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Scheme 1. Ortho-directed ruthenium-catalyzed carbonylative direct arylation.
broadening the scope of this unique transformation, we inves-
tigated the applicability of this method to a variety of five-
membered and condensed heterocycles. This regioselective Cꢀ
H bond functionalization is biased by the pendent ortho-N-di-
recting group, yielding the corresponding diaryl methanone
derivatives in predictable and defined site-selectivity.[26] We
have demonstrated that carbonylative direct arylation can be
deliberately achieved at either the 2- or 3-position of the het-
erocycle by this method. The direct CꢀH bond functionaliza-
tion, presented here, provides a useful and convenient proto-
col for the activation of omnipresent CꢀH bonds. The straight-
forward access to versatile heteroaryl–aryl ketones, starting
from readily available or easily accessible starting materials and
an inexpensive catalyst system is shown and is showcased in
the synthesis of a Raloxifene analogue. Mechanistic experi-
ments have been performed and the key steps of the catalytic
cycle are discussed. The described methodology provides
a useful extension to existing CꢀH bond functionalization strat-
egies and should find broad utility in synthetic applications for
the synthesis of complex target molecules.[27]
Scheme 2. Comparison of the reactivity of 2-phenylpyridine (1a) and 3-(2’-
pyridyl)thiophene.
of the thiophene nucleophile 1b to the corresponding [3-(pyri-
din-2-yl)thiophen-2-yl](o-tolyl)methanone (3ba), which was iso-
lated in 87% yield; whereas the unreacted nucleophile 1a was
isolated quantitatively. Further optimization revealed that an
excess of the nucleophile was beneficial for the arylation of
heteroarenes and significantly accelerated the overall process,
resulting in higher yields of the desired coupling product
(Scheme 3, entry 1). Additional evaluation of different reaction
parameters (e.g., Ru-source, additives, base or solvent) did
not lead to any substantial improvements in yield or rate.[28]
Consequently, the scope for ruthenium-catalyzed carbonylative
direct arylation of heterocyclic nucleophiles and iodoarenes
was investigated under these optimized reaction conditions
(Scheme 2b).
Results and Discussion
Our initial efforts concerning the ruthenium-catalyzed carbony-
lative direct arylation were focused on the ortho-directed CꢀH
bond functionalization of 2-phenylpyridine (1a). Based on a de-
tailed study of the key reaction parameters, the best result was
achieved by using a practical catalytic system comprising of
[RuCl2(cod)]n (cod=1,5-cyclooctadiene), KOAc, and NaHCO3 as
the base. Operating in aqueous solution under carbon monox-
ide pressure (30 bar) created a uniquely active reaction envi-
ronment. In our previous protocol, a 1:2 ratio of the substrates
using the nucleophile 1 as the limiting reactant gave the best
results. However, the reaction proved to be rather sensitive
with respect to substitutions on the phenyl moiety. Gratifying-
ly, we found that pyridine-containing bis(heteroaryls), such as
3-(2’-pyridyl)thiophene (1b), were extremely effective in this
carbonylative coupling reaction (Scheme 2a). Encouraged by
this initial finding we strived to expand the substrate scope of
the reaction, with the goal of elucidating potential limiting fac-
tors of the direct carbonylative ortho-arylation. To this end,
a competition experiment between 2-phenylpyridine (1a) and
3-(2’-pyridyl)thiophene (1b) was conducted. Using an excess of
the competing nucleophiles revealed the selective conversion
Substrate scope for the C2-selective direct arylation
Under our optimized conditions, the ruthenium-catalyzed car-
bonylative direct arylation of 3-(2’-pyridyl)heteroarenes, includ-
ing thiophenyl, furanyl, and pyrrol-based heterocycles, was
conveniently accomplished by using a number of iodoarenes
in the presence of carbon monoxide. The pendent pyridine
moiety selectively biased the carbonylative coupling which al-
lowed for a highly regioselective functionalization at the 2-po-
sition of the investigated five-membered heterocycles. The cor-
responding heteroaryl–aryl ketones were isolated in moderate
to good yields (10–91%, Table 1).
The best result was obtained when 2b was reacted with 2-
iodotoluene (2a), resulting in a 91% of the desired [3-(pyridin-
2-yl)thiophen-2-yl](o-tolyl)methanone (3ba). In general, ortho-
substituted iodoarenes gave superior results relative to other
substitution patterns. Accordingly, 2-iodo-1,1’-biphenyl (2b),
Chem. Eur. J. 2014, 20, 3135 – 3141
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