Synthesis of bifunctionalized nitroxyls via intramolecular epoxide ring opening

Article abstract of DOI:10.1016/S0040-4039(01)02215-8

The syntheses of nitroxyl oxirane and further functionalized derivatives are described. Ring-cleavage reactions of this epoxide have been carried out with a variety of nucleophiles in order to show the general synthetic utility for preparing nitroxyls bearing two functional groups. The relatively facile synthesis of the nitroxyl amino alcohol should prove to be valuable in various spin labeling applications.

Full text of DOI:10.1016/S0040-4039(01)02215-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 553–555
Synthesis of bifunctionalized nitroxyls via intramolecular
epoxide ring opening
Olga A. Ozhogina*
Department of Biochemistry & Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
Received 5 November 2001; revised 19 November 2001; accepted 20 November 2001
Abstract—The syntheses of nitroxyl oxirane and further functionalized derivatives are described. Ring-cleavage reactions of this
epoxide have been carried out with a variety of nucleophiles in order to show the general synthetic utility for preparing nitroxyls
bearing two functional groups. The relatively facile synthesis of the nitroxyl amino alcohol should prove to be valuable in various
spin labeling applications. © 2002 Elsevier Science Ltd. All rights reserved.
Free nitroxyl radicals have had a long history of note-
worthy applications as spin labels. The spin labeling
method has become an important tool in studying the
structure and dynamics of membranes, proteins and
Alkylation of 2 with dimethylsulfonium methylide pro-
ceeds efficiently to produce epoxide 3 in 92% yield; this
transformation is not complicated by side reactions
9
(Scheme 1). The relative concentration of the sulfo-
1
polymers in solution. The synthesis of bifunctionalized
nium salt (1.2 equiv. of ylide) and the reaction temper-
ature (−10°C) are critical for an optimal yield without
side reactions. Epoxide 3 can be purified by flash
chromatography on silica gel without a significant loss
of product. However, 3 is rather easily opened and even
undergoes decomposition during chromatography on
neutral alumina. With the isolated and stable epoxy
nitroxyl in hands, ring opening with almost any nucle-
ophile that is known to open epoxides should present
little difficulty.
nitroxyls is an attractive and powerful challenge in spin
2
label applications. This paper describes a convenient
and practical synthesis of bisfunctionalized nitroxyl
radicals using an epoxide intermediate.
3
Epoxides are important synthons in organic chemistry.
Indeed, the literature confirms that much effort has
been expended on the investigation of epoxide chem-
istry. They are easily prepared from a variety of starting
functional groups and are easily opened under a wide
range of conditions. There are a few methods in the
literature for the syntheses of epoxy nitroxyls. Rozant-
sev and co-workers have shown that 3-bromo-4-
chloroacetyl-2,2,5,5-tetramethyl-pyrroline-1-oxyl could
be reduced to the corresponding chlorohydrin and
Initial attempts to hydrolyze 3 in aqueous THF in the
presence of a Nafion-H perfluorinated resin sulfonic
4
cyclized to the bromo epoxide. The Corey reaction of
carbonyl compounds with sulfur ylides yields an epox-
5
ide as the major or sole product. However, Rosen et
6
al. have reported that the ketone, 2,2,6,6-tetramethyl-
4-piperidone-N-oxyl, did not undergo facile epoxida-
tion by the Corey reaction, and they modified the
procedure to form instead the oxaspiro-oct-N-oxyl. In
the present work, the Corey reaction was applied to the
7
unsaturated aldehyde 2.
*
Present address: Department of Chemistry, Carnegie Mellon Uni-
versity, Pittsburgh, PA 15213, USA. Tel.: 412 268 3134; fax: 412
2
68 1061; e-mail: olgao@andrew.cmu.edu
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02215-8

