Microwave assisted [RuCl2(p-cymene)2]2 catalyzed regioselective endo-tandem cyclization involving imine and alkyne activation: An approach to benzo[4,5]imidazo[2,1-a]pyridine scaffold

Article abstract of DOI:10.1039/c4ra02581d

A microwave assisted efficient route to the synthesis of benzimidazole fused heterocycles through metal catalyzed endo-cyclization strategy involving imine and alkyne activation has been developed. In the presence of [RuCl ₂(p-cymene)₂

Full text of DOI:10.1039/c4ra02581d

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Microwave assisted [RuCl2(p-cymene)2]2 catalyzed
regioselective endo-tandem cyclization involving
imine and alkyne activation: an approach to benzo
[4,5]imidazo[2,1-a]pyridine scaffold†
Cite this: RSC Adv., 2014, 4, 21032
a
ab
*
Sudipta Kumar Manna and Gautam Panda
A microwave assisted efficient route to the synthesis of benzimidazole fused heterocycles through metal
catalyzed endo-cyclization strategy involving imine and alkyne activation has been developed. In the
presence of [RuCl2(p-cymene)2]2, a variety of 2-ethynyl aldehydes underwent cascade cyclization with
substituted benzenediamines to afford the corresponding benzo[4,5]imidazo[2,1-a] pyridine scaffold in
moderate to good yields.
Received 24th March 2014
Accepted 24th April 2014
DOI: 10.1039/c4ra02581d
www.rsc.org/advances
process,7 palladium-catalyzed cross-coupling protocols,8
rhodium-catalyzed dual C–H bond activation,9 and various
multistep routes10 can be employed to synthesize these types of
Introduction
A wide array of medicinally important natural and synthetic
molecules contain isoquinoline or heterocycles fused to iso-
quinoline core.1 Thus development of new synthetic strategies
for the quick assembly of these heterocyclic scaffolds has been
of crucial importance to the synthetic community. Benzimid-
azole fused heterocyclic frameworks are an important class of
pharmacophores displaying an extensive range of therapeutical
and biological activities, such as anti-HIV-1, antimicrobial,
antifungal and anticancer properties.2 Furthermore, a number
of bioactive heterocycles containing this scaffold show a
prominent growth inhibitory effect, inhibit topoisomerase II
and also, induce strong G2/M arrest of the cell cycle followed by
drastic apoptosis, which is in accordance with the DNA inter-
calative binding mode (Fig. 1).3 Therefore, this scaffold con-
taining molecule has been the focus of attention of medicinal
chemists as well as synthetic organic chemists and thus much
effort has been devoted to develop methods for the synthesis of
benzimidazole fused heterocycle ring systems. The most
common strategy to access these types of scaffolds is the
cascade cyclization of 2-ethynyl aldehydes with benzenedi-
amines.4 C–C bond formation via tandem nucleophilic addition
and electrophilic cyclization of various ortho-alkynyl aldehydes,
amines and various carbon based pronucleophiles in the pres-
ence or absence of various alkynophilic Lewis acid catalysts also
give these types of scaffolds.5,6 Copper-catalyzed tandem
scaffolds.
Result and discussion
Sequential reactions in one-pot have played a leading role in the
synthesis of both natural as well as synthetic molecules.11 To the
best of our knowledge, tandem synthesis of benzimidazole
fused derivatives through [RuCl2(p-cymene)2]2 catalyzed endo-
cyclization strategy from ortho-alkynyl aldehydes has not yet
been explored. This cascade strategy involves the formation of
three new N–C bonds and thereby leading to the formation of
two heterocyclic rings in fused polycyclic heterocycles. We are
interested in developing new synthetic methodologies for the
synthesis and bioevaluation of small but smart heterocycles12
and we report here microwave (MW) assisted metal catalyzed
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS
10/1, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. E-mail: gautam.
panda@gmail.com; gautam_panda@cdri.res.in
bAcademy of Scientic and Innovative Research, New Delhi 110001, India. Fax: +91-
522-2771941; Tel: +91-522-2772450, 2772550, Ext 4661, 4662
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02581d
Fig. 1 Representative biologically important benzimidazoles and our
target 1.
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Scheme 1 Synthesis of substituted ortho-alkynyl aldehydes (4a–k). Reagents and conditions: (i) POCl3 (or PBr3, CHCl3), dry DMF, 0 ꢀC-rt, 8–9 h,
68–79%; (ii) Pd(PPh3)2Cl2, CuI, Alkynes, DMF, 5–30 min, rt, 63–85%.
regioselective endo-tandem cyclization involving alkyne activa-
tion for fused benzimidazole derivatives.
In order to optimise the desired reaction conditions, at rst
we used 2,2-dimethyl-4-(p-tolylethynyl)-2H-chromene-3-carbal-
First, the synthesis of ortho-alkynyl aldehydes was under- dehyde 4b as a model substrate with different Ru-metal sources,
taken. All of them were prepared from different substituted solvents and bases at a variety of temperatures (Table 1). When
chromanones and tetralones following two synthetic steps, 10 mol% of RuCl3$3H2O was used as catalyst in presence of
involving Vilsmeier–Haack–Arnold13 reaction and Sonogashira14 K2CO3 and DMF, there was no reaction (entry 1, Table 1).
coupling (Scheme 1). Now with the ortho-alkynyl aldehydes (4a– Similar results were obtained when tert-butylammonium
k) in hand (Table 2), the stage was set to implement the crucial bromide (TBAB) as additive, PPh3 as ligand and also other
catalytic N–C bond formation towards domino cyclization.
solvents DMSO were used for 15 h (entries 2 & 3, Table 1). When
Table 1 Optimization studies for the synthesis of benzimidazoles fused derivatives
Entry
Catalysts
Additive
Solvents
Bases
Ligands
T/oC
Yielda(%)
1
2
3
4
5
6
7
8
RuCl3$3H2O (10 mol%)
RuCl3$3H2O (10 mol%)
RuCl3$3H2O (10 mol%)
—
—
TBAB
TBAB
TBAB
—
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMSO
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
—
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110 (MW)
130 (MW)
NR
NR
NR
Trace
54
PPh3
PPh3
—
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (15 mol%)
—
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
PPh3
PPh3
PPh3
—
32
—
NRb
78(69c)
46
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
9
10
11
12
13
14
15
16
17
NR
35
23
78
NR
NR
65d
78e
—
[RuCl2(p-cymene)2]2 (10 mol%)
[RuCl2(p-cymene)2]2 (10 mol%)
PPh3
PPh3
a
Isolated yield aer column chromatography as well as preparative TLC. b Starting consumed but no desired product i.e., enamine product formed
c
before alkyne activation (U, Fig. 2). 5 mol% of [RuCl2(p-cymene)2]2, 10 mol% of PPh3. All reaction carried out 20–30 h except (entries 15 & 16).
d
Starting not fully consumed within 1 h and extended 0.5 h but no fruitful result obtained. e Reaction time 1.5 h. NR ¼ no reaction.
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Fig. 2 Proposed mechanistic pathway for the synthesis of benzimidazole fused heterocycles.
[RuCl2(p-cymene)2]2 (10 mol%) was used, it provided the equiv) as base at 130 ꢀC in presence of PPh3 (15 mol%) as ligand
product 5d in trace amount only in presence of base and solvent and TBAB as additive for 1.5 h microwave irradiation under
(entry 4, Table 1).
argon atmosphere) we then explored the scope and generality of
Delightfully, we obtained the desired benzimidazole deriva- the present process. We were pleased to nd that this current
ꢀ
tive 5d in 54% yield aer 15 h stirring with dry DMF at 110 C methodology was successful with a variety of substituent on
temperatures (entry 5, Table 1). This observation encouraged us both the ortho-alkynyl aldehydes (4a–k) as well as the benze-
to nd the optimal catalytic conditions for the regioselective nediamines, affording the polycyclic heteroaromatic products
endo-tandem strategy. Upon using reaction conditions similar (5a–s) in moderate to good yields (38–78%, Table 2). Mostly we
to (entry 5, Table 1) but in the absence of TBAB additive, a used symmetrically substituted benzenediamines to avoid
signicant decrease in reaction yield to 32% was observed (entry regioisomeric products. For example, when we used 4-methyl-
6, Table 1). This particular result demonstrates that the additive benzene-1,2-diamine, as expected we got mixture (1 : 1) of
is not necessary but the reaction outcome is additive depen- product (5e, Table 2).
dent. However, we also implemented this reaction in absence of
All the nal molecules were characterized by 1H, 13C, ESI-MS,
base, but didn't get any desired product except benzimidazole HRMS and IR analysis. The nal molecules (5d, 5g) were
intermediate (U, Fig. 2, see ESI†). However, the yield of 5d was conrmed by on the basis of the DEPT, HSQC, HMBC and COSY
further increased to 78% when the substrate was stirred with 10 spectroscopic analysis (see ESI†). With these observations, a
mol% [RuCl2(p-cymene)2]2 and 2 equiv Cs2CO3 in DMF at 110 ꢀC plausible mechanism is proposed in Fig. 2.
under argon atmosphere (entry 8, Table 1). Subsequently,
various other solvent, base and catalytic combination were
screened, which are summarized in Table 1 (entries 9–12).
