DMAP-Catalyzed Reaction of Diethyl 1,3-Acetonedicarboxylate with 2-Hydroxybenzylideneindenediones: Facile Synthesis of Fluorenone-Fused Coumarins

Article abstract of DOI:10.1055/a-1385-2345

The base-catalyzed reaction of diethyl 1,3-acetonedicarboxylate with 2-hydroxybenzylidene indenediones was studied. The reaction provides a facile and expeditious protocol for the synthesis of natural product inspired fluorenone-fused coumarins in good to

Full text of DOI:10.1055/a-1385-2345

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 795–799
letter
795
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M. Shkoor, R. Bayari
Letter
Synlett
DMAP-Catalyzed Reaction of Diethyl 1,3-Acetonedicarboxylate
with 2-Hydroxybenzylideneindenediones: Facile Synthesis of Fluo-
renone-Fused Coumarins
Mohanad Shkoor*
Raghad Bayari
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2
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3
O
O
O
OH
OEt
OH
Department of Chemistry and Earth Sciences, Qatar University,
P.O. Box 2713, Doha, Qatar
mshkoor@qu.edu.qa
O
O
O
DMAP (30 mol%)
EtOH, 70 °C, 2 h
R3
R2
R1
+
EtO
OEt
O
O
R2
O
Dedicated to Professor Adrian Schwan of the University of
Guelph on the occasion of his 60th birthday
R3
R1
R1 = H, OMe, Cl, Br, I, F
R2 = H, OH
R3 = H, OMe, Cl, Br, I, F, NO2
11 examples
up to 62% yield
MDeMeopahaiaClrnotmmarrdsehnSskphtookoonofrdo@Crihqneugm.eAidusuttrh.qyoarand Earth Sciences, Qatar University, P.O. Box 2713, Doha, Qatar
Received: 02.01.2021
Accepted after revision: 07.02.2021
Published online: 07.02.2021
ure 1) displays antimyocardial ischemia activity.22 Substi-
tuted fluorenones are also abundantly present in bioactive
organic molecules23 and photoelectric materials.24,25 As a
result, there has been a growing interest in the synthesis of
substituted fluorenones.26,27
DOI: 10.1055/a-1385-2345; Art ID: st-2021-b0001-l
Abstract The base-catalyzed reaction of diethyl 1,3-acetonedicar-
boxylate with 2-hydroxybenzylidene indenediones was studied. The re-
action provides a facile and expeditious protocol for the synthesis of
natural product inspired fluorenone-fused coumarins in good to very
good yields. This process resembles a combination of domino Michael–
intramolecular Knoevenagel–aromatization–lactonization reactions in a
single step. Although this reaction operates with many bases, the best
yields were obtained with DMAP as a catalyst. This protocol could open
new potential avenues for the synthesis of fused coumarins by the reac-
tion of substituted -keto esters with different 2-(2-hydroxyben-
zylidenes) of 1,3-dicarbonyl compounds.
O
OH
O
O
OMe
OH
fluorenone
gramniphenols D
O
OMe
O
Key words coumarin, fluorenone, indandione, DMAP, ben-
zo[c]chromen-6-ones
O
OH
MeO
HO
OH
Polycyclic organic motifs are abundant in synthetic and
OMe
gramniphenols E
OH
NMe2
naturally occurring molecules that exhibit a diverse spec-
trum of applications.1 However, the complexity and diversi-
ty in their structures bring challenges to synthetic organic
chemists. Therefore, the discovery and development of effi-
cient synthetic routes to polycyclic scaffolds have been a
pivotal research target.2–4
Coumarin is a privileged scaffold that is omnipresent in
natural products, pharmaceuticals, and organic materials.
Coumarins fused to polycyclic systems have received sub-
stantial interest from organic,5–9 medicinal,10–14 and materi-
al chemists for their unique photophysical and photochem-
ical properties.15–19
caulophine
Figure 1 Fluorenone and natural products containing fluorenone
Considering the importance of both coumarin and fluo-
renone, it is anticipated that molecules combining both nu-
clei would find applications in various fields. However, the
synthesis of compounds containing fluorenone fused to
coumarin has been rarely studied. Tanaka and coworkers
reported the synthesis of molecules containing a fluore-
none-fused coumarin core by employing transition-metal
catalyst, ligand, and multistep synthesis of starting materi-
als.28
Fluorenone (Figure 1) is an example of a polycyclic
framework that is widespread in natural products.20 For in-
stance, the natural products Gramniphenols D and E (Figure
1) exhibit anti-HIV activity.21 In addition, Caulophine (Fig-
The base-mediated reactions of diethyl 1,3-acetonedi-
carboxylate with 2-hydroxychalcones have been employed
in the synthesis of benzene fused coumarins (Scheme 1).29–31
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 795–799
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

796
M. Shkoor, R. Bayari
Letter
Synlett
O
OEt
O
OH
O
O
O
2 equiv NaOEt, EtOH
rt, 3 d, then reflux, 1 d
+
OH
Eiden 1987
EtO
OEt
O
O
O
O
OH
O
O
O
2 equiv Cs2CO3, toluene
reflux, 2 h
OEt
OH
Lee 2014
+
EtO
OEt
O
O
O
O
O
O
O
O
O
OH
base (30 mol%), EtOH
70 °C, 2 h
OEt
OH
this work
+
OEt
EtO
O
O
Scheme 1 Reactions of diethyl 1,3-acetonedicarboxylate with 2-hydroxychalcones
However, the reaction of substituted -keto esters with
2-(2-hydroxybenzylidene) of both cyclic and acyclic 1,3-di-
carbonyl compounds have never been studied. This type of
reactions could provide a template for the synthesis of a
wide variety of new fused coumarins.
In view of the importance of coumarin and fluorenone
entities and in continuation of our efforts in the synthesis
of fused coumarins,32,33 we report herein the base-catalyzed
reaction of diethyl 1,3-acetonedicarboxylate with 2-hy-
droxybenzylideneindenediones leading to fluorenone-
fused coumarins.
Our study commenced with the preparation of the pre-
cursors 2-hydroxybenzylideneindenediones 3a–k utilizing
the well-established L-proline-catalyzed condensation of
1,3-indandione (1) with substituted salicylaldehydes 2a–k
(Scheme 2, Table 1).34
analysis indicated completion of the reaction. Upon cooling
and addition of 10% acetic acid aqueous solution, a solid
precipitated. The solid was crystallized from 1,4-dioxane to
afford yellowish needles in 39% yield. The spectroscopic
analysis of the product supported our proposed structure of
resultant fluorenone-fused coumarin 5a.
Motivated by this success, we then directed our efforts
toward the optimization of the reaction conditions for bet-
ter yields (Table 2). Thus, we tested the catalytic effect of
K2CO3 and MeCO2Na (entries 2 and 3), both bases gave low-
er yields than Cs2CO3. The lowest yield was obtained when
piperidine was used as a catalyst (entry 4), presumably due
to its nucleophilicity and ability to react with hydroxyben-
zylideneindenediones.35 On the other hand, other organic
bases such as Et3N and L-proline improved the reaction
yield (entries 5 and 6). The best yield was obtained when 4-
O
O
O
L-proline
R3
R2
(30 mol%)
Table 1 Salicylaldehydes 2a–k and 2-Hydroxybenzylideneindenedi-
ones 3a–k Utilized in this Study
OH
H
+
MeOH, rt
2–12 h
R1
HO
O
O
R1
3a–k
1
2a–k
Compd
R1
R2
R3
R2
R3
2a, 3a
2b, 3b
2c, 3c
2d, 3d
2e, 3e
2f, 3f
H
H
H
Scheme 2 Synthesis of 2-hydroxybenzylideneindenediones 3a–k
OMe
H
H
H
H
H
H
H
H
H
H
H
Cl
Our efforts were then directed toward the investigation
of the reaction of diethyl 1,3-acetonedicarboxylate (4) with
the synthesized 2-hydroxybenzylideneindenediones 3a–k.
