Highly efficient synthesis of 2-amino-3-pyridinecarboxaldehyde

Article abstract of DOI:10.1081/SCC-100104071

2-Amino-3-pyridinecarboxaldehyde is synthesized in a highly efficient process via ortho-lithiation of 2-(pivaloyl-amino)pyridine and reaction with DMF, followed by acid hydrolysis. Major impurities were identified and were cleanly eliminated through careful choice of base and solvent.

Full text of DOI:10.1081/SCC-100104071

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HIGHLY EFFICIENT
SYNTHESIS OF 2-AMINO-3-
PYRIDINECARBOXALDEHYDE
Nelo R. Rivera , Yi Hsiao , Jennifer A. Cowen ,
Christopher McWilliams , Joe Armstrong ,
Nobuyoshi Yasuda & David L. Hughes
Published online: 02 Aug 2010.
To cite this article: Nelo R. Rivera , Yi Hsiao , Jennifer A. Cowen , Christopher
McWilliams , Joe Armstrong , Nobuyoshi Yasuda & David L. Hughes (2001) HIGHLY
EFFICIENT SYNTHESIS OF 2-AMINO-3-PYRIDINECARBOXALDEHYDE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:10, 1573-1579, DOI: 10.1081/SCC-100104071
To link to this article: http://dx.doi.org/10.1081/SCC-100104071
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SYNTHETIC COMMUNICATIONS, 31(10), 1573–1579 (2001)
HIGHLY EFFICIENT SYNTHESIS OF
2-AMINO-3-PYRIDINECARBOXALDEHYDE
Nelo R. Rivera,* Yi Hsiao, Jennifer A. Cowen,
Christopher McWilliams, Joe Armstrong,
Nobuyoshi Yasuda, and David L. Hughes
Department of Process Research, Merck Research
Laboratories, P.O. Box 2000, Rahway, NJ07065
ABSTRACT
2-Amino-3-pyridinecarboxaldehyde is synthesized in a highly
efficient process via ortho-lithiation of 2-(pivaloyl-
amino)pyridine and reaction with DMF, followed by acid
hydrolysis. Major impurities were identified and were cleanly
eliminated through careful choice of base and solvent.
1,8-Naphthyridines are key components of several pharmaceutically
active compounds, including ones having antifungal and antibiotic activ-
ity.1,2 Friedlander condensation between 2-amino-3-pyridinecarboxal-
dehyde 4 and ketones and/or other active methylene compounds has
been one of the most general methods for the preparation of variety of
1,8-naphthyridines.3,4 To provide material to support a combinatorial
approach to 1,8-naphthyridines, and to supply drug development needs
on lead compounds, an efficient preparation of aldehyde 4 was required.
Despite its synthetic use, an efficient route to this intermediate has not been
* Corresponding author. E-mail: nelo_rivera@merck.com
1573
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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RIVERA ET AL.
well developed. Several methods have been reported, including dibromina-
tion of phthalimide protected 2-amino-3-picoline, followed by hydrolysis;5
and hydrolysis of 2-(3-pyridyl)pyrido[2,3-d]pyrimidine6 (52% and 50%
isolated yields, respectively). In 1983, Turner reported the preparation of
aldehyde 3 in 54% yield via ortho-directed lithiation of 2-(pivaloylamino)-
pyridine 2, followed by addition of DMF.7 The low yield of the formylation
product was surprising, given the fact that quenching the dianion with
TMSCl or D2O provided the corresponding products in 86% and 87%
isolated yields, respectively. Herein, we report further studies on this reac-
tion that have led to a highly efficient and simple method for the preparation
of aldehyde 4, as shown in Scheme 1.
Scheme 1.
The starting material pivalamide 2 was prepared in high yield by
pivaloylation of 2-aminopyridine using triethylamine in MTBE.8
Formylation of 2 was carried out using the original conditions reported
by Turner (2.3 equiv. n-BuLi in THF, followed by addition of DMF).7
Two major impurities were isolated from the reaction and identified as
3-propyl-1,8-naphthyridine 5a and 1,8-naphthyridine 5b. Although alde-
hyde 4 is crystalline, the presence of these impurities prevented crystalliza-
tion, resulting only in oiling out, which made purification by direct
crystallization impractical.12 The mechanism for formation of these
impurities and conditions developed to control them are discussed below.
The results of these formylation studies on pivalamide 2 are summarized
in Table 1.
We reasoned that the 3-propyl impurity 5a was generated from the
Friedlander condensation between formyl pivalamide intermediate 3a and
pentanal, generated from n-BuLi and DMF (Scheme 2). As expected,
increasing the amount of n-BuLi to 3 equiv. increased the amount of 5a

