CN105879905A - Polyfunctional chiral phosphine catalyst and its preparation method and use - Google Patents
Polyfunctional chiral phosphine catalyst and its preparation method and use Download PDFInfo
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000003054 catalyst Substances 0.000 title claims description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- -1 phosphine compound Chemical class 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-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
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 4
- 125000003368 amide group Chemical group 0.000 abstract description 3
- 150000007527 lewis bases Chemical group 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229960000581 salicylamide Drugs 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical class C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-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
- 150000001336 alkenes Chemical class 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- OGCGXUGBDJGFFY-UHFFFAOYSA-N diphenylprolinol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1CCCN1 OGCGXUGBDJGFFY-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
本发明涉及一种多官能团手性膦化合物、制备方法及其在不对称分子间交叉Rauhut‑Currier反应(RC反应)中的应用。这类化合物含有酰胺基和酚羟基两个酸的部分和一个三价膦的Lewis碱的部分，能够高效地催化分子间的不对称交叉RC反应，能够以较好的收率和对映选择性得到相应单一的交叉RC反应的产物。是目前报道的首例手性膦催化的分子间交叉RC反应的不对称版本，ee值最高能够达到90％。本发明中多官能团手性膦化合物结构如式。 The invention relates to a multifunctional chiral phosphine compound, a preparation method and its application in asymmetric intermolecular cross Rauhut-Currier reaction (RC reaction). These compounds contain two amide groups and phenolic hydroxyl groups The acid part and the Lewis base part of a trivalent phosphine can efficiently catalyze the asymmetric cross-RC reaction between molecules, and can obtain the corresponding single cross-RC reaction product with better yield and enantioselectivity. It is the first asymmetric version of chiral phosphine-catalyzed intermolecular cross-RC reaction reported so far, and the ee value can reach up to 90%. The structure of the polyfunctional chiral phosphine compound in the present invention is as follows.
Description
技术领域 technical field
本发明涉及一种多官能团手性膦化合物、制备方法及其在不对称分子间交叉Rauhut-Currier反应(RC反应)中的应用。这类化合物含有酰胺基和酚羟基两个酸的部分和一个三价膦的Lewis碱的部分，能够以很好的收率和对映选择性得到相应单一的交叉RC反应的产物。是目前报道的首例手性膦催化的分子间交叉RC反应的不对称版本。 The invention relates to a multifunctional chiral phosphine compound, a preparation method and its application in asymmetric intermolecular cross Rauhut-Currier reaction (RC reaction). These compounds contain two amide groups and phenolic hydroxyl groups The acid moiety and the Lewis base moiety of a trivalent phosphine give the corresponding single cross-RC reaction product in good yield and enantioselectivity. It is the first asymmetric version of chiral phosphine-catalyzed intermolecular cross-RC reaction reported so far.
背景技术 Background technique
Rauhut-Currier反应是在1963年由Rauhut和Currier报道的使用叔膦催化构筑碳-碳键的反应(M.M.Rauhut，H.Currier，U.S.Patent，1963，3074999；Chem.Abstr.，1963，58，11224a.)。由于不同活化烯烃之间的活性差异，使得反应过程中存在交叉RC反应和分子二聚反应的竞争，最多能够得到四种不同的产物。由于缺少对该反应化学选择性的有效控制，使得该反应在有机合成中的应用受到的很大的限制。2002年，Roush和Krische实现了分子内的RC反应，通过调节两种不同烯烃的电性或者引入具有大空间位阻的基团，使得反应具有了很好的化学选择性(S.A.Frank，D.J.Mergott，W.R.Roush，J.Am.Chem.Soc.2002，124，2404-2405；L.Wang，A.L.Lius，K.Agapiou，H.Y.Jang，M.J.Krische，J.Am.Chem.Soc.2002，124，2402-2403.)。