5
54
O. A. Ozhogina / Tetrahedron Letters 43 (2002) 553–555
1
0
acid catalyst met with little success. This procedure
gave extremely low yields of the hydration product and
incomplete conversion. The reaction mixture contained
large proportions of intractable material. Clearly, in
addition to extensive polymerization reactions, one of
the major pathways for loss of the diol is deactivation
of the catalyst (due to reaction with the nitroxyl radi-
cal), which could not be regenerated for further use. To
circumvent these difficulties, we advantageously
employed the alkaline hydrolysis of 3 in dimethyl sulf-
azide moiety would not compete well with the nitroxyl
group. Fortunately, Ph P reduces 5 cleanly to the corre-
3
17
sponding amino alcohol 6. In a typical procedure, a
solution of 5 in THF in the presence of water (1:2
equiv.) at room temperature was treated with
triphenylphosphine until its complete consumption was
observed by TLC. A standard extractive workup
afforded crude amino alcohol 6, which could be iso-
lated chromatographically in 78% yield. In addition,
there is flexibility in the choice of the amine nucleophile
to be used, since opening has also been observed with
allylamine as the nucleophile. In summary, the ease of
the epoxide-opening strategy employed herein is
expected to lead to more efficient syntheses of other
spin labels of biological importance.
11
oxide. It is known from Berti et al. that Me SO is
2
inert to epoxides and it also provides maximum reactiv-
ity for the nucleophile. In view of this fact, when
epoxide 3 is heated with potassium hydroxide in 85%
aqueous dimethyl sulfoxide, the corresponding diol 4 is
12
obtained in fairly good yield (Scheme 2).
1
3
In the Gabriel synthesis, N-substituted phthalimides
are hydrolyzed to afford primary amines and amino
compounds. However, reaction of epoxide 3 with
phthalimide and a catalytic amount of its potassium
salt did not show uniformity in products obtained. All
attempts to find conditions which directly produced the
desired Gabriel product failed; this route was conse-
quently abandoned. Alternatively, we synthesized
Acknowledgements
Financial support by Raphael Lee of the Department
of Surgery is gratefully acknowledged. The author
thanks Viresh Rawal of the Department of Chemistry
for useful discussions and John A. Desjardins of the
Department of Chemistry for his help with the MS
characterization.
14
amino alcohol 5 (Scheme 3) by ring cleavage of 3 with
sodium azide followed by reduction. The conversion of
an epoxide to the corresponding azido alcohol can be
accomplished by treatment with NaN and NH Cl in
References
3
5
4
1
8
0% ethanol at room temperature. Indeed, NaN3
proved to be an excellent nucleophile for the ring
opening of 3. Azidotization of 3 provides the azido
alcohol 5 in 91% yield.
1. (a) Rozantsev, E. G. Free Nitroxyl Radicals; Plenum
Press: New York, 1970; (b) Magnetic Resonance;
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Although nitroxyls are extraordinary stable free radi-
cals, they may be destroyed (with loss of paramag-
1a
netism), under reducing conditions. One of the routes
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4
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Scheme 2.
Scheme 3.

