P. K. Upadhyay, P. Kumar / Tetrahedron Letters 50 (2009) 236–238
237
expect low reactivity of this ylide in a nucleophilic reaction. At the
same time, imidazole being a good leaving group would facilitate
reaction at the carbonyl centre. Thus, the hydroxy carbonyl com-
pound 3 was first heated with NaOMe in xylene at 60 °C for 2 h,
and then reacted with ylide 2 under reflux conditions to afford
phosphoranes 4 which underwent intramolecular Wittig cycliza-
tion to furnish the desired coumarin 5 in good yields (Scheme 2).
Taking into consideration the low nucleophilicity of ylide 2, it
was necessary to use an equimolar amount of an additional base
such as sodium methoxide to generate an alkoxy anion from
hydroxy carbonyl compound 3. The reaction is then followed by
a nucleophilic attack of the alkoxy anion on the carbonyl of ylide
2, ultimately leading to the formation of the intermediate 4 with
the extrusion of imidazole as a by-product. The phosphorane 4
thus formed immediately undergoes ring closure via an intra-
molecular Wittig reaction to afford the desired coumarin 5 in good
yields.
To support our mechanism, the intermediacy of 4 has been
established by spectroscopic means. Although the treatment of
3e with 2 in xylene in the presence of NaOMe at room temperature
did not show any progress in the reaction, the extrusion of imidaz-
ole and the formation of phosphorane 4e could be observed when
the reaction was performed at reflux temperature. Interestingly,
compound 4e9 was found to be stable enough to be isolated after
3 h of the reaction, and was further identified by its spectral data.
Compound 4e on subsequent heating in refluxing xylene for 48 h
gave the desired coumarin 5e. Thus, the above finding indicates
that compound 4e, which results from the extrusion of imidazole,
is an intermediate that undergoes subsequent intramolecular Wit-
tig cyclization at reflux temperature to furnish the desired product
5e.
Table 1
As is apparent from Table 1, the intramolecular Wittig cycliza-
tion involving phosphorus ylide and carbonyl is general for the
One-pot synthesis of substituted coumarins
Entry no.
Hydroxy carbonyl compounds
Productsa
Yield (%)
85
preparation of
a variety of coumarin derivatives. While the
electron-donating or electron-withdrawing substituents in the
aromatic rings (entries 2–4 and 8, respectively) do not have any
considerable effect in terms of the yields of the products obtained,
the steric effect during Wittig cyclization resulting from substitu-
tion in aromatic rings appears to be significant. Thus, propionyl
and benzoyl groups (entries 7 and 10) have pronounced steric hin-
drance due to their close proximity to the carbonyl group, and
hence a longer time (55 h) is required for completion of the reac-
tion affording relatively low yields of the products, 5g and 5j,
respectively. It may be pertinent to mention here that a few appli-
cations of transition-metal catalyzed reactions for coumarin syn-
thesis have been reported, but most of these are of limited
scope.10,11 For example, palladium-catalyzed carbonylative annu-
lation of internal alkynes by o-iodophenols is known to give vary-
ing proportions of two regioisomers of substituted coumarins.12
In this connection, the present methodology for the synthesis of
coumarins is noteworthy.
OH
O
O
O
1
5a
3a
OMe
OMe
O
OH
O
O
2
3
4
5
6
7
70
72
70
75
72
62
O
3b
5b
MeO
OH
MeO
O
O
5c
3c
O
O
OH
O
MeO
MeO
3d
5d
OH
O
O
O
In conclusion, an efficient annulation protocol for a variety of
coumarins has been developed. To the best of our knowledge, this
is the first report of coumarin synthesis via intramolecular Wittig
5e
3e
OH
O
carbonyl olefination using triphenyl (a-carboxymethylene) phos-
O
O
phorane as a C-2 synthon. Currently, work is in progress to extend
the synthetic potential of ylide 2 for the construction of nitrogen
and sulfur heterocycles as well.
3f
5f
OH
O
O
O
Acknowledgements
P.K.U. thanks CSIR, New Delhi, for the award of a senior research
fellowship. We are grateful to Dr. Ganesh Pandey, Head, Organic
division, NCL, Pune for his encouragement and support. This is
NCL communication No. 6711.
5g
3g
OMe
OH
OMe
O
O
O
8
9
70
75
O
O N
2
O N
2
3h
5h
References and notes
O
O
1. (a) Heterocyclic Chemistry, 4th ed.; Joule, J. A., Mills, K., Eds.; Blackwell Science
Ltd: Oxford, 2006; p 170; (b) Murrray, R. D. H. Fortschr. Chem. Org. Naturst.
1978, 35, 199; (c) Green, G. R.; Evans, J. M.; Vong, A. K. In Comprehensive
Heterocyclic Chemistry II, 1st ed.; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon Press Ltd: Oxford, 1984; Vol. 5, pp 469–500.
2. (a) Feuer, G. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.;
North-Holland: New York, 1974; (b) Deana, A. A.; Stokker, G. E.; Schultz, E. M.;
Smith, R. L.; Cragoe, E. J.; Russo, H. F., Jr.; Waston, L. S. J. Med. Chem. 1983, 26,
580; (c) Wenkert, E.; Buckwalter, B. L. J. Am. Chem. Soc. 1972, 94, 4367; (d)
Kostova, I. Curr. Med. Chem. Anticancer Agents 2005, 5, 29.
3. For recent publications on coumarin synthesis, see: (a) Koenigs, P.; Neumann,
O.; Hackeloer, K.; Kataeva, O.; Waldvogel, S. R. Eur. J. Org. Chem. 2008, 343 and
references cited therein; (b) Ramesh, E.; Raghunathan, R. Tetrahedron Lett.
2008, 49, 1812; (c) Ye, F.-F.; Gao, J.-R.; Sheng, W.-J.; Jia, J.-H. Dyes Pigments
2008, 77, 556 and references cited therein; (d) Trost, B. M.; Toste, F. D.;
OH
5i
3i
Ph
O
O
Ph
O
OH
10
60
5j
OMe 3j
OMe
All products were characterized by their satisfactory IR, 1H NMR and mass
spectral data and also by comparison with the literature.
a