A method for base-promoted denitrogenation of 1,2,3-triazoles to construct iminothiazole derivatives

Abstract

The application discloses a method for constructing iminothiazole derivatives by alkali-promoted denitrogenation of 1,2,3-triazole, which uses 1,4-disubstituted-1,2,3-triazole derivatives and isothiocyanate as raw materials, and reacts under the presence of alkali and solvent at 10-120 DEG C. The reaction product is extracted, concentrated, and separated and purified by column chromatography to obtain iminothiazole derivatives. The method is easy to operate, and can provide a convenient and efficient new method for the synthesis of thiazole drugs, pesticides and organic materials.

Description

Technical Field

[0001] This invention relates to a method for constructing iminothiazole derivatives by denitrification of 1,2,3-triazole using an alkali-promoted method, belonging to the fields of pharmaceutical, pesticide, and material intermediates as well as organic synthesis technology. Background Technology

[0002] Iminothiazoles contain both thiazole and imine structures and are an important class of heterocyclic compounds, particularly widely used in the pharmaceutical and pesticide fields. They possess a variety of important biological activities, including anti-inflammatory, antibacterial, anticancer, antileishmaniasis, antimicrobial, herbicidal, and anti-HIV effects (Med. Chem. Res. 2012, 21, 2123; Molecules 2022, 27, 3994). Furthermore, they can be used as platelet GPIIB / IIIA receptor antagonists, alkaline phosphatase inhibitors, neurodegenerative drugs such as polyvinyl fluoride-α analogs, and skin whitening agents (J. Enzyme Inhib. Med. Chem. 2023, 38, 2163394.).

[0003] Therefore, this unique heterocyclic compound has attracted much attention due to its diverse biological activities and wide applications in organic and medicinal chemistry, and numerous synthetic methods have emerged. Safari et al. synthesized iminothiazole derivatives using substituted thiourea and α-halocarbonyl compounds as raw materials based on the Hantzsch method, catalyzed by chitosan nanomaterials. The reaction conditions were relatively simple, but strict control of the reaction conditions was required (Catal Commun. 2016, 77, 108). Periakaruppan used the condensation of 2-amino-1,3-thiazoline with aldehydes to control the selectivity of the product, but the reaction required special substrates and had certain limitations on the compatibility of functional groups (Tetrahedron Lett. 2017, 58, 3057). Shahvelayati et al. synthesized the target compound using a multi-component reaction of isothiocyanate, amino acid, and α-haloketone, using an ionic liquid as a solvent (Chin. Chem. Lett. 2014, 25, 119-122). The above synthesis methods inevitably suffer from disadvantages such as the difficulty in preparing raw materials, harsh reaction conditions, and complex synthesis systems. Summary of the Invention

[0004] To address the problems existing in traditional methods for synthesizing iminothiazoles and their derivatives, this invention provides a method for constructing iminothiazoles by denitrifying 1,2,3-triazoles using an alkali-promoted method. This method uses 1,2,3-triazole derivatives and isothiocyanates as synthetic precursors. Under alkali promotion, iminothiazole derivatives are obtained. The raw materials are readily available, the reaction is simple, the cost is low, the post-processing is convenient, and it is easy to scale up industrial production.

[0005] The method of constructing iminothiazole derivatives by denitrification of 1,2,3-triazole using alkali-promoted method of the present invention involves adding 1,4-disubstituted-1,2,3-triazole derivative, alkali, solvent, and isothiocyanate to a reactor and reacting at 10-120°C for 3-11 h. The product is then extracted, concentrated, and purified by column chromatography to obtain the iminothiazole derivative.

[0006] The structural formula of the iminothiazole derivative is as follows:

[0007]

[0008] Among them, R 1 It is one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, monohalogenated phenyl, and polyhalogenated phenyl; R 2 It is one of phenyl, heterocyclic aryl, alkyl-substituted phenyl, or halophenyl; R 3 It is one of phenyl, heterocyclic aryl, or substituted phenyl.

