Copper-Catalyzed Direct C-H Alkylation of Polyfluoroarenes by Using Hydrocarbons as an Alkylating Source

Article abstract of DOI:10.1021/jacs.0c00169

Construction of carbon-carbon bonds is one of the most important tools in chemical synthesis. In the previously established cross-coupling reactions, prefunctionalized starting materials were usually employed in the form of aryl or alkyl (pseudo)halides or their metalated derivatives. However, the direct use of arenes and alkanes via a 2-fold oxidative C-H bond activation strategy to access chemoselective C(sp2)-C(sp3) cross-couplings is highly challenging due to the low reactivity of carbon-hydrogen (C-H) bonds and the difficulty in suppressing side reactions such as homocouplings. Herein, we present the new development of a copper-catalyzed cross-dehydrogenative coupling of polyfluoroarenes with alkanes under mild conditions. Relatively weak sp3 C-H bonds at the benzylic or allylic positions, and nonactivated hydrocarbons could be alkylated by the newly developed catalyst system. A moderate-to-high site selectivity was observed among various C-H bonds present in hydrocarbon reactants, including gaseous feedstocks and complex molecules. Mechanistic information was obtained by performing combined experimental and computational studies to reveal that the copper catalyst plays a dual role in activating both alkane sp3 C-H bonds and sp2 polyfluoroarene C-H bonds. It was also suggested that the noncovalent π-πinteraction and weak hydrogen bonds formed in situ between the optimal ligand and arene substrates are key to facilitating the current coupling reactions.

Full text of DOI:10.1021/jacs.0c00169

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Article
Copper-Catalyzed Direct C–H Alkylation of Polyfluoroarenes
by Using Hydrocarbons as an Alkylating Source
Weilong Xie, Joon Heo, Dongwook Kim, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00169 • Publication Date (Web): 31 Mar 2020
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Page 1 of 11
Journal of the American Chemical Society
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Copper-Catalyzed Direct C–H Alkylation of Polyfluoroarenes
by Using Hydrocarbons as an Alkylating Source
Weilong Xie,†,‡ Joon Heo,†,‡ Dongwook Kim,‡,† and Sukbok Chang*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 34141, Republic of Korea
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‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea
Supporting Information Placeholder
ABSTRACT: Construction of carbon–carbon bonds is one of the most important tools in chemical synthesis. In the previously established
cross-coupling reactions, pre-functionalized starting materials are employed usually in the form of aryl- or alkyl (pseudo)halides or their
metallated derivatives. However, direct use of arenes and alkanes via a twofold oxidative C–H bond activation strategy to access chemoselective
C(sp2)–C(sp3) cross-couplings is highly challenging due to the low reactivity of carbon–hydrogen (C–H) bonds and the difficulty in
suppressing side reactions such as homocouplings. Herein, we present the new development of a copper-catalyzed cross-dehydrogenative
coupling of polyfluoroarenes with alkanes under mild conditions. Not only relatively weak sp3 C–H bonds being at the benzylic or allylic
positions but also non-activated hydrocarbons could be alkylated by the newly developed catalyst system. A moderate to high site-selectivity
was observed among various C–H bonds present in hydrocarbon reactants even including gaseous feedstocks and complex molecules.
Mechanistic information was obtained by performing combined experimental and computational studies to reveal that copper catalyst plays a
dual role in activating both sp3 C–H bonds of alkanes and sp2 polyfluoroarene C–H bonds. It was also suggested that non-
covalent  interaction and weak hydrogen bonds formed in situ between the optimal ligand and arene substrates are key to facilitate the
current coupling reactions.
products by effectively suppressing the side-pathways such as
 INTRODUCTION
homocoupling or over-alkylation (arylation).6,9
Formation of carbon–carbon bonds is crucial to increase molecular
Based on our previous (NHC)Cu-catalyzed amidation of
diversity in synthesis.1 In particular, arylation reactions serve as an
(hetero)arenes,10 we envisioned that in stiu generated copper-aryl
important toolbox in preparation of numerous chemical building
intermediates might be able to couple with sp3-hybridized carbon
units as well as commercial products containing phenyl chains.
radicals to form the desired alkylation products (Scheme 1c). In the
Transition metal-catalyzed cross-couplings between organo-
Kharasch–Sosnovsky reaction,11 allylic C–H bonds are activated by
nucleophiles and aryl (pseudo)halides are most widely employed in
a copper/peroxide system to afford carbon radicals that eventually
this context.2 This approach has been further expanded its scope to
give rise to ether12 or amine products13. More recently, Cu-catalyzed
include alkyl electrophiles as a coupling partner (Scheme 1a).
oxidative arylation at the benzylic C–H bonds was achieved by using
However, there is room to improve in this case mainly because a key
arylboronic esters to afford diarylalkanes.5c
metal alkyl intermediate is prone to undesired -hydride
Polyfluoroarenes are widely utilized in medicinal chemistry14 and
elimination.3 While direct arylation of inert hydrocarbons via C–H
materials science15 owing to their unique properties derived from the
bond activation is highly attractive,4 on the other hand, catalytic C–
fluorine moiety. Direct functionalization of polyfluoroarenes such as
H arylation of alkanes with aryl nucleophiles/electrophiles has only
arylation16, olefination17, alkynylation18, allylation19 and amination10
recently been reported,5 where a single-electron transfer pathway
has been achieved by several research groups including us. In
contrast, only a few examples of C–H alkylation of polyfluoroarenes
was found to be more effective (Scheme 1b).