O. A. Ozhogina / Tetrahedron Letters 43 (2002) 553–555
555
pared as described by Rozantsev (Ref. 1) and was con-
verted to the acid chloride by treatment with thionyl
chloride and pyridine in benzene solution. Reduction
over MgSO . The solvent was removed to give a crude
4
product which was purified by column chromatography
(silica gel, 2:1 pentane/ethylacetate) to give the azido
alcohol (0.225 g, 91%). Mass spectrum (70 eV), m/z 225
with LiAlH(O-t-Bu) was carried out as described previ-
3
8
+
ously, with a modification in the purification scheme.
(M ).
The crude aldehyde was purified by column chromatogra-
13. Gibson, M. S.; Bradshaw, R. W. Angew. Chem., Int. Ed.
1968, 7, 919.
phy (silica gel, 8:2 pentane/ethylacetate), yielding 65% of
+
2
. Mass spectrum (70 eV), m/z 168 (M ).
14. 3-[Ethyl-1-hydroxy-2-amino]-2,2,5,5-tetramethyl-pyrroline-
1-oxyl 5. The azido alcohol (0.2 g, 0.8 mmol) obtained
from the above reaction in THF (1 mL) was reduced with
triphenylphosphine (0.233 g, 0.8 mmol) to the corre-
sponding amine in the presence of water (0.025 mL). The
reaction mixture was stirred at room temperature for 12
h, the solvent was evaporated, and a mixture of ether and
petroleum ether (1:1) was added. Triphenylphosphine
oxide which formed was removed by filtration, and the
filtrate was concentrated under reduced pressure. The
residue obtained was purified by column chromatography
(silica gel, 1:1 ethyl acetate/methanol) to afford the pure
8
9
. Mustafi, D.; Boisvert, W. E.; Makinen, M. W. J. Am.
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. 3-Epoxyethyl-2,2,5,5-tetramethyl-pyrroline-1-oxyl 3.
A
mixture of 0.15 g (6.29 mmol) of powdered sodium
hydride in 4 mL of dry Me SO was heated at 65°C for 1
2
h under argon. The mixture was cooled to room temper-
ature and diluted with 5 mL of dry THF and cooled in a
NaCl ice bath. A solution of 1.28 g (6.29 mmol) of
trimethylsulfonium iodide in 5 mL of dry Me SO was
2
added, in portions, at −10°C under argon. The mixture
was stirred for 5 min, and 0.88 g (5.24 mmol) of 3-for-
myl-2,2,5,5-tetramethyl-pyrroline-1-oxyl was added. The
reaction was stirred at −10°C for 30 min and at room
temperature for 2 h. It was then poured into 90 mL of
water and extracted with ether (5×50 mL). The combined
amino alcohol in 78% yield (138 mg). Mass spectrum (70
+
eV), m/z 199.1848 (M 199.1446 calcd for C10
H
N
2
O
).
2
19
15. (a) Swift, G.; Swern, D. J. Org. Chem. 1967, 32, 511–517;
(b) Begue, J. P.; Bonnet-Delpon, D.; Fischer-Durand, N.;
Reboud-Ravaux, M. Tetrahedron: Asymmetry 1994, 5,
1099–1110.
organics were dried over MgSO and concentrated. The
4
crude epoxide was chromatographed on silica gel eluted
with 5:1 pentane/ethylacetate to yield 92% of the desired
16. Knouzi, N.; Vaultier, M.; Carrie, R. Bull. Soc. Chim. Fr.
1985, 5, 815–819.
epoxide as a red oil. Mass spectrum (70 eV), m/z
+
1
82.1190 (M 182.1181 calcd for C H NO ).
17. 3-[Ethyl-1,2-diol]-2,2,5,5-tetramethyl-pyrroline-1-oxyl
6.
10
16
2
1
1
1
0. Olah, G. A.; Fung, A. P.; Meidar, D. Synthesis 1981,
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1. Berti, G.; Macchia, B.; Macchia, F. Tetrahedron Lett.
965, 6, 3421.
2. 3-[Ethyl-1-hydroxy-2-azido]-2,2,5,5-tetramethyl-pyrroline-
-oxyl 4. A solution containing 0.2 g (1.1 mmol) of
epoxide 2, NH Cl (0.12 g, 2.2 mmol), and NaN (0.14 g,
Epoxide 2 (0.2 g, 1.1 mmol) was dissolved in DMSO (8.5
mL), and a solution of potassium hydroxide (0.168 g, 3
mmol) in water (1.5 mL) was added. The mixture was
stirred at 100°C for 12 h. When the starting oxirane could
no longer be detected by TLC, the reaction mixture was
cooled to room temperature, neutralized with HCl, and
the solvent was evaporated. The crude product was chro-
matographed on silica gel eluted with ethylacetate to
2
1
1
4
3
2
.2 mmol) in 5 mL of 80% EtOH was stirred at room
temperature for 12 h. Water (5 mL) was added to this
mixture, which was then extracted with ether and dried
yield 60% of the desired diol. Mass spectrum (70 eV), m/z
+
200.1704 (M 200.1286 calcd for C10
H18NO ).
3