Synthesis, photophysical, and electrochemical properties of 2,5-diaryl-indolizines

Article abstract of DOI:10.1016/j.tet.2013.11.105

A variety of novel 2,5-diaryl-indolizines have been prepared through the palladium-catalyzed cross-coupling reactions of organozinc reagents prepared from 2-aryl-indolizines with aromatic halides. The photophysical properties of representative compounds indicate that the 2,5-diaryl-indolizines are promising candidates to be used in optoelectronic devices and biomolecular labeling. In addition, cyclic voltammetry studies of some nitrophenyl-substituted indolizines have shown evidences of an oxidation process without the correspondent reduction peak suggesting a dimerization reaction.

Full text of DOI:10.1016/j.tet.2013.11.105

Tetrahedron 70 (2014) 3249e3258
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, photophysical, and electrochemical properties
of 2,5-diaryl-indolizines
a
,
,
,
,c
Monica F.Z.J. Amaral b, Laila A. Deliberto a d, Camila R. de Souza a b, Rose M.Z.G. Naal a
,
^
Zeki Naal a c, Giuliano C. Clososki a
Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP 14.040-903, Brazil
Nucleo de Pesquisas em Produtos Naturais e Sinteticos, Ribeirao Preto, SP 14.040-903, Brazil
Instituto Nacional de Ciencias e Tecnologia de Bioanalítica, Campinas, SP 13.083-970, Brazil
,
,b,
*
a
^
^
~
~
~
b
c
ꢀ
ꢀ
~
^
d
^
~
~
~
Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP 14040-901, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of novel 2,5-diaryl-indolizines have been prepared through the palladium-catalyzed cross-
coupling reactions of organozinc reagents prepared from 2-aryl-indolizines with aromatic halides. The
photophysical properties of representative compounds indicate that the 2,5-diaryl-indolizines are
promising candidates to be used in optoelectronic devices and biomolecular labeling. In addition, cyclic
voltammetry studies of some nitrophenyl-substituted indolizines have shown evidences of an oxidation
process without the correspondent reduction peak suggesting a dimerization reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 September 2013
Received in revised form 27 November 2013
Accepted 29 November 2013
Available online 7 December 2013
Keywords:
Indolizine
Photophysical properties
Electrochemical properties
Cross-coupling reaction
Organozinc compounds
1. Introduction
electrochemically. Some derivatives have shown a reduction peak
around ꢀ2.5 V (vs SCE) and a return peak suggesting a reversible
The synthesis of fluorescent
p
-conjugated molecules has received
charge transfer.8 The electrochemical studies of biological active
indolizines suggested that some of them may inhibit lipid perox-
idation by an electron transfer mechanism.10 Henry and co-workers
have proposed a mechanism of electro oxidation of indolizine com-
bining electrochemical, spectroscopic, and computational studies
characterizing the plausible products from the oxidation process.11
As a consequence of their importance in many research fields,
there is a growing interest on the synthesis of indolizine de-
rivatives. Although many synthetic methods being available in the
literature,12 a frequently employed approach is the 1,3-dipolar cy-
cloaddition of pyridinium ylides with electron-deficient alkenes
and alkynes.12h,i The electrophilic aromatic substitution of indoli-
zines has been widely investigated and it was established that the
position C-3 is the most reactive of the indolizinyl ring.13 Moreover,
application of metal-mediated CeH bond functionalization strate-
gies also afforded C-3 substituted indolizines as main products.14
On the other hand, pioneering studies on the lithiation of 2-phe-
nyl-indolizine performed by Rernard and Gubin have shown that
the hydrogen at C-5 is the most acidic of the ring.15 Further re-
actions of the lithiated indolizine with different electrophiles led to
the preparation of the functionalized derivatives in good yields.
Babaev and co-workers have improved the lithiation protocol16 and
applied this strategy for the synthesis of haloindolizines that were
considerable attention since these molecules can be used as elec-
troluminescent material for optoelectronic devices,1 dyes,2 sensors,3
and biomarkers.4 Indolizines are 10
p-electron aromatic N-hetero-
cyclic compounds, which are
p-isoelectronic with azulene and
naphthalene.5 Furthermore, they present interesting pharmacologi-
cal effects.6 For example, they can function as anti-inflammatory
agents,6b,c calcium entry blockers,6d,e antileishmania,6f antiviral,6g
and anti-tuberculosis agents.6h,i Due to their strong fluorescence in
the UVevisible region, the photophysical properties of some indo-
lizines have already been reported.3b,4a,7 In contrast, only a few
electrochemical properties of indolizines have been described so far.
For example, Troll and co-workers8 have studied the electrochemical
synthesis of substituted indolizines. They have found that, from
cyclic voltammetry data in acetonitrile media, oxidation peak is only
reversible if there is a substituent at C-1, indicating that the di-
merization of the cation radical occurs at this position. It is also
known that there is an oxidative dimerization on C-3.9
Despite the fact that the aromatic ring of indolizines has a
high electron density, some of them can also be reduced
* Corresponding author. Tel.: þ55 16 3602 4252; fax: þ55 16 3602 4243; e-mail
addresses: gclososki@yahoo.com.br, gclososki@fcfrp.usp.br (G.C. Clososki).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.105

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M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
further submitted to palladium-catalyzed cross-coupling reactions
with boronic acids.17
Aiming to find the best reaction conditions for the Negishi re-
action, we have chosen the 2-phenyl-indolizine (4a) as a model
substrate. Lithiation of 4a was performed with n-BuLi/TMEDA at
ꢀ20 ꢁC for 5 h. After that, some catalysts and reaction conditions
were screened for the cross-coupling reaction. Thus, in the first
experiment, after a transmetallation with zinc chloride, a mixture
of Pd2(dba)3 (0.8 mol %) and P(o-furyl)3 (1.6 mol %) in THF was
added, followed by the addition of 1-chloro-4-iodobenzene (6a).
The reaction temperature was increased to 25 ꢁC and the mixture
was allowed under stirring for 12 h, affording indolizine 7a in only
17% conversion (Table 2, entry 1). When the cross-coupling reaction
was performed at 60 ꢁC, the conversion increased to 92% (Table 2,
entry 2). In contrast, when the amounts of the catalyst and the li-
gand were increased to 2 and 4 mol %, respectively, the yield of 7a
decreased to 50% and the homocoupling product from 6a (4,40-
dichloro-1,10-biphenyl) was observed to a large extent (Table 2,
entry 3). On the other hand, using reaction conditions as presented
in entry 2, the cross-coupling reaction catalyzed by Pd(PPh3)4
(0.8 mol %) yielded compound 7a with 94% conversion (Table 2,
entry 4). Other palladium catalyst such as PdCl2(PPh3)2, PdCl2, and
Pd(OAc)2 were also evaluated but the reactions did not present
better results than Pd(PPh3)4 (Table 2, entries 5e8).
Following our interest in the functionalization of aromatic and
heterocyclic compounds using organometallic reagents, herein we
report the application of the Negishi cross-coupling approach in the
preparation of 2,5-diaryl-indolizines. In addition, the photophysical
and electrochemical properties of representative new compounds
are discussed. In view of the wide application in biological and
technological areas, studies that relate the structure of the fluo-
rophore with their photophysical and electrochemical properties
are relevant and justify the efforts to modify molecules by in-
troducing different substituents on the skeleton of the fluorophore.
2. Results and discussion
2.1. Synthesis of 2,5-diaryl-indolizines
We initiated our study by applying the Tschitschibabin approach
to the synthesis of 2-aryl-indolizines of type 4. Thus, the reaction of
2-picoline with a number of a
-bromo-ketones (2aef)18 led to the
expected quaternary pyridinium halides 3. An intramolecular
condensation of 3 mediated by potassium carbonate followed by
crystallization afforded indolizines 4aef from moderate to good
yields and with high purity (Table 1).
Table 2
Screening for the preparation of indolizine 7a
Table 1
Preparation of 2-aryl-indolizines 4aef.
Entry
Catalyst/mol (%)
Ligand/mol (%)
T (ꢁC)
7aa (%)
1
2
3
4
5
6
7
8
Pd2(dba)3/0.8
Pd2(dba)3/0.8
Pd2(dba)3/2
Pd(PPh3)4/0.8
PdCl2(PPh3)2/0.8
PdCl2/0.8
P(o-furyl)3/1.6
P(o-furyl)3/1.6
P(o-furyl)3/4.0
d
25
60
60
60
60
60
60
60
17
92
50
94
90
65
71
85
Entry
1
a
-Bromo-ketone (2)
Product (4)
Yielda (%)
65
P(o-furyl)3/1.6
P(o-furyl)3/1.6
P(o-furyl)3/1.6
PPh3/1.6
Pd(OAc)2/0.8
Pd2(dba)3/0.8
2
3
89
70
a
Conversions determined by GC analysis.
As observed in Table 2, conditions used in entry 4 appeared to be
the best for this reaction. After the purification step, the desired 5-(4-
chlorophenyl)-2-phenyl-indolizine (7a) was obtained in 79% yield.
Thus, a number of 2,5-diaryl-indolizines were synthesized in good
yields through the cross-coupling reaction of organozinc reagents of
type 8 with different halides catalyzed by Pd(PPh3)4 (Table 3).
Aromatic halides containing other withdrawing groups such as
fluoro, trifluoromethyl, and nitro were also suitable substrates leading
to the desired 5-aryl-2-phenyl-indolizines 7bed with yields ranging
from 75% to 80% (Table 3, entries 2e4). The cross-coupling of 8 with
iodobenzene (6e) also occurred in good yield as well as with aromatic
halides substituted with electron-donating groups such as methyl and
methoxy (Table 3, entries 5e8). Due to the steric hindrance, reactions
of 8 with ortho-substituted iodines such as 1-iodo-2-methylbenzene
(6i) and 1-iodo-2-methoxybenzene (6j) were slow and gave the de-
sired products 7i and 7j in only moderate yields (Table 3, entries 9 and
10). Moreover, due to a competitive formation of homocoupling
products from the corresponding heterocyclic halides,20 the cross-
coupling of 8 with heterocyclic substrates such as 2-bromothiophene
(6k) and 2-bromopyridine (6l) gave the expected products 7k and 7l
in 45% and 65% yields, respectively (Table 3, entries 11 and 12).
Additionally, using the same reaction conditions, we have
synthesized 2,5-diaryl-indolizines through the cross-coupling of
aromatic halides with organozinc reagents prepared from the
2-aryl-indolizines 4bef. As observed in Table 4, most of the desired
4
5
90
60
85
6
a
Isolated yield.
Palladium-catalyzed coupling reactions are among the most
important reactions for the functionalization of aromatics and
heterocyclic substrates and have already been successfully used for
the functionalization of haloindolizines.14a,16,19 In our approach to
2,5-diaryl-indolizines, we have investigated the application of
Negishi cross-coupling reaction for the arylation and hetero-
arylation of the position C-5 of the indolizinyl ring.

M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
3251
Table 3
Table 4
Synthesis of 5-aryl-2-phenyl-indolizines
Synthesis of 2,5-diaryl-indolizines
Entry Halide (6) Substituent
Product (7)
Yield
(4)
(%)
Entry
1
Halide (6)
Time (h)
12
Product (7)
Yield (%)
79
1
4b
68
2
4b
71
2
3
4
12
24
12
79
80
75
3
4c
70
4
5
6
4c
4f
4f
71
79
69
5
6
12
12
82
78
7
12
12
24
24
86
86
64
60
8
9
7
4e
65
10
8
9
4d
4d
35
40
11
12
24
12
45
65

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M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
compounds were obtained in moderate to good yields. In-
terestingly, when the 2-(4-bromophenyl)indolizine (4d) was used
as starting material in cross-coupling reactions with 6a and 6h, the
2,5-diaryl-indolizines 7a and 7h were isolated in poor yields due
to a lithiumebromine exchange side reaction (Table 4, entries 8
and 9).
2.2. Photophysical properties
The photophysical properties of 17 representative compounds
(7aek, 7m, 7n, 7per) were investigated by measuring absorption
and emission spectra in DMSO, seeing as this solvent is largely used
in biological protocols. In addition, some of the highest fluorescent
compounds (7a, 7f, 7k, and 7m) were also studied in other solvents
of different polarities, such as chloroform and 1,4-dioxane, in order
to evaluate their promising applications as optoelectronic devices.
The 2,5-diaryl-indolizines have similar UV/vis spectral data, as
summarized in Table 5, with the longest wavelength absorption
changing from 350 to 382 nm (see Fig. S1dSupplementary data).
Compounds 7d, 7pe7r, which sustain 4-nitrophenyl substituents
on the C-5 of the indolizine skeleton, have their longest wavelength
absorption maxima red-shifted to the 438e442 nm region of the
spectrum. This bathochromic effect is attributed to the strong
withdrawing character of the nitro group, which reduces consid-
erably the LUMO energy of aromatic compounds.21 The two lowest
energy absorption bands for the most molecules are consistent
Fig. 1. Normalized fluorescence and excitation spectra of the representative com-
pounds 2,5-diaryl-indolizines measured in DMSO. Excitation and emission slits were
10 nm and 3 nm, respectively. The samples (2.2
mM) were excited at the low energy
wavelength of each compound (lexc changing from 320 nm to 442 nm). Inset: Ab-
sorption, excitation, and fluorescence of the compound 7a in DMSO. A sample of 10 mM
was used for the absorption spectrum.
with
lAbsw375 nm), the last one with molar extinction coefficient
values (
) smaller than 10,000 Mꢀ1 cmꢀ1. All indolizines in-
p
e
p
*
transition
(
lAbsw325 nm) and n/
p
*
transitions
(
red-shifted (Table S1dSupplementary data) as the solvent polarity
increases (chloroform<1,4-dioxane<DMSO). Therefore, the emis-
sion color changes were not evident.
Fig. 2 shows the normalized fluorescence spectra, in solution, for
some representative compounds, which show blue and green
emission. It is evident that the wavelength emission is highly de-
pendent on the substituents at the C-2 and C-5 position of the
fluorophore core skeleton of the indolizines.
In addition, the electronic character (donor or withdrawing) of
the substituents and the different position assumed on both phenyl
rings of the 2,5-diaryl-indolizines 7 series, are crucial to define the
fluorescence properties of these molecules. As seen in Table 5, for
3
vestigated are colored since they present maximum absorption in
the visible region of the spectra (Table 5). Most of them show in-
tense fluorescence at 450e500 nm when irradiated at the low
energy absorption band (see Fig. 1 for representative compounds),
as previously reported for other indolizine derivatives.5a,8 The inset
in Fig. 2 shows the normalized absorption, excitation, and emission
spectra for one representative compound (7a). The similarity be-
tween absorption and excitation spectra suggests that only one
species is populating the ground state and can be excited to emit
fluorescence. Similar behavior was observed for all studied com-
pounds (data not shown).
Table 5
Photophysical properties of 2,5-diaryl-indolizines 7 series measured in DMSO
Compound
lAbs/nm (
3
ꢂ10ꢀ4/Mꢀ1 cmꢀ1
)
lem/nm
DlSt/nm
FF
s1/ns
s2/ns
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7p
7q
7r
262 (2.16), 379 (0.21)
489
480
515
510
483
474
482
475
471
474
472
517
487
477
501
491
510
110
105
133
68
0.31
0.48
0.10
d
0.43ꢃ0.0.04 (2%)
12.56ꢃ0.02 (98%)
263 (2.63), 321 (0.59), 375 (0.34)
261 (1.69), 324 (0.74), 382 (0.18)
263 (5.25), 347 (0.54), 442 (0.46)
259 (1.83), 377 (0.22)
264 (4.20), 376 (0.42)
270 (2.23), 376 (0.26)
259 (1.61), 327 (0.69), 375 (0.16)
262 (2.20), 308 (0.22), 364 (0.33)
263 (2.73), 356 (0.35)
265 (1.84), 377 (0.20)
278 (2.01), 326 (1.34), 395 (0.04)
265 (4.00), 377 (0.50)
d
d
d
d
d
d
106
107
106
100
107
118
101
122
117
127
63
0.59
0.85
0.71
0.084
0.26
0.78
0.79
0.58
0.63
0.090
d
d
1.22ꢃ0.04 (1%)
16.20ꢃ0.20 (99%)
d
d
d
d
d
d
d
d
3.10ꢃ0.1 (3%)
14.9ꢃ0.02 (97%)
d
d
0.6ꢃ0.09 (1%)
12.44ꢃ0.02 (99%)
264 (2.68), 350 (0.48)
d
d
d
d
d
d
d
d
264 (3.17), 349 (0.49), 375 (0.34)
267 (3.07), 335 (0.96), 400 (0.36)
264 (2.99), 346 (0.52), 438 (0.31)
91
68
0.18
d
The Stokes shift for all of the compounds is high (w90e133 nm),
which suggests these compounds experience geometry changes in
the excited state.
example, a strong bathochromic effect is observed when OCH3
(electron donor), in 7f, is substituted by CF3 (electron-withdrawing)
in 7c.
