Palladium(0)-catalyzed arylative dearomatization of phenols

Article abstract of DOI:10.1021/ja203644q

The palladium-catalyzed arylative dearomatization of phenols to yield spirocyclohexadienone products in good to excellent yields has been developed. Preliminary results demonstrate that the formation of the spirocyclic all-carbon quaternary center can be accomplished with high levels of enantiocontrol (up to 91% ee).

Full text of DOI:10.1021/ja203644q

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Palladium(0)-Catalyzed Arylative Dearomatization of Phenols
Sophie Rousseaux, Jorge García-Fortanet, Miguel Angel Del Aguila Sanchez, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
Scheme 1. Methods for Arylation and/or Dearomatization of
Phenols
ABSTRACT: The palladium-catalyzed arylative dearoma-
tization of phenols to yield spirocyclohexadienone products
in good to excellent yields has been developed. Preliminary
results demonstrate that the formation of the spirocyclic all-
carbon quaternary center can be accomplished with high
levels of enantiocontrol (up to 91% ee).
he dearomatization of aromatic compounds has been widely
T
recognized as a powerful transformation for the generation of
high levels of molecular complexity from simple planar starting
materials.1,2 Of particular interest is the dearomatization of phenols
to cyclohexadienone derivatives. This is in part due to the fact that
this process is involved in the biosynthesis of natural products.3
However, the development of synthetic methods to effect this
transformation has been challenging because of the stability of the
aromatic starting material, problems with a lack of chemoselectivity,
and the potential for undesired product rearomatization. Previous
reports have demonstrated that the dearomatization of phenols
occurs in the presence of main group p-block arylating agents,
providing mixtures of ortho- and para-arylated cyclohexadienones
as well as diaryl ethers (Scheme 1a).4 While these transformations
are important, the use of toxic arylating reagents in some cases and
the product mixtures that are often obtained limit their synthetic
utility. The oxidation of phenols using stoichiometric quantities of
relatively strong oxidants in the presence of nucleophilic arenes can
also lead to similar products.5 We felt that there remained a need to
develop milder, catalytic conditions to effect this type of transfor-
mation in a highly chemoselective fashion.
effective for CÀC bond-forming processes. With Pd(dba)2 (3mol%),
XPhos (4.5 mol %), and KOt-Bu (1.5 equiv) in THF at 100 °C,
product 2a was obtained in 6% yield (Table 1, entry 1). An
evaluation of bases revealed a significant increase in yield to 23% when
K3PO4 was employed (entry 2). A further improvement to 34% was
obtained with K2CO3 (entry 3).14 Switching to [Pd(cinnamyl)Cl]2
as the palladium source led to an additional augmentation to 48%, and
the yield was further enhanced to 77% when the reaction was
performed at 120 °C in 1,4-dioxane (entries 4 and 5). Finally, an
evaluation of biarylphosphine ligands (entries 5À8) revealed L1
to be optimal, providing 2a in 93% GC yield.
Illustrative examples of the scope of this dearomatization pro-
tocol with respect to substitution on the phenol and benzene rings
and to the length of the tether are shown in Table 2. Submitting 1a
to [Pd(cinnamyl)Cl]2 (1 mol %), L1 (3 mol %), and K2CO3
(1.5 equiv) in dioxane at 120 °C for 16 h provided 2a in 81%
isolated yield. Additionally, this transformation could be performed
on a 10 mmol scale, yielding 2a in 91%. Substitution at the position
ortho to the hydroxyl group was well-tolerated, as exemplified by
2b and 2c, which were obtained in 91 and 90% yield, respectively.
Also, substrates bearing substituents ortho to the carbon undergoing
rehybridization were compatible, providing the corresponding
While transition-metal catalysis offers an efficient route to diaryl
ethers via phenol O-arylation and biaryls via direct C-arylation
(Scheme 1b),6,7 complementary dearomatization via C-arylation
remains underdeveloped.8,9 Herein we describe a Pd(0)-catalyzed
protocol for the dearomatization of phenols10 that provides spiro-
cyclic compounds, an important motif in natural products and
material science (Scheme 1c).11 Notably, this transformation is
mechanistically unique in comparison with traditional oxidative
dearomatization processes involving attack of an “activated” electro-
philic phenol by a nucleophile (Scheme 2).1e,f,3 Therefore, this
system offers new opportunities for enantioinduction using asym-
metric catalysis.12,13
The success of this dearomatization strategy relies on the ability
to avoid diaryl ether formation arising from a competitive inter-
molecular CÀO cross-coupling reaction and to favor reductive
elimination of the product from palladacycle I over rearomatiza-
tionprocesses (Scheme 2). With this inmind, weinitially looked at
catalyst systems that are inefficient for CÀO cross-coupling and
Received: April 20, 2011
Published: May 25, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja203644q J. Am. Chem. Soc. 2011, 133, 9282–9285
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Scheme 2. Strategy for Pd(0)-Catalyzed Dearomatization of
Phenols and Potential Challenges
Table 2. Scope of the Pd-Catalyzed Dearomatization of
Phenolsa,b
Table 1. Optimization of the Reaction Conditionsa
Pd
T
yield
entry
(mol %)
ligand
base solvent (°C) (%)b
1
2
3
4
5
6
7
8
Pd(dba)2 (3)
XPhos KOt-Bu THF
XPhos K3PO4 THF
XPhos K2CO3 THF
100
6
Pd(dba)2 (3)
Pd(dba)2 (3)
100 23
100 34
100 48
[Pd(cinnamyl)Cl]2 (1.5) XPhos K2CO3 THF
[Pd(cinnamyl)Cl]2 (1)
[Pd(cinnamyl)Cl]2 (1)
[Pd(cinnamyl)Cl]2 (1)
[Pd(cinnamyl)Cl]2 (1)
XPhos K2CO3 dioxane 120 77
SPhos K2CO3 dioxane 120 43
RuPhos K2CO3 dioxane 120 50
L1
K2CO3 dioxane 120 93
a Reaction conditions: [Pd(cinnamyl)Cl]2 (1 mol %), L1 (3 mol %),
K2CO3 (1.5 equiv), and phenol (1.0 mmol) in 1,4-dioxane (5 mL) at
120 °C for 16 h. b Isolated yields (averages of two runs). c Reaction was
performed on 10 mmol scale. d Concentration = 0.05 M. e [Pd-
(cinnamyl)Cl]2 (2 mol %), L1 (6 mol %). f [Pd(cinnamyl)Cl]2
(2.5 mol %), L1 (7.5 mol %).
a Reaction conditions: Pd source (x mol %), ligand (1.5:1 ligand:
Pd ratio), base (1.5 equiv), and 1a (0.1 mmol) in solvent (0.2 M)
at the indicated temperature for 16 h. b GC yield using dodecane
as an internal standard.
tether between the two aromatic rings could be lengthened
without affecting product formation, as seen with tetralin deri-
vative 2n, which was isolated in 84% yield. Finally, the dear-
omatization of ortho-substituted phenol 1o was examined (eq 1).
Diaryl ether 3 resulting from intramolecular CÀO cross-
coupling was preferentially formed over the spirocyclohexa-2,
4-dienone product.
cyclohexadienones 2dÀf in good yields. It should be noted that
because of the importance of its nucleophilic character in the
reaction, substitution on the phenol ring is at present limited to
electron-neutral or -donating groups. With respect to the aryl
bromide reaction component, electron-neutral (2g and 2m) and
-donating(2h) groups were well-tolerated. Substrates with electron-
withdrawing substituents proved to be more challenging and
required either higher dilution (2j) or increased catalyst loading
(2k). Chlorine-containing products 2i and 2l were obtained in
good yields, providing a useful synthetic handle for further func-
tionalization of the spirocyclohexadienone product. The carbon
We next focused our attention on the development of an
asymmetric version of this reaction, the products of which would
be cyclohexadienones bearing an enantioenriched all-carbon qua-
ternary stereocenter.15 Despite the importance of this motif in
natural product synthesis, few asymmetric methods for its
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Scheme 3. Asymmetric Dearomatization of Phenolsa,b,c
’ ACKNOWLEDGMENT
We thank the National Institutes of Health for financial
support of this work (Grant GM46059). S.R. thanks NSERC
for a CGS-D Postgraduate Fellowship and an MSFSS Award. M.
A.D.A.S. thanks the Spanish MEC for a doctoral fellowship. The
Varian 300 MHz NMR spectrometer used for a portion of this
work was purchased with funds from the National Science
Foundation (Grants CHE 9808061 and DBI 9729592). We also
thank a reviewer for bringing ref 8 to our attention.
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a Reaction conditions: Pd(OAc)2 (4 mol %), H2O (16 mol %), L2 or L3
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adienones bearing all-carbon quaternary centers in good to
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) For a review of the synthesis of spirocyclics, see: Kotha, S.; Deb,
A. C.; Lahiri, K.; Manivanna, E. Synthesis 2009, 165.
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Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.;
Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008,
’ AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
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47, 3787. (b) Up to 50% ee: Quideau, S.; Lyvinec, G.; Marguerit, M.;
Bathany, K.; Ozanne-Beaudenon, A.; Buffeteau, T.; Cavagnat, D.;
Chꢀenꢀedꢀe, A. Angew. Chem., Int. Ed. 2009, 48, 4605. (c) Up to 77% ee:
Boppisetti, J. K.; Birman, V. B. Org. Lett. 2009, 11, 1221. (d) Up to
92% ee: Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010,
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(18) See the Supporting Information for additional details.
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Org. Lett. 2002, 4, 999.
(21) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett.
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