Novel basic hydrogen bond-assisted chiral bicyclic guanidine ion pair catalysts and their preparation and application

Abstract

The invention discloses a novel alkaline hydrogen bond-assisted chiral bicyclic guanidine ion pair catalyst and its preparation and application, the present invention carries out certain structural transformation to traditional PN ion pair catalyst, without destroying the original structural basis, adds the structure of hydrogen bond, makes this novel H PN in various asymmetric catalytic reactions can play the dual role of hydrogen bond and ion pair catalysis, successfully constructs chiral phosphoramide compounds with higher yield (70% 80%) and enantioselectivity (80% 90%), solves the problem that traditional ion pair catalyst is difficult to construct chiral phosphoramide compounds. With phosphoryl chloride or secondary phosphorus oxide as substrate, various primary amine secondary amines as nucleophilic reagent, using 4% 10% catalyst of the present invention, successfully obtains phosphoramide with high yield (60% 80%) and high enantioselectivity (70% 90%).

Description

(1) Technical field

[0001] The present invention relates to the technical field of industrial catalysts, and in particular to a basic hydrogen bond-assisted chiral bicyclic guanidine ion pair catalyst and a preparation and application thereof. (2) Background technology

[0002] In recent years, asymmetric organic catalysis has flourished, among which phase transfer and ion pair catalysis as branches of organic catalysis have also received great attention. Chiral ion pair catalysis has always been an indispensable research direction in the field of asymmetric catalysis. Ion pair catalysts have the advantages of small catalytic dosage, high polarity, easy recovery, mild reaction conditions, and good prospects for industrial application. They have been reported to be successfully used in many enantioselective transformations.

[0003] Ionic quaternary ammonium salts are water-soluble, and further extending their alkyl chains can increase their lipid solubility. This property allows them to be used as phase transfer catalysts to catalyze various reactions and increase reaction rates. The initial success was achieved with a phase transfer catalyst derived from cinchona alkaloid. Professor Maruoka, hoping to develop new designed chiral phase transfer catalysts, prepared a variety of quaternary ammonium salt-type chiral catalysts from inexpensive and readily available chiral binaphthol. These catalysts have been shown to be useful in a variety of asymmetric catalytic reactions, including the asymmetric alkylation of glycine derivatives. Using these catalysts, the large-scale synthesis of various optically active amino acids has become possible. Furthermore, the enantioselective amination of arylbenzofuran derivatives has been achieved.

[0004] Based on organic ion pairs called onium salts, the Ooi group has designed and synthesized numerous specialized ion-pair catalysts capable of efficiently and controllably catalyzing diverse reactions. These catalysts include triazolium salts, betaine-based ammonium salts, and ammonium phosphide catalysts. Ooi and his colleagues pioneered triazolium salt-derived catalysts, which are easy to synthesize and exhibit a wide range of structural diversity. These catalysts have been successfully applied to asymmetric alkylation and asymmetric ring-opening reactions of indolinones. Betaine-based ammonium salts have also been successfully used to generate various carbon-chiral compounds with high enantioselectivity.

[0005] The traditional chiral cation-mediated phase transfer catalysis mode often requires the formation of negatively charged groups on the substrate under alkaline conditions, or the substrate itself is negatively charged. Professor Junfeng Chen of Nanyang Technological University in Singapore used chiral bicyclic guanidine as a chiral strong base catalyst to achieve many asymmetric transformations such as Diels-Alder reaction, Mannich reaction, Michael reaction, decarboxylation reaction, isomerization reaction, amination reaction, etc. Based on the conjugated structure of guanidine, Junfeng Chen's research group designed a chiral guanidine salt Pentanidinium (PN) and Bisguanidinium (BG) as a new type of chiral asymmetric phase transfer catalyst. Different from the traditional sp 3Quaternary ammonium salt phase transfer catalyst, guanidine salt has sp 2 Conjugated structure, with different catalytic activities. These two types of ion pair catalysts use guanidine as the skeleton and have sp 2 Hybridized nitrogen centers, where PN has five conjugated nitrogen atoms, were used as catalysts for enantioselective addition, alkylation, hydroxylation, and oxidation reactions. The successful enantioselective oxidation reaction demonstrates that chiral guanidine salts, unlike quaternary ammonium phase transfer catalysts, are stable in the presence of strong oxidants.

[0006] However, the existing chiral guanidine salt ion pair catalysts have relatively simple functions, and the ionic bond and ability are weaker than those of non-covalent bonds, which limits the application of this type of catalyst. (3) Summary of the invention

[0007] The present invention aims to provide an alkaline hydrogen-bond-assisted chiral bicyclic guanidine ion pair catalyst and its preparation and application. The present invention selects the PN structure in a chiral guanidine salt as a skeleton and attempts to combine hydrogen bonds. By improving part of the structure in PN, a novel alkaline hydrogen-bond-assisted chiral bicyclic guanidine ion pair catalyst, hydrogen bonding pentanidinium (H-PN), which can simultaneously exert ion-pair catalysis and hydrogen bonding effects, is obtained. In the reaction system, the ion-pair catalysis and hydrogen bonding effects can be exerted simultaneously. Nuclear magnetic resonance and mass spectrometry methods demonstrate that the catalyst binds to the phosphine substrate via hydrogen bonds, thus solving the problem that traditional ion-pair catalysts are difficult to construct chiral phosphoramide compounds.

[0008] The technical solution adopted in the present invention is:

[0009] The present invention provides a basic hydrogen bond-assisted chiral bicyclic guanidine ion pair catalyst represented by formula (I), referred to as H-PN catalyst:

[0010]

[0011] In formula (I), R 1 is tert-butyl (tBu), trifluoromethyl (CF3), trimethylsilane (TMS) or methoxy; R 5 is hydrogen or methoxy; R 7 is a hydrogen or bromine atom; R 9 is phenyl or 4-methoxyphenyl; R 11 is phenyl or 4-methoxyphenyl; R 2 , R 3 , R 4 Same as R 1 ; R 6 Same as R 5 ; R 8 Same as R 7 ; R10 Same as R 9 ; R 12 Same as R 11 .

[0012] Furthermore, the H-PN catalyst represented by formula (I) is one of the following:

[0013]

[0014]

[0015] The present invention also provides a method for preparing the HPN catalyst, which is carried out according to the following steps:

[0016] (1) Compound A and N-bromosuccinimide (NBS) were added to a single-necked round-bottom flask containing cyclohexane in sequence, stirred at 80°C for 5 min, and then benzoyl peroxide (BPO) was added and stirred at 80°C for 12 h; the reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to remove the solvent. The concentrate was loaded onto a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column height 15 cm), and petroleum ether was used as the eluent at an elution rate of 5 ml / min for 3 column volumes. , thin layer chromatography monitoring was performed using petroleum ether as a developing solvent, and the component with an Rf value of 0.7-0.75 was collected to obtain a colorless transparent liquid, which was recorded as compound B; the ratio of the amount of compound A to the amount of N-bromosuccinimide feed material was 1:1-3 (preferably 1:1); the volume of cyclohexane used was 0.5-1.0 mL / mmol (preferably 0.8 mL / mmol) based on the amount of compound A; the ratio of the amount of compound A to the amount of benzoyl peroxide feed material was 1:0.01-0.1 (preferably 1:0.05);

[0017] (2) Compound C and K2CO3 were added to a single-necked round-bottom flask containing CH3CN-a in sequence, and stirred at room temperature to mix; then the CH3CN-b solution of compound B was slowly added dropwise, stirred at room temperature for 24 h, and the reaction was monitored by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 10:1 as a developing solvent; after the reaction was completed, the reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the concentrated solution was loaded onto a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column height 15 cm), and eluted with petroleum ether / ethyl acetate in a volume ratio of 50:1 and 30:1 in sequence, with an elution rate of 5 ml / min. The elution volume for each concentration was 3 column volumes, and thin-layer chromatography monitoring was performed using petroleum ether / ethyl acetate in a volume ratio of 10:1 as a developing solvent, and the Rf value was collected. The reaction mixture is concentrated to dryness to obtain compound D; the ratio of the amount of compound C to the amount of K2CO3 feed material is 1:1-3 (preferably 1:2.2); the CH3CN-a and CH3CN-b are both CH3CN. The letters themselves have no meaning. For the convenience of expressing the amount ratio relationship, the volume amount of CH3CN-a is 1-5mL / mmol (preferably 2mL / mmol) based on the amount of compound C feed material, and the volume amount of CH3CN-b is 1-5mL / mmol (preferably 2.5mL / mmol) based on the amount of compound C feed material; the ratio of the amount of compound C to compound B feed material is 1:1-3 (preferably 1:2.05); the CH3CN-b solution of compound B is slowly added at a rate of 10-20mL / h;

