DOI: 10.1002/chem.201502234
Communication
&
Halogenation
Selective Halogenation Using an Aniline Catalyst
Ramesh C. Samanta* and Hisashi Yamamoto*[a]
transfer reactions.[7] Alternatively, electrophilic halogenation of
arenes using expensive metal catalysts (Pd, Rh, etc.) and N-
haloimide as the halogenating reagent has been studied over
the last decade.[8] Very recently, a guanidine-based chlorinating
reagent, chloro-bis(methoxycarbonyl) guanidine (CBMG), was
developed by the Baran group,[9] which showed increased
reactivity together with selectivity compared to classical
reagents, whilst similar brominating and iodinating reagents
are not readily available.
Abstract: Electrophilic halogenation is used to produce
a wide variety of halogenated compounds. Previously
reported methods have been developed mainly using a
reagent-based approach. Unfortunately, a suitable “catalyt-
ic” process for halogen transfer reactions has yet to be
achieved. In this study, arylamines have been found to
generate an N-halo arylamine intermediate, which acts as
a
highly reactive but selective catalytic electrophilic
Aromatic amines 1 are known to form amino halides even at
low temperature, and the intermediately formed compounds 2
are known to rearrange into the ring halogenated products 3
at ambient temperature (Scheme 1).[10] Although this reaction
halogen source. A wide variety of heteroaromatic and aro-
matic compounds are halogenated using commercially
available N-halosuccinimides, for example, NCS, NBS, and
NIS, with good to excellent yields and with very high se-
lectivity. In the case of unactivated double bonds, allylic
chlorides are obtained under chlorination conditions,
whereas bromocyclization occurs for polyolefin. The
reactivity of the catalyst can be tuned by varying the
electronic properties of the arene moiety of catalyst.
The carbon-halogen (CÀX) bond forming process is one of the
most fundamental reactions in organic synthesis, and the
applications of halogenated compounds in pharmaceuticals,
agrochemicals, and the material sciences are of crucial impor-
tance.[1] They are indeed extensively used as precursors for the
synthesis of organometallic reagents.[2] Since the discovery of
cross-coupling reactions, aromatic halides are necessary parts
for the synthesis of complex molecules.[3] Therefore, the devel-
opment of efficient and more selective catalytic methods to
easily access this class of compounds is essential.[4]
Scheme 1. N-halo arylamine, an active electrophilic halogen source.
was known to proceed intramolecularly, the resulting halogen-
ated aniline should be less reactive than starting aniline and
thus the intermolecular reaction may be faster than the intra-
molecular process. We envisioned that, in the presence of a
nucleophilic substrate, the consequential N-haloaniline 2 might
then transfer the halogen atom intermolecularly to regenerate
the aniline. In principle, the reaction could be feasible in
“catalytic aniline” with stoichiometric NXS.
Classical electrophilic halogenation is still the method of
choice.[5] However, regioselectivity is not always satisfactory in
usual halogenation of aromatic and heteroaromatic com-
pounds with multiple reaction centers.[4] Among various halo-
genating reagents, N-halosuccinimides (NXS; X=Cl, Br, I) have
turned out to be practically useful reagents in terms of their
easy and safe handling. Due to their low reactivity, several
methods have been developed to activate NXS by using Lewis
or Brønsted acids, which slightly increase the rate of reac-
tions.[6] Recently, nucleophiles are also being used in halogen
With this hypothesis in hand, the initial experiment was per-
formed with N-pivaloylindole as the nucleophilic substrate
using aniline as a catalyst with an equimolar amount of NCS in
dry DCM at room temperature. After 24 h, the chlorination
product was obtained in 15% yield (Table 1, entry 2). Although
the N-chloro amine was previously identified from N-methyl-
aniline,[10b] the reaction did not proceed. Similarly, N-phenyl-
aniline failed to deliver any chlorination product. Fortunately,
the more nucleophilic aliphatic amine (benzylamine) was used
as a catalyst. To our delight the reaction was successful and
75% of the chlorination product was obtained after 18 h
(Table 1, entry 5). Furthermore, 2,6-dimethylaniline, which
cannot undergo an intramolecular 1,2-chlorine transfer reac-
[a] Dr. R. C. Samanta, Prof. H. Yamamoto
Molecular Catalyst Research Center
Chubu University
1200 Matsumoto, Kasugai, Aichi 487-8501 (Japan)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2015, 21, 11976 – 11979
11976
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