One-pot synthesis of functionalized thioureas by reaction of benzoyl isothiocyanates, secondary amines, and alkyl propiolates

Article abstract of DOI:10.1007/s00706-008-0899-z

An efficient one-pot synthesis of functionalized thioureas is described via three-component reaction of benzoyl isothiocyanates, secondary amines, and alkyl propiolates in the presence of triphenylphosphine (20∈mol%).

Full text of DOI:10.1007/s00706-008-0899-z

Monatsh Chem 139, 1025–1028 (2008)
DOI 10.1007/s00706-008-0899-z
Printed in The Netherlands
One-pot synthesis of functionalized thioureas by reaction of benzoyl
isothiocyanates, secondary amines, and alkyl propiolates
Issa Yavari1;2, S. Zahra Sayyed-Alangi1, Maryam Sabbaghan2, Rahimeh Hajinasiri1, Nasir Iravani1
1
Chemistry Department, Science and Research Campus, Islamic Azad University, Ponak, Tehran, Iran
2
Chemistry Department, Tarbiat Modares University, Tehran, Iran
Received 9 January 2008; Accepted 22 January 2008; Published online 10 March 2008
# Springer-Verlag 2008
Abstract An efficient one-pot synthesis of functional-
ized thioureas is described via three-component re-
action of benzoyl isothiocyanates, secondary amines,
and alkyl propiolates in the presence of triphenylphos-
phine (20 mol%).
dibenzoylacetylene, dicyanoacetylene, or dimethyl
acetylenedicarboxylate (DMAD) generates zwitter-
ionic intermediates [9]. The chemistry of these inter-
mediates has been studied in detail [10, 11]. As part
of our current studies on thioureas [12], we report an
efficient synthesis of functionalized thioureas through
the reaction of alkyl propiolates 1, secondary amines
2, and benzoyl isothiocyanates 3 in the presence of
Ph3P (Scheme 1).
Keywords Benzoyl isothiocyanate; Activated acetylenes;
Secondary amines; Triphenylphosphine; Three-component
reaction.
Introduction
Thiourea and its derivatives are biologically impor-
tant compounds and are useful fungicides, herbicides,
and antibacterial agents [1, 2]. There are several
reports on the synthesis of thioureas, which include
hazardous and toxic procedures [3, 4]. For example,
thioureas have been synthesized by the reaction of
primary and secondary amines with thiophosgene or
isothiocyanates [5–7], which are hazardous protocols.
Therefore, safer, non-toxic, and user-friendly proce-
dures to synthesize thioureas are still required [8].
Zwitterionic species often result from addition of
nucleophiles to activated alkynes. Triphenylphos-
phine (Ph3P) has been the most studied nucleophilic
species. As early as 1961, Tebby observed that the
addition of Ph3P to various activated alkynes like
Results and discussion
The above three-component reaction leads to tetra-
substituted thioureas 4 in 70–90% yields. Structures
of compounds 4a–4g were assigned by IR, 1H NMR,
13C NMR, and mass spectral data. The H and 13C
NMR spectra of 4a–4g are consistent with the pres-
ence of two geometrical isomers, the (Z) isomer be-
ing the major one. The (Z) and (E) isomers were
readily identified by the value of the coupling con-
1
3
stant for their olefinic protons. The JHH value for
3
(Z)-4 was 10.1–10.5 Hz, while the JHH for (E)-4
was 15.0–15.6 Hz. The 13C NMR spectrum of (E)-
4a shows thiocarbonyl (ꢀ ¼ 172.1 ppm), carbonyl
(ꢀ ¼ 164.4 and 168.2 ppm), and olefinic (ꢀ ¼ 120.6
and 140.0 ppm) carbons.
A tentative mechanism for this transformation is
proposed in Scheme 2. It is concievable that the
initial event is the formation of a 1,3-dipolar inter-
mediate 6 from Ph3P and the acetylenic ester, which
Correspondence: Issa Yavari, Chemistry Department, Tarbiat
Modares University, PO Box 14115-175, Tehran, Iran.
