1850 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 12
Pontikis et al.
aqueous NaHCO3, treated in the usual manner, and then
crystallized from ether to give 21 (3.25 g, 95%): mp 73-75
°C; IR (CHCl3) ν 3399, 2960, 1710, 1685, 1466 cm-1; 1H NMR
(CDCl3) δ 0.03 [s, 6H, Si(CH3)2], 0.74 [s, 6H, C(CH3)2], 0.77 [d,
6H, J ) 7 Hz, CH(CH3)2], 1.51 [m, 1H, CH(CH3)2], 1.85 (s, 3H,
CH3), 3.53 and 3.65 (2 × m, 4H, OCH2CH2O), 5.09 (s, 2 H,
OCH2N), 7.07 (s, 1H, H-6), 8.90 (br s, 1H, NH); MS (CI-NH3)
m/ z 360 (M + NH4)+. Anal. (C16H30N2O4Si) C, H, N.
6-(P h en ylth io)-1-[[2-(2-p yr id ylth io)eth oxy]m eth yl]th y-
m in e (27). Compound 27 was isolated (94% yield) from the
reaction of 1 with 2,2′-dipyridyl disulfide after flash chroma-
tography (EtOAc/cyclohexane: 1/1): mp (ether) 137-138 °C;
IR (CHCl3) ν 3375, 2930, 1712, 1689, 1436 cm-1
;
1H NMR
(CDCl3) δ 2.01 (s, 3H, CH3), 3.29 (t, 2H, J ) 6 Hz, CH2S), 3.83
(t, 2H, J ) 6 Hz, OCH2CH2S), 5.59 (s, 2H, OCH2N), 6.96 [m,
1H, SPy-H(5)], 7.10-7.35 (m, 6H, Ar), 7.43 [m, 1H, SPy-H(4)],
8.36 [m, 1H, SPy-H(6)], 9.05 (br s, 1H, NH); MS (CI-NH3) m/ z
402 (M + H)+, 112. Anal. (C19H19N3O3S2) C, H, N.
1-[[2-[(Dim et h ylt h exylsilyl)oxy]et h oxy]m et h yl]-6-(2-
p yr id ylth io)th ym in e (22). Following the method of Pan et
al.23 compound 21 (1.0 g, 2.9 mmol) was lithiated with lithium
diisopropylamide (LDA) at -78 °C (2.5 equiv) and then treated
with 2,2′-dipyridyl disulfide (1.3 g, 5.9 mmol). Flash chroma-
tography (cyclohexane/EtOAc: 1/1) gave 22 (1.2 g, 91%): mp
(ether) 83-84 °C; IR (CHCl3) ν 3396, 2959, 1710, 1680, 1450
1-[[2-(P h en ylt h io)et h oxy]m et h yl]-6-(2-p yr id ylt h io)-
th ym in e (28). Compound 28 was isolated (93% yield) from
the reaction of 23 with diphenyl disulfide after flash chroma-
tography (EtOAc/cyclohexane: 7/3): mp (ether/pentane) 116-
118 °C; IR (CHCl3) ν 3390, 3183, 3051, 1675, 1700, 1581, 1455
cm-1; H NMR (CDCl3) δ 0.01 [s, 6H, Si(CH3)2], 0.74 [s, 6H,
cm-1; H NMR (CDCl3) δ 2.04 (s, 3H, CH3), 3.00 (t, 2H, J )
1
1
C(CH3)2], 0.80 [d, 6H, J ) 7 Hz, CH(CH3)2], 1.51 [m, 1H,
CH(CH3)2], 1.98 (s, 3H, CH3), 3.57 (s, 4H, CH2CH2), 5.50 (s,
2H, OCH2N), 7.05 [m, 1H, SPy-H(5)], 7.14 [d, 1H, J ) 9 Hz,
SPy-H(3)], 7.54 [dt, 1H, J ) 2, 9 Hz, SPy-H(4)], 8.33 [m, 1H,
SPy-H(6)], 8.95 (br s, 1H, NH); MS (CI-NH3) m/ z 452 (M +
H)+, 112. Anal. (C21H33N3O4SSi) C, H, N.
1-[(2-H yd r oxye t h oxy)m e t h yl]-6-(2-p yr id ylt h io)t h y-
m in e (23). A solution of 22 (600 mg, 1.33 mmol) and Bu4NF
(1.0 M solution in THF, 2.7 mL) in THF (10 mL) was stirred
at room temperature for 16 h. After removal of the solvent
under reduced pressure, the residue was flash chromato-
graphed (CH2Cl2/MeOH: 95/5) to give 23 (365 mg, 96%): mp
(MeOH) 128-130 °C; IR (KBr) ν 3400-2800, 1700, 1674, 1419
cm-1; 1H NMR (CDCl3) δ 2.03 (s, 3H, CH3), 2.95 (br s, 1H, OH),
3.59 (m, 2H, CH2OH), 3.72 (m, 2H, CH2CH2OH), 5.61 (s, 2H,
OCH2N), 7.14 [m, 1H, SPy-H(5)], 7.26 [m, 1H, SPy-H(3)], 7.63
[dt, J ) 2, 8.5 Hz, 1H, SPy-H(4)], 8.40 [m, 1H, SPy-H(6)], 9.35
(br s, 1H, NH); MS (CI-NH3) m/ z 310 (M + H)+. Anal.
