Manganese dioxide oxidation of hydroxylamines to nitrones

Article abstract of DOI:10.1016/S0040-4039(01)01222-9

Several structurally differentiated N,N-dialkylhydroxylamines were oxidised to the corresponding nitrones using MnO₂. Manganese dioxide revealed an efficient and mild reagent for oxidation of hydroxylamines, showing a level of regioselectivity

Full text of DOI:10.1016/S0040-4039(01)01222-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6503–6505
Manganese dioxide oxidation of hydroxylamines to nitrones
Stefano Cicchi,* Marco Marradi, Andrea Goti and Alberto Brandi
Dipartimento di Chimica Organica ‘Ugo Schiff’,
Universita` degli Studi di Firenze and Centro di Studio CNR sulla Chimica e la Struttura dei Composti Eterociclici e loro Applica
zioni (CSCEA), via G. Capponi 9, I-50121 Florence, Italy
Received 29 June 2001; accepted 9 July 2001
Abstract—Several structurally differentiated N,N-dialkylhydroxylamines were oxidised to the corresponding nitrones using MnO2.
Manganese dioxide revealed an efficient and mild reagent for oxidation of hydroxylamines, showing a level of regioselectivity
comparable to HgO. Its non-toxicity makes MnO2 the reagent of choice for replacing HgO in this oxidation. © 2001 Elsevier
Science Ltd. All rights reserved.
Nitrones are useful synthetic tools displaying a high
reactivity, mainly as 1,3-dipoles in cycloaddition
reactions1 or as imines in nucleophilic additions,2 that
allows the straightforward synthesis of structurally
complex molecules with a high degree of selectivity.
Condensation of a N-alkylhydroxylamine with a car-
bonyl compound and oxidation of a N,N-dialkylhy-
droxylamine are the two commonest methods for the
synthesis of nitrones (Scheme 1).3 Recently, the second
strategy was used to obtain a variety of enantiopure
five membered cyclic nitrones.4
needed to ensure complete oxidation, raises severe con-
cerns regarding its use and disposal. This issue
prompted the development of alternative methods. Var-
ious metal (copper, silver, lead and ruthenium) salts as
well as organic oxidants and (salen)Mn(III) complexes
proved useful for this oxidation.3,5 Recently, we have
reported an environmentally friendly oxidation method
with bleach;6 this method resulted valuable and general
although it suffered from low yields for water soluble
nitrones and low regioselectivity with non-symmetri-
cally substituted dialkylhydroxylamines. In this com-
munication we propose MnO2 as a valid non-toxic
substitute of HgO for the oxidation of N,N-dialkylhy-
droxylamines. Manganese(IV) oxide is a well known
oxidant for the dehydrogenation of activated alcohols
and amines, as well as for the oxidative cleavage of
1,2-diols and has found broad application due to the
mildness of the reagent.7 A perusal of the literature
showed that MnO2 was used only occasionally for the
oxidation of hydroxylamines with peculiar structures to
the corresponding nitrones,8 and has never reached the
reputation of a first choice reagent for this reaction.
Many methods have been employed for the oxidation
of N,N-dialkylhydroxylamines into the corresponding
nitrones. However, many of them lack generality and
the most widely used oxidant for this transformation is
yellow HgO.3 Mercury oxide has proven a mild and
selective oxidant for this class of compounds, but its
high toxicity together with the large excess that is
O
R’
R
R’’
R’
R’’
2
R NH
OH
+
N
3
-
The oxidation of several structurally differentiated
hydroxylamines with commercial MnO2 (‘activated’,
90% purity, Fluka catalogue no. 63548) gave nitrones in
good to excellent yield (Table 1).
-H2O
O
1
[Ox]
R
N
R
R
N
R
+
4
-
5
OH
O
Open-chain hydroxylamines 6–9 afforded the more sta-
ble Z stereoisomers in over 90% yield, with 8 and 9 the
oxidation took place only on the more reactive benzylic
position. Substituted N-hydroxypyrrolidines, either at
C-2 and C-3, allowed the evaluation of the regioselec-
tivity of the reaction. Hydroxylamine 10 afforded a
Scheme 1.
Keywords: nitrones; hydroxylamines; manganese dioxide; oxidation;
green chemistry.
* Corresponding author. E-mail: stefano.cicchi@unifi.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01222-9

6504
S. Cicchi et al. / Tetrahedron Letters 42 (2001) 6503–6505
Table 1. Oxidations of hydroxylamines with MnO2
Nitrones
Yield (%)
Entry
Hydroxylamines10
N
Reaction
time (h)
N
+
1
2
2
2
90
93
-
O
OH
6
14
Ph
N
O
Ph
Ph
N
Ph
7
+
-
OH
15
Ph
Ph
-
O
HO
+
N
N
3
96
12
O
O
O
O
O
O
O
8
16
O
O
O
O
O
O
O
O
O
-
12
2
96
92
4
N
N
+
HO
O
9
Ph
Ph
17
5
6
N
O
N
N
+
-
+
-
10
19
18
O
OH
5 : 1
Ot-Bu
Ot-Bu
Ot-Bu
2
2
2
11
N
O
N
+
-
N
O
+
-
85
95
7 : 1
OBn
22
20
21
OH
BnO
BnO
OBn
7
12
N
O
+
-
N
OH
O
O
O
O
91
8
13
23
N
N
O
+
-
OH
mixture of the two regioisomeric nitrones 18 and 19 in
5:1 ratio showing a higher selectivity with respect to
HgO (3:1)9 and bleach (2:1).6 Conversely the selectivity
is slightly lower, compared to HgO, in the oxidation of
hydroxylamine 11 (7:1 versus 9:1),4d but still much
higher than with bleach. This selectivity suggests a
common mechanism for MnO2 and HgO in the oxida-
tion of hydroxylamines.4b,d Other commercially avail-
able types of MnO2 were tested in the oxidation. Pure
MnO2 (99%, Riedel de Haen) was found to be a poor
oxidant for hydroxylamines, as already reported for
other substrates,7a while 75% MnO2 (Aldrich) gave in
the oxidation of 10 a similar yield but a lower selectiv-
ity (3.5:1).
tion of the hydroxylamine10 (1–5 mmol) in CH2Cl2 (0.5
M). The resulting dispersion was stirred at rt for the
appropriate time (Table 1) then filtered (gravity)
through a short pad of Celite and Na2SO4. The result-
ing solution was concentrated to afford spectroscopi-
cally pure compounds.
These results show that MnO2 is a suitable and general
oxidant for hydroxylamines, able to give the corre-
sponding nitrones in good to excellent yields. This
reagent allows therefore the replacement of HgO, thus
providing a less hazardous method.11
Acknowledgements
General procedure: All reactions were performed using a
small excess (1.5 equiv.) of commercially available ‘acti-
vated’ MnO2 (90% purity) added to an ice-cooled solu-
We thank MURST-Cofin-2000 for financial support.

S. Cicchi et al. / Tetrahedron Letters 42 (2001) 6503–6505
6505
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