COMMUNICATIONS
doi.org/10.1002/adsc.202100600
Organocatalytic Enantioselective Construction of Acyclic N,N-
Acetals via Aza-Addition of Arylamines to Ketimines
+
a
+c
+c
b
b,
Xiao Lin, Keli Ge, Ningning He, Xuling Chen, Pengfei Li, *
a,
a,
Mingxin Dong, * and Wenjun Li *
a
Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266021, People’s Republic
of China
E-mail: mxdong64@qdu.edu.cn; liwj@qdu.edu.cn
Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern
b
University of Science and Technology (SUSTech), Shenzhen 518055, People’s Republic of China
E-mail: lipf@sustech.edu.cn; flyli1980@gmail.com
School of Basic Medicine, Qingdao University, Qingdao, Shandong, 266021, People’s Republic of China
c
+
These authors contributed equally.
Manuscript received: May 18, 2021; Revised manuscript received: July 6, 2021;
Version of record online: ■■■, ■■■■
catalyzed N-alkylation of 3-substituted indoles to
Abstract: A chiral phosphoric acid catalyzed enan-
[6]
afford propargyl aminals. Furthermore, other enantio-
tioselective aza-addition of arylamines to ketimines
has been developed for the construction of chiral
acyclic N,N-acetal motifs. Under the standard
conditions, arylamines reacted smoothly with keti-
mines from isoquinoline-1,3-dione to afford a series
of acyclic N,N-acetals in 82–99% yield with 80–
selective synthesis of N,N-aminals through ketimine
[7]
intermediates have also been reported. An entirely
different catalyst type for aza-addition of acyclic
arylamines to isatin-derived ketimines was graciously
[8]
established by Lin and Duan et al. (Scheme 1B).
Almost at the same time, we also realized the thiourea/
squaramide-catalyzed asymmetric aza-Mannich reac-
tions of 1,2,4-triazoles, 1H-benzotriazoles, anilines and
9
6% ee.
2
-naphthamines to isatin-derived ketimines, furnishing
Keywords: N,N-Acetal; Arylamine; Enantioselectiv-
ity; Ketimine; Organocatalysis
[9]
diversified acyclic N,N-acetals (Scheme 1C). As a
continuation of this work, we have a high level of
motivation to explore the organocatalytic enantioselec-
tive aza-Mannich reactions to enrich the chemistry of
Acyclic N,N-acetal motif is one of the most important acyclic N,N-acetals.
core unit widely found in biologically active molecules On the other hand, isoquinoline-1,3(2H,4H)-dione
Scheme 1A). Notably, the asymmetric addition of skeleton is also a class of privileged structural motifs
nitrogen nucleophiles to imines provids a robust access found in large amounts of biologically active mole-
[1]
(
[10]
to these chiral N,N-acetals. However, the related cules (Scheme 2A). Accordingly, much effort have
researches were not extensively reported, due to the been devoted to the construction of structurally diverse
[2]
potential sensitivity of N,N-acetals. In particular, isoquinoline-1,3(2H,4H)-dione derivatives. However,
impressive results have been limited to the organo- the existing reports are limited to non-asymmetric
[
11]
catalytic asymmetric addition of amide or its equiv- synthesis.
In 2019, You and Yuan et al. firstly
[3]
alents to aromatic aldimines. As an important break- developed a CPA-catalyzed carbon-addition of pyrroles
through, Trost et al. developed a Zinc complex and indoles for the asymmetric synthesis of optically
mediated N-alkylation of indole and its derivatives active
isoquinoline-1,3(2H,4H)-dione
derivatives
[4]
[12]
with aldimines for the construction of chiral aminals.
(Scheme 2B).
With regard to the importance of
Quite differently, Zeng and Zhong et al. realized a isoquinoline-1,3(2H,4H)-diones, and as a part of our
chiral phosphoric acid (CPA)-catalyzed N-alkylation of ongoing interest in the field of organocatalytic asym-
[
5]
[13]
indoles with in situ formed cyclic N-acyl ketimines.
metric additions of nitrogen nucleophiles
and
[14]
Independently, Sun and Wang et al. disclosed a CPA- ketimines,
herein we report a CPA-catalyzed aza-
Adv. Synth. Catal. 2021, 363, 1–7
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