Synthesis of 3-substituted 2-aminopyridines via displacement of 3-fluoro-2-nitropyridine

Article abstract of DOI:10.1055/s-0031-1290397

An efficient method for the substitution of 3-fluoro-2-nitropyridine with a range of nitrogen-containing heterocycles and aliphatic amines is described. The reaction proceeds in a regioselective manner at moderate temperature and in reasonable yield.

Full text of DOI:10.1055/s-0031-1290397

1816▌
LETTER
lSetyternthesis of 3-Substituted 2-Aminopyridines via Displacement of 3-Fluoro-2-
nitropyridine
Synthesis of 3-Substituted 2-Aminopyridines
Janet D. Culshaw, Jonathan M. Eden,* Susannah J. Ford, Barry Hayter, David R. Perkins,* Kurt G. Pike
Oncology iMed, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
E-mail: jonathan.eden@astrazeneca.com; E-mail: dave.perkins@astrazeneca.com
Received: 06.03.2012; Accepted after revision: 01.05.2012
no substituent, and, in particular, compounds with a nitro-
Abstract: An efficient method for the substitution of 3-fluoro-2-ni-
gen heterocycle in the 3-position. A few examples of
tropyridine with a range of nitrogen-containing heterocycles and al-
simple 2,3-diaminopyridines were commercially avail-
iphatic amines is described. The reaction proceeds in
a
able such as N3-methyl pyridine-2,3-diamine and 3-mor-
pholinopyridin-2-amine but these were relatively
expensive and/or only available in small quantities. Fur-
thermore, the latter was the only example of a compound
with a nitrogen-containing heterocycle in the 3-position.
In fact, there are surprisingly few examples of these syn-
thetically useful compounds reported in the literature, or
the corresponding 3-amino-2-nitropyridines from which it
was envisaged the required diamines could be accessed.
Yao et al. reported that treatment of 3-chloro-2-nitropyri-
dine or 3-bromo-2-nitropyridine with piperidine yielded
2-nitro-3-piperidylpyridine in poor yield due to nonselec-
tive displacement of both the chloro and the nitro group
and nitro group migration (Scheme 1).19 Azev et al. re-
ported similar results using morpholine.20
regioselective manner at moderate temperature and in reasonable
yield.
Key words: nitrogen-containing heterocycles, 3-fluoro-2-nitropyr-
idine, 3-substituted 2-aminopyridines, aliphatic amines
2-Aminopyridines have been used widely in the prepara-
tion of secondary amines,1,2 amides,3,4 cross-coupling
products,5 1,4-conjugate addition products,6,7 imidazopyr-
idines,8–12 sulfonamides,13,14 thioureas,15 and ureas.16–18
However, more fully functionalized 2-aminopyridines
also have synthetic utility. For example, the ALK inhibi-
tor Crizotinib launched in 2011 by Pfizer for the treatment
of non-small cell lung cancer contains a 3-alkoxy-5-pyr-
azolopyridin-2-amine and Nevirapine, a reverse transcrip-
tase inhibitor for the treatment of HIV, contains a 2,3-
diaminopyridine motif (Figure 1).
Due to the increased electronegativity of fluorine com-
pared to chlorine and bromine we reasoned that reaction
with commercially available 3-fluoro-2-nitropyridine
would favour SNAr displacement of the fluorine, leading
to increased selectivity. Herein we describe a facile syn-
thesis of 2,3-diaminopyridines from readily available and
cheap starting materials which proceeds in high selectivi-
ty to give novel 3-substituted 2-aminopyridines.
O
H
N
Cl
N
N
NH
O
F
N
N
N
Cl
H2N
N
Initial trial reactions showed that reaction of 3-fluoro-2-
nitropyridine with an excess of morpholine furnished the
required 4-(2-nitro-3-pyridyl)morpholine in 96% yield
even at room temperature (2a, Table 1, entry 1). In order
to reduce the requirement for excess amine the reactions
were also trialed in acetonitrile with three equivalents of
potassium carbonate to neutralise the hydrogen fluoride
formed in the reaction. At 50 °C excellent conversions
Nevirapine
Crizotinib
Figure 1
As part of our studies towards the synthesis of pharmaceu-
tically active compounds we were interested in utilizing a
wide range of 2-aminopyridines with an additional 3-ami-
NO2
X
H
N
N
X
+
+
+
N
N
N
N
N
NO2
N
NO2
1a X = Cl
1b X = Br
2a (58%)
2b (19%)
3a (18%)
3b (14%)
4a (24%)
4b (17%)
Scheme 1
SYNLETT 2012, 23, 1816–1820
Advanced online publication: 21.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290397; Art ID: ST-2012-D0203-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Substituted 2-Aminopyridines
1817
were observed with only 1.05 equivalents of butylamine was isolated. The required 2,3-diaminopyridines were ob-
and pyrrolidine (2b,c, Table 1, entries 2 and 3). None of tained in good yield by reduction of the nitro group using
the product formed by displacement of the nitro group standard hydrogenation conditions (Table 1).
Table 1 Synthesis of Compounds 2a–c and 3a–c
R1
R1
method
A or B
F
N
N
R2
R2
H2, Pd/C, EtOAc
R1
R2
N
H
+
N
NO2
N
NO2
N
NH2
1a–c
2a–c
3a–c
Entry
1
Substrate
Methoda
A
NO2 pyridine product
Yield (%)
NH2 pyridine product
Yield (%)
100
O
O
H
N
N
N
96
O
N
N
NO2
N
N
N
NH2
N
NH2
2
3
B
B
99
97
93
NH2
NO2
H
N
N
N
100
N
NO2
NH2
N
a Method A: 3-fluoro-2-nitropyridine (1.0 equiv), morpholine (2.5 equiv), r.t.; Method B: 3-fluoro-2-nitropyridine (1.0 equiv), amine (1.05
equiv), K2CO3 (3.0 equiv), MeCN, 50 °C, 18 h.
This method21 was subsequently applied to a wide range chosen as the preferred reducing agent to furnish the di-
of pyrazole, imidazole, and benzimidazole nucleophiles aminopyridines (Table 2, entry 1).
furnishing the 3-amino-2-nitropyridines in yields ranging
from 45–84% (Table 2). For those heterocycles contain-
ing a halogen substituent, iron/ammonium chloride was
Table 2 Synthesis of Compounds 2d–j and 3d–j
NHET
F
NHET
NH2
N
HET
reduction
K2CO3
+
MeCN
50 °C
method
A or B
N
NO2
N
NO2
N
1d–j
2d–j
3d–j
Entry
Substrate
NO2 pyridine product
Yield (%)
57
Methoda
NH2 pyridine product
Yield (%)
60
N
N
Cl
Cl
N
N
N
1
B
Cl
HN
N
NO2
N
N
N
NH2
N
N
N
N
H
N
N
2
3
54
76
A
A
82
91
NH2
N
N
NO2
N
N
N
N
N
HN
NH2
NH2
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1816–1820

1818
J. D. Culshaw et al.
LETTER
Table 2 Synthesis of Compounds 2d–j and 3d–j (continued)
NHET
F
NHET
NH2
N
HET
reduction
K2CO3
+
MeCN
50 °C
method
A or B
N
NO2
N
NO2
N
1d–j
2d–j
3d–j
Entry
Substrate
NO2 pyridine product
Yield (%)
65
Methoda
A
NH2 pyridine product
Yield (%)
N
N
N
N
N
4
100
85
HN
N
N
NO2
N
N
N
NH2
N
N
H
N
N
5
6
77
45
A
A
N
NH2
NO2
H
N
N
N
N
N
77
50
N
N
N
NH2
N
NO2
N
7
84
A
N
N
N
HN
N
NH2
N
NO2
a Method A: 10% Pd/C, H2, EtOH, r.t.; Method B: Fe, NH4Cl, EtOH, H2O, 80 °C.
Given the success of these reactions we expanded the
scope of nucleophiles to include more functionalised het-
erocycles where regioisomeric products could be formed,
H
H
N
H
N
N
N
N
for example 3-methyl-1H-pyrazole (Table 3, entry 1). The
exact regioisomer was determined by NOE experiments.
In this example an NOE was observed between the pyri-
dine hydrogen and the pyrazole hydrogen (and not the
methyl group) indicating that the product formed was iso-
mer 1 (Figure 2).
NO2
N
NO2
3k isomer 1
3k isomer 2
Figure 2
Other functionalised triazoles and imidazoles gave simi-
larly good yields of the 3-substituted-2-nitropyridines and
the corresponding amines (Table 3). The exact structures
were confirmed by 1H NMR studies and/or NOE experi-
ments, further details of which can be found in the Sup-
porting Information. In all but one example only one
regioisomer was isolated from the reaction. However, as
might be expected, reaction with 1,2,3-triazole afforded
the two isomers 2p and 2q in an approximately 4:1 ratio.
In conclusion, we have developed a robust synthesis of
novel 3-substituted-2-aminopyridines from commercially
available 3-fluoro-2-nitropyridine. Our initial success
with morpholine encouraged us to try other aliphatic
amines and subsequently a range of simple heterocyclic
nitrogen nucleophiles. The resulting nitropyridine inter-
mediates were reduced to the desired 2,3-diamino pyri-
dines either by standard hydrogenation conditions or
iron/ammonium chloride reduction. Following the suc-
cess with these nucleophiles we expanded the scope to in-
clude more functionalised heterocycles. In all cases the
reactions furnished the substituted nitropyridines in mod-
erate to good yields and no evidence was seen of the prod-
ucts formed by displacement of the nitro group as reported
by Yao19 for similar reactions with 3-chloro- or 3-bromo-
2-nitropyridine.
Synlett 2012, 23, 1816–1820
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Substituted 2-Aminopyridines
1819
Table 3 Synthesis of Compounds 2f–q and 3k–q
NHET
NH2
N HET
H
F
K2CO3
N
reduction
+
HET
method
A or B
MeCN
50 °C
N
N
NO2
N
NO2
1k–q
2k–q
3k–q
Entry
Substrate
NO2 pyridine product
Yield (%)
82
Methoda
NH2 pyridine product
Yield (%)
81
N
N
N
N
N
1
2
HN
A
N
N
NH2
N
N
NO2
Cl
Cl
N
H
N
N
N
N
N
N
N
53
B
59
N
Cl
NH2
NO2
CF3
N
CF3
N
H
N
N
N
3
4
5
62
89
52
A
A
A
88
99
94
N
CF3
N
N
NH2
N
N
NO2
N
N
N
N
N
N
N
H
N
N
N
NH2
NO2
N
N
N
N
N
N
N
HN
N
N
N
NO2
NH2
N
N
N
N
N
N
N
N
N
N
6
7
36
11
A
A
100
100
HN
N
NO2
NH2
N
N
N
N
N
N
N
HN
N
NH2
NO2
a Method A: 10% Pd/C, H2, EtOH, r.t.; Method B: Fe, NH4Cl, EtOH, H2O, 80 °C.
Acknowledgement
References and Notes
The authors would like to thank Sarah Kate Cantlie and Howard
Beeley for NMR Spectroscopy, Madeleine Vickers and Paul Davey
for mass spectrometry and Professor Joe Sweeney, Tom McGuire,
and Chris De Savi for their contribution to the writing of this paper.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1816–1820

1820
J. D. Culshaw et al.
LETTER
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(2 × 50 mL). The combined extracts were washed with brine
(100 mL), dried (MgSO4), filtered, and evaporated. The
crude product was purified by flash silica chromatography,
elution gradient 30% to 60% CH2Cl2 in heptane. Pure
fractions were evaporated to dryness to afford 3-(4-chloro-
1H-pyrazol-1-yl)-2-nitropyridine (2.40 g, 57%) as a solid;
mp 113–114 °C. 1H NMR (400 MHz, CDCl3): δ = 8.54 (1 H,
dd, J = 4.6, 1.5 Hz), 8.07 (1 H, dd, J = 8.1, 1.5 Hz), 7.75 (1
H, s), 7.69–7.73 (2 H, m). 13C NMR (101 MHz, CDCl3): δ =
114.28, 127.41, 128.00, 128.21, 134.85, 141.77, 147.32,
189.75. HRMS (ES): m/z calcd for (C8H5N4O2Cl)+:
224.0101; found: 224.0103.
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Typical Procedure for the Reduction of Nitropyridines
Using Method A
A suspension of the nitropyridine (2.06 mmol) and 10%
Pd/C (0.03 mmol) in EtOH (20 mL)–EtOAc (3 mL) was
stirred under an atmosphere of hydrogen at ambient
temperature for 16 h. The reaction mixture was filtered
through Celite, evaporated and the crude gum triturated with
Et2O–heptane to give a solid, which was collected by
filtration and dried under vacuum to give the aminopyridine.
Typical Procedure for the Reduction of Nitropyridines
Using Method B
Illustrated for Table 2, entry 1: NH4Cl (2.70 g, 50.53 mmol)
was added to 3-(4-chloro-1H-pyrazol-1-yl)-2-nitropyridine
(2.27 g, 10.11 mmol) and iron (3.61 g, 64.64 mmol) in EtOH
(30 mL) and H2O (5 mL), and the resulting mixture was
stirred at 80 °C for 3 h. The solvent was evaporated, and the
crude product was slurried with MeOH and filtered through
a Whatman No. 3 filter paper before purification by ion-
exchange chromatography, using an SCX 2 column. The
desired product was eluted from the column using 2 M NH3–
MeOH, and pure fractions were evaporated to dryness to
afford crude product. The product was dissolved in CH2Cl2
and washed with H2O (2×). The organic layer was dried over
Mg2SO4, filtered, and evaporated to afford 3-(4-chloro-1H-
pyrazol-1-yl)pyridin-2-amine (1.17 g, 59%) as a solid; mp
134–135.6 °C. 1H NMR (400 MHz, DMSO): δ = 8.44 (1 H,
s), 8.03 (1 H, dd, J = 4.8, 1.6 Hz), 7.89 (1 H, s), 7.62 (1 H,
dd, J = 7.7, 1.6 Hz), 6.70 (1 H, dd, J = 7.7, 4.8 Hz), 6.32 (2
H, s). 13C NMR (101 MHz, DMSO, 30 °C): δ = 110.07,
112.24, 120.09, 128.98, 131.43, 138.69, 147.44, 152.81.
HRMS (ES): m/z calcd for [C8H8N4Cl]+: 195.0432; found:
195.0431.
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(21) Typical Procedure for the Preparation of Nitropyridines
Illustrated for Table 2, entry 1: K2CO3 (5.15 g, 37.23 mmol)
was added in one portion to 3-fluoro-2-nitropyridine (2.65 g,
18.62 mmol) and 4-chloro-1H-pyrazole (2.00 g, 19.55
mmol) in MeCN (50 mL), and the resulting mixture was
stirred at 50 °C for 5 h. The cooled reaction mixture was
diluted with H2O (100 mL) and extracted with EtOAc
Synlett 2012, 23, 1816–1820
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