Synthesis of novel lariat azathia crown macrocycles containing two triazole rings and bis crown macrocycles containing four triazole rings

Article abstract of DOI:10.1016/j.tet.2003.12.005

The 13-hydroxy macrocycles 7a-d were prepared in 40-50% yields by the condensation of 1,ω-bis(4-amino-1,2,4-triazol-3-ylsulfany)alkanes 2a-d with 1,3-bis(2-formyphenoxy)-2-propanol (9). Acylation of 7a-d with 2-chloroacetylchloride gave the corresponding

Full text of DOI:10.1016/j.tet.2003.12.005

Tetrahedron 60 (2004) 1541–1548
Synthesis of novel lariat azathia crown macrocycles containing
two triazole rings and bis crown macrocycles containing four
triazole rings
*
Ashraf A. Abbas
Department of Chemistry, Faculty of Science, Cairo University, 12613 Giza, Egypt
Received 4 September 2003; revised 13 November 2003; accepted 4 December 2003
Abstract—The 13-hydroxy macrocycles 7a-d were prepared in 40–50% yields by the condensation of 1,v-bis(4-amino-1,2,4-triazol-3-
ylsulfany)alkanes 2a-d with 1,3-bis(2-formyphenoxy)-2-propanol (9). Acylation of 7a-d with 2-chloroacetylchloride gave the corresponding
esters 11a,b. Amination of 11a,b with different amines in acetone furnished exclusively the target lariat macrocycles 12a,b and 13 in 60–
70% yields. Reaction of 2 equiv. of the macrocycles 11a,b with 1 equiv. of piperazine afforded the novel bis macrocyles 14a,b in 50–60%
yields. Reduction of 7a-d with NaBH4 afforded the corresponding 13-hydroxyazathia crown ethers 15a-d in 65–70% yields.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
stronger complexes with particular metal ion than the
corresponding monocrown ethers, where it forms
complexes with two crown moieties per cation: ‘sandwich
complexes’ that improve the stability of the complex
especially when the cation is too large to fit the cavity of
the crown ethers.16,17
A progressive interest was directed in the last few years to
the chemistry of the crown ethers containing heterocyclic
rings in the system. These macrocycles were found to
exhibit interesting host-guest complexation characteristic.1,2
Incorporation of heterocyclic moiety within the cavity of the
crown ligands were also provides rigidity and are able to
participate in complexation through their soft donor atoms,
for example, macrocyclic ethers with pyridine and other
nitrogen containing heterocyclic subunits were reported to
form strong and selective interactions with various charged
and neutral guest molecules.3–7 Moreover, lariat crown
ethers which bear side-chain containing donor atoms
possess unique cation binding properties compared with
the parent crown ether containing no extra donor sites.8,9
Also, as efficient organic ligands lariat crown ethers meet
the requirement of rapid, strong and three-dimensional
cation binding and can mimic the properties of natural
ionophores.10 Furthermore, during the last decades con-
siderable attention has been devoted to the chemistry of bis
crown ethers for their applications in various area
especially in ion-selective electrodes.11–15 Moreover, bis
crown ethers show extra binding properties than the
monocrown ethers, where by the cooperatives action of
two adjacent crown units, bis(crown ethers) tend to form
In connection with these findings and in continuation of our
interest in synthesizing macrocyclic crown compounds
containing heterocycles moieties,18–20 and bis macro-
cyles.21 We report here the synthesis of a series of 22–23
membered macrocycles fused with two triazole rings
containing N, O and S inside the macrocyclic ring as
donor atoms and possess pendant hydroxy group as
precursor for the synthesis of lariat macrocycles. In an
attempt to enhance the selectivity of these ligands and the
stability of the complexes formed with both metals and
organic cations. This project also describes the synthesis of
the novel lariat macrocycles containing N,N-diethyamino,
piperidino and morpholinoacetoxy moieties as side arm
containing O and N as donor atoms and the corresponding
bis macrocycles.
2. Results and discussion
Several methods have been described for the reaction of
epichlorohydrin with bisphenols as precursor for the
synthesis of crown ethers with pendant hydroxy group
attached to the crown ether ring.22,23 Heo et al22 reported the
synthesis of hydroxy crown ethers in a good yield 39–60%
by the reaction of epichlorohydrin with the appropriate
Keywords: Triazole; Lariat azathia crown macrocycles; Bis crown
macrocycles.
*
Tel.: þ20-23252831; fax: þ20-25685799;
e-mail addresses: ashraf@chem-sci.cairo.eun.eg;
ashrafaa50@hotmail.com
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.005

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A. A. Abbas / Tetrahedron 60 (2004) 1541–1548
diphenols in basic aqueous media. This project describes the
synthesis of novel 13-hydroxy aza-thia crown ethers
containing two triazole rings as subcyclic unit as shown in
Schemes 1–3.
Two strategies were attempted for the synthesis of the 13-
hydroxy macrocycles 7a-d. In the first one (Scheme 1), we
applied a similar approach to that described by Heo et al.22
Thus, condensation of 1,v-bis(4-amino-1,2,4-triazol-3-
Scheme 1.

A. A. Abbas / Tetrahedron 60 (2004) 1541–1548
1543
Scheme 2.
ylsulfany)alkanes 2a-d with salicylaldehyde (3) in acetic
acid gave the corresponding 1,v-bis(4-o-hydroxybenzyl-
ideneamino-5-aryl-1,2,4-triazol-3-ylsulfany)alkanes 4a,b in
70–75% yield. Reaction of the latter compounds with
methanolic potassiun hydroxide gave the corresponding bis
potassium salt 5a,b. Unfortunately, reaction of the bis
potassium salts 5a,b with epichlorohydrin (6) following the
method described by Heo et al.22 gave only 2% of the target

1544
A. A. Abbas / Tetrahedron 60 (2004) 1541–1548
Scheme 3.
macrocycles 7c,d. This may be attributed for the extent of
the spacing between the terminal bis hydroxy groups. In
anticipation of the low yield of the macrocycles 7c,d we
then applied the second strategy as outlined in Scheme 1.
Thus, reactions of the potassium salt 8 [obtained upon
treatment of salicyaldehyde (3) with methanolic potassium
hydroxide solution] with epichlorohydrin (6) in aqueous
media furnished the corresponding 1,3-bis(2-formy-
phenoxy)-2-propanol (9) in a good yield (65%). Conden-
sation of 9 with the appropriate bis(aminotriazoles) 2a-d in
acetic acid under the high dilution condition which often
used as the most versatile procedure used for the synthesis
of the macrocycles24 gave 50–60% of the target 13-hydroxy
macrocycles Schiff bases 7a-d. Having now available the
13-hydroxy macrocycles Schiff bases 7a-d which stimu-
lated the author to study their transformation into the first
lariat aza-thia crown ethers containing two triazole rings as
sub-cyclic units and their bis macrocycles containing two
macrocyclic units connected by flexible bridge having
piperazine moiety as shown in Schemes 2 and 3.
reaction of compounds 11a,b with a series of secondary
amines namely, N,N-diethylamine, piperidine and morpho-
line in refluxing acetone for 2 h furnished 50–60% yields of
the corresponding lariat macrocycles 12a,b and 13.
Similarly, the synthesis of the novel bis macrocycles
14a,b was performed efficiently through the amination of
esters 11a,b with piperazine as shown in Scheme 2. Thus,
reaction of 2 equiv. of chloroacetoxy macrocycles 11a,b
with 1 equiv. of piperazine in acetone gave the correspond-
ing 1,4-bis[13-acetoxy macrocycles] piperazine derivatives
14a,b in 50–55% yield. In order to increase the donor
characters of the N-benzalimino and subsequently the cation
binding ability of the macrocycle Schiff bases 7a-d we
successfully prepare the 13-hydroxy azathia crown ethers
15a-d through the reduction of 7a-d as shown in Scheme 3.
Reduction of the macrocycles 7a-d with NaBH4 in methanol
afforded the corresponding macrocycles 15a-d in 65–72%
yield. It is important to mention that all attempts for
reduction of 12b did not afford the corresponding lariat
macrocyclic 16 but gave instead the 13-hydroxy macro-
cyclic 15d in 65% yield which may be attributed to the basic
hydrolysis of the ester group of compound 13b in the
reaction medium.
Thus, acylation the hydroxy group of compounds 7a,d with
2-chloroacetylchloride (10) in DMF afforded the corre-
sponding 13-chloroacetoxy macrocycles 11a,b in 65–70%
yields. The latter compound could be used as a key
intermediate for the synthesis of lariat macrocycles 12a,b
and 13 containing different donor atoms in the side-arm. So,
In conclusion of this project we successfully prepared
macrocycles having pendant hydroxy group as a key
intermediate for the synthesis of novel lariat macrocycles

A. A. Abbas / Tetrahedron 60 (2004) 1541–1548
1545
containing a strong donor group as a supporting ligand at the
end of the side-arm and bis macrocycles possess two crown
units connected by flexible bridge. We believe that by
development of the foregoing synthetic methodology lariat
macrocyles and bis macrocycles with a wide variety of side-
chains with different lengths and donor atoms aiming to
improve the cation binding ability and the stability of the
ligands metal complexes could be easily prepared.
solution of KOH (1.14 g, 10 mmol) in methanol (10 ml) was
added each of salicylaldehyde (3) (10 mmol) or bis(phenols)
4a,b (5 mmol). The mixture was stirred at room temperature
for 10 min. The solvent was then removed in vacuo. The
remaining solid was triturated with dry ether, collected,
dried, and used in the next step without further purification.
3.1.5. Reaction of epichlorohydrin with phenolic com-
pounds for preparation of compounds 9 and 7c,d.
General procedure (A). Potassium salts 8 (20 mmol) or
5a,b (10 mmol) were dissolved in boiling water (20 ml).
The solution is cool to 50 8C, epichlorohydrin (10 mmol)
was added drop by drop with stirring over a period of 3 h.
The reaction mixture is stirred at 50 8C for an additional 4 h
and then cooled to room temperature to give 9 and 7c,d.
3. Experimental
3.1. General
All melting points are uncorrected. Compounds prepared by
different procedures were characterized by mixed melting
points and IR. IR spectra (KBr) were recorded on Bruker
Vector 22 spectrophotometer. NMR spectra were measured
with a Varian Gemini 200 spectrometer (200 MHz, 1H
NMR) and chemical shift are given in ppm from TMS. 13C
NMR spectra were recorded using APT pulse sequence.
3.2. Synthesis of compound 9
3.2.1. 1,3-Bis(2-formayphenoxy)-2-propanol (9). With the
use of the general procedure (A) potassium salt 8 gave oily
product which was extracted with chloroform. The organic
layer washed with 1 N NaOH solution, dried with anhydrous
MgSO4. The solvent was then removed in vacuo. The solid
obtained was collected and crystallized from benzene as
yellow crystals, to give (65%) of 9, mp 105 8C [lit.25 109.5–
1
with a Varian Mercury 300 (300 MHz H NMR, 75 MHz
13C NMR). Mass spectra were recorded on a GCMS-QP
1000 EX spectrometer. Elemental analyses were carried out
at the Microanalytical Centre, Cairo University. 1,3-
Dibromopropane, 1,4-dibromobutane, epichlorohydrin,
diethylamine, piperidine, morpholine and piperazine were
used as purchased from Aldrich. The starting bis(4-amino-
1,2,4-triazol-3-ylsulfanyl)alkanes 2a-d were prepared as
reported.18,19
1
110.5 8C]; IR (cm21) 3467 (OH), 1679 (CO); H NMR
(CDCl3) d 3.65 (br s, 1H, OH), 4.32 (d, 4H, J¼5 Hz,
OCH2), 4.53 (quintet, 1H, J¼5.4 Hz, CHOH), 7.02–7.83
(m, 8H, ArH’s), 10.4 (s, 2H, CHO) ppm. (Calcd for
C16H16O5 (288.29): C, 66.66; H, 5.59. Found: C, 66.80;
H, 5.70).
3.1.1. Bis(4-arylmethylideneamino-1,2,4-triazol-3-ylsulf-
anyl)alkanes 4a,b. General procedure. To a solution of
each of 3c,d (5 mmol) in glacial acetic acid (30 ml) was
added salicylaldehyde (3) (10 mmol). The reaction mixture
was heated under reflux for 1 h. The solvent was then
removed in vacuo and the remaining residue washed with
water. The solid obtained was collected and crystallized
from the appropriate solvent to give crystals of 4a,b.
3.3. Synthesis of the macrocycles 7a-d
General procedure (B). To a solution of bis(carbonyl) ether
9 (5 mmol) in glacial acetic acid (50 ml) was added a
solution of the appropriate bis(4-amino-1,2,4-triazol-3-yl-
sulfanyl)alkanes 3a-d (5 mmol) in glacial acetic acid
(30 ml). The reaction mixture was then heated under reflux
for 3 h. The solvent was then removed in vacuo and the
remaining residue washed with water and the solid obtained
was collected and crystallized from the proper solvent to
give colorless crystals of 7a-d.
3.1.2. 1,3-Bis(4-o-hydroxybenzylideneamino-5-benzyl-
1,2,4-triazol-3-ylsulfanyl)propane (4a). With the use of
the general procedure 2c gave crude 4a which was
crystallized from ethanol as colorless crystals (75%), mp
1
3.3.1. 3,23-Diphenyl-13-hydroxy-12,13,27,28-tetra-
hydro-14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo-
[b,q][1,19,5,6,14,15,8,12]dioxatetraazadithiacyclo-
docosine (7a). With the use of the general procedure (B) 9
and 2a gave crude 7a which was crystallized from acetic
164 8C; H NMR (CDCl3) d 2.19 (quintet, 2H, J¼6.8 Hz,
SCH2CH2), 3.27 (t, 4H, J¼7 Hz, SCH2), 4.13 (s, 4H,
PhCH2), 6.85–7.42 (m, 18H, ArH’s), 8.39 (s, 2H, OH), 9.95
(s, 2H, CHvN) ppm. (Calcd for C35H32N8O2S2 (660.82):
C, 63.62; H, 4.88; N, 16.96; S, 9.70. Found: C, 63.41; H,
4.90; N, 16.80; S, 9.60%).
acid as colorless crystals (50%), mp 264–6 8C; IR (cm21
)
3380 (OH), 1599 (CvN); MS: m/z 688 (Mþ, 80%); H
NMR (DMSO) d 2.31 (quintet, 2H, J¼7 Hz, SCH2CH2),
3.34 (m, 4H, SCH2), 4.15–4.41 (m, 5H, OCH2, CH–OH),
5.51 (d, 1H, J¼4.2 Hz, OH), 7.1–8.15 (m, 18H, ArH’s),
9.38 (s, 2H, CHvN) ppm. (Calcd for C36H32N8O3S2
(688.83): C, 62.77; H, 4.68; N, 16.27; S, 9.31. Found: C,
62.90; H, 4.57; N, 16.40; S, 9.20).
1
3.1.3. 1,4-Bis(4-o-hydroxybenzylideneamino-5-benzyl-
1,2,4-triazol-3-ylsulfanyl)butane (4b). With the use of
the general procedure 2d gave crude 4b which was
crystallized from DMF as colorless crystals (70%), mp
1
252–254 8C; IR (cm21) 3400 (CO),1607 (NH); H NMR
(DMSO) d 1.74 (br s, 4H, SCH2CH2), 3.14 (br s, 4H, SCH2),
4.19 (s, 4H, PhCH2), 6.95–7.81 (m, 18H, ArH’s), 8.88 (s,
2H, CHvN), 10.49 (br s, 2H, OH) ppm. (Calcd for
C36H34N8O2S2 (674.85): C, 64.07; H, 5.08; N, 16.60; S,
9.50. Found: C, 63.91; H, 4.90; N, 16.40; S, 9.31%.
3.3.2. 3,23-Diphenyl-13-hydroxy-12,13,27,28,29,30-hexa-
hydro-14H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,r]-
[1,20,5,6,15,16,8,13]dioxatetraazadithiacyclotricosine
(7b). With the use of the general procedure (B) 9 and 2b
gave crude 7b which was crystallized from dioxan as
3.1.4. Preparation of the potassium salts 5a,b and 8. To a

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A. A. Abbas / Tetrahedron 60 (2004) 1541–1548
colorless crystals (45%), mp 240–42 8C; IR (cm21) 3197
(OH), 1595 (CvN); MS: m/z 703 (Mþþ1, 50%); 1H NMR
(DMSO) d 1.9 (br s, 4H, SCH2CH2), 3.23 (m, 4H, SCH2),
4.15–4.54 (m, 5H, OCH2, CH–OH), 5.53 (d, 1H, J¼3.6 Hz,
OH), 7.11–8.03 (m, 18H, ArH’s), 9.40 (s, 2H,
CHvN) ppm. (Calcd for C37H34N8O3S2 (702.86): C,
63.23; H, 4.88; N, 15.94; S, 9.12. Found: C, 62.99; H,
4.77; N, 16.01; S, 9.31).
159.30 (CH’s) ppm. (Calcd for C38H33N8O4S2Cl (765.31):
C, 56.64; H, 4.35; N, 14.64; S, 8.38, Cl, 4.63. Found: C,
59.88; H, 4.44; N, 14.80; S, 8.20; Cl, 4.50).
