Synthesis of Extended 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives in the Suzuki Cross-coupling Reactions

Article abstract of DOI:10.1002/jhet.2743

New derivatives of 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized by a palladium catalyzed Suzuki cross-coupling reaction under the conditions of the phase transfer catalysis. The structure of the products, the absorption and emission spectra wer

Full text of DOI:10.1002/jhet.2743

Month 2016 Synthesis of Extended 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives
in the Suzuki Cross-coupling Reactions
a
a
b
c,d
Monika Wróblowska, Agnieszka Kudelko, Nikodem Kuźnik, Katarzyna Łaba, and Mieczysław Łapkowskic,d
*
aDepartment of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology, Krzywoustego
4, PL-44100 Gliwice, Poland
bDepartment of Organic Chemistry, Bioorganic Chemistry and Biotechnology, The Silesian University of Technology,
Krzywoustego 4, PL-44100 Gliwice, Poland
cDepartment of Physical Chemistry and Technology of Polymers, The Silesian University of Technology, Strzody 9, PL-
44100 Gliwice, Poland
dCentre of Polymer and Carbon Materials of the Polish Academy of Sciences, M. Curie-Sklodowskiej 34, PL-41819
Zabrze, Poland
E-mail: Agnieszka.Kudelko@polsl.pl
Received May 12, 2016
DOI 10.1002/jhet.2743
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
New derivatives of 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized by a palladium catalyzed
Suzuki cross-coupling reaction under the conditions of the phase transfer catalysis. The structure of the prod-
ucts, the absorption and emission spectra were also studied.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
reagentinthe reactions withdiacylhydrazinesresultinforma-
tion of 1,3,4-thiadiazole moiety [21–23].
Heterocyclic compounds have a great contribution to
provide valuable reagents for the synthesis of medicines,
pesticides, and detergents, as well as in related fields like
biochemistry, biotechnology, chemistry of polymers, or
materials science. In the area of this group of compounds
particularly interesting seems to be 1,3,4-oxadiazole and
1,3,4-thiadiazole derivatives. These non-naturally occurring
compounds exhibit a broad range of biological activities
and therefore are widely used in medicine and agriculture
[1–8]. Oxadiazole and thiadiazole derivatives have attracted
attention of scientists because of their precious optical
properties [9–13]. 1,2-Diazole fragment, which is present
in heterocyclic rings such as 1,3,4-oxadiazoles and 1,3,4-
thiadiazoles, functions as electron withdrawing group and
may be found in many linear conductive systems. Its
presence significantly enhances the fluorescence quantum
yield and stability of the final product.
Working earlier on the synthesis of 1,3,4-oxadiazole and
1,3,4-thiadiazole derivatives, we obtained new conjugated
derivatives which exhibited very high rates of fluorescence
quantum yield [20,23]. These findings prompted us to
deeper research on these groups of compounds and extend-
ing substrate scope searching for the most effective
luminophores. This paper describes the efficient synthesis
and properties of novel 3,4-diazole derivatives based on
one of the most popular catalytic methods of C–C bond
construction – the Suzuki cross-coupling reaction [24,25].
RESULTS AND DISCUSSION
Three step methodology was applied to transform
4-bromo-2-methylbenzoic acid (1) to the leading moiety –
2,5-bis(4-bromo-2-methylphenyl)-1,3,4-oxadiazole (4) or
2,5-bis(4-bromo-2-methylphenyl)-1,3,4-thiadiazole
(5).
Numerous methods for synthesis of the 1,3,4-oxadiazole
and 1,3,4-thiadiazole ring are described in literature [14–16].
However, the most common approach towards the prepara-
tion of both of them involves reaction making use of
diacylhydrazines, which are easy accessible. This particular
methodology involves their reactions with a range of
cyclodehydrating agents, just to mention boron trifluoride-
diethyl etherate, the Burgess reagent, polyphosphoric acid,
phosphorus oxychloride, or thionyl chloride, and leads to
the formation of 1,3,4-oxadiazole core [17–20]. Further
applications of diphosphorus pentasulfide or Lawesson’s
The initial acid 1 was heated in the presence of thionyl chlo-
ride in dry toluene giving the corresponding acid chloride 2.
The obtained chloride 2 was treated with hydrazine hydrate
in the presence of triethylamine to give the adequate N,N’-
diacylhydrazine 3. This intermediate heated with appropri-
ate reagent (phosphorus oxychloride for 1,3,4-oxadiazole
core or Lawesson’s reagent for 1,3,4-thiadiazole core) in
non-polar solvent led to the desired compounds 4,5 in
excellent yields (Scheme 1).
The obtained dibromo 3,4-diazole derivatives 4,5 were
subjected to Suzuki cross-coupling reaction. They were
© 2016 Wiley Periodicals, Inc.

M. Wróblowska, A. Kudelko, N. Kuźnik, K. Łaba, and M. Łapkowski
Vol 000
Scheme 1. Synthesis of 2,5-bis(4-bromophenyl)-1,3,4-oxadiazole (4) and 2,5-bis(4-bromophenyl)-1,3,4-thiadiazole (5) scaffold. Reagents and conditions:
(i) SOCl2, toluene, reflux, 15 h; (ii) N2H4•H2O, TEA, CHCl3, rt, 24 h; (iii) POCl3, toluene, reflux, 8 h; and (iv) Lawesson’s reagent, xylene, reflux, 4 h.
