TPAP/NMO system as a novel method for the synthesis of nitronyl nitroxide radicals

Article abstract of DOI:10.1055/s-2006-939045

An easy oxidation of dihydroxyimidazolidine derivatives to nitronyl nitroxide radicals (NNRs) can be achieved using the tetra-N-propylamonium perruthenate/N-methylmorpholine N-oxide (TPAP/NMO) system. The procedure offers several advantages in terms of si

Full text of DOI:10.1055/s-2006-939045

948
LETTER
TPAP/NMO System as a Novel Method for the Synthesis of Nitronyl Nitroxide
Radicals
Synthesis of
N
it
a
ronyl Nitro
p
xide
R
adica
o
ls Gorini,*a Andrea Caneschi,a Stefano Menichettib
a
Laboratory of Molecular Magnetism, INSTM Unit, Dipartimento di Chimica, Università di Firenze,
Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
Fax +39(055)4573531; E-mail: lapo.gorini@unifi.it
b
Dipartimento di Chimica Organica, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Received 16 January 2006
metric amounts. Costs of the oxidizing species and forma-
tion of overoxidized by-products are among the other
problems to face for NNR synthesis.
Abstract: An easy oxidation of dihydroxyimidazolidine deriva-
tives to nitronyl nitroxide radicals (NNRs) can be achieved using
the tetra-N-propylamonium perruthenate/N-methylmorpholine N-
oxide (TPAP/NMO) system. The procedure offers several advan-
tages in terms of simplicity, yield, cost and ‘green’ chemistry.
TPAP/NMO is a well-known oxidizing system working
with catalytic amount of the actual oxidant Ru(VII) spe-
cies, continuously regenerated by a stoichiometric amount
of NMO. The reaction can be easily accomplished in or-
ganic solvents like CH2Cl2 or AcCN and it has been suc-
cessfully utilized for the oxidation of alcohol to carbonyl
compounds11 as well as for the synthesis of imines and ni-
trones from secondary amines12 and hydroxylamines,13 re-
spectively.
Key words: radicals, oxidations, nitronyl nitroxide, green chemis-
try, TPAP/NMO
Since the end of the 20th century, purely organic com-
pounds have been investigated as electrical conductors
and superconductors.1 In this field several efforts were
dedicated to the preparation of organic magnets. From
their first preparation in 1968,2 nitronyl nitroxide radicals
(NNRs, Figure 1) had a vigorous expansion starting from
the nineties3 in the field of physics, chemistry and nano-
technology and found application for the study of surfaces
properties,4 the development of organic magnets5 and the
achievement of single-chain magnets.6
In this light, we decided to verify whether TPAP/NMO
could be exploited for the preparation of NNR starting
from dihydroxyimidazolidines.
To our satisfaction, the reaction of compound 1a [pre-
pared from the corresponding aromatic aldehyde and 2,3-
di(hydroxyamino)-2,3-dimethylbutane]2 with 5% TPAP
and one equivalent of NMO, in CH2Cl2 at room tempera-
ture for three hours, allowed the isolation of NNR 2a as a
blue solid in 81% yield (Scheme 1, Table 1).14
N
N
O
O
To verify the generality and applicability of this new pro-
cedure, we prepared dihydroxyimidazolidines 1a–k,
which were reacted with TPAP/NMO under the above re-
ported conditions to obtain NNRs as summarized in
Table 1. The reaction allowed the preparation of electron-
poor (entries 1–3) and electron-rich aromatic (entries 4–
6), heteroaromatic (entry 11) as well as aliphatic (entry
10) NNRs that were isolated as deep colored powders
(blue for 2a,c–i, green for 2b, red-purple for 2j and purple
in the case of 2k). Yields are usually good and in any case
comparable to those previously reported.2,7–10 Moreover,
due to the short reaction time required to complete the
transformation and the mild reaction conditions required,
no formation of overoxidized by-products was ever de-
tected.
NO2
Figure 1 First example of nitronyl nitroxide radical used as mole-
cular magnet
Classical methods available for the preparation of NNRs
foresee the controlled oxidation of a suitable dihydroxy-
imidazolidine precursor. However, several of these proce-
dures suffer of a number of drawbacks; for example the
general use of NaIO4 often requires the use of an excess of
oxidizing agent and to carry out the reaction in a two-
phase system, a condition obviously unsuitable for water-
sensitive organic compounds.2 In addition, NNRs can be
prepared using toxic species like SeO2,7 or harmful and
pollutant compounds like PbO2,8,2a,c MnO2,9,2c AgO2,10 as
oxidants in stoichiometric or, sometimes, in overstoichio-
TPAP/NMO
N
N
N
N
O
OH
O
HO
CH2Cl2, r.t., 1–12 h, 44–90%
R
R
1a–k
2a–k
SYNLETT 2006, No. 6, pp 0948–0950
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939045; Art ID: G00606ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
4.
2
0
0
6
Scheme 1 General scheme of synthesis of nitronyl nitroxide radi-
cals with TPAP/NMO system

