CN116731042A - 手性吡啶-吡咯并咪唑啉酮三齿氮配体及其在迈克尔加成中的应用 - Google Patents
手性吡啶-吡咯并咪唑啉酮三齿氮配体及其在迈克尔加成中的应用 Download PDFInfo
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 60
- -1 pyridine-pyrroloimidazolone Chemical compound 0.000 title claims abstract description 37
- 239000003446 ligand Substances 0.000 title claims abstract description 34
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 30
- 238000006845 Michael addition reaction Methods 0.000 title claims abstract description 10
- VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 claims abstract description 28
- PMWXGSWIOOVHEQ-UHFFFAOYSA-N pyridine-2,6-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=N1 PMWXGSWIOOVHEQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 239000002841 Lewis acid Substances 0.000 claims abstract 2
- 150000007517 lewis acids Chemical class 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 239000011968 lewis acid catalyst Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005376 alkyl siloxane group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- OKDGPOCKHMGDQY-UHFFFAOYSA-N 3,4-dihydropyrrol-2-one Chemical compound O=C1CCC=N1 OKDGPOCKHMGDQY-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000004809 thin layer chromatography Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000001816 cooling Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WKBALTUBRZPIPZ-UHFFFAOYSA-N 2,6-di(propan-2-yl)aniline Chemical group CC(C)C1=CC=CC(C(C)C)=C1N WKBALTUBRZPIPZ-UHFFFAOYSA-N 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- NSYSSMYQPLSPOD-UHFFFAOYSA-N triacetate lactone Chemical compound CC1=CC(O)=CC(=O)O1 NSYSSMYQPLSPOD-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- DYFFAVRFJWYYQO-UHFFFAOYSA-N n-methyl-n-phenylaniline Chemical group C=1C=CC=CC=1N(C)C1=CC=CC=C1 DYFFAVRFJWYYQO-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- FOYHNROGBXVLLX-KHWBWMQUSA-N 2,6-diethylaniline Chemical group CCC1=CC=CC(CC)=C1[15NH2] FOYHNROGBXVLLX-KHWBWMQUSA-N 0.000 description 1
- CDIDGWDGQGVCIB-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)aniline Chemical group NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CDIDGWDGQGVCIB-UHFFFAOYSA-N 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
- B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
- B01J31/1835—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline comprising aliphatic or saturated rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/845—Cobalt
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/847—Nickel
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
