Parallel Synthesis of Primary and Secondary O-Alkyl Hydroxylamines
3.6, 6.9, 7.1, 7.8, 8.3, 8.75, 10.9; 13C NMR (CDCl3 + DMSO-d6
1 drop, 100 MHz) δ 34.1, 41.6, 114.4, 121.5, 122.7, 128.9, 129.5,
130.7, 131.6, 133.4, 139.9, 156.9, 163.4, 163.5, 165.6; FT-IR
(ATR) νmax 3023, 2920, 1787, 1723, 1648, 1600, 1538, 1507,
1492, 1451, 1302, 1251, 1197, 1179, 1138, 1115, 985, 920, 815,
756, 698 cm-1. Anal. Found: N, 5.19; O, 6.47.
cm-1; ESI MS (+) 483.2 (M + Na + MeOH); HRMS calcd for
C27H28N2O5Na 483.1896, found 483.1917.
N-[4-(But-3-ynyl)phenethyl]-1,3-dioxo-2-(4-phenyl-
butan-2-yloxy)isoindoline-5-carboxamide (61): 1H NMR
(CDCl3, 300 MHz) δ 1.37 (d, J ) 6,2 Hz, 3 H), 1.92 (m, 1 H),
2.12 (m, 1 H), 2.54 (t, J ) 2.3 Hz, 1 H), 2.90 (m, 4 H), 3.72 (m,
2 H), 4.43 (m, 1 H), 4.68 (d, J ) 2.3 Hz, 2 H), 6.31 (m, 1 H),
6.94 (d, J ) 8.6 Hz, 2 H), 7.16 (d, J ) 8.6 Hz, 2 H), 7.27 (m, 5
H), 7.89 (d, J ) 7.7 Hz, 1 H), 8.07 (s, 1 H), 8.14 (d, J ) 7.7 Hz,
1 H); 13C NMR (CDCl3, 75 MHz) δ 18.9, 31.4, 34.6, 36.7, 41.6,
55.8, 75.6, 79.2, 84.0, 115.2, 121.4, 123.8, 125.9, 128.4, 128.4,
129.3, 129.7, 131.0, 131.3, 133.5, 140.6, 141.5, 156.4, 163.4,
163.5, 165.3; FT-IR (ATR) νmax 3282, 2923, 1787, 1726, 1714,
1632 cm-1; ESI MS (+) ESI (+) 551.2 (M + Na + MeOH) and
567.2 (M + K + MeOH).
General Procedures for Synthesis of Alkoxyamines
with Supported Reagent 17. With Betaine Sulfamide.
Resin 17 (0.80 mmol/g, 50 mg, 39 µmol) was loaded into a 6
mL SPE cartridge. The resin was suspended in CH2Cl2 (5 mL).
The SPE cartridge was capped, fixed horizontally onto an
orbital shaker and agitated for 1 h. The resin was drained and
suspended in CH2Cl2. Alcohol (5 equiv) and betaine sulfamide
(99 mg, 6 equiv) were added, and the cartridge capped and
agitated for 24 h at room temperature. The resin was drained
and washed with CH2Cl2 (3 × 5 mL), DMF (3 × 5 mL), MeOH
(3 × 5 mL), CH2Cl2 (5 mL), MeOH (5 mL), and CH2Cl2 (5 mL).
This resin was then subjected to methylaminolysis.
With Ph3P/DIAD/Imidazole. Resin 17 (0.80 mmol/g, 50
mg, 39 µmol) was loaded into a 6 mL SPE cartridge. The resin
was suspended in CH2Cl2 (5 mL). The SPE cartridge was
capped, loaded horizontally onto an orbital shaker and agitated
for 1 h. The resin was drained and suspended in CH2Cl2 (5
mL). Alcohol (5 equiv) and triphenylphosphine (52 mg, 5 equiv)
were added, mixed by inverting the cartridge until dissolution
and DIAD (39.8 µL, 5 equiv) and imidazole (14 mg, 5 equiv)
were added. The cartridge was capped and agitated as previ-
ously for 24 h at room temperature. The resin was drained
and washed with CH2Cl2 (3 × 5 mL), DMF (3 × 5 mL), MeOH
(3 × 5 mL), CH2Cl2 (5 mL), MeOH (5 mL), and CH2Cl2 (5 mL).
