Rapid two-step synthesis of benzimidazo[1′,2′:1,5]pyrrolo[2,3- c ]isoquinolines by a three-component coupling reaction

Article abstract of DOI:10.1021/co500049r

A two-step, three-component coupling reaction on ionic liquid supported 2-cyanomethylbenzimidazoles, methyl 2-formylbenzoate, and isocyanides under microwave activation is explored. Knoevenagel condensation of 2-cyanomethylbenzimidazole with methyl-2-form

Full text of DOI:10.1021/co500049r

Research Article
pubs.acs.org/acscombsci
Rapid Two-Step Synthesis of Benzimidazo[1′,2′:1,5]-
pyrrolo[2,3‑c]isoquinolines by a Three-Component
Coupling Reaction
Bharat D. Narhe, Min-Huan Tsai, and Chung-Ming Sun*
Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10, Taiwan
S
* Supporting Information
ABSTRACT: A two-step, three-component coupling reaction on ionic liquid supported 2-cyanomethylbenzimidazoles, methyl
2-formylbenzoate, and isocyanides under microwave activation is explored. Knoevenagel condensation of 2-cyanomethylbenzi-
midazole with methyl-2-formylbenzoate in the presence of piperidine catalyst is followed by [4 + 1] cycloaddition with an
isocyanide in the next step. Consequent intramolecular δ-lactam formation allows rapid construction of novel aza-pentacycles,
benzimidazo[1′,2′:1,5]pyrrolo[2,3-c]isoquinolines.
KEYWORDS: microwave, ionic liquid support, pyrrolo[1,2-a]benzimidazole, benzimidazo[1′,2′:1,5]pyrrolo[2,3-c]isoquinolines
human tumor cell.5 Polyazaheterocyclic frameworks containing
INTRODUCTION
■
benzimidazole and isoquinoline moieties are the molecules of
choice in search of drug targets with unique pharmacological
properties.6 Recently, many variations in Ugi multicomponent
reaction of heterocyclic aromatic amines with 2-formyl benzoic
acid or 2-formylbenzoates and isocyanides or KCN have been
used for the synthesis of benzimidazole-fused isoquinolines and
their biological studies.6a,7 Yang et al. designed and synthesized
tetracyclic isoquinolinones as a potential CDK kinase inhibitor
employing three-component reaction on 2-amionopyridine,
2-formylbenzoate and isonitrile.7a Choo and co-workers used
similar reaction for the synthesis of polyheterocyclic isoquino-
lines with potent poly(ADP-ribose)polymerase-1 inhibition
activity.6b Guchhait and Madaan used microwave assisted
reaction in aqueous tetrafluoroboric acid to create isoquinoli-
nones with free amide nitrogen.7b However, these reports are
limited to the synthesis of tetracyclic skeletons. The synthetic
and biological studies of fused pentacyclic aza heterocycles are
largely undiscovered due to the lack of short and simple routes
leading to these unique scaffolds. Few examples, Rutaecarpine I is
an indolopyridoquinazolinone alkaloid with antithrombotic,
anticancer, anti-inflammatory, and analgesic activities.8 Its
synthetic analogue II is an antiobesity compound that inhibits
adipogenesis to reduce lipid accumulation in adipocytes.9
Diversity-oriented and effective synthesis of structurally complex
molecules by simple synthetic transformations are much needed
for acceleration of combinatorial drug discovery process.1
Advanced techniques like ionic-liquid supported synthesis,
polymer-supported synthesis, microwave irradiation, and ultra-
sonication-assisted synthesis have proved as promising tools to
speed up several synthetic transformations.2 The reactions under
microwave activation proceed in dramatically shortened reaction
time as compared to that of reactions under conventional heating
because of rapid and uniform dielectric heating. This may lead to
cleaner reactions with lesser side products. Reactions which
employ ionic liquid support simplifies the work up and purification
process as the product can be obtained in pure form just by
precipitation and solvents washing. Synergy of microwave
irradiation and ionic liquid support has greatly enhanced parallel
synthesis of novel molecular frameworks with potential biological
activities that may result in acceleration of drug discovery.2
Benzimidazole represents an important class of azahetero-
cycles and is rightly considered as a “privileged scaffold” because
of their widespread biological properties. It has been applied as a
building block in the synthesis of polyazaheterocycles.3 A large
number of research efforts are focused on the synthesis and
pharmacological studies of benzimidzole fused/linked poly-
azaheterocycles.4 Similarly, isoquinoline-based heterocycles both
of natural and synthetic origin are ubiquitous pharmacophores
that are studied for their distinguished biological properties such
as dopamine D1 agonist and selective inhibition of DNA-PK in
Received: March 24, 2014
Revised: May 24, 2014
© XXXX American Chemical Society
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Luotonin A III is a pyrroloquinazolinoquinoline alkaloid to work
against leukemia by inducing DNA topoisomerase I-dependent
cytotoxicity (Figure 1).10
Thus, the controlling factors in this MCR are isomerization of
s-trans azadiene 9{1,1} to s-cis-azadiene 9{1,1} and δ-lactam ring
formation in PBI 11{1,1,1} using its secondary amine function
which can be affected by bulk of the substituent (R3) in parent
isonitriles.
