Mechanistic Aspects of Pincer Nickel(II)-Catalyzed C-H Bond Alkylation of Azoles with Alkyl Halides

Article abstract of DOI:10.1021/acs.organomet.8b00025

The quinolinyl-based pincer nickel complex, κ^N,κ^N,κ^N-{C₉H₆N-(μ-N)-C₆H₄-NMe₂}NiCl [(^QNNN^Me2)NiCl; (1)] has recently been demonstrated to be an efficient and robust catalyst for the alkylation of azoles with alkyl halides under copper-free conditions. Herein, we report the detailed mechanistic investigation for the alkylation of azoles catalyzed by (^QNNN^Me2)NiCl (1), which highlights an iodine-atom transfer (IAT) mechanism for the reaction involving a Ni^II/Ni^III process. Deuterium labeling experiments indicate reversible cleavage of the benzothiazole C-H bond, and kinetic studies underline a fractional negative rate order with the substrate benzothiazole. The involvement of an alkyl radical during the alkylation is validated by radical clock and external additive experiments. An active intermediate species (^QNNN^Me2)Ni(benzothiazolyl) (5a) has been isolated and structurally characterized. The complex (^QNNN^Me2)Ni(benzothiazolyl) (5a) is found to be the resting state of catalyst 1. Kinetic analysis of electronically different intermediates suggests that the step involving the reaction of 5a with alkyl iodide is crucial and a rate-influencing step. DFT calculations strongly support the experimental findings and corroborate an IAT process for the alkylation reaction.

Full text of DOI:10.1021/acs.organomet.8b00025

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Mechanistic Aspects of Pincer Nickel(II)-Catalyzed C−H Bond
Alkylation of Azoles with Alkyl Halides
Ulhas N. Patel,†,∥ Shailja Jain,‡ Dilip K. Pandey,†,∥ Rajesh G. Gonnade,§ Kumar Vanka,‡
and Benudhar Punji*,†,∥
‡
†Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, Physical and Materials Chemistry Division, and
§Centre for Material Characterization, CSIR−National Chemical Laboratory (CSIR−NCL), Dr. Homi Bhabha Road, Pune 411 008,
India
∥Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 020, India
S
* Supporting Information
ABSTRACT: The quinolinyl-based pincer nickel complex,
κN,κN,κN-{C9H6N-(μ-N)-C6H4−NMe2}NiCl [(QNNNMe2)-
NiCl; (1)] has recently been demonstrated to be an efficient
and robust catalyst for the alkylation of azoles with alkyl
halides under copper-free conditions. Herein, we report the
detailed mechanistic investigation for the alkylation of azoles
catalyzed by (QNNNMe2)NiCl (1), which highlights an iodine-
atom transfer (IAT) mechanism for the reaction involving a
NiII/NiIII process. Deuterium labeling experiments indicate
reversible cleavage of the benzothiazole C−H bond, and
kinetic studies underline a fractional negative rate order with
the substrate benzothiazole. The involvement of an alkyl
radical during the alkylation is validated by radical clock and
external additive experiments. An active intermediate species (QNNNMe2)Ni(benzothiazolyl) (5a) has been isolated and
structurally characterized. The complex (QNNNMe2)Ni(benzothiazolyl) (5a) is found to be the resting state of catalyst 1. Kinetic
analysis of electronically different intermediates suggests that the step involving the reaction of 5a with alkyl iodide is crucial and
a rate-influencing step. DFT calculations strongly support the experimental findings and corroborate an IAT process for the
alkylation reaction.
Despite the significant progress in C−H bond alkylation of
azoles by nickel,9 a comprehensive mechanistic study for this
process is not available.2d,10 This could be partially attributed to
the usage of in situ generated catalysts or a precatalyst, which
were not the actual catalyst during the reaction. The absence of
conclusive mechanistic insight for nickel-catalyzed alkylation
has compelled the assumption of various catalytic pathways.
For example, Ackermann has hypothesized a NiI/NiIII catalytic
cycle for the alkylation with NiI-species as active catalyst for the
reaction,7 whereas Miura has proposed a Ni0/NiII pathway.5b
Unfortunately, both the proposals have been made without
much experimental evidence. Hu has deliberated the
heterogeneous nickel particles as active catalyst during the
alkylation of azoles that were generated upon degradation of
the pincer catalyst (MeNN2)NiCl.6 Recently, we have developed
a well-defined and robust nickel catalyst system, κN,κN,κN-
{C9H6N-(μ-N)-C6H4−NMe2}NiCl [(QNNNMe2)NiCl; (1)] for
the alkylation of benzothiazoles with alkyl halides, and we
found that the catalysis follows a molecular pathway.8 In
addition, we have proposed a speculative pathway on the
INTRODUCTION
■
Transition-metal-catalyzed C−H bond alkylation of hetero-
arenes with unactivated alkyl halides bearing β-hydrogens is one
of the most promising and challenging reactions because of the
trivial β-hydride elimination and/or hydrodehalogenation of
the alkyl electrophiles upon addition to transition-metals.1
Regardless, various metal catalysts are known to efficiently
catalyze the alkylation of heteroarenes under diverse reaction
conditions.2,3 Particularly, the alkylation of azoles by nickel is
significant as azoles are ubiquitously found in many biological
and pharmaceutical compounds,4 and nickel is among the
inexpensive and earth-abundant metals.5 The C-2 alkylation of
azoles employing nickel catalysis has been independently
demonstrated by Hu6 and Ackermann,7 wherein reactions
were performed at high temperature, and an additional copper
cocatalyst was employed. Miura has reported a copper-free
method for the alkylation of azoles.5b However, this was
demonstrated with very limited scope, and the reactions were
reported with extremely low yields of the coupled products.
Our group has reported an improved and robust nickel catalyst
system for the alkylation of azoles under copper-free
conditions, and the reactions were demonstrated at relatively
mild reaction temperatures.8
Received: January 15, 2018
© XXXX American Chemical Society
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working mode of the catalyst system. Herein, we have studied
the in-depth mechanism of the pincer nickel-catalyzed
alkylation of azoles with alkyl halides, wherein a NiII/NiIII
catalytic cycle has been disclosed that proceeds via an iodine
atom transfer (IAT) pathway. Detailed kinetics, controlled
reactivity study, and deuterium labeling experiments have been
performed to obtain information about various steps during the
alkylation. The isolation and reactivity of a crucial intermediate
species (QNNNMe2)Ni(2-benzothiazolyl) has been demonstra-
ted. DFT calculations were carried out for the important
elementary steps to gather information on energetically viable
intermediates during the reaction. All the experimental and
theoretical findings have led us to present an updated
mechanistic cycle for the pincer nickel-catalyzed C−H bond
alkylation of azoles with alkyl halides.
RESULTS AND DISCUSSION
■
Figure 1. Reaction profile for the 1-catalyzed alkylation of
benzothiazole (2a) with 1-iodooctane (3a). Plot was fitted linear
with Origin Pro 8.
