Selective and facile palladium-catalyzed amination of 2-fluoro-4- iodopyridine in the 4-position under microwave conditions

Article abstract of DOI:10.1055/s-0029-1219940

The selective C-N cross-coupling of 2-fluoro-4-iodopyridine with aromatic amines is reported. In contrast to conventional substitutions where C-N bond formation takes place at the 2-position (e.g., 2,4-dichloropyridine), the Buchwald-Hartwig cross-coupling was found to be complementary and exclusive for the 4-position. Reactions were carried out under microwave irradiation typically within 30 minutes. These conditions also allowed a decrease in the amount of base required to 3.5 equivalents compared to 20 equivalents in established protocols. Additionally, use of potassium carbonate as a mild base was sufficient, and good yields of the coupling products were obtained in all cases with the simple system Pd(OAc)₂/BINAP. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219940

LETTER
1505
Selective and Facile Palladium-Catalyzed Amination of
2-Fluoro-4-iodopyridine in the 4-Position under Microwave Conditions
Selective
Aminations
o
o
n 2-Fluoro-
3
u
-iodopyridin
m
e
ita Koley, Michael Schnürch, Marko D. Mihovilovic*
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax +43(1)5880115499; E-mail: mmihovil@pop.tuwien.ac.at
Received 30 November 2009
Dedicated to Prof. Peter Stanetty on the occasion of his 65th birthday
gated, in particular using chlorinated and brominated
compounds.7 However, only a few examples of amination
reactions on dihalogenated pyridines have been reported
in the literature using either palladium8 or nickel cata-
Abstract: The selective C–N cross-coupling of 2-fluoro-4-iodopyr-
idine with aromatic amines is reported. In contrast to conventional
substitutions where C–N bond formation takes place at the 2-posi-
tion (e.g., 2,4-dichloropyridine), the Buchwald–Hartwig cross-
coupling was found to be complementary and exclusive for the 4- lysts.9 2,6-Dichloropyridine, 2,3-dichloropyridine, and
position. Reactions were carried out under microwave irradiation
3,5-dichloropyridine were successfully applied in selec-
typically within 30 minutes. These conditions also allowed a de-
tive C–N cross-coupling reactions with aromatic
crease in the amount of base required to 3.5 equivalents compared
amines.10 In case of symmetric 2,6- and 3,5-dichloropyri-
to 20 equivalents in established protocols. Additionally, use of po-
dine, only one C–N cross-coupling took place leading to a
tassium carbonate as a mild base was sufficient, and good yields of
defined product, whereas 2,3-dichloropyridine reacted se-
lectively at the more activated 2-position. Although re-
giospecific, these protocols have two major drawbacks: a
large excess (usually approx. 20 equivalents) of base
(K2CO3) is required to achieve complete conversion, and
rather long reaction times (18 hours typically) are re-
quired. In general, C–N coupling reactions at the 4-posi-
tion of pyridine are poorly covered in the literature,11 and
the conversion of a 2,4-dihalopyridine was reported only
briefly;12a,b the selectivity and generality of this transfor-
mation was not further elaborated. To the best of our
knowledge, the first detailed investigation on a selective
amination reaction at the 4-position of a 2,4-dihalopyri-
dine is reported within this contribution.
the coupling products were obtained in all cases with the simple sys-
tem Pd(OAc)2/BINAP.
Key words: cross-coupling, heterocycles, catalysis, amines, regio-
selectivity
Transition-metal-catalyzed cross-coupling reactions are
one of the most important tools for bond formation in
modern synthesis.1 Initially limited to the construction of
C–C bonds, the utility of these methods was significantly
broadened by the development of protocols to establish
carbon–heteroatom bonds. Most importantly, the palladi-
um-catalyzed amination reaction, independently devel-
oped by Buchwald and Hartwig, provided synthetic
chemists with a powerful tool to construct C–N bonds.2
Since its discovery, the amination protocol has successful-
ly been applied in the synthesis of numerous arylamino-
substituted arenes and heteroarenes.3 Among heterocy-
cles, pyridine certainly represents a privileged scaffold
and is present in many biologically active compounds
(e.g., alkaloids). In this context, C–N cross-coupling reac-
tions at the 4-position are interesting from a synthetic
point of view since this novel connection holds the pros-
pect of enabling complementary access to compounds
with diverse biological activity (Figure 1). Compounds of
the general structure I were reported as a new class of an-
titumor agents,4 substance II displayed inhibition of the
vascular endothelial growth factor receptor (VEGFR-2)
tyrosine kinase5 and structure III was reported as a phos-
phodiester IV inhibitor.6
The most obvious and convenient dihalo starting material
is 2,4-dichloropyridine (1) due to its commercial avail-
ability and reasonable price (~20/g, Aldrich). However,
the 2- and the 4-positions in pyridine are quite similar in
reactivity and the 2-position is usually only slightly fa-
Me
R4
R1
N
N
R2
N
S
HN
NH
N
II
I
N
R3
R3
O
Consequently, methods for efficiently decorating the
pyridine scaffold are highly important, and Buchwald–
Hartwig reactions of pyridine halides have been investi-
MeO
Cl
HN
Cl
N
SYNLETT 2010, No. 10, pp 1505–1510
Advanced online publication: 12.05.2010
x
x
.x
x
.2
0
1
0
III
DOI: 10.1055/s-0029-1219940; Art ID: S13409ST
Figure 1
© Georg Thieme Verlag Stuttgart · New York

1506
M. Koley et al.
LETTER
MeO
Cl
NH
N
Cl
Pd(OAc)2, (2 mol%),
BINAP (2 mol%)
OMe
OMe
+
+
K2CO3, toluene,
180 °C, MW
N
N
Cl
H
H2N
N
Cl
2
3
1
not selective, yield = <10%
Scheme 1
vored.13 Nevertheless, we investigated the C–N cross- ation was successfully employed to overcome previous
coupling reaction of 1 (Scheme 1). As expected, the reac- limitations of C–N coupling reactions at pyridine such as
tion of 1 with p-anisidine provided both 2- and 4-amino- long reaction times and the need for a large excess of base.
substituted products 2 and 3 in approximately equimolar An additional advantage of this protocol is that none of the
ratios (based on GC-MS), however, in less than 10% reagents are sensitive to air, hence, manipulation of all
yield.
reaction partners can be conducted under ambient condi-
tions, thus avoiding troublesome handling in a glove box;
simple flushing of the reaction vessel with argon before
sealing is sufficient to ensure reproducible yields.
Consequently, 2-fluoro-4-iodopyridine (4) was prepared
as an alternative substrate according to a literature proto-
col starting from 2-fluoropyridine in high yield
(Scheme 2).14 This compound bears iodine in the 4-posi-
tion as a better leaving group for the cross-coupling pro-
cess. Additionally, the fluorine atom in the 2-position is
an excellent leaving group for subsequent nucleophilic
substitution reactions, which could be a competing path-
way to give 2-aminated side-products. We had elaborated
these properties of building block 4 in a C–C coupling ap-
proach towards analogues of the cytostatic Gleevec.14c,15
There, it was found that, under acidic nucleophilic substi-
tution conditions, amination with 3-chloroaniline takes
place preferentially at the 2-position (66%) accompanied
by minor amounts of 2,4-bis-aminated product (9%).15b
This selectivity should be inverted to favor amination at
the 4-position under Buchwald–Hartwig conditions.
I
X
Pd(OAc)2, (2 mol%),
BINAP (2 mol%)
N
X
+
H2N
K2CO3, toluene,
180 °C, MW
( )0,1
( )0,1
F
N
N
F
H
4
5a–j
Scheme 2
A series of substituted aniline derivatives were coupled
under the established conditions in order to assess the
scope of the protocol. All reactions proceeded smoothly,
affording reaction products 5a–j in good yields (Table 1).
It should be emphasized that, in every case, the mono-am-
inated product was formed exclusively and regioselec-
tively in the 4-position; 2,4-bisamino products could not
be detected even after prolonged reaction times in the
presence of an excess of amine. As the 2-position is more
activated towards nucleophilic substitution reactions in
pyridine, and because fluorine is a better leaving group
compared to iodine in case of nucleophilic aromatic sub-
stitutions, it can be concluded that the amination at the 4-
position takes place exclusively via a palladium-catalyzed
C–N cross-coupling reaction in which iodine is a better
leaving group than fluorine.3 This result was confirmed by
a control experiment conducted in the absence of palladi-
um-catalyst, which did not result in any formation of am-
inated products. This finding is also in agreement with
previous reports in the literature for other cross-coupling
reactions.1
In analogy to an already successful amination protocol for
pyridine halides,10 Pd(OAc)2 was used as metal source,
(+/–) BINAP as the ligand, K2CO3 as base, and p-anisi-
dine as the model amine component. As use of BINAP
gave reasonably good yields as well as complete conver-
sion in all cases, and since it is cheaper than other ligands
used for Buchwald–Hartwig coupling reactions, we de-
cided to stay with this readily available system. Reactions
were accelerated by applying microwave irradiation at
180 °C to complete conversions within 30 minutes. A sin-
gle reaction product was formed and identified as the
C–N cross-coupled product 5b with a good yield of 63%
upon selective transformation at the 4-position
(Scheme 2). Neither nucleophilic substitution at the 2-
position nor formation of a 2,4-diaminated product was
observed. Additionally, the use of 3.5 equivalents of the
mild base K2CO3 proved to be sufficient under microwave
conditions (compared to 20 equiv under classical heating
according to reported protocols10). It is also noteworthy
that the widely applied stronger bases t-BuONa or t-
BuOK could be avoided. Although use of these stronger
bases have been reported to give faster reactions, their
high basicity has caused problems when base-sensitive
substrates are employed.3 Gratifyingly, microwave irradi-
The protocol is not sensitive to the nature of aniline reac-
tion partner and both amines bearing electron-donating
(compounds 5b/c and 5g/h) and electron-withdrawing
substituents (compounds 5d–f) were obtained in good
yields. Furthermore, the presence of base-sensitive func-
tional groups was well tolerated (compounds 5e/f). The
cross-coupling reaction proceeded with excellent yield
when o-anisidine was used as the amine source (5c), indi-
cating the applicability of sterically hindered amines in
Synlett 2010, No. 10, 1505–1510 © Thieme Stuttgart · New York

LETTER
Selective Aminations on 2-Fluoro-3-iodopyridine
1507
this transformation. Using benzylamine (5i) or 4-methox-
ybenzylamine (5j) as examples of primary alkylamines
also gave reasonable conversion and no side products
were isolated. However, in these cases, the yield was
somewhat lower (52 and 56%, respectively), and pro-
longed reaction times were required (45 min). Reaction
with the secondary alkylamine piperidine (5k) also gave a
reasonable yield at lower temperature (100 °C) under con-
ventional heating (Scheme 3). However, at higher temper-
ature (130 °C), nucleophilic substitution at the fluorine in
the 2-position predominated over the substitution of
iodine at the 4-position in a ratio of 5:1 (according to
GC-MS); 4-iodo-2-(piperidin-1-yl)pyridine was isolated
as the major product in this reaction with a yield of 42%.
I
Pd(OAc)2, (2 mol%),
BINAP (2 mol%),
K2CO3, toluene
Pd(OAc)2, (2 mol%),
BINAP (2 mol%),
K2CO3, toluene
I
N
N
100 °C
130 °C
F
N
N
N
F
5k (55%)
4
7 (42%)
Scheme 3
stitution is higher than the rate of the Buchwald–Hartwig
cross-coupling process.16 This is not surprising since it
was reported that the nucleophilic substitution of fluorine
in 2-fluoropyridine with piperidine can take place at room
temperature even without base.16a
It seems that at higher temperatures the activation energy
barrier for the nucleophilic substitution is exceeded; under
these conditions the reaction rate of the nucleophilic sub-
Table 1 Scope of the Reaction
Amine
Product
Compound
Time (min)
30
Yield (%)
65
N
5a
F
N
H
H2N
OMe
OMe
N
5b
5c
5d
5e
5f
30
30
30
45
45
30
63
83
74
69
78
75
F
N
H
H2N
MeO
MeO
N
F
N
H
H2N
Cl
Cl
N
F
N
H
H2N
COOEt
CN
COOEt
CN
N
F
N
H
H2N
H2N
H2N
N
F
N
H
O
O
N
5g
F
N
H
O
O
N
N
5h
5i
30
45
84
52
N
F
N
H
H2N
H2N
N
F
N
H
Synlett 2010, No. 10, 1505–1510 © Thieme Stuttgart · New York

1508
M. Koley et al.
LETTER
Table 1 Scope of the Reaction (continued)
Amine
Product
Compound
Time (min)
45
Yield (%)
56
N
OMe
5j
F
F
N
H
H2N
OMe
N
5ka
16 h
55
N
HN
N
N
N
6a
6b
6c
30
30
30
66
79
48
F
F
F
N
H
N
H2N
H2N
N
N
N
N
H
S
S
N
N
N
H
H2N
a Reaction was performed under conventional heating at 100 °C for 16 h.
This demonstrates that the developed protocol is suitable C–N coupling reaction with other polyhalogenated nitro-
for both aromatic and aliphatic amines since even second- gen heterocycles.
ary aliphatic amines can be applied selectively as the C–N
coupling component.
Acknowledgment
Finally, three heterocyclic amines were applied to this
amination protocol. All these reactants provided access to
C–N coupling products (6a–c) upon selective reaction at
We would like to thank the Austrian Ministry of Science (BMWF),
which supported this research via the program ‘Green Chemistry @
Sparkling Science’. M.K. would like to thank the One-World-
the 4-position in moderate to good yields. Furthermore, in
the case of 6c the reaction also worked smoothly and with
complete conversion, however, in lower yield, which can
be attributed to troublesome purification. Hence, this
approach allows facile access to potentially interesting
amino-bridged heterocyclic compounds.
Scholarship Program for granting a fellowship.
References and Notes
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Cross-Coupling Reactions, 2nd ed., Vol. 1 and 2; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004.
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Chem., Int. Ed. Engl. 1995, 34, 1348. (b) Wolfe, J. P.;
Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (d) Wolfe,
J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
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Hartwig, J. F.; Rheingold, A. L.; Liable-Sands, L. M.; Guzei,
I. A. J. Am. Chem. Soc. 2000, 122, 4618. (f) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1144.
In summary, the microwave-assisted C–N cross-coupling
protocol described above can serve as a valuable proce-
dure for the selective amination of pyridines at the 4-posi-
tion.17 The protocol gives access to useful intermediates
for the synthesis of biologically active compounds and
pharmaceuticals that contain the 4-anilino pyridine motif,
and is complementary to nucleophilic substitution reac-
tions with aniline derivatives that take place preferentially
at the 2-position.15b The fluorine atom at the 2-position
can be utilized for further functionalization, e.g., nucleo-
philic substitution. This procedure is superior to previous
protocols due to the straightforward operational condi-
tions (no glove box manipulation), drastically shorter re-
action times, as well as substantially decreased amounts
of base. The use of a mild base, K2CO3, is also advanta-
geous in case of sensitive substrates. The synthesis of an
array of 4-aniline-substituted pyridine derivatives was ac-
complished starting from 2-fluoro-4-iodopyridine. Pres-
ently, we are assessing the scope and limitations of the
microwave-based protocol for the Buchwald–Hartwig
(4) Riou, J. F.; Fosse, P.; Chi Hung, N.; Larsen, A. K.; Bissery,
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Synlett 2010, No. 10, 1505–1510 © Thieme Stuttgart · New York

LETTER
Selective Aminations on 2-Fluoro-3-iodopyridine
1509
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McNamara, J. M. Org. Lett. 2002, 4, 3481. (c) Suzuki, T.;
Igari, S.-i.; Hirasawa, A.; Hata, M.; Ishiguro, M.; Fujieda,
H.; Itoh, Y.; Hirano, T.; Nakagawa, H.; Ogura, M.;
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2008, 51, 7640.
138.9 (s), 147.8 (q, JC–F = 16.6 Hz), 154.5 (d, JC–F = 3.1 Hz),
165.5 (d, JC–F = 221.5 Hz).
2-Fluoro-N-(4-methoxyphenyl)pyridin-4-amine (5b):
Yellow crystals; mp 150 °C; GC-MS: m/z (%) = 218
(79)[M]+, 203 (100), 155 (13); 1H NMR (CDCl3, 200 MHz):
d = 3.83 (s, 3 H), 6.20 (d, J = 1.7 Hz, 1 H), 6.31 (s, 1 H), 6.51
(td, J1 = 5.9 Hz, J2 = 1.9 Hz, 1 H), 6.95 (d, J = 8.9 Hz, 2 H),
7.14 (d, J = 8.8 Hz, 2 H), 7.81 (d, J = 8.8 Hz, 1 H). 13C NMR
(CDCl3, 50 MHz): d = 55.5 (t), 91.6 (q, JC–F = 42.4 Hz),
107.5 (q, JC–F = 2.8 Hz), 114.9 (d), 125.8 (d), 131.4 (s),
147.4 (q, JC–F = 18.7 Hz), 156.5 (d, JC–F = 11.6 Hz), 157.6
(s), 165.5 (d, JC–F = 232.7 Hz).
2-Fluoro-N-(2-methoxyphenyl)pyridin-4-amine (5c):
Brown oil; GC-MS: m/z (%) = 218 (100)[M]+, 203 (83), 175
(33); 1H NMR (CDCl3, 200 MHz): d = 3.85 (s, 3 H), 6.45 (d,
J = 1.9 Hz, 1 H), 6.56 (s, 1 H), 6.70 (d, J = 5.8 Hz, 1 H),
6.96 (t, J = 6.9 Hz, 1 H), 7.04–7.17 (m, 1 H), 7.35 (d,
J = 7.4 Hz, 1 H), 7.87 (d, J = 5.8 Hz, 1 H). 13C NMR
(CDCl3, 50 MHz): d = 55.6 (t), 92.8 (q, JC–F = 42.4), 108.7
(q, JC–F = 2.5 Hz), 111.2 (d), 120.7 (d), 120.8 (d), 124.4 (d),
128.5 (s), 147.6 (q, JC–F = 18.4 Hz), 150.7 (s), 154.6 (d,
JC–F = 10.2 Hz), 165.5 (d, JC–F = 232.1 Hz).
(9) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett.
2001, 42, 247.
(10) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.;
Dommisse, R. Tetrahedron 2001, 57, 7027.
(11) (a) Mack, A. G.; Suschitzky, H.; Wakefield, B. J. J. Chem.
Soc., Perkin Trans. 1 1980, 1682. (b) Zhang, Q.; Liu, Y.;
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J. Org. Chem. 2001, 66, 7729. (d) Shen, Q.; Hartwig, J. F.
J. Am. Chem. Soc. 2007, 129, 7734.
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Chakrabarti, P.; Doherty, E. M.; Gavva, N. R.; Nishimura,
N.; Nixey, T.; Ognyanov, V. I.; Rzasa, R. M.; Stec, M.;
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J. J. S. J. Med. Chem. 2007, 50, 3497. (b) Ji, J.; Li, T.;
Bunnelle, W. H. Org. Lett. 2003, 5, 4611.
N-(4-Chlorophenyl)-2-fluoropyridin-4-amine (5d):
Colorless solid; mp 175–178 °C; GC-MS: m/z (%) = 222
(100)[M]+, 224 (47), 186 (31); 1H NMR (CDCl3, 200 MHz):
d = 6.31 (s, 1 H), 6.35 (d, J = 1.9 Hz, 1 H), 6.63 (d,
J = 5.8 Hz, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.35 (d,
J = 8.6 Hz, 2 H), 7.9 (d, J = 5.8 Hz, 1 H). 13C NMR (CDCl3,
50 MHz): d = 92.9 (q, JC–F = 42.7 Hz), 108.2 (q, JC–F
=
3.5 Hz), 123.8 (d), 129.9 (d), 130.3 (s), 137.5 (s), 148.1 (q,
JC–F = 17.6 Hz), 154.8 (d, JC–F = 14.7 Hz), 165.5 (d,
JC–F = 235.2 Hz).
(13) Eicher, T.; Hauptmann, S. In The Chemistry of
Heterocycles; Wiley-VCH: Weinheim, 2003, 269ff.
(14) (a) Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988,
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Chem. 2005, 70, 5215.
Ethyl 4-(2-fluoropyridin-4-ylamino)benzoate (5e): Light-
yellow solid; mp 170 °C; GC-MS: m/z (%) = 260 (67)[M]+,
232 (25), 215 (100); 1H NMR (CDCl3, 200 MHz): d = 1.40
(t, J = 7.1 Hz, 3 H), 4.39 (q, J = 7.2 Hz, 2 H), 6.56 (d,
J = 1.7 Hz, 1 H), 6.72 (s, 1 H), 6.79 (d, J = 5.6 Hz, 1 H),
7.19–7.26 (m, 2 H), 7.97 (d, J = 5.8 Hz, 1 H), 8.06 (d,
J = 8.8 Hz, 1 H). 13C NMR (CDCl3, 50 MHz): d = 14.4 (q),
60.9 (t), 94.2 (q, JC–F = 41.3 Hz), 109.2 (q, JC–F = 3.5 Hz),
119.5 (d), 125.7 (s), 131.4 (d), 143.5 (s), 148.2 (q,
JC–F = 19.2 Hz), 153.4 (d, JC–F = 11.3 Hz), 165.9 (d,
JC–F = 234.3 Hz).
