Copper catalyzed aerobic oxidative cyclization and ketonization: One pot synthesis of benzoimidazo[1,2-: A] imidazolones

Article abstract of DOI:10.1039/c6cc01828a

A highly efficient synthesis of benzoimidazo[1,2-a]imidazolone through a novel oxidative 5-exo-dig cyclization-ketonization cascade of 2-aminobenzimidazole, aldehyde and terminal alkyne has been explored under aerobic conditions. The reaction proceeds thr

Full text of DOI:10.1039/c6cc01828a

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Copper catalyzed aerobic oxidative cyclization
and ketonization: one pot synthesis of
benzoimidazo[1,2-a]imidazolones†
Cite this:DOI: 10.1039/c6cc01828a
Received 29th February 2016,
Accepted 18th April 2016
Manikandan Selvaraju,a Tzuen-Yang Ye,a Chia-Hsin Li,ab Pei-Heng Hoa and
Chung-Ming Sun*ab
DOI: 10.1039/c6cc01828a
www.rsc.org/chemcomm
A highly efficient synthesis of benzoimidazo[1,2-a]imidazolone through
a novel oxidative 5-exo-dig cyclization-ketonization cascade of
2-aminobenzimidazole, aldehyde and terminal alkyne has been
explored under aerobic conditions. The reaction proceeds through
copper-catalyzed addition of terminal alkynes to imines derived from
2-aminobenzimidazole with aldehyde followed by intramolecular
cyclization. The atmospheric molecular oxygen acts as an oxygen
source for the newly formed carbonyl group in the final product.
Fig. 1 Biologically important benzoimidazo[1,2-a]imidazolones and imidazolo-
[1,2-a]pyridines.
Fused heterocyclic compounds are key structural elements and
are frequently encountered in many natural products and bio-
molecules. Among them, benzimidazole, imidazole and their involves metalation of halides followed by quenching of the result-
derivatives are considerably prestigious heterocycles in the ing carbanions with dialkyl oxalate (Scheme 1, eqn (2)).8 Stepwise,
medicinal and drug discovery research.1,2 More importantly, longer and harsh reaction conditions are some of the setbacks
benzoimidazo[1,2-a]imidazolone, a fused tricyclic benzimidazole, associated with these methods. Owing to these drawbacks, many
has shown interesting medicinal and biological properties.
powerful alternative methods have been developed. A three com-
For example, acylated benzoimidazo[1,2-a]imidazole I inhibits ponent, A3-coupling reaction of amines, aldehydes, and terminal
cyclic nucleotide phosphodiesterases.3 Other active compounds alkynes is one of the most powerful methods to obtain N-fused
include an antianxiety agent II and a neuropsychotic compound heterocycles.9 In particular, many transition metal catalyzed reac-
III among many other medicinally important molecules of this tions were reported to deliver fused imidazolones with the metal
class.4,5 Similarly, imidazo[1,2-a]pyridine is an essential fragment salts such as copper, palladium, gold and silver.10,11
present in several drug molecules and functionalized 3-aroylimid-
Recently, the Hua Cao group reported a gold catalyzed synthesis
azo[1,2-a]pyridine has received considerable attention as a core of imidazo[1,2-a]pyridines using aminopyridines and propargyl
entity in many anticancer compounds (Fig. 1).6 However, the direct aldehydes as substrates (Scheme 1, eqn (3)).12 Similarly, the Monir
synthesis of benzoimidazo[1,2-a]imidazolones is not very well group and Kaswn et al. developed an oxidative coupling of a,b-
explored and development of new methods for the synthesis of unsaturated carbonyl compounds with aminopyridines (Scheme 1,
these structural motifs has attracted great attention. In general, the eqn (3)).13,14 In recent times, many C–C and C–N bond forming
introduction of an acyl/aroyl group on the third position of imid- reactions were developed with highly abundant and inexpensive
azo[1,2-a]benzimidazole is carried out with the aid of acid chlorides copper salts.15 Zhang’s group reported a facile method for the
or acetic anhydrides (Scheme 1, eqn (1)).7 Another approach synthesis of 2-alkenylimidazo[1,2-a]pyridines via copper-catalyzed
aerobic oxidative cyclization of methyl vinyl ketones and 2-amino-
pyridines.16 The main disadvantage of these developed protocols is
the requirement of pre-functionalized carbonyl compounds as one
of the reagents to introduce the acyl/aroyl functionality. Despite
these significant achievements, development of a novel approach to
synthesize benzoimidazo[1,2-a]imidazolones or imidazolo[1,2-a]-
pyridine in a straightforward, one-pot manner is highly desirable.
