Synthesis of New Bis-1,2,4-Oxadiazoline Derivatives via 1,3-Dipolar Cycloaddition Reaction

Article abstract of DOI:10.1002/jhet.2500

A series of novel bis-oxadiazoline derivatives 4 was synthesized via 1,3-dipolar cycloaddition reaction of bis-aldimines 3, and nitrile oxides generated in situ from various benzohydroximinoyl chlorides in the presence of Et₃N. The target products were confirmed by IR,¹H-NMR, and mass spectrometry.

Full text of DOI:10.1002/jhet.2500

Month 2015
Synthesis of New Bis-1,2,4-Oxadiazoline Derivatives via 1,3-
Dipolar Cycloaddition Reaction
a
b
c
*
Fei Chen, Hua Zeng, and Fang-Ming Liu
aDepartment of Medicinal and Organic Chemistry, College of Pharmacy, Xinjiang Medical University,
Urumqi, 830011, China
bImport and Export of Mining Company, Tebian Electric Apparatus Stock Co. Ltd., Changji, 831100, China
cCollege of Materials and Chemical Engineering, Hangzhou Normal University, Hangzhou, 310036, China
*
E-mail: fmliu859@sohu.com
Received April 17, 2015
DOI 10.1002/jhet.2500
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel bis-oxadiazoline derivatives 4 was synthesized via 1,3-dipolar cycloaddition reaction of
bis-aldimines 3, and nitrile oxides generated in situ from various benzohydroximinoyl chlorides in the pres-
1
ence of Et3N. The target products were confirmed by IR, H-NMR, and mass spectrometry.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
useful in enhancing the biological profile and selectivity of
monomeric leads [15–17]. Based on this consideration, we
reported here the synthesis of new 4,5-dihydro-1,2,4-
oxadiazoline dimerics (Scheme 1) through 1,3-dipolar cy-
cloaddition reaction.
The concept of 1,3-dipole was first introduced by
Huisgen in 1963 [1]. Since that time, the 1,3-dipolar cyclo-
addition, consisting of the reaction of a dipolarophile with
a 1,3-dipolar compound, has became the classic reaction in
organic chemistry for the production of various five-
membered heterocycles. Much work has been done on
the reactions and the mechanism of 1,3-dipolar cycloaddi-
tion [2–9]. The asymmetric 1,3-dipolar cycloaddition reac-
tion to an enviable methodology, not only for the
construction of chiral functionalised normal-ring
carbocycles but also for the synthesis of complex natural
products. In addition, different substituents can be included
in the dipole and the dipolarophile, resulting in a broad
range of possible cycloadducts, which can serve as useful
synthetic building blocks [10].
Oxadiazoline was important for both chemical and bio-
logical purposes. Oxadiazolines played a crucial role in
the development of theory in heterocyclic chemistry and
also was extensively used as useful synthon in organic syn-
thesis. Also, a number of oxadiazoline have been reported
to exhibit diverse pharmacological properties such as anti-
microbial, pesticides, insecticides, and antiviral activity
[11,12]. Aware of the multifactorial nature of many disease,
the multi-target-directed ligand approach was accepted as
an effective strategy for designing ligands and inhibitors
and creating new drugs [13,14]. The new dimeric com-
pounds, containing two identical or different structural
units, connected by a linker of suitable length, have proved
RESULTS AND DISCUSSION
A series of novel 4,5-dihydro-1,2,4-oxadiazoline deriva-
tives were synthesized using aniline as a starting material.
Intermediate compound (N,N-bis(4-(4-formoxyl)phenoxy)
ethyl)aniline 2 was synthesized by the SN2 reaction of
compound N,N-bis[2-(p-tolylsulfonoxyl)ethyl]-benzena-
mine 1 [18] with 4-hydroxy benzaldehyde heated to 90°C
for 30h dissolved in EtOH. Compounds imines 3a–d
[19] were synthesized via the nucleophilic addition be-
tween 2 [20] and substituted aniline. Finally, compounds
3a–d underwent 1,3-dipolar cycloadditions with benzohy-
droximinoyl chlorides in the presence of Et3N stirred in
CH2Cl2 leading to the formation of cycloadducts. Various
analytical techniques, such as IR, 1H-NMR, mass spectrum
(MS), and elemental analysis, were utilized to confirm the
structural identities of the new products.
