D.K. Monir and L.M. Harwood
Tetrahedron 84 (2021) 132035
available 2-amino-2-phenylethanol (five steps from the known N-
Boc-protected morpholinone 2). Attempts at improvement of this
in vacuo. The crude product was purified by column chromatog-
raphy, eluting with hexane e ethyl acetate (7 : 1) to give 4 (1.28 g,
ꢁ
1 1
developed pathway and the incorporation of
a
5-(4-
40%) as a yellow oil. IR (ATR):
NMR (400 MHz, CDCl 7.33e7.30 (5H, m, Ph), 5.54 (1H, t,
J ¼ 8.0 Hz, PhCH), 3.79 (1H, d, J ¼ 16.0 Hz, CH N), 3.61 (3H, s, OCH ),
.56 (1H, app d, J ¼ 16.0 Hz, CH N), 3.44e3.38 (2H, bm, CH S), 2.33
(3H, s, CH COS), 1.44 (9H, bs, t-butyl). C NMR (500 MHz, CDCl ):
95.4, 170.7, 154.9, 152.9, 129.0, 128.1, 126.2, 81.7, 72.4, 70.6, 69.8,
28.4, 25.3, 21.9. HRMS calcd for C18 S: 368.1532 and
nmax 3029, 2977, 1756, 1690 cm . H
methoxyphenyl) group on the thiomorpholinone system are
ongoing.
3
) d
2
3
3
2
2
13
4
. Experimental section
3
3
1
4.1. General procedure
H26NO
5
þ
C
18
H
25NO
5
a
SNa: 390.1351, found 368.1524 [MH ] and 390.1346
þ
20
All chemicals and reagents were purchased from Sigma-Aldrich,
(MNa ). [
]
D
ꢁ 10.4 (c 0.3, CHCl
3
).
Alfa Aesar and Tokyo Chemical Industries. Acetonitrile was dried
over 4 Å molecular sieves and tetrahydrofuran was dried by
4.4. Synthesis of (S)eN-(tert-butoxycarbonyl)-N-(2-mercapto-1-
phenylethyl)glycine (5)
1
distillation from sodium benzophenone ketyl. All H NMR spectra
were recorded either at 400 MHz on a Bruker Avance DPX400
1
3
spectrometer or at 500 MHz on a Bruker AVIII500 spectrometer.
NMR spectra were recorded at 100 MHz on the first spectrometer.
NMR solvents used were chloroform-d and dimethyl sulfoxide-d
Spectra are reported on the scale referenced to tetramethylsilane
TMS). The abbreviations s, d, t, m, dd, br, app are used to denote
C
To a solution of 4 (1.16 g, 3.16 mmol, 1.0 equiv) in i-PrOH
(80.0 mL) was added dropwise a solution of lithium hydroxide
(531 mg, 12.6 mmol, 4.0 equiv) in water (50.0 mL) at room tem-
perature under an atmosphere of nitrogen. The reaction mixture
was then stirred at room temperature overnight. Water (50.0 mL)
was then added and the pH of the mixture was adjusted to pH 5
with 1 M HCl. The aqueous mixture was extracted with ethyl ace-
tate (3 ꢂ 100 mL) and the combined organic extracts were dried
6
.
d
(
singlet, doublet, triplet, multiplet, double doublet, broad and
apparent respectively. Infrared spectra were recorded on a Perki-
ꢁ
1
nElmer spectrometer in the frequency range 4000e400 cm . Mass
spectrometry and accurate mass measurements (HRMS) were
determined on a Thermo Scientific LTQ-Orbitrap-XL mass spec-
trometer using electrospray ionization (ESI). Specific rotations were
determined on a PerkinElmer polarimeter at the sodium D line
2 4
over Na SO , filtered and concentrated in vacuo. Purification by
column chromatography, eluting with hexane - ethyl acetate -
formic acid (4 : 1: 0.01) afforded 5 (684 mg, 69%) as a yellow oil. IR
ꢁ1 1
(ATR):
DMSO‑d
3.63 (1H, d, J ¼ 17.5 Hz, CH
(2H, bm, CH SH), 1.37 (9H, bs, t-butyl). C NMR (500 MHz, CDCl
173.4, 154.6, 137.7, 129.0, 128.4, 127.7, 81.3, 61.1, 45.3, 29.8, 28.4.
n
max 3494, 3034, 2977, 1732, 1686 cm . H NMR (400 MHz,
7.35e7.27 (5H, m, Ph), 5.28 (1H, t, J ¼ 8.0 Hz, PhCH),
N), 3.55 (1H, d, J ¼ 17.5 Hz, CH N), 3.09
):
(
589 nm). Melting points were determined with a Büchi melting
6
) d
point apparatus. Thin layer chromatography (TLC) analyses were
performed using 0.25 mm thick silica gel 60 F254 plates in the
appropriate solvent system. Compound visualization was carried
out using a UV source at 254 nm and by staining with potassium
permanganate solution. Column chromatography was conducted
either using silica gel 60 (230e400 mesh).
2
2
13
2
3
HRMS calcd for
334.1089, found 312.1264 (MH ) and 334.1084 (MNa ).
C
15
H
22NO
4
S: 312.1270 and
C
15
H
21NO
4
SNa:
þ
þ
4.5. Synthesis of tert-butyl (S)-2-oxo-5-phenylthiomorpholine-4-
4.2. Synthesis of methyl (S)eN-(tert-butoxycarbonyl)-N-(2-
carboxylate (6)
hydroxy-1-phenylethyl)glycinate (3)
DCC (452 mg, 2.19 mmol, 1.1 equiv) was added to a solution of 5
To a solution of Et
50.0 mL) was added a solution of 2 (3.19 g, 11.5 mmol, 1.0 equiv) in
3
N (6.99 g, 69.1 mmol, 6.0 equiv) in MeOH
(620 mg, 1.99 mmol, 1.0 equiv) in dichloromethane (50.0 mL) and
the reaction mixture was stirred at 0 C for 15 min. DMAP (267 mg,
ꢀ
(
MeOH (5.00 mL). The reaction mixture was stirred for 24 h and then
concentrated in vacuo to give a crude product that was purified over
silica eluting with petroleum ether e diethyl ether (1 : 2) to afford
2.19 mmol, 1.1 equiv) was then added and the mixture was left
overnight at room temperature. Dicyclohexylurea, formed as a
white precipitate, was removed by filtration, the filtrate was
concentrated under reduced pressure and the residue purified over
silica, eluting with hexane e ethyl acetate (4 : 1) giving 6 (322 g,
ester 3 (2.72 g, 76%) as a colourless oil. IR (ATR):
2
(
n
max 3486, 3032,
978, 1762, 1698 cm . H NMR (400 MHz, DMSO‑d 7.40e7.24
5H, m, Ph), 5.22 (1H, app t, J ¼ 8.0 Hz, PhCH), 4.87e4.81 (2H, m,
CH OH), 3.91e3.84 (2H, m, CH N), 3.58 (3H, s, OCH ), 1.35 (9H, bs, t-
butyl). C NMR (100 MHz, DMSO‑d ): 170.9, 154.3, 138.6, 128.1,
27.7, 126.0, 79.4, 60.6, 51.6, 45.5, 27.7. HRMS calcd for C16
ꢁ
1 1
6
) d
55%) as pale yellow oil. IR (ATR):
n
max 3029, 2980, 1697, 1391,
ꢁ
1 1
ꢀ
2
2
3
1156 cm . H NMR (500 MHz, DMSO‑d
6
, 85 C)
d
7.35 (5H, m, Ph),
N),
S), 1.26
): 200.2, 154.7, 142.8,
129.0, 128.1, 126.5, 80.8, 58.1, 51.6, 28.2. HRMS calcd for
13
6
d
5.14 (1H, app t, J ¼ 7.0 Hz, PhCH), 4.52 (1H, d, J ¼ 16.0 Hz, CH
4.33 (1H, d, J ¼ 16.0 Hz, CH N), 3.57 (2H, br d, J ¼ 7.0 Hz, CH
(9H, s, t-butyl). C NMR (500 MHz, DMSO‑d
2
1
H
24NO
5
:
2
2
þ
13
3
3
10.1654 and C16
32.1468 (MNa ).
5
H23NO Na: 332.1474, found 310.1649 (MH ) and
6
þ
þ
20
C
15
H19NO
3
SNa: 316.0983, found 316.0978 (MNa ). [
a
]
D
ꢁ 38.2 (c
4.3. Synthesis of methyl (S)eN-(2-(acetylthio)-1-phenylethyl)-N-
0.3, CHCl ).
3
(
tert-butoxycarbonyl)glycinate (4)
4.6. Synthesis of (S)-5-phenylthiomorpholin-2-one (1)
DIAD (3.49 g, 17.3 mmol, 2.0 equiv) was added dropwise to a
solution of triphenylphosphine (4.53 g, 17.3 mmol, 2.0 equiv) in dry
tetrahydrofuran (100 mL) under an atmosphere of nitrogen at 0 C
for 30 min. A milky white mixture resulted. A solution of 3 (2.67 g,
To a solution of 6 (300 mg, 1.02 mmol, 1.0 equiv) in dichloro-
ꢀ
ꢀ
methane (5.00 mL) was added TFA (5.00 mL) at 0 C and the
mixture stirred at room temperature for 2 h. The reaction was
monitored by TLC until the starting material was consumed. The
resulting mixture was evaporated in vacuo, redissolved in
dichloromethane (5.00 mL), washed with saturated aqueous
8
.64 mmol, 1.0 equiv) and thiolacetic acid (1.32 g, 17.3 mmol, 2.0
equiv) in dry tetrahydrofuran (25.0 mL) was then added dropwise
ꢀ
and the stirring was continued for 1 h at 0 C and the mixture then
left overnight at room temperature resulting in a clear yellow so-
lution. Ether (25.0 mL) was added and the solution was washed
NaHCO
MgSO , filtered and concentrated under reduced pressure to give 1
as a yellow oil (160 mg, 81%). IR (ATR):
3
(2.00 mL) and brine (2.00 mL), dried over anhydrous
4
ꢁ1
with water (50.0 mL), dried over Na
2
SO
4
, filtered and concentrated
nmax 3320, 2931, 1664 cm .
4