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Green Chemistry
The aldehyde with alkyl chain also work well in this 35 method to construct benzimidazoles, which are ubiquitous
transformation. Furthermore, the steric hindrance in alkyl
structural units in a number of biological active compounds.
The catalyst and additive free condition, using air as oxidant
chain does not affect the efficiency (2h-2i, Table 3). In
addition, using molecular oxygen as oxidant, the efficiency of
this chemistry could be improved (entries 2, 3, 5-7, Table 3).
5
practical and attractive. Further studies to clearly understand
Unfortunately, the desired 2-aryl-benzimidazole 3ak was not 40 the reaction mechanism and the synthetic applications are
obtained when aromatic aldehyde was used as the substrate
under the optimal reaction conditions (entry 11, Table 3).
ongoing in our laboratory.
Financial support from National Basic Research Program of
China (973 Program 2009CB825300), National Science
Foundation of China (No. 21172006) and the State Key
45 Laboratory of Drug Research are greatly appreciated. We
thank Yizhi Yuan in this group for reproducing the results of
3ja and 3ae.
Notes and references
a
State Key Laboratory of Natural and Biomimetic Drugs, Peking
10
50 University, School of Pharmaceutical Sciences, Peking University, Xue
Yuan Rd. 38, Beijing 100191, China. Fax: (+86)-010-8280-5297; Tel:
(+86) 01082805297; E-mail: jiaoning@bjmu.edu.cn
Scheme 2. The preparation of dual inducible/neuronal nitric oxide
synthase (iNOS/nNOS) inhibitor.
b
State key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203, China
55 † Electronic Supplementary Information (ESI) available: See
DOI: XXXXXXXX
To test the feasibility of a large-scale reaction, the reaction
by taking 25 mmol of benzene-1, 2-diamine (1a) and
15 cyclopropanecarbaldehyde (2a) (37.5 mmol) was investigated.
The reaction could afford 3.28 g of 3aa in 83% yield by
recrystallization (Scheme 3). Therefore, this protocol could be
used as a practical method to synthesize the precursors of
some important bioactive molecule.
1
D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev. 2003,
108, 893.
60 2
(a) J. E. Payne, C. Bonnefous, K. T. Symons, P. M. Nguyen, M.
Sablad, N. Rozenkrants, Y. Zhang, L. Wang, N. Yazdani, A. K.
Shiau, S. A. Noble, P. Rix, T. S. Rao, C. A. Hassig and N. D. Smith,
J. Med. Chem. 2010, 53, 7739; (b) M. J. Tebbe, W. A. Spitzer, F.
Victor, S. C. Miller, C. C. Lee, T. R. Sattelberg, E. Mckinney and C.
J. Tang, J. Med. Chem. 1997, 40, 3937; (c) T. Roth, M. L.
Morningstar, P. L. Boyer, S. H. Hughes, R. W. Jr. Buckheit and C. J.
Michejda, J. Med. Chem. 1997, 40, 4199; (d) A. M. Palmer, V.
Chiesa, A. Schmid, G. Munch, B. Grobbel, P. J. Zimmermann, C.
Brehm, W. Buhr, W.-A. Simon, W. Kromer, S. Postius, J. Volz and
D. Hess, J. Med. Chem. 2010, 53, 3645.
air (1 atm), 36 h
room temperature
NH2
N
+
O
toluene (100 mL)
N
H
NH2
65
2a
1a
3aa
3.28 g (83%)
20
Scheme 3. The large-scale reaction: 1a (25 mmol), 2a (37.5 mmol) ,
toluene (100 mL), 25 oC, 36 h. Isolated yield by recrystallization.
70
3
For review see: (a) P. N. Preston, Chem. Rev, 1974, 74, 279; For
some selected examples in recent years, see: (b) Y. V. Tomilov, D.
N. Platonov, A. E. Frumkin, D. L. Lipilin and R. F. Salikov,
Tetrohedron Lett. 2010, 51, 5120; (c) J. M. Travins, R. C. Bernotas,
D. H. Kaufman, E. Quinet, P. Nambi, I. Feingold, C. Huselton, A.
Wilhelmsson, A. Goos-Nilsson and J. Wrobel, Bioorg. Med. Chem.
Lett. 2010, 20, 526; (d) M. Sime, A. C. Allan, P. Chapman, C.
Fieldhouse, G. M. P. Giblin, M. P. Healy, M. H. Lambert, L. M.
Leesnitzer, A. Lewis, R. V. Merrihew, R. A. Rutter, R. Sasse, B. G.
Shearer, T. M. Wilson, R. X. Xu and D. J. Virley, Bioorg. Med.
Chem. Lett. 2011, 21, 5568; (e) S.-C. Lee, D. Shin, J. M. Cho, S. Ro
and Y.-G. Suh Bioorg. Med. Chem. Lett. 2012, 22, 1891.
A plausible mechanism for the green and practical method
to construct benzimidazoles is illustrated in Scheme 4.
25 benzene-1, 2-diamine (1a) and cyclopropanecarbaldehyde (2a)
initially dehydrate to form imines (4).12 The intermediate 5 is
generated though the intramolecular 1,2-addition of
intermediate 4.13 Finally, the intermediate 5 is easily oxidized
by air to produce the desired product 3aa with H2O as the
30 byproduct.9
75
80
4
For some selected examples in recent years, see: (a) J. Peng, M. Ye,
C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang and C. Chen, J. Org.
Chem. 2011, 76, 716; (b) S. Gupta, P. K. Agarwal and B. Kundu,
Tetrahedron Lett. 2010, 51, 1887; (c) R.-G. Xing, Y.-N. Li, Q. Liu,
Q.-Y. Meng, J. Li, X.-X. Shen, Z. Liu, B. Zhou, X. Yao and Z.-L.
liu, Eur. J. Org. Chem. 2010, 6627. (d) X. Diao, Y. Wang, Y. Jiang
and D. Ma, J. Org. Chem. 2009, 74, 7974; (e) M. Shen and T. G.
Driver, Org. Lett. 2008, 10, 3367.
85
90
5
For some selected examples in recent years, see: (a) M. M. Heravi,
S. Sadjadi, H. Oskooie, R. H. Shoar and F. F. Bamoharram, Cata.
Commun. 2007, 9, 504; (b) V. K. Tandon and M. Kumar,
Tetrahedron Lett. 2004, 45, 4185; (c) K. Takeda, S. Yano, M. Sato
and E. Yoshii J. Org. Chem. 1987, 52, 4137; (d) S.-Y. Lin, Y. Isome,
E. Stewart, J.-F. Liu, D. Yohannes and L. Yu, Tetrohedron Lett.
2006, 47, 2883; (e) L. M. Dudd, E. Venardou, E. Garcia-Verdugo, P.
Licence, A. J. Blake, C. Wilson, M. Poliakoff, Green Chem., 2003,
5, 187.
95
Scheme 4. A proposed mechanism for the direct transformation.
In summary, we have demonstrated a green and practical
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