CN114682298B - Chiral phosphonamide catalyst and preparation method and application thereof - Google Patents
Chiral phosphonamide catalyst and preparation method and application thereof Download PDFInfo
- Publication number
- CN114682298B CN114682298B CN202210381439.8A CN202210381439A CN114682298B CN 114682298 B CN114682298 B CN 114682298B CN 202210381439 A CN202210381439 A CN 202210381439A CN 114682298 B CN114682298 B CN 114682298B
- Authority
- CN
- China
- Prior art keywords
- compound
- chiral
- catalyst
- phosphonamide
- reaction system
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
- B01J2231/52—Isomerisation reactions
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a chiral phosphonamide catalyst and a preparation method and application thereof, wherein the preparation method of the catalyst comprises the following steps: taking a compound A as a raw material, and obtaining a compound B through MOM protection; iodinating the 3,3' position of the compound B to obtain a compound C; preparing a compound D, and carrying out Kumada coupling on the compound C and the compound D to obtain a compound E; deprotecting the compound E to obtain a compound F; and (3) carrying out amidation and recrystallization on the compound F to obtain the chiral phosphonamide catalyst. The catalyst of the invention can efficiently catalyze [1,3] rearrangement reaction of indole derivatives by changing the steric hindrance of 3,3' position and combining with acetonitrile, and has high yield and high enantioselectivity.
Description
Technical Field
The invention relates to the technical field of chiral catalysts, and particularly relates to a chiral phosphonamide catalyst and a preparation method and application thereof.
Background
Activation of substrates by chiral catalysts is one of the most effective strategies in asymmetric synthesis technology. Meanwhile, chiral phosphoric acid has been proven to be an efficient and versatile catalyst, which is widely used in synthetic transformations. It can lower the energy of the LUMO orbital of the electrophile by protonation, thereby activating the reaction of the substrate with the nucleophile. In the last decade, a phosphate with Binaphthol (BINOL) as a backbone plays an important role in asymmetric synthesis.
However, as further research shows that the chiral phosphoric acid has low acidity, which limits the application of the chiral phosphoric acid to a certain extent, the chiral phosphoramide catalyst with stronger acidity is obtained by amidating the phosphoric acid, and the strength of the acidity is crucial in asymmetric bronsted acid catalysis. Generally, the more acidic, the more reactive. At present, in asymmetric Bronsted acid catalysis, the existing chiral phosphoramide catalyst can not meet the requirements of catalytic activity and high enantioselectivity.
Disclosure of Invention
In order to solve the technical problems, the invention provides a chiral phosphonamide catalyst, and a preparation method and application thereof, so as to achieve the purpose of providing a high-efficiency catalyst for asymmetric Bronsted acid catalysis.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a chiral phosphonamide catalyst NPA-3Cy MeCN comprises two configurations of (R) -NPA-3Cy MeCN and (S) -NPA-3Cy MeCN, and the chemical structural formulas are respectively shown as follows:
a preparation method of a chiral phosphonamide catalyst comprises the following steps:
(1) Taking an R-type or S-type compound A as a raw material, and carrying out MOM protection to obtain a compound B;
(2) Iodinating the 3,3' position of the compound B to obtain a compound C;
(3) Preparing a compound D, and carrying out Kumada coupling on the compound C and the compound D to obtain a compound E;
(4) Deprotecting the compound E to obtain a compound F;
(5) Amidating and recrystallizing the compound F to obtain an R-type or S-type chiral phosphonamide catalyst;
the specific reaction process is shown as the following formula:
in the scheme, the specific method of the step (1) is as follows:
adding compound a to a dry round-bottom flask, followed by adding DMF solution to the round-bottom flask; cooling to 0 ℃, and slowly adding NaH into the reaction system in batches; after the gas in the reaction system is exhausted, slowly dropwise adding MOMCl into the reaction system; after fully stirring, reacting for 1 hour at the temperature of 0 ℃; TLC detecting the reaction system, after the compound A is completely consumed, using saturated NH 4 Quenching the Cl solution, and extracting with ethyl acetate; the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain compound B.
In the scheme, the specific method of the step (2) is as follows:
adding the compound B into a dry mouth-opening bottle, and adding tetrahydrofuran under the protection of nitrogen; slowly adding n-butyl lithium at-78 ℃, and reacting for 1.5 hours at 0 ℃; then slowly adding iodine particles into the reaction system at the temperature of minus 78 ℃; reacting at 0 ℃ for 1 hour, monitoring the reaction system by TLC, and after the reaction is finished, using saturated NH 4 The Cl solution was quenched, extracted with ethyl acetate, and saturated Na was added 2 S 2 O 3 Washing with saline water; anhydrous Na 2 SO 4 After drying, concentrating under reduced pressure, purifying by a silica gel column to obtain the compound C.
