Synthesis method of oxyalkyl isourea and application of oxyalkyl isourea as free radical alkylation reagent

Abstract

The invention discloses a synthesis method of oxyalkyl isourea and application of the oxyalkyl isourea as a free radical alkylation reagent. According to the synthesis method, cheap and rich alcohol compounds and carbodiimide are used as raw materials, oxygen alkyl isourea is synthesized in one step under the mild condition of metal catalysis, the synthesis process is simple and convenient, the yield is high, and hectogram-level large-scale preparation can be achieved. The synthesized oxyalkyl isourea can be used as a free radical alkylation reagent to be applied to a coupling reaction of metal catalysis, so that different alkylate products rich in saturated carbon sequence structures are prepared, and the method has a good application prospect.

Description

Technical Field

[0001] This invention relates to a method for the efficient synthesis of oxoalkylisoureas from alcohols and commercially available carbodiimides under mild conditions using abundant metals (iron, cobalt, nickel) as starting materials, and to the application of oxoalkylisoureas as a free radical alkylating agent in metal-catalyzed coupling reactions. Background Technology

[0002] In recent years, radical cross-coupling reactions have gradually become a promising alternative method due to their superior synthetic selectivity and reaction conditions. This development benefits from advancements in controlled radical generation methodologies (Chem. Rev. 2021, 121, 506-561). This method avoids the need for alkyl metals or alkyl halides as C(sp) in traditional transition metal-catalyzed cross-coupling. 3 Instead of using natural, abundant, and inexpensive bulk chemicals as C(sp) precursors, 3 Sources. Among them, various C(sp) sources. 3 Radical precursors, including carboxylic acids, amines, aldehydes, ketones, and alcohol derivatives, have been successfully applied in metal photocatalysis or electrochemical reactions. Among these precursors, alcohol derivatives have attracted considerable attention due to their greater abundance in nature compared to other chemicals (J.Nat.Prod.2019,82,1258-1263). Although some progress has been made in recent years in activating the deoxygenation cross-coupling of alcohols through benzoxazonium salts, their applicability remains limited to oxidation activation via metal photocatalysis (Nature 2021,598,451-456). Therefore, developing multifunctional alcohol derivatives suitable for alternative activation modes such as reduction activation under metal photocatalysis or thermodynamic conditions is particularly important.

[0003] Since 1955, oxoalkylisoureas synthesized from alcohols and carbodiimides have been widely regarded as electrophilic alkylation precursors stable to air and moisture. Traditional methods utilize raw materials such as urea, aminomethylene, chloramine, cyanamide, organic cyanates, or isocyanates to prepare oxoalkylisoureas, but these techniques typically face challenges such as complex procedures, high costs, and the need for complex metal catalysts. The key to this strategy lies in utilizing suitable metal catalysts or Lewis acid-polarized imides to promote the addition of alcohols to the carbon-nitrogen double bond. Although some progress has been made, such as the Eisen group's use of actinide metal catalysis to achieve the addition of alcohols to carbodiimides, actinides are expensive and structurally complex, limiting their industrial applications, and their substrate applicability is limited (J. Am. Chem. Soc. 2016, 138, 2114-2117, Organic Metallics 2017, 36, 1296-1302). Cantat's group used alkali metal catalysts that required pre-preparation to promote the intermolecular addition of alcohols and carbodiimides, which introduced complexity to the operation (Angew. Chem. Int. Ed. 2018, 57, 3084-3088). In addition, Yao's group used rare earth metal catalysts with more complex structures, but these were only applicable to liquid alcohols (Org. Chem. Front. 2018, 5, 905-908).

[0004] Currently, the oxoalkylisoureas disclosed in existing technologies typically undergo two-electron nucleophilic substitution reactions with nucleophiles (Synlett 2009, 8, 1353-354, Angew. Chem. Int. Ed. 2020, 59, 8460-8463). However, until now, the direct use of oxoalkylisoureas as C(sp...) has not been widely adopted. 3 The application of radical precursors in carbon-carbon and carbon-boron radical cross-coupling via single-electron transfer processes has not yet been explored. Therefore, a novel method for synthesizing oxoalkyl isoureas and utilizing them directly as radical precursors holds great promise. Summary of the Invention

[0005] The purpose of this invention is to provide a simple, high-yield synthetic method for oxoalkylisoureas capable of being prepared on a gram-scale. More importantly, this invention utilizes the synthesized oxoalkylisoureas as a free radical alkylating agent in metal-catalyzed coupling reactions to synthesize various alkylated products rich in saturated carbon sequences, demonstrating promising application prospects.

[0006] To achieve the above objectives, the present invention provides a method for synthesizing oxoalkyl isoureas, using inexpensive and abundant alcohol compounds and commercially available carbodiimides as starting materials. The method involves a one-step synthesis of oxoalkyl isoureas under mild conditions catalyzed by abundant metals (such as iron, cobalt, and nickel). Specifically, the technical solution is as follows: An alcohol compound of Formula I, a carbodiimide of Formula II, and a metal catalyst are added to an organic solvent. The reaction is carried out under inert gas protection at 25–100°C with stirring. After the reaction is complete, the mixture is separated and purified to obtain the oxoalkyl isourea of ​​Formula III. The reaction equation is as follows:

[0007]

[0008] In the formula, R 1 Represents any one of primary, secondary, and tertiary alkyl groups; R 2 and R 3 Each can be independently represented by any one of the following: ethyl, propyl, n-butyl, n-pentyl, benzyl isopropyl, cyclohexyl, tert-butyl, p-tolyl, 3-dimethylaminopropyl, 2,6-diisopropylphenyl, or trimethylsilyl.

[0009] Furthermore, in the above-mentioned method for synthesizing oxyalkyl isoureas, the metal catalyst is selected from any one of ferric chloride, ferric bromide, ferric trifluoromethanesulfonate, ferrous chloride, ferrous bromide, ferrous iodide, ferrous trifluoromethanesulfonate, cobalt chloride, cobalt bromide, cobalt iodide, cobalt acetate, cobalt perchlorate, cobalt acetylacetonate, cobalt trifluoromethanesulfonate, nickel chloride, nickel bromide, nickel iodide, nickel chloride dimethoxyethane, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, nickel trifluoromethanesulfonate, and nickel fluoride.

[0010] Furthermore, in the above-mentioned method for synthesizing oxyalkyl isoureas, the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0011] Furthermore, in the above-mentioned method for synthesizing oxyalkyl isoureas, the amount of carbodiimide used is preferably 1.0 to 4.0 times the molar amount of the alcohol compound.

[0012] Furthermore, in the above-mentioned method for synthesizing oxyalkyl isoureas, the amount of the metal catalyst is preferably 0.001 to 0.1 times the molar amount of the alcohol compound.

[0013] This invention further provides the application of the oxyalkylisourea obtained by the above-mentioned synthesis method as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics. The specific application method is as follows: the oxyalkylisourea of ​​formula III, the haloaromatic compound of formula IV, a nickel catalyst, a ligand, and a base are added to an organic solvent, and the reaction is carried out under inert gas protection and irradiated with ultraviolet light to obtain the alkyl aromatic compound of formula V; the reaction equation is shown below:

[0014]

[0015] In the formula, Ar represents any one of aryl, substituted aryl, heterocyclic aryl, or substituted heterocyclic aryl; X represents Br or Cl.

[0016] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, nickel bromide trihydrate, nickel chloride hexahydrate, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, and nickel trifluoromethanesulfonate.

[0017] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2”-terpyridine, 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine, and 4'-(4-methoxyphenyl)-2,2':6',2”-terpyridine.

[0018] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the base is selected from any one of diisopropylamine, N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N,N-diethylcyclohexylamine, dicyclohexylamine, and N-methyldicyclohexylamine.

[0019] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0020] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the amount of the oxyalkylisourea used is preferably 1.0 to 5.0 times the molar amount of the haloaromatics.

[0021] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the amount of nickel catalyst used is preferably 2% to 20% of the molar amount of oxyalkylisourea.

[0022] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the amount of the ligand used is preferably 2% to 20% of the molar amount of the oxyalkylisourea.

[0023] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, the amount of the base used is preferably 1.0 to 5.0 times the molar amount of the oxyalkylisourea.

[0024] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, it is preferable to react under argon protection with ultraviolet light irradiation at a wavelength of 390-395 nm for 15-20 hours.

[0025] This invention also provides the application of the oxyalkylisourea obtained by the above-mentioned synthesis method as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids. The specific application method is as follows: the oxyalkylisourea of ​​formula III, arylboronic acid of formula VI, a nickel catalyst, and a ligand are added to an organic solvent, and the reaction is carried out under inert gas protection at 70–140 °C with stirring to obtain the alkyl aromatics of formula V; the reaction equation is as follows:

[0026]

[0027] In the formula, Ar represents any one of aryl, substituted aryl, heterocyclic aryl, and substituted heterocyclic aryl.

[0028] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids, the nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, nickel bromide trihydrate, nickel chloride hexahydrate, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, and nickel trifluoromethanesulfonate.

[0029] Furthermore, regarding the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids, the ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2”-tripyridine, 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-tripyridine, and 4'-(4-methoxyphenyl)-2,2':6',2”-tripyridine.

[0030] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids, the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0031] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acid, the amount of arylboronic acid used is preferably 1.0 to 5.0 times the molar amount of oxyalkylisourea.

[0032] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids, the amount of nickel catalyst used is preferably 2% to 20% of the molar amount of the oxyalkylisourea.

[0033] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids, the amount of the ligand used is preferably 2% to 20% of the molar amount of the oxyalkylisourea.

[0034] This invention also provides the application of the oxoalkylisourea obtained by the above-mentioned synthesis method as a free radical alkylating agent in the preparation of alkylboronic acid pinacol esters. The specific application method is as follows: the oxoalkylisourea of ​​formula III, the bis(catechol)boronic acid ester of formula VII, a nickel catalyst, and a ligand are added to an organic solvent, and the reaction is carried out under inert gas protection at 50–100 °C with stirring. After the reaction is completed, the mixture is post-treated with pinacol and triethylamine, and then purified to obtain the alkylboronic acid pinacol ester of formula VIII. The reaction equation is as follows:

[0035]

[0036] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkylboronic acid pinacol ester, the nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, nickel bromide trihydrate, nickel chloride hexahydrate, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, and nickel trifluoromethanesulfonate.

[0037] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkylboronic acid pinacol esters, the ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2"-tripyridine, 4,4',4″-tri-tert-butyl-2,2':6',2"-tripyridine and 4'-(4-methoxyphenyl)-2,2':6',2"-tripyridine;

[0038] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkylboronic acid pinacol esters, the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0039] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkylboronic acid pinacol ester, the amount of the bis(catechol)boronic acid ester is preferably 1.0 to 5.0 times the molar amount of the oxyalkylisourea.

[0040] Furthermore, in the application of the above-mentioned oxyalkylisourea as a free radical alkylating agent in the preparation of alkylboronic acid pinacol ester, the amount of nickel catalyst used is preferably 2% to 20% of the molar amount of oxyalkylisourea.

[0041] Furthermore, in the application of the above-mentioned oxoalkylisourea as a free radical alkylating agent in the preparation of alkylboronic acid pinacol esters, the amount of the ligand used is preferably 2% to 20% of the molar amount of the oxoalkylisourea.

[0042] The beneficial effects of this invention are as follows:

[0043] This invention utilizes inexpensive and abundant metal catalysts to catalyze the reaction of alcohols and carbodiimides to synthesize alkoxyisoureas. The reaction conditions are mild, the process is simpler, and the yield is better, making it suitable for large-scale preparation at the 100-gram scale or above. Furthermore, the substrate applicability of alcohols is broader, and the functional group compatibility is richer. Most importantly, this invention, through the combination of oxoalkylisoureas and transition metal nickel catalysts, develops oxoalkylisoureas for the first time as a universal radical alkylating agent to participate in coupling reactions, thereby preparing compound molecules rich in saturated carbon sequences to construct carbon-carbon and carbon-boron bonds. This aligns with green chemistry principles and demonstrates promising application prospects and commercial value. Detailed Implementation

[0044] 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 these embodiments.

[0045] Example 1

[0046] Synthetic formula III-1 shows an oxoalkyl isourea

[0047] Under an argon atmosphere, N-Boc-4-hydroxypiperidine (40.3 g, 200 mmol, 1.0 equivalent) of Formula I-1, N,N'-diisopropylcarbodiimide (25.2 g, 200 mmol, 1.0 equivalent) of Formula II-1, anhydrous cobalt chloride (129.8 mg, 1 mmol, 0.005 equivalent), and methyl tert-butyl ether (100 mL) were added to a 250 mL round-bottom flask. The flask was sealed and vigorously stirred at 60 °C until the alcohol was completely consumed as monitored by thin-layer chromatography (TLC). After the reaction was complete, the solvent was removed by rotary evaporation, followed by the addition of diethyl ether (200 mL). The suspension was filtered through neutral alumina (Grade I activity) and washed with diethyl ether. The filtrate was evaporated and dried under vacuum to give a white solid product of Formula III-1 in 95% yield.

[0048]

[0049] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ4.97-4.85(m,1H),3.73-3.62(m,1H),3.55-3.44(m,2H),3.37-3.22(m,3H),3.13-3. 02(m,1H),1.82-1.72(m,2H),1.61-1.51(m,2H),1.38(s,9H),1.04(d,J=6.5Hz,6H),0.98(d,J=6.3Hz,6H); 13CNMR(100MHz, CDCl3)δ154.8,149.9,79.2,68.1,46.0,43.3,41.0,30.4,28.4,24.3,23.9; HRMS(ESI)m / z C 17 H 34 N3O3 + [M+H] + Theoretical value: 328.2595, measured value: 328.2598.

[0050] Example 2

[0051] Synthetic formula III-2 shows an oxoalkyl isourea

[0052] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of 3-hydroxytetrahydrofuran as shown in Formula I-2, and the other steps were the same as in Example 1, to obtain a white solid product as shown in Formula III-2 with a yield of 96%.

[0053]

[0054] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ5.29-5.18(m,1H),3.85-3.77(m,2H),3.74(td,J=6.8,6.2,3.2Hz,2H ),3.66(brs,1H),3.34(brs,1H),3.15-2.99(m,1H),2.06-1.88(m,2H),1.07-0.93(m,12H); 13 C NMR(100MHz, CDCl3)δ150.5,74.5,73.5,67.1,46.0,43.4,32.8,24.2,23.9; HRMS(ESI)m / z C 11 H 23 N2O2 + [M+H] + Theoretical value: 215.1754, measured value: 215.1760.

[0055] Example 3

[0056] Synthetic formula III-3 shows an oxoalkyl isourea

[0057] In this embodiment, N-Boc-4-hydroxypiperidinium nitrile of Formula I-3 was replaced with equimolar amounts of 4-(4-hydroxypiperidin-1-yl)benzonitrile, and the other steps were the same as in Example 1, to obtain a white solid product of Formula III-3 with a yield of 94%.

[0058]

[0059] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.44(d,J=9.0Hz,2H),6.84(d,J=9.1Hz,2H),5.13-4.96(m,1H),3.81-3.68(m,1H),3.55-3.46( m,2H),3.42(s,1H),3.36-3.22(m,2H),3.22-3.07(m,1H),2.03-1.91(m,2H),1.83-1.70(m,2H),1.15-1.01(m,12H); 13 C NMR(100MHz, CDCl3)δ153.2,150.1,133.6,120.3,114.1,99.3,67.9,46.2,44.8,43.5,30.0,24.3,24.0; HRMS(ESI)m / z C 19 H 29 N4O + [M+H] + Theoretical value: 329.2336, measured value: 329.2338.

[0060] Example 4

[0061] Synthetic formula III-4 shows an oxoalkyl isourea

[0062] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with isopentane glycol of formula I-4 in equimolar amounts, and the other steps were the same as in Example 1, to obtain a white solid product of formula III-4 with a yield of 96%.

[0063]

[0064] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.17 (s, 1H), 5.10-5.00 (m, 1H), 3.87-3.68 (m, 1H), 3.50 (d, J = 7.6Hz, 1H), 3.22-3.04 (m, 1H), 1.86 (dd,J=14.7,6.4Hz,1H),1.60(dd,J=14.7,3.7Hz,1H),1.26(d,J=6.4Hz,3H),1.16(d,J=8.9Hz,6H),1.14-1.07(m,12H); 13C NMR(100MHz, CDCl3)δ153.0,69.1,68.2,50.8,46.0,43.4,31.1,30.3,24.4,24.1,24.0,23.5,23.0; HRMS(ESI)m / z C 13 H 29 N2O2 + [M+H] + Theoretical value: 245.2224, measured value: 245.2226.

[0065] Example 5

[0066] Synthetic formula III-5 shows an oxoalkyl isourea

[0067] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with an equimolar amount of epiandrolone of Formula I-5, and the other steps were the same as in Example 1, to obtain a white solid product of Formula III-5 with a yield of 92%.

[0068]

[0069] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ4.77-4.61(m,1H),3.79-3.63(m,1H),3.20-3.07(m,1H),2.53-2.33(m,1H),2.11-2.00(m,1H),1.96-1.85(m,2H) ,1.80-1.61(m,5H),1.59-1.38(m,3H),1.35-1.15(m,8H),1.11-1.01(m,13H),0.99-0.92(m,1H),0.88-0.79(m,6H),0.75-0.63(m,1H); 13 C NMR (100MHz, CDCl3) δ221.4,150.8,72.4,54.5,51.5,47.9,46.2,44.6,43.3,43.3,36.9,35.9,3 5.8,35.1,34.2,31.6,31.0,28.5,27.7,24.4,24.4,24.0,21.9,20.6,13.9,12.4; HRMS(ESI)m / z C 26 H 45 N2O2 + [M+H] + Theoretical value: 417.3476, measured value: 417.3484.

[0070] Example 6

[0071] Synthetic formula III-6 shows an oxoalkyl isourea

[0072] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of nobol as shown in Formula I-6, and the other steps were the same as in Example 1, to obtain a white solid product as shown in Formula III-6 with a yield of 93%.

[0073]

[0074] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ5.08 (s, 1H), 3.86 (t, J = 6.5Hz, 2H), 3.78-3.44 (m, 1H), 3.42-3.02 (m, 1H), 3.12-2.74 (m, 1H), 2.2 4-2.14(m,1H),2.13-1.98(m,4H),1.95-1.84(m,2H),1.08(s,3H),1.01-0.97(m,1H),0.97-0.85(m,12H),0.65(s,3H); 13 C NMR (100MHz, CDCl3) δ151.0,144.9,117.5,62.6,45.7,45.5,42.9,40.5,37.6,36.2,31.3,31.1,26.0,23.9,20.7; HRMS (ESI) m / z C 18 H 33 N2O + [M+H] + Theoretical value: 293.2587, measured value: 293.2590.

[0075] Example 7

[0076] Synthetic formula III-7 shows an oxoalkyl isourea

[0077] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of 2-indanol as shown in Formula I-7, and the other steps were the same as in Example 1, to obtain a white solid product as shown in Formula III-7 with a yield of 94%.

[0078]

[0079] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.20-7.13(m,2H),5.57(dt,J=6.9,3.2Hz,1H),3.64(dr,1H),3.50-3.34(m,1H),3 .31(dd,J=16.8,6.6Hz,2H),3.27-3.11(m,1H),3.03(dd,J=16.8,3.6Hz,2H),1.12(d,J=6.4Hz,6H),1.04(d,J=6.4Hz,6H); 13 C NMR (100MHz, CDCl3) δ150.9,141.5,126.4,124.7,75.0,46.3,43.4,39.8,24.5,24.0; HRMS (ESI) m / z C 16 H 25 N2O + [M+H] + Theoretical value: 261.1961, measured value: 261.1962.

[0080] Example 8

[0081] Synthetic formula III-8 shows an oxoalkyl isourea

[0082] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of 4-chlorophenylethanol of Formula I-8, and the other steps were the same as in Example 1, to obtain a colorless oily product of Formula III-8 with a yield of 96%.

[0083]

[0084] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.24(d,J=8.4Hz,2H),7.16(d,J=8.4Hz,2H),4.21(t,J=6.6Hz,2H),3.7 4-3.58(m,1H),3.37(brs,1H),3.21-3.07(m,1H),2.91(t,J=6.6Hz,2H),1.11-1.01(m,12H); 13 C NMR (100MHz, CDCl3) δ151.6,137.8,132.0,130.5,128.4,65.4,46.3,43.5,35.0,24.4,24.1; HRMS (ESI) m / z C 15 H 24 ClN2O + [M+H] +Theoretical value: 283.1572, measured value: 283.1575.

[0085] Example 9

[0086] Synthetic formula III-9 shows an oxoalkyl isourea

[0087] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of 4-hydroxybutylvinyl ether of Formula I-9, and the other steps were the same as in Example 1, to obtain a colorless oily product of Formula III-9 with a yield of 90%.

