Interaction of 1,5-disubstituted 3-methyl-2-oxo-2,3-dihydro- 1H-imidazole-4-carbonitriles with hydrogen sulfide

Article abstract of DOI:10.1007/s10593-011-0839-4

The reaction of 1-alklyl(aryl)-5-alkyl(aryl)amino-3-methyl-2-oxo-2,3- dihydro-1H-imidazole-4-carbo-nitriles with hydrogen sulfide was investigated. Unexpectedly, this led, after treatment of the reaction products with triethyl orthoformate, to 1,2,4-dithi

Full text of DOI:10.1007/s10593-011-0839-4

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
INTERACTION OF 1,5-DISUBSTITUTED
3-METHYL-2-OXO-2,3-DIHYDRO-
1H-IMIDAZOLE-4-CARBONITRILES
WITH HYDROGEN SULFIDE
S. A. Chumachenko1, O. V. Shablykin1,
E. B. Rusanov2, and V. S. Brovarets1*
The reaction of 1-alklyl(aryl)-5-alkyl(aryl)amino-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carbo-
nitriles with hydrogen sulfide was investigated. Unexpectedly, this led, after treatment of the reaction
products with triethyl orthoformate, to 1,2,4-dithiazol-5-ylidene-5-thioxoimidazolidin-2-one derivatives.
Keywords: dithiazoles, 3-methylimidazol-2-ones, hydrogen sulfide, triethyl orthoformate.
We have shown previously that the interaction of substituted 2-oxo-2,3-dihydro-1H-imidazole-4-carbo-
nitriles 1 with hydrogen sulfide in pyridine formed the corresponding thioamides – prospective starting materials
for the preparation of analogs of purine bases [1]. The N-methyl derivatives 2 react with hydrogen sulfide in a
different manner: the reaction does not stop at the stage of forming the expected thioamides 3 or their
prototropic isomers 4, but produce a complex mixture of eleven products, among which are basically (~50%) the
1-R-3-methyl-2-oxo-5-thioxoimidazolidine-4-carbothioamides 5. Their presence in the reaction mixture was
determined by chromato-mass spectrometry: compound 5a (Rf 0.44, m/z 280 [M+1]+); compound 5b (Rf 0.36,
m/z 266 [M+1]+); compound 5c (Rf 0.42, m/z 280 [M+1]+). Similar conversion of N-substituted imine fragments
into thioxy groups by reaction of sulfuring agents has been reported previously in the literature [2, 3]. We did
not succeed in isolating compounds 5a–c in the pure state, but on heating the mixture of the products obtained
with sulfuring agents in the presence of triethyl orthoformate derivatives of 1,2,4-dithiazol-3-ylidene 6a–c were
obtained in moderate yields.
The composition and structure of compounds 6a–c were confirmed by elemental analysis, IR spectros-
1
13
copy, mass spectrometry, H and C NMR spectroscopy, and X-ray crystallography (compound 6a). The C=O
stretching frequencies at ν 1701–1717 cm–1 were characteristic for compounds 6a–c. The H-5' singlet of the
_______
*To whom correspondence should be addressed, e-mail: brovarets@bpci.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1
Murmanska St., Kyiv 02660, Ukraine.
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine. e-mail: rusanov@ioch.kiev.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.7, 987–991, July, 2011. Original article
submitted February 3, 2011. Revised article submitted June 30, 2011.
0009-3122/11/4707-0807©2011 Springer Science+Business Media, Inc.
807

dithiazolylidene unit at δ 9.81–9.86 and the NMe group at δ 3.67–3.73 ppm were present in the 1H NMR spectra.
The NMR spectra and the TLC results indicated the presence of a single geometric isomer in the reaction
products 6a–c.
S
S
Me
N
Me
N
Me
N
Me2SO4
NaOH
H
N
C
N
C
N
H2S/Py
NH2
NHR
NH2
O
O
O
O
N
R
N
R
N
R
N
R
NHR
NHR
NR
1a–c
2a–c
3a–c
4a–c
N
S
S
Me
N
Me
S
S
N
H2S/Py
– RNH2
NH2
1) H2S/[O]
O
O
2) HC(OEt)3
N
R
N
R
S
5a–c
6a–c
1–6 a R = Bn, b R = Ph, c R = 4-MeC6H4
To examine the spatial structure of products 6a–c we carried out an X-ray crystallographic study of
compound 6a (Fig. 1). The central N(1)–N(2)–C(1-3) five-membered heterocycle is planar with in limits of
0.05 Ǻ, and the distribution of bond lengths and valence angles (Table 1) indicates the conjugation of the
nonbonded electron pair of atoms N(1) and N(2) with the π-system of the bonds C=O, C=S, and C=C in the
heterocycle. Thus the sums of the valence angles at the nitrogen atoms are equal to 360°, whereas all of the
formally single C–C and C–N bonds within the ring are considerably shortened in comparison with standard
values for single bonds, which indicates the delocalization of the electron density within bonds of the
heterocycle. Very similar geometric characteristics were found previously for 5-benzylidene-3-methyl-1-phenyl-
1,3-diazacyclopentan-2-one-4-thione [4], but in the compound we have studied the C(2)–C(3) bond is shortened
by 0.06 Ǻ which is apparently connected to stabilization of the structure by secondary interactions. The
dithiazole heterocycle is actually coplanar with the central 5-membered ring because of effective conjugation. In
the structure of molecule 6a, intramolecular attractive interaction between atom S(1) of the dithiazole ring and
atom S(3) to a distance of 2.802 Ǻ is to be observed that is characteristic of similar systems [5].
Fig. 1 Overall form of compound 6a molecule
808

TABLE 1. Basic Bond Lengths (l) and Valence Angles (ω) in Compound
6a
Basic valence lengths
l, Å
Bond angles
ω, deg
C(1)–N(1)
C(3)–N(1)
C(1)–N(2)
C(2)–N(2)
C(2)–C(3)
C(3)–S(3)
C(2)–C(5)
C(5)–N(3)
C(6)–N(3)
C(5)-S(1)
C(6)–S(2)
S(1)–S(2)
1.399(3)
1.369(3)
1.360(3)
1.405(3)
1.411(3)
1.665(2)
1.372(3)
1.362(3)
1.286(3)
1.778(2)
1.707(3)
2.1055(10)
2.802(1)
N(2)–C(1)–N(1)
C(3)–N(1)–C(1)
C(1)–N(2)–C(2)
N(1)–C(3)–C(2)
N(2)–C(2)–C(3)
N(1)–C(3)–S(3)
C(2)–C(3)–S(3)
C(6)–N(3)–C(5)
N(3)–C(5)–S(1)
C(2)–C(5)–S(1)
N(3)–C(6)–S(2)
C(5)–S(1)–S(2)
C(6)–S(2)–S(1)
106.6(2)
110.2(2)
109.6(2)
106.8(2)
106.8(2)
127.0(2)
126.23(19)
115.7(2)
117.69(18)
120.09(19)
122.1(2)
91.56(9)
92.93(10)
176.6(2)

S(1) S(3)

S(2)–S(1) S(3)
The combination in one molecule of the pharmacophoric dithiazolylidene [6, 7] and 5-thioxoimidazo-
lidin-2-one [8] fragments makes the compounds 6a–c potential objects for exploration as bioregulators for
various effects.
EXPERIMENTAL
1
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IR spectra of KBr tablets were recorded on a Vertex-70 spectrometer. H and C NMR spectra were
recorded with a Bruker AVANCE DRX-500 instrument (500 and 125 MHz respectively) in DMSO-d6 solutions
with TMS as internal standard. Chromato-mass spectra were obtained with a high-resolution Agilent 1100 liquid
chromatograph equipped with a diode matrix and a mass selective detector (Agilent LC/MSD SL). Parameters
of the chromato-mass analysis: column Zorbax SB-C18 1.8 μm, 4.6×15 mm (PN 821975-932); solvents: A –
acetonitrile–water, 95:5, 0.1% trifluoroacetic acid, B – 0.1% trifluoroacetic acid; eluent flow 3 ml/min; injection
volume – 1 μl; UV detectors – 215, 254, 285 nm; method of ionization – chemical ionization at atmospheric
pressure (APCI), scanning range m/z 80–1000. Melting points measured with Fisher-Johns apparatus.
1-Benzyl(phenyl)-5-benzyl(phenyl)amino-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carbonitriles 2a,b
were prepared by method [1].
3-Methyl-1-(4-methylphenyl)-5-[(4-methylphenyl)amino]-2-oxo-2,3-dihydro-1H-imidazole-4-carbo-
nitrile (2c) was prepared analogously to compounds 2a,b. Yield 70%; mp 173–175°C. IR spectrum, ν, cm–1:
1
1698 C=O (band with shoulder), 2206 (CN), 3026–3212 (NH). H NMR spectrum, δ, ppm: 2.32 (3H, s, CH3);
2.41 (3H, s, CH3); 3.33 (3H, s, NCH3); 6.96–7.41 (8H, m, H Ar); 8.21 (1H, s, NH). Mass spectrum, m/z: 319
[M+1]+. Found, %: C 71.49; H 5.58; N 17.69. C19H18N4O. Calculated, %: C 71.68; H 5.70; N 17.60.
(4E)-1-R-4-(3H-1,2,4-Dithiazol-3-ylidene)-3-methyl-5-thioxoimidazolidin-2-ones 6a–c (General
Method). The corresponding compound 2a–c (5 mmol) was dissolved in a mixture of pyridine (10 ml) and
triethylamine (1 ml), a rapid flow of hydrogen sulfide was passed in for 1 h, the mixture was stirred for 2 h at
20–25°C, water (50 ml) was added and the mixture was extracted with dichloromethane (3×10 ml). The
dichloromethane was evaporated in vacuum and the oil formed was dissolved in triethyl orthoformate (10 ml),
boiled for 4 h, the precipitate formed was filtered off, washed with diethyl ether and recrystallized from dioxane.
(4E)-1-Benzyl-4-(3H-1,2,4-dithiazol-3-ylidene)-3-methyl-5-thioxoimidazolidin-2-one (6a). Yield
41%; mp 178–180°C. Rf 0.69. IR spectrum, ν, cm–1: 1494, 1568, 1701 (C=O). 1H NMR spectrum, δ, ppm: 3.67
809

