Microwave-Assisted Synthesis of Benzimidazole-Linked Indoline and Indole Hybrids from C-2 Linked (o-Aminobenzyl)benzimidazoles

Article abstract of DOI:10.1002/adsc.201701140

An efficient and novel synthesis of benzimidazole-linked indoline hybrids via an unconventional Pictet-Spengler-type condensation of C-2 linked (o-aminobenzyl)benzimidazoles with aldehydes and ketones under microwave irradiation has been explored. The key

Full text of DOI:10.1002/adsc.201701140

Title: Microwave-Assisted Synthesis of Benzimidazole-Linked
Indoline and Indole Hybrids from C-2-Linked o-Amino Benzyl
Benzimidazoles
Authors: Yun-Ta Lee, Fengyu Chiu, Indrajeet Barve, and Chung-Ming
Sun
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701140
Link to VoR: http://dx.doi.org/10.1002/adsc.201701140

10.1002/adsc.201701140
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Microwave-Assisted Synthesis of Benzimidazole-Linked
Indoline and Indole Hybrids from C-2-Linked o-Amino Benzyl
Benzimidazoles
Yun-Ta Lee,a,b Feng-Yu Chiu,a Indrajeet J. Barve,a and Chung-Ming Sun*a,b
a
Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao-Tung University, Hsinchu 300-10, TAIWAN
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan 1st Road,
b
Kaohsiung 807-08, TAIWAN
Email: cmsun@mail.nctu.edu.tw
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: An efficient and novel synthesis of The scope of this method is further extended to synthesize
benzimidazole-linked
indoline
hybrids
via
an tetracyclic pyrrolo indole benzoimidazole carboxylates
unconventional Pictet-Spengler type condensation of C-2 through 2-carboxyaldehydes.
linked o-aminobenzyl benzimidazole with aldehydes and
ketones under microwave irradiation is explored. The key Keywords: Benzimidazole-linked indolines;benzimidazole-
condensation step consists of acid catalyzed imine linked indoles; indoline synthesis; pyrrolo indole
generation followed by intramolecular C-C bond formation benzoimidazole carboxylate; unconventional Pictet-Spengler
through unique reactivity of benzimidazole moiety.
reaction
the synthesis of functionalized indolines and indoles.
The substituted indoles are prepared mainly through
cyclization of various benzoid precursors,
halogenation of indole followed by cross-coupling or
C-H activation of indole.[3] Similarly, various
methods for the synthesis of indolines have been
reported in the literature which is mostly based on the
use of heavy metals such as Pd, Au, Pt, In, Cu.[4-13]
The use of metal catalyst produces a stoichiometric
amount of waste. In light of this, there is a need to
device a metal-free protocol for the synthesis of
functionalized indolines and indoles.
Introduction
Indoline and indole derivatives are widely
distributed in nature and have received substantial
interest in drug discovery due to their diverse
bioactivities (Figure 1).[1,2] For example, Oxypertine
exhibits antidepressant and antipsychotic activity.[1b]
Benzimidazole scaffold is also an important
pharmacophore and its derivatives show a broad
spectrum of bioactivities including anticancer,[14]
antiviral,[15] anticonvulsant,[16] antifungal,[17] and anti-
inflammatory.[18] Consequently, benzimidazole core
emerged as a significant structural component of the
existed bioactive heterocycles belonging to vast
therapeutic areas.
Figure 1. Representative examples of biologically active
indoline and indole derivatives.
The hybrid molecule strategy that covalently
connects two distinct bioactive pharmacophores in a
single molecule has been a subject of intense
research.[19] In this approach, two molecular scaffolds
which act on different biological targets are
covalently linked to exert a possible synergistic
effect.[20] The dual-acting hybrid molecules can offer
the advantages of synergistic effectiveness towards
Ramosetron acts as a serotonin 5-HT3 receptor
antagonist and it is used for the treatment of irritable
bowel syndrome (IBS),[1c] whereas Strychnine shows
anticancer activity.[1d]
As a consequence, tremendous efforts have been
made to the development of efficient strategies for
1
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10.1002/adsc.201701140
Advanced Synthesis & Catalysis
resistant strain, improved pharmacokinetics and
boosted bioactivity.[21]
and ammonium formate to furnish C-2-linked o-
amino benzyl benzimidazoles 5 in 90-96% yields
(Scheme 1).
Initially, the reaction of methyl 2-(2-aminobenzyl)-
1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-
A comprehensive literature survey revealed the
number of synthetic strategies for the construction of
hybrid molecules utilizing various combinations of
pharmacophores and natural product motifs.[22]
However, there is no single reported precedent on the
synthesis of benzimidazole-linked indole and indoline
hybrid molecules. Lack of the literature report on the
preparation of benzimidazole-indoline and indole
hybrid and our previous experience regarding the
synthesis of functionalized benzimidazoles[23]
prompted us to develop a novel and metal-free
protocol to amalgamate benzimidazole and
indoline/indole pharmacophores into a single hybrid
molecule.
carboxylate
5d
and
1,3-benzodioxole-5-
carboxaldehyde 6f was examined as a model study by
We envisaged that indoline derivatives 7 could be
prepared through non-conventional Pictet-Spengler
type condensation of amine 5 with aldehyde 6
utilizing the unique reactivity of the benzimidazole
core (Figure 2).
Scheme 1. Synthesis of C-2-linked o-amino benzyl
benzimidazole 5.
different bases and solvents under variable reaction
parameters as summarized in Table 1. The treatment
of amine 5d with aldehyde 6f in the presence of
either K2CO3, triethylamine or piperidine in refluxing
acetonitrile failed to give indoline 7g and only
starting material was recovered (Table 1, entries 1-3).
Furthermore, the use of the stronger base, KOtBu in
refluxing acetonitrile or high boiling solvent such as
toluene did not deliver the desired product 7g (Table
1, entries 4 and 5). However, when the amine 5d was
reacted with aldehyde 6f in the presence of catalytic
amount of acetic acid in refluxing acetonitrile, a new
spot was detected which was isolated in 65% yield
and subjected to spectroscopic analysis (Table 1,
entry 6).
Figure 2. The design of benzimidazole-linked indoline
hybrid.
Table 1. Optimization of the reaction conditionsa
Herein, we established an unique synthetic route
for the synthesis of benzimidazole-linked indoline
and indoles through C-2-linked o-amino benzyl
benzimidazole under microwave heating. Our
protocol consists of several advantages including
short reaction time, metal-free synthesis and broad
substrate scope.
Entry
Catalyst
Base
Solvent
Temp
(°C)
Time
(h)
12
12
12
12
12
12
12
Yield
(%)
0
0
0
Results and Discussion
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-
-
K2CO3
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
toluene
CH3CN
toluene
CH3CN
CH3CN
CH3CN
CH3CN
toluene
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
140
140
140
120
reflux
reflux
reflux
Our planned synthesis started with the preparation
of various C-2-linked o-amino benzyl benzimidazoles
5. We first performed esterification of 4-fluoro-3-
nitro benzoic acid and the resulted 4-fluoro-3-nitro
benzoates were reacted with different amines
followed by reduction of the nitro group to afford
corresponding 3,4-diamino benzoates 1.[24] In the next
step, amino benzoates 1 were coupled with 2-(2-
nitrophenyl)acetic acid 2 in the presence of DCC and
DMAP in dichloromethane at room temperature to
obtain amides 3 in 75-95% yields. Intramolecular
cyclodehydration of amides in refluxing 1,2-
dichloroethane and TFA gave C-2-linked o-nitro
benzyl benzimidazoles 4 in 93-98% yields. In a
subsequent step, the nitro group was reduced by zinc
piperidine
-
-
-
KOtBu
0
0
KOtBu
CH3COOH
CH3COOH
BF3.Et2O
piperidine
CH3COOH
-
-
-
-
-
62
70
65
38c
72c
0c
12
0.5
0.5
0.5
0.5
12
12
12
-
K2CO3
K2CO3
-
-
-
-
0c
0
trace
0
TiCl4
AlCl3
Conc. HCl
CH3CN
CH3CN
CH3CN
aReaction conditions: 5d (1.48 mmol), 6f (4.44 mmol),
base (1.2 equiv), catalyst (10 mol %), MgSO4 (2 equiv),
solvent (4 mL); bIsolated yield; cmicrowave irradiation.
2
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10.1002/adsc.201701140
Advanced Synthesis & Catalysis
1
In the H NMR spectrum, corresponding peaks of
amount of acetic acid, the compound 7g was obtained
in 72% yield (Table 1, entry 10). The utilization of
K2CO3 in acetonitrile or toluene did not afford the
product 7g (Table 1, entries 11, 12). The use of the
strong Lewis acid such as TiCl4 did not afford the
desired product 7g and the starting material was
recovered (Table 1, entry 13) whereas AlCl3 yielded
the desired compound 7g in trace amount (Table 1,
entry 14). When the reaction was performed in strong
Brønsted acid like conc. HCl, 7g was not obtained
(Table 1, entry 15).
indoline ring clearly appeared at 4 ~ 6 ppm. 13C NMR
spectrum also showed two extra -CH peaks in the
aliphatic region. The obtained product was further
analyzed by a single X-ray crystallographic study,
which confirmed the newly formed entity as methyl
2-(2-(benzo[d][1,3] dioxol-5-yl) indolin-3-yl)-1-(3-
methoxypropyl)-1H-benzo [d]imidazole-5- carboxylat
e 7g (Figure 3).
With the optimized conditions in hand, we next
turned our attention to assess the substrate scope of
the reaction. Various aldehydes 6 bearing electron
donating and withdrawing groups on aromatic ring
reacted with different C-2-linked o-amino benzyl
benzimidazoles 5 to obtain corresponding products 7
in good yields (Table 2). In addition, various ketones
also afforded the corresponding products 9 in
moderate to good yields (Table 3).
Figure 3. ORTEP diagram of compound 7g.
Table 3. Scope of ketonesa
When the same reaction was performed in refluxing
toluene, the desired product was obtained in 70%
yield (Table 1, entry 7). Use the catalytic amount of
Lewis acid such as BF3.Et2O afforded the desired
product in 65% yield (Table 1, entry 8). In order to
improve the yield of the reaction, a mixture of amine
5d and piperidine in acetonitrile was reacted with
aldehyde 6f under microwave irradiation to deliver
the desired product 7g in only 38% yield (Table 1,
entry 9). When the same reaction was carried out in
catalytic
Table 2. Scope of aldehydesa
aReaction conditions: 5 (1.48 mmol), 8 (4.44 mmol),
AcOH (10 mol %), MgSO4 (2 equiv), CH3CN (4 mL).
A possible mechanistic pathway for the formation
of indoline 7 is illustrated in Scheme 2. Initially,
Scheme 2. A plausible mechanism for the indoline
synthesis.
aReaction conditions: 5 (1.48 mmol), 6 (4.44 mmol),
AcOH (10 mol %), MgSO4 (2 equiv), CH3CN (4 mL).
3
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10.1002/adsc.201701140
Advanced Synthesis & Catalysis
nucleophilic addition of amine 5 to protonated
aldehyde 6 followed by dehydration of A affords
imine B. In the next step, protonation at the nitrogen
atom of the benzimidazole ring of C with subsequent
removal of acidic benzylic proton produces
tautomeric intermediate D. Finally, protonation at the
imine’s nitrogen atom followed by intramolecular
nucleophilic addition affords indoline 7.
In addition, the benzimidazole-linked indoline 7a
was reacted with DDQ in dichloromethane at room
temperature for 30 min to obtain the desired indole
12a in 92% yields (Table 4).[25] 1H NMR of the
isolated indole compound clearly showed the
disappearance of two doublet peaks between 4~6
ppm of the indoline ring due to the formation of the
double bond. Moreover, 13C NMR spectrum also
showed two extra quaternary carbon peaks at ~138
and ~98 ppm in aromatic region respectively.
Subsequently, substrate scope was carried out by the
oxidation of indolines 7 to deliver the respective
indoles 12 in excellent yields.
Figure 4. ORTEP diagram of compound 10a.
carbon C8 forces ring D and E to adopt partial
envelope conformation respectively (Figure 4).
Conclusion
In conclusion, we have developed a novel and metal-
free synthesis of benzimidazole-linked indoline
hybrids via unconventional Pictet-Spengler type
condensation reaction of C-2-linked-o-aminobenzyl
benzimidazoles with aldehydes and ketones under
microwave irradiation. Additionally, benzimidazole-
linked indoline hybrids are further converted into the
corresponding benzimidazole-linked indole hybrids
by oxidation utilizing DDQ as an oxidizing agent,
and the desired products were obtained in excellent
yields. The extension of this method is presented
through the synthesis of tetracyclic Pyrrolo indole
Table 4. Synthesis of benzimidazole-linked indoles 12a
benzoimidazole
carboxyaldehydes.
carboxylates
utilizing
2-
Experimental Section
General Methods
aReaction conditions: 7 (0.53 mmol), DDQ (1.59 mmol),
CH3CN (4 mL).
