Hydroxylated polyfunctionalized benzo[c]coumarins by an organocatalyzed tandem 1,4-conjugate addition, decarboxylation and aromatization reaction

Article abstract of DOI:10.1055/s-0033-1339895

Novel hydroxylated polyfunctionalized benzo[c]coumarins were synthesized by a new one-pot reaction of an unprotected monohydroxy-3-(acetoacetyl)coumarin as an active methylene ?-Michael donor with 4-oxo-4H-chromene-3-carboxylic acid as a ?-Michael accepto

Full text of DOI:10.1055/s-0033-1339895

LETTER
▌2559
letter
Hydroxylated Polyfunctionalized Benzo[c]coumarins by an Organocatalyzed
Tandem 1,4-Conjugate Addition, Decarboxylation and Aromatization Reac-
tion
Hydroxylated Polyfunctionalized Benzo[c]coumarins
Oualid Talhi,a Malika Makhloufi-Chebli,b Diana C. G. A. Pinto,a Maamar Hamdi,*c Artur M. S. Silva*a
a
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt
b
Département de Chimie, UMMTO, Faculté des Sciences, 15000 Tizi ouzou, Algeria
c
Département de Chimie, USTHB, BP32 El alia, Bab ezzouar, 16111 Alger, Algeria
Fax +213(21)247311; E-mail: prhamdi@gmail.com
Received: 23.07.2013; Accepted after revision: 05.09.2013
methods have been developed for their synthesis, of
Abstract: Novel hydroxylated polyfunctionalized benzo[c]couma-
which the Pechmann reaction is among the most widely
rins were synthesized by a new one-pot reaction of an unprotected
used.8 Benzo[c]coumarins, however, constitute a sub-
class that have received less attention as synthetic targets.
monohydroxy-3-(acetoacetyl)coumarin as an active methylene
Michael donor with 4-oxo-4H-chromene-3-carboxylic acid as a
Michael acceptor in the presence of a catalytic amount of 4-pyrro- Several challenges remain in synthesizing these com-
lidin-1-ylpyridine. An organobase-catalyzed tandem 1,4-conjugate
addition, decarboxylation and aromatization reaction mechanism is
proposed.
pounds in optimal yields and by short reactions sequenc-
es, particularly those derivatives bearing free hydroxy and
other functional groups that are most likely to have bio-
logical effects.7b–d A good example of such a synthesis is
Key words: heterocycles, polycycles, ketones, tandem reactions,
addition reactions, catalysis
the total synthesis of the fungal product graphislactone G
(a natural benzo[c]coumarin) in a global yield of 22%
from 5-methylbenzene-1,3-diol (orcinol) and 2,4,6-trihy-
Coumarins (2H-benzopyran-2-ones) are an interesting
class of oxygen-containing heterocycles and they are rec-
ognized as an outstanding category of polyphenolic com-
pounds with valuable biological activities. They are a
common and important family of natural products and, to
date, more than one thousand coumarin derivatives have
been described, most of which were isolated from over
800 plant species.1 Coumarin derivatives exhibit useful
pharmaceutical properties,2 including antioxidant,3 antiin-
flammatory,4 anticancer,5 and molluscicidal activities.6
There is particular interest in the benzo[c]coumarin scaf-
fold, because several of its hydroxylated derivatives and
analogues have shown considerable medicinal benefits,
the most interesting of which are a significant lipid-lower-
ing potential and antioxidant activities.7a Other ben-
zo[c]coumarin structures have been described as potent
and selective antagonists of estrogen receptor subtype β.7b
droxybenzoic acid (phloroglucinic acid) in 13 steps, most
of which involve protection–deprotection procedures.7c
Lubbe and co-workers7d synthesized 7-hydroxy-2-(2-hy-
droxybenzoyl)-6H-benzo[c]chromen-6-ones by sequen-
tial domino reactions of 1,3-bis(silylenol) ethers with
benzopyrylium triflates. Recently, a conjugate addition
approach with electron-deficient C-2 chromones has been
applied in the preparation of a wide range of oxygen-con-
taining heterocyclic systems, such as functionalized 2-hy-
droxybenzophenones,
6H-benzo[c]chromenes,
and
benzo[c]coumarins. Despite its reliability, this method is
strongly dependent on the nature of the substituents at the
3-position of the chromone starting material (the Michael
acceptor), and is not free from the need for additional pro-
tecting steps.8b
Our group has long been involved in studying the synthe-
sis of coumarins as well as their reactivities and related
photophysical properties.9 A particular focus has been on
the synthesis of 3-(acetoacetyl)coumarins, which are ob-
Because of the natural occurrence and range of biological
activities associated with coumarin scaffolds, various
OH
O
OH
O
b)
a)
O
OH
OH
+
O
O
O
O
O
O
R
R
R
1
a) Knoevenagel condensation
b) intramolecular translactonization
Scheme 1 Synthesis of 3-(acetoacetyl)coumarins 1
SYNLETT 2013, 24, 2559–2562
Advanced online publication: 24.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339895; Art ID: ST-2013-D0689-L
© Georg Thieme Verlag Stuttgart · New York

2560
O. Talhi et al.
LETTER
4'''
3'''
5'''
6'''
O
5
4-PPy (cat.)
CHCl3
O
O
2'
2'''
R
6
OH
+
9
6
1'
10
7
reflux
24 h
1''
O
1
O
O
O
CO2H
8
8
R
10b
2
2
10a
7
OH
23–70%
6a
1a
1b
1c
R = H
R = 7-OH
R = 8-OH
3
4a
O
O
3a
3b
3c
R = H
R = 3-OH
R = 4-OH
4
R
1d R = 6-OH
3d R = 2-OH
HO
O
O
O
O
+
OH
OH
CO2H
O
O
1e
O
O
3e
O
2
Scheme 2 Synthesis of benzo[c]coumarins 3a–d
tained from substituted salicylaldehydes and 4-hydroxy- this purpose, we selected electron-deficient 4-oxo-4H-
6-methyl-2H-pyran-2-one (triacetic acid lactone) through chromene-3-carboxylic acid (2) because of its strong Mi-
a tandem microwave-assisted Knoevenagel condensation chael-acceptor character, and we examined its reaction
and intramolecular translactonization process in an or- with the 1,3-dicarbonyl branch of 3-acetoacetylcoumarins
ganobasic medium (Scheme 1).10
1a–e in refluxing chloroform containing a catalytic
amount of 4-pyrrolidin-1-ylpyridine (4-PPy); the reaction
was performed without protecting the free hydroxy
groups of coumarins 1b–d. Monitoring by thin-layer chro-
matography indicated incomplete consumption of the
starting reagents (1a–e and 2) after 24 hours of reaction.
The reactions were therefore worked up after the forma-
tion of substantial amounts of product had been observed
in all cases except that of derivative 1e, which contains a
5,6-benzo[f] group. The products were isolated by column
chromatography. We expected the reaction to give the
The resulting 3-acetoacetylcoumarins 1a–e are strategic
starting materials, as they contain a coumarin nucleus as
well as the active methylene group of the acetoacetyl moi-
ety, which is poised to undergo further useful chemical
transformations. In a continuation of our studies on the es-
tablishment of new synthetic routes to biologically active
coumarins, we developed an efficient one-pot synthesis of
hydroxylated polyfunctionalized benzo[c]coumarins 3a–
d.
