Oxidation of N,N-disubstituted hydroxylamines to nitrones with hydrogen peroxide catalyzed by polymer-supported methylrhenium trioxide systems

Article abstract of DOI:10.1002/adsc.200303223

Poly(4-vinylpyridine)/methylrhenium trioxide (MTO) compounds I-III and microencapsulated polystyrene/MTO systems IV-V are efficient catalysts for the oxidation of secondary hydroxylamines to the corresponding nitrones with H ₂O₂. Com

Full text of DOI:10.1002/adsc.200303223

FULL PAPERS
Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones with
Hydrogen Peroxide Catalyzed by Polymer-Supported
Methylrhenium Trioxide Systems
a,
a
b
b,
Raffaele Saladino, * Veronica Neri, Francesca Cardona, Andrea Goti *
a
Dipartimento di Agrobiologia ed Agrochimica and INFM, Universit a¡ della Tuscia, Via S. Camillo de Lellis s.n.c.,
01100 Viterbo, Italy
Fax: (þ39)-761-357242, e-mail: saladino@unitus.it
b
Dipartimento di Chimica Organica ™Ugo Schiff∫, Universit a¡ di Firenze, via della Lastruccia 13, associated with
ICCOM-CNR, 50019 Sesto Fiorentino (FI), Italy
Fax: (þ39)-55-4573531, e-mail: andrea.goti@unifi.it
Received: December 4, 2003; Accepted: March 22, 2004
Abstract: Poly(4-vinylpyridine)/methylrhenium triox- nitrones applied in the synthesis of alkaloids and bio-
ide (MTO) compounds IÀIII and microencapsulated logically active congeners, have been considered as
polystyrene/MTO systems IVÀV are efficient cata- substrates. The heterogeneous catalysts are stable un-
lysts for the oxidation of secondary hydroxylamines der the reaction conditions and can be recovered and
to the corresponding nitrones with H O . Complete recycled for at least five times without any apprecia-
2
2
conversions of substrates and quantitative yields of ble loss in efficiency.
products are obtained under environmentally friendly
experimental conditions and with the use of simple
work-up procedures. Symmetrically substituted hy- Keywords: green chemistry; hydrogen peroxide;
droxylamines, and non-symmetrical 3-substituted methylrhenium trioxide; nitrones; oxidation; support-
and 2-substituted hydroxypyrrolidines, precursors of ed catalysts
Introduction
(copper, lead, silver) or complex organic oxidants (oxa-
ziridines and quinones), are available for this transfor-
Nitrones are very useful building blocks for the synthesis mation, they are not satisfactory, since they have to be
of biologically active nitrogen-containing compounds. used at least in stoichiometric amounts and often lack
[
4,7]
They have been widely employed either as 1,3-dipoles in generality.
Oxidations of hydroxylamines cata-
[
1]
[8]
in [3þ2] cycloaddition reactions with alkenes or as lyzed by palladium, tetrapropylammonium perruthen-
[
9]
[10]
electrophilic acceptors towards organometallic re- ate or Jacobsen (salen)Mn(III) catalyst have been
[2]
agents. In addition, nitrones are widely used as spin found to be effective. These catalytic procedures cer-
[
3]
trap reagents in biological systems.
tainly have many advantages (use of inexpensive and
Nitrones can be synthesized by a variety of methods, less dangerous stoichiometric oxidants, if any, and sim-
among which the two most general consist in the con- ple work-up procedures), but low yields for water-solu-
densation of N-monosubstituted hydroxylamines with ble nitrones and low regioselectivities with non-sym-
carbonyl compounds and in the oxidation of suitable metrically substituted dialkylhydroxylamines have
[4]
precursors. In this latter case, N,N-disubstituted hy- been reported.
droxylamines or secondary amines have been used as Methylrhenium trioxide (CH ReO , MTO),
[11]
in
3
3
the starting materials. Procedures employing the latter combination with hydrogen peroxide, has become in re-
substrates, generally readily available, are usually cent years an important catalyst for a variety of synthetic
[
12]
more useful, particularly the catalytic ones developed transformations, such as oxidation of olefins,
al-
[
5]
[13]
[14]
[15]
by Murahashi and others. However, some of us have kynes, aromatic derivatives, sulfur compounds,
[
16]
[17]
recently accessed a variety of enantiopure five-mem- phosphines,
bered cyclic nitrones by oxidation of the corresponding oxygen insertion into CÀH bonds.
hydroxylamines. In this particular case, N-hydroxypyr- been recently applied to the oxidation of nitrogen con-
Bayer±Villiger rearrangement,
and
[
18]
MTO has also
[6]
[
5f±i,19]
rolidines are much better precursors and more easily taining organic compounds.
We first reported the
available substrates than the corresponding amines. Al- oxidation of secondary amines to nitrones, replacing hy-
[5f]
though several oxidants, such as metal salts or oxides drogen peroxide with the complex urea-H O (UHP),
2
2
Adv. Synth. Catal. 2004, 346, 639±647
DOI: 10.1002/adsc.200303223
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
639

FULL PAPERS
Raffaele Saladino et al.
which simplifies the work-up procedures and allows the
use of non-aqueous solvents and safe reagents. This
[
5g]
methodology has been scaled-up and optimized and
has already found application for the synthesis of cyclic
[20]
nitrones. Others have independently reported the ox-
idation of secondary amines to nitrones employing the
[
5h, i]
MTO/H O system.
The results reported in the liter-
2
2
ature suggest that hydroxylamines are the intermediates
in the MTO-catalyzed oxidations of secondary amines
to nitrones, since the use of 1 equivalent of H O with re-
2
2
spect to the amine gave the hydroxylamine as the main
product, while the use of an excess of H O led to nitro-
2
2
[
19b]
nes predominantly.
ed hydroxylamines to nitrones with H O catalyzed by
MTO has been subsequently studied concerning its ki-
netic and mechanistic aspects.
The oxidation of N,N-disubstitut-
Figure 1. Structures of poly(4-vinylpyridine)/MTO and poly-
styrene/MTO catalysts I±V.
2
2
[
21]
Recently, with the aim of developing clean oxidation Results and Discussion
processes, we described the preparation of novel heter-
ogeneous rhenium compounds of the general formula The oxidation of hydroxylamines with poly(4-vinylpyri-
(
polymer) /(MTO) (the f/g quotient expresses the ratio dine)/MTO systems IÀIII, and microencapsulated poly-
f
g
by weight of the two components) by heterogenization styrene/MTO systems IVand V were studied using N,N-
[
22]
of MTO on poly(4-vinylpyridine) or polystyrene, ap- diethylhydroxylamine (1), N,N-dibenzylhydroxylamine
[
23]
plying an extension of the ™mediator∫ concept, and (3), N-hydroxypyrrolidine (5), and 3,4-isopropylidene-
[
24]
of the microencapsulation technique,
respectively. dioxy-N-hydroxypyrrolidine (7) as representative mod-
All the new MTO compounds were characterized by el compounds of symmetrically substituted acyclic and
FT-IR, scanning electron microscopy (SEM), and cyclic hydroxylamines (Schemes 1±4). As a general pro-
[
22]
wide-angle X-ray diffraction (WAXS). To the best cedure, the hydroxylamine (1.0 mmol) to be oxidized
of our knowledge, apart from silica supported MTO and H O (35% water solution) were added to a suspen-
2
2
[
25]
complexes,
the NaY zeolite/MTO supercage sys- sion of freshly prepared catalysts IÀV (loading factor
[
26]
[27]
tem, and a niobia supported MTO compound, no 0.5) in EtOH (1.0 mL), and the mixture was stirred at
further data are available in the literature about hetero- 258C. The oxidation results are summarized in Ta-
geneous MTO catalysts. Polymer/MTO catalysts have bles 1±4, entries 2±6 of each Table. For comparison,
already proved to be efficient and selective systems for the reactions with MTO under homogeneous conditions
[
22]
the epoxidation of simple olefins, and for the oxida- were carried out and their results are reported in en-
[
28]
tion of substituted phenol and anisole derivatives.
