A method for preparing isourea compounds catalyzed by di-n-butylmagnesium

Abstract

The present invention provides a method for preparing isourea compounds catalyzed by commercially available di-n-butylmagnesium, belonging to the technical field of green preparation of isourea compounds, and capable of solving the urgent problems to be solved in the preparation method of isourea compounds. The method includes mixing a carbodiimide compound with an alcohol compound or a phenol compound under an inert atmosphere, and then adding di-n-butylmagnesium; the reaction system reacts at 60 °C for 1 to 24 h, and then the reaction is terminated by exposing it to air, and the isourea compound is obtained by column chromatography purification. The inert atmosphere is nitrogen. The present invention solves the urgent problems such as the high price of the catalyst used in the preparation method of the isourea compound, the environmental unfriendliness of the catalyst, and the complex operation process.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of isourea compounds, and particularly to a method for preparing isourea compounds catalyzed by commercially available di-n-butylmagnesium. Background Art

[0002] Isourea compounds are commonly used alkylating agents in organic synthesis. In addition, isourea compounds have also been widely used in the fields of agriculture, medicine, physical chemistry, and biochemistry, and thus have become increasingly important in modern industrial chemistry and academia. Due to their diverse application potential, the synthesis of isourea compounds has become a hot research field, and different synthesis methods have been developed.

[0003] Traditionally, the raw materials used to obtain isourea are urea, chloromethylamine, cyanamide, or organic cyanate. Previous methods usually require transition metals as catalysts, which have problems such as environmental pollution and low atom utilization rate. Based on the reaction of carbodiimide with alcohol to generate isourea compounds, this is the most effective in terms of atom economy, but previous catalysts are mainly lanthanide metals and rare earth metals, which have problems such as complex catalyst preparation processes and long reaction times.

[0004] The literature reports on the catalysis of the synthesis of isourea compounds using actinide metals (R.J. Batrice, C.E. Kefalidis, L. Maron and M.S. Eisen, J. Am. Chem. Soc., 2016, 138, 2114 - 2117.). In this method, under an inert atmosphere, an acylated amine actinide metal complex is used as a catalyst, and the reaction of N,N'-diisopropylcarbodiimide with methanol is carried out at 75 °C for 24 h. The catalyst used in this method is relatively complex to prepare. First, ThCl4 (3.0 g, 8.0 mmol) and Na[N(SiMe3)2] (5.9 g, 32 mmol) are heated under reflux in 100 mL of toluene for 2.5 h, then cooled to room temperature and filtered to obtain a white solid, and the collected solid is washed with ice-cold toluene. All volatiles are removed under a vacuum atmosphere to obtain the required acylated amine actinide metal complex [(Me3Si)2N]2Th[κ 2 -(N,C)-CH2Si(CH3)2N(SiMe3)], the reaction yield is 72%, and the final obtained solid is a white powder. In addition, this method also has problems such as fewer applicable substrates and long reaction times.

[0005] Using commercially available catalysts, expanding the catalytic scope, and shortening the reaction time are urgent problems to be solved in the preparation method of this isourea compound. Summary of the Invention

[0006] The object of the present invention is to provide a method for preparing isourea compounds catalyzed by dibutylmagnesium. By using a commercially available catalyst, the cost of the catalyst is reduced and the reaction time is shortened, thus solving the urgent problems to be solved in the preparation method of isourea compounds.

[0007] The technical solution of the present invention is as follows:

[0008] A method for preparing isourea compounds catalyzed by dibutylmagnesium, which is characterized by comprising the following steps:

[0009] Step 1: Under an inert atmosphere, a carbodiimide compound is mixed with an alcohol compound or a phenol compound, and then toluene and dibutylmagnesium are added respectively;

[0010] Step 2: The reaction system reacts at 60 °C for 1 to 24 h, and then the reaction is terminated by exposing it to air. Toluene is removed under vacuum, and the crude product is purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain isourea compounds.

[0011] The inert atmosphere in Step 1 is nitrogen.

[0012] The carbodiimide compound is N,N'-diisopropylcarbodiimide or N,N'-dicyclohexylcarbodiimide.

[0013] The alcohol compound is an aliphatic alcohol compound or an aromatic alcohol compound.

[0014] The aliphatic alcohol compound is methanol, ethanol, n-propanol, isopropanol or n-butanol.

[0015] The aromatic alcohol compound is benzyl alcohol or p-methoxybenzyl alcohol.

[0016] The phenol compound is phenol, p-bromophenol or o-cresol.

[0017] The molar ratio of the carbodiimide compound to the alcohol compound is 1:(1 to 1.1).

[0018] The volume of toluene in mL is at least 4 times the mass of the carbodiimide compound.

[0019] The molar amount of dibutylmagnesium is 2 to 5% of the molar amount of the carbodiimide compound.

[0020] The present invention provides a method for preparing isourea compounds catalyzed by dibutylmagnesium. Magnesium is a common metal, not a rare earth metal, which is easy to obtain and inexpensive. Moreover, the catalyst dibutylmagnesium is commercially available, solving the problems such as the complex preparation of the catalyst and the long reaction time in the preparation method of isourea compounds. Detailed embodiments

[0021] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0022] Example 1

[0023] According to the technical solution of the present invention, a specific application method includes the following steps:

[0024] (1) Under an inert atmosphere, i.e., in a nitrogen-protected glove box, a carbodiimide compound and an alcohol compound or a phenol compound are mixed in a molar ratio, and then toluene and di-n-butyl magnesium are added respectively;

[0025] (2) The mixed system obtained in (1) is reacted at 60° C. for 1 to 24 hours, and then exposed to air to terminate the reaction. The toluene is removed under vacuum, and the crude product is purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as an elution system to obtain an isourea compound.

[0026] The reaction formula is as follows:

[0027]

[0028] Among them, R 1 isopropyl or cyclohexyl, R 2 is selected from alkyl or aryl.

[0029] Reaction of N,N'-diisopropylcarbodiimide with Methanol Catalyzed by Di-n-Butylmagnesium

[0030] Step 1: In a nitrogen-protected glove box, N,N'-diisopropylcarbodiimide (0.5 mmol) and methanol (0.55 mmol) were mixed in a 10 mL reaction vial. 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were then added via syringe.

[0031] Step 2: The obtained mixture was heated in an oil bath at 60°C for 1 h, and then exposed to air to terminate the reaction. The toluene was removed under vacuum, and the crude product was purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain an isourea compound. The product was dissolved in CDCl3, sampled, and subjected to 1 H NMR and 13 C NMR spectrum test, the nuclear magnetic data of the obtained product are as follows:

[0032] 11H NMR (400 MHz, CDCl3) δ 3.65 (s, 1H, NHCH- i Pr), 3.57 (s, 3H, OCH3), 3.31 (s, 1H, NHCH- i Pr), 3.07 (s, 1H, NCH- i Pr), 1.02 (s, 12H, 2×CH(CH3)2).

[0033] 13 13C NMR (101 MHz, CDCl3) δ 152.28, 52.41, 46.14, 43.32, 24.26, 23.91.

[0034] The calculated yield of the product 1 in 1H-NMR is 99%.

[0035] Example 2

[0036] The isourea compound was prepared by the process of Example 1, except that 0.01 mL (2 mmol%) of 1 mol / L di-n-butylmagnesium was added, and then it was heated in an oil bath at 60 °C for 1 h, and the reaction was terminated by exposure to air. The isourea compound was obtained, and the product was dissolved in CDCl3. The calculated yield of the product 1 in 1H-NMR is 57%.

[0037] Example 3

[0038] The isourea compound was prepared by the process of Example 1, except that it was heated in an oil bath at 50 °C for 1 h, and the reaction was terminated by exposure to air. The isourea compound was obtained, and the product was dissolved in CDCl3. The calculated yield of the product 1 in 1H-NMR is 79%.

[0039] Example 4

[0040] Reaction of di-n-butylmagnesium catalyzing N,N'-diisopropylcarbodiimide and ethanol

[0041] Step 1: Inside a glove box under nitrogen protection, N,N'-diisopropylcarbodiimide (0.5 mmol) and ethanol (0.55 mmol) were mixed in a 10 mL reaction flask, and then 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added using syringes respectively;

[0042] Step 2: The resulting mixed system was heated in an oil bath at 60 °C for 3 h, and then the reaction was terminated by exposure to air. Toluene was removed under vacuum, and the crude product was purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. The product was dissolved in CDCl3, sampled, and subjected to1 1H NMR and 13 13C NMR spectrum tests were carried out, and the NMR data of the obtained product are as follows:

[0043] 1 1H NMR (400 MHz, CDCl3) δ 3.97 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.75 - 3.59 (m, 1H, NHCH- i Pr), 3.30 (s, 1H, NHCH- i Pr), 3.12 - 2.98 (m, 1H, NCH- i Pr), 1.13 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.00 (dd, J = 13.4, 6.5 Hz, 12H, 2×CH(CH3)2).

[0044] 13 13C NMR (101 MHz, CDCl3) δ 151.45, 60.30, 45.85, 42.97, 24.02, 23.60, 14.07.

[0045] Example 5

[0046] Reaction of Di-n-butylmagnesium Catalyzing N,N'-Diisopropylcarbodiimide with n-Propanol

[0047] Step 1: Inside a glove box under nitrogen protection, N,N'-diisopropylcarbodiimide (0.5 mmol) and n-propanol (0.55 mmol) were mixed in a 10 mL reaction flask, and then 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added by syringe respectively;

[0048] Step 2: The obtained mixed system was heated in an oil bath at 60 °C for 3 h, then exposed to air to terminate the reaction, toluene was removed under vacuum, and the crude product was purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. The product was dissolved in CDCl3, sampled, and subjected to 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0049] 1 1H NMR (400 MHz, CDCl3) δ 3.92 (t, J = 6.6 Hz, 2H, OCH2CH2CH3), 3.71 (p, J = 6.4 Hz, 1H, NHCH- i Pr), 3.35 (s, 1H, NHCH- i Pr), 3.11 - 3.08 (m, 1H, NCH-i Pr), 1.60 (q, J=7.1Hz, 2H, OCH2CH2CH3), 1.05 (dd, J=13.9, 6.5Hz, 12H, 2×CH(CH3)2), 0.91 (t, J=7.4Hz, 3H, OCH2CH2CH3).

[0050] 13 C NMR (101MHz, CDCl3) δ152.31,66.84,46.52,43.64,24.67,24.28,22.65,11.09.

[0051] Example 6

[0052] Reaction of N,N'-diisopropylcarbodiimide with Isopropyl Alcohol Catalyzed by Di-n-Butyl Magnesium

[0053] Step 1: In a nitrogen-protected glove box, N,N'-diisopropylcarbodiimide (0.5 mmol) and isopropanol (0.55 mmol) were mixed in a 10 mL reaction vial. 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were then added via syringe.

[0054] Step 2: The obtained mixture was heated in an oil bath at 60°C for 3 h, and then exposed to air to terminate the reaction. The toluene was removed under vacuum, and the crude product was purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain an isourea compound. The product was dissolved in CDCl3, sampled, and subjected to 1 H NMR and 13 C NMR spectrum test, the nuclear magnetic data of the obtained product are as follows:

[0055] 1 H NMR(400MHz, CDCl3)δ4.96(p,J=6.2Hz,1H,OCH(CH3)2),3.70(dd,J=12.7,7.8Hz,1H,NHCH- i Pr),3.31(s,1H,NHCH- i Pr), 3.11(p, J=6.1Hz,1H,NCH- i Pr), 1.16 (d, J=6.3Hz, 6H, OCH(CH3)2), 1.04 (dd, J=11.9, 6.4Hz, 12H, 2×CH(CH3)2).

[0056] 1313C NMR (101 MHz, CDCl3) δ 150.80, 66.54, 46.18, 43.28, 43.19, 24.41, 23.98, 23.94, 21.91.

[0057] Example 7

[0058] Reaction of Di-n-butylmagnesium Catalyzing N,N'-Diisopropylcarbodiimide with n-Butanol

[0059] Step 1: Inside a nitrogen-protected glove box, mix N,N'-diisopropylcarbodiimide (0.5 mmol) and n-butanol (0.55 mmol) in a 10 mL reaction flask. Then, add 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium using syringes respectively;

[0060] Step 2: Heat the resulting mixed system in an oil bath at 60 °C for 12 h. Then, expose it to air to terminate the reaction. Remove toluene under vacuum. The crude product is purified by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. Dissolve the product in CDCl3, take samples, and perform 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0061] 1 1H NMR (400 MHz, CDCl3) δ 3.91 (t, J = 6.5 Hz, 2H, OCH2CH2CH2CH3), 3.71 - 3.60 (m, 1H, NHCH- i Pr), 3.50 (s, 1H, NHCH- i Pr), 3.10 - 2.99 (m, 1H, NCH- i Pr), 1.55 - 1.45 (m, 2H, OCH2CH2CH2CH3), 1.30 (dt, J = 14.6, 7.3 Hz, 2H, OCH2CH2CH2CH3), 1.00 (dd, J = 11.5, 6.4 Hz, 12H, 2×CH(CH3)2), 0.84 (t, J = 7.1 Hz, 3H, OCH2CH2CH2CH3).

[0062] 13 13C NMR (101 MHz, CDCl3) δ 152.15, 64.71, 46.14, 43.22, 34.70, 31.10, 24.12, 23.80, 19.35, 19.00, 13.80.

[0063] Example 8

[0064] Reaction of N,N'-Diisopropylcarbodiimide with Benzyl Alcohol Catalyzed by Dibutylmagnesium

[0065] Step 1: Inside a glove box under nitrogen protection, mix N,N'-diisopropylcarbodiimide (0.5 mmol) and benzyl alcohol (0.55 mmol) in a 10 mL reaction flask. Then, add 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L dibutylmagnesium using syringes respectively;

[0066] Step 2: Heat the resulting mixture in an oil bath at 60 °C for 1 h, then expose it to air to terminate the reaction. Remove toluene under vacuum. Purify the crude product by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. Dissolve the product in CDCl3, take samples, and perform 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0067] 1 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 14.6, 7.2 Hz, 5H, Ph), 7.29 (d, J = 7.0 Hz, 1H, NHCH- i Pr), 3.85 - 3.82 (m, 1H, NHCH- i Pr), 3.22 - 3.19 (m, 1H, NCH- i Pr), 1.14 (dd, J = 6.4, 1.5 Hz, 12H, 2×CH(CH3)2).

[0068] 13 13C NMR (101 MHz, CDCl3) δ 151.62, 138.11, 128.33, 127.73, 127.46, 66.78, 46.40, 43.48, 24.43, 24.12.

[0069] Example 9

[0070] Reaction of N,N'-Diisopropylcarbodiimide with Phenol Catalyzed by Dibutylmagnesium

[0071] Step 1: Inside a glove box under nitrogen protection, mix N,N'-diisopropylcarbodiimide (0.5 mmol) and phenol (0.55 mmol) in a 10 mL reaction flask. Then, add 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L dibutylmagnesium using syringes respectively;

[0072] Step 2: Heat the resulting mixed system in an oil bath at 60 °C for 3 h, then expose it to air to terminate the reaction, remove toluene under vacuum, and purify the crude product by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. Dissolve the product in CDCl3, take samples, and perform 1 1H NMR and 13 13C NMR spectral tests. The NMR data of the obtained product are as follows:

[0073] 1 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.9 Hz, 2H, o-Ph), 7.18 (s, 1H, p-Ph), 7.07 - 6.986.98 (m, 2H, m-Ph), 6.83 (s, 1H, NHCH- i Pr), 3.76 - 3.73 (m, 2H, 2×CH- i Pr), 1.12 - 1.11 (d, J = 6.4 Hz, 12H, 2×CH(CH3)2).

