Concise synthesis of 3-acetoxy- N, N -dialkylbenzo[ b ]thiophene-2- carboxamides from 2-ethylsulfanylbenzoates

Article abstract of DOI:10.1055/s-0030-1260220

A convenient method for the synthesis of 3-acetoxy-N,N-dialkylbenzo[b] thiophene-2-carboxamides has been developed in three steps from 2-ethylsulfanylbenzoates using an interrupted Pummerer reaction of N,N-dialkyl-3-(2-ethylsulfinylphenyl)-3-oxo-propanami

Full text of DOI:10.1055/s-0030-1260220

PAPER
3429
Concise Synthesis of 3-Acetoxy-N,N-dialkylbenzo[b]thiophene-2-carboxamides
from 2-Ethylsulfanylbenzoates
Kazuhiro Kobayashi,* Yuuki Kanbe, Mai Horiuchi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 12 July 2011; revised 4 August 2011
Two starting 2-sulfanylbenzoates were prepared as fol-
Abstract: A convenient method for the synthesis of 3-acetoxy-N,N-
lows. First, S-ethylation of commercially available meth-
yl 2-sulfanylbenzoate (1) with iodoethane in the presence
of sodium hydride as a base gave methyl 2-ethylsulfanyl-
dialkylbenzo[b]thiophene-2-carboxamides has been developed in
three steps from 2-ethylsulfanylbenzoates using an interrupted
Pummerer reaction of N,N-dialkyl-3-(2-ethylsulfinylphenyl)-3-oxo-
propanamides. Thus, treatment of these sulfinyl amides, prepared benzoate (2a) in 93% yield as depicted in Scheme 1.
by the reaction of 2-ethylsulfanylbenzoates with lithium enolates of
N,N-dialkylacetamides followed by oxidation of the resulting N,N-
Then, 5-chloro-2-ethylsulfanylbenzoate (2b) was ob-
tained in 80% yield by substitution of 2-bromo function of
dialkyl-3-(2-ethylsulfanylphenyl)-3-oxopropanamides with sodium
commercially available methyl 2-bromo-5-chloroben-
metaperiodate and acetic anhydride at 100 °C leads to the formation
zoate (3) with ethane thiolate, generated from ethanethiol
of the desired benzo[b]thiophenes.
and sodium hydride as shown in Scheme 2.
Key words: 3-acetoxybenzo[b]thiophene-2-carboxamides, 2-eth-
ylsulfanylbenzoates, interrupted Pummerer reaction, sulfoxides,
acetic anhydride
CO2Me
CO2Me
SH
NaH, EtI, THF, 0 °C
SEt
1
2a 93%
We have recently described the synthesis of 3-arylben-
zo[b]thiophenes by an interrupted Pummerer reaction of
2-ethylsulfinyl-a-arylstyrenes; the sulfoxides are heated
in acetic anhydride at 100 °C to give the 3-arylben-
zo[b]thiophenes in reasonable yields.1 In this paper, we
wish to report that the interrupted Pummerer reaction of
N,N-dialkyl-3-(2-ethylsulfinylphenyl)-3-oxopropanamides,
which can be easily prepared in two step from 2-sulfanyl-
benzoates, provides a concise route for the preparation of
3-acetoxy-N,N-dialkylbenzo[b]thiophene-2-carboxamides.
Several methods for the preparation of 3-hydroxyben-
Scheme 1 Preparation of methyl 2-ethylsulfanylbenzoate (2a)
Cl
CO2Me
Br
Cl
CO2Me
SEt
NaH, EtSH, THF, 0 °C
3
2b 80%
Scheme 2 Preparation of methyl 5-chloro-2-ethylsulfanylbenzoate
(2b)
zo[b]thiophene-2-carboxic acid ester derivatives have al- The procedure developed for the synthesis of N,N-dialkyl-
ready been reported2 due to their biological utilities.3 3- benzo[b]thiophene-2-carboxamides 6 from 2 is illustrated
Hydroxybenzo[b]thiophene-2-carboxamide derivatives in Scheme 3. Thus, compounds 2 were readily converted
are also of biological importance.4 However, as far as we into N,N-dialkyl-3-(2-ethylsulfanylphenyl)-3-oxopropan-
are aware, few general methods for the preparation of 3- amides 4 in excellent yields on treatment with lithium
hydroxybenzo[b]thiophene-2-carboxamide derivatives enolates of N,N-dialkylacetamides in THF at –78 °C.
have been reported, though Lau et al. have demonstrated Reaction of these sulfides with sodium metaperiodate in
the
formation
of
3-hydroxy-N,N-dimethylben- aqueous methanol at room temperature furnished the cor-
zo[b]thiophene-2-carboxamide by a sodium hydroxide- responding sulfoxides, N,N-dialkyl-3-(2-ethylsulfinyl-
catalyzed cyclization of S-(2-acetylphenyl)dimethyl- phenyl)-3-oxopropanamides 5, in excellent yields as well.
thiocarbamate.5 Quite recently Steinmetz et al. have Subsequent cyclization of these substrates was carried out
reported the synthesis of 3-hydroxy-N-methyl-N-phenyl- under the same conditions as previously described for the
benzo[b]thiophene-2-carboxamide from methyl 2-sulfa- preparation of 3-arylbenzo[b]thiophenes (acetic anhy-
nylbenzoate and 2-chloro-N-methyl-N-phenylbenzamide.6 dride, 100 °C). The cyclization occurred relative smoothly
The present paper is the first report on the general synthe- to afford the desired products 6 in fair yields as summa-
sis of 3-hydroxybenzo[b]thiophene-2-carboxamide deriv- rized in Table 1.
atives.
Mechanistically, this cyclization process for the formation
of 3-acetoxybenzo[b]thiophene-2-carboxamides 6 from
3-(2-ethylsulfinylphenyl)-3-oxopropanamides 5 appears
to proceed as illustrated in Scheme 4. Thus, treatment of
5 with acetic anhydride generates an acetoxylated sulfo-
SYNTHESIS 2011, No. 21, pp 3429–3434
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260220; Art ID: F69111SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

3430
K. Kobayashi et al.
PAPER
O
O
5
R1
R1
R1
MeCONR22, 2 LDA, THF, –78 °C
NR2
2
2
Ac2O
SEt
O
4
O
O
OH
O
R1
R1
NR2
NR2
2
O
2
NR2
NaIO4, MeOH–H2O, r. t.
