Catalytic oxidation of imines based on methyltrioxorhenium/urea hydrogen peroxide: A mild and easy chemo- and regioselective entry to nitrones

Article abstract of DOI:10.1021/ol062862w

The first successful catalytic oxidation procedure for the chemoselective conversion of imines to nitrones is reported. The reaction is general, high yielding, and user and environmentally friendly, and furnishes a solution to the yet unanswered issue of

Full text of DOI:10.1021/ol062862w

ORGANIC
LETTERS
2007
Vol. 9, No. 3
473-476
Catalytic Oxidation of Imines Based on
Methyltrioxorhenium/Urea Hydrogen
Peroxide: A Mild and Easy Chemo- and
Regioselective Entry to Nitrones
Gianluca Soldaini, Francesca Cardona, and Andrea Goti*
Dipartimento di Chimica Organica “Ugo Schiff”, Laboratorio di Progettazione,
Sintesi e Studio di Eterocicli Biologicamente AttiVi (HeteroBioLab) and Consorzio
INSTM, UniVersita` di Firenze, Via della Lastruccia 13,
I-50019 Sesto Fiorentino (Firenze), Italy
andrea.goti@unifi.it
Received November 24, 2006
ABSTRACT
The first successful catalytic oxidation procedure for the chemoselective conversion of imines to nitrones is reported. The reaction is general,
high yielding, and user and environmentally friendly, and furnishes a solution to the yet unanswered issue of regioselective access to nitrones
by oxidation of nitrogen derivatives.
Nitrones 1 are useful and versatile intermediates for organic
syntheses. They behave as electrophiles toward organo-
metallics and as 1,3-dipoles in cycloadditions.1 Recently,
novel modes of reaction promoted by metal derivatives have
been discovered.2 Moreover, nitrones have relevant applica-
tions as spin traps in biological studies3 and as therapeutics
in age-related diseases.4 The most common procedures for
the preparation of nitrones consist of condensation of
aldehydes with N-monosubstituted hydroxylamines and
oxidation of secondary amines or N,N-disubstituted hydroxyl-
amines.1,5 The direct catalytic oxidation of amines6 is
particularly convenient, due to the greater availability of
amines compared to hydroxylamines. However, the general
viability of oxidation methods has been hampered by
unresolved regioselectivity issues when unsymmetrical sub-
strates are involved.7,8 In this paper, we report the first
successful catalytic oxidation procedure for the chemo-
selective conversion of imines to nitrones. It represents a
breakthrough in the chemistry of these compounds, which
become accessible regioselectively with a simple and straight-
forward oxidative approach. The reaction is general and
simple, being performed with urea hydrogen peroxide (UHP)
and a catalytic amount (2 mol %) of methyltrioxorhenium
(MTO, CH3ReO3) in MeOH at room temperature. Oxidation
of imines 2, readily available in a regiospecific manner by
(1) Merino, P. In Science of Synthesis; Padwa, A., Ed.; Thieme: Stuttgart,
2004; Vol. 27, pp 511-580.
(2) (a) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem., Int. Ed. 2002, 41,
1772-1775. (b) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003,
26, 3023-3026. (c) For a brief account, see: Cardona, F.; Goti, A. Angew.
Chem., Int. Ed. 2005, 44, 7832-7835.
(6) (a) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S.
J. Org. Chem. 1990, 55, 1736-1744. (b) Murahashi, S.-I.; Shiota, T.;
Tetrahedron Lett. 1987, 28, 2383-2386. (c) Nannelli, L.; Goti, A.
Tetrahedron Lett. 1996, 37, 6025-6028. (d) Goti, A.; Cardona, F.; Soldaini,
G. Org. Synth. 2005, 81, 204-212.
(3) Zhang, H.; Joseph, J.; Vasquez-Vivar, J.; Karoui, H.; Nsanzumuhire,
C.; Marta´sek, P.; Tordo, P.; Kalyanaraman, B. FEBS Lett. 2000, 473, 58-
62.
(7) Ali, Sk. A.; Hashmi, S. M. A.; Siddiqui, M. N.; Wazeer, M. I. M.
Tetrahedron 1996, 52, 14917-14928.
(4) Floyd, R. A. Aging Cell 2006, 5, 51-57.
(5) Breuer, E. In The Chemistry of Amino, Nitroso and Nitro Compounds
and Their DeriVatiVes; Patai, S., Ed.; Wiley: New York, 1982; p 459.
(8) For a regiochemically driven synthesis through decarboxylation of
R-amino acids, see: Murahashi, S.-I.; Imada, Y.; Ohtake, H. J. Org. Chem.
1994, 59, 6170-6172.
10.1021/ol062862w CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/04/2007

