Method for preparing diaryl methane compound through copper / visible light concerted catalysis

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a diaryl methane derivative through a desilicication arylation reaction of a benzyl silicon compound and diaryl iodonium salt under the synergistic catalysis of copper / visible light. The method comprises the following steps: in a nitrogen atmosphere, sequentially adding diaryl iodonium salt, a benzyl silicon compound, a copper catalyst, a ligand, a photocatalyst and alkali into a reaction solvent to obtain a mixture, stirring the mixture at a proper temperature under the irradiation of a blue light LED lamp until the reaction is complete, and performing concentration and column chromatography purification to obtain the diaryl methane compound. The preparation method disclosed by the invention is mild in reaction condition and simple and convenient to operate, most of the adopted raw materials are simple and easy to obtain or commercialized, and the reaction cost is relatively low. The reaction functional group compatibility is good, the substrate application range is wide, and the method is expected to have application prospects in the fields of drug research and development, life science and the like.

Description

Technical Field

[0001] This invention belongs to the technical field of organic synthesis, specifically relating to a method for preparing diarylmethane compounds by desilication arylation reaction of benzylsilane compounds with diaryliodonium salts under the synergistic catalysis of copper catalyst and photocatalyst. Background Technology

[0002] Copper, due to its abundant natural reserves, low price, and low toxicity, is generally considered an ideal alternative to noble metal catalysts in organic synthesis. For example, the copper-catalyzed Ullmann reaction has been widely used in pharmaceutical synthesis due to its economic advantages. However, due to copper's inherent properties, such as its resistance to oxidative addition, copper-catalyzed arylation reactions using aryl halides as starting materials typically require harsh reaction conditions, such as high temperatures and long reaction times, thus limiting the compatibility and broad applicability of these methods with different functional groups. Against this backdrop, diaryliodonium salts, as highly reactive aryl electrophiles, have attracted the attention of chemists. They can undergo oxidative addition reactions with monovalent copper under mild conditions to generate trivalent aryl copper intermediates, which can then participate as aryl electrophiles in various types of ionic reactions. Examples will be given below:

[0003] The method disclosed in Reference 1 (Elise Cahard, Henry PJMale, Matthieu Tissot, Matthew J. Gaunt. J. Am. Chem. Soc. 2015, 137, 7986) involves the addition of aryl trivalent copper to olefins containing amide structures. Different products are obtained depending on the structure of the diaryl iodine salt used: when an electron-rich diaryl iodine salt is used, the addition of trivalent aryl copper to the olefin results in intramolecular cyclization, yielding a six-membered heterocyclic structure; while when an electron-deficient diaryl iodine salt is used as the substrate, β-hydrogen elimination occurs after the addition to the olefin, yielding a Heck-type reaction product. The specific reaction process is shown below:

[0004]

[0005] The method disclosed in Reference 2 (Andrew J. Walkinshaw, Wenshu Xu, Marcos G. Suero, Matthew J. Gaunt. J. Am. Chem. Soc. 2013, 135, 12532) involves reacting an aromatic ring substrate with an alkynyl chain and a diaryliodonium salt under alkaline conditions for 12-36 h at 50 °C using cuprous chloride as a catalyst to yield an aryl trivalent copper addition / intramolecular cyclization product to an alkyne. The specific reaction process is shown below:

[0006]

[0007] In the method disclosed in Reference 3 (Elise Cahard, Nadine Bremeyer, Matthew J. Gaunt. Angew. Chem. Int. Ed. 2013, 52, 9284), a tandem process of trivalent aryl copper addition / intramolecular cyclization of N-allyl amide and diaryl iodonium salts occurs under conditions of 70°C with 1,4-dioxane as solvent and thiophene-2-carboxylate as catalyst. The specific reaction process is as follows:

[0008]

[0009] The method disclosed in Reference 4 (Beatrice S. Collins, Marcos G. Suero, Matthew J. Gaunt. Angew. Chem. Int. Ed. 2013, 52, 5799) involves using a trivalent aryl copper intermediate generated from a diaryl iodonium salt and cuprous chloride to intercept the allenyl alcohol intermediate resulting from the Meyer-Schuster rearrangement of propargyl alcohol, thus yielding an α-arylated α,β-unsaturated ketone. The specific reaction process is shown below:

