Angewandte
Chemie
DOI: 10.1002/anie.201301019
Synthetic Methods
2À
Acetylide Ion (C2 ) as a Synthon To Link Electrophiles and
Nucleophiles: A Simple Method for Enaminone Synthesis**
Dingyi Yu, Yin Ngai Sum, Amanda Chng Cheng Ean, Mei Ping Chin, and Yugen Zhang*
2À
Although the dumbbell structure of the acetylide ion, C2
,
of new methods for enaminone synthesis from simple
molecules is highly desired.[15] We previously developed
a novel catalytic system[4] for the production of propargyl-
amines from calcium carbide by aldehyde–alkyne–amine
(AAA, A3)[16] and alkyne–dihalomethane–amine (AHA)[17]
three-component coupling reactions. In these reactions, it is
believed that the nucleophilic acetylide attacks an iminium
intermediate to form propargylamines.[16] Interestingly, the
presence of enaminones in the reaction mixture was observed
under certain conditions (Scheme 2). This observation trig-
gered our interest on two counts: we could develop a novel,
valuable method for enaminone synthesis and find out how an
acetylide links an electrophile and a nucleophile in one pot.
In a reaction mixture containing an aldehyde, an amine,
acetylide, and a copper(I) catalyst, different potential reac-
tions could occur to afford different products, such as an
amide, an imine, a propargylamine, or a propargyl alco-
hol.[17,18] Thus, tuning of the reaction conditions is crucial for
enaminone production. An initial test was conducted in N,N-
has been known for many years,[1] the direct use of metal
acetylides (MI2C2 or MIIC2) in organic synthesis is quite rare,
mainly because of the low solubility of metal acetylides in
common organic solvents.[2–4] Given the demand for the
alkyne functionality and its nucleophilic properties, the
acetylide ion could play an important role in modern organic
synthesis.[5] It was reported previously that the acetylide
dianion can act as a mild nucleophile to link two identical
electrophiles, such as aryl halides (Sonogashira coupling)[2] or
two carbon dioxide molecules,[6] or an aldehyde with an amine
(Scheme 1).[4] Conditions have also been developed for
Scheme 1. Versatile acetylide synthon for organic synthesis.
acetylides to bridge two different electrophiles to form
asymmetrical internal alkynes.[4] Herein, we report that the
acetylide ion (C22À) can link an electrophile (aldehyde) with
a nucleophile (amine) in one catalytic cycle (Scheme 1). This
remarkable finding constitutes a simple and efficient method
for the synthesis of enaminones from readily accessible small
molecules.
Scheme 2. Different pathways for the three-component coupling of an
aldehyde, calcium carbide, and an amine.
Enaminones show versatile reactivity as both electro-
philes and nucleophiles and have long been used as important
synthetic intermediates for a wide variety of heterocycles
contained in natural products and pharmaceutical com-
pounds.[7,8] Although a number of methods have been
developed for the preparation of enaminones,[9] all are
based on specific multifunctional starting materials, such as
1,3-dicarbonyl compounds,[10] enolates,[11] heterocycles,[9f,12]
propargyl alcohols,[13] or ketones.[14] Thus, the development
dimethylformamide (DMF; AR grade, 0.02 vol% water) with
the catalyst CuI (5 mol%), benzaldehyde, calcium carbide,
and diisopropylamine at 858C for 48 h. The reaction gave
exclusively the enaminone, 3-(diisopropylamino)-1-phenyl-
prop-2-en-1-one (4a), in 60% yield with incomplete con-
version of the aldehyde. Interestingly, when the solvent was
changed to acetonitrile (AR grade), the reaction produced
only the propargylamine, N,N-diisopropyl-1-phenylprop-2-
yn-1-amine (3a), in 55% yield. The reaction in dimethyl
sulfoxide also afforded the enaminone, whereas the prop-
argylamine was formed in THF and toluene (see Table 1 in
the Supporting Information). It was found that the synthesis
of the enaminone could be sped up by adding water (1 vol%)
to the DMF solvent. Under these conditions, the enaminone
was formed in 83% yield in 16 h (see Table 1 in the
Supporting Information). None of the desired product was
observed when anhydrous DMF was used. Further screening
[*] Dr. D. Yu, Y. N. Sum, A. C. C. Ean, M. P. Chin, Dr. Y. Zhang
Institute of Bioengineering and Nanotechnology
31 Biopolis Way, The Nanos, Singapore 138669 (Singapore)
E-mail: ygzhang@ibn.a-star.edu.sg
[**] This research was supported by the Institute of Bioengineering and
Nanotechnology, Biomedical Research Council, Agency for Science,
Technology and Research, Singapore.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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