Recently, we have developed a series of quinolinyl-based pincer
nickel complexes, κN,κN,κN-{C9H6N-(μ-N)-C6H4−NR2}NiX
[(QNNNR2)NiX; R = Me, Et and X = Cl, Br, OAc] and
employed them for the C-2 alkylation of azoles with alkyl
halides.8 Among them, the catalyst (QNNNMe2)NiCl (1) was
demonstrated to be very robust, and the alkylations were
exhibited in the absence of a copper cocatalyst (Scheme 1).
induction period for the production of 4aa, which suggests that
1 acts as an active catalyst.
The rate order of the alkylation reaction in each component
was independently determined at 100 °C in 1,4-dioxane using
the initial rate approximation. The rate of the alkylation
reaction is almost similar to different initial concentrations of 1-
iodooctane, suggesting that the reaction is zeroth-order in the
concentration of 1-iodooctane (see the Supporting Information
for details). Similarly, the rate of the alkylation reaction is
independent of the concentration of LiOtBu, and provides a
zeroth-order behavior for this component. Further, the reaction
rate on various loadings of catalyst 1 was measured by the initial
rate of the product formation (see Figure S3 in the Supporting
Information). The plot of log(rate) vs log(conc. 1) furnished a
slope of 1.3, suggesting a fractional and complex rate order in
the loading of catalyst 1 (Figure 2). Considering the
Scheme 1. Nickel-Catalyzed Alkylation of Benzothiazole
Preliminary findings suggested that the catalysis proceeds via a
homogeneous process, and complex 1 acts as an active catalyst
in the reaction.8 Considering the excellent catalytic activity and
well-defined nature of catalyst 1, we were prompted to perform
a detailed mechanistic study of (QNNNMe2)NiCl (1)-catalyzed
alkylation of azoles with alkyl halides. The coupling of
benzothiazole (2a) with 1-iodooctane (3a), to obtain the
alkylated product 4aa, was chosen as a model reaction for the
mechanistic study (Scheme 1).
Kinetic Analysis of (QNNNMe2)NiCl (1)-Catalyzed
Alkylation of Azoles. All the kinetic experiments were
performed in flame-dried screw cap tubes under an argon
atmosphere. A tube was charged with catalyst 1 (0.02 mmol,
0.01 M), LiOtBu (0.048 g, 0.60 mmol), 1-iodooctane (0.11 mL,
0.60 mmol, 0.30 M), benzothiazole (0.044 mL, 0.40 mmol, 0.20
M), and n-dodecane (0.04 mL, 0.17 mmol, 0.085 M, internal
standard), and 1,4-dioxane (1.81 mL) was added to make the
total volume to 2.0 mL. The tube containing the reaction
mixture was heated at 100 °C in a preheated oil bath and
progress of the alkylation reaction was monitored by gas
chromatography (GC) at regular intervals. The reaction profile
for the nickel-catalyzed alkylation of benzothiazole up to 75
min is shown in Figure 1. The formation of the alkylation
product followed a linear line, and the reaction did not need an
Figure 2. Plot of log(rate) vs log(conc. 1).
involvement of the catalyst in multiple steps in the catalysis,
the observed rate order seems to be reasonable. Notably, the
rate of the reaction decreases upon increasing the concentration
of benzothiazole, and a slope of −0.4 was obtained from the
plot of log(rate) vs log(conc. benzothiazole) (Figure 3). This
fractional negative rate order on benzothiazole suggests the
probable formation of a dormant Ni-species upon increased
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alkylation reaction (Scheme 3). Thus, the reaction of
benzothiazole with 5-bromo-1-pentene (3b) under standard
Scheme 3. Alkylation Reactions for Radical Clock
Experiments
Figure 3. Plot of log (rate) vs log (conc. benzothiazole).
concentration of benzothiazole. Possible formation of a catalytic
inactive Ni-species via the reaction of benzothiazolyl lithium to
any high-valent nickel species, such as (QNNNMe2)Ni-
(benzothiazolyl)(iodide), can be presumed in the presence of
an excess of benzothiazole. This probability has been
considered and examined by DFT energy calculations (see
the Supporting Information for details)
Isotope Labeling Studies. To probe the essence of the
C−H bond cleavage process, we have performed deuterium
labeling experiments. Thus, a reaction between 6-ethoxy
benzothiazole (2b) and 2-D-benzothiazole ([2-D]-2a) in the
presence of LiOtBu (and in the presence/absence of catalyst 1),
at an early reaction time, showed a significant H/D scrambling
between them (Scheme 2). This H/D scrambling suggests that
catalytic conditions afforded exclusively the expected alkylated
product 2-(pent-4-en-1-yl)benzo[d]thiazole (4ab) in 40% yield.
However, the reactions of benzothiazole (2a) with cyclo-
propylmethyl bromide (3c) and 6-bromo-1-hexene (3d)
produced the ring opened 2-(but-3-en-1-yl)benzo[d]thiazole
(4ac) and 5-exocyclized 2-(cyclopentylmethyl)benzo[d]-
thiazole (4ad) as exclusive products, respectively. These
findings strongly support the involvement of an alkyl radical
intermediate during the reaction. Thus, the two-electron
oxidative addition of alkyl halide to nickel catalyst is ruled
out, and the addition of alkyl as a radical to the nickel center
can be presumed.
Controlled Reactivity and Resting State of Catalyst 1.
The status of catalyst (QNNNMe2)NiCl (1) under the catalytic
conditions was followed by 1H NMR spectroscopy to know the
resting state of the catalyst, and to identify any possible catalytic
active intermediates during the alkylation. Thus, the catalyst
(QNNNMe2)NiCl was treated with 1-iodooctane in the presence
of LiOtBu in toluene-d8, and the reaction mixture was heated at
Scheme 2. H/D Scrambling Experiment
1
100 °C (Scheme 4). The H NMR analysis of the reaction
Scheme 4. Controlled Reaction of Complex 1
the C−H bond clevage process is reversible and almost remains
in equilibrium. Further, the rates of the alkylation reactions
employing 2-H-benzothiazole (2a) and 2-D-benzothiazole ([2-
D]-2a) with 1-iodooctane were measured (see Figure S5 in the
Supporting Information). The equilibrium isotope effect (EIE)
value was found to be 0.97 (kH/kD). Both these labeling
experiments highlighted that the C−H bond cleavage is facile,
and is not a rate-influencing step in the alkylation reaction.
Probing the Radical Pathway. Nickel catalysts are known
to execute single-electron transfer (SET) processes during the
catalytic reactions, in addition to the 2e redox pathway.9c,10b,11
Previously, we had performed the radical inhibitor experiments,
wherein addition of TEMPO or galvinoxyl completely
suppressed the (QNNNMe2)NiCl (1)-catalyzed alkylation
reaction.8 This finding gave a preliminary impression that the
reaction might involve a radical intermediate. To gain more
insights into the 1e versus 2e pathway, we have performed
radical clock experiments for the (QNNNMe2)NiCl-catalyzed
mixture shows exclusive presence of the complex (QNNNMe2)-
NiCl (1). Neither the formation of any new species nor the
decomposition of complex 1 was observed, which suggests that
the reaction of 1 with 1-iodooctane is not the first step of the
reaction.
In another experiment, catalyst 1 was treated with
benzothiazole in the presence of LiOtBu in toluene-d8, and
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the reaction mixture was heated at 100 °C (Scheme 4). The 1H
NMR analysis of the reaction mixture showed the formation of
the new complex, (QNNNMe2)Ni(2-benzothiazolyl) (5a) in
93% yield. The synthesis and characterization details of
complex 5a is discussed (vide infra). Surprisingly, the complex
5a could be obtained even at room temperature from the
reaction of 1 with benzothiazole in the presence of LiOtBu,
albeit in lower yield (35% and 48% after 6 and 18 h,
respectively; see Figure S6 in the Supporting Information).
This highlights that the formation of complex 5a is facile, and
the observed complex 5a might be a vital intermediate during
the alkylation. All these observations further suggest that the
reaction of catalyst 1 with benzothiazole is the early step of the
alkylation, rather than the reaction of catalyst 1 with 1-
iodooctane. Furthermore, in order to know whether 5a could
be the resting state of catalyst 1, a standard catalytic reaction
was performed in a J-Young NMR tube employing 20 mol % of
1 in toluene-d8. Upon heating the reaction mixture at 100 °C
for 30 min, the major nickel species observed was (QNNNMe2)-
Ni(2-benzothiazolyl) (5a). This clearly suggests that the
intermediate 5a is the resting state of the catalyst during the
alkylation reaction.
Figure 4. Thermal ellipsoid plot of (QNNNMe2)Ni(2-benzothiazolyl)
(5a). All hydrogen atoms are omitted for clarity. Selected bond lengths
(Å): Ni(1)−C(18), 1.936(8); Ni(1)−N(1), 1.866(7); Ni(1)−N(2),
1.890(7); Ni(1)−N(3), 1.964(7). Selected bond angles (deg): N(1)−
Ni(1)−C(18), 173.2(3); N(1)−Ni(1)−N(2), 84.2(3); N(1)−Ni(1)−
N(3), 85.9(3); N(2)−Ni(1)−N(3), 169.7(3).
Synthesis and Characterization of (QNNNMe2)Ni(2-
Benzothiazolyl) (5a) and Derivatives. The treatment of
complex (QNNNMe2)NiCl (1) with one equivalent of
benzothiazole in the presence of LiOtBu in toluene at 100 °C
produced the complex (QNNNMe2)Ni(2-benzothiazolyl) (5a)
in 91% isolated yield (Scheme 5). Similarly, the reactions of 1
NNN-pincer ring, with the torsion angle of N2−Ni−C18−S1
being around 72°.
Reactivity of (QNNNMe2)Ni(2-Benzothiazolyl) (5a). The
probability of complex (QNNNMe2)Ni(2-benzothiazolyl) (5a)
being an intermediate during the alkylation reaction was
investigated by performing the reaction of 5a with different
electrophiles under various reaction conditions. Thus, the
reaction of 5a (0.012 g, 0.0264 mmol) with 1.0 equiv of 1-
iodooctane in the presence of LiOtBu (1.0 equiv) in toluene-d8
at 100 °C afforded the product 4aa in 86% yield (Scheme 6a).12
Scheme 5. Synthesis of (QNNNMe2)Ni(2-Benzothiazolyl)
(5a) and Derivatives
Scheme 6. Reactivity of (QNNNMe2)Ni(2-Benzothiazolyl)
(5a) with Electrophiles
with 6-ethoxy-benzothiazole and 6-fluoro-benzothiazole af-
forded the complexes (QNNNMe2)Ni(2-(6-ethoxy benzothia-
zolyl)) (5b) and (QNNNMe2)Ni(2-(6-fluoro benzothiazolyl))
(5c), respectively. All the complexes 5a−5c were fully
1
characterized by H and 13C NMR spectroscopy, as well as
by HRMS. The molecular structure of 5a was further confirmed
by a single crystal X-ray diffraction study (Figure 4). The
coordination geometry around nickel in complex 5a is distorted
square planar. Selected bond lengths and bond angles are given
in the figure caption. The Ni−N1(amido) bond length is 1.866(7)
Å, which is slightly longer than the corresponding Ni−N1(amido)
bond length in (QNNNMe2)NiCl (1.8441(18) Å).8 This could
be due to the strong trans influence exerted by benzothiazolyl-
moiety toward nickel in 5a than the trans influence by the Cl-
ligand in the complex 1. The Ni−N2(quinolinyl) and Ni−N3(amino)
bond lengths 1.890(7) and 1.964(7) Å, respectively, are
comparable with the corresponding bond lengths in complex
1 (Ni−N2 = 1.899 and Ni−N3 = 1.955 Å). The N(2)−Ni(1)−
N(3) bite is 169.7(3)°, which is similar to that observed in
other quinolinyl-based nickel complexes (QNNNR2)NiX.8 The
ring of the benzothiazolyl-moiety is almost perpendicular to the
The same reaction in the absence of LiOtBu also produced 4aa
in 75% yield (Scheme 6b). These observations suggest that the
complex 5a is a crucial intermediate during the alkylation
reaction and that the base is not necessary for the addition of
alkyl halide to intermediate 5a. As expected, the reaction of
complex 5a with 6-bromo-1-hexene (3d) produced exclusively
the 5-exocyclized product, 2-(cyclopentylmethyl)benzo[d]-
thiazole (4ad) (Scheme 6c). This highlights the fact that the
oxidative addition of alkyl halide to intermediate 5a proceeds
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through a radical pathway and that the nickel species alone is
responsible for the formation of the radical species.
Surprisingly, in all these reactions, neither the nickel species
nor the free ligand was detected by H NMR, suggesting that
the formation of a paramagnetic nickel species during the
reaction.
findings on the probable reaction pathway of (QNNNMe2)Ni(2-
benzothiazolyl) (5a) with 1-iodooctane.
Quantum Chemical Calculations. Full quantum chemical
calculations were done with density functional theory (DFT) at
the PBE/TZVP level of theory in order to understand the
mechanism for the formation of the alkylated product 4aa by
the Ni(II) catalyst 1. Since the complex (QNNNMe2)Ni(2-
benzothiazolyl) (5a) was found as an active catalytic
intermediate, and the experimental findings strongly support
the involvement of an alkyl radical during the nickel catalyzed
alkylation of benzothiazole, we have investigated the probable
pathway for the reaction of 5a with 1-iodooctane through DFT.
Two pathways have been considered: either (i) the iodide
radical or (ii) the octyl radical can react with 5a to give the
Ni(III) intermediate. The formation of (QNNNMe2)Ni(2-
benzothiazolyl)(octyl) (A) by the reaction of 5a with the
octyl radical is endergonic by 58.6 kcal/mol (Scheme 7) and
1
Reaction Rates of Intermediates (Electronic Influence
on Alkylation). In order to understand the electronic effect of
the substrates on the alkylation reaction, and particularly, on
the step involving the reaction of alkyl iodide with the NiII
species, we have measured the rates of the reactions of
differently substituted intermediates (QNNNMe2)Ni(2-(6-
ethoxy benzothiazolyl)) (5b) and (QNNNMe2)Ni(2-(6-fluoro
benzothiazolyl)) (5c) with 1-iodooctane. Each of the
complexes 5b and 5c was treated with 1-iodooctane (1.0
equiv) in a J-Young NMR tube in toluene-d8 and the formation
1
of coupled product was monitored by H NMR. The rates of
the reactions of 5b and 5c with 1-iodooctane were found to be
2.65 × 10−4 and 1.43 × 10−4 M min−1, respectively (Figure 5).
Scheme 7. Formation of Complex (QNNNMe2)Ni(2-
benzothiazolyl)(octyl) (A) by the Combination 5a with the
a
Octyl Radical
a
The free energy value (in kcal/mol) shows that reaction is highly
unfavorable.
the formation of (QNNNMe2)Ni(2-benzothiazolyl)(iodide) (B)
by reaction with the iodide radical is endergonic by 32.5 kcal/
mol (Figure 6). Considering the given experimental conditions
of elevated temperature (100 °C), formation of B is expected to
Figure 5. Rates of the reactions of (QNNNMe2)Ni(2-(6-ethoxy
benzothiazolyl)) (5b) and (QNNNMe2)Ni(2-(6-fluoro benzothiazol-
yl)) (5c) with 1-iodooctane.
The alkylation reaction is faster with an electronically rich
intermediate (substrate) compared to the electronically
deficient counterpart, which suggests that the nickel species
might be developing an electropositive transition state (high
oxidation state) during the catalysis, and hence, is stabilized by
the electron-donating substituents on the benzothiazole.
Because the impact of electronic factor is significant in this
step, we assume that the reaction involving (QNNNMe2)Ni-
(benzothiazolyl) and 1-iodooctane is very crucial and is the rate
influencing step during the alkylation. Additionally, we have
performed DFT calculations to complement the experimental
Figure 6. Free energy profile for the formation of alkylated product
4aa by Ni(II) catalyst. All values are given in kcal/mol.
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be favorable. The octyl radical then coordinates to the NiIII
center in B to form the Ni(IV) complex C. Complex C can
then undergo reductive elimination to yield the experimentally
observed product 4aa via TS-1. The energy barrier for this
process is 33.9 kcal/mol.
Probable Catalytic Cycle. On the basis of the
experimental results and DFT calculations described here,
and the earlier observations of our group8 and others,10b,c,e,13
we have drawn a more authenticated catalytic cycle for the
(QNNNMe2)NiCl (1) catalyzed alkylation of benzothiazole with
alkyl halides (Figure 7). First, base-assisted reversible C(2)−H
catalyzed by a well-defined (QNNNMe2)NiCl (1) catalyst.
Kinetics analysis, reactivity studies and DFT energy calculations
on the (QNNNMe2)NiCl (1)-catalyzed alkylation of azoles
emphasize a Ni(II)/Ni(III) pathway for the reaction, with the
oxidative addition of alkyl iodide to the (QNNNMe2)Ni(II)-
species via an IAT process. The kinetic rate order of alkylation
reaction with catalyst 1 is quite complex and the reaction has a
fractional negative order for the benzothiazole substrate.
Deuterium labeling experiments highlight that the C−H bond
cleavage of azoles is a reversible process. Further, the reaction
of catalyst 1 with benzothiazole leading to the formation of
inermediate (QNNNMe2)Ni(2-benzothiazolyl) (5a) is very
facile, and the intermediate 5a is demonstrated as the resting
state of catalyst 1. Kinetic analysis of electronically different
nickel intermediates 5b and 5c indicate that the reaction of
(QNNNMe2)Ni(2-benzothiazolyl) with alkyl iodide is very
crucial and might be involved in the rate-limiting step. DFT
calculations strongly support the iodine atom transfer process
for the oxidative addition of alkyl iodide to the intermediate
(QNNNMe2)Ni(2-benzothiazolyl) (5a). All these investigations
provide a significant mechanistic input into the alkylation of
azoles by nickel, which can shed light into other nickel
catalyzed C−H bond alkylation reactions.
EXPERIMENTAL SECTION
■
General Experimental Considerations. All manipulations were
conducted under an argon atmosphere either in a glovebox or using
standard Schlenk techniques in predried glass wares. The catalytic
reactions and kinetic experiments were performed in flame-dried
reaction vessels with Teflon screw cap. Solvents were dried over Na/
benzophenone or CaH2 and distilled prior to use. Liquid reagents were
flushed with argon prior to use. The (QNNNMe2)NiCl (1) was
synthesized according to previously described procedure.8 All other
chemicals were obtained from commercial sources and were used
without further purification. Yields refer to the isolated compounds,
estimated to be >95% pure as determined by 1H NMR. NMR (1H and
13C) spectra were recorded at 200, 400, or 500 (1H), 100 or 125 {13C,
DEPT (distortionless enhancement by polarization transfer)},
respectively, on Bruker AV 400 and AV 500 spectrometers in
CDCl3 or toluene-d8 solutions; chemical shifts (δ) are given in ppm.
GC Method. Gas chromatography analyses were performed using a
Shimadzu GC-2010 gas chromatograph equipped with a Shimadzu
AOC-20s autosampler and a Restek RTX-5 capillary column (30 m x
250 μm). The instrument was set to an injection volume of 1 μL, an
inlet split ratio of 10:1, and inlet and detector temperatures of 250 and
320 °C, respectively. UHP-grade argon was used as carrier gas with a
flow rate of 30 mL/min. The temperature program used for all the
analyses is as follows: 80 °C, 1 min; 30 °C/min to 200 °C, 2 min; 30
°C/min to 260 °C, 3 min; 30 °C/min to 300 °C, 3 min.
