Mechanism of Direct C-H Arylation of Pyridine via a Transient Activator Strategy: A Combined Computational and Experimental Study

Article abstract of DOI:10.1021/acs.joc.8b01480

Recently, we realized the highly selective one-pot synthesis of 2,6-diarylpyridines by using a Pd-catalyzed direct C-H arylation approach via a transient activator strategy. Although methylation reagent as a transient activator and Cu(I) salt or oxide were found to be prerequisites, details regarding the mechanism remained unclear. In this paper, DFT calculations combined with experimental investigations were carried out to elucidate the principle features of this transformation. The results reveal (1) the origin of the exquisite diarylating selectivity of the pyridine under the transient strategy; (2) the possible demethylating reagent as the counteranion of the pyridinium salt; (3) the reason why Cu₂O is a better Cu(I) resource than others.

Full text of DOI:10.1021/acs.joc.8b01480

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Article
Mechanism of Direct C-H Arylation of Pyridine via a Transient Activator
Strategy: A Combined Computational and Experimental Study
Feiyun Jia, Changzhen Yin, Yang Zeng, Rui Sun, Yi-Cen Ge, Dingguo
Xu, Ruixiang Li, Hua Chen, Chunchun Zhang, and Haiyan Fu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Jul 2018
Downloaded from http://pubs.acs.org on July 24, 2018
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Mechanism of Direct C−H Arylation of Pyridine via a Transient
Activator Strategy:
Experimental Study
A
Combined Computational and
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,‡
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Feiyun Jia,
Changzhen Yin, Yang Zeng, Rui Sun, YiꢀCen Ge, Dingguo Xu,
†
†
*,║
*†
Ruixiang Li, Hua Chen, Chunchun Zhang, and Haiyan Fu
†
Key Laboratory of Green Chemistry & Technology, Ministry of Education College
of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
‡
School of Basic Medical Sciences, North Sichuan Medical College, Nanchong,
Sichuan 637007, P. R. China.
§
Division of Chemistry and Biological Chemistry, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
║
Analytical & Testing Center, Sichuan University, Chengdu, Sichuan 610064, P. R.
China.
*
To whom corresponding author should be addressed: scufhy@scu.edu.cn (FX) and
cczh@scu.edu.cn (CZ)
ABSTRACT: Recently, we realized the highly selective oneꢀpot synthesis of 2,
6ꢀdiarylpyridines by using a Pdꢀcatalyzed dire C−H arylation approach via a transient
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activator strategy. Although methylation reagent as a transient activator and Cu(I) salt
or oxide were found prerequisite, details regarding the mechanism remained unclear.
In this article, DFT calculations combined with experimental investigations were
carried out to elucidate the principle features of this transformation. The results reveal:
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(
1) the origin of the exquisite diꢀarylating selectivity of the pyridine under the
transient strategy; (2) the possible demethylating reagent to be the counter anion of
the pyridinium salt; (3) the reason why Cu O is a better Cu(I) resource than others.
2
KEYWORDS: DFT study, C−H functionalization, Nꢀmethylation, transmetalation,
copper.
ꢀ
INTRODUCTION
Arylpyridines are important synthetic motifs which are widely employed in a
variety of bioactive natural products and pharmaceutical synthesis, as well as material
1
ꢀ6
sciences. As the synthesis of arylpyridines remains a compelling goal in modern
7
ꢀ9
chemical research,
transitionꢀmetalꢀcatalyzed direct C−H arylation, enabling
oneꢀstep functionalization of pyridines, has become the most attractive method.
However, this straightꢀforward transformation often suffers from low reactivity and
poor selectivity, due to the electron deficiency and strong Lewis basicity of pyridines.
In such situation, the transitionꢀmetalꢀcatalyzed direct C−H arylation remains rather
10ꢀ13
challenging and still necessary to be further explored.
In order to improve the reactivity and selectivity, preꢀactivation strategy has been
14ꢀ17
widely applied in pyridine arylation reactions.
Although significant progress has
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been achieved by Fagnou, Hartwig, Charrette, Berman and other groups,
the
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problem arises as removing the preꢀinstalled activating groups is required to afford the
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target products. In recent years, traceless or transient directing group strategies have
24ꢀ30
been discovered and applied extensively in organic synthesis.
Inspired by these
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precedent discoveries, we successfully developed a transient activator strategy to
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realize the highly selective Pdꢀcatalyzed C−H 2,6ꢀdiarylation of pyridines.
Methylating reagent as the transient activator was found to define the success of the
reaction, while Cu(I) source as the additive was also important. Generally, it is
believed that Nꢀmethylation, C−H arylation and Nꢀdemethylation occur sequentially
in a oneꢀpot manner during the process.
