Ruthenium-catalyzed C-H bond oxygenations with weakly coordinating ketones

Article abstract of DOI:10.1021/ol302956s

Ruthenium complexes enabled first C(sp²)-H bond oxygenations of aromatic ketones with excellent functional group tolerance, and broad scope as well as high chemoselectivity and site selectivity.

Full text of DOI:10.1021/ol302956s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ruthenium-Catalyzed CꢀH Bond
Oxygenations with Weakly Coordinating
Ketones
Vedhagiri S. Thirunavukkarasu and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received October 26, 2012
ABSTRACT
Ruthenium complexes enabled first C(sp2)ꢀH bond oxygenations of aromatic ketones with excellent functional group tolerance, and broad scope
as well as high chemoselectivity and site selectivity.
Catalyzed functionalizations of unreactive CꢀH bonds
have been recognized as valuable tools for step-economical
syntheses of organic compounds.1 Direct oxygenation
reactions are particularly attractive, and palladium(II)
complexes have emerged as arguably the most versatile
catalysts,2 with recent progress being accomplished by
inter alia Sanford and Yu.3 Despite these advances, CꢀH
bond oxygenations of substrates bearing only weakly
coordinating directing groups continue to be challenging.1ꢀ3
Hence, directC(sp2)ꢀH bond oxygenations of aryl ketones
have thus far proven elusive, because ketones are poor
ligands for palladium(II), and, therefore, are generally
ineffective directing groups for palladium(II/IV)-catalyzed
CꢀH bond oxygenations.3m,4 In order to address these
limitations O-acetyl oximes were utilized in lieu of ketones,
serving as transformable directing groups for palladium-
catalyzed CꢀH bond functionalizations.4
As ofyet, rather inexpensive ruthenium5 complexes have
been underappreciated for C(sp2)ꢀH6 oxygenation reac-
tions. However, we7 and Rao8 very recently developed site-
selective hydroxylations of unactivated C(sp2)ꢀH bonds
in aromatic amides and esters. Within our research pro-
gram on sustainable CꢀH bond functionalizations,9 we
now developed the first CꢀH bond oxygenation of arenes
with weakly coordinating ketones, on which we report herein.
Notably, the thus obtained hydroxylated aryl ketones are
(1) Illustrative recent reviews: (a) Neufeldt, S. R.; Sanford, M. S.
Acc. Chem. Res. 2012, 45, 936–946. (b) Engle, K. M.; Mei, T.-S.; Wasa,
M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (c) Song, G.; Wang, F.;
Li, X. Chem. Soc. Rev. 2012, 41, 3651–3678. (d) Wencel-Delord, J.;
(3) Selected examples: (a) Jiang, T.-S.; Wang, G.-W. J. Org. Chem.
2012, 77, 9504–9509. (b) McMurtrey, K. B.; Racowski, J. M.; Sanford,
M. S. Org. Lett. 2012, 14, 4094–4097. (c) Li, W.; Sun, P. J. Org. Chem.
2012, 77, 8362–8366. (d) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org.
Lett. 2012, 14, 3724–3727. (e) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2012, 134, 134–137. (f) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Chem.;
Eur. J. 2012, 18, 5541–5545. (g) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q. Org.
Lett. 2010, 12, 2511–2513. (h) Gou, F.-R.; Wang, X.-C.; Huo, P.-F.; Bi,
H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett. 2009, 11, 5726–5729. (i)
Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654–14655. (j)
Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 6790–6791. (k) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 12790–12791. (l) Giri, R.; Liang, J.; Lei, J.-G.; Li,
J.-J.; Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 7420–7424. (m) Desai, L. V.;
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542–9543. (n)
Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300–2301. (o) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996,
108, 35–40 and references cited therein.
€
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740–4761. (e)
Ackermann, L. Chem. Rev. 2011, 111, 1315–1345. (f) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–5083. (g)
Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–11222. (h)
Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503–
4513. (i) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84. (j) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (k)
Livendahl, M.; Echavarren, A. M. Isr. J. Chem. 2010, 50, 630–651. (l)
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9792–9826. (m) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15,
5874–5883 and references cited therein.
(2) Recent reviews on C(sp2)ꢀO bond forming reactions: (a) Enthaler,
S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912–4924. (b) Alonso, D. A.;
Najera, C.; Pastor, I. M.; Yus, M. Chem.;Eur. J. 2010, 16, 5274–5284.
(c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169 and
references cited therein.
r
10.1021/ol302956s
XXXX American Chemical Society

key structural motifs in bioactive compounds and repre-
sent versatile intermediates in organic synthesis.10
Table 1. Optimization of CꢀH Bond Oxygenation with Ketone 1aa
We initiated our studies by probing various sacrificial
oxidants and ruthenium complexes for the envisioned
oxygenation of ketone 1a (Table 1). Not surprisingly, in
the absence of a ruthenium complex or an oxidant the
desired CꢀH bond oxygenation was not observed (entries
1 and 2). Among a variety of terminal oxidants, oxone,
K2S2O8, and hypervalent iodine(III) reagents furnished
product 2a, with PhI(OAc)2 being most effective (entries
3ꢀ10). Ruthenium complexes in various oxidation states
served as efficient catalysts (entries 11ꢀ15), and particu-
larly promisingresults wereaccomplishedwith inexpensive
[RuCl3(H2O)n]11 as well as [Ru(O2CMes)2(p-cymene)].12
entry
[Ru]
oxidant
yield (%)
1
2
3
4
5
6
7
8
9
ꢀ
PhI(OAc)2
ꢀ
[Ru(O2CMes)2(p-cymene)] (5.0)
ꢀ
ꢀ
[Ru(O2CMes)2(p-cymene)] (5.0) O2
ꢀ
[Ru(O2CMes)2(p-cymene)] (5.0) Cu(OAc)2 H2O
ꢀ
3
[Ru(O2CMes)2(p-cymene)] (5.0) t-BuOOH
[Ru(O2CMes)2(p-cymene)] (5.0) oxone
[Ru(O2CMes)2(p-cymene)] (5.0) K2S2O8
[Ru(O2CMes)2(p-cymene)] (5.0) PhI(OAc)2
[Ru(O2CMes)2(p-cymene)] (5.0) PhI(TFA)2
ꢀ
46
47
86
85
87
84
83
54
84
85
(4) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532–535.
(5) For selected recent examples of carboxylate assistance in
ruthenium(II)-catalyzed oxidative CꢀH bond functionalizations, see:
(a) Li, J.; Kornhaass, C.; Ackermann, L. Chem. Commun. 2012, 48,
11343–11345. (b) Kornhaass, C.; Li, J.; Ackermann, L. J. Org. Chem.
2012, 77, 9190–9198. (c) Li, B.; Devaraj, K.; Darcel, C.; Dixneuf, P. H.
Green Chem. 2012, 14, 2706–2709. (d) Thirunavukkarasu, V. S.; Donati,
M.; Ackermann, L. Org. Lett. 2012, 14, 3416–3419. (e) Kishor, P.;
Jeganmohan, M. Org. Lett. 2012, 14, 1134–1137. (f) Li, B.; Ma, J.;
Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14, 736–739. (g)
Hashimoto, Y.; Ortloff, T.; Hirano, K.; Satoh, T.; Bolm, C.; Miura, M.
Chem. Lett. 2012, 41, 151–153. (h) Chinnagolla, R. K.; Jeganmohan, M.
Chem. Commun. 2012, 48, 2030–2032. (i) Ackermann, L.; Pospech, J.;
Graczyk, K.; Rauch, K. Org. Lett. 2012, 14, 930–933. (j) Ackermann, L.;
Lygin, A. V. Org. Lett. 2012, 14, 764–767. (k) Ackermann, L.; Wang, L.;
Lygin, A. V. Chem. Sci. 2012, 3, 177–180. (l) Hashimoto, Y.; Ueyama,
T.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2011, 40,
1165–1166. (m) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548–
6551. (n) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–4155. (o)
Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett. 2011, 13, 3278–
3281. (p) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2011, 13, 706–708. (q) Ackermann, L.; Lygin,
A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379–6382. (r)
10 [Ru(O2CMes)2(p-cymene)] (5.0) PhI(OPiv)2
11
[RuCl2(p-cymene)]2 (2.5)
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
12 [RuCl3(H2O)n] (5.0)
13 [Ru2(hp)4Cl] (5.0)
14 [Ru2(OAc)4Cl] (5.0)
15 [Ru(O2CMes)2(p-cymene)] (2.5) PhI(OAc)2
a Reaction conditions: 1a (1.0 mmol), oxidant (1.2 equiv), cat. [Ru],
TFA/TFAA (2.5 mL; 3/2), 22 h, isolated yields.
With an effective catalytic system in hand, we tested the
influence of the ketone substitution pattern on the CꢀH
bond oxygenation (Scheme 1). While acetophenone (1b)
and isobutyrophenone (1c) gave unsatisfactory results,
benzophenone (1d) led to the mono- and dihydroxy-
lated products 2d (28%) and 2d0 (57%) in high isolated
yields. In contrast, annulated ketone 1e was chemose-
lectively oxygenated at the C(sp3)ꢀH bond to deliver
mono-R-hydroxylated ketone 2e as the sole product;a
reaction that also occurred in the absence of the metal
catalyst (64% yield).
ꢀ
Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K.
Synthesis 2010, 2245–2253. (s) A recent review: Kozhushkov, S. I.;
Ackermann, L. Chem. Sci. 2012, DOI:10.1039/C2SC21524A.
(6) Selected examples of ruthenium-catalyzed oxygenations of
C(sp3)ꢀH bonds with lower dissociation energies: (a) McNeill, E.; Du
Bois, J. Chem. Sci. 2012, 3, 1810–1813. (b) 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.
(7) Thirunavukkarasu, V. S.; Hubrich, J.; Ackermann, L. Org. Lett.
2012, 14, 4210–4213.
(8) Yang, Y.; Lin, Y.; Rao, Y. Org. Lett. 2012, 14, 2874–2877.
(9) For recent reviews, see: (a) Kozhushkov, S. I.; Potukuchi, H. K.;
Ackermann, L. Catal. Sci. Technol. 2012, DOI:10.1039/C2CY20505J.
(b) Ackermann, L. Isr. J. Chem. 2010, 50, 652–663. (c) Ackermann, L.
Pure Appl. Chem. 2010, 82, 1403–1413.
Scheme 1. Variation of the Ketone Substitution Pattern
€
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T. J.; Skaltsa, H.; Heilmann, J. J. Nat. Prod. 2012, 75, 1697–1705. (b)
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Am. Chem. Soc. 2012, 134, 15285–15288. (d) Wein, A. N.; Williams,
B. N.; Liu, S.; Ermolinsky, B.; Provenzano, D.; Abagyan, R.; Orry, A.;
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ꢀ
1993, 261, 212–215. (f) Kollar, L., Ed. Modern Carbonylation Methods;
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Weinheim, 2010. (h) Reetz, M. T. J. Org. Chem. 2009, 74, 5767–5778.
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tionalizations: (a) Simon, M.-O.; Genet, J.-P.; Darses, S. Org. Lett.
2010, 12, 3038–3041. (b) McNeill, E.; Du Bois, J. J. Am. Chem. Soc.
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Born, R. Synlett 2007, 2833–2836.
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tions or arylations, see: (a) Ackermann, L.; Pospech, J.; Potukuchi,
H. K. Org. Lett. 2012, 14, 2146–2149. (b) Ackermann, L.; Vicente, R.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Subsequently, we explored the versatility of the CꢀH
bond oxygenation with various para-substituted tert-butyl
ketones 1 (Scheme 2). We were delighted to find that the
ruthenium(II) catalyst proved tolerant of valuable electro-
philic functional groups, including fluoro, chloro, bromo,
or iodo substituents.
Scheme 2. Scope of CꢀH Oxygenation of Aromatic
Ketones 1
Intramolecular competition experiments with meta-
substituted arenes 1mꢀ1p revealed steric interactions to
primarily influence the site selectivity of the CꢀH bond
functionalization process (Scheme 3). In contrast, only
meta-chloro-substituted arene 1q furnished significant
amounts of product 2q00 through oxygenation of the more
sterically hindered CꢀH bond.
The oxygenation of substrate 1r clearly highlighted the
superior directing group ability of the tert-butyl ketone as
compared to an ester moiety (Scheme 4).13
Scheme 4. Competitive Directing Group Abilities
In consideration of the remarkable catalytic activity and
chemoselectivity exerted by the ruthenium complex, we
performed initialmechanistic studiestounravel its mode of
action. To this end, intermolecular competition experiments
Scheme 3. Oxygenations with meta-Substituted Ketones 1
Scheme 5. Intermolecular Competition Experiments
Org. Lett., Vol. XX, No. XX, XXXX
C

In summary, we have disclosed the first catalyzed C(sp2)ꢀ
H bond oxygenations of arenes bearing weakly coordinating
ketones. The intermolecular oxidative CꢀO bond forming
reactions were achieved with oxone, K2S2O8, or PhI(OAc)2
as the terminal oxidant and inexpensive [RuCl3(H2O)n] or
well-defined [Ru(O2CMes)2(p-cymene)] as the catalyst.
Thereby, highly efficient C(sp2)ꢀH bond hydroxylations
proved viable with excellent functional group tolerance and
ample scope.
Scheme 6. Intramolecular Competition Experiment
Acknowledgment. Generous support by the Alexander
von Humboldt Foundation (fellowship to V.S.T.) and the
European Research Council under the European Commu-
nity’s Seventh Framework Program (FP7 2007ꢀ2013)/ERC
Grant Agreement No. 307535 is gratefully acknowledged.
showed electron-rich ketones 1 to be preferentially func-
tionalized (Scheme 5 and Supporting Information).
Furthermore, an intramolecular competition experi-
ment with diaryl ketone 1s highlighted the electron-rich
arene to more readily undergo the direct oxygenation
reaction (Scheme 6).
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Formation of another isomer was not observed by 1H NMR
spectroscopic analysis of the crude reaction mixture.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX