Tetrahedron Letters
Synthesis of N-substituted aryl amidines by strong base activation
of amines
Muhammad M. Khalifa a, Micah J. Bodner a, J. Andrew Berglund a,b, Michael M. Haley a,
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a Department of Chemistry & Biochemistry, University of Oregon, Eugene, OR 97403-1253, USA
b Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe an efficient method for the direct preparation of N-substituted aryl amidines from nitriles
and primary amines. The protocol employs activation of amines by a strong base and provides greater
access to a pharmaceutically relevant functional group. This synthetic approach tolerates deactivated
nitriles, nitriles with competing substitution sites, and aryl amines.
Received 23 April 2015
Revised 7 May 2015
Accepted 8 May 2015
Available online 13 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Amidine
Amine
Nitrile
Base-activation
Strong base
Introduction
lead.22,31 These findings, in conjunction with preceding literature
on amidines, point to the importance of N-substituted amidines
Amidines are a class of pharmaceutically relevant small mole-
cules, in addition to being important building blocks for organic
chemical synthesis and having a number of applications in materi-
als chemistry.1–13 Benzamidine, the simplest aryl amidine, is a
competitive, specific inhibitor of trypsin. Its derivatives act as
antimicrobial and antiparasitic agents and have been used for the
in pharmaceutical chemistry.
Several amidine-containing moieties possess important phar-
maceutical properties in their own right. Tetrahydropyrimidine
derivatives (e.g., 3) display specific m1 receptor agonist activity
and can act as neuromuscular blocking agents.27,32,33
Benzimidazole derivatives have been investigated for their anthel-
minthic and antifungal activity; a new class of benzimidazole
derivatives (e.g., 4) has been identified as antimalarial lead com-
pounds.29,34–36 Both motifs can be considered N-substituted ami-
dines. This pharmaceutical salience is the impetus for studying
new examples of N-substituted amidines and examining methods
for amidine synthesis.
Creation of new N-substituted amidines for study necessitates
functionalization of the amidine group. Direct addition of nitriles
and amines to form amidines is not possible; several strategies
have been described to overcome this synthetic obstacle.37–44 All
possess limitations for use in N-substituted amidine synthesis,
including poor synthetic efficiency, time and material economy,
or starting material compatibility. Methods employing transition
elements or metals have an added disadvantage when considering
environmental impact.40–42
treatment of
a variety of diseases, including pneumocystis
pneumonia, antimony-resistant leishmaniasis, and human African
trypanosomiasis.14–20 Amidines are known to bind nucleic acids;
such action is crucial to their mechanism of action in some disease
models.21–24 This property has been known for some time, and
modulation of long, amidine-containing compounds has been pro-
posed for sequence-specific targeting of both RNA and DNA.25 In
addition to being evaluated for anti-inflammatory, analgesic, and
anti-cancer properties, amidine-containing moieties continue to
be important in the search for treatments against Alzheimer’s
disease, malaria, and myotonic dystrophy type 1 (DM1).16,26–31
Recently, investigations of pentamidine (1, Fig. 1) and related
analogs revealed that N-substituted aryl bis-amidines may be
especially relevant to the development of effective therapeutics
against myotonic dystrophy type 1, as a recent study identified
the triaminotriazine-containing bis-amidine derivative 2 as a
Preparation of unsubstituted amidines under basic conditions
has been described, but the approach is not well studied.16,45,46
Creation of a nucleophile by strong base activation of an amine
presents the possibility of preparing a wider range of N-substituted
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Corresponding author. Tel.: +1 541 346 0456; fax: +1 541 346 0487.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.