Method for preparing gamma-fluorodiphenylmethane compound through copper / visible light concerted catalysis

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing gamma-fluorodiphenylmethane compounds through copper / visible light concerted catalysis of three-component reaction of aryl cyclopropane, diaryl iodonium salt and triethylamine hydrofluoride. The method comprises the following steps: in a nitrogen atmosphere, sequentially adding aryl cyclopropane, diaryl iodonium salt, triethylamine hydrofluoride, a photocatalyst, a copper catalyst and a ligand 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 Y-fluorodiphenylmethane compound. The preparation method disclosed by the invention is simple and convenient to operate and mild in reaction condition, and modular construction of a complex fluorine-containing structure can be quickly realized. The reaction functional group compatibility is good, the substrate application range is wide, and the method is expected to be further applied to the fields of medicine development and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for preparing γ-fluorodiphenylmethane compounds by a three-component reaction of arylcyclopropane, diaryliodonium salt and triethylamine hydrofluoric acid under copper / visible light synergistic catalysis. Background Technology

[0002] Introducing aryl or heteroaryl structures into molecular structures is of great significance in the synthesis of natural products, drug structure modification, and the synthesis of functional materials. To achieve this goal, numerous arylation reactions utilizing transition metal-catalyzed cross-coupling have been developed over the past few decades. These reactions mainly include those between haloaryrines and functionalized substrates catalyzed by transition metals (e.g., Pd, Ni, Co). Furthermore, directed group-assisted C-H bond activation is also a relatively mature arylation strategy.

[0003] Copper, due to its abundant reserves, low price, and numerous variable valence states (+1, 2, 3), is an ideal choice for arylization reactions. However, due to the inherent properties of copper, using aryl halides as aryl electrophiles presents challenges due to their low reactivity; for example, classic Ullmann coupling requires relatively high temperatures to occur. To address this challenge, a series of more reactive aryl electrophiles have been developed, including aryl diazonium salts and diaryl iodonium salts. Examples of these will be provided below:

[0004] Reference 1 (Jasch H, Landais Y, Heinrich MR. Chem. Eur. J. 2013, 19, 8411-8416.) discloses an iron-promoted tandem cyclization reaction of 2-allyloxyphenyl diazonium salt. Under the action of ferrous iron, the aryl diazonium is reduced to an aryl radical, followed by rapid intramolecular 5-exo cyclization. The resulting terminal radical adds to 2,3-dichloropropene in the system, is captured by ferrous iron, and then eliminated to yield the allylated dihydrobenzofuran product. The specific reaction process is shown in the following equation:

[0005]

[0006] Reference 2 (Hering T, Hari DP, BJ Org. Chem. 2012, 77, 10347-10352) discloses a visible-light-catalyzed aryl diazonium salt-based aryl amination reaction of alkenes. In this reaction, an excited-state Ru photocatalyst first reduces the aryl diazonium salt to an aryl radical with a single electron. The resulting benzylic radical, after addition to the alkene, is oxidized to a carbocation by the oxidized-state photocatalyst with a single electron, and then captured by a nitrile in the system to obtain a Ritter-type product. The specific reaction process is shown in the following equation:

[0007]

[0008] Reference 3 (Tang HJ, Zhang X, Zhang YF, et al. Angew. Chem. Int. Ed. 2020, 59, 5242-5247) discloses a gold-catalyzed 1,2-fluoroarylation reaction of allenoate with aryl diazonium salt and triethylamine hydrofluoric acid. Under light irradiation, the aryl diazonium salt undergoes oxidative addition with monovalent gold to yield a trivalent aryl gold intermediate. Subsequently, fluoride ions attack the trivalent aryl gold-activated allenoate, and the fluoroarylation reaction of the allenoate is completed by reductive elimination with trivalent gold. The specific reaction process is shown in the following equation:

[0009]

[0010] Diaryliodonium salts are another class of highly reactive aryl electrophiles. Reference 4 (Phipps RJ, Grimster NP, Gaunt M JJAm. Chem. Soc. 2008, 130, 8172-8174) discloses a copper-catalyzed method for the 3-position arylation of indole. The reaction is initiated by the oxidative addition of diaryliodonium salt to monovalent copper to obtain a highly electrophilic aryl trivalent copper intermediate. The C3 nucleophilic site of indole attacks the aryl trivalent copper intermediate, followed by deprotonation and reductive elimination to yield the product. The specific reaction process is shown in the following equation:

[0011]

[0012] Reference 5 (Harvey JS, Simonovich SP, Jamison CR, et al. J. Am. Chem. Soc. 2011, 133, 13782-13785) discloses a method for the α-position asymmetric arylation of aldehydes synergistically catalyzed by copper / chiral secondary amines. The reaction proceeds through a chiral enamine and an aryl trivalent copper intermediate, and the stereoselectivity of arylation is controlled by the chiral center on the amine, resulting in the synthesis of a series of chiral α-aryl aldehydes, which have been further applied to the synthesis of the oral and local analgesic (S)-ketoprofen.

[0013]

[0014] The methods described above demonstrate the application of aryl diazonium salts and diaryl iodonium salts as arylating agents in synthesis. However, existing methods still have significant limitations in their application scope. For example, aryl diazonium salts can only undergo oxidative addition with noble metals like gold, while with inexpensive metals such as copper and iron, they primarily involve single-electron transfer to generate unstable aryl radicals. The aryl trivalent copper intermediate obtained from the oxidative addition of diaryl iodonium salts with monovalent copper is only suitable for ionic reactions, requiring the presence of a nucleophile in the system. Therefore, developing a novel catalytic reaction mode to expand the applicability of copper-catalyzed arylation reactions remains of great significance. Summary of the Invention

[0015] The purpose of this invention is to develop a copper / visible light synergistic catalytic mode to realize a new type of copper-catalyzed arylation reaction: using inexpensive and readily available triethylamine hydrofluoric acid as a nucleophilic fluorinating agent, a three-component reaction is used to realize the ring-opening fluoroarylation reaction of arylcyclopropane to prepare γ-fluorodiphenylmethane compounds, aiming to overcome the limitations of substrates and reaction types in existing reaction modes.

[0016] The solution adopted by the present invention to achieve the objective includes the following steps: under a nitrogen atmosphere, arylcyclopropane, diaryliodonium salt, triethylamine hydrofluoric acid salt, photocatalyst, copper catalyst and ligand are added sequentially to the reaction solvent to obtain a mixture. The mixture is stirred at a suitable temperature and under blue LED irradiation until the reaction is complete. After concentration and purification by column chromatography, γ-fluorodiphenylmethane compounds can be obtained.

[0017] The reaction formula of the method of the present invention can be expressed as follows:

[0018]

[0019] In this formula, A represents arylcyclopropane, B represents diaryliodonium salt, and C represents γ-fluorodiphenylmethane compounds.

[0020] In equations A and C, Ar 1 It is 4-methoxyphenyl, 4-methylphenyl, 4-phenylphenyl, 4-tert-butylphenyl, 4-trimethylsilylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-methyl ester-4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-naphthyl, 4-benzyloxyphenyl, 4-allyloxyphenyl, 4-(3-azidopropyl)phenyl, 4-(3-benzoyloxypropyl)phenyl, 4-(3-N-phthalimidepropyl)phenyl, 4-(3-thioacetylpropyl)phenyl, 4-cyclopropylphenyl;

[0021] R 1 The derivatives are methyl, ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-hydroxyethyl, vinyl, and phenyl.

[0022] R 2 For hydrogen, methyl, ethyl; R 1 R 2 They may be the same or different, or connected to form a cyclohexyl group;

[0023] In equations B and C, Ar 2 It is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-methylphenyl, 3-cyanophenyl, 2-fluorophenyl, 4-carboxyphenyl, 4-methyl ester phenyl, 5-(3-chloro)pyridyl;

[0024] In formula B, Ar 3 with Ar 2 Same or Ar 3 It is 2,4,6-trimethylphenyl;

[0025] The copper catalyst is one of cuprous thiophene-2-carboxylate, cuprous cyanide, cuprous acetate, and copper hexafluorophosphate tetraacetonitrile, preferably cuprous thiophene-2-carboxylate;

[0026] The photocatalyst is 3,6-di-tert-butyl-9-trimethyl-10-phenylacridin-10-onium tetrafluoroborate.

[0027] 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;

[0028] The solvent is one of tetrahydrofuran, 1,4-dioxane, and acetonitrile, preferably acetonitrile; the concentration of arylcyclopropane in the mixed solution is 0.05-0.5M, preferably 0.1M;

[0029] The molar ratio of the arylcyclopropane, diaryliodonium salt, triethylamine hydrofluoric acid salt, photocatalyst, copper catalyst, and ligand is 1.0:1.5:2.0:0.005:0.15:0.15, and the concentration of arylcyclopropane in the mixed solution is 0.1M.

