Page 5 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
pre-catalyst
Article
2
undergoes H-Cl liberation under the basic X-ray structures. The simplicity, wide substrate, and atom
DOI: 10.1039/C6OB01786J
condition to give the active catalyst 10. Then, O-H activation of economy of this process make it an attractive alternative
alcohol by the catalyst 10 results in the intermediate 11. β-H method for the preparation of α-alkylated amides and C3-
elimination followed by aldehyde dissociation gives the alkylated 3-hydroxyindolin-2-one.
intermediate 12 and free aldehyde. Next, the base-mediated
condensation of an aldehyde with the amide provides the
Acknowledgements
unsaturated amide
intermediate 12 to the β-carbon of the compound
9
.
The addition of Ru-H from the
results
This research was supported by the DST-SERB,
(EMR/2014/000700), India. M.B.C and G.S.B thank IISER-Pune,
for a research fellowship. P. K. thank, CSIR, for a research
fellowship. B.G thanks, IISER-Pune and MHRD-India for the
research support.
9
intermediate 13. The intermediate 13 may shift to the more
stable form 14 through the enolate coordination on the Ru-
centre. Perhaps, the addition of water to the C3-position of the
oxindole bound Ruthenium intermediate 14 and followed by
proton abstraction by Ru-centre affords the intermediate 12
which subsequently liberate molecular hydrogen to form the
active catalyst 10 To confirm the molecular hydrogen
,
Notes and references
.
1
(a) B. C. Challis and J. Challis, In The Chemistry of Amides; J. Zabicky,
Ed.; John Wiley & Sons: London, 1970; pp 731; (b) N. Sewald and H-D.
Jakubke, Peptides: Chemistry and Biology, 2002, Wiley-VCH,
Weinheim, Germany; (c) B. L. Bray, Large-scale manufacture of peptide
liberation, the gaseous component of the reaction mixture was
examined. The GC analysis showed the formation of H2.
Further investigation on the mechanism is in under progress in
our laboratory.
therapeutics by chemical synthesis, Nat. Rev. Drug Discov. 2003,
2,
587. (d) V. Andrushko and N. Andrushko, Stereoselective synthesis of
drugs and natural Products; John Wiley & Sons: New Jersey, 2013;
volume 1, pp 183. (e) R. Mahrwald, Modern methods in stereoselective
Aldol
reactions,
Wiley-VCH,
Weinheim,
Germany.
doi: 10.1002/9783527656714.ch2.
2
(a) S. Peddibhotla, Curr. Bioact. Compd., 2009, 5, 20; (b) Lin, S. ; B. H.
B. Kwok, M. Koldobskiy, C. M.Crews and S. J. Danishefsky, J. Am.
Chem. Soc., 2004, 126, 6347; (c) B. K. Albrecht and R. M. Williams,
Proc. Natl. Acad. Sci., 2004, 101, 11949.
3
Selected reviews for classical reactions, see: (a) J-i. Matsuo and M.
Murakami, Angew. Chem. Int. Ed., 2013, 52, 9109; (b) G. Casiraghi, L.
Battistini, C. Curti, G. Rassu and F. Zanardi, Chem. Rev., 2011, 111
,
3076; (c) C. Palomo, M. Oiarbide and J. M. Garcia, Chem. Soc. Rev.,
2004, 33, 65.
4
Selected examples of classical reactions, see: (a) S. G. Davies, C. J.
Goodwin, D. Hepworth, P.M. Roberts and J. E. Thomson, J. Org.
Chem., 2010, 75, 1214; (b) H. Kim, H. Lee, D. Lee, S. Kim and D. Kim,
J. Am. Chem. Soc., 2007, 129, 2269; (c) D. A. Evans, C. W. Downey
and J. L. Hubbs, J. Am. Chem. Soc., 2003, 125, 8706; (d) C. O’Donnell,
W. L. Zhou and J. Scott, J. Am. Chem. Soc., 1996, 118, 6070.
Selected reviews for acylation using alcohols, see: (a) F. Huang, Z. Liu
and Z. Yu, Angew. Chem. Int. Ed., 2016, 55, 862; (b) C. Gunanathan
and D. Milstein, Science., 2013, 341, 1229712; (c) C. L. Allen and J. M.
J. Williams, Chem. Soc. Rev., 2011, 40, 3405; (d) V. R. Pattabiraman
and J. W. Bode, Nature., 2011, 480, 471.
5
6
7
Selected reviews for alkylation using alcohols, see: (a) E. Elangovan, J-
B. Sortais, M. Beller and C. Darcel, Angew. Chem. Int., Ed. 2015, 54
14483. (b) Y. Obora, ACS Catal., 2014, 4, 3972; (c) S. Pan and T.
Shibata, ACS Catal., 2013, , 704; (d) S. Bähn, S. Imm, L. Neubert, M.
Zhang, H. Neumann and M. Beller, ChemCatChem., 2011, , 1853.
,
Figure 4. Plausible mechanism for the formation of C3-hydroxy-2-oxindole
3
3
In conclusion, Ru-PNN catalyzed direct α-alkylation of amides
using alcohols as the alkylating partner was efficiently
achieved via dehydrogenation-condensation-hydrogenation
steps under simple reaction conditions with high TON. Unlike
the other Ru-catalyst, phosphine based pincer complex
exhibited effective catalytic function for α-alkylation reactions
of several amides with a wide variety of alcohols. A new
approach was discovered for the synthesis of C3-hydroxy 2-
oxindole directly from 2-oxindole using alcohol and Ru-PNN
catalyst without the use of any oxidant. This reaction was
facilitated via double functionalization (C3-alkylation and C3-
hydroxylation) in one step with a high TON. Moreover, these
products are unambiguously characterized and supported By
Selected example for borrowing hydrogen concept, see: (a) G. Zhang,
Z. Yin and S. Zheng, Org. Lett., 2016, 18 , 300; (b) R. Wang, J. Ma and
F. Li, J. Org. Chem., 2015, 80, 10769; (c) K. O. Marichev and J. M.
Takacs, ACS Catal., 2016, 6, 2205; (d) J. Leonard, A. J. Blacker, S. P.
Marsden, M. F. Jones, K. R. Mulholland and R. Newton, Org. Process
Res. Dev., 2015, 19, 1400; (e) T. Kuwahara, T. Fukuyama and I. Ryu,
Org. Lett., 2012, 14, 4703; (f) T. Fukuyama, H. Okamoto and I. Ryu,
Chem. Lett., 2011, 40, 1453; (g) T. Sawaguchi and Y. Obora, Chem.
Lett., 2011, 40, 1055; (h) B. Blank and R. Kempe., J. Am. Chem.
Soc., 2010, 132, 924; (i) G. Onodera, Y. Nishibayashi and S. Uemura,
Angew. Chem. Int. Ed., 2006, 45, 3819; (j) Y. Iuchi, Y. Obora and Y.
Ishii, J. Am. Chem. Soc., 2010, 132, 2536; (k) L. Guo, X. Ma, H Fang, X.
Jia and Z. Huang, Angew. Chem. Int. Ed., 2015, 54, 4023; (l) C.
Schlepphorst, B. Maji and F. Glorius, ACS Catal., 2016, DOI:
10.1021/acscatal.6b01351.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins