Synthetic method of alpha-fluoromethyl aromatic methanol

Abstract

The invention relates to a synthesis method of alpha-fluoromethyl aromatic methanol, which comprises the following steps: by taking a ketone compound or an amide compound as a raw material, adding a monofluoromethyl reagent and a proper photocatalyst, taking alkali as an additive, and carrying out LED (Light Emitting Diode) blue light catalysis in a solvent to carry out monofluoromethyl free radical addition reaction, thereby obtaining the alpha-fluoromethyl aromatic methanol. The method utilizes a photocatalysis method and is green, simple and convenient.

Description

Technical Field

[0001] This invention relates to a method for synthesizing α-monofluoromethylaryl alcohol, and more particularly to a method for synthesizing the target product by photocatalytic addition of a monofluoromethyl free radical to a substituted ketone compound or amide compound as a raw material and a monofluoromethyl reagent. Background Technology

[0002] Fluorine-containing compounds possess unique physicochemical properties and are widely used in drug development, clinical medicine, agricultural chemistry, materials science, and organic synthesis. Monofluoromethyl (-CFH2) derivatives, as multifunctional bioisosteres, can effectively replace traditional -CH3, -CH2OH, or -CH2NH2 groups in drug design, thereby improving metabolic stability and enhancing biological activity. In recent years, α-monofluoromethyl methanol has become an important structural unit in bioactive molecules and drugs. For example, 3-(pyrido[3,2-d]pyrimidin-4-ylamino)-1-fluoroheptane-2-ol, as a novel Toll-like receptor modulator, can be used to treat immune system diseases; 3-(fluoromethyl)-3-hydroxyindole-2-one, as a highly selective muscarinic acetylcholine receptor (mAChR) ligand, has potential applications in the treatment of Alzheimer's disease. Based on these properties, the efficient construction and application of α-monofluoromethyl aromatic methanol derivatives are of great significance for promoting the development of high-value-added chemicals.α-Monofluoromethyl alcohols and their derivatives are important intermediates for the preparation of pharmaceuticals, pesticides and some fluorine-containing fine chemicals. There are few literature reports on compounds containing α-monofluoromethyl alcohols. Currently, there are several methods: (1) Using aldehydes as substrates, a nucleophilic addition reaction is carried out with fluorobis(benzenesulfonyl)methyltrimethylsilane or fluorobis(benzenesulfonyl)methane, followed by a reductive desulfonation reaction to obtain α-monofluoromethyl alcohols [Prakash, GKS; Shao, N.; Zhang, Z.; Ni, C.; Wang, F.; Haiges, R.; Olah, GA]. Chem., 2012, 133, 27-32.];(2) Using ketones and (R)-N-tert-butyldimethylsilyl-S-fluoromethyl-S-phenylsulfoximine as raw materials, nucleophilic fluoroalkylation reaction is carried out, and then converted into enantiomeric pure α-fluoromethylaryl alcohol [Shen, X.;Miao, W.;Ni, C.;Hu, J.DIAD-mediated metal-free cross dehydrogenative coupling between tertiaryamines and α-fluorinated] sulfones.Agnew.Chem.Int.Ed.,2014,53,775-779.];(3) Using in-situ generated fluoroiodomethane-derived LiCH2F to directly nucleophilic monofluoromethylation of ketone compounds to introduce CFH2 groups to synthesize α-monofluoromethylarethanol [Parisi,G.;Colella,M.;Monticelli,S.;Romanazzi,G.;Holzer,W.;Langer,T.;Degennaro,L.;Pace,V.;Luisi,R.Exploiting a“Beast”in CarbenoidChemistry:Development ofa Straightforward DirectNu-cleophilicFluoromethylation Strategy.J.Am.Chem.Soc.,2017,139,13648-13651.].This patent will invent a new method for preparing α-monofluoromethylarmine by using substituted ketone compounds or amide compounds as starting materials and subjecting them to a monofluoromethyl radical addition reaction. Summary of the Invention

[0003] The problem this invention aims to solve is to provide a method for preparing α-monofluoromethylaryl alcohol. This method uses ketone or amide compounds as raw materials and a monofluoromethyl free radical reagent, and generates α-monofluoromethylaryl alcohol via free radical addition under photocatalysis. The operation method is simple and the conditions are green and mild.

[0005] To achieve the purpose of the invention, the technical solution adopted by the present invention is as follows:

[0006] The synthesis method of this invention uses ketone or amide compounds as raw material 1, adds a monofluoromethyl reagent and a suitable photocatalyst, uses a base as an additive, and irradiates with a certain power LED blue light for a certain period of time in a suitable solvent to conduct a monofluoromethyl radical addition reaction to obtain α-monofluoromethylaryl alcohol. The specific reaction formula is as follows (Formula 1):

[0007]

[0008] Where R1 = substituted benzene ring, heterocycle, alkane, and R2 = substituted benzoyl group, substituted benzene ring, substituted heterocycle, alkyl group, aromatic amine, alkyl amine, ester group.

[0009] Preferably, the fluoromethyl reagent of formula 1 is such as sodium fluoromethyl sulfinate, 2-fluoromethyl sulfone benzothiazole, or 2-fluoromethyl sulfone pyridine.

[0010] Preferably, the photocatalyst of Formula 1 is, for example, eosin Y, fac-Ir(py)3, fluorescein, 10-methyl-9-trimethylammonium acridine perchlorate, or Ru(bpy)3Cl2·6H2O.

[0011] Preferably, the additives of Formula 1 include triethylamine, pyridine, sodium carbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate.

[0012] Preferably, the solvent of Formula 1 is such as DMSO, DMF, acetone, toluene, NMP, DCE, or ethanol.

[0013] Preferably, the power of the blue light radiating LED of Formula 1 is 6-60W.

[0014] Preferably, the reaction light irradiation time of Formula 1 is 6-48 hours.

[0015] This invention provides a convenient method for preparing α-fluoromethylaryl alcohol, using readily available raw materials, utilizing photocatalytic free radical addition, with mild reaction conditions and a reaction yield of 33-98%. Detailed Implementation

[0016] The present invention will be further described below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0017] Example 1: 2 mmol of bibenzoyl, 4 mmol of sodium monofluoromethyl sulfinate, and 0.04 mmol of 9-trimethylmethyl-10-methylacridine perchlorate were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of acetone and 3 mmol of triethylamine were added, and the reaction was carried out under an LED blue lamp for 24 hours. After the reaction was completed, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, poured into an Erlenmeyer flask, dried with anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporation, and separated by column chromatography. The product was obtained with a yield of 85%. Its structure and characterization data are as follows: 3-fluoro-2-hydroxy-1,2-diphenylpropan-1-one (1)

[0018]

[0019] 1 H NMR (400MHz, CDCl3): δ7.90-7.82(m,2H),7.52(d,J=6.9Hz,2H),7.45(t,J=7.4Hz,1H),7.40(t,J=7. 3Hz,2H),7.36-7.28(m,3H),5.31(dd,J=46.1,9.1Hz,1H),4.48(dd,J=48.0,9.2Hz,1H),4.05(s,1H). 13 C{1H}NMR (101MHz, CDCl3): δ198.5, 136.8, 134.3, 133.1, 130.4, 129.1, 128.8, 128.2, 125.3, 86.9 (d, J = 177.4Hz), 82.4 (d, J = 19.0Hz). 19 FNMR (377MHz, CDCl3): δ-224.41 (t, J=47.6Hz, 1F). HRMS (ESI): m / z calcd.For C 15 H 13 FNaO2[M+Na] + 267.0797, found 267.0795.

[0020] Example 2: 2 mmol of indigo, 4 mmol of sodium monofluoromethyl sulfinate, 3 mmol of sodium carbonate, and 0.04 mmol of eosin Y were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of ethanol was added, and the reaction was carried out under an LED blue lamp for 10 hours. After the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate in an Erlenmeyer flask, concentrated under reduced pressure, and separated by column chromatography to obtain the intermediate in 55% yield. Its structure and characterization data are as follows:

[0021] 3-(fluoromethyl)-3-hydroxyindolin-2-one(2)

[0022]

[0023] 1 H NMR (400MHz, DMSO-d6): δ10.43(s,1H),7.36(d,J=7.3Hz,1H),7.26(td,J=7.7,1.3Hz,1H),7.00(td,J=7.5, 1.0Hz,1H),6.84(d,J=7.7Hz,1H),6.43(s,1H),4.59(dd,J=22.0,8.7Hz,1H),4.48(dd,J=21.6,8.8Hz,1H). 13 C{1H}NMR (101MHz, Acetone-d6): δ176.5(d,J=10.6Hz), 142.5(d,J=12.4Hz), 129.9,128.9(d ,J=3.3Hz),124.9,122.1,109.9(d,J=4.7Hz),84.6(d,J=175.3Hz),74.5(dd,J=22.0,7.9Hz). 19 F NMR(376MHz,DMSO-d6):δ-222.92-239.32(m,1F).HRMS(ESI):m / z calcd.For C9H8FNNaO2[M+Na] + 204.0437, found 204.0433.

[0024] Example 3: 2 mmol of anthraquinone, 4 mmol of sodium monofluorosulfinate, 30.04 mmol of fac-Ir(py), and 3 mmol of cesium carbonate were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of DMF was added, and the reaction was carried out under an LED blue lamp for 12 hours. After the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried in an Erlenmeyer flask with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography. The product was obtained with a yield of 98%. Its structure and characterization data are as follows: 10-(fluoromethyl)-10-hydroxyanthracen-9(10H)-one(3)

[0025]

[0026] 1 H NMR (400MHz, CDCl3): δ8.21(dd,J=7.8,1.4Hz,2H),7.94(d,J=7.7Hz,2H),7.69(td,J =7.6,1.5Hz,2H),7.53(td,J=7.6,1.2Hz,2H),4.38(s,1H),4.26(s,1H),3.09(s,1H). 13 C{1H}NMR (101MHz, CDCl3): δ 183.2, 142.8 (d, J = 2.1Hz), 133.6, 130.9, 129.0, 127.4, 126.7 (d, J = 1.8Hz), 90.3 (d, J = 188.5Hz), 71.8 (d, J = 19.0Hz). 19 F NMR (376MHz, CDCl3): δ-216.50 (t, J=47.4Hz, 1F). HRMS (ESI): m / z calcd.For C 15 H 12 FO2[M+H] + 243.0821, found 243.0825.

[0027] Example 4: 2 mmol of N-methylphthalimide, 4 mmol of sodium monofluoromethyl sulfinate, and 0.04 mmol of eosin Y were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of DMSO and 3 mmol of pyridine were added, and the reaction was carried out under an LED blue lamp for 8 hours. After the reaction was completed, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, poured into an Erlenmeyer flask, dried over anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporation, and separated by column chromatography. The product was obtained in 85% yield. Its structure and characterization data are as follows:

[0028] 3-(fluoromethyl)-3-hydroxy-2-methylisoindolin-1-one(4)

[0029]

[0030] 1 H NMR (400MHz, CDCl3): δ7.63-7.59(m,2H),7.54(d,J=7.5Hz,1H),7.49-7.39(m,1H),4. 69(dd,J=33.6,12.8Hz,1H),4.58(dd,J=34.5Hz,12.8Hz,1H),4.32(s,1H)2.81(s,3H). 13 C{1H}NMR (101MHz, CDCl3): δ167.8, 143.9, 132.5, 131.3, 130.2, 123.3, 122.3, 87.9 (d, J = 22.0Hz), 82.2 (d, J = 179.6Hz), 23.8. 19 F NMR (376MHz, CDCl3): δ-228.56 (t, J=47.1Hz, 1F). HRMS (ESI): m / z calcd.For C 10 H 10 FNNaO2[M+Na] + 218.0593, found 218.0598.

[0031] Example 5: 2 mmol of acenaphthyl quinone, 4 mmol of sodium monofluoromethyl sulfinate, and 0.04 mmol of fluorescein were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of acetone and 3 mmol of pyridine were added, and the reaction was carried out under an LED blue lamp for 18 hours. After the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, poured into an Erlenmeyer flask, dried with anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporation, and separated by column chromatography. The product was obtained with a yield of 76%. Its structure and characterization data are as follows: 2-(fluoromethyl)-2-hydroxyacenaphthylen-1(2H)-one(5)

[0032]

[0033] 1H NMR (400MHz, CDCl3): δ8.18-8.12(m,1H),7.99(ddd,J=18.4,7.4,1.1Hz,2H ),7.86-7.65(m,3H),4.87-4.72(m,1H),4.65(q,J=9.5Hz,1H),3.37(s,1H). 13 C{1H}NMR(101MHz, CDCl3): δ202.3(d,J=2.9Hz),142.1,135.9(d,J=2.4Hz),132.4,130 .8,130.5,128.8,128.6,126.3,122.7,121.5,84.9(d,J=179.9Hz),78.7(d,J=20.1Hz). 19 F NMR (376MHz, CDCl3): δ-229.23 (t, J=47.9Hz, 1F). HRMS (ESI): m / z calcd.For C 13 H9FNaO2[M+Na] + 239.0484, found 239.0478.

[0034] Example 6: 2 mmol of N-(4-chlorophenyl)-α-hydroxyphenylacetamide, 4 mmol of sodium monofluoromethyl sulfinate, 0.04 mmol of Ru(bpy)3Cl2·6H2O, and 3 mmol of sodium carbonate were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of toluene was added, and the reaction was carried out under an LED blue lamp for 30 hours. After the reaction was completed, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, poured into an Erlenmeyer flask, dried over anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporation, and separated by column chromatography. The product was obtained in 77% yield. Its structure and characterization data are as follows:

[0035] N-(4-chlorophenyl)-3-fluoro-2-hydroxy-2-phenylpropanamide(6)

[0036]

[0037] 1 H NMR (400MHz, CDCl3): δ8.56(s,1H),7.66(dd,J=8.1,1.5Hz,2H),7.51-7.44(m,2H),7.43-7.33(m ,3H),7.29-7.21(m,2H),5.25(dd,J=45.8,9.3Hz,1H),4.53(dd,J=48.4,9.4Hz,1H),3.84(s,1H).13 C{1H}NMR (101MHz, CDCl3): δ169.3(d,J=2.5Hz), 136.2(d,J=5.2Hz), 135.6,129 .8,129.0,129.0,128.8,125.3,121.0,86.5(d,J=176.2Hz),78.9(d,J=19.6Hz). 19 FNMR (376MHz, CDCl3): δ-224.04 (t, J=46.9Hz, 1F).HRMS (ESI): m / zcalcd.For C 15 H 13 ClFNNaO2[M+Na] + 316.0517, found 316.0518.

[0038] Example 7: 2 mmol of ethyl 4-chlorobenzoylformate, 4 mmol of sodium monofluoromethyl sulfinate, 0.04 mmol of fluorescein, and 3 mmol of potassium carbonate were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of NMP was added, and the reaction was carried out under an LED blue lamp for 15 hours. After the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, poured into an Erlenmeyer flask, dried over anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporation, and separated by column chromatography. The product was obtained in 33% yield. Its structure and characterization data are as follows:

[0039] ethyl 2-(4-chlorophenyl)-3-fluoro-2-hydroxypropanoate(7)

[0040]

[0041] 1 H NMR (400MHz, CDCl3): δ7.59(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,2H),4.95(dd,J=46.0,9.3Hz,1H),4.57-4.24(m,3H),3.98(s,1H),1.33(t,J=7.1Hz,3H). 13 C{1H}NMR (101MHz, CDCl3): δ171.8(d,J=2.9Hz),134.9,134.8(d,J=6.6Hz),128.8,127.2,86.7(d,J=180.9Hz),77.9(d,J=19.0Hz),63.4,14.1. 19F NMR (376MHz, CDCl3): δ-223.41 (t, J=46.8Hz, 1F). HRMS (ESI): m / z calcd.For C 11 H 12 O3FNaCl[M+Na] + 269.0357, found 269.0349.

[0042] Example 8: 2 mmol of 9-fluorenone, 4 mmol of sodium monofluoromethyl sulfinate, 30.04 mmol of fac-Ir(py), and 3 mmol of potassium bicarbonate were weighed and added to a Schlenk tube. The tube was evacuated and purged with argon (repeated three times). 10 ml of DMF was added, and the reaction was carried out under an LED blue light for 15 hours. After the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, poured into an Erlenmeyer flask, dried with anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporation, and separated by column chromatography. The product was obtained with a yield of 83%. Its structure and characterization data are as follows: 9-(fluoromethyl)-9H-fluoren-9-ol(8)

[0043]

[0044] 1 H NMR (400MHz, CDCl3): δ7.66-7.63(m,2H),7.60(d,J=7.2Hz,2H),7.43-7.38(m,2H).7.34-7.30(m,2H),4.57(d,J=47.7Hz,2H),2.61(s,1H). 13 C{1H}NMR (101MHz, CDCl3): δ144.7(d,J=3.6Hz), 139.8,129.8,128.1,124.7(d,J=1.5Hz), 120.3,87.4(d,J=181.3Hz), 81.0(d,J=18.3Hz). 19 F NMR (376MHz, CDCl3): δ-223.69 (t, J=48.0Hz, 1F). HRMS (ESI): m / zcalcd.For C 14 H 12 FO[M+H] + 215.0872, found 215.0869.

[0045] Those skilled in the art will recognize that various modifications, variations, and combinations can be made to the above embodiments without departing from the scope of protection of the present invention, and such modifications, variations, and combinations are considered to be within the scope of originality.

Claims

1. A method for synthesizing α-monofluoromethylaryl alcohol, wherein a ketone compound or amide compound is used as raw material 1, a monofluoromethyl reagent and a suitable photocatalyst are added, and a base is used as an additive. In a suitable solvent, the mixture is irradiated with blue light from an LED of a certain power for a certain period of time, resulting in a monofluoromethyl radical addition reaction to obtain α-monofluoromethylaryl alcohol. The specific reaction formula is as follows (Formula 1): Where R1 = substituted benzene ring, heterocycle, alkane, and R2 = substituted benzoyl group, substituted benzene ring, substituted heterocycle, alkyl group, aromatic amine, alkyl amine, ester group.

2. The synthesis method according to claim 1, characterized in that, The monofluoromethyl reagent described in Formula 1 is selected from sodium monofluoromethyl sulfinate, 2-fluoromethyl sulfone benzothiazole, and 2-fluoromethyl sulfone pyridine.

3. The synthesis method according to claim 1, characterized in that, The photocatalyst described in Formula 1 is selected from eosin Y, fac-Ir(py)3, fluorescein, 10-methyl-9-trimethylammonium acridine perchlorate, and Ru(bpy)3Cl2·6H2O.

4. The synthesis method according to claim 1, characterized in that, The additives described in Formula 1 are selected from triethylamine, pyridine, sodium carbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate.

5. The synthesis method according to claim 1, characterized in that, The solvent of Formula 1 is selected from DMSO, DMF, acetone, toluene, NMP, DCE, and ethanol.

6. The synthesis method according to claim 1, characterized in that, The power of the blue-emitting LED described in Formula 1 is 6-60W.

7. The synthesis method according to claim 1, characterized in that, The light irradiation time for Formula 1 is 6-48 hours.

Images