Dienamine and friedel-crafts one-pot synthesis, and antitumor evaluation of diheteroarylalkanals

Article abstract of DOI:10.1002/chem.201500660

An asymmetric synthesis of diheteroarylalkanals through one-pot dienamine and Friedel-Crafts reaction is presented. The reaction tolerates a large variety of substituents at different positions of the starting aldehyde and also in the indole nucleophile, and a range of diheterocyclic alkanals can be achieved. Furthermore, we have studied the antiproliferative activity of these new compounds in representative cancer tumor cell lines. All in one: An asymmetric synthesis of diheteroarylalkanals through a one-pot dienamine and Friedel-Crafts reaction is presented (see scheme). The reaction tolerates a large variety of substituents at different positions of the starting aldehyde, and the use of nucleophiles and different diheterocyclic alkanals can also be achieved. The antiproliferative activity of these new compounds in different cancer tumor cell lines has also been investigated and it was found that, with the appropriate substitution, the compounds are as cytotoxic as Cisplatin.

Full text of DOI:10.1002/chem.201500660

DOI: 10.1002/chem.201500660
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&
Antitumor Agents
Dienamine and Friedel–Crafts One-Pot Synthesis, and Antitumor
Evaluation of Diheteroarylalkanals
[a]
[b]
[a]
Marꢀa Frꢀas, Josꢁ M. Padrꢂn, and Josꢁ Alemꢃn*
Abstract: An asymmetric synthesis of diheteroarylalkanals
through one-pot dienamine and Friedel–Crafts reaction is
presented. The reaction tolerates a large variety of substitu-
ents at different positions of the starting aldehyde and also
in the indole nucleophile, and a range of diheterocyclic alka-
nals can be achieved. Furthermore, we have studied the an-
tiproliferative activity of these new compounds in represen-
tative cancer tumor cell lines.
Introduction
Currently, asymmetric organocatalysis is recognized as an inde-
pendent synthetic toolbox beside asymmetric metallic catalysis
and enzymatic catalysis for the synthesis of chiral organic mol-
[
1]
ecules. Multiple advantages compared with the other two
catalytic areas have provoked the rapid growth and accept-
[
2]
ance of organocatalysis. However, despite the great develop-
ment of organocatalytic methodologies, their application to
other areas such as medicinal chemistry have rarely been re-
ported, although the number of applications has increased in
[
3]
recent years. The absence of transition metals means that or-
ganocatalytic methods are especially attractive for the prepara-
tion of compounds that do not tolerate metal contamination,
such as active pharmaceutical compounds. In this context, di-
heteroarylalkanes are natural compounds of tremendous
chemical and biological importance, mainly due to their anti-
tumor and analgesic properties, among others (see examples
Figure 1. Important diheteroarylalkanes with biological properties.
Friedel–Crafts reaction of indolylmethanol derivatives with an
heteroaryl compound in the presence of metal, and also
[6]
Brønsted acid catalysis (Scheme 1, Equation a). However, the
latter approach only affords the 3 and 3’ substitution pattern
in both heterocycles (see Figure 1, top).
[
4]
in Figure 1). The structures of these compounds and their
potent activity towards a broad range of pharmacological tar-
gets make them excellent synthetic targets, especially those
containing substitution at positions 2 and 3’ in both heterocy-
[
5]
cles (see Figure 1, bottom).
Different approaches have been described for the synthesis
of diheteroarylalkanes. The usual approach is based on the
[a] M. Frꢀas, Dr. J. Alemꢁn
Organic Chemistry Department
Universidad Autꢂnoma de Madrid
2
8049 Madrid (Spain)
E-mail: jose.aleman@uam.es
Homepage: www.uam.es/jose.aleman
[b] Dr. J. M. Padrꢂn
Instituto Universitario de Bio-Orgꢁnica
„
Antonio Gonzꢁlez“ (IUBO-AG)
Centro de Investigaciones Biomꢃdicas
de Canarias (CIBICAN)
Universidad de La Laguna
3
8206 La Laguna (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500660.
Scheme 1. Different approaches and our proposal for the synthesis of dihe-
teroarylalkanals.
Chem. Eur. J. 2015, 21, 1 – 6
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Very recently, to achieve the 2 and 3’ substituted com-
Table 2. Optimization of the one-pot dienamine-Friedel–Crafts reaction
and effect of the base.
[
7]
pounds, Tang et al. started from alkynes and, through
a metal-catalyzed reaction, they constructed the first heterocy-
cle; this was then attacked by an indole moiety in a Friedel–
Crafts type reaction to give the desired compounds in racemic
form (Scheme 1, Equation b). The products were not biological-
ly tested.
[a]
Based on these previous considerations, and on our previous
[
8]
[9]
experience in dienamine and iminium ion chemistry, we hy-
pothesized that the use of both reactions for obtaining the
[
b]
[c]
2,3-substituted diheteroaryl compounds would be an appropri-
Entry
Base [mol%]
Time [h]
ee [%]
Conversion [%]
ate strategy for their synthesis. A number of reasons make this
approach especially attractive: 1) the starting materials are
readily available; 2) an enantioselective organocatalytic ap-
proach is possible; 3) it constitutes a modular synthesis of the
final compounds (X=N, O). Moreover, we wondered whether
the final compounds (2,3’-substituted) would have antitumor
effects because such activity has been shown for other diheter-
oaryl derivatives (3,3’-substituted). Thus, in this work we pres-
ent our synthesis of 2,3’-diheteroaryl compounds by using
a one-pot strategy that includes dienamine and iminium ion
reaction, and we describe the results of our biological evalua-
tion of the obtained compounds.
1
2
3
4
5
6
7
8
9
–
36
72
72
72
36
36
36
36
36
nd
nd
93
89
–
93
95
94
91
15
52
100
100
–
34
45
100
100
Et N (100)
Et
Et
3
3
N (50)
N (30)
3
DBU (50)
DABCO (75)
DABCO (50)
DABCO (30)
DABCO (20)
[a] Reaction conditions: 2a or 2b (0.02 mmol), 1A (0.1 mmol), solvent
0.1 mL). [b] Determined by SFC analysis. [c] Conversion determined by
(
1
H NMR spectroscopic analysis.
indole 4a in the presence of catalyst 2b (20 mol%). Although
the first trial was successful, we could only detect the desired
product 5Aa in the crude mixture with very low conversion.
The nucleophilicity of the 3-position of indole 4a could be in-
creased by the use of an external co-base (Table 2, entries 2–
Results and Discussion
For our initial experiments, dialdehyde 1A was employed in
the presence of the well-known Jørgensen–Hayashi catalyst
[11]
[
10]
8). Thus, including 100 mol% Et N gave the final product
3
2
;
the reactions were stopped at 20 hours (Table 1). Use of
with 52% conversion and good enantiomeric excess (ee), but
a decrease in the amount of this base was beneficial for the
conversion (Table 2, entries 2–4). The use of stronger bases
such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave no con-
version to the final product, whereas 1,4-diazabicyclo[2.2.2]oc-
tane (DABCO) gave the product 4 in moderate conversion
the bulkier catalyst 2a gave 3A in low yield, but this was in-
creased to 37% through the use of catalyst 2b (Table 1, en-
tries 1 and 2). The use of other polar solvents such as chloro-
form, diethyl ether, acetonitrile, or tert-butyl methyl ether did
not increase the yield, but employing the more apolar solvent
toluene gave the product 3A in 85% yield with full
conversion.
(
Table 2, entries 6 and 7), which was increased when the
amount of this base was decreased to 20 and 30 mol%
We then focused on the one-pot dienamine Friedel–Crafts
reaction starting from aldehyde 1A (Table 2, entry 1) and using
[12]
(
Table 2, entries 8 and 9). With these optimized conditions
on hand (Table 2, entry 8), we studied the reaction with
a range of aldehydes 1 (Table 3) and indoles 4 (Table 4).
The use of starting material with electron-withdrawing
groups (EWG) or electron-donating groups (EDG) para to the
oxygen atom gave the final products in good yields and enan-
tioselectivities (5Aa–Da), ranging from 93 to 97%ee. Sub-
strates substituted in the ortho and meta position also allowed
the synthesis of products 5Ea and 5Fa without a decrease in
the final ee (93–94%).
[
a]
Table 1. Optimization of the dineamine reaction.
We then studied the addition of other indole nucleophiles
[
b]
Entry
Cat
Ar
Solvent
Yield [%]
4
a–f (Table 4). Starting indoles with substituents such as
1
2
3
4
5
6
7
2a
2b
2b
2b
2b
2b
2b
3,5-(CF
Ph
Ph
Ph
Ph
3
)
2
C
6
H
3
CH
CH
2
Cl
Cl
2
2
20
37
53
38
46
46
85
bromo (5Ab) or methoxy (5Ac) groups gave satisfactory yields
and ee values (>95%ee). Interestingly, other substituents adja-
cent to the reactive center (methyl, 5Ad), and also next to the
NH of the indole (which is deprotonated by DABCO in the Frie-
del–Crafts reaction, 5Ac) gave products 5Ad and 5Ae in excel-
lent enantioselectivities (96 and 99%ee, respectively). The addi-
tion of the 1H-benzo[g]indole also gave the expected aldehyde
2
CHCl
tBME
Et
CH
toluene
3
2
O
Ph
Ph
3
CN
[
(
a] Reaction conditions: 2a or 2b (0.02 mmol), 1a (0.1 mmol), solvent
0.1 mL). [b] Isolated yield after flash chromatography.
5
Af with excellent ee.
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[
a]
Table 3. Aldehydes 1 in the dienamine-Friedel–Crafts reaction.
Scheme 2. Synthesis of optically enantioenriched bis-indoles by one-pot di-
enamine-Friedel–Crafts reaction.
ble mechanism in Scheme 3. The reaction starts from aldehyde
1
, which undergoes a condensation reaction with aminocata-
lyst 2a to give iminium ion I. Isomerization to dienamine II can
then take place and iminium ion III would be generated
through intramolecular dienamine condensation and dehydra-
tation. Attack of indole 4 on iminium ion III can take place
with enantiocontrol by steric shielding of the bulkier group
(
CPhPhOTMS) to give the final product 5.
[
a] Reaction conditions: 2b (0.02 mmol), 1 (0.1 mmol), 4 (0.12 mmol),
From our experience in the synthesis and evaluation of anti-
DABCO (0.02 mmol), toluene (0.3 mL). [b] Determined by SFC analysis.
[14]
1
cancer complexes,
and because some similar compounds
[c] Conversion determined by H NMR spectroscopic analysis.
have been shown to have biological activity (3,3’-substituted),
we carried out an antitumoral evaluation of this new series of
[4]
bisheterocycle compounds with 2,3’-substitution. The anti-
proliferative activity of 5 was evaluated against a panel of rep-
resentative human tumor cell lines, including HBL-100 (breast),
HeLa (cervix), SW1573 (non-small cell lung), and WiDr (colon),
[
a]
Table 4. Indoles 4 in the dienamine-Friedel–Crafts reaction.
[15]
by using the SRB assay. The experimental GI50 values are out-
lined in Figures 2 and 3, and are compared with those of cis-di-
amminedichloroplatinum(II) (Cisplatin, CDDP), one of the most
important antitumoral compounds on the market, after 48 h
treatment (for more details and for color graphics, see the Sup-
porting Information). Figure 2 shows the results of antiprolifer-
ative activity tests with compounds bearing different substitu-
tion at the furan aromatic ring (5Aa–Af); Figure 3 displays the
GI50 values of compounds with variation in the indole moiety
(
5Ab–Af and 5Gb).
The obtained results indicate that substitution at the aryl
moiety of the benzofurane ring has an important effect in the
antiproliferative activity of the benzoindol 5, and this effect de-
pends on the cell line. Thus, the introduction of strong EWGs
and EDGs provoked a decrease in the antiprolifertive activity,
which was quite remarkable in the case of compounds 5Ca,
5
Da, and 5Ea in WiDr cells. In the case of compounds 5Aa
[
a] Reaction conditions: 2b (0.02 mmol), 1 (0.1 mmol), 4 (0.12 mmol),
and 5Ba, the antiproliferative activity was quite high, and was
even better than that of Cisplatin for the WiDr cancer cell line,
with GI50 value of 16 for 5Ba (5Ab–5Gc, Figure 3). EDGs pro-
voked a decrease in the antiproliferative activity (5Ab and
DABCO (0.02 mmol), toluene (0.3 mL). [b] Determined by SFC analysis.
1
[c] Conversion determined by H NMR spectroscopic analysis.
5
Ae), whereas a methyl group at positions 2 and 7 of the
The synthesis of bis-indoles was also possible by using this
indole moiety increased the biological activity (5Ad and 5Ac).
The bisindol derivatives 5Gb and 5Gc gave results that were
similar to those of the other benzofurane derivatives 5 (3.5–
16 mm). Notably, benzoindole derivative 5Af was the most
active in all the cell lines tested (see Figures 3), and was in the
same order of magnitude as Cisplatin (2–18 mm); in some cases
the GI50 was even better than observed with CDDP. This is re-
methodology (Scheme 2). Thus, starting from aldehyde 1G and
using indoles 4b and 4c allowed the synthesis of bis-indoles
Gb and 5Gc with excellent enantioselectivity.
5
The absolute configuration of product 5 was determined by
[
13]
X-ray crystallographic analysis of 5Ba (Scheme 3, top). To ex-
plain the stereochemical outcome, we have provided a plausi-
Chem. Eur. J. 2015, 21, 1 – 6
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markable in the case of WiDr cell
line, which is mutated in p53
and, in general, is more resistant
[14b]
to different anticancer drugs.
Conclusion
We have developed the asym-
metric synthesis of diheteroaryl-
alkanals through a dienamine-
Friedel–Crafts one-pot reaction
with good ee values and yields.
The reaction could tolerate
a large variety of substituents at
different positions of these new
heteroarylalkanals. In addition,
we have carried out an antiproli-
ferative analysis of the new com-
pounds, and their structure-ac-
tivity relationships indicate that
these compounds, with the ap-
propriate substitution, are as cy-
totoxic as Cisplatin. In some
cases, such as for the WiDr
cancer cell line, which is resistant
to CDDP, the antiproliferative ac-
tivity was superior to that of
Cisplatin.
Experimental Section
General Methods
NMR spectra were acquired with
a Bruker 300 spectrometer, run-
1
ning at 300 and 75 MHz for H and
13
C, respectively. Chemical shifts (d)
are reported in ppm relative to re-
sidual solvent signals (CHCl3,
Scheme 3. Approaches for the synthesis of diheteroarylalkanes.
1
7
.26 ppm for
H NMR, CDCl3,
Figure 2. Antiproliferative activity (GI50, mM) of 5Aa–Fa in HBL-100 (breast),
HeLa (cervix), SW1573 (non-small cell lung), and WiDr (colon) human solid
tumor cells (see the Supporting Information for more details and color
graphics).
Figure 3. Antiproliferative activity (GI50, mM) of 5Ab–Af and 5Gb–Gc in HBL-
100 (breast), HeLa (cervix), SW1573 (non-small cell lung) and WiDr (colon)
human solid tumor cells (see the Supporting Information for more details
and color graphics).
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1
3
7
7.0 ppm). C NMR spectra were acquired on a broad band decou-
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[
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2
014, 24, 4023.
6
0 F254) and visualized by ultraviolet irradiation or KMnO dip. Pu-
4
[
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2
006, 118, 645.
Synthesis of Compounds 5; General Procedure
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The corresponding aldehyde
20 mol%) were dissolved in toluene (0.3 mL) and the resulting
mixture was stirred at RT overnight. Indole 4 (1.1 equiv), DABCO
30 mol%), and toluene (0.2 mL) were added to the solution at
8C. Upon completion of the reaction (determined by TLC), the
1
(0.1 mmol) and catalyst 2b
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(
0
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2
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(
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lowing the general procedure described above, compound 5Aa
was obtained in 79% yield as a red oil. The crude product was pu-
rified by flash column chromatography (hexanes/EtOAc, 3:1).
1
H NMR (300 MHz, CDCl ): d=9.73 (t, J=1.8 Hz, 1H), 8.06 (brs, 1H),
3
7
.51 (d, J=7.9 Hz, 1H), 7.32 (m, 3H), 7.09 (m, 5H), 6.33 (s, 1H), 4.98
13
(
t, J=7.3 Hz, 1H), 3.25–3.10 ppm (m, 2H); C NMR (75 MHz, CDCl3):
d=199.8, 158.1, 153.7, 135.4, 127.5, 125.0, 122.6, 121.6, 121.4,
21.3, 119.6, 118.7, 118.1 113.8, 110.4, 109.9, 102.1, 46.3, 30.3 ppm.
[
1
The enantiomeric excess was determined by supercritical fluid
chromatography (SFC) after reduction of the obtained aldehyde
using
3
+
Chiralpak-IB-3-15–20
column
[CO /MeOH
(85:15);
2
À1
20
.0 mLmin ]: t
=13.81 min, tmajor =15.35 min (94% ee). [a] =
minor
D
+
40.73 (c=0.71, CHCl ). MS (TOF-EI ): m/z calcd for C H NO :
3 19 15 2
+
2
89.1103 [M] ; found: 289.1115.
[
[
10] For a general review, see: K. L. Jensen, G. Dickmeiss, H. Jiang, L. Al-
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version after 48 h. There are examples using co-base for the Friedel–
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tion of the enantiomeric excess under SFC conditions, reduction to the
alcohol was necessary (see the Supporting Information).
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for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgements
Financial support from the Spanish Government (CTQ-2012-
12168) is gratefully acknowledged. J.A. thanks the MICINN for
their “Ramꢂn y Cajal” contract, and M.F. thanks the Universidad
Autꢂnoma of Madrid for a FPI-UAM fellowship. J.M.P. thanks
the EU Research Potential (FP7-REGPOT-2012-CT2012–31637-
IMBRAIN), the European Regional Development Fund (FEDER),
and the Spanish Instituto de Salud Carlos III (PI11/00840) for fi-
nancial support.
[
[
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Keywords: aldehydes
·
antiproliferation
·
asymmetric
synthesis · nitrogen heterocycles · organocatalysis
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Received: February 16, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢄ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
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Antitumor Agents
M. Frꢀas, J. M. Padrꢂn, J. Alemꢁn*
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Dienamine and Friedel–Crafts One-Pot
Synthesis, and Antitumor Evaluation
of Diheteroarylalkanals
All in one: An asymmetric synthesis of
diheteroarylalkanals through a one-pot
dienamine and Friedel–Crafts reaction is
presented (see scheme). The reaction
tolerates a large variety of substituents
at different positions of the starting al-
dehyde, and the use nucleophiles and
different diheterocyclic alkanals can also
be achieved. The antiproliferative activi-
ty of these new compounds in different
cancer tumor cell lines has also been in-
vestigated and it was found that, with
the appropriate substitution, the com-
pounds are as cytotoxic as Cisplatin.
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Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢄ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!