Nickel-catalyzed direct arylation of C(sp3)-H bonds in aliphatic amides via bidentate-chelation assistance

Article abstract of DOI:10.1021/ja411715v

The Ni-catalyzed, direct arylation of C(sp³)-H (methyl and methylene) bonds in aliphatic amides containing an 8-aminoquinoline moiety as a bidentate directing group with aryl halides is described. Deuterium-labeling experiments indicate that the C-H bond cleavage step is fast and reversible. Various nickel complexes including both Ni(II) and Ni(0) show a high catalytic activity. The results of a series of mechanistic experiments indicate that the catalytic reaction does not proceed through a Ni(0)/Ni(II) catalytic cycle, but probably through a Ni(II)/Ni(IV) catalytic cycle.

Full text of DOI:10.1021/ja411715v

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Direct Arylation of C(sp3)−H Bonds in Aliphatic
Amides via Bidentate-Chelation Assistance
Yoshinori Aihara and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
bonds (Scheme 1). To the best of our knowledge, Ni-catalyzed
transformation of C(sp3)−H bonds have been restricted to only
ABSTRACT: The Ni-catalyzed, direct arylation of C-
(sp3)−H (methyl and methylene) bonds in aliphatic
amides containing an 8-aminoquinoline moiety as a
bidentate directing group with aryl halides is described.
Deuterium-labeling experiments indicate that the C−H
bond cleavage step is fast and reversible. Various nickel
complexes including both Ni(II) and Ni(0) show a high
catalytic activity. The results of a series of mechanistic
experiments indicate that the catalytic reaction does not
proceed through a Ni(0)/Ni(II) catalytic cycle, but
probably through a Ni(II)/Ni(IV) catalytic cycle.
Scheme 1. Nickel-Catalyzed Direct Arylation of C(sp3)−H
Bonds in Aliphatic Amides
one example, i.e., the Ni(0)-catalyzed cycloaddition of
formamide with alkynes.9
The reaction of amide 1a (0.3 mmol) with 4-iodoanisole (0.6
mmol) in the presence of Ni(OTf)2 (0.03 mmol) as a catalyst
and Na2CO3 (0.6 mmol) as a base in DMA (0.6 mL) at 140 °C
for 24 h gave the β-arylation product 1b in 40% NMR yield along
with the recovery of 44% of the unreacted 1a, and no evidence of
any biarylated product or any other products produced by
reaction at the methylene or benzene C−H bonds was found
(entry 1, Table 1). The addition of benzoic acid as an additive
improved the yield of 1a to 70% (entry 2). Further investigation
revealed that the addition of a sterically bulky carboxylic acid,
such as 2,4,6-trimethylbenzoic acid (MesCOOH) or [1,1′:3′,1″-
terphenyl]-2′-carboxylic acid (2,6-Ph2C6H3COOH), also im-
proved the product yield (entries 3−7). The efficiency of the
reaction was also significantly affected by the choice of the base
used. Na2CO3 was determined to be the best base for this
reaction (entries 8−11). Among the solvents examined, DMF
was the solvent of choice. Curiously, not only Ni(II) complexes
but also a Ni(0) complex showed a high catalytic activity,
resulting in high yields of the β-arylation product (entry 18).
We next examined the effect of directing groups (Figure 1).
The reaction did not proceed at all when N-2-naphthylbenza-
maide 2 or the ester 3 was used. The use of other directing
groups, such as 4 or 5, also resulted in no reaction.
he transition metal-catalyzed functionalization of C−H
Tbonds has emerged as a powerful tool for the formation of
C−C and C−heteroatom bonds in recent years.1 A wide variety
of catalytic functionalizations of C(sp2)−H has already been
developed to date and have had a significant impact in the field of
organic chemistry. It can now be said that it is no longer difficult
to develop the functionalization of C(sp2)−H bonds. In this
sense, the catalytic functionalization of C(sp2)−H bonds is now
recognized as one of general organic synthetic reactions available
to organic chemists. Because of this, much attention is currently
focused on the functionalization of C(sp3)−H bonds, which
continues to be a challenging issue.2 However, most of the
functionalization reactions of C(sp3)−H bonds reported involve
the use of palladium complexes as catalysts. Transition metal
complexes other than palladium complexes also show catalytic
activity, but only in limited types of functionalizations of
C(sp3)−H bonds, such as dehydrogenation, borylation, carbon-
ylation, and similar reactions.3
Recently, the utilization of a bidentate directing group in the
transformation of C−H bonds has significantly grown in
popularity since the seminal discovery by Daugulis,4 and this
area appears to show a high potential for exploring new types of
transformations of C−H bonds which cannot be achieved using
conventional directing groups.5,6 Various types of functionaliza-
tions of C(sp3)−H bonds have been achieved using the
bidentate-chelation system in conjunction with Pd(II) catalysts.7
We also reported on the Ru3(CO)12-catalyzed carbonylation of
C(sp3)−H bonds in aliphatic amides with a pyridinylmethyla-
mino moiety as the bidentate directing group.6b,c Nakamura
reported on the Fe-catalyzed arylation of C(sp3)−H bonds in
aliphatic amides having an 8-aminoquinolinyl moiety with
Grignard reagents.8 We report here on the Ni-catalyzed β-
arylation of aliphatic amides 1 containing a bidentate directing
group with aryl iodides via the cleavage of unactivated C(sp3)−H
Table 2 shows the scope of the substrates under the standard
reaction conditions. The reaction was sensitive to the structure of
the amides. Some examples of unreactive amides are listed at the
bottom of Table 2. Aliphatic amides possessing no hydrogen at
the α-position reacted efficiently. The reactions proceeded
exclusively at the methyl group in a highly regioselective manner,
as in the cases of 6a, 7a, 8a, and 9a, and methylene and benzene
C−H bonds were not arylated. Although the reaction of
cyclohexanecarboxamide 10a resulted in selective mono-
Received: November 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja411715v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimaization of the Nickel-Catalyzed Direct Arylation of Aliphatic Amide 1a with 4-iodoanisole
b
entry
catalyst
ligand
base
solvent
yield (1b/1a) (%)/(%)
1
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
NiCI2
none
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Li2CO3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
toluene
AcOH
DMF
DMF
DMF
40/44
2
PhCOOH
70/22
3
2-PhC6H4COOH
72/24
4
MesCOOH
82 (78) /17
74/23
5
2,6-iPr2C6H3COOH
2,6-Ph2C6H3COOH
1-AdCOOH
MesCOOH
6
81/21
7
72/27
8
49/35
9
MesCOOH
NaHCO3
K2CO3
14/72
10
11
12
13
15
16
17
18
MesCOOH
0/103
MesCOOH
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
57/42
MesCOOH
88 (83)/12
59/38
MesCOOH
MesCOOH
0/99
MesCOOH
81/10
Ni(OAc)2
Ni(cod)2
MesCOOH
81/10
MesCOOH
79/ 10
a
Reaction conditions: amide 1a (0.3 mmol), 4-iodoanisole (0.6 mmol), catalyst (0.03 mmol), ligand (0.06 mmol), base (0.6 mmol) in solvent (0.6
b
mL) at 140 °C for 24 h. NMR yields. The number in parentheses is the isolated yield.
bonds is rapid and reversible, and it occurs before the reaction
with the aryl iodide. In sharp contrast, Ni(0)-catalyzed
deuterium-labeling experiments gave different results. In the
presence of 4-iodoanisole, H/D exchange in both the product
and the recovered amide was observed, similar to the Ni(II)-
catalyzed reaction. However, in the absence of 4-iodoanisole, no H/
D exchange occurred. These results suggest that the presence of an
aryl iodide is required for the cleavage of C−H bonds to take
place in the case of the Ni(0)-catalyzed reaction.
Product distribution was examined in detail, in order to
develop a better understanding of the difference between the
Ni(0)- and Ni(II)-catalyzed reactions (Scheme 4). In the
reaction of 1a with 4-butyl-1-iodobenzene in the presence of
30 mol % Ni(cod)2, the arylation product 1o was obtained in
67% NMR yield with 32% of the starting amide 1a being
recovered, and butylbenzene was produced in 86% yield/Ni(0)
and no biaryl derivative was formed. In sharp contrast, when
Ni(OTf)2 was used as the catalyst, 1o was obtained in 65% NMR
yield with 36% of the starting amide being recovered, but neither
butylbenzene nor biaryl were detected. It is known that Ni(0)
complexes react with Ar−X to give homocoupling products Ar−
Ar with the generation of a Ni(II) complex;11 however, the
results in Scheme 4 indicate that such a reaction did not take
place under the present reaction. Instead, the results suggest that
the Ni(0) complex was oxidized by 4-butyl-1-iodobenzene with
the generation of butylbenzene. The results of the above analyses
indicate that the catalytic active species in this reaction is not the
Ni(0) complex but rather, the Ni(II) complex.
Figure 1. Ineffective directing groups.
arylation only at the methyl group, cycloheptanecarboxamide
11a gave a mixture of monoarylated 11b and biarylated products
11c, the latter involving the arylation at the cyclic methylene C−
H bonds. When cyclobutanecarboxamide 12a and cyclo-
pentanecarboxamide 13a were used, the arylation of β-
methlyene C−H bonds was the predominant reaction. The
structure of 12c was confirmed from X-ray crystallography data,
which show that the introduced aryl groups are located cis to the
directing group.10 This also indicates the importance of the
directing group.
A 5 mmol scale reaction of 6a was successfully performed in a
30-mL two-necked flask (Scheme 2).
The scope of aryl iodides with various substituents at the para
position was examined using 1a as the substrate. The results
showed that common functional groups, including esters,
iodides, chlorides, and amines, were compatible in the present
reaction. Electron-rich aryl iodides tended to give the products in
slightly higher yields than electron-poor aryl iodides. Ortho-
substituted aryl iodides were unreactive. Phenyl bromides and
triflates did not give arylation products.
To gain insights into the mechanism for the reaction,
deuterium-labeling experiments were carried out. The deuter-
ated amides 1a-d3 were reacted with 4-iodoanisole for 3 h under
standard conditions (Scheme 3). H/D exchange between the
methyl C−D bond and N−H bond was detected. Thus, the D
content in the recovered amide decreased from >99% to 76%,
and the D content of the amide nitrogen increased from 0% to
23%. H/D exchange was also observed, even in the absence of 4-
iodoanisole. These results suggest that the cleavage of C−H
A proposed mechanism for the reaction is shown in Scheme 5.
Coordination of the amide to the Ni center followed by ligand
exchange with the concomitant generation of HX gives the Ni
complex 15, which undergoes reversible cyclometalation to give
16, probably via a concerted-metalation−deprotonation mech-
anism. The oxidative addition of iodobenzene gives the high-
valent Ni(IV) complex 17. The Ni(IV) complex 17 undergoes
B
dx.doi.org/10.1021/ja411715v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Nickel-Catalyzed Direct Arylation of Aliphatic
Amides with Aryliodides
Scheme 2. Large-Scale Reaction of 6a
a
Scheme 3. Deuterium-Labeling Experiments
Scheme 4. Product Distribution
generation of benzene. Alternatively, Ph−Ni−I species would
react with HX to generate Ni(II) with the generation of
benzene.13 In order to gain additional insight into the
mechanism, we performed a radical trapping experiment. The
addition of 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) did
not inhibit the reaction, and the arylation product 1o was
obtained in moderate yield (53%). This suggests that a single
electron transfer (SET) was not involved in this reaction;
however, additional experiments will be needed to exclude a
Ni(I)/Ni(III) catalytic cycle.
In summary, we report on the first example of the nickel-
catalyzed direct arylation of unactivated C(sp3)−H bonds in
aliphatic amides, in which the presence of a bidentate directing
group, such as an 8-aminoquinoline moiety is required for the
a
Reaction conditions: amide (0.3 mmol), aryl iodides (0.6 mmol),
Ni(OTf)2 (0.03 mmol), MesCOOH (0.06 mmol), Na2CO3 (0.6
mmol) in DMF (0.6 mL) at 140 °C for 24 h in 5-mL screw-capped
vial. Isolated yields by column chromatography. The number in
b
c
parentheses is the yield of the recovered starting amide. The
stereochemistry is not determined, but only the single isomer exists.
d
2,6-Ph2C6H3COOH was used instead of MesCOOH, and 4-
e
iodoanisole (0.9 mol) was used. Purified by GPC.
reductive elimination to give 18 which, on protonation, affords
the desired arylation product with the regeneration of Ni(II).12
In the case of the Ni(0)-catalyst, the reaction of the Ni(0)
complex with iodobenzene to form Ph−Ni−I species which
reacts with the amide 1 generates the Ni(II) complex 15 with the
C
dx.doi.org/10.1021/ja411715v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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Scheme 5. Proposed Mechanism
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reaction to proceed. Unlike the Fe-catalyzed arylation of aliphatic
amides with ArMgBr/Ar2Zn using a similar chelation-assisted
system,8 the present reaction shows high functional group
compatibility. Experiments involving stoichiometric reactions are
currently underway, in attempts to isolate or detect the active
catalytic species.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett. 2012, 14, 3724. (l) Rodríguez, N.; Romero-Revilla, J. A.;
AUTHOR INFORMATION
Corresponding Author
chatani@chem.eng.osaka-u.ac.jp
Notes
́
■
Fernan
́
dez-Iban
́
ez, M. A.; Carretero, J. C. Chem. Sci. 2013, 4, 175.
̃
(m) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am.
Chem. Soc. 2013, 135, 2124. (n) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W.
A.; Chen, G. J. Am. Chem. Soc. 2013, 135, 12135. (o) He, G.; Zhang, S.-
Y.; Nack, W. A.; Li, Q.; Chen, G. Angew. Chem., Int. Ed. 2013, 52, 11124.
(p) Parella, R.; Gopalakrishnan, B.; Babu, S. A. Org. Lett. 2013, 15, 3238.
(q) Roman, D. S.; Charette, A. B. Org. Lett. 2013, 15, 4394. (r) Pan, F.;
Shen, P.-X.; Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758.
(s) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F Chem. Sci. 2013, 4, 3906.
(t) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi,
B.-F. Chem. Sci. 2013, 4, 4187. (u) Nadres, E. T.; Santos, G. I. F.;
Shabashov, D.; Daugulis, O. J. Org. Chem. 2013, 78, 9689. (v) Ju, L.; Yao,
J.; Wu, Z.; Liu, Z.; Zhang, Y. J. Org. Chem. 2013, 78, 10821. (w) Hoshiya,
N.; Kobayashi, T.; Arisawa, M.; Shuto, S. Org. Lett. 2013, 15, 6202.
(x) Parella, R.; Gopalakrishnan, B.; Babu, S. A. J. Org. Chem. 2013, 78,
11911.
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 Strategic
Basic Research Programs “Advanced Catalytic Transformation
Program for Carbon Utilization (ACT-C)” from JST.
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dx.doi.org/10.1021/ja411715v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX