Silver-catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole via a domino approach: Evaluation of anti-cancer activity

Article abstract of DOI:10.1039/c7nj03608f

Silver-catalyzed domino synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of pyrrole-derived δ-alkynyl aldehydes and nucleophilic amines was performed. This domino strategy involves the formation of two new C-N bonds and one C-O/C-N bond, resulting in the formation of two new interesting fused heterocycles. Some of the synthesized compounds exhibit promising growth inhibitory activity against leukemia and breast cancer cell lines.

Full text of DOI:10.1039/c7nj03608f

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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DOI: 10.1039/C7NJ03608F
Journal Name
COMMUNICATION
Silver-catalyzed synthesis of pyrrolopiperazine fused with
oxazine/imidazole via domino approach: their evaluation
of anti-cancer activity
Received 00th January 20xx,
Accepted 00th January 20xx
K. Shiva Kumar,*a N. Praveen Kumara, Bandari Rajeshama, Gangulothu
Kishana, Sravani Akulab, Rama Krishna Kanchab
DOI: 10.1039/x0xx00000x
www.rsc.org/
Silver-catalyzed domino synthesis of pyrrolopiperazine fused
with oxazine/imidazole by the reaction of pyrrole derived δ-
alkynyl aldehydes and nucleophilic amines. This domino
strategy would involve the formation of two new C-N and one
C-O/C-N bonds resulting to the formation of two new
intresting fused heterocyclics. Some of the synthesized
compounds showed promising growth inhibition of leukemia
and breast cancer cell lines.
Fig. 1 Examples of bioactive pyrrolopiperazine derivatives.
2) used for the treatment of AIDS9e and A-62176, A-74932 is a
phenoxazine derivative, potent inhibitors of mammalian DNA
topoisomerase II in vivo that showed strong cytotoxic activity
against tumor cell lines.10 Thus, a combination of structural
features of both pyrrolopiperazine and oxazine in a single
molecular entity represented by F (Fig. 2) was expected to
provide new chemical space that might lead to the identification
of novel molecules possessing pharmacological properties.
Accordingly, we decided to synthesize and evaluate the
pyrrolopiperazine fused oxazine derivatives for their anticancer
properties.
Cascade reactions are high in demand in modern organic
synthesis, because they can directly and efficiently construct
complex molecules, without isolating any intermediates, from
readily accessible starting materials and most importantly with
excellent atom economy.1
The pyrrolopiperazine framework has been found to be an
integral part of several natural products, bioactive compounds
and drugs.2 For example, hanishin3 (A) and longamide B methyl
ester4 (B) two natural molecules isolated from marine sponges
and showed cytotoxic activity against NSCLCN6 human
nonsmall-cell lung carcinoma (IC50 9.7 μg/mL), P-388
lymphocytic leukemia cells (ED50 30 μg/mL), respectively.
Longamide B (C) showed activity against african trypanosome
(IC50 1.53 μg/mL) (Fig. 1). Pyrrolopiperazine skeleton (D, Fig.
2) is also widely present in agelastatin alkaloids,5 which is
known for the anticancer activity. Additionally, the synthetic
derivative thieno[3,2-e]pyrrolo[1,2-a]pyrazines,6 pyrido[2,3-
e]pyrrolo[1,2-a]pyrazines7 have shown to be selective 5-HT3
Fig. 2 Design of novel and potential apoptotic agents F.
While as an individual class of heterocycles pyrrolopiperazine11 and
bezoxazine12 are well known in the literature, their combined form
i.e. pyrrolo[2',1':3,4]pyrazino[2,1-b][1,3]oxazine and imidazo[1,2-
a]pyrrolo[2,1-c]pyrazine were rather uncommon.
receptor
agonists
and
the
tricyclic
1,2,3,4-
tetrahydropyrazino[1,2-a]indole act as melatoninergic ligands (Ki
= 7–11 nM).8 On the other hand, oxazine is considered as great
biological and pharmacological interest9 e.g. Efavirenz (E, Fig.
One of the major challenges and aim of the present work is
therefore to develop a suitable methodology leading to the
heterocyclic structure F (Fig 2). In continuation of our interest in
the synthesis of fused heterocyclic scaffolds13, we envisaged that
the one-pot synthesis of pyrrolopiperazine fused with
oxazine/imidazole based on F via a Ag-catalysed δ-alkynyl
aldehydes and amines resulting to form imine, that has embedded
†Electronic Supplementary Information (ESI) available: Experimental
procedures, spectral data for all new compounds, and copies of spectra.
