Deoxygenation of N-oxides with triphenylphosphine, catalyzed by dichlorodioxomolybdenum(VI)

Article abstract of DOI:10.1055/s-2005-868504

Chemoselective deoxygenation of N-oxides was carried out under mild conditions with common phosphines in the presence of dichlorodioxomolybdenum(VI) . Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-868504

LETTER
1389
Deoxygenation of N-Oxides with Triphenylphosphine, Catalyzed by
Dichlorodioxomolybdenum(VI)
D
eoxygenation of
o
N
-Oxides
w
b
ith Tripheny
e
lphosphine
r
,
Catalyz
t
ed by
o
D
ichlorodioxomoly
S
bdenum(VI) anz,* Jaime Escribano, Yolanda Fernández, Rafael Aguado, María R. Pedrosa, Francisco J. Arnáiz*
Departamento de Química, Universidad de Burgos, 09001-Burgos, Spain
Fax +34(947)258831; E-mail: rsd@ubu.es; E-mail: farnaiz@ubu.es
Received 27 January 2005
Dedicated to Prof. Dr. José Barluenga on the occasion of his 65th birthday
tion of sulfoxides to sulfides with P(OR)3.15 Herein, we re-
port the deoxygenation of representative heteroaromatic
N-oxides, nitrones, and azoxycompounds with PPh3,
catalyzed by dichlorodioxomolybenum(VI).
Abstract: Chemoselective deoxygenation of N-oxides was carried
out under mild conditions with common phosphines in the presence
of dichlorodioxomolybdenum(VI).
Key words: N-oxides, azoxy compounds, molybdenum(VI),
nitrones, oxotransfer catalysis
Commercially available 4-picoline-N-oxide (4-MePyO;
1a) was first chosen to test the oxo-transfer process under
dioxomolybdenum(VI) catalysis. A few preliminary tests
were carried out in common solvents, using PPh3 as oxo-
acceptor and MoO2Cl2(dmf)2 as catalyst, in order to opti-
mize the reaction conditions to afford complete conver-
sion to 4-picoline (2a). The results are summarized in
Table 1.
Selective deoxygenation of organic N-oxides is a subject
of considerable interest in heterocyclic synthesis and a
large number of reports are available on the reduction of
the N–O bond in different types of nitrones, azoxy-
benzenes, and N-heteroarene N-oxides.1
Among these compounds, heteroaromatic N-oxides are
especially relevant mainly due to their differential chemi-
cal behavior compared to their parent amines, as a result
several deoxygenation procedures have been developed.
However, the reagent of choice for each particular case
depends on the nature of the substituents on the molecule.
Although, the most frequently used reducing agents are
Table 1 Deoxygenation of 4-Picoline-N-oxide (1a) with PPh3
MoO2Cl2(dmf)2 (1 mol%)
PPh3, solvent, temp, time
N
N
O
1a
2a
trivalent phosphorus compounds,2 especially phosphorus
trihalides, other methods include catalytic hydrogenation
over Raney nickel or Pd/C,3 Fe/HOAc,4 Zn/aq NH4Cl,5
NaBH4/AlCl3,6 NH4CO2H-Pd/C,7 TiCl3,8 AlI3.9
Entry
Solvent
THF
Temperature Time (h)
Conversion (%)
1
2
20 °C
reflux
reflux
20 °C
reflux
reflux
20 °C
reflux
reflux
20 °C
reflux
24
1
16
32
100
8
THF
Many of the methods are limited by side reactions, lack of
chemoselectivity, low yields, or tedious procedures. Thus,
the development of new methods for the selective deoxy-
genation of N-oxides continues to attract considerable at-
tention.10
3
THFa
5.5
4
MeCN
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
24
1
5
51
100
8
Aromatic N-oxides are relatively more stable than aliphat-
ic ones and, for instance, they are not deoxygenated with
PPh3.11 However, Espenson et al. have found that an oxo-
rhenium(V) complex, with the dianion of 2-(mercapto-
methyl)thiophenol as ligand, catalyzes the transfer of
oxygen from numerous pyridine N-oxides to PPh3.12
6
5,5
7
24
1
8
24
100
7
9
20
24
1
During the course of recent investigations on oxomolyb-
denum complexes we have found that MoO2Cl2 and some
of its addition compounds behave as oxo-transfer cata-
lysts in a manner related to that of oxotransferases.13 Thus,
we have recently reported some useful synthetic applica-
tions of these chlorocomplexes in the selective catalyzed
oxidation of thiols to disulfides with DMSO14 and reduc-
10
11
100
a In the absence of catalyst, the N-oxide remained unaffected after
30 h at reflux.
These preliminary experiments show no significant
differences in conversion between CH2Cl2, MeCN, and
toluene as solvents at room temperature. However, the
deoxygenation proceeds faster in THF, which might be
related to the superior solubility of the catalytic active
SYNLETT 2005, No. 9, pp 1389–1392
0
1.
0
6.
2
0
0
5
Advanced online publication: 29.04.2005
DOI: 10.1055/s-2005-868504; Art ID: D02405ST
© Georg Thieme Verlag Stuttgart · New York

1390
R. Sanz et al.
LETTER
Table 2 Deoxygenation of Aromatic N-Oxides 1 with PPh3,
Catalyzed by MoO2Cl2(dmf)2
species in this solvent. Although the concentration of mo-
lybdenum in the solutions was not measured, the primary
catalytic species, MoO2Cl2(dmf)2, is clearly more soluble
in THF. On the other hand, temperature plays a significant
role, as expected. The reaction requires several days to
reach completion when carried out at room temperature,
but less than one hour when the temperature exceeds 100
°C. Thus toluene becomes a good solvent, provided re-
agents and products are stable at the reflux temperature. If
milder conditions are required, THF constitutes the most
appropriate solvent. Moreover, the reaction can be per-
formed with analytical grade solvents in air without spe-
cial precautions, indicating that a trace amount of
peroxides does not destroy the catalyst as occurred with
the previously mentioned oxorhenium(V) catalyst.12 The
use of carefully purified, and dried THF under an inert
atmosphere did not improve either the reaction rate or the
final result.
R
R
MoO2Cl2(dmf)2 (1 mol%)
PPh3, THF reflux, time
N
N
O
1
2
Entry Starting material
Product
Time Yield
(h)
(%)a
1
2
4-MePyO (1a)
2-MePyO (1b)
3-MePyO (1c)
2-ClPyO (1d)
4-ClPyO (1e)
PyO (1f)
4-MePy (2a)
2-MePy (2b)
3-MePy (2c)
2-ClPy (2d)
4-ClPy (2e)
Py (2f)
5.5 88
1
80
3
1.5 75
78
1.5 75
4
3
5
It should be pointed out that the catalyst could not be re-
covered from the reaction, since it is rapidly transformed
into other species as evidenced by coloration changes (see
below). However, addition of new batches of the N-oxide
and PPh3 to the final mixture of products proved the
presence of catalytically active species.
6
1
5
80
87
79
81
85
72
7
2-BrPyO (1g)
2-(OH)PyO (1h)
2-(CO2H)PyO (1i)
2-BrPy (2g)
8
2-(OH)Py (2h)
2-(CO2H)Py (2i)
15
2
9
10
11
12
13
14
15
4-(PhCH2O)PyO (1j) 4-(PhCH2O)Py (2j) 12
We have also observed that alkylphosphines such as PBu3
are also effective as reducing agents towards 1a in the
presence of dioxomolybdenum(VI) catalyst. Although
alkylphosphines seem to be slightly superior to arylphos-
phines, the use of PPh3 is preferred because of its low
vapor pressure at room temperature, availability at low
cost, and ease of handling.
4-(NO2)PyO (1k)
BipyOb (1l)
4-(NO2)Py (2k)
Bipy (2l)
10
2.5 79
BipyO2c (1m)
QuinOd (1n)
Bipy (2m)
Quin (2n)
9
1
82f
85
i-QuinOe (1o)
i-Quin (2o)
0.5 86
Thus, using a slight excess of PPh3 in THF at reflux and
with 1 mol% of MoO2Cl2(dmf)2, efficient deoxygenation
of several aromatic N-oxides 116 was achieved in excellent
yields showing the chemoselectivity and generality of our
catalytic system. Table 2 shows the results obtained when
the reactions were carried with a range of N-oxides to af-
ford exclusively the corresponding reduced compounds 2.
a Isolated yields based on the starting aromatic N-oxide 1.
b 2,2¢-Bipyridine 1-oxide (1l).
c 2,2¢-Bipyridine 1,1¢-dioxide (1m).
d Quinoline N-oxide (1n).
e Isoquinoline N-oxide (1o).
f 2,2¢-Bipyridine 1-oxide (1l) was not detected during the process.
The following considerations are pertinent with regard to
these results. All reactions could be achieved in air with
complete conversion and good isolated yield, which is in-
dicative that all potentially oxidizable species involved in
these processes, including the reduced forms of the cata-
lyst, react faster with the N-oxides than with atmospheric
oxygen. This deoxygenation system tolerates chloro
(Table 2, entries 4,5), bromo (Table 2, entry 7), hydroxy
or alkoxy (Table 2, entries 8,10), carboxy (Table 2, entry
9), and nitro (Table 2, entry 11) substituents. Moreover,
the method could be carried out on a multigram scale and
thus 0.1 mol of 1a was almost quantitatively reduced to 4-
picoline (2a) by using 1 mmol (1%) of the catalyst.
amine due to further reduction, minor amounts of the
hydrolysis products of 4b were obtained probably due to
the presence of traces of water in the reacting system.
Extension of this method to azoxybenzenes 5 (diaryldi-
azene N-oxides) gave the corresponding azobenzenes 6 as
the sole products in excellent yields (Scheme 2). It is im-
N
N
4a (85%)
O
3a
MoO2Cl2(dmf)2 (5%)
Once we had demonstrated the ability of our catalytic
method, we decided to explore the deoxygenation of other
organic N-oxides. Thus, we found that nitrones 317 could
be smoothly deoxygenated in two hours to give the corre-
sponding imines 4 in good yields (Scheme 1). Although
there was no evidence for the formation of a secondary
PPh3 (1.1 equiv)
THF reflux
O
N
Ph
Ph
Ph
N
Ph
3b
4b (84%)
Scheme 1 Deoxygenation of nitrones 3.
Synlett 2005, No. 9, 1389–1392 © Thieme Stuttgart · New York

LETTER
Deoxygenation of N-Oxides with Triphenylphosphine, Catalyzed by Dichlorodioxomolybdenum(VI)
1391
portant to note that we have consistently found symptoms
of degradations of the catalyst in the deoxygenation of ni-
trones 3 and azoxybenzenes 5. Both deoxygenation pro-
cesses could be completed by using 5 mol% of catalyst.18
The necessity of a large excess of PPh3 for the reduction
of azoxy derivatives 5 could be due to the resistance of
these compounds towards deoxygenation.19 Nevertheless,
from a synthetic point of view the excess of PPh3 could be
easily removed by its in situ oxidation with DMSO, a pro-
cess also catalyzed by the dioxomolybdenum(VI) catalyst
present in the reaction.
MoOCl2(dmf)2 + MoO2Cl2(dmf)2
Mo2O3Cl4(dmf)4
Equation 2
This is an equilibrium reaction that we believe is strongly
displaced to the right at room temperature in most com-
mon solvents.
The tendency of oxomolybdenum(IV) and dioxomolyb-
denum(VI) to comproportionate is well documented.20
Furthermore, in an independent experiment we confirmed
the equilibrium proposed in Scheme 3. When a colorless
solution of MoO2Cl2(dmf)2 in THF was treated with PPh3
(molar ratio 1:1), the solution immediately turned brown,
and the reaction stopped when approximately half of the
phosphine added was transformed to OPPh3. A brown sol-
id could be isolated, having analytical data (C, H, N) con-
sistent with the expected product Mo2O3Cl4(dmf)4.
R
R
MoO2Cl2(dmf)2 (5%)
N
O
N
N
R
N
R
PPh3 (5 equiv)
THF reflux
Further studies are needed to elucidate whether the dinu-
clear oxomolybdenum(V), or the mononuclear oxomo-
lybdenum(IV), or both species, are responsible for the
deoxygenation of the N-oxides.
It should be noted that this proposal is also a simplifica-
tion and that we have found clear evidence that other spe-
cies may be dominant in each particular system. In effect,
MoO2Cl2(dmf)2 reacts rapidly in THF with the more basic
N-oxides, via displacement of the coordinated DMF,
leading to the corresponding addition compounds
MoO2Cl2(N-oxide)n. Also, several of the deoxygenation
products are able to displace DMF from the coordination
sphere of Mo(VI, V, IV) centers. This could be observed
by changes in the color of the reacting, and final solution.
Thus, for example, during the deoxygenation of BipyO2
the solution acquires a persistent red coloration which
suggests the presence of Bipy complexes of the reduced
form of molybdenum [colorless MoO2Cl2(Bipy) reacts
with excess PPh3 leading to a red product whose analy-
tical data correspond to those expected for Mo2O3Cl4(Bi-
py)2].
6a (97%)
b (96%)
5a: R = H
b: R = OMe
Scheme 2 Deoxygenation of azoxy derivatives 5.
In our previous study regarding the reduction of sulfox-
ides we proposed a simplified catalytic cycle involving di-
oxomolybdenum(VI) and oxomolybdenum(IV) species.15
At present we believe that the situation is somewhat more
complex and oxomolybdenum(V) species may be domi-
nant in the reduced form of the catalyst. The true catalytic
cycle is likely to approximate to that represented in
Scheme 3.
MoO2Cl2(dmf)2
PPh3
N
Mo2O3Cl4(dmf)4
These observations suggest that a large number of oxomo-
lybdenum chlorocomplexes may act as efficient catalysts
in oxo-transfer processes.
N
O
OPPh3
MoOCl2(dmf)2
In conclusion, we have demonstrated that dichlorodioxo-
molybdenum(VI) complex MoO2Cl2(dmf)2 is an excellent
catalyst for convenient deoxygenation of various types of
N-oxides using PPh3. The present procedure also shows
very good chemoselectivity and its simplicity and good
yields make it a useful addition to the existing methodol-
ogies.
Scheme 3 Representation of the catalytic cycle in the deoxy-
genation of N-oxides with PPh3.
In these processes, the initial step very probably consists
of the rapid reduction of MoO2Cl2(dmf)2 according to
Equation 1.
MoO2Cl2(dmf)2 + PPh3
MoOCl2(dmf)2 + OPPh3
Equation 1
MoO2Cl2(dmf)2
The catalyst can be prepared as previously reported21 or more
readily as we have recently described from Na2MoO4·2H2O.15
The resulting MoOCl2(dmf)2 reacts, as it is formed, with
the remaining MoO2Cl2(dmf)2 leading to the dinuclear, m-
oxo, molybdenum(V) complex, as shown in Equation 2.
Deoxygenation of Pyridine N-Oxides 1 with PPh3 Catalyzed by
MoO2Cl2(dmf)2
To a solution of the pyridine N-oxide (3 mmol) and PPh3 (812 mg,
3.1 mmol) in analytical grade THF (5 mL), MoO2Cl2(dmf)2 (10.3
Synlett 2005, No. 9, 1389–1392 © Thieme Stuttgart · New York

1392
R. Sanz et al.
LETTER
mg, 0,03 mmol) was added, and the resulting solution was stirred at
reflux. The completion of the reduction was monitored by GC-MS
or 1H NMR spectroscopy. For compounds 1a–f, 1n, and 1o, the re-
action mixture was purified by distillation under reduced pressure
to give the pure pyridines. 4-Nitropyridine (2k) was purified by col-
umn chromatography. On the other hand, for 1g–j, 1l, and 1m, the
reaction mixture was treated with EtOAc (5 mL) and extracted with
HCl (1 M) (2 × 10 mL). The aqueous layers were neutralized with
NaOH and extracted with Et2O (3 × 10 mL). The organic extracts
were dried over Na2SO4 and the solvent evaporated under reduced
pressure to give the pure pyridines.
(10) For recent reports, see for instance: (a) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M. M. Tetrahedron Lett. 2000, 41, 2663.
(b) Nicolaou, K. C.; Koumbis, A. E.; Snyder, S. A.;
Simonsen, K. B. Angew. Chem. Int. Ed. 2000, 39, 2529.
(c) Chandrashekar, S.; Reddy, C. R.; Rao, R. J.; Rao, J. M.
Synlett 2002, 349.
(11) PPh3 only deoxygenates pyridine N-oxides at temperatures
over 250 °C.2b
(12) Wang, Y.; Espenson, J. H. Org. Lett. 2000, 2, 3525.
(13) (a) Arnáiz, F. J.; Aguado, R.; Pedrosa, M. R.; de Cian, R.;
Fischer, J. Polyhedron 2000, 19, 2141. (b) Arnáiz, F. J.;
Aguado, R.; Pedrosa, M. R.; Mahía, J.; Maestro, M. A.
Polyhedron 2001, 20, 2781. (c) Arnáiz, F. J.; Aguado, R.;
Pedrosa, M. R.; de Cian, R. Inorg. Chim. Acta 2003, 347, 33.
(14) Sanz, R.; Aguado, R.; Pedrosa, M. R.; Arnáiz, F. J. Synthesis
2002, 856.
(15) Sanz, R.; Escribano, J.; Aguado, R.; Pedrosa, M. R.; Arnáiz,
F. J. Synthesis 2004, 1629.
(16) Aromatic N-oxides were commercially available or prepared
by treatment of the corresponding pyridine with H2O2–
AcOH: Taylor, E. C. Jr.; Crovetti, A. J. Org. Synth. Coll.
Vol. IV; Wiley: New York, 1963, 654.
Acknowledgment
We thank the Ministerio de Educación y Ciencia and FEDER
(BQU2001-1079 and BQU2002-00435) and Junta de Castilla y
León (BU-24/02 and BU-15/03) for financial support. J. Escribano
thanks Junta de Castilla y León for a fellowship.
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Synlett 2005, No. 9, 1389–1392 © Thieme Stuttgart · New York