Bis (alkylaryl) phosphine oxide compound and preparation method thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a bis (alkylaryl) phosphine oxide compound and a preparation method thereof. The preparation method of the bis (alkylaryl) phosphine oxide compound comprises the following steps: by taking a brominated aromatic formaldehyde derivative as an initial raw material, substituting with an alkyl Grignard reagent, oxidizing, substituting with the alkyl Grignard reagent, substituting with alkyl aluminum, reacting with diethylamino phosphorus dichloride, and hydrolyzing to obtain the product bis (alkylaryl) phosphine oxide compound. The synthesis method provided by the invention is safe, mild, practical, simple to operate and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to bis(alkylaryl)phosphine oxide compounds and their preparation methods. Background Technology

[0002] Diarylphosphine oxides are important synthetic precursors for asymmetric ligands, and their synthetic methods have attracted widespread attention. For example, BINAP and spirocyclic ligands can be synthesized by constructing CP bonds through the coupling of diarylphosphine oxides.

[0003]

[0004] Among BINAP ligands, the sterically hindered BINAP ligands synthesized using bis(alkylaryl)oxophosphine exhibit excellent activity in many asymmetric reactions such as asymmetric hydrogenation and epoxidation, attracting considerable interest. Developing original ligands for precise asymmetric synthesis is a core technology for pharmaceuticals or other functional molecules. Therefore, developing synthetic routes for such bis(alkylaryl)oxophosphine compounds for the rapid preparation of asymmetric ligands is crucial. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention proposes a bis(alkylaryl)phosphine oxide compound and its preparation method.

[0006] First, this invention provides a bis(alkylaryl)phosphine oxide compound A, the structural formula of which is as follows:

[0007]

[0008] Where m is an integer of 1 or 2;

[0009] R 1 It can be hydrogen, C1-C12 alkyl, C1-C12 alkoxy, fluorine, chlorine, bromine, phenyl, 1-naphthyl, 2-naphthyl, furanyl, thiophene, or pyridyl.

[0010] R 2 R 3 and R 4 It is hydrogen, a C1-C12 alkyl group, and R 2 R 3 R 4 There can be a maximum of 2 methyl groups.

[0011] Further, the C1-C12 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, n-dodecyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0012] Further, the alkoxy groups of the C1-C12 are methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, neopentoxy, sec-pentoxy, tert-pentoxy, cyclopentoxy, n-hexoxy, isohexoxy, neohexoxy, sec-hexoxy, tert-hexoxy, cyclohexoxy, n-heptoxy, isoheptoxy, neoheptoxy, sec-heptoxy, tert-heptoxy, cycloheptoxy, n-octoxy, isooctoxy, neooctoxy, sec-octoxy, tert-octoxy, and cyclooctoxy.

[0013] Furthermore, the preferred bis(alkylaryl)oxophosphine compound is:

[0014]

[0015] This invention also provides a method for preparing bis(alkylaryl)phosphine oxide compounds, the route of which is as follows:

[0016]

[0017] Starting with bromoaromatic formaldehyde of formula 2, the compound of formula A (bis(alkylaryl)oxophosphine) was prepared by reaction with alkyl Grignard reagent 5-substitution, oxidation, alkyl Grignard reagent 6-substitution, alkylaluminum 7-substitution, and hydrolysis after reaction with diethylaminophosphoric acid. 1 R 2 R 3 R 4 The definition is the same as above.

[0018] Furthermore, the intermediate of formula 5 in the synthetic route is obtained by oxidation of the structure of formula 4 with an oxidizing agent, and the synthetic route is as follows:

[0019]

[0020] Among them, m and R 1 R 2 R 3 R 4 The definition is the same as above;

[0021] The oxidant is a complex composed of one or more of the following: 2,2,6,6-tetramethylpiperidine oxide, Dess-Martin reagent, pyridinium chlorochromate, pyridinium dichromate, Jones reagent, and IBX reagent.

[0022] Furthermore, the intermediate of formula 9 in the synthetic route is obtained by reacting intermediate of formula 7 with an alkylaluminum reagent, and its synthetic route is as follows:

[0023]

[0024] Among them, m and R 1 R 2 R 3 R 4 The definition is the same as above;

[0025] Furthermore, the molar ratio of intermediate formula 7 to alkyl aluminum reagent is 1:1 to 10; more preferably, it is 1:3.

[0026] The alkylaluminum reagent can be trimethylaluminum, triethylaluminum, trioctylaluminum, or triisobutylaluminum; trimethylaluminum is preferred.

[0027] Furthermore, the reaction temperature is -80 to 10°C; more preferably -80 to -70°C.

[0028] A preferred embodiment of the present invention is a method for synthesizing bis(3,5-di-tert-pentylphenyl)oxophosphine:

[0029]

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] 1. The present invention uses bromoaromatic formaldehyde as the starting material, and prepares a bis(alkylaryl)phosphine oxide compound by substitution with alkyl Grignard reagent, oxidation, alkyl Grignard reagent substitution, alkyl aluminum substitution, and hydrolysis after reaction with diethylaminophosphine dichloride. It has the advantages of inexpensive and readily available raw materials, low pollution from reaction reagents, and milder conditions.

[0032] 2. The bis(3,5-di-tert-pentylphenyl)oxophosphine obtained in this invention can be used in the synthesis of various asymmetric ligands and exhibits good catalytic activity. Attached Figure Description

[0033] Appendix Figure 1 Compound 11 prepared in Example 1 1 H NMR spectrum.

[0034] Appendix Figure 2 Compound 12 prepared in Example 1 1 H NMR spectrum.

[0035] Appendix Figure 3 Compound 14 prepared in Example 1 1 H NMR spectrum.

[0036] Appendix Figure 4 Compound 15 prepared in Example 1 1 H NMR spectrum. Detailed Implementation

[0037] To further understand the present invention, a bis(alkylaryl)phosphine oxide compound and its preparation method provided by the present invention are described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.

[0038] Example 1:

[0039] Step 1:

[0040]

[0041] Compound 10 (50.0 g, 234.7 mmol, 1 eq) was dissolved in 1 L of tetrahydrofuran. The reaction was purged with nitrogen three times. Methylmagnesium bromide (234.7 mL, 3 M, 3.0 eq) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 12 h. The reaction was quenched with 1 N HCl (500 mL), extracted with ethyl acetate (400 mL × 3), washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 36.2 g of a yellow oily liquid. The yield was 63.0%. 1 H NMR (400MHz, CDCl3) δ7.39(t,J=1.6Hz,2H),7.26(d,J=2.0Hz,1H),4.82(q,J=6.4Hz,2H),2.39(s,2H),1.45(d,J=6.4Hz,6H).

[0042] Step 2:

[0043]

[0044] Compound 11 (40.0 g, 163.2 mmol, 1 eq) was dissolved in 400 mL of acetone. Jones' reagent (326.4 mL, 2 M, 3.0 eq) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature (25 °C) and stirred for 12 h. The reaction solution was quenched with isopropanol (50 mL) and filtered. The filtrate was extracted with ethyl acetate (400 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained solid was recrystallized from n-hexane:ethyl acetate (20:1) to give 20.0 g of a yellow solid, with a yield of 50.5%. 1 H NMR (400MHz, CDCl3) δ8.34(t,J=1.2Hz,1H),8.18(t,J=1.2Hz,2H),2.58(d,J=0.8Hz,6H).

[0045] Step 3:

[0046]

[0047] Compound 12 (33.0 g, 136.9 mmol, 1.0 eq) was dissolved in 300 mL of tetrahydrofuran. The reaction was purged with nitrogen three times. Ethyl magnesium bromide (136.9 mL, 3 M, 3.0 eq) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature (25 °C) and stirred for 12 h. The reaction was quenched with 1 N HCl (300 mL), extracted with ethyl acetate (200 mL × 3), washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 22.0 g of a yellow oily liquid. The crude product was used directly in the next reaction.

[0048] Step 4:

[0049]

[0050] Compound 13 (22.0 g, 73.0 mmol, 1.0 eq) was dissolved in 220 mL of concentrated hydrochloric acid and stirred at room temperature for 12 h. The reaction solution was extracted with dichloromethane (200 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The resulting product was dissolved in 220 mL of dichloromethane, and the reaction was purged with nitrogen three times and cooled to between -80 and -70 °C. At this temperature, trimethylaluminum (109.6 mL, 2 M, 3.0 eq) was slowly added dropwise, and after the addition was complete, the mixture was brought back to room temperature (25 °C) and stirred for 12 h. The reaction was quenched with 1 N HCl (300 mL), extracted with dichloromethane (200 mL × 3), and the organic phase was washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated by column chromatography (stationary phase: silica gel, eluent: n-hexane). 15.0 g of a colorless oily liquid was obtained. The yield was 69.0%. 1H NMR (400MHz, CDCl3) δ7.18(t,J=1.6Hz,2H),7.11(t,J=1.6Hz,1H),1.54(q,J=7.2Hz,4H),1.18(s,12H),0.59(t,J=7.6Hz,6H).