Figure 7. Plausible alkylation pathway catalyzed by (QNNNMe2)NiCl.
cleavage of benzothiazole occurs, which is followed by the
reaction with (QNNNMe2)NiCl, leading to the formation of
(QNNNMe2)Ni(2-benzothiazolyl) (5a). Complex 5a is found to
be the resting state of the catalyst. Intermediate 5a reacts with
alkyl iodide in the rate-influencing step via the iodine atom
transfer (IAT)11,14 process to produce the Ni(III) species B
and the alkyl radical. The alkyl radical can rebound with B to
produce the Ni(IV) species C. Reductive elimination of the
coupled product from species C will regenerate the Ni(II)
complex and complete the catalytic cycle. Experimental results
strongly support the intermediacy of complex 5a and the
involvement of the alkyl radical, and DFT calculations highlight
the oxidative addition of alkyl iodide to 5a through an IAT
mechanism. Though the nickel-catalyzed alkylation of azoles is
relatively well precedented, the mechanistic proposals are made
quoting the conventional alkylation pathways (Ni(I)/Ni(III))
and with extremely less experimental inputs. Herein, we have
extensively demonstrated a new mechanistic route for the
alkylation of azoles employing the well-defined nickel catalyst.
The alkylation occurs via the Ni(II)/Ni(III) pathway with the
oxidative addition of alkyl iodide to (QNNNMe2)Ni(II)-
(benzothiazolyl) species via the IAT process. This pathway is
strongly supported by experimental findings and DFT
calculations.
Response factors for all the necessary compounds with respect to
standard n-dodecane were calculated from the average of three
independent GC runs.
Synthesis of (QNNNMe2)Ni(2-Benzothiazolyl) (5a). A Schlenk
flask was introduced with (QNNNMe2)NiCl (1) (0.10 g, 0.280 mmol),
benzothiazole (0.038 g, 0.280 mmol), and LiOtBu (0.033 g, 0.420
mmol), and toluene (10 mL) was added into it. The resultant reaction
mixture stirred at 100 °C for 5 h. At ambient temperature, the reaction
mixture was filtered via cannula, concentrated to minimum, and n-
pentane was added to precipitate out the complex 5a. Compound 5a
was recrystallized in n-pentane under slow evaporation to obtain single
crystals suitable for X-ray analysis. Yield: 0.116 g, 91%. mp = 155−157
1
3
°C. H NMR (500 MHz, CDCl3): δ = 8.08 (d, JH−H = 8.1 Hz, 1H,
Ar−H), 8.02 (d, 3JH−H = 8.1 Hz, 1H, Ar−H), 7.91 (d, 3JH−H = 7.8 Hz,
3
1H, Ar−H), 7.61 (d, JH−H = 8.3 Hz, 1H, Ar−H), 7.48−7.38 (m, 3H,
CONCLUSION
In summary, we have demonstrated an in-depth mechanistic
study for the C−H bond alkylation of azoles with alkyl halides,
■
Ar−H), 7.25−7.16 (m, 2H, Ar−H), 7.10−7.08 (m, 2H, Ar−H), 6.94
(dd, 3JH−H = 7.8 Hz, 3JH−H = 5.4 Hz, 1H, Ar−H), 6.86 (d, 3JH−H = 7.8
3
Hz, 1H, Ar−H), 6.33 (vt, JH−H = 7.5 Hz, 1H, Ar−H), 3.06 (s, 6H,
F
DOI: 10.1021/acs.organomet.8b00025
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
CH3). 13C NMR (100 MHz, CDCl3): δ = 194.5 (Cq), 155.0 (Cq),
150.9 (CH), 148.5 (Cq), 148.4 (Cq), 147.6 (Cq), 146.9 (Cq), 139.0
(Cq), 138.3 (CH), 130.0 (Cq), 129.8 (CH), 128.7 (CH), 124.5 (CH),
122.3 (CH), 121.3 (CH), 120.8 (CH), 120.6 (CH), 120.1 (CH),
116.5 (CH), 114.9 (CH), 112.2 (CH), 110.4 (CH), 51.9 (CH3).
HRMS (ESI): m/z calcd for C24H20N4NiS+H+ [M + H]+, 455.0835;
found, 455.0840. Anal. Calcd for C24H20N4NiS: C, 63.33; H, 4.43; N,
12.31; S, 7.04. Found: C, 63.56; H, 4.72; N, 12.55; S, 6.90.
to make the total volume 2.0 mL. The reaction mixture was then
heated at 100 °C in a preheated oil bath. At regular intervals (10, 15,
20, 30, 45, 60 min, etc.), the reaction vessel was cooled to ambient
temperature and an aliquot of sample was withdrawn to the GC vial.
The sample was diluted with acetone and subjected to GC analysis.
The concentration of the product 4aa obtained in each sample was
determined with respect to the internal standard n-dodecane. The data
of the concentration of the product vs time (min) plot was fitted linear
with Origin Pro 8. The slope of the linear fitting represents the
reaction rate for that particular concentration of benzothiazole. The
order of the reaction was then determined by plotting log(rate) vs
log(conc benzothiazole) for benzothiazole substrate.
Computational Details. All DFT calculations were carried out
using the Turbomole 7.1 suite of programs15 and the PBE functional.16
The TZVP basis set has been employed.17 The resolution of identity
(RI),18 along with the multipole accelerated resolution of identity
(marij)19 approximations have been employed for an accurate and
efficient treatment of the electronic Coulomb term in the DFT
calculations. Solvent correction has been incorporated with
optimization calculations using the COSMO model,20 with 1,4-
dioxane (ε = 2.25) as the solvent. The energies reported in the figure
are ΔG values, with zero-point energy corrections, internal energy, and
entropic contributions included through frequency calculations on the
optimized minima, with the temperature taken to be 298.15 K.
Harmonic frequency calculations were performed for all stationary
points to confirm them as local minima or transition state structures.
Synthesis of (QNNNMe2)Ni(2-(6-Ethoxy Benzothiazolyl) (5b).
This compound was synthesized following the procedure similar to
synthesis 5a, using (QNNNMe2)NiCl (1; 0.10 g, 0.280 mmol), 6-ethoxy
benzothiazole (0.053 g, 0.295 mmol) and LiOtBu (0.034 g, 0.420
mmol). Yield: 0.104 g, 74%. mp = 150−153 °C. 1H NMR (200 MHz,
CDCl3): δ = 8.04−7.90 (m, 2H, Ar−H), 7.61−6.88 (m, 10H, Ar−H),
6.62 (bs, 1H, Ar−H), 4.11−4.09 (m, 2H, CH2), 3.11 (bs, 6H, CH3),
1.46 (bs, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ = 190.1 (Cq),
155.2 (Cq), 151.0 (CH), 150.1 (Cq), 148.6 (Cq), 148.4 (Cq), 147.6
(Cq), 146.9 (Cq), 140.0 (Cq), 138.2 (CH), 130.0 (Cq), 129.8 (CH),
128.7 (CH), 121.3 (CH), 120.9 (CH), 120.1 (CH), 116.4 (CH),
114.9 (CH), 113.7 (CH), 112.1 (CH), 110.4 (CH), 104.9 (CH), 64.3
(CH2), 51.9 (CH3) 15.1 (CH3). HRMS (ESI): m/z calcd for
C26H24N4NiOS+H+ [M + H]+, 499.1097; found, 499.1093.
Synthesis of (QNNNMe2)Ni(2-(6-Fluoro Benzothiazolyl) (5c).
This compound was synthesized following the procedure similar to
synthesis of 5a, using (QNNNMe2)NiCl (1; 0.15 g, 0.420 mmol), 6-
fluoro benzothiazole (0.068 g, 0.444 mmol) and LiOtBu (0.053 g, 0.63
mmol). Yield: 0.148 g, 74%. mp = 156−158 °C. 1H NMR (200 MHz,
3
4
CDCl3): δ = 8.05 (dd, JH−H = 8.2 Hz, JH−H = 1.4 Hz, 1H, Ar−H),
7.96 (dd, 3JH−H = 8.8, 4.8 Hz, 1H, Ar−H), 7.62−7.34 (m, 4H, Ar−H),
ASSOCIATED CONTENT
* Supporting Information
■
S
3
7.22−7.07 (m, 4H, Ar−H), 7.00−6.85 (m, 2H, Ar−H), 6.63 (t, JH−H
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00025.
= 8.1 Hz, 1H, Ar−H), 3.07 (s, 6H, CH3). 13C NMR (125 MHz,
CDCl3): δ = 193.6 (Cq), 159.2 (d, 1JC−F = 238.2 Hz, Cq), 151.9 (Cq),
150.8 (CH), 148.4 (2 × Cq), 147.6 (Cq), 146.9 (Cq), 139.9 (Cq),
138.4 (CH), 130.0 (Cq), 129.9 (CH), 128.7 (CH), 121.3 (CH), 120.9
Detailed experimental procedures, analytical data for
compounds, 1H and 13C NMR spectra of nickel
complexes, and alkylated compounds (PDF)
2
(CH), 120.1 (CH), 116.5 (CH), 114.9 (CH), 112.6 (d, JC−F = 20.0
2
Hz, CH), 112.2 (CH), 110.4 (CH), 107.0 (d, JC−F = 22.9 Hz, CH),
51.9 (CH3). 19F-NMR (377 MHz, CDCl3): δ = −121.3. HRMS (ESI):
m/z calcd for C24H19FN4NiS+H+ [M + H]+, 473.0741; found,
473.0737.
Cartesian coordinates of compounds (PDF)
Accession Codes
Representative Procedure for Reaction Rate Determination.
For the rate of alkylation reaction, see Figure 1. A screw cap tube
equipped with magnetic stir bar was introduced with catalyst 1 (0.007
g, 0.02 mmol, 0.01 M), LiOtBu (0.048 g, 0.60 mmol), 1-iodooctane
(0.11 mL, 0.144 g, 0.60 mmol, 0.30 M), benzothiazole (0.044 mL,
0.054 g, 0.4 mmol, 0.20 M), n-dodecane (0.04 mL, 0.17 mmol, internal
standard), and 1,4-dioxane (1.81 mL) was added to make the total
volume 2.0 mL. The reaction mixture was then stirred at 100 °C in a
preheated oil bath. At regular time intervals (10, 15, 20, 30, 45, 60, 75
min, etc.), the reaction vessel was cooled to ambient temperature and
an aliquot of sample was withdrawn to the GC vial under an argon
atmosphere. The sample was diluted with acetone and subjected to
GC analysis. The concentration of the product 4aa obtained in each
sample was determined with respect to the internal standard n-
dodecane. The final data was obtained by averaging the results of three
independent experiments. Plot was drawn for the concentration of
product vs time (min) as shown in Figure 1, and fitted linear with
Origin Pro 8. Slope of the linear fitting represents the reaction rate.
The rate was determined by initial rate method.
Representative Procedure for Rate-Order Determination.
Rate-order determination on benzothiazole is shown in Figure 3 and
Figure S1 in the Supporting Information. To determine the order of
the alkylation reaction on benzothiazole, initial rates at different initial
concentrations of benzothiazole were recorded. The final data was
obtained by averaging the results of three independent experiments for
the same initial concentration. In the standard experiment, a Teflon-
screw cap tube equipped with magnetic stir bar was introduced catalyst
1 (0.02 mmol, 0.01 M), LiOtBu (0.048 g, 0.6 mmol) 1-iodooctane
(0.60 mmol, 0.30 M), specific amount of benzothiazole (as shown in
Table S1 in the Supporting Information), n-dodecane (0.17 mmol,
internal standard), and 1,4-dioxane (appropriate amount) was added
CCDC 1568732 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*B.P.: tel, + 91 20 2590 2733; fax, + 91 20 2590 2621; e-mail, b.
punji@ncl.res.in.
■
ORCID
Rajesh G. Gonnade: 0000-0002-2841-0197
Kumar Vanka: 0000-0001-7301-7573
Benudhar Punji: 0000-0002-9257-5236
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to the SERB, New Delhi, India (EMR/2016/
000989) for financial support. U.N.P. and D.K.P. thank UGC -
New Delhi for the research fellowships.
REFERENCES
■
(1) For reviews on conventional alkylation reaction, see: (a) Luh, T.-
Y.; Leung, M.-k.; Wong, K.-T. Transition Metal-Catalyzed Activation
of Aliphatic C-X Bonds in Carbon-Carbon Bond Formation. Chem.
G
DOI: 10.1021/acs.organomet.8b00025
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Rev. 2000, 100, 3187−3204. (b) Netherton, M. R.; Fu, G. C. Nickel-
Catalyzed Cross-Couplings of Unactivated Alkyl Halides and
Pseudohalides with Organometallic Compounds. Adv. Synth. Catal.
2004, 346, 1525−1532. (c) Netherton, M. R.; Fu, G. C. Topics in
Organometallic Chemistry: Palladium in Organic Synthesis; Tsuji, J., Ed.;
Springer: Berlin, 2005; Vol. 14, pp 85−108. (d) Frisch, A. C.; Beller,
M. Catalysts for Cross-Coupling Reactions with Non-activated Alkyl
Halides. Angew. Chem., Int. Ed. 2005, 44, 674−688. (e) Terao, J.;
Kambe, N. Transition Metal-Catalyzed C-C Bond Formation
Reactions Using Alkyl Halides. Bull. Chem. Soc. Jpn. 2006, 79, 663−
672. (f) Terao, J.; Kambe, N. Cross-Coupling Reaction of Alkyl
Halides with Grignard Reagents Catalyzed by Ni, Pd, or Cu
Complexes with π-Carbon Ligand(s). Acc. Chem. Res. 2008, 41,
1545−1554. (g) Rudolph, A.; Lautens, M. Secondary Alkyl Halides in
Transition-Metal-Catalyzed Cross-Coupling Reactions. Angew. Chem.,
Int. Ed. 2009, 48, 2656−2670.
(2) For reviews, see: (a) Seregin, I. V.; Gevorgyan, V. Direct
Transition Metal-Catalyzed Functionalization of Heteroaromatic
Compounds. Chem. Soc. Rev. 2007, 36, 1173−1193. (b) Ackermann,
L. Metal-Catalyzed Direct Alkylations of (Hetero)Arenes via C-H
Bond Cleavages with Unactivated Alkyl Halides. Chem. Commun.
2010, 46, 4866−4877. (c) Hirano, K.; Miura, M. Direct Carbon−
Hydrogen Bond Functionalization of Heterocyclic Compounds. Synlett
2011, 2011, 294−307. (d) Hu, X. Nickel-Catalyzed Cross Coupling of
Non-Activated Alkyl Halides: A Mechanistic Perspective. Chem. Sci.
2011, 2, 1867−1886.
(3) For selected recent examples, see: (a) Jiao, L.; Bach, T.
Palladium-Catalyzed Direct 2-Alkylation of Indoles by Norbornene-
Mediated Regioselective Cascade C-H Activation. J. Am. Chem. Soc.
2011, 133, 12990−12993. (b) Potukuchi, H. K.; Bach, T. Selective C-2
Alkylation of Tryptophan by a Pd(II)/Norbornene-Promoted C-H
Activation Reaction. J. Org. Chem. 2013, 78, 12263−12267. (c) Jiao,
L.; Bach, T. Regioselective Direct C−H Alkylation of NH Indoles and
Pyrroles by a Palladium/Norbornene-Cocatalyzed Process. Synthesis
2014, 46, 35−41. (d) Nakatani, A.; Hirano, K.; Satoh, T.; Miura, M.
Nickel-Catalyzed Direct Alkylation of Heterocycles with α-Bromo
Carbonyl Compounds: C3-Selective Functionalization of 2-Pyridones.
Chem. - Eur. J. 2013, 19, 7691−7695. (e) Song, W.; Lackner, S.;
Ackermann, L. Nickel-Catalyzed C-H Alkylations: Direct Secondary
Alkylations and Trifluoroethylations of Arenes. Angew. Chem., Int. Ed.
2014, 53, 2477−2480. (f) Wang, H.; Yu, S.; Qi, Z.; Li, X. Rh(III)-
Catalyzed C-H Alkylation of Arenes Using Alkylboron Reagents. Org.
Lett. 2015, 17, 2812−2815. (g) Soni, V.; Jagtap, R. A.; Gonnade, R. G.;
Punji, B. Unified Strategy for Nickel-Catalyzed C-2 Alkylation of
Indoles through Chelation Assistance. ACS Catal. 2016, 6, 5666−
5672.
(4) (a) Okamoto, K.; Eger, B. T.; Nishino, T.; Kondo, S.; Pai, E. F.;
Nishino, T. An Extremely Potent Inhibitor of Xanthine Oxidor-
eductase: Cryatal Structure of the Enzyme-Inhibitor Complex and
Mechanism of Inhibition. J. Biol. Chem. 2003, 278, 1848−1855.
(b) Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman, R. L.;
Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit, S.; Chiang,
K. P.; Dendle, M. T. A.; Sacchettini, J. C.; Kelly, J. W. Benzoxazoles as
Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation, and
Mechanism of Action. Angew. Chem., Int. Ed. 2003, 42, 2758−2761.
(c) Giddens, A. C.; Boshoff, H. I. M.; Franzblau, S. G.; Barry, C. E.;
Copp, B. R. Antimycobacterial Natural Products: Synthesis and
Preliminary Biological Evaluation of the Oxazole-Containing Alkaloid
Texaline. Tetrahedron Lett. 2005, 46, 7355−7357. (d) Biancalana, M.;
Koide, S. Molecular Mechanism of Thioflavin-T Binding to Amyloid
Fibrils. Biochim. Biophys. Acta, Proteins Proteomics 2010, 1804, 1405−
1412. (e) Lee, C. F.; Holownia, A.; Bennett, J. M.; Elkins, J. M.; St.
Denis, J. D.; Adachi, S.; Yudin, A. K. Oxalyl Boronates Enable Modular
Synthesis of Bioactive Imidazoles. Angew. Chem., Int. Ed. 2017, 56,
6264−6267. (f) Larsen, M.; Hansen, C. H.; Rasmussen, T. B.; Islin, J.;
Styrishave, B.; Olsen, L.; Jorgensen, F. S. Structure-based Optimisation
of Non-Steroidal Cytochrome P450 17A1 Inhibitors. Chem. Commun.
2017, 53, 3118−3121.
(5) For alkylation of azoles by other metals, see: (a) Verrier, C.;
Hoarau, C.; Marsais, F. Direct Palladium-Catalyzed Alkenylation,
Benzylation and Alkylation of Ethyl Oxazole-4-Carboxylate with
Alkenyl-, Benzyl- and Alkyl Halides. Org. Biomol. Chem. 2009, 7,
647−650. (b) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Palladium- and
Nickel-Catalyzed Direct Alkylation of Azoles with Unactivated Alkyl
Bromides and Chlorides. Chem. - Eur. J. 2010, 16, 12307−12311.
(c) Ren, P.; Salihu, I.; Scopelliti, R.; Hu, X. Copper-Catalyzed
Alkylation of Benzoxazoles with Secondary Alkyl Halides. Org. Lett.
2012, 14, 1748−1751. (d) Makida, Y.; Ohmiya, H.; Sawamura, M.
Regio- and Stereocontrolled Introduction of Secondary Alkyl Groups
to Electron-Deficient Arenes through Copper-Catalyzed Allylic
Alkylation. Angew. Chem., Int. Ed. 2012, 51, 4122−4127. (e) Yao, T.;
Hirano, K.; Satoh, T.; Miura, M. Nickel- and Cobalt-Catalyzed Direct
Alkylation of Azoles with N-Tosylhydrazones Bearing Unactivated
Alkyl Groups. Angew. Chem., Int. Ed. 2012, 51, 775−779. (f) Wu, Y.;
Wang, J.; Mao, F.; Kwong, F. Y. Palladium-Catalyzed Cross-
Dehydrogenative Functionalization of C(sp2)-H Bonds. Chem. -
Asian J. 2014, 9, 26−47. (g) Wu, X.-L.; See, J. W. T.; Xu, K.; Hirao,
H.; Roger, J.; Hierso, J.-C.; Zhou, J. A General Palladium-Catalyzed
Method for Alkylation of Heteroarenes Using Secondary and Tertiary
Alkyl Halides. Angew. Chem., Int. Ed. 2014, 53, 13573−13577.
(h) Zhao, W.-M.; Chen, X.-L.; Yuan, J.-W.; Qu, L.-B.; Duan, L.-K.;
Zhao, Y.-F. Silver Catalyzed Decarboxylative Direct C2-Alkylation of
Benzothiazoles with Carboxylic Acids. Chem. Commun. 2014, 50,
2018−2020. (i) Wu, X.; Lei, C.; Yue, G.; Zhou, J. Palladium-Catalyzed
Direct Cyclopropylation of Heterocycles. Angew. Chem., Int. Ed. 2015,
54, 9601−9605.
(6) Vechorkin, O.; Proust, V.; Hu, X. The Nickel/Copper-Catalyzed
Direct Alkylation of Heterocyclic C-H Bonds. Angew. Chem., Int. Ed.
2010, 49, 3061−3064.
(7) Ackermann, L.; Punji, B.; Song, W. User-Friendly [(Diglyme)-
NiBr2]-Catalyzed Direct Alkylations of Heteroarenes with Unactivated
Alkyl Halides through C-H Bond Cleavages. Adv. Synth. Catal. 2011,
353, 3325−3329.
(8) Patel, U. N.; Pandey, D. K.; Gonnade, R. G.; Punji, B. Synthesis
of Quinoline-Based NNN-Pincer Nickel(II) Complexes: A Robust and
Improved Catalyst System for C-H Bond Alkylation of Azoles with
Alkyl Halides. Organometallics 2016, 35, 1785−1793.
(9) Alkylation of other arenes by Ni, see: (a) Xin, P.-Y.; Niu, H.-Y.;
Qu, G.-R.; Ding, R.-F.; Guo, H.-M. Nickel Catalyzed Alkylation of N-
Aromatic Heterocycles with Grignard Reagents through Direct C-H
Bond Functionalization. Chem. Commun. 2012, 48, 6717−6719.
(b) Aihara, Y.; Chatani, N. Nickel-Catalyzed Direct Alkylation of C-
H Bonds in Benzamides and Acrylamides with Functionalized Alkyl
Halides via Bidentate-Chelation Assistance. J. Am. Chem. Soc. 2013,
135, 5308−5311. (c) Wu, X.-L.; Zhao, Y.; Ge, H. Nickel-Catalyzed
Site-Selective Alkylation of Unactivated C(sp3)-H Bonds. J. Am. Chem.
Soc. 2014, 136, 1789−1792. (d) Ruan, Z.; Lackner, S.; Ackermann, L.
A General Strategy for the Nickel-Catalyzed C−H Alkylation of
Anilines. Angew. Chem., Int. Ed. 2016, 55, 3153−3157.
(10) For mechanism of Ni-catalyzed conventional alkylation reaction,
see: (a) Morrell, D. G.; Kochi, J. K. Mechanistic Studies of Nickel
Catalysis in the Cross Coupling of Aryl Halides with AlkylMetals. Role
of Arylalkylnickel(II) Species as Intermediates. J. Am. Chem. Soc. 1975,
97, 7262−7270. (b) Anderson, T. J.; Jones, G. D.; Vicic, D. A.
Evidence for a Ni(I) Active Species in the Catalytic Cross-Coupling of
Alkyl Electrophiles. J. Am. Chem. Soc. 2004, 126, 8100−8101.
(c) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R.
E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.;
Pulay, P.; Vicic, D. A. Ligand Redox Effects in the Synthesis, Electronic
Structure, and Reactivity of an Alkyl-Alkyl Cross-Coupling Catalyst. J.
Am. Chem. Soc. 2006, 128, 13175−13183. (d) Lin, X.; Phillips, D. L.
Density Functional Theory Studies of Negishi Alkyl-Alkyl Cross-
Coupling Reactions Catalyzed by a Methylterpyridyl-Ni(I) Complex. J.
Org. Chem. 2008, 73, 3680−3688. (e) Lu, Z.; Wilsily, A.; Fu, G. C.
Stereoconvergent Amine-Directed Alkyl-Alkyl Suzuki Reactions of
Unactivated Secondary Alkyl Chlorides. J. Am. Chem. Soc. 2011, 133,
8154−8157. (f) Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi
H
DOI: 10.1021/acs.organomet.8b00025
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Arylations of Propargylic Bromides: A Mechanistic Investigation. J.
Am. Chem. Soc. 2014, 136, 16588−16593.
(11) Omer, H. M.; Liu, P. Computational Study of Ni-Catalyzed C-H
Functionalization: Factors That Control the Competition of Oxidative
Addition and Radical Pathways. J. Am. Chem. Soc. 2017, 139, 9909−
9920.
(12) The reaction was performed in the presence of base to know
whether the single electron transfer occurs via base-promoted
mechanism. For related example, see: (a) Xu, T.; Cheung, C. W.;
Hu, X. Iron-Catalyzed 1,2-Addition of Perfluoroalkyl Iodides to
Alkynes and Alkenes. Angew. Chem., Int. Ed. 2014, 53, 4910−4914.
(b) Zhang, B.; Studer, A. 6-Perfluoroalkylated Phenanthridines via
Radical Perfluoroalkylation of Isonitriles. Org. Lett. 2014, 16, 3990−
3993.
(13) Zultanski, S. L.; Fu, G. C. Nickel-Catalyzed Carbon-Carbon
Bond-Forming Reactions of Unactivated Tertiary Alkyl Halides:
Suzuki Arylations. J. Am. Chem. Soc. 2013, 135, 624−627.
(14) For a recent example on IAT mechanism, see: Xu, Z.-Y.; Jiang,
Y.-Y.; Yu, H.-Z.; Fu, Y. Mechanism of Nickel(II)-Catalyzed Oxidative
C(sp2)−H/C(sp3)−H Coupling of Benzamides and Toluene De-
rivatives. Chem. - Asian J. 2015, 10, 2479−2483.
(15) Ahlrichs, R.; Bar, M.; Haser, M.; Horn, H.; Kolmel, C.
̈
̈
̈
Electronic Structure Calculations on Workstation Computers: The
Program System Turbomole. Chem. Phys. Lett. 1989, 162, 165−169.
(16) Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized Gradient
Approximation Made Simple. Phys. Rev. Lett. 1996, 77, 3865−3868.
(17) Schafer, A.; Huber, C.; Ahlrichs, R. Fully Optimized Contracted
̈
Gaussian Basis Sets of Triple Zeta Valence Quality for Atoms Li to Kr.
J. Chem. Phys. 1994, 100, 5829−5835.
̈
(18) Eichkorn, K.; Treutler, O.; Ohm, H.; Haser, M.; Ahlrichs, R.
̈
Auxiliary Basis Sets to Approximate Coulomb Potentials. Chem. Phys.
Lett. 1995, 240, 283−290.
(19) Sierka, M.; Hogekamp, A.; Ahlrichs, R. Fast Evaluation of the
Coulomb Potential for Electron Densities using Multipole Accelerated
Resolution of Identity Approximation. J. Chem. Phys. 2003, 118,
9136−9148.
(20) Klamt, A.; Schuurmann, G. COSMO: A New Approach to
Dielectric Screening in Solvents with Explicit Expressions for the
Screening Energy and its Gradient. J. Chem. Soc., Perkin Trans. 2 1993,
2, 799−805.
I
DOI: 10.1021/acs.organomet.8b00025
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