Analytical thin-layer chromatography (TLC) was
performed using 0.25 mm silica gel-coated Kieselgel 60
F254 plates. Compound purification was carried out by
1
flash chromatography on silica gel 60 (230–400 mesh). H
and 13C NMR spectra were recorded on a Bruker DX-300
spectrometer. Chemical shifts are reported in parts per
million (ppm) on the δ scale from an internal standard
(TMS). Mass spectra were recorded on a JEOL TMS-HX
110 mass spectrometer; samples were introduced by the
infusion method using the electrospray ionization
technique. IR spectra were recorded using a HORIBA FT-
720 FREEXACT-II IR spectrophotometer. All starting
materials were purchased from commercial sources and
used without further purification.
The scope of this strategy was further extended by
reacting 5a with 2-phthalaldehydic acid under
optimized conditions to obtain corresponding
tetrahetrocyclic product 10a in 65% yield (Scheme 3).
General procedure for the synthesis of methyl 1-
isobutyl-2-(2-(4-nitrophenyl)indolin-3-yl)-1H-
benzo[d]imidazole-5-carboxylate (7a)
A microwave vial was charged with aniline 5a (500 mg,
1.48 mmol), 4-nitro benzaldehyde 6a (670 mg, 4.44 mmol),
magnesium sulphate (0.5 g), acetic acid (0.0044 gm, 0.07
mmol) and acetonitrile (4 mL) at room temperature. The
reaction mixture was irradiated with microwave (150 W) at
140 oC for 30 min. After completion of the reaction
(monitored by TLC), the reaction mixture was filtered
through a thin bed of celite and the filtrate was
concentrated under reduced pressure. The residue was
diluted with a solution of sat. NaHCO3 (10 mL), and
extracted with ethyl acetate (3 x 10 mL). The combined
organic layers were washed with brine solution, dried over
Scheme 3. Synthesis of pyrrolo indole benzoimidazole
carboxylate 10a.
The single crystal X-ray structure of 10a indicated
that the benzimidazole and indoline ring systems are
intersected at C9 carbon atom. The sp3 hybridized
4
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10.1002/adsc.201701140
Advanced Synthesis & Catalysis
MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash column
chromatography (20% ethyl acetate in hexanes) to obtain
7.01 (m, 6H), 6.95 (d, J = 1.5 Hz, 1H), 6.76-6.64 (m, 5H),
5.81 (dd, J = 19.8, 1.4 Hz, 2H), 5.43 (d, J = 10.3 Hz, 1H),
4.49 (d, J = 10.3 Hz, 1H), 4.28 (s, 1H), 3.94 (s, 3H), 4.05-
3.83 (m, 2H), 3.79 (t, J = 7.9 Hz, 1H), 2.37-1.92 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 167.7, 156.3, 150.4, 148.0,
147.5, 143.4, 143.1, 142.7, 138.2, 136.1, 129.0, 128.9,
128.9, 128.1, 127.6, 127.5, 127.0, 126.9, 124.5, 124.2,
124.1, 122.3, 120.1, 119.7, 109.9, 109.3, 108.4, 106.9,
101.2, 71.0, 52.2, 51.1, 48.8, 42.7, 35.7; HRMS (EI) calcd.
for C39H33N3O4 607.2471; found 607.2466.
methyl
1-isobutyl-2-(2-(4-nitrophenyl)indolin-3-yl)-1H-
benzo[d]imidazole-5-carboxylate 7a (520 mg, 75%).
Methyl-1-(2-methylpropyl)-2-[2-(4-nitrophenyl)-2,3-
dihydro-1H-indol-3-yl]-1H-benzimidazole-5-
carboxylate (7a)
1H NMR (300 MHz, CDCl3) δ 8.49 (d, J = 1.2 Hz, 1H),
8.11 (d, J = 8.7 Hz, 2H), 8.01 (dd, J = 8.5, 1.2 Hz, 1H),
7.66 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.20-
7.07 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 4.5 Hz,
2H), 5.97 (dd, J = 11.0 Hz, 1H), 4.65 (s, NH), 4.60 (d, J =
11.0 Hz, 1H), 3.94 (s, 3H), 3.84 (d, J = 7.7 Hz, 2H), 1.93-
1.77 (m, 1H), 0.81 (d, J = 6.6 Hz, 3H), 0.51 (d, J = 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 167.6, 155.5, 150.1,
149.9, 147.7, 142.5, 138.7, 129.2, 127.8, 127.6, 124.7,
124.3, 123.9, 123.7, 122.2, 120.1, 110.5, 109.9, 69.5, 52.3,
51.2, 50.7, 29.4, 20.2, 19.6; MS (EI) 470.2; HRMS (EI)
calcd. for C27H26N4O4 470.1954; found 470.1944; IR (cm-1,
neat) 2954, 2877, 1708, 1598, 1517, 1342.
Methyl-1-(3-methoxypropyl)-2-[2-(4-nitrophenyl)-2,3-
dihydro-1H-indol-3-yl]-1H-benzimidazole-5-
carboxylate (7f)
1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 1.4 Hz, 1H),
8.09 (d, J = 8.8 Hz, 2H), 8.01 (dd, J = 8.6, 1.4 Hz, 1H),
7.62 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.11 (t, J
= 7.3 Hz, 1H), 6.85-6.64 (m, 3H), 5.86 (d, J = 10.6 Hz, 1H),
4.82 (d, J = 3.6 Hz, 1H), 4.68 (d, J = 10.6 Hz, 1H), 4.29-
4.01 (m, 2H), 3.93 (s, 3H), 3.06 (s, 3H), 3.12-2.91 (m, 2H),
1.77-1.67 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.6,
155.6, 150.2, 150.1, 147.6, 142.5, 138.5, 129.1, 127.7,
127.6, 124.6, 124.3, 123.9, 123.9, 122.1, 119.9, 110.3,
109.6, 69.2, 67.93, 58.5, 52.2, 50.4, 40.7, 30.0; HRMS (EI)
calcd. for C27H26N4O5 486.1903; found 486.1897.
Methyl 2-(2-(3-hydroxyphenyl)indolin-3-yl)-1-isobutyl-
1H-benzo[d]imidazole-5-carboxylate (7b)
1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.82 (d, J = 8.5
Hz, 1H), 7.21-6.97 (m, 4H), 6.91 (s, 1H), 6.74-6.47 (m,
4H), 5.50 (d, J = 11.1 Hz, 1H), 4.56 (d, J = 11.1 Hz, 1H),
3.92 (s, 3H), 3.78 (d, J = 7.6 Hz, 2H), 1.96-1.68 (m, 2H),
0.86 (d, J = 6.5 Hz, 3H), 0.58 (d, J = 6.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 167.4, 157.6, 156.4, 150.3,
143.3, 141.2, 138.0, 130.5, 129.0, 128.1, 124.5, 124.3,
123.5, 120.7, 119.5, 116.8, 115.8, 113.5, 110.3, 109.6, 70.4,
52.1, 51.2, 50.7, 29.2, 20.3, 19.4; HRMS (EI) calcd. for
C27H27N3O3 441.2052; found 441.2046.
Methyl-2-[2-(1,3-benzodioxol-5-yl)-2,3-dihydro-1H-
indol-3-yl]-1-(3-methoxypropyl)-1H-benzimidazole-5-
carboxylate (7g)
1H NMR (300 MHz, CDCl3) δ 8.49 (d, J = 1.2 Hz, 1H),
8.01 (dd, J = 86, 1.4 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H),
7.12 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 6.86-6.65
(m, 5H), 5.92 (s, 2H), 5.56 (dd, J = 10.3, 2.9 Hz, 1H), 4.67
(d, J = 10.4 Hz, 1H), 4.32 (s, NH, 1H), 4.22-4.01 (m, 2H),
3.94 (s, 3H), 3.16 (s, 3H), 3.07 (t, J = 5.5 Hz, 2H), 1.78-
1.67 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.5,
150.4, 148.0, 147.3, 142.6, 138.6, 136.2, 128.9, 128.2,
124.4, 124.1, 124.1, 122.2, 120.1, 119.6, 109.9, 109.5,
108.3, 106.9, 101.1, 70.6, 68.2, 58.6, 52.2, 50.7, 40.5, 30.1;
HRMS (EI) calcd. for C28H27N3O5 485.1951; found
485.1946.
Methyl 1-isobutyl-2-(2-(4-methoxyphenyl)indolin-3-yl)-
1H-benzo[d]imidazole-5-carboxylate (7c)
1H NMR (300 MHz, CDCl3) δ 8.50 (d, J = 1.3 Hz, 1H),
7.99 (dd, J = 8.6, 1.3 Hz, 1H), 7.38-7.26 (m, 3H), 7.18-
7.06 (m, 1H), 6.86-6.65 (m, 5H), 5.61 (d, J = 10.9 Hz, 1H),
4.61 (d, J = 10.9 Hz, 1H), 4.37 (s, NH, 1H), 3.93 (s, 3H),
3.76 (s, 3H), 3.84-3.58 (m, 1H), 1.89-1.70 (m, 2H), 0.78 (d,
J = 6.7 Hz, 3H), 0.62 (d, J = 6.7 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.8, 156.7, 150.6, 148.0, 147.4, 142.6,
138.7, 136.2, 128.9, 128.4, 124.4, 124.1, 124.0, 122.2,
120.2, 119.6, 109.9, 109.4, 108.3, 106.9, 101.2, 70.8, 52.2,
51.0, 43.8, 32.2, 20.0, 13.7; HRMS (EI) calcd. for
C28H29N3O3 455.2209; found 455.2200.
Methyl-1-(3-methoxypropyl)-2-(2-phenyl-2,3-dihydro-
1H-indol-3-yl)-1H-benzimidazole-5-carboxylate (7h)
1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.93 (dd, J =
8.5, 1.4 Hz, 1H), 7.44-7.27 (m, 3H), 7.25-7.12 (m, 3H),
7.04 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 6.64 (t, J
= 7.3 Hz, 1H), 5.56 (d, J = 10.4 Hz, 1H), 4.63 (d, J = 10.4
Hz, 1H), 4.14 -3.87 (m, 3H), 3.86 (s, 3H), 3.03 (s, 3H),
Methyl
1-(3,3-diphenylpropyl)-2-(2-(4-
2.92 (t, J = 5.6 Hz, 2H), 1.57-1.49 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 167.7, 156.5, 150.6, 142.6, 142.3, 138.6,
128.8, 128.7, 128.2, 128.0, 126.6, 124.3, 124.0, 124.0,
122.1, 119.5, 109.9, 109.5, 70.7, 68.1, 58.5, 52.1, 50.7,
40.4, 30.0; HRMS (EI) calcd. for C27H27N3O3 441.2052;
found 441.2047.
nitrophenyl)indolin-3-yl)-1H-benzo[d]imidazole-5-
carboxylate (7d)
1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 1.3 Hz, 1H),
7.96 (d, J = 8.7 Hz, 2H), 7.89 (dd, J = 8.6, 1.3 Hz, 1H),
7.41 (d, J = 8.7 Hz, 2H), 7.21-7.02 (m, 7H), 7.02-6.95 (m,
3H), 6.95-6.86 (m, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.66-6.64
(m, J = 7.8 Hz, 2H), 5.58 (d, J = 10.6 Hz, 1H), 4.47 (d, J =
3.9 Hz, 1H), 4.40 (d, J = 10.6 Hz, 1H), 3.85 (s, 3H), 3.96-
3.70 (m, 2H), 3.66 (t, J = 8.1 Hz, 1H), 2.25-1.87 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 167.6, 155.3, 150.1, 149.8,
147.6, 143.0, 142.9, 142.6, 138.2, 129.2, 129.0, 128.9,
127.5, 127.5, 127.4, 127.3, 127.1, 127.0, 124.8, 124.4,
124.0, 124.0, 122.3, 120.2, 110.4, 109.4, 69.9, 52.3, 51.0,
48.6, 42.7, 36.0; HRMS (EI) calcd. for C38H32N4O4
608.2424; found 608.2429.
Methyl-2-[2-(3-hydroxyphenyl)-2,3-dihydro-1H-indol-
3-yl]-1-(3-methoxypropyl)-1H-benzimidazole-5-
carboxylate (7i)
1H NMR (300 MHz, CDCl3) δ 10.34 (s, OH, 1H), 7.85 (s,
1H), 7.81 (m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.08-6.95 (m,
3H), 6.90 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H),
6.67-6.54 (m, 2H), 6.50 (d, J = 7.8 Hz, 1H), 5.48 (d, J =
11.0 Hz, 1H), 4.59 (d, J = 11.0 Hz, 1H), 4.31-4.02 (m, 2H),
3.92 (s, 3H), 3.24-2.96 (m, 2H), 3.07 (s, 3H), 1.92-1.59 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 167.3, 157.8, 156.4,
150.3, 143.6, 141.0, 137.6, 130.6, 128.9, 127.9, 124.6,
124.5, 123.5, 120.2, 119.3, 116.6, 116.0, 113.1, 110.4,
109.3, 69.7, 68.1, 58.5, 52.1, 50.2, 40.9, 29.8; HRMS (EI)
calcd. for C27H27N3O4 457.2002; found 457.2009.
Methyl-2-[2-(1,3-benzodioxol-5-yl)-2,3-dihydro-1H-
indol-3-yl]-1-(3,3-diphenylpropyl)-1H-benzimidazole-5-
carboxylate (7e)
1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 1.3 Hz, 1H),
7.95 (dd, J = 8.5, 1.3 Hz, 1H), 7.33-7.15 (m, 6H), 7.15-
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701140
Advanced Synthesis & Catalysis
Methyl-1-[2-(cyclohex-1-en-1-yl)ethyl]-2-(2-phenyl-2,3-
dihydro-1H-indol-3-yl)-1H-benzimidazole-5-
carboxylate (7j)
22.3; HRMS (EI) calcd. for C29H31N3O3 469.2365; found
469.2354.
Methyl-2-[2-(1,3-benzodioxol-5-yl)-2,3-dihydro-1H-
indol-3-yl]-1-butyl-1H-benzimidazole-5-carboxylate
(7o)
1H NMR (300 MHz, CDCl3) δ 8.42 (d, J = 1.4 Hz, 1H),
7.92 (dd, J = 8.6, 1.4 Hz, 1H), 7.40-7.29 (m, 2H), 7.27-
7.17 (m, 5H), 7.06 (t, J = 7.5 Hz, 1H), 6.82 – 6.59 (m, 3H),
5.47 (d, J = 10.4 Hz, 1H), 5.06 (s, NH, 1H), 4.61 (d, J =
10.4 Hz, 1H), 3.86 (s, 3H), 4.00 – 3.68 (m, 2H), 2.08 –
1.94 (m, 1H), 1.75 – 1.64 (m, 5H), 1.45 – 1.30 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 167.7, 156.2, 150.6, 142.5,
142.3, 138.4, 133.2, 128.9, 128.9, 128.8, 128.2, 128.0,
126.7, 124.6, 124.3, 123.9, 122.2, 119.6, 109.9, 109.4, 70.9,
52.1, 51.2, 42.9, 38.1, 28.4, 25.1, 22.6, 22.0; HRMS (EI)
calcd. for C41H41N3O2 477.2416; found 477.2420.
1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 1.3 Hz, 1H),
8.00 (dd, J = 8.5, 1.3 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H),
7.12 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.84-6.62
(m, 5H), 5.91 (s, 2H), 5.53 (d, J = 10.4 Hz, 1H), 4.63 (d, J
= 10.4 Hz, 1H), 4.37 (s, NH, 1H), 4.13-3.86 (m, 2H), 3.93
(s, 3H), 1.61-1.27 (m, 2H), 1.20-1.02 (m, 2H), 0.78 (t, J =
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.3,
150.4, 148.0, 147.4, 142.6, 138.4, 136.2, 128.9, 128.2,
124.4, 124.1, 124.0, 122.2, 120.2, 119.7, 109.9, 109.4,
108.3, 106.9, 101.2, 70.8, 52.2, 51.1, 43.8, 32.2, 20.1, 13.7;
HRMS (EI) calcd. for C28H27N3O4 469.2002; found
469.1992.
Methyl-2-[2-(1,3-benzodioxol-5-yl)-2,3-dihydro-1H-
indol-3-yl]-1-(2-methylpropyl)-1H-benzimidazole-5-
carboxylate (7k)
1H NMR (300 MHz, CDCl3) δ 8.49 (d, J = 1.4 Hz, 1H),
7.99 (dd, J = 8.5, 1.4 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H),
7.17-7.06 (m, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.89-6.62 (m,
5H), 5.91 (s, 2H), 5.61 (d, J = 10.7 Hz, 1H), 4.60 (d, J =
10.7 Hz, 1H), 3.93 (s, 3H), 3.87-3.69 (m, 2H), 1.92-1.73
(m, 2H), 0.81 (d, J = 6.6 Hz, 3H), 0.65 (d, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 167.8, 156.6, 150.4, 148.0,
147.4, 142.6, 138.7, 136.1, 128.9, 128.3, 124.4, 124.0,
124.0, 122.2, 120.1, 119.7, 110.0, 109.7, 108.3, 107.0,
101.1, 70.9, 52.2, 51.1, 51.0, 29.6, 20.3, 19.8; HRMS (EI)
calcd. for C28H27N3O4 469.2002; found 469.2000.
2-(2-phenylindolin-3-yl)-1H-benzo[d]imidazole (7p)
1H NMR (400 MHz, Acetone-d6) δ 8.05 (d, J = 7.1 Hz,
1H), 7.53 – 7.48 (m, 1H), 7.47 – 7.43 (m, 2H), 7.32 – 7.21
(m, 3H), 7.20 – 7.15 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.91
(d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.62 (t, J =
7.4 Hz, 1H), 5.58 (d, J = 9.6 Hz, 1H), 4.63 (d, J = 9.6 Hz,
1H); 13C NMR (101 MHz, acetone-d6) δ 154.6, 151.3,
143.5, 132.7, 129.5, 128.4, 128.3, 127.3, 126.5, 124.2,
121.5, 118.1, 109.0, 69.0, 52.6; HRMS (ESI) m/z: [M+ H]+
Calcd for C21H17N3 312.1501, Found 312.1497.
Methyl-1-butyl-2-(2-phenyl-2,3-dihydro-1H-indol-3-yl)-
1H-benzimidazole-5-carboxylate (7l)
7-methyl-2-(2-phenylindolin-3-yl)-1H-
benzo[d]imidazole (7q)
1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 1.4 Hz, 1H),
8.01 (dd, J = 8.5, 1.4 Hz, 1H), 7.46-7.38 (m, 2H), 7.33 (d,
J = 8.6 Hz, 1H), 7.31 – 7.24 (m, 3H), 7.13 (t, J = 7.5 Hz,
1H), 6.83-6.67 (m, 3H), 5.60 (d, J = 10.4 Hz, 1H), 4.69 (d,
J = 10.4 Hz, 1H), 3.93 (s, 3H), 4.08-3.74 (m, 2H), 1.55-
1.17 (m, 3H), 1.14-0.96 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 167.7, 156.4, 150.6, 142.5,
142.3, 138.34, 128.9, 128.9, 128.8, 128.1, 126.6, 124.4,
124.1, 124.0, 122.1, 119.6, 109.9, 109.4, 70.9, 52.2, 51.1,
43.7, 32.0, 20.0, 13.6; HRMS (EI) calcd. for C27H27N3O2
425.2103; found 425.2108.
1H NMR (600 MHz, Acetone-d6) δ 11.42 (s, 1H), 7.45 (d, J
= 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.1 Hz,
1H), 7.06 (t, J = 7.6 Hz, 2H), 6.98 (d, J = 7.3 Hz, 1H), 6.89
(s, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H),
5.66 (s, 1H), 5.63 (s, 1H), 4.61 (d, J = 9.9 Hz, 1H), 2.56 (s,
3H); 13C NMR (151 MHz, acetone-d6) δ 151.2, 143.5,
128.2, 127.3, 126.5, 124.1, 118.0, 109.0, 69.0, 52.8;
HRMS (ESI) m/z: [M+ H]+ Calcd for C22H19N3 326.1657,
Found 326.1652.
Methyl1-phenethyl-2-(spiro[cyclopentane-1,2'-indolin]-
3'-yl)-1H-benzo[d]imidazole-5-carboxylate (9a)
Methyl-1-(3-methylbutyl)-2-[2-(4-nitrophenyl)-2,3-
dihydro-1H-indol-3-yl]-1H-benzimidazole-5-
carboxylate (7m)
1H NMR (400 MHz, Acetone-d6) δ 8.32 (s, 1H), 7.92 (dd, J
= 8.6, 1.6 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.26 – 7.15
(m, 3H), 7.12 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 6.7 Hz, 2H),
6.99 (s, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.67 (t, J = 7.3 Hz,
1H), 5.58 (s, 1H), 4.87 (s, 1H), 4.76 (ddd, J = 14.6, 10.7,
5.6 Hz, 1H), 4.22 (s, 1H), 3.89 (s, 3H), 1.93 (t, J = 7.4 Hz,
2H), 1.78 (p, J = 7.6, 7.0 Hz, 2H), 1.67 – 1.57 (m, 2H),
1.53 – 1.44 (m, 1H), 1.39 – 1.32 (m, 1H); 13C NMR (101
MHz, acetone-d6) δ 166.93, 156.77, 151.03, 142.38,
137.95, 128.95, 128.77, 128.37, 126.50, 125.76, 123.83,
123.35, 121.12, 118.05, 110.04, 109.60, 75.07, 51.29,
45.69, 35.02, 34.27, 22.67, 22.05; HRMS (ESI) m/z:
[M+H]+ Calcd for C29H30N3O2 452.2338, Found 452.2334.
1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.13 (d, J = 8.7
Hz, 2H), 8.02 (dd, J = 8.5, 1.4 Hz, 1H), 7.62 (d, J = 8.7 Hz,
2H), 7.35 (d, J = 8.5 Hz, 1H), 7.18-7.13 (m, 1H), 6.87-6.7
(m, 3H), 5.83 (d, J = 10.4 Hz, 1H), 4.62 (d, J = 10.4 Hz,
1H), 4.17-3.96 (m, 3H), 3.94 (s, 3H), 1.57-1.32 (m, 2H),
1.19-1.09 (m, 1H), 0.76 (t, J = 6.3 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 167.7, 155.2, 150.1, 150.0, 147.8, 142.6,
138.3, 129.3, 127.6, 127.6, 124.7, 124.4, 124.4, 124.0,
122.3, 120.2, 110.4, 109.5, 69.6, 52.3, 51.1, 42.6, 39.0,
25.9, 22.4, 22.3; HRMS (EI) calcd. for C28H28N4O4
484.2111; found 484.2101.
Methyl
2-(2,2-dimethylindolin-3-yl)-1-phenethyl-1H-
Methyl-2-[2-(4-methoxyphenyl)-2,3-dihydro-1H-indol-
3-yl]-1-(3-methylbutyl)-1H-benzimidazole-5-
carboxylate (7n)
benzo[d]imidazole-5-carboxylate (9b)
1H NMR (400 MHz, acetone-d6) δ 8.29 (s, 1H), 7.93 (d, J
= 8.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.23-7.15 (m, 4H),
7.07 (d, J = 5.5 Hz, 3H), 6.66-6.64 (br, 2H), 4.78 – 4.71 (m,
1H), 3.89 (s, 3H), 1.48 (s, 3H), 1.02 (s, 3H); 13C NMR
(101 MHz, acetone-d6) δ 167.08, 156.13, 150.86, 142.51,
142.49, 137.96, 128.93, 128.46, 126.59, 126.19, 123.81,
123.27, 121.14, 110.04, 51.27, 45.67, 24.19; HRMS (ESI)
m/z: [M+H]+ Calcd for C27H28N3O2 426.2180, Found
426.2176.
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.00 (dd, J =
8.5, 1.4 Hz, 1H), 7.36-7.30 (m, 3H), 7.13 (t, J = 7.6 Hz,
1H), 6.87-6.68 (m, 5H), 5.49 (d, J = 10.4 Hz, 1H), 4.64 (d,
J = 10.4 Hz, 1H), 4.37 (s, NH, 1H), 3.94 (s, 3H), 4.05-3.78
(m, 2H), 3.76 (s, 3H), 1.50-1.32 (m, 2H), 1.14-1.00 (m,
1H), 0.79 (t, J = 5.9 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 167.8, 159.6, 156.4, 150.6, 142.7, 138.3, 134.2, 128.9,
128.3, 127.9, 124.4, 124.3, 124.0, 122.3, 119.7, 114.2,
109.9, 109.2, 70.8, 55.4, 52.2, 51.4, 42.4, 38.8, 26.0, 22.4,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701140
Advanced Synthesis & Catalysis
Methyl 2-(2-methyl-2-phenylindolin-3-yl)-1-phenethyl-
Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(2-methyl-2-
phenylindolin-3-yl)-1H-benzo[d]imidazole-5-
carboxylate (9h)
1H-benzo[d]imidazole-5-carboxylate (9c)
1H NMR (400 MHz, acetone-d6) δ 8.32 (s, 1H), 7.93 (d, J
= 8.5 Hz, 1H), 7.63 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H NMR (400 MHz, acetone-d6) δ 8.26 (s, 1H), 7.91 (d, J
1H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.24
– 7.03 (m, 4H), 3.91 (s, 3H), 1.40 (s, 3H); 13C NMR (101
MHz, acetone-d6) δ 166.94, 142.72, 137.72, 128.71,
128.42, 127.13, 126.58, 126.02, 123.89, 123.31, 121.29,
117.87, 110.08, 108.90, 51.28, 45.26, 35.28; HRMS (ESI)
m/z: [M+H]+ Calcd for C32H30N3O2 488.2346, Found
488.2333.
= 8.6 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 7.5 Hz,
1H), 7.00 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.61
(t, J = 7.4 Hz, 1H), 5.34 (s, 1H), 5.13 (brs, 2H), 4.38 (t, J =
7.6 Hz, 2H), 4.24 (s, 2H), 3.89 (s, 3H), 2.24 (t, J = 7.7 Hz,
2H), 2.0-1.96 (m, 2H), 1.93 – 1.85 (m, 2H), 1.63 – 1.55 (m,
2H), 1.54 – 1.46 (m, 2H); 13C NMR (101 MHz, acetone-d6)
δ 167.8, 156.9, 151.7, 143.3, 139.9, 134.7, 129.2, 126.8,
124.7, 124.5, 124.0, 121.9, 118.7, 117.3, 110.8, 110.3, 52.1,
44.1, 38.2, 34.5, 25.7, 25.0, 23.4, 22.7; HRMS (ESI) m/z:
[M+H]+ Calcd for C27H32N3O2 430.2497, Found 430.2489.
Methyl
1-(3-methoxypropyl)-2-(spiro[cyclopentane-
1,2'-indolin]-3'-yl)-1H-benzo[d]imidazole-5-carboxylate
(9d)
Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(2-methyl-2-
phenylindolin-3-yl)-1H-benzo[d]imidazole-5-
carboxylate (9i)
1H NMR (400 MHz, acetone-d6) δ 8.28 (s, 1H), 7.92 (d, J
= 9.3 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.05 (t, J = 7.6 Hz,
1H), 6.96 (d, J = 7.2 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H),
6.61 (t, J = 7.3 Hz, 1H), 5.49 (s, 1H), 4.88 (s, 1H), 4.56
(ddd, J = 14.6, 9.3, 5.3 Hz, 1H), 4.24 (s, 1H), 3.89 (s, 3H),
3.22 (s, 3H), 3.15 (brs, 2H), 1.95 (t, J = 7.3 Hz, 2H), 1.88 –
1.71 (m, 3H), 1.69 – 1.54 (m, 2H), 1.53 – 1.33 (m, 3H);
13C NMR (101 MHz, acetone-d6) δ 166.9, 156.8, 151.0,
142.4, 139.2, 128.4, 125.4, 123.7, 123.2, 121.0, 117.8,
109.8, 109.3, 75.4, 69.0, 57.7, 51.2, 41.6, 41.1, 34.2, 22.6,
22.1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H30N3O3
420.2282, Found 420.2280.
1H NMR (400 MHz, acetone-d6) δ 8.33 (s, 1H), 7.94 (d, J
= 8.5 Hz, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 8.5 Hz,
1H), 7.40 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 6.9 Hz, 1H), 7.11
(t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.78 (d, J =
7.3 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1H), 5.41 (brs, 1H), 5.08
(s, 1H), 4.86 (brs, 1H), 3.90 (s, 3H), 2.21 – 2.10 (m, 1H),
1.83-1.72 (m, 5H), 1.45 (s, 3H), 1.37-1.28 (m, 3H); 13C
NMR (101 MHz, acetone-d6) δ 166.9, 150.7, 142.7, 133.5,
128.4, 127.1, 125.7, 123.8, 123.2, 121.3, 117.9, 110.0,
109.0, 51.2, 27.9, 24.8, 22.4, 21.7; HRMS (ESI) m/z: [M+
H]+ Calcd for C32H34N3O2 492.2661, Found 492.2646.
Methyl
1-(3-methoxypropyl)-2-(2-methyl-2-
phenylindolin-3-yl)-1H-benzo[d]imidazole-5-
carboxylate (9e)
3'-(1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-
yl)spiro[cyclopentane-1,2'-indoline] (9j)
1H NMR (400 MHz, acetone-d6) δ 8.27 (s, 1H), 7.93 (d, J
= 8.4 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 7.4 Hz,
1H), 6.96 (d, J = 5.9 Hz, 1H), 6.70 – 6.57 (m, 2H), 5.13
(brs, 1H), 4.73 (s, 1H), 4.55 (dt, J = 13.8, 6.9 Hz, 1H), 3.89
(s, 3H), 3.24 (s, 5H), 2.01 (t, J = 2 Hz, 1H), 1.51 (s, 3H),
1H NMR (400 MHz, Acetone-d6) δ 7.64 (d, J = 7.7 Hz,
1H), 7.29 (d, J = 7.7 Hz, 1H), 7.18-7.11 (m, 2H), 6.98 –
6.73 (m, 6H), 6.58 (d, J = 7.9 Hz, 1H), 6.51 (t, J = 7.4 Hz,
1H), 5.68 (d, J = 16.4 Hz, 1H), 5.39 (s, 1H), 4.89 (s, 1H),
3.70 (s, 3H), 2.00 – 1.35 (m, 8H); 13C NMR (101 MHz,
acetone-d6) δ 206.2, 159.8, 155.6, 151.6, 143.8, 136.7,
129.6, 128.8, 128.4, 126.0, 125.1, 122.7, 122.3, 122.0,
119.9, 118.4, 114.7, 114.5, 111.3, 109.9, 76.5, 55.4, 51.4,
47.5, 42.1, 36.3, 35.2, 30.4, 30.2, 30.0, 29.8, 29.6, 29.4,
29.2, 23.5, 23.2; HRMS (ESI) m/z: [M+ H]+ Calcd for
C27H27N3O 410.2232, Found 410.2234.
1.35 – 1.19 (m, 1H), 1.05 (s, 3H), 0.93 – 0.79 (m, 1H); 13
C
NMR (101 MHz, acetone-d6) δ 166.9, 156.1, 150.9, 142.6,
125.7, 123.7, 123.1, 121.1, 117.7, 109.8, 109.2, 68.6, 57.7,
51.2, 40.9, 24.2; HRMS (ESI) m/z: [M+H]+ Calcd for
C23H28N3O3 394.2125, Found 394.2125.
Methyl
1-(2-(cyclohex-1-en-1-yl)ethyl)-2-
(spiro[cyclopentane-1,2'-indolin]-3'-yl)-1H-
benzo[d]imidazole-5-carboxylate (9f)
2-(2-methyl-2-phenylindolin-3-yl)-1-propyl-5-
(trifluoromethyl)-1H-benzo[d]imidazole (9k)
1H NMR (400 MHz, acetone-d6) δ 8.33 (d, J = 1.2 Hz, 1H),
7.94 (dd, J = 8.5, 1.5 Hz, 1H), 7.63 (d, J = 7.3 Hz, 2H),
7.56 (d, J = 8.5 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J
= 7.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.3 Hz,
1H), 6.79 (d, J = 7.7 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 4.98
(s, 1H), 4.05 (brs, 1H), 3.90 (s, 3H), 3.57 (brs, 1H), 3.12 (s,
3H), 3.09-3.03 (m, 2H), 2.81 (s, 1H), 1.81 – 1.69 (m, 1H),
1.49 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ 166.9,
154.6, 150.7, 142.8, 138.7, 128.3, 127.0, 125.8, 125.4,
123.9, 123.3, 121.3, 118.0, 109.9, 109.1, 68.2, 57.6, 51.3,
33.6; HRMS (ESI) m/z: [M+H]+ Calcd for C28H30N3O3
456.2288, Found 456.2282.
1H NMR (400 MHz, Acetone-d6) δ 7.99 (s, 1H), 7.71 (d, J
= 8.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.55 (d, J = 8.5 Hz,
1H), 7.38 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.11
(t, J = 7.6 Hz, 1H), 6.87 (d, J = 6.9 Hz, 1H), 6.81 (d, J =
7.6 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 4.94 (s, 1H), 1.66 -
1.56 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
acetone) δ 150.7, 142.6, 128.3, 127.0, 125.7, 125.3, 123.9,
123.8, 123.5, 123.2, 122.9, 118.6, 118.5, 118.5, 118.0,
116.7, 116.7, 116.6, 111.0, 109.0, 45.1, 22.7, 10.4; MS
(EI) 436.1; HRMS (EI) calcd. for C26H25F3N3 436.2001;
found 436.2008.
Methyl
1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(2,2-
2-(2,2-dimethylindolin-3-yl)-1H-benzo[d]imidazole (9l)
dimethylindolin-3-yl)-1H-benzo[d]imidazole-5-
1H NMR (400 MHz, Acetone-d6) δ 11.05 (s, 1H), 7.61 (s,
1H), 7.44 (s, 1H), 7.19 – 7.11 (m, 2H), 7.08 – 7.00 (m, 2H),
6.68 – 6.58 (m, 2H), 5.05 (s, 1H), 4.49 (s, 1H), 1.51 (s, 3H),
0.96 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ 153.2,
151.1, 128.3, 127.6, 125.5, 121.8, 121.0, 118.7, 117.6,
111.0, 109.1, 65.5, 53.8, 23.8; HRMS (ESI) m/z: [M+ H]+
Calcd for C17H17N3 264.1501, Found 264.1494.
carboxylate (9g)
1H NMR (400 MHz, acetone-d6) δ 8.29 (s, 1H), 7.92 (d, J
= 8.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.07 (t, J = 7.6 Hz,
1H), 6.98 (d, J = 7.3 Hz, 1H), 6.71 – 6.59 (m, 2H), 5.56
(brs, 1H), 5.26 (s, 1H), 4.87 (s, 1H), 4.74 – 4.48 (m, 1H),
4.09 (brs, 1H), 3.89 (s, 3H), 1.94 (t, J = 7.3 Hz, 2H), 1.90 –
1.76 (m, 6H), 1.71 – 1.59 (m, 3H), 1.58 – 1.42 (m, 6H),
1.34 – 1.22 (m, 1H); 13C NMR (101 MHz, acetone-d6) δ
166.9, 156.7, 150.9, 142.3, 133.9, 128.5, 125.5, 123.7,
123.4, 123.2, 121.0, 117.9, 109.9, 109.5, 51.2, 43.3, 34.2,
28.0, 24.8, 22.6, 22.5, 22.07, 21.9; HRMS (ESI) m/z: [M+
H]+ Calcd for C29H34N3O2 456.2655, Found 456.2646.
2-(2,2-dimethylindolin-3-yl)-7-methyl-1H-
benzo[d]imidazole (9m)
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701140
Advanced Synthesis & Catalysis
1H NMR (600 MHz, Acetone-d6) δ 11.03 (s, 1H), 7.30 (s,
1H), 7.05-7.02 (m, 3H), 6.96 (d, J = 7.3 Hz, 1H), 6.62 (t, J
= 6.8 Hz, 2H), 5.03 (s, 1H), 4.51 (s, 1H), 2.56 (s, 3H), 1.51
(s, 3H), 0.99 (s, 3H); 13C NMR (151 MHz, acetone-d6) δ
151.0, 128.2, 127.8, 125.5, 121.6, 117.6, 109.1, 65.4, 53.9,
23.9; HRMS (ESI) m/z: [M+ H]+ Calcd for C18H19N3
278.1657, Found 278.1633.
14.5, 7.1 Hz, 2H), 3.92 (s, 3H), 2.48 (t, J = 6.8 Hz, 2H),
1.95 – 1.84 (m, 2H), 1.81 – 1.69 (m, 2H), 1.51 – 1.27 (m,
4H); 13C NMR (101 MHz, acetone-d6) δ 167.1, 166.8,
154.6, 144.77, 142.6, 140.2, 139.1, 137.4, 133.9, 133.6,
132.8, 129.1, 128.5, 124.7, 124.6, 124.3, 124.2, 123.5,
123.2, 121.3, 116.6, 110.5, 70.1, 51.3, 44.7, 43.2, 38.2,
27.9, 24.7, 22.4, 21.7; HRMS (ESI) m/z: [M+H]+ Calcd for
C32H30N3O3 504.2287, Found 504.2288.
General procedure for the synthesis of methyl 1-
isobutyl-2-(2-(4-nitrophenyl)-1H-indol-3-yl)-1H-
benzo[d]imidazole-5-carboxylate (12a)
X-ray Crystal Structure of 7g and 10a
CCDC 844557 (7g) and CCDC 1568072 (10a) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
To
a stirred solution of methyl 1-isobutyl-2-(2-(4-
nitrophenyl)indolin-3-yl)-1H-benzo[d]imidazole-5-
carboxylate 7a (250 mg, 0.53 mmol) in dichloromethane
(10 mL) was added DDQ (360 mg, 1.59 mmol) in
dichloromethane (5 mL) dropwise. The resulting
homogenous mixture was stirred at ambient temperature
for 30 min (monitored by TLC). After completion of the
reaction, the reaction mixture was diluted with sat.
NaHCO3 (10 mL) and extracted with dichloromethane (2 x
20 mL). The combined organic layers were washed with
brine solution (20 mL), dried over MgSO4 and
concentrated in vacuo. The crude product was purified by
flash column chromatography (10% ethyl acetate in
hexanes) to afford methyl 1-isobutyl-2-(2-(4-nitrophenyl)-
1H-indol-3-yl)-1H-benzo[d]imidazole-5-carboxylate 12a
(230 mg, 92%).
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The authors thank Ministry of Science and Technology (MOST)
of Taiwan for financial assistance and the authorities of the
National Chiao Tung University for providing the laboratory
facilities.
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FULL PAPER
Microwave-Assisted Synthesis of Benzimidazole-
Linked Indoline and Indole Hybrids from C-2-
Linked o-Amino Benzyl Benzimidazoles
Adv. Synth. Catal. Year, Volume, Page – Page
Yuan-Ta Lee, Fengyu Chiu, Indrajeet J. Barve, and
Chung-Ming Sun*
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