Facile preparation of 3-substituted-2,6-difluoropyridines: Application to the synthesis of 2,3,6-trisubstituted pyridines

Article abstract of DOI:10.1016/j.tetlet.2015.09.057

We report a facile method for the difluorination of 3-substituted-2,6-dichloropyridines using cesium fluoride as a fluorination reagent in dimethyl sulfoxide. It is proposed that this method for preparing 3-substituted-2,6-difluoropyridines is simpler and easier than those reported in previous literature. To examine the utility of 3-substituted-2,6-difluoropyridines in synthetic chemistry, we also demonstrate a subsequent conversion to 2,3,6-trisubstituted pyridines by a tandem nucleophilic aromatic substitution.

Full text of DOI:10.1016/j.tetlet.2015.09.057

Tetrahedron Letters 56 (2015) 6043–6046
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile preparation of 3-substituted-2,6-difluoropyridines: application
to the synthesis of 2,3,6-trisubstituted pyridines
⇑
Taisuke Katoh , Yoshihide Tomata, Tetsuya Tsukamoto, Yoshihisa Nakada
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2015
Revised 9 September 2015
Accepted 16 September 2015
Available online 21 September 2015
We report a facile method for the difluorination of 3-substituted-2,6-dichloropyridines using cesium flu-
oride as a fluorination reagent in dimethyl sulfoxide. It is proposed that this method for preparing 3-sub-
stituted-2,6-difluoropyridines is simpler and easier than those reported in previous literature. To
examine the utility of 3-substituted-2,6-difluoropyridines in synthetic chemistry, we also demonstrate
a
subsequent conversion to 2,3,6-trisubstituted pyridines by
a tandem nucleophilic aromatic
substitution.
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Difluorination
3-Substituted-2,6-difluoropyridines
2,3,6-Trisubstituted pyridines
Introduction
other methods, freshly prepared TBAF was required. These limita-
tions have prevented the field of synthetic chemistry having easy
access to 3-substituted-2,6-difluoropyridines.
Herein, we describe a facile method for preparing 3-substi-
tuted-2,6-difluoropyridines derived from 3-substituted-2,6-
Fluoropyridines are useful building blocks and easily react with
nucleophiles because the fluorine atom with the highest elec-
tronegativity makes the carbon–fluorine bond susceptible to
nucleophilic aromatic substitutions (SNAr).1 In particular, 3-substi-
tuted-2,6-difluoropyridines are considered as attractive intermedi-
ates in terms of synthetic and medicinal chemistry. Since they have
two distinguishable carbon–fluorine bonds, a tandem SNAr of 3-
substituted-2,6-difluoropyridines can produce 2,3,6-trisubstituted
pyridines, which are used in drug discovery2 and found as scaffolds
of biologically attractive compounds.3
dichloropyridines using
a simple reaction where chlorine is
replaced by fluorine. We also show the utility of these compounds
for chemical synthesis by demonstrating their subsequent conver-
sion to 2,3,6-trisubstituted pyridines (Scheme 1).
Reaction conditions for the difluorination of 3-substituted-2,6-
dichloropyridines
The utility of 3-substituted-2,6-difluoropyridines in synthetic
chemistry has been known for many years. However, only a few
methods for preparing these compounds have been published.
For example, the synthesis of 2,6-difluoro-3-nitropyridine from
2,6-dichloro-3-nitropyridine in low yield using a proton sponge
As many methods for the monofluorination of chloropyridines
have been reported,8 we attempted to modify some of these
procedures for the difluorination of 3-substituted-2,6-dichloropy-
ridines. We started a screening of reaction conditions for the
difluorination of 2,3,6-trichloropyridine (1). The progress of the
fluorination reaction was measured by HPLC while monitoring
UV absorption at 254 nm. Two types of well-known fluorination
reagents [potassium fluoride (KF) and cesium fluoride (CsF)] were
used to replace chlorine atoms at the 2- and 6-positions with
fluoride in DMSO under atmospheric conditions (Table 1, entries
1–3). Both KF and CsF were found to be effective fluorination
reagents for this reaction. When KF was used, a higher tempera-
ture and longer reaction time for completing the difluorination
reaction were required compared to CsF due to the slower reac-
tion rate of KF (Table 1, entries 2 and 3). A solvent screening
revealed that DMSO was better than the other polar aprotic and
non-polar solvents (Table 1, entries 4–8). The combination of
[1,8-bis(dimethylamino)naphthalene]
and
triethylaminetris
(hydrogen fluoride) was reported.4 2,3,6-Trichloropyridine was
converted into 3-chloro-2,6-difluoropyridine in an autoclave reac-
tion.5 Various 3-substituted-2,6-difluoropyridines were prepared
via lithiation of 2,6-difluoropyridine with lithium diisopropy-
lamide.6 The difluorination of methyl 2,6-dichloropyridine-3-car-
boxylate using freshly prepared anhydrous TBAF has been
described.7 In these previous reports, 3-substituted-2,6-difluo-
ropyridines were prepared with only low yields or under either
high temperature (at 200 °C) or low temperature (at À75 °C). Using
⇑
Corresponding author. Tel.: +81 466 32 1171; fax: +81 466 29 4454.
E-mail address: taisuke.katoh@takeda.com (T. Katoh).
http://dx.doi.org/10.1016/j.tetlet.2015.09.057
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6044
T. Katoh et al. / Tetrahedron Letters 56 (2015) 6043–6046
Table 2
Tandem
SNAr
Easy Fluorination
Difluorination of 3-substituted 2,6-dichloropyridines
R
R
R
R
Nu1H
Nu2H
R
R
F
Cl
N
A
Cl
F
N
B
F
Nu1
N
Nu2 Nu2
C
N
Nu1
CsF (4 equiv.)
DMSO
Cl
N
Cl
N
F
R = Cl, Br, I, NO2, CN, CONMe2, CO2Me
B
A
Scheme 1. Synthetic approach to 2,3,6-trisubstituted pyridines C.
Entry
A
R
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
3A
4A
5A
6A
7A
8A
Br
I
NO2
CN
CONMe2
CO2Me
80
90
90
80
100
80
8
64 (3B)
52 (4B)
64 (5B)
56 (6B)
67 (7B)
51 (8B)
CsF and DMSO was the best reaction condition for the
difluorination of 2,3,6-trichloropyridine.9
1.5
0.5
1.5
3
The versatility of the difluorination reaction was confirmed by
applying it to 3-substituted 2,6-dichloropyridines (Table 2). Pyridi-
nes with electron-withdrawing groups at the 3-position reacted
easily with CsF (80–100 °C, 0.5–8 h). Conversely, 2,6-dichloro-3-
methylpyridine was converted into 2,6-difluoro-3-methylpyridine
under harsher conditions (120 °C, 40 h). The yield of 2,6-difluoro-
3-methylpyridine was low (13%, calculated from the NMR spectra
of a crude mixture after a routine work-up) because 2,6-difluoro-3-
methylpyridine was volatilized under the harsh conditions. Hence,
we assume that alkyl substituents such as the methyl on the 3-po-
sition impaired the reactivity toward fluorine substitution and
required a longer reaction time and higher temperature. The diflu-
orinated products were so reactive that some of them may be
hydrolyzed by reacting with moisture in the solvent.10 We
assumed that the moderate yields of the difluorinated products
were due to this side reaction and the volatilization of the products
in purification processes such as evaporation under reduced
pressure.
1
PhCH2NH2
K2CO3
Cl
Cl
Cl
Cl
+
Cl Cl
DMSO
r.t. 2 h
N
1
Cl
PhCH2NH
N
1D
<5%
N
1E
<5%
NHCH2Ph
PhCH2NH2
K2CO3
Cl
F
Cl
Cl
+
F
DMSO
r.t. 2 h
N
F
PhCH2NH
N
F
N
NHCH2Ph
2
2D
66%
2E
9%
Scheme 2. Reactions of 2,3,6-trichloropyridine (1) and 3-chloro-2,6-difluoropy-
ridine (2) with benzylamine.
It was found that the difluorination reaction was applied to the
monofluorination of 3-substituted-2-chloropyridines although it
required more tough reaction conditions (90–130 °C, 4–40 h).11
preferentially at the 2-position (yield of 2D/2E = 66%:9%). Con-
versely, the reaction of 2,3,6-trichloropyridine (1) with benzy-
lamine produced only trace amounts of products.
The reactions of the 3-substituted-2,6-difluoropyridines with
benzylamine were examined (Table 3). The fluorine substitution
smoothly proceeded at room temperature with good yields
although the ratio of D to E was dependent on the substituent
groups on the 3-position.14 When bromine- or nitro-groups were
introduced at the 3-position, the major products were observed
to be 3D and 5D, respectively. (Table 3, entries 1 and 3). However
when cyano- or methyl-ester-groups were introduced at the 3-po-
sition, fluorine substitution preferentially proceeded at the 6-posi-
tion (Table 3, entries 4 and 6).
Next, we examined the reactivity of 3-chloro-2,6-difluoropy-
ridine (2) toward other nucleophiles (Table 4). We found that an
amine 9, amide 10, alcohol 11, and a sulfur 12 were good sub-
strates for the fluorine substitution (Table 4, entries 1–4) although
an aromatic amine such as aniline was unsuitable for this reaction
(data not shown). Note that carbon nucleophiles such as sodium
cyanide (13) and dimethyl malonate (14) easily produced moder-
ate to high yields with good regioselectivity (Table 4, entries 5
and 6).
Preparation of 2,3,6-trisubstituted pyridines by a tandem SNAr
reaction of 3-substituted-2,6-difluoropyridines
It is well-known that fluoropyridines are reacted with nucle-
ophiles.12 Especially, 3-substituted-2,6-difluoropyridines are
known to be transformed into 2,3,6-trisubstituted pyridines by
successive reactions with nucleophiles.13 Herein, we provide new
examples of 2,3,6-trisubstituted pyridines prepared from 3-substi-
tuted-2,6-difluoropyridines. We demonstrate the utility of 3-sub-
stituted-2,6-difluoropyridines in synthetic chemistry by using
them to synthesize 2,3,6-trisubstituted pyridines via a tandem SN-
Ar reaction. Since two fluorine atoms on the pyridine ring make the
scaffold reactive to nucleophiles, the reaction of 3-chloro-2,6-diflu-
oropyridine (2) with benzylamine was completed within 2 h at
room temperature (Scheme 2). The fluorine substitution occurred
Table 1
Screening of reaction conditions for the preparation of 3-chloro-2,6-difluropyridine
(2) from 2,3,6-trichloropyridine (1)
Table 3
Reactions of 3-substituted-2,6-difluoropyridines with benzylamine
Cl
Cl
Cl
F
KF or CsF
(4 equiv.)
PhCH2NH2
K2CO3
R
F
R
R
F
N
1
Cl
N
2
F
solvent
2 h
+
DMSO
N
F
PhCH2NH
N
F
N
NHCH2Ph
B
D
E
Entry
Reagent
Solvent
Temp
2
Mono-F
1
1
2
3
4
5
6
7
8
KF
KF
DMSO
DMSO
DMSO
DMF
80 °C
120 °C (20 h)
80 °C
80 °C
80 °C
80 °C
80 °C
Reflux
0
29
0
0
68
55
0
12
0
71
0
0
6
41
100
88
100
Entry
B
R
Time (h)
Yield (%)
100
100
26
4
0
0
CsF
CsF
CsF
CsF
CsF
CsF
1
2
3
4
5
6
3B
4B
5B
6B
7B
8B
Br
I
NO2
CN
CONMe2
CO2Me
6
51 (3D)
33 (4D)
47 (5D)
25 (6D)
40 (7D)
27 (8D)
13 (3E)
30 (4E)
<5 (5E)
64 (6E)
43 (7E)
60 (8E)
24
0.5
0.5
24
2
NMP
Toluene
CH3CN
THF
0

T. Katoh et al. / Tetrahedron Letters 56 (2015) 6043–6046
6045
Table 4
Since the major products in Tables 3 and 4 still had a carbon–
fluorine bond remaining on the 2- or 6-position, a second fluorine
substitution was performed (Tables 5A and 5B). Although almost
all of the substrates required a slightly higher temperature to com-
plete the second fluorine substitution, it was observed that various
nucleophiles could be used in this reaction producing moderate to
high yield. Consequently, numerous different 2,3,6-trisubstituted
pyridines could be prepared.
Reaction between 3-chloro-2,6-difluoropyridine (2) and nucleophiles
Nu1H
K2CO3
Cl
F
Cl
Cl
F
+
N
F
Nu1
N
F
N
Nu1
DMSO
2
D
E
Entry Nucleophiles
Temp (°C) Time (h)
Yield (%)
We presented a facile method for the difluorination of 3-substi-
tuted-2,6-dichloropyridines, which were used to synthesize 2,3,6-
trisubstituted pyridines using a tandem fluorine substitution.
2,3,6-Trisubstituted pyridine is a popular scaffold found in many
drug candidates and biologically attractive compounds. This syn-
thetic approach provides organic and medicinal chemists with
new insights in designing synthetic routes for their target
materials.
NH
1
2
9
50
0.5
3
83* (9D)
8* (9E)
N
O
10 50
68 (10D)
6 (10E)
NH
3
4
5
6
PhCH2OH
PhCH2SH
NaCN
11 80
12 rt
13 50
20
0.5
0.5
2
78* (11D) 16* (11E)
93 (12D)
55 (13D)
87 (14D)
<5 (12E)
<5 (13E)
7 (14E)
CH2(CO2Me)2 14 80
*
The regioselectivity was calculated from the NMR spectra.
Acknowledgments
The authors would like to thank Dr. Takashi Ichikawa and Dr.
Nobuyuki Negoro for their helpful discussion during the manu-
script preparation.
Table 5A
Second fluorine substitution
Nu2H
Supplementary data
R
R
K2CO3
Nu1
Cl
N
F
Nu1
Cl
N
N
Nu2
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
057.
DMSO
O
N
N
OCH2Ph
PhCH2S
N
N
References and notes
NBoc
15
16
90%
82%
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Cl
Cl
NC
MeO2C
CO2Me
N
SCH2Ph
N
CO2Me
CO2Me
17
18
56%
33%
(100 oC, 3 h)
(100 oC, 1 h)
I
Br
O
N
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N
N
19
OCH2Ph
PhCH2NH
N
20
N
NBoc
61%
43%
(120 oC, 1 h)
(110 oC, 40 h)
O
NO2
PhCH2NH
Me2N
PhCH2NH
9. To complete the difluorination reaction, it was necessary to vigorously stir the
mixture.
N
21
OCH2Ph
N
22
CN
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78%
60%
(100 oC, 20 h)
(90 oC, 2 h)
Table 5B
Second fluorine substitution
Nu2H
K2CO3
R
R
F
N
Nu1
Nu2
NC
N
Nu1
DMSO
MeO2C
N
N
23
NHCH2Ph
PhCH2S
N
24
NHCH2Ph
BocN
73%
88%
(100 oC, 5 h)
(100 oC, 0.75 h)

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T. Katoh et al. / Tetrahedron Letters 56 (2015) 6043–6046
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14. The regiochemistry of the products was determined by the coupling constants
5
(3JHF or JHF). See Supporting information for the details.