Method for selectively preparing benzyl or alkyl phosphine oxide compounds based on benzyl sulfide derivatives

Abstract

The present invention discloses a method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives. The preparation method comprises the following steps: under a nitrogen atmosphere, a P(O)–H compound, a benzyl sulfide compound, a nickel catalyst, and a base are mixed in an organic solvent, and after heating and stirring, benzyl phosphine oxide and alkyl phosphine oxide are obtained through cooling and purification. The preparation method of the present invention can achieve selective C–S bond cleavage of benzyl sulfide compounds by controlling reaction conditions such as nickel catalyst, ligand, base, and reaction temperature, and selectively prepare benzyl or alkyl phosphine oxides with relatively high yields respectively. The reaction process is simple and controllable, and at the same time, it can avoid the problems of poor raw material stability, high toxicity, and poor substrate applicability existing in the prior art. It is green and environmentally friendly, and has good prospects for market promotion and application.

Description

Technical Field

[0001] The present invention relates to the field of organic phosphine synthesis, and particularly relates to a method for selectively preparing benzyl or alkyl phosphine oxide compounds based on benzyl sulfide derivatives. Background Art

[0002] Organic phosphine compounds have rich physiological activities, special chemical reactivity and excellent optoelectronic properties, and have wide and important application values in the fields of medicine, pesticides, chemical fertilizers, industrial extractants, reaction ligands and organic flame retardant materials. Especially due to having various biological activities, such as antiviral, antitumor, antibacterial, enzyme inhibition, etc., their extensive application as ligands in synthetic chemistry and their important biological and pharmacological properties have attracted extensive attention of chemists. For example, in 2017, the FDA approved the new oral ALK inhibitor Brigatinib for the treatment of lung cancer, and its structure contains both aryl carbon-phosphorus bonds and alkyl carbon-phosphorus bonds (Journal of Medicinal Chemistry, 2016, 59, 4948-4964). Alkyl phosphine oxide is also a very key intermediate, which has been widely used in the synthesis of various material main precursors and the direct precursor of olefins in the Horner-Wadsworth-Emmons reaction (Organic Letters, 2008, 10, 5437-5440).

[0003] The traditional methods for synthesizing alkyl phosphine oxides are mainly the nucleophilic substitution reaction of organometallic reagents and phosphorus halide reagents and the Michaelis-Arbuzov reaction of trivalent phosphites and alkyl halides. The reaction requires the use of organometallic reagents and phosphorus reagents with poor stability or highly toxic haloalkanes as raw materials, the conditions are harsh, and the functional group compatibility is relatively poor. The cross-coupling reaction of transition metal-catalyzed P-H compounds has the characteristics of simple and efficient, mild conditions, wide substrate scope, etc., and is an ideal method for preparing alkyl phosphine oxides. However, there has been little progress in constructing sp 3 C-P bonds at present (Journal of the American Chemical Society, 2015, 137, 1782-1785; Organic Letters, 2018, 20, 6746-6749). Simple and easily available, more environmentally friendly sulfide derivatives can be used as coupling reagents to realize the cleavage of C-S bonds and react with P(O)H compounds under the catalysis of nickel or palladium to construct aryl phosphine oxides containing sp 2 C-P bonds (Chemical Communications 2016, 52, 12233-12236; J. Org. Chem. 2020, 85, 14653-14663). For the selective preparation of sp 3The alkyl phosphine oxides with C-P bonds have not been reported. SUMMARY OF THE INVENTION

[0004] Based on this, in view of the deficiencies of the prior art, the present invention provides a simple and efficient method for the selective synthesis of alkyl phosphine oxide compounds by the reaction of nickel-catalyzed benzyl sulfide compounds with P(O)-H compounds. This method has simple and easily available raw materials, is green and stable, and can achieve the selective cleavage of C-S bonds in benzyl sulfide compounds by controlling reaction conditions such as nickel catalysts, ligands, bases, and reaction temperatures, so as to selectively obtain benzyl or alkyl phosphine oxides with relatively high yields respectively, avoiding the problems of poor raw material stability, high toxicity, and poor substrate applicability in the prior art.

[0005] To achieve the above object, the present invention provides a method for selectively preparing benzyl or alkyl phosphine oxide compounds based on benzyl sulfide derivatives, comprising the following steps:

[0006]

[0007] Under a nitrogen atmosphere, a P(O)-H compound, a benzyl sulfide compound, a nickel catalyst, and a base are mixed in an organic solvent, heated and stirred, and then cooled and purified to obtain benzyl phosphine oxide as shown in Formula I and alkyl phosphine oxide as shown in Formula II;

[0008] Among them, R 1 is one of an alkyl group or an aryl group; R 2 and R 3 are each independently selected from one of a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 1-naphthyl group, a cyclohexyl group, or an alkoxy group;

[0009] The nickel catalyst is one of nickel chloride, nickel bromide, nickel acetylacetonate, 1,2-bis(diphenylphosphino)ethane nickel chloride, or bis(triphenylphosphine)nickel chloride;

[0010] The organic solvent is one or more of toluene, 1,4-dioxane, and tetrahydrofuran;

[0011] The base reagent is one or two of lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0012] Preferably, the benzyl sulfide compound is one of benzyl methyl sulfide, p-methylbenzyl methyl sulfide, p-methoxybenzyl methyl sulfide, p-phenylbenzyl methyl sulfide, p-fluorobenzyl methyl sulfide, 3,4-difluorobenzyl methyl sulfide, 3,4,5-trifluorobenzyl methyl sulfide, benzyl ethyl sulfide, benzyl isopropyl sulfide, benzyl n-butyl sulfide, benzyl tert-butyl sulfide, benzyl n-hexyl sulfide, or benzyl phenyl sulfide.

[0013] Preferably, the P(O)-H compound is one of diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(1-naphthyl)phosphine oxide, dicyclohexylphosphine oxide, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite or ethyl phenylphosphonate.

[0014] Preferably, the mixed molar ratio of the P(O)-H compound, benzyl sulfide compound, nickel catalyst and base reagent is 1-4:1:0.01-0.4:1-4.

[0015] Preferably, the P(O)-H compound is one of diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(1-naphthyl)phosphine oxide, dicyclohexylphosphine oxide, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite or ethyl phenylphosphonate.

[0016] Preferably, the reaction temperature is 100-120 °C, the reaction time is 16-18 hours, the catalyst is nickel chloride or nickel bromide, the base is potassium tert-butoxide, the molar ratio of sulfide to P(O)-H compound is 1:1.5-2, the solvent is tetrahydrofuran, and the yield of the benzylphosphine oxide compound in the reaction product is greater than 58%.

[0017] Preferably, the reaction temperature is 130-150 °C, the reaction time is 8-10 hours, the catalyst is nickel acetylacetonate, the ligand is 1,2-bis(diphenylphosphino)ethane, the base is sodium tert-butoxide, the molar ratio of sulfide to P(O)-H compound is 3:10-12, the solvent is 1,4-dioxane, and the yield of the alkylphosphine oxide compound in the reaction product is greater than 57%.

[0018] Preferably, the purification and collection process is as follows: the mixed solution obtained after stirring the reaction is washed and extracted to obtain an organic phase, and the organic phase is dried, distilled to remove the low-boiling solvent, and then subjected to column chromatography to obtain the phosphine oxide compound.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] 1. The method for selectively preparing benzyl or alkyl phosphine oxides from benzyl sulfide derivatives provided by the present invention can change the reaction selectivity by controlling reaction conditions such as reaction temperature, types of catalyst and base, and substrate ratio, and achieve the cleavage of the C-S bond in the selective benzyl sulfide compounds, obtaining benzylated products or alkylated products in relatively high yields respectively: at 100-120 °C, using nickel chloride as the catalyst and potassium tert-butoxide as the base, the yield of the benzylated product obtained by reacting in tetrahydrofuran for 16 hours reaches 58% or more; at 140-160 °C, using nickel acetylacetonate as the catalyst and sodium tert-butoxide as the base, the yield of the alkylated product obtained by reacting in 1,4-dioxane for 8 hours can reach more than 57%;

[0021] 2. The method for preparing benzyl or alkyl phosphine oxides provided by the present invention can highly selectively prepare alkyl phosphine oxides containing sp 3 C-P bonds by selecting appropriate reaction conditions, providing a reliable and efficient synthetic route for the preparation of alkyl phosphine oxides containing sp 3 C-P bonds, and realizing a more green and efficient synthesis of alkyl phosphine oxide compounds;

[0022] 3. This preparation method has the characteristics of cheap and easily available raw materials, green and stable, high reaction selectivity, simple reaction operation, safe and reliable, etc.;

