Ni(II)-catalyzed oxidative coupling between C(sp2)-H in benzamides and C(sp3)-H in toluene derivatives

Article abstract of DOI:10.1021/ja5095342

Oxidative coupling between C(sp²)-H bonds and C(sp³)-H bonds is achieved by the Ni(II)-catalyzed reaction of benzamides containing an 8-aminoquinoline moiety as the directing group with toluene derivatives in the presence of heptafluoroisopropyl iodide as the oxidant. The method has a broad scope and shows high functional group compatibility. Toluene derivatives can be used as the coupling partner in an unreactive solvent.

Full text of DOI:10.1021/ja5095342

Communication
pubs.acs.org/JACS
Ni(II)-Catalyzed Oxidative Coupling between C(sp2)−H in Benzamides
and C(sp3)−H in Toluene Derivatives
Yoshinori Aihara, Mamoru Tobisu, Yoshiya Fukumoto, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
Scheme 1. Oxidative Cross-Coupling of C−H/C−H Bonds
ABSTRACT: Oxidative coupling between C(sp2)−H
bonds and C(sp3)−H bonds is achieved by the Ni(II)-
catalyzed reaction of benzamides containing an 8-amino-
quinoline moiety as the directing group with toluene
derivatives in the presence of heptafluoroisopropyl iodide
as the oxidant. The method has a broad scope and shows
high functional group compatibility. Toluene derivatives
can be used as the coupling partner in an unreactive
functionalized benzyl groups can be introduced with the cleavage
solvent.
of C(sp2)−H bonds.
A key to the success of achieving oxidative C(sp2)−H/
C(sp3)−H coupling would be how to activate C(sp3)−H bonds
rogress in the catalytic functionalization of C−H bonds for
Pthe construction of C−C bonds has advanced significantly,
and efficient and straightforward methods for preparing complex
molecules starting from easily available compounds are now
available.1 Various functionalized compounds such as halides and
organometallic reagents can be used as coupling partners for C−
C bond formation with the cleavage of C−H bonds. In contrast,
oxidative C−H/C−H coupling is an ideal and environmentally
attractive strategy because the reaction does not require
functionalized compounds for coupling and stoichiometric
amounts of halogenated or organometallic byproducts are not
generated. In a pioneering study, Fagnou reported on such a
reaction: the Pd-catalyzed reaction of indole derivatives with
benzene derivatives (solvent) resulting in the formation of
arylation products.2 The reaction involves the sequential
activation of C−H bonds on two aromatic compounds (an
indole C−H bond and a benzene C−H bond) followed by C−C
bond formation. Following this pioneering example, a number of
reactions involving oxidative C−H/C−H coupling have been
reported.3,4 However, most of these examples involve the
coupling of C(sp2)−H/C(sp2)−H bonds with activation of one,
the other, or both of C(sp2)−H bonds, as in C−H bonds in
electron-rich aromatic compounds or acidic C−H bonds.
Oxidative C(sp2)−H/C(sp3)−H coupling represents the next
targeted reaction.5 In fact, Li reported on an oxidative coupling
involving C(sp3)−H bonds in the Ru(II)-catalyzed reaction of 2-
arylpyridines with cycloalkanes, in which only simple cyclo-
alkanes were used as the coupling partner as well as the solvent
and a strong oxidant, such as di-tert-butyl peroxide was used to
generate radical species from the cycloalkanes.5a Oxidative
C(sp2)−H/C(sp3)−H coupling without the use of such strong
oxidants and the introduction of functionalized alkyl groups
continues to be a challenging issue (Scheme 1). Here we report
on the Ni(II)-catalyzed benzylation of ortho C−H bonds in
aromatic amides with toluene derivatives. It is noteworthy that
the toluene derivative need not also be the solvent. Various
without using a strong oxidant such as di-tert-butyl peroxide to
generate a radical species. Thus, a new methodology to promote
the cleavage of C(sp3)−H bonds and to introduce functionalized
alkyl groups needs to be developed. We recently reported on the
Ni(II)-catalyzed functionalization of C−H bonds by taking
advantage of an 8-aminoquinolinyl directing group.6,7 On the
basis of various mechanistic studies, it appears that nickel species
with radical character are involved as a key intermediate in the
Ni-catalyzed functionalization of C−H bonds.7 In addition,
inspired by recent observations that Ni(I) species can catalyze
cross-coupling reactions with alkyl halides,8 we focused our
efforts on the use of our recently developed Ni(II)-catalyzed
chelation system for oxidative C−H/C−H coupling. Our initial
investigation centered on a strategy for generating radical species
without the use of strong oxidizing reagents. Various alkyl halides
were examined as radical sources. The benzylation of ortho C−H
bonds proceeded when heptafluoroisopropyl iodide (iC3F7I) was
used as the halide. The reaction of amide 1a (0.3 mmol) with
iC3F7I (0.6 mmol) in the presence of Ni(OTf)2 (0.03 mmol) as
the catalyst, Na2CO3 (0.6 mmol) as the base, and PPh3 (0.03
mmol) as the ligand in toluene (1 mL) at 140 °C for 24 h gave the
benzylation product 2a in 54% isolated yield and 3 in 33% yield
(Table 1, entry 1). To avoid the formation of 3, the 5-position in
the quinoline ring was blocked by a methoxy group, as in 1b. As
expected, the isolated yield of 2b was dramatically improved to
91% (entry 2). The reaction also produced 2b in 75% NMR yield
in the absence of PPh3 (entry 3). While the presence of PPh3 as a
ligand was not crucial for the reaction to proceed, PPh3 was
added because the product yields were consistently higher than
the yields in the absence of PPh3. Other perfluoroalkyl or -aryl
iodides were not effective (entries 4−7). The reaction was also
dependent on the base used in the reaction. The results indicated
that Na2CO3 was base of choice (entry 2). A decrease in the
Received: September 16, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja5095342 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Reaction Conditions
Table 2. Ni(II)-Catalyzed Ortho-Benzylation of Benzamides
in Toluene
a
b
yields (%)
entry
amide
halide
iC3F7I
iC3F7I
iC3F7I
n-C6F13I
C6F5I
base
2
1
1
2
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
K2CO3
56 (54)
94 (91)
75
3 (2)
trace
13
c
3
4
5
30
40
0
60
d
6
CF3CH2I
39
0
7
C6Br6
0
90
8
iC3F7I
iC3F7I
iC3F7I
iC3F7I
iC3F7I
iC3F7I
iC3F7I
73
13
9
10
73
a
Reactions were conducted on a 0.3 mmol scale. Isolated yields are
10
11
12
NaHCO3
Li2CO3
59
37
b
reported. Q′ = 5-chloro-8-aminoquinolinyl group. Run at 160 °C.
0
63
c
d
iC3F7I (0.9 mmol) was used. The reaction was conducted on a 0.15
NaOAc
Na2CO3
Na2CO3
21
63
mmol scale, and 15 mol % catalyst was used.
e
13
e
94 (91)
96 (94)
trace
0
14
point, benzene was replaced with tert-butylbenzene, which was
also found to be a good solvent. The use of 10 equiv of toluene in
tert-butylbenzene gave 2c in 84% yield. The results for the
reaction of 1c with various toluene derivatives under the newly
optimized conditions are summarized in Table 3. Various
functional groups, even bromides and iodides, are tolerated
under the current catalytic system. The presence of substituents
at the ortho position had no effect on the efficiency of the
reaction, as in 24, 25, 26, and 28.
a
Reaction conditions: 1 (0.3 mmol), Ni(OTf)2 (0.03 mmol), PPh3
(0.03 mmol), Na2CO3 (0.6 mmol), and halide (0.6 mmol) in toluene
(1 mL) at 140 °C for 24 h. NMR yields. Values in parentheses are
isolated yields. No PPh3. 2d was obtained in 58% yield. C3F7I (0.36
b
c
d
e
i
mmol) was used.
amount of iC3F7I (0.36 mmol, 1.2 equiv with respect to 1b) did
not affect the product yield (entry 2 vs 13). Finally, the use of a
chloro group as in 1c gave the benzylation product 2c in 94%
isolated yield (entry 14).
