Bismuth(III) nitrate pentahydrate - A mild and inexpensive reagent for synthesis of coumarins under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2005.07.117

Bismuth(III) nitrate pentahydrate is found to be an efficient catalyst for the Pechmann condensation reaction of phenols and β-ketoesters under solvent-free conditions. The reaction protocol is simple and is followed by aqueous work-up leading to the formation of the corresponding coumarin derivatives in good yield and high purity.

Full text of DOI:10.1016/j.tetlet.2005.07.117

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6957–6959
Bismuth(III) nitrate pentahydrate—a mild and inexpensive
reagent for synthesis of coumarins under mild conditions
Varughese M. Alexander, Ramakrishna P. Bhat and Shriniwas D. Samant*
Department of Chemistry, Institute of Chemical Technology, University of Mumbai, N. M. Parekh Road, Matunga,
Mumbai 400 019, India
Received 3 May 2005; revised 15 July 2005; accepted 21 July 2005
Available online 19 August 2005
This work is dedicated to the late Dr. B. M. Khadilkar
Abstract—Bismuth(III) nitrate pentahydrate is found to be an efficient catalyst for the Pechmann condensation reaction of phenols
and b-ketoesters under solvent-free conditions. The reaction protocol is simple and is followed by aqueous work-up leading to the
formation of the corresponding coumarin derivatives in good yield and high purity.
Ó 2005 Elsevier Ltd. All rights reserved.
Coumarins and their derivatives form an elite class of
compounds, occupying an important place in the realm
of natural products and synthetic organic chemistry.
Their applications range from additives in food, per-
fumes, cosmetics, pharmaceuticals and in the prepara-
tion of insecticides,1 optical brighteners2 and dispersed
fluorescent and tunable laser dyes.3 Also, coumarins
have varied bioactivities, for example, inhibition
of platelet aggregation,4 anticancer5 and inhibition of
steroid 5a-reductase.6 These properties have made
coumarins into interesting targets for organic chemists.
The last decade witnessed a series of publications on
the development of synthetic protocols for this impor-
tant heterocyclic scaffold. Thus, it is clearly evident that
the need for the development of new and flexible proto-
cols is required, especially when they accommodate
important functionalities and are broad in scope.
agents. The use of various reagents such as H2SO4,
P2O5, FeCl3, ZnCl2, POCl3, AlCl3, PPA, HCl, phospho-
ric acid, trifluoroacetic acid, montmorillonite and other
clays are all well documented in the literature.13 Most of
these methods suffer from severe drawbacks including
the use of a large amount of catalysts, sometimes long
reaction times and very often temperatures to the extent
of 150 °C. Some of the recent achievements in the effi-
cient construction of this nucleus include the develop-
ment of cation exchange resins,14 several solid acid
catalysts15a–c and metal nitrates,15d supported polyani-
line catalysts,16 the use of microwave irradiation17 and
very recently, the use of ionic liquids as efficient
catalysts.18
The use of bismuth(III) derivatives as catalysts in
organic synthesis has increased considerably over the
years. This new interest in bismuth is easily justified by
its favourable ecological behaviour.19
Coumarins have been synthesized by several routes
including Pechmann,7 Perkin,8 Knoevenagel,9 Refor-
matsky10 and Wittig reactions11 and by flash vacuum
pyrolysis.12 Among these, the Pechmann reaction is
the most widely used method, as the reaction involves
the use of simple starting materials, that is, phenols
and b-ketoesters, in the presence of acidic condensing
Bismuth(III) nitrate pentahydrate, Bi(NO3)3Æ5H2O is
one such addition to the list of compounds exploited
under this class. It is relatively nontoxic, inexpensive,
insensitive to air and requires no special care during
its handling. The potential of this reagent for aromatic
nitration,20a oxidation of alcohols,20b deprotection of
oximes,20c conversion of thiocarbonyls to the corre-
sponding carbonyl compounds,20d aromatic iodin-
ation20e and Michael reactions20f has been recently
explored. The versatility of this reagent encouraged us
to study its utility for the Pechmann condensation. We
Keywords: Coumarins; Pechmann condensation; Bi(NO3)3Æ5H2O;
Solvent free.
*
Corresponding author. Tel.: +91 022 2414 5616; fax: +91 022 2414
5614; e-mail: mva_sds@yahoo.co.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.117

6958
V. M. Alexander et al. / Tetrahedron Letters 46 (2005) 6957–6959
Table 1 (continued)
O
EtO
OH
O
O
Entry
Phenol
b-Ketoester
Time
(min)
Yieldb
(%)
Bi(NO3)3. 5H2O
O
+
R
R
80ºC
solvent-free
OH
OH
HO
O
O
R'
8
2
0
92
R'
OEt
Scheme 1. Synthesis of coumarins using Bi(NO3)3Æ5H2O, under
solvent-free conditions.
OH
HO
HO
O
O
herein disclose for the first time the catalytic activity of
bismuth(III) nitrate pentahydrate, for the efficient syn-
thesis of coumarins, under solvent-free conditions
(Scheme 1).21
9
30
30
78
80
72
OEt
Ph
OH
OH
O
O
O
O
To study the feasibility of the Bi(NO3)3Æ5H2O catalyzed
Pechmann condensation, the reaction of resorcinol with
ethyl acetoacetate was selected as a model. Our initial
experiments focused on the optimization of the amount
of Bi(NO3)3Æ5H2O. We observed that only 5 mol % of
Bi(NO3)3Æ5H2O could effectively catalyze the reaction
at a comparatively mild reaction temperature of 80 °C.
An increase in the catalyst to 10 mol % showed no
substantial improvement in the yield, though a slight
improvement in the reaction time was observed. In view
of the current interest in environmentally benign cata-
lytic processes, a protocol involving a lower amount of
Bi(NO3)3Æ5H2O would be more appreciable, therefore
we decided to extend the scope of the reaction using only
5 mol % of the catalyst. Thus, to generalize the solvent-
OH
10
OEt
OEt
OH
11c
120
O2N
OH
O
O
O
O
12c
120
300
76
47
OEt
OEt
OH
13c,d
O
O
O
O
Table 1. Synthesis of coumarins from phenols and b-ketoesters using
Bi(NO3)3Æ5H2Oa
OH
OH
HO
HO
14
15
30
2
84
Time Yieldb
(min) (%)
OEt
OEt
Entry Phenol
b-Ketoester
OH
OH
O
O
HO
1
15
2
94
0
77
OEt
O
O
HO
2
0
93
a Phenol (10 mmol); b-ketoester (10 mmol); Bi(NO3)3Æ5H2O (5 mol %);
oil-bath temperature (80 °C); solvent free.
Cl
OEt
b Yields refer to isolated yields of pure products.
c The reaction was performed using 10 mol % Bi(NO3)3Æ5H2O.
d The reaction was carried out at 130 °C.
O
O
OH
OH
HO
3
30
30
2
84
88
OEt
F3C
Ph
O
O
HO
free protocol, we subjected a series of monohydric and
polyhydric phenols to react with a variety of b-ketoest-
ers to obtain the corresponding substituted coumarins
(Table 1).
4
OEt
O
O
O
OH
MeO
5
0
91
A wide range of structurally varied phenols reacted
smoothly to give the corresponding coumarins in good
yield and purity. The remarkable feature of this im-
proved protocol is the wide stability of a variety of func-
tional groups, such as ether, hydroxy, nitro, etc., under
the present reaction conditions. It is worth mentioning
that substrates like phenol, nitrophenols and cresols
which failed to react in many of the protocols reported
in the literature, showed better reactivity giving moder-
ate to excellent yields, under these reaction conditions.
OEt
OEt
O
O
OH
OH
HO
6
30
2
86
HO
O
7
0
90
OEt

V. M. Alexander et al. / Tetrahedron Letters 46 (2005) 6957–6959
6959
7. von Pechmann, H.; Duisberg, C. Chem. Ber. 1884, 17,
929.
8. Johnson, J. R. Org. React. 1942, 1, 210.
9. (a) Jones, G. Org. React. 1967, 15, 204; (b) Brufola, G.;
Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1996,
43, 1257.
Another important feature is that no detectable demeth-
ylation was observed in the case of 3-methoxy phenol
(entry 5). In the case of 1-naphthol (entry 11) and
p-nitrophenol (entry 12), a slightly larger amount of
the catalyst (10 mol %) was required, to obtain the
corresponding coumarin derivative. The reaction of
phenol (entry 13) with ethyl acetoacetate was found to
be the most sluggish, requiring a longer reaction time
and also a higher reaction temperature (130 °C). To
generalize the protocol, we also attempted the condensa-
tion reaction using a further variety of b-ketoesters such
as 4-chloroethyl acetoacetate, x,x,x-trifluoroethyl
acetoacetate, benzoyl acetoacetate, 2-carbethoxy cyclo-
pentanone and also 2-carbethoxy cylcohexanone. In all
these cases, good yields of the corresponding coumarin
derivatives were obtained. Thus, several pharmacologi-
cally relevant substituent patterns could be introduced
with high efficiency under the present conditions. How-
ever, the reaction of resacetophenone and m-cresol with
ethyl acetoacetate failed to give the coumarin derivative
under the present conditions.
10. Shirner, R. L. Org. React. 1942, 1, 1.
11. (a) Narasimhan, N. S.; Mali, R. S.; Barve, M. V. Synthesis
1979, 906; (b) Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A.
Tetrahedron Lett. 1998, 39, 2391.
12. Cartwright, G. A.; McNab, W. J. Chem. Res. (S) 1997,
296.
13. (a) Appel, H. J. Chem. Soc. 1935, 1031; (b) Woods, L. L.;
Sapp, J. J. Org. Chem. 1962, 27, 3703; (c) Ahmad, Z. S.;
Desai, R. D. Proc. Indian Acad. Sci. 1937, 5A, 277; Chem.
Abstr. 1937, 31, 5785; (d) Robinson, R.; Weygand, F. J.
Chem. Soc. 1941, 386; (e) Nadkarni, A. J.; Kudav, N. A.
Ind. J. Chem., Sect. B 1981, 20, 719; (f) Li, T. S.; Zhang, Z.
H.; Yang, F.; Fu, C. G. J. Chem. Res. (S) 1998, 38.
14. John, E. V. O.; Israelstam, S. S. J. Org. Chem. 1961, 26,
240.
15. (a) Hoefnagel, A. J.; Geenewagh, E. A.; Downing, R. S.;
Bekkum, H. V. J. Chem. Soc., Chem. Commun. 1995, 225;
(b) Singh, P. R.; Singh, D. U.; Samant, S. D. Synlett 2004,
11, 1909; (c) Romanelli, G. P.; Bennardi, D.; Ruiz, D. M.;
Baronetti, G.; Thomas, H. J.; Autino, J. C. Tetrahedron
Lett. 2004, 45, 8935; (d) Bahekar, S. S.; Shinde, D. B.
Tetrahedron Lett. 2004, 45, 7999.
In conclusion, we have successfully demonstrated the
catalytic activity of Bi(NO3)3Æ5H2O for the synthesis of
a variety of coumarins under solvent-free conditions.
This practical and simple method led to good yields of
the coumarin derivatives under mild conditions and
within short times. This protocol could serve as a valu-
able alternative to known reaction systems.
16. Palaniappan, S.; Sekhar, R. C. J. Mol. Catal. 2004, 209,
117.
17. (a) Singh, J.; Kaur, J.; Nayyar, S.; Kad, G. L. J. Chem.
Res. (S) 1998, 280; (b) Frere, S.; Thiery, V.; Besson, T.
Tetrahedron Lett. 2001, 42, 2791.
18. (a) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M.
Tetrahedron Lett. 2001, 42, 9285; (b) Khandekar, A. C.;
Khadilkar, B. M. Synlett 2002, 1, 152; (c) Singh, V.; Kaur,
S.; Sapehiyia, V.; Singh, J.; Kad, G. L. Catal. Commun.
2005, 6, 57.
19. The Chemistry of Organic Arsenic, Antimony andBis-
muth Compounds; Patai, S., Ed.; John Wiley: New York,
1994.
Acknowledgements
The authors are thankful to DAE/BRNS (99/37/39/
BRNS/1749) and AICTE-TAPTECH for a Grant of
financial assistance.
20. (a) Samajdar, S.; Becker, F. F.; Banik, B. K. Tetrahedron
Lett. 2000, 41, 8017; (b) Samajdar, S.; Becker, F. F.;
Banik, B. K. Synth. Commun. 2001, 31, 2691; (c) Nattier,
B. A.; Eash, K. J.; Mohan, R. S. Synthesis 2001, 7, 1010;
(d) Baltork, I. M.; Khodaei, M. M.; Nikoofar, K.
Tetrahedron Lett. 2003, 44, 591; (e) Alexander, V. M.;
Khandekar, A. C.; Samant, S. D. Synlett 2003, 12, 1895;
(f) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68,
2109.
21. Typical experimental procedure: To the phenol (10 mmol)
and b-ketoester (10 mmol), the bismuth nitrate pentahy-
drate (5–10 mol %) was added and the contents were
stirred in a pre-heated oil-bath at 80 °C. After completion
of the reaction, after the time indicated in Table 1, the
reaction mixture was cooled to room temperature and the
contents were poured into ice-cold water. The products
were collected by filtration, washed with ice-cold water,
and then recrystallized from hot ethanol to afford the
coumarin derivative. All the coumarin derivatives are well-
known in literature and were identified by comparison of
their physical and spectral data.
References and notes
1. Kennedy, R. O.; Zhorenes, R. D. Coumarins: Biology,
Applications andMode of Action ; John Wiley and Sons:
Chichester, 1997.
2. Zabradnik, M. The Production and Application of Fluo-
rescent Brightening Agents; John Wiley and Sons: New
York, 1992.
3. Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry andBiochemistry ; John
Wiley and Sons: New York, 1982.
4. (a) Mitra, A. K.; De, A.; Karchaudhuri, N.; Misra, S. K.;
Mukopadhyay, A. K. J. Indian Chem. Soc. 1998, 75, 666;
(b) Cravotto, G.; Nano, G. M.; Palmisano, G.; Taglia-
pietra, S. Tetrahedron: Asymmetry 2001, 12, 707.
5. Wang, C. J.; Hsieh, Y. J.; Chu, C. Y.; Lin, Y. L.; Tseng,
T. H. Cancer Lett. 2002, 183, 163.
6. Fan, G. J.; Mar, W.; Park, M. K.; Wook Choi, E.; Kim,
K.; Kim, S. Bioorg. Med. Chem. Lett. 2001, 11, 2361.