J . Org. Chem. 1995,60, 6563-6570
6563
Highly Selective Fluorinating Agents: A Counteranion-Bound N-FluoropyridiniumSalt System Teruo Umemoto* and Ginjiro Tomizawa MEC Laboratory, Daikin Industries, Ltd., Miyukigaoka 3, Tsukuba, Zbaraki 305, J a p a n Received March 13, 1995@
A series of alkyl- or (trifluoromethy1)-substitutedN-fluoropyridinium-2-sulfonates 2a-h, differing in fluorinating power, were synthesized, and assessment was made of the effectiveness of each selective fluorinating agent. N-Fluoropyridinium-3-and -4-sulfonates3 and 4 were also synthesized. Power-variables 2a-h were found to be highly selective fluorinating agents for a wide range of nucleophilic substrates such as activated aromatics, enol trialkylsilyl and alkyl ethers, active methylene compounds, activated olefins, and sulfides. Thus, phenol, naphthol, phenylurethane, and the trimethylsilyl ether of phenol were exclusively or highly selectively fluorinated at the o-position with 2f-h. Conjugated enol trialkylsilyl ethers of a steroid were regioselectively fluorinated at the 6-position with moderately powerful 2b-e. This regioselectivity increased with the bulkiness of the silyl part, and with the most bulky triisopropylsilyl group exclusive 6-fluorination was achieved. Preferential &stereoselective fluorination at the 6-position was observed. N-Fluoropyridinium-2-sulfonateswere activated with an acid. This acid-catalyzed fluorination led to the preferential p-fluorination of anisole. The present results can be explained based on the capacity * ” of the 2-sulfonate anion to interact with the hydroxy group of phenol or naphthol, NH group of phenylurethane, silicon atoms of silyl ethers, or protons of acids.
Introduction Fluorinated organic compounds are becoming increasingly important for the production of medicines and agricultural chemicals and other useful materials owing to the characteristics of fluorine.’ Since molecular fluorine is extremely reactive, much effort has been made to develop mild and selective electrophilic fluorinating agents.2 According, many N-fluoro compounds such as N-fluoroperfl~oropiperidine,~ N-flu~ropyridone,~ N-fluoro~ulfonamide,~ N-fluoropyridinium N-fluoroquinuclidinium salts,7 N-fluorobis(perfluoroalkylsulfony1)imides: N-fluor~amides,~ N-fluorodisulfonimides,10and N-fluoro-”-alkyl- 1,4-diazoniabicyclo[2.2.21octanesalts’ have been produced. A series of N-fluoropyridinium salts developed by the present authors as power and structure-variable fluorinating agents6a!dsf have been successfully applied to the Abstract published in Advance ACS Abstracts, September 1,1995. (1)(a)Biomedical Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y., Eds.; Kodansha, Ltd.: Tokyo, 1982.(b) Kumadaki, I. J. Synth. Org. Chem., Jpn. 1984,42,786.(c) Welch, J . T. Tetrahedron 1987,43, 3123.(d)Fluorine in Bioorganic Chemistry;Welch, J. T., Eswarakrishnan, S.; John Wiley & Sons, Inc.: New York, 1991.(e) Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.(0 Organofluorine Chemistry: Principles and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994. (2)(a) Umemoto, T. Rev. Heteroatom. Chem. 1994,10,123.(b)New Fluorinating Agents in Organic Syntheses; German, L., Zemskov, S., Eds.; Springer-Verlag: New York, 1989.(c) Purrington, S. T.; Kagen, B. S.; Patrick, T. B. Chem. Reu. 1986,86,997.(d) Rozen, S.;Filler, R. Tetrahedron 1985,41,1111. (e) Wilkinson, J. A. Chem. Rev. 1992,92, 505. (3)(a) Banks, R. E.; Williamson, G. E. Chem. Ind. 1964, 1864.(b) Banks, R. E.; Murtagh, V.; Tsiliopoulos, E. J . Fluorine Chem. 1991, 52,389. (4)(a) Purrington, S.T.; Jones, W. A. J . Org. Chem. 1983,48,761. (b) Purrington, S. T.; Jones, W. A. J . Fluorine Chem. 1984,26,43. (5) (a) Barnette, W. E. J . Am. Chem. SOC.1984,106,452. (b) Lee, S.H.; Schwartz, J . J . Am. Chem. SOC.1986,108,2445.(c)Differding, E.; Lang, R. W. Tetrahedron Lett. 1988,29,6087.(d) Differding, E.; Lang, R. W. Helv. Chim. Acta 1989,72,1248.(e)Banks, R. E.; Khazaei, A. J. Fluorine Chem. 1990,46,297. (0 Differding, E.;Ruegg, G. M.; Lang, R. W. Tetrahedron Lett. 1991,32, 1779. @
