DOI: 10.1002/asia.201701287
Communication
Cyclization Reactions
Rhodium(III)-Catalyzed Directed CÀH Amidation of N-
Nitrosoanilines and Subsequent Formation of 1,2-Disubstituted
Benzimidazoles
Yanyu Chen,[a] Rong Zhang,[a] Qiujun Peng,[a] Lanting Xu,*[b] and XianHua Pan*[b]
of Piv-protected anilines with N-nosyloxycarbamates.[8] Soon
Abstract: An efficient rhodium-catalyzed direct CÀH ami-
dation of N-nitrosoanilines with 1,4,2-dioxazol-5-ones as
amidating agents has been developed. This method fea-
tured mild reaction conditions, a wide substrate scope
and satisfactory yields. Besides, the amidated products
could be readily converted to pharmaceutically valuable
1,2-disubstituted benzimidazoles via an HCl-mediated de-
protection/cyclization process in one pot.
after, Zhang had achieved a palladium-catalyzed CÀH amina-
tion of Ac-protected aniline with N-fluorobenzenesulfoni-
mide.[9] More recently, Chang and Li have independently de-
scribed several excellent studies on a [Cp*MIII] catalyzed ortho
amidation of protected anilines by using very efficient amino
sources (dioxazolones or azides).[10] These pieces of work pro-
vided new pathways for direct ortho-amination of aniline.
In 2013, Zhu and co-workers reported an elegant Rh-cata-
lyzed N-nitroso-directed ortho-olefination reaction under mild
conditions.[11] After that, several research groups have devel-
oped ortho functionalizations of anilines, such as acylation, cy-
anation, acyloxylation, alkoxylation and alkynylation by using
N-nitroso as an ideal directing group,[12] which possessed vari-
ous coordination modes to transition-metal centers and could
be easily introduced and transformed under mild reaction con-
ditions and even applied for further chemical transformations
to afford target functional groups. However, despite these sig-
nificant advances, the ortho-amination via CÀH bond activation
by using N-nitroso has never been reported as a directing
group until now, to the best of our knowledge (Scheme 1).
During our continuous studies on direct CÀH bond function-
alizations,[13] herein we report an efficient Rhodium catalyzed
ortho amination of anilines by using nitroso as a directing
group. Its high efficiency, broad substrate scope, excellent
functional group tolerance, and mild operation conditions
make it particularly suitable for late-stage functionalization of
complex substrates such as drug molecules. Furthermore, the
obtained 2-aminoanilide derivatives could be easily trans-
formed to 1,2-disubstituted benzimidazoles which are pharma-
ceutically important heterocycles that display a wide range of
biological activities.[2b,d–f]
2-Aminoanilide derivatives represent an important structural
motif in several biologically and pharmaceutically active com-
pounds.[1] Besides, 2-aminoanilide derivatives have also been
used as dehydration cyclization precursors to synthesize 2-sub-
stituted benzimidazole skeletons that have found applications
as diverse therapeutic agents, organic light-emitting diodes
(OLEDs), and polymers.[2] The typical approaches for assem-
bling these skeletons are highly dependent on using nitration
of anilides or nucleophilic substitution[3] of 2-fluoronitroben-
zenes[4] followed by reduction of the nitro groups. In recent
years, Pd- or Cu-catalyzed coupling reactions of 2-haloanilide
with amines provided effective methods for the synthesis of
these compounds.[5] However, these procedures generally re-
quire aryl (pseudo)halides as the prefunctionalized starting ma-
terials and inevitably provide a stoichiometric amount of
halide salts as side products.
In the last decade, transition-metal-catalyzed CÀH functional-
ization has emerged as a more efficient and eco-friendly proto-
col for the amination of anilines.[6] In these procedures, a
promising approach to overcome the inert nature of CÀH
bonds and control regioselectivity is to use a potential coordi-
nating protecting group of an aniline as a directing group.[7] In
2010, Yu reported a palladium-catalyzed ortho CÀH amidation
As indicated in Table 1, N-nitrosoaniline (1a) was selected as
the model substrate. Our initial attempt focused on finding a
reactive amidating reagent that would be compatible with the
desired catalytic cycle. After we surveyed several amidating re-
agents according to previous reports[14] by using [RhCp*Cl2]2 as
the catalyst precursor in DCE at room temperature, we found
that 3-phenyl-1,4,2-dioxazol-5-one (2a) and 5-phenyl-1,3,2,4-di-
oxathiazole 2-oxide (2d) allowed formation of the desired ami-
nation product 3aa in 35 and 18% yield (entries 1 and 4, re-
spectively). Other amination reagents like 4-methylbenzenesul-
fonyl azide (2b) and 5,5-dimethyl-3-phenyl-1,4,2-dioxazole (2c)
were not reactive with N-nitrosoaniline (1a) and only starting
materials could be recovered (entries 2 and 3). We were
[a] Y. Chen, R. Zhang, Q. Peng
School of Perfume and Aroma Technology
Shanghai Institute of Technology
100 Haiquan Road, Shanghai, 201418 (P.R. China)
[b] Dr. L. Xu, Prof. Dr. X. Pan
Shanghai Research Institute of Fragrance and Flavor Industry
480 Nanning Road, Shanghai 200232 (P.R. China)
Supporting information and the ORCID identification number(s) for the au-
Chem. Asian J. 2017, 00, 0 – 0
1
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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