[0023] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the reaction formula for selectively preparing benzyl or alkyl phosphine oxides from benzyl sulfide derivatives;

[0025] Figure 2 It is the 1H NMR spectrum of diphenylbenzylphosphine oxide obtained in Example 1 of the present invention;

[0026] Figure 3 It is the 1H NMR spectrum of diphenyl(4-methylbenzyl)phosphine oxide obtained in Example 2 of the present invention;

[0027] Figure 4 It is the 1H NMR spectrum of diphenyl(4-methoxybenzyl)phosphine oxide obtained in Example 3 of the present invention;

[0028] Figure 5 It is the 1H NMR spectrum of diphenyl(4-phenylbenzyl)phosphine oxide obtained in Example 4 of the present invention;

[0029] Figure 6 It is the 1H NMR spectrum of diphenyl(4-fluorobenzyl)phosphine oxide obtained in Example 5 of the present invention;

[0030] Figure 7 1H NMR spectrum of diphenyl(3,4-difluoro-benzyl)phosphine oxide obtained in Example 6 of the present invention;

[0031] Figure 8 1H NMR spectrum of diphenyl(3,4,5-trifluoro-benzyl)phosphine oxide obtained in Example 7 of the present invention;

[0032] Figure 9 1H NMR spectrum of bis(4-methylphenyl)benzylphosphine oxide obtained in Example 8 of the present invention;

[0033] Figure 10 1H NMR spectrum of bis(4-methoxyphenyl)benzylphosphine oxide obtained in Example 9 of the present invention;

[0034] Figure 11 1H NMR spectrum of bis(1-naphthyl)benzylphosphine oxide obtained in Example 10 of the present invention;

[0035] Figure 12 1H NMR spectrum of diphenylmethylphosphine oxide obtained in Example 11 of the present invention;

[0036] Figure 13 1H NMR spectrum of diphenylethylphosphine oxide obtained in Example 12 of the present invention;

[0037] Figure 14 1H NMR spectrum of diphenyl-n-butylphosphine oxide obtained in Example 13 of the present invention;

[0038] Figure 15 1H NMR spectrum of bis(4-methylphenyl)methylphosphine oxide obtained in Example 14 of the present invention;

[0039] Figure 16 1H NMR spectrum of bis(4-methoxyphenyl)methylphosphine oxide obtained in Example 15 of the present invention. Detailed implementation mode

[0040] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0041] Example 1

[0042] This example provides a preparation method of diphenylbenzylphosphine oxide, which is specifically as follows:

[0043] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of benzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salts formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 82%. 1 H NMR(400MHz CDCl 3 ):δ7.71-7.64(m,4H),7.50-7.40(m,6H),7.17-7.09(m,5H),3.65(d,J= 13.6Hz,2H), as shown in the specific spectrum Figure 2 as follows.

[0044] Example 2

[0045] This example provides a method for preparing diphenyl(4-methylbenzyl)phosphine oxide, which is as follows:

[0046] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of p-methylbenzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salts formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 72%. 1 H NMR(400 MHz CDCl 3 ):δ7.72-7.67(m,4H),7.52-7.48(m,2H),7.45-7.40(m,4H),6.99(s, 4H),3.62(d,J=13.6Hz,2H),2.25(d,J=1.6Hz,3H), as shown in the specific spectrum Figure 3 as follows.

[0047] Example 3

[0048] This example provides a method for preparing diphenyl(4-methoxybenzyl)phosphine oxide, which is as follows:

[0049] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of p-methoxybenzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salt formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 77%. 1 H NMR (400MHz CDCl 3 ): δ 7.71 - 7.66 (m, 4H), 7.52 - 7.49 (m, 2H), 7.46 - 7.41 (m, 4H), 7.03 - 7.00 (m, 2H), 6.73 (d, J = 8.4Hz, 2H), 3.74 (s, 3H), 3.59 (d, J = 13.2Hz, 2H). The specific spectrum is as shown in Figure 4 shown.

[0050] Example 4

[0051] This example provides a method for preparing diphenyl(4-phenylbenzyl)phosphine oxide, which is as follows:

[0052] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of p-phenylbenzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salt formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 63%. 1 H NMR(400 MHz CDCl 3 ): δ 7.75 - 7.70 (m, 4H), 7.55 - 7.51 (m, 4H), 7.48 - 7.39 (m, 8H), 7.33 - 7.30 (m, 1H), 7.17 (dd, J = 8.0, 2.0Hz, 2H), 3.70 (d, J = 13.6Hz, 2H). The specific spectrum is as shown in Figure 5 shown.

[0053] Example 5

[0054] This example provides a method for preparing diphenyl(4-fluorobenzyl)phosphine oxide, which is as follows:

[0055] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of 4-fluorobenzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salt formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 75%. 1 H NMR(400 MHz CDCl 3 ):δ7.71-7.66(m,4H),7.54-7.49(m,2H),7.46-7.42(m,4H), 7.09-7.05(m,2H),6.87(t,J=8.8Hz,2H),3.62(d,J=13.6Hz,2H), and the specific spectrum is as Figure 6 shown.

[0056] Example 6

[0057] This example provides a method for preparing diphenyl(3,4-difluoro-benzyl)phosphine oxide, which is as follows:

[0058] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of 3,4-difluoro-benzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salt formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 58%. 1 H NMR (400MHz CDCl 3 ):δ7.71-7.67(m,4H),7.55-7.44(m,6H),7.00-6.91(m,2H), 6.85-6.82(m,1H),3.58(d,J=13.2Hz,2H), and the specific spectrum is as Figure 7 shown.

[0059] Example 7

[0060] This example provides a method for preparing diphenyl(3,4,5-trifluoro-benzyl)phosphine oxide, which is as follows:

[0061] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of diphenylphosphine oxide, 0.1 mmol of 3,4,5-trifluoro-benzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salt formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 61%. 1 H NMR (400MHz CDCl 3 ): δ 7.72–7.67 (m, 4H), 7.57–7.46 (m, 6H), 6.78–6.74 (m, 2H), 3.56 (d, J=13.2Hz, 2H), and the specific spectrum is as shown in Figure 8 shown.

[0062] Example 8

[0063] This example provides a method for preparing bis(4-methylphenyl)benzylphosphine oxide, which is as follows:

[0064] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of bis(4-methylphenyl)phosphine oxide, 0.1 mmol of benzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and continuously stirred for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salt formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 71%. 1 H NMR (400MHz CDCl 3 ): δ 7.58 - 7.53 (m, 4H), 7.24 - 7.09 (m, 9H), 3.61 (d, J=13.6Hz, 2H), 2.38 (s, 6H), and the specific spectrum is as shown in Figure 9 shown.

[0065] Example 9

[0066] This example provides a method for preparing bis(4-methoxyphenyl)benzylphosphine oxide, which is as follows:

[0067] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of bis(4-methoxyphenyl)phosphine oxide, 0.1 mmol of benzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and stirred continuously for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salts formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 68%. 1 H NMR (400MHz CDCl 3 ): δ 7.59 - 7.55 (m, 4H), 7.19 - 7.17 (m, 3H), 7.09 - 7.08 (m, 2H), 6.93 (dd, J1 = 8.8Hz, J2 = 2.4Hz, 2H), 3.83 (s, 6H), 3.59 (d, J = 14.0Hz, 2H), and the specific spectrum is as Figure 10 shown.

[0068] Example 10

[0069] This example provides a method for preparing bis(1-naphthyl)benzylphosphine oxide, which is as follows:

[0070] Under a nitrogen atmosphere, 0.005 mmol of nickel chloride, 0.15 mmol of bis(1-naphthyl)phosphine oxide, 0.1 mmol of benzyl methyl sulfide, 0.15 mmol of potassium tert-butoxide, and 1.5 mL of tetrahydrofuran were added to a reactor. After sealing the tube, it was heated to 110 °C and stirred continuously for 16 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salts formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 68%. 1 H NMR(400 MHz CDCl 3 ): δ 8.50 (d, J = 8.8Hz, 2H), 7.98 (d, J = 8.4Hz, 2H), 7.94–7.89 (m, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.47–7.42 (m, 4H), 7.36–7.32 (m, 2H), 7.15–6.99 (m, 5H), 4.01 (d, J = 13.6Hz, 2H), and the specific spectrum is as Figure 11 shown.

[0071] Example 11

[0072] This example provides a method for preparing diphenylmethylphosphine oxide, which is as follows:

[0073] Under a nitrogen atmosphere, 0.03 mmol of nickel acetylacetonate, 0.03 mmol of 1,2-bis(diphenylphosphino)ethane, 0.2 mmol of diphenylphosphine oxide, 0.06 mmol of benzyl methyl sulfide, 0.5 mmol of sodium tert-butoxide, and 2 mL of 1,4-dioxane were added to a reactor. After sealing the tube, it was heated to 140 °C and continuously stirred for 8 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salts formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 78%. 1H NMR (400 MHz CDCl 3 ): δ 7.75–7.70 (m, 4H), 7.53–7.44 (m, 4H), 2.01 (dd, J = 1.0 Hz, J = 13.2 Hz, 3H), and the specific spectrum is as shown in Figure 12 Figure.

[0074] Example 12

[0075] This example provides a method for preparing diphenylethylphosphine oxide, which is as follows:

[0076] Under a nitrogen atmosphere, 0.03 mmol of nickel acetylacetonate, 0.03 mmol of 1,2-bis(diphenylphosphino)ethane, 0.2 mmol of diphenylphosphine oxide, 0.06 mmol of benzyl ethyl sulfide, 0.5 mmol of sodium tert-butoxide, and 2 mL of 1,4-dioxane solvent were added to a reactor. After sealing the tube, it was heated to 140 °C and continuously stirred for 8 h. The reaction was stopped, cooled to room temperature, washed with water to remove the excess base and the salts formed during the reaction, the aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 73%. 1H NMR (400 MHz CDCl 3 ): δ 7.76–7.71 (m, 4H), 7.54–7.44 (m, 6H), 2.33–7.24 (m, 2H), 1.24–1.16 (m, 3H), and the specific spectrum is as shown in Figure 13 Figure.

[0077] Example 13

[0078] This example provides a method for preparing diphenyl-n-butylphosphine oxide, which is as follows:

[0079] Under a nitrogen atmosphere, 0.03 mmol of nickel acetylacetonate, 0.03 mmol of 1,2-bis(diphenylphosphino)ethane, 0.2 mmol of diphenylphosphine oxide, 0.06 mmol of benzyl n-butyl sulfide, 0.5 mmol of sodium tert-butoxide, and 2 mL of 1,4-dioxane solvent were added to a reactor. After sealing the tube, it was heated to 140 °C and continuously stirred for 8 h. The reaction was stopped, cooled to room temperature, and washed with water to remove the excess base and the salts formed during the reaction. The aqueous phase was extracted with dichloromethane to obtain the organic phase, which was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 57%. 1H NMR (400 MHz CDCl 3 ): δ 7.77–7.71 (m, 4H), 7.53–7.43 (m, 6H), 2.30–2.23 (m, 2H), 1.66–1.56 (m, 2H), 1.47–1.38 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H), and the specific spectrum is as shown in Figure 14 Figure.

[0080] Example 14

[0081] This example provides a method for preparing bis(4-methylphenyl)methylphosphine oxide, which is as follows:

[0082] Under a nitrogen atmosphere, 0.03 mmol of nickel acetylacetonate, 0.03 mmol of 1,2-bis(diphenylphosphino)ethane, 0.2 mmol of bis(4-methylphenyl)phosphine oxide, 0.06 mmol of benzyl methyl sulfide, 0.5 mmol of sodium tert-butoxide, and 2 mL of 1,4-dioxane solvent were added to a reactor. After sealing the tube, it was heated to 140 °C and continuously stirred for 8 h. The reaction was stopped, cooled to room temperature, and washed with water to remove the excess base and the salts formed during the reaction. The aqueous phase was extracted with dichloromethane to obtain the organic phase, which was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a separation yield of 67%. 1H NMR (400 MHz CDCl 3 ): δ 7.62–7.57 (m, 4H), 7.26 (s, 4H), 2.39 (s, 6H), 1.97 (d, J = 13.2 Hz, 3H), and the specific spectrum is as shown in Figure 15 Figure.

[0083] Example 15

[0084] This example provides a method for preparing bis(4-methoxyphenyl)methylphosphine oxide, which is as follows:

[0085] Under a nitrogen atmosphere, 0.03 mmol of nickel acetylacetonate, 0.03 mmol of 1,2-bis(diphenylphosphino)ethane, 0.2 mmol of bis(4-methoxyphenyl)phosphine oxide, 0.06 mmol of benzyl methyl sulfide, 0.5 mmol of sodium tert-butoxide, and 2 mL of 1,4-dioxane solvent were added to a reactor. After sealing the tube, it was heated to 140 °C and continuously stirred for 8 h. The reaction was stopped and cooled to room temperature. The excess base and the generated salts in the reaction were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase, which was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The crude product was separated by column chromatography to obtain the target product, and the separation yield was 62%. 1H NMR (400 MHz CDCl 3 ): δ 7.65–7.60 (m, 4H), 6.98–6.95 (m, 4H), 3.83 (s, 6H), 1.96 (d, J = 12.8 Hz, 3H). The specific spectrum is as shown in Figure 16 .

[0086] As can be seen from the above examples, the preparation method of the present invention can efficiently synthesize benzyl or alkyl phosphine oxide compounds. The reaction process is simple and efficient, the raw materials are widely available, the toxicity is small, the substrate scope is wide, and nickel catalysis can reduce the activation energy of C-S bond cleavage, realizing the selective activation of inert C-S bonds, and obtaining benzylated products or alkylated products with relatively high yields respectively. The reaction is also expected to be used for the post-modification of drug molecules containing C-S bonds, and has strong application prospects.

[0087] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

Claims

1. A method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives, characterized in that, it comprises the following steps: ， Under a nitrogen atmosphere, a P(O)-H compound, a benzyl sulfide compound, a nickel catalyst and a base are mixed in an organic solvent, heated and stirred, and then cooled and purified to obtain benzyl phosphine oxide shown in Formula I and alkyl phosphine oxide shown in Formula II; Among them, R 2 and R 3 are each independently selected from phenyl, 4-methylphenyl, 4-methoxyphenyl, 1-naphthyl, cyclohexyl, or one of the P(O)-H compounds is selected from diethyl phosphite, diisopropyl phosphite, dibutyl phosphite, or ethyl phenylphosphonate; The nickel catalyst is one of nickel chloride, nickel bromide, nickel acetylacetonate, 1,2-bis(diphenylphosphino)ethane nickel chloride, and bis(triphenylphosphine) nickel chloride; The organic solvent is one or more of toluene, 1,4-dioxane and tetrahydrofuran; The base reagent is one or two of lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide; The benzyl sulfide compound is one of benzyl methyl sulfide, p-methylbenzyl methyl sulfide, p-methoxybenzyl methyl sulfide, p-phenylbenzyl methyl sulfide, p-fluorobenzyl methyl sulfide, 3,4-difluorobenzyl methyl sulfide, 3,4,5-trifluorobenzyl methyl sulfide, benzyl ethyl sulfide, benzyl isopropyl sulfide, benzyl n-butyl sulfide, benzyl tert-butyl sulfide, benzyl n-hexyl sulfide, and benzyl phenyl sulfide.

2. The method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives according to claim 1, characterized in that, The P(O)-H compound is diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(1-naphthyl)phosphine oxide, or dicyclohexylphosphine oxide.

3. The method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives according to claim 1, characterized in that, The mixing molar ratio of the P(O)-H compound, the benzyl sulfide compound, the nickel catalyst and the base reagent is 1~4:1:0.01~0.4:1~4.

4. The method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives according to claim 1, characterized in that, The reaction temperature is 100~120 °C, the reaction time is 16~18 hours, the catalyst is nickel chloride or nickel bromide, the base is potassium tert-butoxide, the molar ratio of the sulfide to the P(O)-H compound is 1:1.5~2, the solvent is tetrahydrofuran, and the yield of the benzyl phosphine oxide compound in the reaction product is greater than 58%.

5. The method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives according to claim 1, characterized in that, The reaction temperature is 130~150 °C, the reaction time is 8~10 hours, the catalyst is nickel acetylacetonate, the ligand is 1,2-bis(diphenylphosphino)ethane, the base is sodium tert-butoxide, the molar ratio of the sulfide to the P(O)-H compound is 3:10~12, the solvent is 1,4-dioxane, and the yield of the alkyl phosphine oxide compound in the reaction product is greater than 57%.

6. The method for selectively preparing benzyl or alkyl phosphine oxides based on benzyl sulfide derivatives according to claim 1, characterized in that, The purification and collection process is as follows: the mixed solution obtained after stirring reaction is washed and extracted to obtain an organic phase, and the organic phase is dried, distilled to remove low-boiling solvents, and then subjected to column chromatography to obtain the phosphine oxide compound.

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