Sequential meta-/ortho-C-H Functionalizations by One-Pot Ruthenium(II/III) Catalysis

Article abstract of DOI:10.1021/acscatal.7b03648

Sequential twofold meta-C-H/ortho-C-H functionalization was achieved by means of versatile ruthenium(II) biscarboxylate catalysis. The double C-H activation proved viable in a one-pot fashion with the assistance of synthetically useful imidates. The operationally simple twofold C-H functionalization occurred with high levels of positional selectivity control and was conducted in a nonsequential manner by the judicious choice of the reaction temperature. Detailed experimental mechanistic studies, including unprecedented electron paramagnetic resonance (EPR) experiments, provided strong support for homolytic C-X bond cleavage and facile C-H ruthenation, while a computational density functional theory (DFT) analysis was supportive of a novel mechanistic scenario involving synergistic catalysis via cyclometalated ruthenium(III) complexes as key intermediates.

Full text of DOI:10.1021/acscatal.7b03648

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Article
Sequential meta-/ortho-C–H Functionalizations
by One-Pot Ruthenium(II/III) Catalysis
Korkit Korvorapun, Nikolaos Kaplaneris, Torben Rogge,
Svenja Warratz, A. Claudia Stückl, and Lutz Ackermann
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Sequential meta-/ortho-C–H Functionalizations by One-Pot Ruthe-
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nium(II/III) Catalysis
Korkit Korvorapun,† Nikolaos Kaplaneris,† Torben Rogge,† Svenja Warratz,† A. Claudia Stückl,‡
and Lutz Ackermann*,†
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†Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077
Göttingen, Germany
‡Institut für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstraße 4, 37077 Göttingen,
Germany
ABSTRACT: The sequential twofold meta-C–H/ortho-C–H functionalization was achieved by means of versatile rutheni-
um(II) biscarboxylate catalysis. The double C–H activation proved viable in a one-pot fashion by assistance of synthetical-
ly useful imidates. The operationally-simple twofold C–H functionalization occurred with high levels of positional selec-
tivity control, and was conducted in a non-sequential manner by the judicious choice of the reaction temperature. De-
tailed experimental mechanistic studies, including unprecedented EPR experiments, provided strong support for a homo-
lytic C–X cleavage and a facile C–H ruthenation, while a computational DFT analysis was supportive of a novel mechanis-
tic scenario, involving synergistic catalysis via cyclometalated ruthenium(III) complexes as key intermediates.
KEYWORDS: C–H activation, DFT, EPR, remote selectivity, ruthenium, sequential catalysis.
C–H activation has emerged as a transformative plat-
form for molecular syntheses, enabling the step- and
atom-economical synthesis of organic compounds from
easily accessible raw materials.1 The sustainable nature of
this approach has further been improved by the design of
sequential one-pot processes, ideally exploiting a single2
metal catalyst for two mechanistically-distinct transfor-
mations. Despite of considerable advances in the field,
these multicatalytic single-component3 C–H activations
are thus far restricted to entropically-favored intramolec-
ular reactions,4 functionalizations of electronically-biased
heteroarenes,5 or proximity-induced ortho-C–H function-
alizations.6 In sharp contrast, the implementation of chal-
lenging remote meta-C–H functionalizations7 into single-
catalyst component8 one-pot sequential9 catalysis has
thus far proven elusive,10 which contrasts the notable
recent progress in remote C–H functionalizations7, 11 with
ruthenium catalysts by inter alia Frost, Greaney and
Ackermann, among others.12 Within our program directed
towards sustainable C–H activation,13 we have now de-
vised the first strategy for multicatalytic meta-C–H/ortho-
C–H functionalizations, on which we report herein
(Scheme 1). Notable features of our findings include (a) a
versatile ruthenium(II) biscarboxylate catalyst for a posi-
sights into homolytic C–X cleavage. Thus, first electron
paramagnetic resonance (EPR) spectroscopic studies on
remote C–H functionalizations and computational in-
sights provided strong support for a novel rutheni-
um(II/III) catalysis manifold on a single ruthenium cata-
lyst.
Scheme 1. Sequential meta-C–H/ortho-C–H functionali-
zation
We commenced our studies by probing various reaction
conditions for the envisioned meta-C–H functionalization
of aryloxazoline 1a (Table 1, and Table S-1 in the Support-
ing Information).18 Carboxylate assistance19 was found to
be key to success for the remote-C–H alkylation process
(entries 1-7), with best results being accomplished in 1,4-
dioxane as the solvent (entries 5–8). The high catalytic
efficacy of the ruthenium(II)biscarboxylate catalysis
manifold was reflected by comparably high yields under
rather mild reaction conditions,20 featuring a mild base at
a reaction temperature of only 40 °C (entry 9). Control
experiments verified the key role of the carboxylate (entry
tional-selective
meta-C–H
alkylation/ortho-C–H
arylation14,15 manifold, (b) synthetically-meaningful16 im-
idates17 for meta-C–H functionalizations, (c) mild reaction
conditions of 40-60 °C, and (d) detailed mechanistic in-
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3) and phosphine additive (entry 10), illustrating the im-
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portance of a synergistic catalysis regime.
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Table 1. meta-C–H-Alkylation by Oxazoline Assistancea
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[Ru]
Solvent
Yield (%)
entry
-
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
-
1
Ru3(CO)12
-
2
3
4
5
6
7
8
9
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
(<5)
(<5)b, c
(17)
(10)
76
[Ru(O2CMes)2(p-cymene)] PhMe
[Ru(O2CMes)2(p-cymene)] 1,2-DCE
[Ru(O2CMes)2(p-cymene)] 1,4-dioxane
[Ru(O2CAd)2(p-cymene)]
1,4-dioxane
73
65d
traceb
Scheme 2. meta-C–H-Alkylation of Aryloxazolines 1
[Ru(O2CMes)2(p-cymene)] 1,4-dioxane
[Ru(O2CMes)2(p-cymene)] 1,4-dioxane
10
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), [Ru] (10
mol %), PPh3 (10 mol %), K2CO3 (1.0 mmol), solvent (2.0 mL),
60 °C, 20 h, isolated yield. Conversion of 3aa in parentheses by 1H-
NMR with CH2Br2 as internal standard. b Without PPh3. AgSbF6
(20 mol %). d 40 °C.
c
The synergistic ruthenium(II)-catalyzed meta-C–H func-
tionalization was not limited to the assistance of imidates
1 (Scheme 3). Indeed, the versatility of our strategy was
mirrored by efficient meta-C–H alkylations with various
organic electrophiles accomplished on arenes bearing
pyrimidine, removable21 pyrazoles, purine bases or
With the optimized ruthenium(II) biscarboxylate catalyst in
hand, we initially explored its versatility in the remote C–H
functionalization of synthetically useful arylimidates
(Scheme 2). Thus, the ruthenium(II) catalysis proved broadly
applicable, tolerating a wealth of valuable electrophilic func-
tional groups, including ester, chloro and bromoarenes as
well as primary alkyl bromides. The meta-C–H functionaliza-
tion occurred with excellent levels of positional selectivity,
exclusively leading to functionalization in the meta-position.
Here, the ortho-substituted aryloxazolines 1h/i delivered the
more densely-1,2,3-substituted isomers 3ha/3ia as the sole
products. The robustness of the ruthenium(II) biscarboxylate
catalyst was mirrored by the gram-scale synthesis of product
3aa, at the same time featuring a reduced catalyst loading.
ketimines.
Here,
the
ruthenium(II)
complex
[Ru(O2CAd)2(p-cymene)]19 proved to be most generally
applicable, allowing for high-yielding meta-C–H alkyla-
tions under exceedingly mild conditions at 40 °C. There-
by, α-bromo-substituted esters, amides and ketones were
smoothly converted into the desired products 5. In this
context, it is noteworthy that secondary and primary alkyl
groups could be installed in the meta-position, which
among others set the stage for a step-economical ap-
proach to ketoprofen derivatives 5lb/5mb. The connectiv-
ity of the thus obtained products was unambiguously
confirmed by X-ray crystal structure analyses.18 Moreover,
i
t is noteworthy that 2-pyrimidylanilines delivered instead
the para-substituted22 products 5nk-5ok,18 most likely by an
electrophilic mode of action (for detailed DFT calculations
on the para-selectivity, see the Supporting Information).18
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tial catalysis was found to be highly robust, delivering the
1
2
desired arenes 7 with high catalytic efficacy and ample sub-
strate scope.
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Scheme 4. Sequential meta-C–H-Alkylation/ortho-C–H-
Arylation of Aryloxazolines 1
The one-pot meta-C–H/ortho-C–H functionalization strategy
was not limited to arylimidates 1, but further set the stage for
the twofold C–H functionalization with useful pyrazoles and
purine bases 4 (Scheme 5). Again, excellent levels of chemo
and positional selectivity were observed, allowing among
others for the late-stage fluorescence labeling on purine
bases. The molecular structure of product 8e was again es-
tablished by X-ray crystal structure analysis.18
Scheme 3. Scope of meta- and para-C–H-Alkylation
After having established a general strategy for remote meta-
C–H transformations on arylimidates 1, we next explored the
desired sequential meta-C–H/ortho-C–H functionalization
through the action of a single ruthenium(II) catalyst in a
sustainable one-pot operation. After considerable experi-
mentation, we found that the operationally-simple addition
of the second electrophilic aryl bromide 6 upon completion
of the meta-C–H functionalization enabled the twofold one-
pot C–H activation. Thereby, sequential meta-C–H/ortho-C–
H functionalizations proved viable with complete positional
selectivity control (Scheme 4). It is particularly noteworthy
that a change of the catalyst or of the solvent was not re-
quired, significantly reducing the overall footprint of the
sustainable C–H activation strategy. The mass balance was
accounted for by meta-alkylated intermediate 3. The sequen-
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(a) Intermolecular competition experiments
[Ru(O2CMes)2(p-cymene)]
(10 mol %)
N
O
N
O
N
O
4
5
6
PPh3 (10 mol %)
Br
+
+
n-Bu
CO2Me
K2CO3 (2.0 equiv)
1,4-dioxane
60 °C, 20 h, (by 1H-NMR)
CO2Me
CO2Me
F
n-Bu
F/OMe
OMe n-Bu
3da: 44%
7
8
3ea: 26%
2a
1e/1d
(3.0 equiv)
9
N
O
N
O
N
O
as above
Br
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+
+
n-Bu
CO2Me
CO2Me
CO2Me
CF3 n-Bu
3ca: 18%
CF3/Me
Me n-Bu
3ba: 18%
1c/1b
2a
(3.0 equiv)
(b) H/D-Exchange study
2a
[Ru(O2CMes)2(p-cymene)]
(10 mol %)
47% D
47% D 44% D
22% D
O
N
O
N
O
N
PPh3 (10 mol %)
+
H
H
H
H
H
K2CO3 (2.0 equiv)
CD3OD (5 equiv)
1,4-dioxane, 60 °C, 4 h
CO2Me
H
n-Bu
1a
(c) Intermolecular KIE by competition
[D]n-1a: 42%
[D]n-3aa: 53%
N
O
N
O
2a
as above
H5/D5
H4/D4
CO2Me
kH/kD = 1.3
n-Bu
3aa and [D]4-3aa
1a and [D]5-1a
(d) Intermolecular KIE by independent experiments
N
O
N
O
2a
as above
H5/D5
H4/D4
CO2Me
kH/kD = 1.1
n-Bu
3aa or [D]4-3aa
1a or [D]5-1a
Scheme 6. Mechanistic Studies of meta-C–H-Alkylation
by Oxazoline Assistance
Subsequently, we became attracted to better understanding
the nature of the C–X cleavage event. The addition of the
typically used radical trap TEMPO led to complete inhibition
of the catalytic C–H activation (Scheme 7a). The isolation of
the TEMPO-adduct 9 can thus be explained by a homolytic
C–X cleavage. In good agreement with these findings, the
stereochemically well-defined substrate 2l highlighted a
significant loss of stereochemical integrity at the alkyl bro-
mide motif. This observation is again in good agreement with
a single-electron-transfer (SET)-induced C–X cleavage. Fur-
ther support for a radical reaction pathway was gained by
first electron paramagnetic resonance (EPR) spectroscopic
studies in remote C–H functionalization. Hence, the use of
5,5-dimethyl-1-pyrroline-N-Oxide (DMPO) as a spin trap
label unraveled the in-situ generation of an alkyl radical
(Scheme 7c).18
Scheme 5. Scope of sequential one-pot meta-C–H-
Alkylation/ortho-C–H-Arylation
In order to elucidate the working mode of the ruthenium(II)-
catalyzed meta-C–H activation we next conducted experi-
mental mechanistic studies. To this end, intermolecular
competition experiments showed only a minor electronic
influence (Scheme 6a). Reactions with isotopically labeled
cosolvent [D]4-MeOH provided strong support for a facile
reversible H/D-exchange, solely occurring in the ortho-
position (Scheme 6b), while kinetic experiments with the
substrates 1a and [D]5-1a suggested both of the C–H cleavag-
es not to be kinetically relevant.
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330 0
332 0
33 40
3 360
B0 (G )
3 380
3400
Scheme 7. Support for Radical Reaction Mechanism of
meta-C–H-Functionalization
To rationalize the positional selectivity of the meta-C–C
bond formation, computational studies were conducted by
means of a Fukui indices23a analysis for proposed cyclometal-
lated complexes. In this context it is noteworthy that nucleo-
philicity Fukui indices were largely employed in previous
reports to rationalize the site-selectivity in C–H functionali-
zations.12c,f, 23a In stark contrast, we found that radical Fukui
indices were better suited to rationalize the radical C–H
functionalization which were obtained at the B3LYP/def2-
TZVP level of theory (Figure 1).23b-e Thus, our computational
studies are suggestive of an initial SET process to generate a
ruthenium(III) species. Accordingly, we compared the pat-
tern of various cyclometalated ruthenium(III) complexes.
Since the C-3 and C-6 positions are significantly blocked by
steric effects that are not well described by the computation-
al analysis (for the full analysis, please, see the Supporting
Information),18 the schematic presentation in Figure 1b high-
lights the relative C-5/C-4 selectivities. Interestingly, the
synergistic coordination of the phosphine and carboxylate
ligands, the latter in a bidentate fashion, emerged to best
reproduce the experimentally observed meta-selectivity in
the C–C formation through attack of the radical species. It is
noteworthy that the ruthenium(III)bromide complexes D–F
are generally better suited to explain the observed positional
selectivity as compared to the corresponding ruthenium(II)
complexes A–C. Overall, our analysis supports the initial
coordination of the phosphine ligand, along with a SET from
the cyclometalated ruthenium to the alkyl halide, which
upon halide transfer delivers the alkyl radical and the ruthe-
nium(III) bromide.24 Thus, a change of the arene ligand’s
hapticity or, preferentially, its dissociation is proposed to
account for the observed synergistic ruthenium/phosphine
effect. In this context it is noteworthy that arene-ligand-free
ruthenium complexes were thus far employed for ruthenium-
catalyzed ortho-C–H arylations.6b, 25
Figure 1. Calculated Relative Radical Fukui Indices at
the B3LYP/def2-TZVP Level of Theory. L = 1,4-dioxane.
Based on our mechanistic findings, we propose a plausible
catalytic cycle to commence by reversible carboxylate-
assisted C–H ruthenation (Scheme 8). Thereafter, SET occurs
from the ruthenium(II) complex 11 to the alkyl halide 2, gen-
erating after halide transfer the cyclometalated rutheni-
um(III) intermediate 12. Radical attack on the aromatic moi-
ety then proceeds at the para-position to ruthenium, leading
to species 13, while the subsequent rearomatization furnishes
ruthenacycle 14. Finally, protodemetalation delivers the
desired meta-substituted product 3, which at the same time
regenerates the catalytically active ruthenium(II) complex 10.
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Cl
O
N
O
NH
CO2
H
1
aq. HCl
aq. HCl
H
R
2
3
4
105 °C, 20 h
105 °C, 20 h
CO2H
CO2H
n-Bu
CO2Me
n-Bu
n-Bu
15: 76%
16: 89%
3 or 7
Me
5
6
Me
Me
7
8
9
N
Me
ClO4
n-Bu
CO2H
n-Bu
n-Bu
CO2Me
NaOH
(1-4 mol %)
2-pym
2-pym
R
2-pym
R
H
[(4-ClPh)S]2 (10 mol %)
CH2Cl2:MeOH
(9:1)
23 °C, 24 h
R
10
11
12
13
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2,6-lutidine (20 mol %)
DCE, rt (23 °C), 16 h
blue LED
R = H (17a): 94%
R = Ph (17b): 89%
R = H (18a): 88%
R = Ph (18b): 54%
5aa or 8g
Me
Me
Me
N
Me
ClO4
CO2H
CO2H
(2 mol %)
H
H
[(4-ClPh)S]2 (10 mol %)
CO2
n-Bu
H
H
2,6-lutidine (20 mol %)
DCE, 23 °C, 16 h
blue LED
n-Bu
19: 90%
16
Scheme 8. Plausible catalytic cycle with ruthenium(III)
intermediate
Scheme 9. Late-stage modification
The user-friendly nature of the meta-C–H-alkylation/ortho-
C–H-arylation was reflected by performing the desired dou-
ble C–H functionalization in a one-pot fashion. Thus, the
complex mixture of substrate 4a and electrophiles 2a and 6
delivered the tri-substituted product 8g using either the aryl
bromide or the aryl chloride 6 by the judicious choice of the
reaction temperature control (Scheme 10).
Finally, the power of our sequential meta-C–H/ortho-C–H
functionalization strategy was illustrated by the facile
late-stage modification of the thus obtained arylimidates
3 and 7 (Scheme 9). Thus, the efficient transformation of
the imidates to carboxylic derivatives 15 and 16 proved
viable. Moreover, we accomplished the chemo-selective
decarboxylation of the aliphatic carboxylic acids through
a visible-light photoredox26 catalysis reduction manifold.
Scheme 10. One-pot meta-C–H-alkylation/ortho-C–H-
arylation by temperature control
In summary, we have reported on the twofold me-
ta/ortho-C–H functionalizations by a single ruthenium(II)
biscarboxylate catalyst. The well-defined single-
component catalyst proved broadly applicable with excel-
lent levels of positional selectivity. The three-component
reaction could be achieved in a non-sequential fashion by
the judicious temperature control. Detailed mechanistic
studies, including EPR27 findings and computational radi-
cal Fukui indices analysis, provided strong support for a
facile C–H cleavage under mild reaction conditions,
which is followed by radical attack on cyclometalated
ruthenium(III) intermediates.
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S. J. Chem. Commun. 2002, 2310-2311, and cited
references.
1
5.
6.
(a) Jeyachandran, R.; Potukuchi, H. K.; Ackermann,
L. Beilstein J. Org. Chem. 2012, 8, 1771-1777. (b)
Ackermann, L.; Potukuchi, H. K.; Landsberg, D.;
Vicente, R. Org. Lett. 2008, 10, 3081–3084.
(a) Li, B.; Bheeter, C. B.; Darcel, C.; Dixneuf, P. H.
ACS Catal. 2011, 1, 1221-1224. (b) Ackermann, L.;
Born, R.; Álvarez-Bercedo, P. Angew. Chem. In. Ed.
2007, 46, 6364–6367.
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3
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* E-mail: Lutz.Ackermann@chemie.uni-goettingen.de.
Author Contributions
7.
8.
Li, J.; De Sarkar, S.; Ackermann, L. Top. Organomet.
Chem. 2016, 55, 217-257.
K.K. and N.K. contributed equally to this work.
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(a) Reynolds, W. R.; Liu, P. M.; Kociok-Kohn, G.;
Frost, C. G. Synlett 2013, 24, 2687-2690. For reviews
on sequential one-pot reactions, see: (b) Cheng, D.;
Ishihara, Y.; Tan, B.; Barbas, C. F. ACS Catal. 2014, 4,
743-762. (c) Jiang, H.; Albrecht, L.; Jorgensen, K. A.
Chem. Sci. 2013, 4, 2287-2300. (d) Ramachary, D. B.;
Reddy, Y. V. Eur. J. Org. Chem. 2012, 865-887. (e)
Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011,
9, 1277-1300. (f) Grondal, C.; Jeanty, M.; Enders, D.
Nat. Chem. 2010, 2, 167-178. (g) Barbas, C. F. Angew.
Chem. Int. Ed. 2008, 47, 42-47. (h) Erkkilä, A.;
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416-5470. (i) Chapman, C. J.; Frost, C. G. Synthesis
2007, 1-21.
(a) Li, G.; Zhu, B.; Ma, X.; Jia, C.; Lv, X.; Wang, J.;
Zhao, F.; Lv, Y.; Yang, S. Org. Lett. 2017, 19, 5166-
5169. (b) Sarkar, D.; Gulevich, A. V.; Melkonyan, F.
S.; Gevorgyan, V. ACS Catal. 2015, 5, 6792-6801. (c)
Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H.
M. L. J. Am. Chem. Soc. 2013, 135, 6774-6777. (d)
Reynolds, W. R.; Liu, P. M.; Kociok-Köhn, G.; Frost,
C. G. Synlett 2013, 24, 2687-2690. (e) Ackermann, L.;
Jeyachandran, R.; Potukuchi, H. K.; Novák, P.;
Büttner, L. Org. Lett. 2010, 12, 2056-2059.
Notes
The authors declare no competing financial interest.
Supporting Information
Experimental procedures, characterization data, H and 13C
NMR spectra for compounds; DFT calculations; crystal struc-
ture analysis.
1
ACKNOWLEDGMENT
Generous support by the DAAD (fellowship to K.K.), the
Onassis Foundation (fellowship to N.K.), the DFG (Gottfried-
Wilhelm-Leibniz award) is gratefully acknowledged. We
thank Dr. Christopher Golz (University Göttingen) for x-ray
analysis.
9.
REFERENCES
1.
Recent reviews: (a) Yi, H.; Zhang, G.; Wang, H.;
Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Chem. Rev.
2017, 117, 9016-9085. (b) Newton, C. G.; Wang, S.-G.;
Oliveira, C. C.; Cramer, N. Chem. Rev. 2017, 117,
8908-8976. (c) Ma, W.; Gandeepan, P.; Li, J.;
Ackermann, L. Org. Chem. Front. 2017, 4, 1435-1467.
(d) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-
Q. Chem. Rev. 2017, 117, 8754-8786. (e) Shin, K.;
Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040-
1052. (f) Daugulis, O.; Roane, J.; Tran, L. D. Acc.
Chem. Res. 2015, 48, 1053-1064. (g) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879-5918. (h) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215-1292. (i) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48,
5094-5115. (j) Ackermann, L.; Vicente, R.; Kapdi, A.
R. Angew. Chem. Int. Ed. 2009, 48, 9792-9826, (k)
Bergman, R. G. Nature 2007, 446, 391-393, and cited
references.
10.
11.
Li, J.; Korvorapun, K.; De Sarkar, S.; Rogge, T.;
Burns, D. J.; Warratz, S.; Ackermann, L. Nature
Commun. 2017, 8, 15430
(a) Leitch, J. A.; Frost, C. G. Chem. Soc. Rev. 2017,
DOI: 10.1039/C7CS00496F. (b) Leitch, J. A.;
Bhonoah, Y.; Frost, C. G. ACS Catal. 2017, 7, 5618-
5627.
12.
(a) Yuan, C. C.; Chen, X. L.; Zhang, J. Y.; Zhao, Y. S.
Org. Chem. Front. 2017, 4, 1867-1871. (b) Ruan, Z.;
Zhang, S.-K.; Zhu, C.; Ruth, P. N.; Stalke, D.;
Ackermann, L. Angew. Chem. Int. Ed. 2017, 56, 2045-
2049. (c) Paterson, A. J.; Heron, C. J.; McMullin, C.
L.; Mahon, M. F.; Press, N. J.; Frost, C. G. Org.
Biomol. Chem. 2017, 15, 5993-6000. (d) Li, G.; Li, D.;
Zhang, J.; Shi, D.-Q.; Zhao, Y. ACS Catal. 2017, 7,
4138-4143. (e) Li, G.; Gao, P.; Lv, X.; Qu, C.; Yan, Q.;
Wang, Y.; Yang, S.; Wang, J. Org. Lett. 2017, 19,
2682-2685. (f) Leitch, J. A.; McMullin, C. L.; Mahon,
M. F.; Bhonoah, Y.; Frost, C. G. ACS Catal. 2017, 7,
2616-2623. (g) Fan, Z.; Li, J.; Lu, H.; Wang, D.-Y.;
Wang, C.; Uchiyama, M.; Zhang, A. Org. Lett. 2017,
19, 3199-3202. (h) Warratz, S.; Burns, D. J.; Zhu, C.;
Korvorapun, K.; Rogge, T.; Scholz, J.; Jooss, C.;
Gelman, D.; Ackermann, L. Angew. Chem. Int. Ed.
2017, 56, 1557-1560. (i) Fan, Z.; Ni, J.; Zhang, A. J.
Am. Chem. Soc. 2016, 138, 8470-8475. (j) Li, G.; Ma,
X.; Jia, C.; Han, Q.; Wang, Y.; Wang, J.; Yu, L.; Yang,
2.
(a) Lorion, M. M.; Maindan, K.; Kapdi, A. R.;
Ackermann, L. Chem. Soc. Rev. 2017, 46,
DOI:10.1039/C6CS00787B. (b) Catellani, M.; Motti,
E.; Della Ca’, N. Acc. Chem. Res. 2008, 41, 1512–1522.
(c) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc.
Rev. 2004, 33, 302–312.
3.
Teskey, C. J.; Sohel, S. M. A.; Bunting, D. L.; Modha,
S. G.; Greaney, M. F. Angew. Chem. Int. Ed. 2017, 56,
5263-5266.
4.
(a) Bedford, R. B.; Betham, M.; Charmant, J. P. H.;
Weeks, A. L. Tetrahedron 2008, 64, 6038-6050. (b)
Ackermann, L.; Althammer, A. Angew. Chem. Int.
Ed. 2007, 46, 1627-1629. (c) Bedford, R. B.; Cazin, C.
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 9
S. Chem. Commun. 2016, 53, 1261-1264. (k) Teskey, C.
references. The use of oxazolines in organic
synthesis: (k) Hanessian, S.; Vakiti, R. R.; Dorich, S.;
Banerjee, S.; Deschênes-Simard, B. J. Org. Chem.
2012, 77, 9458-9472. (l) Becker, M. H.; Chua, P.;
Downham, R.; Douglas, C. J.; Garg, N. K.; Hiebert,
S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J. A.; Ng,
F. W.; Overman, L. E. J. Am. Chem. Soc. 2007, 129,
11987-12002. (c) Reynolds, A. J.; Scott, A. J.; Turner,
C. I.; Sherburn, M. S. J. Am. Chem. Soc. 2003, 125,
12108-12109.
(a) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50,
2297-2360. (b) Calderari, G.; Seebach, D. Helv.
Chim. Acta 1985, 68, 1592-1604.
For detailed information, see the Supporting
Information.
(a) Ackermann, L.; Novák, P.; Vicente, R.; Hofmann,
N. Angew. Chem. Int. Ed. 2009, 48, 6045-6048.
Reviews: (b) Davies, D. L.; Macgregor, S. A.;
McMullin, C. L. Chem. Rev. 2017, 117, 8649-8709. (c)
Ackermann, L. Chem. Rev. 2011, 111, 1315-1345.
Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-
Delord, J. Chem. Soc. Rev. 2016, 45, 2900-2936.
(a) Gulia, N.; Daugulis, O. Angew. Chem. Int. Ed.
2017, 56, 3630–3634. (b) Moselage, M.; Li, J.; Kramm,
F.; Ackermann, L. Angew. Chem. Int. Ed. 2017, 56,
5341-5344.
Examples of ruthenium-catalyzed para-selctive C–H
functionalizations: (a) Leitch, J. A.; McMullin, C. L.;
Paterson, A. J.; Mahon, M. F.; Bhonoah, Y.; Frost, C.
G. Angew. Chem. Int. Ed. 2017, 56, 15131-15135. (b)
Liu, W.; Ackermann, L. Org. Lett. 2013, 15, 3484-
3486. (c) A review: Dey, A.; Maity, S.; Maiti, D.
Chem. Commun. 2016, 52, 12398-12414.
(a) Boursalian, G. B.; Ham, W. S.; Mazzotti, A. R.;
Ritter, T. Nat. Chem. 2016, 8, 810-815. (b) Stephens,
P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623-11627. (c) Becke, A. D. J.
Chem. Phys. 1993, 98, 5648-5652. (d) Weigend, F.;
Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297-
3305. (e) Schäfer, A.; Horn, H.; Ahlrichs, R. J. Chem.
Phys. 1992, 97, 2571-2557.
1
2
3
4
5
6
7
8
J.; Lui, A. Y. W.; Greaney, M. F. Angew. Chem. Int.
Ed. 2015, 54, 11677-11680. (l) Li, J.; Warratz, S.; Zell,
D.; De Sarkar, S.; Ishikawa, E. E.; Ackermann, L. J.
Am. Chem. Soc. 2015, 137, 13894-13901. (m) Paterson,
A. J.; St John-Campbell, S.; Mahon, M. F.; Press, N.
J.; Frost, C. G. Chem. Commun. 2015, 51, 12807-12810.
(n) Hofmann, N.; Ackermann, L. J. Am. Chem. Soc.
2013, 135, 5877-5884. (o) 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, 19298-19301. (p) Ackermann, L.;
Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875-
1877;
9
17.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18.
19.
13.
(a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281-295.
(b) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403-
1413.
Ackermann, L.; Born, R.; Vicente, R. ChemSusChem
2009, 2, 546-549.
14.
15.
Examples of remote C–H functionalization with
metals other than ruthenium: (a) Bera, M.; Agasti,
S.; Chowdhury, R.; Mondal, R.; Pal, D.; Maiti, D.
Angew. Chem. Int. Ed. 2017, 56, 5272–5276. (b) Bag,
S.; Jayarajan, R.; Mondal, R.; Maiti, D. Angew. Chem.
Int. Ed. 2017, 56, 3182-3186. (c) Chu, L.; Shang, M.;
Tanaka, K.; Chen, Q.; Pissarnitski, N.; Streckfuss, E.;
Yu, J.-Q. ACS Cent. Sci. 2015, 1, 394-399. (d)
Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. Nat.
Chem. 2015, 7, 712-717. (e) Bag, S.; Patra, T.; Modak,
A.; Deb, A.; Maity, S.; Dutta, U.; Dey, A.; Kancherla,
R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D. J. Am.
Chem. Soc. 2015, 137, 11888-11891. (f) Bera, M.; Maji,
A.; Sahoo, S. K.; Maiti, D. Angew. Chem. Int. Ed.
2015, 54, 8515-8519. (g) Tang, R.-Y.; Li, G.; Yu, J.-Q.
Nature 2014, 507, 215-220. (h) Lee, S.; Lee, H.; Tan,
K. L. J. Am. Chem. Soc. 2013, 135, 18778-18781. (i)
Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012,
486, 518-522. (j) Phipps, R. J.; Gaunt, M. J. Science
2009, 323, 1593-1597. (k) Das, S.; Incarvito, C. D.;
Crabtree, R. H.; Brudvig, G. W. Science 2006, 312,
1941-1943.
20.
21.
22.
23.
16.
Examples of C–H activation by imidate assistance:
(a) Mei, R.; Loup, J.; Ackermann, L. ACS Catal. 2016,
6, 793-797. (b) Ebe, Y.; Nishimura, T. J. Am. Chem.
Soc. 2015, 137, 5899-5902. (c) Ogiwara, Y.; Tamura,
M.; Kochi, T.; Matsuura, Y.; Chatani, N.; Kakiuchi, F.
Organometallics 2014, 33, 402-420. (d) Xie, F.; Qi, Z.;
Yu, S.; Li, X. J. Am. Chem. Soc. 2014, 136, 4780-4787.
(e) Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu,
J.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013,
135, 10630-10633. (f) Ackermann, L.; Kozhushkov, S.
I.; Yufit, D. S. Chem. Eur. J. 2012, 18, 12068-12077. (g)
Ouellet, S. G.; Roy, A.; Molinaro, C.; Angelaud, R.;
Marcoux, J.-F.; O’Shea, P. D.; Davies, I. W. J. Org.
Chem. 2011, 76, 1436-1439. (h) Kim, M.; Kwak, J.;
Chang, S. Angew. Chem., Int. Ed. 2009, 48, 8935-
8939. (i) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C.
E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78-79. (j)
Ackermann, L.; Althammer, A.; Born, R. Angew.
Chem. Int. Ed. 2006, 45, 2619-2622, and cited
24.
25.
(a) Kamatchi, T. S.; Chitrapriya, N.; Lee, H.;
Fronczek, C. F.; Fronczekc, F. R.; Natarajan, K.
Dalton Trans. 2012, 41, 2066–2077. (b) Isse, A. A.;
Lin, C. Y.; Coote, M. L.; Gennaro, A. J. Phys. Chem. B
2011, 115, 678–684.
(a) Simonetti, M.; Perry, G. J. P.; Cambeiro, X. C.;
Juliá-Hernández, F.; Arokianathar, J. N.; Larrosa, I. J.
Am. Chem. Soc. 2016, 138, 3596-3606. (b)
Ackermann, L.; Althammer, A.; Born, R.
Tetrahedron 2008, 64, 6115–6124. (c) Ackermann, L.;
Althammer, A.; Born, R. Synlett 2007, 2833-2836.
Cassani, C.; Bergonzini, G.; Wallentin, C.-J. Org.
Lett. 2014, 16, 4228-4231.
26.
27.
(a) Ma, Y.; Zhang, D.; Yan, Z.; Wang, M.; Bian, C.;
Gao, X.; Bunel, E. E.; Lei, A. Org. Lett. 2015, 17, 2174-
2177. (b) Peng, P.; Peng, L.; Wang, G.; Wang, F.; Luo,
Y.; Lei, A. Org. Chem. Front. 2016, 3, 749-752.
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