CN116947761A - Non-tension alicyclic amine ring-expanding molecule editing means for synthesizing cyclic nitrogen heterocyclic compound - Google Patents

Non-tension alicyclic amine ring-expanding molecule editing means for synthesizing cyclic nitrogen heterocyclic compound Download PDF

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CN116947761A
CN116947761A CN202310808728.6A CN202310808728A CN116947761A CN 116947761 A CN116947761 A CN 116947761A CN 202310808728 A CN202310808728 A CN 202310808728A CN 116947761 A CN116947761 A CN 116947761A
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optionally substituted
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aryl
benzyl
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陈宜峰
吴利城
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East China University of Science and Technology
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Abstract

The invention relates to a molecular editing technology for ring-expanding modification construction of alicyclic amine, namely, a ring-expanding reaction of a non-tension alicyclic amine compound and oxazolone or gamma-butenolide is realized under the action of a catalyst and an additive, and a convenient method is provided for efficient synthesis of aza-alicyclic amine. The method has the advantages of simple and convenient operation, economical steps, high functional group tolerance and the like, and has important application value in the fields of post-modification of complex natural products and drug molecules and development of new drugs.

Description

Non-tension alicyclic amine ring-expanding molecule editing means for synthesizing cyclic nitrogen heterocyclic compound
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for constructing an aza-medium ring compound by performing ring expansion reaction on a transition metal catalyzed alicyclic amine structure and oxazolone or gamma-butenolide.
Background
The molecular skeleton editing technology is a very important tool in the field of organic chemistry, and is widely used in synthesis and later modification of complex natural product molecules or drug molecules by modifying the ring skeleton of the core in the existing molecule to obtain a highly functionalized molecular structure [ Jurczyk, J.; woo, j.; kim, s.f.; dherenge, B.D.; sarmong, r.; levin, m.d. nat. Synth.2022,1,352; hui, c.; wang, z.; wang, s.; xu, c.org.chem.front.2022,9,1451]. The compound skeleton greatly influences the molecular topology and the orientation of each functional group, thereby significantly changing the physicochemical properties and biological activity of the compound. The modification of the existing molecules, particularly the complex natural product skeleton, is realized by means of molecular editing to construct an active compound library, and a wide material basis is provided for drug screening. Meanwhile, the modification of the existing structure provides an important means for the framework fragments which are difficult to construct by the traditional method, and complex synthesis from the head is avoided.
Alicyclic amine structures are widely found in various natural products, drug molecules, pesticides and functional materials with biological and physiological activities. For example, in the U.S. drug administration (FDA) approved small molecule drugs, 84% of the drug molecules contain at least one nitrogen atom and 59% of the compounds possess at least one nitrogen-containing heterocycle [ Vitaku, e.; smith, d.t.; njardarson, J.T.J.Med.chem.2014,57,10257]. The method utilizes a molecular editing means to carry out skeleton modification on alicyclic amine fragments in complex molecules, and analogues with different skeletons can be obtained, thereby providing a material basis for drug research. Although molecular editing techniques have evolved dramatically in the opening of cyclic amine fragments and modification of condensed ring backbones, ring expansion modifications to cyclic amines are still currently limited to tensioned ternary and quaternary rings. For non-tension five-membered ring and six-membered ring alicyclic amine with wide sources, the ring expansion reaction still has a plurality of problems due to the high chemical stability by directly inserting the functional group into the C-N bond.
The aza-polycyclic compounds are widely used in the fields of pharmaceutical chemistry and biomedicine due to their unique pharmacological and physiological activities, and also widely exist as core structures in natural products and drug molecules [ Zha, g.f.; rakesh, k.p.; manukumar, h.m.; shatharam, c.s.; long, S.Eur.J.Med.chem.2019,162,465]. For example, bengamide is a compound isolated from a sponge and has a function of inhibiting the growth of cancer cells, and the core structure of Bengamide contains aza Zhuo Pianduan [ the, z.; kinder, f.r.; bair, k.w.; bontempo, j.; czuchta, a.m.; versace, r.w.; phillips, p.e.; sanders, M.L.; wattanasin, S.; crews, P.J.Org.chem.2001,66,1733]. Telcagepat is a class of Calcitonin Gene Related Peptide (CGRP) receptor antagonists used in the treatment of migraine, the backbone of which comprises a 3-aminocaprolactam structure [ Paone, D.V.; shaw, a.w.; nguyen, D.N.; burgey, C.S.; deng, j.z.; kane, s.a.; koblan, k.s.; salvatore, C.A.; mosser, s.d.; johnston, v.k.; wong, b.k.; miller-Stein, C.M.; hershey, J.C.; graham, S.L.; vacca, j.p.; williams, T.M.J.Med.chem.2007,50,5564]. Due to thermodynamic and kinetic challenges, construction of a cyclic system, such as synthesis of multifunctional azepine compounds, often has the limitations of cumbersome steps, reagents requiring pre-preparation for functionalization, and harsh conditions, [ Ouyang, w.; rao, j.; li, Y; liu, x; huo, y; chen, q.; li, X.adv.Synth.catalyst.2020, 362,5576]. Therefore, developing a method capable of realizing the ring-expanding framework modification of alicyclic amine mildly and efficiently to construct an aza ring structure has important research significance and application value for the later modification of complex natural products and drug molecules.
Disclosure of Invention
The invention aims to provide an alicyclic amine ring-expanding molecule editing means, realize the convenient synthesis of functionalized aza ring compounds, and provide an effective method for the later modification of drug molecules and natural products. The catalyst system disclosed by the invention is simple and convenient to operate, good in stability, good in functional group tolerance, capable of realizing diversified ring-expanding modification of alicyclic amine with excellent yield, and capable of providing a high-efficiency, green and practical synthesis method for synthesizing the azepine compound.
[1] The invention provides a method for synthesizing a nitrogen-containing cyclic compound by using alicyclic amine as a substrate through a ring-expanding reaction, which comprises the following steps of reacting a compound shown as a formula 1 and a formula 2 in an organic solvent under the action of a catalyst and an additive under the protection of gas to obtain the compound shown as a formula 3,
wherein R is 1 Is selected from C1-C16 alkyl, C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl or optionally substituted C3-C16 heteroaryl;
R 2 1,2, 3 or 4 substituents independently selected from: hydrogen, optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, nitro, C2-C16 ester, C1-C16 amide, C2-C16 boronate, C1-C16 acyl, C1-C16 aldehyde, C1-C16 cyano, C1-C16 amino, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, R 2 Any two of which may be linked to form a carbocyclic ring or a heterocyclic ring comprising one or more heteroatoms selected from O, N and S;
R 3 is selected from optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, optionally substituted C2-C16 alkenyl;
n is 1 or 2;
x is N or CH;
the "optional substitution" is unsubstituted or substituted with: C1-C16 alkyl, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, nitro, C2-C16 ester, C1-C16 acyl, C1-C16 cyano, C1-C16 aldehyde, C2-C16 boron ester, C1-C16 amide, C1-C16 amino, or optionally substituted C6-C16 aryl, C3-C16 heteroaryl, C5-C16 benzyl; the number of "substitutions" may not be limited;
in the present invention, the catalyst is Shvo catalyst (CAS: 104439-77-2), ru 3 (CO) 12 、RuCl 3 、[Ru(p-cymene)Cl 2 ] 2 、[IrCp * Cl] 2 、Vaska’s cat(CAS:14871-41-1)、Crabtree’s cat(CAS:64536-78-3)、Rh(COD) 2 Cl、Rh(COD) 2 BF 4 One or more of the following; shvo catalysts are preferred.
In the invention, the additive is one or more of acetophenone, 2-trifluoro acetophenone, cyclohexanone, norbornene and 1, 2-diphenyl acetylene; 2, 2-trifluoroacetophenone is preferred.
In the present invention, the organic solvent may be a solvent conventional in such reactions in the art, such as one or more of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl t-butyl ether, cyclopentyl methyl ether, dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, 1, 3-dimethyl-2-imidazolidinone; dioxane is preferred.
In the present invention, the shielding gas may be a shielding gas conventional in this type of reaction in the art, such as the shielding gas including nitrogen, argon, helium, neon, or krypton.
In the invention, the molar concentration of the compound shown as the formula 1 in the organic solvent is 0.01-2.0M; preferably 0.02-1M, for example 0.05M.
In the invention, the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is 5:1-1:5; preferably 1:1 to 1:4, for example 1:1.5.
In the invention, the molar ratio of the compound shown as the formula 1 to the catalyst is 1:0.001-1:0.05; preferably 1:0.001-1:0.02, e.g. 1:0.01.
In the invention, the mol ratio of the compound shown as the formula 1 to the additive is 1:0.5-1:3; preferably 1:1 to 1:2, for example 1:1.
In the invention, the reaction temperature can be a reaction temperature which is conventional in the art, and the reaction temperature is 50-150 ℃; preferably 100-130 c, e.g. 130 c.
In the invention, the reaction time can be the reaction time conventional in the field of such reactions, and the reaction time is 8-72h; preferably 12-48h, for example 24h.
In a preferred embodiment of the present invention, the reaction further comprises a post-treatment step after completion, which may be a post-treatment step conventional in the art, including a chromatography step. The chromatography may be conventional column chromatography in the art.
[2] The invention provides the preparation method of the [1], wherein after the reaction is finished, acid is added into the reaction liquid to heat and hydrolyze to synthesize the cyclic ketoamide compound, the compound shown in the formula 4 is obtained,
wherein R is 1 Is selected from C1-C16 alkyl, C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl or optionally substituted C3-C16 heteroaryl;
R 2 1,2, 3 or 4 substituents independently selected from: hydrogen, optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, nitro, C2-C16 ester, C1-C16 amide, C2-C16 boronate, C1-C16 acyl, C1-C16 aldehyde, C1-C16 cyano, C1-C16 amino, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, R 2 In (a) and (b)Any two may be linked to form a carbocyclic ring or a heterocyclic ring comprising one or more heteroatoms selected from O, N and S;
R 3 is selected from optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, optionally substituted C2-C16 alkenyl;
n is 1 or 2;
the "optional substitution" is unsubstituted or substituted with: C1-C16 alkyl, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, nitro, C2-C16 ester, C1-C16 acyl, C1-C16 cyano, C1-C16 aldehyde, C2-C16 boron ester, C1-C16 amide, C1-C16 amino, or optionally substituted C6-C16 aryl, C3-C16 heteroaryl, C5-C16 benzyl; the number of "substitutions" may not be limited;
in the present invention, the catalyst is Shvo catalyst (CAS: 104439-77-2), ru 3 (CO) 12 、RuCl 3 、[Ru(p-cymene)Cl 2 ] 2 、[IrCp * Cl] 2 、Vaska’s cat(CAS:14871-41-1)、Crabtree’s cat(CAS:64536-78-3)、Rh(COD) 2 Cl、Rh(COD) 2 BF 4 One or more of the following; shvo catalysts are preferred.
In the invention, the additive is one or more of acetophenone, 2-trifluoro acetophenone, cyclohexanone, norbornene and 1, 2-diphenyl acetylene; 2, 2-trifluoroacetophenone is preferred.
In the present invention, the organic solvent may be a solvent conventional in such reactions in the art, such as one or more of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl t-butyl ether, cyclopentyl methyl ether, dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, 1, 3-dimethyl-2-imidazolidinone; dioxane is preferred.
In the present invention, the shielding gas may be a shielding gas conventional in this type of reaction in the art, such as the shielding gas including nitrogen, argon, helium, neon, or krypton.
In the invention, the molar concentration of the compound shown as the formula 1 in the organic solvent is 0.01-2.0M; preferably 0.02-1M, for example 0.05M.
In the invention, the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is 5:1-1:5; preferably 1:1 to 1:4, for example 1:1.5.
In the invention, the molar ratio of the compound shown as the formula 1 to the catalyst is 1:0.001-1:0.05; preferably 1:0.001-1:0.02, e.g. 1:0.01.
In the invention, the mol ratio of the compound shown as the formula 1 to the additive is 1:0.5-1:3; preferably 1:1 to 1:2, for example 1:1.
In the invention, the reaction temperature can be a reaction temperature which is conventional in the art, and the reaction temperature is 50-150 ℃; preferably 100-130 c, e.g. 130 c.
In the invention, the reaction time can be the reaction time conventional in the field of such reactions, and the reaction time is 8-72h; preferably 12-48h, for example 24h.
In the present invention, the acid is trifluoroacetic acid (TFA), 4-8M (e.g., 6M) hydrochloric acid, 48% by mass hydrobromic acid; preferably 4-8M hydrochloric acid, such as 6M hydrochloric acid.
In a preferred embodiment of the present invention, the reaction further comprises a post-treatment step after completion, which may be a post-treatment step conventional in the art, including a chromatography step. The chromatography may be conventional column chromatography in the art.
The invention has the positive progress effects that:
the invention provides a ring-expanding molecule editing technology of alicyclic amine, which can realize ring-expanding reconstruction of an alicyclic amine structure with inert and wide sources, can be used for later modification of drug molecules and natural products, and has important application value in the fields of drug discovery and complex molecule synthesis.
The invention provides an aza-ring compound, which has novel structure, certain medicinal value and positive significance when being used for developing new medicines.
The method has the advantages of simple steps, good regioselectivity, less catalyst consumption, high atom economy, wide sources of reaction raw materials and mature manufacturing process.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the compound produced in example 1.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound produced in example 1.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound produced in example 15.
FIG. 4 is a nuclear magnetic resonance carbon spectrum of the compound produced in example 15.
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the compound produced in example 21.
FIG. 6 is a nuclear magnetic resonance carbon spectrum of the compound produced in example 21.
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the compound produced in example 33.
FIG. 8 is a nuclear magnetic resonance carbon spectrum of the compound produced in example 33.
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of the compound produced in example 43.
FIG. 10 is a nuclear magnetic resonance carbon spectrum of the compound produced in example 43.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1:
to a dry clean reaction tube equipped with a strong stirrer were added Shvo catalyst (0.002 mmol) and oxazolone (0.3 mmol), which was transferred to a glove box, followed by dioxane (4.0 mL), alicyclic amine (0.2 mmol) and 2, 2-trifluoroacetophenone (0.2 mmol). The reaction tube was sealed with a sealing film, and reacted at 130℃for 24 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and silica gel column chromatography gave 50.3mg of a white solid in 79% yield. M.p. =93-94 ℃; r is R f ＝0.29(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.65(s,1H),7.91–7.81(m,2H),7.52–7.46(m,1H),7.43(t,J＝7.2Hz,2H),7.37–7.27(m,5H),7.24(t,J＝6.8Hz,1H),4.71(s,2H),3.42(t,J＝6.0Hz,2H),2.30(q,J＝7.2Hz,2H),1.79(quin,J＝7.2Hz,2H)； 13 CNMR(101MHz,CDCl 3 ):δ167.9,166.1,137.3,134.7,131.8,131.0,128.8,128.7,128.3,127.8,127.1,120.9,51.4,46.8,28.8,23.9；HRMS(ESI):[M+H + ]Calcd for C 20 H 21 N 2 O 2 + :321.1598；found:321.1589。
Example 2:
the procedure is as in example 1. 29.7mg of a yellow solid was obtained in 61% yield. M.p. =136-137 ℃; r is R f ＝0.16(PE/EA/DCM＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.61(s,1H),7.81(d,J＝7.6Hz,2H),7.46(t,J＝7.6Hz,1H),7.39(t,J＝7.6Hz,2H),7.19(t,J＝6.8Hz,1H),3.43(t,J＝6.0Hz,2H),3.11(s,3H),2.31(q,J＝7.2Hz,2H),1.99(quin,J＝6.8Hz,2H)； 13 CNMR(101MHz,CDCl 3 ):δ167.7,166.0,134.6,131.7,131.1,128.6,127.1,120.5,49.1,35.7,28.3,23.8；HRMS(ESI):[M+H + ]Calcd for C 14 H 17 N 2 O 2 + :245.1285；found:245.1277。
Example 3:
the procedure is as in example 1. 33.4mg of a yellow liquid was obtained in 51% yield. R is R f ＝0.56(PE/EA/DCM＝2/1/1)； 1 HNMR(400MHz,CDCl 3 ):δ8.57(s,1H),7.82(dt,J＝6.8,1.2Hz,2H),7.48(tt,J＝6.4,1.2Hz,1H),7.41(t,J＝7.2Hz,2H),7.27(t,J＝6.8Hz,1H),3.48(t,J＝7.6Hz,2H),3.41(t,J＝6.0Hz,2H),2.34(q,J＝7.2Hz,2H),2.04–1.93(m,2H),1.64–1.52(m,2H),1.34–1.24(m,8H),0.87(t,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ167.4,165.9,134.8,131.7,131.2,128.7,127.1,120.1,48.7,47.4,31.8,29.4,29.1,28.6,27.1,24.0,22.7,14.1；HRMS(ESI):[M+H + ]Calcd for C 20 H 29 N 2 O 2 + :329.2224；found:329.2216。
Example 4:
the procedure is as in example 1. 33.4mg of a yellow liquid was obtained in 51% yield. M.p. =146-147 ℃; r is R f ＝0.18(PE/EA/DCM＝2/1/1)。 1 H NMR(400MHz,CDCl 3 ):δ9.28(s,1H),7.97–7.85(m,2H),7.41–7.32(m,5H),7.31–7.26(m,3H),4.74(s,2H),3.58(t,J＝6.4Hz,2H),2.04(t,J＝7.2Hz,2H),1.87(s,3H),1.70(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ169.7,166.7,138.1,135.2,133.3,131.4,128.7,128.4,128.3,127.8,127.5,126.7,50.4,45.9,29.3,28.5,20.0；HRMS(ESI):[M+H + ]Calcd for C 21 H 23 N 2 O 2 + :335.1754；found:335.1746。
Example 5:
the procedure is as in example 1. Obtain brown solid70.4mg of body, 78% yield. M.p. =206-207 ℃; r is R f ＝0.39(PE/EA/DCM＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.76(s,1H),7.94(d,J＝7.2Hz,2H),7.53–7.47(m,1H),7.46(t,J＝7.2Hz,4H),7.35(t,J＝7.2Hz,2H),7.30–7.27(m,1H),5.26(t,J＝6.4Hz,1H),4.75(s,2H),3.81(d,J＝6.4Hz,2H),3.50(t,J＝6.4Hz,2H),2.05(t,J＝7.2Hz,2H),1.70(quin,J＝6.4Hz,2H),1.47(s,9H)； 13 CNMR(101MHz,CDCl 3 ):δ168.9,166.5,156.9,137.6,133.4,132.2,131.7,129.4,128.8,128.4,128.3,128.0,127.6,80.0,50.0,45.3,41.9,28.6,28.4,25.5；HRMS(ESI):[M+H + ]Calcd for C 26 H 32 N 3 O 4 + :450.2387；found:450.2378。
Example 6:
the procedure is as in example 1. 51.6mg of yellow solid was obtained in 56% yield. M.p. =160-161 ℃; r is R f ＝0.32(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.29(s,1H),7.87(d,J＝7.2Hz,2H),7.42–7.34(m,5H),7.34–7.28(m,3H),4.75(s,2H),4.31(s,2H),3.55(t,J＝6.4Hz,2H),2.17(t,J＝7.2Hz,2H),1.71(quin,J＝6.8Hz,2H),0.85(s,9H),0.03(s,6H)； 13 C NMR(101MHz,CDCl 3 ):δ169.0,166.5,137.8,134.7,133.3,131.7,128.8,128.42,128.4,127.8,127.6,126.8,62.7,50.1,45.6,29.2,25.9,24.0,18.4,-5.3；HRMS(ESI):[M+H + ]Calcd for C 27 H 37 N 2 O 3 Si + :465.2568；found:465.2559。
Example 7:
the procedure is as in example 1. 44.9mg of yellow solid was obtained in 62% yield. M.p. =122-124 ℃; r is R f ＝0.21(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.63(s,1H),7.93–7.82(m,2H),7.43–7.34(m,5H),7.32–7.26(m,3H),4.76(s,2H),4.08(s,2H),3.58(t,J＝6.4Hz,2H),3.28(s,3H),2.14(t,J＝7.2Hz,2H),1.73(quin,J＝6.8Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ169.0,166.5,137.7,132.9,132.8,131.7,128.8,128.8,128.4,128.3,127.8,127.6,71.6,58.5,50.3,45.7,29.1,24.3；HRMS(ESI):[M+H + ]Calcd for C 22 H 25 N 2 O 3 + :365.1860；found:365.1851。
Example 8:
the procedure is as in example 1. This gave 27.2mg of a yellow liquid in 36% yield. R is R f ＝0.25(PE/EA/DCM＝3/1/1)；[α] D 18.9 ＝+13.94(c＝0.33,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 ):δ8.44(s,1H),7.87–7.81(m,2H),7.56–7.49(m,1H),7.49–7.42(m,2H),7.39–7.28(m,6H),5.29(1/2ABq,J＝14.8Hz,1H),4.30(1/2ABq,J＝14.4Hz,1H),4.09(dd,J＝6.4,2.4Hz,1H),3.62(s,3H),2.63(dddd,J＝14.0,9.6,7.2,2.8Hz,1H),2.46–2.23(m,2H),1.96(dtd,J＝14.1,6.8,4.8Hz,1H)； 13 C NMR(101MHz,CDCl 3 ):δ171.3,168.5,165.9,136.5,135.0,131.8,131.6,129.0,128.8,128.7,128.2,127.1,119.7,59.4,53.0,52.4,32.1,22.6；HRMS(ESI):[M+H + ]Calcd for C 22 H 23 N 2 O 4 + :379.1652；found:379.1643。
Example 9:
the procedure is as in example 1. This gave 27.2mg of a yellow liquid in 43% yield. M.p. =162-164 ℃; r is R f ＝0.48(PE/EA/DCM＝2/1/1) 1 H NMR(400MHz,CDCl 3 ):δ9.32(s,1H),7.88(d,J＝7.6Hz,2H),7.56(dd,J＝7.6,4.0Hz,1H),7.50(t,J＝7.2Hz,1H),7.45(t,J＝8.0Hz,2H),7.36(t,J＝7.2Hz,2H),7.29(t,J＝7.2Hz,1H),7.18(d,J＝7.2Hz,2H),4.94(dd,J＝8.4,3.2Hz,1H),3.02(s,3H),2.54–2.38(m,2H),2.31–2.10(m,2H)； 13 C NMR(101MHz,CDCl 3 ):166.2,165.9,138.1,135.3,131.7,130.0,128.9,128.7,127.9,127.1,126.8,123.4,63.8,36.7,31.8,24.0；HRMS(ESI):[M+H + ]Calcd for C 20 H 21 N 2 O 2 + :321.1598；found:321.1589。
Example 10:
the procedure is as in example 1. 26.4mg of a white solid was obtained in 36% yield. M.p. =98-100 ℃; r is R f ＝0.37(PE/EA/DCM＝3/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.41(s,1H),7.85(d,J＝7.2Hz,2H),7.52(t,J＝7.2Hz,1H),7.45(t,J＝8.0Hz,2H),7.38–7.28(m,5H),7.16(d,J＝5.2Hz,1H),4.82(1/2ABq,J＝14.4Hz,1H),4.59(1/2ABq,J＝14.4Hz,1H),3.53(ddd,J＝14.4,12.0,4.8Hz,1H),3.28(ddd,J＝14.4,5.2,2.8Hz,1H),2.28(dq,J＝12.0,6.4Hz,1H),1.92–1.81(m,1H),1.73(dq,J＝13.4,6.7Hz,1H),1.55–1.44(m,1H),0.93(d,J＝6.7Hz,3H),0.88(d,J＝6.7Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ167.9,166.0,137.2,134.9,131.8,130.6,128.9,128.8,128.4,127.9,127.1,121.0,51.7,50.1,47.8,30.7,28.1,20.4,20.3；HRMS(ESI):[M+H + ]Calcd for C 23 H 27 N 2 O 2 :363.2067；found:363.2058。
Example 11:
the procedure is as in example 1. This gave 72.8mg of yellow solid in 76% yield. M.p. =40-42 ℃; r is R f ＝0.43(PE/EA＝3/1)； 1 HNMR(400MHz,CDCl 3 ):δ8.62(s,1H),7.88–7.80(m,2H),7.60–7.55(m,1H),7.53–7.47(m,1H),7.47–7.41(m,2H),7.38–7.27(m,5H),4.92(1/2ABq,J＝14.8Hz,1H),4.51(1/2ABq,J＝14.8Hz,1H),3.64(dd,J＝10.8,4.8Hz,1H),3.60–3.53(m,1H),3.50(dd,J＝10.8,5.2Hz,1H),3.37–3.25(m,1H),1.53–1.42(m,2H),1.06(quin,J＝4.8Hz,1H),0.86(s,9H),0.01(d,J＝2.4Hz,6H)； 13 C NMR(101MHz,CDCl 3 ):δ167.0,165.9,136.7,135.0,131.8,128.8,128.8,128.7,128.4,127.8,127.1,122.6,63.2,51.8,48.9,26.1,26.0,25.3,18.4,17.8,-5.1,-5.2；HRMS
(ESI):[M+H + ]Calcd for C 28 H 37 N 2 O 3 Si + :477.2568；found:477.2560。
Example 12:
the procedure is as in example 1. 59.9mg of yellow solid was obtained in 83% yield. M.p. =133-134 ℃; r is R f ＝0.25(PE/EA/DCM＝3/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.68(s,1H),7.90–7.82(m,2H),7.52–7.47(m,1H),7.46–7.40(m,2H),7.38–7.26(m,5H),7.19(d,J＝4.0Hz,1H),4.77(1/2ABq,J＝14.8Hz,1H),4.69(1/2ABq,J＝14.8Hz,1H),3.42(dd,J＝14.0,10.8Hz,1H),3.16(dd,J＝14.4,4.0Hz,1H),2.86(dtd,J＝9.6,7.6,4.0Hz,1H),2.47–2.33(m,1H),2.05–1.93(m,1H),1.83–1.64(m,2H),1.63–1.52(m,1H),1.52–1.39(m,1H),1.19(dq,J＝12.8,8.4Hz,1H)； 13 C NMR(101MHz,CDCl 3 ):δ167.2,165.9,137.1,134.8,131.7,128.8,128.7,128.5,128.1,127.7,127.1,126.9,51.5,51.4,45.4,40.5,35.0,30.4,25.2；HRMS(ESI):[M+H + ]Calcd for C 23 H 25 N 2 O 2 + :361.1911；found:361.1902。
Example 13:
the procedure is as in example 1. 23.6mg of yellow solid was obtained in 51% yield. M.p. =85-86 ℃; r is R f ＝0.16(PE/EA/DCM＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.60(s,1H),7.90–7.81(m,2H),7.51(d,J＝7.2Hz,1H),7.44(t,J＝7.6Hz,2H),7.38–7.29(m,5H),7.22–6.99(m,1H),4.86(1/2ABq,J＝14.0Hz,1H),4.60(1/2ABq,J＝14.4Hz,1H),3.64–3.38(m,4H),3.28(d,J＝12.4Hz,1H),3.05(br,2H),2.57(br,1H),1.44(s,9H)； 13 C NMR(101MHz,CDCl 3 )rotameric mixture,resonances for minor rotamer are enclosed in parentheses:δ(167.3)167.1,166.0,154.1(154.0),(136.8)136.7,134.4(134.3),131.9,(130.9)130.5,128.9,128.7,128.3,128.0,127.1,(122.0)121.3,79.7,52.1,(51.6)51.4,49.6(49.5),49.0,(45.6)44.3,39.7(38.6),28.5；HRMS(ESI):[M+H + ]Calcd for C 27 H 32 N 3 O 4 + :462.2387；found:462.2377。
Example 14:
the procedure is as in example 1. 31.6mg of brown solid was obtained in 54% yield. M.p. =96-98 ℃; r is R f ＝0.32(PE/EA/DCM＝3/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.03(s,1H),8.43(s,1H),7.91(d,J＝7.6Hz,2H),7.54(t,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,2H),7.40(dt,J＝14.0,7.2Hz,2H),7.31(m,2H),4.28(s,2H),3.18(s,3H)； 13 C NMR(101MHz,CDCl 3 ):δ166.0,164.2,135.0,134.7,134.0,132.1,131.3,129.9,128.9,128.7,128.4,127.2,127.0,121.7,53.5,35.7；HRMS(ESI):[M+H + ]Calcd for C 18 H 17 N 2 O 2 + :293.1285；found:293.1277。
Example 15:
the procedure is as in example 1. Obtained as yellow oil 16.4mg in 29% yield. (16.4 mg, 29%). R f ＝0.32(PE/EA/DCM＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.58(s,1H),7.87–7.81(m,2H),7.52–7.46(m,1H),7.46–7.39(m,2H),7.19(dd,J＝8.0,6.0Hz,1H),4.01–3.86(m,2H),3.46–3.33(m,1H),2.39–2.17(m,2H),2.15–2.03(m,1H),1.94–1.77(m,2H),1.77–1.56(m,5H)； 13 C NMR(101MHz,CDCl 3 ):δ167.1,166.0,134.8,131.8,131.6,128.7,127.1,120.5,54.6,40.1,34.1,28.2,23.5,22.9,19.9；HRMS(ESI):[M+H + ]Calcd for C 17 H 21 N 2 O 2 + :285.1598；found:285.1590。
Example 16:
the procedure is as in example 1. 12.9mg of white solid was obtained in 42% yield. M.p. =151-153 ℃; r is R f ＝0.27(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.19(s,1H),7.86–7.81(m,2H),7.75(t,J＝4.8Hz,1H),7.54–7.48(m,1H),7.48–7.42(m,2H),3.92–3.83(m,1H),3.73(ddd,J＝12.8,9.2,7.6Hz,1H),2.85(dd,J＝16.8,1.2Hz,1H),2.74(dt,J＝8.8,4.4Hz,2H),2.64(dd,J＝16.8,1.2Hz,1H),2.47–2.36(m,2H),2.14–1.89(m,4H)； 13 C NMR(101MHz,CDCl 3 ):δ166.1,162.6,135.2,131.8,128.8,128.2,127.0,123.5,116.7,62.3,50.4,40.6,35.4,25.0,23.5,20.7；HRMS(ESI):[M+H + ]Calcd for C 18 H 20 N 3 O 2 + :310.1550；found:310.1543.
Example 17:
the procedure is as in example 1. 23.1mg of brown solid was obtained in 60% yield. M.p. =98-99 ℃; r is R f ＝0.33(PE/EA/DCM＝3/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.39(s,1H),7.87–7.79(m,2H),7.42(t,J＝7.2Hz,1H),7.34–7.24(m,7H),7.15–7.07(m,2H),6.94(s,1H),6.92–6.85(m,2H),4.62(s,2H),4.04(t,J＝7.2Hz,2H),2.99(t,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ168.1,166.3,136.7,135.2,134.0,132.9,132.3,131.8,131.5,130.8,128.7,128.4,128.2,127.6,127.4,126.1,121.8,49.2,47.7,33.8；HRMS(ESI):[M+H + ]Calcd for C 25 H 23 N 2 O 2 + :383.1754；found:383.1746。
Example 18:
the procedure is as in example 1. 16.8mg of yellow solid was obtained in 53% yield. M.p. =97-99 ℃; r is R f ＝0.28(PE/EA/Acetone＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.95(s,1H),7.31–7.20(m,5H),7.20–7.09(m,2H),7.03(dd,J＝7.2,1.6Hz,1H),6.88(dd,J＝7.6,1.6Hz,1H),6.80(s,1H),4.54(s,2H),3.93(t,J＝7.2Hz,2H),2.97(t,J＝7.2Hz,2H),2.03(s,3H)； 13 C NMR(101MHz,CDCl 3 ):δ170.0,168.1,136.4,135.2,134.1,132.3,131.7,130.6,128.7,128.1,127.7,127.5,126.2,120.2,48.8,47.4,33.7,23.2；HRMS(ESI):[M+H + ]Calcd for C 20 H 21 N 2 O 2 + :321.1598；found:321.1589。
Example 19:
the procedure is as in example 1. 21.3mg of yellow solid was obtained in 46% yield. M.p. =224-226 ℃; r is R f ＝0.53(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.51(s,1H),7.87(d,J＝7.6Hz,2H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,2H),7.31–7.26(m,3H),7.23–7.16(m,3H),7.15(d,J＝2.4Hz,1H),7.03(s,1H),6.64(d,J＝8.0Hz,1H),4.57(s,2H),3.95(t,J＝7.2Hz,2H),2.89(t,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.3,166.3,136.5,136.1,134.2,133.3,133.2,133.1,132.9,132.3,130.7,128.8,128.8,128.5,127.7,127.5,120.1,118.5,49.3,47.5,33.5；HRMS(ESI):[M+H + ]Calcd for C 25 H 22 BrN 2 O 2 + :461.0859；found:461.0854。
Example 20:
the procedure is as in example 1. This gave 20.5mg of brown solid in 24% yield. M.p. =146-148 ℃; r is R f ＝0.35(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.65(d,J＝2.4Hz,1H),8.15(t,J＝5.6Hz,1H),8.01–7.94(m,3H),7.60–7.51(m,1H),7.44(t,J＝7.6Hz,2H),7.02(d,J＝8.8Hz,1H),5.57(s,2H),4.24(s,2H),4.14(d,J＝5.6Hz,2H),4.07(s,3H),3.55–3.40(m,4H),2.31(t,J＝7.2Hz,2H),1.96(quin,J＝6.8Hz,2H),1.14(t,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ198.2,171.2,164.2,160.3,139.9,136.8,135.5,133.6,131.2,131.1,129.4,128.8,128.5,122.0,111.8,56.7,45.8,42.4,42.0,39.2,30.4,28.0,14.2；HRMS(ESI):[M+H + ]Calcd for C 28 H 23 N 2 O 2 + :419.1754；found:419.1748。
Example 21:
the procedure is as in example 1. 17.5mg of yellow solid was obtained in 45% yield. M.p. =179-181 ℃; r is R f ＝0.42(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.81(s,1H),7.85(d,J＝7.2Hz,2H),7.47(t,J＝7.6K Hz,1H),7.40–7.27(m,7H),7.17(s,1H),7.04(d,J＝5.2Hz,1H),6.63(d,J＝5.2Hz,1H),4.75(s,2H),4.09(br,2H),3.13(t,J＝6.0Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.8,166.5,136.5,135.8,133.6,132.0,131.6,130.9,129.4,128.9,128.6,128.1,127.7,127.4,122.8,118.3,48.8,46.0,28.2；HRMS(ESI):[M+H + ]Calcd for C 23 H 21 N 2 O 2 S + :389.1318；found:389.1314。
Example 22:
the procedure is as in example 1. Obtained as a yellow solid in 32.5mg,75% yield. M.p. =228-229 ℃; r is R f ＝0.33(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,DMSO-d 6 ):δ10.55(s,1H),8.04(d,J＝7.2Hz,2H),7.68(t,J＝7.2Hz,1H),7.61(t,J＝7.4Hz,2H),7.55–7.48(m,3H),7.44(d,J＝8.4Hz,1H),7.35(t,J＝7.2Hz,2H),7.29(t,J＝7.2Hz,1H),7.23(t,J＝7.6Hz,1H),7.09(t,J＝7.6Hz,1H),6.83(s,1H),5.12(1/2ABq,J＝15.6Hz,1H),4.61(t,J＝13.6Hz,1H),4.18(1/2ABq,J＝15.2Hz,1H),3.72(s,3H),3.59–3.46(m,1H),3.37(d,J＝16.0,4.4Hz,1H),2.87(d,J＝16.4Hz,1H)； 13 C NMR(101MHz,DMSO):δ166.8,166.1,138.2,137.7,134.2,134.0,133.0,130.1,129.5,129.2,128.8,128.7,128.7,127.9,123.2,119.8,119.4,111.2,110.2,109.8,47.06,44.9,30.8,24.0；HRMS(ESI):[M+H + ]Calcd for C 28 H 26 N 3 O 2 + :436.2020；found:436.2015。
Example 23:
the procedure is as in example 1. 53.2mg of white solid was obtained in 79% yield. M.p. =127-128 ℃; r is R f ＝0.30(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.77(s,1H),7.89–7.82(m,2H),7.37–7.28(m,5H),7.13–7.05(m,3H),4.72(s,2H),3.44(t,J＝6.0Hz,2H),2.27(q,J＝7.2Hz,2H),1.79(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ168.0,165.01,164.9(d,J C-F ＝253.0Hz),137.3,131.2,130.7,129.6(d,J C-F ＝9.2Hz),128.9,128.3,127.9,121.4,115.7(d,J C-F ＝22.0Hz),51.4,46.8,28.8,23.8； 19 F NMR(376MHz,CDCl 3 )δ-107.9；HRMS(ESI):[M+H + ]Calcd for C 20 H 20 FN 2 O 2 + :339.1503；found:339.1495。
Example 24:
the procedure is as in example 1. Obtained as a white solid 50.4mg in 71% yield. M.p. =152-154 ℃; r is R f ＝0.27(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.71(s,1H),7.79(d,J＝8.4Hz,2H),7.42–7.29(m,7H),7.20(t,J＝6.8Hz,1H),4.72(s,2H),3.43(t,J＝6.0Hz,2H),2.30(q,J＝7.2Hz,2H),1.80(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.9,164.9,138.1,137.3,133.1,130.9,129.0,128.9,128.6,128.3,127.9,121.5,51.6,46.9,28.8,24.1；HRMS(ESI):[M+H + ]Calcd for C 20 H 20 ClN 2 O 2 + :355.1208；found:355.1200。
Example 25:
the procedure is as in example 1. 45.8mg of white solid was obtained in 57% yield. M.p. =145-147 ℃; r is R f ＝0.44(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.68(s,1H),7.71(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.37–7.29(m,5H),7.21(t,J＝6.8Hz,1H),4.72(s,2H),3.43(t,J＝5.6Hz,2H),2.31(q,J＝7.2Hz,2H),1.80(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.9,165.0,137.3,133.2,131.8,131.2,128.8,128.3,127.8,126.5,121.8,51.4,46.7,28.8,23.8；HRMS(ESI):[M+H + ]Calcd for C 20 H 20 BrN 2 O 2 + :399.0703；found:399.0694。
Example 26:
the procedure is as in example 1. 51.0mg of white solid was obtained in 74% yield. M.p. =128-129 ℃; r is R f ＝0.24(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.07(s,1H),7.94(d,J＝8.4Hz,2H),7.68(d,J＝8.8Hz,2H),7.38–7.30(m,5H),7.09(t,J＝6.8Hz,1H),4.72(s,2H),3.45(t,J＝6.0Hz,2H),2.27(q,J＝7.2Hz,2H),1.81(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.7,164.1,138.3,137.2,132.5,130.9,128.9,128.2,127.9,127.9,122.7,118.1,115.2,51.6,46.8,28.7,24.0；HRMS(ESI):[M+H + ]Calcd for C 21 H 20 N 3 O 2 + :346.1550；found:346.1543。
Example 27:
the procedure is as in example 1. 36.0mg of white solid was obtained in 49% yield. M.p. =150-152 ℃; r is R f ＝0.42(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.03(s,1H),8.25(d,J＝8.8Hz,2H),8.00(d,J＝8.8Hz,2H),7.38–7.31(m,5H),7.19(t,J＝6.4Hz,1H),4.73(s,2H),3.46(t,J＝5.6Hz,2H),2.32(q,J＝7.2Hz,2H),1.83(tt,J＝6.8,6.0Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.6,163.9,149.7,140.1,137.1,130.7,128.9,128.4,128.3,128.0,123.9,122.8,51.7,46.9,28.6,24.2；HRMS(ESI):[M+H + ]Calcd for C 20 H 20 N 3 O 4 + :366.1448；found:366.1440。
Example 28:
the procedure is as in example 1. 40.0mg of white solid was obtained in 51% yield. M.p. =157-158 ℃; r is R f ＝0.50(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.96(s,1H),7.95(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.38–7.28(m,5H),7.15(t,J＝6.8Hz,1H),4.73(s,2H),3.45(t,J＝5.6Hz,2H),2.29(q,J＝7.2Hz,2H),1.81(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ167.8,164.7,137.7,137.3,133.4(q,J C-F ＝32.7Hz),131.0,128.9,128.3,127.9,127.7,125.7(q,J C-F ＝3.8Hz),123.8(q,J C-F ＝273.5Hz),122.2,51.6,46.8,28.7,24.0； 19 F NMR(376MHz,CDCl 3 )δ-63.0；HRMS(ESI):[M+H + ]Calcd for C 21 H 20 F 3 N 2 O 2 + :389.1471；found:389.1463。
Example 29:
the procedure is as in example 1. 42.4mg of white solid was obtained in 63% yield. M.p. =124-126 ℃; r is R f ＝0.46(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.07(s,1H),7.47(d,J＝7.6Hz,1H),7.36–7.28(m,7H),7.23(d,J＝7.6Hz,2H),4.69(s,2H),3.42(t,J＝6.0Hz,2H),2.50(s,3H),2.31(q,J＝7.2Hz,2H),1.80(quin,J＝6.8Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ168.8,167.7,137.4,136.4,136.3,131.3,131.1,130.3,128.8,128.3,127.8,127.0,125.9,120.5,51.4,46.7,28.8,23.9,20.1；HRMS(ESI):[M+H + ]Calcd for C 21 H 23 N 2 O 2 + :335.1754；found:335.1747。
Example 30:
the procedure is as in example 1. 45.8mg of white solid was obtained in 65% yield. M.p. =126-127 ℃; r is R f ＝0.23(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.81(s,1H),7.44–7.38(m,2H),7.35–7.27(m,6H),7.10(t,J＝6.8Hz,1H),7.00(dd,J＝8.4,2.4Hz,1H),4.72(s,2H),3.81(s,3H),3.44(t,J＝6.0Hz,2H),2.26(q,J＝7.2Hz,2H),1.79(quin,J＝6.8Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ168.0,165.9,159.9,137.4,135.9,131.4,129.6,128.8,128.3,127.8,121.1,119.1,118.3,112.1,55.5,51.3,46.6,28.8,23.6；HRMS(ESI):[M+H + ]Calcd for C 21 H 23 N 2 O 3 + :351.1703；found:351.1696。
Example 31:
the procedure is as in example 1. 26.5mg of white solid was obtained in 55% yield. M.p. =150-151 ℃; r is R f ＝0.20(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.78(s,1H),7.95(d,J＝8.4Hz,2H),7.85(d,J＝8.4Hz,2H),7.37–7.29(m,5H),7.24(d,J＝6.8Hz,1H),4.72(s,2H),3.43(t,J＝6.0Hz,2H),3.08,(t,J＝7.6Hz,4H),2.33(q,J＝7.2Hz,2H),1.82(quin,J＝6.8Hz,2H),1.55(sext,J＝7.6Hz,4H),0.87(t,J＝7.6Hz,6H)； 13 C NMR(101MHz,CDCl 3 ):δ167.6,164.6,143.2,138.1,137.2,130.7,128.9,128.3,127.9,127.9,127.4,122.1,51.7,50.1,46.9,28.6,24.3,22.1,11.3；HRMS(ESI):[M+H + ]Calcd for C 26 H 34 N 3 O 4 S + :484.2265；found:484.2256.
Example 32:
the procedure is as in example 1. Obtained as a white solid 31.1mg,73% yield. M.p. =147-148 ℃; r is R f ＝0.21(PE/EA/DCM＝2/1/1)；[α] D 19.8 ＝+96.00(c＝0.25,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 ):δ7.76–7.69(m,4H),7.45(dd,J＝8.4,2.0Hz,1H),7.34–7.24(m,5H),7.17–7.10(m,2H),7.07(t,J＝6.8Hz,1H),4.62(ABq J＝14.4Hz,2H),3.91(s,3H),3.77(q,J＝7.2Hz,1H),3.31(dd,J＝7.2,5.2Hz,2H),2.19(q,J＝7.2Hz,2H),1.69(quin,J＝7.2Hz,2H),1.62(d,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ173.2,167.7,157.8,137.4,136.2,133.9,131.0,129.5,129.1,128.8,128.3,127.8,127.7,126.2,126.2,120.1,119.2,105.8,55.4,51.3,48.1,46.7,28.9,23.6,18.7；HRMS(ESI):[M+H + ]Calcd for C 27 H 29 N 2 O 3 + :429.2173；found:429.2165。
Example 33:
the procedure is as in example 1. 24.8mg of a white solid was obtained in 60% yield. M.p. =108-109 ℃; r is R f ＝0.24(PE/EA/DCM＝2/1/1)；[α] D 18.9 ＝-53.64(c＝0.22,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 ):δ8.07(s,1H),7.37–7.27(m,5H),7.08(t,J＝6.8Hz,1H),5.10(d,J＝8.8Hz,1H),4.67(s,2H),4.06(d,J＝7.2Hz,1H),3.35(t,J＝6.0Hz,2H),2.31–2.14(m,3H),1.75(quin,J＝7.2Hz,3H),1.45(s,9H),1.00(d,J＝6.8Hz,3H),0.93(d,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ170.6,167.5,156.0,137.4,130.6,128.8,128.4,127.8,120.7,80.1,60.5,51.3,46.6,31.3,28.8,28.4,23.8,19.5,17.7.；HRMS(ESI):[M+H + ]Calcd for C 23 H 34 N 3 O 4 + :416.2544；found:416.2535。
Example 34:
the procedure is as in example 1. 43.6mg of white solid was obtained in 63% yield. M.p. =146-147 ℃; r is R f ＝0.29(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.15(s,1H),7.64(d,J＝15.6Hz,1H),7.52–7.46(m,2H),7.38–7.28(m,8H),7.19(t,J＝6.8Hz,1H),6.52(d,J＝15.6Hz,1H),4.71(s,2H),3.40(t,J＝6.0Hz,2H),2.28(q,J＝7.2Hz,2H),1.78(p,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ168.0,165.9,159.9,137.4,135.9,131.4,129.6,128.8,128.3,127.8,121.1,119.1,118.3,112.1,55.5,51.3,46.6,28.8,23.6；HRMS(ESI):[M+H + ]Calcd for C 22 H 23 N 2 O 2 + :347.1754；found:347.1746.
Example 35:
the procedure is as in example 1. 39.6mg of a yellow liquid was obtained in 62% yield. R is R f ＝0.38(PE/EA/DCM＝4/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.02–7.97(m,2H),7.59–7.53(m,1H),7.46(t,J＝7.6Hz,2H),7.35–7.31(m,4H),7.28–7.23(m,1H),6.06(t,J＝7.2Hz,1H),4.71(s,2H),4.14(s,2H),3.56(t,J＝6.4Hz,2H),2.18(q,J＝7.2Hz,2H),1.74(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ198.6,171.3,138.3,136.5,133.8,133.3,132.9,128.7,128.7,128.3,128.1,127.4,50.2,45.7,44.2,29.2,23.7；HRMS(ESI):[M+H + ]Calcd for C 21 H 22 NO 2 + :320.1645；found:320.1639。
Example 36:
the procedure is as in example 1. This gave a yellow liquid, 20.6mg,40% yield. R is R f ＝0.26(PE/EA/DCM＝4/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ7.34–7.27(m,5H),5.98(t,J＝7.2Hz,1H),4.68(s,2H),3.56(s,2H),3.46(t,J＝6.4Hz,2H),2.19(s,3H),2.15(q,J＝7.2Hz,2H),1.72(quin,J＝6.8Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ206.9,171.1,138.2,133.5,133.0,128.7,128.1,127.4,50.2,48.9,45.7,29.7,29.0,23.9；HRMS(ESI):[M+H + ]Calcd for C 16 H 20 NO 2 + :258.1489；found:258.1484。
Example 37:
the procedure is as in example 1. 29.0mg of a yellow liquid was obtained in 41% yield. R is R f ＝0.27(PE/EA/Acetone＝1/1/1)； 1 HNMR(400MHz,CDCl 3 ):δ8.50(s,1H),7.37–7.80(m,2H),7.52–7.48(m,1H),7.47–7.42(m,2H),7.32(t,J＝6.8Hz,1H),7.18–7.11(m,2H),7.05–7.00(m,2H),6.92(dd,J＝6.8,2.4Hz,1H),6.53(dd,J＝8.0,2.0Hz,1H),4.13–4.08(m,2H),4.04(t,J＝6.0Hz,2H),3.74(t,J＝6.8Hz,2H),3.53(t,J＝6.4Hz,2H),3.03(br,4H),2.83(t,J＝6.8Hz,2H),2.63(m,6H),2.46(t,J＝7.2Hz,2H),2.35(q,J＝7.2Hz,2H),2.05–1.98(m,2H),1.82–1.74(m,2H),1.73–1.64(m,2H)； 13 C NMR(101MHz,CDCl 3 ):δ170.8,168.1,166.0,159.1,140.7,134.9,134.1,131.9,130.8,128.8,128.6,127.6(2C),127.1,124.7,121.1,118.7,118.0,108.9,102.5,68.1,58.2,53.3,51.2,48.6,46.6,40.7,32.3,29.0,27.3,24.8,24.2,23.4；HRMS(ESI):[M+H + ]Calcd for C 38 H 44 Cl 2 N 5 O 4 + :704.2765；found:704.2756。
Example 38:
the procedure is as in example 1. 25.3mg of white solid was obtained in 48% yield. M.p. =155-156 ℃; r is R f ＝0.21(PE/EA/DCM＝1/3/3)； 1 H NMR(400MHz,CDCl 3 ):δ8.45(s,1H),8.21(d,J＝8.8Hz,1H),7.89(s,1H),7.82(d,J＝6.8Hz,2H),7.49(m,3H),7.43(t,J＝7.6Hz,2H),7.26(t,J＝7.2Hz,2H),7.00–6.93(m,3H),6.87(d,J＝2.0Hz,1H),4.28(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz,2H),3.83(s,3H),3.62(t,J＝6.0Hz,2H),2.34(q,J＝7.2Hz,2H),2.07(quin,J＝6.8Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ175.9,168.1,166.0,162.8,159.7,158.0,152.2,134.7,131.9,130.9,130.2,128.8,128.2,127.1,125.0,124.2,121.2,118.9,114.6,114.1,100.8,67.02,55.4,49.5,48.6,29.2,23.9；HRMS(ESI):[M+H + ]Calcd for C 31 H 29 N 2 O 6 + :525.2020；found:525.2012。
Example 39:
the procedure is as in example 1. 24.0mg of a yellow liquid was obtained in 47% yield. R is R f ＝0.20(PE/EA/DCM＝2/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.41(s,1H),7.82–7.76(m,2H),7.60(td,J＝4.0,2.0Hz,2H),7.54–7.48(m,1H),7.44(t,J＝7.4Hz,2H),7.31(t,J＝6.8Hz,1H),7.17(d,J＝8.8Hz,1H),6.70(t,J＝74.9Hz,1H),4.52(t,J＝5.2Hz,2H),3.95–3.86(m,4H),3.59–3.46(m,2H),2.35(q,J＝7.2Hz,2H),2.01(quin,J＝7.2Hz,2H),1.30–1.23(m,1H),0.68–0.60(m,2H),0.38–0.31(m,2H)； 13 C NMR(101MHz,CDCl 3 ):δ168.1,166.0,165.6,150.3,144.4,134.7,131.9,131.0,128.8,127.9,127.1,122.9,122.0,120.7,115.85(t,J C-F ＝261.9Hz),113.3,74.2,63.2,48.7,47.8,29.2,24.0,10.1,3.4； 19 F NMR(376MHz,CDCl 3 )δ81.9；HRMS(ESI):[M+H + ]Calcd for C 27 H 29 F 2 N 2 O 6 + :515.1988；found:515.1979。
Example 40:
the procedure is as in example 1. 25.4mg of yellow solid was obtained in 41% yield. M.p. =59-60 ℃; r is R f ＝0.42(PE/EA/DCM＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.39(s,1H),7.85–7.78(m,2H),7.68–7.60(m,2H),7.53–7.48(m,1H),7.48–7.41(m,4H),7.23(t,J＝6.8Hz,1H),6.94(d,J＝2.4Hz,1H),6.86(d,J＝9.2Hz,1H),6.66(dd,J＝8.8,2.4Hz,1H),4.29(t,J＝5.6Hz,2H),3.81(s,3H),3.74(t,J＝5.6Hz,2H),3.69(s,2H),3.31(t,J＝6.0Hz,2H),2.37(s,3H),2.20(q,J＝7.2Hz,2H),1.83(quin,J＝7.2Hz,2H)； 13 CNMR(101MHz,CDCl 3 ):δ170.7,168.4,167.9,166.0,156.2,139.5,136.2,134.8,133.9,131.8,131.3,130.9,130.8,130.7,129.3,128.8,127.1,121.0,115.1,112.3,111.7,101.5,63.2,55.9,48.5,47.6,30.5,29.0,23.9,13.5；HRMS(ESI):[M+H + ]Calcd for C 34 H 33 ClN 3 O 6 + :614.2052；found:614.2042。
Example 41:
the procedure is as in example 1. This gave 27.1mg of a yellow liquid in 36% yield. R is R f ＝0.42(PE/EA/DCM＝1/1/1)；[α] D 18.9 ＝+7.94(c＝0.47,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 ):δ8.42(s,1H),7.83–7.69(m,2H),7.45(t,J＝7.2Hz,1H),7.38(t,J＝7.6Hz,2H),7.28(t,J＝6.8Hz,1H),4.21(t,J＝5.6Hz,2H),3.72(t,J＝5.2Hz,2H),3.52(tt,J＝10.4,4.4Hz,1H),3.45(t,J＝6.0Hz,2H),2.38–2.26(m,3H),2.17(ddd,J＝15.6,10.0,6.4Hz,1H),2.03–1.93(m,2H),1.90–1.83(m,1H),1.80–1.63(m,6H),1.80–1.63(m,2H),1.40–1.24(m,9H),1.21–1.10(m,4H),1.10–0.95(m,5H),0.90–0.80(m,16H),0.56(s,3H),0.00(s,6H)； 13 C NMR(101MHz,CDCl 3 ):δ174.1,167.9,166.0,134.8,131.8,130.9,128.8,127.1,120.7,72.9,62.3,56.5,56.0,48.8,47.9,42.8,42.4,40.3,40.2,37.0,36.0,35.7,35.5,34.7,31.3,31.1,31.1,29.2,28.3,27.4,26.5,26.1,24.3,24.1,23.5,20.9,18.5,18.4,12.1,-4.5；HRMS(ESI):[M+H + ]Calcd for C 45 H 71 N 2 O 5 Si + :747.5127；found:747.5123。
Example 42:
the procedure is as in example 1. 40.8mg of yellow solid was obtained in 77% yield. M.p. =118-119 ℃; r is R f ＝0.30(PE/EA/DCM＝2/1/1)；[α] D 18.9 ＝+66.15(c＝0.13,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 ):δ8.46(s,1H),7.82(d,J＝7.6Hz,2H),7.49(t,J＝7.2Hz,1H),7.43(t,J＝7.2Hz,2H),7.30(d,J＝6.8Hz,1H),7.19(d,J＝8.8Hz,1H),6.70(d,J＝8.4Hz,1H),6.64(s,1H),4.15(t,J＝4.8Hz,2H),3.91(t,J＝4.8Hz,2H),3.60(t,J＝6.0Hz,2H),2.92–2.84(m,2H),2.50(dd,J＝18.4,8.4Hz,1H),2.43–2.28(m,3H),2.24(m,1H),2.18–1.92(m,6H),1.67–1.40(m,6H),0.90(s,3H)； 13 C NMR(101MHz,CDCl 3 ):δ221.0,167.9,166.0,156.6,138.0,134.8,132.6,131.8,131.0,128.7,127.1,126.6,121.0,114.4,112.0,66.5,50.5,49.4,48.9,48.1,44.1,38.4,36.0,31.7,29.8,29.2,26.6,26.0,24.0,21.7,14.0；HRMS(ESI):[M+H + ]Calcd for C 33 H 39 N 2 O 4 + :527.2904；found:527.2894.
Example 43:
the procedure is as in example 1. 38.4mg of white solid was obtained in 83% yield. M.p. =74-76 ℃; r is R f ＝0.34(PE/EA/DCM＝3/1/1)；[α] D 19.8 ＝-81.92(c＝0.26,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 ):δ9.03(s,1H),7.88–7.79(m,2H),7.54–7.48(m,1H),7.48–7.42(m,2H),7.36–7.27(m,5H),6.96(s,1H),5.35(1/2ABq,J＝14.8Hz,1H),4.88(d,J＝7.2Hz,1H),4.15(1/2ABq,J＝14.4Hz,1H),3.75–3.61(m,2H),3.34(t,J＝6.8Hz,1H),1.45(s,9H),1.18(ddd,J＝9.2,6.4,4.8Hz,1H),1.05(ddd,J＝9.2,6.4,4.4Hz,1H),0.91(ddd,J＝9.2,6.4,4.8Hz,1H),0.83(ddd,J＝9.2,6.4,4.4Hz,1H)； 13 C NMR(101MHz,CDCl 3 ):δ166.0,155.7,136.8,135.1,131.8,128.9,128.8,128.4,128.3,127.9,127.6,127.0,80.1,56.2,53.5,49.9,28.4,26.4,20.4,13.8；HRMS(ESI):[M+H + ]Calcd for C 27 H 32 N 3 O 4 + :462.2387；found:462.2378。
Example 44:
the procedure is as in example 1. 74.8mg of white solid was obtained in 71% yield. M.p. =126-127 ℃; r is R f ＝0.37(PE/Acetone/EA＝1/1/1)； 1 H NMR(400MHz,CDCl 3 ):δ9.74(s,1H),7.85(d,J＝7.2Hz,2H),7.47(d,J＝8.8Hz,1H),7.38(t,J＝7.2Hz,1H),7.29(t,J＝7.6Hz,2H),6.72(t,J＝6.0Hz,1H),6.58(d,J＝9.2Hz,1H),4.14(d,J＝6.4Hz,2H),3.85(s,3H),3.77(s,3H),3.49(t,J＝6.4Hz,2H),3.36(q,J＝7.2Hz,2H),2.26(t,J＝6.8Hz,2H),1.98(quin,J＝6.8Hz,2H),1.15(t,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ168.0,166.5,165.5,156.7,154.8,134.2,132.9,132.3,131.8,129.8,128.4,127.8,122.7,108.6,108.3,62.6,56.3,45.7,41.7,41.3,29.3,26.0,13.9；HRMS(ESI):[M+H + ]Calcd for C 25 H 29 BrN 3 O 5 + :530.1285；found:530.1279。
Example 45:
the procedure is as in example 1. Obtained as yellow solid 18.1mg,36% yield. M.p. =97-98 ℃; r is R f ＝0.29(PE/Acetone/EA＝1/2/2)； 1 H NMR(400MHz,CDCl 3 ):δ8.65(d,J＝2.4Hz,1H),8.15(t,J＝5.6Hz,1H),8.01–7.94(m,3H),7.60–7.51(m,1H),7.44(t,J＝7.6Hz,2H),7.02(d,J＝8.8Hz,1H),5.57(s,2H),4.24(s,2H),4.14(d,J＝5.6Hz,2H),4.07(s,3H),3.55–3.40(m,4H),2.31(t,J＝7.2Hz,2H),1.96(quin,J＝6.8Hz,2H),1.14(t,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 ):δ198.2,171.2,164.2,160.3,139.9,136.8,135.5,133.6,131.2,131.1,129.4,128.8,128.5,122.0,111.8,56.7,45.8,42.4,42.0,39.2,30.4,28.0,14.2；HRMS(ESI):[M+H + ]Calcd for C 25 H 30 N 3 O 6 S + :500.1850；found:500.1841。
Example 46:
the procedure is as in example 1. 17.8mg of a yellow solid was obtained in 66% yield. M.p. =90-92 ℃; r is R f ＝0.22(PE/EA/DCM＝1/2/2)； 1 H NMR(400MHz,CDCl 3 ):δ8.38(s,1H),8.01–7.93(m,4H),7.69–7.60(m,1H),7.59–7.51(m,3H),7.43(t,J＝8.0Hz,2H),7.28(s,1H),7.23(d,J＝8.4Hz,1H),6.95(d,J＝2.4Hz,1H),6.91(dd,J＝8.0,2.4Hz,1H),4.34(s,2H),3.55(t,J＝6.4Hz,2H),3.51(s,2H),3.49–3.41(m,2H),3.17–3.08(m,2H),3.05(s,3H),2.18(t,J＝7.2Hz,2H),1.64(quin,J＝6.8Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ198.6,172.3,141.9,139.4,136.7,135.5,133.7,133.4,129.4,128.8,128.6,128.4,128.2,128.0,127.4,123.5,122.8,118.1,112.0,111.6,58.2,47.9,39.6,34.4,30.1,29.2(2C),29.0；HRMS(ESI):[M+H + ]Calcd for C 32 H 33 N 2 O 4 S + :541.2156；found:541.2146。
Example 47:
to a dry clean reaction tube equipped with a strong stirrer were added Shvo catalyst (0.001 mmol) and oxazolone (0.15 mmol), which was transferred to a glove box, followed by dioxane (2.0 mL), alicyclic amine (0.1 mmol) and 2, 2-trifluoroacetophenone (0.1 mmol). The reaction tube was sealed with a sealing film, and reacted at 130℃for 24 hours. After the completion of the reaction, 6.0M hydrochloric acid was added thereto, and the reaction was carried out at 70℃for 1.5 hours. Cooled to room temperature, the pH was adjusted to neutrality with 2.0M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel to give 15.2mg of a white solid in 70% yield. M.p. =84-86 ℃; r is R f ＝0.50(PE/EA/DCM＝3/1-2/1)； 1 H NMR(400MHz,CDCl 3 ):δ8.65(s,1H),7.91–7.81(m,2H),7.52–7.46(m,1H),7.43(t,J＝7.2Hz,2H),7.37–7.27(m,5H),7.24(t,J＝6.8Hz,1H),4.71(s,2H),3.42(t,J＝6.0Hz,2H),2.30(q,J＝7.2Hz,2H),1.79(quin,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ204.6,167.4,136.3,129.0,128.6,128.2,50.0,45.6,38.8,25.8,22.1；HRMS(ESI):[M+H + ]Calcd for C 13 H 16 NO 2 + :218.1176；found:218.1168。
Example 48:
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to a dry clean reaction tube equipped with a strong stirrer were added Shvo catalyst (0.001 mmol) and oxazolone (0.15 mmol), which was transferred to a glove box, followed by dioxane (2.0 mL), alicyclic amine (0.1 mmol) and 2, 2-trifluoroacetophenone (0.1 mmol). The reaction tube was sealed with a sealing film, and reacted at 130℃for 24 hours. After the reaction was completed, 48% by weight hydrobromic acid was added and the reaction was carried out at 70℃for 1 hour. Cooled to room temperature, the pH was adjusted to neutrality with 2.0M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel to give 13.8mg of a white solid in 52% yield. M.p. =52-53 ℃; r is R f ＝0.35(PE/EA＝2/1)； 1 H NMR(400MHz,CDCl 3 ):δ7.36–7.26(m,5H),4.71(1/2ABq,J＝14.4Hz,1H),4.52(1/2ABq,J＝14.4Hz,1H),3.26–3.11(m,2H),2.59–2.36(m,3H),2.22–2.10(m,1H),1.93–1.79(m,1H),1.79–1.54(m,3H),1.46–1.34(m,1H),1.24–1.14(m,1H)； 13 C NMR(101MHz,CDCl 3 ):δ202.7,166.1,136.3,128.9,128.5,128.1,49.8,48.7,41.9,41.4,36.6,30.7,27.5,23.7；；HRMS(ESI):[M+H + ]Calcd for C 16 H 20 NO 2 + :258.1489；found:258.148。
Example 49:
shvo catalyst (0.001 mmol) and oxazolone (0.3 mmol) were added to a dry clean reaction tube equipped with a vigorous stirring bar, transferred to a glove box, and added sequentiallyToluene (2.0 mL), alicyclic amine (0.1 mmol) and 2, 2-trifluoroacetophenone (0.1 mmol) were added. The reaction tube was sealed with a sealing film, and reacted at 100℃for 24 hours. After the completion of the reaction, 6.0M hydrochloric acid was added thereto, and the reaction was carried out at 70℃for 1.5 hours. Cooled to room temperature, the pH was adjusted to neutrality with 2.0M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel to give 10.5mg of a white solid in 38% yield. M.p. =95-97 ℃; r is R f ＝0.35(PE/EA＝3/1)； 1 H NMR(400MHz,CDCl 3 ):δ7.31–7.24(m,2H),7.24–7.19(m,1H),7.19–7.13(m,3H),6.86(d,J＝7.6Hz,1H),6.84–6.78(m,2H),4.34(s,2H),3.97(s,2H),3.51(t,J＝6.8Hz,2H),2.98(t,J＝7.2Hz,2H)； 13 C NMR(101MHz,CDCl 3 ):δ202.6,167.8,136.0,135.3,132.1,131.4,130.4,128.8,128.8,128.2,128.0,127.6,49.4,47.0,46.2,31.4；；HRMS(ESI):[M+H + ]Calcd for C 18 H 18 NO 2 + :280.1332；found:280.1324。

Claims (4)

1. A method for the ring-expanding molecule editing of a non-tensioned alicyclic amine, comprising the steps of:
under the protection gas, mixing alicyclic amine with oxazolone or gamma-butenolide, a catalyst, an additive and an organic solvent, and performing ring expansion reaction to obtain an azepine compound shown in a formula 3;
wherein R is 1 Is optionally substituted alkyl, cycloalkyl, benzyl, aryl or heteroaryl; when said R is 1 When the alkyl is optionally substituted, the alkyl is C1-C16 alkyl; when said R is 1 When the cycloalkyl is optionally substituted, the cycloalkyl is C3-C16 cycloalkyl; when said R is 1 When the benzyl is optionally substituted, the benzyl is C6-C16 benzyl; when said R is 1 When the aryl is optionally substituted aryl, the aryl is C6-C16 aryl; when said R is 1 Is optionalWhen the heteroaryl is substituted, the aryl is C3-C16 heteroaryl;
R 2 1,2, 3 or 4 substituents independently selected from: hydrogen, optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, nitro, C2-C16 ester, C1-C16 amide, C2-C16 boronate, C1-C16 acyl, C1-C16 aldehyde, C1-C16 cyano, C1-C16 amino, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, R 2 Any two of which may be linked to form a carbocyclic ring or a heterocyclic ring comprising one or more heteroatoms selected from O, N and S;
R 3 is selected from optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, optionally substituted C2-C16 alkenyl;
n is 1 or 2;
x is N or CH;
the "optional substitution" is unsubstituted or substituted with: C1-C16 alkyl, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, nitro, C2-C16 ester, C1-C16 acyl, C1-C16 cyano, C1-C16 aldehyde, C2-C16 boron ester, C1-C16 amide, C1-C16 amino, or optionally substituted C6-C16 aryl, C3-C16 heteroaryl, C5-C16 benzyl; the number of "substitutions" may not be limited.
2. The method according to claim 1, wherein,
the protective gas comprises nitrogen, argon, helium, neon or krypton;
and/or the organic solvent comprises one or more selected from methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile and 1, 3-dimethyl-2-imidazolidinone;
and/or the catalyst comprises a catalyst selected from Shvo catalyst (CAS: 104439-77-2), ru 3 (CO) 12 、RuCl 3 、[Ru(p-cymene)Cl 2 ] 2 、[IrCp * Cl] 2 、Vaska’s cat(CAS:14871-41-1)、Crabtree’s cat(CAS:64536-78-3)、Rh(COD) 2 Cl、Rh(COD) 2 BF 4 One or more of the following;
and/or the additive comprises one or more selected from acetophenone, 2-trifluoro acetophenone, cyclohexanone, norbornene and 1, 2-diphenyl acetylene;
and/or the molar ratio of the alicyclic amine to the oxazolone or gamma-butenolide is 5:1-1:5;
and/or the molar ratio of the compound shown as the formula 1 to the catalyst is 1:0.001-1:0.05;
and/or the molar concentration of the compound shown as the formula 1 in the organic solvent is 0.01-2.0M;
and/or the mol ratio of the compound shown as the formula 1 to the additive is 1:0.5-1:3;
and/or the reaction time is 8-72h;
and/or the reaction temperature is 50-150 ℃.
3. The method of manufacturing according to claim 1, comprising the steps of:
under the protection gas, mixing alicyclic amine with oxazolone, a catalyst, an additive and an organic solvent, adding acid into the reaction liquid after the ring-expanding reaction is finished, heating and hydrolyzing to synthesize a cyclic ketoamide compound, and obtaining the compound shown in the formula 4;
wherein R is 1 Is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl or optionally substituted heteroaryl; when said R is 1 When the alkyl is optionally substituted, the alkyl is C1-C16 alkyl; when said R is 1 When the cycloalkyl is optionally substituted, the cycloalkyl is C3-C16 cycloalkyl; when said R is 1 When the benzyl is optionally substituted, the benzyl is C6-C16 benzyl; when said R is 1 When the aryl is optionally substituted aryl, the aryl is C6-C16 aryl; when said R is 1 In the case of optionally substituted heteroaryl, the aryl is a C3-C16 heteroaryl;
R 2 1,2, 3 or 4 substituents independently selected from: hydrogen, optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, nitro, C2-C16 ester, C1-C16 amide, C2-C16 boronate, C1-C16 acyl, C1-C16 aldehyde, C1-C16 cyano, C1-C16 amino, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, R 2 Any two of which may be linked to form a carbocyclic ring or a heterocyclic ring comprising one or more heteroatoms selected from O, N and S;
R 3 is selected from optionally substituted C1-C16 alkyl, optionally substituted C3-C16 cycloalkyl, optionally substituted C6-C16 benzyl, optionally substituted C6-C16 aryl, optionally substituted C3-C16 heteroaryl, optionally substituted C1-C16 alkenyl;
n is 1 or 2;
the "optional substitution" is unsubstituted or substituted with: C1-C16 alkyl, C1-C16 alkyl-oxy, C1-C16 alkyl-S, halogen, nitro, C2-C16 ester, C1-C16 acyl, C1-C16 cyano, C1-C16 aldehyde, C2-C16 boron ester, C1-C16 amide, C1-C16 amino, or optionally substituted C6-C16 aryl, C3-C16 heteroaryl, C6-C16 benzyl; the number of "substitutions" may not be limited.
4. A process according to claim 3, wherein,
the protective gas comprises nitrogen, argon, helium, neon or krypton;
and/or the organic solvent comprises one or more selected from methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile and 1, 3-dimethyl-2-imidazolidinone;
and/or the catalyst comprises a catalyst selected from Shvo catalyst (CAS: 104439-77-2), ru 3 (CO) 12 、RuCl 3 、[Ru(p-cymene)Cl 2 ] 2 、[IrCp * Cl] 2 、Vaska’s cat(CAS:14871-41-1)、Crabtree’s cat(CAS:64536-78-3)、Rh(COD) 2 Cl、Rh(COD) 2 BF 4 One or more of the following;
and/or the additive comprises one or more selected from acetophenone, 2-trifluoro acetophenone, cyclohexanone, norbornene and 1, 2-diphenyl acetylene;
and/or the molar ratio of the alicyclic amine to the oxazolone or gamma-butenolide is 5:1-1:5;
and/or the molar ratio of the compound shown as the formula 1 to the catalyst is 1:0.001-1:0.05;
and/or the molar concentration of the compound shown as the formula 1 in the organic solvent is 0.01-2.0M;
and/or the mol ratio of the compound shown as the formula 1 to the additive is 1:0.5-1:3;
and/or the reaction time is 8-72h;
and/or, the reaction temperature is 50-150 ℃;
and/or the acid is one of trifluoroacetic acid (TFA), 4-8M (e.g., 6M) hydrochloric acid, 48% by mass hydrobromic acid.
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