Regiodirected synthesis of hydroazolic compounds with the use of thiosemicarbazide

Article abstract of DOI:10.1016/j.mencom.2009.01.021

Interaction of α,β-unsaturated ketones of furan series with thiosemicarbazide under basic catalysis leads to 3-furyl-2-thiocarbamoylpyrazolines since nitrous nucleophilic centre of a reagent is activated, whereas the products of intermolecular cyclization

Full text of DOI:10.1016/j.mencom.2009.01.021

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 52–53
Regiodirected synthesis of hydroazolic compounds
with the use of thiosemicarbazide
Aleksandr A. Anis’kov,*a Anton A. Sazonovb and Irina N. Klochkovaa
a Department of Chemistry, N. G. Chernyshevsky Saratov State University, 410012 Saratov, Russian Federation.
Fax: +7 8452 51 6960; e-mail: aniskovaa@mail.ru
b Research Center Nita-Farm, 410030 Saratov, Russian Federation. Fax: +7 8452 55 6685;
e-mail: sazonovaa@gmail.ru
DOI: 10.1016/j.mencom.2009.01.021
Interaction of α,β-unsaturated ketones of furan series with thiosemicarbazide under basic catalysis leads to 3-furyl-2-thio-
carbamoylpyrazolines since nitrous nucleophilic centre of a reagent is activated, whereas the products of intermolecular
cyclization of thiosemicarbazones under conditions of acid activation of sulfureous nucleophile are spirocyclic furylmethylene-
1,3,4-thiadiazolines.
Earlier, we reported that the heterocyclization of α,β-unsaturated
cyclanones with thiourea in basic and acidic media lead to the
formation of compounds of hydroazine series with an annelic
alicyclic fragment.1,2
To develop convenient synthesis of condensed and spirocyclic
hydroazolic compounds, we investigated reactions of carbonyl
substrates of furan series with thiosemicarbazide under various
conditions. These heterocyclic derivatives are of potential bio-
logical activity and can be used in medicine.3
α,β-Unsaturated cyclic and acyclic ketones 1a–d were used
as substrates. Condensations of enones 1 and thiosemicarbazide
were carried out in alcoholic medium, without activation of
reagents and with the use of triethylamine as a basic catalyst.
The interaction without catalyst leads to corresponding thiosemi-
carbazones 2 with a yield of up to 84% (Scheme 1).
In the IR spectra of thiosemicarbazones 2,† there is intense
absorption due to valence vibrations associated with primary
and secondary thioamide groups at 3460–3230 cm–1 (ν NH2,
NH), characterised by three maxima. The signals of protons of
1
thioamidic group are characteristic in the H NMR spectrum,
R2
R2
which gives separate signals for primary (d 9.32–10.55 ppm)
and secondary (d 1.8–2.0 ppm) thioamidic groups.
Reaction does not stop at a stage of formation of a linear
thiosemicarbazone at longer (12–15 h) heating in the presence
R1
R1
H2NHNCSNH2
O
O
O
N
1a–d
HN
†
1H and 13C NMR spectra were recorded on a Bruker-MSL 400 spectro-
H2N
2a–d
S
meter with a working frequency of 400 MHz and 100 MHz, respectively,
for solutions of compounds in [2H6]DMSO, TMS as an internal standard.
IR spectra were measured on a FCM-1201 spectrophotometer for samples
in KBr tablets. A course of reaction and purity of synthesized compounds
were controlled by TLC on Silufol UV-254 plates, in a mixture of hexane,
ethyl acetate and chloroform in a 2:2:1 ratio. GC-MS spectra were recorded
on a TRACE DSQ instrument.
Thiosemicarbazones 2a–d. Solution of 0.05 mol of corresponding
ketone and 0.06 mol of thiosemicarbazide in 60 ml of PriOH was refluxed
for 4 h. Then the reaction mixture was cooled and product of reaction
was filtered off and recrystallized from isopropanol.
2a: yield 84%; mp 143–145 °C (PriOH). IR (n/cm–1): 3362, 3340 (NH2),
3220 (NH), 3150–3100 (=CH), 3180–3160 (CHFur), 2980–2860 (Me),
H2NHNCSNH2,
NEt3, Δ
NEt3, Δ
Py, Δ
R2
R2
R1
R1
SH
O
O
N
N
N
N
NH2
H2N
S
H+
Ac2O – AcOH
R2
1
R2
1605 (C=C), 1200 (C=S). H NMR, d: 1.89 (s, 1H, NH), 2.12 (s, 3H,
R1
R1
Me), 6.19 (d, 1H, =CH–C, J 6.55 Hz), 6.74 (d, 1H, =CH–Fur, J 6.55 Hz),
6.79–6.83 (m, 2H, Fur), 7.29 (d, 1H, Fur), 10.53 (s, 2H, NH2). MS,
m/z (%): 60.2 (100), 66.2 (22), 94.0 (96), 104.5 (8), 114.8 (54), 149.5
(48), 153.3 (54), 209.2 (30). Found (%): C, 51.55; H, 5.28; N, 20.35.
Calc. for C9H11N3OS (%): C, 51.65; H, 5.30; N, 20.08.
2b: yield 75%; mp 173–175 °C (PriOH). IR (n/cm–1): 3400, 3300 (NH2),
3150 (NH), 3100–3000 (=CH), 3170–3150 (CHFur), 2940–2860 (CH2),
O
O
S
N
N
N
H2N
N
NH
COMe
S
3a–d
R2
N
1600 (C=C), 1200 (C=S). H NMR, d: 1.55 (s 1H, NH), 2.12–2.42 (m,
1
a R1 = H, R2 = Me
b R1 + R2 = (CH2)4
c R1 + R2 = (CH2)3
d R1 + R2 = (CH2)5
R1
S
8H, CH2), 6.18 (s 1H, =CH–Fur), 6.79–6.86 (m, 2H, Fur), 7.31 (s 1H,
Fur), 9.56 (s, 2H, NH2). 13C NMR, d: 22.7, 22.9, 23.1, 41.1 (4CH2),
129.5 (=CH–Fur), 115.0 (C4Fur), 112.4 (CF3ur), 140.8 (C2Fur), 148.4 (CF5ur),
142.8 (=C–), 154.8 (C=N), 184.5 (C=S). Found (%): C, 57.57; H, 6.23;
N, 19.97. Calc. for C12H15N3OS (%): C, 57.81; H, 6.06; N, 19.85.
For characteristics of compounds 2c (yield 68%) and 2d (yield 55%),
see Online Supplementary Materials.
O
MeOC
N
NHCOMe
4a–d
Scheme 1
– 52 –
© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 52–53
of catalytic amounts of triethylamine and owing to activation of
nary carbon atom at 60.0–85.5 ppm, carbonyl carbon of acyl
groups (168.1–170.4 ppm), azomethinic carbon (135.8–142.0 ppm),
vinyl carbon of substituents at the 5-position (112.0–113.1 ppm)
and sp2-hybridized carbon of cycloalkane rings (150.1–153.0 ppm)
are observed in 13C NMR spectra.
Under basic catalysis conditions, azacyclization leads to forma-
tion of N-thiocarbamoylpyrazolines 3 with yields of up to 91%.
Physicochemical and spectral characteristics of pyrazolines
coincide with those obtained by condensation of enones with
thiosemicarbazide.
Thus, the interaction of furfurylidene ketones with thiosemi-
carbazide under the influence of temperature depending on condi-
tions can proceed regiodirectively to afford corresponding thio-
semicarbazones or furyl substituted thiocarbamoylpyrazolines.
Heterocyclization of thiosemicarbazones of furan chalcones
2a–d under conditions of acylation proceeds regioselectively to
give 5-furfurylidene-1,3,4-thiadiazolines, including spirocyclic
ones. The use of basic catalysis for heterocyclization of 2a–d
allows one to carry out regiodirected synthesis of N-thiocarbamoyl-
pyrazolines.
the nitrous nucleophilic centre gives N-thiocarbamoylpyrazolines
3 with yields of up to 45%. Vibrations of primary thioamidic
groups are observed in high-frequency area (ν NH2) in IR spectra
of synthesized pyrazolines. In the 13C NMR spectrum, there are
signals of β-carbon atom (d 51.6–53.9 ppm) of synthesized
pyrazolines, whereas in that of thiosemicarbazone sp2-hybridized
α,
β
-carbon atoms of a side chain resound in the area of 115–156 ppm
.
Regiospecific heterocyclization of thiosemicarbazones 2, which
led to thiocarbamoylpyrazolines 3,‡ is confirmed by GC-MS data
and spectral characteristics of compounds 3. The fragmentation
of the molecular ion of 3a led to appearance of the primary
fragmentary ion which consists of dehydroazirinic cycle (C3H6N2S,
m/z 102.2), that is typical of pyrazolinic systems. Formation of a
regioisomeric compound under conditions of exo-azahetero-
cyclization is not observed.
To study the chemical properties of thiosemicarbazones
2a–d, we investigated their heterocyclization reactions under
conditions of acid and basic activation of a reagent.
First, cyclization of thiosemicarbazones 2a–d was carried
out in pyridine in the presence of an acylating agent (acetic
anhydride). Analysis of spectral characteristics of obtained pro-
ducts showed that reaction proceeds regioselectivitely owing to
intramolecular attack of the sulfureous nucleophilic centre at the
carbon atom of azometinic fragment without participation of C=C
bond of chalcone, giving 5-furylmethylene-1,3,4-thiadiazolines
4a–d with yields of up to 82%.§ IR spectra of compounds 4
exhibit bands of valence vibrations of C=C fragment, conjugated
with a benzene ring, with a maximum at 1610–1600 cm–1. This
absorption band also occurs in initial ketones. 1H NMR spectra
show singlet signals of vinyl protons at d 5.75–5.79 ppm (the
presence of two doublets of vinyl protons at 6.18 and 6.24 ppm,
J 6.55 Hz, is characteristic of compound 4a). Signals of quater-
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2009.01.021.
References
1 I. N. Klochkova and A. A. Sazonov, Izv. Vuzov. Khim. Khim. Tekhnol.,
2005, 3, 106 (in Russian).
2 A. A. Sazonov, A. A. Frantsusov and I. N. Klochkova, Izv. Vuzov. Khim.
Khim. Tekhnol., 2005, 3, 127 (in Russian).
3 M.-H. Shih and Ch.-L. Wu, Tetrahedron, 2005, 61, 10917.
‡
Synthesis of N-thiocarbamoylpyrazolines 3a–d.
Procedure I. Solution of 0.06 mol of corresponding ketone and 0.06 mol
of thiosemicarbazide in 60 ml of isopropanol, was refluxed for 15 h in
the presence of 0.12 mol of triethylamine. Then the reaction mixture was
added to 5% water solution of HCl. The product was filtered off and
recrystallized from isopropanol.
Procedure II. Solution of 0.05 mol of corresponding thiosemicarbazone
in 45 ml of isopropanol was refluxed for 4 h in the presence of 0.10 mol
of triethylamine. Then, the reaction mixture was treated analogously to
procedure I.
Received: 10th July 2008; Com. 08/3175
§
Synthesis of 1,3,4-thiadiazolines 4a–d. Solution of 0.015 mol of cor-
responding thiosemicarbazone and 0.03 mol of acetic anhydride in 30 ml
of pyridine was stirred for 4 h. Then the solvent was evaporated in vacuo.
The obtained precipitate was washed with ethanol and recrystallized
from ethanol.
3a: yield 51% (procedure I), 85% (procedure II); mp 186–188 °C
(PriOH). IR (n/cm–1): 3331, 3325 (NH2), 3115–3025 (=CH), 1607 (C=N),
1189 (C=S), 760, 825 (=CH). 1H NMR, d: 2.21 (s, 3H, Me), 2.31–2.59
(d, 2H, CH2), 3.21 (t, 1H, CH–N), 6.41–6.79 (m, 2H, Fur), 7.56 (d, 1H,
Fur), 10.24 (s, 2H, NH2). 13C NMR, d: 19.9 (Me), 38.4 (CH), 53.6 (C–N),
107.9 (CF4ur), 111.0 (CF3ur), 143.5 (CF2ur), 148.9 (C5Fur), 154.3 (Me–C=N),
177.8 (NH2–C=S). MS, m/z (%): 91.2 (40), 102.2 (100), 106.4 (12), 119.0
(10), 134.2 (12), 149.6 (25), 209.2 (10). Found (%): C, 51.77; H, 5.55;
N, 20.23. Calc. for C9H11N3OS (%): C, 51.65; H, 5.30; N, 20.08.
3b: yield 45% (procedure I), 75% (procedure II); mp 182–185 °C
(PriOH). IR (n/cm–1): 3408, 3395 (NH2), 3108 (=CH), 2960–2830 (CH2,
4a: yield 63%; mp 160–162 °C (EtOH). IR (n/cm–1): 3150 (NH), 1690
(Amide I), 1610 (C=N), 1520 (Amide II), 1625 (C=C). 1H NMR, d: 1.52
(s, 3H, COMe), 2.15 (s, 3H, COMe), 2.21 (s, 3H, Me), 6.20 (d, 1H,
=CH–C, J 6.55 Hz), 6.63 (d, 1H, HC=C, J 6.55 Hz), 6.67–6.89 (m, 2H,
β-Fur), 7.32 (d, 1H, α-Fur), 9.6 (s, 1H, NH). Found (%): C, 53.10; H,
5.50; N, 13.96. Calc. for C13H15N3O3S (%): C, 53.61; H, 5.15; N, 14.34.
4b: yield 62%; mp 187–190 °C (EtOH). IR (n/cm–1): 3140 (NH), 1680
(Amide I), 1615 (C=N), 1540 (Amide II), 1630 (C=C). 1H NMR, d:
1.22–2.32 (m, 8H, CH2), 1.92 (s, 3H, COMe), 2.45 (s, 3H, COMe), 5.8
(s, 1H, HC=C), 6.71–6.82 (m, 2H, β-Fur), 7.32 (d, 1H, α-Fur), 8.29 (s, 1H,
NH). 13C NMR, d: 26.8, 28.7, 31.4, 56.2 (4CH2), 85.1 (Cspiro), 36.3 (Me),
38.2 (Me), 129.5 (=CH–Fur), 128.1 (C4Fur), 114.5 (C3Fur), 111.5 (CF2ur),
149.1 (CF5ur), 142.1 (C=N), 144.1 (=C–C), 178.9 (C=O), 179.8 (C=O).
Found (%): C, 57.35; H, 5.63; N, 12.60. Calc. for C16H19N3O3S (%): C,
57.69; H, 5.74; N, 12.60.
4c: yield 59%; mp 167–169 °C (EtOH). IR (n/cm–1): 3390 (NH), 1680
(Amide I), 1600 (C=N), 1500 (Amide II), 1633 (C=C). 1H NMR, d:
1.22–1.72 (m, 6H, CH2), 1.52 (s, 3H, COMe), 2.15 (s, 3H, COMe), 6.1
(s, 1H, HC=C), 6.72–6.82 (m, 2H, β-Fur), 7.29 (d, 1H, α-Fur), 8.8 (s
1H, NH). 13C NMR, d: 27.9, 30.3, 59.2 (3CH2), 83.2 (Cspiro), 39.3 (Me),
44.2 (Me), 129.1 (=CH–Fur), 128.3 (C4Fur), 114.9 (C3Fur), 141.2 (CF2ur),
149.7 (C5Fur), 141.9 (C=N), 150.6 (=C–), 173.9 (C=O), 179.1 (C=O).
Found (%): C, 56.44; H, 5.37; N, 13.96. Calc. for C15H17N3O3S (%): C,
56.41; H, 5.37; N, 13.16.
1
CH), 1690 (C=N), 1190 (C=S). H NMR, d: 1.20–2.10 (m, 8H, CH2),
2.08 (s, 1H, CH), 4.10 (s, 1H, CH–N), 6.06–6.35 (m, 2H, Fur), 7.37 (d,
1H, Fur), 9.56 (s, 2H, NH2). 13C NMR, d: 22.6, 24.1, 25.4, 31.4 (4CH2),
43.5 (CH), 53.9 (C–N), 105.0 (C4Fur), 105.4 (C3Fur), 141.8 (CF2ur), 149.4
(C5Fur), 150.4 (C=N), 175.5 (C=S). Found (%): C, 57.94; H, 6.21; N, 16.79.
Calc. for C12H15N3OS (%): C, 57.81; H, 6.06; N, 16.85.
3c: yield 46% (procedure I), 86% (procedure II); mp 193–194 °C
(PriOH). IR (n/cm–1): 3311, 3309 (NH2), 3100–3020 (=CH), 2880 (CH2,
1
CH), 1600 (C=N), 1200 (C=S). H NMR, d: 1.32–1.94 (m, 6H, CH2),
2.11 (s, 1H, CH), 6.25 (s, 1H, CH–N), 6.45–6.53 (m, 2H, Fur), 7.37 (d,
1H, Fur), 9.31 (s, 2H, NH2). 13C NMR, d: 23.3, 25.4, 25.4, (3CH2), 45.8
(CH), 53.5 (C–N), 105.2 (CF4ur), 110.9 (CF3ur), 142.7 (C2Fur), 150.4 (C5Fur),
160.1 (C=N), 175.8 (C=S). Found (%): C, 56.25; H, 5.57; N, 17.69. Calc.
for C11H13N3OS (%): C, 56.15; H, 5.57; N, 17.86.
For characteristics of 3d, see Online Supplementary Materials.
For characteristics of 4d, see Online Supplementary Materials.
– 53 –