Synthesis of 1,4-dithiocarbonyl piperazines under microwave irradiation in solvent-free conditions

Article abstract of DOI:10.1081/SCC-100000179

A series of 1,4-dithiocarbonyl piperazines was synthesized from aldehydes, piperazine, and elementary sulphur under microwave irradiation in solvent-free conditions. Nonthermal effect of microwave irradiation was studied.

Full text of DOI:10.1081/SCC-100000179

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SYNTHESIS OF 1,4-DITHIOCARBONYL PIPERAZINES
UNDER MICROWAVE IRRADIATION IN SOLVENT-FREE
CONDITIONS
Mukta Gupta a , Satya Paul a & Rajive Gupta b
a Department of Chemistry , University of Jammu , Jammu, 180 006, India
b Department of Chemistry , University of Jammu , Jammu, 180 006, India
Published online: 09 Nov 2006.
To cite this article: Mukta Gupta , Satya Paul & Rajive Gupta (2001) SYNTHESIS OF 1,4-DITHIOCARBONYL PIPERAZINES
UNDER MICROWAVE IRRADIATION IN SOLVENT-FREE CONDITIONS, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:1, 53-59, DOI: 10.1081/SCC-100000179
To link to this article: http://dx.doi.org/10.1081/SCC-100000179
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SYNTHETIC COMMUNICATIONS, 31(1), 53–59 (2001)
SYNTHESIS OF 1,4-DITHIOCARBONYL
PIPERAZINES UNDER MICROWAVE
IRRADIATION IN SOLVENT-FREE
CONDITIONS
Mukta Gupta, Satya Paul, and Rajive Gupta∗
Department of Chemistry, University of Jammu,
Jammu-180 006, India
ABSTRACT
A series of 1,4-dithiocarbonyl piperazines was synthesized
from aldehydes, piperazine, and elementary sulphur under micro-
wave irradiation in solvent-free conditions. Nonthermal effect of
microwave irradiation was studied.
Piperazine derivatives are nowadays an important group of organic com-
pounds that is used as hair stimulating (1,2), antibacterial (3,4), anti-inflammatory
(5–7), antidepressant (8), and antitumor (9,10) agents, and as neurokinin antag-
onists (11,12). However, very few 1,4-dithiocarbonyl piperazines have been pre-
pared (13,14).
The most important method for the preparation of thioamide is Willgerodt-
Kindler reaction (15) wherein arylalkyl ketones in presence of elementary sulphur
and secondary amine give the terminal thioamide as a result of oxidation and re-
arrangement. The Willgerodt-Kindler reaction was extended by Dutron-Woitrin
et al. (16) to aliphatic aldehydes and aliphatic ketones. A most recent synthesis
∗ To whom correspondence should be addressed.
53
Copyright ꢀ 2001 by Marcel Dekker, Inc.
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C

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GUPTA, PAUL, AND GUPTA
of 1,4-dithiocarbonyl piperazines from aliphatic aldehydes, piperazine, and ele-
mentary sulphur was reported by Li and Ye (14) using N,N-dimethylformamide
as solvent.
The solvent-free conditions under microwave irradiation offer several ad-
vantages (17–22): solvents are often expensive, toxic, difficult to remove in case
of aprotic dipolar solvents with high boiling point, and are environmental pollution
agents. The salient features of these high-yield protocols are the enhanced reac-
tion rates, greater selectivity, and the experimental ease of manipulation. Nowa-
days, research and development are directed toward devising fast, economic, and
environment-friendly procedures.
Keeping in view our interest in devising environment-friendly techniques
(23–26), the biological importance of piperazines, and the advantages offered
by solvent-free microwave activation, we describe here a fast, economic, and
environment-friendly method for the synthesis of 1,4-dithiocarbonyl piperazines
(3a–j) from aldehydes, piperazine, and elementary sulphur using microwave acti-
vation and solvent-free conditions.
The synthesis of 1,4-dithiocarbonyl piperazines was studied by taking 3a
as an example. During optimization of reaction conditions, it has been found that
6 mmoles of DMF for 2 mmoles of piperazine was necessary to get the maximum
yield (85%). The reaction also can take place when 6 mmoles of ethylene glycol
for 2 mmoles of piperazine was used (80%).
In order to know the effect of solvent as an energy transfer medium or
homogenizer or both, the reaction also was carried out using 6 mmoles of p-xylene
(microwave inactive) for 2 mmoles of piperazine and also under neat conditions.
It has been found that reactions proceed with lower yield (with p-xylene: 48% and
neat 38%). Lower temperature was recorded also, indicating that solvent is acting
both as an energy transfer medium and a homogenizer (Table 1).
Table 1. Effect of Solvent for 3a under Microwave Activation (MW) and
Thermal Heating (ꢀ) (Power = 300 W)
MW
ꢀ
Time
(min)
Yield
(%)
Temp.a
(◦C)
Time
(min)
Yield
(%)
Temp.a
(◦C)
Solvent
Amount
DMF
EG
p-Xylene
No
6 mmol
6 mmol
6 mmol
—
5
5
5
5
85
80
48
38
100–02
105–07
58–60
54–56
5
5
5
5
48
40
25
20
100–02
105–07
58–60
54–56
EG = Ethylene glycol.
aFinal temperature is measured by immersing a glass thermometer at the end of
exposure to microwave irradiation (approximate temperature range).

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1,4-DITHIOCARBONYL PIPERAZINES
55
Scheme 1.
Finally, the synthesis of 3a was attempted by changing the activation method
using a thermo-regulated oil-bath under the same reaction time and temperature
as for the microwave-assisted method (Table 1). It has been found that lower
yields were obtained under thermal conditions (MW: 5 min, 85%, ∆: 5 min,
48%), demonstrating that the effect of microwave irradiation is not purely
thermal.
The developed protocol was extended to the synthesis of 1,4-dithiocarbonyl
piperazines 3b–j using N,N-dimethylformamide. The results are summarized in
Table 2.
In conclusion, we have developed a simple method for the synthesis of
1,4-dithiocarbonyl piperazines that occurs remarkably fast under mild conditions
using a household microwave oven as the irradiating source. The method leads
to a noticeable improvement in reaction conditions and takes advantage of both
solvent-free conditions and microwave activation. An important specific (non-
thermal) microwave effect is evidenced here by comparison with classical heating
under the same conditions (5 min MW: 85%, ∆: 48%).

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GUPTA, PAUL, AND GUPTA
Table 2. Synthesis of 1,4-Dithiocarbonyl Piperazines
3a–j under Microwave Irradiation (Power = 300 W)
Irradiation
Time (min)
Yielda
(%)
m.p. (◦C)
(Lit. m.p.)
Compd.
3a
5
85
268–70
(266.5)b
258–59
236–38
209–11
215–16
285(d)
212–13
234–36
155(d)
3b
3c
3d
3e
3f
3g
3h
3i
5
5
5
5
5
10
10
10
1.5
82
72
83
71
77
63
53
62
57
3j
235(d)
aYield of isolated products.
bSee Ref. 13.
EXPERIMENTAL
Melting points (uncorrected) were determined by Toshniwal melting point
apparatus. IR spectra (νmax in cm−1) were recorded on Shimadzu-435 spectropho-
1
tometer using KBr disc and HNMR spectra in DMSO-d6 (chemical shifts in δ,
ppm) on Varian EM-390 (90 MHz) or Bruker AM-250 (250 MHz) using TMS as an
internal standard. The mass spectra were performed on Delsi/NERMAG spectral
30 spectrometer. Microwave irradiation was carried out using a BPL BMO 800T
domestic oven with maximum power output of 800 W.
General Procedure for the Synthesis of 1,4-Dithiocarbonyl
Piperazines 3
Anhydrous piperazine (2 mmol), aldehyde (4 mmol), and sulphur (0.05 g-
atom) were put in a beaker (50 mL). DMF (6 mmol) was added and properly
mixed with a glass rod to get a paste. This paste was then irradiated in a mi-
crowave oven for the appropriate time at 300 W. After irradiation, the reac-
tion mixture was cooled and diluted with water (25–30 mL). The solid obtained
was filtered, washed with water (3×10 mL), and crystallized from suitable sol-
vent: boiling methanol, DMF-H2O. The unreacted sulphur was removed during
crystallization.

