Unexpected synthesis of novel condensed heteromacrocycles

Article abstract of DOI:10.1055/s-2002-19809

Alkylation of 4-amino-1,2,4-triazol-3(2H)-thiones 9a-d with 2,3-bis(bromomethyl)quinoxaline (8) in absolute ethanol containing potassium hydroxide gave the corresponding bis(amines) 10a-d. Condensation of the latter with the apprbpriate aromatic aldehydes in refluxing acetic acid afforded the corresponding benzylideneamino derivatives 12a,b. On the other hand, reaction of the bis(amines) 10a-d with the bis(aldehydes) 13a-c in refluxing acetic acid under high dilution conditions did not lead to the formation of the corresponding macrocyclic Schiffs bases 14. Instead, the reaction gave the corresponding novel condensed heteromacrocycles 15a-f.

Full text of DOI:10.1055/s-2002-19809

260
PAPER
Unexpected Synthesis of Novel Condensed Heteromacrocycles
Synthesisof
N
ove
h
l
Condensed
m
H
eteromacrocyclesed H. M. Elwahy,* Ashraf A. Abbas, Refaie M. Kassab
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Fax +20(2)5727556; E-mail: aelwahy@chem-sci.cairo.eun.eg
Received 20 July 2001; revised 2 November 2001
donor atoms. Although many macrocyclic compounds
containing heterocyclic rings such as pyridine, bipyridine,
pyrimidine, triazole, pyrazole, imidazole, and thiophene
have been synthesized and studied,5–12 very little is
Abstract: Alkylation of 4-amino-1,2,4-triazol-3(2H)-thiones 9a–d
with 2,3-bis(bromomethyl)quinoxaline (8) in absolute ethanol con-
taining potassium hydroxide gave the corresponding bis(amines)
10a–d. Condensation of the latter with the appropriate aromatic al-
dehydes in refluxing acetic acid afforded the corresponding ben- known13,14 about using benzoheterocycles as a subunit of
zylideneamino derivatives 12a,b. On the other hand, reaction of the
bis(amines) 10a–d with the bis(aldehydes) 13a–c in refluxing acetic
macrocyclic compounds. As part of an ongoing investiga-
tion aimed at the synthesis of new macrocyclic ligands
acid under high dilution conditions did not lead to the formation of
fused with benzoheterocycles, we report herein our at-
the corresponding macrocyclic Schiffs bases 14. Instead, the reac-
tempts to synthesize novel macrocycles, which are fused
tion gave the corresponding novel condensed heteromacrocycles
to quinoxaline units. Our object in this project is to study
the effect of rigidity provided by these groups on the abil-
ity of the ligands to form stable complexes compared to
other macrocyclic analogues. In this respect, we recently15
described the synthesis of some quinoxaline containing
crown ethers, azacrown ethers, and macrocyclic diamides
and their corresponding dithiodiamides 1–3 (Figure 1).
15a–f.
Key words: alkylation, bis(bromomethyl)quinoxaline, heteromac-
rocycles, bis(amines), bis(aldehydes)
For the past three decades much work has been directed
towards the synthesis of new macrocyclic ligands and the
systematic determination of the parameter that affect their
complex stability with different cations in terms of ther-
modynamic and kinetic data.1–3 Since the discovery of
crown ethers which represent the first class of the macro-
cyclic ligands, various structure changes have been made
to the basic crown ether structure in an attempt to enhance
the selectivity of these ligands and the stability of com-
plexes formed with both metal and organic cations. Some
of these modifications involved the substitutions of ligand
polyether oxygen atoms by sulfur and/or nitrogen atoms.
Other substitution have involved the insertion of aromatic
and/or heterocyclic ring system into the macroring.2–4
Heterocyclic groups provide rigidity and are able to par-
ticipate, in some cases, in complexation through their soft
We have also investigated the reactivity of the bis(alde-
hydes) 415 towards the bis(aminotriazoles) 516 in an at-
tempt to obtain the corresponding novel macrocycles 6 in
which two triazole rings are fused to the macrocycles in
addition to the quinoxaline moiety (Scheme 1). Unfortu-
nately the reaction of 4 with 5 in refluxing acetic acid un-
der high dilution conditions did not lead to the formation
of 6. Instead the reaction gave 2,3-bis(benzo[b]furan-2-
yl)quinoxaline (7) via intramolecular cyclocondensation
of the active methylene with the aldehyde groups. Al-
though we were not able to get the target molcule 6, this
reaction provided a new and easy access to novel dibenzo-
furanylquinoxaline derivatives.
Figure 1 Chemical structures of quinoxaline macrocycles 1–3
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2002,0,02,0260,0264,ftx,en;Z08401SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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Synthesis of Novel Condensed Heteromacrocycles
261
Scheme 1
We now attempted to prepare new quinoxaline containing generation of asymmetric center on the 1H NMR spectra
macrocycles 14 which are isomeric with compound 6 us- of some related compounds.20,21 Additional evidence for
ing a new strategy as outlined in Scheme 2.
structure 15a–f comes from studying the 13C-{1H} NMR
spectra of compounds 15d–f which indicate their exist-
ence as one stable conformer. Moreover, the presence of
two signals at = 34.4–36.6 and 54.7–57.4, respectively,
characteristic for the sp3 CHNH and CHS carbons in the
13C-{1H} NMR spectra (APT) of compounds 15a–f pro-
vide additional proof for the suggested structure. Further-
more, the presence of an absorption band at 3421–3363
cm–1 characteristic for NH group adds also another evi-
dence for the proposed structures.
Thus, 4-amino-1,2,4-triazole-3(2H)-thiones 9a–d17 was
reacted with 2,3-bis(bromomethyl)quinoxaline (8) in ab-
solute ethanol containing KOH to give 61–74% of the
corresponding 1,2-bis(4-amino-1,2,4-triazole-3-ylsulfa-
nylmethyl)quinoxalines 10a–d. The reactivity of the latter
towards aromatic aldehydes was now investigated. Thus,
reaction of 10a with each of benzaldehyde and anisalde-
hyde in refluxing acetic acid afforded 30–35% yields of
the corresponding benzylideneamino derivatives 12a,b.
We now studied the reaction of 10a with 1,2-bis(2- The reaction can proceed via initial formation of the cor-
formylphenoxy)ethane (13a)18 in refluxing acetic acid un- responding macrocyclic Schiffs base 14. Under the reac-
der high dilution conditions aiming at the synthesis of the tion conditions the acid catalyst affords small amounts of
target molecule 14. Unfortunately the reaction did not the tautomeric methylene form A22 (Figure 2), which
lead to the formation of the expected macrocyclic schiff could then react with the benzylideneamino carbon that
base 14. Instead the reaction gave another product, which act as an electrophile to give 15. The reaction was facili-
could be characterized as the condensed heteromacrocy- ated by the enhanced electrophilicity of C-1 caused by
cle 15a. Similarly, were prepared the novel macrocycles protonation of N-2 under the acidic conditions. The reac-
15b–f by reacting the appropriate bis(aldehydes) 13a– tion can also proceed by an intermolecular ene-reaction
c18,19 with the corresponding bis(amines) 10b–d. The mo- with the azomethine group as ene part and the eneamine
lecular structure proposed for the new compounds 15a–f group as enophile part in the proposed intermediate A. In
was confirmed by the presence of the correct molecular both cases, the formation of the six-membered ring is the
ion peak in their mass spectra. Based on the absence of the driving force for the formation of 15. We expect also the
1
characteristic H NMR signal for the aldimine H-atom restricted rotational freedom in the cyclic precursor 14
HC=N at = 8–9,16 the structure 14 was completely ruled caused by the rigidity provided by the heterocycles and
out. The appearance of the OCH2 signal as multiplet in the aromatic groups together with the presence of the two
compound 15a–f together with the fact that its precursors reacting species in close proximity in the same molecule
13a–c exhibit singlet or triplet signals for these protons may assist the intramolecular ring closure of 14 to 15 to
assumes the generation of asymmetric center in these mol- occur in relatively moderate yield.23,24 On the other hand,
ecules which is close enough to this CH2 group to affect the absence of such rigidity in the acyclic schiff bases
such splitting. Recently, we discussed the effect of the 12 did not allow the cyclization of the latter to the cor-
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262
A. H. M. Elwahy et al.
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Scheme 2
responding 2,3-bis(6,7-dihydro-5H-1,2,4-triazolo(4,3-b)- istry and would add another dimension to this difference.
thiadiazine-7-yl)quinoxaline 16a (Figure 2). It is note- Studying the incorporation of a range of heteroatoms into
worthy to mention that we were unable to separate pure the new macrocycles to enhance their potential as ligands
sample of the corresponding schiff base 12 (R = Ph, is now in progress.
R’ = OMe) by condensing 10b with anisaldehyde. The 1H
NMR of the reaction products indicate the presence of a
mixture of each of the corresponding schiff base and the
corresponding cyclic product 16b but we are still unable
to isolate pure samples of each of them. The presence of
phenyl group in the 3-position of the triazole ring may add
some restriction to the rotational freedom in these mole-
cules allowing the formation of some of the cyclic prod-
uct.
In conclusion, we have provided a new access to novel
condensed heteromacrocycles, which represent an impor-
tant point of departure from traditional heterocyclic chem-
Figure 2 Chemical structures of tautomeric methylene form A and
compounds 16a,b
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Synthesis of Novel Condensed Heteromacrocycles
263
1,2-Bis(4-amino-1,2,4-triazole-3-yl-sulfanylmethyl)quinoxa-
lines 10a–d; General Procedure
1,2-Bis(4-benzylideneamino-1,2,4-triazole-3-yl-sulfanylme-
thyl)quinoxaline (12a)
To a stirred solution of KOH (0.12 g, 20 mmol) in absolute EtOH
(15 mL) was added the appropriate triazole 9a–d (20 mmol). To the
formed potassium salt was added 2,3-bis(bromomethyl)quinoxaline
(8; 10mmol). The mixture was heated under reflux for 1 h during
which time a crude solid was precipitated. The product was collect-
ed and recrystallized to give colorless crystals of 10a–d.
By using the general procedure, compounds 10a and 11a gave 12a
which was recrystallized from EtOAc; pale green crystals (22%);
mp 206–207 °C.
1H NMR (CDCl3): = 5.03 (s, 4 H, CH2S), 7.2–8.0 (m, 14 H, ArH),
8.45 (s, 2 H, triazole-H), 8.45 (s, 2 H, CH=N).
Anal. Calcd for C28H22N10S2 (530.5): C, 63.39; H, 4.18; N, 26.24.
Found: C, 63.30; H, 4.10; N, 26.20.
1,2-Bis(4-amino-1,2,4-triazole-3-yl-sulfanylmethyl)quinoxaline
(10a)
1,2-Bis[4-(p-methoxy)benzylideneamino-1,2,4-triazole-3-yl-
sulfanylmethyl]quinoxaline (12b)
By using the general procedure, compounds 10a and 11b gave 12b
which was recrystallized from EtOAc; brown crystals (25%); mp
190 °C.
1H NMR (DMSO-d6): = 3.8 (s, 6 H, OCH3), 5.02 (s, 4 H, CH2S),
7.01–7.92 (m, 12 H, ArH), 8.81 (s, 2 H, triazole-H), 9.27 (s, 2 H,
CH=N).
By using the general procedure, compounds 8 and 9a gave 10a
which was recrystallized from EtOH; brown crystals (71%); mp
170 °C.
IR (KBr): 3256.5, 3343.1 (NH2) cm–1.
1H NMR (DMSO-d6): = 4.96 (s, 4 H, SCH2), 6.21 (s, 4 H, NH2),
7.8–8.1 (m, 4 H, ArH), 8.51 (s, 2 H, triazole-H).
Anal. Calcd for C14H14N10S2 (386.5): C, 43.50; H, 3.65; N, 36.24.
Found: C, 43.30; H, 3.50; N, 36.20.
Anal. Calcd for C30H26N10S2O2 (622.7): C, 57.86; H, 4.21; N, 22.49.
Found: C, 57.70; H, 4.50; N, 22.50.
1,2-Bis(4-amino-5-phenyl-1,2,4-triazole-3-yl-sulfanylmethyl)-
quinoxaline (10b)
By using the general procedure, compounds 8 and 9b gave 10b
which was recrystallized from HOAc; brown crystals (73%); mp
250 °C.
IR (KBr): 3280.5, 3354.4 (NH2) cm–1.
1H NMR (DMSO-d6): = 5.06 (s, 4 H, CH2S), 6.3 (s, 4 H, NH2),
The Macrocycle 15a
By using the general procedure, compounds, 10a and 13a gave
crude 15a which was recrystallized from EtOAc; colorless crystals
(30%); mp 244 °C.
IR (KBr): 3390.2 (NH) cm–1.
1H NMR (DMSO-d6): = 4.6–4.98 (m, 8 H, CHS, CHNH, OCH2),
6.7–7.82 (m, 14 H, ArH, NH), 8.68 (s, 2 H, triazole-H).
7.5–8.1 (m, 14 H, ArH).
Anal. Calcd for C26H22N10S2 (538.7): C, 57.97; H, 4.12; N, 26.00.
Found: C, 57.70; H, 4.10; N, 26.10.
MS: m/z (%) = 621 (M+, 71.4), 342 (78.2), 228 (100), 144 (71.2),
131 (71.4).
Anal. Calcd for C30H24N10O2S2 (620.7): C, 58.05; H, 3.90; N, 22.57.
Found: C, 58.30; H, 4.10; N, 22.80.
1,2-Bis(4-amino-5-benzyl-1,2,4-triazole-3-yl-sulfanylmethyl)-
quinoxaline (10c)
By using the general procedure, compounds 8 and 9c gave 10c
which was recrystallized from EtOH, pale brown crystals (61%);
mp 192 °C.
IR (KBr): 3306, 3334 (NH2) cm–1.
1H NMR (DMSO-d6): = 4.10 (s, 4 H, PhCH2), 4.9 (s, 4 H, CH2S),
6.03 (s, 4 H, NH2), 7.1–8.0 (m, 14 H, ArH).
The Macrocycle 15b
By using the general procedure, compounds, 10d and 13a gave
crude 15b which was recrystallized from EtOAc; colorless crystals
(30%); mp 280 °C.
IR (KBr): 3382.4 (NH) cm–1.
1H NMR (DMSO-d6): = 3.72 (s, 6 H, OCH3), 4.6–5.1 (m, 8 H,
CHS, CHNH, OCH2), 6.8–8.2 (m, 22 H, ArH, NH).
Anal. Calcd for C28H26N10S2 (566.7): C, 59.34; H, 4.62; N, 24.72.
Found: C, 59.30; H, 4.50; N, 24.50.
MS: m/z (%) = 833 (M+, 64.3), 748 (92.8), 491 (100), 288 (64.3),
244 (78.5), 136 (78.5).
1,2-Bis[4-amino-5-(p-methoxyphenyl)-1,2,4-triazole-3-yl-sul-
fanylmethyl]quinoxaline (10d)
By using the general procedure, compounds 8 and 9d gave 10d
which was recrystallized from HOAc; colorless crystals (65%); mp
220 °C.
Anal. Calcd for C44H36N10O4S2 (833.0): C, 63.45; H, 4.36; N, 16.82.
Found: C, 63.40; H, 4.50; N, 16.80.
The Macrocycle 15c
IR (KBr): 3162.1, 3276.6 (NH2) cm–1.
1H NMR (DMSO-d6): = 3.83 (s, 6 H, OCH3), 5.02 (s, 4 H, CH2S),
By using the general procedure, compounds, 10b and 13b gave
crude 15c which was recrystallized from EtOAc; pale yellow crys-
tals (29%); mp 255 °C.
IR (KBr): 3385.4 (NH) cm–1.
1H NMR: (DMSO-d6): = 2.45 (br, 2 H, CH2CH2O), 4.3–5.1 (m, 8
H, CHS, CHNH, OCH2), 6.7–8.23 (m, 24 H, ArH, NH).
6.25 (s, 4 H, NH2), 7.0–8.1 (m, 12 H, ArH).
Anal. Calcd for C28H26N10O2S2 (598.7): C, 56.17; H, 4.38; N, 23.39.
Found: C, 56.30; H, 4.50; N, 23.50.
MS: m/z (%) = 787 (M+, 78.5), 516 (78.5), 379 (71.9), 318 (100), 52
(71.4).
Acyclic Schiff Bases 12a,b and the Condensed
Heteromacrocycles 15a–f; General Procedure
To a solution of each of 13a–c or 11a,b (10 mmol) in glacial HOAc
(50 mL) was added a solution of the appropriate bis(amines) 10a–d
(10 mmol) in glacial HOAc (50 mL). The mixture was then refluxed
for 2 h. The solution was then concentrated to a small volume (ca.
2 mL) and then cold water (ca. 15 mL) was added. The solid ob-
tained was collected and recrystallized to give crystals of 12a,b or
15a–f.
Anal. Calcd for C43H34N10O2S2 (786.9): C, 65.63; H, 4.35; N, 17.8.
Found: C, 65.40; H, 4.50; N, 16.80.
The Macrocycle 15d
By using the general procedure, compounds 10c and 13b gave crude
15d which was recrystallized from EtOAc; colorless crystals
(35%); mp 260 °C.
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A. H. M. Elwahy et al.
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IR (KBr): 3372.2 (NH) cm–1
1H NMR (CDCl3): = 2.3 (br, 2 H, CH2CH2O), 4.0–5.9 (m, 12 H,
Anal. Calcd for C46H40N10O4S2 (860.0): C, 64.17; H, 4.68; N, 16.27.
Found: C, 64.40; H, 4.50; N, 16.40.
CHS, CHNH, CH2O, PhCH2), 6.1–7.7 (m, 24 H, ArH, NH).
13C-{1H} NMR: (CDCl3): = 34.43, 56.80 (aliphatic CH), 26.8,
30.74, 63.47 (aliphatic CH2), 112.35, 122.24, 124.5, 127.08, 128.7,
128.8, 130.69, 131.04 (ArCH), 122.98, 136.41, 140.14, 141.4,
152.5, 152.99, 154.15 (ArC).
MS: m/z (%) = 814 (M+, 62.5), 762 (93.7), 544 (87.5), 403 (100),
238 (93), 191 (81), 125 (75).
References
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Chem. Rev. 1991, 91, 1721.
Anal. Calcd for C45H38N10O2S2 (814.5): C, 66.32; H, 4.70; N, 17.19.
Found: C, 66.40; H, 4.50; N, 17.60.
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The Macrocycle 15e
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By using the general procedure, compounds 10b and 13c gave crude
15e which was recrystallized from EtOAc; pale yellow crystals
(30%); mp 240 °C.
IR: = 3363.5 (NH) cm-1.
1H NMR: (DMSO-d6): = 2.1 (s, 4 H, CH2CH2O), 4.6–5.07 (m, 8
H, CHS, CHNH, OCH2), 6.8–8.3 (m, 24 H, ArH, NH).
13C-{1H} NMR (DMSO-d6): = 36.58, 57.48 (aliphatic CH), 30.2,
67.85 (aliphatic CH2), 111.55, 120.95, 125.85, 127.34, 127.34,
128.12, 128.12, 129.24, 130.18 (ArCH), 123.32, 126.51, 140.18,
141.43, 150.70, 150.85, 154.88 (ArC).
MS: m/z (%) = 800 (M+, 69.23), 712 (92.3), 627 (76.9), 586 (84.6),
512 (69.2), 390 (76.9), 200 (100), 110 (92.3).
Anal. Calcd for C44H36N10O2S2 (800.3): C, 65.98; H, 4.53; N, 17.49.
Found: C, 66.10; H, 4.50; N, 17.60.
The Macrocycle 15f
By using the general procedure, compounds 10d and 13c gave crude
15f which was recrystallized from EtOAc; pale green crystals
(32%); mp 263 °C.
IR (KBr): 3395.4 (NH) cm–1.
1H NMR (DMSO-d6): = 2.15 (br, 4 H, CH2CH2O), 3.77(s, 6 H,
OCH3), 4.15–5.1 (m, 8 H, CHS, CHNH, OCH2), 6.25–8.13 (m, 22
H, ArH, NH).
13C-{1H} NMR (DMSO-d6): = 36.45, 54.79, 56.55 (aliphatic CH,
OCH3), 28.3, 67.5 (aliphatic CH2), 111.09, 113.48, 113.48, 120.41,
125.8, 128.9, 129.37, 130.12 (ArCH), 118.85, 123.27,139.68,
141.09, 150.84, 151.31, 155.77, 160.06 (ArC).
MS: m/z (%) = 860 (M+, 60), 781 (73), 644 (73), 408 (80), 341
(100), 114 (93.3).
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Synthesis 2002, No. 2, 260–264 ISSN 0039-7881 © Thieme Stuttgart · New York