Synthesis method of benzoxazole / benzothiazole compound

Abstract

The invention discloses a synthesis method of a benzoxazole / benzothiazole compound, and belongs to the technical field of organic synthesis. The synthesis method comprises the following steps: by taking a benzaldehyde compound and an ortho-aminophenol compound or an ortho-aminophenol compound as raw materials and potassium ferricyanide and an ionic catalyst as additives, adding an organic solvent, placing the mixture in an oil bath for reflux reaction, then adding 2, 3-dichloro-5, 6, 7-trimethyl-1, 3-pentanediol into the reaction system, and carrying out a reaction to obtain the 2, 3-dichloro-5, 6, 7-trimethyl-1, 3-pentanediol. And 2, 6-dicyanop-benzoquinone or oxygen is subjected to cyclization synthesis to obtain the benzoxazole compound or the benzothiazole compound. According to the synthesis method disclosed by the invention, common raw materials can be completely reacted within a short time under mild reaction conditions through simple steps, and the yield is high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing benzoxazole / benzothiazole compounds. Background Art

[0002] Benzoxazole compounds and benzothiazole compounds are important biologically active molecules and organic synthesis intermediates, and are widely used in the fields of medicine, biochemistry, and pesticides. Regarding the synthesis of benzoxazole compounds and benzothiazole compounds, the following methods are commonly used in recent years:

[0003] (1) Condensation reaction of o-aminophenol / o-aminothiophenol compounds with aldehydes catalyzed by N-heterocyclic carbene

[0004]

[0005] The reaction time of this method requires more than 10 hours, and the reaction is incomplete, and a large amount of tarry by-products will appear [see Zhou Q, Liu S, Ma M, et al. Synthesis, 2018, 50(06): 1315-1322.].

[0006] (2) Protonic acid-catalyzed cyclization of 2-aminophenol / 2-aminothiophenol with β-diketone to prepare benzoxazole and benzothiazole

[0007]

[0008] The reaction system of this method is relatively complicated, for example, it requires not only copper salt catalyst and protonic acid, but also inert gas protection, and the reaction time takes 12-36 hours. Most importantly, this method is not widely adaptable to the reaction substrate, for example, the cyclization reaction of bromine substitution on the benzene ring is very difficult [see Mayo, MS, Yu, X., Zhou, X., Feng, X., Yamamoto, Y., & Bao, M. Organic letters, 2014, 16 (3), 764-767.].

[0009] (3) Cyclization reaction promoted by efficient elemental sulfur

[0010]

[0011] The reaction system of this reaction is complicated. For example, it requires not only oxygen but also a sulfur promoter, which is easy to cause pollution. In addition, this method is not widely adaptable to the reaction substrates. For example, when the side chain has a large group substitution, the cyclization reaction is difficult [see Nguyen, TB, Ermolenko, L., Dean, WA, & Al-Mourabit, A. Organic letters, 2012, 14 (23), 5948-5951.].

[0012] In summary, although there are many methods for synthesizing benzoxazole / benzothiazole compounds in the prior art, these methods basically have the problem of insufficient substrate adaptability; some reaction times are too long and the reaction yields are low; some required reaction preparation processes are cumbersome and difficult to operate; some used compounds are highly polluting and not suitable for large-scale production.

[0013] Therefore, it is necessary to provide a highly efficient and widely adaptable method for synthesizing heterocyclic compounds. Summary of the invention

[0014] In order to overcome the deficiencies in the prior art, the present invention aims to provide a method for synthesizing benzoxazole / benzothiazole compounds, using a simple and readily available ion catalyst to catalyze an amine-aldehyde condensation reaction, and then perform a cyclization reaction to prepare benzoxazole / benzothiazole compounds. The synthesis method of the present invention can use common raw materials through simple steps to completely react in a short time under mild reaction conditions, and has a high yield.

