Method for preparing substituted imidazole by taking acyl chloride as raw material

Abstract

The invention discloses a method for preparing substituted imidazole by taking acyl chloride as a raw material, belongs to the technical field of synthesis of fine chemicals, and aims to solve the problems that the raw material structure is complicated, the source is limited, the raw material needs to be prepared in advance and the cost is low in the existing method for synthesizing substituted imidazole. The reaction conditions are harsh, the reaction time is long, and a transition metal catalyst needs to be used. The method comprises the following steps: synthesizing 2-substituted-4-dimethylamino-5-cyano imidazole from acyl chloride, tetramethylguanidine and a cyaniding reagent at a certain temperature and under an alkaline condition; according to the method disclosed by the invention, the 2-substituted-4-dimethylamino-5-cyano imidazole is synthesized in one step by taking the acyl chloride as the substrate, the reaction rate is greatly accelerated by selecting various acyl chlorides and alkali and synergistically and reasonably controlling the ratio of various substances, efficient synthesis of the 2-substituted-4-dimethylamino-5-cyano imidazole is realized, and the substrate is good in adaptability and high in yield. The method has wide application prospects in the fields of chemistry, biology, medicine and the like.

Description

Technical Field

[0001] This invention relates to the field of fine chemical synthesis technology, and more specifically to a method for preparing substituted imidazoles using acyl chlorides as raw materials. Background Technology

[0002] Imidazoles are a class of heterocyclic compounds with a five-membered ring structure consisting of three carbon atoms and two nitrogen atoms. Many naturally occurring compounds, such as histidine, contain an imidazole ring in their structure. Imidazole derivatives are major components of many bioactive molecules, including drugs, pesticides, and fungicides. In medicinal chemistry, imidazoles are important pharmacophores due to their ability to interact with biological targets such as enzymes, receptors, and ion channels, and have been used to develop various drugs, including antifungal drugs, histamine receptor antagonists, and antiviral drugs. Therefore, developing efficient methods for preparing substituted imidazoles is of great significance in organic synthesis.

[0003] Currently, the synthesis of substituted imidazoles mainly uses amines, amidines, nitriles, and isonitriles as raw materials. For example, 2-aryl-4,5-dicarboxynitrile imidazole can be constructed from 2,3-diaminomaleonitrile and aromatic aldehydes using a one-pot method with cerium ammonium nitrate / nitric acid (CAN / NA) as a catalyst (Polycyclic Aromatic Compounds, 2021, 41(7): 1506-1514.). Although this method does not require the addition of an extra solvent, it also has the problem of using a metal catalyst. 4-hydroxyalkyl-substituted imidazoles and 5-hydroxyalkyl-substituted imidazoles can be selectively prepared from amidine, acetylacetonate, and water under different catalytic systems (The Journal of Organic Chemistry, 2020, 85(23): 14954-14962.). This method has the advantage of strong functional group adaptability. Trisubstituted imidazoles can be synthesized from α-azidochalcone and nitrile under mild conditions via TMSOTf catalysis (ChemistrySelect, 2019, 4(10):). (2954-2958.) This method has a relatively good yield, but it requires 2 hours of reaction under microwave, which consumes a lot of energy, and the substrates containing azide are limited to substituted benzene rings; 1,4,5-trisubstituted imidazoles are synthesized by silver-catalyzed cyclization of isocyanate and nitro ketone under N2 atmosphere (European Journal of Organic Chemistry, 2021, 2021(6): 964-968.). This method is faster, but the substituted imidazoles obtained have an inherent substituent at the 1-position N. Although there are a few examples reported in the existing literature of preparing substituted imidazoles from acyl chloride as starting material (ComptesRendus Chimie, 2012, 15(9): 784-792; Journal of Medicinal Chemistry, 2024, 68(1): 421-447), they are based on multiple step-by-step reactions, and the acyl chloride does not directly participate in the cyclization of the imidazole ring in the reaction.

[0004] Existing methods for synthesizing imidazoles suffer from one or more drawbacks, such as complex raw material structures, limited sources requiring pre-preparation, harsh reaction conditions, long reaction times, and the need for transition metal catalysts, which are costly and environmentally polluting. This invention aims to provide a one-step method for synthesizing substituted imidazoles from structurally simple acyl chlorides. This method requires no pre-preparation of raw materials, operates under mild reaction conditions, has a short reaction time, and does not use metal catalysts. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the present invention provides a method for preparing substituted imidazoles using acyl chlorides as raw materials.