之后DBU，氮杂卡宾，咪唑/LiCl也被用作催化剂替代叔膦用于催化分子间交叉RC反应(J.R.Hwu，G.H.Hakimelahi，C.T.Chou，Tetra.Lett.1992，33，6469-6472；R.L.Atienza，K.A.Scheidt，Aust.J.Chem.2011，64，1158-1164；P.Shanbhag，P.R.Nareddy，M.Dadwal，S.M.Mobin，I.N.N.Namboothiri，Org.Biomol.Chem.2010，8，4867-4873；R.Kumar，T.Kumar，S.M.Mobin，I.N.N.Nambothiri，J.Org.Chem.2013，78，5073-5077；R.Zhou，J.Wang，J.Yu，Z.He，J.Org.Chem.2013，78，10596-10604.)。关于RC反应的不对称的研究大多局限于分子内，采用的催化剂有L-半胱氨酸(C.E.Aroyan，S.J.Miller，J.Am.Chem.Soc.2007，129，256-257.)，二苯基脯氨醇硅醚(E.Marqués-López，R.P.Herrera，T.Marks，W.C.Jacobs，D.R.M.de Figueiredo，M.Christmann，Org.Lett.2009，11，4116-4119.)，手性膦试剂(S.Takizawa，T.M.N.Nguyen，A.Grossmann，D.Enders，H.Sasai，Angew.Chem.2012，124，5519-5522；Angew.Chem.Int.Ed.2012，51，5423-5426；i)S.Takizawa，T.M.N.Nguyen，A.Grossmann，D.Enders，H.Sasai，Tetrahedron 2013，69，1202-1209.)以及其他含氢键的小分子有机催化剂(X.Zhang，M.Shi，Eur.J.Org.Chem.2012，6271-6279.)。对于分子间的交叉RC反应的研究到目前为止只有施敏报道的采用β-环糊精催化的联烯酸酯与马来酰亚胺的交叉RC反应(Q.Zhao，C.Pei，X.Guan，M.Shi，Adv.Synth.Catal.2011，353，1973-1979.)。而对于最初发现的由叔膦催化的RC反应的分子 间的不对称研究至今尚无报道。 The Rauhut-Currier reaction is a reaction in which a tertiary phosphine was used to catalyze the construction of a carbon-carbon bond reported by Rauhut and Currier in 1963 (MMRauhut, H.Currier, US Patent, 1963, 3074999; Chem.Abstr., 1963, 58, 11224a.) . Due to the activity difference between different activated olefins, there is competition between cross-RC reaction and molecular dimerization during the reaction process, and up to four different products can be obtained. Due to the lack of effective control of the chemical selectivity of this reaction, the application of this reaction in organic synthesis is greatly limited. In 2002, Roush and Krische realized the intramolecular RC reaction. By adjusting the electrical properties of two different alkenes or introducing groups with large steric hindrance, the reaction has good chemoselectivity (SAFrank, DJMergott, WRRoush , J. Am. Chem. Soc. 2002, 124, 2404-2405; L. Wang, ALLius, K. Agapiou, HY Jang, MJ Krische, J. Am. Chem. Soc. 2002, 124, 2402-2403.). After that, DBU, azacarbene, imidazole/LiCl were also used as catalysts instead of tertiary phosphine for catalyzing intermolecular cross RC reactions (JRHwu, GHHakimelahi, CTChou, Tetra.Lett.1992, 33, 6469-6472; RLAtienza, KAScheidt, Aust .J.Chem.2011, 64, 1158-1164; P.Shanbhag, PRNareddy, M.Dadwal, SMMobin, INNNamboothiri, Org.Biomol.Chem.2010, 8, 4867-4873; R.Kumar, T.Kumar, SMMobin , INNNambothiri, J.Org.Chem.2013, 78, 5073-5077; R.Zhou, J.Wang, J.Yu, Z.He, J.Org.Chem.2013, 78, 10596-10604.). Most of the studies on the asymmetry of the RC reaction are limited to intramolecular, and the catalysts used include L-cysteine (CEAroyan, SJMiller, J.Am.Chem.Soc.2007, 129, 256-257.), diphenyl Prolinol silyl ether (E.Marqués-López, RP Herrera, T.Marks, WC Jacobs, D. RMde Figueiredo, M.Christmann, Org.Lett.2009, 11, 4116-4119.), chiral phosphine reagents (S.Takizawa, TMNNguyen, A.Grossmann, D.Enders, H.Sasai, Angew.Chem.2012, 124, 5519-5522; Angew. Chem. Int. Ed. 2012, 51, 5423-5426; i) S. Takizawa, TMNNguyen, A. Grossmann, D. Enders, H. Sasai, Tetrahedron 2013, 69, 1202-1209 .) and other small molecule organic catalysts containing hydrogen bonds (X. Zhang, M. Shi, Eur. J. Org. Chem. 2012, 6271-6279.). For the research on the cross RC reaction between molecules, only Shi Min's report adopts the cross RC reaction (Q.Zhao, C.Pei, X. Guan, M. Shi, Adv. Synth. Catal. 2011, 353, 1973-1979.). However, the research on the intermolecular asymmetry of the RC reaction catalyzed by tertiary phosphine has not been reported so far.
近年来双官能团有机催化剂催化的不对称反应的研究越来越多，在这些催化剂之中，胺基(主要以酰胺、硫脲、方胺、脲、二肽的形式)和酚羟基是主要的酸的部分，在反应过程中能够以氢键的形式实现选择性的控制(P.Chauhan，S.S.Chimni，Rsc Advances2012，2，737-758；A.Ting，J.M.Goss，N.T.McDougal，S.E.Schaus，Top.Curr.Chem.2009，291，201-232；X.Liu，L.Lin，X.Feng，Chem.Commun.2009，6145-6158.)。但是多官能团催化剂的研究并不多。Liu认为多官能团催化剂能够以多官能团活化的方式提高催化剂的催化效率、反应的选择性以及反应的速率(J.M.Gamier，C.Anstiss，F.Liu，Adv.Synth.Catal.2009，351，331-338)。我们将酰胺基和酚羟基作为酸的部分，将用于催化RC反应的三价膦作为Lewis碱的部分，以天然氨基酸为骨架设计合成了一种新型的多官能团手性膦催化剂，并将此催化剂成功应用于分子间交叉RC反应。 In recent years, there have been more and more studies on asymmetric reactions catalyzed by bifunctional organocatalysts. Among these catalysts, amine groups (mainly in the form of amides, thioureas, square amines, ureas, dipeptides) and phenolic hydroxyl groups are the main ones. Acid moiety, which can realize selective control in the form of hydrogen bonds during the reaction (P.Chauhan, SSChimni, Rsc Advances2012, 2, 737-758; A.Ting, JMGoss, NTMcDougal, SESchaus, Top.Curr.Chem . 2009, 291, 201-232; X. Liu, L. Lin, X. Feng, Chem. Commun. 2009, 6145-6158.). However, there are not many studies on multifunctional catalysts. Liu thinks that multifunctional catalyst can improve the catalytic efficiency of catalyst, the selectivity of reaction and the rate of reaction (JMGamier, C.Anstiss, F.Liu, Adv.Synth.Catal.2009,351,331-338 in the mode of multifunctional group activation ). We regard the amide group and the phenolic hydroxyl group as As part of the acid, the trivalent phosphine used to catalyze the RC reaction was used as the part of the Lewis base, and a new type of multifunctional chiral phosphine catalyst was designed and synthesized with natural amino acids as the skeleton, and this catalyst was successfully applied to intermolecular crossover RC reaction.
发明内容 Contents of the invention
本发明的目的是提供一种多官能团手性膦化合物。 The object of the present invention is to provide a multifunctional chiral phosphine compound.
本发明的目的还提供一种上述多官能团手性膦化合物的制备方法。 The object of the present invention is also to provide a preparation method of the above-mentioned polyfunctional chiral phosphine compound.
本发明的另一个目的是提供一种上述多官能团手性膦化合物在不对称催化的分子间交叉RC反应中的应用。 Another object of the present invention is to provide an application of the above multifunctional chiral phosphine compound in asymmetrically catalyzed intermolecular cross RC reactions.
本发明中涉及的多官能团手性膦化合物具有如下所示的化合结构式： The polyfunctional chiral phosphine compound involved in the present invention has the compound structural formula shown below:
其中R为烷基、苄基。R1为甲基、C1-C4烷氧基、卤素、硝基。 Wherein R is alkyl, benzyl. R 1 is methyl, C1-C4 alkoxy, halogen, nitro.
本发明的多官能团膦化合物可以由已知化合物与取代水杨酸或者3-羟基2-萘甲酸通过缩合反应而得到。 The polyfunctional phosphine compound of the present invention can be obtained by condensation reaction of known compounds with substituted salicylic acid or 3-hydroxy 2-naphthoic acid.
具体地说是在有机溶剂中0℃条件下，取代的胺基膦化合物与邻羟基芳基甲酸以1∶1-1∶1.5的摩尔比在缩合剂和有机碱存在的条件下反应6-24h，生成多官能团手性膦催化剂。有机溶剂优选N，N-二甲基甲酰胺、四氢呋喃、1，4-二氧六环的一种或多种；缩合剂优选BOP(苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐)、DCC(二环己基碳二亚胺)/DMAP(4-二甲氨基吡啶)、CDI(N，N′-羰基二咪唑)；有机碱优选吡啶、三乙胺。 Specifically, under the condition of 0°C in an organic solvent, the substituted aminophosphine compound and o-hydroxyaryl formic acid are reacted for 6-24h in the presence of a condensing agent and an organic base in a molar ratio of 1:1-1:1.5 , to generate multifunctional chiral phosphine catalysts. One or more of the preferred N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane as the organic solvent; the preferred BOP (benzotriazol-1-yloxyl tri(dimethyl Amino)phosphonium hexafluorophosphate), DCC (dicyclohexylcarbodiimide)/DMAP (4-dimethylaminopyridine), CDI (N,N'-carbonyldiimidazole); organic bases are preferably pyridine, tri Ethylamine.
本发明的多官能团手性膦化合物，可用于不对称催化分子间交叉RC反应，具体反应方程式如下所示： The multifunctional chiral phosphine compound of the present invention can be used for asymmetric catalyzed intermolecular cross RC reaction, and the specific reaction equation is as follows:
实施方式 Implementation
以下实施有助于理解本发明，但不限于本发明的内容。 The following implementations are helpful for understanding the present invention, but are not limited to the content of the present invention.
实施例1：(S)-N-(1-(二苯基膦)-3-甲基丁烷-2-)-2-羟基苯甲酰胺 Example 1: (S)-N-(1-(diphenylphosphine)-3-methylbutane-2-)-2-hydroxybenzamide
将100mg(0.37mmol)(S)-1-(二苯基膦)-3-甲基丁烷-2-胺溶于3mL干燥的THF，于0℃加入58.5mg(0.42mmol)水杨酸，207mg(0.47mmol)BOP，224mg(2.214mmol)三乙胺，于0℃下反应12h，通过TLC监测反应，待反应结束之后，体系中加入饱和碳酸氢钠水溶液和乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋蒸得到残渣，采用硅胶柱层析纯化得到94mg，产率是65％。 Dissolve 100mg (0.37mmol) (S)-1-(diphenylphosphine)-3-methylbutane-2-amine in 3mL dry THF, add 58.5mg (0.42mmol) salicylic acid at 0°C, 207mg (0.47mmol) BOP, 224mg (2.214mmol) triethylamine, react at 0°C for 12h, monitor the reaction by TLC, after the reaction is completed, add saturated aqueous sodium bicarbonate and ethyl acetate to the system for extraction, and combine the organic phases , dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain a residue, which was purified by silica gel column chromatography to obtain 94 mg with a yield of 65%.
