LETTER
Chemoselective Palladium-Catalysed Deoxygenation of Pyridine N-Oxides
2581
cellent yields without reduction or cleavage of other func-
tional groups. The reactions proceeded smoothly in the
presence of amido (entries 1–3), nitro (entry 7), ester (en-
try 6), hydroxy (entry 8), carbonyl (entry 9), and Br (entry
(2) (a) Mandal, P. K.; McMurray, J. S. J. Org. Chem. 2007, 72,
599. (b) Fessard, T. C.; Motoyoshi, H.; Carreira, E. M.
6
Angew. Chem. Int. Ed. 2007, 46, 2078. (c) Leclerc, J.-P.;
Fagnou, K. Angew. Chem. Int. Ed. 2006, 45, 7781.
(
d) Mori, A.; Mizusaki, T.; Miyakawa, Y.; Ohashi, E.; Haga,
T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron
006, 62, 11925. (e) Rahaim, R. J. Jr.; Maleczka, R. E. Jr.
3
) groups, and the position in the pyridine ring of the sub-
stituent does not seem to have any influence in the pro-
cess. When 3-pyridylcarbinol N-oxide was deoxygenated
under the reaction conditions (entry 8), the parent pyridine
was obtained together with (readily separated) nicotinal-
dehyde as a byproduct. This is probably due to a similar
process as the one recently described in the literature for
deoxygenation of N-heteroarene N-oxides using 1-phe-
2
Synthesis 2006, 3316. (f) Campeau, L.-C.; Rousseaux, S.;
Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.
(g) Rahaim, R. J. Jr.; Maleczka, R. E. Jr. Org. Lett. 2005, 7,
5087. (h) Zacharie, B.; Moreau, N.; Dockendorff, C. J. Org.
Chem. 2001, 66, 5264. (i) Xu, S.; Xi, X.; Shi, J.; Cao, S.
J. Mol. Catal. A: Chem. 2000, 160, 287. (j) Islam, S. M.;
Palit, B. K.; Mukherjee, D. K.; Saha, C. R. J. Mol. Catal. A:
Chem. 1997, 124, 5. (k) Petrini, M.; Ballini, R.; Rosini, G.
Synthesis 1987, 713.
1
j
nylethanol as solvent. 4-Acetyl pyridine N-oxide (entry
) also proved to be stable under the reaction conditions
9
(
3) (a) Clarke, M. L.; Fuentes, J. A. Angew. Chem. Int. Ed. 2007,
affording the corresponding deoxygenated pyridine.
46, 930. (b) Fuentes, J. A.; Clarke, M. L.; Slawin, A. M. Z.
Overall high yields using microwave heating in just 60
minutes were obtained. Reactivity for difficult substrates
was improved by increasing the reaction temperature
from 140 to 160 °C, and both preformed Pd-phosphino-
ferrocene complex and in situ formed catalyst can effec-
tively perform in the reaction.
New J. Chem. 2008, 32, 689.
4) Synthesis of Pyridine N-Oxide 2 (Scheme 1)
(
Aryl bromide 1 (67 mg, 0.29 mmol), Pd(OAc) (1.9 mg, 3
mol%), and a stirring bead were placed in a 5 mL microwave
process vial that was placed under a nitrogen atmosphere
2
before the addition of dry DMF (4 mL), Et N (0.12 mL, 0.87
3
mmol), and isobutyl acrylate (0.13 mL, 0.87 mmol). The
reaction mixture was heated by microwave irradiation at
140 °C for 60 min. After being cooled to ambient
temperature, the reaction mixture was concentrated under
reduced pressure. The crude mixture was purified by
In summary, the fortuitous observation of an unexpected
product in the Pd/dippf-catalysed Heck coupling of a py-
ridine N-oxide has led to a convenient procedure for de-
oxygenation of pyridine N-oxides that is characterised by
being catalytic in palladium and being highly tolerant of
sensitive functional groups.
chromatography on a SiO column using EtOAc–MeOH
2
(
(
8:1) as eluent to give the corresponding coupling product 2
74 mg, 0.27 mmol, 92%) as a yellow solid; mp 149–151 °C.
IR (KBr): 3065, 2959, 2876, 1718, 1692, 1639, 1605, 1569,
–
1 1
1
525, 1399 cm . H NMR (300 MHz, CDCl ): d = 0.91 (d,
3
Acknowledgment
J = 6.7 Hz, 6 H, CH ), 1.94 (m, 1 H, CH), 2.26 (s, 3 H, CH ),
3
3
3
=
1
.94 (d, J = 6.7 Hz, 2 H, CH ), 6.38 (d, J = 16.0 Hz, 1 H,
The authors thank the EPSRC for funding. Mrs C. Horsborough and
Mrs M. Smith are also thanked for technical assistance.
2
CH), 7.41 (d, J = 16.0 Hz, 1 H, =CH), 7.43 (d, J = 8.8 Hz,
H, ArCH), 8.33 (s, 1 H, ArCH), 8.39 (d, J = 8.8 Hz, 1 H,
1
3
ArCH), 9.98 (br s, 1 H, NH). C NMR (75 MHz, CDCl ):
3
References and Notes
d = 19.5, 25.4, 28.2, 71.5, 114.7, 121.6, 126.8, 127.0, 136.6,
138.5, 144.9, 166.3, 169.3. MS (TOF-ES): m/z (%) = 301.1
(
1) (a) Toganoh, M.; Fujino, K.; Ikeda, S.; Furuta, H.
Tetrahedron Lett. 2008, 49, 1488. (b) Singh, S. K.; Reddy,
M. S.; Mangle, M.; Ganesh, K. R. Tetrahedron 2006, 63,
+
+
(
100) [M + Na] . HRMS (TOF-ES): m/z [M + Na] calcd for
C H N O Na: 301.1164; found: 301.1173.
1
4
18
2
4
Synthesis of Compound 3 (Scheme 1)
To aryl bromide 1 (134 mg, 0.58 mmol) and [Pd(dippf)Cl2]
126. (c) Yoo, B. W.; Choi, J. W.; Yoon, C. M. Tetrahedron
Lett. 2005, 47, 125. (d) Sanz, R.; Escribano, J.; Fernandez,
Y.; Aguado, R.; Pedrosa, M. R.; Arnaiz, F. J. Synlett 2005,
(10.4 mg, 3 mol%) in a 5 mL microwave process vial were
added dry DMF (4 mL), Et N (0.24 mL, 1.74 mmol), and
3
1389. (e) Kumar, S.; Saini, A.; Sandhu, J. S. Tetrahedron
isobutyl acrylate (0.35 mL, 1.74 mmol). The reaction
mixture was heated by microwave irradiation at 140 °C for
Lett. 2005, 46, 8737. (f) Ilias, M.; Barman, D. C.; Prajapati,
D.; Sandhu, J. S. Tetrahedron Lett. 2002, 43, 1877.
60 min. After being cooled to ambient temperature, the
(
g) Boruah, M.; Konwar, D. Synlett 2001, 795. (h) Nicolau,
reaction mixture was concentrated under reduced pressure.
The crude mixture was purified by chromatography on a
K. C.; Koumbis, A. E.; Snyder, S. A.; Simonsen, K. B.
Angew. Chem. Int. Ed. 2000, 39, 2529. (i) Keith, J. M.
J. Org. Chem. 2006, 71, 9540. (j) Bjorsvik, H.-R.;
Gambarotti, C.; Jensen, V. R.; Gonzalez, R. R. J. Org. Chem.
SiO column using EtOAc–hexane (3:1) as eluent to give the
2
corresponding coupling product 3 (130 mg, 0.47 mmol,
8
3
1%) as a white solid; mp 112–114 °C. IR (KBr): 3245,
095, 2959, 2876, 1720, 1687, 1641, 1604, 1586, 1542, 1369
2
005, 70, 3218. (k) Chandrasekhar, S.; Reddy, C. R.; Rao,
R. J.; Rao, J. M. Synlett 2002, 349. (l) Hwu, J. R.; Tseng,
W. N.; Patel, H. V.; Wong, F. F.; Horng, D.-N.; Liaw, B. R.;
Lin, L. C. J. Org. Chem. 1999, 64, 2211. (m) Rosenau, T.;
Potthast, A.; Ebner, G.; Kosma, P. Synlett 1999, 623.
–1 1
cm . H NMR (300 MHz, CDCl ): d = 0.91 (d, J = 6.7 Hz,
6
3
H, CH ), 1.94 (m, 1 H, CH), 2.17 (s, 3 H, CH ), 3.93 (d,
3
3
J = 6.7 Hz, 2 H, CH ), 6.38 (d, J = 16.0 Hz, 1 H, =CH), 7.56
2
(
d, J = 16.0 Hz, 1 H, =CH), 7.82 (dd, J = 8.7, 2.3 Hz, 1 H,
ArCH), 8.19 (d, J = 8.7 Hz, 1 H, ArCH), 8.31 (d, J = 2.3 Hz,
1
3
1
H, ArCH), 8.58 (br s, 1 H, NH). C NMR (75 MHz,
CDCl ): d = 19.2, 24.8, 27.8, 70.8, 113.9, 118.7, 126.5,
3
1
36.6, 140.3, 148.2, 152.5, 166.7, 168.9. MS (TOF-ES):
+
+
m/z (%) = 263.1 (14) [M + H] , 285.0(100) [M + Na] .
HRMS (TOF-ES): m/z [M + Na] calcd for C H N O Na:
+
1
4
18
2
3
285.1215; found: 285.1206.
Synlett 2008, No. 17, 2579–2582 © Thieme Stuttgart · New York