An efficient one-pot synthesis of bis-1-(aroyl)-3-(aryl)thiourea

Article abstract of DOI:10.3184/174751912X13465099708885

A three-component and one-pot reaction between 2,6-diaminopyridine or 1,2-diaminobenzene and ammonium thiocyanate with the subsequent addition of an aroyl chloride afforded the bis-1-(aroyl)-3-(aryl)thiourea in excellent yields. It was important to make the thiocyanate derivatives first and then to use those to prepare the thiourea derivatives.

Full text of DOI:10.3184/174751912X13465099708885

626 RESEARCH PAPER
NOVEMBER, 626–628
JOURNAL OF CHEMICAL RESEARCH 2012
An efficient one-pot synthesis of bis-1-(aroyl)-3-(aryl)thiourea
Razieh Mohebat* and Gholam Mohammadian
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
A three-component and one-pot reaction between 2,6-diaminopyridine or 1,2-diaminobenzene and ammonium
thiocyanate with the subsequent addition of an aroyl chloride afforded the bis-1-(aroyl)-3-(aryl)thiourea in excellent
yields. It was important to make the thiocyanate derivatives first and then to use those to prepare the thiourea
derivatives.
Keywords: bis-1-(aroyl)-3-(aryl)thiourea, aroyl chlorides, ammonium thiocyanate, 2,6-diaminopyridine, 1,2-diaminobenzine,
three-component reaction
1
Thiourea derivatives are widely used in many fields including
the pharmaceutical industry because of their biological
properties such as anticancer1, antimicrobial1–3, antibacterial4,
antifungal5, antimalarial6 and antituberculosis7 activities. They
have also been found to be organic inhibitors for corrosion
because of the protonation of sulfur atoms that can occur in
acidic solution8,9. Aroylthioureas are usually coordinated to
a metal in a monodentate manner through the sulfur atom.
However, they can also chelate to metal through S and O
atoms, giving a six membered ring system10. The synthesis and
application of monothioureas is progressing at considerable
rate. Recently, the synthesis of their bis-thiourea analogues
such as 1,2-bis[N′-(2,2-dimethylpropionyl) thioureido] cyclo-
hexane,N-(2-methoxybenzoyl)-N′-(4-diphenylamine)thiourea,
two bisthiourea compounds of 1,2-bis[N′-(2-methoxybenzoyl)
thioureido]-4-nitrobenzene and 1,2-bis[N′-(2-methoxybenzoyl)
thioureido]-4-chlorobenzene11 has also received attention.
As part of our current studies,12 we report an efficient one-pot
synthesis of the bis-1-(aroyl)-3-(aryl)thiourea, employing
readily available starting materials.
example, the H NMR spectrum of 5a showed two singlets
(δ = 10.64 and 11.87 ppm) corresponding to the protons of the
NH groups. These disappeared after the addition of a few drops
of D2O to the DMSO solution of 5a. The aromatic protons
resonated between 7.38 and 7.97 ppm.
The 13C NMR spectrum of compound 5a showed nine dis-
tinct signals, which was consistent with the proposed structure.
The C=S group resonance in 13C NMR spectra of 5a appeared
at 178.26 ppm. The mass spectrum of 5a displayed the molec-
ular ion peak at m/z = 435. The IR spectrum of compound 5a
also supported the suggested structure. Strong absorption
bands were observed at 3320 and 1664 cm−1 respectively for
the NH and carbonyl group.
A tentative pathway for this transformation is proposed in
Scheme 3.
It is conceivable that the reaction starts with formation
of aroyl thiocyanate 7, followed by addition of diamine
derivatives to generate 5 or 6.
In conclusion, the reaction of diamine derivatives and
ammonium thiocyanate in the presence of aroyl chlorides
afforded the bis-1-(aroyl)-3-(aryl)thiourea in excellent yields.
The present procedure has the advantage that the reaction is
performed under neutral conditions and the starting material
can be used without any activation or modification.
Results and discussion
The reaction of diamine derivatives and ammonium thiocya-
nate in the presence of aroyl chlorides afforded the bis-1-
(aroyl)-3-(aryl)thiourea in excellent yields. It is important to
make the thiocyanate derivatives first and then to use them to
prepare the thiourea derivatives (Schemes 1 and 2).
Experimental
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Costech ECS
4010 CHNS-O analyser at the analytical laboratory of Islamic Azad
The structures of compounds 5a–f and 6a–f were confirmed
1
by IR, H NMR, 13C NMR, and mass spectroscopic data. For
Scheme 1 Condensation of 2,6-diaminopyridine and ammonium thiocyanate in the presence of aroyl chlorides.
* Correspondent. E-mail: rozitakalami@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 627
Scheme 2 Condensation of 1,2-diaminobenzene and ammonium thiocyanate in the presence of aroyl chlorides.
1
University, Yazd branch. Mass spectra were recorded on
a
(m/z, %): 463 (7). H NMR (500 MHz, d6-DMSO): δ 2.38 (6H, s,
2CH3), 7.30 (2H, d, 3J = 6.8 Hz, 2CH), 7.38 (1H, t, 3J = 6.8 Hz, CH),
7.42 (2H, t, 3J = 7.5 Hz, 2CH), 7.52 (2H, d, 3J = 7.5 Hz, 2CH), 7.82
(2H, d, 3J = 7.5 Hz, 2CH), 8.02 (2H, t, 3J = 7.5 Hz, 2CH), 10.75 and
11.79 (4H, 2s, 4NH) ppm.13C NMR (125.8 MHz, d6-DMSO): δ 19.98
(CH3), 113.58, 126.00, 128.72, 131.13, 131.59, 134.25, 136.69,
140,50 and 150.31 (9C aromatic), 171.19 (C=O), 178.48 (C=S) ppm.
1-(3-Methylbenzoyl)3-{6-[3-(3-methylbenzoyl)thioureido]pyridine
-2-yl}thiourea (5c): Yellow powder; m.p. 197–199 °C, IR (KBr) (νmax
cm−1): 3390, 1673, 1619, 1518, 1448. Anal. Calcd for C23H21N5O2S2:
C, 59.59; H, 4.57; N, 15.11. Found: C, 59.41; H, 4.40; N, 15.30%.
FINNIGAN-MAT 8430 mass spectrometer operating at an ionisation
potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470
spectrometer.1H and 13C NMR spectra were recorded on Bruker DRX-
500 Avance spectrometer at solution in CDCl3 using TMS as internal
standard. The chemicals used in this work were purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
General procedure
The aroyl chloride (2 mmol) was added to ammonium thiocyanate
(0.15 g, 2 mmol) in a 50 mL flask at r.t. via a syringe. The reaction
mixture was stirred in a water bath at about 60 °C for 5 min. Then,
the diamine (1 mmol) was added at this temperature. The resulting
mixture was stirred at r.t. for 2 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, 30 mL distilled
water was added over 5 min to the reaction mixture. The resulting
precipitate was collected by filtration on a Buchner funnel. The
crude product was recrystallised from hot ethanol to obtain the pure
compound.
1
MS (m/z, %): 463 (3). H NMR (500 MHz, d6-DMSO): δ 2.37 (6H,
3
3
s, 2CH3), 7.40 (2H, d, J = 6.4 Hz, 2CH), 7.46 (1H, t, J = 6.4 Hz,
3
CH), 7.65 (2H, d, J = 7.6 Hz, 2CH), 7.82 (2H, s, CH), 7.87 (2H, d,
3J = 7.6 Hz, 2CH), 8.01 (2H, t, J = 7.6 Hz, 2CH), 10.75 and 11.76
3
(4H, 2s, 4NH) ppm.13C NMR (125.8 MHz, d6-DMSO): δ 21.28 (CH3),
113.44, 126.40, 128.81, 129.06, 129.67, 134.34, 138.31, 140.49 and
150.29 (9C aromatic), 168.94 (C=O), 178.57 (C=S) ppm.
1-(4-Chlorobenzoyl)3-{6-[3-(4-chlorobenzoyl)thioureido]pyridine
-2-yl}thiourea (5d): Yellow powder; m.p. 244–246 °C, IR (KBr) (νmax
cm−1): 3327, 1670, 1626, 1580, 1442.Anal. Calcd for C21H15Cl2N5O2S2:
C, 50.00; H, 3.00; N, 13.88. Found: C, 50.11; H, 2.94; N, 13.73%.
1-(Benzoyl)3-{6-[3-(benzoyl)thioureido]pyridine-2-yl}thiourea
(5a): Yellow powder; m.p. 228–230 °C, IR (KBr) (νmax cm−1): 3320,
1664, 1623, 1530, 1447. Anal. Calcd for C21H17N5O2S2: C, 57.91; H,
3.93; N, 16.08. Found: C, 57.75; H, 4.10; N, 16.20%. MS (m/z, %):
435 (5). 1H NMR (500 MHz, d6-DMSO): δ 7.38 (2H, d, 3J = 6.9 Hz,
2CH), 7.46 (1H, t, 3J = 6.9 Hz, CH), 7.54 (2H, t, 3J = 8.0 Hz, 2CH of
1
MS (m/z, %): 503 (5). H NMR (500 MHz, d6-DMSO): δ 7.38 (2H,
d, 3J = 6.4 Hz, 2CH), 7.46 (1H, t, 3J = 6.4 Hz, CH), 7.79 (4H, d, 3J =
8.0 Hz, 4CH), 7.90 (4H, d, 3J = 8.0 Hz, 4CH), 10.54 and 11.90 (4H,
2s, 4NH) ppm.13C NMR (125.8 MHz, d6-DMSO): δ 113.11, 128.80,
129.55, 133.28, 136.12, 140.32 and 150.18 (7C aromatic), 169.18
(C=O), 180.05 (C=S) ppm.
3
3
Ph), 7.64 (4H, t, J = 8.0, 4CH of Ph), 7.97 (4H, d, J = 8.0, 4CH
of Ph), 10.64 and 11.87 (4H, 2s, 4NH) ppm.13C NMR (125.8 MHz,
d6-DMSO): δ 113.24, 128.93, 129.47, 132.91, 134.70, 140.38 and
150.23 (7C aromatic), 171.05 (C=O), 178.26 (C=S) ppm.
1-(4-Bromobenzoyl)3-{6-[3-(4-bromobenzoyl)thioureido]pyridine-
2-yl}thiourea (5e): Yellow powder; m.p. 253–255 °C, IR (KBr) (νmax
cm−1): 3315, 1672, 1620, 1585, 1448.Anal. Calcd for C21H15Br2N5O2S2:
C, 42.51; H, 2.55; N, 11.80. Found: C, 42.41; H, 2.70; N, 11.95%.
1-(2-Methylbenzoyl)3-{6-[3-(2-methylbenzoyl)thioureido]pyridine
-2-yl}thiourea (5b): Yellow powder; m.p. 207–209 °C, IR (KBr) (νmax
cm−1): 3240, 1681, 1619, 1560, 1440. Anal. Calcd for C23H21N5O2S2:
C, 59.59; H, 4.57; N, 15.11. Found: C, 59.41; H, 4.40; N, 15.30%. MS
1
MS (m/z, %): 593 (6). H NMR (500 MHz, d6-DMSO): δ 7.32 (2H,
Scheme 3 Suggested pathway for formation of compound 6.

628 JOURNAL OF CHEMICAL RESEARCH 2012
d, J = 6.5 Hz, 2CH), 7.41 (1H, t, J = 6.5 Hz, CH), 7.71 (4H, d,
3J = 7.0 Hz and 4J = 2.8 Hz, 2CH), 7.55 (2H, dd, 3J = 7.0 Hz and 4J =
2.8 Hz, 2CH), 7.74 (4H, d, 3J = 8.0 Hz, 4CH), 8.02 (4H, d, 3J = 8.0 Hz,
4CH), 10.22 and 11.75 (4H, 2s, 4NH) ppm.13C NMR (125.8 MHz,
d6-DMSO): δ 107.32, 125.17, 127.78, 130.28, 131,68, 132.11, 135.67
and 135.88 (7C aromatic), 168.31 (C=O), 180.43 (C=S) ppm.
3
3
3J = 8.4 Hz, 4CH), 7.92 (4H, d, J = 8.4 Hz, 4CH), 10.63 and 11.98
3
(4H, 2s, 4NH) ppm.13C NMR (125.8 MHz, d6-DMSO): δ 113.19,
127.23, 130.95, 132.38, 135.88, 140.34 and 150.10 (7C aromatic),
169.04 (C=O), 179.78 (C=S) ppm.
1-(3-Nitrobenzoyl)3-{6-[3-(3-nitrobenzoyl)thioureido]pyridine-2-yl}
thiourea (5f): Yellow powder; m.p. 210–212 °C, IR (KBr) (νmax cm−1):
3355, 1670, 1609, 1523, 1447, 1345. Anal. Calcd for C21H15N7O6S2:
C, 48.00; H, 2.88; N, 18.66. Found: C, 48.18; H, 3.02; N, 18.89%. MS
1-(3-Nitrobenzoyl)3-{2-[3-(3-Nitrobenzoyl)thioureido]phenyl}
thiourea (6e): White powder; m.p. 203–205 °C, IR (KBr) (νmax cm−1):
3230, 1671, 1612, 1522, 1471, 1346. Anal. Calcd for C22H16N6O6S2:
C, 50.38; H, 3.07; N, 16.02. Found: C, 50.23; H, 3.20; N, 15.95%.
MS (m/z, %): 524 (3). 1H NMR (500 MHz, d6-DMSO): δ 7.33 (2H, dd,
3J = 6.9 Hz and 4J = 2.6 Hz, 2CH), 7.57 (2H, dd, 3J = 6.9 Hz and 4J =
2.6 Hz, 2CH), 7.85 (2H, d, 3J = 8.0 Hz, 2CH), 8.29 (2H, t, 3J = 8.0 Hz,
1
(m/z, %): 525 (5). H NMR (500 MHz, d6-DMSO): δ 7.44 (2H, d,
3
3
3J = 6.4 Hz, 2CH), 7.53 (1H, t, J = 6.4 Hz, CH), 7.93 (1H, t, J =
6.4 Hz, CH), 8.34 (2H, d, 3J = 7.8 Hz, 2CH), 8.40 (2H, t, 3J = 8.0 Hz,
CH)), 8.76 (2H, s, 2CH), 10.99 and 12.20 (4H, 2s, 4NH) ppm. 13C
NMR (125.8 MHz, d6-DMSO): δ 112.22, 126.92, 127.86, 130.47,
130.57, 134.81, 140,67, 147.76 and 148.03 (9C aromatic), 168.75
(C=O), 178.22 (C=S) ppm.
3
2CH), 8.37 (2H, d, J = 8.0 Hz, 2CH), 8.84 (2H, s, 2CH), 10.37
and 12.10 (4H, 2s, 4NH) ppm.13C NMR (125.8 MHz, d6-DMSO):
δ 108.20, 123.64, 125.85, 127.37, 130.18, 131.17, 134.25, 134.99 and
147.59 (9C aromatic), 167.38 (C=O), 181.49 (C=S) ppm.
1-(Benzoyl)3-{2-[3-(benzoyl)thioureido]phenyl}thiourea (6a): White
powder; m.p. 222–224 °C, IR (KBr) (νmax cm−1): 3200, 1669, 1594,
1509, 1483. Anal. Calcd for C22H18N4O2S2: C, 60.81; H, 4.18; N,
12.89. Found: C, 60.96; H, 4.30; N, 12.65%. MS (m/z, %): 434 (7).
1-(4-Nitrobenzoyl)3-{2-[3-(4-Nitrobenzoyl)thioureido]phenyl}thio-
urea (6f): White powder; m.p. 211–213 °C, IR (KBr) (νmax cm−1):
3255, 1664, 1602, 1526, 1341. Anal. Calcd for C22H16N6O6S2: C,
50.38; H, 3.07; N, 16.02. Found: C, 50.23; H, 3.20; N, 15.95%. MS
3
1H NMR (500 MHz, d6-DMSO): δ 7.34 (2H, dd, J = 7.2 Hz and
1
(m/z, %): 524 (5). H NMR (500 MHz, d6-DMSO): δ 7.32 (2H, dd,
4J = 2.6 Hz, 2CH), 7.42 (2H, dd, 3J = 7.2 Hz and 4J = 2.6 Hz, 2CH),
3J = 7.0 Hz and 4J = 2.5 Hz, 2CH), 7.67 (2H, dd, 3J = 6.9 Hz and 4J =
2.5 Hz, 2CH), 8.08 (4H, d, 3J = 8.7 Hz, 4CH), 8.36 (4H, d, 3J = 8.8 Hz,
4CH), 10.28 and 12.11 (4H, 2s, 4NH) ppm.13C NMR (125.8 MHz,
d6-DMSO): δ 108.04, 123.37, 125.88, 130.20, 133.36, 140.20 and
149.82 (7C aromatic), 166.84 (C=O), 180.10 (C=S) ppm.
7.51 (4H, t, 3J = 7.4 Hz, 4CH of Ph), 7.66 (2H, t, 3J = 7.2, 2CH of Ph),
3
8.01 (4H, d, J = 7.4, 4CH of Ph), 10.12 and 11.74 (4H, 2s, 4NH)
ppm. 13C NMR (125.8 MHz, d6-DMSO): δ 107.36, 125.75, 128.35,
128.66, 131.99, 133.14 and 134.13 (7C aromatic), 168.31 (C=O),
180.43 (C=S) ppm.
1-(2-Methylbenzoyl)3-{2-[3-(2-Methylbenzoyl)thioureido]phenyl}
thiourea (6b): White powder; m.p.195–197 °C, IR (KBr) (νmax cm−1):
3215, 1666, 1599, 1509, 1474. Anal. Calcd for C24H22N4O2S2: C,
62.32; H, 4.79; N, 12.11. Found: C, 62.50; H, 4.90; N, 12.25%. MS
We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Yazd of Iran.
1
(m/z, %): 462 (11). H NMR (500 MHz, d6-DMSO): δ 2.32 (6H, s,
Received 11 July 2012; accepted 22 August 2012
Paper 1201408 doi: 10.3184/174751912X13465099708885
Published online: 12 November 2012
2CH3), 7.29 (2H, dd, 3J = 6.8 Hz and 4J = 2.5 Hz, 2CH), 7.44 (2H, t,
3J = 7.4 Hz, 2CH), 7.51 (2H, dd, 3J = 6.8 Hz and 4J = 2.5 Hz, 2CH),
7.59 (2H, d, 3J = 7.6 Hz, 2CH), 7.71 (2H, t, 3J = 7.4 Hz, 2CH), 7.94
3
(2H, d, J = 7.6 Hz, 2CH), 9.75 and 11.84 (4H, 2s, 4NH) ppm.13C
NMR (125.8 MHz, d6-DMSO): 19.64 (CH3), 107.03, 125.16, 126.05,
128.57, 130.63, 131.04, 131.73, 134.39 and 136.42 (9C aromatic),
168.25 (C=O), 178.83 (C=S) ppm.
References
1
2
3
4
5
S. Saeed, N. Rashid, P.G. Jones, M. Ali and R. Hussain, Eur J. Med. Chem.,
2010, 1323.
A.A. Isab, S. NAwaz, M. Saleem, M. Altaf, M. Monim-al-Mehboob,
A. Ahmad and H.S. Evans. Polyhedron, 2010, 1251.
A. Saeed, U. Shaheen, A. Hameed and S.Z.H. Naqvi, J. Fluor. Chem.,
2009, 1028.
M.K. Rauf, I. Din, A. Badshah, M. Gielen, M. Ebishara, D. Vos and
S. Ahmed, J. Inorg. Biochem., 2009, 1135.
R. del Campo, J.J. Criado, R. Gheorghe, F.J. González, M.R. Hermosa,
F. Sanz, J.L. Manzano, E. Monte and E.R. Fernández, J. Inorg. Biochem.,
2004, 98, 1307.
1-(3-Methylbenzoyl)3-{2-[3-(3-Methylbenzoyl)thioureido]phenyl}
thiourea (6c): White powder; m.p.179–181 °C, IR (KBr) (νmax cm−1):
3265, 1645, 1594, 1525, 1474. Anal. Calcd for C24H22N4O2S2: C,
62.32; H, 4.79; N, 12.11. Found: C, 62.50; H, 4.90; N, 12.25%. MS
1
(m/z, %): 462 (5). H NMR (500 MHz, d6-DMSO): δ 2.35 (6H, s,
2CH3), 7.32 (2H, dd, 3J = 7.0 Hz and 4J = 2.6 Hz, 2CH), 7.57 (2H, dd,
3J = 7.0 Hz and 4J = 2.6 Hz, 2CH), 7.64 (2H, t, 3J = 7.5 Hz, 2CH), 7.70
(2H, d, 3J = 7.5 Hz, 2CH), 7.82 (2H, d, 3J = 7.5 Hz, 2CH), 7.94 (2H,
3
d, J = 7.5 Hz, 2CH), 9.77 and 11.73 (4H, 2s, 4NH) ppm.13C NMR
6
V.R. Solomon, W. Haq, M. Smilkstein, K. Srivastava, S.K. Puri and
S.B. Katti., Eur. J. Med. Chem., 2010, 4990.
(125.8 MHz, d6-DMSO): δ 19.31 (CH3), 105.62, 125.71, 126.20,
127.98, 130.49, 130.90, 135.37, 135.55 and 136.45 (9C aromatic),
168.29 (C=O), 177.96 (C=S) ppm.
7
8
9
S. Karakuş and S. Rollas, I1 Farmaco, 2002, 577.
M.K. Awad, J. Electroanal. Chem., 2004, 219.
M.A. Quraishi, F.A. Ansari and D. Jamal, Mater. Chem. Phys., 2002, 687.
1-(4-Bromobenzoyl)3-{2-[3-(4-Bromobenzoyl)thioureido]phenyl}
thiourea (6d): White powder; m.p. 245–247 °C, IR (KBr) (νmax cm−1):
3256, 1670, 1605, 1520, 1442. Anal. Calcd for C22H16Br2N4O2S2:
C, 44.61; H, 2.72; N, 9.46. Found: C, 44.74; H, 2.60; N, 9.35%. MS
10 H. Arslan, N. Külcü and U. Flörke. Spectrochim. Acta Part A. 2006, 1065.
11 M.S.M. Yusof, N.A.C. Ayob, M.A. KAdir and B.M. Yamin, Acta
Crystallogr., 2008, E64, 937.
12 R. Mohebat, M.H. Mosslemin,A. Dehghan-Darehshiri andA. Hassanabadi,
J. Sulfur Chem., 2011, 32, 557.
1
(m/z, %): 592 (7). H NMR (500 MHz, d6-DMSO): δ 7.36 (2H, dd,

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.