[0088]

[0089] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ6.46(dd,J=14.3,6.8Hz,1H),4.17(dd,J=14.3,1.9Hz,1H),4.05(t,J=6.0Hz,2H),3.97(dd,J=6.9,1.9H z,1H),3.81-3.73(m,1H),3.71(t,J=6.1Hz,2H),3.53-3.29(m,1H),3.25-3.03(m,1H),1.80-1.67(m,4H),1.17-1.02(m,12H); 13 C NMR (100MHz, CDCl3) δ152.0,86.4,77.4,67.8,64.6,46.3,43.5,26.1,25.7,24.4,24.1; HRMS (ESI) m / z C 13 H 27 N2O2 + [M+H] + Theoretical value: 243.2067, measured value: 243.2070.

[0090] Example 10

[0091] Synthetic formula III-10 shows an oxoalkyl isourea

[0092] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of osepimiridine as shown in Formula I-10, and the other steps were the same as in Example 1, to obtain a white solid product as shown in Formula III-10 with a yield of 92%.

[0093]

[0094] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ5.33 (d, J = 5.0Hz, 1H), 4.68-4.54 (m, 1H), 3.83-3.69 (m, 1H), 3.25-3.02(m,1H),2.45(dd,J=13.6,4.8Hz,1H),2.31-2.16(m,1H),2.05-1.90(mm ,3H),1.89-1.75(m,2H),1.63-1.41(m,7H),1.41-1.20(m,5H),1.20-1.08(m,12H) ,1.08-0.99(m,12H),0.95-0.89(m,4H),0.86(dd,J=6.6,1.9Hz,6H),0.67(s,3H); 13 C NMR (100MHz, CDCl3) δ150.6,140.7,121.9,73.1,56.9,56.3,50.2,46.3,43.3,42.4,39.9,39.7,38.5,37.2,36.9,36. 3,35.9,32.1,32.1,28.4,28.1,28.0,24.6,24.4,24.4,24.1,24.0,23.0,22.7,21.2,19.6,18.9,12.0; HRMS(ESI)m / zC 34 H 61 N2O + [M+H] + Theoretical value: 513.4778, measured value: 513.4788.

[0095] Example 11

[0096] Synthetic formula III-11 shows an oxoalkyl isourea

[0097] In this embodiment, N-Boc-4-hydroxypiperidine in Example 1 was replaced with equimolar amounts of stigmasterol of Formula I-11, and the other steps were the same as in Example 1, to obtain a white solid product of Formula III-11 with a yield of 85%.

[0098]

[0099] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ5.33(d,J=5.1Hz,1H),5.15(dd,J=15.2,8.6Hz,1H),5.01(dd,J=15.1,8.5Hz,1H),4 .70-4.54(m,1H),3.85-3.68(m,1H),3.29-3.00(m,1H),2.53-2.41(m,1H),2.28-2.16(m,1H),2.09-1.92 (m,4H),1.81(dt,J=13.3,3.6Hz,1H),1.74-1.65(m,1H),1.60-1.48(m,6H),1.47-1.37(m,3H),1.24-1.1 3(m,5H),1.10(d,J=6.4Hz,6H),1.08-1.01(m,12H),1.00-0.89(m,3H),0.87-0.75(m,10H),0.69(s,3H); 13 C NMR (100MHz, CDCl3) δ150.7,140.8,138.5,129.4,121.9,73.2,57.0,56.1,51.4,50.3,46.3,43.4,42.4,40.7,39.8,38.6 ,37.2,36.9,32.1,32.1,32.0,29.1,28.1,25.6,24.5,24.4,24.1,21.4,21.2,21.2,19.6,19.1,12.4,12.2; HRMS(ESI)m / z C 36 H3N2O + [M+H] + Theoretical value: 539.4935, measured value: 539.4937.

[0100] Example 12

[0101] Synthetic formula III-12 shows an oxoalkyl isourea

[0102] Under an argon atmosphere, naphthaleneethanol (34.4 g, 200 mmol, 1.0 equivalent) of Formula I-12, N,N'-diisopropylcarbodiimide (25.2 g, 200 mmol, 1.0 equivalent) of Formula II-1, nickel chloride (259.2 mg, 2 mmol, 0.01 equivalent), and acetonitrile (100 mL) were added to a 250 mL round-bottom flask. The flask was sealed and vigorously stirred at 60 °C until the alcohol was completely consumed as monitored by thin-layer chromatography (TLC). After the reaction was complete, the solvent was removed by rotary evaporation, followed by the addition of diethyl ether (200 mL). The suspension was filtered through neutral alumina (Grade I activity) and washed with diethyl ether. The filtrate was evaporated and dried under vacuum to obtain a colorless oily product of Formula III-12 in 92% yield.

[0103]

[0104] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.3Hz,1H),7.85(d,J=7.9Hz,1H),7.73(dd,J=5.8,3.7Hz,1H),7.54-7.45(m,2H),7.42-7.36(m,2H ),4.38(t,J=7.2Hz,2H),3.74-3.62(m,1H),3.44(t,J=7.2Hz,2H),3.38(brs,1H),3.23-3.12(m,1H),1.08(dd,J=28.7,6.4Hz,12H); 13 C NMR (100MHz, CDCl3) δ151.5,135.2,133.9,132.5,128.7,127.2,127.1,125.9,125.6,125.5,124.6,65.2,46.3,43.6,32.8,24.5,24.0; HRMS (ESI) m / z C 19 H 27 N2O + [M+H] + Theoretical value: 299.2118, measured value: 299.2118.

[0105] Example 13

[0106] Synthetic formula III-13 shows an oxoalkyl isourea

[0107] Under an argon atmosphere, naphthaleneethanol (34.4 g, 200 mmol, 1.0 equivalent) of Formula I-12, N,N'-dicyclohexylcarbodiimide (41.2 g, 200 mmol, 1.0 equivalent) of Formula II-2, ferric chloride (324.4 mg, 2 mmol, 0.01 equivalent), and acetonitrile (100 mL) were added to a 250 mL round-bottom flask. The flask was sealed and vigorously stirred at 60 °C until the alcohol was completely consumed as monitored by thin-layer chromatography (TLC). After the reaction was complete, the solvent was removed by rotary evaporation, followed by the addition of diethyl ether (200 mL). The suspension was filtered through neutral alumina (Grade I activity) and washed with diethyl ether. The filtrate was evaporated and dried under vacuum to obtain a yellow oily product of Formula III-13, with a yield of 92%.

[0108]

[0109] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.3Hz,1H),7.85(d,J=7.9Hz,1H),7.73(dd,J=5.8,3.7Hz,1H),7.54-7.45(m,2H),7.42-7.36(m,2H ),4.38(t,J=7.2Hz,2H),3.74-3.62(m,1H),3.44(t,J=7.2Hz,2H),3.38(brs,1H),3.23-3.12(m,1H),1.08(dd,J=28.7,6.4Hz,12H); 13 C NMR (100MHz, CDCl3) δ151.5,135.2,133.9,132.5,128.7,127.2,127.1,125.9,125.6,125.5,124.6,65.2,46.3,43.6,32.8,24.5,24.0; HRMS (ESI) m / z C 19 H 27 N2O + [M+H] + Theoretical value: 299.2118, measured value: 299.2118.

[0110] Example 14

[0111] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-1

[0112] Under an argon atmosphere, 12 mmol of oxyalkylisourea (Formula III-1), 6 mmol of 4-bromobenzonitrile (Formula IV-1), 0.6 mmol of nickel bromide trihydrate, 0.6 mmol of 2,2':6',2”-terpyridine (0.6 mmol), 15 mmol of N-methyldicyclohexylamine, and 20 mL of N,N-dimethylacetamide were sequentially added to a 100 mL reaction tube equipped with a magnetic stirrer. The reaction was carried out under ultraviolet light at 390–395 nm for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain the yellow solid product of Formula V-1 in 74% yield.

[0113]

[0114] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3) δ7.59(d,J=8.4Hz,2H),7.29(d,J=8.3Hz,2H),4.38-4.16 (m,2H),2.84-2.66(m,3H),1.84-1.78(m,2H),1.62-1.55(m,2H),1.47(s,9H); 13 C NMR(100MHz, CDCl3)δ154.9,151.3,132.5,127.8,119.0,110.4,79.8,44.2,43.0,32.8,28.6; HRMS(ESI)m / z C 17 H 22 N2NaO2 + [M+Na] + Theoretical value: 309.1573, measured value: 309.1575.

[0115] Example 15

[0116] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-1

[0117] In this embodiment, 4-bromobenzonitrile in Example 14 was replaced with equimolar amounts of 4-bromocyclopropylbenzene of Formula IV-2, and the other steps were the same as in Example 14, to obtain the yellow solid product of Formula V-2 with a yield of 70%.

[0118]

[0119] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.09(d,J=8.2Hz,2H),7.02(d,J=8.2Hz,2H),4.34-4.14(m,2H ),2.89-2.69(m,2H),2.66-2.54(m,1H),1.90-1.83(m,1H),1.83-1.76(m,2H),1.65 -1.56(m,2H),1.48(s,9H),0.97-0.91(m,2H),0.70-0.64(m,2H); 13 C NMR(100MHz, CDCl3)δ155.0,143.0,142.1,126.8,125.9,79.5,44.6,42.4,33.4,28.6,15.1,9.2; HRMS(ESI)m / z C 19 H 27 NNaO2 + [M+Na] + Theoretical value: 324.1934, measured value: 324.1935.

[0120] Example 16

[0121] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-3

[0122] Under an argon atmosphere, 12 mmol of oxyalkylisourea (Formula III-3), 6 mmol of 4-bromotrifluorotoluene (Formula IV-3), 0.6 mmol of nickel bromide trihydrate, 0.6 mmol of 2,2':6',2”-terpyridine (0.6 mmol), 15 mmol of N-methyldicyclohexylamine, and 20 mL of N,N-dimethylacetamide were sequentially added to a 100 mL reaction tube equipped with a magnetic stirrer. The reaction was carried out under ultraviolet light at 390–395 nm for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain the yellow solid product shown in Formula V-3, with a yield of 42%.

[0123]

[0124] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.50(d,J=8.9Hz,2H),7.26-7.21(m,2H),7.16(d,J=8.4Hz,2H),6.91(d,J=8.9H z,2H),4.04-3.94(m,2H),3.05-2.93(m,2H),2.83-2.72(m,1H),2.00-1.92(m,2H),1.86-1.73(m,2H); 13 CNMR (100MHz, CDCl3) δ153.4,147.9,144.1,133.7,133.7,128.1,121.3,119.8(q,J=92.6Hz),114.6,99.9,48.4,42.0,32.8; 19 F NMR (376MHz, CDCl3) δ-57.91; HRMS (ESI-TOF) m / z C 19 H 17 F3N2NaO+ + [M+Na] + Theoretical value: 369.1185, measured value: 369.1189.

[0125] Example 17

[0126] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-6

[0127] Under an argon atmosphere, 12 mmol of oxyalkylisourea (Formula III-6), 6 mmol of 4-bromophenyl(R)-2-(6-methoxynaphthyl-2-yl)propionate (Formula IV-4), 0.6 mmol of nickel bromide trihydrate, 0.6 mmol of 2,2':6',2”-terpyridine (0.6 mmol), 15 mmol of N-methyldicyclohexylamine, and 20 mL of N,N-dimethylacetamide were sequentially added to a 100 mL reaction tube equipped with a magnetic stirrer. The reaction was carried out under ultraviolet light at 390–395 nm for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain the yellow solid product shown in Formula V-4, with a yield of 57%.

[0128]

[0129] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.79-7.70 (m, 3H), 7.50 (dd, J = 8.5, 1.9Hz, 1H), 7.19-7.1 0(m,4H),6.88(d,J=8.5Hz,2H),5.24-5.18(m,1H),4.08(q,J=7.1Hz,1H),3.93( s,3H),2.62(t,J=8.0Hz,2H),2.39-2.32(m,1H),2.27-2.14(m,4H),2.10-2.02 (m,2H),1.69(d,J=7.1Hz,3H),1.27(s,3H),1.13(d,J=8.5Hz,1H),0.82(s,3H); 13 C NMR (100MHz, CDCl3) δ173.5,157.9,148.9,147.8,140.1,135.4,134.0,129.5,129.3,129.2,127.5,126.3,126.3,1 21.2,119.2,116.5,105.8,55.5,46.0,45.7,41.0,38.9,38.1,33.4,31.8,31.4,26.5,21.3,18.7; HRMS(APCI)m / zC 31 H 35 O3 + [M+H] + Theoretical value: 455.2581, measured value: 455.2586.

[0130] Example 18

[0131] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-6

[0132] In this embodiment, 4-bromophenyl(R)-2-(6-methoxynaphthyl-2-yl)propionate in Example 17 was replaced with equimolar amounts of 1-(4-bromophenyl)-5-(p-methylphenyl)-3-(trifluoromethyl)-1-hydropyrazole as shown in Formula IV-5, and the other steps were the same as in Example 17, to obtain the yellow solid product shown in Formula V-5 with a yield of 72%.

[0133]

[0134] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.23-7.14(m,4H),7.14-7.08(m,4H),6.71(s,1H),5.24-5.18(m,1H),2.69(t,J=7.9Hz, 2H),2.40-2.34(m,4H),2.31-2.18(m,4H),2.11-2.04(m,2H),1.29(s,3H),1.13(d,J=8.5Hz,1H),0.83(s,3H); 13 CNMR (100MHz, CDCl3) δ147.5,144.8,143.2,143.1,142.9,129.5,129.1,128.8,126.5,125.5,120. 5,116.8,105.2,105.2,46.0,41.0,38.5,38.1,33.5,31.76,31.4,26.5,21.4,21.4; HRMS(APCI)m / z C 28 H 30 F3N2 + [M+H] + Theoretical value: 451.2356, measured value: 451.2361.

[0135] Example 19

[0136] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-6

[0137] Under an argon atmosphere, 12 mmol of oxyalkylisourea (Formula III-11), 6 mmol of methyl 4-bromobenzoate (Formula IV-6), 0.6 mmol of nickel iodide, 0.6 mmol of 2,2':6',2”-terpyridine (Formula 0.6 mmol), 15 mmol of diisopropylamine, and 20 mL of N,N-dimethylacetamide were sequentially added to a 100 mL reaction tube equipped with a magnetic stirrer. The reaction was carried out under ultraviolet light at 390–395 nm for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 60:1 to obtain the yellow solid product of Formula V-6 in a yield of 62%.

[0138]

[0139] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.89(d,J=7.9Hz,2H),7.25-7.18(m,2H),5.28(d,J=5.0Hz,1H),5.09(dd,J=15.1,8.5Hz ,1H),4.95(dd,J=15.1,8.5Hz,1H),3.82(s,3H),2.57-2.45(m,1H),2.36(t,J=13.3Hz,1H),2.10(dd,J=13.6, 3.6Hz,1H),1.99-1.88(m,3H),1.72-1.65(m,2H),1.57-1.48(m,3H),1.46-1.40(m,3H),1.39-1.32(m,2H),1. 20-1.07(m,6H),1.01(s,4H),1.00-0.91(m,6H),0.82-0.75(m,4H),0.75-0.71(m,5H),0.63(d,J=8.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ167.3,152.6,142.6,138.5,129.9,129.4,128.1,126.9,120.6,57.1,56.1,52.1,51.4,50.6,46.0,42. 4,40.7,40.4,39.9,39.9,37.1,32.1,32.0,29.9,29.1,25.6,24.5,21.4,21.2,21.1,19.7,19.1,12.4,12.2; HRMS(APCI)m / z C 37 H 552 + [M+H] + Theoretical value: 531.4197, measured value: 531.4190.

[0140] Example 20

[0141] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-6

[0142] Under an argon atmosphere, 12 mmol of oxyalkylisourea (Formula III-1), 6 mmol of methyl 4-bromobenzoate (Formula IV-6), 0.6 mmol of nickel iodide, 0.6 mmol of 4,7-diphenyl-1,10-phenanthroline (Formula IV-6), 15 mmol of triethylamine, and 20 mL of N,N-dimethylacetamide were sequentially added to a 100 mL reaction tube equipped with a magnetic stirrer. The reaction was carried out under ultraviolet light irradiation at 390–395 nm for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 60:1 to obtain the yellow solid product shown in Formula V-7, with a yield of 73%.

[0143]

[0144] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.89(d,J=7.9Hz,2H),7.25-7.18(m,2H),5.28(d,J=5.0Hz,1H),5.09(dd,J=15.1,8.5Hz ,1H),4.95(dd,J=15.1,8.5Hz,1H),3.82(s,3H),2.57-2.45(m,1H),2.36(t,J=13.3Hz,1H),2.10(dd,J=13.6, 3.6Hz,1H),1.99-1.88(m,3H),1.72-1.65(m,2H),1.57-1.48(m,3H),1.46-1.40(m,3H),1.39-1.32(m,2H),1. 20-1.07(m,6H),1.01(s,4H),1.00-0.91(m,6H),0.82-0.75(m,4H),0.75-0.71(m,5H),0.63(d,J=8.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ167.3,152.6,142.6,138.5,129.9,129.4,128.1,126.9,120.6,57.1,56.1,52.1,51.4,50.6,46.0,42. 4,40.7,40.4,39.9,39.9,37.1,32.1,32.0,29.9,29.1,25.6,24.5,21.4,21.2,21.1,19.7,19.1,12.4,12.2; HRMS(APCI)m / z C 37 H 552 +[M+H] + Theoretical value: 531.4197, measured value: 531.4190.

[0145] Example 21

[0146] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-2

[0147] Under an argon atmosphere, 0.3 mmol of oxyalkylisourea (Formula III-2), 0.6 mmol of 3,5-dimethylphenylboronic acid (Formula VI-1), 0.03 mmol of nickel iodide, 0.03 mmol of 4,4'-dimethyl-2,2'-bipyridine (Formula VI-1), and 2.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction mixture was stirred at 110 °C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a colorless solid product of Formula V-8 in 58% yield.

[0148]

[0149] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3) δ7.89(d,J=7.9Hz,2H),7.23(d,J=8.0Hz,2H),3.83(s,3H),3.04-2.89( m,1H),1.95-1.86(m,1H),1.78-1.68(m,1H),1.21(d,J=7.0Hz,3H),1.06(d,J=10.6Hz,6H); 13 C NMR(100MHz, CDCl3)δ167.2,154.2,130.1,128.1,127.3,71.5,52.1,51.3,36.7,30.5,29.9,25.0; HRMS(APCI)m / z C 14 H 21 O + [M+H] + Theoretical value: 237.1485, measured value: 237.1486.

[0150] Example 22

[0151] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-4

[0152] Under an argon atmosphere, 0.3 mmol of oxyalkylisourea (Formula III-4), 0.6 mmol of methyl 4-carboxylate phenylboronic acid (Formula VI-2), 0.03 mmol of nickel iodide, 0.03 mmol of 4,4'-dimethyl-2,2'-bipyridine (Formula VI-2), and 2.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction mixture was stirred at 110 °C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain a colorless solid product of Formula V-9 in 55% yield.

[0153]

[0154] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3) δ7.92(d,J=8.0Hz,2H),7.24(d,J=7.9Hz,2H),3.87(s, 3H),2.78-2.71(m,2H),1.94-1.85(m,1H),1.80-1.73(m,2H),1.27(s,6H); 13 C NMR(100MHz, CDCl3)δ167.3,148.4,129.8,128.4,127.8,70.8,52.1,45.3,30.9,29.4; HRMS(APCI)m / z C 13 H 19 O3 + [M+H] + Theoretical value: 223.1329, measured value: 223.1330.

[0155] Example 23

[0156] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-6

[0157] In this embodiment, the oxyalkylisourea in Example 22 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-6, and the other steps were the same as in Example 22, to obtain the colorless solid product shown in Formula V-10, with a yield of 55%.

[0158]

[0159] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.95(d,J=8.2Hz,2H),7.25(d,J=8.1Hz,2H),5.26-5.20(m,1H),3.90(s,3H),2.72(t,J=8.0Hz,2H),2 .40-2.34(m,1H),2.31-2.25(m,2H),2.25-2.13(m,2H),2.12-2.04(m,2H),1.29(s,3H),1.15(d,J=8.5Hz,1H),0.84(s,3H); 13 C NMR (100MHz, CDCl3) δ167.3,148.2,147.5,129.7,128.5,127.8,116.8,52.1,46.0,40.9,38.4,38.1,34.0,31.8,31.4,26.5,21.3; HRMS (APCI) m / zC 19 H 25 O2 + [M+H] + Theoretical value: 285.1849, measured value: 285.1850.

[0160] Example 24

[0161] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-7

[0162] In this embodiment, the oxyalkylisourea in Example 22 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-7, and the other steps were the same as in Example 22, to obtain the colorless solid product shown in Formula V-11 with a yield of 74%.

[0163]

[0164] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),7.26(d,J=4.5Hz,2H),7.22(d,J=4 .6Hz,2H),3.92(s,3H),3.82-3.71(m,1H),3.39(dd,J=15.6,8.3Hz,2H),3.10(dd,J=15.6,8.6Hz,2H); 13 C NMR(100MHz, CDCl3)δ167.2,151.1,142.6,129.9,128.3,127.2,126.7,124.5,52.1,45.4,40.8; HRMS(APCI)m / z C17 H 17 O2 + [M+H] + Theoretical value: 253.1223, measured value: 253.1225.

[0165] Example 25

[0166] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-8

[0167] In this embodiment, the oxyalkylisourea in Example 22 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-8, and the other steps were the same as in Example 22, to obtain the colorless solid product shown in Formula V-12 with a yield of 45%.

[0168]

[0169] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.2Hz, 2H), 7.19 (dd, J = 13.9, 8.3Hz, 4H), 7.03 (d, J = 8.3Hz, 2H), 3.89 (s, 3H), 2.96-2.85 (m, 4H); 13 C NMR(100MHz, CDCl3)δ167.2,146.8,139.6,131.9,129.9,129.8,128.7,128.6,128.2,52.1,37.8,36.8; HRMS(APCI)m / z C 16 H 16 ClO2 + [M+H] + Theoretical value: 275.0833, measured value: 275.0835.

[0170] Example 26

[0171] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-9

[0172] In this embodiment, the oxyalkylisourea in Example 22 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-9, and the other steps were the same as in Example 22, to obtain the colorless solid product shown in Formula V-13 with a yield of 72%.

[0173]

[0174] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR(400MHz, CDCl3) δ7.95(d,J=8.2Hz,2H),7.25(d,J=8.1Hz,2H),6.46(dd,J=14.3,6.8Hz,1H),4.21-4.1 3(m,1H),4.01-3.95(m,1H),3.90(s,3H),3.69(t,J=5.9Hz,2H),2.70(t,J=7.3Hz,2H),1.81-1.68(m,4H); 13 C NMR(100MHz, CDCl3)δ167.3,152.0,147.9,129.8,128.6,128.0,86.5,67.8,52.1,35.7,28.7,27.6; HRMS(APCI)m / z C 14 H 19 O3 + [M+H] + Theoretical value: 235.1329, measured value: 235.1335.

[0175] Example 27

[0176] Application of oxyalkylisourea as a radical alkylating agent as shown in Formula III-10

[0177] In this embodiment, the oxyalkylisourea in Example 21 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-10, and the other steps were the same as in Example 21, to obtain the colorless solid product shown in Formula V-14, with a yield of 56%.

[0178]

[0179] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.42-7.37(m,2H),7.34-7.29(m,3H),7.25-7.20(m,2H),7.19-7.14(m,3H),6.93-6.84(m,3H) ,6.83-6.79(m,2H),6.61-6.55(m,2H),4.03(t,J=7.3Hz,2H),3.44(t,J=7.5Hz,2H),3.01-2.92(m,4H),2.31(s,6H); 13C NMR (100MHz, CDCl3) δ157.2,143.1,141.9,141.2,138.1,135.3,134.9,131.8,129.7,129.5,128. 5,128.5,128.3,128.2,127.1,126.9,126.7,113.6,68.7,43.0,38.7,35.7,21.4; HRMS(APCI)m / z C 32 H 32 ClO + [M+H] + Theoretical value: 467.2136, measured value: 467.2143.

[0180] Example 28

[0181] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-5

[0182] Under an argon atmosphere, 0.3 mmol of oxyalkylisourea (Formula III-5), 0.675 mmol of bis(catechol)boronic acid ester (Formula VII), 0.03 mmol of nickel iodide, 0.03 mmol of 2,2':6',2”-terpyridine (Formula VII), and 1.5 mL of N,N-dimethylpropenylurea were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at 80 °C for 8 hours. After cooling to room temperature, 4.0 equivalents of pinacol and 1.05 mL of triethylamine were added, and the mixture was stirred for another hour at room temperature. After the reaction was completed, the reaction solution was extracted with ethyl acetate and saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 100:1 to obtain a colorless solid product of Formula VIII-1 in 71% yield.

[0183]

[0184] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ2.40 (dd, J=19.3, 8.8Hz, 1H), 2.08-1.99 (m, 1H), 1.93- 1.87(m,1H),1.78-1.72(m,2H),1.71-1.62(m,2H),1.59-1.43(m,3H),1.43- 1.34(m,1H),1.33-1.27(m,2H),1.24(s,3H),1.21(d,J=1.6Hz,14H),1.09-1 .02(m,1H),0.99-0.85(m,3H),0.83(s,3H),0.78(s,3H),0.73-0.67(m,1H); 13 C NMR (100MHz, CDCl3) δ221.7,82.9,54.9,51.7,48.0,47.9,39.5,36.4,36.0, 35.2,31.7,31.1,30.2,28.7,25.1,24.9,24.9,23.5,21.9,20.2,13.9,12.5; 11 B NMR (128MHz, CDCl3) δ = 33.63; HRMS (APCI) m / z C 25 H 42 BO3 + [M+H] + Theoretical value: 401.3222, measured value: 401.3225.

[0185] Example 29

[0186] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-8

[0187] In this embodiment, the oxyalkylisourea in Example 28 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-8, and the other steps were the same as in Example 28, to obtain the white solid product shown in Formula VIII-2 with a yield of 76%.

[0188]

[0189] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.22 (d, J = 8.4Hz, 2H), 7.14 (d, J = 8.5Hz, 2H), 2.71 (t, J = 8.1Hz, 2H), 1.21 (s, 12H), 1.11 (t, J = 8.1Hz, 2H); 13 C NMR (100MHz, CDCl3) δ143.0,131.3,129.5,128.4,83.3,29.5,25.0.11 BNMR (128MHz, CDCl3) δ = 34.11; HRMS (APCI) m / z C 14 H 21 BClO2 + [M+H] + Theoretical value: 267.1318, measured value: 267.1320.

[0190] Example 30

[0191] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-6

[0192] In this embodiment, the oxyalkylisourea in Example 28 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-6, and the other steps were the same as in Example 28, to obtain the white solid product shown in Formula VIII-3 with a yield of 85%.

[0193]

[0194] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ5.17-5.13(m,1H),2.36-2.29(m,1H),2.24-2.14(m,2H),2.08 -1.97(m,4H),1.24(s,3H),1.23(s,12H),1.13(d,J=8.4Hz,1H),0.87-0.80(m,5H); 13 C NMR (100MHz, CDCl3) δ150.3,114.4,83.1,46.1,41.1,38.1,31.7,31.3,30.9,26.5,25.0,24.9,21.3; 11 B NMR (128MHz, CDCl3) δ = 34.11.HRMS (APCI) m / z C 17 H 30 BO2 + [M+H] + Theoretical value: 277.2333, measured value: 277.2334.

[0195] Example 31

[0196] Application of oxyalkylisourea as a free radical alkylating agent as shown in Formula III-11

[0197] In this embodiment, the oxyalkylisourea in Example 28 was replaced with an equimolar amount of the oxyalkylisourea shown in Formula III-11, and the other steps were the same as in Example 28, to obtain the white solid product shown in Formula VIII-4, with a yield of 52%.

