Synthesis of 6-substituted/unsubstituted-7,9-diaryl-1,2,4,8-tetraazaspiro[4.5]- decan-3-thiones

Article abstract of DOI:10.1081/SCC-120018753

Some 2,6-diarylpiperidin-4-one thiosemicarbazones (1a-8a), obtained from the corresponding 2,6-diarylpiperidin-4-ones (1-8) on oxidative cyclization with H₂O₂ at 0°C provide 7,9-diaryl-1,2,4,8-tetraaza spiro[4.5]decan-3-thiones(1b-8b

Full text of DOI:10.1081/SCC-120018753

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Synthesis of 6-Substituted/Unsubstituted- 7,9-
diaryl-1,2,4,8-tetraazaspiro[4.5]- decan-3-thiones
C. Ramalingan a , S. Balasubramanian a & S. Kabilan a
a Department of Chemistry , Annamalai University , Annamalainagar, India
Published online: 16 Aug 2006.
To cite this article: C. Ramalingan , S. Balasubramanian & S. Kabilan (2003) Synthesis of 6-Substituted/Unsubstituted-
7,9-diaryl-1,2,4,8-tetraazaspiro[4.5]- decan-3-thiones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:9, 1443-1448, DOI: 10.1081/SCC-120018753
To link to this article: http://dx.doi.org/10.1081/SCC-120018753
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1443–1448, 2003
Synthesis of 6-Substituted/Unsubstituted-
7,9-diaryl-1,2,4,8-tetraazaspiro[4.5]-
decan-3-thiones
*
C. Ramalingan, S. Balasubramanian, and S. Kabilan
Department of Chemistry, Annamalai University,
Annamalainagar, India
ABSTRACT
Some 2,6-diarylpiperidin-4-one thiosemicarbazones (1a–8a), obtained
from the corresponding 2,6-diarylpiperidin-4-ones (1–8) on oxidative
cyclization with H2O2 at0 ꢀC provide 7,9-diaryl-1,2,4,8-tetraaza
spiro[4.5]decan-3-thiones (1b–8b) in excellent yields. The structures
of these compounds have been established on the basis of their
elemental, analytical and spectral data.
2,6-Disubstituted piperidines forms a biologically important class of
compounds due to their pharmacological activities and their presence in a
variety of alkaloids.[1] The 1,2,4-triazole nucleus[2–5] has been incorpo-
*Correspondence: S. Kabilan, Department of Chemistry, Annamalai University,
Annamalainagar 608 002, India; E-mail: kabilan@satyam.net.in.
1443
DOI: 10.1081/SCC-120018753
Copyright & 2003 by Marcel Dekker, Inc.
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1444
Ramalingan, Balasubramanian, and Kabilan
Scheme 1.
rated in a wide variety of therapeutically interesting drugs including
H1/H2 histamine receptor blockers, cholinesterase active agents, CNS
stimulants, anti anxiety agents, sedatives, analgesic, anti convulsants
etc. Therefore it was planned to synthesize a system which combines
these two biolabile components together to give a compact structure
like title compounds.
1,2,4-Triazolidine-3-thiones were normally obtained from ketone
thiosemicarbazones by oxidative cyclization. Earlier MnO2,[6,7]
FeCl3ꢁ6H2O,[6,8] meta-chloroperbenzoic acid (m-CPBA),[9] H2O2
[10]
had been used for synthesizing 1,2,4-triazolidine-3-thiones from steroidal
and non-steroidal homocyclic ketone thiosemicarbazones. 2,6-
Diarylpiperidin-4-one thiosemicarbazones[11] (1a–8a) upon oxidative
cyclization using MnO2 provides a mixture of 7,9-diaryl-1,2,4,8-tetraaza
spiro[4.5]decan-3-thiones and 7,9-diaryl-1,2,4,8-tetraazaspiro[4.5]decan-
3-ones in equal ratio. The use of FeCl3ꢁ6H2O in the place of MnO2
also produced the same results but in 3:1 ratio. When m-CPBA[12] is
used, predominantly title compounds along with a little of N-hydroxy
piperidin-4-one derivatives and other nonseperable compounds resulted.
When tried with H2O2 at0 ꢀC as cyclizing agentremarkable resulst
are obtained. Herein we report oxidative cyclization of thiosemi-
ꢀ
carbazones of piperidinyl heterocycles using H2O2 at0 C for the first
time to the best of our knowledge, which results solely the title
compounds in excellentyields (Sch. 1).
EXPERIMENTAL
All the reported melting points were taken in open capillaries
and were uncorrected. IR spectra were recorded in KBr (pellet forms)
1
on a Perkin-Elmer 297 IR spectrophotometer. H NMR spectra were
recorded at 400 MHz on Bruker amx 400 MHz spectrophotometer
using CDCl3 as solvent and TMS as internal standard. 13C NMR spectra

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7,9-Diaryl-1,2,4,8-tetraazaspiro[4.5]decan-3-thiones
1445
were recorded at 125 MHz on Brucker amx 400 MHz spectrophotometer
using CDCl3. The mass spectra were recorded on a VG analytical 7070E
instrument equipped with VG 11-250 data acquisition system.
The parentkeotnes ( 1–8) were prepared by adopting the literature
method.[13]
General Method of Preparation of Ketone Thiosemicarbazones[11]
(1a–8a): The mixture of ketone (0.01 mol) and thiosemicarbazide
(0.01 mol) in glacial acetic acid was refluxed for 3 h and was concentrated
to one third of its original volume. After cooling, the mixture was poured
over crushed ice. The solid product thus obtained was filtered off and
recrystallized twice from methanol to give thiosemicarbazone as crystal-
line solid.
Synthesis of 7,9-diphenyl-1,2,4,8-tetraazaspiro[4.5]decan-3-thione (1b):
To a solution of 1a (0.005 mol) in chloroform (40 mL) was treated with
excess hydrogen peroxide (30%, 20 mL) and stirred for 3 h at 0ꢀC. After
completion of reaction, the organic layer was separated and dried over
anhydrous sodium sulphate. The solvents were removed under reduced
pressure. The crude producthtus obatined was purified over silica gel
column (pet. ether–ethyl acetate 5:2) and recrystallized from methanol as
needles.
IR (KBr) (cmꢂ1): 3341.5, 3317.1, 2362.1, 1608.8, 1492.4, 1453.8,
1
1350.0, 1293.8, 1202.9, 1069.9, 1028.0 etc. H NMR (ꢀ ppm): 4.22 (dd,
3J ¼ 11.86 Hz; 2.89 Hz, 2H) H7 and H9, 2.04–2.28 (m, 4H) H6 and H10,
7.30–7.54 (m, 10H) aryl protons, 8.44 (s (broad), 2H) HN–CS–NH, 7.12
(s, 1H) NH at1, 1.93 (s, 1H) NH at8. 13C NMR (ꢀ ppm): 59.534 (C7, C9),
38.849 (C6, C10), 78.659 (C5), 180.386 (C¼S), 124.938, 126.717, 127.260,
147.829 (aryl carbons). Mass (m/z): 324 (Mþ), (M.F: C18H20N4S), 294,
264, 249, 209, 194, 179, 145, 133, 105 (100%), 91, 77, 65, 51. The com-
pounds (2b–8b) were synthesized by adopting the same procedure as
given for (1b). The analytical data of compounds (1b–8b) are given in
Table 1.
6-Methyl-7,9-diphenyl-1,2,4,8-tetraazaspiro[4.5]decan-3-thione (2b).
IR (KBr) (cmꢂ1): 3424.2, 3345.7, 3320.1, 2360.7, 1590.1, 1492.3, 1453.7,
1376.6,1351.0,1268.1,1075.7etc.1H NMR(ꢀ ppm):4.27(dd,3J ¼ 12.01 Hz;
2.67 Hz, 1H) H9, 3.79 (d, 3J ¼ 10.85 Hz, 1H) H7, 2.10–2.34 (m, 3H) H6 and
H10, 7.17–7.48 (m, 10H) aryl protons, 8.39 (br. s, 2H) NH–CS–NH, 6.89
(s, 1H) NH at1, 1.89 (s, 1H) NH at8, 0.82 (d, J ¼ 6.54 Hz, 3H) CH3 at6.
13C NMR (ꢀ ppm): 65.742 (C7), 59.358 (C9), 39.961 (C6), 38.077 (C10),
79.238 (C5), 180.963 (C¼S), 12.050 (CH3), 124.629, 126.125, 126.468,
127.281, 127.578, 139.987, 147.554 (aryl carbons). Mass (m/z): 338
(Mþ), (M.F: C19H22N4S), 308, 278, 263, 222, 208, 194, 189, 179, 147,
132, 118 (100%), 91, 77, 65, 55, 51.

