Fluorescence sensing of Cu(II) based on trisphaeridine derivatives

Article abstract of DOI:10.1016/j.tet.2013.04.009

The design, synthesis, and ion-sensing properties of new 7,11-diaryltrisphaeridines are described. 2-Thiophenyl and 2-furanyl derivatives behave as highly selective fluorescence chemosensors for Cu²⁺ cations, with limits of detection (LOD) of 3

Full text of DOI:10.1016/j.tet.2013.04.009

Tetrahedron xxx (2013) 1e5
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Fluorescence sensing of Cu(II) based on trisphaeridine derivatives
*
Alegría Caballero, Pedro J. Campos, Miguel A. Rodríguez
ꢀ
~
Departamento de Química, Centro de Investigacion en Síntesis Química, Universidad de La Rioja, Madre de Dios, 51, E-26006 Logrono, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The design, synthesis, and ion-sensing properties of new 7,11-diaryltrisphaeridines are described.
2-Thiophenyl and 2-furanyl derivatives behave as highly selective fluorescence chemosensors for Cu2þ
Received 14 February 2013
Received in revised form 27 March 2013
Accepted 1 April 2013
cations, with limits of detection (LOD) of 3.8 and 12.9
(ca. 20
lowers the LOD to 1.1
m
M, respectively, i.e. below the toxic level of Cu2þ
m
M); while the presence of 2-methoxyphenyl groups favors the selective detection of Cu2þ and
Available online xxx
m
M.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Trisphaeridines
Fluorescence
Sensing
Cupric ion
1. Introduction
and molecular sensors. Moreover, the green emission disappears on
addition of HCl and this material can therefore be used as a sensor
for protons. Trisphaeridine, which is found in the plants of the
family Amaryllidaceae, displays excellent antiproliferative effects
on both human and mouse cell lines.18 The ease with which the
substituent can be varied, the diverse and significant pharmaco-
logical and biological activities and the interesting photophysical
properties of trisphaeridine derivatives prompted us to consider
the design of systems that can act as sensors for metals. In this
respect, the presence of another heteroatom to favor the chelation
of metal cations through the formation of six- or seven-membered
rings seems a suitable alternative (Fig. 1).
Metal cations play a major role in many biochemical processes
and, as a result, the development of sensors to detect metal ions has
increased in significance in recent years.1 In particular, fluorescence
sensing has received a great deal of attention because of its sim-
plicity, high sensitivity, and real-time in situ imaging.2 A large
number of luminescent sensors for metal cations have been de-
scribed. A selection of the numerous examples that can be found in
the literature include the following: Zn2þ sensing has been ach-
ieved with fluorescein,3 coumarin,4 and quinoline5 derivatives and
even with silica nanoparticles,6 while boradiazaindazenes7 and
some semi-rigid molecules8 act as a Cd2þ sensors. A number of
structures based on rhodamine9 or iminoquinoline10 have been
described as Cu2þ sensors and structures based on cysteine,11 ter-
penoids12 or azobenzene13 were designed to detect Hg2þ. In addi-
tion, imidazole-annelated ferrocenes,14 naphthalenes,15 and
R
aminophthalimides16 have proven useful as chemosensors for Pb2þ
Fe3þ, and Cr3þ, respectively.
,
I
We recently published the preparation of a series of diaryltri-
sphaeridines by iodination of trisphaeridine and subsequent Suzuki
coupling (Scheme 1).17 The photophysical properties of these
compounds depend on the substituents. Interestingly, the presence
of 4-dimethylaminophenyl groups induces a bright green emission,
thus making this compound promising for fluorescence devices
O
O
O
O
Ar B(OH)2
N
Pd(PPh3)4
DME
K2CO3
N
I
1
2
R = H, Ph, Cl, CN, OMe, NMe2
R
* Corresponding author. Tel.: þ34 941299651; fax: þ34 941299621; e-mail
Scheme 1. Synthesis of diaryltrisphaeridines.
address: miguelangel.rodriguez@unirioja.es (M.A. Rodríguez).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.009
Please cite this article in press as: Caballero, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.009

2
A. Caballero et al. / Tetrahedron xxx (2013) 1e5
useful but as the concentration increases it becomes toxic and in-
terferes with cell metabolism. Therefore, it is very important to
have sensors that are capable of detecting this element.
X
X
The changes in the emission spectrum of 3 in acetonitrile
O
O
M
(40
mM, lexc¼355 nm) upon addition of Cu(ClO4)2 are shown in
N
Fig. 4. It can be observed that the addition of increasing amounts of
Cu2þ cations caused a progressive decrease in the band at 435 nm
and the appearance of a band at 575 nm. Unfortunately, evidence
for the formation of a complex of 3 with Cu2þ could not be obtained
from the ESI-MS spectra or by X-ray crystallography. On the other
hand, as shown in Fig. 4, the presence of 0.96 equiv is sufficient to
induce the greater part of the changes in the emission spectrum,
but further increases in the amounts of Cu2þ induce a subsequent
decrease of the band at 435 nm and an increase in the band at
575 nm. Consistently, coordination of receptor 3 with Cu2þ can be
proposed to occur with a stoichiometry of either 1:1 or 1:2.
6
7
Fig. 1. Chelation of metal cations.
2. Results and discussion
2.1. Fluorescence sensing
Trisphaeridine derivatives 3e5 were synthesized by coupling
diiodinated compound 1 with the corresponding arylboronic acid
under Suzuki coupling conditions (Fig. 2).17,19 The products were
characterized by 1H NMR, 13C NMR, and HRMS. We next evaluated
their binding properties of the compounds with different metal
cations: Hg2þ, Cu2þ, Agþ, Ni2þ, Cd2þ, Naþ, Zn2þ, and Pb2þ
.
O
O
S
O
O
O
O
O
O
N
N
N
O
O
S
3 (23%)
5 (45%)
4 (20%)
Fig. 2. Synthesized trisphaeridine derivatives 3e5.
Fig. 4. Emission spectra of 3 (40
Cu2þ
lexc¼355 nm.
mM, CH3CN) in the presence of increasing amounts of
The response of sensor 3 with metal cations was investigated by
emission spectroscopy. The presence of 0.5 equiv of Hg2þ, Agþ,
Ni2þ, Cd2þ, Naþ or Zn2þ cations did not cause significant changes in
.
We also determined the limit of detection (LOD) and the limit of
quantitation (LOQ).20 A plot of emission data for 3 at
l¼430 nm
the fluorescence spectrum of
3
in acetonitrile (40
mM,
versus the concentration of Cu2þ led to a linear regression (R¼0.99)
with a standard deviation of the intercept of Sa¼0.016 and a slope of
lexc¼355 nm), while a slight decrease of the band at 435 nm and
the emergence of a new band at ca. 575 nm was observed for Pb2þ
,
with the latter effect being much larger for Cu2þ (Fig. 3). These
results prompted us to focus our attention on the interaction of
receptor 3 with Cu2þ. Copper is both beneficial and detrimental for
living beings. It is one of several micronutrients and is essential for
our bodies to work properly. At very low concentrations copper is
b¼9312, from which values of LOD¼3.8
mM and LOQ¼12.6
mM were
obtained.20,21 Considering that the toxic level of Cu2þ is about
20
M,22 7,11-di(thiophen-2-yl)-[1,3]dioxolo[4,5-j]phenanthridine
3 can be used as a sensor for Cu2þ
m
.
Regarding the response of sensor 4 with metal cations, a con-
siderable decrease of the band at 430 nm and the emergence of
a new band at ca. 567 nm was observed in emission spectrum of 4
in acetonitrile (34
m
M, lexc¼280 nm) in the presence of 0.5 equiv of
Cu2þ, while the presence of Hg2þ, Agþ, Ni2þ, Cd2þ, Naþ, Zn2þ or
Pb2þ cations did not lead to significant changes (Fig. 5).
The changes in the emission spectrum of 4 in acetonitrile
(34
m
M, lexc¼280 nm) upon addition of Cu(ClO4)2 are shown in
Fig. 6. Once again, the addition of increasing amounts of Cu2þ in-
duced a progressive decrease in one band (430 nm) and the ap-
pearance of another band (567 nm). On the other hand, a plot of
emission data for 4 at
l
¼430 nm versus the concentration of Cu2þ
showed the limit of detection and quantitation to be LOD¼12.9
mM
and LOQ¼43.0
m
M,23 which indicates that compound 4 can also be
used as a sensor for Cu2þ
.