[0198]

[0199] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3) δ5.33(d,J=5.1Hz,0.12H),5.26(d,J=5.1Hz,0.86H),5.15(dd,J=15.1,8.5Hz,1H) ,5.00(dd,J=15.1,8.5Hz,1H),2.27-2.14(m,1H),2.07-1.90(m,4H),1.85(dt,J=12.7,3.3Hz,1H),1.75 -1.67(m,1H),1.61-1.47(m,6H),1.47-1.35(m,4H),1.30-1.09(m,17H),1 .09-0.95(m,10H),0.86-0.81(m,4H),0.79(d,J=6.9Hz,5H),0.68(s,3H); 13 C NMR (100MHz, CDCl3) δ143.8,138.4,129.2,118.6,82.8,57.0,56.0,51.3,50.6,42.2,40.9,40.6,39.8 ,37.4,33.8,31.9,31.8,29.0,25.4,24.8,24.7,24.4,24.1,21.2,21.1,20.8,19.5,19.0,12.3,12.1; 11 BNMR (128MHz, CDCl3) δ = 35.69; HRMS (APCI) m / z C 35 H 60 BO2 + [M+H] + Theoretical value: 523.4681, measured value: 523.4687.

Claims

1. A method for synthesizing an oxyalkyl isourea, characterized in that: An alcohol compound of Formula I, a carbodiimide of Formula II, and a metal catalyst are added to an organic solvent and stirred at 25–100 °C under inert gas protection. After the reaction is complete, the mixture is separated and purified to obtain an oxoalkyl isourea of ​​Formula III. In the formula, R 1 Represents any one of primary, secondary, and tertiary alkyl groups; R 2 and R 3 Each of these can be independently represented by any one of the following: ethyl, propyl, n-butyl, n-pentyl, benzyl isopropyl, cyclohexyl, tert-butyl, p-tolyl, 3-dimethylaminopropyl, 2,6-diisopropylphenyl, and trimethylsilyl. The metal catalyst is selected from any one of ferric chloride, ferric bromide, ferric trifluoromethanesulfonate, ferrous chloride, ferrous bromide, ferrous iodide, ferrous trifluoromethanesulfonate, cobalt chloride, cobalt bromide, cobalt iodide, cobalt acetate, cobalt perchlorate, cobalt acetylacetonate, cobalt trifluoromethanesulfonate, nickel chloride, nickel bromide, nickel iodide, nickel chloride dimethoxyethane, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, nickel trifluoromethanesulfonate, and nickel fluoride. The organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

2. The method for synthesizing oxyalkyl isourea according to claim 1, characterized in that: The amount of carbodiimide used is 1.0 to 4.0 times the molar amount of the alcohol compound, and the amount of the metal catalyst used is 0.001 to 0.1 times the molar amount of the alcohol compound.

3. The application of the oxyalkylisourea of ​​claim 1 as a free radical alkylating agent in the preparation of alkyl aromatics from haloaromatics, characterized in that: The oxyalkylisourea shown in Formula III, the haloaromatic hydrocarbon shown in Formula IV, a nickel catalyst, a ligand, and a base are added to an organic solvent and reacted under ultraviolet light irradiation under inert gas protection to obtain the alkylaromatic hydrocarbon shown in Formula V. In the formula, Ar represents any one of aryl, substituted aryl, heterocyclic aryl, and substituted heterocyclic aryl; X represents Br or Cl; The nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, nickel bromide trihydrate, nickel chloride hexahydrate, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, and nickel trifluoromethanesulfonate. The ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2"-tripyridine, 4,4',4″-tri-tert-butyl-2,2':6',2"-tripyridine and 4'-(4-methoxyphenyl)-2,2':6',2"-tripyridine; The base is selected from any one of diisopropylamine, N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N,N-diethylcyclohexylamine, dicyclohexylamine, and N-methyldicyclohexylamine; The organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

4. The application of the oxyalkylisourea as a free radical alkylating agent according to claim 3 in the preparation of alkyl aromatics from haloaromatics, characterized in that: The amount of the oxyalkylisourea is 1.0 to 5.0 times the molar amount of the haloaromatic hydrocarbon; the amount of the nickel catalyst is 2% to 20% of the molar amount of the oxyalkylisourea; the amount of the ligand is 2% to 20% of the molar amount of the oxyalkylisourea; and the amount of the base is 1.0 to 5.0 times the molar amount of the oxyalkylisourea.

5. The application of the oxyalkylisourea as a free radical alkylating agent according to claim 3 in the preparation of alkyl aromatics from haloaromatics, characterized in that: The reaction was carried out under argon protection and irradiated with ultraviolet light with a wavelength of 390-395 nm for 15-20 hours.

6. The application of the oxyalkylisourea of ​​claim 1 as a free radical alkylating agent in the preparation of alkyl aromatics from arylboronic acids, characterized in that: The oxyalkylisourea shown in Formula III, along with the arylboronic acid shown in Formula VI, a nickel catalyst, and a ligand, are added to an organic solvent and reacted under inert gas protection at 70–140 °C with stirring to obtain the alkyl aromatic hydrocarbon shown in Formula V. In the formula, Ar represents any one of aryl, substituted aryl, heterocyclic aryl, and substituted heterocyclic aryl; The nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, nickel bromide trihydrate, nickel chloride hexahydrate, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, and nickel trifluoromethanesulfonate. The ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2"-tripyridine, 4,4',4″-tri-tert-butyl-2,2':6',2"-tripyridine and 4'-(4-methoxyphenyl)-2,2':6',2"-tripyridine; The organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

7. The application of the oxyalkylisourea as a free radical alkylating agent according to claim 6 in the preparation of alkyl aromatics from arylboronic acids, characterized in that: The amount of arylboronic acid used is 1.0 to 5.0 times the molar amount of oxyalkylisourea; the amount of nickel catalyst used is 2% to 20% of the molar amount of oxyalkylisourea; and the amount of ligand used is 2% to 20% of the molar amount of oxyalkylisourea.

8. The application of the oxyalkylisourea of ​​claim 1 as a free radical alkylating agent in the preparation of pinacol esters of alkylboronic acid, characterized in that: The oxyalkyl isourea of ​​Formula III, the bis(catechol) boronic acid ester of Formula VII, a nickel catalyst and a ligand are added to an organic solvent and stirred at 50-100°C under inert gas protection. After the reaction is completed, the mixture is post-treated with pinacol and triethylamine and then separated and purified to obtain the alkyl borate pinacol ester of Formula VIII. The nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, nickel bromide trihydrate, nickel chloride hexahydrate, nickel bromide dimethoxyethane, nickel acetate, nickel acetylacetonate, and nickel trifluoromethanesulfonate. The ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2"-tripyridine, 4,4',4″-tri-tert-butyl-2,2':6',2"-tripyridine and 4'-(4-methoxyphenyl)-2,2':6',2"-tripyridine; The organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

9. The application of the oxyalkylisourea as a free radical alkylating agent according to claim 8 in the preparation of alkylboronic acid pinacol esters, characterized in that: The amount of the bis(catechol)boronic acid ester is 1.0 to 5.0 times the molar amount of the oxyalkylisourea; the amount of the nickel catalyst is 2% to 20% of the molar amount of the oxyalkylisourea; and the amount of the ligand is 2% to 20% of the molar amount of the oxyalkylisourea.

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