One-Pot synthesis of coumarin-based oxazabicyclic and oxazatricyclic compounds and their fluorescence redox switching properties

Article abstract of DOI:10.1021/ol901505e

An oxazabicycle and an oxazatricycle were efficiently synthesized by coupling of coumarins and N-alkylquinolium or isoquinolium salt to investigate their fluorescence redox-switchlng properties. Chemical reduction of the strongly fluorescent oxazabicycle

Full text of DOI:10.1021/ol901505e

ORGANIC
LETTERS
2
009
Vol. 11, No. 18
064-4067
One-Pot Synthesis of Coumarin-Based
Oxazabicyclic and Oxazatricyclic
Compounds and Their Fluorescence
Redox Switching Properties
4
Chi-Hui Lin, Jing-Fu Jhang, and Ding-Yah Yang*
Department of Chemistry, Tunghai UniVersity, 181 Taichung-Kang Road Sec.3,
Taichung 407, Taiwan
yang@thu.edu.tw
Received July 1, 2009
ABSTRACT
An oxazabicycle and an oxazatricycle were efficiently synthesized by coupling of coumarins and N-alkylquinolium or isoquinolium salt to
investigate their fluorescence redox-switching properties. Chemical reduction of the strongly fluorescent oxazabicycle and oxazatricycle results
in the ring-opened products with a distinct decrease in emission intensity. Both resulting ring-opened species can be swiftly reverted to the
original ring-closed forms by oxidation.
Partly owing to the increasing interest in molecular electron-
ics and photonics, the properties of molecules or ions which
organic” donor-acceptor system and chemical and elec-
trochemical fluorescent switches were developed by
covalently connecting a fluorophore (the donor, i.e.,
aminonaphthalene) and an active redox switch (the ac-
ceptor, i.e., quinone/hydroquinone) with a conjugated or
unconjugated spacer. The fluorescence emission of the
donors can be reversibly quenched depending upon the
oxidation state of the acceptors.
1
can be switched from one configuration to another by an
external perturbation have received much attention in the
past two decades. Particular interest is devoted to molecular
switches whose emission properties are controlled by redox
potential, as they could find application in biochemical and
5
2
biophysical investigations. Most molecular fluorescent
switching systems operating via a redox couple, consist of a
3
However, a number of the reported organic fluorescent
switching systems suffer from a lack of comparable stability
in the reduced forms; i.e., they tend to slowly revert to the
oxidized form, which substantially limits their practical
applications. For instance, the commonly seen redox-active
unit hydroquinone in the donor-acceptor switches is gradu-
ally reoxidized back to the corresponding quinone by
metal-centered redox couple or a luminescent ion core
4
encircled by a macrocyclic receptor. Recently, an “all-
(
1) Liddell, P. A.; Kodis, G.; Moore, A. L.; Moore, T. A.; Gust, D.
J. Am. Chem. Soc. 2002, 124, 7668–7669.
¨
2) (a) Kartberg, F.; Elsner, M.; Froderberg, L.; Asp, L.; Nilsson, T.
(
Biochim. Biophys. Acta 2005, 1744, 351–363. (b) Yee, D. J.; Balsanek, V.;
Sames, D. J. Am. Chem. Soc. 2004, 126, 2282–2283.
(
3) (a) Bergonzi, R.; Fabbrizzi, L.; Licchelli, M.; Mangano, C. Coord.
Chem. ReV. 1998, 170, 31–46. (b) Wong, Y. L.; Ma, J. F.; Law, W. F.;
Yan, Y.; Wong, W. T.; Zhang, Z. Y.; Mak, T. C. W.; Nag, D. K. P. Eur.
J. Inorg. Chem. 1999, 2, 313–321.
(5) (a) Fave, C.; Leroux, Y.; Trippe, G.; Randriamahazaka, H.; Noel,
V.; Lacroix, J. C. J. Am. Chem. Soc. 2007, 129, 1890–1891. (b) Shie, T. L.;
Lin, C. H.; Lin, S. L.; Yang, D. Y. Eur. J. Org. Chem. 2007, 29, 4831–
4836.
(
4) Impey, G. A.; Stynes, D. V. J. Am. Chem. Soc. 1993, 115, 7868–
7
869.
10.1021/ol901505e CCC: $40.75
Published on Web 08/13/2009
 2009 American Chemical Society

6
standing in the open air for several hours. Perhaps because
structures of 3 and 5 were elucidated by X-ray crystal-
lography as shown in Figure 1, which clearly revealed the
9
of this air-sensitive property, few X-ray crystal structures
of the reduced form of all-organic fluorescence redox
switches were reported in the literature. Thus, development
7
of a redox-active subunit (the control unit) which can exist
in two different oxidation states with comparable stability
(
a bistable system) remains a major challenge in the field of
molecular switches.
In this paper, we report the synthesis and investigation of
the switching behavior of two novel heterocyclic systems
containing a coumarin moiety as the fluorescence active unit
and an oxazabicyclic or oxazatricyclic moiety as the redox-
active fragment. Chemical studies show that this coumarin-
containing two-component system behaves as a molecular
switch whose emission can be controlled by ring-opening and
ring-closing of the oxazatricyclic moiety. Most importantly, both
oxidized and reduced forms of these molecular switches are
relatively stable and can be characterized by single-crystal X-ray
diffraction analysis.
Figure 1. X-ray crystal structures of the oxazabicycle 3 and
oxazatricycle 5.
rigid oxazabicyclic and oxazatricyclic skeletons, respectively.
The mechanism for the formation of 3 presumably involved
a nucleophilic attack of coumarin 2 to the 4-position of 1 to
yield the initial coupling product, followed by the subsequent
intramolecular cyclization reaction to afford the oxazabicycle
Scheme 1 describes the preparation of the oxazabicycle 3
and oxazatricycle 5. The oxazabicycle 3 was realized by
3
. A similar Lewis acid mediated coupling of 4-hydroxy-
Scheme 1
coumarin and 2-phenylflavylium salt to generate the corre-
sponding dioxabicyclic compound has been previously
reported.
1
0
Scheme 2 depicts the proposed mechanism for the forma-
tion of 5. It began with an equilibrium-driven, inverse-
Scheme 2
coupling of N-methyl-2-phenylquinolium iodide (1) and 7-dim-
ethylamino-4-hydroxycoumarin (2) in the presence of triethy-
lamine in 1,2-dichloroethane under reflux conditions in 70%
yield. Compound 1 was prepared by refluxing 2-phenylquinoline
with methyl iodide in benzene. Compound 2 was prepared by
8
the previous reported procedure.
The oxazatricycle 5 was easily accessed via a multicom-
ponent reaction (MCR) of N-ethylisoquinolium iodide (4),
2
, and excess acetone in the presence of a catalytic amount
of triethylamine under reflux conditions in 91% yield.
N-Ethylisoquinolium iodide (4) was prepared by refluxing
isoquinoline with ethyl iodide in benzene. The molecular
electron-demand aza-Diels-Alder reaction of acetone enolate
(
6) (a) Calabrese, G. S.; Buchanan, R. M.; Wrighton, M. S. J. Am. Chem.
and isoquinolinium salt to give the iminium-containing
Soc. 1983, 105, 5594–5600. (b) Hubig, S. M.; Rathore, R.; Kochi, J. K.
J. Am. Chem. Soc. 1999, 121, 617–626.
11
cycloadduct 6. The second step involved a nonequilibrium
trapping of 6 with 2 to afford the target oxazatricycle 5. In
addition to forming three C-C bonds and one C-O bond
in the final product, this MCR was found to be highly
(7) For limited example: Sprutta, N.; Swiderska, M.; Latos-Grazuynski,
L. J. Am. Chem. Soc. 2005, 127, 13108–13109.
8) Chen, Y. S.; Kuo, P. Y.; Shie, T. L.; Yang, D. Y. Tetrahedron 2006,
2, 9410–9416.
9) Crystallographic data (excluding structure factors) for 3, 5, 7,and 8
(
6
(
has been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC-727190, -27191, -00825, and
-
700826, respectively. These data can be obtained free of charge via
(10) Chen, D. U.; Kuo, P. Y.; Yang, D. Y. Bioorg. Med. Chem. Lett.
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.
ac.uk, or by contacting the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
2005, 15, 2665–2668.
(11) Gupta, R. B.; Franck, R. W. J. Am. Chem. Soc. 1987, 109, 5393–
5403.
Org. Lett., Vol. 11, No. 18, 2009
4065

regiospecific and stereoselective, creating a tricyclic system
that contains four chiral centers.
marin group to the nearby tertiary amine to generate the
weakly fluorescent zwitterionic species 8. Note that this
intramolecular hydrogen-transfer reaction was not observed
for amino alcohol 7 because the aniline moiety of 7 is much
less basic than the tertiary amine of 8. Since the protonated
ammonium moiety is less susceptible to oxidation in the air,
the reduced 8 is quite stable at room temperature. It can be
recrystallized and then subjected to single X-ray diffraction
analysis. The crystal structure of zwitterion 8, shown in
1
2
The oxazabicycle 3 emitted strong fluorescence in both
hexane and toluene and was highly solvent-dependent. The
emission intensity decreased as the solvent polarity increased.
External perturbation with a reducing agent by addition of
sodium borohydride to 3 in methanol caused the ring-opening
of the oxazabicyclic moiety and yielded the weakly fluo-
rescent amino alcohol 7, whose crystal structure is shown
9
9
in Figure 2.
Figure 2, indicated that the positive charge mainly located
on the ammonium cation (N2) and the negative charge
partially delocalized on the 1,3-dicarbonyl structure of the
4
-hydroxycoumarin fragment with the C(1)-O(1) bond
length [1.294(2) Å] longer than the C(8)-O(3) bond length
1.222(2) Å]. The distance between the ammonium hydrogen
[
and O(1) oxygen was measured to be 1.549 Å, which is much
longer than the N(2)-H bond length [1.06(3) Å]. This
observation, along with the detection of a downfield am-
1
monium proton absorption peak at 16.62 ppm on H NMR
spectra, provided solid evidence to support the zwitterionic
structure of 8. Similar to the amino alcohol 7, the fluorescent
emission of the reduced 8 can also be instantly switched on
by DDQ oxidation. Scheme 4 shows the redox switch
Figure 2. X-ray crystal structures of the oxazabicycle 7 and
oxazatricycle 8.
The resulting reduced 7 was weakly fluorescent in most
of organic solvents except in hexane, which had the
fluorescence quantum yield of 0.255. Compound 7 can be
swiftly reverted to 3 by 2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone (DDQ) oxidation in methylene chloride at room
temperature. Scheme 3 shows the redox switch between the
Scheme 4
Scheme 3
between the ring-closed oxazatricycle 5 and ring-opened
zwitterion 8. The redox process between 5 and 8 was
repeated more than 10 times without the appearance of
detectable byproducts on TLC plates.
Figures 3 and 4 show the bar graphs of the fluorescence
f
quantum yields (Φ ) of 3, 7 and 5, 8 in different solvents,
ring-closed oxazabicycle 3 and ring-opened amino alcohol
7
. The repeated redox switching between 3 and 7, however,
resulted in the formation of a minor red byproduct, presum-
ably due to the aromatization of tetrahydroquinoline moiety
of 7 to the corresponding quinolium derivative. Theoretically,
this undesired aromatization reaction can be prevented by
introduction of gem-dimethyl groups to the methylene carbon
of the heterocyclic moiety on 3.
The oxazatricycle 5 also emitted strong fluorescence in
various solvents but was solvent-independent. Addition of
sodium borohydride to 5 in methanol induced the ring-
opening of the oxazatricyclic moiety followed by the
intramolecular hydrogen transfer from the 4-hydroxycou-
Figure 3
solvents.
.
Fluorescence quantum yields of 3 and 7 in different
Org. Lett., Vol. 11, No. 18, 2009
(
12) A library of 17 oxazatricycles with various substituents was prepared
via this MCR for biological activity evaluation. The results will be reported
elsewhere.
4
066

13
internal charge-transfer mechanism. It is worth mentioning
that the fluorescence intensity of the oxidized 5 is found to
be up to 180-fold stronger than that of the reduced 8 in
hexane (see Figure 4).
Although the fluorescence quenching mechanisms of these
two heterocycles merit further investigations, the fact that
the highly fluorescent oxazatricycle 5 can be swiftly inter-
converted to the corresponding weakly fluorescent ring-
opened form 8 by redox reaction suggests that the oxaza-
tricyclic moiety may have the potential to function as a
molecular switching scaffold. To the best of our knowledge,
this work represents the first example of a bistable, heterot-
ricyclic ring-controlled fluorescence molecular switch, which
we believe may lead to future development of the fluores-
cence redox switches with novel molecular structures.
In summary, two novel reversible fluorescence redox
switches containing a coumarin moiety as the fluorescence
active unit and an oxazacyclic moiety as the redox active
fragment were efficiently synthesized and characterized. We
have demonstrated that the emission of the fluorophore of
Figure 4. Fluorescence quantum yields of 5 and 8 in different
solvents.
respectively. (The detailed fluorescence parameters of com-
pounds 2, 3, 7, 5, and 8 are listed in the Supporting
Information.) The parent fluorophore 2 was strongly fluo-
rescent in methanol, and the emission was solvent-dependent.
When the coumarin fluorophore was connected to a rigid
bicyclic ring as in the oxazabicycle 3, the emission remained
intense in nonpolar solvents but gradually decreased as the
solvent polarity increased. After reduction, the intrinsic
fluorescence of the coumarin in the ring-opened amino
alcohol 7 was found to be partially quenched by the adjacent
amine group in most of the solvents. Apparently, a more
flexible conformation upon ring-opening of 3 might also
contribute a certain role in quenching the fluorescence of 7.
Interestingly, when the coumarin fluorophore was con-
nected to a rigid oxazatricyclic ring as in the oxazatricycle
4
the oxazatricycle 5 can be controlled by NaBH -induced ring-
opening and DDQ-mediated ring-closing of the heterocyclic
moiety. This work provides a new molecular scaffold for
design of reversible, all-organic, bistable fluorescence redox
switches. Further modifications of 8 by introducing appropri-
ate substituents at the nitrogen atom to function as a potential
chemosensor for metal ion detections are in progress.
Acknowledgment. We thank the National Science Council
of the Republic of China, Taiwan, for financially supporting
this research under Contract No. NSC 97-2113-M-029-004.
Supporting Information Available: Synthesis of com-
pounds 3, 5, 7, and 8, experimental details, and additional
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
5
, the emission remained intense but no longer solvent-
dependent, which might be attributed to the absence of the
-hydroxyl hydrogen atom at the coumarin moiety. After
4
chemical reduction, the intrinsic fluorescence of the coumarin
in the ring-opened zwitterion 8 was substantially quenched
by the excess electrons on the negative charge oxygen atom
at the 4-position of coumarin moiety, presumably via the
OL901505E
(
13) Jones, G., II; Jackson, W. R.; Choi, C.; Bergmark, W. R. J. Phys.
Chem. 1985, 89, 294–300.
Org. Lett., Vol. 11, No. 18, 2009
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