This resin was then subjected to the cleavage step by meth-
ylaminolysis.
With Alkyl Bromides. Resin 17 (0.80 mmol/g, 50 mg, 39
µmol) was loaded into a 6 mL SPE cartridge. The resin was
suspended in DMF (5 mL). The SPE cartridge was capped,
loaded horizontally onto an orbital shaker, and agitated for 1
h. The resin was drained and suspended in DMF (5 mL). Alkyl
bromide (10 equiv) and triethylamine (56.2 µL, 10 equiv) were
added. The cartridge was capped and agitated as previously
for 24 h at room temperature. The resin was drained and
washed with DMF (3 × 5 mL), CH2Cl2 (3 × 5 mL), MeOH (3
× 5 mL), CH2Cl2 (5 mL), MeOH (5 mL) and CH2Cl2 (5 mL).
This resin was then subjected to the cleavage step by meth-
ylaminolysis.
N-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)pheneth-
yl)-2-(4-methoxybenzyloxy)-1,3-dioxoisoindoline-5-car-
boxamide (16). To a magnetically stirred suspension of 13
(300 mg, 0.62 mmol) in THF (3 mL) were added benzyl azide
(77 µL, 0.62 mmol), CuI (12.0 mg, 0.06 mmol, 0.1 equiv), and
DIPEA (0.5 mL). The suspension was stirred at 35 °C for 24
h, filtered, and washed with CH2Cl2 (5 mL), MeOH (5 mL),
water (5 mL), MeOH (5 mL), and CH2Cl2 (5 mL) to give 16
(335 mg, 90% pure (see HPLC), 78%): 1H NMR (CDCl3, 500
MHz) δ 2.80 (t, J ) 7.3 Hz, 2H), 3.48 (td, J ) 8.1 Hz, J ) 16.7
Hz, 2 H), 3.76 (s, 3 H), 5.09 (s, 2 H), 5.10 (s, 2 H), 5.60 (s, 2 H),
6.95 (d, J ) 8.5 Hz, 2 H), 6.95 (d, J ) 8.5 Hz, 2 H), 7.16 (d, J
) 8.5 Hz, 2 H), 7.34 (m, 5 H), 7.43 (d, J ) 8.5 Hz, 2 H), 7.94
(d, J ) 7.7 Hz, 1 H), 8.23 (s, 1 H), 8.25 (dd, J ) 1.5 Hz, J ) 7.7
Hz, 1 H), 8.26 (d, J ) 1.5 Hz, 1 H), 8.92 (t, J ) 5.5 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ 164.0, 162.6, 162.5, 159.8, 156.4,
143.4, 139.9, 135.9, 133.6, 131.5, 131.4, 130.4, 129.5, 128.7,
128.6, 128.0, 127.8, 125.5, 124.4, 123.3, 121.2, 114.5, 113.7,
78.8, 60.9, 55.0, 52.7, 41.1, 33.8; FT-IR (ATR) νmax 2919, 1788,
1722, 1649 cm-1; ESI-MS (+) 640.2 (M + Na); HRMS calcd
for C29H28N2O7Na 640.2172, found 640.2183. The chemical
purity was determined to 90% by HPLC analysis using an
analytical Atlantis-C18 column (150 × 4.6 mm, 5 µm). Detection
was at 234 nm using a photodiode array detector: solvent A,
water; solvent B, acetonitrile; 50% solvent B, 5 min, 50-80%
solvent B in 5 min, 1.0 mL min-1
.
Solution-Phase Mitsunobu Reaction of N-Hydroxy-
phthalimide Model Derivatives. With Sulfamide Be-
taine. Betaine sulfamide (61 mg, 0.15 mmol) was added in
one portion to a solution of the N-hydroxyphthalimide deriva-
tive (0.136 mmol) and 4-phenylbutan-2-ol (32 µL, 0.21 mmol)
in CH2Cl2 (4.5 mL). After the mixture was stirred for 24 h at
room temperature, a new portion of betaine sulfonamide (61
mg, 0.15 mmol) was added and the mixture was stirred for 1
more day. The solution was evaporated under reduced pressure
and the crude product was purified by flash chromatography
on silica gel (heptane-AcOEt mixture). The yields obtained
with N-hydroxyphthalimide, 58 or 14 as substrate are given
in Table 3.
