One-Pot Synthesis of Unsymmetrical Bis(4-Hydroxycoumarin-3-yl)methanes

Article abstract of DOI:10.1055/s-0036-1589065

Unsymmetrical bis(4-hydroxycoumarin-3-yl)methane derivatives have been synthesized from 4-hydroxycoumarins, aldehydes, and secondary amines via 3-(aminoalkyl)-4-hydroxycoumarin intermediates, followed by substitution.

Full text of DOI:10.1055/s-0036-1589065

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
S. Kolita et al.
Letter
Synlett
One-Pot Synthesis of Unsymmetrical Bis(4-Hydroxycoumarin-3-
yl)methanes
R2
O
O
Sinki Kolitaa
Leema Duttaa
Pankaj Dasb
Pulak J Bhuyan*a
O
CH3CN
r.t.
O
N
O
+
+
OH
N
OH
4
R2
H
H
3
2: R2 = Ph, 4-Tol, 4-ClC6H4,
4-BrC6H4, 3-O2NC6H4,
4-MeOC6H4
R1
R1
a Applied Organic Chemistry Group, CSIR-North East Institute
of Science and Technology, Jorhat 785006, Assam, India
b Department of Chemistry, Dibrugarh University, Dibrugarh-
786004, Assam, India
1: R1 = H, Me, Cl
O
O
R2
O
O
MeCN
reflux
O
O
HO
OH
pulak_jyoti@yahoo.com
OH
R4
R4
5: R3 = H, Me, Cl
R4 = H, Me
R3
R1
R3
6a–v
Yield: 74–92%
Received: 25.04.2017
Accepted after revision: 02.06.2017
Published online: 13.07.2017
is not isolable and undergoes nucleophilic attack by a sec-
ond molecule of 4-hydroxycoumarin to produce the sym-
metrical product (Scheme 1).
DOI: 10.1055/s-0036-1589065; Art ID: st-2017-d0288-l
Abstract Unsymmetrical bis(4-hydroxycoumarin-3-yl)methane deriv-
atives have been synthesized from 4-hydroxycoumarins, aldehydes, and
secondary amines via 3-(aminoalkyl)-4-hydroxycoumarin intermedi-
ates, followed by substitution.
O
O
CHO
O
O
OH
+
O
Key words Mannich base, Michael addition, bishydroxycoumarinyl-
methane, methylenebischromenone
4-hydroxycoumarin
benzaldehyde
Intermediate
The demand for rapid preparation of heterocyclic com-
pounds with simple workup and chromatography-free iso-
lation of the products has increased with the advent of
high-throughput pharmaceutical screening.1–4
O
O
O
O
O
O
O
O
HO
OH
+
OH
Coumarins occur widely as secondary plant metabo-
lites,5 and they exhibit biological properties such as antiox-
idant,6 anti-HIV,7 anticancer,8 anticoagulant, vasorelaxant,9
and enzyme-inhibition activities.10 Biscoumarins are an
important class of coumarin derivatives that possess promi-
nent pharmacological and biological activities.11,12 Bis(4-
hydroxycoumarin-3-yl)methane [dicoumarol; 3,3′-methy-
lenebis(4-hydroxy-2H-chromen-2-one)] is a naturally oc-
curring anticoagulant drug. The synthesis and molecular
manipulation of this class of molecule is usually achieved
through the reaction of 4-hydroxycoumarin with aldehydes
in the presence of various catalysts such as tetrabutylam-
monium bromide,13 molecular iodine,14 1-butyl-3-me-
thylimidazolium tetrafluoroborate,15 SO3H-functionalized
ionic liquids or other ionic liquids,16 sodium dodecyl sul-
O
Intermediate
4-hydroxycoumarin bis(4-hydroxycoumarin-3-yl)methane
derivative
Scheme 1 Formation of a symmetrical bis(4-hydroxycoumarin-3-
yl)methane derivative
To date, there has been no report of the synthesis of un-
symmetrical bis(4-hydroxycoumarin-3-yl)methanes. In a
continuation of our research on coumarins,22 we recently
reported the synthesis of dihydrofurocoumarins by the re-
action of 3-(aminoalkyl)-4-hydroxycoumarin derivatives
with N-ylides.23 By adopting this approach, we developed
the first synthesis of unsymmetrical bis(4-hydroxycouma-
rin-3-yl)methanes 6 by generating a 3-(aminoalkyl)-4-hy-
droxycoumarin 4 through the reaction of a 4-hydroxycou-
marin 1, an aldehyde 2, and pyrrolidine (3), followed by
subsequent reaction of intermediate 4 with a second 4-hy-
droxycoumarin derivative 5 in the same pot.
fate,17
piperidine,12a
dodecylbenzenesulfonic
acid,18
nanoparticulate silica chloride,19 ruthenium(III) chloride
hydrate,20 or zinc diprolinate.21 However, all these methods
produce symmetrical bis(4-hydroxycoumarin-3-yl)meth-
anes, because the intermediate aldol condensation product
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. Kolita et al.
Letter
Synlett
O
O
The existing method for the preparation of compound
4a used toluene as solvent in the presence of InCl3 as cata-
lyst. However, we observed that toluene was not suitable
for the second step of the process (Table 1, entry 1). We also
observed that the reaction proceeded in the absence of cat-
alyst in some solvents such as THF, DMF, and ethanol, but
provided a low yield of the compound 4a even after extend-
ed reaction times (entry 4). However, when acetonitrile was
used as solvent, compound 4a was obtained as a solid in
two hours with complete consumption of the starting ma-
terial in the absence of the catalyst (entry 5). Furthermore,
this solvent was found to be appropriate for the second step
of the reaction. The reaction proceeded in DMF, but the iso-
lated yield of the final product 6a was low, possibly as a re-
sult of the workup procedure. We therefore chose acetoni-
trile as the optimum solvent. The first step of the reaction
occurred at room temperature to produce the intermediate
compound 4a, but the second step required heating under
reflux to produce 6a. Thus, under the optimal reaction con-
ditions, equimolar amounts of 4-hydroxycoumarin (1a)
benzaldehyde (2a), and pyrrolidine (3a) in acetonitrile were
stirred at room temperature for two hours until the reac-
tion was complete (TLC monitoring), and then one equiva-
lent of 4-hydroxy-6-methylcoumarin (5a) was added.25 The
mixture was then refluxed for 4.5 hours to give, after work-
up, the unsymmetrical bis(4-hydroxycoumarin-3-yl)meth-
ane derivative 6a in 86% yield. The 1H NMR spectrum of 6a
showed the presence of an isolated methine proton as a sin-
glet at δ = 6.16 and two protons at δ = 11.58 as a broad
peak, assigned to the two OH groups. The methyl group ap-
peared at δ = 2.30 as a singlet, and the aromatic protons ap-
peared at δ = 7.30–8.19. HRMS analysis showed a molecu-
lar-ion peak at 425.1026 (M – H)–.
O
R2
MeCN
O
N
O
+
+
OH
R2
H
OH
r.t., 2 h
N
H
R1
1
3
2
R1
4
O
O
R2
O
O
N
OH
+
OH
R4
R3
R1
5
4
MeCN
R2
reflux, 4–5 h
O
O
O
O
HO
OH
R4
R1
R3
6
Scheme 2 Synthesis of unsymmetrical bis(4-hydroxycoumarin-3-yl)-
methanes
We began by preparing the key intermediate 3-(amino-
alkyl)-4-hydroxycoumarin derivative 4a by one-pot three-
component reaction of 4-hydroxycoumarin (1a), benzaldehyde
(2a) and pyrrolidine (3) in acetonitrile at room temperature
(Table 1), through a modification of the method we used in
our earlier study.24 The intermediate 4a was not isolated,
but was treated directly with 4-hydroxy-6-methylcoumarin
(5a). After workup, we obtained the unsymmetrical bis(4-
hydroxycoumarin-3-yl)methane derivative 6a (Table 1).
Table 1 Optimization of the Reaction Conditions
O
O
OH
O
O
Ph
O
O
Ph
N
H
O
O
O
O
O
N
5a
reflux
Me
3
HO
OH
6a
+
OH
Ph
OH
stirring
1a
2
4a
Me
Entry
Solvent
Catalyst
Timea (h)
Yieldb (%)
1
2
3
4
5
toluene
THF
InCl3
InCl3
InCl3
2 + 6
15
22
35
45
86
2 + 6
DMF
2 + 5
EtOH
MeCN
2 + 4.5
2 + 4.5
–
–
a Stirring time + reflux time.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. Kolita et al.
Letter
Synlett
To establish the generality of the reaction, we synthe-
sized a series of unsymmetrical bis(4-hydroxycouma-
rin)methane derivatives 6a–t (Table 2). We found that aryl
aldehydes were highly reactive and gave the corresponding
products in high yield in crystalline form within short reac-
tion times (Table 2, entries 1–17). The reaction was also sat-
isfactory with formaldehyde (entries 18–20). However, oth-
er aliphatic aldehydes did not afford the desired product.
We also examined the reaction using ketones in place of al-
dehyde in the reaction process but the desired products
were not formed. 4-Hydroxycoumarins possessing elec-
tron-withdrawing groups on the aromatic ring showed bet-
ter reactivities than those possessing electron-donating
groups and gave the corresponding products in better
yields and in shorter reaction times. Other secondary
amines participated in the reaction, but 3-(pyrrolidine-1-
ylalkyl)-4-hydroxycoumarin derivatives were found to be
the most suitable in terms of their workup and the isolation
of the products.
The reaction was also examined by using the same cou-
marin in the second step, and the symmetric bis(4-hy-
droxycoumarin-3-yl)methanes 6u and 6v obtained were
identical in all respects with authentic samples (Table 2, en-
tries 21 and 22).26 However, whereas existing methods for
the synthesis of symmetric bis(4-hydroxycoumarins) usu-
ally require the addition of a catalyst, no catalyst was re-
quired in this protocol.
Table 2 Synthesis of Unsymmetrical or Symmetrical Bis(4-hydroxycoumarin-1-yl)methanes 6a–v
O
O
OH
R2
O
R2
O
O
O
N
H
3
R4
O
O
R3
5
O
N
O
O
HO
+
R2
MeCN
reflux
MeCN
r.t.
OH
OH
OH
R4
1
2
4
6
R1
R1
R1
R3
Entry
R1
R2
Ph
R3
Me
R4
Timea
Product
Yield (%)
1
2
H
H
2 + 4.5
2 + 4
6a
6b
6c
6d
6e
6f
86
92
88
81
87
83
84
90
86
84
89
85
83
90
85
78
75
79
82
80
81
74
H
Ph
Ph
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
3
Me
H
Cl
2 + 4
4
4-Tol
4-Tol
4-Tol
Me
Cl
2 + 5
5
H
2 + 4.5
2 + 4.5
2 + 4.5
2 + 4
6
Me
H
Cl
7
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
Ph
Me
Cl
6g
6h
6i
8
H
9
Me
H
Cl
2 + 4
10
11
12
13
14
15
16
17
18
19
20
21
22
Me
Cl
2 + 4.5
2 + 4
6j
H
6k
6l
Me
H
Cl
2 + 4
Me
Cl
2 + 4.5
2 + 4
6m
6n
6o
6p
6q
6r
H
Me
Me
Cl
Cl
2 + 4
Cl
2 + 4.5
2 + 5
Me
Me
Cl
H
H
2 + 5
H
H
2 + 5
6s
6t
Me
H
H
Cl
2 + 5
Ph
H
2 + 5
6u
6v
Me
Ph
Me
2 + 5
a Stirring time + refluxing time.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
S. Kolita et al.
Letter
Synlett
In conclusion, we have reported the first method for the
synthesis of unsymmetrical bis(4-hydroxycoumarin-3-
yl)methanes by generating 3-(aminoalkyl)-4-hydroxycou-
marins by the reaction of a 4-hydroxycoumarin, an alde-
hyde, and pyrrolidine, followed by subsequent reaction of
the 3-(aminoalkyl)-4-hydroxycoumarin intermediate with
another 4-hydroxycoumarin in the same pot. The products
were obtained in high yields with a simple workup proce-
dure involving filtration and recrystallization. This reaction
can produce unsymmetrical or symmetrical bis(4-hydroxy-
coumarin-3-yl)methanes.
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nyl)methyl]-6-methyl-2H-chromen-2-one (6a); Typical Pro-
cedure
Equimolar amounts of 4-hydroxycoumarin (1a; 0.162 g,
1 mmol), benzaldehyde (2a, 0.106 g, 1 mmol), and pyrrolidine
(3; 0.071 g, 1mmol) in MeCN (5 mL) were stirred at r.t. for 2 h
until the reaction was complete (TLC). During this period a pre-
cipitate appeared. 4-Hydroxy-6-methylcoumarin (5a; 0.176 g, 1
mmol) was added, and the mixture was reflux for 4.5 h until the
reaction was complete (TLC). The mixture was cooled and the
solid product was collected by filtration and crystallized
(MeCN). The filtrate was diluted with hexane (20 mL) and
passed through a short column of silica gel. The pyrrolidine that
remained in the column was eluted with MeOH.
Colorless crystalline solid; yield: 0.366 g (86%); mp 201 °C. IR
(KBr) = 3158.6, 3023.0, 1609.2, 1649.1, 1560.3 cm–1 1H NMR
.
(500 MHz, DMSO-d6): δ = 2.30 (s, 3 H), 6.16 (s, 1 H), 7.30–8.19
(m, 12 H), 11.58 (s, 2 H). 13C NMR (125 MHz, DMSO-d6):
δ = 20.8, 36.4, 103.8 (2C), 119.8, 119.9, 120.2, 120.3, 123.1,
125.1, 126.9 (2 C), 128.0 (2 C), 131.2, 131.9, 132.0, 132.1, 132.2,
142.8, 150.9, 152.8, 164.9 (2 C), 165.0 (2 C). HRMS (–ESI); m/z
[M – H]– Calcd for C26H18O6: 425.1025; found: 425.1026.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D