Unexpected formation of PBI 7 is the result of participation of
solvent, 1,2-dichloroethane, in the reaction. Nucleophilic
displacement of a chloride from ClCH2CH2Cl by the 2-cyano-
methylbenzimidazole and subsequent β-elimination of HCl, then
double bond isomerization generates azadiene 14 that on [4 + 1]
cycloaddition with an isocyanide and aromatization yields PBI 7
(Scheme 4).
Figure 1. Biologically active pentacyclic azaheterocycles.
To avoid solvent interference, we studied the same one pot
transformation in various organic solvents, such as MeOH, IPA,
THF, toluene, ACN, and DMF. The reactions did not progress
well in MeOH, IPA, DMF, and THF. However, only moderate
improvements in the yield (∼40%) were achieved in either
toluene or ACN. This led us to study this MCR in conventional
stepwise manner. The piperidine catalyzed Knoevenagel
condensation of 2-cyanomethylbenzimidazole 3{1} with methyl
2-formylbenzoate in toluene at room temperature gave s-trans-
azadiene 9{1,1} in very good yields. The s-trans conformation of
9{1,1} in both liquid and solid state were assigned unambiguously
by NOE analysis and single crystal X-ray studies respectively
(Figure 1). Irradiation of olefinic proton at δ 8.76 led to 2%
enhancement in the signal for the methylene protons at δ 4.65 of
3-methoxypropyl substituent on benzimidazole to confirm their
special vicinity and s-trans geometry of the diene. Such NOE
enhancement is clearly not possible in s-cis confirmation.
The azadiene 9{1,1} was then treated with benzyl isocyanide
5{2} to minimize the steric influence of R3 on lactamization.
Sealed tube heating of 9{1,1} and benzyl isonitrile 5{2} in
toluene at 180 °C for 12 h with piperidine by a telescoped
reaction approach gave benzimidazoisoquinolinone 6{1,1,2}
along with PBI 16 as a result of reaction of piperidine with the
ester carbonyl group. The formation of PBI 16 was eliminated
by performing the reaction without piperidine which gave an
improved 60% yield of 6{1,1,2}. To achieve better cis−trans
isomerization and overall conversion, we turned to micro-
wave activation that produces an effective and uniform heat-
ing. Microwave irradiation at 150 °C gave better isolated
yield of 70% as well as reduced reaction time to only 15 min
(Scheme 5).
Recently, we developed multicomponent reactions utilizing
2-cyanomethylbenzimidazoles for the synthesis of pyrrolo[1,2-a]-
benzimidazoles11 and benzimidazole-linked 2-aminothiophenes.12
In continuation with our efforts to establish facile reactions using
functionalized benzimidazoles for the synthesis of biologically
interesting polyazaheterocycles, we report a two step protocol
for the synthesis of novel benzimidazo[1′,2′:1,5]pyrrolo[2,3-c]-
isoquinolines (BPIs) that contains a benzimidazole and an
isoquinolinone pharmacophore fused through a pyrrole ring.
RESULTS AND DISCUSSION
■
Our study began with the synthesis of various N-alkylated
2-cyanomethyl benzimidazoles (Scheme 1). Treatment of 3-nitro-
4-fluorobenzoates with various amines and reduction of the nitro
group yielded corresponding 3,4-diaminobenzoates 1. The
condensation of primary amine of 1 with cyanoacetic acid gave a
cyanoacetamide 2 that was cyclized under acidic conditions with
TFA to obtain the desired 2-cyanomethyl benzimidazoles 3 in
good yields.11,12
Initially, we studied a one pot reaction on 2-cyanomethylben-
zinmidazole 3{1}, methyl 2-formyl benzoate, and cyclo-
hexylisonitrile. Heating a dichloroethane solution of reactants
in the presence of piperidine catalyst (30 mol %) at 180 °C
for 12 h in a sealed tube yielded the desired pentacyclic
benzimidazoisoquinolinone 6{1, 1,1} in low yield (25%) along
with pyrrolobenzimidazole (35%, PBI) 7 (Scheme 2).
The postulated mechanism of this MCR involves Knoevenagel
condensation of 2-cyanomethylbenzimidazole with 2-formyl-
benzoate catalyzed by piperidine to yield azadiene 9{1,1}. The
Knoevenagel condensation is believed to yield a s-trans-diene
9{1,1} that on thermal activation at higher temperature
isomerizes to s-cis-diene 9{1,1}, which then undergoes [4 + 1]
cycloaddition with an isocyanide leading to pyrrolo[1,2-a]-
benzimidazole (PBI) 11{1,1,1} after aromatization. The intra-
molecular nucleophilic attack of secondary amine functionality
of PBI 11{1,1,1} on the benzoate carbonyl group delivers the
BPI 6{1,1,1} accompanied by a loss of methanol (Scheme 3).
Knowledge of synergy of ionic liquid (IL)-support with
microwave heating to speed up isolation and purification of
products by precipitation and solvent washing motivated us to
study reactions of IL-bound 2-cyanomethylbenzimidazoles.2,13
Room temperature condensation of IL-bound 2-cyanomethyl-
bemzimidazole IL-3{1} with 2-formyl benzoate in CH3CN using
piperidine catalyst gave IL-bound s-trans-azadiene IL-17{1,1}.
Scheme 1. Synthesis of 2-(Cyanomethyl)-N-alkyl Benzimidazoles
B
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Scheme 2. Synthesis of Benzimidazo[1′,2′:1,5]pyrrolo[2,3-c]isoquinolinones
Scheme 3. Plausible Mechanism for the Cascade Reaction
Scheme 4. Plausible Mechanism for the Formation of PBI 7
Benzyl isocyanate was added to CH3CN solution of azadiene
IL-17{1,1} and heated with microwave irradiation at 150 °C
for 15 min. The reaction mixture was then treated with
KCN/methanol to remove IL-support which afforded a
76% of BPI 6{1,1,2} after flash column purification (Table 1,
entry 2).
Delighted with this observation, we treated a number of
IL-bound 2-cyanomethylbenzimidazoles with methyl 2-formyl
C
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Figure 2. X-ray crystal structure for s-trans-azadiene 9{1,1}.
Scheme 5. Synthesis of Benzimidazo[1′,2′:1,5]pyrrolo[2,3-c]isoquinolines
benzoate and various isonitriles by this two-step protocol (Figure 3).
Various N-alkyl substitutents (R2) on benzimidazole were abided
and good yields of products were obtained with reactive
heteroaromatic 2-furyl, 2-thiofuryl, endocyclic olefin and ether
function on R2 intact. As expected the yields with benzyl
isocyanide were better than that of cyclohexyl or isopropyl
isonitriles. The slightly lower yields with pentyl isocyanide may
be result of steric factors associated with flexible alkyl chain. The
planar pentacyclic structure of 6{1,1,1} was confirmed by single
crystal X-ray diffraction studies (Figure 4).
In conclusion, we have developed a short and rapid synthesis
of novel benzimidazole-fused pentacyclic azaheterocycles. The
two step protocol includes Knoevenagel condensation of
2-cyanomethylbenzimidazole with an aldehyde to deliver azadiene.
These adducts undergo cis−trans isomerization, [4 + 1] cyclo-
addition with an isocyanide, aromatization, and δ-lactam formation
reaction cascade on microwave activation.
completion, the reaction mixture, the precipitate was washed
with cold ether (20 mL × 3). The precipitate was filtered and
dried well to furnish the IL-bound (E)-methyl 2-(1-cyano-2-
(2-(methoxycarbonyl) phenyl)vinyl)-1-(3-methoxypropyl)-1H-
benzo[d]imidazole-5-carboxylate IL-17{1,1} in excellent yield.
IL-17{1,1} was then treated with cyclohexyl isocyanide (164 μL,
1.30 mmol) in acetonitrile under MW (150 °C) irradiation for
15 min. After completion of the reaction, the precipitate was
washed with ether (20 mL × 3) and dried to yield IL-bound
benzimidazopyrroloisoquinolinone that was dissolved in meth-
anol (10 mL) and KCN (0.1 g) was added to the solution. The
reaction mixture was stirred for 12 h. After the reaction
completed, the precipitated ionic liquid was recovered by
filtration and reused. The filtrate was concentrated and the
crude product was purified by flash column chromatography to
remove traces aliphatic impurities to yield methyl 5-cyano-
12-cyclohexyl-6-(3-methoxypropyl)-13-oxo-12,13-dihydro-6
H-benzimidazo[1′,2′:1,5]pyrrolo[2,3- c]isoquinoline-9-carboxy-
late 6{1,1,1} (67% yield). 1H NMR (300 MHz, CDCl3): δ 8.41−
8.36 (m, 3H), 8.18 (dd, J = 8.7, 1.2 Hz, 1H), 7.73−7.68 (m, 1H),
7.46 (d, J = 8.7 Hz, 2H), 4.52 (t, J = 6.6 Hz, 2H), 4.36 (m, 1H),
4.00 (s, 3H), 3.45 (t, J = 5.7 Hz, 2H), 3.35 (s, 3H), 3.11−2.98 (m,
2H), 2.33−2.24 (m, 2H), 2.06−1,92 (m, 4H), 1.84−1.70 (m,
2H), 1.63−1.38 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 166.7,
163.6, 143.6, 140.4, 133.4, 132.6, 129.3, 127.4, 126.5, 126.5,
EXPERIMENTAL SECTION
■
General Procedure for Reaction of IL-Bound 2-
Cyanomethyl Benzimidazoles. Methyl 2-formylbenzoate
(0.22 g, 1.32 mmol) and piperidine (13 μL, 0.13 mmol) were
added to a solution of IL-bound 2-(cyanomethyl) benzimidazole
IL-3{1} (0.17 g, 0.44 mmol) in acetonitrile (5 mL). The reaction
mixture was stirred at ambient temperature for 12 h. After
D
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a
Table 1. Results of two step 3-CR cascade reactions
b
entry
product
yield (%)
1
6{1,1,1}
6{1,1,2}
6{2,1,1}
6{2,1,3}
6{2,1,2}
6{3,1,1}
6{3,1,2}
6{4,1,1}
6{4,1,2}
6{4,1,3}
6{4,1,4}
6{5,1,1}
6{5,1,2}
6{5,1,3}
6{5,1,4}
6{6,1,2}
6{7,1,1}
6{7,1,2}
6{7,1,3}
6{8,1,1}
67
76
70
61
73
68
78
67
82
62
55
73
89
67
46
74
72
82
57
68
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
b
All reactions were performed using 0.44 mmol benzimidazole IL-3, 1.32 mmol methyl2-formylbenzoate, and 1.30 mmol isonitrile. Overall yield of
isolated product.
Figure 3. Substrate scope of the reactions.
125.5, 124.3, 123.1, 121.8, 117.5, 115.1, 109.3, 107.4, 68.9, 63.0,
59.1, 58.7, 52.8, 41.6, 30.0, 29.5, 26.4, 25.4. IR (cm−1, neat):
2929, 2200, 1718. MS (EI-MS): 510.3. HRMS (EI) calcd. for
C30H30N4O4 m/z: 510.2267; found 510.2258 (M+).
E
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Figure 4. Single crystal X-ray structure of BPI 6{1,1,1}.
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental procedures, procedure for synthesis of 1,
1
IL-3, and 6, and H and 13C NMR, IR, LRMS, and HRMS
spectral data and spectra for 6, 9{1,1}, and 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank the National Science Council of
Taiwan for financial support and the authorities of the National
Chiao Tung University for providing the laboratory facilities.
This study was particularly supported by the “Centre for
bioinformatics research of aiming for the Top University Plan” of
the National Chiao Tung University and Ministry of Education,
Taiwan.
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