As part of our continuing interest on the synthesis of N-heterocycles
a Department of Applied Chemistry, National Chiao-Tung University, 1001,
Ta-Hseuh Road, Hsinchu 300-10, Taiwan, Republic of China.
E-mail: cmsun@mail.nctu.edu.tw
b Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
100, Shih-Chuan 1st Road, Kaohsiung 807-08, Taiwan, Republic of China
† Electronic supplementary information (ESI) available: Experimental section.
CCDC 1456718. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c6cc01828a
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Table 1 Optimization of the reaction conditions for the three component
coupling reactiona
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
EtOH
DMF
CH3CN
H2O
Toluene
Toluene
Toluene
35
18
15
12
14
0
22
25
CuCl
CuBr
Cu(OAc)2
CuCl2
InBr3
CuI/Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
—
9
46
10
11
12
13
14
15
77
47c
38
Scheme 1 Several strategies towards the synthesis of benzoimidazo[1,2-a]-
imidazolones and imidazolo[1,2-a]pyridines.
45d
20
Trace
70e
Trace f
0
by copper catalysed cascade reactions,17 we herein reported a three 16
component reaction of 2-aminobenzimidazole, aldehyde and
17
18
alkyne to generate benzoimidazo[1,2-a]imidazolone derivatives.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), 3a (0.36 mmol),
We envisioned that 3-aroylated benzoimidazo [1,2-a]imid-
catalyst (10 mol%), base (0.45 mmol), solvent (2 mL) in O2 under refluxing
azolone could be assembled via copper catalyzed oxidative exo-
dig cyclization followed by ketonization of propargylamine with
molecular oxygen as shown in Scheme 2. The formation of C–N,
C–C and CQO bonds was performed under one-pot conditions
using a single, inexpensive copper catalyst in the current study.
Notably, the oxygen atom of the newly formed carbonyl group is
incorporated from atmospheric molecular oxygen. The developed
copper/oxygen catalytic system under ligand/additive-free con-
ditions could fulfill the increasing requirement of green chem-
istry and efficient processes.
The synthetic sequence commenced with the preparation of
various N-alkylated 2-aminobenzimidazole 1 as shown in Scheme S6
(ESI†).18 Once the key substrate 1a is obtained, we examined a three
component coupling of 2-aminobenzimidazole 1a, benzaldehyde 2a
and phenylacetylene 3a in the presence of copper catalysts under an
oxygen atmosphere and the results are shown in Table 1. We found
that in the presence of CuI and diisopropylethylamine (DIPEA) in
toluene, the desired cascade product 5a was obtained in 35% yield
and the remaining is the non-cyclized propargyl amine 4a in 51%
yield (Table 1, entry 1). Changing the copper(I) source to CuCl and
b
c
d
conditions for 8 h. Isolated yield. Open air conditions. The reaction is
conducted at 100 1C. Used 50 mol% of CuI. Under nitrogen.
e
f
CuBr did not give any satisfactory results (Table 1, entries 2 and 3). It
is noted that copper(II) and In(III) salts were not viable for the same
transformation (Table 1, entries 4–6). However, a poor yield was
obtained when the reaction was performed in a binary catalytic
system CuI/Cu(OAc)2 (Table 1, entry 7). Next, we investigated the
influence of different bases on this one-pot transformation (Table 1,
entries 8–10). When the reaction was carried out in triethylamine,
the product was obtained in 25% yield (entry 8). Switching the base
to K2CO3 increased the reaction yield to 46%. To our delight,
compound 5a was obtained in 77% yield when Cs2CO3 was
employed in refluxing toluene (entry 10).
