CN115260178A - 一种吡啶骨架ncn噁唑啉类配体的合成方法和应用 - Google Patents
一种吡啶骨架ncn噁唑啉类配体的合成方法和应用 Download PDFInfo
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- 239000003446 ligand Substances 0.000 title claims abstract description 53
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 40
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- 150000001414 amino alcohols Chemical class 0.000 claims abstract description 17
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006722 reduction reaction Methods 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000005695 Ammonium acetate Substances 0.000 claims abstract description 8
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 8
- 229940043376 ammonium acetate Drugs 0.000 claims abstract description 8
- 235000019257 ammonium acetate Nutrition 0.000 claims abstract description 8
- ZBYYWKJVSFHYJL-UHFFFAOYSA-L cobalt(2+);diacetate;tetrahydrate Chemical compound O.O.O.O.[Co+2].CC([O-])=O.CC([O-])=O ZBYYWKJVSFHYJL-UHFFFAOYSA-L 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 21
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 16
- -1 2, 6-disubstituted-3, 5-pyridine dicarboxylic acid ester Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000012298 atmosphere Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000006459 hydrosilylation reaction Methods 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- GAURFLBIDLSLQU-UHFFFAOYSA-N diethoxy(methyl)silicon Chemical compound CCO[Si](C)OCC GAURFLBIDLSLQU-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 5
- 238000000605 extraction Methods 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000006555 catalytic reaction Methods 0.000 abstract description 8
- DIIWSYPKAJVXBV-UHFFFAOYSA-N Hantzch dihydropyridine Natural products CCOC(=O)C1=CC(C(=O)OCC)=C(C)N=C1C DIIWSYPKAJVXBV-UHFFFAOYSA-N 0.000 abstract description 5
- LJXTYJXBORAIHX-UHFFFAOYSA-N diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1 LJXTYJXBORAIHX-UHFFFAOYSA-N 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- 239000007787 solid Substances 0.000 description 19
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 15
- 239000012230 colorless oil Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000003921 oil Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- YOCRKHKJFCWTHG-UHFFFAOYSA-N 2-[6-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC(C=2OCCN=2)=N1 YOCRKHKJFCWTHG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 150000002918 oxazolines Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- BSCXJHRXVLREBO-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;quinoline Chemical compound C1CN=CO1.N1=CC=CC2=CC=CC=C21 BSCXJHRXVLREBO-UHFFFAOYSA-N 0.000 description 1
- OGRXSKNMJDPXLY-UHFFFAOYSA-N C(C)(C)C=1NC(=C(CC=1C(=O)OCC)C(=O)OCC)C(C)C Chemical compound C(C)(C)C=1NC(=C(CC=1C(=O)OCC)C(=O)OCC)C(C)C OGRXSKNMJDPXLY-UHFFFAOYSA-N 0.000 description 1
- BZAMECPRQGPGIP-UHFFFAOYSA-N C(C)OC(=O)C=1C(=NC(=C(C=1)C(=O)OCC)C(C)C)C(C)C Chemical compound C(C)OC(=O)C=1C(=NC(=C(C=1)C(=O)OCC)C(C)C)C(C)C BZAMECPRQGPGIP-UHFFFAOYSA-N 0.000 description 1
- BZVUMFGFHSYZQQ-UHFFFAOYSA-N C1(=CC=CC=C1)C1=NC(=C(C=C1C(=O)OCC)C(=O)OCC)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)C1=NC(=C(C=C1C(=O)OCC)C(=O)OCC)C1=CC=CC=C1 BZVUMFGFHSYZQQ-UHFFFAOYSA-N 0.000 description 1
- 238000003775 Density Functional Theory Methods 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 238000003540 Heck arylation reaction Methods 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SJPWEMZQXWYDSY-SNVBAGLBSA-N ethyl (3r)-3-phenylbutanoate Chemical compound CCOC(=O)C[C@@H](C)C1=CC=CC=C1 SJPWEMZQXWYDSY-SNVBAGLBSA-N 0.000 description 1
- FLTSWHBPHUGGDZ-LLVKDONJSA-N ethyl (3r)-3-phenylpentanoate Chemical compound CCOC(=O)C[C@@H](CC)C1=CC=CC=C1 FLTSWHBPHUGGDZ-LLVKDONJSA-N 0.000 description 1
- CFNFDUJWLXMVHH-MDZDMXLPSA-N ethyl (e)-3-(4-methoxyphenyl)but-2-enoate Chemical group CCOC(=O)\C=C(/C)C1=CC=C(OC)C=C1 CFNFDUJWLXMVHH-MDZDMXLPSA-N 0.000 description 1
- BSXHSWOMMFBMLL-MDZDMXLPSA-N ethyl (e)-3-phenylbut-2-enoate Chemical compound CCOC(=O)\C=C(/C)C1=CC=CC=C1 BSXHSWOMMFBMLL-MDZDMXLPSA-N 0.000 description 1
- KUMGWHQGAMTKMB-ZHACJKMWSA-N ethyl (e)-3-phenylpent-2-enoate Chemical compound CCOC(=O)\C=C(/CC)C1=CC=CC=C1 KUMGWHQGAMTKMB-ZHACJKMWSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
- B01J31/182—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine comprising aliphatic or saturated rings
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- C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
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Abstract
本发明涉及一种吡啶骨架NCN噁唑啉类配体及其合成方法和应用，在吡啶的间位引入手性噁唑啉基团，其结构通式为：
其中，R1独立选自于H,Me,iPr,Ph；其中，R2独立选自于Ph,Bn,iPr,tBu。制备方法包括以β‑酮酯为原料，通过醋酸铵和多聚甲醛的作用生成汉斯(Hantzsch)酯，再通过四水合醋酸钴及N‑羟基邻苯二甲酰亚胺(NHPI)的作用氧化生成2,6‑二取代‑3,5‑吡啶二甲酸酯，最后与手性氨基醇作用，生成手性噁唑啉配体。与现有技术相比，本发明的合成扩充了手性噁唑啉配体的范围，为不对称催化领域提供了一种新的配体。本发明所述的合成方法简单高效、合成条件温和、易于操作且重复性好。制得的手性配在用于α,β‑不饱和酯的不对称硅氢还原反应时，具有较高的对映选择性和产率。
Description
技术领域
本发明涉及有机合成领域，尤其是涉及一种吡啶骨架NCN噁唑啉配体的合成方法和应用。
背景技术
噁唑啉类配体是近年来应用较为广泛的配体之一。自1986年Brunner小组开发了第一个含手性噁唑啉的配体(Pyox)以来(Journal of Organometallic Chemistry 1986,316,C1-C3.)，多种噁唑啉环的配体已经广泛合成应用于不对称催化反应中并取得了巨大的成功(Chemical Society Reviews 2018,47(5),1783-1810.)。
传统的吡啶骨架噁唑啉配体多为在吡啶的邻位上生成一个或两个噁唑啉。2008年陆熙炎院士在催化体系中使用手性Pyox配体开发了第一个钯催化的芳基硼与亚胺的不对称加成(Advanced Synthesis&Catalysis 2008,350(2),249-253.)。2012年Sigman教授使用5-三氟甲基-pyox手性配体通过氧化—还原策略对无环烯醇进行了不对称Heck-芳基化(Science 2012,338(6113),1455-1458.)。2013年Michael等人使用Pybox或喹啉—噁唑啉配体实现了烯烃的不对称双胺化(Journal of the American Chemical Society 2013,135(24),8854-8856.)。
有关在吡啶间位引入噁唑啉的方法还没有人报道过。2014年Cundari教授通过对消旋的Ir-Phebox络合物进行模拟DFT计算，考察了芳环上引入杂原子对它的影响。证明了当吡啶间位含有噁唑啉(ParaNbox)时确实与吡啶邻位含有噁唑啉(Pybox)时有很明显的活性差异，但是并没有实际合成出该类配体(Organometallics 2014,33(22),6413-6419.)。因此我们期望能够探索到合适的方法实现在吡啶间位引入噁唑啉。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种吡啶骨架NCN噁唑啉配体的合成方法和应用，该吡啶骨架NCN噁唑啉配体含有新颖的配体骨架，在吡啶间位引入噁唑啉，对现有的噁唑啉配体库进行扩展，有望能应用在不对称催化领域，且具有合成条件温和、易于操作且重复性好等优点。
本发明的目的可以通过以下技术方案来实现：
一种吡啶骨架NCN噁唑啉配体，其结构通式为：
其中，R1独立选自于H,Me,iPr,Ph；
其中，R2独立选自于Ph,Bn,iPr,tBu。
本发明还提供了上述吡啶骨架NCN噁唑啉配体的制备方法，包括以下步骤：
S11、在N2氛围下，将β-酮酯、多聚甲醛、醋酸铵置于85℃下反应4-5个小时，得到汉斯(Hantzsch)酯；
S12、空气下，将汉斯(Hantzsch)酯、四水合醋酸钴、N-羟基邻苯二甲酰亚胺(NHPI)置于乙腈中，40℃下过夜反应，得到2,6-二取代-3,5-吡啶二甲酸酯；
S13、在N2氛围下，将2,6-二取代-3,5-吡啶二甲酸酯、手性氨基醇、NaH置于预热的110-120℃油浴中反应30min，得到手性氨基醇中间体；
S14、在N2氛围下，将手性氨基醇中间体置于-78℃下，在二乙胺基三氟化硫(DAST)作用下得到目标产物。
进一步地，所述β-酮酯、多聚甲醛、醋酸铵的摩尔比为1:0.5:0.75；
所述汉斯(Hantzsch)酯、四水合醋酸钴、N-羟基邻苯二甲酰亚胺(NHPI)的摩尔比为1:0.05:0.1；
所述2,6-二取代-3,5-吡啶二甲酸酯与手性氨基醇的摩尔比为1:(2-3)；所述手性氨基醇中间体与DAST的摩尔比为1:2.3。
本发明还提供一种手性吡啶骨架NCN噁唑啉类配体的应用，将所述吡啶骨架NCN噁唑啉配体用于α,β-不饱和酯的不对称硅氢还原反应。
具体地，所述α,β-不饱和酯的不对称硅氢还原的方法为：无水无氧操作，氮气氛围下在无水甲苯中，吡啶骨架NCN噁唑啉配体与RhCl3·3H2O在50℃下搅拌1-2h，然后加入α,β-不饱和酯，50℃下缓慢滴加甲基二乙氧基硅烷，反应0.5h小时后，于0℃下加入HCl继续搅拌0.5h，后用乙酸乙酯萃取，无水硫酸钠干燥，过滤收集滤液，旋干后200-300目硅胶过柱(PE/EA＝150:1)得到还原产物。其中，吡啶骨架NCN噁唑啉配体、RhCl3·3H2O、α,β-不饱和酯、甲基二乙氧基硅烷和HCl的摩尔比为1：1：100：150：100。无水甲苯与盐酸用量的体积比为1:1，盐酸的浓度为1N。
进一步地，所述的α,β-不饱和酯具有以下结构通式：
其中，R1独立选自于氢、甲基、甲氧基、卤素、三氟甲基、苯基中的一种；R2独立选自于甲基、乙基中的一种；R3独立选自于甲基、乙基、苯基中的一种。
还原产物具有如下结构通式：
其中，R1独立选自于氢、甲基、甲氧基、卤素、三氟甲基、苯基中的一种；R2独立选自于甲基、乙基中的一种；R3独立选自于甲基、乙基、苯基中的一种。
与现有技术相比，本发明具有以下优点：
(1)本发明以β-酮酯为原料，通过醋酸铵和多聚甲醛的作用生成汉斯(Hantzsch)酯，再通过四水合醋酸钴及N-羟基邻苯二甲酰亚胺(NHPI)的作用氧化生成2,6-二取代-3,5-吡啶二甲酸酯，最后与手性氨基醇作用，生成手性噁唑啉配体。与现有噁唑啉配体相比，本发明的合成扩充了手性噁唑啉配体的范围，为不对称催化领域提供了一种新的配体。
(2)本发明所述的合成方法简单高效、合成条件温和、易于操作且重复性好(2)本发明制得的手性配体在用于α,β-不饱和酯的不对称硅氢还原反应时，具有较高的对映选择性和产率。。
附图说明
图1为实施例1中5g的单晶衍射(X-ray)数据的示意图。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
以下实施例中采用的所有溶剂、试剂、金属盐都是从商业来源购买。
所有目标化合物采用NMR(1H)、NMR(13C)、NMR(19F)、FT-IR光谱数据以及HRMS质谱数据表征。
以下实施例中的目标产物的收率均为分离产率。
以下实施例中的目标产物的对映选择性通过HPLC色谱分析测定。
实施例1
吡啶骨架NCN噁唑啉配体的合成，包括以下步骤：
步骤S11按以下反应方程式反应：
具体操作步骤为：
无水无氧操作，N2气氛围下将多聚甲醛、醋酸铵加入50ml Schlenk反应瓶中，加入β-酮酯，置于85℃油浴中反应。4h小时后加入冰水，后用DCM萃取3次，无水硫酸钠干燥，过滤，滤液旋干后硅胶过柱(PE:EA＝20:1)。所述β-酮酯、多聚甲醛、醋酸铵的摩尔比为1:0.5:0.75。
产物2a为2,6-二异丙基-1,4-二氢吡啶-3,5-二羧酸二乙酯，白色固体，54％收率。
1H NMR(400MHz,CDCl3)δ5.73(s,1H),4.17(q,J＝7.2Hz,4H),4.10(dd,J＝14.0,6.8Hz,2H),3.27(s,2H),1.29(t,J＝7.2Hz,6H),1.10(d,J＝6.8Hz,12H).
步骤S12按以下反应方程式反应：
具体操作步骤为：
空气下，将汉斯(Hantzsch)酯、四水合醋酸钴、N-羟基邻苯二甲酰亚胺(NHPI)加入到100ml圆底烧瓶中，加入40ml乙腈，后置于40℃油浴中过夜反应。直接旋干后硅胶过柱(PE:EA＝20:1)。所述汉斯(Hantzsch)酯、四水合醋酸钴、N-羟基邻苯二甲酰亚胺(NHPI)的摩尔比为1:0.05:0.1。
产物3a为2,6-二甲基吡啶-3,5-二羧酸二乙酯，白色固体，75％收率。
1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ8.67(s,1H),4.39(q,J＝7.2Hz,4H),2.84(s,6H),1.41(t,J＝7.2Hz,6H).
产物3b为2,6-二异丙基吡啶-3,5-二羧酸二乙酯，白色固体，73％收率。
1H NMR(400MHz,CDCl3)δ8.46(s,1H),4.40(q,J＝7.2Hz,4H),3.88(m,2H),1.42(t,J＝7.2Hz,6H),1.30(d,J＝6.8Hz,12H).
产物3c为2,6-二苯基吡啶-3,5-二羧酸二乙酯，白色固体，73％收率。
1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.97–7.59(m,4H),7.47–7.38(m,6H),4.21(q,J＝7.2Hz,4H),1.10(t,J＝7.2Hz,6H).
