Cyclization of 1,3-dialkyl-4,5-bis(1-thiosemicarbazido)-imidazolidin-2- ones(thiones) with aromatic aldehydes

Article abstract of DOI:10.1016/j.mencom.2010.09.016

Cyclization of 1,3-dialkyl-4,5-bis(1-thiosemicarbazido)imidazolidin-2- ones(thiones) with aromatic aldehydes under acidic catalysis affords 1,3-dialkyl-4-(arylideneamino)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H) -ones and 5,7-dialkyltetrahydro-1H-imidazo[4,5-e]-1,2,4-triazine-3,6(2H,4H)- dithiones.

Full text of DOI:10.1016/j.mencom.2010.09.016

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 285–287
Cyclization of 1,3-dialkyl-4,5-bis(1-thiosemicarbazido)-
imidazolidin-2-ones(thiones) with aromatic aldehydes
Galina A. Gazieva,*a Sergei V. Vasilevskii,a Pavel A. Belyakov,a
Yulia V. Nelyubina,b Elena D. Lubuzha and Angelina N. Kravchenkoa
a 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
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2010.09.016
Cyclization of 1,3-dialkyl-4,5-bis(1-thiosemicarbazido)imidazolidin-2-ones(thiones) with aromatic aldehydes under acidic
catalysis affords 1,3-dialkyl-4-(arylideneamino)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-ones and 5,7-dialkyltetrahydro-
1H-imidazo[4,5-e]-1,2,4-triazine-3,6(2H,4H)-dithiones.
Thiosemicarbazide derivatives are intensively investigated both
as ligands in complexation reactions1–3 and as synthons for the
O
S
R
H
N
Ar
preparation of N- and S-heterocycles.4–6 According to literature
data,6 1-alkylthiosemicarbazides react with benzaldehyde in the
presence of hydrochloric acid giving thiadiazoline 1 derivatives
(Scheme 1).
H
N
H
NH2
NH2
N
4a Ar = Ph
O
H
4b Ar = 4-BrC6H4
N
N
N
H
i
R
S
O
2a,b
Ph
R
S
Ph
S
H
Ar
S
H
N
NH2
H2N
HN
R
N
NH2
N
N
R
R
3 N
2
N
S
H
H
N
3a
6a
4
N
N
R = Alk
1
NH
+
+
5
O
O
N
Scheme 1
N
1 N
R
N6
H
N
H
S
R
Ar
In the present study, we explored the reaction of 1,3-dialkyl-
4,5-bis(1-thiosemicarbazido)imidazolidin-2-ones(thiones) 2a,b
(3a,b) with benzaldehydes and found that analogous thiadiazoline
derivatives did not form (Scheme 2).
5a R = Me
5b R = Et
6a Ar = Ph
7a R = Me, Ar = Ph
6b Ar = 4-BrC6H4 7b R = Me, Ar = 4-BrC6H4
7c R = Et, Ar = Ph
7d R = Et, Ar = 4-BrC6H4
Ph
Scheme 3 Reagents and conditions: i, MeOH, conc. HCl, reflux, 1.5 h.
S
N
N
S
S
O
H
R
R
H
N
NH2
NH2
Ph
N
N
benzaldehyde 4b caused removal of both thiosemicarbazide
moeities from 2a,b to give imidazolidinediones 8a,b (Scheme 4).
In this case, the yield of 6b increased to 70–73% (cf. the
yield of 6a) and the yields of 7b,d decreased to 20–22% (cf.
the yields of 7a,c).
N
H
NH2
NH2
N
N
X
X
H
N
N
N
N
H
R
R
S
Ph
2a,b X = O a R = Me
3a,b X = S
b R = Et
The structure of thioglycolurils 7a–d was ascertained by
elemental analysis, mass spectrometry and IR, 1H and 13C
NMR spectroscopy data.† The IR spectra of 7a,c,d showed the
absorption bands of stretch vibrations of the NH bond in the
3210–3260 cm–1 region, those of alkyl groups at 2870–2970 cm–1,
and those of the carbonyl group in the region of 1670–1700 cm–1.
Less intensive absorption bands at 1560–1610 cm–1 may be
ascribed to vibrations of the C=N bond as well as of the con-
jugated C=C bonds of the aromatic ring (see ref. 9).
