Palladium catalyzed novel monoarylation and symmetrical/unsymmetrical diarylation of imidazo[1,2-a]pyrazines and their in vitro anticancer activities

Article abstract of DOI:10.1039/c3ra47192f

Palladium catalyzed Suzuki-Miyaura cross-coupling reactions are reported for the synthesis of monoarylated (at the C8 position) and symmetrical diarylated (at the C6 and C8 positions) imidazo[1,2-a]pyrazines. Monoarylated products have also been used to s

Full text of DOI:10.1039/c3ra47192f

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Palladium catalyzed novel monoarylation and
symmetrical/unsymmetrical diarylation of imidazo-
[1,2-a]pyrazines and their in vitro anticancer
activities†
Cite this: RSC Adv., 2014, 4, 9885
Received 2nd December 2013
Accepted 18th December 2013
*
Richa Goel, Vijay Luxami and Kamaldeep Paul
DOI: 10.1039/c3ra47192f
www.rsc.org/advances
Palladium catalyzed Suzuki–Miyaura cross-coupling reactions are coupling reactions. But, the imidazo[1,2-a]pyrazine series
reported for the synthesis of monoarylated (at the C8 position) and remains almost unexplored for palladium catalyzed direct C–C
symmetrical diarylated (at the C6 and C8 positions) imidazo[1,2-a]- monoarylation at C8 and diarylation at C6 and C8 positions.
pyrazines. Monoarylated products have also been used to synthesize Palladium catalyzed cross-coupling reactions of aryl halides
unsymmetrical C6/C8 diarylated products. These compounds were with organometallic reagents serve as a straightforward and
screened for in vitro antitumor activities against a preliminary tumor powerful method for the formation of carbon–carbon bonds.
cell line panel assay.
Most magnesium, tin and zinc reagents are sufficiently reactive
to undergo transmetalation with palladium without the need
for a ligand or an additive; boron and silicon reagents, on the
other hand, are usually reluctant to transmetalate in the
absence of an activator. So Suzuki is typically carried out in the
presence of a ligand, the role of which is to form a higher valent,
more reactive complex.2b Herein we report the monoarylation at
the C8 position and symmetrical/unsymmetrical diarylation at
the C6 and C8 positions of imidazo[1,2-a]pyrazine catalyzed by
palladium with and without ligands.
To obtain 6,8-dibromo-imidazo[1,2-a]pyrazine, we have used
the readily available starting material 2-aminopyrazine 1.
Bromination of 1 with N-bromosuccinamide (NBS) in DMSO
and water at room temperature for 6 h gave 2-amino-3,5-
dibromopyrazine 2 (ref. 16) in 90% yield followed by cyclization
with chloroacetaldehyde in the absence of base to obtain 6,8-
dibromo-imidazo[1,2-a]pyrazine 3 in 80% yield (Scheme 1).
Palladium catalyzed Suzuki–Miyaura coupling of 6,8-
dibromo-imidazo[1,2-a]pyrazine 3 with different aryl boronic
acids afforded substituted monoarylated and symmetrical dia-
rylated products. During our study of imidazo[1,2-a]pyrazine
derivatives, thiophen-2-boronic acid served as a model reactant
for the optimization of the reaction conditions as the thiophene
moiety is considered a structural alert in drug design and
discovery. Thiophene and the thienyl core have attracted the
Fused heterocyclic molecular frameworks are found in a large
number of biologically active natural and synthetic compo-
nents.1 Halogenated heteroaromatic ring systems are valuable
monomers because of their ability to participate in established
cross-coupling reactions including the Heck, Stille and Suzuki
reactions.2 Several procedures for transition-metal-catalyzed
direct C–C functionalization of imidazoazines have been
developed, notably in the imidazo[1,2-a]pyridine3 and imidazo-
[1,2-a]pyrimidine4 series. Imidazo[1,2-a]pyrazine, consisting of
bicyclic N-fused imidazole and pyrazine rings, is a privileged
structural motif present in several natural products and phar-
macologically relevant structures with a wide range of activities
such as aurora kinase inhibitors,5 antiinammatory,6 anti-
bronchospastic,7 antiulcer,8 anticancer9 and controlling allergic
reactions.10
A variety of classical methods have been developed for the
functionalization of imidazo[1,2-a]pyrazine viz., arylation of
8-methoxy or 8-methylthio-6-bromo-imidazo[1,2-a]pyrazines,11
3-aryl/alkylamino and 2-aryl/alkyl substituted imidazo[1,2-a]-
pyrazines,12 diarylurea,13 8-morpholinyl14 and 3,6-di(hetero)aryl-
imidazo[1,2-a]pyrazines15 through palladium catalyzed cross-
School of Chemistry and Biochemistry, Thapar University, Patiala-147004, India.
E-mail: kpaul@thapar.edu; Fax: +91 175 236 4498; Tel: +91 175 236 4498
† Electronic supplementary information (ESI) available: Experimental section, 1H
and 13C NMR spectra of all new compounds 4–12 and 16–30, antitumor
methodology and activities of all selected compounds 4a–b, 5a–b, 7a, 8a–b,
9a–b, 11a–b, 13b, 18–19, 21–23, 27–28 and 30. CCDC 960038 and 960039. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra47192f
Scheme 1 Synthesis of 6,8-dibromo-imidazo[1,2-a]pyrazine.
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attention of the scientic community due to their therapeutic different solvents was also studied and it was observed that the
uses as anti HIV,17 antitubercular,18 antimicrobial,19 tyrosine reaction proceeds in both protic and aprotic solvents although
kinase inhibitor20 and anticancer agents.21
signicant variations in yield were noticed. The polar protic
The Suzuki–Miyaura coupling reaction between 3 and thio- solvents such as MeCN–H2O (Table 1, entries 1–6 and 15–20),
phen-2-boronic acid was carried out with different palladium THF–H2O (Table 1, entry 11) and acetone (Table 1, entry 12)
based catalysts such as Pd(PPh3)4, Pd(PPh3)2Cl2 and were found to be the most effective solvents and gave excellent
Pd2(dba)3.Pd(PPh3)4 proved to be an effective catalyst for mon- results. On the other hand, the protic nonpolar solvent,
oarylated and diarylated products giving 70% and 10% yields toluene–H2O (Table 1, entries 7–10), and aprotic polar solvents
respectively (Table 1, entries 1–3). A survey of different bases viz., DMF and 1,4-dioxane (Table 1, entry 13 and 14) gave
(Cs2CO3, Na2CO3, K2CO3 and DIPEA) revealed that Cs2CO3 was comparatively lower yields. A lower yield was also obtained in
found to be the best choice (Table 1, entries 3–6). Recent the absence of water (Table 1, entry 21). Polar protic solvents
developments have been reported for in Suzuki–Miyaura like isopropyl alcohol ((IPA) (Table 1, entries 22–24)) with
coupling employing ligandless palladium catalysts and phase- Cs2CO3 gave very interesting results as 8-thiophen-2-yl-imidazo-
transfer catalysis or a mixture of organic solvents along with [1,2-a]pyrazine was formed 4c in 60% yield along with 6-bromo-
water as a cosolvent.22 Use of water is suitable in this coupling 8-thiophen-2-yl-imidazo[1,2-a]pyrazine 4a in 30% yield due to
reaction as boronic acids are stable in aqueous conditions. Its dehalogenation and C–C coupling respectively. However, K2CO3
ability to dissolve various bases helps in activating boronic in IPA gave only 8-thiophen-2-yl-imidazo[1,2-a]pyrazine 4c in
acids and enhancing the rate of reaction.23 The effect of 55% yield. A mixture of acetonitrile and water (9 : 1) proved to
Table 1 Optimization of palladium catalyzed Suzuki–Miyaura couplinga
Yieldb (%)
Entry
Time (h)
Catalyst/ligand
Base
Solvent
4a/4b/4c
1
2
3
4
5
6
7
8
12
12
8
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
DIPEA
Na2CO3
K2CO3
DIPEA
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
DIPEA
Na2CO3
K2CO3
DIPEA
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
Toluene–H2O
Toluene–H2O
Toluene–H2O
Toluene–H2O
THF–H2O
Acetone
30/10/0
43/7/0
70/10/0
62/11/0
60/15/0
54/10/0
45/5/0
36/13/0
15/0/0
20/10/0
55/0/0
52/15/0
52/0/0
44/0/0
52/7/0
50/5/0
38/10/0
43/0/0
65/0/0
45/0/0
30/15/0
0/0/45
0/0/55
30/0/60
62/10/0
65/0/0
61/5/0
59/0/0
53/0/0
10
12
12
18
19
18
12
19
10
10
15
14
14
15
12
12
12
20
12
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
DMF
Pd(PPh3)4
1,4-Dioxane
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN
IPA
IPA
IPA
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4 + XantPhos
Pd(PPh3)4 + JohnPhos
Pd(PPh3)4 + cyclohexyl John Phos
Pd(PPh3)4 + BINAP
Pd(PPh3)4 + PPh3
12
11
10
10
9
12
a
Reaction conditions: 1.0 eq. thiophen-2-boronic acid, 5 mol% catalyst, 5 mol% ligand, 1.0 eq. base, solvent : cosolvent (9 : 1), reux, 8–20 h.
