Process for the preparation of 2-pyrrolidone derivatives

Abstract

The application discloses a preparation method of 2-pyrrolidone derivatives, which comprises the following steps: N-allyl bromoacetamide, aryl boronic acid, bis(triphenylphosphine) nickel dichloride, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid, acetic anhydride and sodium carbonate are reacted at 80 DEG C for 16 hours; after the reaction is completed, post-treatment is performed to obtain the 2-pyrrolidone derivatives. The preparation method uses N-allyl bromoacetamide and aryl boronic acid as reactants, uses formic acid as a carbonyl source, has mild reaction conditions, simple operation, a wide functional group tolerance range of a substrate and high reaction efficiency. According to actual needs, a plurality of 2-pyrrolidone derivatives can be synthesized, the operation is convenient, and the practicability of the method is widened.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-pyrrolidone derivatives. BACKGROUND

[0002] 2-pyrrolidone is an important N-heterocyclic compound, which exists in a large number of natural products, bioactive molecules and drug 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, which has good antibacterial activity. (-)-Clausenamide is an active alkaloid isolated from the leaves of Clausena lansium (Lour.) skeels, which has good Aβ 25-35 aggregation inhibitory activity and has good neuroprotective activity. The compound is also a promising candidate for the treatment of Alzheimer's disease. Brivaracetam is one of the main anticonvulsants, which has been used as an auxiliary therapy for the treatment of partial-onset epilepsy. 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, the radical cyclization / coupling reaction has gradually become one of the most useful and effective methods for the synthesis of such compounds in recent years (ACS Catal. 2021, 11, 4263-4270). Although these transformations have been widely used in this field, it is still necessary to explore more efficient and direct synthetic strategies to prepare 2-pyrrolidone derivatives containing various functional groups.

[0003] In the past few decades, transition metal-catalyzed carbonylation reactions have made remarkable advantages in the preparation of carbonyl-containing compounds and have attracted widespread attention in the academic and industrial fields (Chem. Soc. Rev. 2020, 49, 3187-3210). In general, noble metals such as palladium, rhodium and ruthenium are commonly used catalysts in carbonylation reactions due to their excellent reactivity. However, the high price of these noble metals limits their application in industrial production. Therefore, it is necessary to develop the application of inexpensive metals in carbonylation reactions. Nickel, as a rich and low-cost metal, can be used in various chemical transformations. However, the study of nickel catalysts in carbonylation reactions is still very few, and one of the main reasons is the formation of toxic and volatile Ni(CO)4, which will reduce the reactivity of the nickel catalyst. In order to avoid this problem, the use of low-pressure CO gas or alternative carbonyl sources can provide a good choice. Therefore, considering the development prospects of nickel-catalyzed carbonylation reactions and the important biological activity of 2-pyrrolidone, it has a very broad development prospect to develop simple and efficient carbonylation reactions to synthesize 2-pyrrolidone derivatives.

[0004] Based on this, we developed a nickel-catalyzed carbonylation cyclization reaction to synthesize 2-pyrrolidone derivatives. The reaction starts from simple N-allyl bromoacetamide and aryl boronic acid compounds, with formic acid as the carbonyl source, to synthesize a variety of 2-pyrrolidone derivatives. The reaction opens up a new synthetic route for nickel-catalyzed carbonylation to construct 2-pyrrolidone derivatives. SUMMARY

[0005] The present application provides a preparation method of 2-pyrrolidone derivatives, which has simple steps, cheap and readily available reaction raw materials, can be compatible with a variety of functional groups, and has good reaction applicability. The aryl boronic acid is used as a raw material and a promoter, and the formic acid is used as a carbonyl source, which provides a new direction for the synthesis of 2-pyrrolidone derivatives.

[0006] A preparation method of 2-pyrrolidone derivatives, comprising 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 aryl boronic acid at 60-90°C for 12-20 hours, and after the reaction is complete, the 2-pyrrolidone derivative is obtained by post-treatment.

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

[0008]

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

[0010]

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

[0012]

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

[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 substituents on Ar is para or ortho, and the position of the substituents on Ar' is para.

[0016] The reaction formula is as follows:

[0017]

[0018] In the present application, the optional post-treatment process includes filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding 2-pyrrolidone derivative. The column chromatography purification is a common technique in the art.

[0019] As a preferred embodiment, Ar is a substituted or unsubstituted phenyl group, and the substituents on the phenyl group are one or more of methyl, tert-butyl, methoxy, methylenedioxy, or Br. Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, and the substituents on the phenyl group are methyl, methoxy, formyl, or F. In this case, the N-allyl bromoacetamide and aryl boronic acid are readily available, and the reaction yield is high.

[0020] The aryl boronic acid used to prepare the 2-pyrrolidone derivative is inexpensive and widely available in nature. As a preferred embodiment, the molar ratio of N-allyl bromoacetamide: aryl boronic acid: nickel catalyst is 1:1-2:0.05-0.1. As a further preferred embodiment, the molar ratio of N-allyl bromoacetamide: aryl boronic acid: nickel catalyst is 1:1.5:0.1.

[0021] As a preferred embodiment, the reaction time is 16 hours. A longer reaction time increases the cost of the reaction, and on the contrary, it is difficult to ensure the completion of the reaction.

[0022] As a preferred embodiment, the reaction is carried out in tetrahydrofuran. The amount of tetrahydrofuran used is sufficient to dissolve the raw materials. For 0.2 mmol of N-allyl bromoacetamide, the amount of tetrahydrofuran used is about 1-2 mL.

[0023] As a preferred embodiment, the nickel catalyst is bis(triphenylphosphine)nickel dichloride. Among the various nickel catalysts, bis(triphenylphosphine)nickel dichloride is relatively inexpensive, and the use of bis(triphenylphosphine)nickel dichloride as a catalyst has a high reaction efficiency.

[0024] As a further preferred embodiment, 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 aryl boronic 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 present application has the following advantages:

[0028] The preparation method is simple, easy to operate, and simple in post-processing. The starting raw materials are cheap and easy to obtain. The functional groups of the substrates have a wide tolerance range. The reaction efficiency is high. Various 2-pyrrolidone derivatives can be synthesized according to actual needs, and the practicability is relatively strong. DETAILED DESCRIPTION

[0029] The application will be further described below in combination with specific examples.

[0030] Examples 1-15

[0031] According to the raw material ratio in Table 1, N-allyl bromoacetamide (II), aryl boronic acid (III), a pre-reaction product of bis (triphenylphosphine) nickel dichloride, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid and acetic anhydride, sodium carbonate, and then tetrahydrofuran (2 mL) were added in a 15 mL sealed tube. The mixture was stirred uniformly, and the reaction was carried out according to the reaction conditions in Table 2. After the reaction was completed, filtration, silica gel sample mixing, and column chromatography purification were carried out to obtain the corresponding 2-pyrrolidone derivative (I). The reaction process is shown in the following formula:

[0032]

[0033] Table 1: Raw material addition amount of examples 1-15

[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 phenyl, Me is methyl, OMe is methoxy, and tBu is tert-butyl.

[0039] The structure confirmation data of the compounds prepared in examples 1-5 are as follows:

[0040] The nuclear magnetic resonance (H NMR and C NMR) detection data of the 2-pyrrolidone derivative (I-1) prepared from example 1 are as follows: 1 H NMR and 13 C NMR) detection data:

[0041]

[0042] 1H NMR (400 MHz, CDCI3) δ 7.88 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 8.1 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.11 (t, 1 H), 4.11 (dd, J = 9.8, 7.5 Hz, 1 H), 3.44 (t, J = 9.3 Hz, 1 H), 3.25 (dd, J = 17.0, 3.4 Hz, 1 H), 2.99 (dd, J = 17.0, 10.7 Hz, 1 H), 2.83 - 2.73 (m, 1 H), 2.43 (s, 3H), 1.30 (s, 3H), 1.15 (s, 3H).

[0043] 13 C NMR (101 MHz, CDCI3) δ 198.0, 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 2-pyrrolidone derivative (1-2) prepared from Example 2 was detected by H NMR (400 MHz, CDCI3) and C NMR. 1 H NMR and 13 C NMR) detection data:

[0045]

[0046] 1 H NMR (400 MHz, CDCI3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2H), 4.10 (dd, J = 9.8, 7.6 Hz, 1 H), 3.88 (s, 3H), 3.43 (t, J = 9.3 Hz, 1 H), 3.22 (dd, J = 16.8, 3.4 Hz, 1 H), 2.96 (dd, J = 16.8, 10.7 Hz, 1 H), 2.80 - 2.72 (m, 1 H), 1.29 (s, 3H), 1.15 (s, 3H).

