A method for preparing trifluoromethyl ketone compounds based on palladium-catalyzed CN bond cleavage

Abstract

The present invention belongs to the field of pharmaceutical chemistry and related chemical technologies, and discloses a method for preparing trifluoromethyl ketone compounds based on palladium-catalyzed C-N bond cleavage. The method uses arylboronic acid as a raw material and trifluoroacetamide compounds as a trifluoroacetylating agent, and prepares trifluoromethyl ketone compounds under the catalytic action of palladium, thereby achieving its green and efficient synthesis. The method has the advantages of easy preparation and storage of trifluoroacetylating agents, high reaction selectivity, good functional group compatibility, wide substrate application range, and environmental friendliness. Since trifluoromethyl ketone compounds are an important functional molecular skeleton structure, they are widely used in the fields of fine chemicals and pharmacy; therefore, the present invention has great application value and social and economic benefits.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical intermediates and related chemical technologies, and relates to a method for preparing a trifluoromethyl ketone compound based on palladium-catalyzed CN bond cleavage. Background Art

[0002] Trifluoromethyl ketones possess unique physicochemical properties and physiological activities and are widely used as pharmaceutical and functional material molecules. Trifluoromethyl ketones are an important class of synthetic drug or functional molecule skeletal structures and have extensive applications in organic synthesis. Since the synthesis of arylboronic acid compounds, organic chemists have conducted extensive research on their synthesis and functionalization reactions. Among them, the trifluoroacetylation of arylboronic acids has shown great application in the synthesis of pharmaceuticals and pesticides.

[0003] The synthesis of trifluoromethyl ketones is a current research hotspot. With increasing attention to sustainable development and human health, green chemistry, characterized by high efficiency, low pollution, and atom economy, has gained widespread attention. Consequently, efficient and green synthesis methods for trifluoromethyl ketones have attracted considerable attention. In the prior art, common trifluoroacetylation reagents include trifluoroacetate (Heinz, B.; Djukanovic, D.; Ganiek, MA; Martin, B.; Schenkel, B.; Knochel, P. Selective acetylation of aryl- and heteroarylmagnesium reagents with esters in continuous flow. Org. Lett. 2020, 22, 493-496.), thiotrifluoroacetate (Yi X., Cao Y.-F., Wang X., Xu, H.; Ban, S.-R.; Dai, H.-X. Palladium-catalyzed fluoroacetylation of (Hetero)arylboronic acid with fluorothioacetates at ambient temperature. Tetrahedron Lett.2020,61,151780.), trifluoroaceruvate (Wu,W.;Tian,Q.;Chen,T.;Weng,Z.Copper-mediated trifluoroacetylation of arenediazonium saltswith ethyl trifluoropyruvate.Chem.Eur.J.2016,22,16455-16458.), etc. When used as trifluoroacetylation reagents, such reagents have the disadvantages of poor raw material stability (diazo compounds), harsh reaction conditions, poor functional group compatibility (incompatible ortho-substituents), and the use of equivalent metal salts. In the current research, there is no report on the synthesis of trifluoromethyl ketones by cleavage of the CN bond of arylboronic acid compounds and trifluoroacetamide compounds. Summary of the Invention

[0004] To solve the problems existing in the prior art, the present invention utilizes the reaction of aryl boronic acid compounds with trifluoroacetamide compounds to provide a method for synthesizing trifluoromethyl ketone with high selectivity and yield, mild reaction conditions, high atom economy, and good catalytic effect, which is of great significance. This method uses aryl boronic acid compounds and trifluoroacetamide compounds as raw materials to achieve the synthesis of trifluoromethyl ketone catalyzed by palladium. The method has the advantages of a simple catalytic system, good selectivity, mild conditions, good atom economy, environmental friendliness, and easy industrialization. The trifluoroacetylating agent used is solid at room temperature and easy to store and use. The imine compound generated after the reaction can be recycled. The raw materials trifluoroacetic acid or trifluoroacetic anhydride are cheap and easily available, and are scalable. Other fluorine-containing acyl reagents can be synthesized using the same method. The present invention has great application value and social and economic benefits.

[0005] The technical solution adopted in the present invention is:

[0006] A class of trifluoromethyl ketone compounds, the general structural formula of which is as follows:

[0007]

[0008] Wherein: R = one or a combination of two of hydrogen, linear or branched alkyl, cycloalkyl, aryl, amino, alkoxy, phenoxy, trifluoromethyl, trifluoromethoxy, halogen, nitro, cyano, acyl, alkoxycarbonyl, alkylthio, carbazolyl, alkylsulfonyl, and pyridyl.

[0009] A method for preparing a trifluoromethyl ketone compound based on palladium-catalyzed CN bond cleavage, comprising the following steps:

[0010] A series of trifluoromethyl ketone compounds are synthesized using aryl boronic acid compounds and trifluoroacetamide compounds as raw materials through palladium-catalyzed CN bond cleavage reaction of aryl boronic acid compounds and trifluoroacetamide compounds. The synthetic route is as follows:

[0011]

[0012] Wherein: R = one or a combination of hydrogen, linear or branched alkyl, cycloalkyl, aryl, amino, alkoxy, phenoxy, trifluoromethyl, trifluoromethoxy, halogen, nitro, cyano, acyl, alkoxycarbonyl, alkylthio, carbazolyl, alkylsulfonyl, pyridyl;

[0013] R 1 = straight-chain or branched alkyl, aryl, benzyl, straight-chain or branched acyl, straight-chain or branched alkoxycarbonyl, benzyloxycarbonyl, benzoyl, straight-chain or branched alkylsulfonyl, benzylsulfonyl, p-toluenesulfonyl;

[0014] R 2= straight-chain or branched alkyl, aryl, benzyl, straight-chain or branched acyl, straight-chain or branched alkoxycarbonyl, benzyloxycarbonyl, benzoyl, straight-chain or branched alkylsulfonyl, benzylsulfonyl, p-toluenesulfonyl;

[0015] (1) adding an arylboronic acid compound 1, a palladium catalyst, a ligand, a trifluoroacetamide compound 2, a base, and an organic solvent to a reactor in sequence, and reacting at 20-100° C. for 2-48 hours;

[0016] in,

[0017] The molar ratio of the arylboronic acid compound 1 to the trifluoroacetamide compound 2 is 1:1 to 1:5;

[0018] The molar ratio of the arylboronic acid compound 1 to the base is 1:0.5 to 1:4;

[0019] The molar ratio of the arylboronic acid compound 1 to the palladium catalyst is 1:0.01 to 1:0.2;

[0020] The molar ratio of the arylboronic acid compound 1 to the ligand is 1:0.01 to 1:0.4;

[0021] The concentration of arylboronic acid compound 1 in the reaction system is 0.02-0.5 mol / L;

[0022] (2) After the reaction is completed, the solvent is removed by distillation under reduced pressure, and the mixture is separated by silica gel column using an eluent to obtain trifluoromethyl ketone compound 3.

