Structure and properties of metal complexes of a pyridine based oxazolidinone synthesized by atmospheric CO2 fixation

Article abstract of DOI:10.1039/c3nj00990d

We present here the synthesis of a pyridine containing oxazolidinone, 3-(pyridin-2-ylmethyl)oxazolidin-2-one (L) through the fixation of atmospheric CO₂ and without any added base. L has been used to generate three metal complexes [Cu(L)_2<

Full text of DOI:10.1039/c3nj00990d

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Structure and properties of metal complexes of a
pyridine based oxazolidinone synthesized by
Cite this: New J. Chem., 2014,
atmospheric CO fixation†
3
8, 817
2
Amrita Sarkar, Sudipta Bhattacharyya, Suman Kr Dey, Subhendu Karmakar and
Arindam Mukherjee*
We present here the synthesis of a pyridine containing oxazolidinone, 3-(pyridin-2-ylmethyl)oxazolidin-
2
-one (L) through the fixation of atmospheric CO
2
and without any added base. L has been used to
] (2), and trans-[Pd(L) Cl ] (3).
generate three metal complexes [Cu(L) (ClO ] (1), trans-[Pt(L)(DMSO)Cl
2
4
)
2
2
2
2
Complexes 1–3 have been structurally characterized using single crystal X-ray diffraction and other
II
analytical techniques. The activity studies of the three metal complexes show that the Cu complex, 1, is
more cytotoxic against the MCF-7 cancer cell line (IC50 = 114 Æ 2 mM) as compared to a non-carcinogenic
II
mouse fibroblast (NIH 3T3) (IC50 = 198 Æ 1 mM). The Pt complex, 2, is the most toxic among the three
complexes against both human breast adenocarcinoma (MCF-7) (IC50 = 102 Æ 2 mM) and the human lung
II
adenocarcinoma epithelial cell line (A549) (IC50 = 198 Æ 2 mM), whereas the Pd complex, 3, is found to be
Received (in Montpellier, France)
3rd August 2013,
II
2
an effective first generation oxazolidinone based Pd catalyst, for the Suzuki–Miyaura cross coupling of aryl
Accepted 18th November 2013
halides and phenylboronic acids in aerobic conditions, both in a conventional heating method, as well as a
II
II
microwave method. The results show that although Pt and Cu were also complexed with oxazolidinone,
II
DOI: 10.1039/c3nj00990d
Pd seems to be the most likely choice of metal when it comes to C–C bond coupling via C–X bond
www.rsc.org/njc
activation.
Introduction
Oxazolidinone compounds are of high interest for their potential as
antimicrobial agents. Linezolid, the first oxazolidinone compound
to be approved for clinical use, shows excellent antimicrobial
activity against many important resistant pathogens. Eperezolid,
radezolid, posizolid, and torezolid are some of the oxazolidinone
class of compounds (Scheme 1), under clinical investigation,
that are potent against bacterial infections. Cycloserine, an
oxazolidinone derivative, is used for the treatment of tuberculosis
when one or more drugs fails to treat the disease.
Scheme 1 Structure of oxazolidinone based drugs.
Apart from being antimicrobial compounds, oxazolidinone
derivatives also are potential ligands from which to generate
metal complexes. Metal complexes of oxazolidinones are known diamination of alkenes
9
,10
11
or to generate MOFs mostly
1–3
and have been used in catalysis viz. the Diels–Alder reaction,
aldol reaction, Henry reaction, Mukaiyama–Michael reaction,
depending on the choice of metal and the coordination
environment rendered. Although oxazolidinone based metal
complexes have been used in catalysis, C–C bond coupling via
C–X bond activation has never been attempted with oxazolidinone
metal complexes. In addition, despite being of high therapeutic
interest, oxazolidinones metal complexes have not been effectively
probed as therapeutic agents (viz. antimicrobial or anticancer
4–6
7
8
Department of Chemical Sciences Indian Institute of Science Education & Research
Kolkata, Mohanpur Campus, P.O.-BCKV Main Campus, District-Nadia, 741252,
India. E-mail: a.mukherjee@iiserkol.ac.in; Fax: +91-033-25873118;
Tel: +91-033-25873121
†
Electronic supplementary information (ESI) available: Crystallographic data in
1
2–14
1
13
agents).
CIF, schematic representation of catalytic cycle, H-NMR, C-NMR data of products
in catalysis. CCDC 956432 (1) and 956433 (2). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3nj00990d
From a synthetic point of view, oxazolidinone compounds
can be obtained in various ways viz. using urea or epoxides,
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Scheme 2 Synthetic method of pyridine based oxazolidinone compounds
reported earlier and ligand L in this work.
Scheme 3 Representative scheme for syntheses of metal complexes 1–3.
1
5–19
II
II
along with amines,
or from ethanolamine by purging CO gas, (Scheme 3). Complexes 1 and 3, having Cu and Pd , react with
2
20
using the Mitsunobu reaction. There are also a few reports on the two mole equivalent of L, rendering complexes of the type ML
2
.
II
syntheses of oxazolidinones from amino alcohols with purging CO
gas and using electrophiles and bases.
2
Whereas, the Pt containing complex 2 was formed by reaction
However, the synthesis with only one mole equivalent of the oxazolidinone ligand, in
of oxazolidinone using air (which contains CO
) is not reported, spite of having two mole equivalents of ligand per metal ion in
although it should be possible, since air has a significant CO
the reaction solution. Once the composition became known we
content. In addition pyridine containing oxazolidinones are a rare tuned the stoichiometry accordingly, providing a cleaner reaction
21–25
2
2
26,27
find
and no synthesis of pyridine containing oxazolidinone has and a better yield for 2.
been reported through the fixation of atmospheric CO (Scheme 2).
