Practical C-H functionalization of quinones with boronic acids

Article abstract of DOI:10.1021/ja111152z

A direct functionalization of a variety of quinones with several boronic acids has been developed. This scalable reaction proceeds readily at room temperature in an open flask using inexpensive reagents: catalytic silver(I) nitrate in the presence of a persulfate co-oxidant. The scope with respect to quinones is broad, with a variety of alkyl- and arylboronic acids undergoing efficient cross-coupling. The mechanism is presumed to proceed through a nucleophilic radical addition to the quinone with in situ reoxidation of the resulting dihydroquinone. This method has been applied to complex substrates, including a steroid derivative and a farnesyl natural product.

Full text of DOI:10.1021/ja111152z

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pubs.acs.org/JACS
Practical C-H Functionalization of Quinones with Boronic Acids
Yuta Fujiwara, Victoriano Domingo, Ian B. Seiple, Ryan Gianatassio, Matthew Del Bel, and Phil S. Baran*
Department of Chemistry and Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037, United States
S Supporting Information
b
ABSTRACT: A direct functionalization of a variety of
quinones with several boronic acids has been developed.
This scalable reaction proceeds readily at room temperature
in an open flask using inexpensive reagents: catalytic silver-
(I) nitrate in the presence of a persulfate co-oxidant. The
scope with respect to quinones is broad, with a variety of
alkyl- and arylboronic acids undergoing efficient cross-
coupling. The mechanism is presumed to proceed through
a nucleophilic radical addition to the quinone with in situ
reoxidation of the resulting dihydroquinone. This method
has been applied to complex substrates, including a steroid
derivative and a farnesyl natural product.
Figure 1. (A) Traditional access to functionalized quinones. (B) Initial
findings with respect to arylboronic acid reactivity.
as those using alkyl halides/tin hydrides due to competitive
he quinone moiety possesses electron and proton transfer
reduction of the quinone substrate.2a Aryl radicals also react with
T
properties that are essential to nearly every living organism.1
quinones15 but generally can only be accessed through aryldia-
zonium salts, which can be difficult to synthesize, are unstable,
and have been shown to be explosive. For this reason, a more
general method for the functionalization of quinones is in
demand.
Several groups have made notable advances in the direct C-H
functionalization of quinones in recent years. An early commu-
nication from Itahara showed that palladium(II) acetate could
mediate the coupling of benzoquinone to an arene cosolvent at
reflux.16 Engler used stoichiometric titanium to couple arenes
bearing a cyclopropylsilicon moiety to quinones.17 Palladium has
This privileged class of structures pervades the realms of
chemistry, material science, nanotechnology, and medicine.2
They are embedded in several natural products,2b including
sesquiterpenes,3 the kinamycins,4 and terphenylquinones.5 Ad-
ditionally, there are several drugs and therapeutic leads that
contain the quinone subunit.6 Arylated quinones possess unique
visual and electronic properties that make them useful in
photosynthesis7 and appealing structures to the dye industry.8
Quinones also play a key role in cell respiration.9 It is somewhat
surprising, therefore, that methods for the direct functionaliza-
tion of quinones are sparse.
Several common methods for C-C bond formation on R,β-
unsaturated carbonyls (such as the addition of organometallics
and Heck coupling) fail on quinones due to their unique
electronic properties.2a When these methods do succeed, often
a reoxidation step is necessary to revert to the quinone oxidation
state. These difficulties have prompted chemists to employ other
modes of functionalization, including prehalogenation of the
quinone followed by a palladium-catalyzed cross-coupling (2f1,
Figure 1A)10 or radical coupling on the unfunctionalized quinone
(3f1). However, halogenated quinones are often hard to access
due to chemo- and regioselectivity issues during halogenation
reactions. The ability of quinones to act as ligands and oxidants to
transition metals such as palladium poses additional challenges to
cross-coupling approaches.11 Alternative strategies employing
protected halo-dihydroquinones followed by deprotection12
have proven both lengthy and inefficient, as have Diels-Alder/
functionalization/retro Diels-Alder sequences.13 In the case of
the radical coupling approach, alkyl radicals successfully add to
quinones14 but cannot be generated via common methods such
also been used to couple aryl chlorides to benzo- and naphtho-
::
quinones.18 Csꢀaky and Molina developed a method to directly
arylate naphthoquinones with arylboronic acids in the presence
of palladium/copper catalysis followed by reoxidation with
FeCl3.19 Similarly, Demchuk showed that naphthoquinones
could be functionalized with electron-rich aryltrifluoroborates
under rhodium catalysis and elevated temperatures.20 Most
recently, Renaud has accomplished the coupling of customized
catecholboranes to quinones followed by reoxidation.21 Notably,
arylboronic acids have recently been coupled to electron-defi-
cient olefins in excess via a presumed radical mechanism with
stoichiometric manganese(III) acetate (no quinone examples
given).22 Inspired by our recent discovery of the silver-catalyzed
addition of arylboronic acids to protonated heterocycles,23 and
given the inherent reactivity of quinones with radicals,1,2 it was
reasoned that the same reactive intermediate generated from the
Received: December 11, 2010
Published: February 22, 2011
r
2011 American Chemical Society
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Table 1. Scope of the Coupling of Alkyl- and Arylboronic Acids to 1,4-Benzoquinonea
a Benzoquinone (0.25 mmol), boronic acid (0.375 mmol), AgNO3 (0.05 mmol), K2S2O8 (0.75 mmol), 23 °C, 3-12 h; isolated yields of
chromatographically and spectroscopically pure products displayed, unless otherwise noted. (NH4)2S2O8 is also suitable as an oxidant. b Yield of the
reaction performed on gram-scale with no organic solvent (see Figure 2). c Products were unstable to several isolation conditions but proved relatively
stable in solution after extraction. See Supporting Information for more details.
boronic acid precursors could interact with other electrophiles
such as quinones. In addition, the oxidizing conditions used to
generate radicals from boronic acids would serve the dual role of
reoxidizing the dihydroquinones generated from the radical
addition step.
functionalities. Halogenation at ortho, meta, and para positions
was compatible with the reaction conditions (12 - 17), includ-
ing sensitive aryl iodides (which would be incompatible with many
transition-metal-based methods and could serve as further func-
tional handles). Several other functionalities were tolerated,
includingesters (28), ketones (30), and silanes (31). Alkylboronic
acids also provided coupling products in decent to fair yields for
both linear (34, 36), branched (35), and cyclic (37, 38) systems. It
should be noted that the preparation of alkyl quinones from the
corresponding alkyl Grignard or organolithium reagents delivers
predominantly 1,2-addition products. Some cases where the yields
were moderate are attributed to the highly unstable nature of the
substituted quinone products (e.g., 25, 29, 39).
Despite the high level of generality, there are a few limitations
with regard to substrate scope. Very electron-poor arylboronic
acids (e.g., 39) and very hindered alkylboronic acids (e.g., 40)
reacted poorly. Benzylboronic acids were subject to oxidative
decomposition under the reported conditions and failed to
deliver product. Finally, vinylboronic acids failed to deliver appreci-
able amounts of products.
The reaction was screened against a variety of quinones
employing p-tolylboronic acid, and it was found that the use
of trifluorotoluene (an environmentally benign substitute for
dichloromethane) as a cosolvent was essential to achieve a broad
quinone scope (Table 2). Alkyl-, halogen-, and oxygen-substi-
tuted quinones worked in good yields (41-46). Benzannulated
quinones were also tolerated (47-49). Yields were lower with
trisubstituted quinones (50) and sterically demanding substrates.
Two other notable variations of this mode of reactivity are
shown in Figure 2. Aryltrifluoroborates reacted with identical
efficiency under the standard conditions, albeit with a slightly
lower rate, as demonstrated by the reaction of potassium
This prediction was actualized when 1,4-benzoquinone was
exposed to tolylboronic acid (1.5 equiv) in the presence of
catalytic silver(I) nitrate (0.2 equiv) and potassium persul-
fate (3.0 equiv). Within 3 h, the reaction was complete and
delivered the monoarylated quinone 4 in 72% yield after isolation
(Figure 1B). This reaction is operationally trivial to perform, is
run under air at room temperature, is scalable, and exhibits a
broad substrate scope (vide infra). Since the inherent reactivity of
the quinone is utilized, no prefunctionalization is required. The
affordability of the reaction is dictated by the price of the coupling
partners, as the catalyst (silver(I) nitrate) and stoichiometric oxidant
(potassium persulfate) are very cheap (<$1.00 and <$0.01 per gram,
respectively), a notable advantage over existing methods that require
expensive oxidants and transition metal catalysts. The monoselec-
tivity of these reactions is also notable: no bis-arylation was seen on
quinone under these reaction conditions, even with the slight excess
of boronic acid that is necessary to drive the reaction to completion.
Additionally, no O-arylation was observed, which has been encoun-
tered with previously reported methods.21
It was found that the scope with respect to the boronic acid
coupling partner was expansive, allowing for efficient reactivity
with aryl- and alkylboronic acids (Table 1). Arylboronic
acids with alkyl substitution at any position in the ring reacted
well under the standard conditions (4, 6-11). A broad range
of electronic properties were tolerated, from electron-rich
aryl ethers (16-24) to electron-withdrawn arylnitro (29),
arylcyano (25), aryltrifluoromethyl (26), and arylsulfate (27)
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COMMUNICATION
Table 2. Scope of Quinones for the Arylation with p-Tolyl-
boronic Acida
Figure 3. Applications to natural products and natural product hybrids.
biological interest. Figure 3A shows the functionalization of
estrone boronic acid (51)24 with 1,4-benzoquinone, delivering
the estrone-benzoquinone hybrid 52 in 51% yield under the
standard conditions. This reaction proceeds at room temperature
without requiring any protection of the ketone unit on the steroid
backbone. An example of allylboronic acid reactivity is shown in
Figure 3B with the synthesis of the natural product 2-farnesyl-
1,4-benzoquinone (55).25 The pinacolboronate of farnesol (53)
was first converted into its Molander salt 54 (necessitated by
the sluggish reactivity of the boronate ester itself). The crude
Molander salt was then subjected to the standard conditions to
directly attach a 1,4-benzoquinone in 58% yield. Isomerization of
the olefin closest to the boronate center in farnesol was observed
during this reaction, supporting an allyl radical intermediate.
Despite the prevalence of quinones in several fields of science
and technology, universal access to several quinone derivatives
has been hampered by a lack of general methodologies relating to
their synthesis. In fact, many of the products reported in this
Communication represent new chemical entities. The practical
C-H arylation/alkylation of quinones reported herein proceeds
at ambient temperature in an open flask, is scalable, can be run
without organic solvents when desired, demonstrates broad
scope, and is highly chemoselective. This powerfully simple
chemical avenue to aryl- and alkylquinones will allow facile and
affordable access to these structural motifs, thus filling an impor-
tant gap in the capabilities of organic synthesis.
a Quinone (0.25 mmol), p-tolylboronic acid (0.375 mmol), AgNO3
(0.05 mmol), K2S2O8 (0.75 mmol), 23 °C, 3-24 h; isolated yields of
chromatographically and spectroscopically pure products displayed.
c
b (NH4)2S2O8 used as an oxidant. Dichloromethane used instead of
trifluorotoluene. d A second addition of AgNO3 (0.05 mmol) and
K2S2O8 (0.75 mmol) was done after 3 h.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures; copies of all spectral data and full characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
Figure 2. Exploration of Molander salts and purely aqueous conditions.
’ AUTHOR INFORMATION
phenyltrifluoroborate with 1,4-benzoquinone in 95% yield. Ad-
ditionally, it was found that the organic layer of the biphasic
solvent system could be omitted on large scale with no impact on
yield, as demonstrated by the gram-scale reaction of 4-iodophe-
nylboronic acid with 1,4-benzoquinone in 94% yield with no
organic solvent. This is notable for both the scalability and
environmental compatibility of the reported conditions.
Corresponding Author
pbaran@scripps.edu
’ ACKNOWLEDGMENT
We are grateful to Dr. Raju Mohan (Exelixis) for a generous
donation of boronic acids. Financial support for this work
was provided by the NIH/NIGMS (GM-073949), the NSF
Perhaps the most striking demonstration of the utility of this
reaction is displayed in the modification of large molecules of
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COMMUNICATION
(predoctoral fellowship for I.B.S.), Japan Society for the Promo-
tion of Science (JSPS, postdoctoral fellowship for Y.F.), the
Spanish MICINN (predoctoral grant for V.D.), Amgen, and
Bristol-Myers Squibb (unrestricted research support).
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