Synthesis of Some Azamacrocycles Bearing 1,2,4-Oxadiazole and 1,2,3-Triazole Moieties

Article abstract of DOI:10.1134/S1070428020040193

Abstract: A tetraazacrown ether,4,9-di(prop-2-yn-1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione, bearingpropargyl groups on two nitrogens was synthesized starting from1,4,9,12-tetraazacyclohexadecane-2,11-dione and subjected to 1,3-cycloadditionreactio

Full text of DOI:10.1134/S1070428020040193

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 4, pp. 698–705. © Pleiades Publishing, Ltd., 2020.
Synthesis of Some Azamacrocycles Bearing 1,2,4-Oxadiazole
and 1,2,3-Triazole Moieties
B. Özera and Y. Dürüsta,*
a Department of Chemistry, Bolu Abant İzzet Baysal University, Bolu, 14030 Turkey
*e-mail: yasardurust@ibu.edu.tr
Received November 9, 2019; revised February 19, 2020; accepted February 20, 2020
Abstract—A tetraazacrown ether, 4,9-di(prop-2-yn-1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione, bearing
propargyl groups on two nitrogens was synthesized starting from 1,4,9,12-tetraazacyclohexadecane-2,11-dione
and subjected to 1,3-cycloaddition reaction with 5-(azidomethyl)-3-(4-R-phenyl)-1,2,4-oxadiazoles which were
prepared by acylation of the corresponding para-substituted benzamidoximes with chloroacetyl chloride,
followed by azidation. In this way, a series of azacrown ethers bearing 1,2,4-oxadiazole and 1,2,3-triazole rings
were successfully obtained, and their structure elucidation was performed by means of spectral/physical data.
Keywords: azacrown ether, azide, amidoxime, 1,2,4-oxadiazole, 1,2,3-triazole
DOI: 10.1134/S1070428020040193
Polycyclic ethers or crown ethers have first been
reported by Pedersen [1–3] who was awarded by Noble
Prize in 1987 and died just two years later in 1989.
Over the subsequent decades there has been continuing
and increasing interest in the synthesis of various types
of crown compounds, including nitrogen- and sulfur-
containing ones [4–9]. This type of macrocycles has
been shown to form complexes with alkali, alkaline
earth, and heavy metal cations. These complexation
properties make azacrowns interesting to researchers
in many areas [10–12]. Azacrowns have also found
remarkable uses as synthetic receptors in molecular
recognition processes and, in some cases, their anion
complexation properties are quite similar to those in
certain biological systems [13]. Their enhanced com-
plexing ability for ammonium salts and transition
metal ions were reported. On the other hand, azacrowns
are important intermediates for the synthesis of
cryptands (from diazacrowns), nitrogen-pivot lariat
crown ethers, and other species requiring one or two
nitrogens in the macrocycle [14–20].
Taking into account the above considerations and
importance of azamacrocyclic compounds in different
areas, we were inspired to synthesize a series of aza-
crown ethers carrying 1,2,4-oxadiazole moiety and to
carry out their 1,3-dipolar cycloaddition reactions.
Initially, azacrown 4 was synthesized from butane-
1,4-diamine and chloroacetyl chloride according to
modified literature procedures (Scheme 1). The struc-
tures of 3 and 4 were confirmed by spectral and
physical data. Azacrown 4 was then substituted at the
secondary amine nitrogens with propargyl bromide 5
to give azacrown 6 (Scheme 2). The structure of 6 was
confirmed by spectral and physical data. Most charac-
teristic IR bands arose from acetylenic stretching
vibrations around 2100 cm–1 along with the carbonyl
and NH bands. In the 13C NMR spectrum of 6, the
acetylenic carbons resonated at δC 78.16 and
73.40 ppm, and the carbonyl carbon signal appeared at
δC 170.82 ppm.
3-Aryl-5-(azidomethyl)-1,2,4-oxadiazoles 7a–7h
were synthesized according to the previously reported
procedure [26] starting from aryl-substituted 5-(chloro-
methyl)oxadiazoles which were easily prepared by the
action of chloroacetyl chloride on aryl-substituted
monoamidoximes in refluxing benzene (Scheme 3).
Azacrown 6 with acetylenic side chains was then sub-
jected to 1,3-dipolar cycloaddition with azidooxadi-
azoles 7a–7h to yield mixtures of mono- and bis-
cycloadducts 8a–8h and 9a–9h in a regioselective
In addition, there are a number of interesting uses of
azacrowns as catalysts in nucleophilic substitution and
oxidation reactions, in the design of chromogenic
reagents that are sensitive to alkali and alkaline earth
metal cations, and as light emitting materials [21–23].
Furthermore, heterocyclic compounds containing
a 1,2,4-oxadiazole or 1,2,3-triazole ring have been re-
ported to exhibit various biological activities [24–31].
698

SYNTHESIS OF SOME AZAMACROCYCLES
699
Scheme 1.
