Novel N-heterocyclic ylideneamine gold(i) complexes: Synthesis, characterisation and screening for antitumour and antimalarial activity

Article abstract of DOI:10.1039/c0dt01312a

Ylideneamine functionalised heterocyclic ligands, 1,3-dimethyl-1,3-dihydro- benzimidazol-2-ylideneamine (I), 3-methyl-3H-benzothiazol-2-ylideneamine (II) or 3,4-dimethyl-3H-thiazol-2-ylideneamine (III), were employed in the preparation of a series of both charged and neutral gold(i) complexes consisting either of a Au(C₆F₅) fragment (1-3), a [Au(PPh₃)] ⁺ unit (4-6) or a [Au(NHC)]⁺ unit (7) coordinated to the imine nitrogen of the neutral ylideneamine ligand. These complexes were fully characterised by various techniques including X-ray diffraction. In addition, the antitumour and antimalarial potential of selected compounds were assessed in a preliminary study aimed at determining the medicinal value of such compounds. Complexation of the azol-2-ylideneamine ligands with [Au(PPh₃)] ⁺ increases their antitumour as well as antimalarial activity.

Full text of DOI:10.1039/c0dt01312a

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PAPER
Novel N-heterocyclic ylideneamine gold(I) complexes: synthesis,
characterisation and screening for antitumour and antimalarial activity†
Jacorien Coetzee,a Stephanie Cronje,*a Liliana Dobrzan´ska,a Helgard G. Raubenheimer,a Gisela Joone´,b
Margo J. Nellb and Heinrich C. Hoppec
Received 30th September 2010, Accepted 18th November 2010
DOI: 10.1039/c0dt01312a
Ylideneamine functionalised heterocyclic ligands, 1,3-dimethyl-1,3-dihydro-benzimidazol-2-
ylideneamine (I), 3-methyl-3H-benzothiazol-2-ylideneamine (II) or 3,4-dimethyl-3H-thiazol-2-
ylideneamine (III), were employed in the preparation of a series of both charged and neutral gold(I)
complexes consisting either of a Au(C6F5) fragment (1–3), a [Au(PPh3)]+ unit (4–6) or a
[Au(NHC)]+ unit (7) coordinated to the imine nitrogen of the neutral ylideneamine ligand. These
complexes were fully characterised by various techniques including X-ray diffraction. In addition, the
antitumour and antimalarial potential of selected compounds were assessed in a preliminary study
aimed at determining the medicinal value of such compounds. Complexation of the
azol-2-ylideneamine ligands with [Au(PPh3)]+ increases their antitumour as well as antimalarial activity.
Since their discovery, ylideneamines and their transition metal
complexes have attracted considerable interest owing to their
The coordination chemistry of phosphazenido ligands of the
biological activity. Metformin (1,1-dimethylbiguanide) deriva-
tives, in particular, are well known for their medicinal value.
past few decades leading to the discovery of a vast number of
These compounds show significant versatility in their biological
activity and have been employed as therapeutic agents for the
Neutral phosphazene ligands, R3P NH, can be readily prepared
treatment of pain, anxiety, memory disorders, diabetes and
Introduction
general type [R3P N]- has been studied extensively over the
structurally diverse main group and transition metal complexes.1
malaria.4 Similarly, benzimidazol-2-ylamine and benzimidazol-2-
ylideneamine derivatives have been utilised in the formulation of
treatments for severe illnesses such as Parkinson’s disease, multiple
sclerosis, neurological disorders and strokes.5 Moreover, molecules
containing a core 2-aminobenzothiazole scaffold have been found
to reduce parasitaemia (Plasmodium falciparum) by 80% at a
concentration of 10 mM.6 The N–H functionality in ylideneamine
ligands appears to play a fundamental role in their biological
activity, and is believed to participate in the formation of hydrogen
bonds to biomolecules. It is a functionality that could even be
considered as essential for anticancer activity.7
Despite extensive reports on the biological activity of ylide-
neamine derivatives and metal complexes thereof, the literature
provides very little information regarding their antitumour activ-
ity. On the other hand, gold(I) phosphine complexes are renowned
for showing potential as antitumour agents.8 Additionally, the
chloroquine complex of triphenylphosphinegold(I) was found to
be active against two strains of malaria. Against Plasmodium
falciparum, in particular, this complex proved 4–9 times more
active than chloroquinediphosphate and other metal complex
candidates.9 In bi-coordinate linear gold(I) phosphine complexes,
the antitumour activity and cytotoxicity are modulated not only
by the phosphine substituents but also by the nature of the
auxiliary ligands present. Complexes with good leaving groups
positioned trans to the phosphine display reduced antitumour
by the acid catalysed reactions of N-silylized phosphazenes
R3P NSiMe3, with i-propanol or methanol, or by deprotonation
of the corresponding aminophosphonium salts, [R3P NH2]Cl us-
ing sodium amide. These ligands are, however, thermally sensitive
and prone to oxidation in the presence of water affording related
phosphorane oxides.2 Efforts to improve the stability of this class
of compounds have led to the discovery of the related imidazol-2-
ylideneamine and thiazol-2-ylideneamine analogues. Replacement
of the PR3 moiety in phosphazenes with an N-heterocyclic carbene
(NHC) was an initiative that exploited the striking electronic
similarities between the electron rich trialkylphosphines and
NHC’s.3 In contrast to the phosphazenes, their ylideneamine
counterparts are less susceptible to oxidation and may be regarded
as superior in terms of stability.
aDepartment of Chemistry and Polymer Science, University of Stellenbosch,
Private Bag X1, Matieland, 7602, Stellenbosch, South Africa. E-mail:
scron@sun.ac.za, stephanie.cronje@gmail.com; Fax: +27 21 808 3849;
Tel: +27 21 808 2180
bDepartment of Pharmacology, Faculty of Medicine, University of Pretoria,
P.O. Box 2034, Pretoria, 0001, South Africa
cCSIR, Biosciences, P.O. Box 395, Pretoria, 0001, South Africa
† Electronic supplementary information (ESI) available: Synthesis of IV
and crystallographic data of 4a. CCDC reference numbers 801423–801432.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c0dt01312a
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activity. This arises from the reactivity of such complexes towards
thiols, enabling the formation of strong protein bonds to AuPR3,
which in turn prevents gold(I) phosphines from reaching their
intracellular targets.10
Preliminary studies by Baker and co-workers11 have shown that
several dinuclear gold(I) complexes containing bridging NHC lig-
ands induce membrane permeabilisation in rat liver mitochondria.
This suggests that NHC-containing gold(I) complexes may be
considered as promising alternatives to phosphine complexes in
the development of chemotherapeutic agents.
Notwithstanding the variety of existing pentafluorophenyl
(pfp), phosphine and NHC gold(I) complexes, the few such
compounds known to also contain ylideneamine ligands are
limited to simple ketimine or guanidine types.12 Inspired by
this scarcity together with the biological activity displayed by
ylideneamine metal complexes, we now report on the preparation
and extensive characterisation of a series of pfp-, phosphine- and
NHC-containing ylideneamine gold(I) complexes. In addition, to
evaluate whether a possible synergism could be detected between
the different combinations of coordinating functionalities, a
number of these complexes were assessed for their potential as
anticancer and antimalarial agents. The preliminary outcome of
these assays is described in this account.
MeI. Alkylation of the resulting neutral product with CF3SO3Me
and subsequent deprotonation with KH (as for II and III) gave
the neutral ligand I in good yield. Strict temperature control
during the execution of the final deprotonation step proved
crucial in all instances. Reaction temperatures above 66 ◦C
led to the formation of dimeric byproducts, especially when
preparing the thiazole derivatives II and III. X-ray structure
elucidation of a single crystal isolated from a crystallisation
mixture of II aided in identifying the byproduct as 3-methyl-2-(3-
methyl-3H-benzothiazol-2-ylideneamino)benzothiazol-3-ium tri-
fluoromethanesulfonate (IV†), the result of a condensation reac-
tion which entails the loss of ammonia. Compounds similar to
this dimeric byproduct have been prepared by Deligeorgiev and
Gadjev14 by treating 3-methyl-3H-benzothiazol-2-ylideneamine
derivatives with HX, where X = CH3SO3 , ClO4 , Br- or I-.
The highly hygroscopic ligands I–III are soluble in water and
organic solvents such as alcohols, dichloromethane, DMSO, THF,
acetone or diethyl ether, but insoluble in alkanes such as n-pentane
and n-hexane.
-
-
Pentafluorophenyl gold(I) complexes
We have recently again emphasised the value of [Au(C6F5)(tht)]
(tht = tetrahydrothiophene) as a gold(I) precursor complex, which
freely allows the substitution of the tht ligand by ligands with
superior donor abilities.15,16 Ylideneamine ligands are consid-
ered to be strong s-donors and therefore readily replace tht
to form neutral coordination complexes of the general form
[Au(C6F5)(L)], where L refers to the ylideneamine ligand. Scheme 2
depicts the facile preparation of neutral ylideneamine-coordinated
(pfp)gold(I) complexes 1–3. These air and moisture sensitive
compounds were prepared in moderate to high yields by treating
solutions of ligands I–III in THF with equimolar amounts of
[Au(C6F5)(tht)] at room temperature.
