Unexpected intermolecular Pd-catalyzed cross-coupling reaction employing heteroaromatic carboxylic acids as coupling partners

Article abstract of DOI:10.1021/ja063511f

Aryl-substituted five-membered heteroaromatics have attracted great interest over the past years due to their presence in a large number of pharmaceuticals and natural products. Recently, an advance in the preparation of these scaffolds was achieved by employing a C-H functionalization strategy. This method allows easy access to these biaryl motifs by precluding the necessity of preparing specific coupling partners, although poor regioselectivity is sometimes observed when more than one reactive C-H is present on the substrate. In an effort to circumvent this liability, we envisioned the use of a carboxylic acid moiety as a blocking group that could be later functionalized or removed. Remarkably, the coupling was found to occur exclusively at the position previously occupied by the acid, even in the presence of a reactive C-H group. This selective transformation was also found to proceed with other heteroaromatic carboxylic acids, allowing for the preparation of a variety of aryl-substituted heteroaromatics that would be difficult to obtain via other methods. Copyright

Full text of DOI:10.1021/ja063511f

Published on Web 08/12/2006
Unexpected Intermolecular Pd-Catalyzed Cross-Coupling Reaction Employing
Heteroaromatic Carboxylic Acids as Coupling Partners
Pat Forgione,* Marie-Christine Brochu, Miguel St-Onge, Kris H. Thesen, Murray D. Bailey, and
Franc¸ois Bilodeau*
Boehringer Ingelheim (Canada), Limited, Research and DeVelopment, 2100 rue Cunard, LaVal,
Quebec, Canada, H7S 2G5
Received May 19, 2006; E-mail: pforgione@lav.boehringer-ingelheim.com; fbilodeau@lav.boehringer-ingelheim.com
Table 1. Effect of the Additive
Metal-catalyzed cross-coupling reactions continue to draw much
attention and they remain one of the most efficient methods to
access biaryl motifs.1 Over the past years, a number of palladium
mediated cross-coupling methods, such as the Suzuki-Miyaura2
and Stille3 couplings, have been developed. Although employed in
a broad range of applications,4 a potential limitation of these is the
availability of appropriate cross-coupling partners.5
During our drug discovery efforts, compounds of general
structure 2 were required. The C-H functionalization method was
considered an appealing option to access these scaffolds,6 although
it can suffer from poor selectivity. In an attempt to circumvent this
liability, we envisioned employing a carboxylic acid moiety as a
blocking group that could later be functionalized or removed.
Surprisingly, when a Pd-catalyzed cross-coupling reaction between
3a and phenyl bromide was attempted, we did not obtain the C-H
functionalization product 2, but the unexpected formation of 3b
was observed (Scheme 1).7
entry
additive
yield 4bb (%)
% of 5c
1
2
3
4
5
6
7
none
77
64
76
86
74
88
77
9
n-Bu4N+ AcO-
n-Bu4N+I-
18
8
n-Bu4N+Br-
n-Bu4N+Cl-
n-Bu4N+Cl-‚H2O
n-Bu4N+F- d
5
trace
trace
11
a Reaction conditions: additive (0.40 mmol, 1.0 equiv), heterocycle (2.0
equiv), phenyl bromide (1.0 equiv), Pd[P(t-Bu)3]2 (5 mol %), Cs2CO3 (1.5
equiv), DMF (4 mL), µW, 170 °C, 8 min. b Isolated yields. c Crude HPLC
@ 220 nm. d 1 M in THF.
exclusively at the more sterically hindered C2-position despite the
possibility of coupling via C-H functionalization. Removal of the
methyl substituent resulted in a decrease in yield (entries 3 and 5
versus 4 and 6, respectively). The position of the acid that undergoes
coupling is also crucial to this reaction, as exposure of 3-furan-
carboxylic acid to the reaction conditions did not lead to any of
the desired product (entry 9).
Scheme 1 a
a Conditions: PhBr, DMF, n-Bu4N+Br-, Pd(P(t-Bu)3]2, µW, 170 °C, 8
min.
Scheme 2. Postulated Mechanism
A thorough search of the literature revealed a single report of
such a transformation by Steglich and co-workers,8 although in this
intramolecular case, no reactive C-H group was present. Thus,
with a lack of information concerning substrate scope, reactivity
in an intermolecular manifold, chemoselectivity, and mechanism,
we embarked on an investigation of this reaction.
A preliminary study was performed to determine the influence
of ammonium bases9 as additives because they are known to have
an effect on related transformations (Table 1). The heterocycle 4a
was selected as the model substrate because it contains both a C2-
carboxylic acid and a C5-H, which allowed us to evaluate the
selectivity of the reaction. During our investigations, it became clear
that the primary byproduct in this reaction was 5 and the observed
amounts varied with the additive. The absence of the additive (entry
1) did not have a considerable impact on the yield, although some
2,3-diphenylpyrrole 5 was produced. We also observed that
tetrabutylammonium acetate (entry 2) gave lower yields and a
significant amount of 5, whereas tetrabutylammonium chloride
hydrate (entry 6) afforded a clean reaction (i.e., trace amounts of
5 produced) with the best yield. In all cases, no product resulting
from C-H functionalization was observed under these conditions.
In addition to oxazoles (Table 2, entry 1) and pyrroles (entry 2),
we were pleased to observe that other heterocycles can also be
employed, including furans (entries 3 and 4), thiazoles (entries 5
and 6), thiophenes (entry 7), and benzofurans (entry 8). Furthermore,
in the case of both 6a (entry 3) and 8a (entry 5), coupling occurred
Preliminary empirical evidence seems to support the mechanism
shown above (Scheme 2). One of the main byproducts that was
observed with 2-furancarboxylic acid (Table 2, entry 4) as the
substrate was 2,3-diphenylfuran (similar to the pyrrole case, see
Table 1). Thus, we postulate that the electrophilic Pd(II) intermedi-
ate generated from the oxidative addition is first coordinated by
the carboxylate moiety10 prior to an electrophilic palladation at the
C3 position of furan.11 This complex would explain the complete
regioselectivity observed for this transformation. At this stage, two
pathways are possible: first, a C3-C2 palladium migration11a,b and
extrusion of CO2 can occur to produce I, which then undergoes
reductive elimination to yield the 2-substituted furan. Alternatively,
in the case where R ) H, the deprotonation to regenerate the
aromatic furan II can compete, after which reductive elimination
9
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J. AM. CHEM. SOC. 2006, 128, 11350-11351
10.1021/ja063511f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Arylation of Various Heteroaromatic
Table 3. Scope of Aryl Bromide
Carboxylic Acids with PhBr
entry
Ar
−Br
isolated yield (%)
1
2
3
4
5
4-MeO-PhBr
4-NO2-PhBr
2-Br-5-Me-thiophene
3-Br-pyridine
PhBrb
77
66
78
85
57
a See Table 2. b Performed under thermal conditions (140 °C, 1 h).
yield (Table 3). Preliminary results show that thermal conditions
can also be employed (entry 5).
Miura7 reported the use of carboxamides as a sacrificial group
in the arylation of thiazoles, however, multiple arylations were
obtained. An important distinction between our work and that
previously reported7,8 is that it highlights the ability to selectively
perform this reaction in the presence of a reactive C-H group in
an intermolecular fashion and sheds light on the mechanism of this
type of reactivity. Furthermore, it allows for the control of the
arylation such that the monoarylated product is always the major
product observed.
In summary, a decarboxylative cross-coupling reaction for
preparing aryl-substituted heteroaromatics has been disclosed.
Starting from stable and commercially available substrates, this
method allows access to structural motifs that are difficult to obtain
by other methods. The complete control of regiochemistry is an
attractive complement to the existing C-H functionalization
method. Efforts are underway to evaluate the scope and limitation
of this reaction and details will be reported in due course.
Acknowledgment. We wish to thank A. B. Charette for valuable
discussions concerning this work and our colleagues at Boehringer
Ingelheim (Canada), Ltd., R&D for their support and useful
suggestions during the preparation of this manuscript.
a Reaction conditions: heterocycle (0.80 mmol, 2.0 equiv), phenyl
bromide (1.0 equiv), Pd[P(t-Bu)3]2 (5 mol %), n-Bu4N+Cl-‚H2O (1.0 equiv),
Cs2CO3 (1.5 equiv), DMF (4 mL), µW, 170 °C, 8 min. b Isolated yields.
c Yield without additive (yield with n-Bu4N+Cl-‚H2O ) 74% (contains 10%
Supporting Information Available: Experimental procedures and
spectroscopic characeterization of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
of 1-methyl-2-pyrrole-n-butylester by H NMR)).
will generate 3-phenyl-2-furan carboxylic acid III. This product
can in turn re-enter the catalytic cycle and via I (where R ) Ph)
yield 2,3-diphenylfuran, accounting for the lower yields observed
in the unsubstituted cases. Additionally, when 2-phenylfuran was
subjected to the reaction conditions, only 2,5-diphenylfuran was
observed, ruling out 2-phenylfuran as an intermediate for the
formation of 2,3-diphenylfuran under these conditions.
A comparison of this decarboxylative cross-coupling with the
C-H functionalization method was performed to further highlight
its utility (Scheme 3). In contrast to the C-H functionalization,
where a mixture of the two possible products was obtained (10b
and 13b), appropriate selection of either of the heterocyclic acids
(10a and 13a) afforded the corresponding regioisomer.
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a Conditions: PhBr, DMF, n-Bu4N+X-, Pd(P(t-Bu)3]2, µW, 170 °C, 8
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