步骤S13按以下反应方程式反应：
具体操作步骤为：
无水无氧操作，N2气氛围下将2,6-二取代-3,5-吡啶二甲酸酯与手性氨基醇加入到25ml Schlenk瓶中，置于预热的110℃油浴中，待熔化后，加入NaH，加热至120℃反应30min。后处理可以直接加入DCM，后过滤收集滤饼，也可以硅胶过柱(DCM:MeOH＝40:1)。所述2,6-二取代-3,5-吡啶二甲酸酯与手性氨基醇的摩尔比为1:(2-3)。
产物4a为N3,N5-双((R)-2-羟基-1-苯乙基)-2,6-二甲基吡啶-3,5-二甲酰胺，白色固体，98.1％收率。
1H NMR(400MHz,CD3OD)δ7.85(s,1H),7.42–7.33(m,8H),7.32–7.26(m,2H),5.19(dd,J＝8.4,5.6Hz,2H),3.88–3.75(m,4H),2.55(s,6H)；13C{1H}NMR(101MHz,CD3OD)δ170.24,157.64,140.99,135.97,130.67,129.64,128.64,128.08,65.99,57.74,22.42；IRv(neat,cm-1):3601.94,2939.94,2865.95,1453.72,1295.57,1039.29,699.38；HRMS(ESI,m/z):calcd for C25H28N3O4 +[M+H]+:434.2074；found 434.2079.
产物4b为N3,N5-双((S)-1-羟基-3-甲基丁-2-基)-2,6-二甲基吡啶-3,5-二甲酰胺，白色固体，89.7％收率。
1H NMR(400MHz,CD3OD)δ7.78(s,1H),3.92(td,J＝6.8,4.4Hz,2H),3.73(dd,J＝11.2,4.0Hz,2H),3.63(dd,J＝11.6,6.8Hz,2H),2.61(s,6H),1.96(dq,J＝13.6,6.8Hz,2H),1.02(dd,J＝15.6,6.8Hz,12H)；13C{1H}NMR(101MHz,CD3OD)δ170.71,157.23,135.79,131.06,63.07,58.73,30.21,22.47,20.16,19.06；IR v(neat,cm-1):3077.83,2962.24,2875.18,1448.16,1370.50,1316.41,1078.75,748.69；HRMS(ESI,m/z):calcd forC19H32N3O4 +[M+H]+:366.2387；found 366.2381.
产物4c为N3,N5-双((S)-1-羟基-3,3-二甲基丁烷-2-基)-2,6-二甲基吡啶-3,5-二甲酰胺，白色固体，89.9％收率。
1H NMR(400MHz,CD3OD)δ7.79(s,1H),4.01(dd,J＝9.2,3.2Hz,2H),3.90(dd,J＝11.6,3.6Hz,2H),3.52(dd,J＝11.2,9.2Hz,2H),2.63(s,6H),1.01(s,18H)；13C{1H}NMR(101MHz,CD3OD)δ171.22,157.21,135.79,131.25,62.20,61.67,35.01,27.38,22.49；IR v(neat,cm-1):3076.13,2964.18,2873.54,1368.63,1293.34,1158.69,996.68；HRMS(ESI,m/z):calcd for C21H36N3O4 +[M+H]+:394.2700；found 394.2705.
产物4d为N3,N5-双((S)-1-羟基-3-苯基丙-2-基)-2,6-二甲基吡啶-3,5-二甲酰胺，白色固体，90.4％收率。
1H NMR(400MHz,CD3OD)δ7.47(s,1H),7.28(d,J＝4.8Hz,8H),7.24–7.17(m,2H),4.39(dq,J＝11.2,5.6Hz,2H),3.66(qd,J＝11.2,5.2Hz,4H),3.04(dd,J＝13.6,5.6Hz,2H),2.76(dd,J＝14.0,9.6Hz,2H),2.28(s,6H)；13C{1H}NMR(101MHz,CD3OD)δ170.24,157.16,139.79,135.47,130.80,130.37,129.45,127.49,64.63,54.66,38.04,22.07；IR v(neat,cm-1):3060.91,2921.12,2854.56,1441.68,1364.85,1283.85,1039.68,699.84,558.79；HRMS(ESI,m/z):calcd for C27H32N3O4 +[M+H]+:462.2387；found 462.2385.
产物4e为N3,N5-双((R)-2-羟基-1-苯乙基)-2,6-二异丙基吡啶-3,5-二甲酰胺，白色固体，86.2％收率。
1H NMR(400MHz,CD3OD)δ7.68(s,1H),7.43–7.33(m,8H),7.32–7.26(m,2H),5.18(dd,J＝8.0,5.4Hz,2H),3.80(qd,J＝11.2,6.8Hz,4H),3.28(dd,J＝11.6,4.8Hz,2H),1.22(dd,J＝6.8,4.8Hz,12H)；13C{1H}NMR(101MHz,CD3OD)δ171.17,165.55,141.10,134.70,129.58,129.23,128.59,128.06,66.05,57.73,33.79,22.79,22.64；HRMS(ESI,m/z):calcdfor C29H36N3O4 +[M+H]+:490.2700；found 490.2702.