It is worth mentioning that the wavelength of maximum
fluorescence emission of compounds 7a, 7f, 7k, and 7m are slightly
Compounds 7a and 7b, 5-benzoyl-p-substituted with chloro and
fluoro, respectively, showed small effect on the fluorescence

M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
3253
spite of the
p-conjugated system, an opposite behavior was ob-
served in relation to 7e, i.e., a higher quantum yield was obtained
without significant deviation in the wavelength emission.
The fluorescence lifetime decays measured for compounds 7a,
7f, 7k, and 7m, (ff ranging from 0.3 to 0.85), were bi-exponential
with lifetimes (
(97e99%) (Table 5), which contributes mostly to the static
fluorescence emission of the compounds (See also
sf) around 12e16 ns for the largest population
Fig. S4dSupplementary data). A small population (smaller than 3%)
with lifetime between 1 and 3 ns was determined. This could be
ascribed to a possible oxidation reaction, producing a dimer de-
rivative similar to the other indolizines, which have shown an ox-
idation process followed by
a dimerization reaction from
electrochemical data. It is worth pointing out that the electro-
chemical results from the indolizines in this work have shown
similar electrochemical profile. Moreover, this small population is
not significant for the total static fluorescence emission observed
for all indolizines. The lifetime results for the higher population
(12e16 ns) are in the same range of magnitude as those found for
other
p-conjugated molecules, which were indicated as potential
candidates for applications in electroluminescent devices.23c
2.3. Electrochemical properties
Cyclic voltammograms of the nitrophenyl-substituted indoli-
zines 7d, 7r, and 7p are shown in Fig. 3BeD, respectively. All of
indolizines studied in this work have presented oxidation peak
around 1.0 V (vs Ag/AgCl/KCl(sat)). The oxidations are irreversible
Fig. 2. (A) Normalized fluorescence emission of selected indolizines in DMSO. Exci-
tation and emission slits were 10 nm and 3 nm, respectively. (B) Photoluminescence of
indolizines in DMSO excited at 366 nm. From left to right: 7f, 7g, 7m, and 7c.
quantum yield (Ff¼0.31e0.48, respectively) compared to compound
7e
(
FF¼0.59) and similar fluorescence emission wavelength
(480e489 nm). However, p-CF3 substitution in 7c compared to 7e
resulted in a marked reduction of the fluorescence quantum yield
(FF¼0.1) and maximum emission shifted to longer wavelength
(510 nm) due to the strong electron-withdrawing effect of the CF3.
Similar behavior was obtained for all analogs with nitro substituents,
such as compounds 7d, 7p, and 7r, which showed no fluorescence,
consistent with other studies that also observed fluorescence
quenching arising from the nitro group.21,22 In contrast compound
7f, carrying the electron-donating group, methoxy, at the para-po-
sition of the 5-phenyl ring of the indolizine resulted in higher
quantum yield (FF¼0.85) compared to 7e (FF¼0.59). Changing the
OMe substituent from para to ortho position, no significant effect was
observed in fluorescence (FF¼0.78) or in wavelength emission
(
lem¼474 nm). Surprisingly, compounds 7g, 7h, and 7i with methyl
substituents at ortho, para, or meta position, respectively, showed
different behaviors with stronger fluorescence for the meta-methyl-
substituted compound (7g, FF¼0.71) followed by the ortho (7i) and
para (7h) with FF¼0.26 and 0.084, respectively.
The insertion of a second electron-withdrawing substituent,
such as chloride, at the para-position of the 2-phenyl ring of the
indolizine (compound 7m) resulted in fluorescence improvement
compared to 7a. In contrast, fluorescence quenching was observed
when 7e was, simultaneously, substituted by electron-donating
and withdrawing substituents at the para-position of both aryl
substituents of the indolizine (compounds 7n and 7q).
Finally, the substituent pyridine, on the C-5 of the indolizine
(compound 7l) caused no influence on the fluorescence quantum
yield compared to 7e, but its emission was bathochromically shif-
ted to 517 nm. The increased p-conjugation extension arising from
pyridine, associated with its planarity in relation to the indolizine
skeleton, provides high electronic distribution through the orbitals
and explain the substantial bathochromic shift.23 On the other
hand, when thiophenyl was used as substituent (compound 7k), in
Fig. 3. Cyclic voltammograms of DMSO/TBAH 0.1 M solution (A) in presence of 0.5 mM
of 7d (B), 0.5 mM of 7r (C), and 0.5 mM of 7p (D). The scan rate was 100 mV/s, using
a glassy carbon (area 0.0314 cm2) as working electrode.

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M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
without the corresponding radical-cation reduction peaks being
observed during the cathodic scan, suggesting an EC process. This
behavior is similar to the electrochemical oxidations of the indo-
lizine derivatives in which the irreversible oxidation of the
1-unsubstituted indolizines was caused by the dimerization of the
cation radicals to afford the 1,1-bisindolizines.8,10
The electrochemical reduction behavior of these nitro derivative
indolizines can be seen in Fig. 5. The effect of introducing methoxy
as substituent in the 5-phenyl substituent group was not valuable
and it has not produced a change in energy requirements of the
nitro group reduction. On the other hand, the oxidation peak of the
anion radical decreased with one methoxy (7r) (red line) and more
significantly with two methoxy substituents (7p) (blue line). Pos-
sibly, this fact can be explained by the electron donation character
of the methoxy substituent that acts increasing the electronic
density on the nitro group. There was an interesting study
about substituted nitroimidazole in aprotic medium. In this study,
Yanez and co-workers24 have stated that for new substituted
4-nitroimidazole derivatives the corresponding nitro radical anion
decays faster than the nonsubstituted nitro radical. Following an-
other studies from the same group, they have suggested that there
are several possibilities for the chemical decay of the radical anion,
which are: protonation, dimerization, dismutation, or fathereson
reactions.25 Thus, the results in Fig. 4 would be in agreement with
the results from the anion radical of nitroimidazoles. For the case of
these indolizines, it is necessary further studies to suggest the
electrochemical mechanism.
Fig. 5. Cyclic voltammograms of saturated O2 in DMSO/TBAH 0.1 M solution in absence
of indolizine (blue line), presence of 0.5 mM of 7d and 7d in absence of O2(g) at scan
rate 100 mV/s, using a glassy carbon (area 0.0314 cm2) as working electrode.
corresponding to the oxidation of superoxide to oxygen. However,
the presence of a second methoxy group in 7p diminishes the ox-
idation current markedly. It seems that the investigated indolizines
in solution decrease the concentration of oxygen as attested by the
lower current intensity (Figures in Supplementary data).
3. Conclusions
A variety of novel 2,5-diaryl-indolizines have been successfully
prepared using palladium-catalyzed cross-coupling reactions of
organozinc reagents prepared from 2-aryl-indolizines with aromatic
halides. The photophysical properties of representative compounds
of the 2,5-diaryl-indolizines 7 series indicate they are promising
candidates to be used as optoelectronic devices and biomolecule
labeling. These new compounds show strong blue-light fluorescence
in the wavelength range of 471e490 nm with high quantum yields.
Exception was observed for compound 7l, bearing a pyridine sub-
stituent, responsible for the green-shifted to 517 nm. In general,
electron-withdrawing substituents shifted the emission to higher
wavelength, closer to the green region of the spectra. The simulta-
neous insertion of both electron donor and withdrawing sub-
stituents in the molecule decreases significantly the emission
quantum yield. As expected, electrochemical results have shown that
the oxidation process leads to a radical cation with a subsequent
dimerization reaction. The nitrophenyl-substituted indolizines in-
vestigated have the stability of their anion radicals, generated by the
reduction in aprotic medium, affected by the substituent of the
indolizinyl ring. The experiments performed in the presence of ox-
ygen have shown that these compounds are relatively nonsensitive
to reactive oxygen species (ROS). Further studies will be conducted in
order to investigate additional fluorescence and electrochemical
properties of these new compounds. In addition, biological applica-
tions such as antiallergic potential, cytotoxicity, calcium influx in-
hibition, and cell imaging will also be investigated.
Fig. 4. Cyclic voltammograms of DMSO/TBAH 0.1 M solution in presence of 0.5 mM of
7d (black line), 0.5 mM of 7r (red line), and 0.5 mM of 7p (blue line). The scan rate was
100 mV/s, using a glassy carbon (area 0.0314 cm2) as working electrode.
Fig. 5 shows a cyclic voltammogram of a solution of TBAH/DMSO
0.1 M saturated with oxygen. The potentiodynamic profile (blue
line) is in accordance with earlier work published,26 which can be
represented by Eq. 1:
O2 þ eꢀ#Oꢀ2 $
(1)
Cyclic voltammogram from the same solution after the addition
of an aliquot of 7d (red line) has shown that the presence of sub-
strate slightly decreases the oxidation peak of superoxide and
keeps the redox process almost the same compared with its be-
havior without O2(g) (black line). This behavior suggests that this
indolizine is not so active with reactive species of oxygen such as
superoxide.
4. Experimental section
4.1. General
The solvents were purified according to standard procedures.27
The starting materials were purchased from SigmaeAldrich.
All air-sensitive and/or water-sensitive reactions were carried out
with dry solvents under anhydrous conditions and nitrogen at-
mosphere. Standard syringe techniques were applied for the
On the other hand, introduction of a methoxy group into indo-
lizine (7d), to give 7r, does not change significantly the peak

M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
3255
transfer of dry solvents and air-sensitive reagents. The reactions
were monitored by TLC on Merck silica gel (60 F 254) by using UV
light as a visualizing agent and 5% vanillin in 10% H2SO4 with
heating as a developing agent. SigmaeAldrich silica gel (particle
size 0.040e0.063 nm) was used for flash chromatography. NMR
spectra were recorded with a Bruker DPX 300, 400, and 500 (at
300, 400, and 500 MHz for protons and 75, 100, and 125 MHz for
carbon-13, respectively) instrument while using CDCl3, DMSO-d6,
221e223 ꢁC (lit.1 mp 233e236 ꢁC). IR (KBr): 3107, 3080, 1508, 1456,
1298, 775, 729. 1H NMR (400 MHz, pyr-d5)
d
7.96 (d, J¼6.6 Hz, 1H),
7.75 (s, 1H), 7.62e7.60 (m, 2H), 7.52e7.50 (m, 2H), 7.34 (d, J¼8.4 Hz,
1H), 6.76 (s, 1H), 6.57 (t, J¼7.6 Hz, 1H), 6.36 (t, J¼6.6 Hz, 1H). 13C
NMR (pyr-d5, 100 MHz) d 135.1, 134.04, 132.1 (2C), 128.2, 128.1 (2C),
125.7, 120.3, 119.3, 118.0, 111.0, 110.3, 97.0. MS (ESI, 70 eV) m/z 273
(95%), 271 (Mþ, 100%), 191 (77%), 164 (12%), 136 (10%), 95 (65%), 77
(3%). HRMS (ESI) m/z 272.0069 ([MþH]þ calcd for C14H10BrN:
272.0069).
or pyr-d5 as solvent. The chemical shifts are reported as
d units in
parts per million (ppm) relative to the solvent residual peak as the
internal reference. Infrared (IR) spectra of all synthesized com-
pounds were recorded on PerkineElmer mod.1420 in KBr pellets,
the frequencies are given in cmꢀ1. Mass spectra (MS) were mea-
sured with Shimadzu GCeMS-QP2010 mass spectrometer. HRMS
spectra were measured with a Bruker Daltonics micrOTOF QII/ESI-
TOF.
4.2.1.5. 2-(6-Methoxynaphthalen-2-yl)indolizine
-bromo-ketone (2e) (5.58 g, 20 mmol); yield: 3.27 g (60%); yellow
solid; mp 225 ꢁC (dec); IR (KBr): 3078, 3002, 1599, 1511, 1246, 1036,
790, 726. 1H NMR (400 MHz, CDCl3)
7.95 (s,1H), 7.80e7.74 (m,1H),
7.69e7.67 (m, 2H), 7.31 (t, J¼5.9 Hz, 1H), 7.20e7.17 (m, 3H),
7.08e7.05 (m, 2H), 6.72e6.65 (m, 1H), 6.48e6.43 (m, 1H), 3.85 (s,
3H); HRMS (ESI) m/z 274.1221 ([MþH]þ calcd for C19H15NO:
274.1232).
(4e). From
a
d
4.2. Procedures
4.2.1. General procedure for the preparation of 4aef. A solution of 2-
4.2.1.6. 2-(4-Methoxyphenyl)indolizine (4f). From a-bromo-ke-
picoline (1) (20 mmol; 1.86 g; 2 mL) and
a
-bromo-ketone (2)
tone (2f) (4.58 g, 20 mmol); yield: 3.79 (85%); white solid; mp
(20 mmol) in acetone (100 mL) was heated at reflux for 4 h. The
quaternary salt was isolated via filtration and re-dissolved in hot
(60e80 ꢁC) water (100 mL). K2CO3 (2.76 g; 20 mmol) was added
and the mixture heated at 80 ꢁC for 8 h. After filtration and drying
in vacuum, the products of type 4 were obtained.
187 ꢁC (dec) (lit.31 mp 184 ꢁC); IR (KBr): 3090, 3007, 1608, 1521,
1244, 1031, 781, 731; 1H NMR (400 MHz, pyr-d5)
d
7.90 (d, J¼6.4 Hz,
1H), 7.28 (d, J¼8.8 Hz,1H), 6.94 (d, J¼8.4 Hz, 2H), 6.74 (s,1H), 6.50 (t,
J¼6.4 Hz, 1H), 6.27 (t, J¼6.8 Hz, 1H), 3.56 (s, 3H). 13C NMR (100 MHz,
pyr-d5)
d 159.0, 133.9, 129.6, 128.5, 127.6 (2C), 125.6, 119.0, 117.6,
114.7 (2C), 110.5, 109.5, 96.8, 55.1. MS (ESI, 70 eV) m/z 223 (Mþ,
100%), 208 (54%),180 (32%),152 (17%), 89 (5%), 77 (10%). HRMS (ESI)
m/z 224.1075 ([MþH]þ calcd for C15H13NO: 224.1070).
4.2.1.1. 2-Phenyl-indolizine (4a). From
(3.98 g, 20 mmol); yield: 2.51 (65%); white solid; mp
218e220 ꢁC (lit.28 mp 214e215 ꢁC); IR (cmꢀ1): 3101, 3072, 3028,
1514, 1454, 759, 690. 1H NMR (300 MHz, CDCl3)
7.89 (dd,
a-bromo-ketone (2a)
g
d
4.2.2. General procedure for the preparation of (7ae7s). To a 25-mL
round-bottom flask equipped with a magnetic stirring bar and
a septum under a nitrogen atmosphere was added a solution of
the corresponding 2-aryl-indolizine (0.5 mmol) and TMEDA
(1 mmol) in THF (6 mL). This solution was cooled to ꢀ78 ꢁC and
n-BuLi (1.0 mmol; 2 equiv; C¼2.47 mol/L) was added dropwisely.
After the addition was complete, the reaction mixture was
warmed to ꢀ20 ꢁC and stirred at this temperature for 5 h. Then,
this solution was cooled to ꢀ40 ꢁC and a solution of ZnCl2 in THF
was added (1 M, 0.5 mmol, 0.5 mL). After 15 min, a solution of
Pd(PPh3)4 (0.8 mol %, 4.5 mg) in THF (1 mL) and a solution of
corresponding aryl halide RX (1 mmol, 2 equiv) were added and
stirred at 60 ꢁC overnight. The reaction mixture was quenched
with saturated aqueous NH4Cl (20 mL) and extracted with
AcOEt (3ꢂ40 mL). The solvent was evaporated under vacuum.
The crude product was purified by means of chemically active
extraction. Firstly the crude product was solubilized with 50 mL
of AcOEt and extracted with an aqueous solution of 5 M HCl
(50 mL). The aqueous phase was neutralized with a solution of
NaHCO3 until pH 7 and extracted with AcOEt (3ꢂ30 mL). Then,
the organic phase was extracted with aqueous solution of HCl
10% (50 mL). Finally, the combined organic phases were collected
and washed with saturated aqueous NaHCO3 and dried over an-
hydrous MgSO4. After filtration, the solvent was evaporated un-
der vacuum to give the product.
J1¼6.9 Hz, J2¼1.2 Hz, 1H), 7.58e7.55 (m, 2H), 7.49 (d, J¼12 Hz, 1H),
7.32e7.27 (m, 3H), 7.19e7.13 (m, 1H), 6.6 (s, 1H), 6.56 (ddd,
J1¼9.0 Hz, J2¼6.3 Hz, J3¼0.9 Hz, 1H), 6.36 (dt, J1¼6.6 Hz, J2¼12 Hz,
1H). 13C NMR (75 MHz, CDCl3)
d 135.37, 133.6, 129.4, 128.7 (2C),
126.5, 126.2 (2C), 125.0, 119.0, 117.3, 110.5, 109.2, 96.6; MS (ESI,
70 eV) m/z 193 (Mþ, 100%), 165 (15%), 115 (20%), 83 (10%), 77 (5%),
52 (2%). HRMS (ESI) m/z 194.0966 ([MþH]þ calcd for C14H11N:
194.0964).
4.2.1.2. 2-(4-Chlorophenyl)indolizine (4b). From
a-bromo-ke-
tone (2b) (4.66 g, 20 mmol); yield: 4.05 g (89%); white solid; mp
220 ꢁC (dec) (lit.29 mp 240e242 ꢁC); IR (KBr): 3079, 3028, 1598,
1467, 1090, 780, 690; 1H NMR (400 MHz, pyr-d5)
d 8.0 (dd,
J1¼6.8 Hz, J2¼0.8 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J¼8.4 Hz, 2H),
7.43e7.38 (m, 3H), 6.82 (s, 1H), 6.63 (t, J¼6.8 Hz, 1H), 6.41 (t,
J¼6.4 Hz, 1H). 13C NMR (100 MHz, pyr-d5)
d 134.0, 133.4, 132.3,
129.4, 128.9 (2C), 127.4 (2C), 125.2, 119.1, 117.8, 110.8, 109.0, 96.8. MS
(ESI, 70 eV) m/z 229 (32%), 227 (Mþ, 100%), 192 (15%), 165 (10%), 95
(17%), 63 (6%). HRMS (ESI) m/z 228.0593 ([MþH]þ calcd for
C
14H10ClN: 228.0575).
4.2.1.3. 2-(3,4-Dimethoxyphenyl)indolizine (4c). From a-bromo-
ketone (2c) (5.18 g, 20 mmol); yield: 3.54 g (70%); white solid; mp
165e167 ꢁC (lit.30 mp 179 ꢁC); IR (KBr): 3099, 2954, 2837, 1516,
1450, 1259, 1024, 775; 1H NMR (400 MHz, pyr-d5)
d 7.90 (d,
J¼6.8 Hz, 1H), 7.43 (s, 1H), 7.36e7.29 (m, 3H), 6.9 (d, J¼8 Hz, 1H),
4.2.2.1. 5-(4-Chlorophenyl)-2-phenyl-indolizine
(7a). From
6.78 (s, 1H), 6.52 (t, J¼6.4 Hz, 1H), 6.29 (t, J¼6.8 Hz, 1H), 3.71 (s, 3H),
2-aryl-indolizine (4a) (96.5 mg, 0.5 mmol) and 1-chloro-4-
iodobenzene (6a) (238.45 mg, 1 mmol); yield: 120 mg (79%);
dark green solid; mp 101e103 ꢁC; IR (KBr): 3066, 2962, 1597, 1487,
3.64 (s, 3H). 13C NMR (100 MHz, pyr-d5)
d 150.2, 149.0, 133.9, 129.9,
129.1, 125.6, 119.1, 118.9, 117.6, 113.0, 110.8, 110.6, 109.8, 97.0, 55.95,
55.90. MS (ESI, 70 eV) m/z 253 (Mþ, 100%), 238 (32%), 210 (32%), 192
(20%), 180 (15%), 167 (33%), 117 (12%). HRMS (ESI) m/z 254.1176
([MþH]þ calcd for C16H15NO2: 254.1176).
1091, 786, 698; 1H NMR (400 MHz, CDCl3)
d 7.60e7.55 (m, 5H),
7.51e7.48 (m, 2H), 7.38e7.32 (m, 3H), 7.24e7.20 (m, 1H), 6.80 (d,
J¼1.48 Hz, 1H), 6.74 (dd, J1¼9.0 Hz, J2¼6.6 Hz, 1H), 6.37 (dd,
J1¼6.6 Hz, J2¼1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 135.6, 135.2,
4.2.1.4. 2-(4-Bromophenyl)indolizine (4d). From
a-bromo-ke-
135.1, 134.8, 133.8, 129.9 (2C), 129.5 (2C), 129.4, 128.7 (2C), 118.5,
tone (2d) (5.55 g, 20 mmol); yield: 4.89 g (90%); white solid; mp
117.8,111.6, 107.7, 97.6. MS (ESI, 70 eV) m/z 303 (Mþ,100%), 236 (3%),

3256
M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
267 (63%), 191 (10%), 115 (3%), 77 (3%). HRMS (ESI) m/z 304.0884
([MþH]þ calcd for C20H14ClN: 304.0888).
114.3 (2C), 111.1, 107.8, 97.2, 55.3. MS (ESI, 70 eV) m/z 299 (Mþ,
100%), 284 (8%), 267 (5%), 254 (18%), 178 (8%), 77 (3%). HRMS (ESI)
m/z 300.1384 ([MþH]þ calcd for C21H17NO: 300.1383).
4.2.2.2. 5-(4-Fluorophenyl)-2-phenyl-indolizine
(7b). From
2-aryl-indolizine (4a) (96.5 mg, 0.5 mmol) and 4-
fluoroiodobenzene (6b) (222 mg, 1 mmol); yield: 113 mg (79%);
dark green solid; mp 101e103 ꢁC; IR (KBr): 3070, 3030, 1602, 1502,
4.2.2.7. 2-Phenyl-5-(m-tolyl)indolizine (7g). From 2-aryl-indoli-
zine (4a) (96.5 mg, 0.5 mmol) and 3-iodotoluene (6g) (218 mg,
1 mmol); yield: 121 mg (86%); dark green solid; mp 101e103 ꢁC; IR
(KBr): 3064, 3068, 2962, 2922, 1602, 1483, 781, 767, 698; 1H NMR
1222, 767, 692; 1H NMR (500 MHz, CDCl3)
d 7.63e7.58 (m, 4H), 7.54
(s, 1H), 7.38e7.33 (m, 3H), 7.23e7.20 (m, 3H), 6.80 (s, 1H), 6.75 (t,
(500 MHz, CDCl3)
8H), 7.23e7.19 (m, 1H), 6.79e6.74 (m, 2H), 6.4 (d, J¼8.0 Hz,1H), 2.43
(s, 3H). 13C NMR (100 MHz, CDCl3)
137.2, 136.3, 135.3, 134.6, 134.2,
130.5, 129.9, 129.3,129.2,128.6 (2C), 126.43, 126.41 (2C), 117.8, 117.6,
111.1, 108.0, 97.0, 19.0. MS (ESI, 70 eV) m/z 283 (Mþ, 100%), 267
(31%), 206 (35),191 (5%), 91 (15%), 77 (2%). HRMS (ESI) m/z 284.1437
([MþH]þ calcd for C21H17N: 284.1434).
d
7.6 (dd, J1¼10.5 Hz, J2¼1.5 Hz, 2H), 7.46e7.29 (m,
J¼8.0 Hz, 1H), 6.38 (d, J¼6.5 Hz, 1H). 13C NMR (125 MHz, CDCl3)
d
162.9 (d, J1¼247.6 Hz, CeF), 135.7, 135.1, 134.8, 131.4 (d, J4¼3.3 Hz,
d
CeF), 130.4 (d, J3¼8.1 Hz, CeF), 129.2, 129.0, 128.6 (2C), 128.0, 126.5,
126.1 (2C),118.2,117.8,116.1 (d, J2¼21.5 Hz, CeF),111.4,107.6, 97; MS
(ESI, 70 eV) m/z 287 (Mþ, 100%), 268 (1%), 209 (16%), 142 (5%), 77
(3%); HRMS (ESI) m/z 288.1179 ([MþH]þ calcd for C20H14FN:
288.1183).
4.2.2.8. 2-Phenyl-5-(p-tolyl)indolizine (7h). From 2-aryl-indoli-
zine (4a) (96.5 mg, 0.5 mmol) and 4-iodotoluene (6h) (218 mg,
1 mmol); yield: 121 mg (86%); dark green solid; mp 100e102 ꢁC; IR
(KBr): 3062, 3030, 2947, 2920, 1560, 1452, 798, 698; 1H NMR
4.2.2.3. 2-Phenyl-5-(4-(trifluoromethyl)phenyl)indolizine
(7c). From 2-aryl-indolizine (4a) (96.5 mg, 0.5 mmol) and 4-
bromobenzotrifluoride (6c) (225 mg, 1 mmol); yield: 134 mg
(80%); dark green solid; mp 124e126 ꢁC (lit.4 mp 129e131 ꢁC); IR
(cmꢀ1): 3072, 3032, 1616, 1429, 1327, 771, 696. 1H NMR (500 MHz,
(500 MHz, CDCl3)
d
7.63e7.59 (m, 3H), 7.54 (d, J¼8 Hz, 2H),
7.36e7.33 (m, 5H), 6.78 (d, J¼1.5 Hz, 1H), 6.75 (dd, J1¼9.0 Hz,
CDCl3)
d
7.84e7.80 (m, 4H), 7.64e7.61 (m, 3H), 7.44e7.37 (m, 3H),
J2¼6.5 Hz, 1H), 6.38 (dd, J1¼7.0 Hz, J2¼1.0 Hz, 1H), 2.45 (s, 3H). 13
C
7.28e7.25 (m, 1H), 6.86 (s, 1H), 6.80 (t, J¼7.5 Hz, 1H), 6.45 (d,
NMR (125 MHz, CDCl3) d 139.1, 136.9, 135.3, 134.7, 132.5, 129.6 (2C),
J¼6.5 Hz, 1H). 13C NMR (125 MHz, CDCl3)
d
138.9, 135.1, 134.9, 134.8,
128.9, 128.6 (2C), 128.3 (2C), 126.4, 126.1 (2C), 117.9, 117.8, 111.1,
107.9, 97.2, 21.4. MS (ESI, 70 eV) m/z 283 (Mþ, 100%), 268 (27%), 206
(4%), 191 (9%), 91 (3%), 77 (2%). HRMS (ESI) m/z 284.1436 ([MþH]þ
calcd for C21H17N: 284.1434).
131.1 (q, J¼32.8, CeF), 129.5, 128.8 (2C), 128.0, 127.8, 126.6, 126.16
(2C), 126.1, 118.8, 117.7, 111.9, 107.6, 97.8. MS (ESI, 70 eV) m/z 337
(Mþ, 100%), 260 (15%), 192 (7%), 145 (3%), 115 (2%), 77 (35%). HRMS
(ESI) m/z 338.1159 ([MþH]þ calcd for C21H14F3N: 338.115).
4.2.2.9. 2-Phenyl-5-(o-tolyl)indolizine (7i). From 2-aryl-indoli-
zine (4a) (96.5 mg, 0.5 mmol) and 2-iodotoluene (6i) (218 mg,
1 mmol); yield: 90 mg (64%); dark green solid; mp 86e88 ꢁC; IR
(KBr): 3064, 2947, 2927, 1604, 1481, 761, 694; 1H NMR (CDCl3,
4.2.2.4. 5-(4-Nitrophenyl)-2-phenyl-indolizine (7d). From 2-
aryl-indolizine (4a) (96.5 mg, 0.5 mmol) and 1-iodo-4-
nitrobenzene (6d) (249 mg, 1 mmol); yield: 117 mg (75%); dark
red solid; mp 154e156 ꢁC; IR (KBr): 3078, 3037, 2985, 1597, 1510,
500 MHz)
d
7.57 (d, J¼7.5 Hz, 2H), 7.43e7.31 (m, 8H), 7.04 (s, 1H),
1348, 860, 773, 698; 1H NMR (400 MHz, CDCl3)
d
8.30 (d, J¼8.8 Hz,
6.80 (d, J¼1 Hz, 1H), 6.78 (dd, J1¼9.0 Hz, J2¼6.75 Hz, 1H), 6.38 (d,
2H), 7.77 (d, J¼8.8 Hz, 2H), 7.52e7.50 (m, 3H), 7.35 (d, J¼8.9 Hz, 1H),
7.27 (t, J¼7.4 Hz, 2H), 7.17e7.13 (m, 1H), 6.76 (d, J¼1.6 Hz, 1H), 6.70
(dd, J1¼8.9 Hz, J2¼6.72 Hz, 1H), 6.38 (dd, J1¼6.7 Hz, J2¼1.5 Hz, 1H).
J¼7 Hz, 1H), 2.15 (s, 3H). 13C NMR (CDCl3, 125 MHz)
d 137.2, 136.3,
135.3, 134.6, 134.2, 130.5, 129.9, 129.3, 129.2, 128.6 (2C), 126.43,
126.41, 126.1 (2C), 117.8, 117.6, 111.1, 108.05, 97.0, 19.0. MS (ESI,
70 eV) m/z 283 (Mþ,100%), 268 (25%), 206 (5%), 191 (7%), 91 (2%), 77
(4%). HRMS (ESI) m/z 284.1442 ([MþH]þ calcd for C21H17N:
284.1434).
13C NMR (100 MHz, CDCl3)
d 147.9, 141.6, 134.8, 134.7, 134.2, 129.8,
129.2 (2C),128.7 (2C),126.7,126.1 (2C),124.4 (2C),119.4,117.6,112.6,
107.5, 96.2. MS (ESI, 70 eV) m/z 314 (Mþ, 100%), 284 (9%), 267 (50%),
241 (10%), 191 (25%), 132 (16%), 77 (5%). HRMS (ESI) m/z 315.1123
([MþH]þ calcd for C20H14N2O2: 315.1128).
4.2.2.10. 5-(2-Methoxyphenyl)-2-phenyl-indolizine (7j). From 2-
aryl-indolizine (4a) (96.5 mg, 0.5 mmol) and 2-iodoanisole (6j)
(234 mg, 1 mmol); yield: 89 mg (60%); dark green solid; mp
98e100 ꢁC; IR (KBr): 3074, 2999, 2935, 1598, 1487, 1269, 1024, 775,
4.2.2.5. 2,5-Diphenyl-indolizine (7e). From 2-aryl-indolizine
(4a) (96.5 mg, 0.5 mmol) and iodobenzene (6e) (204 mg, 1 mmol);
yield: 80 mg (60%); dark green solid; mp 96e98 ꢁC (lit.4 mp
92e94 ꢁC); IR (KBr): 3057, 3028, 2990,1600,1487,1446, 761, 698. 1H
694. 1H NMR (400 MHz, CDCl3)
d 7.59e7.57 (m, 2H), 7.48 (ddd,
J1¼8.2 Hz, J2¼7.6 Hz, J3¼1.6 Hz, 1H), 7.39 (dd, J1¼7.6 Hz, J2¼1.6 Hz,
1H), 7.39e7.37 (m, 1H), 7.34e7.30 (m, 2H), 7.21e7.17 (m, 2H), 7.09
(td, J1¼7.6 Hz, J2¼1.2 Hz, 1H), 7.06e7.04 (m, 1H), 6.78 (d, J¼2.0 Hz,
1H), 6.74 (dd, J1¼9.0 Hz, J2¼6.6 Hz, 1H), 6.43 (dd, J1¼6.8 Hz,
NMR (400 MHz, CDCl3)
d 7.66e7.59 (m, 5H), 7.54e7.48 (m, 3H),
7.38e7.32 (m, 2H), 7.23e7.19 (m, 1H), 6.79 (d, J¼0.8 Hz, 1H), 6.75
(dd, J1¼9.0 Hz, J2¼6.8 Hz,1H), 6.40 (dd, J1¼6.8 Hz, J2¼1.2 Hz,1H). 13
C
NMR (100 MHz, CDCl3)
d
136.7, 135.3, 135.2, 134.7, 129.1, 129.07,
J2¼1.2 Hz,1H). 13C NMR (100 MHz, CDCl3)
d 157.4, 135.6,134.4,134.1,
129.03 (2C), 128.6 (2C), 128.4 (2C), 126.4, 126.1 (2C), 118.0, 117.9,
111.3, 107.8, 97.3. MS (ESI, 70 eV) m/z 269 (Mþ, 100%), 191 (15%), 133
(6%), 127 (5%), 115 (3%), 77 (3%), 63 (3%). HRMS (ESI) m/z 270.1280
([MþH]þ calcd for C20H15N: 270.1277).
131.3, 128.6, 128.5 (2C), 126.2, 126.1 (2C), 124.9, 120.0, 117.9, 117.3,
111.7, 111.07, 108.7, 96.8, 55.4. MS (ESI, 70 eV) m/z 299 (Mþ, 100%),
191 (13%), 284 (5%), 268 (84%), 222 (4%), 77 (4%). HRMS (ESI) m/z
300.1383 ([MþH]þ calcd for C21H17NO: 300.1383).
