The synthesis and tuberculostatic activity of benzenesulfonohydrazide derivatives

Article abstract of DOI:10.1002/hc.20743

The series of novel N'-aminocarbonothioyl-benzenesulfonohydrazides were synthesized in a reaction of benzenesulphonyl chlorides with various aminocarbothiohydrazides. The structures were confirmed by IR and NMR spectra as well as elemental analysis. All o

Full text of DOI:10.1002/hc.20743

Heteroatom Chemistry
Volume 23, Number 1, 2012
The Synthesis and Tuberculostatic Activity of
Benzenesulfonohydrazide Derivatives
Krystyna Wisterowicz,1 Katarzyna Gobis,1 Henryk Foks,1
and Ewa Augustynowicz-Kopec´2
1Department of Organic Chemistry, Medical University of Gdansk, 107 Gen. Hallera, 80-416
Gdansk, Poland
2Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases,
26 Płocka, 01-138 Warszawa, Poland
Received 24 May 2011; revised 3 June 2011
tics rapidly induce multidrug resistance (MDR) and
ABSTRACT: The series of novel Nꢀ-aminocar-
cause serious side effects, such as hepatotoxicity,
bonothioyl-benzenesulfonohydrazides were synthe-
neurotoxicity, acute pancreatitis, and hypersensitiv-
sized in a reaction of benzenesulphonyl chlorides
ity reactions [3,4]. Therefore, tuberculostatic agent
with various aminocarbothiohydrazides. The struc-
screening and TB drug development are still the pri-
tures were confirmed by IR and NMR spectra as
ority tasks undertaken by many research programs
well as elemental analysis. All of the obtained com-
and scientific groups [5].
pounds were screened in vitro for their tubercu-
One of the first-line chemotherapeutics in the
lostatic activity. Preliminary results indicated that
treatment of TB is morinamide (MZA), which,
some target compounds exhibited promising re-
from a chemical point of view, is morpholinoth-
sults, especially toward Mycobacterium tuberculosis
ioamide. It is worth noting that this compound in-
ꢁ
C
(Mtb) resistant strain 210.
2011 Wiley Periodicals,
cludes a cyclic amine in its structure. In the chem-
ical literature, examples of other thioamides and
thiosemicarbazides exhibiting significant tubercu-
lostatic activity can be found. Examples might be
4-cyclohexylthiobenanilides and 4-phenylsulfonyl-
benzoylhydrazinecarbothioamides [6] as well as 1-
benzoyl-isothiosemicarbazides [7]. Previously, our
research team proved high tuberculostatic activ-
ity (MIC 6.2 μg/mL) of benzoylhydrazinecarboth-
ioamides [8].
There are also many reports about the pharma-
cological activity of benzenesulfonohydrazides and
their derivatives. Among others, they exhibit antimy-
cotic [9,10], antiinflammatory [11], and antibacterial
[12,13] activity. Antineoplastic action of that chemi-
cal group has also been reported [14].
Inc. Heteroatom Chem 23:99–104, 2012; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.20743
INTRODUCTION
Tuberculosis (TB) remains one of the most seri-
ous infectious diseases. It persists as a major pub-
lic health problem. There is a growing number of
Mycobacterium tuberculosis (Mtb) strains, which are
now resistant to the commonly used first-line anti-
TB drugs such as rifampicine (RMF) and isoniazid
(INH) [1]. TB is a leading cause of morbidity and
mortality in adults infected with HIV worldwide [2].
Unfortunately, the most effective chemotherapeu-
Although it is difficult to find reports on the
tuberculostatic activity of sulfonohydrazides in the
chemical literature, no doubt such action has been
described for sulfonamides [15,16]. Other authors
Correspondence to: Katarzyna Gobis; e-mail: kgobis@gumed
.edu.pl.
2011 Wiley Periodicals, Inc.
c
ꢀ
99

100 Wisterowicz et al.
SCHEME 1
described antimalarian activity [17] and γ –secretase
inhibition [18] caused by sulfonamide derivatives
bearing cyclic amine moiety in their structures.
On the basis of all the above considerations and
as an extension of our studies on the development
of novel benzoylhydrazinecarbothioamide antitu-
bercular agents, we decided to synthesize the new Nꢀ-
aminocarbonothioyl-benzenesulfonohydrazides as
their sulfonic analogs containing sulfonohydrazide
and thioamide group with cyclic amine moiety fused
in thiosemicarbazide system.
group in a methyl hydrazinecarbodithioate, were
commercially obtained. For the amines with lower
molecular weights, water was a suitable solvent,
but for 1-phenylpiperazine and its derivatives,
reactions were carried out in ethanol. The yields of
the reactions were not very high, although amines
were used in triple excess to thioester.
Aminocarbothiohydrazides
(1–6)
were
treated with benzenesulfonyl chloride or 4-
toluenesulfonyl chloride to give the corresponding
Nꢀ-aminocarbonothioyl-benzenesulfonohydrazides
(7–18). The reactions were carried out in dry
pyridine for 24 h. However, their yields were rather
average; 4-toluenesulfonohydrazides seemed to
form more easily.
RESULTS AND DISCUSSION
The synthetic route of target compounds was out-
lined in Scheme 1. Starting methyl hydrazinecar-
bodithioate was obtained by the method of Klayman
et al. from hydrazine, potassium hydroxide, carbon
disulfide, and methyl iodide in a water-isopropanol
solution [19].
All the newly synthesized compounds were char-
acterized by IR and NMR spectra as well as the ele-
mental analysis (Table 1) listed in the Experimental
Section. The spectral analyses were in accordance
1
with the assigned structures. In H NMR spectra of
compounds (7–11) and (13–17), the signal of one NH
group proton was visible in the form of a multiplet
common with aromatic protons in the range of 7.20
to 7.93 ppm as a rule. Only in the case of compounds
(12,18), the signal of the NH group proton appeared
in the form of a well-separated singlet at 7.18 (12)
and 7.85 ppm (18). Signals occurring as multiplets
common with aromatic protons in the spectra of
compounds (7–11) and (13–17) undoubtedly came
Cycloaminocarbothiohydrazides (1–6), the
intermediates for the syntheses of correspond-
ing
drazides (7–18), were prepared by the proce-
dure described earlier [20]. The various amines,
such as pyrrolidine, piperidine, morpholine, 1-
phenylpiperazine, 1-(4-methoxyphenyl)piperazine,
and 1-(4-fluorophenyl)piperazine, that were used
for nucleophilic substitution of which thiomethyl
Nꢀ -aminocarbonothioyl-benzenesulfonohy-
Heteroatom Chemistry DOI 10.1002/hc

The Synthesis and Tuberculostatic Activity of Benzenesulfonohydrazide Derivatives 101
TABLE 1 Characteristics of Newly Synthesized Nꢀ-Aminobenzenesulfonohydrazides 7–18
Calcd/Found
H
No
Yield [%]
mp. [◦C] Solvent
Formula MW
C
N
7
29
33
30
35
45
59
15
10
27
57
35
52
145–146 H2O/EtOH
150–153 H2O/EtOH
134–137 EtOH
C11H15N3O2S2285.39
C12H17N3O2S2299.41
C12H17N3O2S2299.41
C13H19N3O2S2313.44
C11H15N3O3S2301.39
C12H17N3O3S2315.41
C17H20N4O2S2376.50
46.29
48.14
48.14
49.81
43.84
45.70
54.23
55.36
51.76
52.92
53.18
54.26
46.38
48.09
48.11
49.85
43.77
45.75
54.29
55.42
51.81
52.86
53.21
54.33
5.30
5.72
5.72
6.11
5.02
5.43
5.35
5.68
4.85
5.18
5.45
5.75
5.29
5.73
5.71
6.10
5.03
5.44
5.36
5.69
4.86
5.19
5.46
5.76
14.72
14.03
14.03
13.41
13.94
13.32
14.88
14.36
14.20
13.71
13.78
13.32
14.68
14.00
14.08
13.46
13.72
13.28
14.91
14.41
14.17
13.73
13.79
13.29
8
9
10
11
12
13
14
15
16
17
18
131–134 AcOH
150–154 H2O/EtOH
127–129 H2O/EtOH
146–148 AcOH
165–169 AcOH
136–138 AcOH
158–160 AcOH
155–157 AcOH
148–151 AcOH
C18H22N4O2S2390.52
C17H19FN4O2S2394.49
C18H21FN4O2S2408.51
C18H22N4O3S2406.52
C19H24N4O3S2420.55
from an NH group. Addition of D2O resulted in an
exchange of an NH proton and the partial extinction
of the multiplets.
tested compounds ranged from 25 to 50 μg/mL
and from 0.5 to 1.1 μg/mL for INH. All com-
pounds exhibited low activity against susceptible
strain 192 (MICs 50 μg/mL) and moderate activ-
ity against standard strain H37Rv (MICs 25 μg/mL).
Unexpectedly, the most sensitive to the tested com-
pounds was the resistant strain 210. The MIC val-
ues determined for most of the tested compounds
against that strain were 25 μg/mL. The pyrrolidine
derivative (7) and two 4-methoxyphenylpiperazine
derivatives (17,18) were the most active against
strain 210 with MIC values of 12.5 μg/mL. These re-
sults allowed us to include the obtained compound,
Nꢀ -aminocarbonothioyl-benzenesulfonohydrazides
Tuberculostatic Activity
The newly synthesized Nꢀ-aminocarbonothioyl-
benzenesulfonohydrazides (7–18) were examined in
vitro for their tuberculostatic activity against the
Mtb H37Rv strain and two “wild” strains isolated
from tuberculotic patients: one (Spec. 210) resis-
tant to p-aminosalicylic acid (PAS), isonicotinic acid
hydrazide (INH), etambutol (ETB), and rifampicine
(RFP) and the other (Spec. 192) fully sensitive to
the administered tuberculostatics (Table 2). Inves-
tigations were performed by a classical test-tube
method of successive dilution in a Proskauer and
Beck modification with a Youmans liquid medium
containing 10% of bovine serum [21,22]. Bacterial
suspensions were prepared from 14-day-old cultures
of slowly growing strains and from 48 h old cul-
tures of saprophytic strains [23,24]. Solutions of
compounds in ethylene glycol were tested. Stock so-
lutions contained 10 mg of compounds in 1 mL.
Dilutions (in geometric progression) were prepared
in a Youmans medium. The medium containing
no investigated substances and containing isoni-
azid (INH) as a reference drug was used for com-
parison. Incubation was performed at 37◦C. The
MIC values were determined as minimum con-
centration inhibiting the growth of tested tubercu-
lous strains in relation to the probe with no tested
compound.
TABLE 2 In Vitro Tuberculostatic Activity of Novel Benzene-
sulfonohydrazide Derivatives 7–18a,b,c
MIC [μg/mL]
Compound Number
R37Rv
Spec. 192
Spec. 210
7
25
25
25
25
25
25
50
25
25
25
25
25
0.5
25
50
50
50
50
50
50
50
50
50
50
50
50
0.5
25
12.5
25
25
25
25
25
25
25
25
8
9
10
11
12
13
14
15
16
17
18
INH
PZA
25
12.5
12.5
1.1
>400
The results of tuberculostatic activity indicated
that some of the title compounds showed moder-
ate activity against tested strains in vitro and were
much less active than when INH was used as a
reference drug. The MIC values for most of the
aMinimum inhibitory concentrations for mycobacterial strains were
detrmined by a two-fold classical test-tube method of successive
dilution.
bINH–isoniazid, PZA–pyrazinamid.
cM. tuberculosis H37Rv, Spec. 192 and Spec. 210.
Heteroatom Chemistry DOI 10.1002/hc

102 Wisterowicz et al.
among the compounds of moderate tuberculostatic
activity.
of methyl mercaptan had ceased almost completely.
Methyl mercaptan was detected by the yellow color it
imparted to the moisten Pb(OAc)2 paper, which was
placed at the mouth of the reflux condenser. In the
case of 1-phenylpiperazine and its derivatives, the
reactions were carried out in ethanol. Then the solu-
tion was neutralized with AcOH. Furthermore, cool-
ing yielded the desired amount of aminocarbothio-
hydrazide, which was filtered off and recrystallized.
Compounds 1–4 have already been described [20].
4-(4-Fluorophenyl)piperazine-1-carbothiohy-
drazide (5). This compound was obtained as col-
orless needles. Yield: 2.74 g (54%). Crystallization
from ethanol; mp 169–171◦C. IR: 3430, 3268 (ν
N H), 2923, 2854 (ν C H), 1513 (δ N H), 815 (γ
CONCLUSION
In summary,
a
series of novel Nꢀ-aminocar-
bonothioyl-benzenesulfonohydrazides with differ-
ent cyclic amine moieties were synthesized success-
fully in reaction of cycloaminocarbothiohydrazides
with benzenesulphonyl chlorides. All these new
compounds were confirmed by IR and NMR spec-
tra as well as through elemental analysis. Their
tuberculostatic activity was evaluated against M.
tuberculosis H37Rv standard strain, sensitive strain
192, and resistant strain 210 to commonly admin-
istered drugs (PAS, INH, ETB, RFP). MIC values
were determined using the two-fold serial diluting
technique. The results showed that most of the
synthesized benzenesulfonohydrazide derivatives
exhibited moderate tuberculostatic activity in vitro.
The most susceptible to tested compounds was
resistant strain 210. The pyrrolidine derivative (7)
and two 4-methoxyphenylpiperazine derivatives
(17,18) were the most active against strain 210 with
MIC values of 12.5 μg/mL. These results allowed
us to include the obtained compound, wording,
Nꢀ-aminocarbonothioyl-benzenesulfonohydrazides
among the compounds of promising tuberculostatic
activity toward resistant Mtb.
1
C H) cm−1. H NMR δ: 3.12–3.26 (s, 4H, 2NCH2),
3.97–4.07 (m, 4H, 2NCH2), 5.93 (brs, 2H, NH2), 6.88
(d, 2H, Ph, J 7.8 Hz), 7.82 (t, 2H, Ph, J 7.8 Hz),
8.28 (s, 1H, NH) ppm. Anal Calcd. for C11H15FN4S
(mw 254.33): C, 51.95; H, 5.94; N, 22.03. Found: C,
51.82;H, 5.95; N, 21.98.
4-(4-Methoxyphenyl)piperazine-1-carbothio-
hydrazide (6). This compound was obtained as
colorless crystals. Yield: 2.62 g (49%). Crystal-
lization from ethanol; mp 151–153◦C. IR: 3399,
3284 (ν N H), 2931, 2849 (ν C H), 1528 (δ N H),
1
1231, 1035 (ν C O), 842 (γ C H) cm−1. H NMR
δ: 3.08–3.18 (m, 4H, NCH2), 3.85 (s, 3H, OCH3),
3.88–3.96 (m, 4H, 2NCH2), 5.85 (brs, 2H, NH2), 7.08
(d, 2H, Ph, J 8.8 Hz), 7.81 (d, 2H, Ph, J 8.8 Hz), 8.55
(s, 1H, NH) ppm. Anal. Calcd. for C12H18N4OS (mw
266.36): C, 54.11; H, 6.81; N, 21.03. Found: C, 54.23;
H, 6.79; N, 20.98.
EXPERIMENTAL
Melting points were determined with Boethius
apparatus (Franz Ku¨stner Nachf. KG, Dresden,
Germany) and were uncorrected. IR spectra were
taken on the Satellite FT-IR spectrophotometer
(Mattson Instruments, Madison, WI) (KBr pellets).
NMR spectra were taken in CDCl3 on the Var-
ian Gemini (200 MHz) instrument (Varian, Palo
Alto, CA). The results of elemental analysis (% C,
H, N) for all of the obtained compounds were in
agreement with calculated values within a range
General procedure for the synthesis of Nꢀ-
benzenesulfonohydrazides (7–18). To a solution
of benzenesulphonyl or 4-toluenesulphonyl chloride
(5 mmol) in 5 mL of dry pyridine, an appropriate
amount of aminocarbothiohydrazide (5 mmol) was
added. The mixture was stirred at room temperature
for 24 h. Then 20 mL of ice cold water was added. The
precipitate was filtered off and recrystallized from a
suitable solvent (Table 1).
of
0.3%. Reaction details and physicochemical
Nꢀ -(Pyrrolidine-1-carbonothioyl)benzenesul-
fonohydrazide (7). IR: 3314 (ν N H), 3107, 2987,
2869 (ν C H), 1528 (δ N H), 1445 (δ C H), 1337,
data for newly synthesized Nꢀ-aminocarbonothioyl-
benzenesulfonohydrazides are given in Table 1.
Methyl hydrazinecarbodithioate, which was re-
quired for further syntheses, was obtained accord-
ing to the method described earlier by Klayman
et al. [19].
1
1165 (ν SO2), 738 cm−1. H NMR δ: 2.25–2.36 (m,
4H, 2CH2), 2.39–2.50 (m, 4H, 2NCH2), 7.46–7.66
(m, 4H, 3H Ph and 1H NH + D2O exchangeable),
7.90–7.99 (m, 2H, Ph), 8.60 (s, 1H, NH + D2O
exchangeable) ppm. 13C NMR: δ 25.6, 51.9, 127.3,
129.0, 131.9, 136.7, 179.2 ppm.
General procedure for the synthesis of cy-
cloaminocarbothiohydrazides (1-6). Methyl hy-
drazinecarbodithioate (2.44 g, 20 mmol) was dis-
solved in 20 mL water. The solution was treated with
the appropriate amount of cyclic amine (60 mmol).
The mixture was refluxed for 6 h until the evolution
4-Methyl-Nꢀ-(pyrrolidine-1-carbonothioyl) ben-
zenesulfonohydrazide (8). IR: 3287 (ν N H), 3080,
2959, 2873 (ν C H), 1596 (δ N H), 1443 (δ C H),
1
1339 (ν SO2), 710 cm−1. H NMR δ: 1.93 (brs, 4H,
Heteroatom Chemistry DOI 10.1002/hc

The Synthesis and Tuberculostatic Activity of Benzenesulfonohydrazide Derivatives 103
2CH2), 2.40 (s, 3H, CH3), 3.43–3.57 (m, 4H, 2NCH2),
(ν N H), 3037, 2956, 2855 (ν C H), 1598 (δ N H),
1427 (δ C H), 1331, 1161 (ν SO2), 715 cm−1. 1H
NMR δ: 2.38 (s, 3H, CH3), 3.18 (t, 4H, NCH2, J
5.0 Hz), 3.94 (t, 4H, 2NCH2, J 5.0 Hz), 6.91–6.98
(m, 3H, Ph), 7.22-7.77 (m, 5H, 4H Ph and 1H
NH + D2O exchangeable), 8.12 (s, 1H, NH + D2O
exchangeable), 8.79 (d, 1H, Ph, J 8.2 Hz) ppm. 13C
NMR: δ 22.7, 54.3, 57.2, 115.7, 122.4, 129.7, 129.8,
130.7, 134.6, 138.1, 150.4, 175.8 ppm.
7.20–7.25 (m, 3H, 2H Ph and 1H NH + D2O ex-
changeable), 7.39 (s, 1H, NH + D2O exchangeable),
7.75–7.79 (m, 2H, Ph) ppm. 13C NMR: δ 22.3, 26.2,
53.4, 128.7, 129.7, 133.4, 137.3, 181.5 ppm.
Nꢀ -(Piperidine-1-carbonothioyl)benzenesul-
fonohydrazide (9). IR: 3269 (ν N H), 3002, 2939,
2854 (ν C H), 1525 (δ N H), 1439 (δ C H), 1377,
1
1161 (ν SO2), 755 cm−1. H NMR δ: 1.45-1.57 (m,
2H, CH2), 1.59-1.70 (m, 4H, 2CH2), 3.62–3.76 (m,
4H, 2NCH2), 7.43–7.65 (m, 4H, 3H Ph and 1H NH
+ D2O exchangeable), 7.92 (d, 2H, Ph, J 7.3 Hz),
8.89 (s, 1H, NH + D2O exchangeable) ppm. 13C
NMR: δ 25.1, 26.3, 55.2, 128.3, 130.1, 132.5, 137.4,
181.3 ppm.
Nꢀ -(4-(4Fluorophenyl)piperazine-1-carbono-
thioyl)benzenesulfonohydrazide (15). IR: 3307
(ν N H), 3056, 2960, 2842 (ν C H), 1583 (δ N H),
1448 (δ C H), 1336, 1166 (ν SO2), 731 cm−1. 1H
NMR δ: 3.08–3.12 (m, 4H, 2NCH2), 3.96–4.00 (m,
4H, 2NCH2), 6.98–7.06 (m, 4H, Ph), 7.45-7.65 (m,
3H, 2H Ph and 1H NH + D2O exchangeable), 7.91
(d, 2H, Ph, J 7.5 Hz), 8.05 (s, 1H, NH + D2O
exchangeable), 8.84 (d, 1H, Ph, J 7.2 Hz) ppm. 13C
NMR: 55.1, 58.3, 116.3, 117.5, 128.0, 129.3, 132.1,
137.2, 146.0, 157.3, 176.1 ppm.
4-Methyl-Nꢀ-(piperidine-1-carbonothioyl)ben-
zenesulfonohydrazide (10). IR: 3245 (ν N H),
3008, 2940, 2853 (ν C H), 1595 (δ N-H), 1438 (δ
1
C H), 1331, 1161 (ν SO2), 713 cm−1. H NMR δ:
1.52-1.64 (m, 6H, 3CH2), 2.42 (s, 3H, CH3), 3.67-3.73
(m, 4H, 2NCH2), 7.24–7.28 (m, 3H, 2H Ph and 1H
NH + D2O exchangeable), 7.55 (s, 1H, NH + D2O
exchangeable), 7.78 (d, 2H, Ph, J 8.3 Hz) ppm. 13C
NMR: δ 22.1, 25.3, 26.7, 55.3, 129.5, 130.8, 134.2,
139.5, 181.1 ppm.
Nꢀ -(4-(4-Fluorophenyl)piperazine-1-carbono-
thioyl)-4-methylbenzenesulfonohydrazide (16).
IR: 3248 (ν N H), 3002, 2927, 2819 (ν C H), 1582
(δ N H), 1430 (δ C H), 1328, 1167 (ν SO2), 709
1
cm−1. H NMR δ: 2.40 (s, 3H, CH3), 3.03–3.22 (m,
Nꢀ-(Morpholine-4-carbonothioyl)benzenesul-
fonohydrazide (11). IR: 3216 (ν N H), 3079, 2921,
2865 (ν C H), 1584 (δ N H), 1464 (δ C H), 1335,
1170 (SO2), 736 cm−1. 1H NMR δ: 3.61 (t, 4H, 2NCH2,
J 5.5 Hz), 3.74 (t, 4H, 2OCH2, J 5.4 Hz), 7.45–7.67
(m, 3H, Ph), 7.85–7.93 (m, 3H, 2H Ph and 1H, NH +
D2O exchangeable), 8.50–9.20 (brs, 1H, NH + D2O
exchangeable) ppm. 13C NMR: δ 50.1, 66.8, 128.1,
129.7, 132.3, 137.4, 174.5 ppm.
4H, 2NCH2), 3.98–4.11 (m, 4H, 2NCH2), 7.05 (d,
2H, Ph, J 8.1 Hz), 7.25–7.29 (m, 3H, 2H Ph and 1H
NH + D2O exchangeable), 7.78 (d, 2H, Ph, J 8.1
Hz), 8.07 (s, 1H, NH + D2O exchangeable), 8.76 (d,
2H, Ph, J 8.2 Hz) ppm. 13C NMR: δ 23.1, 55.2, 58.1,
116.4, 118.2, 128.1, 129.2, 131.8, 137.1, 146.2, 157.8,
175.8 ppm.
Nꢀ -(4-(4-Methoxyphenyl)piperazine-1-carbo-
nothioyl)benzenesulfonohydrazide (17). IR: 3250
(ν N H), 3033, 2938, 2838 (ν C H), 1590 (δ N H),
1449 (δ C H), 1331, 1170 (ν SO2), 752 cm−1. 1H
NMR δ: 3.02–3.22 (brs, 4H, 2NCH2), 3.89 (s, 3H,
OCH3), 3.95–4.04 (m, 4H, 2NCH2), 6.91–7.17 (m,
3H, Ph), 7.15 (s, 1H, NH + D2O exchangeable),
7.46–7.66 (m, 3H, Ph), 7.89–7.93 (m, 3H, 2H Ph and
1H NH + D2O exchangeable), 8.79 (d, 1H, Ph, J 8.1
Hz) ppm. 13C NMR: δ 54.2, 56.3, 57.3, 116.1, 116.9,
127.8, 129.3, 132.3, 134.0, 147.5, 153.4, 175.2 ppm.
Nꢀ -(4-(4-Methoxyphenyl)piperazine-1-carbo-
nothioyl)-4-methylbenzenesulfonohydrazide
(18). IR: 3239 (ν N H), 3032, 2942, 2840 (ν C H),
1596 (δ N—H), 1499 (δ C H), 1329, 1164 (ν SO2),
746 cm−1.1H NMR δ: 2.41 (s, 3H, CH3), 2.98-3.14 (m,
4H, 2NCH2), 3.88 (s, 3H, OCH3), 3.93–4.02 (m, 4H,
2NCH2), 6.94 (d, 2H, Ph, J 8.0 Hz), 7.08 (s, 1H, NH
+ D2O exchangeable), 7.27 (d, 2H, Ph, J 8.0 Hz),
7.78 (d, 2H Ph, J 8.3 Hz), 7.85 (s, 1H, NH + D2O
exchangeable), 8.83 (d, 2H, Ph, J 8.1 Hz) ppm. 13C
NMR: δ 22.8, 54.3, 56.2, 57.1, 116.7, 117.0, 128.9,
129.8, 134.2, 138.6, 147.2, 153.8, 175.5 ppm.
4-Methyl-Nꢀ -(morpholine-1-carbonothioyl)
benzenesulfonohydrazide (12). IR: 3303 (ν N H),
3049, 2914, 2871 (ν C H), 1595 (δ N H), 1466 (δ
1
C H), 1333, 1164 (ν SO2), 709 cm−1. H NMR δ:
2.42 (s, 3H, CH3), 3.58-3.76 (m, 8H, 4CH2), 7.18 (s,
1H, NH + D2O exchangeable), 7.26 (d, 2H Ph J 7.8
Hz), 7.74 (d, 2H, Ph, J = 8.3 Hz), 8.11 (s, 1H, NH
+ D2O exchangeable) ppm. 13C NMR: δ 22.4, 50.2,
67.1, 128.9, 130.0, 134.2, 137.9, 174.7 ppm.
Nꢀ-(4-Phenylpiperazine-1-carbonothioyl)ben-
zenesulfonohydrazide (13). IR: 3298 (ν N H),
3060, 2917, 2842 (ν C H), 1579 (δ N H), 1448 (δ
1
C H), 1326, 1167 (ν SO2), 732 cm−1. H NMR δ:
3.17 (t, 4H, 2NCH2, J 5.1), 3.93 (t, 4H, 2NCH2, J 5.1
Hz), 6.91–6.98 (m, 3H, Ph), 7.25–7.69 (m, 6H, 4H Ph
and 2H 2NH + D2O exchangeable), 7.88–7.94 (m,
2H, Ph), 8.79 (d, 1H, Ph, J 8.1 Hz) ppm. 13C NMR:
δ 54.6, 57.4, 115.3, 122.8, 128.1, 129.9, 130.3, 132.7,
137.5, 150.2, 175.6 ppm.
4-Methyl-Nꢀ -(4-phenylpiperazine-1-carbono-
thioyl)benzenesulfonohydrazide (14). IR: 3268
Heteroatom Chemistry DOI 10.1002/hc

104 Wisterowicz et al.
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