Regiospecific synthesis of 1, 2-disubstituted (hetero)aryl fused imidazoles with tunable fluorescent emission

Article abstract of DOI:10.1021/ol202807d

A palladium-catalyzed two or fourfold amination was established that allows regiospecific synthesis of a diversity-oriented library of 1, 2 disubstituted (hetero)aryl fused imidazoles, and provides an exceptional tool for the discovery of fluorescent scaf

Full text of DOI:10.1021/ol202807d

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6516–6519
Regiospecific Synthesis of
1,2-Disubstituted (Hetero)aryl Fused
Imidazoles with Tunable Fluorescent
Emission
Dongbing Zhao, Junyi Hu, Ningjie Wu, Xiaolei Huang, Xurong Qin, Jingbo Lan, and
Jingsong You*
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, PR China
jsyou@scu.edu.cn
Received October 19, 2011
ABSTRACT
A palladium-catalyzed two or fourfold amination was established that allows regiospecific synthesis of a diversity-oriented library of 1,2-
disubstituted (hetero)aryl fused imidazoles, and provides an exceptional tool for the discovery of fluorescent scaffolds with tunable fluorescence
emission. These fluorophores have been applied as fluorescent probes for live cell imaging.
Exploiting regiospecific and high-yielding synthetic
methodologies for the rapid discovery of small organic
fluorophores is starting to attract increasing interest.1 1,2-
Disubstituted (hetero)aryl fused imidazoles such as N-
arylbenzimidazoles (Type A), N-alkylbenzimidazoles
(Type B), N-substituted 2-aminobenzimidazoles (Type C),
pyrido[1,2-a]benzimidazoles (Type D), and heteroaryl
fused imidazoles are prevalent in advanced materials,
molecules of medicinal interest, and natural products.2 In
particular, the benzimidazolyl scaffolds are frequently
chosen as electron-transporting units and exhibit intense
blue fluorescence emission in OLEDs.2b,d,e However, there
has been little systematic study elucidating the relationship
between the structural and photophysical properties of
(hetero)aryl fused imidazoles due to the limited structural
diversity of the chemical library. Therefore, developing a
regiospecific and modular approach to (hetero)aryl fused
imidazoles with easily tunable substitution patterns
(e.g., N1/C2-substituents and π-extended conjugated systems)
is highly warranted for assembling a diversity-oriented
fluorescence library that spans a wide range of emission
wavelengths.
(1) (a) Shimizu, M.; Takeda, Y.; Higashi, M.; Hiyama, T. Angew.
Chem., Int. Ed. 2009, 48, 3653. (b) Zhao, D.; Wang, W.; Yang, F.; Lan,
J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (c)
Namba, K.; Osawa, A.; Ishizaka, S.; Kitamura, N.; Tanino, K. J. Am.
Chem. Soc. 2011, 133, 11466. (d) Burchak, O. N.; Mugherli, L.; Ostuni,
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M.; Lacapere, J. J.; Balakirev, M. Y. J. Am. Chem. Soc. 2011, 133, 10058.
(e) Siamaki, A. R.; Sakalauskas, M.; Arndtsen, B. A. Angew. Chem., Int.
Ed. 2011, 50, 6552. (f) Kim, E.; Koh, M.; Lim, B. J.; Park, S. B. J. Am.
Chem. Soc. 2011, 133, 6642.
(2) (a) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.;
Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W. M. J. Med.
Chem. 1996, 39, 625. (b) Lai, M.-Y.; Chen, C.-H.; Huang, W.-S.; Lin,
J. T.; Ke, T.-H.; Chen, L.-Y.; Tsai, M.-H.; Wu, C.-C. Angew. Chem., Int.
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Ed. 2008, 47, 581. (c) Hranjec, M.; Piantanida, I.; Kralj, M.; Suman, L.;
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Pavelic, K.; Karminski-Zamola, G. J. Med. Chem. 2008, 51, 4899. (d)
Ge, Z.; Hayakawa, T.; Ando, S.; Ueda, M.; Akiike, T.; Miyamoto, H.;
Kajita, T.; Kakimoto, M. Adv. Funct. Mater. 2008, 18, 584. (e) Thirion,
D.; Rault-Berthelot, J.; Vignau, L.; Poriel, C. Org. Lett. 2011, 13, 4418.
(f) Ndakala, A. J.; Gessner, R. K.; Gitari, P. W.; October, N.; White,
K. L.; Hudson, A.; Fakorede, F.; Shackleford, D. M.; Kaiser, M.;
Yeates, C.; Charman, S. A.; Chibale, K. J. Med. Chem. 2011, 54, 4581.
(g) Xu, Z.; Singh, N. J.; Kim, S. K.; Spring, D. R.; Kim, K. S.; Yoon, J.
Chem.;Eur. J. 2011, 17, 1163. (h) Xu, Z.; Kim, S. K.; Yoon, J. Chem.
Soc. Rev. 2010, 39, 1457.
Although a number of methods for the synthesis of 1- or
2-monosubstituted benzimidazoles havebeenreported, the as-
sembly of 1,2-disubstituted benzimidazoles still encounters
challenges in controlling regioisomeric selectivity, increas-
ing efficiency, and improving generality.3,4 Most of the
methods toward 1,2-disubstituted benzimidazoles such as
r
10.1021/ol202807d
Published on Web 11/15/2011
2011 American Chemical Society

the condensation of carboxylic acids with N-substituted
1,2-diaminoarenes and N-arylation/alkylation reactions of
1H-benzimidazoles have often suffered from a limited
scope4g and led to a mixture of two regioisomers because
of the difficulty of differentiating the two N-atoms.3,4b The
intramolecular CÀH functionalization/CÀN bond forma-
tion mainly accessed 2-substituted 1H-benzo[d]imidazoles
and met regioisomeric hindrances to some extent.4c,d In
2007, Buchwald et al. disclosed a palladium-catalyzed
synthesis of N-arylbenzimidazoles starting from ortho-ha-
loanilides in a regioisomerically pure form.5 However, it
failed to give N-alkylbenzimidazoles in an acceptable yield
due to a competing β-hydride elimination. Yet, the Cu-
catalyzed systems, independently developed by Buchwald
and Ma groups, were restricted to N-alkylbenzimidazoles.6
The twofold amination of N-substituted amidines with
o-dihalo(hetero)arenes would represent an alternative
strategy for the regiospecific synthesis of 1,2-disubstituted
benzimidazoles. However, the reported Cu-catalytic sys-
tem required more expensive and/or not easily accessi-
ble ortho-haloaryl iodides. More importantly, most of
the examples gave low yields (10À40%),7 which greatly
diminished the industrial and academic value of this
method. These drawbacks inspired us to reinvestigate this
transformation. Herein, we disclose the Pd-catalyzedinter-
molecular tandem two- or fourfold amination starting
from N-substituted amidines, guanidines, or 2-aminopyr-
idines with generally more available ortho-haloaryl chlor-
ides or bromides, which constituted a general and highly
regiospecific method for the synthesis of the structurally
diverse (hetero)aryl fused imidazoles. This also assembled
a library of organic fluorophores with the tunable emission
wavelength covering the range 366À591 nm.
Table 1. Twofold Aminations of a Variety of Amidines,
2-Aminopyridines, and Guanidinesa
yield
[%]
entry
compound 2
product
1
R2 = Ph; R3 = Ph
3a
3a
3b
3c
3d
3e
3f
99
96
95
86
99
91
92
89
99
98
81
87
86
96
94
82
99
93
91
86
92
87
84
2b
3
R2 = Ph; R3 = Ph
R2 = o-MePh; R3 = Ph
R2 = p-MePh; R3 = Ph
R2 = 1-naphthyl; R3 = Ph
R2 = 3,5-diMeOPh; R3 = Ph
R2 = p-ClPh; R3 = Ph
R2 = m-NO2Ph; R3 = Ph
R2 = Cy; R3 = Ph
R2 = Ph; R3 = p-Me2NPh
R2 = Ph; R3 = p-Ph2NPh
R2 = Ph; R3 = m-CNPh
R2 = Ph; R3 = p-ClPh
R2 = Ph; R3 = m-pyridyl
R2 = Ph; R3 = p-pyridyl
R2 = Ph; R3 = 2-thienyl
R2 = Ph; R3 = methyl
R2 = p-Me2NPh; R3 = p-pyridyl
R2 = p-Me2NPh; R3 = p-CNPh
2-aminopyridine
4
5
6
7
8
3g
3h
3i
9
10
11
12
13
14
15
16
17
18
19
20c
21c
22c
23c
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
2-amino-5-methylpyridine
2-aminopyrazine
R2 = Ph; R3 = -NHPh
3u
3v
a The experimental details were described in the Supporting Infor-
mation. Yield of isolated product was based on 1,2-dihalobenzene. b o-
Dichlorobenzene was used. c K3PO4/NaOtBu (4.0 equiv, 1/1).