Scheme 2. Suzuki cross-coupling reaction. Reagents and conditions: aryl dibromide 4,5 (1.00 mmol), boronic acid 6 (2.50 mmol), Pd(PPh3)4 (0.05 mmol),
NBu4Br (0.10 mmol), Li2CO3 (10 mmol), toluene/EtOH/H2O (10:6:3 mL), oil bath 130°C, 4–13 h.
refluxed with appropriate boronic acids 6a–f under a
predetermined conditions with similar scaffolds [20,23]
(Scheme 2). The reactions were carried out on the oil-bath
with an excess amount of the adequate boronic acid 6a–f
in the presence of the Li2CO3 as a base to activate boronic
acid and to facilitate the transmetallation step. The reaction
mixtures were heated under the phase transfer catalysis in a
two-phase solvent system (toluene/EtOH/H2O) using
NBu4Br as the phase transfer catalyst and in the presence
of 5 mol% palladium catalyst Pd(PPh3)4. Reaction times
were monitored by TLC until the initial 2,5-bis(4-
bromophenyl)-3,4-diazoles 4,5 were completely consumed.
The research has led to obtain a new symmetrical
1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives in
high yields (72–98% for 7a-f, 72–88% for 8a–f,
Table 1). Interestingly, the lowest yields were obtained
for the least conjugated 1,3,4-oxadiazole 7a and 1,3,4-
thiadiazole 8a, containing a terminal phenyl substituent
(72%, Table 1). Other products with extended terminal
heterocyclic systems were obtained in relatively higher
yields (77–98% for 7b–f, 77–88% for 8b–f, Table 1).
The structures of all of the resulted derivatives were
confirmed by elemental analyses and typical spectro-
scopic methods (1H and 13C NMR, UV, IR, HRMS).
As expected, NMR spectra showed a reduced number
of signals both protons and carbons because these com-
pounds have a symmetrical structure. The symmetrical
structure of one from the obtained products was con-
firmed by X-ray crystal structure analysis (Fig. 1). The
oxadiazole 7a crystallizes in a orthorhombic system
forming long unit cell with a =41.230(8), b= 7.4842(15),
c =6.6745(13) Å with the heterocyclic ring at the plane of
symmetry. The central core is almost planar with 7.17(23)°
twist of the substituted benzene rings from the plane of the
oxadiazole, while the terminal benzene rings are twisted
off by 31.45(19)° from the neighboring substituted benzene
rings. There are no hydrogen bondings; however, there is a
weak intermolecular interaction N1…C1. An interesting
comparison with the crystal structures of structurally related
compounds NAXDIZ [26], IPODEX [27], and PEDQUM
[28] is presented in Figure 2. The methyl substituent in 7a
causes only slight deviation from planarity, similar to the
non-substituted benzene ring in PEDQUM, but surprisingly
not as twisted as in the meta-substituted IPODEX. Also, the
terminal ring is likely twisted to PEDQUM. However, it is
worth noting that ortho-disubstituted benzene ring in
PEDQUM leads to serious deviation (α’) from planarity.
The fluorescence emission spectra were recorded using
the excitation maximum. The highest intensity of emission
was observed for 7a compound. The quantum yields were
estimated by comparison with a quantum yield standards
using comparative method [29–31]. The significant in-
crease of Ф from the 1,3,4-thiadiazole (8a–f) moiety to
1,3,4-oxadiazole (7a–f) was observed, which can be ex-
plained by the heavy atom effect (Table 2).
CONCLUSION
We have prepared two series of new 3,4-diazole deriv-
atives as extended π-conjugated systems. The leading
1,3,4-oxadiazole or 1,3,4-thiadiazole rings have been
coupled at the positions 2 and 5, via a methyl-substituted
phenylene linker, with a range of homoaromatic and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
New Extended 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles
Table 1
2,5-Bis(4-aryl-2-methylphenyl)-1,3,4-oxadiazoles 7a–f and 2,5-bis(4-aryl-2-methylphenyl)-1,3,4-thiadiazoles 8a–f prepared in Suzuki cross-
coupling reactions.
Compound
Central core
Substituent Ar
Reaction time [h]
4
Melting point [°C]
Yield [%]
72
7a
173–174
7b
6
249–251
84
7c
9
299–300
213–214
77
98
7d
10
7e
7
306–308
89
7f
12
5
109–110
143–144
291–293
87
72
84
8a
8b
5
8c
13
11
258–260
206–209
78
88
8d
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Wróblowska, A. Kudelko, N. Kuźnik, K. Łaba, and M. Łapkowski
Vol 000
Table 1
(Continued)
Compound
Central core
Substituent Ar
Reaction time [h]
8
Melting point [°C]
Yield [%]
8e
280–281
85
8f
13
293–295
77
EXPERIMENTAL
Melting points were measured on a Stuart SMP3 melting
point apparatus. NMR spectra were recorded at 25°C on an
1
Agilent 400-NMR spectrometer at 400MHz for H and
100MHz for 13C, using CDCl3 or DMSO as solvents and
TMS as the internal standard. UV spectra were recorded on
a Jasco V-650 spectrophotometer. FT-IR spectra were
recorded between 4000 and 650cmÀ1 on an FT-IR Nicolet
6700 apparatus with a Smart iTR accessory. Elemental
analyses were performed with a VarioEL analyser. High-
resolution mass spectra were obtained by means of a Waters
ACQUITY UPLC/Xevo G2QT instrument. Thin-layer chro-
matography was performed on silica gel 60F254 (Merck)
thin-layer chromatography plates using benzene/ethyl
acetate (9:1v/v) as the mobile phase. Fluorescence spectra
were recorded at room temperature in dichloromethane solu-
tion using Hitachi F-2500 fluorescence spectrophotometer.
X-ray single crystal measurement: measurements of the
diffraction intensities were performed on a KUMA KM4
four-circle diffractometer, MoKα radiation, ω/2Θ scan
mode, Θ range 2.77–25.00°. Crystallographic data for 7a
were deposited with the Cambridge Crystallographic Data
Centre as supplementary publications number: CCDC
1465365. A complete listing of the atomic coordinates of
x, y, and z can be obtained free of charge, on request, from
the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK [fax: (+int) 44-
1223 336 033; e-mail: deposit@ccdc.cam.ac.uk], upon
quoting the depository numbers, names of the authors
and the journal citation.
Figure 1. X-ray structure of 2,5-bis(4-phenyl-2-methylphenyl)-1,3,4-
oxadiazole (7a) with 50% probability ellipsoids. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 2. Comparison of the X-ray structures and the torsion angles of
the structurally related oxadiazoles to 7a.
heteroaromatic arrangements. The presence of methyl
group on the linker enhances the solubility of these deriv-
atives. It is particularly important for their potential appli-
cation in the production of optoelectronic devices.
Products were obtained in excellent yields at each stage
of a few-step methodology. Finally, application of the
Suzuki coupling reaction in the final step allows to get
the desired products in high yields.
4-Bromo-2-methylbenzoyl chloride (2).
4-Bromo-2-
methylbenzoic acid (1, 4.30 g, 0.02mol) and thionyl chloride
SOCl2 (5.0mL, 0.06mol) were refluxed in a dry toluene
(20mL) until the acid was fully consumed (TLC; 15h).
After cooling, the mixture was concentrated on a rotary
evaporator. The solid was recrystallized from toluene to
give 4-bromo-2-methylbenzoyl chloride (2). Beige crystals
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
New Extended 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles
Table 2
Absorption and fluorescent properties of compound 7a–f and 8a–f in methylene chloride.
[nm] (εÁ10À3
)
λex [nm]
λ
[nm]
Stokes shiftb Δ [nm] Quantum yield Фc
abs
max
em
max
Compound
λ
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
314.0 (54.5)
296.0 (42.3), 373.0 (64.4)
243.0 (66.6), 302.0 (54.1), 346.0 (64.5)
243.0 (67.9), 302.5 (54.6), 347.5 (66.6)
242.0 (75.5), 293.0 (48.9), 342.0 (58.0)
261.5 (56.9), 307.5 (35.9)
246.0 (26.2), 319.0 (43.6)
299.0 (38.9), 374.0 (50.8)
244.0 (69.8), 282.5 (46.0), 300.5 (46.1), 352.0 (58.9)
243.5 (67.5), 284.0 (44.5), 301.0 (45.3), 352.0 (54.6)
243.0 (96.6), 293.0 (53.1), 342.5 (65.2)
261.0 (61.8), 310.5 (36.4)
309
368
343
341
339
—
312
366
350
351
340
—
361, 379, 398a
47
92
73
71
82
0.92
0.70
0.80
0.89
0.85
—
0.33
0.41
0.44
0.43
0.58
—
465, 493a
419
419
424
—
390, 407, 431a
503
—
71
129
102
103
103
—
454, 490a
455
446
—
aShoulder maximum.
b
abs
max
Stokes shift from the equation Δ = λemmax – λ
[31].
c9,10-Diphenylanthracene in cyclohexane (for 7b–e, 8b–e) and 1,4-diphenylbutadiene in hexane (for 7a,8a) were used as standards.
(4.30 g, 92% yield); mp 42–44°C; 1H NMR (400MHz,
CDCl3): δ 2.55 (s, 3H), 7.47 (s, 1H), 7.49 (d, J=8.4Hz,
1H), 8.07 (d, J=8.4Hz, 1H); 13C NMR (100MHz, CDCl3):
δ 21.8, 129.6, 129.7, 131.3, 134.9, 135.2, 143.2, 166.9;
UV-VIS: λmax (MeOH) 205.0nm (εÁ10À3 29.1cmÀ1MÀ1),
237.5 (10.3); IR (ATR) ν: 3426, 2996, 1759, 1683,
1588, 1549, 1472, 1458, 1438, 1380, 1327, 1291, 1276,
1202, 1186, 1136, 1091, 1030, 880, 818, 804, 772, 755,
726, 712, 686cmÀ1; Anal. Calcd for C8H6BrClO: C, 41.15;
H, 2.59. Found: C, 41.18; H, 2.62; HRMS Calcd. for
(C8H6BrClO+H+): 232.9363; found: 232.9368.
(3, 1.70g, 4.00mmol) and phosphorous oxychloride
(7.4mL, 0.08mol) in 20mL of dry toluene was refluxed
until the initial compound 3 was fully consumed (TLC,
8h). After cooling, the mixture was concentrated on a
rotary evaporator and then treated with ethanol (20mL).
The solid precipitate was filtered off, washed with EtOH,
and air-dried yielding 2,5-bis(4-bromo-2-methylphenyl)-
1,3,4-oxadiazole (4). White crystals (1.58g, 97% yield);
1
mp 158–159°C. H NMR (400MHz, CDCl3): δ 2.74 (s,
3H), 7.47 (dd, J=8.0 and 1.6Hz, 1H), 7.53 (d, J=1.6Hz,
1H), 7.85 (d, J=8.0Hz); 13C NMR (100MHz, CDCl3): δ
22.1, 121.8, 125.9, 129.5, 130.2, 134.8, 140.5, 163.8; UV-
VIS: λmax (CHCl3) 289.5nm (εÁ10À3 30.9cmÀ1MÀ1); IR
(ATR) ν: 3073, 2974, 1593, 1537, 1475, 1440, 1382,
1272, 1197, 1099, 1084, 1046, 989, 964, 868, 853, 832,
823, 773, 746, 693cmÀ1; Anal. Calcd for C16H12Br2N2O:
C, 47.09; H, 2.96; N, 6.86. Found: C, 47.07; H, 3.00; N,
6.89; HRMS Calcd for (C16H12Br2N2O+H+): 406.9389;
found: 406.9391.
N,N′-Bis(4-bromo-2-methylbenzoyl) hydrazine (3).
4-
Bromo-2-methylbenzoyl chloride (2, 4.30 g, 0.02 mol)
dissolved in 20mL of chloroform was added to a
magnetically agitated solution of hydrazine hydrate
(0.5mL, 0.01mol) and triethylamine (2.9mL, 0.02mol) in
40mL of chloroform placed in an ice bath. After the
addition was completed, the mixture was stirred for 20h at
room temperature. The solid precipitate was collected by
filtration, washed with hexane, a large quantity of water,
air-dried yielding pure N,N′-bis(4-bromo-2-methylbenzoyl)
hydrazine (3). White solid (3.96g, 93% yield); mp 266–
2,5-Bis(4-bromo-2-methylphenyl)-1,3,4-thiadiazole (5).
A
reaction mixture of N,N′-bis(4-bromo-2-methylbenzoyl)
hydrazine (3, 1.70g, 4.00mmol) and Lawesson’s reagent
(1.62g, 4.00mmol) in 30mL of xylene was refluxed until
the initial compound 3 was fully consumed (TLC, 4h).
After cooling, the mixture was evaporated and then
alkalized with a 5% solution of NaOH. The residue was
subjected to the column chromatography (silica gel, eluent:
CHCl3-MeOH 9:1 mixture). The reaction gave the pure
1
267°C; H NMR (400MHz, DMSO): δ 2.42 (s, 3H), 7.37
(d, J=8.0Hz, 1H), 7.50 (dd, J=8.0 and 1.6Hz, 1H), 7.55
(d, J=1.6Hz, 1H), 10.27 (s, 1H); 13C NMR (100MHz,
DMSO): δ 18.9, 123.1, 128.5, 129.3, 133.1, 133.9, 138.8,
167.4; UV-VIS: λmax (MeOH) 205.0nm (εÁ10À3
56.9cmÀ1MÀ1), 235.0 (23.9); IR (ATR) ν: 3427, 3162,
2998, 1600, 1578, 1489, 1456, 1254, 1200, 1099, 868,
833, 820, 810, 772, 753, 728, 669cmÀ1; Anal. Calcd for
C16H14Br2N2O2: C, 45.10; H, 3.31; N, 6.57. Found: C,
45.07; H, 3.31; N, 6.55; HRMS Calcd for
(C16H14Br2N2O2 +H+): 424.9495; found: 424.9499.
2,5-bis(4-bromo-2-methylphenyl)-1,3,4-thiadiazole
(5).
1
Beige solid (1.54g, 91% yield); mp 139–141°C. H NMR
(400MHz, CDCl3): δ 2.63 (s, 3H), 7.46 (dd, J=8.0 and
2.0Hz, 1H), 7.53 (d, J= 2.0 Hz, 1H), 7.63 (d, J=8.0Hz,
1H); 13C NMR (100MHz, CDCl3): δ 21.6, 124.9, 128.0,
129.5, 132.1, 134.6, 139.3, 167.0; UV-VIS: λmax (CHCl3)
299.5nm (εÁ10À3 24.6 cmÀ1MÀ1); IR (ATR) ν: 3072,
2,5-Bis(4-bromo-2-methylphenyl)-1,3,4-oxadiazole (4).
A
mixture of N,N′-bis(4-bromo-2-methylbenzoyl)hydrazine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Wróblowska, A. Kudelko, N. Kuźnik, K. Łaba, and M. Łapkowski
Vol 000
2971, 2163, 1586, 1439, 1391, 1262, 1190, 1122, 1097,
983, 919, 870, 853, 840, 824, 802, 772, 669cmÀ1; Anal.
Calcd for C16H12Br2N2S: C, 45.31; H, 2.85; N, 6.60.
Found: C, 45.35; H, 2.89; N, 6.58; HRMS Calcd for
(C16H12Br2N2S+H+): 422.9161; found: 422.9165.
General procedure for Suzuki coupling reactions. 2,5-
Bis(4-bromo-2-methylphenyl)-1,3,4-oxadiazole (4, 0.20g,
0.50mmol) or 2,5-bis(4-bromo-2-methylphenyl)-1,3,4-
thiadiazole (5, 0.21g, 0.50mmol), the appropriate boronic
acid/pinacol ester (1.25 mmol), Pd(PPh3)4 (0.03g,
0.03mmol), NBu4Br (0.02 g, 0.05mmol), and Na2CO3
(0.27g, 2.50 mmol) were treated with a combination of
toluene (10 mL), H2O (6 mL), and EtOH (3 mL). The
mixture was kept under reflux in an oil bath (130°C) for
4–13h (TLC). After cooling, 200mL of CHCl3 was
added and whole filtered through silica gel (20 mL). The
filtrate was separated, and the organic layer was dried
found to be 0.19 e ÅÀ3, while that of the largest difference
hole was 0.27 e ÅÀ3
.
2,5-Bis[4′-(N,N-diphenylamino)-3-methylbiphenyl-4-yl]-
1,3,4-oxadiazole (7b).
Yellow solid (0.31g, 84%); mp
1
249–251°C. H NMR (400MHz, CDCl3): δ 2.84 (s, 3H),
7.04 (t, J =7.2 Hz, 2H), 7.13 (m, 6H), 7.27 (t, J =7.2 Hz,
4H), 7.52 (d, J =7.2 Hz, 2H), 7.55 (m, 2H), 8.10 (d,
J = 8.4 Hz, 1H); 13C NMR (100MHz, CDCl3): δ 22.5,
121.3, 123.3, 123.5, 124.3, 124.7, 127.8, 129.4, 129.5,
129.8, 133.3, 138.9, 143.3, 147.5, 148.1, 164.3; UV-VIS:
λmax (CHCl3) 296.0 nm (εÁ10À3 42.3 cmÀ1MÀ1), 373.0
(64.4); IR (ATR) ν: 3034, 2921, 2156, 1587, 1535, 1484,
1450, 1330, 1273, 1198, 1185, 1158, 1048, 1032, 888,
822, 749, 729, 693cmÀ1; Anal. Calcd for C52H40N4O: C,
84.75; H, 5.47; N, 7.60. Found: C, 84.78; H, 5.43; N,
7.63; HRMS Calcd for (C52H40N4O + H+): 737.3275;
found: 737.3271.
over MgSO4 and then concentrated on
a
rotary
2,5-Bis[4-(9-methylcarbazol-3-yl)-2-methylphenyl]-1,3,4-
oxadiazole (7c). Beige solid (0.22g, 77%); mp 299–300°C.
