A method for synthesizing organophosphine ligands by iron-catalyzed group migration of organophosphine reagents

Abstract

The invention discloses a method for synthesizing an organic phosphine ligand by group migration of an organic phosphine reagent catalyzed by iron. The method belongs to the technical field of organic chemistry. In the invention, a tertiary phosphine is used as a substrate, and an alkane group is migrated to synthesize an organic phosphine ligand in a catalytic system having an iron catalyst, a base, a reducing agent and a ligand. The iron catalyst is non-toxic and harmless and is inexpensive, thereby avoiding the negative impact of the reaction on the environment. The tertiary phosphine is directly used as a starting substrate to simplify the process of alkylation of organic matter. The yield is high. In addition, the reaction conditions are highly selective. Even if the structures of two alkanes adjacent to phosphorus in the substrate are the same, one molecule of the alkane can be selectively retained during migration, and only one molecule of the alkane group is replaced, thereby broadening the selection range for the modification of the structure of the organic phosphine ligand.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a method for synthesizing an organic phosphine ligand by using iron to catalyze the migration of an organic phosphine reagent group. Background Art

[0002] Customized auxiliary ligands are used to adjust the reactivity of catalysts, and phosphine ligands are the preferred ligands for many applications. A significant advantage of phosphine ligands is that the electronic and steric properties of the ligands can be precisely adjusted by changing the substituents at the phosphorus center. This adjustment ability enables phosphine ligands to exhibit different reactivity and selectivity in catalytic reactions, thereby meeting various catalytic needs. Phosphine compounds are widely used in many fields due to their unique properties, such as organic catalysis, Lewis pair catalysis, and materials science.

[0003] Traditionally, phosphine ligands are synthesized by de novo synthesis methods, such as nucleophilic substitution reactions of phosphine halides with organometallic reagents; reduction reactions of phosphine oxides; reactions of phosphine hydrides with unsaturated compounds or substitution reactions with electrophilic reagents in the presence of bases, metal-catalyzed cross-coupling of phosphine groups with aromatic halides, etc. However, the above reactions usually require many steps and involve toxic or pyrophoric reagents and air-sensitive intermediates, which are challenging to separate the target compounds, resulting in a limited variety of commercially available phosphine ligands.

[0004] Another strategy is to modify tertiary phosphines directly, in which the substituents of the organophosphine are completely changed or exchanged, avoiding the need to handle toxic primary and secondary organophosphines or even PH3. Taking the CH functionalization method as an example, most efforts on tertiary phosphine modification have focused on changing the substituents. The reaction of completely replacing one substituent in an organophosphine compound is still rare. The methods to achieve this goal are limited, mainly through the reaction of organophosphines (aromatically substituted organophosphorus reagents) with highly reactive alkali metals to form metal phosphine compounds that further react with halogenated alkanes to obtain organophosphine structures with substituted substituents; in addition, acyl phosphines can serve as alternative structures for secondary phosphines in metal-catalyzed alkylation and arylation reactions. Although these methods have expanded the modification reactions of organophosphines, they are affected by poor selectivity or limited substrate range, respectively. The prior art discloses a palladium catalytic process that can exchange aryl groups between two different triarylphosphines. Specifically, a phenyl palladium iodide reagent first reacts with an aryl phosphine, and the phenyl group of the phenyl palladium iodide forms a new PC bond with the phosphine atom through a reduction elimination mechanism to generate a palladium-containing intermediate. The palladium-containing intermediate undergoes a reduction elimination reaction with another CP bond, and the aryl group falls off the phosphine species and coordinates with metallic palladium to form a new palladium-containing intermediate. The aryl group on the new palladium-containing intermediate is exchanged with the aryl group in another phosphine starting compound to generate a new triarylphosphine compound, but it is a mixture and is not practical in actual synthesis. Therefore, a new method for directly synthesizing phosphine and other phosphorus-containing compounds is urgently needed. Summary of the invention

[0005] In view of the above-mentioned prior art, the present invention discloses a method for synthesizing an organic phosphine ligand by iron-catalyzed group migration of an organic phosphine reagent, so as to solve the technical problems of high cost, unfriendly environment, complex reaction and low yield in the process of synthesizing an organic phosphine ligand in the prior art.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is: to provide a method for synthesizing an organic phosphine ligand by iron-catalyzed organic phosphine reagent group migration, which comprises the following steps: dissolving compound 1 and compound 2 in a solvent, adding an iron catalyst, a reducing agent, a base and a ligand, and reacting at 90-100° C. to obtain an organic phosphine ligand 3; the structural formulas of the compound 1, compound 2 and organic phosphine ligand 3 are as follows: , , ; Wherein R1 is ethyl; R2 is ethyl or phenyl; R3 is a primary alkyl group containing at least one of ether bond, ester group, silicon, nitrogen and fluorine or a secondary alkyl group containing at least one of ether bond, ester group, silicon, nitrogen and fluorine; the reducing agent is B2pin2 (bis-pinacol borate); the base is t-BuONa; the structural formula of the ligand is as follows,

[0007] Based on the above technical solution, the present invention can also be improved as follows.

[0008] Furthermore, the iron catalyst is FeBr2, Fe(CO2CH3)2 or Fe(OTs)3; and the solvent is n-hexane, cyclohexane, ether or methyl tert-butyl ether.

[0009] Further, compound 1 is one of the compounds having the following structure: , ; Compound 2 is one of the compounds having the following structure: , , , .

[0010] Furthermore, the solid-liquid ratio of compound 1, compound 2, reducing agent, base, iron catalyst, ligand and solvent is 0.2mmol:0.5~0.7mmol:0.8~1mmol:0.4~0.8mmol:0.008~0.012mmol:0.015~0.025mmol:0.5~2mL.

[0011] Furthermore, the reaction time is 5 to 10 hours.

[0012] The beneficial effects of the present invention are: 1. The iron catalyst used in the reaction of the present invention is non-toxic, harmless and inexpensive, thus avoiding the negative impact of the reaction on the environment.

[0013] 2. Under the action of an iron catalyst, a base, a reducing agent and a ligand, group migration is achieved through a one-step reaction, and a halogenated alkane replaces an alkane connected to P in an organic phosphine reagent and retains an aromatic hydrocarbon. In addition, the reaction selectivity is high. Even if the organic phosphine reagent has two molecules of the same alkane connected to P, one molecule of alkane can be selectively retained under the reaction conditions of the present invention, and only one molecule of the alkane group is replaced, thereby broadening the selection range for the modification of the structure of the organic phosphine ligand.

[0014] 3. The yield of the organic phosphine ligand in the synthesis method of the present invention is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is the H NMR spectrum of product 1; Figure 2 is the NMR carbon spectrum of product 1; Figure 3 is the H NMR spectrum of product 2; Figure 4 is the NMR carbon spectrum of product 2; Figure 5 is the H NMR spectrum of product 3; Figure 6 is the NMR carbon spectrum of product 3; Figure 7 is the H NMR spectrum of product 4; Figure 8 This is the carbon NMR spectrum of product 4. DETAILED DESCRIPTION

[0016] The synthesis of the ligand L in the present invention refers to the article (Michael P Crockett, Alexander S Wong, Bo Li, and Jeffery Allen Byers, Rational Design of an Iron-Based Catalyst for Suzuki-Miyaura Cross-Couplings Involving Heteroaromatic Boronic Esters and Tertiary Alkyl Electrophiles, Angew. Chem. Int. Ed. 10.1002 / anie.201914315); the specific implementation methods of the present invention are described in detail below in conjunction with the examples.

[0017] Example 1 A method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent, the synthesis route of which is as follows:

[0018] The synthesis method comprises the following steps: S1: Cut 3g of sodium metal into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of n-hexane and reflux at 100℃ for 3h. Collect the distilled n-hexane and seal it for storage. S2: Put an 8 mL glass bottle with a magnetic stirrer into a glove box, weigh 0.01 mmol ferrous bromide, 0.9 mmol bis-pinacol borate, 0.6 mmol sodium tert-butoxide and 0.02 mmol ligand L, then use a microinjector to add 0.2 mmol ethyldiphenylphosphine and 0.6 mmol 1-bromo-4-methoxybutane, then use a syringe to add 0.5 mL distilled n-hexane and mix well; take the glass bottle out of the glove box and put it into a 95°C constant temperature stirrer to react for 7 hours; S4: After the reaction is completed, the glass bottle is taken out from the constant temperature stirrer, and a clear colorless oil (product 1) is obtained by elution through a flash column chromatography, and the product is stored in dimethyl sulfide borane.

[0019] Example 2 A method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent, the synthesis route of which is as follows:

[0020] The synthesis method comprises the following steps: S1: Cut 3g of sodium metal into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of cyclohexane and reflux at 100℃ for 3h. Collect the distilled cyclohexane and seal it for storage. S2: Put an 8 mL glass bottle with a magnetic stirrer into a glove box, weigh 0.008 mmol ferrous acetate, 0.8 mmol bis-pinacol borate, 0.4 mmol sodium tert-butoxide and 0.025 mmol ligand L, then use a microinjector to add 0.2 mmol ethyldiphenylphosphine and 0.5 mmol 4-phenoxybutyl bromide, then use a syringe to add 2 mL of distilled cyclohexane and mix well; take the glass bottle out of the glove box and put it into a 90°C constant temperature stirrer to react for 5 hours; S4: After the reaction is completed, the glass bottle is taken out from the constant temperature stirrer, and a clear colorless oil (product 2) is obtained by elution through a flash column chromatography, and the product is stored in dimethyl sulfide borane.

[0021] Example 3 A method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent, the synthesis route of which is as follows:

[0022] The synthesis method comprises the following steps: S1: Cut 3g of sodium metal into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of ether and reflux at 100℃ for 3h. Collect the distilled ether and seal it for storage. S2: Put an 8 mL glass bottle with a magnetic stirrer into a glove box, weigh 0.012 mmol iron toluenesulfonate, 1 mmol bis-pinacol borate, 0.8 mmol sodium tert-butoxide and 0.015 mmol ligand L, then use a microinjector to add 0.2 mmol ethyldiphenylphosphine and 0.8 mmol (3-bromopropoxy) tert-butyldimethylsilane, then use a syringe to add 1.5 mL of distilled ether and mix well; take the glass bottle out of the glove box and put it into a constant temperature stirrer at 100 ° C to react for 10 hours; S4: After the reaction is completed, the glass bottle is taken out from the constant temperature stirrer, and a clear colorless oil (product 3) is obtained by elution through a flash column chromatography, and the product is stored in dimethyl sulfide borane.

[0023] Example 4 A method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent, the synthesis route of which is as follows:

[0024] The synthesis method comprises the following steps: S1: Cut 3g of sodium metal into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of n-hexane and reflux at 100℃ for 3h. Collect the distilled n-hexane and seal it for storage. S2: Put an 8 mL glass bottle with a magnetic stirrer into a glove box, weigh 0.012 mmol ferrous bromide, 0.9 mmol bis-pinacol borate, 0.6 mmol sodium tert-butoxide and 0.02 mmol ligand L, then use a microinjector to add 0.2 mmol phenyldiethylphosphine and 0.5 mmol 3,3-dimethyl-1-bromobutane, then use a syringe to add 0.5 mL of distilled n-hexane and mix well; take the glass bottle out of the glove box and put it into a 95°C constant temperature stirrer to react for 7 hours; S4: After the reaction is completed, the glass bottle is taken out from the thermostatic agitator, and a clear colorless oil (product 4) is obtained by elution through a flash column chromatography, and the product is stored in dimethyl sulfide borane.

[0025] Comparative Example 1 A method for synthesizing an organic phosphine ligand The ligand L was replaced by bipyridine, and the other conditions were the same as those in Example 1.

[0026] Comparative Example 2 A method for synthesizing an organic phosphine ligand The ferrous bromide was replaced by NiBr2, and the other conditions were the same as those in Example 1.

[0027] Comparative Example 3 A method for synthesizing an organic phosphine ligand The ferrous bromide was replaced by PdBr2, and the other conditions were the same as those in Example 1.

[0028] Comparative Example 4 A method for synthesizing an organic phosphine ligand Ferrous bromide was omitted, and the remaining conditions were the same as in Example 1.

[0029] Comparative Example 5 A method for synthesizing an organic phosphine ligand Sodium tert-butoxide was replaced by lithium tert-butoxide, and the other conditions were the same as those in Example 1.

[0030] Comparative Example 6 A method for synthesizing an organic phosphine ligand Sodium tert-butoxide was replaced by potassium methoxide, and the other conditions were the same as in Example 1.

[0031] Comparative Example 7 A method for synthesizing an organic phosphine ligand The sodium tert-butoxide was omitted, and the remaining conditions were the same as those in Example 1.

[0032] Comparative Example 8 A method for synthesizing an organic phosphine ligand The bis-pinacol biborate was omitted, and the other conditions were the same as those in Example 1.

[0033] The NMR characterization of product 1 in Example 1 is as follows: 1H NMR (400 MHz, CDCl3) δ7.70-7.61 (m, 4 H), 7.50-7.41 (m, 6 H), 3.36-3.28 (t, J = 8 Hz, 2H), 3.28 (s, 3 H), 2.27-2.20 (m, 2 H), 1.69-1.55 (m,4H).

[0034] 13C NMR (100 MHz, CDCl3) δ132.1 (d, J = 9 Hz), 131.1 (d, J = 2 Hz), 128.8 (d, J = 10), 72.1, 58.6, 31.0 (d, J = 13), 25.6 (d, J = 37), 20.0. The specific NMR spectrum is shown in the figure below. Figure 1~2 shown.

[0035] The NMR characterization of product 2 in Example 2 is as follows: 1H NMR (400 MHz, CDCl3) δ7.69-7.64 (m, 4 H), 7.50-7.41 (m, 6 H), 7.56-7.37 (m, 6H), 7.32-7.20 (m, 2H), 6.93 (t, J = 8 Hz, 1H), 6.84 (d J=8 Hz,2H), 3.94 (t, J = 6Hz, 2H), 2.37-2.22 (m, 2H), 1.88 (p,J = 7 Hz, 2H), 1.79-1.67 (m, 2H).

[0036] 13C NMR (100 MHz, CDCl3) δ132.1 (d, J = 9 Hz), 131.2 (d, J = 2 Hz), 129.4, 128.8 (d, J = 10), 120.7, 114.5, 66.9, 30.4 (d, J = 13), 25.4 (d, J =38), 19.9. The specific NMR spectrum is shown in the figure below. Figure 3~4 shown.

[0037] The NMR characterization of product 3 in Example 3 is as follows: 1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, Chloroform-d) δ 7.71-7.67(m, 4H), 7.56 - 7.37 (m, 6H), 3.64 (t, J = 6 Hz, 2H), 2.40 - 2.21 (m, 2H), 1.78 - 1.67 (m, 2H), 0.89 (d, J = 3 Hz, 12H), 0.02 (s, 6H).

[0038] 13C NMR (100 MHz, CDCl3) δ 132.1 (d, J = 9.0 Hz), 131.1 (d, J = 2.4Hz), 128.8(d, J = 10 Hz), 63.0 (d, J = 15 Hz),26.4, 26.0 (d, J = 10.5 Hz),24.82 22.0 (d, J = 38.7 Hz), -5.34. The specific NMR spectrum is shown in Figures 5 and 6 shown.