2
If by using air, the atmospheric CO2 content could undergo
X-ray crystallographic study of complexes 1–3
reaction efficiently, then the lack of CO
would represent a more convenient way of fixing CO
2
pressurized cylinders
, through
The complexes 1–3 were characterized by single crystal X-ray
crystallography. Complex 1 (Fig. 1) crystallizes in the monoclinic
space group P2(1)/c, and 2 in the triclinic space group P1%. 3
2
organic synthesis. Our interest in pyridine based oxazolidinones
is due to their potential for metal chelation and possible use in
2
8–34
crystallized in the monoclinic space group P2(1). However, although
the crystal structure provides information about the structural
nature of complex 3, is not publishable, due to relatively poor
quality of the data. Single crystals suitable for X-ray crystallography
were grown by the slow evaporation of an acetonitrile–methanol
mixture (1 : 1) for the complex 1. For 2 (Fig. 2), layering a
dichloromethane solution with hexane gave yellow needle shaped
crystals, suitable for X-ray diffraction, whereas complex 3 gave
orange coloured, block shaped crystals on the slow evaporation of
an acetonitrile solution. The important crystallographic para-
meters for 1–3 and selected bond distances and angles of 1 and
therapeutics.
In our attempt to generate a pyridine based oxazolidinone,
we synthesized 3-(pyridin-2-ylmethyl)oxazolidin-2-one (L) in the
presence of SOCl (Scheme 2) using air (atmospheric CO ) and
2
2
without any added base. L is also a potential metal binder and
hence, three metal complexes of the formulae [Cu(L) (ClO
1), trans-[Pt(L)(DMSO)Cl ] (2), and trans-[Pd(L) Cl ] (3) were
2
4 2
) ]
(
2
2
2
synthesized, to probe the potential of the newly designed
pyridyl oxazolidinone ligand. Herein, we present the synthesis,
structure and activity of the above three metal complexes, along
with in vitro cytotoxicity studies against cancerous (MCF-7 and
A549) and non-cancerous mouse fibroblast (NIH 3T3) cell lines.
Our work shows how the oxazolidinone and metal ions (Cu,
Pt, Pd) influence each other’s chemistry, rendering the desired
properties to the resultant complexes. 1 and 2 show toxicity against
2
have been summarised in Table S1 (ESI†) and Table 1.
The copper complex 1 is ML type, with the N O coordina-
2
2 2
tion bearing two weak axial linkages (ca. 2.75 Å, Fig. 1), with two
II
cancer cell lines, whilst the Cu complex (1) is less toxic in the non-
carcinogenic NIH 3T3 cell line. The palladium complex (3) is found
to be a catalyst for the Suzuki–Miyaura coupling of aryl halides and
phenylboronic acids in aerobic conditions, both in a conventional
heating method as well as a microwave method. The results show
that a metal complex of an oxazolidinone has the potential as a C–C
bond cross coupling catalyst, or in therapeutics.
Results
Preparation of ligands and complexes
Fig. 1 Diagram of complex 1 with 50% probability thermal ellipsoids.
The three metal complexes synthesized with 3-(pyridin-2-ylmethyl)-
Hydrogen atoms have been omitted for clarity. Symmetry transformations
oxazolidin-2-one (L) bear different coordination environments used to generate equivalent atoms: A = Àx + 1, Ày, Àz + 2.
8
18 | New J. Chem., 2014, 38, 817--826
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Fig. 2 Diagram of 2 showing one of two independent molecules in the
asymmetric unit with 50% probability thermal ellipsoids. Hydrogen atoms
and solvents have been omitted for clarity.
Fig. 3 Lipophilicity of complexes 1–3 represented by a bar diagram
showing comparative log P values of 1–3 in octanol–water system, where
error bars in the graph represent the standard deviation in measurement.
Table 1 Selected bond distances (Å) and angles (1) of complexes 1–2
Table 2 Log P values of complexes 1–3 in octanol–water system
1
2
a
Compound
Log Po/w
Cu(1)–N(1)
Cu(1)–O(1)
Cu(1)–O(6)
1.987(2)
1.973(2)
2.75(2)
180
Pt(1)–N(1)
Pt(1)–S(1)
Pt(1)–Cl(1)
Pt(1)–Cl(2)
Pt(2)–N(3)
Pt(2)–S(2)
Pt(2)–Cl(3)
Pt(2)–Cl(4)
2.057(3)
2.2183(9)
2.3025(8)
2.2965(9)
2.049(3)
1
2
3
À0.37574 (1)
À0.45707 (2)
À1.40328 (2)
a
N(1)–Cu(1)–N(1A)a
O(1)–Cu(1)–O(1A)
O(1)–Cu(1)–N(1)a
O(1)–Cu(1)–N(1A)
N(1)–Cu(1)–O(6)
O(1)–Cu(1)–O(6)
a
180
The value in parentheses shows standard error. Experiments were
93.75(9)
86.25(9)
95.52(9)
107.66(8)
84.48(9)
72.34(8)
2.2182(8) carried out in triplicate.
2.3019(9)
2.3145(9)
178.16(8)
N(1)–Pt(1)–S(1)
N(1)–Pt(1)–Cl(1)
S(1)–Pt(1)–Cl(1)
N(1)–Pt(1)–Cl(2)
S(1)–Pt(1)–Cl(2)
Cl(1)–Pt(1)–Cl(2)
N(3)–Pt(2)–S(2)
N(3)–Pt(2)–Cl(3)
S(2)–Pt(2)–Cl(3)
N(3)–Pt(2)–Cl(4)
S(2)–Pt(2)–Cl(4)
Cl(3)–Pt(2)–Cl(4)
the logPo/w for the complexes 1–3. We found that all three
a
N(1A) –Cu(1)–O(6)
88.22(8)
90.66(3)
88.27(8)
92.97(3)
174.09(3)
179.13(8)
87.30(8)
92.14(3)
88.33(8)
92.26(3)
a
complexes are hydrophilic in nature and complex 3 is the most
hydrophilic among the three complexes. The lipophilicity order
is 1 > 2 > 3.
O(1A) –Cu(1)–O(6)
Cell cytotoxicity
The complexes 1–3 were tested in vitro against a human breast
adenocarcinoma cell line (MCF-7) and a human lung adeno-
175.23(3) carcinoma epithelial cell line (A549) as well as a mouse
embryonic fibroblast cell line (NIH 3T3) by the MTT assay,
where cisplatin was used as a standard in each 96 well plate.
The data show that the ligand L has an IC50 value greater than
a
A = Àx + 1, Ày, Àz + 2 for 1.
oxygen atoms of two perchlorate anions making the co-ordination 1000 mM in the MCF-7 cell line, so it was not probed in the A549
environment an elongated octahedral type (Fig. 1). Whereas, and NIH 3T3 cell lines. Among the three metal complexes, the
II
complex 2 showed the Pt to be in a trans geometry, with one trans-platinum complex 2 shows the highest cytotoxicity in the
II
L per molecule (Fig. 2). The trans-Pt in complex 2 is coordinated MCF-7 cell line (IC50 = 102 Æ 2 mM), whereas in the A549 cell
II
II
via the pyridine N. Unlike the Cu complex, the carbonyl oxygen is line, the IC50 is 198 Æ 2 mM. The IC of the Cu complex 1 in
50
II
À
not bound to Pt . There are two trans Cl ligands along with a MCF-7 is 114 Æ 2 mM and in A549 it is 455 Æ 3 mM, respectively.
II
DMSO, bound to the Pt centre via the sulphur atom. On the other In the MCF 7 cell line, the palladium complex 3 shows an IC50
II
hand complex 3 is also a trans complex of Pd , with two ligands 260 Æ 3 mM, but in the A549 cell line, it is 236 Æ 1 mM. In the
trans to each other and two chlorides as found from the crystallo- non-cancerous NIH 3T3 cell line, the copper complex 1 is less
graphic studies, but the structural details are not presented, here toxic, with an IC50 of 198 Æ 1 mM, as compared to the MCF-7
since the data obtained do not render a fully publishable structure. cancer cell line. The same is not true for the well known drug
cisplatin or the new synthons, complexes 2 and 3 reported here
Lipophilicity measurement
(
Table 3). The obtained data were plotted and fitted using
s
The partition coefficients between octanol and an aqueous GraphPad Prism 5 Ver 5.03 (Fig. S1–S3, ESI†). The IC50 values
buffer layer, to determine the lipophilicity of the three complexes are summarised in Table 3.
(
1–3), were calculated using the well known formula of log P =
Suzuki–Miyaura cross coupling catalyzed by palladium
complex (3)
Coct/C , where C was the concentration of the complex in the
organic layer and Caq was the concentration of the complex in
aq
oct
the phosphate buffer (20 mM) found through UV-visible spectro- The Suzuki–Miyaura coupling reactions between various aryl
scopy. The results (Fig. 3 and Table 2) show the lipophilicity, or halides and phenylboronic acid catalyzed by the complex 3 were
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Table 3 Cytotoxicity of ligand L and complexes 1–3 on MCF-7, A549 and
NIH 3T3 cell lines from three experimental trials with comparison to
cisplatin, carboplatin and cyclophosphamide
Table 5 Suzuki–Miyaura cross coupling between aryl halides and phenyl-
boronic acid with conventional heating method (80 1C)
a
Catalyst
loading (mol%) Time
Isolated
yield (%) TOF
a
b
IC50 (mM) Æ SD
Entry Aryl halide
1
Compounds
MCF-7
A549
NIH 3T3
0.2
0.2
0.2
1.0
0.5
0.5
0.5
20 min >99
1515
1000
1000
46
L
1
2
3
>1000
n.d.
n.d.
114 Æ 2
102 Æ 2
260 Æ 3
14 Æ 1
62.19
455 Æ 3
198 Æ 2
236 Æ 3
21 Æ 2
—
198 Æ 1
41 Æ 1
151 Æ 1
11 Æ 2
—
2
3
4
5
6
7
30 min >99
30 min >99
Cisplatin
Carboplatin
b
Cyclophosphamide
>3000
n.d.
>3000
a
SD = standard deviation; IC50 values were calculated by variable slope
s
3
2 h
1 h
1 h
92
97
99
model using GraphPad Prism 5 . 6 Â 10 cells per well were treated for
b
4
8 h with increasing concentrations of tested compounds. On drug
35
exposure of 72 h.
194
198
380
carried out both with a conventional heating method, as well as
a microwave method. All the reactions were carried out in
atmospheric conditions, as the palladium catalyst is stable in
air. For both cases, the temperature was 80 1C. We optimized
the solvent system by varying the solvents among water, ethanol
and acetonitrile. Ethanol was preferred as the solvent, since
the precipitation of palladium black, which may indicate the
degradation of the catalyst, was less. The catalytic results were
also good in water, but the precipitation of palladium black
during catalysis was more in an aqueous medium (Table S2,
ESI†). The reaction in the presence of various bases provided
the information that the best results were obtained in the
30 min 95
8
1.0
2.0
4 h
>99
—
24
—
9
12 h
a
Reaction conditions: aryl halides (0.5 mmol), phenylboronic
CO (0.48 g, 1.5 mmol) EtOH (5 mL).
TOF (h ).
acid (0.0915 g, 0.75 mmol), Cs
2
3
b
À1
2 3
presence of Cs CO (Table 4). The test reaction used in these
cases was the cross coupling between 4-bromoanisole and
phenylboronic acid (Table 4).
conversion to its corresponding biaryl in an hour using 0.5%
catalyst at 80 1C (Table 5, entry 5), whereas 4-bromoanisole
needed 2 hours for complete conversion, using 1 mol% catalyst
and 80 1C (Table 5, entry 4). A similar trend was observed using
the microwave method. We found that the microwave method
improved the TOF, since the reaction completion time decreased
Hence forth, Cs CO was used as the base and the coupling
2
3
reactions were performed using various aryl halides with phenyl-
boronic acid in an EtOH medium, by both the conventional
heating method and microwave irradiation methods. The
catalyst loading was varied from 0.2 mol% to 1 mol%, with
respect to the aryl halides. The results are tabulated in Tables 5
and 6. The results show that the catalytic activity depends on the
(
Table 6). The TOF (turn over frequency) was calculated using the
À1
formula, TOF (h ) = (no of moles of the product formed)/{(no of
3
6
moles of the catalyst involved) Â (reaction time for completion in
nature of the aryl halides, which is a well known fact. With
variation of the substitution in the aryl ring, the rate of reaction
also varied significantly i.e. 4-bromoacetophenone gave complete
3
7
hour)}. The yields reported in the table are the isolated yields,
after individual column chromatography.
Table 4 Screening of bases for the reaction of 4-bromoanisole and Discussion
a
phenylboronic acid
There have been several reports where 2-oxazolidinones were
formed from amino ethanol derivatives by the purging of CO
2
2
0–24
and the addition of electrophiles and bases.
Earlier work to
b
form pyridine based oxazolidinone was mostly done with preformed
Entry
Base
Cs CO
Yield (%)
38,39
oxazolidinone derivatives.
substrates, showed that in the presence of SOCl
A recent report, using non-pyridine
and a base,
1
2
3
4
5
6
2
3
92
80
56
74
52
67
K
2
CO
PO
NOH
(iPr) EtN
NaOMe
3
2
K
3
4
1,2 amino alcohols can form oxazolidinones with the inversion
Bu
4
24
or retention of the configuration, depending on the substi-
2
tuents. Based on that proposed mechanism, we should obtain
an inversion of the configuration during product formation and
indeed, we obtained the inverted product in a major yield,
although unlike the earlier report, we had no added base to our
a
Reaction conditions: 4-bromoanisole (0.093 g, 0.5 mmol), phenylboronic
acid (0.0915 g, 0.75 mmol), base (1.5 mmol), EtOH (5 mL). Isolated yield
b
after column chromatography.
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Table 6 Suzuki–Miyaura cross coupling between aryl halides and phenyl- In complexes 1 and 3, the metal to ligand (L) ratio was 1 : 2,
a
boronic acid with microwave irradiation
whereas in 2 it was 1 : 1. The unique electronic property of the metal
leads to a difference in the dissociation of the labile ligands,
leading to a change in the reactivity and redox properties.
Catalyst
loading (mol%) Time
Isolated
yield (%) TOF
b
Entry Aryl halide
1
We probed the reactivity with 3 for C–C bond cross coupling
3000 as a proof of concept, since Pd(OAc) (5–10 mol%) itself can act
2
0.2
0.2
0.2
1.0
0.5
0.5
0.5
10 min >99
as a catalyst for the same purpose. Palladium catalyzed Suzuki–
Miyaura cross coupling reactions between organic halides with
aryl boronic acid are the most effective and widely used method
2
3
4
5
6
7
10 min >99
10 min >99
30 min 84
20 min 98
15 min 92
15 min 98
3000
3000
168
4
0–45
II
for the synthesis of various biaryls.
Pd complexes of
phosphane based ligands have been among the most effective
46–53
ones to perform the Suzuki–Miyaura cross coupling reactions.
The search for alternative ligands has seen a surge during the
5
4–58
past and present decade,
due to the sensitivity and non-
environmentally friendly nature of phosphane based catalysts.
Efficient catalysts for the Suzuki–Miyaura reaction have been made
588
5
9–67
68–70
using N-heterocyclic carbene ligands,
other ligand systems.
palladacycles
and
736
71–73
However, the use of oxazolidinone as a
ligand for such catalysis is unknown. Our work shows that oxazo-
lidinone has the potential as a ligand to palladium, to generate
catalysts for C–C bond cross coupling, using aryl halides and
phenylboronic acids.
Complex 3 act as a good catalyst for the Suzuki–Miyaura
cross-coupling reaction of different aryl halides viz. bromides
and iodides with different electron donating and withdrawing
groups in the para and ortho positions, in considerably good
784
8
1.0
2.0
30 min >99
198
—
9
2 h
—
a
Reaction conditions: aryl halides (0.5 mmol), phenylboronic acid yields. For aryl iodides, with only 0.2 mol% catalyst loading, we
CO (0.48 g, 1.5 mmol), EtOH (5 mL).
Microwave temperature 80 1C, max pressure = 8 bar, max power = 46 W.
(0.0915 g, 0.75 mmol), Cs
2
3
obtained almost full conversion, in 20–30 min, whereas for aryl
bromides, we had to increase the catalyst loading to 0.5–1.0%,
to afford a full conversion, in 0.5–1.0 h. This observation can
be well argued, since iodide is a better leaving group than
bromide. Electronic factors play an important role for the
reaction of aryl halides containing electron donating and
electron withdrawing groups. An electron withdrawing substi-
tuent present in the ortho or para position of the aryl halide
favours the reaction, thus the rate of reaction increases, while
in the presence of an electron donating substituent, the rate of
reaction decreases as it strengthens the C–X bond. Thus, for
b
À1
TOF (h ).
reaction. However, the yield is 60% and hence the pyridine sub-
24
strate may also be acting as a base. We carried out the reaction
in SOCl , which serves as an electrophile and the presence of
2
atmospheric CO2 lead to carbonylation, without any additional
base. Based on the earlier proposed mechanism, we propose the
formation of a transient carbamate species, by the incorporation of
CO
2
, without any added base and the pyridine moiety in the
, the
substrate may stabilise the species. In the presence of SOCl
2
4
-acetyl, 4-nitro and 4-cyanophenylbromides, with 0.5 mol%
hydroxyl oxygen of the amino alcohol is activated and becomes
a good leaving group, which then suffers a nucleophilic attack
from a carbamate oxygen, forming the oxazolidinone ring. The
mechanistic proposal is depicted in Scheme 4.
The single crystal structures of 1, 2 and 3 showed that metal
complexes of a varying ligand to metal stoichiometry are formed.
catalyst loading, we obtained excellent yields within 30 minutes
to 1.0 hours (Table 5, entries 5–7), but for 4-bromoanisole it
needed 2 hours for a complete conversion, using 1 mol%
catalyst and 80 1C (Table 5, entry 4). Using a microwave reactor,
we observed the same trend, although here the completion of
reaction is achieved within 10–30 min. Hence, the microwave
method is better than the conventional heating method.
However, for aryl chlorides we did not get the desired product,
even after 12 hours, hence the Pd complex 3 could not serve as a
catalyst for the Suzuki–Miyaura coupling of aryl chlorides
(Tables 5 and 6, entry 9). The results are still important and
encouraging, since the catalytic C–C bond cross coupling
reaction using L is at its infancy. Complex 3 is proposed to
follow the general mechanistic pathway via oxidative addition,
transmetalation and reductive elimination reported in the
literature for C–C bond cross coupling via C–X bond activation
4
0,41,74
Scheme 4 Mechanistic proposal for preparation of ligand L.
(Scheme S1, ESI†).
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L was also probed for its potential as a ligand in therapeutics. among the three against both the MCF-7 and A549 cell lines, yet
II
II
In vitro studies of L complexed with Cu (1) and Pt (2) it is not as toxic as cisplatin, which might be good to check upon,
show anticancer activity, with an IC50 of 114 Æ 2 mM for 1 and since it has scope for rendering reduced side effects, due to the
II
1
02 Æ 2 mM for 2 in the MCF-7 cancer cell line. 1 is less toxic in ligand being an oxazolidinone, with much less toxicity. The Pd
the non-cancerous mouse cell line (NIH 3T3) (IC = 198 Æ 1 mM) complex (3) is successful in the C–C bond cross coupling
5
0
in vitro, as compared to its toxicity over MCF-7, which is reaction of activated and deactivated aryl bromides, and has
encouraging, since the well known drug cisplatin, which has a scope for tuning, with very simple synthetic modifications. The
much lower IC50 value in MCF-7 or A549, does not exhibit this results warrant further investigation, to tune the ligand and
II
property. However, the Pt complex 2 is relatively more active generate metal complexes which may have potential in catalysis
against the lung cancer cell line (A549), showing an IC50 of and therapeutics.
1
98 Æ 1 mM when compared to 1 (IC = 455 Æ 3 mM). The in vitro
5
0
toxicity data show that the trans-Pt complex is most potent
(
IC50 = 102 Æ 2 mM in MCF-7) among the three metal complexes. Experimental section
The palladium complex is the least active with IC50 values >
00 mM and it is the most hydrophilic among the three candi-
Material and methods
2
All the chemicals and solvents used for this work were purchased
from commercial sources. The solvents were distilled and dried,
prior to use. Silica gel 60–120 mesh size (Merck-India) was used
for the column chromatography. The UV-visible measurements
were done using a Perkin Elmer Lambda 35 spectrophotometer.
The FT-IR spectra were recorded using a Perkin-Elmer 120-000A,
dates. 3 is more active over the A549 cell line (IC50 = 236 Æ 3 mM),
compared to MCF-7 (IC50 = 260 Æ 3 mM), but at the same time it
is also more toxic to the non-cancerous mouse NIH 3T3 cell line
II
(
IC50 = 151 Æ 1 mM). trans-Pt compounds are, in general, less
II
reactive than cis-Pt compounds and the in vitro data are in
accordance with the known literature. The dose required to
achieve a 50% killing is high for the series of complexes, as
compared to many drugs already in the clinic. However, it is
encouraging to see that there are drugs which are widely used in
the clinic, or are in clinical trials and have in vitro toxicity data
from which they seem apparently much less potent (viz. in vitro
1
13
in KBr pellets. The H and C NMR spectra were measured
using either a JEOL ECS 400 MHz or Bruker Avance III spectro-
meter 500 MHz, at room temperature. The chemical shifts are
1
3
reported in parts per million (ppm). The C NMR spectra
recorded are proton decoupled. The elemental analyses were
performed on a Perkin Elmer Inc. EA 2400 CHNS series. The
electro-spray ionization mass spectra were recorded using a
Micromass Q-Tof microTM, Waters, by +ve mode electrospray
ionization. The synthetic yields reported are of the isolated,
analytically pure compounds. The Suzuki–Miyaura cross-
coupling reactions were performed with a conventional heating
method, as well as in a microwave (Anton Paar Monowave 300).
The microwave reactions were performed in 10 mL Teflon
capped glass vials. All the reactions in the microwave were
carried out at 80 1C for a certain period of time (based on the
completion of the reaction) while the pressure and microwave
power were varied. The maximum pressure reached was 8 bar
and the microwave power reached up to 46 W.
7
5
IC50 values: cyclophosphamide >1000 mM on MCF-7, gallium
7
6
nitrate in the range 60–250 mM in HCC lines, ruthenium based
7
7,78
compounds NAMI-A > 500 mM in the MCF-7 cell line
and
7
9
RAPTA-C > 350 mM in the A2780 cell line ). In fact, when we
tested cyclophosphamide against MCF-7, we could not reach an
IC50 value, even at a 3000 mM concentration of the drug. Hence, it
should be noted that having a lower IC50 does not necessarily
mean that the complex would be a better drug candidate, rather
the unwanted side effects might also be more. The obtained IC50
values of 1–3, the success of oxazolidinones as antimicrobial and
the relatively less toxic nature of L on human cells, on its own
(IC50 > 1000 mM in MCF-7), warrants that the complexes are
worth tuning with respect to the oxazolidinone and the labile
ligands.
Caution! Perchlorate salts are explosive and corrosive, so
special care should be given for handling these compounds.
Synthesis of ligands and their precursors
Conclusions
Synthesis of 2-(pyridin-2-ylmethylamino)ethanol. It was
We found that the CO2 present in air is able to convert a synthesised according to a previously reported procedure. To a
pyridine containing amino alcohol into an oxazolidinone, in methanolic solution (20 mL) of pyridine-2-carboxaldehyde (2.14 g,
80
the presence of SOCl
2
as an electrophile. The compound 20 mmol), 2-aminoethanol (1.22 g, 20 mmol) was added drop wise
obtained, 3-(pyridin-2-ylmethyl)oxazolidin-2-one, may act as a in ice cold conditions. The resulting solution was then allowed to
ligand to synthesize late 3d, 4d and 5d transition metal com- come to ambient temperature slowly and stirred for two hours. It
plexes, which would generate potential new candidates in was then subsequently treated with NaBH (1.89 g, 50 mmol) in
4
catalysis and therapeutics. The ligand synthetic method is a small portions. After an additional 2 h, the reaction mixture was
simple way to fix atmospheric CO in organic synthesis. The concentrated to about 20 mL, using a rotary evaporator. The
2
three metal complexes generated as a proof of concept with the remaining solution was added to 30 mL water and extracted
synthesized ligand without tuning it any further, showed that with DCM (3 Â 20 mL). The organic layer was separated and
II
the Cu complex (1) has some degree of selectivity for the MCF-7 subsequently dried with Na
2
SO
4
. Filtration and evaporation
cancer cell line. The platinum complex (2) is the most toxic of the solvent gave the desired product. Yield. 1.8 g (60%).
8
22 | New J. Chem., 2014, 38, 817--826
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Paper
1
H NMR (CDCl
3
, 400 MHz) d 8.52 (d, J = 4.88 Hz, 1H, ArH), 7.62
2 2
Synthesis of trans-[Pd(L) Cl ] (3). Ligand L (0.237 g, 0.5 mmol)
2 2
(m, 1H, ArH), 7.24 (m, 1H, ArH), 7.16 (m, 1H, ArH), 3.91 (s, 2H, was dissolved in 5 mL acetonitrile and [Pd(MeCN) Cl ] (0.130 g,
CH NH), 3.65 (t, J = 4.88 Hz, 2H, CH ), 2.82 (t, J = 4.88 Hz, 2H, 0.5 mmol) dissolved in 50 mL of DCM. The [Pd(MeCN) Cl ]
2
2
2
2
CH2).
solution was slowly added to the ligand solution under stirring.
Synthesis of 3-(pyridin-2-ylmethyl)oxazolidin-2-one (L). 1.6 g The solution was then refluxed for 4 h. Orange coloured crystals
(10.5 mmol) of 2-(pyridin-2-ylmethylamino)ethanol was taken were obtained from the acetonitrile solution. The isolated yield
and 1 mL of SOCl
tions, and stirred for 1 day at 25 1C. Then, the excess SOCl
evaporated at reduced pressure, resulting in a yellow solid. It
2
added drop wise under ice cooled condi- was 0.127 g, 48%. M.p. 190 1C. Anal. calcd for C18
2 4 4
H20Cl N O Pd:
2
was C, 40.5; H, 3.78; N, 10.5. Found C, 39.94; H, 3.81; N, 10.2%.
1
3
H NMR (CDCl , 400 MHz) d 9.21 (d, J = 5.36 Hz, 1H, ArH), 8.87
was then dissolved in 20 mL of water and the pH was adjusted (d, J = 5.32 Hz, 1H, ArH), 8.07 (m, 2H, ArH), 7.67 (m, 4H, ArH),
to 7. The solution was extracted with DCM (3 Â 20 mL) and the 5.50 (s, 2H, CH N), 5.11 (s, 2H, CH N), 4.37 (m, 4H, CH ), 3.53
2
2
2
1
3
organic layer was separated and subsequently dried with (m, 4H, CH ), 3.47 (s, 6H, CH CH SO) ppm. C NMR (CDCl3,
2
3
3
Na SO . Filtration and evaporation of the solvent gave 100 MHz) d 158.4, 156.2, 152.4, 140.4, 125.9, 124.9, 62.19, 49.80,
2
4
À1
3
-(pyridin-2-ylmethyl)oxazolidin-2-one. Yield. 1.10 g (60%). 44.56 ppm. IR (KBr, cm ) 3481 (br), 3076 (m), 2891 (m), 1748 (s),
1
H NMR (CDCl
.69 (m, 1H, ArH), 7.34 (m, 1H, ArH), 7.23 (m, 1H, ArH), 4.55 1249 (s), 1207 (m), 1154 (w), 1085 (w), 1085 (s), 1033 (s), 970 (m),
s, 2H, CH N), 4.37 (t, J = 7.9 Hz, 2H, CH ), 3.64 (t, J = 6.72 Hz, 944 (m), 885 (w), 825 (m), 771 (m), 766 (s), 697 (m), 660 (w), 542
3
, 400 MHz) d 8.56 (d, J = 4.88 Hz, 1H, ArH), 1607 (s), 1571 (m), 1485 (s), 1433 (s), 1412 (s), 1361 (m), 1275 (s),
7
(
2
1
2
2
1
3
3
À1
À1
H, CH
2
) ppm (Fig. S4, ESI†). C NMR (CDCl
3
, 125 MHz) d (w), 445 (s). UV-vis (MeCN) l (nm) (e/dm mol cm ) 400 (241),
À +
58.3, 155.4, 149, 136.7, 122.3, 121.7, 61.64, 49.39, 44.3 ppm 318 (323), 223 (157934). ESI-MS calcd for [M À Cl ] 498.95
(Fig. S5, ESI†).
found 499.14.
Synthesis of [Cu(L) (ClO ) ] (1). To a 6 mL methanolic
2
4 2
X-ray crystallographic study
solution of ligand L (0.348 g, 1.97 mmol), Cu(ClO
4
)
2
Á6H
2
O
(
0.364 g, 0.98 mmol) in 10 mL methanol was added. Immediately Single crystals of 1–3 were mounted using loops on the gonio-
the solution turned green. The solution was then stirred at room meter head of a Bruker Kappa Apex II CCD Duo diffractometer
temperature for 4 h followed by standing for 48 h. A blue with graphite monochromated Mo-Ka radiation (0.71073 Å) and
coloured, crystalline compound separated. The isolated yield the data were collected at a temperature of 100 K. An empirical
was 0.317 g, 52%. M.p. 176 1C. Anal. calcd for C H Cl N O Cu: multi-scan absorption correction was performed using
1
8
20
2 4 12
8
1
C, 34.94; H, 3.26; N, 9.05. Found: C, 34.88; H, 3.21; N, 8.86%. IR SADABS. The structures were solved by direct methods and
KBr, cm ) 3437 (br, m), 3096 (w), 2359 (w), 2024 (w), 1671 (s), all the non-hydrogen atoms were refined anisotropically by
À1
(
1609 (m), 1500 (s), 1464 (m), 1448 (m), 1373 (m), 1330 (w), 1274 full matrix least-squares on F2. The hydrogen atoms were
(
s), 1098 (s), 932 (m), 821 (m), 780 (m), 754 (m), 624 (s), 557 (m). calculated and fixed using SHELXL-97, after hybridization of
3
À1
À1
82
UV-vis (DMF) l (nm) (e/dm mol cm ) 461 (14), 260 (6488). all the non-hydrogen atoms. The ball and stick diagrams
ESI-MS calcd for [M À ClO
À +
4
] 518.03 found 518.12.
were made using Diamond version 2.0f. CCDC 956432 (1) and
Synthesis of trans-[Pt(L)(DMSO)Cl
2
] (2). Ligand L (0.134 g, 956433 (2).
0
.76 mmol) was dissolved in 4 mL DCM and cis-[Pt(DMSO) Cl ]
2
2
Lipophilicity measurement
(0.320 g, 0.76 mmol) dissolved in 50 mL of DCM. The cis-
[
Pt(DMSO) Cl ] solution was slowly added to the ligand The partition coefficients of the three complexes in an octanol–
2 2
solution under stirring conditions. The solution was then water system were determined using a standard shake-flask
8
3
refluxed for 4 h and the solution was then evaporated under method. Octanol and phosphate buffer (20 mM) (each 3 mL)
8
4
reduced pressure. A yellowish sticky mass was obtained, which were pre-equilibrated for 8 hours before the experiment. After
was treated with 0.1 M HCl and then refrigerated overnight. equilibration, the solid samples were added to the mixture of
After several washings with ether, a yellow solid product was solvents and shaken on a dancing shaker overnight, at room
obtained. A yellow, single crystal was obtained from the DCM– temperature. After that, the tubes were centrifuged and left
hexane layering. The yield of the isolated pure product was undisturbed for an hour. Aliquots of the aqueous and octanol
0
.260 g, 78%. M.p. 162 1C. Anal. calcd for C H Cl N O SPt: C, layers were pipetted out separately and the absorbance measured
11 16 2 2 3
2
5.3; H, 3.09; N, 5.36. Found: C, 24.94; H, 3.17; N, 5.14%. using UV-vis spectroscopy. The concentration of the substances
1
3
H NMR (CDCl , 400 MHz) d 8.83 (m, 1H, ArH), 7.92 (m, 1H, in each layer was calculated using the respective molar extinction
ArH), 7.59 (d, J = 7.5 Hz, 1H, ArH), 7.46 (m, 1H, ArH), 5.28 coefficients of 1–3.
s, 2H, CH N), 4.41(m, 2H, CH ), 3.59 (m, 2H, CH ), 3.47 (s, 6H,
CH CH SO) ppm. C NMR (CDCl , 125 MHz) d 158.3, 157.3,
(
2
2
2
1
3
Cell lines and culture condition
3
3
3
1
52.4, 139.9, 126.7, 125, 62.26, 50.16, 44.56, 43.65 ppm. IR The human breast adenocarcinoma cell line (MCF-7), human
À1
(KBr, cm ) 3553 (br), 3014 (m), 2917 (m), 1742 (s), 1609 (m), lung carcinoma cell line (A549) and mouse embryonic fibro-
1
9
484 (s), 1445 (s), 1304 (w), 1322 (w), 1267 (s), 1148 (s), 1030 (s), blast cell line (NIH 3T3) were kind donations of Dr Jayasri Das
38 (w), 762 (m), 751 (s), 696 (m), 539 (w), 442 (s). UV-vis (MeCN) Sarma and Dr Tapas Sengupta, Department of Biological
3
À1
À1
l (nm) (e/dm mol cm ) 439 (12), 314 (266), 263 (5575). ESI- Sciences, IISER-Kolkata, India. The cell lines were maintained
MS calcd for [M + Na ] 543.98 found 545.03.
+
in the logarithmic phase at 37 1C in a 5% carbon dioxide
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atmosphere, using a culture media containing DMEM, 10% The aryl halide (0.5 mmol) in EtOH (5 mL) was added to it. The
À1
foetal bovine serum (GIBCO) and antibiotics (100 units mL
penicillin and 100 mg mL streptomycin).
catalyst (palladium complex) solution in EtOH was added,
varying the loading percentage from 0.2 mol% to 1 mol% with
respect to the aryl halide. The resulting mixture was warmed at
À1
Cell viability assay
80 1C for 10–45 min, under a standard irradiation mode. After
The cytotoxicity of complexes 1–3 on the MCF-7 and A549 cell the completion of the reaction, the solvent was evaporated
lines were evaluated by the MTT (tetrazolium salt reduction) under a reduced pressure. The residue was diluted with water
8
5
3
assay. Briefly, 6 Â 10 cells per well were seeded in 96-well (30 mL) and extracted with dichloromethane (3 Â 20 mL). The
plates in growth medium (200 mL) and then incubated at 37 1C organic layer was dried with Na SO and the solvent was
2
4
in a 5% carbon dioxide atmosphere. After 48 h, the medium removed in vacuo. The resulting product was purified by silica
was removed and replaced with a fresh one and the compounds gel column chromatography (mesh size 60–100) using either
to be studied were added at appropriate concentrations. hexane or a dichloromethane–hexane mixture (3 : 1) depending
Triplicates for each concentration were used in the wells. The on the product polarity. After column chromatography, the
compounds to be added were solubilized in media, or PBS isolated yield was calculated.
containing DMSO (when needed), such that the concentration
of DMSO in each well should not exceed 0.2%. Cisplatin was
1
Biphenyl. White solid. H NMR (CDCl3, 400 MHz) d 7.63
(
(
1
d, J = 7.64 Hz, 4H, ArH), 7.48 (t, J = 7.64 Hz, 4H, ArH), 7.38
dissolved in DMSO just before the experiment and a calculated
amount of the drug solution was added to the growth medium
containing cells, such that the final DMSO concentration in the
wells was no more than 0.2%. After 48 h, the media containing
compound was removed and fresh media was added to each
1
3
t, J = 6.88 Hz, 2H, ArH) ppm (Fig. S6, ESI†). C NMR (CDCl3,
00 MHz) d 141, 128.9, 127.4, 127.3 ppm (Fig. S7, ESI†).
1
4
-Methylbiphenyl. White solid. H NMR (CDCl
3
, 400 MHz,) d
À1
7.51 (d, J = 7.64 Hz, 2H, ArH), 7.42 (d, J = 7.64 Hz, 2H, ArH),
.36 (t, J = 7.64 Hz, 2H, ArH), 7.25 (t, J = 7.64 Hz, 1H, ArH), 7.16
d, J = 7.6 Hz, 2H, ArH), 2.31 (s, 3H, CH ) ppm (Fig. S8, ESI†).
C NMR (CDCl , 100 MHz) d 141, 138, 136, 129, 128, 126, 21
well and successively treated with 20 mL of a 2 mg mL MTT in
7
saline solution, followed by 3 h of incubation at 37 1C in a 5%
carbon dioxide atmosphere. After 3 h, the media were removed
and 100 mL of DMSO (molecular biology grade) added to each
well. The inhibition of cell growth induced by the tested
complexes was detected by measuring the absorbance of each
(
3
1
3
3
ppm (Fig. S9, ESI†).
1
4
-Methoxybiphenyl. White solid. H NMR (CDCl
.59 (m, 2H, ArH), 7.45 (t, J = 7.64 Hz, 2H, ArH), 7.34 (t, J = 7.64
Hz, 1H, ArH), 7.01 (d, J = 8.4 Hz, 2H, ArH), 3.87 (s, 3H, CH
3
, 400 MHz) d
8
6,87
well at 515 nm
using a BIOTEK ELx800 plate reader. All the
7
experiments had the respective controls and standards, as
needed. The IC50 values represent the drug concentration that
reduces the mean absorbance at 515 nm to 50%, as compared
to the untreated control wells.
3
)
13
ppm (Fig. S10, ESI†). C NMR (CDCl
3
, 100 MHz) d 159, 141,
1
33, 129, 128, 126.8, 126.7, 114, 56 ppm (Fig. S11, ESI†).
1
4
-Acetylbiphenyl. White solid. H NMR (CDCl
3
, 400 MHz) d
Catalytic study
8.05 (d, J = 8.4 Hz, 2H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.64
General procedure for the Suzuki–Miyaura cross coupling
reaction
By conventional heating method. A typical 50 mL round
bottom flask containing a magnetic stir bar was charged with
(
t, J = 2.28 Hz, 2H, ArH), 7.49 (t, J = 6.88 Hz, 2H, ArH), 7.42
t, J = 6.88 Hz, 1H, ArH), 2.64 (s, 3H, CH ) ppm (Fig. S12, ESI†).
, 100 MHz) d 197, 146, 140, 135, 129.07, 129.04,
(
3
1
3
C NMR (CDCl
3
1
28.9, 127.40, 127.30, 27 ppm (Fig. S13, ESI†).
phenylboronic acid (0.091 g, 0.75 mmol) and Cs
2 3
CO (0.488 g,
1
1.5 mmol). The aryl halide (0.5 mmol) in EtOH (5 mL) was
4-Nitrobiphenyl. Light yellow solid. H NMR (CDCl , 400
3
added to it. The catalyst (palladium complex) solution in EtOH MHz) d 8.31 (d, J = 9.16 Hz, 2H, ArH), 7.75 (d, J = 8.4 Hz, 2H,
was added, varying the loading percentage from 0.2 mol% to ArH), 7.64 (d, J = 6.88 Hz, 2H, ArH), 7.52 (m, 3H, ArH) ppm
1
3
1
mol%, with respect to the aryl halide. The resulting mixture (Fig. S14, ESI†). C NMR (CDCl , 100 MHz) d 146, 139, 133,
3
was refluxed and after completion of the reaction, the solvent 129.2, 128.8, 127.9, 127.4, 119, 111 ppm (Fig. S15, ESI†).
was evaporated under a reduced pressure. The residue was
1
diluted with water (30 mL) and extracted with dichloromethane
3 Â 20 mL). The organic layer was dried with Na SO
the solvent was removed in vacuo. The resulting product Hz, 2H, ArH), 7.45 (t, J = 7.64 Hz, 1H, ArH) ppm (Fig. S16, ESI†).
4-Cyanobiphenyl. White solid. H NMR (CDCl
3
, 400 MHz) d
(
2
and 7.74 (m, 4H, ArH), 7.60(d, J = 6.88 Hz, 2H, ArH), 7.51 (t, J = 6.88
4
1
3
was purified by silica gel column chromatography (mesh size
0–100) using either hexane or a dichloromethane–hexane 127.9, 127.5, 124 ppm (Fig. S17, ESI†).
3
C NMR (CDCl , 100 MHz) d 148, 147, 139, 129.3, 129.1, 127.9,
6
mixture (3 : 1) depending on the product polarity. After column
chromatography, the isolated yield was calculated.
1
2
-Phenylpyridine. Yellow oil. H NMR (CDCl , 400 MHz) d
3
8
.71 (m, 1H, ArH), 7.99 (m, 2H, ArH), 7.77 (m, 2H, ArH), 7.50
1
3
By microwave method. A typical Teflon capped 10 mL glass (m, 3H, ArH), 7.27 (m, 1H, ArH) ppm (Fig. S18, ESI†). C NMR
vial, containing a magnetic stir bar was charged with phenyl- (CDCl , 100 MHz) d 157, 150, 139, 137, 128.9, 128.7, 127, 122,
3
boronic acid (0.091 g, 0.75 mmol) and Cs
2
CO
3
(0.488 g, 1.5 mmol). 120 ppm (Fig. S19, ESI†).
8
24 | New J. Chem., 2014, 38, 817--826
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Paper
Acknowledgements
20 M. Kodaka, T. Tomohiro and H. Okuno, J. Chem. Soc., Chem.
Commun., 1993, 81–82.
We sincerely acknowledge the DST, India for funding (Vide
Project no-SR/S1/IC-36/2010). We are also thankful to the IISER
Kolkata, for the financial and infra-structural support, including
the NMR and single crystal X-ray facilities. We are thankful to
Dr Tapas K. Sengupta and Dr Jayasri Das Sarma for the donation
of the MCF-7, NIH 3T3 and A549 cell lines. We also thank
Dr Venkataramanan Mahalingam for the microwave reactor used
in this work. A. S. sincerely thanks the IISER Kolkata for a research
fellowship. S. B. and S. K. D. thank the CSIR-India for research
fellowships. S. K. acknowledges the UGC for a research fellowship.
2
2
2
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