J . Org. Chem. 1999, 64, 7243-7245
7243
Sch em e 1
In exp en sive a n d En vir on m en ta lly F r ien d ly
Oxid a tion of Hyd r oxyla m in es to Nitr on es
w ith Blea ch
Stefano Cicchi, Massimo Corsi, and Andrea Goti*
Centro di Studio C.N.R. sulla Chimica e la Struttura dei
Composti Eterociclici e loro Applicazioni (CSCEA),
Dipartimento di Chimica organica “Ugo Schiff”,
Universita` degli Studi di Firenze, via G. Capponi 9,
I-50121 Firenze, Italy
Received March 8, 1999
Nitrones proved to be very useful tools in the construc-
tion of structurally complex molecules, usually allowing a
high degree of diastereocontrol. In this context, either the
nitrone [3 + 2] cycloaddition to alkenes1 and the alkyl-
ation of nitrones by organometallic reagents2 have been
extensively developed and have become extremely reli-
able synthetic procedures. In addition, nitrones are useful
spin trap reagents, widely employed in biological sys-
tems.3
In the last years we have been involved in the search
for alternative and more practical oxidation methodolo-
gies to nitrones,7 and we have recently reported an oxi-
dation of hydroxylamines catalyzed by (salen)Mn(III)
complexes.8 During the latter study, the observation that
sodium hypochlorite is sufficient by itself to promote the
oxidation of hydroxylamines to nitrones has prompted
us to evaluate the use of commercial bleach as an inex-
pensive, convenient, safe, and environmentally benign
(the only byproduct being sodium chloride) alternative
to the use of the currently employed oxidants. In this
paper we report the results of oxidation of various N,N-
disubstituted hydroxylamines to the corresponding ni-
trones with only the use of common, commercial bleach.
Hydroxylamines 1-10, synthesized according to lit-
erature methods (see Experimental Section), have been
subjected to sodium hypochlorite oxidation at 0 °C or
room temperature (Table 1). Commercial bleach was able
to give quantitative conversion of all the studied hydroxyl-
amines in 2-28 h (Table 1, entries a). Workup of the
reaction mixtures followed by column chromatography
purification afforded the desired nitrones 11-20 in good
yields (50-85%), most of which compare well with those
obtained by the known oxidation methods.
Among the synthetic methods for obtaining nitrones,4
two procedures are by far the most useful and utilized
(Scheme 1): (i) the condensation of N-monosubstituted
hydroxylamines with carbonyl compounds, and (ii) the
oxidation of secondary amines or N,N-disubstituted hy-
droxylamines. These latter compounds can be in turn
produced as intermediate oxidation products from sec-
ondary amines, or by nucleophilic attack of N-monosub-
stituted hydroxylamines to different substrates.5 Re-
cently, a new double nucleophilic displacement of ditosyl-
ates, dimesylates, or dibromides with NH2OH developed
in our group allowed an easy access to cyclic hydroxyl-
amines.6 However, the most successful and popular
method for the subsequent oxidation of hydroxylamines
to nitrones requires the use of highly toxic mercury salts
in large amounts, the use of different oxidants being less
universal and satisfactory.4 Other methods involve the
use of metal salts or oxides (copper, lead, silver), or the
use of complex organic oxidants (oxaziridines, quinones).
The acyclic nitrones 11 and 12 were obtained with
opposite stereochemistry. C-Phenyl nitrone 11 was iso-
lated as the Z isomer exclusively, as usual.11 A scale-up
of the reaction on 5 mmol of 1 allowed an almost
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Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; Feuer,
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K. V.; J ørgensen, K. A. Chem. Rev. 1998, 98, 863-909. (g) Goti, A.;
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Pharm. 1995, 280, 343-346. (f) Frejaville, C.; Karoui, H.; Tuccio, B.;
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(6) (a) Cicchi, S.; Ho¨ld, I.; Brandi, A. J . Org. Chem. 1993, 58, 5274-
5275. (b) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J . Org.
Chem. 1997, 62, 3119-3125. (c) Brandi, A.; Cicchi, S.; Goti, A.;
Koprowski, A.; Pietrusiewicz, K. M. J . Org. Chem. 1994, 59, 1315-
1318. (d) Cicchi, S.; Goti, A.; Brandi, A. J . Org. Chem. 1995, 60, 4743-
4748. (e) Cordero, F. M.; Machetti, F.; De Sarlo, F.; Brandi, A. Gazz.
Chim. Ital. 1997, 127, 25-29.
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(8) Cicchi, S.; Cardona, F.; Brandi, A.; Corsi, M.; Goti, A. Tetrahe-
dron Lett. 1999, 40, 1989-1992.
(9) We have reported throughout the text the titer of NaClO
solutions as stated by the companies on the samples, i.e., e5% for
bleach and 13% for the concentrated sodium hypochlorite commercially
available from Fluka. However, we have determined the exact titer
by titration of the solutions with 0.89 M sodium thiosulfate.10 While
the titer of bleach remained always in the range 3.5-4% during all
the time of this study, we observed a dramatic decrease in the NaClO
concentration of the 13% solution. Then, all the reactions with the more
concentrated solution have been carried out at the same time with a
10.2% solution, immediately after titration. In our experience, the use
of bleach is much more practical, requiring no titration providing that
a 1.5-2-fold excess is used. On the other hand, it is advisable to titrate
the 13% NaClO solution before its use: we are indebted to one referee
for warning us about the rapid decline of its titer.
(4) (a) Do¨pp, D.; Do¨pp, H. In Houben-Weyl - Methoden der orga-
nischen Chemie, vol. E14b/Part 2; Klamann, D.; Hagemann, H., Eds.;
Georg Thieme Verlag: Stuttgart, 1990. (b) Breuer, E. In The Chemistry
of Amino, Nitroso and Nitro Compounds and Their Derivatives; Patai,
S.; Ed.; Wiley Interscience: New York, 1982.
(5) Wroblowsky, H.-J . In Houben-Weyl - Methoden der organischen
Chemie, vol. E16a/Part 1; Klamann, D., Ed.; Georg Thieme Verlag:
Stuttgart, 1990.
(10) Larrow, J . F.; Roberts, E.; Verhoeven, T. R.; Ryan, K. M.;
Senanayake, C. H.; Reider, P. J .; J acobsen. E. N. Org. Synth. 1998,
76, 46-56.
10.1021/jo990417r CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999