A metal-free general procedure for oxidation of secondary amines to nitrones

Article abstract of DOI:10.1021/jo901108u

(Chemical Equation Presented) An efficient and metal-free protocol for direct oxidation of secondary amines to nitrones has been developed, using Oxone in a biphasic basic medium as the sole oxidant. The method is general and tolerant with other functiona

Full text of DOI:10.1021/jo901108u

pubs.acs.org/joc
biologically active compounds.1 Traditionally, nitrones
A Metal-Free General Procedure for Oxidation of
Secondary Amines to Nitrones
have been synthesized by condensation of aldehydes with
N-monosubstituted hydroxylamines,1,2 or via oxidation of
the corresponding hydroxylamines,3 imines,4 and amines.5
These last two options are the most attractive methods
because of the greater availability of the required amines or
imines compared to the corresponding hydroxylamines.
Published methodologies concerning the oxidation of imines
to nitrones are scarce and present poor structural diversity
application,4a,4b with the exception of the work developed by
Goti’s group.4c The direct oxidation of amines to nitrones
has been achieved through different procedures, using
oxaziridines,5a dioxiranes,5b or hydroperoxides (including
H2O2) paired with diverse metal-catalytic systems.5c-n
Recently, we have reported a flexible synthetic approach
to several Stemona alkaloids illustrated with the preparation
of the putative structure of stemonidine.6 In this synthesis,
we required an efficient procedure for the preparation of an
enantiopure nitrone as 2 (Scheme 1).
ꢀ
ꢁ
ꢁ
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Carolina Gella, Eric Ferrer, Ramon Alibes, Felıx Busque,*
Pedro de March, Marta Figueredo,* and Josep Font
ꢀ
Universitat Autonoma de Barcelona, Departament de
´
Quımica, 08193 Bellaterra, Spain
felix.busque@uab.es; marta.figueredo@uab.es
Received May 26, 2009
SCHEME 1
An efficient and metal-free protocol for direct oxidation of
secondary amines to nitrones has been developed, using
Oxone in a biphasic basic medium as the sole oxidant. The
method is general and tolerant with other functional groups
or existing stereogenic centers, providing rapid access to
enantiomerically pure compounds in good yields.
We had already published the preparation of this type of
substituted pyrroline N-oxides in enantiopure form by
oxidation of the corresponding amine7 or imine8 with
methyl(trifluoromethyl)dioxirane or dimethyldioxirane, re-
spectively. However, these procedures proved to be difficult
to scale up, essentially because of the problematic prepara-
tion of the mentioned dioxiranes in multigram quantities.
To avoid these difficulties, we envisaged the use of methyl-
(trifluoromethyl)dioxirane generated in situ from tri-
fluoroacetone using potassium hydrogen persulfate, com-
mercially available as Oxone,9 following a methodology
previously described for the epoxidation of several olefins.10
Despite Oxone having been extensively employed as oxidant
in organic synthesis,11 only a few reports have appeared deal-
ing with its use for the oxidation of amines. Thus, the synthesis
Nitrones and their derivatives are highly versatile building
blocks for the synthesis of a variety of natural products and
(1) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; John Wiley
& Sons: New York, 1984; Vol. 2, Chapter 9. (b) Torssell, K. B. G. In Nitrile
Oxides, Nitrones and Nitronates in Organic Synthesis; VCH Verlagsge-
sellschaft: Weinheim, Germany, 1988. (c) Padwa, A.; Pearson, W. H. In Synthetic
Applications of 1,3-Dipolar Cycloadditions. Chemistry Toward Heterocycles
and Natural Products; John Wiley & Sons: Hoboken, NJ, 2003; Chapter 1.
(2) Robl, J. A.; Jih, R. H. J. Org. Chem. 1985, 50, 5913–5916.
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Siddiqui, M. N.; Wazeer, M. I. M. Tetrahedron 1996, 52, 14917–14928. (d)
Cicchi, S.; Corsi, M.; Goti, A. J. Org. Chem. 1999, 64, 7243–7245. (e) Cicchi,
S.; Cardona, F.; Brandi, A.; Corsi, M.; Goti, A. Tetrahedron Lett. 1999, 40,
1989–1992. (f) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett.
2001, 42, 6503–6505. (g) Saladino, R.; Neri, V.; Cardona, F.; Goti, A. Adv.
Synth. Catal. 2004, 346, 639–647.
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G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473–476. (d) Cardona, F.;
Bonanni, M.; Soldaini, G.; Goti, A. ChemSusChem. 2008, 1, 327–332.
(5) (a) Zajac, W. W.; Walters, T. R.; Darcy, M. G. J. Org. Chem. 1988, 53,
5856–5860. (b) Murray, R. W.; Singh, M. J. Org. Chem. 1990, 55, 2954–2957.
(c) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383–2386. (d)
Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem.
1990, 55, 1736–1744. (e) Ballistreri, F. P.; Chiacchio, U.; Rescifina, A.;
Tomaselli, G. A.; Toscano, R. M. Tetrahedron 1992, 48, 8677–8684. (f)
Murahashi, S.-I.; Imada, Y.; Ohtake, H. J. Org. Chem. 1994, 59, 6170–6172.
(g) Marcantoni, E.; Petrini, M.; Polimanti, O. TetrahedronLett. 1995, 36, 3561–
3562. (h) Murray, R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org. Chem.
1996, 61, 8099–8102. (i) Goti, A.; Nannelli, L. TetrahedronLett. 1996, 37, 6025–
6028. (j) Murahashi, S.-I.; Ohtake, H.; Imada, Y. Tetrahedron Lett. 1998, 39,
2765–2766. (k) Forcato, M.; Nugent, W. A.; Licini, G. Tetrahedron Lett. 2003,
44, 49–52. (l) Choudary, B. M.; Reddy, Ch. V.; Prakash, B. V.; Bharathi, B.;
Kantam, M. L. J. Mol. Catal. A: Chem. 2004, 217, 81–85. (m) Colladon, M.;
Scarso, A.; Strukul, G. Green Chem. 2008, 10, 793–798. (n) Zonta, C.; Cazzola,
E.; Mba, M.; Licini, G. Adv. Synth. Catal. 2008, 350, 2503–2506.
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P.; Figueredo, M.; Font, J.; Parella, T. Org. Lett. 2007, 9, 1769–1772.
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Asymmetry 1997, 8, 1031–1037.
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(9) Oxone is a product consisting of a 2:1:1 mixture of the active
ingredient KOSO2OOH, along with KHSO4 and K2SO4, respectively.
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3675. (b) Wei, L.; Fuchs, P. L. Org. Lett. 2003, 5, 2853–2856.
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DOI: 10.1021/jo901108u
r
Published on Web 07/16/2009
J. Org. Chem. 2009, 74, 6365–6367 6365
2009 American Chemical Society

Gella et al.
JOCNote
TABLE 1. Optimization of Oxone Oxidation of Secondary Amines 1 to Nitrones 2 and 3
entrya
amine
oxidant
mixture of solvents
other changes
yield,b %
ratio 2:3
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
Oxone-ketone 4c
Oxone-ketone 4
Oxone-ketone 4
Oxone-ketone 5e
PhSO2NOCHPh
Oxone-ketone 5
Oxone
Oxone
Oxone
Oxone
Oxone
aq 0.01 M Na2EDTA-CH3CN-THF
aq 0.01 M Na2EDTA-CH3CN-THF
aq 0.01 M Na2EDTA-CH3CN-THF
aq 0.01 M Na2EDTA-CH3CN-THF
CHCl3
[1a] = 0.03 M
49
69
30d
58
62
79
88
76
82
78
1:2.8
1:2.2
rt
1: 2.1
1: 1.7
1: 1.8
1.3: 1
1.3: 1
1.3: 1
1.3: 1
1: 1.3
aq 0.01 M Na2EDTA-CH3CN-THF
aq 0.01 M Na2EDTA-CH3CN-THF
aq 0.01 M Na2EDTA-MeOH
aq 0.1 M Na2EDTA-CH3CN-THF
H2O-CH3CN-THF
11
aq 0.1 M Na2EDTA-CH3CN-THF
without NaHCO3
aAll reactions were performed at 5 °C with amine 1 (2 mmol), Oxone (2.1 mmol), and NaHCO3 (10 mmol) in 6.5 mL of a
mixture of (aq 0.01 M Na2EDTA)-CH3CN-THF (1:1:0.25) ([1a] = 0.3 M) and reached complete conversion unless otherwise
indicated. bYields of isolated pure nitrones. cKetone 4: p-F-C6H4-COCF3. d40% conversion. eKetone 5: CH3COCF3.
of nitroso compounds12a,12b or oximes12c from primary
amines, amine oxides from tertiary amines,12d,12e and hydro-
xylamines from the corresponding amines has been descri-
bed.12e Secondary amines are reported to remain intact with
use of Oxone in acid media.12a The unique example describing
the oxidation of a secondary amine to a mixture of nitrones
(31% yield) was reported in a work dealing with the asym-
metric epoxidation of alkenes by Oxone under basic condi-
tions,12f when studying the fate of an enantiopure pyrrolidine
derivative used as catalyst.
reaction, but also on the properties of nitrones 2 and 3. Thus,
oxidation of amine (S)-1b gave a 1.3:1 mixture of nitrones
(S)-2b and 3b in 79% yield (entry 6). These compounds
proved to be separable by means of standard flash column
chromatography through silica gel in multigram quantities.
