Nitration of cinnamic acids using cerium (IV) ammonium nitrate immobilized on silica

Article abstract of DOI:10.1081/SCC-200030569

Treatment of cinnamic acids with cerium (IV) ammonium nitrate supported on silica (CAN/SiO₂) was used to synthesize nitro derivative and ipso substitution products. The position of the substituents defines the type and the yields of the product

Full text of DOI:10.1081/SCC-200030569

This article was downloaded by: [University of Minnesota Libraries, Twin
Cities]
On: 16 July 2013, At: 08:31
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Nitration of Cinnamic Acids
Using Cerium (IV) Ammonium
Nitrate Immobilized on Silica
Anna Messere a , Alessandra Gentili b , Isidoro
Garella a , Fabio Temussi c , Benedetto Di Blasio a
& Antonio Fiorentino b
a Dipartimento di Scienze Ambientali, Seconda
Università di Napoli, Caserta, Italy
b Dipartimento di Scienze della Vita, Seconda
Università di Napoli, Via Vivaldi 43, I‐81100,
Caserta, Italy
c Dipartimento di Chimica Organica e Biochimica,
Università Federico II, Napoli, Italy
Published online: 12 Jan 2011.
To cite this article: Anna Messere , Alessandra Gentili , Isidoro Garella , Fabio
Temussi , Benedetto Di Blasio & Antonio Fiorentino (2004) Nitration of Cinnamic
Acids Using Cerium (IV) Ammonium Nitrate Immobilized on Silica, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:18, 3317-3324, DOI: 10.1081/SCC-200030569
To link to this article: http://dx.doi.org/10.1081/SCC-200030569
PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 18, pp. 3317–3324, 2004
Nitration of Cinnamic Acids Using Cerium
(IV) Ammonium Nitrate Immobilized on
Silica
Anna Messere,1 Alessandra Gentili,2 Isidoro Garella,1
Fabio Temussi,3 Benedetto Di Blasio,1
and Antonio Fiorentino2,
*
1Dipartimento di Scienze Ambientali, and 2Dipartimento di Scienze della
`
Vita, Seconda Universita di Napoli, Caserta, Italy
3Dipartimento di Chimica Organica e Biochimica,
`
Universita Federico II, Napoli, Italy
ABSTRACT
Treatment of cinnamic acids with cerium (IV) ammonium nitrate
supported on silica (CAN/SiO2) was used to synthesize nitro derivative
and ipso substitution products. The position of the substituents defines
the type and the yields of the products. This is the first example of an
ipso substitution reaction by solid-phase approach.
Key Words: Nitration; CAN; Cinnamic acids.
*
Correspondence: Antonio Fiorentino, Dipartimento di Scienze della Vita, Seconda
`
Universita di Napoli, Via Vivaldi 43, I-81100, Caserta, Italy; Fax: þ39-823-274576;
E-mail: antonio.fiorentino@unina2.it.
3317
DOI: 10.1081/SCC-200030569
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3318
Messere et al.
Nitration of aromatic compounds has been extensively reported in recent
years.[1] Generally nitration is performed in a mixture of concentrated nitric
and concentrated sulfuric acids. The mixture of these acids generates the nitro-
nium ion, which is the species that attacks the aromatic ring. Alternatively, the
nitric acid is produced in situ by means of nitrate salts in protic media.[2]
Among the transition metal salts used in nitration reactions, cerium(IV)
nitrate is effectively used to generate NOþ2 .[3]
The treatment of cinnamic acids with cerium (IV) ammonium nitrate
(CAN) in trifluoroacetic acid afforded, in addition to the introduction of the
nitro group into the aromatic ring, nitrostyrenes in good yields. These com-
pounds are formed by an unusual ipso substitution of the carboxylic acid
moiety with a nitro functional center.[4] The dinitrostyrenes are used as
building blocks for the syntheses of benzodiazepines,[5] indoles,[6] etc. In
addition, nitrostyrenes and nitrocinnamic acids are compounds possessing
useful biological activities such as antibacterial, antiprotozoa, or antioxidant
properties.[7]
Because of the importance of the nitrating reagents in organic synthesis,
several mild conditions have been recently developed,[8] and CAN coated on
silica[9] in dichlorometane is a useful mild method for regioselective nitration
of electron-rich aromatic compounds.
In this paper, we describe the nitration reaction of cinnamic acids with
CAN supported on silica (Table 1, entries 1–5). The use of this procedure
allowed, in addition to the nitration of the aromatic ring, the production of
nitrostyrenes, by the substitution of the carboxylic function with the nitro
group (ipso substitution). To the best of our knowledge, even recently reported
syntheses[10,11] of nitrostyrenes have been classically carried out by a
condensation reaction between aromatic aldheyde and nitroalkanes. The
method described in this paper is a useful and simple alternative to
directly obtain nitration of the propenylic chain of cinnamic acid derivatives
and it is the first example of ipso substitution reaction by solid-phase
approach.
We found that 4-hydroxycinnamic acid 1 (entry 1), a natural metabolite
widely diffuse in plants, reacted with quantitative yields in 10 min at room
temperature. Dry MgSO4 was added to the compound in dichloromethane
solution. After 5 min CAN/SiO2 was added and the mixture was kept for
10 min by stirring at room temperature. Chromatographic processes led
to the isolation of four compounds 2–5, which were characterized by
spectroscopic means. The most abundant products were identified as (E)-3-
(4-hydroxy-3-nitrophenyl)propenoic acid (2, 57% yield)[12] and (E)-1
hydroxy-4-(2-nitroethenil)benzene (3, 34% yield).[10] Product yield was
calculated by diode array detector (DAD)-HPLC analysis, using the internal
standard method. It should be noted that, contrary to the nitration in

