Solvent- and catalyst-free synthesis of 2,3-dihydro-1H-benzo[d]imidazoles

Article abstract of DOI:10.1039/c0gc00572j

Reactions of acyclic ketones and o-phenylenediamines under solvent- and catalyst-free conditions have been developed for the preparation of dihydrobenzimidazoles. This method can also be used for the synthesis of other heterocyclic compounds such as dihydrobenzothiazoles and perimidines. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00572j

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COMMUNICATION
Solvent- and catalyst-free synthesis of 2,3-dihydro-1H-benzo[d]imidazoles†
Da-Peng Li,a Guang-Liang Zhang,a Li-Tao An,a Jian-Ping Zou*a and Wei Zhang*b
Received 18th September 2010, Accepted 11th January 2011
DOI: 10.1039/c0gc00572j
Reactions of acyclic ketones and o-phenylenediamines un-
der solvent- and catalyst-free conditions have been de-
veloped for the preparation of dihydrobenzimidazoles.
This method can also be used for the synthesis of other
heterocyclic compounds such as dihydrobenzothiazoles and
perimidines.
dichloromethyl 2,3-dihydro-1H-benzo[d]imidazole 3a (eqn (1)).
This result encouraged us to explore the scope of this unusual
solvent-free reaction.
(1)
Benzimidazole and its analogue dihydrobenzimidazole are
privileged heterocycles that can be found in commercial
medicines such as Liarozole,1 Omeprazole,2 Thiabendazole3
and Domperidone.4 Their derivatives have broad medicinal,5
biological,6 and photochemical7 utilities. It is well-documented
that acid-catalyzed reactions of o-phenylenediamines with
appropriate carbonyl compounds afford benzimidazoles,8
We found that in the absent of a catalyst, reactions of
unsubstituted acyclic ketones with 1a gave benzimidazoles 3 in
low yield. However, the reaction of 2a could afford 3a in good
yield under solvent- and catalyst-free conditions. An optimized
reaction carried out using 1 : 2 of 1a : 2a at room temperature
for 15 min gave 3a in 90% yield. Interestingly, solvents such
as CH3CN and CHCl3 were found to slow down the reaction,
presumably due to unfavorable solvation effects.16
To evaluate the generality of this reaction, 2a was used to react
with several substituted o-phenylenediamines 1 and the results
are summarized in Table 1. Diamines 1 bearing a methyl group
increased the reaction speed (Table 1, entry 2), whereas those
bearing an electron-withdrawing group decreased the reaction
speed and required heating to reach completion (Table 1, entries
3, 5, 7, 9, 10). The reaction of 5-bromo-2,3-diaminopyridine
1f offered product 3f in 82% yield (Table 1, entry 6). Stericly
hindered diamine 1h gave product 3h in 90% yield (Table 1, entry
8). The structures of compounds 3c and 3g were confirmed by
single crystal X-ray anaylsis (see Supporting Information†). It
was found that products containing an electron-withdrawing
group are more stable than those with an electron-donating
group. For example, 3a was only stable for 2 days in the
refrigerator, whereas 3c was stable at room temperature for more
than 3 months.
After exploring the reaction scope of 1,3-dichloroacetone
2a, reactions of 1,3-dihydroxyacetone 2b with diamines were
performed and the results are listed in Table 2. Reactions
of 2b with 1, except with 1c and 1j, could proceed at room
temperature. Reactions of 2b with diamines gave slightly lower
yields than those of 2a, but products 4 are more stable than
3. Extension of the reaction scope using 1,3-dimethoxyacetone
2c to react with diamines were performed at room temperature
and under solvent- and catalyst-free conditions (Table 3). The
product yields are in the range comparable to the reactions of
2b. Products 5 were found to be stable at room temperature.
dihydrobenzimidazoles,9
benzo[1,5]diazepines,10
and
quinoxalines.11 However, only cyclic ketones were reported for
the synthesis of dihydrobenzimidazoles under the catalyst-free
conditions.12 Trichloromethylketone is the only acyclic substrate
that was used for the synthesis of bisbenzimidazoles,13 but not
for dihydrobenzimidazoles. Reported here are new reactions of
acyclic ketones and o-phenylenediamines under catalyst- and
solvent-free conditions for the synthesis of 2,3-dihydro-1H-
benzo[d]imidazoles.14 These condensed products have dichloro,
dihydroxy, and dimethoxy functional groups that are useful for
further derivatizations.
As a part of our continuous efforts toward the development
of new synthetic methods for heterocyclic compounds, we have
reported Ga(OTf)3-catalyzed reactions of o-phenylenediamines
to form benzo[1,5]diazepines15a and quinoxalines.15b Recently,
when carried out a Montmorillonite K10-catalyzed reaction
of o-phenylenediamine 1a and 1,3-dichloroacetone 2a under
the solvent-free conditions, we were surprised to find that
the product was neither the 7-membered benzo[1,5]diazepine
nor the 6-membered quinoxaline, but the 5-membered 2,2-
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou, Jiangsu 215123, China. E-mail: jpzou@suda.edu.cn
bDepartment of Chemistry, University of Massachusetts Boston, 100
Morrissey Boulevard, Boston, MA, 02125, USA.
E-mail: wei2.zhang@umb.edu
† Electronic supplementary information (ESI) available: Experimental
procedures, compound characterizations, and X-ray crystal structures.
CCDC reference numbers 793230–793232. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0gc00572j
594 | Green Chem., 2011, 13, 594–597
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Table 1 Reactions of 1,3-dichloroacetone 2a with diamines 1a
Table 2 Reactions of 1,3-dihydroxyacetone 2b with diamines 1a
Entry Diamine 1
Time (min) Product
15
Yieldb(%)
90c
Entry Diamine 1
Time (h)
2
Product
Yieldb(%)
78
1
1
2
3
4
5
6
1.5
0.5
6
82
93c
70
85
86
2
3
4
5
6
7
15
5
89
92(84)d,e
25
20
10
45
93e
90e
5
82e
7
92e
7
8
9
1
62
84
81d
1.6
0.3
8
45
90
9
125
15
91e
96e
10
a R◦eaction conditions: 1 mmol of 1 and 2 mmol of 2b were ground at
20 C unless mentioned otherwise. b Isolated yield. c 50 ◦C in an oil bath.
d 60 ◦C in an oil bath.
a R◦eaction conditions: 1 mmol of 1 and 2 mmol of 2a were ground at
20 C unless mentioned otherwise. b Isolated yield. c Stable for 2 days in
the refrigerator. d At 30 mmol scale, 84% yield was obtained. e At 60 ◦C
in an oil bath.
C
N bond to yield 7. Electron-withdrawing group Y facilitates
the cyclization process. Intramolecular 1,3-proton transfer of 7
gives benzimidazole 3. Reactions of o-phenylenediamines with
2a, 2b and 2c go through this route. Intermediate 6 may undergo
an alternative pathway to form quinoxaline 8. The reactions
of ketones 2a, 2b and 2c do not follow this pathway because
the Y groups (Cl, OH, OMe) are not good leaving groups.
However, Br and I are better leaving groups so reactions of 1,3-
dibromoacetone and 1,3-diiodoacetone could form quinoxaline
8. The third pathway generates benzo[1,5]diazepine 11 through
the formation of diimine 9 and then the cyclization of its
tautomer 10. This does not seem to be a favored path for
catalyst-free reactions with 1,3-disubstituted ketones. To prove
that imine 6 and 9 are the key intermediates for the proposed
mechanism, the reactions of N1,N2-(1,2-phenylene)diacetamide
and N1,N2-dibenzylbenzene-1,2-diamine were tested, and
Reactions of 1,3-dibromoacetone and 1,3-diiodoacetone with
1a were also conducted. However, both reactions gave compli-
cated mixtures containing benzimidazole, benzo[1,5]diazepine,
and quinoxaline. This result is related to our recent work on the
reactions of o-phenylenediamine to form benzo[1,5]diazepines
and quinoxalines.15 1,3-Disubstituted ketones with less electron-
withdrawing groups such as bromine and iodine may have com-
petitive pathways to form by-products. A mechanism to explain
the possible transformations is proposed in Scheme 1. The first
pathway is the reaction of diamine 1 with ketone 2 to form imine
6, followed by nucleophilic addition of the amino group to the
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Table 3 Reactions of 2c with diamines 1a
Table 4 Synthesis of perimidines and dihydrobenzothiazolesa
Entry Diamine 1
1
Time (min) Product
20
Yieldb(%)
79
Entry Amine 1 Ketone 2 Time (min) Product
Yieldb (%)
93
1
2a
3
2
3
4
5
60
74
63
70
72
2
3
4
5
1k
1k
2b
2c
2b
2c
3
92
92
75
94
20
10
6
30
240
1l
20
6
7
30
50
85
69
a Reaction conditions: 1 mmol of 1 and 2 mmol of 2 were ground at
20 ◦C. b Isolated yield.
benzylbenzene-1,2-diamine 1h gave the desired benzimidazole
3h through the formation of a monoimine (Table 1, entry 8).
This method has been extended for the synthesis of per-
imidines and dihydrobenzothiazoles by the reaction of 1,3-
disubstituted ketones 2 with 1,8-diaminonaphthalene 1k and
2-aminothiophene 1l, respectively (Table 4). These reactions
proceeded at room temperature and gave excellent yields of
products.
a Reaction conditions: 1 mmol of 1 and 2 mmol of 2c were ground at
20 ◦C. b Isolated yield.
In conclusion, a new and green method has been developed
for the synthesis of unique 2,2-disubstituted 2,3-dihydro-1H-
benzo[d]imidazoles by the reaction of o-phenylenediamines and
acyclic acetones under solvent- and catalyst-free conditions.
This method is also suitable for the synthesis of perimidines,
benzothiazoles and potentially other heterocycles. The dichloro,
dihydroxy, and dimethoxy functional groups on the condensed
products are useful for further derivatizations.
JPZ thanks the financial support from the National Nat-
ural Science Foundation of China (20772088), Jiangsu Key
Laboratory for Chemistry of Low-Dimensional Materials
(JSKC08055), and Jiangsu Higher Education Institutions of
China (08KJD150011). WZ thanks the support of UMass
Boston Healey grant.
Notes and references
1 (a) A. H. M. Raeymaekers, E. J. E. Freyne and G. C. Sanz, US patent
4859684, 1989; (b) C. Mahler, J. Verhelst and L. Denis, Cancer, 1993,
71, 1068.
2 H. D. Langtry and M. I. Wilde, Drugs, 1998, 56, 447.
3 V. K. Kapoor, Profiles of Drug Substances, Excipients and Related
Methodology, 1986, 16, 611.
4 J. S. Shindler, G. T. Finnerty, K. Towlso, K. Dolan, C. L. Davies and
J. D. Parkes, Br. J. Clin. Pharmacol., 1984, 18, 959.
Scheme 1 Proposed mechanism for the competitive pathways.
neither of them reacted with 1a because they could not form the
mono- or diimine intermediates. However, we observed that N-
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5 (a) N. R. Thimmegowda, S. N. Swamy, C. S. A. Kumar, Y. C. S.
Kumar, S. Chandrappa, G. W. Yip and K. S. Rangappa, Bioorg. Med.
Chem. Lett., 2008, 18, 432; (b) A. Gellis, H. Kovacic, N. Boufatah
and P. Vanelle, Eur. J. Med. Chem., 2008, 43, 1858.
6 (a) G. I. Shin, J. I. Lee and J. H. Kim, Bull. Korean Chem. Soc., 1996,
17, 29; (b) G. D. Zhu, V. B. Gandhi, J. C. Gong, S. C. Thomas, K.
Jarvis, J. Bouska, K. C. Marsh, S. H. Rosenberg, V. L. Giranda and
T. D. Penning, Bioorg. Med. Chem. Lett., 2008, 18, 3955.
10 (a) J. S. Yadav, B. V. S. Reddy, B. Eshwaraiah and K. Anuradha, Green
Chem., 2002, 4, 592; (b) S. K. De and R. A. Gibbs, Tetrahedron Lett.,
2005, 46, 1811; (c) C. W. Kuo, S. V. More and C. F. Yao, Tetrahedron
Lett., 2006, 47, 8523; (d) R. Varala, R. Enugala, S. Nuvula and S. R.
Adapa, Synlett, 2006, 1009; (e) R. Kumar, P. Chaudhary, S. Nimesh,
A. K. Verma and R. Chandra, Green Chem., 2006, 8, 519; (f) L. T.
An, F. Q. Ding, J. P. Zou and X. H. Lu, Synth. Commun., 2008, 38,
1259.
7 (a) A. Jager, V. Stefani, S. S. Guterres and A. R. Pohlmann,
Int. J. Pharm., 2007, 338, 297; (b) R. M. F. Batista, S. P. G. Costa, M.
Belsley and M. M. M. Raposo, Tetrahedron, 2007, 63, 9842; (c) M. M.
Henary, Y. G. Wu, J. Cody, S. Sumalekshmy, J. Li, S. Mandal and
C. J. Fahrni, J. Org. Chem., 2007, 72, 4784.
8 (a) Z. M. Zhou, W. F. Yu, J. Zhang, X. Q. Zhao and C. X. Yu,
J. Heterocycl. Chem., 2004, 41, 621; (b) B. V. S. Kumar, S. D. Vaidya,
R. V. Kumar, S. B. Bhirud and R. B. Mane, Eur. J. Med. Chem.,
2006, 41, 599; (c) S. Kaul, A. Kumar, B. Sain and A. K. Bhatnagar,
Synth. Commun., 2007, 37, 2457; (d) F. L. Ge, Z. X. Wang, W. Wan,
W. C. Vinodkumar, S. D. Vaidya, B. V. S. Kumar, U. N. Bhise, S. B.
Bhirud and U. C. Mashelkar, Eur. J. Med. Chem., 2008, 43, 986;
(e) A. M. Song, L. Wu, L. Ho and K. S. Lam, Tetrahedron, 2006, 62,
4393; (f) H. Sharghi, M. Aberi and M. M. Doroodmand, Adv. Synth.
Catal., 2008, 350, 2380; (g) H. Sharghi, M. H. Beyzavi and M. M.
Doroodmand, Eur. J. Org. Chem., 2008, 4126.
9 Selected most recent references, see: (a) A. A Mohammad, M. B.
Iraj, Z. Zahra and Y. H. Behrooz, Catal. Commun., 2008, 9, 2496;
(b) G. K. S. Prakash, H. Vaghoo, C. Panja, A. Molna´r, T. Mathew
and G. A. Olah, Synthesis, 2008, 897; (c) A. I. Moskalenko and V. I.
Boev, Russ. J. Org. Chem., 2009, 45, 1018; (d) H.-S. Huang, T.-C.
Chen, R.-H. Chen, K.-F. Huang, F.-C. Huang, J.-R. Jhan, C.-L.
Chen, C.-C. Lee, Y. Lo and J.-J. Lin, Bioorg. Med. Chem., 2009, 17,
7418.
11 (a) J. Borgulya, H. Bruderer, K. Bernauer, G. Zurcher and M.
Daprada, Helv. Chim. Acta, 1989, 72, 952; (b) S. V. Kolhe, A. G.
Doshi and A. W. Raut, Asian J. Chem., 2002, 14, 1050; (c) A.
Shaabani and A. Maleki, Chem. Pharm. Bull., 2008, 56, 79; (d) D.
Sherman, J. Kawakami, H. Y. He, F. Dhun, R. Rios, H. Liu,
W. T. Pan, Y. J. Xu, S. P. Hong, M. Arbour, M. Labelle and
M. A. J. Duncton, Tetrahedron Lett., 2007, 48, 8943; (e) B. Das, K.
Venkateswarlu, K. Suneel and A. Majhi, Tetrahedron Lett., 2007, 48,
5371.
12 (a) J. T. Kuethe, J. Varon and K. G. Childers, Tetrahedron, 2007, 63,
11489; (b) K. E. Davies, G. E. Domany, M. Farhat, J. A. L. Herbert,
A. M. Jefferson, M. D. G. Martin and H. Suschitzky, J. Chem. Soc.,
Perkin Trans. 1, 1984, 2465.
13 (a) For reactions of hexachloroacetone under microwave or sonica-
tion conditions, see: M. C. Rezende, E. L. Dall’Oglio and C. Zucco,
Tetrahedron Lett., 1996, 37, 5265; (b) M. C. Rezende, E. L. Dall’Oglio
and C. Zucco, Synth. Commun., 2001, 31, 607.
14 For a patent application of this work, see: J. Zou, G. Zhang
and L. An, Faming Zhuanli Shenqing Gongkai Shuomingshu, 2008
CN101314593A20081203.
15 (a) X. Q. Pan, J. P. Zou, Z. H. Huang and W. Zhang, Tetrahedron
Lett., 2008, 49, 5302; (b) J. J. Cai, J. P. Zou, X. Q. Pan and W. Zhang,
Tetrahedron Lett., 2008, 49, 7386.
16 F. Toda, Acc. Chem. Res., 1995, 28, 480.
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The Royal Society of Chemistry 2011
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