Tetrahedron Letters
Pd-catalyzed imine-directed intramolecular CAN bond formation
through C(sp3)AH activation: An efficient approach to multisubstituted
pyrroles
a,b,
Ting Yu a,b, Qiang Zhu a,b,c, , Shuang Luo
⇑
⇑
a State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China
b University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China
c College of Chemistry and Materials, Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, Nanning Normal University, Nanning 530001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An atom-economic approach to synthesize 1,2,4-trisubstituted pyrroles through palladium-catalyzed
imine-directed intramolecular C(sp3)AH amination reaction has been developed. The imine group acts
as a directing group as well as an intramolecular nucleophile for the first time in intramolecular CAN
bonds formation reactions.
Received 23 January 2020
Revised 23 March 2020
Accepted 27 March 2020
Available online xxxx
Ó 2020 Published by Elsevier Ltd.
Keywords:
Multisubstituted pyrroles
Palladium-catalyzed reactions
C(sp3)AH amination
CAN bond formation
Introduction
Over the past few decades, an immense effort has been made
in transition metal-catalyzed direct CAN bonds formation from
Multisubstituted pyrroles are key structural units in numerous
natural products [1,2]. They have also been widely used for the
synthesis of bioactive molecules, pharmaceuticals and functional
materials [3–5]. Therefore, a myriad of synthetic methods have
been developed for the construction of multisubstituted pyrroles,
including palladium-catalyzed arylation of 2,4-disubstituted pyr-
roles [6], condensation/cyclization of b-formyl aryl ketones [7,8],
CAH bonds [12–14], for this approach was considered as a step-
efficient and environmentally benign alternative to the traditional
CAN bonds formation methods. However, due to the ubiquity and
robustness of CAH bonds, it is still a challenge to develop highly
efficient catalytic system with excellent region- and chemo-selec-
tivity. A general approach to solve this problem is the use of a
directing group (DG) strategy to allow selective CAH bond activa-
tion by the localized transition-metal catalyst [15–19] (Scheme 1).
The intramolecular version of CAN bonds formation from CAH
bonds, in which the N atoms act as directing groups as well as
nucleophiles, provides a convenient method for the construction
of N-heterocycles with high step efficiency and atom economy
[20,21]. By using this strategy, a variety of N-containing func-
tional groups, such as amines [22,23], amides [24,25], amidines
[26], hydrazones [27,28], pyridines [29,30], have been applied in
and plenty of N-heterocyclic products have been synthesized.
However, imine has never been applied in this process. Herein,
or
c
-bromodypnones with anilines [9], gold-catalyzed hydroami-
-amino aryl ketones with phenylacetylenes
nation/cyclization of
a
[10], and palladium-catalyzed [3+2] cycloaddition of ketoimines
with alkynes [11]. Although most of these approaches are suffi-
ciently powerful, they generally involve special starting materials,
multistep procedures and preliminary preparation of some kind of
intermediates or precursors. From the point of view of atom- and
process-economical chemistry, developing an efficient and general
approach to multisubstituted pyrroles is
importance.
a subject of great
we present
a
novel palladium-catalyzed imine-directed
intramolecular CAN bond formation through allylic sp3 CAH bond
activation to synthesize multisubstituted pyrroles. In this reac-
tion, the iminyl directing group acts as an intramolecular nucle-
ophile as well.
⇑
Corresponding authors at: State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China.
(S. Luo).
0040-4039/Ó 2020 Published by Elsevier Ltd.
Please cite this article as: T. Yu, Q. Zhu and S. Luo, Pd-catalyzed imine-directed intramolecular CAN bond formation through C(sp3)AH activation: An effi-