CN102675015A - Decarboxylation and fluorination method for carboxylic acid - Google Patents

Abstract

The invention relates to a method for decarboxylation and fluorination of carboxylic acid, which is a method for obtaining RF by reacting fatty acid RCOOH, monovalent silver salt catalyst and fluorinating reagent Selectfluor or its hexafluorophosphate derivative in a solvent at room temperature to 80°C ; Using the method of the present invention, the carboxylic acid is efficiently converted into the corresponding decarboxylated fluorinated product in the aqueous phase. The reaction conditions are mild, the operation is very easy, and it has good chemoselectivity and functional group compatibility. It is a very practical method for the synthesis of sp ³ carbon-fluorine bonds.

Description

A method for the decarboxylation and fluorination of carboxylic acids

technical field

The invention relates to the field of fluorine organic compounds, and furthermore relates to a new method for decarboxylation and fluorination of carboxylic acid.

Background technique

The introduction of fluorine atoms into organic compounds can change the physical, chemical and biological properties of molecules, so fluorine-containing organic compounds have very important uses in the fields of medicine, pesticides and materials [1.K.Müller, C.Faeh, F.Diederich, Science 317, 1881–1886(2007); 2.D.O'Hagan, Chem.Soc.Rev.37, 308–319(2008); 3.S.Purser, PRMoore, S.Swallow, V.Gouverneur, Chem.Soc . Rev. 37, 320–330 (2008); 4. KL Kirk, Org. Process Res. Dev. 12, 305–321 (2008).]. Nearly 25% of drugs currently on the market contain at least one fluorine atom, and nearly 30% of pesticides contain fluorine atoms. In addition, ¹⁸ F-labeled molecules have important clinical applications [5. PW Miller, NJ Long, R. Vilar, ADGee, Angew. Chem., Int. Ed. 47, 8998-9033 (2008); 6. T. Furuya, CA, Kuttruff, T. Ritter, Curr. Opin. Drug Discuv. Dev. 11, 803–819 (2008).].

However, only 13 naturally occurring fluorine-containing organic compounds have been discovered so far. Most of the fluorine-containing organic compounds need to be synthesized artificially. Therefore, the formation of carbon-fluorine bonds has become an important research direction in organic synthesis. In recent years, remarkable research results have been obtained on the formation of sp ² carbon-fluorine bonds [7.VVGrushin, Acc.Chem.Res.43, 160-171 (2010); 8.T.Furuya, JEMNKlein, T.Ritter, Synthesis 1804-1821(2010);9.T.Furuya,AS Kamlet,T.Ritter,Nature 473,470-477(2011);10.DA Watson,M.Su,G.Teverovskiy,Y.Zhang,J.García-Fortanet, T. Kinzel, SL Buchwald, Science 325, 1661–1664 (2009); 11. P. Tang, T. Furuya, T. Ritter, J. Am. Chem. Soc. 132, 12150–12154 (2010); 12. E .Lee, ASKamlet, DCPowers, CNNeumann, GBBoursalian, T.Furuya, DCChoi, JMHooker, T.Ritter, Science 334,639-642(2011).], however, progress in the formation of sp ³ carbon-fluorine bonds is slow.

1. At present, there are two main methods for the formation of sp ³ carbon-fluorine bonds: nucleophilic fluorination and electrophilic fluorination. In terms of nucleophilic fluorination, due to the weak nucleophilicity and strong solvation effect of fluorine anions, the substitution reaction using fluoride ions directly as nucleophiles has low efficiency and narrow applicability [13.S.Young, J .Chem.Soc.39,489-497(1881);14.DWKim, CESong,DYChi,J.Am.Chem.Soc.124,10278–10279(2002);15.K.-Y.Kim,BCKim,HBLee, H. Shin, J. Org. Chem. 73, 8106–8108 (2008).]. The more common nucleophilic fluorinated reagents are DAST (diethylaminosulfur trifluoride) and its analogues, which can convert alcohols into fluorinated products, but these reagents are highly toxic, inconvenient to operate, and often accompanied by elimination, heavy Occurrence of side reactions such as row [16.K.-Y.Kim, BCKim, HBLee, H.Shin, J.Org.Chem.73, 8106–8108 (2008); 17.WJMiddleton, J.Org.Chem.40, 574 –578(1975).]. In terms of electrophilic fluorination, it is mainly the reaction of electrophilic fluorinated reagents with carbanions. The commonly used electrophilic fluorinated reagents mainly include NFSI (N, N-diphenylsulfonyl ammonium fluoride) and Selectfluor (1-chloromethyl yl-4-fluorodiazabicyclo[2,2,2]octane bistetrafluoroborate) and its analogues. However, this type of method is generally only suitable for the synthesis of ortho-fluorinated carbonyl compounds [18.RPSingh, JMShreeve, Synthesis 2561-2578 (2002); 19.RPSingh, JMShreeve, Acc.Chem.Res.37,31-44 (2004 ); 20. PTNyffeler, SG Durón, MD Burkart, SP Vincent, C.-H. Wong, Angew. Chem., Int. Ed. 44, 192–212 (2005); 21 Y. Hamashima, M. Sodeoka, Synlett 1467–1478 (2006) ; 22. V. Rauniyar, ADLackner, GL Hamilton, FDToste, Science 334, 1681–1684 (2011).].

