Synthesis and Characterization of New 1-(4-Methylpiperazin-1-yl)thioureas as Potential Antitubercular Agents

Article abstract of DOI:10.1002/jhet.2551

Synthesis, characterization, and preliminary biological assessments of compounds with antitubercular activity.

Full text of DOI:10.1002/jhet.2551

Month 2015
Synthesis and Characterization of New 1-(4-Methylpiperazin-1-yl)-
thioureas as Potential Antitubercular Agents
a
a
b
*
Michael J. Hearn, Tracy Wang, and Michael H. Cynamon
aDepartment of Chemistry, Wellesley College, Wellesley, Massachusetts 02481, USA
bVeterans Affairs Medical Center, Syracuse, New York 13210, USA
*
E-mail: MHearn@Wellesley.edu
Received June 13, 2015
DOI 10.1002/jhet.2551
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis, characterization, and preliminary biological assessments of compounds with antitubercular activity.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
this productive field holds the promise of finding new che-
motherapeutics for the clinic, the study of the interactions of
new heterocyclic materials with Mtb may also lead to a bet-
ter understanding of the life processes of the pathogen.
Novel heterocyclic compounds may thus serve as valuable
biological probes in combatting tuberculosis [13–18].
As part of our ongoing investigation of the scope of anti-
tubercular heterocyclic systems containing the thiourea
moiety [19,20], we now report our results on the preparation
and properties of new 1-(4-methylpiperazin-1-yl)thioureas,
including preliminary findings on their activities against
Mtb. In the event, the reaction of 1-amino-4-methylpiperazine
(I) with a variety of isothiocyanates (II) in ethanol or toluene
formed the corresponding thioureas (III) as stable crystalline
solids in good yield and purity (Scheme 1). The reactions
were exceptionally clean, requiring either no purification
or, at most, washing with small portions of ether. The tracta-
ble products could be characterized in convenient ways by
standard spectrometric techniques and elemental analysis.
In a representative example, compound I was treated
with 3,4-dimethoxyphenethyl isothiocyanate (IIr, R = 3,4-
(OCH3)2C6H3CH2CH2, 1.01 equivalents) in refluxing abso-
lute ethanol for thirty minutes. The reaction mixture was
cooled slowly to room temperature, inducing the precipita-
tion of the product, which was isolated to give IIIr (R =
3,4-(OCH3)2C6H3CH2CH2) as a white crystalline solid
(76%) in pure form (mp 141-142°C. Anal. Calculated for
C16H26N4O2S: C, 56.78; H, 7.74. Found: C, 57.17; H,
7.75. HR-MS (fast atom bombardment, MH+) calculated
for C16H27N4O2S: 339.1855. Found: 339.1850.). Our results
on the preparation of these compounds are summarized in
Table 1, with yields averaging 80%. Table 1 also includes
the calculated logarithm of the partition coefficient (C log P)
between n-octanol and water for each of the compounds
(see Experimental for calculation method). The value of
Well into the twenty-first century, tuberculosis remains
unchallenged as the primary agent of death among infec-
tious diseases [1,2]. Despite the deployment of massive
resources on the part of pharmaceutical companies,
governments, public-private partnerships and the World
Health Organization, the disease continues to kill one and
one-half million people each year. Globally, some three
billion persons are infected. Adding to the urgency of the
situation has been the recent appearance of strains of the
causative agent, Mycobacterium tuberculosis (Mtb), which
are unusually virulent or highly drug resistant [3,4]. Of
special concern among the latter strains are ones which
thrive even in the presence of the best drugs available
today. The rise of extensively drug-resistant tuberculosis
may thus threaten to return therapy of the disease to the
pre-antibiotic age [5]. The poor status of current progress
against tuberculosis is due to a number of factors, includ-
ing the small number of novel materials in the drug discov-
ery pipeline. While it is evident that the continuing problem
of worldwide tuberculosis is multifactorial in its origins,
any realistic estimate of the situation must include the in-
nate intractability of Mtb itself towards chemotherapy [6].
Among diseases caused by bacterial pathogens, tuberculo-
sis is unique in that it requires chemotherapy of 6-20
months. This prolonged chemotherapy may be accompa-
nied by pharmacokinetic interactions with other drugs or a
number of adverse drug events [7]. The organism has
proven its resilience to succeeding generations of chemists,
microbiologists and physicians, underscoring the gravity of
the problem. Some recent discoveries, however, are begin-
ning to redress the balance in the fight against tuberculosis,
and among these discoveries are effective new compounds
bearing heterocyclic structures [8–13]. While research in
© 2015 HeteroCorporation

M. J. Hearn, T. Wang, and M. H. Cynamon
Vol 000
Table 2
Spectrometric Features of 1-(4-Methylpiperazin-1-yl)thioureas III.
Scheme 1
νmax NH
δ 1H NMR
δ 13C NMR
Entry
Compound
(cm-1)
NH
C=S
1
2
3
4
5
6
7
8
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
IIIs
3236, 3175
3268, 3105
3271, 3104
3268, 3118
3264, 3113
3263, 3170
3265, 3167
3266, 3166
3284, 3123
3263, 3106
3281, 3117
3239, 3138
3308, 3138
3231, 3124
3296, 3097
3313, 3310
3327, 3119
3304, 3107
3316, 3112
9.82, 9.48
10.00, 9.72
10.91, 9.58
10.13, 9.57
9.54, 9.25
9.74, 9.43
9.66, 9.36
9.60, 9.34
9.19, 8.90
9.35, 9.05
9.42, 9.13
9.71, 9.40
9.50, 9.17
9.89, 9.70
9.51, 9.32
8.86, 8.43
8.77, 7.74
8.55, 7.46
9.00, 8.11
180
176
177
179
180
177
179
177
180
178
177
177
178
177
177
180
179
179
181
C log P is one characteristic used to evaluate the potential
of a compound to behave as a drug, providing a predictive
indication of a material’s solubility, permeation and
absorption [21]. The geometric mean of the C log P values
in Table 1 is 2.04, which lies well within the C log P distri-
bution of currently traded drugs [22].
