Direct synthesis of fluorescent 1,3a,6a-triazapentalene derivatives via click-cyclization-aromatization cascade reaction

Article abstract of DOI:10.1021/ja203917r

An efficient and versatile method was established for the preparation of 1,3a,6a-triazapentalenes. The 1,3a,6a-triazapentalene skeleton without an additional fused ring system was discovered to be a compact and highly fluorescent chromophore, which exhibi

Full text of DOI:10.1021/ja203917r

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Direct Synthesis of Fluorescent 1,3a,6a-Triazapentalene Derivatives
via ClickÀCyclizationÀAromatization Cascade Reaction
Kosuke Namba,* Ayumi Osawa, Shoji Ishizaka, Noboru Kitamura, and Keiji Tanino*
Division of Chemistry, Graduate School of Science, Hokkaido University, Kita-ku, Sapporo 060-0810, Japan
S Supporting Information
b
ABSTRACT: An efficient and versatile method was estab-
lished for the preparation of 1,3a,6a-triazapentalenes. The
1,3a,6a-triazapentalene skeleton without an additional fused
ring system was discovered to be a compact and highly
fluorescent chromophore, which exhibited various interest-
Figure 1. Structure of 1,3a,6a-triazapentalene (1a) and benzotriaza-
pentalene 2.
ing fluorescent properties such as a noteworthy correlation
of luminescent wavelength with the Hammett σp value and a
strongly positive solvatofluorochromism.
Scheme 1. Synthesis of 1 by the click reaction
luorescent organic molecules constitute an important class of
F
compounds in modern science and technology, and they are
widely used as biological imaging probes, sensors, lasers, light-
emitting devices, etc.1 Thus, the development of useful fluor-
escent organic molecules has been a subject of intensive research
due to their significance in the advancement of many industries.
However, the commonly used fluorescent molecules have thus
far needed to be improved in the following respects. Most highly
fluorescent molecules are large and display limited solubility in
water. Often the methods used to synthesize them do not allow
the facile introduction of functionality and the design of systems
whose luminescent properties span a range of wavelength. To
develop a new system that will solve the above problems, we
focused our attention on 1,3a,6a-triazapentalene (1a) possessing
a compact 10π-electron system (Figure 1).2 Although the
fluorescent properties of 1a have not yet been elucidated,3 it is
expected to be an excellent fluorescent chromophore with
electric and/or structural effects of various substituents on the
triazapentalene ring. Furthermore, the development of an effi-
cient method for the synthesis of 1a by an intermolecular cyclo-
addition reaction in a single step enables the connection of two
functionalized molecules to generate fluorescent function simul-
taneously. Thus, we describe herein a facile synthesis of the
1,3a,6a-triazapentalenes and their interesting fluorescent properties.
There have been several examples of the synthesis of 1,3a,6a-
triazapentalene derivatives with aryl fused and heteroaryl fused
systems such as benzotriazapentalene 2,4 and they are mainly
based on the intramolecular NÀN bond-forming reaction of
pyrazole derivatives with thermally or photochemically gener-
ated nitrenes.5 In addition, intramolecular alkylation reactions of
benzotriazole derivatives have also been reported.6 In contrast,
there have been very few examples of the 1,3a,6a-triazapentalene
derivatives without an aryl fused system,7 and the simple 1,3a,6a-
triazapentalene (1a) has never been synthesized. Thus far,
2-methyl- and 2-phenyl-1,3a,6a-triazapentalene synthesized by
Hirobe are the only examples of monosubstituted triazapenta-
lenes. They were synthesized by different methods using
N-amination of pyrazoles, and their fluorescent properties were
not mentioned.4b We have attempted to establish a versatile and
common method for the synthesis of various triazapentalenes
without aryl fused systems to elucidate the properties of the
triazapentalene skeleton as a fluorescent chromophore. To
achieve a single-step synthesis of 1,3a,6a-triazapentalenes 1, we
planned to apply the click reaction of various alkynes 3 with azide
4, which possesses two leaving groups at each of the C2 and C3
positions, as shown in Scheme 1. The Cu(I)-catalyzed click
reaction8 of alkyne 3 with azide 4 under basic conditions would
afford a triazole A, which should undergo intramolecular cycliza-
tion to give a triazolium ion B. Under basic conditions, the
intermediate B would be subsequently converted to 1 by a
sequential reaction of E2 elimination and deprotonation.
We began the investigation of the click reaction with 3-azido-
propane-1,2-diol bis(trifluoromethanesulfonate) (4a) as an azide
fragment because of its high reactivity and ready availability. The
azide 4a was easily obtained from 3-chloro-1,2-propanediol by a
simple operation in just two steps,9 and it is stable enough to be
purified by column chromatography and stored for several
months in the freezer. After the examination of various reaction
conditions using 1-pentadecyne (3b) as an alkyne fragment, we
found that treatment of 3b with 1.2 equiv of 4a in the presence of
5 mol % of copper(I) iodide, and 5 mol % of bis[2-(N,N-
dimethylamino)ethyl]ether as a ligand, and 5 equiv of
Received: May 10, 2011
Published: July 07, 2011
r
2011 American Chemical Society
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Scheme 2. Click reaction of the pentadecyne 3b with the
azide 4a
Figure 2. ORTEP of the molecular structure and bond lengths of 1h.
Table 1. Click Reaction of 4a with Various Acetylenes
Scheme 3. Synthesis of 1a
which has a coupling site for further reactions, also afforded 1k in
88% yield. Thus, it was confirmed that the established prepara-
tion method for the 1,3a,6a-triazapentalenes 1 is applicable to
various acetylenes.
The structure of 1h was unequivocally established by an X-ray
diffraction study, which elucidated that 1h has a 10π-electron
resonance structure as an aromatic ring, as shown in Figure 2.
The structures of the other 1,3a,6a-triazapentalenes were also
confirmed by the correlation of spectral data with 1h.
a The reaction was conducted by using 1.2 equiv of alkyne and 1.0 equiv
Next, the first synthesis of unsubstituted 1,3a,6a-triazapentalene
(1a) was examined in order to elucidate the properties of the
1,3a,6a-triazapentarene skeleton. A similar click reaction of 4a with
(trimethylsilyl)acetylene (3l) afforded 1l in 71% NMR yield. We
foundthat1l decomposedreadily duringcolumn chromatography.
Therefore, the crude 1l was directly subjected to desilylation with
TBAF to give 1a in 46% overall yield as a volatile oil (Scheme 3).
Having prepared 1aÀk, we investigated their fluorescent
properties. Except for 1a, the characteristic absorption bands of
synthetic 1,3a,6a-triazapentalenes were observed from 300 to
500 nm in dichloromethane (Supporting Information [SI]), and
absorption maxima of selected 1,3a,6a-triazapentalenes are noted
in Table 2. We found that 1aÀk exhibited fluorescent emissions
and studied the emission in several different solvents (see below).
In particular, the fluorescent observation of 1a (excited at
330 nm) is the first direct experimental evidence that the
1,3a,6a-triazapentalene skeleton is a fluorescent chromophore,
although the fluorescent quantum yield (ΦF) is not high, being
0.017 with reference to 9,10-diphenylanthracene. In clear con-
trast, 2 as an aryl fused system, which was prepared according to
the procedure of Bettinetti,5c exhibits almost no fluorescence
(ΦF = < 0.001). Also, the various related analogues of 2 have not
been reported to have noteworthy fluorescent properties. Thus,
we discovered that the absence of an additional fused ring system
is an essential factor for fluorescence of the 1,3a,6a-triazapenta-
lenes. Interestingly, the fluorescent intensities and wavelengths
of 1,3a,6a-triazapentalenes varied widely with 2-substituents
(see Figure 3). For example, the 2-methoxycarbonyl derivative
1e exhibited highly fluorescent emissions despite its compact
molecular size, and the fluorescent quantum yield (ΦF) of 1e was
dramatically increased to 0.21. Therefore, application of 1e as
the most compact highly fluorescent probe might be interesting.
The lithium carboxylate 1o, which was obtained by hydrolysis of
of 4a in 0.01 M THF. b The reaction was conducted in water.
triethylamine as a base in THF (0.2 M) afforded the desired 1b in
quantitative yield by 1H NMR (Scheme 2).10,11 By comparison, a
similar click reaction in the absence of base gave a triazolium ion
5b12 in 29% yield, along with a trace amount of 1b. The
formation of 5b showed that the triazole generated in the click
reaction underwent intramolecular substitution to form the
bicyclic framework. Very little of the elimination product 1b
was produced. The spontaneous substitution of triazole needs
the triflate as a leaving group. A similar click reaction with bis-
mesylate and bis-tosylate instead of bis-triflate (4a) afforded the
corresponding triazoles without the formation of the bicyclic
compound.
Having established a preparative method for 1,3a,6a-triaza-
pentalene (1b), the click reaction of 4a with other acetylenes was
examined (Table 1). The click reaction of 1-hexyne (3c) with 4a
afforded the desired 2-butyl-1,3a,6a-triazapentalene (1c) in 84%
isolated yield. The acetylenes possessing a functional group such
as methyl propargyl ether (3d), methyl propioate (3e), and
phenyl acetylene (3f) also gave the corresponding desired
triazapentales, 1dÀ1f in 80%, 90%, and 89% yields, respectively.
It is especially noteworthy that the reaction of 3f with 4a could
proceed even in water to give 1f in acceptable yield. The reaction
of biphenyl acetylene (3g) afforded triazapentalene (1g) in 81%
yield, and the phenyl acetylene derivatives having an electron-
withdrawing group such as a cyano group (3h) or a nitro group
(3i) also gave the desired triazapentalenes 1h and 1i in 70% and
96% yields, respectively. The reaction of electron-rich derivative
3j showed a slight decline in yield, and triazapentalene 1j was
obtained in 56% yield. The reaction of triflate derivative 3k,
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Figure 4. Emissive behaviors and fluorescence spectra of 1h with
various solvents.
Figure 3. Photonic luminescence of selected 1,3a,6a-triazapentalenes in
dichloromethane.
Scheme 4. Click reaction with substituted azidotriflates 4m
and 4n
Table 2. Fluorescent Properties of Selected 1,3a,6a-Triaza-
pentalenes in Dichloromethane
a very useful factor to suppress the action of background
fluorescence in the various fluorescent analyses.
Furthermore, the synthesized triazapentalenes exhibit strong
positive solvatofluorochromism.14 For example, the fluorescent
emissions and spectra of 2-(4-cyanophenyl)-1,3a,6a-triazapenta-
lene 1h in different solvents are shown in Figure 4. The fluo-
rescence emissions of 1h shifted to longer wavelengths with
increasing solvent polarity. The solvatofluorochromic behavior
of the compact molecule with reasonable fluorescence efficiency
might be very useful as fluorescent probes.
a Measured in water.
Finally, we demonstrated that the substituted azidoditriflates
4m and 4n could also be used in a similar click reaction to give
2,4-disubstituted-1,3a,6a-triazapentalenes 1m and 1n, regardless
of the relative stereochemistry of azidoditriflate (Scheme 4). The
fluorescent emissions of 1m and 1n were confirmed, although
the fluorescent quantum yield (ΦF) is not high (see SI). There-
fore, the click reaction described herein is expected to develop as
a “luminous click reaction”, which connects two functional
materials, simultaneously generating fluorescent function.
In this study, an efficient and versatile method was established
for the preparation of nonaryl fused 1,3a,6a-triazapentalenes, and
the 1,3a,6a-triazapentalene skeleton was proven to be a compact
and highly fluorescent chromophore. The limited synthesis of
1,3a,6a-triazapentalenes without an aryl fused system might be
the main reason that they have been previously unrecognized
as an excellent fluorescent chromophore. The 1,3a,6a-triaza-
pentalenes systems described herein enabled us to design the
luminescent wavelength based on the Hammett σp value of
2-substituents, and they exhibited a strong positive solvatofluor-
ochromism. The 1,3a,6a-triazapentalenes appear to be ideal
fluorescent molecules that have many advantages such as com-
pact molecular size, water solubility, a simple construction
method, facile introduction to various functional materials even
in water, high functional group selectivity, and an easy design
system for luminescent wavelengths. Additional properties of the
1e,13 also showed fluorescent emission even in water. Thus, the
1,3a,6a-triazapentalene was found to serve as a compact fluor-
escent probe having a large Stokes shift (132 nm) in the aqueous
system (Table 2). Furthermore, an amide derivative 1p also
exhibits fluorescence, although ΦF was decreased to 0.039.13 The
simple 1,3a,6a-triazapentalenes 1a, 1e, and 1o are gradually
decomposed by UV irradiation, and 2-methoxyphenyl-1,3a,6a-
triazapentalene (1j) was partly decomposed after sequential irradia-
tion for 5 min. However, 2-phenyl analogues with an electron-
withdrawing group such as 1g, 1h, and 1i are still stable after 5
min, and 1h and 1i are unbreakable even after 1 h (see SI). More
interestingly, the emission maxima of 2-phenyl-1,3a,6a-triaza-
penthalene derivatives exhibit a noteworthy correlation with the
Hammett σp value of substituents on the benzene ring such as
methoxy group 1j (σp À0.28, λmax = 413 nm), phenyl group 1g
(σp 0.04, λmax = 456 nm), cyano group 1h (σp 0.71, λmax
=
509 nm), and nitro group 1i (σp 0.81, λmax = 556 nm). Therefore,
the 1,3a,6a-triazapentalene system easily provides access to
potentially useful fluorescent probes whose emissions span a range
of wavelengths. Furthermore, the Hammett σp value can be of use
in fashioning new systems designed to access additional wave-
lengths. Another standout fluorescent feature of the 1,3a,6a-
triazapentalenes is the large Stokes shifts (83À144 nm), which is
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1,3a,6a-triazapentalene system such as the fluorescence lifetime,
stabilities, and photodecomposition mechanism are currently
being investigated in our laboratory, as are various applications as
functionalized fluorescent probes.
to 4a in 82% yield. The multigram-scale preparation of 4a was actually
conducted several times without incident. The microscopic observation
of thermolytic behavior of 4a (neat) by melting point apparatus revealed
that 4a decomposes and partially volatilizes at 92 °C. Although we found
that a solution of 4a in 1,4-dioxane is stable enough to be heated to
100 °C for 2 h, manipulating 4a at high temperature is not recom-
mended. Further investigation about safety is currently underway.
’ ASSOCIATED CONTENT
1
S
Supporting Information. Experimental details, H and
b
13C NMR spectra, absorption and fluorescent spectra, and
crystallographic data of 1h. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) The use of 2,6-lutidine and DBU as bases did not give 1b
because they reacted with 4a faster than the click reaction. The yield of
1b was reduced to 66% when diisopropylethylamine was used. The
amount of triethylamine could be reduced to 2.0 equiv without a
significant loss of yield.
(11) The isolated yield of 1b was reduced to 71% because a part of
1b was decomposed to blue product, which strongly adsorbed on silica
gel, during column chromatography.
(12) Attempts for isolating the triazolium ion 5b were unsuccessful.
Therefore, the structure of 5b was determined on the basis of the
correlation with triazoium ion 5c, which was easily obtained by a similar
click reaction of 4b with 3c.
’ AUTHOR INFORMATION
Corresponding Author
namba@mail.sci.hokudai.ac.jp; ktanino@sci.hokudai.ac.jp
’ ACKNOWLEDGMENT
We thank professor Hidetoshi Kawai (Tokyo University of
Science) for the X-ray analysis and B3LYP/6-31G* calculation of
2-(4-cyanophenyl)-1,3a,6a-triazapentalene, 1h. This work was
partially supported by the Global COE program (Project No. B01)
and Grant-in-Aid for Scientific Research on Innovative Areas
(Project No. 2105) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
(13) Treatment of 1e with 1.0 equiv of lithium hydroxide afforded
lithium carboxylate 1o in quantitative yield. The amide 1p was prepared
by the coupling of 1o with glycine ethyl ester hydrochloride by the
combined action of EDCI and DMAP in DMF.
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