Microwave-assisted convenient syntheses of 2-indolizine derivatives from Morita-Baylis-Hillman adducts: New in silico potential ion channel modulators

Article abstract of DOI:10.5935/0103-5053.20130056

In this work, a microwave-assisted synthesis study by microwave irradiation to produce indolizine-2-carbonitrile and indolizine-2-carboxylate in good to high yields (70 and 81percent, respectively) in one step from Morita-Baylis-Hillman adducts (MBHA) is presented. These compounds were subsequently transformed to high yields (94 to 100percent, respectively) in three 2-indolizine derivatives. The five synthesized compounds were designed in silico aiming to present potential selective activities as ion channel modulators. These activities were suggested by the score values using Molinspiration Cheminformatics program.

Full text of DOI:10.5935/0103-5053.20130056

http://dx.doi.org/10.5935/0103-5053.20130056
J. Braz. Chem. Soc., Vol. 24, No. 3, 432-438, 2013.
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Article
A
Microwave-Assisted Convenient Syntheses of 2-Indolizine Derivatives from
Morita-Baylis-Hillman Adducts: New in silico Potential Ion Channel Modulators
Saraghina M. D. Cunha, Ramon G. de Oliveira and Mário L. A. A. Vasconcellos*
Departamento de Química, Universidade Federal da Paraíba, Campus I,
5
8059-900 João Pessoa-PB, Brazil
Neste artigo, um estudo sintético assistido por irradiação de micro-ondas para produzir
-indolizina-carbonitrila e 2-indolizina-carboxilato de metila em bons a altos rendimentos (70 e
1%) em uma etapa a partir de adutos de Morita-Baylis-Hillman (AMBH) é apresentado. Estes
2
8
compostos foram subsequentemente transformados em altos rendimentos (94-100%) em três
derivados 2-indolizínicos. Os cinco compostos sintetizados foram idealizados in silico objetivando
potenciais atividades seletivas como moduladores de canais iônicos. Estas atividades foram
sugeridas pelos valores de pontuação usando o programa quimioinformático Molinspiration.
In this work, a microwave-assisted synthesis study by microwave irradiation to produce
indolizine-2-carbonitrile and indolizine-2-carboxylate in good to high yields (70 and 81%,
respectively) in one step from Morita-Baylis-Hillman adducts (MBHA) is presented. These
compounds were subsequently transformed to high yields (94 to 100%, respectively) in three
2-indolizine derivatives. The five synthesized compounds were designed in silico aiming to present
potential selective activities as ion channel modulators. These activities were suggested by the
score values using Molinspiration Cheminformatics program.
Keywords: Morita-Baylis-Hillman adducts, 2-indolizine derivatives, microwave, potential
ion channel modulators, Molinspiration Cheminformatics program
Introduction
Indolizines constitute a class of heteroaromatic
compounds containing two condensed rings (5 and
6-membered) and a bridging nitrogen atom. This structural
Figure 1. Structure and numbering system of indolizine, and a general
moiety (Figure 1) is found in natural products and has
been used as an essential skeleton in pharmaceutics.
Efficient and versatile synthetic methods for producing
2-indolizine moiety.
Even if efficient synthetic methods for producing
indolizine derivatives have been continuously investigated,
1
1
indolizine derivatives have been actively investigated.
Some compounds presenting indolizine moiety have been
reported as L-type calcium channel blockers, leukotriene
many synthetic methods require an organized pyridine
derivative with functionalized alkynyl or homoalkynyl
groups on the 2-position. Therefore, the investigation
of an alternative method having various functional group
variations on the indolizine nucleus is highly desirable for
biological activity studies.
2
3
4
10
synthesis inhibitors, histamine H receptor antagonists,
3
5
5
-HT1A receptor ligands and phosphodiesterase V
inhibitors. The biological diversity of indolizine derivatives
was realized just before the start of this century and has
6
7
been recently revised.
Curiously, according to our knowledge, it is not
described in literature efficient 2-indolizines derivative
syntheses. For example, the best indolizine-2-carbonitrile
7
Among these various classes of bioactivities, it is
noteworthy the significant number of indolizine derivatives
8,9
11
(
Figure 2) acting as ion channel modulators.
synthesis (1, Figure 3) was described by Kaye and Bode
using thermal cyclisation condition in three steps from
2-pyridyl derivative on 32% yield.
*
e-mail: mlaav@quimica.ufpb.br

Vol. 24, No. 3, 2013
Cunha et al.
433
8
Figure 2. Some ion channel blockers based on indolizine moiety (in blue).
Figure 3. Selected structures to be synthesized in this work.
1
2
12
Inarecentwork, ourgroupdescribedmicrowave-assisted
syntheses of new monoacylglycerols (MAGs) from Morita-
Baylis-Hillman reaction (MBHR, Scheme 1). MBHR
described in that article, a reaction between Morita-Baylis-
Hillman adduct under microwave irradiation that produced a
complex compound mixture, among them, the 2-indolizine
(Scheme 2) in very low yields.
2
occurs between an sp electrophilic carbon (i.e., aldehydes,
ketones) and the a position of an alkene connected to an
electron-attractor group (EAG), under a tertiary amine as
nucleophilic catalysis, being 1,4-diazabicyclo[2.2.2]octane
In connection with our interest in the new bioactive
compound synthesis and microwave use on optimizing
synthesis, our group decided to investigate the microwave
irradiation use on synthetic methodologies development
14
13
(DABCO) widely used catalyst (Scheme 1). It was also
4
Scheme 1. General scheme for Morita-Baylis-Hillman reactions.

4
34
Microwave-Assisted Convenient Syntheses of 2-Indolizine Derivatives from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
1
2
Scheme 2. Synthesis with very low yield of 2-indolizine derivative, characterized by CG-MS.
to obtain new and known 2-indolizidine derivatives from
modulators. It is worth noting the very high score value
obtained for 4 (entry 5, Table 1), as well its selectivity as
modulator of ionic channel.
MBHR. It was selected compounds that presented in silico
8
potentiality as ionic channel modulator. The five structures
synthesized in this work are shown in Figure 3. These
compounds did not present up to now efficient syntheses
described in the literature.
Obviously this preliminary in silico approach must be
experimentally validated, but it was considered the use of
Molinspiration Cheminformatics program a good virtual
screening methodology. Recently, some research groups
used the Molinspiration Cheminformatics on rational
The compound selection shown in Figure 3 was
based on in silico evaluation by using Molinspiration
1
5
18
Cheminformatics program. The Molinspiration
Cheminformatics program presents specific activity
scores for each of these six receptor classes (GPCR ligand,
ion channel modulator, kinase inhibitor, nuclear receptor
ligand, protease inhibitor and enzyme inhibitor). Using
this program, it is also possible to calculate the Lipinski’s
approach in drug design.
So, it is presented in this work our experimental results
using microwave-accessing one-pot synthesis of indolizine-
2-carbonitrile (1) and methyl indolizine-2-carboxylate (2)
from MBHA, as well it is described very efficient syntheses
to the derivatives 3, 4 and 5 (Figure 3).
16
rule of five proprieties. Molinspiration Cheminformatics
virtual screening methodology can efficiently separate
drug-likeness from inactive structures. For example, alcohol
Results and Discussion
5
presents a score of +0.51 to ion channel modulator that
are higher than the medium score drug on database program
Table 1). Similarly, structure 4 presents a score of +0.85 to
Our experimental work began on MBHA 6 synthesis
(Scheme 3). Thus, reacting excess of methyl acrylate
(reactant and solvent) with 2-pyridinecarboxaldehyde in
the presence of 1 equiv. of DABCO as a promoter at 0 °C
for 5 h produced quantitatively the pure adduct 6.
(
ion channel modulator that is very higher than the medium
score drug on the same database program (Table 1).
The conditions and results on indolizine-2-carboxylate
(2) synthesis are summarized in Table 2. Acidic dry
amberlyst-15 resin use was inefficient comparing
with wet amberlyst-15 in this transformation (entry 1
vesus 2, Table 2). Curiously, resin-free conditions were
more efficient in all examples (entries 1-2 versus 3-9).
Considering the results presented in Table 2, with methanol
concentration and irradiation time variation, it was
determined that there is an ideal relationship of methanol
Table 1. Molinspiration Cheminformatics virtual screening results for
compounds 1-5 and the medium score drug-like molecules on the database
b
c
entry
Compound
L-R violations
I.C.M. score
-0.65
1
2
3
4
5
6
indolizine
0
0
0
0
0
0
-
1
2
3
4
5
+0.32
+0.39
+0.48
(
1
0.5 mL) to MBHA 6 (1 mmol) under irradiation by
00 min at 100 °C. Finally, differently than described,
+0.85
1
1
+0.51
methyl indolizine-2-carboxylate (2) preparation was
performed in high yields (80-81%, entries 7 and 9, Table 2)
under microwave irradiation at 100 °C using methanol as
solvent. In fact, it was discovered a condition to produce
the 2-indolizine 2, which can be isolated with 100% purity
(evaluated by CG-MS) after methanol evaporation.
a
7
M.S.D.
+0.25
a
Medium score drug-like molecules on the Molinspiration Cheminformatics
b
c
Program database; number of violations of Lipinski’s rule of five; ion
channel modulator score.
In this present work, the structures 1-5 were selected to
be synthesized (Figure 2) after in silico investigating more
than two hundred compounds presenting the privileged
In sequence, the ester 2 was reduced on 100% yield by
using LiAlH on dry tetrahydrofuran (THF), producing
4
17
2
-indolizine structure. It was prioritized structures that
alcohol 5. The alcohol 5 synthesis was described in
19
presented high positive in silico score as ion channel
literature in 80% yield.

Vol. 24, No. 3, 2013
Cunha et al.
435
Scheme 3. (i) Methyl acrylate, 2-pyridinecarboxaldehyde, DABCO (1 equiv.), 0 °C, 30 min, 100%; (ii) microwave irradiation, conditions in Table 2; (iii)
LiAlH , 2 on dry THF, 3 h, 0 ºC → room temperature, 100%.
4
Table 2. Optimizing conditions to prepare indolizine-2-carboxylate (2)
a
entry
MBHA 6 / mmol
Solvent / mL (MeOH)
Catalyst
time / min
20
Yields / %
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
2.5
3.0
5.0
3.0
3.0
3.0
3.0
2.0
1.0
2.0
2.0
2.0
amberlyst-15 wet
51
17
68
55
46
55
80
70
81
amberlyst-15 dry
20
-
-
-
-
-
-
-
20
60
60
60
100
100
100
9
a
Isolated yields. The reactions were performed at 100 ºC.
Acid 3 synthesis was done in accordance to that
described procedure. So, 1 equiv. of ester 2 was reacted
In Table 3, our results are presented, optimizing
indolizine-2-carbonitrile (1) synthesis.
20
with a solution of 6 equiv. of KOH on refluxing ethanol by
As can be seen in entry 1 (Table 3), the amberlyst-15
resin use was ineffective using acetonitrile as solvent. In
fact, acetonitrile proved to be inefficient as solvent to this
transformation, even at 90 min of microwave irradiation
16 h, followed by conventional purification, providing the
acid 3 in quantitative yield (Scheme 4).
(entries 1, 2 and 3, Table 3). Using dimethylformamide
(DMF) as solvent, a complex product mixture was obtained
(entry 4). In a different way, the acetic anhydride use as
solvent produces 1 in a moderate yield (entry 5). The yields
obtained by using ethanol and methanol as solvents were
different. Note that methanol use was unproductive and
ethanol use resulted in 1 formation in the same yield
Scheme 4. (i) Ester 2 (3 mmol), 21 mL of KOH ethanolic solution
-
1
(1 mol L ), 16 h, 100 °C, 100% yield.
1
1
Scheme 5 presents the synthetic route for 1 and
as described in the literature (32%, entry 5 and 6).
4
compounds, from MBHA 7. The 7 synthesis was
made in quantitative yield by reaction between
-pyridinecarboxaldehyde and acrylonitrile assisted by
microwave irradiation (30 min, 80 °C) in a solvent-free
Successfully, the TFE use as solvent improve significantly
to the reaction yield (70%, entry 8). Beside this, the TFE
use facilitates the 1 purification that occurs by solvent
evaporation. Increasing reaction concentration led to the
decrease in the reaction yield (entries 9-10 versus 8).
Scheme 6 presents the general mechanism proposed by
2
21
condition, in the presence of 1 equiv. of DABCO. Pure 7
was obtained after a filtration through silica gel (Scheme 5).

4
36
Microwave-Assisted Convenient Syntheses of 2-Indolizine Derivatives from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
Scheme 5. Synthetic route for the preparation of compounds 1 and 4. (i) microwave irradiation, 80 ºC, 30 min, 100%.; (ii) microwave irradiation,
conditions and results in Table 3; (iii) LiAlH , 2 on dry THF, 2 h, 0 ºC, 98.5%.
4
Table 3. Synthetic studies to prepare indolizine-2-carbonitrile (1)
a
entry
11 / mmol
1.0
Catalyst
Solvent (1 mL)
MeCN
Temperature / °C
time / min
Yield / %
1
2
3
4
5
6
7
8
9
200 mg wet amberlyst-15
100
100
100
100
100
100
100
100
100
100
60
60
90
60
90
60
60
60
60
90
8
1.0
-
-
-
-
-
-
-
-
MeCN
10
15
1.0
MeCN
b
1.0
DMF
< 5
1.0
Ac O
45
2
b
1.0
MeOH
EtOH
< 5
1.0
32
70
56
61
c
1.0
TFE
c
1.5
TFE
c
1
0
1.5
-
TFE
a
b
c
Isolated yields; complex mixture of products; 2,2,2-trifluoroethanol.
1
1,22
19
Bode and Kaye
to indolizine-2-carbonitrile (1) and
efficiently. However, in our study, compound 4 proved to
be easily manipulated at room temperature and could be
used in the next reaction after several days. It is encouraging
us once 4 showed the highest in silico score value as ion
channel modulator at Molinspiration Cheminformatics
program (Table 1).
methyl indolizine-2-carboxylate (2) formation.
Conclusion
It was discovered an efficient route to prepare indolizine-
2
-carbonitrile (1) from MBHA, (microwave irradiation,
11
one-step, 70%) two times better than the described synthesis.
Beside this, an efficient one-step procedure to indolizine-
-carboxylate (2) (microwave irradiation, 81% versus two
2
Scheme 6. Proposed mechanism of indolizine-2-carbonitrile (1) and
methyl indolizine-2-carboxylate (2) formation. EAG = electron-attractor-
11
steps, 70%, by conventional heating) was also described
here. These two compounds were used to prepare in high
yields three compounds described in Figure 3. Syntheses of
carboxylic acid (3), alcohol (5) and amine (4) were performed
in high yields in a chemoselective way. It was also presented
here a strategy based on Molinspiration Cheminformatics
program to select compounds with potential biological
activities as ion channel modulators. The biological studies
22
group; CN or CO CH .
2
3
Indolizin-2-yl-methanamine synthesis (4) was
performed by indolizine-2-carbonitrile (1) with LiAlH4
reduction, stirring for 2 h at 0 °C in dry THF, producing
4
in 98.5% (Scheme 5). Curiously, it is oversized in the
literature that the amine 4 is unstable and cannot be stored

Vol. 24, No. 3, 2013
Cunha et al.
437
of these compounds as antihypertensive and anticancer drugs
are now in evaluation.
General procedure for the microwave-assisted synthesis of
11
methyl indolizine-2-carbonitrile (1)
Experimental
The X mmol of 2-[hydroxy(pyridine-2-yl)methyl]
acrylonitrile (7) and Y mL of solvent were placed in a
10 mL glass microwave tube with magnetic stirrer at
General
8
0 °C (temperature monitored by built-in infrared sensor)
All commercially available reagents and solvent
were obtained from Sigma-Aldrich and used without
for 20-100 min (Table 3). After the complete reaction, the
mixture was brought to room temperature and was directly
filtered through silica gel, using hexane/ethyl acetate (7:3)
as solvent and the reaction product was concentrated
under reduced pressure producing methyl indolizine-
2-carboxylate (1) in Z yield (Table 3).
®
further purification. Reactions were monitored by thin
layer chromatography (TLC) using silica gel 60 UV254
Macherey-Nagel pre-coated silica gel plates; the detection
was made by a UV lamp. Flash column chromatography
was performed on 300-400 mesh silica gel. Organic layers
were dried over anhydrous MgSO or Na SO prior to
General procedure for the microwave-assisted synthesis of
4
2
4
11
evaporation on a rotary evaporator. Reactions requiring
microwave irradiation were performed in a microwave
methyl indolizine-2-carboxylate (2)
®
reactor CEM model system Discover BenchMate with
The X mmol of methyl 2-[hydroxyl(2-pyridinyl)
methyl] acrylate (6) andY mL of solvent were placed in a
10 mL glass microwave tube with magnetic stirrer at 80 °C
(temperature monitored by built-in infrared sensor) for
20-100 min (see Table 3). After the complete reaction, the
mixture was brought to room temperature and was directly
filtered through silica gel, using hexane/ethyl acetate (7:3)
as solvent and the reaction product was concentrated
under reduced pressure producing methyl indolizine-
2-carboxylate (2) in Z yield (see Table 2).
1
temperature monitored by built-in infrared sensor. H and
1
3
C nuclear magnetic resonance (NMR) spectra were
recorded usingVarian Mercury SpectraAC 20 spectrometer
1
13
(
200 and 50 MHz for H and C, respectively). Chemical
shifts were reported relative to internal tetramethylsilane
1
(
d 0.00 ppm) for H, using CHCl -d, CH OH-d or
3
3
4
DMSO-d as solvents. Fourier transform infrared (FTIR)
6
spectra were recorded on a Shimadzu spectrophotometer
model IRPrestige-21 in KBr pellets. Gas chromatography-
mass spectrometry (GC-MS) data were measured with a
Shimadzu GCMS-QP2010 mass spectrometer.
20
Indolizine-2-carboxylic acid (3) preparation
14
–1
Methyl 2-[hydroxyl(2–pyridinyl)methyl] acrylate (6)
Indolizine-2-carboxylate (2) and 21 mL of 1 mol L
KOH ethanolic solution were placed in a 50 mL glass round
bottom flask. This mixture was refluxing by 16 h. After the
end of reaction (verified by TLC), the reaction mixture
(dispersion) was carried to room temperature followed
by water addition (to solubilize the dispersion) and a
Carboxy-2-pyridine (110 mg, 1.0 mmol), excess of
methyl acrylate (2 mL) and DABCO (112 mg, 1.0 mmol)
preparation were placed in a 25 mL flask at 0 °C under
stirrer for 5 h. After that, the reaction medium was directly
filtered through silica gel, using hexane/ethyl acetate (7:3)
as solvent and the reaction products were concentrated
under reduced pressure, producing 100% of pure methyl
–1
HCl solution (1 mol L ) to obtain pH 2-3. The product
was extracted by the organic phase (3 × 20 mL EtOAC),
which, in turn, was dried with sodium sulfate anhydrous
Na SO and concentrated under reduced pressure in which
2-[hydroxyl(2-pyridinyl)methyl] acrylate (6).
2
4
it was obtained 3 on 100% isolated yield.
14
2
-[Hydroxy(pyridine-2-yl)methyl] acrylonitrile (7)
19
Indolizin-2-ylmethanamine (4) preparation
Carboxy-2-pyridine (110 mg, 1.0 mmol), excesses of
acrylonitrile (2 mL) and DABCO (112 mg, 1.5 mmol)
preparation were placed in a 25 mL flask at 0 °C under
stirrer for 30 min. After that, the reaction medium was
directly filtered through silica gel, using hexane/ethyl
acetate (7:3) as solvent and the reaction products were
concentrated under reduced pressure, producing 100% of
pure 2-[hydroxy(pyridine-2-yl)methyl] acrylonitrile (7).
In a 25 mL glass round bottom flask, it was placed
1 mmol of indolizine-2-carboxynitrile (1), 2 mL of dry
THF. 3.0 equiv. of LiAlH was gradually added in small
4
portions at 0 °C. After that, reaction was stirred for 3 h at
room temperature, followed by slow addition of saturated
ammonium hydroxide solution (0.2 mL). Excess THF was
removed by evaporation, followed by partition between

4
38
Microwave-Assisted Convenient Syntheses of 2-Indolizine Derivatives from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
2
5 mL water and 3 × 20 mL dichloromethane, which,
8. Gundersen, L.-L.; Malterud, K. E.; Negussie, A. H.; Rise, F.;
Teklu, S.; Østby, O. B.; Bioorg. Med. Chem. 2003, 11, 5409;
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Hagishita, S.; Sato, T.; Ohtani, M., Miki, K.; J. Biochem. 1998,
in turn, organic phase was dried with sodium sulfate
anhydrous Na SO and concentrated under reduced pressure
in which it was obtained 4 in 98.5% isolated yield.
2
4
19
Indolizin-2-ylmethanol (5) preparation
1
23, 619; Elst, L. V.; Chatelain, P.; Manning, A. S.; Larvel, R.;
In a 25 mL glass round bottom flask, it was placed
mmol of indolizine-2-carboxylate (2), 2 mL of dry
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1
THF. 2.0 equiv. of LiAlH were gradually added in small
4
portions at 0 °C. After that, reaction was stirred for 3 h at
room temperature, followed by slow addition of saturated
ammonium hydroxide solution (0.2 mL). Excess THF was
removed by evaporation, followed by partition between
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1809.
2
5 mL water and 3 × 20 mL dichloromethane, which, in
turn, was dried with sodium sulfate anhydrous Na SO and
concentrated under reduced pressure where 5 was obtained
in 100% isolated yield.
12. Sousa, S. C. O.; Lima-Junior, C. G.; Silva, F. P. L.; Andrade,
N. G.; Barbosa, T. P.;Vasconcellos, M. L. A. A.; J. Braz. Chem.
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2
4
1
3. Morita, K.; Suzuki, Z.; Hirose, H.; Bull. Chem. Soc. Jpn.
1968, 41, 2815; Baylis, A. B.; Hillman, M. E. D.; U.S. Patent
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3,743,669, 1973 (CA 77:197234174q); Basavaiah, D.; Rao,A. J.;
Supplementary data, spectra and chromatograms are
available free of charge at http://jbcs.sbq.org.br as a PDF
file.
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program predictions, http://www.molinspiration.com/cgi-bin/
properties accessed in June 2012.
Acknowledgments
This work has been supported by Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq) and
Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (CAPES).
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Submitted: June 29, 2012
Published online: March 12, 2013