6998 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24
Yano et al.
removed with a stream of argon, and the residue was applied directly
to a TLC plate (20 × 20 cm, 250 µm silica gel) and developed
with an eluant of EtOAc/Hex (5:95, v/v, Rf ) 0.12). The product
band was scraped and eluted with dichloromethane, and the solvent
was removed in vacuo to afford the title compound 14 (6 mg, 68%
yield) as a white film: 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.19
(m, 1H), 7.96 (m, 1H), 7.28 (m, 1H), 6.66 (d, J ) 3.3 Hz, 1H),
6.07 (d, J ) 3.3 Hz, 1H), 3.59 (s, 2H), LRMS (ESI) m/z calcd for
C10H10NOS [M + H]+ 192, found 192.
5-Phenylfuran-2-carboxaldehyde (18). The general Suzuki
coupling procedure was followed. The crude material was chro-
matographed on silica gel (EtOAc/Hex, 10:90, v/v, Rf ) 0.21) to
afford the title compound 18 (201 mg, 90% yield) as an orange
oil: 1H NMR (CDCl3) δ 9.59 (s, 1H), 7.75 (m, 2H), 7.36 (m, 3H),
7.26 (d, J ) 3.9 Hz, 1H), 6.78 (d, J ) 3.6 Hz, 1H); LRMS (ESI)
m/z calcd for C11H9O2 [M + H]+ 173, found 173.
5-Phenylthiophene-2-carboxaldehyde (19). The general Suzuki
coupling procedure was followed. The crude material was combined
and chromatographed on silica gel (EtOAc/Hex, 10:90, v/v, Rf )
0.16) to afford the title compound 19 (410 mg, 84% yield) as a
yellow solid: mp ) 92-93 °C; 1H NMR (CDCl3) δ 9.88 (s, 1H),
7.74 (d, J ) 3.8 Hz, 1H), 7.68-7.65 (m, 2H), 7.46-7.39 (m
containing a doublet, J ) 3.9 Hz, 4H); LRMS (ESI) m/z calcd for
C11H9OS [M + H]+ 189, found 189.
cis/trans-5-Phenylfuran-2-carbaldehyde Oximes (20). To a
solution of 18 (220 mg, 1.28 mmol) in 95% ethanol (6 mL) was
added hydroxylamine hydrochloride (107 mg, 1.53 mmol) and
sodium acetate (126 mg, 1.53 mmol), and the resultant slurry was
heated to reflux and stirred for 25 min. The slurry was diluted with
EtOAc (20 mL), washed with water (3 × 20 mL), dried (Na2SO4),
and filtered, and the solvent was removed in vacuo to afford a cis/
trans mixture of the title compound 20 (228 mg, 95% yield) as a
yellow semisolid that was used in further reactions without further
purification: 1H NMR (CD3OD) δ 7.99 (s, 1.3H), 7.76-7.71 (m,
5H), 7.48 (s, 0.7H), 7.42-7.24 (m, 7H), 6.89-6.71 (m, 4H); LRMS
(ESI) m/z calcd for C11H10NO2 [M + H]+ 188, found 188.
cis/trans-5-Phenylthiophene-2-carboxaldehyde oxime (21). To
a solution of 19 (193 mg, 1.03 mmol) in 95% ethanol (5 mL) was
added hydroxylamine hydrochloride (86 mg, 1.23 mmol) and
sodium acetate (100 mg, 1.23 mmol), and the resultant slurry was
heated to reflux and stirred for 25 min. The slurry was poured into
water (25 mL), extracted with EtOAc (3 × 25 mL), dried (Na2-
SO4), and filtered, and the solvent was removed in vacuo to afford
the cis/trans mixture of the title compound 21 (228 mg, 95% yield)
as a yellow solid, which was used in further reactions without
further purification: mp ) 136-138 °C; 1H NMR (CDCl3) δ 8.27
(s, 1H), 7.72 (s, 1H), 7.68-7.60 (m, 5H), 7.40-7.29 (m, 9H) 7.24
(d, J ) 3.8 Hz, 1H), 7.16 (d, J ) 3.8 Hz, 1H); LRMS (ESI) m/z
calcd for C11H10NO2 [M + H]+ 204, found 204.
(5-Phenylfuran-2-yl)methanamine (22). To a solution of 20
(95 mg, 0.51 mmol) in THF (5 mL) was added dropwise a solution
of lithium aluminum hydride (1.0 M, 0.63 mL, 0.63 mmol), and
the resultant solution was stirred at room temperature for 24 h.
The reaction was poured into MeOH (20 mL), diluted with water
(50 mL), extracted with CHCl3/IPA (3:1, 50 mL, 2 × 20 mL), dried
(Na2SO4), and filtered, and the solvent was removed in vacuo to
afford the title compound 22 (46 mg, 52% yield) as a colorless oil.
Compound 22 was not indefinitely stable and therefore was
converted to the more stable hydrochloride salt. Thirty-five mil-
ligrams of 22 was dissolved in dry Et2O (2 mL) and treated with
ethereal HCl (1 mL). The solid was collected by filtration to afford
the hydrochloride salt of 22 (12 mg) as an off-white foam: 1H
NMR (D2O) δ 7.59 (m, 2H), 7.29 (m, 2H), 7.19 (m, 1H), 6.64 (d,
J ) 3.3, 1H), 6.45 (d, J ) 3.6, 1H), 4.09 (s, 2H); LRMS (ESI) m/z
calcd for C11H9O [M - NH2]+ 157, found 157.
(5-Phenylthiophen-2-yl)methanamine (23). To a solution of 21
(150 mg, 0.74 mmol) in THF (5 mL) was added dropwise a solution
of lithium aluminum hydride (1.0 M, 0.92 mL, 0.92 mmol), and
the resultant solution was stirred at room temperature for 24 h.
The reaction was poured into MeOH (20 mL), diluted with water
(50 mL), extracted with CHCl3/IPA (3:1, 50 mL, 2 × 20 mL), dried
(Na2SO4), and filtered and the solvent was removed in vacuo. The
crude material was chromatographed on silica gel (preparative TLC,
CH3OH/CHCl3, 10:90, v/v, Rf ) 0.18) to afford the title compound
23 (11 mg, 8% yield) as a white film: 1H NMR (CDCl3) δ 7.58-
7.55 (m, 2H), 7.38-7.33 (m, 2H), 7.28-7.23 (m, 1H), 7.14 (d, J
) 3.6, 1H), 6.87 (d, J ) 3.6, 1H), 4.05 (s, 2H); LRMS (ESI) m/z
calcd for C11H9S [M - NH2]+ 173, found 173. HRMS (ESI) m/z
calcd for C11H12NS [M + H]+ 190.2825, found 190.2826.
3-(5-((Methylthio)methyl)furan-2-yl)pyridine (15). To a solu-
tion of 13 (27 mg, 0.12 mmol) in anhydrous CH3OH (3 mL) at 0
°C under argon was added dropwise a solution of sodium methoxide
(15 mg, 0.28 mmol) in anhydrous CH3OH (1 mL) over 10 min,
and the resultant solution was stirred for 30 min. To the resultant
solution was added dropwise methyl iodide (17 µL, 0.28 mmol) in
anhydrous CH3OH (1 mL) over 1 min, and the resultant solution
was stirred for 30 min. The reaction was stopped by the addition
of aqueous sodium bicarbonate (satd. soln., 10 mL). CH3OH was
removed in vacuo, and the aqueous fraction was extracted with
EtOAc (3 × 10 mL). The combined organic fractions were dried
(Na2SO4) and filtered, and the solvent was removed in vacuo. The
crude material was chromatographed on silica gel (EtOAc/Hex, 25:
75, v/v, Rf ) 0.2) to afford the title compound 15 (13 mg, 54%
1
yield) as an off white solid: mp ) 67-68 °C; H NMR (CDCl3)
δ 8.90 (br s, 1H), 8.46 (m, 1H), 7.90 (m, 1H), 7.29 (m, 1H), 6.66
(d, J ) 3.3 Hz, 1H), 6.29 (d, J ) 3.3 Hz, 1H), 3.74 (s, 2H), 2.14
(s, 3H); LRMS (ESI) m/z calcd for C11H12NOS [M + H]+ 206,
found 206.
5-(Pyridin-3-yl)furan-2-carbaldehyde (16). The general Suzuki
coupling procedure was followed. The crude material was chro-
matographed on silica gel (EtOAc/Hex, 50:50, Rf ) 0.19) to afford
the title compound 16 (1.28 g, 95% yield) as an off white solid.
Analytical properties are consistent with published values: mp )
112-115 °C (lit. 113-115 °C);11 1H NMR (CDCl3) δ 9.70 (s, 1H),
9.05 (m, 1H), 8.63 (m, 1H), 8.12 (m, 1H), 7.39 (m, 1H), 7.35 (d,
J ) 4.1 Hz, 1H), 6.94 (d, J ) 4.1 Hz, 1H).
3-(5-[1,3]Dithiolan-2-yl-furan-2-yl)pyridine (17). To a solution
of aldehyde 1611 (44 mg, 0.25 mmol) in anhydrous toluene (5 mL)
was added ethane dithiol (21 µL, 0.25 mmol) followed by
toluenesulfonic acid (approximately 2 mg), and 4 Å molecular
sieves, and the resultant solution was stirred under nitrogen
overnight. An additional 5 mg of toluenesulfonic acid was added,
and the solution was stirred under argon for 2 h. The toluene was
decanted, and the resulting residue was rinsed with hexanes. The
residue was partitioned between EtOAc (20 mL) and aqueous
sodium bicarbonate (satd. soln., 20 mL). The organic fraction was
collected, and the aqueous fraction was extracted with EtOAc (2
× 20 mL). The combined organic fractions were dried (Na2SO4)
and filtered, and the solvent was removed in vacuo. The crude
material was chromatographed on silica gel (EtOAc/Hex, 50:50,
v/v, Rf ) 0.3) to afford the title compound 17 (10 mg, 83% yield)
as a yellow film: 1H NMR (CDCl3) δ 8.88 (m, 1H), 8.47 (m, 1H),
8.89 (m, 1H), 7.28 (m, 1H), 6.63 (m, 1H), 6.41 (m, 1H), 5.65 (s,
1H), 3.50-3.30 (m, 4H); LRMS (ESI) m/z calcd for C12H12NOS2
[M + H]+ 250, found 250.
General Procedure for Suzuki Coupling Reactions. To a dry
glass vial purged with argon containing a magnetic stir bar was
added the heteroarylbromide (1.3 mmol). To the vial was added a
solution of tetrakis(triphenylphosphine)palladium(0) (0.03 mmol)
in dimethoxyethane (2 mL) and sodium carbonate (aq) (2 M, 1.3
mL, 2.6 mmol), and the vial was once again purged with argon.
The resultant solution was stirred at room temperature for 5 min,
and a solution of phenylboronic acid (198 mg, 1.63 mmol) in
ethanol (2 mL) was added; the vial was purged with argon, capped,
heated to 90 °C, and stirred for 1 h (Scheme 2). The solution was
cooled to room temperature and filtered through a pad of Celite by
washing with dichloromethane and dried with anhydrous magne-
sium sulfate (5 g). The solution was then filtered through filter
paper, and the solvent was removed in vacuo to afford the crude
product, which was chromatographed on silica gel.