New tetrasubstituted thioureas containing the 1-iminoethyl moiety

Article abstract of DOI:10.1007/s11172-011-0375-5

The reactions of 1,1,3-trisubstituted thioureas with acetonitrile afforded the corresponding tetrasubstituted thioureas containing the N-(1-iminoethyl) moiety.

Full text of DOI:10.1007/s11172-011-0375-5

Russian Chemical Bulletin, International Edition, Vol. 60, No. 11, pp. 2432—2433, November, 2011
2432
New tetrasubstituted thioureas containing the 1ꢀiminoethyl moiety*
A. N. Proshin,a T. P. Trofimova,b and S. O. Bachurina
aInstitute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: proshin@ipac.ac.ru
bDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation
The reactions of 1,1,3ꢀtrisubstituted thioureas with acetonitrile afforded the corresponding
tetrasubstituted thioureas containing the Nꢀ(1ꢀiminoethyl) moiety.
Key words: thioureas, acetonitrile, amidines.
Thioureas belong to a class of compounds that hold
carbon tetrachloride (method B, product 2g). The reacꢀ
tion produces acetimidoyl halides, which react with thioꢀ
urea to give the corresponding iminoethyl derivatives 2
(Scheme 1).
promise in chemical and pharmacological aspects. In meꢀ
dicinal chemistry, thioureas are used in the synthesis of
neuroactive acyclic isothioureas1,2 and various sulfurꢀconꢀ
taining heterocycles bearing the pharmacophoric isothioꢀ
uronium group.3 Thioureas can suppress HIV reverse tranꢀ
scriptase,5 exhibit antifungal5 and antibacterial6 properꢀ
ties, and inhibit NO synthase.7
Scheme 1
The aim of the present study was to search for new
reactions giving tetrasubstituted thioureas. We developed
a convenient oneꢀpot method for the synthesis of the preꢀ
viously unknown tetrasubstituted thioureas containing the
1ꢀiminoethyl group as one of Nꢀsubstituents. This method
is based on the reaction of 1,1,3ꢀtrisubstituted thioureas
1a—g with acetonitrile. The reaction can be performed
with the use of aqueous solutions of hydrochloric or hydroꢀ
bromic acid (method A, products 2a—f), as well as under
milder conditions with the use of triphenylphosphine and
Comꢀ
pound
a
c
d
R1
R2
R3
X
Me
Me
Me
Me
Me
Me
Ph
Br
Cl
Br
4ꢀMe2CHC6H4
4ꢀMe2CHC6H4
Comꢀ
NR1R2
R3
X
pound
b
Ph
Br
Cl
Br
H(12C)
H(12B)
H(12A)
e
f
4ꢀMe2CHC6H4
C(12)
S(1)
Cl(1)
N(2)
4ꢀMe2CHC6H4
4ꢀMe2CHC6H4
C(10)
H(11A)
H(8C)
H(8A)
H(2)
C(2)
H(11B)
C(11)
H(3)
C(3)
N(1)
H(8B)
H(9B)
C(9)
g
Cl
H(1A)
N(3)
H(1B)
C(8)
H(11C)
C(1)
C(4)
C(7)
H(7)
Conditions: A, HX; B, Ph3P, CCl4.
C(13)
C(14)
C(6)
C(5)
H(5)
H(6)
H(14B)
H(9A)
The structures of the resulting compounds were conꢀ
firmed by the Xꢀray diffraction data for thiourea 2d (Fig. 1).
H(14C)
H(14B)
H(9C)
Fig. 1. Molecular structure of compound 2d in the crystal.
Experimental
1
* Dedicated to Academician of the Russian Academy of Sciences
O. M. Nefedov on the occasion of his 80th birthday.
The H NMR spectra were recorded on a Bruker CXPꢀ200
spectrometer operating at 200 MHz in DMSOꢀd6 with tetrameꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2385—2386, November, 2011.
1066ꢀ5285/11/6011ꢀ2432 © 2011 Springer Science+Business Media, Inc.

Nꢀ(1ꢀIminoethyl)thioureas
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2433
thylsilane as the internal standard. The electrospray ionization
mass spectra were obtained on a Shimadzu LCMSꢀ2010A quaꢀ
drupole mass spectrometer. The elemental analysis was perꢀ
formed on a CarloꢀErba CHN analyzer.
1ꢀ(1ꢀIminoethyl)thioureas 2a—f (general procedure). Methꢀ
od A. The starting thiourea 1a—f (1 mmol) was dissolved with
stirring in acetonitrile (3—4 mL). Then an aqueous solution of
hydrochloric or hydrobromic acid (1 mmol) was added. The
reaction mixture was stirred for 2—4 h and left for 16 h. The
crystalline precipitate that formed was filtered off and washed
with diethyl ether.
phine (0.1 g, 0.38 mmol) was dissolved in acetonitrile (2.6 mL).
Then CCl4 (0.5 mL) was added, and the mixture was kept for 16 h.
The crystalline precipitate that formed was filtered off and reꢀ
crystallized from acetone. Product 2g was obtained in a yield of
0.07 g (63%). M.p. 125—126 °C. Found (%): C, 58.65; H, 7.43;
N, 11.30; S, 8.61. C18H27N3OS•HCl. Calculated (%): C, 58.44;
H, 7.63; N, 11.36; S, 8.67. 1H NMR, δ: 1.25 (d, 6 H, C(CH3)2);
1.3—1.9 (m, 5 H, CH2CH2CH); 2.25 (br.s, 3 H, HN=CCH3);
2.80 (m, 1 H, CH(CH3)2); 3.0—3.4 (m, 4 H, CHNCH, CH2O);
4.30—4.60 (m, 3 H, CHNCH, OH); 7.05—7.50 (m, 4 H, Ar);
9.50—10.30 (br.s, 2 H, NH+N+H). MS, m/z: 333 [M]+, 292
[M – CH3=NH]+, 249 [M – CH3=NH—C(CH3)3]+, 232
[M – CH3=NH—C(CH3)3—OH]+, 219 [M – CH3=NH—
C(CH3)3—CH2OH]+.
Principal crystallographic data for compound 2d. The unit
cell parameters: a = 14.9503(5) Å, b = 9.2691(2) Å, c =
= 12.1751(4) Å, α = 90.00°, β = 110.553(2)°, γ = 90.00°,
V = 1579.78(8) Å3, space group P21/c, Z = 2. The Xꢀray diffracꢀ
tion data were collected on a КAPPA APEX II singleꢀcrystal
diffractometer (MoꢀKα radiation, λ = 0.71073 Å). Single crysꢀ
tals were attached to a glass fiber and mounted on a goniometer.
The crystals were cooled with liquid nitrogen at 100 К. The unit
cell parameters were refined based on the total Xꢀray diffraction
data set. The experimental intensities were corrected for absorpꢀ
tion.8 The structure was solved by direct methods with the use of
the SHELXTL program package9 and refined by the fullꢀmatrix
leastꢀsquares method based on F2 using the total Xꢀray data set
with anisotropic displacement parameters for all nohydrogen
atoms. The structure was deposited to the Cambridge Crystalloꢀ
graphic Data Centre (CCDC 763757).
1ꢀ(1ꢀIminoethyl)ꢀ3,3ꢀdimethylꢀ1ꢀphenylthiourea hydroꢀ
bromide (2a). The yield was 60%, m.p. 143—144 °C. Found (%):
C, 44.02; H, 5.13; N, 14.07; S, 10.43. C11H15N3S•HBr. Calcuꢀ
1
lated (%): C, 43.71; H, 5.34; N, 13.90; S, 10.61. H NMR, δ:
2.30 (s, 3 H, CH3); 3.33 (s, 3 H, CH3); 3.50 (s, 3H, CH3); 7.43—7.95
(m, 5 H, Ar); 9.75 (br.s, 1 H, NH); 10.85 (br.s, 1 H, N+H).
Nꢀ(1ꢀIminoethyl)ꢀNꢀphenylpyrrolidineꢀ1ꢀcarbothioamide hydroꢀ
bromide (2b). The yield was 75%, m.p. 137—138 °C. Found (%):
C, 47.28; H, 5.11; N, 13.06; S, 9.38. C13H17N3S•HBr. Calcuꢀ
1
lated (%): C, 47.57; H, 5.53; N, 12.80; S, 9.77. H NMR, δ:
1.80—2.20 (m, 4 H, CH2CH2); 2.32 (s, 3 H, CH3); 3.40—4.30
(m, 4 H, CH2NCH2); 7.52—7.83 (m, 5 H, Ar); 9.73 (br.s, 1 H,
NH); 10.86 (br.s, 1 H, N+H).
1ꢀ(1ꢀIminoethyl)ꢀ1ꢀ(4ꢀisopropylphenyl)ꢀ3,3ꢀdimethylthiourea
hydrochloride (2c). The yield was 65%, m.p. 168—169 °C. Found
(%): C, 55.81; H, 7.12; N, 13.72; S, 10.24. C14H21N3S•HCl.
Calculated (%): C, 56.08; H, 7.40; N, 14.01; S, 10.69. 1H NMR,
δ: 1.23 (d, 6 H, CH(CH3)2, J = 7.3 Hz); 2.25 (s, 3 H, CH3); 2.95
(m, 1 H, CH(CH3)2); 3.42 (s, 3 H, CH3); 3.50 (s, 3 H, CH3);
7.37 (d, 2 H, Ar, J = 8.6 Hz); 7.75 (d, 2 H, Ar, J = 8.6 Hz); 9.71
(br.s, 1 H, NH); 11.30 (br.s, 1 H, N+H).
1ꢀ(1ꢀIminoethyl)ꢀ1ꢀ(4ꢀisopropylphenyl)ꢀ3,3ꢀdimethylthiourea
hydrobromide (2d). The yield was 85%, m.p. 159—160 °C. Found
(%): C, 48.52; H, 6.14; N, 12.44; S, 9.12. C14H21N3S•HBr.
Calculated (%): C, 48.84; H, 6.404; N, 12.20; S, 9.31. 1H NMR,
δ: 1.28 (d, 6 H, CH(CH3)2, J = 7.3 Hz); 2.25 (s, 3 H, CH3); 3.02
(m, 1 H, CH(CH3)2); 3.40 (s, 3 H, CH3); 3.50 (s, 3 H, CH3);
7.40 (d, 2 H, Ar, J = 8.6); 7.75 (d, 2 H, Ar, J = 8.6 Hz);
8.50—11.20 (br.s, 2 H, N+H+NH).
Nꢀ(1ꢀIminoethyl)ꢀNꢀ(4ꢀisopropylphenyl)piperidineꢀ1ꢀcarboꢀ
thioamide hydrochloride (2e). The yield was 74%, m.p. 178—180 °C.
Found (%): C, 60.32; H, 7.94; N, 12.59; S, 9.08. C17H25N3S•HCl.
Calculated (%): C, 60.07; H, 7.71; N, 12.36; S, 9.43. 1H NMR,
δ: 1.20 (d, 6 H, CH(CH3)2, J = 7.3 Hz); 1.30—1.80 (m, 6 H,
CH2CH2CH2); 2.25 (s, 3 H, CH3); 2.95 (m, 1 H, CH(CH3)2);
3.60—4.50 (m, 4 H, CH2NCH2)); 7.42 (d, 2 H, Ar, J = 8.6 Hz); 7.70
(d, 2 H, Ar, J = 8.6 Hz); 9.80 (br.s, 1 H, NH); 11.20 (br.s, 1 H, N+H).
Nꢀ(1ꢀIminoethyl)ꢀNꢀ(4ꢀisopropylphenyl)piperidineꢀ1ꢀcarboꢀ
thioamide hydrobromide (2f). The yield was 86%, m.p. 175—176 °C.
Found (%): C, 53.44; H, 6.68; N, 10.75; S, 8.12. C17H25N3S•HBr.
Calculated (%): C, 53.12; H, 6.82; N, 10.93; S, 8.34. 1H NMR,
δ: 1.18 (d, 6 H, CH(CH3)2, J = 7.3 Hz); 1.45—1.95 (m, 6 H,
CH2CH2CH2); 2.15 (s, 3 H, CH3); 2.95 (m, 1 H, CH(CH3)2);
3.60—4.60 (m, 4 H, CH2NCH2); 7.35 (d, 2 H, Ar, J = 8.6 Hz);
7.65 (d, 2 H, Ar, J = 8.6 Hz); 9.55 (br.s, 1 H, NH); 10.60 (br.s,
1 H, N+H).
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 11ꢀ03ꢀ00863ꢀa)
and the Ministry of Education and Science of the Russian
Federation (State Contract No. 14.740.11.0810).
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3ꢀHydroxymethylꢀNꢀ(1ꢀiminoethyl)ꢀNꢀ(4ꢀisopropylphenyl)ꢀ
piperidineꢀ1ꢀcarbothioamide hydrochloride (2g). Method B.
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Received September 21, 2011;
in revised form November 7, 2011