[0051] Step 5:

[0052]

[0053] Compound 14 (15.0 g, 47.1 mmol, 1.0 eq) was dissolved in 150 mL of tetrahydrofuran. The reaction was purged with nitrogen three times and cooled to between -80 and -70 °C. At this temperature, a solution of n-butyllithium (43.3 mL, 2.5 M, 2.3 eq) was slowly added dropwise, followed by stirring at -80 to -70 °C for 2 h. Subsequently, diethylaminophosphine dichloride (3.9 g, 60.88 mmol, 1.3 eq) was slowly added dropwise at -80 to -70 °C, followed by stirring at room temperature (25 °C) for 12 h. The reaction was quenched with 1 N HCl (200 mL), extracted with ethyl acetate (200 mL × 3), washed with saturated sodium chloride (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Separation was performed by column chromatography (stationary silica gel, eluent: hexane:ethyl acetate = 3:1). 3.4 g of a yellow oily liquid was obtained. The yield was 33.3%. 1 H NMR (400MHz, CDCl3) δ7.49(q,J=1.6Hz,2H),7.46(d,J=1.6Hz,2H),7.43(d,J=1.6Hz,2H),1.69–1.64(m,8H),1.31(s,25H),0.66(t,J=7.2Hz,13H).

[0054] Example 2

[0055] Following the synthesis steps of Example 1, using a substitute for Jones reagent, the yield of compound 12 was 67.1%.

Claims

1. A bis(alkylaryl)phosphine oxide compound A, the structural formula of which is as follows: in, m is an integer between 1 and 2; R 1 It can be hydrogen, C1-C12 alkyl, C1-C12 alkoxy, fluorine, chlorine, bromine, phenyl, 1-naphthyl, 2-naphthyl, furanyl, thiophene, or pyridyl. R 2 R 3 R 4 Each is independently hydrogen, a C1-C12 alkyl group, and R 2 R 3 R 4 There can be a maximum of 2 methyl groups.

2. The bis(alkylaryl)oxophosphine compound according to claim 1, characterized in that, The C1-C12 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, n-dodecyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; the C1-C12 alkoxy groups are... The compounds are methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, neopentoxy, sec-pentoxy, tert-pentoxy, cyclopentoxy, n-hexoxy, isohexoxy, neohexoxy, sec-hexoxy, tert-hexoxy, cyclohexoxy, n-heptoxy, isoheptoxy, neoheptoxy, sec-heptoxy, tert-heptoxy, cycloheptoxy, n-octoxy, isooctoxy, neooctoxy, sec-octoxy, tert-octoxy, and cyclooctoxy.

3. The bis(alkylaryl)oxophosphine compound according to claim 1, characterized in that, The structural formula of the bis(alkylaryl)oxophosphine compound is:

4. A method for synthesizing a bis(alkylaryl)phosphine oxide compound, characterized in that: Starting with bromoaromatic formaldehyde of Formula 2, a bis(alkylaryl)oxophosphine compound of Formula A was prepared by substitution with an alkyl Grignard reagent, oxidation, substitution with an alkyl Grignard reagent, substitution with an alkylaluminum reagent, and hydrolysis after reaction with diethylaminophosphorus dichloride. Among them, m and R 1 R 2 R 3 R 4 The definition is the same as above.

5. The synthesis method according to claim 4, characterized in that, The method for synthesizing the bis(3,5-di-tert-pentylphenyl)oxophosphine is as follows:

6. The synthesis method according to claim 4 or 5, characterized in that, The oxidant in the oxidation reaction is a complex of one or more of the following: 2,2,6,6-tetramethylpiperidine oxide, Dess-Martin reagent, pyridinium chlorochromate, pyridinium dichromate, Jones reagent, and IBX reagent.

7. The synthesis method according to claim 4 or 5, characterized in that, The intermediate of Formula 9 is prepared by reacting intermediate of Formula 7 with an alkylaluminum reagent. Where m, R 1 R 2 R 3 R 4 The definition is the same as in claim 1.

8. The synthesis method according to claim 7, characterized in that, The molar ratio of intermediate formula 7 to alkyl aluminum reagent is 1:1 to 10.

9. The synthesis method according to claim 8, characterized in that, The alkylaluminum reagent is trimethylaluminum, triethylaluminum, trioctylaluminum, or triisobutylaluminum.

10. The synthesis method according to claim 7, characterized in that, The reaction temperature is -80 to 10°C.

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