2
70
R. Cagnoli et al.
PAPER
4
5
.40 (dd, J = 3.1, 10.1 Hz, 1 H, CH ), 4.46–4.52 (br m, 1 H, CH),
.29 (br d, J = 6.5 Hz, 1 H, NH), 7.31–7.37 (m, 2 H, 3-H, 5-H of
2-(3-Thienyl)ethanethiol (4g)
The general procedure reported for the conversion of alcohols to
2
3
2
Ph), 7.73–7.79 (m, 2 H, 2-H, 6-H of Ph).
thiols via tosylate intermediate was followed. A solution of 2-(3-
thienyl)ethyl-4-methylbenzenesulfonate (5.00 g, 17.7 mmol), thio-
urea (1.35 g, 17.7 mmol) and water (0.7 g, 17.7 mmol) in anhyd
EtOH (10 mL) was refluxed under inert atmosphere for 5 h. Then a
solution of NaOH (1.00 g, 25.0 mmol) in water (12.5 mL) was add-
ed, and the mixture refluxed for 2 h. The reaction mixture was con-
centrated to approximately 5 mL, diluted with water (2 × 5 mL),
neutralized with HCl (37%), extracted with CH Cl (10 mL), dried
1
3
C NMR (100.61 MHz, CDCl ): d = 21.6 (CH Ph), 28.2 (CH of t-
3
3
3
Bu), 52.8 (CH O), 52.9 (CH), 69.4 (CH ), 80.4 (C-1 of t-Bu), 127.0
3
2
(
(
C-3, C-5 of Ph), 129.9 (C-2, C-6 of Ph), 132.4 (C-4 of Ph), 145.1
C-1 of Ph), 154.9 (C=ONH), 168.9 (C=O).
Anal. Calcd for C H NO S: C, 51.46; H, 6.21; N, 3.75; S, 8.59.
Found: C, 51.53; H, 6.29; N, 3.65; S, 8.68.
1
6
23
7
2
2
over Na SO and evaporated. A lacrimatory pale-yellow oil (2.12 g,
2
4
Methyl N-(tert-Butoxycarbonyl)-S-3-thienyl-L-cysteinate (1)
A solution of 3-mercaptothiophene (4d; 4.00 g, 34.5 mmol), methyl
N-(tert-butoxycarbonyl)-O-[(4-methylphenyl)sulfonyl]serinate (5;
8
3%) was obtained, pure enough to be immediately used in the next
reaction.
1
H NMR (400 MHz, CDCl ): d = 1.41 (t, J = 7.9 Hz, 1 H, SH), 2.77–
3
1
2.9 g, 34.5 mmol) and K CO (4.76 g, 34.5 mmol) in anhyd DMF
2 3
2
4
7
.81 (m, 2 H, CH SH), 2.94–2.98 (m, 2 H, CH Th), 6.95 (ddt, J =
2
2
(200 mL) was stirred at 35 °C under inert atmosphere for 1 h. The
.9, 1.3, 0.4 Hz, 1 H, 4-H), 7.02 (ddt, J = 3.0, 1.3, 0.7 Hz, 1 H, 2-H),
.28 (ddt, J = 4.9, 3.0, 0.4 Hz, 1 H, 5-H).
reaction mixture was washed with water (2 × 50 mL) and extracted
with Et O (3 × 70 mL). The combined organic phases were evapo-
2
1
3
rated and the crude product was chromatographed [silica gel, light
C NMR (100.61 MHz, CDCl ): d = 25.4 (CH SH), 34.7 (CH Th),
3
2
2
petroleum–Et O, (50:50)] to give compound 1 (5.54 g, 51%) as a
121.4 (C-2), 125.7 (C-5), 127.9 (C-4), 140.2 (C-3).
2
2
0
solid; mp 48–50 °C; [a]D –45.0 (c = 1.1 in DMSO); the enantio-
meric excess, determined on the trifluoroacetate derivative of 1, was
Anal. Calcd for C H S : C, 49.96; H, 5.59; S, 44.46. Found: C,
6
8 2
5
0.11; H, 5.64; S, 44.21.
9
8%.
1
H NMR (400 MHz, CDCl ): d = 1.42 (s, 9 H, t-Bu), 3.58 (s, 3 H,
Methyl N-(tert-Butoxycarbonyl)-S-[2-(3-thienyl)ethyl]-L-cys-
teinate (2)
3
OCH ), 3.20–3.27 (m, 2 H, CH ), 4.50–4.54 (br m, 1 H, CH), 5.34
3
2
(
(
br d, J = 6.2 Hz, 1 H, NH), 7.04 (dd, J = 4.9, 1.4 Hz, 1 H, 4-H), 7.27
dd, J = 3.0, 1.4 Hz, 1 H, 2-H), 7.30 (dd, J = 4.9, 3.0 Hz, 1 H, 5-H).
Method A: A solution of 2-(3-thienyl)ethyl 4-methylbenzene-
sulfonate (4f; 2.95 g, 10.4 mmol), methyl N-(tert-butoxycarbon-
+
yl)cysteinate (3; 2.45 g, 10.4 mmol) and K CO (1.44 g, 10.4 mmol)
2 3
in anhyd DMF (45 mL) was stirred at 40 °C, under inert atmosphere
MS (EI): m/z = 317 (48) [M ], 261 (32), 200 (96), 158 (26), 141(48),
1
29 (100), 115 (38), 102 (34), 88 (42), 71 (20), 57 (55).
for 17 h. The mixture was washed with water (2 × 10 mL), extracted
Anal. Calcd for C H NO S : C, 49.19; H, 6.03; N, 4.41; S, 20.20.
13
19
4
2
with Et O (2 × 10 mL) and evaporated. The crude product was pu-
2
Found: C, 49.3; H, 5.95; N, 4.49; S, 20.03.
rified by two silica gel chromatographies [100% CH Cl , and light
2
2
petroleum ether–Et O (50:50), respectively] to remove firstly the
2
2
-(3-Thienyl)ethanol (4e)
unreacted reagents, and then elimination and oxidation by-products,
3
1
According to the procedure described in ref. , 4e was obtained as a
colorless oil (2.60 g, 98%) from commercially available 3-thienyl-
acetic acid (3.00 g, 2.11 mmol); bp 67 °C/0.5 mmHg.
1
20
affording 2 (1.98 g, 55%) as a white solid; mp 45–47 °C; [a]D
–
16.1 (c = 1.1 in MeOH); the enantiomeric excess, determined on
the trifluoroacetate derivative of 2, was 98%.
H NMR (400 MHz, CDCl ): d = 1.61 (br s, 1 H, OH), 2.93 (br t,
1
3
H NMR (400 MHz, CDCl ): d = 1.45 (s, 9 H, t-Bu), 2.77–2.81 (m,
3
J = 6.4 Hz, 2 H, CH Th), 3.87 (t, J = 6.4 Hz, 2 H, CH OH), 7.01 (br
2
2
2 H, CH S), 2.90 (t, J = 7.6 Hz, 2 H, CH Th), 2.94–2.98 (m, 2 H,
2
2
dd, J = 5.0, 1.3 Hz, 1 H, 4-H), 7.08 (ddt, J = 3.0, 1.3, 0.9 Hz, 1 H,
2
CH Cy), 3.75 (s, 3 H, OCH ), 4.52–4.54 (br m, 1 H, CH), 5.33 (br
2
3
-H), 7.31 (br dd, J = 5.0, 3.0 Hz, 1 H, 5-H).
d, J = 6.0 Hz, 1 H, NH), 6.94 (ddt, J = 4.9, 1.3, 0.4 Hz, 1 H, 4-H),
7.02 (ddt, J = 3.0, 1.3, 0.7 Hz, 1 H, 2-H), 7.25 (ddt, J = 4.9, 3.0, 0.4
Hz, 1 H, 5-H).
1
3
C NMR (100.61 MHz, CDCl ): d = 33.6 (CH Th), 62.9 (CH O),
21.7 (C-2), 125.9 (C-5), 128.3 (C-4), 138.7 (C-3).
3
2
2
1
+
MS (EI): m/z = 345 (2) [M ], 289 (5), 272 (4), 235 (52), 228 (16),
Anal. Calcd for C H OS: C, 56.22; H, 6.29; S, 25.01. Found: C,
5
6
8
1
94 (21), 179 (23), 157 (16), 110 (100), 97 (42), 57 (96).
6.37; H, 6.18; S, 24.83.
Anal. Calcd for C H NO S : C, 52.15; H, 6.71; N, 4.05; S, 18.56.
Found: C, 52.23; H, 6.64; N, 4.15; S, 18.39.
1
5
23
4 2
2
-(3-Thienyl)ethyl 4-Methylbenzenesulfonate (4f)
2
1
Following the procedure described in ref. compound 4f (5.45 g
Method B: A solution of 3-(2-mercaptoethyl)thiophene (4g; 0.70 g,
7
5
1
3%) was obtained as a white solid from 4e (3.40 g, 26.5 mmol); mp
1–52 °C.
4
.85 mmol), methyl N-(tert-butoxycarbonyl)-O-[(4-methylphe-
nyl)sulfonyl]serinate (5; 1.81 g, 4.85 mmol) and K CO (0.67 g,
2
3
H NMR (400 MHz, CDCl ): d = 2.44 (s, 3 H, CH ). 2.99 (br t, J =
3
3
4.85 mmol) in anhyd DMF (35 mL) was stirred at 40 °C, under inert
6
4
.9 Hz, 2 H, CH Th), 4.21 (t, J = 6.9 Hz, 2 H, CH O), 6.87 (dd, J =
2
2
atmosphere, for 30 min. The mixture was washed with water (2 ×
.9, 1.2 Hz, 1 H, 4-H), 6.97 (ddt, J = 2.9, 1.2, 0.8 Hz, 1 H, 2-H), 7.23
1
0 mL), extracted with Et O (2 × 10 mL) and evaporated. The crude
2
(
dd, J = 4.9, 2.9 Hz, 1 H, 5-H), 7.29–7.33 (m, 2 H, 3-H, 5-H of Ph),
product (1.22 g), purified by silica gel chromatography [petroleum
7
.70–7.74 (m, 2 H, 2-H, 6-H of Ph).
ether–Et O (50:50)], afforded 2 (0.75 g, 45%), as a white solid; the
2
1
3
enantiomeric excess, determined on the trifluoroacetate derivative
C NMR (100.61 MHz, CDCl ): d = 21.6 (CH Ph), 29.8 (CH Th),
3
3
2
2
, was 13%.
6
1
1
9.9 (CH O), 122.1 (C-2 Th), 125.8 (C-5 Th), 127.8 (C-35 Ph),
2
28.0 (C-4 Th), 129.8 (C-26 Ph), 133.1 (C-4 Ph), 136.4 (C-3 Th),
44.7 (C-1 Ph).
Acknowledgment
Anal. Calcd for C H O S : C, 55.30; H, 5.00; S, 22.71. Found: C,
13
14
3 2
5
5.24; H, 4.85; S, 22.39.
The authors are very grateful to Centro Interdipartimentale Grandi
Strumenti of the University of Modena and Reggio Emilia for the
use of Bruker AMX400 and DPX200 spectrometers.
Synthesis 2005, No. 2, 267–271 © Thieme Stuttgart · New York