S+Et
OAc
S+Et
OAc
2
–OAc
–OAc
S(O)Et
OAc
7
7'
5
– AcOH
Ac2O, 100 °C
CONR2
2
O
S
OH
R1
R1
6
CONR2
–OAc
CONR2
2
2
S+
Et
S+
Et
Scheme
3
Preparation of 3-acetoxybenzo[b]thiophene-2-car-
–OAc
boxamides 6 (for R1 and R2, see Table 1)
8
8'
Table 1 Preparation of 3-Acetoxybenzo[b]thiophene-2-carbox-
amides 6
Entry
2
NR2
4 (Yield, 5 (Yield, 6 (Yield,
OH
2
R1
%)a
%)a
%)a
Ac2O
CONR2
6
2
– EtOAc
1
2
2a NMe2
4a (92)
4b (93)
4c (92)
4d (94)
4e (88)
4f (90)
4g (86)
4h (93)
4i (93)
4j (86)
5a (94)
5b (98)
5c (93)
5d (91)
5e (95)
5f (98)
5g (98)
5h (90)
5i (89)
5j (90)
6a (63)
6b (61)
6c (63)
6d (62)
6e (61)
6f (61)
6g (63)
6h (57)
6i (54)
6j (58)
S
9
2a NEt2
Scheme 4 Probable pathway to benzo[b]thiophene-2-carboxamides
3
2a pyrrolidin-1-yl
2a piperidin-1-yl
2a morpholin-4-yl
2b NMe2
6
4
ing materials and the ease of operations make the present
method attractive.
5
6
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were re-
corded on a Shimadzu FTIR-8300 spectrophotometer. H NMR
7
2b NEt2
1
8
2b pyrrolidin-1-yl
2b piperidin-1-yl
2b morpholin-4-yl
spectra were recorded in CDCl3 using TMS as an internal reference
on a JEOL ECP500 FT NMR spectrometer operating at 500 MHz
9
or JEOL LA400FT NMR spectrometer operating at 400 MHz. 13
C
NMR spectra were measured in CDCl3 using TMS as an internal
reference with a JEOL ECP500 FT NMR spectrometer operating at
125 MHz. Low-resolution MS spectra (EI, 70 eV) were obtained by
using a JEOL JMS AX505 HA spectrometer. TLC was carried out
10
a Isolated yields. 4a–e, 5a–e, 6a–e: R1 = H; 4f–j, 5f–j, 6f–j: R1 = Cl.
nium ion intermediate 7, which tautomerizes to its enol on a Merck Kieselgel 60 PF254. Column chromatography was per-
formed using Wako Gel C-200E. All of the organic solvents used in
this study were dried over appropriate drying agents and distilled
prior to use. BuLi was supplied by Asia Lithium Corporation. All
other chemicals used in this study were commercially available. All
of the reactions excluding the conversion of compounds 4 into 5
were carried out under argon.
form 7¢. Trapping of the sulfonium ion center by the enol
moiety of 7¢ with a loss of acetic acid produces a 3-oxo-
2,3-dihydrobenzothiophenium ion intermediate 8, which
tautomerizes to the 3-hydroxybenzothiophenium ion in-
termediate 8¢. Removal of ethyl acetate from this interme-
diate gives a 3-hydroxybenzo[b]thiophene-2-carboxamide
precursor 9, which is finally acetylated with acetic anhy-
dride to lead to 6.
Methyl 2-(Ethylsulfanyl)benzoate (2a)7
This compound was prepared by treating methyl 2-sulfanylbenzoate
(1; 1.96 g, 10 mmol) with EtI (1.72 g, 11 mmol) in the presence of
NaH (0.264 g, 11 mmol) in THF (24 mL) at 0 °C; yield: 1.82 g
In conclusion, we have demonstrated that 3-acetoxy-N,N-
dialkylbenzo[b]thiophene-2-carboxamides, which are dif-
(93%); white solid; mp 29–30 °C (pentane) (Lit.7 mp <30 °C). The
1
ficult to prepare by previous methods, can be convenient- spectral data (IR and H NMR) of this product were identical to
those reported previously.7
ly synthesized from 2-ethylsulfanylbenzoates in three
steps using an interrupted Pummerer reaction of N,N-di-
alkyl-3-(2-ethylsulfinylphenyl)-3-oxopropanamides as
the key and final step. The ready availability of the start-
Methyl 3-Chloro-6-ethylsulfanylbenzoate (2b)
This compound was prepared by treating methyl 2-bromo-5-chlo-
robenzoate (3; 2.5 g, 10 mmol) with NaSEt generated from EtSH
Synthesis 2011, No. 21, 3429–3434 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Acetoxybenzo[b]thiophene-2-carboxamides
3431
(0.744 g, 12 mmol) and NaH (0.288 g, 12 mmol) in DMF (12 mL)
at 0 °C; yield: 1.84 g (80%); white solid; mp 55–58 °C (hexane).
3-(2-Ethylsulfanylphenyl)-1-(piperidin-1-yl)propane-1,3-dione
(4d)
Pale-yellow oil; Rf = 0.25 (EtOAc–hexane, 1:2); observed as a tau-
tomeric mixture with the enol form in CDCl3 (ca. 6:4).
IR (neat): 3500–2500, 1674, 1634 cm–1.
1H NMR (500 MHz): d = 1.32 (t, J = 7.3 Hz, 1.2 H), 1.36 (t, J = 7.3
Hz, 1.8 H), 1.53–1.68 (m, 6 H), 2.93 (q, J = 7.3 Hz, 1.2 H), 2.95 (q,
J = 7.3 Hz, 0.8 H), 3.45–3.59 (m, 4 H), 4.11 (s, 1.2 H), 5.64 (s, 0.4
H), 7.16–7.23 (m, 1 H), 7.32–7.38 (1.4 H), 7.43–7.49 (m, 1 H), 7.97
(d, J = 7.8 Hz, 0.6 H), 10.89 (br s, 0.4 H).
IR (KBr): 1717 cm–1.
1H NMR (400 MHz): d = 1.38 (t, J = 7.3 Hz, 3 H), 2.94 (q, J = 7.3
Hz, 2 H), 3.92 (s, 3 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.40 (dd, J = 8.7,
2.3 Hz, 1 H), 7.94 (d, J = 2.3 Hz, 1 H).
Anal. Calcd for C10H11ClO2S: C, 52.06; H, 4.81. Found: C, 52.05;
H, 4.82.
3-(2-Ethylsulfanylphenyl)-3-oxopropanamides 4; General Pro-
cedure
Anal. Calcd for C16H21NO2S: C, 65.95; H, 7.26; N, 4.81. Found: C,
65.96; H, 7.48; N, 4.75.
The respective ethylsulfanylbenzoate 2a,b (1.0 mmol) was added to
a stirred solution of the appropriate lithium enolate of N,N-dialkyl-
acetamide (1.0 mmol), generated by the treatment of N,N-dialkyl-
acetamides (1.0 mmol) with LDA (2.0 mmol) in THF (4 mL) at
–78 °C. The reaction mixture was stirred at the same temperature
for 30 min before sat. aq NH4Cl (10 mL) was added. The mixture
was warmed to r.t. and extracted with EtOAc (3 × 10 mL). The com-
bined extracts were washed with brine (10 mL) and dried (Na2SO4).
Evaporation of the solvent gave a residue, which was purified by
column chromatography on silica gel [Et2O–hexane (1:2) or
EtOAc–hexane (1:2)] to give 4.
3-(2-Ethylsulfanylphenyl)-1-(morpholin-4-yl)propane-1,3-di-
one (4e)
White solid; mp 90–93 °C (hexane); observed as a tautomeric mix-
ture with the enol form in CDCl3 (ca. 8:2).
IR (KBr): 3500–2500, 1670, 1641, 1626 cm–1.
1H NMR (500 MHz): d = 1.32 (t, J = 7.3 Hz, 0.6 H), 1.36 (t, J = 7.3
Hz, 2.4 H), 2.94 (q, J = 7.3 Hz, 1.6 H), 2.97 (q, J = 7.3 Hz, 0.4 H),
3.55–3.72 (m, 8 H), 4.12 (s, 1.6 H), 5.60 (s, 0.2 H), 7.17–7.25 (m,
1.4 H), 7.38 (d, J = 7.3 Hz, 0.8 H), 7.45–7.50 (m, 1 H), 7.97 (dd,
J = 7.8, 1.4 Hz, 0.8 H), 10.89 (br s, 0.2 H).
3-(2-Ethylsulfanylphenyl)-N,N-dimethyl-3-oxopropanamide
(4a)
Pale-yellow solid; mp 64–69 °C (hexane–Et2O); observed as a tau-
tomeric mixture with the enol form in CDCl3 (ca. 4:6).
Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N, 4.77. Found: C,
61.18; H, 6.58; N, 4.74.
IR (KBr): 3500–2500, 1622 cm–1.
3-(5-Chloro-2-ethylsulfanylphenyl)-N,N-dimethyl-3-oxopro-
panamide (4f)
Yellow solid; mp 67–70 °C (hexane); observed as a tautomeric mix-
ture with the enol form in CDCl3 (ca. 5:5).
1H NMR (400 MHz): d = 1.32 (t, J = 7.3 Hz, 1.8 H), 1.36 (t, J = 7.3
Hz, 1.2 H), 2.93 (q, J = 7.3 Hz, 0.8 H), 2.96 (q, J = 7.3 Hz, 1.2 H),
2.99 (s, 1.2 H), 3.05 (s, 3.6 H), 3.08 (s, 1.2 H), 4.11 (s, 0.8 H), 5.61
(s, 0.6 H), 7.16–7.24 (m, 1 H), 7.30–7.38 (m, 1.6 H), 7.43–7.50 (m,
1 H), 7.95 (dd, J = 7.7, 1.4 Hz, 0.4 H), 10.72 (br s, 0.6 H).
IR (KBr): 3500–2500, 1676, 1636 cm–1.
1H NMR (500 MHz): d = 1.31 (t, J = 7.3 Hz, 1.5 H), 1.34 (t, J = 7.3
Hz, 1.5 H), 2.92 (q, J = 7.3 Hz, 1 H), 2.93 (q, J = 7.3 Hz, 1 H), 2.99
(s, 1.5 H), 3.05 (s, 3 H), 3.08 (s, 1.5 H), 4.09 (s, 1 H), 5.61 (s, 0.5
H), 7.25 (d, J = 8.2 Hz, 0.5 H), 7.29 (dd, J = 8.7, 2.8 Hz, 0.5 H), 7.31
(d, J = 8.7 Hz, 0.5 H), 7.40 (dd, J = 8.2, 2.3 Hz, 0.5 H), 7.48 (d,
J = 2.8 Hz, 0.5 H), 7.86 (d, J = 2.3 Hz, 0.5 H), 10.93 (br s, 0.5 H).
Anal. Calcd for C13H17NO2S: C, 62.12; H, 6.82; N, 5.57. Found: C,
61.91; H, 6.71; N, 5.56.
N,N-Diethyl-3-(2-ethylsulfanylphenyl)-3-oxopropanamide (4b)
Yellow oil; Rf = 0.25 (Et2O–hexane, 1:2); observed as a tautomeric
mixture with the enol form in CDCl3 (ca. 4:6).
IR (neat): 3500–2500, 1632 cm–1.
Anal. Calcd for C13H16ClNO2S: C, 54.63; H, 5.64; N, 4.90. Found:
C, 54.41; H, 5.84; N, 5.00.
1H NMR (500 MHz): d = 1.11–1.37 (m, 9 H), 2.91–2.98 (m, 2 H),
3.34–3.48 (m, 4 H), 4.07 (s, 0.8 H), 5.56 (s, 0.6 H), 7.17–7.34 (m,
2.2 H), 7.37 (d, J = 8.2 Hz, 0.4 H), 7.44 (ddd, J = 8.2, 7.3, 1.4 Hz,
0.4 H), 7.50 (d, J = 7.8 Hz, 0.6 H), 7.97 (d, J = 7.8 Hz, 0.4 H), 10.76
(br s, 0.6 H).
