Discovery of a full-color-tunable fluorescent core framework through direct C-H (hetero)arylation of N-heterocycles

Article abstract of DOI:10.1002/chem.201103329

All the colors of the rainbow! A full coverage of emission wavelengths in the visible region (405-616 nm) with large Stokes shifts in C3-Indo-Fluor may be straightforwardly and succinctly achieved by the palladium-catalyzed direct C-H arylation of indolizines at the C3 position of the pyrrole ring (see figure). The fluorophores have successfully marked A375 cells. Copyright

Full text of DOI:10.1002/chem.201103329

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DOI: 10.1002/chem.201103329
Discovery of a Full-Color-Tunable Fluorescent Core Framework through
À
Direct C H (Hetero)arylation of N-Heterocycles
Bo Liu, Zhi Wang, Ningjie Wu, Mingliang Li, Jingsong You,* and Jingbo Lan*[a]
The importance of fluorescent molecules has been well
documented in various fields of research.[1] The rational dis-
covery of new fluorescent molecular frameworks has recent-
ly been the subject of growing interest.[2] The p-conjugated
heteroaryl–(hetero)aryl motifs have been frequently chosen
as the fluorescent core objects. Conventional routes to these
structural units usually involve multistep condensation reac-
the full color range (420–613 nm) was achieved by fine
tuning of the phenyl moiety at the C1 position of the pyrrole
À
tions, and/or traditional transition-metal-catalyzed Ar X/
À
Ar M coupling reactions. These tiresome multistep synthe-
ses and prefunctionalizations may limit the rapid assessment
of molecular diversity to a certain extent. In particular,
some important types of heteroaryl organometallic com-
pounds and heteroaryl halides or pseudohalides are not
easily accessible and may even be inadequately stable to
participate in the coupling process, which has been recog-
nized as one of the potential bottlenecks for the discovery
of small organic fluorescent core skeletons. Thus, transition-
Scheme 1. Full-color-tunable fluorescent core skeletons based on indoli-
zines.
ring and the R2 group of the pyridine ring (Scheme 1).[4]
During our investigation of the cross-coupling of indolizine-
2-carboxylate 1 with chlorobenzene 2a, we found that the
aryl-substituted indolizine at the C3 position of the pyrrole
ring (3a) exhibited significant photonic luminescence in the
solid state (see reaction (1), below). Following our interest
À
metal-catalyzed direct C H (hetero)arylation of N-heteroar-
enes would be one of the most ideal strategies to solve these
problems. The tools can greatly streamline multistep chemi-
cal processes with a relatively high level of functional-group
compatibility, and thus allow prompt and modular synthesis
to combinatorial libraries of core skeletons.
À
in C H functionalization of N-heteroarenes to construct flu-
Despite significant progress in developing small molecule-
based fluorophores, it is still challenging to design novel
color-tunable fluorescence libraries that span the whole visi-
ble (especially red) region, particularly with large Stokes
shifts. Indolizine derivatives are an important type of N-
fused heterocycles broadly found in biologically important
natural products, synthetic pharmaceuticals, and molecular
materials.[3] Recently, Park and co-workers developed a full-
color-tunable fluorescent core skeleton named Seoul-Fluor,
orescent core skeletons,[5] herein we explain how this concise
strategy helped us to achieve the goal of full-color tunability
of emission wavelength of the indolizine core, named C3-
Indo-Fluor, by modifying the aromatic group at the C3 posi-
tion of the pyrrole ring in combination with the R2 substitu-
ent of the pyridine ring.
In spite of an increasing number of reports, the use of
À
transition-metal-catalyzed C H (hetero)arylation of N-het-
eroarenes to discover full-color-tunable fluorescent core
frameworks still remains less explored. Given that (hetero)-
aryl chlorides are both more readily available and less ex-
pensive than the corresponding iodides and bromides, the
application of aryl chlorides as a coupling partner would
provide us abundant opportunities in the combinatorial syn-
thesis of a diversity-oriented fluorescence library. However,
in the past several years, (hetero)aryl iodides and bromides
represent the most widely used coupling partners because
aryl chlorides are much less reactive.[6] Our investigation
started with the coupling of methyl indolizine-2-carboxylate
1 with chlorobenzene 2a as a model reaction to optimize
the reaction conditions (reaction (1); also see the Support-
ing Information, Table S1). After screening several parame-
ters (e.g., base, solvent, ligand, time, and temperature, etc.),
1,2-dihydropyrroloACHTUNGTRENNUNG[3,4-b]indolizin-3-one, through an intra-
molecular 1,3-dipolar cycloaddition of an olefin with an azo-
methine ylide. The emission wavelength tenability covering
[a] B. Liu, Z. Wang, N. Wu, M. Li, Prof. Dr. J. You, Prof. Dr. J. Lan
Key Laboratory of Green Chemistry and
Technology of Ministry of Education
College of Chemistry, and State Key Laboratory of Biotherapy
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P.R. China)
Fax : (+86)28-85412203
E-mail: jsyou@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103329.
Chem. Eur. J. 2012, 18, 1599 – 1603
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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we found that the best result was obtained in the presence
of a catalyst system comprising three equivalents of Cs2CO3,
PdACHTUNGTRENNUNG(OAc)2 (5 mol%) and P(Cy)3·HBF4 (Cy=cyclohexyl)
(10 mol%) in toluene at 1308C for 24 h, affording 3a in
95% yield.
sion wavelength in the solid state in the range from blue to
red (lem: 444–615 nm) by a simple change of substituents at
one variation point of the single fluorophore core skeleton
(Figure 1a). The emission wavelengths were proven to be
heavily dependent on the substitutents at the C3 position.
Both the electronic character
and the substituent position of
the R1 group on the phenyl
ring are important in deter-
mining
the
photophysical
properties of C3-Indo-Fluor. A
positional switch of the R1 sub-
stituent from ortho to meta
To gain insight into the relationship of structure–photo-
physical property, we tried to assemble a combinatorial li-
brary of 3-aryl-substituted indolizines. Fortunately, our cata-
lytic system was compatible with both a variety of indoli-
zines and (hetero)aryl chlorides, providing a great
and para resulted in a bathochromic shift of the emission
wavelength when R1 is methyl, methoxy, fluoro, and nitro.
For example, the substituent change of the nitro group from
the meta to the para-position on the phenyl moiety gave rise
opportunity for us to conveniently introduce struc-
turally diverse aryl substituents at the C3 position
of the pyrrole ring.
Table 1. Catalytic C-arylation of 1 with various chlorobenzenes and the corresponding
photophysical data of catalytic product in the solid state.[a,b]
Owing to the easy and high-yielding synthesis,[7]
methyl indolizine-2-carboxylate 1 was first chosen
to investigate the effect of the R1 group on the
phenyl moiety on the fluorescence properties. We
were pleased to find that our catalyst system was
suitable for a wide range of (hetero)aryl chlorides.
As shown in Table 1, whether the aryl chlorides
were electron-rich, electron-poor, or sterically hin-
dered, all of them afforded good yields. It is impor-
tant to stress that the reaction conditions were
compatible with the presence of crucial functional
groups such as ester, amide, cyano, aldehyde, and
nitro groups, which may be subjected to further
synthetic transformations. For example, methyl 3-
phenylindolizine-2-carboxylate (3a) was easily
transformed into the corresponding aldehyde, hy-
droxyl, carboxylic acid, and sodium carboxylate
derivatives (3r, 3s, 3t, and 3u), therefore improv-
ing water solubility of the core skeleton
(Scheme 2). The catalytic products 3p and 3q
bearing the aldehyde group underwent the conden-
sation with malononitrile to yield the correspond-
ing dicyanovinyl derivatives 3v and 3w, respective-
ly (Scheme 3).[8]
The design and synthesis of small organic mole-
cules exhibiting highly efficient solid-state lumines-
cence is of great importance for the development
of optoelectronic devices such as OLEDs and
solid-state organic lasers.[9] However, it is a chal-
lenging project, because the molecular aggregation
of chromophores typically results in the quenching
of luminescence in the solid state. Table 1 outlines
the largest absorption maxima and solid state
emission wavelengths of the new fluorescent com-
pounds. With the R3 as a carboxylate group, it is
unprecedented to achieve a full-visible-color emis-
[a] Reactions were carried out using PdACHTUNGRTNEUNG(OAc)2 (5 mol%), P(Cy)3·HBF4 (Cy=cyclo-
hexyl) (10 mol%), Cs2CO3 (3 equiv), methyl indolizine-2-carboxylate 1 (0.5 mmol)
and chlorobenzene (1 mmol) in a 0.5m toluene for 24 h at 1308C. [b] Isolated product
yield. [c] 2 mol% Catalyst loading. [d] 1 mol% Catalyst loading.
