Synthesis, characterization, antifungal, antibacterial, and antitumor activities of some tris(pentafluorophenyl)arsenic(V) derivatives

Article abstract of DOI:10.1002/hc.20594

A series of tris(pentafluorophenyl) arsenic(V) derivatives of the type (C₆F₅₎₃AsL₂, (C₆F ₅₎₃As(a)(L) [L = -OCOC₆H₄(o-OH), -OCOC- (OR)(C₆F₄₎₂, and 2-(6-OCH

Full text of DOI:10.1002/hc.20594

Heteroatom Chemistry
Volume 21, Number 3, 2010
Microwave-Assisted Synthesis of Novel
4-N,N-Dimethylamino- and 4-Cycloamino-
Substituted 1,2,4-Triazole-3-thiones
Katarzyna Gobis and Henryk Foks
Department of Organic Chemistry, Medical University of Gdansk, 107 Gen. Hallera,
80-416 Gdansk, Poland
Received 22 July 2009; revised 26 February 2010
the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
ABSTRACT: 4-N,N-Dimethylamino- and 4-cyclo-
(DBU) and requires long refluxing time [5]. Reac-
amino-5-phenyl-1,2,4-triazole-3-thiones 1–13 have
tion mixture usually contains 1,2,4-triazole-3-thione
been synthesized from benzhydrazides and substituted
and a thiosemicarbazide derivative. Isolation of the
methyl dithiocarbazates under various conditions in-
two products is often cumbersome.
cluding short microwave irradiations. The last method
Various chemical reactions in a microwave re-
seemed faster than the classical refluxing one. The in-
actor have been reported for last 20 years. Peri-
fluence of base and solvent types on the reaction direc-
cyclic reactions such as Diels-Alder reaction, ene
ꢀ
C
tion has been also examined. 2010 Wiley Periodicals,
synthesis, or indole synthesis by Fischer’s method
Inc. Heteroatom Chem 21:188–195, 2010; Published on-
were among first organic syntheses carried out with
line in Wiley InterScience (www.interscience.wiley.com).
microwaves [6]. Many condensation reactions such
DOI 10.1002/hc.20594
as Knovenagel reaction [7,8] and Michael addition
[9] were also carried out with microwaves. Exam-
ples of C-alkylation [10,11], O-alkylation [12,13], and
INTRODUCTION
N-alkylation [14,15] have also been reported. Mi-
crowaves were also used in cases of nucleophilic
substitution [16,17] and oxidation. By this method,
heterocyclic systems such as 1,3,4-oxadiazole and
pyrazole [18], pyrazoline [19], 1,3,4-thiadiazole [20],
triazolidinone [18], and 1,2,4-triazole [21] could also
be synthesized.
In the present work, synthesis of new deriva-
tives of 5-phenyl-1,2,4-triazole-3-thione with alky-
lamine substituent in N-4 position has been un-
dertaken. These are little known compounds.
Only two reports on this class have appeared.
Russian researchers obtained 4-trifluoroalkyl and 4-
fluoroaryl-1,2,4-triazole-5-thiones [22]. We have re-
ported syntheses of 4-alkylamino-5-pyrazine-1,2,4-
triazole-3-thione derivatives [23]. The results of
syntheses under various conditions have been ex-
amined with particular emphasis on microwave
radiation.
1,2,4-Triazole derivatives exhibit multidirectional
biological action. Among others, tuberculostatic [1]
and antibacterial activities toward Bacillus subtilis,
Bacillus cereus, Escherichia coli, and Pseudomonas
solanarium have been reported [2]. Information on
antineoplastic [3] and fungitoxic [4] activities of
1,2,4-triazole-3-thiole derivatives has also been re-
ported. For this reason, interest in these compounds
has increased in recent years.
One method of obtaining 1,2,4-triazole-3-
thiones is the condensation of carboxylic acids
hydrazides with methyl dithiocarbazates. Such syn-
thesis is usually carried out in dry pyridine in
Correspondence to: Katarzyna Gobis; e-mail: kgobis@amg
.gda.pl.
c
ꢀ
2010 Wiley Periodicals, Inc.
188

Microwave-Assisted Synthesis of Novel 4-N,N-Dimethylamino- and 4-Cycloamino-Substituted 1,2,4-Triazole-3-thiones 189
actants refluxing time. Reaction mixture included
two products: 1,2,4-triazole-3-thione (type I) and
thiosemicarbazide derivative (type II). Additional re-
fluxing of the isolated solid in 10% NaOH caused the
cyclization of thiosemicarbazide and the formation
of 1,2,4-triazole-3-thione. The use of dry dioxane in
place of pyridine made it possible to obtain pure
products of type I.
