One-pot, two-step synthesis of imidazo[1,2-a]benzimidazoles via A multicomponent [4 + 1] cycloaddition reaction

Article abstract of DOI:10.1021/co400075z

A one-pot, two-step synthesis of imidazo[1,2-a]benzimidazoles has been achieved by a three-component reaction of 2-aminobenzimidazoles with an aromatic aldehyde and an isocyanide. The reaction involving condensation of 2-aminobenzimidazole with an aldehyd

Full text of DOI:10.1021/co400075z

Research Article
pubs.acs.org/acscombsci
One-Pot, Two-Step Synthesis of Imidazo[1,2‑a]benzimidazoles via A
Multicomponent [4 + 1] Cycloaddition Reaction
Ya-Shan Hsiao, Bharat D. Narhe, Ying-Sheng Chang, and Chung-Ming Sun*
Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10, Taiwan
S
* Supporting Information
ABSTRACT: A one-pot, two-step synthesis of imidazo[1,2-
a]benzimidazoles has been achieved by a three-component
reaction of 2-aminobenzimidazoles with an aromatic aldehyde
and an isocyanide. The reaction involving condensation of 2-
aminobenzimidazole with an aldehyde is run under microwave
activation to generate an imine intermediate under basic
conditions which then undergoes [4 + 1] cycloaddition with an
isocyanide.
KEYWORDS: microwave irradiation, [4 + 1] cycloaddition, imidazo[1,2-a]benzimidazoles, three-component reaction
the study of biological and medicinal properties associated with
this molecular framework.
INTRODUCTION
■
Benzimidazoles are well established as “privileged scaffolds”,
since a large number of these molecular frameworks show
interesting biological activities and are often part of various
pharmaceutical compositions.1 Imidazo[1,2-a]benzimidazoles,
the fused tricyclic derivatives of benzimidazoles are also known
for their medicinal properties. For example, tricyclic N-fused
amino benzimidazoimidazole I shows anticancer activity by
inhibition of topoisomerase IIα.2 Other active compounds
include antianxiety agent II and neuropsychotic compound III
among few other medicinally important molecules of this class
(Figure 1).3,4
Multicomponent reactions (MCRs) are reactions in which
three or more components react to produce complicated
molecules with high atom economy by incorporating all the
starting materials. MCRs are cost and time effective as they
produce desired products in good yields under simple and mild
reaction conditions. These synthetic methods provide quick
access to diverse molecular structures that are often very
difficult to synthesize by conventional methods.13 Additionally,
the products of a MCR can be easily utilized as synthetic hub
for diverse structures by incorporating orthogonal functional
group into the starting materials that subsequently can be used
in further transformations. Isocyanides are widely used
substrates for multicomponent reactions, such as Passenini,
In addition, these skeletons allow easy scaffold hopping with
various bioactive molecules to permit diversity oriented
synthesis of molecular libraries for further drug development.5
Benzimidazoles are suitable substrates for synthesis of various
polycyclic N-heterocycles. Commonly studied benzimidazole
fused polycyclic heterocycles includes benzimidazo[1,2-a]-
quinolines,6 pyrrolo[1,2-a]benzimidazoles,7 pyrido[1,2-a]-
benzimidazoles,8 pyrimido[1,2-a]benzimidazoles,9 benzo[4,5]-
imidazo[2,1-b]thiazoles,1 0 and imidazo[1,2-a]-
benzimidazoles.2−4 However, common synthetic routes for
various functionalized benzimidazo[1,2-a]imidazoles are rare in
the literature, consequently, they are relatively less studied.
We have earlier reported a soluble polymer-supported
́
Ugi, Groebke−Bienayme−Blackburn, Orru, and Van Leusen
reactions.13a,14 Several variations of these reactions are widely
used to afford scaffold diversity in the design of biologically
active molecules. These reactions share a unique characteristic,
that is, attack of isocyanide on a carbonyl function or an imine
followed by subsequent transformations. MCRs are often aided
by microwave activation as uniform heating and rapid
transformation rate makes the process cleaner and more energy
efficient.15
With this knowledge and our interest in development of
novel multicomponent reactions utilizing benzimidazoles
directed toward synthesis of biologically interesting polyhetero-
cycles, we designed a three component reaction of 2-
aminobenzimidazoles for synthesis of imidazobenzimidazoles.
regioselective synthesis of imidazo[1,2-a]benzimidazoles.11
A
similar protocol was used by Han and co-workers for the
synthesis and SAR studies of imidazo[1,2-a]benzimidazoles as
corticotrophin-releasing factor 1 receptor antagonists.3 Langer
et al. synthesized 2-aminoimidazo[1,2-a]imidazoles by [3 + 2]
cycloaddition of dilithiated 2-methylbenzimidazole and oxaldii-
midoyl dichlorides.12 Hence, a simple strategy that allows the
synthesis of substituted imidazobenzimidazoles is required for
Received: June 8, 2013
Revised: August 20, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/co400075z | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Figure 1. Biologically active imidazolo[1,2-a]benzimidazoles.
Scheme 1. Synthesis of Imidazo[1,2-a]benzimidazole
Scheme 2. Plausible Mechanism for Multicomponent [4 + 1] Cycloaddition
at 100 °C for 10 min yielded the desired imidazo[1,2-
a]benzimidazole 5{1,1,1} in 47% yield. The reaction analysis
revealed presence of unreacted starting materials. Mechanisti-
cally, the reaction proceeds via initial condensation of aldehyde
with the free amine of 2-amino-1-butyl-benzimidazole 2{1} to
generate imine 6{1,1}. Piperidine catalyzes the reaction by
forming an iminium hydroxide intermediate with benzaldehyde
that on nucleophilic attack of 2-amino-1-butyl-benzimidazole
2{1} delivers imine 6{1,1} with liberation of piperidine and
water.17 Imine 6{1,1} is expected to exist in s-cis conformation
for cycloaddition reactions, as in the s-trans conformation, there
will be steric repulsion between R1 and olefinic proton of imine
double bond. Attack of reactive isocyanide carbon on imino
carbon of s-cis-4 initiates stepwise [4 + 1] cycloaddition to yield
RESULT AND DISCUSSION
■
Our exploration starts with the synthesis of various N-alkyl-2-
aminobenzimidazoles To obtain various N-alkyl-2-amino-
benzimidazoles, we reacted methyl 4-fluoro-3-nitrobenzoate
with various alkyl amines followed by reduction to the
intermediate diamine 1{1}. Reaction with cyanogen bromide
afforded the 2-aminobenzimidazole 2{1} in good yields
(Scheme 1).11,17
The model study for the multicomponent reaction was
performed on 2-amino-1-butylbenzimidazole 2{1}, with
benzaldehyde 3{1} and t-butylisocyanate 4{1} as the other
reactants in dichloromethane. The reaction using catalytic
amount of piperidine (0.3 equiv) under microwave irradiation
B
dx.doi.org/10.1021/co400075z | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
The imine 6{1,1} was synthesized and isolated using
piperidine as a catalyst under microwave heating at 100 °C
for 10 min.17 Preliminary studies on the [4 + 1] cycloaddition
reaction were performed with imine 6{1,1} and t-butylisocya-
nate 4{1} (Table 1). The reaction of 6{1,1} and t-
butylisonitrile in dichloromethane under microwave heating
gave 43% of imidazo[1,2-a]benzimidazole 5{1,1,1} (entry 1)
along with considerable amount of hydrolysis of unstable imine
6{1,1}. With knowledge of higher stability of imines 6 under
the basic conditions of piperidine, a small amount of piperidine
(0.3 equiv) was added to the reaction mixture that enhanced
the yields of imidazo[1,2-a]benzimidazole 5{1,1,1} up to 70%.
A quick screening for solvent and temperature optimization
indicated that the best reaction condition by microwave heating
is 130 °C for 10 min in dichloroethane. The reaction also
progressed well under conventional heating in a sealed tube but
required 12 h for good conversion to occur at 130 °C (entries
7−9).
A telescoped reaction involves sequential addition of
reagents, one at a time without any workup in a multistep or
multicomponent reaction.16 This considerably reduces the
number of purification processes often boosting reaction
outcome. We performed our reaction by a telescoped approach.
Condensation of 2-amino-1-butylbenzimidazole 2{1} with
benzaldehyde under microwave heating in the presence of
piperidine at 100 °C for 10 min and subsequent addition of t-
butylisocyanide for further 10 min heating at 130 °C yielded
imidazo[1,2-a]benzimidazole 5{1,1,1} in 86% yield. Delighted
with this observation, we explored this telescopic trans-
formation with different aromatic aldehydes and isonitriles
Table 1. Optimization of [4 + 1] Cycloaddition Reaction
a
entry
solvent
temperature
time
yield of 5{1,1,1} (%)
b
1
CH2CI2
CH2CI2
DCE
MW, 100 °C
MW, 100 °C
MW, 100 °C
MW, 100 °C
MW, 100 °C
MW, 100 °C
MW, 100 °C
MW, 110 °C
MW, 120 °C
MW, 130 °C
MW, 140 °C
MW, 150 °C
Sealed tube, 100 °C
Sealed tube, 130 °C
Sealed tube, 150 °C
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
12 h
43
2
72
88
60
80
76
72
77
84
86
77
74
20
75
60
3
4
THF
5
toluene
CH3CN
DMF
DCE
6
7
8
9
DCE
10
11
12
13
14
15
DCE
DCE
DCE
DCE
DCE
12 h
DCE
12 h
a
All reactions were performed using 1.0 mmol 6{1,1}imine, 1.1 mmol
b
f-butyl isonitrile, 0.3 mmol piperidine in 5 mL of CH2CI2 solvent. No
piperidine base was added.
exocyclic imine intermediate 7 that aromatizes to deliver the
observed tricyclic product, imidazo[1,2-a]benzimidazole 5
(Scheme 2).
Absence of imine in the reaction mixture as suggested by lack
1
of olefin proton signal at 9.60 ppm in H NMR spectrum
clearly indicates that the success of this reaction is determined
by formation and reactivity of an imine 6 under reaction
conditions. This led us to study the conventional stepwise
reaction over one-pot MCR.
a
Table 2. Results of Telescopic One Pot 3-CR [4 + 1] Cycloaddition Reaction
a
b
c
entry
product
yield (%)
LRMS
clogP
1
5{1,1,1}
5{1,2,3}
5{1,2,2}
5{1,3,3}
5{2,1,3}
5{2,4,3}
5{2,5,1}
5{2,6,3}
5{2,7,3}
5{2,7,1}
5{2,8,3}
5{3,2,1}
5{3,2,2}
5{3,7,3}
5{3,4,3}
5{3,5,3}
5{4,7,1}
5{4,2,3}
5{5,2,3}
5{5,2,4}
86
83
88
73
78
80
71
89
81
77
85
86
75
84
80
77
77
83
80
82
419
490
478
451
431
481
449
476
456
430
499
480
494
486
511
505
472
518
542
550
7.623
8.183
8.32
7.69
8.86
7.12
6.33
8.62
6.00
6.35
6.51
8.25
7.11
5.74
6.84
9.21
8.70
8.26
9.05
8.57
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
b
c
Isolated yields. LRMS was recorded by ESI ionization method. Estimated clogP by ChemBioOffice 2010.
C
dx.doi.org/10.1021/co400075z | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
product 5{1,1,1} (R1 = n-butyl, R2 = Ph, and R3 = t-butyl)
confirmed its unique fused tricyclic ring system (Figure 3).
Importantly, the design of our present library is relying on
the structure based approach where the basic skeleton
imidazo[1,2-a]benzimidazole was adapted from the medicinally
important scaffolds.2−4 The calculated clogP (5.74−9.21)
values for our library are very well matched with that of
reported bioactive molecules of this class.2−4 The clogP values
for imidazo[1,2-a]benzimidazoles I, II, and III are 6.70, 7.17,
and 6.29, respectively (Figure 1). The clogP values for 5{3,7,3},
5{2,7,3}, and 5{2,5,1} are 5.74, 6.00, and 6.33, respectively,
which make them good candidates for further bioactivity study.
In conclusion, we have developed an efficient one-pot, two-
step, multicomponent reaction for the synthesis of biologically
interesting imidazo[1,2-a]benzimidazoles. Use of microwave
irradiation effectively accelerates the reaction to proceed in
short reaction times. The versatility and utility of this protocol
is demonstrated for a variety of substituents on each of three
reaction components. This simple, rapid, and efficient trans-
formation is expected to enhance study of biological properties
associated with these fused hetero tricyclic molecules.
EXPERIMENTAL PROCEDURES
■
Representative Procedure for Microwave Assisted
Three Component Reaction. To a dichloroethane solution
of 2{1} (192 mg, 1.0 mmol) in a microwave absorbance vessel
was added benzaldehyde (102 μL, 1.0 mmol) and piperidine
(30 μL, 0.3 mmol). The reaction mixture was irradiated under
microwave radiations (100 °C) for 10 min. The reaction
mixture was cooled to room temperature, t-butylisocyanide
(124 μL, 1.1 mmol) was added subsequently and reaction
mixture was irradiated again for further 10 min at 130 °C. The
solvent was removed by rotary evaporation and the product was
purified by column chromatography to obtain 5{1,1,1} (360
mg, 86% yield).
Figure 2. Substrate scope of the reaction.
Methyl 9-Butyl-3-(tert-butylamino)-2-phenyl-9H-imidazo-
1
[1,2-a]benzimidazole-6-carboxylate 5{1,1,1}. H NMR (300
MHz, CDCl3): δ 8.51 (d, J = 1.4 Hz, 1H), 8.00 (dd, J = 8.5, 1.6
Hz, 1H), 7.91 (dd, J = 8.4, 1.4 Hz, 2H), 7.40 (t, J = 7.8 Hz,
2H), 7.27−7.24 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.17 (t, J =
7.3 Hz, 2H), 3.97 (s, 3H), 3.17 (s, 1H), 1.92 (quint, J = 7.5 Hz,
2H), 1.50−1.37 (m, 2H), 1.10 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 167.5, 146.3, 139.5, 137.9,
136.1, 128.6, 128.1, 126.9, 125.1, 125.0, 123.2, 121.5, 113.7,
108.8, 56.7, 52.6, 43.2, 31.0, 30.5, 20.6, 14.1. IR (cm−1, neat):
3332, 1714, 1277. MS (ESI) m/z: 419. HRMS (ESI) m/z calcd.
for C25H31N5O2 [M + H]+: 419.2447. Found: 419.2443.
Figure 3. ORTEP diagram for X-ray crystal structure of 5{1,1,1}.
under the optimized conditions. The results of our study are
summarized in Table 2.
ASSOCIATED CONTENT
■
The effect of various substituents on benzimidazole nitrogen
(R1) was studied. Additional functional groups on R1 such as
ethers or endocyclic olefins were found to have no effect on the
reaction output and comparable yields were obtained in all
cases. The reaction worked very well with various aromatic
aldehydes containing either electron withdrawing or electron
donating groups. Heteroaromatic thiophene-2-aldehyde also
reacted to give the cycloaddition product in good yield (entry
3d). A bulky (t-butyl, cyclohexyl) or linear (pentyl) substituents
on isonitrile also had no effect on yields of the reaction possibly
due to their remoteness from the reaction center. Thus,
tolerance of the reaction to various substituents on each of the
three reactants was studied. X-ray crystallographic analysis of
S
* Supporting Information
Further details are given about the experimental procedures and
1H and 13C NMR spectra of all the compounds; X-ray structure
CIF file for 5{1,1,1}. 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.
D
dx.doi.org/10.1021/co400075z | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
(13) (a) Domling, A.; Wang, W.; Wang, K. Chemistry and biology of
̈
ACKNOWLEDGMENTS
■
multicomponent reactions. Chem. Rev. 2012, 112, 3083−3135.
(b) Vaxelaire, C.; Winter, P.; Christmann, M. One-pot reactions
accelerate the synthesis of active pharmaceutical ingredients. Angew.
Chem., Int. Ed. 2011, 50, 3605−3607. (c) Ruijter, E.; Scheffelaar, R.;
Orru, R. V. A. Multicomponent reaction design in the quest for
molecular complexity and diversity. Angew. Chem., Int. Ed. 2011, 50,
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.
́
6234−6246. (d) Toure, B. B.; Hall, D. G. Natural product synthesis
using multicomponent reaction strategies. Chem. Rev. 2009, 109,
4439−4486.
(14) (a) Pellissier, H. Stereocontrolled domino reactions. Chem. Rev.
REFERENCES
■
2013, 113, 442−524. (b) Domling, A. Recent developments in
̈
(1) (a) Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi,
R.; Rambaldi, M.; Garaliene, V.; Welsh, W.; Arora, S.; Farruggia, G.;
Masotti, L. Antitumor activity of new substituted 3-(5-imidazo[2,1-
b]thiazolylmethylene)-2-indolinones and study of their effect on the
cell cycle. J. Med. Chem. 2005, 48, 5604−5607. (b) Kumar, K.;
Awasthi, D.; Lee, S. Y.; Zanardi, I.; Ruzsicska, B.; Knudson, S.; Tonge,
P. J.; Slayden, R. A.; Ojima, I. 1. Novel trisubstituted benzimidazoles,
targeting Mtb FtsZ, as a new class of antitubercular agents. J. Med.
Chem. 2011, 54, 374−381.
(2) Baviskar, A. T; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.;
Agarwal, A.; Guchhait, S. K.; Kundu, C. N.; Banerjee, U. C.; Bharatam,
P. V. N-Fused imidazoles as novel anticancer agents that inhibit
catalytic activity of topoisomerase IIα and induce apoptosis in G1/S
phase. J. Med. Chem. 2011, 54, 5013−5030.
isocyanide based multicomponent reactions in applied chemistry.
Chem. Rev. 2006, 106, 17−89.
(15) Olofsson, K.; Hallberg, A.; Larhed, M. Microwaves in Organic
Synthesis, Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2002.
(16) (a) Ishikawa, H.; Suzuki, T.; Hayashi, Y. High-yielding synthesis
of the anti-influenza neuramidase inhibitor (−)-Oseltamivir by three
“one-pot” operations. Angew. Chem., Int. Ed. 2009, 48, 1304−1307.
(b) Cuthbertson, J. D.; Taylor, R. J. K. A telescoped route to 2,6-
disubstituted 2,3,4,5-tetrahydropyridines and 2,6-syn-disubstituted
piperidines: Total synthesis of (−)-grandisine G. Angew. Chem., Int.
Ed. 2013, 52, 1490−1493.
(17) Chen, C. H.; Yellol, G. S.; Lin, P. T.; Sun, C. M. Base-catalyzed
Povarov reaction: An unusual [1,3] sigmatropic rearrangement to
dihydropyrimidobenzimidazoles. Org. Lett. 2011, 13, 5120−5123.
(3) Han, X.; Pin, S. S.; Burris, K.; Fung, L. K.; Huang, S.; Taber, M.
T.; Zhang, J.; Dubowchik, G. M. Synthesis and structure−activity
relationship of imidazo[1,2-a]benzimidazoles as corticotropin-releas-
ing factor 1 receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15,
4029−4032.
(4) Morozov, I. S.; Anisimova, V. A.; Avdyunina, N. I.; Lukova, O. A.;
Pyatin, B. M.; Militareva, N. A.; Bykov, N. P.; Dvalishvili, E. G.;
Khranilov, A. A. Synthesis and neuro-psychotropic activity of
adamantylimidazo[1,2-a]-benzimidazoles. Pharm. Chem. J. 2004, 38,
539−543.
(5) Bohm, H. J.; Flohr, A.; Stahl, M. Scaffold hopping. Drug Discovery
̈
Today: Technol. 2004, 1, 217−224.
(6) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K. Synthesis
of aza-fused polycyclic quinolines through copper-catalyzed cascade
reactions. Org. Lett. 2010, 12, 1500−1503.
(7) (a) Suleman, A.; Skibo, E. B. A comprehensive study of the active
site residues of DT-diaphorase: Rational design of benzimidazole-
diones as DT-diaphorase substrates. J. Med. Chem. 2002, 45, 1211−
1220. (b) Schulz, W. G.; Islam, I.; Skibo, E. B. Pyrrolo[1,2-
a]benzimidazole-based quinones and iminoquinones. The role of the
3-substituent on cytotoxicity. J. Med. Chem. 1995, 38, 109−118.
(8) Yan, C. G.; Wang, Q. F.; Song, X. K.; Sun, J. One-step synthesis
of pyrido[1,2-a]benzimidazole derivatives by a novel multicomponent
reaction of chloroacetonitrile, malononitrile, aromatic aldehyde, and
pyridine. J. Org. Chem. 2009, 74, 710−718.
(9) (a) Venepalli, B. R.; Aimone, L. D.; Appell, K. C.; Bell, M. R.;
Dority, J. A.; Goswami, R.; Hall, P. L.; Kumar, V.; Lawrence, K. B.;
Logan, M. E.; Scensny, P. M.; Seelye, J. A.; Tomczuk, B. E.; Yanni, J.
M. Synthesis and substance P receptor binding activity of androstano-
[3,2-b]pyrimido[1,2-a]benzimidazoles. J. Med. Chem. 1992, 35, 374−
378. (b) Zhang, Z. T.; Dong Xue, L. Q.; Wu, J.; Xu, F.-F. Concise
synthesis of 2, 3-diarylpyrimido[1,2-a]benzimidazole based on
isoflavones. J. Comb. Chem. 2010, 12, 225−230.
(10) Xu, H.; Zhang, Y.; Huang, J.; Chen, W. Copper-catalyzed
synthesis of N-fused heterocycles through regioselective 1,2-amino-
thiolation of 1,1-dibromoalkenes. Org. Lett. 2010, 12, 3704−3707.
(11) Chen, L. H.; Hsiao, Y. S.; Yellol, G. S.; Sun, C. M. Microwave
promoted simple, efficient and regioselective synthesis of trisubstituted
imidazo[1,2-a]benzimidazoles on soluble support. ACS Comb.Sci.
2011, 13, 112−119.
(12) Langer, P.; Wuckelt, J.; Doring, M.; Schreiner, P. R.; Gorls, H.
Regioselective anionic [3 + 2] cyclizations of imidazole dinucleophiles
with oxaldiimidoyl dichloridesA combined experimental and
theoretical study. Eur. J. Org. Chem. 2001, 2245−2255.
E
dx.doi.org/10.1021/co400075z | ACS Comb. Sci. XXXX, XXX, XXX−XXX