C6-Selective Direct Arylation of 2-Phenylpyridine via an Activated N-methylpyridinium Salt: A Combined Experimental and Theoretical Study

Article abstract of DOI:10.1002/adsc.201800666

An elegant pre-activation strategy, based on the formation of N-methylpyridinium iodide salts for C₆-selective direct arylation of 2-phenylpyridines using Pd/Cu cooperative catalysis, has been developed. By this methodology, a wide range of unsymmetrical 2, 6-diarylpyridines were synthesized with high reactivity and regioselectivity as well as good functional group tolerance. In particular, challenging substrates bearing electron donating groups (EDGs), such as OMe, NMe₂, were also successfully employed in this reaction. Deuterium incorporation studies revealed that the C?H bond acidity is improved significantly in N-methylpyridinium salts compared with their N-Oxide and N-iminopyridinium ylide counterparts, thus solving the long-standing problem associated with previous strategies for the synthesis of diaryl pyridines. Finally, the control experiments and DFT calculations supported a Pd-catalyzed and Cu-mediated mechanism in which a carbenoid copper species that is formed in-situ from N-methylpyridinium salts, participates in a Pd-catalyzed arylation followed by an iodide-promoted N-demethylation process. (Figure presented.).

Full text of DOI:10.1002/adsc.201800666

Title: C6-Selective Direct Arylation of 2-Phenylpyridine via an Activated
N-methylpyridinium Salt: A Combined Experimental and
Theoretical Study
Authors: Changzhen Yin, Kangbao Zhong, Wengjing Li, Xiao Yang,
Rui Sun, Chunchun Zhang, Xueli Zheng, Maolin Yuan,
Ruixiang Li, Yu Lan, Haiyan Fu, and hua chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800666
Link to VoR: http://dx.doi.org/10.1002/adsc.201800666

10.1002/adsc.201800666
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
C6-Selective Direct Arylation of 2-Phenylpyridine via an
Activated N-methylpyridinium Salt: A Combined Experimental
and Theoretical Study
Changzhen Yin,a Kangbao Zhong,b Wenjing Li,a Xiao Yang,a Rui Sun,a Chunchun
Zhang,c Xueli Zheng,a Maolin Yuan,a Ruixiang Li,a Yu Lan,*b Haiyan Fu,*a and Hua
Chen*a
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education College of Chemistry, Sichuan University
Chengdu 610064, P. R. China
E-mail: scufhy@scu.edu.cn; scuhchen@163.com
School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
b
E-mail: lanyu@cqu.edu.cn
Analytical and Testing Center, Sichuan University, Chengdu 610064, P. R. China
c
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An elegant pre-activation strategy, based on the improved significantly in N-methylpyridinium salts
formation of N-methylpyridinium iodide salts for C6- compared with their N-Oxide and N-iminopyridinium ylide
selective direct arylation of 2-phenylpyridines using Pd/Cu counterparts, thus solving the long-standing problem
cooperative catalysis, has been developed. By this associated with previous strategies for the synthesis of
methodology, a wide range of unsymmetrical 2, 6- diaryl pyridines. Finally, the control experiments and DFT
diarylpyridines were synthesized with high reactivity and calculations supported a Pd-catalyzed and Cu-mediated
regioselectivity as well as good functional group tolerance. mechanism in which a carbenoid copper species that is
In particular, challenging substrates bearing electron formed in-situ from N-methylpyridinium salts, participates
donating groups (EDGs), such as OMe, NMe2, were also in a Pd-catalyzed arylation followed by an iodide-promoted
successfully employed in this reaction. Deuterium N-demethylation process.
incorporation studies revealed that the C-H bond acidity is
Keywords: N-methylpyridinium; C-H arylation; Palladium;
Copper; DFT
Introduction
Copper is among the first transitional metals utilized
in promoting aryl-aryl bond formations, in which an
intermediary aryl copper species is involved as a
cross-coupling partner.[1] While 2-pyridyl copper is
notoriously unstable, it has been demonstrated as an
important intermediate in many successful 2-
arylpyridine synthetic systems. [2]
Conventionally, the generation of 2-pyridyl copper
required the presence of functionality, such as X,
B(OH)2 or COOH, at the C2 position of the
pyridines.[3] Due to the relatively lower acidity of the
C2-H bond, the formation of 2-pyridyl copper through
direct cleavage of the pyridine C-H bond with Cu
remains challenging.[4] While several Cu-catalyzed
pyridine direct C-H arylations have been successfully
realized based on pyridine N-oxide and N-
Scheme 1. Strategies for Synthesis of 2, 6-diaryl pyridines
from 2-arylpyridines via C-H arylation.
