Ruthenium catalyzed oxidation of tertiary nitrogen compounds with molecular oxygen: An easy access to N-oxides under mild conditions

Article abstract of DOI:10.1039/b202744p

A variety of tertiary nitrogen compounds have been efficiently oxidized to their corresponding N-oxides in excellent yields with molecular oxygen as a sole oxidant and ruthenium trichloride as catalyst.

Full text of DOI:10.1039/b202744p

Ruthenium catalyzed oxidation of tertiary nitrogen compounds with
molecular oxygen: an easy access to N-oxides under mild conditions
Suman L. Jain and Bir Sain*
Chemical and Biosciences Division, Indian Institute of Petroleum, Dehradun- 248 005, India.
E-mail: birsain@iip.res.in
Received (in Cambridge, UK) 18th March 2002, Accepted 3rd April 2002
First published as an Advance Article on the web 12th April 2002
Table 1 Oxidation of tertiary nitrogen compounds to N-oxides
A variety of tertiary nitrogen compounds have been effi-
ciently oxidized to their corresponding N-oxides in excellent
yields with molecular oxygen as a sole oxidant and
ruthenium trichloride as catalyst.
Reaction
Yielda
(%)
Entry
Substrate
time/h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4-Picoline
2-Picoline
3-Picoline
Pyridine
4-Cyanopyridine
2-Cyanopyridine
3-Cyanopyridine
Quinoline
6
6
8
95
94
90
85
79
75
65
40
60
98
94
52
98
70
Oxidation of tertiary nitrogen compounds is an important
synthetic transformation as N-oxides find wide applications as
oxidants,1 and offer functional group manipulation and struc-
tural modification possibilities, which are not accessible by
other methods.2 Although a number of effective oxidants have
been used to achieve this transformation, most of them suffer
from drawbacks such as the use of stoichiometric amount of
corrosive acids or toxic metallic compounds that generate
undesirable waste.3 In recent years the oxidation of tertiary
nitrogen compounds with hydrogen peroxide using methyl-
trioxorhenium(VII),4 manganese porphyrin,5 flavin,6 TS-1,7
molecular sieves,8 or tungstate-exchanged Mg–Al layered
double hydroxide9 as catalysts has been reported in pursuit to
the development of ecofriendly synthetic methodologies.
Molecular oxygen is an attractive oxidant and development
of synthetic methodologies using molecular oxygen as the sole
oxidant is a rewarding goal both from environmental and
economic points of view.10 Due to the widest scope of oxidation
states among the transition metals, ruthenium has proved to be
the most versatile catalyst for organic transformations and has
been used for epoxidation of alkenes, oxidation of alkanes and
alcohols with molecular oxygen as oxidant.11 However, to the
best of our knowledge, there is no literature report on oxidation
of tertiary nitrogen compounds to N-oxides with molecular
oxygen as the sole oxidant.12
8
15
20
15
20
20
8
8
12
6
Isoquinoline
N,N-Dimethylaniline
N,N-Diethylaniline
2-Hydroxypyridine
Triethylamine
N-Methylmorpholine
12
a Isolated yield.
phosphine)ruthenium(II) was found to be most efficient catalyst.
In blank experiments under similar conditions, no oxidation was
observed in the absence of catalyst. The oxidation of 4-picoline
to 4-picoline N-oxide was also studied at different temperatures
and it was observed that an increase in temperature had only a
marginal effect on an increase in the reaction rate.
Although the mechanism of this reaction is not clear at this
stage, the reaction probably involves the formation of oxo-
Table 2 Oxidation of 4-Picoline to 4-Picoline N-oxide with different
solvents
In continuation to our studies on oxidation with molecular
oxygen as a primary oxidant,,13 herein we report, a simple and
convenient ruthenium catalyzed oxidation of tertiary nitrogen
compounds to their N-oxides in near quantitative yields using
molecular oxygen as the sole oxidant (Scheme 1).†
Reaction
time/h
Conversiona
(%)
Entry
Substrate
Solvent
1
2
3
4
4-Picoline
4-Picoline
4-Picoline
4-Picoline
Methanol
Ethanol
Acetone
12
12
20
6
50
60
0
A wide variety of tertiary nitrogen compounds were oxidized
to their corresponding N-oxides in near quantitative yields and
results are summarized in Table 1. Pyridines containing electron
donating groups were found to react faster and required lower
reaction times, whereas pyridines bearing electron withdrawing
groups required longer reaction times for their oxidation.
Results obtained on oxidation of 4-picoline to 4-picoline N-
oxide using different solvents under similar conditions are
summarized in Table 2. Among the solvents studied dichlor-
ethane was found to be the best solvent for this reaction.
To evaluate the relative efficiency of various Ru-catalysts,
we prepared a variety of ruthenium complexes14 and studied the
oxidation of 4-picoline under similar conditions employing 5
mol% of these catalysts; the results obtained are presented in
Table 3. Among the catalysts studied dichlorotris(triphenyl-
Dichloroethane
98
a Conversion was determined by HPLC using a C18 Bondapack reverse
phase column (4.6 3 250 mm, 10mm), methanol as eluent (0.5 mL
min21).
Table 3 Oxidation of 4-picoline to 4-picoline N-oxide with different
catalysts
Reaction Conversiona
time/h
Entry Substrate
Catalyst
(%)
1
2
3
4
5
6
4-Picoline RuH(CO)(OCOMe)(PPh3)2 12
42
42
100
91
98
0
4-Picoline RuCl2(PPh3)4
4-Picoline RuCl2(PPh3)3
4-Picoline RuH2(CO)(PPh3)3
4-Picoline RuCl3·nH2O
12
5
8
6
4-Picoline
—
12
a Conversion was determined by HPLC using a C18 Bondapack reverse
phase column (4.6 3 250 mm, 10 mm), methanol as eluent (0.5 mL
min21).
Scheme 1 Tertiary nitrogen compounds 1 are efficiently oxidized to N-
oxides 2 with molecular oxygen in the presence of catalytic amounts of
ruthenium trichloride.
1040
CHEM. COMMUN., 2002, 1040–1041
This journal is © The Royal Society of Chemistry 2002

ruthenium species11a,15 from ruthenium and molecular oxygen
followed by oxygen transfer to tertiary nitrogen, which yields
the corresponding N-oxide.
Ullmann’s Encyclopedia of Industrial Chemistry, VCH, Germany, 5th
edn., 1993, vol. A-22, pp. 399–428.
3 For representative reports see: (a) V. Boekelheide and W. J. Linn, J. Am.
Chem. Soc., 1954, 76, 1286; (b) E. C. Taylor and A. J. Crovetti, Org.
Synth. Coll. Vol., 1963, 4, 828; (c) P. Brougham, M. S. Copper, D. A.
Cummerson, H. Heaney and N. Thompson, Synthesis, 1987, 1015; (d)
R. W. Murray and R. Jeyaraman, J. Org. Chem., 1985, 50, 2847; (e) M.
Ferrer, F. Sanchez-Baeza and A. Messeguer, Tetrahedron, 1997, 53,
1587.
4 (a) C. Coperet, H. Adolfsson, T.-A. V. Khuong, A. K. Yudin and K. B.
Sharpless, J. Org. Chem., 1998, 63, 1740; (b) Z. Zhu and J. H. Espenson,
J. Org. Chem., 1995, 60, 1326; (c) Y. Jiao and H. Yu., Synlett., 2001, 1,
73.
In summary we have demonstrated, for the first time, that
ruthenium catalyzed oxidation of tertiary nitrogen compounds
with molecular oxygen as the sole oxidant yields N-oxides in
excellent yields under mild conditions. The simplicity of the
system, easy separation of the catalysts, simple workup and
excellent yields make this method an attractive, environmen-
tally acceptable synthetic tool for the oxidation of tertiary
nitrogen compounds to their corresponding N-oxides.
We are thankful to Director, IIP for his kind permission to
publish these results. S. L. J. is thankful to CSIR, New Delhi, for
the award of a research fellowship.
5 A. Thellend, P. Battioni, W. Sanderson and D. Mansuy, Synthesis, 1997,
1387.
6 (a) K. Bergstad and J. E. Backvall, J. Org. Chem., 1998, 63, 6650; (b)
S. Ball and T. C. Bruice, J. Am. Chem. Soc., 1980, 102, 6498.
7 D. J. Robinson, P. McMom, D. Bethell, P. C. Bulmanpage, C. Sly, F.
King, F. E. Hangcock and G. J. Hutching, Catal. Lett., 2001, 72, 233.
8 M. R. Prasad, G. Kamalkar, G. Madhavi, S. J. Kulkarni and K. V.
Raghvan, Chem. Commun., 2000, 1577.
Notes and references
†
Experimental procedure: all the substrates and solvents are commer-
9 B. M. Choudhary, B. Bharathi, C. V. Reddy, K. M. Lakshmi and K. V.
Raghavan, Chem. Commun., 2001, 1736.
cially available. A typical procedure for the oxidation of tertiary nitrogen
compound to its N-oxide is as follows: molecular oxygen was bubbled into
a stirred solution of 4-picoline (0.93 g, 10 mmol) and RuCl3·nH2O‡ (0.103
g, 5 mol%) in dichloroethane (10 ml) in a 50 ml double necked round
bottomed flask. The progress of reaction was monitored by TLC (SiO2). At
the end of reaction, the catalyst was removed by filtration and the reaction
mixture thus obtained was purified by passing through a column of basic
alumina using dichloromethane/MeOH (95+5) as eluent. Removal of the
solvent and usual workup gave 4-picoline N-oxide (0.92 g, 95% yield).
Similarity other N-oxides were prepared and the reaction times required and
yields obtained are shown in Table 1. The products were identified by
comparing their physical and spectral data with those of authentic
compounds reported in the literature.
For comparing the efficiency of various solvents, experiments were
similarily conducted with different solvents and the residues obtained after
passing through the basic alumina column were analyzed by HPLC. For
comparing the efficiency of various catalysts, experiments were carried out
with different Ru-catalysts under similar conditions and the residues
obtained after passing through the basic alumina column was analyzed by
HPLC.
10 (a) Y. Nishiyama, Y. Nakagawa and N. Mizuno, Angew. Chem., Int.
Ed., 2001, 40, 3639; (b) J. M. Thomas, R. Raja, G. Sankar and R. G.
Bell, Acc. Chem. Res., 2001, 34, 191; (c) C. Dobler, G. M. Mehltretter,
U. Sundermeier and M. Beller, J. Am. Chem. Soc., 2001, 122, 10289; (d)
J. T. Groves and R. Quinn, J. Am. Chem. Soc., 1985, 107, 5790; (e) S.
Davis. and R. S. Drago, J. Chem. Soc., Chem. Commun., 1990, 250; (f)
R. J. David, S. J. Pugsley and S. Matthew, J. Am. Chem. Soc., 2001, 123,
7475; (g) W. Partenheimer, in The Activation of Dioxygen and
Homogeneous Catalytic Oxidation, ed. D. H. R. Barton, A. E. Martell
and D. T. Sawyer, Plenum Press, New York, 1993; (h) Y. Nishiyama, Y.
Nakagawa and N. Mizuno, Angew. Chem., 2001, 40, 3639; (i) K.
Noboyuki, M. Yasunari, T. Nishimura and S. Uemura, J. Org. Chem.,
2001, 66, 6620.
11 (a) T. Naota, H. Takaya and S. Murahashi, Chem. Rev., 1998, 98, 2599;
(b) A. Miyata, M. Murakami, R. Iric and T. Katsuki, Tetrahedron Lett.,
2001, 42, 7067; (c) T. Konda, T. Okada and T. Mitsudo, J. Am. Chem.
Soc., 2002, 124, 186; (d) J. E. Marko, P. R. Giles, M. Tsukazaki, I.
Chelle-Regnaut, C. J. Urch and S. M. Brown, J. Am. Chem. Soc., 1997,
119, 12661.
‡ One of the referees suggested to prepare purified ruthenium trichloride (by
treating the commercial ruthenium trichloride with conc. HCl and a few
drops of ethanol) and K2[RuCl5(H2O)] from commercial ruthenium
trichloride and use them as catalysts in these reactions. Accordingly we
studied the oxidation of 4-picoline, 2-picoline and pyridine by using
purified ruthenium trichloride and K2[RuCl5(H2O)] as catalysts under
similar conditions; N-oxide yields and reaction times were found to be
comparable to those for commercial RuCl3·nH2O.
12 There are two literature reports on oxidation of tertiary nitrogen
compounds to N-oxides using a molecular oxygen–aldehyde system: (a)
R. S. Dongre, T. V. Rao, B. K. Sharma, B. Sain and V. K. Bhatia, Synth.
Commun., 2001, 31, 167; (b) F. Wang, H. Zhang, G. Song and X. Lu,
Synth. Commun., 1999, 29, 11.
13 (a) T. V. Rao, B. Sain, K. Kumar, P. S. Murthy, T. S. R. Prasada Rao and
G. C. Goshi, Synth. Commun., 1998, 28, 319; (b) B. Sain, P. S. Murthy,
T. V. Rao, T. S. R. Prasada Rao and G. C. Goshi, Tetrahedron Lett.,
1994, 35, 5083; (c) T. V. Rao, B. Sain, P. S. Murthy, T. S. R. Prasada
Rao, A. K. Jain and G. C. Joshi, J. Chem. Res. (S), 1997, 300; (d) T. V.
Rao, B. Sain, P. S. N. Murthy, G. C. Joshi and T. S. R. Prasada Rao,
Stud. Surf. Sci. Catal., 1998, 113, 921; (e) S. L. Jain and B. Sain, J. Mol.
Catal., 2001, 176, 101.
14 For the preparation of RuH(CO)(OCOMe)(PPh3)2, RuCl2(PPh3)4,
RuCl2(PPh3)3, RuH2(CO)(PPh3)3 from RuCl3·3H2O, see: (a) A.
Dobsen, S. D. Robinson and M. F. Uttley, Inorg Synth., 1977, 17, 126;
(b) P. S. Hallman, T. A. Stephenson and G. Wilkinson, Inorg. Synth.,
1970, 12, 238; (c) N. Ahmad, J. J. Levison, S. D. Robinson and M. F.
Uttley, Inorg Synth., 1974, 15, 48.
1 (a) V. Van Rheenen, D. Y. Cha and W. M. Hartley, Org. Synth. Coll.
Vol., 1988, 6, 342; (b) M. Schroder, Chem. Rev., 1980, 80, 187; (c) L.
Ahrgren and L. Sutin, Org. Proc. Res. Dev., 1997, 1, 425; (d) S. V. Ley,
J. Norman, W. P. Griffith and S. P. Marsden, Synthesis, 1994, 639; (e)
V. Franzen and S. Otto, Chem. Ber., 1961, 94, 1360; (f) S. Suzuki, T.
Onishi, Y. Fujita, H. Misawa and J. Otera, Bull. Chem. Soc. Jpn., 1986,
59, 3287; (g) A. G. Godfrey and B. Ganem, Tetrahedron Lett., 1990, 31,
4825; (h) W. P. Griffith, S. V. Ley, G. P. Whitcombe and A. D. White,
J. Chem. Soc., Chem. Commun., 1987, 1625.
2 (a) A. C. Cope and E. Ciganek., Org. Synth. Coll. Vol., 1963, 4, 612; (b)
A. C. Cope and E. R. Trumbull., Org. React., 1960, 11, 317; (c)
15 (a) J. T. Groves and R. Ouinn, J. Am. Chem. Soc., 1985, 107, 5790; (b)
M. M. T. Khan and R. S. Shukla, J. Mol. Catal., 1988, 44, 85.
CHEM. COMMUN., 2002, 1040–1041
1041