EGB-promoted electrochemical synthesis of 6-thioxo-[1,3,5]-triazinane-2,4 dione derivatives

Article abstract of DOI:10.1080/00397911.2016.1166251

A simple method for the synthesis of 6-thioxo-[1,3,5]-triazinane-2,4-dione derivatives was reported. The electrogenerated cyanomethyl base obtained from electroreduction of neat acetonitrile assisted the reaction between thiourea derivatives and alkyl or

Full text of DOI:10.1080/00397911.2016.1166251

Synthetic Communications
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EGB-Promoted Electrochemical Synthesis of 6-
Thioxo-[1,3,5]- Triazinane-2,4 Dione Derivatives
Najoua Sbei, Baya Haouas, Khaled Boujlel, Belen Batanero & Mohamed
Lamine Benkhoud
To cite this article: Najoua Sbei, Baya Haouas, Khaled Boujlel, Belen Batanero &
Mohamed Lamine Benkhoud (2016): EGB-Promoted Electrochemical Synthesis of
6-Thioxo-[1,3,5]- Triazinane-2,4 Dione Derivatives, Synthetic Communications, DOI:
10.1080/00397911.2016.1166251
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Date: 23 March 2016, At: 00:18

EGB-Promoted Electrochemical Synthesis of 6-Thioxo-[1,3,5]- Triazinane-2,4 Dione
Derivatives
Najoua Sbei1, Baya Haouas1, Khaled Boujlel1, Belen Batanero2, Mohamed Lamine
Benkhoud1
1Laboratoire de Chimie Analytique et Electrochimie, Faculté des Sciences de Tunis,
Université Tunis El Manar, Campus Universitaire Farhat Hached, 2092, Tunis,. Tunisie,
2Department of Organic Chemistry, University of Alcala, 28871 Alcala de Henares
Madrid, Spain
Correspondence: Mohamed Lamine Benkhoud, . E-
mail:mohamed.benkhoud@gmail.com
Abstract
A simple method for the synthesis of 6-Thioxo-[1,3,5]-triazinane-2,4-dione derivatives
was reported. The electrogenerated cyanomethyl base obtained from electroreduction of
neat acetonitrile assisted the reaction between thiourea derivatives and alkyl or aryl
isocyanate. This protocol had the advantage of giving good yields using mild conditions.
The obtained products have been identified according to their spectroscopic data, by mass
spectrometry and high-resolution mass spectra or elemental analysis.
KEYWORDS: Thioxo-triazinane-diones; thioureas; isocyanate; EGBs.
INTRODUCTION
The heterocyclic compounds especially those containing triazine moiety find several
applications in pharmaceutical,[1] polymers[2] and agricultural industry.[3] These products
1

are endowed with several activities such as antiviral,[4-6] anti-inflammatory,[7]
insecticidal[8] and some of them are used as antiulcer.[9]
The classical synthesis of harsh pathway triazinane-dione uses phosphonates, nitriles,
aldehydes and isocyanates,[10] and also a combination with additional multicomponent
reactions (MCRs).[11] Some reactions may require the use of tough operating conditions
and involve often harmful compound such as phosgene and thiophosgene which are
examples among many reagents that are restricted from research laboratories because of
their harmfulness.[12]
In this context, organic electrochemistry allows under very mild conditions to generate in
situ, electrophilic substrates, bases and nucleophilic reagents from some harmless and
extremely stable intermediate.[13] The fact of controlling experimental conditions as
amount of base, its strength solvent, applied current density, constitute an excellent
advantage which increases the interest of chemists to this synthetic methods.[14-19] In the
last few years, we have devoted much effort to develop the use of cyanomethyl anion as
an electrogenerated base EGBs in synthetic process.[20-25] This base is strong enough to
remove weak acidic proton from probase such as thiourea. Thus we wish to report the
reactivity of these compounds by using EGBs in the presence of isocyanate as
electrophile in the aim of synthesis 6-Thioxo-1,3,5-triazinane-2,4-diones.
RESULTS AND DISCUSSION
2

Electrolysis of dry acetonitrile was carried out at low temperature under galvanostatic
conditions in an undivided electrochemical cell with a magnesium rod as a sacrificial
anode and a stainless steel grid cathode. The cooled solution was maintained under inert
atmosphere of nitrogen. The acetonitrile reduced at the cathode leaded to the formation in
situ of the cyanomethyl carbanion. This EGB was stabilized as (NC-CH2)2Mg by the
magnesium cation generated from the anode oxidation. Once the desired quantity of EGB
was produced, the electrolysis was stopped and the substituted thiourea 1 was added to
the mixture. Indeed, this later was introduced at the end according to Feroci and al as this
compound is reducible [15, 16]. One hour later, two equivalents of isocyanate were added.
The solution was allowed to reach room temperature and kept under continuous stirring
overnight. Final work-up and column chromatography on silica gel afforded resulting
products 2 (Scheme 1) identified as 6-Thioxo-1,3,5-triazinane-2,4-diones in good yields
(Table 1).
We presumed that the electrogenerated cyanomethyl anion/base formed by the reduction
of acetonitrile at the stainless cathode removed the proton of thiourea 1 to generate the
anion I. This intermediate gave after tautomerisation and two successive attacks on the
additional isocyanate the anionic intermediate III. This latter had an electrophile center
with a leaving group (R’-NH2) in the position 6 allowing intra-cyclization that gave the
thioxo-triazinane-dione 2 (Scheme 2).
However, working in the same experimental conditions except the use of different
electrophiles which are 1, 3 halogenated derivatives, Beya and al. [26] found that the anion
3

I reacts directly with the electrophile center by the negative charge provided by the sulfur
atom and not by the pair of nitrogen. These findings suggest that the reactivity of the
intermediate I depends on the nature of the electrophilic center used.
Obtained products 2 have been identified according to their spectroscopic data (IR, 1H
NMR and 13C NMR), mass spectra, HRMS and elementary analysis.
On IR spectra, we note the absence of any absorption attributed to the N-H stretching
band and the presence of two bands at 1700 and 1220 cm-1 characteristic respectively of
the C=O group and the C=S one .
In 1H NMR spectra, we also note the absence of any peak characteristic of mobile protons
and the apparition of protons peaks attributable to R group from isocyanate introduced.
The 13C NMR spectra confirmed the structure of 2 by the presence of peak characteristic
of carbonyl and the thiocarbonyl function which resonate at 145 and 175 ppm .
The MS spectrums of the substrate 2 shows specially the presence M+ pic (100%) and the
(M+- RNCSNRCO, 60%) one.
HRMS and elementary analysis confirm the obtaining of these heterocyclic compounds.
CONCLUSION
4

The use of an EGB as a new electrochemical methodology that allowed the preparation of
the thioxo-triazinane-diones in comparison with conventional chemistry had several
advantages such as in situ generation of base; a one-pot reaction in good yields under
milder conditions, avoidance of polluting or hazardous chemicals or the addition of base
involved an easy work-up procedure. The compounds reported in this paper are unknown
except the product 2a which was synthesized by two methods based on the reaction even
of methyl isocyanate followed by methyl thioisocyanate on N- phenyl ethylcarbamate[27]
or the reaction of phenyl isocyanate on a salt derived from the 1-(5-
(dimethyl)aminothiazol-2-yl)-1,3-dimethylthiorea[28]
.
EXPERIMENTAL
Anhydrous acetonitrile (10 ppm, anhydroscan®) was purchased from Labscan. All
chemicals were purchased from Sigma-Aldrich and are used without further purifications.
The N,N-disubstituted thiourea are synthesized according to the experimental protocol
reported by Perveen Shahnaz and al.[29]
1H NMR and 13C NMR spectra were recorded using a Bruker Advance 300 MHz
spectrometer in CDCl3 with TMS as internal standard.
Mass spectra (EI, ionizing voltage 70 eV) were determined using a Thermofisher
ITQ-900 DIP/GC-MS mass-selective detector. Elemental analyses were performed on a
Perkin-Elmer Model 240-B analyzer.
5

IR spectra were measured using Bruker Alpha ATR spectrometer; samples were
dissolved in CHCl3.
HRMS (ESI) data were recorded on a high-resolution Micromass micrOTOF-Q II 10027
spectrometer.
Electrochemical Synthesis of Thioxo-Triazinane-Dione
In a typical procedure, electrolyzed was carried out in an undivided cell fitted with a
consumable magnesium as anode and a stainless steel grid (20 cm2) as a cathode. The cell
was first charged with 100 mL of acetonitrile containing 0,1M of tetrabutylammonium
tetrafluoroborate (TBAF4). The mixture was subjected to electrolysis at a constant current
80 mA, under nitrogen at -20 °C. After the flow of 2.2 Faradays, the electrolysis was
stopped, the stirred solution was maintained at -20 °C and 4 mmol of thiourea 1 was
added. One hour later, 8 mmol of isocyanate was added. The solution was allowed to
reach room temperature and kept under continuous stirring overnight. After the removal
of excess acetonitrile, the obtained residue was extracted with ether. Finally, the solvent
was removed and the residue was purified by column chromatography on silica gel 60
using mixture of ethyl acetate/petroleum ether (2:8) as eluent.
ISOLATED PRODUCTS
1, 5-Dimethyl-3-Phenyl-6-Thioxo-1,3,5-Triazinane-2,4-Dione (2a)
Solid. m.p: 141-142 °C; 1H NMR (CDCl3): δ 3.77 (s, 6H), 7.24-7.48 (m, Har); 13C NMR
(CDCl3): δ 36.68, 128.01-133.87, 177.77, 147.61; GC-MS: M+ (m/z=249, 100%),
6

(M+-CH3NCSNCH3CO) (m/z=119, 60 %), m/z (91, 25 %); IR (cm-1): 1700 (C=O),
1603 (C=C), 1220 (C=S); Anal. calcd (%) for C16H11 N3 O2 S: C, 53.0; H, 4.4; N, 16.9; S,
12.8. Found: C, 52.82; H, 4.46; N, 16.60; S, 12.64.
ACKNOWLEDGEMENT
The authors gratefully acknowledge the Ministry of Higher Education and Scientific
Research (MHESR) for the financial support through the lab LR99ES15.
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9

Table I. Synthesized 6-thioxo-1,3,5-triazinane-2,4-dione derivatives 2.
Entry
2a
2b
2c
2d
2e
2f
R1
R2
R’
(*)Yield(% )
90%
CH3
CH3
Ph
CH3
CH3
P-Cl-Ph
n-Propyl
Cyclohexyl
Ph
85%
CH3
CH3
75%
CH3
CH3
80%
CH3-CH2
CH3-CH2
CH3-CH2
(CH3)2CH
CH3
CH3-CH2
CH3-CH2
CH3-CH2
(CH3)2CH
CH3
88%
PCl-Ph
n-Propyl
Ph
95%
2g
2h
2i
50%
40%
Benzyl
Benzyl
n-Propyl
n-Propyl
Ph
40%
2j
CH3-CH2
CH2-Ph
CH2-Ph
CH2-Ph
CH3-CH2
CH2-Ph
CH3-CH2
CH3-CH2
55%
2k
2l
50%
40%
2m
45%
*The yield was calculated in regards to the starting thiourea.
10

Scheme 1. Reaction of thiourea with EGB in acetonitrile.
11

Scheme 2. Mechanism of synthesis of 6-thioxo-1,3,5-triazinane-2,4-dione derivatives 2.
12