Synthesis of some fluorinated pyridines using tetrabutylammonium fluoride

Article abstract of DOI:10.1080/104265091001056

Some bromo- and chloromethyl pyridines were synthesized using radical substitution reactions. Further reaction of these halopyridines with activated tetrabutylammonium fluoride under mild conditions gave the related fluorinated pyridines. The yields of products following recrystallization were of the order of 30-93%. ¹H, ¹³C, and ¹⁹F spectroscopies together with elemental analysis were used characterize products. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/104265091001056

Phosphorus, Sulfur, and Silicon, 181:405–412, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265091001056
Synthesis of Some Fluorinated Pyridines Using
Tetrabutylammonium Fluoride
A. Mobinikhaledi
N. Foroughifar
Department of Chemistry, University of Arak, Arak, Iran
Some bromo- and chloromethyl pyridines were synthesized using radical substi-
tution reactions. Further reaction of these halopyridines with activated tetrabuty-
lammonium fluoride under mild conditions gave the related fluorinated pyridines.
1
The yields of products following recrystallization were of the order of 30–93%. H,
13
19
C, and F spectroscopies together with elemental analysis were used characterize
products.
Keywords Fluromethyl; pyridine; tetrabutylammonium fluoride
INTRODUCTION
Introduction of fluorine at the methyl site of substituted pyridines has
an important role in biological systems due to high NMR sensitivity
of 19F and the lake of natural 19F-containing metabolites compared
to other nuclei. Alkali metal fluorides have been traditionally used
for the synthesis of fluromethylpyridines.1−8 However preparation of
fluorinated pyridines by using alkali metal reagents require vigorous
reaction conditions due to their insolubility in organic solvents. Syn-
thesis of fluorinated pyridines under moderate conditions with an as-
sociated relatively high yield could be achieved through the use of the
alternative fluorinating agents such as tetraalkylammonium fluorides.
These reagents provide a soluble form of fluoride in polar aprotic organic
solvent systems and their reactions are fast at r.t.9 The nucleophilic-
ity of the fluoride ion in these situations is increased relative to alkali
metal fluoride as a consequence of reducing the effect of ion pairing by
replacing the metal ion with a large organic cation. However the diffi-
culty in this approach is that these reagents are very basic and hence
Received January 18, 2005; accepted February 22, 2005.
Address correspondence to A. Mobinikhaledi, University of Arak, Depart-
ment of Chemistry, Faculty of Science, Dr. Beheshti Avenue, Arak. Iran.
E-mail: akbar mobini@yahoo.com
405

406
A. Mobinikhaledi and N. Foroughifar
promote an elimination as well as a displacement reaction. The elimi-
nation reaction is not significant in this work, as benzylic substitution is
required. The purpose of the present work is to extend the preparation
method of fluorinated pyridines using Tetrabutylammonium Fluoride
(TBAF).
RESULTS AND DISCUSSION
The 2- or 4-position of 1, 2, and 3, for making brominated pyridines,
were functionalized by bromine using NBS to give 4a (93%), 4c (4%),
and 5b (60%). In contrast reaction of 4-methylpyridine with NBS was
unsuccessful. In the reaction of 2,3,4,5,6-pentamethylpyridine, 3, with
NBS, some 2,6-bis(bromomethyl)-3,4,5-trimethylpyridine 5c were also
isolated (Scheme 1). In the case of 2 and 3 it was observed that
the 2-bromomethyl compounds were obtained in preference to the
4-derivative. Only a small amount of 4-bromomethyl compound (4–
1
7%) was detected by HNMR. As a result an alternative route using
4-(hydroxymethyl)-2,6-dimethylpyridine10 was adopted for preparation
SCHEME 1

