Direct arylation of electron-poor indolizines

Article abstract of DOI:10.1016/j.tet.2013.11.088

Derivatized indolizines efficiently prepared via direct arylation, exhibit violet, blue or green fluorescence depending on the nature of substituents. By attaching two electron-withdrawing groups to five-membered ring it is possible to access a range of multi-substituted stable indolizine-based fluorophores. Compounds featuring this scaffold display advantageous combination of optical properties including reasonable fluorescence quantum yield combined with large Stokes shifts.

Full text of DOI:10.1016/j.tet.2013.11.088

Tetrahedron 70 (2014) 225e231
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct arylation of electron-poor indolizines
Beata Koszarna a, Rafa1 Matczak b, Maciej Krzeszewski a, Olena Vakuliuk b, Jan Klajn a,
,b,
Mariusz Tasior a, Jan T. Nowicki b, Daniel T. Gryko a
*
a Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2013
Received in revised form 4 November 2013
Accepted 25 November 2013
Available online 3 December 2013
Derivatized indolizines efficiently prepared via direct arylation, exhibit violet, blue or green fluorescence
depending on the nature of substituents. By attaching two electron-withdrawing groups to five-
membered ring it is possible to access a range of multi-substituted stable indolizine-based fluo-
rophores. Compounds featuring this scaffold display advantageous combination of optical properties
including reasonable fluorescence quantum yield combined with large Stokes shifts.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Indolizines
Fluorescence
Heterocycles
Arylation
Dyes
1. Introduction
fluorophores with a high quantum yield.8 Recently, other similar
indolizine-based fluorescent dyes have been described.9 The
The development of new molecular fluorescent sensor plat-
forms for in vivo analysis of cells and in vitro analytical studies has
emerged as an actively investigated research field in recent years.1
As the applications for fluorescent probes in molecular biology (e.g.,
bioorthogonal labelling, selective detection of enzymes, cations,
and antibodies) continue to increase, so does the need for dyes with
diverse spectral and physicochemical properties. In particular,
stable and biocompatible substances possessing high fluorescent
quantum yield, large Stokes shift, and significant molar absorption
coefficient are highly sought. Despite the multitude of available
fluorophores, new fluorophoric systems are eagerly sought for
more challenging applications, including single molecule imaging.2
A key advantage of synthetic luminophores over natural fluo-
rophores (such as tryptophan, fluorescent proteins, etc.) is the
ability to use chemistry to dictate the properties and position of
a fluorescent dye in a biological experiment. In addition to classic
fluorescent platforms such as coumarins,3 fluoresceins,4 and bod-
ipys,5 researchers have also explored new scaffolds.6 One particu-
larly interesting one is indolizine, which, thanks to its high
fluorescent quantum yield, has attracted attention from many
vantage points.7 In particular, indolizino[3,4,5-ab]isoindoles pre-
pared from pyrido[2,1-b]isoindoles have been found to be excellent
chemistry of this class of molecules, although well-known,10 con-
tinues to attract attention.11
New reactions undoubtedly offer unique tools in both the syn-
thesis of aromatic compounds as well as in their functionalization,
directed both towards medicinal as well as materials chemistry.
One of the newest methodologies relies on direct arylation of ar-
omatic heterocycles.12 Various aromatic systems, such as pyrrole,
indole, thiophene, imidazole, etc., have been successfully arylated
to smoothly give biaryl linkages.13,14
For functional dyes based on an indolizine core to fulfil their full
potential, the issues of both stability and the ability to fine-tune the
fluorescence have to be addressed. The promising optical proper-
ties of both unsubstituted indolizine as well as some of its de-
rivatives prompted us to investigate whether electron-poor
indolizines could also be effectively arylated to afford a library of
functional dyes combining beneficial optical properties with in-
creased stability. Herein we would like to present the results of this
investigation.
2. Results and discussion
Indolizines are significantly less studied than indoles, which are
also mirrored in the progress made in their direct arylation. In
2003, Gevorgyan and co-workers were the first to report a syn-
thetic protocol devoted to this subject, demonstrating that both
* Corresponding author. E-mail address: dtgryko@icho.edu.pl (D.T. Gryko).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.088

226
B. Koszarna et al. / Tetrahedron 70 (2014) 225e231
indolizine and its simple derivatives can be efficiently arylated in
the presence of Pd(PPh3)2Cl2 as the catalyst.15 Additional examples
of the same process, albeit under different conditions, were pub-
lished later.16 More recently, direct arylation of the indolizine core
was also achieved via arylotrifluoroboranes.17 Taking into consid-
eration the plausible mechanism of this reaction,13 it is not at all
clear if compounds bearing multiple electron-withdrawing groups
(hence with lowered average electron density) will undergo this
reaction. Finally, we also queried whether arylation with dibro-
moarenes can be performed, affording dyes constructed of two
Analysis of the literature inclined us to perform the direct
arylation of compounds 1aed using three distinct methodolo-
gies: (a) Gevorgyan’s method for the arylation of indolizine;15
(b) Doucet’s, low palladium loading method22 for the aryla-
tion of electron-rich heterocycles (including pyrrole,23 indole,
furan and thiophene groups);24 and (c) a process mediated by
tert-butanolates, reported earlier by our group, which showed
peculiar regioselectivity with regard to unsubstituted
indolizine.16b
From the synthetic point of view, we were eager to investigate
direct arylation using both electron-poor aromatic haloarenes
(which are more reactive in these reactions) as well as electron-
rich ones. This aspect was also critical given the photophysical
aim of this study. Consequently, the following bromoarenes
were chosen: 1-bromo-4-nitrobenzene, 4-bromobenzonitryle, 3-
bromobenzonitryle, 5-acetyl-2-bromothiophene, 4-bromoanisol
and 4-bromo-N,N-diphenylaniline. 1-Bromonaphthalene was also
selected as a representative of sterically hindered arylating agents.
We also wished to entertain the possibility of performing a model
reaction between indolizine derivatives and exemplary dibro-
moarenes, namely 2,7-dibromo-9,9-dioctylfluorene (5a) and 2,5-
dibromothiophene (5b).
indolizine units spanned with p-linkers.
The synthetic objective corroborated the optical goal, which was
based on the necessity to increase oxidation potential via the in-
troduction of multiple electron-withdrawing groups. This particular
choice was mostly based on the desire to investigate the regiose-
lectivity of direct arylation. Given these objectives, we chose the fol-
lowing indolizine derivatives as pivotal building blocks: 2-
cyanoindolizine (1a),18 diethyl indolizine-1,2-dicarboxylate (1b),19
1-cyano-2-ethoxycarbonylindolizine (1c),20 2-(4-trifluoromethyl
ophenyl)indolizine (1d) and 1,2,3-tris(methoxycarbonyl)indolizine
(1e)21 (Fig. 1).
In all cases, palladium-catalyzed reactions led to the expected
arylated products (Table 1, methods A and B). It turned out that the
low catalyst-loading protocol, originally reported for pyrroles,23
showed better efficiency with electron-poor halides (Table 1,
method B). On the other hand, for aryl bromides bearing electron-
donating groups, better yields were achieved using Gevorgyan’s
method15 (Table 1, method A). Most importantly, the presence of
two electron-withdrawing groups at positions 1 and 2 still allowed
us to obtain the corresponding 3-arylated products in good yields
(Table 1, entries 8e17).
Fig. 1. Structures of indolizine building blocks.
Table 1
Results of the direct arylation of indolizines 1aed
R1
R1
[Pd], base
R2
ArBr
R2
N
N
Ar
1
2
3
Entry
Indolizine
R1
R2
Bromoarene
Ar
Product
Meth. A
Meth. B
1
2
3
1a
1a
1a
H
H
H
CN
CN
CN
2a
2b
2c
3aa
3ab
3ac
99%
85%
80%
96%
88%
76%
O2N
NC
MeO
4
1a
H
CN
2d
3ad
82%
83%
NC
5
6
7
1a
1a
1a
H
H
H
CN
CN
CN
2e
2f
3ae
3af
3ag
70%
64%
80%
82%
73%
69%
S
O
Ph2N
2g

B. Koszarna et al. / Tetrahedron 70 (2014) 225e231
227
Table 1 (continued )
Entry
Indolizine
R1
R2
Bromoarene
Ar
Product
Meth. A
94%
Meth. B
8
1b
1b
CO2Et
CO2Et
2a
3ba
88%
67%
O2N
NC
9
CO2Et
CO2Et
CO2Et
CO2Et
2b
2e
3bb
3be
67%
48%
10
1b
1b
50%
64%
S
O
11
CO2Et
CO2Et
2g
3bg
24%
12
13
14
1c
1c
1c
CN
CN
CN
CO2Et
CO2Et
CO2Et
2a
2b
2c
3ca
3cb
3cc
81%
68%
26%
73%
71%
31%
O2N
NC
MeO
15
16
1c
1c
CN
CN
CO2Et
CO2Et
2d
2e
3cd
3ce
60%
40%
70%
55%
NC
O
S
17
12
13
14
1c
1d
1d
1d
CN
H
CO2Et
F3C
2f
3cf
58%
71%
56%
50%
38%
96%
91%
43%
Ph2N
O2N
NC
2a
2b
2c
3da
3db
3dc
H
F3C
H
F3C
MeO
15
1d
H
2d
3dd
83%
94%
F3C
F3C
NC
16
17
1d
1d
H
H
2e
2f
3de
3df
95%
53%
92%
75%
S
O
F3C
Ph2N
Method A. 1/2¼1:1.2, PdCl2(PPh3)2, KOAc, NMP, H2O, 100 ꢀC, 16 h.15
Method B. 1/2¼1.5:1, Pd(OAc)2, KOAc, DMAc, 130 ꢀC, 20 h.23
Following the protocol developed for the arylation of N-alkyl-
pyrroles and consisting of using t-BuOLi/DMF at a higher temper-
ature,16b we could not obtain any identifiable products in the
attempted arylation of indolizines 1aed. The reactions suffered
from low conversion and/or a complex mixture of products, which
probably originated from the hydrolysis of CO2Et and CN groups.
Surprisingly, when indolizine 1c was reacted with 4-bromo-
N,N-diphenylaniline (2f), in addition to the expected 3-arylated
indolizine 3cf, the corresponding 5-arylation product 3cf0 was ob-
tained, albeit in low yield (Fig. 2). This unexpected result cannot be
easily rationalized.
Fig. 2. Structure of product 3cf.

228
B. Koszarna et al. / Tetrahedron 70 (2014) 225e231
We wondered whether an indolizine already possessing an
electron-withdrawing aromatic substituent could be subjected to
the stepwise bis-arylation, potentially leading to the corresponding
1,2,3-tris-arylindolizines. The inherent difference in the substrate
ratio of the two main protocols (arene/bromoarene¼1:1.215 and
1.5:123), suggested that the Gevorgyan method would serve us
better in this particular case. Indeed, the expected products were
obtained following a slightly modified version of protocol A; it
turned out that the incorporation of exclusively electron-poor ar-
omatic groups (4a, 4b and 4c) was possible (Scheme 1). The at-
tempts at the bis-arylation of indolizine 1d with 3-
bromobenzonitrile (2d) or 4-bromoanisole (2c) led to a mixture
of undesired mono-arylated (major) and bisarylated (trace)
products.
6b
Scheme 3. Preparation of bis-indolizine 6b.
Aiming to investigate arylation proceeding at the C5 carbon, we
tested the reactivity of 1,2,3-tris(methoxycarbonyl)-indolizine (1e).
It possesses ester groups at all the positions of the five-membered
ring, which decrease electron density and hence reactivity. In spite
of numerous attempts, experiments performed on indolizine 1e
using palladium-catalyzed protocols15,23 did not afford any prod-
ucts. In the case of the t-BuOLi-mediated procedure,16b an ex-
tremely complex mixture was obtained, likely related to the
liability of ester groups under strongly basic conditions.
The effect of structural variations on photophysical properties
was studied in detail for all new indolizines (Table 2, Figs. 3 and 4).
Acetonitrile was chosen as the solvent for the measurements due to
its ability to dissolve all the tested compounds, making it possible
to investigate the relationship between the structure and optical
properties of these molecules.
Scheme 1. Bis-arylation of indolizines.
Moreover, we demonstrated the possibility of efficient and
convenient preparation of dyes constructed of two indolizine units
connected with arene linkers. Direct coupling of indolizine 1b with
dibromoarenes 5a and 5b was attempted under both Doucet’s23
and Gevorgyan’s15 conditions, as shown in Schemes 2 and 3. As
a result, we obtained structurally unique bis-indolizines 6a and 6b
in satisfactory yields. It is noteworthy that, in both cases, sub-
stantially higher yields were obtained under low palladium loading
conditions.23
Table 2
Optical properties of the arylated indolizines in CH3CN
Product
lmax abs/nm
3
/Mꢁ1 cmꢁ1
lmax em/nm
Stokes
Ffl/%a
shift/cmꢁ1
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ba
3bb
3be
3bg
3ca
3cb
3cc
3cd
3ce
3cf
3da
3db
3dc
3dd
3de
3df
4a
403
359
315
335
383
344
336
347
340
351
330
353
339
356
336
350
328
429
369
323
345
390
336
423
364
399
345
343
9600
12,400
9300
d
d
d
39
10
15
9
455
439
437
497
454
443
d
5950
8970
7150
5720
6960
7460
d
8500
13,600
22,200
6300
10,400
15,600
11,800
9200
9
17
d
21
14
16
d
29
15
21
5
10
d
6
8
2
d
443
490
418
d
6930
7920
6290
d
9300
9200
4800
6500
430
429
412
482
463
d
6070
6540
5500
7990
8710
d
10,200
19,000
7100
7700
4300
6200
6600
479
448
484
d
6900
8600
8920
d
3900
465
d
6270
d
6
d
8
d
47
6
17,300
14,000
14,600
42,500
22,800
4b
4c
6a
6b
483
d
6770
d
425
472
5500
7880
a
Scheme 2. Preparation of bis-indolizine 6a.
Determined using quinine sulfate as the standard.

B. Koszarna et al. / Tetrahedron 70 (2014) 225e231
229
a larger Stokes shift for these molecules. Although the keto group is
known to quench fluorescence since the n/
p transition has the
*
lowest energy (StricklereBerg equation),1c most of the compounds
possessing the 5-acetylthiophene moiety (3be, 3ae and 3ce) dis-
played noticeable fluorescence quantum yields (Table 2, Fig. 3). This
was not true, however, for dyes 3de and 4c, which did not display
any fluorescence. These variations are strongly related to the fact
that n/
p and p/p transitions are probably energetically close
*
*
and slight changes of the structure can invert their order. The di-
esters possessed low to moderate fluorescence quantum yields.
As was expected, in contrast to other scaffolds, the a-naphthyl
substituent (present in compounds 3bg and 3ag), with a steric
nature that prevents the overlap of orbitals, did not alter the ab-
sorption maxima. Moreover, even in the excited state, the in-
teraction between naphthalene and indolizine was prevented,
which was mirrored in the position of the emission maxima (lem
was strongly shifted hypsochromically in contrast to other arylated
analogues).
Fig. 3. Absorption and emission of compounds 3ab (solid line), 3af (dotted line) and
3ae (dashed line) in MeCN (excitation wavelength 315 nm for 3ab and 343 nm for 3af
and 3ae).
The comparison of the properties of 2-cyanoindolizines with
structurally
related
1-cyano-2-carboxyethyl-
and
1,2-
bis(carboxyethyl)indolizines revealed that the fluorescence quan-
tum yields for the these molecules were generally lower, with the
notable exception of 2-cyano-3-(4-cyanophenyl)-indolizine (3ab,
Ffl¼39%). In this group of compounds, the correlations between the
values of the molar extinction coefficients and the Stokes shift were
particularly clear, showing that a higher value of leads to a smaller
3
Stokes shift. This can probably be explained by a lower affinity for
a change in conformation in the exited state. For arylated 2-(4-
trifluoromethylphenyl)indolizines, Ffl turned out to be consis-
tently low.
Regarding the optical properties of tri-arylated indolizines
4aec, bearing one 4-trifluoromethylophenyl substituent, the in-
fluence of substituents on labs followed the general trends (i.e., the
presence of electron-withdrawing groups caused a bathochromic
shift of the absorption band, which for 4a and 4b moved them into
the visible region). Triaryl-substituted indolizines 4aec did not
possess more red-shifted absorption when compared with mono-
aryl substituted indolizines, which most probably occurred due to
the lower degree of planarization.
The comparison of diesters 3bae3bg with the structurally
similar mono-esters 3cae3cf showed that for the latter com-
pounds, the emission was slightly hypsochromically shifted.
Whenever possible, the comparison of dyes possessing 3-
cyanophenyl versus 4-cyanophenyl moieties shows that the latter
ones possess more bathochromically shifted absorption and higher
fluorescence quantum yields (Table 2).
Fig. 4. Absorption and emission of compounds 6a (solid line), 6b (dotted line) in MeCN
(excitation wavelength 345 nm).
All investigated compounds possessed a strong absorption
band, which was typically located between 300 and 400 nm.
Moreover, significant expansion of the
p-system (for 6a and 6b)
was mirrored in the higher extinction coefficients. A strong impact
of the electron-withdrawing groups (reflected in the bathochromic
shift of the absorption band) could be easily detected in the ab-
sorption spectra of 3ba, 3bb, 3be, 3cb, 3cd and 3ce. These results
indicate that the five-membered ring of indolizine, even possessing
two electron-withdrawing substituents, still retains its intrinsic
electron-excessive nature. The presence of electron-withdrawing
substituents at position 3 formed weak pushepull systems, which
are known to have bathochromically shifted absorption.1c The clear
tendency was that the 4-nitrophenyl substituent shifted the ab-
sorption bathochromically the most, such that lmax reached
430 nm. In principle, lmax decreases following the order
NO2>Ac>CN>OMe>NPh2 (Table 2, Fig. 3).
All the investigated molecules, except for compounds bearing
a 4-nitrophenyl substituent (3ba, 3da, 3aa and 3ca), emitted violet,
blue or blue-green light. The absence of fluorescence for the 4-
nitrophenyl compounds was not surprising due to the known
quenching effect of the nitro group.1c For the majority of the new
indolizines, the emission maxima were situated in the violet-blue
region. However, for the dyes 3ae, 3be and 3ce possessing a 5-
acetylthiophene group, lem was shifted bathochromically to the
green region. The effect of this group on the bathochromic shift of
absorption and emission was stronger than for the 4-cyanophenyl
substituent (3be and 3ce vs 3bb and 3cb). This probably origi-
nates from the geometry of the thiophene ring, which allows for
a smaller mean angle between the five-membered ring of indoli-
zine and the thiophene ring (compared to the benzene ring). At the
same time, it allows for a higher degree of planarization in the
excited state, which translates to a stronger emission shift hence
One of the bis-indolizines, compound 6a, displayed the highest
fluorescence quantum yield (Table 2, Fig. 4). It is noteworthy to add
that the labs of arylated indolizines is shifted bathochromically
compared to their pyrrole analogues, such as 3-(4-trifluorophenyl)-
N-methylpyrrole25 or 2-(4-methoxyphenyl)pyrrole.26
3. Conclusion
We demonstrated that the presence of two electron-
withdrawing groups at positions 1 and 2 does not deactivate
indolizines towards direct arylation. Under the reaction conditions
optimized for electron-rich heterocycles, we obtained the expected
arylated products in good yields with very good regioselectivity.
Still, when all positions in the five-membered ring were occupied
by ester groups, the reaction did not proceed at the six-membered
ring under any of the tested conditions. For the first time, we have
reported bis-arylation of the 2-arylindolizine core leading to the
corresponding 1,2,3-trisaryloindolizines in good yields. The low
palladium loading method developed by Doucet and co-workers
was preferred for the synthesis of bis-indolizines from

230
B. Koszarna et al. / Tetrahedron 70 (2014) 225e231
dibromoarenes. Due to the significant expansion of the
these molecules were characterized by increased
p
-system,
stirred at 100 ꢀC for 10 min under an argon atmosphere. After-
wards, water (15 l, 0.85 mmol, 2 equiv) was added to the reaction
3 .
m
We have demonstrated that by arranging various substituents, it
is possible to easily manipulate the emission characteristics of
indolizine derivatives with lmax ranging from 420 nm to 500 nm.
The derivatization of indolizine with substituted aryl rings at po-
sitions 3 and 1 leads to compounds possessing very low fluores-
cence quantum yields. Consequently, dyes bearing ester/cyano
groups were shown to have more attractive optical properties.
The replacement of one ester group at position 1 of the indoli-
zine core with CN did not affect absorption, but hypsochromically
shifted emission (w10e20 nm). At the same time, Ffl remained at
a similar level. Systematic optical studies of multiply substituted
indolizines showed that most of these compounds were charac-
terized with large Stokes shifts. One of the most promising com-
pounds, possessing a fluorene bridge, had high fluorescence
quantum yield (47%) while its Stokes shift remained relatively large
(5500 cmꢁ1). The addition of an additional aryl ring at position 1 to
2,3-diarylindolizines did not shift absorption but considerably in-
mixture and heating was continued overnight at 100 ꢀC. After re-
action completion, the residue was diluted with dichloromethane,
washed with water, dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by means of flash column
chromatography.
4.1.1. 1,3-Bis(4-nitrophenyl)-2-(4-trifluoromethylphenyl)-indolizine
(4a). Following the general procedure, indolizine 1b (222 mg,
0.85 mmol) and 1-bromo-4-nitrobenzene 2a (343 mg, 1.70 mmol)
were reacted. The crude product was purified by means of flash
column chromatography (SiO2, CH2Cl2/hexanes, 1:1). All fractions
containing the expected product were collected and rechromato-
graphed (SiO2, AcOEt/hexanes, 1:4, 1:2) affording 242 mg (56%,
recrystallized from AcOEt/hexanes) of 4a. Rf¼0.46 (SiO2, CH2Cl2/
hexanes, 1:1), mp 242 ꢀC (AcOEt/hexanes); 1H NMR (500 MHz,
CDCl3):
d
6.71 (7, J¼6.7 Hz,1H, ind), 6.98 (dd, J1¼8.6 Hz, J2¼6.9 Hz,1H,
ind), 7.13 (d, J¼7.9 Hz, 2H, C6H4), 7.34 (d, J¼8.8 Hz, 2H, C6H4), 7.47 (m,
2ꢂ2H, C6H4), 7.66 (d, J¼9.1 Hz, 1H, ind), 8.15 (d, J¼7.4 Hz, 1H, ind),
8.17 (d, J¼8.8 Hz, 2H, C6H4), 8.26 (d, J¼8.8 Hz, 2H, C6H4). 13C NMR
creased . The other notable findings are that, in most cases, the
3
five-membered ring of the indolizine chromophore behaves as an
electron-rich moiety, forming pushepull systems with electron-
poor aryl substituents (which results in bathochromically shifted
absorption and emission, when compared with other compounds).
In addition to tuning the intrinsic emission properties of indolizine,
it is also possible to influence the Stokes shift by incorporating
various groups into the core.
(125 MHz, CDCl3): d 112.6,113.1,117.8,121.3,121.5,122.4,123.9,124.4,
125.5, 127.0, 129.3, 129.5, 130.3, 131.1, 131.2, 132.1, 136.9, 137.3, 141.3,
145.8, 147.0. HRMS (EI) obsd 503.1093 [Mꢃþ], calcd 503.1093
(C27H16F3N3O4). UVevis (CH3CN): lmax
(
3
ꢂ10ꢁ3) 423 (17.3) nm.
4.1.2. 1,3-Bis(4-cyanophenyl)-2-(4-trifluoromethylphenyl)-indolizine
(4b). Following the general procedure, indolizine 1d (111 mg,
0.425 mmol) and 4-bromobenzonitrile 2b (155 mg, 0.85 mmol) were
reacted. The crude product was purified by means of flash column
chromatography (SiO2, CH2Cl2/hexanes, 1:4, 1:3), affording 123 mg
(62%, recrystallized from AcOEt/hexanes) of 4b. Rf¼0.6 (SiO2, CH2Cl2/
hexanes, 3:1), mp 227e228 ꢀC (AcOEt/hexanes); 1H NMR (500 MHz,
4. Experimental section
4.1. General procedures for the synthesis of 3-arylindolizines
Method A:15 A solution of indolizine (0.85 mmol, 1 equiv), aryl
bromide (1.02 mmol, 1.2 equiv) and KOAc (166 mg, 1.7 mmol,
2 equiv) was placed in a Schlenk tube previously flushed with ar-
gon. Subsequently, NMP (1.7 ml) and PdCl2(PPh3)2 (30 mg, 5 mol %,
DMSO):
d
6.80(t, J¼6.8 Hz,1H, ind), 7.04 (t, J¼7.8Hz,1H, ind), 7.23, 7.54
(AA0BB0, J¼7.8 Hz, 2ꢂ2H, C6H4), 7.35, 7.62 (AA0BB0, J¼7.9 Hz, 2ꢂ2H,
C6H4), 7.66 (d, J¼9.0 Hz, 1H, ind), 7.78, 7.90 (AA0BB0, J¼7.9 Hz, 2ꢂ2H,
42.5
m
mol) were added and resulting solution was stirred at 100 ꢀC
l,
C6H4), 8.21 (d, J¼7.1 Hz,1H, ind). 13C NMR (125 MHz, DMSO):
d 108.2,
for 10 min under an argon atmosphere. Afterwards, water (27
m
110.4, 111.9, 113.0, 117.2, 118.6, 119.0, 121.4, 121.7, 122.9, 123.1, 125.2,
125.8, 127.2, 127.5, 130.3, 130.9, 131.4, 131.5, 132.3, 132.9, 134.5, 138.0,
138.9. HRMS (EI) obsd 463.1306 [Mꢃþ], calcd 463.1296 (C29H16F3N3).
1.7 mmol, 2 equiv) was added to the reaction mixture and heating
was continued overnight at 100 ꢀC. After reaction completion, the
residue was diluted with dichloromethane, washed with water,
dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by means of flash column chromatography.
