Regioselective synthesis of novel N-aminotriazolophanes

Article abstract of DOI:10.1139/V06-181

Bis-[4-amino-1,2,4-triazoles] were prepared by fusion of dibasic acids and thiosemicarbazide by condensation of aromatic acid hydrazides with hydrazine hydrate and carbon disulphide. Regioselective alkylation of these bis-[4-amino-1,2,4-triazoles] with 1,

Full text of DOI:10.1139/V06-181

21
Regioselective synthesis of novel
N-aminotriazolophanes
Madhukar S. Chande, Pravin A. Barve, Rahul R. Khanwelkar, Shailesh S. Athalye,
and Deepak S. Venkataraman
Abstract: Bis-[4-amino-1,2,4-triazoles] were prepared by fusion of dibasic acids and thiosemicarbazide by condensation
of aromatic acid hydrazides with hydrazine hydrate and carbon disulphide. Regioselective alkylation of these bis-[4-
amino-1,2,4-triazoles] with 1,ω-dihaloalkanes in the presence of potassium hydroxide in aqueous methanol afforded
novel N-aminotriazolophanes. The stereochemistry and antibacterial activity of these N-aminotriazolophanes were stud-
ied. In the case of the triazolophanes 5h, 8d, and 8f, both N-NH2 groups were observed trans to each other, whereas
for case of other triazolophanes both N-NH2 groups were observed cis to each other.
Key words: 4-amino-1,2,4-triazole, 1,ω-dihaloalkane, S-alkylation, regioselective, N-aminotriazolophanes.
Résumé : On a préparé des bis[4-amino-1,2,4-triazoles] par fusion d’acides dibasiques et de thiosemicarbazide, par
condensation d’hydrazides d’acides aromatiques avec de l’hydrate d’hydrazine et du sulfure de carbone. L’alkylation ré-
giosélective de ces bis-[4-amino-1,2,4-triazoles] avec des 1,ω-dihalogénoalcanes en présence d’hydroxyde de potassium,
en solution dans le méthanol, fournit de nouveaux N-aminotriazolophanes. On a étudié la stéréochimie et l’activité anti-
bactérienne de des N-aminotriazolophanes. Dans les cas des triazolophanes 5h, 8d et 8f, on a observé que les deux
groupes N–NH2 sont trans l’un par rapport à l’autre alors que dans les autres cas les deux groupes N–NH2 sont cis.
Mots-clés : 4-amino-1,2,4-triazole, 1,ω-dihalogénoalcane, S-alkylation, régiosélective, N-aminotriazolophanes.
[Traduit par la Rédaction] Chande et al. 28
Introduction
In recent years, attention has been increasingly paid to the
synthesis of bisheterocyclic compounds, which exhibit vari-
ous biological activities (5) including antibacterial, antifun-
gicidal, tuberculostatic, and plant growth regulative properties.
Bisheterocyclic compounds displayed much better antibacte-
rial activity than heterocyclic compounds (6). Various 1,2,4-
triazoles are found to be associated with diverse pharmaco-
logical activities such as antiasthmatic (7), antiviral
(ribavirin) (8), antifungal (fluconazole) (9), antimicrobial (10),
antibacterial (11), insecticidal (12, 11c), amoebicidal (13),
hypnotic (14), cytotoxic (15), and hypotensive (16) activi-
ties. This moiety was also found in potent agonist and antag-
onist receptor ligands (17) in HIV-1 protease inhibitors (18)
and in thrombin inhibitors (19). Along with these significant
pharmaceutical uses, 1,2,4-triazole derivatives are effectively
used in polymers, dyestuff, photographic chemicals, and ag-
ricultural chemicals (20).
We have previously reported on the regioselective synthesis
of novel oxadiazolophanes (21) and N-aminotriazolophanes
(22). In continuation of this ongoing program in the synthe-
sis of novel macrocyclic ligands (21, 22), their computa-
tional studies (21b), and their application as phase transfer
catalysts (PTC) (22c), we now report a facile regioselective
synthesis of novel N-aminotriazolophanes.
Crown compounds have generated considerable interest
during the last three decades because of their ability to form
stable complexes with variety of metal and organic cations
and anions (1). They also have wide application in phase
transfer catalysis (2). In recent years various structural
changes have been made to the basic “crown ether” structure
to enhance the selective activity of the ligands (3). These
changes involve the insertion of aromatic and (or) hetero-
cyclic ring systems into the macrocycles. The incorporation
of a heterocyclic subunit provides rigidity to the macrocycle
and assists in increasing the stability of complexes formed
with both metals and organic cations (3). The development
of crown compounds, especially macrocyclic compounds
containing a heterocyclic subunit, has gained importance be-
cause of their wide range of applications. Many reviews and
monographs have been published that highlight their synthe-
sis and application in synthetic organic chemistry as phase
transfer catalysts and in analytical chemistry as ligands for
complexation (2, 4).
Received 19 April 2006. Accepted 8 November 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 23 January 2007.
M.S. Chande,1 P.A. Barve, R.R. Khanwelkar, S.S. Athalye,
and D.S. Venkataraman. Department of Chemistry, The
Institute of Science, 15, Madam Cama Road, Mumbai
400 032, India.
Results and discussion
Synthesis
The present work describes the versatile synthetic strategy for
the regioselective synthesis of novel N-aminotriazolophanes
1Corresponding author (e-mail: chandems@vsnl.com).
Can. J. Chem. 85: 21–28 (2007)
doi:10.1139/V06-181
© 2007 NRC Canada

22
Can. J. Chem. Vol. 85, 2007
Scheme 1. Synthesis of N-aminotriazolophanes 5. Reagents and conditions: (a) 170 °C, (b) KOH, aq. MeOH (80%), 80 °C.
