Regioselective mononitration of coumarins using chromium nitrate as nitrating agent

Article abstract of DOI:10.1081/SCC-120003630

A very efficient and simple method is presented for the regio-selective mononitration of coumarins, using chromium nitrate in acetic anhydride, in high yields at room temperature.

Full text of DOI:10.1081/SCC-120003630

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REGIOSELECTIVE MONONITRATION OF COUMARINS
USING CHROMIUM NITRATE AS NITRATING AGENT
Vandana Bansal a & R. N. Khanna b
a Department of Chemistry , Loyola University , Lakeshore Campus, Chicago, IL, 60626,
U.S.A.
b Department of Chemistry , Delhi University , Delhi, 110 007, India
Published online: 17 Aug 2006.
To cite this article: Vandana Bansal & R. N. Khanna (2002) REGIOSELECTIVE MONONITRATION OF COUMARINS USING CHROMIUM
NITRATE AS NITRATING AGENT, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:9, 1345-1350, DOI: 10.1081/SCC-120003630
To link to this article: http://dx.doi.org/10.1081/SCC-120003630
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SYNTHETIC COMMUNICATIONS, 32(9), 1345–1350 (2002)
REGIOSELECTIVE MONONITRATION OF
COUMARINS USING CHROMIUM
NITRATE AS NITRATING AGENT
Vandana Bansal1, and R. N. Khanna2
*
1Loyola University, Department of Chemistry,
Lakeshore Campus, Chicago, IL 60626
2Department of Chemistry, Delhi University,
Delhi-110 007, India
ABSTRACT
A very efficient and simple method is presented for the regio-
selective mononitration of coumarins, using chromium nitrate
in acetic anhydride, in high yields at room temperature.
Transition-metal nitrate salts have been used in the presence of strong
mineral acids to nitrate organic compounds and quite a few examples are
cited in patent literature. It was in 1925 when Menke1 showed that transi-
tion-metal nitrate salts such as, copper nitrate in acetic anhydride can be
used to nitrate aromatic compounds. However, not much work has been
reported in the direct nitration of coumarins. Direct nitration of coumarins
has been carried out with mixed acids2 and thallium(III)nitrate,3 but
these methods suffer from the disadvantages of harsh acidic conditions,
long reaction times, polynitration and side reactions such as oxidation,
*Corresponding author.
1345
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1346BANSAL AND KHANNA
e.g., thallium(III)nitrate3 gave nitrocoumarins after 7days along with other
side products.
Apart from the wide natural occurrence and biological activity4 of
coumarins, various nitro coumarins exhibit biological properties,5,6 such
as, 7-hydroxy-8-nitrocoumarin is cytotoxic7 and 3-nitrocoumarin is bio-
antioxidant,8 neurotropic9 and is useful in treatment of asthma, hay
fever and rhinitis.10 Nitrocoumarins are also useful as synthetic intermedi-
ates for the preparation of amino11,12 and mercapto13 coumarins and act
as an activating group in various synthetic preparations of coumarin
derivatives.14,15
The wide biological and synthetic utility of nitrocoumarins and a
relative absence of an efficient nitration method for coumarins, prompted
us to investigate the nitration of coumarins. Chromium nitrate has been
used to nitrate aromatic hydrocarbons,16,17 polymeric compounds18 and
phenols.19 But to the best of our knowledge it has not been used for the
nitration of heterocyclic compounds. In this communication, we report a
mild, efficient and regioselective mononitration of coumarins using chro-
mium nitrate in high yields at room temperature without any side reactions,
such as oxidation and coupling.
In
a typical reaction, coumarins (1a–f) on treatment with
Cr(NO3)3ꢀ9H2O in acetic anhydride at room temperature give mononitrated
products at 6 and 8 positions (2b–f, 3a–c, 4f) in 1–2 h (table, scheme).
Table. Nitration of Coumarins (1a–f) Using Chromium Nitrate in Acetic
Anhydride at Room Temperature Giving Nitro Products (2b–f, 3a–c, 4f )
Time
(h)
Yieldb
(%)
M.P. (lit.)
(ꢁC)
Substrate
Producta
1a
1b
3a
2
1
69
192 (191)20
218 (219)19
246 (245)21
2b
3b
39
40
1c
2c
3c
1.5
36
40
228 (229)22
23
257(256)
1d
1e
1f
2d
2e
1.5
2
68
71
225
125–127
2f
4f
1
41
36
90–92
160
aProducts are characterized by physical and spectral data.
bYields refer to isolated pure products.

MONONITRATION OF COUMARINS
1347
Scheme.
The general reaction shown in Eq. (1) may be written to describe the
nitration of coumarins with chromium nitrate in acetic anhydride.
Coumarin þ CrðNO3Þ3ꢀ9H2O þ excess ðCH3COÞ2O
À! Coumarin À NO2 þ CH3CO2CrðNO3Þ2 þ CH3COOH
ð1Þ
The reaction may proceed via in situ generation of ‘‘acetyl nitrate’’
which may dissociate to yield nitronium ion, as shown in Eq. (2).
À!
À
ðCH3COÞ2O þ CrðNO3Þ3
CH3CðOÞONO þ CH3CðOÞOCrðNO Þ
2
3 2
À
þ
2
À!
CH3CðOÞONO2
CH3COO þ NO
ð2Þ
À
Excess of acetic anhydride keeps the medium anhydrous as the metal salt is
hydrated.
Both 7-hydroxycoumarin (1b) and 7-hydroxy-4-methyl-coumarin (1c)
give 6 and 8-nitro products (2b–c, 3b–c) in 1 to 1.5 h in good yields and
7-methoxy (1d) and 5,7-dimethoxycoumarin (1e) give only 6-nitro product
(2d–e). However, coumarin (1a) gives only 8-nitro product (3a) and takes
comparatively longer time. The yield of the product does not increase even
when the reaction time is increased. This is in accordance with the typical
nitration reaction where nitronium ion favors attack at ortho to the electron

1348
BANSAL AND KHANNA
donating group. In coumarins, the position with the highest electron density
(C-8) is preferably attacked. Interestingly, 7-hydroxy-4-phenylcoumarin (1f)
gives 3-nitro product (4f ) also along with 6-nitro product (2f). It could be
due to the high electron density at C-3 position because of the resonance
stabilization of the positive charge at the C-4 position by phenyl ring. All the
products have been characterized by physical and spectral data (1H NMR,
IR, CHN). The spectral data of the unknown compounds have been
provided.
In conclusion, we have developed a mild and effective method for the
regioselective mononitration of coumarins in good yields and short time.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded on
Shimadzu IR-435 spectrophotometer (values in cmÀ1). NMR spectra were
recorded on Perkin-Elmer R-32 spectrophotometer (90 MHz). Chemical
shifts are given in ppm (d) with respect to tetramethylsilane and coupling
constants (J ) are in Hertz.
General Procedure
To a mixture of coumarin 1a (146 mg, 1 mmol) and chromium
nitrateꢀ9H2O (400 mg, 1 mmol) was added 15 ml of acetic anhydride. The
reaction mixture was stirred at room temperature for 2 h. After the comple-
tion of the reaction, as monitored on TLC, the reaction mixture was filtered
and the filtrate was diluted with 100 ml of water. The contents were extracted
with ether (2 Â 20 ml) and dried over anhydrous sodium sulfate. The solvent
was removed by distillation under reduced pressure and the resulting crude
product was subjected to column chromatography (hexane) when it afforded
8-nitrocoumarin (3a) in 69% yield; m.p. 192ꢁC (lit m.p. 191ꢁC).
SPECTRAL DATA
7-Methoxy-6-nitrocoumarin (2d)
1H NMR (DMSO-d6): 4.00 (s, 3H, OCH3), 6.50 (d, J ¼ 9.5 Hz, 1H,
C3-H), 7.00 (s, 1H, C8-H), 7.80 (d, 1H, J ¼ 9.5 Hz, C4-H), 8.10 (s, 1H,
C5-H); IR (KBr): 910, 1365, 1520, 1725. Anal. calcd for C10H7O5N: C,
54.29; H, 3.16; N, 6.33. Found: C, 54.27; H, 3.16; N, 6.32.

MONONITRATION OF COUMARINS
5,7-Dimethoxy-6-nitrocoumarin (2e)
1349
1H NMR (DMSO-d6): 4.00 (s, 6H, OCH3), 7.60 (d, 1H, J ¼ 7.0 Hz,
C3-H), 7.80 (d, 1H, J ¼ 7.0 Hz, C4-H), 8.00 (s, 1H, C8-H); IR (KBr): 910,
1360, 1520, 1725, 3220. Anal. calcd for C11H9O6N: C, 52.59; H, 3.58; N,
5.57. Found: C, 52.58; H, 3.60; N, 5.59.
7-Hydroxy-6-nitro-4-phenylcoumarin (2f)
1H NMR (DMSO-d6): 6.20 (s, 1H, C3-H), 7.20 (s, 1H, C5-H), 7.30 (m,
5H, Ar-H), 8.10 (s, 1H, C8-H); IR (KBr): 900, 1365, 1520, 1725, 3200.
Anal. calcd for C15H9O5N: C, 63.6; H, 3.17; N, 4.94. Found: C, 63.5; H,
3.18; N, 4.89.
7-Hydroxy-3-nitro-4-phenylcoumarin (4f)
1H NMR (DMSO-d6): 6.80 (d, 1H, J ¼ 7.0 Hz, C6-H), 7.10 (d, 1H,
J ¼ 7.0 Hz, C5-H), 7.20 (m, 5H, Ar-H), 7.70 (s, 1H, C8-H); IR (KBr): 900,
1365, 1520, 1725, 3200. Anal. calcd for C15H9O5N: C, 63.6; H, 3.17; N, 4.94.
Found: C, 63.5; H, 3.15; N, 4.89.
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Received in Japan February 20, 2001