WO2019113874A1 - 基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途 - Google Patents

基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途 Download PDF

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WO2019113874A1
WO2019113874A1 PCT/CN2017/116105 CN2017116105W WO2019113874A1 WO 2019113874 A1 WO2019113874 A1 WO 2019113874A1 CN 2017116105 W CN2017116105 W CN 2017116105W WO 2019113874 A1 WO2019113874 A1 WO 2019113874A1
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compound
reaction
group
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substituted
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林旭锋
姚林曦
常时瑞
王雷
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浙江大学
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Priority to US17/700,500 priority patent/US11866393B2/en

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Definitions

  • the invention relates to the technical field of organic chemistry, and relates to a novel phosphine ligand compound based on tetramethylspiroindole skeleton and an intermediate thereof, and a preparation method and use thereof.
  • ligands can be used in coupling reactions or asymmetric catalytic reactions.
  • Asymmetric catalytic synthesis is one of the most active research fields in the chemical sciences today, and it is the most direct and effective method for obtaining optically active molecules. It has the advantages of chiral proliferation, high enantioselectivity, economy, and easy industrialization. Achieving efficient and highly selective asymmetric catalytic synthesis is a challenging task in the field of synthetic chemistry.
  • One of its core scientific issues is the development and discovery of new and efficient chiral ligands and their catalysts. Although the design and synthesis of chiral ligands have been rapidly developed, many excellent chiral ligands have been synthesized, and quite a few ligands have been used in industrial production, but there are still limited applicability including ligands. There are many problems with the high dependence of the reaction substrate, and no chiral ligand is universal. Therefore, the search for new efficient and highly selective chiral ligands has always been an eternal theme in chiral synthesis.
  • bisphosphine ligands containing electron-deficient substituents can greatly increase the yield of the reaction, or improve the enantioselectivity, or change the regioselectivity of the reaction or provide the opposite ring stereoselectivity (J.Am.Chem .Soc., 2009, 131 (28), pp 9604; Adv. Synth. Catal. 2017, 359, 2762; Angew. Chem. Int. Ed. 2017, 56, 9541; Chemistry-A European Journal (2015), 21 (12), 4561).
  • the double phosphine ligand SDP has a long reaction step, high preparation cost, and practically greatly reduced utility.
  • Tetramethylspirohydroquinol (3,3,3',3'-tetramethyl-1,1'-spirobihydro-6,6'-diol, MSPINOL) was used in 1962. Reports can be obtained from bisphenol series products by acid catalysis directly in high yield, followed by improved scale preparation methods and chiral resolution methods (the following reaction formula, J. Chem. Soc., 1962, 415-418; Org. Lett., 2004, 6, 2341-2343; US 2006/0020150; US4879421; Bull. Chem.. Soc. Japan, 1977, 44, 496-505):
  • Tetramethylspirohydroquinone bisphenol MSPINOL and its derivatives are mainly reported for the preparation of high polymers and have not been used in the preparation or application of any ligands.
  • the corresponding raw material bisphenol is very cheap and can be obtained by condensation reaction of acetone with phenol or its derivatives; and there are many industrial bisphenol products (bisphenol A, bisphenol C, etc.) sold on a large scale, such as bisphenol A.
  • the annual global production and sales volume is more than 3 million tons, and the price is less than 10,000 yuan per ton.
  • the invention intends to design and prepare a corresponding phosphine ligand based on a tetramethylspiroindole skeleton by using inexpensive and easily available tetramethylspirohydroquinonediol; the ligand is compared with a phosphine based on a spiroindoline skeleton
  • ligands such as SDP
  • the raw materials are cheap and rich, the synthesis route is shorter, and the preparation cost is low and practical.
  • a phosphine ligand based on a tetramethylspiroindole skeleton which is a compound of the formula I or formula II or an enantiomer, a racemate or a diastereomer of the compound:
  • R 1 and R 6 are each independently selected from hydrogen, C 1 -C 10 alkyl or perfluoroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or all Fluoroalkoxy, aryloxy or substituted aryloxy, heteroaryloxy or substituted heteroaryloxy, aryl or substituted aryl, heteroaryl or substituted heteroaryl;
  • R 2 , R 3 And R 4 and R 5 are each independently selected from hydrogen, halogen, C 1 -C 10 alkyl or perfluoroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or perfluoro Alkoxy, aryloxy or substituted aryloxy, heteroaryloxy or substituted heteroaryloxy, aryl or substituted aryl, heteroaryl or substituted heteroaryl;
  • R 7 is selected from C 1 a C10 alkyl or perfluoroalkyl group, a C 3
  • An intermediate compound for preparing a phosphine ligand based on a tetramethylspiroindole skeleton which is a compound of the formula III or an enantiomer, a racemate or a diastereomer of the compound:
  • R 1 and R 6 are each independently selected from hydrogen, hydroxy, C 1 -C 10 alkyl or perfluoroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or Perfluoroalkoxy, aryloxy or substituted aryloxy, heteroaryloxy or substituted heteroaryloxy, aryl or substituted aryl, heteroaryl or substituted heteroaryl;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, halogen, C 1 -C 10 alkyl or perfluoroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or all a fluoroalkoxy, aryloxy or substituted aryloxy, heteroaryloxy or substituted heteroaryloxy, aryl or substituted aryl, heteroaryl or substituted heteroaryl; wherein said substituted An aryloxy group, a substituted aryl group or a substituted
  • the tetramethylspiroindane skeleton-based phosphine ligand as shown in Formula I is preferably any of the following compounds:
  • the phosphine ligand based on the tetramethylspiroindane skeleton represented by Formula II is preferably any of the following compounds:
  • the tetramethylspiroindane skeleton-based phosphine ligand intermediate as shown in Formula III is preferably any of the following compounds:
  • R 7 is selected from the group consisting of phenyl, benzyl, pentafluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethyl-phenyl , 3,5-dimethylphenyl, 3,5-difluorophenyl, 3,5-dimethoxyphenyl, 3,5-di-tert-butylphenyl, 3,4,5-trimethoxy Phenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 3,5-dimethyl-4-methyl Oxy-phenyl, 3,5-bis(trifluoromethyl)-phenyl.
  • the intermediate compound of formula III can be prepared by racemic or optically active tetramethylspiritol (Formula 1) starting from the following reaction: a compound of formula 1 (when R 2 and R 5 Not equal to hydrogen) first obtains compound 2 by halogenation reaction, or compound of formula 1 (when at least one of R 2 and R 5 is equal to hydrogen), tert-butylation, halogenation reaction and de-t-butyl reaction to obtain compound 2; compound 2 The compound of the formula III is obtained by etherification reaction, or esterified with trifluoromethanesulfonic anhydride, and then palladium-catalyzed coupling reaction or reduction reaction to prepare a compound of formula III;
  • R 1 to R 6 in the formulae 1, 2, 3, 4, 5 have the meanings as defined in the formula III, and R is selected from a C 1 -C 10 alkyl group or a perfluoroalkyl group, C 3 -C 6 cycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl group; wherein said substituted aryl or substituted heteroaryl having one or more substituents, the substituents Is independently selected from halogen, C 1 -C 4 alkyl or perfluoroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or perfluoroalkoxy, methylenedioxy a aryl group, an aryl group, an aryloxy group, a heteroaryl group; the heteroaryl group is a C 5 -C 14 heteroaryl group;
  • the synthesis method is specifically as follows: when one of R 2 and R 5 is selected from hydrogen, the reaction step of preparing 2 from compound 1 is a reaction of compound 1 with t-butanol in dichloromethane or chloroform in the presence of methanesulfonic acid.
  • intermediate 4 in dichloromethane or ethyl acetate, intermediate 4 and halogenated reagents reacted under p-toluenesulfonic acid catalyzed for 12-24 hours, temperature Controlled at 0 ° C to 40 ° C to give intermediate 5; in toluene or dichloromethane, intermediate 5 is treated with trifluoromethanesulfonic acid for 1-48 hours to give intermediate 2; wherein compound 1, tert-butanol, A The molar ratio between the sulfonic acids is 1:2 to 4:5 to 12, and the molar ratio between the intermediate 4 and the halogenating agent and p-toluenesulfonic acid is 1:2 to 4:0 to 1, and the intermediate 5 is followed by The molar ratio between trifluoromethanesulfonic acid is 1:0.8 to 3;
  • the halogenation reaction step 2 of the preparation of compound 1 is carried out in dichloromethane or ethyl acetate, and compound 1 is reacted with a halogenating reagent under p-toluenesulfonic acid catalysis 12-24 H, the temperature is controlled at 0 ° C to 40 ° C, to obtain intermediate 2; wherein the molar ratio of compound 1 to halogenated reagent and p-toluenesulfonic acid is 1:2 ⁇ 4:0 ⁇ 1;
  • the halogenating agent may be N-halo succinimide, dibromohydantoin, iodine chloride, bromine, chlorine, N-fluorodiphenylsulfonamide;
  • the step of preparing an etherification reaction of Compound III (R 1 and R 6 is not equal to a hydroxyl group) from Compound 2 is carried out in an alkali in N,N-dimethylformamide, dioxane, acetone or dimethyl sulfoxide.
  • the temperature is controlled at 25 ° C to 100 ° C, and the compound 2 is reacted with the etherification reagent RX for 6-36 hours to obtain a compound of the formula III;
  • the base is potassium hydroxide, sodium hydroxide,
  • the step of preparing the esterification reaction of the compound 3 from the compound 2 is carried out in dichloromethane or dichloroethane in the presence of a base at a temperature of 0 ° C to 40 ° C, and the compound 2 is reacted with trifluoromethanesulfonic anhydride 0.2-6.
  • the base is one or any ratio composition of pyridine, triethylamine, potassium hydroxide or sodium hydroxide, and the molar ratio between compound 2, base and trifluoromethanesulfonic anhydride is 1 :2 ⁇ 8:2 ⁇ 6;
  • the step of preparing the reduction reaction of the compound III from the compound 3 is carried out in N,N-dimethylformamide, dioxane or dimethyl sulfoxide in the presence of an organic base as bis(triphenylphosphine)dichloride.
  • Palladium and 1,3-bisdiphenylphosphine propane are used as catalyst systems, the temperature is controlled at 25 ° C to 100 ° C, and compound 3 is reacted with formic acid for 1-6 hours to obtain the compound III; compound 3, formic acid, organic base
  • the molar ratio between bis(triphenylphosphine)palladium dichloride and 1,3-bisdiphenylphosphinepropane is 1:2 to 6:8 to 15:0.05 to 0.2:0.05 to 0.2; the organic base is Triethylamine, tripropylamine or tributylamine;
  • the step of preparing the coupling reaction of Compound III from Compound 3 is in N,N-dimethylformamide, dioxane, water, acetone, dimethyl sulfoxide or a mixed solvent of any ratio described above, in alkali and metal.
  • the temperature is controlled at 25 ° C to 100 ° C, and the compound 3 is reacted with the coupling reagent RB(OH) 2 for 6-36 hours to obtain a compound of the formula III;
  • the base is potassium hydroxide, sodium hydroxide or potassium carbonate.
  • the method for synthesizing the compound I is prepared by using a racemic or optically active compound of the formula III as a raw material, by a double substitution reaction with a disubstituted phosphine halide under a base, or a compound of the formula III under the action of a base and two
  • the compound of the formula 6 is prepared by a double substitution reaction of the substituted oxyphosphine oxide, and is prepared by a reduction reaction;
  • reaction method 1 is carried out in tetrahydrofuran, the reaction temperature is controlled at -78 ° C to -20 ° C, and the reaction is carried out for 3-5 hours under the action of a base, and the X group of the formula III is removed, and then with R 7 2 PCl or R 7 2 PBr is reacted at room temperature for 6-12 hours to obtain the phosphine ligand of formula I; or reaction method 2 is carried out in tetrahydrofuran, the reaction temperature is controlled at -78 ° C to -20 ° C, and reacted under the action of a base.
  • the compound 6 is treated with lithium tetrahydrogen aluminum and methyl trifluoromethanesulfonate, and the reduction reaction is carried out at room temperature for 3-6 hours to obtain the phosphine ligand I; wherein the molar ratio of the base to the compound of the formula III is 2 ⁇ 10:1, the molar ratio of R 7 2 PCl or R 7 2 PBr to the compound of formula III is 2-6:1, and the molar ratio of R 7 2 P(O)Cl to the compound of formula III is 2-6:1.
  • the molar ratio of lithium tetrahydroaluminum to compound 6 is from 3 to 10:1, and the molar ratio of methyl trifluoromethanesulfonate to compound 6 is from 1 to 5:1, and the base is tert-butyllithium.
  • Isopropyl bromide Magnesium, ethyl magnesium bromide, sec-butyl lithium or n-butyl lithium.
  • the method for synthesizing the compound II is prepared by using a racemic or optically active compound of the formula III as a raw material, by a single substitution reaction with a disubstituted phosphine halide under a base, or a compound of the formula III under the action of a base and two
  • the compound of the formula 7 is prepared by a single substitution reaction of the substituted oxyphosphine oxide, and is prepared by a reduction reaction:
  • the reaction method 1 is carried out in tetrahydrofuran, the reaction temperature is controlled at -78 ° C to -20 ° C, and the reaction is carried out for 3-5 hours under the action of a base, and the X group of the formula III is removed, and then with R 7 2 PCl or R 7 2 PBr is reacted at room temperature for 6-12 hours to obtain the phosphine ligand formula II; or the reaction method 2 is carried out in tetrahydrofuran, the reaction temperature is controlled at -78 ° C to -20 ° C, and the reaction is carried out under the action of a base.
  • the molar ratio of lithium tetrahydroaluminum to compound 7 is from 3 to 10:1, and the molar ratio of methyl trifluoromethanesulfonate to compound 7 is from 1 to 3:1, and the base is tert-butyllithium.
  • Isopropyl bromide Magnesium, ethyl magnesium bromide, n-butyllithium or sec-butyllithium.
  • the phosphine ligand of the invention can be independently prepared by complexing with metal salts of iron, ruthenium, gold, silver, copper, platinum, rhodium, ruthenium, iridium, nickel, molybdenum, palladium or cobalt. catalyst.
  • the phosphine ligand can be used independently as an organic small molecule catalyst for the cyclization reaction.
  • the phosphine ligand can be used independently for metal-catalyzed coupling reaction, N-aryl amination reaction, asymmetric reaction, preferably for metal-catalyzed asymmetric hydrogenation, hydrosilylation, hydrogen transfer reaction and asymmetry Allylation reaction.
  • the phosphine ligand of the present invention is obtained by using a cheap and readily available tetramethylspirohydroquinone as a raw material, via a preparation route of the general formula III as a key intermediate.
  • the invention develops a novel class of phosphine ligands which can be used for catalyzing organic reactions, in particular as chiral phosphine ligands, which are widely used in many asymmetric catalytic reactions including asymmetric hydrogenation and asymmetric allyalkylation. Among them, it has economical practicability and industrial application prospects.
  • Figure 1 is an X-ray crystal diffraction pattern of the compound RL-MSPINOL of Example 1;
  • Figure 2 is an X-ray crystal diffraction pattern of the compound SL-HMSPINOL in Example 2;
  • Figure 3 is an X-ray crystal diffraction pattern of the compound RL-HMSPINOL of Example 2;
  • D-menthol chloroformate may be used in place of L-menthol chloroformate in the above process, and another diastereomer (SL-MSPINOL) may also be obtained in a yield of 55%.
  • reaction solution 50 g of bisphenol C and 250 mL of methanesulfonic acid were placed in a 500 mL round bottom flask, and the mixture was stirred at room temperature for 3 days, and then 100 mL of methanesulfonic acid was added thereto, and the reaction was stopped after 1 day.
  • the reaction solution was poured into a beaker containing 300 mL of crushed ice, suction filtered, and the filter cake was washed with a saturated sodium hydrogen carbonate solution and water. After washing, the obtained crude product was transferred to a 500 mL single-necked flask, and an appropriate amount of ethanol was added to dissolve the product at the reflux temperature.
  • reaction liquid was evaporated to dryness under reduced pressure of dichloromethane, and then 200 mL or more of ethyl acetate was added thereto to dissolve all the precipitated solids; the liquid phase was extracted with ethyl acetate, and the organic phase was combined; the organic phase was washed with saturated brine. Dry over anhydrous sodium sulfate, suction-filter, and the filtrate was concentrated to dry white crystals. Dissolve the solid at 80 degrees with an appropriate amount of ethanol so that it is completely dissolved in the reflux state of ethanol. Then, slowly adding hot water under stirring will precipitate solids, heating the water until no more solids are precipitated, hot filtered, and fully hot water washing.
  • the single crystal data is as follows (the structure is shown in Figure 4):
  • reaction is quenched by adding an appropriate amount of dilute hydrochloric acid, ethyl acetate is extracted, and the organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, filtered, and evaporated.
  • reaction is quenched by adding an appropriate amount of dilute hydrochloric acid, ethyl acetate is extracted, and the organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, filtered, and evaporated.
  • Methyl spirophosphine ligand (R)-HMSDP (0.165 mmol, ie compound (R)-Ib) and Ru(C 6 H 6 )Cl 2 (0.08 mmol, 40 mg) were weighed in a glove box under nitrogen atmosphere. Add to the Schlenk reaction tube. Then, 3 ml of dry degassed N,N-dimethylformamide (DMF) was injected under a nitrogen atmosphere, and heated to 100 °C for 2 hours with stirring, followed by cooling to room temperature, and (R, R)-1 was added. 2-Diphenylethylenediamine ((R,R)-DPEN, 0.165 mmol, 35 mg), the reaction was stirred at room temperature for 16 h. The solvent was removed by vacuum under reduced pressure and dried to give a quantitative product to the solid product RuCl 2 -[(R)-HMSDP][(R,R)-DPEN].
  • DMF dry degassed N,N-dimethylformamide
  • III-b 0.05 mmol
  • 0.5 mmol of ethyl acrylate (In-2) and olefin In-1 were added to the reaction flask, and 5 ml of toluene was injected, and the reaction was stirred at room temperature for 12 hours.
  • the reaction solution was concentrated, and then subjected to silica gel column chromatography to give s.