[0010]

[0011] The method disclosed in Reference 5 (Rodolphe Beaud, Robert J. Phipps, Matthew J. Gaunt. J. Am. Chem. Soc. 2016, 138, 13183) involves the reaction of a diaryliodonium salt as an electrophilic aryl source with a secondary phosphine oxide under copper catalysis and ligand action to achieve the arylation of phosphine to obtain a tertiary phosphine oxide. The specific reaction process is shown below:

[0012]

[0013] However, the above strategies are all limited to ionic reactions, requiring the presence of typical nucleophiles to react with trivalent aryl copper, thus restricting the applicable substrate range. Therefore, developing a novel catalytic reaction mode to extend the arylation reaction system of copper / diaryliodonium salts to a wider range of atypical nucleophiles is of great value both in theoretical research and practical application. Summary of the Invention

[0014] The purpose of this invention is to develop a novel catalytic mode that utilizes the synergistic catalysis of copper and visible light to achieve the desilication and arylation reaction of benzylsilane compounds with diaryliodonium salts under mild conditions, providing a method for synthesizing diarylmethane derivatives, aiming to overcome the difficulty of limited substrate types in existing reaction modes.

[0015] The solution adopted by the present invention to achieve the objective includes the following steps: under a nitrogen atmosphere, diaryliodonium salt, benzylsilane compound, copper catalyst, ligand, photocatalyst and base are added sequentially to the reaction solvent to obtain a mixture. The mixture is stirred at a suitable temperature and under blue LED light irradiation until the reaction is complete. After concentration and column chromatography purification, diarylmethane compound can be obtained.

[0016] The reaction formula of the method of the present invention can be expressed as follows:

[0017]

[0018] In this context, formula A represents benzylsilane compounds, formula B represents diaryliodonium salts, and formula (I) represents diarylmethane derivatives.

[0019] In equations A and (I), R 1 For hydrogen, methyl; R 2 It is methyl, phenyl, 2-bromoethyl, 2-azidoethyl, 2-tert-butyldimethylsiloxyethyl, 2-N-phthalimide ethyl, 2-thioacetate ethyl, 2-N,N-dimethylacetamido; or R 2 It is linked with Ar to form a benzocyclohexyl group;

[0020] In equations A and (I), Ar 1 It is phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-naphthyl, 4-bromophenyl, 3-bromophenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2-thienyl, 3-pyridyl, 2,4,6-trimethylphenyl, 4-trimethylsilylmethylphenyl;

[0021] In equations B and (I), Ar 2 It is 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-methoxy-3-bromophenyl, 2-fluorophenyl, 4-iodophenyl, 4-tert-butylphenyl, 2-methylphenyl, phenyl, 4-acetylphenyl, 5-(3-chloro)pyridyl;

[0022] In formula B, Ar 3 with Ar 2 Same or Ar 3 It is 2,4,6-trimethylphenyl;

[0023] The copper catalyst is one of cuprous thiophene-2-carboxylate, cuprous chloride, and copper hexafluorophosphate with tetraacetonitrile, preferably cuprous thiophene-2-carboxylate;

[0024] The photocatalyst is 3,6-di-tert-butyl-9-trimethyl-10-phenylacridin-10-onium tetrafluoroborate;

[0025] The alkali is one of potassium carbonate, cesium carbonate, and potassium fluoride, preferably potassium carbonate;

[0026] The ligand is one of 2,6-bis(2-pyridyl)pyridine and 2,6-bis(1-pyrazolyl)pyridine, preferably 2,6-bis(1-pyrazolyl)pyridine;

[0027] The solvent is one of tetrahydrofuran, 1,4-dioxane, and acetonitrile, preferably acetonitrile; the concentration of benzylsilane in the mixed solution is 0.05-0.5M, preferably 0.1M;

[0028] The molar ratio of the benzylsilane compound, diaryliodonium salt, base, photocatalyst, copper catalyst, and ligand is 1.0:1.5:2.0:0.01:0.15:0.15;

[0029] The reaction temperature is -60 to 20°C, preferably -35°C.

[0030] The reaction time is 10-40 hours, preferably 24 hours;

[0031] The wavelength of the blue light used is 420-470nm, preferably 456nm; the power is 5-40W, preferably 5W.

[0032] Compared with the shortcomings and deficiencies of existing technologies, the present invention has the following advantages:

[0033] (1) This invention provides a method for preparing diarylmethane derivatives by desilication arylation reaction of benzylsilane compounds. The raw materials used are low cost and easy to obtain. The reaction conditions are mild and have high tolerance to a variety of common functional groups.

[0034] (2) This invention provides a new mode of copper / visible light co-catalyzed arylation reaction of diaryliodonium salts. By changing the reaction mechanism, the reaction is extended to unconventional nucleophiles, thus expanding the substrate types applicable to copper-catalyzed arylation reactions. Attached Figure Description

[0035] Figure 1 This is the proton spectrum of compound 1 in the embodiments of the present invention;

[0036] Figure 2 This is the carbon spectrum of compound 1 in the embodiments of the present invention;

[0037] Figure 3 This is the proton spectrum of compound 2 in the embodiments of the present invention;

[0038] Figure 4This is the carbon spectrum of compound 2 in the embodiments of the present invention;

[0039] Figure 5 This is the proton spectrum of compound 3 in the embodiments of the present invention;

[0040] Figure 6 This is the carbon spectrum of compound 3 in the embodiments of the present invention;

[0041] Figure 7 This is the proton spectrum of compound 4 in the embodiments of the present invention;

[0042] Figure 8 This is the fluorine spectrum of compound 4 in the embodiments of the present invention;

[0043] Figure 9 This is the carbon spectrum of compound 4 in the embodiments of the present invention;

[0044] Figure 10 This is the proton spectrum of compound 6 in the embodiments of the present invention;

[0045] Figure 11 This is the fluorine spectrum of compound 6 in the embodiments of the present invention;

[0046] Figure 12 This is the carbon spectrum of compound 6 in the embodiments of the present invention; Detailed Implementation

[0047] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0048] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0049] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0050] Example 1:

[0051]

[0052] Under a nitrogen atmosphere, 4-methoxybenzyltrimethylsilane A1 (0.2 mmol), di-4-methyl phenyl iodonium salt B1 (0.3 mmol), cuprous thiophene-2-carboxylate (0.03 mmol), 2,6-bis(1-pyrazolyl)pyridine (0.03 mmol), 3,6-di-tert-butyl-9-mesethylated-10-phenylacridin-10-onium tetrafluoroborate (0.002 mmol), and potassium carbonate (0.4 mmol) were sequentially added to 2.0 mL of acetonitrile. The resulting mixture was stirred for 24 hours at -35 °C under 5W 456 nm LED light. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 4-(4-methoxybenzyl)benzoate 1 (47.4 mg, 0.180 mmol, colorless oil), with a yield of 85%. 1 H NMR (400MHz, Chloroform-d) δ7.95 (d, J=8.2Hz, 2H), 7.24 (d, J=8.2Hz, 2H), 7.09 (d, J=8.6Hz, 2H), 6.84 (d, J=8.6Hz, 2H), 3.97 (s, 2H), 3.90 (s, 3H), 3.79 (s, 3H). 13 C NMR (101MHz, Chloroform-d) δ167.2, 158.2, 147.1, 132.3, 130.0, 129.9, 128.9, 128.1, 114.1, 55.4, 52.1, 41.1. HRMS (ESI, m / z): calcd for C 16 H 16 O3, [M+H] + :257.1172, found:257.1164.

