A mild, catalyst-free synthesis of 2-aminopyridines

Article abstract of DOI:10.1016/j.tet.2008.09.010

Alkylation of 2-mercaptopyridine with 1,2-dibromoethane affords a cyclic dihydrothiazolopyridinium salt that can serve as a precursor of 2-aminopyridines. Its reaction with primary or secondary amines, either neat or in DMSO, under mild conditions gives the title compounds.

Full text of DOI:10.1016/j.tet.2008.09.010

Tetrahedron 64 (2008) 10798–10801
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Tetrahedron
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A mild, catalyst-free synthesis of 2-aminopyridines
,
Bhaskar Poola a, Wonken Choung b, Michael H. Nantz a
*
a Department of Chemistry, University of Louisville, Louisville, KY 40292, United States
b Department of Chemistry, University of California, Davis, CA 95616, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkylation of 2-mercaptopyridine with 1,2-dibromoethane affords a cyclic dihydrothiazolopyridinium
salt that can serve as a precursor of 2-aminopyridines. Its reaction with primary or secondary amines,
either neat or in DMSO, under mild conditions gives the title compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 29 August 2008
Accepted 3 September 2008
Available online 17 September 2008
Keywords:
Aminopyridine
Heteroaryl amine
Thiazolopyridinium
N-Alkyl pyridinium
1. Introduction
a pyridinium salt having a C(2)-thioether as the leaving group14 and
report herein the results of its nucleophilic addition–elimination
2-Aminopyridines serve as useful chelating ligands in a variety
of inorganic and organometallic applications.1 The high incidence
of pharmacological activity among heteroaromatic amines also has
stimulated many research efforts to prepare compounds of this
structural type.2 The most common syntheses of 2-aminopyridines
involve either the N-alkylation of 2-aminopyridine (side-chain
elaboration)3 or the substitution of a 2-halopyridine by an amine.
The former approach often requires multiple steps to ensure that
over-alkylation does not occur. The latter method has been applied
to fluoro-,4 chloro-,5 bromo-,6 and iodo-pyridines7 using either
lithiated amines, high temperature, transition metal catalysis, or
combinations thereof.8 Indeed, a powerful synthetic approach to
aminopyridines uses the Buchwald–Hartwig amination9 wherein
the halide substitution is facilitated by palladium (e.g., cat.
Pd2(dba)3)10 at an elevated temperature.11 Copper-catalyzed
methods also have been developed for halide to amine sub-
stitutions in heteroaromatic systems.12
reactions.
2. Results and discussion
Treatment of 2-mercaptopyridine (1) with 1,2-dibromoethane
in DMF cleanly furnished dihydrothiazolopyridinium salt 215 as
a tan solid suitable for use in subsequent reactions without further
purification (Scheme 1).16 We next examined the reaction of 2 with
NR1R2
2
NR1R2
HNR1R2
– HBr
S
S
N
N
N
Br
2
3a–k
[4]
Scheme 1. Synthesis of 2-aminopyridines.
In an alternative approach, the formation of N-alkyl pyridinium
salts has been used to improve the nucleophilic addition of amines
to C(2).13 One drawback of this strategy, depending on substitution
pattern, is competing addition to C(4) of the N-alkyl pyridinium
salt. However, given that nucleophilic substitution reactions of
activated aryl halides are highly regioselective, we surmised that
a combination of pyridinium salt activation and a C(2)-leaving
group might provide a mild, regioselective method for pyridyl
C(2)–N bond formation. We tested this concept by preparing
morpholine as a test case. Although the reaction was sluggish and
the yield was low (ca. 23% at 48 h), we were gratified to find that
the reaction of 2 with 2.0 equiv of morpholine in DMSO at room
temperature afforded a single regioadduct, 2-morpholinopyridine
(3a). Doubling the equivalents of amine and warming the reaction
to 50 ꢀC improved the yield of 3a to 75%. We also found that for
simple, liquid amines, such as morpholine, solvent-free conditions
afforded the corresponding 2-aminopyridines regioselectively and
in good yield (Table 1). Presumably, the transformation proceeds
via amine addition to C(2) of 2 leading to adduct [4]. We have
not isolated the postulated intermediates [4] nor observed
* Corresponding author. Tel.: þ1 502 852 8069; fax: þ1 502 852 7214.
E-mail address: michael.nantz@louisville.edu (M.H. Nantz).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.010

B. Poola et al. / Tetrahedron 64 (2008) 10798–10801
10799
Table 1
the reaction was essentially 80% complete within 24 h, but required
more than one week to reach completion. The use of excess amine,
albeit the principal drawback of the present method, improves the
efficiency of the transformation. We also examined the reactions of
2 in water since the salt is freely soluble in water and to explore
whether the carbon–heteroatom bond formation behaves analo-
gous to other click chemistry examples.20 Treatment of 2 with
either piperidine, N,N-dimethylamine, or N-methylbutylamine
(4 equiv of amine in water at 50 ꢀC) gave the corresponding
2-aminopyridines in 41%, 22%, and 19% yields, respectively. The
lower yields in these reactions relative to the neat or DMSO
reactions are due to a faster decomposition of 2 in warm water.
To determine the susceptibility of 2 toward base-induced
elimination, we reacted 2 with the non-nucleophilic base DBU
(Scheme 2). Heating 2 with DBU in DMSO resulted in the formation
of N-vinyl pyridine-2-thione (5) in good yield. We had not observed
this elimination product in any of the aforementioned syntheses of
2-aminopyridines. The two-step synthesis of 5 represents a conve-
nient and improved means for N-vinylation of pyridine-2-thione.21
Synthesis of 2-aminopyridinesa
Entry
a
Amine
Conditionsb
Yield of 3c
O
A
B
C
75
78
94
N
H
b
A
94
N
H
A
B
C
A
B
C
A
B
C
A
B
C
78
77
75
56
63
65
65
57
79
75
59
61
N
H
c
d
e
f
NH2
NH2
Ph
NH2
A
d
36
S
g
BnO2C
NH2
NH2
DBU
48d
2
N
DMSO, 50 °C
76%
h
A
73
5
HO
i
j
A
71
Scheme 2. Synthesis of N-vinyl pyridine-2-thione.
NH2
NH2
EtO
EtO
Finally, we briefly examined extension of this method to quin-
oline. In similar manner to the formation of pyridinium salt 2,
2-mercaptoquinoline (6, Scheme 3) was transformed into the
dihydrothiazoloquinolinium salt 7.22 Reaction of 7 with either
dimethylamine or piperidine under the conditions developed for 2
showed that amine addition occurred to give the 2-substituted
quinolines. Again, the substitution reactions proceeded under
milder conditions relative to previously reported halide displace-
ment methods.23
A
A
86
78
EtO
k
EtO
NH2
2
a
Reactions analyzed after 48 h; the spectral data for products 3a–f and 3h–j are
consistent with the previous reports.
b
A: 4.0 equiv amine, DMSO, 50 ꢀC; B: neat amine (ca. 0.4–0.5 M), rt; C: neat amine
(ca. 0.4–0.5 M), 50 ꢀC.
c
Percent, after chromatography.
Amine (4.0 equiv), DMSO, rt.
d
1,2-dibromoethane
Br
DMF, rt, 72h
N
SH
N
S
71%
sulfur-containing by-products, such as ethylene sulfide or the cor-
responding amino adducts of ethylene sulfide; thus, the mecha-
nism of the reaction remains unclear.
6
7
Amine
Yield (%)
86%
HNR2
From the entries in Table 1, optimal conversions of the pyr-
idinium salt into 2-aminopyridines generally required warming to
50 ꢀC. Reaction temperatures above 50 ꢀC effected a gradual de-
composition of 2. The only case not improved by warming was the
reaction of 2 with benzyl glycine (entry g). We noted that consid-
erable ester cleavage occurred on warming this reaction. A change
to the tert-butyl ester of glycine did not improve the yield (data not
shown). The modest yield obtained for the formation of glycine
derivative 3g, however, does represent an improvement in the
synthesis of such N-pyridyl glycine analogs. Previous attempts to
react glycine or the tert-butyl ester of glycine with 2-fluoropyridine
under various conditions are reported to fail or give polymerized
products.17 Other glycine equivalents, such as allylamine and
ethanolamine, required reaction with 2-fluoropyridine under
microwave irradiation at 190 ꢀC and 210 ꢀC, respectively, to give the
corresponding substituted pyridines in 64% and 74% yield.17 In
comparison, the reactions of allylamine and ethanolamine with 2
(entries h and i) proceeded smoothly under milder conditions. The
mild conditions of the present method also tolerate acetal func-
tionality. The reactions of aminoacetaldehyde diethyl acetal and
4-amino-butyraldehyde diethyl acetal with 2 (entries j and k) gave
3j18 and 3k in good yields.
HNMe2
DMSO
50 °C
N
NR2
82%
HN
8a, b
Scheme 3. Synthesis of 2-aminoquinolines.
3. Conclusion
In summary, we have described a new, two-step synthesis of
2-aminopyridines from 2-mercaptopyridine. Conversion of the
dihydrothiazolopyridinium salt 2 into the title compounds requires
only stirring with excess amines.
4. Experimental section
4.1. General
Prior to use, DMF and DMSO were distilled from CaH2 under
reduced pressure. After reaction work-up, solutions were dried
using Na2SO4 and solvents were subsequently removed by rotary
evaporation. Nuclear magnetic resonance (NMR) spectra were
recorded in CDCl3 unless otherwise indicated. Infrared spectra were
recorded on a Mattson 5020 FTIR spectrometer. Melting points are
In regards to the time dependence of the reaction, an NMR
experiment (DMSO-d6 version of entry c at 50 ꢀC)19 showed that

10800
B. Poola et al. / Tetrahedron 64 (2008) 10798–10801
uncorrected. Elemental analyses were performed by Midwest
Microlabs (Indianapolis, IN).
5.31 (dd, J¼8.0, 1.5 Hz, 1H); 13C NMR (125 MHz)
d 180.1, 138.8, 137.3,
136.2, 134.1, 113.4, 109.2.
4.1.1. 2,3-Dihydrothiazolo[3,2-a]pyridinium bromide (2)
4.2.4. 1,2-Dihydrothiazolo[3,2-a]quinolinium bromide (7)
To a solution of 2-mercaptopyridine (5.0 g, 45 mmol) in DMF
(0.5 L) at room temperature was added 1,2-dibromoethane
(19.4 mL, 225 mmol). The reaction mixture was stirred 72 h
whereupon the precipitate, pyridinium bromide 2, was collected by
To a solution of 2-quinolinethiol (6) (1.0 g, 6.20 mmol) in DMF
(50 mL) at room temperature was added 1,2-dibromoethane
(2.67 mL, 31 mmol). The reaction mixture was stirred for 72 h. Et2O
(200 mL) was added to the reaction mixture to cause precipitation
of the product. The solids were collected by filtration, washed with
a small portion of Et2O, and dried under vacuum to afford 7 (1.17 g,
71%); mp 246–247 ꢀC (lit.22 234 ꢀC); 1H NMR (500 MHz, DMSO-d6)
filtration. The filtrate was washed with
a small portion of
dichloromethane and dried under vacuum to afford 2 (7.2 g, 73%) in
essentially pure form; mp 235–236 ꢀC (lit.15 222 ꢀC). A second crop
of 2 was obtained (1.7 g) by concentrating the mother liquor
d
8.97–8.85 (m,1H), 8.38–8.28 (m,1H), 8.25–8.05 (m, 3H), 7.92–7.80
(m, 1H), 5.41–5.30 (m, 2H), 4.05–3.90 (m, 2H); 13C NMR (125 MHz,
DMSO-d6) 165.3, 144.3, 137.6, 134.7, 130.0, 128.0, 126.0, 118.5, 56.8,
(combined yield: 8.9 g, 91%); 1H NMR (300 MHz)
d 8.94 (d,
J¼6.3 Hz, 1H), 8.31 (m, 1H), 8.14 (d, J¼6.3 Hz, 1H), 7.71 (m, 1H), 5.10
d
(t, J¼6.3 Hz, 2H), 3.82 (t, J¼6.3 Hz, 2H); 13C NMR (75 MHz)
d
159.4,
29.2; Anal. Calcd for C11H10BrNS$1/2H2O: C, 47.62; H, 3.96; N, 5.05.
Found: C, 47.85; H, 3.84; N, 5.09.
144.4, 142.7, 122.9, 122.2, 60.0, 30.0. Anal. Calcd for C7H8BrNS: C,
38.55; H, 3.70; N, 6.42. Found: C, 38.59; H, 3.65; N, 6.42.
Acknowledgements
4.2. General procedure for 2-aminopyridine formation:
method A
Funding from the NIH (NS-040489) is gratefully acknowledged.
To a solution of salt 2 (300 mg, 1.38 mmol) in DMSO (5 mL) at
room temperature was added the amine (4.8 mmol) in one portion.
The reaction mixture was warmed to 50 ꢀC and stirred for 48 h.
After cooling to room temperature, the reaction mixture was
diluted with water (20 mL) and 0.5 M aq NaOH (5 mL). The
resultant solution was extracted with diethyl ether (5ꢁ) and the
combined organic extract was washed with brine and dried (anhyd
Na2SO4). The solvent was removed and the residue purified by
column chromatography (SiO2).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.010.
References and notes
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4.2.1. Synthesis of N-(2-pyridyl)-glycine benzyl ester (3g)
To a solution of pyridinium bromide 2 (300 mg, 1.38 mmol) and
p-toluenesulfonate salt of glycine benzyl ester (1.85 g, 5.5 mmol) in
dry DMSO (7 mL) at room temperature was added triethylamine
(1.16 mL, 8.25 mmol). The reaction mixture was stirred for 48 h at
room temperature and then quenched by addition of water (20 mL)
and saturated aq NaHCO3 (50 mL). The resultant solution was
extracted with Et2O (5ꢁ50 mL), and the combined organic extract
was dried (Na2SO4). The solvents were removed and the residue
was purified by column chromatography (SiO2) eluting with mix-
ture of EtOAc/hexane (35:65) to obtain ester 3g (160 mg, 48%) as
a colorless oil; IR (neat) 3404, 3029, 2931, 1740, 1604 cmꢂ1; 1H NMR
(500 MHz)
d
8.08 (d, J¼4.5 Hz, 1H), 7.42–7.25 (m, 6H), 6.61 (m, 1H),
6.45 (d, J¼8.5 Hz, 1H), 5.20 (s, 2H), 5.01 (br s, NH), 4.19 (d, J¼5.0 Hz,
2H); 13C NMR (125 MHz)
d 171.4, 157.7, 147.9, 137.7, 135.7, 128.8,
128.6, 128.4, 113.9, 108.7, 67.1, 44.0; HRMS m/z [MþH]þ calcd for
7. Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987.
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Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413.
C14H14N2O2: 243.1133, found: 243.1133.
4.2.2. 4-N-(2-Pyridyl)amino-butyraldehyde diethyl acetal (3k)
Following method A outlined above, salt 2 (0.20 g, 0.92 mmol)
was transformed into aminopyridine 3k (0.17 g, 78%); IR (neat)
3376, 3261, 2972, 1602 cmꢂ1 1H NMR (500 MHz)
; d 8.0–7.98 (m,
10. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135.
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1H), 7.31 (t, J¼8 Hz, 1H), 6.46 (t, J¼6 Hz, 1H), 6.29 (d, J¼8.5 Hz, 1H),
4.70 (br s, 1H), 4.45–4.43 (m, 1H), 3.60–3.50 (m, 2H), 3.45–3.40 (m,
2H), 3.24–3.21 (m, 2H), 1.65–1.64 (m, 4H), 1.15–1.10 (m, 6H); 13C
NMR (125 MHz)
d 158.7, 147.9, 137.2, 112.4, 106.4, 102.5, 61.0, 41.8,
31.0, 24.6, 15.2; HRMS m/z [MþH]þ calcd for C13H22N2O2: 239.1759,
found: 239.1753.
4.2.3. N-Vinyl pyridine-2-thione (5)
Following method A, 100 mg (0.46 mmol) of salt 2 was treated
with DBU (0.28 mL, 1.83 mmol) to afford 5 (47 mg, 76%) as yellow
solid, mp 67–68 ꢀC (lit.21 72 ꢀC); 1H NMR (500 MHz)
d 7.86 (dd,
J¼15.5, 8.5 Hz, 1H), 7.75 (d, J¼7.0 Hz, 1H), 7.60 (d, J¼9.0 Hz, 1H), 7.19
(t, J¼8.5 Hz, 1H), 6.66 (t, J¼6.5 Hz, 1H), 5.38 (dd, J¼15.5, 1.5 Hz, 1H),

B. Poola et al. / Tetrahedron 64 (2008) 10798–10801
10801
15. Singh, H.; Malhotra, S. C. Indian J. Chem. 1981, 20B, 213.
16. Although unnecessary for subsequent reactions with amines, pyridinium bro-
mide 2 is readily recrystallized from ethanol.
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18. Previously prepared in 47% yield from 2-aminopyridine; see: Ziegler, R.; Ho, B.;
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19. The reaction progress is conveniently monitored by observing the pyridyl-H
resonances in 1H NMR between
d 6–9 ppm.