Nitration of Cinnamic Acids Using CAN
3319

3320
Messere et al.
trifluoroacetic acid (TFA),[4] where the ipso substitution products were
obtained only after the nitration of the aromatic ring, compound 3
was obtained as a product of substitution in the propenylic chain alone.
In fact, we obtained dinitrostyrene 4[13] as a by-product together with
benzaldehyde 5. When 2-hydroxycinnamic acid (6) underwent the reaction
in the same condition as compound 1 (entry 2), the ipso nitration product
was not recovered, and the most abundant products were the nitro derivative
cinnamic acids. The nitro group was oriented in ortho/para respect to the
hydroxyl and the main product (8),[14] was the less sterically hindered. By-
products 9 and 10 were the dinitrostyrenes formed by the ipso substitution.
The presence of the hydroxyl function in meta respect to the propenylic
chain (11, entry 3) prevented the ipso substitution. In fact, the most abundant
product (90.7%) was the nitro derivative in para to the hydroxyl group (13),
while the ortho nitrophenol derivative (12)[15] was 9.3%. When two oxy-
genated functions in the aromatic ring were present (ferulic acid, 14, entry
4), the substrate is much more reactive and not much organic material was
recovered after the work-up. Only ipso substituted products 15[16] and 16
were isolated from the reaction mixture in little yield. The cinnamic acid 18
(entry 5) gave no product, either with the lengthening of the reaction times
or with the increase of the reactive and/or the temperature.
Therefore, the lack of an electron-donating group in the aromatic ring pre-
vents the nitration of the phenyl (entry 5). The hydroxyls led to the introduc-
tion of the nitro groups in ortho or in para position, because of the major
electronic charge resulting from the resonance. The steric effects of the sub-
stituent influence the yield. In fact, the main nitro derivative of 2-hydroxy cin-
namic acid (entry 2) is the para nitro product 8, which is less hindered in
respect to the corresponding ortho derivative 7.
Generally, the ipso substitution occurs exclusively if position a of the cin-
namic acid is electron rich. The electron release is due to hydroxyl electron
donors in ortho or in para to the side chain. In fact, the 3-hydroxycinnamic
acid (11), with the hydroxyl group in meta to the chain, gave no ipso
substituted products but only nitro phenyl derivatives. These effects have
not been observed in the nitration with CAN in TFA where the meta-methoxy-
cinnamic acids are transformed in the corresponding ipso dinitro derivative.
On the other hand, the exclusive ipso nitration reaction was observed
only when the hydroxyl group was in para position to the chain (entries
1 and 4).
In summary, we have developed a mild method to obtain nitrostyrenes
and/or nitrocinnamic acids in heterogeneous phase. The use of CAN/SiO2
makes the reaction regioselective and piloted by the type and the position
of the substituents in the aromatic ring.

Nitration of Cinnamic Acids Using CAN
EXPERIMENTAL
Representative Procedure: Nitration of 1
3321
The cerium (IV)/SiO2 reagent was prepared according to Fisher and
Henderson.[17] SiO2 (200 g) was added to a stirred solution of cerium (IV)
ammonium nitrate (20 g, 36.5 mmol) in 400 mL of methanol-dichloromethane
(1:1). After 15 min of stirring, the mixture was dried on rotavapor and the
resulting yellow powder was desiccated at 558C on rotavapor.
Dry magnesium sulfate was added to stirred 4-hydroxycinnamic acid (1,
210 mg, 1.28 mmol) in dichloromethane solution, and the mixture was stirred
at room temperature. After 5 min, CAN/SiO2 reagent (14 g, 2.3 mmol) was
added and the mixture was stirred for an additional 10 min. Then the solution
was filtered and the residue was washed with CH2Cl2-EtOAc (1 : 1) solution.
Evaporation of the solvent gave a red residue, which was purified by flash
column chromatography (SiO2) eluting with CHCl3-MeOH (8 : 2) solutions
to give the pure products 2–5.
Spectroscopic Data
Compound 2. 1H-NMR (500 MHz, CD3OD) d: 6.46 (d, 1H, J ¼ 16.2 Hz,
H-2), 7.58 (d, 1H, J ¼ 16.2 Hz, H-3), 8.24 (d, 1H, J ¼ 2.4 Hz, H-20), 7.16
(d, 1H, J ¼ 8.4 Hz, H-50), 7.87 (dd, 1H, J ¼ 8.4 e 2.4 Hz, H-60); 13C-NMR
(125 MHz, CD3OD) d: 171.2 (C-1), 121.7 (C-2), 142.3 (C-3), 128.4 (C-10),
126.2 (C-20), 136.2 (C-30), 156.6 (C-40), 121.4 (C-50), 136.1 (C-60). Compound
1
3. H-NMR (500 MHz, CD3OD) d: 6.85 (d, 2H, J ¼ 7.8 Hz, H-2/H-6), 7.55
(d, 2H, J ¼ 7.8 Hz, H-3/H-5), 7.75 (d, 1H, 13.2 Hz, H-10), 7.89 (d, 1H,
13.2 Hz, H-20); 13C-NMR (125 MHz, CD3OD) d: d 122.9 (C-1), 132.8
(C-2), 117.3 (C-3), 117.3 (C-5), 162.9 (C-4), 132.8 (C-6), 140.6 (C-10),
1
135.8 (C-20). Compound 4. H-NMR (500 MHz, CD3OD) d: 8.33 (1H, d,
J ¼ 2.4 Hz, H-3), 7.06 (1H, d, J ¼ 9.0 Hz, H-6), 7.82 (1H, dd, J ¼ 2.4 e
9.0 Hz, H-5), 7.85 (1H, d, J ¼ 13.8 Hz, H-10), 8.05 (1H, d, J ¼ 13.8 Hz,
1
H-20). Compound 7. H-NMR (500 MHz, CD3OD) d: 7.75 (1H, d, 16.2 Hz,
H-2), 7.82 (1H, d, J ¼ 16.2 Hz, H-3), d: 7.95 (1H, dd, J ¼ 1.8 e 8.4 Hz,
H-40), 6.71 (1H, t, J ¼ 8.0 Hz, H-50), 7.74 (1H, dd, J ¼ 1.8 e 7.6 Hz, H-60);
13C-NMR (125 MHz, CD3OD) d: H127.0 (C-1), 155.9 (C-2), 133.9 (C-3),
123.6 (C-4), 123.4 (C-5), 131.5 (C-6), 131.9 (C-10), 113.1 (C-20), 172.1
(C30). Elemental analysis. Calcd. for C9H7NO5: C 51.68, H 3.37, N 6.70;
found C 51.60, H 3.35, N 6.68. EI-MS: m/z 209 [M]þ. IR cm21: 1627,
1
1667, 1549, 1402. Compound 8. H-NMR (500 MHz, CD3OD) d: 6.61 (1H,

3322
Messere et al.
d, J ¼ 16.0 Hz, H-2), 7.75 (1H, d, J ¼ 16.0 Hz, H-3), 6.63 (1H, d, J ¼ 9.2 Hz,
H-30), 7.94 (1H, dd, J ¼ 3.0 e 9.2 Hz, H-40), 8.30 (1H, d, J ¼ 3.0 Hz, H-60).
Compound 9. 1H-NMR (500 MHz, CD3OD) d: 7.90 (1H, dd, J ¼ 2.0 e
7.6 Hz, H-3), 6.33 (1H, t, J ¼ 7.6 Hz, H-4), 7.49 (1H, dd, J ¼ 2.0 e 7.6 Hz,
H-5), 8.08 (1H, d, J ¼ 13.0 Hz, H-10), 8.61 (1H, d, J ¼ 13.0 Hz, H-20); 13C-
NMR (125 MHz, CD3OD) d: 126.9 (C-1), 150.9 (C-2), 135.8 (C-3), 111.1
(C-4), 137.0 (C-5), 139.4 (C-6), 140.6 (C-10), 137.0 (C-20). Elemental analysis.
Calcd. for C8H6N2O5: C 45.72, H 2.88, N 13.33; found C 45.70, H 2.91, N
13.23. EI-MS: m/z 210 [M]þ. IR cm21: 1621, 1537, 1329. Compound 10.
1H-NMR (500 MHz, CD3OD) d: 6.48 (1H, d, J ¼ 9.6 Hz, H-6), 7.95 (1H,
dd, J ¼ 3.2 e 9.6 Hz, H-5), 8.26 (1H, d, J ¼ 3.2 Hz, H-3), 8.06 (1H, d,
12.8 Hz, H-10), 8.50 (1H, d, J ¼ 12.8 Hz, H-20); 13C-NMR (125 MHz,
CD3OD) d: 122.9 (C-1), 163.9 (C-2), 119.8 (C-3), 129.1 (C-4), 137.0 (C-5),
122.9 (C-6), 139.3 (C-10), 132.0 (C-20). Elemental analysis. Calcd. 10 for
C8H6N2O5: C 45.72, H 2.88, N 13.33; found C 45.65, H 2.68, N 13.21. EI-
1
MS: m/z 210 [M]þ. IR cm21: 1623, 1540, 1328. Compound 12. H-NMR
(500 MHz, CD3OD) d: 6.62 (1H, d, J ¼ 16.0 Hz, H-2), 7.56 (1H, d,
J ¼ 16.0 Hz, H-3), 7.34 (1H, d, J ¼ 1.6 Hz, H-20), 8.09 (1H, d, J ¼ 8.6 Hz,
H-50), 7.26 (1H, dd, J ¼ 1.6 e 8.6 Hz, H-60). Compound 13. 1H-NMR
(500 MHz, CD3OD) d: 6.32 (1H, d, J ¼ 15.6 Hz, H-2), 7.91 (1H, d,
J ¼ 15.6 Hz, H-3), 6.91 (1H, d, J ¼ 2.6 Hz, H-20), 6.77 (1H, dd, J ¼ 2.6 e
9.0 Hz, H-40), 7.98 (1H, d, J ¼ 9.0 Hz, H-50). Elemental analysis. Calcd. 10
for C9H7NO5: C 51.68, H 3.37, N 6.70; found C 51.65, H 3.12, N 6.58. EI-
1
MS: m/z 209 [M]þ. IR cm21: 1682, 1536, 1329. Compound 15. H-NMR
(500 MHz, CD3OD) d: 6.92 (d, 1H, J ¼ 9.4 Hz, H-6), 7.00 (d, 1H,
J ¼ 1.8 Hz, H-3), 7.13 (dd, 1H, J1 ¼ 1.8 HHz, J2 ¼ 9.4 Hz, H-5), 7.52
(d, 1H, J ¼ 16.0 Hz, H-10), 7.94 (d, 1H, J ¼ 16.0 Hz, H-20), 4.01 (3H, s,
CH3). Compound 16. 1H-NMR (500 MHz, CD3OD) d: 7.21 (1H, d,
J ¼ 1.6 Hz, H-3), 7.95 (1H, d, J ¼ 1.6 Hz, H-5), 7.56 (1H, d, J ¼ 13.6 Hz,
H-10), 7.94 (1H, d, J ¼ 13.6 Hz, H-20), 4.01 (3H, s, CH3). Elemental analysis.
Calcd. 10 for C9H8N2O6: C 45.01, H 3.36, N 11.66; found C 44.98, H 3.18, N
11.25. EI-MS: m/z 240 [M]þ. IR cm21: 1549, 1341, 1273, 1042.
ACKNOWLEDGMENTS
`
This work was supported by Ministero dell’Istruzione dell’Universita e
della Riccera (MIUR) (L.488/92) in the frame of the project P2 “Ambiente
terrestre: Chimica per l’Ambiente.” NMR experiments were performed on
500-MHz instruments supplied by INCA (Consorzio Nazionale Interuniversi-
tario “la Chimica per l’Ambiente,” L. 488/92), project P0.

Nitration of Cinnamic Acids Using CAN
REFERENCES
3323
1. Gu, S.; Jing, H.; Wu, J.; Liang, Y. A convenient method of meta-directing
nitration of 3-substituted phenol by lanthanide (III) nitrates. Synth.
Commun. 1997, 27, 2793–2797.
2. Uemura, S.; Toshimitsu, A.; Okano, M. Stereochemistry of the bromina-
tion of acetylenes with bromine and copper(II) bromide. J. Chem. Soc.
Perkin Trans. 1 1978, 9, 1076–1079.
3. Chawla, H.M.; Mittal, R.S. Oxidative nitration by silica gel-supported
cerium(IV) ammonium nitrate. Synthesis 1985, 1, 70–72.
4. Peterson, J.R.; Do, H.D.; Dunham, A. Cerium (IV)-induced nitration of
cinnamic acids. novel remote electrophilic substitution. Can. J. Chem.
1988, 66, 1670–1674.
5. Suh, J.T.; Schnettler, R.A. 2-(Substituted anilino)-4,5-dihydro-3H-1,3-
benzodiazepines. U.S. Patent 3 849 400, 1974; Chem. Abstr., 1975, 82,
73041s.
6. Novellino, L.; d’Ischia, M.; Prota, G. Expedient synthesis of 5,6-dihy-
droxyiindole and derivatives via an improved Zn (II)-assisted 2,b-dinitro-
styrene approach. Synthesis. 1999, 5, 793–796.
7. Grenier, J.L.; Cotelle, N.; Cotelle, P.; Catteau, J.P. Antioxidant properties
of nitrocaffeic acids. Bioorg. Med. Chem. Lett. 1996, 6 (4), 431–434 and
references cited therein.
8. Ganguly, N.C.; Datta, M.; De Romaprosad Chakravarty, P. Studies on
regioselectivity of nitration of coumarins with cerium(IV) ammonium
nitrate: solid-state nitration of 6-hydroxy-coumarins on montmorillonite
k-10 clay support under microwave irradiation. Synth. Commun. 2003,
33 (4), 647–659.
9. Grenier, J.L.; Catteau, J.P.; Cotelle, P. Nitration of electron-rich aromatic
compounds by cerium ammonium nitrate coated on silica. Synth.
Commun. 1999, 29 (7), 1201–1208.
10. Wang, C.; Wang, S. The rapid synthesis of b-nitrostyrenes under micro-
wave irradiation without solvent. Synth. Commun. 2002, 32 (22),
3481–3486.
11. De Micheli, G.; Maggi, R.; Mazzacani, A.; Righi, P.; Sartori, G.; Bigi, F.
Supported organic catalysts: synthesis of (E)-nitrostyrenes from nitro
alkanes and aromatic aldehydes over propylamine supported on
MCM-41 silica as a reusable catalyst. Tetrahedron Lett. 2001, 42 (12),
2401–2404.
12. Schmidtchen, F.P. An artificial molecule for ditopic anions. Tetrahedron
Lett. 1987, 27 (18), 1987–1990.

3324
Messere et al.
13. Bose, A.K.; Ganguly, S.N.; Manhas, M.S.; Srirajan, V.; Bhattacharjee, A.;
Rumthao, S.; Sharma, A.H. Microwave assisted synthesis of an unusual
dinitro phytochemical. Tetrahedron Lett. 2004, 45, 1179–1181.
14. Hershfield, R.; Schmir, G.L. Lactonization of ring-substituted coumarinic
acids. Structural effects on the partitioning of tetrahedral intermediates in
esterification. J. Am. Chem. Soc. 1973, 95 (22), 7359–7369.
15. Mathias, L.J.; Grubb, T.L.; Tullos, G.L. Vapor phase deposition of poly-
benzoxazoles. J. Pol. Sci., Part A. 1998, 36 (8), 1317–1328.
`
16. Blay, G.; Fernandez, I.; Monje, B.; Pedro, J.R. Diastereoselective michael
addition of (S)-mandelic acid enolate to nitroalkenes. Enantioselective
synthesis of a-hydroxy-a,b-diaryl-g-lactams. Tetrahedron 2004, 60,
165–170.
17. Fisher, A.; Henderson, G.N. Oxidation of hydroquinones, cathecols, and
phenols using cerium ammonium nitrate and ammonium dichromate
coated on silica: an efficient and convenient preparation of quinones.
Synthesis. 1985, 6/7, 641–643.
Received in the UK January 19, 2004