A. Anighoro et al. / Bioorg. Med. Chem. 23 (2015) 3040–3058
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7.48 (t, J = 7.5 Hz, 1H), 7.26–7.30 (m, 1H), 7.19 (d, J = 7.5 Hz, 1H),
7.03–7.16 (m, 2H), 5.62 (s, 1H), 3.16–3.21 (m, 2H), 3.11–3.16 (m,
2H), 2.82–2.87 (m, 2H), 2.61 (s, 3H), 2.50–2.55 (m, 2H). MS (ESI)
m/z 334.30 [M+H]+. HPLC 99.4% (UV).
with EtOAc (3ꢂ). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and evaporated to dryness in
vacuo to afford a residue, which was purified by flash chromatog-
raphy in EtOAc/PE gradient from 5:95 to 40:60 affording 75 mg of
the title product. Yield: 51%. 1H NMR (400 MHz, CDCl3) d: 8.84 (d,
J = 2.2 Hz, 1H), 7.90 (dd, J = 2.2, 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H),
5.62 (s, 1H), 3.43–3.58 (m, 4H), 2.61 (t, J = 5.8 Hz, 2H), 2.34 (t,
J = 5.8 Hz, 2H), 1.49 (s, 9H).
4.5.15. 2-{4-[3-(3-Methylphenyl)prop-2-yn-1-ylidene]piperidin-
1-yl}-3-nitropyridine (18)
A mixture of compound 13c (66 mg, 0.271 mmol), 3-iodoto-
luene (36.8 lL, 0.285 mmol), PdCl2(PPh3)2 (9.51 mg, 0.014 mmol),
CuI (6.16 mg, 0.027 mmol) in anhydrous and degassed TEA
(3 mL) was heated at 80 °C under a nitrogen atmosphere for 2 h
in a sealed vessel. The reaction mixture was cooled, poured into
H2O and extracted with EtOAc (3ꢂ). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and evapo-
rated to dryness in vacuo to afford a residue, which was purified by
flash chromatography (EtOAc/PE 1:9) affording 55 mg of the title
compound. Yield: 69%. 1H NMR (400 MHz, CDCl3) d: 8.33–8.42
(m, 1H), 8.14–8.23 (m, 1H), 7.19–7.30 (m, 3H), 7.13 (d, J = 8.1 Hz,
1H), 6.74–6.84 (m, 1H), 5.64 (s, 1H), 3.49–3.61 (m, 4H), 2.77 (t,
J = 5.7 Hz, 2H), 2.50 (t, J = 5.7 Hz, 2H), 2.36 (s, 3H). MS (ESI) m/z
334.30 [M+H]+. HPLC 95.0% (UV).
4.5.18.2.
bonitrile (21b).
6-[3-(4-Piperidylidene)prop-1-ynyl]pyridine-3-car-
The title compound was obtained following
the procedure described for compound 16d, but starting from com-
pound 21a instead of compound 16c. After the usual work-up pro-
cedure, evaporation of the combined EtOAc extracts afforded a
crude of 40 mg used in the following step without any further
purification. Yield: 89%.
4.5.18.3.
dene]prop-1-ynyl]pyridine-3-carbonitrile (21).
of 21b (40 mg, 0.179 mmol), 2-chloro-3-nitro-6-methylpyridine
(35.5 mg, 0.206 mmol), TEA (38.6 L, 0.269 mmol), 4.55 mL of
6-[3-[1-(6-Methyl-3-nitro-2-pyridyl)-4-piperidyli-
A
mixture
l
NMP were reacted overnight at 25 °C under a nitrogen atmosphere.
The reaction mixture was poured into H2O and extracted with
EtOAc (3ꢂ). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and evaporated to dryness in vacuo
to afford a residue, which was purified by flash chromatography
eluting with EtOAc/PE gradient from 5:95 to 40:60 affording
58 mg of the title product as pale yellow oil. Yield: 90.2%. 1H
NMR (400 MHz, CDCl3) d: 8.84 (d, J = 2.1 Hz, 1H), 8.10 (d,
J = 8.2 Hz, 1H), 7.90 (dd, J = 2.1, 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz,
1H), 6.63 (d, J = 8.2 Hz, 1H), 5.67 (s, 1H), 3.46–3.64 (m, 4H), 2.79
(t, J = 5.8 Hz, 2H), 2.52 (t, J = 5.8 Hz, 2H), 2.48 (s, 3H). MS (ESI)
m/z 360.24 [M+H]+. HPLC 98.6% (UV).
4.5.16. 2-[4-[3-(3-Chlorophenyl)prop-2-ynylidene]-1-piperidyl]-
3-nitro-pyridine (19)
A mixture of 13c (56 mg, 0.23 mmol), 1-chloro-3-iodobenzene
(30.5 lL, 0.242 mmol), PdCl2(PPh3)2 (8.07 mg, 0.012 mmol), CuI
(4.38 mg, 0.023 mmol) in anhydrous and degassed TEA (3 mL)
was heated at 80 °C under a nitrogen atmosphere for 2 h in a sealed
vessel. The reaction mixture was cooled, poured into H2O and
extracted with EtOAc (3ꢂ). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4 and evaporated
to dryness in vacuo to afford a residue, which was purified by flash
chromatography (EtOAc/PE 5:95) affording 77 mg of the title com-
pound. Yield: 95%. 1H NMR (400 MHz, CDCl3) d: 8.38 (dd, J = 1.7,
4.5 Hz, 1H), 8.18 (dd, J = 1.7, 8.0 Hz, 1H), 7.44 (t, J = 1.6 Hz, 1H),
7.20–7.36 (m, 3H), 6.80 (dd, J = 4.5, 8.0 Hz, 1H), 5.63 (s, 1H),
3.43–3.68 (m, 4H), 2.76 (t, J = 5.8 Hz, 2H), 2.51 (t, J = 5.8 Hz, 2H).
MS (ESI) m/z 354.2 [M+H]+. HPLC 95.7% (UV).
4.5.19. 3,3-Dimethyl-1-(4-{3-[1-(3-nitropyridin-2-yl)piperidin-
4-ylidene]prop-1-yn-1-yl}phenyl)azetidin-2-one (22)
A mixture of compound 13c (45 mg, 0.185 mmol), 1-(4-iodo-
phenyl)-3,3-dimethylazetidin-2-one
(55.7 mg,
0.185 mmol),
PdCl2(PPh3)2 (7.23 mg, 0.012 mmol), CuI (3.92 mg, 0.206 mmol)
in anhydrous and degassed TEA (3 mL) was heated at 80 °C under
a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mix-
ture was cooled, filtered on Celite, poured into H2O and extracted
with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and evaporated to dryness in vacuo
to afford a residue. Purification was carried out by automated flash
liquid chromatography (HorizonÒ Biotage) eluting with EtOAc/PE
in gradient from 0:100 to 80:20 to afford 32 mg of title compound.
Yield: 42%. 1H NMR (400 MHz, CDCl3) d: 8.36 (d, J = 4.2 Hz, 1H),
8.15 (d, J = 8.2 Hz, 1H), 7.38–7.44 (m, 2H), 7.31 (m, 2H), 6.77 (dd,
J = 4.2, 8.2 Hz, 1H), 5.62 (s, 1H), 3.47–3.60 (m, 4H), 3.46 (s, 2H),
2.66–2.84 (m, 2H), 2.41–2.55 (m, 2H), 1.43 (s, 6H). MS (ESI) m/z
417.5 [M+H]+. HPLC 96.1% (UV).
4.5.17. 3-Chloro-5-[3-[1-(3-nitro-2-pyridyl)-4-piperidylidene]-
prop-1-ynyl]benzonitrile (20)
A mixture of 13c (60 mg, 0.247 mmol), 3-chloro-5-iodobenzoni-
trile (65.1 mg, 0.247 mmol), PdCl2(PPh3)2 (8.68 mg, 0.0124 mmol),
CuI (4.7 mg, 0.0247 mmol) in anhydrous and degassed TEA
(3.6 mL) was heated at 80 °C under a nitrogen atmosphere for 2 h
in a sealed vessel. The reaction mixture was cooled, poured into
H2O and extracted with EtOAc (3ꢂ). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and evapo-
rated to dryness in vacuo to afford a residue, which was purified by
flash chromatography (EtOAc/PE 1:9) affording 68 mg of com-
pound 20. Yield: 73%. 1H NMR (400 MHz, CDCl3) d: 8.38 (dd,
J = 1.9, 4.5 Hz, 1H), 8.17 (dd, J = 1.9, 8.0 Hz, 1H), 7.63 (t, J = 1.6 Hz,
1H), 7.60 (t, J = 1.6 Hz, 1H), 7.56 (t, J = 1.6 Hz, 1H), 6.81 (dd,
J = 4.5, 8.0 Hz, 1H), 5.63 (s, 1H), 3.46–3.66 (m, 4H), 2.75 (t,
J = 5.8 Hz, 2H), 2.52 (t, J = 5.8 Hz, 2H). MS (ESI) m/z 379.10
[M+H]+. HPLC 98.5% (UV).
4.6.
2-[4-[3-(6-Methyl-2-pyridyl)prop-2-ynylidene]-1-
piperidyl]-5-phenyl-pyridine-3-carbonitrile (23)
A solution of compound 16d (86 mg, 0.405 mmol), 2-chloro-5-
phenylnicotinonitrile (95.6 mg, 0.446 mmol) and DIPEA (142 mL)
in 6 mL of NMP was heated in a microwave oven (Biotage) for
15 min at 150 °C giving a conversion of about 60%. A second heat-
ing for 10 min was carried out. After cooling, the reaction was
poured into H2O and extracted with EtOAc (3ꢂ), which was dried
over anhydrous Na2SO4 and evaporated to dryness. Purification
of the crude by flash chromatography with EtOAc/PE gradient from
1:9 to 6:4 afforded 85 mg of product which underwent further LC-
PREP purification giving 13.8 mg of the pure title product. Yield:
4.5.18. 6-[3-[1-(6-Methyl-3-nitro-2-pyridyl)-4-piperidylidene]-
prop-1-ynyl]pyridine-3-carbonitrile (21)
4.5.18.1.
tert-Butyl
4-[3-(5-cyano-2-pyridyl)prop-2-ynyli-
mixture of 16b
dene]piperidine-1-carboxylate (21a).
A
(100 mg, 0.452 mmol), 2-chloro-5-cyanopyridine (76.7 mg,
0.542 mmol), PdCl2(PPh3)2 (15.9 mg, 0.023 mmol), CuI (8.61 mg,
0.045 mmol) in anhydrous and degassed TEA (10 mL) was heated
at 80 °C under a nitrogen atmosphere for 6 h in a sealed vessel.
The reaction mixture was cooled, poured into H2O and extracted