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Full-Color-Tunable Fluorescent Core Frameworks
COMMUNICATION
Scheme 2. Modification of 3a. Reaction conditions: a) 10% NaOH solu-
tion, 508C; b) conc. HCl; c) DIBAL-H, CH2Cl2, À788C, 0.5 h; d) MnO2,
CH2Cl2, 508C, 4 h.
Figure 1. a) Emission spectra of selected indolizines in the solid state. Ex-
citation and emission slit widths were 1.0 nm and 1.0 nm, respectively.
b) Fluorescence images of indolizines in DMF or CHCl3, irradiated at
365 nm. From left to right: 1, 3k, 3m, 3a, 3d, 3p, 3q, and 3w (1, 3k, 3a,
and 3d in DMF; 3m, 3p, 3q, and 3w in CHCl3). c) Fluorescence images
of indolizines (powder, lex =365 nm). From left to right: 1, 3k, 3m, 3a,
3 f, 3p, 3q, and 3v. d) Bright-field transmission image of A375 cells incu-
bated with 3p (20 mm). e) Fluorescence image of A375 cells incubated
with 3p (20 mm). f) Bright-field transmission image of A375 cells incubat-
ed with 3w (20 mm). g) Fluorescence image of A375 cells incubated with
3w (20 mm).
Scheme 3. Modification of 3p and 3q.
to a 168 nm bathochromic shift (Table 1, 3n and 3o). Nota-
bly, most of fluorophores exhibited a large Stokes shift in
the solid state, which is an important factor to suppress the
interference arising from background fluorescence. The con-
densation product 3v starting from 3p showed the longest
emission wavelength (lem =616 nm) in the solid state (Fig-
ure 1c). Whereas the fluorophore 3w was hardly fluorescent
in the solid state, a significant red fluorescence emission was
observed with an emission wavelength of 603 nm in chloro-
form solution (Figure 1b).
Subsequently, we applied the current protocol to the cou-
pling of a wide range of indolizines with 4-chlorotoluene to
synthesize 3-para-tolyl-substituted indolizines in excellent
yields (Table 2). With 4a–4j in hand, a preliminary survey
of photophysical properties was performed; the photophysi-
cal data of which is summarized in Table 2. The largest ab-
sorption maxima of these products appeared in the range of
369 to 409 nm, and the corresponding solid state emission
wavelengths covered the range of 405–537 nm. Interestingly,
when the indolizine 4a was fused by a phenyl ring to form
the benzoindolizine 4b, in spite of a larger p-conjugated
system, its emission color (lem) was greatly hypsochromically
shifted from 460 to 405 nm rather than the bathochromic
shift. The introduction of an electron-withdrawing group
(EWG) such as the cyano group at the C7 position of the
pyridine ring triggered a notable bathochromic shift, and
displayed a large Stokes shift (128 nm; 4j).
Molecular fluorescent-imaging techniques are helpful to
understand biological processes at the molecular level, and
are particularly useful for the early detection of diseases.
Thus, the development of new fluorescent bioimaging
probes still remains an attractive and promising goal. To fur-
ther explore the practical application of new fluorescent
molecules, the human malignant melanoma A375 cells were
incubated with 3p and 3w in a physiological saline solution
containing 1% DMSO for 1 h at 378C after being cultured
in DMEM Dulbeccoꢁs mimimum essential medium (contain-
ing 10% fetal bovine serum (FBS), 100IU mLÀ1 penicillin,
and 100 mgmLÀ1 streptomycin). As shown in Figure 1d–1g,
3p and 3w successfully marked A375 cells, and preferential-
ly accumulated in the cytoplasm, suggesting that this class of
membrane-permeable fluorophores (C3-Indo-Fluor) could
be potentially useful reagents for biological imaging.
Finally, it was gratifying to find that the current catalytic
system was amenable to the arylation of a variety of elec-
tron-rich heteroarenes as well as electron-deficient (hetero)-
Chem. Eur. J. 2012, 18, 1599 – 1603
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J. You, J. Lan et al.
Table 2. Catalytic C-arylation of various indolizines with 4-chlorotoluene
and the corresponding photophysical data of catalytic product in the solid
state.[a,b]
Table 3. Catalytic C-arylation of (hetero)arenes with 4-chlorotoluene.[a,b]
[a] Reactions were carried out using PdACHTNUGTRNE(UNG OAc)2 (5 mol%), P(Cy)3·HBF4
[a] Reactions were carried out using PdACHTNUGTRNE(UNG OAc)2 (5 mol%), P(Cy)3·HBF4
(Cy=cyclohexyl) (10 mol%), Cs2CO3 (3 equiv), indolizine (0.5 mmol) and
4-chlorotoluene (1 mmol) in a 0.5m toluene for 24 h at 1308C. [b] Isolated
product yield. [c] 2 mol% Catalyst loading. [d] 1 mol% Catalyst loading.
(Cy=cyclohexyl) (10 mol%), Cs2CO3 (3 equiv), (hetero)arene (0.5 mmol)
and 4-chlorotoluene (1 mmol) in a 0.5m toluene for 24 h at 1308C. [b] Iso-
lated product yield. [c] 2 mol% Catalyst loading. [d] 1 mol% Catalyst load-
ing. [e] Two equivalents of (hetero)arene were added. [f] Four equivalents
of 4-chlorotoluene were added.
arenes (e.g., xanthines (caffeine, theophyline and theobro-
mine), purines, imidazoles, thiazoles, oxazoles, 1,2,3-tri-
À
azoles, and N-heteroarene N-oxides, etc.) in moderate to ex-
C H arylation of N-heterocycles can serve as a highly effi-
cellent yields (Table 3, 5a–5p). In addition, perfluoroaro-
matics could also couple with aryl chloride in excellent yield
(Table 3, 5q). The (hetero)aryl-aryl motifs are prevalent
substructures of many natural products, pharmaceuticals,
fluorescent materials, and other advanced materials. For in-
stance, 8-aryl or heteroaryl-substituted xanthines are highly
potent and selective antagonists for human A2B adenosine
receptors and luminescent frameworks.[5,10,11] In our previous
report, the compound 5a features significant fluorescent
emission and has proven to be a potentially useful bioimag-
ing fluorescence probe.[5] Further investigations are under-
way to set up full-color-tunable fluorescence libraries
cient and easily tunable synthetic tool for the discovery of a
structurally diverse library of organic fluorophores. It is no-
table that a full coverage of solid state emission wavelengths
in the visible (especially red) region (405–616 nm) with
large Stokes shifts in C3-Indo-Fluor may be straightforward-
ly and succinctly achieved by the direct arylation of indoli-
zines at the C3 position of the pyrrole ring. The fluoro-
phores have successfully marked A375 cells, exhibiting their
future potential as useful bioimaging fluorescence probes.
Further screening of other types of fluorescent core frame-
works and their application in biological imaging are cur-
rently in progress.
À
through the direct C H functionalization of these N-hetero-
À
cycles. Although not yet investigated in detail, the C H
(hetero)arylation of N-heteroarenes with aryl chlorides
could occur in good to excellent yields with a low palladi-
Acknowledgements
This work was supported by grants from the National Natural Science
Foundation ACTHNUTRGNEUG(N NSF) of China (Nos 21025205, 20972102, 21021001,
ACHTUNGTRENNUNGum(II) loading of 1–2 mol% ( Table 1, 3a; Table 2, 4c and
4g; and Table 3, 5a).
In conclusion, we have established a method for the
20872101 and 21172155), Doctoral Foundation of Education Ministry of
China (20090181110045), PCSIRT (No IRT0846) and the National Basic
Research Program of China (973 Program, 2011CB808600). We thank
the Centre of Testing & Analysis, Sichuan University for NMR measure-
ments.
À
direct C H arylation of a wide range of heteroarenes as
well as perfluoroaromatics with a broad spectrum of (het-
ACHTUNGTRENNUNG
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Full-Color-Tunable Fluorescent Core Frameworks
COMMUNICATION
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Keywords: C H arylation · fluorescent probes · full-color-
tunable emission · indolizines · N-heteroarenes · palladium
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Received: October 23, 2011
Published online: January 13, 2012
Chem. Eur. J. 2012, 18, 1599 – 1603
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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