E-mail: yavarisa@modares.ac.ir

1026
I. Yavari et al.
Scheme 1
Scheme 2
is subsequently protonated by the benzoyl thiourea
5, generated from addition of amine 2 to aroyl iso-
thiocyanate 3. Nucleophilic attack of the nitrogen
atom of the conjugate base 8 to the vinylphospho-
nium cation 7 leads to ylide 9, which is converted to
4 by elimination of Ph3P (Scheme 2).
of Ph3P. The advantage of the present procedure is
that the reaction is performed under neutral condi-
tions by simple mixing of the starting materials. The
simplicity of the present procedure makes it an in-
teresting alternative to other approaches.
In conclusion, we described a convenient route to
tetrasubstituted thioureas from the one-pot three-
component reaction of benzoyl isothiocyanates, sec-
ondary amines, and alkyl propiolates, in the presence
Experimental
Compounds 1–3 were obtained from Fluka and were used
without further purification. M.p.: Electrothermal-9100 ap-

One-pot synthesis of functionalized thioureas
1027
1
paratus. IR Spectra: Shimadzu IR-460 spectrometer. H and
13C NMR spectra: Bruker DRX-300 AVANCE instrument; in
CDCl3 at 300 and 75 MHz. EI-MS (70 eV): Finnigan-MAT-
8430 mass spectrometer. Elemental analyses (C, H, N) were
performed with a Heraeus CHN-O-Rapid analyzer. The results
agreed favorably with the calculated values.
(Z)- and (E)-Ethyl 3-[benzoyl(1-piperidylcarbothioyl)-
amino]-2-propenoate (4c, C18H22N2O3S)
Pale yellow oil; yield: 0.62g (90%); IR (KBr): ꢁꢀ¼ 1736,
1553, 1422, 880, 719 cmꢀ1; EI-MS: m=z (%) ¼ 346 (Mþ, 10),
317 (15), 301 (56), 273 (34), 262 (80), 241 (72), 105 (100), 45
(84), 29 (57); (Z)-4c (78%): 1H NMR: ꢀ ¼ 1.30 (t, 3J ¼ 7.1 Hz,
Me), 1.70–1.73 (m, 3CH2), 3.74–3.77 (m, 2CH2), 4.22 (q,
3J ¼ 7.1 Hz, OCH2), 5.94 (d, 3J ¼ 10.1Hz, CH), 7.43 (d,
3J ¼ 10.1Hz, CH), 7.40–7.57 (m, 3CH), 8.13 (dd, 3J ¼
General procedure for the prepration of compounds 4
To a stirred solution of 2 mmol 3 in 10cm3 CH2Cl2 were added
2 mmol 2. After 45min, a solution of 2 mmol alkyl propiolate
in 5 cm3 CH2Cl2 was added slowly. Then, a solution of 0.11 g
Ph3P (20 mol%) in 10 cm3 CH2Cl2 was added drop-wise at r.t.
to the reaction mixture and allowed to stand for 24h. The
solvent was removed under reduced pressure, and the residue
was separated by silica gel (Merck 230–400 mesh) column
chromatography usingn-hexane: EtOAc(1:1) mixture as eluent.
4
8.8, J ¼ 1.8 Hz, 2CH) ppm; 13C NMR: ꢀ ¼ 14.7 (Me), 24.5
(2CH2), 26.2 (CH2), 50.3 (2CH2), 61.1 (OCH2), 116.2 (CH),
128.5 (2CH), 129.8 (2CH), 132.1 (CH), 136.9 (C), 141.3 (N–
CH), 165.3 (C¼O), 166.8 (C¼O), 171.4 (C¼S) ppm; (E)-4c
(22%): 1H NMR: ꢀ ¼ 1.08 (3H, t, 3J ¼ 7.1 Hz, Me), 1.66–
1.69 (6H, m, 3CH2), 3.50–3.53 (4H, m, 2CH2), 4.04 (2H, q,
3J ¼ 7.1 Hz, OCH2), 6.03 (1H, d, 3J ¼ 15.6 Hz, CH), 7.53
(1H, d, 3J ¼ 15.6Hz, CH), 7.40–7.57 (3H, m, 3CH), 8.13
(2H, dd, 3J ¼ 8.8, 4J ¼ 1.8 Hz, 2CH) ppm; 13C NMR:
ꢀ ¼ 14.3 (Me), 24.6 (2CH2), 26.3 (CH2), 50.2 (2CH2), 60.9
(OCH2), 119.4 (CH), 128.4 (2CH), 129.8 (2CH), 131.5 (CH),
136.7 (C), 140.5 (N–CH), 165.4 (C¼O), 166.5 (C¼O), 171.5
(C¼S) ppm.
(Z)- and (E)-Ethyl 3-{[benzoyl(diethylamino)carbothioyl]-
amino}-2-propenoate (4a, C17H22N2O3S)
Pale yellow oil; yield: 0.57g (85%); IR (KBr): ꢁꢀ¼ 1717,
1540, 1449, 874, 715 cmꢀ1; EI-MS: m=z (%) ¼ 334 (Mþ, 5),
305 (50), 289 (66), 262 (28), 261 (64), 229 (85), 105 (100), 45
(43), 29 (60); (Z)-4a (75%): 1H NMR: ꢀ ¼ 0.98 (t, 3J ¼ 7.1 Hz,
3
3
(Z)- and (E)-Methyl 3-[benzoyl(1-piperidylcarbothioyl)-
amino]-2-propenoate (4d, C17H20N2O3S)
2Me), 1.29 (t, J ¼ 7.4 Hz, Me), 3.65 (q, J ¼ 7.1 Hz, 2CH2),
3
3
4.19 (q, J ¼ 7.1 Hz, OCH2), 5.88 (d, J ¼ 10.5Hz, CH), 7.12
3
3
Pale yellow oil; yield: 0.58g (87%); IR (KBr): ꢁꢀ¼ 1733, 1541,
1435, 805, 706 cmꢀ1; EI-MS: m=z (%) ¼ 332 (Mþ, 8), 317
(12), 301 (46), 273 (74), 248 (54), 227 (65), 105 (100), 31 (74),
(d, J ¼ 10.5 Hz, CH), 7.39–7.51 (m, 3CH), 8.11 (dd, J ¼
9.2, 4J ¼ 1.4 Hz, 2CH) ppm; 13C NMR: ꢀ ¼ 13.6 (2Me),
14.6 (Me), 46.2 (2CH2), 61.1 (OCH2), 116.3 (CH), 128.5
(2CH), 129.7 (2CH), 131.9 (CH), 132.9 (C), 141.0 (N–CH),
165.2 (C¼O), 166.6 (C¼O), 170.9 (C¼S) ppm; (E)-4a (25%):
1
15 (54); (Z)-4d (83%): H NMR: ꢀ ¼ 1.71–174 (m, 3CH2),
3
3.72 (s, OMe), 3.80–3.83 (m, 2CH2), 6.02 (d, J ¼ 10.2Hz,
3
1H NMR: ꢀ ¼ 0.91 (t, J ¼ 7.4 Hz, 2Me), 1.27 (t, J ¼ 7.5 Hz,
3
3
CH), 7.51 (d, J ¼ 10.2Hz, CH), 7.43–7.60 (m, 3CH), 8.09
3
4
(dd, J ¼ 8.7 Hz, J ¼ 2.8 Hz, 2CH) ppm; 13C NMR: ꢀ ¼ 24.4
(2CH2), 24.5 (CH2), 49.9 (2CH2), 51.3 (OMe), 115.2 (CH),
128.4 (2CH), 128.7 (2CH), 129.5 (CH), 136.8 (C), 142.5
(N–CH), 162.8 (C¼O), 166.8 (C¼O), 171.4 (C¼S) ppm;
(E)-4d (17%): 1H NMR: ꢀ ¼ 1.60–1.64 (m, 3CH2), 3.48–
Me), 3.62 (q, 3J ¼ 7.1 Hz, 2CH2), 3.95 (q, 3J ¼ 7.1Hz, OCH2),
3
3
6.00 (d, J ¼ 15.6 Hz, CH), 7.47 (d, J ¼ 15.6 Hz, CH), 7.39–
3
4
7.51 (m, 3CH), 8.11 (dd, J ¼ 9.2, J ¼ 1.4Hz, 2CH) ppm;
13C NMR: ꢀ ¼ 11.4 (2Me), 14.2 (Me), 46.1 (2CH2), 60.8
(OCH2), 120.6 (CH), 128.4 (2CH), 130.3 (2CH), 132.1 (CH),
133.7 (C), 140.0 (N–CH), 164.4 (C¼O), 168.2 (C¼O), 172.1
(C¼S) ppm.
