Efficient Synthesis of Conjugated 1,3,4-Thiadiazole Hybrids through Palladium-Catalyzed Cross-Coupling of 2,5-Bis(4-bromophenyl)-1,3,4-thiadiazole with Boronic Acids

Article abstract of DOI:10.1055/s-0034-1378826

New derivatives of 2,5-bis(4-heteroarylphenyl)-1,3,4-thiadiazole were synthesized under Suzuki cross-coupling reactions from 2,5-bis(4-bromophenyl)-1,3,4-thiadiazole and commercially available boronic acids. Reactions were conducted in a two-phase solvent

Full text of DOI:10.1055/s-0034-1378826

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2127–2130
letter
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M. Wróblowska et al.
Letter
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Efficient Synthesis of Conjugated 1,3,4-Thiadiazole Hybrids through
Palladium-Catalyzed Cross-Coupling of 2,5-Bis(4-bromophenyl)-
1,3,4-thiadiazole with Boronic Acids
Monika Wróblowskaa
Agnieszka Kudelko*a
Mieczysław Łapkowskib,c
Pd(PPh3)4
Cs2CO3
NBu4Br
Br
Br
S
Ar
Ar
S
N
N
N
N
toluene, EtOH, H2O
oil bath or sonication
2–6 h
a Department of Chemical Organic Technology and Petrochemistry,
The Silesian University of Technology, Krzywoustego 4, 44100 Gliwice,
Poland
OH
OH
59–92%
Ar
B
Agnieszka.Kudelko@polsl.pl
b Department of Physical Chemistry and Technology of Polymers, The
Silesian University of Technology, Strzody 9, 44100 Gliwice, Poland
c Centre of Polymer and Carbon Materials of the Polish Academy of
Sciences, M. Curie-Sklodowskiej 34, 41-819 Zabrze, Poland
Ar = phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 4-pyridyl, 3-pyridyl
Received: 09.04.2015
Accepted after revision: 29.06.2015
Published online: 10.08.2015
and 1,3,4-oxadiazole,2,2-(1,3-phenylene)bis{5-[4-(1,1-di-
methylethyl)phenyl]} (OXD-7).7 However, 1,3,4-thiadiazoles
also exhibit interesting properties in this area.8 A literature
survey revealed examples of modification of luminophore
electron-transporting properties by direct or indirect con-
jugation to other heteroaromatic systems such as pyridines,
furans, thiophenes, selenophenes, tellurophenes, or 1,3,4-
oxadiazoles.9,10
The most popular method for the synthesis of these het-
erocyclic compounds with substituents in positions 2 and 5
involves spontaneous cyclization and dehydration of N,N′-
diacylhydrazines with diphosphorus pentasulfide11 or
Lawesson’s reagent.12 Other sources also describe exchange
of the oxygen atom in the 1,3,4-oxadiazole to sulfur using
thiourea,13 and the cyclization of bithioureas14 or thiosemi-
carbazides with other compounds containing a carbonyl
group.15
In continuation of our scientific program on the appli-
cation of acid hydrazides in the formation of selected het-
erocycles,16,17 we decided to study the synthesis of conju-
gated 1,3,4-thiadiazole derivatives as 1,3,4-oxadiazole
structural counterparts, conjugated via a phenylene linker
to other homo- and heteroaromatic functionality such as
benzene, pyridine, thiophene, and furan rings, hoping to
obtain new potential monomers for optoelectronics. This
issue seems to be very important due to the fact that elec-
tronic interactions in 1,3,4-thiadiazoles are relatively
scarcely reported in the literature. One efficient approach
features formation of the biaryl system via Suzuki cross-
coupling, one of the most important catalytic methods of
sp2–sp2 C–C construction.18
DOI: 10.1055/s-0034-1378826; Art ID: st-2015-d0257-l
Abstract New derivatives of 2,5-bis(4-heteroarylphenyl)-1,3,4-thiadi-
azole were synthesized under Suzuki cross-coupling reactions from 2,5-
bis(4-bromophenyl)-1,3,4-thiadiazole and commercially available bo-
ronic acids. Reactions were conducted in a two-phase solvent system in
the presence of catalytic amounts of tetrakis(triphenylphosphine)palla-
dium(0), cesium carbonate as a base, and tetrabutylammonium bro-
mide playing a role of a phase-transfer catalyst.
Key words heterocycles, cross-coupling, phase-transfer catalysis, pal-
ladium, catalysis
The thiadiazoles – a class of heterocyclic five-membered
organic compounds containing two nitrogen atoms and a
sulfur atom – exhibit high biological activity and therefore
constitute an important group of compounds for use in
medicine and agriculture.1 From among all of the possible
isomers of thiadiazole, chemists have focused on 1,3,4-thia-
diazole and its derivatives.2
During the past twenty years, there has been a signifi-
cant increase in interest in organic compounds exhibiting
luminescent properties that may be applied in the produc-
tion of efficient organic light-emitting diodes, scintillation
counters, and optical brighteners.3 An optimal organic lu-
minophore is usually an extended π-conjugated chromo-
phore system showing the proper electron-hole transport-
ing properties, a high external quantum efficiency, and
both thermal and chemical stability.4 The literature indi-
cates that, from the family of the five-membered heteroaro-
matic compounds commonly used in the production of new
materials for optoelectronics, 1,3,4-oxadiazole derivatives
have been intensively studied, for instance: 2-(4-biphenylyl)-
5-(4-tertbutylphenyl)-1,3,4-oxadiazole (PBD),5 2,5-bis[2-(4-
tert-butylphenyl)-1,3,4-oxadiazol-5-yl]pyridine (PDPyDP),6
The work reported herein describes a convenient proce-
dure for synthesizing novel, conjugated hybrids containing
a 1,3,4-thiadiazole core from commercially available boron-
ic acids and 2,5-bis(4-bromophenyl)-1,3,4-thiadiazole.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2127–2130

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O
O
O
Br
Br
i
ii
S
Cl
N
H
N
H
N
N
Br
Br
Br
3 (88%)
1
2 (68%)
Scheme 1 Synthesis of 2,5-bis(4-bromophenyl)-1,3,4-thiadiazole (3) scaffold. Reagents and conditions: (i) N2H4·H2O, Et3N, CHCl3, r.t., 4 h; (ii) P4S10
,
xylene, reflux, 4 h.
The key structure 2,5-bis(4-bromophenyl)-1,3,4-thiadi-
azole (3) was obtained according to a two-step procedure
through intermediate the N,N′-diacylhydrazine 2. Commer-
cially available 4-bromobenzoyl chloride (1) was treated
with hydrazine hydrate and triethylamine yielding the cor-
responding hydrazine derivative 2 (Scheme 1). Then the in-
termediate 2 underwent thionation by means of P4S10 and
subsequent cyclization in xylene solution at elevated tem-
perature. The resulting compound 3, representing the bi-
functional precuror for the Suzuki cross-coupling reaction,
was then subjected to reaction with a range of boronic acids
in the presence of a palladium catalyst to obtain conjugated
1,3,4-thiadiazole derivatives.
In order to identify the optimal conditions, the phenyl-
boronic acid (4a) was initially reacted with bifunctional di-
bromo derivative 3 in a mixture of polar solvents, such as
water and ethanol, and gave the final product 5a in a poor
yield (3%, Table 1, entry 1). However, due to the low effi-
ciency and problems with solubility it was decided to intro-
duce a nonpolar solvent: toluene and a phase-transfer cata-
lyst (NBu4Cl, NBu4Br). These operations led to noticeable
improvements in yield (Table 1, entries 2 and 3). The next
modifications comprised the use of various types of base to
activate the boronic acid and to facilitate the transmetala-
tion step. A range of metal carbonates – differing in cation
size – was tested and this study showed that the cation of
base had a moderate impact on the reaction yield (Table 1,
entries 4–7) while the quantity of base played an important
role (Table 1, entry 7 and 8). The best result was obtained
using a small excess of phenylboronic acid (4a, Table 1, en-
try 9). In the final step, ultrasonication was applied and it
was observed that, while maintaining the yield, the reac-
tion time was considerably shortened (Table 1, entry 10).
For these optimized conditions a series of reactions was
carried out with different boronic acids to afford symmetri-
cally substituted derivatives of 2,5-diphenyl-1,3,4-thiadi-
azole (Scheme 2). The starting compound 3 was treated
with a variety of heteroaromatic boronic acids 4b–g used in
excess (1:2.5 molar ratio). The reaction mixture was heated
in an oil-bath in the presence of the 5 mol% palladium cata-
lyst Pd(PPh3)4 and 10 mol% NBu4Br as the phase-transfer
catalyst, using the two-phase, three-component solvent
system (EtOH–H2O–toluene). The base employed in the re-
action was Cs2CO3 containing the largest cation, because it
gave the best results in the synthesis of optimized 1,3,4-
thiadiazole derivative 5a.21
This study resulted in novel symmetrical 2,5-diphenyl-
1,3,4-thiadiazole derivatives 5a–g substituted at the posi-
tion 4 of the phenylene linker with phenyl and heteroaryl
groups in high yields (59–92%, Table 2). The new products
were characterized by elemental analysis and spectroscopic
methods. UV/Vis spectra measurements of the investigated
Table 1 Optimization of the Coupling Reaction to Obtain 5a
Entry
3/4a ratio
(equiv)
Solvents
PTC catalyst
(equiv)
Catalyst Pd(PPh3)4 Base
Reaction time Yield
(h)
(equiv)
(equiv)
(%)a
1
2
1:2
EtOH–H2O
–
0.01
0.01
0.01
0.05
0.05
0.05
0.05
0.05
0.05
0.05
K2CO3 (5)
5
5
5
5
5
5
5
5
5
2
3b
1:2
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
EtOH–H2O–toluene
NBu4Cl (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
NBu4Br (0.1)
K2CO3 (5)
29b
3
1:2
K2CO3 (5)
35b
50b
47b
48b
51b
60b
92b
91c
4
1:2
K2CO3 (5)
5
1:2
Li2CO3 (5)
Na2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
6
1:2
7
1:2
8
1:2
9
1:2.5
1:2.5
10
a Yield with respect to the starting 2,5-bis(4-bromophenyl)-1,3,4-thiadiazole (3).
a Conditions: reaction temperature 80 °C (oil bath).
b Conditions: ultrasonic bath.
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Ar
Ar
Br
Br
OH
OH
S
S
Pd(PPh3)4, Cs2CO3, NBu4Br
Ar
B
+
toluene, EtOH, H2O
oil bath, 2–6 h
N
N
N
N
4a–g
5a–g (59–92%)
3
Ar = phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 4-pyridyl, 3-pyridyl
Scheme 2 Synthesis of 2,5-bis(4-arylphenyl)-1,3,4-thiadiazole 5a–g hybrids. Reagents and conditions: bifunctional dibromo derivative 3 (1.00 mmol),
boronic acid 4 (2.50 mmol), Pd(PPh3)4 (0.05 mmol), TBAB (0.10 mmol), Cs2CO3 (10 mmol), toluene–H2O–EtOH (10:6:3 mL), 80 °C (oil bath), 2–6 h.
compounds registered in CH2Cl2 showed the presence of
two or three absorption maxima depending on the nature
of the terminal aryl group (see Supporting Information).
The five-membered heterocyclic terminal substituents 5d–
g present in the studied hybrids were shifted bathochromi-
cally by 5 to 23 nm (λmax = 340–358 nm), in contrast to the
spectra were composed of three individual signals. Howev-
er, the Stokes’ shifts (Δ) were relatively small which testifies
to the slight change in geometry of the molecules during
the transition from the ground state to the first excited
state. Generally, the absorption maxima of the studied
1,3,4-thiadiazoles were red-shifted (11–25 nm) in contrast
to their 1,3,4-oxadiazole counterparts.19
model 3,5-bis(4-biphenylyl)-1,3,4-thiadiazole (5a, λmax
=
335 nm); while for the pyridine derivatives 5b,c (λmax = 330
nm) the reversed trend was observed. The fluorescence
The reported methodology demonstrates an efficient
way to synthesize extended derivatives of 1,3,4-thiadiazoles
Table 2 Synthesis of 2,5-Bis(4-arylphenyl)-1,3,4-oxadiazoles 5a–g in Suzuki Cross-Coupling Reactions
Compd 5 Substituent ArB(OH)2
Reaction time (h) Mp (°C)
Product
Yield (%)
92
S
5a
5
4
5
296–298 (lit.20 294–296 °C)
N
N
N
N
5b
251–253 (decomp.)
241–243 (decomp.)
270–272 (decomp.)
329–332 (decomp.)
227–228 (decomp.)
280–282 (decomp.)
84
87
65
87
59
77
S
N
N
N
N
5c
N
S
N
N
N
S
S
S
5d
2
4
4
6
S
N
N
N
N
N
S
O
O
S
S
5e
S
S
S
N
N
N
O
O
5f
O
O
5g
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substituted symmetrically with a range of heteroaromatic
arrangements via a 1,4-phenylene linker at positions 2 and
5. The bifunctional precursor: 2,5-bis(4-bromophenyl)-
1,3,4-thiadiazole that was readily prepared from acyclic
N,N'-diacylhydrazines underwent Suzuki cross-coupling re-
actions in the presence of palladium catalyst both under
conventional and ultrasound-assisted conditions. The pres-
ent protocol may be particularly useful in the synthesis of
monomers for linear conjugated systems that may find po-
tential application in materials science.
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Sheu, H.-S.; Lai, C. K. Tetrahedron 2013, 69, 9045. (c) Morikawa,
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378826.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(21) Representative Procedure for Suzuki Coupling
2,5-Bis(4-bromophenyl)-1,3,4-thiadiazole (3, 0.40 g, 1.00
mmol), the appropriate boronic acid (2.50 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.05 mmol),
TBAB (0.03 g, 0.10 mmol), and Cs2CO3 (3.26 g, 10.00 mmol)
were treated with a combination of toluene (10 mL), H2O (6 mL),
and EtOH (3 mL). The mixture was heated to 80 °C (oil bath) for
2–6 h (TLC monitoring). After cooling, CHCl3 (200 mL) was
added and the mixture filtered through silica gel (20 mL). The
filtrate was separated, the organic layer was dried over MgSO4
and then concentrated on a rotary evaporator. The residue was
treated with a mixture of benzene–EtOAc (3:1). The solid pre-
cipitate was filtered off, washed with benzene–EtOAc (3:1) and
air-dried to give the pure 2,5-disubstituted 1,3,4-thiadiazole.
3,5-Bis(4-biphenylyl)-1,3,4-thiadiazole (5a)
White-pearl solid (0.34 g, 92% yield); mp 296–298 °C (lit.16 294–
1
296 °C). H NMR (400 MHz, CDCl3): δ = 7.41 (t, J = 7.6 Hz, 1 H),
7.49 (t, J = 7.6 Hz, 2 H), 7.66 (d, J = 7.6 Hz, 2 H), 7.74 (d, J = 8.4
Hz, 2 H), 8.11 (d, J = 8.4 Hz, 2 H). 13C NMR (400 MHz, CDCl3): δ =
124.4, 127.1, 127.8, 128.1, 128.4, 129.0, 139.9, 143.9, 167.8.
UV/Vis: λmax (CHCl3) 335.0 nm (ε · 10–3 60.3 cm–1 M–1). IR (ATR):
ν = 3060, 3037, 2162, 1946, 1821, 1675, 1604, 1561, 1488, 1451,
1432, 1420, 1401, 1316, 1253, 1185, 1170, 1100, 1040, 1027,
1005, 997, 988, 910, 838, 760,718, 684 cm–1. Anal. Calcd for
C
26H18N2S: C, 79.97; H, 4.65; N, 7.17. Found: C, 79.99; H, 4.63; N,
7.21. HRMS: m/z calcd for [C26H18N2S + H+]: 391.1269; found:
391.1267.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2127–2130