The first part of our synthetic strategy involved covalently
connecting a chromone (benzopyran-4-one) ring with a
coumarin (benzopyran-2-one) to form a bridged dyad. For
1
corresponding Michael adducts, but H NMR spectro-
scopic analysis of the products indicated that, instead, the
hydroxylated polyfunctionalized benzo[c]coumarins 3a–
O
–O
O–
O
O
O
O
OH
COOH
O
O
O
O
2
Michael
addition
O
O
O
OH
O
H
O
O
O
O
O
R
R
base
R
1
decarboxylation
ring opening
– CO2
HO
HO
H
HO
O
H
– H2
O
O
O
O
O
H
O
OH
O
H
R
O
O
O
O–
O
A
O
R
aromatization
R
base
1,6-cyclization
B
3
Scheme 3 Proposed mechanism for the formation of benzo[c]coumarins 3a–d
Synlett 2013, 24, 2559–2562
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydroxylated Polyfunctionalized Benzo[c]coumarins
2561
d had been formed in moderate to good yields (23–70%) avoiding the need to protect free hydroxy groups in the
by a tandem pathway involving 1,4-conjugate addition, starting materials. We have therefore replaced the multi-
decarboxylation and aromatization (Scheme 2).11–15
step reaction methods reported in the literature by a two-
step process that proceeds under mild conditions in the
presence of an organobase catalyst.
This unexpected tandem pathway presumably involves an
initial organobase-catalyzed 1,4-conjugate addition of the
nucleophilic 1,3-dicarbonyl reagent 1 to the electron-defi-
cient carboxylic acid 2 to give the intermediate A after
cleavage of the chromone ring and decarboxylation. Inter-
mediate A then undergoes a base-promoted intramolecu-
lar 1,6-cyclization to give intermediate B. The final step
of the tandem process is oxidative aromatization of B to
give the corresponding benzo[c]coumarin 3, functional-
ized with both acetyl and 2-hydroxybenzoyl groups
(Scheme 3).
Acknowledgment
Thanks are due to the University of Aveiro,the Fundação para a
Ciência e a Tecnologia (FCT, Portugal), the European Union,
QREN, FEDER, and COMPETE for funding the Organic Chemi-
stry Research Unit (QOPNA) (project PEst-C/QUI/ UI0062/2013),
and the Portuguese National NMR Network (RNRMN). We also
acknowledge the receipt of financial support from European Com-
munity’s Seventh Framework Programme (FP7/2007-20139; grant
agreement No. 215009).
Attempts to apply the same strategy with the unsubstituted
chromone as a Michael acceptor for the acid 2 were un-
successful, demonstrating the importance of the 3-car-
boxy functionality. This carboxylic group therefore
promotes the conjugate addition, but can subsequently be
readily eliminated by decarboxylation under mild condi-
tions.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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ton-bearing carbons (Figure 1). Moreover, the NOESY
experiment led us to conclude that there is free rotation of
the 2-hydroxybenzoyl substituents, as evidenced by the
NOE effects between the signals for the H-6′′′ and H-5′′′
atoms and those of the H-1 and H-9 atoms of the ben-
zo[c]coumarin (Figure 1). This free rotation would not be
possible if bulky substituents were present at positions C-
1 and/or C-9 of the benzo[c]coumarin skeleton, which
goes some way toward explaining why derivative 3e, pos-
sessing a fused 1,2-benzo[f] group (Scheme 2), was not
formed, and indicates a limitation of this new methodolo-
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H
5''
HMBC
NOESY
6''
O
H
H
HO
H
H
9
Me
O
H
Me
O
O
H
H
O
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1
OH
OH
O
O
O
O
HO
HO
Figure 1 Main HMBC and NOESY correlations for benzo[c]couma-
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In conclusion, we have established a new and convenient
route to hydroxylated polyfunctionalized benzo[c]couma-
rins in acceptable yields by a one-pot reaction of electron-
deficient 4-oxo-4H-chromene-3-carboxylic acid with
unprotected
monohydroxy-3-(acetoacetyl)coumarins,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2559–2562

2562
O. Talhi et al.
LETTER
1994, 26, 360. (e) Hamdi, M.; Spéziale, V.; Jaud, J. Z.
Kristallogr. 1994, 209, 495. (f) Makhloufi-Chebli, M.;
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4′′′), 8.05 (s, 1 H, H-9), 10.34 (s, 1 H, 3-OH), 11.98 (s, 1 H,
2′′′-OH), 13.30 (s, 1 H, 7-OH). 13C NMR [75.47 MHz,
DMSO-d6–CDCl3 (1:2)]: δ = 31.2 (C-2′), 103.1 (C-4), 106.0
(C-6a), 107.3 (C-10b), 113.8 (C-2), 117.9 (C-3′′′), 119.1 (C-
5′′′), 119.5 (C-1′′′), 121.7 (C-8), 124.6 (C-10), 128.3 (C-1),
132.4 (C-6′′′), 137.0 and 137.3 (C-4′′′ and C-9), 138.1 (C-
10a), 152.3 (C-4a), 161.3 (C-3), 162.2 (C-2′′′), 163.3 (C-7),
164.8 (C-6), 195.4 (C-1′), 201.4 (C-1′′). HRMS (ESI+): m/z
calcd for [C22H14O7 + Na]+: 413.0637; found: 413.0622.
(14) 8-Acetyl-4,7-dihydroxy-10-(2-hydroxybenzoyl)-6H-
benzo[c]chromen-6-one (3c)
(10) Makhloufi-Chebli, M.; Hamdi, M.; Silva, A. M. S.;
Balegroune, F. J. Soc. Alger. Chim. 2008, 18, 91.
(11) 8-Acetyl-7-hydroxy-10-(2-hydroxybenzoyl)-6H-
benzo[c]chromen-6-ones (3a–d)
Carboxylic acid 2 (1.0 g, 5.26 mmol) was added to a soln of
the appropriate 3-(acetoacetyl)coumarin 1a–d (5.26 mmol)
in CHCl3 (20 mL). A catalytic amount of 4-PPy (0.26 mmol,
0.04 g) was added dropwise, and the mixture was refluxed
with stirring for 24 h. Incomplete consumption of the
starting materials was observed (TLC), even after an
extended reaction time. The solvent was evaporated and the
resulting gummy solid was directly purified by column
chromatography [silica gel, PE–CH2Cl2 (gradient 3:1 to 2:1
to 1:1 to 0:1)]. Pure fractions were combined and
White-yellowish powder; yield: 1.091 g (53%); mp 272–
273 °C. 1H NMR [300.13 MHz, DMSO-d6–CDCl3 (1:2)]:
δ = 2.74 (s, 3 H, H-2′), 6.80 (ddd, J = 8.1, 7.3, 1.1 Hz, 1 H,
H-5′′′), 6.93–7.12 (m, 4 H, H-1, H-2, H-3 and H-3′′′), 7.32
(dd, J = 8.1, 1.7 Hz, 1 H, H-6′′′), 7.54 (ddd, J = 8.7, 7.3, 1.7
Hz, 1 H, H-4′′′), 8.07 (s, 1 H, H-9), 10.28 (s, 1 H, 4-OH),
11.68 (s, 1 H, 2′′′-OH), 13.33 (s, 1 H, 7-OH). 13C NMR
[75.47 MHz, DMSO-d6–CDCl3 (1:2)]: δ = 31.3 (C-2′), 107.7
(C-6a), 116.7 (C-10b), 116.9 (C-1), 117.9 (C-3′′′), 118.3 (C-
3), 119.2 (C-5′′′), 119.6 (C-1′′′), 123.3 (C-8), 124.5 (C-2),
126.1 (C-10), 132.5 (C-6′′′), 137.0 (C-4′′′), 137.6 (C-9),
139.5 (C-10a), 145.64 (C-4 and C-4a), 162.0 (C-2′′′), 162.9
(C-7), 164.5 (C-6), 195.5 (C-1′), 201.1 (C-1′′).
precipitated in PE.
