CN112694430A - Preparation method of 1, 5-dihydro-2H-pyrrole-2-ketone compound - Google Patents

Preparation method of 1, 5-dihydro-2H-pyrrole-2-ketone compound Download PDF

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CN112694430A
CN112694430A CN202011529210.1A CN202011529210A CN112694430A CN 112694430 A CN112694430 A CN 112694430A CN 202011529210 A CN202011529210 A CN 202011529210A CN 112694430 A CN112694430 A CN 112694430A
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dihydro
pyrrol
pyrrole
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CN112694430B (en
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应俊
吴小锋
乐铮杰
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones

Abstract

The invention discloses a preparation method of a 1, 5-dihydro-2H-pyrrole-2-ketone compound, which comprises the following steps: adding a palladium catalyst, a ligand, a carbon monoxide substitute, a base, propynylamine and benzyl chloride into an organic solvent, reacting for 24-48 hours at 100-120 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 1, 5-dihydro-2H-pyrrole-2-ketone compound. The preparation method has the advantages of simple operation, cheap and easily obtained starting raw materials, high reaction efficiency, good substrate compatibility, one-step high-efficiency and rapid synthesis of the 1, 5-dihydro-2H-pyrrole-2-ketone compound, convenient operation and widened practicability of the method.

Description

Preparation method of 1, 5-dihydro-2H-pyrrole-2-ketone compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 1, 5-dihydro-2H-pyrrole-2-ketone compound.
Background
1, 5-dihydro-2H-pyrrol-2-one is an important structural framework and is widely present in natural products and bioactive molecules. For example, Althiomycin exhibits significant antibacterial activity (J.Antibiot. 1974,27, 894-896.); glimepiride is an effective hypoglycemic agent (Tetrahedron Lett. 2003,44, 4853-4855.); isomalyngamide A has potential anti-cancer activity (J.Nat.Prod.2000, 63, 1599-1602.).
Figure BDA0002851722010000011
Carbonylation provides an important method for directly and efficiently synthesizing carbonyl compounds (chem. Rev.2019,119, 2090-2127). However, the synthesis of 1, 5-dihydro-2H-pyrrol-2-one skeletons based on carbonylation has few reports and is not widely applied at present, but has great application potential and needs to be studied deeply.
Based on the above, we developed a method for efficiently and rapidly synthesizing 1, 5-dihydro-2H-pyrrol-2-one compounds by palladium-catalyzed bis-carbonylation using propynylamine and benzyl chloride as starting materials.
Disclosure of Invention
The invention provides a preparation method of a 1, 5-dihydro-2H-pyrrole-2-ketone compound, which has simple steps, can be compatible with various functional groups and has good reaction applicability.
A method for preparing a 1, 5-dihydro-2H-pyrrol-2-one compound, comprising the steps of: adding a palladium catalyst, 1' -bis (diphenylphosphino) ferrocene, triethylamine, 1,3, 5-tricarboxylic acid phenol ester, propynylamine and benzyl chloride into an organic solvent, reacting for 24-48 hours at 100-120 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 1, 5-dihydro-2H-pyrrole-2-ketone compound;
the structure of the propargylamine is shown as a formula (II):
Figure BDA0002851722010000021
R1is H, C1～C6Alkyl radical, C1～C6Alkoxy, phenyl, halogen or trifluoromethyl;
the structure of the benzyl chloride is shown as a formula (III):
Figure BDA0002851722010000022
R2is H, C1～C6Alkyl radical, C1～C6Alkoxy, halogen, -CN or trifluoromethyl;
the structure of the 1, 5-dihydro-2H-pyrrole-2-ketone compound is shown as the formula (I):
Figure BDA0002851722010000023
the specific reaction formula is as follows:
Figure BDA0002851722010000024
during the reaction, palladium insertion into benzyl chloride to form benzyl palladium intermediate may be first performed, and carbon monoxide released from phenol 1,3, 5-tricarboxylate is inserted into benzyl palladium intermediate to form acyl palladium intermediate. And secondly, adding the acyl palladium intermediate and propynylamine to obtain a five-membered ring palladium intermediate. Subsequently, a second carbon monoxide molecule is inserted to form a six-membered ring palladium intermediate. Finally, reductive elimination occurs to give the 1, 5-dihydro-2H-pyrrol-2-one compound.
In the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally purifying by column chromatography to obtain the corresponding 1, 5-dihydro-2H-pyrrole-2-ketone compound, wherein the purification by column chromatography is a technical means commonly used in the field.
Preferably, R1、R2Independently H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl, the reaction yield is high.
Preferably, the reaction time is 24-48 hours, and the reaction time is short and is difficult to ensure the completeness of the reaction.
In the present invention, the organic solvent is preferably acetonitrile, in which case various raw materials can be converted into products at a high conversion rate.
The amount of the organic solvent is enough to dissolve the raw material, and the amount of the organic solvent used for 1mmol of the propynylamine is about 4 mL.
Preferably, the catalyst is palladium acetate, and the reaction efficiency is higher in a plurality of palladium catalysts.
The molar ratio of the palladium acetate, the 1,1' -bis (diphenylphosphino) ferrocene, the 1,3, 5-tricarboxylic acid phenol ester to the triethylamine is 0.1:0.2:3: 2;
further preferably, the 1, 5-dihydro-2H-pyrrol-2-one compound is one of compounds represented by the following formulae (I-1) to (I-5):
Figure BDA0002851722010000031
Figure BDA0002851722010000041
in the above preparation method, the palladium acetate, 1' -bis (diphenylphosphino) ferrocene and benzyl chloride are generally commercially available products and can be conveniently obtained from the market, and the propynylamine can be quickly synthesized from corresponding iodobenzene and terminal alkynylamine.
Compared with the prior art, the invention has the beneficial effects that: the preparation method is easy to operate, and the post-treatment is simple and convenient; the initial raw materials for the reaction are cheap and easy to obtain, the tolerance range of the substrate functional groups is wide, the reaction efficiency is high, the 1, 5-dihydro-2H-pyrrole-2-ketone compound is efficiently and quickly synthesized in one step, and the practicability is high.
Detailed Description
The invention is further described with reference to specific examples.
Adding palladium acetate, 1' -bis (diphenylphosphino) ferrocene, triethylamine, 1,3, 5-tricarboxylic acid phenol ester, propynylamine (II), benzyl chloride (III) and 2mL of an organic solvent into a 35mL Schlenk tube according to the raw material ratio shown in Table 1, uniformly mixing and stirring, reacting for 24 hours according to the reaction conditions shown in Table 2, filtering, stirring by silica gel, and purifying by column chromatography to obtain a corresponding 1, 5-dihydro-2H-pyrrole-2-ketone compound (I), wherein the reaction process is shown as the following formula:
Figure BDA0002851722010000042
TABLE 1 raw material addition amounts of examples 1 to 15
Figure BDA0002851722010000051
TABLE 2
Figure BDA0002851722010000052
In tables 1 and 2, T is the reaction temperature, T is the reaction time, Me is methyl, tBu is tert-butyl, OMe is methoxy, and MeCN is acetonitrile.
Examples 1-5 Structure confirmation data for the partial compounds prepared:
nuclear magnetic resonance of 1, 5-dihydro-2H-pyrrol-2-one compound (I-1) obtained in example 1: (1H NMR、13C NMR) and High Resolution (HRMS) detection data:
Figure BDA0002851722010000061
1H NMR(400MHz,CDCl3):δ＝7.83–7.80(m,2H),7.39–7.35(m,4H),7.34–7.28(m, 1H),7.20(s,1H),7.01–6.98(m,2H),4.45(s,2H),3.89(s,3H),1.65(s,6H).
13C NMR(100MHz,CDCl3):δ＝171.3,169.3,160.2,151.1,134.6,131.9,129.7,128.6, 128.4,126.8,122.9,114.0,63.3,55.3,44.1,24.0.
HRMS(ESI):[M+H+]calcd for C21H22NO3 +,336.1594；found,336.1613.
nuclear magnetic resonance of 1, 5-dihydro-2H-pyrrol-2-one compound (I-2) obtained in example 2: (1H NMR、13C NMR) and High Resolution (HRMS) detection data:
Figure BDA0002851722010000062
1H NMR(400MHz,CDCl3):δ＝7.87–7.81(m,2H),7.40–7.28(m,5H),7.26(s,1H), 7.16(t,J＝8.7Hz,2H),4.44(s,2H),1.67(s,6H).
13C NMR(100MHz,CDCl3):δ＝171.3,168.9,163.2(d,JC-F＝249.1),152.5,134.4,131.6, 129.7,129.2(d,JC-F＝8.1),128.5,126.9,126.5,115.7(d,JC-F＝21.6),63.5,44.2,23.9. HRMS(ESI):[M+H+]calcd for C20H19FNO2 +,324.1394；found,324.1411.
nuclear magnetic resonance of 1, 5-dihydro-2H-pyrrol-2-one Compound (I-3) prepared in example 3: (1H NMR、13C NMR) and High Resolution (HRMS) detection data:
Figure BDA0002851722010000071
1H NMR(400MHz,CDCl3):δ＝7.85(dd,J＝8.0,1.3Hz,2H),7.51–7.43(m,3H),7.30 (s,1H),7.27(d,J＝8.0Hz,2H),7.20(d,J＝7.9Hz,2H),4.42(s,2H),2.39(s,3H),1.67(s, 6H).
13C NMR(100MHz,CDCl3):δ＝171.6,169.0,152.9,136.4,132.6,131.4,130.4,129.6, 129.2,129.1,128.6,127.3,63.4,43.8,23.9,21.1.
HRMS(ESI):[M+H+]calcd for C21H22NO2 +,320.1645；found,320.1664.
nuclear magnetic resonance of 1, 5-dihydro-2H-pyrrol-2-one compound (I-4) obtained in example 4: (1H NMR、13C NMR) and High Resolution (HRMS) detection data:
Figure BDA0002851722010000072
1H NMR(400MHz,CDCl3):δ＝7.83(dd,J＝8.0Hz,2H),7.51–7.43(m,3H),7.37– 7.28(m,5H),4.41(s,2H),1.66(s,6H).
13C NMR(100MHz,CDCl3):δ＝170.9,169.0,153.0,132.9,132.8,132.5,131.1,130.2, 129.1,128.6,128.6,127.3,63.5,43.5,23.9.
HRMS(ESI):[M+H+]calcd for C20H19ClNO2 +,340.1099；found,340.1115.
nuclear magnetic resonance of 1, 5-dihydro-2H-pyrrol-2-one compound (I-5) obtained in example 5: (1H NMR、13C NMR) and High Resolution (HRMS) detection data:
Figure BDA0002851722010000081
1H NMR(400MHz,CDCl3):δ＝7.85(dd,J＝8.0Hz,2H),7.65(d,J＝8.1Hz,2H),7.47 (m,5H),7.34(s,1H),4.52(s,2H),1.69(s,6H).
13C NMR(100MHz,CDCl3):δ＝170.4,169.1,153.1,138.6,132.5,130.2,129.2(q,JC-F＝ 32.3Hz),129.2,128.7,127.3,125.4,125.3,124.3(q,JC-F＝271.9Hz),63.6,44.0,23.8. HRMS(ESI):[M+H+]calcd for C21H19F3NO2 +,374.1362；found,374.1375。

Claims (9)

1. a method for producing a 1, 5-dihydro-2H-pyrrol-2-one compound, comprising the steps of: adding a palladium catalyst, a ligand, alkali, a carbon monoxide substitute, propynylamine and benzyl chloride into an organic solvent, reacting for 24-48 hours at 100-120 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 1, 5-dihydro-2H-pyrrole-2-ketone compound;
the structure of the propargylamine is shown as a formula (II):
Figure FDA0002851722000000011
R1is H, C1～C6Alkyl radical, C1～C6Alkoxy, phenyl, halogen or trifluoromethyl;
the structure of the benzyl chloride is shown as a formula (III):
Figure FDA0002851722000000012
R2is H, C1～C6Alkyl radical, C1～C6Alkoxy, halogen, -CN or trifluoromethyl;
the structure of the 1, 5-dihydro-2H-pyrrole-2-ketone compound is shown as the formula (I):
Figure FDA0002851722000000013
2. the process for producing 1, 5-dihydro-2H-pyrrol-2-one compounds according to claim 1, wherein R is1、R2Independently H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl.
3. The process for producing a 1, 5-dihydro-2H-pyrrol-2-one compound according to claim 1, wherein the molar ratio of propynylamine: benzyl chloride: alkali: palladium catalyst: ligand: the carbon monoxide substitute is 1: 1-1.2: 2-2.4: 0.1-0.2: 2-3.
4. The process for producing a 1, 5-dihydro-2H-pyrrol-2-one compound according to claim 1, wherein the organic solvent is acetonitrile.
5. The method for producing a 1, 5-dihydro-2H-pyrrol-2-one compound according to claim 1, wherein the palladium catalyst is palladium acetate.
6. The method for producing a 1, 5-dihydro-2H-pyrrol-2-one compound according to claim 1, wherein the ligand is 1,1' -bis (diphenylphosphino) ferrocene.
7. The method for producing a 1, 5-dihydro-2H-pyrrol-2-one compound according to claim 1, wherein the base is triethylamine.
8. The method of claim 1, 5-dihydro-2H-pyrrol-2-one compounds wherein the carbon monoxide substitute is phenol 1,3, 5-tricarboxylate.
9. The process for producing a 1, 5-dihydro-2H-pyrrol-2-one compound according to claim 1, wherein the 1, 5-dihydro-2H-pyrrol-2-one compound is one of compounds represented by the formulae (I-1) to (I-5):
Figure FDA0002851722000000021
Figure FDA0002851722000000031
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Publication number Priority date Publication date Assignee Title
CN115246786A (en) * 2021-11-30 2022-10-28 浙江理工大学 Preparation method of indole compound or benzoxazine compound

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* Cited by examiner, † Cited by third party
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JUN YING ET AL.: "Palladium-catalyzed double carbonylation of propargylamines and arylhalides to access 1-aroyl-3-aryl-1,5-dihydro-2H-pyrrol-2-ones", 《ORG.CHEM. FRONT.》 *
LIN HE等: "A convenient palladium-catalyzed carbonylative synthesis of 4(3H)-quinazolinones from 2-bromoformanilides and organo nitros with Mo(CO)6 as a multiple promoter", 《GREEN CHEM.》 *
ZHENGKAI CHEN等: "Palladium-catalyzed three-component carbonylative synthesis of 2-(trifluoromethyl)quinazolin-4(3H)-ones from trifluoroacetimidoyl chlorides and amines", 《ORGANIC CHEMISTRY FRONTIERS》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115246786A (en) * 2021-11-30 2022-10-28 浙江理工大学 Preparation method of indole compound or benzoxazine compound
CN115246786B (en) * 2021-11-30 2023-10-03 浙江理工大学 Preparation method of indole compound or benzoxazine compound

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