20 D＝47.69(c 0.52,CHCl3),1H
NMR(100MHz,CDCl3)δ199.6,143.2,134.9,133.5,129.0,128.9,128.3,127.2,120.8,117.7,115.3,57.4,27.0,26.6.HPLC:Chiralcel OD-H column,Detector 254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 17.1min and 18.6min(major).HRMSCalculated for C16H16NO[M+H]+238.1226,found:238.1229.
(R)-(4-Methoxyphenyl)(1,2,3,4-tetrahydroquinolin-2-yl)methanone(2s):36mg,90％yield,pale yellow oil,new compound,Rf＝0.30(hexanes/ethyl acetate 5/1),95％ee,[α]20 D＝32.91(c 0.72,
13C NMR(100MHz,CDCl3)δ197.8,163.8,143.1,130.7,129.0,127.5,127.2,121.1,117.8,115.5,114.1,57.1,55.6,27.1,26.9.HPLC:Chiralcel OD-H column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 18.0min(major)and 25.9min.HRMSCalculated for C17H18NO2[M+H]+268.1332,found:268.1334.
(R)-(1,2,3,4-Tetrahydroquinolin-2-yl)(p-tolyl)methanone(2t):29mg,77％yield,pale yellow oil,new compound,Rf＝0.50(hexanes/ethyl acetate 10/1),94％ee,[α]20 D＝34.89(c 0.45,CHCl3),1H
2.82-2.73(m,1H),2.44(s,3H),2.41-2.35(m,1H),1.82-1.67(m,1H).13C NMR(100MHz,CDCl3)δ198.8,144.5,142.5,132.1,129.6,129.1,128.5,127.3,121.4,118.3,115.9,57.4,26.9,26.6,21.7.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝1.0mL/min,retention time 12.8min and 18.3min(major).HRMS Calculated forC17H18NO[M+H]+252.1383,found:252.1383.
(R)-(4-Fluorophenyl)(1,2,3,4-tetrahydroquinolin-2-yl)methanone(2u):24mg,63％yield,pale yellow oil,new compound,Rf＝0.45(hexanes/ethyl acetate10/1),94％ee,[α]20 D＝22.28(c 0.35,
13C NMR(100MHz,CDCl3)δ197.8,166.0(d,1JF-C＝254.2Hz),142.7,131.1,131.0(d,3JF-C＝9.3Hz),129.1,127.3,121.0,118.1,116.1(d,2JF-C＝21.7Hz),115.6,57.4,26.9,26.6.19F NMR(376MHz,CDCl3)δ-104.0.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝1.0mL/min,retention time 12.2min and 16.7min(major).HRMSCalculated for C16H15FNO[M+H]+256.1132,found:256.1131.
产率为分离收率，产物的对映体过量用手性液相色谱测定。
本发明对2-官能团化的喹啉的不对称氢化得到相应的手性2-官能团化的喹啉化合物，其对映体过量可达到99％。本发明操作简便实用，对映选择性高，产率好，且反应具有原子经济性，对环境友好等优点。
Claims (8)
1.仿生催化不对称氢化合成手性2-官能团化四氢喹啉的方法，其特征在于，反应式和条件如下：
式中：
反应温度：25-100℃；
溶剂：二氯甲烷、甲苯、四氢呋喃、乙酸乙酯、1,4-二氧六环、氯仿、乙腈中的一种或二种以上的混合溶剂；
氢气压力：20-80个大气压；
时间：46-72小时；
催化剂：(4-异丙基甲苯)碘化钌二聚体和布朗斯特酸；
氢源：为基于平面手性环蕃环的可再生NAD(P)H模拟物，结构式为：
所述R为苯基或含取代基的苯基以及为C1-C20的烷基,甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、叔丁氧基，C1-C10的伯胺或四元至六元的环状仲胺或非环状仲胺；其中苯基上的取代基为-CF3、Me、MeO、Ph以及Cl中的一种取代基或二种取代基或三种取代基或四种取代基，取代基的个数为1-5个；
所述Ar为苯基或含取代基的苯基，苯基上的取代基为-CF3、Me、MeO、Ph以及F中的一种取代基或二种取代基或三种取代基或四种取代基，取代基的个数为1-5个；
所述布朗斯特酸为対甲苯磺酸，苯甲酸，乙酸，三氟乙酸，磷酸二苯酯,双(对硝基苯基)磷酸酯等中的一种。
2.如权利要求1所述的方法，其特征在于：将(4-异丙基甲苯)碘化钌二聚体和布朗斯特酸，平面手性环蕃环骨架的NAD(P)H模拟物和底物2-官能团化的喹啉加入溶剂中在室温搅拌2-5分钟；然后充入氢气20-80个大气压，在25-100℃下搅拌反应24-72小时后，柱层析得目标产物。
3.如权利要求1或2所述的方法，其特征在于：所述仿生氢源是基于手性环蕃环骨架的NAD(P)H模拟物，反应中氢源的使用量和底物式1的摩尔比0.01:1～0.1:1。
4.如权利要求1或2所述的方法，其特征在于：所述布朗斯特酸是反应所需的活化剂，反应中布朗斯特酸使用量和底物式1的摩尔比为0.005:1～0.05:1。
5.如权利要求1或2所述的方法，其特征在于：以(4-异丙基甲苯)碘化钌二聚体计，所述(4-异丙基甲苯)碘化钌二聚体摩尔量为氢化底物式1摩尔量的0.01％～0.05％。
6.如权利要求1或2所述的方法，其特征在于：所述溶剂用量为每0.25毫摩尔氢化底物式1用量2～4毫升。
7.如权利要求1所述的方法，其特征在于：所述反应式为对2-官能团化的喹啉通过仿生催化不对称氢化得到相应的手性2-官能团化四氢喹啉，钌金属前体为(4-异丙基甲苯)碘化钌二聚体，10mol％仿生氢源为基于手性环蕃环骨架的NAD(P)H，布朗斯特酸为双(对硝基苯基)磷酸酯，溶剂为乙酸乙酯，温度为60℃，氢气压力为33个大气压，对映体过量可达到99％。
8.如权利要求1所述的方法，其特征在于：反应时间为48-72小时。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1608052A (zh) * | 2001-09-12 | 2005-04-20 | 阿诺麦德股份有限公司 | 对映体纯的氨基取代稠合双环的合成 |
| CN111116471A (zh) * | 2018-10-30 | 2020-05-08 | 中国科学院大连化学物理研究所 | 一类具有面手性环芳烷并喹啉骨架的nad(p)h模拟物及其合成方法与应用 |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1608052A (zh) * | 2001-09-12 | 2005-04-20 | 阿诺麦德股份有限公司 | 对映体纯的氨基取代稠合双环的合成 |
| CN111116471A (zh) * | 2018-10-30 | 2020-05-08 | 中国科学院大连化学物理研究所 | 一类具有面手性环芳烷并喹啉骨架的nad(p)h模拟物及其合成方法与应用 |
Non-Patent Citations (4)
| Title |
|---|
| MAJ, ANNA M.等: "Synthesis of new chiral 2-functionalized-1, 2, 3, 4-tetrahydroquinoline derivatives via asymmetric hydrogenation of substituted quinolines", TETRAHEDRON, vol. 69, no. 44, pages 9324 * |
| WANG JIE等: "Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models", ANGEW. CHEM., INT. ED., vol. 58, no. 6, pages 1813 - 1817, XP072086758, DOI: 10.1002/anie.201813400 * |
| WANG JIE等: "Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric Reduction: Design, Synthesis, Scope, and Mechanistic Studies", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 85, no. 4, pages 2357 - 2359 * |
| ZHU, ZHOU-HAO等: "Design and synthesis of chiral and regenerable [2.2]paracyclophane-based NAD(P)H models and application in biomimetic reduction of flavonoids", CHEMICAL SCIENCE, vol. 11, no. 37, pages 10220 - 10224 * |
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