a 400 MHz Bruker Avance Ultrashield Plus NMR spectrometer, or
a 600 MHz Varian Unity Inova NMR spectrometer. Chemical shifts
4-(2-(4-Fluorophenyl)-4,5-diiodothiophen-3-yl)pyridine (3):
a solution of compound 2 (0.861 g, 3.37 mmol) in AcOH (18 mL)
was added Hg(OAc) (3.23 g, 10.1 mmol). The solution was heated
at 708C for 16 h. Concurrently, I
20.2 mmol) were dissolved in H
To
(
d) were reported in parts per million (ppm) referenced to an inter-
2
1
13
nal standard of residual proteo-solvent ( H NMR, C NMR): CDCl
2
(5.14 g, 20.2 mmol) and KI (3.36 g,
O (38 mL) over 16 h in a separate
2
3
[22]
(
7.26, 77.16), CD OD (3.31, 49.00) or [D ]DMSO (2.50, 39.52). Mul-
3
6
tiplicity is quoted as app. (apparent), br. (broad), s (singlet), d (dou-
blet), t (triplet), q (quartet), p (pentet) and m (multiplet). Coupling
constants (J) are given in Hertz (Hz). Low resolution mass spec-
trometry (LRMS) analyses were performed using a Micromass Plat-
form II single quadrupole mass spectrometer equipped with an at-
mospheric pressure (ESI/APCI) ion source. Sample management
was facilitated by an Agilent 1100 series high performance liquid
chromatography (HPLC) system using MassLynx version 3.5 soft-
ware. High resolution mass spectrometry (HRMS) analyses were
carried out on a Waters Micromass LCT Premier XE Orthogonal Ac-
celeration time-of-flight (TOF) mass spectrometer coupled to an Al-
liance 2795 Separation Module using MassLynx version 4.1 soft-
ware. Liquid chromatography–mass spectrometry (LCMS) was per-
formed on an Agilent 1200 Series Separation Module fitted with
a 6120 quadropole detector and a Phenomenex Luna C8(2) 100 ꢁ
round-bottom flask. After 16 h, the AcOH mixture was concentrat-
ed in vacuo and poured into ice water (100 mL). The resulting
white precipitate was filtered and washed with H
afford the mercuric acetate intermediate as a white powder. The
intermediate was added to the KI solution. THF (1 mL) was added
to break the surface tension, and the mixture was stirred at 258C
for 16 h. Saturated Na S O (100 mL) was added, and the resulting
O then Et O to
2
2
3
2
2
3
yellow solid was filtered and washed with H O (50 mL). The solid
2
was dissolved in THF/EtOAc (100 mL) and washed further with sa-
turated Na S O (3ꢂ50 mL). The organic extract was dried over
2
2
3
MgSO , filtered, and concentrated in vacuo to afford thiophene 3.
4
Recrystallisation from THF/EtOH (1:1) afforded compound 3
(
2
(
C H FI NS: M =507.10) as yellow crystals (1.39 g, 81%): mp
15 8 2 r
1
12.88C (decomp.); H NMR (400 MHz, [D ]DMSO): d=8.59–8.58
6
13
m, 2H), 7.20–7.12 ppm (m, 6H); C NMR (101 MHz, [D ]DMSO):
6
1
d=162.0 (d, J =247.0 Hz), 149.7, 145.1, 145.0, 140.1, 130.9 (d,
(
50ꢂ4.6 mm, internal diameter) 5 mm column. Samples were run in
CF
3
4
2
J =8.5 Hz), 128.4 (d, J =3.2 Hz), 125.5, 115.8 (d, J =21.9 Hz),
a gradient of 5–100% buffer B in buffer A (buffer A: 0.1% aq
CF
CF
CF
+
+
1
:
01.8, 87.6 ppm; HRMS-ToF-ESI: m/z [M+H] calcd for C H FI NS
15 9 2
507.8524, found 507.8521; LCMS (ESI): t =6.4 min, 507.9 [M+H] ;
formic acid; buffer B: 80% CH CN, 19.9% water, 0.1% formic acid)
3
+
R
over 4 min, followed by isocratic 100% buffer B for 3 min then
a gradient of 100–0% buffer B over 3 min at a flow rate of
RP-HPLC: t =8.4 min, >99%.
R
ꢁ1
0
.5 mLmin . Agilent Chemstation software (version B.04.01) man-
[
23]
aged the running and processing of samples. Analytical reversed
phase (RP) HPLC was acquired on a Waters Millenium 2690 system
fitted with a Phenomenex Luna C8 100 ꢁ (50ꢂ4.6 mm, internal di-
ameter) 5 mm column with UV detection at 254 nm. Samples were
run in a gradient of 20–100% buffer B in buffer A (buffer A: 0.1%
(
But-3-yn-1-yloxy)(tert-butyl)dimethylsilane (5):
Compound 5
[23]
was synthesised using a similar procedure by Nadeau et al. To
a solution of 3-butyn-1-ol (3.00 g, 42.8 mmol) in CH Cl (60 mL) was
added imidazole (7.28 g, 107 mmol) and cooled to 58C. TBSCl
(6.45 g, 42.8 mmol) was added and the reaction mixture was stirred
at 258C for 16 h. CH Cl (100 mL) was added and the mixture was
2
2
aq trifluoroacetic acid; buffer B: 80% CH CN, 19.9% water, 0.1% tri-
3
2
2
fluoroacetic acid) over 10 min, followed by isocratic 100% buffer B
for 1 min then a gradient of 100–20% buffer B over 1 min followed
by isocratic 20% buffer B for 10 min at a flow rate of 1.0 mL/
minute. EmPowerPro managed the running and processing of sam-
ples. Microwave chemistry was performed using a Biotage Initiator
Microwave Reactor according to manufacturer’s instructions.
washed with H O (2ꢂ50 mL) and brine (50 mL). The organic layer
2
was dried over MgSO , filtered, and concentrated in vacuo to
4
afford compound 5 (7.73 g, 98%) as a colourless oil. 5: C H OSi
1
0
20
1
(M =184.35); H NMR (400 MHz, CDCl ): d=3.74 (t, J=7.1 Hz, 2H),
r
3
2.40 (td, J=7.1, 2.7 Hz, 2H), 1.95 (t, J=2.7 Hz, 1H), 0.90 (s, 9H),
13
0.07 (s, 6H); C NMR (101 MHz, CDCl ): d=81.6, 69.4, 61.9, 26.0,
3
2
3.0, 18.4, ꢁ5.2 ppm.
4
2
-(2-(4-Fluorophenyl)thiophen-3-yl)pyridine (2): To a solution of
,3-dibromothiophene (2.38 mL, 20.7 mmol) in N,N-dimethylforma-
mide (DMF) (160 mL) was added 4-fluorophenylboronic acid
4-(5-(4-((tert-Butyldimethylsilyl)oxy)but-1-yn-1-yl)-2-(4-fluoro-
phenyl)-4-iodothiophen-3-yl)pyridine (6): Negishi coupling: To
a solution of alkyne 5 (2.06 mL, 9.97 mmol) in THF (15 mL) was
added dropwise nBuLi (1.2m, 8.3 mL, 10 mmol) at 08C. The reac-
(
2.89 g, 20.7 mmol), Na CO ·H O (12.3 g, 99.2 mmol), and H O
2 3 2 2
(
1
40 mL). The reaction mixture was bubbled with nitrogen for
5 min. PdCl (PPh ) (0.725 g, 1.03 mmol) was added, and the reac-
2
3 2
tion mixture was heated at 708C for 3 h. Pyridine-4-boronic acid
3.81 g, 31.0 mmol) and additional PdCl (PPh3)2 (0.725 g,
tion mixture was stirred for 15 min. ZnCl (1.63 g, 12.0 mmol) was
2
(
added, and the reaction mixture was stirred at 08C for 15 min,
then allowed to warm to 258C for 15 min, at which time the zinc
had dissolved. Concurrently, compound 3 (1.23 g, 2.43 mmol) was
dissolved in THF (18 mL), and nitrogen was bubbled through the
solution for 30 min. The metallated alkyne solution was added
dropwise to the thiophene solution followed by addition of tetra-
kis(triphenylphosphine)palladium(0) (0.283 g, 0.245 mmol). The
2
1
1
.03 mmol) were added, and the reaction mixture was heated at
208C for 16 h. The reaction mixture was cooled to RT, passed
through a plug of silica, and washed with EtOAc (160 mL). The or-
ganic layer was washed with H O (5ꢂ100 mL), then brine (50 mL),
2
dried over MgSO , and filtered. The organic layer was evaporated
4
in vacuo and purified by column chromatography using a gradient
elution (0–50% EtOAc/petroleum spirits) to afford a pale yellow
solid. Recrystallisation from Et O gave thiophene 2 (C H FNS:
mixture was stirred at 258C for 70 h. Saturated NH Cl (7.5 mL) was
4
added, and the mixture was stirred for 15 min. EtOAc (150 mL) was
added and the mixture was washed with saturated Na CO (3ꢂ
2
15 10
M =255.31) as a white powder (3.81 g, 71%): mp 95.8–97.68C;
r
2
3
1
H NMR (400 MHz, CDCl ): d=8.51 (br. app. d, J=5.6 Hz, 2H), 7.37
40 mL) and brine (3ꢂ40 mL). The organic layer was dried over
3
(
7
d, J=5.2 Hz, 1H), 7.28–7.23 (m, 2H), 7.18 (d, J=5.3 Hz, 1H), 7.16–
MgSO , filtered, and concentrated in vacuo. The product was puri-
4
13
.15 (m, 2H), 7.04–6.98 ppm (m, 2H); C NMR (101 MHz, CDCl3):
fied by column chromatography using a gradient elution (0–50%
EtOAc/petroleum spirits) to afford thiophene 6 as a pale yellow
solid (1.27 g, 94%). Sonogashira coupling: To a solution of com-
pound 3 (1.30 g, 2.56 mmol) in THF (13 mL) was added alkyne 5
(800 mL, 3.88 mmol), PPh3 (0.010 g, 0.038 mmol), CuI (0.027 g,
0.142 mmol), and bis(triphenylphosphine)palladium(II) dichloride
1
d=162.3 (d, J =248.5 Hz), 149.8, 143.6, 139.7, 135.1, 130.9 (d,
CF
3
4
JCF =8.1 Hz), 129.33 (d, JCF =3.4 Hz), 129.27, 125.0, 123.4,
2
+
1
15.6 ppm (d, J =21.7 Hz); HRMS-ToF-ESI: m/z [M+H] calcd for
CF
+
C H FNS : 256.0591, found 256.0589; LCMS (ESI): t =4.9 min,
2
1
5
11
R
+
56.1 [M+H] ; RP-HPLC: t =6.5 min, 99%.
R
ꢀ
2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemistryOpen 2015, 4, 56 – 64 62