Synthesis and Suzuki Cross-Coupling Reactions of 2,6-Bis(trifluoromethyl)pyridine-4-boronic Acid Pinacol Ester

Article abstract of DOI:10.1055/s-0036-1588344

Iridium-catalyzed aromatic borylation provides quick one-step access to 2,6-bis(trifluoromethyl)pyridine-4-boronic acid pinacol ester. Suzuki couplings of this highly electron-deficient pyridine-4-boronic ester with various (hetero)aryl bromides was successfully carried out and the coupled products were obtained in 46-95% isolated yields. Double and triple Suzuki couplings, with dibromo- and tribromoarenes, respectively, were also achieved. Thus demonstrating that this pyridine-4-boronic ester can be a useful source for the installation of one of the strongest electron-withdrawing aromatic group in organic compounds.

Full text of DOI:10.1055/s-0036-1588344

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
F. Batool et al.
Paper
Synthesis
Synthesis and Suzuki Cross-Coupling Reactions of 2,6-Bis(trifluo-
romethyl)pyridine-4-boronic Acid Pinacol Ester
Farhat Batoola,d
Abdul-Hamid Emwasb
Xin Gaoc
Munawar A. Munaward
Ghayoor A. Chotana*a
F3C
F3C
1.5 equiv HBPin
1 mol% [IrCl(COD)]2
N
H
N
BPin
2 mol% bpy, 80 °C, 4 h
10 mmol scale
94% yield
3.2 gram
F3C
F3C
F3C
1.5 equiv Br−Ar-R, 1 mol% Pd(OAc)2
2 mol% SPhos, 1.5 equiv K3PO4
N
Ar R
a Department of Chemistry, Syed Babar Ali School of Science & Engineering,
Lahore University of Management Sciences, Lahore 54792, Pakistan
b Imaging and Characterization Core Lab, King Abdullah University of Science
and Technology, Thuwal 23955-6900, Saudi Arabia
c King Abdullah University of Science and Technology (KAUST), Computational
Bioscience Research Center (CBRC), Computer, Electrical and Mathematical
Sciences and Engineering (CEMSE) Division, Thuwal, 23955-6900, Saudi
Arabia
d Institute of Chemistry, University of the PunjabLahore 54590, Pakistan
ghayoor.abbas@lums.edu.pk
DME, 80 °C, 24–48 h
F3C
23 examples of single, double, and triple Suzuki coupling
Isolated yields 46–95% R = Me, OMe, NMe2, Cl, CN, CO2Et, CHO, CF3
Ar = aryl, thienyl, furyl, pyridyl, indolyl, naphthyl, anthracenyl, pyrenyl
Received: 11.10.2016
Accepted after revision: 17.10.2016
Published online: 18.11.2016
ious functional groups.6 Taft’s σ* values for 3,5-bis(trifluo-
romethyl)phenyl and pentafluorophenyl groups, which are
currently widely used, are 1.18 and 1.50 respectively (Fig-
ure 1).7 In comparison, the 2,6-bis(trifluoromethyl)pyridin-
4-yl group, with a σ* value of 1.66, is the most powerful flu-
orinated electron-withdrawing aromatic group.8 Recently,
this functional group has been used to synthesize highly
electron-deficient phosphine ligands.8,9 However, 4-bromo-
2,6-bis(trifluoromethyl)pyridine, which was employed for
the incorporation of the 2,6-bis(trifluoromethyl)pyridin-4-
yl group, requires a three-step synthesis from acyclic pre-
cursors. It will be advantageous to directly functionalize
2,6-bis(trifluoromethyl)pyridine for its utilization as a
powerful electron-withdrawing group for the synthesis of
organic materials. In particular, convenient synthesis of the
4-borylated derivative will be highly beneficial as the 4-
arylpyridines10 obtained after Suzuki coupling can have ap-
plications as materials for non-linear optics,11 multi-photon
absorption,12 and biologically active molecules,13 as well as
replacing the 3,5-bis(trifluoromethyl)aryl group in known
useful organic compounds.14
DOI: 10.1055/s-0036-1588344; Art ID: ss-2016-z0509-op
Abstract Iridium-catalyzed aromatic borylation provides quick one-
step access to 2,6-bis(trifluoromethyl)pyridine-4-boronic acid pinacol
ester. Suzuki couplings of this highly electron-deficient pyridine-4-bo-
ronic ester with various (hetero)aryl bromides was successfully carried
out and the coupled products were obtained in 46–95% isolated yields.
Double and triple Suzuki couplings, with dibromo- and tribromoarenes,
respectively, were also achieved. Thus demonstrating that this pyridine-
4-boronic ester can be a useful source for the installation of one of the
strongest electron-withdrawing aromatic group in organic compounds.
Key words iridium catalysis, C–H activation, borylation, boronic es-
ters, Suzuki coupling, 2,6-bis(trifluoromethyl)pyridine, organic elec-
tronic materials
Organic compounds containing powerful electron-with-
drawing (hetero)aromatic groups have important applica-
tions in various fields including organic electronics,1 cataly-
sis,2 and sensors.3 Aromatic rings can be decorated with
various electron-withdrawing groups; however, recently
fluorinated groups have become more common due to their
increased stability and functional group compatibility. Im-
portant fluorinated electron-withdrawing aromatic groups
include pentafluorophenyl, 4-(trifluoromethyl)phenyl, and
3,5-bis(trifluoromethyl)phenyl. Fluorinated tetraarylbo-
rates, such as ‘BARF’, behave as very weakly coordinating
anions thereby enabling the formation of highly reactive
cationic transition-metal complexes for various catalytic
applications.4 A frustrated Lewis pair consisting of tris[3,5-
bis(trifluoromethyl)phenyl]borane and 2,2,6,6-tetrameth-
ylpiperidine has been reported to activate small molecules
such as H2.5
F3C
F3C
N
F
F
F
F
F3C
F
F3C
F3C
F3C
F
F
F
F
0.96
1.18
1.50
1.54
1.66
Figure 1 Taft’s σ* values of selected fluorinated aromatic groups
Direct functionalization of the C–H bonds of 2,6-bis(tri-
fluoromethyl)pyridine has remained a challenge. Despite
being known for over fifty years, its chemistry has been
mainly limited to N-oxide formation.15 The highly electron-
deficient nature of 2,6-bis(trifluoromethyl)pyridine pre-
cludes electrophilic aromatic substitution. Attempted di-
Taft’s polar substituent constant, σ*, has been very use-
ful in quantifying the electron-withdrawing capacity of var-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
F. Batool et al.
Paper
Synthesis
rected orthometalation using butyllithium gave a brown
polymeric tar,16 while controlled reaction with tert-butyl-
lithium resulted in the nucleophilic addition of t-BuLi
across the C–N bond of the pyridine ring, subsequently
yielding the 1,2-dihydropyridine upon acidification. Very
recently, Zheng et al. reported that 2,6-bis(trifluorometh-
yl)pyridine can be lithiated using LDA, however the lithia-
tion was not selective, and resulted in a mixture of 3- and
4-lithiated products.17 The lithiated intermediates were
subsequently trapped with triisopropyl borate to yield the
corresponding boronic acid mixture. The aforementioned
limitations of the traditional functionalization methods
have resulted in an under-utilization of this interesting
group for its incorporation in organic materials, pharma-
ceuticals etc.
