Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4549
6-Br om o-3-a m in o-1,2-ben zisoxa zole (4e). HPLC tR ) 22.6
Exp er im en ta l Section
1
min. H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.74 (d, J )
8.4 Hz, 1H), 7.41 (d, J ) 8.4 Hz, 1H), 6.44 (bs, 2H). MS (ESI)
m/z 213 [79Br, (M + H)+], 215 [81Br, (M + H)+]. Anal. Calcd for
C7H5BrN2O: C, 39.47; H, 2.37; N, 13.15; Br, 37.51. Found: C,
39.30; H, 2.26; N, 13.09; Br, 37.58.
6-Cya n o-3-a m in o-1,2-ben zisoxa zole (4f). HPLC tR (eluent
gradient 5% A to 40% A over 40 min) 17.2 min. 1H NMR (400
MHz, DMSO-d6) δ 8.09 (s, 1H), 7.99 (d, J ) 8.0 Hz, 1H), 7.66 (d,
J ) 8.0 Hz, 1H), 6.67 (bs, 2H). MS (ESI) m/z 160 (M + H)+. Anal.
Calcd for C8H8N2O2: C, 60.38; H, 3.17; N, 26.40. Found: C,
60.17; H, 3.46; N, 24.82.
Gen er a l. Except for compound 2c and 2f, all reagents used
were obtained from commercial sources. Reagents were used
without further purification. Kaiser oxime resin 1 was purchased
from Novabiochem with a loading capacity of 1.07 mmol/g. All
NMR spectra (400 MHz) were recorded on a Varian Gemini-
400 spectrometer. Mass spectra were obtained with either ESI
or FAB as the ionization method. All purifications were carried
out by radial chromatography (Chromatotron model 8924,
Harrison Research) using 1 mm silica gel plates (Analtech).
Crude purities were estimated from integrated peak areas of
HPLC chromatographs with the UV detector monitoring at λ )
215 nm. Analytical HPLC setup: C18 Vydac column with solvent
gradient A ) acetonitrile (0.1% TFA) and B ) water (0.1% TFA)
at 1 mL/min flow rate. Unless otherwise noted, all HPLC tR are
given for an eluent gradient of 10% A to 60% A over 40 min.
The nomenclature for compounds 4a -h and 9a -d is based on
the numbering system given in ref 4a and reproduced here:
5-Nitr o-3-a m in o-1,2-ben zisoxa zole (4g). HPLC tR ) 15.9
1
min. H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J ) 2.8 Hz, 1H),
8.36 (dd, J ) 9.2, 2.8 Hz, 1H), 7.65 (d, J ) 9.2 Hz, 1H), 6.82 (bs,
2H). MS (ESI) m/z 180 (M + H)+. Anal. Calcd for C7H5N3O3: C,
46.94; H, 2.81; N, 23.46. Found: C, 46.85; H, 2.80; N, 23.26.
4-Tr iflu or om eth yl-3-a m in o-1,2-ben zisoxa zole (4h ). HPLC
1
tR ) 21.5 min. H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J ) 8.4
Hz, 1H), 7.71 (t, J ) 8.4 Hz, 1H), 7.64 (d, J ) 7.2 Hz, 1H), 5.81
(bs, 2H). MS (ESI) m/z 203 (M + H)+. Anal. Calcd for
C8H5F3N2O: C, 47.54; H, 2.49; N, 13.86; F, 28.20. Found: C,
47.32; H, 2.62; N, 13.92; F, 27.96.
Gen er a l Syn th esis of 3-Am in oben zisoxa zoles 9a-d . F or -
m a tion of 6-(Acetyla m in om eth yl)-3-a m in o-1,2-ben zisox-
a zole (9a ). To p-nitrobenzophenone oxime polystyrene (Kaiser)
resin (500 mg, 1.07 mmol/g, 0.54 mmol) in a tared 25 mL Kontes
microfilter funnel was added THF (7 mL) and potassium tert-
butoxide (640 µL, 1 M in THF, 0.642 mmol). After being shaken
by hand for several minutes, the resin turned a deep purple color.
To this suspension was added 4-(tert-butoxycarbonylamino-
methyl)-2-fluorobenzonitrile (1.07 mmol, 268 mg). The reaction
vessel was rotated at 55 °C in a Robbins oven for 12 h and
allowed to cool for 1 h. The resin was then rinsed with 2 × 5
mL of CH2Cl2, 2 × 5 mL of 5% TFA/CH2Cl2, 2 × 5 mL of
2-propanol, and 4 × 5 mL of MeOH. The resin was dried in a 35
°C vacuum oven for 12 h to give a ∆wt of 65.0 mg (53% loading
yield). To effect BOC-deprotection, the resin was then suspended
in 25% TFA/CH2Cl2 (7 mL) and rotated for 2 h. The resin was
again rinsed with 2 × 5 mL of CH2Cl2, 2 × 5 mL of 2-propanol,
and 4 × 5 mL of MeOH. The resin was then suspended in DMF
(7 mL), followed by addition of acetic anhydride (505 µL, 6.42
mmol) and N,N-diisopropylethylamine (930 µL, 6.42 mmol).
After the reaction vessel rotated for another 12 h, the resin was
rinsed with 2 × 5 mL of CH2Cl2, 2 × 5 mL of 2-propanol, and 4
× 5 mL of MeOH. TFA (4 mL) and 5 N HClaq (1 mL) were then
added to the resin, and the vessel was rotated for 2 h in a 55 °C
oven. The TFA/HClaq was collected, and the resin was rinsed
with 2 × 5 mL of CH2Cl2. These washings were combined and
concentrated in vacuo to give the crude product 9a (95% purity
by reverse-phase HPLC), which was purified by radial chroma-
tography on a 2 mm plate, eluting with 50% EtOAc/hexanes.
Concentration of the product-containing fractions gave pure 9a
(45 mg; 4 step yield, 41% based on 1.07 mmol/g given by the
manufacturer or 79% yield based on loading yield).
Gen er a l Syn th esis of 3-Am in o-1,2-ben zisoxa zoles 4a -
h . F or m a tion of 3-Am in o-1,2-ben zisoxa zole (4a ). To p-
nitrobenzophenone oxime polystyrene (Kaiser) resin (500 mg,
1.07 mmol/g, 0.54 mmol) in a tared 25 mL Kontes microfilter
funnel was added THF (7 mL) and potassium tert-butoxide (640
µL, 1 M in THF, 0.642 mmol). After being shaken by hand for
several minutes, the resin turned a deep purple color. To this
suspension was added 2-fluorobenzonitrile (1.07 mmol, 214 mg),
and the reaction vessel was rotated at 55 °C in a Robbins oven
for 12 h, removed from the oven, and allowed to cool for 1 h.
The resin was then rinsed with 2 × 5 mL of CH2Cl2, 2 × 5 mL
of 5% TFA/CH2Cl2, 2 × 5 mL of 2-propanol, and 4 × 5 mL of
MeOH and then dried in a 35 °C vacuum oven for 12 h to give
a ∆wt of 36.5 mg (66% loading yield). TFA (4 mL) and 5 N HClaq
(1 mL) were then added to the resin, followed by rotation for 2
h in a 55 °C oven. The TFA/HClaq was collected, and the resin
was rinsed with 2 × 5 mL of CH2Cl2. These washings were
combined and concentrated in vacuo to give the crude product
4a (>96% purity by reverse-phase HPLC), which was purified
by radial chromatography using a 2 mm plate and eluting with
25% EtOAc/hexanes. Concentration of the product-containing
fractions gave pure 4a (35 mg; 2 step yield, 49% based on
theoretical equivalents of oxime in the starting resin or 74%
based on loading yield). 3-Am in o-1,2-ben zisoxa zole (4a ).
HPLC tR ) 12.3 min. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d,
J ) 7.7 Hz, 1H), 7.48 (t, J ) 8.4 Hz, 1H), 7.40 (d, J ) 8.4 Hz,
1H), 7.21 (t, J ) 7.0 Hz, 1H), 6.38 (bs, 2H). MS (ESI) m/z 135
(M + H)+. Anal. Calcd for C7H6N2O: C, 62.68; H, 4.51; N, 20.88.
Found: C, 62.61; H, 4.46; N, 20.83.
6-(Acetyla m in om eth yl)-3-a m in o-1,2-ben zisoxa zole (9a ).
1
HPLC tR ) 10.5 min. H NMR (400 MHz, DMSO-d6) δ 8.39 (bs,
1H), 7.69 (d, J ) 8.0 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J ) 8.0 Hz,
1H), 6.32 (bs, 1H), 4.32 (d, J ) 6.4 Hz, 2H), 1.86 (s, 3H). MS
(ESI) m/z 206 (M + H)+. Anal. Calcd for C10H11N3O2: C, 58.53;
H, 5.40; N,20.48. Found: C, 57.77; H, 5.45; N, 19.92.
7-Tr iflu or m eth yl-3-a m in o-1,2-ben zisoxa zole (4b). HPLC
1
tR ) 21.9 min. H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J ) 8.4
Hz, 1H), 7.71 (t, J ) 8.4 Hz, 1H), 7.64 (d, J ) 7.2 Hz, 1H), 5.82
(bs, 2H). MS (ESI) m/z 203 (M + H)+. Anal. Calcd for
C8H5F3N2O: C, 47.54; H, 2.49; N, 13.86; F, 28.20. Found: C,
47.71; H, 2.60; N, 13.85; F, 28.37.
6-[(p-Br om op h en ylca r bon yl)a m in om eth yl]-3-a m in o-1,2-
1
ben zisoxa zole (9b). HPLC tR ) 21.5 min. H NMR (400 MHz,
DMSO-d6) δ 9.17 (bs, 1H), 7.82 (d, J ) 8.4 Hz, 2H), 7.72 (d, J )
8.1 Hz, 1H), 7.67 (d, J ) 8.4 Hz, 2H), 7.31 (s, 1H), 7.18 (d, J )
8.1 Hz, 1H), 6.34 (bs, 2H), 4.55 (d, J ) 5.9 Hz, 2H). MS (ESI)
m/z 346 [79Br, (M + H)+], 348 [81Br, (M + H)+]. Anal. Calcd for
C15H12BrN3O2: C, 52.05; H, 3.49; N, 12.14. Found: C, 51.80; H,
3.54; N, 11.67.
6-Meth oxy-3-a m in o-1,2-ben zisoxa zole (4c). HPLC tR
)
1
14.2 min. H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J ) 8.4 Hz,
1H), 6.95 (d, J ) 2.4 Hz, 1H), 6.80 (dd, J ) 8.4, 2.4 Hz, 1H),
6.23 (bs, 2H). MS (ESI) m/z 165 (M + H)+. Anal. Calcd for
C8H8N2O2: C, 58.53; H, 4.91; N, 17.06. Found: C, 58.78; H, 4.99;
N, 17.10.
6-[(p -Br om op h e n yla m in oca r b on yl)a m in om e t h yl]-3-
a m in o-1,2-ben zisoxa zole (9c). HPLC tR ) 28.2 min. 1H NMR
(400 MHz, DMSO-d6) δ 8.77 (bs, 1H), 7.71 (d, J ) 8.1 Hz, 1H),
7.35 (s, 4H), 7.29 (s, 1H), 7.15 (d, J ) 8.4 Hz, 1H), 6.76 (t, J )
6.2 Hz, 1H), 6.33 (bs, 2H), 4.38 (d, J ) 6.2 Hz, 2H). MS (ESI)
m/z 361 [79Br, (M + H)+], 363 [81Br, (M + H)+]. Anal. Calcd for
C15H13BrN4O2: C, 49.88; H, 3.63; N, 15.51. Found: C, 49.78; H,
3.93; N, 15.10.
6-Tr iflu or m eth yl-3-a m in o-1,2-ben zisoxa zole (4d ). HPLC
1
tR ) 24.6 min. H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J ) 8.4
Hz, 1H), 7.90 (s, 1H), 7.58 (d, J ) 8.4 Hz, 1H), 6.64 (bs, 2H). MS
(ESI) m/z 203 (M + H)+. Anal. Calcd for C8H5F3N2O: C, 47.54;
H, 2.49; N, 13.86; F, 28.20. Found: C, 47.47; H, 2.50; N, 13.59;
F, 27.96.