Isolated yields.
b
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Table
3
Reactions of 6,8-dibromo-imidazo[1,2-a]pyrazine with
be best solvent for this transformation. Reaction conditions
were also optimized by using a Pd catalyst in the presence of
different ligands. Use of ligands XantPhos, JohnPhos, cyclo-
hexyl JohnPhos, BINAP and PPh3 (Table 1, entries 25–29) were
not able to increase the diarylated products or improve the
yields of the monoarylated products.
different boronic acids
Further, by using 1.5 equivalents of thiophen-2-boronic acid
in the same ratio of Cs2CO3, there was not much variation in
monosubstituted and disubstituted products. But by using
2.0 eq. of boronic acid, monosubstituted and disubstituted
products were formed in 28% and 54% yields respectively.
When 3.0 eq. of boronic acid was used, predominantly disub-
stituted products were formed with monosubstituted products
only in traces (Table 2).
Entry
Time (h)
Ar
Productsa (%)
1
2
8
4a (70)
5a (56)
4b (10)
5b (12)
12
With the optimized reaction conditions in hand, we have
used 1.0 equivalent of thiophen-2-boronic acid, 5 mol% of
Pd(PPh3)4, Cs2CO3 (1 eq.) in MeCN–H2O (9 : 1) and evaluated
the scope of arylation with a variety of aryl boronic acids,
providing a library of monosubstituted (4a–15a) and disubsti-
tuted imidazo[1,2-a]pyrazines (4b–15b) (Table 3). Electron
withdrawing as well as electron donating substituents on aryl
boronic acids were well tolerated. The reaction worked well with
thiophen-2-boronic acid, furan-2-boronic acid, 4-uoro,
4-chloro, 4-bromo, 4-methoxy, 4-formyl and 2-hydroxyphenyl
boronic acids and good yields of monoarylated and diarylated
products were obtained (Table 3, entries 1–8). Among the
halides, 4-chloro and 4-bromo gave higher yields of the mono-
arylated products compared to the 4-uoro analogue. The
structures of all novel compounds were conrmed by NMR
(ESI†) as well as mass spectroscopic techniques. The structure
of compound 9b was also conrmed by X-ray crystallography
(Fig. 1).24 In the case of naphthalen-1-boronic acid, only the
monoarylated product at the C8 position was formed in 64%
yield and arylation at the C6 position did not occur (Table 3,
entry 9). This is due to the steric hindrance of the bulky naph-
thyl ring at the C8 position of the imidazo[1,2-a]pyrazine. In the
case of phenyl boronic acid, 3-methylphenyl boronic acid and 4-
3
4
10
8
6a (52)
7a (70)
6b (25)
7b (16)
5
6
7
8
8
8
7
8
8a (68)
9a (69)
10a (70)
11a (57)
8b (20)
9b (14)
10b (15)
11b (30)
9
10
12a (64)
—
10
11
10
10
13a (50)b
14a (53)b
13b (20)b
14b (10)b
12
11
15a (65)b
15b (13)b
Table
2 Reactions of 6,8-dibromo-imidazo[1,2-a]pyrazine with
varying equivalences of boronic acid
Isolated yields. b GC-MS yields.
a
Yielda (%)
Thiophen-2-boronic
Entry
acid (eq.)
Cs2CO3
4a
4b
1
2
3
4
5
1.0
1.5
2.0
2.5
3.0
1.0
1.5
2.0
2.5
3.0
70
65
28
20
Trace
10
20
54
60
90
Fig. 1 X-ray structure of 9b.
a
Isolated yields.
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ethylphenyl boronic acid, monoaryl and diaryl substituted of growth inhibition over sixty tested cancer cell lines were
imidazo[1,2-a]pyrazine could not be isolated in pure form, but determined25–27 (Tables
and 2, ESI†). Monosubstituted
1
were conrmed by NMR and GCMS (Table 3, entries 10–12). compounds (4a–5a, 7a–9a and 11a) displayed modest potency
Attempting to achieve arylation with 4-acetylphenyl boronic against the tested tumor cell lines and were considered to be the
acid in all the reaction conditions proved unsuccessful and only least effective. Similarly disubstituted compounds (4b, 5b, 9b
the starting material was recovered.
and 13b) showed lower activity for cancer cell lines but were
We took advantage of the monoarylated products to imple- more active than the monosubstituted compounds. Diarylated
ment an additional cross-coupling reaction which aimed at compounds 4-bromophenyl and 2-hydroxyphenyl imidazo[1,2-a]-
providing straightforward access to unsymmetrical imidazo[1,2-a]- pyrazine (8b and 11b) showed a broad spectrum of anticancer
pyrazine. Thus, reactions of C8 monosubstituted imidazo[1,2-a]- activity compared to their corresponding monoarylated prod-
pyrazines were carried out with 1.0 equivalent of a variety of ucts (8a and 11a), indicating that arylation at both C6 and C8
boronic acids in the presence of Pd(PPh3)4 and Cs2CO3 in MeCN– positions is essential for activity. Disubstituted compound 4b
H2O to give unsymmetrical diarylated imidazo[1,2-a]pyrazine showed selective potency towards breast cancer cell lines MCF7,
derivatives. Monoarylation at the C8 position was conrmed by T-47D and MDA-MB-468 with GI values of 75.44%, 78.80% and
considering 2D NOE difference experiments (Fig. 2) that 88.28%, respectively, while compound 5b showed selectivity
showed negative NOE signals for the singlet from the C5H towards breast cancer cell line MCF7 with a GI value of 75.20%.
proton of imidazo[1,2-a]pyrazine and doublet from the C20H of Compound 8b also showed excellent inhibition against
4-formylphenyl (10a). For the unsymmetrical diarylation, leukaemia cancer cell lines K-562 (83.21%), SR (86.61%), non-
substitution of 4-formylphenyl at the C8 position and 2-thio- small cell lung cancer cell line NCI-H460 (83.24%), colon cancer
phene at C6 position (25) was also conrmed by 2D NOE cell lines COLO205 (92.17%), HCT-15 (78.38%), HT29 (90.12%)
experiment (positive NOE signals for the singlet from the C5H and SW-620 (74.59%), melanoma cancer cell line MDA-MB-435
proton of imidazo[1,2-a]pyrazine with a doublet from the (96.92%), ovarian cancer cell line NCI/ADR-RES (80.29%) and
thiophene and negative NOE signals for the singlet from breast cancer cell lines BT-549 (82.44%), MCF7 (77.96%), and is
the C5H proton of imidazo[1,2-a]pyrazine and doublet from lethal to non-small lung cancer cell line NCI-H522. Compound
the C20H of 4-formylphenyl). 4-Fluoro, 4-chloro, 4-methoxy and 11b also showed selectivity towards colon cancer cell line HCT-
4-formylphenyl imidazo[1,2-a]pyrazine derivatives were reacted 15, renal cancer cell line A-498, breast cancer cell lines MCF7
with thiophen-2-boronic acid, furan-2-boronic acid, 4-methoxy, and MDA-MB-231/ATCC with GI values of 59.04%, 68.01%,
2-hydroxy, 4-formyl, 4-chloro and 4-uorophenyl boronic acids 59.64% and 69.32% respectively.
