Tetrahedron Letters
Synthesis of bis(2-imino-1,3-dimethylbenzimidazoline)s via reactions of
a solvothermally prepared benzimidazolium chloride and diamines
Shengli Zuo a, Fan Zhang a, Jianjun Liu a, Ang Zuo b,
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a State Key Laboratory of Chemical Resource Engineering, Department of Applied Chemistry, College of Chemistry, Beijing University of Chemical Technology, Beijing 100124, China
b Department of Chemistry and Biochemistry, The University of Notre Dame, Notre Dame, Indiana 46545, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first solvothermal preparation of benzimidazolium chloride for the synthesis of bis(2-imino-1,3-
dimethylbenzimidazoline) derivatives from readily available diamines is reported, including an opti-
mized preparation of previously reported solvothermal synthesis of the benzimidazolium intermediate.
Several primary diamines including both aliphatic and aromatic linkers were converted to the corre-
sponding bis(guanidine)s in moderate to good yield.
Received 28 November 2020
Revised 20 January 2021
Accepted 8 February 2021
Available online 12 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Solvothermal reaction
Bis(guanidine)s
Imidazolium chloride
Introduction
available bis(thiourea) [17]. This route avoids the formation of bis
(carbodiimide), lead(ll) oxide, and 20 equivalence of amines were
Bis(guanidine)s are essential for various applications in the
fields of coordination chemistry and the pharmaceutical industry
[1]. The resonance stabilization of the conjugate acid of bis(guani-
dine) results in high basicity that broadens its chelating ability
with various metals, such as Ni [2], Cu [3], Zn [4], Ag [5], and Mn
[6]. Bis(guanidine)s can also be used as catalysts and chiral auxil-
iaries for a number of different organic reactions [7–9]. Their bio-
logical activities and use in pharmaceutical applications are
important for the treatment of severe human diseases, for instance,
Human African Trypanosomiasis (HAT) [10] and cancer [11]. As a
consequence, the preparation and functionalization of bis(guani-
dine)s have been intensely studied and a number of approaches
are now well-developed [12–14].
Arising from the structural similarity between bis(guanidine)
and guanidine, many synthetic approaches to bis(guanidine) are
based on prior reports of the syntheses of guanidine, which have
been widely investigated in the past several decades [15]. Common
previously reported methodologies are described in Scheme 1. As
reported by Henkel and coworkers, bis(guanidine) can be prepared
through the reaction of an excess of monoguanidine with 1,3-
dibromopropane [16]. This solvent-free system requires a liquid
starting guanidine and reaction with sodium ethoxide to afford
only modest yield of product. Kretschmer and coworkers recently
described a one-pot synthesis of bis(guanidine) from commercially
used to increase the yield and ease of ,purification. However, both
methodologies exhibit several limitations which include the use of
excess guanidine starting material, ecotoxicity of lead (PbO)
reagents, waste of excess amine, low yield, narrow scope, and pres-
ence of deleterious side reactions. A more efficient preparation of
bis(guanidine) is still lacking and would therefore be of great
interest.
Ishikawa and coworkers reported a synthesis of guanidine
which employed an imidazolinium chloride and a range of primary
amines (Scheme 1) [18]. This stepwise method is convenient
because of the high efficiency, commonly available reagents, and
the use of a stable imidazolinium intermediate, an intermediate
which can be prepared in a straightforward manner from imidazo-
lidinone and oxalyl chloride/triphosgene [19]. Imidazolinium chlo-
ride is a widely applied species in many disparate chemical
processes, such as catalysis [20,21], drug development [22,23],
and carbohydrate chemistry [24]. The synthesis of imidazolinium
chloride has been previously reported [19,25]. however, these
methods are limited due to both tedious synthetic procedures
and harsh reaction conditions. Inspired by the solvothermal reac-
tion in organic synthesis and coordination chemistry [26], we
herein report the first synthesis of benzimidazolium chloride via
a facile and safe solvothermal approach. This process results in a
remarkably easy set-up and a number of advantages over other
reported procedures [27]. Furthermore, we also present the first
stepwise methodology in the synthesis of bis(benziguanidine)s
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Corresponding author.
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