A novel approach to amidines from esters

Article abstract of DOI:10.1016/S0040-4039(01)02162-1

A mild and efficient method for the direct conversion of aromatic, benzylic and aliphatic esters to amidines - in the form of their hydrochlorides - has been developed.

Full text of DOI:10.1016/S0040-4039(01)02162-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 419–421
A novel approach to amidines from esters
Heike Gielen,* Cristina Alonso-Alija, Martin Hendrix, Ulrich Niewo¨hner and Dagmar Schauss
Bayer AG, Business Group Pharma, D-42096 Wuppertal, Germany
Received 25 October 2001; accepted 13 November 2001
Abstract—A mild and efficient method for the direct conversion of aromatic, benzylic and aliphatic esters to amidines—in the
form of their hydrochlorides—has been developed. © 2002 Elsevier Science Ltd. All rights reserved.
Amidines are versatile building blocks for the synthesis
of various heterocyclic compounds.1 Nevertheless, the
methods currently available for the preparation of
amidines often involve multistep processes.2 The most
common precursors are nitriles, which are often expen-
sive or have to be synthesized prior to the amidine
formation. With carboxyclic acids as starting materials,
temperatures above 230°C are needed for the transfor-
mation using benzenesulfonamide as reagent.3
the isolation of either amidines or amides, the amides
would then be the hydrolysis products of the amidines.
We have employed this method for the preparation of
aromatic, heteroaromatic, benzylic and aliphatic ami-
dinium hydrochlorides in moderate to high yields
(Table 1). Even nitriles as further substituents are toler-
ated (entries 4 and 5), in contrast to previous studies
which described the selective transformation of nitriles
to amidines in the presence of esters.6
We have developed a mild and efficient route to ami-
dinium hydrochlorides from the corresponding esters
employing a variation of Garigipati’s reaction,4 which
is based on Weinreb’s procedure5 for the conversion of
esters to amides.
In conclusion, we have developed a mild and efficient
route to amidines from readily available esters using
methylchloroaluminium amide and methanol as
quenching agent.
General experimental procedure
In 1990 Garigipati reported on the conversion of alkyl
and aryl nitriles to amidines in a single step using
methylchloroaluminium amide which was prepared by
addition of ammonium chloride to commercially avail-
able trimethylaluminium.4 This procedure was devel-
oped by Weinreb et al.5 for the conversion of esters to
amides, using 3 equiv. of the aluminium reagent with
subsequent quenching with 5% hydrochloric acid. In
contrast to that, Garigipati employed a slurry of silica
gel in chloroform as quenching agent for the prepara-
tion of amidines.4
1–5 equiv. ammonium chloride was suspended in dry
toluene under an argon atmosphere, and the mixture
was cooled to 0°C. 1–5 equiv. of a 2 M solution of
trimethylaluminium in hexane was added dropwise and
the reaction mixture was stirred at room temperature
until no more evolution of gas was observed. After
addition of 1 equiv. of the ester, the mixture was stirred
at 80°C bath temperature overnight. It was then cooled
down to 0°C and methanol was added with consequent
stirring for 1 h at room temperature. After filtration,
the solid was washed with methanol several times, the
solution evaporated to dryness in vacuo and the residue
washed with methanol. The product can be purified by
crystallization from methanol/dichloromethane or by
flash chromatography.
We observed the conversion of esters to amidines with
1–5 equiv. methylchloroaluminium amide which was
prepared in situ, followed by hydrolysis of the alu-
minium complexes with methanol (Scheme 1). There-
fore, the quenching conditions seem to be crucial for
Keywords: amidine; ester; methylchloroaluminium amide.
* Corresponding author. Tel.: +49(0)202-364855; fax: +49(0)202-
364061; e-mail: heike.gielen.hg@bayer-ag.de
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02162-1

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H. Gielen et al. / Tetrahedron Letters 43 (2002) 419–421
Table 1. Preparation examples

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421
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