Synthesis of novel macrocyclic Di- and tetralactams containing triazole subunits

Article abstract of DOI:10.1002/hc.10191

The new macrocyclic di- and tetralactams 9, 15, and 16 were obtained in 16-24% yields by heating the appropriate bis-amines 7 or 8 with the corresponding bisaldehyde 5 or 14 in refluxing acetic acid under high-dilution conditions.

Full text of DOI:10.1002/hc.10191

Heteroatom Chemistry
Volume 14, Number 6, 2003
Synthesis of Novel Macrocyclic Di- and
Tetralactams Containing Triazole Subunits
Ahmed H. M. Elwahy, Ashraf A. Abbas, and Refaie M. Kassab
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Received 25 June 2002; revised 24 April 2003
amides are precursors in the preparation of aza-
ABSTRACT: The new macrocyclic di- and tetralac-
crown compounds, which are used for the synthe-
tams 9, 15, and 16 were obtained in 16–24%
sis of cryptands [15,16]. These have also been re-
yields by heating the appropriate bis-amines 7 or
ported as new catalysts in the highly regioselective
8 with the corresponding bisaldehyde 5 or 14
cleavage of epoxides with elemental halogens [17].
in refluxing acetic acid under high-dilution condi-
Moreover, heteronuclear metal ion receptors, which
ꢀ
C
tions.
2003 Wiley Periodicals, Inc. Heteroatom Chem
should possess two sets of binding sites, have re-
cently received considerable attention [18,19].
In continuation of our interest in the synthesis
of novel macrocyclic dilactams [20–25], we report
herein our efforts to develop new macrocyclic di-
and tetralactam, fused to two benzene and two 1,2,4-
triazole rings, which can be used for heteronuclear
binding with metal cations.
14:551–559, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10191
INTRODUCTION
Crown ethers were discovered by Pederson at
DuPont in 1967 [1]. Since then various structural
changes have been made to the basic crown ether
structures in an attempt to enhance the selectiv-
ity of these ligands and the stability of complexes
formed with both metal and organic cations. These
changes involve the substitution of ligand polyether
oxygen donor atoms by sulfur and/or nitrogen atoms
[2,3]. Other changes involve the insertion of aro-
matic and/or heterocyclic ring systems [4–10] into
the macrocycles. Heterocyclic groups provide rigid-
ity and are able, in some cases, in complexation
through their soft donor atoms. To improve the bind-
ing ability of macrocyclic receptors for alkali metal
cations, much attention has been paid to the devel-
opment of functional groups in the ring, e.g. incorpo-
ration of an amide linkage in a polyether macrocycle
has been reported to modify the binding proper-
ties of crown ether compounds [11–14]. Macrocyclic
RESULTS AND DISCUSSION
We demonstrate a new method to introduce the
amide groups into macrocycles employing the new
precursors 5 and 7 (as outlined in Scheme 1). Thus,
reaction of chloroacetyl chloride 1 with each of
1,2-diaminoethane, 1,3-diaminopropane, and 1,4-
diaminobutane afforded 70–80% of the correspond-
ing 1,ω-bis(chloroacetylamino)-alkanes 3a–c fol-
lowed the method described by Lin et al. [26] for
3a after some modifications. Reaction of the latter
with the potassium salt of salicylaldehyde in boil-
ing DMF for 5 min afforded the corresponding 1,ω-
bis(2-formylphenoxy-acetamido)alkanes 5a–c in 72–
78% yields. It is noteworthy to mention that Lindoy
et al. [27] reported the synthesis of 5a in 72% yield
by reacting 4 with 3a in DMF containing t-BuOK
at 80◦C overnight. Moreover, reaction of the ap-
propriate 4-amino-1,2,4-triazole-3(2H)-thiones 6a–c
[28] with 3a,b in ethanol/water mixture containing
Correspondence to: Ahmed H. M. Elwahy; e-mail: aelwahy@
chem-sci.cairo.eun.eg.
Contract grant sponsor: Professor Ahmed H. M. Elwahy.
2003 Wiley Periodicals, Inc.
c
ꢀ
551

552 Elwahy, Abbas, and Kassab
SCHEME 1
KOH gave the corresponding 1,ω-bis(4-amino-1,2,4-
triazole-3-ylsulphanylacetamido)-alkane 7a–f in 56–
67% yields. The exclusive formation of the latter is
in accordance with previous results [29–35], which
assure the preferential alkylation of 4-substituted-
1,2,4-triazolethiones on sulfur. The use of Schiff base
condensation of the appropriate bisaldehyde with
the corresponding bisamines under high dilution
conditions should then afford the target molecules
9, 15, and 16 as outlined in Schemes 2 and 3.
Thus, cyclocondensation of the bisaldehyde 5a
[X = (CH2)2] with the bisamines [29] [8a,b, n = 2]
in refluxing acetic acid under high-dilution condi-
tions afforded the corresponding macrocyclic Schiff
bases 9a,b in 18–24% yields. Elongation of the spacer
group of the bis-triazole part from ethylene to 1,3-
propylene (for example 8d) while holding the ethy-
lene spacer in the aldehyde part constant led to
the formation of the expected macrocyclic Schiff
base 9c in 22% yields. On the other hand, when
the spacer group in the aldehyde part (X) is elon-
gated to 1,3-propylene (e.g., 5b) while the spacer
group in the triazole part is ethylene or 1,4-butylene
(n = 2 or 4) (e.g., 8a,f) we did not isolate the cor-
responding macrocyclic Schiff base. Instead, com-
pound 10a,b, respectively, were formed in 35–39%
yields. Compound 10a was alternatively obtained
in 32% yield by cyclocondensation of 5c with 8a
in refluxing acetic acid. The structure proposed
for the new 1,ω-bis{4-[(benzo[b]furan-3-yl)amino]-
1,2,4-triazol-3-ylsulfanyl}alkanes 10a,b are consis-
1
tent with the data obtained from their IR, H NMR,
and mass spectroscopy.
The reaction proceeds via an initial formation of
the corresponding macrocyclic Schiff base 9, (X =
(CH2)3 or (CH2)4, n = 2 or 4) followed by attack of
the active methylene C-1 on the benzylideneamino C-
5 and subsequent aromatization with elimination of
the amide part. Protonation of the benzylideneamino
nitrogen N-6 under the acidic conditions enhanced
the electrophilicity of the carbon atom C-5 and facil-
itate the attack of the methylene group.

Synthesis of Novel Macrocyclic Di- and Tetralactams Containing Triazole Subunits 553
SCHEME 2
Sodium borohydride reduction of 9b,c in
The bisamines 7 were chosen as key intermedi-
ates and their reactivities toward condensation with
aromatic aldehydes were first investigated by reac-
tion with a series of aromatic aldehydes 12a–d in
refluxing acetic acid. As expected, the correspond-
ing bis(benzylideneamino) derivatives 13a–f were
formed in 50–80% yields. We then reacted each of
7b, 7c, and 7a with the appropriate bisaldehydes 14
[22] in refluxing acetic acid under high-dilution con-
ditions to give the macrocycles 15a–c, respectively,
methanol furnished 79 and 80% yields, respec-
tively, of the corresponding macrocyclic dilactams
11a,b. We now studied the synthesis of new
macrocyclic dilactams in which the amide link-
age are located in the triazol part (see Scheme 3).
The alteration of the position of the amide link-
age might modify the binding properties of these
macrocycles. The synthetic route is outlined in
Scheme 3.

554 Elwahy, Abbas, and Kassab
SCHEME 3
in 18–24% yields. Similarly, the macrocyclic tetralac-
tams 16a–c could be obtained in 16–22% yields by
reacting 7a,d with 5a,b in refluxing acetic acid un-
der high-dilution conditions. Attempts to get 15c and
16a by reacting 13e (Rꢁ = o-OH) with the appropri-
ate dihalo compounds in sodium ethoxide solutions
were unsuccessful.
This proves that the use of Schiff base condensa-
tion under high-dilution conditions is still the most
versatile procedure for the synthesis of the target
macrocycles 9, 15, and 16. Unfortunately, repeated
attempts to reduce compounds 15 or 16 to the cor-
responding azamacrocycles in methanolic solution
containing NaBH4 were unsuccessful. This may be

Synthesis of Novel Macrocyclic Di- and Tetralactams Containing Triazole Subunits 555
attributed to the insolubility of the macrocycle Schiff
base 15 and 16 in the reaction media.
Anal. for C22H24N2O6 (412.44). Calcd.: C, 64.07;
H, 5.86; N, 6.79. Found: C, 63.98; H, 5.91; N, 6.69.
In conclusion, we prepared a series of new benzo
substituted macrocyclic di- and tetraamides upon
which are fused two triazole rings and contain N, O,
and S as donor atoms. We could also introduce the
amide linkages in different positions in the macrocy-
cles. We expect this should modify the binding ability
of the new macrocycles. Study of the cation binding
properties of these macrocycles is still underway.
Synthesis of 7a–f, General Procedure
To a solution of potassium hydroxide (0.12 g,
20 mmol), ethanol/water mixture (1:1) (15 ml) was
added with stirring the triazole 6a–d (20 mmol). To
the formed potassium salt was added the appropri-
ate dichloro compound 3a–c (10 mmol). The mix-
ture was heated under reflux for 1 h during which
a colorless solid was precipitated. The product was
collected and recrystallized from acetic acid to give
colorless crystals of 7a–f.
EXPERIMENTAL
All melting points are uncorrected. IR (KBr) spectra
were recorded on a Perkin-Elmer 1430 spectropho-
tometer. NMR spectra were measured with a Var-
1,2-Bis(4-amino-5-phenyl-1,2,4-triazol-3-ylsulfan-
ylacetamido)ethane (7a). Compounds 6b and 3a
gave 7a (61%), mp 250◦C; IR: 3286.5 (NH), 1651
1
ian Gemini 200 spectrometer (200 MHz H NMR).
1
(C O) cm−1; H NMR (DMSO-d6) δ 3.16 (br, 4H,
Mass spectra were recorded on a GC MS-QP1000 EX
(70 eV) or MS 5 988 (15 eV) spectrometers. Elemen-
tal analyses were carried out at the Microanalytical
Centre, Cairo University, Egypt.
CH2NH), 3.92 (s, 4H, SCH2), 6.22 (s, 4H, NH2),
7.5–8.0 (m, 10H, ArH’s), 8.34 (br, 2H, NH).
Anal. for C22H24N10O2S2 (524.62). Calcd.: C,
50.37; H, 4.61; N, 26.70. Found: C, 50.32; H, 4.52;
N, 26.51.
Synthesis of 5a–c, General Procedure
1,2-Bis{4-amino-5-(p-methoxyphenyl)-1,2,4-triaz-
ol-3-ylsulfanylacetamido}ethane (7b). Compounds
6d and 3a gave 7b (55%), mp 228–230◦C; IR: 3278.8
(NH), 1651 (C O) cm−1; 1H NMR (DMSO-d6) δ 3.16
(br, 4H, CH2NH), 3.89 (s, 6H, OCH3), 3.92 (s, 4H,
SCH2), 6.18 (s, 4H, NH2), 7.06–7.98 (m, 8H, ArH’s),
8.33 (br, 2H, NH).
A solution of the potassium salt of salicylaldehyde 4
(20 mmol) and the appropriate dichloro compound
3a–c (10 mmol) in DMF (20 ml) was heated under
reflux for 5 min during which the potassium chlo-
ride was precipitated. The solution was then con-
centrated to small volume (ca. 2 ml) and then cold
water (ca. 10 ml) was added and the precipitate was
collected and recrystallized from acetic acid as pale
yellow crystals of 5a–c.
Anal. for C24H28N10O4S2 (584.68). Calcd.: C, 49.3;
H, 4.30; N, 23.96. Found: C, 49.42; H, 4.35; N, 23.90.
1,2-Bis(4-amino-5-benzyl-1,2,4-triazol-3-ylsulfan-
ylacetamido)ethane (7c). Compounds 6c and 3a
gave 7c (62%), mp 228–230◦C; IR: 3286.5 (NH),
1651.0 (C O) cm−1; 1H NMR (DMSO-d6) δ 3.1 (s, 4H,
CH2NH), 3.8 (s, 4H, SCH2), 4.07 (s, 4H, PhCH2), 5.95
(s, 4H, NH2), 7.28 (m, 10H, ArH’s), 8.25 (br, 2H, NH).
Anal. for C24H28N10O2S2 (552.68). Calcd.: C,
52.16; H, 5.11; N, 25.34. Found: C, 52.05; H, 5.11;
N, 25.2.
1,2-Bis(2-formylphenoxyacetamido)ethane (5a).
The potassium salt of 4 and 3a gave 5a (78%), mp
188–190◦C; (lit. [27] mp 188–189◦C).
1,3-Bis(2-formylphenoxyacetamido)propane (5b).
The potassium salt of 4 and 3b gave 5b (72%), mp
164–165◦C; IR: 3400 (NH), 1650 (C O) cm−1; 1H
NMR (CDCl3) δ 1.83 (t, 2H, J = 6 Hz, CH2CH2NH),
3.42 (q, 4H, J = 6 Hz, CH2NH), 4.57 (s, 4H, OCH2),
6.9–8.0 (m, 10H, ArH’s, NH), 10.28 (s, 2H, CHO).
Anal. for C21H22N2O6 (398.41). Calcd.: C, 63.31;
H, 5.57; N, 7.03. Found: C, 63.33; H, 5.51; N, 7.09.
1,3-Bis(4-amino-5-phenyl-1,2,4-triazol-3-ylsulfan-
ylacetamido)propane (7d). Compounds 6b and 3b
gave 7d (56%), mp 224–225◦C; IR: 3201.6 (NH),
1674.1 (C O) cm−1; 1H NMR (DMSO-d6) δ 1.55
(quintet, 2H, J = 6.8 Hz, CH2CH2NH), 3.1 (q, 4H,
J = 6.2 Hz, CH2NH), 3.9 (s, 4H, SCH2), 6.2 (s,
4H, NH2), 7.5–8.1 (m, 10H, ArH’s), 8.28 (t, 2H,
J = 5.2 Hz, NH).
1,4-Bis(2-formylphenoxyacetamido)butane (5c).
The potassium salt of 4 and 3c gave 5c (75%), mp
1
178◦C, IR: 3400 (NH), 1650 (C O) cm−1; H NMR
(CDCl3) δ 1.73 (br, 4H, CH2CH2NH), 3.4 (q, 4H,
J = 5.8 Hz, CH2NH), 4.58 (s, 4H, OCH2), 6.9–7.79
(m, 10H, ArH’s, NH), 10.16 (s, 2H, CHO).
Anal. for C23H26N10O2S2 (538.65). Calcd.: C,
51.29; H, 4.86; N, 26.00. Found: C, 51.11; H, 4.65;
N, 25.85.

556 Elwahy, Abbas, and Kassab
1,3-Bis[4-amino-5-(p-methoxyphenyl)-1,2,4-tria-
3,28-Diphenyl-15,16,32,33-tetrahydro-12H,19H-
bis[1,2,4]triazolo[4,3-f:3,4-l]dibenzo[b,p][1,18]dioxa-
[8,11]dithia[5,6,13,14,21,24]hexaazahexacosine-13,
18-(14H,17H)dione (9b). Reaction of 5a and 8b
gave crude 9b, which was recrystallized from acetic
acid/ethanol as colorless crystals (18%), mp 273◦C;
1H NMR (DMSO-d6) δ 3.32 (s, 4H, CH2NH), 3.69
(s, 4H, SCH2), 4.62 (s, 4H, OCH2), 7.1–8.02 (m, 8H,
ArH’s), 8.25 (br, 2H, NH), 9.39 (s, 2H, CH N).
Anal. for C38H34N10O4S2 (758.88). Calcd.: C,
60.14; H, 4.52; N, 18.46. Found: C, 59.93; H, 4.55;
N, 18.6.
zol-3-ylsulphanylacetamido]propane
(7e). Com-
pounds 6d and 3b gave 7e (52%), mp 238◦C; IR:
3286.5 (NH), 1643.2 (C O) cm−1; 1H NMR (DMSO-
d6) δ 1.54 (quintet, 2H, J = 6 Hz, CH2CH2NH), 3.1
(q, 4H, J = 5.8 Hz, CH2NH), 3.83 (s, 6H, OCH3),
3.88 (s, 4H, SCH2), 6.16 (s, 4H, NH2), 7.1–7.9 (m,
8H, ArH’s), 8.26 (br, 2H, NH).
Anal. for C25H30N10O4S2 (598.71). Calcd.: C,
50.15; H, 5.05; N, 23.39. Found: C, 50.20; H, 5.60;
N, 23.20.
1,3-Bis(4-amino-5-benzyl-1,2,4-triazol-3-ylsulf-
anylacetamido)propane (7f). Compounds 6c and
3b gave 7f (67%), mp 178–180◦C; IR: 3309 (NH),
1651.0 (C O) cm−1; 1H NMR (DMSO-d6) δ 1.48
(quintet, 2H, J = 4.8 Hz, CH2CH2NH), 3.0 (q, 4H,
J = 5.6 Hz, CH2NH), 3.76 (s, 4H, SCH2), 4.03 (s, 4H,
PhCH2), 5.89 (s, 4H, NH2), 7.29 (m, 10H, ArH’s), 8.2
(t, 2H, J = 5.6 Hz, NH).
3,28-Diphenyl-15,16,32,33-tetrahydro-12H,19H,
34H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,q][1,19]-
dioxa[8,12]dithia[5,6,14,15,22,25]hexaazaheptacosine-
13,18-(14H,17H)dione (9c). Reaction of 5a and 8d
gave crude 9d, which was recrystallized from acetic
acid as colorless crystals (24%), mp 230–232◦C; MS:
m/z 772.45 (M+, 66.7%), 700 (86.7%), 642 (100%),
531 (60%), 496 (15%), 359 (66.7%), 203 (93.3%),
Anal. for C25H30N10O2S2 (566.7). Calcd.: C, 52.99;
H, 5.34; N, 24.72. Found: C, 53.00; H, 5.25; N, 24.60.
1
145 (86.7%), H NMR (DMSO-d6) δ 2.29 (br, 2H, S,
CH2CH2), 3.28 (br, 4H, CH2NH), 3.4 (s, 4H, SCH2),
4.62 (s, 4H, OCH2), 7.15–8.01 (m, 18H, ArH’s), 8.21
(br, 2H, NH), 9.45 (s, 2H, CH N).
Anal. for C39H36N10O4S2 (772.91). Calcd.: C,
60.61; H, 4.69; N, 18.12. Found: C, 60.42; H, 4.46;
N, 17.99.
Synthesis of Macrocyclic Schiff Bases 9a–c,
15a–c, and 16a–c, 1,ω-Bis{(benzofuranyl)-
amino-1,2,4-triazol-3-ylsulfanylacetamido}-
alkanes 10a,b, and Bis-Schiff Bases 13a–f,
General Procedure
To a solution of each of the appropriate bisalde-
hyde 5a,c or 14b,c (10 mmol) or the aromatic alde-
hyde 12a–d (20 mmol) in glacial acetic acid (50 ml)
was added a solution of the bisamine 7a–f or 8a–f
(10 mmol) in glacial acetic acid (50 ml). The reac-
tion mixture was then heated under reflux for 2 h.
The solution was concentrated to small volume (ca.
2 ml). Then cold water (ca. 15 ml) was added and the
precipitate was collected and recrystallized from the
proper solvent to give crystals of 9a–c, 10a,b, 13a–f,
15a–c, and 16a–c.
1,2-Bis{4-(benzo[b]furan-3-yl)amino-1,2,4-tria-
zol-3-ylsulfanylacetamido}ethane (10a). Reaction
of 5b (or 5c) and 8a gave crude 10a, which was
recrystallized from acetic acid as colorless crystals
(35%), mp 257◦C; IR: 3165.0 (NH); MS: m/z 490 (M+,
37.5%), 443 (62.5%), 453 (100%), 302 (41.6%), 229
1
(75%), 119 (75%), 61 (66.6%); H NMR (DMSO-d6)
δ 3.65 (s, 4H, SCH2), 6.9–7.8 (m, 8H, ArH’s), 9.1 (s,
2H, Benzofuran-H), 9.44 (s, 2H, triazole-H), 10.6
(br, 2H, NH).
Anal. for C22H18N8O2S2 (490.0). Calcd.: C, 53.86;
H, 3.70; N, 22.84. Found: C, 53.65; H, 3.50; N, 23.10.
15,16,32,33-Tetrahydro-12H,19H-bis[1,2,4]tria-
zolo[4,3-f:3,4-l]dibenzo[b,p][1,18]dioxa[8,11]dithia-
[5,6,13,14,21,24]hexaazahexacosine-13,18-(14H,17H)-
dione (9a). Reaction of 5a and 8a gave crude 9a,
which was recrystallized from ethanol as colorless
crystals (22%), mp 250◦C; MS: m/z 606 (M+, 68.8%),
537 (62.5%), 405 (68.8%), 365 (68.8%), 213 (100%);
192 (68.8%), 73 (87.5%); 1H NMR (DMSO-d6) δ
3.2 (br, 4H CH2NH), 3.6 (s, 4H, SCH2), 4.7 (s, 4H,
OCH2), 6.8–7.7 (m, 8H, ArH’s), 8.24 (s, 2H, NH),
8.75 (s, 2H, CH N), 9.48 (s, 2H, triazole-H).
Anal. for C26H26N10O4S2 (606.68). Calcd.: C,
51.47; H, 4.32; N, 23.09. Found: C, 51.43; H, 4.51;
N, 22.85.
1,4-Bis{4-(benzo[b]furan-3-yl)amino-5-benzyl-1,
2,4-triazol-3-ylsulfanylacetamido}butane (10b). Re-
action of 5b and 8f gave crude 10b, which was
recrystallized from acetic acid as colorless crystals
(39%), mp 250◦C; IR: 3128 (NH); MS: m/z 698.4 (M+,
22.5%), 569 (22.5%), 389 (32.5%), 326 (30%), 287
1
(37.5%), 118 (77%), 60 (100%); H NMR (CDCl3) δ
1.72 (t, 4H, CH2CH2S), 3.13 (br, 4H, SCH2), 4.19 (s,
4H, PhCH2), 6.9–7.8 (m, 18H, ArH’s), 8.87 (s, 2H,
Benzofuran-H), 10.5 (br, 2H, NH).
Anal. for C38H34N4O2S2 (698.87). Calcd.: C, 65.3;
H, 4.90; N, 16.03. Found: C, 65.20; H, 4.67; N, 16.00.

Synthesis of Novel Macrocyclic Di- and Tetralactams Containing Triazole Subunits 557
1674.1 (C O) cm−1; 1H NMR (DMSO-d6) δ 1.55
(quintet, 2H, J = 2.4 Hz, CH2CH2NH), 3.04 (q, 4H,
J = 6.4 Hz, CH2NH), 3.99 (s, 4H, SCH2), 6.9–7.90
(m, 18H, ArH’s), 8.27 (br, 2H, NH), 8.98 (s, 2H,
CH N), 10.3 (s, 2H, OH).
1,2-Bis(4-benzyledineamino-5-phenyl-1,2,4-tria-
zol-3-ylsulfanylacetamino)ethane (13a). Reaction
of 12a and 7a gave crude 13a, which was recrystal-
lized from acetic acid as colorless crystals (70%), mp
228–230◦C; IR: 3332.8 (NH), 1651.0 (C O) cm−1; 1H
NMR (DMSO-d6) δ 3.14 (br, 4H: CH2NH), 3.97 (s,
4H, SCH2), 7.4–7.94 (m, 20H, ArH’s), 8.31 (br, 2H,
NH), 8.9 (s, 2H, CH N).
Anal. for C37H34N10O4S2 (746.87). Calcd.: C, 59.5;
H, 4.59; N, 18.75. Found: C, 59.25; H, 4.3; N, 18.6.
Anal. for C36H32N10O2S2 (700.8). Calcd.: C, 61.7;
H, 4.6; N, 19.94. Found: C, 61.56; H, 4.43; N, 19.79.
1,3-Bis{4-(p-chloro)benzylideneamino-5-phenyl-1,
2,4-triazol-3-ylsulfanylacetamino)propane
(13f).
Reaction of 12b and 7d gave crude 13f, which
was recrystallized from acetic acid as colorless
crystals (75%), mp 202–224◦C; IR: 3240.2 (NH),
1658.7 (C O) cm−1; 1H NMR (CDCl3) δ 1.7 (br,
2H, CH2CH2NH), 3.40 (q, 4H, CH2NH), 4.02 (s, 4H,
SCH2), 7.26–7.83 (m, 18H, ArH’s), 8.38 (br, 2H, NH),
8.55 (s, 2H, CH N).
Anal. for C37H32Cl2N10O2S2 (783.76). Calcd.: C,
56.7; H. 4.12; N, 17.69. Found: C, 56.6; H, 4.30; N,
17.69.
1,2-Bis{4-(p-methoxy)benzylideneamino-5-phenyl-
1,2,4-triazol-3-ylsulfanylacetamino}ethane
(13b).
Reaction of 12c and 7a gave crude 13b, which was
recrystallized from ethanol/acetic acid as colorless
crystals (75%), mp 232◦C; IR: 3348.2 (NH), 1658.7
1
(C O) cm−1; H NMR (DMSO-d6) δ 3.16 (br, 4H,
CH2NH), 3.87 (s, 6H, OCH2), 3.96 (s, 4H, SCH2),
7.11–7.90 (m, 18H, ArH’s), 8.29 (br, 2H, NH), 8.78
(s, 2H, CH N).
Anal. for C38H36N10O4S2 (760.9). Calcd.: C, 59.98;
H, 4.77; N, 18.41. Found: C, 59.88; H, 4.59; N, 18.23.
3,23-Di(p-methoxyphenyl)-12,13,30,31-tetrahydro-
14H,27H,34H-bis[1,2,4]triazolo-[4,3-f:3,4-r]dibenzo-
[b,v][1,24]dioxa[8,17]dithia[5,6,11,14,19,20]hexaaza-
1,2-Bis{4-(o-hydroxy)benzylideneamino-5-(p-meth-
oxy)phenyl-1,2,4-triazol-3-yl-sulfanylacetamino}-
ethane (13c). Reaction of 12d and 7b gave crude
13c, which was recrystallized from acetic acid as
colorless crystals (80%), mp 220–222◦C; IR: 3220
heptacosine-28,33-(29H,32H)dione
(15a). Reac-
tion of 14b and 7b gave crude 15a, which was
recrystallized from DMF as colorless crystals (21%),
mp 250–252◦C; MS: m/z 832.75 (M+, 64.3%), 826
(71.4%), 709 (100%), 581 (78.6%), 429 (85.7%),
260 (85.7%), 163 (78.5%); IR: 3286.5 (NH), 1674.1
1
(NH), 1651.0 (C O) cm−1; H NMR (DMSO-d6) δ
3.16 (br, 4H, CH2NH), 3.87 (s, 6H, OCH3), 3.96 (s,
4H, SCH2), 6.98–7.89 (m, 16H, ArH’s), 8.33 (br, 2H,
NH), 8.97 (s, 2H, CH N), 8.97 (s, 2H, OH).
Anal. for C38H36N10O6O6S2 (792.8). Calcd.: C,
57.56; H, 4.58; N, 17.67. Found: C, 57.52; H, 4.51;
N, 17.49.
1
(C O) cm−1; H NMR (DMSO-d6) δ 3.08 (br, 2H,
OCH2CH2), 3.2 (br, 4H, CH2NH), 3.71 (s, 6H, OCH3),
3.91 (s, 2H, SCH2), 4.10 (br, 4H, OCH2), 6.9–7.83 (m,
16H, ArH’s), 8.34 (br, 2H, NH), 8.94 (s, 2H, CH N).
Anal. for C41H40N10O6S2 (832.96). Calcd.: C,
59.12; H, 4.84; N, 16.82. Found: C, 58.89; H, 4.60;
N, 16.58.
1,3-Bis{4-(p-chloro)benzylideneamino-5-(p-meth-
oxy)phenyl-1 ,2,4-triazol-3-ylsulfanylacetamino}-
propane (13d). Reaction of 12b and 7e gave crude
13d, which was recrystallized from acetic acid as
colorless crystals (76%), mp 218–220◦C; IR: 3220
3,23-Dibenzyl-12,13,30,31-tetrahydro-14H,27H,
34H-bis[1,2,4]triazolo[4,3-f:3,4-r]dibenzo[b,v][1,24]
dioxa[8,17]dithia[5,6 ,11,14,19,20]hexaazahepta-
cosine-28,33-(29H,32H)dione (15b). Reaction of
14b and 7c gave crude 15b, which was recrystal-
lized from dioxane/acetic acid as colorless crystals
(24%), mp 242–244◦C; MS: m/z 801 (M+, 52.9%),
668 (82.3%), 488 (70.6%), 394 (82.3%), 277 (100%),
131 (82.3); IR: 3201.6 (NH), 1674.1 (C O) cm−1; 1H
NMR (DMSO-d6) δ 2.12 (br, 2H, OCH2CH2), 3.1 (br,
4H, CH2NH), 3.89 (s, 4H, SCH2), 4.12 (s, 4H, OCH2),
4.17 (s, 4H, CH2Ph), 7.1–7.81 (m, 18H, ArH’s), 8.26
(br, 2H, NH), 8.94 (s, 2H, CH N).