O
O
H
N
K2CO3, MeCN, 80°C, 5 h
NH2
Cl
+
H2N
Cl
N
H
Cl
Cl
O
1
2
3
NH
1, Na2CO3, MeCN, reflux, 24 h
NH
O
NH
O
N
H
4
Scheme 2.
N
CH
N
O
Cs2CO3, MeCN, 80°C, 2 h
HC
Br
4
+
HC
NH
O
N
H
5
6
manner (Scheme 4). The products can be easily sepa-
rated and purified by flash column chromatography.
(C≡CH) and 73 ppm (C≡CH). Due to symmetrical
structure of bis-cycloadducts 9, less number of both
proton and carbon NMR signals can be observed. In
addition, no acetylenic stretching vibration band was
present in their IR spectra. Exact mass measurements
also confirmed the assigned structures. Analysis of the
obtained data led us to conclude that the cycloaddition
occurred through a more energetically favored cyclic
transition state leading to 1,4-substituted triazole
derivatives rather than 1,5-regioisomers. These results
coincide with the previous literature findings which
have been observed in the cycloadditions of organic
azides with terminal acetylenic dipolarophiles [32–36].
Despite variation of the reactant molar ratio and
“click chemistry” catalyst in order to obtain only
disubstituted cycloadducts, the reaction ended up each
time to give a mixture of 8 and 9. Their structures were
identified on the basis of spectral and physical data.
The IR spectra of 8a–8h showed basically carbonyl,
1
NH, and C≡C stretching bands. In the H NMR
spectra, the triazole =CH proton resonated at around
δ 7.78 ppm as a singlet, the NHC=O signal appeared as
a singlet at δ 5.91 ppm, and the signal of methylene
protons on the bridging carbon atom between the
oxadiazole and triazole rings was also a singlet at
δ 5.27 ppm. In addition, we observed acetylenic proton
signal at δ 2.20 ppm. The 13C NMR signals were ba-
sically those of carbonyl carbons around δC 172 ppm,
iminic carbons of the oxadiazole rings in the range
δC 171–167 ppm, and acetylenic carbons at δC 78
In summary, we have demonstrated a practical
method to construct some novel azacrown ethers
carrying acetylenic side chain and their 1,3-dipolar
cycloaddition to a series of 1,2,4-oxadiazoles carrying
azidomethyl group. Thus, we have successfully
obtained macroazacyclic compounds carrying both
Scheme 3.
O
NOH
NH2
N
ClCH2C(O)Cl, Et3N
benzene, Δ
CN
N
NH2OH
Cl
R
R
R
O
N
NaN3
N
N3
R
7a–7h
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

ÖZER, DÜRÜST
700
Scheme 4.
R
R
R
N
N
N
O
N
O
N
O
N
N
Sodium ascorbate
CuSO4·5H2O, THF, r.t.
3 days to 2 weeks
N
N
N
6
+
7a–7h
+
N
N
N
N
CH
N
N
N
N
N
O
O
NH
NH
O
O
N
H
N
H
8
9
R = H (a), Me (b), F (c), Cl (d), Br (e), NO2 (f), MeO (g), MeS (h).
R
H
Me
44
F
Cl
30
42
Br
38
56
NO2
35
MeO
36
MeS
38
Yield of 8, %
Yield of 9, %
25
73
30
61
53
41
46
41
1,2,4-oxadiazole and triazole rings on the same mole-
cule and established their structures by physical and
spectroscopic methods.
equipped with a magnetic stirrer, cooling bath, internal
thermometer, and dropping funnel was charged with
a solution of 1,4-diaminobutane (10.0 g, 0.113 mol) in
methylene chloride (100 mL). Distilled water (80 mL)
and potassium carbonate (31.6 g, 0.222 mol) were
added to the solution with stirring, the mixture was ice-
cooled, and chloroacetyl chloride (24.5 mL, 0.222 mol)
was added over a period of 60–90 min, maintaining
the temperature below 10°C. The mixture was then
allowed to warm up to room temperature, and the
precipitate was filtered off. It was taken into 150 mL of
water, the mixture was vigorously stirred for 2 h, and
the product was filtered off and dried overnight in
a vacuum oven at 60°C. Yield 19.84 g (74%), white
solid, mp 132–133°C. IR spectrum (KBr), v, cm–1:
3321, 2939, 2928, 1643, 1610, 1550, 1504, 1454.
1H NMR spectrum, δ, ppm: 8.18 s (2H), 3.99 s (4H),
3.04 d (4H, J = 2.2 Hz), 1.37 s (4H). 13C NMR spec-
trum, δC, ppm: 165.96, 42.61, 39.32, 26.69. Mass spec-
trum (ESI+): m/z 264 [M + H]+.
