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solution of CaCO3 (5.0 equiv) in DMSO (5 vol) at
References and notes
145 ꢁC yielded the aldehyde 7. Pyridine carbaldehydes
1–7 were isolated in moderate to good yield. This hydro-
lysis condition was reported earlier for the synthesis
of 4-bromobenzaldehyde from the corresponding
gem-dibromomethyl intermediate but such simple
hydrolysis conditions have not been applied to pyridine
derivatives.13
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2, 3845–3848.
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Optimization of experimental conditions (temperature,
solvent) allowed us to obtain regioiomers 1–7 in parallel
from the corresponding intermediates 15–21. An amount
of 2.2 equiv of CaCO3 was found optimal for complete
hydrolysis to give the desired carbaldehydes 1–6. A plau-
sible route could involve the formation of bromohydrin
intermediate followed by HBr elimination to give the
product. Analysis of Table 1 showed that every regio-
isomer could be synthesized efficiently. Surprisingly,
2-bromo-4-dibromomethylpyridine 21 was the only reg-
ioisomer, which exhibited different reactivity in an aque-
ous solution of CaCO3. In contrast to the close analogue
19, intermediate 21 exhibited lower solubility. Replace-
ment of CaCO3 by CsCO3 or K2CO3 in water did not im-
prove the reaction. The use of DMSO, a well solubilizing
polar solvent circumvented this issue and 2-bromopyri-
dine-4-carbaldehyde 7 could be obtained in 60% yield
in the presence of 5equiv of CaCO 3. A mixture of sol-
vents, such as a water/dioxane (3/7), led to a better but
not total solubility of the reactants and the formation
of a complex combination of starting material, com-
pound 7 and 2-bromo-pyridine-4-carboxylic acid deriva-
tive were obtained. We presume that the solubility of
reagents could be the limiting factor for this transforma-
tion and was observed only for regioisomer 21.
As an example of scale-up production, a 150 g batch of
2-bromo-5-picoline 8 was transformed into 2-bromo-5-
dibromomethyl-pyridine in an isolated 70% yield. The
further exposure of 201 g of compound 15 to an aqueous
solution of CaCO3 gave 6-bromo-pyridine-3-carbalde-
hyde 1 in 80% yield. This example illustrates the possi-
bility of efficient scale up of bromo-pyridine
carbaldehydes synthesis.
11. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods,
M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem.
1987, 30, 871–880.
12. For 15 and 17: see Ref. 9b and for 18: Boschelli, D. H.;
Wang, Y.; Boschelli, F. C.; Berger, D. M.; Zhang, N.;
Powell, D. W.; Ye, F.; Yamashita, A.; Demorin, F. F.,
Wu, B.; Tsou, H.; Overbeek-Klumpers, E. G.; Wissner, A.
Int. Appl. WO 01/72711, 2001.
13. (a) Coleman, G. H.; Honeywell, G. E. In Organic
Synthesis Collective; John Wiley and Son, 1943; Vol. II,
pp 89–91; (b) Adams, R.; Vollweiler, E. H. J. Am. Chem.
Soc. 1918, 40, 1732–1746. Transformation of gem-di-
bromo-pyridine derivatives into pyridine carbaldehydes
was only perfomed for the preparation of 5-bromo-
3-pyridine carbaldehyde via hydrolysis of bis(morpho-
lino)methylpyridine.9a
14. General procedure for bromo-picolines 8, 9, 10, and 14: at
À20 ꢁC, to a mixture of amino-methyl-pyridine (60.0 g,
0.55 mol) in 48% HBr (1 L) was added Br2 (80 mL,
1.55 mol) dropwise over a period of 20 min. The reaction
mixture was stirred for 30 min at À20 ꢁC. Then a solution
of NaNO2 (101.0 g, 1.47 mol) in water (200 mL) was
added over a period of 30 min. The resulting reaction
mixture was stirred for 2 h at the same temperature, then
quenched with aqueous NaOH (20%) until pH = 10. The
In summary, a general and expedient synthesis of bromo-
pyridine carbaldehydes 1–7 from the corresponding
bromo-gem-dibromomethyl intermediates has been
developed. No drastic difference in reactivity was
observed among the pyridine regioisomers. The simple
and ready availability of starting materials distinguishes
this preparation from other regioisomer-dependent
routes to bromo-pyridine carbaldehydes. Furthermore,
we believe that this protocol will improve the access to
every regioisomer of bromo-pyridine carbaldehyde scaf-
folds and analogues, and increase their use especially in
combinatorial chemistry for structure–activity relation-
ship studies.
Acknowledgments
We would like to thank Stefano Crosignani for his use-
ful comments on the manuscript.