Our initial investigation was aimed at the twofold
amination of N-phenylbenzamidine with 1,2-dibromoben-
zene. After screening several parameters (Table S1), the
tandem reaction afforded 3a in excellent yield when a low
catalyst loading of Pd(OAc)2 or Pddba2 (2.5 mol %) was
heteroaryl (3mÀo, and 3q), all of them afforded
1,2-disubstituted benzimidazoles in good to excellent
yields (Table 1, entries 1À19). The less reactive and
inexpensive 1,2-dichlorobenzene also gave rise to 3a in
96% yield (Table 1, entry 2). It is notable that our catalytic
system could be applied to the synthesis of pyrido[1,-
2-a]benzimidazoles by using 2-aminopyridine derivatives
as the starting material (3sÀ3u). Moreover, the N1-sub-
stituted 2-aminobenzimidazoles could also be obtained
using readily available guanidine residues (3v). Traditional
methods for the preparation of such molecules often
involve multistep approaches starting from o-phenyldia-
mine, aryl amination of 2-halobenzimidazoles, and the
intramolecular aryl guanidinylation.8
˚
employed in combination with Xantphos (2.5 mol %), 4 A
sieves as the additive, and Cs2CO3 or NaOtBu as the base
in toluene at 140 °C for 24 h. With optimized condi-
tions now in hand, a variety of amidines were tested with
1,2-dihalobenzene (1a), and the results are summarized in
Table 1. Gratifyingly, no matter whether the substituent
R2 or R3 of amidines was aryl, alkyl (3h and 3p), or
(3) For the latest review on regioselective synthesis of 1,2-disubsti-
tuted benzimidazoles, see: Carvalho, L. C. R.; Fernandes, E.; Marques,
M. B. Chem.;Eur. J. 2011, 17, 12544.
(4) For the selected examples, see: (a) Brain, C. T.; Steer, J. T. J. Org.
Chem. 2003, 68, 6814. (b) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J.
Org. Chem. 2008, 73, 7841. (c) Brasche, G.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 1932. (d) Xiao, Q.; Wang, W.-H.; Liu, G.;
Meng, F.-K.; Chen, J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009, 15,
7292. (e) Deng, X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74,
To gain insight into the relationship of structureÀ
photophysical properties, we tried to set up a combinator-
ial library of donorÀacceptor (hetero)aryl fused imida-
zoles. Fortunately, we were pleased with the generality
ꢂ
5742. (f) Alonso, J.; Halland, N.; Nazare, M.; R’kyek, O.; Urmann, M.;
Lindenschmidt, A. Eur. J. Org. Chem. 2011, 234. (g) Guru, M. M.; Ali,
M. A.; Punniyamurthy, T. J. Org. Chem. 2011, 76, 5295.
(5) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2007, 46, 7509.
(6) (a) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749. (b) Zou,
B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598.
(7) Deng, X.; Mani, N. S. Eur. J. Org. Chem. 2010, 680.
(8) (a) Barrett, I. C.; Kerr, M. A. Tetrahedron Lett. 1999, 40, 2439.
(b) Bendale, P. M.; Sun, C.-M. J. Comb. Chem. 2002, 4, 359. (c) Evindar,
G.; Batey, R. A. Org. Lett. 2003, 5, 133.
Org. Lett., Vol. 13, No. 24, 2011
6517

of our methodology. First, whether the asymmetrically
substituted o-dihaloarenes bore the neutral, electron-
donating, or electron-withdrawing substituents, all of
them smoothly coupled with a set of amidines to generate
the structurally diverse 1,2-disubstituted aryl fused imid-
azoles in excellent yields. In these tandem twofold amina-
tions, the requirement of o-dihalo(hetero)arene derivatives
containing two different halogen atoms could ensure
a completely regioselective transformation (Scheme 1,
4aÀ4g, 4q). Second, various o-dihaloheteroarenes gave
heteroaryl fused imidazoles in good to excellent yields
(Scheme 1, 4gÀo). Third, 1,2-disubstitutednaphtho[2,3-d]-
imidazole-4,9-diones, which are known as key precursors
for the preparation of organic electronic devices and
previously prepared in three steps,9 could be synthesized
by a single tandem amination of 2,3-dichloronaphthoqui-
none in an excellent yield (4p, 91% yield). Finally, the
reaction conditions were compatible with the presence of
some important functional groups such as cyano, nitro,
chloro, ester, and methoxy groups on the amidines or
o-dihaloarenes, which could then be subjected to further
synthetic transformations (Table 1, 3e, 3f, 3g, 3k, 3l, 3r;
Scheme 1, 4b, 4c, 4f, 4p).
Scheme 1. Twofold Amination of 1,2-Dihalo(hetero)arenesa
Benzobisimidazoles have proven to be the precursors of
versatile electronic and fluorescent materials. The previous
synthesis of these scaffolds provides a 1:1 mixture of
1,7-diphenyl-(5bsyn) and 1,5-diphenylbenzobis(imidazole)s
(5aanti).10 The present tandem protocol could be extended
to the direct and regioselective preparation of benzobisi-
midazoles via the fourfold CÀN coupling. Both the anti-
and syn-products were obtained in good yields using
1,4-dibromo-2,5- and 1,5-dibromo-2,4-diiodobenzene, re-
spectively [eq 1]. Our primary investigation also exhibited
that the fourfold CÀN coupling of a diamidine afforded
the 1,2-disubstituted dibenzimidazole 6a in 83% yield [eq 2].
a The experimental details were described in the Supporting Informa-
tion. Yield of isolated product is given in parentheses. bK3PO4/NaOtBu
(4.0 equiv, 1/1).
systems. Figures 1aÀe and S1 show that the emission colors
could be tuned in the range blue to red (λem: 366À591 nm)
by simply modifying the substituents at the C2/N1 position
and π-extended framework.
The N1-alkyl 3h, C2-alkyl 3p, and 2-aminobenzimida-
zole 3v exhibited weak fluorescent emissions. 1,2-Diphe-
nylbenzimidazole 3a and pyrido[1,2-a]benzimidazoles
3sÀ3t showed blue fluorescent emissions in CH2Cl2. When
the C2 position was occupied by the electron-donating N,
N-dimethyl(aryl)aniline moiety, all of these exhibited
stronger fluorescence in various solvents such as CH2Cl2,
CH3CN, and DMF (Figure 1a, cÀd). The electron-with-
drawing 4-pyridyl or p-cyanophenyl group at the C2-
position in combination with the electron-donating N,-
N-dimethylaniline moiety at the N1-position led to a bath-
ochromically shifted emission maximum (Table 1, 3q, 3r).
Thus, the fluorophore 3r showed the longest emission wave-
length (λem = 591 nm, DMSO). The observations clearly
reflected the existence of a “pushÀpull” π-electron mode, in
which the nitrogen atom of the N,N-dimethyl(aryl)aniline
moiety served as the electron donor and the electron-
deficient groups functioned as the electron acceptor.
Notably, most of the fluorophores exhibited a large
Stokes shift in the range 100À200 nm in CH3CN (Table S2)
and a strongly positive solvatofluorochromism upon
irradiation in different solvents. For example, the fluor-
escence emission maxima of 4m shifted to longer wave-
lengths from 416 to 546 nm with increasing solvent
polarity (Figures 1d and S2).
Having established a preparative method for a library
of structurally diverse 1,2-disubstituted (hetero)aryl
fused imidazoles, we next investigated in detail their
fluorescent properties. Thus, we found that the struc-
tural modifications significantly affected the fluores-
cence characteristics. Clearly, the fluorescence emission
intensity and wavelength depended on the electronic
nature of C2/N1-substituents and π-extended conjugated
(9) Bae, J.-S.; Lee, D.-H.; Lee, D.-W.; Jang, J.-G. WO2007011170A1,
2007.
(10) (a) Boydston, A. J.; Pecinovsky, C. S.; Chao, S. T.; Bielawski,
C. W. J. Am. Chem. Soc. 2007, 129, 14550. (b) Boydston, A. J.; Vu, P. D.;
Dykhno, O. L.; Chang, V.; Wyatt, A. R.; Stockett, A. S., II; Ritschdorff,
E. T.; Shear, J. B.; Bielawski, C. W. J. Am. Chem. Soc. 2008, 130, 3143.
6518
Org. Lett., Vol. 13, No. 24, 2011

It is remarkable that most of the (hetero)aryl fused imida-
zoles exhibited strong solid-state fluorescence with various
emission colors upon excitation with UV light (λex = 365 nm).