[0030] The reaction temperature is -60 to 20°C, preferably -35°C.

[0031] The reaction time is 10-40 hours, preferably 12 hours;

[0032] The wavelength of the blue light used is 420-470nm, preferably 456nm; the power is 5-40W, preferably 5W.

[0033] Compared with the shortcomings and deficiencies of existing technologies, the present invention has the following advantages:

[0034] (1) This method provides an efficient preparation method for γ-fluorodiphenylmethane compounds. The three-component reaction mode can realize the rapid construction of a library of complex fluorine-containing compounds.

[0035] (2) This method provides a novel synergistic catalytic system, which provides a mild and efficient synthetic strategy for the radical ring-opening functionalization of arylcyclopropane. Attached Figure Description

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

[0037] Figure 2 This is the fluorine spectrum of compound 1 in the embodiments of the present invention;

[0038] Figure 3 This is the carbon spectrum of compound 1 in the embodiments of the present invention;

[0039] Figure 4 This is the proton spectrum of compound 2 in the embodiments of the present invention;

[0040] Figure 5 This is the fluorine spectrum of compound 2 in the embodiments of the present invention;

[0041] Figure 6 This is the carbon spectrum of compound 2 in the embodiments of the present invention;

[0042] Figure 7 This is the proton spectrum of compound 3 in the embodiments of the present invention;

[0043] Figure 8 This is the fluorine spectrum of compound 3 in the embodiments of the present invention;

[0044] Figure 9 This is the carbon spectrum of compound 3 in the embodiments of the present invention;

[0045] Figure 10 This is the proton spectrum of compound 4 in the embodiments of the present invention;

[0046] Figure 11 This is the fluorine spectrum of compound 4 in the embodiments of the present invention;

[0047] Figure 12 This is the carbon spectrum of compound 4 in the embodiments of the present invention. Detailed Implementation

[0048] 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.

[0049] 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.

[0050] 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.

[0051] Example 1

[0052]

[0053] Under a nitrogen atmosphere, 1-(2,2-dimethylcyclopropyl)-4-methoxybenzene A1 (0.2 mmol), diphenyliodonium salt B1 (0.3 mmol), triethylamine hydrofluoric acid salt (0.4 mmol), cuprous thiophene-2-carboxylate (0.03 mmol), 2,6-bis(1-pyrazolyl)pyridine (0.03 mmol), and 3,6-di-tert-butyl-9-mesethylated-10-phenylacridin-10-onium tetrafluoroborate (0.001 mmol) were sequentially added to 2.0 mL of acetonitrile. The resulting mixture was stirred for 12 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 give the fluoroarylated product C1 (43.6 mg, 0.160 mmol, colorless oil), with a yield of 80%. 1 H NMR (400MHz, Chloroform-d) δ7.29-7.26(m, 4H), 7.23-7.19(m, 2H), 7.18-7.12(m, 1H), 6.85-6.80(m, 2H), 4.17 (t, J=6.9Hz, 1H), 3.77 (s, 3H), 2.49 (d, J=6.9Hz, 1H), 2.45 (d, J=6.9Hz, 1H), 1.28 (s, 3H), 1.22 (s, 3H). 19 F NMR (376MHz, Chloroform-d) δ-133.52--133.93 (m, 1F). 13C NMR (101MHz, Chloroform-d) δ 158.0, 146.0, 137.6, 128.7, 128.6, 127.6, 126.1, 114.0, 95.8 (d, J=165.7Hz), 55. 2, 47.0 (d, J = 22.8Hz), 46.2 (d, J = 5.2Hz), 27.7 (d, J = 5.8Hz), 27.4 (d, J = 5.8Hz). HRMS (ESI, m / z): calcd.for[M+H] + :273.1649, found:273.1655.

[0054] Examples 2-29

[0055] Examples 2-29 are basically the same as Example 1, except that the arylcyclopropane is different. The specific structures of the γ-fluorodiphenylmethane compounds are shown in the table below:

[0056] Table 1 Examples 2-29

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Example 2

[0063]

[0064] Under a nitrogen atmosphere, 1-(2,2-dimethylcyclopropyl)-4-methoxybenzene A1 (0.2 mmol), di-4-fluorophenyliodonium salt B2 (0.3 mmol), triethylamine hydrofluoric acid salt (0.4 mmol), cuprous thiophene-2-carboxylate (0.03 mmol), 2,6-bis(1-pyrazolyl)pyridine (0.03 mmol), and 3,6-di-tert-butyl-9-mesethylated-10-phenylacridin-10-onium tetrafluoroborate (0.001 mmol) were sequentially added to 2.0 mL of acetonitrile. The resulting mixture was stirred for 12 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 give the fluoroarylated product C30 (46.6 mg, 0.152 mmol, colorless oil), with a yield of 76%. 1H NMR (400MHz, Chloroform-d) δ7.25-7.22(m, 2H), 7.21-7.18(m, 2H), 7.17-7.13(m, 2H), 6.85-6.80(m, 2H), 4.15(t, J =6.9Hz, 1H), 3.77 (s, 3H), 2.45 (d, J = 6.9Hz, 1H), 2.40 (d, J = 6.9Hz, 1H), 1.28 (d, J = 2.3Hz, 3H), 1.22 (d, J = 2.3Hz, 3H). 19 F NMR (376MHz, Chloroform-d) δ-134.58 (dp, J=41.0, 21.2Hz, 1F). 13 C NMR (101MHz, Chloroform-d) δ158.1, 144.4, 137.1, 131.8, 129.0, 128.7, 128.6, 114.1, 95.6 (d, J=166.2Hz), 55.3 , 46.9 (d, J=22.9Hz), 45.6 (d, J=5.0Hz), 27.7 (d, J=24.6Hz), 27.4 (d, J=24.7Hz).HRMS (ESI, m / z): calcd.for[M+H] + :307.1259, found:307.1265.

[0065] Examples 31-41

[0066] Examples 31-41 are basically the same as Example 2, except that they contain diaryliodonium salts Ar 2 The substituents are different; see the table below for specific structures:

[0067] Table 2 Examples 31-41

[0068]

[0069]

[0070] 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 γ-fluorodiphenylmethane compounds, characterized in that, Under the synergistic catalysis of copper catalyst / photocatalyst, arylcyclopropane, diaryliodonium salt and triethylamine hydrofluoric acid salt undergo cyclopropane ring-opening fluoroarylation reaction to give γ-fluorodiphenylmethane compounds; The chemical structural formula of the arylcyclopropane is shown in Formula A below: The structural formula of the diaryliodomonium salt is shown in Formula B below: The structural formula of the γ-fluorodiphenylmethane compound is shown in Formula C below: In equations A and C, Ar 1 It is 4-methoxyphenyl, 4-methylphenyl, 4-phenylphenyl, 4-tert-butylphenyl, 4-trimethylsilylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-methyl ester-4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-naphthyl, 4-benzyloxyphenyl, 4-allyloxyphenyl, 4-(3-azidopropyl)phenyl, 4-(3-benzoyloxypropyl)phenyl, 4-(3-N-phthalimidepropyl)phenyl, 4-(3-thioacetylpropyl)phenyl, 4-cyclopropylphenyl; R 1 The derivatives are methyl, ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-hydroxyethyl, vinyl, and phenyl. R 2 For hydrogen, methyl, ethyl; R 1 R 2 They may be the same or different, or connected to form a cyclohexyl group; In equations B and C, Ar 2 It is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-methylphenyl, 3-cyanophenyl, 2-fluorophenyl, 4-carboxyphenyl, 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 γ-fluorodiphenylmethane compounds according to claim 1, characterized in that, The solution includes the following steps: (1) In a nitrogen atmosphere, arylcyclopropane, diaryliodonium salt, triethylamine hydrofluoric acid salt, photocatalyst, copper catalyst and ligand are added to the reaction solvent in sequence to obtain a mixture; The ligand is 2,6-bis(1-pyrazolyl)pyridine; The molar ratio of the arylcyclopropane, diaryliodonium salt, triethylamine hydrofluoric acid salt, photocatalyst, copper catalyst, and ligand is 1.0:1.5:2.0:0.005:0.15:0.15, and the concentration of arylcyclopropane 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 γ-fluorodiphenylmethane compounds according to claim 2, characterized in that, In step (1), the reaction solvent is acetonitrile.

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