本发明公开了手性吡啶‑吡咯并咪唑啉酮三齿氮配体及其在迈克尔加成中的应用,属于有机化学中不对称催化技术领域。以反‑3‑取代‑L‑脯氨酰胺和吡啶‑2,6‑二甲醛为原料,经过一步缩合,得到手性吡啶‑吡咯并咪唑啉酮三齿氮配体。以路易斯酸和该配体作为催化剂,在用量低至万分之五情况下,应用于4‑羟基香豆素与β,γ‑不饱和α‑酮酸酯的不对称迈克尔加成反应中,取得高收率和优异对映选择性。本发明中配体结构新型,合成方法简单,催化剂用量极低。
Description
技术领域
本发明涉及手性吡啶-吡咯并咪唑啉酮三齿氮配体及其在迈克尔加成反应中的应用,属于有机化学中的不对称催化技术领域。
背景技术
1,3-二羰基化合物与各种迈克尔受体的不对称共轭加成是制备手性化合物的重要方法之一。在过去二十年中,有关4-羟基香豆素与β,γ-不饱和α-酮酸酯的不对称共轭加成反应的相关文献报道,无论是金属络合物催化或者使用有机小分子催化都取得了优异的结果。
然而现有催化系统中催化剂负载范围为2-10mol%,催化剂用量高,为了更加绿色环保,发展更高效催化剂非常有必要的,有关4-羟基香豆素与β,γ-不饱和α-酮酸酯的不对称共轭加成反应使用更低的催化剂负载量至今还未有人报道。
同时在实际催化剂使用过程中仍存在各种缺陷,主要表现在催化剂合成方面需要用到昂贵的试剂以及需要经过多步转化,催化应用中对映选择性欠佳以及催化剂活性低,因此需要寻找更加有效的手性催化剂以进一步解决上述问题。
发明内容
为了克服上述技术缺陷,本发明提供了一种结构新型手性吡啶-吡咯并咪唑啉酮三齿氮配体。以反-3-羟基-L-脯氨酰胺和吡啶-2,6-二甲醛为原料,经过一步缩合后得到高收率的手性吡啶-吡咯并咪唑啉酮三齿氮配体,该配体用于4-羟基香豆素与β,γ-不饱和α-酮酸酯不对称共轭加成反应,得到迈克尔加成产物,取得了高收率和优异的对映选择性。
本发明是通过以下技术方案实现:手性吡啶-吡咯并咪唑啉酮三齿氮配体,结构通式为:
其中:n=0-4;R为C1-C8烷基、二苯基甲基、取代苯基或取代萘基,所述取代为氢、C1-C8烷基、C1-C8烷氧基、三氟甲基、硝基、腈基、卤素、三氟甲基中的一种或多种;R'为氢、卤素、C1-C8烷氧基、苄氧基、羟基、磺酸酯基、叠氮基、C1-C4烷硅氧基、C1-C4烷酰氧基或C1-C4烷酰硫基。
进一步地,在上述技术方案中,所述n=1,2;R为C1-C8烷基、苯基、三氟甲基苯基、二苯甲基苯基;R'为羟基、氢、甲氧基、苄氧基、甲磺酸酯基、氟、乙酰硫基、叠氮基、三甲基硅氧基或二甲基叔丁基硅氧基。
进一步地,在上述技术方案中,所述优选情况下,具体结构为:
本发明还提供了上述手性吡啶-吡咯并咪唑啉酮三齿氮配体在4-羟基香豆素与β,γ-不饱和α-酮酸酯迈克尔加成反应中的应用。
进一步地,在上述技术方案中,所述应用包括如下步骤:以4-羟基香豆素和β,γ-不饱和α-酮酸酯为原料,在路易斯酸催化剂和手性吡啶-吡咯并咪唑啉酮三齿氮配体存在下,有机溶剂中反应,得到迈克尔加成产物;反应方程式如下:
其中:R1选自苯基、取代苯基、取代噻吩基,所述取代为氢、卤素、C1-C4烷基、C1-C4烷氧基、硝基、三氟甲基、硝基、腈基中的一种或多种;R2选自C1-C4烷基。
进一步地,在上述技术方案中,所述路易斯酸催化剂为Cu(OTf)2、Cu(ClO4)2·6H2O、Ni(OTf)2或Co(ClO4)2·6H2O。
进一步地,在上述技术方案中,所述三齿氮配体与4-羟基香豆素摩尔比为0.005-0.0005:1。
进一步地,在上述技术方案中,有机溶剂为二氯甲烷或四氢呋喃;反应温度为0-30℃。
本发明还进一步提供了上述手性吡啶-吡咯并咪唑啉酮三齿氮配体配体的合成方法,包括如下步骤:以反-3-取代-L-脯氨酰胺和吡啶-2,6-二甲醛为原料,经过一步缩合,得到手性吡啶-吡咯并咪唑啉酮三齿氮配体。
发明有益效果:
本发明提供了一种结构新型的手性吡啶-吡咯并咪唑啉酮三齿氮配体,结构丰富,可调节性强。该催化剂原料易得,合成简便、廉价、高效。催化活性高,在4-羟基香豆素与β,γ-不饱和α-酮酸酯的不对称共轭加成反应中,得到迈克尔加成产物,取得了高收率和优异的对映选择性产物立体选择性高,收率最高均可达99%,对映选择性最高均可达97%。
具体实施方式
实施例1
2,6-二异丙基苯胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和2,6-二异丙基衍生反-3-羟基-L-脯氨酰胺(6.0mmol,3.0eq,1.740g),再加入无水乙醇(10mL),80℃油浴中加热搅拌12h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。用石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,在硅胶柱经柱层析,得到白色固体。乙酸乙酯重结晶得到产物1.198g,产率88%,>99%ee。HPLCCHIRALPAKIC,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,λ=256nm,retentiontime:25.58min(major)。
1HNMR(400MHz,CDCl3)δ7.64(t,J=8.0Hz,1H),7.41(d,J=7.6Hz,2H),7.21(t,J=7.6Hz,2H),7.08(d,J=6.0Hz,2H),6.92(d,J=8.0Hz,2H),4.89(s,2H),4.59-4.52(m,4H),3.30(d,J=10.8Hz,2H),3.00(dd,J=10.8,4.4Hz,2H),2.82-2.75(m,2H),2.39-2.19(m,8H),1.14(d,J=6.8Hz,12H),0.99(d,J=6.8Hz,6H),0.14(d,J=6.4Hz,6H).13CNMR(150MHz,CDCl3)δ174.6,157.9,148.0,146.2,137.6,129.7,129.0,124.1,123.8,121.9,87.0,72.2,63.8,63.6,38.0,29.0,28.8,25.0,24.9,23.7,22.8.