1H NMR (400MHz, CDCl3): δ 2.94 (s, 3H), 3.92 (s, 3H),
7.31 (t, J= 8.0 Hz, 1H), 7.46 (d, J =8.0 Hz, 1H), 7.50 (d,
J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.73 (d,
J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H),
8.18 (d, J= 8.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.40 (s,
1H); 13C NMR (100MHz, CDCl3): δ 22.6, 29.3, 108.7,
108.9, 119.0, 119.3, 121.3, 122.9, 124.9, 125.1, 126.1,
128.2, 129.1, 129.5, 130.4, 130.9, 138.8, 139.9, 141.5,
144.8, 167.4; UV-VIS: λmax (CHCl3) 243.0nm (εÁ10À3
66.6 cmÀ1MÀ1), 302.0 (54.1), 346.0 (64.5); IR (ATR) ν:
3426, 3044, 2578, 2161, 2014, 1606, 1474, 1458,
1439, 1418, 1327, 1236, 1044, 844, 824, 771, 755,
742, 730, 712cmÀ1; Anal. Calcd for C42H32N4O: C,
82.87; H, 5.30; N, 9.20. Found: C, 82.84; H, 5.29; N,
9.22; HRMS Calcd for (C42H32N4O + H+): 609.2649;
found: 609.2652.
evaporator. The residue was treated with a mixture of
benzene/ethyl acetate (3:1). The solid precipitate was
filtered off, washed with benzene/ethyl acetate (3:1), and
air-dried to give pure 2,5-disubstituted-1,3,4-oxadiazole
(7a–f) or 2,5-disubstituted-1,3,4-thiadiazole (8a–f).
2,5-Bis(3-methylbiphenyl-4-yl)-1,3,4-oxadiazole (7a).
White solid (0.14 g, 72%); mp 173–174°C. 1H NMR
(400 MHz, CDCl3): δ 2.89 (s, 3H), 7.40 (t, J= 7.2 Hz,
1H), 7.48 (t, J= 7.2 Hz, 2H), 7.60 (m, 2H), 7.66 (d,
J =7.6 Hz, 2H), 8.13 (d, J =7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 22.5, 121.9, 124.9, 127.2, 128.1,
128.9, 129.4, 130.5, 138.9, 139.9, 143.9, 164.3; UV-VIS:
λmax (CHCl3) 314.0 nm (εÁ10À3 54.5 cmÀ1MÀ1); IR
(ATR) ν: 3034, 2994, 1961, 1932, 1607, 1570, 1532,
1470, 1452, 1412, 1281, 1220, 1140, 1079, 1070, 1045,
1034, 1025, 972, 884, 857, 842, 769, 746, 715, 707,
696cmÀ1; Anal. Calcd for C28H22N2O: C, 83.56; H,
5.51; N, 6.96. Found: C, 83.50; H, 5.53; N, 7.00; HRMS
Calcd for (C28H22N2O + H+): 403.1805; found: 403.1801.
Crystal data for compound (7a). The crystal chosen for
X-ray analysis, obtained from recrystallization from
toluene, was a clear colorless block with the approximate
2,5-Bis[4-(9-ethylcarbazol-3-yl)-2-methylphenyl]-1,3,4-
oxadiazole (7d). White solid (0.31 g, 98%); mp 213–
214°C. 1H NMR (400 MHz, CDCl3):
δ 1.48 (t,
J = 6.8 Hz, 3H), 2.93 (s, 3H), 4.41 (q, J = 6.8 Hz, 2H),
7.28 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.51
(m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.79
(d, J = 8.0 Hz, 1H), 8.17 (d, J= 8.0 Hz, 1H), 8.20 (d,
J = 8.0 Hz, 1H), 8.39 (s, 1H); 13C NMR (100MHz,
CDCl3): δ 13.8, 22.6, 37.7, 108.7, 108.8, 119.2, 120.6,
121.0, 123.0, 123.6, 124.9, 125.1, 126.0, 129.0, 129.5,
130.4, 130.8, 138.9, 139.9, 140.5, 144.8, 164.4; UV-
VIS: λmax (CHCl3) 243.0nm (εÁ10À3 67.9 cmÀ1MÀ1),
302.5 (54.6), 347.5 (66.6); IR (ATR) ν: 2974, 2162,
2020, 1596, 1468, 1447, 1382, 1332, 1247, 1232,
1155, 1125, 1054, 1038, 798, 766, 743, 727,
704 cmÀ1; Anal. Calcd for C44H36N4O: C, 82.99; H,
5.70; N, 8.80. Found: C, 82.97; H, 5.73; N, 8.83;
HRMS Calcd for (C44H36N4O + H+): 637.2962; found:
637.2961.
dimensions
of
0.8 × 0.6 × 0.3 mm.
C28H22N2O
(402.48 g mol-1) crystallizes in the orthorhombic system,
space group Cmc21, with a = 41.230(8), b =7.4842(15),
c =6.6745(13) Å, V =2059.6(7) Å3, Z = 4, μ(MoKα)
= 0.079mmÀ1, and Dcalcd = 1.298 cmÀ3. A total of 2170
reflections were collected to 2Θmax = 50.00° (h: 0 → 49 k:
0 → 8, l: À7→ 0), of which 1002 were unique. In refine-
ments, weights were used according to the scheme w =1/
[σ2(Fo2)+ (0.0987P)+20.20P], where P = (Fo2 + 2F2c)/3. The
refinement of 187 parameters (data-to-parameter ratio be-
ing 11.6) converged to the final agreement factors
R = 0.0405 for 801 reflections with Fo >4σ (Fo) and
Rw = 0.1280, and S = 1.042 for all observed reflections.
