Unexpected formation of 4-alkyl-5-(4-alkylthiosemicarbazido)-4,5-dihydro-1, 2,4-triazine-3(2H)-thiones from 1,3-dialkyl-4,5-bis-(4-alkylthiosemicarbazido) imidazolidin-2-ones in acidic medium

Article abstract of DOI:10.1016/j.mencom.2013.12.014

4-Alkyl-5-(4-alkylthiosemicarbazido)-4,5-dihydro-1,2,4-triazine-3(2H) -thiones are obtained either by heating 1,3-dialkyl-4,5-bis-(4- alkylthiosemicarbazido)imidazolidin-2-ones in acidic medium or the reaction of 1,3-dialkyl-4,5-dihydroxyimidazolidin-2-on

Full text of DOI:10.1016/j.mencom.2013.12.014

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 42–44
Unexpected formation of 4-alkyl-5-(4-alkylthiosemicarbazido)-
4,5-dihydro-1,2,4-triazine-3(2H)-thiones from 1,3-dialkyl-4,5-bis-
(4-alkylthiosemicarbazido)imidazolidin-2-ones in acidic medium
Galina A. Gazieva,* Pavel A. Poluboyarov, Natal’ya G. Kolotyrkina,
Elena D. Lubuzh and Angelina N. Kravchenko
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: gaz@ioc.ac.ru
DOI: 10.1016/j.mencom.2013.12.014
4-Alkyl-5-(4-alkylthiosemicarbazido)-4,5-dihydro-1,2,4-triazine-3(2H)-thiones are obtained either by heating 1,3-dialkyl-4,5-bis-
(4-alkylthiosemicarbazido)imidazolidin-2-ones in acidic medium or the reaction of 1,3-dialkyl-4,5-dihydroxyimidazolidin-2-ones
with 4-methylthiosemicarbazide.
S
Thiosemicarbazide derivatives are widely used for the synthesis
of nitrogen- and sulfur-containing heterocyclic compounds.1 They
manifest antitumour,2–4 antimicrobial,2,5,6 antiparasitic2,7–10 and
R
R
H
N
H
N
R'
R'
N
H
H
N
N
H
H
N
N
N
NH
O
+
O
N
o
ther types of biological activity. Therefore, studies on the reactivit
y
N
N
S
N
H
of thiosemicarbazide derivatives remain an issue of current interest.
R
R
R'
S
Our recent interests were aimed at the synthesis and chemical
properties of five- and six-membered heterocyclic thiosemicarb-
azide derivatives.1,11–15 For instance, we studied a-ureidoalkylation
of thiosemicarbazide with 1,3-dialkyl-4,5-dihydroxyimidazolidin-
2-ones under acid catalysis affording 1,3-dialkyl-4,5-bis(thiosemi-
carbazido)imidazolidin-2-ones 1a,b and 5,7-dialkyl-3-thioxo-
perhydroimidazo[4,5-e][1,2,4]triazin-6-ones 2a,b (Scheme 1).11
Treatment of compounds 1a,b with aromatic aldehydes in the
presence of an acid caused their cyclization to give 1,3-dialkyl-
4-{[(1E)-benzylidene]amino}-5-thioxohexahydroimidazo[4,5-d]-
imidazol-2(1H)-ones 3 and traces of imidazotriazines 2.12
1c R = R' = Me
2c R = R' = Me
2d R = Et, R' = Me
1d R = Et, R' = Me
1e R = Me, R' = Bui
i
R
OH
OH
H
H
N
N
N
R'
O
N
+
H2N
S
R
4a R = Me
4b R = Et
5a R' = Me
5b R' = Bui
ii
S
R
H
N
S
N
H
NH2
NH2
N
i
Me
N
+ ArCHO
O
H
N
N
H
+
+
1c,d
2c,d
N
H
N
H
H
N
N
H
N
R
N
Me
S
1a,b
S
6a
Me
S
Ar
H
N
S
N
Me
R
N
R
N
N
N
+
H
H
N
H
H
HN
N
N
NH
N
+
O
O
S
7a
N
R
N
N
H
N
H
S
Scheme 2 Reagents and conditions: i, H2O, 0.1 ml of conc. HCl, 70–80°C,
1 h; ii, EtOH, H2O, conc. HCl (10:1:0.1), reflux, 1 h (R' = Me).
R
3
2a,b
(Scheme 2). The reaction was carried out in water under HCl
catalysis and produced compounds 1c–e in 69–81% yields. In
addition to imidazolidinones 1c,d, imidazotriazines 2c,d were
also formed in 4–14% yields.
Ar = Ph, 4-BrC6H4
a R = Me
b R = Et
Scheme 1 Reagents and conditions: i, MeOH, conc. HCl (cat.), reflux, 1.5 h.
The reaction in aqueous ethanol (EtOH–H2O–conc. HCl,
10:1:0.1) performed by portionwise addition of thiosemicarb-
azide 5a to a solution of dihydroxyimidazolidinone 4a,b afforded
imidazolidinones 1c,d (29–35%), imidazotriazines 2c,d (21–35%),
glyoxal thiosemicarbazone 6a (5–10%) and 4-methyl-5-(4-methyl-
thiosemicarbazido)-4,5-dihydro-1,2,4-triazine-3(2H)-thione 7a
(10–28%) (see Scheme 2). The products were separated by frac-
This paper deals with the behaviour of 1,3-dialkyl-4,5-bis-
(thiosemicarbazido)imidazolidin-2-ones 1a–e on treatment with
hydrochloric acid.
Hitherto unknown imidazolidinones 1c–e were obtained
similarly to derivatives 1a,b11 by a-ureidoalkylation of 4-alkyl-
thiosemicarbazides 5a,b with dihydroxyimidazolidinones 4a,b
© 2014 Mendeleev Communications. All rights reserved.
– 42 –

Mendeleev Commun., 2014, 24, 42–44
S
S
tional crystallization from ethanol and methanol. The formation
R
H
N
of triazine 7a was unexpected. The structure of the latter was
R'
R'
N
H
N
H
N
1
confirmed by the combined IR, H and 13C NMR spectral data
O
and its high resolution mass spectrum.†
H
H
N
N
N
N
H
The IR spectrum of triazinethione 7a contains absorption
bands of NH bonds at 3309, 3261 and 3168 cm–1 and those of
CH bonds at 3044, 2976 and 2918 cm–1. The stretching vibrations
of the C=N and C=S bonds manifest themselves as bands at 1573
and 1527 cm–1. The mass spectrum contains peaks with m/z 233.06
[M+H]+ and 255.05 [M+Na]+. Assignment of the signals of
protons and nitrogen atoms was based on the cross peaks in the
HSQC and HMBC {1H-15N} spectra.
R
1a–e
i
R' = H
R' = Me, Bui
S
5a,b
+
6a,b
+
N
N
H2N
R'
S
H
H
H
N
NH2
S
N
N
R'
†
N
All new compounds 1c–e, 2c,d and 7a,b gave satisfactory elemental
N
H
N
H
analysis data. Their structures were confirmed by 1H and 13C NMR spectro-
scopy and mass spectrometry. The 1H and 13C NMR spectra were recorded
on a BrukerAM-300 spectrometer (300.13 and 75.47 MHz). Chemical shifts
were measured with reference to the residual protons of the DMSO-d6
solvent (d 2.50 ppm). The high resolution mass spectrum (HRMS) of
compound 7a was measured on a Bruker micrOTOF II instrument using
electrospray ionization (ESI).16 The mass spectrum of compound 7a was
measured on an MS 30 spectrometer.
S
HN
6c
N
7a,b
+
Et
H
N
5–7: a R' = Me
b R' = Bui
N
NH
O
N
N
H
S
Et
1,3-Dimethyl-4,5-bis(4-methylthiosemicarbazido)imidazolidin-2-one
1c: yield 69%, mp 247–249°C (decomp.). 1H NMR, d: 2.66 (s, 6H, NMe),
2.93 (d, 6H, NMe, J 4.2 Hz), 3.89 (s, 2H, CH), 5.82 (s, 2H, NH), 8.07 (q,
2H, NH, J 4.2 Hz), 8.66 (s, 2H, NH). 13C NMR, d: 28.47 (NMe), 30.52
(NMe), 73.71 (CH), 158.47 (C=O), 182.80 (C=S).
2b
Scheme 3 Reagents and conditions: i, EtOH, H2O, conc. HCl (10:1:0.1),
reflux, 1–2 h.
1,3-Diethyl-4,5-bis(4-methylthiosemicarbazido)imidazolidin-2-one
1d: yield 81%, mp 252–254°C (decomp.). 1H NMR, d: 0.92 (t, 6H,
Me, J 6.7 Hz), 2.94 (d, 6H, NMe, J 4.2 Hz), 2.97–3.09 (m, 2H, NCH2),
3.28–3.40 (m, 2H, NCH2), 4.10 (s, 2H, CH), 5.77 (s, 2H, NH), 8.00 (q,
2H, NH, J 4.2 Hz), 8.53 (s, 2H, NH). 13C NMR, d: 12.10 (Me), 30.47
(NMe), 34.48 (NCH2), 70.24 (CH), 157.47 (C=O), 182.89 (C=S).
1,3-Dimethyl-4,5-bis(4-isobutylthiosemicarbazido)imidazolidin-2-one
1e: yield 71%, mp 264–266°C (decomp.). 1H NMR, d: 0.85 (d, 12H, Me,
J 6.6 Hz), 1.88–1.93 (m, 2H, CH), 2.66 (s, 6H, NMe), 3.29–3.37 (m, 4H,
CH2), 4.00 (s, 2H, CH), 5.84 (s, 2H, NH), 7.95 (t, 2H, NH, J 4.9 Hz),
8.66 (s, 2H, NH). 13C NMR, d: 20.04 (Me), 27.84 (CH), 28.35 (NMe),
50.28, 50.44 (CH2), 73.88 (CH), 158.36 (C=O), 182.29 (C=S).
4,5,7-Trimethyl-3-thioxoperhydroimidazo[4,5-e][1,2,4]triazin-6-one
2c: yield 35%, mp 269–271°C (decomp.). 1H NMR, d: 2.62 (s, 3H, NMe),
2.75 (s, 3H, NMe), 3.23 (s, 3H, NMe), 4.98 (d, 1H, CH, J 8.6 Hz), 5.05
(d, 1H, CH, J 8.6 Hz), 5.65 (br.s, 1H, NH), 9.40 (s, 1H, NH). 13C NMR,
d: 26.99 (NMe), 30.01 (NMe), 39.70 (NMe), 70.93 (CH), 72.40 (CH),
158.29 (C=O), 188.00 (C=S).
Compounds 6a and 7a are likely to be products of hydrolysis
of imidazolidinones 1c,d. This result was an additional stimulus
to study the conversion of derivatives 1a–e on treatment with an
acid (Scheme 3).
Compound 1a remains unchanged under the conditions speci-
fied in Scheme 3. An increase in the amount of the acid (EtOH–
conc. HCl, 10:1 or 5:1) results in the formation of glyoxal
thiosemicarbazone 6c, 1,3-dimethylurea, 1,3-dimethylhydantoin,
thiosemicarbazide and other unidentified decomposition products.
Compound 1b is converted upon reflux for 1 h to give imidazo-
triazine 2b in 80% yield and glyoxal thiosemicarbazone 6c
(up to 15%). Heating a suspension of derivatives 1c–e for 2 h
affords thiosemicarbazides 5a,b (yield 7–11%), thiosemicarbazones
6a,b (8–15%) and triazines 7a,b (31–42%) (see Scheme 3). The
reaction is likely to start in protonation of nitrogen atoms of the
thiosemicarbazide moiety or ring nitrogen atoms in compounds
1c–e. Protonation at the N(1) or N(1') atom in the thiosemicarb-
azide moiety leads to elimination of a molecule of thiosemi-
5,7-Diethyl-4-methyl-3-thioxoperhydroimidazo[4,5-e][1,2,4]triazin-
6-one 2d: yield 21%, mp 184–186°C (decomp.). 1H NMR, d: 1.01 (t, 6H,
Me, J 7.1 Hz), 3.00–3.10 (m, 2H, NCH2), 3.17–3.26 (m, 2H, NCH2),
3.23 (s, 3H, NMe), 5.09 (d, 1H, CH, J 8.8 Hz), 5.16 (d, 1H, CH, J 8.8 Hz),
5.59 (s, 1H, NH), 9.42 (s, 1H, NH). 13C NMR, d: 12.84 (Me), 13.23 (Me),
30.87 (NCH2), 34.05 (NCH2), 36.68 (NMe), 71.18 (CH), 75.63 (CH),
161.85 (C=O), 189.71 (C=S).
S
R
H
N
1'
2'
4'
R'
R'
N
H
N
H
N
3'
H+
1c–e
O
– H+
H
N
2
H
N
4
1
3
N
4-Methyl-5-(4-methylthiosemicarbazido)-4,5-dihydro-1,2,4-triazine-
3(2H)-thione 7a: yield 42% (from 1c), mp 221–223°C (decomp.). IR
(n/cm–1): 3309, 3261, 3168 (NH), 3044, 2976, 2918 (CH), 1573 (C=N),
1527 (C=S), 1449, 1407, 1296, 1279, 1145, 1048, 1031, 878, 831, 811,
N
R
H
H
S
S
S
S
S
R
H
R
H
N
H
1
751. H NMR, d: 2.87 (d, 3H, NMe, J 4.4 Hz), 3.25 (s, 3H, NMecycle),
R'
R'
R'
R'
N
N
N
H
H
N
N
H
H
N
N
H
H
N
N
N
H+
4.80 (t, 1H, 5-H, J 3.1 Hz), 6.08 (d, 1H, 1'-H, J 3.1 Hz), 6.92 (d, 1H, 6-H,
J 2.9 Hz), 7.95 (q, 1H, 4'-H, J 4.4 Hz), 8.68 (s, 1H, 2'-H), 11.23 (s, 1H, 2-H).
13C NMR, d: 30.50 (NMe), 37.34 (NMecycle), 67.01 (5-C), 135.38 (6-C),
H
O
O
H
N
NH
NH
N
N
173.31 (C=S), 183.20 (C=S). MS, m/z (%): 128 (86) [M–HNHNC(S)NHMe]+
.
R
R
HRMS, m/z: 233.0644 [M+H]+ (C6H12N6S2, D = 2.5 ppm), 255.0459
[M+Na]+ (C6H12N6S2, D = 0.7 ppm). Found (%): C, 31.09; H, 5.20;
N, 36.12; S, 27.49. Calc. for C6H12N6S2 (%): C, 31.02; H, 5.21; N, 36.17;
S, 27.60.
R'
H
H
S
6a,b
7a,b
2'
4'
– H+
– H+
N
R'
N
S
3'
4-Isobutyl-5-(4-isobutylthiosemicarbazido)-4,5-dihydro-1,2,4-triazine-
1'
4
N
H
N
O
5
6
3
1
H
3(2H)-thione 7b: yield 31%, mp 235–237°C (decomp.). H NMR, d:
R
R
–
HN
N
N
N
0.82 (d, 6H, Me, J 6.6 Hz), 0.85 (d, 6H, Me, J 6.6 Hz), 1.89–2.04 (m,
2H, CH), 3.06–3.13 (m, 2H, CH2), 4.34–4.41 (m, 2H, CH2), 4.74 (t, 1H,
5-H, J 3.1 Hz), 6.07 (d, 1H, 1'-H, J 3.0 Hz), 7.04 (d, 1H, 6-H, J 3.1 Hz),
7.79 (t, 1H, 4'-H, J 5.8 Hz), 8.62 (s, 1H, 2'-H), 11.35 (s, 1H, 2-H).
2
H
H
1
8
Scheme 4
– 43 –

Mendeleev Commun., 2014, 24, 42–44
7 R. P. Tenorio, C. S. Carvalho, C. S. Pessanha, J. G. de Lima, A. R. de Faria,
carbazide 5. Protonation at nitrogen atoms of the imidazolidine
ring results in the evolution of a 1,3-dialkylurea molecule to
give carbocation 8 (Scheme 4). Deprotonation of the latter may
involve the formation of a new bond between the C(5) and N(1')
or N(4) atoms to produce thiosemicarbazone 6 or triazine 7,
respectively.
In conclusion, a study of the effect of HCl on 1,3-dialkyl-
4,5-bis(thiosemicarbazido)imidazolidin-2-ones allowed us to
obtain hitherto unknown compounds, 4-alkyl-5-(4-alkylthiosemi-
carbazido)-4,5-dihydro-1,2,4-triazine-3(2H)-thiones 7a,b. Further-
more, another method for synthesizing 5,7-diethyl-3-thioxo-
perhydroimidazo[4,5-e][1,2,4]triazin-6-one 2b from 1,3-diethyl-
4,5-bis(thiosemicarbazido)imidazolidin-2-one 1b in acidic medium
was found.
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Received: 12th July 2013; Com. 13/4161
– 44 –