[0009] The structural formula of the 1,4-disubstituted-1,2,3-triazole derivative is as follows:

[0010]

[0011] Among them, R 1 It is one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, monohalogenated phenyl, and polyhalogenated phenyl; R 2 It is one of phenyl, heterocyclic aryl, alkyl-substituted phenyl, or halophenyl.

[0012] The isothiocyanate structure is as follows:

[0013]

[0014] Among them, R 3 It is one of phenyl, heterocyclic aryl, or substituted phenyl.

[0015] The molar ratio of 1,4-disubstituted-1,2,3-triazole to base is 1:(1-3), the molar ratio of 1,4-disubstituted-1,2,3-triazole to solvent is 1:(20-80), and the molar ratio of 1,4-disubstituted-1,2,3-triazole to isothiocyanate is 1:(1-4).

[0016] The alkali is potassium tert-butoxide ( t BuOK), sodium hydride (NaH), potassium amide (KNH2), n-butyllithium ( n One of the following: BuLi, potassium carbonate, cesium carbonate, and potassium phosphate.

[0017] The solvent is one of benzene, dichloromethane (DCM), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and N,N-dimethylacetamide (DMA).

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] Using 1,4-disubstituted-1,2,3-triazole as the raw material for the synthesis of the target product, the reaction with isothiocyanate under alkaline conditions yields the target product efficiently. The reaction does not require the participation of transition metals, which is in line with the concept of green development. The post-processing is simple and easy to scale up production, providing a convenient and efficient new method for the synthesis of thiazole drugs, pesticides and organic materials. Detailed Implementation

[0020] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to the content described.

[0021] Example 1: Synthesis of 2-benzimido-1,4-diphenylthiazole (3a)

[0022] 1,4-Diphenyl-1,2,3-triazole (1a, 1 mmol), phenyl isothiocyanate (2a, 4 mmol), potassium tert-butoxide (1 mmol), and THF (20 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 10 °C for 3 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined. The extracts were dried and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 114.8 mg of 2-phenylimino-1,4-diphenylthiazole (3a), with a yield of 35%.

[0023] The reaction equation is as follows:

[0024]

[0025] The NMR data for compound 3a are as follows:

[0026] 1 H NMR (600MHz, CDCl3) δ7.60 (d, J = 7.7Hz, 2H), 7.43 (t, J = 7.8Hz, 2H), 7.32 (t, J = 7.0Hz, 2H), 7.30-7.23 (m, 5H), 7.21-7.15 (m, 1H), 7.10-7.02 (m, 4H). 13C NMR (151MHz, CDCl3) δ156.8,151.8,138.6,131.5,129.6,129.3,128.9,127.4,127.2,125.3,124.6,123.6,122.7,121.6,116.0.

[0027] Example 2: Synthesis of 2-benzimido-1-phenyl-4-p-tolylthiazole (3b)

[0028] 1-Phenylene-4-p-methylphenyl-1,2,3-triazole (1b, 1 mmol), phenyl isothiocyanate (2a, 4 mmol), cesium carbonate (2 mmol), and THF (25 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 20 °C for 3 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined. The extracts were dried and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 174 mg of 2-phenylimino-1-phenyl-4-p-tolylthiazole (3b), with a yield of 51%.

[0029] The reaction equation is as follows:

[0030]

[0031] The NMR data for compound 3b are as follows:

[0032] 1 H NMR (500MHz, CDCl3) δ7.65-7.60(m,2H),7.45(t,J=8.0Hz,2H),7.35-7.27(m,3H),7. 21-7.16(m,2H),7.10(d,J=8.0Hz,2H),7.08-7.03(m,3H),7.02(s,1H),2.30(s,3H). 13 C NMR (126MHz, CDCl3) δ156.7,152.0,139.0,137.4,129.7,129.6,129.3,128.9,127.1,125.3,124.7,123.5,122.0,121.6,116.4,21.2.