1
(NH), 1651.0 (C O) cm−1; H NMR (DMSO-d6) δ
1.53 (quintet, 2H, J = 1.2 Hz, CH2CH2NH), 3.04 (q,
4H, J = 5.8 Hz, CH2NH), 3.8 (s, 6H, OCH3), 3.94 (s,
4H, SCH2), 7.04–7.97 (m, 16H, ArH’s), 8.21 (br, 2H,
NH), 8.92 (s, 2H, CH N).
Anal. for C39H36Cl2N10O4S2 (843). Calcd.: C,
55.51; H, 4.30; N, 16.6. Found: C, 55.27; H, 4.52; N,
16.4.
1,3-Bis{4-(o-hydroxy)benzylideneamino-5-phenyl-
1,2,4-triazol-3-ylsulfanylacetamino}propane (13e).
Reaction of 12d and 7d gave crude 13e, which
was recrystallized from ethanol/acetic acid as col-
orless crystals (50%), mp 210◦C; IR: 3317 (NH),
Anal. for C41H40N10O4S2 (800.96). Calcd.: C,
61.48; H, 5.03; N, 17.49. Found: C, 61.6; H, 5.1; N,
17.2.

558 Elwahy, Abbas, and Kassab
3,24-Diphenyl-12,13,14,15,31,32-hexahydro-28H,
35H-bis[1,2,4]triazolo[4,3-f:3,4-r]dibenzo[b,v][1,24]
dioxa[8,17]dithia[5,6,11,14 ,19 ,20]hexaazaoctaa-
cosine-29,34-(30H,33H)dione (15c). Reaction of
14c and 7a gave crude 15c, which was recrystallized
from acetic acid as colorless crystals (18%), mp
250◦C; MS: m/z 787 (M+, 80%), 584 (60%), 484
(86.6%), 371 (100%), 303 (86.6%), 204 (93.3%); IR:
3271 (NH), 1666.4 (C O cm−1; 1H NMR (DMSO-d6)
δ 1.73 (br, 4H, OCH2CH2), 3.2 (s, 4H, CH2NH), 3.9 (s,
4H, SCH2), 4.06 (s, 4H, OCH2), 6.97–7.88 (m, 18H,
ArH’s), 8.28 (br, 2H, NH), 8.91 (s, 2H, CH N).
Anal. for C40H38N10O4S2 (786.93). Calcd.: C,
61.05; H, 4.87; N, 17.80. Found: C, 60.92; H, 4.91;
N, 17.75.
3,28-Diphenyl-15,16,35,36-tetrahydro-12H,19H,
32H,37H,40H-bis[1,2,4]triazolo[4,3-f:3,4-s]dibenzo-
[b,w][1,25]dioxa[8,18]dithia[5,6,11,15,20,21,28,31]-
octaazatritricontin-13,18,33,39-(14H,17H,34H,38H)-
tetraone (16c). Reaction of 5a and 7d gave crude
16c, which was recrystallized from dioxane as pale
yellow crystals (16%), mp 267–269◦C; MS (EI): m/z
886 (M+, 2.74%), 672 (2.60%), 501 (3.23%), 201
(21.1%), 178 (100%), 145 (15.9%); IR: 3271 (NH),
1
1666.4 (C O) cm−1; H NMR (DMSO-d6) δ 1.5 (br,
2H, CH2CH2NH), 3.05 (br, 4H, CH2NH), 3.24 (br,
4H, CH2NHCOCH2O), 3.97 (s, 4H, CH2NHCOCH2S),
4.55 (s, 4H, OCH2), 7.1–8.05 (m, 18H, ArH’s),
8.19 (br, 2H, NH), 8.32 (br, 2H, NH), 9.40 (s, 2H,
CH N).
Anal. for C43H42N12O6S2 (887.01). Calcd.: C,
58.23; H, 4.77; N, 18.95. Found: C, 58.23; H, 4.71;
N, 18.84.
3,28-Diphenyl-15,16,35,36-tetrahydro-12H,19H,
32H,39H-bis[1,2,4]triazolo[4,3-f:3,4-r]dibenzo[b,v]-
[1,24 ]dioxa[8,17]dithia[5,6,11,14,19,20,27,30]octa-
azadotricontin-13 ,18 ,33 ,38 - (14H,17H,34H,37H)-
tetraone (16a). Reaction of 5a and 7a gave crude
16a, which was recrystallized from dioxane as pale
yellow crystals (18%), mp 273–275◦C; MS: m/z (FD)
872 (M+, 100%), IR: 3278.8 (NH), 1666.4 (C O)
cm−1; 1H NMR (CDCl3) δ 3.11 (br, 4H, CH2NH), 3.12
(br, 4H, CH2NH), 3.92 (s, 4H, SCH2), 4.54 (s, 4H,
OCH2), 7.1–8.04 (m, 18H, ArH’s), 8.19 (br, 2H, NH),
8.31 (br, 2H, NH), 9.37 (s, 2H, CH N).