tries 1. In the absence of the catalyst, less than 5% con-
In this paper we report on the applicability of poly- version of substrate took place under otherwise identi-
mer/MTO systems to the selective oxidation of a series cal conditions. Under the appropriate experimental con-
of hydroxylamines with H O , including simple acyclic ditions, all of the catalysts were effective in accomplish-
2
2
hydroxylamines and N-hydroxypyrrolidines, to the cor- ing the oxidation of hydroxylamine 1 to the correspond-
responding nitrones. Among the latter substrates, pro- ing nitrone 2 with complete conversion of substrate and
tected hydroxylated N-hydroxypyrrolidines and enan- quantitative yield of product (Table 1). The efficient ox-
tiomerically pure hydroxypyrrolidines, precursors of ni- idation of 1, under relatively mild experimental condi-
trones applied in the synthesis of alkaloids and biologi- tions, may be attributed to the retained reactivity of
cally active congeners, have been considered. The issue the monoperoxometal [MeRe(O) (O )] and the bisper-
2
2
[29]
of regioselectivity, relevant for synthetic purposes, has oxometal [MeRe(O)(O ) ] intermediate species even
2
2
also been addressed, either with 3-substituted and 2-sub- in the presence of the polymeric supports. On the other
stituted hydroxypyrrolidines. The structures of poly(4- hand, heterogeneous MTO systems showed a lower re-
vinylpyridine)/MTO and polystyrene/MTO catalysts activity with respect to MTO, probably because of the
I±V employed, namely poly(4-vinylpyridine) 2% and presence of a kinetic barrier to the approach of hydrox-
2
2
5% cross-linked (with divinylbenzene)/MTO (PVP- ylamine 1 to polymeric catalysts (Table 1, entries 2±4 vs.
%/MTO, I and PVP-25%/MTO, II, respectively), 1). Among the poly(4-vinylpyridine)/MTO systems I±
poly(4-vinylpyridine-N-oxide) 2% cross-linked/MTO III, compound II, characterized by a high value of retic-
PVPN-2%/MTO, III), microencapsulated polystyrene ulation grade of the matrix, was the best catalyst, giving
% cross-linked/MTO (PS-2%/MTO, IV), and micro- the nitrone 2 faster than compounds I and III (Table 1,
(
2
encapsulated polystyrene/poly(4-vinylpyridine) 2% entries 3 vs. 2 and 4). These data are in agreement with
cross-linked/MTO (PS-2%/PVP-2%/MTO, V), are our results on the selective epoxidation of olefins with
[22]
schematically represented in Figure 1.
polymer-supported methylrhenium trioxide systems.
640
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2004, 346, 639±647

Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones
FULL PAPERS
Compound III, which is characterized by a pyridine N- ported. Microencapsulated polystyrene/MTO systems
oxide moiety as anchorage site for the rhenium atom IVand V were the most reactive catalysts also for the ox-
showed the lowest reactivity, and more oxidant was re- idation of hydroxylamine 3 (Table 2, entries 5 and 6).
quired to complete the oxidation (Table 1, entry 4). Mi- Again, compound II was the best catalyst in the
croencapsulated polystyrene/MTO systems IV and V poly(4-vinylpyridine)/MTO series (Table 2, entry 3 vs.
were the most active catalysts among the heterogeneous 2 and 4).
compounds used (Table 1, entries 5 and 6).
Cyclic hydroxylamines 5 and 7 behaved in a similar
A quantitative conversion of substrate, and excellent way and were efficiently oxidized to give the corre-
yield of nitrone, was also obtained in the oxidation of sponding nitrones 6 and 8 with high conversions and
N,N-dibenzylhydroxylamine (3) either with MTO and quantitative yields (>98% for all of the cases studied,
compounds I±V (Table 2, Scheme 2). As shown in Ta- Tables 3 and 4, Schemes 3 and 4). Again, microencapsu-
ble 2, hydroxylamine 3 was less reactive than 1 under lated polystyrene/MTO systems IVand V were more re-
similar experimental conditions (compare reaction active than catalysts based on poly(4-vinylpyridine).
times for 1 and 3 in Tables 1 and 2). This reactivity pat- Even if we have not studied in detail the mechanism of
tern is in good agreement with the kinetic trends previ- the reaction, data previously collected on the oxidation
ously described for the oxidation of hydroxylamines of cardanol derivatives showed a significant difference
with MTO, in which cases steric effects play a relevant in reactivity, depending on the nature of the matrix
[
21]
[28b]
role on the rate constants of the oxidation. However, used for the heterogenization process of MTO.
it should be noted that an opposite trend is shown by the Thus, while poly(4-vinylpyridine)/MTO systems gave
reaction carried out under homogeneous conditions; selectively ortho- and para-benzoquinones, microen-
this result is not consistent with the data previously re- capsulated polystyrene/MTO catalysts showed a pro-
Scheme 1.
Scheme 2.