9
The spectrometric features of the 1-(4-methylpiperazin-
1-yl)thioureas, were highly characteristic, as shown in
Table 2. Foremost among these were 1) N-H bands in ac-
cord with the thiourea moiety near 3275 and 3140 cm-1
in the infrared spectrum, 2) N-H peaks near δ 9.5 and
9.0 ppm in the hydrogen NMR spectrum and 3) a signal
for the thiocarbonyl unit near δ 178 ppm in the carbon
NMR spectrum [23]. Infrared spectroscopy was particularly
helpful in making a ready bench assessment of the comple-
tion of our reactions, since the spectra of the products were
so different from those of the reactants. Had they been
present in the crystallized products, for example, even small
residual amounts of the parent mustard oils (II) would have
been promptly detected, due to their exceptionally intense
bands in the 2200 cm-1 region of the infrared spectrum
[24,25], but such bands were not observed after as little as
30 to 60 minutes of reaction time. Products III also
displayed the characteristic infrared absorptions associated
with the strong coupling of the C=S stretching mode with
the C-N stretching mode in the ranges of 1570-1395,
1420-1260 and 1140-940 cm-1 [26].
10
11
12
13
14
15
16
17
18
19
We would like to comment on the general chemical stabil-
ity of the products. When heated, thioureas are sometimes
observed to equilibrate with their immediate progenitors
and with other amines and isothiocyanates formed from
thermal breakdown (Scheme 2, Eqn. 1). This is particularly
true for reactions involving weakly nucleophilic precursors
(R1NH2), including some aromatic and heteroaromatic
amines. Under such circumstances, mixtures of products
may be observed, and often the reaction is driven to comple-
tion by a LeChatelier effect towards the highly crystalline
Table 1
1-(4-Methylpiperazin-1-yl)thioureas III.
Entry
Compound
R
% Yield
mp (°C)
C log P
1
2
3
4
5
6
7
8
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
IIIs
C6H5
2-ClC6H4
58
82
89
81
84
88
72
88
89
89
78
65
78
75
97
88
76
76
75
152-153
188-189
197-198
179-180
160-161
189-190
171-172
191-192
153-154
184-185
192-193
192-193
176-177
194-195
188-189
150-151
148-149
141-142
126-128
1.99
2.51
1.95
1.74
2.46
2.46
2.51
3.25
1.74
2.08
2.26
1.30
3.42
3.03
1.24
1.97
2.20
1.70
0.91
2-NO2C6H4
2-CH3O-C6H4
3-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-IC6H4
4-CH3OC6H4
4-CH3SC6H4
4-(CH3)2NC6H4
4-CH3COC6H4
4-C6H5OC6H4
2,4-Cl2C6H3
3,4,5-(CH3O)3C6H2
C6H5CH2
C6H5CH2CH2
3,4-(CH3O)2C6H3CH2CH2
CH2=CHCH2
9
10
11
12
13
14
15
16
17
18
19
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
New 1-(4-Methylpiperazin-1-yl)thioureas
Scheme 2
and relatively insoluble symmetrical thiourea (Scheme 2,
Eqn. 2) [27]. In the present reactions, however, we found that
the aminoheterocycle was sufficiently nucleophilic to lead to
rapid and irreversible formation of the 1-(4-methylpiperazin-
1-yl)thioureas, with no tendency toward thermal fragmenta-
tions and their consequences. This observed stability appears
to be typical of the thioureas derived from these strongly
nucleophilic bases. Similarly, we found no evidence for
any contamination of our products with the thiourethanes
(RNHCSOCH2CH3) that would be formed by the side reac-
tion of the isothiocyanates with the solvent ethanol [27]. The
results of reactions run in ethanol were identical to those run
in toluene (see Experimental).
In preliminary biological evaluations of the 1-(4-
methylpiperazin-1-yl)thioureas, the activity of compound
IIIr (R = 3,4-(OCH3)2C6H3CH2CH2) was representative.
The substance was assayed in vitro against Mycobacterium
bovis BCG Tice using the Kirby-Bauer disc diffusion
method [28]. In this technique, solutions containing known
weights of the compound were applied to porous disks; and
the disks were laid on agar development plates having a
defined cell density of the mycobacteria. The plates were
incubated at 37°C for seven days and then examined for
inhibition of growth using transmitted light. The antimicro-
bial activity of the compound was measured by the dimen-
sions of the circular clear zone surrounding the disk in
which no growth occurred, while the remainder of the plate
showed a luxuriant bacterial lawn. At 200 μg, IIIr showed
a zone of clear inhibition of diameter greater than 40 mm; at
50 μg, the diameter was greater than 30 mm; and at 20 μg,
the diameter was greater than 20 mm. The size of the zone
of inhibition was related to increasing amounts of the test
compound and consistent with a concentration dependence
of growth inhibition (see Experimental). Since a larger zone
of inhibition corresponds to a more effective test compound
[29–31], these results were indicative of promising activity
and will warrant further investigations of the antimyco-
bacterial character of IIIr and its congeners.
features. Preliminary microbiological data suggested that
further examination of the antitubercular properties of these
compounds will be justified.
EXPERIMENTAL
General methods. Elemental analyses were carried out
by Galbraith Laboratories, Knoxville, Tennessee, USA.
Melting points (mp, °C) were taken in open capillary tubes
using
a Mel-Temp apparatus (Laboratory Devices,
Cambridge, MA, USA), and are corrected. Infrared (IR)
spectra were recorded on a Perkin-Elmer Spectrum One
Fourier transform spectrophotometer fitted with a universal
attenuated total reflectance sampling accessory, reported in
wavenumbers (ν, cm–1). Most reactants, reagents and
solvents were obtained from Sigma-Aldrich Chemical
Company (Milwaukee, Wisconsin, USA) and Alfa Aesar
Incorporated (Windham, New Hampshire, USA) and were
used as received. Nuclear magnetic resonance (NMR)
spectra were taken on a Bruker 300 Fourier transform
instrument as dilute solutions in dimethyl sulfoxide-d6
(DMSO-d6) or chloroform-d, recorded at 300 megahertz
(1H NMR) or 75 megahertz (13C NMR) and are reported in
parts per million delta (δ) downfield from internal tetra-
methylsilane as reference; all aromatic coupling constants J
were in the range of 7-9 Hz. In some proton spectra, only
signals in the region 0-10 ppm are reported. Appropriate
solvent blanks were recorded to account for water and
DMSO. High-resolution mass spectroscopy (HR-MS) data
were obtained using the JEOL HX-110 double focusing
mass spectrometer of the Michigan State University Mass
Spectrometry Facility, courtesy of Professor D. Gage and
Ms. B. Chamberlin. This magnetic sector instrument is
equipped with a fast atom bombardment (FAB) ionization
source. It is capable of performing high resolution (peak
matching) and tandem mass spectrometry. Reactions were
conveniently carried out on 10 mmole scale in a 100 mL
round bottom flask fitted for reflux with a temperature-
controlled heating mantle, magnetic stirrer and reflux
condenser, using approximately 20 mL of absolute ethanol
or toluene as solvent. Upon cooling to ambient tem-
perature, the product formed as a crystalline solid, which
was filtered off and dried. Often the product formed was
analytically pure; whenever this was not the case, the
analytical sample was obtained by washing the compound
with small portions of ether, as specified in the individual
procedures. Safety Notes: Gloves were worn during the
chemical syntheses, and the reactions were carried out in
In summary, we found that 1-(4-methylpiperazin-1-yl)
thioureas, useful for the study of the antitubercular activities
of new heterocyclic structures, could be prepared in good
yield by the reaction of 1-amino-4-methylpiperazine with
isothiocyanates in ethanol or toluene. The compounds were
isolated from the reaction mixture in pure form and
required, at most, washing with small portions of ether to
obtain the analytical samples. The stable thioureas were
produced without contaminants resulting from thermal
fragmentation or thiourethane formation and could be reli-
ably identified on the basis of their salient spectrometric
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. J. Hearn, T. Wang, and M. H. Cynamon
Vol 000
the hood. In general, any scale-up of preparations of
compounds with relatively high proportions of nitrogen
and oxygen was done with due caution. No specific safety
problems were encountered with the methods given below.
No attempt was made to optimize yields. Calculated values
of the logarithms of the partition coefficients (C log P
values) were obtained using HyperChem Professional,
Version 8.5, following geometry optimization of structures.
Biological assessments. For screening, Kirby-Bauer disk
diffusion testing was used [32]. The 1-(4-methylpiperazin-
1-yl)thioureas (20 mg) were dissolved in enough DMSO
to prepare solutions that had a concentration of 20 mg/mL.
The solutions were then applied to 6-mm filter paper disks
such that the total weight of test compound per disk was
200, 50 or 20 micrograms. The disks were laid on 7H10
agar plates having a cell density of M. bovis BCG Tice of
three MacFarland units. M. bovis BCG Tice was obtained
from the American Type Culture Collection (ATCC,
Manassas, Virginia, USA). The plates were incubated at
37°C for seven days and then read using transmitted light.
The antimicrobial activity of the compound was measured
by the dimensions of the circular clear zone surrounding
the disk in which no growth occurred, while the remainder
of the plate showed a luxuriant bacterial lawn. At 200 μg,
IIIr showed a diameter of inhibition of greater than 40 mm;
at 50 μg, the diameter was greater than 30 mm; and at
20 μg, the diameter was greater than 20 mm. A plot of the
diameter of inhibition versus weight of IIIr suggests a
linear concentration dependence of growth inhibition.
reflux. The mixture was cooled slowly to room temperature,
and the ethanol was allowed to evaporate, resulting in a
white solid, which was filtered off (1.45 g, 58%). Three
ether washes of the white solid produced the analytical
sample, mp 152-153°C, identified as the stable hydrate; IR
3506 (m), 3236 (w), 3175 (w), 2983 (w), 2948 (w), 2844
(w), 2802 (w), 1669 (w), 1601 (m), 1591 (m), 1543 (s),
1500 (s), 1465 (w), 1446 (m), 1390 (w), 1371 (m), 1328
(w), 1282 (m), 1266 (s), 1198 (m), 1159 (w), 1135 (m),
1175 (w), 1158 (w), 1089 (w), 1077 (w), 1050 (w), 1030
(w), 1005 (s), 930 (w), 899 (w), 834 (s), 761 (s), 740 (m),
1
693 (s), 672 (s); H NMR (DMSO-d6) δ 9.82 (1H, s), 9.48
(1H, s), 7.82 (2H, d), 7.54 (2H, t) 7.36 (1H, t), 3.04 (6H, m),
2.41 (5H, m); 13C NMR (DMSO-d6) δ 180.0, 141.6, 130.6,
127.3, 127.2, 56.8, 56.3, 48.1; HR-MS (fast atom
bombardment, MH+) calculated for C12H19N4S 251.1330,
found 251.1328.
Anal. Calcd. for C12H18N4S · H2O: C, 53.73; H, 7.45.
Found: C, 53.66; H, 7.48.
1-(4-Methylpiperazin-1-yl)-3-(2-chlorophenyl)thiourea (IIIb). 1-
Amino-4-methylpiperazine (1.21 g, 10.5 mmol) reacted with
2-chlorophenyl isothiocyanate (1.76 g, 10.4 mmol) in
absolute ethanol over 30 minutes. The mixture was cooled
to room temperature and the resulting white solid was
filtered off to give IIIb (2.42 g, 82%), identified as the stable
hydrate, mp 188-189°C; IR 3268 (m), 3105 (w), 2940 (w),
2845 (w), 2795 (w), 1593 (s), 1515 (s), 1458 (m), 1443
(m), 1381 (w), 1367 (w), 1278 (m), 1264 (s), 1202 (s),
1155 (m), 1134 (m), 1082 (m), 1073 (m), 1055 (m), 1003
(s), 939 (w), 852 (w), 829 (m), 784 (w), 725 (s), 680 (w);
1H NMR (DMSO-d6) δ 10.00 (1H, s), 9.72 (1H, s), 8.40
(1H, d), 7.63 (1H, d), 7.45 (1H, t), 7.31 (1H, t), 2.96 (6H,
m), 2.29 (5H, m, apparent br s); 13C NMR (DMSO-d6) δ
176.3, 134.8, 128.0, 125.9, 125.2, 125.1, 53.4, 52.5, 44.4;
HR-MS (fast atom bombardment, MH+) calculated for
C12H18ClN4S 285.0941, found 285.0948.