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1,4-DITHIOCARBONYL PIPERAZINES
57
Spectral Data of Compounds 3a–j
1
Compound 3a: H NMR (DMSO-d6): δ 3.85–4.0 (m, 4H, CH2N), 4.25–
4.45 (m, 4H, CH2N), 7.05–7.72 (m, 10H, Ar-H); IR (KBr): 3025, 1477, 1180; MS
(m/z, %) M+: 326 (100%). Anal. calcd. for C18H18N2S2: C, 66.25; H, 5.52; N,
8.58. Found: C, 66.18; H, 5.59; N, 8.52.
1
Compound 3b: H NMR (DMSO-d6): δ 3.72–4.02 (m, 4H, CH2N and
buried s, 6H, 2x-OCH3), 4.18–4.45 (m, 4H, CH2N), 6.90–7.50 (m, 8H, Ar-H); IR
(KBr): 3022, 1482, 1270, 1175; MS (m/z, %) M+: 386 (100%). Anal. calcd. for
C20H22N2O2S2: C, 62.17; H, 5.69; N, 7.25. Found: C, 62.24; H, 5.76; N, 7.18.
Compound 3c: 1H NMR (DMSO-d6): δ 3.88–4.08 (m, 4H, CH2N), 4.25–
4.40 (m, 4H, CH2N), 7.20–8.33 (m, 8H, Ar-H), 9.10 (s, 2H, 2xArC4-H); IR (KBr):
3033, 1482, 1175, 810. Anal. calcd. for C24H18Cl2N4S2: C, 57.94; H, 3.62; N,
11.26. Found: C, 58.02; H, 3.58; N, 11.34.
1
Compound 3d: H NMR (DMSO-d6): δ 3.90–4.10 (m, 4H, CH2N and
buried s, 6H, 2x-OCH3), 4.20–4.42 (m, 4H, CH2N), 7.25–8.30 (m, 6H, Ar-H),
9.03 (s, 2H, 2xArC4-H); IR (KBr): 3020, 1485, 1270, 1188, 805. Anal. calcd.
for C26H22Cl2N4O2S2: C, 66.01; H, 3.94; N, 10.05. Found: C, 66.07; H, 3.85; N,
10.13.
1
Compound 3e: H NMR (DMSO-d6): δ 2.30 (s, 6H, 2xAr-CH3), 3.90–
4.02 m, 4H, CH2N), 4.25–4.42 (m, 4H, CH2N), 7.22–8.32 (m, 6H, Ar-H), 9.10 (s,
2H, 2xArC4-H);IR(KBr):3028, 1482, 1176, 805. Anal. calcd. forC26H22Cl2N4S2:
C, 59.42; H, 4.19; N, 10.66. Found: C, 59.37; H, 4.26; N, 10.73.
Compound 3f: 1H NMR (DMSO-d6): δ 2.32 (s, 6H, 2xAr-CH3), 3.88–4.0
(m, 4H, CH2N), 4.22–4.45 (m, 4H, CH2N), 7.28–8.20 (m, 6H, Ar-H), 9.08 (s, 2H,
2xArC4-H); IR (KBr): 3025, 1478, 1170, 810. Anal. calcd. for C26H22Cl2N4S2:
C, 59.42; H, 4.19; N, 10.66. Found: C, 59.39; H, 4.22; N, 10.62.
Compound 3g: 1H NMR (DMSO-d6): δ 3.92–4.10 (m, 4H, CH2N), 4.25–
4.47 (m, 4H, CH2N), 7.0–8.50 (m, 18H, Ar-H), 9.72 (bs, 2H, 2xNH, exchangeable
with D2O); IR (KBr): 3345, 3015, 1478, 1182. Anal. calcd. for C34H28N4S2: C,
73.38; H, 5.03; N, 10.07. Found: C, 73.31; H, 5.09; N, 9.98.
Compound 3h: 1H NMR (DMSO-d6): δ 2.28 (s, 6H, 2xAr-CH3), 3.90–4.05
(m, 4H, CH2N), 4.22–4.45 (m, 4H, CH2N), 7.0–8.42 (m, 16H, Ar-H), 9.80 (bs,
2H, 2xNH, exchangeable with D2O); IR (KBr): 3345, 3015, 1478, 1172. Anal.
calcd. for C36H32N4S2: C, 73.97; H, 5.47; N, 9.58. Found: C, 74.05; H, 5.41; N,
9.64.
1
Compound 3i: H NMR (DMSO-d6): δ 3.85–4.02 (m, 4H, CH2N), 4.25–
4.47 (m, 4H, CH2N), 7.05–8.46 (m, 16H, Ar-H), 9.85 (bs, 2H, 2xNH, exchangeable
with D2O); IR (KBr): 3348, 3018, 1480, 1177. Anal. calcd. for C34H26Cl2N4S2:
C, 65.28; H, 4.16; N, 8.96. Found: C, 65.34; H, 4.13; N, 9.04.
Compound 3j: 1H NMR (DMSO-d6): δ 2.5–3.2 (m, 4H, Ar-CH2CH2), 3.9–
4.1 (m, 4H, CH2N), 4.22–4.48 (m, 4H, CH2N), 6.98–7.59 (m, 8H, Ar-H); IR

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GUPTA, PAUL, AND GUPTA
(KBr): 3040, 1488, 1185, 813. Anal. calcd. for C26H24Cl2N2S2: C, 62.52; H, 4.80;
N, 5.61. Found: C, 62.47; H, 4.87; N, 5.71.
ACKNOWLEDGMENTS
Financial support from UGC, New Delhi, is gratefully acknowledged.
We thank Dr. Andre Loupy, University of Paris-Sud, France, for helpful
discussions.
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Received February 22, 2000

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