Organic Letters
Letter
employed, deuteration occurred at the 1- and 3-positions with
15% and 97% D-incorporation, respectively. Moreover,
deuteration of drug molecules (2aa) and drug derivatives (2z
and 2ab) gave ortho-deuterated products in 53−98% D-
incorporation. Under the standard reaction conditions, 2,6-
dimethylaniline 2ac was deuterated in 62% D-incorporation at
the methyl substituents. This highly efficient HIE reaction was
limited to primary anilines, while secondary and tertiary
anilines only gave very low levels of deuteration. When N-
methyl-p-toluidine and N,N-dimethyl-p-toluidine were em-
ployed, only 20% and 0% D-incorporation were detected,
respectively.
To further investigate the different regioselectivity and
chemoselectivity of this reaction, Kerr’s catalysts (IMes)Ir-
(cod)Cl 3a18 and (IMes)Ir(PPh3)(cod)+ 3b,19 which were
widely used in HIE reactions, were studied for comparison (see
the SI). Some typical anilines with functional groups, such as
2c, 2h, 2i, 2k, 2l, 2m, 2n, 2o, 2w, and 2ab, were employed as
substrates. With regard to Kerr’s catalysts, the deuteration did
not occur at the ortho-position of amino group in all cases.
Deuteration of substrates 2h, 2i, 2k, 2m, 2o, 2w, and 2ab
occurred at the ortho-position of the functional groups, while
no deuteration occurred with substrates 2c, 2l, and 2n. These
results revealed the unique catalytic reactivity of MIC−Ir
complexes compared with traditional NHC−Ir complexes.
In general, NHC−Ir(I) complexes catalyzed HIE reaction
was achieved via ortho-metalation with the assistance of
directing groups (Scheme 4, intermediate A). Compared with
In summary, we have shown an effective method for ortho-
HIE reaction of anilines by using the MIC−Ir complex as
catalyst. High deuteration level was achieved with low catalyst
loading. The reaction can tolerate various functional groups,
such as acyl, ester, amide, sulfonyl, and nitro, without affecting
regioselectivity. The wide scope, high selectivity, and high
deuteration level make this reaction an appealing choice for
organic synthesis and pharmaceutical applications. Further
catalytic applications of MIC−metal complexes are currently
ongoing in this area.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures, characterizations of new
compounds, crystal structure, NMR spectra data
Accession Codes
CCDC 1977129 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Scheme 4. Proposed Intermediates for Ir-Catalyzed HIE
Reaction of Anilines
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Corresponding Authors
Peng Zhao − School of Materials Science and Engineering, Hubei
University, Wuhan 430062, People’s Republic of China;
Xiaoyu Yan − Department of Chemistry, Renmin University of
China, Beijing 100872, People’s Republic of China;
Authors
Wei Liu − Department of Chemistry, Renmin University of
China, Beijing 100872, People’s Republic of China
Lei Cao − Department of Chemistry, Renmin University of
China, Beijing 100872, People’s Republic of China
Zengyu Zhang − Department of Chemistry, Renmin University
of China, Beijing 100872, People’s Republic of China
Gang Zhang − Department of Chemistry, Renmin University of
China, Beijing 100872, People’s Republic of China
Shiqing Huang − Department of Chemistry, Renmin University
of China, Beijing 100872, People’s Republic of China
Linwei Huang − Department of Chemistry, Renmin University
of China, Beijing 100872, People’s Republic of China
other functional groups, the amino group was often regarded as
a poor directing group due to the reluctant formation of four-
membered metallacycle. Thus, the HIE reaction occurred at
the ortho-position of functional groups other than the amino
group. We proposed another plausible route for MIC−Ir
complex 1a catalyzed HIE reaction of anilines. As investigated
above, the base, K+, and NH2 group were important for this
efficient HIE reaction. We proposed noncovalent interactions
of K+ and NH2 group as well as aryl group of the ligand, which
drew the aniline toward the Ir center and led to activation of
ortho−C-H bond of amino group (Scheme 4, intermediate B).
The disfavor of MIC−Ir catalysts for directing group assisted
ortho-metalation might be due to the strong σ-donating
property of MIC. Unfortunately, stoichiometric reactions
meant to obtain detailed information on possible intermediates
all failed.
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work is supported by the National Natural Science
Foundation of China (21602249).
C
Org. Lett. XXXX, XXX, XXX−XXX