fluorination of a wide range of nucleophilic organic compounds.6 N-Fluoropyridinium-2-sulfonateand its 6-chloro derivative have been shown to have excellent selectivity in but due to low solubility in organic solvents, these reagents exhibited low reactivity or gave products in low yield. N-Fluoropyridiniumsulfonates possessing a lipophilic alkyl or trifluoromethyl substituent(s) should be useful for the enhancing fluori(6)(a) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986,27,3271. (b) Umemoto, T.;Kawada, K.; Tomita, K. Tetrahedron Lett. 1986,27, 4465.(c) Umemoto, T.; Tomizawa, G. Bull. Chem. SOC.Jpn. 1986,59, 3625. (d) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. J . Am. Chem. SOC.1990, 112, 8563. (e) Umemoto, T.;Tomita, T.; Kawada, K. Org. Synth. 1990,69, 129.(0 Umemoto, T.;Harasawa, K.; Tomizawa, G.; Kawada, K.; Tomita, K. Bull. Chem. SOC.Jpn. 1991,64,1081.(g) Umemoto, T.; Harasawa, K.; Tomizawa, G.; Kawada, K.; Tomita, K. J . Fluorine Chem. 1991,53, 369.(h) Shimizu, I.; Ishii, H. Chem. Lett. 1989, 577. (i) Chung, Y.; Duerr, B. F.; McKelvey, T. A.; Nanjappan, P.; Czarnik, A. W. J . Org. Chem. 1989,54, 1018. (j) Page, P. C. B.; Hussain, F.; Maggs, J . L.; Morgan, P.; Park, B. K. Tetrahedron 1990,46,2059. (k) Hebel, D.; Kirk, K. L. J . Fluorine Chem. 1990,47,179.(1) Poss, A. J.; Van der Puy, M.; Nalewajek, D.; Shia, G. A.; Wagner, W. J.; Frenette, R. L. J . Org. Chem. 1991,56,5962. (m) Dauben, W. G.; Greenfield, L. J . J . Org. Chem. 1992,57, 1597.(n) Naruta, Y.; Tani, F.; Maruyama, K. Tetrahedron Lett. 1992,33, 1069.(0)Ihara, M.; Taniguchi, N.; Kai, T.; Fukumoto, K. J. Chem. SOC.,Perkin Trans. 1 1992,221. (p) Sato, M.; Kitazawa, N.; Kaneko, C. Heterocycles 1992,33,105. (7)(a)Banks, R. E.; Du Boisson, R. A,; Tsiliopoulos, E. J. Fluorine Chem. 1986,32,461.(b) Banks, R. E.; Du Boisson, R. A.; Morton, W. D.; Tsiliopoulos, E. J . Chem. Soc., Perkin Trans. 1 1988,2805. ( 8 ) ( a ) S. Singh, S.; DesMarteau, D. D.; Zuberi, S. S.; Witz, M.; Huang, H.-N. J . Am. Chem. SOC. 1987, 109, 7194. (b) Xu, 2.-Q; DesMarteau, D. D.; Gotoh, Y. J . Chem. Soc., Chem. Commun. 1991, 179. (c) Pennington, W. T.; Resnati, G.; DesMarteau, D. D. J . Org. (d) Resnati, G.; DesMarteau, D. D. J . Org. Chem. Chem. 1991,57,1536. 1991,56, 4925. (e) DesMarteau, D.D.; Xu, Z.-Q.; Witz, M. J . Org. DesMarteau, D. D.; Gotoh,Y. J . Chem. 1992, 57, 629. (0 Xu, Z.-Q.; Fluorine Chem. 1992,58,71. (9) Satyamurthy,N.; Bida, G. T.; Phelps, M. E.; Barrio, J. R. J . Org. Chem. 1990,55,3373. (10)(a)Davis, F. A,; Han, W. Tetrahedron Lett. 1991,32,1631.(b) Differding, E.;Ofner, H. Synlett 1991,187.(c)Differding, E.;Duthaler, R. 0.; Krieger, A.; Ruegg, G. M.; Schmit, C. Synlett 1991, 395. (11)(a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992,595.(b) Lal, G. S. J. Org. Chem. 1993,58, 2791.(c) Banks, R. E.; Lawrence, N. J.; and Popplewell, A. L. J . Chem. SOC.,Chem. Commun. 1994,343.(d) Zupan, M.;Iskra, J.; Stavber, S. J. Fluorine Chem. 1995,70, 7. (e) Zupan, M.; Iskra, J.; Stavber, S. J . Org. Chem. 1995,60, 259.
0022-326319511960-6563$09.00/0 0 1995 American Chemical Society
6564 J. Org. Chem., Vol. 60, No. 20,1995
Umemoto and Tomizawa
(runs 10, 13, and 15). The above results indicate that the ease of fluorination depends on N+-H bonding R4 strength in zwitterion form. Thus, weak acids of strong N+-H bonding such as l a (M = H)are inactive, while strong acids of weak N+-H bonding such as lb-h (M = H)are reactive toward Fz. The most acidic l h (M = H) could easily undergo fluorination even at -40 "C (run 15). The nonzwitterionic form may be the species undergoing fluorination (Scheme 2). The addition of a catalytic amount (5-10 mol %) of triethylamine was effective for the fluorination. Thus, the fluorination of pyridinesulfonic acids lb (M = H) and If (M = H) in the presence of 5 mol % of triethylamine gave high yields of 2b and 2f (runs 4 and 11). Under the conditions without triethylamine, 2b and 2f were hardly obtained. Success in the use of catalytic triethylamine for the easy fluorination suggests the basecatalytic action of Et3NH+F- produced through fluorinanating reactivity and yield. According to the power tion. When triethylamine was not used but the solvent variation rule established by the authors,6d,gJ2 an electronwas used in excess to dissolve lf, a high yield of 2f was donating alkyl group should decrease the fluorinating obtained (run 10). power of the N-fluoropyridiniumsulfonate, while an Fluorination capacity depends on the solubility of electron-withdrawing trifluoromethyl group should inpyridinesulfonic acids or their salts in a given solvent. crease it. Thus, a new series of power-variable NAcetonitrile poorly or scarcely dissolves most pyridinefluoropyridinium salts, i.e., a counteranion-boundN-flusulfonic acids. Water or alcohols dissolve these acids, but oropyridinium salt system, was developed as a source of they decompose the products if they are an electronhighly selective and practically useful fluorinating agents. withdrawing group(s)-substituted N-fluoropyridiniumThis paper describes the synthesis of alkyl- and (trifluosulfonates. Polyfluoro alcohols were found to be superior romethy1)-substituted N-fluoropyridinium-2-sulfonates solvents for fluorination. Polyfluoro alcohols easily disand their analogs and highly selective fluorination based solve pyridinesulfonic acids or their salts without the on novel function of SO3- counteranion bound at the product decomposition. Sulfonic acids If (M = H) and 2-position. l g (M = H) could thus be fluorinated in 1,1,1,3,3,3to give sulfonates2f and 2g in high hexafluoro-2-propanol Results and Discussion yields, respectively (runs 12 and 14). Sodium salt l b (M Synthesis of N-Fluoropyridinium-2-Sulfonates = Na) was fluorinated in 2,2,24rifluoroethanol and in and Their Analogs. N-Fluoropyridinium-2-sulfonates hexafluoro-2-propanolto give sulfonate 2b in high yields 2a-h were synthesized by fluorinating the corresponding (runs 5 and 6). pyridinesulfonic acids or sodium or amine salts with N-Fluoropyridinium-2-sulfonate(2) was first synthemolecular fluorine (Fz)diluted with nitrogen in acetonisized by the fluorination of 2-pyridinesulfonic acid in trile, aqueous acetonitrile,or a polyfluoro alcohol (Scheme However, this method aqueous acetonitrile (Figure 1).6f 1 and Table 1). was not applicable to the syntheses of N-fluoropyriThe fluorination of 4,6-dimethylpyridine-2-sulfonicacid dinium-3- and -4-sulfonates 3 and 4, possibly since the (la, M = H), which actually exists in zwitterion form starting 3- and 4-pyridinesulfonic acids were not soluble (Scheme 2),13 with 10%FdNz proceeded very slowly. in the solvent. 3-Sulfonate 3 was synthesized in 87% However, the sodium or amine salt was effectively yield by fluorination in 1,1,1,3,3,3-hexafluoro-2-propanol fluorinated. Thus, N-fluoro-4,6-dimethylpyridinium-2- at 0 "C in the presence of an solid amine resin, Amberlite. sulfonate (2a)was synthesized in high yield by fluorinat2-Sulfonate 2 was prepared in 80% yield in the same ing l a (M = Na) or l a (M = Et3NH) with 10%F& in manner. After fluorination, the solid resin could be aqueous acetonitrile at low temperature (runs 1 and 2 removed by filtration. But, with 4-pyridinesulfonic acid, in Table 1). Pyridinesulfonic acids, more acidic than l a this method hardly afforded 4-sulfonate 4. This may (M = H), were easily fluorinated. The fluorination of have been due to the acidity of 4-pyridinesulfonic acid; 4-methyl-, -ethyl-, -tert-butyl-, and 6-methylpyridinethe pKis of 2-, 3-, and 4-pyridinesulfonicacids were 1.75, sulfonic acids lb-e (M = H) in anhyd acetonitrile or 3.22, and 3.44, re~pective1y.l~Sulfonate 4 was syntheaqueous acetonitrile gave N-fluoro-4-methyl-, -ethyl-, sized in 74% yield by the fluorination of reactive sodium -tert-butyl-, and -6-methylpyridinium-2-sulfonates 2b-e pyridine-4-sulfonate in hexafluoro-2-propanol at 0 "C. in good yields, respectively (runs 3, 7,8, and 9). N-FluoroAll N-fluoropyridiniumsulfonates synthesized above 5-(trifluoromethy1)-, -3-chloro-5-(trifluoromethyl)-, and were stable crystals that could be easily handled. -4,6-bis(trifluoromethyl)pyridinium-2-sulfonates 2f, 2g, The starting materials, 5-(trifluoromethy1)-,3-chloroand 2h were synthesized in high yields by fluorinating 5-(trifluoromethyl)-,and 4,6-bis(trifluoromethyl)pyridinethe corresponding sulfonic acids in anhyd acetonitrile 2-sulfonic acids If (M = H), l g (M= H), and l h (M = H) were prepared in high yields by treating the correspond(12)(a) Hachisuka, H.; Kitano, M.; Umemoto, T. J.Fluorine Chem. ing 2-chloropyridines 5, 6, and 7 with sodium sulfite 1991, 54, 206. (b) Kitano, M.; Hachisuka, H.; Umemoto, T. 16th National Meeting on Fluorine Chemistry, Nagoya, Japan, Oct 1991, (Scheme 3). Scheme 1
Abstract pp 101-102. (c) Sudlow, K.;Woolf, A. A. J.Fluorine Chem. 1994, 66,-9. (13)Uff,B. C. In Comprehensive Heterocyclic Chemistry; Boulton, A. J., Mckillop, A., Eds.; Pergamon Press, Ltd.: Oxford, 1984;Vol.2, Part 2A, p 358.
(14)Scriven, E. F. V. In Comprehensiue Heterocyclic Chemistry; Boulton, A. J., Mckillop, A., Eds.; Pergamon Press, Ltd.: Oxford, 1984; Vol. 2, Part 2A, p 171.
J. Org. Chem., Vol. 60, No. 20, 1995
Highly Selective Fluorinating Agents
6666
Table 1. Synthesis of N-Fluoropyridinium-2-Sulfonates 2a-h
runa
starting material l a (M= Na) 20 mmol l a (M= Et3NH) 2 mmol l b (M= H) 20 mmol l b (M= H) 10 mmol l b (M= Na) 3 mmol lb (M= Na) 3 mmol l c (M= H) 10 mmol Id (M= H) 20 mmol l e (M= H) 60 mmol If (M= H) 1mmol If (M= H) 2 mmol If (M= H) 5 mmol l g (M= H) 10 mmol l g (M= H) 1.82 mmol l h (M= H) 2.64 mmol
1 2 3
4 5 6
7 8 9 10 11 12 13 14 15 a
solvent CH&N/H20 (10/1) 44 mL CH3CN/H20 (100/1) 4.04 mL CH&N/H20 (1011) 66 mL CH3CN 10 mL CF3CHzOH 6mL
additive
Et3N 0.5 mmol
product 2a
yieldC(%)
-20 -40
2a
78
-20
2b
80
-20
2b
91
0
2b
92
0
2b
89
-20
2c
79
-20
2d
84
-20
2e
65
-10
2f
86
-20
2f
95
2f
90
2g
84
2g
88
2h
95
P ("C)
88
~
(CF3)zCHOH 6 mL CH3CN 20 mL CH&N/H20 (20/1) 42 mL CH3CN/Hz0 (10/1) 120 mL CH3CN 65 mL CH3CN 4 mL (CF3)zCHOH 10 mL CH3CN 20 mL (CF3)2CHOH 4 mL CH3CN 6 mL
Et3N 0.1 mmol
0 -10 0 -40
See Experimental Section. Bath temperature. Isolated yields.
