A preparation method of polycyclic 3,4-dihydro-2(1H)-quinolinone compound

Abstract

The invention discloses a method for preparing a polycyclic 3,4-dihydro-2(1H)-quinolinone compound, comprising the steps of: adding 1,7-ene ynes, a palladium catalyst, a ligand, perfluoroiodobutane, carbonyl molybdenum, a base and an additive to an organic solvent, reacting at 100-120° C. for 24-48 hours, and after the reaction is complete, post-processing to obtain the polycyclic 3,4-dihydro-2(1H)-quinolinone compound. The preparation method is simple to operate, has low-cost and readily available starting materials, high reaction efficiency, good substrate compatibility, and can rapidly prepare polycyclic 3,4-dihydro-2(1H)-quinolinone compounds, with relatively strong practicality.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a polycyclic 3,4-dihydro-2(1H)-quinolinone compound. Background Art

[0002] Polycyclic 3,4-dihydro-2(1H)-quinolinone is an important chemical skeleton that is widely present in various drug molecules and natural product molecules, such as the TLR4 antagonist Euodenine A (J.Med.Chem.2014,57,1252-1275), acetylcholinesterase inhibitors and insecticidal antibiotic Yaequinolone J1 (Org.Lett.2005,7,5701-5704).

[0003]

[0004] Despite the great importance of the polycyclic 3,4-dihydro-2(1H)-quinolinone skeleton, the synthesis of polycyclic 3,4-dihydro-2(1H)-quinolinone compounds based on the tandem reaction of free radical cyclization and carbonylation has not been reported, and has great application prospects.

[0005] Based on this, we developed a method to efficiently synthesize polycyclic 3,4-dihydro-2(1H)-quinolinone compounds using 1,7-enyne as the starting material and a transition metal palladium-catalyzed free radical cyclization and carbonylation tandem reaction. Summary of the Invention

[0006] The present invention provides a method for preparing a polycyclic 3,4-dihydro-2(1H)-quinolinone compound. The preparation method has simple steps, is compatible with various functional groups, has good reaction applicability, and can be expanded to the gram level, providing the possibility for large-scale industrial production and application.

[0007] A method for preparing a polycyclic 3,4-dihydro-2(1H)-quinolinone compound comprises the following steps: adding 1,7-enyne, a palladium catalyst, a ligand, perfluoroiodobutane, carbonyl molybdenum, a base, and an additive to an organic solvent, reacting at 100-120° C. for 24-48 hours, and after the reaction is complete, post-treating to obtain the polycyclic 3,4-dihydro-2(1H)-quinolinone compound;

[0008] The structure of the 1,7-enyne is shown in formula (II):

[0009]

[0010] The structure of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound is shown in formula (I):

[0011]

[0012] R 1 is a C1-C4 alkyl group, a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from one or more of a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogen group; R 2 It is a C1~C4 alkyl group.

[0013] 1,7-Enyne: perfluoroiodobutane: carbonyl molybdenum: palladium catalyst: ligand: base: additive = 1:2:2:0.15:0.3:2:2.

[0014] The reaction formula is as follows:

[0015]

[0016] The reaction likely begins with the addition of a fluorine radical to the carbon-carbon double bond of 1,7-enyne to form a radical intermediate. This radical then undergoes intramolecular addition to a palladium(I) species to form an alkenylpalladium(II) intermediate. Subsequently, CH activation forms a five-membered cyclic palladium(II) intermediate. The CO released from the molybdenum carbonyl coordinates with the five-membered cyclic palladium(II) intermediate and undergoes migratory insertion to form a six-membered acylpalladium(II) intermediate. Finally, reductive elimination occurs to yield the polycyclic 3,4-dihydro-2(1H)-quinolinone compound.

[0017] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding polycyclic 3,4-dihydro-2(1H)-quinolinone compound. Column chromatography purification is a commonly used technical means in this field.

[0018] As a preference, R 1 is n-butyl, substituted or unsubstituted phenyl, wherein the substituent on the phenyl group is selected from methyl, ethyl, methoxy, F, Cl or Br; R 2 is methyl, ethyl, n-propyl or n-butyl. The yield of the reaction is high.

[0019] Preferably, the reaction time is 24 to 48 hours. A shorter reaction time makes it difficult to ensure complete reaction.

[0020] In the present invention, preferably, the organic solvent is trifluorotoluene. In this case, various raw materials can be converted into products at a higher conversion rate.

[0021] The amount of the organic solvent used is sufficient to dissolve the raw materials well. The amount of organic solvent used for 1 mmol of 1,7-enyne is about 5 mL.

[0022] Preferably, the catalyst is bistriphenylphosphine palladium dichloride, which has a higher reaction efficiency among many palladium catalysts.

[0023] As a further preference, the polycyclic 3,4-dihydro-2(1H)-quinolinone compound is one of the compounds represented by formula (I-1) to formula (I-5):

[0024]

[0025]

[0026] In the above preparation method, the bistriphenylphosphine palladium dichloride and bis(2-diphenylphosphinophenyl) ether are generally commercially available products and can be easily obtained from the market; the 1,7-enyne can be quickly synthesized from the corresponding o-iodoaniline, terminal alkyne, acyl chloride and other raw materials.

[0027] Compared with the prior art, the beneficial effects of the present invention are reflected in: the preparation method is easy to operate, the post-processing is simple, the reaction starting materials are cheap and easily available, the substrate is highly designable, the substrate functional group tolerance range is wide, the reaction efficiency is high, and polycyclic 3,4-dihydro-2(1H)-quinolinone compounds can be quickly synthesized, and the practicability is strong. DETAILED DESCRIPTION

[0028] The present invention will be further described below with reference to specific embodiments.

[0029] According to the raw material ratio in Table 1, bistriphenylphosphine palladium dichloride, bis(2-diphenylphosphinophenyl) ether, cesium carbonate, sodium pivalate, 1,7-enyne (II), perfluoroiodobutane, carbonyl molybdenum and 2 mL of organic solvent were added to a 15 mL Schlenk tube, mixed and stirred evenly, and reacted for 24 hours according to the reaction conditions in Table 2. The mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding polycyclic 3,4-dihydro-2(1H)-quinolinone compound (I). The reaction process is shown in the following formula:

[0030]

[0031] Table 1 Amount of raw materials added in Examples 1 to 15

[0032]

[0033] Table 2

[0034]

[0035]

[0036] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, Et is ethyl, OMe is methoxy, n Pr is n-propyl, n Bu is n-butyl, and PhCF3 is trifluorotoluene.

[0037] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0038] The nuclear magnetic resonance (NMR) of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound (I-1) prepared in Example 1 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0039]

[0040] 1 H NMR (400MHz, CDCl3) δ7.31(t,J=7.7Hz,1H),7.25–7.20(m,3H),7.08(d,J=7.7Hz,2H),7.01(d ,J=8.2Hz,1H),3.41(s,3H),3.20–3.03(m,1H),2.52–2.39(m,1H),2.39(s,3H),1.67(s,3H).

[0041] 13 C NMR (100MHz, CDCl3) δ196.3,171.5,153.4,138.5,133.6,131.7,129.7,129.2, 128.4,128.1,127.2,118.8,118.1,43.9,39.1(t,J=19.2Hz),29.3,27.6,21.4.

[0042] HRMS (ESI-TOF) Calcd.for C 25 H 19 F9NO2 + [M+H] + :536.1267; found:536.1263.

[0043] The nuclear magnetic resonance (NMR) of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound (I-2) prepared in Example 2 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0044]

[0045] 1H NMR (400MHz, CDCl3) δ7.33–7.28(m,1H),7.22(d,J=7.0Hz,1H),7.12(d,J=8.6Hz,2H),7.01(d,J=8.2Hz, 1H), 6.96 (d, J = 8.7Hz, 2H), 3.84 (s, 3H), 3.40 (s, 3H), 3.22–3.06 (m, 1H), 2.52–2.37 (m, 1H), 1.68 (s, 3H).

[0046] 13 C NMR (100MHz, CDCl3) δ196.5,171.6,159.9,153.5,133.6,132.1,131.7,131.2,128 .5,127.3,123.2,118.9,118.2,114.1,55.4,44.0,39.0(t,J=19.0Hz),29.5,29.4.

[0047] HRMS (ESI-TOF) Calcd.for C 25 H 19 F9NO3 + [M+H] + :552.1216; found:552.1218.

[0048] The nuclear magnetic resonance (NMR) of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound (I-3) prepared in Example 3 was 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0049]

[0050] 1 H NMR (400MHz, CDCl3) δ7.41–7.32(m,3H),7.27–7.22(m,2H),7.20(s,1H),7.10–7.07(m,1H ),7.04(d,J=8.3Hz,1H),3.42(s,3H),3.24–3.08(m,1H),2.45–2.30(m,1H),1.67(s,3H).