2-AMINO-3-PYRIDINECARBOXALDEHYDE
1575
Table 1. Formylation of Pivalamide 2
Yields (%)a
Before Hydrolysis
After Hydrolysis
Entry Base (equiv.) Solvent
3b
2b
4c
5ac
5bc
1
2
3
4
5
6
7
8
9
n-BuLi (2.0) THF
n-BuLi (2.1) THF
n-BuLi (2.2) THF
n-BuLi (3.0) THF
t-BuLi (2.3) THF
84
80
73
56
80
90
67
84
67
8
1.7
0
80
75
63
46
81
84
—
82
67
0.3
4.5
3.7
7.9
0
2.5
3.3
2.4
3.3
18
0
—
0
0
0
1.5
5.0
1.5
1.6
8.0
t-BuLi (2.3) THP
0
e
t-BuLi (2.3) Toluened
t-BuLi (2.3) t-Butylbenzened
t-BuLi (2.1) Butylether
0
0
aassay yields are reported based on starting material 2;
bassay yield after HCl extraction, prior to hydrolysis;
cassay yield after HCl hydrolysis;
d5 eq of THP ligand was added;
ecompound 5c was obtained as Friedlander product (10.2%).
Scheme 2.
(entry 4). Avedano et al.9 reported a one-pot synthesis of substituted qui-
nolines from N-pivaloylanilines. They found that the deprotection of the
pivaloyl group happened spontaneously, allowing for cyclization of the
quinoline ring. In our case, however, the propyl impurity 5a was not
observed until after HCl hydrolysis. Unfortunately, washing the HCl layer
with t-BuOMe (MTBE) prior to hydrolysis, hoping to remove pentanal
from the aqueous layer, did not prevent the formation of 5a.
In an attempt to avoid aldol condensation leading to 3-substituted
naphthyridines, we chose t-BuLi as base, which should generate the
non-enolizable t-BuCHO byproduct upon reaction with DMF. In
doing so, the formation of propyl impurity 5a was avoided. However, the
other impurity, 1,8-naphthyridine 5b, was generated in 18% yield (entry 5).

1576
RIVERA ET AL.
The formation of naphthyridine 5b could be attributed to the
Friedlander condensation between 2-amino-3-pyridinecarboxaldehyde
4 and acetaldehyde, presumably generated from the degradation of THF
solvent in the presence of the stronger base t-BuLi.10 As proof, when THF-
d8 was used as solvent, the naphthyridine byproduct 5b was deuterated at 2
and 3 positions (94% and 54%, respectively), as determined by NMR. As a
result, we tested other solvents that would be suitable for this reaction and
should not generate any aldehydes in the presence of a strong base.
Although using butyl ether as solvent (entry 9) did not produce
the naphthyridine byproduct 5b, the yield was low, and other minor impu-
rities were formed. Best results were obtained when tetrahydropyran (THP)
was used as a solvent, giving an overall assay yield of 84% of 2-amino-
3-pyridinecarboxaldehyde 4 from pivalamide 2. We have found that
toluene could also be used as a solvent in the presence of 5 equiv. of
THP as a ligand. The formylation step afforded 90% crude assay yield
of the formyl pivalamide 3. Upon quenching with 3 N HCl, however,
the yield dropped to 67% and a new byproduct was generated.
The byproduct was identified as 3-phenyl-1,8-naphthyridine 5c, generated
from benzyl lithium and DMF and amino aldehyde 4. This problem
could be circumvented by replacing toluene with t-butylbenzene as a
solvent (entry 8).
In conclusion, we have developed an efficient process for the pre-
paration of 2-amino-3-pyridinecarboxaldehyde 411 starting from cheap
and readily available starting materials. With careful choice of solvent and
base used, major impurities could be avoided. Results show that optimal
yield was obtained when using t-BuLi and THP during the lithiation pro-
cess. Using these conditions, 2-amino-3-pyridinecarboxaldehyde could be
obtained in 78% isolated yield.
ACKNOWLEDGMENTS
We thank Dr. P.G. Dormer and Ms. L.M. DiMichele for their NMR
support and Dr. Z. Guan for high-resolution mass spectra.
REFERENCES AND NOTES
1. Sreenivasulu, B.; Rao, G.R.; Mogilaiah, K.; Reddy, K.R. Ind. J. Chem.
1988, 27B, 200–202.
2. Sreenivasulu, B.; Rao, G.R.; Mogilaiah, K.; Reddy, K.R. Ind. J. Chem.
1996, 35B, 339–344.

