3
156 J . Org. Chem., Vol. 62, No. 10, 1997
Hern a´ ndez and Hodges
spectra were recorded in CD
3
OD, and H coupling constants,
Resin 8c(n )4): IR 1688 cm-1. Anal. Found: C, 86.03; H,
8.57; N, 1.01.
J , are reported in hertz.
Gen er al P r ocedu r e for th e P r epar ation of Diols 2(n )5),11
Resin 8c(n )2): IR 1680 cm-1. Anal. Found: C, 84.55; H,
8.36; N, 1.25.
1
2
13
2
(n )4)
,
a n d 2(n )3)
.
A 1.4 M MeLi/ether solution (250 mol
Resin 8d (n )4): IR 1670, 1655 cm-1. Anal. Found: C, 84.92;
H, 8.19; N, 0.96.
%) was added to a solution of lactone 1 (100 mol %) in dry
THF (1.7 mL/mmol), cooled at -78 °C. The mixture was
stirred for 30 min at -78 °C and for 6 h while being warmed
to rt. AcOH (250 mol %) was added, and the suspension was
stirred overnight at rt. After filtration, the filter cake was
rinsed with THF and the filtrates were evaporated to give the
crude diol 2 which was purified by vacuum distillation.
Gen er a l P r oced u r e for th e P r ep a r a tion of Resin
Bou n d ter t-Alk yl Alcoh ols 4. A 1 M t-BuOK/THF (300 mol
Resin 8d (n )2): IR 1696, 1663 cm-1. Anal. Found: C, 83.78;
H, 8.10; N, 1.19.
Resin 8e(n )4): IR 1698 cm-1. Anal. Found: C, 87.24; H,
8.00; N, 0.56.
Resin 8e(n )2): IR 1698 cm-1. Anal. Found: C, 85.67; H,
7.91; N, 1.00.
Resin 8j(n )2): IR 1750, 1717 cm-1. Anal. Found: C, 80.82;
H, 7.39; N, 0.92.
%) solution was added to a solution of diol 2 (300 mol %) in
dry THF (2.5 mL/mmol), cooled at 0 °C. The solution was
stirred at 0 °C for 45 min and for 3 h while being warmed to
rt. Merrifield resin (100 mol % of chlorine sites, L ) 1.35
mmol/g) was added, and the suspension was shaken for 3.5
days at rt. After filtration, the resin bound tert-alkyl alcohol
Gen er a l P r oced u r e for th e P r ep a r a tion of Resin
Bou n d ter t-Alk yl Ca r ba m a tes 8(n )4) a n d 8(n )4) fr om Am in o
Ester s‚HCl. Et
suspension of the amino ester HCl 7‚HCl (600 mol %) in CH
Cl (9 mL/mmol) and the resulting suspension filtered. The
3
N (600 mol %) was added to a solution/
.
2
-
2
4
was washed with THF (four times), 1/1 DMF/H
times), DMF (two times), 1/1 DMF/H O (two times), DMF (two
times), THF (two times), and CH Cl (two times), and dried.
2
O (two
amino ester solution was transferred via syringe to a stirred
suspension at rt of the resin bound (tert-alkoxycarbonyl)-3-
methylimidazolium triflate 6 (100 mol %) prepared as above.
The mixture was shaken for 5.5 h at rt and filtered. The resin
bound tert-alkyl carbamate 8 was washed with THF (three
times), 1/1 THF/MeOH (three times), THF (three times), and
2
2
2
Resin 4(n )5). Found: C, 86.19; H; 8.13; N, 0.02; Cl, 0.56.
Resin 4(n )4). Found: C, 86.88; H; 8.18; N, 0.07; Cl, 0.19.
Resin 4(n )3). Found: C, 87.35; H; 8.35; N, 0.02; Cl, 0.29.
Resin 4(n )2). Found: C, 86.95; H; 8.43; N, 0.02; Cl, 0.05.
Gen er a l P r oced u r e for th e P r ep a r a tion of Resin
Bou n d (ter t-Alk oxyca r bon yl)im id a zoles 5. DMAP (50 mol
2 2
CH Cl (three times) and dried.
Resin 8f(n )4): IR 1717 (broad) cm-1. Anal. Found: C,
4.03; H, 8.21; N, 0.78.
8
Resin 8f(n )2): IR 1744, 1720 cm-1. Anal. Found: C, 83.56;
%
) and CDI (400 mol %) were added to a suspension of the
1
7
H, 8.08; N, 1.11.
resin 4 (100 mol % of tert-alkyl alcohol sites) in dry DMF
4.5 mL/mmol). The mixture was shaken for 24 h at rt and
filtered. The resin bound (tert-alkoxycarbonyl)imidazole 5 was
washed with CH Cl (three times), THF (three times), CH
Cl (three times) and dried.
R esin 5(n )5): IR 1754 cm-1. Anal. Found: C, 85.50; H,
Resin 8g(n )4): IR 1734, 1717 cm-1. Anal. Found: C, 82.93;
H, 8.11; N, 0.89.
(
Resin 8g(n )2): IR 1734 (broad) cm-1. Anal. Found: C,
2
2
2
-
8
1.93; H, 7.58; N, 1.18.
2
Resin 8h (n )4): IR 1733, 1716 cm-1. Anal. Found: C, 82.98;
H, 7.78; N, 0.92.
7
7
7
7
.58; N, 1.40.
Resin 8h (n )2): IR 1733, 1717 cm-1. Anal. Found: C, 81.99;
H, 7.84; N, 1.12.
R esin 5(n )4): IR 1751 cm-1. Anal. Found: C, 84.20; H,
.75; N, 2.40.
Resin 8i(n )4): IR 1734, 1716 cm-1. Anal. Found: C, 83.52;
H, 7.96; N, 1.57.
R esin 5(n )3): IR 1750 cm-1. Anal. Found: C, 85.90; H,
.95; N, 1.62.
Resin 8i(n )2): IR 1732 (broad) cm-1. Anal. Found: C,
R esin 5(n )2): IR 1747 cm-1. Anal. Found: C, 83.44; H,
.33; N, 2.61.
8
2.26; H, 7.28; N, 2.07.
Gen er a l P r oced u r e for Clea va ge of Resin Bou n d ter t-
Gen er a l P r oced u r e for th e P r ep a r a tion of Resin
Alk yl Ca r ba m a tes 8(n )4) a n d 8(n )2). Resin bound tert-alkyl
carbamates 8(n )4) and 8(n )2) were treated with 10% TFA/CH
Cl (2.5 mL/100 mg of resin) for 3 and 4.5 h, respectively, and
filtered. For both types of resin, the resin was rinsed with
CH Cl (three times) and MeOH (two times) and the filtrates
Bou n d (ter t-Alk oxyca r bon yl)-3-m eth ylim id a zoliu m Tr i-
fla tes 6. Methyl triflate (170 mol %) was added to a suspen-
sion of the resin 5 (100 mol % of carbonylimidazole sites) in
dry 1,2-DCE (16 mL/mmol), cooled at 10 °C. The mixture was
stirred for 15 min at this temperature and for 5-10 min while
2
-
2
2
2
were evaporated and dried (vacuum, overnight) to give back
being warmed to rt. After addition of Et
3
N (500 mol %),
1
amine 7, as its TFA salt. The H NMR spectra of the cleaved
stirring was continued for an additional 5 min and then the
suspension used directly as the tert-alkoxycarbonylating/
anchoring reagent.
amines showed them to be identical to those obtained from
authentic samples of ammonium trifluoroacetates 7‚TFA.
Clea va ge of Resin Bou n d ter t-Alk yl Ca r ba m a te 8h (n )2)
.
Gen er a l P r oced u r e for th e P r ep a r a tion of Resin
Acetyl chloride (10.2 mL, 0.14 mol) was added to a 3/2 CH
Cl /MeOH (40 mL) solution, cooled at 0 °C. The resin 8h (n )2)
36 mg) was treated with the HCl solution (2.5 mL) for 4.5 h
and filtered. The resin was rinsed with CH Cl (four times),
2
-
Bou n d ter t-Alk yl Ca r b a m a t es
Am in es. The amine 7 (600 mol %) was added, neat or as a
solution in CH Cl (7d ) or DMF (7j), to a stirred suspension
8(n )4) a n d 8(n )2) fr om
2
(
2
2
2
2
at rt of the resin bound (tert-alkylcarbonyl)-3-methylimidazo-
lium triflate 6 (100 mol %) prepared as above. The mixture
was shaken for 3.5 h (7a -e) or 5.5 h (7j) at rt and filtered.
The resin bound tert-alkyl carbamate 8 was washed with THF
and the filtrates were evaporated and dried (vacuum, over-
night) to give back methionine ethyl ester (7h ), as its HCl salt
6 mg). A 1H NMR spectrum of the cleaved ammonium
(
hydrochloride 7h ‚HCl showed it to be identical to the one
obtained from an authentic sample of methionine ethyl ester‚
HCl.
(
three times), 1/1 THF/MeOH (three times), THF (three times),
2 2
and CH Cl (three times) and dried.
Resin 8a (n )4): IR 1717 cm-1. Anal. Found: C, 84.01; H,
3
-(Acet oxym et h yl)p ip er id in iu m Tr iflu or oa cet a t e (9‚
7
7
8
7
.46; N, 0.79.
18
2
TF A). Ac O (0.2 mL, 2.12 mmol) was added to a suspension
Resin 8a (n )2): IR 1716 cm-1. Anal. Found: C, 82.54; H,
of the resin 8d (n )4) (171 mg, L ) 0.69 mmol/g) in pyridine (1.6
mL), and the mixture was shaken at rt for 24 h. After
.63; N, 1.22.
Resin 8b(n )4): IR 1714 cm-1. Anal. Found: C, 83.62; H,
filtration, the resin was washed with CH
THF (three times), 1/1 THF/MeOH (three times), THF (three
times), and CH Cl (three times) and dried: weight of resin,
2 2
Cl (three times),
.17; N, 1.48.
Resin 8b(n )2): IR 1713 cm-1. Anal. Found: C, 82.92; H,
2
2
-
1
.86; N, 2.19.
175 mg; IR 1740, 1645 cm . Anal. Found: C, 84.14; H, 7.87;
N, 0.98.
(
17) The theoretical loading of tert-alkyl alcohol was calculated on
the basis of the Cl content of the starting Merrifield resin, assuming
the observed Cl displacement is due to exclusive monoalkylation by
°-alcohol.
(18) Ackerman, J .; Banner, D.; Gubernator, K.; Hadvary, P.; Hilpert,
K.; Mueller, K.; Labler, L.; Schmid, G.; Tschopp, T.; et al. European
Patent Application, EP 468231 A2, 1992.
1