ABB0 three-component reaction (ABB0 3CR)4 of alkyl
propiolates and 1,2-ketoesters or 1,2-ketoamides5 or by
treatment of the corresponding tertiary propargyl alcohol
with alkyl propiolate in the presence of triethylamine.6
We envisioned that the [3,3]-propargyl Claisen rearrange-
ment of these platforms should afford the mixture of the
corresponding β-allenals 4 and their enolic tautomers 5,
which possess a highly electrophilic central allenic carbon
and a reactive hydroxyl enol functionality conveniently
placed to perform a 5-exo-dig O-cyclization reaction
(Scheme 1). The O-cyclization of 5 should afford trisub-
stituted furans 6 bearing a functionalized C2-chain linked
to the heterocyclic ring. The synergistic activation of the
central allene position by the two EWG groups should
allow for the accomplishment of this transformation in
the absence of activating metals.7
4-disubstituted furans and C2-substituted acetic esters (or
amides),8 which cannot be easily obtained by direct cycli-
zation of simple acyclic precursors.9 Because of the
importance of substituted furans in organic,10
pharmaceutical,11 and material chemistry,12 we decided
to carry out the experimental study of this unprecedented
domino transformation. We report herein the results of
these studies.
We undertook this work studying the MWA rearrange-
ment of the PVE 3a, which was synthesized in 78% yield
following our previously reported ABB0 3CR protocol5
(Scheme 2). After exploring different sets of experimental
conditions, we found that the MW irradiation of a solution
of 3a in DMF (closed vessel, 300 W, 150 °C, 1 h) cleanly
afforded the furan derivative 6a in 99% yield. In a previous
report,13 we had shown how the coupling of two domino
processes in just one-pot reaction offered important ad-
vantages in terms of operational simplicity, efficiency, and
work economy. Thus, we assayed conditions to perform
the entire process in a one-pot fashion. After several
experimental trials, we found that furan 6a could be
obtained in 78% yield (Scheme 2) directly from methyl
2-oxo-2-phenylacetate and methyl propiolate, without
isolation of the PVE intermediate 3a.14
Scheme 1. Synthesis of C2-Chain Functionalized Furans 6
Scheme 2. Synthesis and MWA Rearrangement of PVE 3a into
Furan 6a
These trisubstituted furans 6 would represent, to the best
of our knowledge, unprecedented hybrid structures of 3,
ꢀ
(5) Tejedor, D.; Santos-Exposito, A.; Garcıa-Tellado, F. Chem.;
Eur. J. 2007, 13, 1201.
(6) (a) Tejedor, D.; Santos-Exposito, A.; Mendez-Abt, G.;
ꢀ
ꢀ
ꢀ
Ruiz-Perez, C.; Garcıa-Tellado, F. Synlett 2009, 1223. (b) Inanaga, J.;
Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
(7) Furan syntheses based on propargylꢀallenyl interconversion and
subsequent O-cyclization normally requieres metal activation. See ref 2
for selected examples. For selected reviews, see: (a) Kirsch, S. F. Synth-
€
esis 2008, 3183. (b) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev.
2007, 36, 1095. (c) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076. (d)
Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850.
(8) We have not found precedents for these hybrid structures,
featuring this substitution pattern, in our structure-driven search in
SciFinder database.
Once the experimental feasibility of our initial hypoth-
esis was established, we explored the influence of the
electron-withdrawing group allocated at the tertiary pro-
pargylic position by replacing the ester group with an
(9) For selected examples of metal-catalyzed methodologies for the
synthesis of substituted furans bearing a functionalized chain, see: (a)
Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536 and
references cited therein. (b) Albrecht, L.; Ransborg, L. K.; Gschwend,
B.; Jorgensen, K. A. J. Am. Chem. Soc. 2010, 132, 17886. (c) Hashmi,
A. S. K.; Lothar Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285. For recent reviews of general synthetic
methodologies to substituted furans, see: (d) Hou, X. L.; Yang, Z.;
Yeung, K.-S.; Wong, H. N. C. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Joule, J. A., Eds.; Pergamon: Oxford, 2008; Vol. 19, p 176. (e)
Balme, G.; Bouyssi, D.; Monteiro, N. Heterocycles 2007, 73, 87.
(10) For selected reviews, see: (a) Hou, X. L.; Yang, Z.; Wong,
H. N. C. In Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist,
T. L., Eds.; Pergamon: Oxford, 2003; Vol. 15. (b) Keay, B. A.; Dibble, P. W.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Elsevier: Oxford, 1997; Vol. 2. (c) Donnelly,
D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4.
(11) (a) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001,
44, 3838. (b) Francesconi, I.; Wilson, W. D.; Tanious, F. A.; Hall, J. E.;
Bender, B. C.; Tidwell, R. R.; McCurdy, D.; Boykin, D. W. J. Med.
Chem. 1999, 42, 2260. (c) Rahmathullah, S. M.; Hall, J. E.; Bender, B. C.;
McCurdy, D. R.; Tidwell, R. R.; Boykin, D. W. J. Med. Chem. 1999
42, 3994.
(12) Zhang, L. Z.; Chen, C. W.; Lee, C. F.; Wu, C. C.; Luh, T. Y.
Chem.Commun. 2002, 2336.
ꢀ
(13) Tejedor, D.; Gonzalez-Cruz, D.; Garcıa-Tellado, F.; Marrero-
Tellado, J. J.; Rodriguez, M. L. J. Am. Chem. Soc. 2004, 126, 8390.
(14) It has to be noted that although these two-step sequential
processes are defined as one-pot, they require a change of reaction vessel
(from a round-bottom flask to a MW special closed vessel) because the
CEM MW oven requires pressure-resistant special glass flasks.
Org. Lett., Vol. 13, No. 16, 2011
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