2-AMINO-3-PYRIDINECARBOXALDEHYDE
1577
3. Cheng, C.; Yan, S. In The Friedlander Synthesis of Quinolines; Dauten,
W.; Boswell, G.; Danishefsky, S.; Gschwend, H.; Heck, R.;
Hirschmann, R.; Kende, A.; Paquette, L.; Posner, G.; Trost, B.M.;
Eds.; Organic Reactions; John Wiley: New York, 1982; Vol. 28, 37.
4. Thummel, R.P. Synlett 1992, 1.
5. Moorman, A.E.; Yen, C.H.; Yu, S. Syn. Commun. 1987, 17,
1695–1699.
6. Majewicz, T.G.; Caluwe, P. J. Org. Chem. 1974, 39, 720–721.
7. Turner, J. J. Org. Chem. 1983, 48, 3401–3408.
8. Synthesis of 2-(pivaloylamino)pyridine 2. To a 3-L, 3-neck flask
charged with 100 g (1.06 mol) 2-aminopyridine 1 in MTBE (1100 mL)
was added 160 mL (1.17 mol) triethylamine. The solution was then
cooled to 0ꢀC, whereupon 136 mL (1.13 mol) pivaloyl chloride was
added dropwise such that the internal temperature was less than
20ꢀC. The solution was stirred for 2 h at r.t. and a white precipitate
was observed. After the reaction was complete, cooled H2O
(1 ꢁ 300 mL) was added. The layers were separated and the organic
layer was washed with H2O (1 ꢁ 300 mL), sat. NaHCO3 (1 ꢁ 300 mL),
then brine solution (1 ꢁ 300 mL). The organic layer was dried over
Na2SO4. Sodium sulfate was filtered off and MTBE was distilled
under reduced pressure and replaced with THF (other solvents may
be used, see text). The crude material was used in the formylation step
without further purification. Typical assay yield is 94%. 1H NMR
(400 MHz, CDCl3): d 8.25 (m, 2H, H-3, H-6), 8.04 (br, 1H, N-H),
7.70 (m, 1H, H-4), 7.03 (m, 1H, H-5), 1.32 (s, 9H, t-butyl). 13C
NMR (100.6 MHz, CDCl3): d 177.0, 151.6, 147.6, 138.4, 119.7, 113.9,
39.8, 27.5. m.p. 69ꢀ–71ꢀC (lit.6 m.p. 71ꢀ–73ꢀC).
9. Avedano, C.; Ubeda, J.I.; Villacampa, M. Synthesis 1998, 1176–1180.
10. Hegedus, L.; Lipshutz, B.; Nozaki, H.; Reetz, M.; Rittmeyer, P.;
Smith, K.; Totter, F.; Yamamoto, H. In Organometallics in
Synthesis: A Manual; Shlosser, M., Ed.; John Wiley: New York,
1994; 129–133.
11. Typical synthesis of 2-amino-3-pyridinecarboxaldehyde 4. To a 100-mL
flask was charged 2.5 g (14 mmol) of 2-(pivaloylamino)pyridine 2 and
30 mL of THP. This solution was cooled to ꢂ20ꢀC, whereupon t-BuLi
(1.6 M in pentane, 2.3 equiv.) was added over a 30-min period such
that the internal temperature was below ꢂ5ꢀC. The solution was then
aged for 2.5 h at 0ꢀC, after which 2.2 mL DMF (28 mmol) was added
such that the internal temperature was less than 5ꢀC. The solution was
aged at 0ꢀC for 1 h, then allowed to warm slowly to r.t. After the
reaction was complete, the solution was cooled to ꢂ10ꢀC and quenched
with 3 N HCl (77 mmol), keeping the temperature below 0ꢀC. The

