Synthesis of furo[3,2-c]coumarin from the reaction of 3-halochromone and 2-aminochromone; 2-aminochromone as a masked 4-hydroxycoumarin

Article abstract of DOI:10.3184/174751912X13465065026212

Synthesis of 2-(2-hydroxybenzoyl)-4H-furo[3,2-c]chromen-4-one has been accomplished by the reaction of 3-halochromone with 2-aminochromone. In this reaction, 2-aminochromone acts as a masked 4-hydroxycoumarin.

Full text of DOI:10.3184/174751912X13465065026212

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 623
NOVEMBER, 623–625
Synthesis of furo[3,2-c]coumarin from the reaction of 3-halochromone and
2-aminochromone; 2-aminochromone as a masked 4-hydroxycoumarin
b
a
a
a
Pritam Biswas , Jaydip Ghosh , Tapas Sarkar , Sourav Maiti and Chandrakanta
Bandyopadhyayaa*
aDepartment of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata -700 118, West Bengal, India
bChemistry Division, CSIR-Indian Institute of Chemical Biology, Jadavpur - 700 032, West Bengal, India
Synthesis of 2-(2-hydroxybenzoyl)-4H-furo[3,2-c]chromen-4-one has been accomplished by the reaction of
3-halochromone with 2-aminochromone. In this reaction, 2-aminochromone acts as a masked 4-hydroxycoumarin.
Keywords: 3-halochromone, 2-aminochromone, 4-hydroxycoumarin, furo[3,2-c]coumarin, 1-benzopyran
The furocoumarin framework is widely distributed in nature.1,2
Coumestrol, wedelolactone, medicagol and plicadin (Fig. 1)
are some of the naturally occurring compounds containing
this group, which exhibit potent physiologically activities.3
Syntheses of substituted furo[3,2-c]coumarins have been
achieved by the reaction of 4-hydroxycoumarin (i) with termi-
nal alkynes initiated by CAN,4 (ii) with α-haloketone5 (iii) with
3-formylchromone induced by isocyanide,6 (iv) with aldehydes
in polyethylene glycol,7 by (v) rhodium(II)-catalysed hetero-
cyclisation of 3-diazobenzopyran-2,4(3H)-dione8 and also
from (vi) 3-alkynyl-chromones.9
3-Halochromone (1) has attracted the attention of organic
chemists because of its interesting structural feature.10 It con-
tains an α,β–unsaturated carbonyl moiety linked to two leaving
groups (halogen at Cα- and aryloxy group at Cβ- positions) and
it is prone to react with various nucleophiles. Reactions of
amines with 1 have been studied in detail. Primary amines pro-
duce coumarone derivatives.11 Active methylene compounds
like β–diketones or β–ketoesters react with 1 in the presence of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or 1,5-diazabicy-
clo[4,3,0]non-5-ene (DBN) to produce furan derivatives,12
whereas diethyl malonate or alkyl cyanoacetate undergoes
substitution to form chromone-substituted active methine
compounds.13 The reaction of 4-hydroxy-6-methyl-2H-pyran-
2-one (triacetic acid lactone) with 1 affords the formation of
furan derivatives.14 However, the reaction of an enamine with 1
has only been studied a little.Although cyclohexanone enamine
failed to react, the more reactive β–nitroenamine led to the
formation of pyrrole derivatives.14
activated doubly by electron-donating aryloxy group at the
α-position and electron-withdrawing carbonyl group at the
β–position of the enamine moiety. It was of interest to see how
this enamine would behave towards 3-halochromone. The
results of the reactions of 3-halochromone with 2- aminochro-
mone are reported here.
There was no reaction on heating a mixture of 1a (1 mmol)
and 2a (1 mmol) in CH3CN (20 mL) in the presence of K2CO3
(5 mmol) for 10 h and amine 2 remained insoluble (Table 1,
entry 1). Similarly, no reaction was observed when a mixture
of 1a and 2b was heated in methanol in presence of TsOH
(20 mol%) for 6 h (entry 2). However, on heating equimolar
amounts of 1a and 2a in glacial acetic acid for 20 h, a small
amount of a new compound 3 was isolated along with unre-
acted amine 2 (40%) (entry 3). The reaction in DMF alone or
in DMF in the presence of DBU failed to produce any suitable
compound (entries 4 and 5). Addition of 1 equiv. of K2CO3 in
a mixture of 1 (1 mmol) and 2 (1 mmol) in acetic acid yielded
3a (30%)(entry 6). Use of 10 equiv. of K2CO3 in the above
reaction did not improve the yield (entry 7). On changing the
base from K2CO3 to fused NaOAc, the yield of 3b was found
to decrease with an increase in amount of NaOAc (entries
8 and 9). However, use of Cs2CO3 improved the yield and
reduced the reaction time. The optimised condition was the use
of 5 equiv. of Cs2CO3 per equivalent of 1 and 2 (entries 10–17).
Use of 3-iodochromone (1, X = I) in place of 3-bromochro-
mone (1, X = Br) was detrimental (entry 18).
Regarding the structure of 3, four possible structures (4–7)
were initially considered mechanistically on the basis of previ-
ous reports (Fig. 2).10–14 2-Aminochromone (2) can behave as a
primary amine to produce 4 and 5. It can also act as an enamine
to produce 6. Elemental analyses of the faintly yellow com-
pound 3 showed the absence of nitrogen. To check the function
of amino group in 2, N-substituted aminochromones (2d and
2e) were synthesised using our earlier method21 and were
allowed to react with 1. A mixture of 1a (1 mmol), 2-N-methyl-
aminochromone 2d (1 mmol) and Cs2CO3 (5 mmol) in acetic
acid was heated under reflux for 12 h to produce 3b (entry 19).
Similarly 3b was also obtained from the reaction of 2-N-ethyl-
aminochromone (2e) and 1a (entry 20). These results clearly
ruled out 4, 5 or 6 as the probable structure for the compound
3. Structures 3 and 7 bear the same molecular formula and
from the 1H NMR spectrum of the compound, it was difficult
to distinguish them. However, 13C NMR spectrum of the
compound provided a little evidence favouring the structure 3.
The carbonyl carbon of chromone moiety generally appears
at δ 170–176, whereas in the 13C NMR spectrum of the com-
pound two carbonyl carbons appear at δ 184.4 and 163.3 for
the salicyloyl and coumarin carbonyls, respectively. These
results ruled out the possibility of structure 7, which bears a
chromone moiety. To strengthen the evidence supporting struc-
ture 3b, it was methylated with MeI to form 8 (Fig. 2). In the
mass spectrum, fragmentation of the molecular ion peak of 8
Aminochromones are well known for their wide range of
pharmaceutical activites.15,16 2-Aminochromone (2)17 acts as
a very good building block for the construction of different
heterocyclic compounds.18–20 It possesses an enamine moiety
Fig. 1
* Correspondent. E-mail: kantachandra@rediffmail.com

624 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Reaction of 1 and 2 under different conditions
Entry
1
2
Reaction conditions
Time/ h
Product
Yield of 3/%
M.p./°C
R1
X
R2
Z
1
2
H
H
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
H
Me
H
Me
H
H
H
Me
Me
H
H
H
Me
H
Me
Cl
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
CH3CN/K2CO3 (5 equiv.)
MeOH/TsOH (20 mol%)
AcOH
10
6
20
5
6
No reaction
No reaction
3
H
3a
8a
168–170
4
Me
H
DMF
Not isolated
5
DMF/DBU (catalyst)
Not isolated
6
H
AcOH/K2CO3 (1 equiv.)
AcOH/K2CO3 (10 equiv.)
AcOH/NaOAc (5 equiv.)
AcOH/NaOAc (10 equiv.)
AcOH/Cs2CO3 (2.5 equiv.)
AcOH/Cs2CO3 (5 equiv.)
AcOH/Cs2CO3 (10 equiv.)
AcOH/ Cs2CO3 (5 equiv.)
AcOH/Cs2CO3 (5 equiv.)
AcOH/ Cs2CO3 (5 equiv.)
AcOH/Cs2CO3 (5 equiv.)
AcOH/ Cs2CO3 (5 equiv.)
AcOH/ Cs2CO3 (5 equiv.)
AcOH/Cs2CO3 (5 equiv.)
AcOH/Cs2CO3 (5 equiv.)
24
12
12
14
16
8
3a
3a
3b
3b
3a
3a
3a
3b
3c
3d
3e
3f
30
32
28
18
50
65
62
60
70
70
60
55
20
58
56
168–170
168–170
178–180
178–180
168–170
168–170
168–170
178–180
238–240
194–196
256–258
246–248
178–180
178–180
178–180
7
H
8
H
9
H
10
11
12
13
14
15
16
17
18
19
20
H
H
H
8
H
8
Me
Me
H
8
8
8
Cl
H
H
H
15
12
12
12
3b
3b
3b
Br
Br
a 40% 2 was recovered
Reconsidering the reactions of active methylene compounds
having higher enol content with 1,12 it was predicted that
4-hydroxycoumarin can produce 3 by reaction with 1. With
that intention, a mixture of equimolar amounts of 1a and
4-hydroxycoumarin was heated in CH3CN in the presence of
two equivalents of DBU and indeed the same compound 3a
was obtained in good yields.
Formation of 3 may be rationalised as follows; 1,4-Addition
of the enamine moiety of 2 to the α,β-unsaturated carbonyl
moiety of 1 forms the intermediate 9 (Scheme 1), which under-
goes hydrolysis of its iminolactone function to lactone func-
tion to form 10. Cyclisation of 10 via its enol form (→11) and
subsequent pyran ring opening forms 3.
In conclusion, we have described an easy synthetic route
for the synthesis of 2-(2-hydroxybenzoyl)-4H-furo[3,2-c]
chromen-4-ones by the reaction of 3-bromochromone and 2-
aminochromone in which the latter component acted as masked
4-hydroxycoumarin.
Fig. 2
developed peaks at 227 and 135, which arose from the two
possible α-cleavages in 3. NOE experiment was also performed
on 8. Irradiation of protons of OCH3 group at δ 3.83 showed
NOE enhancement (~6%) of the doublet signal corresponding
to C3′-H at δ 7.04.
Experimental
IR spectra were recorded in KBr on a Beckman IR 20A instrument, 1H
NMR spectra in CDCl3 on a Bruker 300 MHz spectrometer, mass
Scheme 1

JOURNAL OF CHEMICAL RESEARCH 2012 625
spectra on a Qtof MicroYA 263 instrument and elemental analysis on
a Perkin-Elmer 240C elemental analyser. Light petroleum refers to the
fraction with a distillation range of 60–80 °C.
with acetonitrile. The filtrate and the washings were mixed together
and the solvent was removed under reduced pressure to give a
semi-solid mass. This was dissolved in benzene, washed with water
and dried over Na2SO4. The benzene solution, on concentration and
chromatographic separation produced 8 when eluted with 50% light
petroleum in benzene.
Synthesis of 2-(2-hydroxybenzoyl)-4H-furo[3,2-c]chromen-4-ones
(3a–g); general procedure
A mixture of 3-bromochromone (1) (1 mmol) and 2-aminochromone
(2) (1 mmol) was dissolved in glacial acetic acid (10 mL) and Cs2CO3
(1.6 g, 5 mmol) was added. The reaction mixture was heated under
reflux for 8 h. Ice water (50 g) was added to the cooled reaction mix-
ture to afford a yellowish solid, which was filtered, washed with water,
dried in air and purified by chromatography over silica gel (100–200)
using 50% petroleum in benzene as eluent to afford yellow crystalline
solids 3a–f.
2-(2-Hydroxybenzoyl)-4H-furo[3,2-c]chromen-4-one (3a): Yield
(200 mg, 65%); m.p. 168–170 °C (lit.7 154–156 °C); IR: νmax 3113,
1765, 1630, 1597, 1535 cm−1; 1H NMR: δ (CDCl3) 7.01–7.06 (1H, m,
8-H), 7.11 (1H, br d, J = 8.1 Hz, 3′-H), 7.42–7.48 (1H, m, ArH), 7.51
(1H, br d, J = 8.4 Hz, 6-H), 7.57–7.75 (2H, m, ArH), 7.82 (1H, s,
3-H), 8.07 (1H, br d, J = 7.2 Hz, 9-H), 8.15 (1H, br d, J = 7.2 Hz,
6′-H), 11.70 (1H, s, exchangeable, OH); 13C NMR: δ 111.5, 111.7,
117.6, 118.1, 118.3, 118.8, 119.4, 121.9, 125.1, 130.7, 132.8, 137.0,
151.9, 153.7, 157.1, 159.7, 163.3, 184.4; m/z 307 (M + H+), 329 (M +
Na+); Anal. Calcd for C18H10O5: C, 70.59; H, 3.29. Found: C, 70.36; H,
3.19%.
2-(2-Methoxybenzoyl)-8-methyl-4H-furo[3,2-c]chromen-4-one (8):
Yield (140 mg, 84%); m.p. 166–168 °C; IR: νmax 2851, 1750, 1725,
1627 cm−1; 1H NMR: δ (CDCl3) 2.47 (3H, s, CH3), 3.83 (3H, s, OCH3),
7.04 (1H, brd, J = 8.1 Hz, 3′-H), 7.08–7.11 (1H, m, ArH), 7.35 (1H,
d, J = 8.4 Hz, 6-H), 7.42 (1H, dd, J = 8.4, 1.5 Hz, 7-H), 7.45 (1H, s,
3-H), 7.48–7.57 (2H, m, ArH), 7.85 (1H, d, J = 1.5 Hz, 9-H); m/z 357
(M + Na+), 335 (M + H+): 227(10%), 200 (10%), 171 (20%), 135
(80%); Anal. Calcd for C20H14O5: C, 71.85; H, 4.22. Found: C, 71.72;
H, 4.28%.
Reaction of 4-hydroxycoumarin with 3-bromochromone: A solution
of 1a (112 mg, 0.5 mmol), 4-hydroxycoumarin (80 mg, 0.5 mmol),
and DBU (150 mg, 1 mmol) in acetonitrile (10 mL) was heated under
reflux for 5 h. The solvent from the reaction mixture was removed
under reduced pressure. The residual mass was stirred with water,
filtered and the solid was washed with water and dried in air. The
crude product was purified by flash chromatography using 1:1 mix-
ture of light petroleum and benzene to produce a compound, which
was identical in all respect with 3a.
2-(2-Hydroxybenzoyl)-8-methyl-4H-furo[3,2-c]chromen-4-one
We gratefully acknowledge CSIR, New Delhi [Project no.
02(0029)/11/EMR-II] for financial assistance; IICB, Jadavpur
for spectral analysis and finally the college authority for
providing research facilities.
(3b): Yield (190 mg, 60%); m.p. 178–180 °C; IR: νmax 3128, 1751,
1
1718, 1616 cm−1; H NMR: δ (CDCl3) 2.50 (3H, s, CH3), 7.02–7.07
(1H, m, 5′-H), 7.11 (1H, br d, J = 8.4 Hz, 3′-H), 7.39 (1H, d, J =
8.4 Hz, 6-H), 7.45 (1H, dd, J = 8.4, 1.5 Hz, 7-H), 7.56–7.62 (1H, m,
4′-H), 7.81 (1H, s, 3-H), 7.85 (1H, d, J = 1.5 Hz, 9-H), 8.15 (1H, dd,
J = 8.1, 1.2 Hz, 6′-H), 11.70 (1H, s, exchangeable, OH); Anal. Calcd
for C19H12O5: C, 71.25; H, 3.78. Found: C, 71.35; H, 3.87%.
2-(2-Hydroxy-5-methylbenzoyl)-4H-furo[3,2-c]chromen-4-one
(3c): Yield (225 mg, 70%); m.p. 238–240 °C; IR: νmax 3130, 1754,
1720, 1635 cm−1; 1H NMR: δ (CDCl3) 2.39 (3H, s, CH3), 7.02 (1H, d,
J = 8.7 Hz, 3′-H), 7.39–7.48 (2H, m, ArH), 7.51 (1H, br d, J = 8.4 Hz,
6-H), 7.63–7.69 (1H, m, 7-H), 7.80 (1H, s, 3-H), 7.89 (1H, br s, 6′-H),
8.06 (1H, dd, J = 7.8, 0.9 Hz, 9-H), 11.70 (1H, s, exchangeable, OH);
m/z 321 (M + H+), 343 (M + Na+); Anal. Calcd for C19H12O5: C, 71.25;
H, 3.78. Found: C, 71.18; H, 3.71%.
Received 11 July 2012; accepted 22 August 2012
Paper 1201405 doi: 10.3184/174751912X13465065026212
Published online: 12 November 2012
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