[0053] Examples 2-23

[0054] Examples 2-23 are basically the same as Example 1, except that the substituents on the benzylsilane are different. The specific structures are shown in the table below:

[0055] Table 1 Examples 2-23

[0056]

[0057]

[0058] Example 24

[0059]

[0060] Under a nitrogen atmosphere, 1-phenylethyltrimethylsilane A14 (0.2 mmol), diphenyliodonium salt B2 (0.3 mmol), cuprous thiophene-2-carboxylate (0.03 mmol), 2,6-bis(1-pyrazolyl)pyridine (0.03 mmol), 3,6-di-tert-butyl-9-mesethyl-10-phenylacridin-10-onium tetrafluoroborate (0.002 mmol), and potassium carbonate (0.4 mmol) were sequentially added to 2.0 mL of acetonitrile. The resulting mixture was stirred for 24 hours at -35 °C under 5W 456 nm LED light. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1,1-diphenylethane 24 (23.0 mg, 0.130 mmol, colorless oil), with a yield of 65%. 1 H NMR (400MHz, Chloroform-d) δ7.33-7.27 (m, 4H), 7.25-7.16 (m, 6H), 4.17 (q, J=7.2Hz, 1H), 1.65 (d, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ146.5, 128.5, 127.7, 126.1, 44.9, 22.0.HRMS (ESI, m / z): calcd forC 14 H 14 [M+H] + :183.1168, found:183.1178.

[0061] Examples 25-39

[0062] Examples 25-39 are basically the same as Example 24, except that different diaryliodomonium salts are used. The specific structures of the diaryliodomonium salts are detailed in the table below:

[0063] Table 2 Examples 25-39

[0064]

[0065]

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a diphenylmethane derivative, characterized in that, Under the synergistic catalysis of copper catalyst / photocatalyst, diaryliodonium salts and benzylsilane compounds undergo desilylation to yield diphenylmethane derivatives; The structure of the diphenylmethane derivative is shown in formula (I) below: The structural formula of the benzylsilane compound is shown in Formula A below: The structural formula of the diaryliodomonium salt is shown in Formula B below: In equations A and (I), R 1 For hydrogen, methyl; R 2 It is methyl, phenyl, 2-bromoethyl, 2-azidoethyl, 2-tert-butyldimethylsiloxyethyl, 2-N-phthalimide ethyl, 2-thioacetate ethyl, 2-N,N-dimethylacetamido; or R 2 It is linked with Ar to form a benzocyclohexyl group; In equations A and (I), Ar 1 It is phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-naphthyl, 4-bromophenyl, 3-bromophenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2-thienyl, 3-pyridyl, 2,4,6-trimethylphenyl, 4-trimethylsilylmethylphenyl; In equations B and (I), Ar 2 It is 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-methoxy-3-bromophenyl, 2-fluorophenyl, 4-iodophenyl, 4-tert-butylphenyl, 2-methylphenyl, phenyl, 4-acetylphenyl, 4-methyl ester phenyl, 5-(3-chloro)pyridyl; In formula B, Ar 3 with Ar 2 Same or Ar 3 It is 2,4,6-trimethylphenyl; The copper catalyst is cuprous thiophene-2-carboxylate; The photocatalyst is 3,6-di-tert-butyl-9-trimethyl-10-phenylacridin-10-onium tetrafluoroborate.

2. The method for preparing the diphenylmethane derivative according to claim 1, characterized in that, The solution includes the following steps: (1) Under a nitrogen atmosphere, benzylsilane compounds, diaryliodonium salts, bases, photocatalysts, copper catalysts, and ligands are added sequentially to the reaction solvent to obtain a mixture; The base is potassium carbonate and the ligand is 2,6-bis(1-pyrazolyl)pyridine; The molar ratio of the benzylsilane compound, diaryliodonium salt, base, photocatalyst, copper catalyst, and ligand is 1.0:1.5:2.0:0.01:0.15:0.15, and the concentration of benzylsilane in the mixed solution is 0.1M. (2) Stir the mixture described in step (1) at a suitable temperature under blue LED light until the reaction is complete. Filter the crude product, concentrate it under reduced pressure, and then separate it by silica gel column chromatography to obtain the diphenylmethane derivative. The mixture was reacted at -35°C for 12 hours, and the blue light used had a wavelength of 456nm and a power of 5W.

3. The method for preparing the diphenylmethane derivative according to claim 2, characterized in that, In step (1), the reaction solvent is acetonitrile.

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