The reaction of diethyl 1,3-acetonedicarboxylate (4) with
the chalcone 3a was chosen as a model reaction (Table 2).
In our initial experiment, 2-hydroxybenzylideneindene-
dione 3a was reacted with diethyl 1,3-acetonedicarboxylate
in refluxing ethanol in the presence of catalytic amount (30
mol%) of Cs2CO3 (entry 1, Table 2). After two hours, TLC
H
OMe
Br
I
H
I
2g, 3g
2h, 3h
2i, 3i
H
NO2
Br
Cl
Br
Cl
F
2j, 3j
F
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 795–799

797
M. Shkoor, R. Bayari
Letter
Synlett
Table 2 Screening of the Reaction Conditions for the Reaction of Di-
ethyl 1,3-Acetonedicarboxylate 4 with Chalcone 3aa
compared to the nonhalogenated versions of those com-
pounds.37 Moreover, halogen substitution is a key strategy
in hit-to-lead or lead optimization strategies in pharmaceu-
tical industry as it enhances various biophysicochemical
processes such as membrane binding and permeation.38
Methoxy-substituted 2-hydroxybenzylideneindenediones
also tolerated the optimized reaction conditions and
yielded 5b and 5d with 46% and 60% yields, respectively. In
addition to that, 2-hydroxybenzylideneindenedione de-
rived from 5-nitrosalicylaldehyde gave the corresponding
nitro-substituted fluorenone-fused coumarin 5g in very
good yield. Although the crude NMR spectrum indicated
that 2,4-dihydroxybenzylideneindenedione managed to
yield the desired coumarin 5k, the compound was tedious
to purify.
O
OH
O
O
3a
conditions
O
O
+
O
O
O
OEt
OH
5a
O
EtO
OEt
4
Entry
Catalyst (loading)
Solvent
Yield (%)b
1
2
Cs2CO3 (30 mol%)
K2CO3 (30 mol%)
MeCO2Na (30 mol%)
piperidine (30 mol%)
Et3N (30 mol%)
L-proline (30 mol%)
DMAP (30 mol%)
DMAP (10 mol%)
DMAP (1 equiv)
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
dioxane
toluene
MeCN
39
Table 3 Substituent Scope of the Coumarins 5a–k
27
O
3
25
4
15
OH
R3
5
54
R1
O
R2
R1
O
6
51
R2
R3
3a–k
7
62
DMAP (30 mol%)
EtOH, 70 °C, 2 h
O
O
+
8
50
O
O
O
OEt
OH
5a–k
O
9
40
EtO
OEt
10
11
12
13
14
traces
32c
52
4
DMAP (30 mol%)
DMAP (30 mol%)
DMAP (30 mol%)
DMAP (30 mol%)
Compd
R1
R2
R3
Yield (%)a
48
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
H
H
H
OH
H
62
46
55
60
58
49
58
50
53
52
~30
42
OMe
H
H
a Reactions were performed as: chalcone 3a (1 equiv), compound 4 (1.2
Cl
equiv) at 70 °C for 2 h.
b Isolated yield.
H
OMe
Br
I
c Reaction was performed at room temperature. The product formed after
overnight stirring.
H
I
5g
5h
5i
H
NO2
Br
Cl
dimethylaminopyridine (DMAP) was used to catalyze the
reaction36 (entry 7). Lowering the catalyst loading de-
creased the reaction yield (entry 8). When a stoichiometric
amount of the catalyst was used, the reaction yield de-
creased (entry 9). The uncatalyzed reaction could also af-
ford the product but with very low yield (entry 10). The de-
sired product needed longer time to form at room tempera-
ture and the yield was relatively low (entry 11). The
reaction was also successful with nonpolar and polar aprot-
ic solvents (entries 12–14).
