Tetrahedron Letters
Copper-mediated ortho CAH primary amination of anilines
a,b,
Tai-Jin Cheng a,b, Xing Wang a,b, Hui Xu a, , Hui-Xiong Dai
⇑
⇑
a Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
b University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein a copper-mediated ortho CAH primary amination of anilines by using cheap and com-
mercially available benzophenone imine as the amination reagent. The protocol show good functional
group tolerance and heterocyclic compatibility. Late-stage diversification of drugs demonstrate the syn-
thetic utility of this protocol.
Received 7 February 2021
Revised 30 March 2021
Accepted 15 April 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
CAH activation
Primary amination
Late-stage diversification
Primary anilines are important structural motifs in organic syn-
thesis, and commonly found in natural products and pharmaceuti-
cals.[1]. Thus, development of an efficient and practical approach
to introduce a primary amino into the target molecular is highly
desirable in organic synthesis [2]. Direct CAH primary amination
is the most straightforward way. Without chelating group assis-
tance, in 2016, Tung [3a] and Nicewicz [3b] independently devel-
oped photocatalyzed CAH bond primary amination by employing
ammonia and ammonium carbamate as amino source. Zhang
developed a radical amination by using TMSN3 as the amino source
[4]. Falck [5a], Morandi [5b], Jiao [5c], and Seko [5d] reported the
Rh-, Fe-, and Cu-catalyzed electrophilic amination. However,
these non-directed protocols often suffer poor regioselectivities,
and a mixture of aniline isomers were formed (Scheme 1a).
Directing-group assisted CAH functionalization is a reliable
approach to regioselectively introduce a functional group in the
ortho, meta, and even remote para positions of the arene [6]. By
employing 8-aminoquinoline, and oxazoline amides as the direct-
ing group, Tan [7a], Gui [7b], Bolm [7c], Chang [7d] and our
group [7e] reported Cu- and Ni-catalyzed CAH primary
amination of aryl carboxylic acid by employing ammonia, NaN3,
oxime, and dibenzothiophene sulfoximine as the amino source
(Scheme 1b-1). In 2016, Uchiyama [8] demonstrated a new strat-
egy to introduce primary amine into arene via directed deprotona-
tive cupration of aromatic CAH bond and subsequent amination
using BnONH2. In 2014, Zhu [9] reported ortho primary amination
of 2-phenylpyridine-type substrate using TMSN3 as the amino
source (Scheme 1b-2). Despite these undisputable achievements,
ortho CAH primary amination of aniline has not been demon-
strated yet. In connection with our interest in copper-catalyzed
CAH functionalization [10] and development of new primary ami-
nation reagents [7e], herein, we report copper-mediated ortho CAH
primary amination of anilines by employing safe and commercially
available benzophenone imine as the amino source (Scheme 1c).
Aqueous ammonia, amide and imine are often employed as the
amino source in the metal-catalyzed CAH amination [3–5,7–9].
Thus, we commenced our studies by treating 1a, aqueous ammonia
2a with 0.2 equiv. Cu(OAc)2 in 3 mL toluene at 80 °C (Table 1, entry
1). However, no desired product was obtained. Next, we screened
various amino sources, including amide, sulfamide, imine, and
oxime. To our delight, imine 2d afforded the desired product 3a
in 11% yield after the hydrolysis (entries 2–5). Among varieties of
copper salts investigated, CuCl was the optimal and could improve
the yield to 21% (entries 6–8). Increase the loading of CuCl to 1
equiv. could significantly improve the yield to 51% (entry 9). DMSO
was also effective, albeit in lower yield (entry 10). When DMF and
MeOH were employed in the reaction, no desired product was
obtained (entries 11 and 12). Lowering or elevating the reaction
temperature to 60 and 100 °C could not improve the yield (entries
13 and 14). Copper-promoted dimerizations of benzophenone
imine were inevitably formed during the optimization process
[11], promote us to further screen the imine equivalent and the
CuCl loading (see supporting information). Finally, we could
improve the yield to 85% in the presence of 1.5 equiv. of CuCl
and 2.5 equiv. of benzophenone imine 2d (entry15).
⇑
Corresponding authors at: Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
(H.-X. Dai).
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Tai-Jin Cheng, X. Wang, H. Xu et al., Copper-mediated ortho CAH primary amination of anilines, Tetrahedron Letters, https://doi.
Cheng, Tai-Jin
