Powerful Antibacterial Activity of Phenyl-Thiolatobismuth(III) Complexes Derived from Oxadiazolethiones

Article abstract of DOI:10.1002/ejic.201500795

Seven novel 5-substituted phenylthiazole oxadiazolethiones: [Me-PTOT(H)], [MeO-PTOT(H)], [MeS-PTOT(H)], [F-PTOT(H)], [Cl-PTOT(H)], [Br-PTOT(H)], and [CF₃-PTOT(H)], {where X-PTOT(H) = 5-[2-(4-X)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione, 4-X = C₆H₄}, were synthesised from their corresponding thioamides. From these seven heteroleptic thiolatobismuth complexes: BiPh(Me-PTOT)₂ 6, BiPh(MeO-PTOT)₂ 7, BiPh(MeS-PTOT)₂ 8, BiPh(F-PTOT)₂ 9, BiPh(Cl-PTOT)₂ 10, BiPh(Br-PTOT)₂ 11 and BiPh(CF₃-PTOT)₂ 12 were synthesised and characterised. Complexes [10(DMSO)₂] and [11(DMSO)₂] were structurally characterised using X-ray diffraction. Evaluation of the antibacterial properties of the thiones and their Bi^III complexes against Mycobacterium smegmatis, Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus (VRE), Enterococcus faecalis (E. faecalis) and Escherichia coli (E. coli) showed that all bismuth(III) complexes were highly effective against all the bacteria, as demonstrated by very low MIC values (1.1-2.1 μM). Complexes BiPh(Me-PTOT)₂ 6, BiPh(Cl-PTOT)₂ 10 and BiPh(Br-PTOT)₂ 11, showed best activity against the multi-drug resistant bacteria VRE and MRSA with an MIC value of 1.0 μM. All these complexes and their corresponding thiones failed to show any prominent activity against M. smegmatis and E. coli, even at high concentrations. These complexes showed little or no toxicity towards mammalian COS-7 cells at 20 μg/mL. Seven heteroleptic thiolatobismuth(III) complexes [BiPh(X-PTOT)₂] derived from a series of 5-substituted phenylthiazole oxadiazolethiones [X-PTOT(H)] provide powerful antibacterial action against the multi-resistant bacteria MRSA and VRE.

Full text of DOI:10.1002/ejic.201500795

FULL PAPER
DOI:10.1002/ejic.201500795
Powerful Antibacterial Activity of Phenyl-
Thiolatobismuth(III) Complexes Derived from
Oxadiazolethiones
Ahmad Luqman,[a] Victoria L. Blair,[a] Rajini Brammananth,[b]
Paul K. Crellin,[b] Ross L. Coppel,[b] and Philip C. Andrews*[a]
Keywords: Drug design / Antibiotics / Medicinal chemistry / Bismuth / Sulfur heterocycles / Nitrogen heterocycles
Seven novel 5-substituted phenylthiazole oxadiazolethiones:
[Me-PTOT(H)], [MeO-PTOT(H)], [MeS-PTOT(H)], [F-
PTOT(H)], [Cl-PTOT(H)], [Br-PTOT(H)], and [CF3-PTOT(H)],
resistant Staphylococcus aureus (MRSA), Vancomycin-resist-
ant Enterococcus (VRE), Enterococcus faecalis (E. faecalis)
and Escherichia coli (E. coli) showed that all bismuth(III)
complexes were highly effective against all the bacteria, as
{where X-PTOT(H)
= 5-[2-(4-X)thiazol-4-yl]-1,3,4-oxadi-
azole-2(3H)-thione, 4-X = C6H4}, were synthesised from their
corresponding thioamides. From these seven heteroleptic
thiolatobismuth complexes: BiPh(Me-PTOT)2 6, BiPh(MeO-
PTOT)2 7, BiPh(MeS-PTOT)2 8, BiPh(F-PTOT)2 9, BiPh(Cl-
PTOT)2 10, BiPh(Br-PTOT)2 11 and BiPh(CF3-PTOT)2 12
were synthesised and characterised. Complexes [10(DMSO)2]
and [11(DMSO)2] were structurally characterised using X-ray
diffraction. Evaluation of the antibacterial properties of the
thiones and their BiIII complexes against Mycobacterium
smegmatis, Staphylococcus aureus (S. aureus), Methicillin-
demonstrated by very low MIC values (1.1–2.1 μM). Com-
plexes BiPh(Me-PTOT)2 6, BiPh(Cl-PTOT)2 10 and BiPh-
(Br-PTOT)2 11, showed best activity against the multi-drug
resistant bacteria VRE and MRSA with an MIC value of
1.0 μM. All these complexes and their corresponding thiones
failed to show any prominent activity against M. smegmatis
and E. coli, even at high concentrations. These complexes
showed little or no toxicity towards mammalian COS-7 cells
at 20 μg/mL.
Introduction
and in biochemical studies.[12] For example Gudipati and
co-workers recently synthesised a series of 5- and 7-substi-
tuted 3-[4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenylimino]-
indolin-2-one derivatives which were screened for antican-
cer activity against HeLa cancer cells. All the compounds
produced a dose dependant inhibition in cell growth with
IC50 values of between 10.64 and 33.62 μm, comparable
with cisplatin.[13] The bactericidal activity of a series of N-
[3-mercapto-5-(2-thienyl)-1,2,4-triazol-4-yl]-NЈ-arylthio-
ureas was reported by Omar et al. and these compounds
demonstrated good activity towards against S. aureus (MIC
values 2–8 μg/mL) but poor activity against towards E.
coli.[14]
5-Substituted 1,3,4-oxadizole-2(3H)-thiones exist in two
tautomeric forms;[15] thione and thiol, as depicted in Fig-
ure 1. The thione form has been calculated to be 9.616 kcal/
mol more stable than the corresponding thiol in the gas
phase, and by 12.12 kcal/mol in aqueous solution. This is
supported by spectroscopic data from UV/Vis and IR stud-
ies.[16]
Oxadiazole is a heterocyclic moiety containing one oxy-
gen and two nitrogen atoms contained within a five mem-
bered ring, and is a significant and important moiety in the
construction of drug-like molecules.[1] Of the four known
isomers, 1,2,3-oxadiazole and 1,3,4-oxadiazole are the bet-
ter understood since they have been identified as having im-
portant chemical and biological properties. Derivatives of
1,3,4-oxadiazole in particular have received considerable
interest in medicinal chemistry because they have both a
proven and potentially wide range of biological applica-
tions, including as anti-HIV,[2] anticancer,[3] antiinflamma-
tory,[4] fungicidal,[5] herbicidal,[6] pesticidal, and analgesic
agents.[7] Raltegravir, an antiretroviral drug[8] and Ziboten-
tan, an anticancer agent,[9] are just two examples of drugs
based on the 1,3,4-oxadiazole motif in today’s market.
A closely related class of compound is the oxadiazole-
thiones (or thiols) which have become important as inter-
mediates in organic synthesis,[10] in theoretical chemistry[11]
[a] School of Chemistry, Monash University,
Clayton, Melbourne, VIC 3800, Australia
E-mail: phil.andrews@monash.edu
http://chem.monash.edu/staff/andrews/
[b] Department of Microbiology, Monash University,
Clayton, Melbourne, VIC 3800, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201500795.
Figure 1. Thiol–thione tautomerism in oxadiazole-thiones.
4935 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Bismuth compounds with a variety of ligand classes have the configurational dependency of the oxadiaziole ligand
been shown to display antimicrobial activity.[17] Recently, on the nature of the metal and co-ligands. Thiolates pre-
we reported on the exceptional antibacterial activity shown dominate for more covalent Sn centres [–SnPh3, –Sn(chex)3,
by a series of novel homo- and heteroleptic bismuth(III) –Sn(nBu)3][26] while in the oxido oligomer [–Sn(Me2)O–] the
thiolates derived from heterocyclic thiones (tetrazole, imid- thioamide configuration is favoured.[25]
azole, thiadiazole and thiazole). Many of the complexes dis-
In this study we report the synthesis of a new class of 5-
played very low μm activities against a range of gram posi- substituted 1,3,4-oxadiazole-2-thiones, derived from vari-
tive bacteria including Methicillin-resistant Staphlyococcus ous thiazoles, and their subsequent conversion to a series
aureus (MRSA), Enterococcus faecalis and Vancomycin-re- of homo- and heteroleptic bismuth(III) thiolates. The anti-
sistant Enterococcus (VRE). From our study several pat- bacterial activity of the BiIII complexes against Mycobacte-
terns were observed; the bactericidal activity was highly de- rium smegmatis, Staphylococcus aureus, Methicillin-resistant
pendent on the nature of the thiolato ligand, the degree of Staphylococcus aureus (MRSA), Vancomycin-resistant En-
substitution at the BiIII atom, and the overall composition terococcus (VRE), Enterococcus faecalis and Escherichia
of the complex – the mono-phenyl bis-thiolato complexes coli, and mammalian cell toxicity towards COS-7 monkey
[BiPh(SR)2] proved more effective than the tris-thiolato kidney cells, has been assessed and is reported alongside a
complexes, [Bi(SR)3]. Subtle changes in the structure of the comparison with our earlier studies into analogous bis-
thiolate ligand itself, for example through ring substitution, muth(III) thiolates. The solid-state structures of two mono-
had a strong influence on the observed activity.
phenyl-bis-thiolatobismuth(III) complexes has been deter-
Oxadiazolethiones, because of the presence of multiple mined and are described.
donor atoms (S, O, N) and the structural flexibility demon-
strated by the tautomeric forms, have the potential to dis-
Results and Discussion
play various binding modes upon complexation with met-
als.[18]
Synthesis of 1,3,4-Oxadiazole-2-thiones
Complexes are known with most of the d-block met-
als,[19] though only a few have been crystallographically
Interestingly, while there are many reports on the bio-
characterised. The heavier metals generally favour direct S– logical applications and structural properties of 1,3,4-oxadi-
M bonding giving rise to thiolates, while the lighter metals azole-2-thione derivatives, there are only a few reports de-
favour N–M bonding and the formation of thioamides. The scribing procedures for their synthesis. The principal syn-
thioamide ligands bond in a monodentate manner and the thetic route to 5-substituted 1,3,4-oxadiazole-2-thiones in-
complexes are invariably octahedral. As an example, 5-(4- volves the reaction of an acid hydrazide with carbon disulf-
pyridyl)-1,3,4-oxadiazole-2-thione results in thiolates with ide in the presence of alcoholic potassium/sodium hydrox-
Hg and Cd,[20] and thioamides with Ni,[21] Cu,[21] Zn,[21] ide solution, followed by acidification of the reaction mix-
and Mn.[22,23] A search of the Cambridge Crystallographic ture (Scheme 1).[27]
Database[24] shows a similar trend is observed with analo-
This is a popular method for the synthesis of oxadiazole
gous ligands 5-(R)-1,3,4-oxadiazole-2-thione, where R = p- derivatives due to the ease of work up and high yields.
MeOPh and 2-Pyr. For ligands in which R = 2-thienyl, 2- However, long reaction times (ca. 12 h) are required. In an
furyl, o-MeOPh and m-Pyr, only complexes of the lighter attempt to shorten the overall reaction time, the synthesis
metals (Cu, Ni, Mn) have been structurally authenticated. of our parent oxadiazole derivatives was carried out using
The only main group examples structurally characterised[25] microwave irradiation as an alternate approach. This
belong to a series of organotin(IV) complexes derived from proved to be highly successful and reduced reaction times
5-(phenyl)-1,3,4-oxadiazole-2-thione. This series highlights to 15 min while increasing yields. Purification of these com-
Scheme 1. General synthesis of target 1,3,4-oxadiazole-2-thione derivatives through conventional reflux and microwave microwave-assisted
methods (R = a: –Me; b: –OMe; c: –SMe; d: –F; e: Cl; f: –Br; g: –CF3).
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pounds was carried out by recrystallization and the purity Table 1. Reaction conditions for the synthesis of complexes 6–12
(colour: pale yellow for all) along with yield and .
of all these derivatives was established by thin-layer
chromatography where a single spot was observed.
Complex
Bismuth Reaction conditions Time Yield
source
[%]
The parent compounds were synthesised using the para-
substituted aromatic nitriles as the starting material. A
series of aromatic primary thioamides 1a–g was synthesised
from the reported method of Manaka et al.[28] using the
corresponding nitriles. These compounds possess a thioam-
ide group which can be converted into the thiazole deriva-
tives 2a–g by treatment with ethyl bromopyruvate in eth-
anol. The substituted phenylthiazole esters 3a–g on reflux
with hydrazine hydrate led to the formation of the para-
substituted phenylthiazole-4-carbohydrazide derivatives 4a–
g. These substituted acid hydrazides were then subjected to
6
7
8
9
[BiPh(Me-PTOT)2]
BiPh3
BiPh3
reflux, toluene
10 h
51
MW, toluene, 115 °C 15 min 50
BiPhCl2 methanol
[BiPh(MeO-PTOT)2] BiPh3 reflux, toluene,
BiPh3
BiPhCl2 methanol
12 h
12 h
75
52
MW, toluene, 105 °C 13 min 50
12 h
8 h
63
54
[BiPh(MeS-PTOT)2]
BiPh3
BiPh3
BiPhCl2 methanol
BiPh3
BiPh3
BiPhCl2 methanol
BiPh3
BiPh3
BiPhCl2 methanol
BiPh3
BiPh3
reflux, toluene,
MW, toluene, 110 °C 10 min 57
12 h
7 h
68
57
[BiPh(F-PTOT)2]
reflux, toluene
MW, toluene, 113 °C 12min 50
12 h
11 h
71
60
56
69
54
cyclization with CS2/KOH in boiling ethanol to afford cor- 10 [BiPh(Cl-PTOT)2]
responding 1,3,4-oxadiazol-2-thiones 5a–g. The composi-
reflux, toluene
MW, toluene, 110 °C 9 min
12 h
11 h
tion of all compounds 5a–g was determined and confirmed
11 [BiPh(Br-PTOT)2]
reflux, toluene
through infra-red spectroscopy, 1H and 13C NMR spec-
MW, toluene, 110 °C 14 min 53
trometry, mass spectrometry, and elemental analysis. The
synthetic and analytical details are provided in full in the
Exp. Section.
BiPhCl2 methanol
12 h
3 h
70
53
12 [BiPh(CF3-PTOT)2]
BiPh3
BiPh3
reflux, toluene
MW, toluene, 110 °C, 14 min 58
3 min 51
BiPhCl2 MW, toluene
Synthesis and Characterisation of Mono-Phenyl-Bis-
thiolatobismuth(III) Complexes 6–12
from the final product by washing with methanol and
water.
All seven N-heterocyclic thiones 5a–g {X-PTOT(H)}, or
their sodium salts where appropriate, were successfully re-
acted with either BiPh3 or BiPhCl2 to synthesise mono-
phenyl-thiolatobismuth(III) complexes 6–12 (Scheme 2).
A summary of the conditions and outcomes of the syn-
thetic procedures for compounds 6–12 is given in Table 1,
and provided in detail in the Exp. section.
Where a particular 1,3,4-oxadiazol-2(3H)-thione (5a–g)
is reacted with BiPh3 in a stoichiometry of 2:1 and heated,
the outcome is invariably the mono-phenyl-bis-thiolatobis-
muth(III) complex (6–12) in approximately the same yield.
The significant detail is that using microwave irradiation
rather than standard reflux results in the product in com-
parable yield but in a fraction of the time, typically 15 min
vs. 12 h. The salt metathesis reaction, which involves treat-
ing one equivalent of BiPhCl2 with two equivalents of the
Na salt of the oxadiazol-thione in methanol, generally pro-
duces the highest yield of the three procedures, though these
Characterisation
All bismuth complexes 6–12 were characterised using
NMR spectrometry, FT-IR, mass spectrometry and elemen-
tal analysis. Each complex was shown to be of the same
composition irrespective of the synthetic method used. Full
details are presented in the Exp. Section. NMR and single-
crystal X-ray diffraction studies are discussed below. Com-
plex composition and atom labelling used in NMR chemi-
cal shift assignment are shown in Figure 2.
Figure 2. Example showing labelling used in identifying atoms
are again conducted over a 12 h period. NaCl was removed NMR spectra.
Scheme 2. Formation of mono-phenyl-bis-thiolatobismuth(III) [BiPh(X-PTOT)2] complexes (6–12) using conventional, microwave, and
salt metathesis methods.
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All NMR studies were carried out using [D6]DMSO as
solvent. The presence of NH signals, in the range of 14.00–
14.80 ppm, in the 1H NMR spectra of the 1,3,4-oxadiazole-
thione derivatives indicate their thione conformation in
1
solution. H NMR spectroscopic data show that the NH
protons in the spectra of all the synthesised thiones are ab-
sent in all complexes 6–12 indicating the formation of a
stable thiolate anion upon deprotonation and binding to
the bismuth(III) atom. In all seven complexes 6–12, the
chemical shifts of the protons on the phenyl group (Bi-Ph)
lie in the ranges of 9.02–8.24 (ortho-), 7.90–7.54 (meta-) and
7.50–7.32 (para-) ppm. These have shifted to a lower fre-
quency relative to BiPh3 (ortho, 7.76; meta, 7.38 and para,
7.31 ppm). These high field shifts support the formation of
mono-phenylbismuth(III) derivatives. The resonances be-
longing to the protons in the phenyl group in the thiolato
ligand (C-Ph) appear in the ranges of 7.80–8.01 (ortho-) and
7.04–7.75 ppm (meta-), and within the ranges of 138.6–
139.3 (o-C), 131.1–133.7 (m-C) and 127.0–127.9 (p-C) ppm
in the 13C NMR spectra. The singlets corresponding to the
methyl, methoxy and thiomethoxy groups in complexes 6–
Figure 3. Molecular structure of [BiPh(Cl-PTOT)2(DMSO)2·
DMSO] {[10(DMSO)2]} with thermal ellipsoids shown at 40%
probability. Hydrogen atoms (except N–H ones) and a non-coordi-
nating DMSO molecule have been omitted for clarity. Selected
bond lengths [Å] and angles [°] for 10: Bi(1)–C(1), 2.229(3); Bi(1)–
O(4), 2.496(3); Bi(1)–O(3), 2.525(4); Bi(1)–S(3), 2.6872(12); Bi(1)–
S(1), 2.7159(12); S(1)–C(7), 1.715(3); S(3)–C(18), 1.728(4); N(4)–
N(10), 1.413(4); C(7)–S(1)–Bi(1), 93.80(12); C(18)–S(3)–Bi(1),
96.11(12); S(5)–O(3)–Bi(1), 136.8(2); S(6)–O(4)–Bi(1), 128.44(16).
1
8 resonate at 2.38, 3.84 and 2.54 respectively in their H
NMR spectra and, in the respective 13C NMR spectra, are
found at δ = 21.3, 55.4 and 14.2 ppm. In addition, reso-
nances attributed to the single proton in the thiazole moiety
in the parent thiones, found at 8.53 (5a), 8.50 (5b), 8.54 (5c),
1
8.58 (5d), 8.61 (5e), 8.64 (5f) and 8.69 (5g) ppm in the H
NMR spectra, all experience a high field shift in their re-
spective bismuth(III) complexes to 8.30 (6), 8.12 (7), 8.23
(8), 8.30 (9), 8.31 (10), 8.30 (11) and 8.35 (12) ppm.
X-Ray Crystallography
Needle-like crystals derived from compounds 10 and 11
were obtained from DMSO solution over a period of four
weeks and from single-crystal X-ray diffraction shown to
be [BiPh(Cl-PTOT)2(DMSO)2·DMSO] {[10(DMSO)2]} and
[BiPh(Br-PTOT)2(DMSO)2·DMSO] {[11(DMSO)2]}. To
the best of our knowledge these represent the first crystallo-
graphically characterised BiIII oxadiazole-thiolate com-
plexes, with both complexes being iso-structural and crys-
tallising in the monoclinic space group P21/c. The molec-
ular structures are shown in Figures 3 and 4 with selected
bond angles (°) and bond lengths (Å) listed.
The geometry of the bismuth atom in complexes
[10(DMSO)2] and [11(DMSO)2] is distorted square pyrami-
dal with a coordination number of five due to one phenyl,
two oxadiazole-thiolate ligands {Cl-PTOT in [10(DMSO)2]
and Br-PTOT in [11(DMSO)2]} and two molecules of
DMSO. In both cases the deprotonated ligands and the
phenyl group are covalently bound to the bismuth atom.
The Bi–S bond lengths in complexes [10(DMSO)2] and
[11(DMSO)2] appear in the range of 2.6770(10)–
Figure 4. Molecular structure of [BiPh(Br-PTOT)2(DMSO)2·
DMSO] {[11(DMSO)2]} with thermal ellipsoids shown at 40%
probability. Hydrogen atoms (except N–H ones) and a non-coordi-
nated molecule of DMSO have been omitted for clarity. Selected
bond lengths [Å] and angles [°] for 11: Bi(1)–C(23), 2.230(3); Bi(1)–
O(4), 2.502(3); Bi(1)–O(3), 2.521(4); Bi(1)–S(3), 2.6770(10); Bi(1)–
S(1), 2.7069(9); S(1)–C(1), 1.708(4); S(3)–C(12), 1.724(4); N(1)–
N(2), 1.402(4); C(1)–S(1)–Bi(1), 93.78(12); C(12)–S(3)–Bi(1),
96.49(12); S(5)–O(3)–Bi(1), 135.2(2); S(6)–O(4)–Bi(1), 128.73(16).
2.7159(12) Å which is comparable with the related BiIII S(Me2C=O)]ϱ {2,5-DMT(H) = 1,2,3-thiadiazole-2-(3H)-
mono-phenyl thiolato complexes [BiPh(5-MMTD)2]2 (5- thione; average Bi–S bond length: 2.709 Å}.[29] Indicative of
MMTD = 5-methyl-1,3,4-thiadiazole-2-thiolate; average the complexes adopting the thiolate anion upon deproton-
Bi–S bond length: 2.640 Å) and [BiPh{2,5-DMTD(H)}-κ- ation, a longer C–S bond length S(1)–C(7), 1.715(3); S(3)–
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C(18), 1.728(4) Å in [10(DMSO)2] and S(1)–C(1), 1.708(4);
The in vitro activity of the thiolatobismuth(III) com-
S(3)–C(12), 1.724(4) Å in [11(DMSO)2] is observed con- plexes, free thiones, and Isoniazid were initially compared
firming single bond character in the BiIII complexes. The using drug-diffusion assays in which filter paper discs con-
Bi–S–C angles {93.80 (12)° and 96.11 (12)° in [10(DMSO)2]; taining the drug were placed onto the surface of agar plates
93.78 (12)° and 96.49 (12)° in [10(DMSO)2]} are obtuse in spread with the bacterial culture. Following overnight incu-
nature and far removed from the expected bond angle of bation, the presence of a zone of inhibition of bacterial
109° seen in other similar Bi–S–C bonded complexes.[30] growth around the disc indicated some degree of antibacte-
These obtuse Bi–S–C angles are similar to the previously rial activity. Compounds that were positive in this initial
reported bismuth(III) thiolate complexes [BiPh(2-MMI)2- screen were then used in minimum inhibitory concentration
{2-MMI(H)}2] (2-MMI
[Bi–S–C average: 93.50°]),[31] and {BiPh(4-MTT)2[4-MTT- The MICs are expressed as μg/mL (and calculated as μm),
(H)]2} (4-MMT
4-methyl-1,2,4-triazole-3-thiolate)[29] as the minimal concentration of the drug within a series of
= 2-thiolate-1-methylimidazole (MIC) assays to quantify their level of antibacterial activity.
=
which adopt the same distorted square pyramidal geometry dilutions that still completely inhibited bacterial growth in
seen in complexes [10(DMSO)2] and [11(DMSO)2]. Look- culture. The comparative in vitro activities of all the com-
ing at the crystal packing of complexes [10(DMSO)2] and pounds are shown in Table 2.
[11(DMSO)2], the discrete molecular units form a head to
Most of the bismuth complexes demonstrated significant
tail arrangement maximising significant intra- (average antimicrobial activity against gram-positive bacteria i.e. S.
centroid distance: 3.717 Å) and intermolecular (average aureus, MRSA, VRE, and E. faecalis but were less active
centroid distance: 3.605 Å) π-stacking of the oxadiazole- against the gram-negative bacterium E. coli. Overall, the
thiolate ligands which can be seen in Figure 5.
studies reveal that the mono-phenylbismuth(III) derivatives
are more potent than the oxadiazolethiones. This is consis-
tent with our previous studies showing that mono-phenyl
thiolates [BiPh(SR)2] are more active than either the parent
thiones, which are not active Ͻ100 μm, or their tris-thiolato
analogues [Bi(SR)3], which while showing some antibacte-
rial activity, tend to be orders of magnitude less effective.[29]
This enhancement of biological activity has also been ob-
served with phenylbismuth sulfonates and carboxylates.[33]
Complexes 6–12 proved to be highly potent inhibitors of
all the gram-positive bacteria tested, with the exception of
M. smegmatis, displaying MIC values in the range 1.0–
1.16 μg/mL (1.98–2.14 μm). In particular, complex
6
[BiPh(Me-PTOT)2] displays excellent activity towards S. au-
reus, MRSA, VRE and E. faecalis with MIC values of 1.2,
1.1, 1.1 and 1.0 μm, respectively. With respect to the multi
drug-resistant bacteria, these activities are comparable to
Vancomycin. Of importance is the fact that this family of
compound is essentially equally toxic to all the strains of
bacteria tested, including those that are drug-resistant. In
contrast to our recent observations with bismuth derivatives
of phenylthiazole-2-thiol, there appears to be little or no
influence on antibacterial activity in changing the substitu-
ents at the para position of the phenyl ring in the oxadiazole
moiety.[31] Of note is the generalised poorer activity towards
M. smegmatis, where the BiIII compounds are an order of
magnitude less effective. One reason for this may be the
waxy, hydrophobic nature of the mycobacterial cell wall is
well known to provide intrinsic resistance to a range of anti-
bacterial compounds. There are unique aspects in mycolic
Figure 5. Extended molecular structure of [BiPh(Cl-PTOT)2-
(DMSO)2·DMSO] [11(DMSO)2] with thermal ellipsoids shown at
40% probability. Hydrogen atoms have been omitted for clarity.
Centroid π-stacking interactions displayed as fragmented lines.
Antibacterial Activity
All the parent oxadiazolethiones and their BiIII com- acids, polysaccharides and peptidoglycans which could
plexes were tested against six different strains of bacteria; possibly chelate and bind bismuth preventing efficient ac-
M. smegmatis, S. aureus, MRSA, VRE, E. faecalis and E. cess to the cell membrane.[34]
coli. For comparison, the activity of the BiPh3 was also as-
In general, these compounds were more active against
sessed. The solvent used for the preparation of sample solu- the gram-positive bacteria studied than the most active
tion of required concentration was DMSO. Isoniazid (iso- compounds we have previously reported: mono-phenyl bis-
nicotinohydrazide), a first-line drug for the treatment of thiolato complexes derived from 1-methyl-1H-tetrazole-5-
tuberculosis, and vancomycin (clinical MIC = 2 μg/mL, thiol, 1-MMTZ(H) and 4-methyl-4H-1,2,4-triazole-3-thiole,
1.38 μm) were used as controls.[32]
4-MMT(H).[29,35] Two of these complexes were unusual in
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Table 2. Antibacterial activities of bis-thiolatobismuth(III) complexes 1–7 and their corresponding free thiones against M. smegmatis, S.
aureus, MRSA, VRE, E. coli and E. faecalis.
MIC μg/mL [μm]
Compound
isoniazid
M. smegmatis
S. aureus
MRSA
VRE
E. faecalis
E. coli
1.0 (7.29)
100
100
100
100
100
5a
5b
5c
5d
5e
5f
5g
6
Me-PTOT(H)
OMe-PTOT(H)
MeS-PTOT(H)
F-PTOT(H)
Cl-PTOT(H)
Br-PTOT(H)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1.2
(1.4)
1.3
(1.4)
1.2
(1.3)
1.8
(2.1)
1.8
(2.1)
1.5
(1.6)
1.5
(1.6)
–
–
–
–
–
–
–
1.0
(2.0)
1.3
(1.4)
1.3
(1.5)
1.7
(2.0)
1.5
(1.7)
1.0
(1.1)
1.2
(1.3)
–
–
–
–
–
–
–
1.0
(2.0)
1.2
(1.4)
1.5
(1.7)
1.7
(2.0)
1.0
(1.1)
1.6
(1.7)
1.6
(1.7)
–
–
–
–
–
–
–
1.1
(2.0)
1.6
(1.9)
1.0
(1.1)
1.6
(1.8)
1.6
(1.8)
1.6
(1.7)
1.6
(1.7)
–
–
–
–
–
–
–
CF3-PTOT(H)
[BiPh(Me-PTOT)2]
100
(120)
40
(46)
40
(44)
40
(47)
40
(46)
40
(41)
40
100
(120)
100
(115)
100
(111)
100
(118)
100
(114)
100
(103)
100
(106)
7
[BiPh(MeO-PTOT)2]
[BiPh(MeS-PTOT)2]
[BiPh(F-PTOT)2]
8
9
10
11
12
[BiPh(Cl-PTOT)2]
[BiPh(Br-PTOT)2]
[BiPh(CF3-PTOT)2]
(42)
BiPh3
Ͼ 100[29]
that they were monomers derived from facile reduction of for the synthesis of such heterocyclic compounds involves
BiV thiolates; [BiPh(4-MMT)2{4-MMT(H)}2] (MIC range the cyclization of acid hydrazides in the presence of CS2/
0.34–6.7 μm) and [BiPh(1-MMTZ)2{1-MMTZ(H)}2] (MIC KOH. The formation of these compounds was achieved by
range 1.33–3.34 μm), while the third was a more simple conventional reflux and microwave irradiation. The syn-
oligomeric complex [BiPh(1-MMTZ)2] (MIC range 4.84– thetic approach involving microwave irradiation proved to
9.68 μm). Only the triazole complex [BiPh(4-MMT)2{4- be more efficient due to excellent yields and short reaction
MMT(H)}2] performed better that complexes 6–12 against times. These compounds usually exist in the thione form as
M. smegmatis (0.67 μm) and VRE (0.34 μm).
judged by solution and solid state studies.
Consistent with our previous studies, and those of Kot-
In exploring the bismuth(III) thiolate complexes of oxad-
ani et al.[17c] on cyclic organobismuth(III) compounds, iazole derivatives, seven new mono-phenyl-bis-thiolatobis-
these complexes did not show inhibitory activity against the muth complexes 6–12 were synthesized from BiPh3 in a 1:2
gram-negative bacterium E. coli. This is possibly due to the (BiPh3:thiol) stoichiometric ratio using conventional reflux
inability of the compounds to permeate the double mem- and microwave irradiation, and through salt metathesis in-
brane of these bacteria.[32]
volving BiPhCl2 under inert conditions for comparative
Although a strong antibacterial activity is essential for studies. The solid-state structures of two complexes
potential new therapeutic agents, the compound must have [BiPh(Cl-PTOT)2(DMSO)2] {[10(DMSO)2]} and [BiPh-
low toxicity towards human or animal eukaryotic cells. Tox- (Br-PTOT)2(DMSO)2] {[11(DMSO)2]} were authenticated
icity assays of these complexes against cultured COS-7 cell by X-ray crystallography. The structural studies reveal the
lines and lysis assays using human red blood cells revealed monodentate nature of the 5-substituted oxadiazolethiolate
that the complexes were non-toxic to mammalian cells at ligands which are attached to the bismuth(III) center
levels approximately 10x the MIC values (see Supporting through the sulfur atoms giving distorted square pyramidal
Information). The high efficiency and low host toxicity of geometries with coordination number of five. All these
these complexes suggest that they are promising leads in the compounds were tested against series of bacteria. Low MIC
development of safe and potent drugs targeting devastating values in the range 1.1–2.1 μm were observed and generally
human pathogens, including drug-resistant bacteria of med- consistent across all compound types and against all the
ical significance.
gram-positive bacteria. In most cases the MICs are superior
to those of Vancomycin. The compounds proved ineffective
against the gram-negative bacterium E. coli. These com-
pounds proved to be non-toxic to mammalian COS-7 cells
Conclusions
A series of seven compounds containing 5-substituted even at 20 μg/mL. Their low MIC values and negligible tox-
phenylthiazol oxadiazolethiones were synthesised and char- icity against animal cells make these compounds future can-
acterised by NMR, IR and mass spectrometery. The route didates for drug development.
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0.25 μg/mL. After incubation, the cultures were examined to deter-
mine the minimum concentration of compound that caused total
inhibition of growth; this value was recorded as the MIC. The anti-
mycobacterial drug isoniazid was included as control.
Experimental Section
General: BiPh3 was synthesised through a standard Grignard me-
tathesis reaction from the treatment of BiCl3 with MgPhBr in dried
diethyl ether at 0 °C, and subsequently recrystallised from ethanol.
PhBiCl2 was synthesised by mixing BiPh3 and BiCl3 in a 2:1 ratio
in dried diethyl ether. Ethanol, DMSO and toluene were used as
solvents for recrystallization. Diethyl ether and THF were dried
prior to use by M-Braun-SPS-800 solvent purification system and
molecular sieves (4 Å) were used to store. All moisture sensitive
reactions were conducted with oven dried glassware under an atmo-
sphere of dry nitrogen using a vacuum/nitrogen line and Schlenk
techniques. Microwave irradiation was carried out in a CEM Dis-
coverer Microwave oven with maximum power 0–300 W, model
number 9080, maximum current 6.38 A with 50/60 MHz frequency.
Cell Toxicity Assays: Toxicities against eukaryotic cells were as-
sayed using the in vitro toxicology assay kit MTT-based (Sigma–
Aldrich; cat. no. TOX1–1KT), according to the manufacturer’s in-
structions. Compounds were added to cultured COS-7 (monkey
kidney-derived) cells at 10 and 20 μg/mL for 1 h prior to addition
of the tetrazolium dye MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-di-
phenyltetrazolium bromide] reagent. OD690 measurements were ex-
pressed as a percentage the DMSO-only negative controls. All as-
says were performed in triplicate. Isoniazid and ethambutol-treated
COS-7 cells were included as controls.
NMR spectra of complexes were recorded on a Bruker DPX 400 General Procedures (GP)
spectrometer in [D6]DMSO with TMS as internal standard at room
GP 1. Synthesis of Aryl-4-carbohydrazide-1,3-thiazole: Synthesis of
aryl-4-carbohydrazide-1,3-thiazole was achieved by the following
reactions.
temperature. Elemental analysis (C, H and N) were performed by
the Campbell Microanalytical lab, department of chemistry, Uni-
versity of Otago, Dunedin, New Zealand. Melting points were de-
termined on a Stuart Scientific SMP3 melting point apparatus.
Mass spectra were recorded on Micromass Platform Electrospray
Mass Spectrometer.
Synthesis of Thioamide:[27] A series of aryl thioamides were synthe-
sised by adding 5.0 g of aryl nitrile in one portion to a slurry of
70% sodium hydrosulfide hydrate and 1.5 mol equivalent of mag-
nesium chloride hexahydrate in 20 mL of DMF. The reaction mix-
ture was stirred for 6 h and resulting slurry was poured into 150 mL
of water. The precipitate obtained was filtered and resuspended in
2 mL of HCl and stirred for 30 min. The desired aryl thioamide
was obtained after filtration and recrystallization.
Crystallographic Data: Crystallographic data of compound
[10(DMSO)2] was collected at the MX1 beamline at the Australian
Synchrotron, Melbourne, Victoria, Australia with wavelength set at
λ = 0.71070 Å (17.4 keV). All data was collected at 100 K, main-
tained using an open flow of nitrogen. The software used for data
collection and reduction of the data were BluIce[36] and XDS.[37]
Crystallographic data of compound [11(DMSO)2] was collected on
a OXFORD Gemini Ultra equipped with an OXFORD Cryosys-
tems 700 Cryostream and cooled to 123(1) K. Data was collected
with monochromatic (graphite) Mo-Kα radiation (λ = 0.71073 Å)
and processed using the CrysAlisProv 1.171.34.3[38] software; Lo-
rentz, polarization and absorption corrections (multi-scan) were
applied. Compounds were solved and refined with SHELX-97.[39]
All non-hydrogen atoms were refined with anisotropic thermal pa-
rameters unless otherwise indicated and hydrogen atoms were
placed in calculated positions using a riding model with C–H =
0.95–0.98 Å and Uiso(H) = xUiso(C), x = 1.2 or 1.5 unless otherwise
indicated. CCDC-1062300 (for [10(DMSO)2]) and -1062301 (for
[11(DMSO)2]) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Synthesis of Aryl-4-ethoxycarbonyl-1,3-thiazole:[40] The equimolar
mixture of aryl thioamide and ethyl bromopyruvate was refluxed
in 25 mL of ethanol for 8 h. The completion of the reaction was
monitored by thin layer chromatography (TLC) and excess of sol-
vent was removed using a rotary evaporator. The reaction mixture
obtained was extracted with dichloromethane. The organic layer
was dried with anhydrous sodium sulfate and the desired aryl-4-
ethoxycarbonyl-1,3-thizole was obtained by filtration and removal
of excess solvent.
Synthesis of Aryl-4-carbohydrazide-1,3-thiazole:[41] Synthesis of
aryl-4-carbohydrazide-1,3-thiazole was achieved by the reaction of
aryl-4-ethoxycarbonyl-1,3-thizole with 2 mol equivalent of hydraz-
ine hydrate (80%) in 20 mL of ethanol. The reaction mixture was
refluxed for 4 h and excess solvent was removed under reduced
pressure. The solid obtained was filtered and recrystallised from
aqueous ethanol.
Synthesis of 5-Substituted 1,3,4-Oxadiazolethione Derivatives: The
synthesis of 5-substituted 1,3,4-oxadiazolethiones was achieved by
following methods.
Antimicrobial Activity: Mycobacterium smegmatis was cultured in
Middlebrook 7H9/7H10 medium (Difco) for 3 d at 37 °C. Escher-
ichia coli was cultured overnight at 37 °C in LB (Luria-Bertani)
medium. Staphylococcus aureus, MRSA (methicillin-resistant S. au-
reus), Enterococcus faecalis and VRE (vancomycin-resistant E. fae-
calis) were cultured in BHI (brain heart infusion) medium (Oxoid)
overnight at 37 °C.
GP2. Conventional Method: Aryl-4-carbohydrazide-1,3-thiazole
(0.50 g) was dissolved in absolute ethanol (20 mL). To this solution,
one equivalent of carbon disulfide was added in the presence of
equimolar potassium hydroxide dissolved in H2O (10 mL). The
mixture was continuously stirred and heated under reflux for 12 h
until the evolution of hydrogen sulfide ceased. The completion of
the reaction was monitored through TLC (silica; ethyl acetate:pe-
troleum ether 2:l). After cooling, the solution was concentrated to
a small volume and the residue was triturated with ice-water. The
solution was acidified to pH 2–3 by addition of dilute hydrochloric
acid. This furnished a white precipitate which was filtered, washed
with diethyl ether and recrystallized from aqueous ethanol.
In initial activity screens, filter paper discs were soaked with 2 μL
of 5 mg/mL compound, then placed on the surface of agar plates
that had been pre-spread with a culture of the bacterial strain of
interest. Following incubation, the plates were examined for the
presence of zones of inhibition of bacterial growth around the discs.
Compounds that were negative in this assay were not examined
further, while minimum inhibitory concentration (MIC) assays
were performed for all positive compounds.
GP3. Microwave-Assisted Synthesis: The equimolar mixture of
aryl-4-carbohydrazide-1,3-thiazole and carbon disulfide was stirred
at room temperature for 2–3 min in absolute ethanol (5.0 mL). To
To determine MICs, liquid cultures of bacteria were prepared con-
taining serial dilutions of the compounds, from 80 μg/mL to
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this solution one mole equivalent of potassium hydroxide dissolved
in H2O (1.0 mL) was added slowly. The reaction mixture was irradi-
ated at 85 °C for 15 min. After cooling, the solution was concen-
trated to a small volume and the residue was poured into cold
water. The solution was acidified to pH 2–3 by the addition of
dilute hydrochloric acid. The solid that formed was filtered off,
washed with water and diethyl ether, dried and finally crystallised
from ethanol. All the reactions were carried out 300 W.
m/z 294 {45%, [LH(H2O)]+}. ESI-MS– (solvent: DMSO/MeOH,
35 eV): m/z 274 (44%, [L]–). C12H9N3OS2 (275.34): calcd. C 52.34,
H 3.29, N 15.26; found C 52.11, H 3.04, N 15.38.
5-[2-(4-Methoxyphenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione,
MeO-PTOT(H) (5b): Conventional method: GP1 was applied for
the synthesis of 2-(4-methoxyphenyl)thiazole-4-carbohydrazide
(0.45 g, 1.81 mmol) which was treated with carbon disulfide
(0.13 mL, 2.14 mmol) and potassium hydroxide (0.12 g, 2.14 mmol)
according to GP2 to obtain 5-[2-(4-methoxyphenyl)thiazol-4-yl]-
1,3,4-oxadiazole-2(3H)-thione, yield 0.45 g, 75%.
GP4. Synthesis by Conventional Reflux: All reactions were con-
ducted using one equivalent of BiPh3 and two equivalents of oxadi-
azolethione for the synthesis of bismuth thiolate complexes. Crys-
talline BiPh3 was ground together with parent thione and the mix-
ture was placed in a small round-bottomed flask using toluene (10–
25 mL) as solvent and refluxed for 4–15 h. The product obtained
was washed with a small amount of toluene, ethanol, diethyl ether
or acetone to remove unreacted BiPh3 or ligands prior to air dry-
ing.
Microwave-Assisted Synthesis: The mixture of 2-(4-methoxyphen-
yl)thiazole-4-carbohydrazide (0.23 g, 0.90 mmol), carbon disulfide
(0.05 mL, 0.90 mmol) and potassium hydroxide (0.05 g, 0.90 mmol)
was irradiated at 85 °C for 15 min following GP3 to yield 5-[2-(4-
methoxyphenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione, yield
0.21 g, 80%; m.p. 238 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
14.1 (s, 1 H, NH), 8.50 (s, 1 H, Hc), 7.96 (d, 2 H, Hg), 7.10 (d, 2
H, Hh), 3.84 (s, 3 H, Hj) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 177.3 (Ca), 169.2 (Ce), 161.4 (Cb), 139.6 (Cd), 138.7 (Cf), 128.2
GP5. Microwave Heating with Solvents: All reactions were con-
ducted using one equivalent of BiPh3 and one or two of the parent
thiones for the synthesis of mono-phenylbismuth(III) thiolate com-
plexes. Crystalline BiPh3 was ground together with the thiones and
placed in an Emery microwave vial followed by the addition of
solvents. The product obtained was washed with a small amount
of toluene, ethanol, diethyl ether or acetone to remove unreacted
BiPh3 or ligands. The microwave power for all reactions was 300 W.
(Ci), 124.8 (Cg), 123.8 (Cc), 114.7 (Ch), 55.48 (Cj) ppm. FT-IR: ν
˜
= 3120 (m), 1635 (m), 1446 (s), 1248 (m), 1162 (m), 1078 (s), 933
(s), 766 (s), 693 (m), 645 (m) cm–1. ESI-MS– (solvent: DMSO/
MeOH, 35 eV): m/z 290 (44%, [L]–). C12H9N3O2S2 (291.34): calcd.
C 49.47, H 3.11, N 14.42; found C 49.51, H 3.04, N 14.38.
5-{2-[4-(Methylthio)phenyl]thiazol-4-yl}-1,3,4-oxadiazole-2(3H)-
thione, MeS-PTOT(H) (5c). Conventional Method: GP1 was ap-
plied for the synthesis of 2-[4-(methylthio)phenyl]thiazole-4-carbo-
hydrazide (0.38 g, 1.41 mmol) which was treated with carbon di-
sulfide (0.09 mL, 1.41 mmol) and potassium hydroxide (0.08 g,
1.41 mmoL) according to GP2 to obtain 5-{2-[4-(methylthio)-
phenyl]thiazol-4-yl}-1,3,4-oxadiazole-2(3H)-thione, yield 0.21 g,
80%.
GP6. Synthesis of Sodium Salt of Thiones: One equivalent of the
parent oxadiazolethione was dissolved in 25 mL of methanol. To
this solution one equivalent of NaOH pellets was added and the
reaction mixture was stirred for 4 h. The clear solution obtained
was concentrated and dried in vacuo prior to use.
GP7. Synthesis of Mono-Phenylthiolatobismuth(III) Complexes by
Salt Metathesis Reaction: All the manipulations were carried out
under a nitrogen atmosphere. Two equivalents of the sodium salt
of the parent thione was placed in a 100 mL Schlenk flask. Ad-
dition of 20 mL of dry methanol resulted in a clear solution which
was allowed to stir for 15 min at room temperature. The solution
was cooled to 0 °C before the addition of one equivalent of
BiPhCl2. The resultant solution was stirred for 10–15 h at room
temperature. The methanol was filtered off and the precipitate was
washed with methanol (3ϫ 10 mL) and water (1ϫ 10 mL) and
dried in vacuo.
Microwave-Assisted Synthesis: The mixture of 2-[4-(methylthio)-
phenyl]thiazole-4-carbohydrazide (0.15 g, 0.57 mmol), carbon di-
sulfide (0.04 mL, 0.57 mmol) and potassium hydroxide (0.03 g,
0.57 mmol) was irradiated at 85 °C for 15 min following GP3 to
yield title compound, yield 0.14 g, 73%; m.p. 256 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 14.8 (s, 1 H, NH), 8.54 (s, 1 H, Hc),
7.93 (d, 2 H, Hg), 7.39 (d, 2 H, Hh), 2.54 (s, 3 H, Hj) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 177.3 (Ca), 168.8 (Ce), 156.5
(Cb), 142.5 (Cd), 138.7 (Cf), 128.2 (Ci), 126.9 (Ch), 125.9 (Cg), 123.9
(Cc), 14.02 (Cj) ppm. FT-IR: ν = 3117 (m), 1633 (m), 1450 (s),1379
˜
Synthesis and Characterisation
(m), 1305 (m), 1273 (m), 1219 (s), 1079 (s), 934 (s), 768 (s), 668
(m), 646 (m) cm–1. ESI-MS– (solvent: DMSO/MeOH, 35 eV): m/z
306 (100%, [L]–). C12H9N3OS3 (307.40): calcd. C 46.88, H 2.95, N
13.67; found C 46.80, H 3.21, N 13.50.
5-[2-(p-Tolyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione,
Me-
PTOT(H) (5a). Conventional Method: GP1 was applied for the syn-
thesis of 2-(p-tolyl)thiazole-4-carbohydrazide (0.50 g, 2.14 mmol)
which was treated with carbon disulfide (0.13 mL, 2.14 mmol) and
potassium hydroxide (0.12 g, 2.14 mmol) according to GP2 to ob-
tain 5-[2-(p-tolyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione, yield
0.51 g, 81%.
5-[2-(4-Fluorophenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione, F-
PTOT(H) (5d). Conventional Method: GP1 was applied for the syn-
thesis of 2-(4-fluorophenyl)thiazole-4-carbohydrazide (0.6 g,
2.52 mmol) which was treated with carbon disulfide (0.15 mL,
2.52 mmol) and potassium hydroxide (0.14 g, 2.52 mmol) according
to GP2 to obtain 5-[2-(4-fluorophenyl)thiazol-4-yl]-1,3,4-oxadi-
azole-2(3H)-thione, yield 0.51 g, 75%.
Microwave-Assisted Synthesis: The mixture of 2-(p-tolyl)thiazole-
4-carbohydrazide (0.25 g, 1.07 mmol), carbon disulfide (0.07 mL,
1.07 mmol) and potassium hydroxide (0.06 g, 1.07 mmol) was irra-
diated at 85 °C for 15 min following GP3 to yield 5-[2-(p-tolyl)thi-
azol-4-yl]-1,3,4-oxadiazole-2(3H)-thione, yield 0.27 g, 84%; m.p.
Microwave-Assisted Synthesis: The mixture of 2-(4-fluorophenyl)-
thiazole-4-carbohydrazide (0.2 g, 0.84 mmol), carbon disulfide
1
271 °C. H NMR (300 MHz, [D6]DMSO): δ = 14.8 (s, 1 H, NH),
8.53 (s, 1 H, Hc), 7.89 (d, 2 H, Hg), 7.36 (d, 2 H, Hh), 2.38 (s, 3 H, (0.05 mL, 0. 84 mmol) and potassium hydroxide (0.05 g,
Hj) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 177.3 (Ca), 169.2 0.84 mmol) was irradiated at 85 °C for 15 min following GP3 to
(Ce), 156.4 (Cb), 141.0 (Cd), 138.6 (Cf), 130.2 (Ci), 129.3 (Ch), 126.4 yield title compound, yield 0.18 g, 83%; m.p. 264 °C. 1H NMR
(Cg), 124.1 (Cc), 21.13 (Cj) ppm. FT-IR: ν = 3116 (m), 1633 (m),
(400 MHz, [D6]DMSO): δ = 14.8 (s, 1 H, NH), 8.57 (s, 1 H, Hc),
˜
1450 (s), 1378 (m), 1274 (m), 1222 (m), 1080 (s), 959 (s), 769 (s), 8.07 (m, 2 H, Hg), 7.39 (t, 2 H, Hh) ppm. 13C NMR (100 MHz,
688 (m), 646 (m) cm–1. ESI-MS+ (solvent: DMSO/MeOH, 35 eV):
[D6]DMSO): δ = 177.6 (Ca), 167.9 (Ce), 164.9 (Cb), 162.1 (Ci), 156.2
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(Cf), 128.9 (Cg), 124.9 (Cc), 116.8 (Ch) ppm. FT-IR: ν = 1621 (m), [D6]DMSO): δ = 177.7 (Ca), 167.5 (Ce), 156.4 (Cb), 139.3 (Cd),
˜
1589 (m), 1473 (s), 1304 (m), 1282 (m), 1233 (s), 1092 (s), 779 (s), 135.7 (Cf), 130.9 (Ci), 127.6 (Cg), 126.6 (Ch), 126.4 (Cc), 125.8 (q,
691 (m), 648 (m) cm–1. ESI-MS– (solvent: DMSO/MeOH, 35 eV):
m/z 278 (100%, [L]–). C11H6FN3OS2 (279.31): calcd. C 47.30, H
2.17, N 15.04; found C 47.59, H 2.14, N 14.92.
CF3) ppm. FT-IR: ν = 3118 (m), 1617 (m), 1454 (s), 1324 (m), 1281
˜
(m), 1066 (s), 962 (s), 777 (s), 671 (m), 637 (m) cm–1. ESI-
MS– (solvent: DMSO/MeOH, 35 eV): m/z 328 (100%, [L]–).
C12H6F3N3OS2 (329.31): calcd. C 43.77, H 1.84, N 12.76; found C
43.76, H 2.06, N 12.53.
5-[2-(4-Chlorophenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione,
Cl-PTOT(H) (5e). Conventional Method: GP1 was applied for the
synthesis of 2-(4-chlorophenyl)thiazole-4-carbohydrazide (0.65 g,
2.56 mmol) which was treated with carbon disulfide (0.15 mL,
2.56 mmol) and potassium hydroxide (0.14 g, 2.56 mmol) according
[BiPh(Me-PTOT)2] (6). Conventional Reflux: The reaction mixture
of 5-[2-(p-tolyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione (0.2 g,
0.72 mmol) and triphenylbismuth (0.16 g, 0.36 mmol) was refluxed
to GP2 to obtain 5-[2-(4-chlorophenyl)thiazol-4-yl]-1,3,4-oxadi- together for 10 h according to GP4. The yellow precipitate ob-
azole-2(3H)-thione, yield 0.61 g, 80%.
tained was collected by filtration and washed with diethyl ether and
acetone, yield 0.18 g, 51%.
Microwave-Assisted Synthesis: The mixture of 2-(4-chlorophenyl)-
thiazole-4-carbohydrazide (0.19 g, 0.83 mmol) carbon disulfide
(0.04 mL, 0. 83 mmol) and potassium hydroxide (0.04 g,
0.83 mmol) was irradiated at 85 °C for 15 min following GP3 to
yield title compound, yield 0.21 g, 82%; m.p. 247 °C. 1H NMR
Microwave-Assisted Synthesis: 5-[2-(p-Tolyl)thiazol-4-yl]-1,3,4-
oxadiazole-2(3H)-thione (0.2 g, 0.72 mmol) and triphenylbismuth
(0.16 g, 0.36 mmol) in 6 mL of toluene was irradiated at 115 °C for
15 min according to GP5 to obtain 6 as a yellow solid, yield 0.17 g,
(400 MHz, [D6]DMSO): δ = 14.8 (s, 1 H, NH), 8.61 (s, 1 H, Hc), 50%.
8.05 (d, 2 H, Hg), 7.62 (d, 2 H, Hh) ppm. 13C NMR (100 MHz,
Salt Metathesis: The sodium salt of 5-[2-(p-tolyl)thiazol-4-yl]-1,3,4-
[D6]DMSO): δ = 177.7 (Ca), 167.9 (Ce), 156.4 (Cb), 138.9 (Cd),
135.7 (Cf), 130.7 (Ci), 129.4 (Ch), 128.2 (Cg), 124.9 (Cc) ppm. FT-
oxadiazole-2(3H)-thione (0.25 g, 0.84 mmol, 2.0 equiv.) and phen-
ylbismuth dichloride (0.25 g, 0.84 mmol, 2.0 equiv.) were reacted
according to GP7 yielding a yellow precipitate of 6, yield 0.32 g,
75%; m.p. 180 °C (dec.). 1H NMR (400 MHz, [D6]DMSO): δ =
9.02 (2 H, HaЈ), 8.30 (s, 2 H, Hc), 7.93 (t, 2 H, HbЈ), 7.83 (d, 4 H,
Hg), 7.48 (t, 1 H, HcЈ), 7.31 (d, 4 H, Hh), 2.36 (s, 6 H, Hj) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 169.3 (Ce), 153.1 (Cb), 141.0
IR: ν = 3119 (m), 1591 (m), 1490 (s), 1282 (m), 1091 (s), 941 (s),
˜
776 (s), 689 (m), 649 (m) cm–1. ESI-MS– (solvent: DMSO/MeOH,
35 eV): m/z 295 (100 %, [L]–). C11H6ClN3OS2 (295.76): calcd. C
44.76, H 2.04, N 14.21; found C 44.72, H 2.23, N 14.37.
5-[2-(4-Bromophenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione,
Br-PTOT(H) (5f). Conventional Method: GP1 was applied for the (Cd), 140.4 (Cf), 138.6 (CaЈ), 133.7 (CbЈ) 130.3 (Ci), 129.4 (Ch),
synthesis of 2-(4-bromophenyl)thiazole-4-carbohydrazide (0.55 g,
1.84 mmol) which was treated with carbon disulfide (0.11 mL,
1.84 mmol) and potassium hydroxide (0.11 mL, 1.84 mmol) accord-
ing to GP2 to obtain 5-[2-(4-bromophenyl)thiazol-4-yl]-1,3,4-oxa-
diazole-2(3H)-thione, yield 0.52 g, 82%.
127.0 (CcЈ), 126.4 (Cg), 123.0 (Cc), 21.25 (Cj) ppm. FT-IR: ν = 1634
˜
(m), 1450 (s), 1376 (m), 1273 (m), 1162 (m), 1080 (s), 996 (s), 932
(s), 808 (m), 709 (s), 688 (m), 647 (m) cm–1. ESI-MS+ (solvent:
DMSO/MeOH, 35 eV): m/z 930 (52%, [BiPhL2(H2O)4 + Na]+), 858
(38%, [BiPhL2 + Na]+), 560 (20%, [BiPhL]+). ESI-MS– (solvent:
DMSO/MeOH, 35 eV): m/z 870 (58%, [BiPhL2 + Cl]–), 274 (44%,
[L]). C30H21BiN6O2S4 (834.76): calcd. C 43.16, H 2.54, N 10.07;
found C 43.10, H 2.24, N 10.18.
Microwave-Assisted Synthesis: The mixture of 2-(4-bromophenyl)-
thiazole-4-carbohydrazide (0.18 g, 0.60 mmol) carbon disulfide
(0.04 mL, 0.60 mmol) and potassium hydroxide (0.04 g, 0.60 mmol)
was irradiated at 85 °C for 15 min following GP3 to yield title com-
[BiPh(MeO-PTOT)2] (7). Conventional Reflux: The reaction
mixture of triphenylbismuth of (0.19 g, 0.43 mmol) and 5-[2-(4-
1
pound, yield 0.22 g, 85%; m.p. 275 °C. H NMR (400 MHz, [D6]-
DMSO): δ = 14.8 (s, 1 H, NH), 8.64 (s, 1 H, Hc), 7.97 (d, 2 H, Hg), methoxyphenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione (0.25 g,
7.76 (d, 2 H, Hh) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 0.85 mmol) was refluxed together for 12 h according to GP4. The
177.4 (Ca), 168.5 (Ce), 156.6 (Cb), 139.2 (Cd), 132.5 (Cf), 131.3 (Ci), yellow precipitate obtained was collected by filtration and washed
128.5 (Ch), 125.2 (Cg), 124.6 (Cc) ppm. FT-IR: ν = 3121 (m), 1636 with diethyl ether and acetone, yield 0.17 g, 51%.
˜
(m), 1489 (s), 1279 (m), 1218 (m), 1093 (s), 956 (s), 765 (s), 663
Microwave-Assisted
Synthesis:
Triphenylbismuth
(0.15 g,
(m), 647 (m) cm–1. ESI-MS– (solvent: DMSO/MeOH, 35 eV):
m/z 339 (50 %, [L]–(79Br isotope)), 341 (40 %, [L]–(81Br isotope)).
C11H6BrN3OS2 (340.21): calcd. C 38.83, H 1.78, N 12.35; found C
38.32, H 1.84, N 12.37.
0.34 mmol) and 5-[2-(4-methoxyphenyl)thiazol-4-yl]-1,3,4-oxadi-
azole-2(3H)-thione (0.2 g, 0.68 mmol) in 6 mL of toluene was irra-
diated at 105 °C for 13 min according to GP5 to obtain 7 as a
yellow solid, yield 0.14 g, 50%.
5-{2-[4-(Trifluoromethyl)phenyl]thiazol-4-yl}-1,3,4-oxadiazole-
2(3H)-thione, CF3-PTOT(H) (5g). Conventional Method: GP1 was
applied for the synthesis of 2-[4-(trifluoromethyl)phenyl]thiazole-4-
carbohydrazide (0.48 g, 1.67 mmol) which was treated with carbon
disulfide (0.10 mL, 1.67 mmol) and potassium hydroxide (0.09 mL,
1.67 mmol) according to GP2 to obtain 5-{2-[4-(trifluoromethyl)-
phenyl]thiazol-4-yl}-1,3,4-oxadiazole-2(3H)-thione, yield 0.36 g,
65%.
Salt Metathesis: The sodium salt of 5-[2-(4-methoxyphenyl)thiazol-
4-yl]-1,3,4-oxadiazole-2(3H)-thione (0.25 g, 0.84 mmol) and phen-
ylbismuth dichloride (0.25 g, 0.84 mmol) were reacted according to
GP7 yielding a yellow precipitate of 7, yield 0.27 g, 63%; m.p.
1
224 °C (dec.). H NMR (400 MHz, [D6]DMSO): δ = 9.03 (d, 2 H,
HaЈ), 8.12 (s, 2 H, Hc), 7.93 (t, 2 H, HbЈ), 7.84 (d, 4 H, Hg), 7.48
(t, 1 H, HcЈ), 7.03 (d, 4 H, Hh), 3.83 (s, 6 H, Hj) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 168.5 (Ce), 161.3 (Cb), 159.8 (Cd),
139.3 (CaЈ), 133.2 (CbЈ) 131.4 (Ci), 128.4 (Ch), 127.9 (CcЈ), 124.8
Microwave-Assisted Synthesis: The mixture of carbon disulfide
(0.04 mL, 0.70 mmol), 2-[4-(trifluoromethyl)phenyl]thiazole-4-
carbohydrazide (0.20 g, 0.70 mmol), and potassium hydroxide
(0.04 g, 0.70 mmol) was irradiated at 85 °C for 15 min following
GP3 to yield title compound, yield 0.16 g, 71%; m.p. 237 °C. 1H
(Cg), 114.6 (Cc), 55.40 (Cj) ppm. FT-IR: ν = 1633 (m), 1447 (s),
˜
1305 (m), 1251 (m), 1078 (s), 948 (s), 710 (m), 690 (m), 649 (m)
cm–1. ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z 890 (45%,
[BiPhL2 + Na]+), 648 (14%, [BiPhL(H2O)4]+). C30H21BiN6O4S4
NMR (400 MHz, [D6]DMSO): δ = 14.7 (s, 1 H, NH), 8.69 (s, 1 H, (866.75): calcd. C 41.57, H 2.44, N 9.70; found C 41.43, H 2.24, N
Hc), 8.24 (d, 2 H, Hg), 7.91 (d, 2 H, Hh) ppm. 13C NMR (100 MHz, 9.70.
Eur. J. Inorg. Chem. 2015, 4935–4945
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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FULL PAPER
[BiPh(MeS-PTOT)2] (8). Conventional Reflux: The reaction mix-
Microwave-Assisted
Synthesis:
Triphenylbismuth
(0.13 g,
ture of triphenylbismuth of (0.25 g, 0.57 mmol) and 5-{2-[4-(meth-
ylthio)phenyl]thiazol-4-yl}-1,3,4-oxadiazole-2(3H)-thione (0.35 g,
1.13 mmol) was refluxed together for 8 h according to GP4. The
yellow precipitate obtained was washed with diethyl ether and acet-
one, yield 0.26 g, 54%.
0.28 mmol) and 5-[2-(4-chlorophenyl)thiazol-4-yl]-1,3,4-oxadi-
azole-2(3H)-thione (0.17 g, 0.57 mmol) in 6 mL of toluene was irra-
diated at 110 °C for 9 min according to GP5 to obtain 10 as a
yellow solid, yield 0.13 g, 56%.
Salt Metathesis: The sodium salt of 5-[2-(4-chlorophenyl)thiazol-4-
yl]-1,3,4-oxadiazole-2(3H)-thione (0.4 g, 1.25 mmol) and phen-
ylbismuth dichloride (0.22 g, 0.62 mmol) were reacted according to
GP7 yielding an orange precipitate of 10, yield 0.30 g, 68%; m.p.
Microwave-Assisted
Synthesis:
Triphenylbismuth
(0.11 g,
0.24 mmol) and 5-{2-[4-(methylthio)phenyl]thiazol-4-yl}-1,3,4-oxa-
diazole-2(3H)-thione (0.15 g, 0.48 mmol) in 6 mL of toluene was
irradiated at 111 °C for 10 min according to GP5 to obtain 8 as a
yellow solid, yield 0.13 g, 57%.
1
228 °C (dec.). H NMR (400 MHz, [D6]DMSO): δ = 9.00 (d, 2 H,
HaЈ), 8.31 (s, 2 H, Hc), 7.96 (d, 4 H, Hg), 7.90 (t, 2 H, HbЈ), 7.62
(d, 4 H, Hh), 7.53 (t, 1 H, HcЈ) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 156.6 (Cb), 140.7 (Cd), 135.5 (Cf), 138.6 (CaЈ), 133.1
Salt Metathesis: The sodium salt of 5-{2-[4-(methylthio)phenyl]thi-
azol-4-yl}-1,3,4-oxadiazole-2(3H)-thione (0.25 g, 0.81 mmol) and
phenylbismuth dichloride (0.15 g, 0.40 mmol) were reacted accord-
ing to GP7 yielding an orange precipitate of 8, yield 0.25 g, 68%;
(CbЈ), 131.1 (Ci), 129.5 (Ch), 128.1 (Cg), 125.2 (Cc) ppm. FT-IR: ν
˜
= 1645 (m), 1591 (m), 1464 (s), 1281 (m), 1229 (s), 1090 (s), 779 (s),
724 (s), 689 (m), 671 (m) cm–1. ESI-MS– (solvent: DMSO/MeOH,
1
m.p. 295 °C (dec.). H NMR (400 MHz, [D6]DMSO): δ = 9.02 (d,
35 eV):
m/z
943
(45%,
[BiPhL2(CH3OH)
+
Cl]–).
2 H, HaЈ), 8.23 (s, 2 H, Hc), 7.96 (t, 2 H, HbЈ), 7.80 (d, 4 H, Hg),
7.50 (t, 1 H, HcЈ), 7.31 (d, 4 H, Hh), 2.52 (s, 6 H, Hj) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 168.4 (Ce), 159.4 (Cb), 142.2
(Cd), 140.1 (Cf), 139.4 (CaЈ), 133.2 (CbЈ) 131.3 (Ci), 128.3 (Ch),
C28H15BiCl2N6O2S4 (875.59): calcd. C 38.41, H 1.73, N 9.60; found
C 38.53, H 1.80, N 9.41.
Synthesis of [BiPh(Br-PTOT)2] (11). Conventional Reflux: The reac-
tion mixture of triphenylbismuth of (0.27 g, 0.62 mmol) and 5-[2-
(4-bromophenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione
(0.42 g, 1.23 mmol) was refluxed together for 11 h according to
GP4. The yellow precipitate obtained was washed with acetone,
yield 0.31 g, 54%.
127.7 (CcЈ), 125.7 (Cg), 121.9 (Cc), 14.2 (Cj) ppm. FT-IR: ν = 1632
˜
(m), 1448 (s), 1306 (m), 1251 (m), 1071 (s), 948 (s), 717 (m), 690
(m), 649 (m) cm–1. ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z
1004 (38%, [BiPhL2(CH3OH)(H2O)4 + H]+), 707 (30%, [BiPhL-
(CH3OH)3(H2O)]+), 647 (20%, [BiPhL(H2O)3]+), 209 (60%, [Bi]+).
C30H21BiN6O2S6 (898.88): calcd. C 40.08, H 2.35, N 9.35; found C
40.03, H 2.30, N 9.13.
Microwave-Assisted
Synthesis:
Triphenylbismuth
(0.13 g,
0.29 mmol) and 5-[2-(4-bromophenyl)thiazol-4-yl]-1,3,4-oxadi-
azole-2(3H)-thione (0.21 g, 0.59 mmol) in 6 mL of toluene was irra-
diated at 111 °C for 4 min according to GP5 to obtain 11 as a
yellow solid, yield 0.15 g, 53%.
Synthesis of [BiPh(F-PTOT)2] (9). Conventional Reflux: The reac-
tion mixture of triphenylbismuth of (0.33 g, 0.75 mmol) and 5-[2-
(4-fluorophenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione
(0.42 g, 1.50 mmol) was refluxed together for 7 h according to GP4.
The yellow precipitate obtained was washed with diethyl ether and
acetone, yield 0.36 g, 57%.
Salt Metathesis: The sodium salt of 5-[2-(4-bromophenyl)thiazol-
4-yl]-1,3,4-oxadiazole-2(3H)-thione (0.3 g, 0.83 mmol) and phen-
ylbismuth dichloride (0.15 g, 0.42 mmol) were reacted according to
GP7 yielding an orange precipitate of 11, yield 0.28 g, 70%; m.p.
Microwave-Assisted
Synthesis:
Triphenylbismuth
(0.10 g,
0.20 mmol) and 5-[2-(4-fluorophenyl)thiazol-4-yl]-1,3,4-oxadi-
azole-2(3H)-thione (0.12 g, 0.40 mmol) in 6 mL of toluene was irra-
diated at 113 °C for 12 min according to GP5 to obtain 9 as a
yellow solid, yield 0.09 g, 50%.
1
257 °C (dec.). H NMR (400 MHz, [D6]DMSO): δ = 9.01 (d, 2 H,
HaЈ), 8.30 (s, 2 H, Hc), 7.96 (t, 2 H, HbЈ), 7.94 (d, 4 H, Hg), 7.50
(t, 1 H, HcЈ), 7.33 (d, 4 H, Hh) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 168.5 (Ce),161.3 (Cb), 140.1 (Cd), 139.4 (CaЈ), 133.1
(CbЈ), 131.1 (Ci), 129.2.1 (Ch), 127.9 (CcЈ) 123.8 (Cc) ppm. FT-IR:
Salt Metathesis Method: The sodium salt of 5-[2-(4-fluorophenyl)-
thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione (0.3 g, 0.99 mmol) and
phenylbismuth dichloride (0.18 g, 0.49 mmol) were reacted accord-
ing to GP7 yielding an orange precipitate of 9, yield 0.25 g, 68%;
ν = 1637 (m), 1445 (s), 1303 (m), 1264 (m), 1006 (s), 956 (s), 765
˜
(s), 723 (s), 706, 663 (m), 635 (m) cm–1. ESI-MS+ (solvent: DMSO/
MeOH, 35 eV): m/z 987 (35%, [BiPhL2
+
Na]+(79Br isotope)),
1
989 (22%, [BiPhL2
+
Na]+(81Br isotope)), 781 (98%, [BiPhL-
m.p. 195 °C (dec.). H NMR (400 MHz, [D6]DMSO): δ = 8.95 (d,
2 H, HaЈ), 8.30 (s, 2 H, Hc), 7.98 (m, 4 H, Hg), 7.98 (m, 2 H, HbЈ),
7.49 (m, 1 H, HcЈ), 7.34 (m, 4 H, Hh) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 167.5 (Ce), 164.8 (Cb), 162.7 (Ci), 140.9 (Cd), 138.8
(CaЈ), 133.2 (CbЈ), 128.9 (Ch), 127.9 (CcЈ), 116.4 (Cc) ppm. FT-IR:
(DMSO)2]+(79Br isotope)), 781 (100%, [BiPhL(DMSO)2]+(81Br isotope)),
209 (80%, [Bi]+). ESI-MS– (solvent: DMSO/MeOH, 35 eV): m/z
995 (100%, [BiPhL2(CH3O)]–(79Br isotope)), 997 (100%, [BiPhL2-
(CH3O)]–(81Br isotope)). C28H15BiBr2N6O2S4 (964.49): calcd. C 34.87,
H 1.57, N 8.71; found C 35.54, H 1.78, N 8.91.
ν = 1615 (m), 1589 (m), 1469 (s), 1297 (m), 1228 (s), 1091 (s), 779
˜
(s), 722 (s), 689 (m), 651 (m) cm–1. ESI-MS+ (solvent: DMSO/
MeOH, 35 eV): m/z 898 (20%, [BiPhL2(H2O)3 + H]+), 844 (65%,
[BiPhL2 + H]+), 665 (30%, [BiPhL(CH3OH)2(H2O)2]+), 618 (13%,
[BiPhL(H2O)3]+), 596 (25%, [BiPhL(CH3OH)]+), 209 (60%, [Bi]+).
ESI-MS– (solvent: DMSO/MeOH, 35 eV): m/z 1018 (23%,
Synthesis of [BiPh(CF3-PTOT)2] (12). Conventional Reflux: The re-
action mixture of triphenylbismuth of (0.17 g, 0.38 mmol) and 5-
{2-[4-(trifluoromethyl)phenyl]thiazol-4-yl}-1,3,4-oxadiazole-2(3H)-
thione (0.25 g, 0.76 mmol) was refluxed together for 5 h according
to GP4. The yellow precipitate obtained was washed with acetone,
yield 0.28 g, 53%.
[BiPhL2(H2O)6(CH3OH) + Cl]–), 986 (10%, [BiPhL2(H2O)6
+
Cl]–), 874 (32%, [BiPhL2 + CH3O]–). C28H15BiF2N6O2S4 (842.68):
calcd. C 39.91, H 1.79, N 9.97; found C 39.93, H 2.10, N 10.02.
Microwave-Assisted
Synthesis:
Triphenylbismuth
(0.10 g,
0.22 mmol) and 5-{2-[4-(trifluoromethyl)phenyl]thiazol-4-yl}-1,3,4-
oxadiazole-2(3H)-thione (0.15 g, 0.45 mmol) in 6 mL of toluene
was irradiated at 90 °C for 3 min according to GP5 to obtain 12 as
a yellow solid, yield 0.11 g, 55%.
Synthesis of [BiPh(Cl-PTOT)2] (10). Conventional Reflux: The reac-
tion mixture of triphenylbismuth of (0.26 g, 0.60 mmol) and 5-[2-
(4-chlorophenyl)thiazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione
(0.35 g, 1.20 mmol) was refluxed together for 11 h according to
GP4. The yellow precipitate obtained was washed with acetone,
yield 0.31 g, 60%.
Salt Metathesis: The sodium salt of 5-{2-[4-(trifluoromethyl)-
phenyl]thiazol-4-yl}-1,3,4-oxadiazole-2(3H)-thione
(0.3 g,
Eur. J. Inorg. Chem. 2015, 4935–4945
4944
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjic.org
FULL PAPER
S. Xie, Inorg. Chem. 2012, 51, 12521; j) M. Li, L. Zhang, M.
Yang, J. Niu, J. Zhou, Bioorg. Med. Chem. Lett. 2012, 22, 2418.
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45, 5785.
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Trans. Met. Chem. 2004, 29, 804.
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0.85 mmol) and phenylbismuth dichloride (0.15 g, 0.42 mmol) were
reacted according to GP7 yielding an orange precipitate of 12, yield
0.24 g, 61%; m.p. 206 °C (dec.). 1H NMR (400 MHz, [D6]DMSO):
δ = 9.01 (d, 2 H, HaЈ), 8.35 (s, 2 H, Hc), 8.02 (d, 4 H, Hg), 7.96 (t,
2 H, HbЈ), 7.73 (d, 4 H, Hh), 7.50 (t, 1 H, HcЈ) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 166.6 (Ce), 159.6 (Cb), 140.6 (Cd),
139.3 (CaЈ), 133.1 (CbЈ), 131.1 (Ci), 127.9 (CaЈ), 126.9 (Cg), 126.1
(q, CF3), 123.4 (Cc) ppm. FT-IR: ν = 1618 (m), 1431 (s), 1326 (m),
˜
1222 (m), 1065 (s), 953 (s), 773 (s), 726 (s), 687 (m), 637 (m) cm–1.
ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z 966 (52%, [BiPhL2
+ Na]+), 209 (60%, [Bi]+). ESI-MS– (solvent: DMSO/MeOH,
35 eV): m/z 974 (68%, [BiPhL2 + CH3O]–), 678 (8%, [BiPhL +
(CH3O)2]–). C30H15BiF6N6O2S4 (942.70): calcd. C 38.22, H 1.60, N
8.91; found C 38.24, H 1.65, N 9.11.
[21] N. Singh, M. Bharty, R. Dulare, R. Butcher, Polyhedron 2009,
28, 2443.
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[24] F. H. Allen, Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58,
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[25] C. Ma, G. Tian, R. Zhang, Inorg. Chim. Acta 2007, 360, 1762.
[26] C.-L. Ma, G.-R. Tian, R.-F. Zhang, Polyhedron 2005, 24, 1773.
[27] a) E. Hoggsrth, J. Chem. Soc. 1952, 4811; b) M. A. Khali,
S. M. El-Khawass, M. G. Kassem, Scientia Pharmaceutica
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(Gainesville, FL, U.S.) 2006, 11; d) J. Sandstrom, I. Wenner-
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Acknowledgments
The authors thank the Australian Research Council
(DP110103812) and Monash University, Australia for financial as-
sistance.
[1] R. R. Gupta, M. Kumar, V. Gupta, Heterocyclic Chemistry,
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Received: May 20, 2015
Published Online: September 11, 2015
Eur. J. Inorg. Chem. 2015, 4935–4945
4945
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