Journal of the American Chemical Society
Article
reaction was evaluated for yields of α-arylnitrile (2a) and
reduced arene (3), a side-product resulting from β-hydride
elimination. The alkenyl nitrile resulting from β-hydride
elimination was also indirectly observed.49 Electron-poor
ligands gave appreciable yield of 2a, including 4-trifluorome-
thylstyrene22,23 and dimethyl fumarate25 (Figure 2b). A
sterically hindered Doyle ligand (Doyle L) gave low yield of
2a.13,50 As a control, the reaction was performed in the absence
of exogenous ligand (“no ligand”), which gave good conversion
with some formation of 2a (36% yield). A thorough screen of
electron-donating ligands was also performed, however these
ligands either inhibited catalysis or had no apparent effect in
comparison to the control (see SI).
The reactivity in the absence of ligand suggested that some
reaction components could be acting as ligands to (i) stabilize
the Ni catalyst, especially low-valent Ni, and (ii) promote the
formation of 2a. We have previously observed that, in the
presence of nitrile-containing intermediates, C−Br reductive
elimination from Ni(II) oxidative addition intermediates can
proceed.51 The groups of Hartwig30−32 and Schoenebeck33
have also demonstrated that nitriles can coordinate Ni(0)
intermediates. To probe if nitriles were facilitating cross-
coupling, benzonitrile (20 mol %) was added to the reaction,
and a modest but reproducible boost in the yield was observed
(49% yield). This beneficial effect was concentration-depend-
ent and could be improved with up to 10 equiv PhCN; vide
infra.
Thus, we sought to design a bidentate benzonitrile ligand to
promote formation of nitrile-bound Ni (Figure 2c). With an
ortho-diphenylphosphine-substituted benzonitrile (L1), poor
yield was achieved, with the remaining mass balance being
unreacted aryl iodide. As alternate Lewis base, an ortho-
pyrazole-substituted benzonitrile was used (L2), which gave
excellent conversion of aryl iodide (93% conv.), and good
selectivity for the desired α-arylated product (70% and 22%
yield of 2a and 3, respectively). The addition of a methoxy
substituent para to the nitrile (L3) resulted in improved
conversion (100% conv.), while maintaining good product
selectivity (73% and 30% yield of 2a and 3, respectively). A
stronger para-electron-donating group (dialkylamino, L4)
resulted in poorer yield (29%), and a para-electron-with-
drawing group (trifluoromethyl, L5) resulted in worse
conversion of aryl iodide (33% conv.). Other Lewis bases
gave worse conversion or selectivity for 2a versus 3 (L6−L7).
Controls demonstrated the importance of Lewis base
proximity to the benzonitrile. In the cases where the pyrazole
was para to the nitrile (para-L2) or where the Lewis basic
nitrogen was removed (pyrrolyl-L2), the selectivity for
formation of 2a over 3 was eroded in comparison to that
observed with L2, suggesting that the role of the Lewis base is
to coordinate Ni and localize it to the nitrile.
We next evaluated the catalytic activity of optimal ligand L3
in the context of decyanation−arylation of disubstituted
malononitriles, which are convenient materials that can be
easily synthesized from commodity chemical malononitrile
(Figure 3). Here, exposure of malononitriles (4) to
PhMgBr·LiBr52 yields PhCN and an α-metalated nitrile in
situ.53−58 Then, treatment with an aryl iodide (1 equiv),
NiCl2(dme) (10 mol %), and L3 (20 mol %) in PhMe/THF at
30 °C yields the α-arylnitrile (2). A number of electrophiles
were viable, including electron-rich (2a−2c, 2e−2g) aryl
iodides and (hetero)aryl iodides (2i, 2m, 2p−2q). Electron-
neutral (2h) and electron-deficient (see SI) aryl iodides gave
Figure 1. (a) π−accepting ligands for challenging Ni-catalyzed
reductive elimination with C(sp3) coupling partners; (b) benzonitrile
effects in Ni catalysis; (c) use of an electron-accepting bidentate
benzonitrile ligand (L3) for Ni-catalyzed α-arylation.
triles undergo decyanation−metalation, followed by Ni-
catalyzed arylation. α-Arylation of tertiary nitriles has been
explored using Pd catalysis,37−40 but related Ni-catalyzed
reactions have been largely limited to secondary nitriles.41,42 As
substrates, disubstituted malononitriles are convenient since
they can be synthesized in one or two steps from commodity
chemical malononitrile.43−46 The arylation step is enabled by
an ortho-pyrazole benzonitrile-containing ligand (L3). Ham-
mett studies reveal that L3 acts as an electron-acceptor, which
attenuates and stabilizes low-valent Ni, favoring reductive
elimination. As a bidentate ligand, L3 promotes formation of
nitrile-bound Ni, which also disfavors β-hydride elimination.
Together, this procedure accesses valuable quaternary α-
arylnitriles,47,48 enabled by L3 as a novel benzonitrile-
containing ligand.
RESULTS AND DISCUSSION
■
Design and Use of the Benzonitrile Ligand (L3). We
began by exploring conditions for Ni-catalyzed arylation of α-
magnesiated nitriles (1a) with 4-iodoanisole (Figure 2). The
10423
J. Am. Chem. Soc. 2021, 143, 10422−10428