(C13H15N3O4S) C, H, N.
6.5 Hz, CH2S), 3.72 (t, 2H, J ) 6.5 Hz, OCH2CH2S), 5.55 (s,
2H, OCH2N), 7.10-7.30 (m, 9H, Ar), 8.80 (br s, 1H, NH); MS
(CI-NH3) m/ z 402 (M + H)+, 112. Anal. (C19H19N3O3S2) C,
H, N.
1-[[2-(2-P yr id ylth io)eth oxy]m eth yl]-6-(2-p yr id ylth io)-
th ym in e (29). Compound 29 was isolated (89% yield) from
the reaction of 23 with 2,2′-dipyridyl disulfide after flash
chromatography (EtOAc/cyclohexane: 4/1): mp (ether/pen-
tane) 94-96 °C; IR (CHCl3) ν 3690, 2945, 1658, 1588, 1426
1
cm-1; H NMR (CDCl3) δ 2.18 (s, 3H, CH3), 3.22 (t, 2H, J )
6.5 Hz, CH2S), 3.81 (t, 2H, J ) 6.5 Hz, OCH2CH2S), 5.66 (s,
2H, OCH2N), 6.90-7.80 (m, 7H, Ar-H), 8.36 [m, 1H, SPy-H(6)],
8.65 (br s, 1H, NH); MS (CI-iC4H10) m/ z 403 (M + H)+, 112.
Anal. (C18H18N4O3S2) C, H, N.
Syn th esis of E-3-Su bstitu ted Allyl Aceta tes 33. Gen -
er a l P r oced u r e: Following the method of Soai et al.,29 to an
ice-cooled mixture of acrylic acids 30b-g (20 mmol) and
triethylamine (3 mL, 21.5 mmol) in THF (50 mL) was added
dropwise ethyl chloroformate (2 mL, 20.9 mmol). After stirring
for an additional 30 min at the same temperature, the
precipitate was filtered and washed with THF (4 × 10 mL).
To the filtrate containing crude 31b-g cooled at 10 °C were
successively added sodium borohydride in one portion (2.0 g,
52.8 mmol; except for 31e: 0.9 g, 23.8 mmol) and then MeOH
(15 mL), dropwise, over a period of 1 h. After this period, the
reaction was quenched with 6 N aqueous HCl (25 mL) and
the mixture extracted in the usual manner with EtOAc to give
crude allylic alcohols 32. The crude alcohols 32b-f (32g must
be purified before being acetylated) were stirred with acetic
anhydride (2.4 mL, 25.2 mmol) and pyridine (2.6 mL, 32.4
mmol) in dry CH2Cl2 (50 mL) for 16 h at room temperature.
The reaction mixtures were then poured into H2O (100 mL)
and worked up to afford the crude acetates 33.
6-(2-P yr id ylt h io)-1-[[2-(t osyloxy)et h oxy]m et h yl]t h y-
m in e (24). Tosylation of 23 (525 mg, 1.7 mmol), as described
for compound 6, afforded 24 (715 mg, 91%): mp (ether) 130-
1
131 °C; IR (CHCl3) ν 3375, 1715, 1686, 1456 cm-1; H NMR
(CDCl3) δ 2.06 (s, 3H, CH3), 2.44 (s, 3H, Ts-CH3), 3.76 (t, 2H,
J ) 5 Hz, OCH2CH2OTs), 4.02 (t, 2H, J ) 5 Hz, CH2OTs),
5.48 (s, 2H, OCH2N), 7.11 [m, 1H, SPy-H(5)], 7.26 [m, 1H, SPy-
H(3)], 7.32 [d, 2H, J ) 8.5 Hz, Ts-H(m)], 7.62 [dt, 1H, J ) 2,
9 Hz, SPy-H(4)], 7.74 (d, 2H, J ) 8.5 Hz, Ts-H(o)], 8.39 [m,
1H, SPy-H(6)], 8.90 (br s, 1H, NH); MS (CI-iC4H10) m/ z 464
(M + H)+, 292, 236 (B + H)+. Anal. (C20H21N3O6S2) C, H, N.