Conclusion
It was noticed that when the reaction time was increased from
20 to 30 h and also catalyst [RuCl2(p-cymene)2]2 loading from 10 In summary, we have developed an efficient protocol for the
to 15 mol% in dry DMF, no effect on the yield of the product 5d synthesis of benzimidazole fused derivatives in moderate to
(entry 13, Table 1) was observed. However, in the absence of good yields with high regioselectivity. These atom economic
catalyst, reactants remain unchanged during the course of the transformations are based on nucleophilic addition of ortho-
reaction (entries 14 & 15, Table 1). Aer successful reaction alkynyl aldehydes and benzenediamines involving dichloro(p-
condition scanning for the synthesis of benzimidazoles, we cymene)ruthenium(II) dimer catalyzed tandem cyclization fol-
turned our attention to reducing the reaction time. Using lowed by formation of three new N–C bonds and two hetero-
microwave heating allowed the reaction to be completed within cyclic rings in one-pot giving fused polycyclic heterocycles.
1.5 h with no change in reaction yield (entries 16 & 17, Table 1). Further investigations are underway in order to expand the
With the optimized reaction condition (DMF as the solvent, applicability of this process as well as building blocks for
[RuCl2(p-cymene)2]2 (10 mol%) as the catalyst and Cs2CO3 (2 material science and pharmaceutical importance.
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Table 2 Synthesis of benzimidazole fused derivatives (5a–s)
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product was extracted with ethyl acetate and water. The organic
layer was dried over Na2SO4, ltered and concentrated in vacuo.
The crude product was puried by silica gel column chroma-
tography eluting with 1–2% ethyl acetate in hexane.
Experimental section
General remarks
All dry reactions were carried out under argon atmosphere in
oven-dried glassware using standard gas-light syringes,
cannulas, septa and also microwave crimp top. All reagents and
solvents were purchased from commercial sources and used
without further purication. Organic solvents were dried by
reported standard methods. Analytical TLC was performed
using 2.5 ꢁ 5 cm aluminum plates coated with a 0.25 mm
thickness of silica gel (60F-254), visualization was accomplished
with iodine and under UV lamp. Column chromatography was
performed using silica gel (60–120 and 100–200 mesh). Some
cases, preparative thin layer chromatography were performed
on GF254 silica by using requisite distilled solvent system as
2,2-Dimethyl-4-(phenylethynyl)-2H-chromene-3-carbaldehyde
(4a). Greenish oily liquid, yield ¼ 81% (0.278 g). Rf ¼ 0.80 (2%
1
ꢀ
EtOAc–hexane). H NMR (300 MHz, CDCl3, 25 C): dH 10.39 (s,
1H), 7.77 (d, J ¼ 6.9 Hz, 1H), 7.62–7.59 (m, 2H), 7.44–7.33 (m,
4H), 7.01 (t, J ¼ 6.9 Hz, 1H), 6.85 (d, J ¼ 7.9 Hz, 1H), 1.66 (s, 6H)
13
ꢀ
ppm. C NMR (50 MHz, CDCl3, 25 C): dC 190.4, 153.9, 139.4,
133.4, 131.9, 129.8, 128.6, 127.0, 121.7, 121.3, 119.9, 117.2, 103.2,
81.1, 78.4, 26.4 ppm. IR (neat, cmꢂ1): 3419, 3022, 2934, 2430,
2198, 1654, 1621, 1525, 1355, 1269, 1213, 977, 776, 664. Mass
(ESI-MS): m/z 289.3 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd
for C20H17O2 289.1229, found 289.1230.
1
2,2-Dimethyl-4-(p-tolylethynyl)-2H-chromene-3-carbaldehyde
(4b). Light brownish oily liquid, yield ¼ 69% (0.468 g). Rf ¼ 0.87
(2% EtOAc–hexane). 1H NMR (300 MHz, CDCl3, 25 ꢀC): dH 10.37
(s, 1H), 7.75 (d, J ¼ 7.7 Hz, 1H), 7.48 (d, J ¼ 7.7 Hz, 2H), 7.35–
7.30 (m, 1H), 7.22 (t, J ¼ 8.3 Hz, 2H), 6.99 (d, J ¼ 7.7 Hz, 1H), 6.83
(d, J ¼ 8.3 Hz, 1H), 2.40 (s, 3H), 1.64 (s, 6H) ppm. 13C NMR (50
mentioned below. H NMR spectra were recorded on 300 and
400 MHz spectrometer in CDCl3 (all signals are reported in ppm
with the internal chloroform signal at 7.26 ppm as standard) at
25 ꢀC. 13C NMR spectra were recorded on 75 and 100 MHz
spectrometer in CDCl3 (all signals are reported in ppm with the
ꢀ
internal chloroform signal at 77.00 ppm as standard) at 25 C.
ꢀ
MHz, CDCl3, 25 C): dC 190.5, 153.8, 140.3, 139.0, 133.9, 133.4,
In a few cases tetramethylsilane (TMS) at 0.00 ppm was used as
1
131.8, 129.4, 127.0, 121.3, 120.0, 118.6, 117.1, 103.6, 80.6, 78.4,
26.4, 21.6 ppm. IR (neat, cmꢂ1): 3433, 3027, 2925, 2430, 2202,
1659, 1619, 1530, 1355, 1266, 1213, 975, 776, 665. Mass (ESI-
MS): m/z 303.2 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for
the reference standard. H NMR multiplicities are reported as
follows: singlet (s), doublet (d), double doublet (dd), triplet (t),
quartet (q) or multiplet (m). The HRMS spectra were recorded as
EI-HRMS on Q-TOF mass spectrometer. IR spectra were recor-
ded using a FTIR spectrophotometer in cmꢂ1. Biotage® Initi-
ator Classic was used for measuring reaction mixture
temperatures during microwave heating with external sensor
type method.
C
21H19O2 303.1385, found 303.1385.
2,2-Dimethyl-4-(m-tolylethynyl)-2H-chromene-3-carbaldehyde
(4c). Light brownish oily liquid, yield ¼ 78% (0.311 g). Rf ¼ 0.86
(2% EtOAc–hexane). 1H NMR (300 MHz, CDCl3, 25 ꢀC): dH 10.37
(s, 1H), 7.75 (d, J ¼ 7.7 Hz, 1H), 7.48 (d, J ¼ 7.7 Hz, 2H), 7.35–
7.30 (m, 1H), 7.22 (t, J ¼ 8.3 Hz, 2H), 6.99 (d, J ¼ 7.7 Hz, 1H), 6.83
(d, J ¼ 8.3 Hz, 1H), 2.40 (s, 3H), 1.64 (s, 6H) ppm. 13C NMR (75
Typical procedure and spectral data of few compounds (3a
and 3c–e) were already reported.12g,15–17
ꢀ
MHz, CDCl3, 25 C): dC 190.4, 153.8, 139.3, 138.5, 133.7, 133.4,
Experimental procedures and characterization data
132.4, 130.7, 129.0, 128.5, 127.0, 121.5, 121.3, 119.9, 117.1,
103.5, 80.8, 78.4, 26.4, 21.2 ppm. IR (neat, cmꢂ1): 3429, 3022,
2928, 2430, 2202, 1659, 1621, 1527, 1355, 1269, 1213, 973, 776,
661. Mass (ESI-MS): m/z 303.2 (100, [M + H]+). ESI-HRMS: m/z
[M + H]+ calcd for C21H19O2 303.1385, found 303.1384.
