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S.-J. Oh et al. / Bioorg. Med. Chem. 12 (2004) 5505–5513
143.2, 149.2, 155.0, 157.0; MS (FAB) m/z 311 (M+H)+.
HRMS calcd for C18H20FN4 311.1672, found 311.1671.
(543.6mg, 4.38mmol) in MeOH (5mL) was adjusted
to pH5 with acetic acid. NaBH3CN (741.5mg,
11.8mmol) was then added and the reaction mixture
was heated at 80ꢁC for 12h. Product isolation (ethyl
acetate) followed by flash column chromatography
4.1.5. 3-[4-(4-Fluorophenyl)piperazin-1-yl]-1H-pyrrolo-
[2,3-b]pyridine (2). To 8 (300mg, 2.05mmol) in methanol
(5mL) was added 1-(4-fluorophenyl)piperazine (370mg,
2.05mmol). The reaction mixture was adjusted with
acetic acid to pH5 and then reacted with NaBH3CN
(348mg, 5.54mmol) at 80ꢁC for 12h. Product isolation
(ethyl acetate) followed by flash column chromatogra-
phy (50:50 ethyl acetate–methanol) afforded 2 (541mg,
(3:1 hexane–ethyl acetate) gave a yellowoil
4-1
(728mg, 56.5%): 1H NMR (200MHz, CDCl3) d 1.43
(s, 9H), 2.34 (t, 4H, J = 5.2Hz), 3.40 (t, 4H,
J = 5.2Hz), 3.44 (s, 2H), 6.97 (t, 2H, J = 8.8Hz), 7.23
(t, 2H, J = 5.6Hz); 13C NMR (50MHz, CDCl3) d
28.24, 52.35, 52.68, 62.09, 79.50, 115.24, 114.81,
128.70, 130.49, 133.56, 159.68; MS (EI) m/z 294 (M+).
HRMS calcd for C16H23FN2O2 294.1744, found
294.1745.
1
85%) as a pale yellowsolid: mp 199–200 ꢁC; H NMR
(300MHz, CDCl3) d 2.67–2.69 (m, 4H), 3.11–3.13 (m,
4H), 3.77 (s, 2H), 6.86–6.88 (m, 2H), 6.91–6.97 (m,
2H), 7.09 (dd, 1H, J = 6.0, 3.6Hz), 7.30 (s, 1H), 8.10
(dd, 1H, J = 6.4, 1.2Hz), 8.24 (dd, 1H, J = 4.0, 1.2Hz);
13C NMR (75MHz, CDCl3) d 50.4, 53.1, 53.6, 110.4,
115,6, 115.8, 118.2, 121.0, 125.0, 128.6, 142.7, 148.1,
148.4, 156.5, 158.4; MS (FAB) m/z 311 (M+H)+. HRMS
calcd for C18H20FN4 311.1672, found 311.1678.
4.1.9. 1-(4-Fluorobenzyl)piperazine (4-2). Trifluoroacetic
acid (1mL) was slowly added to 4-1 (550mg, 2.47mmol)
in CH2Cl2 (3mL) and stirred at rt for 4h. The reaction
mixture was then neutralized with 1N NaOH and ex-
tracted with CH2Cl2. Flash column chromatography
(1:1 ethyl acetate–methanol) yielded a colorless oil
4-2 (167mg, 34.8%): 1H NMR (200MHz, CDCl3 +
CD3OD) d 2.29–2.52 (m, 4H), 2.78–2.89 (m, 4H), 3.39
(s, 2H), 6.93 (t, 2H, J = 8.8Hz), 7.23 (t, 2H,
J = 5.6Hz); 13C NMR (50MHz, CDCl3 + CD3OD) d
45.5, 53.7, 62.5, 114.6, 115.0, 130.4, 130.6, 133.6,
164.3; MS (EI) m/z 194 (M+). HRMS calcd for
C11H15FN2 194.1219, found 194.1212.
4.1.6. 2-Fluoromethyl-6-[4-(1H-pyrrolo[2,3-b]pyridin-3-
yl-methyl)piperazin-1yl]pyridine N-oxide (3). Compound
10 (138mg, 0.64mmol) and Et3N (134lL, 0.96mmol)
were added to 6-chloro-a-fluoro-2-picoline N-oxide
(103mg, 0.64mmol)26 in 0.5mL of DMF and 0.5mL
of isopropyl alcohol in a 5mL Reacti-vialꢂ. The reaction
mixture was then heated at 180ꢁC for 2h. Product isola-
tion (dichloromethane) followed by flash column chro-
matography (98:2 ethyl acetate–methanol) afforded 3
4.1.10.
3-[4-(4-Fluoro-2-hydroxybenzyl)piperazin-1-yl-
(30mg, 14%) as a pale yellowsolid:
1H NMR
methyl]-1H-pyrrolo[2,3-b]pyridine (5). Methanesulfonate
ester 5-3 (0.6g, 2.7mmol) in CH3CN (2mL) was added
slowly to a solution of 10 (0.3g, 1.36mmol) and Et3N
(0.38mL, 2.7mmol) in CH3CN (20mL) in an ice bath,
and the reaction mixture was refluxed for 1h. Product
isolation (ethyl acetate) and purification by flash column
chromatography (10:1 dichloromethane–methanol)
afforded a colorless oil (0.33g, 64%). To this compound
(0.2g, 0.52mmol) in ethyl acetate (10mL) was added 6N
HCl (0.87mL, 5.2mmol). After stirring at rt for 30min,
the reaction mixture was concentrated in vacuo,
quenched by adding excess NaHCO3 (5mL, sat.). Prod-
uct isolation (ethyl acetate) followed by flash column
chromatography (12:1 dichloromethane–methanol) gave
a white solid 5 (0.12g, 65%): 1H NMR (400MHz,
CD3OD) d 2.3–2.7 (m, 8H), 3.66 (s, 2H), 3.71 (s, 2H),
6.67–6.75 (m, 2H), 6.85 (dt, 1H, J = 8.6, 3.2Hz), 7.09
(dd, 1H, J = 7.8, 4.0Hz), 7.24 (s, 1 H), 8.06 (dd, 1H
J = 7.8, 1.5Hz), 8.31 (dd, 1H, J = 4.9, 1.5Hz); 13C
NMR (100MHz, CD3OD) d 54.2, 54.4, 54.6, 63.7,
111.4, 116.6, 116.8, 117.4, 123.2, 127.8, 130.2, 133.2,
133.3, 135.2, 144.1, 149.9, 150.1, 166.0; MS (FAB) m/z
341 (M+H)+. HRMS calcd for C19H22FN4O 341.1778,
found 341.1778.
(200MHz, CDCl3) d 2.58 (t, 4H, J = 5.0Hz), 3.54 (t,
4H, J = 5.0Hz), 3.75 (s, 2H), 5.28 (d, 2H, J = 47.4Hz),
6.54 (d, 1H, J = 8.4Hz), 6.73 (d, 1H, J = 7.4Hz), 7.09
(dd, 1H, J = 8.0, 7.8Hz), 7.30 (s, 1H), 7.48 (t, 1H,
J = 7.9Hz), 8.12 (dd, 1H, J = 7.8, 1.5Hz), 8.32 (dd,
1H, J = 4.6, 1.5Hz), 10.79 (br s, 1H); 13C NMR
(50MHz, CDCl3) d 43.50, 51.13, 52.29, 83.14 (d,
J = 168.0Hz), 104.43, 107.77, 107.89, 109.40, 113.93,
118.92, 122.46, 126.63, 136.39, 141.04, 147.37, 152.75,
153.18; MS (FAB) m/z 341 (M+H)+.
4.1.7.
3-[4-(4-Fluorobenzyl)piperazin-1-yl-methyl]-1H-
pyrrolo[2,3-b]pyridine (4). To 8 (125mg, 0.86mmol) in
methanol (2mL) was added 4-2 (167mg, 0.86mmol).
The reaction mixture was adjusted with acetic acid to
pH5 and then reacted with NaBH3CN (145mg,
2.32mmol) at 80ꢁC for 12h. Product isolation (ethyl
acetate) followed by flash column chromatography
(50:50 ethyl acetate–methanol) afforded 4 (120mg,
1
43%) as a pale yellowsolid: H NMR (300MHz, CDCl3)
d 2.41–2.49 (m, 4H), 2.49–2.58 (m, 4H), 3.45 (s, 2H), 3.71
(s, 2H), 6.95–6.98 (m, 2H), 7.07 (dd, 1H, J = 6.0, 3.6Hz),
7.21–7.25 (m, 2H), 7.26 (s, 1H), 8.06 (dd, 1H, J = 6.4,
1.2Hz), 8.31 (dd, 1H, J = 3.6, 1.2Hz), 11.34 (s, 1H);
13C NMR (75MHz, CDCl3) d 53.2, 53.9, 62.4, 111.2,
115.2, 115.3, 115.8, 120.9, 124.5, 128.4, 130.9, 134.1,
142.9, 149.3, 161.2, 163.2; MS (FAB) m/z 325 (M+H)+.
HRMS calcd for C19H22FN4 325.1828, found 325.1823.
4.1.11. Methyl 4-fluoro-2-(methoxymethoxy)benzoate (5-
1). A slurry of NaH (0.65g, 25.6mmol) in DMF (5mL)
was added dropwise to 4-fluorosalicylic acid (1g,
6.4mmol) in DMF (5mL) in an ice bath. The reaction
mixture was cooled to 0ꢁC and methoxymethyl chloride
(1.95mL, 25.62mmol) was slowly added. After stirring
at rt for 14h, the mixture was filtered, and the filtrate
was poured into NH4Cl (sat.). Product isolation (ethyl
4.1.8. 4-(4-Fluorobenzyl)piperazine 1-tert-butoxycarbonyl
ester (4-1). A solution of 1-tert-butoxycarbonylpipera-
zine (820mg, 4.38mmol) and 4-fluorobenzaldehyde