A simple and efficient method for the preparation of pyridine N-oxides

Full text of DOI:10.1021/jo9723467

1740
J . Org. Chem. 1998, 63, 1740-1741
Ta ble 1. MTO-Ca ta lyzed Oxid a tion of P yr id in es w ith
A Sim p le a n d Efficien t Meth od for th e
a
30% Aqu eou s H2O2
P r ep a r a tion of P yr id in e N-Oxid es
Christophe Cope´ret,‡ Hans Adolfsson,
Tinh-Alfredo V. Khuong, Andrei K. Yudin, and
K. Barry Sharpless*
Department of Chemistry and the Skaggs Institute of
Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La J olla, California 92037
Received December 31, 1997
We report here on a practical and efficient method for
the N-oxidation of pyridines to the corresponding N-
oxides (eq 1). We have recently shown that the addition
of 3-cyanopyridine improves the MTO-catalyzed epoxi-
dation of terminal alkenes with 30% aqueous H2O2.1,2
During this study, we have also observed that oxidation
of the ligand to 3-cyanopyridine N-oxide was taking place
late in the reaction.3 In the absence of alkene, the use
of 2 equiv of H2O2 with 0.5 mol % of MTO converted
3-cyanopyridine to its N-oxide, which was isolated in an
analytically pure form (88% yield) by a simple extractive
workup.4 In the absence of MTO, under otherwise
identical conditions, there was no sign of reaction even
after several days. Oxidation of pyridines to the corre-
sponding N-oxides can be achieved in many ways;
however, methods depending on mCPBA as oxidant seem
to be the most common.5 Such peracid-based procedures
are very reliable for most pyridines, but usually less so
for electron deficient ones. In addition to its sometimes
greater reactivity, this new method is performed very
concentrated (>2 M in substrate) using an environmen-
tally friendly oxidizing agent, i.e. 30% aqueous H2O2, and
does not generate byproducts other than water so that
workup is simple.
(Table 1). One notes that 3- and 4-substituted pyridines,
regardless of their electronic nature, give high yields of
the corresponding N-oxides using only 0.2-0.5 mol % of
MTO. On the other hand, the most simple 2-substituted
pyridines (Table 1, first column) require high catalyst
loading, typically 5 mol %, to reach both full conversion
and high yields. The latter pyridines also reveal little
to no binding to MTO based on 1H NMR experiments,
which may suggest that coordination of the pyridine to
the metal center is somehow helpful for achieving high
turnovers.1,6 However, the rates and catalyst loading in
entries 1-4 in Table 2 indicate that with polysubstituted
pyridines, the deleterious effect of a 2-substituent can
be negated by other factors.
In our studies of the pyridine-assisted MTO-catalyzed
epoxidation process,1,2 we had found that higher concen-
trations of pyridine, instead of further accelerating the
epoxidation catalysis actually retarded it by destroying
the catalyst (vide infra). Hence, it was surprising to find
that providing no olefin was present, MTO can be an
excellent and quite stable catalyst for the oxidation of
pyridines. If excessive amounts of pyridine (>20-50 mol
These features, along with the importance of N-oxides
as synthetic intermediates, led us to investigate its scope
*
To whom correspondence should be addressed. Fax: 619-
7847562. E-mail: sharples@scripps.edu.
(5) (a) For a review on oxidation of pyridines, see: Ochiai, E.
‡ New address: Laboratoire de Chimie Organome´tallique de Surface,
UMR CNRS-CPE 9986, 43 boulevard du 11 Novembre 1918, 69616
Villeurbanne Cedex, France.
Aromatic Amine Oxides; Elsevier: Amsterdam, 1967; Albini, A.; Pietra,
S. Heterocyclic N-Oxides; CRC Press: Boca Raton, FL, 1991. (b) For
some examples of N-oxidation using peracids: Edwards, D. C.; Gillespie
Tetrahedron Lett. 1966, 4867. (c) For oxidation with a combination of
hydrogen peroxides and acids/anhydrides: Chivers, G. E.; Suschitzky,
H. J . Chem. Soc., Chem. Commun. 1971, 28. Takabe, K.; Yamada, T.;
Katagiri, T. Chem. Lett. 1982, 1987. Tortorella, V. J . Chem. Soc., Chem.
Commun. 1966, 308. Kaczmarek; Balicki, R.; Nantka-Namirski, P.
Chem. Ber. 1992, 125, 1965. (d) For oxidation with DMDO: Murray,
R. W.; J eyaraman, R. J . Org. Chem. 1985, 50, 2847. {e) For some
examples of transition metal catalyzed oxidation of pyridines: Tol-
stikov, G. A.; J emilev, U. M.; J urjev, V. P.; Gershanov, P. B.; Rafikov,
S. R. Tetrahedron Lett. 1971, 2807. Cabre, C. J .; Palomo, C. A. Afinidad
1988, 45, 5111 (Chem. Abstr. 1989, 111, 77817). (f) The parent pyridine
has been oxidized to its N-oxide by using anhydrous H2O2 in the
presence of 8 mol % MTO: see ref 3c.
(1) Cope´ret, C.; Adolfsson, H.; Sharpless, K. B. Chem. Commun.
1997, 1565.
(2) (a) Rudolph, J .; Reddy, K. L.; Chiang, J . P.; Sharpless, K. B. J .
Am. Chem. Soc. 1997, 119, 6185. (b) For a related catalytic system
using bis(trimethylsilyl)peroxide as stoichiometric oxidant: Yudin, A.
K.; Sharpless, K. B. Ibid. 1997, 119, 11536.
(3) It is worth pointing out that 3-cyanopyridine N-oxide slows down
the rate of epoxidation.
(4) There have been several reports on MTO-catalyzed oxidations
of amines and anilines: (a) Murray, R. W.; Iyanar, K.; Chen., J .;
Wearing, J . T. Tetrahedron Lett. 1995, 36, 6415. (b) Zhu, Z.; Espenson,
J . H. J . Org. Chem. 1995, 60, 7728. (c) Murray, R. W.; Iyanar, K.; Chen.,
J .; Wearing, J . T. Tetrahedron Lett. 1996, 37, 805. (d) Goti, A.; Nanelli,
L. Ibid. 1996, 37, 6025. (e) Murray, R. W.; Iyanar, K.; Chen, J .;
Wearing, J . T. J . Org. Chem. 1996, 61, 8099. (f) Yamazaki, S. Bull.
Soc. Chem. J pn. 1997, 70, 877.
(6) This was probed by observing the difference in chemical shifts
upon addition of 2 equiv of a ligand to a 20 mM solution of MTO in
CD2Cl2: Cope´ret, C.; Sharpless, K. B. Unpublished results.
S0022-3263(97)02346-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/18/1998

Notes
Ta ble 2. Oxid a tion of P oly- a n d Alk en yl Su bstitu ted
J . Org. Chem., Vol. 63, No. 5, 1998 1741
detected. Finally, N-oxidation of more electron deficient
pyridines was also achieved in high yields (entries 8-11,
Table 2).
P yr id in es
In conclusion, a simple and efficient procedure for the
oxidation of pyridines to their N-oxides has been devel-
oped.10 Moreover, the fact that the MTO catalyst is
especially vulnerable to pyridine-mediated destruction
only when it is catalyzing olefin epoxidation seems to
offer an important mechanistic clue. This phenomenon
and other ligand effects in these MTO-catalyzed epoxi-
dations are under investigation.11
Exp er im en ta l Section
All reagents and solvents were purchased and used without
further purification. All reaction were carried out at 24 °C
(water bath) in scintillation vials or Erlenmeyer flasks under
air.
Gen er a l P r oced u r e. A representative procedure for the
oxidation of pyridines is as follows:
a mixture of methyl
isonicotinate (13.7 g, 100 mmol) and MTO (125 mg, 0.5 mmol)
in CH2Cl2 (40 mL) was treated with 20 mL of 30% aqueous H2O2
(200 mmol) and stirred for 6 h at 24 °C. The biphasic reaction
mixture was then treated with a catalytic amount of MnO2 (25
mg) and stirred until oxygen evolution ceased (1 h). Following
phase separation, the water layer was extracted with CH2Cl2
(2 × 40 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated to give 15.0 g (98%) of an
analytically pure solid: 1H NMR (CDCl3) δ 3.90 (s, 3 H), 7.75-
7.95 (m, 2 H), 8.05-8.3 (m, 2 H); 13C NMR (CDCl3) δ 52.99,
125.36, 126.88, 129.38, 138.93, 142.61, 163.31; high-resolution
MS calcd for C7H7NO3 (M + 1) 154.0504, found 154.0508.
Su p p or tin g In for m a tion Ava ila ble: 1H, and 13C NMR,
and mass spectrometry data of all N-oxides (12 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. We are grateful to the National
Institute of General Medical Sciences, the National
Institutes of Health (GM 28384), the National Science
Foundation (CHE 9521152), the W. M. Keck Founda-
tion, and the Skaggs Institute for Chemical Biology for
financial support. H. A. and C. C. are also grateful to
the Swedish Natural Science Research Council, and the
Association des Amis des Sciences for postdoctoral
fellowships, respectively. T.-A. V. K. was a Ronald E.
McNair scholar during 1997. We also want to thank J .
P. Chiang for participating in related experiments.10
%) are present during epoxidation (eq 2), MTO catalyst
decomposes more rapidly.7,8
J O9723467
(10) Later we found that the combination of bis(trimethylsilyl)
peroxide as stoichiometric oxidant and inorganic rhenium derivatives
as catalysts could also oxidize pyridines into their N-oxides, see:
Cope´ret, C.; Adolfsson, H.; Chiang, J . P.; Yudin, A. K.; Sharpless, K.
B. Tetrahedron Lett., in press.
In light of these trends, we were not surprised to find
that the olefinic pyridine [4-(3′-cyclohexenyl)pyridine,
entry 5, Table 2] undergoes epoxidation (not N-oxidation),
but with poor turnover.9 By contrast, for the entries 6
and 7, having conjugated alkene substituents, the N-
oxidation pathway dominates and no epoxides were
(11) For other results on the MTO-catalyzed epoxidation of alkenes,
see: Hoechst AG (Herrmann, W. A.; Marz, D. W.; Kuchler, J . G.;
Weichselbaumer, G.; Fischer, R. W.) DE 3.902.357, 1989; Herrmann,
W. A.; Fischer, R. W.; Marz, D. W. Angew. Chem., Int. Ed. Engl. 1991,
30, 1638-1641; ARCO Chemical Technology (Crocco, G. L.; Shum, W.
P.; Zajacek, J . G.; Kesling, H. S., J r.) US 5.166.372, 1992. Herrmann,
W. A.; Fischer, R. W.; Rauch, M. U.; Scherer, W. J . Mol. Catal. 1994,
86, 243-266. Al-Ajlouni, A. M.; Espenson, J . H. J . Am. Chem. Soc.
1995, 117, 9243-9250. Pestovsky, O.; van Eldik, R.; Huston, P.;
Espenson, J . H. J . Chem. Soc., Dalton Trans. 2 1995, 133-137.
Herrmann, W. A. J . Organomet. Chem. 1995, 500, 149. Adam, W.;
Mitchell, C. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 533-535.
Boelow, T. R.; Spilling, C. S. Tetrahedron Lett. 1996, 37, 2717-2720.
Al-Ajlouni, A. M.; Espenson, J . H. J . Org. Chem. 1996, 61, 3969-3976.
Herrmann, W. A.; Correia, J . D. G.; Rauch, M. U.; Artus, G. R. J .;
Ku¨hn, F. E. J . Mol. Catal. 1997, 118, 33.
(7) For a comprehensive study on the base-induced decomposition
of MTO, see: Abu-Omar, M. M.; Hansen, P. J .; Espenson, J . H. J . Am.
Chem. Soc. 1996, 118, 4966.
(8) The MTO catalyst decomposes into MeOH plus the bis(pyridine)
adduct of perrhenic acid, which is not an epoxidation catalyst: Yudin,
A. K.; Sharpless, K. B. Unpublished results.
(9) The high “pyridine” concentration brings on the “olefin-depend-
ent” catalyst destruction.