S
COOH
NHNH2
(CH2)n
H2NHN
NH2
N
NH2
N
N
N
2
(CH2)n
HN N
n(H2C)
SH
S
N
HS
(a)
N
S
N
COOH
N
NH2
N
NH
NH2
3A
1
3B
3a: n = 2
3b: n = 3
3c: n = 4
1a: n = 2
1b: n = 3
1c: n = 4
I
I
(CH2)m
(b)
I
I
(b)
4a–4c
4e
N
N
4a: n = 2
4b: n = 3
4c: n = 4
S
N
N
N
NH2
NH2
(CH2)m
n(H2C)
S
N
S
N
NH2
NH2
5a: n = 2, m = 3
5b: n = 2, m = 4
5c: n = 3, m = 2
5d: n = 3, m = 3
5e: n = 3, m = 4
5f: n = 4, m = 2
5g: n = 4, m = 3
n(H2C)
N
N
S
N
5a–5g
N
N
5h: n = 3
that have been specially designed to study their stereo-
chemistry.
The elucidation of the structures of 5a–5h was accom-
plished on the basis of their spectral data and elemental
analysis (Table 1). For example, the reaction of 3b with 1,2
diiodoethane 4a resulted in the formation of the desired N-
aminotriazolophane 5c, which was confirmed on the basis of
NMR spectra. The 1H NMR spectrum of the compound
showed a triplet at δ: 3.37 for the S-CH2 group in the ethane
chain. The absence of a peak for C=S in the 13C NMR spec-
trum confirmed the regioselectivity of S-alkylation. It showed
a signal for S-CH2 carbon at 29.6 ppm. From the above data,
compound 5c was identified as 14,54-diamino-6,9-dithia-
1,5(3,5)-di-(1,2,4-triazola)cyclononaphane (32). The other
N-aminotriazolophanes 5a–5h were similarly synthesized
and characterized.
To improve the solubility of the triazolophanes it was
thought to incorporate a phenyl nucleus into the structure,
which would also help in complexation or phase transfer cat-
alyst (PTC) activity. Hence, the scope of the previous reac-
tion was extended to the synthesis of benztriazolophane 8
(Scheme 2). Bistriazole 7 (33) was synthesized using the
Reid and Heindel method [34] by the condensation of
isophthalic acid dihydrazide 6 with hydrazine hydrate, car-
bon disulphide, and potassium hydroxide in methanol in
high yield.
Aminotriazole derivatives are well-known to be biologi-
cally active (23); e.g., 3-amino-1,2,4-triazole (amitrole) is
known for its biological (24) and herbicidal (25) activities.
4-Amino-1,2,4-triazoles are potentially good corrosion in-
hibitors (26). Bisheterocyclic compounds prepared using 4-
amino-1,2,4-triazoles derivatives exhibit significant biologi-
cal activity (27, 5f). Hence, we decided to incorporate 4-
amino-1,2,4-triazole as a basic unit in heterophane to further
enhance heterophane’s biological activity.
The obtained heterophanes (N-aminotriazolophanes)
would be similar to lariat ether (28) with N-NH2 groups as
side arms. The study of the stereochemistry of these com-
pounds is of interest because the two N-NH2 groups would
be either cis or trans to each other depending on the alkyl
chain joining the two heterocyclic units and the thermody-
namic stability of the molecule. This would in effect influ-
ence the properties of macrocycles such as cavity size.
There are many methods found in the literature for the
synthesis of 3,5-disubstituted-4-amino-1,2,4-triazoles (29),
but none of them concerns the synthesis of heterophanes.
Bis-N-aminotriazoles 3a–3c (30) were prepared in high yield
by direct fusion of aliphatic diacids 1a–1c with thiocarbohy-
drazine 2 (Scheme 1). The compound 3, containing thio-
amido groups, has an amphoteric nature and can exist in
tautomeric forms 3A and 3B. On alkylation of 3 with 1,ω-
dihaloalkane, multiple products could form depending on the
reaction condition.
The reaction of compounds 3a–3c with diiodoalkanes 4a–
4e in aq. methanol (80%) in the presence of potassium hy-
droxide as base gave only products 5a–5h regioselectively in
good yield (Scheme 1, Table 1). The intramolecular alkyla-
tion, which regioselectively occurs at sulfur, is mainly due to
the template formation, which is due to the presence of the
hexadentate potassium ions where the two ligands are water
molecules (31). The reaction was carried out in a large ex-
cess of solvent to ensure intramolecular cyclisation (high
dilution condition). Reaction of compound 3 with dibro-
momethane was unsuccessful, perhaps because of the inabil-
ity of the methyl group to link the two terminal thiol sulphur
atoms.
The reaction of 7 with 4a–4f in aq. methanol (80%) in the
presence of potassium hydroxide as a base gave the desired
benztriazolophanes 8a–8f regioselectively in moderate yield
(Scheme 2, Table 1). The structure of the product was con-
firmed on the basis of spectral data and elemental analysis
(Table 1). For example, the reaction of 7 with 1,2-diiodo-
ethane 4a resulted in the formation of the desired amino-
triazolophane 8a, which was confirmed on the basis of NMR
1
spectra. The H NMR spectrum of the compound showed a
triplet at δ: 2.89 for the S-CH2 group of the ethane chain.
The absence of a peak for C=S in the 13C NMR spectrum
confirmed the regioselectivity of S-alkylation. It showed sig-
nals for S-CH2 carbons at 27.9 and 30.0 ppm.
We have discussed in detail the regioselective N-
alkylation (22c) and S-alkylation (21, 22a, 22b) for the syn-
thesis of aminotriazolophanes. It was thought worthwhile to
use O-alkylation for the synthesis of heterophane with an
amino side arm. Hence, in continuation of this work on
© 2007 NRC Canada

Chande et al.
23
Table 1. Preparation and analytical data of compounds.
