Synthesis of thiophene derivatives on soluble polymer-support using Gewald reaction

Article abstract of DOI:10.1055/s-2004-834895

A variety of thiophene derivatives have been synthesized using poly(ethylene glycol) (PEG) as soluble polymer support. PEG reacted with cyanoacetic acid, DCC and DMAP in CHCl₃ under microwave irradiation to give PEG-bound cyanoacetic ester 1. A mixture of 1, elemental sulfur, DIPEA and 2 carried out Gewald reaction under microwave irradiation to afford 3, which was acylated and treated with 1% KCN in methanol to give thiophene derivatives 6. This synthetic method is simple and mild, and the yields are moderate to high.

Full text of DOI:10.1055/s-2004-834895

PAPER
3055
Synthesis of Thiophene Derivatives on Soluble Polymer-Support Using
Gewald Reaction
Synthesis of
T
hiop
a
hene
D
eriv
i
ative
s
o
q
n
Soluble Po
i
lymer-
n
S
upport g Zhang, Guichun Yang,* Jianian Chen, Zuxing Chen
Faculty of Chemistry and Material Science, Hubei University, Wuhan, Hubei, 430062, P. R. China
E-mail: +86(27)88663043; E-mail: ygc33@163.net
Received 24 May 2004; revised 13 September 2004
difficulty of monitoring the reaction progress and config-
uration of polymer-bound products.
Abstract: A variety of thiophene derivatives have been synthesized
using poly(ethylene glycol) (PEG) as soluble polymer support. PEG
reacted with cyanoacetic acid, DCC and DMAP in CHCl3 under mi-
crowave irradiation to give PEG-bound cyanoacetic ester 1. A mix-
ture of 1, elemental sulfur, DIPEA and 2 carried out Gewald
reaction under microwave irradiation to afford 3, which was acylat-
ed and treated with 1% KCN in methanol to give thiophene deriva-
tives 6. This synthetic method is simple and mild, and the yields are
moderate to high.
Due to emerging problems associated with the heteroge-
neous nature of the ensuing chemistry with ‘on-bead’
spectroscopic characterization,11 soluble polymers as an
alternative matrix have been widely applied in organic
synthesis.13–15 Liquid-phase synthetic approaches using
soluble polymer coupled the advantages of homogeneous
solution chemistry (high reactivity, lack of diffusion phe-
nomena and ease of analysis) with those of solid-phase
methods (use of excessive reagents, easy isolation and pu-
rification of products). Poly(ethylene glycol) (PEG) is
amongst the most studied soluble polymer in organic syn-
thesis,15,16 which is directly linked to its broad solubility in
most organic solvents such as DMF, dichloromethane, ac-
etonitrile and toluene. But it has a strong tendency to pre-
cipitate in certain solvents such as diethyl ether, isopropyl
alcohol and cold ethanol; hence separation of the func-
tionalized matrix could be achieved by solvent precipita-
tion, and membrane filtration.
Key words: thiophene derivatives, synthesis, Gewald reaction, sol-
uble polymer-support, microwave
The core structure of polysubstituted thiophene is not only
used as novel conducting polymers and dyes in industry,1,2
but also found in natural products.3 It is a more important
factor for the extensive potential in medicinal chemistry
and as a starting point for syntheses of a variety of biolog-
ical targets.4–8 Thus, the Gewald synthesis of highly sub-
stituted thiophene has attracted increasing interest since
originally published in 1961 by Gewald.9
The synergistic application of microwave irradiation in
chemical reaction enhancement is useful for high reaction
rates and formation of cleaner products.17,18
However, the most of published Gewald synthesis of
thiophene require long reaction times for the condensation
step and the purification of products for further modifica-
tion is difficult.2,3,10,11 Recently, Hoener and co-workers
reported the Gewald’s synthetic approach to thiophenes
using insoluble polymer as support,12 which shortened the
reaction time and simplified the procedure of product pu-
rification. However, there are some drawbacks such as
Having the above facts in mind, and as a part of our con-
tinuing efforts to utilize soluble polymer-supported sys-
tems in organic synthesis,19–21 we report herein the new
synthetic approach of thiophene derivatives on soluble
support PEG under microwave irradiation using Gewald
reaction as shown in Scheme 1.
