Synthesis and evaluation of 1,2,4-methyltriazines as mGluR5 antagonists

Article abstract of DOI:10.1039/c0ob01190h

In previous studies we showed that 3-(substituted phenylethynyl)-5- methyl[1,2,4]triazine analogues of MPEP were potent antagonists of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. In the present study we report

Full text of DOI:10.1039/c0ob01190h

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Organic &
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PAPER
Synthesis and evaluation of 1,2,4-methyltriazines as mGluR5 antagonists
Jeremy P. Olson, Moses G. Gichinga, Elizabeth Butala, Hernan A. Navarro, Brian P. Gilmour and F. Ivy Carroll*
Received 16th December 2010, Accepted 23rd March 2011
DOI: 10.1039/c0ob01190h
In previous studies we showed that 3-(substituted phenylethynyl)-5-methyl[1,2,4]triazine analogues of
MPEP were potent antagonists of glutamate-mediated mobilization of internal calcium in an mGluR5
in vitro efficacy assay. In the present study we report the synthesis and evaluation of six 3-(substituted
biphenylethynyl)-5-methyl[1,2,4]triazines (5a–f), and five 3-(substituted phenoxyphenylethynyl)-
5-methyltriazines (6a–e). Compound 2-(4-fluorophenyl-5-[2-(5-methyl[1,2,4]triazine-3-
yl)ethynyl]benzonitrile (5f) with an IC50 of 28.2 nM was the most potent analogue.
Introduction
L-Glutamic acid (1, glutamate) is a major excitatory neurotrans-
mitter in the central nervous system (CNS) whose excitatory action
is modulated by metabotropic glutamate receptors (mGluR).
Metabotropic glutamate receptor 5 (mGluR5) has been the subject
of great interest over the last several years as a target for
the development of pharmacotherapies to treat drug addiction
(cocaine, methamphetamine, opioids, nicotine, and alcohol). Chi-
amulera and co-workers reported that mice lacking the mGluR5
gene did not acquire cocaine self-administration (SA) or exhibit
cocaine-induced hyperlocomotor activity at doses that did not
affect responding for food.1 The studies also showed that the
selective mGluR5 antagonist MPEP (2) decreased cocaine SA
in wildtype mice1 and in rats.2 Iso and co-workers showed that
the more selective mGluR5 antagonist MTEP (3), which also
displays higher in vivo potency, prevented the reinstatement of
cocaine SA that can be induced by environmental cues associated
with cocaine availability.3 MPEP (2) decreased nicotine SA in
Fig. 1 mGluR5 antagonists.
rats and mice,4,5 attenuated cocaine- and morphine-induced CPP
in mice,6,7 and decreased ethanol drinking and ethanol seeking
an mGluR5 in vitro assay.13 In
a separate study we
(a relapse model) in rats.8,9 MPEP (2) also attenuated cocaine
SA and cocaine-induced reinstatement of drug seeking in squir-
rel monkeys.10 MTEP (3) dose-dependently inhibited naloxone-
induced symptoms of morphine withdrawal without effects on
locomotor activity.11 More recently, Gass and co-workers12 re-
ported that MTEP (3) attenuated the SA of methamphetamine
as well as the reinforcing efficacy under a progressive ratio (PR)
schedule of reinforcement. These authors also reported that
MTEP (3) dose dependently prevented cue- and drug-priming
induced reinstatement of methamphetamine-seeking behaviour.
In 2004 we reported the synthesis and evaluation of
several phenylethynyl[1,2,4]methyltriazine for antagonism of
glutamate-mediated mobilization of internal calcium in
found that 3-(4-phenoxyphenylethynyl)-5-methyl[1,2,4]triazine
(4a) and 3-(3-methylphenylethynyl)-5-methyl[1,2,4]triazine (4b)
were 41 and 16 times, respectively, more potent than
MPEP in reversing morphine tolerance.14 As
a contin-
uation of our earlier research, we report the synthe-
sis and evaluation of six 3-(substituted biphenylethynyl)-
5-methyl[1,2,4]triazines (5a–f) and five 3-(substituted 4-
phenoxyphenylethynyl-5-methyl[1,2,4]triazines (6a–e) (see Table 1
for structures).
Chemistry
In order to synthesize the highly functionalized biphenyl ana-
logues 5a–f and 6a–e, the substituted biphenyl-alkyne interme-
diates 12a–c, 15a–c, and 20a–e were synthesized using three
different reaction pathways. The first series of biphenyl derivatives
synthesized started with 4-hydroxybenzoate (7) being iodinated
Center for Organic and Medicinal Chemistry, Research Triangle Institute,
P. O. Box 12194, Research Triangle Park, Durham, North Carolina 27709,
USA. E-mail: fic@rti.org; Fax: +1 919-541-8868; Tel: +1 919-541-6679
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Scheme 1 Synthesis of cyanobiphenyl analogues.
with iodine monochloride in acetic acid (Scheme 1).15 3-Iodo-
4-hydroxybenzoate was converted to 8 using copper cyanide
to introduce the cyano groups and trifluoromethanesulfonic
anhydride to add the triflate. This triflate 8 was cross-coupled
with phenyl boronic acid (9a), 3-fluorophenyl boronic acid (9b),
and 4-fluorophenyl boronic acid (9c), to produce the biphenyl
compounds 10a–c. The ester moiety in 10a–c was reduced with
lithium pyrrolidinoborohydride,16 followed by oxidation of the
alcohols to the aldehyde (11a–c) using Dess–Martin periodiate.17
Finally the aldehyde was converted to the alkynes (12a–c) using
the Bestman–Ohira reagent.18
Table 1 Inhibition of human mGluR5-mediated intracellular calcium
mobilization for biphenylethynyltriazine and phenoxyphenylethynyltri-
azine analoguesa
The second series of biphenyl derivatives started with the
reduction of methyl 4-bromo-3-methylbenzoate (13) with lithium
aluminum hydride followed by oxidation to the aldehyde (14) using
Dess–Martin periodinate (Scheme 2). This aldehyde could then
be cross-coupled with the phenylboronic acid (9a), 3-fluorophenyl
boronic acid (9b), and 4-fluorophenyl boronic acid (9c) to produce
Compound
X
R2
R1
IC50/nM
cLogP
MPEP
5a
—
—
H
F
H
H
F
—
H
H
F
H
H
F
13.5 0.8
141 61
247 10
111 16
50.0 18.4
221 12
28.2 9.5
4.21
4.91
5.16
4.84
3.65
3.91
3.59
CH3
CH3
CH3
CN
CN
CN
5b
5c
5d
5e
5f
H
Compound
X
—
CH3
CH3
CH3
CN
CN
R2
—
H
H
F
H
F
R1
—
H
F
H
H
H
IC50/nM
cLogP
4.21
5.14
5.43
5.33
4.42
4.60
MPEP
6a
13.5 0.8
1650 374
1370 323
1480 89
259 110
1320 390
6b
6c
6d
6e
a IC50 data are listed as average SEM of three independent experiments.
Scheme 2 Synthesis of methyl biphenyl analogues.
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the desired biphenyl aldehydes. These aldehydes were converted to
the alkynes (15a–c) using the Bestman–Ohira reagent.
In vitro pharmacology
CHO-K1 cells stably transfected with the human mGluR5 were
used to determine the effects of MPEP and test compounds on
glutamate-stimulated mobilization of internal calcium. Note that
we had difficulty with the mGluR5 clone used in our previous
study13 and changed to a different clone for the IC50 determinations
in the present study. This is the likely reason for the IC50 = 13.5 nM
compared to 1.5 nM in our previous study. CHO-K1-mGluR5
cells were grown in standard Dulbecco’s modified Eagle’s medium
(DMEM) supplemented with 10% fetal bovine serum, 15 mM
Hepes, and 1 ¥ penicillinstreptomycin (Invitrogen, Carlsbad, CA).
Cells were plated in black-walled, clear-bottomed 96-well plates
in 100 mL growth media and incubated overnight at 37 ◦C/5%
CO2. The next day the media was removed, and the cells were
incubated with Hanks balanced salt solution (HBSS; Invitrogen)
containing 20 mM HEPES, 2.74 mM Probenecid (Sigma–Aldrich,
St. Louis, MO), and either 2.5 mg mL-1 Fluo4-AM dye (75-
min incubation; Invitrogen) or Calcium 4 dye from the FLIPR
Calcium 4 assay kit (60-min incubation; Molecular Devices
Corporation, Sunnyvale, CA) at one-half the recommended dye
concentration. For compound concentration–response curves,
cells were pretreated in duplicate with vehicle or one of seven
different concentrations of test compound or MPEP during the
last 15 min of dye incubation. Fluorescence levels in each well
before and after the addition of 530 nM glutamate (~EC60) were
recorded in a FlexStation3 (Molecular Devices Corporation). The
PEAK function of the SoftMax software was used to determine
the change in fluorescence. IC50 values were calculated from a four-
parameter logistic equation fit to the calcium flux concentration-
response data using Prism (GraphPad Software, San Diego, CA).
The phenoxy intermediates 20a–e were synthesized from
4-fluoro-3-methylbenzaldehyde (16), and 2-fluoro-5-formyl-
benzonitrile (17) (Scheme 3). Various phenols (18a–c) could be
coupled with 16 and 17 in acetonitrile using caesium carbonate
to give the aldehydes 19a–e. The aldehydes (19a–e) were then
converted to the alkynes (20a–e) using the Bestman–Ohira reagent.
Scheme 3 Synthesis of phenoxy acetylene compounds.
Results and discussion
These biphenyl and phenoxy acetylenes 12a–c, 15a–c, and 20a–
e were deprotonated with butyl lithium and the corresponding
lithium acetylide used to displace the methylsulfonyl group in
the 5-methyl-3-sulfonyl[1,2,4]triazine (21) to give low to moderate
yields of the desired products 5a–f and 6a–e (Scheme 4). These low
yields were consistent with what has previously been observed for
this type of reaction.13
The six biphenylethynyltriazine analogues 5a–f and five phe-
noxyphenylethynyltriazine analogues 6a–e were synthesized and
evaluated for antagonism of glutamate-mediated mobilization
of internal calcium in an mGluR5 in vitro efficacy assay. The
IC50 values are listed in Table 1 for 5a–f and 6a–e, respectively,
along with the IC50 values for the standard mGluR5 antagonist
Scheme 4 Synthesis of biphenyl acetylene compounds.
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MPEP. The IC50 values for 5a–f ranged from 28.2 to 247 nM. The
highest affinity was observed for analogues with a 4-fluoro
substituent (5c and 5f), followed by an unsubstituted aromatic
ring (5a and 5d), while the fluorine substituent at the 3 position (5b
and 5e) showed the lowest affinity. The results also showed that
the cyano substituted analogues (5d–f) were favored over those
with a methyl group (5a–c) at the same position. Analogue 5f
with the IC50 value of 28.2 nM was the most potent analogue.
Since MPEP has an IC50 value of 13.5 nM, 5f is about one-half
as potent as MPEP in this test. However, the cLogP value for
5f is 0.62 log units lower than that of MPEP, suggesting that
5f may have better brain penetration. In our previous studies
we found that MPEP was 1.5 times more potent than 4b in
the mGluR5 in vitro efficacy assay, yet 4b was 44 and 16 times
more potent than MPEP in blocking the mGluR5 agonist (S)-
3,5-DHPG-induced hyperalgesia and morphine antinociceptive
tolerance, respectively.13,14 These results suggest that these two
compounds will also have good in vivo activity.
In our previous study, we also found that even though 4a was
more than 50 times less potent than MPEP in the mGluR5 in vitro
efficacy assay, it was 26 and 41 times more potent than MPEP in
blocking the mGluR5 agonist (S)-3,5-DHPG-induced hyperalge-
sia and morphine antinociceptive tolerance, respectively.13,14 These
highly encouraging results led us to synthesize and evaluate the
5-phenoxyphenylethynyltriazine analogues 6a–e. These analogues
were about 10 times less potent than the biphenyl analogues but
showed the same trend as the biphenyl analogues where the 3-
cyano substituted analogues (6d and 6e) is preferred over the
methyl substituted analogues. Compound 6d with an IC50 of
259 nM in the mGluR5 in vitro efficacy test was the most potent
analogue. Even though 6d is 19 times less potent than MPEP in
this in vitro efficacy assay, it is much more potent than 4a was
relative to MPEP.13
(grade 62, 60–200 mesh). Fraction elution was monitored using
a hand-held UV lamp. Melting points were uncorrected. 1H
NMR and 13C NMR spectra were measured using a Bruker
Advance DPX-300 MHz spectrometer in CDCl3 or DMSO-
d6, at 300 and 75 MHz, respectively, and were referenced to
internal (CH3)4Si. Purity of compounds (>95%) was established by
elemental analysis. Elemental analysis was conducted by Atlantic
Microlab, Norcross, GA. Results were within 0.4% of calculated
values.
5-Methyl-3-[2-(3-methyl-4-phenylphenyl)ethynyl] [1,2,4]triazine
(5a)
To a well-stirred solution of 660 mg (3.43 mmol) 4-ethynyl-2-
methylbiphenyl (15a) in anhydrous THF at -78 ◦C was added
1.45 mL (3.68 mmol) 2.5 M solution of BuLi in hexanes, and
the mixture was stirred for 1 h. This mixture was transferred by
cannulation under N2 pressure to a well-stirred solution of 540 mg
(3.12 mmol) 5-methyl-3-sulfonyl[1,2,4]triazine (21) in anhydrous
THF at -78 ◦C. The mixture was stirred at -78 ◦C for 30 min and
slowly allowed to warm to room temperature. After the mixture
was stirred for 2 h at room temperature, 25 mL of NaHCO3
(saturated) was added and the organic layers extracted into Et2O,
combined, then dried over anhydrous Na2SO4 and concentrated to
obtain a dark red oil. Column chromatography on silica gel using
EtOAc–hexanes (1 : 1) as the eluent afforded 205 mg (23%) of 5a as
an off-white solid. The analytical sample was recrystallized from
(CH3)2CHOH–heptane (9 : 1): mp 112–114 ◦C. 1H NMR (CDCl3)
d/ppm: 9.05 (s, 1H), 7.64 (s, 1H), 7.57 (d, 1H, J = 3 Hz), 7.34 (m,
6H), 2.63 (s, 3H), 2.29 (s, 3H). 13C NMR (CDCl3) d/ppm: 159.2,
154.3, 147.5, 144.1, 140.9, 135.9, 134.6, 130.1, 130.0, 128.9, 128.2,
127.3, 119.5, 92.4, 85.7, 21.7, 20.3. MS (ESI) m/z 286.5 (M + H)+.
Elemental calcd C 79.98, H 5.30, N 14.73; found C 79.87, H 5.34,
N 14.65.
Conclusions
In
summary,
six
3-(substituted
biphenylethynyl)-5-
3-{2-[4-(3-Fluorophenyl)-3-methylphenyl]ethynyl}-5-methyl-
[1,2,4]triazine (5b). To a well-stirred solution of 656 mg
(3.12 mmol) 4-ethynyl-1-(3-fluorophenyl)-2-methylbenzene (15b)
in anhydrous THF at -78 ◦C was added 1.61 mL (3.62 mmol)
2.25 M solution of BuLi in hexanes, and the mixture was stirred
for 1 h. This mixture was transferred by cannulation under N2
pressure to a well-stirred solution of 660 mg (3.43 mmol) 5-methyl-
3-sulfonyl[1,2,4]triazine (21) in anhydrous THF at -78 ◦C. The
mixture was stirred at -78 ◦C for 1 h and slowly allowed to warm
to room temperature. After the mixture was stirred for 2 h at
room temperature, 25 mL of NaHCO3 (saturated) was added and
the organic layers extracted into Et2O, combined, then dried over
anhydrous Na2SO4 and concentrated to obtain a dark red oil.
Column chromatography on silica gel using EtOAc–hexanes (1 : 1)
as the eluent◦afforded 228 mg (24%) of 5b as an off-white solid:
methyl[1,2,4]triazines (5a–f) and five 3-(substituted 4-phenoxy-
phenylethynyl)-5-methyl[1,2,4]triazines (6a–e) were synthesized
and evaluated for their ability to antagonize glutamate-mediated
mobilization of internal calcium in an mGluR5 in vitro efficacy
assay. The biphenyl analogues 5a–f had low nanomolar potency
in the assay. Analogue 5f with an IC50 of 28.2 nM was the most
potent analogue. Moderate potency was observed for the phenoxy
analogues 6a–e. Analogue 6d with an IC50 of 259 nM was the
most potent in the assay. Since the potencies of 5f and 6d compare
favourably with those of 4a and 4b, which had potent activity
in antagonising morphine tolerance, these compounds may also
have good in vivo activity.
Experimental
1
mp 118–119 C. H NMR (CDCl3) d/ppm: 9.06 (s, 1H), 7.64 (s,
Commercial reagents and solvents were used as received. All
reactions were run under dry N2 in oven-dried glassware. The
NaHCO3 (saturated) used in various procedures refers to saturated
aqueous solution. Unless otherwise specified, all organic solvents
were anhydrous and used as received. Reactions were monitored
by TLC on silica gel GF plates. Preparative separations were
performed using flash column chromatography on silica gel
1H), 7.58 (d, 1H, J = 9 Hz), 7.39 (m, 1H), 7.25 (d, 1H, J = 9 Hz),
7.08 (m, 3H), 2.63 (s, 3H), 2.29 (s, 3H). 13C NMR (CDCl3) d/ppm:
164.2, 160.9, 159.2, 154.2, 147.6, 143.0 (d, Jcf = 8.25 Hz), 142.6 (d,
Jcf = 1.5 Hz), 135.8, 134.7, 130.1, 129.8 (d, Jcf = 9.75 Hz), 124.7 (d,
Jcf = 3 Hz), 120.0, 115.9 (d, Jcf = 21.75 Hz), 114.2 (d, Jcf = 21 Hz),
92.0, 85.9, 21.8, 20.2. MS (ESI) m/z 304.54 (M + H)+. Elemental
calcd C 75.23, H 4.65, N 13.85; found C 75.00, H 4.59, N 13.71.
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white solid. The analytical sample was recrystallized from ethanol:
mp 225–227 ◦C. 1H NMR (CDCl3) d/ppm: 9.11 (s, 1H), 8.09 (d,
1H, J = 3 Hz), 7.95 (dd, 1H, J = 9 Hz, 3 Hz), 7.57 (d, 1H, J =
9 Hz), 7.49 (m, 1H), 7.38 (d, 1H, J = 9 Hz), 7.29 (m, 1H), 7.17 (m,
1H), 2.65 (s, 3H); 13C NMR (CDCl3) d/ppm: 164.4, 161.1, 159.4,
153.7, 148.0, 145.1, 139.1 (d, Jcf = 8.25 Hz), 137.5, 136.5, 130.6 (d,
Jcf = 8.25 Hz), 130.4, 124.5 (d, Jcf = 3 Hz), 121.4, 117.1, 116.3 (d,
Jcf = 21 Hz), 115.8 (d, Jcf = 23.25 Hz), 112.1, 88.4, 87.9, 21.8. MS
(ESI) m/z 315.3 (M + H)+. Elemental calcd C 72.60, H 3.53, N
17.83; found C 72.62, H 3.47, N 17.69.
3-{2-[4-(4-Fluorophenyl)-3-methylphenyl]ethynyl}-5-methyl-
[1,2,4]triazine (5c). To a well-stirred solution of 656 mg
(3.12 mmol) 4-ethynyl-1-(4-fluorophenyl)-2-methylbenzene (15c)
in anhydrous THF at -78 ◦C was added 1.61 mL (3.62 mmol)
2.25 M solution of BuLi in hexanes, and the mixture stirred
for 1 h. This mixture was transferred by cannulation under N2
pressure to a well-stirred solution of 660 mg (3.43 mmol) 5-methyl-
3-sulfonyl[1,2,4]triazine (21) in anhydrous THF at -78 ◦C. The
mixture was stirred at -78 ◦C for 1 h and slowly allowed to warm
to room temperature. After the mixture was stirred for 2 h at
room temperature, 25 mL of NaHCO3 (saturated) was added and
the organic layers were extracted into Et2O, combined, then dried
over anhydrous Na2SO4 and concentrated to obtain a dark red oil.
Column chromatography on silica gel using EtOAc–hexanes (1 : 1)
as the eluent afforded 137 mg (14%) of 5c as an off-white solid: mp
117–119 ◦C. 1H NMR (CDCl3) d/ppm: 9.05 (s, 1H), 7.63 (s, 1H),
7.58 (d, 1H, J = 9 Hz), 7.26 (m, 3H), 7.13 (m, 2H), 2.63 (s, 3H),
2.27 (s, 3H). 13C NMR (CDCl3) d/ppm: 163.8, 160.6, 159.2, 154.2,
147.5, 142.9, 136.8, 135.9, 134.6, 130.6 (d, Jcf = 7.5 Hz), 130.1 (d,
Jcf = 6 Hz), 119.7, 115.3, 115.0, 92.2, 85.8, 21.8, 20.3. MS (ESI)
m/z 304.5 (M + H)+. Elemental calcd C 75.23, H 4.65, N 13.85;
found C 74.99, H 4.62, N 13.73.
2-(4-Fluorophenyl)-5-[2-(5-methyl[1,2,4]triazin-3-yl)ethynyl]-
benzonitrile (5f). To a well-stirred solution of 730 mg (3.30 mmol)
5-ethynyl-2-(4-fluorophenyl)benzonitrile (12c) in anhydrous THF
(20 mL) at -78 ◦C was added 1.40 mL (3.48 mmol) of 2.5 M
solution of BuLi in hexanes, and the mixture was stirred for
1 h. This mixture was transferred by cannulation under N2
pressure to a well-stirred solution of 519 mg (3.00 mmol) 5-
methyl-3-sulfonyl[1,2,4]triazine (21) in anh◦ydrous THF (15 mL)
◦
at -78 C. The mixture was stirred at -78 C for 1 h and slowly
allowed to warm to room temperature. After the mixture was
stirred for 2 h at room temperature, 25 mL of NaHCO3 (saturated)
was added and the organic layers were extracted into Et2O,
combined, then dried over anhydrous Na2SO4 and concentrated
to obtain a dark red oil. Column chromatography on silica gel
using EtOAc–hexanes (1 : 1) as the eluent afforded 188 mg (20%)
of 5f as a yellow solid. The◦analytical sample was recrystallized
5-[2-(5-Methyl[1,2,4]triazin-3-yl)ethynyl]-2-phenylbenzonitrile
(5d). To a well-stirred solution of 671 mg (3.30 mmol) 5-ethynyl-
2-phenylbenzonitrile (12a) in anhydrous THF (20 mL) at -78 ◦C
was added 1.40 mL (3.48 mmol) 2.5 M solution of BuLi in hexanes,
and the mixture stirred for 1 h. This mixture was transferred by
cannulation under N2 pressure to a well-stirred solution of 519 mg
(3.00 mmol) 5-methyl-3-sulfonyl[1,2,4]triazine (21) in anhydrous
1
from ethanol: mp 203–204 C. H NMR (CDCl3) d/ppm: 9.11
(s, 1H), 8.06 (s, 1H), 7.93 (d, 1H, J = 6 Hz), 7.39 (m, 1H), 7.56
(m, 3H), 7.22 (m, 2H), 2.65 (s, 3H). 13C NMR (CDCl3) d/ppm:
165.1, 161.8, 159.5, 153.7, 148.0, 145.5, 137.5, 136.5, 133.2 (d, Jcf =
3.75 Hz), 130.6 (d, Jcf = 8.25 Hz), 130.4, 120.9, 117.4, 116.2, 115.9,
112.0, 88.5, 87.8, 21.8. MS (ESI) m/z 315.3 (M + H)+. Elemental
calcd C 72.60, H 3.53, N 17.83; found C 72.44, H 3.50, N 17.78.
◦
◦
THF (15 mL) at -78 C. The mixture was stirred at -78 C for
1 h and slowly allowed to warm to room temperature. After the
mixture was stirred for 2 h at room temperature, 25 mL of NaHCO3
(saturated) was added and the organic layers extracted into Et2O,
combined, then dried over anhydrous Na2SO4 and concentrated
to obtain a dark red oil. Column chromatography on silica gel
using EtOAc–hexanes (1 : 1) as the eluent afforded 189 mg (21%)
of 5d as a yellow solid. Th◦e analytical sample was recrystallized
from ethanol: mp 172–174 C. 1H NMR (CDCl3) d/ppm: 9.10 (s,
1H), 8.08 (d, 1H, J = 3 Hz), 7.94 (dd, 1H, J = 9 Hz, 3 Hz), 7.58 (m,
6H), 2.65 (s, 3H); 13C NMR (CDCl3) d/ppm: 159.4, 153.7, 147.9,
146.6, 137.5, 137.2, 136.4, 130.5, 129.4, 128.9, 128.7, 120.8, 117.5,
112.1, 88.7, 87.6, 21.8. MS (ESI) m/z 296.9 (M + H)+. Elemental
calcd C 77.01, H 4.08, N 18.91; found C 76.73, H 3.89, N 18.71.
5-Methyl-3-[2-(3-methyl-4-phenoxyphenyl)ethynyl][1,2,4]triazine
(6a). To a well-stirred solution of 481 mg (2.31 mmol) 4-ethynyl-
2-methyl-1-phenoxybenzene (20a) in anhydrous THF at -78 ◦C
was added 1.0 mL (2.54 mmol) 2.5 M solution of BuLi in hexanes,
and the mixture was stirred for 1 h. This mixture was transferred
by cannulation under N2 pressure to a well-stirred solution of
400 mg (2.31 mmol) 5-methyl-3-sulfonyl[1,2,4]triazine (21) in
anhydrous THF at -78 ◦C. The mixture was stirred at -78 ◦C
for 30 min and slowly allowed to warm to room temperature.
After the mixture was stirred for 2 h at room temperature,
25 mL of NaHCO3 (saturated) was added and the organic layers
were extracted into Et2O, combined, then dried over anhydrous
Na2SO4 and concentrated to obtain a dark red oil. Column
chromatography on silica gel using EtOAc–hexanes (1 : 1) as the
eluent afforded 53 mg (8%) of 6a as a white solid. The analytical
sample was recrystallized from ethanol: mp 104–105 ◦C. 1H NMR
(300 MHz, CDCl3) dH/ppm: 9.03 (s, 1H), 7.61 (s, 1H), 7.50 (d,
J = 9 Hz, 1H), 7.36 (m, 2H), 7.14 (t, J = 8 Hz, 1H), 7.00 (d, J =
8 Hz, 2H), 6.83 (d, J = 8 Hz, 1H) 2.61 (s, 3H), 2.32 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) dC/ppm: 159.1, 157.2, 156.5, 154.3,
147.4, 135.9, 131.9, 129.9, 129.7, 123.6, 118.8, 117.9, 115.3, 101.6,
92.4, 85.2, 21.8, 16.1; MS (ESI) m/z 302.6 (M + H)+. Elemental
calcd C 75.73, H 5.02, N 13.94; found C 75.88, H 4.99, N 13.90.
2-(3-Fluorophenyl)-5-[2-(5-methyl[1,2,4]triazin-3-yl)ethynyl]-
benzonitrile (5e). To
a well-stirred solution of 730 mg
(3.30 mmol) 5-ethynyl-2-(3-fluorophenyl)benzonitrile (12b) in an-
hydrous THF (20 mL) at -78 ◦C was added 1.40 mL (3.48 mmol)
2.5 M solution of BuLi in hexanes, and the mixture stirred
for 1 h. This mixture was transferred by cannulation under N2
pressure to a well-stirred solution of 519 mg (3.00 mmol) 5-
methyl-3-sulfonyl[1,2,4]triazine (21) in anhydrous THF (15 mL) at
-78 ◦C. The mixture was stirred at -78 ◦C for 1 h and slowly allowed
to warm to room temperature. After the mixture was stirred for
2 h at room temperature, 25 mL of NaHCO3 (saturated) was
added and the organic layers were extracted into Et2O, combined,
then dried over anhydrous Na2SO4 and concentrated to obtain a
dark red oil. Column chromatography on silica gel using EtOAc–
hexanes (1 : 1) as the eluent afforded 157 mg (17%) of 5e as an off-
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concentrated to obtain a dark red oil. Column chromatography
on silica gel using EtOAc–hexanes (1 : 1) as the eluent afforded
48 mg (6%) of 6d as a yellow solid. The analytical sample was
recrystallized from (CH3)2CHOH: mp 164–165 ◦C. 1H NMR
(300 MHz, CDCl3) dH/ppm: 9.07 (s, 1H), 7.98 (s, 1H), 7.76 (d,
J = 9 Hz 1H), 7.46 (t, J = 8 Hz, 2H), 7.29 (t, J = 8 Hz, 1H), 7.15
(d, J = 7 Hz, 2H), 6.86 (d, J = 8 Hz, 1H), 2.63 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) dC/ppm: 161.0, 159.3, 154.0, 153.8, 147.8,
138.2, 138.0, 130.4, 125.9, 120.6, 116.4, 115.5, 114.7, 104.1, 88.9,
86.4, 21.8. MS (ESI) m/z 313.5 (M + H)+. Elemental calcd C
73.07, H 3.89, N 17.94; found C 73.16, H 3.79, N 17.79.
3-{2-[4-(4-Fluorophenoxy)-3-methylphenyl]ethynyl}-5-methyl-
[1,2,4]triazine (6b). To a well-stirred solution of 523 mg
(2.31 mmol) 4-(4-fluorophenoxy)-3-methylbenzaldehyde (20b) in
anhydrous THF at -78 ◦C was added 1.0 mL (2.54 mmol) 2.5 M
solution of BuLi in hexanes, and the mixture was stirred for 1 h.
This mixture was transferred by cannulation under N2 pressure
to a well-stirred solution of 400 mg (2.31 mmol) 5-methyl-3-
sulfonyl[1,2,4]triazine (21) in anhydrous THF at -78 ◦C. The
◦
mixture was stirred at -78 C for 30 min and slowly allowed to
warm to room temperature. After the mixture was stirred for 2 h at
room temperature, 25 mL of NaHCO3 (saturated) was added, and
the organic layers were extracted into Et2O, combined, then dried
over anhydrous Na2SO4 and concentrated to obtain a dark red
oil. Column chromatography on silica gel using EtOAc–hexanes
(1 : 1) as the eluent afforded 138 mg (19%) of 6b as a yellow solid.
The◦analytical sample was recrystallized from ethanol: mp 115–
117 C. 1H NMR (300 MHz, CDCl3) dH/ppm: 9.03 (s, 1H), 7.61
(s, 1H), 7.49 (d, J = 8 Hz, 1H), 7.06 (t, J = 8 Hz, 2H), 6.99 (m,
2H), 6.76 (d, J = 9 Hz, 1H), 2.61 (s, 3H), 2.31 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) dC/ppm: 160.7, 159.1, 157.5, 154.3, 152.2,
147.4, 135.9, 131.9, 129.3, 120.5, 120.4, 117.1, 116.6, 116.3, 115.3,
92.3, 85.2, 21.8, 16.0. MS (ESI) m/z 320.2 (M + H)+. Elemental
calcd C 71.46, H 4.42, N 13.16; found C 71.19, H 4.27, N 13.02.
2-(3-Fluorophenoxy)-5-[2-(5-methyl[1,2,4]triazin-3-yl)ethynyl]-
benzonitrile (6e). To
a well-stirred solution of 180 mg
(0.76 mmol) 5-ethynyl-2-(3-fluorophenoxy)benzonitrile (20e) in
anhydrous THF at -78 ◦C was added 0.33 mL (0.82 mmol)
2.5 M solution of BuLi in hexanes, and the mixture was stirred
for 1 h. This mixture was transferred by cannulation under N2
pressure to a well-stirred solution of 0.131 g (0.76 mmol) 5-methyl-
3-sulfonyl[1,2,4]triazine (21) in anhydrous THF at -78 ◦C. The
◦
mixture was stirred at -78 C for 30 min and slowly allowed to
warm to room temperature. After the mixture was stirred for 2 h at
room temperature, 25 mL of NaHCO3 (saturated) was added, and
the organic layers were extracted into Et2O, combined, then dried
over anhydrous Na2SO4 and concentrated to obtain a dark red oil.
Column chromatography on silica gel using EtOAc–hexanes (1 : 1)
as the eluent afforded 37 mg (15%) of 6e as a yellow solid. The
analytical sample was recrystallized from ethanol: mp 189–190 ◦C.
1H NMR (300 MHz, CDCl3) dH/ppm: 9.08 (s, 1H), 7.99 (s, 1H),
7.80 (d, J = 9 Hz 1H), 7.41 (m, 1H), 6.90 (m, 4H), 2.63 (s, 3H).
13C NMR (75.5 MHz, CDCl3) dC/ppm: 165.2, 161.9, 160.1, 159.4,
155.3, 155.2, 153.8, 147.9, 138.2, 138.1, 131.3, 131.2, 117.0, 116.3,
116.0, 115.9, 114.4, 113.0, 112.8, 108.5, 108.2, 104.6, 88.5, 86.7,
21.8; MS (ESI) m/z 331.2 (M + H)+. Elemental calcd C 69.09, H
3.36, N 16.96; found C 69.20, H 3.24, N 16.87.
3-{2-[4-(3-Fluorophenoxy)-3-methylphenyl]ethynyl}-5-methyl-
[1,2,4]triazine (6c). To a well-stirred solution of 523 mg
(2.31 mmol) 4-(3-fluorophenoxy)-3-methylbenzaldehyde (20c) in
anhydrous THF at -78 ◦C was added 1.0 mL (2.54 mmol) 2.5 M
solution of BuLi in hexanes, and the mixture was stirred for 1 h.
This mixture was transferred by cannulation under N2 pressure
to a well-stirred solution of 400 mg (2.31 mmol) 5-methyl-3-
sulfonyl[1,2,4]triazine (21) in anhydrous THF at -78 ◦C. The
◦
mixture was stirred at -78 C for 30 min and slowly allowed to
warm to room temperature. After the mixture was stirred for 2 h at
room temperature, 25 mL of NaHCO3 (saturated) was added, and
the organic layers were extracted into Et2O, combined, then dried
over anhydrous Na2SO4 and concentrated to obtain a dark red
oil. Column chromatography on silica gel using EtOAc–hexanes
(1 : 1) as the eluent afforded 63 mg (9%) of 6c as a yellow solid. The
analytical sample was recrystallized from ethanol: mp 110–111 ◦C.
1H NMR (300 MHz, CDCl3) dH/ppm: 9.04 (s, 1H), 7.63 (s, 1H),
7.54 (d, J = 9 Hz, 1H), 7.30 (m, 2H), 6.60–6.92 (m, 4H), 2.62 (s,
3H), 2.27 (s, 3H); 13C NMR (75.5 MHz, CDCl3) dC/ppm: 165.3,
159.1, 156.1, 154.3, 147.5, 136.0, 132.0, 130.7, 130.6, 130.2, 119.0,
116.4, 113.7, 113.6, 110.4, 110.1, 106.1, 105.8, 91.9, 85.4, 21.8,
15.9. MS (ESI) m/z 320.0 (M + H)+. Elemental calcd C 71.46, H
4.42, N 13.16; found C 71.24, H 4.27, N 13.07.
Ethyl 4-hydroxy-3-iodobenzoate. Ethyl 4-hydroxybenzoate (7,
25.6 g, 0.152 mol) was dissolved in AcOH (50 mL) at 65 ◦C. A
solution of ICl (25.0 g, 0.152 mol) in AcOH (125 mL) was added
dropwise, and the mixture was stirred at 65 ◦C for 6 h. The
reaction mixture was added to a mixture of ice-water, filtered,
and the resulting solid was washed with water. The solid was
dissolved in CH2Cl2, dried over Na2SO4, filtered, and concentrated
to obtain the crude product. Column chromatography on silica
using EtOAc–hexanes (1 : 4) as the eluent afforded 39.4 g (88%)
of ethyl 4-hydroxy-3-iodobenzoate as a white solid. Spectral data
matches previously reported data.15
Ethyl
4-hydroxy-3-cyanobenzoate. Ethyl
4-hydroxy-3-
5-[2-(5-Methyl[1,2,4]triazin-3-yl)ethynyl]-2-phenoxybenzonitrile
(6d). To a well-stirred solution of 550 mg (2.51 mmol) 5-ethynyl-
2-phenoxybenzonitrile (20d) in anhydrous THF at -78 ◦C was
added 1.1 mL (2.76 mmol) 2.5 M solution of BuLi in hexanes, and
the mixture was stirred for 1 h. This mixture was transferred by
cannulation under N2 pressure to a well-stirred solution of 434 mg
(2.51 mmol) 5-methyl-3-sulfonyl[1,2,4]triazine (21) in anhydrous
THF at -78 ◦C. The mixture was stirred at -78 ◦C for 30 min and
slowly allowed to warm to room temperature. After the mixture
was stirred for 2 h at room temperature, 25 mL of NaHCO3
(saturated) was added, and the organic layers were extracted
into Et2O, combined, then dried over anhydrous Na2SO4, and
iodobenzoate (39.5 g, 0.135 mol) was dissolved in DMSO
(110 mL) at 100 ◦C. Copper(I) cyanide (13.3 g, 0.149 mol) was
added, and the mixture was stirred at 100 ◦C for 24 h. The
reaction was cooled to room temperature, added to ice–water,
filtered, and the resulting solid washed with water. The solid
was dissolved in EtOAc, filtered through Celite, dried over
Na2SO4, filtered, and concentrated to obtain 15.87 g (61%) of
ethyl 4-hydroxy-3-cyanobenzoate as a white solid. Spectral data
matches previously reported data.15
Ethyl
3-cyano-4-trifluoromethanesulfonyloxybenzoate
(8).
Ethyl 4-hydroxy-3-cyanobenzoate (15.9 g, 0.083 mol) was
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dissolved in CH2Cl2 (333 mL) at 0 ◦C. Triethylamine (12.6 g,
0.124 mol) and DMAP (1.52 g, 0.013 mol) were added, and Tf2O
(35.1 g, 0.125 mol) was added dropwise over 30 min. The reaction
mixture was stirred for 2 h, then concentrated to obtain the crude
product. Column chromatography on silica using EtOAc–hexanes
(1 : 4) as the eluent afforded 22.4 g (84%) of 8 as a white solid.
Spectral data matches previously reported data.15
130.2, 117.4, 116.2. 115.9, 111.6, 61.8, 14.3. MS (ESI) m/z 268.2
(M - H)+. Elemental calcd C 71.37, H 4.49, N 5.20; found C 71.22,
H 4.40, N 5.07.
5-Formyl-2-phenylbenzonitrile
(11a). Ethyl
3-cyano-4-
phenylbenzoate (10a, 3.01 g, 0.0119 mol) was dissolved in
anhydrous THF (50 mL) and cooled to 0 ◦C. A 1 M solution
of lithium pyrrolidinoborohydride (14.4 mL, 14.4 mmol) was
added, and the mixture was stirred for 2 h at room temperature.
The reaction mixture was quenched by dropwise addition of 3 N
HCl, followed by extraction into Et2O. The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. Column chromatography of the resulting
residue on silica gel using EtOAc–hexanes (2 : 5) as the eluent
yielded 2.23 g (89%) of 5-(hydroxymethyl)-2-phenylbenzonitrile as
a white solid. The 5-(hydroxymethyl)-2-phenylbenzonitrile (2.23 g,
Ethyl 3-cyano-4-phenylbenzoate (10a). To a suspension of
ethyl 3-cyano-4-trifluoromethanesulfonyloxybenzoate (8, 5.10 g,
0.0158 mol) and phenylboronic acid (9a, 2.31 g, 0.0189 mol) in
toluene (75 mL) was added K2CO3 (3.26 g, 0.0237 mol) and
Pd(PPh3)4 (911 mg, 0.79 mmol), and the mixture was refluxed
for 2 h. The reaction mixture was cooled to room temperature
and added to a mixture of EtOAc and water (1 : 1). The organic
layer was washed with water and brine, dried (Na2SO4), and
concentrated under reduced pressure. Column chromatography of
the resulting residue on silica gel using Et2O–hexanes (4 : 1) as the
eluent gave 3.51 g (89%) of 10a as a white solid: mp 64–67 ◦C.1H
NMR (CDCl3) d/ppm: 8.44 (s, 1H), 8.28 (d, 1H, J = 9 Hz), 7.58
(m, 5H), 4.45 (q, 2H), 1.43 (t, 3H). 13C NMR (CDCl3) d/ppm:
164.6, 149.2, 137.2, 135.0, 133.6, 130.3, 130.0. 129.4, 128.9, 128.7,
117.9, 111.6, 61.7, 14.3. MS (ESI) m/z 249.2 (M - H)+. Elemental
calcd C 76.48, H 5.21, N 5.57; found C 76.22, H 5.13, N 5.41.
◦
0.0107 mol) was dissolved in CH2Cl2 (100 mL), cooled to 0 C,
and treated with Dess–Martin periodinate (6.78 g, 0.016 mol).
After 3 h the reaction mixture was quenched with a mixture
of saturated sodium thiosulfate-sodium bicarbonate (1 : 1) and
stirred for 30 min. The organic layer was washed with sodium
thiosulfate-sodium bicarbonate, brine, dried (Na2SO4), and
concentrated under reduced pressure. Column chromatography
of the resulting residue on silica gel using Et2O–hexane (2 : 3)
as the eluent gave 2.18 g (99%) of 11a as a white solid: mp
◦
1
Ethyl 3-cyano-4-(3-fluorophenyl)benzoate (10b). To a suspen-
sion of ethyl 3-cyano-4-trifluoromethanesulfonyloxy benzoate (8,
3.23 g, 0.010 mmol) and 3-fluorophenylboronic acid (9b, 1.67 g,
0.012 mol) in toluene (50 mL) was added K2CO3 (2.07 g, 0.015 mol)
and Pd(PPh3)4 (578 mg, 0.5 mmol), and the mixture was refluxed
for 2 h. The reaction mixture was cooled to room temperature
and added to a mixture of EtOAc and water (1 : 1). The organic
layer was washed with water and brine, dried (Na2SO4), and
concentrated under reduced pressure. Column chromatography
of the resulting residue on silica gel using Et2O–hexanes (4 : 1) as
the eluent gave 2.02 g (77%) of 10b as a white solid: mp 92–95 ◦C.
1H NMR (CDCl3) d/ppm: 8.45 (s, 1H), 8.30 (d, 1H, J = 6 Hz),
7.59 (d, 1H, J = 9 Hz), 7.49 (m, 1H), 7.38 (d, 1H, J = 6 Hz), 7.28
(d, 1H, J = 12 Hz), 7.20 (m, 2H), 4.45 (q, 2H), 1.44 (t, 3H). 13C
NMR (CDCl3) d/ppm: 164.4, 161.1, 147.7, 139.2 (d, Jcf = 7 Hz),
135.0, 133.7, 130.6, 130.5 (d, Jcf = 4.5 Hz), 124.5 (d, Jcf = 3 Hz),
117.5, 116.4 (d, Jcf = 21 Hz), 115.8 (d, Jcf = 22.5 Hz), 111.7, 61.8,
14.3. MS (ESI) m/z 268.3 (M - H)+. Elemental calcd C 71.37, H
4.49, N 5.20; found C 70.98, H 4.55, N 5.24.
158–161 C. H NMR (CDCl3) d/ppm: 10.08 (s, 1H), 8.27 (d,
1H, J = 3 Hz), 8.15 (dd, 1H, J = 9 Hz, 4.5 Hz), 7.72 (d, 1H, J =
9 Hz), 7.58 (m, 5H). 13C NMR (CDCl3) d /ppm: 189.7, 150.6,
136.9, 135.2, 132.9, 131.0, 129.7, 128.9, 128.7, 117.6, 112.4. MS
(ESI) m/z 206.3 (M - H)+. Elemental calcd C 81.14, H 4.38, N
6.76; found C 80.99, H 4.32, N 6.80.
2-(3-Fluorophenyl)-5-formylbenzonitrile (11b). Ethyl-3-cyano-
4-(3-fluorophenyl) benzoate (10b, 2.04 g, 0.00758 mol) was
dissolved in anhydrous THF (40 mL) and cooled to 0 ◦C. A 1 M
solution of lithium pyrrolidinoborohydride (9.09 mL, 9.09 mmol)
was added, and the mixture was stirred for 5 h at room
temperature. The reaction mixture was quenched by dropwise
addition of 3 N HCl, followed by extraction into Et2O. The
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel using
EtOAc-hexanes (2 : 3) as the eluent to obtain 1.5 g (87%) of 2-
(3-fluorophenyl)-5-(hydroxymethyl)benzonitrile as a white solid.
The 2-(3-fluorophenyl)-5-(hydroxymethyl) benzonitrile (1.50 g,
0.0066 mol) was dissolved in CH2Cl2 (75 mL), cooled to 0 ◦C,
and treated with Dess–Martin periodinate (4.20 g, 0.009 mol).
After 3 h the reaction mixture was quenched with saturated
sodium thiosulfate-sodium bicarbonate solution (1 : 1) and stirred
for 30 min. The organic layer was washed with sodium thiosulfate-
sodium bicarbonate solution, brine, dried (Na2SO4), and concen-
trated under reduced pressure. The resulting residue was purified
by column chromatography on silica gel using EtOAc–hexanes
(2 : 3) as the ◦eluent to obtain 1.4 g (94%) of 11b as a white solid:
mp 150–153 C. 1H NMR (CDCl3) d/ppm: 10.09 (s, 1H), 8.28 (d,
1H, J = 3 Hz), 8.17 (dd, 1H, J = 9 Hz, 3 Hz), 7.70 (d, 1H, J =
9 Hz), 7.53 (m, 1H), 7.40 (m, 1H), 7.24 (m, 2H). 13C NMR (CDCl3)
d/ppm: 189.5, 164.4, 161.1, 149.1 (d, Jcf = 2.25 Hz), 138.9 (d, Jcf =
8.25 Hz), 135.7, 135.2, 133.1, 130.9, 130.7 (d, Jcf = 8.25 Hz), 124.5
(d, Jcf = 3 Hz), 117.2, 116.7 (d, Jcf = 21 Hz), 115.8 (d, Jcf = 22.5 Hz),
Ethyl 3-cyano-4-(4-fluorophenyl)benzoate (10c). To a suspen-
sion of ethyl 3-cyano-4-trifluoromethanesulfonyloxy benzoate (8,
3.23 g, 0.010 mol) and 4-fluorophenylboronic acid (9c, 1.67 g,
0.012 mol) in toluene (50 mL) was added K2CO3 (2.07 g,
0.015 mmol) and Pd(PPh3)4 (578 mg, 0.5 mmol), and the mixture
was refluxed for 2 h. The reaction mixture was cooled to room
temperature and added into a mixture of EtOAc and water (1 : 1).
The organic layer was washed with water and brine, dried on
(Na2SO4), and concentrated under reduced pressure. Column
chromatography of the resulting residue on silica gel using Et2O–
hexanes (4 : 1) as the eluent gave 2.15 g (82%) of 16c as a white
solid: mp 79–81 ◦C. 1H NMR (CDCl3) d /ppm: 8.44 (d, 1H, J =
3 Hz), 8.29 (d, 1H, J = 6 Hz), 7.57 (m, 3H), 7.22 (m, 2H), 4.44 (q,
2H), 1.44 (t, 3H). 13C NMR (CDCl3) d/ppm: 165.2, 164.5, 161.8,
148.1, 135.0, 133.6, 133.2 (d, Jcf = 3 Hz), 130.6 (d, Jcf = 8.25 Hz),
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112.5. MS (ESI) m/z 224.3 (M - H)+. Elemental calcd C 74.66, H
3.58, N 6.22; found C 74.38, H 3.64, N 5.85.
5 mL anhydrous MeOH and added to the reaction mixture at
room temperature. Progress of the reaction was monitored by
TLC, and when the starting material disappeared, the mixture was
diluted with 150 mL Et2O. The reaction mixture was quenched
with 80 mL of a 5% NaHCO3 solution and the organic layer
separated. The aqueous layer was extracted twice with 100 mL
Et2O, and the combined organic layers washed with 300 mL
brine, dried (Na2SO4), and concentrated under reduced pressure.
The resulting residue was purified by column chromatography
on silica gel using EtOAc–hexanes (3 : 7) as the eluent to obtain
1.27 g (93%) of 12b as a white solid: mp 150–153 C. H NMR
(CDCl3) d/ppm: 7.88 (d, 1H, J = 3 Hz), 7.74 (dd, 1H, J = 9 Hz,
3 Hz), 7.48 (m, 2H), 7.35 (d, 1H, J = 6 Hz), 7.17 (m, 2H), 3.24
(s, 1H). 13C NMR (CDCl3) d/ppm: 164.4, 161.1, 143.9, 139.4
(d, Jcf = 7.5 Hz), 137.1, 136.2, 130.5 (d, Jcf = 8.25 Hz), 130.1,
2-(4-Fluorophenyl)-5-formylbenzonitrile (11c). Ethyl 3-cyano-
4-(4-fluorophenyl) benzoate (10c, 2.05 g, 0.00761 mol) was dis-
solved in anhydrous THF (40 mL) and cooled to 0 ◦C. A 1 M
solution of lithium pyrrolidinoborohydride (9.14 mL, 9.14 mmol)
was added, and the mixture was stirred for 3 h at room temperature.
The reaction mixture was quenched by dropwise addition of 3 N
HCl, followed by extraction into Et2O. The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The resulting residue was purified by
column chromatography on silica gel using EtOAc–hexanes (2 : 5)
as the eluent to obtain 1.53 g (88%) of 2-(4-fluorophenyl)-5-
(hydroxymethyl) benzonitrile as a white solid. 2-(4-Fluorophenyl)-
5-(hydroxymethyl)benzonitrile (1.50 g, 0.0066 mol) was dissolved
in CH2Cl2 (75 mL), cooled to 0 ◦C, and treated with Dess–Martin
periodinate (4.20 g, 0.0099 mol). After 3 h the reaction mixture
was quenched with a mixture of saturated sodium thiosulfate-
sodium bicarbonate solution (1 : 1) and stirred for 30 min.
The organic layer was washed with sodium thiosulfate-sodium
bicarbonate solution, brine, dried (Na2SO4), and concentrated
under reduced pressure. The resulting residue was purified by
column chromatography on silica gel using EtOAc–hexanes (2 : 3)
as the eluent to obtain 1.46 g (98%) of 11c as a white solid: mp
◦
1
124.5 (d, Jcf = 2.25 Hz), 122.7, 117.4, 116.2, 115.9 (d, Jcf
=
2.25 Hz), 115.6, 111.7, 80.9, 80.4. MS (ESI) m/z 222.4 (M + H)+.
Elemental calcd C 81.44, H 3.64, N 6.33; found C 81.19, H 3.59,
N 6.11.
5-Ethynyl-2-(4-fluorophenyl)benzonitrile (12c).
A
round-
bottomed flask equipped with a stirring bar was charged
with 4-(4-fluorophenyl)-3-methylbenzaldehyde (11c, 1.46 g,
0.00648 mol), K2CO3 (1.79 g, 0.0013 mol), and anhydrous MeOH
(60 mL). Ohira–Bestmann reagent (1.55 g, 0.0081 mol) was
dissolved in 10 mL anhydrous MeOH and added to the reaction
mixture at room temperature. Progress of the reaction was
monitored by TLC, and when the starting material disappeared,
the mixture was diluted with 150 mL Et2O. The reaction mixture
was quenched with 80 mL of a 5% NaHCO3 solution and the
organic layer separated. The aqueous layer was extracted twice
with 100 mL Et2O. The combined organic layers were washed
with 300 mL brine, dried (Na2SO4), and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel using EtOAc–hexanes (1 : 3) as
the eluent to obtain 1.29 g (90%) of 12c as a white solid: mp
◦
1
148–151 C. H NMR (CDCl3) d/ppm: 10.08 (s, 1H), 8.27 (d,
1H, J = 3 Hz), 8.15 (dd, 1H, J = 9 Hz, 4.5 Hz), 7.69 (d, 1H,
J = 9 Hz), 7.59 (m, 2H), 7.23 (m, 2H). 13C NMR (CDCl3) d/ppm:
189.5, 165.3, 161.9, 149.5, 135.4, 135.2, 133.0, 130.9, 130.7 (d, Jcf =
9 Hz), 117.4, 116.3, 116.0, 112.4. MS (ESI) m/z 224.3 (M - H)+.
Elemental calcd C 74.66, H 3.58, N 6.22; found C 74.41, H 3.60,
N 6.17.
5-Ethynyl-2-phenylbenzonitrile (12a). A round-bottom flask
equipped with a stirring bar was charged with 5-formyl-2-
phenylbenzonitrile (11a, 2.29 g, 0.0011 mol), K2CO3 (3.05 g,
0.022 mol), and anhydrous MeOH (80 mL). Ohira–Bestmann
reagent (2.65 g, 0.00138 mol) was dissolved in 10 mL anhydrous
MeOH and added to the reaction mixture at room temperature.
Progress of the reaction was monitored by TLC, and when the
starting material disappeared, the mixture was diluted with 150 mL
Et2O. The reaction mixture was quenched with 80 mL of a 5%
NaHCO3 solution and the organic layer separated. The aqueous
layer was extracted twice with 100 mL Et2O, and the combined
organic layers washed with 300 mL brine, dried (Na2SO4), and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel using EtOAc–
hexanes (3 : 7) as the eluent to obtain 2.09 g (93%) of 12a as a
◦
1
151–153 C. H NMR (CDCl3) d/ppm: 7.87 (d, 1H, J = 3 Hz),
7.73 (dd, 1H, J = 9 Hz, 3 Hz), 7.52 (m, 3H), 7.20 (m, 2H), 3.23
(s, 1H). 13C NMR (CDCl3) d/ppm: 164.5, 161.7, 144.3, 137.0,
136.2, 133.4, 130.5 (d, Jcf = 8.25 Hz), 130.1, 122.3, 117.6, 116.0 (d,
Jcf = 21.75 Hz), 111.7, 81.0, 80.1. MS (ESI) m/z 221.4 (M + H)+.
Elemental calcd C 81.44, H 3.64, N 6.33; found C 81.21, H 3.68,
N 6.15.
4-Bromo-3-methylbenzaldehyde (14). A solution of 17.0 g
(0.0742 mol) of methyl-4-bromo-3-methylbenzoate (13) in an-
hydrous THF at 0 ◦C was added 3.03 g (0.115 mol) of lithium
aluminum hydride slowly over 20 min. The reaction mixture was
stirred for 30 min at 0 ◦C and quenched with 6 M HCl added
dropwise until all aluminum salts were dissolved. The product
was extracted into EtOAc, dried (Na2SO4), and concentrated to
obtain (4-bromo-3-methylphenyl)methanol as a brown solid. The
crude (4-bromo-3-methylphenyl)methanol (14.0 g, 0.070 mol) was
dissolved in CH2Cl2 (300 mL) and treated with Dess–Martin
periodinate (44.2 g, 0.105 mol). After 1 h the reaction mixture
was quenched with a mixture of saturated sodium thiosulfate-
sodium bicarbonate solution (1 : 1) and stirred for 30 min.
The organic layer was washed with sodium thiosulfate-sodium
bicarbonate solution, brine, dried (Na2SO4), and concentrated
under reduced pressure. The resulting residue was purified by
◦
1
white solid: mp 140–143 C. H NMR (CDCl3) d/ppm: 7.87 (s,
1H), 7.73 (d, 1H, J = 6 Hz), 7.50 (m, 6H), 3.22 (s, 1H). 13C NMR
(CDCl3) d/ppm: 145.5, 137.4, 137.1, 136.1, 130.2, 129.1, 128.8,
128.6, 122.1, 117.8, 111.7, 81.1, 79.9. MS (ESI) m/z 204.5 (M +
H)+. Elemental calcd C 88.64, H 4.46, N 6.89; found C 88.88, H
4.41, N 6.76.
5-Ethynyl-2-(3-fluorophenyl)benzonitrile (12b).
A
round-
bottom flask equipped with a stirring bar was charged with 2-
(3-fluorophenyl)-5-formylbenzonitrile (11b, 1.40 g, 0.00622 mol),
K2CO3 (1.72 g, 0.0124 mol) and anhydrous MeOH (60 mL).
Ohira–Bestmann reagent (1.49 g, 0.0078 mol) was dissolved in
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column chromatography on silica gel using Et2O–hexanes (9 : 1)
as the eluent to obtain 11.2 g (76% over two steps) of 4-bromo-3-
methylbenzaldehyde (14) as a colourless oil. Spectral data matches
previously reported data.19
Et2O–hexanes (9 : 1) as the eluent to obtain 1.67 g (84%) of 15b as
a yellow oil: bp 150–153 ◦C. 1H NMR (CDCl3) d/ppm: 7.79 (m,
3H), 7.17 (d, 1H, J = 6 Hz), 7.04 (m, 2H), 3.09 (s, 1H), 2.25 (s, 3H).
13C NMR (CDCl3) d/ppm: 164.2, 160.9, 143.4 (d, Jcf = 7.5 Hz),
141.3, 135.5, 134.1, 129.8, 129.6 (d, Jcf = 3.75 Hz), 124.8 (d, Jcf
=
4-Ethynyl-2-methyl-1-phenylbenzene (15a). To a suspension of
4-bromo-3-methylbenzaldehyde (14, 1.99 g, 0.01 mol) and phenyl
boronic acid (9a, 1.46 g, 12 mmol) in toluene (50 mL) was added
K2CO3 (2.07 g, 0.015 mol) and Pd(PPh3)4 (578 mg, 0.5 mmol), and
the mixture was refluxed for 24 h. The reaction mixture was poured
into a mixture of EtOAc and water (1 : 1). The organic layer was
washed with water, brine, dried (Na2SO4), and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel using EtOAc–hexanes (9 : 1) as the
eluent to obtain 1.59 g (81%) of 4-(phenyl)-3-methylbenzaldehyde
as a colourless oil. A round-bottom flask equipped with a
stirring bar was charged with 4-(phenyl)-3-methylbenzaldehyde
(1.59 g, 0.0836 mol), K2CO3 (2.31 g, 0.0167 mol), and anhydrous
MeOH (70 mL). Ohira–Bestmann reagent (1.77 g, 0.0092 mol)
was dissolved in 5 mL anhydrous MeOH and added to the
reaction mixture at room temperature. Progress of the reaction was
monitored by TLC, and when the starting material disappeared,
the mixture was diluted with 150 mL Et2O. The reaction mixture
was quenched with 80 mL of a 5% NaHCO3 solution and the
organic layer separated. The aqueous layer was extracted twice
with 100 mL Et2O, and the combined organic layers washed
with 300 mL brine, dried (Na2SO4), and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel using EtOAc–hexanes (9 : 1) as the
eluent to obtain 1.48 g (92%) of 15a as a white solid: mp 47–50 ◦C.
1H NMR (CDCl3) d/ppm: 7.36 (m, 7H), 7.18 (d, 1H, J = 9 Hz),
3.08 (s, 1H), 2.25 (s, 3H). 13C NMR (CDCl3) d/ppm: 142.6, 141.2,
135.6, 133.9, 129.8, 129.5, 128.9, 128.2, 127.1, 120.9, 83.7, 20.3.
MS (ESI) m/z 191.3 (M + H)+. Elemental calcd C 93.71, H 6.29;
found C 93.94, H 6.26.
2.25 Hz), 121.5, 116.0 (d, Jcf = 21 Hz), 114.0 (d, Jcf = 20.25 Hz),
83.5, 77.5, 20.2. MS (ESI) m/z 209.3 (M + H)+. Elemental calcd
C 85.69, H 5.27; found C 85.57, H 5.28.
4-Ethynyl-1-(4-fluorophenyl)-2-methylbenzene (15c). To a sus-
pension of 4-bromo-3-methylbenzaldehyde (14, 1.99 g, 0.01 mol)
and 4-fluorophenylboronic acid (9c, 1.67 g, 0.012 mol) in toluene
(50 mL) was added K2CO3 (2.07 g, 0.015 mol) and Pd(PPh3)4
(578 mg, 0.5 mmol), and the mixture was refluxed for 24 h.
The reaction mixture was poured into a mixture of EtOAc and
water (1 : 1). The organic layer was washed with water, brine, dried
(Na2SO4), and concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel using
Et2O–hexanes (9 : 1) as the eluent to obtain 1.78 g (83%) of 4-(4-
fluorophenyl)-3-methylbenzaldehyde as a colourless oil. A round-
bottomed flask equipped with a stirring bar was charged with
4-(4-fluorophenyl)-3-methylbenzaldehyde (1.79 g, 0.00836 mol),
K2CO3 (2.31 g, 0.0167 mol) and anhydrous MeOH (70 mL).
Ohira–Bestmann reagent (1.77 g, 0.00919 mol) was dissolved in
5 mL anhydrous MeOH and added to the reaction mixture at
room temperature. Progress of the reaction was monitored by
TLC, and when the starting material disappeared, the mixture was
diluted with 150 mL Et2O. The reaction mixture was quenched
with 80 mL of a 5% NaHCO3 solution and the organic layer
separated. The aqueous layer was extracted twice with 100 mL
Et2O, and the combined organic layers washed with 300 mL brine,
dried (Na2SO4), and concentrated under reduced pressure. The
resulting residue was purified by column chromatography on silica
gel using Et2O–hexanes (9 : 1) as the eluent to obtain 1.7 g (97%) of
15c as a white solid: mp 56–58 ◦C. 1H NMR (CDCl3) d/ppm: 7.79
(m, 3H), 7.17 (d, 1H, J = 6 Hz), 7.04 (m, 2H), 3.09 (s, 1H), 2.25
(s, 3H). 13C NMR (CDCl3) d/ppm: 163.7, 160.5, 141.5, 137.1 (d,
4-Ethynyl-1-(3-fluorophenyl)-2-methylbenzene (15b). To a sus-
pension of 4-bromo-3-methylbenzaldehyde (14, 1.99 g, 0.001 mol)
and 3-fluorophenylboronic acid (9b, 1.67 g, 0.0012 mol) in toluene
(50 mL) was added K2CO3 (2.07 g, 0.0015 mol) and Pd(PPh3)4
(578 mg, 0.5 mmol), and the mixture was refluxed for 24 h. The
reaction mixture was poured into a mixture of EtOAc and water
(1 : 1). The organic layer was washed with water and brine, dried
(Na2SO4), and concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel using
Et2O–hexanes (9 : 1) as the eluent to obtain 2.05 g (96%) of 4-
(3-fluorophenyl)-3-methylbenzaldehyde as a yellow oil. A round-
bottomed flask equipped with a stirring bar was charged with
4-(3-fluorophenyl)-3-methylbenzaldehyde (2.04 g, 0.00952 mol),
K2CO3 (2.63 g, 0.019 mol) and anhydrous MeOH (70 mL). Ohira–
Bestmann reagent (2.29 g, 0.0119 mol) was dissolved in 5 mL
anhydrous MeOH and added to the reaction mixture at room
temperature. Progress of the reaction was monitored by TLC, and
when the starting material disappeared, the mixture was diluted
with 150 mL Et2O. The reaction mixture was quenched with
80 mL of a 5% NaHCO3 solution and the organic layer separated.
The aqueous layer was extracted twice with 100 mL Et2O, and
the combined organic layers washed with 300 mL brine, dried
(Na2SO4), and concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel using
Jcf = 3.75 Hz), 135.6, 133.9, 130.6 (d, Jcf = 7.5 Hz), 129.7 (d, Jcf
=
19.5 Hz), 121.1, 115.1 (d, Jcf = 21.75 Hz), 103.2, 101.6, 83.5, 77.1,
20.2. MS (ESI) m/z 209.3 (M + H)+. Elemental calcd C 85.69, H
5.27; found C 85.56, H 5.24.
3-Methyl-4-phenoxybenzaldehyde (19a). To a solution of 4-
fluoro-3-methylbenzaldehyde (16, 2.03 g, 0.0145 mol) and phenol
(18a, 1.36 g, 0.0145 mol) in 25 mL DMF was added potassium
carbon◦ate (2.01 g, 0.0145mol) and the reaction mixture stirred
at 150 C for 16 h. The reaction mixture was allowed to cool to
ambient temperature and poured into ice–water (50 mL). The
aqueous layer was extracted with diethyl ether (2 ¥ 50 mL).
The combined organic layer was dried (Na2SO4), filtered, and
concentrated to obtain a dark brown oil. Purification by column
chromatography on silica gel using EtOAc–hexanes (1 : 9) as the
1
eluent afforded 1.73 g (56%) of 19a as colourless oil. H NMR
(300 MHz, CDCl3) dH/ppm: 9.91 (s, 1H), 7.79 (s, 1H), 7.64 (d,
J = 8 Hz, 1H), 7.39 (t, J = 8 Hz, 2H), 7.19 (t, J = 8 Hz, 1H), 7.04
(d, J = 8 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 2.39 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) dC/ppm: 191.0, 161.0, 132.7, 131.5, 130.0,
129.6, 129.5, 124.3, 119.5, 116.9, 16.2. MS (ESI) m/z 213.0 (M +
H)+. IR (KBr, cm-1): 3352, 3058, 2355, 1244. Elemental calcd C
73.03, H 4.82; found C 72.37, H 4.68.
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4-(4-Fluorophenoxy)-3-methylbenzaldehyde (19b). To a solu-
tion of 4-fluoro-3-methylbenzaldehyde (16, 2.03 g, 0.0145 mol)
and 4-fluorophenol (18b, 1.62 g, 0.0145 mol) in 25 mL DMF
was added potassium carbonate (2.01 g, 0.0145 mol), and the
reaction mixture stirred at 150 ◦C for 16 h. The reaction mixture
was allowed to cool to ambient temperature and poured into ice-
water (50 mL). The aqueous layer was extracted with diethyl ether
(2 ¥ 50 mL). The combined organic layer was dried (Na2SO4),
filtered, and concentrated to obtain a dark brown oil. Purification
by column chromatography on silica gel using EtOAc–hexanes
(1 : 9) as the eluent afforded 2.03 g (61%) of 19b as a colourless oil.
1H NMR (300 MHz, CDCl3) dH/ppm: 9.90 (s, 1H), 7.78 (s, 1H),
7.65 (d, J = 8 Hz, 1H), 7.69–7.20 (m, 4H), 6.80 (d, J = 9 Hz, 1H),
2.39 (s, 3H). 13C NMR (75.5 MHz, CDCl3) dC/ppm: 190.9, 161.3,
161.0, 157.8, 151.6, 132.7, 131.5, 129.7, 129.2, 121.2, 121.1, 116.8,
116.5, 116.1, 16.2. MS (ESI) m/z 231.4 (M + H)+. IR (KBr, cm-1):
3364, 3066, 2359, 1263. Elemental calcd C 73.03, H 4.82; found C
72.86, H 4.67.
allowed to cool to ambient temperature, poured into ice–water
(50 mL), and stirred vigorously to obtain a precipitate that was
collected by filtration. The precipitate was recrystallized from
ethano◦l to yield 967 mg (61%) of 19e as a brown solid: mp
8.21 (s, 1H), 8.02 (m, 1H), 7.46 (m, 4H), 7.00 (m, 4H). 13C
NMR (75.5 MHz, CDCl3) dC/ppm: 186.6, 163.4, 161.5, 160.0,
152.9, 152.8, 134.2, 133.2, 129.6, 129.5, 114.6, 114.4, 114.3, 112.6,
111.7, 111.4, 106.9, 106.6, 102.6. MS (ESI) m/z 239.9 (M - H)+.
Elemental calcd C 69.71, H 3.34, N 5.81; found C 69.73, H 3.29,
N 5.80.
1
90–93 C. H NMR (300 MHz, CDCl3) dH/ppm: 9.95 (s, 1H),
4-Ethynyl-2-methyl-1-phenoxybenzene (20a). To a suspension
of potassium carbonate (1.97 g, 0.0142 mol) in anhydrous
methanol (100 mL) was added 3-methyl-4-phenoxybenzaldehyde
(19a, 1.51 g, 0.0071 mol) and Bestmann reagent (1.52 g,
0.0078 mol). The reaction mixture was allowed to stir at ambient
temperature under nitrogen blanket for 18 h. The solvent was
evaporated in vacuum and the residue redissolved in CH2Cl2
(100 mL) and washed with saturated NaHCO3 (saturated) (50 mL)
and brine (50 mL). The organic layer was dried (Na2SO4), filtered,
and concentrated. The resulting residue was purified by column
chromatography on silica gel using EtOAc–hexanes (1 : 9) as the
4-(3-Fluorophenoxy)-3-methylbenzaldehyde (19c). To a solu-
tion of 4-fluoro-3-methylbenzaldehyde (16, 2.03 g, 0.0145 mol) and
3-fluorophenol (18c, 1.62 g, 14.5 mmol) in 25 mL DMF was added
potassium carbonate (2.01 g, 0.0145 mol) and the reaction mixture
◦
1
stirred at 150 C for 16 h. The reaction mixture was allowed to
eluent to obtain 1.29 g (87%) of 20a as a yellow oil. H NMR
cool to ambient temperature and poured into ice-water (50 mL).
The aqueous layer was extracted with diethyl ether (2 ¥ 50 mL).
The combined organic layer was dried (Na2SO4), filtered, and
concentrated to obtain a dark brown oil. Purification by column
chromatography on silica gel using EtOAc–hexanes (1 : 9) as the
(300 MHz, CDCl3) dH/ppm: 7.39 (s, 1H), 7.32 (m, 3H), 7.08 (t,
J = 7 Hz, 1H), 6.94 (d, J = 8 Hz, 2H), 6.80 (d, J = 8 Hz, 1H),
3.02 (s, 1H), 2.24 (s, 3H). 13C NMR (75.5 MHz, CDCl3) dC/ppm:
157.2, 155.5, 135.2, 131.1, 129.8, 123.0, 119.6, 118.7, 118.1, 117.2,
83.6, 15.9. MS (ESI) m/z 213.1 (M + H)+. IR (KBr, cm-1): 3291,
3039, 2106, 1247. Elemental calcd C 86.51, H 5.81; found C 86.64,
H 5.82.
1
eluent afforded 1.8 g (54%) of 19c as a colourless oil. H NMR
(300 MHz, CDCl3) dH/ppm: 9.93 (s, 1H), 7.80 (s, 1H), 7.70 (d, J =
8 Hz, 1H), 7.34 (m, 1H), 6.99–7.01 (m, 4H), 2.36 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) dC/ppm: 190.9, 165.3, 161.9, 159.9, 157.5,
132.9, 132.3, 130.9, 130.7, 130.0, 129.6, 118.1, 114.5, 114.4, 111.0,
106.9, 106.5, 16.1. MS (ESI) m/z 231.5 (M + H)+. IR (KBr, cm-1):
3367, 3071, 2370, 1211. Elemental calcd C 79.22, H 5.70; found C
78.52, H 5.65.
4-Ethynyl-1-(4-fluorophenoxy)-2-methylbenzene (20b). To
a
suspension of potassium carbonate (2.11 g, 0.0153 mol) in
anhydrous methanol (100 mL) was added 4-(4-fluorophenoxy)-
3-methylbenzaldehyde (19b, 1.76 g, 0.0076 mol) and Ohira–
Bestmann reagent (1.62 g, 0.0084 mol). The reaction mixture was
allowed to stir at ambient temperature under nitrogen blanket for
18 h. The solvent was evaporated and the residue redissolved in
CH2Cl2 (100 mL) and washed with NaHCO3 (saturated) (50 mL)
and brine (50 mL). The organic layer was dried (Na2SO4), filtered,
evaporated, and purified by column chromatography on silica gel
using EtOAc–hexanes (1 : 9) as the eluent to obtain 1.29 g (75%)
of 20b as a yellow oil. 1H NMR (300 MHz, CDCl3) dH/ppm: 7.38
(s, 1H), 7.25 (d, J = 8 Hz, 1H), 7.02 (t, J = 8 Hz, 2H), 6.91 (m,
2H), 6.73 (d, J = 8 Hz, 1H), 3.01 (s, 1H), 2.25 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) dC/ppm: 160.3, 157.1, 155.9, 152.8, 152.8,
135.2, 131.2, 129.3, 119.8, 119.6, 117.9, 117.1, 116.5, 116.2, 83.3,
15.9. MS (ESI) m/z 249.2 (M + Na)+. IR (KBr, cm-1): 3297, 2924,
2107, 1252. Elemental calcd C 79.63, H 4.90; found C 79.63, H
4.88.
5-Formyl-2-phenoxybenzonitrile (19d). A suspension of 2-
fluoro-5-formylbenzonitrile (17, 2.16 g, 0.0145 mol), phenol (18a,
1.36 g, 0.145 mol) and caesium carbonate (5.19 g, 0.0159 mol)
in acetonitrile (120 mL) was stirred at ambient temperature for
16 h. The reaction mixture was poured into water (100 mL) and
extracted with ether (2 ¥ 200 mL). The combined organic layer was
washed with brine, dried (Na2SO4), filtered, and evaporated. The
crude solid was triturated in hexane and dried in vacuum to yield
◦
2.14 g (66%) of 19d as a cream-coloured solid: mp 107–109 C.
1H NMR (300 MHz, CDCl3) dH/ppm: 9.93 (s, 1H), 8.20 (s, 1H),
7.98 (m, 1H), 7.48 (t, J = 8 Hz, 2H), 7.33 (t, J = 8 Hz, 1H), 7.16
(d, J = 8 Hz, 2H), 6.93 (d, J = 8 Hz, 1H). 13C NMR (75.5 MHz,
CDCl3) dC/ppm: 186.6, 162.3, 151.7, 134.1, 132.9, 128.9, 128.5,
124.4, 118.8, 113.9, 112.8, 102.0. MS (ESI) m/z 220.1 (M + H)+.
Elemental calcd C 75.33, H 4.06, N 6.27; found C 75.30, H 4.00,
N 6.35.
4-Ethynyl-1-(3-fluorophenoxy)-2-methylbenzene (20c). To
a
suspension of potassium carbonate (1.93 g, 0.014 mol) in an-
hydrous methanol (100 mL) was added 4-(3-fluorophenoxy)-3-
methylbenzaldehyde (19c, 1.61 g, 0.007 mol) and Ohira–Bestmann
reagent (1.49 g, 0.0077 mol). The reaction mixture was allowed to
stir at ambient temperature under nitrogen blanket for 18 h. The
solvent was evaporated and the residue redissolved in CH2Cl2
(100 mL) and washed with NaHCO3 (saturated) (50 mL) and
2-(3-Fluorophenoxy)-5-formylbenzonitrile (19e). To a solution
of 2-fluoro-5-formylbenzonitrile (17, 980 mg, 6.58 mmol) and
3-fluorophenol (18c, 737 mg, 6.58 mmol) in 20 mL DMF was
added potassium carbonate (909 mg, 6.58 mmol), and the reaction
mixture stirred at 150 ◦C for 16 h. The reaction mixture was
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brine (50 mL). The organic layer was dried (Na2SO4), filtered,
concentrated, and purified by column chromatography on silica
gel using EtOAc–hexanes (1 : 9) as the eluent to obtain 1.37 g (87%)
of 20c as a yellow oil. 1H NMR (300 MHz, CDCl3) dH/ppm: 7.41
(s, 1H), 7.30 (m, 2H), 6.87 (d, J = 8 Hz, 1H), 6.63 (m, 3H), 3.04 (s,
1H), 2.21 (s, 3H). 13C NMR (75.5 MHz, CDCl3) dC/ppm: 165.3,
161.9, 158.7, 158.6, 154.5, 135.4, 135.2, 131.3, 130.6, 130.5, 130.2,
119.7, 118.1, 116.5, 113.1, 113.0, 109.8, 109.6, 105.4, 105.1, 83.2,
15.9. MS (ESI) m/z 227.0 (M + H)+. IR (KBr, cm-1): 3296, 3073,
2106, 1207. Elemental calcd C 79.63, H 4.90; found C 79.92, H
4.90.
using EtOAc–hexanes (1 : 9) as the eluent to obtain 210 mg (36%)
of 20e as a colourless oil. 1H NMR (300 MHz, CDCl3) dH/ppm:
7.78 (s, 1H), 7.60 (d, J = 8 Hz, 1H), 7.39 (m, 1H), 6.88 (m, 3H),
3.13 (s, 1H). 13C NMR (75.5 MHz, CDCl3) dC/ppm: 165.2, 161.9,
158.9, 155.8, 137.8, 137.5, 131.8, 131.1, 117.9, 117.3, 115.6, 115.5,
114.7, 112.6, 112.3, 108.1, 107.8, 104.5, 80.7, 78.8. MS (ESI) m/z
236.3 (M - H)+. IR (KBr, cm-1): 3301, 3079, 2230, 1276. Elemental
calcd C 75.94, H 3.40, N 5.90; found C 75.89, H 3.28, N 5.97.
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5-Ethynyl-2-phenoxybenzonitrile (20d). To a suspension of
potassium carbonate (1.02 g, 0.0074 mol) in anhydrous methanol
(60 mL) was added 5-formyl-2-phenoxybenzonitrile (19d, 828 mg,
3.71 mmol) and Ohira–Bestmann reagent (792 mg, 3.71 mmol).
The reaction mixture was allowed to stir at ambient temperature
under nitrogen blanket for 18 h. The solvent was evaporated
and the residue redissolved in CH2Cl2 (100 mL) and washed
with saturated NaHCO3 (saturated) (50 mL) and brine (50 mL).
The organic layer was dried (Na2SO4), filtered, evaporated, and
purified by column chromatography on silica gel using EtOAc–
hexanes (1 : 9) as the eluent to obtain 610 mg (75%) of 20d as a
colourless oil. 1H NMR (300 MHz, CDCl3) dH/ppm: 7.76 (s, 1H),
7.56 (m, 1H), 7.43 (t, J = 8 Hz, 2H), 7.26 (t, J = 8 Hz, 1H), 7.11
(d, J = 7 Hz, 2H), 6.79 (d, J = 9 Hz, 1H), 3.11 (s, 1H). 13C NMR
(75.5 MHz, CDCl3) dC/ppm: 159.9, 154.4, 137.7, 137.4, 130.3,
125.6, 120.4, 117.0, 116.6, 115.0, 80.9, 78.4. MS (ESI) m/z 220.7
(M + H)+. IR (KBr, cm-1): 3272, 3064, 2230, 1252. Elemental calcd
C 82.18, H 4.14, N 6.39; found C 82.15, H 4.11, N 6.34.
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5-Ethynyl-2-(3-fluorophenoxy)benzonitrile (20e). To a suspen-
sion of potassium carbonate (915 mg, 6.62 mmol) in an-
hydrous methanol (60 mL) was added 2-(3-fluorophenoxy-5-
formylbenzonitrile (19e, 600 mg, 2.48 mmol) and Bestmann
reagent (708 mg, 3.65 mmol). The reaction mixture was allowed to
stir at ambient temperature under nitrogen blanket for 18 h. The
solvent was evaporated in vacuum and the residue redissolved in
CH2Cl2 (100 mL) and washed with NaHCO3 (saturated) (50 mL)
and brine (50 mL). The organic layer was dried (Na2SO4), filtered,
evaporated, and purified by column chromatography on silica gel
4286 | Org. Biomol. Chem., 2011, 9, 4276–4286
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