MaryAnnT. Robak et al. / Tetrahedron 67 (2011) 4412e4416
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concentrated to remove the THF. The crude product was extracted
deprotonated. The reaction mixture was stirred for 3 h at rt. (D)-
into EtOAc, and the organic layer from the extraction was loaded
onto a silica plug and side products were eluted with 100% EtOAc.
The product was eluted using a mobile phase gradient of 20%e50%
MeOH in EtOAc. Fractions containing the desired product were
concentrated several times from EtOAc and the resulting residue
was redissolved in warm EtOAc and filtered. The filtrate was con-
centrated, and then the white solid was recrystallized from 5 mL of
hexanes. The solids were collected by vacuum filtration and rinsed
with additional hexanes, to yield 0.66 g (73%) of 11 as a white
Proline methyl ester (3.0 mmol) was added via syringe. After
30 min, the reaction was quenched by addition of acetic acid
(0.160 g, 2.66 mmol) and water (8 mL), and the resulting mixture
was concentrated to remove the THF. The crude product was
extracted into EtOAc, and the organic layer was dried (Na2SO4),
filtered, and concentrated. The crude product was loaded onto
a silica plug and side products were eluted with 100% EtOAc. The
product was eluted using 50% MeOH in EtOAc. Fractions containing
the desired product were concentrated several times from EtOAc,
and then the material was redissolved in warm EtOAc and filtered.
The filtrate was concentrated, and then the white solid was
recrystallized from 1 mL of EtOAc. The solids were collected by
vacuum filtration and rinsed with additional EtOAc (3ꢂ0.3 mL) to
powder, mp 170.5e172.0 ꢀC. 1H NMR (600 MHz, CDCl3):
d 1.23 (m,
12H), 1.35 (d, J¼6.9 Hz, 6H), 1.83 (m, 2H), 2.07 (m, 1H), 2.26 (m, 2H),
2.88 (m, 1H), 3.15 (m, 1H), 3.22 (m, 1H), 3.98 (m, 1H), 4.05 (m, 2H),
7.08 (s, 2H). 13C NMR (150 MHz, CDCl3):
d 23.6, 24.0, 24.4, 25.7, 28.6,
30.8, 34.2, 46.9, 61.0, 122.8, 137.1, 148.7, 151.9, 176.3. Exact mass
calcd for C20H32N2O2SNa requires m/z 387.2077, found m/z
387.2087 (MþNaþ, ESI).
yield 0.52
g
(57%) of 14 as
a
white crystalline solid, mp
1.25 (m, 12H), 1.35 (d,
152.5e154.0 ꢀC. 1H NMR (600 MHz, CDCl3):
d
J¼6.9 Hz, 6H), 1.60 (m, 1H), 1.69 (m, 1H), 1.90 (m, 1H), 2.17 (m, 1H),
Compound 12. A solution of (S)-tert-butanesulfinamide (0.303 g,
2.50 mmol) in THF (10 mL) was added to a stirred suspension of KH
(0.105 g, 2.63 mmol) in THF (10 mL), resulting in the evolution of
hydrogen gas as the sulfinamide was deprotonated. The reaction
2.76 (m, 1H), 2.91 (m, 1H), 2.98 (m, 1H), 3.90 (m, 1H), 3.97 (m, 2H),
7.12 (s, 2H). 13C NMR (150 MHz, CDCl3):
d 23.6, 24.0, 24.4, 26.0, 28.5,
30.5, 34.2, 47.1, 60.8, 123.1, 136.0, 148.7, 152.8, 176.1. Exact mass
calcd for C20H32N2O2SNa requires m/z 387.2077, found m/z
387.2086 (MþNaþ, ESI).
mixture was stirred for 3 h at rt, providing a white slurry. (D)-Pro-
line methyl ester (3.0 mmol) was added via syringe, and the white
slurry dissolved within 3 min to provide a clear solution. After
30 min, the reaction was quenched by addition of acetic acid
(0.158 g, 2.63 mmol) and water (1 mL). The crude mixture was
concentrated to remove most of the THF, and the resulting white
precipitate was collected by vacuum filtration and then rinsed on
the filter with small amounts of water and Et2O. The crude product
was dissolved in 100 mL of hot EtOAc, and the resulting solution
was filtered twice to remove insoluble white solids. The filtrate was
concentrated, then recrystallized from approximately 5 mL of
EtOAc. The solids were collected by vacuum filtration and rinsed
with additional EtOAc, to yield 0.22 g (41%) of 12 as a white powder,
4.3. Representative procedure for catalyst screen (Scheme 1)
A reaction vial was equipped with a stir bar and charged with
catalyst 9 (4.4 mg, 0.020 mmol, 0.10 equiv), acetone (0.44 mL,
6.0 mmol, 30 equiv), water (18 mL, 1.0 mmol, 5 equiv), and DMSO-d6
(0.40 mL). After stirring for 15 min, a freshly prepared stock solu-
tion (0.40 mL) containing 4-nitrobenzaldehyde (0.20 mmol,
1.0 equiv) and 1,3,5-trimethoxybenzene (0.067 mmol, 0.33 equiv)
was added, and the vial was sealed with a cap. The resulting mix-
ture was stirred for 90 min, and then a 0.8 mL aliquot was trans-
ferred to an NMR tube and analyzed by 1H NMR. The conversion to
product was determined to be 91% by integration of the product
peak at 5.2 ppm relative to the trimethoxybenzene peak at 6.1 ppm.
No remaining aldehyde was observed. A second aliquot of the re-
mp 149.5e150.0 ꢀC. 1H NMR (500 MHz, CDCl3):
(m, 2H), 1.96 (m, 1H), 2.19 (m, 1H), 2.95 (m, 1H), 3.09 (m, 1H) 3.89
(m, 1H). 13C NMR (126 MHz, CDCl3):
22.1, 26.2, 30.8, 47.2, 56.1, 61.1,
d 1.25 (s, 9H), 1.75
d
176.5. IR (neat): 3651, 3368, 2981, 2888, 1566, 1298, 1270, 935,
599 cmꢁ1. Exact mass calcd for C9H18N2O2S requires m/z 219.1162,
found m/z 219.1162 (MþHþ, ESI).
action mixture (approx. 100 mL) was diluted with 1 mL of EtOAc and
washed with 1 mL of water. The organic layer was filtered through
a plug of silica, eluting with EtOAc and then concentrated. The ee of
this sample was determined to be 96% by chiral HPLC analysis
(Chiralpak AS-H, hexanes/iPrOH 70/30, 1 mL minꢁ1): tR (major)¼
12.6 min, tR (minor)¼16.3 min.
Compound 13. THF (10 mL) was added to a flask containing (S)-
toluenesulfinamide (0.388 g, 2.50 mmol) and KH (0.100 g,
2.50 mmol), resulting in the evolution of hydrogen gas as the sul-
finamide was deprotonated. The reaction mixture was stirred for
1.5 h at rt. (
D
)-Proline methyl ester (3.0 mmol) was added via sy-
4.4. General procedure for the preparation of products listed
in Scheme 2
ringe. After 2 h, the reaction was quenched by addition of acetic
acid (0.150 g, 2.50 mmol), and resulting mixture was stirred for
20 min. The crude mixture in THF was loaded onto a silica plug and
side products were eluted with 100% EtOAc. The mobile phase was
switched to 50:40:10 EtOAc:MeOH:NH4OH, resulting in rapid elu-
tion of the product. Fractions containing the desired product were
concentrated several times from EtOAc, and then the white solid
was dissolved in CH2Cl2 and filtered to remove a white solid
byproduct. The filtrated was concentrated and then recrystallized
from EtOAc. The solids were collected by vacuum filtration and
rinsed with additional EtOAc, to yield 0.21 g (34%) of 13 as a white
The aldehyde (1.0 mmol) was weighed into a reaction vial.
A freshly prepared stock solution containing catalyst 9 (0.20 mmol),
acetone (30.0 mmol), water (5.0 mmol), and DMSO (4.0 mL) were
added by mass, and then the vial was sealed with an airtight cap.
The mixture was stirred for the indicated amount of time. The re-
action mixture was diluted with EtOAc (40 mL), washed with water
(10 mL) and brine (10 mL), and then dried over Na2SO4, filtered, and
concentrated. The product was purified by silica gel chromatogra-
phy (EtOAc/Hexanes).
The ee of each product was determined by chiral HPLC analysis.
Authentic racemic standards for the HPLC analysis were synthe-
sized using pyrrolidine as a catalyst according to a literature
procedure.49
powder, mp 115.0e117.5 ꢀC. 1H NMR (600 MHz, CDCl3):
d
1.70 (m,
2H), 1.99 (m, 1H), 2.20 (m, 1H), 2.43 (s, 3H), 2.79 (m, 1H), 2.98 (m,
1H), 3.88 (m, 1H), 7.34 (d, J¼8.1 Hz, 2H), 7.59 (d, J¼8.1 Hz, 2H). 13C
NMR (150 MHz, CDCl3):
d 21.4, 26.1, 30.7, 47.1, 61.0, 124.6, 130.0,
141.3,142.2, 176.6. Exact mass calcd for C12H16N2O2SNa requires m/z
Compound 3a: The general procedure was followed using
4-nitrobenzaldehyde. After 3 h, 0.17 g (82%) of the desired product
was isolated. The ee of this sample was determined to be 96% by
chiral HPLC analysis (Chiralpak AS-H, hexanes/iPrOH 70/30,
1 mL minꢁ1): tR (major)¼11.7 min, tR (minor)¼15.3 min. The 1H
NMR is consistent with literature reports.22
275.0825, found m/z 275.0836 (MþNaþ, ESI).
Compound 14. A solution of (S)-(1,3,5)-triisopropylbenzene-
sulfinamide (0.669 g, 2.50 mmol) in THF (10 mL) was added to
a flask containing a suspension of KH (0.105 g, 2.63 mmol), resulting
in the evolution of hydrogen gas as the sulfinamide was