产物结构数据表征如下：熔点：98-100℃；[α]29D＝+13.7(c 1.0，CH2Cl2)；1H NMR(400MHz，CDCl3)δ12.33(s，1H)，7.52-7.26(m，11H)，6.93(dt，J＝9.7，4.9Hz，1H)，6.82(dt，J＝8.0，3.9Hz，1H)，6.72-6.65(m，1H)，6.01(d，J＝9.0Hz，1H)，4.29-4.09(m，1H)，2.46-2.29(m，2H)，2.07(dp，J＝13.3，6.7Hz，1H)，0.96(d，J＝1.5Hz，3H)，0.94(d，J＝1.5Hz，3H)；13C NMR(101MHz，CDCl3)δ169.29(s)，161.51(s)，138.13(t，J＝11.9Hz)，134.01(s)，132.83(dd，J＝19.3，9.3Hz)，129.08-128.55(m)，125.16(s)，118.42(d，J＝2.9Hz)，114.26(s)，52.84(d，J＝13.6Hz)，32.77(d，J＝8.2Hz)，31.32(d，J＝15.0Hz)，18.87(s)，18.25(s)；31P NMR(162MHz，CDCl3)δ-23.59(s)；HRMS(ESI)C24H26NO2P[M+H]+：计算值：392.1774：实测值：392.1767。 The structural data of the product are characterized as follows: melting point: 98-100°C; [α] 29 D = +13.7 (c 1.0, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ12.33 (s, 1H), 7.52 -7.26(m, 11H), 6.93(dt, J=9.7, 4.9Hz, 1H), 6.82(dt, J=8.0, 3.9Hz, 1H), 6.72-6.65(m, 1H), 6.01(d, J =9.0Hz, 1H), 4.29-4.09(m, 1H), 2.46-2.29(m, 2H), 2.07(dp, J=13.3, 6.7Hz, 1H), 0.96(d, J=1.5Hz, 3H) , 0.94(d, J=1.5Hz, 3H); 13 C NMR (101MHz, CDCl 3 ) δ169.29(s), 161.51(s), 138.13(t, J=11.9Hz), 134.01(s), 132.83 (dd, J=19.3, 9.3Hz), 129.08-128.55(m), 125.16(s), 118.42(d, J=2.9Hz), 114.26(s), 52.84(d, J=13.6Hz), 32.77( d, J=8.2Hz), 31.32 (d, J=15.0Hz), 18.87(s), 18.25(s); 31 P NMR (162MHz, CDCl 3 ) δ-23.59(s); HRMS (ESI) C 24 H 26 NO 2 P[M+H] + : Calculated: 392.1774: Found: 392.1767.
实施例2：(S)-N-(1-(二苯基膦)-3-苯基丙烷-2-)-2-羟基苯甲酰胺 Example 2: (S)-N-(1-(diphenylphosphine)-3-phenylpropane-2-)-2-hydroxybenzamide
合成方法同实施例1，采用(S)-1-(二苯基膦)-3-苯基丙烷-2-胺作为原料，收率65％。 The synthesis method is the same as in Example 1, using (S)-1-(diphenylphosphine)-3-phenylpropan-2-amine as the raw material, and the yield is 65%.
产物结构数据表征如下：熔点：160-163℃；[α]29 D＝+13.5(c 1.0，CH2Cl2)；1H NMR(400MHz，CDCl3)δ12.27(s，1H)，7.55-7.14(m，16H)，6.93(d，J＝8.3Hz，1H)，6.79-6.60(m，1H)，6.10(d，J＝7.7Hz，1H)，4.61-4.40(m，1H)，3.13(dd，J＝13.6，5.3Hz，1H)，3.04(dd，J＝13.5，7.1Hz，1H)，2.39(qd，J＝14.2，6.8Hz，1H).13C NMR(101MHz，CDCl3)δ169.23(s)，161.56(s)，137.75(dd，J＝12.1，8.1Hz)，137.27(s)，134.10(s)，132.82(dd，J＝19.3，9.1Hz)，129.61(s)，129.29-128.57(m)，126.84(s)，125.19(s)，118.46(s)，114.14(s)，49.18(d，J＝14.7Hz)，41.22(d，J＝8.6Hz)，32.62(d，J＝15.4Hz).31P NMR(162MHz，CDCl3)δ-24.37(s)；HRMS(ESI)C28H26NO2P[M+H]+：计算值：440.1774；实测值：440.1781。 The structural data of the product are characterized as follows: Melting point: 160-163°C; [α] 29 D =+13.5 (c 1.0, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ12.27 (s, 1H), 7.55 -7.14(m, 16H), 6.93(d, J=8.3Hz, 1H), 6.79-6.60(m, 1H), 6.10(d, J=7.7Hz, 1H), 4.61-4.40(m, 1H), 3.13(dd, J=13.6, 5.3Hz, 1H), 3.04(dd, J=13.5, 7.1Hz, 1H), 2.39(qd, J=14.2, 6.8Hz, 1H). 13 C NMR (101MHz, CDCl 3 )δ169.23(s), 161.56(s), 137.75(dd, J=12.1, 8.1Hz), 137.27(s), 134.10(s), 132.82(dd, J=19.3, 9.1Hz), 129.61(s ), 129.29-128.57(m), 126.84(s), 125.19(s), 118.46(s), 114.14(s), 49.18(d, J=14.7Hz), 41.22(d, J=8.6Hz), 32.62 (d, J=15.4Hz). 31 P NMR (162MHz, CDCl 3 ) δ-24.37(s); HRMS (ESI) C 28 H 26 NO 2 P[M+H] + : Calculated: 440.1774; Found : 440.1781.
实施例3：(S)-N-(1-(二苯基膦)-3-甲基戊烷-2-)-2-羟基苯甲酰胺 Example 3: (S)-N-(1-(diphenylphosphine)-3-methylpentane-2-)-2-hydroxybenzamide
合成方法同实施例1，采用(S)-1-(二苯基膦)-3-甲基戊烷-2-胺作为原料，收率67％。 The synthesis method is the same as in Example 1, using (S)-1-(diphenylphosphine)-3-methylpentan-2-amine as the raw material, and the yield is 67%.
产物结构数据表征如下：熔点：73-74℃；[α]29 D＝+8.8(c 1.0，CH2Cl2)；1H NMR(400MHz，CDCl3)δ12.32(s，1H)，7.37(dt，J＝36.5，12.5Hz，11H)，6.94(d，J＝8.2Hz，1H)，6.78(d，J＝7.4Hz，1H)，6.69(t，J＝7.4Hz，1H)，6.00(d，J＝7.7Hz，1H)，4.28(s，1H)，2.41(d，J＝12.0Hz，1H)，2.37-2.29(m，1H)，1.84(m，1H)，1.48(d，J＝6.2Hz，1H)，1.15(dt，J＝21.6，7.6Hz，1H)，0.94(d，J＝6.5Hz，3H)，0.88(t，J＝7.1Hz，3H)；13C NMR(101MHz，CDCl3)δ169.14(s)，161.52(s)，138.12(dd，J＝31.7，12.7Hz)，138.12(dd，J＝31.7，12.7Hz)，133.98(s)，132.82(t，J＝18.8Hz)，129.25-128.49(m)，125.13(s)，118.40(d，J＝6.4Hz)，114.25(s)，51.80(d，J＝13.5Hz)，39.12(d，J＝7.7Hz)，30.33(d，J＝14.7Hz)，25.48(s)，14.90(s)，11.63(s)；31P NMR(162MHz，CDCl3)δ-23.40(s)；HRMS(ESI)m/z C25H28NO2P[M+H]+：计算值：406.1930；实测值：406-1937。 The structural data of the product are characterized as follows: Melting point: 73-74°C; [α] 29 D =+8.8 (c 1.0, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ12.32 (s, 1H), 7.37 (dt, J=36.5, 12.5Hz, 11H), 6.94(d, J=8.2Hz, 1H), 6.78(d, J=7.4Hz, 1H), 6.69(t, J=7.4Hz, 1H), 6.00 (d, J=7.7Hz, 1H), 4.28(s, 1H), 2.41(d, J=12.0Hz, 1H), 2.37-2.29(m, 1H), 1.84(m, 1H), 1.48(d, J=6.2Hz, 1H), 1.15(dt, J=21.6, 7.6Hz, 1H), 0.94(d, J=6.5Hz, 3H), 0.88(t, J=7.1Hz, 3H); 13 C NMR ( 101MHz, CDCl3) δ169.14(s), 161.52(s), 138.12(dd, J=31.7, 12.7Hz), 138.12(dd, J=31.7, 12.7Hz), 133.98(s), 132.82(t, J =18.8Hz), 129.25-128.49(m), 125.13(s), 118.40(d, J=6.4Hz), 114.25(s), 51.80(d, J=13.5Hz), 39.12(d, J=7.7Hz ), 30.33(d, J=14.7Hz), 25.48(s), 14.90(s), 11.63(s); 31 P NMR(162MHz, CDCl 3 )δ-23.40(s); HRMS(ESI) m/z C 25 H 28 NO 2 P[M+H] + : Calculated: 406.1930; Found: 406-1937.
实施例4：(S)-N-(1-(二苯基膦)-3-甲基戊烷-2-)-3-羟基2-萘甲酰胺 Example 4: (S)-N-(1-(diphenylphosphine)-3-methylpentane-2-)-3-hydroxyl 2-naphthylcarboxamide
合成方法同实施例1，采用3-羟基-2-萘甲酸和(S)-1-(二苯基膦)-3-甲基戊烷-2-胺作为原料，收率64％。 The synthesis method is the same as in Example 1, using 3-hydroxy-2-naphthoic acid and (S)-1-(diphenylphosphine)-3-methylpentane-2-amine as raw materials, and the yield is 64%.
产物结构数据表征如下：熔点：118-120℃；[α]29 D＝+141.3(c 1.0，CH2Cl2)；1H NMR(400MHz，CDCl3)δ11.82(s，1H)，7.62(dd，J＝17.6，8.2Hz，2H)，7.45(dt，J＝20.6，6.6Hz，6H)，7.37-7.20(m，10H)，6.20(d，J＝8.6Hz，1H)，4.47-4.26(m，1H)，2.42(q，J＝14.2Hz，2H)，1.88(m，1H)，1.61-1.46(m，1H)，1.19(dd，J＝13.4，7.6Hz，1H)，0.98(d，J＝6.6Hz，4H)，0.90(t，J＝7.2Hz，4H)；13C NMR(101MHz，CDCl3)δ168.96(s)，156.77(s)，138.39(s)，138.07(s)，136.97(s)，132.85(dd，J＝19.4，3.5Hz)，129.29-128.51(m)，128.35(s)，126.97-126.07(m)，123.68(s)，116.91(s)，112.17(s)，52.25(d，J＝13.8Hz)，39.28(d，J＝7.9Hz)，30.24(d，J＝14.5Hz)，29.75(s)，25.62(s)，14.96(s)，11.65(s)；31P NMR(162MHz，CDCl3)δ-23.15(s)；HRMS(ESI)m/zC29H30NO2P[M+H]+：计算值：456.2087；实测值：456.2094。 The structural data of the product are characterized as follows: melting point: 118-120°C; [α] 29 D =+141.3 (c 1.0, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ11.82 (s, 1H), 7.62 (dd, J=17.6, 8.2Hz, 2H), 7.45(dt, J=20.6, 6.6Hz, 6H), 7.37-7.20(m, 10H), 6.20(d, J=8.6Hz, 1H), 4.47- 4.26(m, 1H), 2.42(q, J=14.2Hz, 2H), 1.88(m, 1H), 1.61-1.46(m, 1H), 1.19(dd, J=13.4, 7.6Hz, 1H), 0.98 (d, J=6.6Hz, 4H), 0.90 (t, J=7.2Hz, 4H); 13 C NMR (101MHz, CDCl 3 ) δ168.96(s), 156.77(s), 138.39(s), 138.07 (s), 136.97(s), 132.85(dd, J=19.4, 3.5Hz), 129.29-128.51(m), 128.35(s), 126.97-126.07(m), 123.68(s), 116.91(s), 112.17(s), 52.25(d, J=13.8Hz), 39.28(d, J=7.9Hz), 30.24(d, J=14.5Hz), 29.75(s), 25.62(s), 14.96(s), 11.65(s); 31 P NMR (162 MHz, CDCl 3 ) δ-23.15(s); HRMS (ESI) m/z C 29 H 30 NO 2 P[M+H] + : Calculated: 456.2087; Found: 456.2094 .
实施例5：多官能团手性膦催化剂催化的分子间交叉RC反应的不对称研究 Example 5: Asymmetric study of intermolecular crossover RC reactions catalyzed by multifunctional chiral phosphine catalysts
将0.1mmol底物，10mol％多官能团手性膦催化剂溶于0.5mL氯仿，加入0.3mmol甲基乙烯基酮，于氩气保护的条件下在16℃反应，TLC监测反应，待反应结束之后，直接进行柱层析分离，采用石油醚/乙酸乙酯＝10∶1作为洗脱剂。ee值用手性HPLC测定，结果见表1. Dissolve 0.1 mmol of the substrate and 10 mol% polyfunctional chiral phosphine catalyst in 0.5 mL of chloroform, add 0.3 mmol of methyl vinyl ketone, and react at 16°C under the protection of argon, and monitor the reaction by TLC. After the reaction is completed, Directly carry out column chromatography separation, using petroleum ether/ethyl acetate=10:1 as eluent. The ee value was determined by chiral HPLC, and the results are shown in Table 1.
表1：本发明所涉及的催化剂催化的分子间交叉RC反应的不对称研究 Table 1: Asymmetric research on the intermolecular cross-RC reaction catalyzed by the catalyst involved in the present invention
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