4.2.2.6. 5-(4-Methoxyphenyl)-2-phenyl-indolizine (7f). From 2-
aryl-indolizine (4a) (96.5 mg, 0.5 mmol) and 4-bromoanisole (6f)
(187 mg, 1 mmol); yield: 116 mg (78%); dark green solid; mp
139e141 ꢁC (lit.4 mp 146e148 ꢁC); IR (KBr): 3076, 3008, 2933, 1606,
4.2.2.11. 2-Phenyl-5-(thiophen-3-yl)indolizine (7k). From 2-aryl-
indolizine (4a) (96.5 mg, 0.5 mmol) and 3-bromothiophene (6k)
(163 mg, 1 mmol); yield: 61 mg (45%); dark green solid; mp
102e104 ꢁC. IR (KBr): 3058, 3010, 2996, 1598, 1486, 1440, 761, 755,
1502, 1247, 1026, 773, 698. 1H NMR (400 MHz, CDCl3)
d
7.53e7.48
697; 1H NMR (400 MHz, CDCl3)
d 7.64 (s, 1H), 7.58e7.53 (m, 3H),
(m, 5H), 7.28e7.24 (m, 3H), 7.15e7.11 (m, 1H), 6.96 (d, J¼8.7 Hz, 2H),
7.43e7.37 (m, 2H), 7.30e7.26 (m, 3H), 7.17e7.13 (m, 1H), 6.71 (s, 1H),
6.65 (dd, J1¼9.2 Hz, J2¼6.8 Hz, 1H), 6.42 (dd, J1¼6.4 Hz, J2¼1.2 Hz,
6.7 (s, 1H), 6.67 (dd, J1¼8.7 Hz, J2¼6.8 Hz, 1H), 6.29 (d, J¼6.7 Hz, 1H),
3.8 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
160.0, 136.6, 135.3, 132.1,
1H). 13C NMR (125 MHz, CDCl3)
d 135.8, 135.2, 134.8, 132.2, 129.2,
132.0, 129.8 (2C), 128.6 (2C), 127.7, 126.4, 126.1 (2C), 117.9, 117.7,
128.6 (2C), 127.1, 126.56, 126.51, 126.1 (2C), 124.9, 118.1, 117.6, 111.4,

M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
3257
108.1, 97.4; MS (ESI, 70 eV) m/z 275 (Mþ,100%), 237 (17%),160 (22%),
116 (7%), 89 (10%), 77 (56%); HRMS (ESI) m/z 276.0840 ([MþH]þ
calcd for C18H13NS: 276.0841).
343 (21%), 312 (12%), 237 (10%), 122 (19%), 77 (45%). HRMS (ESI) m/z
375.1341 ([MþH]þ calcd for C22H18N2O4: 375.1339).
4.2.2.17. 5-(4-Chlorophenyl)-2-(4-methoxyphenyl)indolizine
(7q). From 2-aryl-indolizine (4f) (112 mg, 0.5 mmol) and 1-chloro-
4-iodobenzene (6a) (238.45 mg,1 mmol); yield: 131 mg (79%); dark
green solid; mp 108 ꢁC; IR (KBr): 3086, 2937, 2833, 1600, 1427, 1251,
4.2.2.12. 2-Phenyl-5-(pyridin-2-yl)indolizine (7l). From 2-aryl-
indolizine (4a) (96.5 mg, 0.5 mmol) and 2-bromopyridine (6l)
(163 mg, 1 mmol); yield: 61 mg (45%); dark green solid; mp 80 ꢁC
(dec); 1H NMR (400 MHz, CDCl3)
d
8.77e8.76 (m, 1H), 8.2 (s, 1H),
1089, 1028, 790, 725; 1H NMR (400 MHz, CDCl3)
d
7.49 (d, J¼8.4 Hz,
7.86 (td, J1¼8 Hz, J2¼2 Hz, 1H), 7.73 (d, J¼8 Hz, 1H), 7.58 (dd,
J1¼8.4 Hz, J2¼1.2 Hz, 2H), 7.40e7.35 (m, 2H), 7.31e7.27 (m, 2H),
7.18e7.14 (m, 1H), 6.77 (s, 1H), 6.74e6.70 (m, 2H). 13C NMR
2H), 7.43e7.36 (m, 5H), 7.26 (d, J¼8.8 Hz, 1H), 6.83e6.79 (m, 2H),
6.66e6.63 (m, 2H), 6.28 (d, J¼6.8 Hz, 1H), 3.72 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 158.4, 140.1, 134.9, 133.8, 131.9, 130.1, 129.8 (2C),
(100 MHz, CDCl3)
d
152.8, 149.4, 140.2, 138.1, 137.3, 133.3, 130.1,
129.3 (2C), 128.7, 127.2 (2C), 118.1, 114.0 (2C), 113.4, 111.3, 107.0, 97.2,
55.2; MS (ESI, 70 eV) m/z 335 (33%), 333 (Mþ, 100%), 318 (22%), 290
(155), 254 (135), 166 (4%), 149 (17%), 127 (23%), 77 (2%). HRMS (ESI)
m/z 334.0999 ([MþH]þ calcd for C21H16ClNO: 334.0993).
128.8 (2C), 128.1 (2C), 127.8, 124.9, 122.1, 119.6, 117.0, 112.9, 109.2,
97.8. MS (ESI, 70 eV) m/z 270 (Mþ, 5%),193 (18%),192 (12%),115 (5%),
78 (9%), 77 (2%); HRMS (ESI) m/z 271.1239 ([MþH]þ calcd for
C
19H14N2: 271.1230).
4.2.2.18. 2-(4-Methoxyphenyl)-5-(4-nitrophenyl)indolizine
(7r). From 2-aryl-indolizine (4f) (112 mg, 0.5 mmol) and 1-iodo-4-
nitrobenzene (6d) (249 mg, 1 mmol); yield: 120 mg (70%); dark red
solid; mp 100e102 ꢁC; IR (KBr): 3078, 3001, 2954, 1600, 1514, 1431,
4.2.2.13. 2,5-Bis(4-chlorophenyl)indolizine (7m). From 2-aryl-
indolizine (4b) (114 mg, 0.5 mmol) and 1-chloro-4-iodobenzene
(6a) (238.45 mg, 1 mmol); yield: 115 mg (68%); dark green solid;
mp 80 ꢁC (dec); IR (KBr): 3066, 2980, 1485, 1089, 785, 727; 1H NMR
1344, 1253, 1031, 856, 790; 1H NMR (400 MHz, CDCl3)
d 8.30 (d,
(400 MHz, CDCl3)
d
7.50 (d, J¼8.4 Hz, 2H), 7.46e7.42 (m, 4H),
J¼8.8 Hz, 2H), 7.79 (d, J¼8.4 Hz, 2H), 7.44e7.42 (m, 3H), 7.34 (d,
7.33e7.28 (m, 2H), 7.23 (d, J¼8.8 Hz, 2H), 6.71e6.67 (m, 2H), 6.32 (d,
J¼9.2 Hz, 1H), 6.82 (d, J¼8.8 Hz, 2H), 6.74e6.70 (m, 2H), 6.39 (d,
J¼6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d
135.6, 135.2, 133.7, 132.2,
J¼6.4 Hz, 1H), 3.73 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 158.7, 147.9,
132.0, 129.9 (2C), 129.5 (2C), 129.0, 128.8 (2C), 128.2, 127.3 (2C),
118.5, 118.2, 111.8, 107.6, 97.6. MS (ESI, 70 eV) m/z 341 (11%), 339
(65%), 337 (Mþ, 100%), 302 (20%), 265 (16%), 239 (5%),191 (10%), 150
(7%), 77 (2%); HRMS (ESI) m/z 338.0507 ([MþH]þ calcd for
141.6, 132.0, 131.99, 131.97, 129.3 (2C), 128.5, 128.4, 127.3 (2C), 124.4
(2C), 119.3, 117.9, 114.1 (2C), 112.6, 98.2, 55.2; MS (ESI, 70 eV) m/z
344 (Mþ, 100%), 298 (16%), 255 (18%), 228 (8%), 172 (4%), 148 (12%),
127 (15%), 77 (2%). HRMS (ESI) m/z 345.1241 ([MþH]þ calcd for
C
20H13Cl2N: 338.0498).
C21H16N2O3: 345.1234).
4.2.2.14. 2-(4-Chlorophenyl)-5-(p-tolyl)indolizine (7n). From 2-
4.2.2.19. 2-(6-Methoxynaphthalen-2-yl)-5-(p-tolyl)indolizine
aryl-indolizine (4b) (114 mg, 0.5 mmol) and 4-iodotoluene (6h)
(218 mg, 1 mmol); yield: 112 mg (71%); dark green solid; mp
92e94 ꢁC; IR (KBr): 3057, 2927, 2866, 1608, 1502, 1091, 785, 729; 1H
(7s). From 2-aryl-indolizine (4e) (136 mg, 0.5 mmol) and 4-iodo-
toluene (6h) (218 mg, 1 mmol); yield: 117 mg (65%); dark green
solid; mp 90e93 ꢁC; IR (KBr): 3026, 2953, 2916, 2868, 1604, 1502,
NMR (400 MHz, CDCl3)
7.14e7.13 (m, 1H), 6.69e6.65 (m, 2H), 6.31 (d, J¼6.4 Hz, 1H), 2.36 (s,
3H). 13C NMR (100 MHz, CDCl3)
139.1, 136.9, 134.8, 133.8, 132.3,
d
7.50e7.37 (m, 5H), 7.25e7.19 (m, 5H),
1255, 1033, 783; 1H NMR (400 MHz, CDCl3)
d 7.94e7.90 (m, 1H),
7.64 (m, 3H), 7.50 (d, J¼8.0 Hz, 2H), 7.43 (d, J¼8.0 Hz, 1H), 7.31e7.27
(m, 3H), 7.22e7.17 (m, 2H), 6.81 (s, 1H), 6.69 (m, 1H), 6.33 (d,
J¼6.47 Hz, 1H), 3.83 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
131.9, 129.7 (2C), 128.6 (2C), 129.3 (2C), 127.7, 127.2 (2C), 118.1, 117.8,
111.3,107.8, 97.0, 21.3. MS (ESI, 70 eV) m/z 319 (32%), 317 (Mþ,100%),
301 (17%), 281 (18%), 204 (6%), 139 (15%), 132 (37%), 77 (3%). HRMS
(ESI) m/z 318.1067 ([MþH]þ calcd for C21H16ClN: 318.1044).
d
157.2, 155.0, 153.4, 139.1, 136.8, 134.9, 132.4, 130.7, 129.7 (2C),
129.5, 128.6, 128.3 (2C), 126.9, 125.5, 123.9, 118.8, 117.7, 113.9, 111.1,
107.9, 105.6, 97.1, 55.2, 21.3. HRMS (ESI) m/z 364.1694 ([MþH]þ
calcd for C26H21NO: 364.1696).
4.2.2.15. 5-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-indolizine
(7o). From 2-aryl-indolizine (4c) (126 mg, 0.5 mmol) and 1-chloro-
4-iodobenzene (6a) (238.45 mg,1 mmol); yield: 127 mg (70%); dark
green solid; mp 93 ꢁC (dec); IR (KBr): 3086, 2956, 2929, 1624, 1514,
4.3. Photophysical measurements
Absorption spectra were determined in DMSO, using a Shi-
madzu-2550 UVevis spectrophotometer. The fluorescence spectra
were recorded in a PerkineElmer LS-55 by excitation of the sam-
ples in its lower energy wavelengths (320e395 nm). The excitation
and emission slit were 10 nm and 3 nm, respectively. The emission
quantum yields (FF) were determined from corrected fluorescence
spectra using quinine sulfate solution in 0.1 N H2SO4 as a standard
1255, 1024, 732; 1H NMR (400 MHz, CDCl3)
d
7.61e7.55 (m, 3H),
7.46e7.32 (m, 4H), 7.09e7.03 (m, 2H), 6.80e6.71 (m, 2H), 6.36 (m,
1H), 3.85 (s, 3H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3)
149.1,
d
148.1, 141.7, 134.9, 134.1, 132.0, 129.9, 129.7 (2C), 129.2 (2C), 128.3,
119.2, 118.6, 117.5, 112.5, 111.4, 109.6, 107.0, 98.0, 55.98, 55.90; MS
(ESI, 70 eV) m/z 363 (Mþ,100%), 348 (10%), 320 (22%), 241 (12%),181
(8%), 164 (7%), 120 (17%), 77 (2%). HRMS (ESI) m/z 364.1115 ([MþH]þ
calcd for C22H18ClNO2: 364.1099).
(
FF¼0.55). All spectrophotometric measurements were carried out
in 1 cm path length quartz cuvettes. Fluorescence decays were
based on the Stroboscopic technique (Strobe). The excitation source
was a pulsed light source (LED), which measures fluorescence in-
tensity at different time delays after pulse. Fluorescence lifetimes
were determined from the decays by using the Software from Easy
Life VÔ and corrected fits for mono- and bi-exponential decay.
4.2.2.16. 2-(3,4-Dimethoxyphenyl)-5-(4-nitrophenyl)indolizine
(7p). From 2-aryl-indolizine (4c) (126 mg, 0.5 mmol) and 1-iodo-4-
nitrobenzene (6d) (249 mg, 1 mmol); yield: 129 mg (69%); dark red
solid; mp 97 ꢁC (dec); IR (KBr): 3072, 2958, 2835, 1593, 1516, 1342,
1255, 1026, 856, 794; 1H NMR (400 MHz, CDCl3)
d
8.32 (d, J¼8.8 Hz,
2H), 7.84e7.79 (m, 2H), 7.43 (s, 1H), 7.35 (d, J¼8.8 Hz, 1H), 7.07 (dd,
J1¼8 Hz, J2¼2 Hz, 1H), 7.01 (d, J¼2 Hz, 1H), 6.8 (d, J¼8.8 Hz, 1H), 6.71
(m, 2H), 6.39 (dd, J1¼6.4 Hz, J2¼0.8 Hz,1H), 3.84 (s, 3H), 3.81 (s, 3H).
4.4. Electrochemical measurements
Electrochemical assays were carried out with a BAS CV-27
potentiostat. Data were recorded on an Omnigraphic XY recorder.
Conventional electrochemical cells with three electrodes were
employed. A glassy carbon electrode with geometric area of
13C NMR (100 MHz, CDCl3)
d 149.1, 148.1, 141.7, 138.5, 134.8, 134.1,
129.9, 129.2 (2C), 127.8, 124.4 (2C), 119.2, 118.6, 117.5, 112.5, 111.4,
109.6, 107.0, 98.0, 55.91, 55.90; MS (ESI, 70 eV) m/z 374 (Mþ, 100%),

3258
M.F.Z.J. Amaral et al. / Tetrahedron 70 (2014) 3249e3258
0.0314 cm2 was used as working electrode. It was polished prior to
use with 1 alumina water suspension and rinsed thoroughly with
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m
water and acetone. A platinum wire was used as counter electrode
and all potentials are referenced to a sodium saturated silver/silver
chloride electrode (Ag/AgCl/KCl(sat)) without regard for the liquid
junction potential. Cyclic voltammetric studies were carried out at
100 mV/s sweep rate in 5 mL of 0.1 M of TBAH in DMSO solution as
supporting electrolyte, where aliquots of 100 mM of the indolizine
derivatives in DMSO solution were added. Since the cyclic vol-
tammograms were recorded at a window potential including
negative ranges, oxygen-free solution was obtained by bubbling
argon through it. When the potential was scanned, the inert gas
was kept in the solution to ensure that any oxidation reaction was
not begun by oxygen. For the electrochemical process of indolizine
in presence of molecular oxygen, the supporting electrolyte was
previously saturated with O2(g), and the oxygen redox process was
studied in absence and presence of the indolizine. Since the win-
dow potential in this study was between þ1.2 V and ꢀ1.2 V (vs Ag/
AgCl(s)/KCl(sat)), three nitro indolizines were chosen. Reduction of
nitro group in nonaqueous medium is well known from the liter-
ature32 and the potential is much less negative than ꢀ2.5 V (vs SCE)
for the indolizine ring.8 The solutions were stirred for 30 s and
allowed to rest for 30 s for equilibration.
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We are grateful to the Brazilian foundations FAPESP, CAPES and
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Supplementary data
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Absorption and fluorescence emission spectra for all indolizine
compounds in DMSO, fluorescence emission for 7a, 7f, 7m, and 7k
in solvents with different polarities, fluorescence lifetime fitting
curves for 7a, 7f, 7m, and 7k in DMSO, and a table containing
maximum wavelength absorption and fluorescence emission in
different solvents. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.11.105.
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