Synthesis of 2-Alkylamino-3-fluoropyridines Using Buchwald Conditions

Article abstract of DOI:10.1081/SCC-120028348

Synthesis of 2-alkylamino-3-fluoropyridines from 2-chloro-3-fluoropyridine using palladium-catalyzed coupling reaction under Buchwald conditions is described.

Full text of DOI:10.1081/SCC-120028348

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Synthesis of 2‐Alkylamino‐3‐fluoropyridines Using
Buchwald Conditions
a
a
Peter M. Munson & Wayne J. Thompson
a
Merck Research Laboratories, Department of Medicinal Chemistry, WP1H‐3, West Point,
Pennsylvania, 19486, USA
Version of record first published: 20 Aug 2006
To cite this article: Peter M. Munson & Wayne J. Thompson (2004): Synthesis of 2‐Alkylamino‐3‐fluoropyridines Using
Buchwald Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 34:5, 759-766
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 5, pp. 759–766, 2004
Synthesis of 2-Alkylamino-3-fluoropyridines
Using Buchwald Conditions
*
Peter M. Munson and Wayne J. Thompson
Merck Research Laboratories, Department of Medicinal Chemistry,
West Point, Pennsylvania, USA
ABSTRACT
Synthesis of 2-alkylamino-3-fluoropyridines from 2-chloro-3-fluoro-
pyridine using palladium-catalyzed coupling reaction under Buchwald
conditions is described.
Key Words: 2-Alkylamino-3-fluoropyridine; Buchwald conditions;
Tetrahydrofuran; Palladium-catalyst.
The introduction of a fluorine substituent at the 3 or 5 position of a
-aminopyridine can favorably change the chemical and biological properties
2
of the compound.
[
1,2]
An example of this substitution pattern can be found in
the fluoroquinolone antibiotic enoxacin, which contains a fused 3-fluoro-2-
*
Correspondence: Peter M. Munson, Merck Research Laboratories, Department of
Medicinal Chemistry, WP1H-3, West Point, PA 19486, USA; E-mail: peter_munson@
merck.com.
7
59
DOI: 10.1081/SCC-120028348
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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7
60
Munson and Thompson
[
3]
aminopyridine.
requires harsh displacement conditions or special fluorination method-
The synthesis of the parent 2-amino-3-fluoropyridine
[
1,2]
ologies.
Recently, Wagaw and Buchwald reported a novel palladium-
[4]
catalyzed reaction for the preparation of 2-aminopyridines. We were
interested in utilizing this convenient method for preparation of 2-amino-3-
[5]
fluoropyridines from the readily available 2-chloro-3-fluoropyridine. We
found that 2-chloro-3-fluoropyridine does in fact undergo the Buchwald
coupling reaction with a variety of amines. The products are obtained in good
yield by using tetrahydrofuran as the reaction solvent. The broad generality
and good conversion observed is attributed to the electron withdrawing
fluorine substituent, which markedly increases reactivity at C2 of the pyridine
ring.
For example, heating a mixture of cyclohexylamine (R , R ¼ (CH ) ),
1
2
2 5
with 2-chloro-3-fluoropyridine (2.0 equiv.), sodium-tert-butoxide (1.1 equiv.),
palladium acetate (4 mole%), and (+) BINAP (4 mole%) in tetrahydrofuran
at 658C for 3 h gives cyclohexyl(3-fluoropyridin-2-yl)amine in 92% yield after
workup and purification. The results of this reaction with a variety of amines
are summarized in the Table 1. Similar yields (ꢀ90%) of cyclohexyl-pyridin-
2
-yl-amine were obtained with longer reaction time of 22 h at reflux in
a
tetrahydrofuran. Only traces of cyclohexyl-pyridin-2-yl-amine were detected
after 3 h of reflux using 2-chloropyridine in the place of 2-chloro-3-fluoro-
pyridine. It is important to note that although the 3-fluorine substituent
accelerated the alkylation reaction, no reaction was detected with the cyclo-
hexylamine after 22 h of reflux in the absence of palladium catalyst.
In summary, the Buchwald reaction employing 2-chloro-3-fluoropyridine
is a facile and convenient method for the formation of 2-alkylamino-3-
fluoropyridines. The mildness of the reaction conditions allows for the alkyla-
tion of volatile amines (entry 10) and the presence of sensitive protecting
groups (entry 8).
EXPERIMENTAL
1
All melting points were uncorrected. H-NMR spectra were determined in
d-chloroform solution on FT-NMR Varian operating at 400 MHz and reported
in d ppm using tetramethylsilane as the internal standard. The accurate mass
measurements were performed on the Bruker BioApex 7T FTCIR mass
spectrometer. The ionization mode was Electrospray, and the solvent system
a
Wagaw and Buchwald reported a 73% yield of cyclohexyl-pyridin-2-yl-amine after 22
hours at 708C in toluene.

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Synthesis of 2-Alkylamino-3-fluoropyridines
761
Table 1. Conversion of 2-chloro-3-fluoropyridine into 2-alkylamino-3-fluoro-
pyridines.
Yield
(%)
mp
(8C)
Entry
1
HNR
1
R
2
Product
62
44
oil
oil
2
3
90 81–82
4
5
6
77
oil
92 71–72
60 83–84
7
8
9
35 121–122
76 152–153
45
oil
(continued)

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62
Munson and Thompson
Table 1. Continued.
Yield
(%)
mp
(8C)
Entry
HNR
1
R
2
Product
1
0
1
24 41–42
81 47–48
1
used was acetonitrile/water 50/50 þ 0.1% acetic acid. Merck silica gel (230–
00 mesh A.S.T.M) was used for flash column chromatography. All other
reagents were obtained commercially high purity.
4
Preparation of 2-Chloro-3-fluoropyridine
A 200 mL one-neck round bottom flask was charged with 2-chloro-3-
aminopyridine (5.60 g, 43.56 mmol) in ethanol (50 mL). Next, 48% HBF4
(
17.0 mL) was added and the reaction was then cooled to 258 C using dry ice/
acetone bath. After stirring 15 min, isoamyl nitrite (6.0 mL) was added
dropwise over 5 min period keeping the internal temperature of the reaction
below 08 C. The product begins to crystallize out during the addition. After
stirring 30 min, the solid crystalline diazonium salt was filtered and washed by
ethanol (2.0 mL) and diethyl ether (20 mL). Next, the solid was placed into a
200 mL round bottom flask and dried under vacuum for 10 min. Next, heptane
(
50 mL) was added to the flask and the mixture was stirred and heated to reflux
under N for 2 h. The mixture was cooled in an ice bath and 3.0 N NaOH
2
solution (20 mL) was added. Next, the aqueous layer was extracted with
diethyl ether (3 ꢀ 50 mL). The organic layer was collected, dried over
MgSO , and concentrated down to give a liquid. Next, the liquid was
4
placed onto silica gel flash column and eluted with diethyl ether. A total
[5]
of 4.0 g (30.54 mmol) a volatile colorless liquid was obtained. Yield; 70%.

