Insertion-coupling-cycloisomerization domino synthesis and cation-induced halochromic fluorescence of 2,4-diarylpyrano[2,3-b]indoles

Article abstract of DOI:10.1021/ol101709p

2,4-Diarylpyrano[2,3-b]indoles are formed via a Pd-Cu-catalyzed insertion-coupling-cycloisomerization domino reaction in moderate yields. Although the tricyclic systems are nonfluorescent in solution, protonation, quaternation, or complexation with metal ions induces intense green luminescence. Most strikingly, selective halochromic fluorescence of zinc and magnesium over calcium ions classify the title compounds as metal-selective luminescence sensors.

Full text of DOI:10.1021/ol101709p

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4122-4125
Insertion-Coupling-Cycloisomerization
Domino Synthesis and Cation-Induced
Halochromic Fluorescence of
2,4-Diarylpyrano[2,3-b]indoles
Jan Scho¨nhaber,† Walter Frank,‡ and Thomas J. J. Mu¨ller*,†
Institut fu¨r Organische Chemie und Makromolekulare Chemie and Institut fu¨r
Anorganische Chemie und Strukturchemie, Heinrich-Heine-UniVersita¨t Du¨sseldorf,
UniVersita¨tsstr. 1, D-40225 Du¨sseldorf, Germany
thomasjj.mueller@uni-duesseldorf.de
Received July 22, 2010
ABSTRACT
2,4-Diarylpyrano[2,3-b]indoles are formed via a Pd-Cu-catalyzed insertion-coupling-cycloisomerization domino reaction in moderate yields.
Although the tricyclic systems are nonfluorescent in solution, protonation, quaternation, or complexation with metal ions induces intense
green luminescence. Most strikingly, selective halochromic fluorescence of zinc and magnesium over calcium ions classify the title compounds
as metal-selective luminescence sensors.
The synthesis of novel functional organic molecules has
become an important challenge at the cutting edge between
organic chemistry and materials sciences.1 For instance,
functional chromophores are of particular interest in organic
light-emitting diodes,2 dye-sensitized organic solar cells,3
organic field effect transistors,4 or sensor arrays in bioana-
lytics or environmental analytical applications.5 Hence the
quest for rapid, flexible access to new tailor-made functional
π-systems has become increasingly important. In particular,
chromophores containing embedded recognition elements,
such as basic nitrogen atoms or phenolic hydroxyl groups,
for external stimuli are of paramount interest for advanced
applications.6 Typically, by addition of an analyte to a
solution of the functional chromophore, significant changes
in absorption or emission properties can be observed as
instantaneous read-outs. Most prominently among recent
examples based upon specific topologies of constituting
subchromophores are cruciform fluorophores by Bunz,7
tetraethynylethenes and diethynylethenes by Diederich,8 or
tetrakis(arylethynyl)benzenes by Haley.9
† Institut fu¨r Organische Chemie und Makromolekulare Chemie.
‡ Institut fu¨r Anorganische Chemie und Strukturchemie.
(1) For reviews, see: Functional Organic Materials. Syntheses, Strate-
gies, and Applications; Mu¨ller, T. J. J., Bunz, U. H. F., Eds.; Wiley-VCH:
Weinheim, 2007.
(2) (a) Shinar, J.; Shinar, R. J. Phys. D: Appl. Phys. 2008, 41, 133001/
1–133001/26. (b) Williams, J. A. G.; Wilkinson, A. J.; Whittle, V. L.
J. Chem. Soc., Dalton Trans. 2008, 2081–2099. (c) Veinot, J. G. C.; Marks,
T. J. Acc. Chem. Res. 2005, 38, 632–643.
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853. (b) Nilsson, D.; Kugler, T.; Svensson, P.-O.; Berggren, M. Sensors
Actuators B 2002, 86, 193–197.
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M. K. R.; Ba¨uerle, P. Angew. Chem., Int. Ed. 2009, 48, 2474–2499.
