LETTER
In situ Reduction of Pyridine-N-oxides with Tetrahydroxydiboron
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(4) (a) Mai, W.; Yuan, J.; Li, Z.; Sun, G.; Qu, L. Synlett 2012,
145. (b) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li,
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and Mechanistic Organic Chemistry; Springer:
of the reaction provides a significant enthalpic driving
force (ΔΗ = ca. 180 kcal/mol),14 which may in part ex-
plain the rapid and selective manner of this transforma-
tion.
Berlin/Heidelberg, 1976. (d) Dyall, L. K.; Pausacker, K. H.
J. Chem. Soc. 1961, 18.
In conclusion, tetrahydroxydiboron functions as a versa-
tile and remarkably selective reagent for the reduction of
pyridine-N-oxides and is an expedient and atom-econom-
ical alternative to common reducing agents. We believe
the reduction methodology described herein complements
the growing use of pyridine-N-oxides as reactive interme-
diates in new and novel transformations. The mild, selec-
tive, and rapid nature of the reduction protocol should be
amenable to a wide variety of chemistries and will likely
find utility as a method for direct in situ reduction. The
ability to incorporate other reduction-sensitive functional-
ity into reaction substrates should enhance existing and
future methodologies that utilize pyridine-N-oxides as re-
actants. Our laboratory will continue to expand and opti-
mize the use of tetrahydroxydiboron as an in situ
reductant, with our results published in due course.
(5) Catalytic hydrogenation is commonly used to reduce
pyridine-N-oxides. Other contemporary methods include:
(a) Kokatla, H. P.; Thomson, P. F.; Bae, S.; Doddi, V. R.;
Lakshman, M. K. J. Org. Chem. 2011, 76, 7842. (b) Mikami,
Y.; Noujima, A.; Mitsudome, T.; Mizugaki, T.; Jitsukawa,
K.; Kaneda, K. Chem. Eur. J. 2011, 17, 1768. (c) Ponaras, A.
A.; Zaim, O. J. Heterocycl. Chem. 2007, 44, 487. (d) Singh,
K. S.; Reddy, M. S.; Mangle, M.; Ganesh, K. R. Tetrahedron
2007, 63, 126. (e) Yoo, B. W.; Choi, J. W.; Yoon, C. M.
Tetrahedron Lett. 2006, 47, 125. (f) Saini, A.; Kumar, S.;
Sandhu, J. S. Synlett 2006, 395. (g) Sanz, R.; Escribano, J.;
Fernández, Y.; Aguado, R.; Pedrosa, M. R.; Francisco, J.
Synlett 2005, 1389. (h) Bjørsvik, H. R.; Gambarotti, C.;
Jensen, V. R.; Gonzalez, R. R. J. Org. Chem. 2005, 70, 3218.
(i) Kumar, S.; Saini, A.; Sandhu, J. S. Tetrahedron Lett.
2005, 46, 8737. (j) Jie, Z.; Rammoorty, V.; Fischer, B.
J. Org. Chem. 2002, 67, 711. (k) Ilias, M.; Barman, D. C.;
Prajapati, D.; Sandhu, J. S. Tetrahedron Lett. 2002, 43,
1877. (l) Boruah, M.; Konwar, D. Synlett 2001, 795.
(m) Ram, S. R.; Chary, K. P.; Iyengar, D. S. Synth. Commun.
2000, 30, 3511. (n) Yadav, J. S.; Subba Reddy, B. V.;
Muralidhar Reddy, M. Tetrahedron Lett. 2000, 41, 2663.
(o) Malinowski, M. Synthesis 1987, 732. (p) Zhang, Y.; Lin,
R. Synth. Commun. 1987, 17, 329. (q) Hitomi, S.; Naofumi,
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Acknowledgment
We thank Dr. Kevin Hesp, Dr. Spiros Liras, and Dr. Vincent
Mascitti (Pfizer Inc.) for their advice in the preparation of this ma-
nuscript.
(6) Reaction temperatures range from 70–120 °C with reaction
times between 4 h and 24 h.
Supporting Information for this article is available online at
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(7) 2,6-Dimethylpyridine-N-oxide was reported as a
challenging reduction substrate by Lakshman and co-
workers.5a The reduction with bis(catecholato)diboron
required 24 h at 120 °C to afford a 65% yield of 2,6-lutidine.
(8) The use of pinacol and catechol in the synthesis of
bis(alkoxy)diborons is inherently wasteful and inefficient,
see: Molander, G. A.; Trice, S. L.; Kennedy, S. M.; Dreher,
S. D.; Tudge, M. T. J. Am. Chem. Soc. 2012, 134, 11667.
(9) See Supporting Information for additional examples of
pyridine-N-oxide reduction with tetrahydroxydiboron.
(10) Ethylenediamine (20 mol equiv).
References and Notes
(1) (a) Youssif, S. ARKIVOC 2001, (i), 242. (b) Albini, A.;
Silvio, P. Heterocyclic N-Oxides; CRC Press: New York,
1991.
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(12) General Procedure
The appropriate aminopyridine-N-oxide (13, 1.00 equiv) and
carboxylic acid/acid chloride (14, 1.20 equiv) were
combined in DMF (0.50 M) and treated with i-Pr2EtN (2.5
equiv) and HATU (1.2 equiv). The reaction was stirred at r.t.
until the initial coupling was deemed complete by LC–MS
(usually 1–2 h). The reaction was then treated with
tetrahydroxydiboron (5, 2.00 equiv) in a single portion
(Note: exotherm evident). After stirring for 10 min, the
reaction was quenched with H2O (10 mL), which resulted in
the precipitation of most products. The solids were filtered,
washed with H2O, and air-dried to afford the desired
products in sufficient purity. For those reactions where
precipitation of solid was not evident, the desired products
were extracted with EtOAc (3 × 10 mL), washed with brine,
dried (Na2SO4), and evacuated. These crude materials were
purified by silica gel column chromatography.
(3) Recent representative examples: (a) Zhang, S.; Liao, L.;
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2012, 134, 3683. (c) Gosselin, F.; Savage, S. J.; Blaquiere,
N.; Staben, S. T. Org. Lett. 2012, 14, 862. (d) Zhao, H.;
Wang, R.; Chen, P.; Gregg, B. T.; Hsia, M. M.; Zhang, W.
Org. Lett. 2012, 14, 1872. (e) Duric, S.; Tzschucke, C. C.
Org. Lett. 2011, 13, 2310. (f) Sun, H.; Gorelsky, S. I.; Stuart,
D. R.; Campeau, L. C.; Fagnou, K. J. Org. Chem. 2010, 75,
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Chem. Soc. 2008, 130, 3266. (i) Campeau, L. C.; Megan, B.
L.; Leclerc, J. P.; Villemure, E.; Gorelsky, S.; Fagnou, K.
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Analytical Data for Entry 3
1H NMR (400 MHz, CDCl3): δ = 9.30 (br s, 1 H), 8.50 (d,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2695–2700