3-(5-Chloro-2-ethylsulfanylphenyl)-N,N-diethyl-3-oxopropan-
amide (4g)
Pale-yellow solid; mp 76–78 °C (hexane); observed as a tautomeric
mixture with the enol form in CDCl3 (ca. 5:5).
IR (KBr): 3500–2500, 1674, 1620 cm–1.
Anal. Calcd for C15H21NO2S: C, 64.48; H, 7.58; N, 5.01. Found: C,
64.39; H, 7.71; N, 4.90.
1H NMR (500 MHz): d = 1.12–1.35 (m, 9 H), 2.89–2.96 (m, 2 H),
3.35–3.49 (m, 4 H), 4.04 (s, 1 H), 5.56 (s, 0.5 H), 7.25 (d, J = 8.2
Hz, 0.5 H), 7.28–7.31 (m, 1 H), 7.39 (dd, J = 8.2, 2.3 Hz, 0.5 H),
7.50 (d, J = 2.3 Hz, 0.5 H), 7.88 (d, J = 2.3 Hz, 0.5 H), 10.91 (br s,
0.5 H).
3-(2-Ethylsulfanylphenyl)-1-(pyrrolidin-1-yl)propane-1,3-di-
one (4c)
White solid; mp 87–89 °C (hexane); observed as a tautomeric mix-
ture with the enol form in CDCl3 (ca. 2:8).
IR (KBr): 3500–2500, 1626 cm–1.
Anal. Calcd for C15H20ClNO2S: C, 57.40; H, 6.42; N, 4.46. Found:
C, 57.28; H, 6.41; N, 4.21.
1H NMR (500 MHz): d = 1.32 (t, J = 7.3 Hz, 2.4 H), 1.36 (t, J = 7.3
Hz, 0.6 H), 1.87–2.01 (m, 4 H), 2.94 (q, J = 7.3 Hz, 0.4 H), 2.96 (q,
J = 7.3 Hz, 1.6 H), 3.45–3.57 (m, 4 H), 4.05 (s, 0.4 H), 5.47 (s, 0.8
H), 7.16–7.24 (m, 1 H), 7.32–7.33 (m, 1.6 H), 7.37 (d, J = 7.8 Hz,
0.2 H), 7.45 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.2 H), 7.48 (dd, J = 7.8, 1.4
Hz, 0.8 H), 7.99 (dd, J = 7.8, 1.4 Hz, 0.2 H), 10.76 (br s, 0.8 H).
1-(5-Chloro-2-ethylsulfanylphenyl)-3-(pyrrolidin-1-yl)pro-
pane-1,3-dione (4h)
Yellow solid; mp 83–85 °C (hexane); observed as a tautomeric mix-
ture with the enol form in CDCl3 (ca. 4:6).
IR (KBr): 3500–2500, 1624, 1603 cm–1.
1H NMR (500 MHz): d = 1.31 (t, J = 7.3 Hz, 1.8 H), 1.34 (t, J = 7.3
Hz, 1.2 H), 1.86–2.01 (m, 4 H), 2.91 (q, J = 7.3 Hz, 0.8 H), 2.94 (q,
J = 7.3 Hz, 1.2 H), 3.45–3.57 (m, 4 H), 4.02 (s, 0.8 H), 5.48 (s, 0.6
H), 7.25 (d, J = 8.2 Hz, 0.6 H), 7.29 (dd, J = 8.2, 2.3 Hz, 0.6 H), 7.30
Anal. Calcd for C15H19NO2S: C, 64.95; H, 6.90; N, 5.05. Found: C,
64.87; H, 7.17; N, 5.06.
Synthesis 2011, No. 21, 3429–3434 © Thieme Stuttgart · New York

3432
K. Kobayashi et al.
PAPER
(d, J = 8.2 Hz, 0.4 H), 7.40 (dd, J = 8.2, 2.3 Hz, 0.4 H), 7.48 (d,
J = 2.3 Hz, 0.6 H), 7.91 (d, J = 2.3 Hz, 0.4 H), 10.88 (br s, 0.6 H).
IR (neat): 3474, 1682, 1634, 1018 cm–1.
1H NMR (500 MHz): d = 1.14, 1.22, 1.27, and 1.32 (4 t, J = 7.3 Hz
each, combined 9 H), 2.68–2.79 (m, 1 H), 3.16–3.23 (m, 1 H), 3.33–
3.44 (m, 4 H), 3.97 (d, J = 15.1 Hz, 0.4 H), 4.16 (d, J = 15.1 Hz, 0.4
H), 5.59 (s, 0.6 H), 7.49 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.4 H), 7.58 (dd,
J = 7.8, 1.4 Hz, 0.4 H), 7.61–7.66 (m, 1 H), 7.82 (ddd, J = 7.8, 7.3,
1.4 Hz, 0.6 H), 8.11 (dd, J = 7.8, 1.4 Hz, 0.6 H), 8.15 (dd, J = 7.8,
1.4 Hz, 0.4 H), 8.31 (dd, J = 7.8, 1.4 Hz, 0.6 H), 10.83 (br s, 0.6 H).
Anal. Calcd for C15H18ClNO2S: C, 57.78; H, 5.82; N, 4.49. Found:
C, 57.50; H, 5.80; N, 4.41.
1-(5-Chloro-2-ethylsulfanylphenyl)-3-(piperidin-1-yl)propane-
1,3-dione (4i)
Yellow solid; mp 58–60 °C (hexane–CH2Cl2); observed as a tauto-
meric mixture with the enol form in CDCl3 (ca. 6:4).
IR (KBr): 3500–2500, 1676, 1628 cm–1.
Anal. Calcd for C15H21NO3S: C, 60.99; H, 7.17; N, 4.74. Found: C,
60.88; H, 7.30; N, 4.64.
1H NMR (500 MHz): d = 1.31 (t, J = 7.3 Hz, 1.2 H), 1.34 (t, J = 7.3
Hz, 1.8 H), 1.56–1.69 (m, 6 H), 2.91 (q, J = 7.3 Hz, 1.2 H), 2.93 (q,
J = 7.3 Hz, 0.8 H), 3.45 (t, J = 5.0 Hz, 2 H), 3.58 (t, J = 5.0 Hz, 2
H), 4.08 (s, 1.2 H), 5.63 (s, 0.4 H), 7.25 (d, J = 8.7 Hz, 0.4 H), 7.29
(dd, J = 8.7, 2.3 Hz, 0.4 H), 7.30 (d, J = 8.7 Hz, 0.6 H), 7.40 (dd,
J = 8.7, 2.3 Hz, 0.6 H), 7.48 (d, J = 2.3 Hz, 0.4 H), 7.88 (d, J = 2.3
Hz, 0.6 H), 10.87 (br s, 0.4 H).
3-(2-Ethylsulfinylphenyl)-1-(pyrrolidin-1-yl)propane-1,3-di-
one (5c)
Yellow oil; Rf = 0.50 (THF); observed as a tautomeric mixture with
the enol form in CDCl3 (ca. 7:3).
IR (neat): 3460, 1682, 1634, 1015 cm–1.
1H NMR (500 MHz): d = 1.28 (t, J = 7.3 Hz, 0.9 H), 1.31 (t, J = 7.3
Hz, 2.1 H), 1.84–2.04 (m, 4 H), 2.69–2.80 (m, 1 H), 3.16–3.24 (m,
1 H), 3.43–3.57 (m, 4 H), 3.96 (d, J = 14.7 Hz, 0.7 H), 4.14 (d,
J = 14.7 Hz, 0.7 H), 5.51 (s, 0.3 H), 7.48 (ddd, J = 7.8, 7.3, 1.4 Hz,
0.3 H), 7.58 (dd, J = 7.8, 1.4 Hz, 0.3 H), 7.61–7.66 (m, 1 H), 7.83
(ddd, J = 7.8, 7.3, 1.4 Hz, 0.7 H), 8.13–8.16 (m, 1 H), 8.31 (dd,
J = 7.8, 1.4 Hz, 0.7 H), 10.86 (br s, 0.3 H).
Anal. Calcd for C16H20ClNO2S: C, 58.97; H, 6.19; N, 4.30. Found:
C, 58.95; H, 6.40; N, 4.18.
1-(5-Chloro-2-ethylsulfanylphenyl)-3-(morpholin-4-yl)pro-
pane-1,3-dione (4j)
Beige solid; mp 96–99 °C (hexane–EtOAc); observed as a tauto-
meric mixture with the enol form in CDCl3 (ca. 6:4).
Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N, 4.77. Found: C,
61.32; H, 6.54; N, 4.52.
IR (KBr): 3500–2500, 1672, 1651, 1638 cm–1.
1H NMR (500 MHz): d = 1.31 (t, J = 7.3 Hz, 1.2 H), 1.35 (t, J = 7.3
Hz, 1.8 H), 1.92 (q, J = 7.3 Hz, 1.2 H), 2.94 (q, J = 7.3 Hz, 0.8 H),
3.52–3.72 (m, 8 H), 4.09 (s, 1.2 H), 5.60 (s, 0.4 H), 7.25 (d, J = 8.7
Hz, 0.4 H), 7.30 (dd, J = 8.7, 2.3 Hz, 0.4 H), 7.31 (d, J = 8.7 Hz, 0.6
H), 7.42 (dd, J = 8.7, 2.3 Hz, 0.6 H), 7.48 (d, J = 2.3 Hz, 0.4 H), 7.88
(d, J = 2.3 Hz, 0.6 H), 10.91 (br s, 0.4 H).
3-(2-Ethylsulfinylphenyl)-1-(piperidin-1-yl)propane-1,3-dione
(5d)
Pale-yellow oil; Rf = 0.16 (EtOAc); observed as a tautomeric mix-
ture with the enol form in CDCl3 (ca. 8:2).
IR (neat): 3460, 1678, 1633, 1018 cm–1.
Anal. Calcd for C15H18ClNO3S: C, 54.96; H, 5.53; N, 4.27. Found:
C, 54.94; H, 5.67; N, 4.22.
1H NMR (500 MHz): d = 1.28 (t, J = 7.3 Hz, 0.6 H), 1.32 (t, J = 7.3
Hz, 2.4 H), 1.52–1.66 (m, 6 H), 2.69–2.79 (m, 1 H), 3.16–3.23 (m,
1 H), 3.40–3.59 (m, 4 H), 4.05 (d, J = 15.6 Hz, 0.8 H), 4.16 (d,
J = 15.6 Hz, 0.8 H), 5.69 (s, 0.2 H), 7.48 (ddd, J = 7.8, 7.3, 1.4 Hz,
0.2 H), 7.58 (dd, J = 7.8, 1.4 Hz, 0.2 H), 7.61–7.66 (m, 1 H), 7.83
(ddd, J = 7.8, 7.3, 1.4 Hz, 0.8 H), 8.13 (dd, J = 7.8, 1.4 Hz, 0.8 H),
8.15 (dd, J = 7.8, 1.4 Hz, 0.2 H), 8.31 (dd, J = 7.8, 1.4 Hz, 0.8 H),
10.92 (nr s, 0.2 H).
3-(2-Ethylsulfinylphenyl)-N,N-dimethyl-3-oxopropanamides 5;
General Procedure
The amide 4 (0.80 mmol) was stirred with an equimolar amount of
NaIO4 (0.80 mmol) in aq MeOH (1:5, 6 mL) at r.t. overnight. After
most of the MeOH was removed by evaporation, H2O (10 mL) was
added and the mixture was extracted with EtOAc (3 × 10 mL). The
combined extracts were washed with brine (10 mL) and dried
(Na2SO4). Evaporation of the solvent gave a residue, which was pu-
rified by column chromatography on silica gel using the eluents in-
dicated below to give 5.
Anal. Calcd for C16H21NO3S: C, 62.51; H, 6.89; N, 4.56. Found: C,
62.42; H, 7.01; N, 4.55.
