CN114853811A - Method for synthesizing phosphorus center chiral benzo phosphorus heterocycle five-membered ring - Google Patents
Method for synthesizing phosphorus center chiral benzo phosphorus heterocycle five-membered ring Download PDFInfo
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- CN114853811A CN114853811A CN202210468266.3A CN202210468266A CN114853811A CN 114853811 A CN114853811 A CN 114853811A CN 202210468266 A CN202210468266 A CN 202210468266A CN 114853811 A CN114853811 A CN 114853811A
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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Abstract
The invention discloses a method for synthesizing a phosphorus center chiral benzo phosphorus heterocycle five-membered ring, which particularly relates to the field of organic synthesis and comprises the following steps: under the protection of inert gas, adding o-bromobenzaldehyde, tetrahydrofuran serving as a solvent, and tetraisopropyl titanate and (R) -tert-butyl sulfenamide serving as catalysts into a drying reactor, then reacting at 60-70 ℃, stopping the reaction after the reaction is finished, adding water for quenching, concentrating, then adding methanol for pulping, and performing suction filtration to obtain a filter cake, namely (R) -tert-butyl imine sulfoxide; adding (R) -tert-butylimine sulfoxide and TMEDA into a reaction bottle, and adding tetrahydrofuran serving as a solvent. According to the method for synthesizing the phosphorus center chiral benzo phosphorus heterocycle five-membered ring, the tert-butyl sulfenamide which is simple and easy to obtain is used as a chiral group, the phosphorus center is induced to generate chirality, the reaction steps are simple, the yield is high, the obtained phosphorus center chiral ligand is not easy to racemize, the yield is high, the ee value of the final product is high, the ee value is more than 98%, and the market demand can be met.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a phosphorus-center chiral benzo-phosphorus heterocyclic five-membered ring.
Background
In the field of asymmetric catalysis, ligands occupy an important position. Among the numerous chiral ligands, organophosphorus ligands have been the most widely studied. The phosphorus-centered chiral ligands have been the most well developed, and as early as the 70's of the 20 th century, the Knowles research group developed the phosphorus-centered chiral ligands CAMP and DIPAMP. However, the optically active phosphorus-centered chiral organic phosphorus compound is difficult to synthesize, so that the product is not easy to obtain, and racemization is easy to occur under the high-temperature condition. Therefore, the research on various chemical properties and functions of the compounds is lagged for a long time. Until the 90 s of the 20 th century, with the continuous progress of asymmetric synthetic chemistry, there was no new development in stereoselective synthesis of chiral organophosphorus compounds having a phosphorus center. In the catalytic system, the chirality of the phosphorus center is closer to the catalytic center, and the enantioselectivity of the reaction product can be directly and effectively controlled, so that the design of a novel phosphorus center chiral ligand, particularly a phosphorus center chiral ligand containing a dominant configuration framework, is an important challenge for researching catalytic asymmetric reaction.
The phosphorus center chiral benzo phosphorus hetero five-membered ring is formed by clamping a phosphorus atom in the five-membered ring, and racemization is not easy to occur. The literature reports that the synthesis of the benzo-phospho-heterocyclic five-membered ring ligand DuanPhos, chiral at the phosphorus center, is obtained by resolution of dibenzoyltartaric acid. The method is complicated in reaction and requires a chiral resolution reagent. In addition, the Thomujin designed benzo phosphorus heterocycle WingPhos with chiral phosphorus center. The reaction is complicated, the operation is troublesome, the synthesis needs to be carried out by taking the methyl phosphorus dichloride as a starting material through a plurality of steps, and the reaction cost is high.
Therefore, it is necessary to find a simpler, more economical and more suitable method for industrially synthesizing the phosphorus-centered chiral benzo-phospho-heterocyclic five-membered ring.
Disclosure of Invention
Solves the technical problem
Aiming at the defects of the prior art, the invention provides a method for synthesizing a phosphorus center chiral benzo phosphorus five-membered ring, which has the advantages of high yield, low production cost and simple post-treatment, and is suitable for industrial production.
Technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: a method for synthesizing a phosphorus-centered chiral benzo-phosphorus five-membered heterocycle comprises the following steps:
under the protection of inert gas, adding o-bromobenzaldehyde, tetrahydrofuran serving as a solvent, and tetraisopropyl titanate and (R) -tert-butyl sulfenamide serving as catalysts into a drying reactor, then reacting at 60-70 ℃, stopping the reaction after the reaction is finished, adding water for quenching, concentrating, then adding methanol for pulping, and performing suction filtration to obtain a filter cake, namely (R) -tert-butyl imine sulfoxide;
adding (R) -tert-butylimine sulfoxide, TMEDA and tetrahydrofuran serving as a solvent into a reaction bottle, then cooling to-78 ℃, dropwise adding butyl lithium, after dropwise adding and keeping the temperature for 30min, adding phenyl (benzyl) phosphorus chloride, reacting at-78 ℃ for 1h, and after the reaction is finished, performing column chromatography separation to obtain the phosphorus center chiral benzo phosphorus heterocycle five-membered ring.
Preferably, the molar ratio of the o-bromobenzaldehyde to the tetraisopropyl titanate is 1: 0.1-0.2.
Preferably, the molar ratio of the o-bromobenzaldehyde to the (R) -tert-butyl sulfenamide is 1: 1.1-1.2.
Preferably, the molar ratio of (R) -tert-butylimine sulfoxide to TMEDA is 1: 2.1-2.2.
Preferably, the molar ratio of (R) -tert-butylimine sulfoxide to phenyl (benzyl) phosphorus chloride is 1: 2.1-2.2.
Advantageous effects
The invention provides a method for synthesizing a phosphorus center chiral benzo phosphorus heterocycle five-membered ring, which has the following beneficial effects:
according to the method for synthesizing the phosphorus center chiral benzo phosphorus heterocycle five-membered ring, the tert-butyl sulfenamide which is simple and easy to obtain is used as a chiral group, the phosphorus center is induced to generate chirality, the reaction steps are simple, the yield is high, the obtained phosphorus center chiral ligand is not easy to racemize, the yield is high, the ee value of the final product is high, the ee value is more than 98%, and the market demand can be met.
Reference numerals
FIG. 1 is a reaction scheme of the present invention
Detailed Description
All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Referring to the accompanying FIG. 1, this example discloses a method for synthesizing a phosphorus-centered chiral benzo-phosphorus heterocyclic five-membered ring, comprising the following steps:
under the protection of inert gas, adding o-bromobenzaldehyde, tetrahydrofuran serving as a solvent, and tetraisopropyl titanate and (R) -tert-butyl sulfenamide serving as catalysts into a drying reactor, then reacting at 60-70 ℃, stopping the reaction after the reaction is finished, adding water for quenching, concentrating, then adding methanol for pulping, and performing suction filtration to obtain a filter cake, namely (R) -tert-butyl imine sulfoxide;
in this embodiment, specifically, under the protection of inert gas, o-bromobenzaldehyde, tetrahydrofuran as a solvent, and tetraisopropyl titanate and (R) -tert-butylsulfenamide as catalysts are added into a drying reactor, and then the reaction is carried out at 60 to 70 ℃, the reaction is stopped after the reaction is finished, water is added for quenching and then concentration is carried out, then methanol is added for pulping, and suction filtration is carried out, so as to obtain a filter cake which is (R) -tert-butylimine sulfoxide;
adding (R) -tert-butylimine sulfoxide, TMEDA and tetrahydrofuran serving as a solvent into a reaction bottle, then cooling to-78 ℃, dropwise adding butyl lithium, after dropwise adding and keeping the temperature for 30min, adding phenyl (benzyl) phosphorus chloride, reacting at-78 ℃ for 1h, and after the reaction is finished, performing column chromatography separation to obtain the phosphorus center chiral benzo phosphorus heterocycle five-membered ring.
In this embodiment, to be specifically described, the (R) -tert-butylimidosulfoxide, TMEDA, and tetrahydrofuran as a solvent are added into a reaction flask, then butyl lithium is dropped into the reaction flask after the temperature is reduced to-78 ℃, phenyl (benzyl) phosphorus chloride is added after the temperature is dropped and maintained for 30min, the reaction is performed at-78 ℃ for 1h, and after the reaction is completed, column chromatography separation is performed to obtain the phosphorus-center chiral benzo phosphorus heterocycle.
The molar ratio of o-bromobenzaldehyde to tetraisopropyl titanate is 1: 0.1-0.2, the molar ratio of the o-bromobenzaldehyde to the (R) -tert-butyl sulfinamide is 1: 1.1-1.2, the molar ratio of (R) -tert-butylimine sulfoxide to TMEDA is 1: 2.1-2.2, the molar ratio of (R) -tert-butylimine sulfoxide to phenyl (benzyl) phosphorus chloride is 1: 2.1-2.2.
Example 2
Referring to the accompanying FIG. 1, this example discloses a method for synthesizing a phosphorus-centered chiral benzo-phosphorus heterocyclic five-membered ring, comprising the following steps:
under the protection of inert gas, adding o-bromobenzaldehyde, tetrahydrofuran serving as a solvent, and tetraisopropyl titanate and (R) -tert-butyl sulfenamide serving as catalysts into a drying reactor, then reacting at 60-70 ℃, stopping the reaction after the reaction is finished, adding water for quenching, concentrating, then adding methanol for pulping, and performing suction filtration to obtain a filter cake, namely (R) -tert-butyl imine sulfoxide;
in this embodiment, specifically, under the protection of inert gas, o-bromobenzaldehyde, tetrahydrofuran as a solvent, and tetraisopropyl titanate and (R) -tert-butylsulfenamide as catalysts are added into a drying reactor, and then the reaction is carried out at 60 to 70 ℃, the reaction is stopped after the reaction is finished, water is added for quenching and then concentration is carried out, then methanol is added for pulping, and suction filtration is carried out, so as to obtain a filter cake which is (R) -tert-butylimine sulfoxide;
adding (R) -tert-butylimine sulfoxide, TMEDA and tetrahydrofuran serving as a solvent into a reaction bottle, then cooling to-78 ℃, dropwise adding butyl lithium, after dropwise adding and keeping the temperature for 30min, adding phenyl (benzyl) phosphorus chloride, reacting at-78 ℃ for 1h, and after the reaction is finished, performing column chromatography separation to obtain the phosphorus center chiral benzo phosphorus heterocycle five-membered ring.
The molar ratio of o-bromobenzaldehyde to tetraisopropyl titanate is 1: 0.1-0.2, the molar ratio of the o-bromobenzaldehyde to the (R) -tert-butyl sulfinamide is 1: 1.1-1.2, wherein the molar ratio of the (R) -tert-butyl imine sulfoxide to the TMEDA is 1: 2.1-2.2, the molar ratio of (R) -tert-butylimine sulfoxide to phenyl (benzyl) phosphorus chloride is 1: 2.1-2.2.
Under the protection of inert gas, adding 1.85g (10mmol) of o-bromobenzaldehyde, 20ml of tetrahydrofuran, 0.28g (1mmol) of tetraisopropyl titanate and 1.33g (11mmol) of (R) -tert-butylsulfenamide into a drying reactor, then reacting at 60-70 ℃, stopping the reaction after the reaction is finished, adding water for quenching, concentrating, then adding 15ml of methanol for pulping, and filtering to obtain a filter cake (R) -tert-butylimine sulfoxide 2.45g, wherein the yield is 85%
2.45g (8.5mmol) of (R) -tert-butylimine sulfoxide and 2.07g (17.8mmol) of TMEDA, 20ml of tetrahydrofuran are charged into a reaction flask, then the temperature is reduced to-78 ℃, 7.1ml (17.8mmol) of n-butyllithium (2.5M) are added dropwise, after 30min of heat preservation, 4.19g (17.8mmol) of phenyl (benzyl) phosphorus chloride is added, reaction is carried out at-78 ℃ for 1h, and after the reaction is finished, n-hexane: ethyl acetate 10:3 as developing agent to carry out column chromatography separation to obtain 2.83g of benzo phosphorus heterocycle with chiral phosphorus center, and the yield is 72%.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. A method for synthesizing a phosphorus center chiral benzo phosphorus heterocycle five-membered ring is characterized by comprising the following steps: comprises the following steps:
under the protection of inert gas, adding o-bromobenzaldehyde, tetrahydrofuran serving as a solvent, and tetraisopropyl titanate serving as a catalyst and (R) -tert-butyl sulfenamide into a drying reactor, then reacting at 60-70 ℃, stopping the reaction after the reaction is finished, adding water for quenching, concentrating, then adding methanol for pulping, and performing suction filtration to obtain a filter cake, namely (R) -tert-butyl imine sulfoxide;
adding (R) -tert-butylimine sulfoxide, TMEDA and tetrahydrofuran serving as a solvent into a reaction bottle, then cooling to-78 ℃, dropwise adding butyl lithium, after dropwise adding and keeping the temperature for 30min, adding phenyl (benzyl) phosphorus chloride, reacting at-78 ℃ for 1h, and after the reaction is finished, performing column chromatography separation to obtain the phosphorus center chiral benzo phosphorus heterocycle five-membered ring.
2. The method of claim 1, wherein the method comprises the following steps: the molar ratio of the o-bromobenzaldehyde to the tetraisopropyl titanate is 1: 0.1-0.2.
3. The process for preparing (R) -tert-butylimine sulfoxide according to claim 1, wherein the molar ratio of o-bromobenzaldehyde to (R) -tert-butylsulfenamide is 1: 1.1-1.2.
4. The method of claim 1, wherein the method comprises the following steps: the molar ratio of the (R) -tert-butylimine sulfoxide to TMEDA is 1: 2.1-2.2.
5. The method of claim 1, wherein the method comprises the following steps: the molar ratio of the (R) -tert-butylimine sulfoxide to the phenyl (benzyl) phosphorus chloride is 1: 2.1-2.2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198775A (en) * | 2015-10-10 | 2015-12-30 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of chiral N-Boc biphenyl alaninol |
| CN111410611A (en) * | 2020-04-09 | 2020-07-14 | 宁波赜军医药科技有限公司 | Preparation method of (R) -1- (1-naphthyl) -2 ethylamine |
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- 2022-04-29 CN CN202210468266.3A patent/CN114853811A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198775A (en) * | 2015-10-10 | 2015-12-30 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of chiral N-Boc biphenyl alaninol |
| CN111410611A (en) * | 2020-04-09 | 2020-07-14 | 宁波赜军医药科技有限公司 | Preparation method of (R) -1- (1-naphthyl) -2 ethylamine |
Non-Patent Citations (2)
| Title |
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| CHUN-RU CAO等, EUR. J. ORG. CHEM., pages 1144 - 1151 * |
| DUAN LIU等: "Practical P-Chiral Phosphane Ligand for Rh-Catalyzed Asymmetric Hydrogenation", EUR. J. ORG. CHEM, pages 646 - 649 * |
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