Synthesis of catechols from phenols via Pd-catalyzed silanol-directed C-H oxygenation

Article abstract of DOI:10.1021/ja208572v

A silanol-directed, Pd-catalyzed C-H oxygenation of phenols into catechols is presented. This method is highly site selective and general, as it allows for oxygenation of not only electron-neutral but also electron-poor phenols. This method operates via a silanol-directed acetoxylation, followed by a subsequent acid-catalyzed cyclization reaction into a cyclic silicon-protected catechol. A routine desilylation of the silacyle with TBAF uncovers the catechol product.

Full text of DOI:10.1021/ja208572v

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Synthesis of Catechols from Phenols via Pd-Catalyzed Silanol-Directed
CꢀH Oxygenation
Chunhui Huang, Nugzar Ghavtadze, Buddhadeb Chattopadhyay, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S Supporting Information
b
ABSTRACT: A silanol-directed, Pd-catalyzed CꢀH oxyge-
nation of phenols into catechols is presented. This method is
highly site selective and general, as it allows for oxygenation
of not only electron-neutral but also electron-poor phenols.
This method operates via a silanol-directed acetoxylation,
followed by a subsequent acid-catalyzed cyclization reaction
into a cyclic silicon-protected catechol. A routine desilylation
of the silacyle with TBAF uncovers the catechol product.
Figure 1. Catechol-containing natural products and pharmaceuticals.
Table 1. Screening of Reaction Conditions for CꢀO
Cyclization
atechols are widely present in natural products and exten-
C
sively used in nearly every sector of chemical industries.1
They are common structural motifs found in many bioactive
molecules and drugs (Figure 1).1a Due to the regiospecific nature
of biotransformations, synthesis of substituted catechols is pre-
vailed by a fermentation of phenols.2 In addition, a few synthetic
procedures exist for transformation of substituted phenols into
catechols.3 One practical procedure involves ortho-formylation of
phenols followed by a subsequent Dakin oxidation (eq 1, top).3a
However, this process suffers from low selectivity, particularly for
meta-substituted phenols.4 Another method employs oxidation
of phenols to o-quinones and a subsequent reduction of the latter
into catechols (eq 1, bottom). The industrial version of this
method employing H2O2 oxidation usually provides a mixture
of catechol and para-hydroquinone,1a,c while the method using
2-iodoxybenzoic acid (IBX) as an oxidant is restricted to electron-
rich substrates only.3b An improved version of the latter method
somewhat expands the scope of phenols used; however it pro-
vides lower regioselectivity of oxidation.3c Thus, the develop-
ment of efficient, general, and selective methods for conversion
of phenols into catechols is warranted. Herein, we wish to report
a novel approach toward catechols from phenols via the Pd-
catalyzed silanol-directed ortho CꢀH oxygenation (eq 2), a pro-
cess featuring high site selectivity and a broad functional group
tolerance.
yield, %a
entry
1b
Pd cat.
oxidant
solvent
PhMe
2a
2a0
Pd(OPiv)2
PhI(OAc)2
(1.5 equiv)
PhI(OAc)2
(1.5 equiv)
PhI(OAc)2
(1.5 equiv)
PhI(OAc)2
(1.5 equiv)
PhI(OAc)2
(1.5 equiv)
PhI(OAc)2
(1.5 equiv)
PhI(OAc)2
(2.0 equiv)
PhI(OAc)2
(3.0 equiv)
PhI(OAc)2
(1.5 equiv)
43 (74)
2
2
3
4
5
6
7
8
9
Pd(OPiv)2
Pd(OAc)2
Pd(OTf)2
Pd(OPiv)2
Pd(OPiv)2
Pd(OPiv)2
Pd(OPiv)2
none
PhMe
PhMe
PhMe
C6F6
50 (65)
40 (67)
40 (78)
37 (45)
47 (53)
58 (79)
47 (52)
3
3
2
3
PhCF3
PhMe
PhMe
PhMe
14
6
6
0
0
a GC yields against tetradecane as internal standard, brsm yields in the paren-
theses (based on recovered starting material). b Li2CO3 (1 equiv) was added.
Transition-metal-catalyzed directed CꢀH5 oxygenation of
arenes has emerged as one of the most powerful tools for syn-
thesis of phenol derivatives.6 Recently, Yu7 and Liu8 disclosed an
intramolecular hydroxyl group directed Pd-catalyzed oxygenation
Received: September 11, 2011
Published: October 14, 2011
r
2011 American Chemical Society
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|

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Table 2. Scope of Catechol Synthesis
a Isolated yields. b Isolated as bis-acetates by further treatment of the catechols with Ac2O and pyridine in the same pot.12 c Major isomer is shown (34:1).
d PhCF3 was used instead of PhMe, PhI(OAc)2 (1.5 equiv), 120 °C. e 10 mol % Pd(OPiv)2 was used.
of arenes proceeding via a CꢀH activation/CꢀO cyclization
protocol (eq 3). On the other hand, our group has recently
introduced the silanol as a traceless directing group for the Pd-
catalyzed ortho-alkenylation of phenols.9,10Considering the similarity
of the OH functionality in alcohols and in silanols, we hypothesized
that phenoxy silanol 1 could also undergo the Pd-catalyzed CꢀH
activation/CꢀO cyclization reaction into silacycle 2. The latter,
upon subsequent desilylation, would furnish catechol 3.
obtained in the absence of base11 (entry 2). Pd(OPiv)2 was found to
be superior among different palladium sources tested (entries 2ꢀ4).
It was found that, during the reaction, toluene was partially oxidized
into isomeric tolyl acetates. To avoid that, fluorinated solvents were
tested. However, their employmentwasnotbeneficial(entries5ꢀ6).
Employment of larger amounts of PhI(OAc)2 improved the yield to
58% (79% bsrm, entry 7). A further increase of the oxidant resulted
in no improvement (entry 8). Expectedly, there was no reaction
without a palladium catalyst (entry 9).
A routine desilylation of 2a with TBAF quantitatively released
catechol 3a (eq 4). To ease separation, catechol 3a was efficiently
converted into its bis-acetate derivative 4a.
Accordingly, phenoxy silanol 1a was tested in this oxygena-
tion process. The reaction of 1a under the Pd-catalyzed
cyclization conditions developed by Yu7 provided a 43% GC
yield of silacycle 2a along with 3% of an overoxidized bypro-
duct 2a0 (Table 1, entry 1). Gratifyingly, a better yield of 2a was
Next, the scope of the combined semione-pot cyclization/
desilylation procedure from silanols 1 to catechols 3 was
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investigated (Table 2). It was found that substrates with electron-
donating groups typically reacted faster, providing good to
excellent yields of the catechols (3bꢀh). Remarkably, in contrast
to the previous catechol syntheses,3 this transformation demon-
strated excellent site selectivity, directing the newly installed
hydroxyl group to the sterically less hindered CꢀH site. Of note,
estrone highly efficiently and selectively converted into 2-hydro-
xyestrone (3j), an important intermediate of the estrone meta-
bolism in the human body.13
Since the existing synthetic methods are marginally efficient
and/or selective for oxidation of electron-deficient phenols,3 it
was interesting to probe the generality of this new CꢀH func-
tionlization method. Thus, oxygenation of para-ester-substituted
substrate 1k gave a 24% NMR yield of the cyclization product 2k.
Switching to PhCF3 at elevated temperature (120 °C) dramatically
improved the yield of 3k (entry 10). Moreover, phenols possessing
F, Cl, Br, and I reacted well under the modified conditions (entries
11ꢀ15). Substrates possessing aldehyde (1q) and ketone (1r)
functionalities were smoothly oxidized into the corresponding
catechols in moderate yields (entries 16ꢀ17). Phenols possessing
CF3 and CN groups were less efficient providing 35% and 29%
yields, respectively (entries 18ꢀ19). 1- and 2-Naphthol deriva-
tives were also competent reactants in this oxygenation reaction
(entries 20ꢀ21). Remarkably, the silanol-directed oxygenation
reaction allows access to naphthalene-2,3-diol 3v from
2-naphthol derivative 1v (entry 21), demonstrating orthogonal
site selectivity of this method to the existing techniques, which
convert 2-naphthol into regioisomeric naphthalene-1,2-diol 3u.3c
Interestingly, the GC/MS analyses of the oxygenation of 1c at
the early stages of the reaction indicate formation of acetoxylated
product 5c. This was further investigated by a careful monitoring
of the reaction under the standard conditions. The reaction
profile clearly shows the formation and decay of acetoxylated
product 5c during the reaction course (Figure 2). Meanwhile,
increasing amounts of the cyclization product 2c was also ob-
served from the very beginning of the reaction. In order to
understand how the acetoxylated product 5c is transformed into
the silacyle 2c, several experiments with 5c, isolated from the
reaction mixture, have been performed. Thus, simple heating of
5c in PhMe at 100 °C for 12 h gave no reaction. However,
addition of 2 equiv of HOAc led to a full conversion of 5c into 2c
within 10 h. Expectedly, 5c was smoothly transformed into 2c
under the standard reaction conditions. Based on these results,
the transformation of the acetoxylated product 5c into the sila-
cylcle 2c seems to be mediated by HOAc, which is generated
during the reaction course (see Scheme 1).
Figure 2. Reaction profile of PdII-catalyzed silanol-directed CꢀH
acetoxylation and cyclization, picturing the formation and decline of
acetoxylated product 5c as the intermediate in the reaction. Reaction
conditions: 1c (0.2 mmol), Pd(OPiv)2 (0.01 mol), PhI(OAc)2 (0.4
mmol), PhMe (2 mL), 100 °C. The reaction was monitored by GC/MS
with tetradecane as the internal standard.
Scheme 1. Plausible Reaction Pathway
proposed (Scheme 1). First, Pd(OAc)2 (or palladium pivalate)
reacts with silanol 1 producing palladacycle 8,14 in which silanol
acts as a neutral directing group for palladium.15 Next, PdII in
palladacycle 8 is oxidized by PhI(OAc)2 to a higher oxidation
state (PdIV or PdIII)16 to give intermediate 9. The direct CꢀO
reductive cyclization from Pd to form 11 was ruled out by the
18O-labeling studies (vide supra). Instead, a reductive acetoxyla-
tion from 9 regenerates the PdII catalyst and produces the
observed acetoxylated intermediate 10. The latter, presumably
via an acid-catalyzed17 transesterification into 13 and a subse-
quent loss of the 18O labeled acetic acid, produces cyclic silyl-
protected catechol 2.
In summary, we have developed a semione-pot Pd(II)-catalyzed
silanol-directed CꢀH oxygenation of phenols into catechols. This
new method operates via a consecutive CꢀH acetoxylation/acid-
catalyzed transesterification/cyclization sequence. In striking con-
trast to the known alcohol-7 and phenol-directed8 CꢀO cyclization
methods, where the directing group serves as the oxygen source, in
our oxygenation method the oxygen atom of the newly installed
hydroxyl group is delivered by the oxidant. This new method allows
for efficient and site selective construction of substituted catechols,
including electron-defficient catechols, which are not easily acces-
sible via existing synthetic approaches.
In order to verify whether silacyle 2c arises solely through a stepwise
route involving acetoxylated product 5c or it also forms via a direct
CꢀO reductive cyclization,7 the 18O-labeled silanol 6 was subjected to
the standard reaction conditions (eq 5). It was found that 18O-labeled
acetoxylated product 7 was formed and then gradually declined during
the reaction producing the cyclized product 2c with no 18O label
incorporated (eq 5). It deserves mentioning that throughout the
reaction course the abundance of the 18O label in both the starting
silanol 6 and the acetoxylated product 7 remained unchanged.
In light of these observations, a plausible reaction pathway for
the Pd-catalyzed silanol-directed ortho CꢀH oxygenation is
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Journal of the American Chemical Society
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’ ASSOCIATED CONTENT
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’ AUTHOR INFORMATION
Corresponding Author
vlad@uic.edu
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We thank the National Institutes of Health (GM-64444) for
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