One-pot synthesis of highly fluorescent 2,5-disubstituted-1,3a,6a- triazapentalene

Article abstract of DOI:10.1021/ol302668y

A one-pot synthetic method was established for the preparation of 2,5-disubstituted-1,3a,6a-triazapentalenes. The fluorescence observation of the synthetic 2,5-disubstituted-1,3a,6a-triazapentalenes revealed that the introduction of a substituent at the C

Full text of DOI:10.1021/ol302668y

ORGANIC
LETTERS
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Vol. XX, No. XX
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One-Pot Synthesis of Highly Fluorescent
2,5-Disubstituted-1,3a,6a-triazapentalene
Kosuke Namba,*,† Akane Mera,‡ Ayumi Osawa,‡ Eri Sakuda,† Noboru Kitamura,† and
Keiji Tanino*,†
Department of Chemistry, Faculty of Science, Hokkaido University, Kita-ku,
Sapporo 060-0810, Japan, and Graduate School of Chemical Sciences and Engineering,
Hokkaido University, Sapporo 060-0810, Japan
namba@mail.sci.hokudai.ac.jp; ktanino@sci.hokudai.ac.jp
Received September 27, 2012
ABSTRACT
A one-pot synthetic method was established for the preparation of 2,5-disubstituted-1,3a,6a-triazapentalenes. The fluorescence observation of the
synthetic 2,5-disubstituted-1,3a,6a-triazapentalenes revealed that the introduction of a substituent at the C5 position allowed a substantial change
in the fluorescence quantum yield with little effect on the fluorescence wavelength.
Fluorescent organic molecules are an important class of
compounds in modern science and technology and are
widely used for such applications as biological imaging
probes, sensors, lasers, and light-emitting devices.1 Thus,
the development of useful fluorescent organic molecules
has been a subject of intensive research due to their
importance to the advancement of many industries.2 Re-
cently, we discovered that a 1,3a,6a-triazapentalene skele-
ton without an additional fused ring system was a compact
and highlyfluorescent chromophorethatexhibited various
interesting fluorescence properties, such as a strong posi-
tive fluorescence solvatochromism and a noteworthy cor-
relation of the fluorescence wavelength with the inductive
effect of the 2-substituents.3À5 For example, the fluores-
cence of the 1,3a,6a-triazapentalenes shifted to longer
wavelengths along with increases in the Hamett σp value
of substituents on the benzene ring of 2-phenyl analogs
(Figure 1). Therefore, the 1,3a,6a-triazapentalene system
provides a breakthrough fluorescent molecule that en-
ables the same fluorescent chromophore to exhibit various
fluorescence colors. For expansion of the fluorescent
wavelength to the red color region, an introduction of an
additional electron-withdrawing substituent was consid-
ered to be effective. An alternative potential approach is
the introduction of an electron-donating substituent at
the C5 position so that the pushÀpull effect on the 10π-
electron system could be enhanced. Thus, we became intri-
gued with the synthesis of 1,3a,6a-triazapentalenes possessing
† Department of Chemistry.
‡ Graduate School of Chemical Sciences and Engineering.
(1) (a) Shinar, J., Ed. Organic Light-Emitting Devices; Springer:
New York, 2004. (b) Valeur, B. Molecular Fluorescence; WILEY-VCH:
Weinheim, 2002. (c) Willardson, R. K.; Weber, E.; Mueller, G.; Sato, Y.
Electroluminescence 1, Semiconductors and Semimetals Series; Academic
Press: New York, 1999.
(2) For selected recent examples of a fluorescent molecule: (a)
Shimizu, M.; Takeda, M.; Higashi, M.; Hiyama, T. Angew. Chem.,
Int. Ed. 2009, 48, 3653–3656. (b) Lorbach, A.; Molte, M.; Li, H.; Lerner,
€
H.-W.; Holthausen, M. C.; Jakle, F.; Wagner, M. Angew. Chem., Int. Ed.
2009, 48, 4584–4588. (c) Mercier, L. G.; Piers, W. E.; Parvez, M. Angew.
