Synthesis of novel benzopyrano[3,2-c]coumarins via tandem base promoted nucleophilic substitution and intramolecular electrophilic aromatic cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.05.003

Efficient and facile synthesis of 7H-benzopyrano[3,2-c]coumarins has been achieved by mild base promoted reaction of 4-chloro-3-formylcoumarin with diversely functionalized resorcinols. All the products were obtained as pure precipitates from the reaction

Full text of DOI:10.1016/j.tetlet.2014.05.003

Accepted Manuscript
Synthesis of novel benzopyrano[3,2-c] coumarins via tandem base promoted
nucleophilic substitution and intramolecular electrophilic aromatic cyclization
Satyanarayana Reddy Jaggavarapu, Anand Solomon Kamalakaran, Jagadeesh
Babu Nanubolu, Venkata Prasad Jalli, Sravan Kumar Gangisetty, Gopikrishna
Gaddamanugu
PII:
S0040-4039(14)00779-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.003
TETL 44593
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 January 2014
1 May 2014
2 May 2014
Please cite this article as: Jaggavarapu, S.R., Kamalakaran, A.S., Nanubolu, J.B., Jalli, V.P., Gangisetty, S.K.,
Gaddamanugu, G., Synthesis of novel benzopyrano[3,2-c] coumarins via tandem base promoted nucleophilic
substitution and intramolecular electrophilic aromatic cyclization, Tetrahedron Letters (2014), doi:http://dx.doi.org/
10.1016/j.tetlet.2014.05.003
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Synthesis of novel benzopyrano[3,2-c]
coumarins via tandem base promoted
nucleophilic substitution and intramolecular
electrophilic aromatic cyclization
Satyanarayana Reddy Jaggavarapua, Anand Solomon Kamalakarana, Jagadeesh Babu Nanubolub, Venkata
Prasad Jallia, Sravan Kumar Gangisettya, and Gopikrishna Gaddamanugua, ∗
O
O
O
OH
O
O
O
OH
Et3N, rt
+
H
EtOH, 15 min
OH
2a-o
R
Cl
1
3a-o
OH

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of novel benzopyrano[3,2-c]coumarins via tandem base promoted
nucleophilic substitution and intramolecular electrophilic aromatic cyclization
Satyanarayana Reddy Jaggavarapua, Anand Solomon Kamalakarana, Jagadeesh Babu Nanubolub, Venkata
Prasad Jallia, Sravan Kumar Gangisettya and Gopikrishna Gaddamanugu a, ∗
a Department of Chemistry, Sankar Foundation Research Institute, Naiduthota, Vishakapatnam 530047, India
bX-ray crystallography division, Indian Institute of Chemical Technology, Hyderabad 500076, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Efficient and facile synthesis of 7H-benzopyrano[3,2-c]coumarins has been achieved by mild
base promoted reaction of 4-chloro-3-formylcoumarin with diversely functionalized resorcinols.
All the products were obtained as pure precipitates from the reaction mixture and the structure of
the product was confirmed by X-ray analysis.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzopyrano coumarins,
Resorcinol
4-chloro-3-formylcoumarin
Tandem
X-ray crystallography.
Resorcinol and their derivatives have been extensively used in
organic chemistry for the synthesis of broad range of drug
molecules with numerous biological implications.1 They are
admired as versatile starting materials for the development of
photoelectronic materials and macrocyclic molecular scaffolds.2
The positioning of the meta substituted phenols on the aromatic
ring facilitate appropriate electronic features for a variety of
tandem cylization protocols. These electronic features of
resorcinols were exploited extensively for the synthesis of a
variety of important structural scaffolds such as resorcinarenes, 3a
isofalvones, 3b, 3c coumarins, 3d chromenes3e and pyrans3f.
resorcinol, catechol and 1,4-hydroquinones in aqueous medium.8
Wang et al. demonstrated a multicomponent reaction of 4-
hydroxycoumarin, aldehydes and β-naphthol using Zr(HSO4)4 as
catalyst successfully achieving the target benzopyrano [3,2-
c]chromen-6-ones.9 Ma et al. reported a modified experimental
procedure of Wang et al. with melamine trisulfonic acid as
catalyst under solvent-free conditions.10 A. K. Bagdi et al.
accomplished the synthesis of these compounds via copper(II)
triflate catalyzed tandem reaction of 4-hydroxy coumarin with
α,β-unsaturated carbonyl compounds.11 However, most of the
above reported procedures employ harsh reaction conditions to
achieve the target molecules.
Benzopyrano [3, 2-c] chromen-6-ones which are fused
combination of privileged scaffolds such as coumarin and
benzopyran constitute an elite class of structures. In addition to
the individual applications of these scaffolds,4 the fused motifs
append significant contribution to the library of vital drug
molecules with antifungal, insecticidal, anticancer, anti-HIV,
anti-inflammatory, and antibacterial activities.5 Due to the
interesting conjugative properties of these structures,
applications were established in the area of photonic materials.6
The above remarkable biological and synthetic applications
encouraged the development of some interesting procedures for
the synthesis of these structures. For example, I. M. EI-Deen et
al. reported the synthesis of benzopyrano[3, 2-c]chromen-6-ones
using 3-ethoxycarbonylcoumarin and resorcinol in sodium
methoxide conditions.7 Kidwai et al. reported the laccase
enzyme catalyzed synthesis of substituted benzopyrano[3, 2-
Recently, we have reported 4-chloro-3-formylcoumarin as a
versatile starting material with unique structural features
comprising a leaving group, α,β-unsaturated double bond and
reactive aldehyde.12d Our latest endeavors demonstrated its
application for the synthesis of novel heterocyclic scaffolds such
as benzazepines, pyrymidine-N-oxides, quinolines, chromeno-
2,6,9-trioxabicyclo[3.3.1]nonadienes
and
chromeno[4,3-
b]pyridine-2,5-dione heterocyles.12 To achieve the novel
benzopyrano[3,2-c]coumarin target structures 3a-o, we conceived
a mild base promoted tandem protocol involving 4-chloro-3-
formylcoumarin 1 and resorcinols 2a-o, where the cyclized
products can be obtained with intact alcohol moieties. We
conducted a series of initial optimization experiments by
subjecting 4-chloro-3-formylcoumarin 1 and resorcinol 2a to
various base catalyzed reaction conditions (Table 1).
c]chromen-6-ones by reaction of α,β-unsaturated coumarins with
———
∗ Corresponding author. Tel.: +91-0891-2891187; fax: +91-0891-2891186; e-mail: gkrishnagps@gmail.com

2
Tetrahedron Letters
Table 1. Screening studies of the reaction of 1 and 2a with
various bases and solventsa.
readily available bulkier nutraceutical substrates containing
resorcinol scaffolds such as quercetin dihydrate 2n, and chrysin
2o. Interestingly, despite multiple reactive phenolic groups on
these substrates, both the substrates reacted selectively affording
good yields (63-70%) of the corresponding products 3n and 3o as
pure precipitates. In general, all the products were precipitated in
pure form from the reaction mixture which simplified work-up
and purification procedures.
O
O
OH
OH
O
O
O
Base
O
H
Solvent
+
OH
Cl
1
3a
2a
OH
Entry
1
Base
NEt3
Solvent
EtOH
Time(min)
Yeildc (%)
15
60
60
60
15
15
15
60
15
15
15
15
15
65b
NRd
NR
NR
60
55
60
-
O
O
2
3
K2CO3
NaOAc
NaHCO3
DBU
DABCO
DIEA
-
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
CHCl3
DCM
OH
O
O
OH
NEt3 (1 equiv.)
4
+
H
Ethanol (2 ml)
15 min, rt
O
5
6
OH
R
Cl
O
R
1
2a-o
3a-o
7
OH
8
O
O
O
O
O
O
O
9
NEt3
NEt3
40
42
55
55
65
OH
OH
OH
10
11
12
13
O
O
NEt3
NEt3
NEt3
THF
Acetonitrile
Methanol
OH
O
OH
O
OH
3a, 65%
3b, 75%
3c, 82%
a Carried out with 1 mmol of 1 and 1 mmol of 2a in the presence of with 1
equvivalent of base and solvent (3 mL) at at room temperature for 15min,
b pure precipitated yield,
c isolated yields,
d NR=no reaction.
O
O
O
O
O
O
O
O
OH
OH
OH
O
OH
O
O
OH
3d, 83%
Gratifying result was observed when 1 and 2a were treated
with 1 equivalent of triethylamine in ethanol, where the desired
product 3a was obtained directly as pure precipitate in 65% yield
(Table 1, entry 1) within 15 minutes. Additionally, various bases
such as K2CO3, NaOAc, NaHCO3, DBU, DABCO and DIEA
were investigated for the optimization studies. While inorganic
bases such as K2CO3, NaOAc, and NaHCO3 did not afford the
product (Table 1, entries 2-4); organic bases DBU, DABCO and
DIEA gave moderate yields (55-60%) of the desired product
(Table 1, entries 5-7). Further, to ascertain the role of the base, a
blank experiment was by conducted in the absence of base in
ethanol which did not afford required product (Table 1, entry 8).
Among various solvents screened (Table 1, entries 9-13), the
reactions in CHCl3, DCM, THF, CH3CN, and MeOH gave poor
to moderate yields of the product (40-65%). Although ethanol
and methanol gave similar yields, ethanol was chosen for further
experiments, as it facilitated direct precipitation of the product
simplifying the protocol by avoiding the need for tedious column
separations.
OH
O
3e
, 83%
3f, 79%
O
O
O
O
O
O
O
OH
OH
OH
O
O
O
O
OH
O
OH
O
OH
O
3g
, 77%
3h, 75%
3i, 74%
O
O
O
O
O
O
O
OH
OH
OH
O
I
O
O
OH
O
OH
OH
O
3j
3k
,60%
, 55%
3l, 45%
O
O
O
O
O
O
O
O
O
OH
OH
OH
OH
O
OH
O
OH
OH
3m, 50%
OH
O
OH
O
To explore the generality of the methodology, 1 was subjected
to reaction with diversely functionalized resorcinol substrates
under the above optimized experimental conditions (Scheme 1).
Resorcinols possessing acyl substitutions such as acetyl,
propanoyl, butanoyl, isobutyryl, benzoyl, phenacyl, p-
methoxypheanacyl and o-methoxyphenacyl groups at the 4th
position of the resorcinol ring (2b-i), afforded the corresponding
products 3b-i as pure precipitates from the reaction mixture in
good to excellent yields (75-84%). When substrate 2j with a
formyl group in the 4th position of resorcinol was employed
under the reaction conditions, product 3j was obtained in
moderate yield (55%), due to the formation of other unidentified
side products probably resulting from the reactive aldehyde
group. When substrates 2k and 2l with functional groups
positioned between the phenols were employed under the
reaction conditions, moderate yields (45-60%) of their
corresponding products 3k and 3l were obtained. Similarly, 5-
methyl resorcinol 2m under the reaction conditions afforded the
product 3m in moderate yield (50%). The lower yields in case of
2k-m can be attributed to the steric factors which can hinder
either O-alkylation or intramolecular cyclization steps of the
reaction. The scope of the reaction was further investigated with
3n, 65%
3o
, 63%
Scheme 1: Synthesis of benzopyrano coumarins scaffolds13
During close monitoring of the reaction it was observed that
the reaction was initiated instantaneously after the addition of the
reactants where all the reactants were consumed within 15
minutes and prolonged reaction times did not improve the yields
any further. Interestingly, we were successful in isolating O-
alkylated resorcinol precipitates within 30 seconds of the
initiation of the reaction exclusively for the resorcinols 2g-i (see
supplementary data), whereas other substrates reacted more
rapidly to yield the products directly, making the isolation of O-
alkylation intermediates difficult.
The structure of the product was confirmed by X-ray analysis
of 3f as shown in Figure 1. The molecule was crystallized in
monoclinic system with space group P21/c with four molecules in
the unit cell. The crystal was stabilized by O-H...O hydrogen
bonding interaction between two molecules resulting in a dimer
in the unit cell (Also refer crystal data and crystal packing
diagram in supplementary data).

3
Union Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336
033; email: deposit@ccdc.cam.ac.uk].
References and notes
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Chem. 2005, 70, 10151.
Based on the observations from Scheme 1, we envisaged the
mechanism as shown in Scheme 2 to account the formation of the
products 3a-o. As shown in the Scheme 2, triethylamine initiates
the reaction by abstracting the proton from resorcinol 2a
generating resorcinolate anion which participates in
a
nucleophilic substitution reaction at the 4-chloro position of 1
resulting in an O-alkylated intermediate A. Intermediate A, then
undergoes intramolecular electrophilic aromatic substitution
reaction with the formyl group of 1 affording the cyclized
intermediate B, which rearranges to the yield the final product
benzopyrano[3,2-c]coumarin-6-one 3a.
O
O
HCl.NEt3
O
O
H
O
HO
OH
OH
-Cl-
O
Cl
O
O
NEt3
O
1
A
2
2a
O
H
NEt3
OH
O
O
O
O
O
5.
(a) Mali, R. S.; Joshi, P. P.; Sandhu, P. K.; Manekar-Tilve, A. J.
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78.
OH
H
OH
O
B
3a
O
OH
Scheme 2. Mechanism for the formation of 3a.
In conclusion, we have reported a mild and efficient synthesis
of benzopyrano[3,2-c]coumarins via base promoted tandem
nucleophilic addition and electrophilic aromatic cyclization
reaction. The protocol afforded all the products as pure
precipitates in good to excellent yields. Further studies on
biological activities and photochromic applications are currently
being explored.
Acknowledgments
6. Huang, C. N.; Kuo, P. Y.; Lin, C. H.; Yang, D. Y. Tetrahedron
2007, 63, 10025.
We thank the administration of Sankar Foundation for their
kind support.
7. EI-Deen, I. M.; Ibrahim, H. K. Journal of the Korean Chemical
Society. 2003, 47, 137.
8. Kidwai, M.; Poddara, R.; Diwaniyan, S.; Kuhad, R. C. Synthetic
Communications. 2011, 41, 695.
Supplementary data
9. Wang, X.; Lu, G.; Yan, F.; Ma, W.; Wu, L. J. Heterocyclic
Chem., 2011, 48, 1379.
General experimental section, analytical data for compounds
3a-o and the X-ray analysis of 3d can be found in supplementary
data. Crystallographic data of 3d has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 971586 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre (CCDC), 12
10. Ma, W.; Wang, X.; Yan, F.; Wu, L.; Wang, Y. Monatsh Chem.
2011, 142, 163.
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12. (a) Prasad, J. V.; Prabhakar, M.; Manjulatha, K.; Rambabu. D.;
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Solomon, K. A.; Gopikrishna, G. J. Chem. Sci. 2011, 123, 673;
(c) Jalli, V. P.; Jaggavarapu, S, R.; Kamalakaran, A. S.;
Gangisetty, S. K.; Nanubolu, J. B.; Gopikrishna, G. Tetrahedron

4
Tetrahedron Letters
Lett. 2013, 54, 1491; (d) Jaggavarapu, S. R.; Kamalakaran, A.
S.; Gayatri, G.; Shukla, M.; Dorai, K.; Gopikrishna, G.
Tetrahedron, 2013, 69, 2142.
13. Representative experimental procedure for synthesis of
compound 3a: Synthesis of 7, 10-dihydroxy-7H-benzo [5, 6]-
pyrano [3, 2-c] chromen-6-one (3a): A solution of 4-chloro-3-
formyl coumarin (1 mmol), resorcinol (1 mmol) and triethylamine
(1 equivalent) in 5ml ethanol were stirred at room temperature for
15 min. After completion of the reaction the precipitate obtained
was filtered and washed thoroughly with absolute ethanol and re-
crystallized from ethanol to afford pure product 3a. Brown colored
solid, mp 153-154 °C; [Found: C, 68.08; H, 3.56; C16H10O5
requires C, 68.09; H, 3.57;%]; νmax(KBr) 1719, 1702, 1679, 1618,
1583, 1479, 1418, 1240, 1041 cm-1; δH (400 MHz CDCl3) 12.12 (1
H, s), 8.29 (1H, s), 8.18 (1 H, d, J 7.2 Hz), 7.79 (1H, t, J
7.2Hz),7.43-7.13 (4H, m),7.10 (1 H, d, J 6.8 Hz), 5.89 (1H, d,
J6.8Hz); δC (100 MHz, CDCl3) 187.76, 159.84, 159.20,, 152.57,
145.68, 138.61, 137.14, 133.53, 129.78, 129.64,127.02,
126.07,125.98, 125.13, 118.77, 114.50, 103.35, 31.41.; LCMS:
MH+, 332.