Synthesis of Diarylated 4-Pyridylmethyl Ethers via Palladium-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.1002/adsc.201700380

The direct arylation of weakly acidic sp³-hybridized C–H bonds via deprotonated cross-coupling processes (DCCP) is a challenge. Herein, a palladium(NIXANTPHOS)-based catalyst for the monoarylation of 4-pyridylmethyl 2-aryl ethers to generate di

Full text of DOI:10.1002/adsc.201700380

Title: Synthesis of Diarylated 4-Pyridylmethyl Ethers via Palladium-
Catalyzed Cross-Coupling Reactions
Authors: Keyume Ablajan, Grace B. Panetti, Xiaodong Yang, Byeong-
Seon Kim, and Patrick J. Walsh
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700380
Link to VoR: http://dx.doi.org/10.1002/adsc.201700380

10.1002/adsc.201700380
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Diarylated 4-Pyridylmethyl Ethers via Palladium-
Catalyzed Cross-Coupling Reactions
Keyume Ablajan,a Grace B. Panetti,b Xiaodong Yang,c Byeong-Seon Kim,b and Patrick
J. Walsh,b*
a
Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang Uyghur Autonomous Region, College
of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, PR China
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
b
Philadelphia, Pennsylvania 19104-6323, United States
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and
c
Technology, Yunnan University, Kunming, 650091, P.R. China
Fax: (+1)-215-573-6743; e-mail: pwalsh@sas.upenn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The direct arylation of weakly acidic sp3– with aryl bromides has been developed. These methods
hybridized C–H bonds via deprotonated cross–coupling enable the synthesis of new pyridine derivatives, which are
processes (DCCP) is
a
challenge. Herein,
a
common in medicinally active compounds and in application
Pd(NIXANTPHOS)-based catalyst for the mono arylation of in materials science.
4-pyridylmethyl 2-aryl ethers to generate diarylated 4-pyridyl
methyl ethers is introduced. Furthermore, under similar
conditions, the diarylation of 4-pyridylmethyl ethers
Keywords: aryl bromides; arylation; diarylation; 4-
pyridylmethyl ethers; cross-coupling; palladium-catalyzed;
A recent analysis of the shapes of a large pool of
molecules known to exhibit biological activity
indicated that most structures are either linear or disk-
shaped.[7] This study found very few examples of
bioactive compounds that are better described as
sphere-like. We hypothesized that one reason there are
few such sphere-like bioactive compounds is that their
synthesis is more difficult. To address this challenge,
we initiated a program in the exhaustive arylation of
benzylic C–H’s. In our initial publication, we reported
the first general transition metal catalyzed arylation of
di- and triarylmethanes to afford sphere-like
tetraarylmethanes (Scheme 1D).[8] Herein we expand
this approach to the arylation of benzylic ethers to
prepare diaryl(4-pyridyl) ether derivatives (Scheme
1E). It is noteworthy that di- and triaryl
pyridylmethanol derivatives are active in the treatment
for Chagas disease and exhibit in vitro aromatase
inhibitory activity.[9]
Introduction
Efficient catalytic generation of C–C bonds via the
arylation of C(sp3)–H’s has attracted significant recent
attention.[1] We,[2] and other research teams,[3] have
been interested in the arylation of pronucleophiles
bearing weakly acidic C(sp3)–H bonds. Under basic
reaction conditions the pronucleophile C–H is
reversibly deprotonated to generate an organometallic
species that undergoes transition metal catalyzed
coupling with an aryl halide. For example, we have
used this approach for the arylation of diarylmethanes
to prepare triarylmethanes (Scheme 1A),[4] the
arylation of allylbenzenes to prepare 1,1-diaryl prop-
2-enes (Scheme 1B),[5] and the arylation of benzylic
C–H’s situated alpha to heteroatoms,[2b, 6] which can
undergo a subsequent [2,3]-Wittig rearrangement
(Scheme 1C).[2b] These reactions generally exhibit
very high selectivity for mono-arylations, which is
usually due to the increased steric shielding of the
remaining benzylic C–H relative to those in the
starting materials.