[0006] The technical solution of the present invention is as follows: The purpose of this invention is to provide a green and efficient method for preparing 2-substituted-4-dimethylamino-5-cyanoimidazolium from acyl chloride as a raw material, the method comprising the following steps: 4-Dimethylamino-5-cyanoimidazole is prepared by dissolving tetramethylguanidine and cyaniding reagent in an organic solvent and stirring thoroughly for 30 min, then adding acyl chloride and reacting under certain temperature and alkaline conditions for a certain time.

[0007] Further specifying, the general structural formula of 4-dimethylamino-5-cyanoimidazole is:

[0008] In the formula, R represents phenyl, 4-Me-phenyl, 3-Me-phenyl, 2-Me-phenyl, 4-F-phenyl, 2-F-phenyl, 3-F-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 2-Cl-phenyl, 4-Br-phenyl, 3-Br-phenyl, 2-Br-phenyl, 4-CN- phenyl, 4-methoxy-phenyl, 4-tertiary butyl-phenyl, 4-nitro-phenyl, 2-thienyl, 2-furyl, 2-naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, aml y, isoamyl, hexyl, benzyl, phenethyl, chloromethyl, bromomethyl, iodomethyl, 4-pyridyl, 2-quinolyl, 1-piperidyl, 9-acridinyl, dichloromethyl, trichloromethyl, diphenyl.

[0009] Further specifying, the acyl chloride is benzoyl chloride, p-methylbenzoyl chloride, m-methylbenzoyl chloride, o-methylbenzoyl chloride, p-fluorobenzoyl chloride, m-fluorobenzoyl chloride, o-fluorobenzoyl chloride, p-chlorobenzoyl chloride, m-chlorobenzoyl chloride, o-chlorobenzoyl chloride, p-methoxybenzoyl chloride, p-tert-butylbenzoyl chloride, p-nitrobenzoyl chloride, p-bromobenzoyl chloride, m-bromobenzoyl chloride, o-bromobenzoyl chloride, p-cyanobenzoyl chloride, 2-thiophenecarboxyl chloride, 2-furancarboxyl chloride, 2 - Naphthoyl chloride, cyclopropionyl chloride, cyclobutylcarboxyl chloride, cyclopentylcarboxyl chloride, cyclohexyl chloride, trimethylacetyl chloride, propionyl chloride, n-butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, hexanoyl chloride, isohexanoyl chloride, heptanyl chloride, phenylacetyl chloride, phenylpropionyl chloride, chloroacetyl chloride, bromoacetyl chloride, iodoacetyl chloride, succinyl chloride, isonicoyl chloride, quinoline-2-carbonyl chloride, 1-piperidinyl chloride, 9-acrylyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, diphenylacetyl chloride.

[0010] Further specifying, the cyaniding agent is trimethylcyanosilane or acetone cyanohydrin.

[0011] Further specified, the amount of cyaniding reagent used is 2.0-4.0 times the equivalent of acyl chloride, and the amount of tetramethylguanidine used is 2.0-4.0 times the equivalent of acyl chloride.

[0012] Further specifying, the base is selected from DBU (1,8-diazabicycloundec-7-ene), sodium hydride, potassium tert-butoxide, tetramethylguanidine, DMAP (4-dimethylaminopyridine), N,N,N',N'-tetramethylethylenediamine, and 2,6-dimethylpyridine.

[0013] Furthermore, the amount of alkali used is 1.0-2.0 times the equivalent of acyl chloride.

[0014] Further specifying, the reaction temperature is 60-110 ℃.

[0015] The optimal reaction temperature is 80°C.

[0016] Further specifying, the solvent is selected from acetonitrile, N,N - Dimethylformamide, 1,4-dioxane, dimethyl sulfoxide, toluene.

[0017] The optimal solvent is acetonitrile.

[0018] Further limiting, the reaction time is 2.5-4 hours.

[0019] Further specifying, the yield of the substituted imidazole was 81.5%-93.5%.

[0020] The advantages of this invention compared to the prior art are: This invention utilizes structurally simple acyl chlorides as raw materials and low-toxicity, inexpensive trimethylcyanosilane or acetone cyanohydrin as cyaniding reagents. Under alkaline conditions, without the need for cumbersome anhydrous and oxygen-free operations, 2-substituted-4-dimethylamino-5-cyanoimidazole can be efficiently synthesized at a specific temperature. By selecting the appropriate alkaline and simultaneously controlling the rational proportions of each substance, side reactions are suppressed to the maximum extent, achieving the highly efficient synthesis of 2-substituted-4-dimethylamino-5-cyanoimidazole. Compared with conventional methods for synthesizing substituted imidazoles, this invention features a simple operation process, requires no prior preparation of raw materials, has mild reaction conditions, a short reaction time, and does not require a metal catalyst. 2-substituted-4-dimethylamino-5-cyanoimidazole can be synthesized in one step from inexpensive and readily available acyl chlorides. It also has a wide range of substrate applicability and strong application prospects in the fields of pharmaceuticals, pesticides, and functional materials preparation. Attached Figure Description

[0021] Figure 1 The 1H NMR spectrum of 2-phenyl-4-dimethylamino-5-cyanoimidazole (Example 1); Figure 2 The carbon NMR spectrum of 2-phenyl-4-dimethylamino-5-cyanoimidazole (Example 1); Figure 3 High-resolution mass spectra of 2-phenyl-4-dimethylamino-5-cyanoimidazole (Example 1); Figure 4 The infrared spectrum of 2-phenyl-4-dimethylamino-5-cyanoimidazole (Example 1); Figure 5 It is a single crystal structure of 2-o-chlorophenyl-4-dimethylamino-5-cyanoimidazole (Example 31). Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0023] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials, reagents, methods, and instruments used are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0024] The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used in the following embodiments, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0025] Example 1: Synthesis of 2-phenyl-4-dimethylamino-5-cyanoimidazole 2.0 mL of acetonitrile was first added to a flask equipped with a rotor. Then, 0.53 mL of trimethylcyanosilane and 0.36 mL of tetramethylguanidine were added dropwise to the reaction flask. The reaction temperature was 80 °C, and the mixture was stirred for 0.5 h. Then, 200 mg of benzoyl chloride and 0.35 mL of tetramethylguanidine were added dropwise to the reaction system. The reaction was monitored by TLC. After 3 h, the starting material spot disappeared. The mixture was diluted with water, extracted with ethyl acetate, and then washed with water and saturated brine. After drying with anhydrous magnesium sulfate, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (using n-hexane and ethyl acetate (volume ratio 1:1) as the mobile phase) to obtain 270.90 mg of 2-phenyl-4-dimethylamino-5-cyanoimidazole, a yellow solid powder, with a yield of 90.3%.

[0026] Product 2-phenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.90 (s,1H), 7.90 (s, 2H), 7.44 (s, 3H), 3.03 (s, 6H) ppm. 13 C NMR (75 MHz, Chloroform- d ) δ 158.04, 146.31, 129.78, 128.87, 128.57, 125.88, 117.80, 77.24, 39.51ppm. Example 2 The difference between this embodiment and Example 1 is that the cyaniding reagent used is replaced with acetone cyanohydrin instead of trimethylcyanosilane; the other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 255.3 mg, is a yellow solid powder with a yield of 85.1%.

[0027] Example 3 The difference between this example and Example 1 is that the base used is replaced with DBU instead of tetramethylguanidine; all other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 261.3 mg, is a yellow solid powder with a yield of 87.1%.

[0028] Example 4 The difference between this example and Example 1 is that the base added with the acyl chloride is replaced with sodium hydride instead of tetramethylguanidine; the other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 252.3 mg, is a yellow solid powder with a yield of 84.1%.

[0029] Example 5 The difference between this example and Example 1 is that the base added with the acyl chloride is replaced with potassium tert-butoxide instead of tetramethylguanidine; the other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 256.8 mg, is a yellow solid powder with a yield of 85.6%.

[0030] Example 6 The difference between this example and Example 1 is that the base added with the acyl chloride is replaced with DMAP instead of tetramethylguanidine; the other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 251.4 mg, is a yellow solid powder with a yield of 83.8%.

[0031] Example 7 The difference between this example and Example 1 is that the base added with the acyl chloride is replaced by N,N,N',N'-tetramethylethylenediamine instead of tetramethylguanidine; the other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 245.7 mg, is a yellow solid powder with a yield of 81.9%.

[0032] Example 8 The difference between this example and Example 1 is that the base added with the acyl chloride is replaced with 2,6-dimethylpyridine instead of tetramethylguanidine; the other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 241.8 mg, is a yellow solid powder with a yield of 80.6%.

[0033] Example 9 The difference between this embodiment and Embodiment 1 is that the solvent used is replaced with acetonitrile instead of... N,N - Dimethylformamide, with other steps and parameters the same as in Example 1. The resulting product, 256.8 mg, was a yellow solid powder with a yield of 85.6%.

[0034] Example 10 The difference between this example and Example 1 is that the solvent used is replaced with 1,4-dioxane instead of acetonitrile; all other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 246.9 mg, is a yellow solid powder with a yield of 82.3%.

[0035] Example 11 The difference between this example and Example 1 is that the solvent used is replaced with dimethyl sulfoxide instead of acetonitrile; all other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 254.4 mg, is a yellow solid powder with a yield of 84.8%.

[0036] Example 12 The difference between this example and Example 1 is that the solvent used is replaced with toluene instead of acetonitrile; all other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 260.1 mg, is a yellow solid powder with a yield of 86.7%.

[0037] Example 13 The difference between this example and Example 1 is that the reaction temperature is 60 °C, while the other steps and parameters are the same as in Example 1. The obtained product is 2-phenyl-4-dimethylamino-5-cyanoimidazole, 97.8 mg, with a yield of 32.6%.

[0038] Example 14 The difference between this example and Example 1 is that the reaction temperature is 70 °C, while the other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 210.9 mg, is a yellow solid powder with a yield of 70.3%.

[0039] Example 15 The difference between this embodiment and Example 1 is that the reaction temperature is 90 °C, while the other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 266.1 mg, is a yellow solid powder with a yield of 88.7%.

[0040] Example 16 The difference between this example and Example 1 is that the reaction temperature is 100 °C, while the other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 260.1 mg, is a yellow solid powder with a yield of 86.7%.

[0041] Example 17 The difference between this embodiment and Example 1 is that the reaction temperature is 110 °C, while the other steps and parameters are the same as in Example 1. The obtained product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 255.3 mg, is a yellow solid powder with a yield of 85.1%.

[0042] Example 18 The difference between this example and Example 1 is that the amount of trimethylcyanosilane used as the cyaniding reagent was adjusted to 0.36 mL (which is 2.0 equivalents of the substrate benzoyl chloride). All other steps and parameters are the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 228.9 mg, is a yellow solid powder with a yield of 76.3%.

[0043] Example 19 The difference between this example and Example 1 is that the amount of trimethylcyanosilane used as the cyaniding reagent was adjusted to 0.71 mL (equivalent to 4.0 times the substrate benzoyl chloride), while the other steps and parameters were the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 270.3 mg, was a yellow solid powder with a yield of 90.1%.

[0044] Example 20 The difference between this example and Example 1 is that the amount of tetramethylguanidine used was adjusted to 0.36 mL (which is 2.0 equivalents of the substrate benzoyl chloride), while the other steps and parameters were the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 191.1 mg, was a yellow solid powder with a yield of 63.7%.

[0045] Example 21 The difference between this example and Example 1 is that the amount of tetramethylguanidine used was adjusted to 0.54 mL (which is 3.0 equivalents of the substrate benzoyl chloride), while the other steps and parameters were the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 250.2 mg, was a yellow solid powder with a yield of 83.4%.

[0046] Example 22 The difference between this example and Example 1 is that the amount of tetramethylguanidine used was adjusted to 0.89 mL (which is 5.0 equivalents of the substrate benzoyl chloride), while the other steps and parameters were the same as in Example 1. The resulting product, 2-phenyl-4-dimethylamino-5-cyanoimidazole, 270.6 mg, was a yellow solid powder with a yield of 90.2%.

[0047] Example 23 Synthesis of 2-p-Tolyl-4-Dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 210 mg of p-methylbenzoyl chloride, the amount of trimethylcyanosilane used is 0.51 mL, the amount of tetramethylguanidine used is 0.68 mL, and the reaction time is 3.5 h. Other steps and parameters are the same as in Example 1. The obtained product, 259.2 mg of 2-p-tolyl-4-dimethylamino-5-cyanoimidazole, is a brownish-yellow solid powder with a yield of 86.4%.