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1446
Ramalingan, Balasubramanian, and Kabilan
Table 1. Analytical data of compounds (1b–8b).
Elemental analysis
Yield
(%)
M.p
(ꢀC)
Compound
R
R1
C (%) H (%) N (%)
1b
2b
3b
4b
5b
6b
7b
8b
H
H
H
87
79
83
75
84
75
81
72
92
84–85
66.68
67.45
6.17
6.50
6.81
7.11
5.00
4.93
6.26
6.51
17.27
16.57
15.90
15.31
14.29
13.78
14.60
14.09
CH3
H
CH3
101–102 68.19
89 68.84
CH3 CH3
Cl
CH3 Cl
H
123–125 55.09
105–106 56.17
H OCH3
CH3 OCH3
78
67
62.48
63.34
7,9-bis(p-Methylphenyl)-1,2,4,8-tetraazaspiro[4.5]decan-3-thione (3b).
IR (KBr) (cmꢂ1): 3331.3, 3298.2, 2347.3, 1603.9, 1500.7, 1468.1, 1341.0,
1300.8, 1210.4, 1028.9, 1001.0 etc. 1H NMR (ꢀ ppm): 4.24 (dd,
3J ¼ 11.87 Hz; 2.90 Hz, 2H) H7 and H9, 2.03–2.26 (m, 4H) H6 and H10,
7.25, 7.37 (2d, 8H) aromatic, 8.46 (br. s, 2H) NHCSNH, 7.12 (s, 1H) NH
at1, 1.92 (s, 1H) NH at8, 2.40 (s, 6H) aryl CH
.
13C NMR (ꢀ ppm):
3
58.826 (C7, C9), 38.947 (C6, C10), 78.684 (C5), 179.998 (C¼S), 20.574 (aryl
CH3) 127.852, 128.468, 136.974, 146.438 (aryl carbons). Mass (m/z): 352
(Mþ), (M.F: C20H24N4S), 322, 292, 277, 236, 222, 207, 159, 147, 118
(100%), 105, 91, 78, 65, 50.
6-Methyl-7,9-bis( p-methylphenyl)-1,2,4,8-tetraazaspiro[4.5]decan-3-
thione (4b). IR (KBr) (cmꢂ1): 3436.7, 3328.5, 3294.0, 2349.2, 1584.2,
1501.4, 1474.2, 1420.9, 1384.7, 1320.4, 1270.2, 1201.5, 1134.3, 1027.4
etc. 1H NMR (ꢀ ppm): 4.25 (dd, 3J ¼ 12.00 Hz; 2.68 Hz, 1H) H9, 3.80
3
(d, J ¼ 10.84 Hz, 1H) H7, 2.09–2.34 (m, 3H) H6 and H10, 7.29–7.43 (m,
8H) aromatic, 8.38 (br. s, 2H) NH-CS-NH, 6.90 (s, 1H) NH at 1,
2.43 (s, 6H) aryl CH3, 1.88 (s, 1H) NH at8, 0.83 (d, J ¼ 6.54, 3H)
CH3 at6. 13C NMR (ꢀ ppm): 65.008 (C7), 59.574 (C9), 40.018 (C6),
38.178 (C10), 79.274 (C5), 180.894 (C¼S), 11.999 (CH3 at6), 20.987
(aryl CH3), 128.310, 128.522, 129.779, 131.610, 135.679, 137.852,
138.644, 146.135 (aryl carbons). Mass (m/z): 366 (Mþ), (M.F:
C21H26N4S), 336, 306, 291, 250, 236, 222, 203, 161, 146, 132 (100%),
119, 91, 77, 65, 55.
7,9-bis(p-Chlorophenyl)-1,2,4,8-tetraazaspiro[4.5]decan-3-thione (5b).
IR (KBr) (cmꢂ1): 3363.7, 3307.4, 2398.0, 1602.2, 1450.3, 1437.4, 1378.3,
1247.8, 1187.8, 1074.7, 1037.3 etc. 1H NMR (ꢀ ppm): 4.26 (dd,

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7,9-Diaryl-1,2,4,8-tetraazaspiro[4.5]decan-3-thiones
1447
3J ¼ 11.87 Hz; 2.89 Hz, 2H) H7 and H9, 2.05–2.29 (m, 4H) H6 and H10,
7.32, 7.38 (2d, 8H) aromatic, 8.46 (br. s, 2H) NH-CS-NH, 7.07 (s, 1H)
NH at1, 1.87 (s, 1H) NH at8. 13C NMR (ꢀ ppm): 58.695 (C7, C9), 38.750
(C6, C10), 78.641 (C5), 180.102 (C¼S), 128.252, 128.405, 133.204, 146.742
(aryl carbons). Mass (m/z): 392 (Mþ), (M.F: C18H18N4SCl2), 362, 332,
317, 276, 262, 247, 179, 167, 139 (100%), 111, 95, 75, 65, 50.
6-Methyl-7,9-bis( p-chlorophenyl)-1,2,4,8-tetraazaspiro[4.5]decan-3-
thione (6b). IR (KBr) (cmꢂ1): 3418.8, 3375.3, 3299.4, 2394.6, 1587.7,
1488.4, 1474.1, 1361.7, 1348.4, 1241.0, 1091.3 etc. 1H NMR (ꢀ ppm):
3
3
4.27 (dd, J ¼ 12.00 Hz; 2.67 Hz, 1H) H9, 3.81 (d, J ¼ 10.85 Hz, 1H)
H7, 2.09–2.37 (m, 3H) H6 and H10, 7.34–7.47 (m, 8H) aromatic, 8.44
(br. s, 2H) NH-CS-NH, 6.85(s, 1H) NH at1, 1.90 (s, 1H) NH at8,
0.82 (d, J ¼ 6.57 Hz, 3H) CH3 at6. 13C NMR (ꢀ ppm): 64.847 (C7),
59.362 (C9), 39.833 (C6), 38.002 (C10), 79.301 (C5), 180.907 (C¼S),
12.040 (CH3 at6), 127.288, 128.726, 128.990, 131.364, 131.989,
133.922, 138.920, 146.443 (aryl carbons). Mass (m/z): 406 (Mþ), (M.F:
C19H20N4SCl2), 376, 346, 331, 290, 276, 262, 247, 223, 181, 166, 155, 138
(100%), 111, 94, 75, 65, 55, 50.
7,9-bis(p-Chlorophenyl)-1,2,4,8-tetraazaspiro[4.5]decan-3-thione (7b):
IR (KBr) (cmꢂ1): 3369.3, 3305.2, 2347.3, 1603.9, 1500.7, 1468.1, 1341.0,
1300.8, 1210.4, 1028.9, 1001.0 etc. 1H NMR (ꢀ ppm): 4.24 (dd,
3J ¼ 11.84 Hz; 2.86 Hz, 2H) H7 and H9, 2.02–2.26 (m, 4H) H6 and H10,
6.89, 7.35 (2d, 8H) aromatic, 8.43 (br. s, 2H) NH-CS-NH, 7.17 (s, 1H)
NH at1, 1.91 (s, 1H) NH at8, 3.90 (s, 6H) OCH
.
3
13C NMR (ꢀ ppm):
58.847 (C7, C9), 38.974 (C6, C10), 78.630 (C5), 180.159 (C¼S), 54.618
(OCH3), 115.544, 127.837, 141.903, 158.541 (aryl carbons). Mass (m/z):
384 (Mþ), (M.F: C20H24N4SO2), 354, 324, 309, 268, 254, 239, 175, 163,
134 (100%), 117, 107, 75, 65, 50.
6-Methyl-7,9-bis( p-methoxyphenyl)-1,2,4,8-tetraazaspiro[4.5]decan-3-
thione (8b). IR (KBr) (cmꢂ1): 3429.5, 3351.0, 3313.7, 3294.0, 2349.2,
1584.2, 1501.4, 1474.2, 1420.9, 1384.7, 1320.4, 1270.2, 1201.5, 1134.3,
1
3
1027.4 etc. H NMR (ꢀ ppm): 4.26 (dd, J ¼ 12.02 Hz; 2.63 Hz, 1H) H9,
3.80 (d, 3J ¼ 10.89 Hz, 1H) H7, 2.08–2.35 (m, 3H) H6 and H10, 6.85–6.87,
7.36–7.38 (m, 8H) aromatic, 8.44 (br. s, 2H) NH-CS-NH, 6.97 (s, 1H)
NH at1, 1.89 (s, 1H) NH at8, 0.81 (d, J ¼ 6.58 Hz, 3H) CH3 at6, 3.91
(s, 6H) OCH3. 13C NMR (ꢀ ppm): 65.006 (C7), 59.503 (C9), 40.015 (C6),
38.265 (C10), 79.285 (C5), 180.948 (C¼S), 12.124 (CH3 at6), 54.895
(OCH3), 114.383, 115.890, 128.005, 130.955, 134.746, 141.682, 157.266,
159.234 (aryl carbons). Mass (m/z): 398 (Mþ), (M.F: C21H26N4SO2), 368,
338, 323, 282, 268, 254, 239, 219, 177, 162, 148 (100%), 135, 117, 107, 75,
65, 55, 50.

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1448
Ramalingan, Balasubramanian, and Kabilan
ACKNOWLEDGMENT
The authors are grateful to Dr. M. Vasudevan, JSS College of
Pharmacy, Ooty, for his kind help in recording spectra and also to
Prof. C. N. Krishnan, Head, Department of Chemistry, Annamalai
University for providing needed facilities.
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Received in Japan March 27, 2002