Results and discussion
Ylideneamine-functionalised heterocyclic carbene complexes
The most general route towards the preparation of ylideneamine-
functionalised heterocyclic carbenes was developed by Kuhn and
co-workers.13 Their method entails alkylation of the endocyclic
nitrogen atom of a 1-methyl-1H-imidazol-2-ylamine derivative
with MeI to yield a cationic amino compound. The latter can
then be readily converted to the corresponding ylideneamine by
deprotonation with potassium hydride. A similar approach was
followed in the preparation of ligands I–III from the appropriate
amino precursors, with the only variation being the choice of
alkylating agent (Scheme 1).
Scheme 2 Preparation of pfp gold(I) complexes of ligands I–III; X = NMe
or S.
Compounds 1 and 2 are soluble in acetone, THF and DMSO
while compound 3 is soluble in most organic solvents such as
short chain alcohols, acetone, diethyl ether, THF, acetonitrile or
dichloromethane. All of the complexes are insoluble in alkanes
such as pentane and hexane. Gradual decomposition of com-
pounds 1 and 2 was observed when stored under argon at -22 ◦C
Scheme 1 Preparation of ylideneamine-functionalised heterocyclic car-
benes I–III; i = KOH, ii = MeI and iii = CF3SO3Me.
In the case of I, where multiple alkylations were required,
the initial alkylation could be achieved by deprotonation of
the endocyclic N-atom with KOH, followed by treatment with
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for prolonged periods of time in both the solid state and solution.
Compound 3, however, showed greater thermal stability and no
decomposition was observed under the same conditions. Crystals
suitable for X-ray structure determination were either obtained by
vapour diffusion of pentane into a solution of the compound
in THF (1 and 2 respectively) or by slow crystallisation from
a concentrated acetone solution (3). All crystallisation mixtures
were stored under argon at -22 ◦C.
of complex 7 – the first example of an ylideneamine gold(I)
complex to also contain an NHC ligand (Scheme 4). Treatment of
I with an equimolar amount of [Au(1,3-tBuIm-2-ylidene)(NO3)]
in THF at ambient temperature furnished 7.
Phosphine gold(I) complexes
Schmidbaur and co-workers12 have established that one equivalent
of either [Au(PPh3)(SO3CF3)] or [Au(PPh3)(BF4)] reacts quanti-
tatively with tetramethylguanidine or benzhydrylideneamine to
form the corresponding monoaurated ylideneamine complex.
Complexes 4–6 were prepared following a similar protocol
by treating solutions of I, II or III with a suspension of
(triphenylphosphine)gold(I) nitrate, [Au(NO3)(PPh3)]17 in diethyl
ether at room temperature (Scheme 3). Since complexes 4–6 are
insoluble in diethyl ether, free ligand traces could be removed from
the crude product mixtures by washing with this solvent. Drying
of the remaining solids in vacuo afforded the analytically pure
products as colourless solids in high yield.
Scheme 4 Preparation of the NHC gold(I) complex of ligand I.
Complex 7 is an off-white solid that is fairly air and moisture
stable and soluble in organic solvents such as short chain alcohols,
dichloromethane or DMSO but insoluble in water or alkanes.
Crystals suitable for an X-ray structure determination were
◦
obtained under argon at -22 C by vapour diffusion of pentane
into a solution of 7 in dichloromethane.
Attempts at the deprotonation of ylideneamine complexes
From close inspection of recorded 1H NMR data (vide infra) it was
evident that coordination of ligands I–III to a gold(I) centre has
a significant effect on the electronic nature of the imine protons.
This finding prompted deprotonation attempts on ylideneamine
ligands following their coordination to a gold(I) centre. However,
with complexes 4–6 as subjects, such attempts with KH proved
unsuccessful and the bulk of all isolated materials consisted of
the unmodified substrates (diagnostic NH resonances were still
present in the 1H NMR spectra). These findings were further con-
firmed by X-ray structure determination of crystalline materials
isolated from all final product mixtures. Structure elucidation of
colourless single crystals isolated after the deprotonation attempt
on 4 by vapour diffusion of pentane into a solution of the product
in CH2Cl2 at -22 ◦C resulted in the structure 4b. Also, in one
of these trial experiments a variant of 6 that contains triflate
as counterion, 6b (as colourless 6b·CH2Cl2), was crystallised by
vapour diffusion of pentane into a solution of 6 in CH2Cl2 at
-22 ◦C. Both these structures are discussed in the crystallographic
section.
Scheme 3 Preparation of phosphine gold(I) complexes of ligands I–III;
X = NMe or S.
The ‘hard-soft’ adducts 4–6 are neither air nor moisture
sensitive. Moreover, these cationic complexes are soluble in more
polar organic solvents such as short chain alcohols, acetone,
dichloromethane, THF and DMSO. Their stability and good sol-
ubility makes them even more appealing candidates for biological
screening, since the stability of such compounds in solution is a
vital consideration for biological evaluation. All of the complexes
are insoluble in water and alkanes such as hexane or pentane.
Crystals suitable for X-ray crystal structure determinations were
obtained by vapour diffusion of pentane into solutions of the
compounds in acetone (4a) or dichloromethane (5) under argon
at -22 ◦C.
Spectroscopic analysis
Nuclear magnetic resonance
Most signals in the NMR (1H, 13C, 31P, 15N) spectra of the new
compounds appear slightly downfield to the chemical shifts of
the corresponding starting materials. The NMe signals resonate
NHC gold(I) complexes
Finally, the compound 1,3-di-tert-butylimidazol-2-ylidene-gold(I)
nitrate, [Au(1,3-tBuIm-2-ylidene)(NO3)], initially prepared by
Baker and co-workers,18 was utilised in the high yield preparation
1
at a characteristic d 3.2–3.8 in the H NMR and d 27–39 in the
13C NMR spectra. Although differences in concentration are
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known to influence the NH chemical shifts, it is notable that
coordination to a gold(I) centre has a varied, but pronounced
effect on the NH moiety of ligands I–III. In most cases NH
resonances are shifted significantly downfield with respect to free
ligand signals. This effect is most prominent for complex 1 and
declines in the order 1 (Dd 4.27) > 2 (Dd 2.77) > 3 (Dd 1.45) in
the first series of complexes and 5 (Dd 4.20) > 6 (Dd 2.87) in
the second series of complexes, along with decreasing lone pair
electron delocalization over the ligand system. In contrast, the
NH resonances of complexes 4 and 7 experience a significant
upfield shift (Dd 3.13 and 1.98 respectively). Shielding of the
NH proton in 4 and 7 by close association of the nitrate anion
(even in solution), may represent a plausible explanation for this
divergence. Additionally, a hydrogen bond between an oxygen
atom of the anion and NH in the cation exists in the solid
4. Unfortunately, all attempts to detect the metal-bonded nitrogen
atom resonances in complex 4 failed.
In the 31P NMR spectra of compounds 4–6, only one intense
singlet at d 32.0 for 4, d 27.7 for 5 and d 31.0 for 6 is observed. These
resonances all display an insignificant downfield shift relative to
the precursor compound, [Au(NO)3(PPh3)] (d 28.9).
Infrared spectroscopy
Routine FT-IR data were collected for compounds I–III and 1–
7 with all relevant absorption bands listed in the experimental
section. However, an interesting observation made when the FT-
IR spectra of compounds 1–3 were compared to those of 4–7
deserves special mention. From this comparison it was evident that
the coordination of ligands I–III to a neutral Au(C6F5) moiety has
a more pronounced effect on the N–H stretching vibrations (n(N–
H) 3375–3399 cm-1 compared to 3249–3165 cm-1 for 4–7) than
coordination to a positively charged [Au(PPh3)]+ or [Au(NHC)]+
entity, although hydrogen bonding may also be reflected in the
N–H stretching vibrations.
˚
˚
state (NH ◊ ◊ ◊ O distance of 3.054 A in 4 and 2.956 A in 7). A
similar situation was observed for the NC(H)N proton in [{m2-
HCCCH2N C(H)N(CH CH2)CH CH}Co2(CO)6][B(C6H5)]19
and ferrocenyl imidazolium salts.20
1
In the H NMR spectra resonances of the phenyl protons of
benzazole derived ligands clearly show the chemical inequivalence
of the phenyl CCH and CCHCH protons upon changing from an
NMe group (only two doublets of doublets detected) to an S atom
Mass spectrometry
The FAB-MS spectra of compounds I and II display very
little fragmentation owing to the mild nature of this ionization
technique. The only diagnostic peaks present in the spectra of
ligands I–III are those corresponding to the molecular ions and
those resulting from the loss of a methyl group. A higher degree of
fragmentation is evident in the EI-MS spectrum of III exhibiting
an intense peak at m/z 128. Even though no molecular ion
peak is detected in the FAB-MS spectrum of 1, other diagnostic
signals corresponding to the loss of a CH3 group (m/z 511), and
further loss of Au(C6F5) (m/z 147) are present. A molecular ion
peak was detected in the spectrum of 2, while m/z values that
correspond to their cations are present for 4–6. In these spectra,
signals attributable to the homoleptic rearrangement product
[Au(PPh3)2]+ are also present at m/z 720. Although FAB-MS
analysis was executed for 3, this technique, despite the soft nature
thereof, proved unsuccessful for this complex and the acquired
spectra failed to deliver any diagnostic peaks.
1
(4 to 6 sets of signals observed). Interestingly, in the H NMR
spectra of compounds III, 3 and 6 the proton in the 5-position on
the thiazole ring experiences an allylic 4J coupling of ª 1 Hz to the
protons of the methyl substituent on the 4-position, resulting in a
quartet or broad singlet at d 5–6 (CH in 5-position) and a doublet
at d 2 (NCH3).