Chem., Int. Ed. 2009, 48, 6108–6111. (d) Zhao, Z.; Wang, Z.; Lu, P.;
Chan, Y. K.; Liu, D.; Lam, J. W. Y.; Sung, H. H. Y.; Williams, I. D.; Ma,
Y.; Tang, B. Z. Angew. Chem., Int. Ed. 2009, 48, 7608–7611. (e) Caruso,
A., Jr.; Siegler, M. A.; Tovar, J. D. Angew. Chem., Int. Ed. 2010, 49,
4213–4217. (f) Ren, Y.; Baumgartner, T. J. Am. Chem. Soc. 2011, 133,
1328–1340. (g) Siamaki, A. R.; Sakalauskas., M.; Arndtsen, B. A.
Angew. Chem., Int. Ed. 2011, 50, 6552–6556. (h) Zhang, Z.; Xu, B.; Su,
J.; Shen, L.; Xie, Y.; Tian, H. Angew. Chem., Int. Ed. 2011, 50, 11654–
11657. (i) Zhao, D.; Hu, J.; Wu, N.; Huang, X.; Qin, X.; Lan, J.; You, J.
Org. Lett. 2011, 13, 6516–6519. (j) Liu, B.; Wang, Z.; Wu, N.; Li, M.;
You, J.; Lan, J. Chem.;Eur. J. 2012, 18, 1599–1603.
(3) Namba, K.; Osawa, A.; Ishizaka, S.; Kitamura, N.; Tanino, K.
J. Am. Chem. Soc. 2011, 133, 11466–11469.
(4) The 1,3a,6a-triazapentalenes with an aryl fused system exhibit
very little fluorescence (ΦF = 0.0001). See: Albini, A.; Bettinetti, G.;
Minoli, G. J. Am. Chem. Soc. 1991, 113, 6928–6934.
(5) Other examples of the 1,3a,6a-triazapentalene derivatives without
an aryl fused system: (a) Koga, H.; Hirobe, M.; Okamoto, T. Tetra-
hedron Lett. 1978, 19, 1291–1294. (b) Chen, Y.; Wang, D.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. Chem. Commun. 2010, 46, 6147–6149.
r
10.1021/ol302668y
XXXX American Chemical Society

Scheme 2. Synthesis of the Azide Fragments 2a
Figure 1. Fluorescence properties of 1,3a,6a-triazapentalene.
of the chloride with azide followed by selective protection
of the primary alcohol afforded 9, which was oxidized by
SO3•Pyr-DMSO to give ketone 10.7 The acetal formation
reaction of 10 simultaneously induced the removal of a
TBS group to give alcohol 11. Subsequent treatment of 11
with Tf2O at À78 °C afforded the desired 2a as a precursor
of 5-methoxy-1,3a,6a-triazapentalenes (Scheme 2).
Having prepared the azide fragment 2a, we next attem-
pted the cascade reaction leading to 1,3a,6a-triazapenta-
lene. Although the click reaction of 2a with phenylacety-
lene (3a) was stopped at the 1,2,3-triazole 4a, refluxing
after the click reaction induced the cyclization to afford the
bicyclic triazolium ion 5a. However, subsequent direct
elimination of the methoxy group by coexisting triethylamine
did not proceed. The use of DBU as a stronger base and the
use of p-TsOH under acidic conditions were also unsuccess-
ful, whereas the use of KHMDS at À78 °C was later found to
give the desired 2-phenyl-5-methoxy-1,3a,6a-triazapenta-
lene 1a in 64% yield from 2a. This is the first example of
the synthesis of 2,5-disubstituted-1,3a,6a-triazapentalenes
without an additional fused ring system (Scheme 3). Thus,
the one-pot preparative method for the 2,5-disubstituted-
1,3a,6a-triazapentalenes was established.
We next examined the introduction of various substitu-
ents at the C5 position in order to elucidate the effect of the
5-substituent on the fluorescence properties (Table 1).
First, 4-cyanophenyl acetylene (3b) was adopted as an
alkyne fragment because the cyanophenyl group exhib-
ited a high fluorescence quantum yield and the excel-
lent stability to UV irradiation among the various
2-substituents.3 The similar sequential reaction of 2a with
3baffordedthe desired 2-cyanophenyl-5-methoxy-1,3a,6a-
triazapentalene 1b in 60% yield (entry 1). The click reac-
tion of methyl analog 2b8 with 3b afforded the bicyclic
triazolium ion without reflux conditions. Subsequent di-
rect treatment with KHMDS at À78 °C resulted in the
various substituents at the C5 position in order to elucidate
the pushÀpull effect on the fluorescence properties of the
1,3a,6a-triazapentalenes. To this end, we designed an azide
2 having methoxy and triflate groups at the C2 and C3
positions, respectively, which were expected to be more
stable than the corresponding azidoditriflates, as the pre-
cursor of 5-substituted-1,3a,6a-triazapentalenes 1. The
click reaction6 of 2 with an alkyne would give the 1,2,3-
triazole 4 which may undergo a cyclization reaction to
afford the bicyclic triazolium ion 5. Finally, treatment of
the intermediate with a base would give the desired 5-sub-
stituted-1,3a,6a-triazapentalene 1 through elimination of
the methoxy group followed by aromatization (Scheme 1).
