Organic Letters
Letter
Scheme 2. Electroreductive Transformations
Scheme 3. Optimization of Reaction Conditions
n
as metal additive, Na2CO3 (3 equiv) as base, Bu4NClO4 as
electrolyte, a mixed solution of dichloroethane (DCE)/
CH3CN (7/3 mL) as solvent, and graphite rod and nickel
plate as anode and cathode, respectively (for details of
additive led to diminished yields, which suggests it plays a
critical role in the reaction. Without electricity, the above
reaction ceased, and no product was detected. When we
performed the reaction in the cathode part of a divided cell, an
almost same yield (56%) was observed. These results
suggested this reaction did proceed through an electro-
reductive pathway.
Having identified the optimal reaction conditions, the scope
of enones amenable to this method was then evaluated
(Scheme 4). A broad range of enones bearing electron-
donating and -withdrawing groups were investigated (3b−3j),
and the corresponding products were obtained with moderate
yields (27−65% yields). Specifically, the pinacolatoboron
(BPin)-substituent, which could allow for later functionaliza-
tion, proved to be amenable to the reaction conditions, albeit
with a lower yield (3j). The reaction was readily scaled up to 5
g scale, and the desired pyridylation product 3a (5.7 g) was
accessed in synthetically useful yield (51%). Substituents at the
2- or 3-positions were tolerated, including methyl, choro, and
trifluoromethyl, affording the products in 32−59% yields (3k−
3n). Remarkably, fused and hetero rings proceeded smoothly
in the reaction furnishing the expected pyridylation products
with moderate efficiency (3o−3p). This protocol was
compatible with multiple substitution patterns, although the
products were obtained in decreased yields (3q−3s). Notably,
varying the R1 group of 2 to cyclopropyl, adamantyl, or phenyl
has a little effect on the reaction efficiency (3t−3v).
Additionally, aliphatic enones can be successfully employed
in the reductive pyridylation affording the products albeit with
slightly diminished yields (3w−3y). Cyclic enones were further
explored, and corresponding products were obtained with
maintained yields (3z−3ab). To our delight, chromone
underwent the electroreductive pridylation to furnish product
3ac in low yield, which can serve as a synthetic precursor for
selective σ1 receptor antagonist.21 To further expand the
substrate scope, various cyano-pyridines were examined under
optimal conditions. It was found that the substituent and the
position of the cyano group significantly affected the reaction
performance (3ad−3ag). Neither 2-cyano nor 3-cyano
pyridine (3ad−3ae) was tolerated in the reaction; besides, 4-
cyano-2-fluoropyridine failed to afford the desired product.
These results might be attributed to the weaker coordination
between the substrates with Ni(acac)2 owing to the steric
effects of substituents. In contrast, 4-cyano-3-fluoropyridine
proceeded smoothly in the reaction giving a sterically hindered
product 3ag with lower yield.
through a proton-coupled electron transfer process (Scheme
2d).16
To the best of our knowledge, electroreductive pyridylation
of electron-deficient alkenes has never been well-developed.17
There are two main issues hampering development of the
transformation (Scheme 2e): (a) uncontrollable homocoupling
reaction of alkene or pyridine precursors, due to the similar
reductive potential of the reactants;18 (b) low reactivity of
internal alkenes.17 Inspired by our previous work on nickel-
catalyzed 1,4-hydroboration of N-heteroarenes19a and related
work of Dunstan,19b we envisaged that nickel salt might
selectively complex with 4-cyanopyridine, thereby differ-
entiating the reductive potentials of the reaction partners
(Scheme 2e). Thus, as part of our ongoing work in transition-
metal catalysis and synthetic electrochemistry,20 nickel-assisted
electroreductive pyridylation is reported herein. This novel
protocol was readily compatible with a broad range of electron-
poor alkenes, including α,β-unsaturated ketone, ester, amide,
nitrile, and sulfone. This novel electrochemical approach
provided a complementary access to pyridines, which are
challenging for conventional approaches.5
Initially, benzalacetone 2a was chosen as a model electron-
poor alkene, which has received far less attention,5 with 4-
cyanopyridine as a reaction partner in an undivided cell
(Scheme 3). Under direct electrolysis, the optimal result of the
reaction between 1 and 2a was observed (60% yield) with the
employment of Ni(acac)2 (10 mol %) (acac = acetylacetone)
B
Org. Lett. XXXX, XXX, XXX−XXX