In the 13C NMR spectra very small to no changes are observed
for NCN carbon shifts upon complexation in the benzimidazole
compounds, whereas a significant downfield shift (Dd 7.9–10.4)
is observed in the thiazole based derivatives. In the case of the
phenyl carbons of the benzazole ligands some carbons appear
slightly downfield and others slightly upfield. This observation is
not unusual as the total chemical shift s (s = sp + sd) in the
13C NMR reflects more than simply shielding and deshielding
1
as in H NMR.21 In the 13C NMR spectra of 1–3, intricate C–
F coupling patterns detected in the region d 118–151 verify the
presence of a Au(C6F5) unit. Similarly, in the spectra of 4–6, four
additional sets of doublets are detected in the region d 128–135
and correspond to the characteristic C–P coupling of the phenyl
carbons of the [Au(PPh3)]+ moiety. Of these, the doublet at d
128.3–128.7 can be assigned to the C–P coupled ipso-carbon atom,
whilst the doublet at d 129.7 is attributable to the C–P coupled
meta-carbon atom. Resonances of the ortho- and para-carbon
atoms are observed as doublets in the regions d 134.4–134.5 and
d 132.4–132.6, respectively. For the NHC complex 7, a significant
downfield shift of Dd 10.0 is observed for the characteristic carbene
carbon resonance relative to the signal for the same carbon in the
precursor compound, [Au(1,3-tBuIm-2-ylidene)(NO3)].18
The 15N NMR spectrum of I exhibits a singlet at d -278.0
that corresponds to both endocyclic N-atoms of the imidazole
ring which are rendered magnetically and chemically equivalent
by their environment. Despite the use of both indirect and
direct methods, no resonance signal could be obtained for the
exocyclic nitrogen atom. Coordination of I to a gold centre results
in a slight downfield shift (Dd 8.7) of the resonances of the
endocyclic N-atoms as is evident from the 15N NMR spectrum of
Crystallography
The crystal and molecular structures of compounds I, III, IV†
and 1–7 (4a†) were determined by single crystal X-ray diffraction
and are now, to the best of our knowledge, reported for the first
time (Fig. 1–10). In addition, compounds 1–7 represent the first
reported examples of gold complexes to contain 2-ylideneamine-
functionalised heterocycles as ligands. In view of the fact that very
few crystal structures of ylideneamine-functionalised heterocyclic
ligands have been reported in the literature, a discussion of the free
ligand structures is included here to serve as a point of reference
and to place the characterization of this class of compounds on a
firm footing.
Where more than one unique molecule is present in the
asymmetric unit (structures III, IV and 1) no significant differences
in bond lengths and angles of the distinct molecules were ob-
served. Seven of the compounds crystallised with included solvent
molecules (I·3H2O, IV·CH2Cl2, 2·THF, 3·Me2CO, 4a·2Me2CO†,
6b·0.33H2O and 7·0.5CH2Cl2). The very extended network of
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Fig. 3 Molecular structure of 1 showing two unique molecules present
in the asymmetric unit, connected via a weak aurophilic interaction
(thermal ellipsoids drawn◦ at 50% probability level). Selected bond
˚
lengths (A) and angles ( ): Au(1) ◊ ◊ ◊ Au(2) 3.5824(6), Au(1)–C(111)
2.009(7), Au(1)–N(13) 2.041(5), N(13)–C(211) 1.305(8), N(11)–C(211)
1.373(8), N(12)–C(211) 1.374(8), N(11)–C(218) 1.466(8), N(12)–C(219)
1.456(8), N(13)–Au(1)–C(111) 176.4 (2), N(13)–Au(1)–Au(2) 73.4(2),
C(111)–Au(1)–Au(2) 109.9(2), C(211)–N(13)–Au(1) 133.5(5), N(11)–
C(211)–N(13) 126.4(6), N(12)–C(211)–N(13) 126.5(6), N(11)–C(211)–
N(12) 107.3(6).
Fig. 1 Molecular structure of I·3H2O (thermal ellipsoids drawn at 50%
◦
˚
probability level). Selected bond lengths (A) and angles ( ): N(3)–C(1)
1.295(3), N(1)–C(1) 1.375(3), N(2)–C(1) 1.374(2), N(1)–C(8) 1.451(3),
N(2)–C(9) 1.451(3), H(10)–N(3)–C(1) 111(2), N(3)–C(1)–N(1) 123.5(2),
N(3)–C(1)–N(2) 130.2(2), N(1)–C(1)–N(2) 106.3(2).
Fig.
4
Molecular structure of 2·THF showing the numbering
scheme (thermal ellipsoids drawn at 50% probability level). THF
hydrogen atoms are omitted for clarity. Selected bond lengths
(A) and angles (◦): Au(1)–C(111) 2.009(5), Au(1)–N(2) 2.037(5),
˚
N(2)–C(211) 1.294(7), N(1)–C(211) 1.359(7), S(1)–C(211) 1.763(5),
N(1)–C(218) 1.425(7), N(2)–Au(1)–C(111) 177.3(2), C(211)–N(2)–Au(1)
127.0(4), N(1)–C(211)–N(2) 126.6(5), S(1)–C(211)–N(2) 122.3(4),
N(1)–C(211)–S(1) 111.1(4).
compounds consist of either a Au(C6F5) fragment (in 1–3), a
[Au(PPh3)]+ unit (in 4–6b) or a [Au(NHC)]+ unit (in 7) coordinated
to the imine nitrogen of the neutral ligand. This then affords
neutral (1–3) or charged complexes neutralised by nitrate (4, 5 and
7) or triflate (6b) anions hydrogen bonded to the imine proton.
The two ring systems present in 1 and 3 approach co-planarity
with interplanar angles of 6.9◦, 7.4◦ and 9.4◦, whilst being almost
perfectly aligned in 2 (1.6◦). Conversely, the ring systems in 7 take
on an approximate perpendicular disposition (74.7◦) in order to
minimise steric interactions between the ligands.
Fig. 2 Molecular structure of III showing the numbering scheme of the
four unique molecules in the asymmetric unit (thermal ellipsoids drawn at
◦
˚
50% probability level). Selected bond lengths (A) and angles ( ) for only
one of the molecules: N(2)–C(1) 1.280(3), N(1)–C(1) 1.372(4), S(1)–C(1)
1.781(3), N(1)–C(4) 1.455(3), H(8)–N(2)–C(1) 110(2), N(2)–C(1)–N(1)
123.5(3), N(2)–C(1)–S(1) 128.5(2), N(1)–C(1)–S(1) 108.0(2).
hydrogen bonding in I, forming layers consisting of cyclic water
hexamers, is noteworthy. Devoid of any disorder as a result of
solvent inclusion, the crystal structure refinement of 4b is of
superior quality than that of 4a (solvate with acetone†), thus the
more reliable bond lengths and angles obtained for 4b are used in
comparisons in the discussion.
The bi-coordinated gold complexes are all linear or approaching
linearity with L1–Au–L2 angles varying from 174.8(1)◦ in 7 to
178.8(2)◦ in 3. Furthermore, the molecular structures of the
Although a comparison of the solid state FT-IR spectroscopic
data of compounds 1 and 4 suggests that coordination of ligand
I to a Au(C6F5) unit has a more pronounced effect on the
stretching vibrations of the N–H moiety than coordination to
a [Au(PPh3)]+ unit, no appreciable difference between the C
N
bond lengths in 1 and 4 is observed. However, as we have warned
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Fig. 5 Molecular structure of 3·Me2CO showing the numbering scheme
(thermal ellipsoids drawn at 50% probability level). So◦lvent molecules
˚
are not shown. Selected bond lengths (A) and angles ( ): Au(1)–C(11)
Fig.
7
Molecular structure of
5
showing the numbering scheme
2.002(5), Au(1)–N(2) 2.031(4), N(2)–C(21) 1.292 (6), N(1)–C(21) 1.359(6),
S(1)–C(21) 1.748(5), N(1)–C(24) 1.466(6), N(2)–Au(1)–C(11) 178.8(2),
C(21)–N(2)–Au(1) 125.3(3), N(1)–C(21)–N(2) 128.2(5), S(1)–C(21)–N(2)
121.8(4), N(1)–C(21)–S(1) 109.9(4).
(thermal ellipsoids drawn at 50% probability level). Selected bond
lengths (A) and angles (◦): Au(1)–P(1) 2.2245(18), Au(1)–N(2)
˚
2.028(6), N(2)–C(211) 1.289(9), N(1)–C(211) 1.359(9), S(1)–C(211)
1.770(8), N(1)–C(218) 1.421(9), S(1)–C(212) 1.755(7), N(2)–Au(1)–P(1)
178.43(18), C(211)–N(2)–Au(1) 127.3(5), N(2)–C(211)–S(1) 120.0(6),
N(1)–C(211)–N(2) 128.6(7), N(1)–C(211)–S(1) 111.5(5).
Fig. 8 Molecular structure of 6b·0.33H2O showing the numbering
scheme (thermal ellipsoids drawn at 50% probability level). The solvent
molecule as well as the disordered ◦counterion is omitted for clarity.
Fig. 6 Molecular structure of 4b showing the numbering scheme
˚
(thermal ellipsoids drawn at 50% probability level). Selected
Selected bond lengths (A) and angles ( ): Au(1)–P(1) 2.229(1), Au(1)–N(2)
◦
˚
bond lengths (A) and angles ( ): Au(1)–P(1) 2.231(1), Au(1)–N(3)
2.040(3), N(3)–C(211) 1.309(4), N(1)–C(211) 1.373(5), N(2)–C(211)
1.392(4), N(1)–C(218) 1.458(4), N(2)–C(219) 1.460(4), N(3)–Au(1)–P(1)
175.60(8), C(211)–N(3)–Au(1) 129.7(3), N(1)–C(211)–N(3) 125.8(3),
N(2)–C(211)–N(3) 126.7(3), N(1)–C(211)–N(2) 107.5(3).
2.036(4), N(2)–C(211) 1.294(7), N(1)–C(211) 1.353(7), S(1)–C(211)
1.732(6), N(1)–C(215) 1.454(7), S(1)–C(212) 1.732(6), N(2)–Au(1)–P(1)
177.2(1), C(211)–N(2)–Au(1) 124.2(4), N(2)–C(211)–S(1) 122.9(4),
N(1)–C(211)–N(2) 127.0(5), N(1)–C(211)–S(1) 110.1(4).
for [Au{NH C(NMe2)2(PPh3)}][CF3SO3] and [Au(NH CPh2)-
12
˚
˚
before, correlation of such connectivity data with other analytical
results should be interpreted with the utmost caution.22
(PPh3)][BF4] (2.229(2) A and 2.234(2) A, respectively). Fur-
thermore, the Au–P (in 4b, 5, 6b) and Au–C(carbene) (in 7)
separations are significantly larger than in the corresponding
starting gold compounds. This can be ascribed to the larger
trans influence of the ylideneamine ligand (much larger for trans
Au–P than trans Au–C(carbene)) compared to that of the nitrate
Bond lengths and angles in the imine ligand are not significantly
changed by gold(I) coordination and are comparable to those in
1,3-dimethyl-1,3-dihydro-imidazol-2-ylidineamine13 and standard
values for such bonds.23 Contrary to 15N NMR observations in
solution, C N and C–N bond lengths differ significantly and
do not testify to any substantial electron delocalisation over these
bonds in the solid state. The ylideneamine ligands are all essentially
planar with only the methyl hydrogens protruding from the plane.
From a comparison of the bond lengths and angles it is evident
that variations amongst alike bonds are small.
24
17
˚
˚
ligand (2.208(3) A and 1.973(4) A ). Thirdly, the Au–N bond
in the ylideneamine seems to be relatively insensitive to changes
in the ligand itself or to influences by ligands positioned trans
˚
thereto. Values vary between 2.03(4) A (in 3, 5, and 7) and
2.04 A (in 1). These distances are comparable to that reported
for [Au(C6F5){N(H) CPh2}] (2.044(8) A), as well as for other
˚
25
˚
Nevertheless,
a
few observations are in order. The
examples wherein the gold(I) centre is coordinated to an endocyclic
N-atom.16,26 Similar Au–N separations have also been reported
Au–P bond lengths (4b, 5, 6b) are similar to those reported
1476 | Dalton Trans., 2011, 40, 1471–1483
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interactions were observed in the solid state packing of the
remaining complexes. These interactions between neighbouring
molecules are most likely prohibited by the steric demands of
included solvent molecules as well as a strong preference for
the formation of hydrogen bonds. This favouring of hydrogen
bonding over aurophilic associations may well be an enthalpy
effect. Although the energy of an aurophilic interaction (29–
33 kJ mol-1) has been estimated by NMR experiments to be of
the same order of magnitude as a typical hydrogen bond (20–
30 kJ mol-1),29 the hydrogen bond per molecule ratio in the crystal
lattices is 2 : 2 or more whereas the aurophilic bond per molecule
ratio would be 1 : 2. The formation of twice as many hydrogen
bonds therefore results in a much greater energy gain compared to
association via aurophilic bonds. This observation is in agreement
with a report by Laguna and co-workers,25 who have concluded
that hydrogen-bonding may compete with aurophilic interactions.
In the solid state packing of compound 6b, which crystallises
in a high symmetry trigonal system, the molecules are assembled
in groups of six stabilised by a relatively strong hydrogen bond
involving the imine hydrogen atoms and oxygen atoms of the
Fig.
9
Molecular structure of 7·0.5CH2Cl2 showing the number-
ing scheme (thermal ellipsoids drawn at 50% probability level).
Selected bond lengths (A) and angles (◦): Au(1)–C(211) 1.993(4),
˚
Au(1)–N(3) 2.028(3), N(3)–C(111) 1.299(5), N(1)–C(111) 1.373(5),
N(2)–C(111) 1.378(5), N(4)–C(211) 1.363(5), N(5)–C(211) 1.364(5),
N(1)–C(118) 1.458(5), N(2)–C(119) 1.452(5), N(4)–C(218) 1.508(5),
N(5)–C(214) 1.503(5), N(3)–Au(1)–C(211) 174.8(1), C(111)–N(3)–Au(1)
134.5(3), N(1)–C(111)–N(3) 126.0(4), N(2)–C(111)–N(3) 127.0(3),
N(1)–C(111)–N(2) 107.0(3), N(4)–C(211)–Au(1) 126.3(3), N(5)–C(211)–
Au(1) 128.1(3), N(4)–C(211)–N(5) 105.5(3).
˚
triflate counter anion (N–H ◊ ◊ ◊ O, 2.06–2.11 A). This arrangement,
when viewed along the c-axis, bestows a beautiful flower-like
appearance upon the crystal lattice (Fig. 10). The core of the
flower motif consists of six triflate counterions arranged about
a central water molecule whilst the ‘petals’ comprise six cationic
complexes of 6b, connected to the inner part via hydrogen bonding.
It is possible that loss of the originally included solvent molecules
followed by water absorption, to fill the resulting voids, may
account for the presence of water in the crystal lattice. This process
may also have caused the observed disorder in the triflate ion,
as one of the disordered anions interacts weakly with a water
molecule via an O–H ◊ ◊ ◊ F interaction.
Cytotoxicity studies
Anticancer activity
The in vitro cytotoxicity of compounds 4–7, at varying concen-
trations in DMSO, was determined using cervical carcinoma cells
(HeLa; ATCC CCL-2) as the target cell line. Identical assays were
also performed on ligands I–III, serving as control experiments to
ensure that any growth inhibition observed is indeed the result of
auration and not only due to an inherent activity of the free ligands.
Drug-free solvent controls were included. Also reported are the
IC50 data determined under the same conditions for cisplatin, a
well-established anticancer drug frequently used as a standard in
drug performance comparisons. To evaluate whether any cyto-
toxicity observed against HeLa cells may not be tumour specific,
additional dose-response assays were performed to derive IC50
values against resting and phytohaemagglutinin(PHA)-stimulated
human lymphocytes.
The results obtained for these preliminary studies are sum-
marised in Table 1. None of the tested compounds showed
extensive cytotoxic potential, with the free ligands I, II and
III resulting in the least growth inhibition, having IC50 values
greater that 30 mM. The lack of cytotoxicity observed for these
compounds could also reflect a low degree of cellular uptake which
is determined by their hydrophilicity. Although all of complexes 4,
5, 6 and 7 induced a significant increase in growth inhibition with
Fig. 10 Flower-like appearance of the solid state packing of 6b viewed
along the c-axis.
for the [Au(imine)(PPh3)] complexes [Au(NH CPh2)(PPh3)][BF4]
˚
A and
and [Au{NH C(NMe2)2}(PPh3)][CF3SO3] (2.036(7)
2.044(9) A, respectively)12 and also for the [Au(imine)(NHC)] com-
plex [Au2(CH3im(CH2py))2](BF4)2 (2.087(8)).27 Finally, the Au–C
bond distances are very similar in the reactant [Au(C6F5)(tht)],15
product [Au(C6F5)(ylideneamine)] (1–3) or literature example,
[Au(C6F5)(NH CH2)],25,28 suggesting that a rather similar elec-
tronic influence is exercised by these particular S- and N-donor
ligands.
˚
Hydrogen bonding involving the imine nitrogen and either
included solvent molecules (in I, 2 and 3) or the anions (in 4–
7), together with p–p stacking interactions (in I, IV, 1–3, 4a and 7)
govern solid state packing. With the exception of 1, no aurophilic
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Table 1 Cytotoxicity studies against cervical carcinoma cells (HeLa;
A comparison with the IC50 results obtained against mammalian
cells (Table 2) indicates that the selectivity index (parasite vs.
mammalian activity) would require significant improvement be-
fore these compounds could be considered suitable for further
investigation as antimalarials.
ATCC CCL-2)
Lymphocyte
Lymphocyte stimulation Tumor
a
Compound HeLa IC50 (mM) resting (mM) (mM)
specificity
b
b
b
b
b
b
b
b
b
I
> 50
32.2 3.0
> 50
10.2 0.4
27.3 4.0
9.1 0.3
19.2 0.3
0.6
II
Conclusions
III
4
6.4 1.3
3.6 0.3
6.1 1.2
6.5 0.2
30.4 6.7
3.4 2.0
4.0 0.3
4.3 0.7
6.8 1.0
2.2 0.3
0.5
0.08
0.6
0.3
—
Ylideneamine gold(I) complexes, particularly those that contain
trans phosphine ligands, are remarkably air and moisture stable
and the NH functionality seems completely compatible with
these soft metal centres despite the fact that the iso-electronic
gold(I)-oxygen bonds are ‘intrinsically weak’28 and that such com-
plexes with bicovalent oxygen donors (like ketones or phosphine-
oxides) are not known.
5
6
7
cisplatin
a IC50 values refer to the minimum concentration required to effect growth
inhibition in 50% of the cells. b Not performed.
Preliminary screening tests have now indicated that the new
heterocyclic ylideneamine gold complexes, although sometimes
much more active than the free ligands, do not exhibit exceptional
anticancer activity. Further modifications to the ylideneamines or
to the ancillary phosphine or NHC ligands that are also present
could increase antitumour or antimalarial activity.
Table 2 Parasite-inhibitory and haemolytic properties
a
Compound
IC50 (mg ml-1)
50% hemolysis (mg ml-1)
I
40.9 1.0
7.2 1.5
> 100
5.8 1.1
5.2 1.3
4.4 1.1
5.1 1.1
0.0091 0.00086
No haemolysis
No haemolysis
No haemolysis
50
25–50
25–50
II
III
Experimental
4
5
General procedures and instruments
6
7
50–100
No haemolysis
chloroquine
Reactions were carried out under argon using standard Schlenk
and vacuum-line techniques. All solvents were predried on ground
KOH or molecular sieves and freshly distilled prior to use.
Tetrahydrofuran (THF), n-hexane, n-pentane and diethyl ether
were distilled under N2 from sodium benzophenone ketyl, acetone
a IC50 values refer to the compound concentration required to effect a 50%
growth inhibition of the cells.
˚
from 3 A molecular sieves, dichloromethane and methanol from
respect to the free ligands, the measured IC50 values were still not
comparable to that of cisplatin.
CaH2 and ethanol from magnesium. Methyliodide, CF3SO3CH3,
4-methyl-thiazol-2-ylamine and benzothiazol-2-ylamine were
purchased from Aldrich. 1H-benzimidazol-2-ylamine, AgNO3
and KH were purchased from Fluka. Literature methods
were used to prepare [Au(C6F5)(tht)]30 from [Au(Cl)(tht)],31
[Au(Cl)(PPh3)]32 from [HAuCl4],33 [Au(NO3)(PPh3)]17 from
[Au(Cl)(PPh3)] and [Au(1,3-tBuIm-2-ylidene)(NO3)]18 from 1,3-
tBuIm.34 [Au(Cl)(SMe2)] was prepared from [HAuCl4] following
the same method as reported in the literature for the preparation
of [Au(Cl)(tht)].
Melting points were determined on Stuart SMP3 apparatus
and are uncorrected. Mass spectra were recorded on an AMD 604
(EI, 70 eV), VG Quattro (ESI, 70 eV methanol, acetonitrile) or
VG 70 SEQ (FAB, 70 eV) instrument. In the case of EI-MS and
FAB-MS the isotopic distribution patterns were checked against
the theoretical distribution. NMR spectra were recorded on a
Varian 300/400 FT or INOVA 600 MHz spectrometer (1H NMR
at 300/400/600 MHz, 13C NMR at 75/100/150 MHz, 15N NMR
at 60.8 MHz, 31P NMR at 121/161 MHz and 19F NMR at 376
MHz) with the chemical shifts reported relative to TMS with the
solvent resonance as internal reference or NH3NO2 (15N), 85%
H3PO4 (31P) or CFCl3 (19F) as external reference. Infrared spectra
were recorded on a Thermo Nicolet Avatar 330FT-IR with a Smart
OMNI ATR (attenuated total reflectance) sampler. Elemental
analysis was carried out at the School of Chemistry, University
of the Witwatersrand. Prior to elemental analysis, products were
evacuated under high vacuum for 10 h.
However, it can safely be concluded that coordination to
a [Au(PPh3)]+ moiety has the greatest effect on ligand I with
the IC50 value changing from greater than 50 mM to 10.17
mM. Furthermore, gold(I) coordination of ligand II to afford
complex 5 does not bring about any large changes in the cytotoxic
potency; the tumour specificity, however, decreases drastically.
Although complex 6 displays the greatest growth inhibition as
well as tumour specificity, the measured lymphocyte resting and
stimulation values are of intermediate nature in the series. From a
comparison of the effects of complexes 4 and 7, it is evident that the
triphenylphosphine ancillary ligand imparts greater cytotoxicity
and tumour specificity on the complex than its NHC counterpart.
Antimalarial activity
Preliminary in vitro antimalarial activity studies were carried out
by performing dose-response assays against the 3D7 strain of
Plasmodium falciparum. The results (Table 2) indicated that the
azol-2-ylideneamines and the aurated compounds are much less
active than chloroquine (reference drug) against P. falciparum
and, again, that auration increases activity. Significant haemolysis
of the host erythrocytes (observed as haemoglobin released into
the culture supernatant) was present at concentrations of 5–
10 times higher than the corresponding IC50s of the aurated
compounds, suggesting that host cell membrane perturbations
may contribute to the antimalarial activity of the compounds.
1478 | Dalton Trans., 2011, 40, 1471–1483
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Synthesis
Preparation
by evaporation under vacuum the pure product was obtained
as a yellow solid (0.79 g, 79%). Mp 112–114 ◦C. IR nmax/cm-1
of
1,3-dimethyl-1,3-dihydro-benzimidazol-2-
3
3243 s n(N–H), 3047 w n(Caryl–H), 2931 w n(Csp –H), 1596–
ylideneamine, I. Powdered KOH (0.37 g, 6.50 mmol) was added
to a stirring solution of 1H-benzimidazol-2-ylamine (0.43 g,
3.25 mmol) in acetone (13 ml). A thick colourless precipitate was
visible after 10 min. After the addition of CH3I (0.20 ml, 0.46 g,
2.25 mmol) the reaction mixture was stirred vigorously for 10 min
after which the brown solution (with only the excess KOH still
suspended) was transferred to a separating funnel containing
benzene (120 ml). The organic layer was washed with water
(1 ¥ 20 ml) and saturated NaCl solution (20 ml) and subsequently
dried over anhydrous MgSO4. The solvent was removed in vacuo
and the remaining off-white solid was redissolved in CH2Cl2
(30 ml). After cooling the solution to -40 ◦C, CF3SO3CH3
(0.37 ml, 0.53 g, 3.25 mmol) was added and the reaction mixture
stirred at this temperature for 1 h. The mixture was allowed to
reach room temperature, whereafter the volatiles were removed
in vacuo. The remaining colourless residue was washed with
diethyl ether (2 ¥ 20 ml), dried in vacuo and resuspended in THF
(30 ml). KH (0.13 g, 3.25 mmol) in THF (5 ml) was added to
the stirring suspension. Gas evolution was evident after addition
of the KH. The mixture was refluxed for 1 h during which the
colourless suspension cleared up to yield a yellow solution.
The solution was stripped of solvent and the solid residue was
extracted with CH2Cl2. The CH2Cl2 extract was filtered through
anhydrous MgSO4 and reduced to dryness to yield the pure
product as a colourless microcrystalline solid (0.46 g, 88%).
Colourless crystals of I were obtained by slow evaporation
of a concentrated solution of the compound in CH2Cl2. Mp
59–60 ◦C. IR nmax/cm-1 3235 s n(N–H), 3058 w n(Caryl–H), 2931 w
1574 s n(C N), 1474–1417 s n(C Caryl), 1330 m n(C–N), 736 s
b
d
oop(Caryl Caryl). 1H NMR (CD2Cl2): dH 7.26 (1H, ddd, 3J 7.7 Hz,
4J 1.4 Hz, 5J 0.5 Hz, NCCH), 7.24 (1H, td, 3J 7.8 Hz, 4J 1.4 Hz,
NCCHCH), 7.00 (1H, td, 3J 7.8 Hz, 4J 1.3 Hz, SCCHCH), 6.86
3
(1H, dm, J 8.5 Hz, SCCH), 4.95 (1H, bs, NH), 3.37 Hz (3H, s,
NCH3). 13C NMR (CD2Cl2): dC 162.7 (s, NCS), 142.0 (s, NCCH),
126.8 (s, NCCH), 123.2 (s, NCCHCH), 122.1 (s, SCCHCH), 121.9
(s, SCCH), 109.7 (s, SCCH), 29.4 (s, NCH3). m/z (FAB-MS) 165
(100, M+), 150 (6, (M-CH3)+).
Preparation of 3,4-dimethyl-3H-thiazol-2-ylideneamine, III.
Compound III was prepared by the same method as that described
for II with CF3SO3CH3 (1.13 ml, 1.64 g, 10.0 mmol), 4-methyl-
thiazol-2-ylamine (1.14 g, 10.0 mmol) and KH (0.40 g, 10 mmol).
After removal of the solvent by evaporation under vacuum, the
crude product was sublimed under vacuum (0.1 mbar) at 75 ◦C to
achieve the pure product as a colourless crystalline solid (0.79 g,
62%). Colourless crystals of III were obtained by slow evaporation
of a concentrated solution of the compound in CH2Cl2. Mp 46–
48 ◦C. IR nmax/cm-1 3239 w n(N–H), 3062 w n(Caryl–H), 2916
1
3
w n(Csp –H), 1606–1564 s n(C N), 1418–1364 s n(C Caryl). H
4
NMR (CD2Cl2): dH 5.47 (1H, bs, NH), 5.46 (1H, q, J 1.4 Hz,
SCH), 3.17 (3H, s, NCH3), 2.01 (3H, s, J 1.4 Hz, CCH3). 13C
4
NMR (CD2Cl2): dC 166.6 (s, NCS), 136.0 (s, NCCH3), 92.3 (s,
SCC(CH3)N), 30.0 (s, NCH3), 14.9 (s, CCH3). m/z (FAB-MS)
128 (90, M+), 113 (15, (M–CH3)+), 100 (27, (M–NCH3)+), 86 (25,
(M–CH3–NH)+), 56 (100, (CH3NC NH)+).
Preparation
ylideneamine(pentafluorophenyl)gold(I), 1.
of
1,3-dimethyl-1,3-dihydro-benzimidazol-2-
solution of
3
n(Csp –H), 1625–1608 s n(C N), 1500–1392 s n(C Caryl), 1326 w
A
b
n(C–N), 724 s d oop(Caryl Caryl). 1H NMR (CD2Cl2): dH 6.96 (2H,
[Au(C6F5)(tht)] (0.32 g, 0.70 mmol) in THF (10 ml) was
transferred to a Schlenk tube containing I (0.11 g, 0.70 mmol)
dissolved in THF (20 ml). The reaction mixture was allowed
to stir for three days at room temperature, during which minor
decomposition occurred. The resulting yellow solution was
filtered to remove colloidal gold deposits, and subsequently
reduced to dryness in vacuo. The remaining residue was washed
with diethyl ether (2 ¥ 30 ml) and dried to yield the pure product
as a colourless solid (0.26 g, 70%). Mp 94–100 ◦C. Found: C, 34.8;
H, 2.3; N, 7.7. C15H11AuF5N3 requires C, 34.3; H, 2.1; N, 8.0%.
IR nmax/cm-1 3399 s n(N–H), 3174 w n(C–H), 1624 s n(C N),
1498–1450 s n(C Caryl), 1436 m n(C–N), 1498 s, 1058 m, 946 s
3
4
3
dd, J 5.7 Hz, J 3.4 Hz, NCCHCH), 6.81 (2H, dd, J 5.6 Hz,
4J 3.4 Hz, NCCH), 4.16 (1H, bs, NH), 3.28 (6H, s, NCH3). 13C
NMR (CD2Cl2): dC 156.3 (s, NCN), 133.0 (s, NCCH), 120.6
(s, NCCHCH), 106.2 (s, NCCH), 27.7 (s, NCH3). 15N NMR
(CD2Cl2): dN -278.0 (s, NCH3). m/z (FAB-MS) 162 (100, M+),
147 (17, (M–CH3)+).
Preparation of 3-methyl-3H-benzothiazol-2-ylideneamine,‡ II.
The alkylating agent, CF3SO3CH3 (0.68 ml, 1.0 g, 6.0 mmol), was
added dropwise to a solution of benzothiazol-2-ylamine (0.91 g,
6.0 mmol) in diethyl ether (20 ml) at -40 ◦C. Upon addition
of the CF3SO3CH3, a thick colourless precipitate formed. The
reaction mixture was allowed to stir at this temperature for 1 h
and then to slowly reach room temperature. The solvents and
other volatiles were removed in vacuo and the resulting colourless
solid was washed with diethyl ether (2 ¥ 40 ml), dried in vacuo,
and resuspended in THF (20 ml). A suspension of KH (0.24 g,
6.03 mmol) in THF (5 ml) was added to the stirring mixture. The
liberation of hydrogen gas could be observed by the formation
of bubbles. The mixture was refluxed for 1 h, during which time
the colourless suspension cleared up to yield a yellow solution.
The solution was reduced to dryness and the solid residue was
extracted with CH2Cl2. The CH2Cl2 extract was subsequently
filtered through anhydrous MgSO4. After removal of the solvent
b
and 799 s n(C6F5) and d (C6F5). 1H NMR (CD2Cl2): dH 8.43 (1H,
1
2
bs, NH), 7.47 (2H, dd, J 5.9 Hz, J 3.4 Hz, NCCHCH), 7.32
3
4
(2H, dd, J 5.9 Hz, J 3.4 Hz, NCCH), 3.73 (6H, s, NCH3). 13C
1
NMR (CD2Cl2): dC 156.4 (s, NCN), 148.6 (ddm, J 228.3 Hz,
2J 26.9 Hz, o-C6F5), 138.5 (dm, 1J 248.5 Hz, p-C6F5), 137.3
(dm, 1J 226.5 Hz, m-C6F5), 131.4 (s, NCCH), 126.1 (tm, 2J
57.3 Hz, i-C6F5), 124.4 (s, NCCHCH), 110.5 (s, NCCH), 39.2 (s,
NCH3). 19F NMR (CD2Cl2): dF -164.3 (m, p-C6F5), -161.1 (t, 3J
19.6 Hz, m-C6F5), -116.6 (m, o-C6F5). m/z (FAB-MS) 511 (11,
(M–CH3)+), 355 (28, (M–C6F5)+), 162 (89, (M–AuC6F5)+), 147
(46, (M–AuC6F5–CH3)+).
Preparation of 3-methyl-3H-benzothiazol-2-ylideneamine-
(pentafluorophenyl)gold(I), 2. A solution of freshly prepared
[Au(C6F5)(tht)] (0.22 g, 0.48 mmol) in THF (10 ml) was
‡ Caution: 3-methyl-3H-benzothiazol-2-ylideneamine may irritate respi-
ratory tracts when inhaled.
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transferred to a Schlenk tube containing II (0.08 g, 0.49 mmol)
dissolved in THF (20 ml). Minor decomposition occurred after
the addition and the solution was therefore filtered to remove
colloidal gold, and transferred into a clean reaction vessel. The
reaction mixture was allowed to stir for three days at room
temperature. Further decomposition occurred during this stirring
period and the resulting solution was therefore filtered through
anhydrous MgSO4 and reduced to dryness in vacuo to yield
the title compound as a colourless solid (0.20 g, 78%). Mp
128–132 ◦C. Found: C, 32.0; H, 1.6; N, 5.1. C14H8AuF5N2S
requires C, 31.8; H, 1.5; N, 5.3%. IR nmax/cm-1 3375 m n(N–H),
2960 w n(C–H), 1569 s n(C N), 1477–1453 s n(C Caryl), 1438 m
87.9%). Mp 126–128 (decomp.)◦C. Found: C, 47.3; H, 3.9; N, 8.4.
C27H26AuN4O3P requires C, 47.5; H, 3.8; N, 8.2%. IR nmax/cm-1
3249 w n(N–H), 3048 w n(Caryl–H), 1605 s n(C N), 1496–1435
m n(C Caryl), 743 m n(C C). 1H NMR (CD2Cl2): dH 7.61–7.52
(15H, m, PPh), 7.20 (2H, dd, J 5.8 Hz, J 3.1 Hz, NCCHCH),
7.12 (2H, dd, 3J 5.7 Hz, 4J 3.1 Hz, NCCH), 3.76 (6H, s, NCH3),
1.82 (1H, bs, NH). 13C NMR (CD2Cl2): dC 156.3 (s, NCN),
3
4
2
4
134.4 (d, J 13.7 Hz, o-PC6H5), 132.4 (d, J 2.6 Hz, p-PC6H5),
3
1
131.2 (s, NCCH), 129.7 (d, J 12.0 Hz, m-PC6H5), 128.7 (d, J
63.1 Hz, i-PC6H5), 122.9 (s, NCCHCH), 108.7 (s, NCCH), 30.0 (s,
NCH3). 31P NMR (CD2Cl2): dP 32.0 (s). 15N NMR (CD2Cl2): dN
+
-270.7 (s, NCH3). m/z (FAB-MS) 720 (12, Au(PPh3)2 ), 620 (87,
n(C–N), 1501 s, 1058 m, 950 s and 801 s n(C6F5) and d (C6F5). 1H
(M–NO3)+), 606 (5, (M–NO3–CH3)+), 543 (4, (M–NO3–Ph)+),
b
NMR (CD2Cl2): dH 7.72 (1H, bs, NH), 7.56 (1H, dm, 3J 7.8 Hz,
459 (25, AuPPh3 ), 162 (95, (M–NO3–AuPPh3)+).
+
3
4
NCCH), 7.36 (1H, td, J 8.4 Hz, J 1.1 Hz, NCCHCH), 7.23
3
3
4
Preparation of 3-methyl-3H-benzothiazol-2-ylideneamine(tri-
(1H, d, J 8.0 Hz, SCCH), 7.17 (1H, td, J 7.7 Hz, J 1.0 Hz,
SCCHCH), 3.55 (3H, s, NCH3). 13C NMR (CD2Cl2): dC 173.1
phenylphosphine)gold(I)
nitrate,
5.
A
suspension
of
1
2
[Au(NO3)(PPh3)] (0.45 g, 0.81 mmol) in diethyl ether (10 ml)
was added to a stirring solution of II (0.14 g, 0.82 mmol) in
diethyl ether (20 ml). The reaction mixture was allowed to stir for
three days at room temperature. During this period, the yellow
solution had become colourless and a new suspension was visible.
The mixture was filtered, the remaining solid washed with diethyl
ether (2 ¥ 20 ml) and dried in vacuo to yield the pure product as
a colourless solid (0.50 g, 89%). Mp 130–135 ◦C. Found: C, 45.9;
H, 3.5; N, 6.2. C26H23AuN3O3PS requires C, 45.6; H, 3.4; N, 6.1%.
IR nmax/cm-1 3165 w n(N–H), 3059 w n(Caryl–H), 1598–1577 s
(s, NCS), 150.1 (ddm, J 226.3 Hz, J 23.9 Hz, o-C6F5), 141.8
(s, NCCH), 138.7 (dm, 1J 244.0 Hz, p-C6F5), 137.4 (dm, 1J
247.7 Hz, m-C6F5), 127.6 (s, NCCH), 124.4 (s, SCCH), 123.0 (s,
NCCHCH), 122.6 (s, SCCHCH), 118.4 (tm, 2J 57.6 Hz, i-C6F5),
111.6 (s, SCCH), 30.1 (s, NCH3). 19F NMR (CD2Cl2): dF -165.3
(m, p-C6F5), -163.1 (tt, 3J 5.3 Hz, 4J 0.5 Hz, m-C6F5), -116.6 (m,
o-C6F5). m/z (FAB-MS) 528 (8, M+), 514 (3, (M–CH3)+), 361 (4,
(M–C6F5)+), 165 (73, (M–AuC6F5)+).
Preparation
of
3,4-dimethyl-3H-thiazol-2-ylideneamine-
1
n(C N), 1477–1434 m n(C Caryl), 746 m n(C C). H NMR
(CD2Cl2): dH 9.15 (1H, bs, NH), 7.60–7.52 (15H, m, PPh), 7.47
(pentafluorophenyl)gold(I), 3. A solution of freshly prepared
[Au(C6F5)(tht)] (0.30 g, 0.67 mmol) in THF (10 ml) was
transferred to a Schlenk tube containing III (0.09 g, 0.79 mmol)
dissolved in THF (30 ml). The reaction mixture was allowed to
stir for four days at room temperature. Slight decomposition
occurred during this stirring period and the reaction mixture
was filtered through anhydrous Na2SO4 and reduced to dryness
in vacuo. The crude product was washed with diethyl ether (2 ¥
20 ml) and dried under vacuum to yield the title compound as an
off-white solid (0.31 g, 93%). Mp 100–106 ◦C. Found: C, 26.2;
H, 1.4; N, 5.4. C5H8AuF5N2S requires C, 26.8; H, 1.6; N, 5.7%.
IR nmax/cm-1 3379 s n(N–H), 3107 w n(C–H), 1554 s n(C N),
1499–1437 s n(C Caryl), 1435 s n(CN), 1499 s, 1060 m, 949 s and
3
3
4
(1H, d, J 7.8 Hz, NCCH), 7.42 (1H, t, J 8.5 Hz, J 1.1 Hz,
3
3
NCCHCH), 7.23 (1H, t, J 7.8 Hz, SCCHCH), 7.14 (1H, d, J
8.0 Hz, SCCH), 3.69 (3H, s, NCH3). 13C NMR (CD2Cl2): dC 172.4
(s, NCS), 141.1 (s, NCCH), 134.5 (d, 2J 13.3 Hz, o-PC6H5), 132.6
4
3
(d, J 2.6 Hz, p-PC6H5), 129.7 (d, J 12.0 Hz, m-PC6H5), 128.3
(d, 1J 63.6 Hz, i-PC6H5), 127.7 (s, NCCH) 124.6 (s, NCCHCH),
122.4 (s, SCCH), 122.4 (s, SCCHCH), 111.8 (s, SCCH), 31.2 (s,
NCH3). 31P NMR (CD2Cl2): dP 27.7 (s). m/z (FAB-MS) 720 (9,
Au(PPh3)2 ), 623 (100, (M–NO3)+), 459 (6, AuPPh3 ), 164 (34,
(M–NO3–AuPPh3)+).
+
+
b
1
Preparation of 3,4-dimethyl-3H-thiazol-2-ylideneamine(tri-
800 s n(C6F5) and d (C6F5). H NMR (CD2Cl2): dH 6.92 (1H,
bs, NH), 6.12 (1H, bs, SCCH), 3.47 (3H, s, NCH3), 2.24 (3H, d,
4J 1.2 Hz, CCH3). 13C NMR (CD2Cl2): dC 176.1 (s, NCS), 150.1
phenylphosphine)gold(I)
nitrate,
6.
A
suspension
of
[Au(NO3)(PPh3)] (0.36 g, 0.69 mmol) in diethyl ether (10 ml)
was added to a stirring solution of III (0.09 g, 0.69 mmol) in
diethyl ether (10 ml). The reaction mixture was allowed to stir
for two days at room temperature. During this period, the yellow
solution had become colourless and a new suspension formed.
The mixture was filtered, the remaining solid washed with diethyl
ether (2 ¥ 20 ml) and dried in vacuo to yield the pure product as
1
2
1
(ddm, J 226.8 Hz, J 24.5 Hz, o-C6F5), 139.3 (dm, J 248.7 Hz,
1
m-C6F5), 139.2 (s, NCC), 138.0 (dm, J 243.1 Hz, p-C6F5), 97.5
(s, SCCH), 27.1 (s, NCH3), 15.8 (s, CCH3). 19F NMR (CD2Cl2):
dF -169.8 (m, p-C6F5), -167.7 (t, 3J 19.6 Hz, m-C6F5), -121.2 (m,
o-C6F5).
a colourless solid (0.38 g, 84%).§ Mp 95–100 ◦C. Found: C,
35
Preparation
of
1,3-dimethyl-1,3-dihydro-benzimidazol-2-
42.4; H, 3.5; N, 6.6. C23H23AuN3O3PS requires C, 42.5; H, 3.6; N,
6.5%. nmax/cm-1 3186 w n(N–H), 1545 s n(C N), 1478–1434 m
n(C Caryl), 750 m n(C C). 1H NMR (CD2Cl2): dH 8.34 (1H, bs,
NH), 7.59–7.47 (15H, m, PPh), 5.84 (1H, bs, SCH), 3.48 (3H, s,
ylideneamine(triphenylphosphine)gold(I) nitrate, 4. A suspension
of [Au(NO3)(PPh3)] (0.45 g, 0.81 mmol) in diethyl ether (10 ml)
was added to a stirring solution of I (0.13 g, 0.83 mmol) in
diethyl ether (20 ml). The reaction mixture was allowed to stir
for three days at room temperature. During this period, the light
yellow solution became colourless and a new suspension formed.
The mixture was filtered, the remaining solid washed with diethyl
ether (2 ¥ 20 ml), extracted with CH2Cl2 and reduced to dryness
in vacuo to yield the pure product as a colourless solid (0.49 g,
4
NCH3) 2.14 (3H, d, J 1.0 Hz, CCH3). 13C NMR (CD2Cl2): dC
174.5 (s, NCS), 137.6 (s, NCCH3), 134.4 (d, 2J 13.7 Hz, o-PC6H5),
§ Note: Product undergoes a colour change when dissolved in chlorinated
solvents. It may be sensitive towards oxidation; see ref. 35.
1480 | Dalton Trans., 2011, 40, 1471–1483
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4
3
132.5 (d, J 2.6 Hz, p-PC6H5), 129.7 (d, J 12.0 Hz, m-PC6H5),
128.3 (d, 1J 64.0 Hz, i-PC6H5), 96.3 (s, SCH), 31.8 (s, NCH3), 14.9
(s, NCCH3). 31P NMR (CD2Cl2): dP 31.0 (s). m/z (FAB-MS) 720
Antimalarial activity
Plasmodium falciparum (3D7 strain) parasites were routinely
cultured in a medium consisting of RPMI-1640, supplemented
with 50 mM glucose, 25 mM HEPES, 0.65 mM hypoxanthine,
0.2% (w/v) NaHCO3, 0.5% (w/v) Albumax II and 0.048 mg
mL-1 gentamicin. The medium was further supplemented with 2–
4% human erythrocytes (type O+) and cultures were maintained
in sealed tissue culture flasks suffused with 3% CO2, 4% O2,
balance N2. Parasite life-cycle stages were regularly synchronised
by incubating infected erythrocytes in 5% sorbitol for 5 min,
followed by sedimentation and resuspension in culture medium.
For antimalarial activity determinations, cultures containing
parasites in predominantly the early to mid-trophozoite stage
were used. Infected erythrocytes were mixed with fresh culture
medium and uninfected erythrocytes to obtain a 2% parasitaemia,
2% haematocrit suspension, which was distributed in microtitre
plates at a volume of 100 mL per well. Three-fold serial dilutions
of test compounds were prepared in culture medium in a separate
plate and 100 mL per well transferred to the plate containing the
parasite cultures. Four wells contained infected erythrocytes in
medium with compound solvent alone (max. 0.5% v/v; viability
control) and four additional wells contained uninfected erythro-
cytes (background control). The microtitre plates were sealed in
containers with an atmosphere of 3% CO2, 4% O2, balance N2
(18, Au(PPh3)2 ), 587 (71, (M–NO3)+), 459 (82, AuPPh3 ).
+
+
Preparation
of
1,3-dimethyl-1,3-dihydro-benzimidazol-2-
ylideneamine-(1,3-di-tert-butylimidazol-2-ylidine)gold(I) nitrate, 7.
A solution of [Au(NO3)(1,3-tBuIm-2-ylidene)] (0.17 g, 0.39 mmol)
in THF (10 ml) was added to a stirring solution of I (0.06 g, 0.39
mmol) in THF (20 ml). Upon addition a white suspension formed.
The mixture was allowed to stir overnight at room temperature.
The brownish solution was stripped of solvent in vacuo and the
remaining residue was extracted with CH2Cl2, filtered through
MgSO4 and reduced to dryness to yield the product as an
off-white solid (0.23 g, 96%). Mp 127–132 (decomp.)◦C. Found:
C, 40.2; H, 5.4; N, 13.9. C20H31AuN6O3 requires C, 40.0; H,
5.2; N, 14.0%. nmax/cm-1 3193 w n(N–H), 2966 m n(Caryl–H),
1
1628 s n(C N), 1499 m n(C Caryl), 733 m n(C C). H NMR
3
4
(CD2Cl2): dH 7.21 (2H, 2, NCH), 7.20 (2H, dd, J 5.8 Hz, J
3.2 Hz, NCCHCH), 7.11 (2H, dd, 3J 5.9 Hz, 4J 3.2 Hz, NCCH),
3.79 (6H, s, NCH3), 2.18 (1H, bs, NH), 1.89 (18H, s, NCCH3).
13C NMR (CD2Cl2): dC 165.6 (s, AuC), 156.2 (s, NCN), 131.3
(s, NCCH), 122.8 (s, NCCHCH), 117.4 (s, NCH), 108.5 (s,
NCCH), 59.3 (NCCH3), 31.9 (s, NCCH3), 29.7 (s, NCH3). m/z
(FAB-MS) 557 (69, [Au(tBu2Im)2]+), 538 (22, (M–NO3)+]), 524 (5,
(M–NO3–CH3)+), 377 (15, [Au(tBu2Im)2]-(tBu)+).
◦
and incubated for 48 h at 37 C. Percentage parasite viability in
test wells relative to the viability controls was determined by a
colorimetric assay for parasite lactate dehydrogenase.39 The IC50
for each test compound was calculated from dose-response plots
of % parasite viability vs. log(compound concentration), using
the non-linear regression function of GraphPad Prism software.
Each compound concentration was assayed in duplicate wells, and
IC50 determinations were carried out on three separate occasions.
Assessment of haemolytic activity was done in parallel plates
containing compound serial dilutions incubated for 48 h with
uninfected erythrocytes in culture medium. An aliquot of the
supernatant was removed and absorbance at 405 nm measured
as an indication of haemolysis relative to haemolytic controls
consisting of wells treated with 0.2% (w/v) saponin.
Anti-cancer assays
Cytotoxicity assays were performed to establish the sensitivity
of HeLa cells to the compounds I–III and 4–7, at varying con-
centrations, using cervical carcinoma cells (HeLa; ATCC CCL-
2) maintained in EMEM (Sigma Aldrich, St. Louis, MO, USA)
supplemented with 10% heat inactivated fetal calf serum (Sigma
Aldrich, St. Louis, MO, USA) and 1% penicillin-streptomycin
(BioWhittaker, Walkersville, Maryland). 20 mM stock solutions
of experimental compounds were prepared in DMSO. 5 ¥ 102
cells/well were exposed to different concentrations (0.5–50 mM)
of the complexes in 96-well tissue culture plates and incubated in a
5% CO2 incubator for 7 days at 37 ◦C. Drug-free solvent controls
were included. The IC50 data for cisplatin were determined under
the same conditions. A metabolic assay based on the reactivity of
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bro-
mide), originally described by Mosmann36 with modifications by
van Rensburg et al.37 was used to determine the effects of the
experimental compounds on cell growth.
Dose-response assays were performed to derive IC50 values
against resting and phytohaemagglutinin(PHA)-stimulated hu-
man lymphocytes in order to determine whether cytotoxicity
observed against HeLa cells may not be tumour specific. The
final concentration of PHA that was added to the relevant
wells was 5 mg ml-1. Heparinised human blood, obtained from
healthy volunteers, was used to prepare the cell suspensions
using Histopaque-1077 (Sigma Aldrich, St. Louis, MO, USA) as
described by Smit et al.38 The cells were maintained in RPMI
medium supplemented with 10% fetal calf serum and were seeded
at 2 ¥ 105 per well and incubated for 3 days in the presence
of varying concentrations of the experimental compounds as
described above. The MTT assay was used to determine cell
survival after treatment.
X-ray crystal structure determinations
Crystal data collection and refinement details of compounds I,
III, IV, 1–3, 4b, 5, 6b and 7 are summarised in Table 3 and
4. Data sets were collected on a Bruker SMART Apex CCD
diffractometer with graphite monochromated Mo-Ka radiation
40
˚
(l = 0.71073 A). Data reduction was performed according to
standard methods using the software package Bruker SAINT and
data were treated with SADABS.41–43 All the structures were solved
using direct methods or interpretation of a Patterson synthesis,
which yielded the position of the metal atoms, and conventional
difference Fourier methods. All non-hydrogen atoms were refined
anisotropically by full-matrix least squares calculations on F2
using SHELX-9744 within an X-seed environment.45 All hydrogen
atoms, except the imine hydrogen atoms of compounds 7, 6b
and ligand I and hydrogen atoms on the water molecules in
6b and I were fixed in calculated positions. The disordered
-
CF3SO3 counterion of 6b was modelled in two orientations
(58 : 42). Figures were generated with X-seed and POV Ray for
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Table 3 Crystallographic and data collection parameters of I, III, IV, 1 and 2a
Compound reference
I
III
IV
1
2
Chemical formula
Formula mass
C9H17N3O3
215.26
Monoclinic
11.348(3)
12.090(4)
8.619(3)
90.00
98.098(5)
90.00
1170.7(6)
100(2)
P21/c
4
6351
2400
0.0307
0.0614
0.1331
0.0728
0.1390
1.110
C5H8N2S
128.19
C35H30F6N6O6S6
1007.91
Monoclinic
14.381(2)
13.755(2)
20.620(3)
90.00
98.291(3)
90.00
4036.2(10)
100(2)
P21/c
4
20878
7476
0.0682
0.0763
0.1656
0.1260
C15H11AuF5N3
525.23
Monoclinic
13.684(2)
13.522(2)
16.365(2)
90.00
107.753(2)
90.00
2883.9(7)
100(2)
P21/c
8
15450
5763
0.0520
0.0371
0.0742
0.0504
C18H16AuF5N2OS
600.35
Triclinic
9.309(2)
9.355(2)
11.773(3)
99.080(3)
112.817(3)
96.171(3)
917.0(3)
Crystal system
Triclinic
6.949(1)
13.498(3)
14.301(3)
108.286(3)
101.346(3)
91.652(3)
1242.9(4)
100(2)
˚
a/A
˚
b/A
˚
c/A
a (◦)
b (◦)
g (◦)
3
˚
Unit cell volume/A
T/K
Space group
100(2)
¯
¯
P1
P1
No. of formula units per unit cell, Z
No. of reflections measured
No. of independent reflections
Rint
8
2
6852
4625
9785
3994
0.0467
0.0457
0.0807
0.0774
0.0886
0.880
0.0267
0.0315
0.0743
0.0376
0.0776
1.071
a
Final R1 values (I > 2s(I))
b
Final wR2 values (I > 2s(I))
a
Final R1 values (all data)
b
Final wR2 values (all data)
0.1917
1.046
0.0804
1.071
Goodness of fit on F2
a R1 = R[ꢀFo| - |Fcꢀ/R|Fo| b wR2 = {R[w(Fo - Fc2)2]/R[w(Fo2)2]}
2
1/2
Table 4 Crystallographic and data collection parameters of 3, 4b, 5, 6b and 7a
Compound reference
3
4b
5
6b
7
Chemical formula
Formula mass
C14H14AuF5N2OS
550.30
Monoclinic
6.776(1)
17.691(4)
15.393(3)
90.00
114.25(3)
90.00
1682.6(6)
100(2)
P21/c
4
9242
3191
0.0340
0.0278
0.0585
0.0370
C27H26AuN4O3P
682.45
Monoclinic
9.322(2)
15.499(3)
17.446(3)
90.00
96.825(3)
90.00
2502.7(8)
100(2)
P21/c
4
13604
4946
0.0269
0.0254
0.0568
0.0332
C26H23AuN3O3PS
685.48
Triclinic
8.1497(7)
9.462(1)
C72H71Au3F9N6O10P3S6
C41H64Au2Cl2N12O6
1285.88
Triclinic
2227.52
Trigonal
35.318(5)
35.318(5)
11.178(2)
90
90
120
12075(3)
100(2)
¯
R3
Crystal system
˚
a/A
9.109(1)
˚
b/A
10.968(2)
12.293(2)
86.931(2)
85.686(2)
82.015(2)
1211.6(3)
100(2)
˚
c/A
17.913(2)
86.292(2)
80.051(2)
64.497(2)
1227.9(2)
100(2)
a (◦)
b (◦)
g (◦)
3
˚
Unit cell volume/A
T/K
Space group
¯
¯
P1
P1
No. of formula units per unit cell, Z
No. of reflections measured
No. of independent reflections
Rint
2
2
1
11163
4614
22365
5126
12702
4929
0.0505
0.0445
0.0839
0.0574
0.0897
1.036
0.0550
0.0343
0.0713
0.0515
0.0768
1.032
0.0294
0.0265
0.0646
0.0274
0.0652
1.114
a
Final R1 values (I > 2s(I))
b
Final wR2 values (I > 2s(I))
a
Final R1 values (all data)
b
Final wR2 values (all data)
0.0620
0.972
0.0610
1.081
Goodness of fit
a R1 = R[ꢀFo| - |Fcꢀ/R|Fo| b wR2 = {R[w(Fo - Fc2)2]/R[w(Fo2)2]}
2
1/2
Windows, with the displacement ellipsoids at 50% probability
level.
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We thank the NRF (National Research Foundation of South
Africa), CANSA (the Cancer Association of South Africa) and
the Alexander Von Humboldt Foundation (HGR and SC) for
financial support.
1482 | Dalton Trans., 2011, 40, 1471–1483
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The Royal Society of Chemistry 2011
©

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