Aryl annulation of cyclic ketones via a magnesium carbometalation-6-π- electrocyclization protocol

Article abstract of DOI:10.1021/ol047602y

(Chemical Equation Presented) 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

Full text of DOI:10.1021/ol047602y

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
afallis@science.uottawa.ca
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

Scheme 1. Aryl Annulation via a Carbometalation-6-π-
Table 1. Bicyclic Ketones: Synthesis of Triflates, Propargyl
Alcohols, and Cyclized Dienes/Trienes
Electrocyclic Ring Closure Oxidation Strategy
tion patterns may be generated for different objectives as
outlined below.
The triflates were prepared from the corresponding ketones
upon treatment with LDA in THF at -78 °C followed by
exposure to N-phenyl-trifluoromethanesulfonimide. In ad-
dition to the bicyclic systems 73 and 104 the triflates 395
and 4216 (Table 2) have been prepared previously.
The trienes generated from bridged ring bicycle[2.2.1]-
heptanones display a propensity to undergo the electrocy-
clization in situ, in contrast to other more conformationally
mobile ring systems. This behavior is ascribed to the limited
flexibility of the pendant vinyl group in the cyclic chelates
Scheme 2. Bridged Ring Systems: Representative
Cyclizations and Aromatizations
derived from the norbornene (entry a) and bornene (entry
b) skeletons. The product distribution for entries c and d
could be varied depending upon the reaction conditions
(Scheme 2).
Our trienes cyclized over a temperature range that was
consistent with literature precedent. The energy requirement
for 6-π-electrocyclic ring closure varies significantly. Lithium
enolates with adjacent electron-withdrawing groups (esters)
proceeded below room temperature.7 Less activated trienes
also with an ester substituent required temperatures from 100
to 215 °C depending on the substitution pattern.8
(3) Bentz, H.; Subramananian, L. R.; Hanack, M.; Martinez, G. A.; Marin,
M. G.; Perez-Gssorio, R. Tetrahedron Lett. 1977, 9.
(4) McMurray, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 979.
(5) Pal, K. Synthesis 1995, 1485.
(6) Stang, P. J.; Warren, T. Synthesis 1980, 283
(7) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc.
2004, 126, 1624.
768
Org. Lett., Vol. 7, No. 5, 2005

Scheme 3. Reaction of the “Camphor Chelate” with Different
Table 2. Fused Ring Ketones: Synthesis of Triflates,
Propargyl Alcohols, and Trienes
Electrophiles
°C). Consistent with the behavior of 20, further heating of
25 in the presence of DDQ afforded the aldehyde 24.
This protocol is not limited to a proton quench. The
intermediate chelate can be reacted with other electrophiles
such as methyl iodide, iodine, or boron to generate the
compounds in Scheme 3.
The intermediate chelate 27 derived from the camphor
propargylic alcohol 11 was reacted with different electro-
philes for the construction of variably substituted dienes and
aromatic ring systems. Treatment with methyl iodide afforded
the methyl substituted diene 26 in 92% yield. An analogous
reaction in which the quenching agent was trimethyl borate
provided the borinic acid 28, while the parallel treatment
with iodine gave the iodo-alcohol 29 in 73% yield. To
prepare the aromatic compound 30, the diene 28 was treated
with DDQ in refluxing toluene. The iodo-benzaldehyde 31
was generated from 29 in 86% yield after treatment with
excess manganese dioxide in refluxing toluene.
Peracid oxidation (m-CPBA) of aldehyde 31 led, via the
formate (hydrolyzed directly with TsOH), to the iodo-phenol
33, and oxidation in buffered sodium chlorite afforded the
iodobenzoic acid 32. We attempted to convert this ortho-
iodobenzoic acid into organic solvent soluble IBX and Dess-
Martin periodinanes (not illustrated) for the potential kinetic
oxidative resolution of alcohols and asymmetric oxidation
of sulfides. Unfortunately, despite considerable effort, the
solubility inherent in these molecules precluded their suc-
cessful conversion to the periodinanes. Another factor may
be the potential nonbonded interaction that develops between
the periodinane and the adjacent bridgehead methyl group
in the desired product.
Upon treatment of the pinene triene 15 in a sealed tube at
150 °C in toluene, an inseparable mixture of regioisomeric
cyclohexadiene isomers of type 20 was produced (Scheme
2). Additional exposure to toluene (110 °C) containing DDQ
afforded the aldehyde 23. In a similar manner, the chelate
of type 19 was converted directly to the benzyl alcohol 21
after 16 h of heating in toluene/THF (5:1). In some cases, it
was preferable to protect the alcohol in order to minimize
decomposition. Consequently, alcohol 18 was protected as
the methyl ether 22. The methyl ether acts as a transient
protecting group due to its removal by DDQ in the next step.
A related pattern of inseparable diene isomers 25 was
observed when 22 was heated in a sealed tube (toluene, 150
(8) (a) Voigt, K.; von Zezschwitz, P.; Rosauer, K.; Lansky, A.; Adams,
A.; Reiser, O.; de Meijere, A. Eur. J. Org. Chem. 1998, 1521, 1. (b)
Sunnemann, H. W.; de Meijere, A. Angew. Chem., Int. Ed. 2004, 43, 895.
Org. Lett., Vol. 7, No. 5, 2005
769

as 39b cyclized readily in refluxing toluene with DDQ. This
series afforded the aldehyde 44 directly due to methyl ether
cleavage and concomitant oxidation, as illustrated in Scheme
4.
Scheme 4. Fused Ring Systems: Representative Cyclizations
and Aromatizations
In summary, we have developed a versatile aryl annulation
procedure from the enol triflates of various cyclic ketones
via vinylmagnesium chloride addition to the derived prop-
argyl alcohol, followed by 6-π-electrocyclization to generate
the substituted benzene ring after oxidation. In several cases,
if a benzaldehyde is the objective, the complete carbometa-
lation-annulation-oxidation sequence may be conducted in
one reaction flask.
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
for financial support of this research. M. D. Clay thanks
NSERC, as well as OGS for Graduate Scholarships.
The potential of our annulation strategy for attachment of
an aryl ring to cyclohexanones was also examined. These
examples all stopped at the triene stage (Table 2) and
required further heating to effect the electrocyclizations. The
cyclohexanone-derived triene 42b required rather forcing
conditions in a sealed tube in toluene at 250 °C for 16 h to
achieve a 23% yield of 43. In parallel with the observations
for the bridged ring examples, more rigid compounds such
Supporting Information Available: Experimental details
and spectral characterization for these compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL047602Y
770
Org. Lett., Vol. 7, No. 5, 2005