ORGANIC
LETTERS
Ruthenium-Catalyzed Oxidative C(sp2)ꢀH
Bond Hydroxylation: Site-Selective CꢀO
Bond Formation on Benzamides
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Vol. XX, No. XX
000–000
Vedhagiri S. Thirunavukkarasu, Jonathan Hubrich, and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Received July 9, 2012
ABSTRACT
Well-defined ruthenium carboxylate complexes enabled unprecedented ruthenium-catalyzed C(sp2)ꢀH hydroxylations on benzamides with
PhI(OAc)2 as the oxidant at a remarkably low catalyst loading of 1.0 mol %.
Metal-catalyzed oxidative CꢀH bond functionalizations1
significantly improve the step economy in organic synthesis
by avoiding the preparation of prefunctionalized starting
materials.2 Particularly, rather inexpensive ruthenium3 com-
plexes have recently emerged as increasingly viable tools
for oxidative annulations of alkynes through site-selective
CꢀH/HetꢀH bond functionalizations.4 For instance, de-
tailed mechanistic insight into the importance of carbox-
ylate assistance for the key CꢀH bond activation step5 set
the stage for oxidative annulations of alkynes by carboxylic
acids via challenging cleavages of otherwise inert CꢀH bonds
(Scheme 1a).6 Thus, we showed that oxidative CꢀH/OꢀH
bond functionalizations occurred via cascade reactions con-
sisting of an initial CꢀH bond activation, along with a
difficult CꢀO bond forming reductive elimination.6a,b Dur-
ing studies on the working mode of our catalytic system, we
found that a simple change of the terminal oxidant resulted in
a significantly altered chemoselectivity, in that an intermole-
cular C(sp2)ꢀH7 hydroxylation proved viable (Scheme 1b).
The thus-obtained hydroxylated arenes are valuable
intermediates in synthetic chemistry, which were thus far
largely accessed through metal-catalyzed cross-coupling
(1) Illustrative recent reviews on CꢀH bond functionalizations:
(a) Acc. Chem. Res. 2012, 45, Special Issue 6 00CꢀH Functionalization00.
(b) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177–185. (c) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292. (d) Wencel-
€
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
4740–4761. (e) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem.
2010, 8, 4503–4513. (f) Chem. Rev. 2010, 110, Special Issue 2 “Selective
Functionalization of CꢀH Bonds”. (g) Boutadla, Y.; Davies, D. L.;
Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans. 2009,
5820–5831 and references cited therein.
(2) (a) Zhu, C.; Wang, R.; Falck, J. R. Chem.;Asian J. 2012, 1502–
1514. (b) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651–
3678. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068–5083. (d) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16,
11212–11222.
(3) (a) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413.
(b) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–229.
(4) Selected examples: (a) Thirunavukkarasu, V. S.; Donati, M.;
Ackermann, L. Org. Lett. 2012, 14, 3416–3419. (b) Kishor, P.; Jegan-
mohan, M. Org. Lett. 2012, 14, 1134–1137. (c) Li, B.; Ma, J.; Wang, N.;
Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14, 736–739. (d) Ackermann,
L.; Lygin, A. V. Org. Lett. 2012, 14, 764–767. (e) Ackermann, L.; Wang,
L.; Lygin, A. V. Chem. Sci. 2012, 3, 177–180. (f) Hashimoto, Y.;
Ueyama, T.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2011, 40, 1165–1166. (g) Ackermann, L.; Fenner, S. Org. Lett.
2011, 13, 6548–6551. (h) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278–3281. (i) Ackermann, L.; Lygin, A. V.;
Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379–6382.
(5) Reviews: (a) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
(b) Ackermann, L. Chem. Commun. 2010, 46, 4866–4877. (c) Ackermann,
L.; Vicente, R; Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
(6) (a) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–4155. (b)
Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Org. Lett. 2012, 14,
930–933. See also: (c) Chinnagolla, R. K.; Jeganmohan, M. Chem.
Commun. 2012, 48, 2030–2032.
(7) Selected representative examples of ruthenium-catalyzed hydroxyla-
tions of C(sp3)ꢀH bonds with lower dissociation energies: (a) McNeill, E.;
Du Bois, J. Chem. Sci. 2012, 3, 1810–1813. (b) Harvey, M. E.; Musaev,
D. G.; Du Bois, J. J. Am. Chem. Soc. 2011, 133, 17207–17216. (c) Milczek,
E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825–6828. (d)
Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M. Angew.
Chem., Int. Ed. 2002, 41, 3465–3468 and references cited therein.
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10.1021/ol3018819
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