pubs.acs.org/joc
genic activity,5 fungicidal activity,6 acaricidal activity,7 po-
Synthesis of 3-Alkoxymethylcoumarin from
3-Cyanochromene via a Novel Intermediate
2-Phenylimino-3-alkoxymethylchromene
tential anticonvulsant and analgesic activities,8 as well as
other activities.9 The major synthetic methods for the pre-
paration of coumarins include the Pechmann reaction
and its modifications,10 the Knoevenagel condensation,11
the Wittig reaction,12 the Claisen rearrangement,13 the
Vilsmeier-Haack and Suzuki cross-coupling reactions,14
Pd-catalyzed site-selective cross-coupling reactions,15 as well
as other reactions. Despite the large number of syntheses
reported, the synthesis of 3-alkoxymethylcoumarins has
gained little attention. Up to the present, only two methods
which were reported included the chloromethylation of
coumarin, followed by the reaction with alcohol16a and the
reaction of coumarin with an chloromethyl ether.16b How-
ever, only a few target compounds were synthesized in these
reported methods. Other drawbacks include the tedious
reaction condition, long reaction time, and low overall yield.
The recent increased interest is due to the potential antic-
ancer activity exhibited by some coumarin-3-N-arylsulfona-
mides17 and coumarin-3-carboxamides.18 Thus, develop-
ment of a concise, unique, and efficient synthesis for
3-alkoxymethylcoumarins is requisite and significant from
both chemical and biological viewpoints. Herein, we disclose
Jui-Chi Tsai,†,‡, Sie-Rong Li,†,‡, Michael Y. Chiang,§
Lian-Yeu Chen,†,‡ Po-Yuan Chen,†
Yi-Fang Lo,† Chen-Hao Wang,† Chun-Nan Lin,‡ and
Eng-Chi Wang*,†
†Faculty of Medicinal and Applied Chemistry and ‡Institute of
Pharmaceutical Sciences, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan, and §Department of Chemistry,
National Sun Yat-Sen University, Kaohsiung City 804,
Taiwan. These authors contributed equally to the paper.
Received July 22, 2009
(5) Harvey, R. G.; Cortez, C.; Ananthanarayan, T. P.; Schmolka, S.
J. Org. Chem. 1988, 53, 3936–3943.
(6) (a) Liu, C.-L.; Li, M.; Guan, A.-Y.; Zhang, H.; Li, Z.-M. Nat. Prod.
Commun. 2007, 2, 845–848. (b) Singh, R.; Gupta, B. B.; Malik, O. P.; Kataria,
H. R. Pestic. Sci. 1987, 20, 125–130. (c) Daoubi, M.; Duran-Patron, R.;
Hmamouchi, M.; Hernandez-Galan, R.; Benharref, A.; Collado, I. G. Pest.
Manag. Sci. 2004, 60, 927–932.
(7) Gleye, C.; Lewin, G.; Laurens, A.; Jullian, J. -C.; Loiseau, P.; Bories,
C.; Hocquemiller, R. J. Nat. Prod. 2003, 66, 690–692.
(8) Bhat, M. A.; Siddiqui, N.; Khan, S. A. Indian J. Pharm. Sci. 2006, 68,
120–124.
(9) (a) Wang, B.; Wang, W.; Camenisch, G. P.; Elmo, J.; Zhang, H.;
Borchardt, R. T. Chem. Pharm. Bull. 1999, 47, 90–95. (b) Rene, L.; Royer, R.
Eur. Med. Chem. Ther. 1975, 10, 72–78.
(10) (a) Sharghi, H.; Jokar, M. Heterocycles 2007, 71, 2721–2733.
(b) Tyagi, B.; Mishra, M. K.; Jasra, R. V. J. Mol. Catal. A 2007, 276, 47–
In this paper a concise, efficient, and environmentally
benign method for the synthesis of 3-alkoxymethylcou-
marin is described. From the reaction of 3-cyanochro-
mene with an alkoxide and arylamine in THF, (Z)-2-
phenylimino-3-alkoxymethylchromene was obtained as a
novel intermediate via an isomerization of the double
bond, a 1,2-addition of alkoxide, a Michael-type addition
of aniline, an another isomerization of double bond and
an elimination of ammonia. Subsequently, the intermedi-
ate was converted into the desired coumarin by treatment
with 15% HCl in THF in good yield.
€
56. (c) Laufer, M. C.; Hausmann, H.; Holderich, W. F. J. Catal. 2003, 218,
315–320. (d) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett.
2001, 42, 9285–9287. (e) Sharma, G. V. M.; Reddy, J.; Sree Lakshmi, P.;
Radha Krishna, P. Tetrahedron Lett. 2005, 46, 6119–6121. (f) Manhas, M. S.;
Ganguly, S. N.; Mukherjee, S.; Jain, A. K.; Bose, A. K. Tetrahedron Lett.
2006, 47, 2423–2425. (g) Romanelli, G. P.; Bennardi, D.; Ruiz, D. M.;
Baronetti, G.; Thomas, H. J.; Autino, J. C. Tetrahedron Lett. 2004, 45, 8935–
8939.
Coumarins, which are chemical derivatives of benzo-2-
pyrones or chromen-2-ones, are widely distributed in various
species of plants.1,2 In addition, diverse approaches have
been used to synthesize numerous artificial coumarins. Both
naturally occurring and synthetic coumarins have attracted
intensive attention from chemists due to their broad spectral
properties and potential for biological activities. For exam-
ple, the bioactivity of coumarins includes steroid sulfatase
inhibitory activity,3 lipid-lowering activity,4 anticarcino-
(11) (a) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999,
64, 1033–1035. (b) Song, A.; Wang, X.; Lam, K. S. Tetrahedron Lett. 2003, 44,
1755-1758 and references cited therein.
(12) (a) Takeuchi, Y.; Ueda, N.; Uesugi, K.; Abe, H.; Nishioka, H.;
Harayama, T. Heterocycles 2003, 59, 217–224. (b) Maes, D.; Vervisch, S.;
Debenedetti, S.; Davio, C.; Mangelinckx, S.; Giubellina, N.; De Kimpe, N.
Tetrahedron 2005, 61, 2505–2511.
(13) (a) Chattopadhyay, S. K.; Biswas, T.; Neogi, K. Chem. Lett. 2006,
35, 376–377. (b) Majumdar, K. C.; Debnath, P.; Maji, P. K. Tetrahedron
Lett. 2007, 48, 5265–5268. (c) Cairns, N.; Harwood, L. M.; Astles, D. P.
J. Chem. Soc., Chem. Commun. 1986, 16, 1264–1266.
(14) Hesse, S.; Kirsch, G. Tetrahedron Lett. 2002, 43, 1213–1215.
(15) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 7279–
7286.
ꢀ
ꢀ
(1) Estevez-Braun, A.; Gonzalez, A. G. Nat. Prod. Rep. 1997, 14,
465-476 and references cited therein.
(16) (a) Lele, S. S.; Savant, N. G.; Sethna, S. J. Org. Chem. 1960, 25, 1713–
1716. (b) Woods, L. L. J. Org. Chem. 1962, 27, 696–698.
(17) Reddy, N. S.; Mallireddigari, M. R.; Cosenza, S.; Gumireddy, K.;
Bell, S. C.; Reddy, E. P.; Reddy, M. V. R. Bioorg. Med. Chem. Lett. 2004, 14,
4093–4097.
(2) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477-506 and references
cited therein.
(3) Woo, L. W. L.; Purohit, A.; Malini, B.; Reed, M. J.; Potter, B. V. L.
Chem. Biol. 2000, 7, 773–791.
(4) (a) Barlocco, D. Drug Discov. Today 2003, 8, 1051–1052. (b) Madhavan,
G. R.; Balraju, V.; Mallesham, B.; Chakrabarti, R.; Lohray, V. B. Bioorg. Med.
Chem. Lett. 2003, 13, 2547–2551.
(18) Reddy, N. S.; Gumireddy, K.; Mallireddigari, M. R.; Cosenza, S. C.;
Venkatapuram, P.; Bell, S. C.; Reddy, E. P.; Reddy, M. V. R. Bioorg. Med.
Chem. 2005, 13, 3141–3147.
8798 J. Org. Chem. 2009, 74, 8798–8801
Published on Web 10/23/2009
DOI: 10.1021/jo9015634
r
2009 American Chemical Society