condensation of aldehydes with primary amines,9 is obviously
an attractive way for accessing nitrones. Unfortunately,
oxidation of imines to nitrones (Scheme 1, path A) is not an
optimized MTO-catalyzed oxidation of imines 2a-v to the
corresponding nitrones 1a-v are shown in Table 1. Imines
2a-r have been prepared by condensation of aldehydes with
primary amines and pyrrolines 2s-v by HCl elimination
from the corresponding N-chloroamines. Remarkably, pyr-
roline (and tetrahydropyridine) ketimines and aldimines, e.g.,
2u and 2v, are both accessible regioselectively from the same
2-substituted N-chloroamines by elimination with different
bases.19 Oxidations have been performed with 2 mol % of
MTO and urea hydrogen peroxide (UHP) as the stoichio-
metric oxidant. UHP is a solid complex used as a practical
and safe source of H2O2.20 It conveniently replaces hydrogen
peroxide aqueous solutions when compounds sensitive to
hydrolysis, such as 1 and 2, are involved. All of the substrates
reached complete conversion, apart from imine 2q. This
suggested that bulky substituents have detrimental effects
on reactivity, as proved by the low yields in entries 17 and
18. N-Arylnitrones are known to suffer from low stability
under a variety of conditions.21 This may account for the
moderate yield obtained for nitrone 1c (Table 1, entry 3).
The oxidation was highly selective; the crude reaction
mixtures showed no trace of oxaziridines or other oxidation
products, but only minor amounts of hydrolysis compounds
in few cases. Variations in peroxometal catalytic species,
H2O2 source, and solvent used resulted in poorer conversion
and/or yield. MTO was much more effective than other
related catalysts: for example, Na2WO4/UHP in MeOH did
oxidize 2a to nitrone 1a, but only 35% conversion was
achieved after 21 h. We were surprised at the different
chemoselectivity reported for the oxidation of imines with
Na2WO4/H2O2 in acetonitrile, which were claimed to afford
oxaziridines only.14j However, in our hands, this reaction gave
no detectable amount of any oxidation product from imine
2e. Similarly, MTO/H2O2 in acetonitrile gave only 20%
conversion of 2e after 16 h, producing a complex mixture
containing only trace amount of nitrone 1e and oxaziridine
3e. This finding confirmed the paramount importance of
using alcoholic solvents in MTO-catalyzed oxidations of
nitrogenated compounds. Our experimental data suggest that
nitrones are formed by direct N-oxidation,13 i.e., attack of
the lone pair of the imine nitrogen atom to the peroxo moiety
of the active Re catalyst. Accordingly, the reaction is only
barely sensitive to electronic substituent effects. Intermediate
formation of an oxaziridine rearranging to a nitrone was ruled
out. Indeed, oxaziridine 3b, synthesized according to a known
procedure,14f was unaffected by treatment with MTO or
MTO/UHP in MeOH. Concerning the fundamental issue of
regioselective formation of nitrones, entries 9, 15, 21, and
Scheme 1. Oxidation of Imines 2 to Nitrones 1 or
Oxaziridines 3
easy task. Only one procedure, employing excess perman-
ganate under phase-transfer conditions,10 is quite general and
affords reasonable yields. However, serious drawbacks
concerning selectivity10,11 and failure to afford the desired
nitrones from cyclic imines12 were reported. Imines may yield
several products by oxidation and control of selectivity is
challenging.13 Oxaziridines 3 are the most common oxidation
products with a variety of reagents (path B).13,14 In some
instances, they may rearrange to nitrones under acid catalysis
(path C).15 Other oxidants gave amides or rearranged
compounds.11,16 Only a few of these procedures employed
environmentally benign oxidants with metal catalysts.14h-j
It is noteworthy that no catalytic procedure for the oxidation
of imines to nitrones has been reported so far. Recently,
methyltrioxorhenium (MTO) became popular as a catalyst
for alkene epoxidation.17 Hydrogen peroxide is the usual
stoichiometric oxidant, responsible for formation of the
catalytically active peroxorhenium species.17 Several other
functional groups have been oxidized by MTO/H2O2. During
our studies in this area, we noticed that N-oxidation of
nitrogenated compounds by MTO occurs readily.6c,d,18 There-
fore, we envisaged that MTO might serve as a suitable
catalyst for oxidizing imines to nitrones. The results of
(9) Patai, S. The Chemistry of the Carbon-Nitrogen Double Bond;
Wiley: New York, 1970.
(10) Christensen, D.; Jørgensen, K. A. J. Org. Chem. 1989, 54, 126-
131.
(11) Larsen, J.; Jørgensen, K. A.; Christensen, D. J. Chem. Soc., Perkin
Trans. 1 1991, 1187-1190.
(12) Busque´, F.; de March, P.; Figueredo, M.; Font, J.; Gallagher, T.;
Mila´n, S. Tetrahedron: Asymmetry 2002, 13, 437-445.
(13) (a) Ogata, Y.; Sawaki, Y. J. Am. Chem. Soc. 1973, 95, 4687-4692.
(b) Boyd, D. R.; Coulter, P. B.; McGuckin, M. R.; Sharma, N. D. J. Chem.
Soc., Perkin Trans. 1 1990, 301-306.
(14) Peracids: (a) ref 10. (b) Kitagawa, O.; Vander Velde, D.; Dutta,
D.; Morton, M.; Takusagawa, F.; Aube´, J. J. Am. Chem. Soc. 1995, 117,
5169-5178. Sulfonic peracids: (c) Kluge, R.; Schulz, M.; Liebsch, S.
Tetrahedron 1996, 52, 5773-5782. Oxone: (d) Davis, F. A.; Chatto-
padhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J. Org. Chem. 1988, 53,
2087-2089. (e) Hajipour, A. R.; Pyne, S. G. J. Chem. Res., Synop. 1992,
388. Tetrabutylammonium Oxone: (f) Mohajer, D.; Iranpoor, N.; Rezaeifard,
A. Tetrahedron Lett. 2004, 45, 631-634. UHP with maleic anhydride: (g)
Damavandi, J. A.; Karami, B.; Zolfigol, M. A. Synlett 2002, 933-934. O2
and metal catalysts: (h) Martiny, L.; Jørgensen, K. A. J. Chem. Soc., Perkin
Trans. 1 1995, 699-704. (i) Lin, Y.-M.; Miller, M. J. J. Org. Chem. 2001,
66, 8282-8285. H2O2 and cat. Na2WO4: (j) Shailaja, M.; Manjula, A.;
Rao, B. V. Synlett 2005, 1176-1178.
(18) (a) Cardona, F.; Soldaini, G.; Goti, A. Synlett 2004, 1553-1556.
(b) Saladino, R.; Neri, V.; Cardona, F.; Goti, A. AdV. Synth. Catal. 2004,
346, 639-647. For related studies by other groups, see: (c) Murray, R.
W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org. Chem. 1996, 61, 8099-
8102. (d) Yamazaki, S. Bull. Chem. Soc. Jpn. 1997, 70, 877-883. (e)
Zauche, T. H.; Espenson, J. H. Inorg. Chem. 1997, 36, 5257-5261. (f)
Cope´ret, C.; Adolfsson, H.; Khuong, T.-A. V.; Yudin, A. K.; Sharpless, K.
B. J. Org. Chem. 1998, 63, 1740-1741.
(15) Lin, Y.-M.; Miller, M. J. J. Org. Chem. 1999, 64, 7451-7458.
(16) (a) An, G.-i.; Kim, M.; Kim, J. Y.; Rhee, H. Tetrahedron Lett. 2003,
44, 2183-2186. (b) Nongkunsarn, P.; Ramsden, C. A. Tetrahedron 1997,
53, 3805-3830.
(17) For reviews, see: (a) Herrmann, W. A.; Ku¨hn, F. E. Acc. Chem.
Res. 1997, 30, 169-180. (b) Espenson, J. H. Chem. Commun. 1999, 479-
488.
(19) Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.;
Courtney, S. Org. Lett. 2002, 4, 103-106.
(20) Heaney, H. Top. Curr. Chem. 1993, 164, 1-19.
(21) Cordero, F. M.; Barile, I.; Brandi, A.; Kozhushkov, S. I.; de Meijere,
A. Synlett 2000, 1034-1036.
474
Org. Lett., Vol. 9, No. 3, 2007

Table 1. Catalytic Oxidation of Imines 2a-va
a Reaction conditions: imine 2 (1 mmol), CH3ReO3 (2 mol %), H2O2·urea (3 equiv), MeOH (2 mL), rt. All reactions reached complete conversion, unless
otherwise stated. b Yields of isolated pure nitrones. c 50% conversion. d 4 mol % of MTO.
22 nicely illustrate the tremendous advantage of this method
compared to oxidation of amines or hydroxylamines. Ni-
trones 1i, 1o, 1u, and 1v were produced selectively. In
contrast, oxidation with MTO/UHP6c,d of the amines 4 and
5 gave inseparable equimolar mixtures of regioisomeric
nitrones 1i/1i′ and 1u/1v, respectively (Scheme 2). This
method allowed easy access to chiral nitrones (e.g., 1o, 1r,
1t, 1v), useful synthetic intermediates,22 without any loss of
optical purity.23 Particularly meaningful are the syntheses
of nitrones 1o and 1v. Preparation of nitrones related to 1v
via other oxidation procedures was troublesome and occurred
with low yields and an absence of selectivity.24 N-(R-
Methyl)benzylnitrones (such as 1o) have been widely
employed in enantioselective syntheses, the N-appendage
serving as a chiral auxiliary.22 Their synthesis relies on a
lengthy procedure for preparing the chiral hydroxylamine
to be reacted with the desired aldehyde.25 With this method,
(R-methyl)benzylamine, inexpensive and available in both
(23) Comparison of the specific rotation of the known nitrone 1t with
the value reported in the literature (Goti, A.; Cardona, F.; Brandi, A.; Picasso,
S.; Vogel, P. Tetrahedron: Asymmetry 1996, 7, 1659-1674) proved this
assumption: [R]22 +74.9 (c 1.05, CHCl3) [lit. [R]19 +75.8 (c 1.30,
D
D
CHCl3)].
(24) Closa, M.; de March, P.; Figueredo, M.; Font, J. Tetrahedron:
Asymmetry 1997, 8, 1031-1037.
(25) Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron 1985, 41, 3455-
3462.
(22) Gothelf, K.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863-909.
Org. Lett., Vol. 9, No. 3, 2007
475

derivatives by oxidative means. This new reaction is user
and environmentally friendly, being simple to perform,
occurring under mild conditions and with high atom economy,
and releasing only water as coproduct. The scope and
application of this catalytic procedure is currently being
investigated in our laboratories.
Scheme 2. Oxidation of Secondary Amines 4 and 5 to
Nitrones
Acknowledgment. We thank MIUR and INSTM, Italy,
for financial support and Ente Cassa di Risparmio di Firenze,
Italy, for granting a 400 MHz NMR spectrometer. Brunella
Innocenti and Maurizio Passaponti (Dipartimento di Chimica
Organica “Ugo Schiff”, Universita` di Firenze) are acknowl-
edged for technical assistance.
Supporting Information Available: Experimental pro-
enantiomeric forms, can be condensed directly with alde-
hydes to afford imines such as 2o, which are oxidized to
nitrones. In conclusion, we have developed the first catalytic
version of the troublesome oxidation of imines to nitrones,
which offers a solution to the yet unanswered issue of
regiochemical control in the synthesis of nitrones from amine
1
cedures, characterization data of nitrones, and H and 13C
NMR spectra of new compounds 1d-k,m,n,q,r,u,v. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062862W
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Org. Lett., Vol. 9, No. 3, 2007