Cerium(IV) ammonium nitrate mediated nitration of coumarins

Article abstract of DOI:10.1081/SCC-100000214

A new convenient method of nitration of coumarins using cerium(IV) ammonium nitrate (CAN) has been developed. Higher regioselectivity is observed with CAN and hydrogen peroxide in aqueous medium in comparison with CAN in acetic acid for nitration of 7-hydroxycoumarin, 7-hydroxy-4-methylcoumarin and their derivatives.

Full text of DOI:10.1081/SCC-100000214

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CERIUM(IV) AMMONIUM NITRATE MEDIATED NITRATION
OF COUMARINS
N. Ganguly a , A. K. Sukai a & S. De a
a Department of Chemistry , University of Kalyani , Kalyani, W.B., 741 235, India
Published online: 16 Aug 2006.
To cite this article: N. Ganguly , A. K. Sukai & S. De (2001) CERIUM(IV) AMMONIUM NITRATE MEDIATED NITRATION
OF COUMARINS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:2, 301-309, DOI: 10.1081/SCC-100000214
To link to this article: http://dx.doi.org/10.1081/SCC-100000214
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SYNTHETIC COMMUNICATIONS, 31(2), 301–309 (2001)
CERIUM(IV) AMMONIUM NITRATE
MEDIATED NITRATION OF COUMARINS
N. Ganguly,∗ A. K. Sukai, and S. De
Department of Chemistry, University of Kalyani,
Kalyani-741 235, W.B., India
ABSTRACT
A new convenient method of nitration of coumarins using
cerium(IV) ammonium nitrate (CAN) has been developed. Higher
regioselectivity is observed with CAN and hydrogen peroxide in
aqueous medium in comparison with CAN in acetic acid for
nitrationof7-hydroxycoumarin, 7-hydroxy-4-methylcoumarinand
their derivatives.
The search for novel procedures of nitration of aromatics to replace the
classical method based on nitric acid in sulphuric acid is an area of consider-
able current interest (1). Both the replacements of the solvent system (2) and the
reagent (3) have been attempted to achieve higher regioselectivity, particularly to
get less accessible isomers. Recently, aminocoumarins have been put to effective
use as starting materials for the synthesis of bioactive pyrrolocoumarins (4) and
pyrano[3,2-f]benzo[b]thiophenes (5). This led us to develop new simple proce-
dures for the synthesis of nitrocoumarins that may be utilized as precursors of
aminocoumarins. We decided to examine the scope of cerium(IV) ammonium ni-
trate for this purpose in view of its versatile uses (6–8) as the reagent for nitration
∗ To whom correspondence should be addressed.
301
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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GANGULY, SUKAI, AND DE
of aromatic hydrocarbons (9–11). However, few reports (12) are documented con-
cerning its use in this regard for heterocycles. Herein we report the results of CAN
mediated nitration of coumarins with varying degree of electron availabilities in
the carbocyclic as well as α-pyrone ring.
RESULTS AND DISCUSSION
Coumarin (1a) on treatment with one equivalent of CAN in acetic acid gave
6-nitrocoumarin as the sole product in excellent yield (92%). The presence of ac-
tivating hydroxy and methoxy group, as in (1b) and (1c), respectively, also led to
predominant nitration at C-6, accompanied by minor amounts of dinitro derivatives
(3b) and (3c), respectively (Table 1). Regioselectivity in nitration substantially im-
proved for both these substrates when CAN was used along with cooxidant 30%
hydrogen peroxide in water. Thus, the ratio of 7-hydroxy-6-nitrocoumarin (2b)
Table 1. Nitration of Coumarins with CAN
Entry Substrate
Reaction Conditions
Producta (Yield, %) [mp]
1
2
1a
1b
CAN, HOAc, 2 h
(a) CAN, HOAc, 1.5 h
2a (92) [186◦]
2b (68) [219◦], 3b (18)
[198–200◦]
(b) CAN, H2O, 30% H2O2, 2b (71), 3b (8)
1 h, 50–60◦
3
4
1c
(a) CAN, HOAc, 1.5 h
2c (74) [216◦], 3c (10) [121◦]
(b) CAN, H2O, 30% H2O2, 2c (68), 3c (4)
1 h, 50–60◦
1d
(a) CAN, HOAc, 1.5 h
(b) CAN, H2O, 30% H2O2, 2d (76)
45 min, 50◦
2d (72) [195◦], 3d (8) [224◦]
(c) CAN (4moles), 6N
2d (75), 3d (7)
HClO4, 80◦, 1 h
(d) CAN (1 mole), 30%
H2O2 (1 ml per mmol
of substrate), HOAc
(a) CAN, HOAc, 1.5 h
3d (68), 4d (8) [240◦(d)]
5
1e
2e, 3e (1:1)
(b) CAN, H2O, 30% H2O2, 2e, 3e (3:1)
45 min, 50◦
6
7
1f
1g
CAN, HOAc, 2 h
CAN, HOAc, 8 h
No reaction
No reaction
aRefers to isolated yields after chromatography; the products were characterized
from their spectroscopic data.

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COUMARINS NITRATION
303
to 7-hydroxy-6, 8-dinitrocoumarin (3b) increased to 9:1 with CAN in the aque-
ous medium. Interestingly, cleavage of the deactivating lactone ring of (1c) with
methanolic sodium methoxide to methyl 4ꢁ-methoxycoumarate (4c), its nitration
with CAN in acetic acid to (5c) followed by reclosure of the lactone ring, pro-
vided a simple reaction sequence (Scheme 1) leading to (2c) exclusively in high
overall yield. Predominant nitration in the carbocyclic ring was also observed for
7-hydroxy-4-methylcoumarin (1d); however, the presence of C-4 methyl activated
the lactone ring towards nitration, giving some 3,6-dinitrocoumarinderivative (3d).
Attempted oxidation of C-4 methyl of (1d) in 6N perchloric acid failed. Better se-
lectivityinfavorofthemononitrocompoundwasalsofoundintheaqueousmedium
here. Treatment of (1d) with CAN (1 mole) and 30% hydrogen peroxide in acetic
acid led to the formation of some trinitro compound, 7-hydroxy-4-methyl-3,6,8-
trinitrocoumarin(4d), aswellas(2d), suggestingincreasednitratingabilityofCAN
and hydrogen peroxide combination in acetic acid. 7-Methoxy-4methylcoumarin
(1e) gave an inseparable mixture of mono and dinitro products in the ratio of 1:1
(analyzed from 1H NMR spectrum of the mixture). Attempt to bias the nitration in
favor of the mononitro derivative (2e) was a limited success with the ratio of (2e)
to (3e) increasing to 3:1. The presence of deactivating acetoxy group at C-7 (1f)
inhibited nitration in acetic acid (2 h). With 7-hydroxy-8-iodocoumarin (1g), ni-
tration did not occur with CAN in acetic acid even after longer reaction time (8 h),
presumably due to steric effect. The results of these experiments are summarized
in Table 1.
Nitration of coumarins with CAN is unlikely to involve oxidative mecha-
nism (13,14) requiring generation of radical cation intermediate from an electron
deficient benzannelated pyrone system. The nonformation of acetoxylated prod-
ucts (13) formed by solvolytic capture by a carbocation intermediate supports this
view. Our observation that nitration was optimal with one equivalent of CAN per

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GANGULY, SUKAI, AND DE
Scheme 1.
equivalent of substrate is also consistent with a ligand transfer mechanism, with
bidentate nitrato structure (15) of CAN the key to its nitrating ability (Scheme 2).
This mechanism obviates direct involvement of free NO+2 and NO2 in nitration. In
fact, the addition of ammonium nitrate to the nitrating mixture did not affect the rate
of reactions, thereby suggesting noninvolvement of free NO+2 generated by the ac-
tion of acetic acid on NO−3 from CAN. The pruning of nitrating ability of CAN and
H2O2 in water seems to result from the reduced electrophilic character of Ce(IV)
consequent upon entry of the more electron donating ligands water/hydroperoxide
anion into its coordination sphere, replacing one or more NO3.
In conclusion, nitration of coumarins with CAN adds a new reaction mani-
fold of CAN. Coumarin, 7-hydroxycoumarin, 7-hydroxy-4-methylcoumarin, and
Scheme 2.

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COUMARINS NITRATION
305
their derivatives have been nitrated using CAN in acetic acid and water in the
presence of hydrogen peroxide. The combination of CAN and hydrogen peroxide
provides better regioselective nitration at C-6 of 7-hydroxycoumarins and their
derivatives.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were run for KBr disks (solid) or
liquid filmon aPerkin Elmer 1310instrument. 1HNMRwererecorded on aJeolFX
100 (100 MHz) and Bruker AM-300L instruments with TMS as internal standard.
Mass spectra were carried out at RSIC, CDRI, Lucknow. Silica gel (60–120 mesh)
was used for chromatographic separation and silica gel G was used for TLC.
General Procedure for the Nitration of Coumarins with CAN
in Acetic Acid
To an ice-cold solution of coumarin (3 mmol) in acetic acid (5 mL) was
added CAN (3 mmol) in three portions over 10 min. The mixture was then stirred
at room temperature for the specified time (Table 1). After the completion of the
reaction, the reaction mixture was poured into water (30 mL) and extracted with
chloroform/ethyl acetate, washed with brine, sodium bicarbonate solution, and
dried (Na2SO4). Concentration of the combined organic extracts and chromato-
graphic separation afforded the products.
General Procedure for the Nitration of Coumarins with CAN
and Hydrogen Peroxide in Water
The substrate (1 mmol) was charged in two portions to a solution of CAN
(1 mmol) in water (5 mL) to which 30% hydrogen peroxide (1 mL) was already
added. The resulting mixture was heated at 50◦–60◦C with continuous vigourous
stirring for 1 h. After the completion of the reaction, the reaction mixture was
cooled, diluted with water (20 mL), and extracted with chloroform (3 × 30 mL).
Removal of solvent from the dried concentrated extract amd chromatographic
purification afforded the products.
Conversion of 7-Methoxycoumarin (1c) to Methyl
4ꢀ-methoxycoumarate (4c)
Metallic sodium (1.7 g) was dissolved in absolute methanol (20 mL) and the
mixture was refluxed for 1 h. To it was added 1c (175 mg, 1 mmol) and the mixture

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GANGULY, SUKAI, AND DE
was refluxed for 3 h under nitrogen cover. Then the reaction mixture was cooled
and quenched by pouring into ice (40 g), acidified with 6N hydrochloric acid, and
extracted with chloroform (3 × 20 mL). Removal of solvent, drying (Na2SO4), and
chromatographic purification gave a light yellow crystalline product 3c (182 mg,
88%) mp 143◦C (ethyl acetate-light petrol), lit. (16) 140◦–142◦C.
Nitration of (4c) with CAN in Acetic Acid
to Methyl-4ꢀ-Methoxy-5ꢀ-Nitrocoumarate
5c (100 mg, 0.48 mmol) was allowed to react with CAN (260 mg, 0.48 mmol)
in acetic acid (3 mL) for 3 h at room temperature. Usual work-up and chromatog-
raphy yielded yellow crystals (4c) as the sole product (104 mg, 85%), mp 228◦C
(ethylacetate-light petrol).
Ring Closure of (5c) to (2c) in Refluxing N,N-Diethylaniline
A mixture of (5c) (152 mg, 0.6 mmol) in N,N-diethylaniline (3 mL) was
refluxed for 2 h. The reaction mixture was cooled, poured into ice-cold 6N hy-
drochloric acid (20 mL), and extracted with chloroform (3 × 20 mL). The chloro-
form layer was washed with water and dried over Na2SO4. Usual concentration
and chromatography gave (2c) (113 mg, 85%).
Characterization Data for Products
(2b)
IR (KBr) νmax (cm−1) 3220, 1720, 1600, 1560, 1515, 1300, 900, 820. 1H
NMR (100 MHz, DMSO-d6) δ 6.40 (1H, d, J = 9.5 Hz, H-3), 6.98 (1H, s, H-8),
8.04 (1H, d, J = 9.5 Hz, H-4), 8.42 (1H, s, H-5). MS m/z (%) 207 (M+, 100), 190
(6.2), 179 (28.8), 177 (10.8), 149 (22.2). Anal. calcd for C9H5NO5: C, 52.17; H,
2.42; N, 6.76. Found: C, 52.04; H, 2.36; N, 6.71.
(3b)
IR (KBr) νmax (cm−1) 3250, 1735, 1615, 1565, 1530, 1320, 870, 830.
1H NMR (300 MHz, DMSO-d6) δ 6.29 (1H, d, J = 9.6 Hz, H-3), 7.98 (1H, d,
J = 9.6 Hz H-4), 8.45 (1H, s, H-5). MS m/z (%) 252 (M+, 45.2), 224 (3.6), 207
(100), 179 (37). Anal. calcd for C9H4N2O7: C, 42.86; H, 1.59; N, 11.11. Found:
C, 42.75; H, 1.52; N, 10.98.

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(2c)
307
IR (KBr) νmax (cm−1) 3020, 2940, 1720, 1610, 1520, 1310, 1280, 1095,
980, 810. 1H NMR (100 MHz, DMSO-d6) δ 3.97 (3H, s, 7-OMe), 6.36 (1H, d,
J = 10 Hz, H-3), 7.30 (1H, s, H-8), 7.95 (1H, d, J = 10 Hz, H-4), 8.30 (1H, s, H-5).
MS m/z (%) 221 (100), 220 (13), 191 (17.2), 190 (12.3), 175 (11.4). Anal. calcd
for C10H7NO5: C, 54.30; H, 3.17; N, 6.33. Found: C, 54.18; H, 3.34; N, 6.21.
(3c)
IR (KBr) νmax (cm−1) 3040, 2950, 1750, 1620, 1600, 1550, 1530, 1365,
1225, 1020, 980, 835. 1H NMR (100 MHz, CDCl3) δ 4.03 (3H, s, 7-OMe), 6.51
(1H, d, J = 10 Hz, H-3), 7.75 (1H, d, J = 10 Hz, H-4), 8.30 (1H, s, H-5). MS m/z
(%) 266 (100), 236 (37.5), 220 (2.6), 192 (4.2). Anal. calcd for C10,H6N2O7: C,
45.11; H, 2.26; N, 10.53. Found: C, 45.25; H, 2.12; N, 10.48.
(4c)
13C NMR (25 Hz, CDCl3): δC 51.54 (2ꢁ-CO2Me), 55.29 (4ꢁ-OMe), 101.06
(C-3ꢁ), 107.06 (C-6ꢁ), 114.99 (C-5ꢁ), 130.40 (C-2), 140.78 (C-1), 154.88 (C-1ꢁ),
157.04 (C-2ꢁ), 162.58 (C-4ꢁ), 169.23 (2ꢁ-CO2Me). Anal. calcd for C11H12O4: C,
63.46; H, 5.77. Found: C, 63.32; H, 5.65.
(5c)
IR (KBr) νmax (cm−1) 3180, 2950, 1670, 1620, 1575, 1530, 1310, 1210,
1090, 1000, 980, 880, 845. 1H NMR (100 MHz, DMSO-d6) δ 3.72, 3.88 (each
3H, s, CO2Me, OMe), 6.66 (1H, d, J = 16 Hz, H-2), 6.71 (1H, s, H-3ꢁ), 7.70 (1H,
d, J = 16 Hz, H-1), 8.32 (1H, s, H-6ꢁ). MS m/z (%) 253 (65.3), 236 (9.4), 222
(51.5), 221 (100), 194 (3.5), 193 (12.7), 191 (15.3), 163 (11.7). Anal. calcd for
C11H11NO6: C, 52.17; H, 4.35; N, 5.53. Found: C, 51.98; H, 4.24; N, 5.67.
(2d)
IR (KBr) νmax (cm−1) 3125, 3060, 1730, 1620, 1530, 1390. 1H NMR
(300 MHz, DMSO-d6) δ 2.35 (3H, s, 4-Me), 6.39 (1H, s, H-3), 7.39 (1H, s, H-8),
8.47 (1H, s, H-5). MS m/z (%) 221 (100), 220 (11.1), 191 (14.4), 175 (6.1), 174
(4.2), 163 (24.8). Anal. calcd for C10H7NO5: 54.30; H, 3.17; N, 6.33. Found: C,
54.18; H, 3.08; N, 6.46.

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GANGULY, SUKAI, AND DE
(3d)
IR (KBr) νmax (cm−1) 3220, 1730, 1620, 1565, 1520, 1340, 1150, 1060, 850,
1
830, 750. H NMR (100 MHz, DMSO-d6) δ 2.50 (3H, s, 4-Me), 7.08 (1H, s, H-8),
8.52 (1H, s, H-5). MS m/z (%) 266 (100), 249 (10.9), 220 (2.3), 208 (44.2). Anal.
calcd for C10H6N2O7: C, 45.11; H, 2.26; N, 10.53. Found: C, 45.02; H, 2.14; N,
10.41.
(4d)
IR (film) νmax (cm−1) 3160, 3080, 1765, 1640, 1550, 1535, 1365, 1100, 840.
1H NMR (300 MHz, DMSO-d6) δ 2.47 (3H, s, 4-Me), 8.37 (1H, s, H-5), 11.23 (1H,
s, 7-OH). MS m/z (%) 311 (100), 253 (23.3), 208 (4.1), 173 (29.9). Anal. calcd
for C10H5N3O9: C, 38.59; H, 1.60; N, 13.50. Found: C, 38.44; H, 1.47; N, 13.58.
(2e) and (3e) (in 1:1 mixture)
1H NMR (100 MHz, DMSO-d6) δ 2.44, 2.56 [each 3H, s, 4-Me s of (2e)
and (3e)], 4.04, 4.08 [each 3H, s, 7-OMe s of (2e) and (3e)], 6.36 [1H, s, H-3 of
(2e)], 7.36 and 7.56 [each 1H, s, H-8s of (2e) and (3e)], 8.3 and 8.6 [each 1H, s,
H-5s (2e) and (3e)].
ACKNOWLEDGMENTS
AKS is thankful to the University of Kalyani for a research fellowship.
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Received in the UK November 9, 1999

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