In the above scheme, in step (3), the specific method for preparing compound D is as follows:
to anhydrous C 6 H 6 And cyclohexyl bromide is added with anhydrous AlCl 3 Adding the mixture in batches at the temperature of-40 ℃ within 5 minutes without stirring; at this stage, the reaction mixture was gradually warmed to 0 ℃ and then to ambient temperature; the reaction mixture was suspended in n-hexane and poured into saturated NaHCO 3 On the aqueous solution; the organic layer was separated and washed with anhydrous Na 2 SO 4 Drying, filtering and vacuum concentrating; the crude residue 1,3, 5-tricyclohexylbenzene is then filtered through a silica gel column;
the crude 1,3, 5-tricyclohexylbenzene obtained was dissolved in anhydrous CHCl 3 Neutralizing and cooling to 0 ℃, slowly adding bromine within 10 minutes, heating the solution to the ambient temperature, and stirring for 2 hours; the reaction mixture was diluted with dichloromethane and the resulting solution was taken up with Na 2 SO 3 Quenching the aqueous solution; the aqueous layer was extracted with dichloromethane; the combined organic layers were washed with aqueous NaOH and water, then with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure; the resulting crude residue was purified by trituration from ethyl acetate and filtration; the resulting white powder was recrystallized from boiling ethanol to give compound D.
In the above scheme, in step (3), compound E is prepared as follows:
adding the compound D and the magnesium strip into a dry bottle with a mouth, adding THF (tetrahydrofuran) into a reaction system under the protection of nitrogen, and then adding 1 iodine particle into the reaction system, wherein the reaction system turns yellow; pumping nitrogen for three times by using a vacuum pump to ensure that the reaction system is in a nitrogen atmosphere; heating to 60 ℃, adding 1-2 drops of 1, 2-dibromoethane and TMSCl into the mixture; then heating to 80 ℃, heating for 2h at 80 ℃, wherein the color in the reaction system will fade in the heating process to generate a colorless liquid and form a format reagent;
mixing the compound C and NiCl 2 (PPh 3 ) 2 Adding to a dry branched-mouth bottle, and then introducing THF into the branched-mouth bottle; and (2) slowly dripping the newly prepared Grignard reagent into the reaction system through a syringe, reacting for 24 hours at the temperature of 40 ℃, then adding ethyl acetate for extraction, combining organic phases, drying, performing suction filtration, performing spin drying, and purifying by column chromatography to obtain a compound E.
In the scheme, the specific method of the step (4) is as follows:
adding the compound E, HCl and 1, 4-dioxane into a round-bottom flask, and reacting for 3 hours at the temperature of 100 ℃; with saturated NaHCO 3 The solution was quenched, extracted with DCM, washed with brine, na 2 SO 4 Drying, and purifying the crude product by column chromatography to obtain the compound F.
In the above scheme, the specific method of step (5) is as follows:
adding compound F and DCM to a dry branched bottle, and adding Et to the mixture at 0 ℃ under the protection of nitrogen 3 N，POCl 3 And DMAP, after stirring at room temperature for 1 hour, CF 3 SO 2 NH 2 Adding MeCN into the reaction system, reacting for 12 hours at the temperature of 100 ℃, extracting by DCM, and adding NaHCO 3 Washing with HCl, na 2 SO 4 Drying, spin-drying, and recrystallizing with acetonitrile to obtain chiral phosphonamide NPA-3Cy;
the method comprises the steps of dissolving acidified chiral phosphoramide NPA-3Cy powder solid in a DCM solution, slowly dropwise adding MeCN, gradually layering, slowly volatilizing, and recrystallizing to obtain NPA-3 Cy-MeCN crystals, namely the chiral phosphoramide catalyst.
The chiral phosphonamide catalyst can efficiently catalyze the [1,3] rearrangement reaction of indole, indene, benzofuran and benzothiophene derivatives, and has high yield and high enantioselectivity.
By the technical scheme, the chiral phosphonamide catalyst provided by the invention and the preparation method and application thereof have the following characteristics
Has the beneficial effects that:
the chiral phosphonamide NPA-3Cy MeCN crystal prepared by the invention has the following characteristics:
(1) A BINOL skeleton having a controllable axial chirality and rigidity;
(2) The steric hindrance and the electric property of the catalyst can be regulated and controlled by connecting different groups at the 3,3 'position, and the source of the enantioselectivity mainly depends on the steric hindrance at the 3,3' position;
(3) The oxygen atom on the phosphorus-oxygen double bond has a lone pair of electrons and can be used as a Lewis base site;
(4) Chiral phosphate has strong acidity, and contains a Bronsted acid site, so that the chiral phosphate can activate a substrate.
