Study of the different behaviour of thiazolin and thiazin indazole derivatives with palladium(II) acetate

Article abstract of DOI:10.1016/j.jorganchem.2011.11.034

The study of the reactivity of the ligands 2-(indazol-1-yl)-2-thiazoline (1) and 2-(indazol-1-yl)-1,3-thiazine (2) with palladium(II) acetate has allowed the isolation of different compounds. For the thiazolin indazole derivative (1) a cyclopalladated compound: (μ-OAc)₂[Pd(k²-C,N-TnInA)] ₂ (1a) with a bidentate [C(sp²,phenyl),N]^- ligand and a central "Pd(μ-OAc)₂Pd" unit was obtained. Treatment of the dimeric compound 1a with sodium acetylacetonate produced the mononuclear compound [Pd(k²-O,O′-acac)(k²-C,N-TnInA) ] (1c). The reaction of 1a with LiCl followed by the addition of PPh₃ gave the compound [PdCl(PPh₃)(k²-C,N-TnInA)] (1e) where the acetate groups were replaced by Cl^- and PPh₃ ligands, and with the PPh₃ in a cis-arrangement to the metallated carbon atom. The solid-state structure of 1e was determined by single-crystal X-ray diffraction methods. The reaction of 2 with palladium(II) acetate produced, in contrast to ligand 1, the complex cis-[Pd(OAc)₂(k²-N, N′-TzIn)] (2a) with a bidentate [N,N′] ligand. Compound 2a reacted with LiCl giving cis-[PdCl₂(k²-N,N′-TzIn)] (2b), where the acetate groups were exchanged by chloride ligands. DFT calculations suggest that the most favoured compound obtained from the reaction between 1 and palladium(II) acetate should be the cyclopalladated one, while for 2 the formation of the [N,N′] coordinated complex is less unfavoured.

Full text of DOI:10.1016/j.jorganchem.2011.11.034

Journal of Organometallic Chemistry 701 (2012) 36e42
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Study of the different behaviour of thiazolin and thiazin indazole derivatives
with palladium(II) acetate
,
a
b
c
c
Amparo Caubet a , Ramon Bosque , Elies Molins , Fernando J. Barros , Francisco Luna
*
a Departament de Química Inorgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
b Institut de Ciència de Materials de Barcelona (ICMAB-CSIC), Campus de la Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
c Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Extremadura, Av. de Elvas s/n, 06071 Badajoz, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The study of the reactivity of the ligands 2-(indazol-1-yl)-2-thiazoline (1) and 2-(indazol-1-yl)-1,3-
thiazine (2) with palladium(II) acetate has allowed the isolation of different compounds. For the thia-
Received 19 October 2011
Received in revised form
23 November 2011
zolin indazole derivative (1)
a
cyclopalladated compound:
-OAc)2Pd” unit was obtained. Treatment of the
(m
-OAc)2[Pd(k2-C,N-TnInA)]2 (1a) with
a bidentate [C(sp2,phenyl),N]ꢀ ligand and a central “Pd(
m
Accepted 24 November 2011
dimeric compound 1a with sodium acetylacetonate produced the mononuclear compound [Pd(k2-O,O0-
acac)(k2-C,N-TnInA)] (1c). The reaction of 1a with LiCl followed by the addition of PPh3 gave the
compound [PdCl(PPh3)(k2-C,N-TnInA)] (1e) where the acetate groups were replaced by Clꢀ and PPh3
ligands, and with the PPh3 in a cis-arrangement to the metallated carbon atom. The solid-state structure
of 1e was determined by single-crystal X-ray diffraction methods. The reaction of 2 with palladium(II)
acetate produced, in contrast to ligand 1, the complex cis-[Pd(OAc)2(k2-N,N0-TzIn)] (2a) with a bidentate
[N,N0] ligand. Compound 2a reacted with LiCl giving cis-[PdCl2(k2-N,N0-TzIn)] (2b), where the acetate
groups were exchanged by chloride ligands. DFT calculations suggest that the most favoured compound
obtained from the reaction between 1 and palladium(II) acetate should be the cyclopalladated one, while
for 2 the formation of the [N,N0] coordinated complex is less unfavoured.
Keywords:
Palladium(II)
Cyclopalladation
Thiazine
Indazole
Thiazoline
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
oxide receptor, HIV protease inhibition, anticancer and anti-
inflammatory activities [5].
Heterocyclic compounds represent a very important class of
molecules that find a number of applications as pharmaceuticals,
agrochemicals, fine and bulk chemicals as well as ligands for
catalysis [1]. Among the different heterocycles thiazoline, thiazine
and indazole have attracted a great deal of attention from synthetic
and medicinal chemists over the last 20 years.
The thiazoline ring is present in many biologically active prod-
ucts, including natural [2] and synthetic products. Some thiazoline-
containing compounds exhibit anti HIV-1, antimitotic, and biolu-
minescent activities, and have recently found applications as
building blocks in pharmaceutical drug discovery [3]. On the other
hand, thiazines derivatives present antitumoral, antihistaminic,
anti-inflammatory, analgesic and antibiotic properties [4]. Besides,
the range of pharmacological effects of indazole derivatives
includes among others DNA intercalating, activation of the nitric
In some cases, the structural and/or biological properties of
these ligands can be modified when they coordinate a metal ion
[6a].
Indazole and its derivatives may exhibit different binding modes
towards a metal ion. Their coordination chemistry has been the
subject of several investigations in the last years [6]. In particular,
Co(II), Zn(II) and Cd(II) complexes with the ligands 2-(indazol-1-
yl)-2-thiazoline (TnInA) (1) and 2-(indazol-1-yl)-1,3-thiazine
(TzIn) (2) (Fig. 1) have been synthesized [7]. In these compounds,
the ligands are bonded to the metal ions through the indazole and
thiazoline or thiazine (for 1 and 2, respectively) nitrogen atoms,
acting as bidentate groups. In addition to the N donors, these
ligands can coordinate also via the S atoms and may undergo the
activation of the
s(CeH) bond of the phenyl ring generating
cyclometallated compounds.
The most common palladacycles are derived from tertiary
amines and imines and are usually five- or less commonly six-
membered rings. The factors that govern metallation appear to
depend on many parameters, including the hybridization of the
palladated carbon atom, the type and structural characteristics of
* Corresponding author. Tel.: þ34 934037057: fax: þ34 934907725.
E-mail address: amparo.caubet@qi.ub.es (A. Caubet).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.11.034

A. Caubet et al. / Journal of Organometallic Chemistry 701 (2012) 36e42
37
significant separation (142 cmꢀ1) suggested, according to the
bibliography [9], that the AcOꢀ behaved as a [O,O0] bridging
ligand.
It is well known that dimeric cyclopalladated complexes with
acetate groups as bridging ligands may exhibit different isomeric
forms [10]. In these isomers, the two halves of the molecule may be
in a cis- or trans-arrangement. It has been reported that for the
trans-isomers, the resonance of the methyl groups of the bridging
ligands, in the 1H NMR spectra, appears as one singlet; However,
this signal splits into two singlets for the cis-isomer. In spite of the
low solubility of compound 1a in most usual solvents, its 1H NMR
spectrum could be recorded in DMSO-d6. It showed only one singlet
(at 2.08 ppm), suggesting that in 1a the two halves are in a trans
arrangement.
Fig. 1. Structural formulae of the ligands 2-(indazol-1-yl)-2-thiazoline (TnInA) (1)
(n ¼ 1) and 2-(indazol-1-yl)-1,3-thiazine (TzIn) (2) (n ¼ 2).
the ligand, and the palladium source, which ultimately determines
kinetic and thermodynamic preferences for palladation [8]. In the
present paper, we report on the study of the reaction of Pd(OAc)2
with 1 and 2 (which only differ in a CH2 unit) that has lead to PdII
complexes in which L adopts different binding modes, under
identical experimental conditions.
Acetato-bridged cyclopalladated dimers present
a folded
structure (commonly known as open-book structure), in solution as
well as in the solid-state [11]. On this basis we assumed that in 1a
the relative orientation of the acetato ligands corresponds to the
open-book type, with a C2 symmetry. The absence in the spectrum
0
of the signal ascribed to the proton H7 and the high-field shift of
2. Results and discussion
the resonances arising from the aromatic protons of the indazole
ring when compared with the free ligand 1 are consistent with the
metallation of the phenyl ring on position 70. It was not possible to
record the due to the low solubility of the complex.
2.1. Synthesis and characterization of the complexes
Treatment of ligands 2-(indazol-1-yl)-2-thiazoline (1) and 2-
(indazol-1-yl)-1,3-thiazine (2) with an equimolar amount of
Pd(OAc)2 in a mixture of glacial acetic acid and acetic anhydride
(9:1) under reflux for 2 h gave different compounds for ligands 1
and 2, respectively.
When this cyclopalladated complex reacted with py-d5 (in an
NMR scale), Na(acac) or LiCl followed by the addition of PPh3
(Scheme 1), more soluble products were obtained that allow
a better characterization of the starting complex. The addition of an
excess of deuterated pyridine to a CDCl3 suspension of 1a produced
a colourless solution indicating the formation of the corresponding
mononuclear cyclopalladated compound (1b). The deuterated
pyridine was located in a cis position relative to the palladated
carbon [12], which is inferred by the high-field shift of the aromatic
proton in the adjacent position to the palladated carbon, this effect
being caused by the pyridine ring.
The reaction of 1 with Pd(OAc)2 produced a yellow compound
(1a) (Scheme 1). Characterization data of 1a (Section 4) were
consistent with those expected for a cyclopalladated complex: (m-
OAc)2[Pd(k2-C,N-TnInA)]2 that arises from the metallation of the
indazole phenyl ring. The infrared spectrum of 1a showed two
bands due to the symmetric and asymmetric stretchings of the
carboxylato groups at 1580 and 1447 cmꢀ1, respectively. Their
Scheme 1. Synthesis of palladium compounds of the ligand 2-(indazol-1-yl)-2-thiazoline (TnInA) (1).

38
A. Caubet et al. / Journal of Organometallic Chemistry 701 (2012) 36e42
dimensional NMR studies. Elemental analyses were consistent
with the proposed formulae. The IR spectrum showed the typical
bands due to the coordinated PPh3 ligand [9,13] which was
observed as a singlet at 31.05 ppm in the 31P{1H} NMR spectrum.
Besides, in the 13C{1H} NMR spectrum the signal ascribed to the
0
metallated carbon (C7 ) appeared as a doublet due to the phos-
phorus coupling. These results are indicative of a cis-arrangement
of the phosphorus and the metallated carbon.
The structure of compound 1e was established by single-
crystal X-ray diffraction study. Yellow crystals were obtained by
slow evaporation of the solvent of a CH2Cl2 solution of 1e. The
structure of this compound agrees with the palladation of the 70
position of the indazole ring. Thus, the palladium atom is bound to
a chloride atom, the phosphorus of a PPh3 ligand, the N1 of the
thiazoline and the C10 of the indazole ring, confirming a [Csp2,
N]ꢀ binding mode of the ligand (Fig. 2). The palladium is in
a slightly distorted square-planar environment (torsion angle
C9eN1eCl1eP1 ¼ 6.9ꢁ).
The PdeN1 bond length [2.103(5) Å] is longer than the single
bond predicted value of 2.011 Å, and reflects the trans effect of the
phosphorous atom [14]. The PdeC9, PdeP and PdeCl bond
distances [2.027(6), 2.267(2) and 2.381(2) Å, respectively] fall in the
range reported for related palladacycles containing bidentate [Csp2,
N]ꢀ ligands [15]. The value of the C9ePdeP1 angle [92.5(2)ꢁ]
confirms a cis-arrangement between the metallated carbon and the
phosphine ligand. The angles between adjacent atoms in the
coordination sphere of palladium(II) lie in the range 88.4(2)ꢁe
92.5(2)ꢁ, the largest corresponding to the C9ePd1eP1 angle.
The six-membered palladacycle adopts a pseudo-boat confor-
mation with the palladium and the N2 atoms deviating by 0.665
and 0.160 Å, respectively, from the plane formed by N1, C1, C10
and C9.
Fig. 2. ORTEP plot of the crystal structure of the compound [PdCl(PPh3)(k2-C,N-
TnInA)] (1e). Selected bond lengths (in Å) and angles (in ꢁ): Pd1eC10, 2.027(6);
Pd1eN1, 2.103(5); Pd1eCl1, 2.381(2); Pd1eP1, 2.267(2); C1eN1, 1.279(9); C1eN2,
1.34(1); C1eS1, 1.755(7); C2eS1, 1.773(9); C3eN1, 1.472(9); C4eN3, 1.30(1); C10eN2,
1.37(1); C9ePd1eN1, 88.7(2); C9ePd1eP1, 92.5(2); N1ePd1eCl1, 88.4(2);
P1ePd1eCl1, 90.82(6), C3eN1ePd1, 122.9(4); C1eN1eC3, 111.3(6); C1eN1ePd1,
125.6(5); C1eN2eN3, 119.1(6); C10eN2eN3, 112.0(6); C11eP1ePd1, 117.8(2);
C23eP1ePd1, 117.2(2).
The action of sodium acetylacetonate to an acetone suspension
of 1a produced a yellow solution which gave, after concentration
followed by SiO2 column chromatography [Pd(k2-O,O0-acac)(k2-
C,N-TnInA)] (1c) (Scheme 1). Characterization data (Section 4)
agreed with the proposed formula. The resonances of the methyl
protons of the acac ligand (Mea and Meb) appeared as two singlets
at about 2 ppm, and the analysis of the 1D NOESY spectrum allowed
the assignation of the peaks (2.13 and 2.03 ppm, respectively).
A metathesis reaction between 1a and LiCl yielded the expected
In contrast with the results obtained with 1, when the ligand 2
was reacted with Pd(OAc)2 the coordination complex cis-
[Pd(OAc)2(k2-N,N0-TzIn)] (2a) (Scheme 2) is obtained exclusively. In
this product, ligand 2 acts as a [N,N0] bidentate group. Elemental
analyses were consistent with the proposed formula. The infrared
spectrum of 2a showed the typical two bands ascribed to the
symmetric and asymmetric stretchings of the carboxylato groups at
1586 and 1408 cmꢀ1, respectively. The separation between these
two absorption bands (178 cmꢀ1) suggested, according to the
bibliography [9], that the acetate behaved as a monodentate ligand.
chloro-bridged cyclopalladated dimer (m
-Cl)2[Pd(k2-C,N-TnInA)]2
(1d). Compound 1d was characterized directly by 1H and 13C NMR
in DMSO-d6 solution that contained an excess of LiCl and
compound 1a. The most0relevant features were a low-field shift of
the resonance of the H6 proton of the ligand, the absence of the
signal of coordinated acetate (2.08 ppm) and the presence of the
signal corresponding to free acetate (1.69 ppm). Bridge-splitting
reaction of the cyclopalladated dimer 1d with PPh3 produced
a yellow precipitate of mononuclear derivative [PdCl(PPh3)(k2-C,N-
TnInA)] (1e) (Scheme 1). This compound was obtained on
a preparative scale and isolated. Compound 1e was characterized
by elemental analyses, IR and 1H, 13C{1H} and 31P{1H} and two-
The 1H NMR spectrum of 2a showed a doublet at 8.06 ppm due to
0
the H7 proton, thus indicating that metallation was not occurring.
The resonances of the methyl protons of the acetate ligand (Mea
and Meb) appeared as a two singlets at about 2 ppm, and the
analysis of the 1D NOESY spectrum allowed their assignment (2.12
and 2.06 ppm, respectively).
Scheme 2. Synthesis of palladium compounds of the ligand 2-(indazol-1-yl)-1,3-thiazine (TzIn) (2).

A. Caubet et al. / Journal of Organometallic Chemistry 701 (2012) 36e42
39
Fig. 3. Possible compounds that may obtained by reaction of palladium acetate with
TnInA, this ligand acting as a bidentate one.
Fig. 4. Hypothetical compounds where the [Pd(AcO)3]ꢀ moiety is bonded to the
indazole (Nind) or to the dihydrothiazole nitrogen (Ntz) in TnInA.
Compound 2a reacted with LiCl to give cis-[PdCl2(k2-N,N0-
TzIn)2] (2b), with exchange of the acetate groups by chloride
ligands, which has been fully characterized (see Section 4). This
complex can also be obtained with higher yield by direct reaction of
ligand 2 with K2[PdCl4]. The characterization data confirmed that
the two compounds were identical; in both cases, the ligand
cyclometallation is not observed.
isomer, the energy difference with [N,N] decreases from 36 to
16 kcal/mol for TnInA, and from 32 to 11 kcal/mol for TzIn.
The accepted cyclopalladation mechanism involves the coordi-
nation of palladium to the nitrogen atom and subsequently the
activation of the CeH bond [8]. Moreover, the greater stability of
the N-bonded complexes compared to the S bonded isomers
(Table 1) suggests that the first step should be the coordination of
the palladium to one of the nitrogen atoms. In order to discern
which nitrogen is more prone to bind to the palladium we have
2.2. Theoretical calculations
calculated the relative energies of the complexes TnInA-Nind
,
In order to study the regioselectivity of these reactions, we have
performed a theoretical study using density functional theory. The
reaction of the ligands (TnInA or TzIn) with palladium acetate may,
in principle, yield four different complexes forming a chelate; as an
example, the TnInA derivatives are shown in Fig. 3. Two of them
{[N,N] and [S,N]} are neutral; while the other two, that arise from
a cyclometallation reaction {[C,N] and [C,S]} are anionic. We have
calculated the relative energies corresponding to the formation of
the four TnInA and the four TzIn derivatives, both in vacuum and in
acetic acid. For each series, the energy of the [N,N] system has been
taken as the reference; the results are shown in Table 1. It must be
noted that the formation of the cyclometallated complexes [C,N]
and [C,S] implies also the protonation of an acetate anion to give
acetic acid. In both TnInA and TzIn, the [C,N] cyclopalladated
complex is the most energetically favoured, and the relative order
of energies is [C,N] < [C,S] < [N,N] < [N,S]. The inclusion of solvent
effects results in a destabilization of the cyclopalladated complexes,
mainly [C,S], with respect to [N,N], as well as a small destabilization
of the [N,S] isomer. Thus, while [C,N] is again the most stable
TnInA-Ntz, TzIn-Nind and TzIn-Ntz, where the [Pd(OAc)3]ꢀ moiety is
bonded to the indazole (Nind) or dihydrothiazole (in TnInA)/dihy-
drothiazine (in TzIn) nitrogen (Ntz) (Fig. 4). The results of the
calculations, both in vacuum and in acetic acid, are shown in
Table 2.
In the case of TnInA, the most stable isomer is the one with the
palladium coordinated to the dihydrothiazole nitrogen, with the
indazole coordinated isomer is 6.62 kcal/mol higher in energy; the
addition of solvent effects lowers the energy difference to 4.44 kcal/
mol. The nitrogen atoms in both rings are in a trans arrangement;
for this reason, the molecule is oriented in such a way that the
palladium atom is directed to the CeH bond that should be acti-
vated in order to yield the cyclopalladated complex, which is the
most stable.
On the other hand, the situation with TzIn is less straightfor-
ward. Thus, according to Table 2, although the isomer with the
palladium coordinated to the dihydrothiazine ring is again the most
stable, the complex with the metal bound to the indazole nitrogen
is only 0.30 kcal/mol higher in energy (0.22 kcal/mol in solution),
Table 1
Table 2
Relative energies corresponding to the formation of the four TnInA and the four TzIn
derivatives discussed in the text, in vacuum and in acetic acid (kcal/mol).
Relative energies (in kcal/mol) of the different modes of coordination (indazole
nitrogen vs. dihydrothiazole/dihydrothiazine nitrogen) for the [PdL(AcO)3]ꢀ
complexes, where L ¼ TnInA or TzIn. Values in solution are shown in parentheses.
TnInA
TzIn
TnInA
TzIn
Coordination mode
Vacuum
Solution
Vacuum
Solution
[N,N]
arrangement
Nind
coordinated
Ntz
Nind
coordinated
Ntz
coordinated
[N,N]
[N,S]
[C,S]
[C,N]
0.0a
5.99
0.0a
7.45
0.0a
3.56
0.0a
6.19
coordinated
ꢀ25.76
ꢀ3.79
ꢀ22.99
ꢀ0.58
cis
trans
7.20 (4.71)
6.62 (4.44)
2.23 (1.69)
3.20 (1.49)
0.30 (0.22)
6.34 (5.27)
ꢀ35.95
ꢀ16.07
ꢀ31.71
ꢀ10.93
0.00a (0.00a)
0.00a (0.00a)
a
a
Values taken as reference.
Values taken as reference.

40
A. Caubet et al. / Journal of Organometallic Chemistry 701 (2012) 36e42
Table 3
4. Experimental
Crystal data details of the refinement of the crystal structure of compound
[PdCl(PPh3)(k2-C,N-TnInA)] (1e).
4.1. Materials and methods
Crystal size (mm3)
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
0.36 ꢂ 0.24 ꢂ 0.16
28H23ClN3PPdS
606.37
C
Triphenylphosphine, Pd(OAc)2, LiCl and sodium acetylacetonate
were used as purchased from commercial sources. Solvents were
distilled and dried before use [16].
The ligands 2-(indazol-1-yl)-2-thiazoline (TnInA) (1) and 2-
(indazol-1-yl)-1,3-thiazine (TzIn) (2) were synthesized according to
a method described previously [7b and 7c respectively].
Elemental analyses were carried out at the Serveis Científico
Tècnics (Universitat de Barcelona). Infrared spectra were obtained
with a Nicolet 400FTIR using KBr pellets. 1H, 13C{1H}, 1H NOESY and
two-dimensional {1He13C} HSQC, HMBC and {1He1H} NOESY NMR
spectra were recorded with a Mercury-400 MHz spectrometer at
293(2)
0.71073
Monoclinic
P 21/c
10.5020(19)
16.235(2)
14.859(4)
90.35(2)
2533.4(9)
4
1.590
1.007
b (Å)
c (Å)
b
(ꢁ)
V (Å3)
Z
Dcalc (mg ꢂ mꢀ3
)
(mmꢀ1
)
room temperature. The chemical shift values (d) are given in ppm.
m
F(000)
Q
Index ranges
Reflections collected
Independent reflections
1224
1.86e25.98
The solvents for the NMR experiments were DMSO-d6 or CDCl3
(99.9%) and SiMe4 was used as reference and they are indicated in
each case.
range for data collection (ꢁ)
ꢀ12 ꢃ h ꢃ 12, 0 ꢃ k ꢃ 20, 0 ꢃ l ꢃ 18
5436
5436
4.2. Synthesis of the TnInA (1) compounds
Completeness to
Refinement method
Q
100.0%
Full-matrix least-squares on F2
4960/0/316
4.2.1. (m
-OAc)2[Pd(k2-C,N-TnInA)]2 (1a)
Data/restraints/parameters
Goodness-of-fit on F2
0.965
Pd(OAc)2 (0.110 g, 0.49 mmol) and a stoichiometric amount of 1
(0.100 g) were added to 20 mL of a mixture of glacial acetic and
acetic anhydride (9:1). The mixture was heated under reflux for 2 h.
After this period the resulting hot solution was filtered through
celite to remove the black palladium formed. The brown solution
was concentrated under reduced pressure to about 5 mL. The
yellow precipitate formed was filtered off, washed with methanol
and air dried. Yield: 32%. Characterization data: Anal. Calc. for
C24H22O4N6S2Pd2: C, 39.20; H, 3.02; N, 11.43; S, 8.72. Found: C, 39.2;
Final R indices [I > 2
R indices (all data)
s
(I)]
R1 ¼ 0.0559, wR2 ¼ 0.0963
R1 ¼ 0.1395, wR2 ¼ 0.1117
0.500 and ꢀ0.636
Largest diff. peak and hole (e Åꢀ3
)
well inside the error of the calculations. Moreover, the isomer with
the indazole ring coordinated and the nitrogen atoms with cis
orientation, that would yield the [N,N] isomer, is only 1.49 kcal/mol
higher in energy in solution. Therefore, our calculations do not
show a clear trend in the stability of the TzIn derivatives, although
the formation of the TzIn-Nind isomer is less disfavoured than in the
case of TnInA. The coordination of the palladium to the indazole
nitrogen prevents the formation of the cyclometallated ligand
because the carbon that should undergo the metallation is in the
same indazole moiety as the nitrogen coordinated to the metal.