[0015] In order to achieve the above-mentioned invention object and solve the problems existing in the prior art, the technical solution adopted by the present invention is as follows:

[0016] A method for synthesizing benzoxazole / benzothiazole compounds: using a benzaldehyde compound and an o-aminophenol compound or an o-aminothiophenol compound as raw materials, potassium ferrocyanide and an ion catalyst as additives, adding an organic solvent and placing the mixture in an oil bath for reflux reaction, and then adding 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) or oxygen to the reaction system for cyclization to synthesize a series of benzoxazole compounds or benzothiazole compounds. The synthesis route is as follows:

[0017]

[0018] Wherein, R' is one of hydrogen, alkyl, alkoxy, amino, hydroxyl, nitro, alkenyl, alkynyl, aryl or halogen; R is one of aryl, halogen-substituted aryl, biphenyl, methyl-substituted biphenyl, methoxy-substituted biphenyl or trifluoromethyl-substituted biphenyl. Wherein, when X=O, the synthesized product is a benzoxazole compound; when X=S, the synthesized product is a benzothiazole compound.

[0019] The method for synthesizing a benzoxazole / benzothiazole compound comprises the following steps:

[0020] (a) adding a benzaldehyde compound, an o-aminophenol compound or an o-aminothiophenol compound, potassium ferrocyanide and an ion catalyst into a reaction bottle, adding an organic solvent and placing the reaction bottle in an oil bath for reflux reaction, the reaction temperature is controlled at 120-150° C., after reacting for 1-2 hours, 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to the reaction system or air is introduced, and the total reaction time is controlled to be 2-4 hours;

[0021] The molar ratio of the benzaldehyde compound to the o-aminophenol compound or the o-aminothiophenol compound is 1:1.2, the molar ratio of the benzaldehyde compound to potassium ferrocyanide is 1:0.25-0.5, the molar ratio of the benzaldehyde compound to the ion catalyst is 1:0.1-0.33, the molar ratio of the benzaldehyde compound to 2,3-dichloro-5,6-dicyano-p-benzoquinone is 1:2.5-3, and the amount of the organic solvent added is 50-80 times the weight of the benzaldehyde compound;

[0022] The organic solvent is selected from one of xylene, toluene, N,N-dimethylformamide, 1,4-dioxane or dimethyl sulfoxide;

[0023] (b) After the reaction is completed, the mixture is diluted with ethyl acetate and filtered, and n-hexane / ethyl acetate is used as an eluent and separated by a silica gel column to obtain a benzoxazole compound or a benzothiazole compound.

[0024] The ion catalyst (NHCs catalyst) is a new type of ion catalyst (P) synthesized independently, and its structure is as follows:

[0025]

[0026] Wherein, n is greater than or equal to 1, m is greater than or equal to 0, L=Br or I, and the synthesis route is as follows:

[0027]

[0028] The synthesis steps of the ion catalyst are as follows:

[0029] 1) Weigh 20 mmol of 1,2,4-triazole, 10 mmol of 1,4-dibromobutane or other types of halogen-substituted alkyl (such as 1,6-diiodohexane, 1,6-dibromohexane, 1,4-diiodobutane, tetrakis(bromomethyl)methane, tetraiodopentanol, tetrakis(4-bromophenyl)methane and other halogenated alkanes with similar structures), add 30 mL of toluene, and stir under reflux at 105-115°C in air for 24-30 hours;

[0030] 2) After stopping the reaction, the mixture was cooled to room temperature, the upper layer of solvent was separated by a separatory funnel, and the lower layer of product was concentrated to obtain the corresponding triazolium salt.

[0031] The mechanism of the present invention is as follows: first, under the assistance of NHCs catalyst ion catalyst, benzaldehyde compound and o-aminophenol compound / o-aminothiophenol compound first complete the condensation reaction of amine aldehyde to form Schiff base, and then under the action of air or oxidant, the carbon-nitrogen double bond on the Schiff base and the alcohol group or thiol group are oxidized to form a ring. The present invention attempts the reaction of a variety of different substrates, and the results show that the catalyst of the present invention can complete the first step of amine aldehyde condensation reaction. For simply substituted benzaldehyde compounds, the second step of oxidation ring formation can be completed only in air or oxygen environment; for complex substituted benzaldehyde compounds, DDQ is required to participate in the oxidation ring formation.

[0032] Compared with the prior art, the NHCs catalyst ion catalyst used in the present invention is simple and easy to prepare, has stable performance and good catalytic effect. The synthesis method of the present invention has mild reaction conditions and does not require the use of precious metals or highly polluting metal reagents. The reaction system is low in cost, simple and efficient, environmentally friendly, and can synthesize high-yield benzoxazole / benzothiazole compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of Example 1.

[0034] Figure 2 It is the carbon nuclear magnetic resonance spectrum of Example 1.

[0035] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of Example 4.

[0036] Figure 4 It is the carbon NMR spectrum of Example 4.

[0037] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of Example 7.

[0038] Figure 6 This is the carbon NMR spectrum of Example 7.

[0039] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of Example 8.

[0040] Figure 8 This is the carbon NMR spectrum of Example 8.

[0041] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of Example 17.

[0042] Fig.10 This is the carbon NMR spectrum of Example 17.

[0043] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of the ion catalyst P. DETAILED DESCRIPTION

[0044] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described are only used to illustrate and explain the present invention and are not limited to these embodiments. In the embodiments, benzaldehyde compounds, phenol compounds, thiophenol compounds, potassium ferrocyanide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, 1,2,4-triazole, halogen-substituted alkanes, toluene, xylene, N,N-dimethylformamide, 1,4-dioxane, and dimethyl sulfoxide with different substituents are products of Aladdin Biochemical Technology Co., Ltd.

[0045] In the following embodiments, the synthesis method of the ion catalyst P comprises the following steps:

[0046] A. Weigh 20 mmol of 1,2,4-triazole and 10 mmol of 1,4-dibromobutane respectively, add 30 mL of toluene, and stir under reflux at 110°C in air for 24 hours;

[0047] B. After stopping the reaction, cool to room temperature, separate the upper layer of solvent with a separatory funnel, and concentrate the lower layer of product to obtain a transparent and thick product, 1,4-bistriazole bromide, with a yield of 99%.

[0048] Product structure:

[0049]

[0050] Product mass spectrum and NMR spectrum data:

[0051] 1 H NMR(400MHz,D2O)δ9.09-8.73(m,4H),4.41-4.18(m,4H),1.96-1.80(m,4H).ESI-MS:m / z 193.23[M+H + ]

[0052] Example 1

[0053] A method for synthesizing a benzoxazole compound comprises the following steps:

[0054] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 120°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0055] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography using n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a yellow-white solid, namely 2-(2-methylbiphenyl)-5-bromobenzoxazole, with a yield of 92%.

[0056] Product structure:

[0057]

[0058] Product mass spectrum and NMR spectrum data:

[0059] 1 H NMR (400MHz, Chloroform-d) δ8.09 (dd, J=6.8, 2.4Hz, 1H), 7.95 (t, J=1.2Hz, 1H), 7.54-7.31 (m, 9H), 2.61 (s, 3H). 13 C NMR(101MHz,Chloroform-d)δ164.84,149.40,144.14,143.72,141.50,136.55,133.00,129.53,129. 38,128.28,128.10,127.24,126.85,125.74,123.20,117.14,111.77,19.25.ESI-MS:m / z364.24[M+H + ]

[0060] Example 2

[0061] A method for synthesizing a benzoxazole compound comprises the following steps:

[0062] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 5-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 130°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0063] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a yellow-white solid, namely 2-(2-methylbiphenyl)-6-bromobenzoxazole, with a yield of 95%.

[0064] Product structure:

[0065]

[0066] Product mass spectrum and NMR spectrum data:

[0067] 1 H NMR (400MHz, Chloroform-d) δ8.11(dd,J=7.0,2.4Hz,1H),7.81(d,J=1.8Hz,1H),7.70(d,J=8.4Hz,1H),7.54-7.36(m,8H),2.64(s,3H). 13 C NMR(101MHz,Chloroform-d)δ164.18,150.88,144.13,141.51,141.31,136.48,132.95,129.48 ,129.39,128.28,127.87,127.23,126.84,125.75,121.16,118.05,114.08,19.27.ESI-MS:m / z 364.24[M+H + ]

[0068] Example 3

[0069] A method for synthesizing a benzoxazole compound comprises the following steps:

[0070] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 6-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0071] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-(2-methylbiphenyl)-7-bromobenzoxazole, with a yield of 87%.

[0072] Product structure:

[0073]

[0074] Product mass spectrum and NMR spectrum data:

[0075] 1 H NMR(400MHz,Chloroform-d)δ8.19(dd,J=6.7,2.6Hz,1H),7.78(d,J=7.9Hz,1H ),7.55(d,J=7.9Hz,1H),7.50-7.37(m,7H),7.28(d,J=7.9Hz,1H),2.68(s,3H). 13 C NMR(101MHz,Chloroform-d)δ163.86,148.69,144.10,142.74,141.52,136.58,133.06,129.70 ,129.42,128.24,128.27,127.23,126.74,125.78,125.62,119.25,102.53,19.29.ESI-MS:m / z 364.07[M+H + ]

[0076] Example 4

[0077] A method for synthesizing a benzoxazole compound comprises the following steps:

[0078] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-methyl-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 120°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0079] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(2-methylbiphenyl)-5-methylbenzoxazole, with a yield of 91%.

[0080] Product structure:

[0081]

[0082] Product mass spectrum and NMR spectrum data:

[0083] 1H NMR (400MHz, Chloroform-d) δ8.11(dd,J=6.1,3.3Hz,1H),7.68-7.60(m,1H),7.53-7.37(m,8H),7.22(dd,J=8.3,1.7Hz,1H),2.65(s,3H),2.53(s,3H). 13 CNMR(101MHz,Chloroform-d)δ163.84,148.69,143.96,142.28,141.69,136.20,134.23,132.52,1 29.44,129.41,128.24,127.61,127.15,126.22,125.65,120.11,109.92,21.56,19.23.ESI-MS:m / z 300.75[M+H + ]

[0084] Example 5

[0085] A method for synthesizing a benzoxazole compound comprises the following steps:

[0086] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-methoxy-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 120°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0087] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(2-methylbiphenyl)-5-methoxybenzoxazole, with a yield of 92%.

[0088] Product structure:

[0089]

[0090] Product mass spectrum and NMR spectrum data:

[0091] 1 H NMR (400MHz, Chloroform-d) δ8.11(dd,J=5.8,3.5Hz,1H),7.52-7.33(m,9H),7.01(dd,J=8.9,2.5Hz,1H),3.91(s,3H),2.65(s,3H). 13C NMR(101MHz,Chloroform-d)δ164.51,157.29,145.07,144.00,142.88,141.67,136.18,132.56,12 9.41,129.38,128.25,127.50,127.15,125.66,113.88,110.71,102.90,55.98,19.25.ESI-MS:m / z 316.15[M+H + ]

[0092] Example 6

[0093] A method for synthesizing a benzoxazole compound comprises the following steps:

[0094] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-chloro-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 120°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0095] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(2-methylbiphenyl)-5-chlorobenzoxazole, with a yield of 96%.

[0096] Product structure:

[0097]

[0098] Product mass spectrum and NMR spectrum data:

[0099] 1 H NMR(400MHz,Chloroform-d)δ8.12(dd,J=7.1,2.3Hz,1H),7.82(d,J=2.1Hz,1H),7.57-7.35(m,9H),2.65(s,3H).13C NMR(101MHz,Chloroform-d)δ165.03,148.98,144.13,143.22,141.51,136.53,133.00,129.87,129.5 2,129.38,128.28,127.24,126.89,125.74,125.39,120.17,111.26,19.27.ESI-MS:m / z320.11[M+H+]

[0100] Example 7

[0101] A method for synthesizing a benzothiazole compound comprises the following steps:

[0102] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-chloro-2-aminobenzenethiol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 120°C in air for 4 h;

[0103] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(2-methylbiphenyl)-5-chlorobenzothiazole, with a yield of 97%.

[0104] Product structure:

[0105]

[0106] Product mass spectrum and NMR spectrum data:

[0107] 1 H NMR (400MHz, Chloroform-d) δ8.13(d,J=2.0Hz,1H),7.88(d,J=8.5Hz,1H),7.68(dd,J=6.3,2.8Hz,1H),7.50-7.37(m,8H),2.46(s,3H). 13 C NMR(101MHz,Chloroform-d)δ170.41,154.54,143.93,141.58,134.82,134.09,133.75,132.24 ,132.00,129.79,129.34,128.26,127.19,125.76,125.71,123.24,122.16,18.71.ESI-MS:m / z 336.08[M+H + ]

[0108] Example 8

[0109] A method for synthesizing a benzothiazole compound comprises the following steps:

[0110] A. Weigh 0.3 mmol of 4'-(trifluoromethyl)bisphenyl-3-carboxaldehyde, 0.36 mmol of 4-chloro-2-aminobenzenethiol, 0.075 mmol of potassium ferrocyanide, and 0.1 mmol of ion catalyst P, add 3 mL of xylene, and stir under reflux at 120°C in air for 4 h;

[0111] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(4'-(trifluoromethyl)biphenyl)-5-chlorobenzothiazole, with a yield of 98%.