The invention can efficiently catalyze [1,3] rearrangement reaction of indole, indene, benzofuran and benzothiophene derivatives by adjusting the steric hindrance of 3,3' position, and can effectively improve the yield and enantioselectivity compared with the existing catalyst.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below.
The invention provides a chiral phosphonamide catalyst, which comprises two configurations of (R) -NPA-3 Cy-MeCN and (S) -NPA-3 Cy-MeCN, wherein the chemical structural formulas of the two configurations are respectively as follows:
the invention takes (R) -NPA-3Cy & MeCN as an example, and provides a preparation method of the chiral phosphonamide catalyst, and the specific reaction process is shown as the following formula:
the method comprises the following steps:
(1) Taking an R-type compound A as a raw material, and obtaining a compound B through MOM protection, wherein the specific method comprises the following steps:
compound A (10.0 g, 34.9mmol) was added to a dry 250mL round-bottomed flask, followed by 100mL of LDMF solution. Cooled to 0 ℃ and NaH (60% dispersion in minor oil,7.0g,104.7 mmol) was slowly added to the reaction system in portions. After the gas in the reaction system was exhausted, MOMCl (6.63mL, 87.3 mmol) was slowly added dropwise to the reaction system. After stirring sufficiently, the reaction was carried out at 0 ℃ for 1 hour. TLC detection of the reaction system, after complete consumption of compound A, saturated NH 4 The Cl solution was quenched and extracted with ethyl acetate. The organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave the product as a white solid, compound B (13.4g, 98%).
Nuclear magnetic data for compound B are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.96(d,J＝9.0Hz,2H),7.91-7.86(m,2H),7.58(d,J＝9.0Hz,2H),7.35(ddd,J＝8.2,6.7,1.3Hz,2H),7.23(ddd,J＝8.1,6.7,1.3Hz,2H),7.19-7.13(m,2H),5.09(d,J＝6.8Hz,2H),4.98(d,J＝6.8Hz,2H),3.15(s,6H).
13 C NMR(100MHz,Chloroform-d)δ152.7,134.1,130.0,129.5,128.0,126.4,125.6,124.2,121.4,117.4,95.3,55.9.
(2) Iodinating the 3,3' position of the compound B to obtain a compound C, wherein the specific method comprises the following steps:
to a dry 200mL vial was added compound B (5.5g, 14.7 mmol) and, under nitrogen, 100mL tetrahydrofuran. N-butyllithium (2.5M in THF,17.7mL, 44.1mmol) was slowly added at-78 ℃ and reacted at 0 ℃ for 1.5 hours. Then at-78 deg.C, adding the mixture into the reaction bodyTo this was added slowly iodine particles (11.2g, 44.1mmol). The reaction was carried out at 0 ℃ for 1 hour (TLC monitoring). After the reaction is complete, saturated NH is used 4 The Cl solution was quenched, extracted with ethyl acetate, and saturated Na was added 2 S 2 O 3 And washing with brine. Anhydrous Na 2 SO 4 After drying, concentration under reduced pressure and purification by silica gel column, the product was obtained as a yellow solid, i.e., compound C (10.9g, 85%).
Nuclear magnetic data for compound C are as follows:
1 H NMR(400MHz,Chloroform-d)δ8.54(s,2H),7.78(d,J＝8.2Hz,2H),7.43(ddd,J＝8.2,6.7,1.2Hz,2H),7.30(ddd,J＝8.3,6.8,1.3Hz,2H),7.18(dd,J＝8.6,1.2Hz,2H),4.81(d,J＝5.7Hz,2H),4.70(d,J＝5.7Hz,2H),2.59(s,6H).
13 C NMR(100MHz,Chloroform-d)δ152.3,140.1,133.9,132.3,127.2,126.9,126.6,126.4,126.0,99.5,92.6,56.6.
(3) Preparing a compound D, and carrying out Kumada coupling on the compound C and the compound D to obtain a compound E, wherein the specific method comprises the following steps:
to anhydrous C 6 H 6 (3.60mL, 40mmol,1.0 equiv.) and cyclohexyl bromide (19.8mL, 160mmol,4.0 equiv.) to a cooled (-40 ℃ C.) solution anhydrous AlCl was added 3 (10.7g, 80mmol, 2.0equiv.) was added in portions over 5 minutes. During the addition, the color of the reaction mixture gradually changed from colorless to yellow, with vigorous gas evolution, and the reaction mixture became a solid mass (without stirring). At this stage, the reaction mixture was gradually warmed to 0 ℃ (ice/water bath) and then to ambient temperature. The reaction mixture was suspended in n-hexane and poured into saturated NaHCO 3 And (3) adding the mixture to an aqueous solution. The organic layer was separated and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The resulting crude residue was then filtered through a silica gel column (n-hexane/DCM 95. A pale yellow viscous oil was isolated in 99% yield (12.8g, 40mmol). The obtained crude 1,3, 5-tricyclohexylbenzene (9.53g, 29.4mmol, 1.0equiv.) was dissolved in anhydrous CHCl 3 (15 mL) and cooled to 0 deg.C (ice/water bath). Bromine (1.58mL, 30.9mmol, 1.05equiv.) was added slowly over 10 minutes. The solution is heated to the ambient temperature,stirred for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and the resulting solution was taken up with 10% (w/w) Na 2 SO 3 And (4) quenching the aqueous solution. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 10% (w/w) aqueous NaOH and water, then with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The resulting crude residue was purified by trituration from ethyl acetate and filtration. The resulting white powder was recrystallized from boiling ethanol to give compound D as colorless crystals in isolated yield 72% (8.58g, 21.3mmol).
Compound D (2.4 g, 8.39mmol), magnesium rod (305mg, 10.9mmol) was added to a dry 50mL jar, and 20mL THF was added to the reaction under nitrogen. Then 1 iodine particle was added to the reaction system, and the reaction system became yellow. The nitrogen gas was evacuated three times by a vacuum pump to place the reaction system in a nitrogen atmosphere. The temperature was raised to 60 ℃ and 1-2 drops of 1, 2-dibromoethane and TMSCl were added to the mixture. Then the temperature is increased to 80 ℃, the reaction system is heated for 2h at the temperature of 80 ℃, the color in the reaction system will fade in the heating process, and colorless liquid is generated to form the format reagent.
Compounds C (1.5g, 2.4mmol) and 10mol% of NiCl 2 (PPh 3 ) 2 (157mg, 0.24mmol) was added to a 100mL dry vial, followed by introduction of 20mL THF to the vial. The freshly prepared grignard reagent was slowly added dropwise to the reaction via syringe. After 24 hours at 40 ℃, ethyl acetate was added and extracted. The combined organic phases were dried, suction filtered, spin dried and purified by column chromatography to give compound E (1.74g, 72% yield).
Nuclear magnetic data for compound E are as follows:
1 H NMR(400MHz,CD 2 Cl 2 ):δ7.88(2H,d,J 8.2),7.75(2H,s),7.43(2H,td,J1 8.0,J2 1.6),7.27-7.34(4H,m),7.07(4H,s),4.37(2H,d,J 5.2),4.28(2H,d,J 5.2),2.50-2.56(2H,m),2.35-2.41(4H,m),2.27(6H,s),0.87-1.90(60H,m)ppm.
(4) And deprotecting the compound E to obtain a compound F, which comprises the following steps:
the coupling product compound E (856 mg,0.84mmol, 1).0 equiv), 3mL of 12NHCl and 2 mL of 1, 4-dioxane were added to a 100mL round bottom flask. The reaction was carried out at a temperature of 100 ℃ for 3 hours. With saturated NaHCO 3 The solution was quenched, extracted with DCM, washed with brine, na 2 SO 4 Drying and purification of the crude product by column chromatography gave compound F (782 mg).
Nuclear magnetic data for compound F are as follows:
1 H NMR(400MHz,CD 2 Cl 2 ):δ7.90(2H,d,J 8.0),7.72(2H,s),7.39(2H,t,J 7.0),7.33(2H,t,J7.0),7.22(2H,d,J 8.3),7.11(2H,s),7.09(2H,s),4.94(2H,brs),2.55(2H,t,J 9.1),2.43(2H,t,J11.7),2.25(2H,t,J 12.0),0.82-1.94(60H,m)ppm.
(5) Amidating and recrystallizing the compound F to obtain a compound, wherein the specific method is as follows:
compound F (1 equiv) and 5mL DCM were added to a 25mL dry vial. Et is added to the mixture under the protection of nitrogen at 0 DEG C 3 N(7equiv)，POCl 3 (1.2 equiv) and DMAP (2 equiv). After stirring at room temperature for 1 hour, CF was added 3 SO 2 NH 2 (2 equiv) and 5mL of MeCN were added to the reaction system. Reaction at 100 deg.C for 12 hr, DCM extraction, naHCO 3 Wash, 6N HCl Wash, na 2 SO 4 The product obtained after drying and purification on a silica gel column may be a phosphoramidate. The product was washed again with 6N HCl, na 2 SO 4 Drying, spin-drying, and recrystallizing with acetonitrile to obtain chiral phosphoramide product (R) -NPA-3Cy.
The nuclear magnetic data of the chiral phosphoramide product (R) -NPA-3Cy is as follows:
1 H NMR(400MHz,Methylene Chloride-d 2 )δ7.96(d,J＝8.2Hz,2H),7.87(d,J＝3.8Hz,2H),7.53(td,J＝7.5,3.9Hz,2H),7.36–7.27(m,2H),7.23(t,J＝9.2Hz,2H),7.14(d,J＝1.7Hz,1H),7.09–7.01(m,3H),3.34–3.11(m,3H),2.53(dt,J＝11.9,5.9Hz,2H),2.46–2.13(m,4H),2.12–1.68(m,21H),1.63–1.37(m,27H),1.23–1.14(m,5H),0.94–0.81(m,4H).
13 C NMR(100MHz,Methylene Chloride-d 2 )δ148.31,148.09,146.88,146.76,146.58,146.20,145.25,132.49,132.41,132.34,132.17,132.04,131.42,131.26,131.16,130.84,128.37,128.24,126.85,126.80,126.58,126.50,126.05,122.94,122.25,122.09,121.82,121.64,121.24,44.91,44.82,42.32,42.21,41.95,41.64,37.48,37.29,35.60,35.42,34.74,34.50,34.41,34.27,32.96,32.80,32.49,32.44,31.98,29.74,29.41,27.40,27.26,27.03,26.96,26.89,26.76,26.61,26.24,22.74,13.93.
dissolving the acidified chiral phosphoramide (R) -NPA-3Cy powder solid in DCM solution, slowly adding MeCN dropwise to gradually generate layering, and finally recrystallizing through slow volatilization to obtain the crystal of (R) -NPA-3Cy. MeCN.
Nuclear magnetic data of (R) -NPA-3Cy · MeCN crystals are as follows:
1H NMR(400MHz,Methylene Chloride-d2)δ7.97(dd,J＝8.1,3.3Hz,2H),7.91(d,J＝14.6Hz,2H),7.58–7.51(m,2H),7.34(ddd,J＝8.3,6.8,1.3Hz,2H),7.30–7.23(m,2H),7.11(dd,J＝17.2,1.7Hz,3H),7.00(d,J＝1.7Hz,1H),3.61(s,3H),2.52(d,J＝7.9Hz,2H),2.36–2.21(m,3H),2.17–2.07(m,1H),2.00(t,J＝14.2Hz,2H),1.92(s,4H),1.90–1.79(m,11H),1.78–1.63(m,8H),1.62–1.34(m,30H),1.29(dd,J＝12.2,9.3Hz,3H),1.16(dq,J＝19.6,16.0,14.2Hz,7H),1.05–0.57(m,11H).
13C NMR(101MHz,Methylene Chloride-d2)δ149.06,148.53,147.36,147.12,146.69,145.92,133.13,132.49,132.39,131.97,131.68,131.26,130.79,128.81,128.69,127.23,127.14,126.75,123.35,123.01,122.68,122.03,121.41,45.34,45.19,42.84,42.60,42.43,41.95,37.82,37.73,36.08,35.64,34.94,34.78,34.71,33.18,32.94,32.80,30.07,27.71,27.59,27.36,27.32,27.16,27.06,27.00,26.60,26.46.
31P NMR(162MHz,Methylene Chloride-d2)δ-3.62.
19F NMR(376MHz,Methylene Chloride-d2)δ-77.45.
[α] 20 D -2.97(c 0.55,DCM).
similarly, the S-type compound A is used as a raw material, and the (S) -NPA-3Cy & MeCN crystal can be obtained through the reaction process.
Nuclear magnetic data for (S) -NPA-3Cy MeCN crystals are as follows: 1H NMR (400mhz, methyl Chloride-d 2) δ 7.97 (dd, J =8.1,3.3hz, 2h), 7.91 (d, J =14.6hz, 2h), 7.58-7.51 (m, 2H), 7.34 (ddd, J =8.3,6.8,1.3hz, 2h), 7.30-7.23 (m, 2H), 7.11 (dd, J =17.2,1.7hz, 3h), 7.00 (d, J =1.7hz, 1h), 3.61 (s, 3H), 2.52 (d, J =7.9hz, 2h), 2.36-2.21 (m, 3H), 2.17-2.07 (m, 1H), 2.00 (t, J =14.2hz, 2h), 1.92 (s, 4H), 1.90-1.79 (m, 11H), 1.78-1.63 (m, 8H), 1.62-1.34 (m, 30H), 1.29 (dd, J =12.2,9.3hz, 3h), 1.16 (dq, J =19.6,16.0,14.2hz, 7h), 1.05-0.57 (m, 11H).
13C NMR(101MHz,Methylene Chloride-d2)δ149.06,148.53,147.36,147.12,146.69,145.92,133.13,132.49,132.39,131.97,131.68,131.26,130.79,128.81,128.69,127.23,127.14,126.75,123.35,123.01,122.68,122.03,121.41,45.34,45.19,42.84,42.60,42.43,41.95,37.82,37.73,36.08,35.64,34.94,34.78,34.71,33.18,32.94,32.80,30.07,27.71,27.59,27.36,27.32,27.16,27.06,27.00,26.60,26.46.
31P NMR(162MHz,Methylene Chloride-d2)δ-3.62.
19F NMR(376MHz,Methylene Chloride-d2)δ-77.45.
[α] 20 D +3.03(c 0.45,DCM).
The prepared (R) -NPA-3 Cy-MeCN and the existing catalyst are applied to [1,3] rearrangement reaction of indole, indene, benzofuran and benzothiophene derivatives, and the method comprises the following steps:
reaction H and DCM were added to an 8mL vial followed by 20% of the different catalysts and allowed to react overnight at room temperature, and the reaction was complete as determined by spotting plates. Directly spin-drying the reaction solvent, and directly carrying out silica gel column chromatography separation to obtain the desired compound I.
The reaction formula is as follows:
wherein X = C, N, O, S or a heteroatom;
y = O, N, S, se or a heteroatom;
R 1 ＝CO 2 R，CN，NO 2 ，Ac，SO 2 r, aryl containing hetero atoms, orAn alkyl group;
R 2 ，R 3 ，R 4 = halogen, aryl, heteroatom-containing aryl, or alkyl.
The reaction conditions for the different catalysts and the yields and selectivities obtained are shown in table 1:
TABLE 1 reaction conditions and yields and reaction selectivities obtained
| Serial number | Catalyst and process for preparing same | Temperature of | End time of reaction | Conversion rate | Yield of Compound I | Enantioselectivity |
| 1 | NPA1 | 25℃ | 3h | ＞95％ | 50％ | 69％ |
| 2 | NPA2 | 25℃ | 8h | 77％ | 53％ | 87％ |
| 3 | NPA3 | 25℃ | 2h | 90％ | 46％ | 13％ |
| 4 | NPA4 | 25℃ | 48h | 0 | 0 | 0 |
| 5 | NPA5 | 30℃ | 2+4h | 99％ | 93％ | 93％ |
The different catalyst structures are shown in table 2:
TABLE 2 different catalyst structures
The invention selects NPA with stronger acidity as a catalyst. Four commercial (R) -catalysts NPA1-NPA4 are purchased, NPA5 is the chiral phosphonamide (R) -NPA-3Cy MeCN prepared in the invention example, namely the chiral phosphonamide catalyst. As can be seen from Table 1, NPA1-NPA3 can catalyze this reaction, but the yield and enantioselectivity are not optimal. NPA4 failed to catalyze the reaction. The catalyst (R) -NPA-3Cy. MeCN (NPA 5) prepared by changing the catalyst structure and the steric hindrance of the catalyst can achieve high yield and high enantioselectivity. It can be seen that the steric hindrance of the catalyst has an important influence on this reaction.
In addition, the solvent and temperature for this reaction were also selected in the present invention, but the most preferred solvent is DCM, and a temperature in the range of 25-30 ℃ is the most preferred temperature. In experiment 6, the reaction condition was that the catalyst was added in two portions, so that a portion of the catalyst that had been broken during the long-term reaction was prevented, and thus the productivity was improved by adding the catalyst in portions.
The (S) -NPA-3Cy MeCN and the (R) -NPA-3Cy MeCN are different only in spatial configuration and have the same catalytic effect.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. The chiral phosphonamide catalyst NPA-3Cy MeCN comprises two configurations of (R) -NPA-3Cy MeCN and (S) -NPA-3Cy MeCN, and the chemical structural formulas of the two configurations are respectively shown as follows:
2. a process for the preparation of the chiral phosphonamide catalyst as claimed in claim 1, comprising the steps of:
(1) Taking an R-type or S-type compound A as a raw material, and obtaining a compound B through MOM protection;
(2) Iodinating the 3,3' position of the compound B to obtain a compound C;
(3) Preparing a compound D, and carrying out Kumada coupling on the compound C and the compound D to obtain a compound E;
(4) Deprotecting the compound E to obtain a compound F;
(5) Amidating and recrystallizing the compound F to obtain an R-type or S-type chiral phosphonamide catalyst;
the specific reaction process is shown as the following formula:
3. the method for preparing the chiral phosphonamide catalyst as claimed in claim 2, wherein the specific method of step (1) is as follows:
adding compound a to a dry round-bottom flask, followed by adding DMF solution to the round-bottom flask; cooling to 0 ℃, and slowly adding NaH into the reaction system in batches; after the gas in the reaction system is exhausted, slowly dropwise adding MOMCl into the reaction system; after fully stirring, reacting for 1 hour at the temperature of 0 ℃; TLC detection of the reaction system, after complete consumption of compound A, saturated NH 4 Quenching the Cl solution, and extracting with ethyl acetate; the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain compound B.
4. The method for preparing the chiral phosphonamide catalyst as claimed in claim 2, wherein the specific method of step (2) is as follows:
adding the compound B into a dry mouth-opening bottle, and adding tetrahydrofuran under the protection of nitrogen; slowly adding n-butyl at-78 deg.CLithium, at 0 ℃ for 1.5 hours; then slowly adding iodine particles into the reaction system at the temperature of minus 78 ℃; reacting at 0 ℃ for 1 hour, monitoring the reaction system by TLC, and after the reaction is finished, using saturated NH 4 The Cl solution was quenched, extracted with ethyl acetate, and saturated Na was added 2 S 2 O 3 Washing with saline water; anhydrous Na 2 SO 4 After drying, concentrating under reduced pressure, purifying by a silica gel column to obtain the compound C.
5. The method for preparing a chiral phosphonamide catalyst as claimed in claim 2, wherein the specific method for preparing the compound D in the step (3) is as follows:
to anhydrous C 6 H 6 And cyclohexyl bromide to which anhydrous AlCl is added 3 Adding the mixture in batches within 5 minutes at the temperature of-40 ℃ without stirring; at this stage, the reaction mixture was gradually warmed to 0 ℃ and then to ambient temperature; the reaction mixture was suspended in n-hexane and poured into saturated NaHCO 3 On the aqueous solution; the organic layer was separated and washed with anhydrous Na 2 SO 4 Drying, filtering and vacuum concentrating; the crude residue 1,3, 5-tricyclohexylbenzene obtained is then filtered through a silica gel column;
the crude 1,3, 5-tricyclohexylbenzene obtained was dissolved in anhydrous CHCl 3 Neutralizing and cooling to 0 ℃, slowly adding bromine within 10 minutes, heating the solution to the ambient temperature, and stirring for 2 hours; the reaction mixture was diluted with dichloromethane and the resulting solution was taken up with Na 2 SO 3 Quenching the aqueous solution; the aqueous layer was extracted with dichloromethane; the combined organic layers were washed with aqueous NaOH and water, then with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure; the resulting crude residue was purified by trituration from ethyl acetate and filtration; the resulting white powder was recrystallized from boiling ethanol to give compound D.
6. The method for preparing a chiral phosphonamide catalyst as claimed in claim 2, wherein the compound E is prepared as follows in the step (3):
adding the compound D and the magnesium strip into a dry bottle with a mouth, adding THF (tetrahydrofuran) into a reaction system under the protection of nitrogen, and then adding 1 iodine particle into the reaction system, wherein the reaction system turns yellow; pumping nitrogen for three times by using a vacuum pump to ensure that the reaction system is in a nitrogen atmosphere; heating to 60 ℃, adding 1-2 drops of 1, 2-dibromoethane and TMSCl into the mixture; then heating to 80 ℃, heating for 2h at 80 ℃, wherein the color in the reaction system will fade in the heating process, and a colorless liquid is generated to form a format reagent;
mixing the compound C and NiCl 2 (PPh 3 ) 2 Adding to a dry branched-mouth bottle, and then introducing THF into the branched-mouth bottle; and slowly dripping the newly prepared Grignard reagent into the reaction system through an injector, reacting for 24 hours at the temperature of 40 ℃, then adding ethyl acetate for extraction, combining organic phases, drying, carrying out suction filtration, carrying out spin drying, and purifying by column chromatography to obtain the compound E.
7. The method for preparing the chiral phosphonamide catalyst according to claim 2, wherein the specific method of step (4) is as follows:
adding the compound E, HCl and 1, 4-dioxane into a round-bottom flask, and reacting at the temperature of 100 ℃ for 3 hours; with saturated NaHCO 3 The solution was quenched, extracted with DCM, washed with brine, na 2 SO 4 Drying, and purifying the crude product by column chromatography to obtain the compound F.
8. The method for preparing the chiral phosphonamide catalyst according to claim 2, wherein the specific method of step (5) is as follows:
adding compound F and DCM to a dry mouth-opening bottle, and adding Et to the mixture at 0 ℃ under the protection of nitrogen 3 N，POCl 3 And DMAP, after stirring at room temperature for 1 hour, CF 3 SO 2 NH 2 Adding MeCN into the reaction system, reacting at 100 ℃ for 12 hours, extracting with DCM, and adding NaHCO 3 Washing with HCl, na 2 SO 4 Drying, spin-drying, and performing acetonitrile heavy knotCrystallizing to obtain chiral phosphonamide NPA-3Cy;
the method comprises the steps of dissolving acidified chiral phosphoramide NPA-3Cy powder solid in a DCM solution, slowly dropwise adding MeCN, gradually layering, slowly volatilizing, and recrystallizing to obtain NPA-3 Cy-MeCN crystals, namely the chiral phosphoramide catalyst.
9. Use of a chiral phosphonamide catalyst as claimed in claim 1 for catalyzing [1,3] rearrangement reactions of indole, indene, benzofuran and benzothiophene derivatives.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210381439.8A CN114682298B (en) | 2022-04-13 | 2022-04-13 | Chiral phosphonamide catalyst and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210381439.8A CN114682298B (en) | 2022-04-13 | 2022-04-13 | Chiral phosphonamide catalyst and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114682298A CN114682298A (en) | 2022-07-01 |
| CN114682298B true CN114682298B (en) | 2023-02-28 |
Family
ID=82143649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210381439.8A Active CN114682298B (en) | 2022-04-13 | 2022-04-13 | Chiral phosphonamide catalyst and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114682298B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113493479A (en) * | 2021-07-16 | 2021-10-12 | 南京理工大学 | P-chiral N-vinyl phosphonamide, chiral phosphonamide compound and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288876B (en) * | 2012-02-22 | 2015-11-18 | 上海交通大学 | A kind of Chiral phosphamide compound and preparation method thereof |
-
2022
- 2022-04-13 CN CN202210381439.8A patent/CN114682298B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113493479A (en) * | 2021-07-16 | 2021-10-12 | 南京理工大学 | P-chiral N-vinyl phosphonamide, chiral phosphonamide compound and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| A Concise Enantioselective Total Synthesis of (-)-Deoxoapodine;Kei Yoshida et al;《Angewandte Chemie》;20200907;第132卷(第51期);全文 * |
| Biao Wang et al.Enantioselective [2+2] cycloaddition of 1,2-dihydroquinolines with 3-olefinic oxindoles via Brønsted acid catalysis.《Org. Chem. Front》.2022,第9卷第1621-1627页. * |
| Relay Catalytic Cascade Hydrosiloxylation and Asymmetric Hetero-Diels-Alder Reaction;Nan Li et al;《Synthesis》;20141231;第46卷(第10期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114682298A (en) | 2022-07-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2017201846A1 (en) | Preparation method of antibacterial oxazolidinone medicine and intermediate thereof | |
| CN108947894B (en) | Biaryl structure chiral N-methyl pyridoxal catalyst and synthesis and application thereof | |
| CN111760593A (en) | Application of deprotonated phenyl bridged beta-ketimine lithium compound in hydroboration reaction | |
| CN115028849B (en) | Preparation method and application of metal triangle supermolecule with room temperature fluorescence | |
| CN114733566B (en) | Chiral super-strong carbonic acid catalyst based on BINOL framework and preparation method and application thereof | |
| CN113402553B (en) | Phosphine ligand of 2-alkyl-indole skeleton, preparation method and application thereof | |
| CN113244951B (en) | Mesoporous molecular sieve supported catalyst and application thereof | |
| CN110128439B (en) | Oxaspiro compound and synthesis and resolution method thereof | |
| CN114682298B (en) | Chiral phosphonamide catalyst and preparation method and application thereof | |
| CN110683926B (en) | Preparation method of carboxylic acid aryl ester compound | |
| CN109678901B (en) | Synthesis method of tri-substituted phosphine oxide compound | |
| CN110937985A (en) | Synthetic method of paradol | |
| CN111662147B (en) | Process for preparing diynes and analogues thereof | |
| CN112010910B (en) | Chiral ferrocene homoallylamine derivative and synthesis method and application thereof | |
| CN112973789B (en) | Catalyst loaded by novel mesoporous material and application thereof | |
| CN111018899B (en) | Method for preparing 1, 1-boron alkyne compound by metal catalysis of terminal olefin | |
| CN112979513A (en) | Chiral sulfoxide containing styrene monomer and preparation method thereof | |
| CN106588983B (en) | Carbazolyl phosphorus ligand, preparation method and application thereof | |
| CN115703806B (en) | Phosphine ligand of pyrazole-amide framework, and preparation method and application thereof | |
| CN110194760B (en) | Process for preparing 3-benzylidene-2- (7' -quinoline) -2, 3-dihydro-isoindol-1-ones | |
| CN114849787B (en) | Aryl bidentate phosphine ligand polymer in-situ encapsulation rhodium-based catalytic material and preparation method and application thereof | |
| CN116675629A (en) | Chiral dicarboxylic acid tetradentate binuclear rhodium catalyst based on natural amino acid, synthesis method and application thereof | |
| CN115626891B (en) | Synthesis method of nilaparib key intermediate | |
| CN113861237B (en) | Organophosphorus ligand, preparation method and application thereof | |
| CN117247369A (en) | Preparation method of 2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |