阅读说明：本技术 一种含有p-o键或p-s键化合物的制备方法 (Preparation method of compound containing P-O bond or P-S bond ) 是由 杨斌 沈建 王雪 段宝荣 于 2020-06-12 设计创作，主要内容包括：本发明公开了一种含有P-O键或者P-S键化合物的制备方法。所述的方法以含羟基或含巯基的化合物、磷试剂为起始原料,然后,所述起始原料于惰性气体氛围中,在三氟甲烷磺酸酐(Tf<Sub>2</Sub>O)和二甲基亚砜(DMSO)的作用下,按摩尔比,所述含羟基或含巯基的化合物：磷试剂：三氟甲烷磺酸酐:二甲基亚砜为1～5:1～2.5:2～3:2的比例在有机溶剂中于反应温度25～100℃下反应6～20小时后,即得到具有结构通式(I)的化合物。本发明所用试剂低毒、绿色环保,避免了使用价格高昂、毒性较大的贵金属催化剂；本发明中所用试剂三氟甲烷磺酸酐(Tf<Sub>2</Sub>O)和二甲基亚砜(DMSO)不仅毒性低,而且成本十分廉价,这使得本发明绿色环保、经济性高,适合大规模生产。(The invention discloses a preparation method of a compound containing a P-O bond or a P-S bond. The method takes a compound containing hydroxyl or sulfhydryl and a phosphorus reagent as starting materials, and then the starting materials are put into trifluoromethane sulfonic anhydride (Tf) in an inert gas atmosphere 2 O) and dimethyl sulfoxide (DMSO) according to a molar ratio, wherein the hydroxyl-containing or sulfhydryl-containing compound comprises: phosphorus reagent: reacting trifluoromethane sulfonic anhydride and dimethyl sulfoxide in a ratio of 1-5: 1-2.5: 2-3: 2 in an organic solvent at a reaction temperature of 25-100 ℃ for 6-20 hours to obtain the compound with the structural general formula (I). The reagent used in the invention is low in toxicity, green and environment-friendly, and avoids the use of noble metal catalysts with high price and high toxicity; reagent trifluoromethane sulfonic anhydride (Tf) used in the present invention 2 O) and dimethyl sulfoxide (DMSO) not only have low toxicity, but also have very low cost, so that the invention is environment-friendly, has high economical efficiency and is suitable for large-scale production.)

1. A method for preparing a compound containing a P-O bond or a P-S bond is characterized in that the method takes a compound containing hydroxyl or sulfhydryl and a phosphorus reagent as starting materials,

wherein the hydroxyl-containing or thiol-containing compound is:

R¹-X-H

x is O or S, and R¹Adopts one of the following schemes:

when X ═ O, R¹Any one selected from the group consisting of C1-C8 alkyl, 2-hydroxyethyl, 4-chlorobutyl, 3-phenylpropyl, trifluoroethyl, allyl, propynyl, cyclohexyl, cyclopropylmethyl, 3-phenylallyl, 9-fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, 1-naphthylmethyl, ferrocenylmethyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, 4-cyanophenyl, 4-nitrophenyl, 2-phenylphenyl, 3-cyanophenyl, 2-methyl-4-bromophenyl, and 2-naphthyl,

when X ═ S, R¹Is selected from R₃Is any one of C4-C8 alkyl, cyclohexyl, benzyl, 2-naphthyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-methylphenyl and 3-chlorophenyl;

the phosphorus reagent is:

R²any one selected from phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 3, 5-dimethylphenyl, methoxy, ethoxy, isopropoxy, n-butoxy, phenoxy, 9, 10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxy,

R³selected from phenyl, 4-methylphenyl,Any one of 4-methoxyphenyl, 4-tert-butylphenyl, 3, 5-dimethylphenyl, n-butyl, methoxy, ethoxy, isopropoxy, n-butoxy and phenoxy;

then, the starting material was reacted under an inert gas atmosphere in trifluoromethane sulfonic anhydride (Tf)₂O) and dimethyl sulfoxide (DMSO) according to a molar ratio, wherein the hydroxyl-containing or sulfhydryl-containing compound comprises: phosphorus reagent: reacting trifluoromethane sulfonic anhydride and dimethyl sulfoxide in a ratio of 1-5: 1-2.5: 2-3: 2 in an organic solvent at a reaction temperature of 25-100 ℃ for 6-20 hours to obtain a compound with a structural general formula (I),

and X, R in the compound of the general formula (I)¹、R²、R³The designation of (b) is consistent with the foregoing.

2. The method according to claim 1, wherein the organic solvent is selected from the group consisting of N, N-Dimethylformamide (DMF), ethanol, and acetonitrile.

3. The method according to claim 1, wherein the inert gas is N₂、Ar。

4. The method according to claim 1, wherein the hydroxyl-or thiol-group-containing compound is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, n-hexanol, n-octanol, ethylene glycol, 4-chlorobutanol, phenylpropanol, trifluoroethanol, allyl alcohol, propynyl alcohol, cyclohexanol, cyclopropylmethanol, 3-phenylallylalcohol, 9-fluorenylmethanol, benzyl alcohol, p-fluorobenzyl alcohol, p-chlorobenzyl alcohol, 1-naphthalenylmethanol, ferrocenylmethanol, phenol, p-methylphenol, p-methoxyphenol, p-fluorophenol, p-chlorophenol, p-bromophenol, 4-cyanophenol, 4-nitrophenol, 2-phenylphenol, 3-cyanophenol, 2-methyl-4-bromophenol, 2-naphthol, n-butylmercaptan, cyclohexylmercaptan, benzylmercaptan, 2-methyloxyphenol, 2-naphthol, n-butylmercaptan, cyclohexylmercaptan, benzylmercaptan, 2-naphthalene thiol, 4-methyl thiophenol, 4-tert-butyl thiophenol, 4-methoxy thiophenol, 4-fluorobenzothiophenol, 4-chlorobenzothiophenol, 4-bromobenzothiophenol, 2-methyl thiophenol, 3-chlorobenzothiophenol.

5. The method according to claim 1, wherein the phosphorus reagent is selected from the group consisting of diphenylphosphoroxy, bis (4-methylphenyl) phosphoroxy, bis (4-methoxyphenyl) phosphoroxy, bis (4-tert-butylphenyl) phosphoroxy, bis (3, 5-dimethylphenyl) phosphoroxy, dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite, diphenyl phosphite, DOPO (9, 10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide), ethylphenylphosphate, and phenyl n-butylphosphoroxy.

6. The process according to claim 1, wherein when X ═ O, R in the formula (I)¹When the compound is an aliphatic substituent, the molar ratio of the hydroxyl-containing or sulfhydryl-containing compound to the phosphorus reagent, the trifluoromethanesulfonic anhydride and the dimethyl sulfoxide is 1 (2-3) to 2: 2.

7. The process according to claim 1, wherein when X ═ O, R in the formula (I)¹When the compound is an aromatic substituent, the molar ratio of the compound containing hydroxyl or sulfhydryl, the phosphorus reagent, the trifluoromethanesulfonic anhydride and the dimethyl sulfoxide is (3-5) 1:3: 2.

8. The preparation method according to claim 1, wherein when X ═ S in the general formula (I), the molar ratio of the hydroxyl group-or thiol group-containing compound to the phosphorus reagent, trifluoromethanesulfonic anhydride, and dimethyl sulfoxide is 1 (2-3): 2: 2.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a compound containing a P-O bond or a P-S bond.

Background

Compounds containing a P-O bond or a P-S bond are important organic molecules, which are not only essential substances for maintaining normal existence of a living body, but also are widely used in various research fields such as agricultural chemistry, life science, pharmaceutical chemistry, and material science. For example, in the field of life sciences, Adenosine Triphosphate (ATP) is a compound containing a P — O bond present in a living body, which ensures energy supply for various vital activities of cells; in the field of medicinal chemistry, Sofosbuvir (Sofosbuvir) is a drug molecule containing a P-O bond, which has a specific therapeutic effect in treating chronic hepatitis c diseases (Han, m.z.final.in.j.pharm, 2019,50, 1393); in the field of agricultural science, iprobenfos is an organophosphorus pesticide containing a P-S bond (Zhangixin. pesticide, 1989,28, 18); in the field of material science, DOPO-ACA is a highly effective flame retardant containing a P-O bond (Kangxinglong et al, proceedings of Henan university, 2019,49, 567).

Among the methods for preparing compounds having P-O bond/P-S bond which have been developed so far, the coupling reaction of phosphoryl chloride with active hydrogen-containing compounds developed earlier and some conventional synthetic methods such as Atherton-Todd reaction are still dominant. However, these conventional syntheses all have great limitations and certain disadvantages: for example, phosphoryl chloride reagents are unstable, extremely deliquescent, and require prior pre-preparation by chlorination or other synthetic steps; as another example, carbon tetrachloride, which is used as both a reagent and a solvent in most Atherton-Todd reactions, is highly volatile and toxic, and can cause symptoms such as paralysis of the nervous system or acute renal failure after inhalation by the operator. Therefore, the above-mentioned drawbacks of the conventional synthesis methods have greatly limited the mass production and application of the P-O bond/P-S bond-containing compounds. Although novel syntheses such as transition metal promoted coupling reaction ([1] Arisawa, M.et al. tetrahedron Lett.,2005,46, 5669; [2] Kaboudin, B.et al. Synthesis,2013,2323) and radical reaction ([1] Zhang, X.H.et al. J.org.chem.2018,83,1532; [2] Huang, H.et al. org.biomol.chem.,2018,16,4236) have been developed in recent years, these reactions require the addition of noble metal reagents as well as a large amount of additives, which makes them less economical, and the generation of a large amount of metal salt waste is serious to the environment.

It should be noted that all the developed synthetic methods have poor universality, and none of them can simultaneously react with phosphorus reagents such as alcohol, phenol, thiol, thiophenol and aryl phosphorus reagent, phosphite, etc. Therefore, the economic, green and high-universality synthesis method is developed, and the compound containing the P-O bond/P-S bond is efficiently prepared by using cheap, easily-obtained, low-toxicity and harmless chemical reagents, so that the compound has a good application prospect in the field of actual production or scientific research.

Disclosure of Invention

One of the purposes of the invention is to provide a synthesis method for preparing a compound containing a P-O bond or a P-S bond, the method has mild reaction conditions, cheap and easily available starting materials, convenient operation and very wide applicability of reaction substrates, various alcohols, phenols, thiols and thiophenols can be applied to the method, various phosphorus reagents can also be reacted, and various compounds containing the P-O bond or the P-S bond can be synthesized in one step by the method.

The technical scheme for realizing the invention is as follows:

a process for preparing the compound containing P-O bond or P-S bond features that the compound containing hydroxy or mercapto (alcohol, phenol, thiol or thiophenol) and phosphorus reagent are used as raw materials and the trifluoromethane sulfonic anhydride (Tf) is added in the atmosphere of inertial gas₂O) and dimethyl sulfoxide (DMSO) according to a molar ratio, wherein the hydroxyl-containing or sulfhydryl-containing compound comprises: phosphorus reagent: trifluoromethanesulfonic anhydride, namely dimethyl sulfoxide (1-5): 1-2.5): 2-3): 2, in an organic solvent, reacting at a reaction temperature t for 12 hours to prepare a compound with a structural general formula (I), wherein the structural general formula (I) is as follows;

specifically, the specific reaction mode is carried out according to the following three types of reaction formulas according to the specific types of compounds containing hydroxyl or sulfhydryl groups:

reaction mode 1 is shown in reaction formula (II):

the specific operation steps are as follows:

using mercaptan or thiophenol substrate and phosphorus reagent as starting raw materials, under the protection of inert gas, reacting for 12 hours in organic solvent acetonitrile at room temperature under the action of trifluoromethane sulfonic anhydride and dimethyl sulfoxide, removing the solvent by rotary evaporation after the reaction is finished, and performing reaction by using a solvent in a volume ratio of 3:1, taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and carrying out column chromatography to obtain a product;

the thiol or thiophenol substrate is selected from any one of n-butylthiol, cyclohexylthiol, benzylthiol, 2-naphthylthiol, 4-methylthiophenol, 4-tert-butylthiophenol, 4-methoxythiophenol, 4-fluorothiophenol, 4-chlorothiophenol, 4-bromophenylthiophenol, 2-methylthiophenol and 3-chlorothiophenol.

The phosphorus reagent is any one of diphenyl phosphorus oxide, di (4-methylphenyl) phosphorus oxide, di (4-methoxyphenyl) phosphorus oxide, di (4-tert-butylphenyl) phosphorus oxide, di (3, 5-dimethylphenyl) phosphorus oxide, dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite, diphenyl phosphite, DOPO (9, 10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide), ethyl phenylphosphate and phenyl n-butyl phosphorus oxide.

In the reaction mode, the feeding molar ratio of the mercaptan or thiophenol substrate, the phosphorus reagent, the trifluoromethanesulfonic anhydride and the dimethyl sulfoxide is 1 (1.5-2.5) to 2:2, preferably 1: 2:2:2.

Reaction mode 2 is shown in reaction formula (III):

the specific operation steps are as follows:

taking an alcohol substrate and a phosphorus reagent as initial raw materials, reacting for 12 hours at room temperature in an organic solvent DMF under the protection of inert gas and the action of trifluoromethanesulfonic anhydride and dimethyl sulfoxide, adding water for quenching after the reaction is finished, extracting for 3 times by using ethyl acetate, concentrating an organic phase, and reacting at a volume ratio of 3:1, taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and carrying out column chromatography to obtain a product;

the alcohol substrate is selected from any one of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, n-hexanol, n-octanol, ethylene glycol, 4-chlorobutanol, phenylpropanol, trifluoroethanol, allyl alcohol, propiolic alcohol, cyclohexanol, cyclopropylmethanol, 3-phenylallyl alcohol, 9-fluorenylmethanol, benzyl alcohol, p-fluorobenzyl alcohol, p-chlorobenzyl alcohol, 1-naphthylmethanol and ferrocenylmethanol.

