Synthesis and properties of bis(pyrazino[2′,3′:4,5]imidazole)-fused 1,2,5,6-tetrahydro-1,4,5,8,9,10-hexaazaanthracenes: a new fluorescent nitrogen-rich heterocycle

Article abstract of DOI:10.1016/j.tetlet.2010.01.015

Nitrogen-rich heterocycles, bis(pyrazino[2′,3′:4,5]imidazole)-fused 1,2,5,6-tetrahydro-1,4,5,8,9,10-hexaazaanthracenes (BPI-HAAs) were prepared by conventional Pd(OAc)₂/BINAP-catalyzed C-N coupling reactions of 5-aryl-3-bromoaminopyrazines. The BPI-HAA core is a planar structure with aromaticity, and this heterocycle exhibits red fluorescence and moderate electron-accepting characteristics.

Full text of DOI:10.1016/j.tetlet.2010.01.015

Tetrahedron Letters 51 (2010) 1401–1403
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and properties of bis(pyrazino[20,30:4,5]imidazole)-fused
1,2,5,6-tetrahydro-1,4,5,8,9,10-hexaazaanthracenes: a new fluorescent
nitrogen-rich heterocycle
Sojiro Hachiya a, Daisuke Hashizume b, Shojiro Maki a, Haruki Niwa a, Takashi Hirano a,
*
a Department of Applied Physics and Chemistry, The University of Electro-Communications, Chofu, Tokyo 182-8585, Japan
b Advanced Technology Support Division, RIKEN, Wako, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Nitrogen-rich heterocycles, bis(pyrazino[20,30:4,5]imidazole)-fused 1,2,5,6-tetrahydro-1,4,5,8,9,10-hexa-
azaanthracenes (BPI-HAAs) were prepared by conventional Pd(OAc)2/BINAP-catalyzed C–N coupling
reactions of 5-aryl-3-bromoaminopyrazines. The BPI-HAA core is a planar structure with aromaticity,
and this heterocycle exhibits red fluorescence and moderate electron-accepting characteristics.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 5 December 2009
Revised 4 January 2010
Accepted 7 January 2010
Available online 11 January 2010
Fluorescent compounds are widely used in applications such as
fluorescent sensors for live-cell imaging and light-emitting compo-
nents for organic light-emitting devices.1 Many fields depend on ad-
vances in new fluorescent compounds.2 Fluorescent compounds
based on bioluminescence3 are promising because of their high-per-
formancefor lightgeneration. Aminopyrazine is thecore structureof
the bioluminescence-related compound ethioluciferamine, derived
from the ostracod Cypridina,4 and AF-350, derived from the jellyfish
Aequorea.5 Aminopyrazines are also useful precursors for preparing
bioluminescent substrates and light-emitter compounds.4b,6 In this
study we then have attempted to prepare a new fluorescent com-
pound by modification of an aminopyrazine derivative. As one of
our target compounds, we tried to prepare 9,10-dihydro-
1,4,5,8,9,10-hexaazaanthracene by C–N cross-coupling reactions7–
9 with 3-bromoaminopyrazine (1) and serendipitously generated a
fluorescent nitrogen-rich heterocycle, bis(pyrazino[20,30:4,5]imid-
3,5-dialkylphenyl group. The reactions mainly produced red
compounds 2b and 2c in 7% and 6% yields, respectively. Molecular
weights of 2 indicate that four molecules of 1 make up 2, and the
1H NMR spectra of 2 indicate their symmetric structures. X-ray
crystal structure analysis of 2b confirmed its BPI-HAA structure
(Fig. 1A) (cf. Supplementary data). Crystals of 2b contain two chloro-
form molecules per unit cell. The solid-state structure of 2b has a
planar core seven-fused ring system, and 3,5-di-t-butylphenyl
groups are twisted with dihedral angles of 27° (C3 and C11) and
43° (C7 and C15). The core seven-fused ring system shows a bond
length alternation (Fig. 1B).
R
Pd(OAc)
10 11
2
BINAP
Cs2CO3
N
NH
Br
9 N
N12
2
azole)-fused
1,2,5,6-tetrahydro-1,4,5,8,9,10-hexaazaanthracene
(BPI-HAA, 2) (Scheme 1).10 We report herein the synthesis and fun-
damental properties of the new heterocycle 2.
13
N
14
N
toluene
100 °C
8
N
R
N
N
15
R
We applied a typical Pd(OAc)2/BINAP-catalyzed C–N cross-cou-
pling condition [Pd(OAc)2 (3 mol %), BINAP (4 mol %), Cs2CO3,
toluene, 100 °C] reported by Buchwald and co-workers9 to 5-(4-t-
1
7
R
N
N
N
N16
6
5
t-Bu
a: R =
b: R =
4
N
1
N
butylphenyl)-3-bromoaminopyrazine (1a), which produced
a
2
t-Bu
3
complex mixture containing various colored products. Careful
separation of the products using silica gel chromatography resulted
in the isolation of red compound 2a in 13% yield as the major product
together with several purple, green, and red compounds in low
yields (<5%). Because 2a has low solubility in typical organic sol-
vents, including ethyl acetate, chloroform, and methanol, we also
examined C–N coupling reactions with 1b and 1c, which have a
2
R
H
8
1
N9
N
N
2
R
t-Bu
C6H13
7
10
3
6
R
N
N
N
c: R =
5
4
H
C6H13
9,10-dihydro-1,4,5,8,9,10-
hexaazaanthracene
* Corresponding author. Tel.: +81 42 443 5489; fax: +81 42 486 1966.
E-mail address: hirano@pc.uec.ac.jp (T. Hirano).
Scheme 1. Synthesis of BPI-HAA 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.015

1402
S. Hachiya et al. / Tetrahedron Letters 51 (2010) 1401–1403
Abs
Fl
A
side view
top view
4.0
1.0
0.5
0.0
2.0
ε
0.0
300
400
500
600
700
wavelength / nm
Figure 2. UV–vis absorption (Abs) and fluorescence (Fl) spectra of 2a (blue), 2b
(black), and 2c (red) in CHCl3 at 25 °C.
Table 1
UV–vis absorption, fluorescence emission, and reduction potentials of 2
/104]
kfa (nm) [Uf
]
Ered (V)b
a
Compounds
kab (nm) [
e
2a
551 [3.9],
513 [4.2],
425 [4.1],
329 [4.2]
538 [3.6],
503 [3.8],
420 [3.6],
323 [3.7]
550 [3.6],
513 [3.8],
426 [4.0],
334 [3.9]
616, 571
[0.75]
ꢀ1.00
ꢀ1.35
2b
2c
603, 563
[0.71]
ꢀ0.97
ꢀ1.50
1.346 1.381
B
616, 570
[0.75]
ꢀ1.00
ꢀ1.51
N
N
R
1.461
1.436
1N.334
N
N
a
1.379
In CHCl3.
1.380
b
0.10 M n-Bu4NClO4 in CH2Cl2, Pt electrode, scanning rate 100 mV sꢀ1, V versus
1.349
N
1.353
N
Fc/Fc+.
1.341
1.322
1.428
R
structures. The absorption maxima (kab) and fluorescence emission
maxima (kf) of 2b showed a slight blue shift compared to those of
2a and 2c, indicating that the bulky 3,5-di-t-butylphenyl groups of
2b are twisted against the planar BPI-HAA skeleton more than the
4-t-butylphenyl and 3,5-dihexylphenyl groups of 2a and 2c,
respectively. The kab and kf values of 2b in various solvents indicate
a slight dependency on solvent polarity (cf. Supplementary data).
Because the core ring system of 2 is a nitrogen-rich heterocycle,
2 is expected to have electron-accepting characteristics.12 Square
wave voltammograms (SWVs) of 2 showed two reduction peaks
at ꢀ1.0 and ꢀ1.5 V versus Fc/Fc+ in CH2Cl2. Cyclic voltammograms
of 2 indicated that the first reduction at ꢀ1.0 V showed reversible
waves, whereas the waves of the second reduction at ꢀ1.5 V were
semi-reversible (cf. Supplementary data). The values of the first
reduction potentials indicate that 2 has an electron-accepting abil-
ity similar to that of p-benzoquinone.13
Figure 1. Molecular structure of 2b (A) whose hydrogen atoms were omitted for
clarity and selected bond distances in a partial structure of 2b (B).
Generation of 2 suggests that the C–N coupling reactions of 1
produce 9,10-dihydro-1,4,5,8,9,10-hexaazaanthracenes as inter-
mediates, and further condensation reactions of dihydrohexaaza-
anthracenes with
1 produce 2. The reaction processes that
generate 2 include four Pd-catalyzed C–N couplings, two nucleo-
philic C–N couplings, and three dehydrogenations. In an attempt
to regulate the preparation of 2b, we increased the amount of
Pd(OAc)2 (55 mol %) and BINAP (50 mol %), resulting in the gener-
ation of orange compound 3b (22% yield) instead of 2b. Compound
3b consists of three molecules of 1b.11
t-Bu
To better understand the observed properties of 2, DFT calcula-
tions on the core BPI-HAA [2(H), R = H] and tetraphenyl-substi-
tuted BPI-HAA [2(Ph), R = Ph] were conducted at the B3LYP/6-
31G(d) level.14–17 Optimized structures of 2(H) and 2(Ph) have a
planar core seven-fused ring, and bond length alternation of their
core ring systems is similar to that observed by X-ray structure
of 2b. Calculated dihedral angles of the phenyl groups against the
core ring system in 2(Ph) are 16° (C3 and C11) and 3° (C7 and
C15). These values are smaller than the corresponding values ob-
served for 2b in crystals, indicating that steric hindrance between
bulky 3,5-di-t-butylphenyl groups at the C3 and C7 (C11 and C15)
positions causes a twist of the 3,5-di-t-butylphenyl groups. HOMO
and LUMO levels were calculated to be ꢀ6.77 and ꢀ3.57 eV for
2(H), respectively, and ꢀ5.97 and ꢀ3.35 eV for 2(Ph), respectively.
The LUMO levels are similar to that (ꢀ3.53 eV) of p-benzoquinone
calculated by the same method, and this result supports the elec-
tron-accepting property of the BPI-HAA core structure. Transition
t-Bu
t-Bu
N
N
N
N
N
N
N
N
t-Bu
t-Bu
N
3b
t-Bu
Figure 2 shows UV–vis absorption and fluorescence spectra of 2
in CHCl3, and the spectral data are summarized in Table 1. The low-
est energy absorption bands of 2 were observed at around 550 nm,
and fluorescence emission maxima of 2 were observed at around
570 nm with quantum yields (Uf) over 0.7. The lowest energy
absorption and fluorescence emission bands exhibited vibrational

