a study that has assumed great importance in the past
decade.11 Many articles dealing with their synthesis, re-
activity, and spectral profile studies have been published.
In particular, it seems that the presence of an aryl or
heteroaryl moiety on the 3-position of the coumarinic
system induces specific activities.12 We have recently re-
ported a particularly useful, easy, and concise synthesis of
diversified 3-aryl coumarins using Heck coupling reactions
between coumarin and aryl halides.13 A major issue in
expanding the applications of coumarin derivatives is
related to their color spectrum and intensity of their
spectroscopic bands. One solution arises from increasing
the delocalization of the conjugated π-electron system
which will allow us to obtain derivatives of coumarin with
absorption bands to longer wavelengths and with greater
intensity. One can anticipate that the extension of the
π-delocalized system will lead to compounds showing more
promising fluorescent behavior. This would imply a great-
er challenge, the introduction of an unsaturated fragment
carboxylic acid chlorides.17 Here we report a more expe-
ditious synthesis of 3-vinyl and 3-styryl coumarin fluor-
escent dyes from readily available substrates.
When 3-butenoic acid was allowed to react with N,
N0-dicyclohexylcarbodiimide (DCC) the corresponding
intermediate was then coupled to salicylaldehyde in the
presence of 4-N,N0-dimethylaminopyridine (DMAP) to
give 2-formylaryl but-3-enoate (1a).18
Scheme 1. Synthetic Approach to the Synthesis of 3-Vinyl
Coumarins (2) Following a One-Pot Procedure (Pathway A) or
through Isolation of Intermediates 1 or 3 (Pathways B and C)
between the coumarin ring and the aromatic group at-
14
€
tached to the 3-position. This was observed by Bauerle
and Bochkov15 on screening for fluorescent dyes. The
introduction of a double bond at the 3-position required
for the Heck reaction could be foreseen by (1) formylation
of the coumarin ring and (2) olefination by Wittig reaction
but was revealed to be impracticable. The first report16 on
the synthesis of 3-vinylcoumarin was a multistep sequence.
A more versatile synthesis of 3-alkenylcoumarins was
achieved by a variety of 2-acyl-, 2-aroyl-, and 2-formyl-
substituted phenols on reaction with R,β-unsaturated
(9) (a) Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2006, 45, 4900.
(b) Geiβler, D.; Antonenko, Y. N.; Schmidt, R.; Keller, S.; Krylova,
O. O.; Wiesner, B.; Bendig, J.; Pohl, P.; Hagen, V. Angew. Chem., Int. Ed.
2005, 44, 1195. (c) Pinheiro, A. V.; Baptista, P.; Lima, J. C. Nucleic Acids
Res. 2008, 36, e90.
Compound 1a could be converted into the 3-vinyl
coumarin16 (2a) in good to moderate yields under treat-
ment withpotassium tert-butoxide (Scheme 1, pathway B).
However, when treated in situ with cesium carbonate, 1a
afforded 2a in a one-pot reaction which allowed us to
increase the scale and the yield without suffering isomer-
ization of the double bond (Scheme 1, pathway A). Indeed,
when performing the reaction at a larger scale, 1a suffers
a predictable rearrangement to compound 3a as a result
of migration of the double bond to a more stable position.
γ-Deprotonation of 3a was easily accomplished on treat-
ment with potassium carbonate, and 2a was obtained in a
satisfying yield (Scheme 1 , pathway C).17
Although considered labile intermediates in literature,16
we were able to isolate the vinyl coumarins in good yields.
Reaction conditions and yields are presented in Table 1.
As expected, the one-pot reaction (pathway A) gave better
yields of coumarins when compared with other routes
that involved isolation of intermediate 1 (pathway B) or 3
(pathway C). For the synthesis of 2e we started with
2,4-dihydroxybenzaldehyde and the reagents were doubled
(10) (a) Thuong, P. T.; Hung, T. M.; Ngoc, T. M.; Ha, D. T.; Min,
B. S.; Kwack, S. J.; Kang, T. S.; Choi, J. S.; Bae, K. Phytother. Res. 2010,
24, 101. (b) Dayam, R.; Gundla, R.; Al-Mawsawi, L. Q.; Neamati, N.
Med. Res. Rev. 2008, 28, 118. (c) Hoult, J. R. S.; Paya, M. Gen.
Pharmacol. 1996, 27, 713. (d) Borges, F.; Roleira, F.; Milhazes, N.;
Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12, 887. (e) Kostova, I.
Curr. Med. Chem. Anti-Cancer Agents 2005, 5, 29. (f) Kabeya, L. M.; de
Marchi, A. A.; Kanashiro, A.; Lopes, N. P.; da Silva, C.; Pupo, M. T.;
Lucisano-Valima, Y. M. Bioorg. Med. Chem. 2007, 15, 1516. (g) Carotti,
A.; Altomare, C.; Catto, M.; Gnerre, C.; Summo, L.; De Marco, A.;
Rose, S.; Jenner, P.; Testa, B. Chem. Biodiversity 2006, 3, 134. (h)
Coumarins: Biology, Applications and Mode of Action; O'Kennedy, R.,
Thornes, R. D., Eds.; Wiley: Chichester, 1997.
(11) (a) Mizukami, S.; Okada, S.; Kimura, S.; Kikuchi, K. Inorg.
Chem. 2009, 48, 7630. (b) Wagner, B. D. Molecules 2009, 14, 210. (c)
Hara, K.; Kurashige, M.; Dan-oh, Y.; Kasada, C.; Shinpo, A.; Suga, S.;
Sayama, K.; Arakawa, H. New J. Chem. 2003, 27, 783. (d) Camur, M.;
Bulut, M.; Kandaz, M.; Guney, O. Supramol. Chem. 2009, 21, 624.
(12) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley,
A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997,
97, 1515.
(13) Martins, S.; Branco, P. S.; de la Torre, M. C.; Sierra, M. A.;
Pereira, A. Synlett 2010, 2918.
(14) (a) Schiedel, M. S.; Briehn, C. A.; Bauerle, P. Angew. Chem., Int.
Ed. 2001, 40, 4677. (b) Schiedel, M. S.; Briehn, C. A.; Bauerle, P.
J. Organomet. Chem. 2002, 653, 200.
(15) Bochkov, A. Y.; Yarovenko, V. N.; Krayushkin, M. M.; Chibisova,
T. A.; Valova, T. M.; Barachevskii, V. A.; Traven, V. F.; Beletskaya, I. P.
Russ. J. Org. Chem. 2008, 44, 595.
(16) Minami, T.; Matsumoto, Y.; Nakamura, S.; Koyanagi, S.;
Yamaguchi, M. J. Org. Chem. 1992, 57, 167.
(17) Konigs, P.; Neumann, O.; Hackeloer, K.; Kataeva, O.; Waldvogel,
S. R. Eur. J. Org. Chem. 2008, 343.
(18) Lazzarato, L.; Donnola, M.; Rolando, B.; Marini, E.; Cena, C.;
Coruzzi, G.; Guaita, E.; Morini, G.; Fruttero, R.; Gasco, A.; Biondi, S.;
Ongini, E. J. Med. Chem. 2008, 51, 1894.
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