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ChemComm
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COMMUNICATION
Journal Name
D. Willcox, B. G. N. Chappell, K. F. Hogg, J. Calleja, A. P.
S. Ye, W. Yang, T. Coon, D. Fanning, T.DNOeIu: 1b0e.1r0t,39D/.CS7tCaCm0o56s04D
and J.-Q. Yu, Chem. Eur. J., 2016, 22, 4748.
For recent reviews, see: (a) K. E. Gettys, Z. Ye and M. Dai,
Synthesis, 2017, 49, 2589; (b) Z. Ye, K. E. Gettys and M. Dai,
Beilstein J. Org. Chem., 2016, 12, 702.
(a) J. D. Firth, P. O’Brien and L. Ferris, J. Am. Chem. Soc.,
2016, 138, 651; (b) G. Gelardi, G. Barker, P. O’Brien and D. C.
Blakemore, Org. Lett., 2013, 15, 5424; (c) S. P. Robinson, N.
S. Sheikh, C. A. Baxter and I. Coldham, Tetrahedron Lett.,
2010, 51, 3642; (d) B. P. McDermott, A. D. Campbell and A.
Ertan, Synlett, 2008, 875; (e) M. Berkheij, L. van der Sluis, C.
Sewing, D. J. den Boer, J. W. Terpstra, H. Hiemstra, W. I. I.
Bakker, A. van den Hoogenband and J. H. van Maarseveen,
Tetrahedron Lett., 2005, 46, 2369.
5
6
7
may be converted to the corresponding iminium intermediate
Smalley and M. J. Gaunt, Science, 2016, 354, 851.
I
in the presence of ruthenium catalyst via hydrogen transfer.
The intermediate would then give azomethine ylide II along
I
with ruthenium hydride species, after hydrogen abstraction.
The presence of acid might promote the formation of enamine
intermediate III, which would attack the carbonyl group to give
intermediate IV. This would then undergo aromatization via
dehydration to afford intermediate
it could be reduced by the ruthenium hydride species to
furnish the piperazine fused indole
8
V, and the iminium part of
2
.
In conclusion, we have developed an unprecedented
ruthenium catalyzed β-C(sp3)−H functionalization on the
'privileged'
piperazine
nucleus.
Ruthenium-catalyzed
dehydrogenation and hydrogen auto-transfer process appears
to be the key for this successful transformation. This protocol
complements the few available catalytic methods for α-
C(sp3)−H functionalization of piperazines. Various piperazine
fused indole derivatives have been synthesized using the
presented method. The optimized method enabled the gram
scale synthesis of a representative piperazine fused indole
derivative. Explorations are underway on the intermolecular β-
C(sp3)−H functionalization using different coupling partners on
piperazine and related systems using well-defined ruthenium
catalysts.
9
(a) P. R. Payne, P. Garcia, P. Eisenberger, J. C.-H. Yim and L. L.
Schafer, Org. Lett., 2013, 15, 2182; (b) Y. Ishii, N. Chatani, F.
Kakiuchi and S. Murai, Organometallics, 1997, 16, 3615.
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Sci., 2014, 5, 4173; (c) A. McNally, C. K. Prier and D. W. C.
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11 S. Röver, D. R. Adams, A. Bénardeau, J. M. Bentley, M. J.
Bickerdike, A. Bourson, I. A. Cliffe, P. Coassolo, J. E. P.
Davidson, C. T. Dourish, P. Hebeisen, G. A. Kennett, A. R.
Knight, C. S. Malcolm, P. Mattei, A. Misra, J. Mizrahi, M.
Muller, R. H. P. Porter, H. Richter, S. Taylor and S. P. Vickers,
Bioorg. Med. Chem. Lett., 2005, 15, 3604.
We thank the Indo-French Centre for the Promotion of
Advanced Research (CEFIPRA/IFCPAR No. 5105-4) for financial
support. VM thanks UGC, New Delhi for financial support. ARS
thanks CEFIPRA for financial support.
12 (a) Z. Fan, Z.-H. Sun, Z. Liu, Y.-C. Chen, H.-X. Liu, H.-H. Li and
W.-M. Zhang, Mar. Drugs, 2016, 14, 164; (b) S. Soldatouab
and B. J. Baker, Nat. Prod. Rep., 2017, 34, 585.
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Zhao, Y. Zheng and L. Zhuang, World Patent, 2003,
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Bruneau, Angew. Chem. Int. Ed., 2012, 51, 8876.
Notes and references
1
For recent selected reviews on C(sp3)−H activation-
functionalization, see: (a) H. Yi, G. Zhang, H. Wang, Z. Huang,
J. Wang, A. K. Singh and A. Lei, Chem. Rev., 2017, 117, 9016;
(b) J. He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Q. Yu, Chem.
Rev., 2017, 117, 8754; (c) H. M. L. Davies and D. Morton, J.
Org. Chem., 2016, 81, 343; (d) W. Zhang, N.-X. Wang and Y.
Xing, Synlett, 2015, 26, 2088; (e) C. Bruneau, Top.
Organomet. Chem., 2014, 48, 195; (f) G. Rouquet and N.
Chatani, Angew. Chem. Int. Ed., 2013, 52, 11726.
2
For some reviews C(sp3)−H functionalization on the α-carbon
to nitrogen, see: (a) M.-X. Cheng and S.-D. Yang, Synlett,
2017, 28, 159; (b) Y. Qin, J. Lv and S. Luo, Tetrahedron Lett.,
2014, 55, 551; (c) E. A. Mitchell, A. Peschiulli, N. Lefevre, L.
Meerpoel and B. U. W. Maes, Chem. Eur. J., 2012, 18, 10092;
(d) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (e) H. M. L. Davies
and J. R. Manning, Nature, 2008, 451, 417; (f) K. R. Campos,
Chem. Soc. Rev., 2007, 36, 1069; (g) S.-I. Murahashi, Angew.
Chem. Int. Ed. Engl., 1995, 34, 2443.
3
4
(a) Z. Tan, H. Jiang and M. Zhang, Org. Lett., 2016, 18, 3174;
(b) C. He and M. J. Gaunt, Angew. Chem. Int. Ed., 2015, 54
15840; (c) J. Shen, D. Cai, C. Kuai, Y. Liu, M. Wei, G. Cheng
and X. Cui, J. Org. Chem., 2015, 80, 6584; for a review on
,
remote sp2 C−H functionalization, see: (c) J. Li, S. D. Sarkar
and L. Ackermann, Top. Organomet. Chem., 2016, 55, 217.
(a) B. Sundararaju, M. Achard, G. V. M. Sharma and C.
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Z. Sahli, B. Sundararaju, M. Achard, Z. Kabouche, H. Doucet
and C. Bruneau, J. Org. Chem., 2012, 77, 3674; (c) I. Ozdemir,
S. D. Dusunceli, N. Kaloglu, M. Achard and C. Bruneau, J.
Organomet. Chem., 2015, 799-800, 311; (d) F. Jiang, M.
Achard and C. Bruneau, Chem. Eur. J., 2015, 21, 14319.
4 | J. Name., 2012, 00, 1-3
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