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energy from S0 to S1 for 2(Ph) was calculated by TD-DFT [B3LYP/6-
31G(d)] to be 2.30 eV (540 nm, oscillator strength = 0.60), which is
well similar to those of the observed lowest energy absorption
bands of 2. Nucleus induced chemical shift (NICS) values18 at the
centers of the A–D rings in 2(H) were calculated to range from
ꢀ1.3 to ꢀ13.5 at the GIAO-B3LYP/6-31+G(d)//B3LYP/6-31G(d) level
(Fig. 3). The values for the A and D rings are similar to that of pyr-
azine, and the value for the C ring is similar to that of imidazole.18
These negative NICS values for the A, C, and D rings predict that the
BPI-HAA ring system has aromatic characteristics, while the B rings
show a small negative value.
In conclusion, we successfully prepared a heterocyclic seven-
fused ring system, BPI-HAA 2 by conventional Pd(OAc)2/BINAP-cat-
alyzed C–N coupling reactions of 1. The BPI-HAA core is a planar
structure with aromatic characteristics. Because 2 has both fluores-
cent and electron-accepting characteristics, it will be useful as a
new fluorophore and as a new electron-carrier for biological and
materials science. The nitrogen-rich structure of 2 will also be use-
ful as a ligand for making metal ion-complexes, and an investiga-
tion of metal ion-complex formation with 2 is now in progress.
Acknowledgments
11. While 2 were stable compounds under laboratory conditions, 3b was unstable
and slowly decomposed during handling.
This work was supported by a grant from the Japan Science and
Technology Agency for Research for Promoting Technological
Seeds. We acknowledge technical assistance in computing the
quantum chemical calculations from the Information Technology
Center of UEC.
12. (a) Minkin, V. I.; Glukhovtsev, M. N.; Simkin, B. Y. Aromaticity and
Antiaromaticity, Electronic and Structural Aspects; Wiley: New York, 1994. pp
217–229; (b) Stöckner, F.; Beckert, R.; Gleich, D.; Birckner, E.; Günther, W.;
Görls, H.; Vaughan, G. Eur. J. Org. Chem. 2007, 1237–1243; (c) Bunz, U. H. F.
Chem. Eur. J. 2009, 15, 6780–6789.
13. Sawyer, D. T.; Sobkowiak, A.; Roberts, J. L., Jr. Electrochemistry for Chemists, 2nd
ed.; Wiley: New York, 1995. pp 446–451.
Supplementary data
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision C.02; Gaussian: Wallingford, CT, 2004.
Supplementary data (experimental details, 1H NMR spectra of 1,
2, and 3b, single crystal X-ray analysis, UV–vis absorption and fluo-
rescence spectra, and DFT calculation data) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.01.015.
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