Under the basic reaction conditions using
MN(SiMe3)2 (M=Li, Na, K), palladium or nickel, and
van Leewen’s NIXANTPHOS,[10] we found that the
NIXANTPHOS N–H (pKa~21 in DMSO)[11] is
deprotonated under the reaction conditions and that the
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700380
Advanced Synthesis & Catalysis
resulting complex is bimetallic, containing the
transition metal and the main group element (M=Li,
Na, K).[4b] We have demonstrated that the transition
metal and main group metal cooperate to achieve
under otherwise identical reaction conditions afforded
low yields (8–20%, entries 5–6). No product was
obtained using KN(SiMe3)2, NaOtBu or KOtBu
(entries 7–9).
We next examined the impact of reaction times on
the yield. Cutting the reaction time from 12 to 6 h
resulted in a drop in the AY to 46% (entry 10 vs. 4).
No significant change in yield was found when the
reaction time was prolonged to 18 h (entry 11).
Reducing the equivalents of LiN(SiMe3)2 from 3.0 to
1.5 equiv under identical conditions resulted in
incomplete reaction, with 68% AY (entry 12).
levels of reactivity that are typically much higher than
10, 12]
related ligands.[4b,
On the basis of these
investigations, we initiated our studies on the arylation
of 4-pyridyl methyl ether derivatives with the
Pd/NIXANTPHOS-based catalyst.
The impact of different Pd and NIXANTPHOS
loadings on the coupling reaction was examined.
Changing Pd:NIXANTPHOS loading from 5:7.5 to
3:4.5 mol % resulted in similar AY and isolated yield
(entry 4 vs. 13). Further reducing the catalyst loading
significantly decreases the reaction yield. Next,
different reaction temperatures were examined at 3
mol % Pd and 4.5 mol % NIXANTPHOS with a 12 h
reaction time. The results indicated that decreased
yields were observed when the reactions were
conducted at 25, 40 or 80 ℃ (Table 1, entries 14–16).
Table 1. Optimization of arylation of 4-pyridylmethyl
methyl aryl ether 1a with aryl bromide 2c[a, b]
Pd/L
temp
yield
(%)
base (equiv) solvent (mol%) (oC)
1
LiHMDS (3) THF
LiHMDS (3) DME
5/7.5
5/7.5
60
60
60
60
60
60
60
60
60
60
60
60
60
25
40
80
16
47
55
91
20
8
Scheme 1. Transition metal-catalyzed arylation chemistry.
2
3
LiHMDS (3) dioxane 5/7.5
4
LiHMDS (3) CPME
NaHMDS(3) DME
NaHMDS(3) CPME
KHMDS (3) CPME
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
3/4.5
3/4.5
3/4.5
3/4.5
Results and Discussion
5
Initial studies began with 4-pyridylmethyl 2-(4-tert-
butyl-phenyl) ether (1a), 4-chloro-1-bromobenzene
(2c), Pd(OAc)2 (5 mol %) and NIXANTPHOS (7.5
mol %) as the ligand. The acidity of the 4-
pyridylmethyl methyl ether is likely similar to those of
2- and 4-methylpyridine (pKa′s 32–34 in THF).[11, 13]
Solvent and base play an important role in cross-
coupling reactions. We therefore employed 4 solvents
(THF, DME, 1,4-dioxane and CPME) with 5 strong
bases [LiN(SiMe3)2, NaN(SiMe3)2, KN(SiMe3)2,
NaOtBu and KOtBu], and the reactions were
conducted for 18 h at 60 oC. The results are displayed
in Table 1 (entries 1–9). The cross-coupling between
compounds 1a and 2c with LiN(SiMe3)2 afforded poor
assay yields (AY) [16–55%, assay yields determined
6
7
0
8
NaOtBu (3)
KOtBu (3)
CPME
CPME
0
9
0
10
11
12
13
14
15
16
LiHMDS (3) CPME
LiHMDS (3) CPME
LiHMDS (3) CPME
LiHMDS (3) CPME
LiHMDS (3) CPME
LiHMDS (3) CPME
LiHMDS (3) CPME
46[c]
93[d]
68
89[e]
26
62
53
[a] Reactions conducted on a 0.1 mmol scale using 1 equiv of
1a, and 1.2 equiv of 2c for 12 h.
[b] Assay yields determined by 1H NMR spectroscopy of the
crude reaction mixtures.
[c] Reaction time 6 h
[d] Reaction time 18 h
1
by H NMR] when conducted in THF, DME or
dioxane (Table 1, entries 1–3). In contrast,
LiN(SiMe3)2 in CPME resulted in 91% AY (entry 4).
The arylated product 3ac was isolated in 89% yield
after column chromatography.
Substitution of
NaN(SiMe3)2 for LiN(SiMe3)2 in CPME or DME
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700380
Advanced Synthesis & Catalysis
[e] Isolated yield after chromatographic purification.
[a] Reactions conducted on 0.2 mmol scale using 1 equiv of
1, and 1.2 equiv of aryl bromides 2.
With the optimized conditions (Table 1, entry 13),
the scope of the arylation of 4-pyridylmethyl 2-aryl
methyl ethers with different aryl bromides was
explored (Table 2). Continuing with 4-pyridyl aryl
methyl ether 2a, reactions with aryl bromides bearing
electron donating 4-Me and 4-NMe2 groups gave 3aa
and 3ab in 88 and 82% yield, respectively. More
sterically hindered 2-bromotoluene and 1-bromo-
naphthylene failed to yield the corresponding arylated
products despite the use of higher Pd loading (7.5
mol %). Aryl bromides with 4-Cl and 4-F produced
products 3ac and 3ad in 89 and 87% yield,
respectively. Aryl bromides substituted with electron
withdrawing 3-OMe and 3-CF3 gave 3ae and 3af in 91
and 79% yield, respectively. Due to the importance of
heterocycles in medicinal chemistry, heterocyclic
substrates were examined. Use of N-methyl-5-
bromoindole and 5-bromobenzofuran furnished the
arylated products in 80 and 84% yield.
[b] Isolated yields after chromatographic purification.
Using 4-pyridylmethyl aryl ethers where the aryl
bears a 3-methoxy group (1b), coupling with 2-
bromonaphthylene
and
4-N,N-dimethylamino
bromobenzene proceeded in 86 and 84% yield,
respectively. 4-Fluoro bromobenzene, 3-trifluoro
bromobenzene and 5-bromobenzofuran resulted in
coupling products in 81–88% yields. The 4-pyridyl
aryl ethers with the aryl 4-methoxy readily coupled
with 3-trifluoro bromobenzene (87% yield) and 4-
chloro bromobenzene (83% yield).
The 4-
3-
pyridylmethyl aryl methyl ether with
a
trifluorophenyl substituent coupled with 2-naphthyl
bromide,
N-methyl-5-bromoindole,
and
5-
bromobenzofuran in 77–85% yield.
After demonstrating the broad scope of arylation of
4-pyridylmethyl aryl ethers, we next investigated the
diarylation of 4-pyridylmethyl ethers (Table 3). For the
diarylation of 4-pyridylmethyl ethers with aryl
bromides we increased the catalyst loading (5 mol %
Pd and 7.5 mol % NIXANTPHOS) and reaction time
Table 2. Scope of aryl bromides in C-H arylation of 4-
pyridylmethyl 2-aryl ethers 1a–1d [a, b]
o
(16 h) at the same temperature (60 C). Overall, the
diarylated compounds 5aa–5bd were obtained in 78–
94% yield with methyl ethers giving slightly better
yields than ethyl ethers. The 4-pyridylmethyl methyl
ethers coupled with electron neutral and rich aryl
bromides in 84–91% yields, while electron
withdrawing analogues generated products in 84–88%
yield. For the ethyl ethers, yields ranged from 78–86%.
Table 3. Scope of 4-pyridylmethyl ethers in diarylation with
aryl bromides [a, b]
[a] Reactions conducted on a 0.2 mmol scale using 1 equiv of
4-pyridylmethyl ethers 4 and 2.5 equiv of aryl bromides 2.
[b] Isolated yields after chromatographic purification.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700380
Advanced Synthesis & Catalysis
infrared spectra were obtained with KBr plates using a
Perkin-Elmer Spectrum 1600 Series spectrometer. High-
resolution mass spectrometry (HRMS) data were obtained
on a Waters LC-TOF mass spectrometer (model LCT-XE
Premier) using chemical ionization (CI) or electrospray
ionization (ESI) in positive or negative mode, depending on
the analyte. 4-(Chloromethyl)pyridine hydrochloride (98%)
was purchased from Matrix Scientific and used as received.
Under similar conditions to those outlined above, 3-
pyridylmethyl ethers were unreactive, most likely due
to the higher pKa’s of the benzylic hydrogens.
Attempts to diarylate the 2-pyridylmethyl ethers
resulted in monoarylation followed by [2,3]-Wittig
rearrangement (Scheme 1C) under all conditions
explored.[2b] Coupling with the heterocyclic aryl
bromides 3-bromopyridine and 3-bromofuran resulted
in the formation of multiple products and no desired
material could be isolated.
General procedure for the preparation of Pd-catalyzed
monoarylation of 4-pyridylmethyl 2-aryl ethers
An oven-dried 10 mL reaction vial equipped with a stir bar
was charged with 4-pyridylmethyl 2-aryl ether (1, 0.2 mmol,
1.0 equiv) and aryl bromide (2, 0.30 mmol, 1.5 equiv) in dry
CPME (1 mL) in a glove box under a nitrogen atmosphere
at room temperature. A solution (from a stock solution) of
Pd(OAc)2 (1.34 mg, 0.006 mmol, 3 mol %) and
NIXANTPHOS (4.97 mg, 0.009 mmol, 4.5 mol %) in 1 mL
of dry CPME was taken up by syringe and added to the
reaction vial under nitrogen. Then, LiN(SiMe3)2 (110 mg,
0.6 mmol, 3.0 equiv) was added to the reaction mixture. The
vial was capped, removed from the glove box, and stirred
for 12 h at 60 °C until TLC showed complete consumption
of 4-pyridylmethyl 2-aryl ether. The reaction mixture was
quenched with three drops of H2O, diluted with 3 mL of
ethyl acetate, and filtered over a pad of silica and anhydrous
MgSO4. The pad was rinsed with additional ethyl acetate (3
X 2 mL), and the combined solution was concentrated in
vacuo. The crude product was loaded onto a silica gel
column and purified by flash chromatography using 4:1–2:1
hexanes/ethyl acetate as eluent to afford desired products.
Conclusions
In summary, an efficient and versatile approach for the
arylation of 4-pyridylmethyl aryl ether derivatives has
been developed. This study indicates that a
Pd(NIXANTPHOS)-based catalyst in CPME solvent
exhibited high yields. Under the optimized reaction
conditions, a range of 4-pyridylmethyl 2-aryl ethers
underwent coupling with various aryl and heteroaryl
bromides in good to excellent yields. Furthermore,
diarylated products were furnished in high yields by
cross-coupling of 4-pyridylmethyl methyl ethers with
2.5 equivalents of aryl bromides.
General procedure for the preparation of Pd-catalyzed
diarylation of 4-pyridylmethyl ethers
Recent analyses of medicinally active
compounds[7] and databases of known organic
structures[14] indicate that the most bioactive
compounds are linear or disk shaped[7] and that the
An oven-dried 10 mL reaction vial equipped with a stir bar
was charged with 4-pyridylmethyl ether (4, 0.2 mmol, 1.0
equiv), aryl bromide (2, 0.5 mmol, 2.5 equiv) and dry CPME
(1 mL) in a glove box under a nitrogen atmosphere at room
temperature. A solution (from a stock solution) of Pd(OAc)2
(2.23 mg, 0.01 mmol, 5 mol %) and NIXANTPHOS (8.27
mg, 0.015 mmol, 7.5 mol %) in 1 mL of dry CPME was
taken up by syringe and added to the reaction vial under
nitrogen. Then, LiN(SiMe3)2 (110 mg, 0.6 mmol, 3.0 equiv)
was added to the reaction mixture. The vial was capped,
removed from the glove box, and stirred for 16 h at 60 °C
until TLC showed complete consumption of 4-
pyridylmethyl ether. The reaction mixture was quenched
with three drops of H2O, diluted with 3 mL of ethyl acetate,
and filtered over a pad of silica and anhydrous MgSO4. The
pad was rinsed with additional ethyl acetate (3 X 2 mL) and
the combined solution was concentrated in vacuo. The crude
product was loaded onto a silica gel column and purified by
flash chromatography using 4:1- 2:1 hexanes/ethyl acetate
as eluent to afford desired products.
majority of organic structures prepared to date contain
[14]
very limited structural diversity.
A goal of this
work was to develop straightforward methods to
rapidly prepare molecules with less common shapes
and structural frameworks. The compounds produced
herein are more sphere-like, yet several contain
heterocycles that are commonly found in bioactive
compounds, like pyridines and indoles.[15] Thus, we
expect that this method will be of use to medicinal
chemists exploring less conventional molecular space.
Experimental Section
General Methods
Acknowledgements
All reactions were conducted under an inert atmosphere of
dry nitrogen. Anhydrous dioxane and cyclopentyl methyl
ether (CPME) were purchased from Sigma-Aldrich and
used without further purification. Dimethoxyiethane (DME)
and tetrahydrofuran (THF) were dried through activated
alumina columns under nitrogen. Unless otherwise stated,
Silica gel (Silicaflash, P60, 40-63 µm, Silicycle) was used
P. J. W. thanks the National Science Foundation (CHE-1464744)
and National Institutes of Health (NIGMS 104349) for financial
support. K. A. thanks the Program for China Scholarship Council
(201408535034), NSFC (21462041) and Natural Science
Foundation for Distinguished Young Scholars of Xinjiang Uyghur
Autonomous Region (No. Qn2015jq002).
for
air-flashed
chromatography.
Solvents
were
commercially available and used as received without further
purification. Chemicals were purchased from Sigma-
Aldrich, Acros, Fisher Scientific or Matrix Scientific and
solvents were obtained from Fisher Scientific. Thin-layer
chromatography was performed on Whatman precoated
silica gel 60 F-254 plates and visualized by ultraviolet light.
Flash chromatography was performed with Silica gel
(Silicaflash, P60, 40-63 µm, Silicycle). NMR spectra were
obtained using a Brüker 500 MHz Fourier-transform NMR
spectrometer at the University of Pennsylvania NMR
facility. 1H and 13C chemical shifts in parts per million (δ)
were referenced to internal tetramethylsilane (TMS). The
References
[1]a) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res.
2009, 42, 1074-1086; b) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147-1169; c) I. A. I. Mkhalid, J.
H. Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig,
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700380
Advanced Synthesis & Catalysis
Chem. Rev. 2010, 110, 890-931; d) O. Baudoin, Chem.
Soc. Rev. 2011, 40, 4902-4911.
429; b) M. Keenan, M. J. Abbott, P. W. Alexander, T.
Armstrong, W. M. Best, B. Berven, A. Botero, J. H.
Chaplin, S. A. Charman, E. Chatelain, T. W. von
Geldern, M. Kerfoot, A. Khong, T. Nguyen, J. D.
McManus, J. Morizzi, E. Ryan, I. Scandale, R. A.
Thompson, S. Z. Wang, K. L. White, J. Med. Chem.
2012, 55, 4189-4204.
[2] a) A. Bellomo, J. Zhang, N. Trongsiriwat, P. J. Walsh,
Chem. Sci. 2013, 4, 849-857; b) F. Gao, B.-S. Kim, P. J.
Walsh, Chem. Sci. 2016, 7, 976-983; c) M. Li, M.
González-Esguevillas, S. Berritt, X. Yang, A. Bellomo,
P. J. Walsh, Angew. Chem., Int. Ed. 2016, 55, 2825-
2829; d) M. Li, B. Yucel, J. Adrio, A. Bellomo, P. J.
Walsh, Chem. Sci. 2014, 5, 2383-2391; e) G. I. McGrew,
J. Temaismithi, P. J. Carroll, P. J. Walsh, Angew. Chem.,
Int. Ed. 2010, 49, 5541-5544.
[10] L. A. van der Veen, P. H. Keeven, G. C. Schoemaker,
J. N. H. Reek, P. C. J. Kamer, P. W. N. M. van Leeuwen,
M. Lutz, A. L. Spek, Organometallics 2000, 19, 872-883.
[11] F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456-463.
[3] a) M. Nambo, M. Yar, J. D. Smith, C. M. Crudden, Org.
Lett. 2015, 17, 50-53; b) P. Novak, R. Martin, Curr. Org.
Chem. 2011, 15, 3233-3262.
[12] a) P. Buchwalter, J. Rosé, P. Braunstein, Chem. Rev.
2015, 115, 28-126; b) H.-Q. Do, R. M. K. Khan, O.
Daugulis, J. Am. Chem. Soc. 2008, 130, 15185-15192;
c) I. Popov, S. Lindeman, O. Daugulis, J. Am. Chem. Soc.
2011, 133, 9286-9289; d) M. Shibasaki, M. Kanai, S.
Matsunaga, N. Kumagai, Acc. Chem. Res. 2009, 42,
1117-1127; e) L. D. Tran, O. Daugulis, Org. Lett. 2010,
12, 4277-4279; f) J. Zhang, S.-C. Sha, A. Bellomo, N.
Trongsiriwat, F. Gao, N. C. Tomson, P. J. Walsh, J. Am.
Chem. Soc. 2016, 138, 4260-4266.
[4] a) J. Zhang, A. Bellomo, A. D. Creamer, S. D. Dreher,
P. J. Walsh, J. Am. Chem. Soc. 2012, 134, 13765-13772;
b) J. Zhang, A. Bellomo, N. Trongsiriwat, T. Jia, P. J.
Carroll, S. D. Dreher, M. T. Tudge, H. Yin, J. R.
Robinson, E. J. Schelter, P. J. Walsh, J. Am. Chem. Soc.
2014, 136, 6276-6287.
[5] N. Hussain, G. Frensch, J. Zhang, P. J. Walsh, Angew.
Chem., Int. Ed. 2014, 53, 3693-3697.
[13] R. R. Fraser, T. S. Mansour, S. Savard, J. Org. Chem.
1985, 50, 3232-3234.
[6]N. Hussain, B.-S. Kim, P. J. Walsh, Chem. Euro. J. 2015,
21, 11010-11013.
[14] A. H. Lipkus, Q. Yuan, K. A. Lucas, S. A. Funk, W. F.
Bartelt, R. J. Schenck, A. J. Trippe, J. Org. Chem. 2008,
73, 4443-4451.
[7] D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443-
4458.
[15] a) T. J. Ritchie, S. J. F. Macdonald, R. J. Young, S. D.
Pickett, Drug Discovery Today 2011, 16, 164-171; b) T.
J. Ritchie, S. J. F. Macdonald, S. Peace, S. D. Pickett, C.
N. Luscombe, MedChemComm 2012, 3, 1062-1069.
[8] S. Zhang, B.-S. Kim, C. Wu, J. Mao, P. J. Walsh, Nat.
Commun. 2017, 8, 14641.
[9] a) C. D. Jones, M. A. Winter, K. S. Hirsch, N. Stamm,
H. M. Taylor, H. E. Holden, J. D. Davenport, E. V.
Krumkalns, R. G. Suhr, J. Med. Chem. 1990, 33, 416-
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700380
Advanced Synthesis & Catalysis
FULL PAPER
The Synthesis of Diarylated 4-Pyridylmethyl
Ethers via Palladium-Catalyzed Cross-Coupling
Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Author(s), Corresponding Author(s)*
Keyume Ablajan, Grace B. Panetti, Xiaodong
Yang, Byeong-Seon Kim, and Patrick J. Walsh,*
6
This article is protected by copyright. All rights reserved.