Metal-free syntheses of new azocinesviaaddition reactions of enaminones with acenaphthoquinone followed by oxidative cleavages of the corresponding vicinal diols

Article abstract of DOI:10.1039/d0ra02852e

A one-pot, clean and green procedure is described for the syntheses of new azocine derivativesviaaddition reactions of enaminones with acenaphthoquinone followed by periodic acid-mediated oxidative cleavages of the corresponding vicinal diols. Various derivatives of azocine were prepared and well characterized. The excellent yields, simple synthesis procedure, lack of a need to carry out any tedious work-up and column chromatography, metal-free catalysis, and mild reaction conditions are important features of this protocol.

Full text of DOI:10.1039/d0ra02852e

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Metal-free syntheses of new azocines via addition
reactions of enaminones with acenaphthoquinone
followed by oxidative cleavages of the
corresponding vicinal diols†
Cite this: RSC Adv., 2020, 10, 20552
a
a
S. Hekmat Mousavi, Mohammad Reza Mohammadizadeh, Satoru Arimitsu,b
Dariush Saberi,
*
Samira Poorsadeghib and Kojya Gentad
c
A one-pot, clean and green procedure is described for the syntheses of new azocine derivatives via addition
reactions of enaminones with acenaphthoquinone followed by periodic acid-mediated oxidative cleavages of
the corresponding vicinal diols. Various derivatives of azocine were prepared and well characterized. The
excellent yields, simple synthesis procedure, lack of a need to carry out any tedious work-up and column
chromatography, metal-free catalysis, and mild reaction conditions are important features of this protocol.
Received 28th March 2020
Accepted 22nd May 2020
DOI: 10.1039/d0ra02852e
rsc.li/rsc-advances
biologically active compounds.1 Azocine derivatives have also
found applications as therapeutic agents, such as antitussives,
Introduction
antihypertensives, analgesics, nasal decongestants, and anti-
malarials.2 These compounds are also structurally attractive, as
they show interesting conformations. Because of unfavorable
entropy and enthalpy factors, the azocine ring system is
generally difficult to obtain,3 and relatively few methods are
available for its preparation. However, there have been several
general approaches used to construct azocine rings, including
cycloaddition,4 the fragmentation reaction,5 Dieckmann cycli-
zation,6 tandem hydroboration reactions,7 the Michael reac-
tion,8 intramolecular Heck reactions,9 microwave (MW)- and
photo-assisted reactions,10 ring-expansion reactions,11 and ring-
closing metathesis.12 Recently, Soldatova et al. reported a new
Eight-membered azocine rings are N-heterocyclic compounds
that play a pivotal role in the structures of various important
natural products as well as precursors in the syntheses of
aDepartment of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr
75169, Iran. E-mail: mrmohamadizadeh@pgu.ac.ir; Fax: +98-771-4541494
bDepartment of Chemistry, Biology and Marine Science, Faculty of Science, University
of the Ryukyus, 1-Senbaru, Nishihara, Nakagami, Okinawa, 903-0213, Japan
cMarine Chemistry Department, Faculty of Marine Science and Technology, Persian
Gulf University, Bushehr 75169, Iran
dCenter for Research Advancement and Collaboration, University of the Ryukyus,
Senbaru 1, Nishihara, Okinawa 903-0213, Japan
† Electronic supplementary information (ESI) available. CCDC 1976349. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0ra02852e
Scheme 1 Procedure for one-pot syntheses of azocines 3a–t
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Table 1 The structures of the synthesized azocine derivatives 3a–ta
a
Reaction conditions: enaminone (1 mmol), acenaphthoquinone (1 mmol); step 1: EtOH (4 mL), Et3N (1 mmol), reux, 12 h; step 2: H5IO6 (1 mmol),
r.t., 60 min.
pathway for azocine derivative synthesis, with this pathway compounds constitute the driving force for the development of
involving the reaction of an activated acetylene with a b-amino greener methods for synthesizing these compounds. In 2014,
ketone.13 Most of the methods developed for azocine synthesis our research group developed a novel procedure for the
use expensive and inaccessible raw materials. In addition, some synthesis of new azocine derivatives, with this procedure
of the problems associated with the previous methods include involving reactions of acenaphthoquinone with 6-aminouracil
the employment of metals as catalysts, harsh reaction condi- derivatives in the presence of lead(IV) acetate.14 Although this
tions, poor product efficiency and tedious work-up. The inter- method is interesting for forming an eight-membered azocine
esting structures and important biological properties of these ring, both in terms of starting from relatively simple raw
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1
Fig. 1 H-NMR spectra of product 3s recorded at room temperature (A) and 80 ꢀC (B). The aliphatic region of each spectrum is shown.
materials and mild reaction conditions and product efficiency, the metal-free H5IO6-mediated oxidative cleavage of the corre-
the use of toxic lead metal as a catalyst has reduced its popu- sponding vicinal diols resulted in the azocine derivatives with
larity. In the present study, in continuation of our studies on the excellent yields under mild reaction conditions.
oxidative cleavages of cyclic vicinal diols aimed at synthesizing
potentially biologically active heterocycles,15 we developed
a facile and green procedure for the synthesis of new azocine
Results and discussion
derivatives. The addition reactions of enaminones, prepared
from reactions between simple and commercially available b-
diketones and amines, with acenaphthoquinone followed by
Initially, according to
enaminone derivatives 1a–t were synthesized via I2-mediated
condensation reactions of amines and 1,3-dicarbonyls (for
a
previously reported procedure,16
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intermediate was introduced into the second phase of the
reaction—and by adding H5IO6 into the vessel, the reaction was
allowed to continue for another one hour at room temperature.
Aer now carrying out separation and purication of the nal
product, spectral data taken from this product conrmed it to
be structure 3b. The 1H-NMR spectrum of 3b in DMSO-d6
exhibited three sharp singlets, at d ¼ 0.62, 0.84, and 3.83,
attributed to the methyl groups. It also exhibited one sharp
doublet signal (3J ¼ 16.5 Hz) at 2.03 ppm, together with
a multiplet signal in the region 2.12–2.24 ppm and a sharp
doublet signal (3J ¼ 17.6 Hz) at 2.33 ppm related to the meth-
ylene protons. Ten aromatic hydrogens were also indicated by
the presence of three doublets (d ¼ 7.14, 3J ¼ 8.5 Hz), (d ¼ 7.41,
3J ¼ 8.5 Hz), and (d ¼ 7.91, 3J ¼ 6.9 Hz), and one triplet (d ¼ 8.18,
3J ¼ 8.6 Hz) along with a multiplet at d ¼ 7.57–7.80 ppm. The 1H-
decoupled 13C-NMR spectrum of 3b showed 24 distinct signals
in agreement with the proposed structure. The high-resolution
mass spectrum of 3b displayed an [M + H]+ peak at m/z ¼
426.1700, in agreement with the proposed structure.
Subsequently, in order to extend the scope of this reaction, the
wide range of enaminones 1a–m, synthesized via the reactions of
cyclic b-dicarbonyls such as dimedone and 1,3-cyclohexadione
with aromatic amines, were reacted with acenaphthoquinone to
produce azocines, whose structures 3a–m and yields are shown
in Table 1. As can be seen in this table, the products 3a–m were
obtained with high efficiencies, indicating that the type, position,
and number of substituents on the N-linked aromatic ring had
no signicant effect on the reaction rates. Moreover, the enami-
nones 1n–q composed of aliphatic amines such as ethyl and
methyl amines as well as polycyclic amines, that is, 1-naphthyl-
amine, were also subjected to the reaction conditions and the
corresponding azocines 3n–q were isolated in high yields. And
enaminones 1r–t, which were synthesized from the reactions of
linear 1,3-dicarbonyls such as benzyl acetoacetate and isobutyl
acetoacetate, were also successfully subjected to this reaction and
their products 3r–t were obtained in good yields. It is worth
noting that in contrast to the 1H- and 13C-NMR spectra of
compounds 3a–q, which indicated the presence of one
conformer for each compound, the spectra of products 3r–t each
Fig. 2 ORTED representation of 3c. CCDC 1976349.
details see General procedure). The synthesized enaminones
1a–t were then reacted with acenaphthoquinone 2 and con-
verted to the corresponding azocines 3a–t in two steps (addition
and oxidative-cleavage steps) as a one-pot reaction (Scheme 1).
Initial studies were done on the synthesis of product 3b. In
the addition step, which was carried out in ethanol and in the
presence of Et3N serving as a base, all of the starting materials
were consumed aer twelve hours of reaction time (Scheme 1,
step 1). Based on our previous studies on the addition reactions
of various dinucleophiles and diketones,14,15a–d it was predict-
able that vicinal diols would be the reaction products at this
stage. With this precedence in mind and without carrying out
any separation procedure at this stage, the corresponding
Scheme 2 Proposed mechanism for the syntheses of compounds 3a–t
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showed two different conformers; this result may have been due mL) then added and product extracted using ethyl acetate (3 ꢁ 3
to the structural exibilities of 3r–t being relatively high, and mL). The organic layers were collected, washed with an aqueous
greater than those of compounds 3a–q, which have cyclic Na2S2O3 solution and dried over anhydrous Na2SO4. Aer
enaminone moieties. For product 3s, the ratio of its conformers partial vaporization of solvent, the product was precipitated and
was calculated from the 1H-NMR spectrum to be 83 : 17. The the mixture was ltered to give the pure enaminone 1 as a white
methylene protons of the major conformer resonated as two solid.
distinct doublets due to their diastereotopic nature, but they
displayed a simple pattern in the minor conformer (Fig. 1).
General procedure for synthesizing azocine derivatives 3a–t
Surprisingly, the two distinct doublets of methylene protons of
In each case, a mixture of enaminone 3 (1 mmol), Et3N (1
the major conformer of 3s at room temperature converted to
mmol), and acenaphthoquinone 2 (1 mmol) in EtOH (4 mL) was
placed in a ask and the mixture was stirred for 12 hours at
reux conditions. The progress of the reaction was monitored
a sharp singlet when its 1H-NMR spectrum was recorded at 80 ꢀC.
Moreover, the ratio of conformers was determined from the
spectrum recorded at 80 ꢀC to be 94 : 16 (Fig. 1).
by performing TLC using EtOAc/n-hexane as an eluent. Aer
The molecular structures of all products 3a–t were also
completion of the reaction, the reaction mixture was cooled to
elucidated from their IR, 1H-NMR, 13C-NMR and HRMS spectra.
room temperature and H5IO6 (1 mmol) was added to the ask
and the resulting mixture was stirred for an additional 1 hour.
The reaction mixture was ltered and the crude product was
recrystallized from ethanol to afford the pure product 3.
Finally, the structure of product 3c was determined unambig-
uously from an X-ray diffraction study (Fig. 2).
We proposed a general mechanism for the reactions, as
shown in Scheme 2. According to the mechanism, rst enami-
none 1 attacked acenaphthoquinone 2 to form intermediate A,
followed by a rearrangement of A to form intermediate B and
then vicinal diol C. Then reacting C with periodic acid produced
Conflicts of interest
There are no conicts to declare.
intermediate D, which then underwent a rearrangement to form
product 3 with the loss of water and iodic acid molecules.
In summary, we have developed a novel pathway for the
syntheses of new azocine derivatives via the reactions of
enaminones with acenaphthoquinone followed by metal-free
periodic acid-mediated oxidative cleavages of the correspond-
ing vicinal diols. The novelty of the method in combination with
high yields, short reaction times, and mild reaction conditions
makes this procedure an especially attractive method for the
syntheses of the titled compounds.
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