CN110280304B - Chiral amino alcohol derived phosphamide-amine bifunctional catalyst and three-step one-pot synthesis method thereof - Google Patents

Chiral amino alcohol derived phosphamide-amine bifunctional catalyst and three-step one-pot synthesis method thereof Download PDF

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CN110280304B
CN110280304B CN201910613178.6A CN201910613178A CN110280304B CN 110280304 B CN110280304 B CN 110280304B CN 201910613178 A CN201910613178 A CN 201910613178A CN 110280304 B CN110280304 B CN 110280304B
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周剑
丁佩刚
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East China Normal University
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    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
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    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Abstract

A phosphamide-amine bifunctional catalyst derived from chiral amino alcohol and a three-step one-pot synthesis method thereof. The invention discloses a phosphoramide (methylene) amine-tertiary amine bifunctional catalyst and a three-step one-pot synthesis method thereof, wherein the synthesis method comprises the steps of reacting simple and easily-obtained chiral amino alcohol with various phosphorus oxychloride, reacting hydroxyl with methylsulfonyl chloride, and then substituting amine for the chiral amino alcohol by a three-step one-pot method to prepare the phosphoramide-amine bifunctional catalyst with chiral high-efficiency catalytic activity. The catalyst is a bifunctional catalyst with novel structure, stable property and high catalytic activity; the synthesis method is simple, and has the remarkable characteristics of wide application range, mild reaction conditions, simplicity and convenience in operation and the like.

Description

Chiral amino alcohol derived phosphamide-amine bifunctional catalyst and three-step one-pot synthesis method thereof
Technical Field
The invention belongs to the technical field of organic compounds, and relates to a novel chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst and a three-step one-pot synthesis method thereof.
Background
Bifunctional catalysis generally refers to the simultaneous activation of electrophiles and nucleophiles with two functional groups linked by covalent bonds in the same catalyst molecule, resulting in better activation of the reaction substrate; and the reaction is carried out in a manner similar to that in a molecule, so that the activity and the selectivity of the reaction are improved.
By hydrogen bond donor bifunctional catalyst is meant a catalyst molecule containing a hydrogen bond donor functionality such as (thio) urea, sulfonamides, amides, phosphoramides, squaric acids, and the like. Generally, phosphoramides have several distinct features as hydrogen bond donor catalysts compared to other types of hydrogen bond donors: 1) the phosphamide has two substituents with a three-dimensional space structure, and can adjust asymmetric induction effect through steric effect from two different directions; 2) by changing two substituents (such as aryl, alkyl, alkoxy, etc.), the steric hindrance of the catalyst and the pK of the N-H bond of the amide can be easily adjustedaValues to favor chiral induction of the reaction and activation of electrophiles; 3) despite the synthetic convenience and stable nature of phosphoramide type catalysts, little research has been done as hydrogen bond donors. [ a) Master's academic paper of Ding Miao Master university in east China of 2012-protecting group-free 3-substituted oxygenStudy on asymmetric Michael addition reaction of indole and nitroolefin; b) s.e.denmark, angelw.chem.int.ed.2008, 1560.]
Despite the above-mentioned features of phosphoramide catalysts, the use of phosphoramide catalysts as chiral catalysts or chiral ligands in asymmetric catalytic reactions is still rare. The application of the phosphamide group in the chiral bifunctional catalyst in the organic small molecule catalysis is also rarely reported. The sensitisation group and the sony panel reported, respectively, the study of the addition reaction of phosphoramidite-secondary amine as a metal ligand to diethyl zinc reagents on imines and aldehydes [ a) m.shi, w.zhang, Tetrahedron Asymmetric 2003,14,3407.b) h.huang, h.zong, g.dian, l.song, j.org.chem.2012,77, 10427-valent 10434.](ii) a The 2 segmentary group reported that chiral phosphonamides achieved C (sp) as ligands3) Asymmetric arylation of-H [ S. -B.Yan, S. Zhang, W. -L.Duan, org.Lett.2015,17,2458-](ii) a In addition, zhou jia group used a chiral cyclohexyldiamine-derived phosphoramide-secondary amine catalyst for Mukaiyama-Michael addition reaction (j. -s.yu, f. -m.liao, w. -m.gao, k.liao, r. -l.zuo, j.zhou, angelw.chem.int.ed.2015, 54,7381.). A quinine-derived phosphoramide-tertiary amine bifunctional catalyst (M.Ding, F.ZHou, Y. -L.Liu, C. -H.Wang, X. -L.ZHao, J. ZHou, chem.Sci.2011,2,2035.) is developed in 2011 and is applied to the research of asymmetric Michael addition reaction of 3-substituted indole oxide and nitroolefin; although some phosphoramide-amine catalysts have been reported, no bifunctional phosphoramide-amine catalysts based on chiral amino alcohol derivatives have been reported.
Disclosure of Invention
The invention aims to provide a novel chiral amino alcohol derived (sub) phosphoramide-amine bifunctional catalyst and a three-step one-pot synthesis method thereof, wherein the catalyst has a novel structure, stable properties and high catalytic activity. The synthesis method is simple, and has the remarkable characteristics of wide application range, mild reaction conditions, simplicity and convenience in operation and the like.
The specific technical scheme for realizing the purpose of the invention is as follows:
the invention provides a chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst, the structure of which is shown in the following formulas (1) to (5):
Figure BDA0002123066000000021
wherein:
r is aryl or C1-C30 alkyl;
R1、R2is aryl or C1-C30 alkyl, chiral or achiral; r1And R2Form a ring or not form a ring; the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine;
R3、R4is hydrogen, C1-C50 alkyl, aryl or alkyl attached to the support material; r3And R4The ring is formed or not formed, and the ring formation comprises an adipogenic ring and an aliphatic ring containing hetero atoms; wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine, iodine;
r and R3Or R4Are not formed into rings;
R5、R6、R7and R8Is aryl or C1-C50 alkyl, chiral or achiral; r5And R6The ring is formed or not formed, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r7And R8Form a ring or not, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine;
R9、R10and R11Is aryl or C1-C50 alkyl, chiral or achiral; r9And R10R is10And R11Or R is9And R11Form a ring or not, the ring formation comprises an aliphatic ring, an aliphatic ring containing hetero atoms or an aromatic ring, whereinThe heteroatom comprises oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r9、R10And R11Any two or three of them form a ring or are not formed into a ring, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine.
Preferably, the first and second electrodes are formed of a metal,
r is phenyl, benzyl, C1-C10 alkyl;
R1、R2is phenyl, C1-C10 alkyl, chiral or achiral; r1And R2Form a ring or not form a ring; the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine;
R3、R4is hydrogen, C1-C10 alkyl, R3、R4Forming a five-membered or six-membered aliphatic ring with the nitrogen atom;
R5、R6、R7and R8Is C1-C10 alkyl or phenyl, R5And R6With or without rings between, R7And R8The ring is formed or not formed, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine;
R9、R10and R11Is C1-C10 alkyl, phenyl, chiral or achiral; r9And R10R, m10And R11Or R is9And R11Form a ring or not; r9、R10And R11Any two or three of them form a ring or are not formed into a ring, wherein the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, and the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine.
It is further preferred that the first and second liquid crystal compositions,
r is phenyl, isopropyl and benzyl;
R1、R2is phenyl, ethyl, isopropyl;
R3、R4is hydrogen, methyl, R3、R4Forming a five-membered or six-membered aliphatic ring with the nitrogen atom;
R5、R6、R7and R8Is methyl, ethyl, phenyl;
R9、R10and R11Methyl, ethyl and phenyl.
The invention also provides a three-step one-pot synthesis method of the chiral amino alcohol derived phosphoramide-amine bifunctional catalyst, which comprises the following synthesis steps of taking chiral amino alcohol, phosphoryl chloride, methylsulfonyl chloride and amine as reaction raw materials in the presence of a solvent and alkali, and obtaining the chiral amino alcohol derived phosphoramide-amine bifunctional catalyst through three-step reaction, wherein the reaction process is shown in the following reaction formulas (I) - (V):
Figure BDA0002123066000000041
wherein the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
Wherein the base is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
The invention also provides a three-step one-pot synthesis method of the chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst shown as the formula (1), wherein the synthesis reaction is shown as the following reaction formula (I) and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, carrying out substitution reaction on the intermediate 2 and primary amine or secondary amine to generate a target product;
the first two steps of reaction do not need post-treatment, and the three steps can be carried out by a one-pot method.
Figure BDA0002123066000000042
Wherein, R, R1、R2、R3、R4The definitions of (A) are the same as those of formulae (1) to (5).
In the step (1), the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
In the step (1), the alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
In the step (1), the dosage of the solvent is 1-100mL per millimole (mmol) of chiral amino alcohol; preferably, it is 2 mL.
In the step (1), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (1), the reaction time is 1-24 h; preferably, it is 4 h.
In the step (2), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (2), the reaction time is 1-24 h; preferably, it is 5 h.
In the step (3), the reaction temperature is 40-100 ℃; preferably 70 deg.c.
In the step (3), the reaction time is 1-5 d; preferably 1.5 d.
Wherein the molar ratio of the chiral amino alcohol, the alkali, the phosphorus oxychloride, the methylsulfonyl chloride and the amine is (1-10): (1-10): (1-10): (1-10): (1-10); preferably, 1:2:1.1:1.2: 6.
the invention also provides a three-step one-pot synthesis method of the chiral amino alcohol derived (sub) phosphoramide-amine bifunctional catalyst shown as the formula (3), wherein the synthesis reaction is shown as the following reaction formula (II) and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, carrying out substitution reaction on the intermediate 2 and primary amine or secondary amine to generate a target product;
the first two steps of reactions do not need post-treatment, and the three steps can be carried out by a one-pot method.
Figure BDA0002123066000000051
Wherein, R, R1、R3、R4、R5、R6The definitions of (A) are the same as those of formulae (1) to (5).
In the step (1), the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
In the step (1), the alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
In the step (1), the dosage of the solvent is 1-100mL per millimole (mmol) of chiral amino alcohol; preferably, it is 2 mL.
In the step (1), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (1), the reaction time is 1-24 h; preferably, it is 4 h.
In the step (2), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (2), the reaction time is 1-24 h; preferably, it is 5 h.
In the step (3), the reaction temperature is 40-100 ℃; preferably 70 deg.c.
In the step (3), the reaction time is 1-5 d; preferably 1.5 d.
Wherein the molar ratio of the chiral amino alcohol, the alkali, the phosphorus oxychloride, the methylsulfonyl chloride and the amine is (1-10): (1-10): (1-10): (1-10): (1-10); preferably, 1:2:1.1:1.2: 6.
the invention also provides a three-step one-pot synthesis method of the chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst shown as the formula (2), wherein the synthesis reaction is shown as the following reaction formula (III) and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, carrying out substitution reaction on the intermediate 2 and primary amine or secondary amine to generate a target product;
the first two steps of reaction do not need post-treatment, and the three steps can be carried out by a one-pot method.
Figure BDA0002123066000000061
Wherein, R, R3、R4、R5、R6、R7、R8The definitions of (A) are the same as those of formulae (1) to (5).
In the step (1), the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
In the step (1), the alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
In the step (1), the dosage of the solvent is 1-100mL per millimole (mmol) of chiral amino alcohol; preferably, it is 2 mL.
In the step (1), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (1), the reaction time is 1-24 h; preferably, it is 4 h.
In the step (2), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (2), the reaction time is 1-24 h; preferably, it is 5 h.
In the step (3), the reaction temperature is 40-100 ℃; preferably 70 deg.c.
In the step (3), the reaction time is 1-5 d; preferably 1.5 d.
Wherein the molar ratio of the chiral amino alcohol, the alkali, the phosphorus oxychloride, the methylsulfonyl chloride and the amine is (1-10): (1-10): (1-10): (1-10): (1-10); preferably, 1:2:1.1:1.2: 6.
the invention also provides a three-step one-pot synthesis method of the chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst shown as the formula (4), wherein the synthesis reaction is shown as the following reaction formula (IV) and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, carrying out substitution reaction on the intermediate 2 and primary amine or secondary amine to generate a target product;
the first two steps of reaction do not need post-treatment, and the three steps can be carried out by a one-pot method.
Figure BDA0002123066000000071
Wherein, R, R1、R3、R4、R9、R10、R11The definitions of (A) are the same as those of formulae (1) to (5).
In the step (1), the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
In the step (1), the alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
In the step (1), the dosage of the solvent is 1-100mL per millimole (mmol) of chiral amino alcohol; preferably, it is 2 mL.
In the step (1), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (1), the reaction time is 1-24 h; preferably, it is 4 h.
In the step (2), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (2), the reaction time is 1-24 h; preferably, it is 5 h.
In the step (3), the reaction temperature is 40-100 ℃; preferably 70 deg.c.
In the step (3), the reaction time is 1-5 d; preferably 1.5 d.
Wherein the molar ratio of the chiral amino alcohol, the alkali, the phosphorus oxychloride, the methylsulfonyl chloride and the amine is (1-10): (1-10): (1-10): (1-10): (1-10); preferably, 1:2:1.1:1.2: 6.
the invention also provides a three-step one-pot synthesis method of the chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst shown as the formula (5), wherein the synthesis reaction is shown as the following reaction formula (V) and mainly comprises the following steps:
step (1): reacting chiral amino alcohol with phosphorus oxychloride in the presence of a solvent and alkali to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, carrying out substitution reaction on the intermediate 2 and primary amine or secondary amine to generate a target product;
the first two steps of reaction do not need post-treatment, and the three steps can be carried out by a one-pot method.
Figure BDA0002123066000000081
Wherein, R, R3、R4、R5、R6、R9、R10、R11The definitions of (A) are the same as those of formulae (1) to (5).
In the step (1), the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
In the step (1), the alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
In the step (1), the dosage of the solvent is 1-100mL per millimole (mmol) of chiral amino alcohol; preferably, it is 2 mL.
In the step (1), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (1), the reaction time is 1-24 h; preferably, it is 4 h.
In the step (2), the reaction temperature is-20-100 ℃; preferably, from-20 ℃ to room temperature; further preferably, from 0 ℃ to room temperature.
In the step (2), the reaction time is 1-24 h; preferably, it is 5 h.
In the step (3), the reaction temperature is 40-100 ℃; preferably 70 deg.c.
In the step (3), the reaction time is 1-5 d; preferably 1.5 d.
Wherein the molar ratio of the chiral amino alcohol, the alkali, the phosphorus oxychloride, the methylsulfonyl chloride and the amine is (1-10): (1-10): (1-10): (1-10): (1-10); preferably, 1:2:1.1:1.2: 6.
the invention relates to a synthesis method of chiral amino alcohol derived phosphoramidite-amine bifunctional catalyst, which is respectively shown in the following reaction formula (I), reaction formula (II), reaction formula (III), reaction formula (IV) and reaction formula (V):
Figure BDA0002123066000000091
in a specific embodiment, as shown in the reaction formulas (I) - (V), the synthesis method of the chiral amino alcohol derived phosphoramide-amine bifunctional catalyst is as follows: adding chiral amino alcohol of A mol into a reaction vessel, then sequentially adding B ml of solvent and alkali of C mol, cooling to-20 ℃, dropwise adding phosphorus oxychloride of D mol, stirring at the temperature of-20 ℃ to room temperature until TLC shows that the reaction is finished, then cooling to-20 ℃, dropwise adding methylsulfonyl chloride of E mol, stirring at the temperature of-20 ℃ to room temperature until TLC shows that the reaction is finished, then adding amine of F mol, and reacting at the temperature of 40 ℃ to 100 ℃ to obtain a target compound;
in the reaction formulae (I) to (V), a ═ 0.1 to 100; the using amount B of the solvent is 2mL of the corresponding using range of each millimole (mmol) of chiral amino alcohol; c is 0.2-200; d is 0.11-110; e is 0.12-120; f is 0.6-600; the ratio of the different compounds is A: C: D: E: F ═ 1:2:1.1:1.2: 6.
In the synthetic method, a target product is further obtained by petroleum ether extraction.
In the synthetic method of the invention, the different phosphorus oxychloride is respectively represented by the following chemical formulas (A), (B), (C), (D) and (E):
Figure BDA0002123066000000101
wherein R is1、R2、R5、R6、R7、R8、R9、R10、R11The definitions of (1) to (5) are the same.
Wherein the chiral amino alcohol has the formula:
Figure BDA0002123066000000102
wherein the absolute configuration of the amino alcohol is R or S, obtained by reduction of an amino acid or obtained commercially; r is aryl or C1-C30 alkyl;
the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, dimethyl sulfoxide and the like; preferably dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran.
The alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; preferably, DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine.
The invention also provides application of the chiral amino alcohol derived phosphoramide (ylidene) amine bifunctional catalyst in the asymmetric Michael addition reaction of 2-azido ketone and nitroolefin.
The catalyst has the characteristics of novel structure, stable property and high catalytic activity; the synthesis method has the following remarkable characteristics:
(1) the raw materials are commercially available;
(2) the reaction condition is mild, the operation is simple and convenient, and the synthesis step is short;
(3) the synthesized target catalyst can achieve excellent yield and enantioselectivity in the Michael addition reaction.
Detailed Description
The invention will be described in more detail in connection with the following examples, which illustrate different aspects of the invention, but it should be stressed that the invention is in no way limited to the illustrations of a few examples. Meanwhile, the embodiment also shows the application example of the catalyst in the asymmetric Michael addition reaction of alpha-azido ketone and nitroolefin, wherein the enantioselectivity is determined by chiral HPLC.
Example 1
Figure BDA0002123066000000111
At N2To a dry 250mL three-necked flask, L-phenylalaninol Ia (1.0 equiv.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and added via syringeEt3N (2.0 equiv.) and then a solution of freshly distilled diisopropyl chlorophosphate IIa (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.), and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 h), piperidine IVa (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C1.1H NMR(300MHz,CDCl3):δ 7.31-7.26(m,2H),7.23-7.17(m,3H),4.65-3.53(m,2H),3.53-3.47(m,1H),3.19(s,1H),3.13 (ABd,J＝13.3Hz,J＝4.2Hz,1H),2.68(ABd,J＝13.2Hz,J＝7.5Hz,1H),2.36-2.05(m,6H), 1.58-1.50(m,4H),1.43-1.39(m,2H),1.35-1.28(tm,12H)；13C NMR(100MHz,CDCl3):δ138.03, 129.79,128.14,126.11,70.59(d,JC-P＝3.9Hz),70.54(d,JC-P＝3.9Hz),62.27(d,JC-P＝8.5Hz), 54.57,49.80,40.14(d,JC-P＝2.5Hz),26.03,24.34,23.95(d,JC-P＝5.1Hz),23.90(d,JC-P＝5.0Hz), 23.87(d,JC-P＝1.9Hz),23.82(d,JC-P＝2.0Hz)；31P NMR(121MHz,CDCl3):δ7.54(s,1P). HRMS(ESI):Exact mass calcd for C20H36N2O3P[M+H]+:383.2458,found:383.2455.
Example 2
Figure BDA0002123066000000112
In N2To a dry 250mL three-necked flask, L-phenylalaninol Ia (1.0 equiv.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and added via syringeEt3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.), and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 h), piperidine IVa (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtering and vacuum concentrating to obtain pure catalyst C21H NMR(400MHz,CDCl3):δ7.30-7.26(m, 2H),7.22-7.18(m,3H),4.08-3.99(m,3H),3.91-3.85(m,1H),3.53-3.43(m,1H),3.19(t,J＝8.4 Hz,1H),3.01(ABd,J＝13.2Hz,J＝5.2Hz,1H),2.73(ABd,J＝13.4Hz,J＝6.8Hz,1H),2.34 (m,4H),2.22-2.10(m,2H),1.57-1.51(m,4H),1.40(q,J＝6.0Hz,2H),1.39(t,J＝7.2Hz,3H), 1.27(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ138.03,129.71,128.18,126.16,62.63(d, JC-P＝7.6Hz),62.11(d,JC-P＝5.6Hz),62.03(d,JC-P＝5.4Hz),54.64,50.08,40.45(d,JC-P＝2.9 Hz),26.00,24.29,16.25(d,JC-P＝2.7Hz),16.18(d,JC-P＝2.9Hz)；31P NMR(121MHz,CDCl3):δ 9.07(s,1P).HRMS(ESI):Exact mass calcd for C18H31N2O3P[M]+:354.2072,found:354.2074.
Example 3
Figure BDA0002123066000000121
In N2To a dry 250mL three-necked flask, L-phenylalaninol Ia (1.0 equiv.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and Et was added via syringe3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.) and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 h), piperidine IVa (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C3.1H NMR(400MHz,CDCl3):δ7.39-7.18(m, 5H),4.28-4.19(m,2H),3.95-3.89(m,2H),3.83-3.78(m,1H),3.63-3.58(m,1H),2.73-2.56(m, 2H),2.47-2.31(m,2H),2.22-2.10(m,2H),1.59-1.53(m,4H),1.42-1.39(m,2H),1.29(t,J＝7.2 Hz,3H),0.97(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ143.56,128.59,128.53,127.03, 126.95,126.78,67.34,62.18,62.15,46.03,26.04,25.95,24.53,16.27,16.20；31P NMR(121MHz, CDCl3):δ9.46(s,1P).HRMS(ESI):Exact mass calcd for C17H30N2O3P[M+H]+:340.1916, found:340.1913.
Example 4
Figure BDA0002123066000000131
In N2To a dry 250mL three-necked flask, L-tryptophanol Ib (1.0 equivalent) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and Et was added via syringe3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 eq) and fresh distillation was added slowly in sequenceA solution of MsCl III (1.2 equiv.) in anhydrous THF (0.4 mL). After stirring at room temperature until complete conversion by TLC analysis (5 h), piperidine IVa (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C4.1H NMR(300MHz,CDCl3):δ9.03(s,br, 1H),7.70-7.68(m,1H),7.37-7.34(m,1H),7.18-7.06(m,2H),6.99(d,J＝2.4Hz,1H),4.14-4.02 (m,3H),4.00-3.89(m,1H),3.65-3.51(m,1H),3.35-3.29(m,1H),3.22-3.16(m,1H),2.9-2.82(m, 1H),2.34-2.23(m,4H),2.2(dd,J＝7.0Hz,J＝1.2Hz,2H),1.57-1.50(m,4H),1.40-1.38(m,2H), 1.33(td,J＝6.9Hz,J＝0.6Hz,3H),1.25(td,J＝6.9Hz,J＝0.9Hz,3H)；13C NMR(100MHz, CDCl3):δ136.26,128.01,123.17,121.48,118.91(d,JC-P＝3.2Hz),111.17,111.14,111.11,62.93 (d,JC-P＝7.7Hz),62.17(d,JC-P＝5.1Hz),62.12(d,JC-P＝5.1Hz),54.65,49.18,29.78(d,JC-P＝3.1 Hz),25.95,24.28,16.15(d,JC-P＝7.4Hz),16.07(d,JC-P＝7.6Hz)；31P NMR(121MHz,CDCl3):δ 9.45(s,1P).HRMS(EI):Exact mass calcd for C20H32N3O3P[M]+:393.2181,found:393.2188.
Example 5
Figure BDA0002123066000000132
In N2To a dry 250mL three-necked flask, L-valinol Ic (1.0 eq.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and Et was added via syringe3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooledCooling to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.), and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 h), piperidine IVa (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C5.1H NMR(300MHz,CDCl3):4.14-4.03(m, 4H),3.21-3.12(m,1H),3.07-3.02(m,1H),2.48-2.41(m,2H),2.31-2.15(m,4H),2.08-1.98(m, 1H),1.57-1.50(m,4H),1.44-1.39(m,2H),1.34-1.29(m,6H),0.92(d,J＝7.2Hz,3H),0.85(d,J＝ 6.9Hz,3H)；13C NMR(100MHz,CDCl3):62.09(d,JC-P＝2.1Hz),62.03(d,JC-P＝2.0Hz),59.81(d, JC-P＝7.3Hz),54.78,53.50,29.81(d,JC-P＝2.8Hz),25.97,24.32,17.51,17.37,16.22,16.15；31P NMR(121MHz,CDCl3):9.72(s,1P).HRMS(ESI):Exact mass calcd for C14H32N2O3P[M+H]+: 307.2145,found:307.2152.
Example 6
Figure BDA0002123066000000141
In N2To a dry 250mL three-necked flask, L-valinol Ic (1.0 eq.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and Et was added via syringe3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.) and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 h), tetrahydro was addedPyrrole IVb (6 equivalents). The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C6.1H NMR(300MHz,CDCl3): 4.13-4.03(m,4H),3.18-3.07(m,1H),2.95(t,J＝8.4Hz,1H),2.58-2.38(m,6H),2.07-1.96(m, 1H),1.77-1.72(m,4H),1.35-1.29(m,6H),0.95-0.92(m,3H),0.90-0.86(m,3H)；13C NMR(100 MHz,CDCl3):62.13(d,JC-P＝3.3Hz),62.08(d,JC-P＝3.0Hz),57.56(d,JC-P＝6.5Hz),55.48, 54.20,29.86(d,JC-P＝3.4Hz),23.48,17.98,17.22,16.20(d,JC-P＝1.4Hz),16.12(d,JC-P＝1.5Hz)；31P NMR(121MHz,CDCl3):9.50(s,1P).HRMS(EI):Exact mass calcd for C13H29N2O3P[M]+: 292.1916:,found:292.1912.
Example 7
Figure BDA0002123066000000151
In N2To a dry 250mL three-necked flask, L-valinol Ic (1.0 eq.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and Et was added via syringe3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.) and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 hours), morpholine IVc (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. Will be provided withThe organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C7.1H NMR(300MHz,CDCl3):4.13-4.02 (m,4H),3.68(t,J＝4.8Hz,4H),3.25-3.14(m,1H),2.88-2.80(m,1H),2.56-2.50(m,2H), 2.41-2.34(m,2H),2.31-2.22(m,2H),2.06-1.96(m,1H),1.35-1.69(m,6H),0.93(d,J＝6.9Hz, 3H),0.86(d,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):66.98,62.28(d,JC-P＝3.7Hz),62.22 (d,JC-P＝3.6Hz),60.14(d,JC-P＝6.4Hz),53.85,53.30,29.98(d,JC-P＝3.3Hz),17.92,17.24, 16.27,16.20；31P NMR(121MHz,CDCl3):9.44(s,1P).HRMS(EI):Exact mass calcd for C13H29N2O4P[M]+:308.1865:found:308.1879.
Example 8
Figure BDA0002123066000000152
In N2To a dry 250mL three-necked flask, L-valinol Ic (1.0 eq.) and THF (1.6mL) were added under atmosphere. The mixture was then cooled to 0 ℃ and Et was added via syringe3N (2.0 equiv.) and then a solution of freshly distilled diethyl chlorophosphate IIb (1.1 equiv.) in anhydrous THF (0.4mL) was added dropwise. The mixture was then brought to room temperature and after stirring for 4 hours, the reaction mixture was cooled to 0 ℃. Et was then added at 0 ℃3N (1.5 equiv.) and then a freshly distilled solution of MsCl III (1.2 equiv.) in dry THF (0.4mL) was added slowly. After stirring at room temperature until complete conversion by TLC analysis (5 hours), dimethylamine IVd (6 equivalents) was added. The resulting reaction mixture was then stirred at 70 ℃ for 1.5 days. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with petroleum ether. The organic phases were combined and acidified with HCl (2M) and the aqueous phase was washed with PE (3X 20 mL). Then saturated NaHCO3(aq.) solution neutralization. Extracting the aqueous phase with PE, combining the organic phases with Na2SO4Drying, filtration and concentration in vacuo gave pure catalyst C8.1HNMR(300MHz,CDCl3):δ4.16-3.99 (m,4H),3.18-3.07(m,1H),2.86(t,J＝8.4Hz,1H),2.27-2.17(m,8H),2.15-1.98(m,2H), 1.35-1.29(tdd,J＝6.9Hz,2.4Hz,1.2Hz,6H),0.94(d,J＝6.9Hz,3H),0.85(d,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3):δ62.21(d,JC-P＝3.3Hz),62.15(d,JC-P＝3Hz),61.03(d,JC-P＝6.5 Hz),54.23,45.67,29.48(d,JC-P＝3.3Hz),18.04,16.81,16.20(d,JC-P＝7.4Hz)；31P NMR(121 MHz,CDCl3):δ9.49(s,1P).HRMS(ESI):Exact mass calcd for C11H27N2O3P[M]+:266.1759, found:266.1756.
Application example 1
Figure BDA0002123066000000161
A5.0 mL vial was charged with tertiary amine-phosphoramide bifunctional catalyst 3a (23.0mg, 0.06mmol, 20 mol%), α -azidoketone 5(0.3mmol, 1.0 equiv.), and 90mg
Figure BDA0002123066000000162
MS, then dry toluene (1mL, 0.3M) was added. The reaction mixture was stirred at 0 ℃ for about 30 minutes, then nitroolefin 6(0.36mmol, 1.2 equiv.) was added. At this temperature stirring was continued until complete conversion by TLC analysis. To determine the diastereoselectivity of the product, the residue was first dissolved in CDCl3And taking some samples for1H NMR analysis. The sample for analysis and the remaining crude residue were then recombined and passed through silica gel column chromatography (PE: Et)2O10: 1, v/v) to give the desired product syn-7, 76% yield. ir (neat):2925, 2101,1709,1551,1376,1093,978,692cm-1；1H NMR analysis revealed that the dr values is 7:1. HPLC analysis[Chiralcel OZ-H,5％iPrOH/hexane,1.0mL/min,230nm；major diastereomer:tr (major)＝18.80min,tr(minor)＝29.47min,minor diastereomer:tr(major)＝30.04min,tr(minor) ＝25.62min]gave the isomeric composition of major diastereomer:93％ee；[α]D 20＝-13.6(c＝ 0.68,CHCl3).1H NMR(400MHz,CDCl3):δ7.78(d,J＝7.6Hz,1H),7.63-7.59(m,1H),7.42(t,J＝7.6Hz,1H),7.30(d,J＝8.0Hz,1H),7.20-7.18(m,2H),7.13-7.11(m,2H),5.14-5.06(m,2H), 4.04(dd,J＝9.4Hz,J＝5.2Hz,1H),3.34(AB,J＝18.0Hz,1H),3.24(AB,J＝17.6Hz,1H)；13C NMR(125MHz,CDCl3):δ200.29,150.46,136.87,134.73,134.55,132.36,130.19,129.15, 128.74,126.33,124.96,75.71,70.75,49.22,37.56；HRMS(ESI):Exact mass calcd for C17H17ClN5O3[M+NH4]+:374.1014,Found:374.1014。

Claims (10)

1. A chiral amino alcohol derived phosphoramide (methylene) amine bifunctional catalyst, which is characterized in that the structure of the catalyst is shown as the following formulas (1) to (5):
Figure FDA0003542292880000011
wherein, the first and the second end of the pipe are connected with each other,
r is aryl or C1-C30 alkyl;
R1、R2is aryl or C1-C30 alkyl, chiral or achiral; r1And R2The ring is formed or not formed, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine;
R3、R4is hydrogen, C1-C50 alkyl, aryl or alkyl attached to the support material; r is3And R4The ring is formed or not formed, and the ring formation comprises an adipogenic ring and an aliphatic ring containing hetero atoms; wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine, iodine;
r and R3Or R4Are not formed into rings;
R5、R6、R7and R8Is aryl or C1-C50 alkyl, chiral or achiral; r5And R6The ring is formed or not formed, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r7And R8The ring is formed into an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r9、R10And R11Is aryl or C1-C50 alkyl, chiral or achiral; r9And R10R is10And R11Or R is9And R11The ring is formed into an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r9、R10And R11Any two or three of them form a ring or are not formed into a ring, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine.
2. The catalyst of claim 1, wherein R is phenyl, benzyl, C1-C10 alkyl; r is1、R2Is phenyl, C1-C10 alkyl, chiral or achiral; r is1And R2Form a ring or not form a ring; the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r3、R4Is hydrogen, C1-C10 alkyl, R3、R4Forming a five-membered or six-membered aliphatic ring with the nitrogen atom; r5、R6、R7And R8Is C1-C10 alkyl, phenyl, R5And R6With or without rings between, R7And R8Form a ring or not form a ringComprising an aliphatic, heteroatom-containing aliphatic, or aromatic ring, wherein the heteroatom comprises oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine, iodine; r9、R10And R11Is C1-C10 alkyl, phenyl, chiral or achiral, R9And R10R is10And R11Or R is9And R11Form a ring or not, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine; r9、R10And R11Any two or three of them form a ring or are not formed into a ring, the ring formation comprises an aliphatic ring, an aliphatic ring containing heteroatoms or an aromatic ring, wherein the heteroatoms comprise oxygen, nitrogen, sulfur, phosphine, fluorine, chlorine, bromine and iodine.
3. The three-step one-pot synthesis method of the chiral amino alcohol derived (sub) phosphoramide-amine bifunctional catalyst according to claim 1, characterized in that the synthesis method comprises the following synthesis steps, under the condition of existence of solvent and alkali, chiral amino alcohol, phosphoryl chloride, methylsulfonyl chloride and amine are used as reaction raw materials, and the chiral amino alcohol derived (sub) phosphoramide-amine bifunctional catalyst is obtained by three-step reaction, and the reaction processes are shown as the following reaction formulas (I) - (V):
Figure FDA0003542292880000021
4. the three-step one-pot synthesis method of the catalyst according to claim 3, wherein the catalyst is represented by formula (1), and the synthesis reaction is represented by the following reaction formula (I) and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, the intermediate 2 and primary amine or secondary amine are subjected to substitution reaction to generate a target product;
Figure FDA0003542292880000031
5. the three-step one-pot synthesis method of the catalyst according to claim 3, wherein the catalyst is represented by formula (3), and the synthesis reaction is represented by the following reaction formula (II), and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, the intermediate 2 and primary amine or secondary amine are subjected to substitution reaction to generate a target product;
Figure FDA0003542292880000032
6. the three-step one-pot synthesis method of the catalyst according to claim 3, wherein the catalyst is represented by formula (2), and the synthesis reaction is represented by the following reaction formula (III), and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, the intermediate 2 and primary amine or secondary amine are subjected to substitution reaction to generate a target product;
Figure FDA0003542292880000033
7. the three-step one-pot synthesis method of the catalyst according to claim 3, wherein the catalyst is represented by formula (4), and the synthesis reaction is represented by the following reaction formula (IV), and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphorus oxychloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, the intermediate 2 and primary amine or secondary amine are subjected to substitution reaction to generate a target product;
Figure FDA0003542292880000034
8. the three-step one-pot synthesis method of the catalyst according to claim 3, wherein the catalyst is represented by formula (5), and the synthesis reaction is represented by formula (V), and mainly comprises the following steps:
step (1): in the presence of a solvent and alkali, chiral amino alcohol reacts with phosphoryl chloride to obtain an intermediate 1;
step (2): then, reacting the intermediate 1 with methanesulfonyl chloride to obtain an intermediate 2;
and (3): finally, the intermediate 2 and primary amine or secondary amine are subjected to substitution reaction to generate a target product;
Figure FDA0003542292880000041
9. the synthesis process according to any one of claims 4 to 8, wherein in step (1), the reaction temperature is from-20 ℃ to 100 ℃; in the step (1), the dosage of the solvent is 1-100mL per millimole of mmol of chiral amino alcohol; in the step (2), the reaction temperature is-20-100 ℃; in the step (3), the reaction temperature is 40-100 ℃.
10. The synthetic method of any one of claims 3-8 wherein the solvent is one or more of toluene, dichloromethane, diethyl ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, nitromethane, methanol, or dimethylsulfoxide; the alkali is one or more of DMAP, triethylamine, diisopropylethylamine, DBU, DABCO, pyridine, tetrahydropyrrole, diethylamine, N-methylbenzylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; the molar ratio of the chiral amino alcohol, the alkali, the phosphorus oxychloride, the methylsulfonyl chloride and the amine is (1-10): (1-10): (1-10): (1-10): (1-10).
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