Cu-catalyzed mild C(sp2)-H functionalization assisted by carboxylic acids en route to hydroxylated arenes

Article abstract of DOI:10.1021/ja4047894

A formal Cu-catalyzed C(sp²)-H hydroxylation assisted by benzoic acids is described. The procedure is characterized by its mild reaction conditions and wide substrate scope utilizing simple and cheap Cu catalysts, thus becoming a user-friendly

Full text of DOI:10.1021/ja4047894

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Communication
Cu-catalyzed Mild C(sp2)-H Functionalization Assisted
by Carboxylic Acids En Route to Hydroxylated Arenes
Joan Gallardo-Donaire, and Ruben Martin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4047894 • Publication Date (Web): 11 Jun 2013
Downloaded from http://pubs.acs.org on June 14, 2013
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Cu-catalyzed Mild C(sp2)-H Functionalization Assisted by Carbox-
ylic Acids En Route to Hydroxylated Arenes
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Joan Gallardo-Donaire and Ruben Martin*
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007, Tarragona, Spain
Supporting Information Placeholder
ABSTRACT: A formal Cu-catalyzed C(sp2)-H hydrox-
ylation assisted by benzoic acids is described. The pro-
cedure is characterized by its mild reaction conditions
and wide substrate scope utilizing simple and cheap Cu
catalysts, thus becoming a user-friendly and operational-
ly simple protocol for C(sp2)-H hydroxylation.
droxylation of benzoic acids. To the best of our
knowledge, the development of a catalytic C(sp2)-H
functionalization with benzoic acids using cheap Cu
salts remains unexplored. We hypothesized that the use
of Cu catalysts might lead to pharmaceutically-relevant
benzolactones 28 via C(sp2)-H functionalization and
subsequent hydrolysis en route to 3 (Scheme 1). While
benzolactones 2 are typically prepared from the cycliza-
tion of hydroxyacids or via metal-mediated lactonization
of aryl halides under harsh conditions,9 our approach
offers the alternative of using non-prefunctionalized and
much simpler substrates while avoiding the formation of
halide waste. As part of our interest in the field,10 we
present a user-friendly and operationally-simple C-H
hydroxylation using cheap Cu catalysts, thus becoming a
powerful alternative for accessing functionalized arenes
in a direct manner.
The field of C-H functionalization has gained considera-
ble momentum over recent years,1 holding great promise
for preparing highly complex molecules from simple
precursors.2 While synthetically very attractive, most of
these protocols still suffer from relatively high catalyst
loadings, harsh conditions and site-selectivity.3 Despite
formidable advances, the majority of C-H functionaliza-
tion processes are still limited to the use of non-weakly
coordinating groups that are difficult to functionalize;1-3
additionally, the C-H functionalization arena is mainly
limited to the use of expensive noble metals as catalysts
such as Pd, Rh or Ir.4 From a synthetic perspective, the
ability to prepare synthetically relevant scaffolds via C-
H functionalization using weakly coordinating directing
groups with cheaper catalysts and under mild conditions
would be of significant importance.
Table 1. Cu-catalyzed C(sp2)-H Functionalizationa
Scheme 1. Formal C-H Hydroxylation with Cu Catalysts
Hydroxylated arenes rank amongst the most ubiquitous
motifs in pharmaceuticals, agrochemicals and polymers,
among others.5 Indeed, the preparation of hydroxylated
arenes has become an important goal at the community
level.6 Initial studies by Rybak-Akimova and Que7a us-
ing stoichiometric Fe(II) complexes followed by the
pioneering Pd-catalyzed protocol developed by Yu7b
using O2 set up the stage for promoting ortho C-H hy-
a
1a (0.50 mmol), catalyst (10 mol%), oxidant (1.25
b
equiv), HFIP (8 mL/mmol) at 75 ºC. GC yield using
decane as internal standard. Using TFA as solvent (4
mL/mmol) at rt. Using Yu´s conditions (ref. 7b):
c
d
Pd(OAc)2 (10 mol%), KOAc (2.0 equiv), BQ (1.0
e
f
equiv), DMA at 1 atm O2. Air instead of Ar. O2 (1
atm) instead of Ar. g Without [PhCO2]2 and O2 (1 atm)
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h
i
instead of Ar. Phen = 1,10-phenanthroline. Using
regioisomeric mixture (5:1). f Isolated as a regioisomeric
j
k
mixture (3:1). g Isolated as a regioisomeric mixture (4:1).
h Isolated as a regioisomeric mixture (6:1).
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Cu(OAc)2 (5 mol%). Isolated yield. No ortho C-H
functionalization was observed when using these reac-
tion conditions with 3-methylbenzoic acid as substrate.
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With the optimized reaction conditions in hand, the
scope of our Cu-catalyzed remote C-H functionalization
was examined. As shown in Table 2, a host of benzoic
acids could all be coupled with good to excellent
yields.13 While good results were found for electron-rich
or electron-neutral arenes, low yields were obtained with
electron-deficient rings (2d). Substituents in ortho posi-
tion to the targeted C-H bond did not hinder the reaction,
providing 2i in good yields. As shown in Table 2, good
regioselectivities could be obtained with unsymmetrical
substrates; in all cases examined, the most accessible C-
H bond was preferentially activated (2e, 2f, 2g, 2h and
2k),11 even in a relatively crowded environment (2i). As
shown for 2l, a single isomer was obtained with naph-
thalene backbones. Heterocycles could equally be ac-
commodated under our optimized reaction protocol (2j).
Particularly noteworthy was the tolerance of our method
in the presence of benzyl alcohols (2c); under the limits
of detection, no traces of aldehyde or carboxylic acid
were found in the crude reaction mixtures. This is par-
ticularly important, as primary alcohols are susceptible
toward oxidation in the presence of Cu catalysts and
peroxides as oxidants.19 Similarly, benzyl ethers were
also tolerated as well (2g). As for Table 1 (entry 6), we
found that the presence of O2 (1 atm) had a deleterious
effect on reactivity for selected substrates (2a, 2b, 2g
and 2l); similarly, we found that the Pd-catalyzed condi-
tions in Table 1 (entry 1) gave lower yields.20
We started our investigations with 1a as the model sub-
strate, and the effect of metal precatalysts, oxidants and
solvents were systematically examined (Table 1). After
some experimentation,11 we found that Pd(OAc)2 in
combination with K2S2O8 using TFA as solvent (entry 1)
gave 2a in 70% yield.12,13 These results are in sharp
contrast with the known ability of Pd catalysts to pro-
mote ortho C-H hydroxylation of carbonyl-type com-
pounds.7b,14,15 In order to put this result into perspective,
we found no reaction of 1a under Yu´s conditions (entry
2).7b However, the use of TFA as solvent makes the pro-
cess not yet synthetically attractive, particularly when
employing highly functionalized substrates. Therefore,
we turned our attention to Cu-catalyzed processes, as
these have become viable alternatives to the more wide-
ly utilized Pd-catalyzed reactions. Indeed, Cu-based
methods are distinguished by their wide scope, high
efficiency and mild conditions.16 We found that
Cu(OAc)2 as catalyst with benzoyl peroxide provided
excellent results at 75 ºC (entry 6). Other oxidants (en-
tries 3-5), Cu salts (entries 8-10) or additives (entry 11)
did not improve the yield of 2a.17 As shown in entry 7,
the presence of O2 atmospheres inhibited the reaction at
some extent.18 Control experiments showed that in the
absence of Cu(OAc)2 little conversion to 2a was ob-
served (entry 12). Importantly, we observed that reaction
operated equally well at lower catalyst loadings (entry
13). Quite illustrative, we found that the reaction of 3-
methyl benzoic acid under our optimized conditions
(entry 13) did not result in ortho C-H functionalization,
thus showing the critical role of the pendent aryl ring.
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Table 3. Substituent Effects on the Upper Ringa,b
Table 2. Substituent Effects on the Bottom Ringa,b
a As for Table 1, entry 12. b Isolated yields, average of at
least two runs.
Next, we turned our attention to study the electronic as
well as the steric effects on the upper aryl ring (Table 3).
Interestingly, both electron-donating as well as electron-
deficient substituents gave the corresponding products in
moderate to good yields. The chemoselectivity profile of
a As for Table 1, entry 12. b Isolated yields, average of at
c
d
least 2 runs. O2 atmospheres was used instead of Ar.
e
Isolated as a regioisomeric mixture (3:1). Isolated as a
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our method was nicely illustrated by the fact that ethers selectivity could be achieved based on subtle electronic
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(2m), sulfonates (2n), esters (2o) and ketones (2s) were
all well tolerated, giving access to functionalized benzo-
lactones in a straightforward fashion.13 As shown for 2t,
2n and 2o the method also tolerated the presence of aryl
halides and pseudohalides, thus leaving ample opportu-
nities for further functionalization via conventional
cross-coupling techniques. The methodology could be
extended to non-aromatic carboxylic acids as well (2q),
although in lower yields.21 As for Table 2, we found that
unprotected benzyl alcohols did not hinder the reaction,
affording exclusively 2p in high yields.
differences among different C-H bonds (Scheme 2).
Interestingly, 3g was obtained as the only isolated prod-
uct in which the most electron-rich aromatic ring reacted
at a faster rate. Similarly, we obtained a high selectivity
profile for 3h suggesting that our protocol selectively
activates C(sp2)-H bonds in the presence of weak ortho
benzylic C(sp3)-H bonds.
9
Scheme 3. Intermolecular and Intramolecular KIE
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Table 4. Remote C-H Hydroxylationa,b
In order to gain more insights into the mechanism, we
performed a kinetic isotope effect23 by comparing the
initial rates of 1a with 1a-D5 (Scheme 3). We observed a
kH/kD = 1.22, suggesting that C-H bond-cleavage was not
involved in the rate-determining step.11 Such assumption
was confirmed by the similar kH/kD obtained in the in-
tramolecular kinetic isotope effect of 1a-D1.11 In addi-
tion, we found that the reaction of 1a under our opti-
mized reaction conditions was significantly inhibited by
the addition of radical scavengers such as TEMPO, BHT
or 1,1-diphenylethylene, among others.11 While not yet
conclusive, these experiments might suggest that single
electron transfer processes come into play.
Scheme 4. Mechanistic Hypothesis (X=OAc)
a As for Table 1, entry 12. b Overall yield (2 steps).
Scheme 2. Site-selective among different C-H bonds
Although an in-depth discussion should await further
investigations, at present we support a scenario that
starts with the reaction of Cu(II) and [PhCO2]2 to give
rise to a square-planar or square-pyramidal Cu(III) ben-
zoate I24 and a benzyloxy radical II that could undergo
CO2 extrusion (Scheme 4, III). Subsequently, II or III
triggers a hydrogen-atom abstraction to afford IV that
ultimately engages an intramolecular C-O bond-forming
reaction (2a) while recovering the Cu(II) species.25 At
present, we hypothesize that the formation of 2a from
IV might be the rate-determining step of the reaction.
Alternatively, we cannot rule out a different scenario via
concerted metalation deprotonation (CMD)26 from spe-
cies I to V prior reductive elimination.27
In light of the results shown in Tables 2-3, we anticipat-
ed that remote hydroxylated arenes could be within
reach by a sequential hydrolysis event.11 As shown in
Table 4, this was indeed the case; the addition of LiOH
at room temperature was found to be crucial, obtaining
in quantitative conversion to products 3a-3e. The results
compiled in Table 4 indicate that remote C-H hydroxyla-
tion of benzoic acids could be obtained in high overall
yields in a sequential manner from available starting
materials. Of particular importance is the successful
preparation of 3f since the corresponding product lack-
ing the hydroxyl group has shown to be a promising
candidate to prevent arteriosclerosis;22,11 therefore, our
protocol can be utilized as a platform for evaluating the
biological activities of certain pharmacophores. On the
basis of the results in Tables 2-4, we speculated that site-
In summary, we have described a direct and efficient
hydroxylation via Cu-catalyzed C(sp2)-H functionaliza-
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Page 4 of 6
tion with weakly directing groups.28,29 This protocol
constitutes an user-friendly and operationally simple
reaction for preparing hydroxylated arenes under mild
reaction conditions and with excellent chemoselectivity
profile.30 Further mechanistic studies and the extension
to other substrates are currently underway.
2009, 15, 13171–13180 (b) Zhang, Y.-H.; Yu, J.-Q. J. Am.
Chem. Soc. 2009, 131, 14654–14655.
1
2
3
4
(8) For selected references: (a) Koch, K.; Podlech, J.; Pfeiffer, E.;
Metzler, M. J. Org. Chem. 2005, 70, 3275. (b) Garino, C.; Bi-
hel, F.; Pietrancosta, N.; Laras, Y.; Quelever, I.; Woo, I.; Klein,
P.; Bain, J.; Boucher, J.; Kraus, J. Bioorg. Med. Chem. Lett.
2005, 15, 135. (c) Chuder, B. A.; Kalinin, A. V.; Taylor, N. J.;
Snieckus, V. Angew. Chem. Int. Ed. 1999, 38, 1435.
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6
7
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(9) For selected references dealing with the preparation of benzo-
lactones via the corresponding hydroxyacids (Scheme 1,
X=OH), aryl halides (Scheme 1, X = I, Br, Cl) or pseudohalide
(Scheme 1, X = NO2, OTf), see: (a) Luo, J.; Lu, Y.; Liu, S.;
Liu, J.; Deng, G.-J. Adv. Synth. Catal. 2011, 353, 2604. (b)
Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.;
Young, L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379. (c)
Parenty, A.; Moreau, X.; Campagne, J. M. Chem. Rev. 2006,
106, 911. (d) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.;
Siddiqui, M. A.; Snieckus, V.; Josephy, P. D. J. Org. Chem.
1991, 56, 3763.
(10) (a) Flores-Gaspar, A.; Gutiérrez-Bonet, A.; Martin, R. Org.
Lett. 2012, 14, 5234. (b) Novák, P.; Correa, A.; Gallardo-
Donaire, J.; Martin, R. Angew. Chem. Int. Ed. 2011, 50, 12236.
(c) Flores-Gaspar, A.; Martin, R. Adv. Synth. Catal. 2011, 353,
1223. (d) Álvarez-Bercedo, P.; Flores-Gaspar, A.; Correa, A.;
Martin, R. J. Am. Chem. Soc. 2010, 132, 466
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
* rmartinromo@iciq.es
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
We thank ICIQ Foundation, the European Research Coun-
cil (ERC-277883) and MICINN (CTQ2012-34054) for
financial support. Johnson Matthey, Umicore and Nippon
Chemical Industrial are acknowledged for a gift of metal
and ligand sources. Dr. A. Correa at ICIQ is gratefully
acknowledged for insightful discussions. Dr. N. Cabello
and M. Urtasun at ICIQ are acknowledged for HRMS as
well as kinetic studies. R.M and J.G-D sincerely thank
MICINN for a RyC and FPI fellowships.
(11) For more details, see Supporting Information
(12) For a recent synthesis of benzolactones via Pd-catalyzed ortho
C(sp2)-H functionalization: (a) Cheng, X.-F.; Li, Y.; Su, Y.-M.;
Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu,
J.-Q. J. Am. Chem. Soc. 2013, 135, 1236. (b) Yang, M.; Jiang,
X.; Shi, W.-J.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2013, 15, 690.
(c) For a recent synthesis of benzolactones via Pd-catalyzed
C(sp3)-H functionalization see ref.12b
(13) ortho-Hydroxylated arene was not detected by NMR spectros-
copy of the crude material.
(14) For an example of an otherwise similar benzoic acid derivative
that undergoes selective ortho C-H hydroxylation with no trac-
es of the remote C-H bond-functionalization, see: Kimura, S.;
Kobayashi, S.; Kumamoto, T.; Akagi, A.; Sato, N.; Ishikawa, T.
Helv. Chim. Acta. 2011, 94, 578.
REFERENCES
(1) For selected reviews: (a) Wencel-Delord, J.; Dröge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (b) Mkhalid, I. A.
I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F.
Chem. Rev. 2010, 110, 890. (c) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (d) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094.
(2) For selected reviews: (a) Yamaguchi, J.; Yamaguchi, A. D.;
Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960. (b) Chen, D.
Y.-K.; Youn, S. W. Chem. Eur. J. 2012, 18, 9452. (c) Gu-
tekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976.
(d) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev.
2011, 40, 1885.
(3) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(4) For selected examples of meta and para C-H functionalization:
(a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486,
518. (b) Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.;
Mahon, M. F.; Kociok-Köhn, G.; Whittlesey, M. K.; Frost, C.
G. J. Am. Chem. Soc. 2011, 133, 19298. (c) Duong, H. A; Gilli-
gan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J Angew.
Chem. Int. Ed. 2011, 50, 463. (d) Ciana, C.-L.; Phipps, R. J.;
Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem. Int.
Ed. 2011, 50, 458. (e) Nakao, Y. Synthesis 2011, 20, 3209. (f)
Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(15) For recent oxidative ortho C(sp2)-H hydroxylation of other
carbonyl-type compounds: (a) Yang, F.; Ackermann, L. Org.
Lett. 2013, 718. (b) Choy, P. Y.; Kwong, F. Y. Org. Lett. 2013,
15, 270. (c) Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem.
Int. Ed. 2012, 51, 13070. (d) Mo, F.; Trzepkowski, L. J.; Dong,
G. Angew. Chem. Int. Ed. 2012, 51, 13075. (e) Thirunavuk-
karasu, V. S.; Ackermann, L. Org. Lett. 2012, 14, 6206. (f)
Yang, Y.; Lin, Y.; Rao, Y. Org. Lett. 2012, 14, 2874.
(16) For recent selected reviews: (a) Zhang, C.; Tang, C.; Jiao, N.
Chem. Soc. Rev. 2012, 41, 3464–3484. (b) Zhang, C.; Tang, C.;
Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (c) Wendlandt, A. E.;
Suess, A. M.; Stahl, S. S. Angew. Chem. Int. Ed. 2011, 50,
11062. (d) Daugulis, O.; Do, H. –Q.; Shabashov, D. Acc. Chem.
Res. 2009, 42, 1074. (e) Punniyamurthy, T.; Rout, L. Coord.
Chem. Rev. 2008, 252, 134.
(17) For selected intramolecular C-N bond formation under oxida-
tive conditions: (a) Cho, S. H.; Yoon, J.; Chang, S. J. Am.
Chem. Soc. 2011, 133, 5996. (b) Karthikeyan, J.; Cheng, C.-H.
Angew. Chem. Int. Ed. 2011, 50, 9880
(18) As for related processes, this result might suggest the formation
of catalytically deactivated Cu-O2 complexes: (a) Bloom, S.;
Pitts, C. R.; Miller, D. C.; Haselton, N.; Holl, M. G.; Urheim,
E.; Lectka, T. Angew. Chem. Int. Ed. 2012, 51, 10580. (b)
Kitajima, N.; Moro-oka, Y. Chem. Rev. 1994, 94, 737. (c)
Tyeklar, Z.; Jacobson, R.; Wei, N.; Murthy, N. N.; Zubieta, J.;
Karlin, K. D. J. Am. Chem. Soc. 1993, 115, 2677.
(19) For selected examples, see: (a) Hoover, J. M.; Ryland, B. L.;
Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357. (b) Hoover, J.
M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901. (c) Kum-
pulainen, E. T. T.; Koskinen, A. M. P. Chem. Eur. J. 2009, 15,
10901
(5) (a) Rappoport, Z. The Chemistry of Phenols, Wiley- VCH,
2003. (b) Tyman, J. H. P. Synthetic and Natural Phenols, Else-
vier, 1996.
(6) For selected reviews: (a) Enthaler, S.; Company, A Chem. Soc.
Rev. 2011, 40, 4912. (b) Alonso, D. A; Nájera, C.; Pastor, I. M.;
Yus, M. Chem. Eur. J. 2010, 16, 5274.
(7) (a) Makhlynets, O. V; Das, P.; Taktak, S.; Flook, M.; Mas-
Ballesté, R.; Rybak-Akimova, E. V; Que, L. Chem. Eur. J.
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(20) We obtain the following results for a selection of substrates
using Pd-catalyzed conditions (Table 1, entry 1): 2a (70%), 2b
(55%), 2e (44%; 5:1 regioisomeric mixture), 2l (21%, 7:1 regi-
oisomeric mixture). It is worth noting that, upon exposure of
compounds 1a-k to the conditions developed by Yu (ref. 7b),
no reaction took place.
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5
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8
(21) At present, we speculate this result suggests that coplanarity
might be an important factor for success.
(22) Tomokazyu, N. Therapeutic agent for hyperlipemia, arterioscle-
rosis and/or metabolic syndrome. JP2006182668(A), July 13,
2006.
(23) For reviews, see: (a) Gómez-Gallego, M.; Sierra, M. A. Chem.
Rev. 2011, 111, 4857. (b) Simmons, E. M.; Hartwig, J. F. An-
gew. Chem. Int. Ed. 2012, 51, 3066.
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10
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13
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53
54
55
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57
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(24) For selected mechanistic discussions involving Cu(III) species:
(a) Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301. (b) Hick-
man, A. J.; Sanford, M. S. Nature 2012, 484, 177. (c) Gephart,
R. T.; McMullin, C. L.; Sapiezynski, N. G.; Jang, E. S.; Aguila,
M. J. B.; Cundari, T. R.; Warren, T. H. J. Am. Chem. Soc. 2012,
134, 17350. (d) Huffman, L. M.; Stahl, S. S. Dalton Trans.
2011, 40, 8959. (e) Huffman, L. M.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 9196. (f) Casitas, A.; King, A. E.; Parella, T.;
Costas, M.; Stahl, S. S.; Ribas, X. Chem. Sci. 2010, 1, 326.
(25) For an intramolecular C-O bond-reductive elimination from
stoichiometric well-defined Cu(III) intermediates, see: Casitas,
A.; Ioannidis, N.; Mitrikas, G.; Costas, M.; Ribas, X. Dalton
Trans. 2011, 40, 8796.
(26) For a stoichiometric ortho C-H hydroxylation promoted by
Cu(III) complexes: (a) Garcia-Bosch, I.; Company, A.; Frisch,
J. R.; Torrent-Sucarrat, M.; Cardellach, M.; Gamba, I.; Güell,
M.; Casella, L.; Que, L.; Ribas, X.; Luis, J. M.; Costas, M. An-
gew. Chem. Int. Ed. 2010, 49, 2406. (b) King, A. E.; Huffman,
L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am.
Chem. Soc. 2010, 132, 12068
(27) For selected reviews, see: (a) Ackermann, L. Chem. Rev. 2011,
111, 1315. (b) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39,
1118.
(28) For examples a Cu(II)-catalyzed ortho C(sp2)-H oxidation of
pyridine derivatives: (a) Li, L.; Yu, P.; Cheng, J.; Chen, F.; Fan,
C. Chem. Lett. 2012, 41, 600. (b) Chen, X.; Hao, X.-S.; Good-
hue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790.
(29) For an example of a Cu(II)-catalyzed hydroxylation of particu-
larly acidic C(sp2)-H bonds: Liu, Q.; Wu, P.; Yang, Y.; Zeng,
Z.; Liu, J.; Yi, H.; Lei, A. Angew. Chem. Int. Ed. 2012, 51,
4666.
(30) While this manuscript was under revision a related Pd-
catalyzed protocol has been described: Li, Y.; Ding, Y.-J.;
Wang, J.-Y.; Su, Y.-M.; Wang, X.-S. Org. Lett. 2013, DOI:
10.1021/ol400877q.
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