O
R1
O
R2
R1
R2
O
(2)
, S8
NCCH2COOH
O
OCCH2CN
OH
DCC, DMAP
CHCl3, 130 W
DIPEA, 130W
NH2
S
PEG
1
3
O
O
O
R1
R2
R1
R2
R3COCl
DIPEA
OCH3
1% KCN/ CH3OH
R3
r.t.
(4 )
R3
N
S
, 0 °C to r.t.
N
S
H
H
O
O
6
5
6
1 : R3= CH3; 62: R3=Ph
Scheme 1
SYNTHESIS 2004, No. 18, pp 3055–3059
x
x.
x
x
.
2
0
0
4
Advanced online publication: 26.10.2004
DOI: 10.1055/s-2004-834895; Art ID: F07204SS
© Georg Thieme Verlag Stuttgart · New York

3056
H. Zhang et al.
PAPER
Table 1 Synthesis of Thiophene Derivatives Using PEG as Soluble
Polymer Support
Considering the balance between the loading capacity and
the solubility profile of the resulting polymer derivatives,
we chose PEG of molecular weight 3400 as support. As
shown in Scheme 1, PEG reacted with an excess of cyano-
acetic acid in the presence of dicyclohexylcarbodiimide
(DCC) and a catalytic amount of 4-dimethylaminepyri-
dine (DMAP) in CHCl3 under microwave irradiation for 5
minutes to give PEG-bound cyanoacetic ester 1 through
ester linkage. The disappearance of absorption for the hy-
droxy group at 3469 cm–1 and the appearance of ester car-
bonyl and cyano group at 1748 and 2197 cm–1 in the IR
spectrum are clear evidences for the formation of 1. Ge-
wald reactions were carried out in a microwave oven, in
which 1, elemental sulfur, diisopropylethylamine
(DIPEA) and various aldehydes, ketones or 1,3-dicabonyl
compounds 2 were added to a flask and irradiated under
solvent-free condition for 15 min to give 3. The comple-
tion of the reaction was evidenced by the disappearance of
cyano group and the appearance amino at 3426 and 3320
cm–1 in the IR spectrum of the product. Compound 3 was
acylated with acetyl chloride or benzoyl chloride in pres-
ence of DIPEA in CH2Cl2 at 0 °C to room temperature to
give the PEG-bound product 5. Treatment of 5 with 1%
KCN in methanol resulted in a very efficient cleavage
from PEG support to provide the corresponding crude
product 6, which was purified by chromatography. The
overall yields were based on the loading capacity of PEG.
Entry
R1
R2
Yield (%)a
61
62
a
b
c
d
e
f
H
CH3CH2
CH3(CH2)3
CH3(CH2)4
(CH3)2CH
CH3
73
81
72
65
50
53
51
48
84
79
70
38
86
91
84
78
63
66
67
60
95
92
85
45
H
H
H
CH3
CH3
CH3CH2
CH3
(CH2)3
(CH2)4
(CH2)5
CH3
CH3CH2
CH3
g
h
i
CH3CO
j
k
l
CO2CH2CH3
a 61: R3 = CH3; 62: R3 = Ph.
All organic solvents and bases were dried by standard methods.
PEG and PEG-bound compounds were melted at 80 °C in vacuum
for 30 min before use to remove traces of moisture. IR spectra were
recorded on an IR-spectrum one (PE) spectrometer, 1H NMR (600
MHz) and 13C NMR (150 MHz) spectra were recorded on a Varian
Unity INOVA 600 spectrometer in CDCl3 using TMS as internal
standard. Elemental analyses were done on a PE 2400 CHN analyz-
er. Melting points were measured on a WRS-1A digital melting
point apparatus and uncorrected. The microwave irridiation was
performed in a 100 mL rockered glass flask equipped with mechan-
ical stirrer and condenser in a SANLE WP 650W (Sanle General
Electric Corp. Nanjing, P. R. China) microwave oven.
The reaction can be easily carried out and there is an evi-
dent improvement in yield and reaction time by using mi-
crowave technology. Compared to conventional liquid
synthesis methods, the PEG-bound intermediates were
easily isolated and purified by simple precipitation, filtra-
tion, and washing with Et2O to remove the unreacted ma-
terials and low molecular by-products, which could be
detected using TLC. 1H NMR and IR could be used readi-
ly to analyze the configuration of PEG-bound intermedi-
ates and products without detaching material from the
polymer-supports in each step of the sequences in contrast
to insoluble polymers as polymer-supports.
PEG-Supported Cyanoacetic Ester 1
Cyanoacetic acid (0.85 g, 10 mmol), DCC (4.13 g, 20 mmol), and
DMAP (0.12 g, 1 mmol) were added to a solution of PEG (6.00 g,
0.58 mmol/g) in CHCl3 (50 mL). The mixture was irradiated with
microwave under stirring for 5 min at a power of 130 W under N2.
The mixture was cooled to r.t. and filtered to remove the urea. The
filtrate was concentrated and the residue was precipitated with cold
Et2O. The precipitate was then collected on a sintered glass funnel
and thoroughly washed with cold Et2O (3 × 100 mL) and dried un-
der vacuum to give PEG-supported cyanoacetic ester 1 (6.23 g, ca.
100%).
To establish the scope of this reaction, a variety of ke-
tones, aldehydes and 1,3-dicarbonyl compounds were in-
vestigated. Aldehydes and cyclic ketones gave good
results. Chain aliphatic ketones and ethyl acetoacetate re-
sulted in slightly less products than aldehydes and cyclic
ketones. One failed example was benzophenone, which
gave no desired product. And the acetyled yields of ben-
zoyl chloride are obviously higher than acetyl chloride.
The stepwise formation of a variety of thiophene deriva-
tives were illustrated in Scheme 1 and the results are pre-
sented in Table 1.
IR (KBr): 2197 (C≡N), 1748 (C=O) cm–1.
1H NMR: d = 3.34 (s, 2 H, CH2CN), 3.56–3.70 (m).
In summary, we have successfully combined the advan-
tages of microwave technology with liquid phase chemis-
try to facilitate rapid syntheses of thiophene derivatives.
As shown in the experiment results, this method is simple,
the reaction conditions are mild and the yields are moder-
ate to high.
PEG-Supported Thiophenes 3; General Procedure
The appropriate carbonyl compound 2 (4 mmol), elemental sulfur
(0.13 g, 4 mmol) and DIPEA (0.05 mL, 0.3 mmol) were added to
dried compound 1 (2.00 g). The mixture was irradiated with micro-
wave under solvent-free condition for 15 min at a power of 130 W
under N2. The resulting mixture was cooled to r.t. and dissolved in
CH2Cl2 (30 mL) and filtered to remove the excess of sulfur. The fil-
trate was concentrated and precipitated with cold Et2O (3 × 30 mL).
Synthesis 2004, No. 18, 3055–3059 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiophene Derivatives on Soluble Polymer-Support
3057
Then, the solid precipitate was dried under vacuum to afford the re-
spective PEG-supported thiophene 3.
13C NMR: d = 22.81, 25.12 (2 C), 34.89, 51.46, 111.58, 119.46,
135.83, 147.23, 165.72, 167.00.
Anal. Calcd for C11H15NO3S: C, 54.75; H, 6.27; N, 5.80. Found: C,
54.89; H, 6.10; N, 5.63.
Thiophene Derivatives 6; General Procedure
A solution of acid chloride 4 (6 mmol) in CH2Cl2 (15 mL) was add-
ed dropwise to a solution of 3 (2.00 g) and DIPEA (0.17 mL, 1
mmol) in CH2Cl2 (30 mL) at 0 °C and the mixture was stirred at r.t.
for 3 h. The resulting mixture was washed with H2O and the aque-
ous phase was back-extracted with CH2Cl2 (3 × 30 mL). The com-
bined organic layers were washed with 10% NaHCO3 until pH 7,
dried (MgSO4), filtered, concentrated and precipitated with cold
Et2O. The precipitate was filtered, washed with cold Et2O (3 × 30
mL) and dried under vacuum to afford 5, which was treated with 1%
KCN in MeOH at r.t. for overnight. After evaporation of MeOH, the
residue was redissolved in CH2Cl2 (3 mL), the detached PEG was
precipitated by adding cold Et2O and was removed by filtration.
Then, the combined filtrate was evaporated to give crude thiophene
derivatives, which were purified by column chromatography on sil-
ica gel [EtOAc–petroleum ether (bp 60–90 °C), 1:4] to give desired
pure product 6.
61e
Mp 93.6–94.6 °C.
IR (KBr): 3276 (NH), 1667 cm–1 (C=O).
1H NMR: d = 2.26 (m, 9 H), 3.90 (s, 3 H, CO2CH3), 11.02 (s, 1 H,
NH).
13C NMR: d = 12.84, 14.74, 24.18, 51.93, 112.66, 121.75, 128.19,
147.51, 166.90, 167.16.
Anal. Calcd for C10H13NO3S: C, 52.85; H, 5.77; N, 6.16. Found: C,
52.57; H, 5.89; N, 6.33.
61f
Mp 90.8–92.2 °C.
IR (KBr): 3263 (NH), 1675 cm–1 (C=O).
1H NMR: d = 1.26 (t, 3 H, J = 7.5 Hz), 2.26 (m, 6 H), 2.71 (m, 2 H),
61a
3.89 (s, 3 H, CO2CH3), 10.98 (s, 1 H, NH).
Mp 52.3–53.1 °C.
IR (KBr): 3280 (NH), 1672 cm–1 (C=O).
1H NMR: d = 1.28 (t, 3 H, J = 7.2 Hz), 2.27 (s, 3 H, COCH3), 2.73
(m, 2 H), 3.86 (s, 3 H, CO2CH3), 6.85 (s, 1 H, =CHthiophene), 10.85 (s,
1 H, NH).
13C NMR: d = 13.96, 15.67, 22.63, 29.30, 51.51, 112.20, 127.78,
139.28, 147.02, 166.98, 167.15.
Anal. Calcd for C11H15NO3S: C, 54.75; H, 6.27; N, 5.80. Found: C,
54.93; H, 6.46; N, 5.60.
13C NMR: d = 15.30, 22.58, 23.33, 51.40, 111.39, 118.62, 136.75,
146.88, 165.80, 166.68.
61g
Mp 88.1–88.8 °C.
Anal. Calcd for C10H13NO3S: C, 52.85; H, 5.77; N, 6.16. Found: C,
52.75; H, 5.61; N, 6.24.
IR (KBr): 3278 (NH), 1666 cm–1 (C=O).
1H NMR: d = 1.29 (t, 3 H, J = 7.5 Hz), 2.34 (s, 3 H), 2.27 (s, 3 H,
COCH3), 2.70 (m, 2 H), 3.86 (s, 3 H, CO2CH3), 11.08 (s, 1 H, NH).
13C NMR: d = 11.96, 14.75, 21.10, 23.63, 51.39, 111.30, 123.13,
135.14, 147.26, 166.84, 166.86.
61b
Mp 49.8–50.5 °C.
IR (KBr): 3287 (NH), 1677 cm–1 (C=O).
1H NMR: d = 0.92 (t, 3 H, J = 7.5 Hz), 1.36 (m, 2 H), 1.63 (m, 2 H),
2.70 (t, 2 H, J = 7.5 Hz), 2.27 (s, 3 H, COCH3), 3.86 (s, 3 H,
CO2CH3), 6.84 (s, 1 H, =CHthiophene), 10.86 (s, 1 H, NH).
13C NMR: d = 13.66, 21.94, 23.39, 28.98, 33.17, 51.46, 111.47,
119.41, 135.33, 147.00, 165.89, 166.75.
Anal. Calcd for C11H15NO3S: C, 54.75; H, 6.27; N, 5.80. Found: C,
54.89; H, 6.46; N, 5.94.
61h
Mp 87.3–88.4 °C.
IR (KBr): 3284 (NH), 1663 cm–1 (C=O).
1H NMR: d = 2.26 (m, 6 H), 2.60 (s, 3 H), 3.86 (s, 3 H, CO2CH3),
10.95 (s, 1 H, NH).
Anal. Calcd for C12H17NO3S: C, 56.45; H, 6.71; N, 5.49. Found: C,
56.59; H, 6.42; N, 5.60.
13C NMR: d = 14.11, 22.68, 29.64, 51.81, 112.78, 116.12, 123.71,
134.36, 163.65, 166.38, 167.20.
61c
Mp 68.9–69.5 °C.
IR (KBr): 3289 (NH), 1673 cm–1 (C=O).
Anal. Calcd for C11H13NO4S: C, 51.75; H, 5.13; N, 5.49. Found: C,
51.58; H, 5.30; N, 5.31.
1H NMR: d = 0.90 (t, 3 H, J = 6.3 Hz), 1.30 (m, 4 H), 1.67 (m, 2 H),
2.27 (s, 3 H, COCH3), 2.71 (t, 2 H, J = 7.5 Hz), 3.86 (s, 3 H,
CO2CH3), 6.82 (s, 1 H, =CHthiophene), 10.93 (s, 1 H, NH).
13C NMR: d = 13.86, 22.26, 23.37, 29.28, 30.76, 31.04, 51.43,
111.44, 119.38, 135.36, 147.01, 165.87, 166.69.
61i
Mp 131.2–132.0 °C.
IR (KBr): 3276 (NH), 1671 cm–1 (C=O).
1H NMR: d = 2.35 (s, 3 H, COCH3), 2.36 (m, 2 H), 2.82 (t, 2 H,
J = 6.9 Hz), 2.88 (t, 2 H, J = 6.9 Hz), 3.86 (s, 3 H, CO2CH3), 10.95
(s, 1 H, NH).
Anal. Calcd for C13H19NO3S: C, 57.97; H, 7.11; N, 5.20. Found: C,
57.76; H, 6.85; N, 5.31.
13C NMR: d = 23.58, 27.92, 28.82, 30.20, 51.49, 107.65, 132.17,
141.01, 151.71, 166.53, 166.80.
61d
Mp 70.3–70.9 °C.
IR (KBr): 3283 (NH), 1675 cm–1 (C=O).
Anal. Calcd for C11H13NO3S: C, 55.21; H, 5.48; N, 5.85. Found: C,
55.51; H, 5.25; N, 5.64.
1H NMR: d = 1.28 (d, 6 H, J = 4.8 Hz), 2.28 (s, 3 H, COCH3), 2.35
(m, 1 H), 3.90 (s, 3 H, CO2CH3), 6.37 (s, 1 H, = CHthiophene), 10.96
(s, 1 H, NH).
61j
Mp 115.4–116.0 °C.
IR (KBr): 3251 (NH), 1658 cm–1 (C=O).
Synthesis 2004, No. 18, 3055–3059 © Thieme Stuttgart · New York

3058
H. Zhang et al.
PAPER
1H NMR: d = 1.78 (m, 4 H), 2.26 (s, 3 H, COCH3), 2.63 (t, 2 H,
J = 5.7 Hz), 2.75 (t, 2 H, J = 5.7 Hz), 3.86 (s, 3 H, CO2CH3), 11.23
(s, 1 H, NH).
13C NMR: d = 13.89, 22.31, 29.39, 30.80, 31.08, 51.62, 112.22,
119.71, 127.35 (2 C), 128.86 (2 C), 132.12, 132.48, 135.83, 147.49,
163.27, 166.31.
13C NMR: d = 22.77, 22.94, 23.71, 24.29, 26.26, 51.36, 111.04,
126.62, 130.54, 147.76, 166.91, 167.09.
Anal. Calcd for C18H21NO3S: C, 65.23; H, 6.39; N, 4.23. Found: C,
65.38; H, 6.19; N, 4.04.
Anal. Calcd for C12H15NO3S: C, 56.90; H, 5.97; N, 5.53. Found: C,
56.74; H, 5.82; N, 5.71.
62d
Mp 86.7–87.6 °C.
61k
IR (KBr): 3274 (NH), 1664 cm–1 (C=O).
Mp 106.7–107.3 °C.
IR (KBr): 3287 (NH), 1677 cm–1 (C=O).
1H NMR: d = 1.60 (m, 2 H), 1.64 (m, 2 H), 1.84 (m, 2 H), 2.25 (s, 3
H, COCH3), 2.70 (t, 2 H, J = 5.4 Hz), 2.99 (t, 2 H, J = 5.1 Hz), 3.86
(s, 3 H, CO2CH3), 11.15 (s, 1 H, NH).
1H NMR: d = 1.30 (m, 6 H), 2.39 (m, 1 H), 3.95 (s, 3 H, CO2CH3),
7.52 (m, 2 H, ArH), 7.59 (m, 1 H, ArH), 8.02 (d, 2 H, J = 7.8 Hz,
ArH), 12.01 (s, 1 H, NH).
13C NMR: d = 25.41 (2 C), 35.02, 51.70, 112.21, 120.23, 127.36 (2
C), 128.87(2 C), 132.11, 132.64, 135.98, 147.15, 163.46, 167.52.
13C NMR: d = 24.11, 27.47, 28.20, 28.62, 29.03, 32.67, 51.95,
112.85, 131.27, 136.52, 146.16, 167.33, 167.59.
Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C,
63.51; H, 5.75; N, 4.49.
Anal. Calcd for C13H17NO3S: C, 58.40; H, 6.41; N, 5.24. Found: C,
58.62; H, 6.22; N, 5.46.
62e
Mp 101.8–102.3 °C.
61l
IR (KBr): 3269 (NH), 1665 cm–1 (C=O).
Mp 87.8–89.1 °C.
IR (KBr): 3278 (NH), 1662 cm–1 (C=O).
1H NMR: d = 1.35 (t, 3 H), 2.26 (m, 6 H), 3.88 (s, 3 H, CO2CH3),
4.18 (m, 2 H), 10.96 (s, 1 H, NH).
13C NMR: d = 14.35, 16.00, 23.74, 51.02, 60.38, 108.31, 112.76,
134.76, 147.89, 162.82, 166.16, 166.45.
1H NMR: d = 2.26 (s, 3 H), 2.30 (s, 3 H), 3.93 (s, 3 H, CO2CH3),
7.53 (m, 2 H, ArH), 7.59 (m, 1 H, ArH), 8.04 (d, 2 H, J = 7.8Hz,
ArH), 12.32 (s, 1 H, NH).
13C NMR: d = 12.39, 14.26, 51.57, 111.62, 123.59, 127.37 (2 C),
128.93 (2 C), 132.40, 132.52, 141.29, 147.13, 163.40, 167.44.
Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84. Found: C,
62.43; H, 5.07; N, 4.73.
Anal. Calcd for C12H15NO5S: C, 50.52; H, 5.30; N, 4.91. Found: C,
50.65; H, 5.13; N, 5.12.
62f
Mp 99.7–100.5 °C.
IR (KBr): 3258 (NH), 1663 cm–1 (C=O).
62a
Mp 62.5–63.0 °C.
IR (KBr): 3280 (NH), 1664 cm–1 (C=O).
1H NMR: d = 1.27 (t, 3 H, J = 9.6 Hz), 2.29 (s, 3 H), 2.73 (m, 2 H),
3.94 (s, 3 H, CO2CH3), 7.53 (m, 2 H, ArH), 7.59 (m, 1 H, ArH), 8.02
(d, 2 H, J = 7.2 Hz, ArH), 12.32 (s, 1 H, NH).
13C NMR: d = 13.98, 15.65, 33.23, 51.99, 112.47, 127.34, 128.27 (2
C), 129.48 (2 C), 130.08, 132.82, 139.72, 147.46, 167.01, 167.33.
1H NMR: d = 1.32 (t, 3 H, J = 7.5 Hz), 2.78 (m, 2 H), 3.91 (s, 3 H,
CO2CH3), 6.91 (s, 1 H, =CHthiophene), 7.52 (m, 2 H, ArH), 7.59 (m, 1
H, ArH), 8.02 (d, 2 H, J = 7.2 Hz, ArH), 11.91 (s, 1 H, NH).
13C NMR: d = 15.98, 23.31, 52.19, 112.74, 119.53, 127.90 (2 C),
129.42 (2 C), 132.66, 133.05, 137.85, 148.01, 163.85, 166.88.
Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C,
63.29; H, 5.79; N, 4.50.
Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84. Found: C,
62.15; H, 5.06; N, 4.97.
62g
Mp 97.4–98.0 °C.
IR (KBr): 3265 (NH), 1667 cm–1 (C=O).
62b
Mp 69.3–70.0 °C.
IR (KBr): 3284 (NH), 1666 cm–1 (C=O).
1H NMR: d = 1.31 (t, 3 H, J = 7.8 Hz), 2.35 (s, 3 H), 2.75 (m, 2 H),
7.52 (m, 2 H, ArH), 7.58 (m, 1 H, ArH), 8.02 (d, 2 H, J = 7.2 Hz,
ArH), 12.28 (s, 1 H, NH).
13C NMR: d = 11.98, 14.73, 21.12, 51.96, 111.92, 127.30, 128.23 (2
C), 129.44 (2 C), 132.32, 132.78, 135.49, 147.70, 163.30, 167.17.
1H NMR: d = 0.93 (t, 3 H, J = 7.5 Hz), 1.38 (m, 2 H), 1.67 (m, 2 H),
2.71 (t, 2 H, J = 7.5 Hz), 3.89 (s, 3 H, CO2CH3), 7.53 (m, 2 H, ArH),
7.59 (m, 1 H, ArH), 8.03 (d, 2 H, J = 7.2 Hz, ArH), 11.94 (s, 1 H,
NH).
13C NMR: d = 13.74, 22.01, 29.13, 33.24, 51.68, 112.25, 119.76,
127.41 (2 C), 128.92 (2 C), 132.19, 132.53, 135.83, 147.55, 163.35,
166.38.
Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C,
63.47; H, 5.84; N, 4.75.
62h
Anal. Calcd for C17H19NO3S: C, 64.33; H, 6.03; N, 4.42. Found: C,
64.18; H, 5.83; N, 4.58.
Mp 93.7–94.4 °C.
IR (KBr): 3279 (NH), 1666 cm–1 (C=O).
62c
1H NMR: d = 2.28 (s, 3 H) 2.65 (s, 3 H), 3.95 (s, 3 H, CO2CH3), 7.53
(m, 2 H ArH), 7.59 (m, 1 H, ArH), 8.04 (d, 2 H, J = 7.2 Hz, ArH),
12.01 (s, 1 H, NH).
Mp 82.5–83.1 °C.
IR (KBr): 3293 (NH), 1663 cm–1 (C=O).
1H NMR: d = 0.91 (t, 3 H, J = 6.3 Hz), 1.32 (m, 4 H), 1.69 (m, 2 H),
2.73 (t, 2 H, J = 7.5 Hz), 3.86 (s, 3 H, CO2CH3), 6.91 (s, 1
H, =CHthiophene), 7.52 (m, 2 H, ArH), 7.59 (m, 1 H, ArH), 8.02 (d, 2
H, J = 7.8 Hz, ArH), 11.91 (s, 1 H, NH).
13C NMR: d = 17.88, 29.68, 51.86, 53.41, 113.16, 116.33, 123.82,
127.49 (2 C), 129.02 (2 C), 132.58, 134.85, 163.74, 166.46, 167.49.
Synthesis 2004, No. 18, 3055–3059 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiophene Derivatives on Soluble Polymer-Support
3059
Anal. Calcd for C16H15NO4S: C, 60.55; H, 4.76; N, 4.41. Found: C,
60.37; H, 4.93; N, 4.59.
d = 14.50, 16.18, 51.62, 60.62, 108.46, 113.21, 123.93, 127.86 (2
C), 129.02 (2 C), 132.46, 135.36, 148.01, 162.90, 166.54, 167.89.
Anal. Calcd for C17H17NO5S: C, 58.78; H, 4.93; N, 4.03. Found: C,
58.42; H, 5.21; N, 4.32.
62i
Mp 120.2–120.8 °C.
IR (KBr): 3270 (NH), 1662 cm–1 (C=O).
Acknowledgment
1H NMR: d = 2.39 (m, 2 H), 2.87 (t, 2 H, J = 7.2 Hz), 2.92 (t, 2 H,
J = 6.9 Hz), 3.91 (s, 3 H, CO2CH3), 7.53 (m, 2 H, ArH), 7.58 (m, 1
H, ArH), 8.03 (d, 2 H, J = 7.2 Hz, ArH), 12.02 (s, 1 H, NH).
This work is supported by the National Natural Sciences Fundation
of China (No: 20372019).
13C NMR: d = 27.95, 28.91, 30.21, 51.67, 108.38, 127.40 (2 C),
128.93 (2 C), 132.30, 132.48, 132.63, 141.36, 152.14, 163.32,
166.94.
References
(1) Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron
Lett. 2000, 41, 1597.
(2) Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J.
Anal. Calcd for C16H15NO3S: C, 63.77; H, 5.02; N, 4.65. Found: C,
63.61; H, 5.16; N, 4.51.
Heterocycl. Chem. 1999, 36, 333.
(3) Koike, K.; Jia, Z.; Nikaido, T.; Liu, Y.; Zhao, Y.; Guo, D.
Org. Lett. 1999, 1, 197.
(4) Gutschow, M.; Kuerschner, L.; Neumann, U.; Peitsch, M.;
Loser, R.; Kolglin, N.; Eger, K. J. Med. Chem. 1999, 42,
5437.
(5) Moller, K. B.; Moller, N. P. H. J. Biol. Chem. 2000, 275,
10300.
(6) Fujita, M.; Hirayama, T.; Ikeda, N. Bioorg. Med. Chem.
2002, 10, 3113.
(7) Modica, M.; Santiagati, M.; Russo, F.; Parotti, L.; Gioia, L.
D.; Selvaggini, M.; Mennini, T. J. Med. Chem. 1997, 40,
574.
62j
Mp 107.3–108.0 °C.
IR (KBr): 3255 (NH), 1661 cm–1 (C=O).
1H NMR: d = 1.81 (m, 4 H), 2.69 (t, 2 H, J = 5.7 Hz), 2.79 (t, 2 H,
J = 5.7 Hz), 3.91 (s, 3 H, CO2CH3), 7.53 (m, 2 H, ArH), 7.58 (m, 1
H, ArH), 8.02 (d, 2 H, J = 7.8 Hz, ArH), 12.31 (s, 1 H, NH).
13C NMR: d = 22.75, 22.94, 24.35, 26.28, 51.49, 111.71, 127.00,
127.38 (2 C), 128.87 (2 C), 130.89, 132.40, 136.52, 148.19, 163.37,
167.45.
Anal. Calcd for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44. Found: C,
64.89; H, 5.67; N, 4.22.
(8) Webb, T. R.; Melman, N.; Lvovskiy, D.; Ji, X.-D.; Jacobson,
K. A. Bioorg. Med. Chem. Lett. 2000, 10, 31.
(9) Gewald, K. Angew. Chem. 1961, 73, 114.
(10) Mckibben, B. P.; Cartwright, C. H.; Castelhano, A. L.
Tetrahedron Lett. 1999, 40, 5471.
62k
Mp 96.4–97.0 °C.
IR (KBr): 3256 (NH), 1660 cm–1 (C=O).
1H NMR: d = 1.63 (m, 2 H), 1.70 (m, 2 H), 1.86 (t, 2 H, J = 5.4 Hz),
2.76 (t, 2 H, J = 5.4 Hz), 3.05 (t, 2 H), 3.91 (s, 3 H, CO2CH3), 7.52
(m, 2 H, ArH), 7.58 (m, 1 H, ArH), 8.01 (d, 2 H, J = 7.2 Hz, ArH),
12.25 (s, 1 H, NH).
13C NMR: d = 27.05, 27.79, 28.25, 28.69, 32.26, 51.69, 113.04,
127.37 (2 C), 128.91 (2 C), 131.29, 132.37, 132.55, 136.50, 146.25,
163.48, 167.59.
(11) Castanedo, G. M.; Sutherlin, D. P. Tetrahedron Lett. 2001,
42, 7181.
(12) Hoener, A. P. F.; Henkel, B.; Gauvin, J. C. Synlett 2003, 63.
(13) Wentworth, J.; Janda, K. D. Chem. Commun. 1999, 1917.
(14) Parrick, H. Y.; Kim, D. J. Acc. Chem. Res. 2000, 33, 546.
(15) Harris, J. H.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J.
C. J. Org. Chem. 1998, 63, 2407.
(16) Ranu, B. C.; Guchhait, S. K.; Ghosh, K.; Patre, A. Green
Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C,
65.33; H, 5.42; N, 4.02.
Chem. 2000, 2, 5.
(17) Loupy, A.; Perreux, L. Tetrahedron 2001, 57, 9199.
(18) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
62l
Mp 90.3–91.1 °C.
IR (KBr): 3269 (NH), 1661 cm–1 (C=O).
(19) Chen, Z. X.; Yang, G. C.; Zhang, Z. J.; Wang, D. Synthesis
2001, 1483.
1H NMR: d = 1.37 (t, 3 H), 2.29 (s, 3 H), 3.91 (s, 3 H, CO2CH3),
4.22 (m, 2 H, CO2CH2CH3), 7.53 (m, 2 H, ArH), 7.58 (m, 1 H,
ArH), 8.01 (d, 2 H, J = 7.2 Hz, ArH), 12.31 (s, 1 H, NH). 13C NMR:
(20) Yang, G. C.; Chen, Z. X.; Zhang, Z. J. React. Funct. Polym.
2002, 51, 1.
(21) Chen, Z. X.; Yue, G. Z.; Lu, C. F.; Yang, G. C. Synlett 2004,
1231.
Synthesis 2004, No. 18, 3055–3059 © Thieme Stuttgart · New York