Thus, upon a rotation of the dihydrothiazine ring, the [N,N] isomer
could be formed.
H, 3.0; N, 11.3; S, 8.6. IR data (KBr, cmꢀ1): 1580 (nas COOꢀ) and 1447
0
(
nsym COOꢀ). 1H NMR (DMSO-d6):0 d ¼ 8.38 (s, 1H, H3 ), 7.53 (d, 1H,
0
0
J ¼ 7.6, H4 ), 7.21 (d, 1H, J ¼ 7.2, H6 ), 7.16 (t, 1H, J ¼ 7.6, H5 ), 4.38 (br
m, 2H, H3), 3.75 (br m, 2H, H2) and 2.08 [s, 3H, Me (OAc)].
4.2.2. [Pd(OAc)(py-d5)(k2-C,N-TnInA)] (1b)
This product was prepared in an NMR scale and characterized in
solution by 1H NMR. 10 mg of the dimeric compound 1a were
introduced in an NMR tube, and then 0.7 mL of CDCl3 were added.
The resulting suspension was then treated with one drop of
deuterated pyridine (py-d5) and shaked for a few seconds. This
3. Conclusions
produced a colourless solution that contained the desired complex.
0
The reaction of 2-(indazol-1-yl)-2-thiazoline (1) with palladiu-
Characterization data: 1H NMR:
d
¼ 8.15 (s, 1H, H3 ), 7.40 (d, 1H,
0
0
0
m(II) acetate has allowed the isolation of a new cyclopalladated
J ¼ 7.6, H4 ), 6.15 (d, 1H, J ¼ 7,2, H6 ), 6.88 (t, 1H, J ¼ 7.6, H5 ), 4.61 (t,
compound: (
m
-OAc)2[Pd(k2-C,N-TnInA)]2 (1a). This compound is
2H, J ¼ 8.0, H3), 3.56 (t, 2H, J ¼ 8.0, H2) and 1.88 [s, 3H, Me (OAc)]. 130C
0
easily transformed into the dimeric derivative (
m
-Cl)2[Pd(k2-C,N-
{1H} NMR
d
¼ 176.2 [eCO2 (OAc)], 159.1 (C5), 142.5 (C3 ), 138.8 (C9 ),
0
0
0
0
0
TnInA)]2 (1d) or the mononuclear complexes [Pd(k2-O,O0-acac)(k2-
135.9 (C6 ), 124.0 (C5 ), 122.0 (C8 ), 117.7 (C4 ), 117.1 (C7 ), 60.3 (C3),
31.9 (C2) and 24.3 [Me (OAc)].
C,N-TnInA)] (1c) and [PdCl(PPh3)(k2-C,N-TnInA)] (1e).
On the other hand when the reaction was carried out under the
same conditions but with the ligand TzIn, which only differs in that
the heterocyclic ring [N,S] contains one additional methylene
group, the dinuclear cyclometallated compound was not obtained
but instead a mononuclear complex cis-[Pd(OAc)2(k2-N,N0-TzIn)]
(2a) was produced, in which the acetate groups do not act as
bridging ligands to the palladium atoms. The calculations for ligand
TzIn are not conclusive but show that this ligand has a greater
tendency to coordinate through the nitrogen atom of the indazole
ring than in the case of ligand TnInA, and therefore more likely to
act as a bidentate ligand [N,N0].
4.2.3. [Pd(k2-O,O0-acac)(k2-C,N-TnInA)] (1c)
A suspension formed by the complex 1a [42 mg (0.057 mmol)],
16 mg of Na(acac) (0.11 mmol) and 15 mL of acetone was stirred for
18 h at room temperature. The resulting solution was concentrated
under vacuum and the residue was passed through a silica gel
column. Elution with CH2Cl2 produced the release of a yellow band
which was collected and concentrated to dryness on a rotary
evaporator. The solid formed was dried in vacuum. Yield: 77%.
Characterization data: Anal. Calc. for C15H15O2N3SPd: C, 44.18; H,
3.70; N, 10.30; S, 7.86. Found: C, 44.5; H, 3.6; N, 10.2; S, 7.6. IR data
(KBr, cmꢀ1): 1588 (nas COOꢀ) and 1447 (nsym COOꢀ). 1H NMR
Finally, due to the applications in pharmaceutical research of
this family of heterocycles ligands, the new compounds presented
in this work appear to be excellent candidates for further studies in
this field.
0
0
(CDCl3): d0 ¼ 8.16 (s, 1H, H3 ), 7.93 (d, 1H, J ¼ 7.6, H6 ), 7.44 (d, 1H,
0
J ¼ 7.6, H4 ), 7,25 (t, 1H, J ¼ 7.6, H5 ), 5.43 [s, 1H, pCH(acac)], 4.72 (t,
2H, J ¼ 8.0, H3), 3.61 (t, 2H, J ¼ 8.0, H2), 2.13 (s, 3H, Mea) and 2.03 (s,

A. Caubet et al. / Journal of Organometallic Chemistry 701 (2012) 36e42
41
3H, Meb). 13C{1H} NMR
d
¼ 187.9 and 186.7 0[pCO (acac)], 158.8 (C50),
under reflux for 2 h. After this period the orange solid formed was
filtered out, washed with ethanol and air dried. Yield: 75%.
0
0
0
0
142.6 (C3 ), 139.0 (C9 ), 132.5 (C6 ), 123.6 (C5 ), 121.8 (C8 ), 117.7 (C4 ),
0
116.2 (C7 ), 59.1 (C3), 32.2 (C2), 28.0 (Meb) and 27.8 (Mea).
4.3.2.2. Method (b). To a solution containing 50 mg (0.011 mmol) of
2a and 20 mL of ethanol, 90 mg (0.022 mmol) of LiCl were added.
The resulting mixture was stirred at 298 K for 2 h. After this period
the orange solid formed was filtered out, washed with ethanol and
air dried. Yield: 57%.
4.2.4. (m
-Cl)2[Pd(k2-C,N-TnInA)]2 (1d)
This product was prepared in an NMR scale and characterized in
solution by 1H and 13C{1H} NMR. 2 mg of LiCl were added to
a suspension of 10 mg of the dimeric compound 1a in 0.7 mL of
DMSO-d6 in an NMR tube and shaked for a0 few seconds. Charac-
terization data: 1H NMR:
d
¼ 8.39 (s, 1H, H3 ), 8.03 (d, 1H, J ¼ 7.2,
4.3.2.3. Characterization data. Anal. Calc. for C11H11Cl2N3SPd$-
0
0
0
H6 ), 7.40 (d, 1H, J ¼ 7.6, H4 ), 7.00 (t, 1H, J ¼ 7.6, H5 ), 4.70 (br m, 2H,
0.25H2O: C, 33.10; H, 2.90; N, 10.50; S, 8.0. Found: C, 33.5; H, 2.6; N,
0
H3), 3.52 (br m, 2H, H2) and 1.69 [s, 3H, Me (free OAc)]. 13C{1H} NMR
10.5; S, 7.8. 1H NMR (DMSO-d6):
d
¼ 8.90 (s, 1H, H3 ), 8.25 (d, 1H,
0
0
0
0
0
d
¼ 176.4 [eCO2 (free OAc)], 158.4 (C5), 143.8 (C3 ), 143.7 (C9 ), 139.7
J ¼ 8.8, H7 ), 8.10 (d, 1H, J ¼ 8.8, H4 ), 7.85 (t, 1H, J ¼ 7.6, H6 ), 7.55 (t,
0
0
0
0
0
0
(C6 ), 139.0 (C7 ), 124.2 (C5 ), 122.5 (C8 ), 118.0 (C4 ), 63.5 (C3), 32.5
(C2) and 25.9 [Me (free OAc)].
1H, J ¼ 7.6, H5 ), 3.91 (t, 2H, J ¼ 5.6, H4), 3.50 (t, 2H, J ¼ 5.6, H2) and
0
2.11 (br m, 2H, H3). 13C{1H} NMR
d
¼ 156.0 (C6)0, 142.2 (C3 ), 137.9
0
0
0
0
0
(C9 ), 133.2 (C6 ), 126.2 (C5 ), 125.0 (C4 ), 124.2 (C8 ), 112.5 (C7 ), 49.6
(C4), 27.6 (C2) and 21.3 (C3).
4.2.5. [PdCl(PPh3)(k2-C,N-TnInA)] (1e)
44 mg (0.06 mol) of 1a and LiCl (13 mg, 0.3 mmol) were sus-
pended in 20 mL of acetone. The resulting suspension was stirred
for 2 h at room temperature, and after this time triphenylphosphine
(32 mg, 0.2 mmol) was added. The mixture was left to react again
for 1 h at 298 K. The resulting suspension was concentrated under
vacuum and the residue was eluted through a silica gel column
chromatography. Elution with CH2Cl2 produced the release of
a yellow band which was collected and concentrated to dryness on
a rotary evaporator. The solid formed was dried in vacuum. Yield:
48%. Characterization data: Anal. Calc. for C28H23ClN3PPdS: C,
55.46; H, 3.82; N, 6.93; S, 5.29. Found: C, 55.5; H, 4.1; N, 7.0; S, 5.5. IR
4.4. X-ray structural characterization
A selected transparent colourless crystal of 1e was glued at the
end of a glass fibre and mounted on an EnrafeNonius CAD4
diffractometer, where the X-ray diffraction experiment was carried
out. Unit-cell parameters were determinated from automatic cen-
tring of 25 reflections and refined by least-squares method. A
summary of the crystal data obtained is shown in Table 3.
The structural resolution procedure was made using the WinGX
[17] package. Solving for structure factor phases was performed by
the SIR2004 program [18], and the full-matrix refinement by
SHELXL97 [19]. Non-H-atoms were refined anisotropically and H-
atoms were introduced in calculated positions and refined riding
on their parent atoms. A summary of the refinement parameters is
also shown in Table 3.
data (KBr, cmꢀ1): 1090 (PPh3 coordinated ligand). 1H NMR (CDCl3):
0
d
¼ 8.09 (s, 1H, H3 ), 7.30e7.48 (m, 15H, aromatic protons of the
0
0
PPH3 ligand), 7.14 (d,1H, J ¼ 8.0, H4 ), 6.81 (d,1H, J ¼ 8.0, H6 ), 6.39 (t,
0
1H, J ¼ 8.0, H5 ), 5.00 (t, 2H, J ¼ 8.0, H03) and 3.50 (t, 2H, J ¼ 8.0, H2).
0
0
13C0{1H} NMR d0 ¼ 160.3 (C50), 142.5 (C3 ), 141.0 (C6 ), 140.3 (C9 ), 124.7
0
(C8 ), 123.6 (C5 ), 122.9 (C7 ), 117.1 (C4 ), 61.9 (C3), and 32.7 (C2). 31P
{1H} NMR data:
d
¼ 31.05.
4.5. Calculation details
All DFT calculations were carried out with the Gaussian 03 [20]
package of programs using the B3LYP hybrid functional [21]. The
basis set was chosen as follows: for Pd LANL2DZ was used [22],
where an effective core potential was utilized to replace the 36
innermost. For carbon, hydrogen, oxygen, sulphur and nitrogen the
6-31G(d) basis including polarization functions for non-hydrogen
atoms [23] was used. Geometry optimizations and frequency
calculations were performed with no imposed symmetry restric-
tions. Solvent effects were calculated on the preoptimized geom-
etries using the C-PCM model [24].
4.3. Synthesis of the TzIn (2) compounds
4.3.1. Cis-[Pd(OAc)2(k2-N,N0-TzIn)] (2a)
Pd(OAc)2 (0.103 g, 0.46 mmol) and a stoichiometric amount of 2
(0.100 g) were added to 20 mL of a mixture of glacial acetic and
acetic anhydride (9:1). The mixture was heated under reflux for 2 h.
After this period the resulting hot solution was filtered through
celite to remove the black palladium formed. The brown solution
was then concentrated to dryness on a rotary evaporator giving
a brownish solid, that was collected and dried in vacuum. Yield:
56%. Characterization data: Anal. Calc. for C15H17O4N3SPd: C, 40.78;
H, 3.88; N, 9.51; S, 7.26. Found: C, 40.7; H, 4.3; N, 9.4; S, 7.2. IR data
(KBr, cmꢀ1): 1586 (nas COOꢀ) and 1408 (nsym COOꢀ). 1H NMR
Acknowledgements
Financial support from the Spanish Ministerio de Educación y
Ciencia (project CTQ2008-02064/BQU) is gratefully acknowledged.
0
0
(CDCl3): d 0¼ 8.32 (s, 1H, H3 ), 8.06 (d, 1H, J ¼ 8.5, H7 ), 7.83 (d, 1H,
0
0
J ¼ 8.4, H4 ), 7.68 (t, 1H, J ¼ 7.4, H6 ), 7.44 (t, 1H, J ¼ 7.6, H5 ), 3.78 (t,
2H, J ¼ 6.0, H4), 3.41 (t, 2H, J ¼ 6.0, H2), 2.21 (br m, 2H, H3), 2.12 [s,
Appendix A. Supplementary material
3H, Mea (OAc)a] and 2.06 [s, 3H, Meb (OAc)b]. 13C{1H} NMR d0¼ 179.2
0
and 178.8 [eCO2 (OAc)], 156.0 (C6), 143.0 (C3 ), 138.0 (C9 ), 132.4
CCDC 846925 contains 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.
0
0
0
0
0
(C6 ), 125.8 (C5 ), 124.5 (C8 ), 123.4 (C4 ), 112.5 (C7 ), 47.5 (C3), 26.9
(C2), 23.1 [Mea,b (OAc)a,b] and 20.6 (C3).
4.3.2. Cis-[PdCl2(k2-N,N-TzIn)2] (2b)
This product can be obtained by two different procedures using
either the ligand 2 or the coordination compound 2a.
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