Scheme 1. Direct C−H Arylation of Pyridine via a Transient Activator Strategy
3
1
The Proposed Mechanism Based on Experimental Results in Previous Work
N
Ph
N
Ph
PdCl , PPh , (MeO) SO , Cu O
2
3
2
2
2
K CO , DMAc, 150 °C, N , 24 h
2
3
2
Ph
N
Ph Me
Me
N
N
LCu
Y
L2Pd
N
Y
Me
N
Y
Demethylation
Ph
(MeO) SO
I
III
2
2
A and B circle
Reductive
Elimination
IV
Me
N
Me
Y
Transmetalation
Pd0L2
A
B
Y
Ph
Ph
V
N
C–H activation
Oxidative
Addition
+
Br
base
Demethylation
PhBr
I
PdIIL2
Cu X
HX
Ph
Ph
N
Ph
II
-
-
L = PPh ; X = Cl or O; base = K CO ; Y = (MeO)SO
3
3
2
3
Understanding of the Mechanism by DFT Calculations and Experiments in This Work
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Ph
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N-methylation
C–H activation
C–H arylation
Demethylation
(
MeO) SO
Cu
Pd
DFT calculations and experiments reveal:
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The origin for the high diarylation selectivity
The rate-determining step
Identity of the N-demethylation reagent
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A putative mechanism is proposed in Scheme 1. The pyridinium salt derived from
in situ Nꢀmethylation reacts with LCuCl (L=PPh ) in the presence of base to afford
3
the pyridiniumꢀCu(I) complex I. Meanwhile, palladium complex II is generated via
2
oxidative addition of Pd(0)L with PhBr. After transmetalation between I and II, the
palladium intermediate III is furnished, which further gives rise to the monoarylation
product IV by the subsequential reductive elimination. The Nꢀmethylpyridinium salt
IV either undergoes demethylation to afford the monoarylated pyridine, or reꢀenters
the catalytic cycle to give diarylated pyridinium salt V which eventually furnishes the
major product 2, 6ꢀdiarylpyridine after demethylation. Interestingly, our reaction
requires an elevated temperature of 150 ºC, much higher than the usual C−H
3
2ꢀ35
functionalization reactions.
Although experimental efforts have been made to
understand the mechanistic details, some key issues are still not fully addressed, such
as rateꢀlimiting step, temperature dependence and ways to improve the yield of the
reaction.
Theoretical methods represent alternative ways to tackle mechanistic problems in
36
chemical reactions. Recently, great progress has been made via theoretical
calculation on the mechanistic investigations of C−H bond functionalization by Houk,
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7ꢀ41
Wu, Lin and other groups.
In this work, intensive density functional theory
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(
DFT) calculations are employed in combination with experimental characterizations.
We aim to find the plausible answers to some mechanistic issues of the transient
activator strategy for Pdꢀcatalyzed C−H arylation of pyridine: (1) the origin for the
high diarylation selectivity; (2) the rateꢀdetermining step of the reaction; (3) the
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identity of Nꢀdemethylation reagent in the final step, which could be solvent (DMAc:
ꢀ
N,Nꢀdimethylacetamide), ligand (PPh
3
) or counterion (MeOSO
3
); (4) the requirement
of the high reaction temperature of 150 ºC. Herein, we detail the results of performed
investigations on the above questions to acquire a better understanding of the inner
workings relating to this direct arylation reaction. We hope that our explorations will
provide an opportunity to improve the efficiency of arylpyridine synthesis and extend
the current system to other Nꢀheterocyclic compounds.
ꢀ
COMPUTATIONAL DETAILS
42ꢀ43
Full geometry optimizations were carried out using B3LYP
exchange
correlation functional in gas phase with mixed basis sets. In particular, the effective
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core potentials (ECPs) of Hay and Wadt with doubleꢀζ valence basis sets (LanL2DZ)
was applied for atoms of palladium, copper, bromine, and potassium, while the
doubleꢀζ splitꢀvalence 6ꢀ31G(d) basis set for the rest of atoms. Vibrational frequencies
were calculated to confirm minima with all positive frequencies and transition states
with only one imaginary frequency. Meanwhile, thermodynamic quantities like
thermal corrections to enthalpy and Gibbs free energy were performed as the same
45ꢀ46
level of theory. Intrinsic reaction coordinates (IRC)
were applied to connect all
stationary states. In order to obtain the reactive energetic profiles, singleꢀpoint
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calculations were carried out using M06
functional based on the B3LYP optimized
geometries. The M06 functional has been demonstrated to be particularly suitable for
49ꢀ52
describing copper containing systems.
In such calculations, mixed basis sets
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consisting of SDD for palladium, copper, bromine and potassium and 6ꢀ311+G (d, p)
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basis set for other atoms were applied. The solvation model density (SMD)
continuum method was used to account for the solvent effects in all singleꢀpoint
energy calculations. Consistent with the experimental conditions, N,
NꢀDimethylacetamide was selected as the solvent in our computation.
Natural Population Analysis (NPA) charge calculations for some selected species
were employed at the M06//B3LYP single point level of theory within the SMD
solvation model. The temperatureꢀdependent enthalpy corrections and the entropy
effects were computed at 298K and 1 atmosphere of pressure. All calculations were
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performed using Gaussian 09 suite of program.
ꢀ
RESULTS AND DISCUSSION
NꢀMethylation. On the basis of the catalytic mechanism proposed in Scheme 1, we
first investigated the Nꢀmethylation of pyridine with (MeO) SO to form the
intermediate 2. This is a typical S 2 reaction, in which the freeꢀenergy barrier to
complete the Nꢀmethylation via transition state TS1 was calculated to be 16.9
kcal/mol according to Figure 1. The methyl group migrates from (MeO) SO to
pyridine by Walden inversion. TS1 features a nearly planar methyl group at the
middle of pyridine and –OSO OMe group from Figure 1. Once the bond between
2
2
N
2
2
2
pyridine N atom and the methyl group is formed, the dissociation of this methyl group
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from sulfate is accelerated. In fact, a relatively large exothermicity of 23.3 kcal/mol
for the Nꢀmethylation reaction was found, which indicated that the reaction is
thermodynamically favorable.
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Charge development for some key atoms deserves further discussion. Charges of
pyridine and Nꢀmethylpyridine were investigated using Natural Population Analysis
(
NPA) approach. As shown in Scheme 2, along with methylation at the nitrogen atom
of pyridine, hydrogen atoms on the pyridine ring become more acidic, esp. the 2,
ꢀpositions. The NPA charge of the hydrogen atoms increases from 0.198 to 0.250
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upon the formation of pyridinium salt. It is consistent with the experimental finding
that the reactivity of pyridine is significantly enhanced after being methylated,
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especially at the orthoꢀpositions.