3-(2-Ethylsulfinylphenyl)-1-(morpholin-4-yl)propane-1,3-di-
one (5e)
Yellow oil; Rf = 0.67 (THF–hexane, 2:1); observed as a tautomeric
mixture with the enol form in CDCl3 (ca. 8:2).
IR (neat): 3460, 1678, 1634, 1017 cm–1.
3-(2-Ethylsulfinylphenyl)-N,N-dimethyl-3-oxopropanamide
(5a)
Pale-yellow oil; Rf = 0.16 (THF–hexane, 1:2); observed as a tauto-
1H NMR (500 MHz): d = 1.28 (t, J = 7.3 Hz, 0.6 H), 1.32 (t, J = 7.3
Hz, 2.4 H), 2.69–2.79 (m, 1 H), 3.14–3.22 (m, 1 H), 3.49–3.75 (m,
8 H), 4.07 (d, J = 15.1 Hz, 0.8 H), 4.18 (d, J = 15.1 Hz, 0.8 H), 5.65
(s, 0.2 H), 7.49 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.2 H), 7.58 (dd, 7.8, 1.4
Hz, 0.2 H), 7.64 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.8 H), 7.66 (ddd,
J = 7.8, 7.3, 1.4 Hz, 0.2 H), 7.85 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.8 H),
8.12 (dd, J = 7.8, 1.4 Hz, 0.8 H), 8.15 (dd, J = 7.8, 1.4 Hz, 0.2 H),
8.32 (dd, J = 7.8, 1.4 Hz, 0.8 H), 10.89 (br s, 0.2 H).
meric mixture with the enol form in CDCl3 (ca. 7:3).
IR (neat): 3445, 1681, 1633, 1018 cm–1.
1H NMR (500 MHz): d = 1.28 (t, J = 7.3 Hz, 0.9 H), 1.32 (t, J = 7.3
Hz, 2.1 H), 2.69–2.80 (m, 2 H), 3.01 (s, 1.8 H), 3.068 (s, 2.1 H),
3.075 (s, 2.1 H), 4.05 (d, J = 15.1 Hz, 0.7 H), 4.19 (d, J = 15.1 Hz,
0.7 H), 5.66 (s, 0.3 H), 7.49 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.3 H), 7.58–
7.66 (m, 1.3 H), 7.83 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.7 H), 8.10 (dd,
J = 7.8, 1.4 Hz, 0.7 H), 8.15 (dd, J = 7.8, 1.4 Hz, 0.3 H), 8.32 (dd,
J = 7.8, 1.4 Hz, 0.7 H), 10.80 (br s, 0.3 H).
Anal. Calcd for C15H19NO4S: C, 58.23; H, 6.19; N, 4.53. Found: C,
58.19; H, 6.20; N, 4.38.
Anal. Calcd for C13H17NO3S: C, 58.40; H, 6.41; N, 5.24. Found: C,
58.37; H, 6.46; N, 5.10.
3-(5-Chloro-2-ethylsulfinylphenyl)-N,N-dimethyl-3-oxopro-
panamide (5f)
Yellow oil; Rf = 0.30 (THF–hexane, 1:1); observed as a tautomeric
mixture with the enol form in CDCl3 (ca. 5:5).
N,N-Diethyl-3-(2-ethylsulfinylphenyl)3-oxopropanamide (5b)
Yellow oil; Rf = 0.26 (THF–hexane, 1:1); observed as a tautomeric
mixture with the enol form in CDCl3 (ca. 4:6).
IR (neat): 3360, 1683, 1643, 1605, 1022 cm–1.
Synthesis 2011, No. 21, 3429–3434 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Acetoxybenzo[b]thiophene-2-carboxamides
3433
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 1.5 H), 1.31 (t, J = 7.3
Hz, 1.5 H), 2.68–2.79 (m, 1 H), 3.01 (s, 1.5 H), 3.08 (br s, 4.5 H),
3.14–3.23 (m, 1 H), 3.99 (d, J = 15.6 Hz, 0.5 H), 4.15 (d, J = 15.6
Hz, 0.5 H), 5.64 (s, 0.5 H), 7.56 (d, J = 2.3 Hz, 0.5 H), 7.61 (dd,
J = 8.2, 2.3 Hz, 0.5 H), 7.78 (dd, J = 8.2, 2.3 Hz, 0.5 H), 8.02 (d,
J = 1.8 Hz, 0.5 H), 8.09 (d, J = 8.2 Hz, 0.5 H), 8.24 (d, J = 8.2 Hz,
0.5 H), 10.88 (br s, 0.5 H).
8 H), 4.02 (d, J = 15.1 Hz, 0.6 H), 4.15 (d, J = 15.1 Hz, 0.6 H), 5.64
(s, 0.4 H), 7.55 (d, J = 1.8 Hz, 0.4 H), 7.61 (dd, J = 8.2, 1.8 Hz, 0.4
H), 7.80 (dd, J = 8.7, 1.8 Hz, 0.6 H), 8.05 (d, J = 1.8 Hz, 0.6 H), 8.09
(d, J = 8.2 Hz, 0.4 H), 8.25 (d, J = 8.7 Hz, 0.6 H), 10.91 (br s, 0.4 H).
Anal. Calcd for C15H18ClNO4S: C, 52.40; H, 5.28; N, 4.07. Found:
C, 52.29; H, 5.26; N, 4.07.
Anal. Calcd for C13H16ClNO3S: C, 51.74; H, 5.34; N, 4.64. Found:
C, 51.52; H, 5.34; N, 4.53.
3-Acetoxy-N,N-dimethylbenzo[b]thiophene-2-carboxamide
(6a); Typical Procedure
A solution of 5a (0.17 g, 0.63 mmol) in Ac2O (2 mL) was heated at
100 °C under stirring until the disappearance of 5a had been con-
firmed by TLC analyses (SiO2; THF–hexane, 1:2). After cooling,
excess Ac2O was removed under reduced pressure, and the residue
was purified by preparative TLC on silica gel to give 6a (0.10 g,
63%) as a pale-orange oil; Rf = 0.21 (THF–hexane, 1:2).
IR (neat): 1778, 1633 cm–1.