3
3.51 (m, 2CH2), 3.71 (s, OMe), 6.08 (d, J ¼ 15.5 Hz, CH),
3
7.71 (d, J ¼ 15.5Hz, CH), 7.43–7.60 (m, 3CH), 7.97 (dd,
3J ¼ 8.7, 4J ¼ 2.8 Hz, 2CH) ppm; 13C NMR: ꢀ ¼ 24.2 (2CH2),
24.1 (CH2), 48.1 (2CH2), 51.6 (OMe), 116.5 (CH), 128.3
(2CH), 128.5 (2CH), 129.7 (CH), 136.7 (C), 141.4 (N–CH),
161.3 (C¼O), 166.3 (C¼O), 171.4 (C¼S) ppm.
(Z)- and (E)-Methyl 3-{[benzoyl(diethylamino)carbothioyl]-
amino}-2-propenoate (4b, C16H20N2O3S)
Pale yellow oil; yield: 0.51g (80%); IR (KBr): ꢁꢀ¼ 1701,
1596, 1419, 931, 772 cmꢀ1; EI-MS: m=z (%) ¼ 320 (Mþ, 7),
305 (60), 289 (60), 261 (74), 248 (75), 215 (85), 105 (100), 29
(Z)- and (E)-Ethyl 3-[(4-bromobenzoyl)(1-piperidylcarbo-
thioyl)amino]-2-propenoate (4e, C18H21BrN2O3S)
1
(65), 15 (32); (Z)-4b (67%): IR (KBr): H NMR: ꢀ ¼ 0.95 (t,
3J ¼ 7.4 Hz, 2Me), 3.72 (s, OMe), 3.76 (q, 3J ¼ 7.1 Hz, 2CH2),
Yellow oil; yield: 0.64g (75%); IR (KBr): ꢁꢀ¼ 1699, 1538,
1418, 836, 711 cmꢀ1; EI-MS: m=z (%) ¼ 425 (Mþ, 4), 396
(9), 390 (15), 380 (58), 352 (84), 341 (67), 285 (90), 140 (34),
84 (100), 45 (64), 29 (57); (Z)-4e (66%): 1H NMR: ꢀ ¼ 1.26 (t,
3J ¼ 7.1 Hz, Me), 1.74–1.77 (m, 3CH2), 3.83–3.86 (m, 2CH2),
4.19 (q, 3J ¼ 7.1 Hz, OCH2), 6.02 (d, 3J ¼ 10.1 Hz, CH),
3
3
5.97 (d, J ¼ 10.4 Hz, CH), 7.23 (d, J ¼ 10.4 Hz, CH), 7.43–
3
4
7.78 (m, 3CH), 8.01 (dd, J ¼ 8.1, J ¼ 1.3Hz, 2CH) ppm;
13C NMR: ꢀ ¼ 13.8 (2Me), 45.9 (2CH2), 51.4 (OMe), 115.3
(CH), 128.4 (2CH), 130.8 (2CH), 131.9 (CH), 142.1 (N–CH),
161.5 (C¼O), 166.5 (C¼O), 171.6 (C¼S) ppm; (E)-4b (33%):
3
3
3
1H NMR: ꢀ ¼ 0.91 (t, J ¼ 7.4 Hz, 2Me), 3.50 (s, OMe), 3.73
7.40 (d, J ¼ 10.1Hz, CH), 7.63 (d, J ¼ 6.7 Hz, CH), 7.71
(d, 3J ¼ 8.6 Hz, CH), 7.87 (d, 3J ¼ 8.6 Hz, CH), 8.02 (d,
3J ¼ 6.7 Hz, CH) ppm; 13C NMR: ꢀ ¼ 14.0 (Me), 24.3
(2CH2), 26.1 (CH2), 50.1 (2CH2), 60.6 (OCH2), 115.8 (CH),
126.0 (C), 131.5 (2CH), 131.6 (2CH), 136.5 (C), 141.8 (N–
CH), 164.4 (C¼O), 166.1 (C¼O), 169.9 (C¼S) ppm; (E)-4e
(34%): 1H NMR: ꢀ ¼ 1.09 (t, 3J ¼ 7.1 Hz, Me), 1.74–1.77 (m,
3
3
(q, J ¼ 7.1 Hz, 2CH2), 6.07 (d, J ¼ 15.6Hz, CH), 7.45 (d,
3J ¼ 15.6Hz, CH), 7.43–7.78 (m, 3CH), 8.01 (dd, J ¼ 8.1,
3
4J ¼ 1.3 Hz, 2CH) ppm; 13C NMR: ꢀ ¼ 13.0 (2Me), 43.2
(2CH2), 51.2 (OMe), 116.0 (CH), 128.1 (2CH), 130.2 (2CH),
132.4 (CH), 139.8 (C), 141.0 (N–CH), 160.5 (C¼O), 165.3
(C¼O), 170.8 (C¼S) ppm.

1028
3CH2), 3.83–3.86 (m, 2CH2), 4.02 (q, J ¼ 7.1 Hz, OCH2),
I. Yavari et al.
3
3
CH), 7.48 (d, J ¼ 11.8Hz, CH), 7.42–7.55 (m, 3CH), 7.93
(dd, 3J ¼ 8.8, 4J ¼ 2.0 Hz, CH), 8.10 (dd, 3J ¼ 8.8, 4J ¼
2.2 Hz, CH) ppm; 13C NMR: ꢀ ¼ 49.13 (2CH2), 51.4 (OMe),
66.4 (2CH2), 115.5 (CH), 127.8 (2CH), 128.6 (2CH), 129.6
(CH), 132.2 (C), 142.2 (N–CH), 162.0 (C¼O), 166.5 (C¼O),
169.4 (C¼S) ppm; (E)-4g (25%): 1H NMR: ꢀ ¼ 3.41–3.43 (m,
2CH2), 3.51–3.54 (m, 2CH2), 3.71 (s, OMe), 6.10 (d,
3J ¼ 15.4Hz, CH), 7.75 (d, 3J ¼ 15.4Hz, CH), 7.42–7.55
(m, 3CH), 7.93 (dd, 3J ¼ 8.8, 4J ¼ 2.2Hz, CH), 8.10 (dd,
3J ¼ 8.8 Hz, 4J ¼ 2.0 Hz, CH) ppm; 13C NMR: ꢀ ¼ 49.1
(2CH2), 51.4 (OMe), 66.7 (2CH2), 116.7 (CH), 128.4 (2CH),
128.7 (2CH), 129.7 (CH), 131.6 (C), 139.6 (N–CH), 160.2
(C¼O), 165.9 (C¼O), 167.9 (C¼S) ppm.
3
3
6.08 (d, J ¼ 15.6Hz, CH), 7.53 (d, J ¼ 15.6Hz, CH), 7.65
3
3
3
(d, J ¼ 8.1 Hz, CH), 7.73 (d, J ¼ 7.4 Hz, CH), 7.86 (d, J ¼
7.4 Hz, CH), 8.00 (d, 3J ¼ 8.1 Hz, 2CH) ppm; 13C NMR:
ꢀ ¼ 13.8 (Me), 24.3 (2CH2), 26.1 (CH2), 50.0 (2CH2), 60.4
(OCH2), 120.0 (CH), 126.0 (C), 131.5 (2CH), 131.6 (2CH),
136.4 (C), 140.6 (N–CH), 160.6 (C¼O), 164.0 (C¼O), 170.4
(C¼S) ppm.
(Z)- and (E)-Ethyl 3-[benzoyl(1-pyrrolidinylcarbothioyl)-
amino]-2-propenoate (4f, C17H20N2O3S)
Pale yellow oil; yield: 0.56g (85%); IR (KBr): ꢁꢀ¼ 1713,
1556, 1449, 904, 707 cmꢀ1; EI-MS: m=z (%) ¼ 332 (Mþ, 5),
303 (5), 287 (66), 262 (64), 259 (64), 227 (85), 105 (100), 45
(84), 29 (68); (Z)-4f (80%): 1H NMR: ꢀ ¼ 1.32 (t, 3J ¼ 7.1 Hz,
Me), 2.00–2.04 (m, 2CH2), 2.64–2.68 (m, 2CH2), 4.26
References
3
3
(q, J ¼ 7.1Hz, OCH2), 6.03 (d, J ¼ 10.2Hz, CH), 7.94 (d,
1. Walpole C, Ko SY, Brown M, Beattie D, Campbell E,
Dickenson F, Ewan S, Hughes GA, Lemaira M,
Lerpiniere J, Patel S, Urban L (1998) J Med Chem
41:3159
2. Chalina EG, Chakarova L (1998) Eur J Med Chem 33:975
3. Aoyama T, Murata S, Nagata Y, Takido T, Kodamari M
(2005) Tetrahedron Lett 46:4875
4. Kodomari M, Suzuki M, Tanigawa K, Aoyama T (2005)
Tetrahedron Lett 46:5841
5. Sharma S (1978) Synthesis:803
6. Staab HA (1962) Angew Chem Int Ed Engl 1:351
7. Sridevi G, Rao J, Reddy KK (1989) Synth Commun
19:965
3J ¼ 10.2Hz, CH), 7.42–7.45 (m, 3CH), 8.13 (dd, J ¼ 8.2,
3
4J ¼ 1.5 Hz, 2CH) ppm; 13C NMR: ꢀ ¼ 14.1 (Me), 25.3
(2CH2), 60.0 (2CH2), 60.6 (OCH2), 115.5 (CH), 128.3 (2CH),
129.6 (2CH), 131.6 (CH), 137.5 (C), 141.5 (N–CH), 162.0
1
(C¼O), 166.3 (C¼O), 169.6 (C¼S) ppm; (E)-4f (20%): H
3
NMR: ꢀ ¼ 1.16 (t, J ¼ 7.1 Hz, Me), 2.00–2.04 (m, 2CH2),
3
2.63–2.68 (m, 2CH2), 4.11 (q, J ¼ 7.1 Hz, OCH2), 6.07 (d,
3J ¼ 15.0Hz, CH), 7.95 (d, 3J ¼ 15.0Hz, CH), 7.38–7.56
(m, 3CH), 8.14 (dd, 3J ¼ 8.4, 4J ¼ 1.6 Hz, 2CH) ppm; 13C
NMR: ꢀ ¼ 13.9 (Me), 25.5 (2CH2), 60.2 (2CH2), 60.8
(OCH2), 118.8 (CH), 128.6 (2CH), 129.3 (2CH), 131.8 (CH),
137.7 (C), 140.9 (N–CH), 160.1 (C¼O), 164.3 (C¼O), 169.0
(C¼S) ppm.
8. Katritzky AR, Ledoux S, Witek RM, Nair SK (2004) J Org
Chem 69:2976
(Z)- and (E)-Methyl 3-[benzoyl(morpholin-4-ylcarbothioyl)-
amino]-2-propenoate (4g, C16H18N2O4S)
9. Tebby JC, Wilson IF, Grifiths DV (1979) J Chem Soc
Perkin Trans 1:2133
Pale yellow oil; yield: 0.60g (90%); IR (KBr): ꢁꢀ¼ 1732, 1577,
1447, 801, 696 cmꢀ1; EI-MS: m=z (%) ¼ 334 (Mþ, 9); 319
(6), 303 (46), 275 (76), 248 (57), 229 (46), 105 (100), 31 (67),
10. Nicolaou KC, Harter MW, Gunzner JL, Nadin A (1997)
Liebigs Ann Chem:1283
11. Holmes RR (2004) Acc Chem Res 37:746
12. Yavari I, Bagheri M, Porshamsian Kh, Ali-Askari S
(2007) J Sulfur Chem 28:269
1
15 (50); (Z)-4g (75%): H NMR: ꢀ ¼ 3.52–3.58 (m, 2CH2),
3
3.66–3.68 (m, 2CH2), 3.81 (s, OMe), 6.02 (d, J ¼ 11.8 Hz,