Found (required) (%)
Compound
3a
Yield (%)
MP (°C)
220
Formulae
C
H
N
S
82
72
74
42
44
38
45
32
43
47
35
82
25
30
33
35
47
44
80
65
35
36
80
65
28
C6H10N8S2
—
—
—
—
—
—
3b
3c
203
C7H12N8S2
—
—
—
221
C8H14N8S2
—
—
—
5a
208
C9H14N8S2
36.23 (36.01)
38.44 (38.23)
36.23 (36.02)
38.44 (38.23)
40.47 (40.35)
40.47 (40.34)
38.44 (38.32)
48.11 (48.00)
39.22 (39.01)
43.37 (43.25)
45.09 (44.90)
46.67 (46.44)
48.13 (48.01)
52.94 (52.71)
44.68 (44.55)
46.15 (46.02)
49.57 (49.46)
52.23 (52.11)
52.08 (52.00)
46.15 (46.01)
51.64 (51.51)
56.52 (56.39)
4.73 (4.60)
5.16 (5.01)
4.73 (4.52)
5.16 (5.01)
5.56 (5.45)
5.56 (5.46)
5.16 (5.03)
4.84 (4.72)
3.27 (3.05)
3.61 (3.50)
4.05 (3.87)
4.44 (4.23)
4.81 (4.58)
3.92 (3.78)
4.26 (4.12)
3.85 (3.72)
5.22 (5.10)
4.84 (4.60)
5.66 (5.43)
3.85 (3.62)
5.74 (5.62)
5.78 (5.55)
37.55 (37.43)
35.87 (35.75)
37.55 (37.32)
35.87 (35.62)
34.33 (34.31)
34.33 (34.20)
35.87 (35.75)
29.92 (29.80)
36.60 (36.38)
33.74 (33.61)
32.37 (32.13)
31.11 (31.00)
29.95 (29.72)
27.45 (27.31)
29.79 (29.56)
26.93 (26.72)
24.35 (24.23)
22.58 (22.36)
21.13 (21.01)
26.93 (26.70)
24.35 (24.23)
20.29 (20.15)
21.49 (21.28)
20.53 (20.32)
21.49 (21.38)
20.53 (20.40)
19.65 (19.42)
19.65 (19.43)
20.53 (20.32)
17.13 (17.02)
20.91 (20.80)
19.28 (19.05)
18.49 (18.35)
17.78 (17.55)
17.11 (17.00)
15.69 (15.46)
17.02 (16.80)
15.38 (15.15)
13.91 (13.78)
12.90 (12.66)
12.08 (11.92)
15.38 (15.24)
13.11 (13.00)
11.59 (11.38)
5b
5c
197
C10H16N8S2
C9H14N8S2
216
5d
5e
204
C10H16N8S2
C11H18N8S2
C11H18N8S2
C10H16N8S2
C15H18N8S2
C10H14N8S2
C12H12N8S2
C13H14N8S2
C14H16N8S2
C15H18N8S2
C18H20N8S2
C14H20N8S2O
C8H8N4SO
197
5f
112
5g
122
5h
7
141
>250
175
8a
8b
8c
245
210
8d
8e
>250
235
8f
>250
192
10
11
205
C19H20N8S2O2
C22H24N8S2O2
C23H26N8S2O3
C8H8N4SO
12a
12b
14
>250
220
>250
228
15
C21H24N8S2O2
C26H32N8S2O2
16
>250
The benztriazolophanes 12a and 12b were synthesized
regioselectively as the only products in moderate yield by
reacting 11 with dihaloalkanes in aq. methanol (80%) con-
taining potassium hydroxide (Scheme 3, Table 1). The struc-
ture of the product was confirmed on the basis of spectral
data and elemental analysis (Table 1). For example, reaction
of 11 with 1,3-dibromopropane resulted in the formation of
the desired compound 12a, which was confirmed on the ba-
Scheme 2. Synthesis of benztriazolophanes 8. Reagents and con-
ditions: (a) CS2, (NH2)2·H2O, KOH, MeOH, 0–5 °C, (b) KOH,
aq. MeOH (80%), 80 °C.
N
N
SH
SH
CONHNH2
N
NH2
NH2
(a)
I
N
O
CONHNH2
I
1
N
N
sis of NMR spectra. The H NMR spectrum of the com-
6
I
N
4f
N
7
(b)
pound showed a triplet at δ: 3.66 for the S-CH2 group of the
propane chain and a triplet at δ: 4.08 for the O-CH2 group of
the propane chain. An M+ peak at m/z 496 in the mass spec-
trum confirmed the formation of 12a.
Similar reaction conditions were used to prepare com-
pound 16 from p-hydroxy benzoic acid hydrazide 13. When
13 was reacted with hydrazine hydrate, carbon disulphide,
and potassium hydroxide in methanol, compound 14 was ob-
tained in high yield. Compound 14 was reacted with 1,5-
dibromopentane to afford 15 in moderate yield (Scheme 4,
Table 1). Compound 15 was then reacted with 1,5-dibro-
mopentane in methanolic potassium hydroxide to afford 16
in low yield (Scheme 4, Table 1).
I
I
4e
S
N
NH2
NH2
(b)
(CH2)m
(b)
I
O
4a–4d
4a: m=2
4b: m=3
4c: m=4
4d: m=5
N
N
S
N
S
N
NH2
NH2
N
N
N
N
8f
S
N
S
N
NH2
NH2
(CH2)m
N
N
S
N
8a: m=2
8b: m=3
8c: m=4
8d: m=5
8e
N
N
8a–8d
benztriazolophanes, salicylic acid hydrazide 9 was reacted
with hydrazine hydrate, carbon disulphide, and potassium
hydroxide in methanol to give compound 10 in high yield
(Scheme 3). When 10 was reacted with 1,3-dibromopropane
in methanolic potassium hydroxide, compound 11 was af-
forded regioselectively in good yield (Scheme 3, Table 1).
Stereochemistry
The stereochemistry of these N-aminotriazolophanes was
1
studied using H NMR spectral analysis and molecular mod-
eling studies (35). It was observed that in compounds 5a–5g,
© 2007 NRC Canada

24
Can. J. Chem. Vol. 85, 2007
Scheme 3. Synthesis of N-aminotriazolophanes 12. Reagents and conditions: (a) CS2, (NH2)2·H2O, KOH, MeOH, 0–5 °C, (b) KOH,
aq. MeOH (80%), 80 °C.
N
N
(CH2)3
N
N
N
N
S
S
N
(CH2)n
Br
N
SH
N
NH2
NH2
OH
H2N
Br
CONHNH2
OH
(a)
HO
(b)
OH
11
9
10
I
(b)
Br
(CH2)3
O
(b)
I
Br
O
N
N
N
NH2
O
N
N
N
NH2
S
S
(H2C)3
S
S
(H2C)3
O
N
N
NH
N
2
N
N
NH
N
2
O
O
12a
12b
Scheme 4. Synthesis of N-aminotriazolophanes 16. Reagents and conditions: (a) CS2, (NH2)2·H2O, KOH, MeOH, 0–5 °C, (b) KOH,
aq. MeOH (80%), 80 °C.
N
N
(CH2)5
S
N
N
N
N
S
N
NH2
(CH2)5
Br
N
SH
N
NH2
Br
H2N
CONHNH2
(a)
HO
OH
(b)
15
HO
HO
14
Br
13
(b)
(CH2)5
Br
O
N
N
N
NH2
S
(H2C)5
S
N
N
N
NH
2
O
16
8a–8c, and 8e both N-NH2 groups appeared as a single peak
in the 1H NMR, indicating that both N-NH2 groups are cis to
each other. This was also supported by the molecular model-
ing study. For compounds 5h, 8d, and 8f (Fig. 1), two dif-
ferent peaks were observed for the N-NH2 groups, indicating
the presence of these groups in different magnetic environ-
ments. This showed that both N-NH2 groups are trans to
each other. The molecular model of 5h, 8d, and 8f (Fig.1)
showed that one of the NH2 groups was hydrogen bonded to
lone pairs of the ring nitrogen atoms, thus changing the
magnetic environment.
5h, 8d, and 8f, both N-NH2 groups are observed in different
magnetic environments.
Experimental
General procedure for the synthesis of bis-(4-amino-5-
mercapto-1,2,4-triazol-3yl)alkanes (3a–3c)
Compounds 3a–3c were synthesized using a method from
the literature [31].
General procedure for the synthesis of 5a–5h, 8a–8f, 11,
12a-12c, 15, and 16
Compounds 3a–3c, 7, 10, 11, 14, and 15 (for the synthesis
of 5a–5h, 8a–8f, 11, 12a–12b, 15 and 16, respectively)
(0.01 mol) were dissolved in aq. methanol (methanol–water,
80:20, 200 mL) containing potassium hydroxide (0.02 mol).
A solution of 1,ω-dihaloalkane (0.01 mol) in methanol was
Conclusion
In this paper, we have reported on a versatile and conve-
nient route for the synthesis of novel N-aminotriazolophanes
from aliphatic and aromatic acid hydrazides. For compounds
© 2007 NRC Canada

Chande et al.
25
14,54-Diamino-6,10-dithia-1,5(3,5)-di(1,2,4-
triazola)cyclodecaphane (5d)
Fig. 1. Stereochemistry of N-aminotriazolophanes.
1H NMR (500 MHz, DMSO-d6) δ: 1.75 (p, 2H, CH2),
2.05 (p, 2H, CH2), 2.75 (t, 4H, 2 × CH2), 3.11 (t, 4H, 2 × S-
CH2), 5.87 (s, 4H, 2 × NH2, D2O exchangeable). 13C NMR
could not be scanned because of poor solubility.
14,54-Diamino-6,11-dithia-1,5(3,5)-di(1,2,4-
triazola)cycloundecaphane (5e)
1H NMR (500 MHz, DMSO-d6) δ: 1.74 (m, 4H, 2 × CH2),
2.03 (p, 2H, CH2), 2.70 (t, 4H, 2 × CH2), 3.07 (t, 4H, 2 × S-
CH2), 5.80 (s, 4H, 2 × NH2, D2O exchangeable). 13C NMR
could not be scanned because of poor solubility.
14,64-Diamino-7,10-dithia-1,6(3,5)-di(1,2,4-
triazola)cyclodecaphane (5f)
1H NMR (500 MHz, DMSO-d6) δ: 1.88 (m, 4H, 2 × CH2),
2.51 (m, 4H, 2 × CH2), 2.89 (t, 4H, 2 × S-CH2), 5.75 (s, 4H,
2 × NH2, D2O exchangeable). 13C NMR could not be
scanned because of poor solubility.
14,64-Diamino-7,11-dithia-1,6(3,5)-di(1,2,4-
triazola)cycloundecaphane (5g)
1H NMR (500 MHz, DMSO-d6) δ: 1.70 (m, 4H, 2 × CH2),
2.02 (p, 2H, CH2), 2.69 (m, 4H, 2 × CH2), 3.33 (t, 4H, 2 ×
S-CH2), 5.85 (s, 4H, 2 × NH2, D2O exchangeable). 13C
NMR could not be scanned because of poor solubility.
14,54-Diamino-8(1,2)-benzena-6,10-dithia-1,5(3,5)-
di(1,2,4-triazola)cyclodecaphane (5h)
1H NMR (500 MHz, DMSO-d6) δ: 2.02 (p, 2H, CH2),
2.70 (t, 4H, 2 × CH2), 4.45 (s, 4H, 2 × S-CH2), 5.81(s, 2H,
NH2, D2O exchangeable), 5.85(s, 2H, NH2, D2O exchange-
able), 7.16–7.33 (d, 4H, aromatic H). 13C NMR (500 MHz,
DMSO-d6, ppm) δ: 22.1, 24.0, 33.5 (5 × CH2), 126.9, 130.8,
135.5 (aromatic C), 152.8 (2 × S-C=N), 160.7 (2 × C=N).
added dropwise for 1 h. This reaction mixture was then
refluxed with stirring on a magnetic stirrer for 8 h. On cool-
ing to 10–15 °C, solid separated out. The obtained solid was
then filtered, washed with cold water, and recrystallized
from aq. dimethyl formamide (DMF).
14,34-Diamino-2(1,3)-benzena-4,7-dithia-1,3(3,5)-di(1,2,4-
triazola)cycloheptaphane (8a)
14,44-Diamino-5,9-dithia-1,4(3,5)-di(1,2,4-
triazola)cyclononaphane (5a)
1H NMR (300 MHz, DMSO-d6) δ: 2.89 (s, 4H, 2 × S-
CH2), 5.03 (s, 4H, 2 × NH2, D2O exchangeable), 6.84–7.56
(m, 4H, aromatic H). 13C NMR (300 MHz, DMSO-d6, ppm)
δ: 30.0 (2 × S-CH2), 127.1, 128.7, 130.1, 131.2 (aromatic C),
144.4 (2 × S-C=N), 153.7 (2 × C=N).
1H NMR (500 MHz, DMSO-d6) δ: 2.04 (p, 2H, CH2), 3.21
(s, 4H, 2 × CH2), 3.33 (t, 4H, 2 × S-CH2), 5.95 (s, 4H, 2 ×
NH2, D2O exchangeable). 13C NMR could not be scanned
because of poor solubility.
14,34-Diamino-2(1,3)-benzena-4,8-dithia-1,3(3,5)-di(1,2,4-
triazola)cycloctaphane (8b)
14,44-Diamino-5,10-dithia-1,4(3,5)-di(1,2,4-
triazola)cyclodecaphane (5b)
1H NMR (300 MHz, DMSO-d6) δ: 1.96 (p, 2H, CH2),
3.86 (t, 4H, 2 × S-CH2), 5.51 (s, 4H, 2 × N-NH2, D2O ex-
changeable), 7.63 – 8.57 (m, 4H, aromatic H). MS (DI) m/z:
346 (M+), 322, 304, 284, 243, 202, 129, 102, 91, 76, 59.
1H NMR (500 MHz, DMSO-d6) δ: 1.78 (p, 4H, 2 × CH2),
3.12 (s, 4H, 2 × CH2), 3.33 (t, 4H, 2 × S-CH2), 5.95 (s, 4H,
2 × NH2, D2O exchangeable). 13C NMR (500 MHz, DMSO-
d6, ppm) δ: 21.0, 28.1 (4 × CH2), 30.3 (2 × S-CH2), 151.2
(2 × S-C=N), 155.3 (2 × C=N).
14,34-Diamino-2(1,3)-benzena-4,9-dithia-1,3(3,5)-di(1,2,4-
triazola)cyclononaphane (8c)
14,54-Diamino-6,9-dithia-1,5(3,5)-di(1,2,4-
triazola)cyclononaphane (5c)
1H NMR (500 MHz, DMSO-d6) δ: 1.06 (m, 4H, 2 × CH2),
3.86 (t, 4H, 2 × S-CH2), 6.18 (s, 4H, 2 × NH2, D2O ex-
changeable), 7.62 – 8.54 (m, 4H, aromatic H). 13C NMR
(500 MHz, DMSO-d6, ppm) δ: 28.3 (2 × CH2), 30.6, 30.7
(2 × S-CH2), 127.1 – 134.3 (aromatic C), 141.3 (2 ×
S-C=N), 153.8 (2 × C=N). MS (DI) m/z: 360 (M+), 330,
298, 256, 202, 171, 156, 143, 129, 102, 91, 77.
1H NMR (500 MHz, DMSO-d6) δ: 2.38 (p, 2H, CH2),
2.78 (t, 4H, 2 × CH2), 3.37 (t, 4H, 2 × S-CH2), 5.14 (s, 4H,
2 × NH2, D2O exchangeable). 13C NMR (500 MHz, DMSO-
d6, ppm) δ: 22.1, 24.5, 29.7, (5 × CH2), 148.7 (2 × S-C=N),
156.8 (2 × C=N).
© 2007 NRC Canada

26
Can. J. Chem. Vol. 85, 2007
14,34-Diamino-2(1,3)-benzena-4,10-dithia-1,3(3,5)-
di(1,2,4-triazola)cyclodecaphane (8d)
S-CH2), 115.2, 117.7, 129.4, 138.7 (aromatic C), 152.7 (2 ×
S-C=N), 154.0 (2 × C=N).
1H NMR (300 MHz, DMSO-d6) δ: 1.29 (m, 2H, CH2),
1.69 (m, 4H, 2 × CH2), 3.13 (t, 4H, 2 × S-CH2), 6.11 (s, 4H,
2 × NH2, D2O exchangeable), 7.38- 7.81 (m, 4H, aromatic
H). MS (DI) m/z: 374 (M+), 358, 324, 304, 182, 144, 128,
102, 91, 80, 77.
14,114-Diamino-2,10(1,4)-dibenzena-3,9-dioxa-12,18-
dithia-1(3,5)11(5,3)-di(1,2,4-triazola)cyclooctadecaphane
(16)
1H NMR (500 MHz, DMSO-d6) δ: 1.20 (p, 2H, CH2),
1.43 (p, 2H, CH2), 1.53 (p, 4H, 2 × CH2), 3.12 (t, 4H, 2 × S-
CH2), 4.00 (t, 4H, 2 × O-CH2), 6.00 (s, 4H, 2 × NH2, D2O
exchangeable), 6.82–7.88 (dd, 8 H, aromatic H). MS (DI)
m/z: 552 (M+), 536, 520, 489, 446, 412, 396, 292, 239, 198,
137, 101, 91, 77.
14,34-Diamino-2(1,3)-6(1,2)-dibenzena-4,8-dithia-1,3(3,5)-
di(1,2,4-triazola)cyclooctaphane (8e)
1H NMR (500 MHz, DMSO-d6) δ: 4.69 (t, 4H, 2 × S-
CH2), 6.21 (d, 4H, 2 × NH2, D2O exchangeable), 7.31- 8.61
(m, 8H, aromatic H). 13C NMR (500 MHz, DMSO-d6, ppm)
δ: 32.6 (2 × S-CH2), 127.1, 128.1, 128.8, 130.6, 131.2,
132.1, 135.6 (aromatic C), 147.5 (2 × S-C=N), 159.2 (2 ×
C=N). MS (DI) m/z: 408 (M+), 322, 304, 288, 250, 220, 216,
192, 180, 128, 102, 90, 76.
General procedure for the synthesis of 7
Isophthalic acid dihydrazide 6 (0.01 mol) was dissolved in
ethanol (20 mL) in the presence of potassium hydroxide
(0.02 mol) and cooled to 5 °C. To this cold solution was
added carbon disulphide (0.02 mol) under stirring. The po-
tassium dithiacarbamate salt precipitated out and was fil-
tered, washed with petroleum ether, and dried. This salt was
fused with hydrazine hydrate (99%, 0.022 mol) at 90 °C for
4 h. The reaction mixture was poured onto cold water and
filtered to remove traces of inorganic material. The filtrate
was then treated with dilute hydrochloric acid until the pH
of the solution became neutral. The obtained white product
was then filtered, washed with cold water, and recrystallized
from aq. DMF.
