Nickel-catalyzed selective oxidative radical cross-coupling: An effective strategy for inert Csp3-H functionalization

Article abstract of DOI:10.1021/acs.orglett.5b00104

An effective strategy for inert Csp³-H functionalization through nickel-catalyzed selective radical cross-couplings was demonstrated. Density functional theory calculations were conducted and strongly supported the radical cross-coupling pathway assisted by nickel catalyst, which was further confirmed by radical-trapping experiments. Different arylborates including arylboronic acids, arylboronic acid esters and 2,4,6-triarylboroxin were all good coupling partners, generating the corresponding Csp³-H arylation products in good yields.

Full text of DOI:10.1021/acs.orglett.5b00104

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Selective Oxidative Radical Cross-Coupling:
An Effective Strategy for Inert Csp3−H Functionalization
Dong Liu,†,∥ Yuxiu Li,†,∥ Xiaotian Qi,‡ Chao Liu,† Yu Lan,*,‡ and Aiwen Lei*,†,§
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
‡School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, PR China
§National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, PR China
S
* Supporting Information
ABSTRACT: An effective strategy for inert Csp3−H
functionalization through nickel-catalyzed selective radical
cross-couplings was demonstrated. Density functional theory
calculations were conducted and strongly supported the radical
cross-coupling pathway assisted by nickel catalyst, which was
further confirmed by radical-trapping experiments. Different
arylborates including arylboronic acids, arylboronic acid esters
and 2,4,6-triarylboroxin were all good coupling partners,
generating the corresponding Csp3−H arylation products in good yields.
−H functionalization has emerged as a powerful synthetic
reactions. Considering the great significance and challenge of
inert Csp3−H functionalization, we communicate herein an
effective strategy for inert Csp3−H functionalization through
selective radical cross-coupling assisted by nickel catalyst
(Scheme 1).
1
Cmethod during the past several decades and has also
been widely employed in the syntheses of various pharmaceut-
icals and biologically active molecules,2 due to its environ-
mental sustainability and its lack of need for prefunctionaliza-
tion. Direct Csp3−H functionalization is highly attractive, but it
has been rarely developed,3 attributing to the relatively inert
properties of Csp3−H bonds. Previous reports on direct
functionalization of heteroatom adjacent Csp3−H bonds were
relatively common,4 probably owing to the activation effect of
heteroatoms to the adjacent Csp3−H bonds. However, it is still
a challenging task to achieve direct functionalization of inert
Csp3−H bonds, especially simple alkanes. Until now, only
isolated examples on oxidative inert Csp3−H functionalization
have been demonstrated.5 Oxidative arylation of simple alkanes
has also been very rare.6
Scheme 1. Effective Strategy for Inert Csp3−H
Functionalization through Selective Radical Cross-Coupling
Assisted by Nickel Catalyst
Recently, radical oxidative coupling reactions have gone
through an extremely rapid development in organic synthesis,7
in which different radical species were generally involved in
bond formations. However, selective bond formations between
two radical species were rarely developed, probably due to the
competition of unavoidable radical homocoupling reactions.
Normally, radical cross-coupling could selectively occur
between a persistent radical and a transient radical.8 However,
most radicals in chemical transformations are transient radicals,
and therefore, it is difficult to achieve selective cross-coupling.9
One effective strategy is to tranform one of the transient
radicals into a persistent radical. During the past several
decades, transition metal catalysts have been demonstrated to
interact with radicals through redox bond formation,
coordination or atom transfer, etc.10 Notably, some of these
transformations were reversible, which could slowly release one
radical to cross-couple with the other, thus providing a novel
and efficient strategy for selective radical cross-coupling
In our initial study, phenylboronic acid (1a) and cyclohexane
(2a) were chosen as the coupling partners, since both of them
could generate the corresponding phenyl radical and cyclohexyl
radical respectively in the presence of transition metal catalyst
and oxidant.3g−i,k−m,p,11 Then, with the assistance and
stabilization of nickel catalyst, selective radical cross-coupling
between phenyl radical and cyclohexyl radical could deliver the
desired Csp3−H functionalized product. With this assumption
in mind, we started to conduct detailed investigation of this
Received: January 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00104
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction. After a considerable test of different reaction
parameters, we obtained the desired product 3a in 73% GC
yield in the presence of Ni(acac)2 as the catalyst, Ph3P and
dppb (1,4-bis(diphenylphosphino)butane) as the ligand, K3PO4
as the base, DTBP (di-tert-butyl peroxide) as the oxidant at 130
°C for 10 h (for detailed condition optimizations, see
Supporting Information).
