Ortho-and para-selective ruthenium-catalyzed C(sp2)-H oxygenations of phenol derivatives

Article abstract of DOI:10.1021/ol401535k

Versatile ruthenium catalysts allowed for efficient direct oxygenations of aryl carbamates under remarkably mild reaction conditions. In addition to chelation-assisted C-H activation, the optimized ruthenium catalyst proved amenable to para-selective hydroxylations of anisoles without Lewis basic directing groups.

Full text of DOI:10.1021/ol401535k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ortho- and Para-Selective Ruthenium-
Catalyzed C(sp2)ÀH Oxygenations of
Phenol Derivatives
Weiping Liu and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstr. 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received May 31, 2013
ABSTRACT
Versatile ruthenium catalysts allowed for efficient direct oxygenations of aryl carbamates under remarkably mild reaction conditions. In addition
to chelation-assisted CÀH activation, the optimized ruthenium catalyst proved amenable to para-selective hydroxylations of anisoles without
Lewis basic directing groups.
The catalytic direct oxygenation of otherwise unreactive
C(sp2)ÀH bonds represents the most step-economical
approach to substituted phenols.1,2 While palladium com-
plexes have proven to be useful catalysts for direct CÀO
bond formations,3 a very recent success was accomplished
with versatile ruthenium(II)4 catalysts. Hence, arenes
bearing weakly coordinating directing groups, such as
amides, esters, or ketones, were efficiently converted into
the corresponding phenol derivatives.5 While these studies
constituted notable progress in the direct oxygenation of
electron-deficient substrates bearing electron-withdrawing
directing groups, ruthenium(II)-catalyzed direct CÀH
bond oxygenations of phenol derivatives have as of yet
proven elusive, despite the practical importance of
phenols in medicinal chemistry, organic synthesis, material
(3) Recent progress and selected pioneering studies: (a) Yan, Y.;
Feng, P.; Zheng, Q.-Z.; Liang, Y.-F.; Lu, J.-F.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2013, 52, 5827–5831. (b) Mo, F.; Trzepkowski, L. J.;
Dong, G. Angew. Chem., Int. Ed. 2012, 51, 13075–13079. (c) Shan, G.;
Yang, X.; Ma, L.; Rao, Y. Angew. Chem., Int. Ed. 2012, 51, 13070–
13074. (d) Jiang, T.-S.; Wang, G.-W. J. Org. Chem. 2012, 77, 9504–9509.
(e) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett. 2012,
14, 4094–4097. (f) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134,
134–137. (g) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
14654–14655. (h) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790–6791. (i) Dick, A. R.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790–12791. (j) 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. (k) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 2300–2301. (l) Yoneyama, T.; Crabtree, R. H. J. Mol.
Catal. A 1996, 108, 35–40.
(4) Recent reviews on ruthenium(II)-catalyzed CÀH bond functio-
nalization: (a) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744–
5767. (b) Ackermann, L. Acc. Chem. Res. 2013, 46, DOI:10.1021/
ar3002798. (c) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem.
Rev. 2012, 112, 5879–5918. (d) Ackermann, L.; Vicente, R. Top. Curr.
Chem. 2010, 292, 211–229.
(5) (a) Shan, G.; Han, X.; Lin, Y.; Yu, S.; Rao, Y. Org. Biomol. Chem.
2013, 11, 2318–2322. (b) Yang, F.; Ackermann, L. Org. Lett. 2013, 15,
718–720. (c) Thirunavukkarasu, V. S.; Ackermann, L. Org. Lett. 2012,
14, 6206–6209. (d) Thirunavukkarasu, V. S.; Hubrich, J.; Ackermann, L.
Org. Lett. 2012, 14, 4210–4213. (e) Yang, Y.; Lin, Y.; Rao, Y. Org. Lett.
2012, 14, 2874–2877. (f) During the preparation of our manuscript an
ortho-selective CÀH functionalization on anilides was independently
reported: Yang, X.; Shan, G.; Rao, Y. Org. Lett. 2013, 15, 2334–2337.
(1) Selected recent reviews on oxidative CÀH bond functionaliza-
tions: (a) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369–375.
(b) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886–896.
(c) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
788–802. (d) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3381–3430. (e) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177–
185. (f) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011,
40, 1885–1898. (g) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84.
(h) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624–655. (i) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–
11222. (j) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–
685. (k) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874–
5883 and references cited therein.
(2) Reviews on metal-catalyzed C(sp2)ÀO 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/ol401535k
XXXX American Chemical Society

sciences, and crop protection.6 Within our research pro-
gram on sustainable CÀH bond functionalizations for
organic synthesis,7 we now established first ruthenium-
catalyzed hydroxylations of aryl carbamates, on which we
report herein. Notably, the optimized catalytic system
allowed for direct oxygenations under remarkably mild
reaction conditions8 and was not restricted to substrates
displaying Lewis basic directing groups,9 proving to be
also applicable to direct para-selective10 oxygenations with
anisole derivatives.
carbamates 1 (Scheme 1). We were pleased to find that the
catalyst was widely applicable and efficiently converted
para-, meta-, and even more sterically hindered ortho-
substituted aryl carbamates bearing various valuable elec-
trophilic functional groups, such as chloro, bromo, or iodo
substituents. It is noteworthy that the reactions generally
proceeded with excellent chemo- and site-selectivities to
deliver the mono-ortho-substituted products 2.
Scheme 1. Scope of CÀH Hydroxylation with Carbamates 1
Table 1. Optimization of CÀH Oxygenation with Carbamate 1aa
entry
[Ru]
]
solvent
DCE
yield (%)
1
À
À
2
[Ru3(CO)12
DCE
39
46
53
54
65
30b
24c
57
67d
3
[Ru(O2CMes)2(p-cymene)]
[RuCl2(PPh3)3]
DCE
4
DCE
5
[RuCl3(H2O)n]
DCE
6
7
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
DCE
TFA/TFAA
1,4-dioxane
PhMe
DCE
8
9
10
a Reaction conditions: 1a (0.5 mmol), PhI(TFA)2 (1.0 mmol), solvent
(2.0 mL), 80 °C, 3 h, isolated yield. b K2S2O8 (2.0 equiv) instead of
PhI(FTA)2. c 1H NMR conversion with CH2Br2 as the internal standard.
d 50 °C, 24 h.
At the outset of our studies, we probed representative
ruthenium precursors for the envisioned direct oxygena-
tion of carbamate 1a (Table 1). While the desired product
2a was not formed in the absence of a ruthenium catalyst
(entry 1), different ruthenium precursors enabled the
desired transformation, with optimal results being ob-
tained with [RuCl2(p-cymene)]2 (entries 2À6). Further-
more, PhI(TFA)2 and DCE were identified as the best
oxidant and solvent, respectively (entries 6À9). Impor-
tantly, under the optimized conditions the ruthenium-
catalyzed CÀH bond oxygenation even proved viable at
a rather low reaction temperature of 50 °C (entry 10).
The versatility of the catalytic system was thereafter
probed in the direct oxygenation of differently substituted
Given the high catalytic efficacy achieved within direct
CÀH bond oxygenations with aryl carbamates 1, we
became attracted by establishing the order of relative
directing group abilities through competition experiments.
Thus, an intramolecular competition experiment with
bifunctional substrate 1w clearly highlighted carbamates
to be more potent directing groups as compared with esters
(Scheme 2). This selectivity pattern is notable, since the
CÀH bond activation with aryl carbamates proceeds
through the formation of less favorable six-membered
ruthenacycles as the key intermediates.
(6) (a) Ding, Q.; Ye, Y.; Fan, R. Synthesis 2013, 45, 1–16. (b) Li, B.-J.;
Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.;Eur. J. 2011, 17, 1728–1759. (c)
Rappoport, Z. The Chemistry of Phenols; Wiley-VCH: Weinheim, 2003.
(7) A review: Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413.
(8) Wencel-Delord, J.; Droege, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740–4761.
Scheme 2. Intramolecular Competition Experiment
(9) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 10236–10254.
(10) For elegant examples of para-selective CÀH bond functionali-
zations with metal catalysts, see: (a) Wang, X.; Leow, D.; Yu, J.-Q.
J. Am. Chem. Soc. 2011, 133, 13864–1386. (b) Kamata, K.; Yamaura, T.;
Mizuno, N. Angew. Chem., Int. Ed. 2012, 51, 7275–7278. (c) Ciana,
C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2011, 50, 458–462.
In good agreement with this observation, intermolecular
competition experiments between differently substituted
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Intermolecular Competition Experiments
Scheme 5. Para-Selective CÀH Oxygenation of Anisoles 7
by the ruthenium(II) catalyst12 to the corresponding hy-
droxylated phenols 8aÀd10b in a para-selective fashion
(Scheme 5).
As to the reaction mechanism, oxygenations of anisole
7a in the presence of catalytic (10 mol %) or stoichiometric
(1 equiv) amounts of TEMPO furnished product 8a in
significantly reduced yields of 43% and 5%, respectively,
which inter alia can be rationalized in terms of a single-
electron-transfer oxidation. However, more detailed me-
chanistic studies are required to delineate the catalyst’s
exact mode of action.
Scheme 4. Kinetic Isotope Effect Study
In summary, we have reported on the first ruthenium-
catalyzed C(sp2)ÀH bond oxygenation of phenol deriva-
tives. Thus, direct hydroxylations of aryl carbamates
proceeded with high catalytic efficacy as well as excellent
chemo- and ortho-selectivities. In contrast, the ruthenium-
(II) catalyst also allowed for the direct CÀH bond func-
tionalization on anisole derivatives, which occurred with
para-selectivity.
arenes established the following order of directing group
ability: amide > carbamate > ester (Scheme 3).
As to the CÀH metalation step, studies with isotopically
labeled substrate 1n-[D5] were suggestive of a kinetically
relevant CÀH activation with a KIE ≈ 2.2 (Scheme 4).
Thus far, ruthenium-catalyzed C(sp2)ÀH bond oxyge-
nations were to the best of our knowledge largely limited
to substrates bearing Lewis basic directing groups,4,5
consequently leading to ortho-substitution.11 Thus, it is
noteworthy that anisole derivatives 7 were also converted
Acknowledgment. Support by the European Research
Council under the European Community’s Seventh Frame-
work Program (FP7 2007À2013)/ERC Grant Agreement
No. 307535, and the Chinese Scholarship Council
(fellowship to W.L.) is gratefully acknowledged.
(11) For recent ruthenium-catalyzed meta-selective CÀH bond func-
tionalizations, see: (a) Hofmann, N.; Ackermann, L. J. Am. Chem. Soc.
2013, 135, 5877–5884. (b) Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu,
P. M.; Mahon, M. F.; Kociok-Kohn, G.; Whittlesey, M. K.; Frost, C. G.
J. Am. Chem. Soc. 2011, 133, 19298–19301.
(12) Under otherwise identical reaction conditions the use of AlCl3 or
FeCl3 as the catalyst led only to <5% of product 8a, as determined by
GC analysis.
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.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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