14,34-Diamino-2(1,3)-benzena-7-oxa-4,10-dithia-1,3(3,5)-
di(1,2,4-triazola)cyclodecaphane (8f)
1H NMR (500 MHz, DMSO-d6) δ: 3.08 (t, 2H, S-CH2),
3.54 (t, 2H, O-CH2), 5.90 (s, 2H, NH2, D2O exchangeable),
5.94 (s, 2H, NH2, D2O exchangeable), 7.40- 8.55 (m, 4H, ar-
omatic H). 13C NMR (500 MHz, DMSO-d6, ppm) δ: 31.2 (2
× S-CH2), 69.2, 70.7 (O-CH2), 127.6, 129.3, 129.6, 131.3
(aromatic C), 154.1 (2 × S-C=N), 163.2 (2 × C=N). MS (DI)
m/z: 376 (M+), 299, 267, 223, 208, 170, 128, 102, 91, 76,
66.
1,3-Bis-(4′-amino-5′-mercapto-1,2,4-triazol-3-yl)benzene
(7)
1,3-Di-[4-amino-5(2′-hydroxyphenyl)-1,2,4-triazol-3-
yl]mercapto propane (11)
1H NMR (500 MHz, DMSO-d6) δ: 5.72 (s, 4H, 2 × NH2,
D2O exchangeable), 7.65- 8.41 (m, 4H, aromatic H), 13.98
(s, 2H, 2 × NH, D2O exchangeable). 13C NMR (500 MHz,
DMSO-d6, ppm) δ: 126.1, 127.4, 128.6, 129.8 (aromatic C),
148.8 (2 × C=N), 167.1 (2 × C=S).
1H NMR (500 MHz, DMSO-d6) δ: 2.22 (p, 2H, CH2), 3.37
(t, 4H, 2 × S-CH2) 6.06 (s, 4H, 2 × NH2, D2O exchange-
able), 6.97–7.93 (m, 8H, aromatic H), 11.11 (s, 2H, 2 × OH,
D2O exchangeable). 13C NMR (500 MHz, DMSO-d6, ppm)
δ: 29.5 (CH2), 30.2 (2 × S-CH2), 113.2, 116.9, 119.6, 129.7,
131.9, 156.2 (aromatic C), 153.9 (2 × S-C=N), 154.0 (2 ×
C=N).
General procedure for the synthesis of 10 and 14
Salicylic acid hydrazide 9 and p-hydroxy benzoic acid
hydrazide 13 (for 10 and 14, respectively) (0.01 mole) were
dissolved in ethanol (20 mL) in the presence of potassium
hydroxide (0.02 mole) and cooled to 5 °C. To this cold solu-
tion was added carbon disulphide (0.01 mole) under stirring.
The potassium dithiacarbamate salt precipitated out and was
filtered, washed with petroleum ether, and dried. This salt
was fused with hydrazine hydrate (99%, 0.011 mole) at
90 °C for 4 h. The reaction mixture was then poured onto
cold water and filtered to remove traces of inorganic mate-
rial. The filtrate was treated with dilute hydrochloric acid
until the pH of the solution became neutral. The obtained
white product was then filtered, washed with cold water, and
recrystallized from aq. DMF.
14,94-Diamino-2,8(1,2)-dibenzena-3,7-dioxa-10,14-dithia-
1(3,5)9(5,3)-di(1,2,4-triazola)cyclotetradecaphane (12a)
1H NMR (500 MHz, DMSO-d6) δ: 0.73 (p, 2H, CH2),
1.12 (p, 2H, CH2), 3.66 (t, 4H, 2 × S-CH2), 4.08 (t, 4H, 2 ×
O-CH2), 5.17 (s, 4H, 2 × NH2, D2O exchangeable), 6.87 –
7.45 (m, 8 H, aromatic H). MS (DI) m/z: 496 (M+), 480,
443, 405, 318, 209, 167, 91, 84, 77.
14,94-Diamino-2,8(1,2)-dibenzena-3,7-dioxa-10,14-dithia-
1(3,5)9(5,3)-di(1,2,4-triazola)cyclotetradecaphane (12b)
1H NMR (500 MHz, DMSO-d6) δ: 1.12 (p, 2H, CH2),
3.66 (t, 4H, 2 × S-CH2), 4.03 (t, 8H, 4 × O-CH2), 5.62 (s,
4H, 2 × NH2, D2O exchangeable), 7.03–7.46(m, 8 H, aro-
matic H).
4-Amino-5(2′-hydroxyphenyl)-3-meracpto-1,2,4-triazole
(10)
1,5-Di-[4-amino-5-(2′-hydroxyphenyl)-1,2,4-triazol-3-
yl]mercapto pentane (15)
1H NMR (500 MHz, DMSO-d6) δ: 5.63 (s, 4H, 2 × NH2,
D2O exchangeable) 6.92–7.44 (m, 4H, aromatic H), 10.37 (s,
1H, OH, D2O exchangeable), 13.896 (s, 1H, S=C-NH, D2O
exchangeable). 13C NMR (500 MHz, DMSO-d6, ppm) 113.1,
116.2, 119.0, 130.9, 132.9, 156.1 (aromatic C), 149.2 (2 ×
C=N), 165.1 (2 × C=S).
1H NMR (500 MHz, DMSO-d6) δ: 1.56 (p, 2H, CH2),
1.75 (p, 4H, 2 × CH2), 3.16 (t, 4H, 2 × S-CH2), 6.01 (s, 4H,
2 × NH2, D2O exchangeable), 6.86–7.80 (dd, 8 H, aromatic
H), 9.89 (s, 2H, 2 × OH, D2O exchangeable). 13C NMR
(500 MHz, DMSO-d6, ppm) 27.1, 28.6 (3 × CH2), 30.9 (2 ×
© 2007 NRC Canada

Chande et al.
27
11. (a) T. George, D.V. Mehta, R. Tahilramani, J. David, and P.K.
Talwalker. J. Med. Chem. 14, 335 (1971); (b) S.
Papakonstantinou-Garoufalias, N. Pouli, P. Marakos, and A.
Chytyroglou-Ladas. Farmaco, 57, 973 (2002); (c) A.K.
Sengupta and H.K. Misra. J. Indian Chem. Soc. 58, 508 (1981).
12. M.M. Ghorab, S.G. Abdel- Hamide, M.S.A. El-Gaby, and
S.M. El- Sayed. Acta Pharm. 49, 1 (1999).
4-Amino-5(4′-hydroxyphenyl)-3-meracpto-1,2,4-triazole
(14)
1H NMR (300 MHz, DMSO-d6) δ: 5.73 (s, 4H 2 × N-NH2,
D2O exchangeable), 6.85, 7.84 (dd, 4H, aromatic H), 10.02
(s, 1H, OH, D2O exchangeable), 13.76 (s, 1H, S=C-NH,
D2O exchangeable). 13C NMR (300 MHz, DMSO-d6, ppm)
115.3, 116.5, 129.7, 159.4 (aromatic C), 149.6 (2 × C=N),
166.4 (2 × C=S).
13. C.S. Andotra and S.K. Sharma. Proc. Natl. Acad. Sci. India
Sect. A, 58, 215 (1988).
14. J.B. Hester, A.D. Rudzik, and B.V. Kamdar. J. Med. Chem. 14,
1078 (1977).
Acknowledgement
15. N.G.N. Milton. Neurotoxicology, 22, 767 (2001).
16. (a) G. Burell, J.M. Evans, M.S. Hadley, F. Hicks, and G.
Stemp. Bioorg. Med. Chem. Lett. 4, 1285 (1994); (b) M.M.
Ghorab, S.G. Abdel-Hamide, G.M. Ali, El Sayed, and H.
Shaurub. Pestic. Sci. 48, 31 (1996); (c) M.K. Mody, A.R.
Prasad, T. Ramalingham, and P.B. Suttur. J. Indian Chem. Soc.
59, 769 (1982).
17. (a) J.H. Wadsworth, S.M. Jenkins, B.S. Orlek, F. Cassidy,
M.S.G. Clark, F. Brown, G.J. Riley, D. Graves, J. Hawkins,
and C.B. Naylor. J. Med. Chem. 35, 1280 (1992); (b) S.M.
Jenkins, H. Wadsworth, S. Bromidge, B.S. Orlek, P.A.
Wyman, G.J. Riley, and J. Hawkins. J. Med. Chem. 35, 2392
(1992); (c) C. Chen, R. Dagnino, C.Q. Huang, J.R. McCarthy,
D.E. Grigoriadis. Bioorg. Med. Chem. Lett. 11, 3165 (2001);
(d) B. Neumann-Schultz, L. Unger, K. Blumbach, D. Starck,
D. Schoebel, and H. Treiber. International Patent WO-2000-
0042038, 20 August 2000.
18. S.K. Thompson, A.M. Eppley, J.S. Frazee, M.G. Darcy, R.T.
Lum, T.A. Tomaszeck, L.A. Ivanoff, J.F. Morris, E.J. Stern-
berg, D.M. Lambert, A.V. Fernandez, S.R. Patteway, T.D.
Meek, B.W. Metcalf, and J.G. Gleason. Bioorg. Med. Chem.
Lett. 4, 2441 (1994).
19. J.V. Duncia, J.B. Santella, C.A. Higley, M.K. VanAtten, P.C.
Weber, R.S. Alexander, C.A. Kettner, J.R. Pruitt, A.Y. Liauw,
M.L. Quan, R.M. Knabb, and R.R. Wexler. Bioorg. Med.
Chem. Lett. 8, 775 (1998).
The help rendered by the Regional Sophisticated Instru-
mentation Centres (RSIC), the Indian Istitute of Technology
(IIT), and the Tata Institute of Fundamental Research
(TIFR), the Department of Chemistry, University of Pune,
and the Department of Chemistry, Institute of Science,
Mumbai, are gratefully acknowledged. We also thank “Lady
Tata memorial trust” for their financial support.
References
1. (a) E. Graf and J.M. Lehn. Helv. Chim. Acta, 64, 1040 (1981);
(b) B. Dietrich, M.W. Hosseini, J.M. Lehn, and R.B. Session.
Helv. Chim. Acta, 66, 1262 (1983); (c) M.W. Hosseini, J.M.
Lehn, and M.P. Mertes. Helv. Chim. Acta, 66, 2444 (1983);
(d) A. Kumar, S. Mageswaran, and I.O. Sutherland. Tetrahe-
dron, 42, 3291 (1986); (e) J.S. Bradshaw and R.M. Izatt. Acc.
Chem. Res. 30, 338 (1997).
2. (a) G.R. Newkome, J.G. Traynham, and G.R. Baker. In Crown
ethers and cryptands in compendium of heterocyclic com-
pounds. Vol. 5. Edited by A.R. Katritzky. Pergamon Press,
London, U.K. 1984. p. 763; (b) Phase transfer catalysis, funda-
mentals, applications and industrial perspective. Edited by
C.M. Stark, C. Liotta, and M. Halpern. Chapman and Hall,
New York. 1994.
20. K.T. Potts. Chem. Rev. 61, 87 (1961).
3. J.S. Bradshaw, R.M. Izzat, A.V. Bordunov, C.Y. Zhu, and J.K.
Hathaway. In Comprehensive supramolecular chemistry.
Vol. 1. Edited by G.W. Gokel. Pergamon Press, New York.
1996. p. 35.
21. (a) M.S. Chande, A.A. Godbole, and C. Sajithkumar. Heteroat.
Chem. 14, 273 (2003); (b) M.S. Chande, A.A. Godbole, E.
Coutinho, and P. Desai. Indian J. Chem. Sect. B, 42, 397
(2002).
22. (a) M.S. Chande and S.S. Athalye. Synth. Commun. 29, 1711
(1999); (b) M.S. Chande, and S.S. Athalye. Synth. Commun.
30, 1667 (2000); (c) M.S. Chande, S.S. Athalye, and A.A.
Godbole. Indian J. Chem. Sect. B, 43, 670 (2004); (d) M.S.
Chande, M.H. Uchil, and P.A. Barve. Heteroat. Chem. 17, 329
(2006).
4. C.J. Pedersen. J. Am. Chem. Soc. 89, 2495 (1970).
5. (a) H. Singh, L.D.S. Yadav, and B.K. Bhattacharya. J. Indian
Chem. Soc. 56, 1013 (1979); (b) N.C. Desai. Indian J. Chem.
Sect. B, 32, 343 (1993); (c) X.M. Feng, R. Chen, X.C. Liu,
and Z.Y. Zhang. Chin. J. Appl. Chem. 8, 28 (1991); (d) P.S.
Upadhyay, R.N. Vansdadia, and A.J. Baxi. Indian J. Chem.
Sect. B, 29, 793 (1990); (e) J. Mohan, G.S.R. Anjaneyula, S.
Sudhir, and D.R. Arora. J. Indian Chem. Soc. 66, 330 (1989);
(f) M.M. Ghorab, Sh. A.M. El-Sharief, Y.A. Ammar, and Sh. I.
Mohamed. Farmaco, 55, 354 (2000).
23. A.R. Katritzky, B.V. Rogovoy, V.Y. Vvedensky, K. Kovalenko,
P.J. Steel, V.I. Markov, and B. Forood. Synthesis, 6, 897
(2001).
24. (a) L. Ventura, J.A. Perez-Gonzales, and D. Ramon. FEMS
Microbiol. Lett. 149, 207 (1997); (b) G. Stemp and G. Burrell.
Eur. Patent Appl. EP399834, 28 November 1990; (c) J.W.
Clitherow. Eur. Patent Appl. EP367484, 9 May 1990.
25. (a) K. Wermann, M. Hartmann, and H.J. Bauer. Z. Chem. 24,
120 (1984); (b) M. Hartmann, H.J. Bauer, and K. Wermann.
Polym. Bull. 195 (1985); (c) J.L. Hilton. J. Agric. Food Chem.
17, 182 (1969); (c) S.A. Lang and B.L. Walworth. US. Patent
4-169-838, 2 October 1979.
26. (a) B. Mernari, H. Elattari, M. Traisnel, F. Bentiss, and M.
Lagrenee. Corros. Sci. 40, 391 (1998); (b) F. Bentiss, M.
Lagrenee, M. Traisnel, and J.C. Hornez. Corros. Sci. 41, 789
(1999).
6. Z.Y. Zhang, X.L. Chen, L. Wei, and Z.L. Ma. Chem. Res.
Chin. Univ. 7, 129 (1991).
7. Y. Naito, F. Akahoshi, S. Takeda, T. Okada, M. Kajii, H.
Nishimura, M. Sugiura, C. Fukaya, and Y. Kagitani. J. Med.
Chem. 39, 3019 (1996).
8. (a) A.S. Narang and R. Vince. J. Med. Chem. 20, 1684 (1977);
(b) E. De Clercq. J. Clin. Virol. 30, 115 (2004).
9. (a) X. Collin, A. Sauleau, and J. Coulon. Bioorg. Med. Chem.
Lett. 13, 2601 (2003); (b) B.S. Holla and B. Kalluraya. Indian
J. Chem. Sect. B, 27, 683 (1988); (c) S. Giri, H. Singh, L.D.S.
Yadav, and R.K. Khare. J. Indian Chem. Soc. 55, 168 (1978).
10. M. Kidwai, P. Sapra, P. Misra, R.K. Saxena, and M. Singh.
Bioorg. Med. Chem. 9, 217 (2001).
© 2007 NRC Canada

28
Can. J. Chem. Vol. 85, 2007
27. (a) B.S. Holla, B.M. Veerendra, K. Shivananda, and N.S.
Kumari. Indian J. Chem. Sect. B, 43, 2010 (2003); (b) B.S.
Holla and R. Gonsalves. Boll. Chem. Farm. 137, 467 (1998);
(c) B.S. Holla, R. Gonsalves, and S. Shenoy. Farmaco, 53, 574
(1998).
149 (1999); (i) F. Bentiss, M. Lagrenee, and D. Barbry. Tetra-
hedron Lett. 41, 1539 (2000).
30. P.-F. Xu, X.-W. Sun, L.-M. Zhang, and Z.-Y. Zhang. J. Chem.
Res. Synop. 2, 170 (1999).
31. (a) D.H. Busch. Rec. Chem. Prog. 25, 107 (1965); (b) D.H.
Busch and L.H. Lindoy. Preparative inorganic reactions.
Vol. 6. Edited by W.L. Jolly. Wiley-Interscience, New York.
1971.
32. For nomenclature please see: (a) W.H. Powell. Pure Appl.
Chem. 70, 1513 (1998); (b) H.A. Favre, D. Hellwinkel, W.H.
Powel, and H.A. Smith. Pure Appl. Chem. 74, 809 (2002).
33. A. Dubey, S. Kumar, and K. Naresh. Indian J. Heterocycl.
Chem. 3, 277 (1994).
28. G.W. Gokel, D.M. Dishang, and C.J. Dimond. J. Chem. Soc.
Chem. Commun. 1053 (1980).
29. (a) E. Muller and L. Herrdegen. J. Prackt. Chem. 102, 113
(1921); (b) F. Dallacker. Monatsh. Chem. 91, 294 (1960);
(c) W.W. Zajact, J.F. Siuda, M.J. Nolan, and T.M. Santossusso.
J. Org. Chem. 36, 3539 (1971); (d) M.O. Abdel-Rahman,
M.A.M. Kira, and N. Tolba. Tetrahedron Lett. 9, 3871 (1968);
(e) R.A. Bowie, M.D. Gardner, D.G. Neilson, K.M. Watson, S.
Mahmood, V.J. Ridd. J. Chem. Soc. Perkin Trans. 1, 2395
(1972); ( f ) J.F. Geldard and F.J. Lions. J. Org. Chem. 30, 318
(1965); (g) K. Matsukawa, J. Setsune, K. Takagi, and T. Kitao.
Dyes Pigm. 3, 307 (1982); (h) F. Bentiss, M. Lagrenee, M.
Traisnel, B. Mernari, and H. Elattari. J. Heterocycl. Chem. 36,
34. J.R. Reid and N.D. Heindel. J. Heterocycl. Chem. 13, 925
(1976).
35. CS Chem 3D Pro [computer program]. Version 5.
CambridgeSoft, Cambridge, Mass. 1999.
© 2007 NRC Canada