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Synthesis of 2-Alkylamino-3-fluoropyridines
763
1
H-NMR: (CDCl , 400 MHz) d 8.25 (d, J ¼ 3.5 Hz, 1H), 7.50 (m, 1H), 7.25
3
(
m, 1H) ppm.
General Procedure for the Synthesis of 2-Alkylamino-3-
fluoropyridines
A round bottom flask was charged with amine (0.84 mmol) (see Table 1),
-chloro-3-fluoropyridine (0.220 g, 1.68 mmol), palladium (II) acetate
2
0
0
(
0.005 g, 0.02 mmol), racemic-2,2 -Bis(diphenylphosphino)-1,1 -dinapthyl
0.020 g, 0.03 mmol), and dry tetrahydrofuran (10 mL). The reaction was
(
placed under nitrogen, sodium tert-butoxide (0.165 g, 1.72 mmol) was added
and the mixture was heated at reflux. The reaction was monitored by TLC to
evaluate the disappearance of amine. The total reaction time was 3 h. The
reaction mixture was cooled to room temperature and concentrated under
reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed
with sat. Na CO and sat. NaCl, and dried over Na SO . The organic layer was
2
3
2
4
concentrated, and the crude product was purified by chromatography eluting
with hexane/diethyl ether (9 : 1). The solvents were then removed under
reduced pressure to give the desired product (see Table 1).
1
H-NMR, HRMS, and CHN spectral data of the products (entries 1–11)
are given below:
Entry 1: Benzyl-(3-fluoro-pyridin-2-yl)-amine
1
H NMR (CDCl , 400 MHz) d 7.91 (d, J ¼ 5.0 Hz, 1H), 7.39–7.30
3
(
m, 4H), 7.29–7.25 (m, 1H), 7.15 (t, J ¼ 9.30 Hz, J ¼ 10.2 Hz, 1H), 6.56–
1
2
6
.52 (m, 1H), 4.85 (bs, 1H), 4.75 (d, J ¼ 5.67 Hz, 2H); HRMS calcd for
C H FN 202.0904, found 202.0906. CHN analysis calcd for C H FN : C,
12 11 2 12 11 2
71.27; H, 5.48; N, 13.85; found: C, 71.48; H, 5.28; N, 14.10.
Entry 2: (3-Fluoro-pyridin-2-yl)-4-benzylpiperdine
1
H NMR (CDCl , 400 MHz) d 7.98 (d, J ¼ 4.75 Hz, 1H), 7.31–7.21
3
(
m, 2H), 7.19–7.16 (m, 5H), 6.72–6.68 (m, 1H), 4.02 (d, J ¼ 8.96 Hz, 2H),
1 2
2
.81 (t, J ¼ 12.89 Hz, J ¼ 12.70 Hz, 2H), 2.58 (d, J ¼ 6.68 Hz, 2H), 1.75
(
d, J ¼ 2.74 Hz, 2H), 1.40 (q, J ¼ 3.39 Hz, J ¼ 3.11 Hz, J ¼ 11.97 Hz,
1 2 3
2H); HRMS calcd for C H FN 271.1605, found 217.1600; CHN analysis
calcd for C H FN : C, 75.53; H, 7.08; N, 10.42; found: C, 75.48; H, 7.12; N,
17 19 2
1
7
19
2
10.42.

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64
Munson and Thompson
Entry 3: (4-Ethyl-1-piperidinylcarboxylate)-(3-fluoro-
pyridin-2-yl)-amine
1
H NMR (CDCl , 400 MHz) d 7.83 (d, J ¼ 5.03 Hz, 1H), 7.10 (m, 1H),
3
6
.47 (m, 1H), 4.45 (bs, 1H), 4.47–4.06 (m, 5H), 3.01 (t, J ¼ 12.16 Hz,
1
J ¼ 12.16 Hz, 2H), 2.05 (d, J ¼ 4.57 Hz, 2H), 1.43–1.33 (m, 2H), 1.24
2
(
found 268.1456; CHN analysis calcd for C H FN : C, 58.41; H, 6.79; N,
t, J ¼ 7.13 Hz, J ¼ 7.13 Hz, 3H); HRMS calcd for C H FN 268.1467,
17 19 2
1
2
17 19
2
15.72; found: C, 58.32; H, 6.86; N, 15.61.
Entry 4: (1-Benzyl-pyrrolidin-3-yl)-(3-fluoro-pyridin-2-yl)-
amine
1
H NMR (CDCl , 400 MHz) d 7.85 (d, J ¼ 5.03 Hz, 1H), 7.35–7.31
3
(
m, 4H), 7.29–7.23 (m, 1H), 7.10 (m, 1H), 6.48 (m, 1H), 4.88 (bs, 1H), 4.63
bs, 1H), 3.64 (s, 2H), 2.86 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.41–2.34
m, 2H), 1.72–1.67 (m, 1H); HRMS calcd for C H FN 272.1576, found
(
(
1
6
18
3
.
2
72.1558; CHN analysis calcd for C H FN 0.20 H O (MW ¼ 274.94):
1
6
18
3
2
C, 69.90; H, 6.75; N, 15.28; found: C, 69.51; H, 6.75; N, 15.23.
Entry 5: Cyclohexyl-(3-fluoro-pyridin-2-yl)-amine
1
H NMR (CDCl , 400 MHz) d 7.86 (d, J ¼ 4.74 Hz, 1H), 7.10–7.05
3
(
m, 4H), 6.47–6.43 (m, 1H), 4.45 (bs, 1H), 3.98–3.89 (m, 1H), 2.06
d, J ¼ 9.14 Hz, 2H), 1.80–1.72 (m, 2H), 1.66–1.62 (m, 1H), 1.49–1.27
m, 2H), 1.24–1.15 (m, 3H); HRMS calcd for C H FN 195.1292, found
(
(
1
1
15
2
195.1307; CHN analysis calcd for C H FN : C, 68.01; H, 7.78; N, 14.42;
found: C, 67.81; H, 7.90; N, 14.31.
11 15 2
Entry 6: 4-Benzylpiperidinyl-(3-fluoro-pyridin-2-yl)-amine
1
H NMR (CDCl , 400 MHz) d 7.85 (d, J ¼ 5.03 Hz, 1H), 7.33–7.29
3
(
(
m, 4H), 7.27–7.24 (m, 1H), 7.12–7.07 (m, 1H), 6.49–6.45 (m, 1H), 4.45
d, J ¼ 6.68 Hz, 1H), 4.02–3.94 (m, 1H), 3.53 (s, 2H), 2.84 (d, J ¼ 11.89 Hz,
2
H), 2.24 (t, J ¼ 9.51 Hz, J ¼ 9.42 Hz, 2H), 2.08 (d, J ¼ 1.92 Hz, 2H), 1.53
1
2
(
q, 2H); HRMS calcd for C H FN 286.1714, found 286.1734; CHN
17 20 3
.
analysis calcd for C H FN 0.20 H O (MW ¼ 288.97): C, 70.66; H, 7.12;
1
7
20
3
2
N, 14.54; found: C, 70.66; H, 6.93; N, 14.46.

