8140
M. Adamczyk et al. / Tetrahedron 59 (2003) 8129–8142
Compound 5h (17%) was isolated as an orange red fluffy
powder. Analytical RP-HPLC (30:70 acetonitrile/water,
2.0 mL/min, UV225 nm) 9.95 min, 96%; 1H NMR (CD3OD)
d 7.89–7.85 (m, 2H), 7.75 (s, 1H), 7.65–7.60 (m, 2H),
7.38–7.34 (m, 2H), 7.16–7.12 (m, 2H), 6.91–6.86 (m, 2H),
6.69–6.65 (m, 2H), 4.04 (s, 2H), 2.41 (s, 3H); ESI-MS m/z
424 (MþH)þ, 446 (MþNa)þ, 847 (2MþH)þ, 869 (2Mþ
Na)þ; HRMS (FAB) m/z calcd for C26H21N3O3, 423.1583
(M)þ, observed 423.1588.
acid (5l). The title compound was obtained from 2-amino-
pyrazine 3k and a-ketoacetal 4a after preparative RP-HPLC
(35:65). Compound 5l (41%) was isolated as a yellow fluffy
powder. Analytical HPLC (Waters Novapak C18, 25:75
acetonitrile/water, 2.0 mL/min, UV254 nm) 7.27 min, .99%;
1H NMR (CD3OD) d 7.68 (s, 1H), 7.58 (d, 2H, J¼7.6 Hz),
7.37 (d, 2H, J¼6.6 Hz), 7.27–7.20 (m, 5H), 7.15 (d, 2H,
J¼8.8 Hz), 7.01 (d, 2H, J¼8.8 Hz), 6.67 (d, 2H, J¼8.5 Hz),
4.39 (s, 2H), 4.05 - 4.02 (m, 4H), 2.39 (t, 2H, J¼7.2 Hz),
2.08–2.03 (m, 2H); ESI-MS m/z 510 (MþH)þ; HRMS
(FAB) m/z calcd for C30H27N3O5, 519.1951 (M)þ, observed
519.1955.
4.6.9. 2-(4-Hydroxybenzyl)-6-(4-hydroxyphenyl)-8-phenyl-
imidazo[1,2-a]pyrazin-3(7H)-one (5i). The title compound
was obtained from 2-aminopyrazine 3i and a-ketoacetal 4a
after preparative RP-HPLC (25:75). Compound 5i (43%)
was isolated as an orange red fluffy powder. Analytical
4.6.13. 4-[2-(4-Hydroxybenzyl)-6-(4-hydroxyphenyl)-3-
oxo-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl]butanoic
acid (5m). The title compound was obtained from 2-amino-
pyrazine 3m and a-ketoacetal 4a after preparative
RP-HPLC (25:75). Compound 5m (41%) was isolated as a
yellow fluffy powder. Analytical RP-HPLC (Waters Nova-
Pak C18, 20:70 acetonitrile/0.1% aq. trifluoroacetic acid,
1.0 mL/min, UV215 nm) 4.78 min, 97%; 1H NMR (CD3OD)
d 7.89 (s, 1H), 7.62 (d, 2H, J¼8.7 Hz), 7.10 (d, 2H, J¼
8.4 Hz), 6.90 (d, 2H, J¼8.4 Hz), 6.68 (d, 2H, J¼8.7 Hz),
4.08 (s, 2H), 3.14 (t, 2H, J¼7.5 Hz), 2.38 (t, 2H, J¼7.5 Hz),
1.90–1.84 (m, 2H), 1.80–1.68 (m, 2H); ESI-MS m/z 434
(MþH)þ; HRMS (FAB) m/z calcd for C24H23N3O5,
433.1638 (M)þ, observed 433.1646.
RP-HPLC (25:75 acetonitrile/water, 2.0 mL/min, UV 225 nm
)
1
12.74 min, 99%; H NMR (CD3OD) d 8.02–7.98 (m, 2H),
7.83 (s, 1H), 7.69–7.65 (m, 2H), 7.61–7.56 (m, 3H), 7.16–
7.12 (m, 2H), 6.92–6.87 (m, 2H), 6.70–6.66 (m, 2H), 4.05
(s, 2H); ESI-MS m/z 410 (MþH)þ, 432 (MþNa)þ819,
(2MþH)þ841, (2MþNa)þ; HRMS (FAB) m/z calcd for
C25H19N3O3 409.1426 (M)þ, observed 409.1413.
4.6.10. 2-(4-Hydroxybenzyl)-6-(4-hydroxyphenyl)-8-
(phenylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one, coel-
enterazine (5j). The title compound was obtained from
2-aminopyrazine 3j and a-ketoacetal 4a after preparative
RP-HPLC (30:70). Compound 5j (63%) was isolated as an
orange red fluffy powder. TLC Rf 0.4 (10% methanol in
dichloromethane); mp 176–1818C (dec), lit.21 175–1788C
(dec); analytical RP-HPLC (Waters NovaPak C18, 25:75
4.6.14. 4-(4-{[2-(4-Hydroxybenzyl)-6-(4-hydroxyphenyl)-
3-oxo-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl]methyl}-
phenoxy)butanoic acid (5n). The title compound was
obtained from 2-aminopyrazine 3m and a-ketoacetal 4a
after preparative RP-HPLC (27:73 acetonitrile/0.1% aq.
trifluorocaetic acid/, 40 mL/min, UV215 nm). Compound 5n
(32%) was isolated as a yellow fluffy powder. Analytical
RP-HPLC (Waters Novapak C18, 30:70 acetonitrile/0.1%
aq. trifluoroacetic acid, 1.0 mL/min, UV 215 nm) 3.37 min,
93%; 1H NMR (CD3OD) d 7.94 (s, 1H), 7.60 (d, 2H,
J¼8.7 Hz), 7.32–7.28 (m, 2H), 7.15–7.10 (m, 2H), 6.92–
6.82 (m, 4H), 6.74–6.69 (m, 2H), 4.39 (s, 2H), 4.12 (s, 2H),
3.97 (t, 2H, J¼6.3 Hz), 2.46 (t, 2H, J¼7.2 Hz), 2.0 21.98
(m, 2H); ESI-MS m/z 526 (MþH)þ; HRMS (FAB) m/z
calcd for C30H27N3O6, 525.1900, observed 525.1905.
acetonitrile/water, 2.0 mL/min, UV
.99%; IR (KBr): 3191, 3063, 3029, 1611, 1564, 1513,
) 7.55 min,
254 nm
1
1453, 1242, 1172, 838, 698 cm21; H NMR (CD3OD) d
7.58 (br s, 1H), 7.47 (d, 2H, J¼8.2 Hz), 7.38 (d, 2H, J¼
6.9 Hz), 7.28 (d, 2H, J¼7.7 Hz), 7.24 (m, 1H), 7.15 (d, 2H,
J¼8.7 Hz), 6.87 (d, 2H, J¼8.8 Hz), 6.69 (d, 2H, J¼8.5 Hz),
4.39 (s, 2H), 4.06 (s, 2H); 1H NMR (dimethylformamide-d7)
d 8.01 (s, 2H), 7.69 (br s, 2H), 7.53 (d, 2H, J¼7.1 Hz), 7.29
(t, 2H, J¼7.3 Hz), 7.22 (d, 2H, J¼8.5 Hz), 6.94 (d, 2H,
J¼8.5 Hz), 6.76 (d, 2H, J¼8.5 Hz), 4.40 (s, 2H), 4.03 (s,
2H); ESI-MS m/z 424 (MþH)þ; HRMS (FAB) m/z calcd for
C26H21N3O3 423.1583, observed: 423.1598; analysis calcd
for C26H21N3O3H2O: C, 70.74, H, 5.25, N, 9.52, found: C,
71.15, H, 5.26, N, 9.67.
4.6.15. Ethyl 4-[4-(5-amino-6-benzyl-2-pyrazinyl)phen-
oxy]butanoate (3m). NaH (95%, 0.104 g, 4.33 mmol,
150 mol%) was added to a solution of 4-(5-amino-6-
benzyl-2-pyrazinyl)phenol (3j, 0.800 g, 2.89 mmol) in
anhydrous DMF (20 mL) at 0–58C (ice bath) under
nitrogen. After stirring for 30 min, ethyl 4-bromobutylate
(1.033 mL, 7.22 mmol, 250 mol%) was added at 0–58C via
syringe. After stirring an additional 5 min, the cooling bath
was removed and the mixture was allowed warm to room
temperature. The mixture was stirred for an additional for
3 h then quenched with saturated aqueous sodium chloride
(30 mL). The mixture was extracted with dichloromethane
(3£50 mL); the combined organic layers were dried over
anhydrous sodium sulfate and concentrated on a rotary
evaporator. The residue was purified by silica gel column
chromatograph (50% ethyl acetate in hexanes) to afford
4.6.11. 4-(4-{[8-Benzyl-6-(4-hydroxyphenyl)-3-oxo-3,7-
dihydroimidazo[1,2-a]pyrazin-2-yl]methyl}phenoxy)-
butanoic acid (5k). The title compound was obtained from
2-aminopyrazine 3k and a-ketoacetal 4b after preparative
RP-HPLC (35:65). Compound 5k (56%) was isolated as a
yellow fluffy powder. Analytical RP-HPLC (Waters Nova-
pak C18, 25:75 acetonitrile/water, 2.0 mL/min, UV
)
254 nm
11.0 min, .99%; 1H NMR (CD3OD) d 7.53 (br s, 1H), 7.46
(br s, 2H), 7.38 (d, 2H, J¼6.6 Hz), 7.28 - 7.21 (m, 5H), 6.88
(d, 2H, J¼8.8 Hz), 6.83 (d, 2H, J¼8.8 Hz), 4.39 (s, 2H),
4.09 (s, 2H), 3.96 (t, 2H, J¼8.1 Hz), 2.45 (t, 2H, J¼7.2 Hz),
2.04–2.01 (m, 2H); ESI-MS m/z 510 (MþH)þ; HRMS
(FAB) m/z calcd for C30H27N3O5, 509.1951 (M)þ, observed
509.1974.
1
compound 3m (1.028 g, 91%). H NMR (CDCl3) d 8.31 (s,
1H), 7.86 (d, 2H, J¼4.7 Hz), 7.30–7.23 (m, 5H), 6.96 (d, 2H,
4.6.12. 4-{4-[8-Benzyl-2-(4-hydroxybenzyl)-3-oxo-3,7-
dihydroimidazo[1,2-a]pyrazin-6-yl]phenoxy}butanoic
J¼4.7 Hz), 4.34 (s, 2H), 4.18–4.14 (m, 4H), 4.04 (t, 2H,