In IR spectra of the final compounds, there was a moder-
ate strong absorption at 1682–1692 cmꢀ1 due to the pres-
ence of C¼N. A strong absorption at 1247–1252 and
1163–1175cmꢀ1 for C–O–C and C–N single bond of the
1
1,2,4-oxadiazoline moiety, respectively. In the H-NMR
spectra of the titled compounds, the presence of a singlet
© 2015 HeteroCorporation

F. Chen, H. Zeng, and F.-M. Liu
Vol 000
Scheme 1. Synthetic process of the title compounds.
Scheme 2. Proposed intramolecular 1,3-diploar cycloaddition mechanism of cycloadduct 4a.
at δ 6.30–6.45ppm was ascribed to the CH of 1,2,4-
oxadiazoline ring, the multiplet at δ 6.67–7.81 was attrib-
uted to the aromatic protons, and the triplet at δ 4.20–4.23,
3.89–3.91 were attributed to OCH2 and NCH2, respectively.
In addition, the signal for OCH3 and CH3 appeared at δ
3.70–3.80 and 2.23–2.35ppm, respectively. To speak of,
in the IR spectra of the compound 2, there was a strong ab-
sorption at 1678 and 1597 cmꢀ1 due to the presence of
A conceivable intramolecular 1,3-dipolar cycloaddition
mechanism was proposed in Scheme 2. In the presence of
Et3N, the nitrile oxide generated in situ and C¼N double
bond forms a cyclic transition state and the σ-bonds of
C–N and C–O were formed simultaneously to obtain the
1,2,4-oxadiazole ring; the plausible mechanism of com-
pounds 4b–p was proposed analogously.
1
CHO and C¼N; in H-NMR, the singlet at δ 9.88 ppm
CONCLUSION
was attributed to the aldehyde protons. In the MS, molecu-
lar ions plus hydrogen signals of all target compounds were
attained from electrospray ionization–mass spectrometry
(ESI-MS).
In summary, we have synthesized a series of novel bis-
oxadiazoline derivatives 4a–p via 1,3-dipolar cycloaddi-
tion reaction of bis-aldimines and para-substituted aniline,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis via 1,3-Dipolar Cycloaddition Reaction
N,N-Bis(2-(4-(phenylimino-methyl)phenoxy)ethyl)aniline (3a).
and nitrile oxides, generated in situ from various
benzohydroximinoyl chlorides in the presence of Et3N.
The new dimeric compounds, containing two identical
structural units, connected by a linker of suitable length,
it is probably useful in enhancing the biological profile
and selectivity of monomeric leads.
Pale white solid (89%); mp 143–144°C; FTIR ν 1602
(C¼N), 1364, 1163 (C–N), 1245 (C–O–C) cmꢀ1
;
1H-
NMR (CDCl3, 400MHz) δ 7.39–6.70 (m, 23H, ArH), 6.64
(s, 2H, CH¼N), 4.19 (t, 4H, J=5.9Hz, OCH2), 3.90 (t,
4H, J=5.9Hz, NCH2); MS (ESI): m/z 540 (M++1). Anal.
Calcd for C36H33N3O2: C, 80.12; H, 6.16; N, 7.79. Found:
C, 80.01; H, 6.12; N, 7.58.
EXPERIMENTAL
N,N-Bis(2-(4-(((4-chlorophenyl)imino)methyl)phenoxy)ethyl)aniline
(3b).
Yellow solid (90%); mp 174–176°C; FTIR ν 1607
All reagents were of commercial availability. All the synthe-
sis reactions were performed under open air. Reactions were
monitored by thin-layer chromatography (TLC). Melting
points were measured on a mettler FP-5 capillary melting
point apparatus and were uncorrected. The IR spectra were
determined as potassium bromide pellet on a Bruker Equi-
nox 55 FTIR spectrophotometer. 1H-NMR spectra were re-
corded on a Bruker 400MHz spectrometer in CDCl3 using
tetramethylsilane (TMS) as internal reference. Mass spec-
tra were recorded on an Agilent 5975 apparatus. Elemental
analyses were conducted on a Perkin-Elmer 2400 elemen-
tal analyzer. Compounds 1 [18], 2,2′-(phenylazanediyl)
diethanol [21], and benzohydroximinoyl chlorides [22]
(C¼N), 1363, 1165 (C–N), 1247 (C–O–C) cmꢀ1; H-NMR
(CDCl3, 400 MHz) δ 7.68–6.70 (m, 21H, ArH), 6.67 (s, 2H,
CH¼N), 4.27 (t, 4H, J=5.9Hz, OCH2), 3.92 (t, 4H,
J=5.9Hz, NCH2); MS (ESI): m/z 608 (M++1). Anal. Calcd
for C36H31Cl2N3O2: C, 71.05; H, 5.13; N, 6.91. Found: C,
1
70.98; H, 5.10; N, 6.82.
N,N1-Bis(2-(4-((4-tolylimino)methyl)phenoxy)ethyl)aniline
(3c). Pale yellow solid (91%); mp 157–158°C; FTIR ν
1600 (C¼N), \1166 (C–N), 1247 (C–O–C) cmꢀ1; H-
1
NMR (CDCl3, 400 MHz) δ 7.44–6.73 (m, 21H, ArH),
6.64 (s, 2H, CH¼N), 4.20 (t, 4H, J = 6.1 Hz, OCH2),
3.89 (t, 4H, J = 6.1 Hz, NCH2), 2.32 (s, 6H, CH3); MS
(ESI): m/z 568 (M++1). Anal. Calcd for C38H37N3O2: C,
were synthesized according to the reported literatures.
General procedure for the synthesis of (N,N-bis(4-(4-
formoxyl)phenoxy)ethyl)aniline 2 [20]. In a 150ml round-
80.39; H, 6.57; N, 7.40. Found: C, 80.12; H, 6.56; N, 7.24.
N,N-Bis(2-(4-(((4-methoxyphenyl)imino)methyl)phenoxy)
ethyl)aniline (3d). Pale white solid (93%); mp 175–176°C;
bottomed three-necked flask equipped with a condenser
and drying tube, KOH (1.71 g, 30.6 mmol) was dissolved
in EtOH (90 cm3), and 4-hydroxy benzaldehyde (3.74 g,
30.6 mmol) was added while stirring; 30 min later, 1
(4.92 g, 10.05mmol) was added and the solution was
heated at 90°C for 30 h (using TLC to judge the
termination of the reaction). The reaction mixture was
cooled and poured into water (60 cm3), and the
precipitate was collected and washed with water and
ethanol, in sequence, and purified by silica gel column
chromatography (ethylacetate/petroleum ether = 1:4, v/v)
to afford the pale yellow solid.
FTIR ν 1603 (C¼N), 1359, 1165 (C–N), 1242 (C–O–C)
1
cmꢀ1; H-NMR (CDCl3, 400MHz) δ 7.44–6.74 (m, 21H,
ArH), 6.67 (s, 2H, CH¼N), 4.20 (t, 4H, J =6.0 Hz,
OCH2), 3.89 (t, 4H, J =6.0 Hz, NCH2), 3.78 (s, 6H,
OCH3); MS (ESI): m/z 600 (M++1). Anal. Calcd for
C38H37N3O4: C, 76.10; H, 6.22; N, 7.01. Found: C,
76.03; H, 6.17; N, 6.89.
General procedure for the preparation of N,N-bis(2-(4-
(3,4-di-substituted phenyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)
phenoxy)ethyl)anilines (4a–p).
A
mixture of the
appropriate benzohydroximinoyl chlorides (2.1 mmol)
and the imine 3 (1 mmol) was stirred in CH2Cl2 (5 cm3).
Pale yellow solid (72%); mp 99–101°C; FTIR ν 1678
After dissolution of the reactants,
a solution of
(CHO) 1597 (C¼N), 1349 (C–N), 1261 (C–O–C) cmꢀ1
;
triethylamine (0.5 cm3) was added dropwise. Then, the
solution was stirred at room temperature for a further
2 days. The solid mass separated out was filtered off, and
the filtrate was evaporated under reduced pressure, and
the residue was chromatographed on a silica gel column
using ethylacetate : petroleum ether (1:3, v/v) as eluent to
afford the corresponding 4,5-dihydro-1,2,4-oxadiazolines
derivatives 4.