[0112] Product structure:

[0113]

[0114] Product mass spectrum and NMR spectrum data:

[0115] 1 H NMR(400MHz,Chloroform-d)δ8.35(t,J=1.9Hz,1H),8.10-8.08(m,2H),7.86(d,J=8 .5Hz,1H),7.84-7.72(m,5H),7.63(t,J=7.8Hz,1H),7.41(dd,J=8.5,2.0Hz,1H).13C NMR (101MHz, Chloroform-d) δ 169.36, 154.95, 143.65, 140.81, 134.02, 133.32, 132.50, 129.96 (q, J = 30Hz), 129.77, 127. 60,127.38,126.28,125.91,125.90(q,J=12Hz),125.88,124.21(q,J=270Hz),123.15,122.40.ESI-MS:m / z390.38[M+H+]

[0116] Example 9

[0117] A method for synthesizing a benzoxazole compound comprises the following steps:

[0118] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 3-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0119] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-(2-methylbiphenyl)-4-bromobenzoxazole, with a yield of 88%.

[0120] Product structure:

[0121]

[0122] Product mass spectrum and NMR spectrum data:

[0123] 1 H NMR (400MHz, Chloroform-d) δ8.13(dd,J=7.2,2.2Hz,1H),7.58(m,2H),7.51-7.34(m,7H),7.28(t,J=8.0Hz,1H),2.65(s,3H). 13 C NMR(101MHz,Chloroform-d)δ164.27,150.56,144.02,141.54,141.51,136.56,133.00,129.72 ,129.39,128.26,127.67,127.21,126.93,125.95,125.69,112.90,109.73,19.23.ESI-MS:m / z 364.07[M+H + ]

[0124] Example 10

[0125] A method for synthesizing a benzoxazole compound comprises the following steps:

[0126] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-trifluoromethyl-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 130°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0127] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(2-methylbiphenyl)-5-trifluoromethylbenzoxazole, with a yield of 93%.

[0128] Product structure:

[0129]

[0130] Product mass spectrum and NMR spectrum data:

[0131] 1 H NMR (400MHz, Chloroform-d) δ8.24-8.05(m,2H),7.78-7.64(m,2H),7.53-7.34(m,7H),2.67(s,3H). 13 C NMR(101MHz,Chloroform-d)δ165.33,152.09,144.21,142.22,141.43,136.74,133.20,129.55,129.37,128.29,127.27,1 27.21(q,J=32Hz),126.60,125.79,124.27(q,J=270Hz),122.36(q,J=4Hz),117.94(q,J=4Hz),110.98,19.28.ESI-MS:m / z 354.34[M+H + ]

[0132] Embodiment 11

[0133] A method for synthesizing a benzoxazole compound comprises the following steps:

[0134] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-nitro-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 140°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0135] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a yellow solid, namely 2-(2-methylbiphenyl)-5-nitrobenzoxazole, with a yield of 94%.

[0136] Product structure:

[0137]

[0138] Product mass spectrum and NMR spectrum data:

[0139] 1 H NMR(400MHz,Chloroform-d)δ8.73(d,J=2.3Hz,1H),8.38(dd,J=8.9,2.3Hz,1H),8 .17(dd,J=7.5,1.9Hz,1H),7.73(d,J=8.9Hz,1H),7.52-7.36(m,7H),2.68(s,3H). 13 C NMR(101MHz,Chloroform-d)δ166.55,153.88,145.30,144.36,142.55,141.28,137.06,133.62 ,129.61,129.35,128.33,127.35,126.05,125.88,121.21,116.56,110.68,19.35.ESI-MS:m / z 331.16[M+H + ]

[0140] Example 12

[0141] A method for synthesizing a benzoxazole compound comprises the following steps:

[0142] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 6-chloro-4-nitro-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0143] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-(2-methylbiphenyl)-5-nitro-6-chlorobenzoxazole, with a yield of 96%.

[0144] Product structure:

[0145]

[0146] Product mass spectrum and NMR spectrum data:

[0147] 1H NMR (400MHz, Chloroform-d) δ8.63(d,J=2.1Hz,1H),8.38(d,J=2.1Hz,1H),8.22(dd,J=7.6,1.8Hz,1H),7.52-7.36(m,7H),2.68(s,3H). 13 C NMR(101MHz,Chloroform-d)δ166.69,150.69,145.43,144.45,143.12,141.15,137.34,134.01 ,129.81,129.35,128.35,127.41,125.97,125.44,121.36,116.65,114.98,19.38.ESI-MS:m / z 364.05[M+H + ]

[0148] Example 13

[0149] A method for synthesizing a benzoxazole compound comprises the following steps:

[0150] A. Weigh 0.3 mmol of biphenyl formaldehyde, 0.36 mmol of 4-bromo-2-aminophenol, 0.075 mmol of potassium ferrocyanide, and 0.1 mmol of ion catalyst P, add 3 mL of xylene, and stir under reflux at 120°C in air for 4 h;

[0151] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-(2-methylbiphenyl)-5-nitro-6-chlorobenzoxazole, with a yield of 90%.

[0152] Product structure:

[0153]

[0154] Product mass spectrum and NMR spectrum data:

[0155] 1 H NMR(400MHz,Chloroform-d)δ8.50(t,J=1.8Hz,1H),8.25-8.21(m,1H),7.95(d,J=1.3Hz,1H),7. 83-7.79(m,1H),7.74-7.69(m,2H),7.63(t,J=7.8Hz,1H),7.54-7.49(m,4H),7.46-7.41(m,1H). 13C NMR(101MHz,Chloroform-d)δ164.13,149.79,143.74,142.13,139.95,130.65,129.51,128 .96,128.20,127.95,127.23,127.16,126.53,126.44,123.04,117.39,111.86.ESI-MS:m / z 350.39[M+H + ]

[0156] Embodiment 14

[0157] A method for synthesizing a benzoxazole compound comprises the following steps:

[0158] A. Weigh 0.3 mmol 4'-(trifluoromethyl)bisphenyl-3-carboxaldehyde, 0.36 mmol 4-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 140°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0159] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-(4'-(trifluoromethyl)biphenyl)-5-bromobenzoxazole, with a yield of 89%.

[0160] Product structure:

[0161]

[0162] Product mass spectrum and NMR spectrum data:

[0163] 1 H NMR (400MHz, Chloroform-d) δ8.49(d,J=1.8Hz,1H),8.28(d,J=7.8Hz,1H),7.94(s,1H),7.83-7.75(m,5H),7.66(t,J=7.8Hz,1H),7.51(s,2H). 13C NMR (101MHz, Chloroform-d) δ 163.74, 149.79, 143.64, 143.43, 140.65, 130.66, 130.01 (q, J = 33Hz), 129.75, 128. 37,127.55,127.44,127.35,126.51,125.92(q,J=4Hz),124.19(q,J=270Hz),123.11,117.50,111.90.ESI-MS:m / z 418.38[M+H + ]

[0164] Embodiment 15

[0165] A method for synthesizing a benzoxazole compound comprises the following steps:

[0166] A. Weigh 0.3 mmol 3'-methyl[1,1'-biphenyl]-3-carboxaldehyde, 0.36 mmol 4-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0167] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(3'-(methyl)biphenyl)-5-bromobenzoxazole, with a yield of 87%.

[0168] Product structure:

[0169]

[0170] Product mass spectrum and NMR spectrum data:

[0171] 1 H NMR(400MHz,Chloroform-d)δ8.49(t,J=1.8Hz,1H),8.24-8.20(m,1H),7.95(t,J=1.2Hz,1H),7.82-7.78 (m,1H),7.62(t,J=7.6Hz,1H),7.56-7.47(m,4H),7.40(t,J=7.6Hz,1H),7.29-7.24(m,1H),2.48(s,3H). 13C NMR(101MHz,Chloroform-d)δ164.19,149.79,143.74,142.25,139.91,138.62,130.68,129.45,128.86,128. 69,128.18,127.99,127.08,126.45,126.41,124.33,123.03,117.38,111.87,21.58.ESI-MS:m / z364.05[M+H + ]

[0172] Example 16

[0173] A method for synthesizing a benzoxazole compound comprises the following steps:

[0174] A. Weigh 0.3 mmol of 4'-methyl[1,1'-biphenyl]-3-carboxaldehyde, 0.36 mmol of 4-bromo-2-aminophenol, 0.075 mmol of potassium ferrocyanide, and 0.1 mmol of ion catalyst P, add 3 mL of xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol of 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0175] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(4'-(methyl)biphenyl)-5-bromobenzoxazole, with a yield of 89%.

[0176] Product structure:

[0177]

[0178] Product mass spectrum and NMR spectrum data:

[0179] 1 H NMR(400MHz,Chloroform-d)δ8.48(t,J=1.8Hz,1H),8.25-8.17(m,1H),7.95-7.94(m,1H),7 .81-7.78(m,1H),7.63-7.58(m,3H),7.50-7.49(m,2H),7.32(d,J=8.0Hz,2H),2.45(s,3H). 13C NMR(101MHz,Chloroform-d)δ164.21,149.78,143.75,142.01,137.83,137.02,130.45,129.68 ,129.45,128.16,127.09,127.04,126.26,126.18,123.02,117.37,111.86,21.20.ESI-MS:m / z 364.02[M+H + ]

[0180] Embodiment 17

[0181] A method for synthesizing a benzothiazole compound comprises the following steps:

[0182] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 5-bromo-2-aminothiophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 140°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0183] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain an off-white solid, namely 2-(2-methylbiphenyl)-6-bromobenzothiazole, with a yield of 97%.

[0184] Product structure:

[0185]

[0186] Product mass spectrum and NMR spectrum data:

[0187] 1H NMR(400MHz,Chloroform-d)δ8.10(d,J=2.0Hz,1H),7.99(d,J=8.8Hz,1H),7.69-7.63(m,2H),7.50-7.45(m,2H),7.43-7.36(m,5H),2.46(s,3H).13C NMR(101MHz,Chloroform-d)δ169.00,152.57,143.93,141.58,137.48,134.79,133.66,131.96,129.7 9,129.72,129.33,128.26,127.19,125.76,124.53,123.97,118.83,18.74.ESI-MS:m / z380.02[M+H+]

[0188] Embodiment 18

[0189] A method for synthesizing a benzoxazole compound comprises the following steps:

[0190] A. Weigh 0.3 mmol 2-methylbiphenylaldehyde, 0.36 mmol 4-fluoro-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0191] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a white solid, namely 2-(2-methylbiphenyl)-5-fluorobenzoxazole, with a yield of 94%.

[0192] Product structure:

[0193]

[0194] Product mass spectrum and NMR spectrum data:

[0195] 1 H NMR (400MHz, Chloroform-d) δ8.13 (dd, J = 7.0, 2.4Hz, 1H), 7.59-7.36 (m, 9H), 7.14 (m, 1H), 2.66 (s, 3H). 13C NMR(101MHz,Chloroform-d)δ165.48,160.07(d,J=241Hz),146.75,144.12,142.87(d,J=13Hz),141.55,136.44,132.92,129 .49,129.40,128.29,127.23,127.06,125.74,112.76(d,J=26Hz),110.81(d,J=10Hz),106.57(d,J=25Hz),19.26.ESI-MS:m / z 354.66[M+H + ]

[0196] Embodiment 19

[0197] A method for synthesizing a benzoxazole compound comprises the following steps:

[0198] A. Weigh 0.3 mmol 2-fluorobenzaldehyde, 0.36 mmol 4-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 150°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0199] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-(2-fluorophenyl)-5-bromobenzoxazole, with a yield of 95%.

[0200] Product structure:

[0201]

[0202] Product mass spectrum and NMR spectrum data:

[0203] 1 H NMR (400MHz, Chloroform-d) δ8.24 (td, J=7.6, 1.8Hz, 1H), 7.98 (t, J=1.2Hz, 1H), 7.59-7.28 (m, 5H). 13C NMR(101MHz,Chloroform-d)δ162.18,159.60,149.50,133.62(d,J=9Hz),130.64(d,J=1Hz),128 .54,124.62(d,J=4Hz),123.31,117.48,117.31,117.10,115.04(d,J=11Hz),111.98.ESI-MS:m / z 292.00[M+H + Embodiment 20

[0204] A method for synthesizing a benzoxazole compound comprises the following steps:

[0205] A. Weigh 0.3 mmol benzaldehyde, 0.36 mmol 4-bromo-2-aminophenol, 0.075 mmol potassium ferrocyanide, and 0.1 mmol ion catalyst P, add 3 mL xylene, and stir under reflux at 120°C in air for 1 h. Weigh 0.75 mmol 2,3-dichloro-5,6-dicyano-p-benzoquinone and add it to the reaction system, and continue to reflux for 3 h;

[0206] B. After stopping the reaction, cool to room temperature, extract with ethyl acetate and saturated brine three times, and dry the obtained organic phase with anhydrous magnesium sulfate, concentrate, and separate and purify by silica gel column chromatography with n-hexane / ethyl acetate (volume ratio of 10:1) as eluent to obtain a light yellow solid, namely 2-phenyl-5-bromobenzoxazole, with a yield of 96%.

[0207] Product structure:

[0208]

[0209] Product mass spectrum and NMR spectrum data:

[0210] 1 H NMR (400MHz, Chloroform-d) δ8.30-8.23(m,2H),7.93(t,J=1.2Hz,1H),7.62-7.52(m,3H),7.49(d,J=1.2Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ164.19,149.78,143.75,131.98,129.02,128.11,127.80,126.66,123.00,117.33,111.84.ESI-MS:m / z274.18[M+H + ].

Claims

1. A method for synthesizing a benzoxazole / benzothiazole compound, characterized in that: The following steps are involved: (a) adding a benzaldehyde compound, an o-aminophenol compound or an o-aminothiophenol compound, potassium ferrocyanide and an ion catalyst into a reaction bottle, adding an organic solvent and placing the reaction bottle in an oil bath for reflux reaction, controlling the reaction temperature at 120-150° C., and reacting for 2-4 hours; The structure of the ion catalyst is as follows: Wherein, n is greater than or equal to 1, m is greater than or equal to 0, and L = Br or I; (b) after the reaction is completed, dilute with ethyl acetate and filter, use n-hexane / ethyl acetate as eluent, separate on a silica gel column, and obtain a benzoxazole compound or a benzothiazole compound; The structural formula of the benzoxazole compound or benzothiazole compound is as follows: Wherein, R' is one of hydrogen, alkyl, alkoxy, amino, hydroxyl, nitro, alkenyl, alkynyl, aryl or halogen; R is one of aryl, halogen-substituted aryl, biphenyl, methyl-substituted biphenyl, methoxy-substituted biphenyl or trifluoromethyl-substituted biphenyl; X=O or S. When X=O, the synthesized product is a benzoxazole compound; when X=S, the synthesized product is a benzothiazole compound.

2. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: The synthesis steps of the ion catalyst are as follows: 1) Weigh 1,2,4-triazole and halogen-substituted alkyl respectively, add toluene, and stir under reflux at 105-115°C in air for 24-30h; 2) After stopping the reaction, the mixture was cooled to room temperature, the upper layer of solvent was separated by a separatory funnel, and the lower layer of product was concentrated to obtain a triazolium salt.

3. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 2, characterized in that: The halogen-substituted alkyl group is 1,4-dibromobutane, 1,6-diiodohexane, 1,6-dibromohexane, 1,4-diiodobutane, tetrakis(bromomethyl)methane, tetraiodopentanol or tetrakis(4-bromophenyl)methane.

4. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: Step (a) After reflux reaction in an oil bath for 1-2 hours, 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to the reaction system or oxygen is introduced, and the total reaction time is controlled to be 2-4 hours.

5. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 3, characterized in that: The molar ratio of the benzaldehyde compound to 2,3-dichloro-5,6-dicyano-p-benzoquinone is 1:2.5-3.

6. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: The molar ratio of the benzaldehyde compound to the o-aminophenol compound or the o-aminothiophenol compound is 1:1.

2.

7. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: The molar ratio of the benzaldehyde compound to potassium ferrocyanide is 1:0.25-0.

5.

8. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: The molar ratio of the benzaldehyde compound to the ion catalyst is 1:0.1-0.

33.

9. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: The amount of the organic solvent added is 50-80 times the weight of the benzaldehyde compound.

10. The method for synthesizing a benzoxazole / benzothiazole compound according to claim 1, characterized in that: The organic solvent is selected from one of xylene, toluene, N,N-dimethylformamide, 1,4-dioxane or dimethyl sulfoxide.

Images