Synthesis of crown compounds containing a 1,3,4-oxadiazole moiety: Microwave-assisted synthesis

Article abstract of DOI:10.1002/jhet.201

(Chemical Equation Presented) New macrocyclic polyether compounds containing a 2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole moiety are quickly prepared by a nucleophilic substitution reaction involving ethylene glycol ditosylate or polyethylene glycol ditosylate and a biphenol, the 2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole, with solid anhydrous potassium carbonate as a base under microwave irradiation (monomode and multimode). The structures of new macrocyclic polyether compounds were confirmed by ¹H, ¹³C NMR, mass spectrometry, and elemental analysis.

Full text of DOI:10.1002/jhet.201

May 2010
Synthesis of Crown Compounds Containing a 1,3,4-Oxadiazole
Moiety: Microwave-Assisted Synthesis
555
a
Moha Outirite, Mounim Lebrini, Michel Lagrenee, * and Fouad Bentiss
a
a
b
´
a
´
Unite de Catalyse et de Chimie du Solide, CNRS UMR 8181, ENSCL, B.P. 90108, F-59652
Villeneuve d’Ascq Cedex, France
Laboratoire de Chimie de Coordination et d’Analytique, Faculte des Sciences,
b
´
Universite Chouaib Doukkali, B.P. 20, M-24000 El Jadida, Morocco
´
*E-mail: michel.lagrenee@ensc-lille.fr
Received February 5, 2009
DOI 10.1002/jhet.201
Published online 15 April 2010 in Wiley InterScience (www.interscience.wiley.com).
New macrocyclic polyether compounds containing a 2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole moi-
ety are quickly prepared by a nucleophilic substitution reaction involving ethylene glycol ditosylate or
polyethylene glycol ditosylate and a biphenol, the 2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole, with solid
anhydrous potassium carbonate as a base under microwave irradiation (monomode and multimode). The
1
structures of new macrocyclic polyether compounds were confirmed by H, 13C NMR, mass spectrome-
try, and elemental analysis.
J. Heterocyclic Chem., 47, 555 (2010).
INTRODUCTION
In this article we report the microwave-assisted synthe-
sis of crown compounds containing a 1,3,4-oxadiazole
moiety.
The design and synthesis of artificial hart mimics pos-
sessing specific weak interactions and complexation
properties to ion and neutral molecules has inspired
many scientists during the past decades [1,2]. The Ped-
ersen’s [3] synthesis of crown ethers and the demon-
strated ability of these molecules to chelate cations
launched a whole search for further novel polyether
macrocyclic structures that promote similar recognition
phenomena [4]. The 1,3,4-oxadiazole ring is very rigid
and as for the crown compounds containing a 1,3,4-thia-
diazole moiety [5], the macrocyclic polyether containing
it has potentially planar conformation [6]. A synthesis
of such compounds containing 1,3,4-oxadiazole moiety
has been previously effectuated by condensation of eth-
ylene glycol or polyethylene glycol derivatives with the
2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole by direct dis-
placement reaction of halide with the bisphenolate and
using the classical heating process. This synthesis
requires long reaction time, and poor yields were
obtained [7]. No macrocyclic compounds were found
when we tried the heterocyclisation of the 2,5-bis(2-
hydroxyphenyl)-1,3,4-oxadiazole with ethylene glycol
ditosylate or polyethylene glycol ditosylate under classi-
cal heating using a previously described procedure [5].
RESULTS AND DISCUSSION
Macrocyclic compounds 2a–d were prepared by a
nucleophilic substitution reaction involving a glycol
ditosylate with the bisphenoloxadiazole (1) (Scheme 1).
This reaction was easily achieved by microwave
irradiation and the macrocycles 2a–d were obtained in
moderate yields and excellent state of purity as in ref. 6
(Table 1).
A good achievement of this synthesis requires longer
times (9 h) under irradiation using multimode micro-
wave reaction compared with monomode one (2 h).
However, no reaction product has been isolated using
classical conventional heating.
To understand the pathway mechanisms that occur in
the nucleophilic substitution reaction for cyclization of
ditosyl polyether, quantum calculations at density func-
tional theory (DFT) level were performed with thiadi-
phenol, both in vacuum and acetonitrile solvent, using
polarized continuum method (PCM) method. The
obtained results in the case of 1,3,4-thiadiazole moiety
C
V
2010 HeteroCorporation

´
M. Outirite, M. Lebrini, M. Lagrenee, and F. Bentiss
556
Vol 47
Scheme 1. Synthesis of marcocyclic compounds containing a 1,3,4-
oxadiazole moiety.
Vernaison, France. All starting materials were of reagent grade
and used as purchased.
General procedure for the synthesis of macrocycles
2a–d. A mixture of 2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole
1 (0.75 g, 2.95 mmoles), anhydrous potassium carbonate (1.65 g,
12 mmoles), and ethylene glycol ditosylate or polyethylene
glycol ditosylate (2.78 mmoles) in 30 mL of a nonprotic polar
solvent, such as DMF or acetonitrile, was introduced into a
fluoropolymeric cylindrical flask placed in a MARS5 XP-1500
PLUS CEM multimode microwave and irradiated for 9 h
(300 W) at 150ꢀC or irradiated for 2 h (150 W) in a CEM
monomode microwave in DMF at 150ꢀC with vigorous
stirring. The precipitate was heated under reflux with 20 mL of
aqueous potassium hydroxide solution for 1 h to destroy the
unreacted tosylate, oxadiazole derivative 1, or the open-chain
intermediate of 2. After cooling, the crude product was
filtered, washed with water, recrystallized from ethanol, and
dried under high vacuum. Yields, melting points, and results of
the elemental analysis (C, H, and N) for compounds 2a–d were
given in Table 1.
are analyzed in term of electronic energy of the calcu-
lated molecule conformations [6].
Specific microwave effect was observed in this reac-
tion, the polarity is increased during the reaction from
the ground state toward the transition state, and the sta-
bilization of the transition state is more effective than
that of the ground state (Scheme 2), this result in an
enhancement of reactivity by a decrease in the activa-
tion energy [8].
The general formula of the parent macrocyclic compound
with corresponding numbering scheme is given later.
Localization of the methylene groups in the polyether macro-
cycle has been made using the International Union of Pure and
Applied Chemistry rules concerning the different bicyclic
systems.
Using the monomode irradiation process, the notable
enhancement in the yields of the crown compounds syn-
thesis, and the shorter time of the reaction, can be
explained by the fact that the microwaves are focused
through a wave guide on the reaction vessel. The power
density is, therefore, higher than using a multimode
microwave apparatus.
EXPERIMENTAL
Melting points were determined with on an IA 9000 series
electrothermal apparatus and are uncorrected. 1H and 13C
NMR spectra were recorded on a Bruker F.T. AC 300 spec-
2,3,11,12-Dibenzo-4,7,10,16-tetraoxa-14,15-diazabicyclo[11.2.1]-
1
hexadeca-13,15-diene (2a). H NMR (CDCl3): d (ppm) 3.95–
1
trometer (300 MHz for H NMR and 75 MHz for 13C NMR)
using chloroform-d1 (CDCl3) as solvent. Matrix-assisted laser
desorption ionization (MALDI) and time-of-flight mass spec-
trometry (TOF-MS) are used to record the mass spectra of the
macrocyclic polyether compounds 2a–d. Elemental analyses
were performed by the elemental analysis service of CNRS,
3.99 (m, 4H, CH2 (6) and CH2 (8)), 4.26–4.29 (m, 4H, CH2
(5) and CH2 (9)), 7.01 (d, J ¼ 8.6 Hz, 2H, 6-H), 7.08 (dd, J ¼
7.7 Hz, 2H, 4-H), 7.48 (dd, J ¼ 7.9 Hz, 2H, 5-H), 8.11 (d,
J ¼ 7.7 Hz, 2H, 3-H). 13C NMR (CDCl3): d (ppm) 61.5 (CH2
(5) and CH2 (9)), 63.4 (CH2 (6) and CH2 (8)), 110.8 (C6),
Table 1
Physical and analytical data of compounds 2a–d.
Yield (%)
Monomode (2 h)
Analysis (%) found/calcd.
Compound
Multimode (9 h)
36
Mp (ꢀC)
175
Molecular formula
C18H16N2O4
C
H
N
2a (n ¼ 2)
47
51
42
39
66.52
66.66
65.01
65.21
63.95
64.07
62.98
63.15
5.10
4.97
5.63
5.47
6.06
5.87
6.33
6.18
8.71
8.64
7.84
7.60
6.82
6.79
6.27
6.14
2b (n ¼ 3)
2c (n ¼ 4)
2d (n ¼ 5)
33
30
27
200
185
187
C20H20N2O5
C22H24N2O6
C24H28N2O7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Synthesis of Crown Compounds Containing a 1,3,4-Oxadiazole Moiety:
Microwave-Assisted Synthesis
557
Scheme 2
d (ppm) 3.56 (s, 4H, CH2 (11) and CH2 (12)), 3.56–3.78 (m,
8H, CH2 (9), CH2 (14), CH2 (17) and CH2 (18)), 4.09 (t, J ¼
5.1 Hz, 4H, CH2 (6) and CH2 (17)), 4.38 (t, J ¼ 5.1 Hz, 4H,
CH2 (5) and CH2 (18)), 7.08 (d, J ¼ 7.5 Hz, 2H, 6-H), 7.13
(dd, J ¼ 6.7 Hz, 2H, 4-H), 7.44 (dd, J ¼ 7.0 Hz, 2H, 5-H),
8.54 (d, J ¼ 8.4 Hz, 2H, 3-H). 13C NMR (CDCl3): d (ppm)
60.8 (CH2 (5) and CH2 (18)), 62.6 (CH2 (6) and CH2 (17)),
64.1 (CH2 (8) and CH2 (15)), 64.1 (CH2 (9, 11, 12 and 14),
108.9 (C6), 114.9 (C4), 122.0 (C2), 126.5 (C3), 138.8 (C5),
152.7 (C7), 164.7 (C1-oxadiazole). MALDI-TOF-MS: m/z 457
(M þ 1).
113.5 (C4), 122.5 (C2), 127.2 (C3), 138.6 (C5), 150.1 (C7),
163.4 (C1-oxadiazole). MALDI-TOF-MS: m/z 325 (M þ1).
2,3,14,15-Dibenzo-4,7,10,13,19-pentaoxa-17,18-diazabicy-
1
clo[14.2.1]nonadeca-16,18-diene (2b). H NMR (CDCl3): d
REFERENCES AND NOTES
(ppm) 3.54 (s, 4H, CH2 (8) and CH2 (9)), 3.87–3.91 (m, 4H,
CH2 (6) and CH2 (11)), 4.24–4.28 (m, 4H, CH2 (5) and CH2
(12)), 7.04 (d, J ¼ 8.3 Hz, 2H, 6-H), 7.08 (dd, J ¼ 8.0 Hz,
2H, 4-H), 7.49 (dd, J ¼ 8.0 Hz, 2H, 5-H), 7.90 (d, J ¼ 7.6
Hz, 2H, 3-H). 13C NMR (CDCl3): d (ppm) 60.3 (CH2 (5) and
CH2 (12)), 62.7 (CH2 (8) and CH2 (9)), 73.2 (CH2 (6) and
CH2 (11)), 108.1 (C6), 114.5 (C4), 121.3 (C2), 126.3 (C3),
138.3 (C5), 152.8 (C7), 164.0 (C1-oxadiazole). MALDI-TOF-
MS: m/z 369 (M þ 1).
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1
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d
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5.6 Hz, 4H, CH2 (6) and CH2 (14)), 4.33 (t, J ¼ 5.6 Hz, 4H,
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(dd, J ¼ 7.5 Hz, 2H, 4-H), 7.45 (dd, J ¼ 7.8 Hz, 2H, 5-H),
8.53 (d, J ¼ 8.5 Hz, 2H, 3-H). 13C NMR (CDCl3): d (ppm)
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63.1 (CH2 (8) and CH2 (12)), 64.0 (CH2 (9) and CH2 (11)),
108.8 (C6), 115.4 (C4), 123.1 (C2), 128.72 (C3), 135.0 (C5),
153.4 (C7), 165.5 (C1-oxadiazole). MALDI-TOF-MS: m/z 413
(M þ 1).
´
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1
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet