Nickel-catalyzed chelation-assisted direct arylation of unactivated C(sp3)-H bonds with aryl halides

Article abstract of DOI:10.1039/c4cc00716f

In this work, we have disclosed the nickel-catalyzed unactivated β-C(sp³)-H bond arylation of aliphatic acid derivatives with aryl iodides/bromides via bidentate chelation-assistance of an 8-aminoquinoline moiety. These preliminary results indi

Full text of DOI:10.1039/c4cc00716f

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Nickel-catalyzed chelation-assisted direct
arylation of unactivated C(sp3)–H bonds with
aryl halides†
Cite this: Chem. Commun., 2014,
50, 3944
Received 27th January 2014,
Accepted 19th February 2014
Mingliang Li, Jiaxing Dong, Xiaolei Huang, Kaizhi Li, Qian Wu, Feijie Song and
Jingsong You*
DOI: 10.1039/c4cc00716f
www.rsc.org/chemcomm
In this work, we have disclosed the nickel-catalyzed unactivated wider and wider attention since the seminal work by Daugulis
b-C(sp3)–H bond arylation of aliphatic acid derivatives with aryl in 2005.3a,d,j Various metal catalysts (e.g., Pd, Rh, and Ru) have
iodides/bromides via bidentate chelation-assistance of an 8-amino- been applied extensively, whereas the chelation-assisted examples
quinoline moiety. These preliminary results indicate the intrinsic involving nickel catalysts are rare. In 2011, Chatani and co-workers
catalytic potential of nickel metal for unactivated C(sp3)–H bond uncovered the first nickel-catalyzed ortho-C(sp2)–H bond activa-
arylation.
tion to achieve regioselective oxidative cycloaddition of aro-
matic amides to alkynes using the bidentate auxiliary strategy.5c
The C(sp2)–C(sp3) bonds extensively exist in synthetic products, Lately, the same group developed the nickel-catalyzed chelation-
naturally occurring molecules, pharmaceuticals, and bioactive assisted ortho-C(sp2)–H alkylation of aromatic amides.5d Inspired
compounds. The construction of C(sp2)–C(sp3) bonds has by these pioneering studies, it is reasonable to assume that the
attracted great interest from organic chemists for a long time. activation of unactivated C(sp3)–H bonds would be achieved
Transition metal-catalyzed direct C–H bond functionalization through nickel catalysis with the assistance of a bidentate
has been one of the most promising methods for the C–C bond directing group.9 Herein, we wish to report the nickel-catalyzed
formation.1 The C(sp2)–C(sp3) bond formation via catalytic unactivated primary b-C(sp3)–H bond arylation of aliphatic acid
direct C(sp3)–H bond arylation relies heavily on palladium(II) derivatives with aryl iodides/bromides (eqn (1)). During the
catalysis.2–4 In recent years, the nickel-catalyzed direct C–H submission of this manuscript, Chatani et al. reported the direct
bond functionalization has received more and more attentions arylation of C(sp3)–H bonds of aliphatic amides by using the
due to the abundance, low cost and particular electronic same directing group.10 However, only aryl iodides were
properties of nickel metal.5 In spite of significant efforts, the employed as the coupling partner in their work.
Ni-catalyzed direct C(sp3)–H arylation remains rare. In 2011,
Hartwig and co-workers disclosed the nickel-catalyzed a-arylation
and heteroarylation of ketones with aryl halides.6 Very recently,
(1)
Lei and co-workers reported the nickel-catalyzed oxidative C(sp3)–
H bond arylation of tetrahydrofuran and 1,4-dioxane with aryl-
boronic acids.7 However, these direct arylation reactions occurred
Considering that 8-aminoquinoline has been proven to be a
at the activated a-C(sp3)–H bonds adjacent to oxygen atoms (ether powerful bidentate auxiliary in transition metal-catalyzed direct
derivatives) and carbonyl groups (ketones), and the nickel- C–H bond activation, a variety of a,a-disubstituted propionic
catalyzed arylation of unactivated C(sp3)–H bonds is still a highly acids were first decorated with 8-aminoquinoline to N-(quinolin-
challenging topic.
8-yl)propanamide derivatives. In our initial exploration, it was
The chelation-assistance strategy has become an efficient found that the reaction of 2-benzyl-3-(4-methoxyphenyl)-2-
means for the functionalization of unactivated C–H bonds.8 In methyl-N-(quinolin-8-yl)propanamide 1a with 1-iodo-4-methoxy-
particular, the 8-aminoquinoline group has recently attracted benzene 2a gave the desired product 3a in 24% yield in the
presence of Ni(OTf)2, PPh3 and K2CO3 in 1,4-dioxane at 140 1C
Key Laboratory of Green Chemistry and Technology of Ministry of Education,
for 24 h (ESI,† Table S1, entry 1). After screening various bases
(e.g., K2CO3, Na2CO3, K3PO4 and Li2CO3), Na2CO3 gave the best
yield of 35% (ESI,† Table S1, entries 1–4). Upon addition of
College of Chemistry, and State Key Laboratory of Biotherapy, West China Medical
School, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.
E-mail: jsyou@scu.edu.cn; Fax: +86 28-85412203
DMSO and PivOH, the product yield was improved greatly to
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. See DOI: 10.1039/c4cc00716f
83% at 160 1C (ESI,† Table S1, entry 9). Other nickel(II) catalysts
3944 | Chem. Commun., 2014, 50, 3944--3946
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Table 2 Nickel-catalyzed b-C(sp3)–H bond arylation of various aliphatic
amides with 1-iodo-4-methoxybenzene 2aa
such as Ni(OAc)2 and NiCl2 provided 3a in moderate yields
under otherwise identical conditions (ESI,† Table S1, entries 13
and 14). Interestingly, a nickel(0) catalyst such as Ni(cod)2 could
also deliver 3a in 62% yield (ESI,† Table S1, entry 15). The yield
decreased to 54% when the reaction was performed in the absence
of PPh3 (ESI,† Table S1, entry 10). In addition, other frequently
used directing groups such as pyridin-2-ylmethanamine and
2-(methylthio)aniline could not promote arylation. Thus, the
best result was obtained by using Ni(OTf)2 (10 mol%) as the
catalyst, PPh3 (20 mol%) as the ligand, Na2CO3 (2.0 equiv.) as
the base, PivOH (0.2 equiv.) and DMSO (3.5 equiv.) as the
additives in dry 1,4-dioxane at 160 1C.
With the optimized reaction conditions in hand, we inves-
tigated the generality of the reaction of 1a with aryl iodides as
shown in Table 1. We found that the reactions of aryl iodides
with electron-donating groups (except the ortho-substituted
methoxy group) could deliver the cross-coupled products in
a
Conditions: Ni(OTf)2 (10 mol%), PPh3 (20 mol%), Na2CO3 (2.0 equiv.),
PivOH (0.2 equiv.), DMSO (3.5 equiv.), amide 1 (0.2 mmol) and 2a
satisfactory yields (Table 1, 3a–3e). Aryl iodides bearing (3.0 equiv.) in dry 1,4-dioxane (1 mL) at 160 1C for 36 h. Isolated yields.
electron-withdrawing groups such as p-CH3CO–, p-CO2Me,
and p-CONEt2 also proceeded smoothly to afford the desired results indicated the intrinsic potential of nickel catalysis in the
products 3f, 3g and 3h in 55%, 60% and 62% yields, respec- C(sp3)–H bond arylation with aryl bromides.
tively. Notably, a variety of functional groups such as alkyloxy,
To explore the effect of the R substituent of the phenyl ring
ketone, ester, amide, acetamido, and even free amino groups of aliphatic acid derivatives 1 on the primary b-C(sp3)–H bond
were tolerated under the optimized reaction conditions, which arylation, an array of amides 1 were investigated accordingly.
is useful in further synthetic transformations. We were pleased To our delight, a,a-dibenzyl substituted propionic acid deriva-
to find that aryl bromides could also undergo the b-C(sp3)–H tives bearing either electron-donating or electron-withdrawing
bond arylation in synthetically useful yields (Table 1). It is substituents on the phenyl ring afforded the desired products
worth noting that transition metal-catalyzed direct C(sp3)–H in synthetically useful yields (Table 1, 3a; Table 2, 3f–3l).
bond arylation with aryl bromides is still a difficult task in the Notably, the current methodology was compatible with some
synthetic organic community and is underrepresented to date. important functional groups such as Ac, CO2Me, CONEt2, CN
To the best of our knowledge, this is the first attempt to achieve and CHO. The coupling reaction of 2-methyl-2-(naphthalen-2-
transition metal-catalyzed chelation-assisted direct arylation of ylmethyl)-3-phenyl-N-(quinolin-8-yl)propanamide with 2a could
unactivated C(sp3)–H bonds with aryl bromides. These preliminary also generate the b-arylated product 3m in 79% yield.
To examine the synthetic usefulness of our protocol, we turned
our attention to other aliphatic acid derivatives, while 2,2-dibenzyl-
Table 1 Nickel-catalyzed b-C(sp3)–H bond arylation of aliphatic amide 1a
substituted propanamides could smoothly afford the arylated pro-
with aryl halidesa
ducts 3. As shown in Table 3, the nickel-catalyzed C(sp3)–H bond
arylation exhibited a relatively broad substrate scope for aliphatic
acid derivatives. 2-Methyl-3-phenyl-acrylamide reacted with 1-iodo-4-
methoxybenzene 2a to afford the coupled product 4 in 58% yield.
Isobutyramides could couple with 2a to afford the single arylated
products. For example, the reaction of 2,2-dimethyl-3-phenylpropan-
amide with 2a delivered the desired product 5 in 60% yield.
Isobutyramide with an a-ethyl substituent proceeded well to yield
the arylated product 6 in 64% yield. Interestingly, the diarylated
products could be obtained by increasing the amount of 1-iodo-
4-methoxybenzene 2a (Table 3, 7 and 8). It should be noted that
2-methyl-2-phenylpropanamide selectively underwent C(sp3)–H bond
activation of the methyl group instead of the C(sp2)–H bond of the
phenyl ring to generate the arylated product 8. In addition to the
methyl group of quaternary carbon centers, the methyl group of
tertiary carbon centers could also undergo direct C(sp3)–H bond
a
Conditions: Ni(OTf)2 (10 mol%), PPh3 (20 mol%), Na2CO3 (2.0 equiv.), arylation with aryl iodides. The reaction of N-(quinolin-8-yl)isobutyr-
PivOH (0.2 equiv.), DMSO (3.5 equiv.), amide 1a (0.2 mmol), and aryl
iodide (3.0 equiv.) or aryl bromide (4.0 equiv.) in dry 1,4-dioxane (1 mL)
at 160 1C for 36 h. Isolated yields. 2a (2.0 equiv.) for 24 h. 22% of 1a
was recovered.
amide with 2a provided the desired product 9 in 50% yield.
b
c
In summary, we have developed the nickel-catalyzed unacti-
vated b-C(sp3)–H bond arylation of aliphatic acid derivatives
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Table 3 Scope of aliphatic amides in Ni-catalyzed b-C(sp3)–H bond
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with aryl iodides via bidentate chelation-assistance of an
8-aminoquinoline moiety. Besides aryl iodides, aryl bromides
are also capable of undergoing the cross-coupling reactions to a
certain extent. Further studies to extend the scope and clarify
the detailed mechanism11 are ongoing in our laboratory.
We thank the National Basic Research Program of China
(973 Program, 2011CB808601), and the National NSF of China
(No. 21272160, 21025205, and 21321061) for financial support.
Notes and references
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H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; 11 Although the detailed mechanism is not clear at this stage, a plausible
(h) S.-Y. Zhang, F.-M. Zhang and Y.-Q. Tu, Chem. Soc. Rev., 2011,
catalytic cycle is proposed in ESI† (Scheme S1).
3946 | Chem. Commun., 2014, 50, 3944--3946
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