[0074] 13 13C NMR (101 MHz, CDCl3) δ 154.44, 129.50, 129.19, 123.03, 117.10, 115.78, 44.83, 24.42, 23.50.

[0075] Example 10

[0076] Reaction of Di-n-butylmagnesium Catalyzed N,N'-Diisopropylcarbodiimide with o-Cresol

[0077] Step 1: In a glove box under nitrogen protection, mix N,N'-diisopropylcarbodiimide (0.5 mmol) and o-cresol (0.55 mmol) in a 10 mL reaction flask, and then add 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium using syringes respectively;

[0078] Step 2: Heat the resulting mixed system in an oil bath at 60 °C for 3 h, then expose it to air to terminate the reaction, remove toluene under vacuum, and purify the crude product by column chromatography using ethyl acetate / ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. Dissolve the product in CDCl3, take samples, and perform 1 1H NMR and 13 13C NMR spectral tests. The NMR data of the obtained product are as follows:

[0079] 11H NMR (400 MHz, CDCl3) δ 7.22 - 7.08 (m, 1H, o-Ph), 7.08 - 6.99 (m, 1H, p-Ph), 6.95 (d, J = 8.0 Hz, 1H, NHCH- i Pr), 6.78 (dd, J = 11.8, 7.6 Hz, 2H, m-Ph), 4.54 (s, 1H, NHCH- i Pr), 3.76 (s, 1H, NCH- i Pr), 2.25 (d, J = 7.3 Hz, 3H, (2-CH3)Ph), 1.12 - 1.11 (d, J = 6.5 Hz, 12H, 2×CH(CH3)2).

[0080] 13 13C NMR (101 MHz, CDCl3) δ 153.81, 129.81, 125.76, 123.30, 122.73, 118.68, 114.00, 43.87, 22.70, 14.98.

[0081] Example 11

[0082] Reaction of Di-n-butylmagnesium Catalyzed N,N'-Diisopropylcarbodiimide with p-Bromophenol

[0083] Step 1: Under the protection of nitrogen in a glove box, N,N'-diisopropylcarbodiimide (0.5 mmol) and p-bromophenol (0.55 mmol) were mixed in a 10 mL reaction flask, and then 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added by syringe respectively;

[0084] Step 2: The obtained mixed system was heated in an oil bath at 60 °C for 3 h, then exposed to air to terminate the reaction, toluene was removed under vacuum, and the crude product was purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. The product was dissolved in CDCl3, sampled, and subjected to 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0085] 1 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 1H, o-Ph), 7.24 (d, J = 2.6 Hz, 1H, o-Ph), 6.86 (d, J = 8.9 Hz, 1H, m-Ph), 6.66 (d, J = 8.8 Hz, 1H, m-Ph), 5.64 (s, 1H, NHCH- i Pr), 3.84 - 3.59 (m, 2H, 2×CH-i Pr), 1.10 (d, J = 6.4 Hz, 12H, 2×CH(CH3)2).

[0086] 13 C NMR (101 MHz, CDCl3) δ 156.35, 153.50, 132.75, 132.34, 119.76, 117.79, 111.54, 45.47, 23.77.

[0087] Example 12

[0088] Reaction of N,N'-dicyclohexylcarbodiimide with methanol catalyzed by di-n-butylmagnesium

[0089] Step 1: Inside a nitrogen-protected glove box, N,N'-dicyclohexylcarbodiimide (0.5 mmol) and methanol (0.55 mmol) were mixed in a 10 mL reaction flask, and then 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added using syringes respectively;

[0090] Step 2: The resulting mixed system was heated in an oil bath at 60 °C for 5 h, then exposed to air to terminate the reaction, toluene was removed under vacuum, the crude product was purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain an isourea compound, the product was dissolved in CDCl3, sampled, and subjected to 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0091] 1 1H NMR (400 MHz, CDCl3) δ 3.59 (s, 3H, OCH3), 3.31 (s, 2H, NHCH-Cy), 2.71 (s, 1H, NCH-Cy), 1.91 - 1.48 (m, 10H, NHCH-Cy), 1.34 - 0.92 (m, 10H, NCH-Cy).

[0092] 13 13C NMR (101 MHz, CDCl3) δ 151.84, 54.64, 52.14, 50.00, 34.24, 34.17, 25.71, 25.42, 25.07, 24.78.

[0093] Example 13

[0094] Reaction of N,N'-dicyclohexylcarbodiimide with ethanol catalyzed by di-n-butylmagnesium

[0095] Step 1: In a nitrogen-protected glove box, N,N'-dicyclohexylcarbodiimide (0.5 mmol) and ethanol (0.55 mmol) were mixed in a 10 mL reaction flask. Then, 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added separately using a syringe.

[0096] Step 2: The resulting mixed system was heated in an oil bath at 60 °C for 8 h, and then the reaction was terminated by exposure to air. Toluene was removed under vacuum. The crude product was purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. The product was dissolved in CDCl3, sampled, and 1 H NMR and 13 13C NMR spectra were measured. The NMR data of the obtained product are as follows:

[0097] 1 H NMR (400 MHz, CDCl3) δ 4.02 (q, J = 7.1 Hz, 3H, OCH2CH3), 3.64 (s, 1H, NHCH-Cy), 3.34 (t, J = 10.5 Hz, 1H, NCH-Cy), 2.71 (s, 1H, NH), 1.92 - 1.49 (m, 10H, NHCH-Cy), 1.33 - 0.74 (m, 13H, NCH-Cy + OCH2CH3).

[0098] 13 13C NMR (101 MHz, CDCl3) δ 151.76, 60.60, 54.87, 50.08, 34.31, 34.21, 25.82, 25.57, 25.24, 24.87, 18.08, 14.25.

[0099] Example 14

[0100] Reaction of Di-n-butylmagnesium Catalyzed N,N'-Dicyclohexylcarbodiimide with n-Propanol

[0101] Step 1: In a nitrogen-protected glove box, N,N'-dicyclohexylcarbodiimide (0.5 mmol) and n-propanol (0.55 mmol) were mixed in a 10 mL reaction flask. Then, 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added separately using a syringe.

[0102] Step 2: The resulting mixed system was heated in an oil bath at 60 °C for 10 h, and then the reaction was terminated by exposure to air. Toluene was removed under vacuum. The crude product was purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. The product was dissolved in CDCl3, sampled, and 1 H NMR and13 13C NMR spectrum test. The NMR data of the obtained product are as follows:

[0103] 1 1H NMR (400 MHz, CDCl3) δ 3.90 (t, J = 6.6 Hz, 2H, OCH2CH2CH3), 3.32 (t, J = 10.4 Hz, 1H, NHCH-Cy), 2.69 (s, 1H, NCH-Cy), 1.85 (d, J = 9.7 Hz, 2H, OCH2CH2CH3), 1.70 - 1.49 (m, 10H, NHCH-Cy), 1.29 - 0.98 (m, 10H, NCH-Cy), 0.88 (t, J = 7.5 Hz, 3H, OCH2CH2CH3).

[0104] 13 13C NMR (101 MHz, CDCl3) δ 151.67, 66.37, 54.90, 50.27, 34.54, 34.38, 25.99, 25.72, 25.33, 25.02, 22.27, 10.69.