to form the corresponding unsymmetrical imidazo[1,2-a]pyr-
Compounds 18, 27 and 28 are the least effective in the
azines (16–30) in 52–85% yields (Table 4). The reaction of unsymmetrical disubstituted imidazo[1,2-a]pyrazine series
monosubstituted 4-methoxyphenyl derivative was slow and indicating that 4-chlorophenyl, 2-hydroxyphenyl and 4-uoro-
only traces of the desired product was observed when naph- phenyl at the C6 position to their corresponding 4-uorophenyl
thalen-1-boronic acid was reacted under the same reaction and 4-methoxyphenyl at C8 positions of imidazo[1,2-a]pyrazine
conditions. The structure of compound 20 was also conrmed is not essential for activity. Compounds 23 and 30, having 4-
by measuring X-ray crystallography (Fig. 3).24 All synthesized uorophenyl and 2-thiophene moieties at the C8 position with
compounds were screened for in vitro anticancer activity.
respective 4-chlorophenyl and 4-methoxyphenyl groups at the
Preliminary anticancer activity studies revealed that mono- C6 position of imidazo[1,2-a]pyrazine, showed moderate anti-
arylated, symmetrical diarylated compounds (4a, 4b, 5a, 5b, 7a, tumor activity while compounds 21 and 22, with 2-hydroxy-
8a, 8b, 9a, 9b, 11a, 11b and 13b) and unsymmetrical diarylated phenyl and 2-furan at the C6 position with 4-chlorophenyl at the
compounds (18, 19, 21–23, 27, 28 and 30) were selected by C8 positions showed a broad spectrum of antitumor activity.
National Cancer Institute, Bethesda, Maryland, USA on the Leukaemia cancer cell line K-562 proved to be sensitive
basis of structure variation for evaluation of their anticancer towards compounds 19, 21 and 23 with GI values of 73.90%,
activity. The selected compounds were subjected to in vitro 78.51% and 70.71% respectively. Non-small lung cancer cell
anticancer assay against tumor cells in a full panel of 60-cell lines NCI-H322M and NCI-H460 showed sensitivity towards
lines at single dose concentration of 10 mM, and the percentages compound 22 with GI values of 88.56% and 85.47% respec-
tively while NCI-H522 showed sensitivity towards compound
21 with a GI value of 82.59%. Compound 19 showed selectivity
towards melanoma cancer cell line MDA-MB-435, breast
cancer cell lines MCF7 and T-47D with GI values of 76.92%,
80.94% and 83.67% respectively. Compound 22 showed
selectivity towards CNS cancer cell line SF-295 with a GI value
of 84.86% and renal cancer cell line ACHN, TK-10 and UO-31
with GI values of 91.41%, 88.07% and 92.94% respectively.
These results revealed that unsymmetrical diarylated
compounds have been found to be more effective for anti-
cancer activity than monoarylated or symmetrical diarylated
compounds.
1
1
Fig. 2 2D NOE H, H correlations used for structural assignment of
compounds 10a and 25.
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Table 4 Reactions of 8-aryl-6-bromo-imidazo[1,2-a]pyrazines with aryl boronic acids
Entry
1
Time (h)
6
Monoarylated imidazopyrazine
Ar'B(OH)2
Product
Yield (%)
mp (ꢀC)
(16) 82
(17) 80
208–210
2
3
4
7
6
9
158–160
136–138
135–137
(18) 62
(19) 70
5
6
7
8
8
(20) 65
(21) 68
(22) 72
204–207
172–174
159–161
10
8
7
(23) 70
134–135
9
7
9
(24) 74
(25) 52
115–117
165–167
10
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Table 4 (Contd.)
Entry
11
Time (h)
Monoarylated imidazopyrazine
Ar'B(OH)2
Product
Yield (%)
mp (ꢀC)
7
(26) 85
190–192
12
13
14
7
10
10
(27) 75
(28) 68
(29) 76
125–127
108–110
119–121
15
12
(30) 70
120–122
the cancer cell lines. (iii) Unsymmetrical diaryl imidazo[1,2-a]-
pyrazine showed a broader spectrum of antitumor activity than
symmetrical diaryl analogues. (iv) Introduction of 2-hydroxy-
phenyl (21), 2-furanyl (22) and 4-uorophenyl (23) at the C6
position with 4-chlorophenyl at the C8 position of imidazo[1,2-a]-
pyrazine led to a broad spectrum of antitumor activity. Thus 4-
chlorophenyl at the C8 position of imidazo[1,2-a]pyrazine plays
an important role for the activity. (v) The presence of 4-chlor-
ophenyl (19) and 4-methoxyphenyl (30) at the C8 position and 2-
thiophene at the C6 position of imidazo[1,2-a]pyrazine has
slightly improved the activity. (vi) Amongst the symmetrical
diaryl analogues, 4-bromophenyl at the C6 and C8 positions of
imidazo[1,2-a]pyrazine (8b) has improved the antitumor
activity.
Fig. 3 X-ray structure of 20.
The structure–activity relationship (SAR) determined from
the activity results showed that monoaryl and diaryl imidazo-
[1,2-a]pyrazines were well tolerated for in vitro anticancer
activities. (i) The monosubstituted and disubstituted imidazo-
[1,2-a]pyrazines with variations of different functional groups
on the aryl moiety play a key role in varying the efficiency of
antitumor activities. (ii) The diaryl imidazo[1,2-a]pyrazines
positively inuence the antitumor effectiveness, inducing better
activity than monoaryl imidazo[1,2-a]pyrazines against most of
Conclusion
In summary, palladium catalyzed direct C–C coupling has been
developed from easily accessible 6,8-dibromo-imidazo[1,2-a]-
pyrazine, allowing the straightforward functionalization at both
C6 and C8 positions to produce a series of monoarylation and
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symmetrical diarylation products. In addition, facile access to 8-
functionalized imidazo[1,2-a]pyrazines were also demonstrated
by implementing unsymmetrical diarylation in moderate to
high yields. Preliminary analysis of the anticancer activities
revealed that unsymmetrical diarylated imidazo[1,2-a]pyrazines
showed more selectivity than monoarylated and symmetrical
diarylated analogues. Compounds 21 and 22 showed a broad
spectrum antitumour activities in most of the cancer cell lines
amongst these series. Overall, we believe that the developed
reaction method and novel series of arylated imidazo[1,2-a]-
pyrazines should be considered as an important advance in
medicinal and pharmaceutical chemistry.
M. Matteucci, J. Reynisson, N. Brown, B. Atrash, J. Blagg,
E. McDonald, S. Linardopoulos, R. Bayliss and V. Bavetsias,
Bioorg. Med. Chem. Lett., 2010, 20, 5988–5993; (c)
M. E. Voss, M. P. Rainka, M. Fleming, L. H. Peterson,
D. B. Belanger, M. A. Siddiqui, A. Hruza, J. Voigt, K. Gray
and A. D. Basso, Bioorg. Med. Chem. Lett., 2012, 22, 3544–
3549; (d) D. B. Belanger, P. J. Curran, A. Hruza, J. Voigt,
Z. Meng, A. K. Mandal, M. A. Siddiqui, A. D. Basso and
K. Gray, Bioorg. Med. Chem. Lett., 2010, 20, 5170–5174.
6 M. G. Rimoli, L. Avallone, P. De Caprariis, E. Luraschi,
E. Abignente, W. Filippelli, L. Berrino and F. Rossi, Eur. J.
Med. Chem., 1997, 32, 195–203.
7 P. A. Bonnet, A. Michel, F. Laurent, C. Sablayrolles,
E. Rechencq, J. C. Mani, M. Boucard and J. P. Chapat, J.
Med. Chem., 1992, 35, 3353–3358.
Acknowledgements
KP wishes to thank CSIR, New Delhi (02(0034)/11/EMR-II) for
providing funds. RG is indebted to CSIR for SRF (09/677(0020)/
2013.EMR-I). We wish to thank IISER, Mohali and Punjab
University, Chandigarh for carrying out crystallographic and
8 P. J. Zimmermann, C. Brehm, W. Buhr, A. M. Palmer, J. Volz
and W.-A. Simon, Bioorg. Med. Chem., 2008, 16, 536–541.
9 S. Myadaraboina, M. Alla, V. Saddanapu, V. R. Bommena and
A. Addlagatta, Eur. J. Med. Chem., 2010, 45, 5208–5216.
mass analysis respectively. NCI, USA is greatly acknowledged for 10 A. Brown, A. Heenderson, C. Lane, M. Lansdell, G. Maw and
anticancer activity studies.
S. Monaghan, Bioorg. Med. Chem. Lett., 2006, 16, 4697–4700.
11 V. Gembus, J.-F. Bonfanti, O. Querolle, P. Jubault,
V. Levacher and C. Hoarau, Org. Lett., 2012, 14, 6012–6015.
12 S. K. Guchhait, S. Kandekar, M. Kashyap, N. Taxak and
P. V. Bharatam, J. Org. Chem., 2012, 77, 8321–8328.
References
1 (a) A. Padwa and S. K. Bur, Tetrahedron, 2007, 63, 5341–5378;
(b) D. M. D'Souza and T. J. J. Muller, Chem. Soc. Rev., 2007, 13 S. A. Mitchell, M. D. Danca, P. A. Blomgren, J. W. Darrow,
36, 1095–1108.
K. S. Currie, J. E. Kropf, S. H. Lee, S. L. Gallion,
J.-M. Xiong, D. A. Pippin, R. W. DeSimone, D. R. Brittelli,
D. C. Eustice, A. Bourret, M. H. Drzewi, P. M. Maciejewski
and L. L. Elkin, Bioorg. Med. Chem. Lett., 2009, 19, 6991–
6995.
2 (a) C. Fu. Gregory, Acc. Chem. Res., 2009, 41, 1555–1564; (b)
A. F. Littke and C. Fu. Gregory, Angew. Chem., Int. Ed.,
2002, 41, 4176–4211.
3 (a) B. B. Toure, B. S. Lane and D. Sames, Org. Lett., 2006, 8,
´
´
1979–1982; (b) J. Koubachi, S. El. Kazzouli, S. Berteina- 14 S. M. Gonzalez, A. I. Hernandez, C. Varela, S. Rodrıguez-
´
´
Raboin, A. Mouaddib and G. Guillaumet, J. Org. Chem.,
2007, 72, 7650–7655; (c) J. Koubachi, S. El. Kazzouli,
S. Berteina-Raboin, A. Mouaddib and G. Guillaumet,
Synthesis, 2008, 2537–2542; (d) R. R. Singhaus,
Arıstegui, R. M. Alvarez, A. B. Garcıa, M. Lorenzo,
V. Rivero, J. Oyarzabal, O. Rabal, J. R. Bischoff,
M. Albarran, A. Cebria, P. Alfonso, W. Link, J. Fominaya
and J. Pastor, Bioorg. Med. Chem. Lett., 2012, 22, 1874–1878.
´
´
R. C. Bernotas, R. Steffan, E. Matelan, E. Quinet, P. Nambi, 15 T. P. Matthews, T. McHardy, S. Klair, K. Boxall, M. Fisher,
I. Feingold, C. Huselton, A. Wilhelmsson, A. Goos-Nilsson
and J. Wrobel, Bioorg. Med. Chem. Lett., 2010, 20, 521–525;
(e) J. Koubachi, S. Berteina-Raboin, A. Mouaddib and
G. Guillaumet, Tetrahedron, 2010, 66, 1937–1946; (f)
M. Cherry, C. E. Allen, G. J. Addison, J. Ellard,
G. W. Aherne, I. M. Westwood, R. Montfort, M. D. Garrett,
J. C. Reader and I. Collins, Bioorg. Med. Chem. Lett., 2010,
20, 4045–4049.
P. V. Kumar, W.-S. Lin, J.-S. Shen, D. Nandi and H. M. Lee, 16 B. Jiang, C.-G. Yang, W.-N. Xiong and J. Wang, Bioorg. Med.
Organometallics, 2011, 30, 5160–5169; (g) H. Cao, H. Zhan,
Chem., 2001, 9, 1149–1154.