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Abstract

本发明公开了一种基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途。所述的膦配体化合物是具有通式（I）或通式（II）所示结构的化合物或所述化合物的对映体、消旋体或非对映异构体。该膦配体以廉价易得的四甲基螺二氢茚二酚为原料，经由通式（III）作为关键中间体的制备路线获得。本发明开发了一类新型的膦配体，可用于催化有机反应，特别是可作为手性的膦配体广泛用于包括不对称氢化和不对称烯丙基烷基化等许多不对称催化反应中，具有经济实用性和工业应用前景。

Description

基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途 技术领域
本发明涉及有机化学技术领域，涉及一种新型的基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途。该类配体可用于偶联反应或不对称催化反应。
背景技术
不对称催化合成是当今化学科学中最为活跃的研究领域之一,该技术是获得光学活性分子最直接的、最有效的方法。它具有手性增殖、高对映选择性、经济性，易于实现工业化的优点。实现高效高选择性的不对称催化合成反应是合成化学领域中一项挑战性的课题，其核心科学问题之一是发展和发现新型高效的手性配体及其催化剂。尽管手性配体的设计合成已经取得快速发展，有如下众多的优秀手性配体被合成出来，并有相当一些配体已经应用于工业化生产，但仍然存在包括配体的适用性有限，对反应底物高度依赖等很多问题，没有任何一种手性配体是通用的。因而寻求新型高效高选择性的手性配体一直是手性合成中的永恒主题。
Figure PCTCN2017116105-appb-000001
手性配体的合成设计(如何提高催化活性和立体选择性)有一些规律，主要考虑电性和结构因素(如二面角、位阻和骨架刚性等)。当前普遍认为，二面角对于不对称催化的立体选择性有极大影响(Acc.Chem.Res.2007,40,1385–1393【Figure 2】；Tetrahedron:Asymmetry 15(2004)2185–2188；EP1002801；US6333291；J.Org.Chem.1999,65,6223；CN 1331871C；J.Org.Chem.2000,65,6223；J.AM.CHEM.SOC.2006,128,5955)。另外含有缺电子取代基的双膦配体很多时候会极大提高反应产率、或改善对映选择性、或改变反应的区域选择性或提供相反的关环立体选择性(J.Am.Chem.Soc.,2009,131(28),pp 9604；Adv.Synth.Catal.2017,359,2762；Angew.Chem.Int.Ed.2017,56,9541；Chemistry-A European Journal(2015),21(12),4561)。
1999年，Birman等人从间甲氧基苯甲醛出发，经过六步反应合成得到了外消旋的螺二氢茚二酚SPINOL(1,1'-螺二氢茚-7,7'-二醇)，又通过化学拆分获得了相应的光学对映体(Tetrahedron:Asymmetry 1999,10,12)，并指出了该化合物可用于合成各种手性配体；不过显然，按照此路线或者其他其他公开方法都是无法获得相应的3,3,3',3'-四甲基-1,1'-螺二氢茚-7,7'-二醇。在2003年，周其林等以这种光学活性的螺二氢茚二酚SPINOL为原料，经过五步反应合成了基于螺二氢茚骨架的双膦配体SDP，可成功用于不对称催化氢化反应(CN1439643)。不过，基于他们的偶联反应为基础的合成路线，无法获得磷原子的苯基上带有吸电子基团(如对三氟甲基及3，5-二(三氟甲基)等取代基团)的双膦配体(南开大学，2003年，博士学位论文《手性螺环双膦配体的设计合成及其应用研究》的第26页，作者：谢建华；J.AM.CHEM.SOC.2003,125,4404-4405)；而且从工业可用的原料间甲氧基苯甲醛出发，至少经过11步合成反应和1步手性拆分才能得到相应的基于螺二氢茚骨架的手性双膦配体SDP，反应步骤冗长，制备成本高，实用性显然大打折扣。
四甲基螺二氢茚二酚(3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二醇，MSPINOL)在1962年就已被报道可从双酚系列产品通过酸催化直接高产率得到，后续已有改良的规模化制备方法和手性拆分方法(如下反应式，J.Chem.Soc.,1962,415-418；Org.Lett.,2004,6,2341-2343；US 2006/0020150；US4879421；Bull.Chem..Soc.Japan,1977,44,496-505)：
Figure PCTCN2017116105-appb-000002
四甲基螺二氢茚二酚MSPINOL及其衍生物主要报道用于制备高聚物，尚无用于任何配体的制备或应用。相应的原料双酚非常廉价，可从丙酮和苯酚或其衍生物进行缩合反应获得；并且工业上有很多双酚系列产品(双酚A，双酚C等等)大规模销售，比如双酚A在全球年产销量高达三百多万吨，价格每吨不到1万元。本发明拟利用廉价易得的四甲基螺二氢茚二酚，设计制备相应的基于四甲基螺二氢茚骨架的膦配体；该类配体相比基于螺二氢茚骨架的膦配体(比如SDP)来说，螺环骨架上无活泼的芳亚甲基，四甲基螺二氢茚骨架更稳定并且刚性更强，原料廉价丰富，合成路线更短，制备成本低廉，实用性强，有独特的二面角预示着不同的催化效果或用途；尤其是利用本发明可获得磷原子的苯基上带有吸电子基团(如对三氟甲基及3，5-二(三氟甲基)等取代基团)的膦配体，将大大丰富膦配体衍生物。基于本发明公开的方法，制备基于四甲基螺二氢茚骨架的膦配体，从工业化大吨位原料双酚出发，一般只要五步合成反应路线即可：
Figure PCTCN2017116105-appb-000003
或者使用七步合成反应路线：
Figure PCTCN2017116105-appb-000004
发明内容
本发明的目的是提供一种基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途。
一种基于四甲基螺二氢茚骨架的膦配体，是具有如下通式I或通式II的化合物或所述化合物的对映体、消旋体或非对映异构体：
Figure PCTCN2017116105-appb-000005
各式中：R1和R6分别独立选自氢、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；R2、R3、R4、R5分别独立选自氢、卤素、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；R7选自C1～C10的烷基或全氟烷基、C3～C6的环烷基、C6～C14芳基、取代的芳基、C5～C14杂芳基、取代的杂芳基；其中所述取代的芳氧基、取代的芳基或取代的杂芳基是具有一个或多个取代基，所述取代基是独立选自卤素、N-二甲基胺基、C1～C4的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、亚甲二氧基、C6～C14芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基。
一种制备基于四甲基螺二氢茚骨架的膦配体的中间体化合物，是具有如下通式III的化合物或所述化合物的对映体、消旋体或非对映异构体：
Figure PCTCN2017116105-appb-000006
式中：R1和R6分别独立选自氢、羟基、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；R2、R3、R4、R5分别独立选自氢、卤素、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；其中所述取代的芳氧基、取代的芳基或取代的杂芳基是具有一个或多个取代基，所述取代基是独立选自卤素，C1～C4的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基。
所述如式I所示的基于四甲基螺二氢茚骨架的膦配体优选是如下任一化合物：
Figure PCTCN2017116105-appb-000007
所述如式II所示的基于四甲基螺二氢茚骨架的膦配体优选是如下任一化合物：
Figure PCTCN2017116105-appb-000008
所述如式III所示的基于四甲基螺二氢茚骨架的膦配体中间体优选是如下任一化合物：
Figure PCTCN2017116105-appb-000009
所述的式I和式II化合物中，R7选自苯基、苄基、五氟苯基、4-甲基苯基、4-甲氧基苯基、4-三氟甲基-苯基、3,5-二甲基苯基、3,5-二氟苯基、3,5-二甲氧基苯基、3,5-二叔丁基苯基、3,4,5-三甲氧基苯基、3,5-二甲基-4-甲氧基-苯基、3,5-二叔丁基-4-甲氧基-苯基、3,5-二甲基-4-甲氧基-苯基、3,5-二(三氟甲基)-苯基。
如式III所示的中间体化合物可以消旋的或旋光活性的四甲基螺二氢茚二酚(式1)为起始原料，经以下反应制备：式1化合物(当R2和R5不等于氢)首先经卤代反应得到化合物2，或式1化合物(当R2和R5至少一个等于氢)经叔丁基化、卤代反应和脱叔丁基反应得到化合物2；化合物2经醚化反应制备得到式III化合物，或先用三氟甲磺酸酐酯化，再经钯催化偶联反应或还原反应制备得到式III化合物；
Figure PCTCN2017116105-appb-000010
Figure PCTCN2017116105-appb-000011
其中，式1、2、3、4、5中X和R1～R6的含义如式III中所述,R选自C1～C10的烷基或全氟烷基、C3～C6的环烷基、芳基或取代的芳基、杂芳基或取代的杂芳基；其中所述取代的芳基或取代的杂芳基是具有一个或多个取代基，所述取代基是独立选自卤素，C1～C4的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基；
其合成方法具体如下：当R2和R5中有一个选自氢，从化合物1制备2的反应步骤是在二氯甲烷或氯仿中，在甲磺酸存在下，化合物1跟叔丁醇反应2-6小时，温度控制在0℃至40℃，得到中间体4；在二氯甲烷或乙酸乙酯中，中间体4跟卤代试剂在对甲苯磺酸催化下反应12-24小时，温度控制在0℃至40℃，得到中间体5；在甲苯或二氯甲烷中，中间体5用三氟甲磺酸处理1-48小时，得到中间体2；其中化合物1、叔丁醇、甲磺酸之间的摩尔比例是1：2～4：5～12，中间体4跟卤代试剂和对甲苯磺酸之间的摩尔比例是1：2～4：0～1，中间体5跟三氟甲磺酸之间的摩尔比例是1：0.8～3；
当R2和R5均不选自氢，从化合物1制备2的卤代反应步骤是在二氯甲烷或乙酸乙酯中，化合物1跟卤代试剂在对甲苯磺酸催化下反应12-24小时，温度控制在0℃至40℃，得到中间体2；其中化合物1跟卤代试剂和对甲苯磺酸之间的摩尔比例是1：2～4：0～1；
卤代试剂可以是N-卤代丁二酰亚胺、二溴海因、氯化碘、溴素、氯气、N-氟二苯磺酰胺；
当R1和R6选自羟基时，式III的化合物就等于是化合物2；
从化合物2制备化合物III(R1和R6不等于羟基)的醚化反应的步骤是在N,N-二甲基甲酰胺、二氧六环、丙酮或二甲亚砜中，在碱存在下，以碘化亚铜为催化剂，温度控制在25℃至100℃，化合物2跟醚化试剂RX反应6-36小时得到式III的化合物；所述的碱是氢氧化钾、氢氧化钠、碳酸钾、碳酸铯、碳酸钠、脯氨酸、N,N-二甲基甘氨酸的一种或任意比例组合物，化合物2、碱和碘化亚铜之间的摩尔比例是1:0.1～5：0～0.2；化合物2和醚化试剂RX之间的摩尔比例是1:2～4；
从化合物2制备化合物3的酯化反应的步骤是在二氯甲烷或二氯乙烷中，在碱存在下，温度控制在0℃至40℃，化合物2跟三氟甲磺酸酐反应0.2-6小时，得到化合物3；所述的碱是吡啶、三乙胺、氢氧化钾或氢氧化钠的一种或任意比例组合物，化合物2、碱和三氟甲磺酸酐之间的摩尔比例是1:2～8:2～6；
从化合物3制备化合物III的还原反应的步骤是在N,N-二甲基甲酰胺、二氧六环或二甲亚砜中，在有机碱存在下，以双(三苯基膦)二氯化钯和1,3-双二苯基膦丙烷为催化剂体系，温度控制在25℃至100℃，化合物3跟甲酸反应1-6小时，得到所述的化合物III；化合物3、甲酸、有机碱、双(三苯基膦)二氯化钯和1,3-双二苯基膦丙烷之间的摩尔比例是1:2～6:8～15:0.05～0.2:0.05～0.2；有机碱是三乙胺、三丙胺或三丁胺；
从化合物3制备化合物III的偶联反应的步骤是在N,N-二甲基甲酰胺、二氧六环、水、丙酮、二甲亚砜或上述任意比例的混合溶剂中，在碱和金属催化剂存在下，温度控制在25℃至 100℃，化合物3跟偶联试剂RB(OH)2反应6-36小时得到式III的化合物；所述的碱是氢氧化钾、氢氧化钠、碳酸钾、碳酸铯、碳酸钠的一种或任意比例组合物，化合物3、碱和金属催化剂之间的摩尔比例是1:0.1～5：0.05～0.2；化合物3和偶联试剂RB(OH)2之间的摩尔比例是1:2～4；所述的金属催化剂是Pd(OAc)2、Pd(PPh3)4、PdCl2、Pd(PPh3)2Cl2、Pd2(dba)3、CuI、dpppNiCl2的至少一种或任意比例组合物。
所述的化合物I的合成方法：以消旋的或旋光活性的式III化合物为原料，在碱作用下与二取代基卤化膦经双取代反应制备得到，或式III化合物在碱作用下与二取代基卤化氧膦经双取代反应制备式6化合物，并经还原反应制备得到；
Figure PCTCN2017116105-appb-000012
其中，X为卤素，式6中R1～R7的含义如式I中所述；
具体为：反应方法①是在四氢呋喃中，反应温度控制在-78℃至-20℃，在碱的作用下反应3-5小时，将式III的X基团脱除后，再与R7 2PCl或R7 2PBr室温反应6-12小时，得到所述的膦配体式I；或者反应方法②是在四氢呋喃中，反应温度控制在-78℃至-20℃，在碱的作用下反应3-5小时，将式III的X基团脱除后，再与R7 2P(O)Cl室温反应6-16小时，得到化合物6,再以乙二醇二甲醚或四氢呋喃为反应溶剂，用四氢铝锂和三氟甲磺酸甲酯处理化合物6，在室温进行还原反应3-6小时得到所述的膦配体I；其中所述碱与式III化合物的摩尔比例都为2～10：1，R7 2PCl或R7 2PBr与式III化合物的摩尔比例都为2～6：1，R7 2P(O)Cl与式III化合物的摩尔比例为2～6：1，四氢铝锂与化合物6的的摩尔比例为3～10：1，三氟甲磺酸甲酯与化合物6的的摩尔比例为1～5：1，所述的碱为叔丁基锂、异丙基溴化镁、乙基溴化镁、仲丁基锂或正丁基锂。
所述的化合物II的合成方法：以消旋的或旋光活性的式III化合物为原料，在碱作用下与二取代基卤化膦经单取代反应制备得到，或式III化合物在碱作用下与二取代基卤化氧膦经单取代反应制备式7化合物，并经还原反应制备得到：
Figure PCTCN2017116105-appb-000013
其中，X为卤素，和R1～R7的含义如式II中所述；
具体为：反应方法①是在四氢呋喃中，反应温度控制在-78℃至-20℃，在碱的作用下反应3-5小时，将式III的X基团脱除后，再与R7 2PCl或R7 2PBr室温反应6-12小时，得到所述的膦配体式II；或者反应方法②是在四氢呋喃中，反应温度控制在-78℃至-20℃，在碱的作用下反应3-5小时，将式III的X基团脱除后，再与R7 2P(O)Cl室温反应6-16小时，得到化合物7,再以乙二醇二甲醚或四氢呋喃为反应溶剂，用四氢铝锂和三氟甲磺酸甲酯处理化合物6，在室温进行还原反应3-6小时得到所述的膦配体II；其中所述碱与式III化合物的摩尔比例都为2～10：1，R7 2PCl或R7 2PBr与式III化合物的摩尔比例都为1～2：1，R7 2P(O)Cl与式III化合物的摩尔比例为1～2：1，四氢铝锂与化合物7的的摩尔比例为3～10：1，三氟甲磺酸甲酯与化合物7的的摩尔比例为1～3：1，所述的碱为叔丁基锂、异丙基溴化镁、乙基溴化镁、仲丁基锂或正丁基锂。
本发明的膦配体的用途：所述的膦配体可独立与铁、锇、金、银、铜、铂、铑、钌、铱、镍、钼、钯或钴等的金属盐络合制备催化剂。
所述的膦配体可独立作为有机小分子催化剂用于环化反应中。
所述的膦配体可独立用于金属催化的偶联反应、N-芳基胺化反应、不对称反应，优选用于金属催化的不对称氢化反应、硅氢化反应、氢转移反应和不对称烯丙基化反应。
本发明的膦配体是以廉价易得的四甲基螺二氢茚二酚为原料，经由通式III作为关键中间体的制备路线获得。本发明开发了一类新型的膦配体，可用于催化有机反应，特别是可作为手性的膦配体广泛用于包括不对称氢化和不对称烯丙基烷基化等许多不对称催化反应中，具有经济实用性和工业应用前景。
应理解，在本发明范围中，本发明的上述各种技术特征和在下文实施例中具体描述的各种技术特征之间都可以互相组合，从而构成新的或优先的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是实施例1中化合物RL-MSPINOL的X射线晶体衍射图；
图2是实施例2中化合物SL-HMSPINOL的X射线晶体衍射图；
图3是实施例2中化合物RL-HMSPINOL的X射线晶体衍射图；
图4是实施例4中化合物(R)-III-f的X射线晶体衍射图。
具体实施方式
以下实施例将有助于理解本发明，但不限于本发明的内容。
通用反应条件说明：当使用了对空气敏感的试剂的所有反应和控制在充满氮气的手套箱中进行或使用标准的Schlenk技术进行。反应溶剂用通用的标准过程干燥处理。
实施例1
333'3'-四甲基-11'-螺二氢茚-66'-二醇(MSPINOL)的合成
Figure PCTCN2017116105-appb-000014
在反应瓶中加入100g双酚A，和500mL甲基磺酸，搅拌溶解，得一深红色溶液。室温搅拌反应96小时后，将反应液倒入600mL水，冷却后抽滤，所得固体用水洗涤。用乙醇在回流状态下溶解该固体，加50度热水至不再有固体析出，趁热过滤，并用热水洗涤滤饼。烘干，得近白色絮状固体45g，即为3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二醇(MSPINOL)，产率大于99％。
消旋体MSPINOL的拆分过程：
Figure PCTCN2017116105-appb-000015
23克消旋体MSPINOL，26毫升三乙胺和0.22克的4-(N，N-二甲基氨基)吡啶(DMAP)溶解在200毫升二氯甲烷中，冰浴冷却，在30分钟内添加32.6克L-薄荷醇氯甲酸酯。然后继续在室温搅拌反应6小时，TLC确认反应进程使得反应充分。接着该反应液依次用稀盐酸和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩至干得到一对非对映体中间体(RSL-MSPINOL)，接着用正己烷重结晶2次，即可以60％的收率得到单一的非对映体(RL-MSPINOL)；该化合物的保留时间23.5min(HPLC:C18柱,流动相甲醇：水＝98：2,流速0.8mL/min,254nm)。结晶母液用正己烷重结晶3次，可以30％收率得到另一非对映体(SL-MSPINOL)，该化合物的保留时间25min(HPLC:C18柱,流动相甲醇：水＝98：2,流速0.8mL/min,254nm)。另外，可用D-薄荷醇氯甲酸酯代替上述过程中的L-薄荷醇氯甲酸酯，也可以55％的收率获得另一非对映体(SL-MSPINOL)。
1.5克化合物RL-HMSPINOL溶解在10毫升甲醇中，加入0.66克氢氧化钾，回流1小时，浓缩，然后加入20毫升二氯甲烷，依次用稀盐酸和饱和食盐水洗涤，有机相用硫酸钠干燥，抽滤，滤液浓缩后进行快速柱层析可得到98％以上收率的(R)-MSPINOL。同理，SL-MSPINOL用上述一样的过程水解即可定量得到到(S)-MSPINOL。
化合物RL-MSPINOL的单晶数据如下(图1)：
Cell:a＝9.6816(3)b＝10.6124(4)c＝39.6866(13)
alpha＝90 beta＝90 gamma＝90；Temperature:293K
Volume 4077.6(2)；Space group P 21 21 21；Hall group P 2ac 2ab
实施例2
3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-6,6'-二醇(HMSPINOL)的合成
Figure PCTCN2017116105-appb-000016
在500mL圆底烧瓶中加入50g双酚C和250mL甲烷磺酸，室温搅拌反应3天后，补加100mL甲烷磺酸，继续反应1天后停止反应。将反应液倒入盛有300mL碎冰的烧杯中，抽滤，滤饼依次用饱和碳酸氢钠溶液和水洗涤。洗涤完后，将所得的粗产品转移至500mL的单口烧瓶中,加入适量乙醇使得产品在回流温度下恰好溶解，加水至有固体明显析出，充分搅匀后冷却，析出大量固体，抽滤，洗涤，滤饼烘干即可得到20g白色粉末状固体，即为3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-6,6'-二醇(HMSPINOL)。收率92％，mp：250-251℃。1H NMR(400MHz,CDCl3):δ＝ 6.92(s,2H),5.85(s,2H),3.95(s,2H),2.30(d,J＝13.0Hz,2H),2.21(s,6H),2.17(d,J＝13.0Hz,2H),1.39(s,6H),1.30(s,6H)；13C NMR(100MHz,CDCl3):δ＝153.18,150.05,144.54,123.55,122.95,110.50,59.40,57.00,43.12,31.88,30.15,15.97；HRMS(EI-TOF):calcd for C23H28O2 336.2089,found 336.2085.
消旋体HMSPINOL的拆分过程：
Figure PCTCN2017116105-appb-000017
5克消旋体HMSPINOL，9.6毫升三乙胺和0.18克的4-(N，N-二甲基氨基)吡啶(DMAP)溶解在50毫升二氯甲烷中，在30分钟内添加7.3毫升L-薄荷醇氯甲酸酯。然后继续在室温搅拌反应3小时，TLC确认反应进程使得反应充分。接着该反应液依次用稀盐酸和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩至干得到一对非对映体中间体(RSL-HMSPINOL)，接着用正己烷重结晶。向这个浓缩液残留物中加入10毫升的正己烷，搅拌溶解，然冷却到-20度保持12小时析出固体，抽滤(滤液也就是结晶母液，单独收集待用)，用冷正己烷洗涤得到的固体重复以上重结晶过程2次，可以以50％的收率得到单一的非对映体(SL-HMSPINOL)；该化合物的保留时间28.02min(HPLC:C18柱,100％MeOH流动相,流速1.0mL/min,254nm)。上述单独收集的结晶母液，浓缩至干后加入13毫升的正己烷，冷却到-4℃保温结晶48小时析出固体，抽滤，用冷正己烷洗涤，即可以35％的收率得到另一单一的非对映体(RL-HMSPINOL)；该化合物的保留时间24.67min(HPLC:C18柱,100％MeOH流动相,流速1.0mL/min,254nm)。
1.5克化合物SL-HMSPINOL溶解在20毫升乙醇中，加入0.66克氢氧化钾，回流2小时，浓缩，然后加入20毫升二氯甲烷，依次用稀盐酸和饱和食盐水洗涤，有机相用硫酸钠干燥，抽滤，滤液浓缩后进行快速柱层析可得到98％以上收率的(S)-HMSPINOL。同理，RL-HMSPINOL用上述一样的过程水解即可定量得到到(R)-HMSPINOL。
如下是化合物SL-HMSPINOL的单晶数据(图2)：
Cell:a＝10.53555(14)b＝16.17984(19)c＝24.4076(3)；
alpha＝90 beta＝90 gamma＝90；Volume 4160.61(9)；
Space group P 21 21 21；Hall group P 2ac 2ab；
化合物SL-HMSPINOL的核磁氢谱1H NMR(400MHz,CDCl3)δ6.99(s,2H),6.55(s,2H),4.55(td,J＝10.9,4.4Hz,2H),2.32(d,J＝13.1Hz,2H),2.27–2.19(m,8H),2.12(dd,J＝6.8,5.0Hz,2H),2.01(dtd,J＝13.9,7.0,2.6Hz,2H),1.74–1.62(m,4H),1.53–1.23(m,17H),1.15–0.82(m,19H),0.79(d,J＝7.0Hz,6H).
如下是化合物RL-HMSPINOL的单晶数据(图3)：
Cell:a＝8.02988(12)b＝14.0700(2)c＝37.5353(6)
alpha＝90 beta＝90 gamma＝90；Temperature:171K；
Volume 4240.75(11)；Space group P 21 21 21；Hall group P 2ac 2ab
化合物RL-HMSPINOL的核磁氢谱1H NMR(400 MHz,CDCl3)δ6.98(s,2H),6.54(s,2H),4.55(td,J=10.9,4.4 Hz,2H),2.33(d,J=13.1 Hz,2H),2.22(m,8H),2.10(d,J=11.9 Hz,2H),2.05–1.92(m,2H),1.69(dd,J=8.9,6.9 Hz,4H),1.54–1.23(m,18H),1.14–0.98(m,4H),0.96–0.85(m,14H),0.79(d,J=7.0 Hz,6H).
实施例3
(R)-3,3,3',3'-四甲基-7,7'-二溴-1,1'-螺二氢茚（(R)-III-a）的合成
Figure PCTCN2017116105-appb-000018
在反应瓶中，加入15.4g化合物(R)-MSPINOL（分子量308，0.05摩尔），15mL叔丁醇（0.156摩尔），180mL二氯甲烷。搅拌均匀（悬浊液）后，在冰水浴冷却下滴加27mL甲磺酸（0.41摩尔），浑浊逐渐消失；滴加完毕，撤去冰水浴后，反应液会重新变得浑浊，继续搅拌反应2小时后，加100mL冰水淬灭反应。反应液减压蒸除二氯甲烷，然后搅拌下加入200mL以上的乙酸乙酯使析出的固体全部溶解；分液，水相用乙酸乙酯萃取，合并有机相；有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩至干得类白色固体，用乙醇-水快速重结晶提纯。在80度用适量乙醇溶解该固体，使得在乙醇回流状态下恰好全溶，接着搅拌下缓缓加入热水会析出固体，加热水直到不再有固体析出，趁热抽滤，并用热水充分洗涤。将滤饼烘干即得20.2g白色固体化合物(R)-BMSPINOL，收率96%；1H NMR(400 MHz,CDCl3)δ7.05(s,2H),5.41(s,2H),3.05(s,2H),2.28(d,J=13.0 Hz,2H),2.10(d,J=13.0 Hz,2H),1.42(s,6H),1.35(s,18H),1.28(s,6H)。
氮气氛围下，19.6g化合物(R)-BMSPINOL溶解在200毫升的乙酸乙酯中，分批加入18.3g的N-溴代丁二酰亚胺（NBS），室温搅拌16小时即完成反应。向所得的黄色溶液中加入50mL饱和亚硫酸氢钠溶液，剧烈搅拌30分钟，分液，有机相用饱和食盐水洗涤，用无水硫酸钠干燥后，抽滤，滤液浓缩至干，接着用甲醇重结晶。加入50mL甲醇，回流搅拌5分钟，充分冷却至室温，抽滤，滤饼用少量甲醇洗涤，烘干，得25.4g的浅黄色粉末即为化合物(R)-III-ef（收率90%）；1H NMR(400MHz,CDCl3)δ6.98(s,2H),5.80(s,2H),2.49(d,J=13.1 Hz,2H),2.25(d,J=13.1Hz,2H),1.41(s,18H),1.39(s,6H),1.32(s,6H)。
在反应瓶中加入15g化合物(R)-III-ef，用105mL甲苯溶解。冰水浴冷却下，加入2mL三氟甲磺酸，搅拌反应1小时，TLC监控至反应完全，加入30mL冰水淬灭反应，减压旋蒸除去甲苯，用乙酸乙酯萃取，依次用饱和食盐水、饱和碳酸氢钠溶液及饱和食盐水各洗涤1遍，有机相经无水硫酸钠干燥后减压浓缩除去乙酸乙酯；向浓缩物中加入30mL热的正己烷，回流搅拌15分钟后冷至室温，抽滤，滤饼用正己烷洗涤后烘干，得10.8g的白色粉末即为化合物(R)-III-e，，收率89%；1H NMR(400 MHz,CDCl3)δ7.03(d,J=8.2 Hz,2H),6.95(d,J=8.2 Hz,2H),5.47(s,2H),2.52(d,J=13.1 Hz,2H),2.29(d,J=13.1 Hz,2H),1.41(s,6H),1.34(s, 6H)。
氮气氛围下，在反应瓶中加入8.8g化合物(R)-III-e，40mL二氯甲烷和3.8mL吡啶，搅拌溶解后，用冰水浴冷却；接着慢慢滴加6.5毫升的三氟甲磺酸酐，室温下搅拌反应1小时，TLC监控至反应完全；反应液依次用稀盐酸、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，抽滤，滤液浓缩至干后，用快速硅胶柱层析纯化可以得到13.2g白色固体粉末即为化合物(R)-III-e’，收率96％。1H NMR(400MHz,CDCl3)δ7.26(d,J＝8.3Hz,2H),7.19(d,J＝8.3Hz,2H),2.59(d,J＝13.3Hz,2H),2.36(d,J＝13.2Hz,2H),1.45(s,6H),1.39(s,6H).
氮气氛围下，在反应瓶中加入12g化合物(R)-III-e’，460mg双(三苯基膦)二氯化钯和351mg的1,3-双(二苯基膦丙烷)。然后在搅拌下向反应瓶中依次注入170mL的N,N-二甲基甲酰胺(DMF)，27mL的三乙胺，4.8mL的甲酸。接着该体系在80℃搅拌反应80分钟，TLC监控至反应完全。冷却至室温，向反应液中加入150mL水和50mL稀盐酸(3M)，200毫升乙酸乙酯；萃取分液，水相用乙酸乙酯再次萃取，合并有机相。该有机相用饱和食盐水洗涤后，再用5毫升双氧水(30％)震荡洗涤(氧化其中的膦配体DPPP)，然后有机相再次用饱和食盐水洗涤；有机相用无水硫酸钠干燥后减压浓缩干得一类白色固体。最后用快速柱层析(200-300目硅胶，E/P＝1:20)，可以得到6.8g白色固体，即为化合物(R)-III-a(收率95％)。1H NMR(400MHz,CDCl3)δ7.29(dd,J＝7.2,1.2Hz,2H),7.16–7.07(m,4H),2.56(d,J＝13.1Hz,2H),2.27(d,J＝13.1Hz,2H),1.44(s,6H),1.36(s,6H).