Despite the recent promise, a direct coupling between alkanes and
are known; Pd or Cu-catalyzed benzylation with benzyl
arenes via a twofold oxidative C–H bond activation to yield C(sp2)–
chlorides20a,16b and Cu-catalyzed alkylation with diazo
compounds20b. In the palladium catalysis system, the coupling
reagents were limited to primary benzyl halides, probably due to the
C(sp3) bonds is largely underdeveloped as a synthetic tool.6,7 Indeed,
only a few examples have been revealed with limited scope and/or
under harsh conditions. For instance, a ruthenium-catalyzed cross-
competing -hydride elimination pathway of alkyl-metal species. In
dehydrogenative coupling (CDC) of arenes with cycloalkanes (135
addition, Rh-catalyzed conjugate addition of polyfluoroarenes to
oC) was reported while it requires directing groups to facilitate an
activated olefins was reported to form alkylated polyfluoroarenes.20c
ortho-metallacyclic intermediate.7a A copper/pyridine-mediated
The paucity of the alkylation procedure can be ascribed to the low
stoichiometric reaction of methyl C–H bonds of aliphatic quinoline
reactivity of the polyfluoroaryl–metal intermediates (due to the
strong σ-bonds of M–C6F5) towards alkyl electrophiles.21
Meanwhile, a competing path for the homocoupling of
o
amides with polyfluoroarenes (140 C) was recently developed.7d
Additionally, direct alkylation of N-heteroarenes with alkanes via a
Minisci-type pathway was well investigated.8 The biggest challenge
in the coupling of arenes with alkanes via a twofold C–H activation
approach without relying on the chelation-assistance is to secure its
high chemoselectivity to maximize the desired cross-coupled
polyfluoroarenes would also give rise to
chemoselectivity issue.18,22
a challenging
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Scheme 1. Ligand-Enabled Cu-Catalyzed Alkylation of Polyfluoroarenes with Hydrocarbons
1
a Conventional Methods for C(sp2)–C(sp3) Bond Formation
b Alkylation of Pre-functionalized Arenes with Alkanes
2
M
X
Y
H
3
4
+
TM
Ar
+
TM
Ar
Ar
Ar
5
6
7
= MgX, ZnX, B(OR)2, SiR3, SnR3, or pseudohalides
M
i) B(OR)2 : Cu or Ni catalysis
Y
= (pseudo)halides; Cl, Br, I, etc
X
ii) Br : Metallaphotoredox catalysis (W + Ni + Photo)
8
9
c Direct Coupling of Hydrocarbons with Polyfluoroarenes
Key strategy
C(sp3)–H
C(sp2)–H
Feedstocks
BDE
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Dual
activation
Radical path
Kharasch reaction
kcal/mol
Ionic path
89
89
H
Fn
benzylic
Cu catalysis
H
via HAA
via deprot.
Cu
Fn
x = 1
2
Fn
H
Ar
+
Cux
Ar
3
[LCu]–OR
H–OR
L
Cu
allylic
Fn
Cu–aryl intermediate
(our previous work)ref.10
100
H
H
C(sp2)–C(sp3)
Dual activation
mode of C–H bonds
aliphatic
H
bond formation
RO
side pathways
Fn
101(pri)
99(sec)
up to 99% yield
+
Fn
gaseous
Efficient suppression of side path
C(sp2)–C(sp3) Bond Formation



Broad scope including gaseous feedstocks (> 60 examples)
Mild reaction conditions / scalable (50 mmol)
Late-stage functionalizations



Selectivity favoring secondary C–H bonds over primary/tertiary
Combined mechanistic studies (computations/experiments)
Dual activation mode: radical and ionic pathways
The importance of alkylated fluoroarene moieties (i.e., sitagliptin,
omarigliptin and isavuconazole) in the pharmaceutical industry
further drew our interest to develop a general and practical strategy
for the alkylation reactions. Herein, we report the development of a
copper-catalyzed direct alkylation of polyfluoroarenes with various
types of hydrocarbons (Scheme 1c). Not only benzylic and allylic
C–H bonds (bond dissociation energy; BDE = ~90 kcal/mol) but
also more challenging hydrocarbon C–H bonds (BDE = ~100
kcal/mol) are readily coupled under the currently developed
catalytic conditions.23 It was found that the electronic and steric
properties of the optimized β‐diketimine ligand are crucial in
achieving the desired chemoselectivity by harnessing the high
reactivity of key intermediates. Mechanistically, the present copper
catalyst system was found to induce selective dual activation of both
fluoroarenes and alkanes, eventually merging them into a combined
product-generating process. Non-covalent – interaction and
weak hydrogen bonds formed in situ between ligands and arene
substrates were rationalized to facilitate the current cross-
couplings.24 The developed alkylation of polyfluoroarenes is
convenient to operate even in a decagram scale and is broad in scope
of hydrocarbons including gaseous hydrocarbons and complex
molecules.
moderate to low product yields were obtained with such
conventional ligands as bisoxazolines, NHCs, phosphines,
bipyridines or trispyrazolylborate, the use of β‐diketimine ligand (L1)
showed a promise by effectively surprising side products (Table 1).
From the additional screening of synthetically readily accessible
β‐diketimine scaffolds, the most optimal ligand turned out to be L10
giving rise to the desired product 3 in 85% yield with <5% of side
o
products (4 + 5) at 80 C. Notably, electronic and/or steric
variations on β‐diketimines greatly affected the reaction efficiency
and chemoselectivity. For instance, while ligands with highly
electron-deficient or electron-rich aryl moieties (i.e. L2–L6, L12–
L14) gave lower product yields and the presence of ortho-methyl
group on the phenyl imine displayed high reactivity. When ligand L4
having 2,6-bistrifluoromethyl substituents was applied, the
alkylation took place with lower efficiency and decreased selectivity
compared to L1, thus demonstrating that the ligand structure
displays a high impact on the reaction performance. In the same line,
ligands containing sterically hindered substituents such as 2,6-
isopropyl group on the phenyl ring could not form the desired
product (L16). It is worth mentioning that β‐diketimine copper
complexes were elegantly utilized in the etherification and
amidation reactions by Warren et al.12,13b While a base additive were
essential, catalytic amounts of tBuONa were found to be viable albeit
with longer reaction time (Figure 1a, 71% of 3 with 0.8 equiv of
tBuONa in 24 h and 72% with 0.2 equiv of tBuONa in 40 h). The
result that weak bases such as K2CO3 and Cs2CO3 were ineffective
was rationalized to be closely related to the efficiency in generating
the catalytically active copper species (vide infra and see also the
Mechanistic Studies in the Supporting Information). Further
investigations on the reaction temperature disclosed that the
 RESULTS AND DISCUSSIONS
Reaction Optimization. We embarked on our studies by examining
a model reaction of ethylbenzene (1) with 2,3,5,6-tetrafluoroanisole
(2) under various conditions (see Tables S1–S7 in the Supporting
Information for details). Various types of ligands were extensively
screened in combination with catalytic amounts of copper salts in
the presence of oxidants and bases. The desired C(sp2)–C(sp3)
cross-coupled product (3) was observed to form along with a homo-
coupled bisarene (4)22 and an ether byproduct (5)12. While
o
catalytic system showed the highest coupling efficiency at 80 C
(Figure 1b). Among various oxidants evaluated in combination with
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Journal of the American Chemical Society
selective arylation at the secondary benzylic C–H bonds (19–21),
L10, di-tert-butyl peroxide (DTBP) was especially effective in
1
2
3
4
5
6
7
8
obtaining the desired coupling. Other oxidants such as
(PhMe2CO)2, (BzO)2, tBuOOBz and NFSI gave lower product
yields, and various first row metal catalysts including iron, cobalt and
nickel were observed to be ineffective for the cross-coupling reaction.
The alkylation efficiency was slightly decreased by employing
reduced equivalents of the alkane reactant (e.g, 64% product yield
with 5 equiv of ethylbenzene and 78% with 10 equiv of
ethylbenzene). It is worth mentioning that most of unreacted
ethylbenzene could be recovered (89%) and a trace amount (<5%)
of dimerization byproduct of ethylbenzene was observed under the
optimal conditions.
and the structure of the product 19 was confirmed by an X-ray
crystallographic analysis. Of special note is that a readily obtained
product 21 can serve as a precursor to pharmaceutically relevant
derivatives of 3,3-diarylpropylamines such as tolpropamine and
segontin. 1-Ethylnaphthalene was arylated in good yield (22) and
cyclic benzyl C–H bonds were also highly facile (23 and 24).
Heterocyclic moieties were competent as demonstrated in an
arylation of 2-ethylthiophene (25).
a
Influence of base amounts (t = 24 h)
b
Influence of temperature (0.2 equiv. tBuONa)
9
40 h
10
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60
72
71
52
Table 1. Ligand Screening for the C–H Alkylation of
Tetrafluoroanisole with Ethylbenzenea
42
60
side products
OMe
H
[Cu] (cat.)
F
F
34
H
F
F
F
F
L
(cat.)
56
F
F
F
F
OtBu
Me
DTBP
54
54
+
+
+
MeO
OMe
F
F
tBuONa (cat.)
PhEt, 80 oC, 24 h
52
Ph
OMe
F
F
F
F
22
40 h
2.0 equiv.
tBuONa
1
2
3, desired product
4
5
13
Various types of ligand systems
Ph Ph
Ts NH HN Ts
<1
<1
5
O
O
N
N
N
N
N
OH HO
N
N
Ph
/ 6 / -)
Ar
Ar
Ph
L-BOX1
tBuONa (equiv.)
T (oC)
L-Am1
-
L-pyIm
-
2
L-Sal -
( / - / -)
(
/ - / -)
(
/ - / -)
(
Figure 1. (a) Influence of the base amounts for the current alkylation
reactions with ligand L1. (b) Influence of the reaction temperature for
the alkylation system with ligand L1.
Table 2. Scope of Hydrocarbons Reacting at the Benzylica and
N
N
H
B
N
Cl
N
N
N
Ph
Ph
N
P
K
N
Ph
N
N
H
L-NHC3
8
L-Tp
4
L-Phos1 30
L-Phen2 20
(
/ 16 / -)
(
/ 9 / -)
(
/ 6 / -)
(
/ 16 / -)
Me
Allylicb C–H Bonds
Pdt =
Me
CuBr SMe
2 (10 mol%)
(15 mol%)
DTBP (4.0 equiv.)
O
N
O
N
H
N
L10
F
F
F
F
H
N
HN
Me NH HN Me
F
F
F
F
H
Ar
N
N
+
OR
Ar
tBuONa (80 mol%)
C6H6, 60–80 oC, 24 h
OR =
L-pyBOX2 10
L-Bipy 31
L-Am2 24
L1 54
( / 2 / -)
(
/ 18 / 3)
(
/ 18 / -)
(
/ 27 / -)
OR
Abundant
Feedstocks
high chemoselectivity
& reactivity
6
O
5–10 equiv.
-Diketiminate ligand system
Benzylic C–H bonds
Me
Me
F
F
F
F
Cl
Cl
F3
C
CF3
Ar
Ar
Ar
Ar
Ar
N
HN
Ar
Ar
F
F
F3
C
CF3
F
L1–L17
MeO
3
(
/ 4 / 5)
L2
L3 26
(
L4 33
L5 32
L6 40
(
(- / - / -)
/ 18 / -)
(
/ 23 / -)
(
/ 13 / -)
Me
/ 10 / 14)
OMe
7
8,
9
10
15
11
16
, 80%
81%
, 63%
Ar
, 94%
, 86%
H
H
Me
Me
Me
Me
Ar
Ar
Ar
Ar
Me
L9
Me
Me
L11 26
/ 11 / -)
Me
Cl
Br
I
F
L7 10
(
L8 31
(
-
L10 85
/ 10 / -)
/ 12 / -)
(
/ - / -)
(
/ - / 2)
(
L1 71
(
/ - / -)
12
13
14
, 84%
, 84%
, 84%
, 57%
, 53%
MeO
OMe
OMe
Et
Et iPr
iPr
Ar
Ar
Ar
Ar
MeO
L13 54
NMe2
L12 54
(
L14 31
L15 13
(
L16
-
L17 14
( / 7 / 3)
/ 5 / -)
(
/ 5 / -)
(
/ 13 / -)
/ 2 / -)
(
/ 2 / -)
aSee the Supporting Information for the experimental details.
17
21
18
22
19
23
19
20
25
, 91%
, 79%
Ar
, 63%
(X-ray of
)
, 45%
Scope of Hydrocarbons and Polyfluoroarenes. With the
optimized conditions in hands, the scope of alkanes was next
Ar
Ar
Ar
Ar
Cl
explored
in
reaction
with
naphthalen-2-oxy-2,3,5,6-
S
tetrafluorobenzene (6) as a representative arene counterpart in
benzene solvent (Table 2). The choice of this model substrate 6 was
based on the ease of isolation of alkylated products although the
scope of fluoroarenes was found to be broad (vide infra). Secondary
benzylic C–H bonds were readily arylated to provide the desired
alkylation products in high yields (7 and 8). Primary benzylic C–H
bonds were also viable irrespective of the presence of positional
substituents with 63%–94% yields of the corresponding products
(9–12). Halide substituents were all compatible with the current
conditions (13–16). Monoarylated products were obtained
efficiently from the reaction of mesitylene or 1,3,5-triethylbenzene
(17 and 18). Substrates bearing longer alkyl chains displayed a
24
, 51%
, 75%
, 85%
, 89%
, 84%
Allylic C–H bonds
Ar
Ar
Ar
Ar
26
27
28
29
, 99%
, 91%
, 70%
, 49%
aFor the arylation of benzylic C–H bonds: alkylarenes (2 mmol, 10
equiv.), fluoroarene (0.2 mmol), CuBr•SMe2 (0.02 mmol), ligand L10
(0.03 mmol), tBuONa (0.16 mmol) and oxidant DTBP (0.8 mmol) in
o
b
benzene solvent at 80 C for 24 h. Isolated product yields. For the
arylation of allylic C–H bonds: reactions were carried out with alkenes
(1 mmol, 5 equiv.) and fluoroarene (0.2 mmol) at 60 oC.
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Given the versatile utility of an allyl phenyl scaffold as synthetic alkane feedstocks) having similar BDE of C–H bonds (~100
and medicinal/materials building units,19,25 the feasibility of direct
allylic C–H arylation was subsequently examined in reaction with
fluorobenzene (6) as a representative arene counterpart (Table 2).
Pleasingly, we observed that cyclohexene (5 equiv) was smoothly
kcal/mol) are extremely difficult to functionalize.26 This
consideration led us to investigate their feasibility in the current
cross-coupling system (Table 3). We were pleased to observe that
cycloalkanes (10 equiv) were readily reacted with naphthalen-2-oxy-
2,3,5,6-tetrafluorobenzene (6) in satisfactory yields (56%–69%)
irrespective of the ring size (30–34). Norbornane was reacted
exclusively at the ethylene C–H bonds in 43% yield with high
exo/endo selectivity (10:1, 35), and the structure of a major
isomeric product was confirmed by an X-ray diffraction analysis.
Significantly, acyclic hydroalkanes were also viable under the present
reaction conditions leading to arylated products albeit in moderate
yields. For instance, n-hexane was reacted mainly at the secondary
C–H bonds along with minor arylation at the primary C–H bonds
(36) in 36% yield. n-Pentane showed the similar reactivity and
selectivity (37). 2-Methylbutane was reacted preferentially at the
secondary C–H bonds (38), and interestingly, no arylation was
observed at the tertiary C–H bond. In contrast, primary C–H bonds
were reacted more favorably when the secondary position is
sterically congested (39). However, reaction of substrates having
tertiary benzylic C–H bond (e.g. cumene) did not afford the desired
product under the present conditions.
1
2
3
4
5
6
7
8
o
reacted at 60 C to afford 26 exclusively in 91% yield (see the
Supporting Information for the optimization conditions). Seven-
and eight-membered cycloalkenes were also readily arylated at the
allylic position (27 and 28). A reaction of tetramethylethylene
smoothly took place to provide the corresponding product 29 in
quantitative yield.
9
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
Table 3. Scope of Aliphatic, Gaseous Hydrocarbons and Complex
Moleculesa
Pdt =
CuBr SMe
2 (10 mol%)
H
L10
(15 mol%)
F
F
F
F
H
F
F
F
F
H
Ar
DTBP (4.0 equiv.)
+
OR
Ar
tBuONa (80 mol%)
C6H6, 60–80 oC, 24 h
OR =
OR
Abundant
Feedstocks
6
O
5–10 equiv.
Aliphatic C–H bondsa
Ar
Ar
Ar
30
33
31
32
32
(X-ray of
, 57%
, 56%
, 68%
)
Ar
Ar
Table 4. Scope of Polyfluoroarene Substratesa
Ar
CuBr SMe
2 (10 mol%)
L10
(15 mol%)
H
Pdt =
H
35,
H
43%
34
37
35
)
, 69%
, 58%
(X-ray of
DTBP (4 equiv.)
(exo : endo = 10 : 1)
Hep
+
Hep
tBuONa (80 mol%)
C6H6, 80 oC, 24 h
Fn
Fn
Ar
b
Ar
c
Ar
Fn
b
Ar
a
c
a
b
a
b
a
c
Hep
Hep
Hep
Hep
Hep
36,
38
39
, 23%
a b
( / = 3.6 : 1)
36%
= 6.1 : 4.5 : 1)
, 38%
, 28%
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
a b c
a b c
a b c
(
/
/
(
/
/
= 5.4 : 2 : 1)
(
/
/
= 4.3 : 2 : 1)
Natural feedstocks and bio-active molecules
F
F
F
TBS protection
TBS protection
Arylation
-Estradiolb
(+)--Tocopherolb
Arylation
OtBu
Hep
OMe
Ph
Me
52
Ph
Desilylation
Desilylation
40
41
HO
Ar
49
50
51
53
, 87%
, 61%
, 71%
, 65%
, 69%
a
HO
Me
Me
Me
Me
Hep
H
H
Hep
Hep
Hep
Hep
F
F
OH
40
(X-ray of
)
O
Ar
Me
H
F
F
F
F
b
F
F
F
F
F
F
F
F
F
F
F
F
41,
76%
d.r.
F
F
40
d.r.
a/b
( = 5.1 : 1,
, 55% (
= 1.6 : 1)
= 1.2 : 1)
(-)-Ambroxide
N
SiiPr3
, 64%
TBS protection
Arylation
Geraniolb
CF3
F
Br
Geranyl ethyl ether
Eucalyptol
Desilylation
Ar
Ar
Ar
42
b
c
b
57
58
, 80%
54
55
56
, 81%
, 82%
, 66%
b
Me
OH
OEt
O
O
Ar
a
Hep
Me
S
F
F
Me
Me
H
Hep
Hep
Hep
F
F
F
F
43
44
45,
(d.r.
F
F
, 67%
E/Z = 3.3 : 1 )
, 44%
40%
= 1.6 : 1)
42,
51%
(E/Z = 4 : 1)
F
F
F
F
a/b
= 6.7 : 1)
(
(
N
Gaseous feedstocksc
Br
F
Cl
Cl
N
N
N
propylene
n-butane
propane
Ar
Ar
Ar
59
60
61
62
63
, 34%
, 58%
, 68%
, 76%
, 52%
a
b
a
b
aReaction conditions: polyfluoroarene (0.2 mmol), cycloheptene (2
mmol, 10 equiv), CuBr•SMe2 (0.02 mmol), ligand L10 (0.03 mmol),
tBuONa (0.16 mmol), and oxidant DTBP (0.8 mmol) in benzene
solvent at 80 oC for 24 h. btBuONa (0.6 equiv.). ctBuOLi was employed
as the base.
47
(
48
(
, 51% (0.53 g)
a b
, 39% (0.39 g)
a b =
46
, 49% (0.45 g)
/
= 6.7 : 1)
/
3.0 : 1)
aFor the arylation of alphatic C–H bonds: alkanes (2 mmol, 10 equiv.),
fluoroarene (0.2 mmol), CuBr•SMe2 (0.02 mmol), ligand L10 (0.03
mmol), tBuONa (0.16 mmol), and oxidant DTBP (0.8 mmol) in
benzene solvent at 80 oC for 24 h. Isolated product yields. Orange circles
denote sites where regiomeric products are formed. bThree-step
sequence constitutes: (i) silyl protection of free hydroxyl group, (ii)
arene-alkane coupling, and (iii) silyl deprotection. cFor gaseous
feedstocks: 3 mmol scale reactions.
The present cross-coupling procedure was successfully applied to
the C–H arylation of naturally occurring hydrocarbons or bio-active
synthetic compounds (Table 3). For instance, -estradiol was
reacted selectively at the secondary benzylic C–H bonds in 55% (40,
d.r. = 1.6) and its structure was confirmed by an X-ray
crystallographic analysis. (+)-δ-Tocopherol (a type of vitamin E)
was converted to its arylated derivative by reacting mainly at the
secondary C–H bond of the benzylic positions in high yield (41).
Geraniol was also viable for this transformation leading to -aryl
As shown in Scheme 1, while the bond dissociation energy (BDE)
of benzylic and allylic C–H bonds is in the range of ~90 kcal/mol,
that of cycloalkanes is higher by ~10 kcal/mol, thus achieving a
direct coupling of those hydrocarbons to be more challenging.23 In
turn, low molecular weight acyclic hydrocarbons (mainly gaseous
4
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Journal of the American Chemical Society
After surveying the scope of hydrocarbon reactants, the availability
alcohol product (42) in 51%. Significantly, this arylation was found
1
2
3
4
5
6
7
8
of fluoroarene substrates was further investigated in reaction with
cycloheptane as a representive coupling partner (Table 4).
Tetrafluorobenzenes bearing a methoxy or t-butoxy substituent
were smoothly reacted to afford good yields of the desired products
(49 and 50, 61% and 71%, respectively). Derivatives substituted
with phenyl or alkyl groups were also viable for the alkylation with
cycloheptane with similar efficiency (51 and 52). Of note was that a
weaker benzylic tertiary C–H bond23 in the latter substrate was
compatible with the current reaction conditions. When two
chemically equivalent sp2 C–H bonds are present as in case of
1,2,4,5-tetrafluorobenzene, bis-alkylation could be achieved in high
efficiency by increasing the stoichiometry of cycloheptane and
oxidant (53). Pentafluorobenzene and its analogue were facile for
this alkylation (54 and 55). Functional group tolerance was
examined to reveal that bromo, silyl, indole, and indazole groups
were all tolerant to the present conditions (56–59). When two non-
equivalent C–H bonds are present, the alkylation was found to occur
selectively at the more acidic position in good yields (60 and 61).
3,5-Ddifluoropyridine was alkylated exclusively at the C4-position
(62) in high yield, and no reaction occurred at the C2-position.
Finally, a reaction of 3,5-difluoropyridine with 2-propylthiophene
was also fruitful to afford 1,1-diheteroarylalkane in 52% yield (63).
However, the current alkylation protocol was not applied to such
arenes as 1,2,3-trifluorobenzene, fluorobenzene, 1,2,4,5-
tetrachlorobenzene, or 1,2,4,5-tetrabromobenzene, wherein no
alkylation product was observed.
to be selective at the -allyl silylether site even in the presence of 5
additional types of allylic C–H bonds. Likewise, geranyl ethyl ether
was reacted at the allylic C–H bonds adjacent to the heteroatom in
good yield (43, 67%). Alcoholic hydrocarbons were subjected to a
three-step arylation sequence: (i) hydroxyl group protection as silyl
ethers, (ii) C–H arylation, and (iii) silyl deprotection. A biomass-
drived chemical of eucalyptol was reacted at the secondary C–H
bonds with good regioselectivity (44, a/b = 6.7:1) in 44%, and (-)-
ambroxide was arylated at the secondary C–H bonds adjacent to the
oxygen atom in moderate yield (45). It needs to be mentioned that
excessive amounts of the complex hydrocarbon reactants could be
recovered in the current system. For instance, the recovered yields
of unreacted β-estradiol and (+)--tocopherol were 89% and 88%,
respectively (see S30–S37 in the Supporting Information for details).
Taking one step forward, we attempted to employ gaseous
hydrocarbon feedstocks as an alkylating source27 under the current
copper catalyst system. A reaction of propylene (3.0 mmol scale, 8
bar, 70 oC) furnished an isomerized (E)-vinylarene product in 49%
(46).19c n-Butane (2 bar) and propane (5 bar) were reacted
preferentially at the secondary C–H bonds albeit in moderate yields
(47 and 48) at 80 oC.
9
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
Scheme 2. Synthetic Applications
a
Large-scale reactiona and subsequent transformationsb
H
F
Me
F
CuBr SMe2 (3 mol%)
L10
H
F
F
F
F
(4 mol%)
+
tBuONa (80 mol%)
DTBP (4 equiv)
80 oC, 24 h
Synthetic Application. The synthetic utility of the current cross-
dehydrogenative coupling of alkanes with polyfluoroarenes was
briefly examined, as summarized in Scheme 2 (see also Synthetic
Application in Supporting Information for details). Practicability of
the present alkylation protocol was tested in a decagram-scale
reaction of 2,3,5,6-tetrafluoroanisole (2, 50.0 mmol) with
ethylbenzene (1) by using 3 mol % of CuBr•SMe2 and 4 mol % of
ligand L10 at 80 oC to afford the desired product 3 in 80% yield (11.4
g). The obtained products could be further utilized in subsequent
transformations. For instance, a catalytic hydrodefluorination of 3
(NiCl2) was readily performed to obtain 1,1-diarylethane 64 in high
yield (90%).28 Moreover, a nucleophilic aromatic substitution of
fluorine atom in fluoroarenes is an established procedure in the
F
MeO
OMe
F
1
2
3
11.4 g
Yield: 80% ( )
(50 mmol)
(50 mL)
NiCl2 (40 mol%)
LiBEt3H (20 equiv)
THF, reflux, 20 h
Me
Me
Ph
Me
Ph
Me
R2N
RO
RS
Ph
MeO
MeO
MeO
MeO
F3
F3
F3
Nucleophilic aromatic substitution (SNAr)
(known transformations)
hydrodefluorination
64
, 90%
b
Building unit syntheses with fluoroarenesc
known procedures to
"fluorinated" drug derivatives
O
N
literatures.14d Given that 1,1-diarylalkanes constitute
a
Cl
3
NH
N
Cl
F
H
pharmacophore in numerous drugs,29 our protocol was briefly
examined as a viable route to fluorinated analogues (Scheme 2b).
Indeed, fluorinated drug precursors such as lidoflazine, indatraline,
and nafenopin were readily obtained in good to high yields (65–67).
1-(4-Chlorobutyl)-4-fluorobenzene reacted with 1,5-dichloro-2,4-
difluorobenzene under the current cross-dehydrogenative coupling
system to afford a benzylic C–H arylation product 65 in 45% yield.
Interestingly, a trans-configured product 66 was formed in 56% over
two steps from an abundant chemical of indane via two steps:
benzylic C–H arylation with the current system and then direct
amination at the other secondary benzylic C–H bonds by a reported
manganese system.30 Finally, 1,2,3,4-tetrahydronaphthalene was
also facile to couple with 2,3,5,6-tetrafluoroanisole to furnish an
arylation product, which subsequently underwent demethylation
with boron tribromide (BBr3) leading to 67 (80%).
standard
conditions
3
Cl
F
F
F
+
H
Cl
F
F
Cl
Cl
F
F
F
Cl
Cl
65
, 45%
Lidoflazine derivative
Me
HN
N(H)ces
H
i) standard
conditions
F
F
F
F
+
ii) Cbenzylic–N
H
bond formation
F
Cl
F
Cl
Cl
Cl
Cl
, 56% (2 steps)
Cl
66
Indatraline derivative
F
H
F
F
i) standard
conditions
F
F
F
F
F
F
O
+
ii) demethylation
F
OH
F
OH
H
OMe
F
O
67
, 80% (2 steps)
Nafenopin derivative
5
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Journal of the American Chemical Society
Page 6 of 11
methylphenol (BHT), and p-quinone, suggesting that the current
 MECHANISTIC STUDIES
1
2
3
4
5
6
7
8
alkane-polyfluoroarene coupling reaction proceeds likely via a
radical pathway. The proposed sp3-carbon centered radical was
trapped by TEMPO in 89% NMR yield.31 In addition, 1,1-
diphenylethylene and 9,10-dihydroanthracene also displayed
apparent inhibition effects on the reaction efficiency. Next, a radical
clock experiment was carried out to show that a ring-opened
compound (68’) was formed albeit in low yield along with 68
(Scheme 3b), thus supporting the intermediacy of alkyl radicals.32 As
shown in Scheme 3c, a series of kinetic isotope effect (KIE)
Scheme 3. Mechanistic Experiments
a
Influence of Radical Scavengers
H
F
F
F
F
H
CuBr SMe2 (10 mol%)
L10
OR =
O
F
F
F
F
(15 mol%)
Radical
Scavenger
+
+
OR
tBuONa (80 mol%)
(2.0 equiv)
DTBP (4 equiv)
OR
C6H6, 80 oC, 24 h
1
6
7
Radical Scavenger None TEMPO BHT p-Quinone 1,1-Diphenylethylene 9,10-Dihydroanthracene
Yield(%)
80
Ph
< 1
<1
<1
28
29
OH
tBu
tBu
O
CH2
Ph
Me
Me
Me
Me
Me
Me
O
N
N
9
Me
Me
O
O
Me
o
Ph
experiments was subsequently performed at 80 C by using a
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
Me
TEMPO
89%
BHT
p-Quinone 1,1-Diphenylethylene 9,10-Dihydroanthracene
pregenerated species A (Scheme 3d), and significant KIE value was
observed in parallel comparison reactions between ethylbenzene (1)
and its deuterated derivative (1-d10) (kH/kD = 2.4). Moreover, an
intramolecular KIE value of (ethyl-1-d)benzene was measured to be
4.2. These results imply that the sp3 C−H cleavage of alkanes is
probably involved in the rate-limiting step.33 On the other hand, a
lower KIE effect was observed (kH/kD = 1.3) in a competition
reaction between tetrafluoroarene (6) and its deuterated derivative
(6-d1). The base effect on the formation of active copper species was
further investigated (Scheme 3d). Treatment of ligand L10 and
CuBr•SMe2 with a range of bases revealed that tBuONa worked best
in forming an active copper species A while weak bases such as
K2CO3 or Cs2CO3 were ineffective (see the Supporting Information
for details). The yellow copper complex A was isolated in a dimer
form and its solid structure was fully characterized by an X-ray
diffraction analysis. Importantly, this isolated species A was found to
run a catalytic coupling reaction. Electron paramagnetic resonance
(EPR) study was performed to see whether plausible copper
intermediates could be observed (Scheme 3e, and also see the
Supporting Information for details). While the isolated Cu(I)
complex A was treated with DTBP oxidant in benzene, a four-
hyperfine-line signal was observed at 100 K (Conditions i; black
curve), which were assigned to be [LCu]–OtBu. When 2,3,5,6-
tetrafluoroanisole 2 was added to a solution of complex A and DTBP
b
Radical Clock Experiment
OR
F
H
F
F
F
F
CuBr SMe2 (10 mol%)
L10
F
OR
F
H
F
F
(15 mol%)
+
+
Ph
Ph
tBuONa (80 mol%)
F
F
DTBP (4 equiv)
F
Ph
68
OR
C6H6, 80 oC, 24 h
6
, 45%
68'
, 9%
c
Kinetic Isotope Effects (KIE)
1
1-d
6
6-d
&
1
i) Intermolecular KIE of ethylbenzene (
&
)
iii) Intermolecular KIE of polyfluoroarene (
)
10
■
■
6
■
■
PhEt
6-d1
PhEt-d10
y = 0.2901x
R2 = 0.9970
H/D
y = 0.2901x
R2 = 0.9970
F
F
F
F
H10/D10
OR
6 & 6-d1
1 & 1-d10
y = 0.2183x
R2 = 0.9903
y = 0.1203x
R2 = 0.9952
kH/kD = 2.4
kH/kD = 1.3
ii) Intramolecular KIE of (ethyl-1-d)benzene
H
CuBr SMe2 (3 mol%)
H
D
F
F
F
F
F
F
F
F
F
F
NMR yield: 71%
L10
(4 mol%)
+
+
7
7
(
': 57%, : 14%)
D
OR
H
OR
tBuONa (80 mol%)
DTBP (4 equiv)
C6H6, 80 oC, 24 h
kH/kD = 4.2
OR
F
F
6
7'
7
d
Formation of the Active Copper Species
i) Effect of the base
Me
Me
Me
Me
N
N
CuI
C6D6
80 oC, 30 min
CuBr SMe2
+
+
Base
+ SMe2
N
HN
d6
L10
A
Base
Yield(%)
tBuONa
tBuOLi
tBuOK
K2CO3
<1
Cs2CO3
<1
o
in benzene for 1 h at 80 C, a new set of EPR signals appeaerd
59
39
38
(Conditions ii; green curve), which was assumed to be the propsoed
(aryl)Cu(II) intermediate. Based on the above experiments and
literature precedents,11,12,22b,34 Cu(II) intermediates are proposed to
be involved in the present reaction system.
Active copper complex A
A
ii) Catalytic reaction with copper complex
H
F
F
F
H
F
F
F
F
A
Dimer of (5 mol%)
+
OR
tBuONa (20 mol%)
DTBP (4 equiv)
80 oC, 24 h
OR
dimeric form
(X-ray)
F
1
6
7
, NMR Yield: 71%
 COMPUTATIONAL STUDIES
e
EPR Experiments for the Detection of Cu(II) Species
To provide further mechanistic aspects, computational studies with
density functional theory were also carried out. Based on the
previous studies that copper(I) species mediate a homolytic
cleavage of peroxides,12a it was postulated that the copper complex A
will react with DTBP to furnish 1 equiv of [LCu]–OtBu (C) along
with tBuO• radical (G = –10.3 kcal/mol, Figure 2a, see also SI for
detailed mechanism with full energy profiles). Upon the formation
of C, two pathways were then envisaged to operate in the activation
of sp3 C–H bonds of alkanes as illustrated in Figure 2b. While a direct
hydrogen atom abstraction (HAA) by a free tBuO• radical could be
conceived (Path a), a copper-mediated activation was also
considered (Path b). The observation of the primary kinetic isotope
effects of ethylbenzene implies that the irreversible cleavage of sp3
C−H bonds would be relevant to be rate-limiting, which was
consistent with the computational investigations (G‡ = 26.0
kcal/mol). In SOMO of the alkoxy copper species C, the radical
character was found to be delocalized both in the copper center
To obtain mechanistic insights into the present cross-coupling
reactions, a number of experimental studies were carried out
(Scheme 3 and also see the Supporting Information for details). The
effect of radical scavengers on the current alkylation system was
examined (Scheme 3a). No desired product (7) was observed in the
presence of several radical inhibitors such as (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO), 2,6-di-tert-butyl-4-
6
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Journal of the American Chemical Society
Figure 2. DFT calculations for the activations of C(sp3)–H and C(sp2)–
H bonds.
Analysis on the transition states of the proposed Cu-mediated
(0.46 e–) and in the oxygen atom (0.24 e–), as shown in Figure 2a.
1
2
3
4
5
6
7
8
Considering the fact that free alkoxy radicals are generally known to
activate tertiary C–H bonds preferentially in the presence of
secondary and primary countrerparts,35 our observation that tertiary
C–H bonds are intact under the current conditions (e.g. products 35,
38–41, 44, 45) led us to propose that the alkane activation mainly
operates via a copper-mediated process (Path b). In fact, certain
Cu(II) species were reported to mediate sp3 C–H bond activation.36
This process is postulated to proceed via a transition state C-TS-1
leading to Cu(I) species D-1 which then interacts with tBuO• radical
to afford eventually an alkyl radical. This type of copper-mediated
alkyl radical-releasing process was proposed independently by
Kochi and Dong.37 As we previously proved the facile activation of
polyfluoroarenes by (NHC)Cu-alkoxide,10 the present [LCu]–
OtBu (C) is proposed to readily deprotonate fluoroarene leading to
an (aryl)CuII intermediate D-2 (Ionic pathway, G‡ = 25.9
kcal/mol). In the final stage, the in situ generated alkyl radical is
interacted with the aryl copper intermediate D-2 to furnish the
desired alkyl-aryl coupled product via an (alkyl)(aryl)CuIII species F
with negligible energy barriers (Figure 2c, see the Supporting
Information for details). However, we were not able to observe
distinct experimental signals which can be assignable to Cu(III)
species. In fact, reductive elimination of the proposed
(alkyl)(aryl)CuIII intermediate F was calculated to proceed with
very low activation barrier (G‡ = 0.3 kcal/mol) as shown in Figure
2c.38
dual activation of sp3 and sp2 C–H bonds (C-TS-1 and C-TS-2,
respectively) revealed a notable difference in the spin density. In the
former process, a significant radical character is located on the
oxygen (0.18 e–) of t-butoxy ligand along with benzylic carbon atom
(0.33 e–) of approaching ethylbenzene, implicating a radical
pathway (HAA).39 In stark contrast, spin density in C-TS-2 is
localized mainly at the copper center (0.48 e–), thus leading us to
propose that the C–H bond activation of polyfluoroarene will take
place most likely via an ionic pathway (see the Supporting
Information for frontier molecular orbital analysis). Of special note
is that strong  interaction was shown to be present between the
employed ligand L10 and fluoroarene substrates (~3.5 Å), wherein
fluorine atom serves as a temporary directing group to form weak
hydrogen bonds with the benzylic hydrogens of the mesityl ligand.
These non-covalent interactions were assumed to facilitate the sp2
C–H bond activation as well as the stabilization of the corresponding
copper aryl intermediates.40,41
9
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
Scheme 4. Proposed Mechanism
Me
Me
tBuO
H
H
Me
Me
F
F
F
Me
N
N
CuI
A
tBuOOtBu
OMe
N
N
Me
CuI
F
Product
H
Me
tBuO
D-1
Me
N
Me
Me
Me
tBuO
a
Generation of [LCu]–OtBu complex
N
CuIII
N
N
Cu
Me
Me
SOMO of C
Me Me
F4
Me
Me
O
Spin Density
Me
N
Me
N
N
O
Me
N
N
CuI
Cu = 0.458
+
Cu
O
+
DTBP
N
Me
F
Me
Me
O
= 0.241
Me
OMe
Ar
Ar
Cu
C
H
Me
Me
Me
Me
O
sharing
radical character
G = –10.3
(1 eq. of C)
Me
Me
Me
Me
Me
Me
A
C
F
F
F
F
N N
CuIII
N
CuII
N
Spin Density
Cu
O
C
OMe
b
Activations of C(sp3)–H and C(sp2)–H bonds
Me
Me
Me
O
tBuOH
C-TS-1
C-TS-2
0.231 0.182 0.327
0.479 0.062 0.032
Me
E-1
Radical pathway
Me
Me
D-2
F4
H
MeO
+
OtBu
Path a
Me
Me
–H
OtBu
In accordance with the above mechanistic investigations, a
proposed pathway of the current alkane-fluoroarene coupling
reaction is depicted in Scheme 4. First, the active copper complex A,
formed from the copper precursor by reacting with tBuONa and
ligand L10, promotes the homolytic cleavage of DTBP to afford the
key intermediate [LCu]–OtBu (C) along with tBuO• radical. An
alkoxy copper complex C activates sp3 C–H bonds of ethylbenzene
via a radical pathway to give an alkyl radical-coordinated
intermediate D-1 that will interact with tBuO• radical resulting in an
(alkyl)(alkoxy)Cu(III) intermediate E-1. Then, an alkyl radical will
be released with the regeneration of the intermediate C. It is
proposed that alkane activation takes place mainly via a copper-
mediated process leading to an alkyl radical although an alkoxy
radical-mediated direct cleavage of sp3 C–H bonds cannot be
completely ruled out. On the other hand, the copper alkoxide
complex C is believed to activate fluoroarnes via an ionic pathway to
give an (aryl)CuII intermediate D-2 that interacts with an alkyl
radical to generate a (alkyl)(aryl)Cu(III) intermediate F. Product
will be released upon the reductive elimination of F along with the
regeneration of the active copper complex A.
C(sp3)–H
Me
Ph
Me
Me
N
Me
N
N
N
CuI
Path b
CuI
+ C
G‡ = 26.0
–H
OtBu
G = –34.2

H
H
Me
Me
H
O
C
Me
Me
Cbenzyl
Me
D-1
C-TS-1
Ionic pathway
Me
Me
Me
Me
N
H
N
N
N
F
F
GCD-2 = 5.0
CuII
+ C
CuII
G‡ = 25.9
–H
OtBu
F
F
Me
Me
O
C
H
OMe
C(sp2)–H
OMe
Cipso
F4
F4
OMe
Me
C-TS-2
D-2
Non-Covalent Interactions in C-TS-2
DFT-optimized structure
•  interaction
 interaction
Me
Me
N
CuII
~3.5 Å
N
EDG
Ar
d4
H
O
EWG
H
• weak H-bonds
d3
Me
Me
d1
weak H-bonds
d2
H
N
N
d1
d2
d3
d4
2.48 Å
2.53 Å
2.54 Å
2.85 Å
CuII
F
H
F
H
H
O
H
F
c
Product formation and catalyst regeneration
Me Me
G = –29.1
Me
Me
F
F
F
N
N
N
N
G‡ = 0.3
CuII
CuIII
G = 5.7
Me
+
OMe
F
 CONCLUSION
Me
Me
A
F4
F4
OMe
OMe
Catalyst
regeneration
sp3-hybridized
radical
Desired
product
The present study demonstrates for the first time that a copper-
catalyzed selective alkylation of polyfluoroarenes is enabled by using
D-2
F
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nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl
hydrocarbons. A broad range of alkanes could be successfully
utilized to include non-activated hydrocarbons with moderate to
high site-selectivity. Dual activation mode was postulated to operate
in activating sp3 C–H and sp2 C–H bonds via a radical and ionic
pathway, respectively. Non-covalent interactions formed in situ
between the copper ligand and fluoroarenes such as  interaction
and hydrogen bonds are proposed to facilitate the arene activation
process. Upon further improvement of reaction conditions and
arene scope, our approach offers a future research direction to utilize
hydrocarbon feedstocks directly in synthesis.
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 ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI.
Experimental procedures, experimental details, computational
details, characterization data, and crystallographic data for 19, 32, 35,
40, Copper Complex A (PDF)
Crystallographic data of 19 (CIF)
Crystallographic data of 32 (CIF)
Crystallographic data of 35 (CIF)
Crystallographic data of 40 (CIF)
Crystallographic data of Copper Complex A (CIF)
 AUTHOR INFORMATION
Corresponding Authors
*E-mail for S. C.: sbchang@kaist.ac.kr
ORCID
Joon Heo: 0000-0001-5275-9279
Sukbok Chang: 0000-0001-9069-0946
Notes
The authors declare no competing financial interest.
 ACKNODGEMENTS
This research was supported by the Institute for Basic Science (IBS-
R010-D1) in Korea. The authors acknowledge Prof. Mi Hee Lim, Mr.
Jong-Min Suh, Ms. Yelim Yi (KAIST) for helpful discussion in EPR
spectroscopy, and thank Prof. Mu-Hyun Baik for grateful advice in
computational study.
(8) Antonchick, A. P.; Burgmann, L. Direct selective oxidative cross-
coupling of simple alkanes with heteroarenes. Angew. Chem., Int. Ed. 2013,
52, 3267−3271.
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Table of Contents
1
2
3
Abundant
feedstocks
Cu catalysis
H
Ar
x
= 1
2
Selective C(sp2)–C(sp3)
bond formation
4
5
+
Cux
3
Ar
H
Fn
benzylic
6
7
8
9
Ligand-enabled catalysis
Features in the catalytic system
H
Broad scope including gaseous feedstocks > 60 examples

allylic
Ligand-regulated chemoselectivity

H
effiective suppression of side pathways
Dual activation mode: radical and ionic pathways
Mild reaction conditions
aliphatic



H
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
H
Non-covalent interactions
• weak H-bonds •  interaction
Scalable reaction (50 mmol), Late-stage transformations
gaseous
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