Direct C-H Functionalization of Pyridine via a Transient Activator Strategy: Synthesis of 2,6-Diarylpyridines

Article abstract of DOI:10.1021/acs.orglett.7b00498

A Pd-catalyzed highly selective direct diarylation of pyridines has been developed using a transient activator strategy. Both (MeO)₂SO₂ and Cu₂O are required for this transformation. The in situ generated N-methylpyridinium salt can be arylated at both 2- and 6-positions under the cooperative Pd/Cu catalysis. A subsequent N-demethylation then gives the 2,6-diarylpyridines. This protocol provides a novel synthetic route for the symmetric 2,6-diarylpyridines.

Full text of DOI:10.1021/acs.orglett.7b00498

Letter
pubs.acs.org/OrgLett
Direct C−H Functionalization of Pyridine via a Transient Activator
Strategy: Synthesis of 2,6-Diarylpyridines
Yang Zeng,† Chunchun Zhang,‡ Changzhen Yin,† Maoshen Sun,† Haiyan Fu,*,† Xueli Zheng,†
Maolin Yuan,† Ruixiang Li,† and Hua Chen*,†
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
‡Analytical and Testing Center, Sichuan University, Chengdu 610064, P. R. China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed highly selective direct diarylation of pyridines has been developed using a transient activator
strategy. Both (MeO)2SO2 and Cu2O are required for this transformation. The in situ generated N-methylpyridinium salt can be
arylated at both 2- and 6-positions under the cooperative Pd/Cu catalysis. A subsequent N-demethylation then gives the 2,6-
diarylpyridines. This protocol provides a novel synthetic route for the symmetric 2,6-diarylpyridines.
strategies have a major limitation in that an additional step is
required for installation and removal of the activating group.
Therefore, the direct C−H arylation of a stoichiometric amount
of unmasked pyridine without using a preactivation strategy is
especially appealing. Additionally, symmetric 2,6-diarylpyridines
are very important structural motifs and are found in many
biologically active compounds and functional materials;7
however, a highly selective synthesis of 2,6-diarylpyridines via a
double C−H functionalization remains, to the best of our
knowledge, undocumented.
Recently, traceless or transient directing group strategies have
attracted much attention.8 Such approaches allow for sequential
installationofthedirectinggroup, C−Hbondfunctionalizationof
the substrate, and removal of the directing group in one reaction.
These protocols not only avoid additional steps to remove the
undesired directing group but also offer unique positional
selectivity. Inspired by these strategies, a transient activator
strategy has been proposed to activate the unmasked pyridine
substrates. In this strategy, the pyridine would be activated by in
situ formation of the N-alkylpyridinium salt in the presence of an
alkylating reagent, which may facilitate C−H arylation at both the
C-2 and C-6 positions of pyridine. Subsequent dealkylation of the
resulting pyridinium salt would give the 2,6-diarylpyridines. In
2009, Hu reported a direct Pd-catalyzed ortho-arylation of
pyridinebyusingapre-alkylatedpyridine(N-phenacylpyridinium
he transition-metal-catalyzed direct C−H arylation of
Tpyridine is of great interest to the chemical community
due to the presence of arylpyridines in natural products,
pharmaceuticalagents, andotherorganicmaterials.1 Thepyridine
ring suffers from low reactivity due to its electronically deficient
nature and strong Lewis basicity; thus, direct pyridine C−H
functionalization is particularly challenging.2 Although significant
progress has been made in the development of methodologies for
direct arylation on the pyridine ring,3 a large excess of pyridine is
often required.4 A pyridine preactivation strategy has been widely
applied in pyridine arylation reactions. Pioneering work in this
field has been reported by Fagnou, Hiyama, Hartwig, Charette,
and other groups, who have demonstrated a selective direct ortho-
monoarylation of pyridine using N-oxides5 or N-imino-
pyridiniumylides6 (Scheme 1). However, these preactivation
Scheme 1. Activation Strategies for Pyridine Arylation
Received: February 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00498
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Letter
a
Table 1. Identification of the Transient Activator
entry
alkylating reagent
copper source
solvent
yield (%) 3a+4a
ratio 4a/3a
1
MeI
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuCl
CuCl2
CuSO4
CuO
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
trace
11
−
−
−
−
10:1
6:1
1:1
2:1
3:1
−
2:1
8:1
−
2
p-MeC6H4SO3Me
BnBr
3
6.4
trace
46
4
PhCOCH2Br
(MeO)2SO2
(MeO)2SO2
(MeO)2SO2
(MeO)2SO2
(MeO)2SO2
none
5
6
43
7
36
8
15
9
38
10
11
12
13
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
NR
43
(MeO)2SO2
(MeO)2SO2
(MeO)2SO2
(MeO)2SO2
Diglyme
NMP
44
8
b
14
DMAc
62
8:1
a
Reaction conditions: 1a (0.75 mmol), 2a (0.5 mmol), PdCl2 (5 mol %), PPh3 (10 mol %), K2CO3 (2.0 equiv), copper source (0.75 equiv),
alkylating reagent (0.8 equiv), solvent (2.5 mL), 4 Å MS (100 mg), 120 °C, 24 h, nitrogen atmosphere. Yield was determined by 1H NMR analysis of
a crude product with CH2Br2 as an internal standard. Reaction run at 150 °C.
b
bromide) as a substrate; however, the di-/monoarylation
selectivity could not be controlled9 (Scheme 1). We anticipated
that a proper alkylating reagent could be adopted as a transient
activator, which can be installed and removed in situ, as well as
serve as a directing group to control the selectivity. Herein, we
report that a combination of the N-alkylating reagent dimethyl
sulfate (MeO)2SO2 with Cu2O allows for the activation of both
the C2−H and C6−H bonds of pyridine for a highly selective
diarylation in the presence of a Pd(II) catalyst (Scheme 1).
Our initial studies began by testing different alkylating reagents
usingthe following reaction conditions: pyridine 1a(0.75 mmol),
1-bromo-4-methylbenzene 2a (0.5 mmol), PdCl2 (5.0 mol %),
PPh3 (10 mol %), and K2CO3 (2.0 equiv) in N,N-
dimethylacetamide (DMAc) at 120 °C under a nitrogen
atmosphere. Unfortunately, commonly used alkylating reagents
such as MeI, (MeO)2SO2, p-MeC6H4SO3Me, BnBr, and
PhCOCH2Br were all inefficient, and no desired diarylation
product was detected (see the Supporting Information (SI) Table
1). However, the diarylation was able to proceed in the presence
of both an alkylating reagent and a copper source (Table 1, entries
1−5 and SI Table 1). The optimal combination was found to be
Cu2O and (MeO)2SO2, wherein the arylation products could be
obtained in46%yield witha di/mono ratio of 10:1 (Table 1, entry
5). Cu(II) sources including CuCl2, CuSO4, and CuO gave lower
yields, with poor di/mono selectivity ranging from 1:1 to 3:1
(Table 1, entries 7−9). CuCl was found to be as active as Cu2O,
affordingthearylation product incomparable yieldbutwith lower
selectivity (Table 1, entry 6). No product was produced in the
absence of either Cu2O or (MeO)2SO2 (Table 1, entry 10, and SI
Table 1, entry 5). It appears that some cooperative effect exists
betweentheCuspeciesand(MeO)2SO2,10 whichisimportantfor
the double C−H arylation process.
However, altering other reaction parameters at this stage failed to
further improve the yield (see SI Tables 1 and 2). Although the
diarylation of pyridine provided only a moderate yield of the
desired product, it still represents remarkable progress, since it
avoids the use of a large excess of pyridine.
With the optimal reaction conditions in hand, we subsequently
examined the substrate scope and the limitations of the reaction
by employing a variety of pyridines and aryl halides as coupling
partners (Schemes 2 and 3). Various aryl bromides could couple
with pyridine (Scheme 2), giving the corresponding diarylation
product 4a−h in synthetically useful yields with high di/mono
selectivity. Of note is that 2,4- or 2,5-dimethylbromobenzene
could also be coupled with pyridine to give 4d and 4f in 42% and
38% yields, respectively, regardless of the steric hindrance. It
Scheme 2. Scope of the Arylation of Pyridine with
a
Bromoarenes
Solvent screening showed that N,N-dimethylformamide
(DMF), Diglyme, and DMAc afforded the arylation product in
comparable yield, while the highest diselectivity was obtained in
DMAc (Table 1, entries 5, 11−13). Elevation of the temperature
to150°Cincreasedtheyieldmarkedlyto62%(Table1,entry14).
a
Reaction conditions: (MeO)2SO2 (0.8 equiv), Cu2O (0.75 equiv),
150 °C; the others are the same as those described in Table 1; isolated
b
yields reported as the average of two experiments. Only trace amount
c
of monoarylation product was detected. 1 (0.5 mmol), 2 (1.5 mmol);
the other conditions are the same as those described in Table 1
B
DOI: 10.1021/acs.orglett.7b00498
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Letter
potential handle for further transformations. Furthermore, the
reaction could be easily scaled up: 4-tert-butylpyridine reacted
with 4-tert-butylbromobenzene smoothly by 32-fold to give
product 5i in 60% isolated yield. In the case of 4-dimethylamino-
pyridine, which contains the strong electron-donating group
−NMe2 at the 4-position, a longer reaction time was required to
achieve comparable yields. This might be attributed in part to the
relatively low demethylation reactivity of the corresponding N-
methyl diarylpyridinium salt.11 Significantly, the unsymmetrically
substituted pyridine, 3-phenylpyridine with a congested 2-
position, also afforded its corresponding diarylation product 5x
with high selectivity, albeit in only 34% isolated yield.
Scheme 3. Scope of the Arylation of Substituted Pyridine with
Bromoarenes
a
This high-level site-selective C−H arylation method would
greatly improve its applicability in the late stages of synthesis of
biologically active compounds. For example, by employing our
methodology, a neurotrophic factor 5z could be synthesized from
1y in only two steps with a 48% overall isolated yield (Scheme 4),
demonstrating the efficiency of this approach.
Scheme 4. Synthesis of Neurotrophic Factor
An intermolecular competition experiment was conducted
using 4-tert-butylpyridine with anequimolar ratio of4-methyl and
4-fluorobromobenzene (Scheme 5). An unsymmetric diary-
Scheme 5. Intermolecular Competition Studies
a
Reaction conditions: 1 (0.125 mmol), 2 (0.375 mmol), PdCl2 (10
lpyridine 5kn was formed with a much higher 1H NMR yield than
both the symmetrical diarylpyridines 5k and 5n (31% versus 15%
and 18%, respectively). Almost no monoarylation product was
detected. This provides a potential opportunity for the synthesis
of unsymmetrical diarylpyridines using a one-pot process. We
reasoned that, in the presence of transient activator (MeO)2SO2,
the pyridine reactivity was significantly enhanced via in situ
formation of a N-methylpyridinium salt. The arylation process
was so fast that once the monoarylation product of N-
methylpyridinium salt was generated, the second arylation
occurred to give the diarylated pyridinium compound, which
was more prone to undergo the N-demethylation to give a final
product. It was reported that N-methyl-pyridinium salt could be
demethylated by heating in amide solvent under reflux.11
Thereby, the strategy features high reactivity and exquisite di/
mono selectivity. The existence of both the mono- and diarylated
pyridinium compounds was evidenced by HRMS analysis of the
crude reaction mixture at the initial stage of the reaction (see SI
Figure 2). Indeed, the reaction of the prepared N-methyl 4-tert-
butylpyridinium methyl sulfate with 1-bromo-4-methylbenzene
couldfurnishtheexpected2,6-diarylated product5k(seeSIeq1).
mol %), PPh3 (20 mol %), K2CO3 (2.0 equiv), (MeO)2SO2 (1.6
equiv), Cu2O (1.5 equiv), DMAc (2.5 mL), 150 °C, 4 Å MS (50 mg),
24 h, N2 atmosphere. Isolated yields reported as the average of two
experiments. The reaction was scaled up to 32-fold. Reaction
conditions: 1 (0.5 mmol), 2 (1.5 mmol), PdCl2 (5 mol %), PPh3 (10
mol %), K2CO3 (4.0 equiv), (MeO)2SO2 (0.8 equiv), Cu2O (0.5
equiv), DMAc (2.5 mL), 150 °C, 4 Å MS (100 mg), 72 h, N2
atmosphere.
b
c
should be mentioned that even using pyridine as the limiting
reagent (1/2e or 2h = 1:3) also successfully afforded diarylation
products (4e or 4h).
Next the substituted pyridines, used as the limiting reagent,
were investigated under slightly modified reaction conditions
(Scheme 3). Gratifyingly, the coupling of symmetrically
substituted pyridines with aryl bromides bearing various
substitution patterns afforded the expected products 5a−w in
moderate to good yields. In all cases, the 2,6-diarylpyridine was
almost exclusively formed, with only a trace amount of
monoarylation product being detected. It should also be noted
that the Cl atom was also tolerated (5a and 5m), serving as a
C
DOI: 10.1021/acs.orglett.7b00498
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Organic Letters
Letter
ORCID
These results further proved that the N-methylpyridinium salt
was an important intermediate.
Haiyan Fu: 0000-0002-7185-2062
Ruixiang Li: 0000-0003-0756-3722
Notes
However, when the reaction between the N-methylpyridinium
methyl sulfate and the 1-bromo-4-methylbenzene was performed
in the absence of Cu2O, no 2,6-diarylated pyridine was detected
(see SI eq 2). We supposed that the Cu2O might play an
important role in the ortho C−H bond cleavage of the pyridinium
salt. Indeed, an HRMS spectrum of the reaction solution of N-
methylpyridinium methyl sulfate with Cu2O showed a peak at
212.0492 m/z, indicating the involvement of a Cu-pyridinium
species in the reaction (see SI eq 3 and Figure 3). We also carried
out the kinetic isotope effect (KIE) studies (see SI eq 4). A typical
secondary KIE of 1.08 indicated that the C−H bond breaking of
pyridine may not be related to the rate-limiting step.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21202104 and 21572137) for their financial support. We
also thank the Centre of Testing & Analysis, Sichuan University,
for NMR measurements and X-ray analyses.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00498.
Typical experimental procedures, characterization data, 1H
and 13C NMR spectra for new compounds, and X-ray
crystallographic analysis (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: scufhy@scu.edu.cn.
*E-mail: scuhchen@scu.edu.cn.
D
DOI: 10.1021/acs.orglett.7b00498
Org. Lett. XXXX, XXX, XXX−XXX