The electron density of the largest difference peak was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
New Extended 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles
2,5-Bis[4′-(carbazol-9-yl)-3-methylbiphenyl-4-yl]-1,3,4-
oxadiazole (7e). White solid (0.33g, 89%); mp 306–308°C.
1H NMR (400 MHz, CDCl3): δ 2.95 (s, 3H), 7.32 (t,
J =8.0 Hz, 2H), 7.44 (t, J =8.0 Hz, 2H), 7.50 (d,
J =8.0 Hz, 2H), 7.72 (m, 4H), 7.91 (d, J= 8.0Hz, 2H),
8.17 (d, J = 8.0 Hz, 2H), 8.23 (d, J= 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 22.6, 109.8, 120.1, 120.4,
122.2, 123.5, 124.9, 126.0, 127.5, 128.6, 129.7, 130.5,
137.7, 138.9, 139.2, 140.8, 142.9, 164.3; UV-VIS: λmax
(CHCl3) 242.0 nm (εÁ10À3 75.5cmÀ1MÀ1), 293.0 (48.9),
342.0 (58.0); IR (ATR) ν: 3053, 2182, 1604, 1535, 1489,
1477, 1449, 1385, 1361, 1334, 1307, 1225, 1171, 1042,
1015, 826, 815, 750, 740, 724, 718, 703, 658 cmÀ1; Anal.
Calcd for C52H36N4O: C, 85.22; H, 4.95; N, 7.64. Found:
C, 85.26; H, 4.97; N, 7.60; HRMS Calcd for
(C52H36N4O + H+): 733.2962; found: 733.2966.
2,5-Bis[4-(thiantren-1-yl)-2-methylphenyl]-1,3,4-oxadiazole
(7f). Beige solid (0.29 g, 87%); mp 109–110°C. 1H NMR
(400 MHz, CDCl3): δ 2.90 (s, 3H), 7.20 (m, 2H), 7.29 (m,
2H), 7.39 (dd, J= 7.6 and 1.2 Hz, 1H), 7.43 (m, 2H), 7.50
(dd, J= 7.6 and 1.2 Hz, 1H), 7.56 (dd, J = 7.6 and 1.2 Hz,
1H), 8.19 (d, J = 8.0 Hz, 1H); 13C NMR (100MHz,
CDCl3): δ 22.5, 122.4, 127.2, 127.4, 127.7, 127.9, 128.3,
128.6, 128.8, 128.9, 129.0, 132.9, 135.0, 135.6, 135.9,
136.3, 138.5, 141.4, 143.1, 164.3; UV-VIS: λmax (CHCl3)
261.5 nm (εÁ10À3 56.9cmÀ1MÀ1), 307.5 (35.9); IR
(ATR) ν: 34258, 3044,2 2162, 2036, 1607, 1474, 1458,
1439, 1327, 1236, 1063, 1044, 843, 824, 771, 754, 742,
727, 712 cmÀ1; Anal. Calcd for C40H26N2OS4: C, 70.76;
H, 3.86; N, 4.13; S, 18.89. Found: C, 70.72; H, 3.82; N,
4.09; S, 18.90; HRMS Calcd for (C40H26N2OS4 +H+):
679.1001; found: 679.0997.
142.6, 146.6, 147.5, 147.9, 167.4; UV-VIS: λmax (CHCl3)
299.0 nm (εÁ10À3 38.9 cmÀ1MÀ1), 374.0 (50.8); IR
(ATR) ν: 3033, 2157, 1950, 1587, 1519, 1484, 1444,
1329, 1317, 1273, 1194, 1178, 1075, 1028, 985, 816,
769, 753, 724, 685 cmÀ1; Anal. Calcd for C52H40N4S: C,
82.95; H, 5.35; N, 7.44; S, 4.26. Found: C, 82.98; H,
5.39; N, 7.41 S, 4.25; HRMS Calcd for (C52H40N4S
+ H+): 753.3046; found: 753.3041.
2,5-Bis[4-(9-methylcarbazol-3-yl)-2-methylphenyl]-1,3,4-
thiadiazole (8c). Green solid (0.24 g, 78%); mp 258–260°C.
1H NMR (400MHz, CDCl3): δ 2.81 (s, 3H), 3.89 (s, 3H),
7.27 (t, J= 8.0 Hz, 1H), 7.42 (d, J =8.0 Hz, 1H), 7.47 (d,
J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.68 (d,
J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H),
7.92 (d, J= 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.37 (s,
1H); 13C NMR (100MHz, CDCl3): δ 22.3, 29.3, 108.7,
108.8, 118.9, 119.2, 120.4, 122.9, 123.4, 125.0, 125.1,
126.1, 127.2, 130.4, 131.0, 131.4, 137.7, 140.9, 141.5,
144.1, 167.7; UV-VIS: λmax (CHCl3) 244.0nm (εÁ10À3
69.8 cmÀ1MÀ1), 282.5 (46.0), 300.5 (46.1), 352.0 (58.9);
IR (ATR) ν: 3048, 2924, 2156, 2022, 1596, 1493, 1479,
1469, 1443, 1393, 1363, 1325, 1260, 1246, 1154, 1124,
1104, 1019, 986, 878, 816, 793, 764, 744, 725,
693 cmÀ1; Anal. Calcd for C42H32N4S: C, 80.74; H, 5.16;
N, 8.97; S, 5.13. Found: C, 80.70; H, 5.18; N, 9.00; S,
5.10; HRMS Calcd for (C42H32N4S+ H+): 625.2420;
found: 625.2427.
2,5-Bis[4-(9-ethylcarbazol-3-yl)-2-methylphenyl]-1,3,4-
thiadiazole (8d).
Yellow solid (0.29 g, 88%); mp 206–
1
209°C. H NMR (400 MHz, CDCl3): δ 1.47 (t, J =6.8Hz,
3H), 2.81 (s, 3H), 4.40 (q, J= 6.8 Hz, 2H), 7.26 (t,
J = 8.0 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.49 (m, 2H),
7.68 (d, J= 8.0 Hz, 1H), 7.72 (s, 1H), 7.77 (d, J =8.0 Hz,
1H), 7.93 (d, J =8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H),
8.39 (s, 1H); 13C NMR (100MHz, CDCl3): δ 13.8, 22.3,
37.7, 108.7, 108.8, 119.0, 120.6, 123.0, 123.6, 125.0,
125.1, 126.0, 127.1, 128.3, 130.4, 130.9, 131.4, 137.7,
139.8, 140.5, 144.1, 167.8; UV-VIS: λmax (CHCl3)
243.5 nm (εÁ10À3 67.5cmÀ1MÀ1), 284.0 (44.5), 301.0
(45.3), 352.0 (54.6); IR (ATR) ν: 3050, 2923, 2179,
2021, 1596, 1478, 1470, 1443, 1393, 1363, 1326, 1305,
1285, 1259, 1247, 1233, 1155, 1125, 986, 878, 814, 793,
765, 745, 725, 694 cmÀ1; Anal. Calcd for C44H36N4S: C,
80.95; H, 5.56; N, 8.58; S, 4.91. Found: C, 80.98; H,
5.53; N, 8.54; S, 4.90; HRMS Calcd for (C44H36N4S
+ H+): 653.2733; found: 653.2730
2,5-Bis(3-methylbiphenyl-4-yl)-1,3,4-thiadiazole
(8a).
White solid (0.15 g, 72%); mp 143–144°C. 1H NMR
(400 MHz, CDCl3): δ 2.75 (s, 3H), 7.38 (t, J= 7.6 Hz,
1H), 7.46 (t, J = 7.6 Hz, 2H), 7.54 (d, J= 8.0 Hz, 1H),
7.59 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.87 (d, J= 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 22.1, 125.0, 127.2,
127.9, 128.1, 128.9, 130.4, 131.4, 137.7, 140.0, 143.1,
167.6; UV-VIS: λmax (CHCl3) 246.0 nm (εÁ10À3
26.2cmÀ1MÀ1), 319.0 (43.6); IR (ATR) ν: 3031, 2982,
2926, 2162, 1959, 1607, 1556, 1487, 1445, 1437, 1391,
1220, 1097, 1077, 1024, 988, 882, 835, 763, 730, 714,
697cmÀ1; Anal. Calcd for C28H22N2S: C, 80.35; H, 5.30;
N, 6.69; S, 7.66. Found: C, 80.37; H, 5.31; N, 6.63; S,
7.68; HRMS Calcd for (C28H22N2S + H+): 419.1576;
found: 419.1572.
2,5-Bis[4′-(carbazol-9-yl)-3-methylbiphenyl-4-yl]-1,3,4-
thiadiazole (8e). Grey solid (0.32g, 85%); mp 280–281°C.
1H NMR (400MHz, CDCl3): δ 2.82 (s, 3H), 7.30 (t,
J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.48 (d,
J = 8.0 Hz, 2H), 7.65 (d, J= 8.0 Hz, 1H), 7.68 (d,
J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H),
7.97 (d, J= 8.0 Hz, 1H), 8.15 (d, J =8.0 Hz, 2H); 13C
NMR (100MHz, CDCl3): δ 22.2, 109.8, 120.1, 120.4,
2,5-Bis[4′-(N,N-diphenylamino)-3-methylbiphenyl-4-yl]-
1,3,4-thiadiazole (8b).
Yellow solid (0.32 g, 84%); mp
1
291–293°C. H NMR (400 MHz, CDCl3): δ 2.74 (s, 3H),
7.05 (t, J= 7.6Hz, 2H), 7.14 (m, 6H), 7.27 (t, J= 7.6 Hz,
4H), 7.51 (m, 3H), 7.56 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 22.2, 123.2, 123.5,
124.4, 124.7, 127.8, 128.3, 129.3, 129.8, 131.4, 137.7,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Wróblowska, A. Kudelko, N. Kuźnik, K. Łaba, and M. Łapkowski
Vol 000
[7] Haider, S.; Alam, M. S.; Hamid, H. Eur J Med Chem 2015, 92,
[8] Sharma, B.; Verma, A.; Prajapati, S.; Sharma, U. K. Int J Med
Chem 2013, 2013, 1.
[9] Schulz, B.; Orgzall, I.; Freydank, A.; Xii, C. Adv Colloid
Interface Sci 2005, 116, 143.
123.5, 125.0, 126.0, 127.5, 128.3, 128.4, 128.6, 130.4,
131.6, 137.6, 138.0, 140.8, 142.2, 167.6; UV-VIS: λmax
(CHCl3) 243.0 nm (εÁ10À3 96.6cmÀ1MÀ1), 293.0 (53.1),
342.5 (65.2); IR (ATR) ν: 3047, 3924, 2156, 2018, 1596,
1521, 1494, 1479, 1444, 1392, 1364, 1335, 1317, 1260,
1232, 1154, 1120, 1019, 986, 878, 816, 792, 746, 724,
695cmÀ1; Anal. Calcd for C52H36N4S: C, 83.39; H, 4.84;
N, 7.48; S, 4.28. Found: C, 83.35; H, 4.80; N, 7.43; S,
4.31; HRMS Calcd for (C52H36N4S + H+): 749.2733;
found: 749.2737.
2,5-Bis[4-(thiantren-1-yl)-2-methylphenyl]-1,3,4-thiadiazole
(8f). Beige solid (0.27g, 77%); mp 293–295°C. 1H NMR
(400 MHz, CDCl3): δ 2.77 (s, 3H), 7.21 (m, 2H), 7.29
(m, 2H), 7.40 (m, 3H), 7.50 (dd, J =7.6 and 1.2Hz, 1H),
7.54 (dd, J =7.6 and 1.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 22.0, 122.3, 127.2,
127.5, 127.7, 127.9, 128.3, 128.7, 128.9, 129.1, 130.7,
132.8, 135.1, 135.6, 136.0, 136.3, 138.5, 141.2, 143.1,
167.3; UV-VIS: λmax (CHCl3) 261.0 nm (εÁ10À3
61.8cmÀ1MÀ1), 310.5 (36.4); IR (ATR) ν: 3046, 2914,
2168, 1970, 1607, 1559, 1441, 1376, 1278, 1246, 1107,
1066, 1033, 990, 885, 840, 790, 753, 731, 722cmÀ1; Anal.
Calcd for C40H26N2S5: C, 69.13; H, 3.77; N, 4.03; S,
23.07. Found: C, 69.09; H, 3.72; N, 4.07; S, 23.00; HRMS
Calcd for (C40H26N2S5 + H+): 695.0772; found: 695.0777.
156.
[10] Tamoto, N.; Adachi, C.; Nagai, K. Chem Mater 1997, 9, 1077.
[11] Tambe, S. M.; Tasaganva, R. G.; Inamdar, S. R.;
Kariduraganavar, M. Y. J Appl Polym Sci 2012, 125, 1049.
[12] Wang, C.; Jung, G. Y.; Hua, Y.; Pearson, C.; Bryce, M. R.;
Petty, M. C.; Batsanov, A. S.; Goeta, A. E.; Howard, J. A. K. Chem Mater
2001, 13, 1167.
[13] Grykien, R.; Luszczynska, B.; Glowacki, I.; Kurach, E.;
Rybakiewicz, R.; Kotwica, K.; Zagorska, M.; Pron, A.; Tassini, P.;
Maglione, M. G.; Del Mauro, A. D. G.; Fasolino, T.; Rega, R.;
Pandolfi, G.; Minarini, C.; Aprano, S. Opt Mater 2014, 37, 193.
[14] Oliveira, C. S.; Lira, B. F.; Barbosa-Filho, J. M.; Lorenzo, J. G. F.;
Athayde-Filho, P. F. Molecules 2012, 17, 10192.
[15] Subin, M. Z.; Mridula, R.; Namy, G.; Mohammad, S. A. Res
J Pharm Biol Chem Sci 2015, 6, 205.
[16] Sharma, B.; Verma, A.; Prajapati, S.; Sharma, U. K. Int J Med
Chem 2013 1.
[17] Kudelko, A.; Wróblowska, M. Tetrahedron Lett 2014, 55, 3252.
[18] Tandon, V. K.; Chhor, R. B. Synth Commun 2001, 31, 1727.
[19] Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J Tetrahedron
Lett 1999, 40, 3275.
[20] Kudelko, A.; Wróblowska, M.; Jarosz, T.; Łaba, K.;
Łapkowski, M. Arkivoc 2015, 5, 287.
[21] Lin, K.-T.; Kuo, H.-M.; Sheu, H.-S.; Lai, C. K. Tetrahedron
2013, 69, 9045.
[22] Deokar, H.; Chaskar, J.; Chaskar, A. J Heterocyclic Chem
2014, 51, 719.
[23] Wróblowska, M.; Kudelko, A.; Łapkowski, M. Synlett 2015,
26, 2127.
[24] Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F.; Stang, P. J. Eds.; Wiley-VCH: Weinheim, 1998, Chap. 2,
pp 49–97.
REFERENCES AND NOTES
[25] Suzuki, A. J Organomett Chem 2002, 653, 83.
[26] Kuznetsov, V. P.; Patsenker, L. D.; Lokshin, A. I.;
Tolmachev, A. V. Funct Mater 1996, 3, 460.
[27] Hoffmann, K.; Dietzel, B.; Schulz, B.; Reck, G.; Hoffmann, A.;
Orgzall, I.; Resch-Genger, U.; Emmerling, F. J Mol Struct 2011,
988, 35.
[1] Sangshetti, J. N.; Chabukswar, A. R.; Shinde, D. B. Bioorg
Med Chem Lett 2011, 21, 444.
[2] Chandrakantha, B.; Shetty, P.; Nambiyar, V.; Isloor, N.;
Isloor, A. M. Eur J Med Chem 2010, 45, 1206.
[3] Basedia, D. K.; Shrivastava, B.; Dubey, B. K.; Sharma, P. Int J
Biom Res 2014, 5, 13.
[28] Emmerling, F.; Orgzall, I.; Dietzel, B.; Schulz, B.; Larrucea, J.
J Mol Struct 2012, 1030, 209.
[4] Bankar, G. R.; Nampurath, G. K.; Nayak, P. G.; Bhattcharya, S.
Chem Biol Interact 2010, 183, 327.
[29] Williams, A. T. R. Analyst 1983, 108, 1067.
[30] Brouwer, A. M. Pure Appl Chem 2011, 83, 2213.
[31] Mitschke, U.; Debaerdemaeker, T.; Bäuerle, P. Eur J Org
Chem 2000, 3, 425.
[5] Liu, K.; Lu, X.; Zhang, H. J.; Sun, J.; Zhu, H. L. Eur J Med
Chem 2012, 47, 473.
[6] Zou, X. J.; Lai, L. H.; Zhang, Z. X. J Agric Food Chem 2002,
50, 3757.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet