Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki Cross-coupling Reactions

Article abstract of DOI:10.1002/jhet.3478

In an attempt to improve anticancer activity, a series of retinoids–chromene hybrids was described. The novel heterocyclic chromene–retinoids hybrid including oxygen as a heteroatom in a six-membered cyclic ring (2H-chromene or 2H-1-benzopyran) was design

Full text of DOI:10.1002/jhet.3478

Month 2019 Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by
Suzuki Cross-coupling Reactions
Larbi Belachemi,a Mohammed Lahcini,a Marie-Claude Viaud Massuard,b and Cécile Croixb
a
*
Asma Kaoukabi,
aLaboratory of Organometallic and Macromolecular Chemistry—Composites Materials, Department of Chemistry,
Faculty of Sciences and Technology, University Cadi Ayyad of Marrakech, Marrakesh, Morocco
bCNRS UMR 7292 GICC, Molecular and Therapeutical Innovation, University of Tours, 31, Avenue Monge, Tours,
France
*E-mail: kaoukabi1985@gmail.com
Received May 24, 2018
DOI 10.1002/jhet.3478
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
In an attempt to improve anticancer activity, a series of retinoids–chromene hybrids was described. The
novel heterocyclic chromene–retinoids hybrid including oxygen as a heteroatom in a six-membered cyclic
ring (2H-chromene or 2H-1-benzopyran) was designed and synthesized by introducing different groups
such as an aromatic or styrylphenyl ring in 6-position of 2H-chromene. These novel compounds were syn-
thesized by using the efficient cascades one-pot process involving Wittig–Horner–Emmons reaction and
Suzuki–Miyaura cross-coupling pallado-catalyzed reactions with 60% to 90% overall yields. These new
compounds were tested against glioblastoma multiforme brain cancer, medulloblastoma, neuroblastoma cell
lines, and breast cancer MCF-7 cell lines. Two of them exhibited an appreciable anti-tumor activity in the
low micromolar range, which opens new perspectives for therapeutic application on humans.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
A
number of synthetic retinoids that interact
selectively with their receptors have been synthesized
[3–6]. These ATRA analogs have been synthesized
with the aim of improving the therapeutic efficacy, to
toxicity index as well as to secure better selectivity for
various therapeutic applications. These analogs involve
changes in the lipophilic or the hydrophilic part, the
spacer, or a combination of changes in the parent
compound ATRA [7].
Retinoids are analogs of all-trans-retinoic acid (ATRA),
a powerful hormone that mediates many fundamental
biological processes. Most of the physiological actions of
retinoids can be accounted by the transcriptional
regulatory activity of ATRA and 9-cis RA (9-CRA)
through their nuclear receptors, known as RA receptors
(RARs), (bind ATRA and 9-CRA), and retinoid X
receptors (bind 9-CRA) [1], which associate with RA
response elements within the promoters of retinoid-
responsive genes [2].
Cancer and other serious hyperproliferative diseases are
attractive therapeutic targets for retinoids [8–11]. However,
the therapeutic use of retinoids is limited due to their severe
© 2019 Wiley Periodicals, Inc.

A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
Vol 000
toxicity. ATRA is the first clinically useful cyto-
differentiating agent, being employed in the treatment of
acute promyelocytic leukemia [12]. For this purpose,
there is interest in expanding the therapeutic use of
ATRA and derivatives to breast cancer [13].
The selectivity, the high receptor binding affinity, and
the ability of retinoids to directly modulate gene
expression programs present a distinct pharmacological
opportunity for cancer treatment and prevention [14].
Therefore, the ATRA and retinoids derivatives (Fig. 1)
are largely exploited for therapy of malignant diseases
[15–26].
Despite the richness of pharmacological benefits of
retinoids, the toxicity represents the main limitation to
their chronic use. Therefore, it is imperative to develop a
new strategy to minimize the toxicity effect without
compromising their therapeutic effectiveness [27–29].
Indeed, systemic retinoid toxicity in adults is similar to
hypervitaminosis A, which manifests in skin dryness,
conjunctivitis, and hair loss. The cutaneous and metabolic
side effects of retinoid treatment are dose-dependent and
reversible. It should be noted that only a low percentage
of acute promyelocytic leukemia patients receiving RA
(14–16%) develop RA syndrome, encompassing dyspnea,
fever, pulmonary hemorrhage, and renal and respiratory
failures [11,30].
Several studies that have been described in the literature
suggest that the toxicity of structural analogs of RAs may
be considerably reduced if a heterocyclic is incorporated
in the structure of the product. For instance, the presence
of a substituted chromene moiety in RA backbone, such
as in the oxaretinoids, has reduced considerably the
toxicity of compound [31–35].
development of some more potent and significant
compounds. The derivatives of chromene moiety can be
able of interacting with a variety of cellular targets that
leads to their wide ranging biological activities [36–38],
such as anticancer agents [39–44] and as a human aldose
reductase like protein inhibitors [45,46], and chromene
derivatives with antiviral activity [47].
For this purpose, the chromene ring constitutes an
important pharmacophore in retinoids drug discovery.
Examples of oxaretinoids were reported recently bearing
the 2H-chromene motif with boron-containing derivative
of the RARα specific agonist Am-580 [31]. This new
derivative, BD4, binds to the RARα receptor with a
higher affinity and exhibits less cellular toxicity than Am-
580 and ATRA. Other authors have described the
synthesis of novel monofluoro lead compound 2-fluoro-
4-[8-bromo-2,2-dimethyl-4-(4-methylphenyl)-chromen-6-
yl]-4-aminocarbonylbenzoic acid as selective RARα
antagonist. Antagonist effects of this fluoro compound
were evaluated on the classical ligand-sensitive promoter
activation by RARα in MCF7 breast cancer cells [48].
Based on these findings and considering the importance
of the therapeutic potential of retinoids, we were interested
in designing and synthesizing a small library of new
chromene–retinoids hybrid derivatives (I–III) that
included a combination of changes in the lipophilic part
and spacer in the parent compound ATRA (Fig. 2). These
chromene–retinoids hybrid analogs were designed to
present variable electron density, lipophilicity, and steric
bulk in the heterocyclic ring. These compounds were
screened for bioactivity in glioblastoma multiforme brain
cancer and in breast cancer MCF-7 cells.
Indeed, chromene (benzopyran) is one of the privileged
medicinal pharmacophore that appears as an important
structural component in various natural compounds and
generated great attention because of its interesting
biological activity [36,37]. The potency of these clinically
useful pharmacophores in the treatment of cancer and
inflammation and other activities encouraged the
RESULTS AND DISCUSSIONS
The main for the preparation of these new chromene–
retinoids hybrid compounds (I–III) was based on the
previously mentioned work described by Brion et al.
[49]. These new compounds have been produced by
Figure 1. Retinoids derivatives exploited for therapy of cancer diseases.
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Month 2019
Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
Cross-coupling Reactions
Figure 2. Structures of the new 2H-chromene retinoids hybrid derivatives. [Color figure can be viewed at wileyonlinelibrary.com]
incorporation of the oxygen atom and by substitution of one
of the trans double bond of ATRA in the 2H-chromene ring.
These compounds have shown the absence of toxicity, and
they have shown an anti-resorbant, anti-proliferative, and
proapoptotic properties in preliminary experiments.
Indeed, the presence of an oxygen atom in the heterocyclic
ring changes the lipophilic nature of the molecule and
provides new opportunities for interaction with the target
zones of receptors. Furthermore, the SAR studies showed
that the incorporation of oxygen atom decrease the toxicity
by retarding metabolic oxidation, and the substitution in
the 6-position of chromene ring moiety has an important
role in the activity [50]. This work was also inspired by
the works more recently mentioned in the literature [51,52].
The novel chromene–retinoids hybrid compounds (Ia–f)
were designed with shortening of the chain and introducing
the phenyl groups in the 6-position; novel compound (II)
was designed with 1-methyl-4-(phenyl)sulfonyl)piperazine
as bioisostere and in compounds (IIIa–d), changes in the
lipophilic part, phenyl in 6-position was replaced by
substituted stilbenylgroup as bioisostere ring.
synthetic concept, which was based on heterocyclization
reaction for the synthesis of heterocyclic, the one-pot
cascade process Wittig–Horner reaction [58,59] and
Suzuki–Miyaura palladium-catalyzed Csp2–Csp2 cross-
coupling reactions [60–63].
The heterocyclic intermediates 6-bromo-2H-chromenes
carboxaldehyde 3a and ethanone 3b have been synthesized
from commercially available 5-bromosalicylaldehyd 1,
and acrolein 2a (or methylvinylketone 2b) by oxa-Michael/
aldol reactions using organic or inorganic bases (piperidine,
pyridine, DABCO, potassium carbonate, etc.) in dioxane or
toluene. The best results were obtained by using potassium
carbonate as base and dioxane as solvent (85% yield with
acrolein and 65% yield with methylvinylketone)
[31,51,64], as shown in Scheme 1.
In our retrosynthetic perspective, we first envisaged that
the target molecules chromene retinoid hybrid analogs
(Ia–d) could be achieved from precursors 3a–b, 4a–b,
and 5 according to the following retrosynthetic analysis
represented in the Figure 3.
Phosphonate esters [58] and phosphonium salts [7,59]
have often been used in the assembly of retinoid
spacers. We first sought to synthesize the heterocyclic
intermediate with bromide in 6-positions 6a and 6b via
Wittig–Horner reactions between commercially available
ethoxycarbonylmethylphosphonium bromide 4a or ethyl
phosphonoacetate 4b and 6-bromo-3-formyl-2H-chromene
3a or 6-bromo-3-acylchromene 3b by two methods: first,
Traditionally, polyene chain construction for the total
synthesis of ATRA and analogs was accomplished using
Wittig reaction [53], Horner–Wadsworth–Emmons, Julia,
and Stobbe reactions [54]; more recently, palladium-
catalyzed cross-coupling reactions were applied [55–57].
In order to prepare these new chromene–retinoids hybrid
derivatives (I–III), we decided to develop an efficient
Scheme 1. Synthesis of 6-bromo-2H-chromenes carboxaldehyde and ethanone 3a–b. [Color figure can be viewed at wileyonlinelibrary.com]
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A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
Vol 000
2 mol in hexane) as base is more efficient and more
stereoselective using phosphonium salt 4a than
phosphonate 4b.
Palladium-catalyzed Suzuki–Miyaura cross-coupling
reactions of aryl halides with arylboronic acids are among
the most efficient methods to selectively construct biaryl
compounds in organic synthesis [60], [65–70]. To date,
Suzuki reactions have been extensively used for the
synthesis of natural products, herbicides, pharmaceuticals,
and other products [60,71].
To synthesize the new compounds (Ia–f), we tested two
strategies based on palladium-catalyzed Suzuki coupling
reactions under homogenous catalysis reaction [72]. The
first strategy that operates two successive and independent
steps applying the Suzuki cross-coupling of the brominated
compounds 6a–b, serving as the key intermediates, which
have been obtained by the Wittig–Horner reaction after
isolation and purification of a chemical intermediate. The
intermediate is then coupled with phenylboronic acid
derivative in the presence of the catalyst Pd (OAc)2
(8 mol %) and P(C6H5)3 (30 mol %), lithium chloride (1
equiv) and potassium carbonate (2 equiv) in THF at
60°C, to give the target molecules in moderate yields
(45% to 55%). During the Suzuki cross-coupling
reaction, monitoring of the progress of the reaction by
TLC revealed that some of the reactants are still present
in the mixture. Increasing the amount of the catalyst (Pd
(OAc)2, 15 mol %) and prolonging the reaction time
(48 h) did not improve the yields.
Figure 3. Retrosynthetic analysis for access to new chromene–retinoids
hybrid analogs (Ia–f). [Color figure can be viewed at wileyonlinelibrary.
com]
using BuLi in THF or sodium hydride in toluene as
deprotonating agent at ꢀ78°C under nitrogen atmosphere
for 48 h. The Compounds ethyl (2E)-3-(6-bromo-2H-1-
benzopyran-3-yl)propenoate 6a were isolated and purified
by chromatography with good overall yields (70%) as
mixture of E and Z isomers in the ratio of 95:05 (Table 1,
entry 1) (Scheme 2). Unfortunately, this reaction using
6-bromochromene with 3-acyl group 3b produced ethyl
(2E)-[3-(6-bromo-2H-1-benzopyran-3-yl]butenoate 6b in
an overall moderate yield (45%) (Table 1, entry 2) as
mixture of geometric isomers cis and trans in the ratio of
90/10, based on the chemical shift of ethylenic proton at
5.65 and 5.85 ppm for the E and Z isomers, respectively.
(Only the trans isomer is drawn).
In the second strategy and in order to optimize the
experimental conditions and improve the yields, we
The analysis of the intermediates synthesis results 6a–b
shows that the method using the butyllithium (n-BuLi,
Table 1
Results of the preparation of the compounds 6a–b by two methods.
Reagents and conditions
n-BuLi (1.3 eq), 4a/4b (2 equiv)
THF, ꢀ78°C then 50°C; NaH (3 eq),
4a/4b (4 equiv) toluene, ꢀ78°C then
Yields (%) with 3a or 3b at
mixture of isomers (E:Z ratio)
Entry
1
Compound
R6
Br
R
H
65°C (base/time)
6a
n-BuLi/8 h
78 (98:02)/75 (96:04)
65 (96:04)/60 (95:05)
55 (92:08)/50 (93:07)
50 (92:08)/45 (90:10)
NaH/10 h
n-BuLi/10 h
NaH/20 h
2
6b
Br
CH3
Scheme 2. Synthesis of ethyl (2E)-3-[(6-bromo)-2H-1-benzopyran-3-yl]propenoate 6a (or butenoate) 6b. [Color figure can be viewed at
wileyonlinelibrary.com]
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Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
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decided to develop an alternative methodology for the
preparation of the novel compounds (Ia–f) based on the
new concept one-pot cascades that exploit the Wittig–
Horner reaction and Suzuki–Miyaura cross-coupling
reaction without isolation of intermediates 6a–b. First,
ethoxycarbonylmethylphosphonium bromide 4a was
condensed with aldehyd 3a (or ketone 3b) in the
presence of n-BuLi (2 equiv), in THF at ꢀ78°C, and
solvent were evaporated and DMF (10 mL), Pd (OAc)2
(2 mol %), phenylboronic acid and potassium carbonate
(2 equiv) have been added under nitrogen without using
lithium chloride and triphenylphosphine. The mixture
was heated at 90°C for 4 h. The progress of reaction was
monitored by TLC. Surprisingly, after only 4 h of
heating, all the reagents were consumed. Usual post-
reaction treatment by extraction of mixture and
chromatography leads to the expected purified coupling
product Ia with a good yield (85%).
Moreover, we have already carried out successfully
similar concept based on the cascades one-pot,
Sonogashira reaction, heterocyclization, and Heck cross-
coupling without the isolation of the intermediates in
previous work with good yields for the preparation of
new chromenimines and furanimines [73] but never
tested for Wittig–Horner reaction and Suzuki cross-
coupling reaction.
Miyaura cross-coupling reaction, which is followed by
Suzuki coupling reaction without isolation of the ethylenic
intermediate, we examined various bases and solvents.
When n-BuLi was replaced by LDA, NaH or EtONa or
BuOK (Table 2, entries 3, 4, and 5) as bases in THF for
the Wittig reaction, we observed that the Suzuki reaction
by evaporation of THF and addition of DMF in the
mixture as solvent, phenylboronic acid, Pd (OAc)2, and
K2CO3 did not accomplished (Table 2), but interestingly,
when BuLi or LDA was used as base in THF, the one-pot
cascade process Wittig–Horner reaction and Suzuki–
Miyaura cross-coupling reaction was successfully
achieved, and coupling product was obtained with 80% to
90% yield (Table 2, entry 2). These observations indicate
that the bases with lithium cation participate in the
transmetallation during the mechanism of the catalytic
cycle of palladium and triphenylphosphine present in the
mixture play an important role in the reduction of Pd (II)
to Pd (0), which is the active form in catalysis. For this
purpose, only 2 mol % of the catalyst Pd (OAc)2 was
required to carry out Suzuki coupling reaction. In order to
validate this hypothesis of the participation of the species
present in the mixture during the cascades one-pot to the
catalytic mechanism of palladium, Suzuki coupling
reaction was carried out between the 6-brominated
compound 6a and the phenylboronic acid under catalysis
by Pd (OAc)2 (2 mol %) without lithium chloride and
triphenylphosphine; the monitoring of the reaction by TLC
To further explore the factors that influence of this one-
pot cascade process Wittig–Horner reaction and Suzuki–
Table 2
Study of base effects of cascade one-pot Horner and Suzuki reaction.
Experimental conditionsa of the one-pot cascades process
4a or 4b (1.3 equiv), THF, ꢀ78°C to 25°C, and the solvent
(THF) was evaporated and replaced by DMF, phenylboronic acid
(1.1 equiv), K2CO3 (2 equiv): with 3a without PPh3 or LiCl, 90°C;
with 3b, Pd (OAc)2 (2 mol %), PPh3 (8 mol %), 90°C (Base, 2 equiv/time)
Entry
1
Product yield (%)
n-BuLi
with 4a, 8 h
with 4b, 16 h
Ia (90)
(30)
with 4b, 6 h, and PPh3 (8 mol %) was added, 24 h
(65)
2
3
4
5
LDA
with 4a, 6 h
with 4b, 24 h
with 4a, and PPh3 (8 mol %) was added, 6 h
Ia (85)
(15)
(55)
NaH
with 4a, 20 h
with 4b,, 24 h
with 4b, and PPh3 (8 mol %) was added, 24 h
Ia (25)
(05)
(15)
MeONa
with 4a, 20 h
with 4b, 24 h
with 4b, and PPh3 (8 mol %) was added, 24 h
Ia (20)
(05)
(12)
t-BuOK
with 4a, 16 h
with 4b, 24 h
Ia (15)
(03)
with 4b, and PPh3 (8 mol %) was added, 20 h
(10)
aAll reactions were performed using THF for Horner–Wittig reactions. THF was evaporated and replaced by DMF under nitrogen atmosphere.
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A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
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showed that the starting products are always present in the
mixture, and no trace of coupling product is detected. In
the case where the one-pot cascade Horner reaction and
Suzuki coupling reaction is carried out with the
phosphonates 4b without isolation of ethylenic
intermediate 6a, in the presence of butyllithium, without
lithium chloride and triphenylphosphine, no trace of
coupling product was detected (Table 2, entry 1). The
addition of triphenylphosphine (8 mol %) to the mixture
with the catalyst Pd (OAc)2 (2 mol %) allows the
formation of the coupling product Ia in (Table 2, entry 1).
These results confirm our hypothesis of the role of lithium
ions in the transmetallation and participation of
triphenylphosphine in the reduction of Pd (II) to Pd (0).
Analysis of the results in Table 2 shows very different
yields depending on the bases used. The BuLi and LDA
lithium bases clearly lead to the highest yields confirming
the role of lithium ions in transmetallation during Suzuki
cross-coupling reaction. Sodium and potassium ions do
not perform this role effectively.
In fact, the one-pot approach of synthesis has shown
several practical advantages: the lithium bases BuLi and
LDA allow both the Wittig condensation and the lithium
and triphenylphosphine participate to the reduction of
palladium (II) to palladium (0) and transmetallation.
Furthermore, the synthesis can be performed within a
short reaction time and without using lithium chloride or
triphenylphosphine, which is the conventional reagent in
these processes. Furthermore, it is known that the
presence of triphenylphosphine in the mixture makes the
purification of the coupling product more difficult. With
this one-pot cascade process Wittig reaction Suzuki
cross-coupling reaction does not require adding
triphenylphosphine and lithium chloride, which are
usually added in the Suzuki coupling reaction. Secondly,
this one-pot cascade process Wittig reaction and Suzuki
cross-coupling reaction has several practical advantages:
it avoids the separation and purification of the ethylenic
intermediate and therefore saves solvents and silica for
chromatography and energy and avoids the risks of loss
of valuable materials during the purification. To confirm
the advantages of this one-pot cascade process, we
carried out a comparative study between this concept and
the one in two successive and independent steps, namely,
the Wittig reaction, and then, separation and purification
of the heterocyclic ethylenic bromine compounds 6a–b,
and Suzuki cross-coupling reaction under the
conventional conditions in the presence of 8 mol % of
catalyst Pd (OAc)2, lithium chloride (1.2 equiv),
triphenylphosphine (40 mol %) and potassium carbonate
(4 equiv). The Suzuki cross-coupling reaction efficiency
was about 60–75% overall yield, but over a longer
chromatography TLC). On the other hand, the Suzuki
cross-coupling reaction that was carried out using the
same substrates of phenylboronic acid and the
heterocyclic ethyl compound 6b, using Pd (OAc)2 8 mol
% as catalyst, but in the absence of lithium chloride and
triphenylphosphine, does not make it possible to obtain
the expected C–C catalyzed coupling product, and the
monitoring of the reaction by TLC chromatography
shows that only the starting reagents are present in the
reaction mixture.
For this purpose, we applied successfully the optimized
one-pot cascades process Wittig reaction and Suzuki
cross-coupling reaction by condensing compounds 3a–b
with ethoxycarbonylmethylphosphonium bromide 4a.
The bromide compounds 6a–b formed is not isolated but
reacts with various boronic phenyl acids to give a
diversified corresponding new chromene–retinoids hybrid
analogs (Ia–f) with good yields (75–95%), as illustrated
in Scheme 3.
Compounds Ia–f were prepared by two methods
(Table 3) and fully characterized by their 1H and 13C
NMR and IR, and their mass were checked by HRMS
(Supporting Information).
Although those overall results are not easy to explain, as are
the differences between the reactivity of the phosphonium
salts 4a and the phosphonates 4b, and the link with the
palladium catalytic activity, one possible explanation could
be that the presence of triphenylphosphine in the reaction
mixture would promote in situ the reduction of palladium
(II) to palladium (0) and maintain this reduced form of the
catalyst and increases its catalytic activity. When
phosphonates are used, the triphenylphosphine (8 mol %)
must be added with the catalyst (2 mol %) to promote its
reduction. On the other hand, the lithium ions that
originate from n-BuLi still present in the mixture promote
the transmetallation step to the Suzuki cross-coupling
reaction. In fact, it may be assumed that in this one-pot
concept, the experimental conditions of the Wittig
reaction are consistent with the Suzuki cross-coupling
step and the reagents used for the Wittig reaction can also
be used to carry out the Suzuki cross-coupling reaction.
Therefore, a smaller amount of the catalyst Pd (0) form
(2 mol %) become sufficient to achieve the C–C cross-
coupling reaction without lithium chloride and
triphenylphosphine that are usually used in this type of
reactions [60], [61,62,74].
Encouraged by the aforementioned results and the
importance of the bioisostere 1-methyl-4-(phenyl)
sulfonyl)piperazine in increasing the activity of bioactive
molecules [75], we applied the same one-pot cascade
process successfully to extend the bioisosterie in 6-
position of the chromene by introducing the 1-methyl-
4-(phenyl)sulfonyl)piperazine to give new chromene
retinoid hybrid II. For this purpose, the access to
reaction time of 26
h to observe the complete
disappearance of the starting reagents (monitored by
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Month 2019
Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
Cross-coupling Reactions
Scheme 3. Reagents and reaction conditions: Way A: (i) (EtO)2OPCH2COOEt or ethoxycarbonylmethylphosphonium bromide, BuLi (1.3 equiv), THF,
ꢀ78°C then 50°C during 4 h; (ii) K2CO3, LiCl (1 equiv), Pd (OAc)2 (8 mol %), PPh3 (20 mol %) toluene/EtOH (8:2), 70°C, 14–16 h. Way B: (iii) first
ethoxycarbonylmethylphosphonium bromide 4a or (EtO)2OPCH2COOEt 4b, appropriate base (2 equiv), THF, ꢀ78°C then 50°C for 4 h, and the solvent
was evaporated and replaced by DMF (10 mL), and Pd (OAc)2 (2 mol %), (PPh3 (8 mol %) with 3b), and appropriate phenyl boronic acid derivative were
added under nitrogen, 90°C, 4–10 h. [Color figure can be viewed at wileyonlinelibrary.com]
Table 3
Results of the preparation of new compounds Ia–f by two ways.
Time t1 for two successive steps/t2
for the one-pot cascade process
Yield (%) in two successive steps; catalyst
(8 mol %)/yield (%) by the one-pot cascade process
Entry
Compound
R
R″
1
2
3
4
5
6
Ia
Ib
Ic
Id
Ie
If
H
H
H
H
H
H
OMe
F
CH3
Cl
H
24/8
36/8
36/8
30/8
36/7
32/10
50/85
45/90
40/80
50/75
45/90
40/75
CH3
Way A: Time t1 for two successive steps, Pd (OAc)2 catalyst (8 mol %). Way B: t2 for the one-pot cascade process Pd (OAc)2 catalyst (2 mol %) without
LiCl or P(C6H5)3 with 4a.
compound II through the one-pot concept has been
explored using the Suzuki cross-coupling reaction
between compound 6a, phosphonium salt 4a, and 1-
methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl]sulfonyl)piperazine 11 in which the synthesis has
already been described in the literature [76]. The first step
involved the preparation of the 1-[(4-bromophenyl)
sulfonyl)-4-methylpiperazine precursor 9, which was
afford the novel chromene–retinoids hybrid II in 85%
yield as shown in Scheme 4.
This concept of the one-pot cascade process involving
Wittig reaction and cross-coupling Suzuki reaction has
again been proved very effective for the preparation of
the new hybrid analog (II). The product was
1
characterized by H and 13C proton NMR spectroscopy,
and its chemical structure was confirmed by mass
spectroscopy. The characteristic signals of the ethylenic
protons H2 and H3 appear at chemical shifts of 5.80 and
7.38 ppm respectively in the form of two doublets. The
coupling constant J1,3 = 16 Hz coupling of the ethylenic
protons is in favor of the trans configuration of the
double bond. The protons of the piperazine ring appear at
2.48 ppm (2CH2) and 3.07 ppm (2CH2–N) in the form of
two triplets with a 6.5 Hz coupling constant. The four
aromatic protons of the phenyl at 6-position of the
chromene heterocycle appear at 7.65 and 7.78 ppm as a
doublet with a coupling constant J1.3 = 8 Hz. The proton
signals at 2-position of the heterocycle appear in their
usual zone at 5.02 ppm as a singlet. The signal of the
prepared from 1-methylpiperazine
bromobenzene)]sulfonylchloride
7
and 4-[(4-
8
in THF with
quantitative yield. The 1-methyl-4-((4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine 11 was
obtained from the intermediate compound
9 and
pinacolatodiboron 10 using potassium carbonate K2CO3
and PdCl2(dppf)2 (2 mol %) as catalyst in THF/DMSO
solvents mixture to afford compound 11 in 50% yield.
Next step implies the one-pot cascade process involving
Wittig and Suzuki cross-coupling reactions that was
described previously between the brominated heterocyclic
derivative 6a and 1-methyl-4-((4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine 11 to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
Vol 000
Scheme 4. Reagents and reaction conditions: (i) THF, RT, 4 h, 95% yield; (ii) KOAc, PdCl2(dppf)2, dioxane, DMSO, 100°C, 16 h, 50% yield; (iii) Pd
(OAc)2, 2 mol %, PPh3 4 mol %, DMF, 90°C, 8 h, 80% yield. [Color figure can be viewed at wileyonlinelibrary.com]
methyl group in piperazine appears at 2.27 ppm as a
singlet. The H4 and H5, H7 and H8 proton signals appear
at 6.79 ppm (singlet), 7.29 ppm (d, J1.4 = 1.8 Hz),
7.38 ppm (doublet of doublet, J1.3 = 7 Hz and
J1.4 = 1.8 Hz), and 6.93 ppm (doublet, J1.3 = 7 Hz),
respectively.
band at 613.20 cmꢀ1. The vibrating band of the carbonyl
ester group appears in its usual zone at 1711 cmꢀ1
.
Moreover, we considered extending the bioisostere by
the elongation of the skeleton in its lipophilic part, to
access to the new chromene–retinoids hybrid analogs
(III) by introducing the styryl group on the phenyl to
which we have attached various substituents from
precursors 3a–b, 12a–c, and phenylboronic acid 13
according to the following retrosynthetic analysis as
shown in Figure 4.
According to the strategy based in the one-pot cascade
Wittig–Horner reaction and Suzuki–Miyaura cross-
coupling reaction described previously and the
heterocyclic bromide compounds 3a–b, phosphonium salt
4a, and 4-formylphenylboronic acid 13 as the substrates,
the aldehyde Ie containing heterocyclic ring system was
prepared with 80% yield as a yellow solid.
Analysis of the 13C NMR spectrum of the product
revealed the characteristic signals of the carbon atoms of
the piperazine heterocycle at 45.69, 45.97, and
54.03 ppm. The signal of the carbon atom at 2-position
of the heterocycle appears at 65.37 ppm, and the
carbonyl signal of the ester appears at 166.64 ppm. The
signals from the ethyl group of the ester appear at 14.30
and 60.66 ppm. The chemical formula of the product was
confirmed by mass spectroscopy (calcd for C25H29N2O5S
[M + H]+, 469.17983; found, 469.17686).
Analysis of the FTIR spectrum showed the presence of
the elongation vibration bands of the sulfone group
1172.65, 1311.17, and 1346.92 cmꢀ1 and a deformation
The required primary phosphonium salts 12a–c were
readily obtained by the treatment of the benzyl bromide
Figure 4. Retrosynthetic analysis to access to chromene–retinoids hybrid compounds (IIIa–d). [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2019
Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
Cross-coupling Reactions
with triphenylphosphine in THF at 60°C for 12 h with a
quantitative yield.
″ = F or Cl, 85% yield, during a shorter time 14 h). This
Wittig reaction was shown to be fairly stereoselective for
all ethyl propenoate analogs (IIIa,c). On the other hand,
for the ethyl butenoate heterocyclic derivative (IIId)
(R3 = Me), the Wittig reaction is less stereoseletive
(Table 4, entry 4, mixture of isomers ratio E/Z 85/15). In
this case, a mixture of stereoisomers containing about
15% of the Z isomer is obtained (the Z isomer is not
described in this paper). All these products have been
characterized by NMR spectroscopy of 1H proton and
13C carbon and by FTIR spectroscopy. Their chemical
formulas have been confirmed by mass spectroscopy. For
example, the proton H4 signal of compound IIIa appears
as 6.55 ppm as a singlet, and the ethylenic protons H2
and H3 appear at 6.47 and 7.65 ppm as a doublet with a
coupling constant J1.3 = 15 Hz (trans configuration of
double bond). The phenyl protons at the 6-position of the
chromene appear at 8.12 and 7.53 ppm as a doublet
(J1.3 = 8 Hz). The signal of the protons in 2-position of
the heterocycle appears in their usual zone at 5.11 ppm.
The FTIR spectrum of product IIIa shows the carbonyl
group elongation vibration band of the ester function at
1716 cmꢀ1 and the vibration bands of aromatics (C═C)
According to a convergent strategy, the Wittig reaction
between the phosphonium salt 12a–c and the aldehyde Ig
in THF is performed in the presence of BuLi as base at
ꢀ78°C to give the corresponding ethylenic compounds
IIIa–d (Table 2) with good yields in the form of a
mixture of isomer in which the trans isomer has a large
majority (E/Z: 98/02) and readily separated by
chromatography. (Only the trans isomer is drawn).
Encouraged by the success of this strategy, we have
synthesized, in the same experimental conditions, a series
of analogs with different substituents (R = H, R0 = H, F, Cl,
Table 3, entries 1, 2, 3, and R = CH3, R = H, entry 4) in
good yields. When R3 = CH3 (Table 3, entry 4), the
compound IIId was isolated with 85% yield as (85/15)
(E/Z) ratio, and (E) isomer was successfully separated by
column chromatography using SiO2 and mixture
hexane/dichloromethane (80/20 ratio) as eluent. The
general scheme for access to the new chromene–retinoids
hybrid derivatives IIIa–d is presented in Scheme 5.
The analysis of the experimental results described in
Table 4 makes it possible to conclude that the Wittig
condensation reactions for access to the chromene–
retinoids hybrid IIIa–d analogs are carried out with
satisfactory overall yields (Table 4, entries 2 and 3, R
and (═CH) at 3028 cmꢀ1 between 1368 and 1639 cmꢀ1
,
respectively, thus confirm the existence of the phenyl
groups.
Scheme 5. Reagents and reaction conditions: (i) first Br, (C6H5)3PCH2COOEt 4a, BuLi (2 equiv), THF, ꢀ78°C, then 50°C for 12 h; (ii) the solvent was
evaporated, and DMF, Pd (OAc)2 (2 mol %), K2CO3 (2 equiv) were added, 90°C, 10 h; (iii) phosphonium salts and n-BuLi (1.2 equiv) in THF, ꢀ78°C
then 25°C, 8 h. [Color figure can be viewed at wileyonlinelibrary.com]
Table 4
Results of synthesis of chromene–retinoids hybrid derivatives IIIa–d.
Entry
Compound
R
R‴
Time of reaction (h)
Yield (%)
Ratio (E/Z)
1
2
3
4
IIIa
IIIb
IIIc
IIId
H
H
H
H
Cl
F
16
14
14
18
80
85
85
70
95/05
96/04
95/05
85/15
CH3
H
Journal of Heterocyclic Chemistry
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A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
Vol 000
Table 5
Results of preparation of 6-bromo-2H-chromenes carboxaldehyde and ethanone 3a–b by two methods.
Reagents conditions: Method A—pyridine,
100°C; Method B—K2CO3, (2 eq) dioxane, 90°C
Entry
1
Compound
R
H
R5
Br
Yields (%)
3a
With acrolein (2 eq)
Method A, 16 h
55
85
Method B, 6 h
2
3b
CH3
Br
With methylvinylketone (3.5 eq) and:
Method A, 24 h
50
65
Method B, 20 h
Table 6
Cytotoxic activity (tests in brain cancer cell).
Cell line IC50 (μM)
Entry
Compound
IC50 (U87)
IC50 (U251)
IC50 (U118)
1
2
3
Ia
Ib
Ic
>1000
>150
10
NIa
>100
10
NIa
>150
10
4
Id
100
100
100
5
Ie
10
10
10
6
7
8
9
10
11
12
If
Ig
II
IIIa
IIIb
IIIc
IIId
>100
>100
NDb
>100
>100
10
>100
>100
NDb
>100
>100
10
>100
>100
NDb
>100
>100
10
>100
>100
>100
aNI, non inhibition.
bNot determined.
Table 7
PHARMACOLOGY
Cytotoxic activity (tests in medulloblastoma and neuroblastoma cell).
Preliminary evaluation of these 2H-chromene retinoids
hybrid analogs concerning their ability to inhibit the
proliferation of human brain cancer cell and human breast
cancer MCF-7 cells. First provisionally, these new
compounds were tested in glioblastoma multiforme brain
cancer (U87, U251, and U118 cell lines). According to
the results described in Table 6, the compounds Ie and
IIIc showed a cytotoxic activity at 10 μM after 72 h,
which inhibits cell growth (Table 6, entries 3 and 11). In
contrast, the other compounds Ia–d (Table 5, entries
Cell line IC50 (μM)
IC50
IC50
Entry Compound (medulloblastoma cell) (neuroblastoma cell)
1
2
Ie
IIIc
100
10
100
10
Further studies are now in progress in order to develop
more active compounds and also to determine the
mechanisms through which analogs Ie and IIIc exerts its
antiproliferative and cytotoxic activities. The results of
these studies will be published subsequently.
1–4), If,g, and IIIa,b,d showed
a
moderate
antiproliferative activity (Table 6, entries 9–10, 12).
However, the compound Ia proved inactive against these
three malicious cancer cell lines.
Then, the target-to-hit compounds Ie and IIIc were
tested in other two brain cancers medulloblastoma and
neuroblastoma cell lines, and we found that IIIc is active
at 10 μM against these two brain cancers (Table 7, entry 2).
In contrast, the compound Ie showed a moderate cytotoxicity
(Table 7, entry 1).
CONCLUSION
We report for the first time the success at synthesizing
novel chromene–retinoids hybrid derivatives. The concept
that was based on the one-pot cascade process involving
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Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
Cross-coupling Reactions
Wittig reaction and Suzuki cross-coupling reaction without
isolation of the intermediate and using the existing species
in the reaction mixture such as triphenylphosphine for
reduction of Pd (II) and lithium ions for transmetallation
showed more advantage than successive multistep
synthesis because of faster method and provides better
overall yields. In addition, the one pot cascade process
was carried out without lithium chloride and
triphenylphosphine, which is the usual reagent of the
Suzuki cross-coupling reaction, and using lesser amount
of the catalyst (2 mol %), and it was possible to
economize on the solvents and purification materials of
intermediates. The preliminary evaluation of these
chromene–retinoids hybrid products to inhibit the
proliferation of human brain cancer cell have shown very
encouraging results.
135.48, 132.55, 131.37 122.19, 118.49, 113.96, 63.33. IR
(KBr): ν (cmꢀ1): 2928–2857, 1670, 1275, 750.
Way B.
A mixture of 5-bromosalicylaldehyde 1
(10 mmol) and acrolein 2a (20 mmol) in a dry pyridine
(20 mL) was stirred at 90°C for 12 h under nitrogen
atmosphere. After completion of the reaction as indicated
by TLC, the reaction mixture was quenched with water
(10 mL) and extracted with ethyl acetate (3 × 15 mL).
The organic layer was washed with aqueous solution of
sodium hydrogenocarbonate (5%) (20 mL) and brine
solution (20 mL), respectively, then dried under
anhydrous Na2SO4. Evaporation of the solvent followed
by purification on silica gel column chromatography
using hexanes/ethyl acetate (9:1) as eluent afforded pure
(6-bromo-2H-chromen-3-yl)-carboxaldehyde 3a in 65%
yield.
Synthesis
(3b).
of
2-(6-bromo-2H-chromen-3-yl)-ethanone
To a mixture of 5-bromosalicylaldehyde 1
EXPERIMENTAL
(10 mmol) and methylvinylketone 2b (35 mmol) in a dry
dioxane (30 mL) and potassium carbonate (40 mmol) was
added, and the reaction mixture was stirred at 90°C for
24 h under nitrogen atmosphere. After completion of the
reaction as indicated by TLC, the reaction mixture was
quenched with water (10 mL) and extracted with ethyl
acetate (3 × 15 mL). The organic layer was washed with
aqueous solution of sodium hydrogenocarbonate (5%)
(20 mL) and brine solution (20 mL), respectively, then
dried under anhydrous Na2SO4. Evaporation of the
solvent followed by purification on a silica gel column
chromatography using hexanes/ethyl acetate (9:1) as
eluent afforded pure 2-(6-bromo-2H-chromen-3-yl)-
All reactions were carried out under inert atmosphere,
unless mentioned otherwise. Solvents were dried and
purified by standard methods. All reagents were
purchased from commercial sources unless otherwise
indicated. The progress of all reactions was monitored by
TLC using glass plates precoated with silica gel 60 F254
to a thickness of 0.5 mm. Column chromatography was
performed on a silica gel (60 mesh) using ethyl acetate
and hexane as eluents. IR spectra were recorded on a
Perkin-Elmert FTIR spectrometer. 1H and 13C NMR
spectra were recorded on a Bruker Avance 300 and
75 MHz respectively, using TMS as an international
standard in CDCl3. Mass spectra were recorded on a
Micromass VG-7070H for IE.
1
ethanone 3b. 60% yield. H NMR (300 MHz, CDCl3): δ
(ppm) 7.35–7.39 (m, 2H), 7.18 (d, 1H, J1.4 = 1.5 Hz),
6.68 (s, 1H), 5.03 (s, 2H), 2.48 (s, 3H). 13C NMR
(300 MHz, CDCl3): 152.0, 138.47, 134.48, 130.56,
129.37, 121.19, 116.49, 111.96, 66.6, 62.4. Rf: 0.40
(hexane/dichloromethane 80:20) Rdt: 75%; mp 92–94°C,
C11H9O2Br, Mr: 253 g/mol, IR (KBr): ν (cmꢀ1): 2925–
2857, 1662, 1205, 716.
Synthesis of (6-bromo-2H-chromene-3-yl)-carboxaldehyde
(3a). Way A. A mixture of 5-bromosalicylaldehyde 1
(10 mmol), acrolein 2a (15 mmol), and potassium
carbonate (30 mmol) in a dry dioxane (30 mL) was
stirred at 90°C for 8 h under nitrogen atmosphere. After
completion of the reaction as indicated by TLC, the
reaction mixture was quenched with water (10 mL) and
extracted with ethyl acetate (3 × 15 mL). The organic
layer was washed with aqueous solution of sodium
hydrogenocarbonate (5%) (20 mL) and brine solution
(20 mL), respectively, then dried under anhydrous
Na2SO4. Evaporation of the solvent followed by
purification on silica gel column chromatography using
hexanes/ethyl acetate (9:1) as eluent afforded pure 6-
bromo-2H-chromene-3-carbaldehyde 3a. 85% yield,
C10H7O2 Br, Mr: 239 g/mol; mp 95–97°C. 1H NMR
(300 MHz, CDCl3): δ (ppm): 9.61 (s, 1H), 7.31–7.40 (dd,
1H, J1.3 = 8 and J1.4 = 1.2 Hz), 7.35 (d, 1H,
J1.4 = 1.2 Hz), 7.19 (s, 1H), 6.65 (d, 1H, 8 Hz), 5.08 (s,
2H). 13C NMR (75 MHz, CDCl3): 189.36, 154.0, 139.49,
Standard procedure for preparation of ethyl 6-bromo-3-
[2H-chromen-3-yl]propenoate 6a and but-2-enoate 6b.
Processed in two successive steps. A mixture of 6-bromo-
2H-chromene-3-carboxaldehyde 3a (10 mmol) and THF
(30 mL) was taken in a three-necked flask. To this
solution, 12 mmol of phosphonium salt 4a or ethyl
phosphonoacetate 4b was added with magnetic stirring
under nitrogen atmosphere. The mixture was allowed to
cool at ꢀ78°C, and then butyllithium in hexane
(24 mmol) was added dropwise. After 2 h at room
temperature, the reaction mixture was stirred at 60°C for
12 h. After completion of the reaction as indicated by
TLC, the reaction mixture was quenched with NaCl
solution (15 mL) and extracted with ethyl acetate
(2 × 15 mL). The combined organic layers were dried
Journal of Heterocyclic Chemistry
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A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
Vol 000
over Na2SO4. Evaporation of the solvent followed by
purification on a silica gel column chromatography using
hexanes/ethyl acetate (9:1) as eluent afforded pure ethyl
(2E)-6-bromo-3-[2H-chromen-3-yl]propenoate 6a as a
yellow solid: mp 166–168°C, in 75% yield, C14H13O3Br,
(849 mg, 1.16 mmol) were added under argon
atmosphere. The mixture was stirred at 100°C for 16 h.
After filtration and evaporation of the solvent, the residue
was extracted with ethyl acetate. The organic layer was
washed with saturated sodium chloride, dried over
magnesium sulfate, and concentrated under reduce
pressure. The crude product was purified by flash column
chromatography using dichloromethane/methanol (95/5)
v/v to afford 4.24 g (50% yield) of 11 as a solid. 1H
NMR (300 MHz, CDCl3): δ (ppm) 7.94 (d, J = 8.3 Hz,
2H), 7.72 (d, J = 8.3 Hz, 2H), 3.03 (s, 4H), 2.47 (s, 4H),
2.26 (s, 3H), 1.35 (s, 12H).
1
Mr: 309 g/mol. Rf = 0.3 (hexane/ethyl acetate 8:2). H
NMR (300 MHz, CDCl3): δ (ppm) 7.32 (1H, d,
J1.3 = 15.5 Hz), 7.20–7.10 (2H, m), 6.75 (1H, s), 6.61
(1H, d, J1.3 = 7.2 Hz), 5.72 (1H, d, J1.3 = 15.5 Hz), 4.95
(2H, s), 4.24 (2H, q, J1.3 = 7 Hz), 1.29 (3H, t,
J1.3 = 7 Hz). 13C NMR (75 MHz, CDCl3): 168.7, 154.0,
149.05, 140.49, 135.48, 132.55, 131.37 122.19, 118.49,
113.96, 63.33, 60.05, 16.87. IR (KBr): ν (cmꢀ1): 3050–
2910, 1705, 1240, 1311, 1184, 750; HRMS (EI, m/z):
[M + H]+, calcd for C14H14BrO3: 310.16372, found:
310.16204.
Similarly, we prepared ethyl (2E)-6-bromo-3-[2H-
chromen-3-yl]but-2-enoate 6b from 2-(3-bromo-2H-
chromen-3-yl)ethanone 3b and phosphonium salt 4a or
ethyl phosphonoacetate 4b. Reaction times and
temperatures are given in Table 1. mp 152–156°C, in
55% yield, C15H15O3Br, Mr: 323 g/mol. Rf = 0.28
(hexane/ethyl acetate) = 9:1)
1H NMR (300 MHz, CDCl3, TMS): δ (ppm): 7.15 (2H,
m), 6.7 (1H, s), 6.6 (1H, d, J1.3 = 7.8 Hz), 5.7 (1H, s), 4.92
(2H, s), 4.2 (2H, q, J1.3 = 7 Hz), 2.4 (3H, s), 1.3 (3H, t,
J1.3 = 7 Hz). 13C NMR (75 MHz, CDCl3): 167.8, 153.5,
149.69, 140.39, 135.45, 132.25, 131.32, 121.99, 116.38,
113.12, 63.02, 60.02, 23.45, 16.87. IR (KBr): ν (cmꢀ1):
3045–2915, 1700, 1311, 1245, 1180, 750. HRMS (EI, m/
z): [M + H]+, calcd for C15H16BrO3: 324.19034, found:
324.1887.
General procedure for the Suzuki cross-coupling reaction
of aryl bromide 6a and 6b with aryl boronic acids 5a–e.
The aryl bromide (0.5 mmol), arylboronic acid
(0.75 mmol), catalyst palladium acetate Pd (OAc)2 (5 mol
%), triphenylphosphine (20 mol %), lithium chloride
(0.75 mmol), potassium carbonate K2CO3 (1.5 mmol),
and mixture of solvents—toluene : ethanol : water
(0.75:0.15:0.10 v/v) 10 mL—were successively added,
under nitrogen, into a 25 mL round bottom flask. The
mixture was stirred vigorously at 90°C for the varying
specific length of time based on each different substrates.
After reaction completion, the solid was filtered off, and
the filtrate was extracted with ethyl acetate (3 × 5 mL),
washed with water and brine three times, and then dried
over anhydrous MgSO4. After removing the solvent, the
crude product was purified by column chromatography
over a silica gel (eluent : petroleum ether/ethyl acetate,
90/10) to give the desired product and calculate the yield.
Reaction times and yield and temperatures are given in
Table 2.
General procedure for cascades one-pot Wittig (or Horner
Emmons) and Suzuki cross-coupling reactions without
isolation of the reaction intermediates. In a three-necked
Procedure for preparation of 1-methyl-4-((4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)
piperazine 11.
To a solution of 4-[(4-bromobenzene)]
(6.00 g, 23.48 mmol) in
flask, to
a solution of (6-bromo-2H-chromen-3-yl)
sulfonylchloride
8
carboxaldehyde 3a (10 mmol) in 20 mL of anhydrous
THF was added phosphonium salt 4a or ethyl
phosphonoacetate 4b (12 mmol) under nitrogen and
under stirring. The mixture was allowed to cool to
ꢀ78°C, and then butyllithium (1.6 M in hexane, 2 equiv,
24 mmol) was added dropwise. The mixture reaction was
allowed to return to room temperature for 2 h and stirred
at 60°C for the additional time t1 indicated in Table 3 to
complete the reaction (monitored by TLC). Then THF
was removed under vacuo. Under a nitrogen atmosphere,
in the case where the reaction is carried out with ethyl
phosphonate 4b, anhydrous DMF (10 mL), palladium
acetate Pd (OAc)2 (2% mol), (triphenylphosphine (8 mol %)
and potassium carbonate (2 equiv) and appropriate
phenylboronic acid (15 mmol) were sequentially added.
When the reaction is carried out with the phosphonium salt
4a, triphenylphosphine is not added to the mixture. The
reaction was stirred at 90°C for the time t2 indicated in
tetrahydrofuran (40 mL), 1-methylpiperazine 7 (3.9 mL,
35.22 mmol) was added. The resulting reaction mixture
was stirred at room temperature for
4 h. After
evaporation of the solvent, the residue was dissolved in
dichloromethane (100 mL) and washed with saturated
sodium hydrogen carbonate aqueous solution (three
times), saturated sodium chloride aqueous solution, dried
over magnesium sulfate, and concentrated under reduced
pressure to give 7.41 g (quantitative yield) of 9 as white
1
solid. H NMR (300 MHz, CDCl3): δ (ppm) 7.70–7.64
(m, 2H), 7.64–7.56 (m, 2H), 3.10–2.95 (m, 4H), 2.59–
2.38 (m, 4H), 2.26 (s, 3H).
1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl)sulfonyl)piperazine 11.
To a solution of 1-((4-
bromophenyl)sulfonyl)-4-methylpiperazine (7.4 g,
9
23.20 mmol) in 1,4-dioxane (89 mL) and DMSO
(7.4 mL) pinacolatodiboron 10 (17.67 g, 69.59 mmol),
potassium acetate (4.56 g, 46.39 mmol), and PdCl2(dppf)
Journal of Heterocyclic Chemistry
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Month 2019
Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
Cross-coupling Reactions
Table 3. The deep brown color mixture was allowed to cool to
25°C and was poured into water (20 mL). The mixture was
filtered and extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were washed with water (15 mL)
and dried over anhydrous Na2SO4, and the solvent was
removed. The residue was purified by chromatography on a
silica gel using 5% ethyl acetate/hexane as eluent, to afford
compounds (Ia–f) with the yields indicated in Table 2.
141.45, 166.62. IR (KBr): ν (cmꢀ1): 3414, 2979, 2362,
1705, 1612, 1486, 1317, 1169, 813. HRMS (ESI) m/z:
calcd for C21H21O3 [M + H]+, 321.14918; found,
321.14674.
Ethyl 3-(6-(4-chlorophenyl)-2H-chromen-3-yl)prop-2-enoate
(Ie).
mp 156–158°C (hexane/dichloromethane 7:3),
1
C20H17ClO3: 340 g/mol. H NMR (CDCl3, 300 MHz): δ
(ppm): 1.33 (t, 3H, J = 7 Hz), 4.26 (q, 2H, J1.3 = 7 Hz),
5 (s, 2H), 5.76 (d, 1H, J1.3 = 15.5 Hz), 6.73 (s, 1H), 6.91
(d, 1H, J1.3 = 15.5 Hz), 7.02–7.46 (m, 7H). 13C NMR
(CDCl3, 300 MHz): δ: 14.02, 43.96, 46.65, 60.38, 71.42,
116.22, 118.35, 122.02, 123.13, 126.23, 127.85, 129.24,
130.29, 133.16, 134.55, 139.09, 141.19, 146.70, 155.32,
165.40. IR (KBr): ν (cmꢀ1): 3413, 2980, 1709, 1622,
1481, 1313, 820. HRMS (ESI) m/z: calcd for
C20H18ClO3 [M + H]+, 341.09456; found, 341.09207.
Ethyl 3-(6-(4-phenyl)-2H-chromen-3-yl)but-2-enoate (If).
mp 150–152°C (hexane/dichloromethane 5:5), C21H20O3:
Ethyl
(Ia).
(2E)-3-(6-phenyl-2H-chromen-3-yl)prop-2-enoate
mp 142–144°C (hexane/ethyl acetate 8:2),
C20H18O3: 306 g/mol. 1H NMR (CDCl3, 300 MHz,
TMS): δ (ppm) 1.33 (t, 3H, J1.3 = 7 Hz), 4.17 (q, 2H,
J1.3 = 7 Hz), 5.01 (s, 2H), 5.7 (d, 1H, J1.3 = 15.8 Hz),
6.75 (s, 1H), 6.8 (d, 1H, J1.3 = 15.8 Hz), 7.26–7.54 (m,
8H). 13C NMR (CDCl3, 300 MHz): δ (ppm) 14.31,
60.61, 65.25, 116.13, 117.36, 121.94, 126.46, 126.66,
127.03, 128.80, 129.50, 130.68, 134.99, 140.27, 153.94,
166.77. IR (KBr): ν (cmꢀ1): 2982, 1709, 1630, 1620,
1
1482,
750.
HRMS
(ESI)
m/z:
Calcd
for
320 g/mol. H NMR (CDCl3, 300 MHz): δ (ppm): 1.33
C20H19O3[M + H]+, 307.13353; found, 307.13108.
(t, 3H, J1.3 = 7 Hz), 2.46 (s, 3H), 4.21 (q, 2H,
J1.3 = 7 Hz), 5.02 (s, 2H), 5.68 (s, 1H), 6.92–7.54 (m,
9H). 13C NMR (CDCl3, 300 MHz): δ (ppm) 14.32,
60.06, 66.29, 115.07, 115.91, 122.17, 125.54, 125.79,
126.50, 126.66, 128.22, 128.78, 129.06, 132.08, 134.90,
140.41, 149.25, 153.59, 166.85. IR (KBr): ν (cmꢀ1):
3415, 2977, 2364, 1708, 1599, 1165, 762. HRMS (ESI)
m/z: calcd for C21H21O3 [M + H]+, 321.14918; found,
321.14684.
Ethyl (2E)-3-(6-(4-methoxyphenyl)-2H-chromen-3-yl)prop-
2-enoate (Ib). mp 138–140°C (hexane/dichloromethane
1
6:4), C21H20O4: 336 g/mol. H NMR (CDCl3, 300 MHz),
δ (ppm): 1.32 (t, 3H, J1.3 = 7 Hz), 3.85 (s, 3H), 4.23 (q,
2H, J1.3 = 7 Hz), 4.99 (s, 2H), 5.75 (d, 1H, J1.3 = 15 Hz),
6.78 (s, 1H), 6.89 (d, 1H, J1.3 = 15 Hz), 7.24–7.47 (m,
7H). 13C NMR (CDCl3, 300 MHz): δ (ppm): 14.31,
55.36, 60.60, 65.21, 114.23, 116.07, 117.27, 126.03,
127.68, 128.77, 129.11, 130.79, 141.45, 153.45, 153.49,
158.95, 166.80. IR (KBr): ν (cmꢀ1): 3409, 2954, 1718,
1621, 1517, 1487, 740. HRMS (ESI) m/z: calcd for
Ethyl (2E)-3-[6-(4-(4-methylpiperazinyl)sulfonyl)-phenyl)-
2H-chromen-3-yl]prop-2-enoate (II).
mp 188–190°C
(hexane/dichloromethane 6:4), C25H28N2O5S: 468 g/mol.
1H NMR (CDCl3, 300 MHz): δ (ppm) 1.32 (t, 3H,
J1.3 = 7 Hz), 2.27 (s, 3H), 2.52 (t, 2H, J1.3 = 6.8 Hz),
3.07 (t, 2H, J1.3 = 6.8 Hz), 4.26 (q, 2H, J = 7 Hz), 5.03
(s, 2H), 5.77 (s, 1H), 6.79 (d, 1H), 7.26–7.80 (m, 8H).
13C NMR (CDCl3, 300 MHz), δ (ppm): 14.30, 45.69,
45.97, 51.81, 54.03, 60.66, 65.37, 116.50, 117.30,
122.15, 126.60, 127.04, 128.41, 129.60, 130.06, 130.25,
132.87, 141.12, 141.38, 144.88, 154.87, 166.64. IR
(KBr): ν (cmꢀ1): 3415, 2891, 2810, 2361, 1711, 1621,
1311, 943, 755. HRMS (ESI) m/z: calcd for
C25H29N2O5S [M + H]+, 469.17983; found, 469.17686.
C21H21O4 [M + H]+, 337.1441; found, 337.14136.
Ethyl (2E)-3-(6-(4-fluoro)-2H-chromen-3-yl)prop-2-enoate
(Ic).
mp 120–122°C (hexane/dichloromethane 8:2),
1
C20H17FO3: 324 g/mol. H NMR (CDCl3, 300 MHz): δ
(ppm) 1.32 (t, 3H, J1.3 = 7 Hz), 4.24 (q, 2H, J1.3 = 7 Hz),
5 (s, 2H), 5.76 (d, 1H, J1.3 = 15 Hz), 6.78 (s, 1H), 6.91
(d, 1H, J1.3 = 15 Hz), 7.11–7.50 (m, 7H). 19F NMR
(CDCl3, 300 MHz): δ = ꢀ115.92. 13C NMR (CDCl3,
300 MHz): δ (ppm) 14.33, 60.65, 65.27, 115.52, 115.80,
116.20, 117.49, 122.00, 126.33, 128.16, 128.16, 130.52,
134.05, 141.05, 153.91, 160.65, 166.77. IR (KBr): ν
(cmꢀ1): 3403, 2989, 1706, 1620, 1487, 1232, 820.
HRMS (ESI) m/z: calcd for C20H18FO3 [M + H]+,
Standard procedure for preparation of chromene–retinoids
hybrid derivatives (IIIa–d). In a three-necked flask, to a
325.12411; found, 325.12147.
solution of ethyl 3-[6-(4-formylphenyl-2H-chromen-3-yl]
propenoate If (10 mmol) in 10 mL of THF was added
appropriate phosphonium salt 12a–c (15 mmol) under
stirring and under nitrogen. The mixture was allowed to
cool to ꢀ78°C, and then butyllithium in hexane
(15 mmol) was added dropwise. Then the mixture was
stirred at ꢀ78°C for 4 h and brought to room temperature
for 5 h to room and refluxed at 65°C for 4 h. The mixture
was allowed to cool to 25°C, and a saturated NaCl
solution was added (15 mL). Next, to extract with ethyl
Ethyl (2E)-3-(6-(4-methylphenyl)-2H-chromen-3-yl)prop-2-
enoate (Id). Rf = 0.40 (hexane/dichloromethane 6:4). mp
160–162°C
(hexane/dichloromethane
6:4),
C21H20O3:320 g/mol. 1H NMR (CDCl3, 300 MHz): δ
(ppm): 1.33 (t, 3H, J = 7 Hz), 1.6 (s, 3H), 4.25 (q, 2H,
J1.3 = 7 Hz), 4.99 (s, 2H), 5.75 (d, 1H, J1.3 = 15 Hz), 6.7
(s, 1H), 6.9 (d, 1H, J1.3 = 15 Hz), 7.24–7.45 (m, 7H). 13C
NMR (CDCl3, 300 MHz): δ (ppm): 14.31, 21.07, 60.60,
65.18, 115.81, 116.07, 117.28, 118.15, 121.75, 126.49,
127.96, 129.51, 10.78, 133.78, 136.79, 137.39, 140.91,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Kaoukabi, L. Belachemi, M. Lahcini, M.-C. V. Massuard, and C. Croix
Vol 000
acetate (2 × 20 mL) and to combine the organic layers that
have been dried over MgSO4, and the solvent was
removed. The residue was purified by flash
chromatography (silica gel, mixture 95:05 hexane/ethyl
acetate), to afford compounds IIIa–d as a yellow solid in
66.30, 115.10, 115.97, 122.21, 125.51, 126.25, 126.81,
126.97, 127.15, 127.65, 127.86, 128.16, 128.28, 128.71,
128.87, 129.37, 129.76, 130.34, 132.11, 134.33, 136.08,
137.34, 139.51, 149.22, 153.68, 166.84. IR (KBr): ν
(cmꢀ1): 3413, 2979, 1714, 1598, 1408, 1168, 1043, 962,
845, 691. HRMS (ESI) m/z: calcd for C29H27O3
[M + H]+, 423.19336; found, 423.19336.
the yields indicated in Table 2.
Ethyl (2E)-3-[6-(4-styryl-phenyl)-2H-chromen-3-yl]prop-2-
enoate (IIIa).
mp 182–184°C (hexane/dichloromethane
1
6:4), C28H24O3: 408 g/mol. H NMR (CDCl3, 300 MHz):
δ (ppm): 1.34 (t, 3H, J1.3 = 7 Hz), 4.39 (q, 2H,
J1.3 = 7 Hz), 5.11 (s, 2H), 6.45 (d, 1H, J1.3 = 16 Hz),
6.89 (s, 1H), 6.95 (d, 1H, J1.3 = 16 Hz), 7.04 (d, 2H,
J1.3 = 16 Hz), 7.52–8.15 (m, 8H, J = 8 Hz). 13C NMR
(CDCl3, 300 MHz): δ (ppm) 14.36, 29.69, 61, 65.56,
115.51, 121.57, 124.43, 126.69, 126.95, 127.19, 127.56,
129.25, 130.11, 130.23, 131.23, 138.05, 139.02, 144.83,
153.72, 166.50. IR (KBr): ν (cmꢀ1): 3413, 3028, 2922,
2854, 1716, 1276, 1109, 873, 768. HRMS (ESI) m/z:
calcd for C28H24O3 [M + H]+, 409.168; found, 409.16686.
Acknowledgments. We gratefully thank Dr. Enrico Garattini,
Laboratory of Molecular Biology, IRCCS—Instituto di Ricerche
Farmacologiche “Mario Negri” via La Masa 19–20156 Milano,
Italy, and Dr. Bhaskar Das, Department of Nuclear Medicine,
Albert Einstein College of Medicine, Bronx, USA, for their help
to carry out some of the pharmacological tests in their
laboratories.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Efficient Synthesis of New 2H-Chromene Retinoids Hybrid Derivatives by Suzuki
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet