Method for preparing N-fluoropyridinium salts

Abstract: When N-fluoropyridinium salt of the following formula is prepared by reacting a pyridine compound with a Brønsted acid and fluorine, an excess amount of the pyridine compound relative to the amount of the Brønsted acid being used, a high yield results.

Description: The present invention relates to a method for preparing N-fluoropyridinium salts. More particularly, the present invention relates to a method for preparing N-fluoropyridinium salts with a high yield. In reactions with organic compounds, fluorine, contrary to chlorine, bromine and iodine, reacts very violently, readily giving rise to the fission of the C-C bond of organic compounds and in cases where the reaction is excessively violent, fire or explosion in turn can break out. For the purpose of resolving the above problem, a fluorinating agent which can introduce fluorine to organic compounds under mild conditions has been developed. The present applicant has earlier found that N-fluoropyridinium salts obtained by reacting pyridine compounds with Brønsted acids or Lewis acids are excellent fluorinating agents which satisfy these requirements (Patent Specification No. EP 0204535-A1). Having high reactivity and selectivity to a variety of organic compounds, N-fluoropyridinium salts are very useful for preparing fluorocompounds. However, there is a problem in that the above mentioned EP 0204535-A1's method for preparing N-fluoropyridinium salts produces the desired compound with a low yield, so a more improved method for preparing the same on an industrial scale has been required. As a result of intensive research to overcome this problem, the present inventors have found, surprisingly, that the use of an amount of a pyridine compound greater than an equimolar amount of a Brønsted acid improves the yield remarkably. Accordingly, the present invention provides a method for preparing N-fluoropyridinium salts of the general formula (I): by reacting a pyridine compound of the following formula (II) with a Brønsted acid of the general formula XH and fluorine characterized by using an amount of pyridine compound greater than an equimolar amount of Brønsted acid: wherein R¹ to R⁵ represent any group or groups compatible with preparation of N-fluoropyridinium salts and compatible with fluorinating activity of the N-fluoropyridinium salts, and may, in particular, be selected from the groups:- a hydrogen atom, a halogen atom, an alkyl, aryl, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, nitro, cyano, alkylsulfonyl, arylsulfonyl, hydroxy, alkoxy, aryloxy, acyloxy, acylthio, amido, alkanesulfonyloxy or arenesulfonyloxy group; X ⊖ represents a conjugate base of a Brønsted acid except for F ⊖ , Cl ⊖ , Br ⊖ and I ⊖; R¹, R², R³, R⁴ and R⁵ may combine directly or through a hetero-atom or atoms to form a cyclic structure; while X ⊖ may replace one of R¹, R², R³, R⁴ and R⁵ and be directly attached to the pyridinium moiety; or may combine directly or through a hetero-atom or atoms with R¹, R², R³, R⁴ and R⁵. The present invention is illustrated by way of example in the following. Examples of pyridine compounds of general formula (II) used in the method of the present invention include: straight, branched or cyclic alkylated pyridine such as pyridine, (trifluoromethyl)pyridine, bis(trifluoromethyl)pyridine, tris(trifluoromethyl)pyridine, (trichloromethyl)pyridine, (pentafluoroethyl)pyridine, (pentafluorooctyl)pyridine, (methoxymethyl)pyridine, ethyl pyridylacetate, pyridylacetonitrile, pyridylacetone and the like; halopyridine such as chloropyridine, bromopyridine, fluoropyridine, dichloropyridine, difluoropyridine, trichloropyridine, tetrachloropyridine, pentachloropyridine, difluoropyridine, trifluoropyridine, pentafluoropyridine, chlorofluoropyridine, dichlorofluoropyridine and the like; (alkoxycarbonyl) or (aryloxycarbonyl)pyridine such as (trifluoromethyl)chloropyridine, (trifluoromethyl)dichloropyridine, (trifluoromethyl)trichloropyridine, (trifluoromethyl)fluoropyridine, methylchloropyridine, phenylpyridine, diphenylpyridine, triphenylpyridine, dipyridyl, acetylpyridine, bisacetylpyridine, (methoxycarbonyl)pyridine, (ethoxycarbonyl)pyridine, (butoxycarbonyl)pyridine, bis(ethoxycarbonyl)pyridine, bis(trifluoroethoxycarbonyl)pyridine, tris(methoxycarbonyl)pyridine, (phenoxycarbonyl)pyridine and the like; and 2,3-pyridinedicarboxylic anhydride, nitropyridine, cyanopyridine, dicyanopyridine, tricyanopyridine, benzenesulfonylpyridine, methylsulfonylpyridine, chlorocyanopyridine, folmylpyridine, (haloformyl) pyridine, nicotinamide, picolinamide, (dimethylaminocarbonyl) pyridine, methoxypyridine, dimethoxypyridine, propoxypyridine, butoxypyridine, menthoxypyridine, trifluoromethoxypyridine, acetoxypyridine, trifluoroacetoxypyridine, phenoxypyridine, acetylthiopyridine, methansulfonyloxypyridine, benzenesulfonyloxypyridine, acetylaminopyridine, 2,3-tetramethylenepyridine, 3-hydroxypyridine, 1,2,3,4,5,6,7,8,-octahydroacridine and the like. (Brønsted acids) Examples of Brønsted acids having a general formula XH include: sulfonic acids such as methanesulfonic acid, butanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, dinitrobenzenesulfonic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid, perfluorobutanesulfonic acid, perfluorooctanesulfonic acid, trichloromethanesulfonic acid, difluoromethanesulfonic acid, trifluoroethanesulfonic acid, fluorosulfonic acid, chlorosulfonic acid, monomethylsulfuric acid, sulfuric acid, camphorsulfonic acid, bromocamphorsulfonic acid, Δ⁴-cholestene-3-on-6-sulfonic acid, 1-hydroxy-p-methane-2-sulfonic acid, p-styrenesulfonic acid, β-styrenesulfonic acid, poly(p-styrenesulfonic acid), vinylsulfonic acid, poly(vinylsulfonic acid), poly(2-acrylamide-2-methyl-1-propanesulfonic acid) and a copolymer of said propanesulfonic acid with styrene, perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid, poly(perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid) and a copolymer of said octenesulfonic acid with tetrafluoroethylene; phosphoric acid; nitric acid; halogenoacids such as perchloric acid, perbromic acid, periodic acid, chloric acid, bromic acid and the like; carboxylic acids such as acetic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, pentafluoropropionic acid, dichloroacetic acid, acrylic acid, poly(acrylic acid) or poly(perfluoro-3,6-dioxa-4-methyl-7-octenenic acid), a copolymer of said octenoic acid with tetrafluoroethylene and the like; HBF₄, HPF₆, HSbF₄, HSbF₆, HAsF₆, HBC1₃F and the like. Hydrogen halide is excluded from the Brønsted acid according to the present invention. When X ⊖ in N-fluoropyridinium salt used in the method of the present invention is F ⊖ , a conjugate base to hydrogen halide, there is a serious disadvantage in that explosions may break out at above -2°C because the pyridine-F₂ complex is unstable. Furthermore, if X ⊖ is Cl ⊖ , Br ⊖ and I ⊖ , it is difficult to prepare the corresponding N-fluoropyridinium salt. In the present invention, it is necessary to use amounts of pyridine compounds greater than an equimolar amount of Brønsted acids. In the above mentioned EP 0204535-A1 (Page 10, lines 19-22) it is described that 'The Brønsted acid compounds for achieving better reaction efficiencies should be equal to or in excess molar amounts to that of the host material, but preferably should be in an equimolar amount from an economic view.' (for 'host material' read 'pyridine compound'). However, the prior art does not describe at all the technique of the present invention in which an excess amount of pyridine is used. For example, in the above mentioned EP 0204535-A1 a less than equimolar amount of pyridine is used relative to an amount of Brønsted acid, and the yield of N-fluoropyridinium salt is as low as 44%. The present inventors have found the surprising fact that the use of an excess amount of pyridine compound relative to the Brønsted acid dramatically improves the yield almost as much as 100% quantitatively. As the pyridine compound is used in an amount greater than an equimolar amount of Brønsted acid in the method of the present invention, the amount of pyridine compound is preferably from 1.01 to 1.2 times, more preferably from 1.02 to 1.08 times that of the Brønsted acid. Fluorine employed in the present invention is preferably used with 99.9% to 50% by volume of an inert gas. Examples of inert gases include nitrogen, helium, argon, tetrafluoromethane, sulfur hexafluoride and the like. Although the amount of fluorine may be equimolar to or greater than an amount of a pyridine compound, the amount of fluorine required may be appropriately selected when the pyridine compounds are eliminated by reacting with fluorine because the amount of fluorine depends on the introducing methods, reaction temperatures, reaction solvents, reaction apparatus and the like. A reaction solvent is preferably used in the reaction caused by the method of the present invention. Examples of reaction solvents include acetonitrile, methylene chloride, chloroform, carbon tetrachloride, trichlorofluoromethane, trichlorofluoroethane, ethyl acetate, diethyl ether, tetrahydrofuran and the like or mixture thereof A reaction temperature may be selected in the range of -100°C to +40°C, and a temperature of -20°C to 0°C leads to preferably a better yield. The method of the present invention may be illustrated with reference to the following examples by using pyridine and 3,5-dichloropyridine as the pyridine compound, and trifluoromethanesulphonic acid and methanesulfonic acid as the Brønsted acid. However, the present invention is not intended to be limited only to the following examples. Example 1 The following reaction was carried out in the present Example. To 40 ml of acetonitrile as solvent were added 1.592 g (20.136 mmol) of pyridine and 2.940 g (19.588 mmol) of trifluoromethanesulfonic acid (i.e., the amount of pyridine was 1.03 times that of trifluoromethanesulfonic acid in a molar ratio), and the mixture was cooled to -20°C. A mixed gas of fluorine and nitrogen in a volumetric ratio of 1:4 was then introduced to the mixture at a rate of 50 ml/min under starring. The amount of fluorine gas introduced was 40.0 mmol. After completion of the reaction, the solvent was distilled off, and 4.716 g (19.097 mmol) of N-fluoropyridinium - trifluoromethanesulfonate was obtained by crystallizing with ether. The yield was 97.4%. Characteristics and spectrum data of the compound are shown as follows. Melting point: 175-178°C F-NMR (ppm, CFCl₃ internal standard in CD₃CN) -48.75 (1F, NF) 77.61 (3F, CF₃) H-NMR (ppm, CD₃CN) 9.4 (2H) 8.8 (1H) 8.4 (2H) Examples 2-6 The reactions in Examples 2-6 were conducted as in Example 1 except that the molar ratio of pyridine to trifluoromethanesulfonic acid was changed. The results are shown in Table 1. Example pyridine mmol CF₃SO₃H mmol pyridine:CF₃SO₃H (molar ratio) yield (%) 2 19.896 19.888 1.00:1.00 38.8 3 20.224 20.617 0.981:1.00 5.2 4 20.148 21.091 0.955:1.00 2.0 5 20.946 19.362 1.08:1.00 97.5 6 24.271 20.230 1.20:1.00 93.2 Example 7 The following reaction was carried out in the present Example. To 40 ml of acetonitrile were added 3.087 g (20.860 mmol) of 3,5-dichloropyridine and 3.039 g (20.250 mmol) of trifluoromethanesulfonic acid (i.e., the amount of pyridine compound was 1.03 times that of trifluoromethanesulfonic acid in a molar ratio), and the mixture was cooled to -20°C. The following procedures were conducted as in Example 1, and 5.774 g (18.3 mmol) of N-fluoro-3,5-dichloropyridinium trifluoromethanesulfonate were obtained with a yield of 90.0%. Characteristics and spectrum data of the compound are shown as follows. Melting point: 116.5-118°C F-NMR (ppm, CFCl₃ internal standard in CD₃CN) -52.13 (1F, J H-F =14.0 Hz, NF) 77.63 (3F, CF₃) H-NMR (ppm, CD₃CN) 9.6 (2H, J H-F =14.0 Hz) 8.9 (1H) Example 8 The following reaction was carried out in the present Example. To 40 ml of acetonitrile were added 1.655 g (20.923 mmol) of pyridine and 1.961 g (20.406 mmol) of methanesulfonic acid (i.e., the amount of pyridine was 1.025 times that of methanesulfonic acid in a molar ratio), and the mixture was cooled to -20°C. A mixed gas of fluorine and nitrogen in a volumetric ratio of 1:4 was then introduced to the mixture at a rate of 50 ml/min under stirring. The amount of fluorine gas introduced was 40.0 mmol. After completion of the reaction, the solvent was distilled off, and 3.691 g (19.103 mmol) of N-fluoropyridinium methanesulfonate was obtained by crystallising with ether. The yield was 93.6%. The NMR spectrum data are shown as follows. F-NMR (ppm, CFCl₃ internal standard in CD₃CN) -48.75 (NF) As described above, the method of the present invention leads to a high yield, and does not require filtering out and recrystallization procedures because hydrogen fluoride (HF) produced as a by-product from using Brønsted acids is a compound having a low boiling point (19.5°C). Therefore, the method of the present invention, which can shorten said Japanese Patent's process of preparing N-fluoropyridinium salt, is an epoch-making method for preparing the compound on an industrial scale.

Claims: A method for preparing N-fluoropyridinium salt of the general formula (I): by reacting a pyridine compound of the following formula (II) with a Brønsted acid of the general formula XH and fluorine characterized by using an amount of pyridine compound greater than an equimolar amount of Brønsted acid: wherein R¹ to R⁵ represent any group or groups compatible with preparation of N-fluoropyridinium salts and compatible with fluorinating activity of the N-fluoropyridinium salts, and may, in particular, be selected from the groups:- a hydrogen atom, a halogen atom, an alkyl, aryl, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, nitro, cyano, alkylsulfonyl, arylsulfonyl, hydroxy, alkoxy, aryloxy, acyloxy, acylthio, amido, alkanesulfonyloxy or arenesulfonyloxy group; X ⊖ represents a conjugate base to a Brønsted acid except for F ⊖, Cl ⊖ , Br ⊖ and I ⊖; R¹, R², R³, R⁴ and R⁵ may combine directly or through a hetero-atom or atoms to form a cyclic structure; while X ⊖ may replace one of R¹, R², R³, R⁴ and R⁵ and be directly attached to the pyridinium moiety; or may combine directly or through a hetero-atom or atoms with R¹, R², R³, R⁴ and R⁵. The method as claimed in claim 1 wherein 1.01 to 1.2 moles of a pyridine compound relative to 1 mole of Brønsted acid is used. The method as claimed in claim 1 wherein 1.02 to 1.08 moles of a pyridine compound relative to 1 mole of Brønsted acid is used.

Inventors: NUKUI KAZUNORI C O ADVANCED TE, SAIKI YUKINORI C O ADVANCED TE, NUKUI, KAZUNORI, C/O ADVANCED TECHNOLOGY RESEARCH, SAIKI, YUKINORI, C/O ADVANCED TECHNOLOGY RESEARCH
Applicants: ONODA CEMENT CO LTD, ONODA CEMENT COMPANY, LTD.
Application year: 1992
Main classification: C07D213
IPC codes: C07D213