First acetylenic derivatives of stable 3-imidazoline nitroxides

Article abstract of DOI:10.1016/j.tetlet.2004.08.063

The Stephens-Castro reaction of copper(I) salts of 1-aryl(hetaryl)alkynes with 2,2,5,5-tetramethyl-4-[2-(4-iodophenyl)-vinyl]imidazoline-3-oxide-1-ol proved to be a general method for the preparation of 2,2,5,5-tetramethyl-4-[2- (p-aryl(hetaryl)ethynylphe

Full text of DOI:10.1016/j.tetlet.2004.08.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7741–7743
First acetylenic derivatives of stable 3-imidazoline nitroxides
Sergei F. Vasilevsky,a,* Svetlana V. Klyatskaya,a Olga L. Korovnikova,a Dmitri V. Stass,a
d,
Svetlana A. Amitina,b Igor A. GrigirÕevb,c, and Jose Elguero
*
*
´
aInstitute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk,
Russian Federation
bNovosibirskInstitute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk,
Russian Federation
cNovosibirskState University, 630090 Novosibirsk, Russian Federation
d
´ ´
Instituto de Quımica Medica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Received 16 June 2004; revised 11 August 2004; accepted 11 August 2004
Abstract—The Stephens–Castro reaction of copper(I) salts of 1-aryl(hetaryl)alkynes with 2,2,5,5-tetramethyl-4-[2-(4-iodophenyl)-
vinyl]imidazoline-3-oxide-1-ol proved to be a general method for the preparation of 2,2,5,5-tetramethyl-4-[2-(p-aryl(hetaryl)ethynyl-
phenyl)]vinyl-3-imidazoline-3-oxide-1-oxyles.
ꢀ 2004 Elsevier Ltd. All rights reserved.
We have recently reported the synthesis and properties
of a series of spin-labelled charge acceptors that produce
three-spin systems in non-polar and non-viscous alkane
solutions upon X-ray irradiation.1 These products are 2-
imidazoline-1-oxyl derivatives such as 1. Although very
interesting, the 2-imidazoline derivatives present some
drawbacks due to the fact that the radical is conjugated
with the lateral chain, which shortens considerably the
lifetime of the radical, destroying the spin correlation.
To avoid this shortcoming, we thought of compounds
having structure 2; the fact that the chain is now at posi-
tion 4 of the 3-imidazoline ring interrupts the conjuga-
tion and should allow an easier measurement of
magnetic and optical properties.
In general, the field of polyfunctional stable nitroxylic
radicals together with their coordination chemistry and
their physical properties has been often explored.2–5 We
will report in this communication our attempts to synthe-
size a new family of stable nitroxides of the 3-imidazo-
line-3-oxide-1-oles series—the acetylenylnitroxides 2.
Although many studies have been devoted to the chemis-
try of 3-imidazoline-3-oxide-1-oxyls, no acetylenic deriv-
atives of this series have been reported because there were
no known procedures for their synthesis.3,4 Note that an
acetylene bridge is a convenient rigid fragment, which al-
lows to obtain compounds with precise distances between
functional groups, which is fundamental in the design
of high dimensional molecular systems.
O
O
CH3
CH3
CH3
H
3 N
N
CH3
2
C
R
C
C
2
4
5
N
CH3
CH3
N
R
C
C
C
1
O
H3C
CH3
O
H
2
1
Keywords: Imidazoline; Nitroxides; Radicals; Stephens–Castro reaction.
*
Corresponding authors. Tel.: +34 91 4110874; fax: +34 91 5644853 (J.E.); fax: +7 3832 342350 (S.F.V.); e-mail addresses: vasilev@
ns.kinetics.nsc.ru; iqmbe17@iqm.csic.es
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.063

7742
S. F. Vasilevsky et al. / Tetrahedron Letters 45 (2004) 7741–7743
Previously we have developed procedures for the synthe-
sis of spin-labelled acetylenes of the 2-imidazoline-1-
oxyl series, for example, 1, containing either heterocyclic
or carbocyclic residues.1,6,7 Compounds of this general
type are useful model systems for the investigation of
the phenomenon of spin catalysis in recombination of
radical–ion pairs generated upon radiolysis.1,8 For the
reason explained in the introduction, we are interested
in developing a method of synthesis of acetylenic deriv-
atives of 3-imidazoline-3-oxide-1-oxyls, like 2.
tion of a iodoimidazoline with a terminal acetylene using
the Pd(PPh3)2Cl2–CuI–NEt3 system under argon atmos-
phere.6 However, all our attempts to carry out the cata-
lytic variant of the cross-coupling of a bromide bearing
the spin label with 1-alkynes were also unsuccessful: the
reaction resulted in the formation of diamagnetic deriv-
atives, accompanied by the homo-coupling of 1-alkynes.
Probably, the successful application of cross-coupling in
the 2-imidazoline series and the negative result of the
same reaction for 3-imidazoline ones is related to the
strong oxidative properties of the nitroxide group in 3-
imidazoline-3-oxide-1-oxyls compared with the corre-
sponding one in 2-imidazoline-3-oxide-1-oxyl deriva-
tives.5 For this reason, and taking into account the
difference in the mechanisms of Cu- and Pd-catalyzed
reactions, we supposed that the difficulties could be
overcome by using the acetylide synthesis to obtain the
desired alkynylnitroxyles.9,10 Iodoimidazoline (7,
Scheme 2, note that the transformation of hydroxylam-
ine 6 into the radical 7 implies a concomitant oxidation
probably by molecular oxygen),5 prepared by reacting 5
and 6, was introduced into the reaction flask with the
Our first approach aimed at preparing 4 and related
compounds. However, all attempts to use a classical
method for the synthesis of the desired acetylenes—
dehydrobromination
of
vic-dibromoolefins—were
unsuccessful. For instance, reaction of dibromoethylene
3 with either KOH in boiling EtOH, KOH in the pres-
ence of TBAB (tetrabutylammonium bromide), or
KOH in DMSO (Scheme 1) gave a large number of
products, from which acetylene 4 could not be isolated.
Another possible way to prepare acetylenic derivatives
of 3-imidazoline-3-oxide-1-oxyls could be the condensa-
O
CH3
CH3
O
CH3
Br
N
CH3
N
KOH, EtOH
(KOH, TBAB)
N
N
O
O
H3C
Br
CH3
H3C
CH3
3
4
Scheme 1.
O
CH3
CH3
O
H
N
H3C
H
O
N
NaOH
MeOH
N
+
I
I
H3C
H3C
CH3
CH3
O
H3C
O
CH3
N
H
7
OH
5
6
CH3
H
N
CH3
Py
N
+
R
R
Cu
7
O
H3C
CH3
H
8a-8f
2a-2f (56-95%)
CH2
N
O
R =
N
N
O
O
O
CH3O
CH3
O
H3C
3
a
c
d
e
f
b
Scheme 2.

