RXR Selective Diaryl Sulfide Analogs of RA
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18 3561
146.2, 146.8, 146.9, 166.2; MS (EI, 70 eV) 340 (M+, 55), 325
(100); HRMS calcd for C21H24O2S 340.1497, found 340.1493.
Eth yl 4-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-
n a p h th yl)th io]ben zoa te (12). Sodium hydride (65 mg, 60%
dispersion in oil, 1.62 mmol) was rinsed three times with
hexane and dried under vacuum. The vacuum was broken
with dry argon, and 2.5 mL of HMPA and 5,6,7,8-tetrahydro-
3,5,5,8,8-pentamethyl-2-naphthalenethiol17 (0.38 g, 1.62 mmol)
were added sequentially. After 30 min at 50 °C, copper(I)
iodide (257 mg, 1.35 mmol) was added, which caused the
solution to become deep green. The solution was stirred for
15 min, and ethyl 4-iodobenzoate (373 mg, 1.35 mmol) was
added. The solution was heated to 90 °C for 5 h, the bath
was removed, and stirring was continued overnight at room
temperature. Water was added, and the products were
extracted with diethyl ether (3×). The combined ether layers
were washed with brine, dried (MgSO4), and filtered, and the
solvent was removed in vacuo. The residue was purified by
flash chromatography on silica gel (5% ethyl acetate in
hexanes) to give 12 as a light yellow solid (260 mg, 50%): mp
vacuo, the residue was treated with brine and acidified with
10% aqueous HCl, and the product was extracted with ether
(2×). The combined ether layers were dried (MgSO4) and
filtered, and the solvents were removed in vacuo to give 3 as
1
a white solid (0.39 mg, 72%): mp 235-240 °C dec; H NMR
(300 MHz, CDCl3) δ 1.22 (s, 3 H), 1.24 (s, 3 H), 1.26 (s, 3 H),
1.29 (s, 3 H), 1.66 (s, 4 H), 2.34 (s, 3 H), 7.10 (s, 1 H), 7.70 (d,
2 H, J ) 8.3 Hz), 7.76 (s, 1 H), 8.17 (d, 2 H, J ) 8.3 Hz); 13C
NMR (75 MHz, CDCl3) δ 18.2, 31.5, 31.6, 31.8, 34.3, 34.4, 34.7,
124.0, 125.6, 129.6, 130.8, 131.6, 132.9, 138.5, 144.6, 149.1,
150.2, 169.9; MS (EI, 70 eV) m/ z 370 (M+, 25), 357 (100). Anal.
(C22H26O3S) C, H.
Eth yl 4-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-
n a p h th yl)su lfon yl]ben zoa te. To a solution of 69 mg (0.18
mmol) of 12 in 2.0 mL of methylene chloride was added a
solution of m-chloroperoxybenzoic acid (80 mg, 50-60%, 0.27
mmol) and 2.0 mL of methylene chloride. The resulting
solution was stirred at room temperature for 3 h and diluted
with water, and the products were extracted with methylene
chloride (2×). The combined organic layers were dried (Mg-
SO4) and filtered, and the solvents were removed in vacuo.
The crude product was purified by flash chromatography on
silica gel (10% ethyl acetate in hexanes) to give the title
compound as a white solid (51 mg, 94%): mp 130-131 °C; IR
106-107.5 °C; IR 1716 (CdO) cm-1 1H NMR (300 MHz,
;
CDCl3) δ 1.24 (s, 6 H), 1.30 (s, 6 H), 1.36 (t, 3 H, J ) 7.1 Hz),
1.69 (s, 4 H), 2.28 (s, 3 H), 4.33 (q, 2 H, J ) 7.1 Hz), 7.05 (d,
2 H, J ) 8.6 Hz), 7.23 (s, 1 H), 7.26 (s, 1 H), 8.87 (d, 2 H, J )
8.6 Hz); 13C NMR (75 MHz, CDCl3) δ 14.3, 20.3, 31.7, 31.8,
34.0, 34.2, 34.9, 35.0, 60.8, 125.7, 126.7, 126.9, 129.1, 129.9,
134.4, 138.8, 144.1, 145.2, 145.8, 166.3; MS (EI, 70 eV) m/ z
382 (M+, 42), 367 (67), 171 (100). Anal. (C24H30O2S) C, H, S.
4-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-n a p h th -
yl)t h io]b en zoic Acid (2). Ethyl 4-[(5,6,7,8-tetrahydro-
3,5,5,8,8-pentamethyl-2-naphthyl)thio]benzoate (12; 170 mg,
0.44 mmol) was dissolved in ethyl alcohol (4 mL) and the
solution treated with 2 M aqueous KOH (2 mL). The solution
was heated to 50 °C for 4 h and concentrated in vacuo. The
residue was treated with diethyl ether, cooled to 0 °C, and
acidified with 10% aqueous HCl. The product was extracted
with ether, washed with water and brine, dried (MgSO4), and
filtered, and the solvent was removed under reduced pressure
to give 2 as a yellow solid (158 mg, 100%): mp 249-250 °C;
IR 3300-2400 (COOH), 1672 (CdO) cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.25 (s, 6 H), 1.31 (s, 6 H), 1.69 (s, 4 H), 2.29 (s, 3 H),
7.05 (d, 2 H, J ) 8.5 Hz), 7.25 (s, 1 H), 7.26 (s, 1 H), 7.92 (d,
2 H, J ) 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ 20.3, 31.7, 31.8,
34.1, 34.2, 34.9, 35.0, 125.4, 125.5, 126.3, 129.1, 130.6, 134.6,
139.0, 144.2, 146.9, 147.1, 171.0; MS (EI, 70 eV) m/ z 354 (M+,
41), 335 (67), 173 (100). Anal. (C22H26O2S) C, H, S.
Eth yl 4-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-
n a p h th yl)su lfoxy]ben zoa te. To a solution of 12 (0.12 g, 0.31
mmol) and 4 mL of dioxane was added 1.0 mL of a 0.42 M
solution of sodium periodate (prepared by dissolving 180 mg
of sodium periodate in 0.7 mL of water and 1.3 mL of
methanol). An additional 6.0 mL of methanol was added, and
the resulting mixture was stirred at room temperature for 42
h and then heated to 50 °C for 8 days. Additional sodium
periodate (80 mg, 0.38 mmol) and 2.0 mL of dioxane were
added periodically during this time. The reaction mixture was
cooled to room temperature, brine was added, and the mixture
was extracted with ether (2×). The organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure.
The resulting oil was purified by flash chromatography on
silica gel (15% ethyl acetate in hexanes) to give the title
compound as a clear oil (65 mg, 52%): 1H NMR (300 MHz,
CDCl3) δ 1.23 (s, 3 H), 1.24 (s, 3 H), 1.26 (s, 3 H), 1.30 (s, 3 H),
1.39 (t, 3 H, J ) 7.1 Hz), 1.67 (s, 4 H), 2.31 (s, 3 H), 4.38 (q, 2
H, J ) 7.1 Hz), 7.08 (s, 1 H), 7.66 (d, 2 H, J ) 8.4 Hz), 7.76 (s,
1 H), 8.12 (d, 2 H, J ) 8.4 Hz); 13C NMR (75 MHz, CDCl3) δ
14.2, 18.2, 31.6, 31.8, 34.3, 34.4, 34.8, 61.4, 123.7, 125.4, 129.5,
130.2, 132.5, 132.7, 139.1, 144.4, 148.8, 149.8, 165.6; MS (EI,
70 eV) m/ z 398 (M+, 12), 382 (23), 367 (34), 352 (100).
1
2962, 1724 cm-1; H NMR (300 MHz, CDCl3) δ 1.25 (s, 6 H),
1.34 (s, 6 H), 1.39 (t, 3 H, J ) 7.1 Hz), 1.70 (s, 4 H), 2.33 (s, 3
H), 4.40 (q, 2 H, J ) 7.1 Hz), 7.11 (s, 1 H), 7.90 (d, 2 H, J )
8.5 Hz), 8.15 (s, 1 H), 8.16 (d, 2 H, J ) 8.5 Hz); 13C NMR (75
MHz, CDCl3) δ 14.2, 19.8, 31.5, 31.7, 34.3, 34.5, 34.7, 61.7,
127.5, 128.1, 130.1, 131.0, 134.1, 134.3, 135.0, 143.9, 145.5,
151.7, 165.1; MS (EI, 70 eV) m/ z 416 (MH+, 9), 414 (9), 399
(76), 305 (86), 77 (100). Anal. (C24H30O4S) C, H.
4-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-n a p h th -
yl)su lfon yl]ben zoic Acid (4). To a solution of 50 mg (0.12
mmol) of ethyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-
naphthyl)sulfonyl]benzoate and 3.0 mL of THF was added 1.0
mL of 1 N aqueous LiOH. The solution was heated to 50 °C
for 3 h, cooled to room temperature, and concentrated in vacuo.
The residue was diluted with brine and acidified with 10%
aqueous HCl, and the products were extracted with ether (2×).
The combined ether layers were dried (MgSO4) and filtered,
and the solvents were removed in vacuo to give 4 as a white
solid (45 mg, 98%): mp 228-231 °C; IR 3300-2500, 1695 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.25 (s, 6 H), 1.34 (s, 6 H), 1.70
(s, 4 H), 2.33 (s, 3 H), 7.12 (s, 1 H), 7.95 (d, 2 H, J ) 8.4 Hz),
8.15 (s, 1 H), 8.22 (d, 2 H, J ) 8.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 19.9, 31.5, 31.7, 34.3, 34.5, 34.7, 127.7, 128.2, 130.8,
131.1, 134.1, 134.8, 144.0, 146.5, 151.9, 165.0; MS (EI, 70 eV)
387 m/ z 387 (MH+, 33), 371 (100). Anal. (C22H26O4S) C, H,
S.
Eth yl 6-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-
n a p h th yl)th io]n icotin a te (14). Sodium hydride (171 mg,
60% dispersion in oil, 4.3 mmol) was rinsed three times with
hexane and dried under vacuum. The vacuum was broken
with dry argon, and 6.6 mL of HMPA and 5,6,7,8-tetrahydro-
3,5,5,8,8-pentamethyl-2-naphthalenethiol (1.0 g, 4.27 mmol)
were added sequentially. After 30 min at 50 °C, copper(I)
iodide (678 mg, 3.56 mmol) was added, which caused the
solution to become deep green. The solution was stirred for
an additional 15 min at 50 °C, ethyl 2-iodonicotinate (986 mg,
3.56 mmol) was added, and the solution was heated to 90 °C
for 5 h. The heating bath was removed, and the reaction
mixture was stirred overnight at room temperature. Water
was added, and the products were extracted with diethyl ether
(3×). The combined ether layers were washed with brine,
dried (MgSO4), and filtered, and the solvent was removed in
vacuo. The residue was purified by flash chromatography on
silica gel (5% ethyl acetate in hexanes) to give 14 as a light
yellow solid (642 mg, 47%): mp 110-111 °C; 1H NMR (300
MHz, CDCl3) δ 1.26 (s, 6 H), 1.31 (s, 6 H), 1.37 (t, 3 H, J ) 7.1
Hz), 1.69 (s, 4 H), 2.32 (s, 3 H), 4.36 (q, 2 H, J ) 7.1 Hz), 6.68
(d, 1 H, J ) 8.0 Hz), 7.23 (s, 1 H), 7.53 (s, 1 H), 7.99 (dd, 1 H,
J ) 2.3, 8.0 Hz), 9.00 (d, 1 H, J ) 2.3 Hz); 13C NMR (75 MHz,
CDCl3) δ 14.3, 20.4, 31.7, 31.8, 34.1, 34.2, 34.9, 34.9, 61.1,
118.9, 121.8, 125.3, 129.3, 135.1, 137.2, 139.2, 144.4, 147.6,
4-[(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-2-n a p h th -
yl)su lfoxy]ben zoic Acid (3). To a solution of 58 mg (0.15
mmol) of ethyl 4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-
naphthyl)sulfoxy]benzoate and 4.0 mL of THF were added 1.0
mL of 2 M aqueous LiOH and 2.0 mL of MeOH. The solution
was heated at 55 °C for 2 h, cooled to room temperature, and
stirred for 8 h. The reaction mixture was concentrated in