With Ph3P/DIAD. DIAD (30 µL, 0.15 mmol) was added
dropwise to a solution of the N-hydroxyphthalimide derivative
(0.136 mmol), triphenylphosphine (39 mg, 0.15 mmol), and
4-phenylbutan-2-ol (32 µL, 0.21 mmol) in dry THF (2.1 mL)
at room temperature. The yellow solution was stirred for 24 h
and concentrated under reduced pressure, and the crude
product was purified by flash chromatography on silica gel
(heptane-AcOEt mixture). The yields obtained with N-hydroxy-
phthalimide, 58, or 14 as substrate are given in Table 3.
2-(4-Phenylbutan-2-yloxy)isoindoline-1,3-dione (59):
1H NMR (CDCl3, 300 MHz) δ 1.35 (d, J ) 6.2 Hz, 3 H), 1.92
(m,1 H), 2,10 (m, 1 H), 2.87 (t, J ) 8.0 Hz, 2 H), 4.42 (m, 1 H),
7.10-7.30 (m, 5 H), 7.73 (dd, J ) 3.1, J ) 5.5 Hz, 2 H), 7.83
(dd, J ) 3.1, J ) 5.5 Hz, 2 H); 13C NMR (CDCl3, 75 MHz) 18.9,
31.4, 36.8, 83.8, 123.5, 125.9, 128.4, 128.5, 129.0, 134.4, 141.7,
164.4; FT-IR (ATR) νmax 2931, 1788, 1727 cm-1; ESI MS (+)
318.2 (M + Na); HRMS calcd for C18H17NO3Na 318.1106, found
318.1104.
Cleavage. The resin was suspended in CHCl3-MeOH (9:1,
5 mL), the SPE cartridge was capped, loaded horizontally onto
an orbital shaker and agitated for 1 h. The resin was drained,
suspended in 5 mL of a 0.05 M methylamine solution in
CHCl3-MeOH (9:1, 5 mL), and agitated for 2 h at room
temperature. The solution was collected by filtration, the resin
was washed with CHCl3 (1 mL) and the filtrate collected and
evaporated under reduced pressure (higher than 20 mbar) to
afford the O-alkyl hydroxylamine. Yields were determined by
NMR titration as described above.
N-Benzyl-1,3-dioxo-2-(4-phenylbutan-2-yloxy)isoindo-
line-5-carboxamide (60): 1H NMR (CDCl3, 300 MHz) 1.35
(d, J ) 6.0 Hz, 3 H), 1.84 (m, 1 H), 2.10 (m, 1 H), 2.80 (t, J )
8.0 Hz, 2 H), 4.35 (m, 1 H), 4.55 (d, J ) 5.9 Hz, 2 H), 6.60 (m,
1 H), 7.25-7.35 (m, 10 H), 7.80 (d, J ) 7.9 Hz, 1 H), 8.10 (s,
1 H), 8.20 (d, J ) 7.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) 14.1,
31.4, 36.7, 44.5, 84.0, 121.1, 123.9, 125.9, 127.9, 128.0, 128.4,
128.5, 128.9, 129.30, 131.1, 133.8, 137.3, 140.3, 141.5, 163.5,
163.6, 165.0; FT-IR (ATR) νmax 3316, 2925, 1785, 1731, 1644
O-Alkyl hydroxylamine Analysis. All the alkoxyamines
were analyzed by NMR and GC-MS or HPLC. GC-MS
analyses were realized with a solution of the O-alkyl hydroxyl-
amine in MeOH using HP-5 (cross-linked 5% PH ME siloxane,
30 m × 0.32 mm × 0.25 mm) as the stationary phase. Helium
flow: 1.5 mL /min. Temperature program: 120 °C for 2min,
then 10 °C/min to 280 °C. HPLC separations were performed
using an analytical Aquasil-C18 column (100 × 3 mm, 3 µm,
provided from Thermoelectron) with a flow rate of 0.8 mL
J. Org. Chem, Vol. 70, No. 16, 2005 6311