2. In contrast, the third method of forming sp ³ carbon-fluorine bonds - free radical fluorination has little research, and its application value in organic synthesis has not been reflected. Existing literature reports mainly use _F2 [23.V.Grakauskas, J.Org.Chem.34, 2446–2450 (1969)] or _XeF2 [24.TBPatrick, KKJohri, DHWhite, J.Org.Chem. 48, 4158–4159 (1983); 25.TB Patrick, KK Johri, DH White, WS Bertrand, R. Mokhtar, MRKilbourn, MJ Welch, Can. J. Chem. 64, 138–141 (1986); 26.TB Patrick, S.Khazaeli, S. Nadji, K.Hering-Smith, D.Reif, J.Org.Chem.58,705-708(1993).] carry out decarboxylation and fluorination of carboxylic acids, but these reactions are inefficient, and both reagents are highly toxic and inconvenient to operate . Recently, it has been reported that tert-butyl peracid reacts with NFSI to generate corresponding decarboxylated fluorinated products [27.TBPatrick, S.Khazaeli, S.Nadji, K.Hering-Smith, D.Reif, J.Org.Chem.58,705 -708(1993).]. However, this method must first prepare tert-butyl peracid from carboxylic acid, and the reaction efficiency is low. In addition, since the generation of alkyl radicals is accompanied by the generation of more active tert-butoxy radicals, the reaction has relatively large limitations. Therefore, it is very necessary to develop an efficient and universal method for decarboxylation and fluorination.

The patent of the present invention reports a brand-new decarboxylation fluorination method, using monovalent silver salt as a catalyst, 1-chloromethyl-4-fluorodiazabicyclo[2,2,2]octane bistetrafluoroborate ( Selectfluor) is a fluorinating reagent that efficiently converts carboxylic acids into the corresponding decarboxylated fluorinated products in aqueous phase. The reaction conditions are mild, the operation is very easy, and it has good chemoselectivity and functional group compatibility. It is a very practical method for the synthesis of sp ³ carbon-fluorine bonds.

Contents of the invention

The problem to be solved by the present invention is to provide a new method for decarboxylation and fluorination of carboxylic acid.

Reaction formula of the present invention is as follows:

Carboxylic acid: A variety of fatty acids with or without functional groups.

Silver salts: silver nitrate, silver tetrafluoroborate, silver trifluoromethanesulfonate, silver acetate, etc.

Solvent: water, water/acetone, water/acetonitrile, water/dichloromethane, etc.

Fluorinating agent: Selectfluor or its hexafluorophosphate analog

Reaction 1

In the method of the present invention, applicable R is C1～C100 hydrocarbon group, preferably C1～C20 hydrocarbon group, and described carboxylic acid comprises various primary carbon, secondary carbon and tertiary carbon carboxylic acid, and R can contain one to Three substituents as follows: carbonyl, phenyl, C2-C10 ester group, C1-C10 alkoxy group, amido group, cyano group, carboxyl group, halogenated phenyl group, C5-C7 cycloalkyl group, halogenated phenoxy group Base, phenylcarbonyl, tetrahydropyrrole-2,5-diketonyl, phthalimide, halogenated benzoyl, halogen, phenyl substituted C1~4 alkyl, adamantyl, containing N five-membered or six-membered heterocyclic rings, or N-containing five-membered or six-membered heterocyclic rings with benzo, C1~6 hydrocarbon groups, halogenated, C2~C10 ester groups, C1~C10 alkoxy groups, etc.

In another preferred example, R is selected from C1-C20 alkyl, C1-C20 substituted alkyl, adamantyl, C5-C20 substituted cycloalkyl, C6-C20 substituted piperidinyl , or C6-C20 substituted hexahydropiperidinyl, etc. The alkyl group can be primary carbon, secondary carbon or tertiary carbon alkyl. The substituents of the substituted alkyl group, substituted cycloalkyl group, substituted piperidinyl group and substituted hexahydropiperidinyl group are as mentioned above, especially preferably one to three of the following substituent groups: C1～ C10 alkyl, C5-C7 cycloalkyl, halogenated phenyl, halogenated phenoxy, C2-C10 ester, phenylcarbonyl, tetrahydropyrrole-2,5-diketonyl, phthaloyl imino group, halobenzoyl group or halogen, etc. RF such as 1-fluoroheptadecane, 3-fluoropentadecane, 1,3-dicyclohexyl-2-fluoropropane, 1-fluoro-1-octylcyclopentane, 1,3-di(4-chloro Phenyl)-2-fluoropropane, 2-fluoro-2-methyldodecane, 1-fluoro-1-octylcyclohexane, 1,3-acetoxy-2-fluoro-2-methylpropane , 4-fluoro-4-methylpentanoic acid cyclohexyl ester, 4-fluoro-1-phenyl-1-hexanone, (2-fluorocyclohexyl) phenyl ketone, (4-fluoro-4-methyl- 1-piperidinyl)phenylmethanone, 1-(2-fluoropropyl)tetrahydropyrrole-2,5-dione, 1-(1-fluoro2-phenylethyl)tetrahydropyrrole-2, 5-Diketone, 2-(fluorobutyl)benzene, N-((4-fluorocyclohexyl)methyl)phthalimide, 4-fluoro-N-(4-chlorobenzoyl)hexa Hydropiperidine, 1-fluorotridecane, 1-bromo-10-fluorodecane, N-(5-fluoropentyl)phthalimide, 1-fluoroadamantane, 1-chloro-4- (fluoromethoxy)benzene, N-(fluoromethyl)phthalimide, etc.