1578
RIVERA ET AL.
aqueous layer was separated and excess THP was distilled in vacuo.
The aqueous layer was heated overnight at 100ꢀC. The reaction mix-
ture was cooled to room temperature, then washed with MTBE
(2 ꢁ 10 mL). The aqueous layer was cooled to 0ꢀC after the addition
of 15 mL of isopropyl acetate (IPAC) and 5 g NaCl. To the mixture
was added 5 N NaOH at a rate such that the internal temperature was
less than 15ꢀC until pH 10.3. The organic layer was separated. The
aqueous layer was re-extracted with IPAC (2 ꢁ 15 mL). The combined
organic layers were concentrated under reduced pressure to give 1.59 g
crude material consisting mainly of product and traces of starting
material. The desired 2-amino-3-pyridinecarboxal-dehyde was easily
purified by SiO2 column chromatography, eluting first with 2:1
hexane:EtOAc then with 1:1 hexane:EtOAc after pivalamide staring
material had eluted completely. Fractions containing desired com-
pound were concentrated under vacuum to give 1.33 g yellow crystals
(78% isolated yield based on pivalamide 2 starting material). 1H NMR
(400 MHz, CDCl3): d 9.82 (s, 1H, CHO), 8.22 (m, 1H, H-6), 7.76 (m,
1H, H-4), 7.04 (br, 2H, N-H), 6.69 (m, 1H, H-5). 13C NMR
(100.6 MHz, CDCl3) d 192.6, 158.4, 154.6, 144.2, 113.8, 112.8. m.p.
97ꢀ–99ꢀC (lit.6 m.p. 98ꢀ–99ꢀC).
12. On large-scale synthesis (0.49 mol of 2, nBuLi and THF conditions),
the IPAc solution containing crude 4 was passed through a silica-gel
pad (2:1 wt/wt silica : crude wt. of 4). The filtered solution was
concentrated under reduced pressure to give 46.0 g of 4 in 96 wt%
purity. This material was heated to 70ꢀC in EtOAc (75 mL), then gra-
dually cooled to 50ꢀC and seeded. After 30 min stirring at 50ꢀC,
methylcyclohexane (295 mL) was added (50 mL/h) and allowed to
cool overnight. The crystals were filtered and washed with 4:1 methyl-
cyclohexane, then dried to give 37.5 g of 4 (97.9 wt% purity by HPLC
method based on analytical standard, 58% overall yield from 1).
13. Analytical data: 5a:1H NMR (400 MHz, CDCl3): d 9.02 (dd, J ¼ 2.0,
4.3 Hz, 1H), 8.94 (d, J ¼ 2.5 Hz, 1H), 8.05 (dd, J ¼ 2.0, 8.1 Hz, 1H), 7.89
(d, J ¼ 2.5 Hz, 1H), 7.42 (dd, J ¼ 4.3, 8.1 Hz, 1H), 2.76 (t, J ¼ 7.6 Hz,
2H), 1.70 (m, 2H), 0.96 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3) d 155.2, 155.0, 152.5, 136.6, 136.4, 134.9, 122.5, 122.0,
34.9, 24.1, 13.6. HRMS m/z calc. for C11H12N (MþH) 173.1073,
1
found 173.1077. 5b: H NMR (400 MHz, CDCl3): d 9.05 (m, 2H),
8.15 (m, 2H), 7.42 (m, 2H). 13C NMR (100.6 MHz, CDCl3): d 156.1,
153.6, 137.1, 122.8, 122.1. m.p. 91ꢀ–93ꢀC. 5c: H NMR (400 MHz,
1
CDCl3): d 9.44 (d, J ¼ 2.4 Hz, 1H), 9.14 (d, J ¼ 3.9 Hz, 1H), 8.33 (d,
J ¼ 2.4 Hz, 1H), 8.27 (d, J ¼ 8.1 Hz, 1H), 7.73 (m, 2H), 7.50 (m, 4H).
13C NMR (75.5 MHz, CDCl3): d 155.5, 153.4, 153.1, 137.2, 137.0,

2-AMINO-3-PYRIDINECARBOXALDEHYDE
1579
135.0, 133.9, 129.3, 128.5, 127.5, 122.6, 122.5. Anal. calc. for
C14H10N2: C, 81.53; H, 4.89; N, 13.58. Found: C, 81.24; H, 4.74; N,
13.60. m.p. 128.5ꢀ–129.5ꢀC.
Received in the USA August 3, 2000