[0033] Example 3: Synthesis of 2-benzimido-1-p-tolyl-4-m-tolylthiazole (3c)

[0034] 1-p-methylphenyl-4-m-methylphenyl-1,2,3-triazole (1c, 1 mmol), phenyl isothiocyanate (2a, 3 mmol), potassium tert-butoxide (3 mmol), and THF (30 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 30 °C for 4 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 163 mg of 2-phenylimino-1-p-tolyl-4-m-tolylthiazole (3c), with a yield of 46%.

[0035] The reaction equation is as follows:

[0036]

[0037] The NMR data of compound 3c are as follows:

[0038] 1 H NMR (600MHz, CDCl3) δ7.54(d,J=8.1Hz,2H),7.36(t,J=7.7Hz,2H),7.29(d,J=8.0Hz,2H), 7.22(t,J=7.6Hz,1H),7.13(d,J=7.7Hz,2H),7.11-7.03(m,5H),2.40(s,3H),2.34(s,3H). 13 C NMR (151MHz, CDCl3) δ157.2,152.1,138.7,137.3,136.2,131.6,130.0,129.6 ,128.9,128.2,125.4,125.3,123.5,122.8,121.7,121.6,115.9,21.5,21.3.

[0039] Example 4: Synthesis of 2-benzimido-1,4-bis(p-tolyl)thiazole (3d)

[0040] 1,4-Di-p-methylphenyl-1,2,3-triazole (1d, 1 mmol), phenyl isothiocyanate (2a, 3 mmol), sodium hydride (3 mmol), and DMA (35 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 35 °C for 5 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 156.9 mg of 2-phenylimino-1-p-tolyl-4-p-tolylthiazole (3d), with a yield of 44%.

[0041] The reaction equation is as follows:

[0042]

[0043] The NMR data of the compound are as follows:

[0044] 1 H NMR (600MHz, CDCl3) δ7.54(d,J=8.2Hz,2H),7.36(t,J=7.6Hz,3H),7.30(d,J=8.1Hz,2H),7.22(d, J=8.0Hz,2H),7.15(d,J=8.0Hz,2H),7.10(d,J=7.8Hz,3H),7.05(s,1H),2.41(s,3H),2.35(s,3H). 13 C NMR (126MHz, CDCl3) δ157.0,152.1,137.3,137.2,136.5,130.0,129.7,129.5,129.0,125.3,124.7,123.4,122.3,121.7,116.1,21.3,21.2.

[0045] Example 5: Synthesis of 2-benzimido-1,4-bis(o-tolyl)thiazole (3e)

[0046] 1,4-Di-o-methylphenyl-1,2,3-triazole (1e, 1 mmol), phenyl isothiocyanate (2a, 2 mmol), sodium hydride (2 mmol), and DMA (40 mmol) were added sequentially to a 10 mL reactor equipped with a stir bar in a molar ratio of 1:2:2:40, and reacted at 40 °C for 5 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate was 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 185.4 mg of 2-phenylimino-1-o-tolyl-4-o-tolylthiazole (3e), with a yield of 52%.

[0047] The reaction equation is as follows:

[0048]

[0049] The NMR data for the 3e compound are as follows:

[0050] 1 H NMR (500MHz, CDCl3) δ7.45-7.42(m,1H),7.40-7.37(m,1H),7.37-7.30(m,5H) ,7.25-7.17(m,3H),7.09-7.03(m,3H),6.64(s,1H),2.46(s,3H),2.44(s,3H). 13 C NMR (126MHz, CDCl3) δ157.4,152.2,138.0,136.4,136.1,131.5,131.1,129.6,129.4 ,129.2,129.0,128.2,128.0,127.2,126.4,125.4,123.3,121.7,114.8,21.5,18.3.

[0051] Example 6: Synthesis of 2-benzimido-1-o-tolyl-4-p-tolylthiazole (3f)

[0052] 1-o-methylphenyl-4-p-methylphenyl-1,2,3-triazole (1f, 1 mmol), phenyl isothiocyanate (2a, 2 mmol), n-butyllithium (1 mmol), and DMA (45 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 45 °C for 5 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 142.6 mg of 2-phenylimino-1-o-tolyl-4-p-tolylthiazole (3f), with a yield of 40%.

[0053] The reaction equation is as follows:

[0054]

[0055] The NMR data for compound 3f are as follows:

[0056] 1 H NMR (500MHz, CDCl3) δ7.43-7.39(m,1H),7.39-7.32(m,5H),7.22(d,J=8.2Hz,2H) ,7.14(d,J=8.1Hz,2H),7.09-7.04(m,3H),6.88(s,1H),2.41(s,3H),2.35(s,3H). 13 CNMR (126MHz, CDCl3) δ157.0,152.3,138.0,137.3,136.5,131.5,129.7,129. 5,129.1,129.0,128.1,127.2,124.6,123.4,122.4,121.7,116.0,21.2,18.3.

[0057] Example 7: Synthesis of 2-benzimido-1-m-tolyl-4-p-tolylthiazole (3g)

[0058] 1-m-methylphenyl-4-p-methylphenyl-1,2,3-triazole (1 g, 1 mmol), phenyl isothiocyanate (2a, 1 mmol), n-butyllithium (2 mmol), and DMA (50 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 50 °C for 5 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 181.8 mg of 2-phenylimino-1-m-tolyl-4-p-tolylthiazole (3 g), with a yield of 51%.

[0059] The reaction equation is as follows:

[0060]

[0061] The NMR data for the 3g compound are as follows:

[0062] 1 H NMR (500MHz, CDCl3) δ7.49-7.44(m,2H),7.39-7.33(m,3H),7.22(d,J=8.2Hz,2H),7 .14(t,J=7.8Hz,3H),7.09(d,J=7.5Hz,3H),7.05(s,1H),2.43(s,3H),2.34(s,3H). 13 C NMR (126MHz, CDCl3) δ157.0,152.2,139.4,139.0,137.4,129.7,129.6,129.2 ,129.0,128.1,126.1,124.7,123.5,122.7,122.3,121.7,116.2,21.6,21.3.

[0063] Example 8: Synthesis of 2-benzimido-1-m-tolyl-4-m-fluorophenylthiazole (3h)

[0064] 1-Methylphenyl-4-m-fluorophenyl-1,2,3-triazole (1h, 1mmol), phenyl isothiocyanate (2a, 1mmol), potassium tert-butoxide (2mmol), and DMF (25mmol) were added sequentially to a 10mL reactor equipped with a stirrer at a molar ratio of 1:1:2:55, and reacted at 55℃ for 6 hours. After dilution with 40mL of deionized water, the mixture was extracted three times with 150mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45℃ to obtain 169.4mg of 2-phenylimino-1-m-tolyl-4-m-fluorophenylthiazole (3h), with a yield of 47%.

[0065] The reaction equation is as follows:

[0066]

[0067] The NMR data of the 3h compound are as follows:

[0068] 1 H NMR(600MHz, CDCl3)δ7.49(d,J=8.2Hz,2H),7.34(t,J=7.8Hz,2H),7.29-7.22(m,3 H),7.10-7.02(m,5H),6.98(d,J=10.0Hz,1H),6.90(t,J=8.3Hz,1H),2.37(s,3H). 13 CNMR(151MHz, CDCl3)δ163.2(d,J=246.3Hz),156.7,151.9,137.5,135.9,133.9(d,J=8.4Hz),130.5(d,J=8.6Hz),130.0,1 29.6,125.3,124.0,123.7,121.5,120.2(d,J=2.7Hz),114.5(d,J=2.8Hz),114.1(d,J=21.3Hz),111.3(d,J=23.2Hz),21.3.

[0069] Example 9: Synthesis of 2-benzimido-1-m-tolyl-4-p-fluorophenylthiazole (3i)

[0070] 1-m-methylphenyl-4-p-fluorophenyl-1,2,3-triazole (1i, 1 mmol), phenyl isothiocyanate (2a, 4 mmol), potassium carbonate (2 mmol), and DMF (60 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 60 °C for 7 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 123.6 mg of 2-phenylimino-1-m-tolyl-4-p-fluorophenylthiazole (3i), with a yield of 35%.

[0071] The reaction equation is as follows:

[0072]

[0073] The NMR data for compound 3i are as follows:

[0074] 1 H NMR (600MHz, CDCl3) δ7.50 (d, J = 8.2Hz, 2H), 7.33 (t, J = 7.7Hz, 2H), 7.29-7.22 (m, 4H), 7.06 (t, J = 8.5Hz, 3H), 7.03-6.97 (m, 3H), 2.38 (s, 3H). 13 C NMR (151MHz, CDCl3) δ162.0 (d, J = 247.5Hz), 157.0, 152.0, 137.4, 136.1 130.0, 129.6, 127.9 (d, J = 3.3Hz), 126.3 (d, J = 8.0Hz), 125.3, 123.6, 122.8, 121.6, 116.0 (d, J = 22.0Hz), 114.8, 21.3.

[0075] Example 10: Synthesis of 2-benzimido-1-m-tolyl-4-p-methoxyphenylthiazole (3j)

[0076] 1-m-methylphenyl-4-p-methoxyphenyl-1,2,3-triazole (1j, 1 mmol), phenyl isothiocyanate (2a, 3 mmol), potassium carbonate (3 mmol), and DMF (20 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 65 °C for 8 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 178.5 mg of 2-phenylimino-1-m-tolyl-4-p-methoxyphenylthiazole (3j), with a yield of 48%.

[0077] The reaction equation is as follows:

[0078]

[0079] The NMR data of the compound are as follows:

[0080] 1 H NMR(600MHz, CDCl3)δ7.51(d,J=8.1Hz,2H),7.33(t,J=7.7Hz,2H),7.27(s,1H),7.25-7.2 1(m,3H),7.08-7.04(m,3H),6.94(s,1H),6.85(d,J=8.5Hz,2H),3.79(s,3H),2.38(s,3H). 13 C NMR (151MHz, CDCl3) δ159.1,157.3,152.2,137.2,136.3,130.0,129.6,126.0,125.3,124.4,123.4,121.7,121.6,115.7,114.4,55.5,21.3.

[0081] Example 11: Synthesis of 2-benzimido-1-m-tolyl-4-thienylthiazole (3k)

[0082] 1-m-methylphenyl-4-thiophene-1,2,3-triazole (1k, 1mmol), phenyl isothiocyanate (2a, 2mmol), n-butyllithium (3mmol), and DMF (30mmol) were added sequentially to a 10mL reactor equipped with a stir bar in a molar ratio of 1:2:3:30, and reacted at 70℃ for 6 hours. After dilution with 40mL of deionized water, the mixture was extracted three times with 150mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45℃ to obtain 139.3mg of 2-phenylimino-1-m-tolyl-4-thiophenethiazole (3k), with a yield of 40%.

[0083] The reaction equation is as follows:

[0084]

[0085] The NMR data for the 3k compound are as follows:

[0086] 1 H NMR (600MHz, CDCl3) δ7.49(d,J=8.2Hz,2H),7.33(t,J=7.8Hz,2H),7.27(d,J=8.0Hz,2H),7.1 3(d,J=5.0Hz,1H),7.09-7.03(m,3H),6.97-6.92(m,2H),6.86(d,J=3.4Hz,1H),2.38(s,3H). 13 C NMR (126MHz, CDCl3) δ156.5,151.9,137.4,136.2,134.5,130.0,129.6,127.7,125.3,123.8,123.6,123.0,121.6,110.1,21.2.

[0087] Example 12: Synthesis of 2-m-tolueneimino-1-p-toluyl-4-phenylthiazole (3l)

[0088] 1-p-methylphenyl-4-phenyl-1,2,3-triazole (1 l, 1 mmol), m-methylphenyl isothiocyanate (2 b, 1 mmol), potassium phosphate (3 mmol), and DMF (40 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 80 °C for 7 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined. The extracts were dried and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 131.7 mg of 2-m-toluimino-1-p-toluyl-4-phenylthiazole (3 l), with a yield of 37%.

[0089] The reaction equation is as follows:

[0090]

[0091] The NMR data for compound 3l are as follows:

[0092] 1 H NMR(500MHz, CDCl3) δ7.56(d,J=7.1Hz,2H),7.39-7.34(m,4H),7.32(d,J=7.8Hz,2H ),7.30-7.26(m,2H),7.12(s,1H),6.94(d,J=5.8Hz,3H),2.44(s,3H),2.39(s,3H). 13 C NMR (126MHz, CDCl3) δ156.7,152.0,139.3,137.2,136.4,131.9,129.9,129.4 ,129.0,127.3,125.3,124.7,124.3,122.9,122.4,118.4,115.9,21.6,21.2.

[0093] Example 13: Synthesis of 2-p-toluimino-1-p-toluyl-4-phenylthiazole (3m)

[0094] 1-p-methylphenyl-4-phenyl-1,2,3-triazole (1 L, 1 mmol), p-methylphenyl isothiocyanate (2 C, 1 mmol), potassium carbonate (1 mmol), and DMF (50 mmol) were added to a 10 mL reactor equipped with a stir bar and reacted at 85 °C for 8 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45 °C to obtain 73.2 mg of 2-p-toluimino-1-p-toluyl-4-phenylthiazole (3 M), with a yield of 22%.

[0095] The reaction equation is as follows:

[0096]

[0097] The NMR data for the 3m compound are as follows:

[0098] 1 H NMR(500MHz, CDCl3)δ7.51(d,J=6.8Hz,2H),7.32-7.29(m,4H),7.28(s,1H),7.25-7.19(m,2H) ,7.14(d,J=7.4Hz,2H),7.06(d,J=1.7Hz,1H),6.96(d,J=6.7Hz,2H),2.38(s,3H),2.32(s,3H). 13 C NMR (126MHz, CDCl3) δ156.8,149.6,137.2,136.5,132.9,132.0,130.2,130.0,129.0,127.3,125.4 124.7,123.0,121.4,115.9,21.2,21.1.

[0099] Example 14: Synthesis of 2-p-fluorobenzimido-1-p-tolyl-4-phenylthiazole (3n)

[0100] 1-p-methylbenzyl-4-phenyl-1,2,3-triazole (1 L, 1 mmol), p-fluorophenyl isothiocyanate (2 D, 3 mmol), sodium hydride (1 mmol), and DMF (40 mmol) were added sequentially to a 10 mL reactor equipped with a stir bar in a molar ratio of 1:3:1:40, and reacted at 100 °C for 10 hours. After dilution with 40 mL of deionized water, the mixture was extracted three times with 150 mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. The eluent was obtained by rotary evaporation at 45 °C, using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate volume ratio of 1:10). The eluent was collected and dried to obtain 161.9 mg of 2-p-fluorobenzimido-1-p-tolyl-4-phenylthiazole (3n), with a yield of 45%.

[0101] The reaction equation is as follows:

[0102]

[0103] The NMR data for the 3n compound are as follows:

[0104] 1 H NMR (500MHz, CDCl3) δ7.54(d,J=8.3Hz,2H),7.39-7.30(m,7H),7.30-7.25(m,1H),7.11(s,1H),7.06(d,J=2.2Hz,2H),7.05(s,1H),2.43(s,3H). 13 C NMR (126MHz, CDCl3) δ159.4 (d, J = 241.4Hz), 157.5, 148.2 (d, J = 2.6Hz), 137.4, 136.3, 131.8, 13 0.0,129.0,127.5,125.4,124.7,123.0,122.9(d,J=8.0Hz),116.3,116.0(d,J=12.1Hz),21.2.

[0105] Example 15: Synthesis of 2-p-nitrophenylimino-1-p-tolyl-4-phenylthiazole (3o)

[0106] 1-p-methylphenyl-4-phenyl-1,2,3-triazole (1L, 1mmol), p-nitrophenyl isothiocyanate (2e, 4mmol), cesium carbonate (3mmol), and DCM (30mmol) were added sequentially to a 10mL reactor equipped with a stir bar in a molar ratio of 1:4:3:30, and reacted at 110℃ for 11 hours. After dilution with 40mL of deionized water, the mixture was extracted three times with 150mL of ethyl acetate. The ethyl acetate extracts were collected and combined, dried, and the solvent was removed by vacuum evaporation to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography. Petroleum ether and ethyl acetate (volume ratio of petroleum ether:ethyl acetate was 1:10) were used as the eluent. The eluent was collected and dried by rotary evaporation at 45℃ to obtain 196.3mg of 2-p-nitrophenylimino-1-p-tolyl-4-phenylthiazole (3o), with a yield of 53%.

[0107] The reaction equation is as follows:

[0108]

[0109] The NMR data for compound 3o are as follows:

[0110] 1 H NMR (500MHz, CDCl3) δ8.23-8.17(m,2H),7.48(d,J=8.3Hz,2H),7.39-7.26(m,7H),7.20-7.16(m,2H),7.13(s,1H),2.42(s,3H). 13 C NMR (126MHz, CDCl3) δ157.8,157.5,143.2,138.2,135.9,131.1,130.1,129.2,128.0,125.6,125.6,125.0,123.1,121.9,117.1,21.3.

Claims

1. A method for constructing an iminothiazole derivative by base-promoted denitrogenation of 1,2,3-triazole, characterized in that: Using 1,4-disubstituted-1,2,3-triazole derivatives and isothiocyanates as raw materials, the reaction was carried out in the presence of alkali and solvent at 10–120 °C. The reaction products were extracted, concentrated, and purified by column chromatography to obtain iminothiazole derivatives. The structural formula of the 1,4-disubstituted-1,2,3-triazole derivative is as follows: The structural formula of isothiocyanate is: The structural formula of the iminothiazole derivative is as follows: In the above structural formula, R 1 It is one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, monohalogenated phenyl, and polyhalogenated phenyl; R 2 It is one of phenyl, heterocyclic aryl, alkyl-substituted phenyl, or halophenyl; R 3 It is one of phenyl, heterocyclic aryl, or substituted phenyl.

2. The method for constructing an iminothiazole derivative by base-promoted denitrogenation of 1,2,3-triazole according to claim 1, characterized in that: The molar ratio of 1,4-disubstituted-1,2,3-triazole to isothiocyanate is 1:(1-4), and the molar ratio of 1,4-disubstituted-1,2,3-triazole to base is 1:(1-3).

3. The method for constructing an iminothiazole derivative by base-promoted denitrogenation of 1,2,3-triazole according to claim 1, characterized in that: The solvent is selected from benzene, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, and N,N-dimethylacetamide.

4. The method for constructing an iminothiazole derivative by base-promoted denitrogenation of 1,2,3-triazole according to claim 1, characterized in that: The alkali is one of potassium tert-butoxide, sodium hydride, potassium amino, n-butyllithium, potassium carbonate, cesium carbonate, and potassium phosphate.

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