3.4.2. 13-Chloroacetoxy-3,23-dibenzyl-12,13,27,28,
29,30-hexahydro-14H-bis[1,2,4]triazolo[4,3-f:3,4-m]-
dibenzo[b,r][1,20,5,6,15,16,8,13]dioxatetraazadithia-
cyclotricosine (11b). With the use of the general procedure
7d gave 11b (70%), mp 170–72 8C; IR (cm21) 1766 (CO),
1600 (CvN); 1H NMR (CDCl3) d 1.93 (br s, 4H,
SCH2CH2), 3.27 (br s, 4H, SCH2), 3.96 (s, 2H, CH2Cl),
4.25 (s, 4H, CH2Ph), 4.36 (d, 4H, J¼5.6 Hz, OCH2), 5.79
(quintet, 1H, J¼5.4 Hz, CH–OCO), 6.93–7.99 (m, 18H,
ArH’s), 9.16 (s, 2H, CHvN) ppm. (Calcd for C41H39N8-
O4S2Cl (807.40): C, 60.99; H, 4.87; N, 13.88; S, 7.94, Cl,
4.39. Found: C, 60.70; H, 4.74; N, 13.95; S, 8.10; Cl, 4.52).
3.3.3. 3,23-Dibenzyl-13-hydroxy-12,13,27,28-tetrahydro-
14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,r]-
[1,19,5,6,14,15,8,12]dioxatetraazadithiacyclodocosine
(7c). (a) With the use of the general procedure (B) 9 and 2c
gave crude 7c which was crystallized from ethanol as
colorless crystals (40%), mp 182–84 8C; IR (cm21) 3197
1
(OH), 1596 (CvN); MS: m/z 716 (Mþ, 53%); H NMR
(DMSO) d 2.23 (quintet, 2H, J¼5.6 Hz, SCH2CH2), 3.28 (t,
4H, J¼6.6 Hz, SCH2), 4.1–4.35 (m, 5H, OCH2, CH–OH),
4.22 (s, 4H, CH2Ph), 5.5 (d, 1H, J¼4.4 Hz, OH), 7.10–7.97
(m, 18H, ArH’s), 9.28 (s, 2H, CHvN) ppm. (Calcd for
C38H36N8O3S2 (716.89): C, 63.67; H, 5.06; N, 15.63; S,
8.95. Found: C, 62.92; H, 5.22; N, 15.80; S, 9.21).
3.5. Reaction of esters 11a,b with secondary amines
(synthesis of compounds 12a,b, 13 and 14a,b)
General procedure. A mixture of each of 11a,b (5 mmol)
and excess of the appropriate secondary amines (N,N-
diethylamine, morpholine, piperidine and piperazine)
[6 mmol for compounds 13a,b, 14 and 2.5 mmol of
piperazine for compounds 11a,b] in acetone (30 ml) was
heated under reflux for 2 h. The solvent was then removed in
vacuo. The solid obtained was crystallized from the proper
solvent to give compounds 12a,b, 13 and 14a,b,
respectively.
(b) With the use of the general procedure (A) 4a gave 2% of
7c
3.3.4. 3,23-Dibenzyl-13-hydroxy-12,13,27,28,29,30-hexa-
hydro-14H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,r]-
[1,20,5,6,15,16,8,13]dioxatetraazadithiacyclotricosine
(7d). (a) With the use of the general procedure (B) 9 and 2d
gave crude 7d which was crystallized from dioxan as
colorless crystals (50%), mp 170–72 8C; IR (cm21) 3199
3.5.1. 3,23-Diphenyl-13-[2-(N-piperidino)acetoxy]-
12,13,27,28-tetrahydro-14H,29H-bis[1,2,4]triazolo[4,3-
f:3,4-m]dibenzo[b,q][1,19,5,6,14,15,8,12]dioxatetra-
azadithiacyclodocosine (12a). With the use of the general
procedure 11a and morpholine gave crude 12b which was
crystallized from ethanol as colorless crystals (70%), mp
216–18 8C; 1H NMR (CDCl3) d 1.32 (quintet, 2H,
J¼4.6 Hz, N–CH2CH2CH2), 1.49 (quintet, 4H, J¼4.8 Hz,
N–CH2CH2CH2), 2.4 (m, 6H, SCH2CH2, N–CH2CH2-
CH2), 3.17 (s, 2H, CH2CO), 3.48 (br s, 4H, SCH2), 4.41 (d,
4H, J¼5.4 Hz, OCH2), 5.68 (quintet, 1H, J¼5.2 Hz, CH–
OCO), 7.02–8.08 (m, 18H, ArH’s), 9.16 (s, 2H,
CHvN) ppm. (Calcd for C43H43N9O4S2 (814.00): C,
63.45; H, 5.32; N, 15.49; S, 7.88. Found: C, 63.30; H,
5.50; N, 15.52; S, 7.80).
1
(OH), 1599 (CvN); MS: m/z 730 (Mþ, 62%); H NMR
(DMSO) d 1.8 (br s, 4H, SCH2CH2), 3.15 (m, 4H, SCH2),
4.19 (s, 4H, CH2Ph), 4.05–4.32 (m, 5H, OCH2, CH–OH),
5.51 (d, 1H, J¼4 Hz, OH), 7.10–7.99 (m, 18H, ArH’s), 9.29
(s, 2H, CHvN) ppm. (Calcd for C39H38N8O3S2 (730.91):
C, 64.09; H, 5.24; N, 15.33; S, 8.77. Found: C, 63.99; H,
4.97; N, 15.11; S, 8.59).
(b) With the use of the general procedure (A) 4b 2% of 7d
3.4. Synthesis of chloroacetoxy macrocycles 11a,b
General procedure. A solution of each of macrocycles 7a,d
(5 mmol) in DMF (10 ml) was added 2-chloroacetyl
chloride (5 mmol). The reaction mixture was stirred at
room temperature for 3 h. then poured on cursed ice. The
solid obtained was collected by filtration and crystallized
from benzene to afforded colorless crystals of 11a,b.
3.5.2. 3,23-Dibenzyl-13-[2-(N-morpholino)acetoxy]-
12,13,27,28,29,30-hexahydro-14H-bis[1,2,4]triazolo[4,3-
f:3,4-m]dibenzo[b,r][1,20,5,6,15,16,8,13]dioxatetra-
azadithiacyclotricosine (12b). (a) With the use of the
general procedure 11b and morpholine gave crude 12b
which was crystallized from benzene as colorless crystals
(65%), mp 204–6 8C; IR (cm21) 1749 (CO), 1599 (CvN),
1H NMR (CDCl3) d 1.89 (br s, 4H, SCH2CH2), 2.43 (t, 4H,
J¼4.4 Hz, N–CH2CH2–O), 3.17 (s, 2H, CH2CO), 3.23 (br
s, 4H, SCH2), 3.58 (t, 4H, J¼4.4 Hz, N–CH2CH2–O), 4.25
(s, 4H, CH2Ph), 4.35 (d, 4H, J¼4.8 Hz, OCH2), 5.73
(quintet, 1H, J¼5 Hz, CH–OCO), 6.94–8.03 (m, 18H,
ArH’s), 9.18 (s, 2H, CHvN) ppm; 13C (CDCl3) d 27.72,
31.58, 33.21, 52.88, 59.15, 66.58, 66.93, 120.82, 135.83,
144.82, 154.02, 157.62, 168.99 (CH2‘s and C’s); 70.16,
112.04, 121.96, 126.65, 127.02, 128.37, 128.79, 134.10,
156.35 (CH’s) ppm. (Calcd for C45H47N9O5S2 (858.06): C,
3.4.1. 13-Chloroacetoxy-3,23-diphenyl-12,13,27,28-
tetrahydro-14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-m]-
dibenzo[b,q][1,19,5,6,14,15,8,12]dioxatetraazadithia-
cyclodocosine (11a). With the use of the general procedure
7a gave 11a (65%), mp 182–84 8C; IR (cm21) 1749 (CO),
1599 (CvN); 1H NMR (CDCl3) d 2.43 (m, 2H, SCH2CH2),
3.48 (m, 4H, SCH2), 4.02 (s, 2H, CH2Cl), 4.42 (d, 4H,
J¼5 Hz, OCH2), 5.74 (quintet, 1H, J¼5.4 Hz, CH–OCO),
7.0–8.06 (m, 18H, ArH’s), 9.15 (s, 2H, CHvN) ppm; 13C
(CDCl3) d 27.18, 32.77, 40.50, 66.90, 120.90, 126.65,
145.71, 152.80, 157.87, 166.44 (CH2’s and C’s); 72.36,
112.61, 122.28, 127.62, 128.29, 128.45, 129.75, 134.38,

A. A. Abbas / Tetrahedron 60 (2004) 1541–1548
1547
62.99; H, 5.52; N, 14.69; S, 7.47. Found: C, 63.10; H, 5.37;
N, 14.80; S, 7.36).