LETTER
Synthesis of Nitronyl Nitroxide Radicals
949
Table 1 Synthesis of Aromatic and Aliphatic NNRs 2 with TPAP/
NMO System
In conclusion, a reliable preparation of aromatic, heteroar-
omatic and aliphatic NNRs bringing also redox-sensitive
groups has been developed by means of the TPAP/NMO
system. This new procedure is competitive in term of gen-
erality, simplicity cost and eco-compatibility with the ox-
idation procedures known so far.
Entry R
Time (h) Producta Yield (%)b
1
3
1
2a15
2b3
2cc
81
79
49
MeOOC
2
3
O2N
Acknowledgment
Work carried out in the framework of the National Projects: ‘Pro-
gettazione ed auto-organizzazione di architetture molecolari per
nanomagneti e sistemi optoelettronici’, ‘Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni’ and FIRB 2001-
RBNE01YLKN, supported by the Ministero dell’Istruzione della
Università e della Ricerca (MIUR), Italy; EC QuEMolNa MRTN-
CT-2003-404880. A special thanks to Prof. Andrea Goti of the De-
partment of Organic Chemistry in Florence who inspired this work.
12
H2O3P
O
4
2.5
2d
87
MeO
MeO
5
6
1.5
2
2e
90
80
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9
1.5
3.5
2i
2j
72
44
10
CH3–(CH2)13
–
11
1
2k
72
N
a All compounds gave satisfactory elemental analysis (C, H, N
0.4%). EPR signals: giso = 2.006, aiso = 7.59 0.1 G.
b Yields of a single run without optimization.
c Reaction carried out in methanol.
Operatively, after mixing of the reagents in CH2Cl2 at
room temperature the reactions were monitored by TLC
until complete consumption of dihydroxyimidazolidine
(1–12 h), the organic phase washed with water and evap-
orated to give the crude NNRs which were purified by sil-
ica gel column chromatography.14 Reagents and solvents
were used without any previous purification and any other
work up manipulations are required before chromatogra-
phy. Dichloromethane revealed to be the solvent of choice
for this procedure, however, derivative 1c, due to its poor
solubility in such solvent, was successfully oxidized to
NNR 2c in MeOH. In addition, to confirm the versatility
of this novel method, TPAP/NMO oxidation was effec-
tively used also in the case of derivatives 1h and 1i
without affecting the oxidation sensitive sulfide sulfur
functionality (i.e. no evidence of the corresponding sulf-
oxides or sulfones was pointed out in the crude reaction
mixture).
Synlett 2006, No. 6, 948–950 © Thieme Stuttgart · New York

950
L. Gorini et al.
LETTER
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starting material monitored by TLC. After 3 h the crude was
washed with H2O, evaporated to dryness and purified by
silica gel column chromatography, using Et2O as eluent.
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yield), characterized by EPR and elemental analysis.
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mmol) in CH2Cl2 (3 mL), TPAP (0.05 equiv) and NMO (1
equiv) were added in sequence and the reaction mixture left
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Synlett 2006, No. 6, 948–950 © Thieme Stuttgart · New York