944 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 4
Polychronopoulos et al.
Da ta for (2′Z,3′E)-6-Ch lor oin d ir u bin -3′-oxim e (7d ). 1H
NMR (acetone, 400 MHz, δ ppm, J in Hz) 13.60 (1H, s, NOH),
11.76 (1H, s, N′-H), 10.10 (1H, s, N-H), 8.71 (1H, d, J ) 8.8
Hz, H-4), 8.37 (1H, d, J ) 7.5 Hz, H-4′), 7.48 (1H, t, J ) 7.5
Hz, H-6′), 7.38 (1H, d, J ) 7.5 Hz, H-7′) 7.12 (1H, t, J ) 7.5
Hz, H-5′), 7.04 (1H, d, J ) 2.2 Hz, H-7) 7.12 (1H, dd, J ) 8.8,
2.2 Hz, H-5); CI-MS m/z 312, 314 (M + H)+. Anal. (C16H10N3O2-
Cl) C, H, N.
Da ta for (2′Z,3′E)-5,6-Dich lor oin d ir u bin -3′-oxim e (7e).
1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.76 (1H, br s,
NOH), 11.88 (1H, s, N′-H), 10.90 (1H, s, N-H), 8.80 (1H, s,
H-4), 8.25 (1H, d, J ) 7.5 Hz, H-4′), 7.44 (1H, d, J ) 7.9 Hz,
H-7′), 7.39 (1H, t, J ) 7.9 Hz, H-6′) 7.06 (1H, t, J ) 7.9 Hz,
H-5′) 7.03 (1H, s, H-7); CI-MS m/z 346, 348, 350 (M + H)+.
Anal. (C16H9N3O2Cl2) C, H, N.
Da ta for (2′Z,3′E)-6-Br om oin d ir u bin -3′-a cetoxim e (8a ).
1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.60 (1H, s, N′-
H), 11.01 (1H, s, N-H), 9.02 (1H, d, J ) 8.5 Hz, H-4), 8.24
(1H, d, J ) 7.8, H-4′), 7.52 (1H, d, J ) 7.8, H-7′), 7.49 (1H, t,
J ) 7.8 Hz, H-6′), 7.10 (1H, t, J ) 7.8 Hz, H-5′), 7.09 (1H, d,
J ) 8.5 Hz, H-5), 7.04 (1H, s, H-7), 2.47 (3H, s, OCOCH3); CI-
MS m/z 397, 399 (M + H)+. Anal. (C18H12N3O3Br) C, H, N.
Da ta for (2′Z,3′E)-6-F lu or oin d ir u bin -3′-a cetoxim e (8b).
1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.50 (1H, s, N′-
H), 11.03 (1H, s, N-H), 9.12 (1H, dd, J ) 8.7, 5.8 Hz, H-4),
8.25 (1H, d, J ) 7.5, H-4′), 7.52 (1H, t, J ) 7.5, H-6′), 7.46
(1H, d, J ) 7.5 Hz, H-7′), 7.08 (1H, t, J ) 7.5 Hz, H-5′), 6.73
(2H, m, H- 5, 7), 2.46 (3H, s, OCOCH3); CI-MS m/z 338 (M +
H)+. Anal. (C18H12N3O3F) C, H, N.
Da ta for (2′Z,3′E)-6-Iod oin d ir u bin -3′-a cetoxim e (8c). 1H
NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.57 (1H, s, N′-H),
10.92 (1H, s, N-H), 8.83 (1H, d, J ) 8.3 Hz, H-4), 8.21 (1H, d,
J ) 7.9, H-4′), 7.50 (1H, d, J ) 7.9, H-7′), 7.45 (1H, t, J ) 7.9
Hz, H-6′), 7.25 (1H, d, J ) 8.3 Hz, H-5), 7.18 (1H, s, H-7), 7.06
(1H, t, J ) 7.9 Hz, H-5′), 2.47 (3H, s, OCOCH3); CI-MS m/z
446 (M + H)+. Anal. (C18H12N3O3I) C, H, N.
Da ta for (2′Z,3′E)-6-Br om o-5-m eth ylin d ir u bin -3′-oxim e
1
(7f). H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.56 (1H,
br s, NOH), 11.74 (1H, s, N′-H), 10.69 (1H, s, N-H), 8.62 (1H,
s, H-4), 8.22 (1H, d, J ) 7.9 Hz, H-4′), 7.39 (2H, m, H-6′, 7′),
7.03 (1H, s, H-7), 7.04 (1H, dd, J ) 8.1, 2.1 Hz, H-5′), 2.37
(3H, s, 5-CH3); CI-MS m/z 370, 372 (M + H)+. Anal. (C17H12N3O2-
Br) C, H, N.
Da ta for (2′Z,3′E)-6-Ch lor oin d ir u bin -3′-a cetoxim e (8d ).
1H NMR (DMSO, 400 MHz, d ppm, J in Hz) 11.59 (1H, s, N′-
H), 11.02 (1H, s, N-H), 9.09 (1H, d, J ) 8.2 Hz, H-4), 8.25
(1H, d, J ) 7.8 Hz, H-4′), 7.50 (2H, m, H-6′, 7′), 7.10 (1H, t, J
) 7.8 Hz, H-5′), 6.96 (1H, dd, J ) 2.3, 8.2 Hz, H-5), 6.91 (1H,
d, J ) 2.3 Hz, H-7), 2.47 (3H, s, OCOCH3); CI-MS m/z 354,
356 (M + H)+. Anal. (C18H12N3O3Cl) C, H, N.
Da ta for (2′Z,3′E)-6-Br om o-5-n itr oin d ir u bin -3′-oxim e
1
(7g). H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.90 (1H,
br s, NOH), 11.91 (1H, s, N′-H), 11.33 (1H, s, N-H), 9.20 (1H,
s, H-4), 8.24 (1H, d, J ) 7.5 Hz, H-4′), 7.50 (1H, d, J ) 7.5 Hz,
H-7′), 7.43 (1H, t, J ) 7.5 Hz, H-6′) 7.23 (1H, s, H-7), 7.10
(1H, t, J ) 7.5 Hz, H-5′); CI-MS m/z 401, 403 (M + H)+. Anal.
(C16H9N4O4Br) C, H, N.
Da ta for (2′Z,3′E)-5,6-Dich lor oin d ir u bin -3′-a cetoxim e
1
Da ta for (2′Z,3′E)-6-Vin ylin d ir u bin -3′-oxim e (7i). 1H
NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.57 (1H, br s,
NOH), 11.72 (1H, s, N′-H), 10.76 (1H, s, N-H), 8.60 (1H, d, J
) 8.3 Hz, H-4), 8.23 (1H, d, J ) 7.3 Hz, H-4′), 7.41 (2H, m,
H-6′, 7′), 7.03 (3H, m, H-5, 5′, 7), 6.74 (1H, dd, J ) 17.6, 10.8
Hz, H-1′′) 5.77 (1H, d, J ) 17.6 Hz, H-2b′′) 5.22 (1H, d, J )
10.8 Hz, H-2a′′); CI-MS m/z 304 (M + H)+. Anal. (C18H13N3O2)
C, H, N.
(8e). H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.65 (1H,
s, N′-H), 11.08 (1H, s, N-H), 9.33 (1H, s, H-4), 8.24 (1H, d, J
) 7.4 Hz, H-4′), 7.52 (2H, m, H-6′, 7′), 7.12 (1H, t, J ) 7.4 Hz,
H-5′) 7.04 (1H, s, H-7) 2.48 (3H, s, OCOCH3); CI-MS m/z 388,
390, 392 (M + H)+. Anal. (C18H11N3O3Cl2) C, H, N.
Da ta for (2′Z,3′E)-6-Br om o-5-m eth ylin d ir u bin -3′-a cet-
oxim e (8f). 1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.56
(1H, s, N′-H), 10.87 (1H, s, N-H), 9.16 (1H, s, H-4), 8.26 (1H,
d, J ) 7.8 Hz, H-4′), 7.50 (2H, m, H-6′, 7′), 7.10 (1H, t, J ) 7.8
Hz, H-5′), 7.05 (1H, s, H-7), 2.48 (3H, s, OCOCH3), 2.39 (3H,
s, 5-CH3); CI-MS m/z 412, 414 (M + H)+. Anal. (C19H14N3O3-
Br) C, H, N.
Da t a for (2′Z,3′E)-6-Br om o-5-n it r oin d ir u b in -3′-a cet -
oxim e (8g). 1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.73
(1H, s, N′-H), 11.41 (1H, s, N-H), 9.56 (1H, s, H-4), 8.22 (1H,
d, J ) 7.8 Hz, H-4′), 7.53 (2H, m, H-6′, 7′), 7.21 (1H, s, H-7),
7.13 (1H, t, J ) 7.8 Hz, H-5′) 2.46 (3H, s, OCOCH3); CI-MS
m/z 443, 445 (M + H)+. Anal. (C18H11N4O5Br) C, H, N.
Da ta for (2′Z,3′E)-In d ir u bin -3′-a cetoxim e (8h ). 1H NMR
(DMSO, 400 MHz, δ ppm, J in Hz) 11.59 (1H, s, N′-H), 10.87
(1H, s, N-H), 9.08 (1H, d, J ) 7.8 Hz, H-4), 8.26 (1H, d, J )
7.8 Hz, H-4′), 7.52 (1H, t, J ) 7.8 Hz, H-6′), 7.46 (1H, t, J )
7.8 Hz, H-7′) 7.20 (1H, t, J ) 7.8 Hz, H-6), 7.08 (1H, t, J ) 7.8
Hz, H-5), 6.97 (1H, t, J ) 7.8 Hz, H-5′), 6.90 (1H, d, J ) 7.8
Hz, H-7), 2.47 (3H, s, OCOCH3); CI-MS m/z 320 (M + H)+.
Anal. (C18H13N3O3) C, H, N.
Da ta for (2′Z,3′E)-6-Vin ylin d ir u bin -3′-a cetoxim e (8i).
1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.57 (1H, s, N′-
H), 10.90 (1H, s, N-H), 9.05 (1H, d, J ) 8.2 Hz, H-4), 8.25
(1H, d, J ) 7.4 Hz, H-4′), 7.49 (2H, m, H-6′, 7′), 7.08 (2H, m,
H-5, 5′) 6.99 (1H, s, H-7), 6.76 (1H, dd, J ) 17.6, 11.3 Hz, H-1′′),
5.81 (1H, d, J ) 17.6 Hz, H-2b′′), 5.25 (1H, d, J ) 10.9 Hz,
H-2a′′), 2.47 (3H, s, OCOCH3); CI-MS m/z 346 (M + H)+. Anal.
(C20H15N3O3) C, H, N.
Da ta for (2′Z,3′E)-6-Br om o-1-m eth ylin d ir u bin -3′-a cet-
oxim e (14). 1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.63
(1H, s, N′-H), 9.06 (1H, d, J ) 8.3 Hz, H-4), 8.25 (1H, d, J )
7.4 Hz, H-4′), 7.51 (2H, m, H-6′, 7′), 7.34 (1H, d, J ) 1.7 Hz,
H-7), 7.16 (1H, dd, J ) 1.7, 8.3 Hz, H-5), 7.11 (1H, t, J ) 7.4
Hz, H-5′), 3.31 (3H, s, N-CH3), 2.48 (3H, s, OCOCH3); CI-MS
m/z 412, 414 (M + H)+. Anal. (C19H14N3O3Br) C, H, N.
(2′Z,3′E)-6-Br om oin d ir u bin -3′-m eth oxim e (9a ). To a
solution of 6-bromoindirubin (5a ) (26 mg, 0.076 mmol) in
pyridine (2 mL) was added methoxylamine hydrochloride (30
mg), and the mixture was heated under reflux (120 °C) for 12
Da ta for (2′Z,3′E)-6′-Br om o-in d ir u bin -3′-oxim e (12a ).
1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.75 (1H, br s,
NOH), 11.70 (1H, s, N′-H), 10.72 (1H, s, N-H), 8.61 (1H, d, J
) 7.9 Hz, H-4), 8.12 (1H, d, J ) 8.3 Hz, H-4′), 7.63 (1H, d, J
) 1.2 Hz, H-7′), 7.19 (1H, dd, J ) 1.2, 8.3 Hz, H-5′), 7.14 (1H,
d, J ) 7.9 Hz, H-6), 6.95 (1H, t, J ) 7.9 Hz, H-5), 6.91 (1H, d,
J
) 7.9 Hz, H-7); CI-MS m/z 356, 358 (M + H)+. Anal.
(C16H10N3O2Br) C, H, N.
Data for (2′Z,3′E)-6,6′-Dibr om o-in dir u bin -3′-oxim e (12b).
1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.84 (1H, br s,
NOH), 11.70 (1H, s, N′-H), 10.85 (1H, s, N-H), 8.51 (1H, d, J
) 8.7 Hz, H-4), 8.10 (1H, d, J ) 8.3 Hz, H-4′), 7.63 (1H, s,
H-7′), 7.20 (1H, d, J ) 8.3 Hz, H-5′), 7.08 (1H, d, J ) 8.7 Hz,
H-5), 7.06 (1H, s, H-7); CI-MS m/z 434, 436,438 (M + H)+. Anal.
(C16H9N3O2Br2) C, H, N.
Da ta for (2′Z,3′E)-6-Br om o-1-m eth ylin d ir u bin -3′-oxim e
1
(12c). H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.69 (1H,
br s, NOH), 11.78 (1H, s, N′-H), 8.61 (1H, d, J ) 8.1 Hz, H-4),
8.23 (1H, d, J ) 7.3 Hz, H-4′), 7.44 (2H, m, H-6′, 7′), 7.31 (1H,
s, H-7), 7.17 (1H, d, J ) 8.1 Hz, H-5), 7.07 (1H, br s, H-5′),
3.32 (3H, s, N-CH3); CI-MS m/z 370, 372 (M + H)+. Anal.
(C17H12N3O2Br) C, H, N.
Da ta for (2′Z,3′E)-1-Meth ylin d ir u bin -3′-oxim e (12d ). 1H
NMR (DMSO, 400 MHz, δ ppm, J in Hz) 13.56 (1H, br s,
NOH), 11.74 (1H, s, N′-H), 8.69 (1H, d, J ) 7.8 Hz, H-4), 8.23
(1H, d, J ) 7.5 Hz, H-4′), 7.41 (2H, m, H-6′, 7′), 7.23 (1H, t, J
) 7.8, Hz, H-6), 7.04 (3H, m, H-5′, 5, 7), 3.31 (3H, s, N-CH3);
CI-MS m/z 292 (M + H)+. Anal. (C17H13N3O2) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Acet-
oxim es 8a -i a n d 14. The appropriate indirubin-3′-oxime
derivative 7a -i and 13c (0.2 mmol) was dissolved in pyridine
(10 mL). Ac2O was added (0.5 mL), and the mixture was stirred
for 30 min at 0 °C. Then water (1 mL) was added, and the
solvents were evaporated under reduced pressure. The residue
was washed with water and cyclohexane to afford quantita-
tively the corresponding 3′-acetoxime selectively in a (2′Z,3′E)
form.