2,2-Dimethyl-4-(thiophen-3-ylethynyl)-2H-chromene-3-carbal-
dehyde (4d). Brownish oily liquid, yield ¼ 82% (0.176 g). Rf ¼
0.81 (2% EtOAc–hexane). 1H NMR (400 MHz, CDCl3, 25 ꢀC): dH
11.01 (s, 1H), 8.39 (dd, J1 ¼ 1.5, J2 ¼ 7.7 Hz, 1H), 8.34 (dd, J1 ¼
1.1, J2 ¼ 2.9 Hz, 1H), 8.05–7.98 (m, 2H), 7.92–7.91 (m, 1H), 7.69–
7.65 (m, 1H), 7.51 (d, J ¼ 8.1 Hz, 1H), 2.31 (s, 6H) ppm. 13C NMR
(100 MHz, CDCl3, 25 ꢀC): dC 190.4, 153.8, 139.2, 133.6, 133.4,
130.6, 129.6, 127.0, 126.1, 121.7, 120.7, 119.8, 117.2, 98.4, 80.9,
78.4, 26.4 ppm. IR (neat, cmꢂ1): 3428, 3019, 2928, 2411, 2202,
4-Chloro-7-methoxy-2,2-dimethyl-2H-chromene-3-carbaldehyde
(3b). Light greenish oily liquid, yield ¼ 78% (2.124 g). Rf ¼ 0.5
(1% EtOAc–hexane). 1H NMR (400 MHz, CDCl3): dH 10.18 (s,
1H), 7.58 (d, J ¼ 7.2 Hz, 1H), 6.54 (dd, J1 ¼ 1.3, J2 ¼ 8.9 Hz, 1H),
6.36 (d, J ¼ 2.3 Hz, 1H), 3.82 (s, 3H), 1.62 (s, 6H) ppm. 13C NMR
(75 MHz, CDCl3): dC 188.5, 164.9, 156.4, 144.6, 129.3, 127.5,
112.8, 108.8, 101.5, 80.9, 55.6, 26.4 ppm. IR (neat, cmꢂ1): 3041,
2335, 1232, 1043, 764, 661. Mass (ESI-MS): m/z 253.3 (100, [M +
H]+). ESI-HRMS: m/z [M + H]+ calcd for C13H14ClO3 253.0631,
found 253.0635.
General experimental procedure of Sonogashira coupling for
the synthesis of 2-ethynylaldehydes (4a–k)
The halogenated aldehyde (1 equiv, 4.21 mmol) was dissolved in 1651, 1607, 1541, 1355, 1250, 1213, 973, 759, 664. Mass (ESI-
dry DMF (5 mL) and added Pd(PPh3)2Cl2 (0.03 equiv, 0.13 MS): m/z 295.1 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for
mmol), CuI (0.07 equiv, 0.30 mmol), and was stirred for 10 min
C
18H15O2S 295.0793, found 295.0789.
at room temperature under nitrogen atmosphere. Aer 10 min
7-Methoxy-2,2-dimethyl-4-(p-tolylethynyl)-2H-chromene-3-
substituted alkyne (1.5 equiv, 6.32 mmol) and triethylamine carbaldehyde (4e). Light greenish oily liquid, yield ¼ 74%
(2.70 equiv, 11.38 mmol) were added and the reaction mixture (0.238 g). Rf ¼ 0.82 (2% EtOAc–hexane). 1H NMR (300 MHz,
was monitored by TLC. Within 5–15 min reaction was CDCl3, 25 ꢀC): dH 10.31 (s, 1H), 7.66 (d, J ¼ 8.4 Hz, 1H), 7.47 (d,
completed. Aer completion of the reaction, the mixture was J ¼ 7.5 Hz, 2H), 7.21 (d, J ¼ 7.5 Hz, 2H), 6.57 (d, J ¼ 8.4 Hz, 1H),
diluted with saturated aqueous ammonium chloride and the 6.38 (s, 1H), 3.82 (s, 3H), 2.40 (s, 3H), 1.64 (s, 6H) ppm. 13C NMR
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(75 MHz, CDCl3, 25 ꢀC): dC 190.1, 164.4, 156.6, 140.2, 136.3, 0.85 (2% EtOAc–hexane). 1H NMR (400 MHz, CDCl3, 25 ꢀC): dH
134.0, 131.8, 129.4, 128.5, 118.7, 113.3, 108.6, 103.2, 101.5, 80.9, 10.49 (s, 1H), 7.50 (d, J ¼ 2.7 Hz, 1H), 7.47 (d, J ¼ 7.9 Hz, 2H),
78.9, 55.5, 26.5, 21.6 ppm. IR (neat, cmꢂ1): 3417, 3019, 2928, 7.20 (d, J ¼ 7.9 Hz, 2H), 7.12 (d, J ¼ 7.9 Hz, 1H), 6.89 (dd, J1 ¼
2421, 2202, 1662, 1607, 1544, 1355, 1267, 1213, 983, 769, 665. 2.7, J2 ¼ 8.4 Hz, 1H), 3.85 (s, 3H), 2.77 (t, J ¼ 7.9 Hz, 2H), 2.61 (t,
Mass (ESI-MS): m/z 333.3 (100, [M + H]+). ESI-HRMS: m/z [M + J ¼ 8.3 Hz, 2H), 2.39 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3,
H]+ calcd for C22H21O3 333.1491, found 333.1492.
ꢀ
25 C): dC 192.3, 158.5, 140.3, 139.8, 136.1, 133.2, 131.7, 129.7,
7-Methoxy-2,2-dimethyl-4-(m-tolylethynyl)-2H-chromene-3- 129.3, 128.5, 118.9, 115.9, 112.8, 101.5, 82.4, 55.3, 25.8, 21.5,
carbaldehyde (4f). Light brownish oily liquid, yield ¼ 85% 20.2 ppm. IR (neat, cmꢂ1): 3428, 3020, 2930, 2408, 2201, 1652,
1
(0.298 g). Rf ¼ 0.87 (2% EtOAc–hexane). H NMR (400 MHz, 1604, 1317, 1368, 1215, 1034 760, 670. Mass (ESI-MS): m/z 303.6
CDCl3, 25 ꢀC): dH 10.23 (s, 1H), 7.58 (d, J ¼ 8.8 Hz, 1H), 7.32 (d, (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C21H19O2
J ¼ 9.6 Hz, 2H), 7.21 (t, J ¼ 8.1 Hz, 1H), 7.17–7.14 (m, 1H), 6.48 303.1385, found 303.1385.
(dd, J1 ¼ 2.4, J2 ¼ 8.8 Hz, 1H), 6.30 (d, J ¼ 2.4 Hz, 1H), 3.74 (s,
7-Methoxy-1-(m-tolylethynyl)-3,4-dihydronaphthalene-2-car-
3H), 2.30 (s, 3H), 1.56 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3, baldehyde (4k). Light brownish oily liquid, yield ¼ 67%
25 ꢀC): dC 190.1, 164.4, 155.6, 138.4, 136.5, 133.9, 132.4, 130.6, (0.530 g). Rf ¼ 0.82 (2% EtOAc–hexane). 1H NMR (400 MHz,
128.9, 128.5, 128.4, 121.5, 113.3, 108.6, 103.1, 101.5, 80.9, CDCl3, 25 ꢀC): dH 10.43 (s, 1H), 7.43 (d, J ¼ 2.4 Hz, 1H), 7.32 (d,
78.9, 55.5, 26.4, 21.2 ppm. IR (neat, cmꢂ1): 3427, 3019, 2928, J ¼ 8.9 Hz, 2H), 7.21 (d, J ¼ 7.5 Hz, 1H), 7.15 (d, J ¼ 7.5 Hz, 1H),
2401, 2202, 1659, 1607, 1541, 1355, 1280, 1213, 983, 759, 669. 7.07 (d, J ¼ 8.3 Hz, 1H), 6.83 (dd, J1 ¼ 2.8, J2 ¼ 8.3 Hz, 1H), 3.79
Mass (ESI-MS): m/z 333.3 (100, [M + H]+). ESI-HRMS: m/z [M + (s, 3H), 2.71 (t, J ¼ 7.5 Hz, 2H), 2.55 (t, J ¼ 8.8 Hz, 2H), 2.31 (s,
H]+ calcd for C22H21O3 333.1491, found 333.1492.