EXPERIMENTAL
Reagents were purchased from commercial sources
and used as received. Melting points were measured in
capillary tubes on a Meltemp apparatus and are uncor-
1
13
rected. The H and C NMR spectra were recorded in
CDCl3 on Jeol and Varian spectrometers operating at
400 (1H) and 100 MHz (13C); the chemical shifts were
determined relative to the residual proton and carbon
signals of the solvent (CHCl3, δ 7.26 ppm; CDCl3,
δC 77.20 ppm). The IR spectra were recorded in KBr
on a Shimadzu S8000 spectrometer. HRMS measure-
ments were performed on Waters Synapt and Agilent
Technologies 6224 spectrometers using the ionization
modes specified. Routine TLC analyses were carried
out on pre-coated silica gel plates with fluorescent
indicator. Flash column chromatography was per-
formed on silica gel (230–400 mesh ASTM). A rotary
TLC apparatus (Chromatotron) was utilized for further
separation and purifications. Stain solutions of potas-
sium permanganate and iodine were used for visual-
ization of TLC spots.
1,4,9,12-Tetraazacyclohexadecane-2,11-dione (4)
[39, 40]. Compound 3 (5.0 g, 0.02 mol) and 1,4-bu-
tanediamine (1.83 g, 0.021 mol) were mixed in aceto-
nitrile (100 mL) under nitrogen, and sodium carbonate
(48.51 g, 0.46 mol) was added in portions with
mechanical stirring. The mixture was further stirred at
80°C for 24 h. When the reaction was complete (TLC),
the mixture was filtered, the filtrate was evaporated
N,N′-(Butane-1,4-diyl)bis(2-chloroacetamide) (3)
[37, 38]. A 500-mL three-necked round-bottomed flask
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

SYNTHESIS OF SOME AZAMACROCYCLES
701
under reduced pressure, and the residue was purified
by column chromatography on silica gel (CH2Cl2/
MeOH, 3:1). Yield 1.161 g (21%), white solid,
mp 141–142°C, Rf 0.25 (CH2Cl2/MeOH, 5:2). IR spec-
trum (KBr), ν, cm–1: 3356, 3321, 3267, 2943, 2874,
1643, 1539, 1442, 1242, 1153, 848. 1H NMR spectrum,
δ, ppm: 7.40 s (2H), 3.37–3.28 m (4H), 3.23 s (4H),
2.60 t (4H, J = 6.5 Hz), 1.63–1.48 m (10H). 13C NMR
spectrum, δC, ppm: 171.94, 52.89, 50.12, 37.77, 27.75,
27.52. Mass spectrum (ESI+): m/z 257 [M + H]+.
trum, δ, ppm: 8.01 d (2H, J = 9.6 Hz), 7.78 s (1H),
7.56–7.40 m (4H), 7.31–7.26 m (1H), 5.91 s (2H),
5.27 s (1H), 3.82 s (2H), 3.35 s (1H), 3.26 d (4H, J =
14.8 Hz), 3.34 d (1H, J = 1.6 Hz), 3.26 d (2H, J =
14.8 Hz), 3.09 d (2H, J = 5.6 Hz), 2.62–2.46 d.t (2H,
J = 24.4, 6.8, 6.4 Hz), 2.19 br.s (1H), 1.57–1.35 m
(8H). 13C NMR spectrum, δC, ppm: 172.32, 171.14,
171.09, 168.95, 145.36, 131.85, 129.09, 128.92,
127.60, 125.82, 123.54, 78.19, 73.39, 58.45, 58.36,
58.31, 55.73, 54.98, 50.55, 45.33, 44.76, 38.12, 38.03,
27.60, 26.14, 25.93. HRMS (ESI-TOF): m/z 534.2920
[M + H]+. C27H36N9O3. Calculated: M + H 534.2941.
1,12-Di(prop-2-yn-1-yl)-1,4,9,12-tetraazacyclo-
hexadecane-2,11-dione (6) [41]. 1,4,9,12-Tetraaza-
cyclohexadecane-2,11-dione (4, 519 mg, 2.025 mmol)
was dissolved in acetonitrile (30 mL), cesium carbon-
ate (2.836 g, 8.71 mmol), propargyl bromide
(0.721 mL, 8.096 mmol), and 4Å molecular sieves
were added in succession, and the mixture was stirred
under reflux for 2.5 h. After the reaction was complete
(TLC), the mixture was filtered, and the precipitate
was washed with acetonitrile. The solvent was evap-
orated under reduced pressure, and the residue was
purified by flash column chromatography (EtOAc/
MeOH, 5:1). Yield 362 mg (54%), white solid,
mp 164–165°C. IR spectrum (KBr), ν, cm–1: 3344,
3308, 3273, 3232, 2939, 2868, 2818, 2096, 1647, 1529,
Compound (9a). Yield 100 mg (73%), yellow oil,
Rf 0.378 (EtOAc/MeOH, 5:1). IR spectrum (KBr), ν,
cm–1: 3348, 3136, 3055, 2939, 2862, 2831, 1662, 1600,
1
1527, 1446, 1350, 1269, 1114. H NMR spectrum, δ,
ppm: 8.00–7.93 m (4H), 7.82 s (2H), 7.52–7.37 m
(8H), 5.89 s (4H), 3.76 s (4H), 3.19 s (4H), 3.05 s (4H),
2.49 s (4H), 1.49 d (8H, J = 6.7 Hz). 13C NMR spec-
trum, δC, ppm: 172.47, 171.37, 168.86, 145.52, 131.83,
129.41, 129.07, 128.88, 127.54, 125.80, 123.71, 58.50,
55.79, 50.52, 45.32, 38.12, 27.32, 26.03. HRMS (ESI-
TOF): m/z 735.3581 [M + H]+. C36H43N14O4. Calculat-
ed: M + H 735.3592.
Compounds 8b–8h and 9b–9h were synthesized in
a similar way.
1
1464, 1334, 1280, 1124. H NMR spectrum, δ, ppm:
7.20 br.s (2H), 3.35 s (4H), 3.29 s (4H), 3.10 s (4H),
2.53 s (4H), 2.20 s (2H), 1.53 s (4H), 1.44 s (4H).
13C NMR spectrum, δC, ppm: 170.82, 78.16, 73.40,
58.42, 54.90, 44.71, 37.96, 27.85, 26.06. Mass spec-
trum (ESI+): m/z 333 [M + H]+.
4-[(1-{[3-(4-Methylphenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-1H-1,2,3-triazol-4-yl)methyl]-9-(prop-2-yn-
1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione
(8b). Yield 30 mg (44%), white solid, mp 146–147°C,
Rf 0.480 (EtOAc/MeOH, 5:1). IR spectrum (KBr), ν,
cm–1: 3348, 3302, 3140, 3051, 2935, 2862, 1662, 1597,
4-({1-[(3-Phenyl-1,2,4-oxadiazol-5-yl)methyl]-
1H-1,2,3-triazol-4-yl}methyl)-9-(prop-2-yn-1-yl)-
1,4,9,12-tetraazacyclohexadecane-2,11-dione (8a)
and 4,9-bis({1-[(3-phenyl-1,2,4-oxadiazol-5-yl)-
methyl]-1H-1,2,3-triazol-4-yl}methyl)-1,4,9,12-
tetraazacyclohexadecane-2,11-dione (9a). Copper(II)
sulfate pentahydrate (13.7 mg, 0.055 mmol) was added
with stirring to a solution of 5-(azidomethyl)-3-phenyl-
1,2,4-oxadiazole (7a, 55 mg, 0.274 mmol) and aza-
crown alkyne 6 (50 mg, 0.150 mmol) in THF (25 mL).
Sodium ascorbate (27.1 mg, 0.137 mmol) was then
added in portions over a period of 10 min, and the mix-
ture was stirred for 3 days to 2 weeks at room tempera-
ture. The solvent was evaporated, and the crude
material was purified by flash column chromatography
(EtOAc/MeOH, 6:1) to give 8a and 9a.
1
1531, 1450, 1269, 1230. H NMR spectrum, δ, ppm:
7.90–7.86 m (2H), 7.77 s (1H), 7.25 d.d (4H, J = 4.4,
3.5 Hz), 5.89 d (2H, J = 1.0 Hz), 3.81 s (2H), 3.33 d
(2H, J = 9.4 Hz), 3.31–3.20 m (4H), 3.09 d (4H, J =
6.0 Hz), 2.54 d.d (2H, J = 13.2, 6.8 Hz), 2.49 t (2H, J =
6.4 Hz), 2.38 s (3H), 2.18 d (1H, J = 1.4 Hz), 1.53 s
13
(4H), 1.47 d.d (4H, J = 18.9, 8.7 Hz). C NMR spec-
trum, δC, ppm: 171.97, 168.86, 142.19, 129.67, 127.42,
122.91, 77.98, 73.31, 61.75, 58.31, 55.55, 54.80, 50.52,
45.27, 44.58, 38.00, 27.48, 25.70, 21.58. Mass spec-
trum (ESI+): m/z 548 [M + H]+. HRMS (ESI-TOF):
m/z 548.3099 [M + H]+. C28H38N9O3. Calculated:
M + H 548.3089.
4,9-Bis[(1-{[3-(4-methylphenyl)-1,2,4-oxadiazol-
5-yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-1,4,9,12-
tetraazacyclohexadecane-2,11-dione (9b). Yield
50 mg (53%), yellow oil, Rf 0.375 (EtOAc/MeOH,
5:1). IR spectrum (KBr), ν, cm–1: 3348, 3136, 2939,
Compound 8a. Yield 20 mg (25%), yellow oil,
Rf 0.489 (EtOAc/MeOH, 5:1). IR spectrum (KBr), ν,
cm–1: 3344, 3302, 3136, 3070, 2935, 2862, 2380, 1638,
1
1600, 1527, 1446, 1350, 1276, 1114. H NMR spec-
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ÖZER, DÜRÜST
702
1
2862, 1658, 1597, 1531, 1481, 1454, 1411, 1346, 1273,
1226. H NMR spectrum, δ, ppm: 7.87 d (4H, J =
1384, 1342, 1265. H NMR spectrum, δ, ppm: 7.98–
1
7.93 d.d (2H, J = 8.4, 1.2 Hz), 7.76 s (1H), 7.47–
7.41 d.d (3H, J = 8.4, 1.2 Hz), 7.29–7.26 m (1H),
5.91 s (2H), 3.81 s (2H), 3.40–3.01 m (5H), 2.60–
2.48 d.t (4H, J = 20.8, 12.0, 5.6 Hz), 2.21–2.16 m (2H),
1.90–1.65 br.s (4H), 1.60–1.15 m (8H). 13C NMR spec-
trum, δC, ppm: 172.63, 171.39, 168.13, 145.62, 138.04,
129.42, 128.88, 124.30, 123.60, 78.23, 73.37, 58.49,
58.42, 55.73, 55.11, 54.93, 50.46, 45.28, 44.88, 44.73,
38.13, 38.04, 37.98, 29.78, 27.85, 27.63, 27.58, 26.13,
26.09, 25.99. HRMS (ESI-TOF): m/z 568.2539
[M + H]+. C27H35ClN9O3. Calculated: M + H 568.2551.
7.6 Hz), 7.80 s (2H), 7.50 t (2H, J = 5.2 Hz), 7.26–
7.24 m (4H), 5.88 s (4H), 3.78 s (4H), 3.23 s (4H),
3.07 s (4H), 2.51 s (4H), 2.37 s (6H), 1.52 d (8H, J =
10.7 Hz). 13C NMR spectrum, δC, ppm: 172.03,
168.83, 142.16, 130.85, 127.40, 122.92, 58.44, 55.40,
50.55, 45.27, 38.09, 27.24, 25.83, 21.55. Mass spec-
trum (ESI+): m/z 763 [M + H]+. HRMS (ESI-TOF):
m/z 763.3916 [M + H]+. C38H47N14O4. Calculated:
M + H 763.3905.
4-[(1-{[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-1H-1,2,3-triazol-4-yl)methyl]-9-(prop-2-yn-
1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione
(8c). Yield 25 mg (30%), yellow oil, Rf 0.405 (EtOAc/
MeOH, 5:1). IR spectrum (KBr), ν, cm–1: 3348, 3302,
3140, 2858, 1662, 1585, 1531, 1481, 1450, 1419, 1342,
4,9-Bis[(1-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-
5-yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-1,4,9,12-
tetraazacyclohexadecane-2,11-dione (9d). Yield
60 mg (42%), yellow oil, Rf 0.320 (EtOAc/MeOH,
5:1). IR spectrum (KBr), ν, cm–1: 3348, 3136, 2928,
2854, 1658, 1597, 1570, 1527, 1465, 1408, 1342, 1265.
1H NMR spectrum, δ, ppm: 7.95–7.89 m (4H), 7.80 s
(2H), 7.51–7.45 br.t (2H, J = 5.6 Hz), 7.44–7.38 d.d
(4H, J = 8.8, 2.4 Hz), 5.89 s (4H), 3.77 s (4H),
3.21 br.s (4H), 3.05 br.s (4H), 2.50 br.s (4H), 1.21 br.s
(8H). 13C NMR spectrum, δC, ppm: 172.63, 171.39,
168.13, 145.62, 138.04, 129.42, 128.88, 124.30,
123.60, 58.52, 55.89, 50.56, 45.28, 38.15, 31.99,
30.36, 29.77, 29.73, 29.69, 29.58, 29.43, 29.23, 27.35,
26.08. HRMS (ESI-TOF): m/z 803.2804 [M + H]+.
C36H41Cl2N14O4. Calculated: M + H 803.2812.
1
1226. H NMR spectrum, δ, ppm: 8.06–7.98 d.d (2H,
J = 8.0, 5.6 Hz), 7.77 s (1H), 7.46 br.s (1H), 7.26 d
(1H, J = 6.4 Hz), 7.18–7.11 t (2H, J = 8.0 Hz), 5.91 s
(2H), 3.80 s (2H), 3.35 s (2H), 3.25 d (4H, J = 9.2 Hz),
3.09 s (4H), 2.63–2.44 d.t (4H, J = 16.0, 12.0, 5.6 Hz),
2.19 s (1H), 1.61–1.38 m (8H). 13C NMR spectrum, δC,
ppm: 172.46, 171.13, 168.13, 164.91 d (C–F, J =
251.3 Hz), 145.40, 129.90, 129.81, 123.54, 122.09,
122.06, 116.47, 116.25, 78.21, 73.39, 58.47, 58.32,
55.73, 55.06, 45.29, 44.84, 38.12, 38.04, 27.61, 27.58,
26.12, 25.96. HRMS (ESI-TOF): m/z 552.2827
[M + H]+. C27H35FN9O3. Calculated: M + H 552.2847.
4-[(1-{[3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-1H-1,2,3-triazol-4-yl)methyl]-9-(prop-2-yn-
1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione
(8e). Yield 35 mg (38%), yellow oil, Rf 0.410 (EtOAc/
MeOH, 5:1). IR spectrum (KBr), ν, cm–1: 3425, 3360,
3302, 3055, 2935, 2866, 1666, 1597, 1527, 1469, 1423,
4,9-Bis[(1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-
yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-1,4,9,12-
tetraazacyclohexadecane-2,11-dione (9c). Yield
70 mg (61%), white solid, Rf 0.262 (EtOAc/MeOH,
5:1). IR spectrum (KBr), ν, cm–1: 3348, 3140, 3055,
2939, 2862, 2831, 1666, 1597, 1566,1527, 1469, 1408,
1
1404, 1342, 1265. H NMR spectrum, δ, ppm: 7.91–
1
1342, 1265. H NMR spectrum, δ, ppm: 8.04–7.95 m
7.87 d (2H, J = 8.4 Hz), 7.76 br.s (1H), 7.62–7.58 d
(2H, J = 8.4 Hz), 7.45 br.s (1H), 7.28–7.22 m (1H),
5.91 s (2H), 3.82 s (2H), 3.57 s (1H), 3.36 s (1H),
3.27 d (4H, J = 16.0 Hz), 3.09 s (4H), 2.61–2.48 d.t
(4H, J = 22.8, 16.4, 6.4 Hz), 1.70 br.s (6H), 1.60–
1.40 m (4H). 13C NMR spectrum, δC, ppm: 172.46,
171.12, 167.99, 132.42, 132.23, 129.09, 126.52,
124.77, 123.47, 78.04, 74.10, 58.49, 58.34, 55.29,
50.48, 45.29, 44.88, 38.13, 38.04, 27.64, 27.58, 26.11,
25.98. HRMS (ESI-TOF): m/z 612.2026 [M + H]+.
C27H35BrN9O3. Calculated: M + H 612.2046.
(4H), 7.82 d (2H, J = 14.6 Hz), 7.53–7.44 m (2H),
7.12 t (4H, J = 8.2 Hz), 5.90 s (4H), 3.76 d (4H, J =
15.2 Hz), 3.21 s (4H), 3.04 d (4H, J = 15.1 Hz), 2.51 s
(4H), 1.52 s (8H). 13C NMR spectrum, δC, ppm:
172.53, 171.36, 168.08, 164.87 d (C–F, (J = 251.3 Hz),
145.58, 129.86, 129.77, 123.62, 122.07, 122.03, 116.44,
116.22, 60.49, 58.51, 55.87, 50.54, 45.28, 38.13, 27.35,
26.07. HRMS (ESI-TOF): m/z 771. 3391 [M + H]+.
C36H41F2N14O4. Calculated: M + H 771.3401.
4-[(1-{[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-1H-1,2,3-triazol-4-yl)methyl]-9-(prop-2-yn-
1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione
(8d). Yield 30 mg (30%), yellow oil, Rf 0.420 (EtOAc/
MeOH, 5:1). IR spectrum (KBr), ν, cm–1: 3348, 3302,
3136, 3055, 2935, 2862, 1662, 1597, 1527, 1465, 1408,
4,9-Bis[(1-{[3-(4-bromophenyl)-1,2,4-oxadiazol-
5-yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-1,4,9,12-
tetraazacyclohexadecane-2,11-dione (9e). Yield
75 mg (56%), yellow oil, Rf 0.273 (EtOAc/MeOH,
5:1). IR spectrum (KBr), ν, cm–1: 3348, 3140, 3055,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

SYNTHESIS OF SOME AZAMACROCYCLES
703
2939, 2862, 2831, 1666, 1597, 1566, 1527, 1469, 1408,
1342, 1265. H NMR spectrum, δ, ppm: 7.89–7.85 m
6.96–6.93 m (2H), 5.88 s (2H), 3.82 t (3H, J = 3.3 Hz),
3.80 s (2H), 3.34 d (2H, J = 1.2 Hz), 3.26 d (4H, J =
14.7 Hz), 3.08 d (4H, J = 3.1 Hz), 2.52 d.t (4H, J =
13.0, 6.0 Hz), 2.18 d (1H, J = 0.9 Hz), 1.53 s (4H),
1.50–1.43 m (4H). 13C NMR spectrum, δC, ppm:
172.01, 171.19, 168.62, 162.39, 145.37, 129.26,
123.51, 118.19, 114.47, 78.19, 72.87, 58.47, 55.76,
54.96, 53.55, 50.54, 45.32, 44.72, 38.10, 38.01, 27.63,
26.18, 25.93. HRMS (ESI-TOF): m/z 564.3041
[M + H]+. C28H38N9O4. Calculated: M + H 564.3047.
1
(4H), 7.79 s (2H), 7.59 d.d (4H, J = 11.1, 3.4 Hz),
7.49 t (2H, J = 5.3 Hz), 5.91 s (4H), 3.80 s (4H), 3.24 s
(4H), 3.08 s (4H), 2.53 s (4H), 1.53 d (8H, J = 9.6 Hz).
13C NMR spectrum, δC, ppm: 172.59, 171.32, 168.26,
132.41, 129.06, 126.52, 124.75, 123.52, 58.54, 55.89,
50.62, 45.28, 38.17, 27.36, 26.08. HRMS (ESI-TOF):
m/z 891.1828 [M + H]+. C36H41Br2N14O4. Calculated:
M + H 891.1802.
4-[(1-{[3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-1H-1,2,3-triazol-4-yl)methyl]-9-(prop-2-yn-
1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-dione
(8f). Yield 45 mg (35%), yellow oil, Rf 0.522 (EtOAc/
MeOH, 5:1). IR spectrum (KBr), ν, cm–1: 3448, 3302,
3140, 3101, 2939, 2862, 1662, 1612, 1531, 1450, 1415,
4,9-Bis[(1-{[3-(4-methoxyphenyl)-1,2,4-oxadi-
azol-5-yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-
1,4,9,12-tetraazacyclohexadecane-2,11-dione (9g).
Yield 54 mg (46%), white solid, mp 191–192°C,
Rf 0.180 (EtOAc/MeOH, 5:1). IR spectrum (KBr), ν,
cm–1: 3332, 3124, 2935, 2839, 1658, 1612, 1597, 1573,
1
1
1342, 1292. H NMR spectrum, δ, ppm: 8.31 d (2H,
1527, 1481, 1346, 1303. H NMR spectrum, δ, ppm:
J = 8.9 Hz), 8.20 d.d (2H, J = 7.3, 6.7 Hz), 7.79 s (1H),
7.41 t (1H, J = 5.2 Hz), 7.29–7.25 m (1H), 5.96 s (2H),
3.81 s (2H), 3.35 d (2H, J = 1.7 Hz), 3.32–3.20 m (4H),
3.06 d (4H, J = 12.5 Hz), 2.53 d.t (4H, J = 13.1,
5.9 Hz), 2.19 s (1H), 1.53 s (4H), 1.52–1.43 m (4H).
13C NMR spectrum, δC, ppm: 173.37, 171.22, 171.15,
170.92, 167.41, 149.78, 145.51, 131.68, 128.67,
124.31, 123.64, 78.25, 73.38, 58.51, 58.29, 50.29,
45.24, 45.00, 38.13, 38.04, 27.64, 27.49, 26.07. HRMS
(ESI-TOF): m/z 579.2771 [M + H]+. C27H35N10O5.
Calculated: M + H 579.2792.
7.90 d (4H, J = 8.2 Hz), 7.79 s (2H), 7.46 d.d (2H, J =
12.7, 7.3 Hz), 6.91 t (4H, J = 7.5 Hz), 5.86 s (4H),
3.81 d (6H, J = 0.8 Hz), 3.78–3.74 m (4H), 3.21 s (4H),
3.05 s (4H), 2.49 s (4H), 1.50 d (8H, J = 11.0 Hz).
13C NMR spectrum, δC, ppm: 172.10, 171.33, 168.57,
162.35, 145.57, 129.22, 123.59, 118.18, 114.44, 58.56,
55.78, 55.50, 50.55, 45.31, 38.11, 27.37, 26.07. HRMS
(ESI-TOF): m/z 795.3804 [M + H]+. C38H47N14O6.
Calculated: M + H 795.3803.
4-{[1-({3-[4-(Methylsulfanyl)phenyl]-1,2,4-oxadi-
azol-5-yl}methyl)-1H-1,2,3-triazol-4-yl]methyl}-9-
(prop-2-yn-1-yl)-1,4,9,12-tetraazacyclohexadecane-
2,11-dione (8h). Yield 40 mg (38%), yellow oil,
Rf 0.522 (EtOAc/MeOH, 5:1). IR spectrum (KBr), ν,
cm–1: 3448, 3302, 3136, 3055, 2931, 2858, 1662, 1597,
4,9-Bis[(1-{[3-(4-nitrophenyl)-1,2,4-oxadiazol-5-
yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-1,4,9,12-
tetraazacyclohexadecane-2,11-dione (9f). Yield
75 mg (41%), yellow solid, mp 133–134°C, Rf 0.370
(EtOAc/MeOH, 5:1). IR spectrum (KBr), ν, cm–1:
3348, 3136, 2928, 2854, 1658, 1597, 1570, 1527, 1465,
1
1527, 1469, 1408, 1346, 1269. H NMR spectrum, δ,
ppm: 7.91 d (2H, J = 8.1 Hz), 7.76 s (1H), 7.47 t (1H,
J = 5.3 Hz), 7.27 t (3H, J = 6.1 Hz), 5.90 s (2H), 3.81 s
(2H), 3.35 t (2H, J = 3.9 Hz), 3.26 d (4H, J = 15.1 Hz),
3.09 d (4H, J = 3.7 Hz), 2.59–2.53 m (3H), 2.52–
2.46 m (4H), 2.19 d.d (1H, J = 2.2, 1.5 Hz), 1.54 s
(4H), 1.52–1.42 m (4H). 13C NMR spectrum, δC, ppm:
172.29, 171.38, 168.56, 145.61, 143.90, 127.78,
125.79, 123.61, 121.92, 78.22, 73.37, 58.48, 55.74,
55.02, 50.53, 45.32, 44.78, 38.11, 38.03, 27.61, 26.16,
25.96, 15.04. HRMS (ESI-TOF): m/z 580.2803
[M + H]+. C28H38N9O3S. Calculated: M + H 580.2818.
1
1408, 1342, 1265. H NMR spectrum, δ, ppm: 8.29 d
(4H, J = 8.0 Hz), 8.18 d (4H, J = 8.4 Hz), 7.82 s (2H),
7.48 t (2H, J = 5.2 Hz), 5.96 s (4H), 3.81 s (4H),
3.21 br.s (4H), 3.06 s (4H), 2.53 s (4H), 1.53 br.s (8H).
13C NMR spectrum, δC, ppm: 173.36, 171.38, 167.39,
149.76, 145.62, 131.65, 128.65, 124.30, 123.65, 58.48,
55.98, 50.54, 45.25, 38.16, 27.37, 26.09. HRMS
(ESI-TOF): m/z 825.3261 [M + H]+. C36H41N16O8.
Calculated: M + H 825.3293.
4-[(1-{[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-
yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-9-(prop-2-
yn-1-yl)-1,4,9,12-tetraazacyclohexadecane-2,11-
dione (8g). Yield 30 mg (36%), white solid, mp 124–
125°C, Rf 0.300 (EtOAc/MeOH, 5:1). IR spectrum
(KBr), ν, cm–1: 3441, 3348, 3302, 3136, 3059, 2939,
2839, 1662, 1573, 1531, 1481, 1423, 1346, 1257.
1H NMR spectrum, δ, ppm: 7.95–7.92 m (2H), 7.76 s
(1H), 7.48 t (1H, J = 5.3 Hz), 7.25 t (1H, J = 4.3 Hz),
4,9-Bis{[1-({3-[4-(methylsulfanyl)phenyl]-1,2,4-
oxadiazol-5-yl}methyl)-1H-1,2,3-triazol-4-yl]-
methyl}-1,4,9,12-tetraazacyclohexadecane-2,11-
dione (9h). Yield 60 mg (41%), white solid, mp 184–
185°C, Rf 0.370 (EtOAc/MeOH, 5:1). IR spectrum
(KBr), ν, cm–1: 3441, 3147, 2924, 2854, 1647, 1593,
1
1527, 1465, 1465, 1408, 1384, 1346. H NMR spec-
trum, δ, ppm: 7.86 d (4H, J = 8.0 Hz), 7.80 s (2H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

ÖZER, DÜRÜST
704
12. Gokel, G.W., Barbour, L.J., Ferdani, R., and Hu, J., Acc.
Chem. Res., 2002, vol. 35, p. 878.
https://doi.org/10.1021/ar000093p
13. Li, C., Cui, F., Mao, R., Huo, R., and Qu, G., Org.
Biomol. Chem., 2012, vol. 10, p. 869.
7.48 t (2H, J = 5.5 Hz), 7.27–7.24 m (4H), 5.88 s (4H),
3.76 s (4H), 3.21 s (4H), 3.05 s (4H), 2.49 d.d (10H,
13
J = 11.4, 3.4 Hz), 1.50 d (8H, J = 10.8 Hz). C NMR
spectrum, δC, ppm: 172.29, 171.38, 168.56, 145.61,
143.90, 127.78, 125.79, 123.61, 121.92, 58.56, 55.82,
50.56, 45.31, 38.13, 27.35, 26.07, 15.01. HRMS
(ESI-TOF): m/z 827.3316 [M + H]+. C38H47N14O4S2.
Calculated: M + H 827.3346.
https://doi.org/10.1039/C1OB06241G
14. Lamb, J.D., Izatt, R.M., Christensen, J.J., and
Eatough, D.J., Coordination Chemistry of Macrocyclic
Compounds, Melson, G.A., Ed., New York: Plenum,
1979, p. 145.
15. Dietrich, B., Lehn, J.M., Sauvage, J.P., and Blanzat, J.,
Tetrahedron, 1973, vol. 29, p. 1629.
FUNDING
This study was performed under financial support by the
Directorate of Research Projects Commission, Bolu Abant
İzzet Baysal University (BAP grant no. 2013.03.03.624).
https://doi.org/10.1016/S0040-4020(01)83409-8
16. Lehn, J.M., Acc. Chem. Res., 1978, vol. 11, p. 49.
https://doi.org/10.1021/ar50122a001
CONFLICT OF INTEREST
No conflict of interest is declared by the authors.
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