S. F. Vasilevsky et al. / Tetrahedron Letters 45 (2004) 7741–7743
7743
5. Imidazoline Nitroxides; Volodarsky, L. B., Ed.; CRC:
Boca Raton, Florida, 1988, Synthesis and Properties, Vol.
1, 222 pp and Applications, Vol. 2, 160 pp.
6. Vasilevsky, S. F.; Tretyakov, E. V.; Usov, O. M.; Molin,
Yu. N.; Fokin, S. V.; Shwedenkov, Yu. G.; Ikorskii, V.
N.; Romanenko, G. V.; Sagdeev, R. Z.; Ovcharenko, V. I.
Mendeleev Commun. 1998, 6, 216.
7. Tretyakov, E. V.; Samoilova, R. I.; Ivanov, Yu. V.;
Plyusnin, V. F.; Pashchenko, S. V.; Vasilevsky, S. F.
Mendeleev Commun. 1999, 3, 92.
8. Tretyakov, E. V.; Novikova, T. V.; Korolev, V. V.; Usov,
O. M.; Vasilevsky, S. F.; Molin, Yu. N. Russ. Chem. Bull.
Int. Ed. 2000, 49, 1409.
9. Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J.
Chem. Soc., Perkin Trans. 1 1999, 3713.
3330
3340
3350
3360
3370
3380
3390
Magnetic field, G
Figure 1. ESR spectrum of 10À4 M 2a in degassed toluene, room
temperature, microwave power 2mW, modulation amplitude
0.005mT.
10. Vasilevsky, S. F.; Tretyakov, E. V.; Elguero, J. Adv.
Heterocycl. Chem. 2002, 82, 1.
11. Full analytical and spectroscopic data consistent with the
proposed structures have been obtained for all compounds
reported herein. In all cases the ESR spectra were
measured in toluene with 10À5–10À4 M concentration of
radicals. For example, 4-(2-{4-[1-(1-ethoxyethyl)-1H-
pyrazol-4-ylethynyl]-phenyl}-vinyl)-2,2,5,5-tetramethyl-3-
oxide-3-imidazoline-1-oxyl (2d): yield 111mg (94%), mp
169.1–169.9ꢁC (from benzene). IR, cmÀ1: mmax = 2214
(CC); 2935, 2984, 3047 (CH3); 3438 (br); 1H
NMR (200MHz, CDCl3) d, 1.67 (t, OCH2CH3,
J = 7Hz), 1.65 (d, CH–CH3, J = 6Hz), 3.33–3.53 (m,
OCH2CH3), 5.51 (q, CH–CH3, J = 6Hz), 6.72 (br s, Ph–
CH@CH), 7.35–7.73 (m, 3- and 5-H Pz), 7.83 (br s, Ph–
CH@CH). Anal. Calcd for C24H29N4O3: C, 68.39; H, 6.93;
N, 11.39. Found: C, 66.35; H, 7.07; N, 12.09. ESR, G:
previously prepared copper acetylides [8a–f: a, R = Ph;
b, R = Ph–O–CH2; c, R = p–MeO–C6H4; d, 1-(1-ethoxy-
ethyl)-1H-4-pyrazolyl; e, R = 2-pyridyl; f, R = crown
ether] in boiling pyridine.7 The structure of all new com-
pounds, obtained in excellent yields—90–95%—save in
the case of the crown ether 2f, were established by ele-
mental analyses and spectroscopic data.11,12
The ESR spectra of the nitroxides 2 are typical for a 3-
imidazoline radical with spin density localized only at
the N(1)–OÅ fragment (see Fig. 1) contrary to what hap-
pens for 2-imidazoline-1-oxyl derivatives 1 where the
spin density is localized on the two equivalent NO frag-
ments and on the C(2).4–6
giso = 2.0058 AN = 14.11 AH(CH ) (12H) = 0.23, A(13C) =
3
5.93. The yield of compound 2a is 91%, mp 197.3–198.5ꢁC
(from benzene); that of 2b is 92%, mp 161.5–163.3ꢁC
(from benzene–hexane); finally that of 2c is 90%, mp
165.8–167.3ꢁC (from benzene–hexane mixture).
The new compounds 2 show increased stability com-
pared with the previous ones 1, for instance, 2 remain
unaltered after several weeks at room temperature while
1 must be stored in a refrigerator to prevent decomposi-
tion. This is consistent with the behaviour of both
classes of imidazoline nitroxides.5
Compound 2e: yield 84mg (93%), mp 179.9–180.0ꢁC
(from benzene–hexane). IR, cmÀ1: mmax = 2221 (C„C);
2862, 2936, 2981 (CH3); 3423 (br); 1H NMR (200MHz,
CDCl3) d, 6.70 (br s, 1H, Ph–CH@CH), 7.16–7.22 (m, 4H,
H
Ar), 7.47 (d, 1H, H-3(Py), J = 7Hz), 7.71 [t, 1H, H-4(Py),
J = 6Hz], 7.97 (br s, 1H, Ph–CH@CH), 8.64 [d, 1H, H-
6(Py), J = 5Hz]. Anal. Calcd for C22H22N3O3: C, 73.31;
H, 6.15; N, 11.66. ESR, G: giso = 2.0058 AN = 14.11
Acknowledgements
AH(CH ) (12H) = 0.23, A(13C) = 5.93.
3
Compound 2f: yield 90mg (56%), mp 178.8–180ꢁC (from
benzene–hexane). IR, cmÀ1: mmax = 2205 (C„C); 2868,
2934, 2930, 2983 (CH3); 3440 (br); 1H NMR (200MHz,
CDCl3) d, 7.75 (s, 8H, OCH2–CH2O),3.89–3.92 (m, 4H,
OCH2–CH2O), 4.11–4.15 (m, 4H, OCH2–CH2O), 6.91 (d,
1H, Ph–CH@CH), 7.35 (s, 7H, HAr), 7.78 (br s, 1H, Ph–
The research described in this publication was made
possible in part by RFBR Grant No. 02-03-32265 and
Award No. NO-008-X1 of the U.S. Civilian Research
and Development Foundation for the Independent
States of the Former Soviet Union (CRDF). D.V.S. is
grateful to the Science Support Foundation for award-
ing a personal scholarship.
CH@CH). ESR, G: giso = 2.0058AN = 14.11 AH(CH )
3
(12H) = 0.23, A(13C) = 5.93.
12. General procedures of cross-coupling reaction: A stirred
mixture of copper(I) salt of acetylenes 8a–f (0.36mmol)
and iodide 7 (130mg, 0.33mmol) in 10mL of pyridine is
heated to 80–85ꢁC in an argon stream. The heating is
continued for next 3.5–4h until no more iodide 7 is left
(TLC-control). Then CHCl3 (30mL) and water (40mL)
were added. The organic layer is separated and the water
layer is extracted with CHCl3 (2 · 25mL), the combined
organic extracts were washed with 25% NH3 (aq) and then
the organic phase was dried over sodium sulfate, filtered
and evaporated to dryness under reduced pressure. Puri-
fication of the resulting residue by column chromatogra-
phy on silica gel (elution with chloroform) followed by
crystallization gave the corresponding compounds 2a–f.
References and notes
1. Sviridenko, F. B.; Stass, D. V.; Kobzeva, T. V.; Tret-
yakov, E. V.; Klyatskaya, S. V.; Mshvidobadze, E. V.;
Vasilevsky, S. F.; Molin, Y. N. J. Am. Chem. Soc. 2004,
126, 2807.
2. Caneschi, A.; Gatteschi, D.; Rey, P. Prog. Inorg. Chem.
1991, 39, 331.
3. Voldarsky, L. B.; Reznikov, V. A.; Ovcharenko, V. I.
Synthetic Chemistry of Stable Nitroxides; CRC: Boca
Raton, 1994; p 221.
4. Kahn, O. Molecular Magnetism; VCH: New York, 1993.