Anal. Calcd. for C12H17ClN4S · 0.25 H2O: C, 49.82; H,
6.10. Found: C, 50.00; H, 6.02.
1-(4-Methylpiperazin-1-yl)-3-(2-nitrophenylthiourea (IIIc).
The reaction of 1.18 g (10.2 mmol) of 1-amino-4-
methylpiperazine with 1.80 g (10.0 mmol) of 2-nitrophenyl
isothiocyanate in absolute ethanol was completed after one
hour of reflux. The reaction mixture was allowed to cool
to room temperature, depositing 2.17 g (89%) of yellow
crystals, which were filtered off. Three sequential washes
of the yellow solid with small portions of ether produced
the analytical sample, mp 197-198°C; IR 3271 (m), 3104
(m), 2969 (w), 2952 (m), 2838 (w), 2801 (w), 1607 (m),
1580 (m), 1523 (w), 1504 (s), 1452 (s), 1383 (w), 1366
(m), 1337 (s), 1317 (w), 1260 (s), 1197 (s), 1159 (w),
1134 (s), 1075 (m), 1046 (m), 1004 (s), 935 (m), 926 (w),
In the same vein, at 200 μg, compound IIIm displayed a
diameter of inhibition of greater than 10mm.
1-(4-Methylpiperazin-1-yl)-3-phenylthiourea (IIIa). The
reaction of 1.16 g (10.1 mmol) of 1-amino-4-methyl
piperazine with 1.49 g (11.0 mmol) of phenyl isothiocyanate
in absolute ethanol was completed during 30 minutes of
1
854 (m), 832 (m), 780 (s), 741 (m), 706 (s), 670 (m); H
NMR (DMSO-d6) δ 10.91 (1H, s), 9.58 (1H, s), 8.48 (1H,
d), 7.87 (1H, d), 7.49 (1H, t), 7.09 (1H, t), 2.62 (6H, m),
2.02 (5H, m, apparent br s); 13C NMR (DMSO-d6) δ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
New 1-(4-Methylpiperazin-1-yl)thioureas
177.3, 140.4, 134.1, 133.9, 125.9, 125.1, 124.6, 54.5, 54.2,
45.4; HR-MS (fast atom bombardment, MH+) calculated
for C12H18N5O2S 296.1181, found 296.1184.
Anal. Calcd. for C12H17N5O2S: C, 48.80; H, 5.80.
Found: C, 48.54; H, 5.66.
form (2.31 g, 88%), mp 189-190°C; IR 3263 (m), 3170
(m), 2988 (w), 2956 (w), 2887 (w), 2840 (w), 2802 (w),
1589 (m), 1537 (s), 1500 (s), 1461 (m), 1410 (w), 1383
(w), 1372 (w), 1332 (w), 1314 (w), 1301 (w), 1286 (m),
1262 (s), 1196 (s), 1145 (s), 1133 (s), 1090 (m), 1078
(m), 1052 (w), 1020 (w), 1005 (s), 942 (w), 930 (w), 843
(m), 814 (s), 797 (m), 730 (m), 699 (w); 1H NMR
(DMSO-d6) δ 9.74 (1H, s), 9.43 (1H, s), 7.68 (2H, d),
7.35 (2H, d), 3.59 (6H, m), 3.04 (5H, m), 2.42 (3H, s);
13C NMR (DMSO-d6) δ 177.4, 136.4, 133.9, 128.4,
124.6, 54.1, 53.6, 45.3, 20.5; HR-MS (fast atom
bombardment, MH+) calculated for C13H21N4S 265.1487,
found 265.1482.
1-(4-Methylpiperazin-1-yl)-3-(2-methoxyphenyl)thiourea (IIId).
1-Amino-4-methylpiperazine (1.14 g, 9.90 mmol) was
refluxed with 2-methoxyphenyl isothiocyanate (1.63 g,
9.87 mmol) in absolute ethanol for an hour. The mixture
was cooled to room temperature, forming a solid,
filtration of which gave the white crystalline product in
analytically pure form (2.23 g, 81%), mp 179-180°C; IR
3268 (m), 3118 (w), 2948 (w), 2932 (w), 2838 (m), 2800
(m), 1597 (m), 1533 (s), 1489 (m), 1457 (s), 1436 (m),
1385 (w), 1372 (w), 1340 (w), 1311 (w), 1282 (m), 1268
(s), 1233 (s), 1195 (s), 1174 (w), 1156 (m), 1138 (m),
1111 (w), 1090 (m), 1078 (w), 1046 (m), 1028 (s), 1005
(s), 940 (m), 919 (m), 830 (m), 786 (m), 751 (s), 658
Anal. Calcd. for C13H20N4S: C, 59.06; H, 7.62. Found:
C, 58.86; H, 7.99.
1-(4-Methylpiperazin-1-yl)-3-(4-cholorophenyl)thiourea (IIIg).
The reaction of 1.16 g (10.1 mmol) of 1-amino-4-
methylpiperazine with 1.67 g (9.84 mmol) of 4-chlorophenyl
isothiocyanate in toluene was complete during one hour
of reflux. The reaction mixture was cooled to room
temperature, producing a beige solid, which was filtered
off (2.02 g, 72%). The analytical sample was obtained by
washing the beige solid with small portions of ether, mp
171-172°C; IR 3265 (m), 3167 (m), 2983 (w), 2952 (w),
2885 (w), 2838 (w), 2794 (w), 1585 (m), 1541 (s), 1498
(s), 1453 (m), 1406 (w), 1371 (w), 1331 (w), 1305 (w),
1286 (s), 1259 (s), 1200 (s), 1178 (w), 1153 (m), 1132
(m), 1089 (s), 1077 (m), 1054 (w), 1005 (s), 935 (w), 839
(s), 829 (s), 816 (m), 786 (w), 759 (m), 715 (m), 676 (w);
1H NMR (DMSO-d6) δ 9.66 (1H, s), 9.36 (1H, s), 7.65
(2H, d), 7.37 (2H, d), 3.82 (6H, m), 2.19 (5H, m); 13C
NMR (DMSO-d6) δ 177.9, 138.5, 129.0, 128.3, 126.8,
54.5, 54.2, 46.0; HR-MS (fast atom bombardment, MH+)
calculated for C12H18ClN4S 285.0941, found 285.0950.
