Yin et al.
NOTE
Scheme 1 Synthesis of thiepin and (S)-thiepin
the reaction mixture was stirred for 15 min. At the end
of the reaction, water (2 mL) was added to quench the
reaction, and the organic phase was extracted with ethyl
ether, washed with saturated brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure
to give a residue.
S
Br
Br
S
b
c
S
a
S
OHC
OHC
S
A mixture of Et3N (0.5 mL) in DCM (2 mL) was
added to the obtained residue and the mixture was
stirred for another 0.5 h at room temperature, then the
mixture was concentrated under reduced pressure and
purified on silica gel with hexane/EtOAc (V∶V=2∶1)
as eluent to give normal Baylis-Hillman products.
3-[Hydroxy-(4-nitro-phenyl)-methyl]-but-3-en-2-one
(9a): 1H NMR (CDCl3, 300 MHz) δ: 8.16 (d, J=8.7 Hz,
2H), 7.53 (d, J=8.7 Hz, 2H), 6.26 (s, 1H), 6.04 (s, 1H),
5.66 (s, 1H), 3.42 (br, 1H, OH), 2.33 (s, 3H); IR ν: 3480,
3076, 1662, 1523, 1346, 1049 cm−1.
1
2
Br
Br
S
Br
S
Br
Br
S
S
S
e
Br
d
Br
HOH2C
HOH2C
S
S
Br
5
3
4
Br
Br
Br
Br
g
S
f
h
S
2
HOH2C
HOOC
(S)-7
HOOC
S
S
HOH2C
3-[(4-Chloro-phenyl)-hydroxy-methyl]-but-3-en-2-
one (9b): 1H NMR (CDCl3, 300 MHz) δ: 7.32-7.28 (m,
5H), 6.21 (s, 1H), 5.99 (s, 1H), 5.59 (s, 1H), 3.21 (br,
1H, OH), 2.34 (s, 3H); IR ν: 3420, 1675, 1491, 1367,
1092 cm−1.
6
Br
Br
Br
S
S
Br
S
Br
i
S
Br
j
Br
HOH2C
HOH2C
S
S
S
1
3-(Hydroxy-phenyl-methyl)-but-3-en-2-one (9c): H
Br
(S)-5
(S)-3
(S)-4
NMR (CDCl3, 300 MHz) δ: 7.34-7.30 (m, 5H), 6.19 (s,
1H), 5.99 (s, 1H), 5.61 (s, 1H), 3.0 (br, 1H, OH), 2.33 (s,
3H); IR ν: 3444, 3061, 3031, 1674, 1628, 1454, 1020
cm−1.
3-[Hydroxy-(4-methoxy-phenyl)-methyl]-but-3-en-
2-one (9d): 1H NMR (CDCl3, 300 MHz) δ: 7.22 (d, J=
9.2 Hz, 2H), 6.80 (d, J=9.2 Hz, 2H), 6.12 (s, 1H), 5.93
(d, J=1.1 Hz, 1H), 5.51 (d, J=1.1 Hz, 1H), 3.73 (s,
3H), 2.94 (br, 1H, OH), 2.27 (s, 3H); IR ν: 3451, 2933,
1673, 1464, 1031 cm−1.
Reagents and conditions: (a) (i) Br2, HBr, Et2O; (ii) Zn, HOAc,
Et2O, reflux; (iii) n-BuLi, Et2O, −78 ℃, then CuCl2, Et2O, r.t.; (b) (i)
Br2, (ii) n-C4H9Li, Et2O, 0 ℃, then H2O; (iii) n-C4H9Li, Et2O, 0 ℃,
then DMF; (c) NaBH4, (CH3OCH2CH2)2O, r.t.; (d) PBr3, benzene,
reflux; (e) Na2S•H2O, ethanol, reflux; (f) KOH, reflux; (g) brucine,
1
95% ethanol, then 5 mol•L− HCl; (h) LiAlH4, AlCl3, Et2O, reflux; (i)
PBr3, benzene, reflux; (j) Na2S•H2O, CH3CN, reflux.
thiepin (S)-5 were synthesized from commercially
available thiophene according to reported procedures [4a]
.
3-Chloromethyl-4-(4-nitro-phenyl)-but-3-en-2-one
1
(10a): H NMR (CDCl3, 300 MHz) δ: 8.35 (d, J=8.8
Bromination of thiophene followed by reduction of
2,3,5-tribromothiophene and coupling reaction of
3-thiophen gave 3,3'-bithiophen (1) in large quantities.
Bromination and twice transmetallations led to 4,4'-di-
bromo-2,2'-diformyl-3,3'-bithienyl (2). Reduction, bro-
mination, and cyclization transferred 2 to thiepin 5. Fi-
nally, thiepin 5 was obtained in 30% yields after 9 steps.
In alternative, 2 was transferred to (S)-(−)-thiepin
through intramolecular Cammizzaro reaction, chiral
separation with brucine, reduction, bromination and
cyclization. Finally, optical active (S)-5 was obtained in
17% yields after 11 steps.
Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.70 (s, 1H), 4.38 (s,
2H), 2.55 (s, 3H); IR ν: 2919, 2849, 1668, 1519, 1347,
1271, 739, 694 cm−1.
3-Chloromethyl-4-(4-chloro-phenyl)-but-3-en-2-one
(10b): 1H NMR (CDCl3, 300 MHz) δ: 7.64 (s, 1H), 7.60
(d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 4.42 (s,
2H), 2.6 (s, 3H); IR ν: 3075, 2983, 1668, 1494, 719
cm−1.
3-Chloromethyl-4-phenyl-but-3-en-2-one (10c): 1H
NMR (CDCl3, 300 MHz) δ: 7.71 (s, 1H), 7.56-7.50 (m,
5H), 4.46 (s, 2H), 2.51 (s, 3H); IR ν: 3056, 1668, 1431,
1388, 700 cm−1.
(S)-1,9-Dibromo-4,6-dihydro-3,5,7-trithia-cyclopenta-
[e]azulene [(S)-5]: [α]19 −62.6 (c 0.36, dioxane); H
1
3-Chloromethyl-4-(4-methoxy-phenyl)-but-3-en-2-
one (10d): 1H NMR (CDCl3, 300 MHz) δ: 7.66 (s, 1H),
7.61 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.6 Hz, 2H), 4.50
(s, 2H), 3.88 (s, 3H), 2.50 (s, 3H); IR ν: 3003, 2837,
1659, 1604, 1509, 1483, 1177, 1030, 721 cm−1.
2-[Hydroxy-(4-nitro-phenyl)-methyl]-acrylonitrile
NMR (300 MHz, CDCl3) δ: 7.20 (s, 2H), 3.80 (d, J=
13.8 Hz, 2H), 3.38 (d, J=13.8 Hz, 2H); IR ν: 3107,
3099, 2912, 1210, 1089, 734 cm−1.
General procedures of Chalcogenide-Baylis-Hillman
reaction
1
(12a): H NMR (CDCl3, 300 MHz) δ: 8.26 (d, J=8.7
Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 6.20 (s, 1H), 6.12 (s,
1H), 5.46 (s, 1H), 2.95 (br, 1H, OH); IR ν: 3448, 3116,
3082, 2229, 1607, 1521, 1409, 1342, 1058 cm−1.
Thiepin 5 or (S)-5 (0.02 mmol), dry DCM (2 mL),
Lewis acid (0.2 mmol) and aldehyde (0.2 mmol) in dry
DCM (2 mL) were frequently added to a dry vial under
argon. Then active alkene (0.24 mmol) was added after
2-[Hydroxy-(4-nitro-phenyl)-methyl]-acrylic
acid
366
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 365—369