Apart from the traditional functionalization methods
for aromatic compounds, the newly developed transition-
metal-catalyzed C–H functionalizations provide alternative
protocols. Specially, the iridium-catalyzed C–H borylation
reaction, developed by the groups of Smith–Maleczka and
Hartwig–Miyuara, has revolutionized the art of aromatic
functionalization.18 Generally sterics, not electronics, dic-
tate the product regioselectivity in this new reaction. Inter-
estingly, electron-deficient arenes react faster than elec-
tron-rich ones,19 a characteristic useful for the functional-
ization of pyridines. This new methodology, when applied
to 2,6-disubstituted pyridines, has been reported to yield 4-
borylated pyridines as a single product.18a,19a,20 We there-
fore decided to apply iridium-catalyzed C–H borylation to
2,6-bis(trifluoromethyl)pyridine, expecting it to yield a sin-
gle 4-borylated product isomer (Scheme 1) which could po-
tentially be a highly useful coupling agent for the Suzuki re-
action.
ed product with a bromoalkene to synthesize a styrene de-
rivative. Studies on the Suzuki coupling reactions of 2,6-
bis(trifluoromethyl)pyridine-4-boronic acid pinacol ester
with (hetero)aryl halides for the synthesis of biaryls are
lacking. Herein, we describe the scope of Suzuki coupling
reactions of this pyridine-4-boronic ester with various (het-
ero)aryl halides.
After synthesizing the 2,6-bis(trifluoromethyl)pyridine-
4-boronic acid pinacol ester (1), a major concern was the
feasibility of its use in the Suzuki coupling reaction, since
the Suzuki coupling reaction of electron-deficient pyridine-
boronic esters has been known to be problematic.13a We
were pleased to observe that this highly electron-deficient
pyridineboronic ester easily underwent Suzuki couplings
with
(hetero)aryl
bromides
using
Buchwald’s
Pd(OAc)2/SPhos catalyst system23 as well as by the Pd(PPh3)4
catalyst (Scheme 2).
F3C
N
F3C
N
1.5 equiv Ar–Br, 1 mol% Pd(OAc)2
BPin
Ar
2 mol% SPhos, 1.5 equiv K3PO4
DME, 80 °C, 24–48 h
1
2a–r
F3C
F3C
F3C
F3C
N
F3C
N
N
Me
OMe
CN
NMe2
F3C
F3C
F3C
F3C
F3C
F3C
2a 76%
2b 86%
2e 63%
2h 85%a
2c 71%
2f 46%
2i 79%
N
CF3
N
N
CO2Et
F3C
F3C
F3C
F3C
F3C
F3C
2d 77%
Cl
Cl
Cl
OMe
OMe
OMe
N
N
N
2g 95%a
F3C
F3C
F3C
F3C
F3C
F3C
F3C
N
F3C
N
1.5 equiv HBPin
1 mol% [IrCl(COD)]2
N
N
N
CF3
94% yield on
10 mmol scale
(3.22 g)
N
H
BPin
93%
2 mol% bpy
80 °C, 4 h
F3C
F3C
NMe2
F C
3
F3C
F3C
2j 61%
2k 64%
2l 73%
HN
1
F3C
F3C
F3C
N
Scheme 1 Iridium-catalyzed borylation of 2,6-bis(trifluoromethyl)pyri-
dine
N
F3C
F3C
N
N
F3C
F3C
N
S
S
O
Cl
CHO
CO2Me
2m 73%a
2n 48%
2o 74%
F3C
F3C
N
Catalytic borylation of 2,6-bis(trifluoromethyl)pyridine
was attempted using the [IrCl(COD)]/bpy catalyst system,18b
without employing a glovebox or Schlenk line.21 We were
pleased to observe that the borylation was complete in 4
hours at 80 °C, and the 4-borylated pyridine 1 was readily
isolated in excellent yield by eluting the crude reaction
mixture through a short silica plug using dichloromethane
as a solvent. Isolated yield was reproducible (94%, 3.22 g)
when the reaction was scaled-up to 10 mmol even though
the catalyst loading was reduced to half. While our work
was in progress, Lahm et al. also reported a similar route,
employing high catalyst loading (10 mol% Ir/bpy), B2Pin2,
and heptane solvent, for the preparation of 4-borylated 2,6-
bis(trifluoromethyl)pyridine.22 They coupled the 4-borylat-
2p 86%
2q 69%
2r
60%
F3C
F3C
F3C
Scheme 2 Suzuki cross-coupling reactions of 1 with (hetero)aryl bro-
mides a 3 mol% Pd(PPh3)4 was used as catalyst.
Both, electron-rich (2a–c,i,j) and electron-deficient cou-
pling partners (2d–f,l) gave good yields of the Suzuki cou-
pled product. Homocoupling of the pyridineboronic ester
was observed as a minor side product (<5%) for reactions
with electron-rich aryl bromides. Fused polycyclic aryl bro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
F. Batool et al.
Paper
Synthesis
mides such as those of naphthalene, anthracene, and
pyrene also proved to be good coupling partner (2p–r).
However, steric hindrance in case of 9-bromoanthracene
and 1-bromopyrene resulted in reduced yields of the Suzuki
products. For chloro-substituted aryl bromides (2g,h,m),
Suzuki coupling was carried out using Pd(PPh3)4, which re-
sulted in the formation of small amounts of phenyl-transfer
product from PPh3, however the desired pure products were
isolated in good yields. In addition to aryl bromides, het-
eroaryl bromides such as those of indole, thiophene, furan,
and pyridine were also utilized as coupling partners and
the corresponding Suzuki products were isolated in good
yields (2k–o). All the heterobiaryl Suzuki products were
solid at room temperature, and some were colored (2c,m,n:
light yellow; 2k: faint purple; 2r: light orange). Some of the
synthesized biaryl products can be potentially interesting
organic materials. For example, 2c due to its photophysical
properties,12b,24 and 2l for its use in the synthesis of
OLEDs.17
Double Suzuki coupling with dibromoarenes was also
carried out (Scheme 3). Small amounts (5–10%) of mono-
Suzuki coupling appeared as a side product during these
double Suzuki coupling reactions. However, we were suc-
cessful in isolating the pure dicoupled products in moder-
ate to good yields (3a–d). Finally, tris(4-bromophe-
nyl)amine was used as coupling partner and the triple Su-
zuki product was isolated in 68% yield (Scheme 4).
Structurally related tris[(pyridin-4-yl)phenyl]amine mole-
cules lacking the CF3 groups have been studied as octupolar
push–pull molecules,25 and as fluorescent pH sensors.26
F3C
N
1 equiv tris(4-bromophenyl)amine
BPin
CF3
4 equiv
4
3 mol% Pd(OAc)2, 6 mol% SPhos
4.5 equiv K3PO4, DME, 80 °C, 48 h
F3C
CF3
N
N
F3C
CF3
N
4
68%
F3C
N
CF3
Scheme 4 Triple Suzuki cross-coupling reaction of 1 with tris(4-bro-
mophenyl)amine
expected that this new route will be highly beneficial for
the synthesis of new organic electronic materials, catalysts,
and bioactive molecules.
All reactions were carried out under N2 atmosphere, without the use
of glovebox or Schlenk line. All commercially available chemicals and
reagents were used without further purification unless otherwise
noted. EtOAc, hexanes, and CH2Cl2 were distilled before use. Reactions
were carried out in air-free 25-mL Schlenk flask (0–4 mm Valve, 175-
mm OAH). Analytical TLC was carried out using 250-μm thick
SiliaPlate™ TLC Plates. Visualization was achieved under a UV lamp
(254 nm and 365 nm). Column chromatography was carried out using
SiliaFlash® (particle size: 40–63 μm, 230–400 mesh). All reported
yields are for isolated materials. Reaction times and yields are not op-
timized. SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl;
F3C
N
F3C
N
CF3
1 equiv Br-Ar−Br
2 mol% Pd(OAc)2
2.5
equiv
BPin
Ar
4 mol% XPhos
2.5 equiv K3PO4
XPhos
=
2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl;
HBPin = pinacolborane.
1
3a–d
F3C
F3C
CF3
DME, 80 °C, 24–48 h
Infrared spectra were recorded as neat using a Bruker Alpha-P IR in-
strument in the ATR geometry with a diamond ATR unit. Melting
points were taken on Electrothermal IA9100 melting point apparatus.
Reactions were monitored by a GC-MS operating in EI mode. Accurate
mass determinations (HRMS) were obtained using an Orbitrap mass
F3C
CF3
N
F3C
N
CF3
N
N
F3C
CF3
F3C
CF3
3b 50%
3a 55%
spectrometer. 1H NMR spectra were recorded at 700.130 MHz and 13
C
Me
NMR spectra were recorded at 176.048 MHz at ambient tempera-
tures. The chemical shifts in 1H NMR spectra are reported using TMS
as internal standard and were referenced with the residual proton
resonances of the corresponding deuterated solvent (CDCl3: δ = 7.26).
The chemical shifts in the 13C NMR spectra are reported relative to
TMS (δ = 0) or the central peak of CDCl3 (δ = 77.23) for calibration.
F3C
CF3
F3C
CF3
S
N
N
N
N
3c 82%
3d 77%
F3C
CF3
CF3
CF3
Scheme 3 Double Suzuki cross-coupling reactions of 1 with dibromo-
arenes
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trifluoro-
methyl)pyridine (1)
In a fume hood, an oven-dried Schlenk flask equipped with magnetic
stirring bar was filled with N2 and evacuated (three cycles). Under N2
atmosphere, [IrCl(COD)]2 (6.7 mg, 0.01 mmol, 2 mol% Ir), 2,2′-bipyr-
idyl (3.1 mg, 0.02 mmol, 2 mol%), HBPin (218 μL, 192 mg, 1.5 mmol,
1.5 equiv), and 2,6-bis(trifluoromethyl)pyridine (215 mg, 1 mmol, 1
equiv) were added. The Schlenk flask was closed and the mixture was
heated at 80 °C for 4 h in an oil bath. After 4 h, the Schlenk flask was
In conclusion, iridium-catalyzed borylation provides
ready access to 2,6-bis(trifluoromethyl)-4-pyridine-4-bo-
ronic acid pinacol ester. Suzuki coupling of this pyridinebo-
ronic ester provides a convenient route for the incorpora-
tion of the most electron-deficient 2,6-bis(trifluorometh-
yl)pyridin-4-yl group in various organic molecules. It is
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
F. Batool et al.
Paper
Synthesis
cooled to r.t. and exposed to air. The mixture was taken out by dis-
solving in CH2Cl2 and the volatiles were removed under reduced pres-
sure. The crude product was purified by column chromatography;
white solid; yield: 318 mg (93%); mp 87–88 °C; Rf = 0.5 (CH2Cl2).
1H NMR (700 MHz, CDCl3): δ = 8.01 (s, 2 H), 7.67 (d, J = 8.6 Hz, 2 H),
7.06 (d, J = 8.6 Hz, 2 H), 3.90 (s, 3 H).
2
13C NMR (176 MHz, CDCl3): δ = 161.8 (C), 151.9 (C), 149.3 (q, JC–F
=
35.5 Hz, 2 C), 128.6 (2 CH), 127.7 (C), 121.0 (q, 1JC–F = 274.8 Hz, 2 CF3),
FT-IR (ATR): 2983, 2963, 1310, 1272, 1139, 964, 912, 875, 844 cm–1
.
120.1 (2 CH), 115.1 (2 CH), 55.6 (OCH3).
1H NMR (700 MHz, CDCl3): δ = 8.21 (s, 2 H), 1.38 (br s, 12 H, 4 CH3 of
GC-MS (EI): m/z (%) = 321 (95) [M]+, 306 (14), 291 (19), 278 (100), 252
BPin).
(18), 238 (18), 189 (12).
13C NMR (176 MHz, CDCl3): δ = 148.1 (q, 2JC–F = 35.7 Hz, 2 C), 128.1 (2
CH), 121.0 (q, 1JC–F = 274.6 Hz, 2 CF3), 85.6 (2 C), 24.8 (4 CH3 of BPin).
Carbon atom attached to the boron atom of BPin group not observed
due to broadening from and coupling with boron.
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H10F6NO: 322.06611;
found: 322.06486.
4-[2,6-Bis(trifluoromethyl)pyridin-4-yl]-N,N-dimethylaniline (2c)
GC-MS (EI): m/z (%) = 341 (5) [M]+, 326 (100), 322 (15), 299 (14), 281
Light yellow (needles) solid; yield: 118 mg (71%); mp 128–132 °C; Rf =
(9), 255 (11).
0.5 (hexanes–CH2Cl2 1:1).
HRMS (ESI-Orbitrap): m/z [M
342.10945; found: 342.10860.
+
H]+ calcd for C13H15BF6NO2:
FT-IR (ATR): 2952, 2923, 2869, 1589, 1537, 1389, 1281, 1125, 1060,
996, 887, 853, 812, 694 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.98 (s, 2 H), 7.63 (d, J = 8.8 Hz, 2 H),
6.79 (d, J = 8.8 Hz, 2 H), 3.08 (s, 6 H).
Suzuki Coupling; General Procedure
In a fume hood, an oven-dried Schlenk flask equipped with magnetic
stirring bar was filled with N2 and evacuated (three cycles). Under N2
atmosphere, Pd(OAc)2 (1.1 mg, 0.005 mmol, 1 mol% Pd), SPhos (4.1
mg, 0.01 mmol, 2 mol%), K3PO4 (160 mg, 1.5 mmol, 1.5 equiv), 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trifluorometh-
yl)pyridine (1, 171 mg, 0.5 mmol, 1 equiv), aryl bromide (0.75 mmol,
1.5 equiv), and DME (2 mL) were added in order. The Schlenk flask
was closed and the mixture was heated at 80 °C in an oil bath for 24–
48 h. The progress of reaction was monitored by GC-MS and TLC.
Upon completion of reaction, the Schlenk flask was cooled to r.t. and
exposed to air. The mixture was extracted into EtOAc, washed with
water and brine, and dried (anhyd Na2SO4). The crude product was
purified by column chromatography (silica gel).
2
13C NMR (176 MHz, CDCl3): δ = 152.0 (C), 151.9 (C), 149.0 (q, JC–F
=
35.2 Hz, 2 C), 128.0 (2 CH), 121.9 (C), 121.2 (q, 1JC–F = 274.7 Hz, 2 CF3),
118.8 (2 CH), 112.4 (2 CH), 40.2 (2 CH3).
GC-MS (EI): m/z (%) = 334 (97) [M]+, 333 (100), 318 (10), 317 (12), 315
(9), 290 (8), 270 (24), 220 (30), 202 (9), 195 (9).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C15H13F6N2: 335.09774;
found: 335.09647.
2,6-Bis(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]pyridine
(2d)
Colorless solid; yield: 136 mg (77%); mp 82–83 °C; Rf = 0.6 (hexanes–
CH2Cl2 1:1).
For chloro-substituted bromoarenes (2g, 2h, and 2m), Pd(PPh3)4 (23
mg, 0.02 mmol, 4 mol% Pd) was used (for 1-mmol scale reaction) in
place of Pd(OAc)2 and SPhos. Unless otherwise noted, reactions were
performed on a 0.5-mmol 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-2,6-bis(trifluoromethyl)pyridine (1) scale.
FT-IR (ATR): 2924, 2854, 1611, 1395, 1325, 1296, 1273, 1195, 1110,
1054, 1015, 905, 835, 725, 695 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.07 (s, 2 H), 7.84 (d, J = 8.4 Hz, 2 H),
7.82 (d, J = 8.4 Hz, 2 H).
13C NMR (176 MHz, CDCl3): δ = 151.1 (C), 149.7 (q, 2JC–F = 35.9 Hz, 2 C),
139.2 (C), 132.6 (q, 2JC–F = 33.0 Hz, C), 127.8 (2 CH), 126.7 (q, 3JC–F = 3.7
Hz, 2 CH), 123.6 (q, 1JC–F = 272.3 Hz, CF3), 121.2 (d, 4JC–F = 1.4 Hz, 2 CH),
120.8 (q, 1JC–F = 274.7 Hz, 2 CF3).
GC-MS (EI): m/z (%) = 359 (51) [M]+, 340 (15), 309 (10), 290 (100), 270
(46), 243 (11), 220 (31), 201 (9), 145 (6).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H7F9N: 360.04293;
found: 360.04173.
4-(p-Tolyl)-2,6-bis(trifluoromethyl)pyridine (2a)
Colorless solid, 1-mmol scale; yield: 233 mg (76%); mp 57–58 °C; Rf =
0.6 (hexanes–CH2Cl2 4:1).
FT-IR (ATR): 2927, 2857, 1608, 1391, 1288, 1262, 1138, 1097, 1063,
896, 856, 816, 717, 695 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.04 (s, 2 H), 7.61 (d, J = 7.9 Hz, 2 H),
7.37 (d, J = 7.9 Hz, 2 H), 2.45 (s, 3 H).
13C NMR (176 MHz, CDCl3): δ = 152.4 (C), 149.3 (q, 2JC–F = 35.6 Hz, 2 C),
141.3 (C), 132.7 (C), 130.4 (2 CH), 127.1 (2 CH), 121.0 (q, 1JC–F = 274.7
Hz, 2 CF3), 120.6 (2 CH), 21.4 (CH3).
GC-MS (EI): m/z (%) = 305 (65) [M]+, 286 (10), 236 (92), 216 (100), 189
(17), 167 (9).
4-[2,6-Bis(trifluoromethyl)pyridin-4-yl]benzonitrile (2e)
Colorless solid, 1-mmol scale; yield: 198 mg (63%); mp 194 °C; Rf =
0.25 (hexanes–CH2Cl2 1:1).
FT-IR (ATR): 3086, 3042, 2238, 1615, 1392, 1294, 1270, 1194, 1117,
1064, 918, 835, 708, 694, 558 cm–1
.
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H10F6N: 306.07120;
found: 306.07030.
1H NMR (700 MHz, CDCl3): δ = 8.07 (s, 2 H), 7.89–7.88 (m, 2 H), 7.83–
7.82 (m, 2 H).
13C NMR (176 MHz, CDCl3): δ = 150.6 (C), 149.8 (q, 2JC–F = 35.9 Hz, 2 C),
4-(4-Methoxyphenyl)-2,6-bis(trifluoromethyl)pyridine (2b)
1
139.9 (C), 133.4 (2 CH), 128.0 (2 CH), 121.2 (2 CH), 120.7 (q, JC–F
=
Colorless solid; yield: 138 mg (86%); mp 81–84 °C; Rf = 0.6 (hexanes–
CH2Cl2 1:1).
274.7 Hz, 2 CF3), 117.8 (C), 114.5 (C).
GC-MS (EI): m/z (%) = 316 (68) [M]+, 297 (7), 247 (100), 227 (37), 220
(6), 207 (12), 200 (19), 197 (5), 177 (11), 170 (4), 158 (22), 151 (9).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H7F6N2: 317.05079;
FT-IR (ATR): 2977, 2944, 2919, 2848, 1604, 1521, 1464, 1390, 1265,
1133, 1064, 1023, 897, 855, 828, 718, 696 cm–1
.
found: 317.05029.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
F. Batool et al.
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Synthesis
Ethyl 4-[2,6-Bis(trifluoromethyl)pyridin-4-yl]benzoate (2f)
13C NMR (176 MHz, CDCl3): δ = 154.1 (2 C), 152.6 (C), 149.2 (q, 2JC–F
35.6 Hz, 2 C), 140.2 (C), 131.1 (C), 120.9 (q, JC–F = 274.7 Hz, 2 CF3),
120.8 (2 CH), 104.5 (2 CH), 61.1 (OCH3), 56.4 (2 OCH3).
GC-MS (EI): m/z (%) = 381 (50) [M]+, 366 (32), 338 (56), 323 (27), 306
(46), 295 (16), 286 (23), 278 (66), 252 (100), 220 (10), 214 (10).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C16H14F6NO3: 382.08724;
found: 382.08609.
=
1
Colorless solid, 1-mmol scale; yield: 167 mg (46%); mp 134 °C; Rf = 0.3
(hexanes–CH2Cl2 2:1).
FT-IR (ATR): 3082, 2990, 2922, 1710, 1609, 1465, 1445, 1392, 1369,
1286, 1258, 1183, 1124, 1061, 1016, 910, 860, 825, 773 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.24–8.23 (m, 2 H), 8.09 (s, 2 H), 7.77–
7.76 (m, 2 H), 4.44 (q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H).
2
13C NMR (176 MHz, CDCl3): δ = 165.7 (C=O), 151.5 (C), 149.5 (q, JC–F
=
2-[2,6-Bis(trifluoromethyl]pyridin-4-yl)-N,N-dimethylaniline (2j)
35.9 Hz, 2 C), 139.6 (C), 132.4 (C), 130.8 (2 CH), 127.3 (2 CH), 121.1 (2
CH), 120.8 (q, 1JC–F = 274.7 Hz, 2 CF3), 61.6 (CH2), 14.3 (CH3).
Very light greenish solid; yield: 102 mg (61%); mp 111–113 °C; Rf =
0.6 (hexanes–CH2Cl2 1:1).
GC-MS (EI): m/z (%) = 363 (11) [M]+, 344 (6), 335 (62), 318 (94), 290
FT-IR (ATR): 3084, 3013, 2987, 2919, 2795, 1607, 1573, 1495, 1391,
(10), 270 (68), 220 (100), 200 (11), 175 (6), 171 (7), 152 (7), 149 (7).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C16H12F6NO2: 364.07667;
found: 364.07595.
1189, 1101, 947, 899, 831, 765, 716, 694 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.17 (s, 2 H), 7.41 (t, J = 7.5 Hz, 1 H),
7.28 (d, J = 7.6 Hz, 1 H), 7.15 (d, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1 H),
2.59 (s, 6 H).
4-(3-Chlorophenyl)-2,6-bis(trifluoromethyl)pyridine (2g)
2
13C NMR (176 MHz, CDCl3): δ = 153.9 (C), 151.6 (C), 149.0 (q, JC–F
=
Colorless solid, 1-mmol scale; yield: 310 mg (95%); mp 94–95 °C; Rf =
35.5 Hz, 2 C), 131.3 (CH), 131.1 (CH), 128.5 (C), 122.6 (2 CH), 121.1 (q,
1JC–F = 274.7 Hz, 2 CF3), 118.7 (CH), 43.9 (2 CH3). One CH carbon peak
overlapped with any of the other CH peaks.
GC-MS (EI): m/z (%) = 334 (90) [M]+, 333 (45), 318 (27), 316 (69), 293
(12), 265 (100), 249 (28), 245 (23), 223 (17), 220 (19), 196 (23).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C15H13F6N2: 335.09774;
0.8 (hexanes–CH2Cl2 1:1).
FT-IR (ATR): 3099, 1610, 1560, 1389, 1284, 1126, 906, 883, 868, 853,
795 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.04 (s, 2 H), 7.67 (app t, J = 1.6 Hz, 1
H), 7.58 (dt, J = 7.2, 1.6 Hz, 1 H), 7.54 (dt, J = 8.1, 1.6 Hz, 1 H), 7.51 (app
t, J = 7.9 Hz, 1 H).
13C NMR (176 MHz, CDCl3): δ = 151.2 (C), 149.6 (q, 2JC–F = 35.9 Hz, 2 C),
137.4 (C), 135.8 (C), 131.0 (CH), 130.7 (CH), 127.4 (CH), 125.4 (CH),
121.0 (2 CH), 120.8 (q, 1JC–F = 275 Hz, 2 CF3).
found: 335.09620.
7-[2,6-Bis(trifluoromethyl)pyridin-4-yl]-1H-indole (2k)
Light purplish-white solid; yield: 105 mg (64%); mp 129–131 °C; Rf =
0.4 (hexanes–CH2Cl2 5:1).
GC-MS (EI): m/z (%) = 325 (84) [M]+, 327 (26) [M + 2]+, 306 (9), 258
(29), 256 (100), 236 (30), 220 (30), 200 (15), 167 (20).
FT-IR (ATR): 3471, 3139, 3113, 1611, 1425, 1330, 1190, 1129, 966,
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H7ClF6N: 326.01657;
found: 326.01568.
894, 857, 798, 736 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.40 (s, NH), 8.15 (s, 2 H), 7.81 (d, J =
7.33 Hz, 1 H), 7.33 (app t, J = 2.7 Hz, 1 H), 7.31–7.28 (m, 2 H), 6.71
(app t, J = 2.7 Hz, 1 H).
13C NMR (176 MHz, CDCl3): δ = 151.6 (C), 149.7 (q, 2JC–F = 35.8 Hz, 2 C),
132.8 (C), 129.4 (C), 125.4 (CH), 123.4 (CH), 122.7 (CH), 122.1 (CH),
120.9 (q, 1JC–F = 275 Hz, 2 CF3), 120.8 (CH), 120.1 (C), 104.0 (CH).
GC-MS (EI): m/z (%) = 330 (43) [M]+, 309 (37), 260 (11), 241 (100), 221
(13), 191 (8).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C15H9F6N2: 331.06644;
found: 331.06495.
4-(3,5-Dichlorophenyl)-2,6-bis(trifluoromethyl)pyridine (2h)
Colorless solid; yield: 153 mg (85%); mp 131–133 °C; Rf = 0.8 (hex-
anes–CH2Cl2 1:1).
FT-IR (ATR): 3063, 1611, 1557, 1444, 1382, 1275, 1125, 1088, 869,
851, 802 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.01 (s, 2 H), 7.56 (d, J = 1.5 Hz, 2 H),
7.55 (t, J = 1.5 Hz, 1 H).
13C NMR (176 MHz, CDCl3): δ = 149.9 (C), 149.7 (q, 2JC–F = 36 Hz, 2 C),
138.6 (C), 136.5 (2 C), 130.5 (CH), 125.7 (2 CH), 121.0 (2 CH), 120.7 (q,
1JC–F = 275 Hz, 2 CF3).
GC-MS (EI): m/z (%) = 359 (88) [M]+, 361 (54) [M + 2]+, 340 (8), 304
(16), 290 (100), 270 (23), 255 (31), 235 (15), 220 (53), 201 (29).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H6Cl2F6N: 359.97760;
found: 359.97646.
2′,5,6′-Tris(trifluoromethyl)-2,4′-bipyridine (2l)
Colorless solid; yield: 132 mg (73%); mp 91–93 °C; Rf = 0.5 (hexanes–
CH2Cl2 1:1).
FT-IR (ATR): 3103, 1605, 1385, 1328, 1278, 1128, 1066, 1015, 911,
845, 775, 727, 694 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 9.07 (s, 1 H), 8.55 (s, 2 H), 8.17 (dd, J =
8.2, 1.7 Hz, 1 H), 8.07 (d, J = 8.2 Hz, 1 H).
2,6-Bis(trifluoromethyl)-4-(3,4,5-trimethoxyphenyl)pyridine (2i)
Colorless solid, 1-mmol scale; yield: 300 mg (79%); mp 129–132 °C;
Rf = 0.5 (hexanes–CH2Cl2 1:1).
2
13C NMR (176 MHz, CDCl3): δ = 154.9 (C), 149.8 (q, JC–F = 35.9 Hz, 2
3
3
C),148.9 (C), 147.5 (q, JC–F = 3.8 Hz, CH), 135.0 (q, JC–F = 3.7 Hz, CH),
127.9 (q, 2JC–F = 34.0 Hz, C), 123.1 (q, 1JC–F = 273.2 Hz, CF3), 120.8 (q,
1JC–F = 274.8 Hz, 2 CF3), 120.8 (CH), 120.7 (2 CH).
FT-IR (ATR): 2955, 2829, 1589, 1509, 1462, 1394, 1278, 1241, 1191,
1122, 992, 909, 828 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.99 (s, 2 H), 6.83 (s, 2 H), 3.97 (s, 6 H),
3.93 (s, 3 H).
GC-MS (EI): m/z (%) = 360 (22) [M]+, 341 (10), 291 (100), 271 (47), 221
(14), 202 (12), 194 (6).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H6F9N2: 361.03818;
found: 361.03683.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Synthesis
4-(5-Chlorothiophen-2-yl)-2,6-bis(trifluoromethyl)pyridine (2m)
13C NMR (176 MHz, CDCl3): δ = 152.4 (C), 149.4 (q, 2JC–F = 35.6 Hz, 2 C),
134.0 (C), 133.3 (C), 132.7 (C), 129.7 (CH), 128.7 (CH), 127.86 (CH),
127.82 (CH), 127.34 (CH), 127.31 (CH), 123.8 (CH), 121.0 (2 CH),
120.96 (q, 1JC–F = 275 Hz, 2 CF3).
GC-MS (EI): m/z (%) = 341 (100) [M]+, 320 (14), 272 (15), 252 (63), 232
(19), 202 (23), 176 (8).
Light yellow solid, 1-mmol scale; yield: 243 mg (73%); mp 81–83 °C;
Rf = 0.6 (hexanes–CH2Cl2 1:1).
FT-IR (ATR): 3108, 3086, 1607, 1427, 1384, 1281, 1178, 1135, 990,
895, 854, 799, 713 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.88 (s, 2 H), 7.47 (d, J = 4.0 Hz, 1 H),
7.04 (d, J = 4.0 Hz, 1 H).
13C NMR (176 MHz, CDCl3): δ = 149.7 (q, 2JC–F = 35.9 Hz, 2 C), 144.5 (C),
136.7 (C), 135.0 (C), 128.3 (CH), 127.1 (CH), 120.7 (q, 1JC–F = 274.7 Hz,
2 CF3), 118.3 (2 CH).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C17H10F6N: 342.07120;
found: 342.06992.
4-(Anthracen-9-yl)-2,6-bis(trifluoromethyl)pyridine (2q)
Very light greenish-yellow solid; yield: 135 mg (69%); mp 227–230
°C; Rf = 0.6 (hexanes–CH2Cl2 1:1).
GC-MS (EI): m/z (%) = 331 (100) [M]+, 333 (36) [M + 2]+, 312 (10), 292
(12), 276 (27), 262 (35), 252 (51), 242 (18), 227 (30), 182 (10).
FT-IR (ATR): 3084, 3051, 2924, 2852, 1608, 1331, 1273, 1189, 1127,
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C11H5ClF6NS: 331.97299;
found: 331.97202.
982, 900, 856, 788, 738 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.64 (s, 1 H), 8.12 (d, J = 8.5 Hz, 2 H),
8.01 (s, 2 H), 7.54 (ddd, J = 8.4, 6.5, 0.9 Hz, 2 H), 7.48 (ddd, J = 8.7, 6.5,
1.2 Hz, 2 H), 7.40 (dd, J = 8.7, 0.7 Hz, 2 H).
5-[2,6-Bis(trifluoromethyl)pyridin-4-yl]thiophene-2-carbalde-
hyde (2n)
13C NMR (176 MHz, CDCl3): δ = 152.1 (C), 149.3 (q, 2JC–F = 35.8 Hz, 2 C),
Light yellow solid, 1-mmol scale; yield: 156 mg (48%); mp 114 °C; Rf =
0.5 (hexanes–CH2Cl2 2:1).
131.1 (2 C), 130.3 (C), 129.3 (2 C), 129.1 (CH), 128.9 (2 CH), 127.2 (2
1
CH), 126.0 (2 CH), 125.7 (2 CH), 124.7 (2 CH), 121.0 (q, JC–F = 274.8
FT-IR (ATR): 3108, 3081, 2826, 1672, 1612, 1530, 1382, 1321, 1282,
Hz, 2 CF3).
1124, 1066, 989, 905, 855, 785, 755 cm–1
.
GC-MS (EI): m/z (%) = 391 (87) [M]+, 370 (20), 322 (51), 302 (100), 282
(30), 251 (48), 225 (20).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C21H12F6N: 392.08685;
found: 392.08564.
1H NMR (700 MHz, CDCl3): δ = 10.01 (s, 1 H), 8.07 (s, 2 H), 7.87 (d, J =
4.0 Hz, 1 H), 7.76 (d, J = 4.0 Hz, 1 H).
13C NMR (176 MHz, CDCl3): δ = 182.6 (C=O), 149.9 (q, 2JC–F = 35.9 Hz, 2
1JC–F = 274.7 Hz, 2 CF3), 119.5 (2 CH).
GC-MS (EI): m/z (%) = 325 (60) [M]+, 324 (76) [M–1]+, 306 (7), 297 (6),
258 (4), 252 (100), 233 (4), 228 (8), 212 (5), 208 (12), 202 (6), 182 (9),
163 (4), 152 (4), 137 (4).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H6OF6NS: 326.00688;
found: 326.0679.
4-(Pyren-1-yl)-2,6-bis(trifluoromethyl)pyridine (2r)
Light orange solid; yield: 125 mg (60%); mp 212–214 °C; Rf = 0.8 (hex-
anes–CH2Cl2 1:1).
FT-IR (ATR): 3083, 3042, 2917, 1605, 1394, 1274, 1190, 1121, 841,
759, 722 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.29 (d, J = 7.5 Hz, 1 H), 8.28 (d, J = 7.8
Hz, 1 H), 8.26 (d, J = 7.5 Hz, 1 H), 8.20 (d, J = 8.9 Hz, 1 H), 8.17 (s, 2 H),
8.16 (d, J = 9.1 Hz, 1 H), 8.14 (d, J = 8.9 Hz, 1 H), 8.10 (t, J = 7.6 Hz, 1 H),
7.99 (d, J = 9.1 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H).
13C NMR (176 MHz, CDCl3): δ = 153.5 (C), 149.0 (q, 2JC–F = 35.7 Hz, 2 C),
132.4 (C), 131.4 (C), 131.3 (C), 130.7 (C), 129.5 (CH), 129.0 (CH), 128.1
Methyl 5-[2,6-Bis(trifluoromethyl)pyridin-4-yl]furan-2-carboxyl-
ate (2o)
Colorless solid; yield: 125 mg (74%); mp 168–170 °C; Rf = 0.5 (hex-
anes–CH2Cl2 1:1).
FT-IR (ATR): 3129, 3087, 2967, 1725, 1689, 1616, 1460, 1376, 1285,
1134, 1034, 987, 902, 855, 821, 764, 712 cm–1
.
(C), 127.2 (CH), 127.0 (CH), 126.7 (CH), 126.4 (CH), 125.9 (CH), 125.0
1H NMR (700 MHz, CDCl3): δ = 8.14 (s, 2 H), 7.33 (br s, 1 H), 7.18 (br s,
1 H), 3.97 (s, 3 H).
1
(CH), 124.9 (C), 124.8 (CH), 124.5 (C), 122.9 (CH), 121.0 (q, JC–F
=
274.8 Hz, 2 CF3).
2
13C NMR (176 MHz, CDCl3): δ = 158.5 (C), 151.7 (C), 149.7 (q, JC–F
=
GC-MS (EI): m/z (%) = 415 (100) [M]+, 394 (27), 345 (20), 326 (56), 306
(16), 276 (28).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C23H12F6N: 416.08685;
found: 416.08519.
1
36.2 Hz, 2 C), 146.5 (C), 139.9 (C), 120.7 (q, JC–F = 274.9 Hz, 2 CF3),
119.7 (CH), 117.7 (CH), 112.7 (CH), 52.5 (CH3).
GC-MS (EI): m/z (%) = 339 (36) [M]+, 308 (100), 281 (16), 252 (72), 182
(9).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H8F6NO3: 340.04029;
Double Suzuki Coupling; General Procedure
found: 340.03889.
In a fume hood, an oven-dried Schlenk flask equipped with magnetic
stirring bar was filled with N2 and evacuated (three cycles). Under N2
atmosphere, Pd(OAc)2 (1.1 mg, 0.005 mmol, 2 mol% Pd), XPhos (4.8
mg, 0.01 mmol, 4 mol%), K3PO4 (133 mg, 0.625 mmol, 2.5 equiv), 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trifluorometh-
yl)pyridine (1, 213 mg, 0.625 mmol, 2.5 equiv), aryl bromide (0.25
mmol, 1 equiv), and DME (2 mL) were added in order. The Schlenk
flask was closed and the mixture was heated at 80 °C in an oil bath for
24–48 h. The progress of reaction was monitored by GC-MS and TLC.
Upon completion of reaction, the Schlenk flask was cooled to r.t. and
exposed to air. The mixture was extracted into EtOAc, washed with
4-(Naphthalen-2-yl)-2,6-bis(trifluoromethyl)pyridine (2p)
Colorless solid; yield: 146 mg (86%); mp 153–154 °C; Rf = 0.7 (hex-
anes–CH2Cl2 1:1).
FT-IR (ATR): 3095, 3065, 1614, 1396, 1276, 1178, 1128, 1059, 885,
864, 815, 748 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.19 (s, 3 H), 8.03 (d, J = 8.5 Hz, 1 H),
7.99–7.92 (m, 2 H), 7.70 (dd, J = 8.5, 1.7 Hz, 1 H), 7.62–7.60 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
F. Batool et al.
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Synthesis
water and brine, and dried (anhyd Na2SO4). The crude product was
purified by column chromatography (silica gel). All experiments be-
low were conducted on a 0.25-mmol aryl bromide scale.
FT-IR (ATR): 3102, 1609, 1383, 1279, 1184, 1127, 1096, 1031, 890,
856, 814, 788, 711 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.05 (s, 4 H), 7.78 (s, 2 H).
13C NMR (176 MHz, CDCl3): δ = 149.9 (q, 2JC–F = 35.9 Hz, 4 C), 143.9 (2
C), 141.7 (2 C), 128.9 (2 CH), 120.6 (q, 1JC–F = 275 Hz, 4 CF3), 118.9 (d,
3JC–F = 1.5 Hz, 4 CH).
GC-MS (EI): m/z (%) = 510 (M+, 100), 491 (12), 441 (22), 421 (24), 371
(13), 351 (15), 283 (13), 271 (10), 258 (80), 252 (20), 207 (18).
1,4-Bis[2,6-bis(trifluoromethyl)pyridin-4-yl]benzene (3a)
Colorless solid; yield: 69 mg (55%); mp 215–217 °C; Rf = 0.7 (hexanes–
CH2Cl2 1:1).
FT-IR (ATR): 3105, 1608, 1385, 1293, 1264, 1191, 1126, 1070, 904,
836, 809, 717, 695 cm–1
.
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C18H7F12N2S: 511.01328;
found: 511.01118.
1H NMR (700 MHz, CDCl3): δ = 8.11 (s, 4 H), 7.91 (s, 4 H).
13C NMR (176 MHz, CDCl3): δ = 151.1 (2 C), 149.7 (q, 2JC–F = 35.9 Hz, 4
3
C), 137.9 (2 C), 128.6 (4 CH), 121.0 (d, JC–F = 1.4 Hz, 4 CH), 120.8 (q,
Tris{4-[2,6-bis(trifluoromethyl)pyridin-4-yl]phenyl}amine (4)
1JC–F = 274.8 Hz, 4 CF3).
In a fume hood, an oven-dried Schlenk flask equipped with magnetic
stirring bar was filled with N2 and evacuated (three cycles). Under N2
atmosphere, Pd(OAc)2 (1.7 mg, 0.0075 mmol, 3 mol% Pd), SPhos (6.2
mg, 0.015 mmol, 6 mol%), K3PO4 (239 mg, 1.125 mmol, 4.5 equiv), 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trifluorometh-
yl)pyridine (341 mg, 1 mmol, 4 equiv), tris(4-bromophenyl)amine
(121 mg, 0.25 mmol, 1 equiv), and DME (2 mL) were added in order.
The Schlenk flask was closed and the mixture was heated at 80 °C in
an oil bath for 48 h. The progress of reaction was monitored by GC-MS
and TLC. Upon completion of reaction, the Schlenk flask was cooled to
r.t. and exposed to air. The mixture was extracted into EtOAc, washed
with water and brine, and dried (anhyd Na2SO4). The crude product
was purified by column chromatography (silica gel); light yellow sol-
id; yield: 151 mg (0.25 mmol, 68%); mp 262–263 °C; Rf = 0.4 (hex-
anes–CH2Cl2 1:1).
GC-MS (EI): m/z (%) = 504 (100) [M]+, 485 (12), 435 (51), 415 (47), 395
(12), 365 (18), 345 (29), 295 (14), 277 (16), 270 (15), 252 (25), 250
(16), 220 (15), 218 (24), 208 (21), 183 (35), 173 (16).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C20H9F12N2: 505.05686;
found: 505.05524.
9,10-Bis[2,6-bis(trifluoromethyl)pyridin-4-yl]anthracene (3b)
Colorless solid; yield: 76 mg (50%); mp 314–315 °C; Rf = 0.6 (hexanes–
CH2Cl2 1:1).
FT-IR (ATR): 3044, 2922, 2850, 1606, 1426, 1338, 1278, 1186, 1132,
983, 915, 855, 805, 762 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.03 (s, 4 H), 7.54 (dd, J = 6.8, 3.1 Hz, 4
H), 7.47 (dd, J = 6.8, 3.1 Hz, 4 H).
FT-IR (ATR): 1593, 1515, 1389, 1329, 1260, 1187, 1129, 1064, 898,
13C NMR (176 MHz, CDCl3): δ = 151.5 (2 C), 149.5 (q, 2JC–F = 36.1 Hz, 4
C), 132.9 (2 C), 128.9 (4 C), 127.4 (4 CH), 125.7 (4 CH), 125.6 (4 CH),
120.9 (q, 1JC–F = 275 Hz, 4 CF3).
GC-MS (EI): m/z (%) = 604 (100) [M]+, 585 (10), 535 (26), 515 (342),
390 (20), 370 (56), 321 (32), 320 (23), 300 (41), 282 (21), 275 (15),
251 (46), 247 (20), 222 (20).
855, 824, 725 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 8.05 (s, 6 H), 7.69 (d, J = 8.6 Hz, 6 H),
7.34 (d, J = 8.6 Hz, 6 H).
13C NMR (176 MHz, CDCl3): δ = 151.3 (3 C), 149.4 (q, 2JC–F = 35.6 Hz, 6
C), 148.6 (3 C), 131.0 (3 C), 128.7 (6 CH), 125.1 (6 CH), 120.9 (q, 1JC–F
=
274.7 Hz, 6 CF3), 120.3 (6 CH).
GC-MS (EI): m/z (%) = 884 (100) [M]+, 865 (10), 756 (7), 670 (11), 554
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C28H13F12N2: 605.08816;
found: 605.08593.
(27), 432 (32), 301 (38).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C39H19F18N4: 885.13168;
4,4′-(5-Methyl-1,3-phenylene)bis[2,6-bis(trifluoromethyl)pyri-
dine] (3c)
found: 885.12840.
Colorless solid; yield: 106 mg (82%); mp 189–192 °C; Rf = 0.7 (hex-
anes–CH2Cl2 1:1).
Acknowledgment
FT-IR (ATR): 3097, 2928, 1613, 1421, 1359, 1281, 1188, 1133, 993,
891, 852, 765 cm–1
.
We thank Lahore University of Management Sciences for providing
generous financial support for this research through start-up grant
and through faculty initiative fund to GAC. This work was partly sup-
ported by King Abdullah University of Science and Technology
(KAUST), and by University of the Punjab, Lahore, Pakistan. We are
thankful to SBA for financial support for the purchase of GC-MS. We
are thankful to Ms. Noor-ul-Ann for her assistance in some part of the
experimental work. We extend our acknowledgement to KAUST core
labs facilities for NMR and HRMS measurements.
1H NMR (700 MHz, CDCl3): δ = 8.10 (s, 4 H), 7.72 (s, 1 H), 7.66 (m, 2 H),
2.62 (s, 3 H).
13C NMR (176 MHz, CDCl3): δ = 151.7 (2 C), 149.6 (q, 2JC–F = 36.0 Hz, 4
C), 141.4 (C), 137.6 (2 C), 130.1 (2 CH), 123.3 (CH), 121.2 (d, 3JC–F = 1.3
Hz, 4 CH), 120.8 (q, 1JC–F = 274.8 Hz, 4 CF3), 21.6 (CH3).
GC-MS (EI): m/z (%) = 518 (61) [M]+, 499 (10), 450 (20), 429 (73), 402
(12), 380 (13), 304 (32), 284 (23), 264 (23), 259 (27), 215 (51), 190
(44).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C21H11F12N2: 519.07251;
found: 519.07092.
Supporting Information
2,5-Bis[2,6-bis(trifluoromethyl)pyridin-4-yl]thiophene (3d)
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588344.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Light orange solid; yield: 98 mg (77%); mp 164–168 °C; Rf = 0.7 (hex-
anes–CH2Cl2 1:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
F. Batool et al.
Paper
Synthesis
References
(14) For recent examples of the use of 3,5-bis(trifluoromethyl)aryl
group see (a) Larsen, M. A.; Wilson, C. V.; Hartwig, J. F. J. Am.
Chem. Soc. 2015, 137, 8633. (b) Kuninobu, Y.; Ida, H.; Nishi, M.;
Kanai, M. Nat. Chem. 2015, 7, 712.
(1) (a) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Chem. Rev. 2012,
112, 2208. (b) Zhao, Y.; Guo, Y.; Liu, Y. Adv. Mater. (Weinheim,
Ger.) 2013, 25, 5372. (c) Bures, F. RSC Adv. 2014, 4, 58826.
(2) (a) Dimitrijević, E.; Taylor, M. S. ACS Catal. 2013, 3, 945.
(b) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem.
Soc. Rev. 2014, 43, 2714. (c) Ishihara, K.; Kondo, S.; Yamamoto,
H. J. Org. Chem. 2000, 65, 9125.
(3) (a) Reddy, V. P.; Sinn, E.; Hosmane, N. J. Organomet. Chem. 2015,
798, 5. (b) Van Rossom, W.; Terentyeva, T. G.; Sodeyama, K.;
Matsushita, Y.; Tateyama, Y.; Ariga, K.; Hill, J. P. Org. Biomol.
Chem. 2014, 12, 5492. (c) Nam, H.; Kwon, J. E.; Choi, M.-W.; Seo,
J.; Shin, S.; Kim, S.; Park, S. Y. ACS Sens. 2016, 1, 392.
(4) (a) Brookhart, M.; Grant, B.; Volpe, A. F. Organometallics 1992,
11, 3920. (b) Yakelis, N. A.; Bergman, R. G. Organometallics 2005,
24, 3579.
(5) Herrington, T. J.; Thom, A. J. W.; White, A. J. P.; Ashley, A. E.
Dalton Trans. 2012, 41, 9019.
(6) Taft, R. W. J. Am. Chem. Soc. 1953, 75, 4231.
(7) Korenaga, T.; Kadowaki, K.; Ema, T.; Sakai, T. J. Org. Chem. 2004,
69, 7340.
(8) Korenaga, T.; Ko, A.; Uotani, K.; Tanaka, Y.; Sakai, T. Angew.
Chem. Int. Ed. 2011, 50, 10703.
(15) Kobayashi, Y.; Kumadaki, I. Chem. Pharm. Bull. 1969, 17, 510.
(16) Porwisiak, J.; Dmowski, W. Tetrahedron 1994, 50, 12259.
(17) Xu, Q.-L.; Liang, X.; Zhang, S.; Jing, Y.-M.; Liu, X.; Lu, G.-Z.;
Zheng, Y.-X.; Zuo, J.-L. J. Mater. Chem. C 2015, 3, 3694.
(18) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E. Jr.; Smith, M.
R. III Science (Washington, D. C.) 2002, 295, 305. (b) Ishiyama, T.;
Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F.
J. Am. Chem. Soc. 2002, 124, 390. (c) Mkhalid, I. A. I.; Barnard, J.
H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010,
110, 890.
(19) (a) Cho, J.-Y.; Iverson, C. N.; Smith, M. R. III J. Am. Chem. Soc.
2000, 122, 12868. (b) Boller, T. M.; Murphy, J. M.; Hapke, M.;
Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
127, 14263.
(20) For Ir-catalyzed borylation of 2-CF3 substituted pyridine, see:
Sadler, S. A.; Tajuddin, H.; Mkhalid, I. A. I.; Batsanov, A. S.;
Albesa-Jove, D.; Cheung, M. S.; Maxwell, A. C.; Shukla, L.;
Roberts, B.; Blakemore, D. C.; Lin, Z.; Marder, T. B.; Steel, P. G.
Org. Biomol. Chem. 2014, 12, 7318.
(21) Batool, F.; Parveen, S.; Emwas, A.-H.; Sioud, S.; Gao, X.;
Munawar, M. A.; Chotana, G. A. Org. Lett. 2015, 17, 4256.
(22) Lahm, G. P.; Cordova, D.; Barry, J. D.; Pahutski, T. F.; Smith, B. K.;
Long, J. K.; Benner, E. A.; Holyoke, C. W.; Joraski, K.; Xu, M.;
Schroeder, M. E.; Wagerle, T.; Mahaffey, M. J.; Smith, R. M.;
Tong, M.-H. Bioorg. Med. Chem. Lett. 2013, 23, 3001.
(23) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.
Int. Ed. 2006, 45, 3484.
(9) (a) Korenaga, T.; Sasaki, R.; Shimada, K. Dalton Trans. 2015, 44,
19642. (b) Korenaga, T.; Suzuki, N.; Sueda, M.; Shimada, K.
J. Organomet. Chem. 2015, 780, 63.
(10) Sergei, P. G.; Marina, V. F. Russ. Chem. Rev. 2008, 77, 1055.
(11) (a) Machado, V. G.; Stock, R. I.; Reichardt, C. Chem. Rev. 2014,
114, 10429. (b) Diemer, V.; Chaumeil, H.; Defoin, A.; Fort, A.;
Boeglin, A.; Carré, C. Eur. J. Org. Chem. 2008, 1767. (c) Diemer,
V.; Chaumeil, H.; Defoin, A.; Fort, A.; Boeglin, A.; Carré, C. Eur. J.
Org. Chem. 2006, 2727. (d) Letrun, R.; Koch, M.; Dekhtyar, M. L.;
Kurdyukov, V. V.; Tolmachev, A. I.; Rettig, W.; Vauthey, E. J. Phys.
Chem. A 2013, 117, 13112.
(12) (a) He, G. S.; Tan, L.-S.; Zheng, Q.; Prasad, P. N. Chem. Rev. 2008,
108, 1245. (b) Abbotto, A.; Beverina, L.; Bozio, R.; Bradamante,
S.; Ferrante, C.; Pagani, G. A.; Signorini, R. Adv. Mater. (Weinheim,
Ger.) 2000, 12, 1963.
(24) Bulgarevich, D. S.; Kajimoto, O.; Hara, K. J. Phys. Chem. 1994, 98,
2278.
(25) (a) Vivas, M. G.; Silva, D. L.; Rodriguez, R. D. F.; Canuto, S.;
Malinge, J.; Ishow, E.; Mendonca, C. R.; De Boni, L. J. Phys. Chem.
C 2015, 119, 12589. (b) Melanova, K.; Cvejn, D.; Bures, F.; Zima,
V.; Svoboda, J.; Benes, L.; Mikysek, T.; Pytela, O.; Knotek, P.
Dalton Trans. 2014, 43, 10462.
(26) Hu, B.; Chen, X.; Wang, Y.; Lu, P.; Wang, Y. Chem. Asian J. 2013,
8, 1144.
(13) (a) Clapham, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. Org.
Biomol. Chem. 2009, 7, 2155. (b) Wilson, J. N.; Ladefoged, L. K.;
Babinchak, W. M.; Schiøtt, B. ACS Chem. Neurosci. 2014, 5, 296.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H