Page 3 of 4
ChemComm
DOI: 10.1039/C5CC02110C
30 effective oxidant in these transformations. This mild synthetic
method provides a highly attractive practical strategy in organic
synthesis, medicinal and material chemistry. Ongoing research
involves detail mechanism and further broadening the synthetic
scope of the methodology is currently underway in our
35 laboratory, and the results will be reported in due course.
We are grateful for the financial support from the National
natural Science Foundation of China (2117276 and
21420102003), the National Basic Research Program of China
40 (973 Program) (2011CB808600), the China Postdoctoral Science
Foundation Funded Project (2014M562165), and Guangdong
Natural Science Foundation (10351064101000000).
Scheme 2. Investigation into the reaction mechanism
According to the above experimental results and previous
reports,15 a plausible mechanism is illustrated in Scheme 3.
Firstly, benzamidine 1a was reacted with the acyl radical 6 which
was formed from the oxidation of toluene to generate the
intermediate 7 by a radical addition process. Subsequently, a
singleꢀelectronꢀoxidation process occurred to give intermediate 8.
10 Then, intermediate 4 was formed by losing a proton. Further, the
intermediate 4 was transformed to intermediate 9 by an enol
isomerization. Intermediate 9 was coordinated with copper
catalyst to give intermediate 10. Finally, with the release of H+,
intermediate 10 was converted to intermediate 11, which
15 underwent reductive elimination and afforded the desired product
3aa.
Notes and references
5
45 a School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, China. Fax: +86 20-87112906; Tel:
b Key laboratory of organo-pharmaceutical chemistry of Jiangxi province,
Gannan Normal University, Ganzhou, 341000, China
50 † Electronic Supplementary Information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
spectra for selected compounds. See DOI: 10.1039/b000000x/
1 (a) D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435; (b) A. Seed, Chem.
55
Soc. Rev., 2007, 36, 2046; (c) J. Boström, A. Hogner, A. Llinàs, E.
Wellner and A. T. Plowright, J. Med. Chem., 2012, 55, 1817. (d) C.ꢀG.
Zhen, Z.ꢀK. Chen, Q.ꢀE. Liu, Y.ꢀF. Dai, R. Y. C. Shin, S.ꢀY. Chang and
J. Kieffer, Adv. Mater., 2009, 21, 2425; (e) A. Pace and P. Pierro, Org.
Biomol. Chem., 2009, 7, 4337.
60 2 (a) J. T. Palmer, R. M. Rydzewski, R. V. Mendonca, D. Sperandio, J. R.
Spencer, B. L. Hirschbein, J. Lohman, J. Beltman, M. Nguyen and L.
Liu, Bioorg. Med. Chem. Lett., 2006, 16, 3434; (b) J. Garfunkle, C.
Ezzili, T. J. Rayl, D. G. Hochstatter, I. Hwang and D. L. Boger, J. Med.
Chem., 2008, 51, 4392.
65 3 (a) M. Farooqui, R. Bora and C.R. Patil, Eur. J. Med. Chem., 2009, 44,
794; (b) N. M. M. Bezerra, S. P. De Oliveira, R. M. Srivastava and J.
R. Da Silva, Il Farmaco, 2005, 60, 955; (c) M. A. WeidnerꢀWells, T.
C. Henninger, S. A. FragaꢀSpano, C. M. Boggs, M. Matheis, D. M.
Ritchie, D. C. Argentieri, M. P. Wachter and D. J. Hlasta, Bioorg. Med.
70
Chem. Lett., 2004, 14, 4307.
4 R. M. Jones, J. N. Leonard, D. J. Buzard and J. Lehmann, Expert Opin.
Ther. Pat., 2009, 19, 1339.
5 M. H. Gezginci, A. R. Martin and S. G. Franzblau, J. Med. Chem., 2001,
44, 1560.
75 6 (a) D. Kumar, G. Patel, E. O. Johnson and K. Shah, Bioorg. Med. Chem.
Lett., 2009, 19, 2739; (b) H.ꢀZ. Zhang, S. Kasibhatla, J. Kuemmerle, W.
Kemnitzer, K. OllisꢀMason, L. Qiu, C. CroganꢀGrundy, B. Tseng, J.
Drewe and S. X. Cai, J. Med. Chem., 2005, 48, 5215; (c) G. L. Khatik,
J. Kaur, V. Kumar, K. Tikoo and V. A. Nair, Bioorg. Med. Chem. Lett.,
80
85
90
95
2012, 22, 1912.
7 For selected examples, see: (a) K. Itoh, H. Sakamaki and C. A. Horiuchi,
Synthesis, 2005, 12, 1935; (b) Y. Wang, R. L. Miller, D. R. Sauer and S.
W. Djuric, Org. Lett., 2005, 7, 925; (c) D. Grant, R. Dahl and N. D. P.
Cosford, J. Org. Chem., 2008, 73, 7219; (d) J. K. Augustine, V.
Akabote, S. G. Hegde and P. Alagarsamy, J. Org. Chem., 2009, 74,
5640.
8 For selected examples, see: (a) K. K. D. Amarasinghe, M. B. Maier, A.
Srivastava and J. L. Gray, Tetrahedron Lett., 2006, 47, 3629; (b) M.
Adib, A. H. Jahromi, N. Tavoosi, M. Mahdavi and H. R. Bijanzadeh,
Tetrahedron Lett., 2006, 47, 2965; (c) B. Kaboudin and F. Saadati,
Tetrahedron Lett., 2007, 48, 2829; (d) B. Kaboudin and L. Malekzadeh,
Tetrahedron Lett., 2011, 52, 6424; (e) D. Suresh, K. Kanagaraj and K.
Pitchumani, Tetrahedron Lett., 2014, 55, 3678.
20
Scheme 3. Possible reaction mechanism
In conclusion, we have developed a novel straightforward
synthesis of 3,5ꢀdisubstitutedꢀ1,2,4ꢀoxadiazoles via copperꢀ
catalyzed amidines with methylarenes. This process involved acyl
radical formation and NꢀO/CꢀN/NꢀO bondsformation. The
25 reaction occupied good functional group methylarenes. In
16
addition, easily available amidines and low toxic, stable and
commercially available methylarenes were used as important
synthetic blocks. Moreover, inexpensive, safe, and
environmentally benign TBHP was also employed to be an
9 P. K. Gupta, M. K. Hussain, M. Asad, R. Kant, R. Mahar, S. K. Shukla
and K. Hajela, New J. Chem., 2014, 38, 3062.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3