Sc(OTf)3 promoted multicomponent synthesis of fluorescent imidazo[1,2-c]pyrazolo[3,4-d]pyrimidine

Article abstract of DOI:10.1016/j.tetlet.2013.06.136

A three-component condensation reaction between aminopyrazolo[3,4-d] pyrimidine, an aldehyde, and an isocyanide catalyzed by scandium triflate yields a series of heterocyclic derivatives of imidazo[1,2-c]pyrazolo[3,4-d]pyrimidine in good yields, exhibiting interesting fluorescent properties.

Full text of DOI:10.1016/j.tetlet.2013.06.136

Accepted Manuscript
Sc(OTf)3 promoted multicomponent synthesis of fluorescent imidazo[1,2-
c]pyrazolo[3,4-d]pyridimidine
Asma Agrebi, Fatma Allouche, Fakher Chabchoub, Laurent El-Kaim, Sérgio
Alves, Carlos Baleizão, José Paulo Farinha
PII:
S0040-4039(13)01121-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.136
TETL 43189
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 May 2013
24 June 2013
26 June 2013
Please cite this article as: Agrebi, A., Allouche, F., Chabchoub, F., El-Kaim, L., Alves, S., Baleizão, C., Farinha,
J.P., Sc(OTf)3 promoted multicomponent synthesis of fluorescent imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.136
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Asma Agrebi, Fatma Allouche, Fakher Chabchoub, Laurent El-Kaim, Sérgio Alves, Carlos Baleizão, José Paulo
Farinha
Ph
N
N
N
H
N
R3
N
R1
N
R2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Sc(OTf)3 promoted multicomponent synthesis of fluorescent
imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine
Asma Agrebia , Fatma Allouchea∗, Fakher Chabchouba , Laurent El-Kaimb , Sérgio Alvesc , Carlos
Baleizãoc and José Paulo Farinhac∗
aLaboratoire de Chimie Appliquée: Hétérocycles, Corps Gras et Polymères, Faculté des Sciences, University of Sfax, 3018 Sfax, Tunisie.
bLaboratoire Chimie et Procédés, DCSO, UMR 7652, École Nationale Supérieure de Techniques Avancées, 828 Bd des Maréchaux, 91120 Palaiseau, France.
cCQFM - Centro de Química-Física Molecular and IN - Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico, 1049-001 Lisboa, Portugal
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A three-component condensation reaction between aminopyrazolo[3,4-d]pyrimidine, an
aldehyde and an isocyanide catalyzed by scandium triflate yields a series of heterocyclic
derivatives of imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine in good yields, exhibiting interesting
fluorescent properties.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions (MCRs)
Scandium triflate
Pyrazolopyrimidine
Imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine
Fluorescent probes
———
∗Corresponding author. José Paulo Farinha Tel.: +0-351-218419221; fax: +0-351-218464455; e-mail: farinha@ist.utl.pt
∗Corresponding author. Fatma Allouche Tel.: +0-216-26299719; fax: +0-216-74253596; e-mail: fatmaallouch@yahoo.fr

2
Tetrahedron
1. Introduction
Table 1. Synthesis of imidazo[1,2-c]pyrazolo-
[3,4-d]pyridimidine derivatives 4
Multicomponent reactions (MCRs) offer a convenient strategy
Yield %
to easily obtain complex molecules with interesting properties.1
MCRs offer the elegance of one-pot reactions, atom and bond-
forming economy, and the feasibility of introducing maximum
diversity elements in one chemical event operation,2 allowing the
construction of architecturally complex molecules having a wide
range of biological and pharmaceutical activities.3
R1
R2
R3
two-step
one-pot
method
method
62
63
60
55
56
57
--
4a
4b
4c
4d
4e
4f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
4-Cl
4-Cl
tert-butyl
cyclohexyl
tert-butyl
--
78
73
61
--
4-OMe
4-OMe
2,5-di-Cl
3-NO2
3-NO2
4-Cl
The reaction involving an isocyanide, an aldehyde and a
2-aminoazine was reported simultaneously by Groebke et al,4
Bienayme et al,5 and Blackburn et al.6 The pre-formation of the
imine was not necessary, but the reaction requires the use of
either a Brönsted acid (AcOH,4 HClO4 5) or a Lewis acid
(Sc(OTf)3).6 This one-step coupling constitutes a very efficient
route for imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives.
The presence of multi-functional groups increases the range of
possible applications. On one hand, imidazopyrimidines are
important structural moieties, found in pharmacological
compounds such as anti-inflammatory agents,7 anti-bacterials,8
anticancer,9 antimicrobial agents10 and also used for their
antituberculosis activity.11 These compounds also provide a route
to synthesize condensed nucleobases, such as adenine, guanine
and cytosine,12 and can also be used as Adenosine Receptor
Antagonists due to their similarity to purine derivatives.13 On the
other hand, pyrazolopyrimidines have been shown to inhibit
glycogen synthase kinase-3 (GSK-3),14 and act as potent ligands
for the peripheral benzodiazepine receptor.15
cyclohexyl
cyclohexyl
cyclohexyl
tert-butyl
72
72
73
74
64
4g
4h
4i
cyclohexyl
cyclohexyl
cyclohexyl
--
H
4-OMe
4-NO2
--
4j
H
--
The two-steps strategy produces target compounds 4 in good
yields (55% to 63%). However this method requires long reaction
times and the purification of the imine is not straightforward. As
part of our ongoing efforts on the development of new synthetic
protocols for the synthesis of biologically active heterocyclic
compounds through MCRs, we have used scandium triflate
(Sc(OTf)3)
as
catalyst
for
the
synthesis
of
imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives 4. A three
component condensation of benzaldehydes, pyrazolopyrimidines,
and isocyanides is reported for the synthesis of
imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine
(Scheme 2), and catalyzed efficiently by Sc(OTf)3, an
environmental friendly catalyst.
Development of an MCR-based approach to new fluorescent
substituted imidazo[1,2-c]pyrazolo[3,4-d]pyridimidines capable
of further transformations was the goal of our present work. In
particular, we were interested in the synthesis of
imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives catalyzed
by Sc(OTf)3, which are easily accessible thanks to the
development of microwave assisted synthetic methodologies.
derivatives
4
2. Results and discussion
2.1. Synthesis
The imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives
were prepared using either a multi-component coupling reaction
between an aldehyde 2, an isocyanide 3 and an amino
pyrazolo[3,4-d]pyrimidine16 1, or using a two-steps synthesis via
the formation of an imine. When optimizing the reaction
conditions we have faced problems in both methods. In the two-
step method, different catalysts and temperatures were tested, but
the pre-formation of the imine needs higher temperature and the
best results were obtained using Sc(OTf)3 as catalyst and
microwave. The one-step method was also tested using different
catalysts, with the best results again obtained using Sc(OTf)3.17
Scheme 1 shows the synthetic strategy to obtain the target
compounds by the two-steps method (Table 1).
Scheme 2. One-step three component condensation of
benzaldehydes, pyrazolopyrimidines, and isocyanides catalyzed by
Sc(OTf)3.
As starting materials we used 4-aminopyrazolo-
[3,4-d]pyrimidine derivatives 1, which were subjected to
condensation with substituted benzaldehydes 2, in the presence
of isocyanides 3 in presence of catalytic amount of Sc(OTf)3
(5 mol%). The mixture was heated over night at 150°C in DMF,
and after chromatographic purification
4 derivatives were
obtained. Two isocyanides were tested successfully in this
coupling, namely cyclohexyl isocyanide and tert-butyl
isocyanide. Different benzaldehydes have been tested, with
4-chlorobenzaldehyde proving to be the most efficient in both
methods. In Table
1 we show the different imidazo-
[1,2-c]pyrazolo[3,4-d]pyridimidine 4 derivatives obtained by the
one-pot condensation reaction. For example, in the synthesis of
4f using 4-aminopyrazolo[3,4-d]pyrimidine, 4-nitrobenzaldehyde
and cyclohexylisocyanide, the yields for the two-steps and one-
pot methods were 57% and 72%, respectively. Likewise, the
yields of imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives
Scheme 1. Synthetic strategy used in the two-steps method

3
4b, 4c and 4d synthesized by the one-pot procedure are always
4b
4c
4d
4f
1.5
2.0
1.5
1.1
89%
12%
88%
47%
4.6
5.7
5.2
1.9
11%
88%
12%
53%
1.8
5.3
1.9
1.5
4-Cl
cyclohexyl
higher than those obtained in two-steps.
4-OMe
tert-butyl
2.2. Fluorescence
4-OMe cyclohexyl
3-NO2 cyclohexyl
The absorption and fluorescence properties of derivatives 4a,
4b, 4c, 4d and 4f were studied in chloroform solution at 10 ꢀM.
We observed that these compounds feature similar molar
absorptivities (in the range of ca. 4 ×104 to 6 ×104 M-1cm-1) but
very different fluorescence intensities (Figure 1). The
fluorescence intensity of 4f, featuring a 3-NO2 substituent in the
R2 position, is the lowest, although this derivative presents a
slightly higher absorption efficiency. On the other hand, the
highest fluorescence intensity is observed for 4d, which contains
a
Conclusions
In summary, we have devised a simple, efficient and
environmentally friendly protocol for the one-pot synthesis of
imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives catalyzed
by Sc(OTf)3 under mild reaction conditions. Moreover, the
present protocol possesses several unique merits such as
simplicity, non-aqueous work-up and most importantly, high
yield of the products. We obtained a new family of fluorescent
imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives that offer
good prospects for fluorescence-based clinical and biomedical
applications.
4-OMe substituent at the R2 position. Interestingly, maintaining
the same substituent in the R2 position but changing the
cyclohexyl substituent in the R3 position (4d) to a tert-butyl
substituent (4c), the fluorescence intensity decreases markedly,
probably because the bulky tert-butyl R3 group of 4c forces the
4
1
x
6 10
4f
4c
4d
Experimental
4a
4d
General procedure for the synthesis of imidazo-
[1,2-c]pyrazolo[3,4-d]pyridimidine (4) using the two-steps
method
4b
ε
4
0.5
x
3 10
4a
4b
Benzaldehyde derivative 2 (1 mmol) and scandium triflate (5
mol%) were added to
a solution of 4-aminopyrazolo-
[3,4-d]pyrimidine derivative 116 (1 mmol) in toluene (1 mL) at
room temperature. The mixture was heated with microwave
radiation (200 W) for 30 min at 150°C. Then toluene was
evaporated and isocyanide derivative 3 (1 mmol) and acetonitrile
(1 mL) were added. The solution was heated at 70°C overnight,
and afterwards the solvent was removed and the residue purified
by flash chromatography on silica gel (petroleum ether/CH2Cl2
2:8).
4c
4f
0
0
300
400
500
600
Wavelength [nm]
phenyl ring containing R2 to twist.
Figure 1. Absorption (thin lines) and emission (thick lines) spectra
of imidazo[1,2-c]pyrazolo[3,4-d]pyridimidine derivatives 4a (dark
blue), 4b (red), 4c (green), 4d (orange) and 4f (light blue) in
chloroform solution (10 ꢀM).
Compound 4a was obtained (62%) as a pale yellow solid, mp
249 °C. H NMR (CDCl3, 400 MHz) ꢁ 9.95 (s, 1H), 8.16 (d,
1
J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.60-7.39 (m, 5H), 3.20
(s, 1H), 2.95 (s, 3H), 1.14 (s, 9H) ppm. 13C NMR (CDCl3, 100
MHz) ꢁ 145.5, 143.2, 138.9, 138.2, 137.6, 137.1, 133.6, 132.9,
129.5, 129.2, 128.7, 126.8, 123.1, 122.0, 103.9, 56.4, 30.4, 14.2
ppm. HRMS calculated for C24H23ClN6: 430.1673; found:
430.1666. Elemental Analysis calculated (%): 66.89 C , 5.38 H ,
19.50 N ; found (%): 66.34 C , 5.26 H , 19.72 N .
We also measured the fluorescence lifetimes of derivatives 4a,
4b, 4c, 4d and 4f with laser excitation at ꢀexc = 340 nm and
collecting the emission at ꢀem = 425 nm (Table 2). The decays
were analyzed with a sum of two exponential functions, yielding
good fitting results.18 We observed very similar short and long
lifetime components for all the samples, except 4f which
presented a faster decay, probably due to the R2=NO2 substituent.
The decay of 4c, featuring OMe and tert-butyl substituents, is
somehow unexpected because the longer decay component has a
weight of ca. 90%, contrarily to 4a, 4b, and 4d, for which the
weight of this component is ca. 10-20%. Therefore, 4c has a
much larger average decay lifetime. This causes the decrease in
the radiative rate constant that results in lower fluorescence
intensity of 4c compared to that of 4d in Figure 1.
Compound 4b was obtained (63%) as a pale yellow solid, mp
201 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.83 (s, 1H), 8.16 (d,
1
J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.60-7.40 (m, 5H), 3.16
(s, 1H), 3.03 (s, 1H), 2.94 (s, 3H), 1.90-1.20 (m, 10 H) ppm.
13C NMR (CDCl3, 100 MHz) ꢁ 143.2, 138.9, 137.7, 136.4,
134.9, 133.4, 132.2, 129.2, 128.9, 128.4, 126.7, 124.5, 122.0,
57.5, 34.2, 25.6, 24.8, 14.1 ppm. HRMS calculated for
C26H25ClN6: 456.1829; found 456.1834. Elemental Analysis
calculated (%): 68.34 C , 5.51 H , 18.39 N ; found (%): 67.78 C ,
5.41 H , 18.56 N .
Table 2. Fluorescence decay lifetimes obtained by fitting the
decay curves of derivatives 4a, 4b, 4c, 4d and 4f with a sum
of two exponential functions (the weights w1 and w2 of each
decay component are indicated). The average decay lifetime is
calculated as <τ> = w1×τ + w2×τ . R1 is CH3 in all cases.
Compound 4c was obtained (60%) as a yellow solid, mp
227 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.93 (s, 1H), 8.17 (d,
J=8.8 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H), 7.60-7.04 (m, 5H), 3.91
(s, 3H), 3.21 (s, 1H), 2.95 (s, 3H), 1.12 (s, 9H) ppm. 13C NMR
(CDCl3, 100 MHz) ꢁ 159.3, 145.5, 143.2, 138.9, 138.6, 137.2,
129.5, 129.2, 126.6, 122.4, 121.9, 113.9, 103.9, 56.2, 55.3, 30.3,
14.2 ppm. HRMS calculated for C25H26N6: 426.2168; found
1
1
2
τ [ns]
w1
τ [ns]
w2
<τ> [ns]
R2
R3
1
2
4a
1.5
80%
4.8
20%
2.1
4-Cl
tert-butyl

4
Tetrahedron
426.2174. Elemental Analysis calculated (%): 70.40 C , 6.14 H
119.4, 114.2, 112.1, 104.9, 57.5, 55.4, 33.0, 25.6, 24.8 ppm.
, 19.70 N ; found (%): 69.7 C , 6.00 H , 19.68 N .
HRMS calculated for C26H26N6O2: 438.2168; found 438.2160.
Compound 4d was obtained (55%) as a pale yellow solid, mp
Compound 4j was obtained (64%) as a brown solid, mp
1
1
198 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.86 (s 1H), 8.17 (d,
182 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.90 (s, 1H), 8.59 (s,
J=8.0 Hz, 2H), 8.05 (d, J=8.0 Hz, 2H), 7.58-7.06 (m, 5H), 3.93
(s, 3H), 3.20 (s, 1H), 3.04 (s, 1H), 2.95 (s, 3H), 1.76-1.22 (m,
10H) ppm. 13C NMR (CDCl3, 100 MHz) ꢁ 159.2, 145.4, 143.2,
139.0, 136.5, 135.8, 129.2, 129.2, 128.4, 126.6, 126.3, 123.5,
121.9, 114.1, 103.9, 57.4, 55.4, 34.1, 25.7, 24.8, 14.2 ppm.
HRMS calculated for C27H28N6O: 452.2325; found: 452.2317.
Elemental Analysis calculated (%): 71.66 C , 6.24 H , 18.57 N ;
found (%): 71.10 C , 6.14 H , 18.86 N .
1H), 8.37 (m, 4H), 8.19 (d, J=8.4 Hz, 2H), 7.62 (t, J=7.6 Hz,
2H), 7.46 (d, J=8.4 Hz, 1H), 3.27 (s, 1H), 3.09 (s, 1H), 1.20-1.96
(m, 10H) ppm.13C NMR (CDCl3, 100 MHz) ꢁ 153.8, 140.7,
146.83, 140.1, 136.4, 133.6, 132.8, 131.6, 129.3, 127.5, 127.4,
126.6, 124.1, 122.3, 104.9, 57.8, 34.3, 25.5, 24.8 ppm. HRMS
calculated for C25H23N7O2: 453.1913; found 453.1934.
Absorption and Fluorescence Measurements
Compound 4e was obtained (56%) as a brown solid, mp
1
194 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.77 (s, 1H), 8.01 (d,
Absorption and steady-state fluorescence spectra, as well as
time resolved fluorescence of the different imidazo[1,2-
c]pyrazolo-[3,4-d]pyridimidine derivatives were measured in
chloroform solutions. All the samples were prepared at the
concentration of 10 ꢀM, corresponding to an optical density of A
≈ 0.1 at 350 nm. UV-visible absorption spectra were obtained in
a JASCO V-660 spectrometer, using quartz cells (l = 1 cm),
unless indicated otherwise. The fluorescence spectra were
J=8.4 Hz, 2H), 7.44-7.22 (m, 6H), 2.87 (s, 1H), 2.71 (s, 1H), 2.65
(s, 3H), 1.71-1.01 (m, 10H) ppm. 13C NMR (CDCl3, 100 MHz)
ꢁ 156.8, 145.3, 143.2, 138.9, 136.6, 136.6, 130.4, 129.9, 129.2,
128.3, 126.8, 126.4, 122.1, 121.5, 101.5, 57.3, 33.8, 25.6, 24.6,
14.4 ppm. HRMS calculated for C26H24Cl2N6: 456.1829; found
456.1824.
Compound 4f was obtained (57%) as a yellow solid, mp
recorded on
a
Horiba Jobin Yvon Fluorolog 3-22
1
204 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.93 (s, 1H), 8.68 (s,
spectrofluorimeter using quartz cells (l = 1 cm), excitation slits
with 3 nm bandwidth, emission slits with 1 nm bandwidth,
integration time of 1 s/point, maximum sensitivity, and right
angle mode. The emission spectra were recorded between 360
1H), 8.44 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 2H), 8.02 (m,
1H), 7.58-7.19 (m, 5H), 3.08 (s, 3H), 2.93 (s, 1H), 2.82 (s, 3H),
1.84-1.09 (m, 10H). 13C NMR (CDCl3, 100 MHz) ꢁ 148.5,
145.4, 143.3, 138.3, 137.9, 136.9, 135.5, 133.6, 132.9, 129.6,
129.2, 126.8, 125.3, 122.2, 121.9, 121.5, 103.9, 57.7, 34.3, 25.6,
24.8, 14.1 ppm. HRMS calculated for C26H25N7O2: 467.2070;
found 467.2060. Elemental Analysis calculated (%): 66.79 C ,
5.39 H , 20.97 N ; found (%): 66.34 C , 5.40 H , 20.91 N .
and 690 nm using as excitation wavelength λ = 350 nm.
ex
Fluorescence intensity decay curves with picosecond resolution
were obtained by the single photon timing technique using two
different laser excitation systems. One of the systems consists of
a
de-locked Coherent Inova 440-10 argon ion laser
General procedure for the synthesis of imidazo-
[1,2-c]pyrazolo[3,4-d]pyridimidine (4) using the one-pot method
synchronously pumping a cavity dumped Coherent 701-2 dye
laser using rhodamine, which delivers 5-6 ps pulses at a
repetition rate of 460 kHz. The second experimental system
consists of a Spectra-Physics Millenia Xs Nd:YVO4 diode laser,
pumping a pulse picked Spectra-Physics Tsunami titanium-
sapphire laser, delivering 100 fs frequency-doubled in LBO
crystal (360 nm–480 nm) pulses at a repetition rate of 4 MHz. In
both cases, intensity decay measurements were made by alternate
collection of excitation and decay curves, using an emission
polarizer set at the magic angle. The excitation profile was
To a solution of 4-aminopyrazolo[3,4-d]pyrimidine 116 (1
mmol) in DMF (1 mL), benzaldehyde derivative 2 (1 mmol),
scandium triflate (5 mol %) and isocyanide derivative 3 (1 mmol)
were added. The mixture was heated over night at 150°C, and
after removing the solvent the residue was purified by flash
chromatography on silica gel (petroleum ether/CH2Cl2 2:8).
Compound 4g was obtained (72%) as a yellow solid, mp
1
recorded at the excitation wavelength with
suspension. For the decays, a cut-off filter was used to remove all
excitation light. The emission signal passed through
a scattering
234 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.93 (s, 1H), 8.82 (s,
1H), 8.39 (d, J=7.6 Hz, 1H), 8.12 (dd, J=8.0 Hz, 1H), 8.04 (d, J=
7.6 Hz, 2H), 7.58-7.29 (m, 5H), 3.08 (s, 1H), 1.07 (s, 9H) ppm.
13C NMR (CDCl3, 100 MHz) ꢁ 148.3, 145.5, 143.3, 137.0,
136.1, 133.9, 129.5, 129.2, 126.9, 126.7, 123.8, 122.7, 122.4,
122.0, 103.8, 56.6, 30.6, 14.1 ppm. HRMS calculated for
C24H23N7O2: 441.1913; found 441.1906. Elemental Analysis
calculated (%): 65.29 C , 5.25 H , 22.21 N ; found (%): 64.86 C ,
5.19 H , 22.38 N .
a
depolarizer, a Jobin Yvon HR-320 monochromator with a grating
of 100 lines/mm and was detected with a Hamamatsu 2809U-01
microchannel plate photomultiplier (MCP-PT). The instrument
response had as effective FWHM of 35 ps.
Fluorescence intensity decay curves were obtained by
excitation light at 290 nm using the rhodamine dye laser and at
400 nm using the titanium sapphire laser, with emission collected
at 525 nm. The decay curves were analyzed using home-made
non-linear least-square reconvolution software based on the
Marquard algorithm,18 and the quality of the fit was evaluated by
Compound 4h was obtained (73%) as a pale yellow solid, mp
1
219 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.74 (s, 1H), 8.43 (s,
1H), 8.06 (d, J=8.4 Hz, 2H), 7.80 (d, J=6 Hz, 2H), 7.45-7.35 (m,
5H), 3.05 (s, 1H), 1.74-1.07 (m, 10H) ppm. 13C NMR (CDCl3,
100 MHz) ꢁ 144.1, 141.3, 139.0, 137.3, 136.5, 135.8, 131.5,
130.9, 129.8, 129.2, 128.9, 128.3, 124.8, 122.2, 105.1, 57.5, 34.2,
27.3, 24.8 ppm. HRMS calculated for C25H23ClN6: 442.1673;
found 442.1673.
2,
the reduced χ the weight residuals and the autocorrelation of the
residuals.
Acknowledgments
Compound 4i was obtained (74%) as a yellow solid, mp
1
251 °C. H NMR (CDCl3, 400 MHz) ꢁ 8.75 (s, 1H), 8.42 (s,
This work was partially supported by Fundação para a Ciência
1H), 8.09 (d, J=8.0 Hz, 2H), 7.57-7.28 (m, 6H), 6.82 (d, J= 8.0
Hz, 1H) ppm.13C NMR (CDCl3, 100 MHz) ꢁ 159.9, 144.6,
138.9, 136.5, 134.8, 132.7, 129.7, 129.2, 127.1, 125.0, 122.2,
e
a
Tecnologia (FCT, Portugal) project PTDC/CTM-
NAN/115110/2009. S. A. acknowledges funding by
postdoctoral grant SFRH/BPD/74654/2010 (FCT, Portugal).
a

5
References and notes
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17. Different
conditions
tested
for
the
two
methods
(solvent/catalyst/temperature and final yield). Two-step method:
MeCN/LiClO4/80ºC, 32% yield; MeCN/LiClO4/40ºC, 0% yield;
toluene/APTS/MW 150ºC, 0% yield; toluene/LiClO4/MW 150ºC,
0% yield. One-step method: MeOH/AcOH/80ºC, 0% yield;
MeOH/ZnCl2/40ºC, 0% yield; MeOH/LiClO4/40ºC, 40% yield.
18. Farinha, J.P.S.; Martinho, J. M. G.; Pogliani, L. J. Math. Chem.
1997, 21, 131–139.