Tetrahedron Letters
Acid promoted dimerization of b-amino-a,b-unsaturated amides
affording bis(functionalized) pyrrolinones
a,b,
Sho Hirai a, Haruyasu Asahara a,b, , Nagatoshi Nishiwaki
⇑
⇑
a School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
b Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Polysubstituted pyrrolinones were synthesized by the dimerization of 3-amino-2-butenamides via treat-
ment with 0.5 equiv p-TsOH under mild reaction conditions, including oxidation and 1,2-migration of the
methyl group. This method is practically advantageous compared to the conventional methods for the
preparation of pyrrolinones, because it does not require difficult experimental manipulations and special
Received 14 October 2016
Revised 11 November 2016
Accepted 16 November 2016
Available online xxxx
reagents such as metal catalysts and oxidants. Because the structures of b-amino-a,b-unsaturated amides
can be easily modified by changing the precursors, b-keto amide and amine, synthesis of diverse pyrroli-
nones is possible.
Keywords:
Pyrrolinones
Dimerization
1,2-Migration
Oxidation
Ó 2016 Elsevier Ltd. All rights reserved.
Enamide
Pyrroline-4-ones are one of the attractive frameworks because
these scaffolds are widely found in optical materials1 and biologi-
cally active compounds such as HIV-1 protease inhibitors,2 anti-
malarials,3 and antimicrobials.4 Despite the highly valuable and
versatile applications, only a few synthetic methods have been
reported for pyrrolinones. The most common approach to synthe-
bulky amines involved substitution at the amide moiety. Ami-
nobutenamides may serve as useful building blocks in the organic
synthesis because of both multifunctionality and the biased elec-
tron density of the carbon-carbon double bond also known as
push-pull alkene.10 During our studies on chemical conversion of
aminated enamides, polysubstituted pyrrolinone were obtained
when exposed to air at room temperature. A similar dimerization
of enamides has been reported by two groups: hypervalent
iodine(III)-mediated cyclization (Scheme 2, Method E) and Cu(II)-
catalyzed oxidative tandem cyclization (Scheme 2, Method
F).11,12 Although bis(functionalized) pyrrolinones can be prepared
in good yields by these protocols, highly toxic trifluoroacetic acid
is used in both the cases, and substituents can be present on the
amide function of aryl groups. Contrary to these methods, the pre-
sent dimerization proceeded at room temperature without using
any special reagent. This advantageous feature encouraged us to
study this reaction in detail for developing a practical method for
the synthesis of polyfunctionalized pyrrolinones.
size pyrrolinones is condensation of a-amino acid esters with alde-
hydes, facilitating stereo-controlled synthesis (Scheme 1, Method
A).5 The formal [3+2] cycloaddition reactions of diphenylcyclo-
propenones with imines (Method B) and
ketenes have also been used for this purpose.6 The transition-
metal-catalyzed intramolecular cyclization of -aminoynones and
a-diazoimines with
a
the condensation of imines with vicinal tricarbonyl compounds
are acceptable methods (Methods C and D).7,8 However, these meth-
ods suffer from some drawbacks such as low availability of the start-
ing materials and narrow substrate scope. Furthermore, it is difficult
to introduce multiple functional groups into the pyrrolinone
framework. Thus, the development of a facile method for multifunc-
tionalized pyrrolinones remains one of the challenging projects.
Recently, we reported a systematic study on the regioselective
amination of acetoacetamides (3-oxobutanamides).9 The reaction
with less hindered amines involved condensation at the b-keto
moiety, affording 3-amino-2-butenamides while the reaction with
The substrates, 3-amino-2-butenamides 1, were easily prepared
in 76–97% yields by heating acetoacetamide with amines such as
propylamine isobutylamine, sec-butylamine and benzylamine at
60 °C for 3 h in THF. When 3-propylamino-2-butenamide (1a) was
exposed to air at room temperature for 3 days, crystalline precipi-
tates were obtained in the chloroform solution. Based on spectral
data, this crystalline product was determined to be 1-propyl-2,5-
⇑
Corresponding authors at: School of Environmental Science and Engineering,
Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan.
dimethyl-3-oxo-2,3-dihydro-1H-pyrrole-2,4-dicarboxiamide (2a),
dimeric product of 1a, and the structure was finally confirmed by
a
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.