Table 1. Oxidation of N,N-diethylhydroxylamine (1) with poly(4-vinylpyridine)/MTO systems IÀIII, and microencapsulated
polystyrene/MTO systems IV and V.
[a]
[a]
Entry
Catalyst
H O (equivs.)
Solvent
Conversion (%)
Yield (%)
Reaction time
2
2
[
b]
1
2
3
4
5
6
MTO 2%
1.5
2.0
2.0
5.0
1.5
1.5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
45 min
7 h
4 h
9 h
2 h
PVP-2%/MTO (I)
PVP-25%/MTO (II)
PVPN-2%/MTO (III)
PS-2%/MTO (IV)
PS-2%/PVPy-2%/MTO (V)
2 h
[
[
a]
b]
1
Calculated by integration of the H NMR of the crude mixture.
1
0% molar amount of pyridine added.
Table 2. Oxidation of N,N-dibenzylhydroxylamine (3) with poly(4-vinylpyridine)/MTO systems IÀIII, and microencapsulated
polystyrene/MTO systems IV and V.
[a]
[b]
Entry
Catalyst
H O (equivs.)
Solvent
Conversion (%)
Yield (%)
Reaction time
2
2
[
b]
1
2
3
4
5
6
MTO 2%
1.5
4.0
3.0
4.0
1.5
1.5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
>98
>98
>98
>98
>98
>98
93
>98
>98
>98
>98
>98
15 min
10 h
6 h
12 h
3 h
PVP-2%/MTO (I)
PVP-25%/MTO (II)
PVPN-2%/MTO (III)
PS-2%/MTO (IV)
PS-2%/PVPy-2%/MTO (V)
5 h
[
[
a]
b]
1
Calculated by integration of the H NMR of the crude mixture.
1
0% molar amount of pyridine added.
Adv. Synth. Catal. 2004, 346, 639±647
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Raffaele Saladino et al.
nounced reactivity affording an unprecedented g-lac- trixes. In the tests for recyclability of the catalyst, the re-
tone, a product of oxidative aromatic ring degradation action mixture was filtered after the hydroxylamine 1
[
28b]
and subsequent rearrangement.
had completely oxidized. The remaining solid was wash-
Some experiments were then performed to evaluate ed with EtOH, dried and used in successive oxidations of
the leaching and stability of the catalysts, using com- the same substrate. Table 5 shows that catalysts II and
pounds II and IVas representative models. In a test for IV are stable enough to perform at least five recycling
checking the leaching of II and IV, the oxidation of hy- experiments maintaining essentially the same efficiency
droxylamine 1 was stopped at ca. 50% conversion. After in terms of conversion and selectivity.
centrifugation, the obtained solutions were colorless
Next, we addressed the issue of regioselectivity with
and lost their catalytic activity, indicating that no appre- the oxidation of non symmetric hydroxylamines. Al-
ciable amount of MTO had been removed from the ma- though in some cases good selectivities have been ob-
[
6b,d,30]
served,
regioselective oxidation of non-symmetri-
cal hydroxylamines (or secondary amines) still remains
a problem which needs a general solution. A tricky re-
gioselective formation of nitrones has been reported
by means of a decarboxylative oxidation of a-amino
[
31]
acids. N-Hydroxypyrrolidines 9 and 12, possessing a
substituent at C-3 and C-2, respectively, were consid-
ered and were reacted under similar experimental con-
ditions (Tables 6 and 7, Schemes 5 and 6). Non-symmet-
rical hydroxylamines gave rise to a couple of isomeric ni-
trones, since the elimination reaction can involve the ab-
straction of hydrogen at either the a or the a× carbon
atom. The ratios of the two nitrones were determined
Scheme 3.
1
by H NMR and are reported in Tables 6 and 7.
The oxidation of the protected 3-hydroxypyrrolidine 9
with catalysts I±Vunder the previouslydescribedexper-
imental conditions gave a mixture of nitrones 10 and 11
with quantitative conversion of substrate and yield of
products (Scheme 5, Table 6). On the basis of the results
Scheme 4.
Table 3. Oxidation of N-hydroxypyrrolidine (5) with poly(4-vinylpyridine)/MTO systems IÀIII, and microencapsulated poly-
styrene/MTO systems IV and V.
[a]
[a]
Entry
Catalyst
H O (equivs.)
