Reaction of caffeic acid derivatives with acidic nitrite

Article abstract of DOI:10.1016/S0040-4039(01)00441-5

Caffeic derivatives were reacted with acidic nitrite at controlled pH in order to mimic the gastric juice conditions. At pH 2, whereas caffeic acid reacts exclusively on the side chain, its esters are readily nitrated. Under more acidic conditions (pH 1),

Full text of DOI:10.1016/S0040-4039(01)00441-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3303–3305
Reaction of caffeic acid derivatives with acidic nitrite
Philippe Cotelle* and Herve´ Vezin
Laboratoire de Chimie Organique Physique associe´ au CNRS, ENSCL, Universite´ de Lille 1, F-59655 Villeneuve d’Ascq, France
Received 24 February 2001; revised 15 March 2001; accepted 16 March 2001
Abstract—Caffeic derivatives were reacted with acidic nitrite at controlled pH in order to mimic the gastric juice conditions. At
pH 2, whereas caffeic acid reacts exclusively on the side chain, its esters are readily nitrated. Under more acidic conditions (pH
1), caffeic acid methyl ester undergoes a dimerisation into a norlignan derivative. © 2001 Published by Elsevier Science Ltd.
1. Introduction
nitrite. This paper describes the characterisation of the
products obtained from the reaction of caffeic acid
methyl ester 1, caffeic acid 2 and chlorogenic acid 3
with nitrite at pH 1 or 2. Reaction of caffeic acid and
related derivatives with nitrite at acidic pH has been
carried out according to Rousseau and Rosazza.8
Caffeic acid and related compounds are widely dis-
tributed in fruits, vegetables, wine, olive oil, teas and
coffee beans. Caffeic acid is generally not found as free
acid but more likely esterified in chlorogenic acid (the
quinic acid ester of caffeic acid).
2. Results and discussion
Many studies have demonstrated that caffeic acid and
related compounds are potent inhibitors of the N-nitro-
sation reactions.1–3 N-Nitrosation is a potentially muta-
genic reaction since N-nitrosamines have been
implicated in human carcinogenesis. Precursors of N-
nitrosamines are secondary amines and nitrite and the
acidity of gastric juice is appropriate for N-nitrosation.4
There are still complicated effects, inhibition or stimu-
lation, on the formation of N-nitrosamines with chloro-
genic acid depending upon the conditions used.2,5
The reaction of caffeic acid with acidic nitrite results in
a mixture of three products, which have been character-
ised by spectroscopic analysis. The main product (50%
1
calculated from the H NMR spectrum of the crude
extract) has been identified as the furoxan derivative 4.
Its H NMR spectrum12 presents the characteristic pat-
1
tern of a 1,2,4-trisubstituted benzene ring and a singlet
at 9.06 ppm, which can be attributed to the heterocyclic
proton. The second one (40%) has been identified as the
1,2-(4H)-benzoxazin-4-one derivative 6.12 Its simple H
1
The reactivity of caffeic acid derivatives with acidic
nitrite is well documented,1,3,5 but very little is known
about the products formed. It has been reported that
para-coumaric acid and ferulic acid react with acidic
nitrite to give a mixture of several compounds, which
are all issued from the reaction of nitrite on the side
chain. For example, from the reaction of ferulic acid
with acidic nitrite were isolated two minor products: the
structure of one of them may be attributed to a furoxan
heterocycle 5,6,7 the other one has been identified
recently8 as 7-hydroxy-6-methoxy-1,2-(4H)-benzoxazin-
4-one 6 (Scheme 1). In connection with our continuing
interests in nitrocatechol derivatives,9–11 we examined
the reaction of caffeic acid derivatives with acidic
NMR spectrum contained only three uncoupled aro-
matic proton signals. The third one (10%) is the known
6-nitro-3,4-dihydroxybenzaldehyde 8.13
Conversely, the reaction of the caffeic acid esters 2 and
3 with acidic nitrite gives the 6-nitroderivatives 1014 and
1115 as the sole products in 89 and 11% yield, respec-
1
tively. The low field region of their H NMR spectra
contained only two uncoupled aromatic proton signals
and two doublets (3J=15.8 Hz) which correspond to
the double bond protons. Compound 10 has also been
prepared from the known 6-nitrocaffeic acid 99 and
methanol in the presence of thionyl chloride and the
hydrolysis of the ester function of 11 also gives 9.
The difference in reactivity between caffeic acid and its
esters can be explained by the mechanism depicted in
Scheme 2. The caffeic acid derivatives may be oxidised
Keywords: nitrous acid and derivatives; nitro compounds; neolignans.
* Corresponding author. Tel.: 33 (0)320337231; fax: 33 (0)320336309;
e-mail: philippe.cotelle@univ-lille1.fr
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00441-5

3304
P. Cotelle, H. Vezin / Tetrahedron Letters 42 (2001) 3303–3305
_
O
+
COOR2
HO
HO
N
O
N
RO
HO
R1
1: R1=R2= H
2: R1= H; R2=CH3
4: R= H
5: R= CH3
3: R1=H;R2=
O
OH
OH
O
OH
RO
HO
9: R1=NO2;R2= H
10: R1= NO2; R2=CH3
N
O
11: R1=NO2;R2=
O
6: R= H
7: R= CH3
OH
OH
CHO
NO2
HO
HO
OH
H3COOC
8
COOCH3
OH
12
O
OH
OH
Scheme 1.
NO2
O
COOR
HO
HO
HO
HO
HNO2, NO+
O
N
R
O
NO2
N
O
O
NO2
HO
HO
HO
HO
O
H
4 and 6
NOH
R'
H
O
R'
O
2
12
10 or 11
HO
O
NO2
Scheme 2.
by nitrite, nitrous acid or the other nitrogen species
present in the medium to give the o-quinone probably
through disproportionation of the semiquinonic
radical16 or they may react with nitrite and nitrosonium
ions.7 In the case of caffeic acid, the product of addi-
tion of nitrite and nitrosonium ions may undergo an
irreversible decarboxylation leading to 4, 6 and proba-
bly 3,4-dihydroxybenzaldehyde which was finally
nitrated to give 8. For the caffeic acid esters, the
decarboxylation cannot occur and the o-quinone reacts
with nitrite to give 10 or 11.
Since gastric juice pH is about 1, caffeic acid and its
methyl ester (1 and 2) were also treated with nitrite at
pH 1. At this pH value, the nitrite concentration is
expected to be very low and the o-quinone of 2 may
react in a different way. Under this condition, in the
two cases, dark polymeric precipitates were obtained.
However, the extraction with ethyl acetate of the
aqueous layer in the case of 2 allowed us to isolate a
dimer that was identified as the benzofuran derivative
1217 in 20% yield. Under this pH condition, the nitrite
concentration is expected to be too low and the nucle-

P. Cotelle, H. Vezin / Tetrahedron Letters 42 (2001) 3303–3305
3305
ophilic reaction of nitrite on the caffeic ester o-quinone
does not occur. The unstable o-quinone may react
therefore with 2 to give 12. These results show that
nitrite under strong acidic conditions may promote the
oxidative dimerisation of caffeic acid ester leading to
neolignan compound. The oxidative dimerisation of
caffeic acid has also been demonstrated in the isolated
perfused rat liver18 but affords lignan derivatives.
7. Plu¨cken, U.; Winter, W.; Meier, H. Liebigs Ann. Chem.
1980, 1557–1572.
8. Rousseau, B.; Rosazza, J. P. N. J. Agric. Food Chem.
1998, 46, 3314–3317.
9. Grenier, J. L.; Cotelle, N.; Cotelle, P.; Catteau, J. P.
Bioorg. Med. Chem. Lett. 1996, 6, 431–434.
10. Grenier, J. L.; Cotelle, P.; Cotelle, N.; Catteau, J. P. J.
Chim. Phys. 1995, 92, 97–103.
11. Grenier, J. L.; Cotelle, N.; Catteau, J. P.; Cotelle, P. J.
Phys. Org. Chem. 2000, 13, 511–517.
3. Conclusion
12. Compounds 4, 6 and 8 have been separated by flash
chromatography. Compounds 4 and 6 have only been
characterised by their 1H NMR spectra because they
degraded within a few hours at room temperature.
3-(3,4-Dihydroxyphenyl)furazan-2-oxide 4: 1H NMR
The nitration of catechols with nitric oxide19,20 at phys-
iologic pH or nitrite under acidic conditions20 is well-
known and 6-nitrodopamine has been implicated in the
neuronal degeneration.21 On the other hand, it has been
reported that caffeic acid and related compounds are
potent scavengers of highly reactive nitrogen species
such as peroxynitrite22 or nitrogen dioxide radical.23
Chlorogenic acid and related compounds that are
widely present in various agricultural products in sub-
stantial quantities are important in human health and
may be useful as antioxidants and anticancer agents.
Therefore, it appears crucial to evaluate the toxicity of
nitrocaffeic acids and related compounds. In summary,
the present investigation has revealed that caffeates can
react with nitrite under physiologic acidic conditions to
differential extents depending on the function (ester or
acid) to give nitroderivatives, nitrogen heterocycles or
benzofuran dimers.
3
3
(methanol-d4): 6.99 (d, J=7.4 Hz, 1H), 7.43 (dd, J=7.4
Hz, 4J=2.0 Hz, 1H), 7.63 (d, 4J=2.0 Hz, 1H), 9.06 (s,
1H).
6,7-Dihydroxy-1,2-(4H)-benzoxazin-4-one 6: 1H NMR
(methanol-d4): 6.95 (s, 1H), 7.33 (s 1H), 8.13 (s, 1H).
13. Murphy, B. P. J. Org. Chem. 1985, 50, 5873–5875.
14. Methyl 2-nitrocaffeate 10 (89% yield): elemental analyses
for C10H9NO6; calcd C, 50.22; H, 3.79; N, 5.86; O, 40.13;
found C, 50.54; H, 3.53; N, 6.04; O, 40.51; mp 132–
133°C; 1H NMR (methanol-d4): 3.69 (s, 3H), 6.19 (d,
3J=15.9 Hz, 1H), 6.96 (s, 1H), 7.44 (s, 1H), 8.01 (d,
3J=15.9 Hz, 1H); IEMS (60 eV): 239 (19%), 225 (69%),
179 (56%), 51 (100%).
15. 2-Nitrochlorogenic acid 11 (11% yield): elemental analy-
ses for C16H17NO11; calcd C, 48.13; H, 4.29; N, 3.51; O,
44.07; found C, 48.14; H, 4.21; N, 3.34; O, 44.31; mp
1
2
240–245°C; H NMR (DMSO-d6): 1.79 (dd, J=13.0 Hz,
3J=7.2 Hz, 1H), 1.99 (m, 3H), 3.57 (dd, 3J=7.2 Hz,
4J=2.5 Hz, 1H), 3.93 (m, 1H), 5.10 (m, 1H), 6.21 (d,
3J=15.8 Hz, 1H), 7.11 (s, 1H), 7.54 (s, 1H), 7.96 (d,
3J=15.8 Hz, 1H); IEMS (60 eV): 339 (6%), 225 (45%),
179 (62%), 174 (38%), 51 (100%).
Acknowledgements
We acknowledge the Centre National de la Recherche
Scientifique (CNRS) for financial supports.
16. Hapiot, P.; Neudeck, A.; Pinson, J.; Fulcrand, H.; Neta,
P.; Rolando, C. J. Electroanal. Chem. 1996, 405, 169–176.
17. Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.;
Vlietinck, A.; Lemie`re, G. J. Med. Chem. 1999, 42,
5475–5481.
18. Gumbinger, H. G.; Vahlensieck, U.; Winterhoff, H.
Planta Med. 1993, 59, 491–493.
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