Chemical Physics Letters
derivatives and their electrochemical oxidation to 2-pyridones
Rufus Smits∗, Baiba Turovska, Sergey Belyakov, Aiva Plotniece, Gunars Duburs
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of variously substituted 5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives were
synthesized and their oxidation potentials determined by cyclic voltammetry. The resulting 2-
pyridone structure and a tricyclic heterocycle which was formed during an attempted synthesis of
4-(2-hydroxyphenyl) substituted 3,4-dihydro-2(1H)-pyridone were confirmed by single crystal X-ray
crystallography.
Received 21 October 2015
In final form 17 February 2016
Available online 24 February 2016
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
Hantzsch-like reaction from Meldrum’s acid, acetoacetate, alde-
hyde, and NH4OAc in a 1:1:1:1 ratio in boiling glacial acetic acid
ucts and also possess interesting pharmacological properties such
as reverse transcriptase inhibition of human immunodeficiency
virus-1 (HIV-1) [1,2], cardiotonic for the treatment of heart failure
[3], antitumor [4,5], antibacterial [6], and other biological activities
[7,8].
according to a published procedure [10] in yields ranging from 10%
to 80% (Scheme 1).
The N-benzyl 4-unsubstituted 3,4-dihydropyridone
3
was obtained by deprotonating the 4-unsubstituted 3,4-
dihydropyridone [11] with sodium hydride and subsequently
reacting with benzylbromide.
Since we are interested in using the 3,4-dihydropyridone scaf-
fold as a linker for constructing amphiphilic compounds for use
in drug delivery applications [9], the main goal of this work
is to provide oxidation potentials of variously substituted 3,4-
dihydropyridones. This is important in metabolic studies and also
in chemical modifications. In our work we require bromination
of the allylic methyl group at position 6 and in our experi-
ence 1,4-dihydropyridines are oxidized with liquid bromine thus
the oxidation potentials would provide some indication how
the 3,4-dihydropyridones would behave under similar bromina-
tion conditions. The 3,4-dihydropyridone oxidation potentials are
compared to the extensively studied 1,4-dihydropyridine (DHP)
oxidation potentials, some of which are good antioxidants.
During the reaction with salicylaldehyde, and methyl ace-
toacetate a product mixture was isolated which according to
LC/MS analysis indicated 2 compounds with different masses one
in 40% and the other in 46% yield. The product mixture was
fractionally crystallized from EtOAc and EtOH and a diastere-
omeric mixture of compounds separated. NMR analysis indicated
that the mixture was made up of the known tricyclic com-
pound 1 and a new tricyclic compound 2 [12]. Compound 1
has been synthesized using Meldrum’s acid, salicylaldehyde, and
urea in 67% yield, a possible mechanism was also proposed
[13].
According to this mechanism, a substituted coumarine inter-
mediate in our case would retain the ester group to form
compound 2 and not undergo decarboxylation like in com-
2. Results and discussion
pound 1. The structure of compound
2 was confirmed by
single crystal X-ray crystallography (Figure 1), which indicated
that the compound crystallizes as a dimer with its antipode
(Figure 2).
2.1. Synthesis of
5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives
parameter a are formed by means of intermolecular hydrogen
The variously substituted 5-carboxy-6-methyl-3,4-dihydro-
2(1H)-pyridone derivatives 4–13 were synthesized using
a
˚
˚
bonds of NH· · ·O type with length of 2.993(4) A (H· · ·O14 = 2.05 A,
N11–H· · ·O14 = 160◦). Formation of the chains is shown in
(Figure 2). Also in the crystal structure there are weak CH· · ·O type
hydrogen bonds; the shortest of them is C19–H· · ·O14 with length
∗
Corresponding author.
˚
of 3.241(4) A.
0009-2614/© 2016 Elsevier B.V. All rights reserved.