(4) Facchetti, A. Mater. Today 2007, 10, 28–37.
(6) Zucchero, A. J.; Wilson, J. N.; Bunz, U. H. F. J. Am. Chem. Soc.
2006, 128, 11872–11881.
10.1021/ol101709p  2010 American Chemical Society
Published on Web 08/24/2010

In the past years we have established and developed
diversity-oriented syntheses of chromophores10 based upon
transition-metal catalysis as an entry to consecutive multi-
component11 and domino reactions.12 These concepts open
excellent synthetic accesses to luminescent indolone termi-
nated push-pull dienes, pyrazoles, benzodiazepines, furans,
and pyrroles by multicomponent reactions13 and to highly
emissive spirocycles in a domino fashion.12a,b Here, we
communicate a concise insertion-coupling-cycloisomerization
domino synthesis of 2,4-diaryl-pyrano[2,3-b]indoles, a hith-
erto unknown substance class with peculiar halochromic
luminescence. The vestigial literature precedence on pyra-
noindoles is limited to pyrano[3,4-b]indoles as useful precur-
sors in the synthesis of carbazoles by Diels-Alder reactions14
and a single paper on the synthesis of pyrano[2,3-b]indol-
4-ones from oxindole and acetoacetate.15 In a previous work
we have already shown that alkynoyl o-iodo anilides 1 are
useful building blocks for developing novel domino
reactions.12a,b Now we have discovered a novel reaction
starting from the same type of substrate.
Upon reacting alkynoyl o-iodo anilides 1 with terminal
arylacetylenes 2 under the Sonogashira conditions16 in a
mixture of THF and triethylamine, first at room temperature
and then at reflux temperature, the novel class of 2,4-diaryl-
pyrano[2,3-b]indoles 3 were formed in moderate yields
(Scheme 1, Table 1). The structures of the 2,4-diaryl-
pyrano[2,3-b]indoles 3 were unambiguously supported by
1H and 13C NMR spectroscopy, by EI-MS spectrometry, and
by elemental analysis. Additionally, the structure of 3a was
later corroborated by an X-ray structure analysis (Figure 1).17
On the basis of the product analysis and the possibility to
isolate the conjugated enynes 6 after a room temperature
reaction,12a the mechanistic rationale of this one-pot sequence
Scheme 1. One-Pot Insertion-Coupling-Cycloisomerization
Synthesis of Novel 2,4-Diphenylpyrano[2,3-b]indoles
can be rationalized as follows (Scheme 1). After oxidative
addition an aryl-Pd species 4 readily inserts into the tethered
amido alkynyl triple bond to furnish vinyl-Pd species 5.
Subsequent alkynylation with the copper acetylide concludes
the coupling by forming conjugated enyne 6 as a mixture of
geometrical isomers, presumably as a consequence of a
precoupling stereomutation from the expected initial syn-
insertion product 5-E. For geometrical reasons only the
Z-configured stereoisomer 6-Z can participate in the final
cycloisomerization. A post-coupling E/Z-isomerization of 6
can be excluded due to the failure of attempted triethylamine
catalyzed equilibration with isolated 6-E. The concluding
cycloisomerization furnishes, as supported by DFT calcula-
tions (see Supporting Information), the thermodynamically
most stable isomer in a series of isomers, i.e., the 2,4-
diarylpyrano[2,3-b]indole 3. Within this efficient sequence
four new bonds, i.e., two carbon-carbon bonds, a carbon-
oxygen, and a carbon-hydrogen bond, are formed with an
average yield per bond-forming step ranging from 62% to
86%. Already, upon workup of the reaction mixture under
mildly acidic conditions (silica gel flash chromatography)
the peculiar appearance of green luminescence prompted us
to more closely scrutinize this phenomenon instead of
pushing forward the methodological and mechanistic studies
on the formation of 2,4-diarylpyrano[2,3-b]indoles 3.
(7) (a) Wilson, J. N.; Bunz, U. H. F. J. Am. Chem. Soc. 2005, 127,
4124–4125. (b) Hauck, M.; Scho¨nhaber, J.; Zucchero, A. J.; Hardcastle,
K. I.; Mu¨ller, T. J. J.; Bunz, U. H. F. J. Org. Chem. 2007, 72, 6714–6725.
(c) McGrier, P. L.; Solntsev, K. M.; Scho¨nhaber, J.; Brombosz, S. M.;
Tolbert, L. M.; Bunz, U. H. F. Chem. Commun. 2007, 2127–2129.
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38, 674–678. (b) Diederich, F. Chem. Commun. 2001, 219–227. (c) Mitzel,
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Chim. Acta 2004, 87, 1130–1157.
(9) Spitler, E. L.; Shirtcliff, L. D.; Haley, M. M. J. Org. Chem. 2007,
72, 86–96.
(10) For reviews, see: (a) Mu¨ller, T. J. J.; D’Souza, D. M. Pure Appl.
Chem. 2008, 80, 609–620. (b) Mu¨ller, T. J. J. In Functional Organic
Materials. Syntheses, Strategies, and Applications; Wiley-VCH: Weinheim,
2007; pp 179-223.
(11) (a) Willy, B.; Mu¨ller, T. J. J. Curr. Org. Chem. 2009, 13, 1777–
1790. (b) Willy, B.; Mu¨ller, T. J. J. ARKIVOC 2008, Part I, 195–208. (c)
Mu¨ller, T. J. J. Targets Heterocycl. Syst.s 2006, 10, 54–65.
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Chem.sEur. J. 2008, 14, 529–547. (b) D’Souza, D. M.; Rominger, F.;
Mu¨ller, T. J. J. Angew. Chem., Int. Ed. 2005, 44, 153–158. (c) D’Souza,
D. M.; Rominger, F.; Mu¨ller, T. J. J. Chem. Commun. 2006, 4096–4098.
(d) D’Souza, D. M.; Liao, W.-W.; Rominger, F.; Mu¨ller, T. J. J. Org.
Biomol. Chem. 2008, 6, 532–539.
The UV-vis spectra of the pure compounds 3 show two
intense major absorption maxima around 380 and 280 nm
(Table 2). Moreover the free bases 3 fluoresce neither in
solution nor in the solid state. However, upon protonation
of the 2,4-diarylpyrano[2,3-b]indoles 3 with trifluoroacetic
acid a significant bathochromic and hyperchromic shift of
the longest wavelength absorption maxima between 403 and
465 nm with large molar extinction coefficients appears in
(13) (a) D’Souza, D. M.; Muschelknautz, C.; Rominger, F.; Mu¨ller,
T. J. J. Org. Lett. 2010, 12, 3364–3367. (b) Willy, B.; Mu¨ller, T. J. J. Eur.
J. Org. Chem. 2008, 4157–4168. (c) Willy, B.; Dallos, T.; Rominger, F.;
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Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297–3300.
(17) Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC 785242 (3a).
Copies of the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, U.K. (Fax: +44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk).
(14) Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1985, 2505–2508.
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Org. Lett., Vol. 12, No. 18, 2010
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Table 1. Domino Reaction Consisting of Insertion, Coupling, and Cycloisomerization Steps Yielding 2,4-Diarylpyrano[2,3-b]indoles 3
entry
o-iodo alkynylanilide 1
alkyne 2
R2 ) Ph (2a)
2,4-diarylpyrano[2,3-b]indole 3a
1
2
3
4
5
6
7
8
9
R1 ) Ph (1a)
1a
3a (35%)
3b (15%)
3c (54%)
3d (32%)
3e (41%)
3f (24%)
3g (24%)
3h (14%)
3i (25%)
3j (17%)
R2 ) p-NCC6H4 (2b)
R2 ) p-MeOC6H4 (2c)
R2 ) p-ClC6H4 (2d)
2c
1a
1a
R1 ) p-ClC6H4 (1b)
R1 ) p-ClC6H4 (1b)
2a
2d
R1 ) p-ClC6H4 (1b)
1a
1a
1a
R2 ) p-tBu-C6H4 (2e)
R2 ) p-Me-C6H4 (2f)
R2 ) p-CO2Me-C6H4 (2g)
10
a Reaction conditions: 1.00 equiv of alkynoyl o-iodo anilides 6 (0.1 M in THF/NEt3 1:1), 1.10 equiv of terminal alkynes 2, 0.05 equiv of PdCl2(PPh3)2,
0.05 equiv of CuI; after stirring for 20 h at room temp heating to 85 °C temp for 48 h in a sealed tube.
fluorescence quantum yields Φf, determined with coumarin
153 as a standard.18
The Stokes shifts ∆ν˜ (λmax,abs - λmax,em) are dependent on
the electronic nature of the 2-aryl substituents and range from
2300 cm-1 for electron-rich anisyl substituents to 5000 cm-1
for electron-deficient and electro-neutral moieties. The
electron-deficient p-cyano substituent (compound 3b-H+)
causes a hypsochromic shift in comparison to the electro
neutral phenyl derivative 3a-H+, whereas the electron-rich
anisyl moiety (compound 3c-H+) leads to a considerable red
shift. As indicated by the emission data, the electronic
structure in the vibrationally relaxed excited state of 3-H+
is essentially unaffected by substitution. A stronger push-pull
character as in the cases of 3c-H+ and 3e-H+also results in
smaller Stokes shifts. Since trifluoroacetic acid is completely
dissociated in dichloromethane19 a pKa value of 4.53 of the
protonated species 3d-H+ was determined in a titration
experiment. This pKa value is comparable to that of a
pyridinium ion,20 and thus, protonation of the pyranoindoles
3 on the indole nitrogen atom can be assumed.
Figure 1. ORTEP plot of the crystal structure of the 2,4-diphenyl-
pyrano[2,3-b]indole (3a).
the UV-vis spectra and a distinct second absorption band
around 355 nm is detected.
Most interestingly, the protonated 2,4-diarylpyrano[2,3-
b]indoles 3-H+ display an intense green luminescence with
a narrow, unstructured longest wavelength maximum around
520 nm (Figure 2). This protochromicity is most pronounced
for the donor-substituted diphenyl-pyrano[2,3-b]indoles 3c-
H+ and 3e-H+, also with respect to the efficacy of the
fluorescence as represented by the considerable higher
In addition, the efficacy of the emission (vide supra)
strongly depends on the electronic nature of the substituent
in position 2. In contrast, caused by conformational torsion
out of coplanarity with the pyranoindole, only a minor
Table 2. Photophysical Data of the 2,4-Diarylpyrano[2,3-b]indoles 3a-e Recorded in Dichloromethane at 298 K
λmax,abs
λmax,abs
λmax,em
[nm] (Φf)a protonated
compound
[nm] (ε) [L cm-1 mol-1] unprotonated
[nm] (ε) [L cm-1 mol-1] protonated
Stokes shift ∆ν˜b
3a
3b
3c
3d
3e
3f
3g
3h
3i
383 (17400)
383 (19300)
393 (17200)
384 (26700)
397 (25200)
384 (26700)
386 (20500)
385 (22300)
386 (19700)
389 (18700)
415 (19600)
403 (19300)
462 (26400)
417 (28900)
465 (39100)
417 (28900)
421 (23400)
428 (30600)
430 (25900)
413 (18200)
522 (0.1%)
513 (0.1%)
519 (15.0%)
523 (0.1%)
522 (11.2%)
523 (0.1%)
523 (0.1%)
511 (0.1%)
511 (0.1%)
519 (0.1%)
5000
5400
2300
4800
2300
4800
4600
3800
3700
4900
3j
a Determined against coumarin 153 as a standard (Φf ) 38%); b Stokes shift only for protonated pyranoindoles.
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Org. Lett., Vol. 12, No. 18, 2010

in good yields. The quaternized derivatives 7 display almost
superimposable absorption and emission spectra with the
analogous protonated pyranoindoles 3c-H+ and 3e-H+ (see
Supporting Information), and the fluorescence quantum yields
of 7a and 7b appear with Φf ) 10% just in the same range.
The peculiar halochromic luminescence behavior of pyra-
noindoles 3 with donor substituents in position 2 prompted
us to check if this turning on of fluorescence could also be
effective for sensing cations. Therefore, solutions of pyra-
noindole 3c were exposed to biologically relevant metal ions
in the form of their salts, such as zinc triflate, calcium triflate,
or magnesium triflate. Upon eyesight (Figure 3) but also
Figure 2. UV-vis and emission spectra of 3c and 3c-H+ recorded
in CH2Cl2 at 298 K. Absorption spectra of 3c (solid line) and 3c-
H+ (after protonation with TFA, dashed line); emission spectrum
of 3c-H+ (dotted line).
substituent effect can be expected at position 4. This
prediction is supported by the comparison of compounds 3c
and 3e, where the electron-withdrawing p-chlorophenyl
substituent causes only a slight bathochromic shift of the
absorption and emission bands. Finally, the influence of
substituents on the absorption maxima of the neutral and the
protonated pyrano[2,3-b]indoles can easily rationalized by
ZINDO-CI calculations. The experimental spectra are re-
produced in good agreement and the calculated maxima only
deviate in a range of a few nanometers (see also Supporting
Information).
Encouraged by the observation of the protonation induced
emission enhancement of the pyranoindoles, we decided to
prepare the corresponding quaternized derivatives 7 by
reacting the pyranoindoles 3c and 3e in dichloromethane with
an equimolar amount of trimethyloxonium tetrafluoroborate
(Scheme 2). After stirring at room temperature for 4 days,
Figure 3. From left to right: compound 3c dissolved in CH2Cl2;
compound 3c after the addition of trifluoroacetic acid; compound
7a, compound 3c after the addition of Ca+II triflate; compound 3c
after the addition of Zn+II triflate; compound 3c after the addition
of Mg+II triflate; (irradiation at λexc ) 354 nm).
confirmed by fluorescence spectroscopy, intense green
fluorescence can be observed with pronounced selectivity
for the biologically relevant cations zinc and magnesium over
calcium. As shown before in the protonation experiments
the absorption maximum was shifted bathochromically with
concomitant switching on green light emission.
In conclusion we have developed a domino synthesis of
hitherto unknown 2,4-diarylpyrano[2,3-b]indoles, a class of
compounds with unique photophysical properties. Displaying
no fluorescence as a free base halochromic green fluorescence
can be switched on upon protonation, methylation, or
complexation with various metal cations, also displaying
considerable fluorescence sensitivity. Since the 2,4-dia-
rylpyrano[2,3-b]indoles are also readily soluble in an aqueous
solution containing 1% of 2-propanol, more detailed studies
of the complexation behavior of metal salts various solvents
and solvent systems such as cell buffers are currently
underway.
Scheme 2. Quaternation of Pyranoindoles 3c and 3e by
Methylation with Trimethyloxonium Tetrafluoroborate
Acknowledgment. Dedicated to Prof. Dr. Günter Helmchen
on the occasion of his 70th birthday. This work was supported
by the Fonds der Chemischen Industrie.
precipitation, and washing with diethyl ether, the N-methyl
pyranoindolium tetrafluoroborates 7a and 7b were obtained
Supporting Information Available: Experimental details,
NMR and selected absorption and emission spectra of
compounds 3 and 7, computational data and X-ray data of
compound 3a including CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Chem.sEur. J. 2009, 15, 13075–13081.
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