Carpino et al.
Z-Aib-ODh a t. In an ice bath, 0.3168 g of EDC-HCl (1.65
mmol) was added with stirring to a suspension of Z-Aib-OH
(0.3555 g; 1.5 mmol) and HODhat 5 (0.246 g, 1.5 mmol) in 10
mL of THF and 5 mL of DMF. The resulting mixture was
stirred at rt for 3 h. Solvents were removed in vacuo, and the
oily residue was extracted with 40 mL of EtOAc. The EtOAc
solution was washed with 5% aqueous citric acid (3 × 10 mL),
10% NaHCO3 solution (3 × 10 mL), and brine (3 × 10 mL)
and dried over MgSO4. Evaporation of the solvent gave a
yellow oily residue, which solidified after drying in vacuo over
P205 overnight. The crude solid was purified by flash chroma-
tography with EtOAc as eluent to give 0.46 g (80%) of the ester
as a cream yellow solid. For characterization data see Table
1, Supporting Information. Other Aib esters were made
similarly.
Me3CCOODh a t. Under an atmosphere of dry N2, TEA (0.42
mL, 3 mmol) was added to a suspension of HODhat 5 (0.3282
g, 2 mmol) in 10 mL of dry methylene chloride. The resulting
mixture was cooled to 0 °C, and a solution of pivaloyl chloride
(0.27 mL, 2.2 mmol) in 5 mL of dry methylene chloride was
introduced dropwise with stirring. The stirring was continued
for 30 min in an ice bath, and the temperature was allowed to
rise to rt. After 4 h, the mixture was diluted with 30 mL of
CH2Cl2, and the whole mixture was washed with saturated
NaHCO3 (3 × 20 mL), brine (2 × 20 mL), and water (2 × 20
mL) and finally dried over anhydrous MgSO4. Evaporation of
solvent gave a pale yellow solid, which was recrystallized from
EtOAc-hexane to give 0.31 g (61%) of the analytically pure
ester as colorless needles. For characterization data see Table
1, Supporting Information. Other pivaloyl esters were made
similarly.
O -(3 ,4 -D i h y d r o -4 -o x o -5 -a z a b e n z o -1 ,2 ,3 -t r i a z i n -
3-yl)-1,1,3,3-tetr a m eth ylu r on iu m Hexa flu or op h osp h a te
(HDATU, 12). Under an atmosphere of dry N2, 0.22 mL (1.65
mmol) of TEA was added to a suspension of HODhat, 5 (0.246
g, 1.5 mmol), in 10 mL of dry CH2Cl2. After being stirred for
5 min, the resulting clear light yellow solution was cooled to
0 °C in an ice bath and 0.4209 g (1.5 mmol) of TCFH was
introduced protionwise with stirring. The stirring was contin-
ued for 30 min in an ice bath and then at rt for 1.5 h. The
precipitate was collected by filtration, washed twice with
methylene chloride, and recrystallized twice from MeCN-
ether to give 0.42 g (69%) of analytically pure hexafluorophos-
phate 12 as a white solid: mp 152 °C (explodes); 1H NMR
(CD3CN) δ 9.19 (dd, l), 8.69 (dd, 1), 8.13 (dd, l), 3.21 (s, 12); IR
(KBr) 1738 (vs), 1702 (vs) cm-l. Anal. Calcd for C11H15N6O2-
PF6: C, 32.36; H, 3.70; N, 20.58. Found: C, 32.14; H, 3.79; N,
20.47.
uronium salt 14 as cream yellow crystals: mp 124 °C (ex-
plodes); 1H NMR (CD3CN) δ 8.34 (m, 2), 8.17 (m, 1), 8.00 (m,1),
3.74 (t, 8), 1.97 (m, 8); IR (KBr) 1716 (vs), 1676 (vs) cm-1. Anal.
Calcd for C16H20N5O2PF6: C, 41.83; H, 4.39; N, 15.25. Found:
C, 41.64; H, 4.27; N, 15.16.
O-(3,4-Dih yd r o-4-oxo-5-a za b e n zo-1,2,3-t r ia zin -3-y)-
1,1,3,3-bis(tetr a m eth ylen e) u r on iu m Hexa flu or op h os-
p h a te (HDAP yU, 15). To a mixture of 0.4923 g (3 mmol) of
HODhat 5 and 0.46 mL (3.3 mmol) of TEA in 25 mL of dry
CH2Cl2 at 0 °C was added 1.0 g (3 mmol) of PyClU portionwise
with stirring under an atmosphere of dry N2. Stirring was
continued for 1 h in an ice bath and then at rt overnight. The
clear light yellow mixture was diluted with CH2Cl2 to 50 mL,
washed with ice-cold water (2 × 15 mL), and dried over MgSO4.
The solvent was removed, the oily residue was dissolved in 5
mL of MeCN to which 30 mL of ether was added, and the
whole mixture was stored at -20 °C for several days until the
oil solidified. The solid was collected by filtration and redis-
solved in 20 mL of CH2Cl2, and the solution was washed with
ice-cold water (2 × 5 ml) and dried over MgSO4. Removal of
the solvent gave a pink-yellow solid which was recrystallized
from MeCN-ether to give 0.42 g (30%) of the uronium salt 15
1
as off-white crystals: mp 136.5 °C (explodes); H NMR (CD3-
CN) δ 9.17 (dd, 1), 8.67 (dd, 1), 8.11 (dd, 1), 3.75 (t, 8), 1.97
(m, 8); IR (KBr) 1734 (vs), 1679 (vs) cm-1. Anal. Calcd for
C
15H19N6O2PF6: C, 39.13; H, 4.16; N, 18.26. Found: C, 38.94;
H, 4.08; N, 18.30.
[1-(3,4-Dih ydr o-4-oxo-5-azaben zo-1,2,3-tr iazin -3-yl)oxy]-
tr is(pyr r olidin o)ph osph on in m Hexaflu or oph osph ate (P y-
DAOP , 17). To a mixture of 0.2462 g (1.5 mmol) of HODhat 5
and 0.24 mL (1.65 mmol) of TEA in 10 mL of dry CH2Cl2 at 0
°C was added 0.6993 g (1.5 mmol) of PyBrOP portionwise with
stirring under an atmosphere of dry N2. Stirring was continued
for 1 h in an ice bath and then at rt overnight. The clear light
yellow mixture was diluted with CH2Cl2 to 25 mL, and the
solution was washed with ice-cold water (2 × 10 mL) and dried
over MgSO4. The resulting clear light yellow solution was
treated with 50 mL of ether, and the solid which separated
was collected by filtration to give 0.45 g (54%) of analytically
pure phosphoniumn salt 17 as a white solid after recrystalli-
zation from MeCN-ether: mp 149 °C dec; 1H NMR (CD3CN)
δ 9.20 (dd, 1), 8.67 (dd, 1), 8.13 (dd, 1), 3.42 (td, 12), 1.96 (td,
8); IR (KBr) 1742 (vs), 1566 (m), 1462 (sh, w) cm-1. Anal. Calcd
for C18H27N7O2P2F6: C, 39.34; H, 4.95; N, 17.84. Found: C,
39.36; H, 5.09; N, 17.90.
Syn th esis of F m oc-Ile-ODh a t. Meth od A.15 Under an
atmosphere of dry N2, a suspension of Fmoc-Ile-OH (0.3534 g,
1 mmol), HODhat 5 (0.1805 g, 1.1 mmol), and SOCl2 (0.73 mL,
10 mmol) in 8 mL of dry CH2Cl2 was refluxed overnight.
Evaporation of CH2Cl2 and the excess of SOCl2 gave a yellow
solid which was purified by flash chromatography through a
short silica gel column with a mixture of EtOAc-CH2Cl2 (1:1
v/v) as eluent to give, after two recrystallizations from CH2-
Cl2-benzene-ether-hexane, 0.42 g (81%) of the analytically
pure ester as a white solid: mp 160.5-162 °C; 1H NMR
(CDCl3) δ 9.15 (dd, 1), 8.58 (dd, 1), 7.96 (dd, 1); 7.76 (dd,2),
7.61 (dd, 2), 7.27-7.44 (m, 4), 5.20 (d, 1), 4.88 (q, 1), 4.49 (d,
2), 4.26 (t, 1), 2.21 (m, 1), l.70 (m, 1), 1.34 (m, 1), 1.15 (d,3),
1.05 (t, 3); IR (KBr) 1811 (s, COO), 1738 (vs, CONN), 1692
(vs, NHCO) cm-l. Anal. Calcd for C27H25N5O5: C, 64.91; H,
5.04; N, 14.02. Found: C, 64.77; H, 5.23; N, 13.94.
O-(3,4-Dih ydr o-4-oxo-5-azaben zo-1,3-diazin -3-yl)-1,1,3,3-
tetr am eth ylu r on iu m Hexaflu or oph osph ate (HDADU, 13).
As described for HDATU 12, diazine HODhad 6 (0.2447 g, 1.5
mmol) was treated with TCFH (0.4209 g, 1.5 mmol) in 10 ml
of dry CH2Cl2 in the presence of TEA (0.30 mL, 2.1 mmol) to
give 0.55 g (90%) of the hexafluorophosphate 13 as a white
solid, which was recrystallized twice from MeCN-ether to give
0.48 g (79%) of analytically pure salt as a white solid: mp 203-
1
205 °C dec; H NMR (CD3CN) δ 8.91 (dd, l), 8.64 (s, 1), 8.22
(dd, 1), 7.88 (dd, 1), 3.17 (s, 12); IR (KBr) 1701(vs) cm-1. Anal.
Calcd for C12H16N5O2PF6: C, 35.38; H, 3.96; N, 17.19. Found:
C, 35.51; H, 3.86; N, 17.33.
O-(3,4-Dih yd r o-4-oxo-1,2,3-b en zot r ia zin -3-yl)-1,1,3,3-
bis(tetr a m eth ylen e)u r on iu m Hexa flu or op h osp h a te (HD-
P yU, 14). To a mixture of 0.8157 g (5 mmol) of HODhbt 1
and 0.70 mL (5 mmol) of TEA in 25 mL of dry CH2Cl2 at 0 °C
was added 1.6633 g (5 mmol) of PyClU portionwise with
stirring under an atmosphere of dry N2. Stirring was continued
for 1 h in an ice bath and then at rt overnight, and 50 mL of
ether was added causing an oily material to separate. The
mixture was stored at -20 °C for 2 days until the oil solidified.
The yellow solid was collected by filtration and washed with
ice-cold water (4 × 5 mL) to remove TEA‚HCl and the residue
recrystallized from MeCN-ether to give 1.1 g (44%) of the
Meth od B. Under an atmosphere of dry N2, 0.1854 g (0.5
mmol) of Fmoc-Ile-Cl was added with stirring to a solution of
HODhat 5 (0.0821 g, 0.5 nmol) and DIEA (95.8 µL, 0.55 mmol)
in 10 mL of CH2Cl2 at 0 °C. Stirring was continued at 0 °C for
30 min and then at rt for 5 h. The resulting light yellow
solution was diluted to 30 mL with CH2Cl2 and washed quickly
with ice-cold brine (2 × 15 mL). After drying over MgSO4 and
removing the solvent, the light yellow sticky solid was recrys-
tallized twice from CH2Cl2 ether-hexane to give the analyti-
cally pure ester as a white solid: mp 161-162 °C. NMR and
IR spectra were identical with those of the sample obtained
by method A.
60 J . Org. Chem., Vol. 69, No. 1, 2004