Microwave-assisted synthesis of 2-aminonicotinic acids by reacting 2-chloronicotinic acid with amines

Article abstract of DOI:10.1016/j.tetlet.2009.03.034

2-(Methylamino)nicotinic acid was readily prepared in high yield by reacting 2-chloronicotinic acid with 40% aq MeNH₂ under microwave irradiation either at 120 °C for 2 h or at 140 °C for 1.5 h. Subsequently, we found that a range of 2-aminonicotinic acids could be obtained under microwave heating. The optimal reaction conditions involved the use of 3 equiv of amine, water as the solvent and heating at 200 °C for 2 h in the presence of diisopropylethylamine (3 equiv).

Full text of DOI:10.1016/j.tetlet.2009.03.034

Tetrahedron Letters 50 (2009) 2481–2483
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of 2-aminonicotinic acids by reacting
2-chloronicotinic acid with amines
*
*
Camilo E. Quevedo, Vassilios Bavetsias , Edward McDonald
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(Methylamino)nicotinic acid was readily prepared in high yield by reacting 2-chloronicotinic acid with
40% aq MeNH2 under microwave irradiation either at 120 °C for 2 h or at 140 °C for 1.5 h. Subsequently,
we found that a range of 2-aminonicotinic acids could be obtained under microwave heating. The optimal
reaction conditions involved the use of 3 equiv of amine, water as the solvent and heating at 200 °C for
2 h in the presence of diisopropylethylamine (3 equiv).
Received 22 December 2008
Revised 23 February 2009
Accepted 6 March 2009
Available online 13 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminonicotinic acid
Microwave irradiation
2-Chloronicotinic acid
2-Aminonicotinic acids are valuable intermediates for the prep-
aration of compounds with potential as chemotherapeutic agents.
For example, 2-(butylamino)nicotinic acid is an intermediate in the
synthesis of the 1,8-naphthyridine ring for SMP-797, an acyl-
CoA:cholesterol acyltransferase (ACAT) inhibitor with potential
utility for the treatment of hypercholesterolemia and atherosclero-
sis.1 Also, 2-aminonicotinic acids are intermediates in the synthesis
of 1,8-naphthyridin-2(1H)-ones with potential as antiallergy
agents,2 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-ones, possessing
anti-inflammatory activity3 and 2-amino-N-phenyl nicotinamides,
which are reported as potent inhibitors of kinase insert-domain-
containing receptor (Kdr).4
ing conditions: (a) reaction with 40% aq MeNH2 in a sealed tube at
120 °C for 15 h,8 (b) reaction with 33% MeNH2 in EtOH in a pres-
sure vessel at 100 °C for 18 h,9 and (c) reaction with MeNH2ÁHCl
in DMF at 100 °C for 18 h in the presence of K2CO3 and CuBr.10
Initially, we prepared 4 by the first of these methods. We then
attempted to improve the reaction conditions for this nucleophilic
COOH
Cl
COOH
NR1R2
CN
HNR1R2
heat
aq. NaOH
reflux
N
2
N
3
NR1R2
N
1
The nucleophilic aromatic substitution of 2-chloronicotinic acid
with appropriate amines (Scheme 1) is a well-established method
for the preparation of 2-aminonicotinic acids,1,5,6 but harsh condi-
tions involving prolonged heating are normally required. For
example, 2-(butylamino)nicotinic acid was obtained by heating a
mixture of 2-chloronicotinic acid and butylamine at reflux for
2 days.1
In an alternative approach, 2-(4-methylpiperazin-1-yl)nicotinic
acid was obtained from 3-cyano-2-(4-methylpiperazin-1-yl)pyri-
dine by alkaline hydrolysis (Scheme 1).7 In connection with current
work aimed at the production of a compound library directed
against kinase anticancer targets, we were interested in the syn-
thesis of 2-(methylamino)nicotinic acid (4). In literature reports,
acid 4 was obtained from 2-chloronicotinic acid under the follow-
Scheme 1. Synthesis of 2-aminonicotinic acids.
Table 1
Synthesis of 2-(methylamino)nicotinic acid
COOH
NHMe
Comments
COOH
40% aq MeNH2
heating, µW
N
Cl
N
4
1
Entry 40% MeNH2
(equiv)
Temp
Reaction time
(°C)
(h)
1
2
15
15
120
120
0.17
1.0
Some product
Nearly to
completion
Nearly to
completion
Completion
Completion
3
7
120
1.5
* Corresponding authors. Tel.: +44 0 20 86438901x4601 (V.B.); tel.: +44 0 20
87224294 (E.M.).
E-mail addresses: vassilios.bavetsias@icr.ac.uk (V. Bavetsias), Ted.McDonald@
icr.ac.uk (E. McDonald).
4
5
7
7
140
120
1.5
2.0
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.034

2482
C. E. Quevedo et al. / Tetrahedron Letters 50 (2009) 2481–2483
Table 2
COOH
Ph
COOH
N
Synthesis of 2-aminonicotinic acids by reaction of 2-chloronicotinic acid with amines
N
15
S
N
H
16
COOH
NR1R2
H2O, HNR1R2 (3 equiv)
COOH
Cl
iPr NEt (3 equiv), µ
W
Figure 1.
2
N
N
200 oC, 2 h
Entry
1
Product
Yield (%)
70
aromatic substitution by exploring the use of microwave
irradiation. A detailed investigation to identify the optimal condi-
tions for this transformation gave the results that are summarised
in Table 1.
COOH
N
N
N
N
H
5
6
In our hands, the optimal conditions for obtaining 4 under
microwave irradiation involved the use of 7 equiv of 40% aq
MeNH2 and heating the reaction mixture either at 140 °C for
1.5 h or at 120 °C for 2 h (Table 1, entries 4 and 5).11 Having estab-
lished the optimal conditions for obtaining 4, the scope of this
reaction was investigated by reacting 2-chloronicotinic acid with
a range of aliphatic amines, anilines and benzylamines. Again,
water was used as the solvent but the reaction conditions were fur-
ther optimised to accommodate the differences in amine reactivity.
The temperature was raised to 200 °C, and the reaction time was
set to 2 h in an effort to reduce the amount of amine required.
Using n-butylamine, complete conversion of 2-chloronicotinic acid
into 5 could be achieved with 3 equiv of the amine and 3 equiv of
the tertiary amine base, diisopropylethylamine (Table 2).11 Under
these conditions, primary or secondary aliphatic amines, benzyl-
amines and anilines gave the corresponding 2-aminonicotinic
acids in moderate to high isolated yields (Table 2).
Subsequently, we briefly explored the reactivity of oxygen and
sulfur-based nucleophiles with 2-chloronicotinic acid, under the
conditions described in Table 2. Although, benzyl mercaptan gave
the expected sulfide 15 (Fig. 1) in 45% yield, n-butanol failed to give
any product as judged by LC–MS. It should be noted that 4-(meth-
ylamino)nicotinic acid (16) (Fig. 1) was also prepared from 4-chlo-
ronicotinic acid under microwave irradiation using conditions
analogous to those described for the synthesis of 4, though the
reaction mixture was heated at 165 °C for 4 h. By following the
work-up procedure described for 4,11 4-(methylamino)nicotinic
acid (16) was precipitated out during the final pH adjustment
(i.e., pH 6.5), and subsequently was isolated by filtration in 83%
yield.
COOH
2
3
52
75
O
N
H
COOH
NH
7
COOH
N
4
5
47
74
N
8
COOH
N
N
N
9
COOH
NH
N
6
83
10
OMe
COOH
In conclusion, 2-(methylamino)nicotinic acid was readily pre-
pared in high yield by reacting 2-chloronicotinic acid with 40%
aq MeNH2 at 140 °C under microwave heating for 1.5 h. The 4-
methylamino isomer was prepared similarly by heating at 165 °C
for 4 h. 2-Chloronicotinic acid also reacted with primary or second-
ary aliphatic amines, benzylamines and anilines under microwave
irradiation to provide a range of 2-aminonicotinic acids. The opti-
mal reaction conditions involved the use of 3 equiv of amine, water
as the solvent and heating at 200 °C for 2 h in the presence of diiso-
propylethylamine (3 equiv).
N
N
7
63
11
Cl
COOH
8
9
63
80
50
N
N
H
12
COOH
Acknowledgements
N
N
H
Financial support from the Institute of Cancer Research (stu-
dentship to C.E.Q.) is gratefully acknowledged. We acknowledge
NHS funding to the NIHR Biomedical Research Centre. This work
was supported by Cancer Research UK [CUK] grant numbers
C309/A8274. The authors also thank Dr. Amin Mirza and Mr. Mei-
rion Richards for their assistance with NMR and mass
spectrometry.
13
Cl
COOH
N
10
N
N
14

C. E. Quevedo et al. / Tetrahedron Letters 50 (2009) 2481–2483
2483
white solid which was dissolved in water (3.5 mL). The pH of the solution was
adjusted to 6.5 with concd HCl; no precipitation of the product was observed.
The water was removed under reduced pressure, and the resultant white solid
was treated with warm MeOH (ꢀ50 mL). The insoluble material was removed,
and the solution was concentrated under reduced pressure to afford the title
compound as a white solid which was dried in vacuo over P2O5 (0.550 g, 98%).
Rf 0.14 (EtOAc, neat); mp 256–258 °C (MeOH); dH (500 MHz; DMSO-d6) 12.90
(1H, br s, exchangeable with D2O, COOH), 8.25 (1H, dd, J1 = 4.7, J2 = 1.8,
NCHCHCH), 8.03 (1H, dd, J1 = 7.7, J2 = 1.8, NCHCHCH), 7.92 (1H, br s,
exchangeable with D2O, NHMe), 6.56 (1H, dd, J1 = 7.6, J2 = 4.8, NCHCHCH),
2.93 (3H, s, NCH3); dC (126 MHz; DMSO-d6) 168.8, 158.8, 153.1, 139.9, 110.7,
106.2, 27.6; LC (3.5 min gradient: MeOH/0.1% formic acid)—MS (ESI, m/z):
retention time = 0.60 min (99% purity)—153 [(M+H)+, 100%].B. Synthesis of 2-
aminonicotinic acids (Table 2)-General procedure: To a stirred suspension of 2-
chloronicotinic acid and water (0.1 M) contained in a microwave vial was
added diisopropylethylamine (3 equiv) followed by the amine (3 equiv). The
reaction mixture was stirred at room temperature for 5–10 min, and then it
References and notes
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TM
was placed into a Biotage Initiator Sixty microwave apparatus and heated at
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11. Experimental procedures: A. 2-(Methylamino)nicotinic acid (4): 2-Chloronicotinic
acid (0.585 g, 3.7 mmol) was added to a solution of methylamine in H2O (40%,
2.0 g, 26.0 mmol), and the reaction mixture was heated at 140 °C for 1.5 h
under microwave conditions (Biotage InitiatorTM Sixty, absorption level set to
high; Caution: pressure may develop). After completion of the reaction, the
solution was concentrated in vacuo, and the resultant viscous oily residue was
treated with aqueous NaOH (1 M, 5 mL). The clear solution obtained was
stirred at room temperature for 5 min, then concentrated in vacuo to afford a
200 °C for 2 h (absorption level set to high; Caution: pressure may develop).
Next, the solution was basified to pH 12 with 1 M NaOH solution and extracted
with dichloromethane (3 Â 20 mL). Finally, the pH of the aqueous layer was
adjusted to 6.5. At this point, if a precipitate was obtained, it was collected by
filtration, washed with Et2O and dried. If a precipitate was not observed, the
aqueous layer was extracted with ethyl acetate or was evaporated to dryness
and the solid suspended in ethyl acetate (40 mL) and stirred for 15 min. The
solid was then separated by filtration and the organics were collected and
evaporated to give the desired products in 47–83% yields.