Ruthenium-indolizinone complexes as a new class of metalated heterocyclic compounds: Insight into unconventional alkyne activation pathways, revelation of unexpected electronic properties and exploration of medicinal application

Article abstract of DOI:10.1039/c8dt02408a

The two series of ruthenium-indolizinone complexes prepared by Ru-mediated cyclization of pyridine-tethered alkynes represent the first examples of metalated indolizinone complexes. Joint experimental-theoretical investigation suggests an unconventional 5-endo-dig cyclization pathway as their formation mechanism. They also exhibit moderate cytotoxicity against several human cancer cell lines.

Full text of DOI:10.1039/c8dt02408a

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Ruthenium−Indolizinone Complexes as a New Class of Metalated
Heterocyclic Compound: Insight into Unconventional Alkyne
Activation Pathway, Revelation of Unexpected Electronic
Properties and Exploration of Medicinal Application
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Lai-Hon Chung,a,† Sze-Wing Ng,a,b,† Chi-Fung Yeung,a,b,c Hau-Lam Shek,a Sheung-Ying Tse,a Hoi-Shing
Lo,a,c Siu-Chung Chan,a Man-Kit Tse,a Shek-Man Yiu,a and Chun-Yuen Wong*a,b,c
www.rsc.org/
The two series of ruthenium−indolizinone complexes prepared by efforts on probing and isolating the proposed metalated
Ru-mediated cyclization of pyridine-tethered alkyne represent the heterocyclic intermediates are rare. These overlooked
first examples of metalated indolizinone complexes. Joint intermediates are not only of mechanistic importance but they
experimental-theoretical
unconventional 5-endo-dig cyclization pathway as their formation heterocyclic complexes. With this idea in mind, we have
mechanism. They also exhibit moderate cytotoxicity against recently initiated research activities for isolable
heterocyclic complexes from reactions between
investigation
suggests
an also offer insights into the preparation of isolable metalated
several human cancer cell lines.
metal−
heteroatom-functionalized alkynes and structurally well-
Heterocycles has been a research focus for years in synthetic
chemistry due to their versatile applications in medicinal
chemistry and materials science.1 While organic heterocycles
represent the mainstream research in the field of heterocyclic
chemistry, development of metal-containing heterocyclic
compounds have been picking up its pace. More specifically,
the modulable coordination spheres together with rich
oxidation states offered by the metal centers make the
metalated heterocyclic complexes an attractive class of
functional compounds. Despite these advantages, studies in
defined low-valent transition-metal complexes. Through this
approach,
many
interesting
and
unprecedented
metal
−
heterocyclic complexes have been isolated,4 and this
strategy undoubtedly broadens the spectrum of metalated
heterocyclic complexes. As an extension of our previous work,
we herein report the first examples of isolable and structurally
characterized ruthenium−indolizinone complexes prepared by
Ru-assisted activation of pyridine-tethered alkynes.
Significantly, although the Ru–vinylidene intermediacy is
prevalent
transformations,5
investigation suggests an unconventional 5-endo-dig
cyclization pathway for the formation of Ru indolizinone
in
numerous
Ru(II)-mediated
alkyne
metalated heterocyclic complexes are dominated by metal−N-
this joint
experimental-theoretical
heterocyclic carbene complexes,2 whereas investigations on
other metalated heterocyclic systems are far lagged behind,
presumably due to the lack of general synthetic approaches,
−
complexes. Besides, the potential application of the Ru–
indolizinone complexes as anticancer agents was explored in
view of the captivating antitumoral activity of indolizinone-
based camptothecins.6
which hampers further development of metal
chemistry.
−heterocycle
In recent years, breakthroughs in transition-metal- and
Lewis-acid-catalyzed cyclization of alkynes with heteroatom
functionalities have dramatically improved the efficiency of
organic heterocycle synthesis.3 While most studies have
focused on the cyclization products and reaction efficiencies,
Ru(II)
−
complexes bearing indolizinone zwitterion)
indolizinone complexes (or more correctly Ru(II)
were obtained
1−4
in high yield (73–95%) by reacting pyridyl-ynone RC≡C(C=O)(2-
py) with [Ru([9]aneS3)(bpy)(H2O)]2+ and cis-[Ru([14]aneS4)Cl2]
respectively (Scheme 1; [9]aneS3 = 1,4,7-trithiacyclononane,
bpy
tetrathiacyclotetradecane). Acetonitrile-ligated complexes (
and ) were obtained from reaction between chloride-ligated
complexes ( and ) and chloride abstracting agent AgClO4 in
CH3CN. All these complexes are stable towards air, moisture,
and ambient radiation. The molecular structures for (ClO4)2,
(ClO4)2·(CH3CN)2, (ClO4) and (ClO4)2·(CH3CN)2 determined
=
2,2'-bipyridine,
[14]aneS4
=
1,4,8,11-
5
6
3
4
1
2
4
6
by X-ray crystallography (Fig. 1, Table 1) represent the first
examples of indolizinone-ligated metal complexes. In each
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case, the indolizinone moiety behaves as a monodentate [Ru([14]aneS4)Cl2]
ligand and metalates at the C-2 position of the indolizinone HC≡C(C=O)(2-thienyl) yields ruthenafuran complex
with
nucleophile-tethered
ynone
as the
7
skeleton, and the ten non-hydrogen atoms on the indolizinone only product (Scheme 3(a), Fig. 1), and the formation of
moiety are essentially coplanar. The Ru–C distances (2.019(3)– ruthenafuran complex from the reaction between cis-
2.104(3) Å) are indicative of Ru–C single bond character. The [Ru([14]aneS4)Cl2] and HC≡C(C=O)Ph was previously reported
slightly longer Ru–C distance in
that in (2.057(4)–2.062(4) Å) is probably originated from the
bulkiness of the C-3 substituent (Ph for vs. H for ). The C–O
2
(2.104(3) Å) compared with to proceed via a vinylidene-involving pathway (Scheme 3(b)).4c
1
Table 1 Selected Bond Lengths (Å) for Cations 1, 2, 4, 6 and 7 Determined by X-ray
2
1
Crystallography.
distances determined (1.204(5)–1.213(4) Å), together with the
νCO for all the indolizinone complexes (1701–1710 cm–1), are
standard for carbonyl group.
1a
2
4
6
7
Ru(1)−C(1)
C(1)−C(2)
C(2)−C(3)
C(3)−N(1)
C(4)−N(1)
C(1)−C(4)
C(2)−O(1)
2.057(4),
2.062(4)
1.499(5),
1.488(5)
1.503(5),
1.517(5)
1.345(5),
1.342(5)
1.460(5),
1.441(5)
1.326(5),
1.339(5)
1.212(4),
1.213(4)
−
2.104(3)
2.019(3)
2.037(3)
2.015(4)
2+
2+
OH2
1.499(4)
1.504(4)
1.352(4)
1.482(3)
1.351(4)
1.208(4)
1.513(4)
1.500(4)
1.358(4)
1.473(3)
1.360(4)
1.210(3)
1.503(5)
1.499(5)
1.355(5)
1.475(4)
1.370(5)
1.204(5)
1.377(6)
O
S
N
N
Ru
S
1
3
N
R
S
O
1.395(6)
2
R
N
S
N
Ru
S
THF
−
−
−
−
N
S
S
S
Cl
Cl
Ru
S
1: R = H 2: R = Ph
S
/ MeOH
+
2+
O
O
S
S
S
S
1
1
AgClO4
CH3CN
2
2
Ru Cl
Ru
N
C
CH3
C(3)−O(1)
Ru(1)−O(1)
−
−
−
−
−
−
1.284(5)
2.121(3)
N
N
3R
3R
5: R = H 6: R = Ph
Synthetic routes for ruthenium−indolizinone complexes, and the
S
S
S
S
−
a
The crystal contains two crystallographically independent cations in the
asymmetric unit; structural data are listed in the order of Ru(1) moiety, followed
by Ru(2) moiety.
3: R = H 4: R = Ph
Scheme 1
numbering of the ring system.
A
Pathway
N
O
C
O
1,2-
R Shift
5ꢀExoꢀDig
Cyclization
R
C
C
C
O
C
C
R
N
N
R
[Ru]
[Ru]
[Ru]
Ru−PyridylꢀYnone
πꢀIntermediate
Ru−Vinylidene
Intermediate
Ru−Indolizinone
(Cꢀ3 metalated)
B
Pathway
N
Further
Transformations
5ꢀEndo ꢀDig
Cyclization
N
Fig. 1
Perspective view of cations 1 (left), 4 (middle) and 7 (right) as
C
O
C
C R
O
R
represented by 50% probability ellipsoids; hydrogen atoms are omitted for
clarity.
[Ru]
[Ru]
Ru−Indolizinone
(Cꢀ2 metalated)
Ru−PyridylꢀYnone
πꢀIntermediate
Two plausible mechanisms for the formation of
Ru−indolizinone complexes, which are inspired by the
mechanisms proposed for metal- or Lewis-acid-catalyzed
cyclization of functionalized alkynes, are depicted in Scheme 2.
Considering a Ru–pyridyl-ynone π complex as the reactant,
Scheme 2
Two plausible reaction mechanisms for the formation of
Ru−indolizinone complexes.
The facts that (1) reaction between pyridyl-ynones
RC≡C(C=O)(2-py) and cis-[Ru([14]aneS4)Cl2] yields
Ru indolizinone complex instead of ruthenafuran complex,
and (2) no C-3 metalated Ru indolizinone complex (proposed
in pathway ) was isolated in this work, clearly suggest the
possibility of non-vinylidene-involving pathway for the
formation of Ru indolizinone complexes. In this regard,
density functional theory (DFT) calculations suggest that the
formation of from a Ru pyridyl-ynone π-intermediate 1-π via
a 5-endo-dig cyclization (pathway ) has a lower activation
Ru
Ru
−
−
indolizinone complex may be formed via the formation of
vinylidene intermediate followed by some subsequent
−
transformations (pathway
A) or a direct 5-endo-dig cyclization
−
(pathway ). The former vinylidene-involving pathway is
B
A
prevalent in Ru-mediated alkyne transformations,5 whereas
the latter one is commonly proposed in coinage-metal- or
Lewis-acid-catalyzed cyclization of functionalized alkynes3 but
is rarely known for Ru(II)-mediated alkyne transformations. At
this juncture, it is important to note that reacting cis-
−
1
−
B
2 | J. Name., 2012, 00, 1-3
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barrier than the formation of Ru–vinylidene species 1v (Fig. 2): LUMO has greater indolizinone contribution (92%) than that in
the formation of 1v from 1-π via 1,2-H shift proceeds through HOMO (22%). Thus the lowest-energy transitions for
the formation of intermediate 1v-INT with an overall energy and are assigned to be dπ(Ru) π*(indolizinone) MLCT in
barrier of 22.7 kcal mol–1 (relative to 1-π), whereas the energy nature. The electronic difference density plot for
in its
barrier for the formation of from 1-π via a direct 5-endo-dig lowest-energy excited state (generated by taking the
cyclization pathway is 7.7 kcal mol− . Even though calculations difference between the excited state electron density and
1, 2, 5
6
→
5
1
1
were not performed on the transformation from 1v to 1, the ground state electron density) also clearly shows that
current calculation results signify that pathway
B
is electronic charge is depleted from dπ(Ru) and accumulated at
energetically more favorable than pathway
A
.
the π*(indolizinone) (Fig. 4). The first oxidation (E1/2 = 0.72 to
0.80 V vs Cp2Fe+/0) and reduction couples (E1/2
= −0.82 to −0.79
V) for the complexes are assigned to Ru-centered oxidation
and indolizinone-centered reduction respectively based on the
HOMO and LUMO composition calculated. Surprisingly, these
+
(a)
S
Ru
S
S
O
R
O
ꢀ
S
Cl
Cl
H
S
R
H
Ru
S
R = Ph [4c]
R = 2ꢀthienyl (7)
S
S
OMe
MeOH
findings reveal that Ru−indolizinone complexes have
remarkably low-lying LUMOs when compared with structurally
ꢀ
R
=
R
R
O
O
O
where Ru
Ru
Ru
ꢀ
related
Ru
−
indolizine
complex
H
H
H
[Ru([14]aneS4)(indolizine)(CH3CN)]2+ (dπ(Ru)
→
π*(indolizine)
OMe
OMe
OMe
A
B
MLCT absorption at λmax = 426 nm; first reduction at Epc
=
(b)
R
−
1.96 V vs Cp2Fe+/0); where indolizine = 1-hydroxy-1-methyl-
R
Nucleophilic Attack
H
1H-indolizinium-2-yl.4b It is beyond expectation that
substitution of a ketone group for a tetrahedral carbon centre
contributes to such a starkly different electronic property.
by MeO− at Cα
C
O
R
H
C
C
+
C
C
C
H
1,2-
H Shift
C
C
OꢀCoordination
to Ru
O
O
C OMe
[Ru]
[Ru]
6
[Ru]
MeOH
(a)
Ru−Ynone
πꢀIntermediate
Ru−Vinylidene
Intermediate
Ruthenafuran
Complex
4
2
0
Scheme 3
(a) Synthetic routes for 7 and (b) plausible formation mechanism
for ruthenafuran complexes previously reported.4c
‡
‡
N
400
600
800
1000
N
‡
Wavelength / nm
H
H
C
O
C
C
O
N
(b)
1v-TS2
C
O
H
C
22.7
[Ru]
10 ꢁA
C
[Ru]
1v-TS1
[Ru]
1-TS
7.7
13.8
1-π
0.0
ꢀ1.5
ꢀ1.0
ꢀ0.5
0.0
0.5
1.0
1.5
Potential / V vs Cp2Fe+/0
1v-INT
1v
N
−5.5
−7.1
C
C
H
Fig 3.
voltammogram (supporting electrolyte: 0.1 M [Bu4N]PF6 in CH3CN; 298 K; scan
rate = 100 mV s−1) of
(a) UV/Vis absorption spectrum (CH3CN, 298 K) and (b) cyclic
O
N
N
N
C
[Ru]
5.
H
H
O
H
O
C
O
C
[Ru]
C
[Ru]
1
[Ru]
−32.3
5-Endo-Dig
Cyclization
Vinylidene Formation
via 1,2-H Shift
Fig 2.
solvent = THF) for the formation of
shift. [Ru] = [Ru([9]aneS3)(bpy)]2+
Potential energy surfaces calculated at DFT level (functional = PBE0;
1
via 5-endo-dig cyclization and 1v via 1,2-H
.
Because the chloride ligands for complexes
substituted by CH3CN to give complexes and
spectroscopic and electrochemical studies on Ru
complexes in CH3CN were only performed on complexes
and (Fig. 3). Each of these complexes feature a low-energy
visible absorption band (λmax = 602 663 nm; εmax = 2
103
dm3 mol− cm− ). Time-dependent DFT (TD-DFT) calculation on
suggests that this transition mainly originates from the
HOMO LUMO transition. The HOMO has greater Ru
3
and
respectively,
indolizinone
4 can be
5
6
−
1, 2, 5
Fig 4.
au) and (b) electronic difference density plot of
(a) Surface plots of the HOMO and LUMO of
5
5
in its lowest-energy excited
(surface isovalue = 0.04
6
state (corresponding to the vertical transition marked with * in Fig. S10 (ESI‡);
isodensity value = 0.003 au).
−
−4×
1
1
The fascinating anticancer properties of indolizinone-based
camptothecin6 prompted us to explore the potential
application of metalated indolizinone complexes as anticancer
5
→
contribution (52%) than that in LUMO (3%), whereas the
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Ru−indolizinone complexes against breast adenocarcinoma
(MCF-7), cervical carcinoma (HeLa), fibrosarcoma (HT1080),
hepatocarcinoma (HepG2), and lung adenocarcinoma (A549)
human cell lines were evaluated by MTT assay and
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exhibit moderate cytotoxicity against HepG2, HT1080 and
MCF-7 cell lines, whereas shows moderate and low
4 and 6
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Table 2 Cytotoxicity (IC50, ꢁM) of Ru−indolizinone complexes.a
HeLa
NC
A549
NC
HepG2
42 ± 2
NC
HT1080
61 ± 13
NC
MCF-7
17 ± 1
80 ± 2
19 ± 2
46 ± 4
4(ClO4)
5(ClO4)2
6(ClO4)2
cisplatin
NC
219 ± 3
NC
NC
75 ± 3
52 ± 1
87 ± 5
15 ± 1
18 ± 1
19 ± 1
a
All indolizinone complexes are non-cytotoxic (NC) against HeLa cells, and
1(ClO4)2, 2(ClO4)2 and 3(ClO4) are NC against all cancer cell lines tested; maximum
complex concentration tested = 400 ꢁM (complexes 1−6) and 250 ꢁM (cisplatin).
In conclusion, two series of isolable and structurally
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−
−
properties and potential medicinal applications.
The work described in this paper was supported by the
Research Grants Council of Hong Kong SAR (CityU 11228316,
CityU 11207117 and T42-103/16-N), the Science Technology
and Innovation Committee of Shenzhen Municipality
(JCYJ20160229165216275), and by the Shenzhen Research
Institute, City University of Hong Kong.
4
Conflicts of interest
There are no conflicts to declare.
5
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Notes and references
1
2
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Dalton Transactions
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DOI: 10.1039/C8DT02408A
The first examples of metal-indolizinone complexes prepared by Ru-assisted activation of
pyridine-tethered alkynes exhibit moderate cytotoxicity against several human cancer cell lines.