Organic Letters
Letter
syn configuration as the major outcome (syn/anti 5:1; SI,
section 5.2). Next, aniline-derived dichlorocinnamides 4b and
4c were generated in ∼60% yields. A dramatic contrast in
diastereoselectivity between 4b and 4c was observed. We
speculated that the formation of 4b might undergo rigid
intermediates and that the formation of 4c would be more
flexible due to the electronic effect. This electronic effect was
also found in products 4d−4j. Substrates bearing furan and
thiophene moieties could be well tolerated, and corresponding
products 4k and 4l were achieved in acceptable yields with
moderate to good diastereoselectivities. α-Methyl cinnamide
was also converted to the corresponding dichloro product 4m
in 51% yield with a 10:1 dr ratio. Subsequently, product 4n
without a N−H moiety was obtained in 83% yield. The benzyl-
amine-derived product 4o was prepared in 62% yield. Other
α,β-unsaturated compounds, such as ethyl cinnamate, trans-
stilbene, and ethyl 3-phenylpropiolate, were dichlorinated
smoothly, giving products 4p, 4q, and 4r in good yields.
Next, to gain more information on this reaction, we used the
reported12,19 probe 5 to identify the chloride species present in
the reaction. By applying 5 as the substrate, we isolated the
tetra-chlorinated product 6 in 76% yield, which supported the
existence of chlorine; on the contrary, the cyclized product 7 as
an indicator of the chloride radical was not detected (Scheme
5a). In addition, the reaction atmosphere on the 1 mol scale of
Scheme 6. Plausible Reaction Pathways of Electrochemical
Chlorination Using Cl3CCN
two chloride anion produces chlorine, which in situ reacts with
aromatic compounds and furnishes the final product 2. The
generated chloride anion can be recycled during the next cycle
of anodic oxidation, and the proton can combine with anion B
to give dichloroacetonitrile C. Intermediate C can release the
remaining chloride anion at the cathode in a similar manner to
give chloroacetonitrile D, and, in turn, acetonitrile. In
comparison, the chlorination of α,β-unsaturated compounds
3 shares similarities and differences (Scheme 6b). In this
transformation, the anodic reduction provides the chloride
anion and dichloroacetonitrile anion B. At the anode, chlorine
is produced from both the chloride anion generated at cathode
and that from the supporting electrolyte TEAC. This anodic
oxidation will release a tetraethylammonium cation, which
forms a salt with anion B. The generated chlorine is
independent of the electrochemical process and gives the
final dichlorinated compounds 4 in the manner of electrophilic
addition. Because a proton was not generated during the
chlorination of cinnamide, 1 equiv of TEAC was required to
supply the chloride anion and the ammonium cation. This
chlorination process is independent of the electrochemical
process and might also work in the electrochemical
chlorination of an aromatic compound via the common
chloride anion species.
Scheme 5. Experiments to Explore the Reaction Mechanism
In summary, we developed an electrochemical chlorination
reaction using Cl3CCN as the chloride source via paired
electrolysis. The reaction proceeds under neutral conditions
and tolerates a variety of functional groups labile under acidic
conditions. This electrochemical reaction utilizes the in-situ-
generated chlorine as a reactive species, making the electro-
chemical process independent of the chemical process in an
on-demand manner. With this approach, both electron-rich
aromatic compounds and electron-deficient α,β-unsaturated
compounds could be efficiently chlorinated. The protocol was
successfully applied in the preparation of commercialized
pharmaceutical products and corresponding intermediates.
1b (Scheme 3b) showed a positive effect in the KI−starch
experiment (SI, section 5), also confirming the presence of
chlorine. Next, cyclic voltammetry (CV) analysis was
performed to elucidate the electrode conditions for the
generation of chlorine. Scan loops with a positive or a negative
start both showed almost identical patterns, suggesting that a
highly predominant pathway could exist (Scheme 5b). In two
mixtures containing acetyl aniline 1b and cinnamide 3a,
respectively, the CVs shared similar peaks at −1.7 V vs SCE
and +1.8 V vs SCE, suggesting the reduction of CCl3CN and
the oxidation of the chloride anion in both cases.
With these results, a plausible reaction pathway is proposed
in Scheme 6. For example, in the chlorination reaction of
aromatic compound 1 (Scheme 6a), at first, the cathodic
reduction of Cl3CCN releases a chloride anion and a neutral
radical A. A second electron transfer to A gives rise to
dichloroacetonitrile anion B. At the anode, the oxidation of
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
Experimental procedures, electrochemistry analytical
data, and NMR spectra (PDF)
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Org. Lett. 2021, 23, 3015−3020