Attempts to replace DBU with other bases
(10% NaOH, 5% K2CO3, and solid K2CO3) have also
been undertaken. This is possible, but it also re-
quires long refluxing time (Tables 1 and 2). Thus, the
possibility of obtaining 4-amino-substituted 1,2,4-
triazole-3-thiones in a microwave reactor has been
investigated. Influence of heating time, solvent, and
base type on the direction and yield of the reaction
has been studied. Reactions were carried out un-
der the following conditions: pyridine/DBU, T = 90–
100◦C, t = 5 min; dioxane/5% K2CO3, T = 90–100◦C,
t = 5 min; dioxane/10% NaOH, T = 100–105◦C, t = 20
or 30 min; dioxane/10% NaOH, T = 110–115◦C, t =
5 min; DMSO/solid K2CO3, T = 80–85◦C, t = 10 min;
and DMSO/solid K2CO3, T = 105–110◦C, t = 20 min.
Reactions under reflux in a microwave reactor were
also performed. Yields for reactions carried out un-
der reflux were similar to those of syntheses per-
SCHEME 1
RESULTS AND DISCUSSION
formed under milder conditions.
Methyl dithiocarbazates required for further syn-
theses were obtained by the treatment of N,N-
dimethylhydrazine, N-aminopiperidine, N-amino-
morpholine, and N-methyl-1-aminopiperazine with
carbon disulfide in the presence of triethy-
lamine, followed by methylation with methyl io-
dide (Scheme 1). Reactions carried out in ethanol
gave satisfactory yields [24]. Synthesis of N-methyl-
1-aminopiperazine derivative has been described in
the Experimental section.
These reactions have proved that structure of
the product depends on process parameters and the
structures of both reactants. 2-Chlorobenzhydrazide
with a substituent in C-2 position gave thiosemi-
carbazide derivative 15. With progression of the re-
action, mixed triazole and thiosemicarbazide prod-
ucts were obtained. In contrast, all reactions of
4-aminobenzhydrazide gave only triazoles (8–10) af-
ter a short time as that reported in the case of
unsubstituted benzhydrazide (1–3).
Obtained dithioesters were treated with benzhy-
drazide and its derivatives with various substituents
in benzene ring to give 4-amino-5-phenyl-1,2,4-
triazole-3-thiones 1–13. Obtained 1,2,4-triazole-3-
thiones can exist in thiol-thione tautomer forms. In
alkaline solution, they undergo alkylation on sulfur
atom and give sulfides [5]. Thione seems to be the
basic form for 1,2,4-triazoles 1–13 both in the solid
state and in the neutral solution. There is an absence
of a band for S H bond in the range 2600–2550 cm−1
in IR spectra. 1H NMR spectra also support this sug-
gestion. A peak of N H proton was found at a chem-
ical shift (δ) value in the range of 13–14 ppm in all
spectra, whereas S H proton at δ 1.0–3.7 ppm was
not detected.
The structure of another reactant also influ-
enced reaction results. Reactions with piperidin-
1-yl-dithiocarbamic acid methyl ester led mainly
to noncyclic products (17 and 18). In contrast,
morpholine-4-yl-dithiocarbamic acid methyl ester
gave triazole products (3 and 10).
Taking into consideration the influence of base
on reaction direction, it has been observed that
the DMSO/solid K2CO3 system favored thiosemi-
carbazide formation. To obtain triazole products,
reactions were performed for longer duration.
Application of a stronger base (10% NaOH) caused
cyclization and led to triazole, but the product was
impure, with appropriate carboxylic acid obtained
by the hydrolysis of starting hydrazide material
(4–6).
Conditions established previously for the synthe-
sis such as dry pyridine and addition of DBU have
been applied [5]. These conditions required long re-
On comparing classical method and reactions
carried out in a microwave reactor, it must be
Heteroatom Chemistry DOI 10.1002/hc

190 Gobis and Foks
TABLE 1 Methods of 4-Amino-5-phenyl-1,2,4-triazole-3-thione Synthesis (Type I Products)
H
N N
S
R
N
R′
Compound
R
Rꢁ
Reaction Conditions
Yield (%)
5
1
Ph
N(CH3)2
Dioxane/DBU A
t = 4 h
Dioxane/5% K2CO3 B
t = 10 h
23
aDMSO/10% NaOH C
t = 20 min, T = 100–105◦C
Dioxane/5% K2CO3 A
t = 10 h
40
2
3
Ph
Ph
Piperidine
11
aDMSO/10% NaOH B
t = 20 min, T = 100–105◦C
Pyridine/DBU A
50
Morpholine
27
t = 3 h
aPyridine/DBU B
t = 5 min, T = 95–100◦C
Dioxane/5% K2CO3 C
t = 7 h
65
36
Dioxane/DBU D
39
t = 6 h
aDMSO/10% NaOH E
t = 20 min, T = 95–100◦C
Dioxane/DBU A
50
4
5
6
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
N(CH3)2
22
t = 4 h
DMSO/10% NaOH B
t = 1 h
25
NaHCO3, t = 15 min
Dioxane/5% K2CO3 A
t = 7 h
Piperidine
Morpholine
27
39
aDMSO/10% NaOH B
t = 20 min, T = 95–100◦C
NaHCO3, t = 15 min
Dioxane/5% K2CO3 A
t = 5 h
26
38
10% NaOH, t = 2 h
DMSO/10% NaOH B
t = 2.5 h
NaHCO3, t = 15 min
aDMSO/K2CO3 solid C
t = 10 min, T = 80–85◦C
Dioxane/5% K2CO3 A
t = 10 h
52
15
30
22
7
8
4-F-Ph
Morpholine
N(CH3)2
aDioxane/10% NaOH B
t = 30 min, T = 105–110◦C
DMSO/10% NaOH A
t = 1 h
4-NH2-Ph
NaHCO3, t = 15 min
aDMSO/10% NaOH B
t = 20 min, T = 100–105◦C
aDMSO/K2CO3 solid
t = 15 min, T = 80–85◦C
aDMSO/K2CO3 solid
t = 10 min, T = 80–85◦C
24
42
41
9
4-NH2-Ph
4-NH2-Ph
Piperidine
10
Morpholine
(Continued)
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Synthesis of Novel 4-N,N-Dimethylamino- and 4-Cycloamino-Substituted 1,2,4-Triazole-3-thiones 191
TABLE 1 Continued
H
N N
S
R
N
R′
Compound
R
Rꢁ
Reaction Conditions
Yield (%)
11
4-OCH3-Ph
Morpholine
N(CH3)2
Pyridine/DBU A
t = 3 h
7
25
38
24
19
Dioxane/DBU B
t = 3 h
aDioxane/10% NaOH C
t = 30 min, T = 105–110◦C
aDioxane/10% NaOH A
t = 20 min, T = 105–110◦C
DMSO/10% NaOH B
t = 1 h
12
13
3,4-Cl2-Ph
NaHCO3, t = 15 min
Pyridine/DBU A
t = 3 h
3,5-(OCH3)2-Ph
4-Methyl-piperazine
1.4
13
Dioxane/DBU B
t = 3 h
A, B, C, D, and E indicate different methods used for the synthesis; as given in the Experimental section.
aReactions performed in a microwave reactor.
pointed out that microwave processes occurred
faster and gave similar yields in shorter time. De-
tailed conditions of reactions carried out are given
in Tables 1 and 2. In conclusion, there are several
factors that determine the rate of the reaction be-
tween benzhydrazides and methyl dithiocarbazates
and there is no universal synthesis method. Every re-
action should be analyzed individually with respect
to reactants and expected product structures.
EXPERIMENTAL
A
monomode microwave reactor RM 2001
(Plazmatronika, Wroclaw, Poland), with frequency
TABLE 2 Methods of 4-Amino-1-benzoyl-thiosemicarbazide Synthesis (Type II Products)
O
R
C
S
NH NH C
NH R′
Compound
R
Rꢁ
Reaction Conditions
Yield (%)
14
4-Cl-Ph
Morpholine
Dioxane/DBU
30
46
66
27
69
24
t = 4 h
aDioxane/10% NaOH
t = 30 min, T = 105–110◦C
Dioxane/DBU
15
16
17
18
2-Cl-Ph
Morpholine
N(CH3)2
t = 3 h
4-NH2-Ph
4-NH2-Ph
4-OCH3-Ph
aDMSO/K2CO3 solid
t = 10 min, T = 80–85◦C
aDMSO/10% NaOH
t = 20 min, T = 100–105◦C
aDMSO/10% NaOH
t = 20 min, T = 100–105◦C
Piperidine
Piperidine
aReactions performed in a microwave reactor.
Heteroatom Chemistry DOI 10.1002/hc

192 Gobis and Foks
of 2.45 GHz and maximum microwave power
of 800 W, was used. Reaction temperature was
measured in a reaction flask. Measurement was
noncontact (IR temperature measurement). Melting
points were determined with Boethius apparatus
(Franz Ku¨stner Nachf. KG, Dresden, Germany) and
were uncorrected. IR spectra were recorded on a
Satellite FT-IR spectrophotometer (Mattson Instru-
ments, Madison, WI) (KBr pellets). 1H NMR spectra
were recorded on Varian Gemini (200 MHz) and
Varian Unity Plus (500 MHz) instruments (Varian,
Palo Alto, CA). The results of elemental analysis
(% C, H, and N) for all of the obtained compounds
were in agreement with calculated values within
0.3% range.
refluxed for 2 h, cooled, acidified with acetic acid,
and filtered.
4-Chlorobenzoic acid was obtained during the
synthesis of compounds 4 and 5. To separate it from
the product, obtained solid was stirred with 15 mL
of a saturated solution of sodium bicarbonate for
15 min at room temperature, filtered, and finally
dried.
General Protocol for Microwave Method
Appropriate amounts of N-amino-dithiocarbamic
acid methyl ester (2.5 mmol) and hydrazide
(2.5 mmol) were suspended in 3 mL of the sol-
vent and an equimolar quantity of the base was
added. The reaction mixture was heated in a mi-
crowave reactor. Then, 15 g of ice was added and the
mixture was acidified with acetic acid. Precipitate
was filtered, dried, and recrystallized. In the case of
compound 16, concentrated hydrochloric acid was
used. All details of reactions proceeding are given in
Tables 1 and 2.
N-Aminodithiocarbamic acid methyl esters re-
quired for further syntheses were obtained accord-
ing to the method described earlier by Podgornaya
and coworkers [24].
(1-Methyl-piperazin-4-yl)-dithiocarbamic Acid
Methyl Ester
1-Methyl-piperazine (12 mL, 0.1 mol) was added to
30 mL of ethanol and then treated with triethylamine
(16 mL, 0.1 mol) and carbon disulfide (6.4 mL,
0.1 mol). The reaction mixture was stirred for 15 min
and some water was added to dissolve the precip-
itate. Then, methyl iodide (6.2 mL, 0.1 mol) was
added. The mixture was stirred for about 15 min, and
the solid precipitate of S-methyl ester was filtered af-
ter cooling. Yield: 11.4 g, 56%, m.p. 162–163◦C from
methanol. IR: 3088, 2950, 2841, 2803, 1526, 1331,
1278, 1034, 1003, 832, 588 cm−1. 1H NMR (200 MHz,
CDCl3) δ: 1.44 (m, 2H, NCH2), 2.35 (s, 3H, NCH3),
2.39 (m, 2H, NCH2), 2.52 (s, 3H, SCH3), 2.59 (m, 2H,
NCH2), 3.15 (m, 2H, NCH2), 8.28 (s, 1H, NH) ppm.
Anal. Calcd. for: C, 40.9; H, 7.4; N, 20.5. Found: C,
41.1; H, 7.5; N, 20.2.
4-Dimethylamino-5-phenyl-2,4-dihydro-[1,2,4]
triazole-3-thione (1)
Method A. Yield: 0.055 g, 5%. Crystallization
from methanol; m.p. 236–237◦C. IR: 3254, 3169,
2990, 2861, 1672, 1540, 1484, 1307, 1250, 714 cm−1.
1H NMR (500 MHz, DMSO-d6) δ: 3.15 (s, 6H, 2CH3),
7.51 (m, 3H, Ph), 7.80 (m, 2H, Ph), 13.85 (s, 1H, NH)
ppm. Anal. Calcd. for C10H12N4S: C, 54.5; H, 5.5; N,
25.4. Found: C, 54.2; H, 5.7; N, 25.3. Method B. Yield:
0.253 g, 23%. Method C. Yield: 0.220 g, 40%.
5-Phenyl-4-piperidin-1-yl-2,4-dihydro-[1,2,4]
triazole-3-thione (2)
Method A. Yield: 0.143 g, 11%. Crystallization
from diluted ethanol; m.p. 232–234◦C. IR: 3159,
2941, 2860, 2360, 1524, 1481, 1313, 1208, 1153, 902,
1
719 cm−1. H NMR (200 MHz, DMSO-d6) δ: 1.35–
General Protocol for the Classical Method
1.75 (m, 6H, 3CH2), 2.97 (m, 2H, NCH2), 4.40 (t, 2H,
NCH2, J = 10 Hz), 7.49 (m, 3H, Ph), 7.85 (m, 2H, Ph),
13.65 (s, 1H, NH) ppm. Anal. Calcd. for C13H16N4S:
C, 60.0; H, 6.2; 21.5. Found: C, 60.2; H, 6.3; N, 21.4.
Method B. Yield: 0.325 g, 50%.
To a stirred solution of N-amino-dithiocarbamic
acid methyl ester (5 mmol) in 5 mL of a proper
solvent, hydrazide (5 mmol) and equimolar amount
of base were added. The mixture was refluxed for
the appropriate time. The mixture was evaporated,
10 mL of water was added to the residue, and then
the mixture was acidified with acetic acid. Precipi-
tate was filtered, dried, and recrystallized. All details
of reactions are given in Tables 1 and 2.
4-Morpholin-4-yl-5-phenyl-2,4-dihydro-[1,2,4]
triazole-3-thione (3)
Method A. Yield: 0.354 g, 27%. Crystallization
For compounds 6–8, separated solid consisted of
A- and B-type products. Then, dried precipitate was
dissolved in 15 mL of 10% sodium hydroxide and
from methanol; m.p. 239–240◦C. IR: 3113, 2926,
1
2850, 1554, 1507, 1274, 1109, 692 cm−1. H NMR
(200 MHz, CDCl3) δ: 2.92 (m, 2H, NCH2), 3.64 (m,
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Synthesis of Novel 4-N,N-Dimethylamino- and 4-Cycloamino-Substituted 1,2,4-Triazole-3-thiones 193
2H, NCH2), 3.95 (m, 2H, OCH2), 4.86 (m, 2H, OCH2),
7.51 (m, 3H, Ph), 8.90 (m, 2H, Ph), 13.75 (s, 1H, NH)
ppm. Anal. Calcd. for C12H14N4OS: C, 54.9; H, 5.4;
21.4. Found: C, 55.0; H, 5.3; N, 21.2. Method B. Yield:
0.426 g, 65%. Method C. Yield: 0.472 g, 36%. Method
D. Yield: 0.511 g, 39%. Method E. Yield: 0.328 g, 50%.
J = 8.8 Hz), 7.94 (d, 2H, Ph, J = 8.8 Hz), 13.91 (s, 1H,
NH) ppm. Anal. Calcd. for C12H13FN4OS: C, 51.4; H,
4.7; N, 20.0. Found: C, 51.5; H, 4.9; N, 19.9. Method
B. Yield: 0.216 g, 30%.
5-(4-Amino-phenyl)-4-dimethylamino-2,4-
dihydro-[1,2,4]triazole-3-thione (8)
5-(4-Chloro-phenyl)-4-dimethylamino-2,4-
Method A. Yield: 0.130 g, 22%. Crystallization
from diluted ethanol; m.p. 252–253◦C. IR: 3358,
2928, 1518, 1392, 1295, 1176, 963, 829, 594 cm−1. 1H
NMR (200 MHz, DMSO-d6) δ: 3.15 (s, 6H, 2NCH3),
3.50 (s, 2H, NH2), 7.14 (d, 2H, Ph, J = 8.5 Hz), 7.78
(d, 2H, Ph, J = 8.7 Hz), 13.86 (s, 1H, NH) ppm. Anal.
Calcd. for C10H13N5S: C, 51.0; H, 5.6; N, 29.8. Found:
C, 50.9; H, 5.5; N, 30.0. Method B. Yield: 0.071 g,
24%.
dihydro-[1,2,4]triazole-3-thione (4)
Method A. Yield: 0.298 g, 22%. Crystallization
from diluted ethanol; m.p. 236–237◦C. IR: 3289,
3148, 2964, 2861, 1541, 1495, 1313, 1091, 1011 cm−1.