Anal. Calcd. for C12H17ClN4S: C, 50.61; H, 6.02.
Found: C, 50.52; H, 5.69.
1
(w); H NMR (DMSO-d6) δ 10.13 (1H, s), 9.57 (1H, s),
8.82 (1H, d)), 7.23 (2H, m), 7.06 (1H, t), 4.01 (3H, s),
2.94 (6H, m), 2.24 (5H, m); 13C NMR (DMSO-d6) δ
178.5, 151.8, 130.3, 126.6, 123.3, 122.2, 113.3, 58.5,
57.1, 55.9, 47.9; HR-MS (fast atom bombardment, MH+)
calculated for C13H21N4OS 281.1436, found 281.1433.
Anal. Calcd. for C13H20N4OS: C, 55.69; H, 7.19. Found:
C, 55.99; H, 7.07.
1-(4-Methylpiperazin-1-yl)-3-(3-tolyl)thiourea (IIIe). The
reaction of 1.20 g (10.4 mmol) of 1-amino-4-methyl
piperazine with 1.26 g (8.44 mmol) of 3-tolyl iso-
thiocyanate in absolute ethanol was completed in one hour
of reflux. The mixture was cooled to room temperature and
excess solvent was allowed to evaporate. The white
crystalline product was filtered off and dried (1.88 g, 84%).
The analytical sample was obtained by washing the product
with three small portions of ether, and the compound was
identified as the stable hydrate, mp 160-161°C; IR 3264
(m), 3113 (w), 2942 (m), 2831 (w), 2795 (w), 1608 (m),
1556 (m), 1524 (s), 1504 (s), 1458 (s), 1380 (m), 1369 (m),
1323 (s), 1280 (s), 1269 (s), 1216 (s), 1158 (m), 1137 (s),
1074 (m), 1046 (m), 1006 (s), 969 (w), 860 (m), 817 (m),
780 (w), 722 (s), 691 (s); 1H NMR (DMSO-d6) δ 9.54 (1H,
s), 9.25 (1H, s), 7.47 (1H, d), 7.38 (1H, s), 7.20 (1H, t),
6.95 (1H, d), 2.81 (6H, m), 2.30 (5H, m), 2.19 (3H, s); 13C
NMR (DMSO-d6) δ 180.0, 141.6, 140.0, 130.6, 128.0,
127.7, 124.3, 56.9, 56.5, 48.2, 23.7; HR-MS (fast atom
bombardment, MH+) calculated for C13H21N4S 265.1487,
found 265.1483.
1-(4-Methylpiperazin-1-yl)-3-(4-iodophenyl)thiourea (IIIh).
Treatment of 1-amino-4-methylpiperazine (1.10 g, 9.55
mmol) with 1.34
g (5.13 mmol) of 4-iodophenyl
isothiocyanate in refluxing toluene for one hour, followed
by cooling to room temperature and the evaporation of
excess toluene, led to the crystallization of the light yellow
product IIIi (1.70 g, 88%). The analytical sample was
obtained by washing the material with small portions of
ether, mp 186-187°C; IR 3266 (m), 3166 (m), 2979 (w),
2947 (w), 2881 (w), 2834 (w), 2800 (w), 1576 (m), 1537
(s), 1496 (s), 1460 (s), 1443 (w), 1398 (m), 1368 (w),
1328 (w), 1280 (s), 1260 (s), 1199 (m), 1157 (w), 1139
(m), 1132 (m), 1090 (m), 1077 (w), 1063 (w), 1002 (s),
929 (m), 832 (s), 840 (s), 810 (s), 786 (w), 751 (s), 707
Anal. Calcd. for C13H20N4S · 0.125 H2O: C, 58.56; H,
7.65. Found: C, 58.59; H, 7.54.
1-(4-Methylpiperazin-1-yl)-3-(4-tolyl)thiourea (IIIf). Refluxing
1.15 g (9.98 mmol) of 1-amino-4-methylpiperazine with
1.51 g (10.10 mmol) of 4-tolyl isothiocyanate in absolute
ethanol for an hour, followed by cooling and filtration
gave the white crystalline product in analytically pure
1
(m), 663 (w); H NMR (DMSO-d6) δ 9.60 (1H, s), 9.34
(1H, s), 7.63 (2H, d), 7.35 (2H, d), 2.79 (6H, m), 2.16
(5H, m); 13C NMR (DMSO-d6) δ 177.2, 138.9, 136.5,
126.7, 88.9, 54.0, 53.6, 44.4; HR-MS (fast atom
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. J. Hearn, T. Wang, and M. H. Cynamon
Vol 000
bombardment, MH+) calculated for C12H18IN4S 377.0297,
found 377.0283.
Anal. Calcd. for C12H17IN4S: C, 38.31; H, 4.55. Found:
C, 38.25; H, 4.49.
1-(4-Methylpiperazin-1-yl)-3-(4-methoxyphenyl)thiourea (IIIi).
The reaction of 1.29 g (11.2 mmol) of 1-amino-4-
1459 (s), 1447 (s), 1359 (s), 1269 (s), 1208 (s), 1182 (m),
1158 (m), 1138 (s), 1076 (m), 1048 (w), 1008 (s), 953 (w),
836 (m), 808 (s), 784 (m), 769 (m), 731 (m), 690 (w); H
NMR (DMSO-d6) δ 9.42 (1H, s), 9.13 (1H, s), 7.38 (2H, d),
6.77 (2H, d), 2.98 (12H, m), 2.28 (5H, m); 13C NMR
(DMSO-d6) δ 176.8, 147.2, 127.3, 125.3, 110.8, 53.2, 52.8,
44.5, 39.5; HR-MS (fast atom bombardment, MH+)
calculated for C14H24N5S 203.0933, found 203.0927.