实施例4
(R)-3,3,5,3',3',5'-六甲基-7,7'-二溴-1,1'-螺二氢茚((R)-III-b)的合成
Figure PCTCN2017116105-appb-000019
在500mL的三口烧瓶中加入18g(R)-HMSPINOL，加入200mL二氯甲烷，电磁搅拌下分批加入19.8g N-溴代丁二酰亚胺，室温下搅拌1小时，TLC(石油醚：乙酸乙酯＝5:1)确认反应结束，加入过量的饱和亚硫酸氢钠溶液，继续搅拌1小时，分液，并用100mL二氯甲烷洗涤水相，合并有机相，并用饱和食盐水洗涤，有机相用无水硫酸钠干燥，抽滤，滤液除去溶剂即可得到26.4g淡黄色固体粉末(R)-III-f，收率99.8％，mp：228℃。1H NMR(400MHz,CDCl3)δ＝6.88(s,2H),5.57(s,2H),2.47(d,J＝13.1Hz,2H),2.31(s,6H),2.25(d,J＝13.0Hz,2H),1.39(s,6H),1.33(s,6H).13C NMR(101MHz,CDCl3)δ＝149.25,145.61,142.67,124.51, 123.60,107.15,60.85,55.57,43.06,32.58,29.28,17.11；HRMS(EI-TOF):calcd for C23H26Br2O2 492.0300,found 492.0302；
单晶数据如下(结构图如图4)：
Cell:a＝7.5979(5)b＝14.0001(10)c＝19.6290(12)
alpha＝90 beta＝90 gamma＝90；Temperature:171K
Space group P 21 21 21；Hall group P 2ac 2ab
Figure PCTCN2017116105-appb-000020
在三口烧瓶中加入(R)-III-f(9g，18.2mmol)氮气保护，依次加入二氯甲烷(150mL)，吡啶(7.7mL)，冰浴下缓慢加入三氟甲磺酸酐(7.7mL)，室温下搅拌反应1小时，TLC监控反应结束；反应液依次用稀盐酸、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，抽滤，滤液浓缩至干后，用快速硅胶柱层析(淋洗液：石油醚：乙酸乙酯＝10:1)，得到白色固体粉末(R)-III-f’(13.2g，收率96％)，mp:206℃。1H NMR(400MHz,CDCl3):δ＝7.02(s,2H),2.55(d,J＝13.2Hz,2H),2.45(s,6H),2.30(d,J＝13.2Hz,2H),1.42(s,6H),1.36(s,6H)；19F NMR(400MHz,CDCl3):δ＝-72.18(s)；13C NMR(100MHz,CDCl3):δ＝153.74,145.12,144.55,132.61,124.80,123.33,120.14,116.95,113.77,113.37,61.28,54.92,43.43,32.37,28.81,18.16；HRMS(EI-TOF):calcd for C25H24F2Br2O2S2 755.9285,found755.9285；
Figure PCTCN2017116105-appb-000021
在三口烧瓶中加入(R)-III-f’(12.9g)，双(三苯基膦)氯化钯(515mg)，1,3-双(二苯基膦丙烷)(361mg)，氮气保护，依次加入N,N-二甲基甲酰胺(150mL，DMF)和三丙胺(38.5mL)，0℃下缓慢加入甲酸(5.1mL)，油浴80℃下搅拌反应1小时。反应结束后，冷却至室温，加水淬灭反应，加入乙酸乙酯进行分液萃取，水相用乙酸乙酯再萃取一遍，合并有机相后用30％的过氧化氢溶液充分洗涤5分钟，再依次用4Mol/L的HCl溶液、饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤， 无水硫酸钠干燥，抽滤，滤液浓缩至干，硅胶柱快速柱层析(淋洗液：石油醚：乙酸乙酯＝50:1)得到白色粉末状固体(R)-III-b，收率：95％，mp：202℃。1H NMR(400MHz,CDCl3):δ＝7.18(s,J＝7.4Hz,2H),6.97(s,2H),2.57(d,J＝13.1Hz,2H),2.38(s,6H),2.28(d,J＝13.1Hz,2H),1.43(s,6H),1.38(s,J＝8.2Hz,6H)；13C NMR(100MHz,CDCl3)：δ＝154.92,142.48,138.92,131.88,122.32,119.14,59.79,55.36,43.42,32.56,28.94,20.98.
实施例5
3,3,3',3'-四甲基-5,5'-二叔丁基-7,7'-二碘-1,1'-螺二氢茚-6,6'-二醇(III-bg)的合成
Figure PCTCN2017116105-appb-000022
在反应瓶中加入1.5g的HMSPINOL和0.15g的对甲苯磺酸，加入45mL二氯甲烷，磁搅拌下缓缓加入2.1g N-碘代丁二酰亚胺，室温下搅拌6小时至TLC(石油醚：乙酸乙酯＝5:1)确认反应结束，加入过量的饱和亚硫酸氢钠溶液，继续搅拌1小时，分液，并用20mL二氯甲烷洗涤水相，合并有机相，并用饱和食盐水洗涤，有机相用无水硫酸钠干燥，抽滤，滤液除去溶剂即可得到2.24g固体粉末III-bg。1H NMR(400MHz,CDCl3)δ7.01(s,2H),5.68(s,2H),2.45(d,J＝13.1Hz,2H),2.25(d,J＝13.1Hz,2H),1.42(s,6H),1.41(s,18H),1.33(s,6H).
实施例6
3,3,5,3',3',5'-六甲基-7,7'-二碘-1,1'-螺二氢茚-6,6'-二醇(III-h)的合成
Figure PCTCN2017116105-appb-000023
在反应瓶中加入1.5g的HMSPINOL和0.195g的对甲苯磺酸，加入45mL二氯甲烷，磁搅拌下缓缓加入2.254g N-碘代丁二酰亚胺，室温下搅拌5小时至TLC(石油醚：乙酸乙酯＝5:1)确认反应结束，加入过量的饱和亚硫酸氢钠溶液，继续搅拌1小时，分液，并用20mL二氯甲烷洗涤水相，合并有机相，并用饱和食盐水洗涤，有机相用无水硫酸钠干燥，抽滤，滤液除去溶剂即可得到2.44g黄色固体粉末III-h，收率93％
实施例7
(R)-3,3,3',3'-四甲基-6,6'-二甲氧基-7,7'-二溴-1,1'-螺二氢茚(III-h)的合成
Figure PCTCN2017116105-appb-000024
在反应瓶中加入3g的MSPINOL和3.56g的碳酸钾，加入30mL丙酮，注入1.6mL的碘甲烷，升温至35度，搅拌反应12小时至TLC监控原料消失并完全成为一个产物点；加入浓氨水60mL,继续搅拌2小时。降至室温后，抽滤，热水洗涤3次，烘干得到白色粉末3.04g的III-j，收率96％。1H NMR(400MHz,CDCl3)δ7.08(dd,J＝8.2,4.4Hz,2H),6.82(dd,J＝8.2,4.4Hz,2H),3.85(6H),2.61(d,J＝13.0Hz,2H),2.27(d,J＝13.0Hz,2H),1.42(s,6H),1.35(s,6H)。
实施例8
(R)-3,3,5,3',3',5'-六甲基-6,6'-二苯基-7,7'-二溴-1,1'-螺二氢茚((R)-III-ff)的合成
Figure PCTCN2017116105-appb-000025
氮气保护，在反应瓶中加入(R)-III-f’(0.22g)，苯基硼酸0.3g，溴化钾0.1g，四(三苯基膦)钯(50mg)，再加入2mL乙二醇二甲醚(DME)和1mL水以及0.45g的3水合磷酸钾，90℃下搅拌反应24小时。反应结束后，加水淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，抽滤，滤液浓缩至干，硅胶柱快速柱层析得到粉末状固体(R)-III-ff，收率：55％。
实施例9
(R)-3,3,3',3'-四甲基-7,7'-二碘-1,1'-螺二氢茚((R)-III-aa)的合成
Figure PCTCN2017116105-appb-000026
氮气氛围下，在烧瓶中加入(R)-III-a(1g)，和10毫升的无水脱气的四氢呋喃，降温到-78度，滴加叔丁基锂的正己烷溶液(8mL,2mol/L)，搅拌反应1小时，然后加入碘(10mmol)，接着自然升温到室温反应过夜，加水淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，抽滤，滤液浓缩至干，硅胶柱快速柱层析得到(R)-III-aa，收率：80％。1H NMR(400MHz,CDCl3)δ7.63(dd,J＝7.7,0.9Hz,2H),7.19(dd,J＝7.5,0.9Hz,2H),6.94(dd,J＝14.4,6.8Hz,2H),2.49(d,J＝13.1Hz,2H),2.27(d,J＝13.0Hz,2H),1.47(s,6H),1.36(s,6H).
实施例10
(R)-3,3,5,3',3',5'-六甲基-7,7'-二(二苯基膦基)-1,1'-螺二氢茚((R)-I-b)的合成方法一:
Figure PCTCN2017116105-appb-000027
氮气氛围下，在反应瓶中加入(R)-III-b(1g,1.08mmol)，加入15mL的脱气无水四氢呋喃，降至-78℃，加入叔丁基锂的正己烷溶液(6mL,1.6M)，反应三个小时后加入二苯基氯化膦(6mmol)，30分钟后自然升至室温，继续反应6小时。反应结束后，加入适量的稀盐酸淬灭反应，乙酸乙酯 萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶快速柱层析(淋洗液：石油醚：乙酸乙酯＝50:1)得到固体(R)-I-b，该配体也可命名为(R)-HMSDP；收率60％，熔点269-270℃,[α]D 20＝96.3o(c 0.12,CH2Cl2)；1H NMR(400MHz,CDCl3):δ＝7.23–7.21(m,6H),7.16(t,J＝7.3Hz,2H),7.05–6.98(m,10H),6.85–6.79(m,6H),2.33(d,J＝13.4Hz,2H),2.29(s,6H),2.14(d,J＝13.4Hz,2H),1.25(s,6H),1.15(s,6H)；31PNMR(162MHz,CDCl3):δ＝-20.81(s)；HRMS(EI-TOF):calcd forC47H46P2 672.3075,found672.3079.
方法二：
Figure PCTCN2017116105-appb-000028
氮气氛围下，在反应瓶中加入(R)-III-b(1g,1.08mmol)，加入15mL的脱气无水四氢呋喃，降至-78℃，加入叔丁基锂的正己烷溶液(4mL,1.6M)，反应三个小时后加入二苯基磷酰氯(6mmol)，30分钟后自然升至室温，继续反应16小时。反应结束后，加入适量的稀盐酸淬灭反应，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶快速柱层析(淋洗液：石油醚：乙酸乙酯＝2:1)得到白色固体的六甲基双(二苯基氧磷)螺环二氢茚，收率72％；核磁表征数据为1H NMR(400MHz,CDCl3):δ＝7.57–7.48(m,4H),7.43(td,J＝7.3,1.3Hz,2H),7.35(ddd,J＝8.3,5.1,2.1Hz,4H),7.27(q,J＝7.5Hz,6H),7.12(s,2H),7.07(td,J＝7.9,2.7Hz,4H),6.81(d,J＝14.1Hz,2H),2.43(d,J＝12.8Hz,2H),2.24(s,6H),2.16(d,J＝12.8Hz,2H),1.37(s,6H),1.27(s,6H)；31P NMR(400MHz,CDCl3):δ＝31.22(s)；HRMS(EI-TOF):calcd forC47H46O2P2 704.2973,found 704.2977；
氮气氛围下，在反应瓶中加入1g的六甲基双(二苯基氧磷)螺环二氢茚和12毫升的乙二醇二甲醚，并加0.1毫升的三氟甲磺酸甲酯，室温搅拌3小时后，冷却到0℃加6.6毫升的四氢铝锂的四氢呋喃溶液(2.5mol/L)，0℃下反应约3小时，TLC跟踪，确认反应结束。用稀盐酸淬灭反应，乙醚萃取，依次用饱和NaHCO3溶液洗涤，饱和NaCl洗涤，然后有机相用无水硫酸钠干燥，抽滤，滤液浓缩，柱层析(EA:PE＝1:100)得到固体(R)-I-b，收率90％。
实施例11
(R)-3,3,5,3',3',5'-六甲基-7-(二苯基膦基)-1,1'-螺二氢茚((R)-II-b)的合成
Figure PCTCN2017116105-appb-000029
氮气氛围下，在反应瓶中加入(R)-III-b(1g)，加入15mL的脱气无水四氢呋喃，降至-78℃，加入叔丁基锂的正己烷溶液(6mL,1.6M)，反应三个小时后加入二苯基氯化膦(1.2mmol)，30分钟后自然升至室温，继续反应6小时。反应结束后，加入适量的稀盐酸淬灭反应，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶快速柱层析(淋洗液：石油醚：乙酸乙酯＝50:1)得到固体(R)-II-b，收率66％，熔点197-198℃；[α]D 20＝5.8o(c 0.06,CH2Cl2)。1H NMR(400MHz,CDCl3):δ＝7.20(4H),7.18–7.12(m,2H),7.02(3H),6.93–6.87(m,3H),6.78–6.73(m,1H),6.25(2H),3.02–2.91(m,1H),2.36(1H),2.24(s,6H),2.22(1H)2.12(1H),1.50(s,3H),1.38(s,3H),1.35(s,3H),1.32(s,3H). 31P NMR(162MHz,CDCl3):δ＝-22.47(s).13C NMR(101MHz,CDCl3):δ＝152.28,152.20,151.08,150.84,150.76(d,J＝2.9Hz),148.07(d,J＝4.1Hz),138.64(d,J＝14.7Hz),135.69(t,J＝6.7Hz),135.04(d,J＝2.8Hz),134.79,132.75,132.54,131.98,131.79,131.57,131.36,130.86(d,J＝9.1Hz),126.97,126.91(d,J＝1.7Hz),126.53–126.32(m),126.13,122.73(d,J＝4.2Hz),121.02,59.69,57.24(d,J＝6.9Hz),57.07(d,J＝2.7Hz),42.56,41.89,31.86(d,J＝2.7Hz),31.18,29.16,27.35(d,J＝2.6Hz),20.30(d,J＝11.9Hz).HRMS(EI-TOF):calcd forC35H37P 488.2633,found 488.2639
实施例12
(R)-3,3,5,3',3',5'-六甲基-7,7'-二(二(4-三氟甲基苯基)膦基)-1,1'-螺二氢茚((R)-I-bg)的合成
Figure PCTCN2017116105-appb-000030
氮气氛围下，在反应瓶中加入(R)-III-b(1g,1.08mmol)，加入15mL的脱气无水四氢呋喃，降至-78℃，加入叔丁基锂的正己烷溶液(6mL,1.6M)，反应三个小时后加入二(4-三氟甲基苯基)氯化膦(6mmol)，30分钟后自然升至室温，继续反应6小时。反应结束后，加入适量的稀盐酸淬灭反应，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶快速柱层析(淋洗液：石油醚：乙酸乙酯＝50:1)得到固体(R)-I-bg，收率55％；[α]D 20＝120.4o(c0.07,CH2Cl2)。1H NMR(400MHz,CDCl3):δ＝7.47(d,J＝7.8Hz,4H),7.22(d,J＝7.7Hz,4H),7.06(s,2H),7.04–6.96(m,4H),6.81(t,J＝7.3Hz,6H),2.34(m,8H),2.32(s,2H),1.29(s,6H),1.23(s,6H).31P NMR(162MHz,CDCl3):δ＝-21.54.
实施例13
(R)-3,3,5,3',3',5'-六甲基-7,7'-二(二(3,5-双(三氟甲基)苯基)膦基)-1,1'-螺二氢茚((R)-I-bbg)的合成
Figure PCTCN2017116105-appb-000031
氮气氛围下，在反应瓶中加入(R)-III-b(1g,1.08mmol)，加入15mL的脱气无水四氢呋喃，降至-78℃，加入叔丁基锂的正己烷溶液(4mL,1.6M)，反应三个小时后加入二(3,5-双(三氟甲基)苯基)氯化膦(6mmol)，30分钟后自然升至室温，继续反应6小时。反应结束后，加入适量的稀盐酸淬灭反应，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶快速柱层析(淋洗液：石油醚：乙酸乙酯＝40:1)得到固体(R)-I-bbg，收率65％。
实施例14
按照实施例13同样的反应过程，用二(3,4-二甲基苯基)氯化膦代替二(3,5-双(三氟甲基)苯基)氯化膦，则以73％的收率得到了(R)-3,3,5,3',3',5'-六甲基-7,7'-二(二(3,4-二甲基苯基)膦基)-1,1'-螺二氢茚((R)-I-bbb)；熔点121-122度，[α]D 20＝17.9o(c 0.11,CH2Cl2).
实施例15
按照实施例13同样的反应过程，用二(4-甲氧基苯基)氯化膦代替二(3,5-双(三氟甲基)苯 基)氯化膦，则以75％的收率得到了(R)-3,3,5,3',3',5'-六甲基-7,7'-二(二(4-甲氧基苯基)膦基)-1,1'-螺二氢茚((R)-I-bbo)。
实施例16
(R)-3,3,3',3'-四甲基-7,7'-二(二苯基膦基)-1,1'-螺二氢茚((R)-I-a)的合成
Figure PCTCN2017116105-appb-000032
氮气氛围下，在反应瓶中加入(R)-III-a(1g)，加入15mL的脱气无水四氢呋喃，降至-78℃，加入叔丁基锂的正己烷溶液(5mL,1.6M)，反应三个小时后加入二苯基氯化膦(6mmol)，30分钟后自然升至室温，继续反应6小时。反应结束后，加入稀盐酸淬灭反应，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶快速柱层析(淋洗液：石油醚：乙酸乙酯＝50:1)得到固体(R)-I-a,该配体也可命名为(R)-MSDP，收率72％。1H NMR(400MHz,CDCl3)δ7.27(t,J＝7.5Hz,2H),7.23–7.15(m,10H),7.09–7.01(m,6H),7.00–6.94(m,4H),6.79(t,J＝7.1Hz,4H),2.36(d,J＝13.2Hz,2H),2.19(d,J＝13.2Hz,2H),1.27(s,6H),1.17(s,6H).HRMS(EI-TOF)for C45H42P2：644.2764。
实施例17
按照实施例16同样的反应过程，用二(3,5-双(三氟甲基)苯基)氯化膦代替二苯基氯化膦，则以60％的收率得到了(R)-3,3,3',3'-四甲基-7,7'-二(二(3,5-双(三氟甲基)苯基)膦基)-1,1'-螺二氢茚((R)-I-af)，HRMS(EI-TOF)for C53H34F24P2:1188.1755。
实施例18
按照实施例16同样的反应过程，用二(4-(三氟甲基)苯基)氯化膦代替二苯基氯化膦，则以68％的收率得到了(R)-3,3,3',3'-四甲基-7,7'-二(二(4-(三氟甲基)苯基)膦基)-1,1'-螺二氢茚((R)-I-aa)，HRMS(EI-TOF)for C49H38F12P2:916.2257。
实施例19
PdCl2((S)-HMSDP)的合成
在氮气氛围下，向反应瓶中加入甲基螺环膦配体(S)-I-b(该配体也称为(R)-HMSDP，0.178mmol)和2毫升苯，搅拌溶解充分，然后加入含有46毫克的二乙腈合氯化钯(0.178mmol,PdCl2(MeCN)2)的4毫升苯溶液。室温搅拌12小时，析出固体，抽滤，苯洗涤，真空干燥得到PdCl2((S)-HMSDP)络合物，收率85％。1H NMR(400MHz,CDCl3)δ＝7.88–7.69(m,4H),7.29(m,4.2Hz,6H),7.14(m,4H),7.03(m,2.2Hz,4H),6.62(s,2H),2.13(s,6H),2.09(d,J＝12.5Hz,2H),1.64(d,J＝12.5Hz,2H),1.17(s,6H),0.52(s,6H).31P NMR(162MHz,CDCl3)δ＝37.65(s).
实施例20
络合物RuCl2-[(R)-HMSDP][(R,R)-DPEN]的合成
Figure PCTCN2017116105-appb-000033
在氮气氛围的手套箱中称取甲基螺环膦配体(R)-HMSDP(0.165mmol，即化合物(R)-I-b)和Ru(C6H6)Cl2(0.08mmol,40mg)，加入到Schlenk反应管中。然后在氮气氛围下注入3毫升的干 燥脱气的N,N-二甲基甲酰胺（DMF），搅拌下加热到100度反应2小时，接着冷却到室温后，加入(R,R)-1,2-二苯基乙二胺（(R,R)-DPEN,0.165mmol,35mg），该反应继续室温搅拌16小时。使用减压真空脱去溶剂并干燥，即得定量的到固体产物RuCl2-[(R)-HMSDP][(R,R)-DPEN]。
实施例21
Figure PCTCN2017116105-appb-000034
在氮气氛围下，反应瓶中加入0.4克对甲基苯硼酸、0.2克环己烯酮、23毫克醋酸钯、0.6克碳酸铯和83毫克甲基螺环膦配体(±)-I-b（消旋体），然后注入8毫升甲苯和30微升的氯仿，在80度搅拌反应48小时，反应液用饱和食盐水洗涤，有机相用硫酸钠干燥后柱层析，获得330毫克产物3-对甲苯基-环己酮，产率85%。1H NMR(400 MHz,CDCl3)δ=7.20–7.03(m,4H),2.98(m,1H),2.57(m,1H),2.52(m,1H),2.49–2.42(m,1H),2.42–2.35(m,1H),2.33(s,3H),2.18–2.10(m,1H),2.06(m,1H),1.89–1.70(m,2H).
实施例22
Figure PCTCN2017116105-appb-000035
在氮气氛围下，称取4.8mg的手性甲基螺环膦配体(S)-HMSDP和1mg金属[Pd（C3H5）Cl]2）于Schlenk反应管中，加入1mL甲苯，室温下搅拌2小时，接着冷却到-25℃，加入32毫克的1，3-二（邻氯苯基）-2-烯丙基醋酸酯；然后加入已经提前混合搅拌30分钟的丙二酸二苄酯（45ul）、Et2Zn（300ul,1M in hexane）和1mL的甲苯溶液，在-25℃保温反应2小时。接着加入饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤、无水硫酸钠干燥脱溶后硅胶柱层析（乙酸乙酯:石油醚=1:20）即可得到手性的烯丙基化目标产物，收率90%，ee=88%；HPLC条件为：Chiralcel IA，iPrOH:Hexane=85:15，流速：1.0mL/min,室温，254nm,t1:9.66min(次要产物)，t2:11.88min（主要产物）。1H NMR(400 MHz,CDCl3)δ=7.39–7.27(m,1H),7.27–7.20(m,10H),7.20–7.08(m,7H),6.84(d,J=15.8 Hz,1H),6.29(m,1H),5.13(d,J=1.0 Hz,2H),4.98(q,J=12.3 Hz,2H),4.89(t,J=9.6 Hz,1H),4.24(d,J=10.5Hz,1H)。
实施例23
Figure PCTCN2017116105-appb-000036
在氮气氛围下，称取二乙腈合氯化钯（26mg，0.1mmol）和(R)-MSDP（0.1mmol），混合于2毫升甲苯中，搅拌反应2小时，减压蒸除溶剂至干，加入6毫升二氯甲烷；然后继续加入含有三氟甲磺酸银（51mg，0.2mmol）的3毫升乙腈，搅拌反应5分钟，抽滤，滤饼用二氯甲烷洗涤，滤液浓缩并高真空抽干得到定量收率的[(R)-MSDP]Pd(OTf)2。在氮气氛围下，向反应瓶中加入0.01mmol的催化剂[(R)-MSDP]Pd(OTf)2，新蒸馏的0.5mmol苯胺和0.75mmol的2-萘基乙烯，并注入无水脱气的1毫升甲苯，然后在75度搅拌反应40小时结束反应，用硅胶柱层析（乙酸乙酯:石油醚=1:35）纯化得到不对称氢胺化反应的目标产物，收率61%，41%ee。HPLC条件为：ChiralpakOD-H,n-hexane/EtOH=98/2,流速：0.8mL/min,室温，254nm,t1:20.8min(主要产物)，t2:22.8 min(次要产物)。1H NMR(400MHz,CDCl3)δ7.79(dd,J＝10.9,5.5Hz,4H),7.53-7.39(m,3H),7.12-7.03(m,2H),6.63(t,J＝7.3Hz,1H),6.59-6.51(m,2H),4.63(q,J＝6.7Hz,1H),4.11(s,1H),1.58(d,J＝6.7Hz,3H)。
作为比较，按照上述过程，用(R)-SDP代替(R)-MSDP，则所得的不对称氢胺化反应的目标产物，收率10％，0％ee，即产物是消旋体。
实施例24
Figure PCTCN2017116105-appb-000037
在氮气氛围下，向反应瓶加入0.05mmol的三氟甲磺酸铜和0.06mmol的(±)-TMSDP，注入1毫升的1,2-二氯乙烷，室温搅拌30分钟，接着加入0.5mmol的2-(1-苯乙烯基)苯甲酸和1mmol的吗啉苯甲酸酯，回流反应1小时。该反应液加二氯乙烷并用饱和碳酸氢钠洗涤，接着用饱和食盐水洗涤，有机相用无水硫酸钠干燥后浓缩，并用硅胶柱层析(乙酸乙酯:石油醚＝1:2)纯化得到环化反应的目标产物，收率81％。1H NMR(CDCl3,400MHz):δ7.91(d,J＝7.6Hz,1H),7.66–7.49(m,5H),7.41–7.29(m,3H),3.48–3.40(m,2H),3.38–3.29(m,2H),3.21(d,J＝14.2
Hz,1H),3.14(d,J＝14.2Hz,1H),2.60–2.50(m,2H),2.27–2.17(m,2H)。
实施例25
氮气氛围下，在反应瓶中加入(R)-III-b(1mmol)，加入5毫升乙醇，回流搅拌溶解，把该溶液缓缓加入到溶解了HAuCl4·4H2O(206mg,0.5mmol)的3毫升乙醇溶液，接着室温反应搅拌2小时后，抽滤，滤饼溶解在5毫升二氯甲烷中，然后加入50毫升石油醚析出沉淀物，抽滤，滤饼真空干燥得到一价金盐的络合物[(R)-III-b]AuCl，收率80％。
实施例26
Figure PCTCN2017116105-appb-000038
氮气氛围下，在反应瓶中加入III-b(0.05mmol)和0.5毫摩尔的丙二烯基甲酸乙酯(In-2)以及烯烃In-1，注入5毫升甲苯，室温搅拌反应12小时，反应液浓缩后硅胶柱层析，获得[3+2]的环化产物In-3，收率80％。
用消旋体的MSDP代替III-b，进行上述反应，可以得到[3+2]的环化产物In-3，收率71％。

Claims (13)

  1. 一种基于四甲基螺二氢茚骨架的膦配体，其特征在于，是具有如下通式I或通式II的化合物或所述化合物的对映体、消旋体或非对映异构体：
    Figure PCTCN2017116105-appb-100001
    各式中：R1和R6分别独立选自氢、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；R2、R3、R4、R5分别独立选自氢、卤素、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；R7选自C1～C10的烷基或全氟烷基、C3～C6的环烷基、C6～C14芳基、取代的芳基、C5～C14杂芳基、取代的杂芳基；其中所述取代的芳氧基、取代的芳基或取代的杂芳基是具有一个或多个取代基，所述取代基是独立选自卤素、N-二甲基胺基、C1～C4的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、亚甲二氧基、C6～C14芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基。
  2. 如权利要求1所述的基于四甲基螺二氢茚骨架的膦配体，其特征在于，所述如式I所示的化合物是如下任一化合物：
    Figure PCTCN2017116105-appb-100002
  3. 如权利要求1所述的基于四甲基螺二氢茚骨架的膦配体，其特征在于，所述如式II所示的化合物是如下任一化合物：
    Figure PCTCN2017116105-appb-100003
  4. 如权利要求1所述的式I和式II化合物，其特征在于，R7选自苯基、苄基、五氟苯基、4-甲基苯基、4-甲氧基苯基、4-三氟甲基-苯基、3,5-二甲基苯基、3,5-二氟苯基、3,5-二甲氧基苯基、3,5-二叔丁基苯基、3,4,5-三甲氧基苯基、3,5-二甲基-4-甲氧基-苯基、3,5-二叔丁基-4-甲氧基-苯基、3,5-二甲基-4-甲氧基-苯基、3,5-二(三氟甲基)-苯基。
  5. 一种制备权利要求1所述的基于四甲基螺二氢茚骨架的膦配体的中间体化合物，其特征在于，是具有如下通式III的化合物或所述化合物的对映体、消旋体或非对映异构体：
    Figure PCTCN2017116105-appb-100004
    式中：R1和R6分别独立选自氢、羟基、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；R2、R3、R4、R5分别独立选自氢、卤素、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基或取代的芳基、杂芳基或取代的杂芳基；其中所述取代的芳氧基、取代的芳基或取代的杂芳基是具有一个或多个取代基，所述取代基是独立选自卤素，C1～C4的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基；X为卤素。
  6. 如权利要求5所述的中间体化合物，其特征在于，所述如式III所示的化合物是如下任一化合物：
    Figure PCTCN2017116105-appb-100005
  7. 权利要求5所述的如式III所示的中间体化合物的合成方法，其特征在于，以消旋的或旋光活性的四甲基螺二氢茚二酚(式1)为起始原料，经以下反应制备：
    式1化合物首先经卤代反应得到化合物2，化合物2经醚化反应制备得到式III化合物，或化合物2先用三氟甲磺酸酐酯化得到化合物3，化合物3再经钯催化偶联反应或还原反应制备得到式III化合物；
    Figure PCTCN2017116105-appb-100006
    式中的X为卤素、R1～R6如权利要求5中所述,R选自C1～C10的烷基或全氟烷基、C3～C6的环烷基、芳基或取代的芳基、杂芳基或取代的杂芳基；其中所述取代的芳基或取代的杂芳基是具有一个或多个取代基，所述取代基是独立选自卤素，C1～C4的烷基或全氟烷基、C3～C6的环烷基、C1～C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基。
  8. 权利要求1所述的如式I所示化合物的合成方法，其特征在于，以消旋的或旋光活性的式III化合物为原料，在碱作用下与二取代基卤化膦经双取代反应制备得到式I化合物，其反应式为：
    Figure PCTCN2017116105-appb-100007
    或者，式III化合物在碱作用下与二取代基卤化氧膦经双取代反应制备式6化合物，经还原反应制备得到式I化合物；其反应式为：
    Figure PCTCN2017116105-appb-100008
    式中X为卤素，R1～R7如权利要求1中所述。
  9. 权利要求1所述的如式II化合物的合成方法，其特征在于，以消旋的或旋光活性的式III 化合物为原料，在碱作用下与二取代基卤化膦经单取代反应制备得到式II化合物，其反应式为：
    Figure PCTCN2017116105-appb-100009
    或者，式III化合物在碱作用下与二取代基卤化氧膦经单取代反应制备式7化合物，经还原反应制备得到式II化合物，其反应式为：
    Figure PCTCN2017116105-appb-100010
    式中X为卤素，R1～R7如权利要求1中所述。
  10. 一种如权利要求1所述的基于四甲基螺二氢茚骨架的膦配体的应用，其特征在于，所述的膦配体与铁、锇、金、银、铜、铂、铑、钌、铱、镍、钼、钯或钴的金属盐络合制备催化剂。
  11. 一种如权利要求1所述的基于四甲基螺二氢茚骨架的膦配体的应用，其特征在于，所述的膦配体单独作为有机小分子催化剂用于环化反应中。
  12. 一种权利要求1所述的基于四甲基螺二氢茚骨架的膦配体的用途，其特征在于，所述磷配体用于金属催化的偶联反应、N-芳基胺化反应、不对称反应。
  13. 如权利要求12所述的基于四甲基螺二氢茚骨架的膦配体的用途，其特征在于，所述的磷配体用于金属催化的不对称氢化反应、硅氢化反应、氢转移反应和不对称烯丙基化反应。
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