2 2
Figure 1. Reaction energy profile of Nꢀmethylation of pyridine with (MeO) SO .
Scheme 2. NPA charge analysis to rationalize the H atomic acidity change at the
ꢀposition of pyridine before and after Nꢀmethylation.
2
N
H
+0.198
N
H +0.250
C
Nꢀmethylation
C
+
0.053
+0.131
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C–H Arylation. The following step is the C−H arylation of the corresponding
Nꢀmethylpyridinium salt. In comparison to pyridine, the pyridinium salt has increased
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proton acidity of C−H bond, and therefore increased C−H arylation reactivity. It is
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proposed that this process consists of copperꢀinduced activation of C−H bond and
palladium catalyzed arylation. With regard to the C−H activation step, two possible
pathways need to be systematically evaluated, which mainly differ in the role of base
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according to precedent studies on baseꢀassisted C−H activation reactions.
In
consistency with our arylation selectivity, we only investigated the activation of C
in this section.
2
−H
In pathway I (Figure 2, the black line), a double salt KCl·LCuCO
structure shown in Figure 2, is generated first via ligand exchange of chloride with
carbonate (K CO ). The reaction is thermodynamically favored due to the large
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K 4 with the
2
3
exothermicity (-10.9 kcal/mol) and the absence of energy barrier height. The leaving
of KCl from the double salt gives LCuCO K 5, with which a concerted
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metalationꢀdeprotonation (CMD) process of 2 occurs subsequently. It is indicated
that the proton transfers from the C2ꢀposition of pyridinium salt to the carbonate via a
distorted sixꢀmembered ring transition state TS2 which produces the copper(I)
Nꢀmethylpyridinium intermediate 6. The overall freeꢀenergy barrier for this
baseꢀassisted pathway I is calculated to be 17.4 kcal/mol.
On the contrary, another C−H activation pathway II (Figure 2, the blue line) does
2 3
not need to generate the double salt 4. Instead, K CO as base directly participates the
C−H activation without the assist of CuCl. Basically, pathway II is believed involving
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two processes: (a) proton abstraction from pyridinium salt with potassium carbonate,
(b) transmetalation to give the copper(I)ꢀpyridinium complex. First, via a
sixꢀmembered ring transition state TS3, proton transfer occurs at the C2ꢀposition of
the pyridinium ring with the oxygen atom of carbonate, which affords the potassium
Nꢀmethylpyridinium intermediate 7. Calculations demonstrate that the freeꢀenergy
barrier of this step is 14.4 kcal/mol. After that, intermediate 7 undergoes
transmetalation with copper (I) salt to form 6 via the transition state TS4, with a
relatively low freeꢀenergy barrier of 1.5 kcal/mol. As shown in Figure 2, the overall
freeꢀenergy barrier for the pathway II is calculated to be 14.5 kcal/mol, which is much
lower than pathway I. Thus, the kinetically favored pathway II is more likely
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responsible for C−H activation process, whereas K CO acts as a base at the very first
beginning.
Meanwhile, we have also examined the direct C−H activation between LCuCl and
Nꢀmethylpyridium salt in the absence of any additional bases. The corresponding
energy barrier is found to be 45.4 kcal/mol (see SI, Figure S1). It is much higher than
the baseꢀassisted pathway II, which is rationalized as the carbonate is a stronger base
than chloride. In such situation, our computation clearly demonstrates the importance
of K
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as the base in the C−H activation step with the current system.
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. (a) Energy profile for the C−H activation of Nꢀmethylpyridine, involving two
baseꢀassisted pathways. (b) Computed structures of transition states with select bond distances
shown in Å.
In the above calculations, CuCl is chosen as the additive. In our previous work, we
found that Cu
superior diarylation selectivity comparing to CuCl. Herein, the C−H activation
reaction involving Cu O is further discussed, while the role of PPh is also
2
O exhibited similar efficiency to afford arylation products but with
31
2
3
investigated. As summarized in Figure 3, two putative C−H activation pathways were
computed, with and without PPh , respectively. K CO is not included in the present
3
2
3
simulation. Similar to the previous baseꢀassisted C−H activation, the current step also
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features a CMD mechanism. In the first pathway III (Figure 3, the black line), the
2
oxygen atom of Cu O directly abstracts the most acidic proton of pyridinium to form
the intermediate 8 via the transition state TS6 with a 12.2 kcal/mol barrier. In the
second pathway IV (Figure 3, the blue line), the deprotonation occurs in the presence
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
of LCu
ligand PPh
necessity of PPh
implys the superiority of basic Cu
2
O to give the intermediate 6 via the transition state TS5. In the presence of
, the freeꢀenergy barrier is further reduced to 10.7 kcal/mol, revealing the
to enhance the reactivity. The advantage in kinetics by 3.8 kcal/mol
O in the presence of PPh for C−H activation
3
3
2
3
compared to CuCl in pathway II. These computational results revealed the Cu O is an
2
additive superior to CuCl. In addition, a series of deuterium incorporation
experimental results for pyridinium salt i as demonstrated in Table 1 further supported
above conclusion: Nearly no deuterium incorporation was observed when the
pyridinium salt i was treated with CuCl alone in D
deuterium incorporation product (ia and iaa) could be achieved with the assistance of
CO (Table 1, entry 2), moreover, the percentage was significantly increased to
2% when replacing CuCl with Cu O (Table 1, entry 3).
2
O (Table 1, entry 1), while 44%
K
2
3
9
2
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1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
6
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Reaction energy profiles of the C−H activation of Nꢀmethylpyridium with Cu
2
O and
LCu O.
2
a
Table 1. Deuterium Incorporation Study
metal, base
+
N
N
D
D
N
D
D O 100 oC
-
-
-
2
(CH O)SO3
(
CH O)SO3
3
(CH O)SO3
3
3
1
h
i
ia
iaa
entry
additive
CuCl
base
ꢀ
D incorporation (%)
b
1
N.D.
44
b
2
CuCl
K
2
2
CO
3
3
3
2
Cu O
K
CO
92
a
Reaction condition: i (0.25 mmol, 1.0 equiv.), additive (0.125 mmol, 0.5 equiv.), base (0.25
1
mmol, 1 equiv.), D
2
O (0.3 mL), 100 °C for 1 h under N
2
. Yields were determined by H NMR
b
analysis of a crude product with CH Br as internal standard. 0.25 mmol additive was used.
2
2
The next step after C−H activation is the palladium catalyzed arylation which
includes oxidative addition, transmetalation and reductive elimination. Figure 4(a)
shows the energy profile for the complete catalytic cycle. The oxidative addition of
2
PhBr to L Pd(0) is a concerted process via a threeꢀmembered ring transition state TS7,
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which requires 17.9 kcal/mol to generate the Pd(II) intermediate 10. Subsequently, the
3
complex 10 releases one ligand (PPh ) and interacts with complex 6 to form the
metastable adduct 11. With a low energy barrier of 1.5 kcal/mol, the transmetalation
then occurs easily via a fourꢀmembered ring transition state TS8, which finally gives
the intermediate 12. Interestingly, our calculation results suggest that in TS8 dPd−Br is
elongated to 2.78 Å and dCu−C changes to 2.71 Å, from 2.65 Å and 1.96 Å in the
intermediate 10 and intermediate 6, respectively. Thus, the ligand transfer of
Nꢀmethylpyridinium from Cu to Pd is facilitated. From 12, reductive elimination takes
place via a threeꢀmembered ring transition state TS9 with the freeꢀenergy barrier of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6.7 kcal/mol, leading to 2ꢀphenylꢀNꢀmethylpyridinium salt and recovering the catalyst
9 (L Pd). The palladium catalytic cycle is exergonic by 39.5 kcal/mol, which indicates
2
the whole process is thermodynamically favorable. All structures of transition states
involved in the palladium catalytic cycle are illuminated in Figure 4(b).
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. (a) Energy profile calculated for the Palladium catalytic cycle. (b) Computed structures
of transition states with selected bond distances shown in Å.
NꢀDemethylation. Once the 2ꢀarylꢀNꢀmethylpyridinium salt is formed, two possible
processes might further take place with our system. One features a direct
demethylation reaction to generate the monoarylated pyridine, while the other is
assumed to reꢀenter the catalytic cycle of diarylation. Generally, many methods have
58ꢀ59
been reported to demethylate the Nꢀmethylpyridinium salts.
most common way is the S
Among them, the
N
2ꢀtype nucleophilic attack on pyridinium salts with
60
elevated reaction temperature. In our system, there are multiple potential
nucleophiles, such as the ligand PPh , the solvent DMAc and the counterion of the
3
ꢀ
3
pyridnium salts (MeOSO
). Moreover, a higher temperature of 150 ºC is required in
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the demethylation step with our system. In order for a better understanding of the
detailed mechanism, a careful exploration of the demethylation step is highly desired.
Thus, the demethylation processes were then simulated based on density functional
theory, with the corresponding energetic profiles plotted in Figure 5. Clearly, the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
lowest energy barrier (∆G = 33.5 kcal/mol) is observed in the case of PPh
3
, which has
been reported as an efficient demethylating reagent. In the current system, however,
PPh is unlikely the main demethylation reagent because only 0.2 equivalents (based
58
3
on the pyridine) was employed and hence seriously inadequate. On the other hand,
DMAc is also less likely due to the high energy barrier (40.6 kcal/mol). Therefore, we
ꢀ
believe that the counter anion (MeO)SO
3
actually acts as the demethylating reagent.
Indeed, our calculation shows that the activation energy is 2.3 kcal/mol lower than the
case of DMAc. To further support our hypothesis, we designed a series of coupling
reaction between 4ꢀtolyl iodide and Nꢀmethylꢀ2ꢀphenylpyridinium salts ii bearing
different counter anions. Impressively, different yields of arylation products were
observed, which have good correlations with freeꢀenergy barriers of the
N-demethylation of the corresponding diaryl pyridinium salts: the lower energy
barrier led to higher yield (as shown in Table 2).
a
Table 2. The Effect of Counter Anions of the Pyridinium ii on Yield
ꢀ
b
cal
cal
c
entry
Y
yield (%)
ꢁG [ꢁH ] (kcal/mol)
ꢀ
1
2
I
83
67
27.7 [20.7]
ꢀ
NO3
33.4 [22.7]
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ
3
4
5
CF COO
61
47
41
34.7 [22.4]
3
ꢀ
TsO
37.0 [25.8]
39.1 [27.9]
ꢀ
3
CH OSO3
a
2 2
Reaction conditions: ii (0.5 mmol, 1 equiv.), 4ꢀtolyl iodide (1.0 mmol, 2 equiv.), Pd(PhCN) Cl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
5 mol%), TFP (10 mol%), Cu O (0.25 mmol, 0.5 equiv.), PivOK (1.0 mmol, 2 equiv.), 150 °C, 16
b
c
h, under N ; TFP = triꢀ2ꢀfurylphosphine; Isolated yields; The calculated freeꢀenergy barriers for
2
Nꢀdemethylation of the diaryl pyridinium salts. See the SI, figure S2.
Figure 5. (a) Energy profiles calculated for the demethylation reactions with different
demethylating reagents. (b) The computed structures of transition states with selected bond
distances shown in Å.
Rateꢀdetermining Step and Siteꢀselectivity. The overall freeꢀenergy profile of the
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reaction is shown in Figure 6. For clarification, all energy barrier heights are scaled in
2 2
accord with the reactant 1 and (MeO) SO . As demonstrated in Figure 6, the barrier of
the demethylation step is much higher than the others. Thus, the calculation result
well explains why our system requires such a high reaction temperature which differs
from the previous reports, and Nꢀdemethylation is proposed to be the rateꢀdetermining
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2–35
step.
pyridinium ring would greatly slow down the Nꢀdemethylation process,
ꢀdimethylaminopyridine (DMAP) was further tested as the substrate with our system
Table 3). As expected, DMAP exhibited a relatively low reactivity, with only 36%
Since it has been reported that the electronꢀdonating group on the
58
4
(
yield of diarylated product obtained after 24 h. If the reaction time was prolonged to
three days, the yield was successfully increased to a moderate level of 65%. The
freeꢀenergy barrier for demethylation of the corresponding Nꢀmethyl diarylated
pyridinium salt is calculated as high as 43.4 kcal/mol (see SI, Figure S3), which
possibly accounts for the requirement of a longer reaction time. In a word, the
experimental results help to support Nꢀdemethylation as the rateꢀdetermining step.
In order to gain insights into the origin of high diarylation selectivity, we further
carried out more computational investigations on the related steps. After the first
reaction cycle, the monoarylated Nꢀmethylpyridinium salt is supposed to either
undergo the demethylation to afford the monoarylated pyridine or reꢀenter the second
catalytic arylation cycle to produce 2, 6ꢀdiarylꢀNꢀmethylpyridinium salt. According to
Figure 6, the barrier height for demethylation of the monoarylated pyridinium salt is
much higher than the other steps. Therefore, reꢀentering the catalytic cycle is more
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
favored. Furthermore, the barrier of demethylation process for diarylation product is
found slightly lower than that for the monoarylated counterparts (38.3 vs. 39.4
58
kcal/mol), possibly due to the releasing of more strain in the former case. Hence, we
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
can conclude that the demethylation process prefers to occur after the diarylation,
rather than the monoarylation, which deciphers the observed diꢀ/monoꢀarylation
selectivity with this transient activator strategy.
a
Table 3. The Effect of Reaction Time on Yield
b
entry
reaction time (h)
yield (%)
1
2
3
24
48
72
36
59
65
a
iii (0.5 mmol), 4ꢀtolyl iodide (1.5 mmol), PdCl
2
(5 mol %), PPh
3
(10 mol %), K
2
CO
3
(4.0 equiv),
o
o
(MeO)
2
SO
2
(0.8 equiv), Cu
2
O (0.5 equiv), DMAc (2.5 mL), 150 C, 4Å MS (100 mg), 150 C,
b
under N ; Isolated yields.
2
O
S
O
16.9
N
O
O
K
[9.3]
L
L
O
S
O
O
H
N
O
N
O
O
(
MeO)
2
SO
2
TS1
Pd
TS1
N
Cu
Br
L
O
Cl
K
N
N
0
.0
TS3
K
TS13
[0.0]
ꢀ8.8
ꢀ18.2]
Pd
L
ꢀ
8.9
TS4
KCl
[
TS8
1
N
L
[
ꢀ18.0]
ꢀ10.3
[ꢀ7.2]
(MeO)SO ꢀ
TS9
ꢀ20.3
ꢀ10.6
[ꢀ4.4]
3
TS4
ꢀ17.1
[ꢀ17.4]
TS3
ꢀ23.3
L
ꢀ18.6
[ꢀ17.3]
7
L
[ꢀ21.4]
TS13
2 2
(MeO) SO
KHCO
3
TS8
N
LꢀCuCl [ꢀ22.0]
1
K
2
CO
3
K
ꢀ25.6
ꢀ22.9]
2
11
[
ꢀ27.0
ꢀ29.7]
TS9
[
ꢀ34.8
[ꢀ16.3]
6
L
(MeO)SO
3
ꢀ
38.3
[27.6]
7
N
12
Br
N
Pd
Cu L
Pd L
L
ꢀ50.0
[ꢀ33.4]
16
Br
PdL
2
(MeO)SO3ꢀ
TS11
N
2
N
Pd
15
10.1
6
L
L
2 2
MeO) SO
[12.3]
(
11
L
ꢀ43.5
[ꢀ45.0]
0.0
[0.0]
O
12
14
∆
[
G
sol
?H]sol
kcal/mol
L=PPh
S
O
O
N
O
reꢀenter the catalytic
cycle to give 13
13
N
N
N
N
3
TS11
16
15
1
3
14
Nꢀmethylation
CꢀH arylation
Demethylation
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Figure 6. The overall energy profile calculated for the direct C−H arylation of pyridine.
ꢀ
CONCLUSIONS
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In this work, by using DFT calculations combined with experimental investigations,
we disclose the detail mechanism of Pdꢀcatalyzed C−H arylation of pyridine via the
transient activator strategy. The whole process comprises three key steps, including
Nꢀmethylation, C−H arylation, and Nꢀdemethylation. The Nꢀmethylation enhances the
acidity of protons on pyridine significantly, thereby improving the arylation reactivity.
The resulting pyridinium salt reacts with LCuCl in the presence of the base (K
to give copper(I) pyridinium intermediate. Herein, two possible pathways for C−H
activation step were calculated. The concerted metalationꢀdeprotonation with K CO
followed by transmetalation with Cu(I) species, with a lower freeꢀenergy barrier of
4.5 kcal/mol, is therefore the more favorable pathway. From the resulting Cu(I)
2 3
CO )
2
3
1
pyridinium species, the transmetalation with palladium and the subsequent reductive
elimination occur to give the first monoarylation product. Between the following two
competitive pathways, the calculation results suggest that monoarylation product
undergoes the second arylation first rather than being directly demethylated.
Selectively affording the diarylation product is more favored in the aspect of
energetics, which is well consistent with our previous explorations. In addition,
according to our calculations and experimental investigations, we believe that the
ꢀ
ꢀ
counter anion Y (MeOSO
3
) is more likely to be the demethylation reagent.
ꢀ
SUPPORTING INFORMATION
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Supplementary experimental data.
Energy profile for the CꢀH activation of Nꢀmethylpyridine with CuCl (or CuClꢀL)
without baseꢀassisted.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
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Energy profiles for the Nꢀdemethylation reactions of the three diaryl pyridinium
salts.
Energy profiles of the rateꢀdetermining step of DMAP diarylation reaction.
Cartesian coordinates，computed total energies，enthalpy and Gibbs free energy of
optimized structures.
ꢀ
ACKNOWLEDGEMENT
This work was funded by the National Natural Science Foundation of China (No.
21473117, No. 21572137) and the Key Program of Sichuan Science and Technology
Project (No. 2018GZ0312). Some of the results described in this work were obtained
with the help of the Supercomputing Center of Chinese Academy of Science.
ꢀ
REFERENCES
. Desimoni, G.; Faita, G.; Quadrelli, P., Pyridine-2,6-bis(oxazolines), Helpful Ligands
for Asymmetric Catalysts. Chem. Rev. 2003, 103, 3119−3154.
1
2
6
3
. Henry, G. D., De novo synthesis of substituted pyridines. Tetrahedron. 2004, 60,
043–6061.
. Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B., Synthesis of pyridine and
dihydropyridine derivatives by regio- and stereoselective addition to N-activated
pyridines. Chem. Rev. 2012, 112, 2642−2713.
4. Wang, Y.-F.; Chiba, S., Mn(III)-Mediated Reactions of Cyclopropanols with Vinyl
20
ACS Paragon Plus Environment

Page 21 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Azides Synthesis of Pyridine and 2-Azabicyclo[3.3.1]non-2-en-1-ol Derivatives. J. Am.
Chem. Soc. 2009, 131, 12570–12572.
5
. Hagui, W.; Besbes, N.; Srasra, E.; Soulé, J.-F.; Doucet, H., Direct access to
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-(hetero)arylated pyridines from 6-substituted 2-bromopyridines via phosphine-free
palladium-catalyzed C–H bond arylations: the importance of the C6 substituent. RSC.
Adv. 2016, 6, 17110–17117.
6
. Isley, N. A.; Wang, Y.; Gallou, F.; Handa, S.; Aue, D. H.; Lipshutz, B. H., A Micellar
Catalysis Strategy for Suzuki–Miyaura Cross-Couplings of 2-Pyridyl MIDA Boronates:
No Copper, in Water, Very Mild Conditions. ACS Catal. 2017, 7, 8331–8337.
7
. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T., Analysis of the reactions
used for the preparation of drug candidate molecules. Org. Biomol. Chem. 2006, 4,
337–2347.
2
8. Schlosser, M.; Mongin, F., Pyridine elaboration through organometallic
intermediates: regiochemical control and completeness. Chem. Soc. Rev. 2007, 36,
1
9
161–1172.
. Ackermann, L.; Potukuchi, H. K.; Kapdi, A. R.; Schulzke, C., Kumada–Corriu
Cross-Couplings with 2-Pyridyl Grignard Reagents. Chem. Eur. J. 2010, 16, 3300–3303.
0. Tobisu, M.; Hyodo, I.; Chatani, N., Nickel-Catalyzed Reaction of Arylzinc Reagents
1
with N-Aromatic Heterocycles: A Straightforward Approach to C-H Bond Arylation of
Electron-Deficient Heteroaromatic Compounds. J. Am. Chem. Soc. 2009, 131,
1
2070–12071.
11. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D., C-H arylation of pyridines: high
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 28
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
regioselectivity as a consequence of the electronic character of C-H bonds and
heteroarene ring. J. Am. Chem. Soc. 2011, 133, 16338–16341.
1
2. Ye, M.; Gao, G. L.; Edmunds, A. J.; Worthington, P. A.; Morris, J. A.; Yu, J. Q.,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ligand-promoted C3-selective arylation of pyridines with Pd catalysts: gram-scale
synthesis of (+/-)-preclamol. J. Am. Chem. Soc. 2011, 133, 19090–19093.
1
3. Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K., C-H Functionalization of Azines.
Chem. Rev. 2017, 117, 9302–9332.
4. Campeau, L.-C.; Rousseaux, S.; Fagnou, K., A Solution to the 2-Pyridyl
1
Organometallic Cross-Coupling Problem: Regioselective Catalytic Direct Arylation of
Pyridine N -Oxides. J. Am. Chem. Soc. 2005, 127, 18020–18021.
15. Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J., Palladium-catalyzed oxidative C-H/C-H
cross-coupling of indoles and pyrroles with heteroarenes. Angew. Chem. Int. Ed. 2011,
50, 5365 –5369.
1
6. Ackermann, L.; Fenner, S., Direct arylations of electron-deficient (hetero)arenes
with aryl or alkenyl tosylates and mesylates. Chem. Commun. 2011, 47, 430–432.
7. Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F., Mechanistic studies on direct arylation
1
of pyridine N-oxide: evidence for cooperative catalysis between two distinct
palladium centers. J. Am. Chem. Soc. 2012, 134, 3683−3686.
1
8. Mousseau, J. J.; Bull, J. A.; Charette, A. B., Copper-catalyzed direct alkenylation of
N-iminopyridinium ylides. Angew. Chem., Int. Ed. 2010, 49, 1133 –1136.
9. Larivee, A.; Mousseau, J. J.; Charette, A. B., Palladium-Catalyzed Direct C-H
Arylation of N -Iminopyridinium Ylides: Application to the Synthesis of (+)-Anabasine.
1
22
ACS Paragon Plus Environment

Page 23 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J. Am. Chem. Soc. 2008, 130, 52–54.
20. Ding, S.; Yan, Y.; Jiao, N., Copper-catalyzed direct oxidative annulation of
N-iminopyridinium ylides with terminal alkynes using O2 as oxidant. Chem. Commun.
2013, 49, 4250–4252.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1. Chau, S. T.; Lutz, J. P.; Wu, K.; Doyle, A. G., Nickel-catalyzed enantioselective
arylation of pyridinium ions: harnessing an iminium ion activation mode. Angew.
Chem. Int. Ed. 2013, 52, 9153 –9156.
2
2. Berman, A. M.; Bergman, R. G.; Ellman, J. A., Rh(I)-catalyzed direct arylation of
azines. J. Org. Chem. 2010, 75, 7863-8.
3. Schipper, D. J.; El-Salfiti, M.; Whipp, C. J.; Fagnou, K., Direct arylation of azine
N-oxides with aryl triflates. Tetrahedron. 2009, 65, 4977–4983.
4. Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.;
Smith, M. R. I., A traceless directing group for C-H borylation. Angew. Chem. Int. Ed.
2
2
2
013, 52, 13153 –13157.
2
5. Huang, X.; Huang, J.; Du, C.; Zhang, X.; Song, F.; You, J., N-oxide as a traceless
oxidizing directing group: mild rhodium(III)-catalyzed C-H olefination for the synthesis
of ortho-alkenylated tertiary anilines. Angew. Chem. Int. Ed. 2013, 52, 12970 –12974.
26. Luo, J.; Preciado, S.; Larrosa, I., Overriding ortho-para selectivity via a traceless
directing group relay strategy: the meta-selective arylation of phenols. J. Am. Chem.
Soc. 2014, 136, 4109−4112.
27. Zhang, F.; Spring, D. R., Arene C-H functionalisation using
a
removable/modifiable or a traceless directing group strategy. Chem. Soc. Rev. 2014,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 28
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
3, 6906–6919.
28. Zhang., F.-L.; Hong., K.; Li., T.-J.; Park., H.; Yu., J.-Q., Functionalization of C(sp3)–H
bonds using atransient directing group. Science. 2016, 351, 252–256.
29. Besset, T.; Zhao, Q.; Poisson, T.; Pannecoucke, X., The Transient Directing Group
Strategy: A New Trend in Transition-Metal-Catalyzed C–H Bond Functionalization.
Synthesis 2017, 49, 4808-4826.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
0. Gandeepan, P.; Ackermann, L., Transient Directing Groups for Transformative C–H
Activation by Synergistic Metal Catalysis. Chem 2018, 4, 199-222.
1. Zeng, Y.; Zhang, C.; Yin, C.; Sun, M.; Fu, H.; Zheng, X.; Yuan, M.; Li, R.; Chen, H.,
3
Direct C-H Functionalization of Pyridine via a Transient Activator Strategy: Synthesis
of 2,6-Diarylpyridines. Org. Lett. 2017, 19, 1970–1973.
3
2. Yamaguchi, A. D.; Chepiga, K. M.; Yamaguchi, J.; Itami, K.; Davies, H. M., Concise
syntheses of dictyodendrins A and F by a sequential C-H functionalization strategy. J.
Am. Chem. Soc. 2015, 137, 644–647.
3
3. Hwang, H.; Kim, J.; Jeong, J.; Chang, S., Regioselective introduction of
heteroatoms at the C-8 position of quinoline N-oxides: remote C-H activation using
N-oxide as a stepping stone. J. Am. Chem. Soc. 2014, 136, 10770−10776.
3
4. Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S. G., Transition metal-catalyzed site- and
regio-divergent C-H bond functionalization. Chem. Soc. Rev. 2017, 46, 4299-4328.
35. Ye, F.; Qu, S.; Zhou, L.; Peng, C.; Wang, C.; Cheng, J.; Hossain, M. L.; Liu, Y.; Zhang,
Y.; Wang, Z. X.; Wang, J., Palladium-catalyzed C-H functionalization of
acyldiazomethane and tandem cross-coupling reactions. J. Am. Chem. Soc. 2015, 137,
2
4
ACS Paragon Plus Environment

Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
435−4444.
36. Cheng, G. J.; Zhang, X.; Chung, L. W.; Xu, L.; Wu, Y. D., Computational organic
chemistry: bridging theory and experiment in establishing the mechanisms of
chemical reactions. J. Am. Chem. Soc. 2015, 137, 1706−1725.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37. Liu, W. B.; Schuman, D. P.; Yang, Y. F.; Toutov, A. A.; Liang, Y.; Klare, H. F. T.; Nesnas,
N.; Oestreich, M.; Blackmond, D. G.; Virgil, S. C.; Banerjee, S.; Zare, R. N.; Grubbs, R.
H.; Houk, K. N.; Stoltz, B. M., Potassium tert-Butoxide-Catalyzed Dehydrogenative C-H
Silylation of Heteroaromatics: A Combined Experimental and Computational
Mechanistic Study. J. Am. Chem. Soc. 2017, 139, 6867–6879.
3
8. Deng, C.; Lam, W. H.; Lin, Z., Computational Studies on Rhodium(III) Catalyzed
C–H Functionalization versus Deoxygenation of Quinoline N-Oxides with Diazo
Compounds. Organometallics. 2017, 36, 650–656.
39. Davies, D. L.; Macgregor, S. A.; McMullin, C. L., Computational Studies of
Carboxylate-Assisted C-H Activation and Functionalization at Group 8-10 Transition
Metal Centers. Chem. Rev. 2017, 117, 8649–8709.
4
0. Yang, Y. F.; Chung, L. W.; Zhang, X.; Houk, K. N.; Wu, Y. D., Ligand-controlled
reactivity, selectivity, and mechanism of cationic ruthenium-catalyzed
hydrosilylations of alkynes, ketones, and nitriles: a theoretical study. J. Org. Chem.
2
014, 79, 8856−8864.
41. Zhang, X.; Chung, L. W.; Wu, Y. D., New Mechanistic Insights on the Selectivity of
Transition-Metal-Catalyzed Organic Reactions: The Role of Computational Chemistry.
Acc. Chem. Res. 2016, 49, 1302−1310.
2
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
2. Becke, A. D., Density ‐functional thermochemistry. III. The role of exact
exchange. The Journal of Chemical Physics. J. Chem. Phys. 1993, 98, 5648–5652.
3. Lee, C.; Yang, W.; Parr, R. G., Development of the Colle-Salvetti
correlation-energy formula into a functional of the electron density. Phys. Rev. B.
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
988, 37, 785–789.
4
4. Hay, P. J.; Wadt, W. R., Ab initio effective core potentials for molecular
calculations. Potentials for K to Au including the outermost core orbitals. J. Chem.
Phys. 1985, 82, 299–310.
4
4
5. Fukuil, K., A Formulation of the Reaction Coordinate. J. Phys. Chem. 1970, 74,
161–4163.
46. Fukui, K., The Path of Chemical Reactions — The IRC Approach. Acc. Chem. Res.
981, 14, 363–368.
1
47. Zhao, Y.; Truhlar, D. G., The M06 suite of density functionals for main group
thermochemistry, thermochemical kinetics, noncovalent interactions, excited states,
and transition elements: two new functionals and systematic testing of four
M06-class functionals and 12 other functionals. Theor. Chem. Account. 2008, 120,
2
4
15–241.
8. ZHao, Y.; Truhlar, D. G., Density Functionals with Broad Applicability in Chemistry.
Acc. Chem. Res. 2008, 41, 157–167.
49. Cheng, G.-J.; Song, L.-J.; Yang, Y.-F.; Zhang, X.; Wiest, O.; Wu, Y.-D., Computational
Studies on the Mechanism of the Copper-Catalyzed sp3-C-H Cross-Dehydrogenative
Coupling Reaction. ChemPlusChem. 2013, 78, 943–951.
26
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5
0. Valero, R.; Costa, R.; Moreira, I. d. P. R.; Truhlar, D. G.; Illas, F., Performance of the
M06 family of exchange-correlation functionals for predicting magnetic coupling in
organic and inorganic molecules. J. Chem. Phys. 2008, 128, 114103,1–8.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
51. Park, K.; Pak, Y.; Kim, Y., Large Tunneling Effect on the Hydrogen Transfer in
Bis(μ-oxo)dicopper Enzyme: A Theoretical Study. J. Am. Chem. Soc. 2012, 134,
3
5
524–3531.
2. Golub, I. E.; Filippov, O. A.; Gutsul, E. I.; Belkova, N. V.; Epstein, L. M.; Rossin, A.;
Peruzzini,
M.;
Shubina,
E.
S.,
Dimerization
Mechanism
of
Bis(triphenylphosphine)copper(I) Tetrahydroborate: Proton Transfer via a Dihydrogen
Bond. Inorg. Chem. 2012, 51, 6486–6497.
53. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G., Universal Solvation Model Based on
Solute Electron Density and on a Continuum Model of the Solvent Defined by the
Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B. 2009, 113,
6
5
378–6396.
4. Frisch, M. J. T., G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.
R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.;
Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi,
M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.;Dapprich, S.;Daniels,A.D.; Farkas,Ö .; Foresman, J.
B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. , Gaussian 09, revision D.01; Gaussian, Inc.:
Wallingford, CT, 2010.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
5. Yuan, R.; Lin, Z., Mechanism for the Carboxylative Coupling Reaction of a
Terminal Alkyne, CO2, and an Allylic Chloride Catalyzed by the Cu(I) Complex: A DFT
Study. ACS Catal. 2014, 4, 4466–4473.
5
6. Ackermann, L., Carboxylate-Assisted Transition-Metal-Catalyzed C-H Bond
Functionalizations: Mechanism and Scope. Chem. Rev. 2011, 111, 1315–1345.
57. Lapointe, D.; Fagnou, K., Overview of the Mechanistic Work on the Concerted
Metallation–Deprotonation Pathway. Chem. Lett. 2010, 39, 1118–1126.
58. Berg, U.; Gallo, R.; Metzger, J., Demethylations of Quaternary Pyridinium Salts by
a Soft Nucleophile, Triphenylphosphine. Electronic and Steric Accelerations. J. Org.
Chem. 1976, 41, 2621–2624.
5
9. Aumann, D.; Deady, L. W., Simple Method for Demethylation of Quaternised
Nitrogen Heterocyclic Compounds. J. C. S. Chem. Comm. 1973, 32–33.
0. Kutney, J. P.; Greenhouse, R., The Protection and Deprotection of the Pyridine
Nitrogen. Synt. Comm. 1975, 5, 119–124.
6
28
ACS Paragon Plus Environment