[0018] (3) Compound D and K2CO3 were added to a round-bottom flask containing dichloromethane (DCM) and water in sequence, stirred at room temperature, thiophosgene was added, stirred at room temperature for 2 h, and petroleum ether / ethyl acetate in a volume ratio of 10:1 was used as a developing solvent, and the reaction was monitored by thin-layer chromatography; after the reaction was complete, the reaction solution was extracted with water and DCM in a volume ratio of 1:1, the lower organic phase was removed, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The concentrate was loaded onto a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column height 15 cm), and petroleum ether / ethyl acetate in a volume ratio of 30:1 was used as an eluent. Elution was performed at a rate of 5 ml / min and an elution volume of 3 column volumes; thin layer chromatography was performed using petroleum ether / ethyl acetate in a volume ratio of 30:1 as a developing solvent, and components with an Rf value of 0.3-0.35 were collected and concentrated to dryness under reduced pressure to obtain compound E; the ratio of the amount of compound D to the K2CO3 feed material was 1:1-3 (preferably 1:2.2); the volume ratio of dichloromethane to water was 1:1, and the volume of dichloromethane was 1-5 mL / mmol (preferably 2 mL / mmol) based on the amount of compound D; the ratio of the amount of compound D to thiophosgene feed material was 1:1-5 (preferably 1:3);

[0019] (4) Compound E was placed in a single-necked round-bottom flask, the system was evacuated, and nitrogen was replaced to ensure anhydrous and oxygen-free conditions. Ultra-dry toluene and oxalyl chloride ((COCl)2) were added, and stirred at 80°C for 12 hours. After the reaction, the mixture was immediately evacuated and dried to obtain Compound F; the ratio of the amount of Compound E to the amount of oxalyl chloride was 1:5-10 (preferably 1:8); the volume of toluene used was 1-5 mL / mmol (preferably 2.5 mL / mmol) based on the amount of Compound E;

[0020] (5) Compound C is placed in a single-necked round-bottom flask, and nitrogen is replaced to ensure anhydrous and oxygen-free conditions. Ultra-dry acetonitrile a is added, BrCN is dissolved in acetonitrile b, and injected into the reaction system under a flowing nitrogen environment. The mixture is heated to reflux for 12 hours. After the reaction, the mixture is immediately spin-dried to obtain compound G without post-treatment. The ratio of the amount of compound C to BrCN is 1:1-3 (preferably 1:1.2). The acetonitrile a and acetonitrile b are both acetonitrile. They are named for the convenience of distinguishing the dosage relationship. The letters themselves have no meaning. The volume dosage of acetonitrile a is 1-5 mL / mmol (preferably 1 mL / mmol) based on the amount of compound C. The volume ratio of acetonitrile b to acetonitrile a is 0.1-2:1 (preferably 0.4:);

[0021] (6) All the compound F in step (4) were placed in a single-necked round-bottom flask, the system was evacuated and replaced with nitrogen, and the compound G in step (5) was quickly poured in under nitrogen protection, and the evacuation was continued for 2 hours, and then the nitrogen was replaced to ensure that the system was free of water and oxygen. Ultra-dry acetonitrile was added under circulating nitrogen, and ultra-dry triethylamine was added under stirring, and the system was heated to reflux for 12 hours; the system was monitored by thin-layer chromatography, using petroleum ether / ethyl acetate in a volume ratio of 1:1 as the developing solvent; after the reaction was complete, the reaction solution was dried by rotary evaporation, and water and DCM in a volume ratio of 1:1 were added for extraction, the lower organic phase was removed, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The concentrate was loaded onto a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm) m, column height 15 cm), elution was performed using petroleum ether / ethyl acetate in a volume ratio of 1:1 as an eluent, the elution rate was 5 ml / min, the elution volume was 3 column volumes, thin layer chromatography monitoring was performed using petroleum ether / ethyl acetate in a volume ratio of 1:1 as a developing solvent, and components with an Rf value of 0.5-0.6 were collected, and concentrated to dryness under reduced pressure to obtain the H-PN catalyst represented by formula (I); the molar ratio of the compound E to the compound G feed substance is 1:1-3 (preferably 1:1.2); the volume of acetonitrile used is 1-5 mL / mmol (preferably 2.5 mL / mmol) based on the amount of the compound E substance; and the molar ratio of the triethylamine to the compound E substance is 1-5:1 (preferably 4:1).

[0022]

[0023] R in A 1 is tert-butyl (tBu), trifluoromethyl (CF3), trimethylsilane (TMS) or methoxy, R 5 is hydrogen or methoxy, R 7 is a hydrogen or bromine atom; R 2 Same as R 1 ; R in C 9 is phenyl or 4-methoxyphenyl, R 10 Same as R 9 ; R in B, D, E, F 1 、R 2 、R 5 、R 7 Same as A; R in D, E, and F 3 、R 4 Same as R in A 1 ; R in D, E, F 6 Same as R in A 5 ; R in D, E, F 8 Same as R in A 7 ; R in G 11 、R 12 Same as R in C 9 .

[0024] The present invention also provides an application of the H-PN catalyst in the preparation of chiral phosphoramide compounds. Under the action of the catalyst, phosphorus oxychloride or a phosphine compound that can generate phosphorus oxychloride in situ is used as a substrate to undergo an enantioselective nucleophilic substitution reaction with various nucleophilic reagents.

[0025] Furthermore, the application method is:

[0026] The catalyst was added into the reaction tube equipped with a stirrer, and then Molecular sieve, phosphine compound 1, the system is sealed, anhydrous ether is added, and the mixture is stirred at -20°C for 30 minutes. Then, amine compound 2 is quickly added to the reaction tube with a microsyringe, and the reaction is stirred at -20°C for 24 hours; sodium methoxide is then added to the reaction tube for quenching, and stirring is continued at -20°C for 12 hours. The reaction solution is filtered through dichloromethane using diatomaceous earth, and silica gel column chromatography (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column packing height 15 cm) is performed using petroleum ether / ethyl acetate in a volume ratio of 5:1 as an eluent. The elution rate is 5 ml / min, the elution volume is 3 column volumes, and petroleum ether / ethyl acetate in a volume ratio of 1:1 is used as a developing solvent for monitoring. The component with an Rf value of 0.3-0.4 is collected to obtain a colorless transparent liquid to obtain chiral phosphoramide compound 3;

[0027]

[0028] 1 in R 1 They are 4-bromo, 4-nitro, 2 in R 2 Isobutyl, benzyl, 2 R 3 They are isobutyl, benzyl, 3-nitrobenzyl, 2-methylbenzyl, 4-fluorobenzyl, 4-tert-butylbenzyl, 4-trifluoromethylbenzyl, 3,5-dibromobenzyl, 3 R 1 Same as R in 1 1 , R 2 , R 3 Same as R in 2 2 , R 3 .

[0029] Furthermore, the ratio of the amount of the phosphine compound 1 to the amount of the catalyst substance is 1:0.01-0.1 (preferably 1:0.05); The mass dosage of the molecular sieve is 0.1-2 g / mmol (preferably 1 g / mmol) based on the amount of the phosphine compound 1; the molar ratio of the amine compound 2 to the phosphine compound 1 is 1-5:1 (3.5:1); the volume dosage of the anhydrous ether is 5-15 mL / mmol (preferably 10 mL / mmol) based on the amount of the phosphine compound 1; and the molar ratio of the sodium methoxide to the phosphine compound 1 is 5-15:1 (preferably 10:1).

[0030] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0031] The present invention structurally modifies the traditional PN ion-pair catalyst, adding a hydrogen bonding structure without destroying the original structure. This allows the novel H-PN to exert the dual effects of hydrogen bonding and ion-pair catalysis in various asymmetric catalytic reactions. Chiral phosphoramide compounds are successfully constructed with high yields (70%-80%) and enantioselectivities (80%-90%). Nuclear magnetic resonance and mass spectrometry demonstrate that the catalyst binds to the phosphine substrate via hydrogen bonding, resolving the difficulty of conventional ion-pair catalysts in constructing chiral phosphoramide compounds. Using phosphoryl chloride or secondary phosphorus oxides as substrates and various primary and secondary amines as nucleophiles, and using 4%-10% of the catalyst described herein, phosphoramides are successfully obtained with high yields (60%-80%) and high enantioselectivities (70%-90%). (IV) Description of the accompanying drawings

[0032] Figure 1 is the NMR spectrum of the H-PN catalyst (I-1) prepared in Example 1; a is 1 H spectrum, b is 13 C spectrum.

