Synthesis of anacardic acids by nucleophilic substitution on 2-aryloxazolines

Article abstract of DOI:10.1016/j.tetlet.2003.12.127

A new direct synthesis for anacardic acids based in a nucleophilic substitution of a methoxy group in 2-aryloxazolines by long-chained Grignard reagents is reported.

Full text of DOI:10.1016/j.tetlet.2003.12.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1937–1939
Synthesis of anacardic acids by nucleophilic substitution
on 2-aryloxazolines
*
*
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Julio A. Seijas, M. Pilar Vazquez-Tato, M. Montserrat Martınez and Veronica Santiso
ꢀ
ꢀ
Departamento de Quꢀımica Orgꢀanica, Facultad de Ciencias, Universidad de Santiago de Compostela, Aptdo, 280, 27080 Lugo, Spain
Received 9 December 2003; accepted 23 December 2003
Abstract—A new direct synthesis for anacardic acids based in a nucleophilic substitution of a methoxy group in 2-aryloxazolines by
long-chained Grignard reagents is reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Anacardic acids are natural products isolated mainly
from cashew-nut shell (Anacardium occidentale). Essen-
tially they are salicylic acid derivatives bearing a C15
alkyl, alkenyl or alkatrienyl group in the 6-position.1
Some other examples are the C14, ginkgolinic acid2 iso-
lated from Ginkgo biloba or C11, anagigatic acid3 iso-
lated from the pericarp of Anacardium giganteum and
from Schistochila appendiculata. They are not exclusive
of superior plants, but are also present in fungi as
Phlebia radiata and Hapalopilus mutans4 and marine
organisms as Pseudomonas sp.5 or Haliclona sp.6
Previous studies15 on the carbolithiation chemistry of
styrene derivatives (where the 1,6-conjugated addition to
o-vinylphenyloxazolines of alkyl and phenyllithium
compounds occurs in good yields), suggest that this
methodology can be a good alternative to the synthesis
of anacardic acids, by starting from 2-methoxy-6-
vinylphenyloxazoline 1. However, it was observed that
2-vinylphenyloxazoline with a methoxy substituent in
position-6, had a lack of reactivity when the reaction
was carried out in diethyl ether.
An enhancement of the reactivity could be achieved by
changing the solvent (i.e., THF), but the addition of
n-BuLi to oxazoline 1 gave a low yield of a mixture of 2,
the expected addition product, and 3, resulting from the
addition of the benzylic anion on a molecule of starting
material (Scheme 1). Other different attempts were
checked to improve the reaction: solvents (THF, ether
and hexane), temperatures ()55, )78 °C), reaction times
These compounds are of interest because of their wide
biological properties: antimicrobial,7 antitumoural,8
molluscicide,9 antifungal,10 insecticide,11 regulation of
gene expression,12 etc. and have applications as anti-
bacterial detergents, cosmetics, etc.13 Therefore, several
synthetic methods for anacardic acids have been
reported.14
OMe O
OMe O
OMe O
N
n-BuLi, THF
-78ºC
N
N
+
N
1
2, 12%
3, 20%
O
OMe
Scheme 1.
Keywords: Anacardic acid; Grignard reagent; Oxazoline.
* Corresponding authors. Tel.: +34-98-2285-900; fax: +34-98-2285-872; e-mail addresses: qoseijas@lugo.usc.es; pilarvt@lugo.usc.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.127

