M-CAr-H Bond Alkylations and Difluoromethylation of Tertiary Phosphines Using a Ruthenium Catalyst

Article abstract of DOI:10.1021/acs.orglett.0c03377

m-CAr-H bond functionalization of tertiary phosphines was developed using [Ru(p-cymene)Cl2]2 as a catalyst. Desired product structures were confirmed by single-crystal X-ray diffraction. Mechanistic experiments indicated that m-CAr-H bond functionalization was a radical reaction and that a hexagonal ruthenacycle complex was a crucial intermediate in the process. Therefore, this study provides a novel method for the late-stage meta-position modification of biphenyl monophosphine ligands.

Full text of DOI:10.1021/acs.orglett.0c03377

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Letter
m‑CAr−H Bond Alkylations and Difluoromethylation of Tertiary
Phosphines Using a Ruthenium Catalyst
Gang Li,* Jiangzhen An, Chunqi Jia, Bingxu Yan, Lei Zhong, Junjie Wang, and Suling Yang
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ABSTRACT: m-CAr−H bond functionalization of tertiary phos-
phines was developed using [Ru(p-cymene)Cl2]2 as a catalyst.
Desired product structures were confirmed by single-crystal X-ray
diffraction. Mechanistic experiments indicated that m-CAr−H bond
functionalization was a radical reaction and that a hexagonal
ruthenacycle complex was a crucial intermediate in the process.
Therefore, this study provides a novel method for the late-stage
meta-position modification of biphenyl monophosphine ligands.
Scheme 1. PO or P-Assisted CAr−H Bond
ertiary phosphines (PAr3) are important molecular
skeletons widely found in agricultural chemicals, bio-
Functionalization
T
logically active molecules, and functional materials, and as
ligands in transition-metal catalysts.1 Their characteristics,
including physicochemical, steric, and electronic properties,
and biological and catalytic activities, are significantly changed
by different R group structures.2 In particular, biphenyl
monophosphines that are air-stable and have greater steric
hindrance are often employed as highly efficient ligands in the
transition-metal catalysis of diverse C−X bond construction (X
= C, O, N, and others).3 Consequently, the straightforward
and efficient synthesis of biphenyl monophosphines has
attracted considerable research interest. In recent years,
transition-metal-catalyzed C−H bond functionalization has
seen intensive development and extensive applications in
organic synthesis owing to its atom and step efficiency
compared with traditional functional group chemistry.4
Initially, as the strong chelating properties of undisguised
monophosphines readily poison the metal catalyst, P(V)O
was often employed as a directing group to realize transition-
metal-catalyzed selective CAr−H bond functionalization,5 with
subsequent reduction providing various biphenyl mono-
phosphine derivatives. Recently, undisguised P(III) atom-
directed transition-metal-catalyzed selective CAr−H bond
functionalization has been reported, providing a step-
economical method for the late-stage modification of mono-
phosphine ligands.6 However, these modification and
functionalization methods for biphenyl monophosphines are
limited to the ortho position relative to the directing group
(Scheme 1). Therefore, remote CAr−H bond functionalization
of biphenyl monophosphines remains challenging.
directing effect of the Ru−CAr bond.13 In these m-CAr−H bond
functionalization strategies, the ruthenium-catalyzed m-CAr−H
bond functionalization reaction type is diverse, the ruthenium
catalyst is relatively inexpensive, and the reaction system is
relatively simple. Furthermore, special substrate structures,
large U-shaped directing groups, directing group removal, and
the addition of an extra cocatalyst are not needed. However,
ruthenium-catalyzed m-CAr−H bond functionalizations have
been limited to nitrogen-containing groups as directing groups.
Using other atoms, such as phosphine and oxygen, to assist
ruthenium-catalyzed m-CAr−H bond functionalization remains
challenging. Herein, we report P atom-directed m-CAr−H bond
functionalization catalyzed by ruthenium, which provides a
Received: October 9, 2020
In recent years, remote CAr−H bond functionalization has
made important progress through several ingenious strategies,
including using steric effects,7 electronic effects,8 U-shaped
templates,9 a norbornene relay,10 traceless directing groups,11
a
copper-promoted four-ring intermediate,12 and the ortho/para-
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A

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Letter
new approach to the meta-position-modified synthesis of
biphenyl monophosphine ligands.
bromides, as shown in Scheme 2. Initially, several [1,1′-
biphenyl]-2-yldiarylphosphane molecules with various sub-
To realize the phosphine-assisted modification and deco-
ration of m-CAr−H bonds, [1,1′-biphenyl]-2-yldiphenylphos-
phane and methyl-2-bromopropanoate were selected as classic
reactants, and [Ru(p-cymene)Cl2]2 and K2CO3 were used as
the catalyst and base, respectively, to explore and optimize the
C−H bond functionalization conditions. In a thick-walled
pressure Schlenk tube under a N2 atmosphere, the reaction was
carried out at 100 °C for 9 h, as shown in Table 1. Pleasingly, a
c
Scheme 2. Substrate Scope
Table 1. Screening of Reaction Conditions
entry
Ru catalyst
base
solvent
yield (%)
1
2
3
4
5
6
7
8
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
[Ru(p-cymene)Cl2]
Ru(p-cymene)(OAc)2
Ru(PPh3)3Cl2
K2CO3
KOAc
Cs2CO3
Na2CO3
CsOAc
NaOAc
K3PO4
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
benzene
benzene
benzene
benzene
benzene
benzene
benzene
toluene
xylene
1,4-dioxane
THF
CH3CN
DMF
13
73
18
25
56
70
30
62
45
22
28
0
0
42
0
0
0
9
10
11
12
13
14
15
16
17
benzene
benzene
benzene
benzene
RuCl3
Ru3(CO)12
a
b
c
For 3.5 h. For 12 h. Reaction conditions: 1 (0.2 mmol), 2 (2
equiv), [Ru(p-cymene)Cl2]2 (3 mol %), KOAc (2 equiv), benzene
(0.5 mL), N2, 100 °C, 9 h. Isolated yield.
small amount of the desired product was obtained in the
benzene solvent (entry 1). Base screening indicated that KOAc
was the most suitable base for the transformation, providing
desired product 3a in 73% isolated yield (entry 2). Other
bases, such as Na2CO3, Cs2CO3, CsOAc, NaOAc, and K3PO4,
were also effective in the process (entries 3−7, respectively),
although the yields were lower than that obtained using KOAc.
The target product was also obtained in other aromatic
solvents, such as toluene, xylene, 1,4-dioxane, and THF
(entries 8−11, respectively). The reaction did not proceed in
CH3CN and DMF as solvents (entries 12 and 13,
respectively). Further investigation indicated that Ru-
(PPh3)3Cl2 was also an effective catalyst for m-CAr−H bond
alkylation, giving the target product in a moderate yield (entry
14). Other ruthenium complexes, such as RuCl3 and
Ru3(CO)12, were ineffective in the process (entries 15 and
16, respectively). The desired product was not obtained when
no catalyst was added to the system (entry 17). Furthermore,
additional experiments indicated that the temperature and
reaction time were critical factors in the transformation. Both
prolonging the reaction time and increasing the reaction
temperature resulted in product decomposition and reduced
yields.
stituents in different positions on the phenyl ring were selected
as substrates. [1,1′-Biphenyl]-2-yldiphenylphosphanes with
different alkyl (3b and 3c) and aryl (3d) groups were suitable
substrates for the transformation. Although the bulky tert-butyl
group usually has a marked steric effect in many organic
reactions, the desired product was afforded in a moderate yield
under the optimized conditions (3c). Halogen substituents
survived in the m-CAr−H bond alkylation, offering the
potential opportunity to construct complex functional
molecules (3e, 3f, 3h, and 3i). Further experiments indicated
that the electronic effect of the reactive phenyl ring was
obvious in the transformation. An electron-donating sub-
stituent (-OCH3, 3g) was favorable for transformation, while
an electron-withdrawing (-CF3) group completely impeded the
reaction. The electronic effect of the directing group on the
phenyl ring was not obvious in the process. Neither electron-
withdrawing groups nor electron-donating groups had a
significant effect on the reaction (3h−3l). Fluorine-containing
groups with unique chemical, biological, and physical proper-
ties were also compatible with the m-CAr−H bond function-
alization (3i−3k). Notably, [2-(naphthalen-2-yl)phenyl]-
diphenylphosphane was also tolerated in the process, providing
the product in a moderate isolated yield (3m). Furthermore,
various alkyl bromides were employed as alkylating reagents in
the transformation. The results showed that both sec-alkyl and
With optimized conditions in hand, we next investigated the
scope and generality of this phosphine-assisted ruthenium-
catalyzed m-CAr−H bond alkylation of arenes with alkyl
B
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tert-alkyl bromides were good coupling reagents in the
phosphine-assisted m-CAr−H bond alkylation (3b−3s).
However, no alkylated products were found in the system
when primary alkyl bromides, such as ethyl 2-bromoacetate
and ethyl 4-bromobutanoate, were employed as alkylation
reagents. To our delight, the alkylation conditions were also
extended to phosphine-assisted m-CAr−H bond difluoroalky-
lation (3t), providing a novel method for preparing meta-
fluoroalkylated biphenyl monophosphine compounds. Un-
fortunately, when alkyl phosphine was used as the directing
group, the desired product was not found in the system.
To further confirm the product structures obtained by
phosphine-assisted m-CAr−H bond alkylation, the liquid
desired products were oxidized to solid phosphine oxides in
a H2O/CH3CN solvent [1:10 (v/v)] at room temperature for
5 min using Selectfluor as an oxidant (Scheme 3).14 The
Scheme 5. First, when (2′,6′-dimethyl-[1,1′-biphenyl]-2-yl)-
diphenylphosphane, in which the two ortho sites of the tertiary
Scheme 5. Designed Experiment
Scheme 3. Oxidation of Desired Products and Single-Crystal
X-ray Structures
phosphine oxide single crystals were grown in a CH2Cl2/
petroleum ether mixed solvent by slow evaporation at room
temperature, and their crystal structures were determined by
single-crystal X-ray diffraction.
In a gram-scale experiment, the phosphine-assisted ruthe-
nium-catalyzed m-CAr−H bond alkylation of arenes with alkyl
bromides also proceeded smoothly, giving the target product in
a moderate yield (Scheme 4). This development provides a
novel and practical strategy for the late-stage meta-position
modification of biphenyl monophosphine ligands.
To clarify the mechanism of this ruthenium-catalyzed
tertiary phosphine m-CAr−H bond functionalization, some
experiments were designed and conducted, as shown in
phosphine directing group were blocked by two methyl groups,
was employed as the substrate, the desired product was not
found in the system under the optimized conditions (Scheme
5a). The results showed that o-CAr−H bond ruthenation was
essential for m-CAr−H bond functionalization. Second,
hexagonal ruthenacycle complex I was synthesized by the
reaction of [1,1′-biphenyl]-2-yldiphenylphosphane with
[Ru(p-cymene)Cl2]2 in CH2Cl2 at rt for 24 h (for details,
see the Supporting Information).6c The desired product was
obtained in excellent yield when complex I was used as the
substrate, indicating that the hexagonal ruthenacycle was a
crucial intermediate in the m-CAr−H bond functionalization
process (Scheme 5b). Third, obvious H/D exchange was
observed in the residual substrate and desired product when 10
equiv of D2O was injected into the m-CAr−H bond
functionalization process. This phenomenon showed not
only that o-C−H ruthenation was a reversible process but
also that water was tolerated in the reaction system (Scheme
5c). Fourth, the desired product was not observed when free
radical quenchers, such as TEMPO and BQ, were added to the
reaction tube (Scheme 5d), showing that m-CAr−H bond
Scheme 4. Gram-Scale Experiment
C
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Accession Codes
functionalization might be a single-electron-transfer (SET)
radical process. Finally, intermolecular competition experi-
ments of two reactant analogues were conducted to evaluate
the impact of electrons and structure on the transformation
(Scheme 5e). The results showed that tertiary phosphines with
higher electron density showed higher reactivity, and that α-
bromocarboxylates showed better reactivity than alkyl
bromides.
CCDC 2026486 and 2026500 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of our experimental results and literature
reports relating to ruthenium-catalyzed CAr−H bond function-
alization,13 a plausible mechanism for the m-CAr−H bond
alkylation process was proposed, as shown in Scheme 6. First,
AUTHOR INFORMATION
Corresponding Author
■
Gang Li − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P. R. China; orcid.org/0000-0002-1609-449X;
Email: ligang@aynu.edu.cn
Scheme 6. Plausible Mechanism
Authors
Jiangzhen An − College of Chemistry and Chemical
Engineering, Henan Province Key Laboratory of New
Optoelectronic Functional Materials, Anyang Normal
University, Anyang 455002, P. R. China
Chunqi Jia − Engineering Research Center of Molecular
Medicine of Ministry of Education, Key Laboratory of Fujian
Molecular Medicine, Key Laboratory of Xiamen Marine and
Gene Drugs, School of Biomedical Sciences, Huaqiao
University, Xiamen 361021, P. R. China
Bingxu Yan − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P. R. China
Lei Zhong − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P. R. China
Junjie Wang − College of Chemistry and Chemical
Engineering, Henan Province Key Laboratory of New
Optoelectronic Functional Materials, Anyang Normal
University, Anyang 455002, P. R. China
Suling Yang − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P. R. China
reversible o-CAr−H bond ruthenation of substrate 1a by [Ru(p-
cymene)Cl2]2 assisted by the phosphine directing group gives
key hexagonal ruthenacycle(II) intermediate I. SET from
ruthenacycle(II) intermediate I to the alkyl bromide generates
an alkyl radical and ruthenium(III) complex II after bromide
transfer. Then, the radical reacts with intermediate II at the
directing group meta position, aided by the CAr−Ru ortho/
para-directing effect, to provide active intermediate III.
Deprotonation of intermediate III generates stable intermedi-
ate IV. Finally, ligand exchange of intermediate IV with 1a
gives the desired product and regenerates intermediate I for
the next catalytic cycle.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03377
In summary, we have developed a m-CAr−H bond alkylation
and fluoroalkylation of tertiary phosphines with alkyl bromides
using [Ru(p-cymene)Cl2]2 as the catalyst. Mechanistic experi-
ments indicated that the m-CAr−H bond functionalization of
tertiary phosphines was a radical process, and that a hexagonal
ruthenacycle complex was a crucial reaction intermediate. This
study provides a novel approach to accessing meta-position-
modified biphenyl monophosphine ligands. Further inves-
tigations to develop new m-CAr−H bond functionalization
reactions of tertiary phosphines and apply this chemistry in
synthesis are underway.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the Program of Science
and Technology Innovation Talents of Henan Province
(19HASTIT035).
REFERENCES
■
́
́
(1) (a) Fernandez-Perez, H.; Etayo, P.; Panossian, A.; Vidal-Ferran,
A. Phosphine-phosphinite and phosphine-phosphite ligands: prepara-
tion and applications in asymmetric catalysis. Chem. Rev. 2011, 111,
2119−2176. (b) Baumgartner, T. Insights on the design and electron-
acceptor properties of conjugated organophosphorus materials. Acc.
Chem. Res. 2014, 47, 1613−1622.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03377.
Detailed experimental procedures and compound
characterization data (PDF)
(2) (a) Wu, K.; Doyle, A. G. Parameterization of phosphine ligands
demonstrates enhancement of nickel catalysis via remote steric effects.
D
https://dx.doi.org/10.1021/acs.orglett.0c03377
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Nat. Chem. 2017, 9, 779−784. (b) Wu, L.; Fleischer, I.; Jackstell, R.;
Profir, I.; Franke, R.; Beller, M. Ruthenium-catalyzed hydro-
formylation/reduction of olefins to alcohols: extending the scope to
internal alkenes. J. Am. Chem. Soc. 2013, 135, 14306−14312. (c) Wu,
L.; Fleischer, I.; Jackstell, R.; Beller, M. Efficient and regioselective
ruthenium-catalyzed hydro-aminomethylation of olefins. J. Am. Chem.
Soc. 2013, 135, 3989−3996. (d) Li, H.; Dong, K.; Jiao, H.; Neumann,
H.; Jackstell, R.; Beller, M. The scope and mechanism of palladium-
catalysed Markovnikov alkoxycarbonylation of alkenes. Nat. Chem.
2016, 8, 1159−1166. (e) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong,
F. K. A mild and efficient palladium-catalyzed cyanation of aryl
mesylates in water or tBuOH/Water. Angew. Chem., Int. Ed. 2010, 49,
8918−8922.
Solorzano, S.; Stewart, T. N.; Miller, C. D.; Morris, K. C.; Daley, C. J.
A.; Clark, T. B. Accessing ambiphilic phosphine boronates through C-
H borylation by an unforeseen cationic Iridium complex. Angew.
Chem., Int. Ed. 2019, 58, 2834−2838. (f) Wen, J.; Wang, D.; Qian, J.;
Wang, D.; Zhu, C.; Zhao, Y.; Shi, Z. Rhodium-catalyzed PIII-directed
ortho-C-H borylation of arylphosphines. Angew. Chem., Int. Ed. 2019,
58, 2078−2082. (g) Fukuda, K.; Iwasawa, N.; Takaya, J. Ruthenium-
catalyzed ortho C-H borylation of arylphosphines. Angew. Chem., Int.
Ed. 2019, 58, 2850−2853. (h) Qiu, X.; Wang, M.; Zhao, Y.; Shi, Z.
Rhodium(I)-catalyzed tertiary phosphine directed C-H arylation:
rapid construction of ligand libraries. Angew. Chem., Int. Ed. 2017, 56,
7233−7237. (i) Li, J.-W.; Wang, L.-N.; Li, M.; Tang, P.-T.; Luo, X.-P.;
Kurmoo, M.; Liu, Y.-J.; Zeng, M.-H. Ruthenium-catalyzed gram-scale
preferential C-H arylation of tertiary phosphine. Org. Lett. 2019, 21,
2885−2889. (j) Wang, D.; Zhao, Y.; Yuan, C.; Wen, J.; Zhao, Y.; Shi,
Z. Rhodium(II)-catalyzed dehydrogenative silylation of biaryl-type
monophosphines with hydrosilanes. Angew. Chem., Int. Ed. 2019, 58,
12529−12533. (k) Wang, D.; Dong, B.; Wang, Y.; Qian, J.; Zhu, J.;
Zhao, Y.; Shi, Z. Rhodium-catalysed direct hydroarylation of alkenes
and alkynes with phosphines through phosphorous-assisted C-H
(3) (a) Ruiz-Castillo, P.; Buchwald, S. L. Applications of palladium-
catalyzed C-N cross-coupling reactions. Chem. Rev. 2016, 116,
12564−12649. (b) Sather, A. C.; Buchwald, S. L. The evolution of
Pd0/PdII-catalyzed aromatic fluorination. Acc. Chem. Res. 2016, 49,
2146−2157.
(4) (a) Gandeepan, P.; Muller, T.; Zell, D.; Cera, G.; Warratz, S.;
̈
Ackermann, L. 3d Transition metals for C-H activation. Chem. Rev.
2019, 119, 2192−2452. (b) Evano, G.; Theunissen, C. Beyond friedel
and crafts: directed alkylation of C-H bonds in arenes. Angew. Chem.,
activation. Nat. Commun. 2019, 10, 3539. (l) Zhang, Z.; Roisnel, T.;
I
́
Dixneuf, P. H.; Soule, J.-F. Rh -catalyzed PIII-directed C-H bond
̈
Int. Ed. 2019, 58, 7202−7236. (c) Sambiagio, C.; Schonbauer, D.;
alkylation: design of multifunctional phosphines for carboxylation of
aryl bromides with carbon dioxide. Angew. Chem., Int. Ed. 2019, 58,
14110−14114. (m) Li, J.-W.; Wang, L.-N.; Li, M.; Tang, P.-T.; Zhang,
N.-J.; Li, T.; Luo, X.-P.; Kurmoo, M.; Liu, Y.-J.; Zeng, M.-H. Late-
stage modification of tertiary phosphines via ruthenium(II)-catalyzed
C-H alkylation. Org. Lett. 2020, 22, 1331−1335.
Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.;
Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch,
̈
M. A comprehensive overview of directing groups applied in metal-
catalysed C-H functionalisation chemistry. Chem. Soc. Rev. 2018, 47,
6603−6743. (d) Qin, Y.; Zhu, L.; Luo, S. Organocatalysis in inert C-
H bond functionalization. Chem. Rev. 2017, 117 (13), 9433−9520.
(e) Xue, X.-S.; Ji, P.; Zhou, B.; Cheng, J.-P. The essential role of bond
energetics in C-H activation/functionalization. Chem. Rev. 2017, 117
(13), 8622−8648. (f) Wu, S.; Wu, X.; Wu, Z.; Zhu, C. Regioselective
introduction of vinyl trifluoromethylthioether to remote unactivated
C(sp3)-H bonds via radical translocation cascade. Sci. China: Chem.
2019, 62, 1507−1511. (g) Zhang, D.; Huang, Z.; Lei, A. Oxidation-
induced ortho-selective C-H bond functionalization of 2-naphthyl-
amine derivative. Sci. China: Chem. 2018, 61, 1274−1277.
(7) (a) Cheng, C.; Hartwig, J. F. Rhodium-catalyzed intermolecular
C-H silylation of arenes with high steric regiocontrol. Science 2014,
343, 853−857. (b) Bisht, R.; Hoque, E.; Chattopadhyay, B. Amide
effects in C-H activation: noncovalent interactions with L-shaped
ligand for meta borylation of aromatic amides. Angew. Chem., Int. Ed.
2018, 57, 15762−15766.
(8) Ye, M.; Gao, G.-L.; Yu, J.-Q. Ligand-promoted C-3 selective C-H
olefination of pyridines with Pd catalysts. J. Am. Chem. Soc. 2011, 133,
6964−6967.
(5) (a) Liu, Z.; Wu, J.-Q.; Yang, S.-D. Ir(III)-catalyzed direct C-H
functionalization of arylphosphine oxides: a strategy for MOP-type
ligands synthesis. Org. Lett. 2017, 19, 5434−5437. (b) Du, Z.-J.;
Guan, J.; Wu, G.-J.; Xu, P.; Gao, L.-X.; Han, F.-S. Pd(II)-catalyzed
enantioselective synthesis of P-stereogenic phosphinamides via
desymmetric C-H arylation. J. Am. Chem. Soc. 2015, 137, 632−635.
(c) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z. J. Palladium-catalyzed
C-H arylation of indoles at the C7 position. J. Am. Chem. Soc. 2016,
138, 495−498. (d) Unoh, Y.; Satoh, T.; Hirano, K.; Miura, M.
Rhodium(III)-catalyzed direct coupling of arylphosphine derivatives
with heterobicyclic alkenes: a concise route to biarylphosphines and
dibenzophosphole derivatives. ACS Catal. 2015, 5, 6634−6639.
(e) Kim, Y.; Li, C.-J. Perspectives on green synthesis and catalysis.
Green Synth. Catal. 2020, 1, 1−11. (f) Ma, Y.-N.; Li, S.-X.; Yang, S.-D.
New approaches for biaryl-based phosphine ligand synthesis via P = O
directed C-H functionalizations. Acc. Chem. Res. 2017, 50, 1480−
1492. (g) Zhang, H.; Yang, S. Palladium-catalyzed R2(O)P-directed
C(sp2)-H activation. Sci. China: Chem. 2015, 58, 1280−1285.
(6) (a) Qiu, X.; Wang, M.; Zhao, Y.; Shi, Z. Rhodium(I)-catalyzed
tertiary phosphine directed C-H arylation: rapid construction of
ligand libraries. Angew. Chem., Int. Ed. 2017, 56, 7233−7237. (b) Qiu,
X.; Wang, P.; Wang, D.; Wang, M.; Yuan, Y.; Shi, Z. P(III)-chelation-
assisted indole C7-arylation, olefination, methylation, and acylation
with carboxylic acids/anhydrides by rhodium catalysis. Angew. Chem.,
Int. Ed. 2019, 58, 1504−1508. (c) Luo, X.; Yuan, J.; Yue, C.-D.;
Zhang, Z.-Y.; Chen, J.; Yu, G.-A.; Che, C.-M. Synthesis of peri-
substituted (naphthalen-1-yl)phosphine Ligands by rhodium(I)-
catalyzed phosphine-directed C-H arylation. Org. Lett. 2018, 20,
1810−1814. (d) Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.;
Clark, T. B. Phosphine-directed C-H borylation reactions: facile and
selective access to ambiphilic phosphine boronate esters. Angew.
Chem., Int. Ed. 2014, 53, 7589−7593. (e) Wright, S. E.; Richardson-
(9) (a) Tang, R.-Y.; Li, G.; Yu, J.-Q. Conformation-induced remote
meta-C-H activation of amines. Nature 2014, 507, 215−220. (b) Xu,
H.-J.; Kang, Y.-S.; Shi, H.; Zhang, P.; Chen, Y.-K.; Zhang, B.; Liu, Z.-
Q.; Zhao, J.; Sun, W.-Y.; Yu, J.-Q.; Lu, Y. Rh(III)-catalyzed meta-C-H
alkenylation with alkynes. J. Am. Chem. Soc. 2019, 141, 76−79.
(c) Jayarajan, R.; Das, J.; Bag, S.; Chowdhury, R.; Maiti, D. Diverse
meta-C-H functionalization of arenes across different linker lengths.
Angew. Chem., Int. Ed. 2018, 57, 7659−7663. (d) Xu, J.-C.; Chen, J.-J.;
Gao, F.; Xie, S.-G.; Xu, X.-H.; Jin, Z.; Yu, J.-Q. Sequential
functionalization of meta-C-H and ipso-C-O bonds of phenols. J.
Am. Chem. Soc. 2019, 141, 1903−1907. (e) Li, S.; Cai, L.; Ji, H.; Yang,
L.; Li, G. Pd(II)-catalysed meta-C-H functionalizations of benzoic
acid derivatives. Nat. Commun. 2016, 7, 10443.
(10) (a) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.;
Engle, K. M.; Yu, J.-Q. Ligand-enabled meta-C-H activation using a
transient mediator. Nature 2015, 519, 334−338. (b) Dong, Z.; Wang,
J.-C.; Dong, G.-B. Simple amine-directed meta-selective C-H arylation
via Pd/norbornene catalysis. J. Am. Chem. Soc. 2015, 137, 5887−
5890.
(11) (a) Kumar, N. Y. P.; Bechtoldt, A.; Raghuvanshi, K.;
Ackermann, L. Ruthenium(II)-catalyzed decarboxylative C-H activa-
tion: versatile routes to meta-alkenylated arenes. Angew. Chem., Int. Ed.
2016, 55, 6929−6932. (b) Qin, X.; Sun, D.; You, Q.; Cheng, Y.; Lan,
J.; You, J. Rh(III)-catalyzed decarboxylative ortho-heteroarylation of
aromatic carboxylic acids by using the carboxylic acid as a traceless
directing group. Org. Lett. 2015, 17, 1762−1765. (c) Yu, D.-G.; de
Azambuja, F.; Glorius, F. Direct functionalization with complete and
switchable positional control: free phenol as a role model. Angew.
Chem., Int. Ed. 2014, 53, 7710−7712. (d) Luo, J.; Preciado, S.;
Larrosa, I. Overriding ortho-para selectivity via a traceless directing
group relay strategy: The meta-selective arylation of phenols. J. Am.
Chem. Soc. 2014, 136, 4109−4112. (e) Zhang, Y.; Zhao, H.; Zhang,
E
https://dx.doi.org/10.1021/acs.orglett.0c03377
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
M.; Su, W.-P. Carboxylic acids as traceless directing groups for the
rhodium(III)-catalyzed decarboxylative C-H arylation of thiophenes.
Angew. Chem., Int. Ed. 2015, 54, 3817−3821.
(v) Fumagalli, F.; Warratz, S.; Zhang, S.-K.; Rogge, T.; Zhu, C.;
Stu
̈
ckl, A. C.; Ackermann, L. Arene-ligand-free ruthenium(II/III)
manifold for meta-C-H alkylation: remote purine diversification.
Chem. - Eur. J. 2018, 24, 3984−3988. (w) Paterson, A. J.; St John-
Campbell, S.; Mahon, M. F.; Press, N. J.; Frost, C. G. Catalytic meta-
selective C-H functionalization to construct quaternary carbon
centres. Chem. Commun. 2015, 51, 12807−12810. (x) Paterson, A.
J.; Heron, C. J.; McMullin, C. L.; Mahon, M. F.; Press, N. J.; Frost, C.
G. α-Halo carbonyls enable meta selective primary, secondary and
tertiary C-H alkylations by ruthenium catalysis. Org. Biomol. Chem.
2017, 15, 5993−6000.
(12) (a) Phipps, R. J.; Gaunt, M. J. A meta-selective copper-catalyzed
C-H bond arylation. Science 2009, 323, 1593−1597. (b) Yang, Y.-Q.;
Li, R.-R.; Zhao, Y.; Zhao, D.-B.; Shi, Z.-Z. Cu-catalyzed direct C6-
arylation of indoles. J. Am. Chem. Soc. 2016, 138, 8734−8737.
(13) (a) Leitch, J. A.; Frost, C. G. Ruthenium-catalysed σ-activation
for remote meta-selective C-H functionalization. Chem. Soc. Rev. 2017,
46, 7145−7153. (b) Ruan, Z.; Zhang, S.-K.; Zhu, C.; Ruth, P. N.;
Stalke, D.; Ackermann, L. Ruthenium(II)-catalyzed meta C-H mono-
and difluoromethylations by phosphine/carboxylate cooperation.
Angew. Chem., Int. Ed. 2017, 56, 2045−2049. (c) Yu, Q.; Hu, L. A.;
Wang, Y.; Zheng, S.-S.; Huang, J.-H. Directed meta-selective
bromination of arenes with ruthenium catalysts. Angew. Chem., Int.
Ed. 2015, 54, 15284−15288. (d) Fan, Z.-L.; Ni, J.-B.; Zhang, A. meta-
Selective CAr-H nitration of arenes through a Ru3(CO)12-catalyzed
ortho-metalation strategy. J. Am. Chem. Soc. 2016, 138, 8470−8475.
(e) Li, B.; Li, D.-Z.; Zhang, J.-Y.; Shi, D.-Q.; Zhao, Y.-S. Ligand-
enabled regioselectivity in the oxidative cross-coupling of arenes with
toluenes and cycloalkanes using ruthenium catalysts: tuning the site-
selectivity from the ortho to meta positions. ACS Catal. 2017, 7,
4138−4143. (f) Li, B.; Fang, S.-L.; Huang, D.-Y.; Shi, B.-F. Ru-
catalyzed meta-C-H benzylation of arenes with toluene derivatives.
Org. Lett. 2017, 19, 3950−3953. (g) Jing, K.; Li, Z.-Y.; Wang, G.-W.
Direct decarboxylative meta-selective acylation of arenes via an ortho-
ruthenation strategy. ACS Catal. 2018, 8, 11875−11881. (h) Li, G.;
Jia, C. Q.; Cai, X. F.; Zhong, L.; Zou, L.; Cui, X. L. Ruthenium-
catalyzed meta-C-H bond alkylation of aryl 2-pyridyl ketones. Chem.
Commun. 2020, 56, 293−296. (i) Gandeepan, P.; Koeller, J.;
Korvorapun, K.; Mohr, J.; Ackermann, L. Visible-light-enabled
ruthenium-catalyzed meta-C-H alkylation at room temperature.
Angew. Chem., Int. Ed. 2019, 58, 9820−9825. (j) Wang, X.-G.; Li,
Y. K.; Liu, H.-C.; Zhang, B.-S.; Gou, X.-Y.; Wang, Q.; Ma, J. W.;
Liang, Y.-M. Three-component ruthenium-catalyzed direct meta-
selective C-H activation of arenes: A new approach to the
alkylarylation of alkenes. J. Am. Chem. Soc. 2019, 141, 13914−
14922. (k) Sagadevan, A.; Greaney, M. F. meta-Selective C-H
activation of arenes at room temperature using visible light: dual-
function ruthenium catalysis. Angew. Chem., Int. Ed. 2019, 58, 9826−
9830. (l) Li, J.; Korvorapun, K.; De Sarkar, S.; Rogge, T.; Burns, D. J.;
Warratz, S.; Ackermann, L. Ruthenium(II)-catalysed remote C-H
alkylations as a versatile platform to meta-decorated arenes. Nat.
Commun. 2017, 8, 15430. (m) Reddy, G. M.; Rao, N. S.; Maheswaran,
H. Highly meta-Selective halogenation of 2-phenylpyridine with a
ruthenium(I) catalyst. Org. Chem. Front. 2018, 5, 1118−1123.
(n) Yuan, C. C.; Chen, X. L.; Zhang, J. Y.; Zhao, Y. S. meta-Selective
C-H difluoromethylation of various arenes with a versatile ruthenium
catalyst. Org. Chem. Front. 2017, 4, 1867−1871. (o) Khan, F. F.;
Sinha, S. K.; Lahiri, G. K.; Maiti, D. Ruthenium-mediated distal C-H
activation. Chem. - Asian J. 2018, 13, 2243−2256. (p) Sasmal, S.;
Sinha, S. K.; Lahiri, G. K.; Maiti, D. A directing group-assisted
ruthenium-catalyzed approach to access meta-nitrated phenols. Chem.
Commun. 2020, 56, 7100−7103. (q) Hofmann, N.; Ackermann, L.
meta-Selective C-H bond alkylation with secondary alkyl halides. J.
Am. Chem. Soc. 2013, 135, 5877−5884. (r) Li, J.; Warratz, S.; Zell, D.;
De Sarkar, S.; Ishikawa, E. E.; Ackermann, L. N-Acyl amino acid
ligands for ruthenium(II)-catalyzed meta-C-H tert-alkylation with
removable auxiliaries. J. Am. Chem. Soc. 2015, 137, 13894−13901.
(14) Chen, Q.; Zeng, J.; Yan, X.; Huang, Y.; Du, Z.; Zhang, K.; Wen,
C. Mild and efficient oxidation of phosphorus(III) compounds with
Selectfluor. Tetrahedron Lett. 2016, 57, 3379−3381.
(s) Korvorapun, K.; Kaplaneris, N.; Rogge, T.; Warratz, S.; Stuckl, A.
̈
C.; Ackermann, L. Sequential meta-/ortho-C-H functionalizations by
one-pot ruthenium(II/III) catalysis. ACS Catal. 2018, 8, 886−892.
(t) Korvorapun, K.; Kuniyil, R.; Ackermann, L. Late-stage
diversification by selectivity switch in meta-C-H activation: evidence
for singlet stabilization. ACS Catal. 2020, 10, 435−440. (u) Korvor-
apun, K.; Moselage, M.; Struwe, J.; Rogge, T.; Messinis, A. M.;
Ackermann, L. Regiodivergent C-H and decarboxylative C-C
alkylation by ruthenium catalysis: ortho versus meta position-
selectivity. Angew. Chem., Int. Ed. 2020, 59, 18795−18803.
F
https://dx.doi.org/10.1021/acs.orglett.0c03377
Org. Lett. XXXX, XXX, XXX−XXX