Synthesis of fluorescent 1,3-diarylated imidazo[1,5-α]pyridines: Oxidative condensation-cyclization of aryl-2-pyridylmethylamines and aldehydes with elemental sulfur as an oxidant

Article abstract of DOI:10.1021/jo900415y

Oxidative condensation - cyclization of aldehydes and aryl-2- pyridylmethylamines proceeded in the presence of a stoichiometric amount of elemental sulfur as an oxidant in the absence of catalyst. The reaction gave a variety of 1,3-diarylated imidazo[l,5-a]pyridines in good to high yields. The products showed fluorescence emission in a wavelength range of 454-524 nm. The quantum yields of 1,3-diarylated imidazopyridines were greatly improved compared to those of the parent 3-monosubstituted compounds.

Full text of DOI:10.1021/jo900415y

example, the compounds including an imidazo[1,5-a]pyridine
moiety show interesting properties applicable to OLED2 and
FET.3 They also give a new class of N-heterocyclic carbens.4
However, efficient and common synthetic routes to imidazo[1,5-
a]pyridines have not been established.5-9 Therefore, it has been
difficult to investigate their properties systematically. In the
course of our studies on thioamide transformations,10 we
developed a synthesis of 3-substituted imidazo[1,5-a]pyridines
via the oxidative desulfurization-cyclization of readily available
N-2-pyridiylmethylthioamides using iodine as an oxidant.11 This
reaction gives a series of imidazo[1,5-a]pyridine derivatives in
good to excellent yields, and the resulting 3-substituted imi-
dazo[1,5-a]pyridines and their sulfur-bridged dimers show a
variety of fluorescence emissions. It is promising that the
introduction of additional π-systems into imidazo[1,5-a]py-
ridines influences their photophysical properties. To prepare 1,3-
diarylated imidazo[1,5-a]pyridines with added π-systems, we
attempted to synthesize the thioamide substrates N-(aryl-2-
pyridylmethyl)thioamides by the Willgerodt-Kindler reaction
of benzaldehyde, aryl-2-pyridylmethylamine, and elemental
sulfur.12 As a result, elemental sulfur acted not only as a
sulfurizing agent but also as a simple oxidant under the reaction
conditions, and the aldehyde and amine underwent formal
oxidative condensation-cyclization to give the 1,3-diarylated
imidazo[1,5-a]pyridines directly in low yields. To our knowl-
edge, there has been no previous report of oxidative cyclization
of this type with such a mild oxidant in the absence of a
catalyst.13 We report here an oxidative condensation-cyclization
of aromatic aldehydes and aryl-2-pyridylmethylamines using a
stoichiometric amount of elemental sulfur as an oxidant in the
absence of a catalyst.
Synthesis of Fluorescent 1,3-Diarylated
Imidazo[1,5-a]pyridines: Oxidative
Condensation-Cyclization of
Aryl-2-Pyridylmethylamines and Aldehydes with
Elemental Sulfur as an Oxidant
Fumitoshi Shibahara,* Rie Sugiura, Eiji Yamaguchi,
Asumi Kitagawa, and Toshiaki Murai*
Department of Chemistry, Faculty of Engineering, Gifu
UniVersity, Yanagido, Gifu 501-1193, Japan
fshiba@gifu-u.ac.jp; mtoshi@gifu-u.ac.jp
ReceiVed February 24, 2009
Oxidative condensation-cyclization of aldehydes and aryl-
2-pyridylmethylamines proceeded in the presence of a
stoichiometric amount of elemental sulfur as an oxidant in
the absence of catalyst. The reaction gave a variety of 1,3-
diarylated imidazo[1,5-a]pyridines in good to high yields.
The products showed fluorescence emission in a wavelength
range of 454-524 nm. The quantum yields of 1,3-diarylated
imidazopyridines were greatly improved compared to those
of the parent 3-monosubstituted compounds.
As an example of our attempt to synthesize the thioamide
substrates 4, 2-pyridyl-4-tolylmethylamine (2c) was reacted with
benzaldehyde (1b) in the presence of a stoichiometric amount
(5) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2834.
(6) El Khadem, H. S.; Kawai, J.; Swartz, D. L. Heterocycles 1989, 28, 239.
