Copper(II)/copper(I)-catalyzed aza-michael addition/click reaction of in situ generated α-azidohydrazones: Synthesis of novel pyrazolone-triazole framework

Article abstract of DOI:10.1021/ol902642z

[Chemical equaction presented] A one-pot Cu(II)-catalyzed aza-Michael addition of trlmethylsllyl azide to 1, 2-diaza-1, 3-dlenes and Cu(I)-catalyzed 1, 3-dipolar cycloaddition of in situ generated α-azidohydrazones with alkynes is reported. This process combining two consecutive steps with recycling of the catalyst (Cu(OAc)²-H₂O) represents a useful protocol for the smooth synthesis of novel pyrazolone-trlazole derivatives.

Full text of DOI:10.1021/ol902642z

ORGANIC
LETTERS
2010
Vol. 12, No. 3
468-471
Copper(II)/Copper(I)-Catalyzed Aza-Michael
Addition/Click Reaction of in Situ
Generated r-Azidohydrazones: Synthesis
of Novel Pyrazolone-Triazole Framework
Orazio A. Attanasi, Gianfranco Favi,* Paolino Filippone, Fabio Mantellini,
Giada Moscatelli, and Francesca R. Perrulli
Istituto di Chimica Organica, UniVersita` degli Studi di Urbino “Carlo Bo”, Via I
Maggetti 24, 61029 Urbino (PU), Italy
gianfranco.faVi@uniurb.it
Received November 16, 2009
ABSTRACT
A one-pot Cu(II)-catalyzed aza-Michael addition of trimethylsilyl azide to 1,2-diaza-1,3-dienes and Cu(I)-catalyzed 1,3-dipolar cycloaddition of in
situ generated r-azidohydrazones with alkynes is reported. This process combining two consecutive steps with recycling of the catalyst
(Cu(OAc)2·H2O) represents a useful protocol for the smooth synthesis of novel pyrazolone-triazole derivatives.
Nitrogen-containing heterocycles (azaheterocycles) occur in a
wide variety of natural and biologically active compounds.1
From a recent survey of GMP bulk reactions run in a research
facility (Pfizer-Groton) it is estimated that over 90% of
pharmaceutical have at least one nitrogen atom in their structure
and about one reaction out of seven in the pharmaceutical
industry involves the formation of a carbon-nitrogen bond.2
For these reasons, efficient methods for the synthesis of
nitrogen-containing molecules merits further investigations.
Surprisingly, little attention has been focused on the copper-
promoted C-N bond formation-based protocols.3 Among them,
undoubtedly, “click reaction”4 and in particular Huisgen [3 +
2] cycloaddition5 has emerged as a “near perfect” (very fast,
selective, high-yield, and wide scope) carbon-nitrogen bond
forming reaction toward the synthesis of N-substituted 1,2,3-
triazoles. This process that occurs between organic azides and
alkynes is significantly accelerated by Cu(I) catalysis,6 and it
offers easy access to the 1,4-disubstituted isomer. 1,2,3-Triazoles
have found numerous applications ranging from chemical and
combinatorial synthesis, bioconjugation and biology, to material
science, especially polymer and dendrimer synthesis.7 Despite
(4) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021.
(5) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; Vol. 1, pp 1-177.
(6) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057–3062. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
(7) For general reviews on the chemistry of 1,2,3-triazoles, see: (a) Fan,
W.-Q.; Katritzky, A. R. ComprehensiVe Heterocyclic Chemistry II; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford,
1986; Vol. 4, pp 1-126. For some applications in organic synthesis, see:
(b) Dichtel, W. R.; Miljanic, O. S.; Spruel, J. M.; Health, J. R.; Stoddart,
J. F. J. Am. Chem. Soc. 2006, 128, 10388–10390. In combinatorial
chemistry, see: (c) Rodriguez-Loaiza, P.; Lo¨ber, S.; Hu¨bner, H.; Gmeiner,
P. J. Comb. Chem. 2006, 8, 252–261. In bioconjugation, see: (d) Cavalli,
S.; Tipton, A. R.; Ovarhand, M.; Kros, A. Chem. Commun. 2006, 3193–
3195. In materials and surface science, see: (e) Such, G. K.; Quinn, J. F.;
Quinn, A.; Tjipto, E.; Caruso, F. J. Am. Chem. Soc. 2006, 128, 9318–9319.
(1) See, for example: The Alkaloids: Chemistry and Biology; Cordell,
G. A., Ed.; Academic Press: San Diego, CA, 2000; Vol. 54;and others in
this series.
(2) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337–2347. (b) Duggers, R. W.; Ragan, J. A.;
Brown Ripin, D. H. Org. Process Res. DeV. 2005, 9, 253–258.
(3) For a review on copper-mediated coupling reactions and their
applications in natural products and designed biomolecules synthesis, see:
Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054–3131.
10.1021/ol902642z  2010 American Chemical Society
Published on Web 12/31/2009

their importance as reported from a myriad of synthetic methods
existing for their preparation,8 relatively few examples are
known to give N-triazole-based heterobicycles. For example, a
series of 4-(1-aryl-triazol-4-yl)-tetrahydropyridines was identi-
fied as an orally active new class of metabotropic glutamate
receptor 1 (mGluR1) antagonist.9 Also, a synthesis of a large
library of pure fluorescent triazolylcoumarin dyes using
azide-alkyne ligation was reported.10
Scheme 1
. One-Pot Copper-Catalyzed Azidation (Aza-Michael)/
Huisgen 1,3-Dipolar Cycloaddition Reaction
Here, we report an interesting application of the “click
reaction” to R-azidohydrazones with the aim to obtain new
heterobicyclic scaffolds.
The previous experience of some of us in the use of
2-chlorohydrazones for the synthesis of 2-oxohydrazones via
R-azidohydrazone intermediates11 has prompted us to investi-
gate alternative synthetic applications of these and related
substrates. Thus, based on this study and continuing our
investigations on the utility of the 1,2-diaza-1,3-dienes (DDs)12
in organic synthesis, we postulated that R-azidohydrazones
could be directly employed in copper-mediated azide-alkyne
1,3-dipolar cycloaddition (CuAAC) to give R-triazolehydra-
zones, which could be a useful precursor for the construction
of linked small heterocycles. We reasoned that in the presence
of an opportune reagent of azidation reaction, DD compound
1 would be transformed into the corresponding azido derivative
A (and AI) which, in turn, could be converted in situ into 1,4-
disubstituted-1,2,3-triazoles 3. Thus, the process would provide
a one-pot conversion of the azo-ene systems of DDs into
R-triazolehydrazone, where the copper(II) acetate monohydrate
would fulfill a dual role, acting as a catalyst in both steps. The
essential element of this procedure is the generation of a Cu(I)
species required for the azide-alkyne cycloaddition by adding
a reducing agent (sodium ascorbate) after complete Cu(II)-
catalyzed azido addition (Scheme 1).
reaction was observed in the absence of Cu(I) or when Cu(I)
salts (CuCl in THF or toluene at rt or reflux) were employed.
In addition, the use of acqueous solvent systems such as polar
solvents (for example THF, CH3CN, MeOH, DMF) led to the
formation of undesirable 2-oxohydrazone byproduct11 with
consequent lower yields. Among all of the solvents examined,
dichloromethane was the only one where the reaction proceeded
without appreciable amount of byproducts.
On the other hand, we also found that the copper(II)-catalyzed
aza-Michael additions proceeded smoothly to completion (15
min at rt as analyzed by TLC) in CH2Cl2 and almost quantitative
yields to give hydrazonic 1,4-adducts A (and AI). Various
copper(II) Lewis acids such as CuSO4·5H2O, Cu(OAc)2·H2O,
CuCl2, Cu(TfO)2, Cu(NO3)2, and CuO exhibited remarkable
catalytic activity. Our choice of Cu(OAc)2·H2O14 was based
on the higher stability, greater affinity for soft ligands (e.g.,
alkynes), together with lower cost with respect to other tested
catalysts.
Given this designed strategy, we chose the DD 1a as the
standard substrate in our efforts to find an effective condition
for a sequential one-pot procedure.
In orienting experiments, we showed that the presence of
the copper(II)/sodium ascorbate13 system [Cu(OAc)2·H2O/Na
ascorbate (1:2)/THF-H2O (1:1) (yield ) 47%), CuSO4·5H2O/
Naascorbate(1:2)/THF-H2O(1:1)(yield)43%),andCuSO4·5H2O/
Na ascorbate (1:2)/t-Bu-H2O (1:1) (yield ) 52%)] proved to
be essential for the Huisgen 1,3-dipolar cycloaddition. No
Therefore, 1,4-addition of trimethylsilyl azide (TM-
SN3)15,16 to DD 1a was carried out in the presence of
(8) For recent reviews on the preparation of a wide variety of triazole-
containing molecules by CuAAC, see: (a) Meldal, M.; Tornøe, C. W. Chem.
ReV. 2008, 108, 2952–3015. (b) Bock, V. D.; Hiemstra, H.; van Maarseveen,
J. H. Eur. J. Org. Chem. 2006, 51–68. (c) Kolb, H. C.; Sharpless, K. B.
Drug. Disc. Today 2003, 8, 1128–1137.
17,18
catalytic amount of Cu(OAc)2·H2O in CH2Cl2
at room
temperature (Table 1, entry 1). After the disappearance of
the starting DD, the check of the crude mixtures by the TLC
analysis revealed the presence of two products as major
components, easily identified as the desilylated (A) and the
(9) Ito, S.; Satoh, A.; Nagatomi, Y.; Hirata, Y.; Suzuki, G.; Kimura, T.;
Satow, A.; Maehara, S.; Hikichi, H.; Hata, M.; Kawamoto, H.; Ohta, H.
Bioorg. Med. Chem. 2008, 16, 9817–9829.
(10) Sivakumar, K.; Xie, F.; Cash, B. M.; Long, S.; Barnhill, H. N.;
Wang, Q. Org. Lett. 2004, 6, 4603–4606.
(14) For copper(II) acetate monohydrate as catalyst in the Michael
reaction, see: Coda, A. C.; Desimoni, G.; Rigetti, P.; Tacconi, G. Gazz.
Chim. Ital. 1984, 114, 417–420.
(11) Attanasi, O. A.; Serra-Zanetti, F.; Liao, Z. Tetrahedron 1992, 48,
2785–2792.
(12) For review on the chemistry of DDs, see: (a) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.;
Santeusanio, S. Eur. J. Org. Chem. 2009, 3109–3127. For recent examples,
see: (b) Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.; Giorgi,
G.; Mantellini, F. AdV. Synth. Catal. 2009, 351, 715–719. (c) Attanasi, O. A.;
Favi, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S. Org. Lett. 2008, 11,
309–312.
(15) TMSN3 has been frequently employed for introduction of the azido
group because of its handy property: Groutas, W. C.; Felker, D. Synthesis
1980, 861–868. For use of TMSN3 as versatile reagent in organic synthesis,
see: Jafarzadeh, M. Synlett 2009, 2144–2145
.
(16) For examples of TMSN3 as azide source in Michael addition, see:
(a) Castrica, L.; Fringuelli, F.; Gregoli, L.; Pizzo, F.; Vaccaro, L. J. Org.
Chem. 2006, 71, 9536–9539, and references cited herein. (b) Adamo, I.;
Benedetti, F.; Berti, F.; Campaner, P. Org. Lett. 2006, 8, 51–54. (c) Guerin,
(13) For use of L-ascorbic acid in organic synthesis, see: Fu¨ger, B. Synlett
2009, 848–849.
D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999, 1, 1107–1109
.
Org. Lett., Vol. 12, No. 3, 2010
469

Table 1. One-pot Synthesis of the R-Triazolehydrazones 3a-g
and 3a′-d′ from DDs 1a-g, TMSN3, and Phenylacetylene 2a.
Table 2. One-Pot Synthesis of the R-Triazolehydrazones 3h-n
and 3h′-n′ from DD 1a, TMSN3, and Alkynes 2b-h.
1,2-diaza-1,3-diene 1
R1
R-triazolehydrazone 3
yield
t (h) (%)b
alkyne 1
R3
R-triazolehydrazone 3
yield
(%)b,c
1
R
R2
Me 3a/3a′ (53/47) 1.5
Me 3b/3b′ (49/51)
Me 3c/3c′ (50/50) 2.5
3a
2
3a
t (h)
1a t-BuO
1b EtO
1c Me2N
1d MeO
H
H
H
H
60c
54c
43c
47c
45d
48d
59d
2b
2c
2d
2e
2f
n-Bu
CH2OH
SiMe3
p-Me-C6H5
p-OMe-C6H5
CO2Et
3h/3h′ (62/38)
3i/3i′ (71/29)
3j/3j′ (68/32)
3k/3k′ (59/41)
3l/3l′ (81/19)
3m/3m′ (65/35)
3n/3n′ (78/22)
2
5
5
1.5
3
65
41
54
52
58
40
51
2
Et 3d/3d′ (46/54)
Me 3e (100)
Me 3f (100)
2
4
2
4
1e MeO(CH2)2O Ph
1f EtO
Ph
2g
2h
4
0.6
1g MeO
m-F-C6H4 Me 3g (100)
COMe
a Ratio was determined by 1H NMR spectroscopy on the mixture of the
purified products. b Yield of the isolated purified compounds 3a-g and
3a′-d′ based on the phenylacetylene 2a. c Conditions: DD (1 mmol), CH2Cl2
(5 mL), Cu(OAc)2·H2O (0.2 mmol), TMSN3 (1.1 mmol), phenylacetylene
(1.0 mmol), sodium ascorbate (0.4 mmol), H2O (5 drops). d Phenylacetylene
2a (0.5 mmol) was used.
a Ratio was determined by 1H NMR spectroscopy on the mixture of the
purified products. b Yield of the isolated purified compounds 3h-n and
3h′-n′ based on the alkynes 2b-h. c Conditions: DD (1 mmol), CH2Cl2
(5 mL), Cu(OAc)2·H2O (0.2 mmol), TMSN3 (1.1 mmol), alkyne (1.0 mmol),
sodium ascorbate (0.4 mmol), H2O (5 drops).
Encouraged by these results, we examined the feasibility
of a one-pot copper(II) acetate-catalyzed aza-Michael addi-
tion/click reaction with various DDs20 under these optimized
conditions. It was found that this procedure works well for
a wide range of different DDs 1a-g21 (Table 1, entries 1-7).
So R-triazolehydrazones 3a-g and 3a′-d′ were obtained
in moderate to good yields (43-60%).
Motivated by the importance of the final target to develop
new general method toward widely functionalized pyrazolone-
triazole framework, we next examined the extension of this
procedure to other alkynes. The reaction proceeded effectively
with aliphatic and aromatic terminal acetylenes to give the
corresponding R-triazolehydrazones 3h-n and 3h′-n′ (Table 2).
Thus, a variety of 1,4-disubstituted-1,2,3-triazoles, con-
taining alkylic residue (enty 1), primary aliphatic alcohol
(entry 2), silyl group (entry 3) as well as electron-donating
aryl groups (entries 4 and 5), electron-withdrawing groups
(carboxy and carbonyl; entries 6 and 7) at the C-4 position
of the triazole ring were obtained.
silylated (AI) azidohydrazonic 1,4-adducts, respectively.
Similar behavior was observed by our group during the
Mukaiyama-Michael addition of enolsilyl derivatives to
DDs.19 After complete conversion of DD 1a, phenylacety-
lene, sodium ascorbate reducing agent, and five drops of
water were added directly to the reaction mixture without
any workup procedure. Also in this step, both R-triazolehy-
drazones 3a and 3a′ were observed from the TLC analysis.
In an attempt to optimize the efficiency of this reaction,
we have changed the ratio of the alkyne employed. It was
observed that upon increasing the amount of phenylacetylene
no significant improvement of the yield was observed.
Moreover, the best results were obtained using 20% mol of
Cu(OAc)2·H2O and 40% of sodium ascorbate; only in this
case did the TLC analysis of crude reaction mixture reveal
that starting DD 1a and successively R-azidohydrazone
intermediates (A and AI) were completely consumed.
Moreover, as expected, disubstituted acetylene, such as
diphenylacetylenes and dimethyl acetylene dicarboxylate, did
not react under these reaction conditions.
(17) Attention: The main concern about this one-pot procedure may
appear a serious safety issue. In fact it is well documented in the literature
that ionic azides react with dichloromethane to form explosive azido-
chloromethane and/or diazidomethane. See: (a) Conrow, R. E.; Dean, W. D.
Org. Process Res. DeV. 2008, 12, 1285–1286. (b) Hassner, A.; Stern, M.;
Gottlieb, H. E. J. Org. Chem. 1990, 55, 2304–2306. Luckily, under our
reaction conditions (short reaction times, stoichiometric amount of TMSN3),
the possible competitive nucleophilic substitution on CH2Cl2 is effectively
suppressed since the Michael addition is the favorite and exclusive pathway.
(18) Caution: organic azides are potentially explosive compounds (when
dry) and should be handled with great care. During our studies we used
TMSN3 and we encountered no problem.
(20) For representative examples of one-pot synthesis of 1,2,3-triazoles,
see: (a) Li, J.; Wang, D.; Zhang, Y.; Li, J.; Chen, B. Org. Lett. 2009, 11,
3024–3027. (b) Jaroslaw, K.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008,
10, 3171–3174. (c) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.;
Vicente, R. Org. Lett. 2008, 10, 3081–3084. (d) Beckmann, H. S. G.;
Wittmann, V. Org. Lett. 2007, 9, 1–4. (e) Appukkuttan, P.; Dehaen, W.;
Fokin, V. V.; Van der Eycken, E. Org. Lett. 2004, 6, 4223–4225.
(21) DDs 1a-g were synthesized from the corresponding chlorohydra-
zones by treatment with base (see Supporting Information).
(19) Attanasi, O. A.; Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.;
Spinelli, D.; Stenta, M. AdV. Synth. Catal. 2007, 349, 907–915.
470
Org. Lett., Vol. 12, No. 3, 2010

Table 3. Synthesis of 1-(3-Oxo-2,3-dihydro-1H-pyrazol-4-yl)-1,2,3-triazoles 4a-k from R-Triazolehydrazones 3a-n and 3a′-d′,
h′-n′.
R-triazolehydrazone 3
pyrazolone-triazole 4
3a
R
R1
R2
R3
4
t (h)
yield (%)b,c,d
3a/3a′ (53/47)
3b/3b′ (49/51)
3c/3c′ (50/50)
3d/3d′ (46/54)
3e (100)
t-BuO
EtO
Me2N
MeO
MeO(CH2)2O
EtO
H
H
H
H
Ph
Ph
Me
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
CH2OH
SiMe3
p-Me-C6H5
p-OMe-C6H5
CO2Et
4a
4a
4a
4b
4c
4c
4d
4e
4f
4g
4h
4i
4j
4k
0.1
0.1
2
99
95
98
93
97
99
94
87
98
78
94
96
95
97
0.1
0.1
0.2
0.2
0.3
0.5
0.3
0.3
0.8
0.3
0.3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3f(100)
3g (100)
MeO
m-F-C6H4
3h/3h′ (62/38)
3i/3i′ (71/29)
3j/3j′ (68/32)
3k/3k′ (59/41)
3l/3l′ (81/19)
3m/3m′ (65/35)
3n/3n′ (78/22)
a
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
1
H
H
H
H
H
H
H
COMe
Ratio was determined by H NMR spectroscopy on the mixture of the purified products. b Yield of the isolated purified compounds 4a-k based on
R-triazolehydrazones3a-nand3a′-d′,h′-n′.c Conditions:R-triazolehydrazones(1mmol),CH3OH(5mL),K2CO3(1mmol).d 1-(3-Oxo-2,3-dihydro-1H-pyrazol-4-yl)-1,2,3-triazoles
were obtained after treatment with cation-exchange resin [Dowex HCRS(E)].
These studies revealed that a single inexpensive copper
catalyst (Cu(OAc)2·H2O) sequentially enabled two sustainable
catalytic transformations, aza-Michael addition and “click
reactions”, to furnish R-triazolehydrazone derivatives. Thus,
the process internally recycles an upstream reaction catalyst
to provide a new catalyst for a downstream reaction.22
Therefore, with the identification of such a system, we
disclosed an attractive synthetic approach that could serve
as the basis for the future developments toward planning
reaction cascade, particularly useful when active, unstable
intermediates as well as organic azides are involved.
Finally, the whole utility of this procedure was demonstrated
in the synthesis of different novel pyrazolone-triazole frame-
works. Thus, a subsequent cyclization process to give the
pyrazol-5-one ring was carried out under basic conditions
(potassium carbonate). The reaction proceeds by means of the
intramolecular nucleophilic attack of the nitrogen atom of the
hydrazino moiety (CdN-NH) on the ester/amide function in
the γ position with loss of an alcohol/amine molecule to give
the pyrazole ring closure. By this procedure, 1-(3-oxo-2,3-
dihydro-1H-pyrazol-4-yl)-1,2,3-triazoles 4a-k from 1,4-disub-
stituted-1,2,3-triazoles 3a-n and 3a′-d′,h′-n′ were easily
achieved (Table 3). It is noteworthy that the overall process
(1f4) involved the formation of four C-N bonds and two
heterocyclic scaffolds in a selective and efficient manner.
In conclusion, we developed an efficient pyrazolone-triazoles
synthesis relying on click reactions with in situ generated
R-azidohydrazones. Thus, we described the use of DDs for the
title heterobicyclic scaffold through a reaction sequence com-
prising “aza-Michael addition/1,3-dipolar cycloaddition/azahet-
erocyclization”. The copper-“assisted-tandem catalysis” involves
internal recycling catalyst avoiding isolation and handling of
potentially unstable organic azide intermediates. Further inves-
tigations are still in progress in our laboratory to improve utility
and application of this synthetic methodology.
Acknowledgment. This work was supported by the
financial assistance from the Ministero dell’Universita`,
dell’Istruzione e della Ricerca (MIUR)-Roma and the Uni-
versita` degli Studi di Urbino “Carlo Bo”.
(22) For reviews on single-pot catalysis of different transformations,
see: (a) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.sEur. J. 2009, 15,
12168–12179. (b) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. Engl.
2004, 43, 3754–3760. For some interesting examples of sustainable synthetic
methods, see: (c) Alaimo, P. G.; O’Brien, R., III.; Johnson, A. W.; Slauson,
S. R.; O’Brien, J. M.; Tyson, E. L.; Marshall, A.-L.; Ottinger, C. E.; Chacon,
J. G.; Wallace, L.; Paulino, C. Y.; Connell, S. Org. Lett. 2008, 10, 5111–
5114. (d) Heutling, A.; Pohlki, F.; Byschkov, I.; Doye, S. Angew. Chem.,
Int. Ed. 2005, 44, 2951–2954. (e) Tan, K.-T.; Chng, S.-S.; Cheng, H.-S.;
Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 2958–2963.
Supporting Information Available: Experimental pro-
cedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL902642Z
Org. Lett., Vol. 12, No. 3, 2010
471