G Model
CCLET 3893 No. of Pages 5
Chinese Chemical Letters
Original article
Palladium-catalyzed amination of chloro-substituted
5-nitropyrimidines with amines
Meng-Meng Liua,b, Qiong Meia,b, Yi-Xiao Zhanga,b, Peng Baia,b, Xiang-Hai Guoa,b,
*
a
Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
b
Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300350, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A concise and efficient approach was developed for the synthesis of mono-substituted and di-substituted
pyrimidines products via palladium-catalyzed amination of chloro-substituted 5-nitropyrimidines and
amines. This synthetic methodology can produce various di-substituted pyrimidines in high yields with
good functional group tolerance, and provide a complementary tool for the syntheses of important
intermediates of nucleosides and purines with bioactivities.
Received 8 October 2016
Received in revised form 25 October 2016
Accepted 31 October 2016
Available online xxx
Keywords:
© 2016 Xiang-Hai Guo. Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of
Medical Sciences. Published by Elsevier B.V. All rights reserved.
Pd-catalyzed
C–N coupling reaction
Aryl halide
Amines
Pyrimidines
1. Introduction
low selectivity, long reaction time and troublesome operation
procedure [8]. On the other hand, palladium-catalyzed coupling
Growing efforts in the past decades were paid to develop
methods toward the functionalization of pyrimidine derivatives
[1]. These six-membered heterocycles are an important class of
nitrogen-containing heterocyclic compounds, which either display
a wide variety of biological activities by themselves [2] or can be
used as key intermediates of medicinally relevant molecules [3]. A
particularly interesting subset of these molecules is chloro-
substituted 5-nitropyrimidines, which are intermediates of several
bioactive nucleoside analogs. For example, clitocine, an antitumor
nucleoside isolated from the mushroom Clitocybe inversa, is
featured with a 5-nitropyrimidine moiety [4]. Reverse transcrip-
tase inhibitors tenofovir [5] and kinase inhibitor purinone
derivatives [6] can also be synthesized from chloro-substituted
5-nitropyrimidines, which demonstrates their unique roles as
milestones for substituted purine syntheses (Fig. 1) [7].
processes have become an indispensable tool for the synthesis of
bioactive substance and organic building blocks, and C–N coupling
reactions of aryl halides with amines catalyzed by palladium have
become an important tool for aromatic amines [9]. But to our
surprise, there have been scarce investigations on Pd-catalyzed
coupling of pyrimidine halides and amines [10], presumably due to
their ability to inhibit and/or deactivate the palladium catalyst [11].
In this contribution, we report the scope of Pd-catalyzed amination
for
a number of chloro-substituted 5-nitropyrimidines with
different amines.
2. Results and discussion
We initiated our studies by screening conditions for the
coupling of 4,6-dichloro-5-nitropyrimidine 1 and 4-anisidine 2
(Table 1) [12]. To improve the yield of the reaction, various
temperatures, molar ratios, solvents, bases and ligands were
examined. For this Pd-catalyzed coupling reaction system, the best
yield is 10%–20% higher than that under original nucleophilic
reaction conditions [8a]. The experimental results also prove that
palladium and ligand are beneficial for this reaction (Table 1,
entries 1–3). The Pd-catalyzed aryl amination reactions most likely
proceed by the oxidative addition of chloro-substituted 5-nitro-
pyrimidines to a Pd0 species, followed by the formation of an
intermediate “(BINAP)Pd(Ar)(Cl)(NR1R2)” which BINAP may switch
In the course of our ongoing syntheses of clitocine analogs, a
series of modified bases are needed for studies on structure-
activity relationships. The present synthetic method under
aromatic nucleophilic
substitution
reaction
(SNAr
)
of
4,6-dichloro-5-nitropyrimidine and nucleophiles suffers from
* Corresponding author at: Department of Pharmaceutical Engineering, School of
Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China.
1001-8417/© 2016 Xiang-Hai Guo. Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights
reserved.
Please cite this article in press as: M.-M. Liu, et al., Palladium-catalyzed amination of chloro-substituted 5-nitropyrimidines with amines, Chin.