UVevis (CH3CN): lmax
(
3
ꢂ10ꢁ3) 367 (14.0) nm.
4.1.3. 1,3-Bis(5-acetyltiophen-2-yl)-2-(4-trifluoromethylphenyl)-in-
dolizine (4c). Following the general procedure, indolizine 1b
(222 mg, 0.85 mmol) and 5-acetyl-2-bromothiophene 2e (349 mg,
1.70 mmol) were reacted. The crude product was purified by means
of flash column chromatography (SiO2, CH2Cl2/hexanes, 1:1). All
fractions containing the expected product were collected and
rechromatographed (SiO2, AcOEt/hexanes, 2:3) affording 93 mg
(22%, recrystallized from AcOEt/hexanes) of 4c. Rf¼0.5 (SiO2,
CH2Cl2), mp 177e178 ꢀC (AcOEt/hexanes); 1H NMR (500 MHz,
Method B:23 A solution of the corresponding aryl bromide
(0.85 mmol, 1 equiv), indolizine (1.28 mmol, 1.5 equiv), KOAc
(166 mg, 1.7 mmol, 2 equiv) and Pd(OAc)2 (2.9 mg, 12.8
mmol,
1.5 mol %) was placed in a Schlenk tube previously flushed with
argon. Subsequently, DMAc (2.55 ml) was added and the resulting
mixture was stirred at 130 ꢀC for 20 h under an argon atmosphere.
After reaction completion, the residue was diluted with dichloro-
methane, washed with water, dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by means of flash column
chromatography.
CDCl3):
d
2.52 (s, 3H, Ac), 2.55 (s, 3H, Ac), 6.91 (d, J¼3.4 Hz, 1H,
thiophene), 6.74 (t, J¼6.5 Hz, 1H, ind), 6.95 (d, J¼3.2 Hz, 1H, thio-
phene), 7.02 (t, J¼7.6 Hz, 1H, ind), 7.33, 7.55 (AA0BB0, J¼8.2 Hz,
2ꢂ2H, C6H4), 7.54 (m, 1H, thiophene), 7.62 (d, J¼3.2 Hz, 1H, thio-
Method C:16b Aryl bromide (0.6 mmol, 1 equiv) and indolizine
(9 mmol, 15 equiv) were placed in a glass tube previously flushed
with argon. Subsequently 750
m
l of a stock solution of the base in
phene), 7.90 (d, J¼9.0 Hz, 1H, ind), 8.29 (d, J¼7.1 Hz, 1H, ind). 13
C
DMF (containing 1.2 mmol of t-BuOLi) was added. The resulting
reaction mixture was stirred overnight at 145 ꢀC. Subsequently, it
was evaporated under reduced pressure and purified by column
chromatography.
Bis-arylation of indolizines was performed according a slightly
modified procedure:15 A solution of indolizine (0.425 mmol,
1 equiv), aryl bromide (0.85 mmol, 2 equiv) and KOAc (83 mg,
0.85 mol, 2 equiv) was placed in a Schlenk tube previously flushed
with argon. Subsequently, NMP (0.85 ml) and PdCl2(PPh3)2 (15 mg,
NMR (125 MHz, CDCl3): d 26.5, 26.7, 107.1, 113.1, 116.1, 118.3, 121.6,
123.3, 125.3, 126.7, 128.5, 129.6, 129.8, 129.9, 131.2, 132.5, 132.6,
133.1, 137.5, 138.9, 142.2, 144.9, 145.0, 190.3, 190.4. HRMS (EI) obsd
509.0727 [Mꢃþ], calcd 509.0731 (C27H18F3NO2S2). UVevis (CH3CN):
lmax
(
3
ꢂ10ꢁ3) 399 (14.6) nm.
Acknowledgements
Financial support for our work from the Foundation for
Polish Science (grant number TEAM/2009-4/3) is gratefully
5 mol %, 21.2 mmol) were added and the resulting solution was

B. Koszarna et al. / Tetrahedron 70 (2014) 225e231
231
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264362).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.088.
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