(15) (a) Stanetty, P.; Schnürch, M.; Mihovilovic, M. D. Synlett
2003, 1862. (b) Stanetty, P.; Röhrling, J.; Schnürch, M.;
Mihovilovic, M. D. Tetrahedron 2006, 62, 2380.
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Goralski, C. T.; Singaram, B. Tetrahedron Lett. 2004, 45,
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Angiolini, M. Tetrahedron Lett. 2003, 44, 519. (c) Perron-
Sierra, F.; Dizier, S. D.; Bertrand, M.; Genton, A.; Tucker,
G. C.; Casara, P. Bioorg. Med. Chem. Lett. 2002, 12, 3291.
(17) General Procedure: 2-Fluoro-4-iodopyridine (4; 1 equiv),
aryl/alkyl amine (1.2 equiv), K2CO3 (3.5 equiv), Pd(OAc)2
(2 mol%), and BINAP (2 mol%) were charged into a
microwave vial and anhydrous toluene (2 mL) was added.
The vial was then sealed, evacuated and flushed with argon.
Then the reaction mixture was irradiated at 180 °C in a CEM
Explorer™ microwave unit for 30 min with stirring. After
cooling to r.t., the solid material was removed by filtration
and washed with CH2Cl2 (10 mL). The solvent was
evaporated and the resulting crude product was purified by
flash column chromatography.
4-(2-Fluoropyridin-4-ylamino)benzonitrile(5f): Yellow
solid; mp 195–197 °C; GC-MS: m/z (%) = 213 (100)[M]+,
212 (45), 192 (16); 1H NMR (CD3OD, 200 MHz): d = 6.68
(d, J = 1.7 Hz, 1 H), 6.98 (d, J = 5.8 Hz, 1 H), 7.35 (d,
J = 8.6 Hz, 2 H), 7.70 (d, J = 8.6 Hz, 2 H), 7.92 (d,
J = 6.6 Hz, 1 H). 13C NMR (CD3OD, 50 MHz): d = 97.6 (q,
JC–F = 39.9 Hz), 108.8 (d), 113.2 (q, JC–F = 3.2 Hz), 122.16
(s), 123.1 (d), 137.4 (d), 148.67 (d), 151.1 (q, JC–F
15.8 Hz), 158.0 (d, JC–F = 11.6 Hz), 169.2 (d, JC–F
234.1 Hz).
=
=
2-Fluoro-N-(4-phenoxyphenyl)pyridin-4-amine (5g):
Brown crystals; mp 149 °C; GC-MS: m/z (%) = 280
(100)[M]+, 203 (63), 77 (41); 1H NMR (CDCl3, 200 MHz):
d = 6.51 (d, J = 1.9 Hz, 1 H), 6.61 (s, 1 H), 6.81 (d,
J = 5.8 Hz, 1 H), 7.23 (d, J = 2.1 Hz, 2 H), 7.37 (m, 3 H),
7.48 (s, 1 H), 7.57 (t, J = 7.9 Hz, 3 H), 8.80 (d, J = 5.8 Hz,
1 H). 13C NMR (CDCl3, 50 MHz): d = 92.0 (q, JC–F
=
2-Fluoro-N-phenylpyridin-4-amine (5a): Yellow solid;
mp 148–150 °C; GC-MS: m/z (%) = 188 (100) [M]+, 187
(65), 167 (20); 1H NMR (CDCl3, 200 MHz): d = 6.45 (d,
J = 1.7 Hz, 1 H), 6.67–6.78 (m, 2 H), 7.23 (d, J = 6.8 Hz,
39.5 Hz), 107.8 (q, JC–F = 3.2 Hz), 118.9 (d), 119.9 (d),
123.5 (d), 125.0 (d), 129.9 (d), 133.9 (s), 147.9 (q, JC–F
22.9 Hz), 154.8 (s), 155.8 (d, JC–F = 11.9 Hz), 157.0 (s),
165.6 (d, JC–F = 233.0 Hz).
2-Fluoro-N-(4-morpholinophenyl)pyridin-4-amine (5h):
Colorless crystals; mp 154 °C; GC-MS: m/z (%) = 273
(100)[M]+, 215 (80), 214 (21); 1H NMR (CDCl3, 200 MHz):
=
3 H), 7.44 (t, J = 7.1 Hz, 2 H), 7.86 (d, J = 7.8 Hz, 1 H). 13
C
NMR (CDCl3, 50 MHz): d = 92.5 (q, JC–F = 44.1 Hz), 108.2
(q, JC–F = 3.1 Hz), 122.4 (d), 129.7 (d), 138.9 (s), 147.8 (d),
Synlett 2010, No. 10, 1505–1510 © Thieme Stuttgart · New York

1510
M. Koley et al.
LETTER
d = 3.16 (s, 4 H), 3.88 (t, J = 4.8 Hz, 4 H), 6.21 (s, 1 H), 6.28
(s, 1 H), 6.50 (d, J = 5.6 Hz, 1 H), 6.93 (d, J = 6.9 Hz, 2 H),
7.10 (d, J = 8.6 Hz, 2 H), 7.81 (d, J = 6.3 Hz, 1 H). 13C NMR
N-(2-Fluoropyridin-4-yl)pyridin-2-amine (6a): Yellow
solid; mp 143 °C; GC-MS: m/z (%) = 188 (100), 189
(30)[M]+, 168 (8); 1H NMR (CDCl3, 200 MHz): d = 6.80–
6.90 (m, 2 H), 7.09 (d, J = 6.1 Hz, 1 H), 7.15 (s, 1 H), 7.32
(d, J = 1.8 Hz, 1 H), 7.64 (m, 1 H), 7.99 (d, J = 5.4 Hz, 1 H),
8.34 (d, J = 3.5 Hz, 1 H). 13C NMR (CDCl3, 50 MHz): d =
95.9 (q, JC–F = 43.2 Hz), 110.2 (q, JC–F = 3.1 Hz), 11.7 (d),
(CDCl3, 50 MHz): d = 49.4 (t), 66.8 (t), 91.7 (q, JC–F
=
43.7 Hz), 107.6 (q, JC–F = 3.2 Hz), 116.6 (d), 125.2 (d),
130.9 (s), 147.4 (q, JC–F = 17.3 Hz), 149.1 (s), 156.4 (d,
JC–F = 13.7 Hz), 165.5 (d, JC–F = 233.0 Hz).
N-Benzyl-2-fluoropyridin-4-amine (5i): Yellow oil; GC-
MS: m/z (%) = 202 (42)[M]+, 91 (100), 65 (11); 1H NMR
(CDCl3, 200 MHz): d = 4.36 (d, J = 4.4 Hz, 2 H), 5.03 (s,
1 H), 6.00 (d, J = 1.8 Hz, 1 H), 6.32–6.40 (m, 1 H), 7.27–
7.38 (m, 5 H), 7.75 (d, J = 5.4 Hz, 1 H). 13C NMR (CDCl3,
50 MHz): d = 45.2 (t), 88.5 (q, JC–F = 51.2 Hz), 104.9 (q,
JC–F = 2.4 Hz), 125.8 (d), 126.1 (d), 135.5 (s), 145.1 (q,
JC–F = 19.1 Hz), 155.5 (d, JC–F = 12.3 Hz), 161.3 (d), 165.8
(d, JC–F = 232.2 Hz).
117.5 (d), 138.1 (d), 147.7 (q, JC–F = 17.3 Hz), 148.2 (d, JC–F
12.6 Hz), 151.8 (d), 153.5 (s), 165.2 (d, JC–F = 233.4 Hz).
=
N-(2-Fluoropyridin-4-yl)pyridin-3-amine (6b): Colorless
crystals; mp 152 °C; GC-MS: m/z (%) = 189 (100)[M]+, 188
(37), 168 (22); 1H NMR (CDCl3, 200 MHz): d = 6.39 (d,
J = 1.9 Hz, 1 H), 6.71 (d, J = 5.8 Hz, 1 H), 7.22–7.42 (m,
2 H), 7.61 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 5.9 Hz, 1 H),
8.40 (d, J = 4.1 Hz, 1 H), 8.51 (s, 1 H). 13C NMR (CDCl3,
50 MHz): d = 92.9 (q, JC–F = 43.0 Hz), 108.3 (q, JC–F
=
2-Fluoro-N-(4-methoxybenzyl)pyridin-4-amine (5j):
Yellow solid; mp 123–124 °C; GC-MS: m/z (%) = 121
(100), 122 (9), 232 (7)[M]+; 1H NMR (CDCl3, 200 MHz):
d = 3.73 (s, 3 H), 4.20 (d, J = 5.3 Hz, 2 H), 4.75 (s, 1 H), 5.92
(d, J = 1.8 Hz, 1 H), 6.27 (td, J1 = 5.9 Hz, J2 = 1.8 Hz, 1 H),
6.82 (d, J = 8.8 Hz, 2 H), 7.16 (d, J = 8.8 Hz, 2 H), 7.69 (d,
J = 5.5 Hz, 1 H). 13C NMR (CDCl3, 50 MHz): d = 46.7 (t),
55.3 (q), 90.4 (q, JC–F = 42.7 Hz), 106.9 (q, JC–F = 2.5 Hz),
114.3 (d), 128.8 (d), 129.2 (s), 147.2 (q, JC–F = 18.7 Hz),
3.1 Hz), 124.1 (d), 129.1 (d), 136.2 (s), 143.8 (d), 145.4 (d),
148.0 (q, JC–F = 18.0 Hz), 154.6 (d, JC–F = 12.0 Hz), 165.5
(d, JC–F = 234.0 Hz).
N-(2-Fluoropyridin-4-yl)-4-phenylthiazol-2-amine (6c):
Colorless crystals; mp 195 °C; GC-MS: m/z (%) = 271
(100)[M]+, 134 (49), 270 (39); 1H NMR (CD3OD,
200 MHz): d = 7.27 (s, 1 H), 7.39–7.49 (m, 4 H), 7.70 (d,
J = 1.6 Hz, 1 H), 7.94 (d, J = 7.0 Hz, 2 H), 7.98 (d,
J = 5.8 Hz, 1 H). 13C NMR (CD3OD, 50 MHz): d = 95.9 (q,
JC–F = 49.4 Hz), 111.1 (q, JC–F = 3.0 Hz), 127.0 (d), 128.9
(d), 143.8 (s), 148.0 (q, JC–F = 19.4 Hz), 152.9 (d), 153.7 (d),
155.2 (q, JC–F = 12.4 Hz), 165.2 (d, JC–F = 239.3 Hz).
4-Iodo-2-(piperidin-1-yl)pyridine (7): Yellow oil; GC-
MS: m/z (%) = 288 (100)[M]+, 258 (63), 204 (34); 1H NMR
(CDCl3, 200 MHz): d = 1.62 (s, 6 H), 3.50 (d, J = 5.5 Hz,
4 H), 6.89 (dd, J1 = 5.1 Hz, J2 = 1.2 Hz, 1 H), 6.99 (s, 1 H),
7.79 (d, J = 5.1 Hz, 1 H).13C NMR (CDCl3, 50 MHz): d =
24.6 (t), 25.4 (t), 46.1 (t), 106.6 (s), 115.9 (d), 120.9 (d),
148.2 (d), 159.7 (s).
157.3 (d, JC–F = 12.0 Hz), 159.2 (s), 165.5 (d, JC–F
=
232.1 Hz).
2-Fluoro-4-(piperidin-1-yl)pyridine (5k): Yellow oil. GC-
MS: m/z (%) = 180 (59)[M]+, 179 (100), 123 (22); 1H NMR
(CDCl3, 200 MHz): d = 1.51–1.63 (m, 6 H), 3.22–3.31 (m,
4 H), 6.11 (s, 1 H), 6.54 (dt, J1 = 6.1 Hz, J2 = 1.9 Hz, 1 H),
7.83 (d, J = 6.1 Hz, 1 H). 13C NMR (CDCl3, 50 MHz): d =
24.2 (t), 25.0 (t), 91.3 (q, JC–F = 42.0 Hz), 105.5 (s), 147.5 (q,
JC–F = 10.1 Hz), 158.8 (q, JC–F = 11.7 Hz), 166.1 (d, JC–F
=
232.1 Hz).
Synlett 2010, No. 10, 1505–1510 © Thieme Stuttgart · New York

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