Direct C-H arylation of electron-deficient heterocycles with arylboronic acids

Article abstract of DOI:10.1021/ja1066459

A direct arylation of a variety of electron-deficient heterocycles with arylboronic acids has been developed. This new reaction proceeds readily at room temperature using inexpensive reagents: catalytic silver(I) nitrate in the presence of persulfate co-oxidant. The scope with respect to heterocycle and boronic acid coupling partner is broad, and sensitive functional groups are tolerated. This method allows for rapid access to a variety of arylated heterocycles that would be more difficult to access with traditional methods.

Full text of DOI:10.1021/ja1066459

Published on Web 09/02/2010
Direct C-H Arylation of Electron-Deficient Heterocycles with Arylboronic Acids
Ian B. Seiple, Shun Su, Rodrigo A. Rodriguez, Ryan Gianatassio, Yuta Fujiwara, Adam L. Sobel, and
Phil S. Baran*
Department of Chemistry and Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received July 27, 2010; E-mail: pbaran@scripps.edu
Abstract: A direct arylation of a variety of electron-deficient het-
erocycles with arylboronic acids has been developed. This new
reaction proceeds readily at room temperature using inexpensive
reagents: catalytic silver(I) nitrate in the presence of persulfate co-
oxidant. The scope with respect to heterocycle and boronic acid
coupling partner is broad, and sensitive functional groups are
tolerated. This method allows for rapid access to a variety of arylated
heterocycles that would be more difficult to access with traditional
methods.
Methods for the cross-coupling of heterocycles with aryl groups
are of fundamental importance in nearly all areas of chemical science.
Among these, the Pd-catalyzed coupling of arylboronic acids with
aromatic halides (Suzuki reaction) is widely employed.1 A far less
studied and underappreciated coupling reaction is the Ag-catalyzed
Figure 1. (A) Overview of the addition of arylboronic acids to electron-
deficient heterocycles. (B) Initial findings with respect to arylboronic acid
reactivity.
addition of nucleophilic, alkyl-centered radicals to electron-deficient
heterocycles (Minisci reaction).2 One drawback of the Minisci reaction
is the limited access to nucleophilic radicals, especially of the aryl
variety.3 Our recent studies involving chemoselective silver-mediated
conditions for the oxidative decarboxylation of alkylcarboxylates
oxidation reactions on highly complex alkaloids such as palau’amine4
fails on their aryl counterparts (Figure 1B). It was surmised that
led us to reexamine this gap in the scope of the classic Minisci reaction.
homolytic cleavage of the C-B bond in an arylboronic acid could
be induced in a manner similar to decarboxylation. The widespread
Herein we report the development of a silver(I)-catalyzed addition of
arylboronic acids to a range of electron-deficient heterocycles (see
availability and unique reactivity patterns of boronic acids have
Figure 1A). This net C-H arylation proceeds at room temperature
inspired many groups to explore chemistry beyond the Suzuki
reaction.15 However, to the best of our knowledge, a mild protocol
and is operationally simple, is scalable, and has broad functional group
compatibility and substrate scope.
for the generation of aryl radicals from arylboronic acids is
unknown.16 By employing conditions similar to those used in the
The most common method to arylate electron-deficient heterocycles
is by the direct addition of an arylmetallate followed by rearomatiza-
tion.5 However, this method often furnishes products in low to
moderate yield, is only effective on electron-deficient heterocycles,
and has low functional group compatibility. Due to these drawbacks,
several powerful alternative methods have arisen in the literature to
functionalize heterocycles.6 The direct coupling of heterocycles to aryl
halides has been accomplished using palladium,7 rhodium,8 gold,9 and
copper10 catalysis. Additionally, pyridine has been coupled to arylzinc
reagents under nickel catalysis in good yield,11 and directed metalation
of pyridine derivatives followed by Negishi coupling to aryl halides
has demonstrated unique selectivity.12 Finally, preactivation of het-
erocycles as their N-oxides has been shown to allow heterocycles to
be directly arylated under palladium catalysis with a broad range of
aryl halides.13
Minisci reaction with alkyl carboxylic acids (catalytic silver(I)
nitrate in the presence of persulfate), it was found that arylboronic
acids can directly unite with protonated electron-deficient hetero-
cycles at room temperature (Figure 1B). As opposed to prior work
on aryl radical coupling to pyridines, the heterocycles can be used
as limiting reagents rather than as solvent.14,16
The procedure for the direct arylation is very simple: to a
vigorously stirred solution of the in situ generated heterocycle•TFA
salt (1.0 equiv) and arylboronic acid (1.5 equiv) in DCM/H2O (1:1
v:v) at room temperature was added silver(I) nitrate (0.2 equiv)
and K2S2O8 (3.0 equiv) followed by a basic workup after 3-12 h.
Trifluorotoluene can be substituted for dichloromethane as an
environmentally friendly alternative, and an inert atmosphere or
purification of solvents/reagents is unnecessary. Irrespective of
isolated yield, analysis of the crude mixtures by NMR spectroscopy
reveals only product(s) and unreacted starting material (the byprod-
ucts are easily removed during aqueous workup), suggesting that
this reaction would be amenable to library synthesis. Performing
the reaction without the silver catalyst or persulfate failed to produce
any product, while TFA improved rate and conversion,3 but was
not essential to achieve the desired reactivity in some cases. These
In principle, a mild C-H arylation of heterocycles that paralleled
the Minisci reaction (Figure 1A) would require a facile route to
aryl radicals. Specifically, mild generation of these reactive
intermediates from stable, readily available starting materials would
be greatly enabling, obviating the need for harsh, impractical, or
environmentally hazardous reaction conditions commonly employed
to access these reactive intermediates.3,14 Unfortunately, Minisci’s
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C O M M U N I C A T I O N S
standard conditions could be applied to a range of heterocycles as
shown in Table 1, using p-tolylboronic acid as a standard aryl
coupling partner.
cycles such as indole or imidazole (21 and 22) performed well. In
this regard, the current reaction is orthogonal to other C-H arylation
approaches.6-10 The reaction proved scalable, with pyrimidine (4)
performing well on gram scale, delivering 96% of the desired
product. It should be noted that oxidative dimerization of the boronic
acid is observed but the rate appears to be much slower than that
of the desired transformation.
Table 1. Scope of the Coupling of Arylboronic Acids to
Heterocyclesa
The scope of arylboronic acid was explored, and the results are
displayed in Table 2. Several electron-poor to electron-rich aryl-
boronic acids were tolerated, with the more electron-rich substrates
demonstrating shorter reaction times. Many of the more electron-
poor boronic acids required a second addition of AgNO3/K2S2O8
to drive the reaction to completion. Halogenated arylboronic acids
performed well (27-30, 33), as well as alkoxy- and aryloxyphe-
nylboronic acids (32-33). Ortho-substitution was tolerated, but only
with electron-donating substituents (e.g., 23, 31) and in reduced
yield.
Table 2. Scope of Boronic Acids for the Arylation of 4-tert-
Butylpyridinea
a 4-tert-Butylpyridine (0.25 mmol), arylboronic acid (0.375 mmol),
TFA (0.25 mmol), AgNO3 (0.05 mmol), K2S2O8 (0.75 mmol), 23 °C,
3-24 h; isolated yields of chromatographically and spectroscopically
pure products displayed. For reactions over 3 h, second additions of
AgNO3 (0.05 mmol) and K2S2O8 (0.75 mmol) were added after 3 h.
(NH4)2S2O8 also suitable as an oxidant. b Reaction was performed on
1.0 g of 4-tert-butylpyridine with a modified procedure; 23% starting
material was recovered. See Supporting Information for details.
a Heterocycle (0.25 mmol), p-tolylboronic acid (0.375 mmol), TFA
(0.25 mmol), AgNO3 (0.05 mmol), K2S2O8 (0.75 mmol), 23 °C, 3-12 h;
isolated yields of chromatographically and spectroscopically pure
products displayed. (NH4)2S2O8 also suitable as an oxidant. b 2-Hy-
droxyethyl ester byproduct arising from oxidation of the benzylic
position and hydrolysis. c Reaction run at 0.02 M to prevent formation
of dimeric byproducts.
Perhaps the most notable example of the generality and functional
group tolerance of the title reaction is the direct arylation of quinine
(39, Scheme 1). This natural product contains an oxidizable benzyl
alcohol, an electron-rich monosubstituted alkene, and a highly
nucleophilic quinuclidine-type nitrogen. However, under the re-
ported reaction conditions, p-phenoxyphenylboronic acid can be
directly coupled to the 2-position of this natural product in 40%
isolated yield, obviating the need for multistep sequences involving
protecting groups and prefunctionalization of the heterocycle. The
direct arylation of a natural product such as quinine displays the
utility of this reaction in the functionalization and diversification
of sensitive late-stage intermediates.
The reaction proved fairly general for several classes of electron-
poor heterocycles of varying substitution, with yields ranging from
30% to >90%. Regioselectivity on the heterocycle was predomi-
nantly for the 2- and 4- positions, and bis-addition proved to be
minimal. Diazines such as pyrimidine, pyridazine, and pyrimidine
(4-6) all proved to be viable substrates, as well as benzannulated
derivatives (13-18). Aryl halides were tolerated (e.g., 9, 11),
providing handles for further functionalization (e.g., with a Suzuki
reaction). Electron-withdrawing groups (including ketone function-
alities) appeared to enhance the reactivity of the substrate, but
sometimes with the loss of selectivity (e.g., 10 and 11). Neither
2-halogenated pyrazine derivatives (19) nor electron-rich hetero-
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C O M M U N I C A T I O N S
Scheme 1. Direct Arylation of Quininea
species (tentatively assumed to be radicals) from arylboronic acids,
a platform that may find use in other areas of reaction design.
Acknowledgment. We are grateful to Dr. Raju Mohan (Ex-
elixis) for a generous donation of boronic acids. Financial support
for this work was provided by the NIH/NIGMS (GM-073949), the
NSF (predoctoral fellowships for I.B.S. and R.A.R.), Japan Society
for the Promotion of Science (JSPS, postdoctoral fellowship for
Y.F.), Amgen, and Bristol-Myers Squibb (postdoctoral funding for
S.S. and unrestricted research support).
a Quinine (0.125 mmol), arylboronic acid (0.25 + 0.125 mmol), TFA
(0.375 mmol), AgNO3 (0.025 mmol), K2S2O8 (0.25 mmol), 23 °C, 3-24
h; isolated yield of chromatographically and spectroscopically pure product
displayed.
Note Added after ASAP Publication. Reference citations were
corrected in the eighth paragraph of text on September 8, 2010.
Supporting Information Available: Detailed experimental proce-
dures, copies of all spectral data, and full characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
A postulated mechanistic scenario that is consistent with experi-
mental data and literature precedent is summarized in Figure 2. It has
been shown2 that in the presence of silver(I) salts, persulfate anion
disproportionates into sulfate dianion and sulfate radical anion. This
radical could react with the boronic acid through an unexplored process
(to be the subject of future investigations), providing an aryl radical.
It is probable that this aryl radical reacts with protonated heterocycle
41 to form radical cation 42, which is reoxidized by silver(II),
delivering the desired product 43 and regenerating the silver(I) catalyst.2
It is worth noting that this reaction fails with the use of stoichiometric
silver(II) as the sole oxidant or with the use of persulfate in the absence
of silver catalyst. Further, product distributions are similar to those
seen previously for phenyl radical addition to pyridine,3 strongly
suggesting the same reactive intermediate.
References
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reactivity of the substrates. Second, the yields are mediocre in some
cases and do not necessarily follow a predictable trend. Finally,
ortho- substitution on the boronic acid greatly hinders the reaction,
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addition to a detailed exploration of the mechanism of this reaction,
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In summary, a reaction to achieve the direct coupling of
arylboronic acids to electron-deficient heterocycles using an
inexpensive silver catalyst (<$1.00/g) and co-oxidant (ca. 1 cent/
g) has been invented. The reaction proceeds under ambient
conditions, displays a broad scope with respect to both the
heterocycle and boronic acid partners, and does not require
prefunctionalization of the heterocycle. It has a high functional
group tolerance, is operationally trivial to execute, is scalable, and
can be used to directly functionalize sensitive natural products such
as quinine (39). These features will likely render it a useful tool in
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