The solid-state emission wavelengths were observed from
386 to 532 nm (Figure 1b, e). These characteristics make
them potential candidates for organic emitters and solid-
state lighting devices.
Molecular fluorescent imaging techniques help us un-
derstand biological processes at a molecular level and
identify diseases in their early stage. Although many
luminescent probes have been used in cell imaging, the
exploitation of small fluorescent labeling molecules for
intracellular targets still remains an attractive and promis-
ing goal. To demonstrate the potential of structurally
diverse 1,2-disubstituted (hetero)aryl fused imidazoles as
bioimaging probes, human hepatocellular carcinoma cells
(SMMC-7721) and human lung adenocarcinoma epithe-
lial cells (A549) were incubated with these fluorophores
(3r, 4i, 4m, and 4n) in DMEM Dulbecco’s mimimum
essential medium for 40 min at 37 °C (Figures 1fÀh and
S3). Gratifyingly, 4i successfully marked SMMC-7721, thus
suggesting that the donorÀacceptor (hetero)aryl fused imid-
azoles would be potentially useful reagents for fluorescence
imaging in clinical diagnostics and biomedical research.
In summary, we have developed a palladium-catalyzed
cascade amination that allows, for the first time, regiospe-
cific and modular synthesis of a library of structurally
diverse 1,2-disubstituted (hetero)aryl fused imidazoles
comprising all the above-mentioned four structures
(Tpye A, B, C, and D) and heteroaryl fused imidazoles,
which exhibits various interesting fluorescent properties
and elucidates the correlation between chemical structures
and fluorescent characteristics. These “pushÀpull” fluor-
ophores can accommodate tunable emission wavelengths
from 366 to 591 nm by switching the N1/C2-substituents
and π-extended conjugated systems. The fluorophores
have proven to be potentially useful bioimaging fluores-
cence probes.
Figure 1. (a) Fluorescent spectra of benzimidazoles in CH3CN
(signal intensities have been normalized). From left to right: 3i,
4e, 3j, 4i, 4l, 4m, and 3r. (b) Solid-state fluorescent spectra of
benzimidazoles in powder (signal intensities have been
normalized). From left to right: 4e, 3i, 5a, 3q, 4k, 4l, 4i, 3r,
and 4n. (c) Fluorescence images of benzimidazoles in CH3CN,
irradiated at 365 nm. From left to right: 3i, 4e, 3j, 4i, 4l, 4m, 3q,
and 3r. (d) Fluorescence images of solvatofluorochromism upon
irradiation of 4m in different solvents. From left to right:
hexane, CH2Cl2, acetone, CH3CN, and DMSO. (e) Fluores-
cence images of benzimidazoles (powder, λex = 365 nm). From
left to right: 3i, 4e, 5a, 4k, 4j, 4l, 4i, 3q, 3r, 4m, and 4n. (fÀh)
Bright-field transmission image, fluorescence image, and over-
lay of the fluorescence and bright-field transmission image of
SMMC-7721 cells incubated with 4i (20 μM), respectively.
Acknowledgment. This work was supported by grants
from the National NSF of China (Nos. 21025205,
20972102, 21021001, and 20872101), PCSIRT (No
IRT0846), and the National Basic Research Program of
China (973 Program, 2011CB808600). We thank the Cen-
tre of Testing & Analysis, Sichuan University for NMR
and ESI-MS measurements.
It is a challenging project for the design and synthesis of
small organic molecules exhibiting highly efficient solid-
state luminescence for the development of optoelectronic
devices such as OLEDs and solid-state organic lasers.11
(11) (a) Hudson, A. J.; Weaver, M. S. In Functional Organic and
Polymeric Materials: Molecular Functionality-Macroscopic Reality;
Richardson, T. H., Ed.; Wiley: New York, 2000; p 365. (b) Chen, C. T. Chem.
Mater. 2004, 16, 4389. (c) Organic Light-Emitting Devices. Synthesis
Properties and Applications; M€ullen, K., Scherf, U., Eds.; Wiley-VCH:
Weinheim, 2006. (d) Samuel, I. D. W.; Turnbull, G. A. Chem. Rev. 2007,
107, 1272.
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
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