In order to clarify the probable nickel-assisted radical cross-
coupling pathway of this reaction, relative radical stabilities
were investigated using density functional theory (DFT)
calculation employing the method B3LYP.12 Initially, as
shown in Figure 1a,b, either cyclohexane 2a or phenylboronic
Figure 2. Geometry of complex 13. The numbers in parentheses are
respective Mulliken spin densities on each atom.
suggests that most spin is located on the nickel atom.
Consequently, the homocoupling of cyclohexyl radical 6
could be avoided with the aid of Ni(acac)2 catalyst, and the
cross-coupling product is preferred, which provides strong
support for nickel-assisted radical cross-coupling pathway.
Further radical-trapping experiments support the radical
process of this reaction (Scheme 2). When equivalent amount
Scheme 2. Radical-Trapping Experiments
Figure 1. Free energy profile for the following: (a) The generation of
cyclohexyl radical 6. (b) The generation of phenyl radical 9. (c)
Radical substitution between radical 9 and cyclohexane 2a. (d) The
generation of product 3a in the presence of Ni(acac)2.
acid 1a could react with tert-butoxyl radical 4, leading to the
generation of corresponding cyclohexyl radical 6 or phenyl
radical 9 via transition state 5-ts or 8-ts. The activation energies
of these two reactions are 18.3 and 18.0 kcal/mol, respectively,
which is nearly the same. However, the radical substitution
between radical 9 and cyclohexane 2a shown in Figure 1c
reveals the huge difference between relative radical stabilities of
radicals 9 and 6. Through transition state 11-ts with a barrier of
13.5 kcal/mol, radical 6 could be generated with 31.1 kcal/mol
exothermic, which indicates that radical 6 is more stable than
radical 9 by 17.6 kcal/mol. Therefore, as the most stable radical,
cyclohexyl radical 6 is supposed to be the main radical species
under these reaction conditions. Moreover, in the presence of
Ni(acac)2 catalyst, radical 6 could be further stabilized by 1.8
kcal/mol through the generation of a nickel(III) complex 13
(Figure 1d), and subsequent cross coupling irreversibly affords
the desired product 3a with 71.8 kcal/mol exothermic. Besides,
the Mulliken spin density of complex 13 shown in Figure 2
of TEMPO was added into the reaction system, the reaction
was totally shut down, along with the formation of trapping
product of cyclohexyl radical detected by GC−MS analysis
(Scheme 2, eq 1, see Supporting Information for more details).
Moreover, when 1,1-diphenylethene was employed as the
radical-trapping reagent, the main reaction was greatly
inhibited, only trace amount of the target product was
obtained. Notably, cyclohexyl radical was also successfully
trapped by 1,1-diphenylethene, generating the corresponding
trapping products in 17% and 23% NMR yields, respectively
(Scheme 2, eq 2, see Supporting Information for more details).
These results strongly support that cyclohexyl radical is the
most stable radical in the whole reaction.
Moreover, two parallel reactions were carried out with
cyclohexane and cyclohexane-d12 as the substrates respectively
to determine the kinetic isotopic effect (KIE) (Scheme 3). As a
result, a kH/kD = 2.2 was obtained (see Supporting Information
for details). We further did an intermolecular KIE experiment.
B
DOI: 10.1021/acs.orglett.5b00104
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Organic Letters
Letter
substituents could be well tolerated, affording the correspond-
ing oxidative alkylation products in good yields (3b and 3c).
And also, halogenated phenylboronic acids such as p-F-
PhB(OH)2 could cross-couple smoothly with cyclohexane in
good yield (3d). However, phenylboronic acids with electron-
rich substituents such as OMe generated the desired oxidative
alkylation product in a slightly lower yield (3e). While
phenylboronic acids with electron-poor substituents such as
COOMe and CN groups were good coupling partners (3f and
3g). In addition, ortho- and meta-substituted arylboronic acids
could also be well tolerated, generating the desired Csp3−H
functionalized products in moderate yields (3h and 3i). Second,
we tried to test the reactivity of different arylboronic acid esters,
during which we found that arylboronic acid neopentylglycol
esters were good coupling partners. Notably, these types of
reactions could proceed smoothly in the presence of dppb as
the sole ligand, in which electron-rich (3l), electron-poor (3f,
3g and 3j) and halogen substituents (3k and 3m) could all be
well tolerated, delivering the corresponding products in good
yields. Finally, 52% yield of the desired arylation product could
be obtained with 2,4,6-triphenylboroxin as the arylborate. It
should be noted that reactions of other simple alkanes are not
efficient enough. The reaction of (4-(methoxycarbonyl)-
phenyl)boronic acid with cyclopentane only afforded 30%
yield of the desired product. And with n-hexane as the
substrate, only 19% yield of the desired products were obtained
with a poor selectivity (see Supporting Information for details).
According to the above research and previous reports, we
proposed a plausible pathway for this reaction.13 As depicted in
Scheme 5, the most stable cyclohexyl radical is preferred to be
Scheme 3. Kinetic Isotopic Effect (KIE) Experiment
This time,a significant KIE value of kH/kD = 5.7 was observed
(see Supporting Information for details). These experiments
indicated that the C−H cleavage of cyclohexane was probably
involved in the rate-determining step.
Furthermore, considerable efforts have been made to test the
substrate generality of this reaction under the optimized
reaction conditions. Notably, different arylborates such as
arylboronic acids, arylboronic acid neopentylglycol esters and
even 2,4,6-triphenylboroxin could cross-couple smoothly with
cyclohexane to afford the corresponding products in good
yields (Scheme 4). First, different arylboronic acids were tested.
Notably, this reaction has a good compatibility of different
groups on aryl rings. Phenylboronic acids with p-Me and p-tBu
Scheme 4. Substrate Scope for Nickel-Catalyzed Selective
a
Radical Cross-Coupling Reactions
Scheme 5. Plausible Reaction Mechanism
formed through the radical substitution under the standard
reaction condition, followed by coordination toward the nickel
catalyst to afford a nickel(III) complex 13. Subsequent
generated phenyl radical 9 could react with 13 to give the
desired radical cross-coupling product 3a.
In summary, we have demonstrated an effective strategy for
inert Csp3−H functionalization through nickel-catalyzed
selective radical cross-couplings. DFT calculations have been
conducted and strongly supported the radical cross-coupling
pathway assisted by nickel catalyst, which were further
confirmed by radical-trapping experiments. Different arylbo-
rates including arylboronic acids, arylboronic acid esters and
2,4,6-triarylboroxin were all shown to be good coupling
partners with cyclohexane. This reaction provides an effective
protocol for inert Csp3−H functionalization via selective radical
cross-couplings. Further studies on substrate scope and more
a
Reaction conditions: [a] Arylboronic acids were used as the
substrates. 1 (0.5 mmol), 2a (5.0 mL), Ni(acac)2 (10 mol %), Ph3P
(20 mol %), dppb (5 mol %), K3PO4 (0.75 mmol), DTBP (1.0 mmol),
130 °C, 10 h. [b] Arylboronic acid neopentylglycol esters were used as
the substrates. 1 (0.5 mmol), 2a (5.0 mL), Ni(acac)2 (10 mol %),
dppb (10 mol %), K3PO4 (0.75 mmol), DTBP (1.0 mmol), 130 °C, 10
h. [c] 2,4,6-Triphenylboroxin was used as the substrate. 1 (0.17
mmol), 2a (5.0 mL), Ni(acac)2 (10 mol %), Ph3P (20 mol %), dppb
(5 mol %), K3PO4 (0.75 mmol), DTBP (1.0 mmol), 130 °C, 10 h.
C
DOI: 10.1021/acs.orglett.5b00104
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experiment details and spectral data for all compounds are
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*E-mail: lanyu@cqu.edu.cn.
*E-mail: aiwenlei@whu.edu.cn.
Author Contributions
∥D. Liu and Y. Li contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program (2011CB808600,
2012CB725302), the National Natural Science Foundation of
China (21390400, 21025206, 21272180, 21302148 and
21372266), and the Research Fund for the Doctoral Program
of Higher Education of China (20120141130002) and the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT1030). The Program of Introducing
Talents of Discipline to Universities of China (111 Program) is
also appreciated.
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