The phosphorus reagent is any one of diphenyl phosphorus oxygen, di (4-methylphenyl) phosphorus oxygen, di (4-methoxyphenyl) phosphorus oxygen, di (4-tert-butylphenyl) phosphorus oxygen and di (3, 5-dimethylphenyl) phosphorus oxygen.

In the reaction mode, the feeding molar ratio of alcohol to phosphorus reagent to trifluoromethanesulfonic anhydride to dimethyl sulfoxide is 1 (2-3) to 2:2, preferably 1: 2.5:2:2.

Reaction mode 3 is shown in reaction formula (IV):

the specific operation steps are as follows:

taking a phenol substrate and a phosphorus reagent as initial raw materials, reacting for 12 hours in an organic solvent acetonitrile at the reaction temperature of 90 ℃ under the protection of inert gas and the action of trifluoromethanesulfonic anhydride and dimethyl sulfoxide, removing the solvent through rotary evaporation after the reaction is finished, and performing reaction in a volume ratio of 3:1, taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and carrying out column chromatography to obtain a product;

the phenolic substrate is any one of phenol, p-methyl phenol, p-methoxy phenol, p-fluorophenol, p-chlorophenol, p-bromophenol, 4-cyanophenol, 4-nitrophenol, 2-phenylphenol, 3-cyanophenol, 2-methyl-4-bromophenol and 2-naphthol.

The phosphorus reagent is any one of diphenyl phosphorus oxygen, di (4-methylphenyl) phosphorus oxygen, di (4-methoxyphenyl) phosphorus oxygen, di (4-tert-butylphenyl) phosphorus oxygen and di (3, 5-dimethylphenyl) phosphorus oxygen.

In the reaction mode, the feeding molar ratio of the phenol substrate, the phosphorus reagent, the trifluoromethanesulfonic anhydride and the dimethyl sulfoxide is (4-6) to (1: 3):2, preferably 5: 1:3:2.

The outstanding substantive characteristics of the invention are that the phosphorus reagent and the trifluoromethanesulfonic anhydride (Tf)₂O) reacting to generate an electrophilic phosphorus positive ion intermediate, carrying out nucleophilic substitution reaction on the intermediate by a compound containing hydroxyl or sulfhydryl to obtain a trivalent phosphorus intermediate product, and further carrying out in-situ oxidation to obtain a pentavalent phosphorus target product. The key point is that dimethyl sulfoxide (DMSO) reagent is used as a mild alkaline reagent to enhance the nucleophilicity of a compound containing hydroxyl or sulfhydryl, and promote the conversion of a trivalent phosphorus intermediate product into a pentavalent phosphorus target product, and correspondingly, the selection of DMSO avoids the use of a strong oxidant and the damage of the strong oxidant to a substrate structure, and the invention can be compatible with the reaction of alcohol, phenol, mercaptan, thiophenol containing various functional groups and phosphorus reagents such as aryl phosphorus reagent and phosphite ester, and further can synthesize various compounds containing P-O bonds or P-S bonds by a one-pot method.

Compared with the prior art, the invention has the following advantages:

1, the reagent used in the invention is low in toxicity, green and environment-friendly, and noble metal catalysts (Pd, Pt, Rh, Ag and the like) with high price and high toxicity are avoided; reagent trifluoromethane sulfonic anhydride (Tf) used in the present invention₂O) and dimethyl sulfoxide (DMSO) are not only low in toxicity, but also very inexpensive in cost (DMSO: 99%, 10L,380 yuan; tf₂99.5 percent of O, 1kg of O, 850 yuan), which ensures that the invention is environment-friendly, has high economical efficiency and is suitable for large-scale production.

2, the reaction substrate used in the invention is simple and easy to obtain, has wide selection range, and is suitable for hydroxyl-containing or sulfhydryl-containing compounds, such as alcohol, thiol, phenol and thiophenol, which contain various functional groups; as the phosphorus reagent, various aryl phosphorus reagents, phosphate ester reagents and alkyl phosphorus reagents can be reacted. In addition, the two types of reaction substrates related by the invention do not need to be modified by functional groups, so that the waste of atoms and the generation of a large number of byproducts are avoided, and the method has higher atom economy and step economy;

3, the reaction conditions of the invention are mild, most reactions are carried out at room temperature, no additional heating device is needed to provide a heat source, and dangerous and harsh reaction conditions such as high temperature, high pressure and the like are avoided, so that the safety is high when the invention is used for production, and the used production equipment is simple and easy to operate.

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.