iminopyridinium ylides,[5] the limitation of these
methodologies are apparent: Firstly, the substrates
1
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10.1002/adsc.201800666
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.a)
bearing electron donating groups (EDGs) make
pyridine deprotonation unfavorable and show
extremely low activation reactivity.[6] Secondly, most
of these strategies require additional individual steps
to remove the activating groups from the target
products, though some examples wherein the auto-
deoxygenation occurs after C-H arylation of pyridine
N-oxides have been reported (Scheme 1).[7]
Pyridines can be easily transformed into N-
methylpyridinium salts by methylation at the N atom.
The Brönsted acidity of the adjacent pyridyl C-H
bonds increases significantly and even stronger than
Entry Ligand Additive Concentration
(M)
Yield
(%)
1b)
2c)
3
4
5
PPh3
PPh3
PPh3
-
-
-
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
0.125
0.125
0.125
0.25
0.5
1
trace
N.R.
50
59
59
73
75
79
its
N-Oxide
and
N-iminopyridinium ylide
counterparts.[8] Therefore, it would be quite appealing
to explore C-H activation properties of the N-
methylpyridinium salts. However, the instability of
the N-methyl pyridinium salts arising from the N-
demethylation[9] would preclude the activation of C-H
bond. We envision that a pyridinium-derived copper
complex can be readily achieved by deprotonation of
corresponding pyridinium salts in the presence of a
copper source, which then resonates to the carbenoid
copper species—2-pyridylene copper complex
(Scheme 1). It would happen to avoid the instability
of pyridinium salts and smoothly participate in the
following transitional-metal catalyzed reaction giving
the C2 position functionalized pyridinium salts.
Importantly, these salts are prone to undergo N-
demethylation automatically due to increased steric
repulsion. Accordingly, the employment of N-
methylpyridinium salts as an activator strategy, in
combination with a copper salt or oxide, would
provide a platform with unforeseen opportunities for
6
7
PPh3
1
8
AsPh3 Cu2O
1
9
10
11
TFP
TFP
TFP
TFP
Cu2O
CuO
CuCl
Ag2O
1
1
1
1
83(84)d)
trace
80
12
42
a)
Reaction condition: 1a (0.5 mmol, 1.0 equiv), 2a (1.0
mmol, 2.0 equiv), PdCl2 (5 mol %), ligand (10 mol %),
PivOK (1.0 mmol, 2 equiv), DMAc (0.125 M) at 150 °C
for 16 h under N2. Isolated yield determined. b) 1-Bromo-4-
c)
methylbenzene was used. 4-methylphenyl tosylate was
d)
used, N.R. = No reaction.
DMAc N,
triphenylphosphine, TFP = tri-2-furylphosphine.
Pd(PhCN)2Cl2 was used;
=
N-dimethylacetamide,
PPh3 =
base, PdCl2 (5 mol %) and PPh3 (10 mol %) as the
catalyst, and Cu2O (0.5 equiv) as additive, in N, N-
dimethylacetamide (0.125 M) at 150 °C under a
nitrogen atmosphere for 16 h. However, only a trace
amount of the desired C6-H arylation product 3aa
was detected. After a brief survey of various aryl
reagents, we found that 4-tolyl iodide is the most
efficient and gave the product in 50% yield. To our
delight, the yield could be increased significantly to
75% upon increasing the pyridinium salt
concentration to 1 M. The replacement of PPh3 and
PdCl2 with tri-2-furylphosphine (TFP)[15] and
Pd(PhCN)2Cl2 further improved the yield to 84%.
Other additives, Such as CuO and Ag2O, were
inferior to Cu2O. No product was observed in the
absence of either PdCl2 or Cu2O (Tables S1 and S2).