Several substituted 2-hydroxybenzylideneindenediones
tolerated the optimized reaction conditions and gave the
desired corresponding products (Table 3). Mono- and diha-
lo-substituted fluorenone-fused coumarins 5c, 5e, 5f, 5h,
5i, and 5j were obtained in good yields. The importance of
halogenation originates from a well-established drug dis-
covery hypothesis that addition of halogens to bioactive
molecules would induce antagonistic or agonist responses
Br
Cl
F
5j
F
5k
H
H
a Isolated yields.
Based on our findings and the literature,30 the reaction
presumably proceeds via domino Michael–intramolecular
Knoevenagel–aromatization–lactonization reactions. A ten-
tative mechanism is depicted in Scheme 3. The Michael ad-
dition of anion A to the 2-hydroxybenzylideneindenedione
3a leads to the formation of the intermediate B. Subsequent
intramolecular Knoevenagel condensation and lactoniza-
tion results in the formation of intermediate C which upon
enolization and oxidation gives the desired fluorenone-
fused coumarin 5a.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 795–799

798
M. Shkoor, R. Bayari
Letter
Synlett
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O
O
O
O
O
O
O
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Kumar, N.; Kinarivala, N.; Sharma, S. Bioorg. Med. Chem. 2019,
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Nat. Prod. Rep. 2015, 32, 1472.
EtO
OEt
EtO
OEt
Michael addition
4
A
O
BH+
B:
O
O
OH
OEt
OH
EtO
O
(8) Calcio Gaudino, E.; Tagliapietra, S.; Martina, K.; Palmisano, G.;
Cravotto, G. RSC Adv. 2016, 6, 46394.
O
3a
(9) Wang, Y.; Wang, S.; Chen, B.; Li, M.; Hu, X.; Hu, B.; Jin, L.; Sun,
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Chem. 2020, 103, 104163.
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Chem. Rev. 2019, 119, 10403.
O
B
B:
B:
– H2O
intramolecular Knoevenagel
– EtOH lactonization
OEt
OEt
OH
O
O
O
O
enolization
oxidation
O
O
O
O
5a
O
C
(16) Sun, X.; Liu, T.; Sun, J.; Wang, X. RSC Adv. 2020, 10, 10826.
(17) Tasior, M.; Kim, D.; Singha, S.; Krzeszewski, M.; Ahn, K. H.;
Gryko, D. T. J. Mater. Chem. C 2015, 3, 1421.
Scheme 3 A plausible mechanism for the formation of fluorenone-
fused coumarins 5a
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104, 3059.
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In summary, we have developed a new facile and expe-
ditious protocol of the synthesis of substituted fluorenone-
fused coumarins by the base-catalyzed reaction of diethyl
1,3-acetonedicarboxylate with 2-hydroxybenzylidenein-
denediones. This reaction represents the first cyclization of
diethyl 1,3-acetonedicarboxylate with 2-(2-hydroxyben-
zylidene) of 1,3-dicarbonyl compounds. The reaction oper-
ates with many bases and solvents. However, the optimized
conditions required the use of DMAP as a catalyst.
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Funding Information
(26) Revankar, H. M.; Bukhari, S. N. A.; Kumar, G. B.; Qin, H.-L.;
Stefanachi, A.; Leonetti, F.; Pisani, L.; Catto, M.; Carotti, A.; Ibrar,
A.; Shehzadi, S. A.; Saeed, F.; Khan, I.; Medina, F. G.; Marrero, J.
G.; Macías-Alonso, M.; González, M. C.; Córdova-Guerrero, I.;
Teissier, García. A. G.; Osegueda-Robles, S.; Thakur, A.; Singla, R.;
Jaitak, V.; Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.;
Uriarte, E. Molecules 2018, 23, 250.
(27) Manick, A.-D.; Salgues, B.; Parrain, J.-L.; Zaborova, E.; Fages, F.;
Amatore, M.; Commeiras, L. Org. Lett. 2020, 22, 1894.
(28) Tanaka, K.; Fukawa, N.; Suda, T.; Noguchi, K. Angew. Chem. Int.
Ed. 2009, 48, 5470.
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(30) Poudel, T. N.; Lee, Y. R. Org. Biomol. Chem. 2014, 12, 919.
(31) Masesane, B. I.; Mazimba, O. Bull. Chem. Soc. Ethiop. 2014, 28,
289.
This work was supported by Qatar University (Student Grant, Grant
No. QUST-2-CAS-2019-28).Qtar
U
n
i
versiyt(Q
U
S
T-2-C
A
S-2
0
1
9-28)
Acknowledgment
We thank Central Laboratories Unit and Environmental Science Cen-
ter, Qatar University for their support in compounds analysis.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1385-2345. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
References and Notes
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D.; Gevorgyan, A.; Langer, P. Synlett 2010, 1533.
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© 2021. Thieme. All rights reserved. Synlett 2021, 32, 795–799

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Letter
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(36) General Procedure for the Synthesis of Ethyl 7-Hydroxy-6,13-
dioxo-6,13-dihydrofluoreno[2,1-c]chromene-8-carboxyl-
ates 5a–k
(600 MHz, CDCl3):  = 1.46 (t, 3 H, J = 7.2 Hz), 4.75 (q, 2 H, J = 7.2
Hz), 7.63 (dd, 1 H, J = 8.2, 1.2 Hz), 7.40–7.44 (m, 1 H), 7.45–7.55
(m, 3 H), 7.57–7.63 (m, 1 H), 7.75 (dt, 1 H, J = 7.3, 0.9 Hz), 9.58
(dd, 1 H, J = 8.3, 1.5 Hz), 13.21 (s, 1 H). 13CNMR (150 MHz,
CDCl3):  = 190.0, 165.7, 165.6, 165.5, 151.0, 150.7, 139.0, 138.5,
135.7, 134.7, 133.1, 131.6, 131.0, 125.1, 124.5, 122.9, 120.6,
117.9, 117.2, 117.0, 106.2, 62.6, 14.1. FTIR: 2988, 1698.9,
1732.7, 1666.8, 1584, 1217.7, 761.1 cm–1. Anal. Calcd for
C23H14O6: C, 71.50; H, 3.65. Found: C, 71.58; H, 3.68. MS (ESI):
m/z (%): 386 [M]+ (100), 341.0 (81), 312 (88), 200 (70), 341.0
(85.6).
4-Dimethylaminopyridine (DMAP, 0.3 equiv, 0.3 mmol) was
added to a solution of 2-hydroxybenzylideneindenediones 3a–k
(1 equiv, 1 mmol) and diethyl 1,3-acetonedicarboxylate (4, 1.2
equiv, 1.2 mmol) in ethanol (10 mL). The reaction solution was
heated at 70 °C until completion of the reaction as indicated by
TLC analysis (ca. 2 h). The reaction solution was then allowed to
cool down to room temperature after which an aqueous acetic
acid solution (10%) was added. The formed precipitate was fil-
tered and the solid obtained was crystallized from dioxane.
(37) Hernandes, M.; Cavalcanti, S. M.; Moreira, D. R.; de Azevedo
Junior, W. F.; Leite, A. C. Curr. Drug Targets 2010, 11, 303.
(38) Gerebtzoff, G.; Li-Blatter, X.; Fischer, H.; Frentzel, A.; Seelig, A.
ChemBioChem 2004, 5, 676.
Ethyl
7-Hydroxy-6,13-dioxo-6,13-dihydrofluoreno[2,1-
c]chromene-8-carboxylate (5a)
Yellow crystals; yield: 0.24 g (62%); mp 239–241 ℃. 1H NMR
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 795–799