ORGANIC
LETTERS
2005
Vol. 7, No. 5
767-770
Aryl Annulation of Cyclic Ketones via a
Magnesium Carbometalation
Electrocyclization Protocol
−6-π-
Pierre E. Tessier,† Natalie Nguyen, Matthew D. Clay, and Alex G. Fallis*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa,
Ontario, Canada K1N 6N5
Received November 22, 2004 (Revised Manuscript Received January 9, 2005)
ABSTRACT
A new strategy for the aryl annulation of cyclic ketones is described. Palladium(0) coupling of a propargyl alcohol with the enol triflate of a
ketone and addition of vinylmagnesium chloride generates a triene as a magnesium chelate that may be quenched with an electrophile. In
some cases, the triene cyclizes under the reaction conditions. Aromatization is accomplished by exposure to manganese dioxide or
dichlorodicyanoquinone (DDQ).
We have previously described some of the attributes and
versatility of the magnesium-mediated carbometalation of
propargyl alcohols to assemble several diverse compounds
generated in a single reaction, for a variety of objectives.1
These reactions have included the regio- and stereoselective
generation of diene-halides, diene-diols, enediynes, furans,
furanones, taxoid intermediates and palladium(0) cross-
couplings for dienes, and the stereospecific synthesis of (Z)-
Tamoxifen.2
The common feature of this chemistry is the reaction of a
propargyl alcohol either directly or in situ with a Grignard
reagent, subsequent generation of the magnesium chelate,
followed by reaction with an appropriate electrophile.
We report a new annulation procedure to attach substituted
benzene rings to cyclic ketones. This aryl annulation strategy
involves a regio- and stereospecific magnesium-mediated
carbometalation followed by 6-π-electrocyclic ring closure
of the resulting triene and oxidation as illustrated in Scheme
1. This method employs a vinyl triflate 1 derived from an
appropriate cyclic ketone, which is coupled in the presence
of palladium(0) with propargyl alcohol to give 2. Addition
of vinylmagnesium chloride generates the magnesium chelate
3, and an in situ reaction with an electrophile such as iodide
(Y ) I) affords a triene of type 4. In the case of some bicyclic
ketones, this triene undergoes spontaneous electrocyclic
cyclization to 5 in the same reaction vessel; otherwise,
additional heating is required. Oxidation with MnO2 or DDQ
affords an iodo-benzaldehyde 6. However, various substitu-
(2) (a) Wong, T.; Tjepkema, M. W.; Audrain, H.; Wilson, P. D.; Fallis,
A. G. Tetrahedron Lett. 1996, 37, 755. (b) Forgione P.; Fallis, A. G.
Tetrahedron Lett. 2000, 41, 11. (c) Forgione, P.; Wilson, P. D.; Fallis,
A. G. Tetrahedron Lett. 2000, 41, 17. (d) Forgione P.; Wilson, P. D.;
Yap, G. P. A.; Fallis, A. G. Synthesis 2000, 921. (e) Tessier, P. J.; Penwell,
A. J.; Souza, F. E. S.; Fallis A. G. Org. Lett. 2003, 5, 2989. (f) Villava-
Serin, N. P.; Laurent, A. Fallis, A. G. Synlett 2003, 1263. (g) Smil, D.
V.; Laurent, A.; Villava-Serin, N. P.; Forgione, P.; Wilson, P. D.; Fallis,
A. G. Can. J. Chem. 2004, 82, 215. (h) Smil, D. V.; Laurent, A.; Villava-
Serin, N. P.; F. Souza, F. E. S.; Fallis, A. G. Can. J. Chem. 2004, 82,
227.
† Present address: Methyl Gene, Inc., 7220 Frederick Banting, Montreal,
Que´bec, Canada, H4S 2A1.
(1) For a review, see: (a) Fallis, A. G.; Forgione, P. Tetrahedron 2001,
57, 589. For earlier studies, see: (b) Eisch, J. J.; Merkley, J. H. J.
Organomet. Chem. 1969, 20, 27. (c) Richey, H. G., Jr.; Von Rein, F. W. J.
Organomet. Chem. 1969, 20, 32. (d) Negishi, E.; Zhang, Y.; Cederbaum,
F. E.; Webb, M. B. J. Org. Chem. 1986, 51, 4080. (e) Labaundinie`re, L.;
Hanaizi, J.; Normant, J.-F. J. Org. Chem. 1992, 57, 6903.
10.1021/ol047602y CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/29/2005