[0023] The aromatic boronic acid compound 1 includes phenylboronic acid, linear or branched alkylphenylboronic acid, cycloalkylphenylboronic acid, biphenylboronic acid, morpholinophenylboronic acid, alkoxyphenylboronic acid, phenoxyphenylboronic acid, trifluoromethylphenylboronic acid, trifluoromethoxyphenylboronic acid, halogenated phenylboronic acid, nitrobenzeneboronic acid, cyanophenylboronic acid, acylphenylboronic acid, alkoxyformylphenylboronic acid, alkylthiophenylboronic acid, carbazolylphenylboronic acid, alkylsulfonylphenylboronic acid, pyridylphenylboronic acid, naphthaleneboronic acid, linear or branched alkylnaphthaleneboronic acid, methoxynaphthaleneboronic acid, anthraceneboronic acid, phenanthreneboronic acid, fluoreneboronic acid, pyreneboronic acid, indoleboric acid, five-membered heterocyclic boronic acid, six-membered heterocyclic boronic acid; the trifluoroacetamide compound 2 includes N-methyl-N-phenyltrifluoroacetamide, N-ethyl-N-phenyltrifluoroacetamide, N-n-propyl N-phenyltrifluoroacetamide, N-tert-butyl-N-phenyltrifluoroacetamide, N-n-pentyl-N-phenyltrifluoroacetamide, N-n-hexyl-N-phenyltrifluoroacetamide, N-phenyl-N-acetyl trifluoroacetamide, N-phenyl-N-propionyl trifluoroacetamide, N-phenyl-N-benzoyl trifluoroacetamide, N-phenyl-N-methoxycarbonyl trifluoroacetamide, N-phenyl-N-ethoxycarbonyl trifluoroacetamide, N-phenyl-N-tert-butoxycarbonyl trifluoroacetamide, N-phenyl-N-benzyloxycarbonyl trifluoroacetamide, N-phenyl-N-methanesulfonyl trifluoroacetamide, N-phenyl-N-ethanesulfonyl trifluoroacetamide, N-phenyl-N-benzenesulfonyl trifluoroacetamide, N-phenyl-N-p-toluenesulfonyl trifluoroacetamide.

[0024] The reaction temperature ranges from 20 to 100°C, preferably from 30 to 60°C.

[0025] The reaction time ranges from 2 to 48 hours, preferably from 4 to 20 hours.

[0026] The palladium catalyst is selected from palladium chloride, palladium bromide, palladium iodide, palladium nitrate, palladium acetate, palladium trifluoroacetate, palladium trifluoromethanesulfonate, palladium / carbon, palladium hydroxide / carbon, bis(acetylacetone)palladium, bis(benzylideneacetone)palladium, tris(benzylideneacetone)dipalladium, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, (1,5-cyclooctadiene)palladium dichloride, and (2,2'-bipyridine)palladium dichloride.

[0027] The ligand is selected from triphenylphosphine, tri(2-methylphenyl)phosphine, tri(dimethylamino)phosphine, tricyclopentylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, dicyclohexylphenylphosphine, tri-(1-adamantyl)phosphine, bis(dicyclohexylphosphino)methane, 1,3-bis(dicyclohexylphosphino)propane, 1,4-bis(dicyclohexylphosphino)butane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tri(4-trifluoromethylphenyl)phosphine, tri(1-naphthyl)phosphine, 2-diphenylphosphine Phosphine-2',6'-dimethoxybiphenyl, tri(2-furyl)phosphine, tri(2-thienyl)phosphine, (2-methoxyphenyl)diphenylphosphine, tri(3-methylphenyl)phosphine, bis(dicyclohexylphosphinophenyl)ether, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 2,2'-bipyridine, 2,2'-biquinoline, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,9-diphenyl-1,10-phenanthroline.

[0028] The base used is selected from lithium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium formate, sodium acetate, potassium acetate, sodium pivalate, potassium pivalate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium tert-butoxide, sodium methoxide, and potassium ethoxide.

[0029] The organic solvent is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 1,2-dichloroethane, cyclohexane, n-hexane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, benzene, toluene, xylene, fluorobenzene, trifluorotoluene, dimethyl carbonate, and diethyl carbonate.

[0030] The trifluoromethyl ketone compound is used in the preparation of medicines and pesticides.

[0031] Beneficial effects of the present invention: The present invention relates to a method for preparing trifluoromethyl ketone compounds based on palladium-catalyzed CN bond cleavage, which has the advantages of easy preparation and storage of trifluoroacetylation reagents, high reaction selectivity, good functional group compatibility, wide substrate application range, and environmental friendliness. Specifically:

[0032] (1) This method is directed to the CN bond cleavage trifluoroacetylation reaction of arylboronic acid compounds with trifluoroacetamide compounds. The prior art has disadvantages such as difficulty in preparing and storing trifluoroacetylation reagents, low reaction yields, and harsh reaction conditions. In the present application, trifluoroacetamide compounds are used as trifluoroacetylation reagents to synthesize trifluoromethyl ketones through a CN bond cleavage trifluoroacetylation reaction with arylboronic acid. This method has the advantages of easy preparation and storage, a simple reaction system, and mild reaction conditions.

[0033] (2) The trifluoroacetylating agent used in this method is easy to prepare and store. The trifluoroacetylating agents used in the prior art, such as trifluoroacetate, thiotrifluoroacetate, and trifluoropyruvate, have the disadvantages of being difficult to store and use, being expensive, and having a complicated preparation method.

[0034] (3) The catalyst has high catalytic efficiency, and the reaction selectivity and yield are both high. In summary, the method is a method for preparing trifluoromethyl ketone, which has a trifluoroacetylation reagent that is easy to prepare and store, high catalytic efficiency, good reaction selectivity, and high product yield. Since trifluoromethyl ketone is an important functional molecular skeleton structure, it has a wide range of applications in the fields of medicine, pesticides, and materials. Therefore, the present invention has great application value and social and economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 For compound 3a 1 H-NMR.

[0036] Figure 2 For compound 3a 13 C-NMR.

[0037] Figure 3 For compound 3a 19 F-NMR.

[0038] Figure 4 For compound 3b 1 H-NMR.

[0039] Figure 5 For compound 3b 13 C-NMR.

[0040] Figure 6 For compound 3b 19 F-NMR.

[0041] Figure 7 For compound 3c 1 H-NMR.

[0042] Figure 8 For compound 3c 13 C-NMR.

[0043] Figure 9 For compound 3c 19 F-NMR.

[0044] Figure 10 For compound 3d 1 H-NMR.

[0045] Figure 11 For compound 3d 13 C-NMR.

[0046] Figure 12 For compound 3d 19 F-NMR.

[0047] Figure 13 For compound 3e 1 H-NMR.

[0048] Figure 14 For compound 3e 13 C-NMR.

[0049] Figure 15 For compound 3e 19 F-NMR.

[0050] Figure 16 For compound 3f 1 H-NMR.

[0051] Figure 17 For compound 3f 13 C-NMR.

[0052] Figure 18 For compound 3f 19 F-NMR. DETAILED DESCRIPTION

[0053] The specific implementation of the present invention is further described below in conjunction with the accompanying drawings and technical solutions.

[0054] The method for preparing trifluoromethyl ketone of the present invention has the advantages of easy preparation and storage of trifluoroacetylating reagent, high catalytic efficiency, good reaction selectivity, high product yield, etc., and shows good application prospects.

[0055] The present invention will be further described below in conjunction with specific examples. These examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. Simple substitutions or improvements made by those skilled in the art to the present invention fall within the technical solutions protected by the present invention.

[0056] The preparation method of trifluoromethyl ketone is:

[0057] (1) adding an aryl boronic acid compound 1, a palladium catalyst, a trifluoroacetamide compound 2, a base and an organic solvent to a reactor in sequence, and reacting at 20-100° C. for 2-48 hours; the molar ratio of the aryl boronic acid compound to the trifluoroacetamide compound is 1:1-1:5, the molar ratio of the aryl boronic acid compound to the base is 1:0.5-1:4, the molar ratio of the aryl boronic acid compound to the palladium catalyst is 1:0.01-1:0.2, and the molar ratio of the aryl boronic acid compound to the ligand is 1:0.01-1:0.4;

[0058] (2) After the reaction is completed, the solvent is removed by distillation under reduced pressure, and the mixture is separated on a silica gel column using an eluent to obtain trifluoromethyl ketone 3.

[0059]

[0060]

[0061]

[0062] The above method was used to carry out Examples 1 to 6. The following lists only the detailed preparation processes of several representative compounds, specifically:

[0063] Example 1: Synthesis of 4-phenyltrifluoroacetylbenzene (3a)

[0064]

[0065] 4-Phenylboronic acid (0.40 g, 2.0 mmol), N-methyl-N-phenyltrifluoroacetamide (0.43 g, 2.1 mmol), palladium chloride (8.8 mg, 0.05 mmol), triphenylphosphine (26.2 mg, 0.10 mmol), and potassium formate (0.17 g, 2.0 mmol) were accurately weighed and added to a 50 mL Schlenk flask in sequence. Dimethyl sulfoxide (8.0 mL) was added and the mixture was placed in a 30°C oil bath to react for 16 h. After the reaction was completed, the solvent was distilled off under reduced pressure and the product was separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v 50:1) as the eluent. The yield of the product, 4-phenyltrifluoroacetylbenzene, was 99%, and nuclear magnetic resonance spectroscopy (NMR) was performed on the product. 1 HNMR, 13 C NMR and 19 F NMR) characterization, see attached Figure 1-3 . 1 H NMR (500MHz, CDCl3) δ8.19(d,J=8.0Hz,2H),7.80(d,J=8.4Hz,2H),7.68(d,J=7.2Hz,2H),7.55–7.47(m,3H). 13 C

[0066] NMR (126 MHz, CDCl3) δ 180.1 (q, J C-F =35.1Hz),148.2,139.1,130.8,129.2,

[0067] 128.9,128.6,127.7,127.4,116.8(q,J C-F =291.9Hz). 19F NMR(471MHz, CDCl3)δ-71.3(s,3F).

[0068] Example 2: Synthesis of 4-morpholinyltrifluoroacetylbenzene (3b)

[0069]

[0070] 4-Morpholinophenylboronic acid (0.21 g, 1.0 mmol), N-phenyl-N-toluenesulfonyl trifluoroacetamide (0.52 g, 1.5 mmol), palladium acetate (5.6 mg, 0.025 mmol), 1,3-bis(diphenylphosphino)propane (20.6 mg, 0.05 mmol), and potassium carbonate (0.21 g, 1.5 mmol) were accurately weighed and added to a 50 mL Schlenk flask in sequence. Tetrahydrofuran (4.0 mL) was added and the mixture was placed in a 60°C oil bath to react for 8 h. After the reaction, the solvent was distilled off under reduced pressure and the product was separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v 50:1) as the eluent. The yield of the product, 4-morpholinotrifluoroacetylbenzene, was 97%, and nuclear magnetic resonance spectroscopy (NMR) was performed on the product. 1 H NMR, 13 C NMR and 19 F NMR) characterization, see attached Figure 4-6 . 1 H NMR (600MHz, CDCl3) δ7.98 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.87 (t, J = 4.9 Hz, 4H), 3.42 (t, J = 5.0 Hz, 4H). 13 C NMR(151MHz,CDCl3)δ178.2(q,J C-F =33.9Hz),155.3,132.6,119.6,117.2(q,J C-F =291.7Hz),112.8,66.4,46.7. 19 F NMR (565MHz, CDCl3) δ-70.6 (s, 3F).

[0071] Example 3: Synthesis of 4-(N,N-diphenylamino)trifluoroacetylbenzene (3c)

[0072]

