A convenient synthetic route to a useful synthon: 4-bromo-2-pyridinecarboxaldehyde

Article abstract of DOI:10.1016/j.tetlet.2008.10.027

We have developed a novel four-step method to synthesise 4-bromo-2-pyridinecarboxaldehyde, from 2-picoline-N-oxide via 4-nitro-2-pyridinecarboxaldehyde, under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2008.10.027

Tetrahedron Letters 49 (2008) 7274–7275
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient synthetic route to a useful synthon:
4-bromo-2-pyridinecarboxaldehyde
*
Nicolas Zaman, Régis Guillot, Katell Sénéchal-David , Marie-Laure Boillot
Institut de Chimie Moléculaire et des Matériaux d’Orsay, ECI, UMR8182, Université Paris Sud XI, 15 rue G. Clémenceau, 91405 ORSAY Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a novel four-step method to synthesise 4-bromo-2-pyridinecarboxaldehyde, from
2-picoline-N-oxide via 4-nitro-2-pyridinecarboxaldehyde, under mild reaction conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 1 September 2008
Revised 2 October 2008
Accepted 6 October 2008
Available online 11 October 2008
Keywords:
4-(Substituted)-pyridine derivatives
Nitration
Oxidation
Bromination
4-Bromo-2-pyridinecarboxaldehyde is
a versatile synthon,
widely used in various processes such as pharmaceutical multi-
step syntheses (as described in recent patents).1 The bromine
group allows a large range of functionalisations via Suzuki2 or
Stille3 cross-coupling, for example, while the carboxaldehyde
group gives access to a panel of dissymmetric condensation
reactions.
Scheme 1. Synthetic procedure described previously.4,5
Despite its interest as a useful versatile synthon, the synthesis
of 4-bromo-2-pyridinecarboxaldehyde remains tedious with ill-
defined or drastic reaction conditions, and had only been described
by two groups in the last two decades.4,5
hydrolysis of the intermediate acetate gave the 4-bromo-2-pyr-
idylmethanol 2, (v) finally oxidised with DMSO and oxalyl chlo-
ride.4 Yields of the first two steps are uncertain.7
Ashimori et al. preferred a six-step procedure via 4-bromo-2-
picoline:5 (i) nitration of 2-picoline-N-oxide as well with fuming
nitric acid, (ii) followed by the reduction with PCl3 converted 4-ni-
tro-2-picoline-N-oxide 4 to 4-nitro-2-picoline. Subsequent treat-
ments with (iii) acetyl bromide, (iv) oxidation to carboxylic acid
with KMnO4, (v) conversion to mixed anhydride with ClCO2Et
and then (vi) a final reduction with LiAlH4 permitted to obtain 4-
bromo-2-pyridylmethanol 2 with three more steps. The global
yield is then around 5% after the final (vii) Swern oxidation step.5
The harsh reaction conditions associated with these protocols,
the poor description of some key steps and the relatively low yields
prompted us to design a new synthetic pathway to 4-bromo-2-pyr-
idinecarboxaldehyde 3.
Both procedures start from 2-picoline-N-oxide 1 and involve a
Swern oxidation of 4-bromo-2-pyridylmethanol 2 as the final step
to give 4-bromo-2-pyridinecarboxaldehyde 3 (Scheme 1).4,5
The difficulty lies in the introduction of the bromine atom at the
4-position of the pyridine ring, even activated as its N-oxide deriv-
ative. In fact, direct bromination of 2-picoline-N-oxide, described
by Profft,6 requires the use of concentrated HBr heated at 160 °C
inside a glass autoclave, followed by an arduous isolation step.
The introduction of the bromine atom at the 4-position of the pyr-
idine ring, seems more convenient via a nitro group substitution.4,5
Jones et al. choose a five-step procedure with the bromine
group introduction in the second one:4 (i) nitration of 2-picoline-
N-oxide with fuming nitric acid, (ii) then bromination of 4-nitro-
2-picoline-N-oxide 4, with drastic use of 48% HBr and urea, at
160 °C, as described by Suzuki.7 (iii) A Boekelheide rearrange-
ment,8 using an excess of acetic anhydride, (iv) followed by the
We report here this synthesis, using mild reaction conditions,
also starting from 2-picoline-N-oxide 1, the substitution of the ni-
tro group for the bromine atom being performed during the final
step (Scheme 2).9
(i) Nitration of 2-picoline-N-oxide 1 is realised by in situ nitric
acid generation to afford 4-nitro-2-picoline-N-oxide 4. At this
stage, the substitution of the nitro group for bromine atom is not
* Corresponding author. Tel.: +33 01 69 15 74 36; fax: +33 01 69 15 47 54.
E-mail address: ksenechal@icmo.u-psud.fr (K. Sénéchal-David).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.027

N. Zaman et al. / Tetrahedron Letters 49 (2008) 7274–7275
7275
3. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
4. Jones, G. J.; Pitman, M. A.; Lunt, E.; Lythgoe, D. J.; Abarca, B.; Ballesteros, R.;
Elmasnaouy, M. Tetrahedron 1997, 53, 8257.
5. Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.; Watanabe, M.;
Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446.
6. Von Profft, E.; Richter, H. J. Prakt. Chem. 1959, 164.
NO2
N
NO2
a
b
OH
N
O
65%
N
5
65%
1
4
O
7. Suzuki, I. Yakugaku Zasshi 1948, 68, 126.
8. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286.
c
68%
9. General procedure: (a) Preparation of 4-nitro-2-picoline-N-oxide 4: To a solution
of 2-picoline-N-oxide 1 (9.06 g, 83 mmol) and H2SO4 32% (50 mL), kept in an ice
bath, NaNO3 (7.77 g, 91 mmol) was added slowly. After complete dissolution,
the colourless solution was heated at 95–100 °C, for 2 h. After cooling to room
temperature, the yellow solution was poured onto crushed ice, and basified
with K2CO3. The yellow precipitate was filtered off, dissolved in
dichloromethane. The organic layer was dried over MgSO4, and the solvent
was removed under pressure to yield a pale yellow solid (8.32 g, 54 mmol,
65%). 1H NMR (300 MHz, CDCl3): d 2.47 (s, 3H), 8.00 (dd, J = 7.6 Hz J = 3.2 Hz,
1H), 8.15 (d, J = 3.2 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H). 13C NMR (300 MHz, CDCl3):
d 17.8, 117.7, 120.3, 139.5, 141.4, 150.3. IR (KBr): 3114, 3080, 3049, 1611, 1514,
1457, 1345, 1337, 1286, 1269, 1200, 1092, 933, 844, 786, 750, 661 cmÀ1. Anal.
Calcd for C6H6N2O3: C, 46.76; H, 3.92; N, 18.18. Found: C, 46.40; H, 3.76; N,
18.20. (b) Preparation of 4-nitro-2-pyridylmethanol 5: To a yellow solution of 4-
nitro-2-picoline-N-oxide 4 (0.92 g, 6 mmol) in dichloromethane (25 mL), a
solution of trifluoroacetic anhyd (2.5 mL, 18 mmol) in dichloromethane (5 mL)
was added dropwise. The red solution was stirred at room temperature for 3
days. Solvent was evaporated. Methanol (20 mL) and an aqueous saturated
K2CO3 solution (10 mL) were added, and the mixture was stirred at room
temperature for 4 h. Methanol was evaporated, and the compound was
extracted with dichloromethane (3 Â 25 mL). Combined organic layers were
washed with brine solution (25 mL), dried over MgSO4, and the solvent
removed was under vacuum. A yellow solid (0.58 g, 4 mmol, 65%) was isolated.
1H NMR (300 MHz, CDCl3): d 3.40 (s large, 1H), 4.88 (s, 2H), 7.90 (dd, J = 5.2 Hz,
J = 1.7 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 5.2 Hz, 1H). 13C NMR
(300 MHz, CDCl3): d 64.6, 113.4, 115.2, 151.2, 154.6, 163.6. IR (KBr): 3260,
3114, 3056, 3027, 2960, 1581, 1539, 1416, 1366, 1352, 1305, 1233, 1045, 1003,
935, 855, 741, 689 cmÀ1. Anal. Calcd for C6H6N2O3: C, 46.76; H, 3.92; N, 18.18.
Found: C, 46.80; H, 3.90; N, 18.17. (c) Preparation of 4-nitro-2-
pyridinecarboxaldehyde 6: A mixture of 4-nitro-2-pyridylmethanol 5 (1.77 g,
11.5 mmol), dichloromethane (300 mL), MnO2 (6 g, 69 mmol) was stirred at
25 °C, for 3 days. The heterogeneous solution was filtrated through Celite and
dichloromethane was evaporated. The crude was purified by column
NO2
Br
d
N
6
60%
N
3
O
O
Scheme 2. Reagents and conditions: (a) NaNO3, H2SO4, 95–100 °C; (b) (i)
(CF3CO)2O, CH2Cl2, 25 °C, 3 days; (ii) K2CO3, CH3OH, rt, 4 h; (c) MnO2, CH2Cl2,
25 °C, 3 days; (d) AcBr, 60 °C, 8 h.9
possible using acetyl bromide. In fact, an undesired product is
mainly obtained.10 (ii) The Boekelheide rearrangement is per-
formed using trifluoroacetic anhydride, at 25 °C. After solvent
and excess reagent evaporation, the crude ester intermediate is di-
rectly saponified by stirring it with K2CO3 in a methanol solution to
give 4-nitro-2-pyridylmethanol 5, in good yield. (iii) Instead of
using a Swern oxidation to get aldehyde 6, we preferred a simpler
method, using MnO2 as the oxidising reagent11 at 25 °C. (iv) Final-
ly, acetyl bromide allows the substitution of the nitro group for the
bromine atom in good yield. This synthesis is carried out under an
argon atmosphere due to the extreme air sensitivity of the 4-bro-
mo-2-pyridinecarboxaldehyde 3 towards oxidation to the corre-
sponding carboxylic acid. Compound 3 is obtained as crystals
without any purification (the X-ray diffraction study is reported
in the Supplementary data). Moreover, it is necessary to store this
compound under an inert atmosphere and to use it rapidly.
In conclusion, we have elaborated a novel, convenient four-step
synthetic route to the versatile synthon 4-bromo-2-pyridinecar-
boxaldehyde, in a 17% global yield. This method makes this inter-
esting synthon easily accessible in a few synthetic steps performed
under mild reaction conditions.
chromatography (silica gel, dichloromethane) to give compound
6 as a
yellow oil (1.15 g, 7.6 mmol, 68%). 1H NMR (300 MHz, CDCl3): d 8.24 (dd,
J = 5.4 Hz, J = 2.3 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H), 9.09 (d, J = 5.4 Hz, 1H), 10.15
(s, 1H). 13C NMR (300 MHz, CDCl3): d 114.4, 120.0, 152.7, 154.9, 155.9, 191.2. IR
(KBr plates): 3096, 2852, 2708, 1714, 1602, 1575, 1537, 1355, 1216, 1079, 994,
923, 863, 738, 682, 659 cmÀ1. Anal. Calcd for C6H4N2O3: C, 47.38; H, 2.65; N,
18.42. Found: C, 47.00; H, 2.62; N, 18.07. (d) Preparation of 4-bromo-2-
pyridinecarboxaldehyde 3: Under argon atmosphere, into a 2-necked round-
bottomed flask, acetyl bromide (30 mL, 403 mmol) was added rapidly to 4-
nitro-2-pyridinecarboxaldehyde 6 (1.90 g, 12.5 mmol). The red mixture was
heated at 60 °C overnight. A red solid was precipitated. After cooling to room
temperature, the mixture was poured onto crushed ice, and the resulting
solution was basified with Na2CO3. The compound was extracted with
diethylether (3 Â 100 mL). Combined organic layers were washed with brine
solution (25 mL), dried over MgSO4, and the solvent was removed under
vacuum. A yellow oily crude (1.45 g, 7.5 mmol) crystallised to give compound 3
in 60% yield. 1H NMR (300 MHz, CDCl3): d 7.65 (dd, J = 5.2 Hz J = 2.3 Hz, 1H),
8.06 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 10.00 (s, 1H). 13C NMR (300 MHz,
CDCl3): d 125.3, 131.1, 134.3, 151.1, 153.8, 192.2. IR (KBr): 3051, 2925, 2847,
1765, 1569, 1371, 1235, 1200, 1017, 837, 682 cmÀ1. X-ray diffraction study is
reported in Supplementary data.
Supplementary data
Supplementary data (X-ray diffraction study of 4-bromo-2-pyr-
idine-carboxaldehyde) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.027.
References and notes
1. (a) Johnson, C. N.; Macpherson, D. T.; Trani, G. PCT Int. Appl. WO2008017691,
2008. (b) Herold, P.; Stutz, S.; Mah, R.; Tschinke, V.; Stojanovic, A.; Jotterand, N.;
Quirmbach, M.; Behnke, D., Marti, C. PCT Int. Appl., WO2005090304, 2005.
2. Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
10. Bisagni, E.; Rautureau, M.; Huel, C. Heterocycles 1989, 29, 1815.
11. Negi, S.; Matsukura, M.; Mizuno, M.; Miyake, K.; Minami, N. Synthesis 1996,
991.