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Synthesis of 2-Alkylamino-3-fluoropyridines
Entry 7: Adamantyl-(3-fluoro-pyridin-2-yl)-amine
765
1
H NMR (CDCl , 400 MHz) d 7.81 (d, J ¼ 4.94 Hz, 1H), 7.07–7.02
3
(
m, 1H), 6.44–6.41 (m, 1H), 4.37 (bs, 1H), 2.14 (s, 4H), 2.11 (s, 1H), 1.76–
1.71 (m, 6H), 1.44–1.41 (m, 1H), 1.25 (s, 1H), 1.22 (s, 1H); HRMS calcd for
C H FN 247.1618, found 247.1605.
1
5
19
2
Entry 8: (4-Methyl-1-N-tert-butoxycarbonyl-piperidine)-
3-fluoro-pyridin-2-yl)-amine
(
1
H NMR (CDCl , 400 MHz) d 7.88 (d, J ¼ 4.02 Hz, 1H), 7.14–7.08
3
(
(
(
t, 1H), 6.50–6.48 (m, 1H), 4.65 (bs, 1H), 4.15–4.07 (bs, 2H), 3.37
d, J ¼ 5.85 Hz, 2H), 2.70 (m, 2H), 1.82–1.74 (m, 3H), 1.45 (s, 9H), 1.21
q, 2H); HRMS calcd for C H FN O 310.1937, found 310.1926. CHN
1
6
24
3 2
.
analysis calcd for C H FN O 0.55 H O (MW ¼ 319.29): C, 60.19; H,
1
6
24
3
2
2
7
.92; N, 13.16; found: C, 60.34; H, 7.67; N, 12.79.
Entry 9: 4-(3-Fluoro-pyridin-2-yl)-morpholine
1
H NMR (CDCl , 400 MHz) d 8.01 (d, J ¼ 3.47 Hz, 1H), 7.26–7.21
3
(
m, 1H), 6.79–6.75 (m, 1H), 3.85–3.83 (m, 4H), 3.84–3.46 (m, 4H), 2.06
d, J ¼ 9.14 Hz, 2H); HRMS calcd for C H FN O 183.0928, found
(
9
11
2
183.0937; CHN analysis calcd for C H FN O: C, 59.33; H, 6.09; N, 15.38;
found: C, 59.72; H, 6.01; N, 15.08.
9 11 2
Entry 10: Cyclobutyl-(3-fluoro-pyridin-2-yl)-amine
1
H NMR (CDCl , 400 MHz) d 7.86 (d, J ¼ 5.04 Hz, 1H), 7.26–7.07
3
(
m, 1H), 6.50–6.46 (m, 1H), 4.72–4.52 (bs, 1H), 4.50 (q, J ¼ 7.60 Hz,
1
J ¼ 8.33 Hz, J ¼ 7.51 Hz, 4H), 2.48–2.41 (m, 2H), 1.91–1.84 (m, 2H),
2
3
1
.79–1.70 (m, 2H); HRMS calcd for C H FN 167.0979, found 167.0980.
9 11 2
Entry 11: Cyclopentyl-(3-fluoro-pyridin-2-yl)-amine
1
H NMR (CDCl , 400 MHz) d 7.84 (d, J ¼ 4.12 Hz, 1H), 7.26–7.01
3
(
(
m, 1H), 6.43–6.39 (m, 1H), 4.51 (bs, 1H), 4.37–4.28 (m, 4H), 2.48–2.41
m, 2H), 2.09–1.99 (m, 2H), 1.73–1.67 (m, 2H), 1.66–1.55 (m, 2H), 1.46–
1.21 (m, 2H); HRMS calcd for C H FN 181.1136, found 181.1139; CHN
10 13 2

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7
66
Munson and Thompson
analysis calcd C H FN : C, 66.64; H, 7.27; N, 15.54; found: C, 66.50;
1
0
13
2
H, 7.38; N, 15.42.
ACKNOWLEDGMENTS
The authors wish to thank Ms. Jean Kaysen for assistance with manuscript
preparation and Drs. Charles Ross and Harri Ramjit for mass spectrometric
measurements.
REFERENCES
1. Hand, E.S.; Baker, D.C. Syntheses of 2-chloro- and 2-amino-
5-fluoropyridines and isolation of a novel difluoroboryl imidate. Synthesis
1989, 12, 905.
2
. de Viedma, A.G.; Martinez-Barrasa, V.; Burgos, C.; Izquierdo, M.L.;
Alvarez-Builla, J. N-Azinylpyridinium N-aminides: intermediates for the
ragioselective synthesis of 3-fluoro-2-aminopyridine derivatives. J. Org.
Chem. 1999, 64, 1007.
3
4
. Sanchez, J.P.; Rogowski, J.W. An efficient synthesis of 6-fluoronalidixic
acid and its conversion to enoxacin. J. Heterocycl. Chem. 1987, 24, 215.
. Wagaw, S.; Buchwald, S.L. The synthesis of aminopyridines: a method
employing palladium-catalyzed carbon-nitrogen bond formation. J. Org.
Chem. 1996, 61, 7240.
5. Link, W.J.; Borne, R.F.; Setliff, F.L. New 2,3-dinalopyridines. Potential
precursors for 2,3-dehydropyridine. J. Heterocycl. Chem. 1967, 4, 641.
Received in the USA September 3, 2003

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