[0048] Product 2-p-Tolyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.78(s, 1H), 7.79 (d, 2H), 7.25 (d, 2H), 3.13–2.91 (m, 6H), 2.32 (d, 3H) ppm. Example 24 Synthesis of 2-m-Tolyl-4-Dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 230 mg of m-methylbenzoyl chloride, the amount of trimethylcyanosilane used is 0.56 mL, the amount of tetramethylguanidine used is 0.75 mL, and the reaction time is 3.6 h. Other steps and parameters are the same as in Example 1. The obtained product, 292.1 mg of 2-m-tolyl-4-dimethylamino-5-cyanoimidazole, is a pale yellow solid powder with a yield of 88.5%.

[0049] Product 2-m-Tolyl-4-Dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.88(s, 1H), 7.74 (t, 2H), 7.45–7.09 (m, 2H), 3.02 (s, 6H), 2.34 (s, 3H) ppm. Example 25 Synthesis of 2-o-tolyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 220 mg of o-methylbenzoyl chloride, the amount of trimethylcyanosilane used is 0.53 mL, the amount of tetramethylguanidine used is 0.71 mL, and the reaction time is 3.8 h. Other steps and parameters are the same as in Example 1. The obtained product, 269.8 mg of 2-o-tolyl-4-dimethylamino-5-cyanoimidazole, is a yellow solid powder with a yield of 84.3%.

[0050] Product 2-o-tolyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, Chloroform- d ) δ9.91 (s, 1H), 7.32 (s, 1H), 7.20 (m, 3H), 3.09 (m, 6H), 2.49–2.34 (m, 3H)ppm. Example 26 Synthesis of 2-p-fluorophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 190 mg of p-fluorobenzoyl chloride, the amount of trimethylcyanosilane used is 0.45 mL, the amount of tetramethylguanidine used is 0.60 mL, and the reaction time is 2.5 h. Other steps and parameters are the same as in Example 1. The obtained product, 246.5 mg of 2-p-fluorophenyl-4-dimethylamino-5-cyanoimidazole, is a yellow solid powder with a yield of 91.3%.

[0051] Product 2-p-fluorophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.89(s, 1H), 7.93 (s, 2H), 7.29 (d, 2H), 3.11–2.98 (m, 6H) ppm. Example 27 Synthesis of 2-m-fluorophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 220 mg of m-fluorobenzoyl chloride, the amount of trimethylcyanosilane used is 0.52 mL, the amount of tetramethylguanidine used is 0.70 mL, and the reaction time is 2.6 h. Other steps and parameters are the same as in Example 1. The obtained product, 2-m-fluorophenyl-4-dimethylamino-5-cyanoimidazole, 299.2 mg, is a pale yellow solid powder with a yield of 93.5%.

[0052] Product 2-m-fluorophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.98(s, 1H), 7.69 (dd, 2H), 7.46 (s, 1H), 7.20 (s, 1H), 3.16–2.87 (m, 6H) ppm. Example 28 Synthesis of 2-o-fluorophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 200 mg of o-fluorobenzoyl chloride, the amount of trimethylcyanosilane used is 0.47 mL, the amount of tetramethylguanidine used is 0.63 mL, and the reaction time is 2.8 h. Other steps and parameters are the same as in Example 1. The obtained product, 2-o-fluorophenyl-4-dimethylamino-5-cyanoimidazole, 267.1 mg, is a brownish-yellow solid powder with a yield of 92.1%.

[0053] Product 2-o-fluorophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d6) δ 12.63(s, 1H), 7.83 (d, 1H), 7.46 (s, 1H), 7.40–7.19 (m, 2H), 3.10–2.94 (m, 6H)ppm. Example 29 Synthesis of 2-p-chlorophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 210 mg of p-chlorobenzoyl chloride, the amount of trimethylcyanosilane used is 0.45 mL, the amount of tetramethylguanidine used is 0.60 mL, and the reaction time is 2.7 h. Other steps and parameters are the same as in Example 1. The obtained product, 271.2 mg of 2-p-chlorophenyl-4-dimethylamino-5-cyanoimidazole, is a pale yellow solid powder with a yield of 90.4%.

[0054] Product 2-p-chlorophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.98(s, 1H), 7.97–7.78 (m, 2H), 7.50 (d, 2H), 3.16–2.87 (m, 6H) ppm. Example 30 Synthesis of 2-m-chlorophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 200 mg of m-chlorobenzoyl chloride, the amount of trimethylcyanosilane used is 0.43 mL, the amount of tetramethylguanidine used is 0.57 mL, and the reaction time is 2.8 h. Other steps and parameters are the same as in Example 1. The resulting 2-m-chlorophenyl-4-dimethylamino-5-cyanoimidazole, 255.6 mg, is a yellow solid powder with a yield of 91.3%.

[0055] Product 2-m-chlorophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 13.03(s, 1H), 8.05–7.76 (m, 2H), 7.46 (s, 2H), 3.04 (d, 6H) ppm. Example 31 Synthesis of 2-o-chlorophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 220 mg of o-chlorobenzoyl chloride, the amount of trimethylcyanosilane used is 0.47 mL, the amount of tetramethylguanidine used is 0.63 mL, and the reaction time is 3.1 h. Other steps and parameters are the same as in Example 1. The obtained product, 277.5 mg of 2-o-chlorophenyl-4-dimethylamino-5-cyanoimidazole, is a light yellow solid powder with a yield of 89.5%.

[0056] Product 2-o-chlorophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 12.98(m, 1H), 7.90 (dd, 2H), 7.51 (d, 2H), 3.12–2.87 (m, 6H) ppm. Example 32 Synthesis of 2-p-methoxyphenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 230 mg of p-methoxybenzoyl chloride, the amount of trimethylcyanosilane used is 0.51 mL, the amount of tetramethylguanidine used is 0.68 mL, the reaction time is 4 h, and other steps and parameters are the same as in Example 1. The obtained product, 2-p-methoxyphenyl-4-dimethylamino-5-cyanoimidazole, 275.2 mg, is a light yellow solid powder with a yield of 83.4%.

[0057] Product 2-p-methoxyphenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ12.67 (s, 1H), 7.84 (s, 2H), 7.01 (d, 2H), 3.89–3.66 (m, 3H), 3.09–2.91 (m,6H) ppm. Example 33 Synthesis of 2-p-tert-butylphenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 190 mg of p-tert-butylbenzoyl chloride, the amount of trimethylcyanosilane used is 0.36 mL, the amount of tetramethylguanidine used is 0.49 mL, and the reaction time is 3.8 h. Other steps and parameters are the same as in Example 1. The obtained product, 2-p-tert-butylphenyl-4-dimethylamino-5-cyanoimidazole, 214.5 mg, is a white solid powder with a yield of 82.5%.

[0058] Product 2-p-tert-butylphenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO-d 6) δ12.80 (s, 1H), 7.83 (s, 2H), 7.47 (s, 2H), 3.16–2.89 (m, 6H), 1.28 (dt, 9H)ppm. Example 34 Synthesis of 2-p-nitrophenyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 240 mg of p-nitrobenzoyl chloride, the amount of trimethylcyanosilane used is 0.48 mL, the amount of tetramethylguanidine used is 0.65 mL, and the reaction time is 2.9 h. Other steps and parameters are the same as in Example 1. The obtained product, 284.8 mg of 2-p-nitrophenyl-4-dimethylamino-5-cyanoimidazole, is an orange-yellow solid powder with a yield of 86.3%.

[0059] Product 2-p-nitrophenyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ13.04 (s, 1H), 8.33–8.23 (m, 2H), 8.15–8.05 (m, 2H), 3.06 (d, 6H) ppm. Example 35 Synthesis of 2-(2-thienyl)-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 210 mg of 2-thienylcarboxyl chloride, the amount of trimethylcyanosilane used is 0.54 mL, the amount of tetramethylguanidine used is 0.72 mL, and the reaction time is 3.5 h. Other steps and parameters are the same as in Example 1. The obtained product, 255.4 mg of 2-(2-thienyl)-4-dimethylamino-5-cyanoimidazole, is a yellow solid powder with a yield of 82.4%.

[0060] Product 2-(2-thienyl)-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ12.93 (s, 1H), 7.59 (s, 2H), 7.13 (s, 1H), 3.00 (d, 6H) ppm. Example 36 Synthesis of 2-(2-furanyl)-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 230 mg of 2-furanoyl chloride, the amount of trimethylcyanosilane used is 0.66 mL, the amount of tetramethylguanidine used is 0.89 mL, and the reaction time is 3.8 h. Other steps and parameters are the same as in Example 1. The obtained product, 2-(2-furanyl)-4-dimethylamino-5-cyanoimidazole, 293.4 mg, is a pale yellow solid powder with a yield of 81.5%.

[0061] Product 2-(2-furanyl)-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ12.93 (s, 1H), 7.81 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 3.01 (d, 6H) ppm. Example 37 Synthesis of 2-(2-naphthyl)-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 250 mg of 2-naphthoyl chloride, the amount of trimethylcyanosilane used is 0.49 mL, the amount of tetramethylguanidine used is 0.66 mL, and the reaction time is 4 h. Other steps and parameters are the same as in Example 1. The obtained product, 2-(2-naphthyl)-4-dimethylamino-5-cyanoimidazole, 283.2 mg, is a yellow solid powder with a yield of 83.3%.

[0062] Product 2-(2-naphthyl)-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ13.06 (s, 1H), 8.47 (s, 1H), 7.98 (d, 4H), 7.55 (s, 2H), 3.07 (d, 6H) ppm. Example 38 Synthesis of 2-cyclopropyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 210 mg of cyclopropionyl chloride, the amount of trimethylcyanosilane used is 0.75 mL, the amount of tetramethylguanidine used is 1.00 mL, and the reaction time is 2.6 h. Other steps and parameters are the same as in Example 1. The obtained product, 299.6 mg of 2-cyclopropyl-4-dimethylamino-5-cyanoimidazole, is a white solid powder with a yield of 85.6%.

[0063] Product 2-cyclopropyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d6) δ 12.07(s, 1H), 2.99–2.80 (m, 6H), 1.81 (d, 1H), 1.00–0.69 (m, 4H) ppm. Example 39 Synthesis of 2-cyclohexyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 230 mg of cyclohexyl chloride, the amount of trimethylcyanosilane used is 0.59 mL, the amount of tetramethylguanidine used is 0.79 mL, and the reaction time is 2.7 h. Other steps and parameters are the same as in Example 1. The obtained product, 297.5 mg of 2-cyclohexyl-4-dimethylamino-5-cyanoimidazole, is a white solid powder with a yield of 87.5%.

[0064] Product 2-cyclohexyl-4-dimethylamino-5-cyanoimidazol: 1 H NMR (300 MHz, Chloroform- d ) δ10.73 (s, 1H), 3.12–2.85 (m, 6H), 1.90 (d, 2H), 1.73 (d, 2H), 1.64 (d, 1H), 1.39 (d, 2H), 1.20 (q, 4H) ppm. Example 40 Synthesis of 2-tert-butyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 210 mg of trimethylacetyl chloride, the amount of trimethylcyanosilane used is 0.62 mL, the amount of tetramethylguanidine used is 0.83 mL, and the reaction time is 2.8 h. Other steps and parameters are the same as in Example 1. The obtained product, 277.1 mg of 2-tert-butyl-4-dimethylamino-5-cyanoimidazole, is a light yellow solid powder with a yield of 86.6%.

[0065] Product 2-tert-butyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 11.93(s, 1H), 2.94 (m, 6H), 1.23 (p, 9H) ppm. Example 41 Synthesis of 2-propyl-4-dimethylamino-5-cyanoimidazole The difference between this example and Example 1 is that the reaction substrate is 200 mg of n-butyryl chloride, the amount of trimethylcyanosilane used is 0.71 mL, the amount of tetramethylguanidine used is 0.95 mL, and the reaction time is 2.5 h. Other steps and parameters are the same as in Example 1. The obtained product, 293.4 mg of 2-propyl-4-dimethylamino-5-cyanoimidazole, is a white solid powder with a yield of 88.9%.

[0066] Product 2-propyl-4-dimethylamino-5-cyanoimidazole: 1 H NMR (300 MHz, DMSO- d 6) δ 11.93 (s,1H), 2.94 (dt, 6H), 1.23 (p, 9H) ppm.

[0067] Table 1 Results of the Example

[0068] As shown in Examples 1-41, the method of the present invention starts from various readily available aromatic acyl chlorides, fatty acyl chlorides, and heterocyclic acyl chlorides, using inexpensive and low-toxicity trimethylcyanosilane or acetone cyanohydrin as cyaniding reagents, and achieves efficient synthesis of 2-substituted-4-dimethylamino-5-cyanoimidazoles under the action of a base. This method has good compatibility with functional groups on the aromatic ring and is a novel, green, and universal synthetic method.

[0070] The above description is merely a preferred embodiment of the present invention. These specific embodiments are different implementations based on the overall concept of the present invention, and the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing substituted imidazoles from acyl chlorides, characterized in that: The preparation of substituted imidazoles includes the following steps: dissolving tetramethylguanidine and a cyaniding reagent in an organic solvent and stirring thoroughly for 30 min, then adding an acyl chloride, and reacting under certain temperature and alkaline conditions for a certain time to obtain 4-dimethylamino-5-cyanoimidazole; the general structural formula of 4-dimethylamino-5-cyanoimidazole is: ； In the formula, R represents phenyl, 4-Me-phenyl, 3-Me-phenyl, 2-Me-phenyl, 4-F-phenyl, 2-F-phenyl, 3-F-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 2-Cl-phenyl, 4-Br-phenyl, 3-Br-phenyl, 2-Br-phenyl 4-CN- phenyl, 4-methoxy-phenyl, 4-tertiary butyl-phenyl, 4-nitro-phenyl, 2-thienyl, 2-furyl, 2-naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, aml y, isoamyl, hexyl, benzyl, phenethyl, chloromethyl, bromomethyl, iodomethyl, 4-pyridyl, 2-quinolyl, 1-piperidyl, 9-acridinyl, dichloromethyl, trichloromethyl, diphenyl.

2. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The acyl chloride is selected from benzoyl chloride, p-methylbenzoyl chloride, m-methylbenzoyl chloride, o-methylbenzoyl chloride, p-fluorobenzoyl chloride, m-fluorobenzoyl chloride, o-fluorobenzoyl chloride, p-chlorobenzoyl chloride, m-chlorobenzoyl chloride, o-chlorobenzoyl chloride, p-methoxybenzoyl chloride, p-tert-butylbenzoyl chloride, p-nitrobenzoyl chloride, p-bromobenzoyl chloride, m-bromobenzoyl chloride, o-bromobenzoyl chloride, p-cyanobenzoyl chloride, 2-thiophenecarboxyl chloride, 2-furanoyl chloride, and 2-naphthalene. Formicyl chloride, cyclopropionic acid chloride, cyclobutylformyl chloride, cyclopentylformyl chloride, cyclohexylformyl chloride, trimethylacetyl chloride, propionyl chloride, n-butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, hexanoyl chloride, isohexanoyl chloride, heptanyl chloride, phenylacetyl chloride, phenylpropionic acid chloride, chloroacetyl chloride, bromoacetyl chloride, iodoacetyl chloride, succinyl chloride, isonicoyl chloride, quinoline-2-carbonyl chloride, 1-piperidinyl chloride, 9-acrylformyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, diphenylacetyl chloride.

3. The method for preparing substituted imidazoles using acyl chlorides as raw materials according to claim 1, characterized in that; The cyaniding reagent is acetone cyanohydrin or trimethylcyanosilane.

4. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The amount of cyaniding reagent used is 2.0-4.0 times the equivalent of acyl chloride, and the amount of tetramethylguanidine used is 2.0-4.0 times the equivalent of acyl chloride.

5. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The base is selected from DBU (1,8-diazabicycloundec-7-ene), sodium hydride, potassium tert-butoxide, tetramethylguanidine, DMAP (4-dimethylaminopyridine), N,N,N',N'-tetramethylethylenediamine, and 2,6-dimethylpyridine.

6. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The amount of alkali used is 1.0-2.0 times the equivalent of acyl chloride.

7. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The reaction temperature is 60-110℃, preferably 80℃.

8. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The solvent is selected from acetonitrile, N,N -Dimethylformamide, 1,4-dioxane, dimethyl sulfoxide, toluene, preferably acetonitrile.

9. The method for preparing substituted imidazoles from acyl chlorides according to claim 1, characterized in that: The reaction time is 2.5-4 h.

10. The substituted imidazoles prepared by the method according to any one of claims 1-9 have a yield of 81.5%-93.5%.

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