Palladium-catalyzed reactions of cyclohexadienones: Regioselective cyclizations triggered by alkyne acetoxylation

Article abstract of DOI:10.1021/ol901642w

Regioselective cyclizations of alkyne-tethered cyclohexadienones can be accomplished under palladium catalysis. The cyclization involves an initial Pd-mediated acetoxylation of the alkyne, followed by migratory insertion and protonolysis of the resulting

Full text of DOI:10.1021/ol901642w

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3998-4000
Palladium-Catalyzed Reactions of
Cyclohexadienones: Regioselective
Cyclizations Triggered by Alkyne
Acetoxylation
Rodolfo Tello-Aburto and Andrew M. Harned*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
harned@umn.edu
Received July 18, 2009
ABSTRACT
Regioselective cyclizations of alkyne-tethered cyclohexadienones can be accomplished under palladium catalysis. The cyclization involves an
initial Pd-mediated acetoxylation of the alkyne, followed by migratory insertion and protonolysis of the resulting palladium enolate. The predictable
regioselectivity of these atom-economical and stereoselective reactions is influenced by developing steric interactions during migratory insertion
of a vinyl palladium intermediate.
As a class, cyclohexa-2,5-dienones have proven to be
excellent motifs for natural product synthesis.1,2 While
several methodology studies have examined the reactivity
of these compounds,3 little work has been done exploring
the use of these substrates in catalytic transformations other
than hydrogenations.4-7 There are several aspects of cyclo-
hexadienones that make them particularly attractive substrates
for catalytic processes. First, they can be synthesized in a
modular fashion allowing for the facile tethering of various
“reactive” partners (e.g., olefins, alkynes, aryl halides).
Second, the electronics of the dienones allow for predictable
outcomes of the reactions of interest. Third, by judicious
substitution around the ring, one should be able to direct
the reaction to a particular olefin based on either electronics
or sterics. Finally, by tethering the reactive partner to the
fully substituted carbon atom, stereoselective reactions can
be realized through either substrate or reagent control. We
(1) Reviews: (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV.
2004, 104, 1383–1429. (b) Rodr´ıguez, S.; Wipf, P. Synthesis 2004, 2767–
2783. (c) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang,
J.; Chai, D. Synthesis 2007, 3759–3772. (d) Quideau, S.; Pouyse´gu, L.;
Deffieux, D. Synlett 2008, 467–495
.
(2) Recent examples: (a) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew.
Chem., Int. Ed. 2002, 41, 2194–2197. (b) Lei, X.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2006, 128, 14790–14791. (c) Mejorado, L. H.; Pettus, T. R. R.
J. Am. Chem. Soc. 2006, 128, 15625–15631. (d) You, Z.; Hoveyda, A. H.;
Snapper, M. L. Angew. Chem., Int. Ed. 2009, 48, 547–550. (e) Wenderski,
(5) Copper-catalyzed conjugate additions: (a) Takemoto, Y.; Kuraoka,
S.; Hamaue, N.; Iwata, C. Tetrahedron: Asymmetry 1996, 7, 993–996. (b)
Takemoto, Y.; Kuraoka, S.; Hamaue, N.; Aoe, K.; Hiramatsu, H.; Iwata,
C. Tetrahedron 1996, 52, 14177–14188. (c) Imbos, R.; Brilman, M. H. G.;
Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1, 623–625. (d) Imbos, R.;
T. A.; Huang, S.; Pettus, T. R. R. J. Org. Chem. 2009, 74, 4104–4109
.
(3) Selected examples: (a) Fringuelli, F.; Minuti, L.; Pizzo, F.; Taticchi,
A.; Halls, T. D. J.; Wenkert, E. J. Org. Chem. 1983, 48, 1810–1813. (b)
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678–11688. (c) Wang,
J.; Pettus, L. H.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45, 1793–1796.
(d) Hoarau, C.; Pettus, T. R. R. Org. Lett. 2006, 8, 2843–2846. (e) Varin,
M.; Chiaroni, A.; Lallemand, J.-Y.; Iorga, B.; Guillou, C. J. Org. Chem.
2007, 72, 6421–6426. (f) Clive, D. L. J.; Sunasee, R.; Chen, Z. Org. Biomol.
Chem. 2008, 6, 2434–2441. (g) Merino, E.; Melo, R. P. A.; Ortega-Guerra,
Minnaard, A. J.; Feringa, B. L. Tetrahedron 2001, 57, 2485–2489
(6) Symmetry-breaking intramolecular Heck reaction: Imbos, R.; Min-
naard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 184–185
.
.
(7) Symmetry-breaking organocatalytic reactions: (a) Hayashi, Y.; Gotoh,
H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc.
2005, 127, 16028–16029. (b) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006,
128, 2552–2553. (c) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J.
M.; Ribagorda, M.; Carren˜o, M. C. J. Org. Chem. 2009, 74, 2824–2831
(4) For a hydrogenation example, see: Mejorado, L. H.; Hoarau, C.;
Pettus, T. R. R. Org. Lett. 2004, 6, 1535–1538
.
.
J. Am. Chem. Soc. 2008, 130, 404–405.
10.1021/ol901642w CCC: $40.75
Published on Web 08/11/2009
 2009 American Chemical Society

herein report our initial foray into the area of transition metal-
catalyzed transformations of cyclohexadienones and that the
regioselectivity of these reactions proceeds in a predictable
manner.
as a single regioisomer. This result could also be extended
to the formation of carbocyclic products 3c and 3d. We were
curious as to whether the regioselectivity observed with
2b-d was due to electronics or sterics, so methyl-substituted
substrates were examined. Interestingly, the product distribu-
tion appeared to be dependent on the position of the methyl
group. In the case of an “ortho” methyl group,11 only one
cyclized product was observed. However, a “meta” methyl
group resulted in a 1.25:1 mixture of regioisomeric products.
We hypothesized that cyclohexadienones with tethered
alkynes would serve as excellent substrates for Pd-catalyzed
cyclizations.8 We began our investigation by heating 1 with 5
mol % Pd(OAc)2 in AcOH, both with and without bipy as a
ligand (Scheme 1). While these experiments resulted in
complete consumption of starting material, low yields of
unidentifiable reaction products were obtained. Believing that
the terminal alkyne was responsible for the untoward reactivity,
we constructed substrate 2a. When this alkyne was treated with
5 mol % Pd(OAc)2 in AcOH at 80 °C, the NMR and TLC
were very messy. To our delight, when 10 mol % of bipy was
used as a ligand, a remarkably clean NMR was obtained on
the crude reaction mixture and compound 3a was isolated in
80% yield.9 Attempting to promote the reaction with Pd(dpp-
b)(OTf)2 only resulted in decomposition.10
Scheme 2. Investigating Ring Substitution
Scheme 1. Initial Cyclization Attempts
Because the previously reported catalytic transforma-
tions all involved a symmetry-breaking event,5-7 we felt
it would be important for future reaction development to
determine how the regioselectivity of the cyclization is
affected by nonsymmetric substitution around the cyclo-
hexadienone (Scheme 2). We were pleased to find that
bromosubstituted dienone 2b could be cyclized to give 3b
(8) (a) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604–7605. (b)
Zhang, Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676–7684. (c) Zhao,
L.; Lu, X.; Xu, W. J. Org. Chem. 2005, 70, 4059–4063.
Unfortunately, substrates with acetylenic esters or ketones
could not be persuaded to cyclize. This was surprising
considering other literature reports of Pd-catalyzed cyclative
acetoxylations of propiolates.8a,b,12 We were also unable to
cyclize substrates containing an extra methylene unit in the
tether. In both cases only products arising from addition of
AcOH across the alkyne were observed.
We believe that these reactions proceed through a
mechanism similar to that proposed by Lu and co-workers
for the cyclization of enynes (Scheme 3).8 Coordination
of the Pd(II) catalyst to 2 will activate the alkyne for trans-
acetoxypalladation, as shown in 4. Vinyl palladium
intermediate 5 then undergoes syn-migratory insertion into
the less-substituted olefin of the cyclohexadienone, form-
ing palladium enolate 6.13 Protonolysis affords 3 and
regenerates the catalyst. The tolerance of the reaction to
brominated substrates provides evidence that the palladium
remains in the +2 oxidation state throughout the reaction.
(9) Along with the isolated products, some reactions also yielded small
amounts of an uncyclized product arising from Pd-catalyzed addition of
AcOH across the alkyne as well as what appears to be the product of six
membered ring formation. See Supporting Information for details.
(10) When 2a was heated in the absence of Pd(OAc)2, only starting
material (TLC) was present after 12 h.
(11) We choose to refer to the substitution around the cyclohexadienone
in the same manner as the phenolic precursor.
(12) (a) Welbes, L. L.; Lyons, T. W.; Cychosz, K. A.; Sanford, M. S.
J. Am. Chem. Soc. 2007, 129, 5836–5837. (b) Tong, X.; Beller, M.; Tse,
M. K. J. Am. Chem. Soc. 2007, 129, 4906–4907. (c) Liu, H.; Yu, J.; Wang,
L.; Tong, X. Tetrahedron Lett. 2008, 49, 6924–6928. (d) Tsujihara, T.;
Takenaka, K.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Am. Chem. Soc.
2009, 131, 3452–3453.
(13) Though it is still too early to come to a conclusion, at this time we
prefer an O-bound Pd enolate, rather than a C-bound enolate. See: Keith, J. A.;
Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz,
B. M.; Goddard, W. A., III. J. Am. Chem. Soc. 2007, 129, 11876–11877.
(14) While NOE analysis established the stereochemistry of the allylic
alcohol contained in 7, the unambiguous determination of the methyl ketone
stereochemistry was not possible. Molecular modelling indicates that the
diastereomer shown is the more stable one.
Org. Lett., Vol. 11, No. 17, 2009
3999

Scheme 3
.
Proposed Mechanism
Scheme 5. Testing the Regioselectivity Model
Recognizing that the vinyl acetate generated in these
reactions can function as a latent ketone, we designed a short
sequence to further elaborate the bicyclic products (Scheme
6). Thus enone 3b was cleanly reduced under Luche
conditions and the methyl ketone was revealed to afford 7
as a single diastereomer.14 The vinyl bromide was then
converted to 8 via Suzuki coupling.
The product distributions observed with substrates 2e
and 2f can be rationalized if one considers the possible
reactive conformations of intermediate 5 (Scheme 4). In
the case of cyclohexadienones with ortho substituents (eq
1) the vinyl Pd intermediate can sample conformations
5a and 5b, but will prefer to react via 5a in order to avoid
the developing steric interactions between R1 and Pd. This
allows for the selective formation of one regioisomeric
product. On the other hand, meta-substituted cyclohexa-
dienones (eq 2) will sample conformations 5c and 5d. In
this case, the Pd center is less apt to feel the steric
crowding afforded by R2, thereby giving rise to a mixture
of two regioisomeric products.
Scheme 6. Product Elaboration
Scheme 4. Proposed Regioselectivity Model
In conclusion, we have shown that alkyne-tethered cyclo-
hexadienones are competent substrates for Pd(II)-catalyzed
cyclization reactions. While the regioselectivity of these reac-
tions appears to be governed primarily by developing steric
interactions between the enone and a vinyl Pd intermediate,
electronic effects are very important as well. The knowledge
gained about the regioselectivity of this atom-economical
transformation will be quite useful for designing other transition
metal-catalyzed reactions with cyclohexadienones. We are
currently working to expand the scope of these Pd-catalyzed
reactions and will report these results in due course.
Acknowledgment. We thank the University of Minnesota
and the Department of Chemistry for financial support, Dr.
Letitia Yao (U of MN) for NMR assistance, and Profs. Tom
Hoye (U of MN) and Chris Douglas (U of MN) for helpful
discussions.
To further test this model we attempted the cyclizations of
cyclohexadienones 2g and 2h (Scheme 5). Gratifyingly, the
reactions proceeded to give compounds 3g and 3h as the only
cyclization products. These examples show that a single
substituent at the ortho position of a cyclohexadienone or an
electron-donating substituent at the meta position is sufficient
to shift the 5c/5d equilibrium and generate a single regioisomer.
Supporting Information Available: Experimental pro-
cedures and spectral information are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901642W
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Org. Lett., Vol. 11, No. 17, 2009