(12) 8-Acetyl-7-hydroxy-10-(2-hydroxybenzoyl)-6H-
benzo[c]chromen-6-one (3a)
White powder; yield: 1.371 g (70%); mp 197–198 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 2.79 (s, 3 H, H-2′), 6.79
(ddd, J = 8.2, 7.2, 1.1 Hz, 1 H, H-5′′′), 7.20–7.10 (m, 2 H, H-
2 and H-3′′′), 7.28 (dd, J = 8.2, 1.4 Hz, 1 H, H-6′′′), 7.42 (dd,
J = 8.3, 1.1 Hz, 1 H, H-4), 7.58–7.49 (m, 2 H, H-3 and H-
4′′′), 7.65 (dd, J = 8.3, 1.3 Hz, 1 H, H-1), 8.19 (s, 1 H, H-9),
11.99 (s, 1 H, 2′′′-OH), 13.24 (s, 1 H, 7-OH). 13C NMR
(75.47 MHz, CDCl3): δ = 31.9 (C-2′), 108.0 (C-6a), 116.2
(C-10b), 118.0 (C-4), 118.8 (C-3′′′), 119.3 (C-1′′′), 119.6 (C-
5′′′), 124.2 (C-8), 125.4 (C-2), 125.7 (C-10), 127.5 (C-1),
132.4 (C-3), 132.8 (C-6′′′), 137.7 (C-10a), 137.9 (C-4′′′),
138.3 (C-9), 151.0 (C-4a), 163.6 (C-2′′′), 163.8 (C-7), 165.3
(C-6), 196.2 (C-1′), 202.3 (C-1′′). HRMS (ESI+): m/z calcd
for [C22H14O6 + Na]+: 397.0688; found: 397.0688.
(13) 8-Acetyl-3,7-dihydroxy-10-(2-hydroxybenzoyl)-6H-
benzo[c]chromen-6-one (3b)
HRMS (ESI+): m/z calcd for [C22H14O7 + Na]+: 413.0637;
found: 413.0617.
(15) 8-Acetyl-2,7-dihydroxy-10-(2-hydroxybenzoyl)-6H-
benzo[c]chromen-6-one (3d)
White-yellowish powder; yield: 0.474 g (23%); mp 134–
135 °C. 1H NMR [300.13 MHz, DMSO-d6–CDCl3 (1:2)]:
δ = 2.72 (s, 3 H, H-2′), 6.84 (t, J = 7.8 Hz, 1 H, H-5′′′), 7.02
(dd, J = 8.9, 2.7 Hz, 1 H, H-3), 7.06–7.10 (m, 2 H, H-1 and
H-3′′′), 7.30 (d, J = 8.9 Hz, 1 H, H-4), 7.36 (d, J = 7.8 Hz, 1
H, H-6′′′), 7.53–7.61 (m, 1 H, H-4′′′), 8.04 (s, 1 H, H-9), 9.78
(s, 1 H, 2-OH), 11.70 (s, 1 H, 2′′′-OH), 13.33 (s, 1 H, 7-OH).
13C NMR [75.47 MHz, DMSO-d6–CDCl3 (1:2)]: δ = 31.3
(C-2′), 107.7 (C-6a), 112.0 (C-1), 116.3 (C-10b), 117.9 (C-
3′′′), 118.3 (C-4), 119.1 (C-5′′′), 120.0 (C-1′′′), 120.3 (C-3),
123.3 (C-8), 126.2 (C-10), 132.6 (C-6′′′), 136.9 and 137.0
(C-4′′′ and C-9), 137.1 (C-10a), 143.6 (C-4a), 154.1 (C-2),
162.1 (C-2′′′), 162.9 (C-7), 165.0 (C-6), 195.4 (C-1′), 200.6
(C-1′′). HRMS (ESI+): m/z calcd for [C22H14O7 + Na]+:
413.0637; found: 413.0627.
White-yellowish powder; yield: 0.920 g (45%); mp 279–
280 °C. 1H NMR [300.13 MHz, DMSO-d6–CDCl3 (1:2)]:
δ = 2.72 (s, 3 H, H-2′), 6.64 (dd, J = 9.0, 2.5 Hz, 1 H, H-2),
6.76–6.85 (m, 2 H, H-4 and H-5′′′), 7.07 (dd, J = 8.5, 1.0 Hz,
1 H, H-3′′′), 7.32 (dd, J = 8.0, 1.7 Hz, 1 H, H-6′′′), 7.39 (d,
J = 9.0 Hz, 1 H, H-1), 7.55 (ddd, J = 8.5, 7.2, 1.7 Hz, 1 H, H-
Synlett 2013, 24, 2559–2562
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