Scheme 2
qsoi I
F
k
3
4
H
Figure 1.
Zwitterion form
Fluorination with N-Fluoropyridinium-2-sulfonates and Their Analogs. Since the fluorinating power of the N-fluoropyridinium salt system correlates with the pK, of the pyridines,"?gJ2the fluorinating power of 2a-h should increase in the order 2a < 2b 2c 2d 2e < 2f < 2g < 2h. These substituted N-fluoropyridinium-2-sulfonates were successfully used as highly selective fluorinating agents according to ow fluorination concept; the more powerful N-fluoropyridinium salts effectively fluorinate less reactive nucleophiles such as aromatics and olefins, while less powerful N-fluoro salts effectively fluorinate more reactive nucleophiles such as carbanions and heteroatom compounds and intermediately powerful N-fluoro salts effectively fluorinate intermediately reactive nucleophiles such as enol alkyl and trialkylsilyl ethers.6d Table 2 shows the results of the fluorination of phenol with N-fluoropyridinium-2-,-3-, and -4-sulfonates 2,2b, 2f-h, 3, and 4. The most powerful 2h smoothly fluorinated phenol in dichloromethane under mild conditions to give almost exclusively o-fluorinated phenol (olp 2 401 1) in high yield (runs 5 and 6). p-Fluorophenol(4 2%) could be detected only in trace amounts by gas chromatography. Sulfonates 2g, 2f, and 2b underwent similar exclusive o-fluorination (olp 2 57/11, though a higher temperature or longer reaction time was needed in the order of 2g 2f < 2b (runs 3, 2, and 1). Methylsubstituted 2b was faster than unsubstituted 2 (runs 1 and lo), although the actual fluorinating power of 2b is
-
- -
Scheme 3 R
QC,
R 1) Na2S03
*
2) H+
5; R=5-CF3
l f (M=H); 88%
6; R=3-CI-5-CF3
l g (MsH); 92%
7; R=4,6-di-CF3
l h (M=H); 97%
less than 2 since the 4-methyl substituent increases the This demonstatesthe effectiveness of the lipophilic alkyl substituent. 3-Sulfonate 3 was much slower in fluorinationthan 2, and its o-selectivity decreased greatly (run 11). 4-Sulfonate 4 underwent virtually no reaction even afier 11 days (run 12). A non-counteranion-bound salt, N-fluoro-3,5-dichloropyridiniumtriflate, gave a reduced olp ratio (3.311) of phenol.6d Thus, the almost exclusive o-fluorination by counteranion-boundN-fluoro salts may be explained by hydrogen bonding interactions between SOS- anions and phenol hydroxy groups in transition state 8 through n-complexation between the n-electron-deficientpyridinium ring and n-electron-rich phenol ring (Scheme 4), as previously proposed.6d This possibility is further supported by the new findings that polar acetonitrile and 1,1,1,3,3,3-hexafluoro-2-propanol solvent gave reduced olp ratios (3.311in run 7 and 411 in run 8)and that the addition of triflic acid led to a reduced (15)Katritzky, A. R.Handbook of Heterocyclic Chemistry; Pergamon Press, Ltd.: Oxford, 1985; p 153.
6666 J . Org. Chem., Vol. 60, No. 20, 1995
run 1
2 3 4 5 6 7 8 9 10 11
12d
“F+” 2b 2f 2g 2h 2h 2h 2h 2h 2h 2 3 4
solvent ClzCHCHzCl ClzCHCHzCl ClzCHCHzCl ClzCHCHzCl CHzClz CHzClz CH3CN (CF3)zCHOH CHzClz ClzCHCHzCl ClzCHCHzCl ClzCHCHzCl
Umemoto and Tomizawa
Table 2. Fluorination of Phenol with N-Fluoropyridiniumsulfonates productC(%) T(“C) timea (h) additive convn*(%) o-fluorophenol p-fluorophenol 2,4-difluorophenol 100 24 81 57