实施例2
2,6-二乙基苯胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和2,6-二乙基衍生反-3-羟基-L-脯氨酰胺(6.0mmol,3.0eq,1.573g),再加入无水乙醇(10mL),80℃油浴中加热搅拌8h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,硅胶柱经柱层析,得到白色固体产物0.998g,产率80%。
1HNMR(600MHz,CDCl3)δ7.65(t,J=7.8Hz,1H),7.46(d,J=7.8Hz,2H),7.17(t,J=7.8Hz,2H),7.03(d,J=7.2Hz,2H),6.89(d,J=6.6Hz,2H),4.84(s,2H),4.56(s,2H),4.38(t,J=7.2Hz,2H),3.32(d,J=10.8Hz,2H),2.99(dd,J=10.8,4.2Hz,2H),2.45-2.38(m,2H),2.35-2.30(m,7H),1.88-1.82(m,2H),1.30-1.24(m,3H),1.15(t,J=7.8Hz,6H),0.67(t,J=7.2Hz,6H).13CNMR(150MHz,CDCl3)δ173.6,156.8,142.9,141.3,137.8,131.8,128.4,126.3,125.7,120.7,84.6,72.2,63.4,63.1,37.7,24.6,23.0,14.7,13.7.
实施例3
苯胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL的耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和苯胺衍生的反-3-羟基-L-脯氨酰胺(6.0mmol,3.0eq,1.237g),再加入无水乙醇(10mL),80℃油浴中加热搅拌8h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。用石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,在硅胶柱经柱层析,得到白色固体产物0.940g,产率92%。
1HNMR(600MHz,CDCl3)δ7.64(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,4H),7.20-7.18(m,6H),7.06(t,J=7.2Hz,2H),5.67(s,2H),4.34(s,2H),4.22(q,J=4.8Hz,2H),3.42(d,J=10.2Hz,2H),3.33(br,2H),2.92(dd,J=10.2,4.2Hz,2H),2.37-2.33(m,2H),2.08-2.04(m,2H).13CNMR(150MHz,CDCl3)δ174.9,157.8,138.8,137.3,129.2,125.4,121.2,121.1,83.5,71.5,63.4,63.2,37.1.
实施例4
3,5-双三氟甲基苯胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和3,5-双三氟甲基衍生反-3-羟基-L-脯氨酰胺(6.0mmol,3.0eq,2.052g),再加入无水乙醇(10mL),80℃油浴中加热搅拌10h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。用石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,硅胶柱经柱层析,得到白色固体。乙酸乙酯重结晶得到产物0.894g,产率57%。1HNMR(600MHz,CDCl3)δ8.00(s,4H),7.83(t,J=7.8Hz,1H),7.57(s,2H),7.41(d,J=7.8Hz,2H),5.77(s,2H),4.50-4.42(m,2H),3.95(q,J=4.8Hz,2H),3.44(d,J=10.2Hz,2H),2.93(dd,J=10.2,4.2Hz,2H),2.45-2.41(m,2H),2.23-2.16(m,2H),1.89(d,J=6.6Hz,2H).13CNMR(150MHz,CDCl3)δ175.1,156.8,139.5,139.3,132.5(q,JC-F=33.0Hz),123.0(q,JC-F=273.0Hz),121.9,119.3,118.2,82.3,71.6,63.0,62.9,37.3.
实施例5
二苯基甲胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和二苯基甲胺衍生反-3-羟基-L-脯氨酰胺(6.0mmol,3.0eq,1.776g),再加入无水乙醇(10mL),80℃油浴中加热搅拌8h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,硅胶柱经柱层析,得到白色固体。乙酸乙酯重结晶得到产物1.14g,产率82%。1HNMR(600MHz,(CD3)2SO)δ7.30(t,J=7.8Hz,4H),7.25-7.21(m,3H),7.07(d,J=7.2Hz,4H),7.05-7.02(m,6H),6.96-6.95(m,4H),6.63(d,J=7.8Hz,2H),5.72(s,2H),5.14(s,2H),4.92(d,J=3.6Hz,2H),4.27-4.25(m,2H),4.20(q,J=4.8Hz,2H),3.16(dd,J=10.8,3.6Hz,2H),2.94(q,J=5.4Hz,2H),2.09-2.06(m,2H),1.93-1.89(m,2H).13CNMR(150MHz,(CD3)2SO)δ175.2,158.4,140.4,138.5,137.1,129.1,128.3,128.0,127.6,127.1,127.0,120.4,82.7,69.5,63.2,63.0,60.6,36.8.
实施例6
2,6-二异丙基苯胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和2,6-二异丙基衍生L-脯氨酰胺(6.0mmol,3.0eq,1.644g),再加入无水乙醇(10mL),80℃油浴中加热搅拌8h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,硅胶柱经柱层析,得到白色固体。乙酸乙酯通过重结晶得到产物0.988g,产率76%。1HNMR(600MHz,CDCl3)δ7.61(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,2H),7.21(t,J=7.2Hz,2H),7.09(dd,J=7.2,1.2Hz,2H),6.92(dd,J=7.8,1.2Hz,2H),4.90(s,2H),4.34(dd,J=8.4,4.8Hz,2H),3.28-3.24(m,2H),2.89-2.84(m,4H),2.35-2.24(m,4H),2.17-2.11(m,2H),1.93-1.84(m,4H),1.18(d,J=6.6Hz,6H),1.16(d,J=6.6Hz,6H),0.99(d,J=7.2Hz,6H),0.14(d,J=6.6Hz,6H).13CNMR(150MHz,CDCl3)δ174.8,158.4,148.1,146.3,137.4,130.3,128.8,124.0,123.8,121.6,87.4,65.4,57.1,29.5,29.0,28.8,25.6,25.0,24.9,23.7,22.8.
实施例7
2,6-二异丙基苯胺取代的手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(2.0mmol,0.270g)和2,6-二异丙基衍生L-脯氨酰胺(6.0mmol,3.0eq,1.824g),再加入无水乙醇(10mL),80℃油浴中加热搅拌8h后,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,硅胶柱经柱层析,得到白色固体。乙酸乙酯重结晶得到产物1.276g,产率90%。1HNMR(600MHz,CDCl3)δ7.68(t,J=7.8Hz,1H),7.53(d,J=7.8Hz,2H),7.20(t,J=7.8Hz,2H),7.07(dd,J=7.8,1.2Hz,2H),6.91(dd,J=7.8,1.2Hz,2H),4.80(s,2H),4.42(t,J=6.6Hz,2H),4.10-4.07(m,2H),3.37(s,6H),3.32(dd,J=10.2,3.0Hz,2H),2.92(q,J=5.4Hz,2H),2.76(sept,J=6.6Hz,2H),2.43-2.38(m,2H),2.25-2.18(m,4H),1.15(d,J=7.2Hz,6H),1.12(d,J=7.2Hz,6H),0.97(d,J=6.6Hz,6H),0.16(d,J=6.6Hz,6H).13CNMR(150MHz,CDCl3)δ174.0,157.7,148.0,146.2,137.8,130.0,128.9,123.9,123.8,121.8,87.5,80.9,64.0,61.1,57.2,34.5,29.1,28.8,25.0,24.8,23.8,22.7.
实施例8
2,6-二异丙基苯胺取代手性吡啶-吡咯并咪唑啉酮三齿氮配体的合成
在15mL耐压管中,加入2,6-吡啶二甲醛(20.0mmol,2.702g)和2,6-二异丙基衍生反-羟基-L-脯氨酰胺(60.0mmol,3.0eq,17.40g),再加入无水乙醇(80mL),80℃油浴中加热搅拌12h,冷却至室温。薄层色谱(TLC)检测反应,检测原料2,6-吡啶二甲醛完全反应,真空浓缩反应液除去无水乙醇得到粗产物。用石油醚/乙酸乙酯(5/1-2/1)作为洗脱液,在硅胶柱经柱层析,得到白色固体。进一步使用乙酸乙酯通过重结晶得到产物10.6g,产率78%,>99%ee。
实施例9
在反应管中,加入路易斯酸(1mol%)、手性配体(1mol%)和THF1mL溶解后,在真空下去除THF。然后加入β,γ-不饱和α-酮酯2a(20.9mg,0.11mmol)和二氯甲烷(1.0mL),在25℃下搅拌反应0.5h。随后在25℃下加入4-羟基香豆素1a(16.2mg,0.1mmol),在25℃下搅拌反应,直到4-羟基香豆素1a消失(薄层色谱检测)。快速过柱色谱法(Pet/EtOAc=5/1-2/1)纯化,得到相应产物3a,白色固体。1HNMR(600MHz,CDCl3):δ7.86-7.80(m,1H),7.59-7.53(m,1H),7.38-7.23(m,7H),4.96(s,0.66H),4.63(s,0.30H),4.35(dd,J=7.8,3.6Hz,0.32H),4.22(t,J=9.0Hz,0.71H),3.93(s,1H),3.86(s,2H),2.81(dd,J=14.4,7.8Hz,0.32H),2.55(dd,J=14.4,3.6Hz,0.33H),2.48(d,J=9.0Hz,1.39H).实验结果如下:
实施例10
在实施例9优化的基础上,继续对催化剂和配体用量进行筛选
在25.0mL容量瓶中,加入Co(ClO4)2·6H2O(4.6mg,0.0125mmol),然后加入THF,使总体积达到25.0mL;在25.0mL容量瓶中,加入L1(8.5mg,0.0125mmol),然后加入THF,使总体积达到25.0mL。
在反应管中加入100μL Co(ClO4)2·6H2O(0.05mol%)和100μL L1(0.05mol%),然后在真空下去除THF。加入β,γ-不饱和α-酮酯2a(20.9mg,0.11mmol)和二氯甲烷(1.0mL),在25℃下搅拌反应0.5h。随后在25℃下加入4-羟基香豆素1a(16.2mg,0.1mmol)搅拌反应,直到4-羟基香豆素1a消失(薄层色谱检测)。快速过柱色谱法(Pet/EtOAc=5/1-2/1)纯化,得到34.5mg产物3a,白色固体,产率98%,96%ee。
实施例11
a除非特别说明,反应的步骤如下:底物浓度(0.1mmol),溶剂体积(1.0mL),b分离收率cee值通过高效液相色谱分离。
实施例12
在反应管中,加入100μL Co(ClO4)2·6H2O(0.05mol%)和100μL L1(0.05mol%),然后在真空下去除THF。加入β,γ-不饱和α-酮酯2a(20.9mg,0.11mmol)和二氯甲烷(1.0mL),在25℃下搅拌反应0.5h。随后在25℃下加入4-羟基-6-甲基-2-吡喃酮(12.6mg,0.1mmol)搅拌反应,直到4-羟基-6-甲基-2-吡喃酮消耗完(薄层色谱检测)。快速过柱色谱法(Pet/EtOAc=5/1-2/1)直接纯化相应产物,得到白色固体产物28.6mg,产率91%,93%ee。1HNMR(600MHz,CDCl3):δ7.31-7.27(m,2H),7.23-7.19(m,3H),5.88(d,J=1.2Hz,0.29H),5.81(d,J=0.6Hz,0.67H),4.71(s,0.67H),4.39(d,J=1.8Hz,0.30H),4.17(q,J=3.6Hz,0.31H),4.04(t,J=9.0Hz,0.72H),3.87(s,1H),3.79(s,2H),2.69-2.65(m,0.32H),2.44(dd,J=13.8,3.0Hz,0.34H),2.33(d,J=8.4Hz,1.43H),2.25(s,1H),2.21(s,2H).
实施例13
在反应管中,加入500μL Co(ClO4)2·6H2O(0.05mol%)和500μL L1(0.05mol%),然后在真空下去除THF。加入β,γ-不饱和α-酮酯2a(19.0mg,0.1mmol)和二氯甲烷(1.0mL),在25℃下搅拌反应0.5h。随后在25℃下加入1,3-环己二酮(12.3mg,0.11mmol)搅拌反应,直到1,3-环己二酮消耗完(薄层色谱检测)。最后,用快速过柱色谱法(Pet/EtOAc=5/1-2/1)直接纯化相应产物,白色固体产物26.3mg,产率为87%,96%ee。
1HNMR(600MHz,CDCl3):δ7.27-7.24(m,2H),7.17-7.15(m,3H),4.72(s,0.68H),4.31(s,0.38H),4.10-4.09(m,0.35H),3.90(t,J=8.4Hz,0.69H),3.84(s,1H),3.74(s,2H),2.63-2.34(m,4H),2.29-2.22(m,2H),2.11-1.99(m,2H).
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (9)
1.手性吡啶-吡咯并咪唑啉酮三齿氮配体,其特征在于,结构通式为:或其对映异构体;其中:n=0-4;R为C1-C8烷基、二苯基甲基、取代苯基或取代萘基,所述取代为氢、C1-C8烷基、C1-C8烷氧基、三氟甲基、硝基、腈基、卤素、三氟甲基中的一种或多种;R'为氢、卤素、C1-C8烷氧基、苄氧基、羟基、磺酸酯基、叠氮基、C1-C4烷硅氧基、C1-C4烷酰氧基或C1-C4烷酰硫基。
2.根据权利要求1所述手性吡啶-吡咯并咪唑啉酮三齿氮配体,其特征在于:n=1,2;R为C1-C8烷基、苯基、三氟甲基苯基、二苯甲基苯基;R'为羟基、氢、甲氧基、苄氧基、甲磺酸酯基、氟、乙酰硫基、叠氮基、三甲基硅氧基或二甲基叔丁基硅氧基。
3.根据权利要求1所述手性吡啶-吡咯并咪唑啉酮三齿氮配体,其特征在于,具体结构如下:
4.如权利要求1所述的手性吡啶-吡咯并咪唑啉酮三齿氮配体在4-羟基香豆素与β,γ-不饱和α-酮酸酯迈克尔加成反应中的应用。
5.根据权利要求4所述的应用,其特征在于,包括如下步骤:
以4-羟基香豆素和β,γ-不饱和α-酮酸酯为原料,在路易斯酸催化剂和手性吡啶-吡咯并咪唑啉酮三齿氮配体存在下,有机溶剂中反应,得到迈克尔加成产物;其中:R1选自苯基、取代苯基、取代噻吩基,所述取代为氢、卤素、C1-C4烷基、C1-C4烷氧基、硝基、三氟甲基、硝基、腈基中的一种或多种;R2选自C1-C4烷基。
6.根据权利要求5所述的应用,其特征在于:所述路易斯酸催化剂为Cu(ClO4)2·6H2O、Co(ClO4)2·6H2O、Cu(OTf)2或Ni(OTf)2。
7.根据权利要求5所述的应用,其特征在于:所述三齿氮配体与4-羟基香豆素摩尔比为0.005-0.0005:1。
8.根据权利要求5所述的应用,其特征在于:所述有机溶剂为二氯甲烷或四氢呋喃;反应温度为0-30℃。
9.如权利要求1所述手性吡啶-吡咯并咪唑啉酮三齿氮配体的制备方法,其特征在于,包括如下步骤:以反-3-取代-L-脯氨酰胺和吡啶-2,6-二甲醛为原料,经过一步缩合,得到手性吡啶-吡咯并咪唑啉酮三齿氮配体。
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