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SELECTFLUORTM F-TEDA-BF4 MEDIATED INTRODUCTION OF PERFLUOROALKYL-CONTAINING GROUPS IN THE BENZYLIC POSITION
OF HEXAMETHYLBENZENE
Stojan Stavber,* Petra Kralj, Marko Zupan
Laboratory for Organic and Bioorganic Chemistry, "Jožef Stefan" Institute and Department of Chemistry, University of Ljubljana, Jamova 39, SI-1000 Ljubljana, SLOVENIA, Fax: ++386 1 477 3811;
stojan.stavber@ijs.si
Received 18-02-2002
Abstract
An effective synthetic pathway for direct introduction of a perfluoroalkyl moiety-containing functional groups at the benzylic position in hexamethylbenzene involved treatment of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetra-fluoroborate) (SelectfluorTM F-TEDA-BF4 ) with hexamethylbenzene in the presence of polyfluoro alcohols or potassium salts of perfluoroalkane carboxylic acids.
Introduction
Bonding of fluorine atoms to organic molecules dramatically changes their physical properties and chemical and biological reactivities, thus giving a constant impetus to basic and applied research in the field of the organic chemistry of fluorine compounds,1,2 as manifested in comprehensive commercial applications of fluorinated organic materials.3,4 The properties of compounds containing the perfluoroalkyl (Rf) group are considerably different from those of their hydrocarbon or partially fluorinated counterparts. These differences are the result of the high ionization potential of the fluorine atom, its extreme electronegativity and low polarizability, implying the stability, very weak intermolecular forces and low surface energy of perfluoroalkylated organic compounds. Due to the importance of these kinds of materials many reagents and methods for introducing the Rf group into organic molecules have been developed and the results reviewed.1,3,4,5
The introduction of organic molecules bearing a reactive N-F bond as selective fluorinating reagents under mild reaction conditions was very soon followed by their versatile application in synthetic organic chemistry.1,6 N-F organic compounds possess moderate to strong oxidative power7 which might cause a certain competition between fluorination and oxidation of the target molecule, but, on the other hand, opens the
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possibility for the use of N-F reagents as mediators of several other types of functionalisation of organic compounds.8,9 We now report that one of the most popular N-F reagents, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-borate) (1), known under the commercial name of SelectfluorTM F-TEDA-BF4 10, could be used as a mediator for introduction of some perfluoro functional groups at the benzylic position in hexamethylbenzene.
Results and Discussion
We recently developed a synthetic method for effective and versatile direct functionalisation of the benzylic position in hexamethylbenzene (HMB) mediated by NF reagents in the presence of alcohols, carboxylic acids or nitriles as the source of nucleophiles.9 Although the formation of the corresponding pentamethylbenzyl ether (4a, Table ) after reaction in the presence of 2,2,2-trifluoroethanol was not so effective as when using ethanol, the only moderate drop of efficiency of the reaction encouraged us to extend this method to the introduction of perfluoroalkyl-containing functional groups. In a typical experiment we treated HMB with F-TEDA-BF4 in a mixture of acetonitrile and a polyfluoro alcohol (MeCN/RfOH 9.5 : 0.5) and established that the use of 2,2,3,3,3-pentafluoropropan-1-ol, 1H,1H-heptafluoro-1-butanol, as well as hexafluoroisopropanol, gave the expected pentamethylbenzyl ethers 4b, 4c and 4d in high yield. Unfortunately, reactions in the presence of higher polyfluorinated n-alcohols (hexanol, decanol …) or perfluoro-tert-butanol resulted in the formation of reaction mixtures too complex to have any synthetic value.
The reaction of HMB with F-TEDA-BF4 in trifluoroacetic acid readily gave pentamethylbenzyl trifluoroacetate (4e) almost quantitatively. For the preparation of the corresponding pentamethylbenzyl perfluoroalkyl esters (4f-i) we had to use potassium salts of perfluorocarboxylic acids (R = K, Table) and MeCN as solvent, since reactions in the pure acids would be too inconvenient, whereas in a MeCN/acid mixture Rittertype benzylic amidation was observed to take place9. Under these reaction conditions esters 4f-4i were formed in high to excellent yield.
