Ligand-Controlled Nickel-Catalyzed Reductive Relay Cross-Coupling of Alkyl Bromides and Aryl Bromides

Article abstract of DOI:10.1021/acscatal.7b03388

1,1-Diarylalkanes are important structural frameworks which are widespread in biologically active molecules. Herein, we report a reductive relay cross-coupling of alkyl bromides with aryl bromides by nickel catalysis with a simple nitrogen-containing ligand. This method selectively affords 1,1-diarylalkane derivatives with good to excellent yields and regioselectivity.

Full text of DOI:10.1021/acscatal.7b03388

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Letter
Ligand-Controlled Nickel-Catalyzed Reductive Relay
Cross-Coupling of Alkyl Bromides and Aryl Bromides
Long Peng, Yuqiang Li, Yangyang Li, Wang Wang, Hailiang Pang, and Guoyin Yin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03388 • Publication Date (Web): 01 Dec 2017
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Ligand-Controlled Nickel-Catalyzed Reductive Relay Cross-Cou-
pling of Alkyl Bromides and Aryl Bromides
Long Peng‡, Yuqiang Li‡, Yangyang Li, Wang Wang, Hailiang Pang and Guoyin Yin*
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The Institute for Advanced Studies (IAS), Wuhan University (WHU), Wuhan, Hubei 430072, P. R. China
ABSTRACT: 1,1-Diarylalkanes are important structural frameworks which are widespread in biologically active molecules.
Herein, we report a reductive relay cross-coupling of alkyl bromides with aryl bromides by nickel catalysis with a simple
nitrogen-containing ligand. This method selectively affords 1,1-diarylalkane derivatives with good to excellent yields and
regioselectivity.
KEYWORDS: Alkyl electrophiles, -Hydride elimination, 1,1-Diarylalkanes, Migratory cross-coupling, High-valent nickel
Transition metal-catalyzed carbon-carbon bond for-
mation reactions play an essential role in the synthesis of
complex molecules which are relevant to pharmaceuticals,
argochemicals and material sciences as highlighted by the
2010 Nobel prize in chemistry.1 Alkyl electrophiles, which
are abundant and cheap, are ideal precursors to build
C(sp3)-C bonds. However, coupling reactions of alkyl elec-
trophiles are always of low efficiency due to the fact that
the alkyl-metal complexes formed through oxidative addi-
tion readily undergo -hydride elimination to form alkene
side products.2 On the other hand, taking advantage of the
propensity of -hydride elimination and the reverse, mi-
gratory insertion, to change the reacting site of alkyl elec-
trophiles through a transition metal redox-relay process,3
unlocks unique opportunities for remote-site functionali-
zation and has recently drawn increasing attention
(Scheme 1a).4
Selective cross-coupling of two different electrophiles
catalyzed by earth-abundant transition metals has been
well-established as a general protocol in synthesis.5 Addi-
Scheme 1. Transition Metal-Catalyzed Cross-Coupling
of Alkyl Electrophiles
tionally, this strategy avoids using sensitive and dangerous
metal reagents. A wide number of electrophiles have been
successfully used to construct C(sp3)-C(sp2), C(sp2)-C(sp2)
and C(sp3)-C(sp3) bonds via catalysis with nickel, cobalt, or
iron catalysts.5c Investigations on the efficiency and
chemo-selectivity of reductive cross-coupling reactions
have received much attention recently.5d-f By contrast, the
regioselectivity of these transformations has been less ex-
plored and previous studies mainly report the formation of
ipso-selective products.5c
The framework of 1,1-diarylalkanes is widespread in
natural products as well as synthetic biologically active
molecules,6 which has attracted many efforts towards ex-
ploration of efficient protocols to access these structural
skeletons in the synthetic community. Transition metal
catalysis plays an essential role in synthetic approach to
these types of compounds, among which, the cross cou-
pling of benzylic electrophiles and aryl organometallic re-
agents is one of the most general method.7 However, ben-
zylic electrophiles, especially benzylic halides are not al-
ways easy to prepare and often limited stability that pre-
vents storage. The direct arylation of benzylic C-H bonds
is an attractive protocol to access the 1,1-diarylalkanes. Re-
cently, major progress in the synthesis of 1,1-diarylalkanes
was made by Stahl8 and Liu9 simultaneously; they disclosed
a copper-catalyzed direct oxidative arylation of benzylic C-
H bonds via a radical relay strategy, with an extraordinarily
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broad substrate scope and good functional group toler-
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With optimal conditions in hand, we turned our at-
tention to the generality of this Ni-catalyzed relay cross-
coupling reaction. As shown in Table 2, C2-C5 aryl-substi-
tuted alkyl bromides were examined in the reductive relay
cross-coupling transformations and all type of alkyl bro-
mides were capable to furnish the 1,1-diarylalkane prod-
ucts, albeit longer carbon chain substrates with slightly
lower yield. Furthermore, it was found that the electronic
properties of substituents on aryl groups did not signifi-
cantly affect the reactivity. A variety of functional groups
such as chlorides (4c, 4d and 4n), unprotected indoles (4h,
4i), amines (4l, 4q), alcohols (4r), amides (4k) and elec-
tron-rich pyridines (4l) were all well tolerated in this re-
mote-arylation reaction. Notably, aryl bromide with strong
electron-withdrawing group afforded low yield and poor
regioselectivity (4u). Secondary alkyl bromides could also
give rise to the benzylic arylation products with moderate
yields and excellent benzylic selectivity (4a, 4v and 4w). A
gram-scale experiment (4k) showcased the scalability of
this cross-coupling reaction.
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ance. In addition, a nickel-catalyzed benzylic arylation re-
action by merging nickel hydride catalyzed alkene isomer-
ization with cross-coupling of aryl iodides was recently re-
ported by Zhu and coworkers.10 Herein, we report a novel
reductive relay cross-coupling of non-activated alkyl elec-
trophiles and aryl bromides by ligand-controlled nickel ca-
talysis. This method selectively affords 1,1-diarylalkane de-
rivatives with excellent regioselectivity and a broad sub-
strate scope. Preliminary mechanistic investigations imply
that this migratory cross-coupling transformation involves
a key step of rapid Ni(III) migratory chain-walking
(Scheme 1b).11
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Table 1. Ligands Evaluation in Ni-Catalyzed Reductive
Cross-Coupling of 1-Bromo-3-phenylpropane and Bro-
mobenzene.a
Finally, to highlight the synthetic application of this
method, a strand of anti-cancer isoerianin analogues were
prepared starting from the commercially available and in-
expensive starting materials (3,4,5-trimethoxylbromo-ben-
zene (2.5 $/gram)) in good yields (4n, 4o and 4p).12
a
General conditions: 1a (0.2 mmol), 2a (0.24 mmol), anhy-
drous NiI2 (0.02 mmol), Ligand (0.02 mmol), n-Bu4NBr (0.2
mmol), Zn dust (0.3 mmol), DMA (2.0 mL), RT, 16 h; yields
and ratios 3a/4a were determined by GC by using naphthalene
as the internal standard. bIsolated yield (0.5 mmol scale).
70
We commenced this study with 1-bromo-3-phenylpro-
pane (1a) and bromobenzene (2a) as the model substrates,
a stable two-valent nickel salt as the catalyst and zinc dust
as the reductant. After evaluation of ligands, we were de-
lighted to find that we could tune the regioselectivity of
this coupling reaction as illustrated in Table 1. Employment
of bipyridines (L1, L2, L3), and 1,10-phenanthrolines (L4,
L5, L6) selectively gave the ipso-site cross-coupling prod-
uct 3a, with 5,5’-dimethylbipyridine (L3) affording the best
result, in 82% isolated yield and with exclusive regioselec-
tivity. To our surprise, the reaction with 6,6’-dimethyl sub-
stituted bipyridine (L7) and 2,9-dimethyl substituted 1,10-
phenanthrolines (L8, L9) selectively yielded the benzylic
phenylation product 4a, amongst them bathocurproine
(L9) proved to be the most efficient with 85% isolated yield
and 28/1 regioisomeric ratio on a 0.5 mmol scale. Addition-
ally, control experiments showed that the catalyst, ligand
and reductant were all crucial to the reductive relay cross-
coupling reaction, and that the addition of tetrabutyla-
monium bromide greatly improved the yields (see SI Table
S7 for details).
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w TEMPO
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w/o TEMPO
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t (min)
Figure 1. The Impact of TEMPO on the Reductive Relay
Cross-Coupling Reactions.
In order to gain some mechanistic insights on this
nickel-catalyzed cross-electrophiles coupling reaction,
several control experiments were conducted (more control
experiments see SI Table S8). The nickel-catalyzed Suzuki
cross-coupling reaction of alkylboronic acid 5 with 2a un-
der redox-neutral conditions did not yield any coupling
products (Eq.1), while the Suzuki reaction of 1a with phenyl
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Table 2. Scopes for Ni-Catalyzed Reductive Relay Cross-Coupling Reaction.a
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a Standard conditions: 1 (0.5 mmol), 2 (0.6 mmol), anhydrous NiI2 (0.05 mmol, 15.6 mg), Bathocuproine (0.05 mmol, 18.0 mg), n-
Bu4NBr (0.5 mmol, 161.2 mg), Zn dust (0.75 mmol, 49 mg), anhydrous DMA (4.0 mL), RT, 12-24 h; Isolated yield of 4; Ratios in
parentheses are regioisomeric ratio, representing the ratio of remote-/ipso-product, which determined by GC-MS. bfrom the sec-
ondary alkyl bromide. c6.0 mmol scale.
boronic acid (6) was able to furnish the coupling product
in moderate yield with 9/1 regioisomeric ratio (Eq.2).13
These results suggest that the -hydride elimination and
migratory insertion steps, namely the chain-walking pro-
cess, probably happen on the high-valent Ni(III) species
which is formed after the oxidative addition of alkyl bro-
mide to the aryl-Ni(I)L complex.14 We also examined the
impact of TEMPO on the reductive relay cross-coupling re-
actions (Eq. 3). As shown in Figure 1, during the first 90 min,
no cross-coupling products were detected. Then, the car-
bon-carbon bond formation was observed. In addition, the
product of TEMPO with alkyl radical could be detected by
HRMS. Comparatively, the reaction without TEMPO did
not show any induction period. These results are con-
sistent with the radical chain mechanism.15,16
Based on the above results and previous studies on the
cross-electrophiles coupling reactions,16 we tentatively
propose a mechanistic scenario for the Ni-catalyzed reduc-
tive relay transformation as depicted in Figure 2. Firstly,
the active catalyst species [Ni0L] (I) is formed via reduction
of the precatalyst Ni(II) with Zn dust. Then selective oxi-
dative addition of Ni(0), by a two-electron-transfer path-
way, into aryl bromide 2 generates aryl-Ni(II) intermediate
II, which reacts with the alkyl radical generated through
single-electron transfer process.16 As a consequence, the
Ni(III) intermediate is formed. Two pathways are possible
in the following step: (A) direct reductive elimination to
yield the ipso-coupling product 3; (B) multiple rapid and
reversible -hydride elimination and reinsertion steps,17 via
the intermediates IV and V, during which the thermody-
namically stable benzylic-Ni(III) intermediate VI is ob-
tained. Reductive elimination yields the 1,1-diarylalkane 4
and the Ni(I) species VII. Then the nickel(II) complex VIII
is generated from intermediate VII, followed by zinc dust
reduction to regenerate the catalyst I. The experimental re-
sults imply that the ligand controls the two pathways.
Pathway A is preferred in the reaction with L3 as the ligand,
while pathway B is more favorable when bathocurproine
(L9) was used. In other words, the ligands dictate the regi-
oselectivity of the cross-electrophile reactions.
In summary, we have developed a site-controllable re-
ductive cross-coupling reaction by the choice of ligand.
This novel protocol allows to construct the 1,1-diarylalkane
pharmacophore from simple alkyl bromides and aryl bro-
mides under mild conditions by earth-abundant nickel ca-
talysis. In addition, it benefits from wide substrate scope,
good functional group compatibility and excellent regiose-
lectivity. The preliminary mechanistic studies suggest the
transformation involves a high-valent nickel(III) chain-
walking key step. Additional investigations to provide fur-
ther mechanistic insights are currently ongoing in our la-
boratory.
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B.; Fu, Y. J. Am. Chem. Soc. 2017, 139, 12632-12637.
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2014, 136, 17645-17651.
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isomerizations: (a) Buslov, I.; Becouse, J.; Mazza, S.; Montandon-
Clerc, M.; Hu, X. Angew. Chem. Int. Ed. 2015, 54, 14523-14526. (b)
Buslov, I.; Keller, S. C.; Hu, X. Org. Lett. 2016, 18, 1928-1931. (c)
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Figure 2. Proposed Mechanistic Profile for Ni-Cata-
lyzed Reductive Relay Cross-Coupling Reaction.
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.” Condition investigation, extended data
about mechanism study, NMR data and characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: yinguoyin@whu.edu.cn
ORCID
Guoyin Yin: 0000-0002-2179-4634
Author Contributions
‡ These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Great appreciation was shown to Prof. Q. Zhou and W.-B. Liu
@WHU for the lent of lab space and share the basic instru-
ments. Many thanks to Prof. A. Lei (WHU) and Prof. T. Xu
(TJU) for their helpful discussion, and Dr. T. Sperger (RWTH)
and Dr. W. B. Reid (UD) for polishing the manuscript. Grate-
ful for the financial support from WHU and NSF of China
(21702151).
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