Proline-Derived N-Sulfonylcarboxamides
FULL PAPERS
Chemie. All commercially available chemicals were used with-
out further purification. BOC-proline 4-nitrophenyl ester (7)
was synthesized from BOC-proline and p-nitrophenol in
3.18 (m, 2H), 3.76–3.81 (m, 1H), 4.49–4.58 (m, 2H), 7.01 (s, 2
1
3
H), NH protons not visible; C NMR (DMSO-d , 75 MHz):
6
d¼23.52 (t), 23.62 (t), 24.70 (q), 24.76 (q), 28.08 (d), 29.02
(t), 33.30 (d), 45.19 (t), 61.82 (d), 122.12 (d), 139.30 (s),
148.60 (s), 149.07 (s), 170.92 (s), (number of signals higher
than expected due to amide rotamers); IR (CsI): n˜ ¼2961,
1586, 1464, 1379, 1323, 1276, 1126, 1043, 996, 881, 822, 765,
[20]
73% yield according to a literature procedure.
Solvents
were distilled prior to use and dried, if necessary, using stan-
[21]
dard techniques. NMR spectra were recorded on a Bruker
AC300 NMR spectrometer, FT-IR spectra were recorded on
a Perkin Elmer FT-IR 1600 instrument. Melting points were
determined on a Büchi melting point apparatus and are uncor-
rected. Elemental analysis was performed on a Vario EL ele-
mentar CHN-apparatus. HPLC analysis was carried out on
Merck-Hitachi HPLC equipment using HPLC grade solvents
from Fisher Scientific.
À1
688, 655, 556, 463 cm ; an analytically pure sample was ob-
tained by recrystallization from methanol; elemental analysis:
calcd. for C H N O S: C 63.12, H 8.48, N 7.36; found: C 62.80,
1
7
32
2
3
H 8.45, N 7.28.
[
22]
N-4-Nitrobenzenesulfonyl-l-proline Amide 6c
N-Toluenesulfonyl-l-proline Amide 6a
BOC-l-proline (8, 472 mg, 2.19 mmol), DMAP (803 mg,
.57 mmol), EDCI (850 mg, 5.48 mmol), and 4-nitrobenzene-
sulfonamide (9c, 307 mg, 1.52 mmol) were dissolved in 20 mL
of a 1:1 mixture of tert-butyl alcohol and 1,2-dichloroethane.
The solution was stirred overnight at ambient temperature.
Ethyl acetate (5 ml) and Amberlyst-15 (protonated form,
6
To a solution of p-toluenesulfonamide (9a, 1.00 g, 5.8 mmol) in
2
6
0
0 mL of absolute DMF was added sodium hydride (268 mg,
0% dispersion in mineral oil, 6.69 mmol). After stirring for
.5 h at ambient temperature, l-proline (4-nitrophenyl) ester,
(
7, 1.50 g, 4.46 mmol), dissolved in 5 mL of absolute DMF,
2
.0 g) were added, and stirring was continued for 2 h. The mix-
was added. The yellow solution was stirred overnight at ambi-
ent temperature and then poured onto crushed ice. The pH was
adjusted to 3 by addition of citric acid. The aqueous layer was
extracted with ethyl acetate (3Â20 mL). The organic layer was
washed with water (5Â20 mL), dried over magnesium sulfate
and concentrated under vacuum. The semi-solid residue was
triturated with ether (10 mL), and the resulting colourless solid
was collected by filtration to afford the BOC-protected N-sul-
fonylcarboxamide; yield: 1.00 g (61%). Deprotection was per-
formed using 50% TFA in dichloromethane (10 mL) for one
hour at room temperature. After rotary evaporation, TFA salts
were removed by triturating the residue with 10 mL of metha-
nol (saturated with ammonia). The acylsulfonamide 6a was ob-
tained as a colourless powder; yield: 693 mg (42% overall); mp
ture was passed through a plug of silica gel (1 cm) and washed
with ethyl acetate. The filtrate was concentrated under vac-
uum, and the residue was purified by flash chromatography
on silica gel (dichloromethane/methanol, 40:1) to give protect-
ed 6c as a brown solid; yield: 400 mg (78%). Deprotection was
performed using 50% TFA in dichloromethane (10 mL) for
one hour at room temperature. After rotary evaporation,
TFA salts were removed by triturating the residue with
1
0 mL of methanol (saturated with ammonia). The acylsulfon-
amide 6c was obtained as a colourless solid; yield: 300 mg (66%
1
overall); mp 1988C; H NMR (DMSO-d , 300 MHz): d¼1.67–
6
1
.87 (m, 3H), 2.09–2.18 (m, 1H), 2.98–3.07 (m, 2H), 3.83–3.87
(
m, 1H), 7.98–8.01 (m, 2H), 8.24–8.27 (m, 2H), NH-protons
1
3
not visible; C NMR (DMSO-d , 75 MHz): d¼23.31 (t),
6
2
178C. Recrystallization from methanol gave colourless crys-
2
9.00 (t), 45.27 (t), 61.89 (d), 123.29 (d), 128.38 (d), 148.36
1
tals suitable for X-ray analysis. H NMR (DMSO-d6,
(
1
s), 151.08 (s), 172.09 (s); IR (CsI): n˜ ¼3114, 1680, 1606, 1529,
3
2
00 MHz): d¼1.64–1.86, 2.06–2.16 (m, 4H), 2.30 (s, 3H),
À1
354, 1268, 1203, 1148, 836, 740, 614 cm ; an analytically
.99–3.07, 3.11–3.19 (m, 2H), 3.78–3.83 (m, 1H), 7.17–7.20
pure sample was obtained by recrystallization from methanol;
elemental analysis: calcd. for C H N O S: C 44.14, H, 4.38, N
(
m, 2H), 7.65–7.67 (m, 2 H), NH-protons not visible;
13
11 13
2
5
C NMR (DMSO-d , 75 MHz): d¼20.87 (q), 23.36 (t), 29.08
6
1
4.04; found: C 44.02, H 4.34, N 13.97.
(
t), 45.31 (t), 61.88 (d), 126.84 (d), 128.16 (d), 139.97 (s),
1
1
42.42 (s), 171.27 (s); IR (CsI): n˜ ¼3088 1619, 1586 1403,
À1
326, 1241, 1128, 1085, 1046 947, 872, 811, 709, 646, 555 cm
;
elemental analysis: calcd. for C H N O S: C 53.71, H 6.01,
N 10.44; found: C 53.37, H 6.05, N 10.30.
1
2
16
2
3
General Procedure for Aldol Reactions between 4-
Nitrobenzaldehyde and Acetone
In a 10 mL test tube, 4-nitrobenzaldehyde (76 mg, 0.5 mmol)
was dissolved in 5 mL of a 4:1 mixture of the solvent stated
in Table 1 and acetone. Then the catalysts 6a – c (30 mol %:
N-2,4,6-Tris-(isopropylbenzene)sulfonyl-l-proline
Amide 6b
6
a: 40.3 mg; 6b: 57.1 mg, 6c: 44.9 mg) were added, and the re-
In analogy to the preparation of 6a, 2,4,6-tris(isopropylbenz-
ene)sulfonamide (9b, 2.00 g, 7.06 mmol) was reacted with so-
dium hydride (325 mg, 60% dispersion in mineral oil,
sulting homogeneous solutions were stirred at 208C for 24 h.
Samples of 100 mL were withdrawn, diluted with 1 mL di-
chloromethane, and conversion and enantiomeric excess was
determined immediately by HPLC (Chiralcel-OJ, n-hexane/
isopropanol, 9:1, 1.0 mL/min). Quantification was performed
using integrated wavelengths from 240–261 nm. Conversion
was determined by comparison to the peak areas of stock so-
lutions of 4-nitrobenzaldehyde and the racemic aldol adduct
4 in dichloromethane (8.27 mmol/L each). Retention times:
tR [min]: 19.73 4-nitrobenzaldehyde; 31.52 (R)-4-hydroxy-4-
8
5
.14 mmol) and l-proline 4-nitrophenyl ester (7, 1.83 g,
.43 mmol). Work-up as described above afforded the BOC-
protected N-sulfonylcarboxamide; yield: 1.45 g (55%). Depro-
tection and removal of TFA salts as described for 6a afforded
6
2
1
b as a colourless powder; yield: 1.45 mg (39% overall); mp
1
208C; H NMR (DMSO-d , 300 MHz): d¼1.13 (br. s, 18H),
6
.70–1.90, 2.11–2.18 (both m, 4H), 2.77–2.86 (m, 1H), 3.01–
Adv. Synth. Catal. 2004, 346, 1141–1146
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1145