Preparation method of 2-pyrrolidone derivative

Abstract

The invention discloses a preparation method of a 2-pyrrolidone derivative, which comprises the following steps: reacting N-allyl bromoacetamide, arylboronic acid, bis (triphenylphosphine) nickel dichloride, 3, 4, 7, 8-tetramethyl-1, 10-phenanthroline, formic acid, acetic anhydride and sodium carbonate at 80 DEG C for 16 hours, and after the reaction is completed, performing post-treatment to obtain the 2-pyrrolidone derivative. According to the preparation method, N-allyl bromoacetamide and arylboronic acid are taken as reactants, formic acid is taken as a carbonyl source, the reaction condition is mild, the operation is simple, the tolerance range of substrate functional groups is wide, and the reaction efficiency is high. Various 2-pyrrolidone derivatives can be synthesized according to actual needs, so that the method is convenient to operate, and the practicability of the method is widened.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a 2-pyrrolidone derivative. Background Art

[0002] 2-Pyrrolidone is an important N-heterocyclic compound that exists in a large number of natural products, bioactive molecules and pharmaceutical compounds, and has attracted widespread attention due to its excellent biological activity (Angew. Chem., Int. Ed. 2003, 42, 355–357). (-)-Pramanicin is a natural product found in fungi with good antibacterial activity. (-)-Clausenamide is an active alkaloid isolated from the leaves of Clausena lansium (Lour.) skeels, which has a strong antibacterial effect on Aβ. 25-35 It has good neuroprotective activity. The compound is also a promising candidate for the treatment of Alzheimer's disease. Brivaracetam is one of the main anticonvulsant drugs and has been used as an adjuvant therapy for the treatment of partial seizures. In addition, 2-pyrrolidone is widely used as an important building block in organic synthesis and drug design. Therefore, the synthesis of 2-pyrrolidone has attracted widespread attention from chemists. Among them, free radical cyclization / coupling reactions have gradually become one of the most useful and effective methods for synthesizing such compounds in recent years (ACS Catal. 2021, 11, 4263-4270). Although these transformations have been widely used in this field, there is still a need to explore more efficient and direct synthetic strategies to prepare 2-pyrrolidone derivatives with a variety of functional groups.

[0003] In the past few decades, transition metal-catalyzed carbonylation reactions have achieved significant advantages in the preparation of carbonyl compounds and have received widespread attention in academia and industry (Chem. Soc. Rev. 2020, 49, 3187-3210). In general, noble metals such as palladium, rhodium and ruthenium have become commonly used catalysts in carbonylation reactions due to their excellent reactivity. However, the high prices of these noble metals limit their application in industrial production. Therefore, it is necessary to develop the application of cheap metals in carbonylation reactions. Nickel, as an abundant and inexpensive metal, can be used in a variety of chemical transformations. However, research on nickel catalysts in carbonylation reactions is still rare, one of the main reasons being the formation of toxic and volatile Ni(CO)4, which reduces the reactivity of nickel catalysts. To avoid this problem, the use of low-pressure CO gas or alternative carbonyl sources can provide a good option. Therefore, considering the development prospects of nickel-catalyzed carbonylation reactions and the important biological activity of 2-pyrrolidone, the development of simple and efficient carbonylation reactions to synthesize 2-pyrrolidone derivatives has a very broad development prospect.

[0004] Based on this, we developed a nickel-catalyzed carbonylation cyclization reaction to synthesize 2-pyrrolidone derivatives. Starting from the simple and readily available N-allyl bromoacetamide and arylboronic acid compounds, the reaction used formic acid as the carbonyl source to synthesize a variety of 2-pyrrolidone derivatives. This reaction has opened up a new synthetic route for the nickel-catalyzed carbonylation to construct 2-pyrrolidone derivatives. Summary of the invention

[0005] The invention provides a preparation method of 2-pyrrolidone derivatives. The preparation method has simple steps, and reaction raw materials are cheap and readily available, and are compatible with various functional groups and have good reaction applicability. Aryl boronic acid is used as a raw material and a promoter, and formic acid is used as a carbonyl source, thereby providing a new direction for the synthesis of 2-pyrrolidone derivatives.

[0006] A method for preparing a 2-pyrrolidone derivative comprises the following steps: reacting a nickel catalyst, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid, acetic anhydride, sodium carbonate, N-allyl bromoacetamide and arylboronic acid at 60-90° C. for 12-20 hours, and after the reaction is complete, post-treating to obtain the 2-pyrrolidone derivative;

[0007] The structure of the N-allyl bromoacetamide is shown in formula (II):

[0008]

[0009] The structure of the arylboronic acid is shown in formula (III):

[0010]

[0011] The structure of the 2-pyrrolidone derivative is shown in formula (I):

[0012]

[0013] In formulas (I) to (III), Ar is a substituted or unsubstituted phenyl group, the substituent on the phenyl group is one or more of a C1-C4 alkyl group, a C1-C4 alkoxy group, a methylenedioxy group or a halogen group, and Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, the substituent on the phenyl group is a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 acyl group or a halogen group.

[0014] The molar ratio of the nickel catalyst, 3,4,7,8-tetramethyl-1,10-phenanthroline and sodium carbonate is 0.1:0.1:1.5;

[0015] The position of the substituent on Ar is para or ortho; the position of the substituent on Ar' is para.

[0016] The reaction formula is as follows:

[0017]

[0018] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding 2-pyrrolidone derivatives. Column chromatography purification is a commonly used technical means in the art.

[0019] Preferably, Ar is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is one or more of methyl, tert-butyl, methoxy, methylenedioxy or Br. Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is methyl, methoxy, formyl or F. In this case, the N-allyl bromoacetamide and arylboronic acid are easily obtained, and the yield of the reaction is high.

[0020] The aryl boronic acid used to prepare the 2-pyrrolidone derivative is relatively cheap and widely exists in nature. Preferably, on a molar basis, the ratio of N-allyl bromoacetamide: aryl boronic acid: nickel catalyst is 1:1-2:0.05-0.1; and further preferably, on a molar basis, the ratio of N-allyl bromoacetamide: aryl boronic acid: nickel catalyst is 1:1.5:0.1.

[0021] Preferably, the reaction time is 16 hours. Too long a reaction time will increase the reaction cost, and conversely it will be difficult to ensure the completeness of the reaction.

[0022] Preferably, the reaction is carried out in tetrahydrofuran, and the amount of tetrahydrofuran used is sufficient to dissolve the raw materials well. The amount of tetrahydrofuran used for 0.2 mmol of N-allyl bromoacetamide is about 1-2 mL.

[0023] Preferably, the nickel catalyst is bis(triphenylphosphine)nickel dichloride. Among many nickel catalysts, bis(triphenylphosphine)nickel dichloride is relatively cheap, and the reaction efficiency is higher when bis(triphenylphosphine)nickel dichloride is used as a catalyst.

[0024] As a further preference, the 2-pyrrolidone derivative is one of the compounds represented by formula (I-1) to formula (I-5):

[0025]

[0026] In the above preparation method, the arylboric acid, formic acid, acetic anhydride, bis(triphenylphosphine)nickel dichloride, 3,4,7,8-tetramethyl-1,10-phenanthroline and sodium carbonate are generally commercially available products and can be easily obtained from the market.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] Using N-allyl bromoacetamide and arylboronic acid as raw materials, the preparation method is simple, easy to operate, and the post-treatment is simple. The starting materials for the reaction are cheap and easy to obtain, the substrate functional group tolerance range is wide, and the reaction efficiency is high. A variety of 2-pyrrolidone derivatives can be synthesized according to actual needs, and the practicability is strong. DETAILED DESCRIPTION

[0029] The present invention is further described below in conjunction with specific embodiments.

[0030] Examples 1 to 15

[0031] According to the raw material ratio in Table 1, N-allyl bromoacetamide (II), arylboronic acid (III), bis(triphenylphosphine)nickel dichloride, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid acetic anhydride and sodium carbonate, which are the products of the pre-reaction of formic acid and acetic anhydride, are added to a 15 mL sealed tube, and then tetrahydrofuran (2 mL) is added, mixed and stirred evenly, and reacted according to the reaction conditions in Table 2. After the reaction is completed, the mixture is filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding 2-pyrrolidone derivative (I). The reaction process is shown in the following formula:

[0032]

[0033] Table 1 Amount of raw materials added in Examples 1 to 15

[0034]

[0035]

[0036] Table 2

[0037]

[0038] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is a phenyl group, Me is a methyl group, OMe is a methoxy group, and tBu is a tert-butyl group.

[0039] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0040] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0041]

[0042] 1H NMR (400MHz, CDCl3) δ7.88(d,J=7.9Hz,2H),7.65(d,J=8.8Hz,2H),7.34(t,J=8.1Hz,2H),7.29(d,J=7.9Hz,2H),7.11(t,1H),4.11(dd,J=9.8,7.5Hz ,1H),3.44(t,J=9.3Hz,1H),3.25(dd,J=17.0,3.4Hz,1H),2.99(dd,J=17. 0,10.7Hz,1H),2.83–2.73(m,1H),2.43(s,3H),1.30(s,3H),1.15(s,3H).

[0043] 13 C NMR (101MHz, CDCl3) δ198.0,178.3,144.4,139.5,134.1,129.4,128.7,128.1,124.3,119.6,50.9,44.3,38.6,37.2,23.9,21.6,19.3.

[0044] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0045]

[0046] 1 H NMR(400MHz, CDCl3) δ7.96(d,J=8.8Hz,2H),7.65(d,J=8.3Hz,2H),7.34(t,J =7.9Hz,2H),7.11(t,J=7.4Hz,1H),6.96(d,J=8.8Hz,2H),4.10(dd,J=9.8,7 .6Hz,1H),3.88(s,3H),3.43(t,J=9.3Hz,1H),3.22(dd,J=16.8,3.4Hz,1H), 2.96(dd,J=16.8,10.7Hz,1H),2.80–2.72(m,1H),1.29(s,3H),1.15(s,3H).

[0047] 13 C NMR (101MHz, CDCl3) δ196.9,178.3,163.7,139.5,130.3,129.6,128.7,124.2,119.5,113.8,55.5,50.9,44.3,38.6,36.9,23.9,19.2.

[0048] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0049]

[0050] 1 H NMR (400MHz, CDCl3) δ10.13(s,1H),8.13(d,J=8.2Hz,2H),8.01(d,J=8.2Hz, 2H),7.65(d,J=7.9Hz,2H),7.36(t,J=8.0Hz,2H),7.13(t,J=7.4Hz,1H),4.1 5(dd,J=9.8,7.6Hz,1H),3.45(t,J=9.2Hz,1H),3.32(dd,J=17.6,3.4Hz,1H) ,3.07(dd,J=17.6,10.6Hz,1H),2.84–2.77(m,1H),1.31(s,3H),1.17(s,3H).

[0051] 13 C NMR (101MHz, CDCl3) δ197.8,191.4,178.0,140.6,139.4,139.3,129.9,128.8,128.5,124.4,119.7,50.9,44.3,38.4,38.0,24.0,19.4.

[0052] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0053]

[0054] 1H NMR (400MHz, CDCl3) δ7.88(d,J=8.2Hz,2H),7.58(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H),7.29(d,J=8.1Hz,2H),4.10(dd,J=9.8,7.5Hz,1H),3. 42(t,1H),3.25(dd,J=17.0,3.5Hz,1H),2.99(dd,J=17.0,10.7Hz,1H), 2.80–2.73(m,1H),2.43(s,3H),1.30(s,9H),1.29(s,3H),1.14(s,3H).

[0055] 13 C NMR (101MHz, CDCl3) δ198.1,178.1,147.1,144.3,136.9,134.1,129.4,128.1,125.5,119.2,50.9,44.2,38.6,37.2,34.3,31.3,23.9,21.6,19.3.

[0056] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0057]

[0058] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.2Hz,2H),7.58(dd,J=9.1,4.8Hz,2H),7.27(d,J=8.1Hz,2H),7.00(t,J=8.7Hz,2H),4.06(dd,J=9.7,7.6Hz,1H ),3.40(t,J=9.3Hz,1H),3.24(dd,J=17.1,3.4Hz,1H),2.97(dd,J=17.1,10.8Hz,1H),2.78–2.71(m,1H),2.41(s,3H),1.28(s,3H),1.13(s,3H).

[0059] 13C NMR(101MHz,CDCl3)δ197.9,178.1,159.20(d,J=243.8Hz),,144.4,135.6,135.5,134.0,129.4,128.0,121.23(d,J=7.9Hz),115.28(d,J=22.3Hz),51.1,44.1,38.5,37.0,23.8,21.6,19.2。

Claims

1. A method for preparing a 2-pyrrolidone derivative, characterized in that: The method comprises the following steps: reacting a nickel catalyst, a ligand, formic acid, acetic anhydride, a base, N-allyl bromoacetamide and an aromatic boronic acid at 60 to 90° C. for 12 to 20 hours, and after the reaction is complete, post-treating to obtain the 2-pyrrolidone derivative; The structure of the N-allyl bromoacetamide is shown in formula (II): The structure of the arylboronic acid is shown in formula (III): The structure of the 2-pyrrolidone derivative is shown in formula (I): In formulas (I) to (III), Ar is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is one or more of a C1-C4 alkyl group, a C1-C4 alkoxy group, a methylenedioxy group or a halogen; Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 acyl group or a halogen.

2. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: Ar is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is one or more of methyl, tert-butyl, methoxy, methylenedioxy or Br.

3. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group, a methoxy group, a formyl group or F.

4. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: In terms of molar amount, N-allyl bromoacetamide: aryl boronic acid: formic acid: acetic anhydride: nickel catalyst: ligand: base = 1: 1-2: 5-10: 5-10: 0.05-0.1: 0.05-0.1: 1.5-2.

5. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: Tetrahydrofuran was used as the reaction solvent.

6. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: The nickel catalyst is bis(triphenylphosphine)nickel dichloride.

7. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: The ligand is 3,4,7,8-tetramethyl-1,10-phenanthroline.

8. The method for preparing a 2-pyrrolidone derivative according to claim 1, characterized in that: The alkali is sodium carbonate.

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