[0073] 4-(N,N-diphenylamino)phenylboronic acid (1.16 g, 4.0 mmol), N-methyl-N-propanesulfonyl trifluoroacetamide (1.17 g, 5.0 mmol), palladium hydroxide / carbon (58 mg, 5 wt%), 1,2-bis(diphenylphosphino)ethane (79.7 mg, 0.20 mmol), and sodium carbonate (1.06 g, 10.0 mmol) were accurately weighed and added to a 100 mL Schlenk flask in sequence. Benzene (15.0 mL) was added and the mixture was placed in an 80°C oil bath for 24 h. After the reaction, the solvent was removed by distillation under reduced pressure and the product was separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v 20:1) as the eluent. The yield of the product, 4-(N,N-diphenylamino)trifluoroacetylbenzene, was 94%. Nuclear magnetic resonance spectroscopy ( 1 H NMR, 13 C NMR and 19 F NMR) characterization, see attached Figure 7-9 . 1 H NMR (600MHz, CDCl3) δ7.93 (d, J = 8.6 Hz, 2H), 7.43–7.40 (m, 4H), 7.29–7.24 (m, 6H), 7.01 (d, J = 9.0 Hz, 2H). 13 C NMR(151MHz,CDCl3)δ178.2(q,J C-F =292.9Hz),154.1,145.5,132.1,130.0,126.8,125.9,121.2,118.1,117.2(q,J C-F =292.9Hz). 19 F NMR (565MHz, CDCl3) δ-70.7 (s, 3F).

[0074] Example 4: Synthesis of 5-trifluoroacetylindole (3d)

[0075]

[0076] 2-Naphthylboronic acid (0.97 g, 6.0 mmol), N-phenyl-N-methanesulfonyltrifluoroacetamide (1.76 g, 6.6 mmol), di(benzylideneacetone)palladium (17.3 mg, 0.03 mmol), dicyclohexylphenylphosphine (16.5 mg, 0.06 mmol), and potassium phosphate (2.12 g, 10.0 mmol) were accurately weighed and added to a 50 mL Schlenk flask in sequence. Toluene (15.0 mL) was added and the flask was placed in a 100°C oil bath to react for 30 h. After the reaction, the solvent was distilled off under reduced pressure and the product was separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v 50:1) as the eluent. The yield of the product, 5-trifluoroacetylindole, was 96%, and its nuclear magnetic resonance spectrum was analyzed ( 1 H NMR, 13 C NMR and 19 F NMR) characterization, see attached Figure 10-12 . 1 H NMR (600MHz, CDCl3) δ8.48(d,J=8.3Hz,1H),7.63(d,J=7.7Hz,1H),7.53–7.51(m,1H),7.48–7.45(m,1H),7.42–7.40(m,1H),6.81(d,J=3.8Hz,1H). 13 C NMR(151MHz,CDCl3)δ154.1(q,J C-F =39.3Hz),135.8,130.4,126.2,125.7,124.0(q,J C-F =4.5Hz),121.4,116.9,115.6(q,J C-F =288.1Hz),112.6. 19 F NMR(565MHz,CDCl3)δ-69.3(s,3F).HRMS(EI)m / z:[M] + Calcd for C 10 H6F3NO 213.0401; Found213.0399.

[0077] Example 5: Synthesis of 9-trifluoroacetylphenanthrene (3e)

[0078]

[0079] 9-Phenanthreneboric acid (0.44 g, 2.0 mmol), N-methyl-N-ethylsulfonyl trifluoroacetamide (0.55 g, 2.5 mmol), bis(acetylacetonate) palladium (15.2 mg, 0.05 mmol), tricyclohexylphosphine (33.7 mg, 0.12 mmol), and potassium acetate (0.49 g, 5.0 mmol) were accurately weighed and added to a 50 mL Schlenk flask in sequence. 1,4-dioxane (8.0 mL) was added and the mixture was placed in a 35°C oil bath to react for 20 h. After the reaction was completed, the solvent was distilled off under reduced pressure and the product was separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v 50:1) as the eluent. The yield of the product, 9-trifluoroacetylphenanthrene, was 83%, and nuclear magnetic resonance spectroscopy was performed on it ( 1 H NMR, 13 CNMR and 19 F NMR) characterization, see attached Figure 13-15 . 1 H NMR (600MHz, CDCl3) δ8.83–8.79(m,1H),8.62–8.59(m,1H),8.54(dd,J=11.7,8.1Hz,1H), 8.43(s,1H),7.94-7.91(m,1H),7.78-7.75(m,1H),7.73–7.67(m,2H),7.65-7.61(m,1H). 13 C NMR(151MHz,CDCl3)δ182.2(q,J C-F =33.9Hz),135.1(q,J C-F =3.6Hz),132.9,130.9,130.72,130.69,128.9,128.3,128.1,127.7,127.5,126.0,125.4,122.9,122.7,116.8(q,J C-F =293.4Hz). 19 F NMR (565MHz, CDCl3) δ-69.6 (s, 3F).

[0080] Example 6: Synthesis of 9,9-dimethyl-2-trifluoroacetylfluorene (3f)

[0081]

[0082] 9,9-dimethyl-2-fluoreneboronic acid (0.24 g, 1.0 mmol), N-methyl-N-methylsulfonyl trifluoroacetamide (0.41 g, 2.0 mmol), palladium carbon (24.0 mg, 10 wt%), tri-tert-butylphosphine (20.2 mg, 0.10 mmol), and cesium carbonate (0.49 g, 1.5 mmol) were accurately weighed and added to a 50 mL Schlenk bottle in sequence. 2-Methyltetrahydrofuran (6.0 mL) was added and the mixture was placed in a 70°C oil bath to react for 30 h. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v 50:1) as the eluent. The yield of the product, 9,9-dimethyl-2-trifluoroacetylfluorene, was 93%. Nuclear magnetic resonance spectroscopy ( 1 HNMR, 13 C NMR and 19 F NMR) characterization, see attached Figure 16-18 . 1 H NMR (600MHz, CDCl3) δ8.21(s,1H),8.14(d,J=8.1Hz,1H),7.88(d,J=8.1Hz,1H) ,7.86(d,J=7.2Hz,1H),7.54(d,J=7.3Hz,1H),7.50–7.43(m,2H),1.58(s,6H). 13 C NMR(151MHz,CDCl3)δ180.2(q,J C-F =34.4Hz),155.2,154.2,146.8,137.2,130.1(q,J C-F =2.5Hz),129.6,128.6,127.6,124.4,123.0,121.6,120.3,117.0(q,J C-F =291.7Hz),47.2,26.8. 19 F NMR (565MHz, CDCl3) δ-70.7 (s, 3F).

[0083] It can be concluded from the examples that when the R group is a substituent with electron-withdrawing or electron-donating properties, the reaction yield is high, and the method is applicable to the trifluoroacetylation of naphthylboronic acid, phenanthrenylboronic acid, fluorenylboronic acid, etc.

Claims

1. A method for preparing a trifluoromethyl ketone compound based on palladium-catalyzed CN bond cleavage, characterized in that: Here are the steps: A series of trifluoromethyl ketone compounds were synthesized by using arylboronic acid compounds and trifluoroacetamide compounds as raw materials through the CN bond cleavage reaction catalyzed by palladium catalyst. (1) Add arylboronic acid compound 1, palladium catalyst, ligand, trifluoroacetamide compound 2, base and organic solvent to the reactor in sequence. The reaction conditions are: 20-100 ºC for 2-48 h. in, The molar ratio of the arylboronic acid compound 1 to the trifluoroacetamide compound 2 is 1:1 to 1:5; The molar ratio of the arylboronic acid compound 1 to the base is 1:0.5 to 1:4; The molar ratio of the arylboronic acid compound 1 to the palladium catalyst is 1:0.01 to 1:0.2; The molar ratio of the arylboronic acid compound 1 to the ligand is 1:0.01 to 1:0.4; The concentration of arylboronic acid compound 1 in the reaction system is 0.02~0.5 mol / L; (2) After the reaction is completed, the solvent is removed by distillation under reduced pressure, and the mixture is separated by silica gel column using an eluent to obtain trifluoromethyl ketone compound 3; The aromatic boronic acid compound 1 includes phenylboronic acid, biphenylboronic acid, morpholinylphenylboronic acid, phenoxyphenylboronic acid, trifluoromethylphenylboronic acid, trifluoromethoxyphenylboronic acid, halogenated phenylboronic acid, nitrobenzeneboronic acid, cyanophenylboronic acid, carbazolylphenylboronic acid, pyridylphenylboronic acid, naphthaleneboronic acid, methoxynaphthaleneboronic acid, anthraceneboronic acid, phenanthreneboronic acid, fluoreneboronic acid, pyreneboronic acid, indoleboric acid, five-membered heterocyclic boronic acid, and six-membered heterocyclic boronic acid; The trifluoroacetamide compounds 2 include N-methyl-N-phenyl trifluoroacetamide, N-ethyl-N-phenyl trifluoroacetamide, N-n-propyl-N-phenyl trifluoroacetamide, N-tert-butyl-N-phenyl trifluoroacetamide, N-n-pentyl-N-phenyl trifluoroacetamide, N-n-hexyl-N-phenyl trifluoroacetamide, N-phenyl-N-acetyl trifluoroacetamide, N-phenyl-N-propionyl trifluoroacetamide, N-phenyl-N-phenyl trifluoroacetamide, Formyltrifluoroacetamide, N-phenyl-N-methoxycarbonyltrifluoroacetamide, N-phenyl-N-ethoxycarbonyltrifluoroacetamide, N-phenyl-N-tert-butoxycarbonyltrifluoroacetamide, N-phenyl-N-benzyloxycarbonyltrifluoroacetamide, N-phenyl-N-methanesulfonyltrifluoroacetamide, N-phenyl-N-ethanesulfonyltrifluoroacetamide, N-phenyl-N-benzenesulfonyltrifluoroacetamide, N-phenyl-N-p-toluenesulfonyltrifluoroacetamide.

2. The method for preparing a trifluoromethyl ketone compound according to claim 1, wherein The palladium catalyst is selected from palladium chloride, palladium bromide, palladium iodide, palladium nitrate, palladium acetate, palladium trifluoroacetate, palladium trifluoromethanesulfonate, palladium / carbon, palladium hydroxide / carbon, bis(acetylacetone)palladium, bis(benzylideneacetone)palladium, tris(benzylideneacetone)dipalladium, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, (1,5-cyclooctadiene)palladium dichloride, and (2,2'-bipyridine)palladium dichloride.

3. The method for preparing a trifluoromethyl ketone compound according to claim 1, wherein The ligand is selected from triphenylphosphine, tri(2-methylphenyl)phosphine, tri(dimethylamino)phosphine, tricyclopentylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, dicyclohexylphenylphosphine, tri-(1-adamantyl)phosphine, bis(dicyclohexylphosphino)methane, 1,3-bis(dicyclohexylphosphino)propane, 1,4-bis(dicyclohexylphosphino)butane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tri(4-trifluoromethylphenyl)phosphine, tri(1-naphthyl)phosphine, 2-diphenylphosphino-2',6'-dimethoxybiphenyl, tri(2-furyl)phosphine, tri(2-thienyl)phosphine, (2-Methoxyphenyl)diphenylphosphine, tris(3-methylphenyl)phosphine, bis(dicyclohexylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 2,2'-bipyridine, 2,2'-biquinoline, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,9-diphenyl-1,10-phenanthroline.

4. The method for preparing a trifluoromethyl ketone compound according to claim 1, wherein The base used is selected from lithium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium formate, sodium acetate, potassium acetate, sodium pivalate, potassium pivalate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium tert-butoxide, sodium methoxide, and potassium ethoxide.

5. The method for preparing a trifluoromethyl ketone compound according to claim 1, wherein The organic solvent is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 1,2-dichloroethane, cyclohexane, n-hexane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, benzene, toluene, xylene, fluorobenzene, trifluorotoluene, dimethyl carbonate, and diethyl carbonate.

6. The method for preparing a trifluoromethyl ketone compound according to claim 1, wherein The reaction conditions are: temperature 30~60 ºC, reaction time 4~20 h.

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