J. Am. Chem. Soc., 2005, 127, 10784; (c) R. S. Butler, P. Cohn,
P. Tenzel, K. A. Abboud and R. K. Castellano, J. Am. Chem. Soc.,
2009, 131, 623; (d) Y. K. Kim, H.-H. Ha, J.-S. Lee, X. Bi, Y.-H. Ahn,
S. Hajar, J.-J. Lee and Y.-T. Chang, J. Am. Chem. Soc., 2010, 132, 576;
(e) O. N. Burchak, L. Mugherli, M. Ostuni, J. J. Lacapere and
M. Y. Balakirev, J. Am. Chem. Soc., 2011, 133, 10058; (f) E. Kim,
M. Koh, B. J. Lim and S. B. Park, J. Am. Chem. Soc., 2011, 133, 6642.
3 N. B. Gaied, N. Glasser, N. Ramalanjaona, H. Beltz, P. Wolff,
R. Marquet, A. Burger and Y. Me
4 For selected examples, see: (a) E. Sharon, S. A. Lvesque,
M. N. Munkonda, J. Sevigny, D. Ecke, G. Reiser and B. Fischer,
´
ly, Nucleic Acids Res., 2005, 33, 1031.
´
ChemBioChem, 2006, 7, 1361; (b) N. J. Greco and Y. Tor, Tetrahedron,
2007, 63, 3515; (c) D. Zhao, W. Wang, F. Yang, J. Lan, L. Yang,
G. Gao and J. You, Angew. Chem., Int. Ed., 2009, 48, 3296;
(d) D. Kim, H. Jun, H. Lee, S.-S. Hong and S. Hong, Org. Lett.,
2010, 12, 1212.
5 For selected examples, see: (a) F. Besselievre, S. Piguel, F. Mahuteau-
Betzer and D. S. Grierson, Org. Lett., 2008, 10, 4029; (b) C. Verrier,
C. Hoarau and F. Marsais, Org. Biomol. Chem., 2009, 7, 647;
(c) J. J. Mousseau, J. A. Bull and A. B. Charette, Angew. Chem.,
Int. Ed., 2010, 49, 1115; (d) S. Sahnoun, S. Messaoudi, J.-D. Brion
and M. Alami, Eur. J. Org. Chem., 2010, 6097; (e) R. Vabre,
F. Chevot, M. Legraverend and S. Piguel, J. Org. Chem., 2011,
76, 9542.
6 For reviews, see: (a) C. Jia, T. Kitamura and Y. Fujiwara,
Acc. Chem. Res., 2001, 34, 633; (b) E. M. Beccalli, G. Broggini,
M. Martinelli and S. Sottocornola, Chem. Rev., 2007, 107, 5318;
(c) B. Karimi, H. Behzadnia, D. Elhamifar, P. F. Akhavan,
F. K. Esfahani and A. Zamani, Synthesis, 2010, 1399; (d) J. Le
Bras and J. Muzart, Chem. Rev., 2011, 111, 1170; (e) C. S. Yeung
and V. M. Dong, Chem. Rev., 2011, 111, 1215.
Fig. 1 (a) Fluorescent spectra of alkenylated N-heteroarenes 3 and 4
in CH2Cl2 (signal intensities have been normalized). From left to right:
3e, 3a, 4k, 4j, 4e, and 4f. (b) Solid-state fluorescent spectra of 3 and 4 in
powder (signal intensities have been normalized). From left to right:
3c, 3a, 4c, 4k, 4e, and 4f. (c) Fluorescence images in CH2Cl2, irradiated
at 365 nm. From left to right: 3e, 3a, 4k, 4j, 4e, and 4f. (d) Fluorescence
images of powder samples (lex = 365 nm). From left to right: 3c, 3a,
4c, 4k, 4e, and 4f. (e) Fluorescence image of SMMC-7721 cells incubated
with 4f (5 mM). (f) Bright-field transmission image of SMMC-7721 cells
incubated with 4f (5 mM). (g) Overlay of the fluorescence and bright-field
transmission images of SMMC-7721 cells incubated with 4f (5 mM).
7 For selected examples, see: (a) N. P. Grimster, C. Gauntlett, C. R.
A. Godfrey and M. J. Gaunt, Angew. Chem., Int. Ed., 2005,
44, 3125; (b) E. M. Beck, N. P. Grimster, R. Hatley and
M. J. Gaunt, J. Am. Chem. Soc., 2006, 128, 2528;
(c) A. Maehara, H. Tsurugi, T. Satoh and M. Miura, Org. Lett.,
2008, 10, 1159; (d) S. H. Cho, S. J. Hwang and S. Chang, J. Am.
Given that nucleobase analogues are capable of undergoing
base pairing, live cell imaging experiments were performed
with the alkenylated purine 4f as a representative example. The
human hepatocellular carcinoma cells (SMMC-7721) were
incubated with 4f in a physiological saline solution containing
1% DMSO for 40 min at 37 1C after being cultured in DMEM
Dulbecco’s minimum essential medium (containing 10% fetal
bovine serum (FBS), 100 IU mLÀ1 penicillin, and 100 mg mLÀ1
streptomycin). As shown in Fig. 1e–g, 4f successfully marked
SMMC-7721. In addition, the MTT assays on HepG2 cells and
A549 cells exhibited low toxicity of 4e, 4f and 3g to cultured cells
(Fig. S1 and S2, ESIw). These primary results demonstrated that
the biologically relevant alkenylated N-heteroarenes would be
valuable sources of imaging probes for biomarker discovery.
In summary, we have developed an efficient and versatile
palladium/copper bimetallic catalyst system for the dehydro-
genative Heck coupling of biologically relevant N-heteroarenes
with alkenes, and elucidated how this strategy rapidly trans-
forms the alkaloid scaffolds into fluorescent molecules. These
resulting p-extended conjugated N-heteroarenes exhibit interesting
fluorescent properties and have proven to be potentially useful
reagents for biological imaging.
Chem. Soc., 2008, 130, 9254; (e) A. Garcıa-Rubia, R. G. Arrayas
´ ´
and J. C. Carretero, Angew. Chem., Int. Ed., 2009, 48, 6511;
(f) C. Aouf, E. Thiery, J. Le Bras and J. Muzart, Org. Lett.,
2009, 11, 4096; (g) Y. Yang, K. Cheng and Y. Zhang, Org. Lett.,
2009, 11, 5606; (h) J. Wu, X. Cui, L. Chen, G. Jiang and Y. Wu,
J. Am. Chem. Soc., 2009, 131, 13888; (i) S.-K. Xiang, B. Zhang,
L.-H. Zhang, Y. Cui and N. Jiao, Chem. Commun., 2011, 47, 8097;
(j) A. Vasseur, J. Muzart and J. Le Bras, Chem.–Eur. J., 2011,
17, 12556; (k) M. Ye, G. L. Gao and Y. Q. Yu, J. Am. Chem. Soc.,
2011, 133, 6964.
8 (a) M. Miyasaka, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2010, 75, 5421; (b) S. Cui, L. Wojtas and J. C. Antilla,
Org. Lett., 2011, 13, 5040.
9 (a) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and
J. You, J. Am. Chem. Soc., 2010, 132, 1822; (b) Z. Wang, K. Li,
D. Zhao, J. Lan and J. You, Angew. Chem., Int. Ed., 2011, 50, 5365.
10 For the palladium-catalyzed C-arylation of xanthines with simple
arenes via double C–H activation, see: C. C. Malakar, D. Schmidt,
J. Conrad and U. Beifuss, Org. Lett., 2011, 13, 1378.
11 (a) R. H. Erickson, R. N. Hiner, S. W. Feeney, P. R. Blake,
W. J. Rzeszotarski, R. P. Hicks, D. G. Costello and M. E. Abreu,
J. Med. Chem., 1991, 34, 1431; (b) Y. Nonaka, J. Shimada,
H. Nonaka, N. Koike, N. Aoki, H. Kobayashi, H. Kase,
K. Yamaguchi and F. Suzuki, J. Med. Chem., 1993, 36, 3731;
(c) J. Shimada, N. Koike, H. Nonaka, S. Shiozaki, K. Yanagawa,
T. Kanda, H. Kobayashi, M. Ichimura, J. Nakamura, H. Kase and
F. Suzuki, Bioorg. Med. Chem. Lett., 1997, 7, 2349; (d) C. E. Muller,
¨
U. Geis, J. Hipp, U. Schobert, W. Frobenius, M. Paw"owski,
F. Suzuki and J. Sandoval-Ramırez, J. Med. Chem., 1997, 40, 4396;
´
(e) C. E. Muller, M. Thorand, R. Qurishi, M. Diekmann,
¨
Notes and references
K. A. Jacobson, W. L. Padgett and J. W. Daly, J. Med. Chem.,
2002, 45, 3440; (f) J. P. Petzer, S. Steyn, K. P. Castagnoli, J. F. Chen,
M. A. Schwarzschild, C. J. Van der Schyf and N. Castagnoli, Bioorg.
Med. Chem., 2003, 11, 1299; (g) N. Vlok, S. F. Malan, N. Castagnoli,
Jr., J. J. Bergh and J. P. Petzer, Bioorg. Med. Chem., 2006, 14, 3512;
(h) D. van den Berg, K. R. Zoellner, M. O. Ogunrombi, S. F. Malan,
G. Terre’Blanche, N. Castagnoli, Jr., J. J. Bergh and J. P. Petzer,
Bioorg. Med. Chem., 2007, 15, 3692.
1 (a) W. Rettig, B. Strehmel, S. Schrader and H. Seifert, Applied
Fluorescence in Chemistry, Biology, and Medicine, Springer, New
York, 1999. For reviews, see: (b) M. S. T. Gonc¸ alves, Chem. Rev.,
2009, 109, 190; (c) M. Vendrell, J.-S. Lee and Y.-T. Chang, Curr.
Opin. Chem. Biol., 2010, 14, 383.
2 (a) G. R. Rosania, J. W. Lee, L. Ding, H.-S. Yoon and Y.-T. Chang,
J. Am. Chem. Soc., 2003, 125, 1130; (b) N. J. Greco and Y. Tor,
c
2866 Chem. Commun., 2012, 48, 2864–2866
This journal is The Royal Society of Chemistry 2012