A process for the preparation of a beta-ketoxime derivative

Abstract

The application discloses a preparation method of a beta-ketonitrile derivative, which comprises the following steps: reacting alpha-bromoacetonitrile, aryl boronic acid, bis(triphenylphosphine)nickel chloride, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid, acetic anhydride and sodium carbonate in C at 80 o for 20 hours, and after the reaction is completed, post-treatment is performed to obtain the beta-ketonitrile derivative. The preparation method uses alpha-bromoacetonitrile 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 beta-ketonitrile derivatives can be synthesized, and the method is convenient to operate and wide in practicability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a β-ketonitrile derivative. Background Technology

[0002] β-Ketonitriles, as an important and indispensable structural unit in organic and medicinal chemistry, play a crucial role in the synthesis of various heterocyclic compounds (such as pyrrole, furan, pyridine, thiophene, and thiazole) due to their excellent reactivity. Furthermore, many molecules with biological and pharmacological activities can also be prepared from them, such as anti-inflammatory agents, antidepressants, NHE-1 inhibitors, and antibacterial agents. Therefore, various synthetic strategies have been developed for the preparation of β-ketonitriles, with traditional methods including the acylation of alkyl nitriles under strongly basic conditions and the cyanation of cyanide ions with α-haloketones. However, these classic methods often have drawbacks, such as harsh reaction conditions, a narrow substrate range, and the use of toxic reagents. Therefore, the development of novel and efficient synthetic methods for β-ketonitriles is of great interest and urgently needed.

[0003] In recent years, palladium-catalyzed carbonylation reactions have proven to be a highly efficient method for synthesizing β-keto nitriles. In 2012, Lee and colleagues first reported the palladium-catalyzed carbonylation of aryl iodides with (trimethylsilyl)acetonitrile to prepare β-keto nitriles. Subsequently, the same research group and the Skrydstrup group developed two similar palladium-catalyzed carbonylation-decarboxylation tandem reactions. Furthermore, the Beller and Skrydstrup groups also proposed carbonylation methods for synthesizing α-substituted β-keto nitriles. Although these methods provide practical and efficient pathways for the synthesis of β-keto nitriles, they are still limited by the need for highly toxic carbon monoxide gas, organometallic reagents, and expensive transition metal catalysts. Therefore, exploring synthetic routes using alternative carbonyl sources and lower-cost catalysts remains a core objective in this field.

[0004] Nickel, as a naturally abundant and inexpensive metal, holds great potential in the field of catalysis. However, its application in carbonylation reactions is severely limited due to its strong affinity for carbon monoxide, which readily forms volatile and highly toxic nickel tetracarbonyl. To address this issue, previous studies have found that using low-pressure carbon monoxide gas or carbon monoxide substitutes is a feasible solution. Based on this, we developed a reaction for the nickel-catalyzed carbonylation synthesis of β-ketonitriles. Starting from α-bromoacetonitrile and arylboronic acid, and using formic acid as a carbon monoxide precursor, we synthesized various β-ketonitrile derivatives, opening a new synthetic route for the carbonylation preparation of β-ketonitriles. Summary of the Invention

[0005] This invention provides a method for preparing β-ketonitrile derivatives. The method is simple, uses inexpensive and readily available raw materials, is compatible with a variety of functional groups, and has good applicability. It uses α-bromoacetonitrile and arylboronic acid as raw materials and formic acid as the carbonyl source, providing a new direction for the synthesis of β-ketonitrile derivatives.

[0006] A method for preparing a β-ketonitrile derivative includes the following steps: reacting a nickel catalyst, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid, acetic anhydride, sodium carbonate, α-bromoacetonitrile, and arylboronic acid at 60-90 °C. o The reaction proceeds for 20-24 hours. After the reaction is complete, post-treatment is performed to obtain the β-ketonitrile derivative.

[0007] The structure of the α-bromoacetonitrile is shown in formula (II):

[0008] (II);

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

[0010] (III);

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

[0012] (I);

[0013] In formulas (I) to (III), R is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; Ar is naphthyl, thiophene, substituted or unsubstituted phenyl, wherein the substituent on the phenyl is C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy, trifluoromethyl or halogen.

[0014] The molar ratio of the nickel catalyst, 3,4,7,8-tetramethyl-1,10-phenanthroline, and sodium carbonate is 0.1:0.1:2.0.

[0015] The substituent on Ar is located in the para or meta position.

[0016] The reaction formula is as follows:

[0017]

[0018] In this invention, the optional post-processing steps include: filtration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding β-ketonitrile derivative. Column chromatography purification is a commonly used technique in this field.

[0019] Preferably, R is hydrogen, methyl, isopropyl, isobutyl, or cyclohexyl. Ar is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, tert-butyl, methoxy, phenyl, trifluoromethoxy, F, or Cl. In this case, the α-bromoacetonitrile and arylboronic acid are readily available, and the reaction yield is high.

[0020] The arylboronic acid used to prepare β-ketonitrile derivatives is inexpensive and widely available in nature. Preferably, the molar ratio of α-bromoacetonitrile:arylboronic acid:nickel catalyst is 1:1~2:0.05~0.1; more preferably, the molar ratio of α-bromoacetonitrile:arylboronic acid:nickel catalyst is 1:1.5:0.1.

[0021] Preferably, the reaction time is 20 hours. A reaction time that is too long increases the reaction cost, while a reaction that is too long makes it difficult to guarantee the completeness of the reaction.

[0022] Preferably, the reaction is carried out in ethylene glycol diethyl ether, and the amount of ethylene glycol diethyl ether used is sufficient to dissolve the raw material well. The amount of ethylene glycol diethyl ether used for 0.2 mmol of α-bromoacetonitrile is about 1~2 mL.

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

[0024] As a further preferred embodiment, the β-ketonitrile derivative is one of the compounds shown in formulas (I-1) to (I-5):

[0025] (I-1)

[0026] (I-2)

[0027] (I-3)

[0028] (I-4)

[0029] (I-5).

[0030] All of the above compounds are known compounds.

[0031] In the above preparation method, the arylboronic acid, formic acid, acetic anhydride, bis(triphenylphosphine)nickel chloride, 3,4,7,8-tetramethyl-1,10-phenanthroline and sodium carbonate are generally commercially available products that can be easily obtained from the market.

[0032] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0033] Using α-bromoacetonitrile and arylboronic acid as raw materials, the preparation method is simple, easy to operate, and requires minimal post-processing. The starting materials are inexpensive and readily available, the substrates have a wide range of functional group tolerances, and the reaction efficiency is high. Various β-ketonitrile derivatives can be synthesized according to practical needs, making it highly practical. Detailed Implementation

[0034] The present invention will be further described below with reference to specific embodiments.

[0035] Examples 1-15

[0036] According to the raw material ratio in Table 1, α-bromoacetonitrile (II), arylboronic acid (III), bis(triphenylphosphine)nickel chloride, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid, and the pre-reaction products of acetic anhydride and sodium carbonate were added to a 15 mL sealed tube. Then, ethylene glycol diethyl ether (2 mL) was added, and the mixture was stirred evenly. The reaction was carried out according to the reaction conditions in Table 2. After the reaction was completed, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding β-ketonitrile derivative (I). The reaction process is shown in the following formula:

[0037]

[0038] Table 1. Amounts of raw materials added in Examples 1-15

[0039]

[0040] Table 2

[0041]

[0042] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Ph represents phenyl, Me represents methyl, OMe represents methoxy, tBu represents tert-butyl, OCF3 represents trifluoromethoxy, and iPr represents isopropyl.

[0043] Structural confirmation data of the compounds prepared in Examples 1-5:

[0044] Nuclear magnetic resonance (NMR) of the β-ketonitrile derivative (I-1) prepared in Example 1 1 H NMR and 13 The C NMR detection data are as follows:

[0045] (I-1)

[0046] 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.4 Hz, 2H), 7.66 (t, J = 7.4Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 4.10 (s, 2H).

[0047] 13 C NMR (101 MHz, CDCl3) δ 187.1, 134.7, 134.2, 129.1, 128.4, 113.8,29.4.

[0048] Nuclear magnetic resonance (NMR) of the β-ketonitrile derivative (I-2) prepared in Example 2 1 H NMR and 13 The C NMR detection data are as follows:

[0049] (I-2)

[0050] 1 H NMR (400 MHz, CDCl3) δ 7.98 – 7.95 (m, 2H), 7.20 (t, J = 8.5 Hz, 2H), 4.08 (s, 2H).

[0051] 13 C NMR (101 MHz, CDCl3) δ 185.6, 166.6 (d, J = 258.1 Hz), 131.3 (d, J= 9.7 Hz), 130.7 (d, J = 2.8 Hz), 116.4 (d, J = 22.2 Hz), 113.6, 29.4.

[0052] Nuclear magnetic resonance (NMR) of the β-ketonitrile derivative (I-3) prepared in Example 3 1 H NMR and 13 The C NMR detection data are as follows:

[0053] (I-3)

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.5Hz, 2H), 7.63 (d, J = 7.1 Hz, 2H), 7.51 – 7.42 (m, 3H), 4.12 (s, 2H).

[0055] 13 C NMR (101 MHz, CDCl3) δ 186.6, 147.3, 139.1, 132.8, 129.0, 128.7,127.6, 127.2, 113.9, 29.4.

[0056] Nuclear magnetic resonance (NMR) of the β-ketonitrile derivative (I-4) prepared in Example 4 1 H NMR and 13 The C NMR detection data are as follows:

[0057] (I-4)

[0058] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.4Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 4.39 (q, J = 7.2 Hz, 1H), 1.64 (d, J = 7.2Hz, 3H).

[0059] 13 C NMR (101 MHz, CDCl3) δ 190.7, 134.5, 133.6, 129.1, 128.8, 118.1,33.7, 14.9.

[0060] Nuclear magnetic resonance (NMR) of the β-ketonitrile derivative (I-5) prepared in Example 5 1 H NMR and 13 The C NMR detection data are as follows:

[0061] (I-5).

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.3 Hz, 2H), 7.65 (t, J = 7.4Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 4.29 (d, J = 5.9 Hz, 1H), 2.13 – 2.06 (m,1H), 1.86 – 1.75 (m, 4H), 1.36 – 1.15 (m, 6H).

[0063] 13C NMR (101 MHz, CDCl3) δ 191.0, 134.5, 134.3, 129.1, 128.6, 116.5,47.0, 38.9, 31.8, 29.3, 25.9, 25.6, 25.4。

Claims

1. A method for preparing a β-ketonitrile derivative, characterized in that, The process includes the following steps: reacting a nickel catalyst, ligand, formic acid, acetic anhydride, base, α-bromoacetonitrile, and arylboronic acid at 60-90 °C. o C. The reaction is carried out for 20-24 hours. After the reaction is complete, post-treatment is performed to obtain the β-ketonitrile derivative. The structure of the α-bromoacetonitrile is shown in formula (II): ； The structure of the arylboronic acid is shown in formula (III): ； The structure of the β-ketonitrile derivative is shown in formula (I): ； In formulas (I) to (III), R is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; Ar is naphthyl, thiophene, substituted or unsubstituted phenyl, wherein the substituent on the phenyl is C1-C4 alkyl, C1-C4 alkoxy, phenyl, cyano, trifluoromethoxy, trifluoromethyl or halogen.

2. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, Ar is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, tert-butyl, methoxy, phenyl, trifluoromethoxy, F or Cl.

3. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, R can be hydrogen, methyl, isopropyl, isobutyl or cyclohexyl.

4. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, In molar amounts, the ratio of α-bromoacetonitrile: arylboronic acid: formic acid: acetic anhydride: nickel catalyst: ligand: base is 1:1~2: 10~15: 10~15:0.05~0.1: 0.05~0.1:1.5~2.

5. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, The reaction was carried out using ethylene glycol diethyl ether as a solvent.

6. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, The nickel catalyst is bis(triphenylphosphine)nickel chloride.

7. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, The ligand is 3,4,7,8-tetramethyl-1,10-phenanthroline.

8. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, The alkali mentioned is sodium carbonate.

9. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, The formic acid and acetic anhydride are first pre-reacted to form the product formic acid and acetic anhydride, and then added to the reaction system for further reaction.

10. The method for preparing the β-ketonitrile derivative according to claim 1, characterized in that, The β-ketonitrile derivative is one of the compounds shown in formulas (I-1) to (I-5): 。

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