Organic Letters
Letter
thalimide ester did not form (LiOH, NaOAc), (2) N-
hydroxyphthalimide ester formed, but the desired product
did not form in appreciable yields (Cs2CO3, t-BuONa, PhLi),
or (3) N-hydroxyphthalimide ester formed and the desired
product formed in moderate yield (NaH).
Collectively, the use of organic and inorganic bases resulted
in yields that were unsatisfactory. In an attempt to deprotonate
carboxylic acid 1a using sodium acetate, we observed that the
N-hydroxyphthalimide ester of the acetate had formed in
addition to the desired ester (SI Figure S2). Thus, we engaged
the carboxylate salt 1b in the cross-coupling reaction without
additional base. As hypothesized, successful conversion to the
desired product 3a was observed in high yield (Scheme 1).
Preforming the acetate derivatives of carboxylic acids using
stoichiometric aqueous NaOH gave the best yield for cross-
coupling under our optimized conditions.
iodobenzoate (3g), whereas steric hindrance from the ortho-
substituted methyl iodobenzoate (3h) presumably interferes
with the oxidative addition of nickel to the phenyl ring
resulting in diminished yield. However, when comparing the
substitution pattern for trifluoromethyliodobenzene, which
does not have a resonance stabilization contribution, the meta-
substitution (3f) gave higher yields than the para-substitution
(3j). Markedly, when the iodobenzene has one or more
halogens (i.e., chloro, bromo, fluoro, and not iodo), complete
selectivity for the iodo was observed (3b, 3l, 3m). Overall, the
reaction demonstrated high yields when the aryl iodides were
substituted with electron-withdrawing groups.
Substitution with electron-donating groups on iodobenzene,
on the other hand (3n, 3q), gave lower yields aside from the
para-substituted tert-butyl group (3e). The low yields may be
caused by the decreased reactivity toward oxidative addition by
nickel. Unfortunately, heteroatoms such as boronic pinacol
ester (3p), N-acetylindole (3o), Boc-protected aniline (3s),
and pyridine (3r) gave low yields under the current working
conditions, with only unreacted aryl-iodide remaining after the
reaction. Notably, N-hydroxyphthalimide ester was completely
consumed, presumably through degradation of the alkyl radical
onto the electrode (without any detectable homocoupling or
β-hydride elimination). Intriguingly, when benzoyl chloride
was coupled instead of an aryl iodide, nickel added to the
carbonyl to form the ketone cross-coupled product (3t) in
good yield. However, coupling with benzoic anhydride was not
successful.
Scheme 1. Reaction Scope of Sodium Hydrocinnamate with
a
Aryl Iodide
Ar−I cross-coupling with a focused substrate scope of
sodium carboxylate derivatives was also explored (Scheme 2).
Cross-coupling reactions involving cyclopropyl acetate (5a)
and cyclic alkanes with secondary carboxylates consistently
demonstrated the highest isolated yields (5b, 5c, 5d), with an
exception of cyclopropane (5l). Modest isolated yields were
observed for cross-couplings with primary carboxylates
containing ether, ester, and halide (5h, 5f, 5g, respectively).
Similar yields were observed for secondary carboxylates
containing ether, sulfone, and ester (5e or 5j, 5i, 5m,
respectively), whereas for reactions involving carboxylate
analogues containing either quaternary centers, adamantyl
(5k), or nitrogen N-Boc-pyrrolidine (5n) showed low
conversions. In brief, the reaction scope is compatible with
primary and secondary sodium carboxylate salts, which opens
the way for a new structural landscape and diversification of
molecules.
With respect to the reaction mechanism, the higher observed
cross-coupling yields with electron-deficient aryl iodides
relative to electron-rich aryl iodides may suggest that the rate
of oxidative addition of the nickel appears to be an important
factor in forming the cross-coupled product. These result are in
agreement with the proposed mechanism by Weix and co-
workers24 for their zinc powder reductive coupling of redox-
active esters with aryl iodides. The proposed mechanism
(Figure 3) is further supported by the reduction potential of
the redox-active ester (broad peaks at −1.03 and −1.21 V)
being higher than the reduction potential of nickel (−0.75 V),
a
Standard reaction conditions: 1b (0.563 mmol), PITU (0.563
mmol) (1b and PITU mixed first in 1 mL of DMA for 15 min), 2a−t
(0.375 mmol), NiCl2dme (0.0375 mmol), L1 (0.0375 mmol), NaI
(0.825 mmol), N,N-dimethylacetamide (DMA, 3 mL), rt, 3 mA, 2.0
b
F, 7 h. Benzoyl chloride was used instead of an aryl iodide.
Starting with acetate derivative 1b, we examined and
explored the substrate scope of the cross-coupling reaction
(Scheme 1). Initial studies began by holding the carboxylate
reagent constant (i.e., sodium hydrocinnamate 1b) when
coupling aryl iodides with various substitution groups/patterns.
Notably, the reaction tolerated a range of functional groups
including ketones (3a, 3i), nitriles (3d), and esters (3c, 3g,
3h). When the ester group was walked around the ring, the
yield ranked para > meta > ortho in the substitution pattern,
with the para-substituted methyl iodobenzoate (3c) generating
the highest yield. This result is likely promoted by resonance
stabilization aiding in the oxidative addition of the nickel
catalyst when compared with the meta-substituted methyl
The higher reduction potential of N-hydroxyphthalimide
ester derivative when compared with nickel catalyst supports
the proposed initial reduction of NiII to Ni0 on the cathode
followed by an oxidative addition to the aryl iodide that
generates the NiII complex (Figure 3). The NiII complex then
captures the alkyl radical formed by NiI to generate the NiIII
C
Org. Lett. XXXX, XXX, XXX−XXX