(3H, s, NCH3); 5.06 (2H, s, CH2); 7.25–7.43 (5H, m, H Ph); 9.81 (1H, s H-5'). 13C NMR spectrum, δ, ppm: 39.5,
45.8, 126.1, 128.08, 128.12, 129.0, 136.2, 153.7, 159.9, 171.0, 171.4. Mass spectrum, m/z: 322 [M+1]+. Found,
%: C 48.67; H 3.51; N 13.21; S 30.07. C13H11N3OS3. Calculated, %: C 48.57; H 3.45; N 13.07; S 29.93.
(4E)-4-(3H-1,2,4-Dithiazol-3-ylidene)-3-methyl-1-phenyl-5-thioxoimidazolidin-2-one (6b). Yield
1
35%; mp 219–221°C. Rf 0.63. IR spectrum, ν, cm–1: 1309, 1399, 1421, 1488, 1565, 1717 (C=O). H NMR
spectrum, δ, ppm: 3.73 (3H, s, NCH3); 7.45–7.58 (5H, m, H Ph); 9.85 (1H, s, H-5'). 13C NMR spectrum, δ, ppm:
31.5, 116.1, 127.6, 128.5, 130.5, 137.1, 153.8, 160.1, 171.2, 171.5. Mass spectrum, m/z: 308 [M+1]+. Found, %:
C 46.72; H 2.84; N 13.56; S 31.45. C12H9N3OS3. Calculated, %: C 46.88; H 2.95; N 13.67; S 31.29.
(4E)-4-(3H-1,2,4-Dithiazol-3-yliden)-3-methyl-1-(4-methylphenyl)-5-thioxoimidazolidin-2-one (6c).
Yield 37%; mp 221–223°C. Rf 0.65. IR spectrum, ν, cm–1: 1403, 1421, 1488, 1518, 1568, 1716 (C=O). 1H NMR
spectrum, δ, ppm: 2.40 (3H, s, CH3); 3.73 (3H, s, NCH3); 7.29 (4H, s, H Ar); 9.86 (1H, s, H-5'). 13C NMR
spectrum, δ, ppm: 39.4, 39.5, 126.6, 127.8, 130.3, 132.1, 139.0, 153.3, 160.3, 171.2, 171.3. Mass spectrum, m/z:
322 [M+1]+. Found, %: C 48.61; H 3.29; N 13.15; S 29.84. C13H11N3OS3. Calculated, %: C 48.57; H 3.45;
N 13.07; S 29.92.
X-Ray structural study of a monocrystal of compound 6a with dimensions 0.06×0.22×0.28 mm at
room temperature using a Bruker Apex II diffractometer (λ MoKα radiation, graphite monochromator,
θ
max 26.31°, segment of the sphere –8 ≤ h ≤ 13, –9 ≤ k ≤ 8, –21 ≤ l ≤ 22). 7857 reflections were collected of
which 2809 were independent (average R factor 0.0367). Absorptions were correlated using the SADABS
program using the multiscanning method (Tmin/Tmax = 0.8659/0.9689). The crystal of compound 6a was
monoclinic, space group P21/c, a = 10.5041(8), b = 7.2532(4), c = 18.3171(10) Ǻ, β = 93.701(4)°,
V = 1392.64(15) Ǻ3, Z = 4, dc = 1.533, μ = 0.530 mm–1, F(000) 664. The structure was solved by direct method
with refinement by least squares analysis in the full matrix anisotropic approximation using the SHELXS97 and
SHELXL97 programs [9, 10]. Hydrogen atoms were found and refined isotropically. In the refinement 1980
reflections with I > 2σ(I) were used, 225 refined parameters, number of reflections per parameter 8.8, the
weighting scheme used was ω = 1[σ2(Fo2) + (0.0289P)2 + 0.5289P] where P = (Fo2 + 2Fc2)/3, the ratio of the
maximal (average) shift to the error in the last cycle 0.041(0.002). The final values of the divergence factors for
reflections with I > 2σ(I), R1(F) = 0.0384, wR2(F2) = 0.0743, R1(F) = 0.0694, wR2(F2) = 0.0867, GOOF 1.02 for
all independent reflections. The residual electron density from the difference Fourier after the last cycle of
refinement were 0.23 and –0.25e/Ǻ3. The results of the X-ray crystallographic study have been deposited in the
Cambridge Crystallographic Data Center (deposit CCDC 805442).
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