(7) For recent advances in the synthesis of imidazo[1,5-a]pyridines via an
acetic acid-mediated condensation pathway, see: (a) Wang, J.; Mason, R.;
VanDerveer, K.; Feng, D.; Bu, X. R. J. Org. Chem. 2003, 68, 5415. (b) Dyers,
J. W. L., Jr.; Mason, R., Jr.; Amoyaw, P.; Bu, X. R. J. Org. Chem. 2005, 70,
2353. (c) Siddiqui, S. A.; Potewar, T. M.; Lahoti, R. J.; Srinivasan, K. V.
Synthesis 2006, 17, 2849, and references cited therein.
Recently, considerable interest has been focused on imi-
dazo[1,5-a]pyridines because of their wide applicability.1-4 For
(1) For examples of pharmaceutical applications, see: (a) El Khadem, H. S.;
Kawai, J.; Swartz, D. L. Carbohydr. Res. 1989, 189, 149. (b) Degoey, D. A.;
Flentge, C. A.; Flosi, W. J.; Grampovnik, D. J.; Kempf, D. J.; Klein, L. L.;
Yeung, M. C.; Randolph, J. T.; Wang, X. C.; Yu, S. U.S. Pat. Appl. Publ. U.S.
2005148623;. Chem. Abstr. 2005, 143, 133693. (c) Kim, D.; et al. Bioorg. Med.
Chem. Lett. 2005, 15, 2129. See the Supporting Information for full list of
authors. (d) Kimura, K.; Tsuchiya, E.; Shibahara, F.; Murai, T. Jpn. Kokai Tokkyo
Koho JP2008105963;. Chem. Abstr. 2008, 148, 509911.
(2) For examples of organic light-emitting diodes (OLED), see: (a) Nakatsuka,
M.; Shimamura, T. Jpn. Kokai Tokkyo Koho JP2001035664;. Chem. Abstr. 2001,
134, 170632. (b) Tominaga, G.; Kohama, R.; Takano, A. Jpn. Kokai Tokkyo
Koho JP2001006877;. Chem. Abstr. 2001, 134, 93136. (c) Kitazawa, D.;
Tominaga, G.; Takano, A. Jpn. Kokai Tokkyo Koho JP 2001057292;. Chem.
Abstr. 2001, 134, 200276. (d) Salassa, L.; Garino, C.; Albertino, A.; Volpi, G.;
Nervi, C.; Gobrtto, R.; Hardcastle, K. I. Organometallics 2008, 27, 1427.
(3) For an example of organic thin-layer field effect transistors (FET), see:
Nakamura, H.; Yamamoto, H. PCT Int. Appl. WO 2005043630;. Chem. Abstr.
2005, 142, 440277.
(8) For recent advances in the synthesis of imidazo[1,5-a]pyridines via an
oxidative pathway, see: (a) Bluhm, M. E.; Ciesielski, M.; Go¨rls, H.; Do¨ring, M.
Angew. Chem., Int. Ed. 2002, 41, 2962. (b) Bluhm, M. E.; Folli, C.; Pufky, D.;
Kro¨er, M.; Walter, O.; Do¨ring, M. Organometallics 2005, 24, 4139. (c)
Ostermeier, M.; Limberg, C.; Ziemer, B.; Karunakaran, V. Angew. Chem., Int.
Ed. 2007, 46, 5329, and references cited therein.
(9) Moulin, A.; Garcia, S.; Martinez, J.; Fehrentz, J.-A. Synthesis 2007, 17,
2667.
(10) (a) Murai, T.; Niwa, H.; Kimura, T.; Shibahara, F. Chem. Lett. 2004,
33, 508. (b) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc.
2004, 126, 5968. (c) Murai, T.; Sano, H.; Kawai, H.; Aso, H.; Shibahara, F. J.
Org. Chem. 2005, 70, 8148. (d) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron
2006, 62, 6312. (e) Shibahara, F.; Suenami, A.; Yoshida, A.; Murai, T. Chem.
Commun. 2007, 2354. (f) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780.
(g) Shibahara, F.; Yoshida, A.; Murai, T. Chem. Lett. 2008, 37, 646. (h) Murai,
T.; Asai, F. J. Org. Chem. 2008, 73, 9518.
(11) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett. 2006,
8, 5621–5624.
(12) For the Willgerodt-Kindler reaction, see:Brown, E. V. Synthesis 1975,
358.
(4) For examples of N-heterocyclic carbenes precursors, see: (a) Alcarazo,
M.; Roseblade, S. J.; Cowley, A. R.; Fernan´dez, R.; Brown, J. M.; Lassaletta,
J. M. J. Am. Chem. Soc. 2005, 127, 3290. (b) Burstein, C.; Lehmann, C. W.;
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2006, 45, 1348.
(13) The copper-catalyzed oxidative cyclization of the corresponding N-(2-
pyridyl)arylmethylimines with molecular oxygen as an oxidant has been reported.
See ref 8a.
3566 J. Org. Chem. 2009, 74, 3566–3568
10.1021/jo900415y CCC: $40.75 2009 American Chemical Society
Published on Web 04/02/2009

TABLE 1. Oxidative Condensation- Cyclization of Aldehydes and
Aryl-2-pyridylmethylamines in the Presence of Elemental Sulfura, b
SCHEME 1. Attempted Synthesis of N-(Aryl-2-pyridylmethyl)-
thioamidea
a The yields were determined by 1H NMR with 1,1,2,2-tetrachloroethane
as an internal standard.
of elemental sulfur at 80 °C in DMF for 3.5 h. The reaction
gave 1-(4-tolyl)-3-phenylimidazo[1,5-a]pyridine (3bc) and N-(2-
pyridyl-4-tolylmethyl)benzencarbothioamide (4bc) in respective
yields of 46% and 33%. The reaction was allowed to run for a
longer time to improve the yield of imidazopyridine 3bc, but
the product distribution did not change after 24 h (Scheme 1).
The solvent system was then optimized, and we found that the
cyclization reaction took place efficiently in DMSO; 3bc was
obtained in 75% NMR yield (64% isolated yield) with no
thioamide formation.
The scope of substrates was investigated, and the results are
summarized in Table 1. Under the optimal conditions, the
desired cyclization products were obtained in good to high yields
regardless of the substituents. On the other hand, the time
dependence of the product yields revealed the reactivities of
the substrates and the stabilities of the products under the
reaction conditions. For example, the reaction of an electron-
rich aldehyde 1c and amine 2d proceeded quite rapidly to gave
the cyclization product 3cd in 78% yield after 3.5 h, and most
of the starting materials were consumed at this stage. The yield
then significantly dropped to 41% after 24 h and multiple spots
were observed in TLC analysis. These results suggest that while
such electron-rich substrates are highly reactive, the correspond-
ing products may be unstable under these conditions. In contrast,
even after a prolonged reaction time, no significant decomposi-
tion of the products was detected in the reaction of electron-
deficient substrates, particularly p-CF3-phenyl-substituted amine
2a. The reactions with 2a furnished the cyclized products
3aa-ca in yields of 69-82% after 12-30 h.
a All reactions were carried out with 1 (0.5 mmol), 2 (0.55 mmol),
and S8 (0.55 mmol) in DMSO (0.5 mL) at 80 °C. b Isolated yields.
Optmal yields are listed in boldface.
SCHEME 2. Simple Oxidation of Diarylmethylamine
During our investigation of the reaction conditions, the
formation of ketone 5, which may occur via the oxidation of
an aryl-2-pyridylmethylamine moiety followed by hydrolysis,
was observed (Scheme 2). A similar oxidation of 2b in the
absence of aldehyde took place to give the ketone 5b in 66%
yield, though the reaction required a longer time for conversion.
These results indicate that oxidation of the diarylmethylamine
moiety by elemental sulfur as an oxidant takes place under these
reaction conditions.14
A reaction sequence that includes the formation of thioamide
4 under the Willgerodt-Kindler reaction conditions15 followed
by cyclization involving the elimination of H2S is a possible
pathway for the present reaction. However, thioamides scarcely
undergo such an elimination of H2S under neutral conditions.
(14) (a) Sasaki, Y.; Olsen, F. P. Can. J. Chem. 1971, 49, 283. (b) Mori, K.;
Nakamura, Y. J. Org. Chem. 1971, 36, 3041.
(15) (a) Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319. (b) Kanbara, T.;
Kawai, Y.; Hasegawa, K.; Morita, H.; Yamamoto, T. J. Polym. Sci., Part A:
Polym. Chem. 2001, 39, 3739. (c) Purrello, G. Heterocycles 2005, 65, 411, and
references cited therein.
In fact, the resulting thioamides 4 were intact under these
reaction conditions in DMF even for a long reaction time, while
significant amounts of the corresponding imidazopyridines 3
were formed in the same reaction solution (Scheme 1). Also,
J. Org. Chem. Vol. 74, No. 9, 2009 3567

TABLE 2. Representative Photophysical Properties of the
quantum yields of emissions are increased 3- to 4-fold to ΦF )
0.14-0.22 (entries 1-3 vs. 7-9). Although the reason for this
result is not yet clear, 3cc shows a dramatically red-shifted
emission (λem ) 521 nm, entry 4). A similar large red-shifted
emission is observed with imidazopyridine bearing a highly
electron-donating 4-dimethylaminophenyl group at C1 (3be17)
(λem ) 524 nm, entry 5). In contrast, imidazopyridine bearing
a similar electron-donating 4-dimethylaminobiphenyl group at
Obtained Imidazo[1,5-a]pyridinesa
C3 (6) does not show such large red-shifted emission (λem
)
488 nm, entry 6) though the quantum yield is greatly improved
(ΦF ) 0.32). Notably, Stork’s shifts (∆λem - λmax) of 3cc and
3be reach over 210 nm.
In summary, we have developed an oxidative condensation-
cyclization of aromatic aldehydes 1 and aryl-2-pyridylmethyl
amines 2 leading to 1,3-diarylated imidazo[1,5-a]pyridines 3.
The reaction took place efficiently with a stoichiometric amount
of elemental sulfur as a mild oxidant in the absence of a catalyst,
and this simple protocol readily furnishes 1,3-diarylated imi-
dazo[1,5-a]pyridines on demand. In addition, the products
showed a wide variety of fluorescent emissions at wavelengths
of 454-524 nm. Also, the quantum yields of 1,3-diarylated
imidazopyridines 3 were greatly improved compared to those
of the parent 3-monosubstituted compounds. These synthetic
improvements and photofunctional diversity imply that the
imidazo[1,5-a]pyridines can be potentially used as easily tunable
photofunctional materials. Further studies on the development
of a diversity-oriented introduction of a π-conjugated system
into an imidazo[1,5-a]pyridine skeleton and theoretical studies
on the absorption and emission properties of these substances
are underway.
Experimental Section
General Procedure for the Synthesis of 1,3-Diarylated
Imidazo[1,5-a]pyridines. To a solution of aldehyde (0.5 mmol)
in DMSO (0.5 mL) at room temperature was added elemental sulfur
(0.55 mmol). To the resulting solution was added aryl-2-pyridiyl-
methylamine (0.55 mmol), and the mixture was stirred at 80 °C.
At the indicated time, the reaction mixture was poured onto ice
and extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with 20 mL of brine. The organic layer was
dried over MgSO4 and concentrated in vacuo. The residue was
subjected to column chromatography on silica gel to give the desired
1,3-diarylated imidazo[1,5-a]pyridine. The yields of the products
except for 3be are listed in Table 1.
a Measured in CHCl3. b Quantum yields (ΦF) were determined with
reference to quinine sulfate in 0.1 M aqueous sulfuric acid (excited at
350 nm).18 c See ref 11.
isolated thioamide 4bd was heated at 80 °C in DMSO for 4 h
in the presence or absence of elemental sulfur, but no reaction
took place and the starting 4bd was recovered quantitatively in
both cases. These results suggest that the present cyclization
did not proceed via the formation of thioamide. On the other
hand, although the details of the oxidation step in the present
reaction are unclear, the reduced sulfur species, hydrogen sulfide,
was detected by a lead(II) acetate test of the atmosphere over
the reaction mixture after the reaction. This result obviously
suggests that elemental sulfur acted as a stoichiometric oxidant
in the present reaction.
An additional aryl group at C1 greatly influences the emission
maxima (λem) and fluorescent quantum yields of the imidazo[1,5-
a]pyridines. Selected results are shown in Table 2.16 Imida-
zopyridines bearing the same aryl groups on C1 and C3 (3aa,
3bb, and 3cd) show emission colors similar to those of parents
7 (λem ) 454-480 nm vs λem ) 459-469 nm), whereas the
Acknowledgement. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (no. 19020020,
“Advanced Molecular Transformations of Carbon Resources”)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
Supporting Information Available: General experimental
procedures for the synthesis of amine 2, characterization data,
1
and copies of H NMR and 13C NMR for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900415Y
(17) Imidazopyridine 3be was prepared by the present cyclization. See the
Supporting Information for details.
(18) Demas, J. N.; Crosby, G. A. J. Phys. Chem. 1971, 75, 991.
(16) For previous results of photophysical properties, See: Shibahara, F.;
Yamaguchi, E.; Kitagawa, A; Imai, A.; Murai, T. Tetrahedron. 2009, in press.
3568 J. Org. Chem. Vol. 74, No. 9, 2009