[0033] Figure 2 is the NMR spectrum of the H-PN catalyst (I-2) prepared in Example 2; a is 1 H spectrum, b is 13 C spectrum.

[0034] Figure 3 is the NMR spectrum of the H-PN catalyst (I-3) prepared in Example 3; a is 1 H spectrum, b is 13 C spectrum, c is 19 F spectrum.

[0035] Figure 4 is the NMR spectrum of the H-PN catalyst (I-4) prepared in Example 4; a is 1 H spectrum, b is 13 C spectrum.

[0036] Figure 5 is the NMR spectrum of the H-PN catalyst (I-5) prepared in Example 5; a is 1 H spectrum, b is 13 C spectrum.

[0037] Figure 6 is the NMR spectrum of the H-PN catalyst (I-6) prepared in Example 6; a is 1 H spectrum, b is 13 C spectrum.

[0038] Figure 7 is the NMR spectrum of the H-PN catalyst (I-7) prepared in Example 7; a is 1 H spectrum, b is 13 C spectrum.

[0039] Figure 8 is the NMR spectrum of the H-PN catalyst (I-8) prepared in Example 8; a is 1 H spectrum, b is 13 C spectrum.

[0040] Figure 9 is the NMR spectrum of the H-PN catalyst (I-9) prepared in Example 9; a is 1 H spectrum, b is 13 C spectrum.

[0041] Figure 10 is the NMR spectrum of the H-PN catalyst (I-10) prepared in Example 10; a is 1 H spectrum, b is 13 C spectrum.

[0042] Figure 11 is the NMR spectrum of the H-PN catalyst (I-11) prepared in Example 11; a is 1 H spectrum, b is 13 C spectrum.

[0043] Figure 12 is the NMR spectrum of the product 3a of Example 13, a is 1 H spectrum, b represents 13 C spectrum, c is 31 P spectrum.

[0044] Figure 13 is the NMR spectrum of the product 3b of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0045] Figure 14 is the NMR spectrum of the product 3c of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0046] Figure 15 is the NMR spectrum of product 3d of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0047] Figure 16 is the NMR spectrum of the product 3e of Example 13, a is 1 H spectrum, b is13 C spectrum, c is 31 P spectrum.

[0048] Figure 17 is the NMR spectrum of the product 3f of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0049] Figure 18 This is the NMR spectrum of the product 3g of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0050] Figure 19 is the NMR spectrum of the product 3h of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0051] Figure 20 is the NMR spectrum of the product 3i of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0052] Figure 21 is the NMR spectrum of the product 3j of Example 13, a is 1 H spectrum, b is 13 C spectrum, c is 31 P spectrum.

[0053] Figure 22 This is the HPLC spectrum of the product 3a of Example 13, where a is racemic 3a and b is chiral 3a.

[0054] Figure 23 This is the HPLC spectrum of the product 3b of Example 13, where a is racemic 3b and b is chiral 3b.

[0055] Figure 24 This is the HPLC spectrum of the product 3c of Example 13, a is racemic 3c, and b is chiral 3c.

[0056] Figure 25 This is the HPLC spectrum of the product 3d in Example 13, a is racemic 3d, and b is chiral 3d.

[0057] Figure 26 This is the HPLC spectrum of the product 3e of Example 13, a is racemic 3e, and b is chiral 3e.

[0058] Figure 27This is the HPLC spectrum of the product 3f in Example 13, a is the HPLC spectrum of racemic 3f, and b is the HPLC spectrum of chiral 3f.

[0059] Figure 28 This is the HPLC spectrum of the product 3g of Example 13, a is racemic 3g, and b is chiral 3g.

[0060] Figure 29 This is the HPLC spectrum of the product 3h in Example 13, where a is racemic 3h and b is chiral 3h.

[0061] Figure 30 This is the HPLC spectrum of the product 3i of Example 13, a is racemic 3i, and b is chiral 3i.

[0062] Figure 31 This is the HPLC spectrum of the product 3j in Example 13, where a is racemic 3j and b is chiral 3j. (V) Specific implementation methods

[0063] The present invention is further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto:

[0064] In the embodiment of the present invention, silica gel column chromatography uses a 2×30 cm Hinville glass column; commercially available 200-300 mesh silica gel powder. The room temperature in the present invention refers to 25-30°C. In the embodiment of the present invention, 1 H spectrum 500MHz, 13 C spectrum 126MHz, 19 F spectrum 376MHz, 31 P spectrum 202MHz.

[0065] Example 1, Preparation of H-PN Catalyst Represented by Formula (I-1):

[0066]

[0067] (1) Compound A-1 (10.209 g, 50.0 mmol, 1.0 equiv.) and NBS (N-bromosuccinimide, N-bromosuccinimide, 8.847 g, 50.0 mmol, 1.0 equiv.) were added sequentially to a 250 ml single-necked round-bottom flask containing cyclohexane (40 ml), and the mixture was stirred at 80°C for 5 min. Then, BPO (benzoyl peroxide, 605.57 mg, 2.5 mmol, 0.05 equiv.) was added and stirred at 80°C for 12 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was rotary evaporated under reduced pressure to remove the solvent. The concentrate was applied to a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column packing height 15 cm) with petroleum ether as the eluent at a rate of 5 ml / min for 3 column volumes. Thin layer chromatography was performed using petroleum ether as the developing solvent, and the components with Rf values ​​of 0.7-0.75 were collected to obtain 12 g (43 mmol) of a colorless, transparent liquid, recorded as compound B-1, with a yield of 86%.

[0068] (2) Compound C-1 (2.123 g, 10 mmol, 1.0 equiv.) and K2CO3 (3.041 g, 22 mmol, 2.2 equiv.) were added to a 150 ml single-necked round-bottom flask containing CH3CN (20 ml) in sequence and stirred at room temperature. Compound B-1 (5.807 g, 20.5 mmol, 2.05 equiv.) was dissolved in 25 ml CH3CN and placed in a constant pressure dropping funnel. The mixture was slowly dripped into the single-necked round-bottom flask at a rate of 10-20 mL / h (t>1 h) and stirred at room temperature for 24 h. The reaction was monitored by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 10:1 as the developing solvent. The reaction was completed when the raw material spot of B-1 (Rf value of 0.4-0.5) disappeared. The reaction solution was filtered and the filtrate was evaporated under reduced pressure to remove the solvent. The concentrate was loaded onto a silica gel chromatography column (silica gel particle size 200-300 mesh, The column was 30 cm high, 2.5 cm in diameter, and packed at a height of 15 cm. The column was eluted with petroleum ether / ethyl acetate in a volume ratio of 50:1 and 30:1, respectively, at a rate of 5 ml / min. The elution volume for each concentration was 3 column volumes. Petroleum ether / ethyl acetate in a volume ratio of 10:1 was used as the developing solvent. Fractions with an Rf value of 0.2-0.3 were collected and concentrated to dryness under reduced pressure to obtain 3.7 g (6 mmol) of white solid D-1, with a yield of 60%.

[0069] (3) Compound D-1 (3.085 g, 5.0 mmol, 1.0 equiv.) and K2CO3 (1.520 g, 11.0 mmol, 2.2 equiv.) were added to a 250 ml round-bottom flask containing dichloromethane (DCM, 10 ml) and water (10 ml) in sequence, and stirred at room temperature. Thiophosgene (1.14 ml, 15.0 mmol, 3.0 equiv.) was added and stirred at room temperature for 2 h. Thin layer chromatography was used for monitoring using petroleum ether / ethyl acetate in a volume ratio of 10:1 as the developing solvent. After the disappearance of the raw material spot of compound D-1 (Rf value 0.6-0.7), indicating the completion of the reaction, the mixture was added. Extract with water and DCM in a volume ratio of 1:1, remove the lower organic phase, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure, and apply the concentrate to a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column packing height 15 cm). Elution was performed with petroleum ether / ethyl acetate in a volume ratio of 30:1 at a rate of 5 ml / min over 3 column volumes. The eluent was petroleum ether / ethyl acetate in a volume ratio of 30:1. Fractions with Rf values ​​of 0.3-0.35 were collected and concentrated to dryness under reduced pressure to obtain 3.1 g (4.75 mmol) of white solid E-1 with a yield of 95%.