[0039] The NMR characterization of product 4 in Example 4 is as follows: 1H NMR (400 MHz, CDCl3) δ 7.74-7.64 (m, 2H), 7.49 (s, 3H), 1.99 -1.72 (m, 4H), 1.40 (tt, J = 12.8, 6.1 Hz, 1H), 1.18 (tt, J = 12.7, 6.2 Hz,1H), 1.06 (ddd, J = 15.5, 8.4, 6.8 Hz, 3H), 0.86 (d, J = 1.5 Hz, 9H).

[0040] 13C NMR (101 MHz, CDCl3) δ 131.98 (d, J = 8.4 Hz), 131.20 (d, J = 2.5Hz), 128.76 (d, J = 9.5 Hz), 36.14, 30.54, 28.80, 20.19 (d, J = 36.7 Hz),18.69 (d, J = 37.2 Hz), 7.01. The specific NMR spectrum is shown in Figure 7-8 shown.

[0041] The product yields in Examples 1 to 4 and Comparative Examples 1 to 8 are shown in the following table, where nd means that the product was not detected.

[0042] Table 1

[0043] In Comparative Example 1, the yield decreased by replacing the ligand with a bipyridine ligand; in Comparative Example 5, the base t-BuONa was replaced with t-BuOLi, resulting in a decrease in yield; Comparative Examples 2 and 3 show that the reaction cannot occur when a nickel catalyst or a palladium catalyst is used instead of an iron catalyst; Comparative Example 4 shows that the reaction cannot proceed when an iron catalyst is not added; Comparative Example 6 shows that the yield decreases when potassium methoxide replaces lithium tert-butoxide; Comparative Examples 7 and 8 show that the reaction cannot proceed when no base lithium tert-butoxide or reducing agent B2pin2 is added. In summary, the reaction conditions in the embodiment allow the reaction to proceed smoothly and the product yield is high.

[0044] Although the specific implementation of the present invention is described in detail in conjunction with the embodiments, it should not be understood as limiting the scope of protection of this patent. Within the scope described in the claims, various modifications and variations that can be made by those skilled in the art without creative work still fall within the scope of protection of this patent.

Claims

1. A method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent, characterized in that: The method comprises the following steps: dissolving compound 1 and compound 2 in a solvent, adding an iron catalyst, a reducing agent, a base and a ligand, and reacting at 90-100° C. to obtain an organic phosphine ligand 3; the structural formulas of compound 1, compound 2 and organic phosphine ligand 3 are as follows: 、 、 ； Wherein R1 is ethyl; R2 is ethyl or phenyl; R3 is a primary alkyl group containing at least one of ether bond, ester group, silicon, nitrogen and fluorine, or a secondary alkyl group containing at least one of ether bond, ester group, silicon, nitrogen and fluorine; The reducing agent is B2pin2; the base is t-BuONa; the structural formula of the ligand is as follows: 。 2. The method for synthesizing an organophosphine ligand by group migration of an organophosphine reagent catalyzed by iron according to claim 1, characterized in that: The iron catalyst is FeBr2, Fe(CO2CH3)2 or Fe(OTs)3; the solvent is n-hexane, cyclohexane, ether or methyl tert-butyl ether.

3. The method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent according to claim 1, characterized in that: The compound 1 is one of the compounds having the following structure: 、 ； The compound 2 is one of the compounds having the following structure: 、 、 、 。 4. The method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent according to claim 3, characterized in that: The solid-liquid ratio of compound 1, compound 2, reducing agent, base, iron catalyst, ligand and solvent is 0.2mmol: 0.5~0.7mmol: 0.8~1mmol: 0.4~0.8mmol: 0.008~0.012mmol: 0.015~0.025mmol:0.5~2mL.

5. The method for synthesizing an organophosphine ligand by iron-catalyzed group migration of an organophosphine reagent according to claim 3, characterized in that: The reaction time is 5~10h.

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