New Inverted Oxime Ethers of Oxiconazole
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22 4909
aqueous 1 N NaOH (12 mL) obtaining the precipitation of the
desired alcohol 12 as a pure solid; mp 134 °C (6.03 g, 95%).
1H NMR (CDCl3): δ 1.70 (brs, 1H, exchangeable D2O), 3.90
(dd, J ) 14.1, 8.0 Hz, 1 H), 4.25 (dd, J ) 14.1, 3.2 Hz, 1 H),
NMR (CDCl3): δ 4.77 (d, J ) 4.8 Hz, 2H), 5.87 (t, J ) 4.8 Hz,
1H), 7.05-7.63 (m, 9H), 8.55 (s, 1H). EIMS m/z: 427 (1,
M-2(-HCl)), 348 (2), 241 (1). Anal. (C18H14Cl5N3O) C H N.
(E)-1-[1-(2,4-Dich or op h en yl)et h ylid en ea m in oxy)]-1-
(2,4-d ich lor op h en yl)-2-(1H-im id a zol-1-yl)eth a n (7b). The
compound was prepared from 16‚HCl and 2,4-dichloro-
acetophenone by following the general procedure. Compound
7b was purified by flash chromatography on silica using 67%
EtOAc in hexane as the eluent and obtained as an oil (66%).
1H NMR (CDCl3): δ 2.31 (s, 3H), 4.34 (dd, J ) 10.4, 5.6 Hz,
1H), 4.57 (dd, J ) 10.4, 3.2 Hz, 1H), 5.62 (dd, J ) 5.6, 3.2 Hz,
1H), 6.80-7.54 (m, 9H). EIMS m/z: 407 (2, M+-HCl), 241 (1),
203 (6). Anal. (C19H15Cl4N3O) C H N. [The previous fractions
5.28 (dd, J ) 8, 3.2 Hz,1H), 6.8-7.7 (m, 6H). Anal. (C11H10
-
Cl2N2O) C H N. Treatment of 11‚HNO3 in the same conditions
gave 13 as a pure solid; mp 106-107 °C (97%). 1H NMR
(CDCl3): δ 3.92 (dd, J ) 13.6, 7.2 Hz, 1 H), 4.16 (dd, J ) 13.6,
3.2 Hz, 1 H), 5.17 (dd, J ) 7.2, 3.2 Hz, 1H), 6.6-7.7 (m, 6H).
Anal. (C11H10F2N2O) C H N.
1-(2,4-Dich lor oph en yl)-2-(1H-im idazol-1-yl)eth an -1-oxy-
N-p h th a lim id e (14) a n d 1-(2,4-Diflu or op h en yl)-2-(1H-
im id a zol-1-yl)eth a n -1-oxy-N-p h th a lim id e (15). A suspen-
sion of alcohol 12 (0.26 g, 1.0 mmol), triphenylphosphine (0.26
g, 1.0 mmol), and N-hydroxyphthalimide (0.16 g, 1.0 mmol)
in anhydrous benzene (7 mL) was refluxed under Ar, and the
azeotropic mixture (3.5 mL) was collected by means of a Dean-
Stark apparatus. DEAD (0.19 g, 1.08 mmol) was added to the
resulting mixture and cooled at room temperature, and the
reaction was maintained in the same conditions for 24 h.
Evaporation in vacuo of the solvent gave an oil, which was
purified by flash chromatography on silica (75% EtOAc in
hexane) giving 14 as a pure solid; mp 141 °C (0.24 g, 60%). 1H
NMR (CDCl3): δ 4.46 (dd, J ) 4.8, 4.0 Hz, 2 H), 5.98 (t, J )
4.0 Hz, 1 H), 6.97-8.00 (m, 10H). EIMS m/z: 367 (3, M+-Cl),
320 (5), 241 (30), 205 (22) 163 (7). Anal. (C19H13Cl2N3O3) C H
N. Treatment of 13 in the same conditions gave 15 as a pure
1
gave the Z isomer of 7b as an oil (10%). H NMR (CDCl3): δ
1.95 (s, 3H), 4.20 (dd, J ) 10.2, 5.6 Hz, 1H), 4.37 (dd, J )
10.2, 3.2 Hz, 1H), 5.59 (dd, J ) 5.6, 3.2 Hz, 1H), 6.80-7.54
(m, 9H).]
(E)-1-[1-(2,4-Dich or op h en yl)p r op ylid en ea m in oxy)]-1-
(2,4-d ich lor op h en yl)-2-(1H-im id a zol-1-yl)eth a n (7c). The
compound was prepared from 16‚HCl and 2,4-dichloropro-
piophenone 21 by following the general procedure. Compound
7c was purified by flash chromatography on silica using 50%
EtOAc in hexane as the eluent and was obtained as an oil
1
(25%). H NMR (CDCl3): δ 1.05 (t, J ) 7.6 Hz, 3H), 2.83 (q, J
) 7.6, Hz, 2H), 4.29 (dd, J ) 14.8, 5.6 Hz, 1H), 4.56 (dd, J )
14.8, 2.8 Hz, 1H), 5.76 (dd, J ) 5.6, 2.8 Hz, 1H), 6.79-7.27
(m, 9H). EIMS m/z: 457 (1, M+), 256 (1), 241 (2), 217 (1). Anal.
(C20H17Cl4N3O) C H N. [The previous fractions gave the Z
isomer of 7c as an oil (∼ 5%). 1H NMR (CDCl3): δ 1.03 (t, J )
7.5 Hz, 3H), 2.42 (m, 2H), 4.10 (m, 1H), 4.65 (m, 1H), 5.30 (m,
1H).]
1
solid; mp 162-163 °C (34%). H NMR (CDCl3): δ 4.51 (d, J )
4.8 Hz, 2 H), 5.80 (t, J ) 4.8 Hz, 1H), 6.80-7.80 (m, 10H).
EIMS m/z: 369 (M+), 207 (22), 163 (3). Anal. (C19H13F2N3O3)
C H N.
1-(2,4-Dich lor op h en yl)-2-(1H-im id a zol-1-yl)eth a n -1-O-
h yd r oxyla m in e H yd r och lor id e (16)‚H Cl a n d 1-(2,4-Di-
flu or op h en yl)-2-(1H -im id a zol-1-yl)et h a n -1-O-h yd r oxyl-
a m in e Hyd r och lor id e (17)‚HCl. A mixture of the phthal-
imido derivative 14 (0.37 g, 0.92 mmol) and hydrazine hydrate
(0.029 mL, 0.92 mmol) in absolute EtOH (5 mL) was refluxed
for 3 h. After this period, the reaction was cooled at room
temperature obtaining a solid residue, which was eliminated
by filtration. The resulting solution was evaporated at reduced
pressure, yielding an oily residue, which was solubilized in
EtOH (2 mL) and treated with Et2O‚HCl, obtaining the
precipitation of hydroxylamine hydrochloride 16 as a pure
solid; mp 199 °C (0.17 g, 61%). 1H NMR (DMSO-d6): δ 4.74
(d, J ) 4.8 Hz, 2H), 5.87 (t, J ) 4.8 Hz, 1H), 7.20-7.70 (m,
6H), 9.15 (s, 1H). EIMS m/z: 241 (63,M+-NH2OHCl), 205 (28),
174 (29). Anal. (C11H11Cl3N3O) C H N. Treatment of 15 in the
same conditions gave 17‚HCl as a pure solid; mp 162 °C (47%).
1H NMR (DMSO-d6): δ 4.75 (d, J ) 5.6 Hz, 2H), 5.75 (t, J )
5.6 Hz, 1H), 7.10-8.00 (m, 6H), 9.16 (s, 1H). EIMS m/z: 239
(4, M+-HCl), 207 (100), 141 (43). Anal. (C11H11ClF2N3O) C H
N.
(E)-1-[1-(2,4-Dich or op h en yl)b u t ylid en ea m in oxy)]-1-
(2,4-d ich lor op h en yl)-2-(1H-im id a zol-1-yl)eth a n (7d ). The
compound was prepared from 16‚HCl and 2,4-dichlorobuty-
rophenone 22 by following the general procedure. Compound
7d was purified by flash chromatography on silica using 50%
EtOAc in hexane as the eluent and was obtained as an oil
1
(63%). H NMR (CDCl3): δ 0.98 (t, J ) 7.5 Hz, 3H), 1.44 (m,
2H), 2.81 (t, J ) 7.5 Hz, 2H), 4.32 (dd, J ) 14.9, 5.6 Hz, 1H),
5.06 (dd, J ) 14.9, 2.9 Hz, 1H), 5.78 (dd, J ) 5.6, 2.9 Hz, 1H),
6.81-7.44 (m, 9H). EIMS m/z: 471 (1, M+), 257 (2), 241 (2),
217 (5). Anal. (C21H19Cl4N3O) C H N. [The previous fractions
1
gave the Z isomer of 7d as an oil (∼ 5%). H NMR (CDCl3): δ
2.40 (m, 2H), 4.10 (m, 1H), 4.65 (m, 1H), 5.63 (m, 1H)].
(E)-1-(2,4-Diflu or oben zylid en ea m in oxy)-1-(2,4-d iflu o-
r op h en yl)-2-(1H-im id a zol-1-yl)eth a n Hyd r och lor id e (7e)‚
HCl. The compound was prepared from 17‚HCl and 2,4-
difluorobenzaldeyde by following the general procedure.
Compound 7e‚HCl was a white solid (45%); mp 179 °C. 1H
NMR (DMSO-d6): δ 4.82 (m, 2H), 5.86 (t, J ) 4.8 Hz, 1H),
7.02-7.76 (m, 9H), 8.39 (s, 1H). EIMS m/z: 363 (4, M+-HCl),
283 (2), 207 (5). Anal. (C18H14ClF4N3O) C H N.
Gen er a l P r oced u r e for P r ep a r a tion of Im id a zolyl
Oxim e Eth er s 7 a n d 8. A solution of the hydroxylamine
hydrochloride 16 or 17 (0.32 mmol) and the appropriate
aldehyde or ketone (0.32 mmol) in CH3CN (3.5 mL) (for
compounds 7a ,e,g,j) or in MeOH (3.0 mL) (for compounds 7b-
d ,f,h ,i,k -o and 8a ,b) was stirred at room temperature for 5
days. After this period, the solvent was evaporated under a
vacuum giving a semisolid residue. In the case of compounds
7a ,e,g,j, the residue was solubilized in MeOH (1.5 mL) and
supplemented with Et2O‚HCl to pH 3, yielding their pure
hydrochlorides. In the case of 7b-d ,f,h ,i,k -o and 8a ,b
compounds, a solution of the residue in EtOAc (12 mL) was
sequentially alkalinized with aqueous NaHCO3, washed with
brine, dried on Na2SO4, filtered, and evaporated under a
vacuum to give a pure oily residue consisting of 7k ,m -o and
8a ,b compounds. In the case of 7b-d ,f,h ,i,l, their crude oily
residues were purified by flash chromatography.
(E)-1-[1-(2,4-Diflu or op h en yl)et h ylid en ea m in oxy)]-1-
(2,4-d iflu or op h en yl)-2-(1H-im id a zol-1-yl)eth a n (7f). The
compound was prepared from 17‚HCl and 2,4-difluoro-
acetophenone by following the general procedure. Compound
7f was purified by flash chromatography on silica using 50%
EtOAc in hexane as the eluent and was obtained as an oil
(53%). 1H NMR (CDCl3): δ 2.34 (s, 3H), 4.33 (dd, J ) 14.6, 5.9
Hz, 1H), 4.52 (dd, J ) 14.6, 3.6 Hz, 1H), 5.73 (dd, J ) 5.9, 3.6
Hz, 1H), 6.82-7.37 (m, 9H). EIMS m/z: 377 (1, M+), 296 (1),
207 (1), 154 (20). Anal. (C19H15F4N3O) C H N. [The previous
fractions gave the Z isomer of 7f as an oil (8%). 1H NMR
(CDCl3): δ 2.15 (s, 3H), 4.18 (dd, J ) 14.6, 5.6 Hz, 1H), 4.60
(dd, J ) 14.6, 3.2 Hz, 1H), 5.61 (dd, J ) 5.6, 3.2 Hz, 1H), 6.80-
7.54 (m, 9H)].
(E)-1-(2,6-Diflu or oben zylid en ea m in oxy)-1-(2,4-d iflu o-
r op h en yl)-2-(1H-im id a zol-1-yl)eth a n Hyd r och lor id e (7g)‚
HCl. The compound was prepared from 17‚HCl and 2,6-
difluorobenzaldeyde by following the general procedure.
Compound 7g‚HCl was a white solid (45%); mp 156-157 °C.
1H NMR (DMSO-d6): δ 4.80 (m, 2H), 5.86 (t, J ) 6.4 Hz, 1H),
7.04-7.76 (m, 9H), 8.36 (s, 1H). EIMS m/z: 363 (3, M+-HCl),
283 (1), 207 (4). Anal. (C18H14ClF4N3O) C H N.
(E)-1-(2,4-Dich lor oben zylid en ea m in oxy)-1-(2,4-d ich lo-
r op h en yl)-2-(1H-im id a zol-1-yl)eth a n Hyd r och lor id e (7a )‚
HCl. The compound was prepared from 16‚HCl and 2,4-
dichlorobenzaldehyde by following the general procedure.
Compound 7a ‚HCl was a white solid (60%); mp 198 °C. 1H