1H-NMR (CDCl3, 400 MHz) δ 9.88 (s, 2H, CHO),
7.82–6.78 (m, 13H, ArH), 4.28 (t, 4H, J = 5.9 Hz, OCH2),
3.94 (t, 4H, J =5.9 Hz, NCH2); MS (EI): m/z 389 (M+).
Anal. Calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60.
Found: C, 73.93; H, 5.91; N, 3.52.
General procedure for the synthesis of N,N-bis(2-(4-
(substituted phenyl methyl)phenoxy)ethyl)anilines (3a–d)
[19].
To aniline or 4-substituted aniline, 2 mmol was
N,N-Bis(2-(4-(3,4-diphenyl-4,5-dihydro-1,2,4-oxadiazol-5-
added a solution of the compound 2 (1mmol) in anhydrous
ethanol (10cm3), after dissolution of the reactants, then
refluxed in the presence of a catalytic amount of glacial
acetic acid for 2–4h (monitored by TLC). The solution was
filtered and concentrated under reduced pressure to afford
crude produce, which was purified by silica gel column
chromatography (ethylacetate/petroleum ether=1:4, v/v) to
afford the corresponding imines 3.
yl)phenoxy)ethyl)aniline (4a).
Pale yellow solid (62%);
mp 67–68°C; FTIR ν 1684 (C¼N), 1375, 1171 (C–N),
1247 (C–O–C) cmꢀ1 1H-NMR (CDCl3, 400MHz) δ
;
7.44–6.67 (m, 33H, ArH), 6.32 (s, 2H, 1,2,4-oxadiazoline
ring CH), 4.20 (t, 4H, J=5.7Hz, OCH2), 3.89 (t, 4H,
J=5.7Hz, NCH2); MS (ESI): m/z 778 (M++1). Anal.
Calcd for C50H43N5O4: C, 77.20; H, 5.57; N, 9.00. Found:
C, 77.10; H, 5.58; N, 8.87.
Journal of Heterocyclic Chemistry
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F. Chen, H. Zeng, and F.-M. Liu
Vol 000
N,N-Bis(2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-
1,2,4-oxadiazol-5-yl)phenoxy)ethyl)aniline (4b).
N,N-Bis(2-(4-(4-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-
dihydro-1,2,4-oxadiazol-5-yl)phenoxy)ethyl)aniline (4h).
Pale
Pale
yellow solid (65%); mp 83–84°C; FTIR ν 1692 (C¼N),
1381, 1175 (C–N), 1252 (C–O–C) cmꢀ1 1H-NMR
yellow solid (68%); mp 74–75°C; FTIR ν 1689
1
(C¼N), 1389, 1163 (C–N), 1252 (C–O–C) cmꢀ1; H-
;
NMR (CDCl3, 400 MHz) δ 7.68–6.68 (m, 31H, ArH),
6.30 (s, 2H, 1,2,4-oxadiazoline ring CH), 4.20 (t, 4H,
J = 5.7 Hz, OCH2), 3.89 (t, 4H, J = 5.7 Hz, NCH2); MS
(ESI): m/z 846 (M++1). Anal. Calcd for
C50H41Cl2N5O4: C, 70.92; H, 4.88; N, 8.27. Found:
(CDCl3, 400 MHz) δ 7.47–6.69 (m, 29H, ArH), 6.41 (s,
2H, 1,2,4-oxadiazoline ring CH), 4.20 (t, 4H, J=5.7Hz,
OCH2), 3.90 (t, 4H, J=5.7Hz, NCH2), 3.80 (s, 6H,
OCH3); MS (ESI): m/z 906 (M++1). Anal. Calcd for
C52H45Cl2N5O6: C, 68.87; H, 5.00; N, 7.72. Found: C,
C, 70.81; H, 4.84; N, 8.18.
N,N-Bis(2-(4-(4-phenyl-3-(4-tolyl)-4,5-dihydro-1,2,4-oxadiazol-
5-yl)phenoxy)ethyl)aniline (4c). Pale yellow solid (69%); mp
68.65; H, 4.93; N, 7.61.
N,N-Bis(2-(4-(3-phenyl-4-(4-tolyl)-4,5-dihydro-1,2,4-oxadiazol-
5-yl)phenoxy)ethyl)aniline (4i). Pale yellow solid (67%); mp
77–78°C; FTIR ν 1685 (C¼N), 1378, 1171 (C–N), 1248 (C–
72–74°C; FTIR ν 1685 (C¼N), 1378, 1171 (C–N), 1247
1
O–C) cmꢀ1; H-NMR (CDCl3, 400MHz) δ 7.47–6.77 (m,
1
(C–O–C) cmꢀ1; H-NMR (CDCl3, 400MHz) δ 7.44–6.68
31H, ArH), 6.45 (s, 2H, 1,2,4-oxadiazoline ring CH), 4.21
(t, 4H, J=5.7Hz, OCH2), 3.89 (m, 4H, J=5.7Hz, NCH2),
2.33 (s, 6H, CH3); MS (ESI): m/z 806 (M++1). Anal. Calcd
for C52H47N5O4: C, 77.49; H, 5.88; N, 8.69. Found: C,
(m, 31H, ArH), 6.32 (s, 2H, 1,2,4-oxadiazoline ring CH),
4.20 (t, 4H, J=5.9Hz, OCH2), 3.89 (t, 4H, J=5.9Hz,
NCH2), 2.23 (s, 6H, CH3); MS (ESI): m/z 806 (M++1).
Anal. Calcd for C52H47Cl2N5O4: C, 77.49; H, 5.88; N,
77.36; H, 5.79; N, 8.53.
N,N-Bis(2-(4-(3-(4-methoxyphenyl)-4-phenyl-4,5-dihydro-1,2,4-
oxadiazol-5-yl)phenoxy)ethyl)aniline (4d). Pale yellow solid
8.69. Found: C, 77.36; H, 5.89; N, 8.54.
N,N-Bis(2-(4-(3-(4-chlorophenyl)-4-(4-tolyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl)phenoxy)ethyl)aniline (4j).
Pale yellow solid
(69%); mp 75–77°C; FTIR ν 1684 (C¼N), 1378, 1171
(70%); mp 73–74°C; FTIR ν 1692 (C¼N), 1379, 1171 (C–
(C–N), 1249 (C–O–C) cmꢀ1
;
1H-NMR (CDCl3,
1
N), 1248 (C–O–C) cmꢀ1; H-NMR (CDCl3, 400MHz) δ
400 MHz) δ 7.44–6.68 (m, 31H, ArH), 6.33 (s, 2H,
1,2,4-oxadiazoline ring CH), 4.20 (t, 4H, J = 5.9 Hz,
OCH2), 3.89 (t, 4H, J = 5.9 Hz, NCH2), 3.78 (s, 6H,
OCH3); MS (ESI): m/z 838 (M++1). Anal. Calcd for
C52H47N5O6: C, 74.53; H, 5.65; N, 8.36. Found: C,
74.38; H, 5.54; N, 8.28.
N,N-Bis(2-(4-(4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1,2,4-
oxadiazol-5-yl)phenoxy)ethyl)aniline (4e). Pale yellow solid
7.76–6.68 (m, 29H, ArH), 6.34 (s, 2H, 1,2,4-oxadiazoline
ring CH), 4.20 (t, 4H, J=5.9Hz, OCH2), 3.89 (t, 4H,
J=5.9Hz, NCH2), 2.24 (s, 6H, CH3); MS (ESI): m/z 874
(M++1). Anal. Calcd for C52H45Cl2N5O4: C, 71.39; H, 5.18;
N, 8.01. Found: C, 71.30; H, 5.18; N, 7.96.
N,N-Bis(2-(4-(3,4-di-4-tolyl-4,5-dihydro-1,2,4-oxadiazol-5-
yl)phenoxy)ethyl)aniline (4k).
Pale yellow solid (67%);
mp 65–66°C; FTIR ν 1685 (C¼N), 1375, 1171 (C–N),
1248 (C–O–C) cmꢀ1 1H-NMR (CDCl3, 400MHz) δ
(67%); mp 73–74°C; FTIR ν 1690 (C¼N), 1389, 1163
;
(C–N), 1252 (C–O–C) cmꢀ1
;
1H-NMR (CDCl3,
7.44–6.68 (m, 29H, ArH), 6.34 (s, 2H, 1,2,4-oxadiazoline
ring CH), 4.20 (t, 4H, J=5.9Hz, OCH2), 3.88 (t, 4H,
J=5.9Hz, NCH2), 2.23 (s, 12H, CH3); MS (ESI): m/z 834
(M++1). Anal. Calcd for C54H51N5O4: C, 77.77; H, 6.16;
400MHz) δ 7.78–6.69 (m, 31H, ArH), 6.38 (s, 2H, 1,2,4-
oxadiazoline ring CH), 4.20 (t, 4H, J=5.7Hz, OCH2),
3.90 (t, 4H, J=5.7Hz, NCH2); MS (ESI): m/z 846
(M++1). Anal. Calcd for C50H41Cl2N5O4: C, 70.92; H,
N, 8.40. Found: C, 77.59; H, 6.11; N, 8.32.
N,N-Bis(2-(4-(3-(4-methoxyphenyl)-4-(4-tolyl)-4,5-dihydro-
1,2,4-oxadiazol-5-yl)phenoxy)ethyl)aniline (4l). Pale yellow
4.88; N, 8.27. Found: C, 70.86; H, 4.85; N, 8.20.
N,N-Bis(2-(4-(3,4-bis(4-chlorophenyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl)phenoxy)ethyl)aniline (4f).
Pale yellow
solid (65%); mp 76–78°C; FTIR ν 1690 (C¼N), 1378,
1163 (C–N), 1251 (C–O–C) cmꢀ1 1H-NMR (CDCl3,
solid (65%); mp 79–80°C; FTIR ν 1684 (C¼N), 1376,
1172 (C–N), 1248 (C–O–C) cmꢀ1 1H-NMR (CDCl3,
;
;
400MHz) δ 7.48–6.68 (m, 29H, ArH), 6.38 (s, 2H, 1,2,4-
oxadiazoline ring CH), 4.20 (t, 4H, J=6.0Hz, OCH2),
3.89 (t, 4H, J=6.0Hz, NCH2), 3.78 (s, 6H, OCH3), 2.23
(s, 6H, CH3); MS (ESI): m/z 866 (M++1). Anal. Calcd for
C54H51N5O6: C, 74.89; H, 5.94; N, 8.09. Found: C,
400 MHz) δ 7.81–6.73 (m, 29H, ArH), 6.38 (s, 2H, 1,2,4-
oxadiazoline ring CH), 4.22 (t, 4H, J=5.7Hz, OCH2), 3.91
(t, 4H, J=5.7Hz, NCH2); MS (ESI): m/z 916 (M++1).
Anal. Calcd for C50H39Cl4N5O4: C, 65.58; H, 4.29; N,
7.65. Found: C, 65.46; H, 4.28; N, 7.56.
N,N-Bis(2-(4-(4-(4-chlorophenyl)-3-(4-tolyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl)phenoxy)ethyl)aniline (4g). Pale yellow solid
74.68; H, 5.95; N, 8.00.
N,N-Bis(2-(4-(4-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-
1,2,4-oxadiazol-5-yl)phenoxy)ethyl)aniline (4m). Pale yellow
(70%); mp 78–79°C; FTIR ν 1684 (C¼N), 1387, 1172
solid (66%); mp 69–70°C; FTIR ν 1684 (C¼N), 1375,
1
(C–N), 1248 (C–O–C) cmꢀ1; H-NMR (CDCl3, 400MHz)
1
1171 (C–N), 1248 (C–O–C) cmꢀ1; H-NMR (CDCl3) δ
δ 7.44–6.68 (m, 29H, ArH), 6.41 (s, 2H, 1,2,4-oxadiazoline
ring CH), 4.23 (s, 4H, J=4.8Hz, OCH2), 3.91 (t, 4H,
J=4.8Hz, NCH2), 2.35 (s, 6H, CH3); MS (ESI): m/z 874
(M++1). Anal. Calcd for C52H45Cl2N5O4: C, 71.39; H,
5.18; N, 8.01. Found: C, 71.30; H, 5.13; N, 7.96.
7.45–6.68 (m, 31H, ArH), 6.32 (s, 2H, 1,2,4-oxadiazoline
ring CH), 4.20 (t, 4H, J=6.1Hz, OCH2), 3.89 (t, 4H,
J=6.1Hz, NCH2), 3.70 (s, 6H, OCH3); MS (ESI): m/z 838
(M++1). Anal. Calcd for C54H47N5O6: C, 74.53; H, 5.65;
N, 8.36. Found: C, 74.34; H, 5.59; N, 8.27.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis via 1,3-Dipolar Cycloaddition Reaction
REFERENCES AND NOTES
N,N-Bis(2-(4-(3-(4-chlorophenyl)-4-(4-methoxyphenyl)-4,5-
dihydro-1,2,4-oxadiazol-5-yl)phenoxy)ethyl)aniline (4n).
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[3] Tufariello, J. J. 1,3-Dipolar Cycloaddition; Wiley-Interscience:
New York, 1984; p 83.
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Eur J Med Chem 2007, 42, 669.
Pale yellow solid (65%); mp 77–78°C; FTIR ν 1684 (C¼N),
1
1369, 1170 (C–N), 1248 (C–O–C) cmꢀ1; H-NMR (CDCl3,
400MHz) δ 7.80–6.71 (m, 29H, ArH), 6.33 (s, 2H, 1,2,4-
oxadiazoline ring CH), 4.20 (t, 4H, J=5.9Hz, OCH2), 3.90
(t, 4H, J=5.9Hz, NCH2), 3.70 (s, 6H, OCH3); MS (ESI): m/
z 906 (M++1). Anal. Calcd for C52H45Cl2N5O6: C, 68.87; H,
5.00; N, 7.72. Found: C, 68.61; H, 4.86; N, 7.53.
N,N-Bis(2-(4-(4-(4-methoxyphenyl)-3-(4-tolyl)-4,5-dihydro-
1,2,4-oxadiazol-5-yl)phenoxy)ethyl)aniline (4o).
Pale yellow
solid (65%); mp 86–87°C; FTIR ν 1687 (C¼N), 1376, 1171
(C–N), 1248 (C–O–C) cmꢀ1; 1H-NMR (CDCl3, 400 MHz) δ
7.44–6.67 (m, 29H, ArH), 6.32 (s, 2H, 1,2,4-oxadiazoline
ring CH), 4.23 (t, 4H, J=5.9Hz, OCH2), 3.91 (t, 4H,
J=5.9Hz, NCH2), 3.70 (s, 6H, OCH3), 2.32 (s, 6H, CH3);
MS (ESI): m/z 866 (M++1). Anal. Calcd for C54H51N5O6: C,
74.89; H, 5.94; N, 8.09. Found: C, 74.71; H, 5.87; N, 8.02.
N,N-Bis(2-(4-(3,4-bis(4-methoxyphenyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl)phenoxy)ethyl)aniline (4p).
Pale yellow
solid (68%); mp 78–79°C; FTIR ν 1682 (C¼N), 1374,
1172 (C–N), 1250 (C–O–C) cmꢀ1 1H-NMR (CDCl3,
;
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400MHz) δ 7.45–6.67 (m, 29H, ArH), 6.33 (s, 2H, 1,2,4-
oxadiazoline ring CH), 4.20 (t, 4H, J=6.1Hz, OCH2),
3.90 (t, 4H, J=6.1Hz, NCH2), 3.71 (s, 12H, OCH3); MS
(ESI): m/z 898 (M++1). Anal. Calcd for C54H51N5O8: C,
72.22; H, 5.72; N, 7.81. Found: C, 71.99; H, 5.67; N, 7.73.
Acknowledgments. We were grateful to the Key SCI-Tech
Innovation Team of Zhejiang Province (2010R50017) for
financial help.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet