Mono-nitration of Coumarins by Nitric Oxide

Article abstract of DOI:10.1081/SCC-120028628

A novel methodology for the efficient and selective nitration of coumarins has been developed. The reaction of coumarins containing a hydroxy group with nitric oxide in CH₂Cl₂ or CH₃CN gave aromatic mono- and regio-specifi

Full text of DOI:10.1081/SCC-120028628

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Mono‐nitration of Coumarins by Nitric Oxide
Liandi Lei a , Desuo Yang a , Zhongquan Liu a & Longmin Wu a
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou,
730000, China
Published online: 21 Aug 2006.
To cite this article: Liandi Lei , Desuo Yang , Zhongquan Liu & Longmin Wu (2004) Mono‐nitration of Coumarins by Nitric
Oxide, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:6, 985-992, DOI: 10.1081/SCC-120028628
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 985–992, 2004
Mono-nitration of Coumarins by
Nitric Oxide
*
Liandi Lei, Desuo Yang, Zhongquan Liu, and Longmin Wu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, China
ABSTRACT
A novel methodology for the efficient and selective nitration of coumarins
has been developed. The reaction of coumarins containing a hydroxy
group with nitric oxide in CH2Cl2 or CH3CN gave aromatic mono- and
regio-specific-nitrated coumarins in various yields.
Key Words: Coumarins; Nitration; Nitric oxide.
It is well known that coumarin derivatives exhibit pronounced medicinal
effects.[1] In particular, the nitrated and hydroxylated coumarins play a thera-
peutic role in the treatment of renal cell carcinoma.[1a] Otherwise, nitro-
coumarins may be utilized as precursors of aminocoumarins, which have
become important raw materials for the production of bioactive chemicals.[2,3]
*
Correspondence: Longmin Wu, State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China; E-mail: nlaoc@lzu.edu.cn.
985
DOI: 10.1081/SCC-120028628
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
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986
Lei et al.
Usually, nitration of coumarins is catalyzed by concentrated strong acids.[4]
Several methods have also been reported to it, including thallium salts in dry
methanol,[5] cerium ammonium nitrate in acetic acid and hydrogen peroxide in
water.[6] However, most of them have some drawbacks such as poor regio-
selectivity, over-nitration, and competitive oxidation of substrates. In
addition, the Kyotai-nitration of various kinds of aromatic compounds and
the nitration of aromatic hydrocarbons with NO2 were reported by Suzuki[7a]
and Kochi,[7b] respectively. Although phenols[8] could be nitrated by NO2,
however, it gave various products except for nitro phenols, such as dienone,
quinone, aldehyde and multi-nitro-compounds. Therefore, to seek mild and
selective methods for the nitration of coumarins is still a challenge for organic
synthesis.
Since nitric oxide (NO) plays a significant role in a variety of physio-
logical processes,[9] papers involving its chemical reactions with biologically
active compounds[10–13] have been increasing in recent years. The application
of NO to the organic synthesis as a nitration or nitroso reagent was also
developed.[14] Our interest in NO promoted us to study the reaction of NO
with a series of coumarins containing a hydroxy group. We report herein a
simple and effective method to nitrate selectively coumarins containing a
hydroxy group with a gas mixture of NO and a small amount of O2 in CH2Cl2
or CH3CN. A representative reaction is outlined in Sch. 1.
Scheme 1.

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Mono-nitration of Coumarins by Nitric Oxide
RESULTS AND DISCUSSION
987
All the compounds tested were nitrated to give almost exclusively the
corresponding mono-nitro coumarins. Among them, coumarins 1a–b, 1d and
1f–g gave unique products 2a–b, 2d and 2f–g, respectively, in moderate to
high yields (Table 1). Coumarins 1c and 1e, however, gave more than one
product in different yields. The reactions were completed normally during 2 to
4 hours. It is worth pointing out especially that neither multi-nitro- nor nitroso-
coumarins were detected in any case. We found that NO2 or a more fraction of
oxygen in the gas mixture of NO and O2 led a complexity of products, as
indicated in the literature,[8] so that decreased dramatically the yield of mono-
nitro products. In the absence of oxygen, no products were obtained. Attempted
nitration of coumarin itself failed under the present conditions. This indicated
that the hydroxy group really activated coumarins towards nitration by NO.
Four issues of regioselectivity could be approached from the results: (a)
the nitration occurred preferentially at the ortho-position with respect to the
hydroxy group (entry 1–5); (b) if its ortho-position was occupied, the nitration
would take place at the vinylogously para (entry 6) or the para (entry 7) to the
hydroxy group; (c) when its ortho-position was alternative, the nitration
occurred mainly at one. It seemed possible for 1a that the nitration would
occur at either the C-5 or C-7. The unique product 2a indicated that the
nitration occurred in favor at the C-5. Likewise, the nitration of 1d took place
only at the C-6. Although both the C-6 and C-8 in 1c lied at as an ortho-
position of the hydroxy group, the nitration tended to favor occur at the C-6;
and (d) the C-8 was unavailable for the nitration.
Table 1. Nitration of coumarins with NO in CH2Cl2.
Entry
Substrate
Reaction condition
Product (yield, %)a
1
2
3
1a
1b
1c
CH2Cl2, 4h
CH2Cl2, 1.5h
CH2Cl2, 3h
2a
2b
(78)
(95)
(63)
(20)
(5)
2c1
2c2
2c3
2d
4
5b
1d
1e
CH2Cl2, 3h
CH3CN, 2h
(80)
(58)
(31)
(56)
(72)
2e1
2e2
2f
6
7
1f
1g
CH2Cl2, 4.5h
CH2Cl2, 3h
2g
aRefer to isolated products.
bThe reaction of 1e was carried out in dry acetanitrile.

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Lei et al.
Experiments involving the influence of solvents on the product yields
indicated that no significant solvent effects were observed. Thus, dichloro-
methane, chloroform, 2-dichloroethane, benzene and acetonitrile were in
favour for reactions, being subject to the solubility of substrates.
The above results and our EPR detection of radical intermediates formed
in the reactions seem to assume that mechanistic pathways for the reaction via
radicals are possible, as given in Sch. 2. NO oxidizes the phenolic function of
coumarins to produce the phenoxyl radicals.[9,15] In general, phenoxyl radicals
with an unpaired electron on the oxygen atom have a short life and tend to
resonate to give rise to aromatic radicals.[16] As a radical species, NO2 couples
with one of the resonance forms of the phenoxyl radical to produce mono-
nitrated coumarins.
In summary, we have found that NO could serve as an effective nitration
agent for coumarins containing a hydroxy group. This reaction was quite general
and gave the corresponding mono-nitro coumarins in moderate to high yields. In
addition, the reaction conditions were mild and the reagents readily available.
More significantly, this reaction has been used to achieve selective nitration of
coumarins containing hydroxy group. We expect that this approach would be
applied to the nitration of the other compounds in organic synthesis.
EXPERIMENTAL
7-Hydroxycoumarin and 4-hydroxycoumarin were purchased from
Aldrich. Other chemicals were synthesized by reported methods.[17,18] 1
H
NMR spectra data were recorded on a Bruker Avance 200 or AM 400
spectrometer. GC-MS was performed on a HP5988 spectrometer with an EI
source. High resolution FTMS spectra were recorded with a Bruker Daltonics
APEX II 47e spectrometer with an ESI source and had a precision of less than
1 ppm unless an individual sample (2d). IR (KBr) spectra were run on a
Nicolet NEXUS 670 FT-IR instrument. Principal absorptions are reported in
wave numbers (cm21). Melting points were measured on a Kofler apparatus
and were uncorrected.
General Procedure for the Nitration of Coumarins
To a solution of coumarin (1 mmol) in dry CH2Cl2 (30 ml) was bubbled
Ar gas for 10 min. Subsequently, a gas mixture of NO and O2 (100 : 1 in vol.)
was introduced to the solution for a specified time (Table 1). Reaction
proceeding was inspected by TLC on silica gel GF254 plates with petroleum
ether and ethyl acetone (3 : 1–8 : 1 v/v). The solvent was evaporated off after

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Mono-nitration of Coumarins by Nitric Oxide
989
Scheme 2.
completion of the reaction and the crude product was separated and purified by
silica gel (200–300 mesh) column with a total length of 50 cm, using a mobile
phase of petroleum ether and acetone (3 : 1–8 : 1 v/v).
Characterization Data for Products
2a: m.p. 158–1608C. IR (KBr) ymax cm21 3077, 2917, 1741, 1662, 1548,
1
1381. H NMR (200 MHz, acetone-d6) d 6.64 (d, J ¼ 10 Hz, 1H, 3-H), 7.39
(d, J ¼ 9.4 Hz, 1H, 5-H), 7.50 (d, J ¼ 9.2 Hz, 1H, 8-H), 7.89 (d, J ¼ 10 Hz,
1H, 4-H). MS (EI) m/z: 207 (Mþ, 100%), 161 (21), 133 (16). HRMS (ESI):
Found M-H ¼ 206.0085, C9H5O5N require M-H ¼ 206.0084.
2b: m.p. 166–1688C (from methanol). IR (KBr) ymax cm21 3214, 3066,
1752, 1608, 1541, 1337. 1H NMR (200 MHz, acetone-d6) d 7.18
(d, J ¼ 8.0 Hz, 1H, 5-H), 7.25 (t, J ¼ 7.2 Hz, 1H, 6-H), 7.61 (t, J ¼ 7.2 Hz,
1H, 7-H), 8.08 (d, J ¼ 8.0 Hz, 1H, 8-H). MS (EI) m/z: 207 (Mþ, 100%), 163
(16). HRMS (ESI): Found M þ H ¼ 208.0239, C9H5O5N require
M þ H ¼ 208.0240.