[0047] 13 C NMR (101 MHz, CDCI3) δ 196.9, 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 nuclear magnetic resonance (1H NMR and 13C NMR) detection data of the 2-pyrrolidone derivative (I-3) prepared from Example 3 are as follows: 1 H NMR and 13 C NMR) detection data are as follows:

[0049]

[0050] 1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 4.15 (dd, J = 9.8, 7.6 Hz, 1H), 3.45 (t, J = 9.2 Hz, 1H), 3.32 (dd, J = 17.6, 3.4 Hz, 1H), 3.07 (dd, J = 17.6, 10.6 Hz, 1H), 2.84 - 2.77 (m, 1H), 1.31 (s, 3H), 1.17 (s, 3H).

[0051] 13 C NMR (101 MHz, CDCl3) δ 197.8, 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 nuclear magnetic resonance (1H NMR and 13C NMR) detection data of the 2-pyrrolidone derivative (I-3) prepared from Example 3 are as follows: 1 H NMR and 13 C NMR) detection data are as follows:

[0053]

[0054] 1H NMR (400 MHz, CDC13) δ 7.87 (d, J = 8.2 Hz, 2H), 7.58 (dd, J = 9.1, 4.8 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 4.06 (dd, J = 9.7, 7.6 Hz, 1H), 3.40 (t, J = 9.3 Hz, 1H), 3.24 (dd, J = 17.1, 3.4 Hz, 1H), 2.97 (dd, J = 17.1, 10.8 Hz, 1H), 2.78 - 2.71 (m, 1H), 2.41 (s, 3H), 1.28 (s, 3H), 1.13 (s, 3H).

[0055] 13 C NMR (101 MHz, CDC13) δ 198.1, 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 2-pyrrolidone derivative (I-5) prepared from Example 5 was detected by nuclear magnetic resonance (H NMR and C NMR) to have the following data: 1 H NMR and 13 C NMR) detection data:

[0057]

[0058] 1 H NMR (400 MHz, CDC13) δ 7.87 (d, J = 8.2 Hz, 2H), 7.58 (dd, J = 9.1, 4.8 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 4.06 (dd, J = 9.7, 7.6 Hz, 1H), 3.40 (t, J = 9.3 Hz, 1H), 3.24 (dd, J = 17.1, 3.4 Hz, 1H), 2.97 (dd, J = 17.1, 10.8 Hz, 1H), 2.78 - 2.71 (m, 1H), 2.41 (s, 3H), 1.28 (s, 3H), 1.13 (s, 3H).

[0059] 13C NMR (101 MHz, CDC13) δ 197.9, 178.1, 159.20 (d, J = 243.8 Hz),, 144.4, 135.6, 135.5, 134.0, 129.4, 128.0, 121.23 (d, J = 7.9 Hz), 115.28 (d, J = 22.3 Hz), 51.1, 44.1, 38.5, 37.0, 23.8, 21.6, 19.2.

Claims

1. A process for the preparation of a 2-pyrrolidone derivative, characterized in that, comprising the steps of: a nickel catalyst, a ligand, formic acid, acetic anhydride, a base, N - allyl bromoacetamide and arylboronic acid at 60-90 o C for 12-20 hours, after the reaction is complete, the post-processing to obtain the said 2-pyrrolidone derivatives; The N - the structure of allyl bromoacetamide is shown in formula (II): (II); The structure of the aryl boronic acid is shown in formula (III): (III); The structure of the 2-pyrrolidone derivative is shown in formula (I): （I）； In formula (I)-(III), Ar is substituted or unsubstituted phenyl, and the substituent group on the phenyl is one or more of C1-C4 alkyl, C1-C4 alkoxy, methylenedioxy or halogen; Ar' is naphthyl, substituted or unsubstituted phenyl, and the substituent group on the phenyl is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 acyl or halogen; The nickel catalyst is bis(triphenylphosphine)nickel dichloride. The ligand is 3,4,7,8-tetramethyl-1,10-phenanthroline. The base is sodium carbonate.

2. The process for the preparation of 2-pyrrolidone derivatives according to claim 1, characterized in that, Ar is substituted or unsubstituted phenyl, and the substituent group on the phenyl 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, wherein: Ar' is naphthyl, substituted or unsubstituted phenyl, and the substituent group on the phenyl is methyl, methoxy, formyl or F.

4. The method for preparing a 2-pyrrolidone derivative according to claim 1, wherein: in terms of molar amounts, N - allyl bromoacetamide: arylboronic 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, wherein: The reaction is carried out in tetrahydrofuran as a solvent.

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