In this case, the ratio between nitrones 2b and 3b can be easily
established by integration of the H-10 proton signals in the
1H NMR spectrum of the mixtures.
Remarkably, the reaction worked equally well with Oxone
as oxidant without the addition of any trifluoroketone (entry
7). This last reaction was repeated starting from the enan-
tiomer of amine (S)-1b, affording the corresponding nitrones
(R)-2b and 3b. The optical rotation values of nitrones (S)-2b
{[R]D -13.0 (c 1.56, CH2Cl2)} and (R)-2b {[R]D þ13.3 (c 1.58,
CH2Cl2)} proved to be consistent. The enantiomeric purity
of nitrones (S)-2b and (R)-2b was confirmed by chiral HPLC
of a derivative.14
Replacement of the solvent mixture of CH3CN-THF by
MeOH (entry 8) or the use of more concentrated solutions of
aqueous Na2EDTA (entry 9) did not alter the course of the
reaction. On the contrary, when the aqueous Na2EDTA
solution was substituted by water, an undesired change in
the regioselectivity of the reaction was observed (entry 10).
As expected,12a when the amine 1b was submitted to the
action of Oxone in acid medium without addition of NaH-
CO3, only starting amine unaltered with several degradation
products was obtained (entry 11).
Herein, we report that Oxone can be used effectively, in a
biphasic basic medium as the sole oxidant, for the direct
conversion of secondary amines to nitrones through a
straightforward and simple procedure.
Initially, oxidation of amine (S)-1a (Scheme 1) was performed
in similar experimental conditions to those previously described
for the epoxidation of olefins10 (Table 1, entry 1), leading to a
chromatographically inseparable 1:2.8 mixture of the desired
aldonitrone 2a and ketonitrone 3a in 49% overall yield.
Increasing the amine concentration in the biphasic system
showed little influence on the regioselectivity of the reaction.
Thus, when the amine concentration was changed from 0.03
to 0.3 M, a 1:2.2 mixture of nitrones 2a and 3a was obtained
in 69% yield (entry 2). This higher concentration was
adopted for the general procedure because it was advanta-
geous in order to scale up the process.
Changing the temperature from 5 °C to room temperature
decreased the conversion of the transformation, due to
Oxone decomposition13 at the basic pH of reaction condi-
tions (entry 3). A modification of the fluorinated ketone did
not show any significant influence in the outcome of the
reaction (entry 4). When Davis oxaziridine5a was used as the
oxidant, no substantial change was observed on the regios-
electivity of the reaction either (entry 5). In all these cases, the
ratio between nitrones 2a and 3a could not be determined by
NMR analysis of the mixtures, and it was estimated from the
ratio between their 1,3-dipolar cycloaddition products with
dimethyl acetylenedicarboxylate. Similar yields of cycload-
ducts were obtained by performing the cycloaddition in situ
in the oxidation media, after amine consumption, or with the
crude material after workup of the oxidation reaction.
It is noteworthy that the nature of the protecting group
showed an influence not only on the regiochemistry of the
In summary, after much experimentation, we have devel-
oped a new procedure for the preparation of enantiopure
nitrone 2b from the corresponding amine in 50% yield
(Table 1, entry 7). It was possible to scale up the reaction
to obtain 10 g of nitrone without detriment of yield or optical
purity. This nitrone was used by our research group for the
synthesis of the putative structure of stemonidine,6 and this
methodology has recently been applied by another research
group in the synthesis of an enantiopure nitrone from the
corresponding pyrrolidine.15
The experimental procedure herein described was judged
specially interesting owing to its low cost, simplicity, and
environmentally friendly character, considering the absence
(14) The enantiomeric purity of nitrones 2b and ent-2b can be easily
confirmed by chiral HPLC of the corresponding endo cycloadducts derived
from the 1,3-dipolar cycloaddition with (E)-2-hexenedioic acid dimethyl
ester. See the Supporting Information1 for more details.
(13) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J. S.; Wilde, R.
G. J. Org. Chem. 1995, 60, 1391–1407.
(15) Cordero, F. M.; Bonanno, P.; Neudeck, S.; Vurchio, C.; Brandi, A.
Adv. Synth. Catal. 2009, 351, 1155–1161.
6366 J. Org. Chem. Vol. 74, No. 16, 2009

Gella et al.
JOCNote
TABLE 2. Scope of Oxone Oxidation of Secondary Amines to Nitrones
1:1 mixture of regioisomeric conjugated and nonconjugated
nitrones (entry 5). The experiment performed in entry 7
showed too that the ester moiety is stable under the reaction
conditions of the present oxidation protocol. Similarly,
hydroxyl and carbamate moieties proved to be stable,
according to the experiment of entry 8, where the starting
material was recovered unaltered. As previously described
with use of other methodologies,5f when L-proline was sub-
mitted to this oxidation protocol, the decarboxylated nitrone
was obtained as the main product (entry 9).
Remarkably, oxidation of amine 14 (entry 10) afforded a
2.5:1 mixture of regioisomeric nitrones 15 and 16 in 83%
total yield. These compounds proved to be easily separable
by means of standard chromatography through silica gel,
furnishing synthetically valuable16 nitrone 15 in multigram
quantities. Again, the ratio between nitrones 15 and 16 was
established from 1H NMR analysis of the mixture.
It has to be pointed out that when an imine was exposed to
the oxidation conditions (entry 11), only degradation pro-
ducts were obtained. This result discards the hypothesis of an
imine as intermediate in the reaction mechanism.
In conclusion, an efficient and metal-free general protocol
for direct oxidation of secondary amines to nitrones has been
developed, using Oxone in a biphasic basic medium as the sole
oxidant. The method is general and tolerant with other func-
tional groups or existing stereogenic centers, providing rapid
access to enantiomerically pure compounds in good yields.
Experimental Section
General Procedure for the Oxidation. To a stirred solution of
amine (2.0 mmol) in a mixture of acetonitrile-THF 4:1 (3.5 mL)
and 0.01 M aqueous EDTA solution (2.8 mL) at 5 °C was added
NaHCO3 (0.84 g, 10.0 mmol). While cooling to maintain the
temperature at 5 °C, Oxone (1.29 g, 2.1 mmol) was added over 2 h
under vigorous stirring. The mixturewas stirred for 20min at5 °C
and then ethyl acetate (10 mL) was added. The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (2ꢀ10 mL). The combined organic extracts were dried
over anhydrous MgSO4 and concentrated under reduced pres-
sure. In most cases, the remaining crude material does not need
further purification. If necessary, regioisomeric nitrones were
separated and purified by flash column chromatography over
silica gel.
Acknowledgment. We acknowledge financial support from
DGES (projects CTQ2004-2539 and CTQ2007-60613/BQU)
and a grant from Generalitat de Catalunya (E.F.) and acknowl-
ꢁ
edge MCYT-ERDF for a Ramon y Cajal contract (F.B.). We
aYields of isolated pure nitrones All reactions reached
complete conversion unless otherwise indicated.
also want to acknowledge graduate student Nuria Bardajı for
some work related to the development of the general oxidation
procedure.
of unstable reagents as dioxiranes,5b,7 metals, and haloge-
nated compounds or solvents, usually present in other
methodologies previously described.5a,5c-l Therefore, we
decided to study the scope of this protocol extending it to
other amines (Table 2). In most of the cases, the oxidation
proceeds efficiently with yields over 70%.
Symmetrically substituted secondary amines (Table 2, en-
tries 1-4) were cleanly converted to the corresponding
nitrones with yields between 72% and 86% without any
further purification needed. Asymmetrically substituted
amines (entries 5-7) were oxidized in similar yields to the
corresponding conjugated nitrones (entries 6 and 7), or to a
Supporting Information Available: General experimental
procedures, experimental details, and characterization data of
new compounds (3b, 13, 14, 15, 16), 1H and 13C NMR spectra of
1
all new compounds and H NMR of the known nitrones, and
CHPLC chromatograms of derivatives of nitrones 2b and
ent-2b. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) (a) Goti, A.; Cacciarini, M.; Cardona, F.; Brandi, A. Tetrahedron
Lett. 1999, 40, 2853–2856. (b) Cordero, F. M.; Gensini, M.; Goti, A.; Brandi,
ꢁ
A. Org. Lett. 2000, 2, 2475–2477. (c) Alibes, R.; Blanco, P.; Casas, E.; Closa,
M.; de March, P.; Figueredo, M.; Font, J.; Sanfeliu, E.; Alvarez-Larena, A. J.
Org. Chem. 2005, 70, 3157–3167.
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