We proceeded to investigate the ion-sensing properties of 2-
methoxyphenyl derivative 5. The emission spectra of 5 (acetoni-
trile, 23
m
M, lexc¼355 nm, 0.5 equiv of cations) are shown in Fig. 7.
Interestingly, a slight increase in the band at 350 nm was recorded
Fig. 3. Emission spectra of
(0.5 equiv). lexc¼355 nm.
3 (40 mM, CH3CN) in the presence of metal cations
for Hg2þ, Agþ, Ni2þ, Cd2þ, Naþ, Zn2þ or Pb2þ cations, while
Please cite this article in press as: Caballero, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.009

A. Caballero et al. / Tetrahedron xxx (2013) 1e5
3
once again, the greatest effect is associated with the presence of Cu
(II). The changes in the emission spectrum of 5 upon addition of
increasing amounts of Cu(ClO4)2 are shown in Fig. 8. From the
emission data of 5 at
l
¼390 nm it was possible to determine limits
of detection and quantitation of LOD¼1.1
m
M and LOQ¼3.8
m
M.24
However, coordination of receptor 5 to Cu2þ with a stoichiometry
of either 1:1 or 1:2 can once again be proposed.
Fig. 5. Emission spectra of
(0.5 equiv). lexc¼280 nm.
4 (34 mM, CH3CN) in the presence of metal cations
Fig. 8. Emission spectra of 5 (23
Cu2þ
lexc¼355 nm.
mM, CH3CN) in the presence of increasing amounts of
.
3. Theoretical calculations
In an effort to understand the experimental results, we per-
formed calculations on diaryltrisphaeridines 5 in the presence of
two Cu2þ cations (5ꢀꢀ2Cu2þ), at the B3-LYP variant of density func-
tional theory with the standard split-valence 6-31G* basis set for C,
N, O, and H, and the pseudorelativistic effective core potential (ECP)
by Hay and Wadt for Cu.25,26 As shown in Fig. 9, the calculated OeCu
2þ
ꢁ
bond distances in 5ꢀꢀ2Cu are 2.026, 2.227, 2.045, and 3.305 A. The
first three represent typical values for OeCu interactions, but
ꢁ
3.305 A is too long to be considered as an interaction. These results
Fig. 6. Emission spectra of 4 (34
Cu2þ
lexc¼280 nm.
mM, CH3CN) in the presence of increasing amounts of
seem to indicate that 5 forms a chelate complex easily with one
copper ion, resulting in the formation of a seven-membered ring,
.
Fig. 7. Emission spectra of
(0.5 equiv). lexc¼355 nm.
5 (23 mM, CH3CN) in the presence of metal cations
a considerable decrease in this band was found for Cu2þ. This di-
vergent behavior favors the selective detection of the copper
dication.
In all cases, the variation of the band at 350 nm was accompa-
nied by the appearance of a new band centered at 500 nm, where,
Fig. 9. Computer plot of the optimized structure and selected geometrical distances
2þ
[A] for model 5ꢀꢀ2Cu
.
ꢁ
Please cite this article in press as: Caballero, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.009

4
A. Caballero et al. / Tetrahedron xxx (2013) 1e5
but interacts more weakly with the second Cu2þ cation. This situa-
tion is consistent with the experimental findings. Finally, to estimate
if the pyridine nitrogen atom plays some role on the binding effect,
a model where 5ꢀꢀ2Cu2þ was protonated at the nitrogen was opti-
mized (See Supplementary data). The calculated OeCu bond dis-
tances resulted to be 2.081 (MeOeCu), 3.897, 2.077 (MeOeCu), and
5.3.1. 7,11-Bis(2-thiophenyl)-[1,3]dioxolo[4,5-j]phenanthridine
(3). Yield: 19 mg, 23%. Yellow solid. Mp: 188e190 ꢁC; 1H NMR
(400 MHz, 25 ꢁC):
d
¼9.44 (s, 1H), 8.14 (d, J¼8.1 Hz, 1H), 7.77 (d,
J¼8.6 Hz, 1H), 7.67e7.63 (m, 2H), 7.63e7.60 (m, 1H), 7.40e7.38 (m,
1H), 7.34e7.30 (m, 2H), 7.27e7.26 (m, 1H), 7.24 (dd, J¼3.5, 1.0 Hz,
13
1H), 6.22 ppm (s, 2H); C NMR (400 MHz, 25 ꢁC):
d 149.8, 145.4,
ꢁ
4.629 A, that clearly indicates a decrease in the interaction of copper
145.1,136.3,132.0,130.1,129.8,128.2,128.0,127.8,127.7,127.5,125.9,
cations with oxygen atoms of the dioxolo ring. This can be explained
by considering that protonation should induce an increase of con-
jugation of oxygen lone electron pairs with the aromatic structure.
