Process for the preparation of alpha-alkyl ketone derivatives

Abstract

The application belongs to the technical field of organic chemistry, and specifically discloses a preparation method of alpha-alkyl ketone derivatives, which comprises the following steps: under the protection of inert gas, 1-substituted ethanol, aromatic primary alcohol, methanol and alkali are mixed, and then the mixture is stirred and reacted at 100-140 DEG C for 12-36 h under the catalysis of cyclopentadienyl iron to obtain alpha-alkyl ketone derivatives. In the application, the cyclopentadienyl iron can efficiently catalyze the three-component hydrogen borrowing reaction of 1-substituted ethanol, aromatic primary alcohol and methanol under the action of alkali, so that the alpha-alkyl ketone derivatives are obtained. Compared with the prior art, the method has the advantages of low energy consumption, high atom economy, green environmental protection, high safety and easy industrialization.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemistry, and particularly relates to a preparation method of an alpha-alkyl ketone derivative. BACKGROUND

[0002] In the field of pharmaceutical chemicals, methylation reactions are widely used in the synthesis of raw pharmaceuticals, pharmaceutical intermediates and the structural modification of active pharmaceutical molecules. By hydrogen transfer mechanism, methanol as a methylating agent to construct C-C bond has become a very important method, which has the advantages of green environmental protection, high atom utilization rate, etc. In the existing drugs, such as tolperisone and eperisone, both are central muscle relaxants, the chemical name of tolperisone is 2,4'-dimethyl-3-piperidyl phenylpropanone, and the chemical name of eperisone is 4'-ethyl-2-methyl-3-piperidyl phenylpropanone, both of which have a methyl group at the alpha position, belonging to alpha-alkyl ketone compounds.

[0003] The main method for traditional synthesis of alpha-alkyl ketone is to use halide and phenylacetone as substrate, which has low atom utilization rate and most of the halides are toxic and harmful. In 2017, Kundu group (Organic Letters, 2017, 19(18): 4750-4753) reported a three-component tandem alkylation reaction system of ketone, alcohol and methanol catalyzed by non-phosphine-based catalyst Ru-1. The system uses Ru complex as catalyst to obtain methylene ketone alpha-alkylation product with a yield of 52-81%, but the reaction uses noble metal ruthenium as catalyst, which is high in cost and difficult to industrialize. In recent years, iron-catalyzed hydrogen borrowing reaction has the characteristics of low energy consumption, high atom economy and strong practicability, and is an important method to obtain alpha-alkyl ketone derivatives. SUMMARY

[0004] In order to solve the above problems, the application provides a preparation method of alpha-alkyl ketone derivative, which uses cyclopentadienyl iron as catalyst, and under the action of base, the cyclopentadienyl iron can efficiently catalyze the three-component hydrogen borrowing reaction of 1-substituted ethanol, aryl primary alcohol and methanol to obtain alpha-alkyl ketone derivative.

[0005] The technical scheme of the application is as follows:

[0006] The preparation method of alpha-alkyl ketone derivative provided by the application is characterized in that the reaction formula is as shown below, which comprises the following steps: under the protection of inert gas, using cyclopentadienyl iron as catalyst, mixing 1-substituted ethanol as shown in formula (I), aryl primary alcohol as shown in formula (II), methanol and base, and stirring at 100-140 DEG C for 12-36 h to obtain alpha-alkyl ketone derivative as shown in formula (III);

[0007] wherein, in formula (I), R is phenyl, substituted phenyl, naphthyl or cyclopropyl, and the substituent in the substituted phenyl is alkyl, alkoxy, halogen or haloalkyl; in formula (II), R is phenyl, substituted phenyl or heterocyclic aryl, and the substituent in the substituted phenyl is alkyl, alkoxy, halogen or haloalkyl. 1 wherein, in formula (I), R is phenyl, substituted phenyl, naphthyl or cyclopropyl, and the substituent in the substituted phenyl is alkyl, alkoxy, halogen or haloalkyl; in formula (II), R is phenyl, substituted phenyl or heterocyclic aryl, and the substituent in the substituted phenyl is alkyl, alkoxy, halogen or haloalkyl.

[0008]

[0009] In an embodiment of the present application, preferably, after the reaction, water is added to quench the reaction, and then the reaction mixture is extracted with an organic solvent; the separated organic solvent layer is concentrated under reduced pressure, and then separated by column chromatography to obtain the alpha-alkyl ketone derivative as shown in formula (III).

[0010] In an embodiment of the present application, preferably, the organic solvent used for the extraction is ethyl acetate or dichloromethane.

[0011] In an embodiment of the present application, preferably, the solvent used for the column chromatography separation is petroleum ether / ethyl acetate, and the volume ratio is 10:1 to 50:1.

[0012] In an embodiment of the present application, preferably, the molar ratio of the 1-substituted ethanol as shown in formula (I), methanol, the aromatic primary alcohol as shown in formula (II), the base and the cyclopentadienone iron as shown in formula (VI) is 1:1.5 to 10:1.5 to 5:1 to 5:0.02 to 0.1.

[0013] In an embodiment of the present application, preferably, the molar ratio of the 1-substituted ethanol as shown in formula (I), methanol, the aromatic primary alcohol as shown in formula (II), the base and the cyclopentadienone iron as shown in formula (VI) is 1:3:4:3:0.02.

[0014] In an embodiment of the present application, preferably, the base is one or more of potassium phosphate, potassium carbonate, potassium tert-butoxide or cesium carbonate.

[0015] In an embodiment of the present application, preferably, the base is potassium phosphate.

[0016] Compared with the prior art, the present application has the following advantages:

[0017] Compared with the prior art, the present application has the following advantages: BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application

[0019] Figure 2 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application

[0020] Figure 3 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application

[0021] Figure 4 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application

[0022] Figure 5 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application

[0023] Figure 6 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application

[0024] Figure 7 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application 1 H NMR spectrum of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) of Example 1 of the present application DETAILED DESCRIPTION

[0025] In order to make the above objectives, features and advantages of the present application more apparent, the specific embodiments of the present application will be described in detail below with reference to the accompanying drawings.

[0026] In the following description, a lot of specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be practiced in a variety of ways different from those described herein without departing from the scope of the present application, and those skilled in the art can make similar modifications without departing from the scope of the present application, and therefore the present application is not limited to the specific embodiments disclosed below.

[0027] The raw materials used in the present application can be obtained by commercial means, and the cyclopentadienyl iron catalyst represented by formula (VI) can be prepared by the following method:

[0028]

[0029] To a pressure tube equipped with a magnetic stir bar was added compound V (1.28 g, 5.0 mmol), methanol (5 mL) and compound VI (710 mg, 5.0 mmol) under nitrogen. After heating to reflux for about 12 h, the reaction was cooled, quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was concentrated. The concentrated organic was then added to a Schlenk tube containing diiron nonyl (1.82 g, 5.0 mmol) and toluene (dry and degassed, 10 mL) under nitrogen. The reaction was heated to reflux for about 24 h, cooled and transferred to a round bottom flask. The mixture was washed with toluene (3 x 10 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to give an orange-yellow solid (588.4 mg, 56%).

[0030] Structural characterization of catalyst VI: yellow solid as shown in Figure 7 1 HNMR (400 MHz, CDC13 ) δ 7.65 (d, J = 7.4 Hz, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.42 - 7.33 (m, 6H), 3.18 (d, J = 9.6 Hz, 1H), 2.51 (td, J = 8.5, 4.7 Hz, 1H), 2.43 (s, 3H), 2.33 (s, 3H), 2.28 (d, J = 3.3 Hz, 1H), 2.17 (d, J = 9.4 Hz, 1H), 1.88 (d, J = 9.5 Hz, 2H), 1.36 - 1.27 (m, 4H); 13 CNMR (100 MHz, CDC13 ) δ 210.3, 165.0, 131.9 (d, J = 11.9 Hz), 128.3 (d, J = 19.0 Hz), 127.7 (d, J = 4.4 Hz), 123.7, 108.3, 73.1, 69.1, 63.4, 60.6, 37.9, 35.5, 28.7 (d, J = 4.5 Hz), 24.3 (d, J = 7.5 Hz). ppm; HRMS (ESI) calculated for C 29 H 29 FeN2O4[M+H] + : 524.1623, found: 524.1614.

[0031] Example 1:

[0032]

[0033] ​Into a pressure tube equipped with a magnetic stirrer, 1-phenylethanol (61 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), cyclopentadienyl iron catalyst (5.3 mg, 2.0 mol%) of formula (VI) and potassium phosphate (261 mg, 1.5 mmol) were added under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 101 mg of 2-methyl-1,3-diphenylpropan-1-one (III-3aa) product, yield: 90%.

[0034] 2-methyl-1,3-diphenylpropan-1-one (III-3aa) was characterized by structure: Colorless oil; 90% yield, 1 H NMR (400 MHz, CDCl3) δ 7.98-7.96 (m, 2H), 7.59-7.56 (m, 1H), 7.50-7.46 (m, J = 7.4 Hz, 2H), 7.33-7.29 (m, 2H), 7.25-7.20 (m, 3H), 3.84-3.75 (m, 1H), 3.22 (dd, J = 13.8, 6.2 Hz, 1H), 2.74 (dd, J = 13.6, 8.0 Hz, 1H), 1.25 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 203.8, 140.0, 136.5, 132.9, 129.1, 128.6, 128.4, 128.3, 126.2, 42.8, 39.4, 17.4 ppm; HRMS (ESI) calculated for C 16 H 17 O[M+H] + :225.1201, found:225.1203.

[0035] At the same time, the effects of reaction stability, reaction time, type of base and amount of raw material on the reaction were investigated by single factor variable method, and the rest of the experimental process and parameters were the same as in Example 1. The reaction results are shown in Table 1:

[0036] Table 1

[0037]

[0038]

[0039] Example 2:

[0040]

[0041] To a pressure tube equipped with a magnet under an argon atmosphere, 1-(p- tolyl)ethanol (68 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) of formula (VI) and potassium phosphate (261 mg, 1.5 mmol) were added. After replacement with argon, it was placed at 120 °C for 24 h. After completion of the reaction, it was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 101 mg of 2-methyl-3-phenyl-1-(p-tolyl)propan-1-one (III-3ba) product, yield: 85%.

[0042] 2-methyl-3-phenyl-1-(p-tolyl)propan-1-one (III-3ba) structural characterization: Colorless oil; 85% yield, 1 H NMR (400 MHz, CDC13) δ 7.89-7.86 (m, 2H), 7.30-7.27 (m, 4H), 7.24-7.19 (m, 3H), 3.81-3.72 (m, 1H), 3.20 (dd, J = 13.8, 6.2 Hz, 1H), 2.74 (dd, J = 13.6, 8.0 Hz, 1H), 2.43 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.4, 143.7, 140.1, 133.9, 129.4, 129.1, 128.5, 128.4, 126.2, 42.6, 39.4, 21.6, 17.5 ppm; HRMS (ESI) calculated for C 17 H 19 O[M+H] + : 239.1358, found: 239.1355.

[0043] Example 3:

[0044]

[0045] Into a pressure tube equipped with a magnetic stir bar, was placed 1-(4- methoxyphenyl)ethanol (76 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) of formula (VI) and potassium phosphate (261 mg, 1.5 mmol) under argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 102 mg of 1-(4-methoxyphenyl)-2-methyl-3- phenylpropan-1-one (III-3ca) product, yield: 80%.

[0046] 1-(4- methoxyphenyl)-2-methyl-3-phenylpropan-1-one (III-3ca) was characterized by structure: Colorless oil; 80% yield, 1 H NMR (400 MHz, CDC13) δ 7.96 (d, J = 8.8 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.24 - 7.19 (m, 3H), 6.97 - 6.93 (m, 2H), 3.87 (s, 3H), 3.80 - 3.78 (m, 1H), 3.20 (dd, J = 13.6, 6.4 Hz, 1H), 2.72 (dd, J = 13.6, 7.6 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 202.3, 163.4, 140.1, 130.6, 129.4, 129.1, 128.4, 126.2, 113.8, 55.5, 42.4, 39.5, 17.6 ppm; HRMS (ESI) calculated for C 17 H 19 O2[M+H] + :255.1307, found:255.1309.

[0047] Example 4:

[0048]

[0049] Into a pressure tube equipped with a magnetic stir bar, was placed 1-(4-tert- butylphenyl)ethanol (89 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron complex of cyclopentadienyl (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 116 mg of 1-(4-(tert-butyl)phenyl)-2-methyl-3- phenylpropan-1-one (III-3da) product, yield: 83%.

[0050] 1-(4-(tert-butyl)phenyl)-2-methyl-3-phenylpropan-1-one (III-3da) was characterized by structure: Colorless oil; 83% yield, 1 H NMR (400 MHz, CDC13) δ 7.89 (d, J = 8.4 Hz, 2H), 7.47 - 7.45 (m, 2H), 7.26 - 7.21 (m, 2H), 7.19 - 7.15 (m, 3H), 3.78 - 3.69 (m, 1H), 3.17 (dd, J = 13.6, 6.4 Hz, 1H), 2.67 (dd, J = 13.6, 8.0 Hz, 1H), 1.33 (s, 3H), 1.19 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.3, 156.7, 140.1, 133.8, 129.1, 128.4, 128.3, 126.2, 125.6, 42.7, 39.4, 35.1, 31.1, 17.5 ppm; HRMS (ESI) calculated for C 20 H 19 O[M+H] + : 281.1827, found: 281.1829.

[0051] Example 5:

[0052]

[0053] Into a pressure tube equipped with a magnetic stir bar, was placed 1- m-tolyl-ethanol (68 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst of formula (VI) (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 89 mg of 2-methyl-3-phenyl-1-(m-tolyl)propan-1-one (III-3ea) as a product in 75% yield.

[0054] 2-methyl-3-phenyl-1-(m-tolyl)propan-1-one (III-3ea) was characterized by structure: Colorless oil; 75% yield, 1 H NMR (400 MHz, CDC13) δ 7.76 (d, J = 8.8 Hz, 2H), 7.40 - 7.36 (m, 2H), 7.32 - 7.28 (m, 2H), 7.25 - 7.20 (m, 3H), 3.82 - 3.73 (m, 1H), 3.20 (dd, J = 13.6, 6.4 Hz, 1H), 2.73 (dd, J = 13.6, 7.6 Hz, 1H), 2.43 (s, 3H), 1.23 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 204.4, 140.1, 138.5, 136.5, 133.7, 129.1, 128.9, 128.5, 128.4, 126.2, 125.5, 42.8, 39.4, 21.4, 17.5 ppm; HRMS (ESI) calculated for C 16 H 16 BrO[M+H] + : 239.1358, found: 239.1356.

[0055] Example 6:

[0056]

[0057] Into a pressure tube equipped with a magnetic stir bar, was placed 1- methoxyphenethyl alcohol (76 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) of formula (VI) and potassium phosphate (261 mg, 1.5 mmol). After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 93 mg of 2-methyl-3-phenyl-1-(m-methoxyphenyl)propan-1-one (III-3fa) product, yield: 73%.

[0058] 2-methyl-3-phenyl-1-(m-methoxyphenyl)propan-1-one (III-3fa) was characterized by structure: Colorless oil; 73% yield, 1 H NMR (400 MHz, CDC13) δ 7.53 (d, J = 7.6 Hz, 1H), 7.48-7.47 (m, 1H), 7.40-7.36 (m, 1H), 7.31-7.27 (m, 2H), 7.27-7.19 (m, 3H), 7.13-7.10 (m, 1H), 3.87 (s, 3H), 3.79-3.70 (m, 1H), 3.19 (dd, J = 14.0, 6.2 Hz, 1H), 2.71 (dd, J = 14.0, 7.8 Hz, 1H), 1.23 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 202.3, 163.4, 140.2, 130.6, 129.4, 129.1, 128.4, 126.2, 113.8, 55.5, 42.4, 39.6, 17.6 ppm; HRMS (ESI) calculated for C 17 H 19 O2[M+H] + :255.1307, found:255.1303.

[0059] Example 7:

[0060]

[0061] Into a pressure tube equipped with a magnetic stir bar, was placed 1-3,4- dimethylphenyl ethanol (75 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst of formula (VI) (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 88 mg of 1-(3,4-dimethylphenyl)-2-methyl-3- phenylpropan-1-one (III-3ga) product, yield: 70%.

[0062] 1-(3,4-Dimethylphenyl)-2-methyl-3-phenylpropan-1-one (III-3ga) was characterized by structure: Colorless oil; 70% yield, 1 H NMR (400 MHz, CDC13) δ 7.73 - 7.65 (m, 2H), 7.30 - 7.24 (m, 3H), 7.21 - 7.17 (m, 3H), 3.76 - 3.66 (m, 1H), 3.16 (dd, J = 14.0, 6.2 Hz, 1H), 2.67 (dd, J = 13.6, 8.0 Hz, 1H), 2.30 (s, 6H), 1.18 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.7, 142.5, 140.2, 137.0, 134.3, 129.8, 129.5, 129.1, 128.4, 126.1, 126.0, 42.6, 39.4, 20.0, 19.8, 17.6 ppm; HRMS (ESI) calculated for C 17 H 19 O[M+H] + : 253.1514, found: 225.1519.

[0063] Example 8:

[0064]

[0065] Into a pressure tube equipped with a magnetic stir bar, 1-naphthalen-2- ylethan-1-ol (86 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), cyclopentadienyl iron catalyst (5.3 mg, 2.0 mol%) of formula (VI) and potassium phosphate (261 mg, 1.5 mmol) were added under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 114 mg of 2-methyl-1-(naphthalen-2-yl)-3-phenylpropan-1-one (III-3ha) product, yield: 83%.

[0066] 2-methyl-1-(naphthalen-2-yl)-3-phenylpropan-1-one (III-3ha) was characterized by structure: Colorless oil; 83% yield, 1 H NMR (400 MHz, CDC13) δ 8.40 (s, 1H), 8.01 - 7.99 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.89 - 7.85 (m, 2H), 7.60 - 7.52 (m, 2H), 7.29 - 7.22 (m, 4H), 7.20 - 7.15 (m, 1H), 3.95 - 3.87 (m, 1H), 3.23 (dd, J = 14.0, 6.4 Hz, 1H), 2.76 (dd, J = 13.6, 7.0 Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.7, 140.0, 135.5, 133.9, 132.6, 129.8, 129.6, 129.1, 128.5, 128.4, 127.7, 126.7, 126.2, 124.2, 42.9, 39.6, 17.7 ppm; HRMS (ESI) calculated for C 20 H 19 O[M+H] + : 275.1358, found: 275.1355.

[0067] Example 9:

[0068]

[0069] To a pressure tube equipped with a magnetic stir bar was placed 1-(4- bromophenyl)ethanol (101 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron complex of cyclopentadienyl of formula (VI) (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 120 mg of 1-(4-bromophenyl)-2-methyl-3- phenylpropan-1-one (III-3ia) as a product in 79% yield.

[0070] 1-(4-Bromophenyl)-2-methyl-3-phenylpropan-1-one (III-3ia) was characterized by structure: Colorless oil; 79%, 1 H NMR (400 MHz, CDC13) δ 7.92 (d, J = 7.6 Hz, 2H), 7.56 - 7.52 (m, 1H), 7.46 - 7.42 (m, 2H), 7.28 - 7.24 (m, 2H), 7.21 - 7.16 (m, 2H), 3.79 - 3.70 (m, 1H), 3.17 (dd, J = 14.0, 6.4 Hz, 1H), 2.69 (dd, J = 14.0, 8.0 Hz, 1H), 1.20 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.7, 140.0, 136.5, 132.9, 129.1, 128.6, 128.4, 128.3, 126.2, 42.8, 39.4, 17.4 ppm; HRMS (ESI) calculated for C 16 H 16 BrO[M+H] + :303.0306, found:303.0302.

[0071] Example 10:

[0072]

[0073] Into a pressure tube equipped with a magnetic stir bar, was placed 1-(4- chlorophenyl)ethanol (95 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron complex of cyclopentadienyl ketone (5.3 mg, 2.0 mol%) of formula (VI) and potassium phosphate (261 mg, 1.5 mmol). After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 80 mg of 2-methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-one (III-3ja) product, yield: 55%.

[0074] 2-methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-one (III-3ja) was characterized by structure: Colorless oil; 55% yield, 1 H NMR (400 MHz, CDC13) δ 7.92 - 7.90 (m, 2H), 7.58 - 7.50 (m, 3H), 7.47 - 7.43 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.81 - 3.72 (m, 1H), 3.23 (dd, J = 14.0, 7.0 Hz, 1H), 2.78 (dd, J = 13.6, 7.2 Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.1, 144.1, 136.1, 133.1, 129.4, 128.6 (d, J = 30 Hz), 128.2, 125.3 (d, J = 3.7 Hz), 125.27 (d, J = 3.8 Hz), 124.3 (d, J = 270 Hz), 42.5, 38.9, 17.7 ppm; 19 F NMR (376 MHz, CDC13) δ -62.3, HRMS (ESI) calculated for C 17 H 16 F3O[M+H] + : 293.1075, found: 293.1079.

[0075] Example 11:

[0076]

[0077] To a pressure tube equipped with a magnetic stir bar, was added 1- o-fluorophenylethanol (70 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 46 mg of 1-(2-fluorophenyl)-2-methyl-3- phenylpropan-1-one (III-3ka) as a product, yield: 38%.

[0078] 1-(2-Fluorophenyl)-2-methyl-3-phenylpropan-1-one (III-3ka) was characterized by structure: Colorless oil; 38% yield, 1 H NMR (400 MHz, CDC13) δ 7.84 - 7.82 (m, 2H), 7.50 - 7.45 (m, 2H), 7.39 - 7.35 (m, 2H), 7.09 - 7.05 (m, 2H), 6.88 - 6.84 (m, 2H), 3.69 - 3.60 (m, 1H), 3.06 (dd, J = 14.0, 6.8 Hz, 1H), 2.61 (dd, J = 14.0, 7.4 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.7, 136.5, 135.7, 134.4 (d, J = 253 Hz), 130.6 (d, J = 7.7 Hz), 128.8, 128.4, 115.2 (d, J = 21 Hz), 43.0, 38.6, 17.7 ppm; 19 F NMR (376 MHz, CDC13) δ -118.0; HRMS (ESI) calculated for C 16 H 16 FO[M + H] + : 243.1107, found: 242.1109.

[0079] Example 12:

[0080]

[0081] Into a pressure tube equipped with a magnetic stir bar, 1-cyclopropylethanol (43 mg, 0.5 mmol), benzyl alcohol (216 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron complex of cyclopentadienyl of formula (VI) (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) were added under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 52 mg of 1-cyclopropyl-2-methyl-3-phenylpropan-1-one (III-3la) as a colorless oil in 55% yield.

[0082] 1-cyclopropyl-2-methyl-3-phenylpropan-1-one (III-3la) was characterized by the following structure: Colorless oil; 55% yield, 1 H NMR (400 MHz, CDC13) δ 7.32 - 7.29 (m, 2H), 7.24 - 7.19 (m, 3H), 3.11 - 3.10 (m, 1H), 3.04 - 2.96 (m, 1H), 2.62 (dd, J = 13.6, 7.6 Hz, 1H), 1.97 - 1.91 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H), 1.01 - 0.97 (m, 1H), 0.88 - 0.81 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 213.9, 139.9, 129.1, 128.3, 126.2, 49.0, 39.0, 19.7, 16.3, 11.0, 10.9 ppm; HRMS (ESI) calculated for C 13 H 17 O[M+H] + : 189.1201, found: 189.1203.

[0083] Example 13:

[0084]

[0085] Into a pressure tube equipped with a magnetic stir bar, 1-phenylethanol (61 mg, 0.5 mmol), p-tolylmethanol (245 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron catalyst of cyclopentadienyl ketone (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) were added under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 98 mg of 2-methyl-1-phenyl-3-(p-tolyl)propan-1-one (III-3ab) product, yield: 82%.

[0086] 2-methyl-1-phenyl-3-(p-tolyl)propan-1-one (III-3ab) was characterized by structure: Colorless oil; 82% yield, 1 H NMR (400 MHz, CDCl3) δ 7.95-7.92 (m, 2H), 7.57-7.53 (m, 1H), 7.47-7.43 (m, 2H), 7.11-7.06 (m, 4H), 3.77-3.68 (m, 1H), 3.13 (dd, J = 13.6, 6.0 Hz, 1H), 2.65 (dd, J = 13.6, 8.0 Hz, 1H), 2.30 (s, 3H), 1.19 (d, J = 8.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 203.9, 136.8, 136.5, 135.7, 133.0, 129.1, 129.0, 128.6, 128.3, 42.8, 38.9, 21.0, 17.3 ppm; HRMS (ESI) calculated for C 17 H 19 O[M+H] + : 239.1358, found: 239.1356.

[0087] Example 14:

[0088]

[0089] To a pressure tube equipped with a magnetic stir bar, was added 1-phenylethanol (61 mg, 0.5 mmol), p-methoxybenzyl alcohol (277 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 106 mg of 3-(4-methoxyphenyl)-2-methyl-1-phenylpropan-1-one (III-3ac) product, yield: 83%.

[0090] 3-(4-methoxyphenyl)-2-methyl-1-phenylpropan-1-one (III-3ac) was characterized by structure: Colorless oil; 83% yield, 1 H NMR (400 MHz, CDC13) δ 7.92 (d, J = 7.2 Hz, 2H), 7.56 - 7.52 (m, 1H), 7.46 - 7.43 (m, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.78 (s, 3H), 3.73 - 3.68 (m, 1H), 3.11 (dd, J = 13.6, 6.2 Hz, 1H), 2.64 (dd, J = 14.0, 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 204.0, 158.0, 136.5, 132.9, 132.0, 130.0, 128.6, 128.3, 113.8, 55.2, 43.0, 38.5, 17.3 ppm; HRMS (ESI) calculated for C 17 H 19 O[M+H] + :255.1307, found:255.1310.

[0091] Example 15:

[0092]

[0093] Into a pressure tube equipped with a magnetic stir bar, was placed 1-phenylethanol (61 mg, 0.5 mmol), o-tolylmethanol (245 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron catalyst of cyclopentadienyl ketone (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 88 mg of 2-methyl-1-phenyl-3-(o-tolyl)propan-1-one (III-3ad) product, yield: 74%.

[0094] 2-methyl-1-phenyl-3-(o-tolyl)propan-1-one (III-3ad) was characterized by structure: Colorless oil; 74% yield, 1 H NMR (400 MHz, CDC13) δ 7.97 (d, J = 6.8 Hz, 2H), 7.59 - 7.56 (m, 1H), 7.50 - 7.46 (m, 2H), 7.14 - 7.10 (m, 4H), 3.80 - 3.72 (m, 1H), 3.17 (dd, J = 13.6, 6.2 Hz, 1H), 2.68 (dd, J = 14.0, 8.0 Hz, 1H), 2.33 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.9, 136.8, 136.5, 135.7, 133.0, 129.1, 129.0, 128.7, 128.3, 42.9, 39.0, 21.0, 17.3 ppm; HRMS (ESI) calculated for C 17 H 19 O[M+H] + : 239.1358, found: 239.1356.

[0095] Example 16:

[0096]

[0097] Into a pressure tube equipped with a magnetic stir bar, 1-phenylethanol (61 mg, 0.5 mmol), 3,4-dimethylbenzene methanol (272 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron catalyst of cyclopentadienone (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) were added under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 96 mg of 3-(3,4-dimethylphenyl)-2-methyl-1-phenylpropan-1-one (III-3ae) product, yield: 76%.

[0098] 3-(3,4-Dimethylphenyl)-2-methyl-1-phenylpropan-1-one (III-3ae) was characterized by structure: Colorless oil; 76% yield, 1 H NMR (400 MHz, CDC13) δ 7.95-7.93 (m, 2H), 7.56-7.53 (m, 1H), 7.47-7.43 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.96-6.90 (m, 2H), 3.76-3.67 (m, 1H), 3.10 (dd, J = 13.6, 5.8 Hz, 1H), 2.61 (dd, J = 13.6, 8.0 Hz, 1H), 2.22 (d, J = 4.8 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.9, 137.3, 136.5, 134.3, 132.9, 130.4, 130.0, 129.6, 128.6, 128.3, 126.4, 42.8, 38.9, 19.8, 19.3, 17.3 ppm; HRMS (ESI) calculated for C 18 H 21 O[M+H] + : 253.1314, found: 253.1315.

[0099] Example 17:

[0100]

[0101] To a pressure tube equipped with a magnetic stir bar, was added 1-phenylethanol (61 mg, 0.5 mmol), 4-bromobenzyl alcohol (373 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 123 mg of 3-(4-bromophenyl)-2-methyl-1-phenylpropan-1-one (III-3af) product, yield: 81%.

[0102] 3-(4-Bromophenyl)-2-methyl-1-phenylpropan-1-one (III-3af) was characterized by structure: Colorless oil; 81% yield, 1 H NMR (400 MHz, CDC13) δ 7.95-7.92 (m, 2H), 7.59-7.56 (m, 1H), 7.49-7.45 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 3.79-3.70 (m, 1H), 3.15 (dd, J = 13.6, 6.8 Hz, 1H), 2.42 (dd, J = 13.6, 7.6 Hz, 1H), 1.23 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.4, 139.0, 136.3, 133.1, 131.5, 130.9, 128.7, 128.3, 120.0, 42.6, 38.6, 17.7 ppm; HRMS (ESI) calculated for C 16 H 17 BrO[M+H] + : 304.0306, found: 304.0309.

[0103] Example 18:

[0104]

[0105] To a pressure tube equipped with a magnetic stir bar, was added 1-phenylethanol (61 mg, 0.5 mmol), 4-fluorobenzene methanol (253 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 84 mg of 3-(4-fluorophenyl)-2-methyl-1-phenylpropan-1-one (III-3ag) product, yield: 69%.

[0106] 3-(4-Fluorophenyl)-2-methyl-1-phenylpropan-1-one (III-3ag) was characterized by structure: Colorless oil; 69% yield, 1 H NMR (400 MHz, CDC13) δ 7.91 - 7.88 (m, 2H), 7.56 - 7.52 (m, 2H), 7.45 - 7.42 (m, 2H), 7.15 - 7.12 (m, 2H), 6.95 - 6.90 (m, 2H), 3.75 - 3.66 (m, 1H), 3.12 (dd, J = 13.6, 6.6 Hz, 1H), 2.67 (dd, J = 13.6, 7.4 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.6, 136.4, 134.3 (d, J = 253 Hz), 130.5 (d, J = 7.7 Hz), 128.7, 128.3, 115.1 (d, J = 21 Hz), 42.9, 38.5, 17.6 ppm; 19 F NMR (376 MHz, CDC13) δ -117.1; HRMS (ESI) calculated for C 16 H 16 FO[M + H] + : 243.1107, found: 243.1109.

[0107] Example 19:

[0108]

[0109] Into a pressure tube equipped with a magnetic stir bar, was placed 1-phenylethanol (61 mg, 0.5 mmol), p-trifluoromethylbenzyl alcohol (352 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst of formula (VI) (5.3 mg, 2.0 mol%), and potassium phosphate (261 mg, 1.5 mmol). After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 103 mg of 3-(4-trifluorophenyl)-2-methyl-1-phenylpropan-1-one (III-3ah) product, yield: 70%.

[0110] 3-(4-trifluorophenyl)-2-methyl-1-phenylpropan-1-one (III-3ah) was characterized by structure: Colorless oil; 70% yield, 1 H NMR (400 MHz, CDC13) δ 7.91 (d, J = 7.2 Hz, 2H), 7.57 - 7.54 (m, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.47 - 7.43 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.81 - 3.72 (m, 1H), 3.23 (dd, J = 13.6, 6.8 Hz, 1H), 2.78 (dd, J = 13.6, 7.4 Hz, 1H), 1.23 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.1, 144.1, 136.2, 133.2, 129.4, 128.6 (d, J = 30 Hz), 128.3, 125.3 (d, J = 3.7 Hz), 125.27 (d, J = 3.8 Hz), 124.3 (d, J = 270 Hz), 42.5, 40.0, 17.8 ppm; 19 F NMR (376 MHz, CDC13) δ -62.4; HRMS (ESI) calculated for C 17 H 16 F3O[M+H] + : 293.1075, found: 293.1079.

[0111] Example 20:

[0112]

[0113] Into a pressure tube equipped with a magnetic stir bar, was placed 1-phenylethanol (61 mg, 0.5 mmol), furan-2-ylmethanol (197 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst of formula (VI) (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 81 mg of 3-(furan-2-yl)-2-methyl-1-phenylpropan-1-one (III-3ai) as a product in 75% yield.

[0114] 3-(Furan-2-yl)-2-methyl-1-phenylpropan-1-one (III-3ai) was characterized by structure: Colorless oil; 75% yield, 1 H NMR (400 MHz, CDC13) δ 7.95 (d, J = 7.6 Hz, 2H), 7.57 - 7.54 (m, 1H), 7.48 - 7.44 (m, 2H), 7.285 (s, 1H), 6.24 (d, J = 2.4 Hz, 1H), 6.01 (d, J = 3.2 Hz, 1H), 3.91 - 3.82 (m, 1H), 3.15 (dd, J = 14.8, 6.4 Hz, 1H), 2.76 (dd, J = 15.2, 7.6 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H); 13 CNMR (100 MHz, CDC13) δ 203.3, 153.7, 141.2, 136.2, 133.0, 128.7, 128.4, 110.2, 106.5, 40.0, 31.6, 17.5 ppm; HRMS (ESI) calculated for C 14 H 15 O2[M+H] + : 215.0994, found: 215.0996.

[0115] Example 21:

[0116]

[0117] Into a pressure tube equipped with a magnetic stir bar, was placed 1-phenylethanol (61 mg, 0.5 mmol), thiophen-2-ylmethanol (229 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron cyclopentadienyl catalyst of formula (VI) (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 72 mg of 2-methyl-1-phenyl-3-(thiophen-2-yl)propan-1-one (III-3aj) as a product in 62% yield.

[0118] 2-methyl-1-phenyl-3-(thiophen-2-yl)propan-1-one (III-3aj) was characterized by structure: Colorless oil; 62% yield, 1 H NMR (400 MHz, CDC13) δ 7.96 - 7.95 (m, 2H), 7.58 - 7.54 (m, 1H), 7.48 - 7.44 (m, 2H), 7.11 - 7.10 (m, 1H), 6.89 - 6.87 (m, 1H), 6.81 - 6.80 (m, 1H), 3.80 - 3.75 (m, 1H), 3.38 (dd, J = 14.8, 7.0 Hz, 1H), 2.95 (dd, J = 14.8, 7.2 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 203.3, 142.4, 136.3, 133.1, 128.7, 128.3, 126.8, 125.6, 123.6, 43.3, 33.3, 17.8 ppm; HRMS (ESI) calculated for C 14 H 15 OS[M+H] + : 231.0765, found: 231.0763.

[0119] Example 22:

[0120]

[0121] Into a pressure tube equipped with a magnetic stir bar, 1-(4-methoxyphenyl)ethanol (76 mg, 0.5 mmol), thiophen-2-ylmethanol (229 mg, 2.0 mmol), methanol (162 mg, 1.5 mmol), iron catalyst of cyclopentadienyl (5.3 mg, 2.0 mol%) and potassium phosphate (261 mg, 1.5 mmol) were added under an argon atmosphere. After purging with argon, the reaction mixture was heated at 120 °C for 24 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 99 mg of 1-(4-methoxyphenyl)-2-methyl-3-(thiophen-2-yl)propan-1-one (III-3cj) product, yield: 76%.

[0122] 1-(4-methoxyphenyl)-2-methyl-3-(thiophen-2-yl)propan-1-one (III-3cj) was characterized by structure: Colorless oil; 76% yield, 1 H NMR (400 MHz, CDCl3) δ 7.98-7.96 (m, 2H), 7.31-7.28 (m, 1H), 6.97-6.95 (m, 2H), 6.27-6.25 (m, 1H), 6.03 (d, J = 3.2 Hz, 1H), 3.89 (s, 3H), 3.87-3.81 (m, 1H), 3.15 (dd, J = 14.8, 6.4 Hz, 1H), 2.77 (dd, J = 15.2, 7.6 Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 201.8, 163.5, 153.9, 141.2, 130.6, 129.1, 113.8, 110.2, 106.4, 55.5, 39.6, 31.8, 17.7 ppm; HRMS (ESI) calculated for C 15 H 17 O2S[M+H] + : 261.0871, found: 261.0872.

[0123] The preferred embodiments of the application disclosed above are only to facilitate the elucidation of the application. The preferred embodiments do not describe all the details of the application and limit the application to the specific embodiments described. Obviously, many modifications and variations can be made in light of the teachings above. The description is chosen and described in order to best explain the principles of the application and its practical application to thereby enable others skilled in the art to best utilize the application and get the best results from the application. The application is only limited by the claims and their full scope and equivalents.

Claims

1. A method for preparing an α-alkyl ketone derivative, characterized in that, The reaction formula is shown below. The process includes the following steps: Under an inert gas atmosphere, using cyclopentadienone iron as a catalyst as shown in formula (VI), a mixture of 1-substituted ethanol as shown in formula (I), aromatic primary alcohol as shown in formula (II), methanol, and a base is stirred at 100-140 °C for 12-36 h to obtain the mixture shown in formula (III). α - Alkyl ketone derivatives; the base is one or more of potassium phosphate, potassium carbonate, potassium tert-butoxide, or cesium carbonate; In formula (I), R is phenyl, substituted phenyl, naphthyl, or cyclopropyl, and the substituent in the substituted phenyl group is alkyl, alkoxy, halogen, or haloalkyl; in formula (II), R 1 It is a phenyl, a substituted phenyl or a heterocyclic aryl group, wherein the substituent in the substituted phenyl is an alkyl, alkoxy, halogen or haloalkyl; 。 2. The method for preparing α-alkyl ketone derivatives according to claim 1, characterized in that, This also includes quenching the reaction with water after it is complete, extracting with an organic solvent, concentrating the separated organic solvent layer under reduced pressure, and then separating it by column chromatography to obtain the result shown in (III). α - Alkyl ketone derivatives.

3. The method for preparing α-alkyl ketone derivatives according to claim 2, characterized in that, The organic solvent used for the extraction is ethyl acetate or dichloromethane.

4. The method for preparing α-alkyl ketone derivatives according to claim 2, characterized in that, The solvent used for column chromatography separation is petroleum ether / ethyl acetate, with a volume ratio of 10:1 to 50:

1.

5. The method for preparing α-alkyl ketone derivatives according to claim 1, characterized in that, The molar ratio of 1-substituted ethanol, methanol, aromatic primary alcohol as shown in formula (II), alkali and cyclopentadienone iron as shown in formula (VI) is 1:1.5~10:1.5~5:1~5:0.02~0.

1.

6. The method for preparing α-alkyl ketone derivatives according to claim 5, characterized in that, The molar ratio of 1-substituted ethanol, methanol, aromatic primary alcohol as shown in formula (II), base and cyclopentadienone iron as shown in formula (VI) is 1:3:4:3:0.

02.

7. The method for preparing α-alkyl ketone derivatives according to claim 1, characterized in that, The alkali mentioned is potassium phosphate.

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