AlCl3-mediated hydroarylation-heteroarylation in a single pot: A direct access to densely functionalized olefins of pharmacological interest

Article abstract of DOI:10.1039/c3cc42840k

An unprecedented AlCl₃-mediated method has been developed involving aromatic C-H bond addition to an alkyne and heteroarylation of an arene in a single pot leading to densely functionalized novel olefins, e.g. 2-(2,2-diarylvinyl)-3-arylquinoxalines, as potential inhibitors of sirtuins.

Full text of DOI:10.1039/c3cc42840k

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AlCl3-mediated hydroarylation–heteroarylation in a
single pot: a direct access to densely functionalized
olefins of pharmacological interest†
Ali Nakhi,a Sivakumar Archana,ab Guru Pavan Kumar Seerapu,a
Keerthana Sarma Chennubhotla,ac Kummari Lalith Kumar,a Pushkar Kulkarni,ac
Devyani Haldara and Manojit Pal*a
Cite this: Chem. Commun., 2013,
49, 6268
Received 17th April 2013,
Accepted 21st May 2013
DOI: 10.1039/c3cc42840k
www.rsc.org/chemcomm
An unprecedented AlCl3-mediated method has been developed
involving aromatic C–H bond addition to an alkyne and heteroarylation
of an arene in a single pot leading to densely functionalized novel
olefins, e.g. 2-(2,2-diarylvinyl)-3-arylquinoxalines, as potential inhibitors
of sirtuins.
The discovery of new and direct chemical approaches leading to
densely functionalized olefins is of fundamental interest as it allows
easy access to this class of compounds for potential applications in
chemical/pharmaceutical industries.1 Highly substituted hetero-
aromatics on the other hand has often played a key role in the early
stage of drug discovery. Thus an appropriate assembly of olefin with
a particular (hetero)arene in a single molecular species is expected to
show valuable pharmacological properties (cf. tamoxifen1c). This and
our interest in novel heteroaromatics2 prompted us to explore a new
route to 2-(2,2-diarylvinyl)-3-arylquinoxaline (B, Fig. 1) as potential
inhibitors of sirtuins. Because of their up-regulation in various
types of cancer, sirtuins (class III NAD-dependent deacetylases) are
considered promising targets for cancer therapeutics.3 Inhibition
of sirtuins leads to reduced growth of cancer cells due to the
re-expression of silenced tumor suppressor genes. Our earlier observa-
tion of activities of 3-enynyl flavones4 A against a panel of cancer cell
lines prompted us to design structurally similar B that was supported
by the in silico binding studies of a representative compound C (Fig. 1)
in the catalytic pocket of yeast Sir2 (Fig. 2). The study showed binding
of C deep into the active site (docking score ꢀ8.0) along with two
Fig. 1 Design of B/C as novel inhibitors of sirtuins.
Fig. 2 Binding mode of C in yeast Sir2 (PDB ID: 2HJH).
Recently, in addition to olefin metathesis1a,b the transition
H-bond interactions of the –OH group with the backbone –NH of Asp metal mediated hydroarylation of alkynes has emerged as an
498 and the side chain amino group of Asn 496 (see ESI†).
effective tool for the quick access to substituted olefins.5 Some
metal triflates [M(OTf)n; M = Sc, Zr, In] alone or in an ionic liquid
are also known to catalyze these reactions.6 These reports triggered
us to envision the possibility of an AlCl3-mediated hydroarylation of
alkyne and heteroarylation7 of arene in a single pot leading to B/
a Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
b Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, C. Herein we report our preliminary results on hydroarylation–
India
heteroarylation of 2-chloro-3-(arylethynyl)quinoxaline 2 leading
to 2-(2,2-diarylvinyl)-3-arylquinoxaline 4 (or B, Scheme 1).
c Zephase Therapeutics (an incubated company at the DRILS), University of
Hyderabad Campus, Gachibowli, Hyderabad 500046, India
The key starting material 2 required was prepared via a
† Electronic supplementary information (ESI) available: Experimental proce-
selective mono alkynylation of 2,3-dichloroquinoxaline (1) via
dures, spectral data for all new compounds, results of in vitro/in vivo and docking
study. See DOI: 10.1039/c3cc42840k
Pd/C–Cu catalysis (Table 1).
c
6268 Chem. Commun., 2013, 49, 6268--6270
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e.g. Me (2b) and NO2 (2c) on the quinoxaline ring and aryl (2a–e)
and alkyl (2e) substituents on the triple bond participated well in
the reaction. However, the arene 3 containing electron donating
groups only participated in the present reaction and the use of
unactivated or deactivated arenes was not successful. Nevertheless,
thirty new compounds synthesized by this method were well
characterized by spectral (NMR, IR and MS) data. The Z-geometry
of –CQC– was assigned by the NOE experiment using 4aa, the
vinylic H of which interacted with the Ph protons indicating that
they are on the same side of the double bond.
Scheme 1 AlCl3-mediated hydroarylation–heteroarylation of 2.
Table 1 Synthesis of 3-alkynyl-2-chloroquinoxalines 2a
Mechanistically (Scheme 2), the reaction proceeds through
the complexation of AlCl3 with N-4 of 2 that facilitates a
nucleophilic attack by the arene 3 at the adjacent alkynyl
moiety of E-1 (the hydroarylation step). The release of AlCl3
afforded E-2 the second nitrogen of which on complexation
with AlCl3 followed by the attack of 3 at the adjacent carbon
afforded the product 4 (the heteroarylation7 step).8 Since
nucleophilicity of the reacting arenes is crucial, the reaction
therefore proceeded smoothly with electron-rich arenes.
Entry Halide (1); R0= Alkyne; R= T (h) Product (2) Yieldb (%)
1
2
3
4
5
6
1a; H
1a
1a
1b; Me
1b
1c; NO2
Ph
2
3
3
4
4
4
2a
2b
2c
2d
2e
2f
76
70
64
66
68
63
C6H4Me-p
CMe3
Ph
C6H4Me-p
Ph
Table 3 Synthesis of 2-(2,2-diarylvinyl)-3-arylquinoxaline 4a
a
All reactions were performed using 1 (1.256 mmol), a terminal alkyne
(1.256 mmol), 10% Pd/C (0.0125 mmol), PPh3 (0.0502 mmol), CuI
b
(0.0125 mmol), and Et3N (1.8844 mmol) in EtOH (4 mL). Isolated
yield.
Initially the possibility of hydroarylation–heteroarylation of
2-chloro-3-(phenylethynyl)quinoxaline 2a was examined by using
resorcinol 3a in the presence of AlCl3 (2 equiv.) in 1,2-dichloroethane
(DCE) at 50 1C for 15–60 min when a mixture of 5 and 6 was obtained
(entries 1 and 2, Table 2). The use of 3 equiv. of AlCl3 for 30–60 min
did not change the outcome significantly (entries 3 and 4, Table 2). A
further increase in AlCl3 quantity to 4 equiv. afforded the desired
hydroarylation–heteroarylation product 4aa in good yield (entry 5,
Table 2). An attempt to perform the reaction at room temperature
was not successful as the yield of 4aa decreased significantly (entry 6,
Table 2). Thus the conditions of entry 5 (Table 2) were found to be
optimum and were used for our further studies.
Alkyne (2)
Entry R1, R2
Arene (3)
Time Product Yieldb
R3, R4, R5
(min) (4)
(%)
1
2
H, Ph; 2a
2a
H, H, OH; 3a
H, CH3, OH; 3b
CH3, H, OCH3; 3c 15
CH3, CH3, OCH3; 3d 15
Et, H, OEt; 3e
H, CH3, H; 3f
H, H, CH3; 3g
3a
3b
3c
3d
3e
3a
15
15
4aa
4ab
4ac
4ad
4ae
4af
82
79
64
68
65
62c
55c
80
78
73
71
66
60
71
69
63
67
58
55
74
71
64
60
56
58
55
62
60
63
61
3
4
2a
2a
5
6
2a
2a
30
30
30
15
15
15
30
30
30
15
15
15
30
30
30
15
15
15
15
30
30
30
30
30
30
30
7
8
2a
4ag
4ba
4bb
4bc
4bd
4be
4ca
4da
4db
4dc
4dd
4de
4dh
4ea
4eb
4ec
4ed
4ee
4eh
4fa
CH3, Ph; 2b
We then examined the substrate scope and generality of this
method (Table 3). The alkyne 2 containing contrasting groups
9
2b
2b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2b
2b
Table 2 Effect of conditions on hydroarylation–heteroarylation of 2aa
NO2, Ph; 2c
H, C6H4Me-p 2d 3a
2d
2d
2d
2d
2d
Me, C6H4Me-p 2e 3a
2e
2e
2e
3b
3c
3d
3e
Et, Me, OEt 3h
3b
3c
3d
3e
3h
3a
3b
3c
3d
3e
Yieldb (%)
2e
2e
Entry Alkyne 3a (equiv.) AlCl3 (equiv.) Time (min) 4aa
5
6
1
2
3
4
5
6
2
2
3
3
4
4
2
2
3
3
4
4
15
60
30
60
15
60c
0
0
0
0
82
48
35 45
32 40
30 47
30 47
H, CMe3; 2f
2f
2f
2f
2f
4fb
4fc
4fd
4fe
5
0
0
10
a
All reactions were carried out using 2 (0.3787 mmol), 3 (1.5151 mmol)
a
b
c
Reaction conditions: 2a (0.19 mmol), 3a (mmol), AlCl3 in DCE (2 mL) at
AlCl3 (1.5151 mmol) in DCE (4 mL) at 50 1C. Isolated yield. A 1 : 1
mixture of two regioisomers was isolated (see ESI for further details).
b
c
50 1C. Isolated yield. Reaction was performed at room temperature.
c
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Scheme 2 The proposed reaction mechanism.
The compounds 4 and Splitomicin3b were tested at 50 mM
for their ability to inhibit the Sir2 protein [yeast sirtuin family
NAD-dependent histone deacetylase (HDAC)] by estimating the
inhibition of growth of a yeast strain containing the URA3 gene
at the telomeric locus, in the presence of 5-fluoroorotic acid
(5-FOA) (the yeast cell based reporter silencing assay, see ESI†).9 As
the Sir2 protein is inhibited, the URA3 gene would be de-repressed
resulting in the death of the yeast cell in the presence of 5-FOA.
A parallel screen was performed in the absence of 5-FOA to check
the cytotoxicity of the compounds tested. Among them 4bb (or C,
Fig. 2) showed significant inhibition (B85%) in the presence of
5-FOA and no significant toxic effect in the absence of 5-FOA
(Fig. 3). It showed IC50 B 13.5 mM (comparable to Splitomicin’s
4.2 mM) in a dose response study (Fig. 4) and no adverse effects
when tested for toxicity in a zebrafish embryo (Fig. 5) in a range
10 nM–30 mM [with No Observed Adverse Effect Level (NOAEL)
B 10 mM]. It also showed IC50 B 32.9 mM against mammalian
SIRT1 comparable to Splitomicin’s 60 mM.3b At 50 mM 4bb inhibited
cell growth when tested against human hepatocellular liver
carcinoma (HepG2) cells (MTT assay, see ESI†).
Fig. 5 (a) Control embryo showing
a
normal body; embryo treated with
(b) phenobarbital (positive control) showing severe abnormalities, body bent;
(c) 4bb (10 mM) showing slight abnormality in the swim bladder; (d) 4bb (30 mM)
showing moderate abnormality in the swim bladder and body shape.
In conclusion, 2-(2,2-diarylvinyl)-3-arylquinoxalines are
synthesized for the first time as a novel and unique class of
densely functionalized olefins via an AlCl3-mediated hydro-
arylation–heteroarylation in a single pot. A representative com-
pound showed promising pharmacological properties in vitro/
in vivo and is of further interest.
The authors thank DBT (Grant BT/PR13997/Med/30/310/
2010) and Prof. J. Iqbal for support. AN thanks CSIR for a
research fellowship.
Notes and references
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M. Sreenivasulu, A. A. Jafar, D. Rambabu, G. R. Krishna, C. M. Reddy,
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Commun., 2011, 47, 5010; (b) K. S. Kumar, P. M. Kumar, M. A. Reddy,
M. Ferozuddin, M. Sreenivasulu, A. A. Jafar, G. R. Krishna, C. M. Reddy,
D. Rambabu, K. S. Kumar, S. Pal and M. Pal, Chem. Commun., 2011,
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R. Kapavarapu, K. V. L. Parsa and M. Pal, Chem. Commun., 2012, 48, 431;
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C. M. Reddy, G. S. Deora, K. V. L. Parsa and M. Pal, Chem. Commun.,
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3 (a) S. Michan and D. Sinclair, Biochem. J., 2007, 404, 1; (b) A. Bedalov,
T. Gatbonton, W. P. Irvine, D. E. Gottschling and J. A. Simon, Proc.
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Fig. 3 URA3 silencing assay of the known inhibitor Splitomicin and 4bb (NONTEL =
non telomeric, TEL = telomeric, ꢀFOA = absence of FOA, +FOA = presence of FOA).
4 M. Pal, R. Dakarapu, K. Parasuraman and V. Subramanian, J. Org.
Chem., 2005, 70, 7179.
5 For in depth reviews, see: (a) C. Nevado and A. M. Echavarren,
Synthesis, 2005, 167; (b) X. Wang, L. Zhou and W. Lu, Curr. Org.
Chem., 2010, 14, 289; (c) T. Kitamura, Eur. J. Org. Chem., 2009, 1111.
6 (a) T. Tsuchimoto, T. Maeda, E. Shirakawa and Y. Kawakami, Chem.
Commun., 2000, 1573; (b) C. E. Song, D.-u. Jung, S. Y. Choung,
E. J. Roh and S.-g. Lee, Angew. Chem., Int. Ed., 2004, 43, 6183.
7 For selected reports, see: (a) M. Pal, V. R. Batchu, K. Parasuraman and
K. R. Yeleswarapu, J. Org. Chem., 2003, 68, 6806; (b) M. Pal, V. R. Batchu,
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8 While the alternative path i.e. heteroarylation followed by hydro-
arylation can not be ruled out completely the isolation of 6 seems to
support the former one. Moreover, the AlCl3 mediated reaction of
5 with 3a did not provide 4aa.
9 C. M. Grozinger, E. D. Chao, H. E. Blackwell, D. Moazed and S. L.
Schreiber, J. Biol. Chem., 2001, 276, 38837.
Fig. 4 Dose dependent URA3 silencing assay of 4bb.
6270 Chem. Commun., 2013, 49, 6268--6270
c
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