3-Methylene-2,4-chromandione in situ trapping: Introducing molecular diversity on 4-hydroxycoumarin

Article abstract of DOI:10.1039/c5ra22440c

3-Methylene-2,4-chromandione trapped in a solid-state stable Mannich adduct, is released in solution. In the presence of different nucleophiles, this highly reactive intermediate allows the introduction of molecular diversity on C-3 position of 4-hydroxycoumarin.

Full text of DOI:10.1039/c5ra22440c

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3-Methylene-2,4-chromandione in situ trapping :
Introducing molecular diversity on 4-hydroxycoumarin
Cite this: DOI: 10.1039/x0xx00000x
Adrien Montagut-Romans, Manon Boulven, Marc Lemaire and Florence Popowycz*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract. 3-Methylene-2,4-chromandione trapped in a solid-
state stable Mannich adduct, is released in solution. In the
presence of different nucleophiles, this highly reactive
intermediate allows the introduction of molecular diversity
on C-3 position of 4-hydroxycoumarin.
The reactivity of ortho-quinone methides (o-QMs) has been
largely exploited in natural product, total synthesis, medicinal
chemistry and biochemistry. And yet, for a long time, o-QMs
have been underused, mainly due to their transient nature.1
Quinone methides have been hardly ever isolated, due to fast
reactions favored by rearomatization into phenol, acting as the
driving force (Scheme 1, eq. a). Gardner2 detected their
existence in 1963 by spectroscopy at -100°C, even if more than
fifty years before, in 1907, Fries got preliminary suspicion of
the reality of such molecular species.3 Their high reactivity
makes it attractive, in particular for multi-component
reactions.4 Over the past years, they have regained a new
interest for drug targeting or fluorescent probe.5 Biomimetic
Scheme 1. Structural and reactivity analogy of ortho-quinone
methide and 3-methylene-2,4-chromandione.
Recently, our laboratory reported an effective procedure
for C-3 reductive alkylation of 4-hydroxycoumarin by
a
dehydrogenative oxidation of benzylic alcohols in the presence of
RuCl2(PPh3)2 (5 mol%), KOH (0.2 eq) in tertamyl alcohol under
microwave irradiation at 140°C in 2 hours.9 Supposed mechanism is
described as a first step of activation of the alcoholic substrate by
metallo-catalyzed dehydrogenative oxidation, followed by
Knoevenagel condensation / reduction sequence, under one pot
conditions. The Knoevenagel adduct (3-methylene-2,4-
a
synthesis of Schefflone,
a monoterpenoid was recently
performed by oxidative trimerization of o-QM.6 A large
spectrum for their biological activities was highlighted with the
understanding of DNA alkylation, anti-tumoral or anti-bacterial
properties and so on.7 As a notorious example, anti-diabetic
Troglitazone was withdrawn in 2000 due to in vivo formation of
o-QM metabolite displaying prejudicial secondary effects.8
chromandione) displaying similar structural analogy (Scheme 1, eq.
b) with classical o-QM, is a versatile substrate for cycloaddition
reactions.10 To a larger extent, 3-methylene-2,4-chromandione have
been reported as in situ generated partner for multi-component
reactions (MCRs), providing a powerful platform to access diversity
as well as complexity. Following this strategy, pyranocoumarins
were obtained by Knoevenagel-electrocyclic reaction starting from
4-hydroxycoumarin, an enal and an amine.11 o-QMs analogs have
been involved in numerous cycloadditions ([4+2]12 or [4+1]13) and
Equipe Chimie Organique et Bioorganique, Institut de Chimie et Biochimie
Moléculaires et Supramoléculaires, Institut National des Sciences Appliquées other multi-component or domino reactions.14 The common points of
(INSA Lyon), Bâtiment Jules Verne, 20 Avenue Albert Einstein, F-69621
Villeurbanne Cedex .
E-mail : florence.popowycz@insa-lyon.fr; Fax +33 4 72 43 88 96 ; Tel: + 33
4 72 43 82 21
Electronic Supplementary Information (ESI) available: Synthetic
procedures, characterisation of compounds, NMR spectra. See
DOI: 10.1039/c000000x
this strategy were to access the high added value molecules in a
linear synthetic strategy.
The approach developed in the laboratory is to trap the 3-
methylene-2,4-chromandione highly reactive intermediate in a
solid-state stable Mannich adduct. In solution, the equilibrium
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is more favourable for the o-QM adduct which upon treatment aryl aldehyde do not affect the issue of the reaction. Halogen was
with various nucleophilic species can react in excellent yields also well tolerated (1e). Other substituted benzaldehydes such as 4-
(Scheme 2). Therefore, we decided to focus on an elegant (pyridin-4-yl)benzaldehyde,
2,2-difluorobenzo[d][1,3]dioxole-5-
approach to trap this intermediate by different methods carbaldehyde, 4-phenoxybenzaldehyde or 4-benzylbenzaldehyde
including simple reduction methods. The methodology deviced were coupled with good to excellent yields (1h-1k). Replacement of
should also limit the percentage of undesired DIM, which is 4-hydroxycoumarin scaffold either by quinolone-2,4-diol (1l, 1m) or
often observable in all the synthesis reported in literature (Table by 4-hydroxythiocoumarin (1n, 1o) resulted in similar yields.
1).15
Table 2. Mannich reaction of 4-hydroxycoumarin (and analogs) with
aldehydes
Scheme 2. Equilibrium between Mannich adduct and methylene
chromandione.
Preliminary study began with the choice of the amine
partner involved in the Mannich reaction (Table 1). A set of
primary and secondary amines were screened and pyrrolidine
was the sole amine affording the desired Mannich adduct
without any trace of dimer. Other amines (piperidine,
morpholine and isopropylamine) led to 10% of undesired dimer
adduct (entries 2, 4, 7). Dimethylamine, diethylamine (entries
3, 5) were less efficient with almost 40% of dimer. Aniline and
proline (entries 6, 8) led to partial conversion in favour of
expected product with in both cases, dimer as the major
product. These results were almost in accordance with the
nucleophilicity scale developed by Mayr and co-workers in
2009.16
a
Conditions : 4-hydroxycoumarin (1 mmol), aldehyde (1 mmol), pyrrolidine (1 mmol),
Table 1. Nature of nucleophilic amine
CH2Cl2 (2 ml), rt, 2 h.
To our delight, the reaction could be performed on 10
gram scale for compound 1a, our benchmark compound for the
following studies. Three reactions were selected for evaluation of the
reactivity of the Mannich adduct, as pointed out in Scheme 3:
hydrogenation, Michael addition or tandem Michael addition-
cyclization (Scheme 3). Hydrogenation allows the formation of
linear C-3 alkylated compounds, which are not so obvious to
obtain.18 Treating Mannich adduct 1a under H2 atmosphere (1 bar) in
anhydrous ethanol with 10% Pd/C (5 mol%) afforded compound 2a
quantitatively.
Entry
Amine
Ratio
Product
100
90
69
91
60
27
93
15
DIM
0
1
2
3
4
5
6
7
8
pyrrolidine
piperidine
dimethylamine
morpholine
diethylamine
aniline
1017
31
9
40
73
7
isopropylamine
proline
85
Using the conditions outlined in entry 1 (Table 1), we
tested the scope of this procedure with a range of aromatic
aldehydes. The three-component reaction of 4-hydroxycoumarin,
pyrrolidine and a set of benzaldehydes was effective in good to
excellent yields, regarding the stoichiometric ratio of each partner
(Table 2). No trace of bis-coumarin product was detected for
compounds 1a-k. Dichloromethane was the best solvent, allowing
the precipitation of the Mannich adduct at the end of the reaction and
thus facilitating its isolation, by simple filtration.
The electronic nature of the substituent on aromatic ring
did not affect the reaction and excellent yields were obtained for all
substrates described in Table 2. Electronic effects (electron-donating Scheme 3. Overview of the reactivity of intermediate 1a
group such as 1c, 1d or electron-withdrawing group for 1f, 1g) on
2 | J. Name., 2012, 00, 1-3
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Non-symmetrical dimer 3a was obtained in an excellent 97% yield
by reaction of 1a with stoichiometric quantity of 4- Table 3. Formation of non-symmetrical dimersa
hydroxythiocoumarin in acetonitrile at 50°C during 3 hours. In this
case, the mechanism reaction is supposed to be assimilated to
Michael addition with nucleophilic 4-hydroxythiocoumarin reacting
on o-QM liberated in solution. The last reaction explored is the
MCR tandem reaction of Michael addition followed by cyclization
to provide dihydropyrano[2,3-c]chromene skeleton. The reaction of
1a with malononitrile (1 eq) in MeCN at 50°C during 3 hours
furnished derivative 4a in 98% yield. Thermal stability of compound
1a supplied important information on the equilibrium between
Mannich adduct and o-QM. Heating a solution of 1a in MeCN
[0.25M] at 50°C during 15 min only led to recovery of the starting
material. After 15 min at 90°C, a significant ratio of dimer could be
quantified by 1H NMR at a level of 10%. The 1/9 mixture of
dimer/1a was heating at 15 min at 110°C leading to a displacement
of the equilibrium in favour of a more important ratio of the dimer:
33% of DIM and 67% of substrate 1a. The stability experiments
a Conditions : 1 (1 mmol), 4-hydroxythiocoumarin (1 mmol), CH3CN (2.5 ml), 50°C, 3 h
were run under microwave irradiation to speed up the kinetics and
evaluate the stability of 1a. In regard with these observations, to
limit the formation of the dimer, classic thermal activation was
selected to the detriment of microwave irradiation.