125.6, 124.2, 122.8, 113.5, 111.1, 102.2 ppm; UV/vis (CH3CN): lmax
(
3
)¼192 (34,948), 235 (34,948), 281 (35,765), 323 (11,505), 342
(6530), 362 nm (3494 molꢃ1 dm3 cmꢃ1); Exact mass ESI(þ)
(C22H13NO2S2þH) calculated 388.0460, measured 388.0450.
4. Conclusions
5.3.2. 7,11-Bis(2-furanyl)-[1,3]dioxolo[4,5-j]phenanthridine
(4). Yield: 10 mg, 20%. Brown solid. Mp: 128e130 ꢁC; 1H NMR
We have designed and synthesized new 7,11-diaryltrisphaeridines
and have studied their ion-sensing properties. 2-Thiophenyl, 2-
furanyl, and 2-methoxyphenyl derivatives behave as highly selec-
tive fluorescence chemosensors for Cu2þ cations. These sensors can
detect and quantify Cu2þ below its toxic level and, therefore, they
have a great potential for monitoring biological processes. Our results
show that the sensing properties of the compounds depend on the
substituent in the aryl groups. Further efforts are planned to expand
the sensing properties and to facilitate the use of these systems in an
aqueous medium.
(400 MHz, 25 ꢁC):
d
¼9.75 (s, 1H), 8.12 (d, J¼8.2 Hz, 1H), 7.72 (d,
J¼1.2 Hz, 1H), 7.63 (d, J¼0.9 Hz, 1H), 7.62e7.58 (m, 1H), 7.35e7.28
(m, 1H), 7.19 (d, J¼8.1 Hz, 1H), 6.97 (d, J¼3.3 Hz, 1H), 6.74e6.69 (m,
2H), 6.67 (dd, J¼3.3, 1.8 Hz, 1H), 6.24 ppm (s, 2H); 13C NMR
(400 MHz, 25 ꢁC):
d
¼150.4, 150.1, 146.6, 146.2, 145.1, 144.5, 143.4,
142.8, 129.8, 129.6, 127.9, 125.8, 125.3, 124.1, 121.1, 113.4, 111.9, 111.6,
111.0, 110.4, 107.3, 102.3 ppm; UV/vis (CH3CN): lmax
(
3
)¼249
(12,988), 282 (8816), 337 nm (1745 molꢃ1 dm3 cmꢃ1); Exact mass
ESI(þ) (C22H13NO4þH) calculated 356.0923, measured 356.0917.
5.3.3. 7,11-Bis(2-methoxyphenyl)-[1,3]dioxolo[4,5-j]phenanthridine
5. Experimental section
5.1. General
(5). Yield: 22 mg, 45%. Orange solid. Mp: 88e90 ꢁC; 1H NMR
(400 MHz, 25 ꢁC):
J¼8.7 Hz, 1H), 7.61e7.52 (m, 4H), 7.50 (d, J¼1.5 Hz, 1H), 7.47 (ddd,
J¼7.4, 3.6, 1.7 Hz, 1H), 7.38e7.35 (m, 1H), 7.22e7.14 (m, 3H), 6.12 (s,
2H), 3.83 (s, 3H), 3.75 ppm (s, 3H); 13C NMR (400 MHz, 25 ꢁC):
d
¼8.97 (s, 1H), 8.10 (d, J¼8.1 Hz, 1H), 7.78 (d,
1H and 13C NMR spectra were recorded in CDCl3 with TMS as
internal standard. Melting points are uncorrected. All solvents were
purified by standard procedures. Reagents were of commercial
grades.
d
¼157.3, 157.0, 151.0, 149.3, 144.8, 136.8, 132.7, 132.3, 131.1, 130.3,
130.1,129.6,128.9, 127.1, 125.5,125.4,125.2,122.6,121.5, 121.1, 120.8,
116.2, 114.5, 111.7, 111.3, 101.6, 55.7, 55.6 ppm; UV/vis (CH3CN): lmax
(
3
)¼264 (3066), 300 (1250), 316 (1833), 339 (867), 357 nm
(1016 mole1 dm3 cmꢃ1); Exact mass ESI(þ) (C28H21NO4þH) calcu-
5.2. Synthesis of 7,11-diiodo-[1,3]dioxolo[4,5-j]phenan-
thridine (1)17
lated 436.1543, measured 436.1542.
Bis(pyridine)iodonium(I) tetrafluoroborate (Ipy2BF4) (17 mmol,
6.5 g) was dissolved in dry CH2Cl2 (50 mL) in an oven-dried flask at
room temperature under argon. The trisphaeridine (4.4 mmol,
0.9 g) was dissolved in dry CH2Cl2 in another flask under argon and
this solution was added to the Ipy2BF4 solution. A solution of
CF3SO3H (35 mmol, 3.1 mL) in CH2Cl2 (5 mL) was added over a pe-
riod of 3 min to the magnetically stirred mixture. Finally, the re-
action mixture was stirred overnight at room temperature. The
reaction was treated with aqueous sodium thiosulfate, extracted
with CH2Cl2, washed with brine, and dried (Na2SO4). The solvent
was removed under reduced pressure. The residue was washed
with chloroform and the resulting solid was filtered off to give
compound 1 as a brown solid.
Acknowledgements
This work was partially supported by the Ministerio de Econo-
mía y Competitividad of Spain/FEDER (CTQ2011-24800). A.C.
thanks the CSIC for her fellowship.
Supplementary data
Absorption spectra of compounds 3e5 and Cartesian
coordinates for the calculated geometries discussed in the text.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2013.04.009.
5.3. General procedure for the preparation of
diaryltrisphaeridines
References and notes
1. For representative reviews of chemosensors, see: (a) Saha, K.; Agasti, S. S.;
Kim, C.; Li, X.; Rotello, V. M. Chem. Rev. 2012, 112, 2739; (b) Kreno, L. E.;
Leong, K.; Farha, O. K.; Allendorf, M.; Van Duyne, R. P.; Hupp, J. T. Chem. Rev.
2012, 112, 1105; (c) Joseph, R.; Rao, C. P. Chem. Rev. 2011, 111, 4658; (d) Aragay,
G.; Pons, J.; Markoc¸ i, A. Chem. Rev. 2011, 111, 3433; (e) Ma, Z.; Jacobsen, F. ,E.;
Giedroc, D. P. Chem. Rev. 2009, 109, 4644.
2. For representative reviews of fluorescent chemosensors, see: (a) Meng, X.-M.;
Wang, S.-X.; Zhu, M.-Z. Quinoline-based fluorescence sensors. In Molecular
PhotochemistrydVarious Aspects; Saha, S., Ed.; InTech: Rijeka, Croatia, 2012; (b)
Chen, X.; Pradhan, T.; Wang, F.; Kim, J. S.; Yoon, J. Chem. Rev. 2012, 112, 1910; (c)
Nolan, E. M.; Lippard, S. J. Chem. Rev. 2008, 108, 3443; (d) Kim, J. S.; Quang, D. T.
Chem. Rev. 2007, 107, 3780; (e) Callan, J. F.; Prasanna de Silva, A.; Magri, D. C.
Tetrahedron 2005, 61, 8551.
The diiodinated trisphaeridine 1 (0.2 mmol, 0.1 g) and tetra-
kis(triphenylphosphine)palladium(0) (0.05 mmol, 50 mg) were
dissolved in 1,2-dimethoxyethane (50 mL) and the mixture was
stirred for 20 min at room temperature. A solution of potassium
carbonate (0.7 mmol, 0.1 g) and phenylboronic acid (0.9 mmol,
0.1 g) in water (8 mL) was added and the resulting mixture was
heated at 92 ꢁC for 3e7 days. The mixture was extracted with ether
(3ꢂ50 mL). The organic layer was dried (Na2SO4), filtered, and
evaporated under reduced pressure. The resulting diaryltri-
sphaeridine was purified by column chromatography (silica gel,
hexane/EtOAc, 7:3). The coupling reaction should be repeated twice
for complete conversion of 2 to diaryltrisphaeridines 3e5.
3. (a) Woodroofe, C. C.; Masalha, R.; Barnes, K. R.; Frederickson, C. J.; Lippard, S. J.
Chem. Biol. 2004, 11, 1659; (b) Woodroofe, C. C.; Lippard, S. J. J. Am. Chem. Soc.
2003, 125, 11458.
4. Mizukami, S.; Okada, S.; Kimura, S.; Kikuchi, K. Inorg. Chem. 2009, 48, 7630.
Please cite this article in press as: Caballero, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.009

A. Caballero et al. / Tetrahedron xxx (2013) 1e5
5
5. (a) Xue, L.; Liu, C.; Jiang, H. Chem. Commun. 2009, 1061; (b) Pearce, D. A.;
Jotterand, N.; Carrico, I. S.; Imperiali, B. J. Am. Chem. Soc. 2001, 123, 5160.
6. Teolato, P.; Rampazzo, E.; Arduini, M.; Mancin, F.; Tecilla, P.; Tonellato, U.
Chem.dEur. J. 2007, 13, 2238.
7. (a) Xue, L.; Li, G.; Liu, Q.; Wang, H.; Liu, C.; Ding, X.; He, S.; Jiang, H. Inorg. Chem.
2011, 50, 3680; (b) Xue, L.; Liu, Q.; Jiang, H. Org. Lett. 2009, 11, 3454.
8. Tang, X.-L.; Peng, X.-H.; Dou, W.; Mao, J.; Zheng, J.-R.; Qin, W.-W.; Liu, W.-S.;
Chang, J.; Yao, X.-J. Org. Lett. 2008, 10, 3653.
19. Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
20. In general, the LOD is taken as the lowest concentration of an analyte in
a sample that can be detected, but not necessarily quantified, and the QOD is
the lowest concentration of an analyte in a sample that can be determined with
acceptable precision and accuracy: (a) Shrivastava, A.; Gupta, V. B. Chron. Young
Sci. 2011, 2, 21; (b) Thomsen, V.; Schatzlein, D.; Mercuro, D. Spectroscopy 2003,
18, 112.
21. y¼aþ x; LOD¼3Sa/b; LOQ¼10Sa/b, where Sa is the standard deviation of the
9. Dujols, V.; Ford, F.; Czarnik, A. W. J. Am. Chem. Soc. 1997, 119, 7386.
10. Li, G.-K.; Xu, Z.-X.; Chen, C.-F.; Huang, Z.-T. Chem. Commun. 2008, 1774.
11. Joshi, B. P.; Lohani, C. R.; Lee, K.-H. Org. Biomol. Chem. 2010, 8, 3220.
12. Bhalla, V.; Tejpal, R.; Kumar, M.; Sethi, A. Inorg. Chem. 2009, 48, 11677.
13. Cheng, X.; Li, Q.; Li, C.; Qin, J.; Li, Z. Chem.dEur. J. 2011, 17, 7276.
intercept a and b is the slope.
22. Georgopoulos, P. G.; Roy, A.; Yonone-Lioy, M. J.; Opiekun, R. E.; Lioy, P. J. J. Toxicol.
Environ. Health, Part B 2001, 4, 341.
23. R¼0.99; Sa¼0.0038; b¼3280.
24. R¼0.99; Sa¼0.0017; b¼11,182.
ꢀ
14. Zapata, F.; Caballero, A.; Espinosa, A.; Tarraga, A.; Molina, P. J. Org. Chem. 2009,
25. All calculations were carried out using the Gaussian 03 program package.
Geometry was fully optimized at the ground-state without any symmetry
constraint for the model compound at the B3-LYP variant of density func-
tional theory with the standard split-valence 6-31G* basis set for C, N, O, and
H, and the pseudorelativistic effective core potential (ECP) by Hay and Wadt
for Cu.
74, 4787.
15. Wolf, C.; Mei, X.; Rokadia, H. K. Tetrahedron Lett. 2004, 45, 7867.
16. Sarkar, M.; Banthia, S.; Samanta, A. Tetrahedron Lett. 2006, 47, 7575.
17. Caballero, A.; Campos, P. J.; Rodríguez, M. A. Eur. J. Org. Chem. 2012, 6357.
ꢀ
ꢀ
ꢀ
18. Zupko, I.; Rethy, B.; Hohmann, J.; Molnar, J.; Ocsovszki, I.; Falkay, G. In Vivo
2009, 23, 41.
26. Gaussian 03, Revision C.02; Gaussian,: Wallingford, CT, 2004.
Please cite this article in press as: Caballero, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.009