It is noteworthy that the reaction yield was reduced to 47% when
air was used instead of oxygen (entry 11). After identification of CuI/
Cs2CO3/O2 as the best catalytic system, we undertook a systematic
evaluation of other solvents for possible enhancement of reaction
conversion. Other solvents such as EtOH, DMF and CH3CN were
proved to be ineffective for this transformation and resulted in lower
yields (Table 1, entries 12–14). Only a trace amount of product 4a was
observed and product 5a was not formed at all due to the rapid
hydrolysis of imine rather than the addition of alkyne when the
coupling reaction was carried out under aqueous conditions
(entry 15). Moreover, an increase in the amount of catalyst to
50 mol% failed to improve the reaction yield, probably due to the
deactivation of the amine nucleophilicity by the coordination of the
copper catalyst (entry 16). It is noted that the same reaction under a
nitrogen atmosphere failed to give any cyclized product and 4a is
obtained as a sole product (entry 17). However, in the absence of any
copper catalyst, no desired product was obtained (entry 18). Thus the
Scheme 2 A copper catalysed coupling, cyclization and ketonization
cascade for the synthesis of benzoimidazo[1,2-a]imidazolones.
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Table 2 Three component synthesis of benzoimidazo[1,2-a]imidazolonesa
Entry
Yieldb (%)
5a
5b
5c
5d
5e
5f
77
81
73
77
75
61
70
72
73
5g
5h
5i
Scheme 3 Substrate scope for the reaction of 2-aminobenzimidazoles
1a–1i, benzaldehyde 2a and phenylacetylene 3a.
5j
70
51
5k
a
Only representative examples are shown in Table 1, remaining com-
b
pounds are included in the ESI. Isolated yields.
combination of CuI (10 mol%) and Cs2CO3 in toluene under mole-
cular oxygen gave the best yield for this cascade reaction (entry 10).
To extend the generality of the reaction, the coupling reaction was
carried out under optimized conditions using variously substituted
amines, aldehydes and alkynes. The results are displayed in Table 2.
Various aromatic, heterocyclic aldehydes and alkynes were smoothly
transformed into the corresponding C3-carbonylated imidazobenz-
imidazoles in moderate to excellent yields.
Next, we focused on the substrate scope in terms of variously
substituted 2-aminobenzimidazoles and the results are sum-
marized in Scheme 3.
From the observed results, it is found that the electronic nature of
the substituents does not have a significant impact on the product
outcome. The neutral and electron-donating groups were well
Scheme 4 Control experiments to elucidate the reaction pathway.
tolerated under these reaction conditions and their reaction pro- in the presence of water (1.2 equiv.) under an inert atmosphere,
ceeded smoothly to give the corresponding derivatives in good yields formation of product 5a was not observed and only a trace
(Scheme 3, entries 5aa, 5da, 5ea and 5ga). Similarly, 2-aminobenz- amount of intermediate 4a was detected. Furthermore, product
imidazoles 1 having electron withdrawing groups such as chloro, 5a was not formed at all and most of intermediate 4a was
cyano, nitro, trifluoro methyl and methyl ester were compatible with isolated when the reaction was run under a nitrogen atmosphere
the present catalytic cycle and furnished the corresponding imidazo- (eqn (2)). However, product 5a was obtained in 80% yield when
pyridines in moderate yields (Scheme 3, entries 5ba, 5ca, 5fa, the reaction was carried out using intermediate 4a as a substrate
5ha and 5ia). To further expand the scope, 2-aminopyridine and under optimized aerobic conditions (eqn (3)).
2-aminopyrazines were successfully employed as suitable sub-
All these results demonstrated that ynamine 4a is the possible
strates for the same transformation (Scheme 3, entries 6a–6c). intermediate for this tandem reaction and the oxygen atom in the
However, aliphatic aldehydes and alkynes were found to be product originated from molecular oxygen rather than H2O. On the
non-feasible substrates for the current transformation.
basis of earlier reports19 and our own experimental observation,
To elucidate the mechanism, some control experiments were a plausible mechanism for the formation of 5 is depicted in
carried out as shown in Scheme 4. When the reaction was run Scheme 5. In situ formation of imine from 2-aminobenzimidazole
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laboratory are directed toward establishment of the generality
of this protocol on other heterocyclic syntheses.
The authors wish to thank the Ministry of Science and
Technology of Taiwan, ROC, for financial support.
Notes and references
1 (a) K. Kumar, D. Awasthi, S. Y. Lee, I. Zanardi, B. Ruzsicska,
S. Knudson, P. J. Tonge, R. A. Slayden and I. Ojima, J. Med. Chem.,
2011, 54, 374; (b) Y. Lu, J. Chen, J. Wang, C. M. Li, S. Ahn,
C. M. Barrett, J. T. Dalton, W. Li and D. D. Miller, J. Med. Chem.,
2014, 57, 7355; (c) H. Nimesh, S. Sur, D. Sinha, P. Yadav, P. Anand,
P. Bajaj, S. J. Virdi and V. Tandon, J. Med. Chem., 2014, 57, 5238.
2 (a) D. Kim, Bioorg. Med. Chem. Lett., 2005, 15, 2129; (b) A. J. Stasyuk,
M. Banasiewicz, M. K. Cyranski and D. T. Gryko, J. Org. Chem., 2012,
77, 5552; (c) C. E. Gueiffier and A. Gueiffier, Mini-Rev. Med. Chem.,
2007, 7, 888.
3 D. Demirbas, O. Ceyhan, A. R. Wyman, F. D. Ivey, C. Allain, L. Wang, M. N.
Sharuk, S. H. Francis and C. S. Hoffman, Cell. Signalling, 2011, 23, 594.
4 X. Han, S. S. Pin, K. Burris, L. K. Fung, S. Huang, M. T. Taber, J. Zhang
and G. M. Dubowchik, Bioorg. Med. Chem. Lett., 2005, 15, 4029.
5 I. S. Morozov, V. A. Anisimova, N. I. Avdyunina, O. A. Lukova, B. M. Pyatin,
N. A. Militareva, N. P. Bykov, E. G. Dvalishvili and A. Khranilov, Pharm.
Chem. J., 2004, 38, 539.
Scheme 5 A plausible mechanism for the formation of 5.
6 (a) T. S. Harrison and G. M. Keating, CNS Drugs, 2005, 19, 65;
(b) T. Okubo, R. Yoshikawa, S. Chaki, S. Okuyamac and A. Nakazato,
Bioorg. Med. Chem., 2004, 12, 423; (c) A. N. Jain, J. Med. Chem., 2004,
47, 947; (d) Y. S. Tung, M. S. Coumar, Y. S. Wu, H. Y. Shiao, J. Y.
Chang, J. P. Liou, P. Shukla, C. W. Chang, C. Y. Chang, C. C. Kuo,
T. K. Yeh, C. Y. Lin, J. S. Wu, S. Y. Wu, C. C. Liao and H. P. Hsieh,
J. Med. Chem., 2011, 54, 3076.
Fig. 2 ORTEP diagram of 5b.
7 (a) V. A. Anisimova and I. E. Tolpygin, Russ. J. Org. Chem., 2011, 47, 1354;
(b) I. A. Zamkova, O. O. Chekotylo, O. V. Geraschenko, O. O. Grygorenko,
P. K. Mykhailiuk and A. A. Tolmachev, Synthesis, 2010, 1692.x.
8 J. R. Clayton, C. G. Diefenbacher, T. A. Engler, K. W. Furness, J. R. Henry,
S. Malhotra, A. L. Marquart, J. A. McLean, D. Mendel, T. P. Burkholder,
Y. Li and J. K. Reel, WO03076442, 2003 (Chem. Abstr., 2003, 139, 261331).
9 (a) C. J. Li, Acc. Chem. Res., 2010, 43, 581; (b) W. J. Yoo, L. Zhao and
C. J. Li, Aldrichimica Acta, 2011, 44, 43; (c) V. A. Peshkov, O. P. Pereshivko
and E. V. Van der Eycken, Chem. Soc. Rev., 2012, 41, 3790.
and aldehyde is the first step of this cascade process. In the presence
of copper iodide and base, alkyne will react with the initially formed
imine intermediate to afford propargylic amine. Complexation of the
copper catalyst with the propargylic amine yields intermediate A
which will undergo 5-exo dig cyclization to give intermediate B.
Oxidative addition of oxygen with intermediate B leads to the peroxy-
copper(II) intermediate C. Reductive elimination of intermediate C
gives rise to the formation of the peroxycopper(I) complex D. Finally,
10 (a) H. Y. Fu, L. Chen and H. Doucet, J. Org. Chem., 2012, 77, 4473;
(b) C. He, J. Hao, H. Xu, Y. P. Mo, H. Y. Liu, J. J. Han and A. W. Lei,
Chem. Commun., 2012, 48, 11073.
the peroxide intermediate D undergoes a sequential O–O bond cleav- 11 (a) N. Chernyak and V. Gevorgyan, Angew. Chem., Int. Ed., 2010, 49, 2743;
(b) H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang and Q. Zhu, Angew.
Chem., Int. Ed., 2011, 50, 5677; (c) P. Liu, C. L. Deng, X. Lei and G. Q. Lin,
Eur. J. Org. Chem., 2011, 7308; (d) T. Palani, K. Park, M. R. Kumar,
age and isomerization to deliver the target molecule 5 and CuOH.
The catalytic cycle could be regenerated with the formation of copper
iodide by the reaction of CuOH with hydrogen iodide. Apparently,
copper iodide plays a dual role in this catalytic cycle: it activates the
acetylenes for the formation of propargylic amine and supports the
subsequent oxidative cyclization to furnish the target molecule.
Finally, the structure of a newly synthesized compound was
unambiguously confirmed by single crystal X-ray diffraction
studies (Fig. 2). The benzimidazole and the imidazole rings are
fused perpendicular to each other.
In conclusion, we have developed a copper catalyzed one-pot
strategy for the synthesis of benzoimidazo[1,2-a]imidazolone by
three component coupling of 2-aminobenzimidazole, aldehyde,
and alkyne. The present protocol offers a novel approach to a
series of benzoimidazo[1,2-a]imidazolones in moderate to high
yields by the sequential C–N, C–C and CQO bond formation.
Most importantly, the substrate scope was extended by successful
execution of 2-aminopyridine and 2-aminopyrazines as suitable
substrates for this transformation. The present protocol provides
an alternative to implant a carbonyl oxygen from molecular
oxygen into the imidazole framework. Ongoing efforts in our
H. M. Jung and S. Lee, Eur. J. Org. Chem., 2012, 5038; (e) D. C. Mohan,
S. N. Rao and S. Adimurthy, J. Org. Chem., 2013, 78, 1266.
12 (a) H. Cao, X. Liu, J. Liao, J. Huang, H. Qiu, Q. Chen and Y. Chen,
J. Org. Chem., 2014, 79, 11209; (b) H. Zhan, L. Zhao, J. Liao, J. Li,
Q. Chen, S. Qiu and H. Cao, Adv. Synth. Catal., 2015, 357, 46.
13 K. Monir, A. K. Bagdi, S. Mishra, A. Majee and A. Hajra, Adv. Synth.
Catal., 2014, 356, 1105.
14 (a) P. Kaswan, K. Pericherla, Rajnikant and A. Kumar, Tetrahedron,
2014, 70, 8539; (b) P. Kaswan, K. Pericherla, H. K. Saini and
A. Kumar, RSC Adv., 2015, 5, 3670.
15 (a) S. Ueda and H. Nagasawa, J. Am. Chem. Soc., 2009, 131, 15080;
(b) H. Cao, H. Y. Zhan, Y. G. Lin, X. L. Lin, Z. D. Du and H. F. Jiang,
Org. Lett., 2012, 14, 1688.
16 Y. Zhang, Z. Chen, W. Wu, Y. Zhang and W. Su, J. Org. Chem., 2013,
78, 12494.
17 (a) Y. S. Hsiao, B. D. Narhe, Y. S. Chang and C. M. Sun, ACS Comb.
Sci., 2013, 13, 551; (b) B. Maiti, K. Chanda, M. Selvaraju, C. C. Tseng
and C. M. Sun, ACS Comb. Sci., 2013, 15, 291; (c) M. Selvaraju and
C. M. Sun, Adv. Synth. Catal., 2014, 356, 1329.
18 (a) C. H. Chen, G. S. Yellol, P. T. Lin and C. M. Sun, Org. Lett., 2011,
13, 5120; (b) M. Selvaraju, W. S. Shiu, M. V. Kulkarni and C. M. Sun,
RSC Adv., 2013, 3, 22314.
19 (a) C. Zhang and N. Jiao, J. Am. Chem. Soc., 2010, 132, 28; (b) K. K. Toh,
Y. F. Wang, E. P. J. Ng and S. Chiba, J. Am. Chem. Soc., 2011, 133, 13942;
(c) E. A. Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047.
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