[0051] 13C NMR (100MHz, CDCl3) δ195.4,171.4,154.6,134.7,134.0,133.2,132.3,130.8,130. 1,129.9,128.9,128.4,128.2,126.8,119.1,118.4,44.1,39.2(t,J=19.0Hz),29.5.

[0052] HRMS (ESI-TOF) Calcd.for C 24 H 16 ClF9NO2 + [M+H] + :556.0720; found:556.0723.

[0053] The nuclear magnetic resonance (NMR) of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound (I-4) prepared in Example 4 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0054]

[0055] 1 H NMR (400MHz, CDCl3) δ7.21(t,J=7.7Hz,1H),7.11(d,J=7.1Hz,1H),6.93(d,J=8.2Hz,1H),3.50–3.39(m,1H),3.38(s, 3H),2.83–2.60(m,1H),2.39–2.30(m,1H),2.26–2.15(m,1H),1.69(s,3H),1.55–1.34(m,4H),0.93(t,J=7.1Hz,3H).

[0056] 13 C NMR (100MHz, CDCl3) δ197.5,171.6,150.8,132.8,132.6,130.9,128.8,127.9 ,118.7,117.7,43.6,39.4(t,J=19.5Hz),31.1,29.5,28.4,24.9,23.4,14.0.

[0057] HRMS (ESI-TOF) Calcd.for C 22 H 21 F9NO2 + [M+H] + :502.1423; found:502.1420.

[0058] The nuclear magnetic resonance (NMR) of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound (I-5) prepared in Example 5 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0059]

[0060] 1 H NMR(400MHz, CDCl3)δ7.46–7.36(m,3H),7.32(t,J=7.7Hz,1H),7.24–7.17(m,3H),7.01(d,J=8.3Hz,1H),4.2 1–4.06(m,1H),3.95–3.78(m,1H),3.24–3.00(m,1H),2.48–2.29(m,1H),1.67(s,3H),1.24(t,J=7.0Hz,3H).

[0061] 13 C NMR (100MHz, CDCl3) δ196.1,171.1,153.9,132.8,132.2,131.9,131.3,130.0,128 .9,128.7,128.6,127.3,118.9,118.1,43.9,39.1(t,J=19.2Hz),37.3,29.5,12.1.

[0062] HRMS (ESI-TOF) Calcd.for C 25 H 19 F9NO2 + [M+H] + :536.1267;found:536.1265.

Claims

1. A method for preparing a polycyclic 3,4-dihydro-2(1H)-quinolinone compound, characterized in that: The method comprises the following steps: adding 1,7-enyne, a palladium catalyst, a ligand, perfluoroiodobutane, carbonyl molybdenum, a base and an additive into an organic solvent, reacting at 100-120° C. for 24-48 hours, and after the reaction is complete, post-treating to obtain the polycyclic 3,4-dihydro-2(1H)-quinolinone compound; The structure of the 1,7-enyne is shown in formula (II): The structure of the polycyclic 3,4-dihydro-2(1H)-quinolinone compound is shown in formula (I): R 1 is a C1-C4 alkyl group, a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from one or more of a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogen group; R 2 is a C1-C4 alkyl group; The organic solvent is trifluorotoluene; The palladium catalyst is bistriphenylphosphine palladium dichloride; The ligand is bis(2-diphenylphosphinophenyl) ether; The base is cesium carbonate; The additive is sodium pivalate.

2. The method for preparing the polycyclic 3,4-dihydro-2(1H)-quinolinone compound according to claim 1, wherein: R 1 is n-butyl, substituted or unsubstituted phenyl, wherein the substituent on the phenyl group is selected from methyl, ethyl, methoxy, F, Cl or Br; R 2 is methyl, ethyl, n-propyl or n-butyl.

3. The method for preparing the polycyclic 3,4-dihydro-2(1H)-quinolinone compound according to claim 1, wherein: In terms of molar amount, 1,7-enyne: perfluoroiodobutane: carbonyl molybdenum: palladium catalyst: ligand: base: additive = 1: 2-2.2: 2-2.2: 0.15-0.20: 0.3-0.4: 2-2.2: 2-2.

2.

4. The method for preparing the polycyclic 3,4-dihydro-2(1H)-quinolinone compound according to claim 1, wherein: The polycyclic 3,4-dihydro-2(1H)-quinolinone compound is one of the compounds represented by formula (I-1) to formula (I-5):

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