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990
Lei et al.
2c1: m.p. 188–1908C. IR (KBr) ymax cm21 3237, 3066, 1732, 1635, 1528,
1357. 1H NMR (400 MHz, CDCl3) d 6.43 (d, J ¼ 9.7 Hz, 1H, H-3), 7.05 (s, 1H,
H-8), 7.70 (d, J ¼ 9.7 Hz, 1H, H-4), 8.35 (s, 1H, H-5), 10.88 (s, 1H, 7-OH).
MS (EI) m/z: 207 (Mþ, 100%), 179 (58), 162 (10), 133 (21). HRMS (ESI):
Found M-H ¼ 206.0085, C9H5O5N require M-H ¼ 206.0084.
2c2: m.p. 178–1808C. IR (KBr) ymax cm21 3277, 1742, 1618, 1601, 1560,
1
1381. H NMR (400 MHz, acetone-d6) d 6.85 (d, J ¼ 2.2 Hz, 1H, 8-H), 7.02
(dd, J ¼ 8.8 Hz and 2.2 Hz, 1H, 6-H), 7.88 (d, J ¼ 8.8 Hz, 1H, 5-H), 9.01
(s, 1H, 4-H). MS (EI) m/z: 207 (Mþ, 100%), 179 (7), 162 (7). HRMS (ESI):
Found M þ H ¼ 208.0242, C9H5O5N require M þ H ¼ 208.0240.
2c3: decomposed at 2188C. IR (KBr) ymax cm21 3240, 3120, 1732, 1617,
1535, 1377. 1H NMR (200 MHz, acetone-d6) d 6.33 (d, J ¼ 9.7 Hz, 1H, 3-H),
7.12 (d, J ¼ 8.8 Hz, 1H, 5-H), 7.72 (d, J ¼ 8.8 Hz, 1H, 6-H), 8.00
(d, J ¼ 9.7 Hz, 1H, 4-H). MS (EI) m/z: 207 (Mþ, 100%), 179 (21), 162
(15), 133 (21). HRMS (ESI): Found M-H ¼ 206.0086, C9H5O5N require
M-H ¼ 206.0084.
2d: m.p. 252–2548C. IR (KBr) ymax cm21 3234, 3051, 1730, 1633, 1531,
1
1377. H NMR (200 MHz, acetone-d6) d 2.57 (s, 3H, 4-CH3), 6.50 (s, 1H,
3-H), 7.16 (s, 1H, 8-H), 8.45 (s, 1H, 5-H). MS (EI) m/z: 221 (Mþ, 100%), 193
(89), 176 (9), 147 (24). HRMS (ESI): Found M þ H ¼ 222.0417, C10H7O5N
require M þ H ¼ 222.0397.
2e1: decomposed at 2148C. IR (KBr) ymax cm21 3450, 1767, 1730, 1599,
1
1541, 1369. H NMR (200 MHz, acetone-d6) d 3.15 (s, 3H, 8-COCH3), 6.96
(d, J ¼ 8.9 Hz, 1H, 3-H), 7.97 (d, J ¼ 8.9 Hz, 1H, 4-H), 9.02 (s, 1H, 5-H). MS
(EI) m/z: 249 (Mþ, 100%), 234 (60), 204 (20), 189 (28). HRMS (ESI): Found
M-H ¼ 248.0202, C10H7O5N require M-H ¼ 248.0201.
2e2: m.p. 1228C. IR (KBr) ymax cm21 3442, 1610, 1552, 15241, 1345. 1H
NMR (300 MHz, acetone-d6) d 2.82 (s, 8-COCH3), 6.51 (d, J ¼ 9.9 Hz, 1H,
6-H), 8.15 (d, J ¼ 9.9 Hz, 1H, 5-H), 8.64 (s, 1H, 4-H). MS (EI) m/z: 249 (Mþ,
39%), 234 (100), 217 (89), 204 (5), 189 (14). HRMS (ESI): Found
M-H ¼ 248.0199, C10H7O5N require M-H ¼ 248.0201.
2f: m.p. 176–1788C. IR (KBr) ymax cm21 3415, 3064, 1759, 1645, 1574,
1371. 1H NMR (200 MHz, acetone-d6) d 2.84 (s, 3H, 6-COCH3), 6.92 (s, 1H,
5-H), 8.78 (s, 1H, 8-H), 9.09 (s, 1H, 4-H). MS (EI) m/z: 249 (Mþ, 79%), 234
(100), 204 (15). HRMS (ESI): Found M-H ¼ 248.0187, C10H7O5N require
M-H ¼ 248.0190.
2g: m.p. 209–2108C. IR (KBr) ymax cm21 3348, 2925, 1729, 1617, 1518,
1368. 1H NMR (200 MHz, acetone-d6) d 5.35 (s, 2H, 7-OCH2), 6.51
(d, J ¼ 10.0 Hz, 1H, 3-H), 7.26–7.33 (m, 3H, Ph), 7.45–7.49 (m, 2H, Ph),
7.84 (s, 1H, 6-H), 8.52 (d, J ¼ 10.2 Hz, 1H, 4-H). MS (EI) m/z: 313 (Mþ,
70%), 285 (60), 236 (100). HRMS (ESI): found M þ H ¼ 314.0653,
C10H7O5N require M þ H ¼ 314.0659.

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Mono-nitration of Coumarins by Nitric Oxide
ACKNOWLEDGMENT
991
The authors thank The Natural Science Foundation of China for the
financial support (The grant No 20272022).
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Received in Japan July 25, 2003

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