6146 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lucas et al.
equivalents). The mixture was then refluxed for 12-18 h, cooled
to room temperature, diluted with water, and extracted several times
with ethyl acetate. The combined extracts were dried over MgSO4,
concentrated, and purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate mixtures) and/or crystallization. If
an oil was obtained, it was dissolved in diethyl ether/methanol and
transferred into the hydrochloride salt by 1N HCl solution in
isopropanol/diethyl ether, followed by filtration and optional
crystallization from acetone. Analytical data refer to the free base
unless otherwise noted.
66%), mp (HCl salt) 161-162 °C. MS m/z 326.02 (MH+). Anal.
(C23H19NO·HCl·0.6H2O) C, H, N.
3-[3-(4-Methoxybenzyl)naphthalen-2-yl]pyridine (16). The
compound was obtained according to procedure A from 16a (476
mg, 1.20 mmol) and 3-pyridineboronic acid (92 mg, 0.75 mmol)
after flash chromatography on silica gel (petroleum ether/ethyl
acetate, 4/1, Rf ) 0.14) as a colorless oil (199 mg, 0.56 mmol,
75%), mp (HCl salt) 180-182 °C. 1H NMR (500 MHz, CDCl3): δ
) 3.75 (s, 3H), 4.00 (s, 2H), 6.72 (d, 3J ) 8.8 Hz, 2H), 6.82 (d, 3J
) 8.8 Hz, 2H), 7.26 (ddd, 3J ) 7.9 Hz, 3J ) 4.7 Hz, 5J ) 0.9 Hz,
1H), 7.45-7.52 (m, 3H), 7.68 (s, 1H), 7.70 (s, 1H), 7.79-7.83
Procedure C.33,34 To a 0.6 M solution of NaI (6 equiv) in
acetonitrile was added chlorotrimethylsilane (6 equiv) at room
temperature, and the mixture was stirred for 30 min before cooling
to 0 °C with an ice-water bath. Then, a 1 M solution of the
phenylnaphthylalcohol (1 equiv) in acetonitrile was added dropwise.
After complete addition, the mixture was heated at 55 °C for 3 h.
After recooling to room temperature, the reaction was quenched
by addition of saturated aqueous NaHCO3 solution. The layers were
separated, and the aqueous layer extracted twice with ethyl acetate
The combined organic layers were washed with a solution of
Na2S2O3, water, and brine. The extracts were dried over MgSO4,
concentrated, and purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate mixtures). If an oil was obtained, it
was dissolved in diethyl ether/methanol and tranferred into the
hydrochloride salt by 1N HCl solution in isopropanol/diethyl ether,
followed by filtration and optional crystallization from acetone.
Analytical data refer to the free base unless otherwise noted.
Procedure D. To a 0.05 M solution of benzoylnaphthalene in
dry methanol was added sodium borohydride (2 equiv) at such a
rate as to maintain the internal reaction temperature below 5 °C.
The reaction mixture was stirred for 1 h, diluted with diehtylether,
and treated with saturated aqueous NaHCO3 solution. The mixture
was then extracted three times with ethyl acetate, washed twice
with saturated aqueous NaHCO3 solution and once with brine, and
dried over MgSO4. The filtrate was concentrated in vacuo, and the
residue was flash chromatographed on silica gel (petroleum ether/
ethyl acetate mixtures) to afford the corresponding alcohols.
3-(3-Phenylnaphthalen-2-yl)pyridine (11). The compound was
obtained according to procedure A from 11a (657 mg, 1.86 mmol)
and phenylboronic acid (854 mg, 4.00 mmol) after flash chroma-
tography on silica gel (petroleum ether/ethyl acetate, 7/3, Rf ) 0.22)
as a colorless oil (195 mg, 0.69 mmol, 37%). Precipitation of the
hydrochloride salt afforded a highly hygroscopic solid, mp (HCl
salt) 106-109 °C. MS m/z 282.70 (MH+). Anal. (C21H15N·HCl·
1.5H2O) C, H, N.
3-(3-Benzylnaphthalen-2-yl)pyridine (12). The compound was
obtained according to procedure A from 12a (433 mg, 1.18 mmol)
and 3-pyridineboronic acid (105 mg, 0.85 mmol) after flash
chromatography on silica gel (petroleum ether/ethyl acetate, 4/1,
Rf ) 0.19) as a colorless oil (186 mg, 0.63 mmol, 74%), mp (HCl
salt) 197-198 °C. MS m/z 296.14 (MH+). Anal. (C22H17N·HCl·
0.6H2O) C, H, N.
3-(3-Benzyl-6-methoxynaphthalen-2-yl)pyridine (13). The com-
pound was obtained according to procedure A from 13a (462 mg,
1.17 mmol) and 3-pyridineboronic acid (100 mg, 0.81 mmol) after
flash chromatography on silica gel (petroleum ether/ethyl acetate,
4/1, Rf ) 0.18) as a colorless oil (196 mg, 0.60 mmol, 74%),
mp (HCl salt) 170-172 °C. MS m/z 326.09 (MH+). Anal.
(C23H19NO·HCl·0.6H2O) C, H, N.
3-[3-(2-Methoxybenzyl)naphthalen-2-yl]pyridine (14). The
compound was obtained according to procedure A from 14a (462
mg, 1.17 mmol) and 3-pyridineboronic acid (100 mg, 0.81 mmol)
after flash chromatography on silica gel (petroleum ether/ethyl
acetate, 7/3, Rf ) 0.26) as colorless oil (161 mg, 0.50 mmol, 61%),
mp (HCl salt) 214-216 °C. MS m/z 326.02 (MH+). Anal.
(C23H19NO·HCl·0.6H2O) C, H, N.
3-[3-(3-Methoxybenzyl)naphthalen-2-yl]pyridine (15). The
compound was obtained according to procedure A from 15a (433
mg, 1.09 mmol) and 3-pyridineboronic acid (92 mg, 0.75 mmol)
after flash chromatography on silica gel (petroleum ether/ethyl
acetate, 4/1, Rf ) 0.13) as a colorless oil (162 mg, 0.50 mmol,
4
5
3
(m, 2H), 8.55 (dd, J ) 2.2 Hz, J ) 0.9 Hz, 1H), 8.59 (dd, J )
4.7 Hz, 4J ) 1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ ) 39.0,
55.2, 113.7, 122.7, 126.0, 126.4, 127.3, 127.6, 128.9, 129.4, 129.7,
132.0, 132.4, 133.1, 136.6, 137.06, 137.13, 148.2, 149.9, 157.9.
MS m/z 326.16 (MH+). Anal. (C23H19NO·HCl·0.6H2O) C, H, N.
4-(3-Pyridin-3-yl-naphthalen-2-ylmethyl)benzonitrile (17).
The compound was obtained according to procedure C from 33
(841 mg, 2.50 mmol), sodium iodide (2.25 g, 15.0 mmol), and
chlorotrimethylsilane (1.63 g, 15.0 mmol) after flash chromato-
graphy on silica gel (petroleum ether/ethyl acetate, 7/3, Rf ) 0.15)
as a colorless oil (486 mg, 1.52 mmol, 61%), mp (HCl salt)
130-131 °C. MS m/z 321.33 (MH+). Anal. (C23H16N2 · HCl ·
0.8H2O) C, H, N.
3-[3-(4-Trifluoromethoxybenzyl)naphthalen-2-yl]pyridine (18).
The compound was obtained according to procedure C from 34
(395 mg, 1.00 mmol), sodium iodide (899 mg, 6.0 mmol), and
chlorotrimethylsilane (652 mg, 6.0 mmol) after flash chromato-
graphy on silica gel (petroleum ether/ethyl acetate, 4/1, Rf ) 0.28)
as a colorless oil (292 mg, 0.77 mmol, 77%). Precipitation of the
hydrochloride salt afforded a highly hygroscopic solid, mp (HCl
salt) 139-142 °C. MS m/z 379.90 (MH+). Anal. (C24H17F3NO·HCl·
0.2H2O) C, H, N.
3-[6-Methoxy-3-(4-methoxybenzyl)naphthalen-2-yl]pyridine
(19). The compound was obtained according to procedure A from
19a (512 mg, 1.20 mmol) and 3-pyridineboronic acid (113 mg,
0.92 mmol) after flash chromatography on silica gel (petroleum
ether/ethyl acetate, 7/3, Rf ) 0.18) as a colorless oil (189 mg, 0.55
mmol, 60%), mp (HCl salt) 114-115 °C. 1H NMR (500 MHz,
CDCl3): δ ) 3.75 (s, 3H), 3.91 (s, 3H), 3.98 (s, 2H), 6.73 (d, 3J )
8.5 Hz, 2H), 6.84 (d, 3J ) 8.5 Hz, 2H), 7.09 (d, 4J ) 2.5 Hz, 1H),
7.13 (dd, 3J ) 9.0 Hz, 4J ) 2.5 Hz, 1H), 7.25 (dd, 3J ) 8.0 Hz, 3J
) 4.8 Hz, 1H), 7.51 (m, 1H), 7.57 (s, 1H), 7.60 (s, 1H), 7.71 (d,
4
3
3J ) 8.9 Hz, 1H), 8.54 (d, J ) 1.9 Hz, 1H), 8.56 (dd, J ) 4.8
Hz, J ) 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ ) 38.9,
4
55.2, 55.3, 105.2, 113.7, 119.0, 122.8, 127.5, 127.8, 129.1, 129.2,
129.8, 132.6, 134.4, 134.8, 136.8, 137.3, 137.6, 148.1, 150.1, 157.9,
158.1. MS m/z 356.25 (MH+). Anal. (C24H21NO2 ·HCl·0.8H2O)
C, H, N.
3-[7-Methoxy-3-(4-methoxybenzyl)naphthalen-2-yl]pyridine
(20). The compound was obtained according to procedure C from
20a (400 mg, 1.08 mmol), sodium iodide (1.65 g, 11.0 mmol), and
chlorotrimethylsilane (1.20 g, 11.0 mmol) after flash chromato-
graphy on silica gel (petroleum ether/ethyl acetate, 7/3, Rf ) 0.11)
as a colorless oil (148 mg, 0.42 mmol, 39%), mp (HCl salt)
101-103 °C. MS m/z 356.04 (MH+). Anal. (C24H21NO2 · HCl ·
0.1H2O) C, H, N.
3-Methoxy-5-[3-(4-methoxybenzyl)naphthalen-2-yl]pyridine
(21). The compound was obtained according to procedure A from
16a (396 mg, 1.00 mmol) and 5-methoxy-3-pyridineboronic acid
(130 mg, 0.85 mmol) after flash chromatography on silica gel
(petroleum ether/ethyl acetate, 7/3, Rf ) 0.21) as a colorless oil
(149 mg, 0.42 mmol, 49%), mp (HCl salt) 106-108 °C. MS m/z
356.09 (MH+). Anal. (C24H21NO2 ·HCl·0.5H2O) C, H, N.
3-Methoxy-5-[6-methoxy-3-(4-methoxybenzyl)naphthalen-2-
yl]pyridine (22). The compound was obtained according to
procedure A from 19a (426 mg, 1.00 mmol) and 5-methoxy-3-
pyridineboronic acid (130 mg, 0.85 mmol) after flash chromato-
graphy on silica gel (petroleum ether/ethyl acetate, 7/3, Rf ) 0.18)
as colorless plates (244 mg, 0.63 mmol, 75%), mp 129-130 °C.
MS m/z 385.91 (MH+). Anal. (C25H23NO3) C, H, N.