Y. Lin, X. Lin, Z. Du and H. Jiang, Org. Lett., 2012, 14, 17 C. Bonini, L. Chiummiento, M. D. Bonis, M. Funicello,
1688–1691; (h) H. Y. Fu, L. Chen and H. Doucet, J. Org.
Chem., 2012, 77, 4473–4478; (i) K. Pericherla, P. Khedar,
P. Lupattelli, G. Suanno, F. Berti and P. Campaner,
Tetrahedron, 2005, 61, 6580–6589.
B. Khungar and A. Kumar, Chem. Commun., 2013, 49, 18 X. Lu, B. Wan, S. G. Franzblau and Q. You, Eur. J. Med. Chem.,
2924–2926. 2011, 46, 3551–3563.
4 (a) W. Li, D. P. Nelson, M. S. Jensen, R. S. Hoerrner, 19 M. Z. Elsabee, E. A. Ali, S. M. Mokhtar and M. Eweis, React.
G. J. Javadi, D. Cai and R. D. Larsen, Org. Lett., 2003, 5,
Funct. Polym., 2011, 71, 1187–1194.
4835–4837; (b) M. Parisien, D. Valette and K. Fagnou, J. 20 W. Brandt, L. Mologni, L. Preu, T. Lemcke, C. Gambacorti-
Org. Chem., 2005, 70, 7578–7584.
5 (a) A. D. Kerekes, S. J. Esposite, R. J. Doll, J. R. Tagat, T. Yu,
Passerini and C. Kunick, Eur. J. Med. Chem., 2010, 45,
2919–2927.
Y. Xiao, Y. Zhang, D. B. Prelusky, S. Tevar, K. Gray, 21 (a) R. Romagnoli, P. G. Baraldi, M. D. Carrion, C. L. Cara,
G. A. Terracina, S. Lee, J. Jones, M. Liu, A. D. Basso and
E. B. Smith, J. Med. Chem., 2011, 54, 201–210; (b)
N. Bouloc, J. M. Large, M. Kosmopoulou, C. Sun, A. Faisal,
O. Cruz-Lopez, D. Preti, M. Tolomeo, S. Grimaudo,
A. D. Cristina and N. Zonta, Bioorg. Med. Chem., 2008, 16,
5367–5376; (b) P. Diana, A. Carbone, P. Barraja,
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RSC Advances
Communication
A. Montalbano, A. Martorana, G. Dattolo, O. Gia, L. D. Via
and G. Cirrincione, Bioorg. Med. Chem. Lett., 2007, 17,
R. D. Rogers and K. H. Shaughnessy, Organometallics,
2005, 24, 962–971.
2342–2346; (c) M. A. Gouda, M. A. Berghot, E. A. Baz and 23 M. Mondal and U. Bora, Green Chem., 2012, 14, 1873–1876.
W. S. Hamama, Med. Chem. Res., 2012, 21, 1062–1070; (d) 24 ESI.†
C. Medower, L. Wen and W. W. Johnson, Chem. Res. 25 M. R. Grever, S. A. Sehepartz and B. A. Chabners, Semin.
Toxicol., 2008, 21, 1570–1577; (e) L. Brault, E. Migianu,
Oncol., 1992, 19, 622.
A. Ne guesque, E. Battaglia, D. Bagrel and G. Kirsch, Eur. J. 26 A. Monks, D. Schudiero, P. Skehan, R. Shoemaker, K. Paull,
Med. Chem., 2005, 40, 757.
22 (a) R. B. DeVasher, L. R. Moore and K. H. Shaughnessy, J.
Org. Chem., 2004, 69, 7919–7927; (b) R. B. DeVasher,
D. Vistica, C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff,
M. Gray-Goodrich, H. Campbell, J. Mayo and M. Boyd, J.
Natl. Cancer Inst., 1991, 83, 757.
J. M. Spruell, D. A. Dixon, G. A. Broker, S. T. Griffin, 27 M. R. Boyd and K. D. Paull, Drug Dev. Res., 1995, 34, 91.
9892 | RSC Adv., 2014, 4, 9885–9892
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