CCDC 1555220. For ESI and crystallographic data in CIF and other
electronic format see DOI: 10.1039/b000000x/
nucleophiles
(oxygen/nitrogen)
through
intermolecular
condensation would provide the oxazine/imidazole, which in the
presence of the appropriate alkyne via 6-exo dig cyclization
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Journal Name
would afford pyrrolopiperazine fused with oxazine/imidazole
(Scheme 1). This domino approach would involve the
regioselective formation of two new C−N and one C-O/C-N
bonds, resulting in the formation of two heterocyclic rings. To
the best of our knowledge, the use of this or a similar strategy for
A decrease in AgNO3 loading decreased the producVtieywieAlrdticl(eTOanblinlee
DOI: 10.1039/C7NJ03608F
1, entry 11) and higher catalyst loading did not increase the yield
(Table 1, entry 12). A further increase in the reaction time and
temperature did not improve the yield (Table 1, entry 13).
Overall, it was observed that the conditions of entry 5 are the
optimum reaction condition for obtaining the desired product 3a
in best yield. The compound 3a was characterized by the
appearance (i) a singlet at δ 5.85 due to the proton attached to the
tertiary carbon (ii) diastereotopic doublets of =N–CH2– at δ 5.17,
5.07 and diastereotopic doublets of –O–CH2– at δ 4.77 and 4.60
(iii) a singlet at δ 6.19 due to the vinylic proton. (iv) 13C NMR
signals at 51.4 and 66.7 ppm due to =N-CH2= and -O-CH2-
respectively and (v) tertery carbon signal appear at 81.9 ppm.
the
construction
of
core
pyrrolopiperazine
fused
oxazine/imidazole ring system is unreported. Moreover, we also
report the preliminary results of the evaluation of the
pharmacological activities of the synthesized compounds.
Table 1. Optimization of the reaction conditions.a
Scheme 1. Retrosynthetic analysis of pyrrolopiperazine fused
with oxazine/imidazole.
Transition-metal-catalyzed domino reactions in the synthesis of
structurally diverse poly-heterocycle scaffolds from δ-alkynyl
aldehydes are used extensively by Larock,14 Yamamoto,15 Wu,16
and Verma.17 However, use of δ-alkynyl aldehydes are less
studied towards the synthesis of poly-heterocycle scaffolds via
domino approach. Nagarajan et al.11a reported the copper
catalysed tandem synthesis of fused benzimidazolopiperazine via
tandem imidazole formation followed by 6-exo-dig cyclization.
Abbiati and co-workers11b have developed a microwave mediated
Time
Entry
1
Catalyst
Solvent
%Yieldb
35
(h)
3
CuI (10 mol%)
ClCH2CH2Cl
2
3
Cu(OTf)3 (10 mol%)
AgOAc (10 mol%)
Ag(OTf)3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (5 mol%)
AgNO3 (15 mol%)
AgNO3 (10 mol%)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
DMF
3
3
3
3
3
3
3
3
3
3
3
4
50
70
78
82
40
50
65
78
75
70
80
78c
4
5
6
synthesis of pyrazino[1,2-a]indoles
via intramolecular
7
Toluene
cyclization of 2-carbonyl-1-alkynylindoles in the presence of
ammonia. In 2009, the same group reported the microwave
promoted synthesis of pyrrolo[1,2-a]pyrazines and isoquinolines
through the domino imination/annulation of alkynes bearing a
proximate carbonyl group in the presence of ammonia.11c
Recently, Balci et al.11d demonstrated the gold-catalyzed
intramolecular cyclization of N-propargyl indole provide a
pyrazino[1,2-a]indole. However, these methods suffering from
lack of regioselective cyclization lead to form mixture of isomers
or harsh reaction conditions and also not suitable for the
preparation of our target compounds F (Fig. 2). We, therefore,
decided to develop a highly regioselective, mild, practical and
one-pot method for the synthesis of pyrrolopiperazine fused with
oxazine/imidazole derivatives.
8
EtOAc
9
CH3CN
10
11
12
13
DCM
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
aAll the reactions were carried out using compound 1a (1.0 equiv), 2a (1.3
equiv) and catalyst in a solvent (5 mL) at 60 oC. bIsolated yield. cThe reaction
was carried out at 80 oC.
With the optimization conditions in hand, we decided to explore
the scope and generality of the present AgNO3 catalyzed domino
reaction. Accordingly, a variety of δ-alkynyl aldehydes (1) were
reacted with aminobenzyl alcohols. A variety of different aryl-
The metal catalyzed domino reaction of 3a was then performed substituted groups at the R1 position such as phenyl (3a, 3e and
under a variety of conditions (Table 1) to establish the optimized 3i), p-anisyl (3c, 3g and 3j), p-tolyl (3b, 3f and 3k), m-trifluoro
reaction condition. Initially, 1-(3-phenylprop-2-yn-1-yl)-1H- (3l) and p-fluoro (3m) were successfully converted into desired
pyrrole-2-carbaldehyde (1a, 1.0 equiv) was made to react with products in moderate to good yields. Interestingly, the R1
(2-aminophenyl)methanol (2a, 1.3 equiv) in 1,2-dichloroethane replaced with thiophene (3d and 3h) substrates were smoothly
(5 mL) in the presence of 10 mol% CuI at 60 ºC for 3 h, when the converted into corresponding pyrrolopiperazine fused with
product 3a was isolated in 35% yield (Table 1, entry 1). Inspired oxazines. The δ-alkynyl aldehydes used other than pyrrole
by these results, further optimization of the reaction conditions include indole (1b) to generate corresponding products (3g, 3i, 3j
was carried out. Various transitional metal catalyst such as and 3k) in good yields. Further, the scope of the reaction was
Cu(OTf)3, AgOAc, Ag(OTf)3 and AgNO3 (Table 1, entries 2–5) demonstrated with (2-amino-5-chlorophenyl)methanol (2b) and
and AgNO3 was found to be the optimal catalyst for the reaction the respective compounds were isolated (3c, 3e, 3f, 3g, 3h and
process. Solvents such as DMF, toluene, EtOAc, CH3CN and 3m).
DCE were also evaluated (Table 1, entries 6–10), and a 82%
yield of 3a was afforded when DCE was used (Table 1, entry 5).
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Table 2. Synthesis of pyrrolopiperazine fused with oxazine (3).a,b
COMMUNICATION
Scheme 2. Preparation of pyrazino[2,1-b][1,3]imidazole fused with
View Article Online
pyrrole (3n-p).
DOI: 10.1039/C7NJ03608F
The structure and olifine geometry of 3p was further conformed
by the single crystal X-ray data analysis (Fig. 3)18.
3a (82%)
3b (82%)
3c (80%)
3e (80%)
Fig. 3. X-ray crystal structure 3p (ORTEP diagram). Thermal
ellipsoids are drawn at 50% probability level.
3d (80%)
3g (76%)
3f (75%)
3i (82%)
Based on literature precedent and our experimental observations,
a plausible mechanism is proposed in Scheme-3.17 Initially, the
reaction of δ-alkynyl aldehydes 1 with nucleophilic amine 2
produced condensation species E-1. After this, two possibilities
exist for the formation of compounds 3, either C-O/C-N bond
forms first and then C-N bond (path-A) or vice versa (path-B).
(i.e., either ring A forms first and then ring B or vice versa). The
Path-A involves (i) a nucleophile (Y) attack at imine carbon to
give E-2 (ii) intramolecular proton transfer would then leading to
E-3 (iii) subsequent activation of the triple bond by AgNO3,
would undergo a second intramolecular nucleophilic attack of the
nitrogen onto the triple bond to afford 3. The path-B involves (i)
the activation of the triple bond by AgNO3 to give E-4 (ii)
subsequent by a nucleophile (Y) attack at imine carbon to furnish
E-5 (iii) which on subsequent deprotonation gives the desired
product 3.
3h (78%)
3k (78%)
3j (80%)
3l (82%)
Most of the pyrrolopiperazine fused with oxazine/imidazole (3)
synthesized, were tested for their anti-proliferative properties in
vitro using three different cancer cell lines including K562
(leukemia cells), BT-474 (human breast cancer cells) and MCF-7
(breast cancer cells). 4OH-Tamoxifene was used as a reference
compound. Some of the compounds were examined at various
concentrations in an Alamar Blue (AB) assay and the IC50 values
obtained for each compound are presented in Table 3. Some
compounds showed inhibition of leukemia cancer cell growth as
reflected by their IC50 values, but the best results were obtained
for compounds 3e, 3g, 3h and 3i (IC50 <15 µM, Table 3).
Compounds 3g (IC50 17.6 µM, Table 3) and 3h (IC50<21 µM,
Table 3) also showed inhibition against the human breast cancer
cells. Among all the compounds, 3i showed interesting activities
against the leukemia cells and human breast cancer cells (IC50 <4
µM, Table 3). It is interesting to note that the compound 3i
3m (84%)
aAll the reactions were carried out using compound 1 (1.0 equiv), 2 (1.3
equiv) and AgNO3 (10 mol%) in a DCE (5 mL) at 60 ºC for 3 h. bIsolated
yield.
In order to explore more diversity and complexity, we treated δ-
alkynyl
aminophenyl)benzenesulfonamide (2c) to give pyrazino[2,1-
b][1,3]imidazole fused with pyrrole (3n-p) (Scheme-2).
aldehydes
(1)
with
N-(2-
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Notes and references
View Article Online
DOI: 10.1039/C7NJ03608F
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Scheme 3. The proposed reaction mechanism.
exhibited maximum activity in p53-deficient cell lines K562
(IC50=3.0 µM) and BT-474 (IC50=4.0 µM) but not in p53-
wildtype MCF7 cells (IC50=19.6+1.5 µM) (Table 3). Similar
observations were made with 3g and 3k where cytotoxic activity
was specifically observed in p53-deficient cells hence the present
class of molecules indicating both the ‘cell type specific’ as well
as ‘p53 status dependent’ anti-cancer activity (Table 3). These
findings
suggest
that
pyrrolopiperazine
fused
with
oxazine/imidazol framework could be a new template for the
design and development of molecules for the for the
identification of novel anticancer agents.
Table 3. In vitro growth inhibition of cancer cell lines by
pyrrolopiperazine fused with oxazine/imidazole (3).a
IC50 valuesa (µM)
Compound
K562
BT-474
MCF-7
3b
3c
3e
3f
3g
3h
3i
3k
3n
12.3+3.2
19.3+3.0
14.6+2.5
20.6+1.5
9+1.7
14+2
3+0
22+2.6
23+2.6
6.0+0
>50
>50
>50
41.3+0.5
17.6+0.5
21.3+0.5
4+0
8.3+1.5
27+4.3
6.0+0
>50
>50
>50
>50
>50
29.6+0.5
19.6+1.5
41.3+1.5
>50
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In conclusion, we have successfully developed a domino protocol
for the synthesis of various pyrrolopiperazine fused with
oxazine/imidazole via Ag catalysed
C-N bond formation
followed by regioselective 6-exo-dig cyclization. The present
methodology is regioselective, mild, practical and one-pot
method. Some of these compounds showed anti-proliferative
properties when tested against leukemia and breast cancer cells.
KSK thanks University Grants Commission (UGC), New Delhi,
for Assistant Professor under FRP and CSIR, India,
[02(0234)/15/EMR-II] for the financial support. B. R thanks
CSIR, New Delhi for a Senior Research Fellowship.
Conflicts of interest
The authors confirm that this article content has no conflict
of interest.
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18. Crystal data of (3p): CCDC 1555220, Single crystals
suitable for X-ray diffraction of 3p DCM: EtOAc (1:1).
Molecular formula = C28 H25 N3 O2 S, Formula weight =
467.57, Crystal system = Triclinic, space group = P -1, a =
9.0323(6) Å, b = 10.9047(7) Å, c = 12.9519(9) Å, V =
1185.55(14) Å3, T = 296(2) K, Z = 2, Dc = 1.310 Mg/m3,
18387 Reflections collected, 3324 [R(int) = 0.1105]
independent reflections, Goodness of fit = 1.01.
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New Journal of Chemistry
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DOI: 10.1039/C7NJ03608F
GRAPHICAL ABSTRACT
Agꢀcatalysed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction
of δꢀalkynyl aldehydes and nucleophilic amine. Several of these compounds were found
antiꢀcancer activity properties against cancer cell lines.