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Table:
Reaction of hexamethylbenzene with F-TEDA-BF4 (2) in MeCNa) in the presence of polyfluoroalkylalcohols or potassium salts of perfluoroalkyl carboxylic acid at 55 oC
F
N*
N I CH2Cl
2
(BF4-)2
MeCN
R-Y-Rf (3) R = H, Y = O R = K, Y =OC(O)
CH2-Y-Rf
a
Entry	3	R	Y	Rf	Reaction time (min)	Yield b) of 4 (%)
1	a	H	O	CF3CH2	75	75
2	b	H	O	CF3CF2CH2	80	70
3	c	H	O	CF3(CF2)2CH2	80	70
4	d	H	O	(CF3)2CH	120	71
5	e	H	OC(O)	CF3	30	97
6	f	K	OC(O)	CF3CF2	60	97
7	g	K	OC(O)	CF3CF2CF2	90	72
8	h	K	OC(O)	CF3(CF2)4	75	96
9	i	K	OC(O)	CF3(CF2)6	60	90
a) in the case of 3e (entry 5) the solvent was TFA; b) from the 19F nmr spectra of crude reaction mixtures using octafluoronaphthalene as internal reference
Further, we tried to apply the protocol for benzylic amidation of HMB9 using perfluorinated nitriles. Unfortunately the reactions with perfluoroalkanenitriles failed; with pentafluorobenzonitrile (5), however, 2,3,4,5,6-pentafluoro-N-(pentamethyl-benzyl)benzamide (6, Scheme) was obtained in high yield.
CH2NHCOC6F5
+   F-TEDA-BF4
TFA
C6F5CN (5)
6
(81%)
Scheme

1
4
1
2
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Experimental
SelectfluorTM F-TEDA-BF4, polyfluorinated alcohols 3a-d, perfluorinated acids 3e-i, and pentafluorobenzonitrile 5 were purchased from Apollo and used as received. Preparative GLC was carried out on a Varian 3300 instrument. 1H and 19F NMR spectra were recorded on a Varian 360L spectrometer using TMS and CCl3F as internal standards, respectively, at 60 MHz for 1H and 56.4 MHz for 19F resonance. IR spectra were recorded on a Perkin Elmer 1310 spectrometer using KBr as supporting material. Mass spectral measurements were carried out on an Autospec Q instrument using electron ionisation (EI) at 70 eV. Melting points were determined on a Büchi 535 apparatus and are uncorrected. Elemental analyses were carried out on a Perkin-Elmer 2400 CHN analyser.
Synthesis of Pentamethylbenzyl Polyfluoroalkyl Ethers: General Procedure
HMB 1 (2 mmol) and F-TEDA-BF4 2 (2 mmol) were dissolved in 19 mL of MeCN, 1 mL of polyfluorinated alcohol 3a, 3b, 3c or 3d was added and the solution stirred at 55 oC until KI-starch paper showed consumption of 2 (0.5-2 hours). The solvent was removed under reduced pressure, the crude reaction mixture dissolved in CH2Cl2 (50 mL), insoluble material filtered off, the solution washed with water (25 mL), dried over anhydrous Na2SO4, and the solvent evaporated in vacuo. The pure products 4a-d were isolated from the thus obtained crude reaction mixtures by preparative gas chromatography (FFAP 5%, Chromosorb W/AW 80/100, T = 130 oC) in order to obtain satisfactory elemental analyses.
Pentamethylbenzyl 2,2,2-trifluoroethyl ether (4a)
White crystals, mp 70-72 oC. 1H NMR (CDCl3) ?(ppm): 2.2 (s, 3H), 2.3 (s, 12H), 3.8 (q,
J=9.4 Hz, 2H), 4.8 (s, 2H). 19F NMR (CDCl3) ?(ppm): –75.0 (t, J=9.4 Hz, 3F). MS: m/z:
260 (M+, 35%), 245 (20), 161 (100), 160 (95), 145 (25), 91 (18). IR(cm-1): 1280, 1155,
1110, 990. Anal. Calcd for C14H19F3O: C, 64.59%; H, 7.36%. Found: C, 64.28%; H,
7.41%.
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2,2,3,3-Pentafluoropropyl pentamethylbenzyl ether (4b)
White crystals, mp 60-62 oC. 1H NMR (CDCl3) ?(ppm): 2.2 (s, 3H), 2.3 (s, 12H), 4.0 (t, J=9.4 Hz, 2H), 4.8 (s, 2H). 19F NMR (CDCl3) ?(ppm): –84.2 (broad s, 3F), –123.7 (t, J=9.4 Hz, 2F). MS: m/z: 310 (M+, 50%), 295 (25), 161 (93), 160 (100), 145 (26), 91 (23). IR(cm-1): 1250, 1185, 1150, 1100, 1040, 975. HRMS: m/z calcd for C15H19F5O (M+): 310.1356; found: 310.1366.
2,2,3,3,4,4,4-Heptafluorobutyl pentamethylbenzyl ether (4c)
White crystals, mp 67-68 oC. 1H NMR (CDCl3) ?(ppm): 2.3 (s, 3H), 2.4 (s, 12H), 4.0 (t, J=9.4 Hz, 2H), 4.8 (s, 2H). 19F NMR (CDCl3) ?(ppm): –81.3 (t, J=9.4 Hz, 3F), –120.7 (m, 2F), –128.0 (broad s, 2F). MS m/z(relative intensity): 360 (M+, 45%), 345 (25), 161 (92), 160 (100), 145 (25), 91 (17). IR(cm-1): 1230, 1170, 1110, 995. Anal. Calcd for C16H19F7O: C, 53.33%; H, 5.32%. Found: C, 53.32%; H, 5.15%.
Pentamethylbenzyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (4d) White crystals, mp 87-88 oC. 1H NMR (CDCl3) ?(ppm): 2.3 (s, 3H), 2.4 (s, 12H), 4.1 (sept, J=6.6 Hz, 1H), 5.0 (s, 2H). 19F NMR (CDCl3) ?(ppm): –74.7 (d, J=6.6 Hz, 6F). MS m/z(relative intensity): 328 (M+, 60%), 313 (20), 161 (100), 160 (50), 145 (12), 91 (16), 69 (26). IR (cm-1): 1280, 1220, 1180, 1110, 1090, 970. Anal. Calcd for C15H18OF6: C, 54.88%; H, 5.53%. Found: C, 54.61%; H, 5.44%.
Synthesis of Pentamethylbenzyl Perfluoroalkyl Esters: General Procedure Aqueous solutions of perfluorocarboxylic acids 3f-i (R=H) were neutralised by KOH (10% in water), water evaporated by slow heating and potassium salts 3f-i thus obtained dried in vacuo for a few hours. HMB 1 (2 mmol), F-TEDA-BF4 2 (2.2 mmol) and 3f, 3g, 3h or 3i (2.4 mmol) were dissolved in 20 mL of MeCN (in the case of preparation of 4e TFA (3e) was used as solvent) and the solution stirred at 55 oC until KI-starch paper showed consumption of 2 (0.5-2 hours). The solvent was removed under reduced pressure, the crude reaction mixture dissolved in CH2Cl2 (50 mL), insoluble material filtered off, the solution washed twice with 5% aqueous KOH (25 ml) and water (25 mL), dried over anhydrous Na2SO4, and the solvent evaporated in vacuo. The pure
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products 4d-h were isolated from the crude reaction mixtures thus obtained by gas chromatography (FFAP 5%, Chromosorb W/AW 80/100, T=130 oC). Data for pentamethylbenzyl trifluoroacetate 4e were in agreement with those already published11, while products 4f-i were crystallised from methanol in order to obtain satisfactory elemental analyses.
Pentamethylbenzyl pentafluoropropanoate (4f)
White crystals, mp 125-126.5 oC. 1H NMR (CDCl3) ?(ppm): 2.2 (s, 6H), 2.3 (s, 9H), 5.5 (s, 2H). 19F NMR (CDCl3) ?(ppm): –83.8 (t, J=1.5 Hz, 3F), –121.7 (q, J=1.5 Hz, 2F). MS m/z(relative intensity): 324 (M+, 60%), 161 (100), 160 (90), 145 (18), 91 (15), 69 (20). IR (cm-1): 1765, 1300, 1220, 1180, 1145, 1020, 900. Anal. Calcd for C15H17F5O2: C, 55.55%; H, 5.28%. Found: C, 55.79%; H, 5.12%.
Pentamethylbenzyl heptafluorobutanoate (4g)
White crystals, mp 73-74 oC. 1H NMR (CDCl3) ?(ppm): 2.2 (s, 6H), 2.3 (s, 9H), 5.5 (s, 2H). 19F NMR (CDCl3) ?(ppm): –82.0 (t, J = 9.4 Hz, 3F), –120.0 (q, J = 9.4 Hz, 2F), -128.0 (broad s, 2F). MS m/z(relative intensity): 374 (M+, 28%), 161 (98), 160 (100), 145 (18), 91 (17), 69 (16). IR(cm-1): 1775, 1305, 1265, 1225, 1145, 1120, 900. Anal. Calcd for C16H17F7O2: C, 51.34%; H, 4.58%. Found: C, 51.29%; H, 4.47%.
Pentamethylbenzyl undecafluorohexanoate (4h)
White crystals, mp 62.5-63.5 oC. 1H NMR (CDCl3) ?(ppm): 2.2 (s, 6H), 2.3 (m, 9H), 5.6 (s, 2H). 19F NMR (CDCl3): ? = –81.7 (m, 3F), –118.7 (m, 2F), -123.3 (m, 4F), -126.7 (m, 2F). MS m/z (relative intensity): 474 (M+, 27%), 161 (77), 160 (100), 145 (18), 91 (15), 69 (75). IR(cm-1): 1772, 1318, 1260, 1220, 1200, 1140, 1100, 900. Anal. Calcd for C18H17F11O2: C, 45.58%; H, 3.61%; found: C, 45.87%; H, 3.70%.
Pentamethylbenzyl pentadecafluorooctanoate (4i)
White crystals, mp 69.5-71 oC. 1H NMR (CDCl3) ?(ppm): 2.2(s, 6H), 2.3 (s, 9H), 5.7 (s, 2H). 19F NMR (CDCl3) ?(ppm): –81.3 (m, 3F), –119.0 (m, 2F), -121 to -124 (m, 8F), -127.0 (m, 2F). MS m/z (relative intensity): 574 (M+, 30%), 161 (98), 160 (100), 145(27),
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91 (23), 69 (30). IR(cm-1): 1770, 1326, 1200, 1140, 1010, 905. Anal. Calcd for C20H17F15O2: C, 41.82%; H, 2.98%; found: C, 42.39%; H, 2.79%.
2,3,4,5,6-Pentafluoro-N-(pentamethylbenzyl)benzamide (6)
To a solution of 2 mmol of HMB in TFA (20 mL) 6 mmol of pentafluorobenzonitrile (5) and 2 mmol of F-TEDA-BF4 were added and the reaction mixture was stirred at 55 °C for 2.5 hours. The solvent was removed under reduced pressure and the crude reaction mixture dissolved in 50 mL of CH2Cl2, insoluble material filtered off, the solution washed with 2% aqueous KOH (25 mL) and water (25 mL), dried over anhydrous Na2SO4, and the solvent evaporated to half its volume. The product 6 was precipitated from this solution by n-hexane, filtered off, dried and crystallised from acetone/n-hexane 1:2.
White crystals, mp 233-235 oC. 1H NMR (CDCl3) ?(ppm): 2.2 (s, 6H), 2.3 (s, 9H), 4.7 (d, J=5 Hz, 2H), 5.9 (broad s, 1H). 19F NMR (CDCl3): ? = –140.7 (m, 2F), –151.3 (tt, J=18 Hz, 2 Hz, 1F), –161.0 (m, 2F). MS m/z (relative intensity): 371 (M+, 25%), 356 (15), 195 (35), 161 (28), 160 (100), 145 (28), 91 (12). IR (cm-1): 3280, 1650, 1540, 1500, 1320, 1110, 990. Anal. Calcd for C19H18NF5O: C, 61.45%; H 4.89%; N 3.77%; found: C, 60.93%; H, 4.85%; N 3.58%.
Acknowledgement
The authors are grateful to the Ministry of Education, Science and Sport of the Republic of Slovenia for financial support, and to T. Stipanoviè and Prof. B. Stanovnik for elemental combustion analysis.
References
(1)          Baasner, B.; Hagemann, H.; Tatlow, J. C. (Eds), Methods of Organic Chemistry (Houben-Weyl) Vol. E 10a and 10b: Organofluorine Compounds, Thieme, New York, 1999.
(2)          Schofield, H. J. Fluorine Chem. 1999, 100, 7–11.
(3)          Banks, R. E.; Smart, B. E.; Tatlow, J. C. (Eds.); Organofluorine Chemistry, Principles and Commercial Applications, Plenum Press, New York, 1994.
(4)          Hiyama, T. (Ed.), Organofluorine Compounds, Chemistry and Applications, Springer, Berlin, 2000.
(5)          Umemoto, T. Chem. Rev. 1996, 96 , 1757–1777.
(6)          a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737–1757.
b) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431–-12477.
c) Furin, G. G.; Fainzilberg, A. A. Russian Chem. Rev. 1999, 68, 653–684.
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(7)          a) Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.; Lal, G.S. J. Fluorine Chem. 1992, 59, 157–162. b) Differding, E.; Bersier, P. M. Tetrahedron 1992, 48, 1595–1604.
(8)          Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron Lett. 1997, 38, 6305–6306.
(9)          Stavber, S.; Kralj, P.; Zupan, M. Synlett 2001, 1152–1154.
(10)        Banks, R. E. J. Fluorine Chem. 1998, 87, 1–17.
(11)       Zupan, M. Chimia 1976, 30, 305–306.
Povzetek
Reakcije heksametilbenzena z 1-klorometil-4-fluoro-1,4-diazoniabiciklo[2.2.2] oktan bis(tetrafluoro boratom) (SelectfluorTM F-TEDA-BF4) ob prisotnosti polifluoro alkoholov ali kalijevih soli perfluoroalkil karboksilnih kislin predstavljajo uèinkovito sintetsko metodo za uvedbo funkcionalnih skupin, ki vsebujejo perfluoroalkilno verigo, na benzilno mesto v heksametilbenzenu.
S. Stavber, P. Kralj, M. Zupan: SelectfluorTM F-TEDA-BF4 Mediated Introduction of Perfluoroalkyl…..