Synthesis of difluorinated pyridinecarboxaldehyde via electrophilic fluorination

Article abstract of DOI:10.1016/j.jfluchem.2006.02.009

An efficient synthesis of novel 3,5-difluoropyridine-4-carboxaldehyde using N-fluoro-benzenesulfonimide (NSFi) is described. Difluorination was achieved through the reaction of 3,5-dihalo-1,3-dioxolane pyridine with n-butyllithium followed by N-fluorobenzenesulfonimide at -120 °C in good to high yields. Maintaining the low temperature during the transmetallation was found to be critical for the selective formation of the difluoro-susbstitution over the monofluoro one.

Full text of DOI:10.1016/j.jfluchem.2006.02.009

Journal of Fluorine Chemistry 127 (2006) 755–759
www.elsevier.com/locate/fluor
Synthesis of difluorinated pyridinecarboxaldehyde via
electrophilic fluorination
*
Yoon-Joo Ko, Kyung-Bae Park, Seung-Bo Shim, Jung-Hyu Shin
School of Chemistry, Seoul National University, Seoul 151-742, Republic of Korea
Received 25 January 2006; received in revised form 13 February 2006; accepted 15 February 2006
Available online 28 February 2006
Abstract
An efficient synthesis of novel 3,5-difluoropyridine-4-carboxaldehyde using N-fluoro-benzenesulfonimide (NSFi) is described. Difluorination
was achieved through the reaction of 3,5-dihalo-1,3-dioxolane pyridine with n-butyllithium followed by N-fluorobenzenesulfonimide at À120 8C
in good to high yields. Maintaining the low temperature during the transmetallation was found to be critical for the selective formation of the
difluoro-susbstitution over the monofluoro one.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Difluoropyridine; 3,5-Difluoropyridine-4-carboxaldehyde
1. Introduction
reagents has grown in popularity and applications abound in
recent years as methods for the selective fluorination of
activated aromatics, alkenes, and enolates [9]. Despite
increased use of these regents, reports of electrophilic N-F
difluorinations in the literature are few in number.
Selectively fluorinated heterocyclic compounds are of a
considerable importance in bioorganic and medicinal chemistry
since these products possess unique properties [1] that allow a
variety of applications [2] in the design of bioactive compounds
[3]. Therefore, the development of efficient methodologies for
the preparation of new selectively fluorinated compounds is still
a challenge in heterocyclic chemistry.
Previously, we reported the synthesis of compounds 1, 3a,
and 3b (Fig. 1) [10]. These compounds were prepared as
precursors for the synthesis of fluoropyridyl-porphyrins used as
acetylcholine esterase (AChE) inhibitors in connection with
treatment for Alzheimer’s disease. The activity of AChE
inhibition was higher for the porphyrin derivatives derived from
more fluorine-substituted compound 3b than for the porphyrin
derivatives from 1. However, these compounds (3a and 3b) are
sparingly soluble in water. Thus, we envisioned preparing
difluorinated pyridine derivatives 2 in order to circumvent the
solubility problem. In this vein, to the best of our knowledge,
synthesis of 3,5-difluoropyridine-4-carboxaldehyde 2 has not
been reported. Herein, we report a new efficient synthetic
method of compound 2 via electrophilic difluorination using N-
fluorobenzenesulfinimide (NFSi).
The most commonly used methods for the synthesis of
fluorinated heterocyclic compounds include the nucleophilic
displacement of halogen substituents with a fluoride ion source
(Halex reaction) [4] and fluorodiazotisation of appropriate
amino-heterocycles (Balz-Schiemann process) [5,6]. However,
the synthetic utility of these methods depends on the
availability of the appropriate halo and amino heterocyclic
precursors and, furthermore, in some cases harsh reaction
conditions are required to achieve the fluorination. Alterna-
tively, selective replacement of hydrogen by fluorine offers a
more direct strategy for the synthesis of fluoro-heterocycles and
a limited number of electrophilic fluorination processes
involving the use of XeF2 [7] and AcOF [8] have been
reported in this context. Electrophilic fluorination using N-F
2. Results and discussion
Our initial attempt to synthesize 3,5-difluoropyridine-4-
carboxaldehyde involved defluorination from 2,3,5,6-tetra-
fluoropyridine-4-carboxaldehyde. A trifluoropyridine deriva-
tive 3a was synthesized starting with reduction of 2,3,5,
* Corresponding author. Tel.: +82 2 880 6655; fax: +82 2 886 4578.
E-mail address: junghyu@snu.ac.kr (J.-H. Shin).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.02.009

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Y.-J. Ko et al. / Journal of Fluorine Chemistry 127 (2006) 755–759
Table 1
Difluorination of pyridine derivatives with NFSi
Fig. 1. Fluorinated pyridinecarboaldehydes.
6-tetrafluoropyridine-4-carbonitrile with diisobutyl-aluminum
hydride (DIBAH) at low temperature [11], followed by
reduction of highly volatile aldehyde to alcohol. Selective
displacement of 6-fluorine in a tetrafluoropyridine ring with
hydrazine provided 6-hydrazinopyridine-4-carbinol [12].
Sequential removal of hydrazine by copper sulfate and Swern
oxidation of the subsequent alcohol gave 2,3,6-trifluoropyr-
idine-carboxaldehyde 3a in 78% yield. Unfortunately, this
methodology could not be applied to the synthesis of 3,5-
difluoropyridine-4-carboxaldehyde 2 due to the resistance of 3a
against further displacement with hydrazine at the 2-position.
The synthesis started with the formylation and methylation
of 3,5-dihalopyridine at the 4-position. Lithiation of 3,5-
dibromopyridines 4 using lithium diisopropylamide (LDA) and
subsequent reaction with methyl formate introduced the formyl
group (5) exclusively at the 4-position of the pyridine in good
yields (Scheme 1) [13]. However, treatment of 3,5-dibromo-
pyridine-4-carboxaldehyde 5 with 2.5 equiv. n-BuLi at À78 8C
in THF followed by 2.5 equiv. of NFSi resulted only undesired
side (polymerized) products. It may presumably be due to the
deactivation of the pyridine ring by a substituted formyl group
since this type of reaction involves the direct reaction of the F+
reagent. Thus, electron-rich substituents are often necessary to
promote the electrophilic fluorination reaction [14]. To
circumvent the deactivation through the formyl substitution,
we then decided to use methoxymethyl (MOM) ether pyridine
derivatives 6 [13] and dibromo-1,3-dioxolanylpyridine deriva-
tives 8 in the lithium–halogen exchange reaction (Scheme 1),
followed by treatment with NFSi, to generate 3,5-difluoropyr-
idine-4-carboxaldehyde 2 as depicted in Scheme 1. After
converting the formyl group into a MOM ether group or 1,3-
Entry
Substrate
Base
Temperature (8C)
Yieldsa (%)
Type A
Type B
1
2
6
6
6
6
6
6
8
8
8
8
8
8
n-BuLi
n-BuLi
s-BuLi
s-BuLi
t-BuLi
t-BuLi
n-BuLi
n-BuLi
s-BuLi
s-BuLi
t-BuLi
t-BuLi
À78
À120
À78
20
33
23
30
13
23
57
76
52
78
43
64
4
10
4
3
4
À120
À78
8
5
7
6
À120
À78
20
24
20
11
21
7
7
8
À120
À78
9
10
11
12
À120
À78
À120
15
a
Isolated yields; structures were determined by 1H NMR, 13C NMR, 19F
NMR, and MS.
dioxolane group via conventional protection protocols, we
examined an NFSi-mediated difluorination whether the yield
could be improved by performing the reaction in a stepwise
fashion using a variety of bases and reaction conditions listed in
Table 1.
Interestingly, the yields and selectivity of the reaction were
highly dependent upon the protecting group of the aldehyde.
When compound 6 was subjected to the lithiation using n-BuLi,
s-BuLi or t-BuLi followed by fluorination, the reaction yields
were only moderate and a marginal degree of chemoselectivity
was observed favoring the formation of difluorination product
Scheme 1.

Y.-J. Ko et al. / Journal of Fluorine Chemistry 127 (2006) 755–759
757
(entries 1–6). In all the cases, performing the reaction at lower
temperature (À120 8C) provided higher yields of the products
(entries 2, 4, and 6). However, fluorination using compound 8
was much more desirable in terms of yields and selective
formation of the desired difluorinated product was possible.
When compound 8 was treated with n-BuLi at À78 8C followed
by 2.5 equiv. of NFSi, a mixture of difluorinated compound 9a
and monofluorinated compound 9b were obtained in 57% and
24% yield, respectively (entry 7). Surprisingly, lowering the
reaction temperature to À120 8C afforded more selective
formation of the desired difluoronated compound 9a (76%),
which is readily separable by conventional chromatography.
Use of s-BuLi at À120 8C gave similar yields (78%) of the
difluorinated product (entry 10). However, treatment with t-
BuLi at À120 8C gave difluorinated compounds 9a in a
noticeably diminished yield (64%) than that of reaction using s-
BuLi (entry 12). The noticeable difference in the reaction
efficiency depending upon the protecting groups may
presumably due to their different ability to stabilize the
intermediate during the lithiation process. In this respect, 1,3-
dioxolane protecting group was more efficient compared to the
MOM ether group.
recorded on a Bruker Avance 500 (500 MHz) or Avance 600
(600 MHz). Tetramethylsilane (TMS) was used as an internal
1
standard for H and 13C NMR, and CCl3F was used as an
external standard for 19F NMR. All chemical shifts are quoted
in d (ppm), and coupling constants in Hz. Infrared (IR) spectra
were recorded on a JASCO FT/IR-660 Plus spectrometer and
are reported in wave numbers (cmÀ1). Mass spectra were
obtained on a JEOL, JMS-AX505WA spectrometer at 70 eV
ionizing voltage (EI).
4.1. Preparation of 3,5-dibromo-4-[1,3]dioxolan-2-yl-
pyridine, 8
Compound 5 (1.00 g, 3.78 mmol), ethane-1,2,-diol (0.5 mL,
8.7 mmol) and p-toluenesulfonic acid monohydrate (0.35 g,
1.84 mmol) in benzene (30 mL) were refluxed using Dean-
Stark reflux condenser for 12 h. The reaction mixture was
cooled to room temperature. The solvent was evaporated under
reduced pressure, and to the residue was added 10% aq NaOH
solution (20 mL). The mixture was extracted with dichlor-
omethane (3 Â 20 mL) and the combined organic layer was
dried over MgSO4. After removal of the solvent, the residue
was purified by silica gel column chromatography (eluting with
ethyl acetate/hexane, 1:5) to provide 1.14 g (98% yield) of the
3,5-dibromo-4-[1,3]dioxolan-2-yl-pyridine (8) as yellow solid:
Deprotection of the 1,3-dioxolane in compound 9a by the
usual acid-catalyzed hydrolysis [15] or metal Lewis acid
hydrolysis [16] was unsuccessful, presumably due to the strong
electron-withdrawing effect of the 3,5-difluoro group adjacent
to this protecting group. Fortunately, efficient deprotection
could be achieved in 12 N aq HCl solution at reflux (Scheme 1).
The resulting product 3,5-difluoro-pyridine-4-carboxaldehyde
2 was stable even under strongly acidic and high temperature
(100 8C) conditions. Furthermore, MOM group in difluorinated
compound 7a was cleanly deprotected with dilute aq. HCl in
methanol and treatment of the resulting alcohols with PCC or
under Swern oxidation conditions provided compound 2 in
78% or 84% yields, respectively (Scheme 1).
1
mp 74–75 8C; H NMR (500 MHz, CDCl3): d 4.10–4.12 (2H,
m, H-4 and H-5 in dioxolan), 4.35–4.37 (2H, m, H-4 and H-5 in
dioxolan), 6.30 (1H, s, H-2 in dioxolan), 8.66 (2H, s, H-2 and H-
6); 13C NMR (125 MHz, CDCl3): d 66.2 (C-4 and C-5 in
dioxolan), 102.9 (C-2 in dioxolan), 122.1 (C-3), 141.1 (C-2),
152 (C-4); IR (neat) 3020, 2898, 1525, 1407, 1217, 772 cmÀ1
;
EIMS (70 eV, m/z): 311 [M + 4]+ (11), 309 [M + 2]+ (19), 307
[M]+ (10).
4.2. Difluorination of compounds 6 and 8 with NFSi
3. Conclusion
4.2.1. A typical experimental procedure
To a stirred solution of 1.00 g of compound 6 or 8 in dry THF
(60 mL) was added 2.5 equiv. n-, s-, or t-BuLi slowly under
argon at À78 or À120 8C (ethanol/liquid N2). The resulting
mixture was stirred for 30 min and then 2.5 equiv. N-
fluorobenzenesulfonimide in dry THF (15 mL) was added
dropwise. The reaction mixture was stirred for an additional 3 h
at À78 or À120 8C and then allowed to warm to room
temperature. The reaction was quenched with sat aq NH4Cl
solution and the mixture was extracted with dichloromethane
(3 Â 30 mL). The combined organic extracts were washed with
brine, dried over MgSO4, filtered, and concentrated. The
resulting crude residue was purified by silica gel column
chromatography (eluting with ethyl acetate/hexane, 1:2).
In conclusion, we have successfully prepared 3,4-difluor-
opyridine-4-carboxaldehyde 2 via electrophilic fluorination.
This result represents the first synthetically useful NFSi-
mediated difluorination of unactivated pyridine carboxalde-
hyde 5. Study on the synthetic applications of fluorinated
aromatic compounds, in particular, for the design of bioactive
compounds is in progress and the results will be reported in due
course.
4. Experimental
N-fluorobenzenesulfonimide (NFSi) was obtained from
Aldrich, and all reagents were purchased from commercial
sources. Thin layer chromatography (TLC) analyses were
performed on Merck F254 silica gel plates. Flash chromato-
graphy was carried out on Merck silica gel 60 (230–400 mesh).
THF was distilled under nitrogen over sodium in a recycling
still using benzophenone as indicator. Dichloromethane was
distilled from P2O5. 1H, 13C, and 19F NMR spectra were
4.2.2. 3,5-Difluoro-4-methoxymethoxymethyl-pyridine, 7a
This product was prepared from 6 as described above: Red
1
liquid; H NMR (600 MHz, CDCl3): d 3.39 (3H, s, CH3 in
MOM), 4.71 (2H, s, CH2–C4), 4.72 (s, 2H, CH2 in MOM), 8.37
(2H, s, H-2); 13C NMR (150 MHz, CDCl3): d 55.30 (CH3 in
3
MOM), 55.69 (d, JC–F = 3 Hz, CH2–C4), 96.32 (CH2 in

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Y.-J. Ko et al. / Journal of Fluorine Chemistry 127 (2006) 755–759
2
2
MOM), 121.44 (t, JC–F = 16.4 Hz, C-4), 134.19 (dd, JC–
F = 23.4 Hz and 4JC–F = 4.6 Hz, C-2 and C-6), 157.05 (dd, 1JC–
F = 262.6 Hz, 3JC–F = 3 Hz, C-3 and C-5); 19F NMR (470 MHz,
CDCl3): d À131.67 (s, 2F, CF); IR (neat) 3020, 2927, 1520,
1423, 1219, 773 cmÀ1; EIMS (70 eV, m/z): 189 [M]+ (14), 159
[M + H–OCH3] (75), 128 [M À OMOM] (100); HRMS (EI):
calcd. for C8H9O2NF2: 189.0601, found: 189.0565.
mixture was cooled to 0 8C and then treated with sat aq NaCO3
solution (10 mL). The product was extracted with dichlor-
omethane (3 Â 30 mL), dried over MgSO4, filtered, and
carefully concentrated under reduced pressure at room
temperature. The crude material was purified by silica gel
column chromatography (eluting with ethyl acetate/hexane,
1:3) to provide 75 mg (97% yield) of the desired product as a
1
white solid: mp 99–101 8C; H NMR (600 MHz, CDCl3): d
4.2.3. 3-Bromo-5-fluoro-4-methoxymethoxymethylpyridine,
7b
Red liquid; 1H NMR (600 MHz, CDCl3): d 3.41 (3H, s, CH3
in MOM), 4.74 (2H, s, CH2–C4), 4.75 (2H, s, CH2 in MOM),
8.42 (1H, s, H-6), 8.59(1H, s, H-2); 13C NMR (150 MHz,
4.84 (2H, s, C4–CH2), 8.35 (2H, s, H-2 and H-6); 13C NMR
(150 MHz, CDCl3): d 52.6 (t, 3JC–F = 3.6 Hz, CH2–C4), 124.2
2
2
3
(t, JC–F = 16.5 Hz, C-4), 134.5 (dd, JC–F = 23.8 Hz and JC–
1
3
F = 4.6 Hz, C-2 and C-6), 157.8 (dd, JC–F = 262 Hz and JC–
F = 3.2 Hz, C-3 and C-5); 19F NMR (470 MHz, CDCl3): d
À132.72 (s, 2F, CF); IR (neat) 3020, 1522, 1425, 1402, 1217,
771 cmÀ1; EIMS (70 eV, m/z): 145 [M]+ (100), 116 [M + H–
CH2OH] (40), 96 [M–CH2OH–F] (20); HRMS (EI): calcd. for
C8H9O2NF2: 145.0339, found: 145.0344.
3
CDCl3): d 55.80 (CH3 in MOM), 61.66 (d, JC–F = 2.6 Hz,
CH2–C4), 96.86 (CH2 in MOM), 123.40 (C-3), 133.31 (d, 2JC–
2
F = 14.8 Hz, C-4), 137.20 (d, JC–F = 25 Hz, C-6), 148.19 (d,
4JC–F = 4.9 Hz, C-2), 158.29 (d, JC–F = 263.6 Hz, C-5); 19F
1
NMR (470 MHz, CDCl3): d À129.56 (s, 1F, CF); IR (neat)
3020, 2927, 1520, 1423, 1219, 773 cmÀ1; EIMS (70 eV, m/z)
250 [M + 2]+ (14), 248 [M]+ (12), 219 [M À 2H–OCH3] (38),
204 [M À H À MOM] (24), 188 [M À H À OMOM] (100);
HRMS (EI): calcd. for C8H9O2NBrF: 248.9801, found:
248.9806.
4.4. Preparation of 3,5-difluoro-pyridine-4-carbaldehyde,
2
4.4.1. Method A: from (3,5-difluoro-pyridin-4-yl)methanol
4.4.1.1. Swern oxidation. To a solution of oxalyl chloride
(0.15 mL, 1.73 mmol) in dichloromethane (10 mL) under N2 at
À60 8C was added dropwise a solution of DMSO (0.25 mL,
3.45 mmol) in dichloromethane (2 mL). The mixture was
stirred for 10 min, and then a solution of (3,5-difluoro-pyridin-
4-yl)methanol (100 mg, 0.69 mmol) in dichloromethane
(2 mL) was added dropwise. The reaction mixture was stirred
for 20 min, and the mixture was warmed to room temperature.
Next, Et3N (0.6 mL, 4.31 mmol) was added flowed by H2O.
The organic layer was separated and the aqueous phase
extracted with dichloromethane (3 Â 30 mL). The combined
organic layer were washed with H2O, 5% aq NaHCO3 solution,
and brine. Removal of the solvent afforded a crude residue,
which was filtered through a plug of silica gel using
dichloromethane and the filtrate was carefully concentrated
under reduced pressure at room temperature. Finally, the
product 2 (very volatile!) was purified through a bulb-to-bulb
distillation. A white solid (83 mg, 84% yield) was obtained.
4.2.4. 4-[1,3]Dioxolan-2-yl-3,5-difluoropyridine, 9a
This product was prepared from 8 as described above:
Yellow solid; mp 121–123 8C; 1H NMR (500 MHz, CDCl3): d
4.05–4.08 (2H, m, H-4 and H-5 in dioxolan), 4.21–4.24 (2H, m,
H-4 and H-5 in dioxolan), 6.26 (1H, s, H-2 in dioxolan), 8.35
(1H, s, H-2 and H-6); 13C NMR (125 MHz, CDCl3): d 66.3 (C-4
and C-5 in dioxolan), 96.3 (t, 3JC–F = 3.5 Hz, C-2 in dioxolan),
2
122.2 (t, JC–F = 11.9 Hz, C-4), 135 (dd, JC–F = 23.8 Hz and
1
4JC–F = 5.3 Hz, C-2 and C-6), 157.4 (dd, JC–F = 265 Hz and
3JC–F = 3 Hz, C-3 and C-5); 19F NMR (470 MHz, CDCl3): d
À136.80 (s, 2F, CF); IR (neat) 3020, 1520, 1450, 1402, 1219,
773 cmÀ1; EIMS (70 eV, m/z): 187 [M]+ (66), 186 [M À H]
(55), 142 [M À H–CH2CH2O] (52); HRMS (EI): calcd. for
C8H7O2NF2: 187.0445, found: 187.0408.
4.2.5. 3-Bromo-4-[1,3]dioxolan-2-yl-5-fluoropyridine, 9b
1
Yellow liquid; H NMR (600 MHz, CDCl3): d 4.07–4.10
(2H, m, H-4 and H-5 in dioxolan), 4.24–4.27 (2H, m, H-4 and
H-5 in dioxolan), 6.27 (1H, s, H-2 in dioxolan), 8.40 (1H, s, H-
6), 8.56 (1H, s, H-2); 13C NMR (150 MHz, CDCl3): d 66.4 (C-4
and C-5 in dioxolan), 101 (C-2 in dioxolan), 121 (C-3), 132.6
(d, 2JC–F = 10 Hz, C-4), 138.2 (d, 2JC–F = 25.6 Hz, C-6), 148.6
(d, JC–F = 5.2 Hz, C-2), 158 (d, JC–F = 267.5 Hz, C-5); 19F
NMR (470 MHz, CDCl3): d À129.22 (s, 1F, CF); IR (neat)
3020, 1558, 1410, 1219, 1101, 773 cmÀ1; EIMS (70 eV, m/z):
249 [M + 2]+ (72), 247 [M]+ (73), 204 [M + 2–CH2CH2O] (52),
202 [M–CH2CH2O] (52); HRMS (EI): calcd. for C8H7O2NBrF:
246.9644, found: 246.9658.
4.4.1.2. Oxidation with PCC. To a stirred suspension of PCC
˚
(450 mg, 2.1 mmol) and molecular sieve 4 A (300 mg) in
dichloromethane (100 mL) was added dropwise a solution of
(3,5-difluoro-pyridin-4-yl)-methanol (100 mg, 0.69 mmol) in
dichloromethane (5 mL). The reaction mixture was vigorously
stirred at room temperature under N2 for 1 h. The resulting dark
brown slurry was filtered through a short column of silica and
eluted with dichloromethane and carefully concentrated under
reduced pressure at room temperature. Finally, the product 2
(very volatile!) was purified through a bulb-to-bulb distillation
to provide 77 mg of a white solid (78% yield).
3
1
4.3. Preparation of (3,5-Difluoro-pyridin-4-yl)methanol
4.4.2. Method B: from compound 8
Compound 8 (1.0 g, 5.3 mmol) was dissolved in 12 N aq
HCl solution (15 mL) and the mixture was refluxed with stirring
Compound 7a (100 mg, 0.53 mmol) was dissolved in 10%
aq HCl solution (10 mL) and stirred for 1 h at 60 8C. The

Y.-J. Ko et al. / Journal of Fluorine Chemistry 127 (2006) 755–759
759
for 2 h. The mixture was cooled to 0 8C and then treated with
References
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(90% yield) as a white solid: mp 51–52 8C; 1H NMR
(500 MHz, CDCl3): d 8.55(2H, s, H-2 and H-6), 10.42 (1 H,
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Acknowledgment
Support of this work from the Brain Korea 21 program is
greatly appreciated.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.jfluchem.
2006.02.009.