3.6.1. 3,23-Diphenyl-13-hydroxy-5,6,12,13,20,21,27,28-
octahydro-14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-m]-
dibenzo[b,q][1,19,5,6,14,15,8,12]dioxatetraazadithia-
cyclodocosine (15a). With the use of the general procedure
7a gave crude 15a which was crystallized from dil. ethanol
as colorless crystals (70%), mp 270–72 8C; IR (cm21) 3347
3.5.3. 3,23-Dibenzyl-13-[2-(N,N-diethylamino)acetoxy]-
12,13,27,28,29,30-hexahydro-14H-bis[1,2,4]triazolo-
[4,3-f:3,4-m]dibenzo[b,r][1,20,5,6,15,16,8,13]dioxate-
traazadithiacyclotricosine (13). With the use of the
general procedure 11b and diethylamine gave crude 13
which was crystallized from ethanol as colorless crystals
(60%), mp 162–4 8C; IR (cm21) 1599 (CvN), 1746 (CO);
1H NMR ((CDCl3) d 0.84 (t, 6H, J¼7.2 Hz, CH3), 1.81 (br s,
4H, SCH2CH2), 2.47 (q, 4H, J¼7.2 Hz, CH2CH3), 3.13 (br
s, 4H, SCH2), 3.28 (s, 2H, CH2CO), 4.18 (s, 4H, CH2Ph),
4.34 (d, 4H, J¼5.8 Hz, OCH2), 5.75 (quintet, 1H, J¼5.4 Hz,
CH–OCO), 6.97–8.15 (m, 18H, ArH’s), 9.25 (s, 2H,
CHvN) ppm. (Calcd for C45H49N9O4S2 (844.07): C, 64.03;
H, 5.85; N, 14.93; S, 7.60. Found: C, 63.91; H, 5.75; N,
14.79; S, 7.40).
1
(NH), 3181 (OH); H NMR (DMSO) d 2.15 (quintet, 2H,
J¼6.8 Hz, SCH2CH2), 3.23 (t, 4H, J¼6.8 Hz, SCH2), 3.91–
4.25 (m, 9H, OCH2, Ar–CH2, CH–OH), 4.39 (t, 2H,
J¼5 Hz, NH), 5.26 (d, 1H, J¼4.6 Hz, OH), 6.83–8.06 (m,
18H, ArH’s) ppm. (Calcd for C36H36N8O3S2 (692.86): C,
62.41; H, 5.24; N, 16.17; S, 9.26. Found: C, 62.60; H, 5.33;
N, 16.23; S, 9.10).
3.6.2. 3,23-Diphenyl-13-hydroxy-5,6,12,13,20,21,
27,28,29,30-decahydro-14H-bis[1,2,4]triazolo[4,3-f:3,4-
m]-dibenzo[b,r][1,20,5,6,15,16,8,13]dioxatetraazadithia-
cyclotricosine (15b). With the use of the general procedure
7b gave crude 15b which was crystallized from acetic/
ethanol mixture as colorless crystals (70%), mp 262–64 8C;
IR (cm21) 3537 (NH), 3276 (OH); 1H NMR (DMSO) d 1.79
(br s, 4H, SCH2CH2), 3.2 (br s, 4H, SCH2), 3.9–4.35 (m,
9H, OCH2, Ar–CH2, CH–OH), 5.3 (br s, 1H, OH), 6.81–
8.05 (m, 20H, ArH’s, NH) ppm. (Calcd for C37H38N8O3S2
(706.89): C, 62.87; H, 5.42; N, 15.85; S, 9.07. Found: C,
62.59; H, 5.60; N, 15.70; S, 8.90).
3.5.4. 1,4-Bis{(3,23-diphenyl-12,13,27,28-tetrahydro-
14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,q]-
[1,19,5,6,14,15,8,12]dioxatetraazadithiacyclodocosine)-
13-yloxycarbonylmethyl}piperazine (14a). With the use
of the general procedure 11a and piperazine gave crude 14a
which was crystallized from acetic acid as colorless crystals
(50%), mp 204–205 8C; IR (cm21) 1747 (CO), 1600
1
(CvN); H NMR (CDCl3) d 2.42 (quintet, 4H, J¼6.4 Hz,
SCH2CH2), 2.77 (br s, 8H, NCH2), 3.38 (s, 4H, CH2CO),
3.48 (m, 8H, SCH2), 4.41 (m, 8H, OCH2),5.79 (br s, 2H,
CH–OCO), 7.02–8.04 (m, 36H, ArH’s), 9.15 (s, 4H,
CHvN) ppm. (Calcd for C80H74N18O8S4 (1543.84): C,
62.24; H, 4.83; N, 16.33; S, 8.31. Found: C, 62.33; H, 4.92;
N, 16.45; S, 8.51).
3.6.3. 3,23-Dibenzyl-13-hydroxy-5,6,12,13,20,21,27,28-
tetrahydro-14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-m]-
dibenzo][b,q[1,19,5,6,14,15,8,12]dioxatetraazadithia-
cyclodocosine (15c). With the use of the general procedure
7c gave crude 15c which was crystallized from ethanol as
colorless crystals (65%), mp 268–70 8C; IR (cm21) 3347
1
(NH), 3181 (OH); H NMR (DMSO) d 2.09 (br s, 2H,
3.5.5. 1,4-Bis{(3,23-dibenzyl-12,13,27,28,29,30-hexa-
hydro-14H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,r]-
[1,20,5,6,15,16,8,13]dioxatetraazadithiacyclotricosine)-
13-yloxycarbonylmethyl}piperazine (14b). With the use
of the general procedure 11b and piperazine gave crude 14b
which was crystallized from acetic acid as colorless crystals
(60%), mp 236–38 8C; IR (cm21) 1759 (CO), 1600 (CvN);
1H NMR (CDCl3) d 1.8 (br s, 8H, SCH2CH2), 2.26 (s, 8H,
NCH2), 3.02 (s, 4H, CH2CO), 3.14 (br s, 8H, SCH2), 4.14 (s,
8H, CH2Ph), 4.27 (d, 8H, J¼5.2 Hz, OCH2), 5.66 (quintet,
2H, J¼5 Hz, CH–OCO), 6.89–7.93 (m, 36H, ArH’s), 9.10
(s, 4H, CHvN) ppm; 13C NMR (DMSO) d 26.65, 29.98,
31.91, 50.63, 57.35, 66.55, 119.28, 135.36, 143.48, 152.32,
157.15, 168.26 (CH2‘s and C’s), 69.43, 112.31, 120.75,
125.81, 125.91, 127.61, 127.89, 133.90, 157.87 (CH’s).
(Calcd for C86H86N18O8S4 (1628.01): C, 63.45; H, 5.32; N,
15.49; S, 7.88. Found: C, 63.52; H, 5.42; N, 15.60; S, 7.72).
SCH2CH2), 3.22 (br s, 4H, SCH2), 3.98–4.35 (m, 13H,
PhCH2, OCH2, Ar–CH2, CH–OH), 5.21 (s, 1H, OH),
6.72 (t, 2H, J¼5.2 Hz, NH), 6.92–7.33 (m, 18H,
ArH’s) ppm. (Calcd for C38H40N8O3S2 (720.92): C, 63.31;
H, 5.59; N, 15.54; S, 8.90. Found: C, 63.20; H, 5.65; N,
15.31; S, 8.74).
3.6.4. 3,23-Dibenzyl-13-hydroxy-5,6,12,13,20,21,
27,28,29,30-decahydro-14H-bis[1,2,4]triazolo[4,3-f:3,4-
m]-dibenzo[b,r][1,20,5,6,15,16,8,13]dioxatetraazadithia-
cyclotricosine (15d). (a) With the use of the general
procedure 7d gave crude 15d which was crystallized from
acetic / ethanol mixture as colorless crystals (68%), mp
1
138–40 8C; IR (cm21) 3300 (NH), 3230 (OH); H NMR
(CDCl3) d 1.82 (br s, 4H, SCH2CH2), 3.2 (m, 4H, SCH2),
3.71–4.13 (m, 9H, OCH2, Ar–CH2, CH–OH), 4.01 (s, 4H,
CH2Ph), 4.54 (br s, 1H, OH), 5.35 (t, 2H, J¼6.4 Hz, NH),
6.85–7.35 (m, 18H, ArH’s) ppm. (Calcd for C39H42N8O3S2
(734.94): C, 63.74; H, 5.76; N, 15.25; S, 8.73. Found: C,
63.59; H, 5.63; N, 15.45; S, 8.70).
3.6. Action of sodium borohydride on 7a-d and 12b.
Synthesis of 15a-d
General procedure. To a stirred boiling solution of each of
7a-d and 12b (0.7 mmol) in methanol (30 ml) was added
sodium borohydride (0.4 g) 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 remaining
residue washed with water. The solid obtained was collected
and crystallized from the proper solvent to give colorless
crystals of 15a-d.
(b) Compound 12b gave 65% of 15d.
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