3H) ppm. 13C NMR (75 MHz, CDCl3, 25 ꢀC): dC 192.4, 158.5,
1-(Phenylethynyl)-3,4-dihydronaphthalene-2-carbaldehyde 140.6, 138.41, 136.0, 133.2, 132.3, 130.4, 129.8, 128.9, 128.6,
(4g). Light brownish oily liquid, yield ¼ 68% (0.295 g). Rf ¼ 0.82 128.5, 121.9, 115.9, 112.9, 101.4, 82.6, 55.4, 31.9, 25.9, 21.2, 20.3
(2% EtOAc–hexane). 1H NMR (300 MHz, CDCl3, 25 ꢀC): dH 10.51 ppm. IR (neat, cmꢂ1): 3426, 3022, 2918, 2401, 2202, 1613, 1659,
(s, 1H), 7.95–7.92 (m, 1H), 7.61–7.58 (m, 2H), 7.41–7.40 (m, 3H), 1532, 1355, 1283, 1213, 983, 775, 664. Mass (ESI-MS): m/z 303.1
7.36–7.33 (m, 2H), 7.25–7.20 (m, 1H), 2.85 (t, J ¼ 7.5 Hz, 2H), (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C21H19O2
2.64 (d, J ¼ 8.6 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3, 25 ꢀC): 303.1385, found 303.1388.
dC 192.2, 140.2, 137.6, 135.9, 132.1, 131.8, 130.7, 129.4, 128.6,
127.8, 127.2, 126.9, 122.0, 101.1, 82.9, 26.7, 19.9. IR (neat,
cmꢂ1): 3019, 2205, 1659, 1406, 1215, 757, 669. Mass (ESI-MS): m/
General procedure for synthesis of benzimidazole fused
z 259.0 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for
heterocycles (5a–s)
C
19H15O 259.1123, found 259.1121.
A microwave crimp top vial equipped with a stir bar was charged
6-Methoxy-1-(p-tolylethynyl)-3,4-dihydronaphthalene-2-car- with ortho-alkynylaldehydes (4a–k) (1.0 equiv, 0.16 mmol),
baldehyde (4h). Light brownish oily liquid, yield ¼ 81% (0.310 substituted benzenediamines (1.2 equiv, 0.20 mmol), and
1
g). Rf ¼ 0.81 (2% EtOAc–hexane). H NMR (300 MHz, CDCl3, Cs2CO3 (2.0 equiv, 0.33 mmol). To this mixture catalytic amount
25 ꢀC): dH 10.45 (s, 1H), 7.86 (d, J ¼ 8.3 Hz, 1H), 7.48 (d, J ¼ 7.6 of TBAB was added followed by 1 mL of dry DMF at room
Hz, 2H), 7.20 (d, J ¼ 6.9 Hz, 2H), 6.85 (d, J ¼ 7.6 Hz, 1H), 6.75 temperature. Then 10 mol% of [RuCl2(p-cymene)2]2, 15 mol% of
(s, 1H), 3.85 (s, 3H), 2.82 (t, J ¼ 6.6 Hz, 2H), 2.63 (t, J ¼ 7.7 Hz, PPh3, DMF (1 mL) were added under argon atmosphere. The
2H), 2.39 (s, 3H) ppm. 13C NMR (50 MHz, CDCl3, 25 ꢀC): dC reaction mixture was stirred at 130 C for 1.5 h. Finally, aer
ꢀ
192.0, 161.6, 139.9, 139.7, 137.7, 136.2, 131.7, 129.3, 129.1, completion of the reaction (as monitored by TLC), the mixture
125.3, 119.0, 113.5, 112.0, 101.1, 82.6, 77.6, 55.3, 27.3, 21.6, was cooled to room temperature, diluted with ethyl acetate
19.8 ppm. IR (neat, cmꢂ1): 3429, 3020, 2206, 1603, 1428, 1368, (10 mL) and ltered through celite bed. The ltrate was then
1216, 759, 670. Mass (ESI-MS): m/z 303.1 (100, [M + H]+). ESI- mixed with water, and extracted with (2 ꢁ 10 mL) ethyl acetate.
HRMS: m/z [M + H]+ calcd for C21H19O2 303.1385, found The combined organic extracts were dried over anhydrous
303.1386.
sodium sulfate, ltered, and concentrated in vacuo. The crude
7-Methoxy-1-(phenylethynyl)-3,4-dihydronaphthalene-2-car- product was then puried by ash chromatography as well as
baldehyde (4i). Brownish oily liquid, yield ¼ 63% (0.346 g). Rf ¼ preparative thin layer chromatography, eluting with 1–3% ethyl
0.82 (2% EtOAc–hexane). 1H NMR (300 MHz, CDCl3, 25 ꢀC): dH acetate in hexane.
10.51 (s, 1H), 7.60–7.59 (m, 2H), 7.51 (s, 1H), 7.42–7.40 (m, 3H),
1,1-Dimethyl-8-phenyl-1H-benzo[4,5]imidazo[1,2-a]chromeno-
7.14 (d, J ¼ 8.2 Hz, 1H), 6.91 (d, J ¼ 8.2 Hz, 2H), 3.86 (s, 3H), 2.79 [3,4-c]pyridine (5a). Light greenish oily liquid, yield ¼ 53%
(t, J ¼ 7.8 Hz, 2H), 2.63 (t, J ¼ 7.9 Hz, 2H) ppm. 13C NMR (100 (0.050 g). Rf ¼ 0.76 (2% EtOAc–hexane). 1H NMR (400 MHz,
ꢀ
ꢀ
MHz, CDCl3, 25 C): dC 192.3, 158.5, 140.7, 135.9, 133.2, 131.8, CDCl3, 25 C): dH 7.94 (d, J ¼ 6.86 Hz, 1H), 7.68–7.58 (m, 6H),
129.8, 129.4, 128.6, 122.0, 115.9, 112.8, 101.1, 82.9, 55.4, 25.9, 7.39 (d, J ¼ 7.50 Hz, 1H), 7.32–7.28 (m, 1H), 7.05 (s, 1H), 7.01 (t, J
20.3 ppm. IR (neat, cmꢂ1): 3426, 3019, 2216, 1603, 1432, 1368, ¼ 7.5 Hz, 2H), 6.95 (t, J ¼ 7.8 Hz, 1H), 6.50 (d, J ¼ 7.9 Hz, 1H),
1215, 759, 667. Mass (ESI-MS): m/z 289.3 (100, [M + H]+). ESI- 2.13 (s, 6H) ppm. C NMR (100 MHz, CDCl3, 25 C): dC 153.4,
13
ꢀ
HRMS: m/z [M + H]+ calcd for C20H17O2 289.1229, found 140.5, 134.5, 131.0, 130.1, 129.1, 129.0, 125.1, 124.4, 123.5,
289.1227.
121.4, 120.6, 119.8, 119.6, 118.0, 114.4, 107.4, 78.4, 27.1 ppm. IR
7-Methoxy-1-(p-tolylethynyl)-3,4-dihydronaphthalene-2-car- (neat, cmꢂ1): 3423, 3050, 2962, 1745, 1631, 1420, 1319, 1235,
baldehyde (4j). Brownish oily liquid, yield ¼ 73% (0.413 g). Rf ¼ 1055, 765, 665. Mass (ESI-MS): m/z 377.5 (100, [M + H]+). ESI-
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HRMS: m/z [M + H]+ calcd for C26H21N2O 377.1654, found Mass (ESI-MS): m/z 405.6 (100, [M + H]+). ESI-HRMS: m/z [M +
377.1656.
1,1,11,12-Tetramethyl-8-phenyl-1H-benzo[4,5]imidazo[1,2-a]-
H]+ calcd for C28H25N2O 405.1967, found 405.1968.
11,12-Dichloro-1,1-dimethyl-8-(p-tolyl)-1H-benzo[4,5]imidazo-
chromeno[3,4-c]pyridine (5b). Light greenish oily liquid, yield ¼ [1,2-a]chromeno[3,4-c]pyridine (5f). Greenish oily liquid, yield ¼
64% (0.063 g). Rf ¼ 0.72 (2% EtOAc–hexane). 1H NMR (400 MHz, 74% (0.041 g). Rf ¼ 0.75 (2% EtOAc–hexane). 1H NMR (400 MHz,
CDCl3, 25 ꢀC): dH 7.67–7.66 (m, 1H), 7.65–7.63 (m, 1H), 7.61 (s, CDCl3, 25 ꢀC): dH 7.96 (s, 1H), 7.60 (dd, J1 ¼ 1.4, J2 ¼ 7.6 Hz, 1H),
2H), 7.59–7.57 (m, 3H), 7.30–7.28 (m, 1H), 7.01–6.98 (m, 3H), 7.45 (s, 4H), 7.33–7.29 (m, 1H), 7.04 (s, 1H), 7.03–6.99 (m, 2H),
6.23 (s, 1H), 2.36 (s, 3H), 2.12 (s, 3H), 2.11 (s, 6H) ppm. 13C NMR 6.64 (s, 1Hꢀ), 2.56 (s, 3H), 2.08 (s, 6H) ppm. 13C NMR (100 MHz,
(100 MHz, CDCl3, 25 ꢀC): dC 153.3, 140.2, 134.7, 134.5, 130.8, CDCl3, 25 C): dC 153.5, 148.1, 144.3, 140.8, 140.5, 131.3, 130.7,
129.9, 129.1, 129.0, 128.1, 127.6, 124.3, 123.4, 121.3, 120.0, 130.0, 129.9, 129.0, 128.8, 128.7, 128.3, 124.3, 123.8, 123.6, 121.5,
119.4, 117.9, 114.4, 106.8, 78.4, 27.07, 20.7, 20.4 ppm. IR (neat, 120.4, 119.6, 118.0, 115.6, 107.8, 78.3, 26.9, 21.6 ppm. IR (neat,
cmꢂ1): 3417, 3028, 2927, 1635, 1424, 1331, 1225, 762, 661. Mass cmꢂ1): 3430, 3048, 2962, 2416, 1623, 1421, 1236, 1055, 767, 664.
(ESI-MS): m/z 405.1 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ Mass (ESI-MS): m/z 459.3 (100, [M + H]+). ESI-HRMS: m/z [M + H]+
calcd for C28H25N2O 405.1967, found 405.1964.
calcd for C27H21Cl2N2O 459.1031, found 459.1030.
1,1-Dimethyl-8-(p-tolyl)-1H-benzo[4,5]imidazo[1,2-a]chromeno-
1,1-Dimethyl-8-(m-tolyl)-1H-benzo[4,5]imidazo[1,2-a]chromeno-
[3,4-c]pyridine (5c). Light greenish oily liquid, yield ¼ 75% [3,4-c]pyridine (5g). Light greenish oily liquid, yield ¼ 75% (0.055
(0.051 g). Rf ¼ 0.72 (2% EtOAc–hexane). 1H NMR (400 MHz, g). Rf ¼ 0.71 (2% EtOAc–hexane). 1H NMR (400 MHz, CDCl3,
CDCl3, 25 ꢀC): dH 7.89 (d, J ¼ 8.2 Hz, 1H), 7.59 (d, J ¼ 7.2 Hz, 1H), 25 ꢀC): dH 8.04 (dd, J1 ¼ 1.1, J2 ¼ 7.7 Hz, 1H), 7.86–7.83 (m, 2H),
7.47 (d, J ¼ 8.2 Hz, 2H), 7.42–7.35 (m, 3H), 7.30–7.26 (m, 1H), 7.53–7.48 (m, 1H), 7.49–7.42 (m, 3H), 7.29–7.24 (m, 2H), 6.99–
7.01–6.93 (m, 4H), 6.60 (s, 1H), 2.54 (s, 3H), 2.12 (s, 6H) ppm. 13
C
6.92 (m, 2H), 6.40–6.36 (m, 1H), 5.96 (s, 1H), 2.23 (s, 3H), 1.66 (s,
13
NMR (100 MHz, CDCl3, 25 ꢀC): dC 153.4, 146.7, 145.1, 140.6, 6H) ppm. C NMR (100 MHz, CDCl3, 25 C): dC 155.2, 152.6,
140.1, 131.7, 130.9, 129.8, 129.3, 128.9, 128.7, 124.9, 124.3, 139.0, 138.4, 135.8, 133.1, 130.1, 130.0, 129.9, 128.7, 128.4,
123.5, 121.3, 120.4, 119.9, 119.7, 117.9, 114.5, 107.1, 78.5, 27.0, 127.7, 127.1, 126.8, 126.1, 125.2, 120.6, 120.0, 119.2, 117.8,
21.6 ppm. IR (neat, cmꢂ1): 3425, 3020, 2927, 1631, 1404, 1318, 113.4, 113.3, 107.9, 75.3, 27.9, 21.2 ppm. IR (neat, cmꢂ1): 3430,
1215, 758, 669. Mass (ESI-MS): m/z 391.1 (100, [M + H]+). ESI- 3019, 1655, 1404, 1215, 1130, 756, 668. Mass (ESI-MS): m/z 391.1
HRMS: m/z [M + H]+ calcd for C27H23N2O 391.1810, found (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C27H23N2O
ꢀ
391.1809.
1,1,11,12-Tetramethyl-8-(p-tolyl)-1H-benzo[4,5]imidazo[1,2-a]-
391.1810, found 391.1807.
1,1,11,12-Tetramethyl-8-(m-tolyl)-1H-benzo[4,5]imidazo[1,2-a]-
chromeno[3,4-c]pyridine (5d). Greenish oily liquid, yield ¼ 78% chromeno[3,4-c]pyridine (5h). Brownish oily liquid, yield ¼ 48%
(0.059 g). Rf ¼ 0.71 (2% EtOAc–hexane). 1H NMR (400 MHz, (0.051 g). Rf ¼ 0.77 (2% EtOAc–hexane). 1H NMR (400 MHz,
ꢀ
CDCl3, 25 ꢀC): dH 7.67 (s, 1H), 7.61–7.58 (m, 1H), 7.47 (d, J ¼ 8.4 CDCl3, 25 C): dH 7.61 (d, J ¼ 6.9 Hz, 1H), 7.52–7.46 (m, 2H),
Hz, 2H), 7.41 (d, J ¼ 7.7 Hz, 2H), 7.28 (dd, J1 ¼ 1.4, J2 ¼ 7.7 Hz, 7.40–7.37 (m, 2H), 7.31–7.27 (m, 1H), 7.04–6.98 (m, 4H), 6.28 (s,
1H), 7.01–6.96 (m, 3H), 6.33 (s, 1H), 2.55 (s, 3H), 2.36 (s, 3H), 2.14 1H), 2.49 (s, 3H), 2.36 (s, 3H), 2.14 (s, 6H), 2.13 (s, 3H) ppm. 13
C
(s, 3H), 2.11 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3, 25 ꢀC): dC NMR (75 MHz, CDCl3, 25 ꢀC): dC 153.5, 140.6, 139.0, 134.0,
153.3, 146.2, 143.9, 140.3, 139.9, 134.2, 131.9, 130.6, 129.6, 128.9, 131.3, 130.9, 129.6, 128.9, 128.8, 128.0, 126.1, 123.6, 121.5,
127.9, 127.7, 124.2, 123.4, 121.3, 120.1, 119.5, 117.9, 114.5, 106.7, 119.7, 118.8, 118.0, 114.6, 78.2, 26.9, 21.4, 20.7, 20.3 ppm. IR
78.4, 27.0, 21.5, 20.7, 20.4 ppm. IR (neat, cmꢂ1): 3427, 3028, 2932, (neat, cmꢂ1): 3431, 3049, 2962, 2406, 1623, 1420, 1236, 1055,
1625, 1424, 1323, 1225, 772, 664. Mass (ESI-MS): m/z 419.6 (100, 757, 661. Mass (ESI-MS): m/z 419.7 (100, [M + H]+). ESI-HRMS:
[M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C29H27N2O 419.2123, m/z [M + H]+ calcd for C29H27N2O 419.2123, found 419.2118.
found 419.2122.
