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Published on the web January 30, 2010
An Unexpected Guanidine-catalyzed Amination Reaction Leading to (Z)-¡-Aminocinnamamides
Bo Jiang1,2 and Shu-Jiang Tu*1,2
1College of Chemistry, Chemical Engineering and Materials Science, Suzhou University, Suzhou, P. R. China
2School of Chemistry and Chemical Engineering, Xuzhou Normal University, Jiangsu 221116, P. R. China
(Received December 16, 2009; CL-091114; E-mail: laotu@xznu.edu.cn)
An unexpected guanidine-catalyzed amination reaction
between 4-(arylmethylidene)-2-phenyloxazol-5-ones and N,N-
dimethylformamide in water for selective synthesis of new (Z)-
¡-aminocinnamamides was described. This method has the
advantages of short synthetic route, operational simplicity, and
minimal environment impact.
Ar
N
O
Ph
NH
O
O
Guanidine
Me
O
+
N
H
N
H2O
100 °C
O
Me
Ar
Ph
2
1
3
Scheme 1. Synthetic route of (Z)-¡-aminocinnamamides.
The development of efficient and environmentally friendly
chemical processes for the preparation of new biologically
active molecules constitutes a major challenge for chemists in
organic synthesis.1 In this regard, organic reactions in water
without using harmful organic solvents have received much
attention. In addition to being a safe, readily available, and
environmentally friendly solvent,2 water has also been recog-
nized as an effective reaction medium with unique properties
and possibilities for many organic reactions such as Mannich
reactions,3 Kröhnke reactions,4 and esterification reactions.5 The
continued development of new reaction types in aqueous media
is becoming an interesting area for chemists.
O
Ph
NH
O
Ar
O
Me
N
O
DMF/ H2O
NH2
NH
N
+
Ph
Me
100 °C
H2N
Ar
3a
1a
Ar
H
N
Ph
N
Ar = 4-chlorophenyl
O
H2N
N
H
O
4
Catalytic amination reactions are among the oldest and most
often used reactions in organic synthetic chemistry extensively
employed for the protection and further manipulation of the
carboxylic acid functional group.6 Amination processes are
widespread in the industrial synthesis of a variety of end-
products. In view of their importance, amination protocols
should occupy a prominent place in the desire to advance benign
and sustainable chemical technologies into industrial process
development. However, amination reactions are equilibrium
reactions and generally require removal of water and/or use of
excess amount of the reactants for satisfactory conversion rate.7
For the preparation of substituted amines, the major drawbacks
of these common methods are separation of the metal catalyst
supported on a solid support and, moreover, the removal of
adsorbed products from the catalyst is quite difficult and requires
a large excess of volatile organic solvents.8 Therefore, numerous
modern versions of the amination reaction have been developed
to overcome the drawbacks of the classical method. In general,
the improved methodology relies on the screening of catalytic
systems.9 Quite surprisingly, mild base-catalyzed amination
reactions in water using 4-(arylmethylidene)-2-phenyloxazol-5-
ones as precursors have not stimulated much interest so far. As a
continuation of our research devoted to the development of
green organic chemistry using water as reaction media,10 herein
we report unexpected solvent-involved amination reactions
for environmentally benign synthesis of (Z)-¡-aminocinnam-
amides11 using guanidine carbonate as a mild base catalyst and
water as reaction media (Scheme 1).
Scheme 2. The optimized conditions for formation of 3.
our recent efforts aiming at synthesizing pyrimidines 4, the
treatment of 4-(arylmethylidene)oxazol-5-ones 1a with guani-
dine carbonate in DMF were performed at 100 °C (Scheme 2).
After six hours, white product was obtained. Surprisingly,
1
spectroscopic data (IR and H NMR) indicated that this product
was not the desired compound 4. Suitable crystals of the purified
product 3f were grown and the relative stereochemistry was
elucidated by X-ray diffraction in the case of (Z)-¡-amino-
cinnamamides 3f (Figure 1).12
Next, the model reaction of 4-(arylmethylidene)oxazol-5-
ones 1a with DMF and guanidine carbonate was carried out to
optimize the catalysis conditions, including solvents and amount
of catalyst, in order to achieve the best results in the amination
reactions (Table 1). The experimental results showed that
guanidine carbonate in a medium consisting of 1:1 DMF-H2O
was highly efficient, and 100 °C as reaction temperature could
provide high yield. In order to evaluate the influence of
guanidine carbonate concentration, this reaction was carried
out using different amounts of guanidine carbonate. The reaction
proceeded in the presence of 0.1 equivalent of guanidine to give
the product 3a in 42% yield at 100 °C. Increasing the reagent to
0.15 equivalent, 0.2 equivalent, and 0.3 equivalent successively
resulted in the increasing of the yield to 51%, 60%, and 74%,
respectively. Use of just 0.4 equivalent was sufficient to reach
the highest yield. Further increase of the amount of the catalyst
failed to improve the yield.
Our strategy for synthesizing the (Z)-¡-aminocinnamamides
was through the reaction of preformed 4-(arylmethylidene)-2-
phenyloxazol-5-ones with N,N-dimethylformamide (DMF). In
To extend the scope of this amination procedure for the syn-
thesis of ¡-aminocinnamamides, substrates 1b-1h, with elec-
Chem. Lett. 2010, 39, 210-211
© 2010 The Chemical Society of Japan