Our previous study showed that the basic treatment of the
corresponding free alcohol of 5, which was obtained by the
epoxide ring-opening reaction, afforded alkanenitrile un-
expectedly. Therefore, the methoxy group was adopted as
a leaving group. Herein, we describe the synthesis of 2,5-
disustituted-1,3a,6a-triazapentalenes and their interesting
fluorescence properties.
Scheme 1. Synthetic Plan of 2,5-Disubstituted-1,3a,6a-triaza-
pentalene
(7) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(8) The methyl substituent 2b was easily obtained from β-methallyl
alcohol 12 by a sequential operation of a haloetherification, a substitu-
tion with azide, and a triflation.
The synthesis of azide fragment 2a started with easily avail-
able 3-chloro-1,2-propanediol 8. Nucleophilic displacement
(6) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004–2021. (b) Rostovtsev, V. V.; Green, L. G.; Fokin,
V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (c)
Tornøe, C. W.; Christnesen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064. (d) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7–17.
B
Org. Lett., Vol. XX, No. XX, XXXX

Having prepared the various 5-substituents of 2-cyano-
phenyl-1,3a,6a-triazapentalenes, we investigated their
fluorescence properties (excited at 370 nm) (Table 2).
Although the introduction of an electron-donating group
at the C5 position was expected to induce a longer-
wavelength shift, the methoxy-substituted analog 1b ex-
hibited a similar absorption and fluorescence maxima with
those of unsubstituted 1f.3 The methyl analog 1c also
showed a small longer-wavelength shift of the fluorescence
maximum. Neither shift was assigned to the wavelength
shift of the phenyl analog 1e despite the extended π-
conjugation system. In contrast, the fluorescence maxi-
mum of cyano analog 1d shifted to a shorter wavelength,
indicating that the electron-withdrawing group has an
effect on the fluorescence wavelength. Although the ex-
pected shifts of the fluorescence wavelength were not
observed, it was especially noteworthy that the fluores-
cence quantum yields (ΦF) of all 5-substituted-1,3a,6a-
triazapentalenes 1bÀ1e were dramatically increased.11
This suggested that the introduction of an electron-donat-
ing group at the C5 position allowed a substantial increase
in ΦF without any effect on the fluorescence wavelength,
and the 5-substituted-1,3a,6a-triazapentalene system eas-
ily provides access to potentially useful fluorescent probes
exhibiting a high fluorescence quantum yield.
Scheme 3. Synthesis of 2-Phenyl-5-methoxy-1,3a,6a-triazapen-
talene 1a
desired 5-methylsubstituted-1,3a,6a-triazapentalene 1c in
63% yield (entry 2). Next, the reaction of cyano analog 2c9
was attempted in order to examine the opposite effect of
the electron-withdrawing group, and the desired 5-cyano-
1,3a,6a-triazapentalene 1d was obtained in 57% yield
(entry 3). In addition, the effect of the aromatic substituent
was also intriguing. Since the corresponding triflate of 2d10
easily induced the [1,2]-shift of the phenyl group during
column purification, the synthesis was started with a
triflation reaction of alcohol 2d to afford the desired
5-phenyl analog 1e in 19% yield (entry 4).
Table 2. Fluorescence Properties of 5-Substituted-1,3a,6a-tria-
zapentalenes 1bÀe and Unsubstituted 1f in Dichloromethane
Table 1. Synthesis of the Various 5-Substituents of
2-(4-Cyanopheyl)-1,3a,6a-triazapentalenes
Finally, we examined the effect of the application of a
5-substituent in the variously colored 1,3a,6a-triazapenta-
lenes on the increment of ΦF without a significant shift of
the fluorescence wavelength (Table 3). The methyl analog
2b was adopted as the azide fragment due to its ready
availability and high fluorescence quantum yield of 1c. The
click reaction of 2bwithphenyl acethylene(3a) followed by
basic treatment afforded a desired 2-phenyl-5-methyl-
1,3a,6a-triazapentalene 1g in 81% yield. As we expected,
(9) The cyano substituent 2c was converted from ketone 10 via a
cyanohydrin forming reaction followed by methylation reactions; see
Supporting Information.
(10) The phenyl substituted analog 2d was prepared from 2-phenyl-2-
propene-1-ol in the same manner as 2b.
(11) Fluorescence quantum yields were estimated by using 9,10-
a Isolated yield. b Reflux condition was not needed. c Corresponding
triflate was used without purification.
diphenylanthracene (9,10-DPA) in cyclohexane as a standard (ΦF
0.91).
=
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toward a slightly longer shift (entries 3 and 4). Therefore, it
was found that the introduction of a C-5 substituent did
not entirely increase the ΦF of the 1,3a,6a-triazapentalenes.
However, we found that the change in ΦF in the case of the
electron-withdrawing substituents (Hammet σp value 0 (H)
∼ 0.71 (CN)) at the C-2 position increased ΦF, whereas an
electron-donating (σp e À0.28 (OMe)) and the much stron-
ger electron-withdrawing substituent (σp g 0.81 (NO2))
exhibited a substantial decline in ΦF. Thus, the 1,3a,6a-
triazapentalenes provide a useful fluorescent system in which
the ΦF value can be easily modified by introducing 5-sub-
stituents based on the Hammet σp value of 2-substituents.
In this study, an efficient and versatile method was esta-
blished for the preparation of 2,5-disubstituted-1,3a,6a-
triazapentalene, and the effect of a 5-substituent on the
fluorescence properties was elucidated. The introduction
of a 5-substituent substantially enhanced the fluorescence
quantum yield (ΦF) of the 1,3a,6a-triazapentalenes with
little effect on the fluorescence wavelength, and the ten-
dency for the ΦF value could be estimated from the
Hammet σp value of the 2-substituent. Therefore, the
1,3a,6a-triazapentalenesasfluorescent chromophorespro-
vide an innovative fluorescent system that can tune both
the fluorescence wavelength and quantum yield. That is,
the fluorescence wavelength and quantum yield can be
controlled by the 2- and 5-substituents, respectively. Ap-
plications of the 1,3a,6a-triazapentalene system as functio-
nalized fluorescent probes in the life sciences fields are
currently being investigated in our laboratory.
Table 3. Click Reaction of 2b with Various Acetylenes 3 and
Fluorescence Properties of Various 5-Methyl-1,3a,6a-triaza-
pentalenes in Dichloromethane
a Excited at 340 nm. b Excited at 370 nm. c The reaction was con-
ducted at À78 to 0 °C by using Et2NLi as a base. d Isolated yield.
e Fluorescence maximum of corresponding 5-unsubstituted analog.
Fluorescence quantum yield of corresponding 5-unsubstituted analog.
f
Acknowledgment. This work was partially supported
by the Global COE program (Project No. B01: Catalysis as
the Basis for Innovation in Material Science), Grant-in-
Aid for Scientific Research (Grant No. 24310162), and
Grant-in-Aid for Scientific Research on Innovative Areas
(Project No. 2105: Organic Synthesis Based on Reaction
Integration and No. 2301: Chemical Biology of Natural
Products) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
the ΦF value of 1g was substantially increased compared
with that of the corresponding 5-unsubstituted-1,3a,6a-
triazapentalene, and the fluorescence wavelength showed
a small longer-wavelength shift (Table 3, entry 1). The
similar one-pot reaction of 2b with 4-biphenylacetylene 3c
afforded 2-(4-biphenyl)-5-methyl-1,3a,6a-triazapentalene
1h in 59% yield, and 1h also exhibited an increase of ΦF
with a small longer-wavelength shift (entry 2). The reac-
tions of (4-methoxyphenyl)acetylene 3d and (4-nitro-
phenyl)acetylene 3e also gave the corresponding 2,5-dis-
ubstituted-1,3a,6a-triazapentalenes 1i and 1j in 72%
and 27% yields, respectively. Surprisingly, however, 1i
and 1j showed a considerable decline in ΦF, although the
fluorescence spectral shifts exhibited the same tendency
Supporting Information Available. Experimental de-
tails, absorption and fluorescent spectra, and 1H and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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