1938
J. A. Seijas et al. / Tetrahedron Letters 45 (2004) 1937–1939
(5–120 min), even at high dilution. However from
alkyllithium reagents a mixture of compounds 2 and 3
was always obtained. These unsuccessful experiments
can be understood as a consequence of the steric hin-
drance of both substituents in ortho-positions, avoiding
the coplanarity of phenyl and oxazoline ring.
C11H29MgCl (Table 1, entries 7–8). Therefore, it may be
concluded that it is possible to obtain the substitution
product in good yields (Table 1, entries 5–8) in the case
of long chain Grignard reagents, although, as with n-
BuMgBr, oxazolines 5b require higher temperatures
than 5a. Notice that in all cases the oxazoline ring resists
the reaction conditions without any observable addition
product to the C@N bond by the Grignard.
However, the use of an oxazoline-based strategy to
anacardic acids by the enhancement of previously
reported low reactivity16 of 2,6-dimethoxyphenyloxazo-
lines towards organometallics could be quite useful.
Thus, the reactivity of 5a and 5b, obtained from 4a and
4b, respectively,16 with Grignard reagents was com-
pared. The Grignard reagent methyl magnesium bro-
mide led, as expected, to the substituted product 6a from
5a (yield 78%). However, 2,6-dimethoxyphenyloxazoline
5b did not react after 4 days at room temperature. To
the contrary, instead of replacing one of its methoxy
groups, when the reaction was heated at reflux, experi-
enced demethylation yielding phenol 7 (72% yield). This
easy cleavage of O–C bond of the methoxy group of a
phenyloxazoline with two methoxy groups in ortho was
according with previously reported results by Meyers.16
Finally, to prepare the anacardic acids 11 and 12 it is
necessary to cleave the oxazoline ring and the methoxy
group. This was done in one step by using 57% HI and
heating at reflux during 12 h, affording the correspond-
ing alkyl salicylic acids in 75% and 88% yield,
respectively (Scheme 3).
To sum up, a successful and direct way to prepare
anacardic acids via o-methoxyphenyloxazolines and the
corresponding Grignard reagents to introduce the alkyl
branch is reported. All reactions proceed in good overall
yield (50% for 9b from 2,6-dimethoxybenzoic acid), and
are highly competitive with previously reported synthe-
sis for anacardic acids.17
The behaviour of the reactivity of both oxazolines (5a–
b) towards long carbon-chain Grignard reagents (C14H29
and C11H23) was studied, since it was observed that
butyl magnesium bromide afforded the substitution
product 8a–b (Table 1, entries 3–4), although reaction of
5b required higher temperature than 5a and proceed in
moderate yield. Thus, the oxazoline 5b reacted with
Grignard reagent C14H29MgCl after refluxing for 24 h,
giving 9b in 88% yield. However, for 5a it was not
necessary to reflux and after 1 day at room temperature
compound 9a was obtained in 64% yield (Scheme 2,
Table 1, entries 5–6). Similar results were obtained for
OH
O
OMe
O
57% HI
OH
N
R3
R3
9a, 10a
11, R3=C14H29
12, R3=C11H23
Scheme 3.
Table 1. Reactivity of 2-aryloxazolines with Grignard reagents
Entry
Oxazoline
R3MgX
Temperature
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5a
5b
5a
5b
5a
5b
MeMgBr
MeMgBr
Rt
Reflux
Rt
12
12
17
24
24
24
24
24
6a
7
78
72
88
49
64
88
88
71
C4H9MgBr
C4H9MgBr
8a
8b
Reflux
Rt
C14H29MgCl
9a
9b
C14H29MgCl
C11H23MgCl
C11H23MgCl
Reflux
Rt
Reflux
10a
10b
R1
R2
O
R1
R2
O
R1
R2
O
1. SOCl2
2. H2NMe2CCH2OH
N
N
R3MgX
OH
OMe
R3
OMe
5a-b
3. SOCl2
4a-b
6a, R3= Me
7, R1= OH, R2= H, R3= OMe
8a-b, R3= C4H9
9a-b, R3=C14H29
10a-b, R3=C11H23
a: R1= H, R2= OMe
b: R1= OMe, R2= H
Scheme 2.

J. A. Seijas et al. / Tetrahedron Letters 45 (2004) 1937–1939
1939
9. Sullivan, J. T.; Richards, C. S.; Lloyd, H. A.; Krishna, G.
Planta Med. 1982, 44, 175.
Acknowledgements
10. Prithiviraj, B.; Manickam, M.; Singh, U. P.; Ray, A. B.
Can. J. Bot. 1997, 75, 207–211.
11. Mwalongo, G. C. J.; Mkayula, L. L.; Dawson-Andoh, B.;
Mubofu, E. B.; Shields, J.; Mwingira, B. A. Green Chem.
1999, 13–16.
Xunta de Galicia (PR405A 98/59-0 and PGIDT01P-
XI26203PR) is thanked for financial support.
References and notes
12. Balasubramanyam, K.; Swaminathan, V.; Ranganathan,
A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134–19140.
13. Shimomura, K.; Nakatani, Y.; Nakamua, M.; Takamatsu,
S.; Fujiwara, Y.; Nomura, M. JP 06329516, 1994; Chem.
Abstr. 122, 196554; Kowata, K.; Onishi, M. JP10036887,
1998; Chem. Abstr. 128, 181864; Kuwata, K.; Konixhi, M.
JP 10036884, 1998; Chem. Abstr. 128, 193997.
14. Tyman, J. H. P.; Visani, N. Chem. Phys. Lipids 1997, 85,
157–174.
1. Tyman, J. H. P. Chem. Soc. Rev. 1979, 8, 499–537.
2. Yeddanapalli, P. V. J. Nature (London) 1954, 174, 604.
3. Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier:
Amsterdam, 1996. pp 465–557.
4. Gill, M. Nat. Prod. Rep. 1999, 301–317; Sontag, B.;
Dasenbrock, J.; Arnold, N.; Steglich, W. Eur. J. Org.
Chem. 1999, 1051–1055.
ꢀ
ꢀ
15. Seijas, J. A.; Vazquez-Tato, M. P.; Castedo, L.; Estevez,
R. J.; Ruiz, M. J. Org. Chem. 1992, 57, 5283–5284;
5. Kobayashi, S.; Hidaka, S.; Kawamura, Y.; Ozaki, M.;
Hayase, Y. J. Antibiot. 1998, 51, 323; Kobayash, S.;
Nakai, H.; Ikenishi, Y.; Sun, W.-Y.; Ozaki, M.; Hayase,
Y.; Takeda, R. J. Antibiot. 1998, 51, 328; Ino, A.;
Hasegawa, Y.; Murabayashi, A. Tetrahedron Lett. 1998,
39, 3509.
ꢀ
Martınez, M. M.; Onega, M. G.; Seijas, J. A.; Vazquez-
Tato, M. P. Tetrahedron 1997, 53, 14127–14130.
ꢀ
16. Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem.
1978, 43, 1372–1379.
6. Erikson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd,
M. R. J. Org. Chem. 1997, 62, 8188.
17. Green, I. R.; Tocoli, F. E. J. Chem. Res. (S) 2002, 105–
106; Satoh, M.; Takeuchi, N.; Nishimura, T.; Ohta, T.;
Tobinaga, S. Chem. Pharm. Bull. 2001, 49, 18–22; Satoh,
M.; Takeuchi, N.; Fujita, T.; Yamazaki, K.; Tobinaga, S.
Chem. Pharm. Bull. 1998, 46, 1501–1505; Ino, A.; Hase-
gawa, Y.; Murabayashi, A. Tetrahedron Lett. 1998, 39,
3509–3512; Tyman, J. H. P.; Visani, N. Chem. Phys. Lipids
1997, 85, 157–174; Nishikawa, A.; Hashimoto, Y.; Shirai,
R. Tetrahedron Lett. 1998, 39, 7307–7308.
7. Kasemura, K.; Nomura, M.; Tada, T.; Fujihara, Y.;
Shimomura, K. J. Oleo Sci. 2002, 51, 637–642; Kubo, I.;
Muroi, H.; Himejima, M.; Yamgiwa, Y.; Mera, H.;
Tokuxhima, K.; Ohta, S.; Kamikawa, T. J. Agric. Food
Chem. 1993, 41, 1012.
8. Kubo, I.; Ochi, M.; Vieira, P. C.; Komatsu, S. J. Agric.
Food Chem. 1993, 41, 553.