Preparation method of 1-benzyl alcohol-3-alkyl bicyclo [1.1. 1] pentane

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 1-benzyl alcohol-3-alkyl bicyclo [1.1. 1] pentane, which comprises the following steps: by taking aromatic aldehyde, [1.1. 1] propeller alkane and 4-alkyl substituted Hanss ester synthesized by aldehyde as initial raw materials and dichloroethane and the like as a solvent, carrying out a reaction under the protection of inert gas to obtain 1-benzyl alcohol-3-alkyl bicyclo [1.1. 1] pentane, and separating the 1-benzyl alcohol-3-alkyl bicyclo [1.1. 1] pentane from the 1-benzyl alcohol-3-alkyl bicyclo [1.1. 1] pentane. A three-component free radical coupling reaction is carried out under the illumination condition, and a 1-benzyl alcohol-3-alkyl bicyclo [1.1. 1] pentane product is synthesized in one step. The method has the advantages of mild reaction conditions, high reaction efficiency, low cost, simplicity and convenience in operation and the like, and a new method is provided for later structural modification of diaryl methanol drug molecules.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane. Background Technology

[0002] The diaryl methanol structure is a building block widely used in organic synthesis. Compounds with this structure are precursor compounds for the synthesis of various active pharmaceutical ingredients and have important application value in the field of drug synthesis.

[0003] Bicyclic [1.1.1]pentane (BCP) is a bridged ring skeleton with a three-dimensional structure. As a bioisostere of a 1,4-disubstituted aromatic ring, it has been widely used in medicinal chemistry. Introducing the BCP group into drug molecules can significantly improve their physicochemical properties such as solubility, permeability, and metabolic stability. Therefore, the synthetic research on the structure of BCP benzyl alcohol is of great significance for new drug development and structural modification.

[0004] Currently, the synthesis methods for BCP benzyl alcohol are mostly characterized by cumbersome synthetic steps, harsh reaction conditions, poor substrate universality, low synthesis efficiency, and the need for metal catalysts. Therefore, there is an urgent need to develop new, green, economical, and efficient methods for the synthesis of BCP benzyl alcohol.

[0005] Based on this, the present invention provides a method for synthesizing BCP benzyl alcohol in one step by using aromatic aldehydes, [1.1.1]spiroalkyl and 4-alkyl-substituted hens esters synthesized from aldehydes as raw materials and undergoing a three-component free radical coupling reaction under light conditions. This method aims to solve the problems of the prior art and provide technical support for the later structural modification of diaryl methanol drug molecules. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The preparation method of 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to the present invention comprises the following steps: In a nitrogen atmosphere, the aromatic aldehyde shown in Formula I and the 4-alkyl-substituted hesperidin synthesized from the aldehyde shown in Formula III are added to a reaction vessel to replace the nitrogen atmosphere. Then, [1.1.1]spiroline shown in Formula II and a solvent are added, and the reaction is carried out under light irradiation. After the reaction is completed, the product is purified by column chromatography to obtain the 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane product shown in Formula IV. The reaction equation is as follows: ; In the formula: R1 is selected from hydrogen, chlorine, bromine, trifluoromethyl, cyano; Ar is selected from benzene, biphenyl, naphthalene, pyridine, benzofuran, dibenzofuran, quinoline; R2 is selected from cyclohexyl, cyclopentyl, dimethoxymethyl; The [1.1.1]spiroline is a 0.9~1.2 mol / L [1.1.1]spiroline diethyl ether solution; The solvent is any one of dichloroethane, ethyl acetate, and dichloromethane; The wavelength range of the light source under the illumination conditions is 365~370nm, 390~395nm or 460~465nm; The reaction time is 1 to 12 hours.

[0008] Preferably, in the preparation method of 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention, the aromatic aldehyde represented by Formula I is specifically any one of benzaldehyde, 4-biphenylaldehyde, 4-trifluoromethylbenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-cyanobenzaldehyde, 1-naphthaldehyde, 3-bromobenzaldehyde, 2-pyridinecarboxaldehyde, 2-benzofurancarboxaldehyde, dibenzofuran-2-carboxaldehyde, and quinoline-2-carboxaldehyde.