1-[(2-An ilin o e t h o x y )m e t h y l]-6-(2-p y r id y lt h io )t h y -
m in e (25). A solution of 24 (150 mg, 0.32 mmol) and aniline
(0.5 mL, 5.5 mmol) in 5 mL of pyridine was stirred at room
temperature for 18 h and heated for 1 h at 80 °C. Pyridine
was removed in vacuo, and the residue was extracted with
EtOAc in the usual manner. The residue was flash chromato-
graphed (EtOAc/cyclohexane: 4/2) to give 25 (89 mg, 75%):
mp (ether/pentane) 156-157 °C; IR (KBr) ν 3393, 2958, 1712,
(E)-3-(3-P yr id yl)a llyl a ceta te (33b):31 pale yellow oil
(0.74 g, 21%) after purification by flash chromatography
(cyclohexane/EtOAc: 1/1); mp (EtOAc) 70 °C; IR (CHCl3) ν
1
3036, 2947, 1737, 1664 cm-1; H NMR (CDCl3) δ 2.13 (s, 3H,
COCH3), 4.78 (d, 2H, J ) 6 Hz, CH2), 6.37 (dt, 1H, J ) 6, 16
Hz, CH-CH2), 6.70 (d, 1H, J ) 16 Hz, CH-Py), 7.30 [m, 1H,
Py-H(5)], 7.77 [m, 1H, Py-H(4)], 8.55 [m, 1H, Py-H(6)], 8.68
[m, 1H, Py-H(2)].
1
1687, 1606, 1456 cm-1; H NMR (CDCl3) δ 2.04 (s, 3H, CH3),
3.17 (t, 2H, J ) 5 Hz, CH2NH), 3.77 (t, 2H, J ) 5 Hz,
OCH2CH2N), 4.05 (br s, 1H, NHPh), 5.54 (s, 2H, OCH2N), 6.54
[d, 2H, J ) 7 Hz, Ph-H(o)], 6.68 [t, 1H, J ) 7 Hz, Ph-H(p)],
7.05-7.15 (m, 4H, Ar), 7.58 [dt, J ) 2, 8 Hz, 1H, SPy-H(4)],
8.40 [m, 1H, SPy-H(6)], 9.60 (br s, 1H, NH); MS (CI-NH3) m/ z
385 (M + H)+. Anal. (C19H20N4O3S) C, H, N.
(E)-3-(2-F u r yl)a llyl a ceta te (33c):31 pale yellow oil (3.14
g, 78%) after purification by flash chromatography (cyclohex-
ane/EtOAc: 8/2); IR (CHCl3) ν 2956, 1729, 1661 cm-1; 1H NMR
(CDCl3) δ 2.09 (s, 3H, COCH3), 4.69 (d, 2H, J ) 6 Hz, CH2),
6.21 (dt, 1H, J ) 6, 15.5 Hz, CH-CH2), 6.28 [m, 1H, Fur-H(3)],
6.37 [m, 1H, Fur-H(4)], 6.46 (d, 1H, J ) 15.5 Hz, CH-Fur),
7.36 [m, 1H, Fur-H(5)].
Gen er a l P r oced u r e for th e P r ep a r a tion of Bis-th ioa r yl
Com p ou n d s 26-29. A mixture of alcohol derivative 1 or 23
(1 mmol), tributylphosphine (2.5 mmol), and the appropriate
diaryl disulfide (2.5 mmol) in THF (15-20 mL) was refluxed
for 30 min. The solution was evaporated, and the crude
residue was purified by flash chromatography.
(E)-3-(2-Th ien yl)a llyl a ceta te (33d ):31 pale yellow oil (3.2
g, 88%) after purification by flash chromatography (cyclohex-
ane/EtOAc: 8/2); IR (CHCl3) ν 2947, 1734, 1651 cm-1; 1H NMR
(CDCl3) δ 2.10 (s, 3H, COCH3), 4.69 (d, 2H, J ) 6.5 Hz, CH2),
6.12 (dt, 1H, J ) 6.5, 15.5 Hz, CH-CH2), 6.78 (d, 1H, J ) 15.5
Hz, CH-Thie), 6.98 [m, 2H, Thie-H(3,4)], 7.18 [m, 1H, Thie-
H(5)].
1-[[2-(P h en ylt h io)et h oxy]m et h yl]-6-(p h en ylt h io)t h y-
m in e (26). Compound 26 was isolated (91% yield) from the
reaction of 1 with diphenyl disulfide after flash chromatogra-
phy (EtOAc/cyclohexane: 7/3): mp (ether) 122-124 °C; IR
(CHCl3) ν 3393, 1710, 1684, 1441 cm-1
;
1H NMR (CDCl3) δ
(E)-3-(5-Nitr o-2-th ien yl)a llyl a ceta te (33e): yellow solid
(2.3 g, 51%) after purification by flash chromatography (cy-
clohexane/EtOAc: 7/3); mp (EtOAc) 70 °C; IR (CHCl3) ν 1741,
2.02 (s, 3H, CH3), 2.98 (t, 2H, J ) 6 Hz, CH2SPh), 3.72 (t, 2H,
J ) 6 Hz, OCH2CH2SPh), 5.53 (s, 2H, OCH2N), 7.15-7.30 (m,
10H, 2 × SPh), 8.95 (br s, 1H, NH); MS (CI-NH3) m/ z 418 (M
+ NH4)+, 401 (M + H)+, 167. Anal. (C20H20N2O3S2) C, H, N.
1
1534, 1504, 1434, 1338 cm-1; H NMR (CDCl3) δ 2.13 (s, 3H,
COCH3), 4.73 (d, 2H, J ) 6 Hz, CH2), 6.33 (dt, 1H, J ) 6, 16.5