Hetero-Cope rearrangement for the synthesis of potassium 5-tert-butyl-2-(tert-butyl-aminoxy)-benzoate, a highly water-soluble stable free radical

Article abstract of DOI:10.1016/S0040-4039(02)00311-8

The hetero-Cope rearrangement of 4-tert-butyl-phenyl-tert-butylhydroxylamine provides an easy access to the corresponding ortho-bromoaniline, converted to the new highly water-soluble nitroxide, potassium 5-tert-butyl-2-(tert-butyl-aminoxy)-benzoate. The parent carboxylic acid was found to be very persistent in water at pH 1.

Full text of DOI:10.1016/S0040-4039(02)00311-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2613–2614
Hetero-Cope rearrangement for the synthesis of potassium
5-tert-butyl-2-(tert-butyl-aminoxy)-benzoate, a highly
water-soluble stable free radical
Lucien Marx and Andre´ Rassat*
Ecole Normale Supe´rieure and CNRS, 24 rue Lhomond, F75231 Paris, Cedex 05, France
Received 6 February 2002; accepted 8 February 2002
Abstract—The hetero-Cope rearrangement of 4-tert-butyl-phenyl-tert-butylhydroxylamine provides an easy access to the corre-
sponding ortho-bromoaniline, converted to the new highly water-soluble nitroxide, potassium 5-tert-butyl-2-(tert-butyl-aminoxy)-
benzoate. The parent carboxylic acid was found to be very persistent in water at pH 1. © 2002 Elsevier Science Ltd. All rights
reserved.
A high solubility in water of nitroxide free radicals is
requested in different applications such as electron spin
resonance1 or magnetic resonance imaging,2 protection
from oxidative stress and radiative damage,3 radical
polymerization,4 and spin labeling.5 Some carboxylate
nitroxides6 in which the negative charge increases the
hydrophilicity have been isolated, but to our knowledge
no aromatic one. We present here the synthesis of a
water-soluble aromatic carboxylate nitroxide 1, in
which the tert-butyl substituent on the aromatic ring
provides a convenient protection from the usual
bimolecular disproportionation.7 To our knowledge,
such nitroxides have not been tested yet in controlled
radical polymerization4 in water.
Scheme 1. Reagents and conditions: (i) tert-BuLi, THF, −78°C, then 0°C, 2 h; (ii) tert-BuNO, −78°C, 95%; (iii) SOBr2 (1.1 equiv.),
Et3N (1.1 equiv.), CH2Cl2, 0°C then rt, 24 h; (iv) tert-BuLi (3.3 equiv.), THF, −78°C, then −10°C, 45 min; (v) (MeO)2CO (5
equiv.), −78°C, then rt 10 h; (vi) m-CPBA, CH2Cl2, rt; (vii) tBuOK, H2O, THF, 24 h; (viii) HCl (1 mM).
Keywords: nitroxides; hydroxylamines; carboxylate; hetero-Cope rearrangement; decomposition.
* Corresponding author. Tel.: +33 (0)144323325; fax: +33 (0)144323325; e-mail: andre.rassat@ens.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00311-8

2614
L. Marx, A. Rassat / Tetrahedron Letters 43 (2002) 2613–2614
The hydroxylamine 2, easily prepared in high yield
(95%)8 by a modification (lithiation of 4-tert-butyl-bro-
mobenzene) of the published procedure9 (Scheme 1) is a
convenient starting material. Functionalization at the
nitrogen ortho position of 2 was achieved by a hetero-
Cope rearrangement, analogous to the one reported by
Nikrad.10
8070–8073.
4. Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.;
Hamer, G. K. Macromolecules 1993, 26, 2987–2988.
5. Berliner, L. In Biological Magnetic Resonance; Berliner,
L., Ed.; Plenum Press: New York, 1998; Vol. 14.
6. (a) Hideg, K.; Lex, L. J. Chem. Soc., Perkin Trans. 1
1987, 1117–1121; (b) Keana, J. F. W.; Pou, S. J. Org.
Chem. 1989, 54, 2417–2420; (c) Reid, D. A.; Bottle, S. E.;
Micallef, A. S. Chem. Commun. 1998, 1907.
7. Calder, A.; Forrester, A. R. Chem. Commun. 1967, 682.
8. Isolated yield after column chromatography.
9. Torssell, K.; Goldman, J.; Petersen, T. E. Liebigs Ann.
Chem. 1973, 231–240.
Thus, reaction of 2 with thionyl bromide gave the
brominated aromatic amine 3a11 (61%)9 and the amine
3b12 (10%).9 The lithio-derivative of 3a was reacted with
dimethylcarbonate13 to afford 414 (19%)9 and 3b (57%).9
Compound 4 was oxidized by m-CPBA to the nitroxide
515 (47%)9 which was then hydrolyzed with freshly
prepared KOH.16 Evaporation to dryness and tritura-
tion of the residue with ether led to carboxylate 1,17 an
orange solid, indefinitely stable in the solid state. Com-
pound 1 was found to be soluble in water at a concen-
tration of 40 mM, one of the highest reported solubility
for a nitroxide.6c
10. Ayyangar, R. N.; Kalkote, U. R.; Nikrad, P. V. Tetra-
hedron Lett. 1982, 23, 1099–1102.
11. (2-Bromo-4-tert-butyl-phenyl)-tert-butyl-amine 3a: lH
(CDCl3, 250 MHz): 7.366 (d, J=2.29 Hz, 1H); 7.084 (dd,
J=2.29, 8.63 Hz, 1H); 6.846 (d, J=8.63 Hz, 1H); 4.09 (s,
1H); 1.31 (s, 9H); 1.193 (s, 9H); l13C (CDCl3, 50 MHz):
141.4, 141.2, 129.4, 124.7, 115, 112.3, 51.5, 33.7, 31.3,
29.8; EIMS: m/z (%) 284, 286 (M, 85.8, 82.8), 214 (31.3),
206 (20.2), 150 (21.7), 106 (100). Anal. calcd for
C14H22BrN: C, 59.15; H, 7.74; N, 4.92. Found: C, 59.28;
H, 7.72; N, 4.9%.
12. Nelsen, S. F.; Landis, R. T.; Kiehle, L. H.; Leung, T. H.
J. Am. Chem. Soc. 1972, 94, 1610–1614.
13. Satyanarayana, G.; Sivaram, S. Synth. Commun. 1990,
20, 3273–3276.
14. 5-tert-Butyl-2-tert-butylamino-benzoic acid methyl ester
4: lH (CDCl3, 250 MHz): 7.837 (d, J=2.56 Hz, 1H);
7.296 (dd, J=2.56, 9 Hz, 1H); 6.827 (d, J=9 Hz, 1H);
1.364 (s, 9H); 1.207 (s, 9H); 3.773 (s, 3H); l13C(CDCl3, 50
MHz): 169.22, 148.22, 136.02, 131.17, 127.74, 113.56,
109.60, 51.16, 50.26, 33.42, 31.12, 29.60; EIMS: m/z (%)
263 (M−15, 42.6), 248 (100), 216 (92.2), 192 (75.2). Anal.
calcd for C16H25NO2: C, 72.97; H, 9.57; N, 5.32. Found:
C, 72.82; H, 9.67; N, 5.22%
15. 5-tert-Butyl-2-(tert-butyl-aminoxy)-benzoic acid methyl
ester 5: red oil; EIMS: m/z (%) 263 (M−15, 10) 207 (26.3)
192 (100). Anal. calcd for C16H24NO3: C, 69.04; H, 8.69;
N, 5.03%. Found: C, 68.87; H, 8.89; N, 4.94%. EPR,
toluene, aN=13.63 G, (unresolved aH); EtOH, aN=14.2
G, (unresolved aH).
A solution of carboxylic acid 6 was obtained by dissolv-
ing 1 (5×10−3 M) in molar hydrochloric acid. When 6
was kept under these very acidic conditions during 24 h
at room temperature, the intensity of its ESR signal
only lost half of its initial value. Contrary to other
nitroxides, 6 is thus extremely persistent at pH 1: under
the same conditions, a typical nitroxide, TEMPOL has
a half-life of 5.5 h while another carboxylic acid nitrox-
ide decomposes even much more rapidly.6b
In conclusion we have developed a short synthesis of a
highly water-soluble aromatic nitroxide in five steps.
The bromoaniline 3a, easily available on a gram-scale,
is a potentially useful derivative for the synthesis of
highly substituted aromatic nitroxides, since it may
allow the introduction of a variety of substituents, as
illustrated here by the preparation of 5.
References
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16. Gassman, P. G.; Schenlk, W. N. J. Org. Chem. 1977, 42,
918–920.
17. Potassium 5-tert-Butyl-2-(tert-butyl-aminoxy)-benzoate:
orange solid, mp]250°C; MS (FAB): m/z (%)=264.27
([M−(K+)]−, 59), 248.26 (100). EPR, EtOH, aN=15.64 G,
(unresolved aH); H2O, aN=16.29 G, (unresolved aH).
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