[0009] Preferably, in the preparation method of 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention, the solvent is dichloroethane.

[0010] Preferably, in the preparation method of 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention, the wavelength range of the light source under the illumination conditions is 390~395nm.

[0011] Preferably, in the preparation method of 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention, the reaction time is 2-8 h.

[0012] In a further preferred embodiment, the reaction time in the preparation method of 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention is 4 hours.

[0013] Preferably, in the method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention, the molar ratio of the aromatic aldehyde, [1.1.1]spiroalkyl and the 4-alkyl-substituted Hans ester synthesized from the aldehyde is 1~3:1:1~3.

[0014] More preferably, in the method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane of the present invention, the molar ratio of the aromatic aldehyde, [1.1.1]spiroalkyl and the 4-alkyl-substituted Hans ester synthesized from the aldehyde is 2.5:1:2.5.

[0015] The beneficial effects of this invention are: This invention provides a method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane. This method features a simple reaction system, mild reaction conditions, and requires no metals or photosensitizers. Using readily available and inexpensive aromatic aldehydes and 4-alkyl-substituted hess esters synthesized from aldehydes as raw materials, a one-step multi-component radical coupling reaction with [1.1.1]spiroline is achieved under light irradiation, synthesizing a series of high-value-added BCP benzyl alcohol building blocks suitable for later functionalization. This invention aligns with current pursuits of economical and green chemistry and the global carbon neutrality strategy, and possesses extremely important application prospects. Attached Figure Description

[0016] Figure 1 The (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol 1 HNMR spectrum; Figure 2 The (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol 13 CNMR plot; Figure 3 [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 1 HNMR spectrum; Figure 4 [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 13 CNMR plot; Figure 5 The (4-chlorophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 1 HNMR spectrum; Figure 6 The (4-chlorophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 13 CNMR plot; Figure 7 The (4-bromophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 1 HNMR spectrum; Figure 8 The (4-bromophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 13 CNMR image. Detailed Implementation

[0017] The technical solution of the present invention will be described in detail below with reference to specific embodiments. The following embodiments are for explanation and illustration only, and do not constitute a limitation on the technical solution of the present invention.

[0018] Example 1 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, benzaldehyde (0.50 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 27 mg of a white solid (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol, with a yield of 53%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.34 – 7.30 (m,2H), 7.27 – 7.24 (m, 3H), 4.70 (s, 1H), 1.81 (brs, 1H), 1.71 – 1.54 (m, 5H), 1.43 – 1.36 (m, 6H), 1.29 – 1.24 (m, 1H), 1.21 – 1.12 (m, 2H), 1.09 – 1.03 (m, 1H), 0.83 – 0.75 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 142.1, 128.2, 127.3,126.1, 74.3, 45.7, 44.1, 42.1, 38.2, 29.3, 26.4, 26.2. HRMS(ESI) m / z calcd.for C 18 H 24 NaO [M+Na] + Theoretical value: 279.1719, measured value: 279.1717.

[0019] The product (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol 1 H NMR image as follows Figure 1 As shown, 13 CNMR image as follows Figure 2 As shown.

[0020] Example 2 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and 4-biphenylcarboxaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 38 mg of a white solid [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 57%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 7.3Hz, 2H), 7.57 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.36 – 7.31 (m,3H), 4.75 (s, 1H), 1.93 (brs, 1H), 1.73 – 1.55 (m, 5H), 1.48 – 1.40 (m, 6H), 1.32 – 1.26 (m, 1H), 1.23 – 1.13 (m, 2H), 1.11 – 1.01 (m, 1H), 0.86 – 0.77(m, 2H). 13 C NMR (150 MHz, CDCl3) δ 141.13, 141.1, 140.2, 128.9, 127.3, 127.2,126.9, 126.5, 74.0, 45.8, 44.1, 42.1, 38.2, 29.4, 26.4, 26.2. HRMS(ESI) m / zcalcd. for C 24 H 28 NaO [M+Na] + Theoretical value: 355.2032, measured value: 355.2026.

[0021] The product [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol1 H NMR image as follows Figure 3 As shown, 13 C NMR spectrum as shown Figure 4 As shown.

[0022] Example 3 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, 4-trifluoromethylbenzaldehyde (0.50 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluent by petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 45 mg of a white solid (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(4-(trifluoromethyl)phenyl)methanol, with a yield of 69%. The structural formula is as follows; ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 7.6Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 4.75 (s, 1H), 1.96 (brs, 1H), 1.72 – 1.53(m, 5H), 1.43 – 1.34 (m, 6H), 1.30 – 1.24 (m, 1H), 1.21 – 1.11 (m, 2H), 1.09 – 1.00 (m, 1H), 0.83 – 0.73 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 145.9, 129.5,126.3, 125.1, 124.4 (q, J = 270.3 Hz), 73.7, 45.7, 44.2, 42.0, 38.2, 29.3,26.4, 26.1. 19 F NMR (565 MHz, CDCl3) δ -62.36 (s). HRMS(ESI) m / z calcd. forC 19 H 23 F3NaO [M+Na]+ Theoretical value: 347.1593, measured value: 347.1592.

[0023] Example 4 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and 4-chlorobenzaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 36 mg of a white solid (4-chlorophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 62%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.31 – 7.27 (m,2H), 7.18 (d, J = 8.4 Hz, 2H), 4.66 (s, 1H), 1.96 (brs, 1H), 1.70 – 1.53 (m,5H), 1.41 – 1.33 (m, 6H), 1.29 – 1.26 (m, 1H), 1.20 – 1.12 (m, 2H), 1.09 –1.01 (m, 1H), 0.82 – 0.74 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 140.5, 132.9,128.3, 127.4, 73.6, 45.6, 44.1, 42.0, 38.2, 29.3, 26.4, 26.1. HRMS(ESI) m / zcalcd. for C 18 H 23 ClNaO [M+Na] + Theoretical value: 313.1330, measured value: 313.1328.

[0024] The product (4-chlorophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol 1 H NMR image as follows Figure 5 As shown, 13 C NMR spectrum as shown Figure 6 As shown.

[0025] Example 5 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and 4-bromobenzaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 49 mg of a white solid (4-bromophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 73%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 7.0Hz, 2H), 7.13 (d, J = 7.2 Hz, 2H), 4.66 (s, 1H), 1.82 (brs, 1H), 1.70 – 1.55(m, 5H), 1.42 – 1.33 (m, 6H), 1.29 – 1.23 (m, 1H), 1.21 – 1.12 (m, 2H), 1.09 – 1.00 (m, 1H), 0.83 – 0.73 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 141.0, 131.2,127.8, 121.1, 73.6, 45.6, 44.1, 41.9, 38.1, 29.3, 26.3, 26.1. HRMS(ESI) m / zcalcd. for C 18 H 23 BrNaO [M+Na] + Theoretical value: 357.0824, measured value: 357.0822.

[0026] The product (4-bromophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol1 H NMR image as follows Figure 7 As shown, 13 C NMR spectrum as shown Figure 8 As shown.

[0027] Example 6 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and 4-cyanobenzaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 34 mg of a pale yellow solid 4-((3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(hydroxy)methyl)benzonitrile, with a yield of 60%. The structure is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.2Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.74 (s, 1H), 2.13 (brs, 1H), 1.69 – 1.51(m, 5H), 1.41 – 1.32 (m, 6H), 1.28 – 1.23 (m, 1H), 1.19 – 1.10 (m, 2H), 1.07 – 0.99 (m, 1H), 0.80 – 0.72 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 147.4, 132.0,126.7, 119.1, 110.9, 73.5, 45.6, 44.2, 41.8, 38.1, 29.2, 26.3, 26.1. HRMS(ESI) m / z calcd. for C 19 H 24 NO + [M+H] + Theoretical value: 282.1852, measured value: 282.1847.

[0028] Example 7 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, 1-naphthaldehyde (0.50 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluent by petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 31 mg of a colorless oily substance (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(naphthalen-1-yl)methanol, with a yield of 51%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.05 – 8.01 (m,1H), 7.89 – 7.81 (m, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.50 – 7.45 (m, 3H), 5.60 (s, 1H), 1.99 (brs, 1H), 1.67 – 1.50 (m, 5H), 1.48 – 1.36 (m, 6H), 1.26 – 1.19 (m, 1H), 1.18 – 1.10 (m, 2H), 1.06 – 0.98 (m,1H), 0.79 – 0.70 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 138.3, 133.7, 131.0,128.8, 127.6, 125.6, 125.5, 125.4, 123.7, 123.2, 70.5, 46.4, 43.1, 42.4,38.1, 29.3, 26.4, 26.2. HRMS(ESI) m / z calcd. for C 22 H 26 NaO [M+Na] + Theoretical value: 329.1876, measured value: 329.1870.

[0029] Example 8 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, 3-bromobenzaldehyde (0.50 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 40 mg of a colorless oily substance (3-bromophenyl)(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 60%. The structure is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.41 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.21 – 7.14 (m, 2H), 4.66 (s, 1H), 1.93 (brs, 1H), 1.70– 1.55 (m, 5H), 1.43 – 1.35 (m, 6H), 1.30 – 1.25 (m, 1H), 1.21 – 1.12 (m, 2H), 1.09 – 1.00 (m, 1H), 0.83 – 0.74 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ144.4, 130.4, 129.7, 129.1, 124.7, 122.4, 73.6, 45.7, 44.1, 42.0, 38.2, 29.3,26.4, 26.1. HRMS(ESI) m / z calcd. for C 18 H 23 BrNaO [M+Na] + Theoretical value: 357.0824, measured value: 357.0822.

[0030] Example 9 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, 2-pyridinecarboxaldehyde (0.50 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluent by petroleum ether and ethyl acetate in a volume ratio of 6:1, and separated by column chromatography to obtain 32 mg of a yellow oily substance (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(pyridin-2-yl)methanol, with a yield of 62%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.7Hz, 1H), 7.64 (td, J = 7.7, 1.7 Hz, 1H), 7.19 (ddd, J = 7.4, 4.9, 0.9 Hz,1H), 7.15 (d, J = 7.9 Hz, 1H), 4.70 (s, 1H), 1.68 – 1.52 (m, 5H), 1.39 (s,6H), 1.26 – 1.21 (m, 1H), 1.18 – 1.10 (m, 2H), 1.07 – 0.99 (m, 1H), 0.81 –0.72 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 159.7, 148.1, 136.3, 122.3, 121.2,72.7, 46.0, 44.2, 41.6, 38.2, 29.3, 26.4, 26.1. HRMS(ESI) m / z calcd. forC 17 H 24 NO + [M+H] + Theoretical value: 258.1852, measured value: 258.1844.

[0031] Example 10 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, 2-benzofuranaldehyde (0.50 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 32 mg of a white solid benzofuran-2-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 54%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.5Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 7.21 (t, J = 7.4 Hz, 1H), 6.61 (s, 1H), 4.82 (s, 1H), 1.73 – 1.60 (m, 5H), 1.60 – 1.53 (m, 6H), 1.33 –1.29 (m, 1H), 1.23 – 1.15 (m, 2H), 1.11 – 1.03 (m, 1H), 0.87 – 0.78 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 158.1, 154.9, 128.3, 124.0, 122.8, 121.1, 111.3,102.8, 68.6, 46.5, 43.8, 40.6, 38.2, 29.3, 26.4, 26.2. HRMS(ESI) m / z calcd.for C 20 H 24 NaO2 [M+Na] + Theoretical value: 319.1669, measured value: 319.1660. Example 11 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and dibenzofuran-2-carboxaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluent by petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 30 mg of a pale yellow solid (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(dibenzo[b,d]furan-2-yl)methanol, with a yield of 43%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.97 – 7.93 (m,1H), 7.87 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.4 Hz,1H), 7.47 – 7.42 (m, 1H), 7.36 – 7.32 (m, 2H), 4.88 (s, 1H), 2.02 (brs, 1H), 1.69 – 1.55 (m, 5H), 1.47 – 1.38 (m, 6H), 1.29 – 1.24 (m, 1H), 1.20 – 1.12(m, 2H), 1.08 – 1.00 (m, 1H), 0.82 – 0.74 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ156.6, 155.7, 136.8, 127.2, 125.5, 124.4, 124.2, 122.8, 120.8, 118.0, 111.8,111.2, 74.3, 45.7, 44.1, 42.4, 38.2, 29.3, 26.4, 26.2. HRMS(ESI) m / z calcd.for C 24 H 26 NaO2 [M+Na] + Theoretical value: 369.1825, measured value: 369.1815.

[0032] Example 12 Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and quinoline-2-carboxaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and ethyl acetate in a volume ratio of 12:1, and separated by column chromatography to obtain 38 mg of a yellow solid (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(quinoline-2-yl)methanol, with a yield of 62%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.6Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 4.88 (s, 1H), 1.69 – 1.53 (m, 5H), 1.50 – 1.43 (m, 6H), 1.28 – 1.22 (m, 1H), 1.20 – 1.10(m, 2H), 1.08 – 0.99 (m, 1H), 0.82 – 0.73 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ159.8, 146.7, 136.2, 129.7, 129.69, 128.9, 127.7, 126.4, 119.4, 72.7, 46.3,44.4, 41.4, 38.3, 29.3, 26.4, 26.2. HRMS(ESI) m / z calcd. for C 21 H 26 NO + [M+H] +Theoretical value: 308.2009, measured value: 308.2002.

[0033] Example 13 Under a nitrogen atmosphere, diethyl 4-cyclopentyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and 4-bromobenzaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain 46 mg of a white solid (4-bromophenyl)(3-cyclopentylbicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 72%. The structural formula is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.4Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.65 (s, 1H), 1.92 (brs, 1H), 1.91 – 1.86(m, 1H), 1.57 – 1.45 (m, 6H), 1.42 – 1.34 (m, 6H), 1.20 – 1.13 (m, 2H). 13 CNMR (151 MHz, CDCl3) δ 141.0, 131.3, 127.8, 121.1, 73.6, 46.3, 43.0, 42.7,40.4, 29.1, 25.8. HRMS(ESI) m / z calcd. for C 17 H 21 BrNaO [M+Na] + Theoretical value: 343.0668, measured value: 343.0666.

[0034] Example 14 Under a nitrogen atmosphere, diethyl 4-(dimethoxymethyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.50 mmol, 2.5 equivalents) and 4-bromobenzaldehyde (0.50 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and ethyl acetate in a volume ratio of 10:1, and separated by column chromatography to obtain 28 mg of a pale yellow oily substance (4-bromophenyl)(3-(dimethoxymethyl)bicyclo[1.1.1]pentan-1-yl)methanol, with a yield of 43%. The structure is as follows: ; The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.4Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.68 (s, 1H), 4.20 (s, 1H), 3.33 (d, J =1.7 Hz, 6H), 1.93 (brs, 1H), 1.65 – 1.57 (m, 6H). 13 C NMR (150 MHz, CDCl3) δ140.6, 131.4, 127.7, 121.3, 102.8, 73.2, 54.6, 47.0, 43.5, 40.5. HRMS(ESI) m / z calcd. for C 15 H 19 BrNaO3 [M+Na] + Theoretical value: 349.0410, measured value: 349.0408.

[0035] Example 15 The preparation method of (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol in Example 1 is as follows: Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.5 mmol, 2.5 equivalents) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, benzaldehyde (0.5 mmol, 2.5 equivalents), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and ethyl acetate (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 365–370 nm for 1 h. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain a white solid (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol.

[0036] Example 16 The preparation method of (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol in Example 1 is as follows: Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.6 mmol, 3.0 equivalent) was added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, benzaldehyde (0.6 mmol, 3.0 equivalent), [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O), and ethyl acetate (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 390–395 nm for 12 h. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was eluented with petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1, and separated by column chromatography to obtain a white solid (3-cyclohexylbicyclo[1.1.1]pentan-1-yl)(phenyl)methanol.

[0037] Example 17 The preparation method of [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol in Example 2 is as follows: Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (0.2 mmol, 1.0 equivalent) and 4-biphenylcarboxaldehyde (0.2 mmol, 1.0 equivalent) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloromethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with ultraviolet light at 365–370 nm for 8 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was separated by column chromatography using petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1 as eluents to obtain a white solid [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol.

[0038] Example 18 The preparation method of [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol in Example 2 is as follows: Under a nitrogen atmosphere, diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.5 mmol, 2.5 equivalents) and 4-biphenylcarboxaldehyde (0.5 mmol, 2.5 equivalents) were added to a 10 mL reaction flask equipped with a magnetic stirrer. The flask was then evacuated and purged three times with nitrogen. Subsequently, [1.1.1]spiropropane (0.2 mmol, 1.0 equivalent, 0.9–1.2 M in Et₂O) and dichloroethane (4.0 mL) were added under a nitrogen atmosphere. The reaction mixture was irradiated with blue light at 460–465 nm for 4 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was separated by column chromatography using petroleum ether and dichloromethane in a volume ratio of 2:1 to 1:1 as eluents to obtain a white solid [1,1'-biphenyl]-4-yl(3-cyclohexylbicyclo[1.1.1]pentan-1-yl)methanol.

[0039] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A 1-benzyl alcohol-3-alkyl bicyclic [ 1.1.1] A method for preparing pentane, characterized in that, The preparation method is as follows: Under a nitrogen atmosphere, the aromatic aldehyde shown in Formula I and the 4-alkyl-substituted hensyl ester synthesized from the aldehyde shown in Formula III are added to a reaction vessel to replace the nitrogen atmosphere. Then, [1.1.1]spiroalkyl ester shown in Formula II and a solvent are added, and the reaction is carried out under light irradiation. After the reaction is complete, the product is purified by column chromatography to obtain the 1-benzyl alcohol-3-alkyl bicyclic [1.1.1]pentane product shown in Formula IV. The reaction equation is as follows: ； In the formula: R1 is selected from hydrogen, chlorine, bromine, trifluoromethyl, cyano; Ar is selected from benzene, biphenyl, naphthalene, pyridine, benzofuran, dibenzofuran, quinoline; R2 is selected from cyclohexyl, cyclopentyl, dimethoxymethyl; The [1.1.1]spiroalkane is a 0.9~1.2 mol / L [1.1.1]spiroalkane diethyl ether solution; The solvent is any one of dichloroethane, ethyl acetate, and dichloromethane; The wavelength range of the light source under the illumination conditions is 365~370 nm, 390~395 nm or 460~465 nm; The reaction time is 1 to 12 hours.

2. The method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to claim 1, characterized in that, The aromatic aldehyde represented by Formula I is specifically any one of benzaldehyde, 4-biphenylaldehyde, 4-trifluoromethylbenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-cyanobenzaldehyde, 1-naphthaldehyde, 3-bromobenzaldehyde, 2-pyridinecarboxaldehyde, 2-benzofurancarboxaldehyde, dibenzofuran-2-carboxaldehyde, and quinoline-2-carboxaldehyde.

3. The method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to claim 1, characterized in that, The solvent is dichloroethane.

4. The method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to claim 1, characterized in that, The wavelength range of the light source under the illumination conditions is 390~395 nm.

5. The method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to claim 1, characterized in that, The reaction time is 2 to 8 hours.

6. The method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to claim 5, characterized in that, The reaction time was 4 hours.

7. The method for preparing 1-benzyl alcohol-3-alkylbicyclo[1.1.1]pentane according to claim 1, characterized in that, The molar ratio of the aromatic aldehyde, [1.1.1]spiroalkyl and the 4-alkyl-substituted Hans ester synthesized from the aldehyde is 1~3:1:1~3.

8. The 1-benzyl alcohol-3-alkylbicyclo[] according to claim 7 1.1.1] A method for preparing pentane, characterized in that, The molar ratio of the aromatic aldehyde, [1.1.1]spiroline, and the 4-alkyl-substituted hans ester synthesized from the aldehyde is 2.5:1:2.5.

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