All the Mannich adducts 1 (obtained in table 2) were submitted to
hydrogenation in conditions described in Scheme 3 to allow the
formation of C-3 alkylated coumarins (Figure 1). Excellent yields
were obtained for most of the cases engaged in the reduction (11
successful reactions on 15 compounds) with isolation by simple
filtration (no need to additional column chromatography for
increasing the compounds purity).
We decided to apply our methodology to the synthesis of 2-
amino-4H-pyrans prepared by a tandem Michael addition-
cyclization sequence (Table 4). The access to functionalized 2-
amino-3-cyano-4H-pyrans annulated heterocycle
4 has been
already published by simple multi-component reaction between
aldehydes, malononitriles and 4-hydroxycoumarin in the
presence of a wide range of catalysts such as (NH4)2HPO4,19
proline,15 TBAB,20 meglumine,21 fermented Baker’s yeast,22
ZnFe2O4,23 urea.24 Simple aqueous conditions25 were also
efficient due to the hydrophobic effect as the driving force.
Catalyst-free conditions in recyclable glycerol were recently
developed.26 In a direct comparison to the above cited
strategies, our approach is a stepwise process, based on the
isolation of the o-QM intermediate and benefits from catalyst
free conditions. With the optimized conditions, the scope and
generality of this protocol was next examined by employing
Figure 1. Hydrogenation scopea
various o-QM intermediates 1.
Table 4. Tandem Michael addition / Cyclizationa
a Conditions : 1a, H2, Pd/C, EtOH, rt, 24 h.
As expected, derivatives 1e-1g could not be reduced with good
chemoselectivity and complete reduction of para substituent was
observed. In the case of 1f, nitrile group was reduced into CH3
within 13% yield. Substrates with quinolone diol skeleton were
reduced successfully into 2i and 2j, whereas compound 2k bearing
4-hydroxythiocoumarin, was obtained in poor yield of 23%,
probably due to poisoning of the catalyst. Same observation was
reported for the reduction for 1n and thus was not reported.
As in solution, Mannich adduct and o-QM intermediate are in
equilibrium, any nucleophile could be selected to perform Michael
addition and trap irreversibly the conjugated enone, with recovery of
the aromaticity. Litterature has reported many conditions for the
formation of dicoumarols such as DIM. To our delight, no reference
was found concerning the formation of unsymmetrical dimers.
Pyrrolidinyl derivatives 1 were dissolved in acetonitrile, in the
presence of a stoichiometric quantity of 4-hydroxythiocoumarin, at
50°C. In 3 hours, the reaction ran to completion in all cases with
excellent isolated yields higher than 89%. Symmetrical DIM could
be also obtained successfully in these conditions in 98% yield.
a Conditions : 1 (1 mmol), malononitrile (1 mmol), CH3CN (2.5 ml), 50°C, 3 h
A family of eight new 2-amino-4H-pyran compounds
4 was
synthesized using this protocol (Table 4). Good to excellent
yields were obtained when 4-hydroxycoumarin skeleton was
involved, whereas in the presence of 4-hydroxythiocoumarin,
compound 4h was prepared with a poor yield of 25% due to
problems in the solubility of the starting material, resulting in a
low kinetics in this set of experimental conditions. In some
cases such as 4b or 4e, the decrease of the yield could be also
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quantities. As a perspective of these preliminary studies on the
o-QM intermediates, we decided to study simple thiophenol
nucleophiles and examine their reactivity towards o-QM
intermediate 1 27
.
Scheme 4. Introduction of simple nucleophiles
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accordance with the ratio measured in our experiments.
Compounds 5a-5c were obtained in moderate yield of 57-76%
and conditions are under optimisation due do the problems of
separation and the requirement of additional step of purification
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activation (80°C, 1 h).28
Conclusions
An efficient synthesis of 4-hydroxycoumarin derivatives in C-3
position has been developed by taking advantage of o-QM
intermediate. A wide range of reagents H2, malononitrile, 4-
hydroxythiocoumarin, thiophenols were used and broadened
the scope. Due to the easily scalable step to generate derivatives
1
, the challenging point is to generalize the second step of the
reaction to any nucleophilic species. Aliphatic aldehydes were
not tested in the first stage of the reaction and will deserve also
some attention in the future.
21
R.-Y. Guo, Z.-M. An, L.-P. Mo, R.-Z. Wang, H.-X. Liu, S.-W. Wang and
Z.-H. Zhang, ACS Comb. Sci. 2013, 15, 557.
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16, 1426.
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4 | J. Name., 2012, 00, 1-3
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