It should be noted that the iodide anion of the
pyridinium salts plays an important role on the
reaction efficiency and switching I- to other counter
ions led to the lower yields (Tables S3).
Having established the optimized reaction
conditions, we next investigated the scope and
limitations of this new 2, 6-diaryl pyridine synthesis.
First, the scope of the (hetero) aryl iodides was tested
and the results are summarized in Table 2. The
system turned out to be applicable to a wide range of
aryl iodides. The aryl iodides, irrespective of being
electron rich, neutral or poor, underwent the reaction
to afford the corresponding arylation products in
good to excellent yields (3aa-3fe), in addition, the
electron-deficient aryl bromides could also be viable
transitional-metal
catalyzed
pyridine
C-H
functionalization. Surprisingly, however, this field
has not been well developed.[10]
Unsymmetrical 2, 6-diaryl pyridines are very
important structural motifs and are found in many
biologically active compounds.[11] Their synthesis
commonly relies on
a
lengthy and tedious
construction of the pyridine ring.[12] Upon employing
direct C-H arylation strategies, 2-arylpyridines would
be good candidate substrates for the synthesis of
unsymmetrical 2, 6-diarylpyridines. Yet the innate
electron deficient nature of the pyridine ring leads to
low reactivity.[13] Moreover, the pyridyl group, acting
as a strong directing group, tends to preferentially
guide the arylation to the ortho position of the phenyl
ring,[14] To address this limitation, herein, we report
the N-methylpyridinium salts as a new pre-activation
strategy for C6-selective arylation of 2-
phenylpyridine. It provides
a
new synthetic
methodology for the preparation of unsymmetrical 2,
6-diaryl pyridines with high regioselectivity and good
functional group tolerance.
Results and Discussion
We initiated our investigation by coupling N-methyl-
2-phenylpyridinium iodide 1a with 4-tolyl bromide
(2.0 equiv) using potassium pivalate (2.0 equiv) as
2
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10.1002/adsc.201800666
Advanced Synthesis & Catalysis
Table 2. Scope of aryl Iodides.a)
thiophenyl iodides (3ay, 3az). Finally, the order of
the arylation appears to influence the yields to some
extent (3cd versus 3dc; 3ef versus 3fe). The reaction
was also carried out on a gram scale without a
noticeable decrease in product yield (3aa),
highlighting the potential application of this
methodology.
Table
3.
Scope
of
substituted
N-methyl-2-
phenylpyridinium iodide. a)
a)
Standard reaction conditions as in Table 1, entry 9.
Isolated yields are shown. b) isolated yield for a gram-scale
reaction. aryl bromides were used. d) reaction was run at
c)
100 °C.
as an arylating reagent in the present system, they
exhibited similar reactivity as their iodinated
counterparts (3ag, 3ai, and 3aj). Generally, the
electron neutral aryl iodides gave higher yields than
the electron-rich or electron-poor substrates. For
example, 4-chloro-2-methoxy phenyl iodide afforded
the product 3at in 89% yield, much higher than either
2-methoxyl or 4-chloro phenyl iodide (3af, 75% and
3an, 69%, respectively). This may be due to its
relatively electron-neutral property, counterbalanced
a)
Standard reaction conditions as in Table 1, entry 9.
b)
c)
Isolated yields are shown. Reaction run for 48 h. 5-
Fluoro-1-methyl-2-phenylpyridin-1-ium iodide was used. d)
1-methylpyridin-1-ium iodide was used, 2 (1.5 mmol),
Cu2O (0.375 mmol), PivOK (1.25 mmol).
iodophenoxy)methyl)-1-methyl-2-phenylpyridin-1-ium
iodide was used; n.d. = not detected.
e)
5-((2-
by the electron-donating (ortho-MeO) and
–
withdrawing (para-Cl) groups. Likewise, the meta-
MeO-phenyliodide substrate gave a higher yield of
product than its ortho- or para- counterpart, due to
both the mesomeric and inductive effect being
weaker at the meta position (81% for 3ak, versus
69% and 73% for 3an and 3ac, respectively). The
steric hindrance also had some influence on the
reaction rate and the bis-ortho-substitution
completely inhibited the reaction (3ar and 3as).
Importantly, the aryl iodides show good compatibility
with various functional groups. Although a substrate
bearing an ester group only led to a low yield of the
corresponding product due to partial hydrolysis (3aq),
the yield could be improved significantly to 65% just
by lowering the temperature to 100 °C. We reasoned
that the relatively low temperature retards the
hydrolysis of the ester group. The reaction was also
compatible with some heteroaryl compounds, such as
Next, the substrate scope in terms of the N-methyl-
2-phenylpyridinium iodide was further explored by
using 4-tolyl iodide as the coupling partner. We
observed that the reaction outcome was dependent on
the substitution pattern and the electronic nature of
the pyridinium salts, and was particularly sensitive
towards the electronic properties of the pyridine ring.
Electron-rich substituents, such as alkyl, aryl, alkoxyl
and amido groups led to the expected products in
29% to 93% isolated yields (Table 3, 5aa-5da, 5ga-
5ja). Steric hindrance was responsible for the
relatively lower yields for 5ba (74%) and 5ea (29%)
in comparison with 5aa (93%) and 5da (92%),
respectively. Especially noteworthy are the excellent
yields obtained with pyridines containing very strong
3
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10.1002/adsc.201800666
Advanced Synthesis & Catalysis
electron-donating –NR2 groups at the para position
(5ha-5ja), which are difficult to be arylated using the
pyridine N-oxide strategy,[16] although a longer
reaction time was required to achieve high yields.
The sluggish reaction rate may be attributed to both
the relatively weak Brönsted acidity of the C-H bonds
and the low demethylation reactivity of the
corresponding N-methyl diarylpyridinium salts.[17]
The substitution pattern was also an influential factor
in this reaction. For example, differing from the 3-
methoxylpyridinium salt 4g, the use of 4-
methoxylpyridinium iodide 4f tended to result in a
nucleophilic substitution reaction with water to form
unlikely to be the rate-limiting step. When 1a-d1 was
treated with PivOK in DMAc at 100°C for 0.5 h, a
significant amount of protonated product 1a was
detected in 14% NMR yield (Figure S10), revealing
that the cleavage of the C-H bond is reversible, thus
clarifying the reason as to why the C-H cleavage is
not the rate-determining step. The proton source most
likely originates from the trace amount of water in
DMAc.
a
4-pyridinone compound (5fa).
A
similar
phenomenon was also observed for 4-fluoro-
substituted pyridines.[18] In contrast, the reaction of
the 5-fluoro-substituted 1-methy-2-phenylpyridinium
iodide could successfully provide three C-H arylation
compounds (5ka, 7%, 5la, 20%, and 5ma 37%)
under the standard conditions. However, pyridinium
substrates bearing strong electron-withdrawing
substituents failed to give any of the desired products
(5oa-5pa) and instead resulted in a complicated
mixture, possibly due to the decomposition of such
compounds via a nucleophilic attack pathway.[19] Of
note, when N-methylpyridinium salt was used as the
substrate, the corresponding product 2, 6-di-p-
tolylpyridine was isolated with even higher
selectivity and yield compared with our previous
work.[20] Unfortunately, an attempt to realize
intramolecular coupling was unsuccessful, probably
because of the difficult transmetallation arising from
the sterically crowded environment around in the
transition state [21] (Table 3).
Scheme 3. Proposed three possible pathways.
To further probe the exact role of palladium and
Cu2O in the reaction, and which species coordinates
with the pyridinium salt, we have proposed three
possible pathways (Scheme 3, pathway 1, 2, or 3)
according to literature precedent. In pathway 1, the
pyridinium salt coordinates to palladium(II) through a
base assisted concerted metallation–deprotonation
(CMD) process, affording intermediate (I), which
then undergoes oxidative addition with PhI to form 2-
pyridylidene-Pd(IV) species (II).[23] From this, the
arylated N-methyl pyridinium salt is generated via
reductive elimination steps. The possible role of
Cu2O is to aid in removing the iodide ligands from
the Pd center. Likewise, in pathway 2, pyridinium
salts also complex with Pd(II), but in this case, the
Pd(II) species is generated from the oxidative
addition of ArI to the in-situ formed Pd(0). Thus,
arylated pyridinium salt is released from the Pd(II)
instead of the Pd(IV) center. Similarly, the Cu2O also
assists in the removal of the iodide. In pathway 3,
however, Cu2O plays quite a different role and
instead reacts first with the 2-phenyl-N-methyl-
pyridinium salt in the presence of base to yield a 2-
pyridyl Cu(I) complex (IV), which in turn
transmetalate with ArPdILn to give 2-pyridylidene-
Pd(II) species(V), upon which the 2, 6-diaryl N-
methylpyridinium salt is produced via a reductive
elimination step. This pathway is widely accepted in
bimetallic Pd/Cu systems.[24] Finally, the N-
demethylation of the 2, 6-diaryl N-methylpyridinium
salt gives the desired 2, 6-diarylpyridine.
To gain insights into the reaction mechanism,
deuterium labeling experiments were carried out by
treating 1a with various metal oxides, salts and bases
in a solvent mixture of DMAc/D2O (1:1) at 150 °C
for 1 h under N2 (Table S4). When 1a was treated
with PivOK, the deuterium incorporate selectively at
C6 position in almost quantitative yield, whereas no
H/D
exchange
with
N-oxides
and
N-
iminopyridiniumylides[22] under the identical
conditions (Figure S7 and S8 ), revealing that the N-
methylpyridinium salt pre-activation strategy
decreases the pKa of the C-H bonds more
significantly than the other two strategies.
Scheme 2. Kinetic experiments.
Next, two competing reactions between 1a and 1a-
d4 were conducted in a parallel or intermolecular
manner, respectively, as shown in (Scheme 2). Both
the observed kinetic isotopic effects (KIE) of 1.32
and 1.22 indicate that the C-H bond cleavage is
To determine which pathway was likely operative,
we synthesized two important related intermediates:
4
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10.1002/adsc.201800666
Advanced Synthesis & Catalysis
A
2-pyridyl Palladium complex 4rA[25] and
methylpyridinium salt through a concerted metalation
deprotonation (CMD) process via a six-center
transition state TS-7,[29] with a free energy barrier of
31.3 kcal/mol to yield carbenoid copper intermediate
8, reversibly, the presence of which was detected by
the mass spectrometry in our previous work.[20b]
Alternatively, the intermediate 8 could also be
generated by a PivOK-promoted deprotonation
process followed by a transmetalation from K to
Cu[5b]. But such a deprotonation-transmetallation
process can be ruled out since the free energy is as
high as 35.2 kcal/mol (Figures S 16).
Pd(PPh3)2(I)(p-tolyl) 2A, and conducted several
experiments (Scheme 4). Firstly, the reaction
between 4rA and 2a was carried out under the
standard conditions with and without Cu2O. Only 2%
of the diarylation product (5ra) was detected in the
absence of Cu2O, along with 44% of the
monoarylation product 2-(p-tolyl)pyridine (5rA). In
sharp contrast, in the presence of Cu2O, around 30%
of the diarylation product was isolated, without any
of 5rA being detected. The comparison of these data
clearly indicated that although monoarylation could
occur on the 2-pyridylidene palladium intermediate
via Pd(II)/Pd(IV) catalysis, the second C-H arylation
was difficult to achieve without Cu2O, proving it be
essential for this step. Thus, the Cu2O is believed to
not only assist in removal of the halide but also
enables the monoarylated N-methyl pyridinium salt to
partake in the second C-H arylation cycle.
Nevertheless, the overall yield for pathway 1 was still
much lower than that obtained under the standard
conditions. Thus, pathway 1 does not completely
account for the outcome of this reaction.
Figure 1. Calculated energy profiles of the copper cycle.
The bond lengths in the geometries are given in angstroms.
Scheme 4. Control experiments.
In pathway 2, N-methylpyridinium iodide (4r) was
reacted with 1.0 equiv 2A and only a trace amount of
5rA was obtained, with no 5ra being observed in the
absence of Cu2O; however, when Cu2O was added,
5rA and 5ra were isolated in 53% and 24% yield,
respectively. Cu2O proved to be a prerequisite as well
in this pathway.
Based on the above experimental observations, we
believed the pathway 3 is most likely the operative
mechanism for the reaction, although the control
experimental results for which are lacking, due to our
failure in obtaining the synthetically challenging 2-
pyridylene copper.[26]
In order to gain a better understanding of the
mechanism, density functional theory calculations,
M11-L[27] with a standard 6-311+G (d,p) basis set
(SDD basis set for Pd, Cu, and I) were employed to
investigate the mechanism of the N-methylpyridinium
salt arylation process. For pathway 3, the energy
profile can be divided into three sections: the copper-
cycle, the palladium-cycle and the iodine-cycle. For
copper-cycle (Figure 1),
a
Cu(I)-ate-complex
bis(pivaloyloxy)copper 6, known as a good C-H bond
cleavage species,[28] is set to the relative zero point. It
cleaves the adjacent pyridyl C-H bond of the N-
Figure 2. Calculated energy profiles of the palladium cycle.
The bond lengths in the geometries are given in angstroms.
5
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10.1002/adsc.201800666
Advanced Synthesis & Catalysis
The free energy profiles of the palladium-catalyzed
energy barrier (31.3 kcal/mol). Therefore, pathway 3
is kinetically favorable and most likely the operative
mechanism, which is consistent with conclusion of
the control experimental results.
cycle are shown in Figure 2. Bis-phosphine-
coordinated Pd(0) species 9 is chosen as the relative
zero point in this free energy profile. The oxidative
addition with iodobenzene takes place via transition
state TS-10 with a free energy barrier of only 13.5
kcal/mol to form Pd(II) intermediate 11. The
transmetallation of 11 with carbenoid copper species
8 takes place via transition state TS-12 with a barrier
of 13.9 kcal/mol, which affords pyridylpalladium
intermediate 13. The reductive elimination of
Conclusion
A new pre-activation strategy based on the formation
of N-methylpyridinium salts for the selective C6-H
arylation of 2-phenylpyridines has been developed.
This strategy has two main advantages: Firstly, the C-
H bond acidity of the pyridinium salt is much higher
than that in the corresponding N-oxides or N-
iminopyridinium ylides, thus C-H activation
reactivity is enhanced and beneficial for substrates
bearing EDGs. Second, the N-methyl group readily
departs due to the increasing steric repulsion after the
C-H arylation reaction, thus obviating an additional
step to remove the N-methyl group. This protocol
provides a rapid and practical access to a wide range
of unsymmetrical 2, 6-diarylpyridines with high
reactivity and regioselectivity as well as good
functional group tolerance. With the help of a
combination of experimental and theoretical methods,
the reaction mechanism has been explored. DFT
calculations show that the total process of the
arylation can be divided into three sections: ate-
complex bis(pivaloyloxy)copper-mediated C-H bond
intermediate
13 releases
2, 6-diaryl
N-
methylpyridinium 15 with a free energy barrier of
10.5 kcal/mol, which regenerates the active Pd(0)
species 9. The generated 2, 6-diaryl N-
methylpyridinium salt 15 could then demethylate in
the presence of iodide. As shown in Figure 3, an SN2
substitution of N-methylpyridinium salt 15 occurs
through transition state TS-17 to generate pyridine
product 3aa and iodomethane 18 with a free energy
barrier of 31.3 kcal/mol. Subsequently, another SN2
nucleophilic substitution with pivalate takes place via
transition state TS-19 to release the iodide ion and
generate the methyl pivalate. Indeed, the presence of
the methyl pivalate was determined by gas
chromatography.
cleavage
affording
a
carbenoid
copper,
transmetallation of carbenoid copper with aryliodide-
palladium following by C-C bond reductive
elimination, and final demethylation under the
assistance of iodide generating 2, 6-diarylpyridines.
On the basis our results, N-methylpyridinium salts
can be used as activators for new, scalable and
effective strategies for the functionalization of
pyridine.
Experimental Section
Figure 3. Calculated energy profiles of the iodine cycle for
2, 6-diaryl N-methylpyridinium salt. The bond lengths in
the geometries are given in angstroms.
General Procedure for the Preparation of N-
methylpyridinium salts
To a solution of appropriate arylpyridine (15.0 mmol, 1.0
equiv) in acetonitrile (5 mL, 3 M) was added CH3I (8.52 g,
60.0 mmol, 4.0 equiv) under argon in a two-necked flask.
The mixture was heated at 90°C for 16 h, and then cooled
to room temperature. After removal of the solvent under
reduced pressure to afford the crude product, which was
purified by recrystallization in CH3CN/EtOAc.
For comparison, the pathways 1 and 2 were also
considered in this study, and the calculated results are
summarized (Figures S14 and S15). Both of the
highest energies in pathways 1[30] and 2 are higher
than the overall activation free energy of the
demethylation of the 2-phenyl N-methylpyridinium
salt, which was determined to be 33.5 kcal/mol.
General procedures for the Synthesis unsymmetrical 2,
6-diaryl pyridines
These
energetic
discrepancies
reveal
that
An oven-dried 25 mL Schlenk tube equipped with
magnetic stirring bar were charged with aryl iodide (1.0
mmol), appropriate N-methylpyridinium salt (0.5 mmol),
and Pd(PhCN)2Cl2 (9.6 mg, 0.025 mmol, 5 mol %), TFP
(11.6 mg, 0.05 mmol, 10 mol %), PivOK (140.0 mg, 1.0
mmol, 2 equiv), Cu2O (36.0 mg, 0.25 mmol, 0.5 equiv).
The tube was sealed and the mixture was charged with
nitrogen gas three times, then dry DMAc (0.5 mL, 1 M)
was added to the sealed reaction vessel by syringe. The
resulting solution was stirred at 150 °C for 16 h. After
cooling to room temperature, the mixture was diluted with
demethylation of the 2-phenyl N-methylpyridinium
salt would likely take place preferentially, thus the N-
demethylation becomes an annoying competitive side
reaction. Therefore, the pathways 1 and 2 can be
ruled out because the stability of the pyridinium salts
cannot be guaranteed. By contrast, in pathway 3 the
N-methylpyridinium salt could be easily transformed
into the carbenoid copper species with a lower free
6
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10.1002/adsc.201800666
Advanced Synthesis & Catalysis
ethyl acetate and filtered through a short pad of celite, the
volatiles were removed under vacuum and the residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate) to give the pure products.
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General Procedure for Deuterium incorporation
studies
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An oven-dried 25 mL Schlenk tube equipped with
magnetic stirring bar was charged with appropriate starting
material (0.25 mmol), and PivOK (70.0 mg, 0.5 mmol, 2.0
equiv), The tube was sealed and the mixture was charged
with nitrogen gas three times, then DMAc (0.25 mL) and
D2O (0.25 mL) was added to the sealed reaction vessel by
syringe. The resulting solution was stirred at 150 °C for 16
h. After cooling to room temperature, the mixture was
diluted with CH3CN and filtered through a short pad of
celite, the volatiles were removed under vacuum and crude
product was analyzed by 1H NMR.
Computational Methods
All of the DFT calculations conducted in this study were
carried out using the GAUSSIAN 09 series of programs.
DFT method B3-LYP8 with a standard 6-31G(d) basis set
(SDD basis set for Pd, Cu and I) was used for the geometry
optimizations. The M11-L functional, proposed by Truhlar
et al., was used with a 6-311+G(d,p) basis set (SDD basis
set for Pd, Cu and I) to calculate the single point energies.
The solvent effects were taken into consideration using
single point calculations based on the gas-phase stationary
points with a SMD continuum solvation model.9 The
energies presented in this paper are the M11-L calculated
Gibbs free energies in toluene solvent with B3-LYP
calculated thermodynamic corrections.
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Acknowledgements
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Chem. Soc. 1989, 111, 2896-2900. b) J. S. Owen, J. A.
Labinger, J. E. Bercaw, J. Am. Chem. Soc. 2004, 126,
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We thank the National Natural Science Foundation of China (No.
21572137) and the Key Program of Sichuan Science and
Technology Project (No. 2018GZ0312) for their financial support.
We are grateful to the Comprehensive Training Platform of
Specialized Laboratory, College of Chemistry, Sichuan
University. We also thank the Centre of Testing & Analysis,
Sichuan University, for NMR measurements.
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