The molar ratio of the fatty acid, the monovalent silver salt catalyst and the fluorinating reagent is 1:0.1-0.5:1-5. It is recommended to be 1:0.1~0.2:1~2.

The monovalent silver salts used are catalytic amounts, and can be silver nitrate, silver tetrafluoroborate or silver trifluoromethanesulfonate, etc.

The reaction solvent can be pure water or a mixed solvent of water and organic solvent, such as water-acetone, water-acetonitrile, water-dichloromethane or water-1,2-dichloroethane, etc.

The fluorinating reagent can be Selectfluor or its hexafluorophosphate derivative.

The reaction is generally carried out between room temperature and reflux temperature, and the reaction time is 1 to 20 hours.

(2) Typical reaction example

Using silver nitrate as the catalyst and Selectfluor as the fluorinated reagent, typical reaction examples are shown in Table 1 and Table 2. It can be seen that the fluorination reaction has very good functional group compatibility, and can effectively decarboxylate and fluorinate primary, secondary and tertiary carbon carboxylic acids. However, aromatic carboxylic acids are inert under the above conditions. The activity of carboxylic acids decreases in the following order: tertiary carbon carboxylic acid>secondary carbon carboxylic acid>primary carbon carboxylic acid>>aromatic acid.

Table 1. Using acetone/water as a mixed solvent, the decarboxylation and fluorination reaction is catalyzed by silver nitrate

Among them, reflux means reflux temperature; rt means room temperature.

Table 2. Using water as solvent, decarboxylation and fluorination reaction under the catalyst of silver nitrate

(3) Reaction mechanism

It is speculated that the possible mechanism of the reaction is as follows: First, monovalent silver ions react with Selectfluor to generate trivalent silver fluoride F-Ag(III). radical, and then quickly remove CO ₂ to generate the corresponding alkyl radical, and F-Ag(III) becomes divalent silver fluoride F-Ag(II) after gaining an electron, and finally, F-Ag(II) Then carry out fluorine atom transfer with alkyl radicals, so as to obtain the final product R-F, and regenerate monovalent silver ions at the same time, as shown in reaction formula 2.

Equation 2. Possible mechanism of the reaction

Detailed ways

The following examples will help to understand the present invention, but the content of the present invention cannot be limited.

Example 1

Synthesis of 3-fluoropentadecane (1a)

2-Ethyltetradecanoic acid (A-1a, 51.2 mg, 0.20 mmol), AgNO ₃ (6.8 mg, 0.04 mmol) and Selectfluor (141.6 mg, 0.4 mmol) were sequentially added into the reaction tube under nitrogen atmosphere. Then 2 ml each of acetone and water were added. The reaction solution was refluxed for 10 hours with stirring. The system was cooled to room temperature, and then extracted with dichloromethane (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtrate, concentrate the filtrate, and purify the crude product by silica gel column chromatography with hexane as the eluent to obtain the product 3-fluoropentadecane as a colorless liquid. Yield: 42.7 mg (93%). IR (neat): ν(cm ^-1 )2926,2855,1465; ¹ H NMR(400MHz, CDCl ₃ )δ0.88(3H,t,J=7.2Hz),0.96(3H,t,J=7.6Hz),1.26-1.69 (24H,m),4.29-4.49(1H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ9.4(d,J=5.9Hz),14.1,22.7,25.2(d,J=4.4Hz), ¹⁹ F NMR ( 282MHz,CDCl ₃ )δ-181.6(1F,m);EIMS:m/z(rel intensity)210(M-HF,7),182(5),152(8),111(49),97(89 ), 83(85), 69(100), 57(77), 43(73); HRMS calculated value (calcd for) C ₁₅ H ₃₁ F: 230.2410, found value (found) 230.2414.

Example 2

Synthesis of 1,3-dicyclohexyl-2-fluoropropane (1b)

The method is the same as that of 1a, and the reaction time is 10 hours. It is yellow oily liquid. Yellow oil.IR(neat):ν(cm ^-1 )2923,1558,1275,1261,764,750; ¹ H NMR(400MHz,CDCl ₃ )δ0.74-1.76(26H,m),4.52-4.75(1H, m); ¹³ C NMR(100MHz,CDCl ₃ )δ25.2,25.3,25.5,31.9,33.0,33.1(d,J=3.7Hz),42.5(d,J=20.5Hz),89.4(d,J= 164.8Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-177.2(1F,m);EIMS:m/z(rel intensity)206(M-HF,10),178(2),135(8), 110(22), 96(45), 82(100), 67(33), 55(62), 41(24); HRMS calculated value (calcd for) C ₁₅ H ₂₆ (M-HF): 206.2035, measured Value (found) 206.2032.

Example 3

Synthesis of 1,3-bis(4-chlorophenyl)-2-fluoropropane (1c)

The method is the same as that of 1a, and the reaction time is 10 hours. It is yellow oily liquid. IR(neat):ν(cm ^-1 )2925,1492,1275,1261,1091,1016,805,764,750; ¹ H NMR(400MHz,CDCl ₃ )δ2.73-2.89(4H,m),4.66-4.84(1H ,m)7.06(4H,d,J=8.4Hz),7.20(4H,d,J=8.4Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ40.3(d,J=21.2Hz),94.0( d,J=174.3Hz),128.7,130.8,132.7,135.3(d,J=3.6Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-178.6(1F,m);EIMS:m/z(rel intensity )282(M ⁺ ,27),254(4),227(3),192(2),157(17),125(100),101(11),91(14),75(7),51 (3); HRMS calculated value (calcd for) C ₁₅ H ₁₃ Cl ₂ F: 282.0378, found value (found) 282.0380.

Example 4

Synthesis of 4-fluoro-1-phenyl-1-hexanone (1d)

The method is the same as that of 1a, and the reaction time is 10 hours. It is yellow oily liquid. IR(neat):ν(cm ^-1 )2989,2936,1809,1556,1484,1452,1389,1354,1193,1042,777,712; ¹ H NMR(400MHz,CDCl ₃ )δ1.31(3H,dd, J=23.6,6.0Hz),1.88-2.10(2H,m),2.98-3.14(2H,m),4.57-4.79(1H,m),7.38(2H,t,J=7.6Hz),7.48(1H ,t,J=7.6Hz),7.89(2H,d,J=7.2Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ21.1(d,J=22.6Hz),31.1(d,J=20.4Hz ),33.9(d,J=3.0Hz),90.3(d,J=164Hz),128.0,128.6,133.1,136.9,199.4; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-175.5(1F,m);EIMS :m/z(rel intensity)180(M ⁺ ,2),160(1),120(34),105(100),91(1),77(32),51(6),47(2) ; HRMS calculated value (calcd for) C ₁₁ H ₁₃ FO: 180.0950, found value (found) 180.0947.

Example 5

Synthesis of 2-(fluorobutyl)benzene (1e)

The method is the same as that of 1a, and the reaction time is 10 hours. Appears as colorless liquid. ¹ H NMR (400MHz, CDCl ₃ ) δ1.00(3H,t,J=7.2Hz),1.53-1.71(2H,m),2.81-3.01(2H,m),4.53-4.70(1H,m), 7.21-7.32(5H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ9.35(d,J=5.9Hz),27.7(d,J=21.1Hz),41.2(d,J=21.9Hz), 95.7(d,J=170.6Hz),126.5,128.4,129.4,137.5; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-180.2(1F,m).

Example 6

Synthesis of N-((4-fluorocyclohexyl)methyl)phthalimide (1f)

The method is the same as that of 1a, and the reaction time is 10 hours. The compound is a mixture of cis and trans isomers (trans:cis=1:2.4). White solid. Mp 104-106℃;IR(KBr):ν(cm ^-1 )2933,1772,1712,1466,1433,1398,1275,1261,1139,1051,948,764,750,721; ¹ H NMR(400MHz,CDCl ₃ )(mixture of twostereoisomers) δ1.30-1.50(5H,m),1.71-1.80(2H,m),1.92-2.04(2H,m),3.46-3.52(2H,m),4.30-4.50(0.3H,m) ,4.71(0.7H,d,J=48.4Hz),7.63-7.66(2H,m),7.74-7.78(2H,m); ¹³ CNMR(100MHz,CDCl ₃ )δ24.6,27.8(d,J= ¹⁹ F NMR ( 282MHz,CDCl ₃ )δ-170.8/-184.5(1F,m);EIMS:m/z(rel intensity)262(M ⁺ +1,31),241(1),200(1),160(100) , 148(26), 130(14), 104(15), 77(17), 50(4); HRMS calculated value (calcdfor) C ₁₅ H ₁₆ FNO ₂ : 261.1165, found value (found) 261.1166.

Example 7

Synthesis of (2-fluorocyclohexyl)phenyl ketone (1 g)

The method is the same as that of 1a, and the reaction time is 10 hours. The product 1g consists of 1:1 cis-trans isomers. Among them, cis-isomer: white solid. Mp 80-81℃; IR(KBr):ν(cm ^-1 )2939,1685,1447,1275,1260,764,750; ¹ H NMR(400MHz,CDCl ₃ )δ1.25-1.99(7H,m),2.20 -2.36(1H,m),3.53-3.59(1H,m),4.83-5.02(1H,m),7.47(2H,t,J=7.6Hz),7.57(1H,t,J=7.2Hz), 7.98(2H,d,J=7.2Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ23.7(d,J=10.9Hz),24.6,29.0(d,J=8.0Hz),31.8(d,J =17.5Hz),50.8(d,J=18.9Hz),92.4(d,J=172.1Hz),128.4,128.6,133.1,136.9,201.3; ¹⁹ FNMR(282MHz,CDCl ₃ )δ-171.3(1F,m );EIMS:m/z(rel intensity)206(M ⁺ ,7),186(2),149(1),105(100),82(27),77(40),67(14),51 (9); HRMS calculated value (calcd for) C ₁₃ H ₁₅ FO: 206.1107, found value (found) 206.1111. Trans isomer: White solid. Mp 103-104°C; IR(KBr):ν(cm ^{- 1} )2939,2865,1685,1447,1275,1260,764,750; ¹ H NMR(400MHz,CDCl ₃ )δ1.26-2.14(8H,m),3.25-3.42(1H,m),4.96-5.13(1H ,m),7.39(2H,t,J=8.0Hz),7.48(1H,t,J=7.6Hz),7.79(2H,d,J=7.2Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ20 .0,22.2,24.3,31.0(d,J=21.1Hz),48.8(d,J=21.1Hz),89.2(d,J=175Hz),128.2,128.7,132.8,136.4,200.2; ¹⁹ F NMR( 282MHz,CDCl ₃ )δ-193.8(1F,m);EIMS:m/z(rel intensity)206(M ⁺ ,3),186(4),151(1),133(1),105(100) , 77(38), 67(17), 51(8); HRMS calculation Value (calcd for) C ₁₃ H ₁₅ FO: 206.1107, measured value (found) 206.1111.

Example 8

Synthesis of 4-fluoro-N-(4-chlorobenzoyl)hexahydropiperidine (1h)

N-(4-chlorobenzoyl) hexahydropiperidine-4-acid (A-1h, 53.4mg, 0.20mmol), AgNO ₃ (6.8mg, 0.04mmol) and Selectfluor (141.6mg, 0.4 mmol) into the reaction tube in turn. Then 2 ml each of acetone and water were added. The reaction solution was stirred at 45°C for 10 hours. The system was cooled to room temperature, and then extracted with dichloromethane (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtrate, concentrate the filtrate, and purify the crude product by silica gel column chromatography, the eluent is ethyl acetate/hexane (1:10, v:v) to obtain the product 4-fluoro-N-(4-chlorobenzoyl) Hexahydropiperidine, yellow liquid, yield: 28.8mg(60%).Yellow oil.IR(neat):ν(cm ^-1 )1637,1436,1364,1092,1016,799; ¹ H NMR (400MHz ,CDCl ₃ )δ1.68-2.07(4H,m),3.29-3.72(3H,m),3.89-4.14(1H,m),4.81-5.01(1H,m),7.35(2H,d,J= 8.8Hz),7.40(2H,d,J=8.8Hz); ¹³ CNMR(100MHz,CDCl ₃ )δ31.3,43.5,87.5(d,J=170.6Hz),128.4,128.8,134.2,135.9,169.4; ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-184.0 (1F, m); EIMS: m/z (rel intensity) 241 (M ⁺ , 19), 240 (49), 209 (7), 191 (10), 167(14), 139(100), 111(31), 91(7), 75(12); HRMS calculated value (calcd for) C ₁₂ H ₁₃ ClFNO: 241.0670, found value (found) 241.0671.

Example 9

Synthesis of 2-fluoro-2-methyldodecane (1i)

2,2-Dimethyldodecanoic acid (A-1i, 45.6 mg, 0.20 mmol), AgNO ₃ (6.8 mg, 0.04 mmol) and Selectfluor (141.6 mg, 0.4 mmol) were sequentially added to the reaction tube under nitrogen atmosphere . Then 2 ml each of acetone and water were added. The reaction solution was stirred at room temperature for 10 hours. It was then extracted with dichloromethane (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtrate, concentrate the filtrate, and purify the crude product by silica gel column chromatography with hexane as the eluent to obtain the product 2-fluoro-2-methyldodecane as a yellow liquid. Yield: 33.1mg (82%).Yellow oil.IR(neat):ν(cm ^-1 )2926,2855,1467,1384,1373,881,763,750; ¹ H NMR(400MHz,CDCl ₃ )δ0.81(3H,t,J=6.4Hz),1.10- 1.40(22H,m),1.47-1.56(2H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ14.1,22.6,22.7,24.0(d,J=5.1Hz),26.6(d,J=24.8 Hz),29.4,29.5,29.6,29.7,30.0,31.9,41.5(d,J=22.6Hz),95.8(d,J=162.6Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-137.4(1F, m);EIMS:m/z(rel intensity)182(M-HF,8),167(6),154(15),126(19),111(22),97(30),83(34) , 69(65), 56(100), 43(36); HRMS calculated value (calcd for) C ₁₃ H ₂₆ (M-HF): 182.2035, found value (found) 182.2031.

Example 10

Synthesis of 1-fluoro-1-octylcyclopentane (1j)

The method is the same as that of 1i. It is yellow oily liquid. IR(neat):ν(cm ^-1 )2927,2855,1466; ¹ H NMR(400MHz,CDCl ₃ )δ0.88(3H,t,J=7.2Hz),1.28-1.92(22H,m); ¹³ C NMR (100MHz, CDCl ₃ ) δ14.1, 22.7, 23.9, 24.5(d, J=3.7Hz), 29.3, 29.6, 30.1, 31.9, 37.5(d, J=24.0Hz), 38.6(d, J= 24.1Hz),107.3(d,J=171.4Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-143.1(1F,m);EIMS:m/z(rel intensity)180(M-HF,7), 152(4), 123(18), 109(12), 82(100), 67(74), 55(32), 41(32); HRMS calculated value (calcd for) for C ₁₃ H ₂₄ (M- HF): 180.1878, measured value (found) 180.1879.

Example 11

Synthesis of 1-fluoro-1-octylcyclohexane (1k)

The method is the same as that of 1i. It is yellow oily liquid. IR(neat):ν(cm ^-1 )2931,2855,1450; ¹ H NMR(400MHz,CDCl ₃ )δ0.88(3H,t,J=7.2Hz),1.20-1.63(22H,m),1.76 -1.82(2H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ14.1,22.1(d,J=2.9Hz),22.7,22.9(d,J=4.4Hz),25.5,29.3,29.6,30.1 ,31.9,35.1(d,J=22.6Hz),40.4(d,J=22.6Hz),96.0(d,J=168.4Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-155.9(1F,m) ;EIMS:m/z(rel intensity)194(M-HF,14),166(5),138(3),101(53),81(100),67(13),55(21),43 (10); HRMS calculated value (calcd for) C ₁₄ H ₂₆ (M-HF): 194.2035, found value (found) 194.2037.

Example 12

Synthesis of 4-fluoro-4-methylpentanoic acid cyclohexyl ester (1l)

The method is the same as that of 1i. It is yellow oily liquid. IR(neat):ν(cm ^-1 )2939,1732,1456,1387,1260,1174,1124,1016,750; ¹ H NMR(400MHz,CDCl ₃ )δ1.13-1.95(18H,m),2.34 (2H,t,J=8.0Hz),4.66-4.71(1H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ23.7,25.4,26.5(d,J=24.1Hz),29.4(d,J =4.4Hz),31.6,36.1(d,J=23.3Hz),72.6,94.6(d,J=165.5Hz),172.8; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-141.1(1F,m);EIMS :m/z(rel intensity)196(M-HF,1),171(1),143(2),115(100),97(90),82(45),69(57),55(31 ); HRMS calculated value (calcd for) C ₁₂ H ₂₀ O ₂ (M-HF): 196.1463, found value (found) 196.1460.

Example 13

Synthesis of (4-fluoro-4-methyl-1-piperidinyl)phenylmethanone (1m)

The method is the same as that of 1i. It is yellow oily liquid. IR(neat):ν(cm ^-1 )2922,1634,1444,1380,1278,1261,967,764,750; ¹ H NMR(400MHz,CDCl ₃ )δ1.40(3H,d,J=21.2Hz),1.53- 1.94(4H,m),3.09-3.60(3H,m),4.39-4.63(1H,m),7.39(5H,br); ¹³ C NMR(100MHz,CDCl ₃ )δ27.0(d,J=24.1 Hz),36.2,37.2,38.4,43.8,92.2(d,J=167.7Hz),126.9,128.5,129.7,136.1,170.5; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-154.2(1F,m);EIMS :m/z(rel intensity)221(M ⁺ ,30),220(70),200(5),160(3),134(1),105(100),77(43),51(9) ,42(4); HRMS calcd for C ₁₃ H ₁₆ FNO: 221.1216, Found 221.1212.

Example 14

Synthesis of 1,3-Acetoxy-2-fluoro-2-methylpropane (1n)

The method is the same as the synthesis of 1h. It is yellow oily liquid. IR(neat):ν(cm ^-1 )1747,1387,1275,1259,1053,902,764,750; ¹ H NMR(400MHz,CDCl ₃ )δ1.34(3H,d,J=21.6Hz),2.04(6H, s),4.06-4.20(4H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ19.4(d,J=22.6Hz),20.6,65.6(d,J=27.0Hz),93.0(d,J =174.3Hz),170.4; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-161.2(1F,m);EIMS:m/z(rel intensity)192(M ⁺ +1,1),181(1),130 (7), 112(3), 103(35), 73(6), 60(15), 43(100); HRMS calcd for C ₈ H ₁₃ FO ₄ : 192.0798, found 192.0802.

Example 15

Synthesis of 1-Fluoroheptadecane (1o) Synthesis

Octadecanoic acid (A-1o, 56.9 mg, 0.20 mmol), AgNO ₃ (6.8 mg, 0.04 mmol) and Selectfluor (283.2 mg, 0.8 mmol) were sequentially added into the reaction tube under nitrogen atmosphere. Then 2 ml of acetone and 0.5 ml of water were added. The reaction solution was refluxed for 10 hours with stirring. Then it was cooled to room temperature and extracted with dichloromethane (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtrate, concentrate the filtrate, and purify the crude product by silica gel column chromatography with hexane as the eluent to obtain the product 1-fluoroheptadecane as a yellow liquid. Yield: 28.9mg (56%).Yellow oil.IR(neat ):ν(cm ^-1 )2925,2854,1466,1261,1015,804,750; ¹ H NMR(400MHz,CDCl ₃ )δ0.88(3H,t,J=6.8Hz),1.18-1.73(30H,m ),4.43(2H,dt,J=47.2,6.4Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ14.1,22.7,25.1,25.2,29.2,29.3,29.4,29.5,29.6,29.7,29.8,30.3 ,30.5,31.9,35.2(d,J=20.5Hz),84.2(d,J=162.6Hz); ¹⁹ F NMR(282MHz,CDCl3)δ-215.5(1F,m);EIMS:m/z(relintensity) 258(M+,1),240(2),182(2),154(3),125(9),111(20),97(37),71(64),57(100); HRMS calculated value (calcd for) C ₁₇ H ₃₅ F: 258.2723, found value (found) 258.2720.

Example 16

Synthesis of 1-fluorotridecane (1p)

The method is the same as that of 1o. Appears as colorless liquid. ¹ H NMR (400MHz, CDCl ₃ )δ0.88(3H,t,J=6.4Hz),1.25-1.41(20H,m),1.63-1.74(2H,m),4.43(2H,dt,J=47.2 ,6.4Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ14.1,22.7,25.1(d,J=5.8Hz),29.3,29.4,29.5,29.56,29.64,29.7,30.4(d,J=20.7Hz ),31.9,84.2(d,J=163.3Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-218.4(1F,m).

Example 17

Synthesis of 1-bromo-10-fluorodecane (1q)

The method is the same as that of 1o, and the reaction time is 10 hours. It is a colorless oily liquid. ¹ H NMR(400MHz, CDCl ₃ )δ1.25-1.45(12H,m),1.63-1.75(2H,m),1.81-1.89(2H,m),3.40(2H,t,J=7.2Hz), 4.43(2H,dt,J=47.2,6.4Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ25.1(d,J=5.1Hz),28.2,28.7,29.2,29.3,29.4,30.4(d,J =20.7Hz),32.8,33.7,84.2(d,J=162.6Hz); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-218.5(1F,m).

Example 18

Synthesis of N-(5-fluoropentyl)phthalimide (1r)[28]

Under nitrogen atmosphere, N-(5-hydroxycarbonyl)phthalimide (A-1r, 52.2mg, 0.20mmol), AgNO ₃ (6.8mg, 0.04mmol), Selectfluor (141.6mg, 0.4 mmol) were sequentially added to the reaction tube. Then 2 ml of water was added to the reaction solution and stirred at 55°C for 10 hours. The system was cooled to room temperature, and then extracted with dichloromethane (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtrate, concentrate the filtrate, and purify the crude product by silica gel column chromatography. The eluent is hexyl acetate/petroleum ether to obtain the product N-(5-fluoropentyl)phthalimide as a colorless liquid. Rate: 37.6 mg (80%). ¹ H NMR(400MHz, CDCl ₃ )δ1.42-1.51(2H,m),1.67-1.82(4H,m),3.71(2H,t,J=7.2Hz),4.43(2H,dt,J=47.2 ,6.0Hz),7.70-7.72(2H,m),7.83-7.85(2H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ22.6(d,J=5.8Hz),28.2,29.9(d, J = 19.0 Hz), 37.8, 83.8 (d, J = 163.3 Hz), 123.2, 132.2, 133.9, 168.4; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ-218.8 (1 F, m).

Example 19

Synthesis of 1-(2-fluoropropyl)tetrahydropyrrole-2,5-dione (1s)

The method is the same as that of 1r, and the reaction time is 10 hours. It is a colorless oily liquid. IR(neat):ν(cm ^-1 )2959,2930,1702,1424,1403,1326,1260,1197,1122,1090,750; ¹ H NMR(400MHz,CDCl ₃ )δ1.30(3H,dd, J=23.6,6.4Hz),2.68(4H,s),3.38-3.50(1H,m),3.71-3.81(1H,m),4.70-4.90(1H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ18.6(J=21.1Hz),28.1,43.7(J=22.6Hz),87.0(J=169.9Hz),177.0; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-181.1(1F,m);ESI -MS: m/z 182 (M+Na). HRMS calculated value (calcd for) C ₇ H ₁₀ FNNaO ₂ (M+Na) 182.0588, found value (found) 182.0591.

Example 20

Synthesis of 1-fluoroadamantane (1t)

The method is the same as the synthesis of 1r. The reaction time is 3 hours. white solid. Mp 199-200℃(lit.200-204℃); ¹ HNMR(400MHz, CDCl ₃ )δ1.59-1.66(6H,m),1.88(6H,br),2.23(3H,br); ¹³ C NMR (100MHz, CDCl ₃ )δ31.5(d,J=9.5Hz),35.9,42.8(d,J=16.8Hz),92.5(d,J=180.8Hz); ¹⁹ FNMR(282MHz,CDCl ₃ )δ- 128.8(1F, s).

Example 21

Synthesis of 1-chloro-4-(fluoromethoxy)benzene (1u)

The method is the same as the synthesis of 1r. Reaction time 1 hour. Appears as colorless liquid. ¹ H NMR(400MHz, CDCl ₃ )δ5.60(2H,d,J=54.4Hz),6.94(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz); ¹³ C NMR (100MHz, CDCl ₃ )δ100.8(d,J=218.0Hz),118.1,128.7,129.7,155.4; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-145.2(1F,t,J=53.3Hz).

Example 22

Synthesis of N-(fluoromethyl)phthalimide (1v)

The method is the same as the synthesis of 1r. Reaction time 1 hour. white solid. Mp 93-94℃(lit.mp.93.5℃); ¹ HNMR(400MHz, CDCl ₃ )δ5.77(2H,d,J=52.0Hz),7.82(2H,dd,J=3.2,5.6Hz), 7.96(2H,dd,J=3.2,5.6Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ74.9(d,J=197.6Hz),124.2,131.7,134.9,166.5; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-174.5(1F,t,J=50.8Hz).

Example 23

Synthesis of 1-(1-fluoro2-phenylethyl)tetrahydropyrrole-2,5-dione (1w)

The method is the same as the synthesis of 1r. Reaction time 8 hours. white solid. Mp 115-117℃;IR(KBr):ν(cm ^-1 )1788,1712,1456,1386,1229,1170,1057,1039,974,860,819,731,697; ¹ H NMR(400MHz,CDCl ₃ )δ2.65(4H, s),3.49-3.74(2H,m),6.18(1H,dt,J=46.8,7.2Hz),7.20-7.32(5H,m); ¹³ C NMR(100MHz,CDCl ₃ )δ27.9,36.8( d,J=26.3Hz),90.7(d,J=203.4Hz),127.4,128.8,129.2,134.5(d,J=7.3Hz),175.7; ¹⁹ F NMR(282MHz,CDCl ₃ )δ-152.1(1F ,m);EIMS:m/z(rel intensity)201(M-HF,63),178(1),165(3),139(3),122(100),102(5),91(21 ), 74(6), 55(16); HRMS calculated value (calcd for) C ₁₂ H ₁₁ NO ₂ (M-HF): 201.0790, found value (found) 201.0787.

Claims (4)

1. carboxylic acid decarboxylation fluoric method, it is characterized in that in solvent with room temperature under reflux temperature, lipid acid RCOOH, the agent of monovalence silver catalyst and fluorination reagent reaction obtained RF in 1～20 hour;

Wherein, R be contain among C1～C100 alkyl, the R a kind of to three kinds of following substituting groups: carbonyl, phenyl, C2～C10 ester group, C1～C10 alkoxyl group; Carboxamido-group, cyanic acid, carboxyl, halogenophenyl; The naphthenic base of C5～C7, halogenated phenoxy, phenylcarbonyl group, Pyrrolidine-2; The 5-diketo, phthalimide-based, halogeno-benzene formyl radical, halogen; Phenyl replaces C1 ~ 4 alkyl, and adamantyl contains five yuan or the hexa-member heterocycle of N, perhaps has five yuan or the hexa-member heterocycle containing N of benzo base, C1 ~ 6 alkyl, halo, C2～C10 ester group, C1～C10 alkoxyl group;

The mol ratio of described lipid acid, the agent of monovalence silver catalyst and fluorination reagent is 1:0.1～0.5:1～5; Be recommended as 1:0.1～0.2:1～2;

Described monovalence silver salt is a Silver Nitrate, silver tetrafluoroborate or silver trifluoromethanesulfonate;

Described fluorination reagent is Selectfluor or its phosphofluoric acid salt derivative with following structural formula:

Described solvent is the mixed solvent of pure water or water and organic solvent composition.

2. a kind of carboxylic acid decarboxylation fluoric method as claimed in claim 1, the mol ratio that it is characterized in that described lipid acid, the agent of monovalence silver catalyst and fluorination reagent is 1:0.1～0.2:1～2.

3. a kind of carboxylic acid decarboxylation fluoric method as claimed in claim 1 is characterized in that described R is C1～C20 alkyl.

4. a kind of carboxylic acid decarboxylation fluoric method as claimed in claim 1 is characterized in that described organic solvent is acetone, acetonitrile, methylene dichloride or 1, the 2-ethylene dichloride.