An efficient one-pot synthesis of strongly fluorescent (hetero)arenes polysubstituted with amino and cyano groups

Article abstract of DOI:10.1016/j.tet.2008.07.084

An efficient one-pot synthesis simultaneously results in three types of densely substituted mono-, di- and tetracyclic π-systems, which can easily be isolated. Each chromophore presents a strong fluorescence emission, either in the red, green or blue part of the spectrum.

Full text of DOI:10.1016/j.tet.2008.07.084

Tetrahedron 64 (2008) 9437–9441
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient one-pot synthesis of strongly fluorescent (hetero)arenes
polysubstituted with amino and cyano groups
,
a
b
c
Chenyi Yi a, Carmen Blum a, Shi-Xia Liu a , Gabriela Frei , Antonia Neels , Helen Stoeckli-Evans ,
*
Samuel Leutwyler a, Silvio Decurtins a
a
¨
Departement fu¨r Chemie und Biochemie, Universitat Bern, Freiestrasse 3, CH-3012 Bern, Switzerland
XRD Application LAB, CSEM Centre Suisse d’Electronique et de Microtechnique SA, Jaquet-Droz 1, Case Postale, CH-2002 Neuchatel, Switzerland
Laboratory of Physical Chemistry of Surfaces and Crystallography, Institute of Physics, University of Neuchatel, Rue Emile-Argand 11, CP 158, CH-2009 Neuchatel, Switzerland
b
c
ˆ
ˆ
ˆ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2008
Received in revised form 16 July 2008
Accepted 18 July 2008
Available online 24 July 2008
An efficient one-pot synthesis simultaneously results in three types of densely substituted mono-,
di- and tetracyclic
rescence emission, either in the red, green or blue part of the spectrum.
Ó 2008 Elsevier Ltd. All rights reserved.
p-systems, which can easily be isolated. Each chromophore presents a strong fluo-
Keywords:
Cyclization
Fluorescence
(Hetero)arenes
Photophysics
Solid-state structures
1. Introduction
a sequence without isolation offers an additional advantage to
achieve brevity and efficiency of the synthetic pathway. It is be-
cause of the rate at which molecular intricacy is increased, that
domino/cascade reactions have received considerable attention
from the synthetic organic community.5 It is equally clear that for
multisubstituted compounds, the control of both regio- and che-
moselectivity also arises as a crucial factor, which even becomes
more difficult in compounds containing a number of similar func-
tional groups.
To underscore the above issues, we have been exploring
a strategy for the construction of densely substituted aromatic and
heteroaromatic molecules with specific domino/cascade reactions
while combining several steps of bond-forming sequences into
a one-pot operation. Thereby, derivatives of penta-1,4-diyn-3-one
were reacted under mild conditions with malononitrile in the
presence of triethylamine (Scheme 1). Remarkably, this one-pot
The creation and stereospecific functionalization of
p-systems
represent an important and fundamental challenge in organic
chemistry.1 From this perspective, Burke and Schreiber recently
reviewed the diversity-oriented synthesis (DOS) concept, which
aims for the efficient preparation of small molecules having
skeletal and stereochemical diversity and complexity of high
levels.2–4 The subject requires one to identify complexity-gener-
ating reactions that rapidly assemble different and also intricate
molecular skeletons while sharing some common inherent
chemical reactivity. As a case in point, Schreiber et al. used this
approach for the transformation of the specific Fallis-type3 triene
substrate into a collection of products with different molecular
skeletons, all based on the action of different reagents.4 Such
reagent-based transformations are referred to as differentiating
processes.
strategy yields, at the same time, three aromatic (6þ10
p-, 10
Alternatively, a diversity of molecular skeletons can be accessed
starting with only one set of substrate, diversity generating actions
then take place in parallel processes during the reaction sequence.
Furthermore, a combination of such multiple reaction steps into
p
- and 6 -electrons), densely substituted (poly)cyclic substances
p
based on either a novel tetracyclic skeleton (1) or a naphthalene (2)
or a benzene (3) core. Interestingly, in 1, the two heterocycles,
pyrimidine and pyrrole, are fused to each other and then to the
isoindole unit and therefore, one needs to identify the new
molecular-skeleton parent as pyrrolizine.6 We report the first rep-
resentative of this new class of heteroacene, benzo[a]pyr-
imido[2,1,6-cd]pyrrolizine.
* Corresponding author. Tel.: þ41 31 6314296; fax: þ41 31 6313995.
E-mail address: liu@iac.unibe.ch (S.-X. Liu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.084

9438
C. Yi et al. / Tetrahedron 64 (2008) 9437–9441
Scheme 1. The one-pot and parallel synthetic routes to chromophores 1–3.
2. Results and discussion
Scheme 2. Most plausible mechanisms for the formation of 1–2.
Recently, we probed the base-catalyzed reactivity of malono-
nitrile with a series of penta-1,4-diyn-3-one derivatives and iso-
lated a range of 2,6-dicyanoanilines (3 and analogues).7 Although
diversifications at positions C3, C4 and C5 of the dicyanoaniline
core have produced a large number of compound libraries,8 up to
now there have no examples been reported with the acetylenic
functionality. In fact, an alkynyl residue is difficult to handle during
multicomponent coupling methods since it opens many pathways
for side reactions. Importantly, a type-3 compound offers a useful
functionality for Sonogashira coupling reactions and conjugate
time, but gives comparable yields (Table 1). However, the micro-
wave irradiation in CH2Cl2 improved the yield of 1 substantially. It
is worth mentioning that the reaction of malononitrile with a ke-
tone in the presence of Al2O3 or b-alanine as catalyst only afforded
the corresponding dicyanodiethynylethene.11 Obviously, Et3N plays
a key role in the formation of 1–3.
Crystallizations of products 1–3 from CH2Cl2/CHCl3, CH3OH
and CH2Cl2, respectively, gave crystals in the form of different
solvates suitable for X-ray analysis. Both compounds 1 and 3
crystallize in the triclinic crystal system, space group P-1, and 2 in
the monoclinic crystal system, space group P21/c (Fig. 1). The
structural data of 3 have recently been reported.7 In accordance
with their aromaticity, all molecules have planar geometries;
largest deviations from the least-squares planes [all atoms ex-
cluding the Si(Me)3] are 0.055(5) Å for atom N3 for 1, and
0.047(2) Å for atom C1 for 2. The bond lengths of the skeleton of
2 agree well with the reported data for naphthalene.12 The tet-
racyclic core of 1 may structurally best be compared with the
indolizino[3,4,5-ab]isoindole skeleton.13 In an analogous manner,
one can divide the skeleton of 1 into two aromatic fragments,
a benzene and a pyrrolopyrimidine, and this is reflected by the
connecting bond distances, C4–C5 and C11–C12, which accord-
ingly are relatively long: 1.439 Å and 1.477 Å.
The UV–vis spectra of the chromophores 1–3 recorded in CH2Cl2
show strong absorption bands in the UV, but also strikingly intense
absorption bands in the visible region, lying in the yellow, blue and
near-UV, respectively (Fig. 2). Upon photoexcitation, compounds 1–3
show strong red, green and blue fluorescence with quantum yields
of 72%, 52% and 25%, respectively. These high quantum yields
compare well with those of the above-mentioned isoindole
additions. First attempts along this line resulted in a novel
p-con-
jugated anion, (E)-3-(3-amino-2,4-dicyanophenyl)-1,1-dicyanoprop-
2-en-1-ide.9 It was on this basis that we have undertaken a detailed
investigation on the reaction of 1,5-bis(trimethylsilyl)penta-1,4-
diyn-3-one with malononitrile in the presence of Et3N as catalyst. It
turned out that three different compounds (1–3) form via a one-pot
reaction. Notably, compound 2 reveals a dense substitution pattern
where electronic donor (NH2) and acceptor (C^N) groups are
mixed, a result, which could hardly be achieved otherwise, e.g.,
through substitution reactions on a naphthalene core.10 The same
clearly holds for 1 as well.
As we discussed in our previous paper,7 the formation of 3 starts
either with a Knoevenagel condensation of a penta-1,4-diyn-3-one
with malononitrile and/or with its conjugate addition followed by
a conjugate addition with a second equivalent of malononitrile
leading to the tautomeric intermediates. A further conjugate ad-
dition of malononitrile and consecutive Thorpe–Ziegler cyclizations
together with an elimination of 1,1,1-tricyanomethyl affords 3.
However and most importantly, one acetylenic group stays intact
during the reaction process for 3. Now, it is reasonable that the
acetylenic group from the tautomeric intermediates can alterna-
tively undergo a further cycloaddition with malononitrile to afford
2, while a participation of the carbonitrile in ortho-position to the
acetylenic substituent leads to the formation of 1 (Scheme 2). Their
yields can be individually optimized between 15% and 70%
depending on the reaction conditions. Increasing the molar ratio of
malononitrile and 1,5-bis(trimethylsilyl)penta-1,4-diyn-3-one
from 4:1 to 10:1 has no substantial effect on the outcome of the
reaction. A comparison of heating and microwave irradiation in-
dicates that the latter in toluene apparently shortens the reaction
Table 1
A comparison of heating and microwave irradiation applied for the reactiona
1
2
3
Microwave (120 ꢀC, 10 min)
Heat (120 ꢀC, 2 h)
13.2 mg (6%)
14.2 mg (7%)
22.1 mg (14%)
23.8 mg (16%)
87.0 mg (56%)
104.3 mg (67%)
a
1,5-Bis(trimethylsilyl)pent-1,4-diyn-3-one/malononitrile/triethylami-
ne¼0.5 mmol/2.0 mmol/0.5 mmol in 3 ml toluene.

C. Yi et al. / Tetrahedron 64 (2008) 9437–9441
9439
To understand the ground and excited state electronic proper-
ties of chromophores 1–3, density functional theory (DFT) as well
as time-dependent DFT (TD-DFT) calculations was performed with
the B3LYP functional and the TZVP basis set with TURBOMOLE
V5.9.14 In each case, the minimum-energy geometry is calculated to
have Cs symmetry. The central aromatic framework is planar in
both S0 ground and S1 excited states. The former is in line with the
corresponding crystal structures.
For 1, the vertical TD-DFT calculations predict the electronic
S0/S1 excitation to be an intense pp
transition at 19,900 cmꢁ1
*
(503 nm) with an oscillator strength fcalcd¼0.23, as shown with the
stick spectrum in Figure 2. Both the transition energy and intensity
are in fair but still acceptable agreement with the longest-wave-
length absorption, for which the 16,530–19,230 cmꢁ1 energy-in-
tegrated absorption yields an oscillator strength fexp¼0.04.
According to the TD-DFT calculation, the S0/S1 electronic excita-
tion is dominated by the HOMO/LUMO contribution (95%), which
corresponds to redistribution of
p-electron density over the main
part of the molecular skeleton (Fig. 3).
For 2, the vertical TD-DFT calculations predict the electronic
S0/S1 excitation to be a pp
transition at 23,700 cmꢁ1 (422 nm)
*
with fcalcd¼0.06. Both the transition energy and intensity are in
very good agreement with the longest-wavelength absorption,
for which the 20,000–26,700 cmꢁ1 energy-integrated absorption
yields an oscillator strength fexp¼0.04. The S0/S1 excitation is
dominated (97%) by the HOMO/LUMO contribution. As Figure 4
shows, the
p-electron charge transfer occurs mainly from the
two amino groups towards the naphthalene core and the cyano
group C15–N3 (Fig. 1). This transition is qualitatively similar to
that of the S0/S1 excitation recently reported for 3.7 There, the
intense (fexp¼0.16, fcalcd¼0.21) pp
*
excitation, calculated at
charge
28,400 cmꢁ1 (352 nm), also has strong intramolecular
p
transfer character from the amino group to the proximal cyano
groups.
Figure 1. X-ray crystal structures of 1 (top) and 2 (bottom) (ORTEP, thermal ellipsoids
set at the 50% probability level). Hydrogen atoms and solvents are omitted for clarity.
derivatives.13 The emission maxima lie at 17,300 cmꢁ1 (578 nm),
20,500 cmꢁ1 (488 nm) and 24,700 cmꢁ1 (405 nm). The fluores-
cence excitation spectra, measured at 630, 550 and 430 nm emis-
sion wavelengths, agree well with the corresponding absorption
profiles. The blue shifts in both the absorption and emission bands
on going from 1 to 3 are not unexpected on the basis of the de-
creased size of the p-conjugated frameworks.
Figure 2. Electronic absorption (solid line) and fluorescence emission (dashed line)
spectra of 1–3 in deaerated dichloromethane solution at room temperature, together
with the calculated oscillator strengths. The arrows indicate the S0/S1 transition
dipole moment orientations.
Figure 3. The HOMO and LUMO of 1 that are involved in the lowest-energy pp
transition.
*

9440
C. Yi et al. / Tetrahedron 64 (2008) 9437–9441
180 frames with
4
¼0ꢀ and 0ꢀ<
u
<180ꢀ and 80 frames with
4
¼90ꢀ
and 0<
u
<80ꢀ, with the crystal oscillating through 1ꢀ in
u. The
resolution was DminꢁDmax 0.72–17.78 Å. The structures were solved
by direct methods using the program SHELXS-9716 and refined by
full matrix least squares on F2 with SHELXL-97.17 The hydrogen
atoms were included in calculated positions and treated as riding
atoms using SHELXL-97 default parameters, except for the OH hy-
drogen atoms in 2, which were found and refined. All non-hydro-
gen atoms were refined anisotropically. No absorption correction
was applied. Crystal data have been deposited at the Cambridge
Crystallographic Data Centre, CCDC-679352 (1), CCDC-679353 (2)
and CCDC-656928 (3). Copy of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.3. Materials
All reagents were purchased from commercial sources and used
without additional purification. 1,5-Bis(trimethylsilyl)penta-1,4-
diyn-3-one was prepared according to literature procedure.18
4.3.1. A conventional heating procedure
A
mixture of 1,5-bis(trimethylsilyl)penta-1,4-diyn-3-one
(110 mg, 0.5 mmol), malononitrile (100 mg, 1.5 mmol) and tri-
ethylamine (50 mg, 0.5 mmol) in toluene (2.0 ml) was refluxed with
stirring at 120 ꢀC for 2 h. The solvent was removed under reduced
pressure. Purification of the brownish oily residue by column
chromatography on silica gel, eluting subsequently with CH2Cl2,
CH2Cl2/diethyl ether (100:1 and then 100:2), gave compounds 1–3,
respectively.
Figure 4. The HOMO and LUMO of 2 that are involved in the lowest-energy pp
transition.
*
3. Conclusion
2,9-Diamino-5,7-bis(trimethylsilyl)benzo[a]pyrimido[2,1,6-cd]-
pyrrolizine-3,4,8-tricarbonitrile (1). As a red solid. Yield 13 mg
In summary, we have shown the base-catalyzed reactivity of
malononitrile with 1,5-bis(trimethylsilyl)penta-1,4-diyn-3-one,
leading to the formation of three densely substituted fluorescent
(hetero)arenes via a one-pot reaction. This novel sequence of cy-
cloadditions offers a new route to functionalized (hetero)arenes
that would be difficult to produce conventionally, especially that
corresponding to the tetracyclic core of 1. Further studies on the
generality and application of this type of reaction to produce
polycyclic substances with different functional groups are in
progress.
(6%). 286 ꢀC (dec). 1H NMR (CD2Cl2)
d: 7.53 (s, 1H), 6.04 (s, 2H), 5.86
(s, 2H), 0.60 (s, 9H), 0.48 (s, 9H). Selected IR data (KBr, cmꢁ1): 3436,
2924, 2854, 2203, 1632, 1460, 1242, 844. MS (ESI-TOF): [M]þ calcd
411.1553; found 411.1561.
2,5-Diamino-7-(trimethylsilyl)naphthalene-1,3,6-tricarbonitrile
(2). As a pale yellow solid. Yield 20 mg (13%). 212 ꢀC (dec). 1H NMR
(CD3OD) d d:
: 8.69 (s, 1H), 7.22 (s, 1H), 0.43 (s, 9H). 13C NMR (CD3OD)
153.00, 152.35, 147.87, 139.16, 136.49, 119.91, 118.27, 116.48, 116.21,
114.54, 99.52, 91.18, 89.53, ꢁ1.65. Selected IR data (KBr, cmꢁ1): 3435,
2923, 2852, 2206, 1631, 1453, 1121, 844. MS (ESI-TOF): [MþH]þ calcd
306.1175; found 306.1186.
4. Experimental
4.1. Equipment
2-Amino-4-(trimethylsilylethynyl)-6-(trimethylsilyl)benzene-1,3-
dicarbonitrile (3).7 As a white solid. Yield 110.5 mg (70%). Mp 122–
124 ꢀC. 1H NMR (CDCl3)
(s, 9H). 13C NMR (CDCl3)
d
: 6.97 (s, 1H), 5.15 (s, 2H), 0.41 (s, 9H), 0.30
: 152.93, 152.90, 131.81, 128.13, 118.34,
1H and 13C NMR spectra were obtained on a Bruker AC 300
spectrometer operating at 300.18 and 75.5 MHz, respectively:
chemical shifts are reported in parts per million relative toTMS. The
following abbreviations were used: s (singlet), d (doublet), t (trip-
let) and m (multiplet). Melting points were determined using
a Bu¨chi 510 instrument and are uncorrected. ESI-MS was carried
out with an FTMS 4.7 TBioAPEX II TOF apparatus. Photophysical
measurements were performed on solutions of 1–3 in CH2Cl2 at
room temperature. UV–vis absorption and emission spectra were
recorded on a Perkin–Elmer Lambda 900 spectrometer and a Per-
kin–Elmer Luminescence spectrometer LS 50B.
d
116.43, 107.34, 102.31, 102.20, 102.08, 1.22, 0.002. Selected IR data
(KBr, cmꢁ1): 3479, 3362, 2959, 2924, 2218, 2160, 1735, 1637, 1538,
1403, 1253, 1062, 946, 845, 759, 671. MS (ESI-TOF): [MþNa]þ calcd
334.1172; found 334.1171.
4.3.2. A microwave assisted synthesis
In the presence of triethylamine (50 mg, 0.5 mmol), a mixture of
1,5-bis(trimethylsilyl)pent-1,4-diyn-3-one (110 mg, 0.5 mmol) and
malononitrile (120 mg, 1.8 mmol) in 2 ml of CH2Cl2 was treated
under microwave irradiation (110 ꢀC, 10 min). Following the same
work-up procedure as stated above, pure compounds 1–3 were
obtained in yields of 15% (30 mg), 10% (16 mg) and 52% (82 mg),
respectively.
4.2. Crystallography
A red plate-like crystal of 1 and an orange rod-like crystal of
compound 2 were mounted on a Stoe Mark II-Imaging Plate Dif-
fractometer System15 equipped with a graphite monochromator. In
Acknowledgements
each case, data collection was performed at ꢁ100 ꢀC using Mo K
a
radiation (
l
¼0.71073 Å). Two hundred and forty exposures (3 min
This work was supported by the Swiss National Science Foun-
dation (Grant No. 200020-116003).
per exposure) were obtained at an image plate distance of 135 mm,

C. Yi et al. / Tetrahedron 64 (2008) 9437–9441
9441
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