RU2420515C2 - Method of producing 3,4,5-trifluoroaniline - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to an improved method of producing partially fluorinated aromatic amines, particularly 3,4,5-trifluoroaniline of formula: , which can be used in synthesis of biologically active compounds. The disclosed three-step process involves acylation of pentafluoroaniline on the amine group with a derivative of mono- or di- lower aliphatic or benzene carboxylic acid, reductive hydrodefluorination of the obtained acylpentafluoroaniline in the presence of a catalyst - a complex compound of nickel and/or cobalt with heterocyclic nitrogen-containing compounds or phosphorus-containing ligands, such as 2,2'-bipyridyl, 1,10- phenanthroline, alkyl- or arylphosphines, using ionic liquids as solvents, selected from a 1,3-dialkylimidazolinium salt of general formula: where: R1 and R2 are C1-C10 alkyl groups which can contain different substitutes, X is an inorganic or organic anion such as Cl-, Br-, BF4Çè-, OAc- at temperature 20-150C under the effect of a metal reducing agent, for example zinc or magnesium, in the presence of proton sources such as water, in a solvent medium while heating, with subsequent alkaline or acid hydrolysis of the reaction mixture. The ionic liquid used as the solvent can be recycled. ^ EFFECT: method shortens reaction time by increasing catalytic activity of the used catalyst while maintaining high output and quality of the obtained product. ^ 5 cl, 5 tbl, 38 ex

Description

The invention relates to methods for producing partially fluorinated aromatic amines containing at least one hydrogen atom in the ortho position to the amino group, of the general formula 1:

where X = F (1a) or H (1b), which can be used as starting materials in the synthesis of fluorinated heterocyclic compounds exhibiting a wide range of biological activity (LA Mitscher, Chem. Rev. 2005, vol. 105, pp.559-592 ) The use of incompletely fluorinated aromatic amines can reduce the number of stages in the preparation of fluoroquinolone series preparations (see, for example, A. Jackson, O. Meth-Cohn. J. Chem. Soc. - Chem. Commun. 1995, vol.13, p .1319) compared with other methods for the preparation of similar compounds (LA Mitscher, Chem. Rev. 2005, vol. 105, No. 2, pp.559-592).

A known method of producing polyfluorinated anilines of the general formula F _n C ₆ H _(5-n) NH ₂ , where n = 1 to 4, by reducing compounds of the type X _m F _n C ₆ H _(5-mn) NO ₂ , where X is an atom chlorine or bromine, m = 1 to 4, under the influence of hydrogen in the presence of a palladium catalyst, an amine insoluble in water and not forming water-soluble salts with hydrohalic acids, and, if necessary, an inert solvent (US 5498794, C07D 213/73, 12.03 .1999).

Also described is a method for the reduction of similar compounds with hydrogen in a solution containing a palladium, nickel or platinum catalyst (US 5856577, C07B 61/00, C07C 209/36, 01/05/1999).

The disadvantage of both of the described methods is the low availability of the starting compounds X _m F _n C ₆ H _(5-mn) NO ₂ .

The known method of non-catalytic hydrodefluorination of pentafluoroacetanilide (SS Laev, L. Yu. Gurskaya, GA Selivanova, IV Beregovaya, LN Shchegoleva, NV Vasil'eva, MM Shakirov, VD Shteingarts; Eur. J. Org. Chem., 2007, vol. 2, pp.306-316). The reaction is carried out under the influence of zinc in aqueous ammonia in the presence of stoichiometric amounts of salts of Zn (II) or Cu (II). The main disadvantage of this method is that the authors were unable to achieve hydrodefluorination of the substrate solely at the ortho positions to the acetanilide group. In addition, the formation of 3,4,5-trifluoroacetanilide, the precursor of compound 1b, was not detected.

Also described is a method for producing 3,4,5-trifluoroaniline 1b by the interaction of 1,3,4,5-tetrafluorobenzene with sodium amide in liquid ammonia at a temperature not higher than -33 ° C (A.A. Shtark, T.V. Chuykova, G .A. Selivanova, V.D. Shteingarts, Journal of Organ.Chemistry, 1987, v.23, p. 2574-2577). The disadvantages of this method are the low availability of the starting compound, the need for the reaction at low temperatures, and the need for disposal of liquid ammonia after the reaction.

The closest analogue to the proposed method for producing 3,4,5-trifluoroaniline 1b according to the achieved result is the method described in S.A. Prikhod'ko, N.Yu. Adonin, D.E. Babushkin and V.N. Parmon, Mendeleev Communications, 2008, v. 18, no. 4, pp. 211-212. This work describes the preparation of 2,3,4,5-tetrafluoroaniline and 3,4,5-trifluoroaniline by selective hydrodefluorination of pentafluoroacetanilide under the action of zinc in the presence of catalytic amounts of nickel complex compounds, followed by hydrolysis of the resulting products. The hydrodefluorination reaction is carried out in a mixture of water and an aprotic dipolar solvent (DMF).

The proposed method for producing compound 1b differs from the known one in that ionic liquids, such as 1,3-dialkylimidazolium salts, are used as a medium for the catalytic hydrodefluorination of pentafluoroaniline derivatives, which can significantly increase the catalytic activity of the system and thereby reduce the reaction time. In addition, it is possible to reuse ionic liquids to carry out the hydrodefluorination reaction.

In the proposed method, 3,4,5-trifluoroaniline 1b is obtained as a result of a three-stage process, including functionalization of pentafluoroaniline in the amino group, reductive hydrodefluorination of pentafluoroaniline derivatives (selective catalytic hydrogenolysis of CF bonds in the ortho-positions to the amino group) under the action of a reducing metal (zinc or magnesium) in the presence of a metal complex catalyst, such as nickel and / or cobalt compounds with heterocyclic nitrogen or phosphorus-containing ligands, such as 2,2'-bipyrid silt, 1,10-phenanthroline, alkyl or arylphosphines in ionic liquids such as 1,3-dialkylimidazolium salts, at a temperature of 20-150 ° C, preferably 35-85 ° C, in the presence of proton sources such as water, with a catalyst-substrate ratio of from 0.001 to 1 and a reducing agent-substrate of 1 to 15, followed by alkaline or acid hydrolysis of the reaction mixture to form the corresponding amine (Scheme 1). Moreover, at the stage of hydrodefluorination of the pentafluoroaniline derivative, multiple use of ionic liquids is possible.

The functionalization of pentafluoroaniline is carried out by known methods, namely by reaction with the corresponding anhydrides, acid chlorides or carboxylic acids. Selective catalytic hydrogenolysis of aromatic C-F bonds occurs under the influence of a reducing metal, which is zinc or magnesium, in the presence of catalytic amounts of complex compounds of nickel or cobalt, in the medium of ionic liquids, in the presence of proton sources. The reaction can be carried out at a temperature of from 20 to 150 ° C. The lower temperature limit is determined by the fact that at temperatures below 20 ° C the time required for the reaction to increase significantly. The upper limit is determined by the stability of the nickel complex. The optimum temperature for the reaction is between 35 and 85 ° C.

The substituents R ¹ and R ² may be:

1. Non-cyclic acyl substituents: R ¹ = H, R ² = —OC (O) R ³ , where R ³ is an alkyl group from C ₁ to C ₁₀ that may contain various substituents or unsaturated fragments, such as double or triple C -C bonds, or an aryl group; R ¹ = —OC (O) R ³ , R ² = —OC (O) R ³ , where R ³ is the substituent described previously.

2. Cyclic acyl substituents: (R ¹ R ² ) = (- C (O) - (CH ₂ ) _n -C (O) -), where n = from 1 to 10; (R ¹ R ² ) = (- C (O) -CH = CH-C (O) -); (R ¹ R ² ) = (- C (O) - (o-Ar) -C (O) -), where o-Ar is an o-phenylene, 1,2-naphthylidene or 2,3-naphthylidene group, which may contain various substituents at other positions of the aromatic ring.

ML _n - complex compounds of Nickel (II) or cobalt (II), used in the form of finished compounds or prepared in situ. As L ligands, nitrogen-containing compounds can be used, such as 2,2'-bipyridyl (Вру) or 1,10-phenanthroline (Phen), alkyl- or arylphosphines, bidentate phosphorus-containing ligands Ph ₂ P (CH ₂ ) _n PPh ₂ , where n = 1 to 4, or mixed bidentate ligands containing phosphorus and nitrogen. It is also possible to use complexes including nitrogen and phosphorus compounds as ligands.

Catalytic complexes can be obtained in situ from salts of nickel or cobalt and the corresponding ligand, or ready-made complex compounds can be used. The amount of the catalytic complex with respect to the substrate can be from 0.1 to 100% (in moles). The optimal amount of catalyst is from 1 to 5% (in moles). When using a smaller amount of catalyst, an unreasonably long time is required for the reaction to take place, and the upper limit of the load is determined for reasons of rational consumption of the catalyst.

As a reducing agent, zinc or magnesium is used in an amount of from 1 to 15 equivalents with respect to the substrate. The most acceptable is the use of a reducing agent in an amount of from 3 to 10 equivalents with respect to the substrate, since the use of a smaller amount sharply reduces the conversion of the substrate 2 to defluorinated products 3, and the use of a larger amount of reducing agent leads to an excessive consumption of reagent.

The reaction proceeds in an ionic liquid medium with a melting point not higher than the reaction temperature, such as salts of 1,3-dialkylimidazolium with inorganic or organic anions, of the general formula 4:

where R ¹ and R ² are alkyl groups from C ₁ to C ₁₀ that may contain various substituents, X ^- an inorganic or organic anion, such as Cl ^- , Br ^- , BF ₄ ^- , OAc ^- and others.

The optimum reaction temperature is from 35 to 85 ° C and is determined by the fact that at a lower temperature the time required for the reaction to increase, and at a temperature above 85 ° C the energy intensity of the process unreasonably increases.

As sources of protons, water, alcohol, and also some organic and inorganic acids can be used.

The hydrolysis of derivatives 3, as well as the isolation and purification of the target product 1b are carried out by known methods.

The non-obviousness of the proposed solution to the problem is illustrated by the fact that aprotic dipolar solvents are a class of compounds characterized by high solubility of both organic and inorganic substrates, as well as the phenomena of specific solvation of reagents that have a significant effect on their chemical, including catalytic, properties. The effect of replacing aprotic solvents with melts of ionic compounds, which are essentially ionic liquids, on the reduction and catalytic properties of the Zn (Mg) system — the metal complex — the H ⁺ source was not known a priori.

The invention is illustrated by the following examples.

Example 0. The functionalization of pentafluoroaniline at the amino group

5 g (27 mmol) of pentafluoroaniline and 21.6 g (20 ml, 212 mmol) of acetic anhydride are placed in a flask equipped with a reflux condenser, a magnetic stirrer and an oil bath with a temperature regulator. The resulting mixture was boiled under stirring under reflux for 5 hours. After this, the reaction mixture was diluted with 50 ml of water, the product was filtered off, washed with 2 times 10 ml of cold water and dried in a vacuum desiccator over potassium hydroxide. 6.1 g (90%) of pentafluoroacetanilide are obtained.

Example 1. Obtaining 3,4,5-trifluoroaniline

300 mg (0.6 mmol) of Ni (Phen) ₂ Cl ₂ , 8.01 g (122.4 mmol) of zinc dust, 13 ml of 1-butyl melt, 3- are placed in a flask equipped with a thermometer, gas tube, magnetic stirrer and an oil bath with a temperature regulator. methylimidazolium bromide (BMIMBr) and 2.5 ml of water. The reaction mixture was stirred at 70 ° C. for 10 minutes and 2.76 g (12.3 mmol) of pentafluoroacetanilide were added. The resulting mixture was stirred for 2 hours at 70 ° C, then poured into 50 ml of water, the solid was filtered off, washed with another 50 ml of water. The product is washed from the solid phase with 50 ml of acetonitrile. The solvent was evaporated, 50 ml of water and sodium hydroxide were added to the residue to pH 13-14, the resulting mixture was stirred for 1 h at room temperature. The product is distilled off with steam, extracted with sulfuric ether, the extract is dried with magnesium sulfate, the ether is distilled off in vacuo.

Obtain 1.25 g of the substance, the content of 3,4,5-tetrafluoroaniline is 90%.

Examples 2-17. Preparation of 3,4,5-trifluoroaniline

The composition of the catalytic complex and the nature of the ionic liquid vary. The reaction medium used was 1-butyl, 3-methylimidazolium bromide (BMIMBr), 1-butyl, 3-methylimidazolium chloride (BMIMCl), 1-butyl, 3-methylimidazolium tetrafluoroborate (BMIMBF ₄ ), 1-butyl, 3- methylimidazolium acetate (BMIMOAc), 1-methyl, 3-ethylimidazolium bromide (EMIMBr), 1-methyl, 3-ethylimidazolium tetrafluoroborate (EMIMBF ₄ ).

30 mg (0.125 mmol) of NiCl ₂ · 6H ₂ O (examples 2-16) or 30 mg (0.125 mmol) of CoCl ₂ · 6Н ₂ О (placed in a flask equipped with a thermometer, gas tube, magnetic stirrer and oil bath with a temperature controller) Example 17), the required amount (1, 2 or 3 equivalents with respect to the nickel or cobalt salt) of Vru or Phen · H ₂ O, 2.5 ml of the melt of the corresponding ionic liquid and 0.5 ml of water. The reaction mixture was stirred at 70 ° C for 1 h, then 1.64 g (25 mmol) of zinc dust was added, stirred for another 10 minutes and 563 mg (2.5 mmol) of pentafluoroacetanilide was added. The reaction mixture is stirred at a temperature of 70 ° C. Processing of the reaction mixture, hydrolysis of 3,4,5-tetrafluoroacetanilide and isolation of the product are carried out analogously to the procedure described in example 1.

The results are shown in table 1.

Table 1 Example No. Catalytic complex Reaction time, h Ionic liquid Conversion rate 2 Content 1b 2 NiCl ₂ - Lying 2 BMIMCl one hundred% 87% 3 NiCl ₂ - 2Vru 2 BMIMCl one hundred% 78% four NiCl ₂ - 3Vru 2 BMIMCl one hundred% 88% 5 NiCl ₂ - 3Vru 0.5 BMIMBr one hundred% 63% 6 NiCl ₂ - 2Phen 2 BMIMBr one hundred% 95% 7 NiCl ₂ - 2Vru 6 BMIMBF ₄ 98% 87% 8 NiCl ₂ - 2Phen 6 BMIMBF ₄ one hundred% 62% 9 NiCl ₂ - 3Phen 6 BMIMBF ₄ one hundred% 87% 10 NiCl ₂ - 2Phen 6 BMIMOAc one hundred% 41% eleven NiCl ₂ - 3Vru 0.5 EMIMBr one hundred% 69% 12 NiCl ₂ - 2Phen 2 EMIMBr one hundred% 77% 13 NiCl ₂ - 2Vru 6 EMIMBF ₄ one hundred% 80% fourteen NiCl ₂ - 3Vru 6 EMIMBF ₄ one hundred% 81% fifteen NiCl ₂ - 2Phen 6 EMIMBF ₄ one hundred% 82% 16 NiCl ₂ - 3Phen 6 EMIMBF ₄ one hundred% 78% 17 CoCl ₂ - 2Phen 6 BMIMBr 85% 10%

Examples 18-20. Preparation of 3,4,5-trifluoroaniline

The composition of the catalytic complex and the nature of the solvent vary.

82 mg (0.125 mmol) of Ni (PPh ₃ ) ₂ Cl ₂ , 20 mg (0.125 mmol) of Vru or 25 mg (0.125 mmol) of Phen · Н ₂ О, 1635 mg (25 mmol) of zinc dust and 563 mg ( 2.5 mmol) of pentafluoroacetanilide and 2.5 ml of the melt of the corresponding ionic liquid. The flask is evacuated, then filled with argon. Using a syringe, add 0.5 ml of water. The reaction mass is stirred at 70 ° C for 7 hours. Processing of the reaction mixture, hydrolysis and isolation of products are carried out similarly to the procedure described in example 1.

The results are shown in table 2.

table 2 Example No. Catalytic complex Solvent Conversion rate 2 Content 1b eighteen Ni (PPh ₃ ) ₂ Cl ₂ - Phen BMIMBr one hundred% 62% 19 Ni (PPh ₃ ) ₂ Cl ₂ - Lying BMIMBr one hundred% 51% twenty Ni (PPh ₃ ) ₂ Cl ₂ - Phen BMIMCl one hundred% 68%

Examples 21-24. Preparation of 3,4,5-trifluoroaniline

The temperature of the reaction is varied.

61 mg (0.125 mmol) Ni (Phen) ₂ Cl ₂ , 2.5 ml BMIMBF ₄ , 0.5 ml water and 1635 mg (25 mmol) zinc dust are placed in a flask equipped with a thermometer, gas tube, magnetic stirrer and an oil bath with a temperature controller. The mixture is stirred for 10 minutes and 563 mg (2.5 mmol) of pentafluoroacetanilide are added. The reaction mixture is stirred at the appropriate temperature for 6 hours. Processing of the reaction mixture, hydrolysis of 3,4,5-trifluoroacetanilide and isolation of the product are carried out analogously to the procedure described in example 1.

The results are shown in table 3.

Table 3 Example No. The temperature of the reaction, ° C Conversion rate Content 1b 2 3a 21 35 fifteen% 0% 0% 22 fifty 89% 35% 35% 23 70 one hundred% one hundred% 87% 24 85 one hundred% one hundred% 75%

Examples 25-33. Preparation of 3,4,5-trifluoroaniline

The reaction time and the reductant / substrate ratio are varied.

61 mg (0.125 mmol) Ni (Phen) ₂ Cl ₂ , 2.5 ml BMIMBr and 0.5 ml water, corresponding to the amount of zinc dust, are placed in a flask equipped with a thermometer, gas tube, magnetic stirrer and an oil bath with a temperature regulator. The mixture is stirred for 10 minutes and 563 mg (2.5 mmol) of pentafluoroacetanilide are added. The reaction mixture is stirred at a temperature of 70 ° C for the required time. Processing of the reaction mixture, hydrolysis of 3,4,5-trifluoroacetanilide and isolation of the product are carried out analogously to the procedure described in example 1.

The results are shown in table 4.

Table 4 Example No. The ratio of reducing agent / substrate Reaction time Conversion rate Content 1b 2 3a 25 one 6 h 24% 0% 0% 26 2 6 h 38% 0% 0% 27 3 6 h 78% fifteen% fifteen% 28 four 6 h one hundred% 45% 45% 29th 5 6 h one hundred% 73% 73% thirty 10 2 h one hundred% one hundred% 96% 31 10 7 h one hundred% one hundred% 81% 32 fifteen 2 h one hundred% one hundred% 84% 33 fifteen 7 h one hundred% one hundred% 78%

Examples 34-36. Hydrodefluorination of various pentafluoroaniline derivatives. As acylating agents for the preparation of pentafluoroaniline derivatives, benzoic acid anhydride (Example 34), succinic acid anhydride (Example 35), and phthalic anhydride (Example 36) were used. Acylation was carried out by analogy with known methods.

30 mg (0.125 mmol) of NiCl ₂ · 6Н ₂ О, 50 mg (0.250 mmol) of Phen · H ₂ O, 2.5 ml of BMIMBr melt and 0.5 ml are placed in a flask equipped with a thermometer, gas tube, magnetic stirrer and an oil bath with a temperature regulator. water. The reaction mixture was stirred at 70 ° C for 1 h, then 1635 mg (25 mmol) of zinc dust was added, stirred for another 10 minutes and 2.5 mmol of the corresponding substrate was added. The reaction mixture was stirred for 6 hours at a temperature of 70 ° C. Processing of the reaction mass, hydrolysis of a mixture of N-acylpolyfluoroanilines and isolation of the product are carried out similarly to the procedure described in example 1.

The results are shown in table 5.

Table 5 Example No. Substrate The degree of conversion of the substrate Content 1b 34

one hundred% 87% 35

one hundred% 72% 36

one hundred% 67%

Example 37. The use of magnesium as a metal reducing agent to obtain 3,4,5-trifluoroaniline, acid hydrolysis

300 mg (0.6 mmol) of Ni (Phen) ₂ Cl ₂ , 2.98 g (122.4 mmol) of magnesium chips, 13 ml of BMIMBr melt and 2.5 ml of water are placed in a flask equipped with a thermometer, a gas tube, a magnetic stirrer and an oil bath with a temperature regulator. The reaction mixture was stirred at 70 ° C. for 10 minutes and 2.76 g (12.3 mmol) of pentafluoroacetanilide were added. The resulting mixture was stirred for 2 hours at 70 ° C, then poured into 50 ml of water, the solid was filtered off, washed with another 50 ml of water. The product is washed from the solid phase with 50 ml of acetonitrile. The solvent was evaporated, 50 ml of water and concentrated hydrochloric acid were added to the residue to pH 2-3, the resulting mixture was stirred for 1 h at room temperature. The product is distilled off with steam, extracted with sulfuric ether, the extract is dried with magnesium sulfate, the ether is distilled off in vacuo.

Obtain 1.01 g of substance, the content of 3,4,5-tetrafluoroaniline is 62%.

Example 38. Reuse of ionic liquid to obtain 3,4,5-trifluoroaniline

300 mg (0.6 mmol) Ni (Phen) ₂ Cl ₂ , 8.01 g (122.4 mmol) of zinc dust, 13 ml of BMIMBr melt and 2.5 ml of water are placed in a flask equipped with a thermometer, a gas tube, a magnetic stirrer and an oil bath with a temperature regulator. The reaction mixture was stirred at 70 ° C. for 10 minutes and 2.76 g (12.3 mmol) of pentafluoroacetanilide were added. The reaction mixture was stirred for 2 hours at 70 ° C, then diluted with 10 ml of acetonitrile, the solid was filtered off, washed with another 10 ml of acetonitrile. Acetonitrile is evaporated in a vacuum of a rotary evaporator. The product is extracted from the reaction mass 5 times in 10 ml of hot ethyl acetate. Ethyl acetate was evaporated. Hydrolysis and isolation of the product is carried out similarly to the procedure described in example 1. Obtain 1.2 g of substance, the content of 3,4,5-tetrafluoroaniline is 87%. The ionic liquid remaining after extraction of the product is dried in high vacuum and used in the second reaction cycle.

The second cycle (the conditions of the reaction, isolation of the product and preparation of the ionic liquid for the next cycle are similar to the procedure described for the first reaction cycle): reagent and catalyst loading: 300 mg (0.6 mmol) Ni (Phen) ₂ Cl ₂ , 8.01 g (122.4 mmol ) zinc dust, 2.5 ml of water, 2.76 g (12.3 mmol) of pentafluoroacetanilide. Obtain 1.2 g of the substance, the content of 3,4,5-trifluoroaniline 75%.

Third cycle (reaction conditions and product isolation are similar to those described for the first cycle): reagent and catalyst loading: 300 mg (0.6 mmol) Ni (Phen) ₂ Cl ₂ , 8.01 g (122.4 mmol) zinc dust, 2.5 ml of water, 2.76 g (12.3 mmol) of pentafluoroacetanilide. 1.1 g of substance are obtained, the content of 3,4,5-trifluoroaniline is 73%.

Thus, the above method allows to obtain 3,4,5-trifluoroaniline in high yields under mild conditions using available reagents.

Claims (5)

1. The method of obtaining 3,4,5-trifluoroaniline of the formula:

as a result of a three-stage process, including acylation of pentafluoroaniline at the amino group, reductive hydrodefluorination of pentafluoroaniline derivatives under the influence of a reducing metal in the presence of proton sources in a solvent medium, when heated with subsequent alkaline or acid hydrolysis of the reaction mixture with the formation of the corresponding amine, characterized in that as the acylating agent uses a derivative of mono- or di-lower aliphatic or benzene carboxylic acid, the stage of recovery A substantial hydrodefluorination of the obtained acylpentafluoroaniline is carried out in the presence of a catalyst - a complex compound of nickel and / or cobalt with heterocyclic nitrogen-containing compounds or phosphorus-containing ligands, such as 2,2'-bipyridyl, 1,10-phenanthroline, alkyl- or arylphosphines, using as solvents ionic liquids selected from a 1,3-dialkylimidazolium salt of the general formula:

where R ¹ and R ² are alkyl groups from C ₁ to C ₁₀ that may contain various substituents, X is an inorganic or organic anion, such as Cl ^- , Br ^- , BF ₄ ^- , OAc ^- , at a temperature of 20-150 ° FROM. 2. The method according to claim 1, characterized in that the solvent after isolation of the final product can be used repeatedly without further purification. 3. The method according to claim 1, characterized in that reductive hydrodefluorination is carried out at a temperature of 35-85 ° C using water as sources of protons. 4. The method according to claim 1, characterized in that zinc or magnesium is used as the reducing metal. 5. The method according to claim 1, characterized in that reductive hydrodefluorination is carried out at a ratio of catalyst-substrate from 0.01 to 1 and a reducing agent-substrate from 3 to 15.