Spectra of 2D proton–proton, proton–carbon, and proton–
nitrogen correlations were recorded for compound 7a. In the
1H-{13C} HSQC spectrum, a cross-peak of the proton signal
with d 9.13 ppm and the carbon atom signal with d 151.5 ppm
was observed. Judging from d 151.5 ppm and 1J 167.0 Hz, this
carbon atom of CH group had sp2-hybridization and was bound
to the electron-acceptor atom (N). The 1H-{13C} HMBC spectrum
displayed a cross-peak of the proton signal with d 9.13 ppm and
Scheme 2
In fact, treatment of compounds 2a,b with the equimolar
amount of benzaldehyde 4a or p-bromobenzaldehyde 4b in
methanol in the presence of HCl furnished 5,7-dialkyl-3-thioxo-
octahydro-6H-imidazo[4,5-e]-1,2,4-triazin-6-ones7 5a,b, known
aldehyde thiosemicarbazones 6a,b, and previously unknown
1,3-dialkyl-4-(E-arylideneamino)-5-thioxohexahydroimidazo-
[4,5-d]imidazol-2(1H)-ones (thioglycolurils of a new substitu-
tion type) 7a–d (Scheme 3).
When 2 moles of benzaldehyde per 1 mole of starting 2a or
2b were used, yields of thiosemicarbazone 6a and thioglycol-
urils 7a,c increased (Scheme 4). Yield of thiosemicarbazone 6a
was 35–37% (theoretically, 2 moles of 6 can be obtained from
1 mole of starting 2); yields of 7a,c were 55–58%. 4-Bromo-
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 285–287
signals from ipso and ortho carbon atoms of the benzene ring,
to which this CH group was directly bound.
S
S
R
H
N
The proton and nitrogen atom signals assignment was based
on the cross-peaks in the HMBC 1H-{15N} spectrum.
Originating from the NOESY and TOCSY spectra of 7a,
protons for the methyl group at the N1 atom had correlations
with protons at the C6a atom and N6 atom only (for the
numeration of atoms, see Scheme 3). The methyl group protons
at N3 had correlations with protons at C3a and at the C=N group
carbon atom as well as with the benzene ring protons. In the
TOCSY spectrum, two isolated spin systems formed by the C3a,
C6a, and N6 protons as well as by the N=C group proton and
benzene ring protons were detected.
Compounds 7a–d can exist in the form of either E or Z
isomers. According to literature data for aldoximes,10–12 the
spin–spin 15N=CH interaction constant J < 4 Hz is only charac-
teristic of E isomers and 2J > 10 Hz of Z isomers. Judging from
the value of 2.62 Hz of the spin–spin 15N=CH coupling constant
for 7a, we may conclude that this compound possesses the E
configuration.
N
H
NH2
NH2
N
4a,b
O
2a,b
H
N
N
N
R
HO
H
Ar
S
R
H
N
N
NH2
N
H+
H
6a,b
+
O
– H2O
N
R
4b
– H+
5a,b
Ar
HO
H
S
4a,b
R
N
N
H
NH2
To expand the scope of the discovered reaction, thio analogues
3a,b were tested. Boiling of 3a,b with benzaldehyde in methanol
with the catalytic amount of HCl gave derivatives of imidazo-
N
O
Ar
N
HO
H
R
R
N
†
All compounds 7a–d gave satisfactory elemental analysis data. The 1H
N
NH
– H2O H2O
Ar
and 13C NMR spectra were recorded on a Bruker AM-300 spectrometer
(300.13 MHz for 1H and 75.47 MHz for 13C). Chemical shifts were
measured with reference to the residual protons of a DMSO-d6 solvent
(d 2.50 ppm). Mass spectra were measured on an MS 30 spectrometer.
IR spectra were recorded on a Specord M80-2 instrument.
O
N
N
H
S
R
HO
H
S
R
– H2O
N
For 7a: yield 55%, mp 239–241 °C (decomp.). 1H NMR, d: 2.75 (s,
3H, MeN1), 2.86 (s, 3H, MeN3), 5.41 (d, 1H, HC6a, J 8.1 Hz), 5.98 (d,
1H, HC3a, J 8.1 Hz), 7.47 (m, 3H, m-HPh, p-HPh), 7.77 (m, 2H, o-HPh),
9.13 (s, 1H, N=CH), 10.02 (s, 1H, NH). 13C{1H} NMR, d: 28.2 (MeN1),
30.1 (MeN3), 68.1 (HC6a), 74.9 (HC3a), 127.3 (o-CPh), 128.9 (m-CPh),
130.6 (p-CPh), 133.9 (ipso-CPh), 151.5 (N=CH), 157.5 (C=O), 179.0 (C=S).
MS, m/z (%): 289 (M+, 3), 230 (0.4), 186 (6), 153 (6), 127 (13), 112 (100),
111 (34), 104 (37), 103 (34), 98 (39), 89 (26), 88 (26), 83 (48), 77 (29).
IR (n/cm–1): 3256 (NH), 2960 (Me), 1700, 1692 (CO), 1572, 1560 (C=N,
C=C), 1508, 1488, 1404, 1272, 1248, 1228, 1208, 1056, 1032, 848.
N
H
NH2
N
O
H
N
H
Ar
O
H
R
R
N
N
NH
O
N
N
H
S
R
R
N
O
+ 6b
– H+
1
N
For 7b: yield 20%, mp 217–219 °C (decomp.). H NMR, d: 2.75 (s,
OH
R
3H, MeN1), 2.86 (s, 3H, MeN3), 5.41 (d, 1H, HC6a, J 8.2 Hz), 5.98 (d,
1H, HC3a, J 8.2 Hz), 7.69 (m, 4H, o-HPh, m-HPh), 9.06 (s, 1H, N=CH),
10.07 (s, 1H, NH). 13C{1H} NMR, d: 28.2 (MeN1), 30.2 (MeN3), 68.1
(HC6a), 74.6 (HC3a), 123.8 (Ar), 129.1 (Ar), 131.9 (Ar), 133.3 (Ar),
149.0 (N=CH), 157.5 (C=O), 179.1 (C=S). MS, m/z (%): 369 (M+ + 1,
8), 368 (M+, 8), 310 (19), 186 (50), 183 (33), 153 (45), 144 (37), 127
(55), 125 (40), 112 (100), 102 (43), 104 (37), 98 (92), 82 (55).
R
7a–d
– H+
N
O
N
O
1
For 7c: yield 58%, mp 226–228 °C (decomp.). H NMR, d: 1.06 (m,
R
6H, Me), 3.10–3.43 (m, 4H, NCH2), 5.51 (d, 1H, HC6a, J 8.8 Hz), 5.99
(d, 1H, HCNN, J 8.8 Hz), 7.47 (m, 3H, m-HPh, p-HPh), 7.76 (m, 3H,
o-HPh), 9.27 (s, 1H, N=CH), 9.96 (s, 1H, NH). 13C{1H} NMR, d: 12.9
(Me), 13.4 (Me), 35.9 (NCH2), 37.1 (NCH2), 66.2 (HC6a), 74.7 (HC3a),
127.4 (o-CPh), 128.9 (m-CPh), 130.8 (p-CPh), 133.7 (ipso-CPh), 153.8
(N=CH), 156.8 (C=O), 178.6 (C=S). MS, m/z (%): 317 (M+, 50), 258
(40), 214 (18), 179 (19), 172 (35), 155 (13), 140 (81), 127 (21), 125
(47), 112 (57), 103 (42), 101 (80), 97 (32), 82 (54), 76 (37), 59 (100).
IR (n/cm–1): 3212 (NH), 2972, 2932, 2876 (Et), 1692, 1684 (CO), 1608,
1572 (C=N, C=C), 1504, 1480, 1448, 1400, 1336, 1276, 1252, 1232,
1196, 1072, 1060, 916, 832, 804.
8a R = Me
8b R = Et
Scheme 4
[4,5-e]-1,2,4-triazine 9a,b‡ and thiosemicarbazone of benzalde-
hyde 6a (Scheme 5). In a similar manner, 3a,b reacted with
4-bromobenzaldehyde resulting in bicyclic compounds 9a,b and
thiosemicarbazone 6b. Yields of imidazotriazines 9a,b were
55–63% and those of thiosemicarbazones 6a,b were 85–93%
(at the equimolar ratio of 3a,b and aldehyde).
The reaction may be regarded as a new preparative method
for the synthesis of 9a,b. Previously,13 such compounds were
obtained in 5–15% yields as by-products in the synthesis of 3a,b
being the result of the aldehyde-assisted cyclization of vicinal
dithiosemicarbazides.
The imidazotriazine structure of compound 9b was proven
by NMR spectroscopy‡ and supported by single crystal X-ray
diffraction§ (Figure 1), The geometric parameters of the mole-
cule of 9b are within the values expected for the compounds of
this type.14,15 The conformation of the imidazole ring is a flat-
1
For 7d: yield 22%, mp 232–234 °C (decomp.). H NMR, d: 1.05 (m,
6H, Me), 3.09–3.42 (m, 4H, NCH2), 5.51 (d, 1H, HC6a, J 8.4 Hz), 5.99
(d, 1H, HCNN, J 8.4 Hz), 7.70 (br. s, 4H, o-HPh, m-HPh), 9.24 (s, 1H,
N=CH), 10.02 (s, 1H, NH). 13C{1H} NMR, d: 12.9 (Me), 13.4 (Me),
35.9 (NCH2), 37.2 (NCH2), 66.2 (HC6a), 74.4 (HC3a), 124.1 (CAr), 129.1
(CAr), 132.0 (CAr), 133.1 (ipso-CAr), 151.6 (N=CH), 156.8 (C=O), 178.6
(C=S). MS, m/z (%): 397 (M+ + 1, 14), 396 (M+, 15), 338 (39), 336 (41),
214 (19), 184 (29), 181 (50), 172 (26), 156 (16), 154 (41), 140 (100),
125 (41), 112 (87), 102 (43), 82 (30). IR (n/cm–1): 3224 (NH), 2972,
2932, 2872 (Et), 1684, 1676 (CO), 1588 (C=N, C=C), 1504, 1480, 1452,
1400, 1336, 1272, 1252, 1236, 1196, 1072, 1008, 912, 828, 800.
– 286 –

Mendeleev Commun., 2010, 20, 285–287
is piramidalized; the sums of the corresponding valence angles
R
are 353.1(1)–359.6(1) and 328.2(1)°, respectively. As in the
case of the phenyl analogue of 9b,15 N(4)H and N(5)H are in
the equatorial plane of the triazine cycle, and the N(3)H is
axial. This allows the molecules of 9b to form the 3D-frame-
work in a crystal through the N–H···S hydrogen bonds [N···S
3.3051(14)–3.3626(14) Å, ÐNHS 159(1)–175(1)°], which are
complemented by weaker C–H···S contacts [the smallest C···S
distance is 3.6501(14) Å].
H
N
N
4a,b
NH
+
3a,b
6a,b
S
i
N
N
H
S
R
9a R = Me, 63%
9b R = Et, 55%
Scheme 5 Reagents and conditions: i, MeOH, conc. HCl, reflux, 2 h.
In summary, we discovered a new route of the cyclization of
1,3-dialkyl-4,5-bis(1-thiosemicarbazido)imidazolidin-2-ones 2a,b
with aromatic aldehydes that led to 1,3-dialkyl-4-(E-arylidene-
amino)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-ones
7a–d. Interestingly, similar reaction of thio analogues 3 gives
mostly their intramolecular cyclization products containing
nothing of benzaldehyde moieties, the benzaldehydes serving
here as cyclization promoters.
tened envelope with the N(1) atom deviating by 0.05(1) Å, that
of the triazine moiety is a boat with the C(1) and C(3) atoms
deviating by 0.53(1) and 0.35(1) Å, respectively. The N(1),
N(2), N(4), and N(5) atoms are planar, whereas the N(3) atom
C(8)
C(7)
N(3)
References
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1
2
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N(1)
C(5)
N(5)
S(2)
C(6)
5
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Figure 1 General view of the molecule of 9b in representation of atoms
via thermal ellipsoids at 50% probability level.
‡
5,7-Dimethyltetrahydro-1H-imidazo[4,5-e]-1,2,4-triazine-3,6(2H,4H)-
dithione 9a: yield 63% (lit.,13 10%), mp 206–208 °C (decomp.). H and
13C NMR spectra were described previously.13
1
5,7-Diethyltetrahydro-1H-imidazo[4,5-e]-1,2,4-triazine-3,6(2H,4H)-
dithione 9b: yield 55% (lit.,13 15%), mp 238–240 °C (decomp.). 1H and
13C NMR, and mass spectra were described previously.13
6
7
K. A. Jensen, U. Anthoni, B. Kägi, C. Larsen and C. T. Pedersen, Acta
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§
Crystallographic data. Crystals of 9b (C8H15N5S2, M = 245.37) are
orthorhombic, space group Pbca, at 120 K: a = 14.4098(8), b = 9.8694(6)
and c = 16.3533(9) Å, V = 2325.7(2) Å3, Z = 8 (Z' = 1), dcalc = 1.402 g cm–3,
m(MoKα) = 4.35 cm–1, F(000) = 1040. Intensities of 24006 reflections were
measured with a Bruker SMART 1000 CCD diffractometer [l(MoKα) =
8
= 0.71072 Å, w-scans, 2q < 58°] and 3087 independent reflections (Rint
=
9
D. M. Wiles and T. Suprunchuk, Can. J. Chem., 1969, 47, 1087.
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15 S. V. Vasilevskii, Yu. V. Nelyubina and A. N. Kravchenko, Mendeleev
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= 0.0221) were used in further refinement. The structure was solved by
direct method and refined by the full-matrix least-squares technique
against F2 in the anisotropic-isotropic approximation. Hydrogen atoms of
NH groups were located from the Fourier synthesis of the electron density.
The H(C) atom positions were calculated. All hydrogen atoms were
refined in the isotropic approximation in riding model with the Uiso(H)
parameters equal to 1.2Ueq(Ci), for methyl groups equal to 1.5Ueq(Cii),
where U(Ci) and U(Cii) are respectively the equivalent thermal parameters
of the carbon atoms to which corresponding H atoms are bonded. The
refinement converged to wR2 = 0.1210 and GOF = 1.002 for all inde-
pendent reflections [R1 = 0.0437 was calculated against F for 2736
observed reflections with I > 2s(I)]. All calculations were performed
using SHELXTL PLUS 5.0.16
16 G. M. Sheldrick, Acta Crystallogr., Sect. A, 2008, 64, 112.
CCDC 786199 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
Received: 19th April 2010; Com. 10/3509
– 287 –