Solvent
Conversion (%)
Yield (%)
Reaction time
2
2
[
b]
1
2
3
4
5
6
MTO 2%
1.5
5.0
2.0
6.0
2.0
2.0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
10 min
11 h
8 h
14 h
6 h
PVP-2%/MTO (I)
PVP-25%/MTO (II)
PVPN-2%/MTO (III)
PS-2%/MTO (IV)
PS-2%/PVPy-2%/MTO (V)
6 h
[
[
a]
b]
1
Calculated by integration of the H NMR of the crude mixture.
1
0% molar amount of pyridine added.
Table 4. Oxidation of 3,4-isopropylidenedioxy-N-hydroxypyrrolidine (7) with poly(4-vinylpyridine)/MTO systems IÀIII, and
microencapsulated polystyrene/MTO systems IV and V.
[a]
[a]
Entry
Catalyst
H O (equivs.)
Solvent
Conversion (%)
Yield (%)
Reaction Time
2
2
[
b]
1
2
3
4
5
6
MTO 2%
1.5
9.0
2.0
9.0
1.0
3.0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
15 min
22 h
4 h
21 h
1.5 h
3 h
PVP-2%/MTO (I)
PVP-25%/MTO (II)
PVPN-2%/MTO (III)
PS-2%/MTO (IV)
PS-2%/PVPy-2%/MTO (V)
[
[
a]
b]
1
Calculated by integration of the H NMR of the crude mixture.
1
0% molar amount of pyridine added.
642
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones
FULL PAPERS
Table 5. Stability of polymer-supported MTO catalysts II and IV in the oxidation of hydroxylamine 1.
[a]
[b]
Catalyst
Conversion (%)
Run No. 1
Run No. 2
Run No. 3
Run No. 4
Run No. 5
[a]
II
IV
>98 (>98)
>98 (>98)
>98 (>98)
>98 (>98)
>98 (95)
>98 (>98)
>98 (97)
>98 (96)
>98 (97)
>98 (>98)
[
[
a]
b]
Catalyst: PVP-25%/MTO, II, PS-2%/MTO, IV.
Values of nitrone 2 yields are given in parentheses. Reaction time: 4 h for II, 2 h for IV.
Table 6. Oxidation of 3(S)-tert-butoxy-N-hydroxypyrrolidine (9) with poly(4-vinylpyridine)/MTO systems IÀIII, and microen-
capsulated polystyrene/MTO systems IV and V.
Entry
Catalyst
H O
Solvent
Conversion
(%)
Yield
(%)
10:11
[a]
Reaction
time
2
2
[a]
[a]
(
equivs.)
Ratio
[
b]
1
2
3
4
5
6
MTO 2%
1.5
1.5
2.0
1.5
3.0
1.5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
1.40
1.77
2.57
2.45
1.50
1.77
20 min
8 h
9 h
7 h
11 h
8 h
PVP-2%/MTO (I)
PVP-25%/MTO (II)
PVPN-2%/MTO (III)
PS-2%/MTO (IV)
PS-2%/PVPy-2%/MTO (V)
[
[
a]
b]
1
Calculated by integration of the H NMR of the crude mixture.
1
0% molar amount of pyridine added.
reported in Table 6, all catalysts I±V were found to be thesis of nitrone 10 concerning the selectivity of the ox-
more selective than MTO, giving the nitrone 10 in higher idation (Table 6, entry 3). It is interesting to note that in
yields (entries 2±6 vs. 1). The observed regioselectivity this case microencapsulated polystyrene/MTO systems
is in qualitative agreement, albeit poorer, with that ob- and poly(4-vinylpyridine)/MTO compounds showed a
tained in the stoichiometric oxidation of 9 with HgO, similar reactivity.
in which case the electronegative substituent at C-3 en-
hanced the rate of the adjacent CÀH bond cleavage by the more electron-rich 2-methyl-N-hydroxypyrrolidine
stabilizing the incipient negative charge at C-2. (12) showed with all catalysts a higher reactivity with re-
As expected for reagents with electrophilic properties,
[
6b, d]
Compound II was the best catalyst system for the syn- spect to all the previous substrates (Table 7, Scheme 6).
However, the difference in reactivity for the heterogen-
Scheme 5.
Scheme 6.
Table 7. Oxidation of 2-methyl-N-hydroxypyrrolidine (12) with poly(4-vinylpyridine)/MTO systems IÀIII, and microencapsu-
lated polystyrene/MTO systems IV and V.
Entry
Catalyst
H O
Solvent
Conversion
(%)
Yield
(%)
13:14
[a]
Reaction
time
2
2
[a]
[a]
(
equivs.)
Ratio
[
b]
1
2
3
4
5
6
MTO 2%
1.5
1.0
1.0
1.0
2.0
1.0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
>98
>98
>98
>98
>98
>98
46
>98
>98
>98
>98
>98
1.6
<15 min
10 min
5 min
15 min
10 min
10 min
PVP-2%/MTO (I)
1.4
2.0
2.2
PVP-25%/MTO (II)
PVPN-2%/MTO (III)
PS-2%/MTO (IV)
>98
PS-2%/PVPy-2%/MTO (V)
4
[
[
a]
b]
1
Calculated by integration of the H NMR of the crude mixture.
0
% molar amount of pyridine added.
Adv. Synth. Catal. 2004, 346, 639±647
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
643

FULL PAPERS
Raffaele Saladino et al.
ized catalysts is striking and the observed reaction times with these data it is reasonable to suggest that the coor-
must be considered abnormal for reactions occurring dination of the rhenium atom by pyridine ligands in
under heterogeneous conditions. In this case, MTO poly(4-vinylpyridine)/MTO compounds partially de-
and polymer-supported MTO systems showed a similar creases the reactivity of the peroxorhenium intermedi-
behavior giving a quantitative conversion of substrate ate toward hydroxylamines, even if the possibility of a
with a reaction time that ranged from 5 min (PVP- concentration process of the substrates inside the low
2
5%/MTO, Table 7, entry 3) to 15 min (PVPN-2%/ polar microenvironment of polystyrene microcapsules
MTO, Table 7, entry 4). The more stable keto nitrone cannot be completely ruled out. From the practical point
3 was obtained as the major product, prevailing over of view, all the supported catalysts perform well and are
1
its aldonitrone isomer 14 in all oxidations. This behavior equally simple in use. However, on the basis of the re-
is in agreement with results obtained with different oxi- ported experimental results, the polystyrene/MTO sys-
dants.[7,30] It must be stressed that a remarkably high tem is to be preferred for the shorter reaction times. In
selectivity, compared to the other catalysts used, was ob- the case of 3-substituted and 2-substituted N-hydroxy-
tained in the case of microencapsulated PS-2%/MTO. In pyrrolidines, oxidation at C-2 prevailed, to afford the
this case, nitrone 13 was the only recovered product (Ta- a-substituted nitrone and the most stable ketonitrone,
ble 7, entry 5), which result is unprecedented and paves respectively, as the major products, although the selec-
the way to a possible selective access to ketonitrones tivity is generally poor. However, the completely selec-
from the corresponding 2-substituted cyclic hydroxyla- tive ketonitrone formation from 2-methyl-N-hydroxy-
mines.
pyrrolidine in the presence of the microencapsulated
polystyrene system IV is particularly remarkable from
the synthetic point of view. It constitutes one more,
strong reason for choosing the polystyrene resin in the
oxidation of a-substituted hydroxylamines. Polymer-
Conclusion
Poly(4-vinylpyridine)/MTO compounds IÀIII and mi- supported MTO compounds, which can be easily recov-
croencapsulated polystyrene/MTO systems IV and V ered by filtration from the reaction mixture and used for
were efficient and selective catalysts for the oxidation successive transformations, confirm their high versatili-
of N,N-disubstituted hydroxylamines to the correspond- ty and broaden their use as catalysts for the oxidation of
ing nitrones, affording quantitative conversion of sub- organic compounds.
strates and yield of products, under environmental
friendly conditions and employing simple work-up pro-
cedures. It is worth noting that these oxidations occur at
room temperature in ethanol, thus avoiding the use of
Experimental Section
chlorinated organic solvents or of glacial acetic acid of-
ten used in MTO-catalyzed oxidations. Symmetrically General Remarks
substituted hydroxylamines, and non-symmetrical 3-
substituted and 2-substituted N-hydroxypyrrolidines,
precursors of nitrones applied in the synthesis of alka-
N,N-Diethylhydroxylamine (1), N,N-dibenzylhydroxylamine
(
3), 35% hydrogen peroxide, methylrhenium trioxide, poly(4-
vinylpyridine) 2% and 25% cross-linked with divinylbenzene,
loids and biologically active congeners, have been con- polystyrene 2% cross-linked with divinylbenzene, and analyti-
sidered. Presumably, the high catalyst activity observed cal reagent grade organic solvents were purchased (Aldrich)
and used without any further purification. N-Hydroxypyrroli-
for all the heterogeneous MTO systems is to be ascribed
to the formation of the known MTO peroxo intermedi-
ates [MeRe(O) (O )] and [MeRe(O)(O ) ] even in the
[32]
dine (5),
3,4-isopropylidenedioxy-N-hydroxypyrrolidine
[6e]
[6d]
(
7),
3(S)-tert-butoxy-N-hydroxypyrrolidine (9),
and 2-
2
2
2
2
[30a]
methyl-N-hydroxypyrrolidine (12)
were prepared accord-
presence of the polymeric support. Irrespective from
the catalyst used in the oxidation, values of the loading
factor of the catalyst higher than 0.5 did not give an ap-
preciable increase of the reactivity. As in the case of ole-
ing to the literature methods. NMR spectra were recorded in
1
CDCl on a Bruker spectrometer ( H, 200 MHz).
3
[22]
fin epoxidation, polymer-supported MTO systems II
and IV were stable enough to perform at least five recy-
cling experiments with similar conversion and selectivi-
ty. The reticulation grade of the polymer appears to be a
crucial variable for the reactivity of poly(4-vinylpyri-
dine)/MTO compounds. Thus, the most reticulated
PVP-25%/MTO, II, that is characterized by particles
with a regular spherical shape, was the best catalyst.
On the other hand, the microencapsulated polystyrene
derivatives IV and V were, in general, more reactive core dispersed in the medium and hexane (5 mL) was added to
Preparation of Heterogeneous MTO Catalysts
Poly(4-vinylpyridine)/MTO [PVP-2%/MTO (I), PVP-25%/
MTO (II), and PVPN-2%/MTO (III)] and polystyrene/MTO
[
PS-2%/MTO (IV), and PS/PVP-2%/MTO (V)] catalysts
[22]
were prepared as previously reported. In summary, MTO
77 mg, 0.3 mmol) was added to a suspension of the appropri-
(
ate resin (600 mg) in ethanol (4 mL), or tetrahydrofuran in
the case of polystyrene. The mixture was stirred for 1 h using
a magnetic stirrer. Coacervates were found to envelop the solid
[
22]
than poly(4-vinylpyridine)/MTO compounds. In accord harden the capsule walls. The solvent was removed by filtra-
644
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 639±647

Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones
FULL PAPERS
tion, and the solid residue was washed with ethyl acetate and
finally dried under high vacuum. In every case, MTO was com-
pletely included into the polymer. This result was confirmed by
spectroscopic analysis of the residue obtained after evapora-
tion of the organic layers. The catalysts were used without
any further purification.
135.6 (N¼CH), 62.4 (CH ), 29.0 (CH ), 19.4 (CH ); MS (EI):
2
2
2
m/z¼85.
1
Nitrone 8: H NMR: d¼6.89 (m, 1H, CH), 5.25 (d, 1H, J¼
6.3 Hz, CH), 4.86 (ddd, 1H, J¼5.7, 5.1, 1.5 Hz, CH), 3.95±
4.18 (m, 2H, CH ), 1.40 (s, 3H, CH ), 1.30 (s, 3H, CH );
2
3
3
1
3
C NMR: d¼132.6 (N¼CH), 112.1 (C), 79.8 (CH), 73.6
(
CH), 67.9 (CH ), 25.6, 27.1 (CH ); MS (EI): m/z¼157.
2
3
1
Nitrone 10: H NMR: d¼6.90 (m, 1H, CH), 4.75 (m, 1H,
CH), 4.10±3.70 (m, 2H, CH ), 2.50±2.00 (m, 2H, CH ), 1.18
2
2
1
3
(
6
s, 9H); C NMR: d¼135.6 (N¼CH), 74.5 (CH), 71.2 (C),
1.0 (CH ), 29.1 (CH ), 28.0 (CH ); MS (EI): m/z¼157.
Oxidation of Hydroxylamines; General Procedures
2
2
3
1
Homogeneous oxidation; general procedure: A 5-mL reaction
Nitrone 11: H NMR: d¼6.90 (m, 1H, CH), 4.40 (m, 1H,
flask was charged sequentially with MTO (0.01 mmol), ethanol
CH), 4.10±3.70 (m, 2H, CH ), 3.00±2.50 (m, 2H, CH ), 1.17
2
2
[33]
1
3
(
0.5 mL), pyridine (4 mL, 0.05 mmol) and H O (35% aque-
¼
2
2
(s, 9H); C NMR: d¼133.4 (N CH), 71.7 (C), 69.1 (CH ),
2
ous solution, 0.75 mmol, 73 mL). The stirred solution became
yellow due to the formation of peroxo species and, after having
been cooled to 08C with an ice bath, a solution of the hydroxyl-
amine (0.5 mmol) in ethanol (0.5 mL) was added dropwise.
The mixture was stirred at room temperature until no more
6
5.3 (CH), 38.9 (CH ), 27.7 (CH ); MS (EI): m/z¼157.
2
3
1
Nitrone 13: H NMR: d¼3.80 (m, 2H, CH ), 2.80 (m, 2H,
2
1
3
CH), 2.10 (m, 2H, CH ), 2.00 (s, 3H, CH ); C NMR: d¼
2
3
1
43.6 (N C), 60.6 (CH ), 31.4 (CH ), 15.0 (CH ), 10.8 (CH );
¼
2
2
2
3
MS (EI): m/z¼99.
1
starting material could be detected on TLC, after which H O
2
Nitrone 14: H NMR: d¼6.82 (m, 1H, CH), 4.01 (m, 1H,
CH), 2.62 (m, 2H, CH ), 1.85 (m, 2H, CH ), 1.46 (d, 3H, J¼
(
(
5 mL) was added. The mixture was extracted with AcOEt
2
2
1
3
3Â15 mL), dried over Na SO , and then concentrated, fur-
¼
2
4
7.1 Hz, CH ); C NMR: d¼142.3 (N CH), 71.86 (CH), 31.02
3
1
nishing pure nitrones by H NMR analysis. The nitrones ob-
tained from hydroxylamines 1, 5, 7 and 11 are highly soluble
in water; therefore, the mixture was directly evaporated under
reduced pressure when no more starting material could be de-
tected on TLC.
(
CH ), 27.41 (CH ), 14.38 (CH ); MS (EI): m/z¼99.
2
2
3
Acknowledgements
Heterogeneous oxidation; general procedure: To the solu-
tion/suspension of the hydroxylamine (1.0 mmol) in EtOH
MIUR (PRIN COFIN 2002 and 2003) and CNR (Agenzia 2000
Progetto Giovani) are acknowledged for financial support.
±
(
(
(
1 mL) were added the appropriate heterogeneous catalyst
23 mg, 0.01 mmol of MTO, loading factor 0.5) and H O
35% aqueous solution, amount indicated in the Tables) as pri-
2
2
mary oxidant. The mixture was stirred at room temperature
until no more starting material could be detected on TLC
References and Notes
(
see Tables). The suspension was filtered off, and the recovered
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2
4
1
13
1
2 produced two nitrones. Their ratios were determined by in-
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Characterization of Nitrones
All of the synthesized nitrones have been reported previous-
ly. Representative NMR spectroscopic data are reported be-
low.
[
34]
1
Nitrone 2: H NMR: d¼6.80 (q, 1H, J¼5.8 Hz, CH), 3.75 (q,
7
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J¼7.2 Hz, CH ); C NMR: d¼134.6 (CH), 59.8 (CH ), 13.2
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1
3
9
H, ArHþCH¼N), 5.10 (s, 2H, CH ); C NMR: d¼134.1
2
(
(
(
N¼CH), 133.3 (C), 130.5 (CH), 130.3 (CH), 131.4 (C), 129.2
CH), 128.9 (CH), 128.6 (CH), 128.4 (CH), 71.3 (CH ); MS
2
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Nitrone 6: H NMR: d¼6.90 (m, 1H, CH), 4.00 (m, 2H,
1
3
CH ), 2.75 (m, 2H, CH ), 2.25 (m, 2H, CH ); C NMR: d¼
2
2
2
Adv. Synth. Catal. 2004, 346, 639±647
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asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 639±647

Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones
cione, O. A. Attanasi, P. Filippone Pure Appl. Chem.
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Chem. 1997, 62, 3537±3541; nitrone 4: Refs.
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[6e]
[6d]
[
[
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
647