Synthesis of Some Fluorinated Pyridines
407
of 4c (82%). The preference for 2-bromination over 4- is consistent with
the lack of success in brominating 4-methylpyridine. All fluorinated
compounds were prepared by the reaction of the appropriate substi-
tuted bromo- or chloromethylpyridines with activated TBAF as a com-
1
mon fluoride ion source. The HNMR spectra of the synthesized com-
pounds are simple and show two distinct aliphatic and aromatic pro-
ton rersonances. The aromatic protons resonate at 6.93–7.58 ppm and
the methyl protons resonate as a singlet or doublet at 1.35–2.54 ppm.
The protons of the CH2Br and CH2Cl groups appear as a singlet at
4.32–4.58 ppm. However the CH2F protons resonate as a doublet at
5.51–5.34 ppm.
EXPERIMENTAL
Activated TBAF was prepared according to the literature.11 TBAF hy-
drate (0.30 g) was heated in a 25-mL flask with stirring at 40–45◦C
under vacuum (1 mm Hg) for 48 h until constant weight (0.20 g) was
obtained. Column chromatography was carried out using Merck sil-
ica gel #9385 with a loading ratio of 1:60 (crude material:adsorbent).
Solvent ratio is given as volume percentages. The precursors 1 and 2
were commercially available and 3 was synthesized according to the
literature.12−14 1H and 13C NMR spectra were recorded at 25◦C on Var-
ian VXRS 300 MHz spectrometer using Me4Si (TMS) as an internal
standard and CDCl3 as a solvent. 19F NMR spectra were referenced to
external fluorotrichloromethane in CDCl3. Reaction courses were mon-
itored by thin layer chromatography.
4-(Bromomethyl)-2,6-di-tert-butylpyridine (4a)
A mixture of 2,6-di-tert-butyl-4-methylpyridine, 1, (0.21 g, 1.0 mmol),
NBS (0.18 g, 1 mmol), and dibenzoyl peroxide (0.025 g, 1 mmol) in dry
carbon tetrachloride (15 mL) was refluxed under N2 for 3 h. The mixture
was then cooled in an ice bath and the precipitated succinimide was
removed by filtration. The solvent was evaporated to give a brown oily
mixture. This mixture was dissolved in carbon tetrachloride (15 mL).
NBS (0.036 g, 0.20 mmol) and dibenzoyl peroxide (0.0050 g, 0.021 mmol)
added and refluxed under N2 for another 2 h. The crude product was
distilled at 90–110◦C/2 mm Hg to give pure compound 4a (93%).
1H NMR (CDCl3): δ (ppm): 1.35 (18H, s, 2 × t-butyl), 4.38 (2H, s,
CH2Br), 7.09 (2H, s, Ar). 13C NMR (CDCl3): δ (ppm): 30.1 (2 × t-butyl),
32.2 (CH2Br), 37.7 (2 × C), 115.3 (2 × CH, Ar), 145.7 (1 × C, Ar), 168.4
(2 × C, Ar).

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A. Mobinikhaledi and N. Foroughifar
2,6-Di-tert-Butyl-4-(Fluoromethyl)pyridine (4b)
A solution of 4-(bromomethyl)-2,6-di-tert-butylpyridine, 4a, (0.15 g,
0.53 mmole) in dry dichloromethane (5.0 mL) was added to activated
tetrabutylammonium fluoride (0.15 g, 0.57 mmol) under an inert atmo-
sphere at r.t. The solvent was removed under reduced pressure and the
mixture was kept at 25◦C for 8 h in a closed vessel. The reaction mixture
was extracted with pentane (5 × 10 mL) and the solvent evaporated to
give a crude material. Chromatography on silica gel using hexane as
an eluent gave the desired compound 4b (0.057 g, 48%) as a white oily
product.
1H NMR (CDCl3): δ (ppm): 1.35 (18H, s, 2 × t-butyl), 5.42 (2H, d, J =
48.0 Hz, CH2F), 7.18 (2H, s, Ar).
13C NMR (CDCl3): δ(ppm): 30.1 (2 × t-butyl), 38.0 (2 × C), 82.6 (d,
J = 169.2 Hz, CH2F), 112.7 (d, J = 7.4 Hz, 2 × CH, Ar), 144.8 (d, J =
18.3 Hz, 1 × C, Ar), 168.1 (2×C, Ar).
19F NMR (CDCl3): δ(ppm): −217.4 (t, J = 48.2 Hz, CH2F).
Anal. cald. for C14H22FN: C, 75.4; H, 9.9; F, 8.5; N, 6.3. Found: C,
75.4; H, 9.6; F, 8.2; N, 5.9%.
4-(Bromomethyl)-2,6-Dimethylpyridine (4c)
A solution of 4-(hydroxymethyl)-2,6-dimethylpyridine10 (1.5 g, 11 mmol)
in 48% HBr (35 mL) was refluxed for 4 h. The solvent was evaporated
under reduced pressure to give a brown thick paste that was washed
with cold absolute ethanol (3 × 15 mL). The residue was dissolved in wa-
ter (10 mL) and made basic (pH > 10) with sodium hydrogen carbonate.
The aqueous solution was extracted with diethyl ether (3 × 20 mL) and
dried with MgSO4. After evaporation of the solvent the crude product
was chromatographed on silica gel. Elution with chloroform:methanol
(9:1) gave the product 4c as a white oily liquid (1.8 g, 82%).
1H NMR (CDCl3): δ (ppm): 2.52 (6H s, 2 × CH3), 4.32 (2H, s, CH2Br),
6.97 (2H, s, Ar).
13C NMR (CDCl3): δ (ppm): 24.4 (2 × CH3), 30.9 (CH2Br), 120.1 (2 ×
CH, Ar), 146.6 (1 × C, Ar), 158.5 (2 × C, Ar).
Anal. cald. for C8H10BrN: C, 48.0; H, 5.7; Br, 39.6; N, 6.8. Found: C,
48.3; H, 5.4; Br, 39.8; N, 6.9%.
4-(Fluoromethyl)-2,6-Dimethylpyridine (4d)
A solution of 4-(bromomethyl)-2,6-dimethylpyridine, 4c, (0.50 g,
2.5 mmol) in dichloromethane (5 mL) was added to activated TBAF
(0.8 g, 3.1 mmol). The solvent was then evaporated in vacuo and the

Synthesis of Some Fluorinated Pyridines
409
mixture stirred for 8 h at r.t. in a closed vessel. The reaction mixture
was extracted with pentane (5 × 5 mL) to give the crude product, which
was chromatographed on silica gel. Elution with chloroform: methanol
(9:1) afforded the desired compound 4d as a white oily liquid (0.16 g,
45%).
1H NMR (CDCl3): δ (ppm): 2.54 (6H s, 2 × CH3), 5.34 (2H, d, J =
47.3 Hz, CH2F), 6.93 (1H, s, Ar).
13C NMR (CDCl3): δ(ppm): 24.5 (2 × CH3), 80.6 (d, J = 171.7 Hz,
CH2F), 117.1 (d, J = 6.1 Hz, 2 × CH, Ar) 145.9 (d, J = 17.2 Hz, 1 × C,
Ar), 158.2 (2 × C, Ar).
19F NMR (CDCl3): δ(ppm): −222.5 (t, J = 47.3 Hz, CH2F).
Anal.cald.for C8H10FN: C, 69.1; H, 7.2; F, 13.6; N, 10.1. Found: C,
68.9; H, 7.3; F, 13.8; N, 10.0%.
2-(Fluoromethyl)-4,6-Dimethylpyridine (5a)
2-(bromomethyl)-4,6-dimethylpyridine15 (0.2 g,
1 mmol) in dry
dichloromethane (5.0 mL) was added to activated tetrabutylammonium
fluoride (0.31 g, 1.2 mmol) under an inert atmosphere at r.t. The sol-
vent was removed under reduced pressure and the mixture was stirred
for 48 h in a closed vessel at r.t. The reaction mixture was extracted
with pentane (5 × 10 mL) and the combined extracts were evaporated
under reduced pressure to give the crude product. The crude product
was chromatographed on silica gel. Elution with a mixture of acetoni-
trile:dichloromethane:hexane (1:2:1) gave the pure product 5a (0.050 g,
35%). A 60% yield was achieved by using excess (1:3) of TBAF. b.p.
50–54◦C/1 mm Hg.
1H NMR (CDCl3): δ (ppm): 2.34 (3H, s, CH3), 2.51 (3H, s, CH3), 5.42
(2H, d, J = 47.2 Hz, CH2F), 6.94 (1H, s, Ar), 7.09 (1H, s, Ar).
13C NMR (CDCl3): δ (ppm): 21.1 (CH3), 24.2 (CH3), 84.7 (d, J =
168.7 Hz, CH2F), 118.6 (d, J = 5.8 Hz, CH, Ar), 123.6 (CH, Ar), 148.4
(C, Ar), 155.5 (d, J = 20.3 Hz, C, Ar), 157.9 (C, Ar).
19F NMR (CDCl3) : δ (ppm): −220.4 (t, J = 47.1 Hz, CH2F).
Anal. cald. for C8H10FN: C, 69.1; H, 7.2; F, 13.6; N, 10.1. Found: C,
68.9; H, 7.3; F, 13.7; N, 10.1%.
2-(Bromomethyl)-3,4,5,6-Tetramethylpyridine (5b)
A mixture of 2,3,4,5,6-pentamethylpyridine, 3, (0.80 g, 4.8 mmol), NBS
(0.90 g, 5 mmol), and dibenzoyl peroxide (0.025 g, 0.10 mmol) in dry
carbon tetrachloride (20 mL) was refluxed under N2 atmosphere for 3 h.
The mixture was cooled in an ice bath and the precipitated succinimide

410
A. Mobinikhaledi and N. Foroughifar
removed by filtration. The solvent was evaporated in vacuo at r.t. to
give a brown oily crude product.
1H NMR spectroscopy showed that the product is a mixture
of 70% 2-(bromomethyl)-3,4,5,6-tetramethylpyridine (δ = 4.55 ppm,
CH2Br) and 20% 2,6-bis(bromomethyl)-3,4,5,-trimethylpyridine (δ =
4.51 ppm, CH2Br). Chromatography on silica gel and elution with
acetonitrile:hexane:dichloromethane (2:1:1) gave 2-(bromomethyl)-
3,4,5,6-tetramethylpyridine 5b (0.54 g, 60%).
1H NMR (CDCl3) : δ (ppm): 2.20 (3H, s, CH3), 2.32 (3H, s, CH3), 2.52
(3H, s, CH3), 2.60 (3H, s, CH3), 4.55 (2H, s, CH2Br).
13C NMR (CDCl3): δ(ppm): 14.8 (CH3), 15.5 (CH3), 21.3 (CH3), 24.7
(CH3), 30.8 (CH2Br), 122.9 (C, Ar), 125.1 (C, Ar), 144.8 (C, Ar), 154.9
(C, Ar), 156.7 (C, Ar).
Anal. cald. for C10H14BrN: C, 52.6; H, 6.1; Br, 35.2; N, 6.1.
Found: C, 52.9; H, 6.2; Br, 34.8; N, 5.9%. 2,6-bis(bromomethyl)-3,4,5-
trimethylpyridine 5c was also isolated (0.32 g 30%).
1H NMR (CDCl3) : δ(ppm): 2.41 (3H, s, CH3), 2.59 (6H, s, 2 × CH3),
4.51 (2H, s, 2 × CHBr2).
13C NMR (CDCl3) : δ (ppm): 15.5 (2 × CH3), 21.3 (CH3), 31.4 (2 ×
CH2Br), 127.1 (2 × C, Ar), 144.8 (C, Ar), 156.7 (2 × C, Ar).
Anal. cald. for C10H13Br2N: C, 39.1; H, 4.2; Br, 52.1; N, 4.6. Found:
C, 38.9; H, 4.2; Br, 51.8; N, 4.9%.
2-(Fluoromethyl)-3,4,5,6-Tetramethylpyridine (5d)
A solution of 2-(bromomethyl)-3,4,5,6-tetramethylpyridine, 5b, (0.60 g,
2.6 mmol) in dry dichloromethane (5 mL) was added to activated TBAF
(1.1 g, 4.2 mmol). The solvent was removed under reduced pressure
and the reaction mixture was stirred for 8 h at 25◦C in a closed vessel.
The product was extracted with dry pentane (5 × 5 mL) then evapo-
rated to give a crude yellow oily product. Distillation at 150◦C/ 22 Hg
gave white crystals of 2-(fluoromethyl)-3,4,5,6-tetramethylpyridine 5d
(0.2 g, 45%).
1H NMR (CDCl3) : δ (ppm): 2.21 (3H s, CH3), 2.33 (3H, d, J = 2.1 Hz,
CH3), 2.51 (3H, d, J = 3.3 Hz, CH3), 2.59 (3H, d, J = 2.1 Hz, CH3), 5.51
(2H, d, J = 48.2 Hz, CH2F).
13C NMR (CDCl3): δ (ppm): 15.1 (CH3), 15.4 (CH3), 22.2 (CH3), 23.5
(CH3), 79.2 (d, J = 172.3 Hz, CH2F), 125.2 (d, J = 22.7 Hz, C, Ar), 128.1
(C, Ar), 146.1 (C, Ar), 154.2 (d, J = 6.3 Hz, C, Ar), 156.7 (C, Ar).
19F NMR (CDCl3): δ (ppm): −206.9 (t, J = 48.1 Hz, CH2F).
Anal. cald. for C8H14FN: C, 71.8; H, 8.4; F, 11.4; N, 8.4. Found: C,
71.8; H, 8.4; F, 11.4; N, 8.3%.

Synthesis of Some Fluorinated Pyridines
411
3,5-Bis(chloromomethyl)-2,6-Dimethylpyridine (6a)
Freshly distilled thionyl chloride (5.0 g) was added to the 3,3-
bis(hydroxymethyl)-2,6-dimethylpyridine (0.90 g, 5.4 mmol) and cooled
at 0◦C. The mixture was kept at 0◦C for 15 min and then heated un-
der reflux for 1 h. The excess thionyl chloride was removed in vacuo to
give a thick brown paste. Ice-cooled water (10 mL) was added and the
mixture was made basic (pH > 11) with 10% sodium hydroxide solu-
tion. The cream precipitate was extracted with diethyl ether to give a
crude product (0.89 g, 81%), which was purified by distillation at 150–
160◦C/1 mm Hg to give white crystals 6a b.p.: 150◦C/1 mm Hg.
1H NMR (CDCl3): δ( ppm): 2.61 (6H, s, 2 × CH3), 4.58 (4H, s, 2 ×
CH2Cl), 7.54 (1H, s, Ar). 13C NMR (CDCl3) : δ (ppm): 24.2 (2 × CH3),
45.9 (2 × CH2Cl), 131.4 (2 × C, Ar), 141.0 (CH, Ar), 159.6 (2 × C, Ar).
3,5-Bis(fluoromethyl)-2,6-Dimethylpyridine (6b)
A solution of 3,5-bis(chloromomethyl)-2,6-dimethylpyridine, 6a, (0.12 g,
0.59 mmol) in dichloromethane (2 mL) was added to the activated TBAF
(0.22 g, 0.84 mmol). The solvent was removed in vacuo and the mixture
stirred for 48 h at 25◦C in a closed vessel. The reaction mixture was ex-
tracted with dry pentane (5 × 5 mL) and the organic extracts were evap-
orated in vacuo to give a yellow oily crude product. Chromatography
silica gel and elution with acetonitrile:hexane:dichloromethane (2:3:5)
gave 3,5-bis(fluoromethyl)-2,6-dimethylpyridine, 6b, (0.045, 45%).
1H NMR (CDCl3) : δ (ppm): 2.56 (6H, s, 2 × CH3), 5.41 (4H, d, J =
48.3 Hz, 2 × CH2F), 7.58 (H, s, Ar).
13C NMR (CDCl3): δ(ppm): 21.6 (2 × CH3), 81.8 (d, J = 167.4 Hz, 2
× CH2F), 127.1 (d, J = 16.5 Hz, 2 × C, Ar), 136.4 (d, J = 7.5 Hz, CH,
Ar), 156.9 (2 × C, Ar).
Anal. cald. for C9H11F2N: C, 63.2; H, 6.4; F, 22.2; N, 8.2. Found: C,
62.8; H, 6.6; F, 22.1; N, 7.9%.
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