B. Yin, Yu-Feng Du, Yan-Zuo Chen et al.
Tetrahedron Letters xxx (xxxx) xxx
84% (Entry 10) respectively under the conditions of proper heating
to 60 ℃. Entry 5, 11 and 12 showed that lower or higher reaction
temperature displayed negative effect on the yields of coupling
product 3a. Therefore, properly heating to 60 ℃ was suitable for
our reaction. In summary, 2-pyridineacetonitrile 1a and 1-
bromo-4-tert-butylbenzene 2a were used as substrates, Pd(OAc)2/
NixantPhos (5 mol%/7.5 mol%) was used as the catalyst system.
Under the influence of basic t-BuOK in solvent 1,4-dioxane, the
reaction was the most suitable. When heated to 60 ℃ for about
10 h, the substrate 2-pyridylacetylene 1a completely disappeared.
After screening the reaction conditions, 2-pyridyl acetonitrile
1a and a series of aryl bromide 2a-i were used as substrates to
investigate the applicable range of reaction conditions (Scheme 2).
Generally, high yield products can be obtained from substrates
with electron withdrawing or electron donating groups and sub-
stituents such as small steric hindrance groups. From the experi-
mental results of 3a-f, we knew that examined reaction
conditions had good adaptability and tolerance for bromobenzene
compounds with electron-withdrawing and electron-donating
groups. In addition, 1-bromonaphthalene 2g, 3-bromopyridine 2h
and 5-bromo-2-methylquinoline 2i were coupled with 2-pyridy-
lacetonitrile 1a to investigate the adaptability of different bromi-
nated aromatic compounds to reaction conditions, especially the
substrates with sterically hindered substituents. Under the opti-
mized conditions, the yields of 3g, 3h and 3i were 84%, 92% and
91%, respectively. In conclusion, for brominated aromatic com-
pounds with general steric hindrance, the reaction conditions
determined by us are generally tolerable.
substrates to combine 4-tert-butyl-1-bromobenzene 2a. Products
3k, 3l and 3m obtained high yields of 83% , 90% and 95% respec-
tively. Finally, 2-(6-(4-chlorophenyl) pyridine-2-)acetonitrile 1n
and 6-(2-thiophenyl)-2-pyridine acetonitrile 1o were coupled with
4-tert-butyl-1-bromobenzene 2a to investigate the effects of steric
hindrances on the reaction of electron-rich aromatic rings. Unsur-
prisingly, products 3n and 3o were obtained in high yields of 96%
and 87% respectively. These 3j-o experimental results indicated
that some common substituents on the pyridine group had little
effect on the reaction, and the reaction conditions we selected
could provide high yield for the combination of 2-pyridylacetoni-
trile derivatives and aryl brominated derivatives.
In 2015, Walsh et al. reported that Pd(OAc)2/NixantPhos was
used as catalytic system to construct sp3-sp2 CAC bond through
deprotonative cross-coupling [13]. By comparison, we found that
the two works were very similar. Therefore, we inferred that our
mechanism was credible by referring to the mechanism they pro-
After studying the arylation of 2-pyridylacetonitrile 1a with a
variety of brominated aryl compounds 2a-i, we briefly explored
the arylation of 2-pyridylacetonitrile derivatives 1j-o and 4-tert-
butyl-1-bromobenzene 2a substrates with substitutive groups to
understand the universal applicability of Pd(OAc)2/NixantPhos cat-
alytic conditions (Scheme 3). Successfully, 2-pyridylacetonitrile
derivatives 1j-o and 4-tert-butyl-1-bromobenzene 2a as substrates
got ideal yields in 83%-96% for products 3j-o. To begin with, we
tried to react 4-methyl-2-pyridine acetonitrile 1j with the sub-
strate 4-tert-butyl-1-bromobenzene 2a under optimized condition.
The high yield of product 3j was 92%. At the same time, taking the
trend of widespread application of electron-withdrawing groups
such as halogen atoms in drug development into consideration,
we selected 3-bromo-2-pyridine acetonitrile 1k, 5-chloro-2-pyri-
dine acetonitrile 1l and (6-fluoropyridine-2-yl)acetonitrile 1m as
Scheme 3. Range of 4-tert-1-bromobenzene 2a in direct
lacetonitrile derivatives 1j-o.
a-arylationof 2-pyridy-
Scheme 2. Range of bromoaryl compound 2a-i in direct
pyridylacetonitrile1a.
a-arylation of 2-
Scheme 4. Proposed mechanism [13].
3
Please cite this article as: B. Yin, Yu-Feng Du, Yan-Zuo Chen et al., Palladium-catalyzed direct deprotonative arylation of 2-pyridylacetonitriles: Facile syn-