11,12-Dichloro-1,1-dimethyl-8-(thiophen-3-yl)-1H-benzo[4,5]-
Mixture (1 : 1) of 1,1,12-trimethyl-8-(p-tolyl)-1H-benzo[4,5] imidazo[1,2-a]chromeno[3,4-c]pyridine (5i). Light brownish oily
imidazo[1,2-a]chromeno[3,4-c]pyridine and 1,1,11-trimethyl-8- liquid, yield ¼ 63% (0.071 g). Rf ¼ 0.74 (2% EtOAc–hexane). 1H
(p-tolyl)-1H-benzo[4,5]imidazo[1,2-a]chromeno[3,4-c]pyridine NMR (400 MHz, CDCl3, 25 ꢀC): dH 7.97 (s, 1H), 7.28–7.69 (m, 2H),
(5e). Light greenish oily liquid, yield ¼ 77% (0.066 g). Rf ¼ 0.79 7.68–7.65 (m, 1H), 7.54–7.51 (m, 2H), 7.12 (s, 1H), 7.04–6.98 (m,
(2% EtOAc–hexane). 1H NMR (400 MHz, CDCl3, 25 ꢀC): dH 7.78 2H), 6.66 (s, 1H), 2.07 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3,
ꢀ
(d, J ¼ 8.2 Hz, 1H), 7.72–7.69 (m, 2H), 7.61–7.59 (m, 2H), 7.53 25 C): dC 167.7, 153.5, 145.0, 135.4, 132.4, 131.4, 130.9, 129.8,
(dd, J1 ¼ 3.4, J2 ¼ 5.7 Hz, 1H), 7.48–7.46 (m, 4H), 7.43–7.40 (m, 128.8, 128.2, 127.8, 126.6, 124.2, 123.6, 121.5, 120.5, 118.1,
4H), 7.30–7.26 (m, 2H), 7.21 (dd, J1 ¼ 1.2, J2 ¼ 8.4 Hz, 1H), 7.00– 115.2, 108.3, 78.3, 26.9 ppm. IR (neat, cmꢂ1): 3427, 3018, 2932,
6.97 (m, 4H), 6.78 (dd, J1 ¼ 1.4, J2 ¼ 8.6 Hz, 1H), 6.46 (d, J ¼ 8.6 1632, 1421, 1323, 1232, 772, 665. Mass (ESI-MS): m/z 451.3 (100,
Hz, 1H), 6.36 (s, 1H), 2.55 (s, 3H), 2.54 (s, 3H), 2.46 (s, 3H), 2.26 [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C24H17C12N2OS
(s, 3H), 2.11 (s, 12H) ppm. 13C NMR (100 MHz, CDCl3, 25 ꢀC): dC 451.0439, found 451.0441.
167.7, 153.3, 146.7, 146.4, 145.5, 143.2, 140.4, 140.0, 134.8,
4-methoxy-1,1-Dimethyl-8-(p-tolyl)-1H-benzo[4,5]imidazo[1,2-a]-
132.4, 132.3, 131.8, 131.7, 130.9, 130.8, 130.7, 130.1, 129.7, chromeno[3,4-c]pyridine (5j). Light greenish oily liquid, yield ¼
129.6, 129.4, 128.9, 128.8, 128.7, 128.5, 128.1, 127.4, 126.6, 63% (0.067 g). Rf ¼ 0.69 (2% EtOAc–hexane). 1H NMR (400 MHz,
124.3, 124.2, 123.4, 122.0, 121.3, 120.0, 119.2, 119.1, 117.9, CDCl3, 25 ꢀC): dH 7.87 (d, J ¼ 8.5 Hz, 1H), 7.51–7.45 (m, 3H), 7.41–
114.3, 113.9, 106.9, 106.6, 78.4, 27.0, 21.9, 21.6, 21.5 ppm. IR 7.34 (m, 3H), 6.94–6.90 (m, 2H), 6.57 (s, 1H), 6.55 (s, 2H), 3.84 (s,
(neat, cmꢂ1): 3423, 3028, 2944, 1635, 1427, 1333, 1271, 773, 666. 3H), 2.54 (s, 3H), 2.11 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3,
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25 ꢀC): dC 162.3, 154.9, 146.9, 145.1, 140.5, 140.0, 131.8, 129.7, ESI-HRMS: m/z [M + H]+ calcd for C27H23N2 375.1861, found
129.0, 128.9, 124.8, 124.5, 122.1, 120.1, 119.5, 114.4, 112.9, 108.3, 375.1858.
107.0, 102.5, 78.9, 55.4, 27.1, 21.5 ppm. IR (neat, cmꢂ1): 3402, 3023,
4-Methoxy-11,12-dimethyl-8-(p-tolyl)-1,2-dihydrobenzo[f]benzo-
2919, 1625, 1424, 1323, 1255, 767, 660. Mass (ESI-MS): m/z 421.2 [4,5]imidazo[2,1-a]-isoquinoline (5o). Brownish oily liquid, yield ¼
(100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C28H25N2O2 38% (0.027 g). Rf ¼ 0.72 (2% EtOAc–hexane). 1H NMR (400 MHz,
421.1916, found 421.1913.
CDCl3, 25 ꢀC): dH 8.00 (d, J ¼ 8.5 Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H),
4-Methoxy-1,1-dimethyl-8-(m-tolyl)-1H-benzo[4,5]imidazo[1,2- 7.60 (s, 1H), 7.84 (d, J ¼ 7.5 Hz, 1H), 7.12 (d, J ¼ 7.5 Hz, 2H), 6.77 (s,
a]chromeno[3,4-c]pyridine (5k). Light greenish oily liquid, yield 1H), 6.18–6.09 (m, 2H), 3.74 (s, 3H), 2.89–2.86 (m, 4H), 2.46 (s, 3H),
¼ 67% (0.039 g). Rf ¼ 0.76 (2% EtOAc–hexane). H NMR (400 2.39 (s, 3H), 2.37(s, 3H) ppm. IR (neat, cmꢂ1): 3403, 3021, 2961,
1
MHz, CDCl3, 25 ꢀC): dH 8.02 (s, 1H), 7.53–7.46 (m, 3H), 7.40–7.37 1653, 1409, 1205, 929, 775, 676. Mass (ESI-MS): m/z 419.8 (100,
(m, 3H), 7.03 (s, 1H), 6.96 (t, J ¼ 7.9 Hz, 1H), 6.57–6.56 (m, 2H), [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C29H27N2O 419.2123,
6.50 (d, J ¼ 8.6 Hz, 1H), 3.84 (s, 3H), 2.48 (s, 3H), 2.15 (s, 3H), 2.14 found 419.2125.
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3, 25 ꢀC): dC 163.0, 155.3,
5-Methoxy-8-phenyl-1,2-dihydrobenzo[f]benzo[4,5]imidazo-
141.0, 139.3, 131.1, 129.5, 129.2, 128.5, 126.0, 124.9, 121.4, 118.7, [2,1-a]isoquinoline (5p). Light yellowish oily liquid, yield ¼
114.5, 108.9, 102.6, 78.6, 55.5, 26.9, 21.5 ppm. IR (neat, cmꢂ1): 34% (0.016 g). Rf ¼ 0.70 (2% EtOAc–hexane). 1H NMR (400
3431, 3019, 2406, 1613, 1404, 1216, 757, 669. Mass (ESI-MS): m/z MHz, CDCl3, 25 ꢀC): dH 8.04 (dd, J1 ¼ 1.2, J2 ¼ 7.99 Hz, 1H), 7.95
421.5 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for (s, 1H), 7.86 (d, J ¼ 8.2 Hz, 1H), 7.73–7.71 (m, 2H), 7.54–7.50
C28H25N2O2 421.1916, found 421.1913.
(m, 1H), 7.46–7.39 (m, 2H), 7.36–7.32 (m, 2H), 7.12 (d, J ¼ 8.2
4-Methoxy-1,1,11,12-tetramethyl-8-(m-tolyl)-1H-benzo[4,5]- Hz, 1H), 6.56 (dd, J1 ¼ 2.7, J2 ¼ 8.4 Hz, 1H), 5.90 (s, 1H), 3.18 (s,
imidazo[1,2-a]chromeno[3,4-c]pyridine (5l). Greenish oily 3H), 2.91–2.85 (m, 4H) ppm. IR (neat, cmꢂ1): 3419, 3025, 2962,
liquid, yield ¼ 65% (0.047 g). Rf ¼ 0.72 (2% EtOAc–hexane). 1H 1703, 1420, 1235, 1055, 929, 758, 664. Mass (ESI-MS): m/z 377.3
NMR (400 MHz, CDCl3, 25 C): dH 7.64 (s, 1H), 7.51–7.44 (m, (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C26H21N2O
ꢀ
3H), 7.39–7.36 (m, 2H), 6.90 (s, 1H), 6.57–6.55 (m, 2H), 6.26 (s, 377.1654, found 377.1649.
1H), 3.83 (s, 3H), 2.47 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H), 2.09 (d,
5-Methoxy-8-(p-tolyl)-1,2-dihydrobenzo[f]benzo[4,5]imidazo-
J ¼ 4.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3, 25 ꢀC): dC [2,1-a]isoquinoline (5q). Light greenish oily liquid, yield ¼ 73%
162.0, 154.8, 140.3, 138.8, 134.7, 134.1, 130.5, 129.6, 128.8, (0.051 g). Rf ¼ 0.69 (2% EtOAc–hexane). 1H NMR (400 MHz,
127.8, 126.1, 124.4, 119.3, 114.4, 113.1, 108.2, 106.4, 102.5, CDCl3, 25 ꢀC): dH 8.02 (dd, J1 ¼ 1.4, J2 ¼ 7.8 Hz, 1H), 7.92 (s, 1H),
78.9, 55.4, 27.0, 21.4, 20.6, 20.4 ppm. IR (neat, cmꢂ1): 3423, 7.85–7.83 (m, 1H), 7.60 (d, J ¼ 7.8 Hz, 2H), 7.57–7.48 (m, 1H),
3019, 2402, 1613, 1515, 1406, 1215, 928, 756, 669. Mass (ESI- 7.45–7.41 (m, 1H), 7.15 (d, J ¼ 7.8 Hz, 2H), 7.12 (d, J ¼ 8.3 Hz,
MS): m/z 449.7 (100, [M + H]+). ESI-HRMS: m/z [M + H]+ calcd 1H), 6.56 (dd, J1 ¼ 2.7, J2 ¼ 8.3 Hz, 1H), 5.92 (s, 1H), 3.19 (s, 3H),
for C30H29N2O2 449.2229, found 449.2225.
2.91–2.83 (m, 4H), 2.37 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3,
ꢀ
8-Phenyl-1,2-dihydrobenzo[f]benzo[4,5]imidazo[2,1-a]isoquino- 25 C): dC157.1, 154.3, 139.6, 136.8, 135.9, 131.7, 129.9, 129.4,
line (5m). Brownish oily liquid, yield ¼ 65% (0.061 g). Rf ¼ 0.78 129.0, 128.8, 128.0, 127.5, 126.6, 124.8, 119.6, 119.5, 113.9,
(2% EtOAc–hexane). 1H NMR (400 MHz, CDCl3, 25 ꢀC): dH 8.04 112.8, 113.2, 110.7, 54.5, 30.0, 22.1, 21.3 ppm. IR (neat, cmꢂ1):
(d, J ¼ 7.6 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J ¼ 8.7 Hz, 1H), 7.62 (d, 3402, 3023, 2949, 1745, 1620, 1424, 1323, 1255, 765, 652. Mass
J ¼ 7.3 Hz, 2H), 7.52 (t, J ¼ 7.5 Hz, 1H), 7.44 (t, J ¼ 7.7 Hz, 1H), (ESI-MS): m/z 391.3 (100, [M + H]+). ESI-HRMS: m/z [M + H]+
7.38 (d, J ¼ 7.1 Hz, 1H), 7.33–7.25 (m, 2H), 7.20 (d, J ¼ 7.3 Hz, calcd for C27H23N2O 391.1810, found 391.1811.
1H), 6.95 (t, J ¼ 7.5 Hz, 1H), 6.60 (t, J ¼ 7.7 Hz, 1H), 6.19 (s, 1H),
5-Methoxy-8-(m-tolyl)-1,2-dihydrobenzo[f]benzo[4,5]imidazo-
2.94–2.88 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3, 25 ꢀC): dC [2,1-a]isoquinoline (5r). Light brownish oily liquid, yield ¼ 64%
154.7, 139.5, 137.1, 135.9, 130.7, 129.9, 129.3, 129.1, 128.9, (0.054 g). Rf ¼ 0.80 (2% EtOAc–hexane). 1H NMR (400 MHz,
128.6, 128.4, 127.6, 127.3, 126.8, 125.3, 124.8, 119.6, 119.4, CDCl3, 25 ꢀC): dH 8.04 (d, J ¼ 7.7 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J ¼
113.3, 110.7, 30.9, 21.7 ppm. IR (neat, cmꢂ1): 3423, 3049, 2946, 7.7 Hz, 1H), 7.55 (s, 1H), 7.51 (t, J ¼ 7.6 Hz, 1H), 7.45–7.41 (m,
1613, 1433, 1215, 942, 768, 660. Mass (ESI-MS): m/z 347.3 (100, 2H), 7.20 (s, 2H), 7.11 (d, J ¼ 8.1 Hz, 1H), 6.57 (d, J ¼ 8.1 Hz, 1H),
[M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C25H19N2 347.1548, 5.89 (s, 1H), 3.19 (s, 3H), 2.87 (s, 4H), 2.25 (s, 3H) ppm. 13C NMR
found 347.1547.
(100 MHz, CDCl3, 25 ꢀC): dC 157.0, 154.4, 139.2, 138.1, 135.9,
11,12-Dimethyl-8-phenyl-1,2-dihydrobenzo[f]benzo[4,5]imi- 131.7, 130.3, 130.0, 129.9, 129.4, 128.8, 128.3, 128.0, 127.6,
dazo[2,1-a]isoquinoline (5n). Light yellowish oily liquid, yield 126.7, 126.6, 124.8, 119.7, 119.4, 113.5, 113.3, 113.0, 110.7, 54.6,
1
¼ 57% (0.044 g). Rf ¼ 0.77 (2% EtOAc–hexane). H NMR (400 30.0, 22.1, 21.2 ppm. IR (neat, cmꢂ1): 3416, 3025, 2927, 1635,
ꢀ
MHz, CDCl3, 25 C): dH 8.00 (s, 1H), 7.67 (d, J ¼ 9.4 Hz, 3H), 1441, 1330, 1225, 1054, 772, 662. Mass (ESI-MS): m/z 391.3 (100,
7.44 (t, J ¼ 5.9 Hz, 1H), 7.34 (t, J ¼ 7.1 Hz, 2H), 7.29 (d, J ¼ 8.3 [M + H]+). ESI-HRMS: m/z [M + H]+ calcd for C27H23N2O
Hz, 1H), 7.20 (d, J ¼ 8.3 Hz, 1H), 6.96 (t, J ¼ 8.3 Hz, 1H), 5.59 (t, 391.1810, found 391.1811.
J ¼ 8.6 Hz, 1H), 6.14 (s, 1H), 2.95–2.93 (m, 2H), 2.89–2.86 (m,
5-Methoxy-11,12-dimethyl-8-(m-tolyl)-1,2-dihydrobenzo[f]-
2H), 2.48 (s, 3H), 2.42 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3, benzo[4,5]imidazo[2,1-a]isoquinoline (5s). Light brownish
25 ꢀC): dC 152.1, 138.1, 137.3, 130.7, 129.9, 129.8, 129.1, 128.9, oily liquid, yield ¼ 35% (0.021 g). Rf ¼ 0.77 (2% EtOAc–hexane).
1
ꢀ
128.7, 128.4, 127.6, 126.2, 125.5, 124.4, 118.8, 113.9, 30.6, 21.6,
H NMR (400 MHz, CDCl3, 25 C): dH 8.03 (s, 1H), 7.65 (s, 1H),
20.5, 19.6 ppm. IR (neat, cmꢂ1): 3442, 3059, 2961, 1653, 1403, 7.59 (s, 1H), 7.54 (d, J ¼ 10.7 Hz, 1H), 7.27–7.26 (m, 3H), 7.11 (t,
1219, 914, 758, 654. Mass (ESI-MS): m/z 375.3 (100, [M + H]+). J ¼ 8.0 Hz, 1H), 6.61–6.59 (m, 1H), 5.82 (s, 1H), 3.20 (s, 3H),
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2.89–2.88 (m, 4H), 2.49 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H) ppm. IR
(neat, cmꢂ1): 3423, 3019, 2961, 1613, 1403, 1215, 929, 758, 669.
Mass (ESI-MS): m/z 419.5 (100, [M + H]+). ESI-HRMS: m/z [M +
H]+calcd for C29H27N2O 419.2123, found 419.2121.
4 (a) Q. Sun and E. J. LaVoie, Heterocycles, 1996, 43, 737; (b)
H.-C. Ouyang, R.-Y. Tang, P. Zhong, X.-G. Zhang and
J.-H. Li, J. Org. Chem., 2011, 76, 223; (c) Y. Ohta, Y. Kubota,
T. Watabe, H. Chiba, S. Oishi, N. Fujii and H. Ohno, J. Org.
Chem., 2009, 74, 6299; (d) G. Dyker, W. Stirner and
G. Henkel, Eur. J. Org. Chem., 2000, 8, 1433; (e)
T. K. Chaitanya, K. S. Prakash and R. Nagarajan,
Tetrahedron, 2011, 67, 6934; (f) N. Rustagi, T. Aggarwal and
A. K. Verma, Green Chem., 2011, 13, 1640; (g) N. Okamoto,
K. Sakurai, M. Ishikur, K. Takeda and R. Yanada,
Tetrahedron Lett., 2009, 50, 4167; (h) S. K. Manna,
S. K. Mondal, A. Ahmed, A. Mandal, A. Jana, M. Ikbal,
S. Samanta and J. K. Ray, RSC Adv., 2014, 4, 2474; (i)
V. Rustagi, R. Tiwari and A. K. Verma, Eur. J. Org. Chem.,
2012, 24, 4590; (j) N. T. Patil, A. Konala, S. Sravanti,
A. Singh, R. Ummanni and B. Sridhar, Chem. Commun.,
2013, 49, 10109.
2-(1-(Phenylethynyl)-3,4-dihydronaphthalen-2-yl)-1H-benzo[d]-
imidazole (U). Light greenish oily liquid, yield ¼ 57% (0.042 g).
Rf ¼ 0.27 (10% EtOAc–hexane). 1H NMR (300 MHz, CDCl3,
25 ꢀC): dH 11.7 (s, 1H), 7.85 (d, J ¼ 6.9 Hz, 2H), 7.66 (t, J ¼ 3.4 Hz,
2H), 7.48–7.42 (m, 4H), 7.35–7.21 (m, 5H), 3.32 (t, J ¼ 8.2 Hz,
2H), 2.97 (t, J ¼ 7.5 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3,
ꢀ
25 C): dC 150.9, 143.0, 136.1, 133.6, 133.5, 133.1, 131.1, 129.5,
128.9, 128.6, 127.4, 126.8, 126.3, 124.0, 122.7, 122.0, 119.9,
118.8, 110.6, 98.8, 87.9, 27.3, 25.3 ppm. IR (neat, cmꢂ1): 3427,
3023, 2928, 2428, 2202, 1662, 1627, 1544, 1375, 1267, 1213, 984,
769, 660. Mass (ESI-MS): m/z 347.2 (90, [M + H]+). ESI-HRMS: m/z
[M + H]+ calcd for C25H19N2 347.1548, found 347.1550.
5 N. Asao, K. Iso and S. S. Yudha, Org. Lett., 2006, 8, 4149.
6 (a) H. Gao and J. Zhang, Adv. Synth. Catal., 2009, 351, 85; (b)
S. Obika, H. Kono, Y. Yasui, R. Yanada and Y. Takemoto, J.
Org. Chem., 2007, 72, 4462; (c) H. Zhou, H. Jin, S. Ye, X. He
and J. Wu, Tetrahedron Lett., 2009, 50, 4616; (d) Q. Ding,
B. Wang and J. Wu, Tetrahedron, 2007, 63, 12166; (e)
R. Yanada, S. Obika, H. Kono and Y. Takemoto, Angew.
Chem., Int. Ed., 2006, 45, 3822; (f) N. Asao, Y. S. Salprima,
T. Nogami and Y. Yamamoto, Angew. Chem., Int. Ed., 2005,
44, 5526; (g) Y. Ye, Q. Ding and J. Wu, Tetrahedron, 2008,
64, 1378; (h) M. Yu, Y. Wang, C.-J. Li and X. Yao,
Tetrahedron Lett., 2009, 50, 6791; (i) K. Gao and J. Wu, J.
Org. Chem., 2007, 72, 8611.
Acknowledgements
This research project was partly supported by ICMR and DST,
New Delhi, India. Sudipta thanks the Council of Scientic and
Industrial Research (CSIR), India for research fellowship.
Instrumental facilities from SAIF, CDRI is acknowledged. We
are also grateful to the referees for their valuable suggestions
(CDRI Communication no. 8658).
References
1 (a) R. J. Griffin, G. Fontana, B. T. Golding, S. Guiard,
I. R. Hardcastle, J. J. J. Leahy, N. Martin, C. Richardson,
L. Rigoreau, M. Stockley and G. C. M. Smith, J. Med. Chem.,
2005, 48, 569; (b) K. W. Bentley, Nat. Prod. Rep., 2006, 23,
444; (c) A. D. C. Parenty, L. V. Smith, K. M. Guthrie,
D. L. Long, J. Plumb, R. Brown and L. Cronin, J. Med.
Chem., 2005, 48, 4504; (d) M. Chrzanowska and
M. D. Rozwadowska, Chem. Rev., 2004, 104, 3341; (e)
K. W. Bentley, Nat. Prod. Rep., 2005, 22, 249; (f) S. D. Riedl,
S. B. Felix, W. J. Houlihan, M. Zafferani, G. Steinhauser,
D. Oberberg, H. Kalvelage, R. Busch, J. Rastetterand and
7 A. K. Verma, R. R. Jha, R. Chaudhary, R. Tiwari, K. S. K. Reddy
and A. Danodia, J. Org. Chem., 2012, 77, 8191.
ˇ
´
´
8 (a) I. Cerna, R. Pohl, B. Klepetarova and M. Hocek, J. Org.
Chem., 2010, 75, 2302; (b) S. Philipp, H. Holger,
J. Dominik, P. Christof, G. Anja and B. Esther, PCT Int.
Appl. WO 2010086089, August 5 2010; (c) C. Venkatesh,
G. S. M. Sundaram, H. Ila and H. Junjappa, J. Org. Chem.,
2006, 71, 1280.
9 J.-R. Huang, L. Dong, B. Han, C. Peng and Y.-C. Chen, Chem.–
Eur. J., 2012, 18, 8896.
W. E. Berdel, Cancer Res., 1991, 51, 43; (g) D. Scholz, 10 L. W. Deady and T. Rodemann, Aust. J. Chem., 2001, 54, 529.
H. Schmidt, E. E. Prieschl, R. Csonga, W. Scheirer, 11 D. B. Ramachary and S. Jain, Org. Biomol. Chem., 2011, 9,
V. Weber, A. Lembachner, G. Seidl, G. Werner, P. Mayer
and T. Baumruker, J. Med. Chem., 1998, 41, 1050.
1277.
12 (a) R. Singh, M. K. Parai and G. Panda, Org. Biomol. Chem.,
2009, 7, 1858; (b) R. Singh and G. Panda, Org. Biomol.
Chem., 2010, 8, 1097; (c) R. Singh and G. Panda, Org.
Biomol. Chem., 2011, 9, 4782; (d) K. Samanta and
G. Panda, Org. Biomol. Chem., 2011, 9, 7365; (e)
K. Samanta, N. Srivastava, S. Saha and G. Panda, Org.
Biomol. Chem., 2012, 10, 1553; (f) A. K. Jana, S. K. Das and
G. Panda, Tetrahedron, 2009, 68, 10114; (g) S. K. Manna,
M. K. Parai and G. Panda, Tetrahedron Lett., 2011, 52,
5951; (h) S. K. Manna and G. Panda, RSC Adv., 2013, 3,
18332.
2 (a) V. K. Pandey and A. Shukla, Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem., 1999, 38, 1381; (b) S. M. Rida,
S. A. M. El-Hawash, H. T. Y. Fahmy, A. A. Hazzaa and
M. M. M. El-Meligy, Arch. Pharmacal Res., 2006, 29, 826; (c)
R. L. Weinkauf, A. Y. Chen, C. Yu, L. Liu, L. Barrows and
E. LaVoie, Bioorg. Med. Chem., 1994, 2, 781; (d)
L. W. Deady, T. Rodemann, G. J. Finlay, B. C. Baguley and
W. A. Denny, Anti-Cancer Drug Des., 2001, 15, 339.
´
¨
3 (a) M. Hranjec, M. Kralj, I. Piantanida, M. Sedic, L. Syuman,
´
K. Pavelic and G. Karminski-Zamola, J. Med. Chem., 2007, 50,
5696; (b) M. Hranjec, I. Piantanida, M. Kralj, L. Suman, 13 (a) M. I. Hegab and M. M. Abdulla, Arch. Pharm. Chem. Life
´
K. Pavelic and G. Karminski-Zamola, J. Med. Chem., 2008,
Sci., 2006, 339, 41; (b) Z. Arnold and J. Zemlicka, Collect.
Czech. Chem. Commun., 1959, 24, 2385.
51, 4899.
21040 | RSC Adv., 2014, 4, 21032–21041
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
14 H. A. Oskooie, M. M. Heravi and K. F. Behbahani, Molecules, 16 S. S. Moleele, J. P. Michel and C. B. De Koning, Tetrahedron,
2007, 12, 1438. 2006, 62, 2831.
15 T. L. Gilchrist and M. A. M. Hearly, Tetrahedron, 1993, 49, 17 R. Jana, I. Chatterjee, S. Samanta and J. K. Ray, Org. Lett.,
2543.
2008, 10, 4795.
This journal is © The Royal Society of Chemistry 2014
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