1H NMR (500 MHz, DMSO-d6) δ: 2.50 (s, 6H, 2CH3),
7.58 (d, 2H, Ph, J = 8.7 Hz), 7.70 (d, 2H, Ph,
J = 8.8 Hz), 13.51 (s, 1H, NH) ppm. Anal. Calcd. for
C10H11ClN4S: C, 47.2; H, 4.4; N, 22.0. Found: C, 47.2;
H, 4.2; N, 21.9. Method B. Yield: 0.169 g, 25%.
5-(4-Amino-phenyl)-4-piperidin-1-yl-2,4-
dihydro-[1,2,4]triazole-3-thione (9)
5-(4-Chloro-phenyl)-4-piperidin-1-yl-2,4-
dihydro-[1,2,4]triazole-3-thione (5)
Yield: 0.289 g, 42%. Crystallization from diluted
ethanol; m.p. 272–273◦C. IR: 3111, 2939, 2824, 1515,
1323, 1046, 1032, 951, 793, 621 cm−1. 1H NMR
(500 MHz, DMSO-d6) δ: 1.65 (m, 6H, 3CH2), 2.45
(m, 2H, NCH2), 2.99 (m, 2H, NCH2), 3.61 (s, 2H,
NH2), 7.10 (d, 2H, Ph, J = 8.5 Hz), 7.79 (d, 2H, Ph,
J = 8.5 Hz), 13.89 (s, 1H, NH) ppm. Anal. Calcd. for
C13H17N5S: C, 56.7; H, 6.2;N,25.4. Found: C, 56.5; H,
6.4; N 25.5.
Method A. Yield: 0.398 g, 27%. Crystallization
from diluted ethanol; m.p. 228–229◦C. IR: 3097,
3031, 2986, 2933, 1501, 1421, 1314, 1277, 1096, 1015,
834, 747 cm−1. 1H NMR (200 MHz, DMSO-d6) δ: 1.64
(m, 6H, 3CH2), 3.02 (m, 2H, NCH2), 4.27 (m, 2H,
NCH2), 7.34 (d, 2H, Ph, J = 8.8 Hz), 7.91 (d, 2H, Ph,
J = 8.7 Hz) 13.82 (s, 1H, NH) ppm. Anal. Calcd. for
C13H15ClN4S: C, 53.0; H, 5.1; N, 19.0. Found: C, 53.2,
H, 5.2; N 18.9. Method B. Yield: 0.297 g, 39%.
5-(4-Amino-phenyl)-4-morpholin-4-yl-2,4-
dihydro-[1,2,4]triazole-3-thione (10)
5-(4-Chloro-phenyl)-4-morpholin-4-yl-2,4-
dihydro-[1,2,4]triazole-3-thione (6)
Yield: 0.284 g, 41%. Crystallization from diluted
ethanol; m.p. 264–266◦C. IR: 3110, 2977, 2836, 1517,
1326, 1108, 1048, 1005, 952, 863, 692 cm−1. 1H
NMR (200 MHz, DMSO-d6) δ: 2.91 (d, 2H, NCH2,
J = 10 Hz), 3.47 (t, 2H, NCH2, J = 11 Hz), 3.56 (s,
2H, NH2), 3.85 (d, 2H, OCH2, J = 11 Hz), 4.65 (t, 2H,
OCH2, J = 10 Hz), 7.05 (d, 2H, Ph, J = 8.8 Hz), 7.72
(d, 2H, Ph, J = 8.8 Hz), 13.75 (s, 1H, NH) ppm.
Anal. Calcd. for C12H15N5OS: C, 52.0; H, 5.5; N, 25.3.
Found: C, 52.2; H, 5.4; N, 25.0.
Method A. Yield: 0.386 g, 26%. Crystallization
from diluted ethanol; m.p. 255–256◦C. IR: 3222,
3067, 2961, 2912, 2858, 1496, 1263, 1109, 845,
751 cm−1. 1H NMR (200 MHz, DMSO-d6) δ: 2.97 (m,
2H, NCH2), 3.38 (m, 2H, NCH2), 3.81 (m, 2H, OCH2),
4.60 (m, 2H, OCH2), 7.52 (d, 2H, Ph, J = 8.7 Hz),
7.84 (d, 2H, Ph, J = 8.7 Hz), 13.94 (s, 1H, NH) ppm.
