Intercepting wacker intermediates with arenes: C-H functionalization and dearomatization

Article abstract of DOI:10.1021/ol202881q

An intramolecular cyclization cascade reaction has been developed utilizing a high valent palladium intermediate that generates a carbon-carbon and carbon-oxygen bond in a single transformation. This method provides rapid access to highly functionalized t

Full text of DOI:10.1021/ol202881q

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6320–6323
Intercepting Wacker Intermediates with
Arenes: CÀH Functionalization and
Dearomatization
Bryan S. Matsuura, Allison G. Condie, Ryan C. Buff, Gregory J. Karahalis, and
Corey R. J. Stephenson*
DepartmentofChemistry, BostonUniversity, Boston, Massachusetts 02215, UnitedStates
crjsteph@bu.edu
Received October 25, 2011
ABSTRACT
An intramolecular cyclization cascade reaction has been developed utilizing a high valent palladium intermediate that generates a carbonÀcarbon
and carbonÀoxygen bond in a single transformation. This method provides rapid access to highly functionalized tricyclic scaffolds, including
spirocyclic cyclohexadienones. Good yields and mild conditions are reported with high tolerance toward oxygen and water.
High valent palladium mediated olefin difunctionali-
zations are versatile transformations in organic chemi-
stry. Recent examples of palladium mediated amino
acetoxylations,1 dihydroxylations,2 and diaminations3
have greatly expanded the scope of synthetic methods
available to organic chemists.4 Seminal contributions by
Semmelhackand HegedusexploitedWackerintermediates
generated from PdII-mediated cyclization reactions to
make the key CÀC bonds (Figure 1).5 Methods inspired
by their synthetic strategies have been successful in gen-
erating a high degree of molecular diversity6 and found
application in natural product synthesis.7 Although CÀC
bond forming olefin difunctionalizations have been well
developed in the context of Heck8 and π-allyl palladium9
chemistry, high valent palladium mediated CÀC bond
(5) (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem.
Soc. 1976, 98, 2674. (b) Hayashi, T.; Hegedus, L. S. J. Am. Chem. Soc.
1977, 99, 7093. (c) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman,
E. L. J. Am. Chem. Soc. 1978, 100, 5800. (d) Semmelhack, M. F.;
Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496. (e) Semmelhack, M. F.;
Zhang, N. J. Org. Chem. 1989, 54, 4483. (f) Semmelhack, M. F.; Epa,
W. R. Tetrahedron Lett. 1993, 34, 7205. (g) Wolfe, J. P.; Rossi, M. A.
J. Am. Chem. Soc. 2004, 126, 1620. (h) Lira, R.; Wolfe, J. P.
J. Am. Chem. Soc. 2004, 126, 13906. (i) Leathen, M. L.; Rosen, B. R.;
Wolfe, J. P. J. Org. Chem. 2009, 74, 5107. (j) Rosen, B. R.; Ney, J. E.;Wolfe,
J. P. J. Org. Chem. 2010, 75, 2756. (k) Bloome, K. S.; Alexanian, E. J. J. Am.
Chem. Soc. 2010, 132, 12823.
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2005, 127, 7690. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128,
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Yang, Z.; Shi, Z. J. Chem. Soc. Rev. 2010, 39, 712.
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r
10.1021/ol202881q
Published on Web 11/09/2011
2011 American Chemical Society

Figure 2. Natural product synthesis as inspiration for methods
development.
ineffective toward oxidative dearomatization, often causing
extensive substrate oligomerization or decomposition.12,13
Consequently, we decided to address these shortcomings
using a PdII/IV catalytic cycle.
Figure 1. Pd-mediated oxidative CÀC bond forming cyclizations.
forming alkene difunctionalization has not been studied to
the same extent.
As illustrated in Table 1, our initial results provided only
trace quantities of the desired dearomatized cyclohexa-
dienes (Table 1, entries 1À3). After extensive optimization,
the electrophilicfluorination reagent Selectfluor was found
to provide the best results, affording spirocycle 2 in 43%
yield as a single diastereoisomer. Treating substrate 1 with
oxidants in the absence of a PdII source (Table 1, entries 5
and 6) afforded only the oxygen trapping product 2a. We
proceeded to screen for the optimal nucleopalladation
coupling partners other than pendant alcohols (Figure 3).
Unfortunately, carboxylic acid and cyanohydrin deriva-
tives (see 3 and 4, respectively, for representative examples)
gave comparable yields without providing deeper insight
into reaction optimization alternatives. In spite of low
isolated yields, this transformation remains a useful method
of generating complex polycyclic compounds and represents
a unique example of a high valent palladium-mediated
CÀC bond forming oxidative dearomatization reaction.14
We subsequently explored the effects of different sub-
stituents on the arene moiety. In the event, we decided to
investigate substrates with pendant carboxylic acids due to
their known ability to participate in nucleopalladation
processes. Thus, upon exposure of 7 to our reaction
conditions, we isolated the desired adduct 8a in only
Recently, the Michael group reported an intermolecular
carboamination reaction using Pd(OAc)2 and N-fluoro-
benzenesulfonimide (NFSI) to synthesize substituted pyr-
rolidines from tethered amino alkenes in moderate to high
yields.10 Another report by Waser and co-workers de-
scribed an intermolecular oxyalkynylation of olefins em-
ploying an alkynyl λ3-iodane oxidant, which enabled them
to generate substituted tetrahydrofuran and benzofuran
derivatives.4f Furthermore, the groups of Kita12b,dÀf and
Swenton12a,c have synthesized spirocyclohexadieneones
through chemical and electrochemical dearomatization
of phenols, respectively. Hypervalent iodine or anodic
oxidations are most effective in forging carbonÀheteroatom
bonds, although there are a few reported examples of CÀC
bond forming dearomatizations that produce ipso substi-
tuted dienones. With this in mind, we envisioned using the
increased reactivity of high valent palladium obtained by
oxidizing Wacker intermediates to allow for the formation
of multiple bonds in a single operation, without the need to
prefunctionalize our substrates.
Our research in transition metal catalyzed olefin
difunctionalization was initiated during efforts direc-
ted toward the synthesis of the terpenoid antibiotic
platensimycin.11 The key transformation in our propo-
sal was an oxidative dearomatization of a para-sub-
stituted phenol to form a spirocyclic cyclohexadienone
as a precursor for a radical conjugate addition to
efficiently provide the bicyclic fragment of platensimy-
cin (Figure 2).
(12) For oxidative cyclizations of phenols: (a) Morrow, G. W.;
Swenton, J. S. Tetrahedron Lett. 1987, 28, 5445. (b) Tamura, Y.; Yakura,
T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927. (c) Callinan, A.;
Chen, Y.; Morrow, G. W.; Swenton, J. S. Tetrahedron Lett. 1990, 31,
4551. (d) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T.
J. Org. Chem. 1991, 56, 435. (e) Dohi, T.; Maruyama, A.; Minamitsuji,
Y.; Takenaga, N.; Kita, Y. Chem. Commun. 2007, 1224. (f) Dohi, T.;
Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka,
H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787.
(13) For CÀC bond forming dearomatization reactions, see:
(a) Moriarty, R. M.; Prakash, O.; Duncan, M. P.; Vaid, R. K.; Musal-
lam, H. A. J. Org. Chem. 1987, 52, 150. (b) Kita, Y.; Tohma, H.; Inagaki,
M.; Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992, 114, 2175. (c)
Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray, J. P. J. Chem. Soc.,
Perkin Trans. 1 1999, 1251. (d) Zhang, X.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 12230. (e) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921.
(f) Andrez, J. C.; Giroux, M. A.; Lucien, J.; Canesi, S. Org. Lett. 2010,
12, 4368. (g) Desjardins, S.; Andrez, J.-S.; Canesi, S. Org. Lett. 2011, 13,
3406.
Unfortunately, hypervalent iodine, halocyclization, or
conventional Wacker cyclization conditions proved to be
(10) (a) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E.
J. Am. Chem. Soc. 2009, 131, 9488. (b) Sibbald, P. A.; Rosewall, C. F.;
Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
(11) (a) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.;
Galgoci, A.; Painter, R.; Parthasarathy, G.; Tang, Y. S.; Cummings, R.;
Ha, S.; Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.;
Zhang, C.; Hernandez, L.; Alloco, J.; Basilio, A.; Tormo, J. R.; Genilloud,
O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.; Michael, B.; Felcetto, T.;
Gill, C.; Silver, L. L.; Hermes, J. D.; Bartizal, K.; Barret, J.; Schmatz, D.;
Becker, J. W.; Cully, D.; Singh, S. B. Nature 2006, 441, 358. (b) Saleem, M.;
Hussain, H.; Ahmed, I.; van Ree, T.; Krohn, K. Nat. Prod. Rep. 2011,
28, 1534.
(14) For palladium mediated arene dearomatization reactions, see:
(a) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.;
ꢀ
Hamada, Y. Org. Lett. 2010, 12, 5020. (b) Rousseaux, S.; Garcia-Fortanet,
J.; Angel Del Aguila Sanchez, M.; Buchwald, S. L. J. Am. Chem. Soc. 2011,
133, 9282.
Org. Lett., Vol. 13, No. 23, 2011
6321