Anal. Calcd. for C14H23N5S: C, 57.30; H, 7.90. Found:
C, 56.90; H, 7.71.
1-(4-Methylpiperazin-1-yl)-3-(4-acetylphenyl)thiourea (IIIl).
Refluxing 1-amino-4-methylpiperazine (1.17 g, 10.2
mmol) with 4-acetylphenyl isothiocyanate (1.80 g, 10.2
mmol) in absolute ethanol for an hour, followed by
cooling to room temperature, produced a white crystalline
solid, which was filtered off and dried (1.92 g, 65%), in
analytically pure form, mp 192-193°C; IR 3239 (m),
3138 (m), 2980 (w), 2943 (m), 2840 (m), 2790 (m), 1674
(s), 1601 (s), 1543 (s), 1514 (m), 1489 (s), 1456 (m),
1420 (w), 1358 (m), 1282 (w), 1257 (s), 1214 (s), 1179 (m),
1154 (s), 1133 (m), 1086 (w), 1076 (w), 1052 (w), 1005 (s),
957 (m), 928 (w), 857 (m), 849 (w), 831 (m), 788 (w), 769
(w), 745 (m), 687 (m); 1H NMR (DMSO-d6) δ 9.71 (1H, s),
9.40 (1H, s), 7.79 (4H, m apparent br s), 2.71 (6H, m), 2.43
(3H, s), 2.07 (5H, m apparent br s); 13C NMR (DMSO-d6)
δ 196.8, 176.9, 143.4, 132.5, 128.3, 122.9, 54.0, 53.7, 45.4,
26.5; HR-MS (fast atom bombardment, MH+) calculated for
C14H21N4OS 293.1436, found 293.1439.
1
methylpiperazine with 1.69
g (10.2 mmol) of 4-
methoxyphenyl isothiocyanate in absolute ethanol was
carried out for 30 minutes, followed by cooling to room
temperature, evaporation of excess ethanol and filtration of
the resulting analytically pure beige solid (2.54 g, 89%), mp
153-154°C; IR 3284 (w), 3244 (w), 3123 (w), 2945 (w),
2833 (w), 2794 (w), 1512 (s), 1457 (m), 1440 (m), 1412
(w), 1382 (w), 1297 (w), 1263 (m), 1240 (s), 1196 (s),
1178 (w), 1157 (m), 1136 (m), 1086 (m), 1047 (w), 1028
(m), 1004 (s), 934 (w), 821 (s), 796 (w), 782 (w), 750
1
(m); H NMR (DMSO-d6) δ 9.19 (1H, s), 8.90 (1H, s),
7.15 (2H, d), 6.63 (2H, d), 3.49 (3H, s), 2.56 (6H, m),
1.93 (5H, m); 13C NMR (DMSO-d6) δ 179.69, 158.3,
133.7, 128.5, 114.9, 57.0, 55.9, 55.5, 47.3; HR-MS (fast
atom bombardment, MH+) calculated for C13H21N4OS
281.1436, found 281.1441.
Anal. Calcd. for C13H20N4OS: C, 55.69; H, 7.19. Found:
C, 55.57; H, 7.05.
1-(4-Methylpiperazin-1-yl)-3-(4-methylthiophenyl)thiourea (IIIj).
Refluxing 1-amino-4-methylpiperazine (1.14 g, 9.90 mmol)
with 1.18
g
(9.98 mmol) of 4-methylthiophenyl
isothiocyanate in absolute ethanol for one hour, followed by
cooling to room temperature, deposited a white crystalline
solid, which was filtered off and dried (2.62 g, 89%).
Washing the white solid with small portions of ether
produced the analytical sample, mp 184-185°C; IR 3263 (s),
3106 (w), 2944 (m), 2911 (w), 2831 (m), 2797 (w), 1503
(s), 1459 (m), 1436 (m), 1381 (w), 1302 (w), 1279 (s), 1206
(s), 1160 (m), 1139 (s), 1090 (m), 1077 (m), 1047 (w), 1006
(s), 973 (w), 931 (w), 919 (w), 838 (m), 817 (s), 783 (m),
761 (s), 724 (m), 714 (m), 671 (m); 1H NMR (DMSO-d6) δ
9.35 (1H, s), 9.05 (1H, s), 7.33 (2H, d), 7.02 (2H, d), 2.61
(6H, m), 2.26 (3H, s), 1.98 (5H, m); 13C NMR (DMSO-d6)
δ 177.8, 136.6, 134.0, 126.2, 125.7, 54.5, 54.1, 45.8, 15.6;
HR-MS (fast atom bombardment, MH+) calculated for
C13H21N4S2 297.1208, found 297.1201.
Anal. Calcd. for C14H20N4OS: C, 57.51; H, 6.89. Found:
C, 57.36; H, 6.79.
1-(4-Methylpiperazin-1-yl)-3-(4-phenoxyphenyl)thiourea (IIIm).
Treatment of 1-amino-4-methylpiperazine (1.16 g, 10.1
mmol) with 2.28 g (10.0 mmol) of 4-phenoxyphenyl
isothiocyanate in refluxing absolute ethanol for an hour,
followed by cooling to room temperature and evaporation
of excess ethanol, led to the formation of 2.67 g (78%) of
white crystalline solid, which was washed with small
portions of ether to obtain the analytical sample,
mp 189-190°C; IR 3308 (m), 3138 (m), 2945 (w), 2842
(w), 2796 (m), 2769 (w), 1588 (m), 1529 (s), 1508 (s),
1484 (s), 1416 (w), 1387 (w), 1375 (w), 1286 (m), 1225
(s), 1195 (s), 1164 (m), 1154 (m), 1134 (w), 1085 (m),
1006 (s), 934 (w), 914 (w), 866 (m), 844 (m), 800 (m),
Anal. Calcd. for C13H20N4S2: C, 52.67; H, 6.80. Found:
C, 52.84; H, 6.56.
1
765 (m), 738 (m), 694 (s); H NMR (DMSO-d6) δ 9.50
(1H, s), 9.17 (1H, s), 7.49 (2H, d), 7.32 (2H, t), 7.05
(2H, t), 6.91 (3H, t), 2.74 (6H, m, apparent br s), 2.10
(5H, m); 13C NMR (DMSO-d6) δ 178.4, 157.9, 154.1,
135.5, 130.9, 127.4, 124.1, 119.2, 119.0, 54.9, 54.5,
46.3; HR-MS (fast atom bombardment, MH+) calculated
for C18H23N4OS 343.1593, found 343.1578.
Anal. Calcd. for C18H22N4OS: C, 63.13; H, 6.48. Found:
C, 63.10; H, 6.58.
1-(4-Methylpiperazin-1-yl)-3-(2,4-dichlorophenyl)thiourea (IIIn).
The reaction of 1.19 g (10.3 mmol) of 1-amino-4-
1-(4-Methylpiperazin-1-yl)-3-(4-dimethylaminophenyl)thiourea
(IIIk). The reaction of 1.22 g (10.6 mmol) of 1-amino-4-
4methylpiperazine with 1.55
g (8.70 mmol) of 4-
dimethylaimnophenyl isothiocyanate in absolute ethanol at
reflux was ended after one hour. Cooling the reaction
mixture to room temperature led to the formation of a white
crystalline solid, which was filtered off and dried (1.98 g,
798%). Washing the solid with small portions of ether gave
the analytical sample, mp 192-193°C; IR 3281 (m), 3117
(m), 2944 (m), 2794 (m), 1616 (m), 1528 (s), 1505 (s),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
New 1-(4-Methylpiperazin-1-yl)thioureas
1
methylpiperazine with 2.15 g (10.5 mmol) of 2,4-
dichlorophenyl isothiocyanate in absolute ethanol was
complete within 30 minutes. The mixture was cooled to
room temperature, occasioning the precipitation of ana-
lytically pure white crystalline product, which was filtered
off and dried (2.49 g, 75%), mp 194-195°C; IR 3231 (w),
3124 (w), 2949 (w), 2841 (w), 2797 (m), 1589 (w), 1572
(s), 1530 (s), 1511 (s), 1461 (m), 1446 (m), 1385 (m),
1372 (m), 1319 (m), 1270 (s), 1196 (s), 1156 (s), 1137 (s),
1097 (m), 1077 (m), 1051 (m), 1005 (s), 938 (w), 860 (s),
(w), 846 (m), 793 (m), 731 (s), 693 (s), 662 (s); H NMR
(DMSO-d6) δ 8.86 (1H, s), 8.43 (1H, t), 7.22 (5H, m), 4.67
(2H, m), 2.66 (6H, m), 2.09 (5H, m); 13C NMR (DMSO-d6)
δ 179.8, 140.3, 128.6, 127.4, 127.0, 54.7, 54.2, 46.5,
45.9; HR-MS (fast atom bombardment, MH+) calculated
for C13H21N4S 265.1487, found 265.1482.
Anal. Calcd. for C13H20N4S: C, 59.06; H, 7.62. Found:
C, 59.36; H, 7.63.
1-(4-Methylpiperazin-1-yl)-3-phenethylthiourea (IIIq). When
1-amino-4-methylpiperazine (1.15 g, 9.98 mmol) was treated
with β-phenethyl isothiocyanate (1.68 g, 10.3 mmol) for one
hour in refluxing absolute ethanol, followed by cooling to
room temperature, a white crystalline solid was formed,
which was filtered off and dried (2.10 g, 76%), in
analytically pure form, mp 148-149°C; IR 3327 (m), 3119
(m), 2943 (m), 2848 (m), 2934 (m), 2805 (w), 1604 (w),
1524 (s), 1486 (m), 1455 (m), 1447 (m), 1418 (w), 1379
(w), 1363 (w), 1330 (w), 1281 (m), 1228 (m), 1176 (m),
1156 (w), 1119 (w), 1137 (m), 1086 (w), 1076 (w), 1050
(w), 947 (m), 925 (w), 889 (w), 831 (m), 786 (m), 767 (s),
1
837 (s), 822 (s), 805 (s), 781 (w), 691 (m), 661 (s); H
NMR (DMSO-d6) δ 9.89 (1H, s), 9.70 (1H, s), 8.25 (1H,
d), 7.71 (1H, s), 7.46 (1H, d), 2.88 (6H, m), 2.22 (5H, m);
13C NMR (DMSO-d6) δ 177.4, 135.2, 129.4, 128.4, 127.6,
127.0, 54.3, 53.5, 45.4; HR-MS (fast atom bombardment,
MH+) calculated for C12H17Cl2N4S 319.0551, found
319.0561.
Anal. Calcd. for C12H16Cl2N4S: C, 45.15; H, 5.05.
Found: C, 45.01; H, 4.92.
1-(4-Methylpiperazin-1-yl)-3-(3,4,5-trimethoxyphenyl)thiourea
1
(IIIo).
When 1-amino-4-methylpiperazine (0.65 g, 5.64
759 (s), 702 (s); H NMR (DMSO-d6) δ 8.77 (1H, s), 7.74
mmol) was allowed to react over one hour with 3,4,5-
trimethoxyphenyl isothiocyanate (1.44 g, 6.39 mmol) in
refluxing absolute ethanol, then cooled to ambient
temperature, a light grey-brown crystalline solid was
formed, which was filtered off and dried (1.86 g, 97%).
Washing with small portions of ether gave the analytical
sample, mp 188-189°C; IR 3296 (m), 3097 (w), 2937 (w),
2842 (w), 1597 (s), 1504 (s), 1451 (s), 1419 (s), 1384 (w),
1368 (w), 1345 (m), 1298 (w), 1281 (w), 1270 (w), 1228
(s), 1192 (m), 1157 (w), 1120 (s), 1082 (m), 1045 (w), 998
(s), 932 (w), 859 (w), 843 (m), 812 (m), 779 (m), 746 (w),
(1H, t), 7.27 (2H, m), 7.16 (3H, m), 3.63 (2H, m), 2.77 (2H,
m), 2.58 (6H, m, apparent br s), 2.11 (3H, s), 1.98 (2H, m);
13C NMR (DMSO-d6) δ 178.9, 139.6, 129.0, 128.6, 128.4,
55.5, 53.8, 45.7, 44.4, 35.1; HR-MS (fast atom
bombardment, MH+) calculated for C14H23N4S 279.1643,
found 279.1636.
Anal. Calcd. for C14H22N4S: C, 60.40; H, 7.96. Found:
C, 60.17; H, 8.09.
1-(4-Methylpiperazin-1-yl)-3-(3,4-dimethoxyphenethyl)thiourea
(IIIr). The reaction of 1.15 g (9.98 mmol) of 1-amino-4-
methylpiperazine with 2.25 g (10.1 mmol) of 3,4-
dimethoxyphenethylisothiocyanate in absolute ethanol was
completed during 30 minutes of reflux. Cooling the mixture
slowly to ambient temperature, produced white crystals,
which were filtered off and dried (2.57 g, 76%) in
analytically pure form; mp 141-142°C; IR 3304 (m), 3107
(w), 2937 (m), 2840 (m), 2794 (w), 1589 (w), 1514 (s),
1465 (m), 1443 (m), 1419 (w), 1385 (w), 1344 (w), 1292
(w), 1260 (s), 1227 (s), 1210 (m), 1193 (w), 1145 (s), 1095
(w), 1074 (w), 1034 (w), 1027 (s), 1003 (s), 924 (w), 897
(w), 856 (m), 827 (s), 786 (m), 759 (m); 1H NMR
(DMSO-d6) δ 8.55 (1H, s), 7.46 (1H, m), 6.60 (2H, m),
6.47 (1H, m), 3.49 (8H, m), 2.53 (2H, m), 2.35 (6H, m),
1.89-1.75 (5H, m); 13C NMR (DMSO-d6) δ 179.2, 149.3,
147.8, 132.3, 121.1, 113.0, 112.4, 56.1, 55.9, 54.8, 54.1,
46.0, 44.8, 34.9; HR-MS (fast atom bombardment, MH+)
calculated for C16H27N4O2S 339.1855, found 339.1850.
Anal. Calcd. for C16H26N4O2S: C, 56.78; H, 7.74.
Found: C, 57.17; H, 7.75.
1
714 (m), 658 (m); H NMR (DMSO-d6) δ 9.51 (1H, s),
9.32 (1H, s), 7.09 (2H, s), 3.81 (6H, s), 3.70 (3H, s), 2.87
(6H, m), 2.25 (5H, m); 13C NMR (DMSO-d6) δ 177.0,
152.0, 134.8, 134.3, 102.2, 60.0, 55.8, 54.0, 53.7, 45.4;
HR-MS (fast atom bombardment, MH+) calculated for
C15H25N4O3S 341.1647, found 341.1639.
Anal. Calcd. for C15H24N4O3S: C, 52.92; H, 7.11.
Found: C, 52.80; H, 6.84.
1-(4-Methylpiperazin-1-yl)-3-benzylthiourea (IIIp). 1-Amino-
4-methylpiperazine (1.16 g, 10.1 mmol) and benzyl
isothiocyanate (1.50 g, 10.1 mmol) were weighed into a
100 mL round bottom flask fitted for stirring and reflux and
brought to the boil in absolute ethanol (ca. 20 mL). After
an hour at reflux, the solution was cooled to room
temperature and the excess ethanol evaporated to give a
pale yellow solid, which was filtered off and dried (2.35 g,
88%). The analytical sample was prepared by washing the
yellow solid with small portions of ether, mp 150-151°C;
IR 3313 (m), 3310 (m), 2944 (m), 2836 (w), 2795 (w),
1521 (s), 1494 (m), 1452 (m), 1383 (w), 1359 (w), 1279
(s), 1268 (s), 1219 (m), 1192 (m), 1158 (m), 1138 (s), 1095
(w), 1073 (m), 1047 (w), 1029 (w), 1006 (s), 967 (s), 932
1-(4-Methylpiperazin-1-yl)-3-allylthiourea (IIIs). Treatment
of 1-amino-4-methylpiperazine (1.19 g, 10.3 mmol) with
allyl isothiocyanate (0.99 g, 9.98 mmol) in refluxing
absolute ethanol for 30 minutes was followed by cooling
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. J. Hearn, T. Wang, and M. H. Cynamon
Vol 000
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slowly to room temperature. The excess ethanol was
evaporated, producing a tan solid, which was isolated and
dried (1.61 g, 75%). Washing with small portions of ether
gave the analytical sample, mp 126-128°C; IR 3316 (m),
3112 (w), 3074 (w), 2982 (w), 2943 (m), 2891 (w), 2834
(m), 2799 (w), 2056 (w), 1644 (m), 1517 (s), 1459 (m),
1439 (w), 1407 (w), 1382 (w), 1360 (w), 1280 (s), 1267 (s),
1216 (s), 1159 (w), 1136 (s), 1095 (w), 1083 (w), 1075 (m),
1047 (w), 1032 (w), 1006 (s), 965 (s), 930 (w), 912 (m),
1
857 (s), 840 (m), 788 (m), 659 (s); H NMR (DMSO-d6) δ
9.00 (1H, s), 8.11 (1H, m), 5.99 (1H, m), 5.21 (2H, m),
4.25 (2H, m), 3.55 (4H, m), 2.84 (7H, m); 13C NMR
(DMSO-d6) δ 181.2, 137.8, 117.2, 56.5, 56.0, 47.8, 47.4;
HR-MS (fast atom bombardment, MH+) calculated for
C9H19N4S 215.1330, found 215.1335.
Anal. Calcd. for C9H18N4S: C, 50.43; H, 8.46. Found: C,
50.43; H, 8.46.
Repetition of this preparation using toluene instead of
ethanol as the solvent gave a similar yield (78%), with
spectrometric and analytical characteristics identical to
those noted above.
[20] Hearn, M. United States Patent 6,600,063 (2003); CAN
136:340480 (2002).
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Sakharkar, M.; Chandra, R., Eds.; River Publishers: Aalborg, Denmark,
2015, pp 166ff.
Acknowledgments. Support from the Brachman Hoffman Program
at Wellesley College is gratefully acknowledged. MJH thanks
Wellesley College for the grant of a sabbatical.
[23] Katritzky, A.; Sobiak, S.; Marson, C. Magn Reson Chem
1988, 26, 665.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet