Organic Letters
Letter
hemilabile DAF core remains synthetically challenging.12
Consequently, the fixed properties of DAF have limited its
application in the reactions requiring careful electronic and
steric control.
The modified protocol allowed the conversion of various
pyrazolopyridines, prepared by Cu-catalyzed or base-mediated
reactions of halopyridines and pyrazoles, to the corresponding
annulation products (Scheme 2). To explore the electronic
A general strategy for the Pd-catalyzed oxidative reactions of
a wide range of arenes in a sustainable manner requires the
development of electronically and sterically tunable ligands
that can be systematically tailored to function under aerobic
conditions. To develop a new class of nitrogen ligands that can
afford electrophilic Pd(II) complexes for the metalation of
electron-rich arenes, we envisioned the incorporation of
pyrazole, a modular subunit with weaker electron-donating
properties than pyridine. The presence of adjacent nitrogen
atoms in the five-membered ring renders pyrazole less Lewis-
basic than pyridine.13 Considering its wide application scope
for ligand development,14 pyrazole has been used to replace
one of the pyridine rings in bipyridine systems, leading to the
formation of organometallic complexes with useful photo-
electronic and electrochemical properties.15 However, the use
of such pyrazolopyridine ligands in Pd-catalyzed reactions
remains limited to a few examples of cross-coupling
reactions.16 Furthermore, the synthesis of conformationally
fixed pyrazolopyridine compounds with fused ring systems and
their applications as ligands have not been reported to the best
of our knowledge.
Scheme 2. Scope of the C−H Annulation: Heterocycles
Herein we report the preparation of a pyrazolopyridine
ligand platform that enables highly efficient Pd-catalyzed C−H
alkenylations of electron-rich arenes (Figure 1B). The Rh-
catalyzed C−H annulation of conformationally flexible
pyrazolopyridine (PzPy) compounds with alkynes should
provide a variety of conformationally fixed pyrazolonaphthyr-
idine (PzNPy) ligands.17 Furthermore, we explore the
prepared PzNPy ligands in the C−H alkenylation of
substituted arenes. In addition, tailoring the electronic
properties of the PzNPy ligands renders subtle differences in
the electronic character of the substrates to be addressed.18 In
these processes, the PzNPy ligands promote the oxidation of
Pd(0) species with oxygen as the oxidant.
effect of FG1 and FG2, we prepared a series of rigid annulated
products bearing ester and methoxy substituents (2−6). In
addition, methyl- and phenyl-substituted pyrazolyl pyridines
underwent annulation reactions, generating sterically dissimilar
ligands (7−11). To provide more electron-deficient ligands
than PzNPy, pyrazine analogues 12 and 13 were synthesized.
Furthermore, the incorporation of quinoline and indazole led
to the preparation of the π-extended structures (14−17). The
ready availability of numerous pyrazoles enhances the
structural diversity of the ligand library attainable by this
streamlined synthetic route.
The annulation reactions were performed with different
alkynes, including aryl alkynes containing electron-donating or
-withdrawing groups and an alkyl alkyne (Scheme 3, 18a−c).
The scope of alkynes was further explored using 2-(1H-
pyrazol-1-yl)quinoline, which afforded generally higher yields
than the pyridine counterpart. In addition to aryl and alkyl
alkynes (19a−g), both regioisomers of thienyl alkynes were
successfully coupled (19h and 19i). Furthermore, 2-naphthyl
and 3-quinolyl alkynes were used to give polycyclic
heteroaromatic compounds (19j and 19k).
The binding modes and strength of the Pz(N)Py ligands
were analyzed using parent compounds 1a and 1b. In contrast
with DAF, whose hemilabile behavior is revealed by the
existence of multiple equilibrating complexes upon reaction
with Pd(OAc)2,10a both 1a and 1b cleanly afforded the 1:1
complexes 20 and 21, respectively, which were characterized
by X-ray crystallography (Figure 2). The geometry of the
Pz(N)PyPd(OAc)2 complexes was more similar to that of the
complex derived from PHEN (a 6/6/6-fused tricyclic ligand)
than to that of the complex containing DAF (a 6/5/6-fused
tricyclic ligand). A distance of ∼2.6 Å between the two Lewis-
Initially, we optimized the C−H annulation of 2-(1H-
pyrazol-1-yl)pyridine 1a with diphenyl acetylene on the basis
of the reported Rh-catalyzed reactions of N-aryl pyrazoles with
alkynes17 to selectively obtain the desired annulation product,
1b (Scheme 1 and Table S1). The use of a nonpolar solvent
a
Scheme 1. Rh-catalyzed C−H Annulation
a
1H NMR yields. Reaction conditions: heterocycle (1.0 mmol),
alkyne (1.5 mmol), Cu(OAc)2 (3.0 mmol), PivOH (1.0 mmol),
b
[RhCp*Cl2]2 (0.05 mmol), PhCl (2.0 mL), 140 °C, 6 h. Isolated
yield.
(chlorobenzene) and an additive (pivalic acid) was critical to
the successful C−H activation of the pyridine ring en route to
the formation of the desired 1:1 annulation products, whereas
C−H alkenylation (1c) and 1:2 annulation (1d) occurred at
the pyrazole core in the presence of silver salts and DMF,
respectively.17d
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Org. Lett. 2021, 23, 3657−3662