[0070] (4) Compound E-1 (1.318 g, 2.0 mmol, 1.0 equiv.) was placed in a 100 ml single-necked round-bottom flask. The system was evacuated and replaced with nitrogen to ensure anhydrous and oxygen-free conditions. Ultra-dry toluene (5 ml) and oxalyl chloride ((COCl)2) (1.36 ml, 16.0 mmol, 8.0 equiv.) were added. After stirring at 80°C for 12 h, the reaction solution was immediately evacuated and dried to obtain a yellow-brown solid F-1.

[0071] (5) Compound C-1 (1.061 g, 5.0 mmol, 1.0 equiv.) was placed in a 100 ml single-necked round-bottom flask and replaced with nitrogen to ensure anhydrous and oxygen-free conditions. Ultra-dry acetonitrile (5 ml) was added, and BrCN (635.52 g, 6 mmol, 1.2 equiv.) was dissolved in 2 ml of acetonitrile and injected into the single-necked round-bottom flask under flowing nitrogen. The mixture was heated under reflux for 12 h. After the reaction, it was immediately dried by spin drying to obtain 1.585 g (5 mmol) of yellow solid G-1. No post-treatment was required.

[0072] (6) Step (4) All of compound F-1 was placed in a 100 ml single-necked round-bottom flask, the system was evacuated and replaced with nitrogen, and G-1 (760.8 mg, 2.4 mmol, 1.2 equiv.) was quickly poured into the flask under nitrogen protection. The evacuation was continued for 2 h, and then nitrogen was replaced to ensure that the system was free of water and oxygen. Ultra-dry acetonitrile (5 ml) was added under circulating nitrogen, and ultra-dry triethylamine (1.11 ml, 8.0 mmol, 4.0 equiv.) was added under stirring, and the mixture was heated under reflux for 12 h. The reaction was monitored by thin layer chromatography using a volume ratio of 1:1 petroleum ether / ethyl acetate as a developing solvent. When the reaction raw material spot (Rf value of 0.5-0.6) disappeared, the reaction was complete. The reaction solution was dried and extracted with water and DCM in a volume ratio of 1:1. The lower organic phase was removed and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The concentrate was loaded onto a silica gel chromatography column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column height 15 cm), and eluted with a volume ratio of 1:1 petroleum ether / ethyl acetate as an eluent. The elution rate was 5 ml / min and the elution volume was 3 column volumes. Thin layer chromatography was monitored using a volume ratio of 1:1 petroleum ether / ethyl acetate as a developing solvent. The component with an Rf value of 0.5-0.6 was collected and concentrated to dryness under reduced pressure to obtain 1.16 g (1.3 mmol) of a white solid, which was compound I-1, with a yield of 65%. Compound (I-1) 1 H spectrum and 13 C spectrum Figure 1 shown.

[0073] The chemical name of compound (I-1) is: (4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazole chloride.

[0074] (4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-1)

[0075]

[0076] 1H NMR (500MHz, CDCl3) δ7.37-7.32(m,6H),7.30(dd,J=7.5,1.9Hz,4H),7.25-7.20(m,6H),7.18-7. 10(m,6H),6.94(d,J=1.7Hz,4H),4.92(s,2H),4.78(s,2H),4.68(q,J=15.1Hz,4H),1.25(s,36H). 13 C NMR(126MHz, CDCl3)δ163.89(s),159.40(s),151.00(s),139.05(s),135.65(s),134.32(s),129.15(s),129.08(s),128.73(s) ,128.70(s),128.60(s),126.86(s),123.25(s),121.66(s),71.43(s),67.88(s),51.18(s),34.81(s),31.51(s).HRMS(ESI)m / z 862.5782[M+H] + calcd for C 60 H 72 N5 + 862.5798.

[0077] Example 2, H-PN catalyst (I-2)

[0078] A-1 in step 1 of Example 1 was replaced by A-2, and other operations were performed in the same manner to obtain 884.83 mg (0.84 mmol) of compound (I-2) as a white solid with a yield of 42%. 1 H spectrum and 13 C spectrum Figure 2 shown.

[0079]

[0080] (4S,5S)-1,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0081] (4S,5S)-1,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-2)

[0082] 1 H NMR(500MHz, CDCl3)δ7.36(m,J=7.0,4.7,2.4Hz,10H),7.29(d,J=2.4Hz,2H),7.19-7.07(m,10H),6.7 8(d,J=2.3Hz,2H),4.97(s,2H),4.96-4.86(m,4H),4.56(s,2H),1.51(s,18H),1.14(s,J=8.4Hz,18H); 13 C NMR(126MHz,CDCl3)δ13C NMR (126MHz, CDCl3) δ162.55(s),159.30(s),149.21(s),147.64(s),139.04(s),136.28( s),134.67(s),129.17-129.17(m),129.00(s),128.62(s,J=20.5Hz),128.46(s),128.37( s),128.25(s,J=14.7Hz),127.61(s),126.92(s),125.18(s),121.92(s),71.35(s),67.7 5(s),53.34(s),37.31(s),34.48(s),31.11(s),30.01(s).HRMS(ESI)m / z1021.4009[M+H] + calcd for C 60 H 70 Br2N5 + ,1021.4006.

[0083] Example 3, H-PN catalyst (I-3)

[0084] A-1 in step 1 of Example 1 was replaced by A-3, and other operations were performed in the same manner to obtain 794.01 mg (0.84 mmol) of compound (I-3) as a light brown solid with a yield of 43%. 1 H spectrum and 13 C spectrum Figure 3 shown.

[0085]

[0086] (4S,5S)-1,3-bis(3,5-ditrifluoromethylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0087] (4S,5S)-1,3-bis(3,5-bis(trifluoromethyl)benzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)am ino)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-3)

[0088] 1 H NMR (500MHz, CDCl3) δ7.73 (s, 2H), 7.55 (s, 4H), 7.38 (d, J = 2.0Hz, 1H), 7.34-7.31 ( m,6H),7.27(s,1H),7.25-7.15(m,12H),5.02-4.88(m,3H),4.66(d,J=15.9Hz,1H); 13 C NMR (126MHz, CDCl3) δ163.41 (s), 158.78 (s), 138.09 (d, J = 10.5Hz), 133.73 (s), 132.09 (s), 131.82 (s), 129.66 (s), 129.10(s),129.05(s),128.93(s),128.53(s),126.59(s),124.01(s),121.84(s),71.80(s),67.66(s),49.69(s); 19 F NMR(376MHz,CDCl3)δ-63.05.HRMS(ESI)m / z 910.2790[M+H] + calcd for C 48 H 36 F 12 N5 + ,910.2774.

[0089] Example 4, H-PN catalyst (I-4)

[0090] A-1 in step 1 of Example 1 was replaced by A-4, and other operations were performed in the same manner to obtain 745.74 mg (0.94 mmol) of compound (I-4) as a white solid with a yield of 47%. 1 H spectrum and 13 C spectrum Figure 4 shown.

[0091]

[0092] (4S,5S)-1,3-bis(3,5-dimethoxybenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0093] (4S,5S)-1,3-bis(3,5-dimethoxybenzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-4)

[0094] 1 H NMR (500MHz, CDCl3) δ7.33 (dd, J=5.0, 1.7Hz, 10H), 7.23 (d, J=2.0Hz, 10H), 6 .33(s,6H),4.99(s,2H),4.88(s,2H),4.57(q,J=15.7Hz,4H),3.72(s,12H); 13 C NMR(126MHz, CDCl3)δ162.65(s),160.77(s),158.19(s),138.51(s),137.76(s),134.94(s),129.10(s),128.90(s),128.64 (s),128.59(s),126.66(s),106.06(s),99.67(s),71.24(s),67.62(s),55.29(s),49.81(s); HRMS(ESI)m / z758.3710[M+H] + calcd for C 48 H 48 N5O4 + ,758.3701.

[0095] Example 5, H-PN catalyst (I-5)

[0096] A-1 in step 1 of Example 1 was replaced by A-5, and other operations were performed in the same manner to obtain 980.69 mg (1.02 mmol) of compound (I-5) as a white solid with a yield of 51%. 1 H spectrum and 13 C spectrum Figure 5 shown.

[0097]

[0098] (4S,5S)-1,3-bis(3,5-ditrimethylsilylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0099] (4S,5S)-1,3-bis(3,5-bis(trimethylsilyl)benzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)ami no)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-5)

[0100] 1 H NMR (500MHz, CDCl3) δ7.50(s,2H),7.38-7.31(m,10H),7.25-7.15(m,14H),4.95(s,2H),4.83(s,2H),4.69(s,4H),0.25-0.18(m,36H); 13 C NMR(126MHz, CDCl3)δ163.55(s),158.74(s),139.74(s),138.81(s),137.49(s),135.41(s),134.50(s),133.35(s),129.0 8(s),129.04(s),128.79(s),128.70(s),128.67(s),126.81(s),71.47(s),67.70(s),50.84(s),-1.06(s); HRMS(ESI)m / z 926.4883[M+H] + calcd for C 56 H 72 N5Si4 + ,926.4859.

[0101] Example 6, H-PN catalyst (I-6)

[0102] A-1 in step 1 of Example 1 was replaced by A-6, and other operations were performed in the same manner to obtain 1.24 g (1.30 mmol) of compound (I-6) as a white solid with a yield of 65%. 1 H spectrum and 13 C spectrum Figure 6 shown.

[0103]

[0104] (4S,5S)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0105] (4S,5S)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-6)

[0106] 1 H NMR (500MHz, CDCl3) δ7.34 (m, 10H), 7.15 (s, 10H), 6.95 (s, 4H), 4.96 (s, 2H), 4.72 (s, 2H), 4.60 (d, J = 10.6Hz, 4H), 3.61 (s, 6H), 1.33 (s, 36H); 13 C NMR(126MHz, CDCl3)δ163.64(s),159.08(s),159.04(s),143.68(s),139.06(s),135.79(s),129.11(s),128.90(s),128. 75(s),128.64(s),127.41(s),126.86(s),71.28(s),67.78(s),64.29(s),50.79(s),35.68(s),32.11(s); HRMS(ESI)m / z 922.5994[M+H] + calcd for C 62 H 76 N5O2 + ,922.5983.

[0107] Example 7, H-PN catalyst (I-7)

[0108] C-1 in step 5 of Example 1 was replaced by C-2, and other operations were performed in the same manner to obtain 1.15 g (1.20 mmol) of compound (I-7) as a white solid with a yield of 60%. 1 H spectrum and 13 C spectrum Figure 7 shown.

[0109]

[0110] (4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0111] (4S,5S)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolidin-2-ylidene)amino)-1,3-bis(3,5-di-tert-bu tylbenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-7)

[0112] 1 H NMR(500MHz, CDCl3) δ7.23(d,J=8.7Hz,10H),7.19-7.12(m,6H),6.95(d,J=1.6Hz,4H),6.8 8(d,J=8.7Hz,4H),4.86(s,2H),4.80(s,2H),4.75-4.59(m,4H),3.81(s,6H),1.26(s,36H); 13 C NMR (126MHz, CDCl3) δ163.39(s),159.72(s),158.58(s),150.81(s),135.47(s),134.33(s),130.68(s),129.02(s),128.58(s),128. 45(s),128.06(s),123.03(s),121.46(s),114.27(s),71.26(s),67.36(s),55.26(s),50.97(s),34.64(s),31.37(s); HRMS(ESI)m / z 922.6016[M+H] + calcd for C 62 H 76 N5O2 + ,922.5994.

[0113] Example 8, H-PN catalyst (I-8)

[0114] The C-1 in step 2 of Example 1 was replaced by C-2, and the other operations were the same to obtain 793.44 mg (0.86 mmol) of compound (I-8). 1 H spectrum and 13 C spectrum Figure 8 shown.

[0115] (4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-imidazolium chloride

[0116] (4S,5S)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolidin-2-ylidene)amino)-1,3-bis(3,5-di-tert-bu tylbenzyl)-4,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-imidazol-3-ium chloride(I-8)

[0117]

[0118] The product was a light brown solid with a yield of 43%. 1 H NMR (500MHz, CDCl3) δ7.25-7.20(m,10H),7.17-7.11(m,6H),6.93(d,J=1.6Hz,4H),6.8 8-6.85(m,4H),4.84(s,2H),4.78(s,2H),4.69-4.61(m,4H),3.79(s,6H),1.24(s,36H); 13 C NMR(126MHz, CDCl3)δ163.18(s),159.59(s),158.59(s),150.81(s),138.88(s),134.52(s),130.39(s),128.94(s),128.57(s),127.28(s), 126.74(s),123.01(s),121.42(s),113.79(s),70.74(s),67.58(s),5 5.01(s),50.76(s),34.65(s),31.37(s); HRMS(ESI)m / z922.6016[M+H] + calcd for C62 H 76 N5O2 + ,922.5994.

[0119] Example 9, H-PN catalyst (I-9)

[0120] A-1 in step 1 of Example 1 was replaced by A-7, and other operations were performed in the same manner to obtain 708.28 mg (1.02 mmol) of compound (I-9) as a white solid with a yield of 51%. 1 H spectrum and 13 C spectrum Figure 9 shown.

[0121]

[0122] (4S,5S)-1,3-bis(3,5-dimethylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0123] (4S,5S)-1,3-bis(3,5-dimethylbenzyl)-2-(((4S,5S)-4,5-diphenylimidazolidin-2-ylidene)amino)-4,5-di phenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-9)

[0124] 1 H NMR (500MHz, CDCl3) δ7.36-7.31(m,6H),7.29-7.26(m,3H),7.24(d,J=1.5Hz,5H),7.23-7.17(m,6H ),6.87(s,2H),6.75(s,4H),4.91(s,2H),4.85(s,2H),4.56(dd,J=51.5,15.5Hz,4H),2.25(s,12H); 13 C NMR(126MHz, CDCl3)δ162.66(s),158.56(s),138.89(s),138.10(s),135.47(s),135.16(s),129.36(s),129.00(s), 128.97(s),128.84(s),128.66(s),126.79(s),126.23(s),70.85(s),67.64(s),49.60(s),21.30(s).HRMS(ESI)m / z 694.3904[M+H] +calcd for C 48 H 48 N5 + ,694.3904.

[0125] Example 10, H-PN catalyst (I-10)

[0126] A-1 in step 1 of Example 1 was replaced by A-5, and other operations were performed in the same manner to obtain 927.31 mg (0.94 mmol) of compound (I-10) as a light yellow solid with a yield of 47%. 1 H spectrum and 13 C spectrum Figure 10 shown.

[0127]

[0128] (4S,5S)-1,3-bis(3,5-bis(trimethylsilyl)benzyl)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0129] (4S,5S)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolidin-2-ylidene)amino)-1,3-bis(3,5-bis(trimet hylsilyl)benzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-10)

[0130] 1 H NMR (500MHz, CDCl3) δ7.48 (s, 2H), 7.25-7.13 (m, 18H), 6.87 (d, J = 8.7Hz, 4H ),4.83(d,J=22.2Hz),4.81(s,2H),4.67(s,4H),3.80(s,6H),0.21(s,36H); 13C NMR(126MHz, CDCl3)δ163.43(s),159.74(s),158.51(s),139.63(s),137.38(s),135.34(s),134.42(s),133.33(s),130.55(s) ,129.02(s),128.69(s),128.57(s),128.05(s),114.28(s),71.40(s),67.35(s),55.25(s),50.76(s),26.83(s); HRMS(ESI)m / z 986.5101[M+H] + calcd for C 58 H 76 N5O2Si4 + ,986.5071.

[0131] Example 11, H-PN catalyst (I-11)

[0132] The A-1 in step 1 of Example 1 was replaced by A-6, and the C-1 in step 6 was replaced by C-2. The other operations were the same to obtain 1.04 g (1.06 mmol) of compound (I-11). The product was a light yellow solid with a yield of 53%. 1 H spectrum and 13 C spectrum Figure 11 shown.

[0133] (4S,5S)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolin-2-ylidene)amino)-4,5-diphenyl-4,5-dihydro-1H-imidazolium chloride

[0134] (4S,5S)-2-(((4S,5S)-4,5-bis(4-methoxyphenyl)imidazolidin-2-ylidene)amino)-1,3-bis(3,5-di-tert-bu tyl-4-methoxybenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium chloride(I-11)

[0135]

[0136] 1H NMR (500MHz, CDCl3) δ7.18 (m, 1H), 6.94 (s, 1H), 6.87 (d, J = 8.7Hz, 1H), 4.87 (s ,1H),4.74(s,1H),4.67-4.51(m,1H),3.79(s,1H),3.61(s,1H),1.33(s,3H); 13 C NMR(126MHz, CDCl3)δ163.59(s),159.77(s),158.92(s),158.70(s),143.52(s),135.65(s),130.78(s),129.11(s),128.93(s),128.56(s) ),128.45(s),128.04(s),127.27(s),114.32(s),71.30(s),67.30(s),64.14(s),55.27(s),50.77(s),35.55(s),31.99(s); HRMS(ESI)m / z 983.6259[M+H] + calcd for C 64 H 81 N5O4 + ,983.6278.

[0137] Example 12: Effect of Catalyst Type on the Synthesis of Chiral Phosphoramide Compounds

[0138] Take a dry 5ml thick-walled ground-mouth test tube, put in a stirrer, add the catalyst in Table 1 (5 mol%, 0.01 mmol), put it in a glove box, and add Molecular sieves (200 mg), dichlorophosphine 1a (1.0 equiv., 0.2 mmol), the system was sealed, taken out, and 2 mL of anhydrous ether was added. The mixture was stirred in a low-temperature reactor at -20°C for 30 min. Then, secondary amine 2a (3.5 equiv., 0.7 mmol) was quickly added to the reaction tube using a microsyringe. The reaction was stirred at -20°C for 24 h, and the reaction solution became turbid milky white. Sodium methoxide (10.0 equiv., 2 mmol) was then added to the reaction tube for quenching. The mixture was stirred at -20°C for 12 h. The reaction was completed, and the reaction solution became turbid milky white. The product was filtered through dichloromethane using diatomaceous earth and chromatographed on a silica gel column (silica gel particle size 200-300 mesh, column height 30 cm, diameter 2.5 cm, column packing height 15 cm) using a 5:1 by volume petroleum ether / ethyl acetate eluent at an elution rate of 5 ml / min over 3 column volumes. The product was monitored using a 1:1 by volume petroleum ether / ethyl acetate eluent. Components with an Rf value of 0.3-0.4 were collected to obtain a colorless, transparent liquid. The product concentration was determined by high performance liquid chromatography, and the product yield and enantiomeric excess (ee) were calculated to obtain chiral phosphoramide 3a.

[0139] HPLC detection conditions were as follows: chromatographic column CHIRALPAK AD-H, mobile phase 3% isopropyl alcohol / hexanes (iPrOH / hexanes), flow rate 1.0 mL / min, and UV detector wavelength 210 nm.

[0140]

[0141] Table 1 Comparison of the reaction results of different ion pair catalysts for the synthesis of chiral phosphoramides

[0142]

[0143]

[0144] [a]Reaction conditions unless otherwise noted:1a(0.2mmol),2b(0.7mmol),H-PN,in Et2O(2mL)under a N2 atmosphere at-20℃.[b]Yields of theisolated products.[c]The ee were determined by chiral HPLC.

[0145] The catalyst described in the present invention successfully prepared chiral phosphoramide compounds with high yields (60%-80%) and enantioselectivities (80%-83%). Compared with other commercially available ion-pair catalysts and ion-pair catalysts developed by other research groups, the catalyst showed superior catalytic performance. Nuclear magnetic resonance and mass spectrometry methods also demonstrated that the catalyst binds to the phosphine substrate through hydrogen bonds, thus solving the problem that traditional ion-pair catalysts are difficult to construct chiral phosphoramide compounds.

[0146] Example 13: Hydrogen bond-assisted chiral bicyclic guanidine salt catalyzes the synthesis of chiral phosphoramide compounds from different substrates

[0147] Based on Example 12, the HPN catalyst (I-1) synthesized in Example 1 of the present invention was used as a catalyst to synthesize chiral phosphoramide compounds 3 using phosphorus oxychloride 1 and amine 2 of different structures as substrates, demonstrating the potential application value of the present invention.

[0148]

[0149] 1 in R 1 They are 4-bromo, 4-nitro, 2 in R 2 Isobutyl, benzyl, 2 R 3 They are isobutyl, benzyl, 3-nitrobenzyl, 2-methylbenzyl, 4-fluorobenzyl, 4-tert-butylbenzyl, 4-trifluoromethylbenzyl, 3,5-dibromobenzyl, 3 R 1 Same as R in 1 1 , R 2 , R 3 Same as R in 2 2 , R 3 .

[0150] The experimental operation was the same as that in Example 12, except that 1a in Example 12 was replaced by 1 and 2a was replaced by 2. Other operations were the same to obtain chiral phosphoramide compound 3. The results are shown in Table 2.

[0151] 1 H spectrum, 13 C spectrum and 31 P spectrum Figure 12-21 The results are shown in Table 2.

[0152] Under the same conditions, the catalyst was removed and other conditions and operations were the same. The HPLC spectrum of the reaction solution was shown in Figure 22-31 .

[0153] Table 2. Yields and ee values ​​of different products

[0154]

[0155]

[0156] methyl N,N-diisobutyl-P-phenylphosphonamidate(3a)

[0157] 1 H NMR(500 MHz,CDCl3)δ7.78-7.71(m,2H),7.49-7.39(m,3H),3.71(d,J=11.0Hz,3H),2.87-2.74(m,4H),1.86-1.78(m,2H),0.82(d,J=6.6 Hz,6H),0.76(d,J=6.7 Hz,6H); 13 C NMR(126MHz,CDCl3)δ131.8(s),131.6(d,J=9.1 Hz),131.3(d,J=2.4 Hz),128.2(d,J=14.0 Hz),52.9(d,J=3.5 Hz),51.4(d,J=5.8 Hz),26.5(d,J=2.2 Hz),20.2(d,J=23.94 Hz); 31 P NMR(202 MHz,CDCl3)δ25.00;HRMS(ESI)m / z 306.1598[M+Na] + calcd.forC 15 H 26 NO2P,306.1599.

[0158] methyl N-isobutyl-N-(3-nitrobenzyl)-P-phenylphosphonamidate(3b)

[0159] 1 H NMR(500 MHz,CDCl3)δ8.14-8.04(m,2H),7.80-7.72(m,2H),7.63(dt,J=7.7,1.3 Hz,1H),7.56-7.49(m,1H),7.49-7.42(m,3H),4.42-4.29(m,2H),3.77(d,J=11.0 Hz,3H),2.78-2.63(m,2H),1.76(dt,J=13.7,6.8 Hz,1H),0.77(d,J=6.6 Hz,3H),0.69(d,J=6.6 Hz,3H). 13C NMR(126 MHz,CDCl3)δ148.46,140.74(d,J=2.3 Hz),134.47,132.09(d,J=3.0 Hz),131.81(d,J=9.3 Hz),130.91,129.48,128.76(d,J=14.1 Hz),123.12,122.47,53.01(d,J=3.6 Hz),52.06(d,J=5.7 Hz),48.86(d,J=5.1 Hz),26.41(d,J=2.9 Hz),20.15(d,J=24.9 Hz). 31 P NMR(202 MHz,CDCl3)δ25.24.HRMS(ESI)m / zcalculated for C 18 H 23 N2O4P + [M+Na] + :385.1293,found:385.1282.

[0160] methyl N-isobutyl-N-(2-methylbenzyl)-P-phenylphosphonamidate(3c)

[0161] 1 H NMR(500 MHz,CDCl3)δ7.83-7.73(m,2H),7.53-7.41(m,3H),7.26-7.23(m,1H),7.14-7.07(m,3H),4.32-4.19(m,2H),3.74(d,J=11.0 Hz,3H),2.86-2.70(m,2H),2.24(s,3H),1.73-1.65(m,1H),0.75(d,J=6.6 Hz,3H),0.71(d,J=6.6 Hz,3H). 13 C NMR(126 MHz,CDCl3)δ136.08,135.90(d,J=3.4 Hz),131.93(d,J=9.2 Hz),131.74(d,J=2.9 Hz),131.36,130.38,129.99,128.54(d,J=14.1 Hz),128.17,127.01,125.93,53.27(d,J=3.7Hz),52.03(d,J=5.7 Hz),47.14(d,J=4.8 Hz),27.05(d,J=2.2 Hz),20.36(d,J=21.3Hz),19.32. 31P NMR(202 MHz,CDCl3)δ25.54.HRMS(ESI)m / z calculated for C 19 H 26 NO2P + [M+Na] + :354.1599,found:354.1590.