Action of Sodium Borohydride on 9b,d,
General Procedure
To a stirred hot (40–50◦C) solution of each of 9b,d
(10 mmol) in methanol (10 ml) was added sodium
borohydride (0.4 g, 13 mmol) over a period of 15 min.
The reaction mixture was heated under reflux for 1 h.
The solvent was then removed in vacuo and the re-
maining solid was collected, washed with water, and
crystallized from the proper solvent to give colorless
crystals of 11a,b.
Anal. for C42H40N12O6S2 (872.98). Calcd.: C,
57.79; H, 4.62; N, 19.25. Found: C, 57.61; H, 4.8; N,
19.00.
3,28-Diphenyl-5,6,15,16,25,26,32,33-octahydro-
12H,19H-bis[1,2,4]triazolo[4,3-f:3,4-l]dibenzo[b,p]-
[1,18]dioxa[8,11]dithia[5,6,13,14,21,24]hexaazahexa-
3,29-Diphenyl-15,16,36,37-tetrahydro-12H,17H,
20H,33H,40H-bis[1,2,4]triazolo[4,3-f:3,4-r]dibenzo-
[b,v][1,24]dioxa[8,17]dithia[5,6,11,14,19,20,27,31]-
octaazatritricontin-13,19,34,39-(14H,18H,35H,38H)-
tetraone (16b). Reaction of 5b and 7a gave crude
16b, which was recrystallized from dioxane as
pale yellow crystals (20%), mp 250◦C; MS (EI): m/z
886 (12%), 540 (22.2%), 300 (18.5%), 198 (100%),
81 (57.41%); IR: 3278.8 (NH), 1651 (C O) cm−1;
1H NMR (DMSO-d6) δ 1.4 (br, 2H, CH2CH2NH),
3.09 (br, 8H, 2CH2NH), 3.86 (s, 4H, SCH2), 4.48
(s, 4H, OCH2), 7.1–8.26 (m, 18H, ArH’s, 2NH),
9.42 (s, 2H, CH N); 13C NMR (DMSO-d6) (APT) δ
28.55, 34.27, 36.18, 37.91, 66.69 (CH2’S), 119.06,
125.60, 145.87, 156.73, 156.77, 166.07, 166.25
(ArC’s, Triazole C’s); 112.792, 121.215, 126.967,
127.271, 129.183, 134.472, 163.332, 164.212 (ArCH’s,
CH N).
cosine-13,18-(14H,17H)dione
(11a). Compound
9b gave crude 11a, which was recrystallized from
dil. acetic acid as colorless crystals (79%), mp
251–253◦C; IR: 3278.8 (NH), 1666.4 (C O) cm−1;
1H NMR (DMSO-d6) δ 3.32 (br, 4H, CH2NH), 3.55
(s, 4H, SCH2), 3.89 (br, 2H, NHCH2), 4.17 (br, 4H,
ArCH2), 4.42 (s, 4H, OCH2), 6.79–7.94 (m, 20H,
ArH’s, NHC O).
Anal. for C38H38N10O2S2 (762.91). Calcd.: C,
59.83; H, 5.02; N, 18.36. Found: C, 59.75; H, 4.92;
N, 18.05.
3,28-Diphenyl-5,6,15,16,25,26,32,33-octahydro-
12H,19H,34H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo-
[b,q][1,19]dioxa[8,12]dithia[5,6,14,15,22,25]hexaaza-
heptacosine-13,18-(14H,17H)dione
(11b). Com-
pound 9d gave crude 11b, which was recrystallized
from acetic acid as colorless crystals (18%), mp
252◦C; 1H NMR (DMSO-d6) δ 1.64 (br, 2H, SCH2CH2),
3.16 (q, 4H, J = 2.8 Hz, CH2NH), 3.47 (s, 4H, SCH2),
4.13 (d, 4H, J = 5 Hz, ArCH2), 4.45 (s, 4H, OCH2),
Anal. for C43H40N12O6S2 (887.01). Calcd.: C,
58.23; H, 4.77; N, 18.95. Found: C, 58.51; H, 4.81;
N, 18.70.

Synthesis of Novel Macrocyclic Di- and Tetralactams Containing Triazole Subunits 559
[16] Dietrich, B. In Comprehensive Supramolecular
4.62 (t, 2H, J = 5.4 Hz, NHCH2), 6.8–7.94 (m, 20H,
Chemistry; Gokel, G. W. (Ed.); Pergamon: New York,
1996; p. 153.
[17] Sharghi, H.; Massah, A. R.; Eshgi, H.; Niknam, K. J
Org Chem 1998, 63, 1455.
[18] Bordunov, A. V.; Bradshaw, J. S.; Pastushok, V. N.;
Zhang, X. X.; Kou, X.; Dalley, N. K.; Yang, Z.; Savage,
P. B.; Izatt, R. M. Tetrahedron 1997, 53, 17595.
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ArH’s, NHC O).
Anal. for C39H40N10O4S2 (776.96). Calcd.: C,
60.29; H, 5.19; N, 18.03. Found: C, 60.15; H, 5.00;
N, 17.95.
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