Copper-mediated synthesis of coumestans via C(sp2)-H functionalization: Protective group free route to coumestrol and 4′-O-methylcoumestrol

Article abstract of DOI:10.1016/j.tet.2017.07.057

A simple and efficient two step synthesis of coumestans is described. The key reaction in the synthesis is the use of easily available Cu(OAc)₂ for C[sbnd]H functionalization of 3-(2-hydroxyphenyl)coumarin to give coumestan ring system via formal oxidative cyclization. This approach provided a short protective group free route to naturally occurring coumestrol and 4′-O-methylcoumestrol.

Full text of DOI:10.1016/j.tet.2017.07.057

Accepted Manuscript
2
Copper-mediated synthesis of coumestans via C(sp )-H functionalization: Protective
group free route to coumestrol and 4′-O-methylcoumestrol
Mayuri M. Naik, Vijayendra P. Kamat, Santosh G. Tilve
PII:
S0040-4020(17)30808-6
10.1016/j.tet.2017.07.057
TET 28889
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 May 2017
Revised Date: 18 July 2017
Accepted Date: 29 July 2017
Please cite this article as: Naik MM, Kamat VP, Tilve SG, Copper-mediated synthesis of coumestans
2
via C(sp )-H functionalization: Protective group free route to coumestrol and 4′-O-methylcoumestrol,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.057.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Copper-mediated synthesis of coumestans via
C(sp2)-H functionalization: Protective group
free route to coumestrol and 4’-O-
methylcoumestrol
Leave this area blank for abstract info.
Mayuri M. Naik, Vijayendra P. Kamat and Santosh G. Tilve
1.0 equiv. Cu(OAc)2
HO
OH
O
O
O
O
HO
O
O
O
O
diphenyl ether
258 O
R
R
C
O
R'
O
O
H
HO
C-H to C-O
bond formation
R'
OMe
25 examples
Upto 80 % yields
Natural coumestans
1

ACCEPTED MANUSCRIPT
Copper-mediated synthesis of coumestans via C(sp2)-H functionalization:
Protective group free route to coumestrol and 4’-O-methylcoumestrol
Mayuri M. Naika, Vijayendra P. Kamata and Santosh G. Tilvea, b,
a Department of Chemistry, Goa University, Taleigao-Plateau, Goa 403 206, India
b Organic Chemistry Department, RUDN University, 6 Miklukcho-Maklaya str., Moscow 117198, Russian
Federation
*Phone: 0832-6519317; Email: stilve@unigoa.ac.in
Key words: Coumestans, copper acetate, C-H functionalization, coumestrol, 4’-O-
methylcoumestrol
Abstract: A simple and efficient two step synthesis of coumestans is described. The key
reaction in the synthesis is the use of easily available Cu(OAc)2 for C-H functionalization of
3-(2-hydroxyphenyl)coumarin to give coumestan ring system via formal oxidative
cyclization. This approach provided a short protective group free route to naturally occurring
coumestrol and 4’-O-methylcoumestrol.
1. Introduction: 6H-Benzofuro[3,2-c]chromen-6-ones, commonly known as coumestans are
polycyclic ring systems having a coumarin ring and a benzofuran ring fused together. This
ring system is found in many naturally occurring compounds distributed widely in plants.1
Members belonging to this class of compounds includes wedelolactone, coumestrol,
psoralidin, medicagol, lucernol, 4’-O-methylcoumestrol, desmethylwedelolactone, etc.
(Figure 1). They exhibit numerous biological activities such as anticancer, estrogenic,
phytoalexin activities, anti-venom, antibacterial, antifungal, cytotoxic, and antidepressant.2
Some coumestans inhibit protein-tyrosine phosphatase 1B3a and some are used in the
treatment of liver diseases.3b These immense biological activities of coumestans have been
attracting chemists since decades as an interesting synthetic target.
Fig 1. Naturally occurring coumestans.
2

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Coumestans have been constructed via several synthetic approaches.4,5 However many of
these methods have their own limitations such as multistep syntheses, expensive
reagents/catalysts usage, hazardous metal catalysts, difficulty in handling of reagents and/or
its excessive requirement, troublesome reaction work up and product isolation. Hence
continuous search for new method/reagent/catalyst for coumestan synthesis is pursued.
2. Results and discussion:
Our retrosynthetic analysis of coumestan ring system 1 suggested a straight forward two step
approach via oxidative cyclization of 3-(2-hydroxyphenyl)coumarin 2 (Scheme 1). The
required 3-(2-hydroxyphenyl)coumarin 2 can be conveniently obtained by condensation of
salicylaldehyde 3 and 2-coumaranone 4 or 2-hydroxyphenylacetic acid 5.
O
O
O
O
O
O
4
CHO
OH
or
R
R
R
+
COOH
OH
R'
O
R'
R'
HO
3
1
2
5
Scheme 1. Retrosynthetic analysis of coumestan 1.
For the oxidative cyclization of 2 four conditions are reported in literature (Scheme 2).6 First
Pb(OAc)4 in refluxing anhydrous benzene,6a later DDQ in refluxing anhydrous benzene,6b
then PdCl2 in presence of sodium acetate in DMF at 150 OC6c and recently iodine in refluxing
pyridine.6d These oxidative cyclization methods have some limitations including low product
yields, utilization of expensive reagent and limited substrate scope. Hence there is a need to
develop a method involving a suitable reagent which can overcome these limitations. To our
knowledge Cu(OAc)2 was not employed for coumestan synthesis via oxidative cyclization
until the completion of this work.
"Previous work"
O
O
O
O
R
R
reaction conditions
R'
O
1
2
HO
R'
1. Pb(OAc)4 (1.5 equiv), anhyd. benzene (30 mL), reflux, 30 min6a
2. DDQ (1.0 equiv), benzene, reflux, 72 h6b
3. PdCl2 (1.0 equiv), NaOAc (13.6 equiv.), DMF, 150 oC, 24 h6c
4. I2 (1.0 equiv), anhy. pyridine, reflux, 15 h6d
3

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Scheme 2. Reported syntheses of coumestans 1 from 2 using various oxidizing agents.
Copper salts have been widely used in organic reactions owing to its cheap availability and
low toxicity. Several reviews have appeared on its role either as reagent and/or catalyst.7 In
particular Cu(OAc)2 is a mild reagent/catalyst known for the synthesis of several
heterocycles.8 It has gained considerable attention for its role in the intramolecular C-O
cyclization via C-H functionalization8c-d for the construction of heterocyclic compounds. For
example a combination of 1.2 equiv Cu(OAc)2 and 0.2 equiv of Zn(OTf)2 in toluene:DMSO
(20:1) has provided 11-H-benzofuro[3,2-b]chromen-11-ones and 6H-benzofuro[2,3-
c]chromen-6-ones via insertion of oxygen into electron rich aromatic rings.8c Interestingly, it
has not been explored for the isomeric naturally occurring 6H-benzofuro[3,2-c]chromen-6-
ones (coumestans). Continuing our interest in copper chemistry9 we envisioned the role of
Cu(OAc)2 in the intramolecular C-O cyclization of 3-(2-hydroxyphenyl)coumarin 2 to form
coumestan 1 under forcing conditions.
Table 1. Optimization of the reaction conditions for the synthesis of coumestansa
O
O
O
O
conditions
O
2a
1a
HO
Entry
Reagent
Solvent
Temperature
Time
(h)
Yield
(%)b
7
(OC)
110
120
1
2c
Cu(OAc)2
Toluene
Toluene:DMSO
(20:1)
24
Cu(OAc)2:Zn(OTf)2
24
7
3
4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2.H2O
CuCl2
p-Xylene
138
118
153
165
180
189
258
258
258
258
258
258
24
24
24
24
24
24
6
20
0
Acetic acid
DMF
5
15
6
6
DMA
7
o-DCB
30
ND
76
55
69
48
19
75
8
DMSO
9
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
10
11
12
13
14
5
24
24
24
24
CuBr2
CuI
Cu2O
4

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15
16
CuO
Cu(OTf)2
Diphenyl ether
p-xylene
258
138
258
258
258
258
258
258
258
258
258
258
16
24
16
24
24
18
24
24
12
12
12
12
60
40
63
74
72
86
RI
RI
RI
RI
RI
78
17
Cu(OTf)2
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
Diphenyl ether
18
Cu (nanopowder)
Cu (metal powder)
Pd(OAc)2
19
20
21d
22d
23e
24f
25g
26h
Pd(OAc)2
PdCl2
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
a Conditions: 2a (0.4 mmol), reagent (0.4 mmol) and solvent 10 mL, under open air.
b Isolated yields.
c 0.48 mmol of Cu(OAc)2:0.08 mmol of Zn(OTf)2 were used.
d 0.04 mmol of reagent was used.
e, f, g, h 10, 20, 30, 50 wt% of reagent was used respectively.
ND: Not determined.
RI: Reaction incomplete.
At the outset 3-(2-hydroxyphenyl)-2H-chromen-2-one 2a was treated with anhydrous
Cu(OAc)2 (1.0 equiv) in toluene under refluxing condition. To our delight the desired product
1a was formed albeit in poor yield (Table 1, entry 1). Encouraged with this finding, we
examined the reported Cu(OAc)2:Zn(OTf)2 in toluene:DMSO (20:1) procedure used for the
synthesis of 11-H-benzofuro[3,2-b]chromen-11-ones.8c However, the yield did not increase.
The reported C-H activation were achieved on aryl systems which were electron rich systems
while in the present case we had to activate an elecron deficient double bond. Hence we
envisaged that higher temperature of the reaction may give us the desired prouct. Hence,
solvents having higher boiling points (entries 3-9) were examined. Among these solvents,
diphenyl ether proved to be the ideal solvent as the product yield increased substantially to
76% (entry 9). With this result, we further screened different metal reagents (entries 9-26).
Employing Cu(OAc)2.H2O diminished the product yield. Alternative Cu reagents such as
CuCl2, CuBr2, CuI, Cu2O and CuO also showed the formation of product among which Cu2O
gave highest yield of 75% (entries 10-15). The more reactive Cu(OTf)2 gave 40% yield on
5

ACCEPTED MANUSCRIPT
refluxing in p-xylene (entry 16) and in diphenyl ether the yield was increased to 63% with
reduced time (entry 17). Cu metal also proved effective for this cyclization (entries 18-19).
Due to the shorter reaction time and the easy availability, anhydrous Cu(OAc)2 was chosen
for further studies with respect to its concentration and temperature (Table 2). It must be
noted that the absence of Cu(OAc)2 showed no product formation (entry 1). Catalytic amount
of Cu(OAc)2 was effective in producing 66 and 70 % yields with longer reaction time
(entries 2-3) and 1.0 equiv proved to be optimum Cu(OAc)2 concentration giving maximum
yield at a faster rate (entry 4). Furthermore on increasing its concentration resulted in
decreased product yield (entries 5-6). With 1.0 equiv of Cu(OAc)2 reactions were performed
at different temperatures (entries 7-10) which revealed that the product yield increases with
increase in temperature. Hence 258 OC was found to be the optimum temperature (entry 4).
Table 2. Optimization of Cu(OAc)2 concentration and temperature for the synthesis of coumestan 1a from 2aa
Entry
Temperature
(OC)
258
Cu(OAc)2
(equiv.)
0.0
Time
(h)
6
Yield
(%)b
00
1
2
258
0.2
24
12
6
66
3
258
0.5
70
4
258
1.0
76
5
258
1.2
11
14
24
24
12
10
70
6
258
2.0
56
7
100
1.0
25
8
150
1.0
50
9
170-180
200
1.0
62
10
1.0
64
a Conditions: 2a (0.4 mmol), Cu(OAc)2 and diphenyl ether (10 mL) at above mentioned temperature under open
air.
b Isolated yields
The optimum reaction conditions were then studied for the substrate scope (Table 3).
Substituents on both the phenyl rings A and B were evaluated. Study on ring A revealed that
the electron releasing methoxy and ethoxy substituent’s reacted smoothly to give the desired
products 1b-1d in good yields. Naphthol group was very reactive to provide the expected
coumestan 1e in 80% yield. Monomethyl and dimethyl substituents were also successfully
converted into the desired products 1f and 1g. Coumestans 1h-1j were formed when
6

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dimethoxy and methylenedioxy substitutions were examined on ring A. Hydroxy substituents
also reacted to produce the required coumestans 1k and 1l without any need of protection
thus exhibiting good efficiency and practicability of this method. Coumestans bearing
electron withdrawing bromo and chloro groups 1m and 1n were synthesised in 53 and 67%
yields respectively. Strong electron withdrawing nitro group was quite reactive enough to
offer the desired product 1o.
a,b
Table 3. Synthesis of coumestans via C-H activation using Cu(OAc)2
O
O
O
O
1.0 equiv Cu(OAc)2
Diphenyl ether
A
R
R
A
R'
B
O
B
2
1
258 O
C
HO
R'
Sr. No.
Substituted 3-(2-
hydroxyphenyl)-2H-
chromen-2-one (2)
Time
(h)
Coumestan
(1)
Yielda
(%)
O
O
O
O
O
1
2
3
4
6
13
6
76
66
72
70
O
HO
2a
2b
2c
1a
MeO
O
MeO
O
O
O
HO
1b
1c
O
O
O
O
MeO
MeO
O
HO
O
O
O
O
O
O
O
13
O
HO
2d
2e
2f
1d
1e
1f
O
O
O
5
6
8
80
65
O
HO
O
O
O
O
10
O
HO
7

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O
O
O
O
7
8
17
67
80
O
HO
OMe
2g
2h
1g
OMe
MeO
O
O
MeO
O
O
6
O
HO
1h
MeO
O
O
MeO
O
O
9
8
77
61
62
MeO
MeO
O
HO
2i
2j
1i
1j
O
O
O
O
O
O
O
O
10
11
14
16
O
HO
OH
OH
O
O
O
O
O
HO
2k
1k
HO
O
O
HO
O
O
12
13
14
15
16
14
68
O
HO
O
2l
1l
O
O
O
24
30
Br
Br
18 c
53 c
O
HO
2m
1m
O
O
O
O
24
13
5
67
54
70
Cl
Cl
O
HO
O
2n
2o
2p
1n
1o
O
O
O
O2N
O2N
O
HO
O
O
O
O
O
HO
OMe
OMe
O
1p
1q
MeO
O
MeO
O
O
17
5
65
O
HO
OMe
2q
OMe
8

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O
O
O
O
O
O
18
19
20
5
55
66
60
O
HO
OMe
2r
2s
OMe
OMe
1r
O
O
6
O
HO
OMe
1s
OMe
OMe
MeO
O
O
MeO
O
O
4
O
HO
OMe
2t
OMe
1t
MeO
O
O
MeO
MeO
O
O
21
7
54
MeO
O
HO
OMe
2u
OMe
1u
O
O
O
O
22
23
24
10
65
60
59
O
HO
2v
1v
O
O
O
O
7
O
HO
2w
1w
HO
O
O
HO
O
O
O
12
O
HO
OMe
2x
2y
OMe
1x
HO
O
O
HO
O
25
18
55
O
HO
OH
OH
1y
a Conditions: 2 (0.4 mmol), Cu(OAc)2 (0.4 mmol) and diphenyl ether (10 mL), reflux under open air for 4-24 h.
b Isolated yields.
c Cu(OAc)2 (0.6 mmol) was used.
On successfully synthesising above derivatives, we went on to explore the substitution on
ring B. When methoxy substituent was employed on ring B with or without substituents on
ring A, reaction went on smoothly to afford diverse coumestans 1p-1u in moderate to good
9

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yields. Among these the isolation of naturally occurring10 coumestrol dimethyl ether 1q,
dimethyl ether of sativol 1t and trimethyl ether of lucernol 1u was quite pleasing. The
synthesis of coumestrol 1y from compound 1q is well known.11 The presence of methyl
group on ring B also successfully delivered coumestans 1v and 1w in 65 and 60% yields
respectively without affecting the side chain.
Encouraged by the formation of hydroxyl coumestans 1k and 1l we applied this methodology
towards the protective group free synthesis of naturally occurring 4’-O-methylcoumestrol1g,12
1x and coumestrol1c,13 1y. 4’-O-Methylcoumestrol was isolated from alfalfa and various other
plant species whereas coumestrol was isolated from alfalfa, ladino clover and many forage
crops. The higher binding affinity of coumestrol for ERβ than other phytoestrogens makes it
one of the most potent phytoestrogen.14 Several total syntheses of coumestrol4f,4q,11,15 while a
few of 4’-O-methylcoumestrol4n,15d,16 have been reported. On subjecting the necessary
starting materials to the above reaction conditions it was endearing to get both coumestans 1x
and 1y in 59 and 55% yields respectively thus eliminating the need of protection-deprotection
stratergies adopted in earlier reported synthetic methods. As most of the naturally occurring
coumestans contain hydroxyl and/or methoxy group/s, our methodology provides a broad
scope for synthesis of such natural members of coumestan family.
The protocol was then successfully tested for the preparation of 1a from 2a on a larger scale
(2.0 mmol) thus demonstrating its utility. Further, a one pot procedure was attempted by
mixing 2- coumaranone 4, salicylaldehyde 3a, Cu(OAc)2 and NEt3 in diphenyl ether as the
solvent system. However, no formation of 1a was observed (Scheme 3-A). Hence a stepwise
one pot approach was developed wherein NEt3 was removed before addition of Cu(OAc)2
giving product 1a in good yield (Scheme 3-B).
Onepot approach
A
1.0 equiv Cu(OAc)2
NEt3, Diphenyl ether
reflux, 6 h
CHO
OH
1a
O
1.0 equiv Cu(OAc)2
+
O
i. NEt3, reflux, 1 h
2a
4
ii. NEt3 removed
under vacuo
3a
Diphenyl ether
reflux, 6 h, 71%
Stepwise onepot approach
B
Scheme 3. Stepwise one pot synthesis of coumestan 1a
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It is known that the presence of other metal impurity or “homeopathic” metal can also be
responsible for such results.17 Initially we had studied Pd metal for this oxidative cyclization.
Pd(OAc)2 when used in stoichiometric quantities gave coumestan in 86% yield (Table 1-
entry 20). Catalytic amount of Pd(OAc)2 or PdCl2 resulted in incomplete reaction (entries 21-
22). Similar findings were also observed for Pd/C (entries 23-26). When 50 wt% of 10%
Pd/C was used 78% of coumestan was formed after 12 h (entry 26). However, due to
requirement of stoichiometric amount of expensive Pd metal we had not pursued it further.
Subsequently it was concluded that Cu(OAc)2 was the best source for the present C-H
activation. But, it was essential to confirm that presence of Pd impurity was not responsible
for this Cu(OAc)2 mediated cylization. Hence ICP-MS analysis of Cu(OAc)2 sample was
carried out. It showed the presence of 1817.97 ppb palladium in Cu(OAc)2. Hence to study
whether Pd has any role in this oxidative cyclization we added 0.01 equiv of Pd(OAc)2 in
Cu(OAc)2 and repeated the experiment. However, there was not much change in the yield of
the product or duration of reaction. Similar was the case when 0.1 equiv of PdCl2 was added.
Previously, Gong et al.6c had employed stoichiometric amount of PdCl2 for such cyclization.
Our attempt to use PdCl2 under Wacker oxidation conditions [CuCl2 in DMF:DMA (1:1)
solvent] at 150 OC produced only trace amount of product. All these results suggest the trace
amount of Pd impurity in Cu(OAc)2 may not be responsible factor for this oxidative
cyclization. However the role of Pd present in ppb level in contact with copper and a
synergestic effect of this cannot be ruled out completely. Further study on the synergestic
effects of other metal dopants/additives is a subject of future study.
To check whether the mechanism is following a radical pathway the reaction was performed
in presence of a radical scavenger TEMPO. It had no effect on the yield of product 1a
suggesting an alternative mechanism. Based on this observation a speculative mechanism is
proposed for this intramolecular C-O cyclization (Scheme 4). Cu(II) from Cu(OAc)2 binds to
electronegative hydroxyl oxygen atom of substrate 2 with the liberation of one molecule of
acetic acid to form intermediate 6. Intramolecular oxidative addition of copper to the C-H
bond renders 8 via the elimination of another molecule of acetic acid from 7. Finally the
reductive elimination of 8 furnishes coumestan 1 and metallic copper. The formation of
metallic copper was confirmed from recorded XRD (see supporting information) of the
residue left after the reaction and also from the copper mirror deposits on the walls of the
11

ACCEPTED MANUSCRIPT
reaction flask. The presence of Cu2O seen in the XRD could be due to the aerobic oxidation
of Cu at high reaction temperature.
Recently, after our studies, Zou et al.18 have reported a synthesis of naturally occurring
coumestrol and aureol via a combination of a Perkin condensation and a Cu(II)-catalyzed
hydroxylation/aerobic oxidative microwave mediated coupling reaction.
O
O
O
O
O
O
II Cu(OAc)2
R
R
R
R'
H
R'
R'
-AcOH
II
O
O
Cu O
O
Cu
II
HO
2
O
6
O
7
-AcOH
O
O
O
O
reductive elimination
R
R
R'
O
Cu
II
R'
O
0 Cu
1
8
1/2 O2
Cu2O
Scheme 4. Proposed mechanism for the formation of coumestans using Cu(OAc)2
3. Conclusion
In conclusion, we have developed an efficient methodology for the synthesis of coumestans.
The method implements economical Cu(OAc)2 as the reagent in absence of any additional
reagent/additive in diphenyl ether solvent via C-H activation. Although the reaction
temperature is high, simple reaction procedure, large substrate scope, effortless product
isolation & good yields make this method attractive over reported methods. Also direct
synthesis of hydroxy substituted coumestans without protection strategies makes the method
noteworthy. Additional advantages are the one pot synthesis and possible use of catalytic
amount of Cu(OAc)2. Further scope of Cu(OAc)2 as an oxidative cyclizing agent employing
ligands will be undertaken in near future.
4. Experimental
4.1. General remarks. All the compounds were characterized by spectral analysis (IR; 1H
13
NMR; C NMR) and comparison of their melting points with the literature reports. All the
12

ACCEPTED MANUSCRIPT
melting points were uncorrected. Infrared (IR) spectra were recorded in a FTIR instrument
using KBr and wavenumbers given in cm-1. 1H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded in DMSO-d6/CDCl3 as solvent and TMS as an internal standard. Coupling
constants are reported in Hz. High resolution mass spectra (HRMS) were recorded on Q-TOF
MS instrument with an electrospray source in ESI mode at IISc, Bangalore. Quantification of
palladium impurity in Cu(OAc)2 was detected by using ICP-MS. All the solvents were
distilled prior to use. Column chromatography was performed on 60-120 mesh silica gel. All
the chemical reagents and diphenyl ether were purchased from commercial sources and used
without further purification unless otherwise stated. Anhydrous Cu(OAc)2 was purchased
from Sigma Aldrich. Substrates 2a to 2o were synthesized using literature procedure from 2-
coumaranone 4 and substituted salicylaldehyde derivatives 3.19 Similarly 2p to 2y were
synthesized from substituted salicylaldehyde derivatives 3 and 2-hydroxyphenylacetic acid
derivatives 5 using literature procedure.6c All the reactions were carried out under
atmospheric conditions without any special cautions unless otherwise stated.
4.2. General procedures
(I) General procedure for the synthesis of substrates 2a-2o19
Substituted salicylaldehyde derivative 3 (455 mg, 3.7 mmol) and 2-coumaranone 4 (500 mg,
3.7 mmol) were mixed together in a round bottom flask. To it triethylamine (15 mL) was
added and refluxed for 1 h. After 1 h triethylamine was removed under vacuum and the crude
solid was recrystallized from ethanol to afford pure product 3-(2-hydroxyphenyl)-2H-
chromen-2-one 2a-2o.
(II) General procedure for the synthesis of substrates 2p-2y6c
Substituted salicylaldehyde derivative
3
(122 mg, 1.0 mmol), substituted 2-
hydroxyphenylacetic acid 5 (182 mg, 1.0 mmol), sodium acetate (410 mg, 5.0 mmol) and
acetic anhydride (245 mg, 2.4 mmol) were mixed together in a round bottom flask. To it
acetic acid (4 mL) was added and refluxed for 24 h. After 24 h the solvent was removed
under vacuum and water was added to it. The crude solid obtained was filtered and then
loaded on column (eluent: petroleum ether/ethyl acetate) to afford pure product 3-(2-
hydroxyphenyl)-2H-chromen-2-one 2p-2y.
(III) General procedure for the synthesis of coumestans 1a-1y
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Cu(OAc)2 (77 mg, 0.4 mmol) was added to substituted 3-(2-hydroxyphenyl)-2H-chromen-2-
one 2a-2y (100 mg, 0.4 mmol) in a 25 mL round bottom flask. To it 10 mL of diphenyl ether
was added. The resulting mixture was then heated to reflux for 4-24 h. After completion of
the reaction (monitored by TLC) the reaction mass was cooled to room temperature. Without
any further work up it was directly loaded on column (eluent: petroleum ether/ethyl acetate)
to afford pure product 6H-benzofuro[3,2-c]chromen-6-one 1a-1y.
(IV) Procedure for the synthesis of coumestan 1a on 0.5 g scale
Cu(OAc)2 (382 mg, 2.1 mmol) was added to 3-(2-hydroxyphenyl)-2H-chromen-2-one 2a
(500 mg, 2.1 mmol) in a 50 mL round bottom flask. To it 20 mL of diphenyl ether was added.
The resulting mixture was then heated to reflux for 21 h. After completion of the reaction
(monitored by TLC) the reaction mass was cooled to room temperature. Without any further
work up it was directly loaded on column (eluent: petroleum ether/ethyl acetate, v/v = 10/1.5)
to afford product 6H-benzofuro[3,2-c]chromen-6-one 1a as colorless solid (296 mg, 60%).
(V) Procedure for stepwise one pot synthesis of coumestan 1a
2-coumaranone 4 (57 mg, 0.4 mmol) and salicylaldehyde 3a (52 mg, 0.4 mmol) were mixed
together in a 25 mL round bottom flask. To it triethylamine (5 mL) was added and refluxed
for 1 h. Triethylamine was removed under vacuum and to the product formed 3-(2-
hydroxyphenyl)-2H-chromen-2-one 2a, Cu(OAc)2 (77 mg, 0.4 mmol) and 10 mL of diphenyl
ether were added. The resulting mixture was then heated to reflux for 6 h. After completion
of the reaction (monitored by TLC) the reaction mass was cooled to room temperature.
Without any further work up it was directly loaded on column (eluent: petroleum ether/ethyl
acetate, v/v = 10/1.5) to afford product 6H-benzofuro[3,2-c]chromen-6-one 1a as colorless
solid (70 mg, 71%).
5. Acknowledgment
Mayuri M. Naik is thankful to CSIR, New Delhi for awarding Junior and senior research
fellowships. Authors also acknowledge DST with project number EMR/2016/000091, New
Delhi for financial assistance and IISc, Bangalore and Syngenta Biosciences Pvt., Ltd., Goa
for providing HRMS facilities. We also thank SAIF-IIT Bombay for providing ICP-MS data.
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