[0162] methyl N-benzyl-N-(2-methylbenzyl)-P-phenylphosphonamidate(3d)

[0163] 1 H NMR(500 MHz,CDCl3)δ7.84-7.8(m,2H),7.54-7.49(m,1H),7.47-7.43(m,2H),7.25-7.19(m,4H),7.15-7.11(m,2H),7.10-7.05(m,3H),4.19-4.09(m,4H),3.76(d,J=11.1 Hz,3H),2.01(s,3H). 13 C NMR(126 MHz,CDCl3)δ137.48,136.44,134.95(d,J=3.7Hz),131.96,131.89,131.15,130.44,129.77,128.74,128.63,128.43,128.06,127.38,127.07,126.00,52.16(d,J=5.6 Hz),48.32(d,J=4.7 Hz),45.18(d,J=5.0 Hz),19.12. 31 P NMR(202 MHz,CDCl3)δ25.32.HRMS(ESI)m / zcalculated for C 22 H 24 NO2P + [M+Na] + :388.1442,found:388.1436.

[0164] methyl N-benzyl-N-(4-fluorobenzyl)-P-phenylphosphonamidate(3e)

[0165] 1H NMR(500 MHz,CDCl3)δ7.85-7.77(m,2H),7.56-7.50(m,1H),7.49-7.43(m,2H),7.30-7.26(m,2H),7.26-7.21(m,1H),7.16-7.07(m,4H),6.98-6.91(m,2H),4.15-4.02(m,4H),3.75(d,J=11.1Hz,3H). 13 C NMR(126 MHz,CDCl3)δ163.23,161.28,137.23(d,J=2.9Hz),133.19(t,J=2.9 Hz),132.05(d,J=3.1 Hz),131.84(d,J=9.2 Hz),131.19,130.49(d,J=8.0 Hz),129.80,128.82,128.72,128.57,127.54,115.33(d,J=21.3 Hz),51.94(d,J=5.7 Hz),47.96(d,J=4.9 Hz),47.21(d,J=5.0Hz). 31 P NMR(202 MHz,CDCl3)δ24.89.HRMS(ESI)m / z calculated for C 21 H 21 FNO2P + [M+Na] + :392.1192,found:392.1192.

[0166] methyl N-benzyl-N-(4-(tert-butyl)benzyl)-P-phenylphosphonamidate(3f)

[0167] 1 H NMR(500MHz,CDCl3)δ7.84-7.77(m,2H),7.54-7.48(m,1H),7.47-7.43(m,2H),7.32-7.27(m,4H),7.26-7.22(m,1H),7.20-7.16(m,2H),7.10-7.05(m,2H),4.12(dd,J=10.1,3.6Hz,2H),4.07(d,J=9.9Hz,2H),3.75(d,J=11.1Hz,3H),1.31(s,9H). 13C NMR(126MHz,CDCl3)δ150.38,137.62(d,J=2.6Hz),134.29(d,J=2.8Hz),131.87(d,J=9.3Hz),131.44,130.04,128.88,128.70,128.57,128.45,127.38,125.37,51.80(d,J=5.8Hz),47.83(d,J=4.9Hz),47.56(d,J=5.0Hz),34.59,31.48. 31 P NMR(202MHz,CDCl3)δ24.91.HRMS(ESI)m / z calculated for C 25 H 30 NO2P + [M+Na] + :430.1912,found:430.1909.

[0168] methyl N-benzyl-P-phenyl-N-(4-(trifluoromethyl)benzyl)phosphonamidite(3g)

[0169] 1 H NMR(500MHz,CDCl3)δ7.86-7.77(m,2H),7.56-7.45(m,5H),7.26(d,J=5.5Hz,4H),7.24(d,J=1.8Hz,1H),7.10(dd,J=7.5,1.9Hz,2H),4.22-4.12(m,2H),4.12-4.02(m,2H),3.77(d,J=11.1Hz,3H). 13 C NMR(126MHz,CDCl3)δ141.81,136.93(d,J=2.9Hz),132.18(d,J=2.9Hz),131.84(d,J=9.3Hz),130.95,129.84,129.58(d,J=2.7Hz),128.92(d,J=4.6Hz),128.77(d,J=4.1Hz),128.62,127.67,125.44(d,J=3.8Hz),52.08(d,J=5.6Hz),48.36(d,J=4.7Hz),47.64(d,J=5.1Hz),29.82. 31 P NMR(202MHz,CDCl3)δ24.91.HRMS(ESI)m / z calculated for C 22 H21 F3NO2P + [M+Na] + :442.1160,found:442.1158.

[0170] methyl N-(3,5-dibromobenzyl)-N-isobutyl-P-phenylphosphonamidate(3h)

[0171] 1 H NMR(500MHz,CDCl3)δ7.80-7.71(m,2H),7.56-7.49(m,2H),7.48-7.44(m,2H),7.28(d,J=1.7Hz,2H),4.19(d,J=11.0Hz,2H),3.75(d,J=11.1Hz,3H),2.77-2.63(m,2H),1.76(dt,J=13.7,6.9Hz,1H),0.74(dd,J=40.9,6.6Hz,6H). 13 C NMR(126MHz,CDCl3)δ142.44,133.00,132.06(d,J=3.0Hz),131.75(d,J=9.1Hz),131.09,130.13,129.71,128.74(d,J=14.0Hz),123.02,52.74(d,J=3.5Hz),51.97(d,J=5.7Hz),48.44(d,J=5.1Hz),26.35(d,J=2.7Hz),20.18(d,J=25.0Hz). 31 PNMR(202MHz,CDCl3)δ24.90.HRMS(ESI)m / z calculated for C 18 H 22 Br2NO2P + [M+Na] + :495.9653,found:495.9659.

[0172] methyl P-(4-bromophenyl)-N,N-diisobutylphosphonamidate(3i)

[0173] 1H NMR(500MHz,CDCl3)δ7.65-7.50(m,4H),3.69(d,J=11.0Hz,3H),2.85-2.71(m,4H),1.82(dp,J=13.7,6.8Hz,2H),0.79(dd,J=21.7,6.6Hz,12H). 13 C NMR(126MHz,CDCl3)δ133.30(d,J=9.7Hz),131.65(d,J=14.5Hz),130.45(d,J=174.5Hz),126.38(d,J=4.0Hz),53.01(d,J=3.8Hz),51.63(d,J=5.7Hz),26.59(d,J=2.8Hz),20.38(d,J=19.2Hz). 31 P NMR(202MHz,CDCl3)δ23.86.HRMS(ESI)m / z calculated for C 15 H 25 BrNO2P + [M+Na] + :384.0704,found:384.0716.

[0174] methyl N,N-dibenzyl-P-(4-nitrophenyl)phosphonamidite(3j)

[0175] 1 H NMR(500MHz,CDCl3)δ8.28-8.23(m,2H),7.96-7.89(m,2H),7.33-7.27(m,6H),7.17-7.11(m,4H),4.14(dd,J=10.0,3.1Hz,4H),3.78(d,J=11.2Hz,3H). 13 C NMR(126MHz,CDCl3)δ149.87,139.20,137.82,136.79(d,J=2.6Hz),132.85(d,J=10.2Hz),128.74(d,J=4.5Hz),127.82,123.52(d,J=14.6Hz),52.01(d,J=6.0Hz),48.12(d,J=5.0Hz). 31 PNMR(202MHz,CDCl3)δ21.06.HRMS(ESI)m / z calculated for C 21 H 21 N2O4P + [M+Na]+ :419.1137,found:419.1135.

[0176] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention should not be limited by the above embodiments. The above embodiments and the contents described in the specification are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may also have various optimizations and improvements, and these optimizations and improvements all fall within the scope of protection of the present invention.

Claims

1. A basic hydrogen bond-assisted chiral bicyclic guanidine ion pair catalyst represented by formula (I), referred to as H-PN catalyst: In formula (I), R 1 is tert-butyl, trifluoromethyl, trimethylsilyl or methoxy, R 5 is hydrogen or methoxy, R 7 is a hydrogen or bromine atom, R 9 is phenyl or 4-methoxyphenyl, R 11 is phenyl or 4-methoxyphenyl; R 2 , R 3 , R 4 Same as R 1 ; R 6 Same as R 5 ; R 8 Same as R 7 ; R 10 Same as R 9 ; R 12 Same as R 11 .

2. The H-PN catalyst according to claim 1, wherein The H-PN catalyst represented by formula (I) is one of the following:

3. A method for preparing the H-PN catalyst according to claim 1, characterized in that: The method is carried out as follows: (1) Compound A and N-bromosuccinimide were added to a single-necked round-bottom flask containing cyclohexane in sequence, stirred at 80°C for 5 minutes, and then benzoyl peroxide was added and stirred at 80°C for 12 hours; the reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to remove the solvent. The concentrate was loaded onto a silica gel chromatography column with petroleum ether as the eluent at a rate of 5 ml / min for 3 column volumes. Thin layer chromatography was performed using petroleum ether as the developing solvent, and the component with an Rf value of 0.7-0.75 was collected to obtain a colorless transparent liquid, which was compound B; (2) Compound C and K2CO3 were added to a single-necked round-bottom flask containing CH3CN-a in sequence and stirred at room temperature; then the CH3CN-b solution of compound B was slowly added dropwise and stirred at room temperature for 24 h. The reaction was monitored by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 10:1 as a developing solvent; after the reaction was completed, the reaction solution was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the concentrated solution was loaded onto a silica gel chromatography column and eluted with petroleum ether / ethyl acetate in a volume ratio of 50:1 and 30:1 in sequence. The elution rate was 5 ml / min, and the elution volume for each concentration was 3 column volumes. Thin-layer chromatography was performed using petroleum ether / ethyl acetate in a volume ratio of 10:1 as a developing solvent, and the components with Rf values ​​of 0.2-0.3 were collected and concentrated to dryness under reduced pressure to obtain compound D; (3) Compound D and K2CO3 were added to a round-bottom flask containing dichloromethane and water in sequence, stirred at room temperature, thiophosgene was added, stirred at room temperature for 2 h, and the reaction was monitored by thin-layer chromatography using a 10:1 volume ratio of petroleum ether / ethyl acetate as a developing solvent. After the reaction was complete, the reaction solution was extracted with a 1:1 volume ratio of water and dichloromethane, the lower organic phase was removed and dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the concentrate was loaded onto a silica gel chromatography column and eluted with a 30:1 volume ratio of petroleum ether / ethyl acetate as an eluent at an elution rate of 5 ml / min and an elution volume of 3 column volumes. Thin-layer chromatography was performed using a 30:1 volume ratio of petroleum ether / ethyl acetate as a developing solvent, and the components with an Rf value of 0.3-0.35 were collected and concentrated to dryness under reduced pressure to obtain compound E. (4) Compound E was placed in a single-necked round-bottom flask, the system was evacuated, and nitrogen was replaced to ensure anhydrous and oxygen-free conditions. Ultra-dry toluene and oxalyl chloride were added, and the mixture was stirred at 80° C. for 12 h. After the reaction, the mixture was immediately evacuated and dried to obtain Compound F; the ratio of the amount of Compound E to the amount of oxalyl chloride was 1:5-10; the volume of toluene was 1-5 mL / mmol based on the amount of Compound E; (5) Compound C was placed in a single-necked round-bottom flask, and nitrogen was replaced to ensure anhydrous and oxygen-free conditions. Ultra-dry acetonitrile a was added, BrCN was dissolved in acetonitrile b, and injected into the reaction system under a flowing nitrogen environment. The mixture was heated and refluxed for 12 hours. After the reaction, the mixture was immediately spin-dried to obtain compound G without post-treatment. The ratio of the amount of compound C to BrCN was 1:1-3. The volume of acetonitrile a was 1-5 mL / mmol based on the amount of compound C, and the volume ratio of acetonitrile b to acetonitrile a was 0.1-2:

1. (6) All the compound F in step (4) was placed in a single-necked round-bottom flask, the system was evacuated, nitrogen was replaced, and compound G in step (5) was quickly poured under nitrogen protection. The evacuation was continued for 2 hours, and then nitrogen was replaced to ensure that the system was free of water and oxygen. Ultra-dry acetonitrile was added under circulating nitrogen, and ultra-dry triethylamine was added under stirring. The system was heated to reflux for 12 hours; thin-layer chromatography was used for monitoring, and petroleum ether / ethyl acetate in a volume ratio of 1:1 was used as the developing solvent; after the reaction was complete, the reaction solution was spin-dried and added with a volume ratio of 1:

1. Extract with water and dichloromethane, remove the lower organic phase, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure, apply the concentrate to a silica gel chromatography column, elute with petroleum ether / ethyl acetate in a volume ratio of 1:1 as an eluent, the elution rate is 5 ml / min, the elution volume is 3 column volumes, and monitor thin layer chromatography with petroleum ether / ethyl acetate in a volume ratio of 1:1 as a developing solvent, collect the components with an Rf value of 0.5-0.6, and concentrate to dryness under reduced pressure to obtain the H-PN catalyst represented by formula (I); R in A 1 is tert-butyl, trifluoromethyl, trimethylsilyl or methoxy, R 5 is hydrogen or methoxy, R 7 is a hydrogen or bromine atom; R 2 Same as R 1 ; R in C 9 is phenyl or 4-methoxyphenyl, R 10 Same as R 9 ; R in B, D, E, F 1 、R 2 、R 5 、R 7 Same as A; R in D, E, and F 3 、R 4 Same as R in A 1 ; R in D, E, F 6 Same as R in A 5 ; R in D, E, F 8 Same as R in A 7 ; R in G 11 、R 12 Same as R in C 9 .

4. The preparation method according to claim 3, wherein In step (1), the ratio of the amount of compound A to the amount of N-bromosuccinimide is 1:1-3; the volume of cyclohexane used is 0.5-1.0 mL / mmol based on the amount of compound A; and the ratio of the amount of compound A to the amount of benzoyl peroxide is 1:0.01-0.

1.

5. The preparation method according to claim 3, wherein In step (2), the ratio of the amount of compound C to the amount of K2CO3 feed material is 1:1-3; the volume amount of CH3CN-a is 1-5mL / mmol based on the amount of compound C feed material, and the volume amount of CH3CN-b is 1-5mL / mmol based on the amount of compound C feed material; the ratio of the amount of compound C to compound B feed material is 1:1-3.

6. The preparation method according to claim 3, wherein In step (3), the ratio of the amount of compound D to the K2CO3 feed material is 1:1-3; the volume ratio of dichloromethane to water is 1:1, and the volume of dichloromethane used is 1-5mL / mmol based on the amount of compound D; the ratio of the amount of compound D to thiophosgene feed material is 1:1-5.

7. The preparation method according to claim 3, wherein In step (6), the ratio of the amount of compound E to compound G is 1:1-3; the volume of acetonitrile used is 1-5 mL / mmol based on the amount of compound E; and the ratio of the amount of triethylamine to compound E is 1-5:

1.

8. Use of the H-PN catalyst according to claim 1 in the preparation of chiral phosphoramide compounds.

9. The use according to claim 8, characterized in that The application method is as follows: take a dry reaction tube, put in a stirrer, add the catalyst H-PN, and add Molecular sieves, phosphine compound 1, the system was sealed, anhydrous ether was added, and the mixture was stirred at -20°C for 30 minutes. Then, amine compound 2 was quickly added to the reaction tube with a microsyringe, and the reaction was stirred at -20°C for 24 hours; sodium methoxide was then added to the reaction tube for quenching, and stirring was continued at -20°C for 12 hours. The reaction solution was filtered through dichloromethane using diatomaceous earth, and silica gel column chromatography was performed using petroleum ether / ethyl acetate in a volume ratio of 5:1 as the eluent. The elution rate was 5 ml / min and the elution volume was 3 column volumes. The mixture was monitored using petroleum ether / ethyl acetate in a volume ratio of 1:1 as the developing solvent. The components with Rf values ​​of 0.3-0.4 were collected to obtain a colorless transparent liquid to obtain chiral phosphoramide compound 3; 1 in R 1 They are 4-bromo, 4-nitro, 2 in R 2 Isobutyl, benzyl, 2 R 3 They are isobutyl, benzyl, 3-nitrobenzyl, 2-methylbenzyl, 4-fluorobenzyl, 4-tert-butylbenzyl, 4-trifluoromethylbenzyl, 3,5-dibromobenzyl, 3 R 1 Same as R in 1 1 , R 2 , R 3 Same as R in 2 2 , R 3 .

10. The use according to claim 9, characterized in that The ratio of the amount of the phosphine compound 1 to the amount of the catalyst substance is 1:0.01-0.1; The molecular sieve mass dosage is 0.1-2 g / mmol based on the amount of the phosphine compound 1; the ratio of the amount of the amine compound 2 to the amount of the phosphine compound 1 is 1-5:1; The volume of the anhydrous ether is 5-15 mL / mmol based on the amount of the phosphine compound 1; the ratio of the amount of the sodium methoxide to the amount of the phosphine compound 1 is 5-15:1.

Images