To gain insights into the reaction mechanism, deuterium-
labeling experiments were performed. When the deuterated
benzamide 1c-d7 was reacted under the standard reaction
conditions, but for 4 h, 2c was produced in 52% isolated yield
along with recovery of 41% of 1c-d7 in which H/D exchange was
observed between only the ortho C−H bond and the NH bond.
The D content at the ortho C−H bond was decreased to 0.48D
(Scheme 2a). This result clearly indicates that C−H bond
activation in benzamides is reversible under the reaction
conditions. When toluene-d8 was used as the solvent in the
reaction of 1c, the reaction was slower than the reaction in
toluene (Scheme 2b). Furthermore, no H atom was detected in
the benzylic position in the product, and no deuterium atom was
incorporated into the recovered 1c. In the 1H NMR spectrum of
the product, 1.52H was observed in the benzylic position,
indicating that the reaction in toluene is 3.2 times faster when
toluene-d8 is used (1.52/0.48) when the reaction of 1c in a 1:1
mixture of toluene and toluene-d8 was carried out (Scheme 2c)
The most important issue to be addressed is what the actual
benzylation species is and how it is generated. It was found that a
With the optimized reaction conditions in hand, the reaction
of various benzamides in toluene as the solvent was examined
(Table 2). A wide variety of functional groups on the benzamide
are tolerated in the reaction. The less hindered C−H bonds were
exclusively activated to give benzylation products 4−8, 11, and
15 in the reaction of meta-substituted aromatic amides. In the
case of an m-fluoro substrate and a simple benzamide,
dibenzylation products 12 and 13, respectively, were obtained
in high yields. In all cases, no coupling between the ortho C−H
bonds in the benzamide and C(sp2)−H bonds in toluene was
observed.
In the benzylation (Table 2), toluene was used as the coupling
partner as well as the solvent. In order to develop a more useful
reaction for organic synthesis, we examined the reaction with
functionalized toluene derivatives in a common unreactive
solvent. The use of 3 equiv of toluene in 0.7 mL of
methycyclohexane, octane, ethylbenzene, n-butylbenzene, cu-
mene, and 4-methyltetrahydropyran gave no reaction. To our
delight, when 3 equiv of toluene in 0.7 mL of benzene as the
solvent was used under otherwise standard reaction conditions,
2c was obtained in 49% NMR yield. Because of its low boiling
i
reaction of C3F7I in the presence of Ni(OTf)2/Na2CO3 in
toluene at 140 °C for 24 h generated benzyl iodide in 40% NMR
yield. Curiously, a nickel complex was not required to generate
the benzyl iodide, as benzyl iodide was formed in 21% NMR yield
even in the absence of Ni(OTf)2. Although benzyl iodide was
formed only in 40% yield, catalytic C−H benzylation proceeded
smoothly as shown in Table 2. These results suggest that benzyl
iodide is formed to some extent under the reaction conditions
but that it does not contribute to the benzylation as the major
B
dx.doi.org/10.1021/ja5095342 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Ni(II)-Catalyzed Ortho-Benzylation of Benzamides
with Toluene Derivatives
Scheme 2. Deuterium-Labeling Experiments
a
Scheme 3. Reaction Mechanism
a
Reactions were conducted on a 0.3 mmol scale. Isolated yields are
b
reported. Toluene derivative (1.0 mL) was used as the solvent.
path because the benzylation of C−H bonds proceeded
smoothly even when the generation of benzyl iodides was not
efficient.
On the basis of the above results and data taken from previous
reports, a plausible reaction mechanism is proposed in Scheme 3.
Coordination of amide A to the Ni(II) center gives Ni(II)
complex B with the generation of HX, which is trapped by
Na2CO3. The C−H bonds in complex B then undergo reversible
cleavage to give nickelacycle C. Base-promoted single-electron
transfer (SET) of Rf−I9 followed by abstraction of a hydrogen
from toluene generates a benzyl radical and Rf−H.10 The
reaction of complex C with the benzyl radical affords Ni(III)
species D, from which reductive elimination and protonation
occurs to give the final product with generation of the Ni(I)
complex. The reaction of Ni(I)X with Rf−I regenerates the
Ni(II) complex with the generation of an Rf radical.11 The
addition of TEMPO completely quenched the reaction. These
results suggest that the reaction involves the formation of a free
radical.
Another alternative mechanism involves the oxidative addition
of Rf−I to complex C to give Ni(IV) complex F, which reacts
with toluene to afford complex G via the complex H. The step
from F to G would be expected to proceed via a radical
mechanism because the oxidative addition of iC3F7I to transition-
metal complexes12 and the abstraction of a H atom radical by a
heptafluoroisopropyl radical are known.13 As shown in Table 1,
n-C6F13I was not effective, although iC3F7I showed high activity.
It is known that secondary perfluoroalkyl radicals undergo H
atom abstraction faster than primary perfluoroalkyl radicals.13 If
perfluoroalkyl anion were involved in the reaction, perfluor-
oalkene would be generated by β-fluoro elimination.14 However,
no perfluoroalkene was detected.
C
dx.doi.org/10.1021/ja5095342 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Chem. Soc. 2011, 133, 13864. (h) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You,
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In summary, we have reported on a unique strategy that
enables oxidative C(sp2)−H/C(sp3)−H coupling via a Ni(II)-
catalyzed reaction of benzamides with toluene derivatives. The
presence of heptafluoroisopropyl iodide is essential for the
reaction to proceed. Its role is to generate a benzyl radical via H
atom abstraction from the toluene derivative. The reaction does
not require a toluene derivative as the solvent. The scope of the
reaction is broad with regard to both benzamides and coupling
partners. Although the reaction mechanism is not clear, we
anticipate that the strategy developed here may provide
inspirations for the design of new functionalizations of C−H
bonds.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) (a) Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624.
(b) Biswas, S.; Wiex, D. J. J. Am. Chem. Soc. 2013, 135, 16192. (c) Xu, H.;
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(10) The formation of Rf−H was confirmed by 19F NMR spectra of the
reaction mixtures. See the Supporting Information.
AUTHOR INFORMATION
Corresponding Author
chatani@chem.eng.osaka-u.ac.jp
■
Notes
(11) Mikhaylov, D.; Gryaznova, T.; Dudkina, Y.; Khrizanphorov, M.;
Latypov, S.; Kataeva, O.; Vicic, D. A.; Sinyashin, O. G.; Budnikova, Y.
Dalton Trans. 2012, 41, 165.
(12) Bourgeois, C. J.; Hughes, R. P.; Husebo, T. L.; Smith, J. M.; Guzei,
I. M.; Liable-Sands, L. M.; Zakharov, L. N.; Rheingold, A. L.
Organometallics 2005, 24, 6431.
(13) Brace, N. O. J. Org. Chem. 1963, 28, 3093.
(14) Hughes, R. P.; Maddock, S. M.; Guzei, I. A.; Liable-Sands, L. M.;
Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 3279.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from MEXT and by JST
Strategic Basic Research Programs “Advanced Catalytic Trans-
formation Program for Carbon Utilization (ACT-C)” from JST.
Y.A. expresses his special thanks for a JSPS Research Fellowship
for Young Scientists.
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D
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