[0105] Example 15

[0106] Reaction of Di-n-butylmagnesium Catalyzed N,N'-Dicyclohexylcarbodiimide with Isopropanol

[0107] Step 1: Inside a nitrogen-protected glove box, mix N,N'-dicyclohexylcarbodiimide (0.5 mmol) and isopropanol (0.55 mmol) in a 10 mL reaction flask. Then, add 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium using syringes respectively;

[0108] Step 2: Heat the obtained mixed system in an oil bath at 60 °C for 10 h. Then, expose it to air to terminate the reaction. Remove toluene under vacuum. The crude product is purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain an isourea compound. Dissolve the product in CDCl3, take samples, and conduct 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0109] 11H NMR (400 MHz, CDCl3) δ 4.94 (s, 1H, OCH(CH3)2), 3.63 (s, 1H, NHCH-Cy), 3.31 (s, 1H, NHCH-Cy), 2.73 (s, 1H, NCH-Cy), 1.97 - 1.45 (m, 10H, NHCH-Cy), 1.40 - 0.88 (m, 16H, NCH-Cy + OCH(CH3)2).

[0110] 13 13C NMR (101 MHz, CDCl3) δ 150.60, 66.46, 54.61, 49.91, 34.30, 34.17, 25.85, 25.56, 25.40, 25.05, 24.84, 21.65, 18.01.

[0111] Example 16

[0112] Reaction of N,N'-dicyclohexylcarbodiimide with n-butanol catalyzed by di-n-butylmagnesium

[0113] Step 1: Inside a nitrogen-protected glove box, N,N'-dicyclohexylcarbodiimide (0.5 mmol) and n-butanol (0.55 mmol) were mixed in a 10 mL reaction flask. Then, 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added using syringes respectively.

[0114] Step 2: The resulting mixed system was heated in an oil bath at 60 °C for 24 h. Then, the reaction was terminated by exposing it to air. Toluene was removed under vacuum. The crude product was purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain an isourea compound. The product was dissolved in CDCl3, sampled, and subjected to 1 1H NMR and 13 13C NMR spectrum tests. The NMR data of the obtained product are as follows:

[0115] 1 1H NMR (400 MHz, CDCl3) δ 3.89 (t, J = 6.4 Hz, 2H, OCH2CH2CH2CH3), 3.50 (s, 1H, NHCH-Cy), 3.26 (s, 1H, NHCH-Cy), 2.63 (s, 1H, NCH-Cy), 1.83 - 1.37 (m, 12H, NHCH-Cy + OCH2CH2CH2CH3), 1.35 - 0.90 (m, 12H, NCH-Cy + OCH2CH2CH2CH3), 0.82 (t, J = 6.8 Hz, 3H, OCH2CH2CH2CH3).

[0116] 1313C NMR (101 MHz, CDCl3) δ 151.90, 64.70, 55.04, 50.36, 34.61, 34.46, 31.19, 26.05, 25.80, 25.45, 25.10, 19.46, 19.07, 13.99.

[0117] Example 17

[0118] Reaction of N,N'-dicyclohexylcarbodiimide with p-methoxybenzyl alcohol catalyzed by di-n-butylmagnesium

[0119] Step 1: Inside a nitrogen-protected glove box, N,N'-dicyclohexylcarbodiimide (0.5 mmol) and p-methoxybenzyl alcohol (0.55 mmol) were mixed in a 10 mL reaction flask. Then, 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium were added separately using syringes.

[0120] Step 2: The resulting mixed system was heated in an oil bath at 60 °C for 3 h. Then, the reaction was terminated by exposing it to air. Toluene was removed under vacuum. The crude product was purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. The product was dissolved in CDCl3, sampled, and subjected to 1 1H NMR and 13 13C NMR spectral tests. The NMR data of the obtained product are as follows:

[0121] 1 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 4H, o-Ph), 6.87 (d, J = 8.7 Hz, 2H, m-Ph), 5.03 (s, 2H, OCH2Ph), 3.80 (s, 3H, OCH3), 3.41 (t, J = 3.9 Hz, 1H, NHCH-Cy), 2.80 (s, 1H, NHCH-Cy), 1.90 - 1.05 (m, 20H, 2×Cy).

[0122] 13 13C NMR (101 MHz, CDCl3) δ 157.92, 150.36, 129.23, 128.23, 112.56, 65.30, 54.20, 53.93, 49.23, 33.90, 33.53, 33.40, 24.99, 24.67, 24.28, 23.95.

[0123] Example 18

[0124] Reaction of N,N'-dicyclohexylcarbodiimide with phenol catalyzed by di-n-butylmagnesium

[0125] Step 1: In a nitrogen-protected glove box, mix N,N'-dicyclohexylcarbodiimide (0.5 mmol) and phenol (0.55 mmol) in a 10 mL reaction flask. Then, add 0.55 mL of toluene and 0.025 mL (5 mmol%) of 1 mol / L di-n-butylmagnesium to the mixture using syringes respectively.

[0126] Step 2: Heat the resulting mixture in an oil bath at 60 °C for 16 h. Then, expose it to air to terminate the reaction. Remove toluene under vacuum. The crude product is purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain the isourea compound. Dissolve the product in CDCl3, take samples, and perform 1 1H NMR and 13 13C NMR spectral tests. The NMR data of the obtained product are as follows:

[0127] 1 1H NMR (400 MHz, CDCl3) δ 7.30 - 6.79 (m, 5H, Ph), 6.38 (s, 1H, NHCH-Cy), 3.40 - 3.34 (m, 1H, NHCH-Cy), 3.20 (d, J = 4.2 Hz, 1H, NCH-Cy), 1.99 - 1.48 (m, 10H, NHCH-Cy), 1.42 - 0.89 (m, 10H, NCH-Cy).

[0128] 13 13C NMR (101 MHz, CDCl3) δ 154.71, 140.05, 129.77, 129.49, 55.91, 52.71, 35.02, 34.10, 25.74, 25.55, 25.09, 24.81.

Claims

1. A method for preparing isourea compounds catalyzed by di-n-butylmagnesium, characterized in that Comprising the following steps: Step 1: Under an inert atmosphere, a carbodiimide compound is mixed with an alcohol compound or a phenol compound, and then toluene and dibutylmagnesium are added respectively; Step 2: The reaction system reacts at 60 °C for 1 to 24 h, and then the reaction is terminated by exposure to air. Toluene is removed under a vacuum atmosphere. The crude product is purified by column chromatography using ethyl acetate / petroleum ether as the elution system to obtain an isourea compound. The reaction general formula is as follows: Wherein: R 1 selected from isopropyl or cyclohexyl; R 2 selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, p-methoxybenzyl, phenyl, o-tolyl or p-bromophenyl.

2. The preparation method of the isourea compound according to claim 1, characterized in that: The inert atmosphere in Step 1 is nitrogen.

3. The preparation method of the isourea compound according to claim 1, wherein: The carbodiimide compound is N,N'-diisopropylcarbodiimide or N,N'-dicyclohexylcarbodiimide.

4. The preparation method of the isourea compound according to claim 1, characterized in that: The alcohol compound is methanol, ethanol, n-propanol, isopropanol, n-butanol, benzyl alcohol or p-methoxybenzyl alcohol.

5. The preparation method of the isourea compound according to claim 1, characterized in that: The phenol compound is phenol, o-cresol or p-bromophenol.

6. The preparation method of the isourea compound according to claim 1, characterized in that: The molar ratio of the carbodiimide compound to the alcohol compound or the phenol compound is 1:(1 - 1.1).

7. The method for preparing the isourea compound according to claim 1, characterized in that: The molar amount of the dibutylmagnesium is 2 - 5% of the molar amount of the carbodiimide compound.

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