Anal. Calcd. for C12H13ClN4OS: C, 48.6; H, 4.4; N,
18.9. Found: C, 48.8; H, 4.4; N, 18.8. Method B. Yield:
0.207 g, 28%. Method C. Yield: 0.386 g, 52%.
5-(4-Methoxy-phenyl)-4-morpholin-4-yl-2,4-
dihydro-[1,2,4]triazole-3-thione (11)
5-(4-Fluoro-phenyl)-4-morpholin-4-yl-2,4-
dihydro-[1,2,4]triazole-3-thione (7)
Method A. Yield: 0.102 g, 7%. Crystallization
from diluted ethanol; m.p. 287–288◦C. IR: 3093,
2930, 2853, 1517, 1430, 1255, 1110, 1023, 835,
720 cm−1. 1H NMR (200 MHz, DMSO-d6) δ: 2.92 (m,
2H, NCH2), 3.45 (t, 2H, NCH2, J = 11 Hz), 3.82 (s,
3H, OCH3), 3.98 (m, 2H, OCH2), 4.62 (t, 2H, OCH2,
J = 10 Hz), 7.07 (d, 2H, Ph, J = 8.8 Hz), 7.81 (d, 2H,
Method A. Yield: 0.210 g, 15%. Crystallization
from diluted ethanol; m.p. 224–225◦C. IR: 3238,
3001, 2978, 2926, 2872, 2849, 1508, 1426, 1308, 1265,
1
1101, 844 cm−1. H NMR (200 MHz, DMSO-d6) δ:
2.98 (m, 2H, NCH2), 3.44 (m, 2H, NCH2), 3.82 (m,
2H, OCH2), 4.62 (m, 2H, OCH2), 7.41 (d, 2H, Ph,
Heteroatom Chemistry DOI 10.1002/hc

194 Gobis and Foks
Ph, J = 8.8 Hz), 13.79 (s, 1H, NH) ppm. Anal. Calcd.
for C13H16N4O2S: C, 53.4; H, 5.5; N, 19.2. Found: C,
53.2; H, 5.6; N, 19.3. Method B. Yield: 0.365 g, 25%.
Method C. Yield: 0.277 g, 38%.
9.98 (s, 1H, NH), 10.40 (s, 1H, NH) ppm. Anal. Calcd.
for C12H15ClN4O2S: C, 45.8; H, 4.8; N, 17.8. Found:
C, 45.6; H, 4.7; N, 17.6.
1-(4-Amino-benzoyl)-4-dimethylamino-
thiosemicarbazide (16)
5-(3,4-Dichloro-phenyl)-4-dimethylamino-2,4-
dihydro-[1,2,4]triazole-3-thione (12)
Yield: 0.171 g, 27%. Crystallization from diluted
ethanol; m.p. 186–188◦C. IR: 3289, 3153, 2984, 2361,
Method A. Yield: 0.174 g, 24%. Crystallization
from diluted ethanol; m.p. 255–257◦C. IR: 3089,
2923, 2360, 1588, 1422, 1316, 1249, 1118, 1035, 762,
1654, 1602, 1493, 1296, 1267, 1182, 843 cm−1. H
1
NMR (200 MHz, DMSO-d6) δ: 3.05 (s, 6H, 2 NCH2),
3.58 (s, 2H, NH2), 7.53 (d, 2H, Ph, J = 8.7 Hz), 7.94
(d, 2H, Ph, J = 8.6 Hz), 9.32 (s, 1H, NH), 9.58 (s,
1H, NH), 10.23 (s, 1H, NH) ppm. Anal. Calcd. for
C10H15N5OS: C, 47.4; H, 6.0; N, 27.6. Found: C, 47.6;
H, 5.9; N, 27.8.
1
741 cm−1. H NMR (200 MHz, DMSO-d6) δ: 2.90 (s,
6H, 2 NCH3), 7.82 (s, 2H, Ph), 8.13 (s, 1H, Ph), 13.94
(s, 1H, NH) ppm. Anal. Calcd. for C10H10Cl2N4S: C,
41.5; H, 3.5; N, 19.4. Found: C, 41.3; H 3.6; N, 19.6.
Method B. Yield: 0.274 g, 19%.
4-(4-Methyl-piperazin-1-yl)-5-(3,5-dimethoxy-
phenyl)-2,4-dihydro-[1,2,4]triazole-3-thione (13)
1-(4-Amino-benzoyl)-4-piperidin-1-yl-
thiosemicarbazide (17)
Method A. Yield: 0.023 g, 1.4%. Crystallization
from diluted ethanol; m.p. 240–242◦C. IR: 3346,
2943, 2364, 1590, 1528, 1352, 1208, 1154, 1071,
879, 687 cm−1. 1H NMR (500 MHz, DMSO-d6) δ:
2.04 (t, 2H, NCH2, J = 11 Hz), 2.18 (s, 3H, NCH3),
2.78 (d, 2H, NCH2, J = 11 Hz), 2.92 (d, 2H, NCH2,
J = 10 Hz), 3.81 (s, 6H, 2 OCH3), 4.62 (t, 2H, NCH2,
J = 10 Hz), 6.62 (d, 1H, Ph, J = 2 Hz), 7.07 (s,
2H, Ph), 13.89 (s, 1H, NH) ppm. Anal. Calcd. for
C15H21N5O2S: C, 53.7; H, 6.3; N, 20.9. Found: C, 53.4;
H, 6.2; N, 20.8. Method B. Yield: 0.218 g, 13%.
Yield: 0.506 g, 69%. Crystallization from diluted
ethanol; m.p. 196–198◦C. IR: 3354, 3179, 2937, 2360,
1
1635, 1603, 1529, 1486, 1302, 1079, 836 cm−1. H
NMR (200 MHz, DMSO-d6) δ: 1.63 (m, 6H, 3 CH2),
2.48 (m, 2H, NCH2), 7.18 (d, 2H, Ph, J = 8.4 Hz), 7.81
(d, 2H, Ph, J = Anal. Calcd. for C13H19N5OS: C, 53.2;
H, 6.5; N, 23.9. Found: C, 53.4; H, 6.6; N, 23.8.
1-(4-Methoxy-benzoyl)-4-piperidin-1-yl-
thiosemicarbazide (18)
Yield: 0.185 g, 24%. Crystallization from diluted
ethanol; m.p. 209–244◦C IR: 3165, 2940, 2360, 1650,
1-(4-Chloro-benzoyl)-4-morpholin-4-yl-
thiosemicarbazide (14)
1
1605, 1508, 1486, 1256, 1172, 1025, 767 cm−1. H
NMR (500 MHz, DMSO-d6) δ: 1.61 (m, 6H, 3 CH2),
2.45 (m, 2H, NCH2), 2.93 (m, 2H, NCH2), 3.85 (s, 3H,
OCH3), 7.08 (d, 2H, Ph, J = 8.8 Hz) 7.81 (d, 2H, Ph,
J = 8.8 Hz), 9.25 (s, 1H, NH), 9.54 (s, 1H, NH), 10.30
(s, 1H, NH) ppm. Anal. Calcd. for C14H20N4O2S: C,
54.5; H, 6.5; N, 18.2. Found: C, 54.4; H, 6.3; 18.4.
Method A. Yield: 0.472 g, 30%. Crystallization
from diluted ethanol; m.p. 222–223◦C. IR: 3189,
2977, 2823, 1667, 1517, 1346, 1109, 1013, 870 cm−1.
1H NMR (200 MHz, DMSO-d6) δ: 2.64 (m, 2H, NCH2),
2.82 (m, 2H, NCH2), 3.54–3.80 (m, 2H, OCH2), 4.25–
4.39 (m, 2H, OCH2), m7.55 (d, 2H, Ph, J = 8.6 Hz),
7.92 (d, 2H, Ph, J = 8.7 Hz), 9.37 (s, 1H, NH), 9.81
(s, 1H, NH), 10.59 (s, 1H, NH) ppm. Anal. Calcd. for
C12H15ClN4O2S: C, 45.8; H, 4.8; N, 17.8. Found: C,
45.7; H, 4.8; N, 17.7. Method B. Yield: 0.362 g, 46%.
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Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Synthesis of Novel 4-N,N-Dimethylamino- and 4-Cycloamino-Substituted 1,2,4-Triazole-3-thiones 195
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Heteroatom Chemistry DOI 10.1002/hc