Iodine mediated synthesis of coumarins from chromenes

Article abstract of DOI:10.1016/j.tetlet.2015.11.019

Iodine mediated rapid conversion of 2-amino-3-cyano-4-aryl-4H chromenes to the corresponding coumarins in the presence of water is described. Several chromenes are obtained in high yields without chromatographic purification. Under anhydrous conditions, 2

Full text of DOI:10.1016/j.tetlet.2015.11.019

Tetrahedron Letters 56 (2015) 7100–7104
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodine mediated synthesis of coumarins from chromenes
Himanshu Sharma, Mohini Mourya, Lokesh K. Soni, Debanjan Guin, Yogesh C. Joshi, Mahaveer P. Dobhal,
⇑
Ashok K. Basak
Department of Chemistry, University of Rajasthan, JLN Marg, Jaipur 302004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine mediated rapid conversion of 2-amino-3-cyano-4-aryl-4H chromenes to the corresponding cou-
marins in the presence of water is described. Several chromenes are obtained in high yields without chro-
matographic purification. Under anhydrous conditions, 2-iminochromenes are obtained as major
products.
Received 13 October 2015
Revised 5 November 2015
Accepted 6 November 2015
Available online 11 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
2-Amino-3-cyano-4-aryl-4H-chromene
Imino-chromenes
Iodine
3-Cyano-4-aryl coumarin
Hydrolysis
Previous work:
2-Amino-3-cyano-4-aryl-4H chromenes and their derivatives
are important structural motifs found in various biologically active
compounds. They have been found to exhibit potent anticancer,
antibacterial, antifungal, and antirheumatic activities.1 Several 2-
amino-3-cyano-4-aryl-4H chromenes act as antagonist for anti-
apoptotic Bcl-2 proteins. They also act as potent apoptosis inducer
by inhibiting tubulin polymerization and vascular disruption. A
few chromenes have been found to be active in multidrug resistant
MES-SA/DX5 animal tumor cells.2
Coumarins are structurally closely related to chromenes and
show various biological activities.3 3-Cyano-4-aryl coumarins are
known as potent apoptosis inducers.4 2-Amino-3-cyano-4-aryl-
4H chromenes can be converted to the corresponding coumarins
using literature conditions that are summarized in Scheme 1.5,6
Cai et al. reported a two-step procedure for coumarin synthesis
which relies upon DDQ mediated oxidation of chromenes.6a
Bavantula et al. reported the synthesis of coumarin under
Vilsmeier conditions.6b While screening iodine based reagent for
difunctionalization of 2-amino-3-cyano-4-aryl-4H chromenes,
Alla et al. also observed the formation of coumarin.5e Herein we
report iodine mediated rapid conversion of 2-amino-3-cyano-4-
aryl-4H chromenes to the corresponding coumarins.
N
N
O
NH2
CN
O
O
i) DDQ, DCM, rt
a)
b)
ii) 10% aq HCl
MeOH, rt
CN
Ar
Ar
O
NH2
CN
O
O
SOCl2/DMF
120 o
C
CN
Ar
O
Ar
This work:
I2
NH2
CN
O
O
t-BuOH/H2O
reflux
CN
Ar
Ar
Scheme 1. Synthetic methods for 3-cyano-4-aryl coumarins.
CHO
OMe
OH
O
NH2
CN
piperazine hydrate
Condensation of an aromatic aldehyde, malononitrile, and
a
-
CN
CN
+
+
naphthol in presence of piperazine hydrate produced 2-amino-3-
EtOH, reflux, 3h
OMe
cyano-4H chromenes in 86% yield (Scheme 2).7 The conditions
86%
2
3
1
4d
OMe
OMe
⇑
Corresponding author. Tel.: +91 1412702306.
E-mail address: akb31377@gmail.com (A.K. Basak).
Scheme 2. Synthesis of 2-amino-3-cyano-4H chromene.
http://dx.doi.org/10.1016/j.tetlet.2015.11.019
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

H. Sharma et al. / Tetrahedron Letters 56 (2015) 7100–7104
7101
Table 1
Optimization of conditions for coumarin synthesis
O
O
O
NH
CN
O
NH2
CN
I2, solvent
conditions
+
CN
5a
6a
4a
Cl
Cl
Cl
Cl
Cl
Cl
Entry
Solvent
I2 (equiv)
H2O (equiv)
conditions
Yield (%)
5a
6a
a
b
c
d
e
f
g
h
i
EtOH
EtOH
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
1.1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
—
—
—
—
—
5.0
10
5.0
—
rt, 24 h
15a
55
45
65
63
70
68
71
73
—
—
—
—
10
80
72
75
—
—
—
—
—
—
—
—
—
Reflux, 2 h
Reflux, 3 h
Reflux, 1 h
Reflux, 4 h
90 °C, 1 h
Reflux, 2 h
rt, 6 h
MeOH
i-PrOH
THF
Dioxane
CH3CN
DMSO
DMF
rt, 5 h
—
j
DCM
DCE
Reflux, 6 h
Reflux, 4 h
Reflux, 3 h
Reflux, 2 h
Reflux, 6 h
Reflux, 1 h
Reflux, 1 h
53b
68b
65b
72b
45b
—
k
1
m
n
o
p
q
r
Benzene
Toluene
CHCI3
t-BuOH
t-BuOH
t-BuOH
H2O
—
—
—
Reflux, 0.5 h
Reflux, 1 h
a
Unreacted SM recovered.
Anhydrous solvent was used.
b
Table 2
Synthesis of coumarins from chromenes
I2 (1.1 eq)
H2O (5 eq), t-BuOH
O
O
O
NH2
CN
CN
reflux
R
R
Entry
Chromene
Coumarin
Time (h)
Yield (%)
O
NH2
CN
O
O
CN
Cl
a
1.0
80
82
84
5a
4a
Cl
Cl
O
Cl
O
O
NH2
CN
CN
b
1.0
5b
4b
Cl
Cl
O
NH2
CN
O
O
CN
c
1.0
4c
5c
Cl
Cl
(continued on next page)

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H. Sharma et al. / Tetrahedron Letters 56 (2015) 7100–7104
Table 2 (continued)
Entry
Chromene
Coumarin
Time (h)
Yield (%)
O
O
NH2
O
O
O
d
CN
OMe
2.0
65
CN
OMe
5d
4d
MeO
MeO
NH2
CN
O
CN
e
2.5
1.0
1.5
66
56
55
5e
4e
OMe
OMe
OMe
O
OMe
O
NH2
CN
O
CN
f
4f
5f
MeO
OMe
MeO
OMe
OMe
O
OMe
O
NH2
CN
O
CN
g
5g
4g
NO2
O
NO2
O
HO
NH2
HO
O
CN
CN
4h
5h
h
1.0
2.0
1.0
88
79
85
Cl
Cl
O
Cl
O
Cl
O
HO
NH2
CN
HO
HO
CN
i
4i
5i
5j
HO
O
NH2
CN
O
O
CN
j
4j
OMe
NH2
CN
OMe
O
OMe
O
OMe
O
HO
HO
HO
CN
4k
5k
k
3.0
2.0
58
NO2
O
NO2
O
HO
NH2
CN
O
l
78a
CN
4l
5l
O
O

H. Sharma et al. / Tetrahedron Letters 56 (2015) 7100–7104
7103
Table 2 (continued)
Entry
Chromene
Coumarin
Time (h)
Yield (%)
O
NH2
CN
O
O
CN
m
6.0
30b
5m
4m
OMe
NH2
CN
OMe
O
OMe
O
OMe
O
CN
n
4.0
4.5
45
5n
4n
Cl
Cl
O
Cl
O
Cl
O
NH2
CN
CN
o
42
5o
4o
OMe
OMe
a
Reaction was carried out in DMF at rt.
20% unreacted SM was recovered.
b
I
O
NH2
O
NH
CN
O
NH2
I
O
NH2
work-up
I
I
CN
+ HI
CN
CN
8
H
Ar
6
7
Ar
4
Ar
I
Ar
I
H2O
O
NH2
H
I
H
O
H
NH2
O
O
O
O
O
NH3
CN
CN
H
CN
11
R
CN
Ar
+ NH4I
10
9
Ar
5
Ar
Scheme 3. Mechanism of iodine mediated coumarin synthesis from chromene.
worked well with b-naphthol as well as resorcinol. During our
unsuccessful efforts to protect the amino group of chromene 4a
as its t-butyl carbamate with Boc2O in the presence of 20 mol %
iodine in t-BuOH at 85 °C, we observed 15% formation of coumarin
5a. When we run the reaction with 1.1 equiv of iodine in the
absence of Boc2O, complete conversion of chromene to the corre-
sponding coumarin took place and the compound was isolated as
a yellow solid after aqueous work-up.
A quick screening of solvents revealed that the reaction worked
well in a number of solvents with addition of 5.0 equiv of water
(Table 1). Reactions in non-nucleophilic alcoholic solvents pro-
vided better results. Using DMSO and DMF as solvents the reaction
can be carried out at room temperature (35 °C) (entries h and i,
Table 1). Under anhydrous conditions, 2-iminochromene 6a
(entries j–n, Table 1) was obtained as the major product. The cou-
marin synthesis produced best result in t-BuOH as a solvent using
5.0 equiv of water (entry o, Table 1). When the ratio of water was
increased, polar unidentified byproducts were observed, leading to
diminished yield (entry p, Table 1). Similarly, when 2.0 equiv of
iodine was used, reaction was complete within 30 min but the iso-
lated yield of coumarin was lower than that obtained by using
1.1 equiv of iodine (entry q, Table 1). No reaction occurred when
water was used as a solvent.
With optimal condition in hand, we tested various chromenes
synthesized from aromatic aldehydes, malononitrile, and -naph-
a
thol. As shown in Table 2, high yields were obtained for most of
the coumarins. Coumarin 5c was obtained with 84% yield while
coumarin 5g was obtained with only 55% yield. Coumarin 5f con-
taining three methoxyl groups in the phenyl ring at 4-position
was obtained in moderate yield (56%). Similarly, chromene 4g
which contains a nitro group in the phenyl ring produced coumarin
5g (entry g, Table 2) in moderate yield (55%). Chromenes derived
from resorcinol (entries h–l, Table 2) underwent smooth conver-
sion into corresponding coumarins. Except 5k, all coumarins were
obtained in high yields. In case of chromene 4l (entry l, Table 2), a
complex reaction mixture was obtained when the reaction was
carried out in t-BuOH under reflux conditions. However, clean
reaction was observed using DMF as a solvent at room tempera-
ture. Chromenes derived from b-naphthol (entries m–o, Table 2)
underwent slow conversion and produced the corresponding
coumarins in low yields. Coumarins 5a–5c, 5h–5j, and 5l were
purified by recrystallization and do not require chromatographic
purification.8 The method is compatible with cyano, nitro, ether,
ester, and phenolic hydroxyl groups. The method yields best
results for chromenes derived from resorcinol. The synthesized
coumarins can be stored at room temperature for several weeks.

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H. Sharma et al. / Tetrahedron Letters 56 (2015) 7100–7104
Hamelin, B.; Desputeau, C.; Dong, K.; Kianicka, I.; Custeau, D.; Bourdeau, C.;
Geerts, L.; Cai, S. X.; Drewe, J.; Labrecque, D.; Kasibhatla, S.; Tseng, B. Mol. Cancer
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Kasibhatla, S.; Cai, S. X. J. Med. Chem. 2007, 50, 2858–2864.
All chromenes showed intense yellow spot on TLC when visualized
under short-UV.
The probable mechanism of iodine mediated coumarin synthe-
sis is depicted in Scheme 3. Electrophilic addition of iodine to chro-
mene leads to intermediate 7. Iodide mediated elimination of
hydroiodic acid would result into intermediate 8. Loss of a proton
from the intermediate 8 will generate iminochromene 6 whereas
hydrolysis will generate coumarin 5. In case of chromenes derived
from b-naphthol, formation of iodo-intermediate 11 appears to be
difficult due to steric congestion of aryl groups.
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Kasibhatla, S. J. Med. Chem. 2003, 46, 2474–2481; (b) Kemnitzer, W.;
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Med. Chem. Lett. 2005, 15, 4745–4751.
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Med. Chem. Lett. 2008, 18, 5571–5575; (b) Banothu, J.; Velpula, R.; Gali, R.;
Bavantula, R.; Crooks, P. A. Tetrahedron Lett. 2013, 54, 3862–3864.
In summary, we have developed a rapid and efficient method
for the synthesis of pharmaceutically important coumarins from
2-amino-3-cyano-4-aryl-4H chromenes mediated by molecular
iodine under mild reaction conditions. Several coumarins were iso-
lated without silica gel column chromatography. Thus, the method
will be suitable for large scale synthesis. Under anhydrous condi-
tions, the method provides 2-iminochromenes as a major product.
The iminium ion intermediate 8 might be useful in functionaliza-
tion of chromenes. We will explore these and publish a detailed
account of this methodology soon.
Acknowledgements
7. (a) Solhy, A.; Elmakssoudi, A.; Tahir, R.; Karkouri, M.; Larzek, M.; Bousmina, M.;
Zahouily, M. Green Chem. 2010, 12, 2261–2267; (b) Kumar, D.; Reddy, V. B.;
Mishra, B. G.; Rana, R. K.; Nadagouda, M. N.; Varma, R. S. Tetrahedron 2007, 63,
3093–3097; (c) Magara, R. L.; Throrata, P. B.; Jadhava, V. B.; Tekalea, S. U.; Dakea,
S. A.; Patil, B. R.; Pawar, R. P. J. Mol. Catal. A: Chem. 2013, 374–375, 118–124.
8. Experimental procedure for the synthesis of coumarin 5h: A mixture of chromene
4h (300 mg, 0.90 mmol), iodine (253 mg, 1.0 mmol) in t-BuOH (5 mL) containing
H.S., M.M., L.K.S. thank UGC, New Delhi for research fellowship.
A.K.B. and D.G. thank UGC-FRP for financial support. We would like
to thank MNIT, Jaipur for NMR spectra. A.K.B. thanks Prof. Anshu
Dandia, Head, Department of Chemistry, University of Rajasthan
for her support.
H2O (81 lL) was heated under reflux for 1 h. TLC analysis indicated complete
conversion. The reaction mixture was cooled to rt and quenched with saturated
aqueous Na2S2O3 solution. t-BuOH was removed under reduced pressure and
the solid appeared was filtered off. Recrystallization of the solid from hot EtOH
produced coumarin 5h (264 mg, 88% yield) as a yellow solid; data for compound
5d: light yellow solid, mp 188–189 °C; 1H NMR (400 MHz, CDCl3) d 8.60 (d,
J = 7.2 Hz, 1H), 7.86 (dd, J = 1.2, 6.8 Hz, 1H), 7.75–7.66 (m, 2H), 7.61 (d, J = 8.4 Hz,
1H), 7.18 (d, J = 8.8 Hz, 1H), 7.11–7.03 (m, 2H), 6.83 (d, J = 2.8 Hz, 1H), 3.75 (s,
3H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 162.8, 157.5, 153.7, 152.2, 150.2,
136.3, 130.5, 128.0, 127.9, 125.1, 123.3, 122.9, 122.8, 121.7, 117.4, 115.2, 114.0,
113.9, 113.1, 102.0, 56.2, 56.0; HRMS (ES) calcd for C22H16NO4 [M+H]: 358.1079;
found 358.1065; compound 5h: mp 210–211 °C; 1H NMR (400 MHz, DMSO-d6) d
7.90–7.85 (m, 2H), 7.50 (d, J = 6.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.87–6.77 (m,
2H), 3.12 (br s, 1H, OH); 13C NMR (100 MHz, DMSO-d6) d 165.6, 161.5, 158.0,
156.4, 134.0, 133.4, 132.4, 131.8, 131.0, 130.8, 129.3, 115.4, 115.1, 110.8, 103.4,
96.9; HRMS (ES) calcd for C16H8Cl2NO3 [M+H]: 331.9881; found 331.9861.
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