to substrate 5 afforded tricyclic compound 6 in excellent
yield (92%) with a 1.75:1 diastereomeric ratio (Table 2,
entry 1). High conversions were observed for electron-rich
and -neutral substrates providing the tricyclic products in
good to moderate yields (Table 1). Substrates that formed
smaller fused ring systems (entries 3À9) showed a consis-
tent decline in yield compared with entries 1 and 2. Further
analysis of the reaction mixture obtained upon conversion
of 11 to 12 (Table 2, entry 4) indicated that the attenuated
yield was due to the competitive formation of pyranone
(24) and olefin acetoxylation (23) side products. Preven-
tion of these side products proved challenging; however
they provided some mechanistic insight for this reaction
(vide infra).
A plausible catalytic cycle is outlined in Figure 4.
Beginning with the CÀH functionalization pathway
(Section I, Path A), PdII coordinates to the olefin of the
substrate and undergoes an oxypalladation to form a
Wacker intermediate. A PdII CÀH metalation, followed
by oxidation by PhI(OAc)2 provides a palladacycle that
undergoes reductive elimination, producing the CÀH in-
sertion product.17 For phenols, the catalytic cycle proceeds
through a dearomatization pathway (Path B). In turn, the
Wacker intermediate undergoes oxidation by Selectfluor,
generating the highly electrophilic alkylpalladiumIV inter-
mediate. This undergoes a direct reductive nucleophilic
substitution by the phenol to form the spirocyclohexadie-
none product.
With the proposed mechanistic hypothesis established,
we began to formulate an explanation for the unavoidable
formation of the olefin acetoxylation (23) and pyranone
(24) side products (Figure 4, Section II). Using substrate 11
as a representative example, we hypothesized that 23 and
24 were generated as a consequence of the relative config-
uration of the Wacker intermediate formed during the
initial nucleopalladation step, which can result in either a
trans or cis substituted lactone (intermediates A and B,
Figure 4, Section II). Since the subsequent reductive
elimination of B would yield a highly strained trans-fused
[3.3.0] bicyclic system (compound C),18 intermediate B can
undergo a MeerweinÀWagner shift19,20 to form an oxo-
carbenium intermediate with concomitant trapping by
Table 1. Optimization for Oxidative Dearomatization
entry
1
conditions
yield of 2a
Pd(OAc)2 (10 mol %), PhI(OAc)2 (2.0 equiv),
PhMe, rt, 12 h
0%
2
3
4
Pd(OAc)2 (10 mol %), PhI(OAc)2 (2.0 equiv),
CH3CN, rt, 12 h
5À10%
N. R.
43%
Pd(OAc)2 (10 mol %), PhI=O, (3.0 equiv),
CH3CN, rt, 12 h
Pd(OAc)2 (10 mol %), Selectfluor (2.0 equiv),
CH3CN, rt, 12 h
5
6
PhI(OAc)2 (1.1 equiv), CH3CN
PhI(O2CCF3)2 (1.1 equiv), (F3C)2CHOH
0%b
0%b
a Isolated yield (%) after purification by chromatography on SiO2.
b 2a was the only isolable product.
20% yield. Further analysis of the reaction mixture re-
vealed CÀH insertion product 8 to be the major product
(isolated in 68% yield). Intrigued by the crossover between
oxidative dearomatization and CÀH functionalization, we
sought to explore the possibility of utilizing the ω-unsatu-
rated carboxylic acids for oxidative CÀH functionaliza-
tion reactions. We sought to favor this transformation by
varying the substitution pattern and electronic properties
of the arene and to suppress the formation of dearomatiza-
tion products.15,16
Figure 3. Examples of Wacker cyclization/dearomatization.
(17) The oxidation of the alkylpalladium complex may occur prior to
CÀH metallation. Control experiments on substrate 5 revealed the
necessity of a high valent palladium cycle. Stoichiometric Pd(OAc)2 or
catalytic variants using CuII salts failed to produce any of 6. For an
example of a PdIV mediated CÀH metallation, see: Racowski, J. M.;
Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2011, DOI: 10.1021/
ja2051099.
(18) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; John Murdzek, Ed.; University Science Books: CA, 2006; p 111.
(19) (a) Boontanonda, P.; Grigg, R. J. Chem. Soc., Chem. Commun.
1977, 583. (b) Clark, G. R.; Thiensathit, S. Tetrahedron Lett. 1985, 26,
2503.
Upon screening oxidants and palladium complexes to
promote CÀH functionalization (not shown), it was found
that PhI(OAc)2 (2 equiv) and Pd(OAc)2 (10 mol %) in
CH3CN provided optimal conditions for this transforma-
tion. These reactions were unsucessful when performed
under traditional Pd0/II wacker oxidation conditions
(stoichiometric and catalytic). Applying these conditions
(20) This byproduct may also be the result of β-carbon elimination/
endo cyclization. For examples of β-carbon elimination, see: (a) Nishimura,
T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 2645. (b) Nishimura,
T.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 11010. For a review on the
subject, see:(c) Leemans, K.; D’hooge, M.; De Kimpe, N. Chem. Rev. 2011,
111, 3268.
(15) (a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 7134. (b) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem.,
Int. Ed. 2008, 47, 5993. (c) Wang, X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 7520.
(16) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2011, 50, 1478.
(21) When Selectfluor was used as the stoichiometric oxidant, there
was extensive decomposition of the starting material.
6322
Org. Lett., Vol. 13, No. 23, 2011

acetate (i.e., 22). As an alternative pathway, intermediateB
can also undergo acetoxylation to form acetate 23.
To further support our mechanistic hypothesis, we
exposed acid 11 to our reaction conditions, using the
deficient oxidant PhI(O2CCF3)2 as the stoichiometric
underwent oxidative dearomatization in moderate yields,
an unprecedented transformation in high valent palladium
catalysis. Further investigations on the mechanism, scope,
and applications of this reaction, especially in the context of
the oxidative dearomatization, are currently being explored.
Table 2. Substrate Scope for CÀH Functionalizationa
Figure 4. Proposed mechanisms for difunctionalization cascade
and degradation pathways.
a Reaction conditions: Pd(OAc)2 (10 mol %), PhI(OAc)2 (2.0 equiv),
CH3CN, rt, 12 h. b Isolated yield (%) after purification by chromato-
graphy on SiO2. c dr 1.75:1. d dr 1.3:1. e See ref 21.
Acknowledgment. The authors are grateful to Dr. David
Freeman (Boston University) for helpful suggestions and
comments on this manuscript. Financial support for this
research from the NIH-NIGMS (R01-GM096129), Alfred P.
Sloan Foundation, Amgen, Boehringer Ingelheim, and
Boston University is gratefully acknowledged. G.J.K.
thanks the Boston University Undergraduate Research
Program for research support. NMR (CHE-0619339)
and MS (CHE-0443618) facilities at BU are supported
by the NSF.
oxidant. As a result, the trifluoroacetate derivative of pyra-
none 24 was isolated as the major product in 30% yield
along with trace amounts of the trifluoroacetate deri-
vativeof 23 which was also observed. We speculate that the
poor level of substrate-directed diastereoselectivity in the
nucleopalladation step is the most likely explanation for
the low overall yield of the reaction (Table 2, entries 3À9),
which is consistent with the observed side product.
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have developed a mild, CÀC bond
forming olefin difunctionalization methodology employ-
ing a PdII/IVcatalytic cycle. In addition, phenolic substrates
Org. Lett., Vol. 13, No. 23, 2011
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