ORGANIC
LETTERS
2012
Vol. 14, No. 18
4906–4909
N‑Heterocyclic Carbene-Catalyzed
Annulation of r‑Cyano-1,4-diketones
with Ynals
ꢀ
Fedor Romanov-Michailidis, Celine Besnard, and Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, quai Ernest Ansermet 30,
CH-1211 Geneva 4, Switzerland
Received August 13, 2012
ABSTRACT
In this paper, the first stereoselective annulation reaction between r-cyano-1,4-diketones and ynals, mediated by catalytic amounts of a triazolium
salt precatalyst and cocatalytic amounts of a weak carboxylate base, is disclosed. The title transformation proceeds smoothly under mild reaction
conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon. This reaction tolerates a wide variety
of electronically distinct substituents on both reaction partners and affords privileged bicyclic scaffolds in 61À90% isolated yields and with up to
20:1 diastereomeric preference.
A thiamine diphosphate (vitamin B1) derived R,β-un-
saturated acylazolium ion was recently shown to be an
intermediate in the biosynthesisofclavulanic acid, a potent
β-lactamase inhibitor.1 The use of transiently formed R,β-
unsaturated acylazolium species to conduct modern orga-
nocatalytic transformations has gained wide popularity in
the course of the past decade. The most commonly used
method to access these key intermediates relies on internal
redox activation of R-oxidizable aldehydes with N-hetero-
cyclic carbenes.2 Stemming from the seminal works of
Lupton et al.3 and Bode et al.,4 many enolizable compounds
were used as nucleophiles to trap catalytically formed R,β-
unsaturated acylazoliums. Among which, 1,2-dicarbonyl,4
1,3-dicarbonyl,5 vinylogous amides,6 and oxindoles7 are of
particular importance. All of the title NHC-catalyzed reac-
tions afforded (spiro)annulated products based on the
dihydropyranone skeleton. Moreover, very recent mechan-
istic and theoretical studies further emphasize the utility of
NHC-derived R,β-unsaturated acylazolium ions as reactive
intermediates in organic synthesis.8
Acetals, molecular substructures that contain two oxy-
gen atoms bound to the same sp3-hybridized carbon atom,
represent a ubiquitous motif widely found in natural
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15750.
(6) Wanner, B.; Mahatthananchai, J.; Bode, J. W. Org. Lett. 2011, 13,
5378.
(2) For early examples of NHC-catalyzed internal redox processes,
see: (a) Zeitler, K. Org. Lett. 2006, 8, 637. (b) Maki, B. E.; Chan, A.;
Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371.
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(4) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W.
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Int. Ed. 2011, 50, 1673. (b) Samanta, R. C.; Maji, B.; De Sarkar, S.;
Bergander, K.; Frohlich, R.; Muck-Lichtenfeld, C.; Mayr, H.; Studer,
A. Angew. Chem., Int. Ed. 2012, 51, 5234. (c) Lyngri, E.; Bode, J. W.;
Schoenebeck, F. Chem. Sci. 2012, 3, 2346.
(5) (a) Zhu, Z.-Q.; Xiao, J.-C. Adv. Synth. Catal. 2010, 352, 2455. (b) Zhu,
Z.-Q.; Zheng, X.-L.; Jiang, N.-F.; Wan, X.; Xiao, J.-C. Chem. Commun.
2011, 47, 8670. (c) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49,
9266. (d) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080.
(e) Sun, F.-G.; Sun, L.-H.; Ye, S. Adv. Synth. Catal. 2011, 353, 3134.
(9) (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.
(b) Francke, W.; Heeman, V.; Gerken, B.; Renwick, J. A. A.; Vite, J. P.
Naturwissenschaften 1977, 64, 590. (c) Francke, W.; Hindorf, G.; Reith, W.
Angew. Chem., Int. Ed. 1978, 17, 862. (d) Francke, W.; Reith, W. Liebigs
Ann. Chem. 1979, 1.
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10.1021/ol3022287
Published on Web 09/12/2012
2012 American Chemical Society