产物4f为N3,N5-双((S)-1-羟基-3-甲基丁-2-基)-2,6-二异丙基吡啶-3,5-二甲酰胺，白色固体，88.3％收率。
1H NMR(400MHz,CD3OD)δ7.61(s,1H),3.92(td,J＝6.8,4.6Hz,2H),3.71(dd,J＝11.0,4.6Hz,2H),3.62(dd,J＝11.2,6.8Hz,2H),3.46–3.37(m,2H),1.96(dq,J＝13.6,6.8Hz,2H),1.35–1.21(m,12H),1.01(dd,J＝19.0,6.8Hz,12H)；13C{1H}NMR(101MHz,CD3OD)δ171.68,165.17,134.68,129.61,63.14,58.65,33.89,30.17,22.95,22.70,20.18,18.92；HRMS(ESI,m/z):calcd for C23H40N3O4 +[M+H]+:422.3013；found 422.3016.
产物4g为N3,N5-双((R)-2-羟基-1-苯乙基)-2,6-二苯基吡啶-3,5-二甲酰胺，白色固体，88％收率。
1H NMR(400MHz,CD3OD)δ8.09(s,1H),7.69–7.64(m,4H),7.39–7.33(m,2H),7.32–7.23(m,10H),7.20–7.15(m,4H),5.10(t,J＝6.4Hz,2H),3.74–3.70(m,4H).
步骤S14按以下反应方程式反应：
具体操作步骤为：
无水无氧操作，N2气氛围下将氨基醇加入50ml Schlenk瓶中，加入20ml DCM，-78℃(干冰丙酮浴)下缓慢滴加二乙胺基三氟化硫(DAST)。4-6h小时后，加入NaHCO3溶液淬灭，DCM萃取3次，NaCl洗涤，无水硫酸钠干燥，过滤，滤液旋干后硅胶过柱(PE:EA＝2:1)。手性氨基醇中间体与二乙胺基三氟化硫的摩尔比为1:2.3。
产物5a为(4R,4'R)-2,2'-(2,6-二甲基吡啶-3,5-二基)双(4-苯基-4,5-二氢噁唑)，白色固体(mp:97-98℃)，81.6％收率。
1H NMR(400MHz,CDCl3)δ8.68(s,1H),7.41–7.35(m,4H),7.34–7.28(m,6H),5.47(dd,J＝10.0,8.4Hz,2H),4.78(dd,J＝10.0,8.0Hz,2H),4.24(t,J＝8.4Hz,2H),2.94(s,6H)；13C{1H}NMR(101MHz,CDCl3)δ163.40,160.34,142.27,139.60,128.96,127.84,126.75,120.27,74.41,70.84,25.33；IR v(neat,cm-1):3028.63,2963.96,2901.21,1453.69,1268.20,1066.13,748.98,699.00；HRMS(ESI,m/z):calcd for C25H24N3O2 +[M+H]+:398.1863；found 398.1865.
产物5b为(4S,4'S)-2,2'-(2,6-二甲基吡啶-3,5-二基)双(4-异丙基-4,5-二氢噁唑)，白色固体(mp:33-35℃)，73.4％收率。
1H NMR(400MHz,CDCl3)δ8.44(s,1H),4.37(t,J＝8.0Hz,2H),4.18–4.05(m,4H),2.84(s,6H),1.84(dq,J＝13.2,6.8Hz,2H),1.03(d,J＝6.8Hz,6H),0.94(d,J＝6.8Hz,6H)；13C{1H}NMR(101MHz,CDCl3)δ161.95,159.69,139.05,120.54,73.45,69.85,33.09,25.00,18.98,18.46；IR v(neat,cm-1):2960.00,2927.44,2873.47,1457.15,1366.14,1271.18,1066.00,951.62；HRMS(ESI,m/z):calcd for C19H28N3O2 +[M+H]+:330.2176；found330.2172.
产物5c为(4S,4'S)-2,2'-(2,6-二甲基吡啶-3,5-二基)双(4-(叔丁基)-4,5-二氢噁唑)，白色固体(mp:121-123℃)，72.8％收率。
1H NMR(400MHz,CDCl3)δ8.41(s,1H),4.30(t,J＝9.2Hz,2H),4.18(t,J＝8.0Hz,2H),4.09(t,J＝9.2Hz,2H),2.86(s,6H),0.95(s,18H)；13C{1H}NMR(101MHz,CDCl3)δ161.80,159.72,138.89,120.50,77.09,68.25,34.12,26.02,25.04；IR v(neat,cm-1):2958.88,2903.60,2867.42,1477.18,1455.93,1304.78,1051.48,941.02；HRMS(ESI,m/z):calcd for C21H32N3O2 +[M+H]+:358.2489；found 358.2483.
产物5d为(4S,4'S)-2,2'-(2,6-二甲基吡啶-3,5-二基)双(4-苄基-4,5-二氢噁唑)，白色固体(mp:79-80℃)，76.5％收率。
1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.35–7.19(m,10H),4.69–4.58(m,2H),4.32(t,J＝8.8Hz,2H),4.12(t,J＝8.0Hz,2H),3.21(dd,J＝13.6,5.2Hz,2H),2.84(s,6H),2.77(dd,J＝14.0,8.4Hz,2H)；13C{1H}NMR(101MHz,CDCl3)δ162.62,159.87,139.25,137.90,129.45,128.68,126.72,120.37,71.36,68.59,41.89,25.06；IR v(neat,cm-1):3046.63,2915.26,2892.81,2362.38,1954.70,1880.38,1003.25,698.33；HRMS(ESI,m/z):calcdfor C27H28N3O2 +[M+H]+:426.2176；found 426.2179.
产物5e为(4R,4'R)-2,2'-(2,6-二异丙基吡啶-3,5-二基)双(4-苯基-4,5-二氢噁唑)，白色固体(mp:31-33℃)，83.3％收率。
1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.42–7.35(m,4H),7.34–7.28(m,6H),5.46(dd,J＝10.0,8.4Hz,2H),4.78(dd,J＝10.4,8.4Hz,2H),4.22(t,J＝8.4Hz,2H),4.14(dt,J＝13.6,6.8Hz,2H),1.32(d,J＝6.8Hz,12H)；13C{1H}NMR(101MHz,CDCl3)δ168.06,163.78,142.45,139.79,128.91,127.75,126.74,118.76,74.48,70.79,32.82,22.44,22.25；IR v(neat,cm-1):2962.53,2925.33,1544.18,1069.17,938.78,698.50；HRMS(ESI,m/z):calcdfor C29H32N3O2 +[M+H]+:454.2489；found 454.2482.
产物5f为(4R,4'R)-2,2'-(2,6-二异丙基吡啶-3,5-二基)双(4-异丙基-4,5-二氢噁唑)，白色固体(mp:28-30℃)，82.1％收率。
1H NMR(400MHz,CDCl3)δ8.26(s,1H),4.42–4.29(m,2H),4.17–4.05(m,4H),4.02–3.90(m,2H),1.94–1.76(m,2H),1.26(dd,J＝9.6,6.8Hz,12H),1.02(d,J＝6.8Hz,6H),0.94(d,J＝6.8Hz,6H)；13C NMR(101MHz,CDCl3)δ167.33,162.37,139.14,119.11,73.27,69.88,33.05,32.69,22.39,22.16,18.97,18.41；IR v(neat,cm-1):2960.80,1544.45,1274.98,1261.03,1069.32,947.73,735.33；HRMS(ESI,m/z):calcd for C23H36N3O2 +[M+H]+:386.2802；found 386.2808.
产物5g为(4R,4'R)-2,2'-(2,6-二苯基吡啶-3,5-二基)双(4-苯基-4,5-二氢噁唑)，白色固体，85％收率。
1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.79(dd,J＝6.6,2.9Hz,4H),7.49–7.43(m,6H),7.38(t,J＝7.4Hz,4H),7.34–7.26(m,5H),5.36(t,J＝9.4Hz,2H),4.63(dd,J＝10.2,8.6Hz,2H),4.11(t,J＝8.6Hz,2H).13C NMR(101MHz,CDCl3)δ164.66,159.27,141.73,141.58,139.60,129.31,129.14,128.92,128.25,127.82,126.81,121.22,75.28,70.39.
(4R,4'R)-2,2'-(2,6-二苯基吡啶-3,5-二基)双(4-苯基-4,5-二氢噁唑)的X-ray数据：
产物5g的结构鉴定是基于化合物的1H NMR、13C NMR核磁共振谱以及X-ray单晶衍射数据(如图1所示)分析而确定的。
产物5h为3,5-双((R)-4-苯基-4,5-二氢噁唑-2-基)吡啶，白色固体，90％收率。
1H NMR(400MHz,CDCl3)δ9.36(s,2H),8.91(s,1H),7.41–7.34(m,4H),7.34–7.28(m,6H),5.44(dd,J＝10.2,8.4Hz,2H),4.85(dd,J＝10.2,8.4Hz,2H),4.33(t,J＝8.4Hz,2H).
应用实施例
将上述实施例1制得的手性吡啶骨架NCN噁唑啉类配体用于α,β-不饱和酯的不对称硅氢还原反应。具体步骤如下：
(1)α,β-不饱和酯的制备：
方法一：按以下反应方程式反应：
具体操作步骤为:
无水无氧操作，氮气氛围下将NaH(16mmol)加入100mL Schlenk瓶中，加入THF(50mL)，置于0℃下缓慢滴加磷酸酯叶立德(15mmol)，搅拌20min后将酮(10mmol)加入体系中恢复至室温过夜反应。带反应完全后加入冰水淬灭，用EA萃取三次，无水硫酸钠干燥，收集旋干过柱(PE/EA＝150/1)。
产物6a为(E)-3-苯基丁-2-烯酸乙酯，无色油状物。
1H NMR(400MHz,CDCl3)δ7.51–7.44(m,2H),7.41–7.30(m,3H),6.14(s,1H),4.22(q,J＝7.2Hz,2H),2.58(s,3H),1.32(t,J＝7.2Hz,3H).
产物6b为(E)-3-(4-甲氧基苯基)丁-2-烯酸乙酯，无色油状物。
1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),6.11(s,1H),4.20(q,J＝7.2Hz,2H),3.83(s,3H),2.56(s,3H),1.31(t,J＝7.2Hz,3H).
产物6c为(E)-3-(4-氟苯基)丁-2-烯酸乙酯，无色油状物。
1H NMR(400MHz,CDCl3)δ7.48–7.37(m,2H),7.01(t,J＝8.4Hz,2H),6.06(s,1H),4.18(q,J＝7.2Hz,2H),2.52(s,3H),1.28(t,J＝7.2Hz,3H)。
产物6d为(E)-3-苯基戊-2-烯酸乙酯，无色油状物。
1H NMR(400MHz,CDCl3)δ7.48–7.41(m,2H),7.41–7.32(m,3H),6.02(s,1H),4.21(q,J＝6.8Hz,2H),3.11(q,J＝7.6Hz,2H),1.32(t,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H)。
方法二：按以下反应方程式反应：
具体操作步骤为:
无水无氧操作，氮气氛围下将对甲氧基苯硼酸(16.6mmol)、苯乙炔乙酸乙酯(10.3mmol)、醋酸亚铜(0.059mmol)置于100mL Schlenk瓶中室温下过夜反应。待反应完全后用硅藻土过滤，收集滤液，旋干后过柱(PE/EA＝10/1)。
产物6e为(E)-3-苯基-3-(对甲苯基)丙烯酸乙酯，无色油状物。
1H NMR(400MHz,CDCl3)δ7.41–7.36(m,3H),7.25–7.18(m,4H),6.84(d,J＝9.2Hz,2H),6.31(s,1H),4.04(q,J＝7.8Hz,2H),3.81(s,3H),1.11(t,J＝7.2Hz,3H).
(2)不对称硅氢还原反应：
按以下反应方程式反应：
具体操作步骤为:
无水无氧操作，氮气氛围下在1mL无水甲苯中，将实施例1制得的化合物5b(0.011mmol)与RhCl3 .3H2O(0.01mmol)在50℃下搅拌1-2h，然后加入1mmol上述方法一及方法二制得的化合物6a-6e，50℃下缓慢滴加1.5mmol甲基二乙氧基硅烷，反应0.5h小时后0℃下加入1mL 1N HCl继续搅拌0.5h，后用乙酸乙酯萃取3次，无水硫酸钠干燥，过滤收集滤液，旋干后200-300目硅胶过柱(PE/EA＝150:1)，还原产物7a-e的对映选择性通过高效液相色谱分析测定。
7a为(R)-3-苯基丁酸乙酯，无色油状物，98％ee，95％收率。
[α]D 25＝-23.50(c＝0.17,CHCl3)；1H NMR(400MHz,CDCl3)δ7.32(t,J＝7.6Hz,2H),7.28–7.19(m,3H),4.10(q,J＝7.2Hz,2H),3.37–3.26(m,1H),2.60(qd,J＝14.8,7.2Hz,2H),1.33(d,J＝6.8Hz,3H),1.20(t,J＝7.2Hz,3H)；13C{1H}NMR(101MHz,CDCl3)δ172.31,145.72,128.46,126.75,126.37,60.21,42.97,36.53,21.81,14.17.
7b为(R)-3-(4-甲氧基苯基)丁酸乙酯，无色油状物，96％ee，95％收率。
[α]D 25＝-3.43(c＝0.12,CHCl3)；1H NMR(400MHz,CDCl3)δ7.14(d,J＝7.2Hz,2H),6.84(d,J＝7.2Hz,2H),4.07(q,J＝7.2Hz,1H),3.78(s,3H),3.33–3.14(m,1H),2.65–2.43(m,2H),1.27(d,J＝7.2Hz,3H),1.18(t,J＝6.8Hz,3H；13C{1H}NMR(101MHz,CDCl3)δ172.59,158.14,137.95,127.77,113.91,60.35,55.34,43.36,35.84,22.11,14.31.
7c为(R)-3-(4-氟苯基)丁酸乙酯，无色油状物，96％ee，92％收率。
1H NMR(400MHz,CDCl3)δ7.17(t,J＝6.4Hz,2H),6.97(t,J＝8.4Hz,2H),4.06(q,J＝6.8,2H),3.26(dd,J＝14.4,7.2Hz,1H),2.62–2.44(m,2H),1.27(d,J＝7.2Hz,3H),1.16(t,J＝6.8Hz,3H)；13C{1H}NMR(101MHz,CDCl3)δ172.29,162.71,160.29,141.41(d,J＝3.1Hz),128.26(d,J＝7.9Hz),115.27(d,J＝21.2Hz),60.40,43.17,35.94,22.08,14.24；19F NMR(376MHz,CDCl3)δ-116.93.
7d为(R)-3-苯基戊酸乙酯，无色油状物，96％ee，92％收率。
1H NMR(400MHz,CDCl3)δ7.32–7.24(m,2H),7.23–7.15(m,3H),4.03(q,J＝7.2Hz,2H),3.05–2.95(m,1H),2.60(qd,J＝14.8,7.2Hz,2H),1.78–1.54(m,2H),1.13(t,J＝7.2Hz,3H),0.79(t,J＝7.2Hz,3H)；13C{1H}NMR(101MHz,CDCl3)δ172.66,144.01,128.45,127.67,126.49,60.33,44.07,41.64,29.26,14.25,12.06.
7e为(S)-3-苯基-3-(对甲苯基)丙酸甲酯，无色油状物，98％ee，98％收率。
[α]D 25＝-1.00(c＝0.10,CHCl3)；1H NMR(400MHz,CDCl3)δ7.32–7.12(m,7H),6.86–6.79(m,2H),4.51(t,J＝8.0Hz,1H),4.04(q,J＝7.2Hz,2H),3.77(s,3H),3.02(d,J＝8.0Hz,2H),1.12(t,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ172.01,158.28,144.00,135.79,128.78,128.64,127.72,126.56,114.03,60.54,55.35,46.43,41.20,14.23.
从上述应用实例可以看出，将本发明制得的手性配体在用于氧α,β-不饱和酯的不对称硅氢还原反应时，具有较高的产率。
本发明提供了一种吡啶骨架的NCN噁唑啉配体的合成方法和应用，该方法简单高效、合成条件温和、易于操作且重复性好。本发明为不对称催化领域提供了一种新型的噁唑啉配体，在不对称催化α,β-不饱和酯的硅氢还原反应中表现出高效的催化活性，其在不对称催化领域有着明显的潜在价值。上述对实施例的描述是为了便于该技术领域的普通技术人员能理解和使用发明。对于噁唑啉配体结构通式中的R1范围不局限于H、甲基、异丙基、苯基，它适用于各种烷基和芳基。对于结构通式中的R2基团不局限于苯基、苄基、异丙基、叔丁基，它适应于一系列手性或消旋氨基醇，不脱离本发明结构通式范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种吡啶骨架NCN噁唑啉类配体，其特征在于，在吡啶的间位引入手性噁唑啉，其结构通式为：
其中，R1独立选自于H,Me,iPr,Ph；
其中，R2独立选自于Ph,Bn,iPr,tBu。
2.一种如权利要求1所述吡啶骨架NCN噁唑啉类配体的合成方法，其特征在于，该方法包括以下步骤：
S11、在N2氛围下，将β-酮酯、多聚甲醛、醋酸铵置于85℃下反应4-5个小时，得到汉斯酯；
S12、空气下，将所得汉斯酯与四水合醋酸钴、N-羟基邻苯二甲酰亚胺置于乙腈中，40℃下过夜反应，得到2,6-二取代-3,5-吡啶二甲酸酯；
S13、在N2氛围下，将所得2,6-二取代-3,5-吡啶二甲酸酯与手性氨基醇、NaH置于预热的110-120℃油浴中反应30min，得到手性氨基醇中间体；
S14、在N2氛围下，将所得手性氨基醇中间体置于-78℃下，在二乙胺基三氟化硫作用下得到目标产物。
3.根据权利要求2所述吡啶骨架NCN噁唑啉类配体的合成方法，其特征在于，步骤S11中β-酮酯、多聚甲醛、醋酸铵的摩尔比为1:0.5:0.75。
4.根据权利要求2所述吡啶骨架NCN噁唑啉类配体的合成方法，其特征在于，步骤S12中汉斯酯、四水合醋酸钴、N-羟基邻苯二甲酰亚胺的摩尔比为1:0.05:0.1。
5.根据权利要求2所述的一种吡啶骨架NCN噁唑啉配体的合成方法，其特征在于，步骤S13中2,6-二取代-3,5-吡啶二甲酸酯与手性氨基醇的摩尔比为1:(2-3)。
6.根据权利要求2所述的一种吡啶骨架NCN噁唑啉配体的合成方法，其特征在于，步骤S14中手性氨基醇与二乙胺基三氟化硫的摩尔比为1:2.3。
7.一种如权利要求1所述吡啶骨架NCN噁唑啉配体的应用，其特征在于，将所述吡啶骨架NCN噁唑啉配体用于α,β-不饱和酯的不对称硅氢还原反应。
8.根据权利要求7所述的吡啶骨架NCN噁唑啉配体的应用，其特征在于，所述α,β-不饱和酯的不对称硅氢还原的方法为：无水无氧操作，氮气氛围下在无水甲苯中，将所述吡啶骨架NCN噁唑啉配体与RhCl3 .3H2O在50℃下搅拌1-2h，然后加入α,β-不饱和酯，50℃下缓慢滴加甲基二乙氧基硅烷，反应0.5h小时后，于0℃下加入HCl继续搅拌0.5h，后萃取，干燥，过滤收集滤液，旋干和过柱后得到还原产物。
9.根据权利要求8所述的α,β-不饱和酯的不对称硅氢还原的方法，其特征在于，所述的吡啶骨架NCN噁唑啉配体、RhCl3 .3H2O、α,β-不饱和酯、甲基二乙氧基硅烷和HCl的摩尔比为1：1：100：150：100。
10.根据权利要求7所述的吡啶骨架NCN噁唑啉配体的应用，其特征在于所述的α,β-不饱和酯具有以下结构通式：
其中，R1独立选自于氢、甲基、甲氧基、卤素、三氟甲基、苯基中的一种；R2独立选自于甲基、乙基中的一种；R3独立选自于甲基、乙基、苯基中的一种；
还原产物具有如下结构通式：
其中，R1独立选自于氢、甲基、甲氧基、卤素、三氟甲基、苯基中的一种；R2独立选自于甲基、乙基中的一种；R3独立选自于甲基、乙基、苯基中的一种。
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| CN115926190B9 (zh) * | 2023-02-24 | 2024-05-31 | 浙江师范大学 | 一种基于非手性原料合成的手性金属有机框架材料及其制备方法 |
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