1H NMR (500 MHz): d = 2.39 (s, 3 H), 3.11 (s, 6 H), 7.38–7.44 (m,
2 H), 7.58–7.62 (m, 1 H), 7.76–7.80 (m, 1 H).
3-(5-Chloro-2-ethylsulfinylphenyl)-N,N-diethyl-3-oxopropan-
amide (5g)
Pale-yellow oil; Rf = 0.34 (EtOAc–hexane, 5:1); observed as a tau-
tomeric mixture with the enol form in CDCl3 (ca. 4:6).
IR (neat): 3422, 1684, 1634, 1022 cm–1.
1H NMR (500 MHz): d = 1.25, 1.26, 1.27, and 1.30 (4t, J = 7.3 Hz
each, combined 9 H), 2.69–2.80 (m, 1 H), 3.17–3.23 (m, 1 H), 3.35–
3.48 (m, 4 H), 3.93 (d, J = 15.1 Hz, 0.4 H), 4.13 (d, J = 15.1 Hz, 0.4
H), 5.57 (s, 0.6 H), 7.55 (d, J = 1.8 Hz, 0.6 H), 7.60 (dd, J = 8.2, 1.8
Hz, 0.6 H), 7.77 (dd, J = 8.2, 1.8 Hz, 0.4 H), 8.03 (d, J = 1.8 Hz, 0.4
H), 8.09 (d, J = 8.2 Hz, 0.6 H), 8.24 (d, J = 8.2 Hz, 0.4 H), 10.92 (br
s, 0.6 H).
13C NMR: d = 20.6, 35.5, 121.3, 122.7, 122.8, 124.9, 126.3, 132.0,
136.4, 138.9, 163.2, 168.0.
MS: m/z (%) = 263 (8.7, [M+]), 221 (100).
Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C,
59.27; H, 5.01; N, 5.16.
Anal. Calcd for C15H20ClNO3S: C, 54.62; H, 6.11; N, 4.25. Found:
C, 54.58; H, 6.12; N, 4.24.
3-Acetoxy-N,N-diethylbenzo[b]thiophene-2-carboxamide (6b)
Beige oil; Rf = 0.12 (THF–hexane, 1:3).
IR (neat): 1778, 1634 cm–1.
1H NMR (500 MHz): d = 1.21 (t, J = 7.3 Hz, 6 H), 2.37 (s, 3 H),
3.50 (q, J = 7.3 Hz, 4 H), 7.39–7.43 (m, 2 H), 7.59–7.62 (m, 1 H),
7.76–7.79 (m, 1 H).
13C NMR: d = 13.9, 20.6, 41.8, 121.2, 122.7, 122.8, 124.9, 126.2,
132.0, 136.1, 138.8, 162.4, 168.1.
MS: m/z (%) = 291 (9.2, [M+]), 249 (100).
1-(5-Chloro-2-ethylsulfinylphenyl)-3-(pyrrolidin-1-yl)propane-
1,3-dione (5h)
Yellow oil; Rf = 0.30 (THF–hexane, 1:1); observed as a tautomeric
mixture with the enol form in CDCl3 (ca. 4:6).
IR (neat): 3325, 1682, 1634, 1022 cm–1.
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 1.8 H), 1.30 (t, J = 7.3
Hz, 1.2 H), 1.92–2.06 (m, 4 H), 2.70–2.78 (m, 1 H), 3.16–3.22 (m,
1 H), 3.47–3.56 (m, 4 H), 3.91 (d, J = 14.7 Hz, 0.4 H), 4.11 (d,
J = 14.7 Hz, 0.4 H), 5.51 (s, 0.6 H), 7.56 (d, J = 2.3 Hz, 0.6 H), 7.60
(dd, J = 8.2, 2.3 Hz, 0.6 H), 7.78 (dd, J = 8.2, 2.3 Hz, 0.4 H), 8.07
(d, J = 2.3 Hz, 0.4 H), 8.09 (d, J = 8.2 Hz, 0.6 H), 8.24 (d, J = 8.2
Hz, 0.4 H), 10.90 (br s, 0.6 H).
Anal. Calcd for C15H17NO3S: C, 61.83; H, 5.88; N, 4.81. Found: C,
61.62; H, 5.90; N, 4.69.
Anal. Calcd for C15H18ClNO3S: C, 54.96; H, 5.53; N, 4.27. Found:
C, 54.95; H, 5.54; N, 4.24.
2-(Pyrrolidin-1-ylcarbonyl)benzo[b]thiophen-3-yl Acetate (6c)
Pale-yellow oil; Rf = 0.18 (EtOAc–hexane, 1:2).
IR (neat): 1775, 1623 cm–1.
1H NMR (500 MHz): d = 1.94 (br s, 4 H), 2.40 (s, 3 H), 3.61–3.64
(m, 4 H), 7.39–7.44 (m, 2 H), 7.63–7.65 (m, 1 H), 7.76–7.78 (m, 1
H).
13C NMR: d = 20.8, 24.4, 46.4, 121.3, 122.7, 122.9, 124.9, 126.4,
132.1, 136.2, 139.7, 161.5, 168.1.
MS: m/z (%) = 289 (7.0, [M+]), 247 (100).
1-(5-Chloro-2-ethylsulfinylphenyl)-3-(piperidin-1-yl)propane-
1,3-dione (5i)
Pale-yellow oil; Rf = 0.30 (EtOAc–hexane, 1:2); observed as a tau-
tomeric mixture with the enol form in CDCl3 (ca. 6:4).
IR (neat): 3420, 1683, 1634, 1020 cm–1.
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 1.2 H), 1.30 (t, J = 7.3
Hz, 1.8 H), 1.56–1.71 (m, 6 H), 2.69–2.80 (m, 1 H), 3.15–3.23 (m,
1 H), 3.40–3.60 (m, 4 H), 3.99 (d, J = 15.1 Hz, 0.6 H), 4.12 (d,
J = 15.1 Hz, 0.6 H), 5.68 (s, 0.4 H), 7.56 (d, J = 1.8 Hz, 0.4 H), 7.60
(dd, J = 8.7, 1.8 Hz, 0.4 H), 7.78 (dd, J = 8.2, 2.3 Hz, 0.6 H), 8.04
(d, J = 2.3 Hz, 0.6 H), 8.08 (d, J = 8.7 Hz, 0.4 H), 8.24 (d, J = 8.2
Hz, 0.6 H), 10.87 (br s, 0.4 H).
Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84. Found: C,
62.25; H, 5.31; N, 4.78.
2-(Piperidin-1-ylcarbonyl)benzo[b]thiophen-3-yl Acetate (6d)
Beige oil; Rf = 0.22 (EtOAc–hexane, 1:3).
IR (neat): 1778, 1634 cm–1.
1H NMR (500 MHz): d = 1.58–1.68 (m, 6 H), 2.40 (s, 3 H), 3.60 (br,
4 H), 7.39–7.43 (m, 2 H), 7.57–7.60 (m, 1 H), 7.66–7.78 (m, 1 H).
13C NMR: d = 20.7, 25.8, 29.9, 47.7, 121.2, 122.8, 122.8, 124.9,
126.2, 132.1, 136.3, 138.7, 161.6, 168.0.
MS: m/z (%) = 303 (6.5, [M+]), 261 (100).
Anal. Calcd for C16H20ClNO3S: C, 56.21; H, 5.90; N, 4.10. Found:
C, 56.18; H, 5.90; N, 4.08.
1-(5-Chloro-2-ethylsulfinylphenyl)-3-(morpholin-4-yl)pro-
pane-1,3-dione (5j)
Pale-yellow oil; Rf = 0.41 (EtOAc); observed as a tautomeric mix-
ture with the enol form in CDCl3 (ca. 6:4).
IR (neat): 3420, 1682, 1639, 1020 cm–1.
Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C,
63.17; H, 5.68; N, 4.50.
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 1.2 H), 1.31 (t, J = 7.3
Hz, 1.8 H), 2.70–2.80 (m, 1 H), 3.13–3.21 (m, 1 H), 3.49–3.76 (m,
Synthesis 2011, No. 21, 3429–3434 © Thieme Stuttgart · New York

3434
K. Kobayashi et al.
PAPER
2-(Morpholin-4-ylcarbonyl)benzo[b]thiophen-3-yl Acetate (6e)
Yellow oil; Rf = 0.73 (THF–pentane, 1:1).
13C NMR: d = 20.6, 23.7, 26.5, 35.5, 121.2, 122.7, 122.8, 124.9,
126.2, 132.1, 136.1, 138.8, 162.4, 168.1.
IR (neat): 1778, 1634 cm–1.
MS: m/z (%) = 337 (4.4, [M+]), 295 (100).
1H NMR (500 MHz): d = 2.41 (s, 3 H), 3.69–3.76 (m, 8 H), 7.40–
7.46 (m, 2 H), 7.61–7.63 (m, 1 H), 7.77–7.79 (m, 1 H).
Anal. Calcd for C16H16ClNO3S: C, 56.89; H, 4.77; N, 4.15. Found:
C, 56.95; H, 5.05; N, 4.12.
13C NMR: d = 20.7, 49.1, 57.2, 121.3, 121.5, 122.8, 126.0, 126.5,
5-Chloro-2-(morpholin-1-ylcarbonyl)benzo[b]thiophen-3-yl
Acetate (6j)
Pale-yellow oil; Rf = 0.30 (EtOAc–hexane, 2:3).
132.0, 136.4, 139.2, 162.1, 167.8.
MS: m/z (%) = 305 (9.6, [M+]), 263 (100).
IR (neat): 1780, 1636 cm–1.
Anal. Calcd for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59. Found: C,
58.86; H, 5.13; N, 4.53.
1H NMR (500 MHz): d = 2.42 (s, 3 H), 3.68–3.72 (m, 8 H), 7.40
(dd, J = 8.7, 1.8 Hz, 1 H), 7.60 (d, J = 1.8 Hz, 1 H), 7.70 (d, J = 8.7
Hz, 1 H).
13C NMR: d = 20.6, 50.1, 58.8, 121.0, 123.4, 123.9, 127.1, 131.6,
133.2, 134.4, 138.3, 161.6, 167.7.
3-Acetoxy-5-chloro-N,N-dimethylbenzo[b]thiophene-2-carbox-
amide (6f)
Pale-yellow oil; Rf = 0.36 (THF–hexane, 1:1).
IR (neat): 1778, 1636 cm–1.
1H NMR (500 MHz): d = 2.40 (s, 3 H), 3.10 (s, 6 H), 7.38 (dd,
J = 8.7, 1.8 Hz, 1 H), 7.58 (d, J = 1.8 Hz, 1 H), 7.69 (d, J = 8.7 Hz,
1 H).
MS: m/z (%) = 339 (4.0, [M+]), 297 (100).
Anal. Calcd for C15H14ClNO4S: C, 53.02; H, 4.15; N, 4.12. Found:
C, 52.92; H, 4.15; N, 3.94.
13C NMR: d = 20.6, 38.7, 121.0, 123.9, 124.6, 126.9, 131.5, 133.2,
134.5, 138.0, 162.7, 167.8.
MS: m/z (%) = 297 (8.4, [M+]), 255 (100).
Acknowledgment
We thank Mrs. Miyuki Tanmatsu of this university for recording
mass spectra and performing combustion analyses.
Anal. Calcd for C13H12ClNO3S: C, 52.44; H, 4.06; N, 4.70. Found:
C, 52.32; H, 4.14; N, 4.65.
3-Acetoxy-5-chloro-N,N-diethylbenzo[b]thiophene-2-carbox-
amide (6g)
Yellow oil; Rf = 0.36 (EtOAc–hexane, 1:2).
IR (neat): 1780, 1633 cm–1.
1H NMR (400 MHz): d = 1.21 (t, J = 7.3 Hz, 6 H), 2.38 (s, 3 H),
3.49 (br s, 4 H), 7.38 (dd, J = 8.3, 2.0 Hz, 1 H), 7.59 (d, J = 2.0 Hz,
1 H), 7.69 (d, J = 8.3 Hz, 1 H).
References
(1) Kobayashi, K.; Horiuchi, M.; Fukamachi, S.; Konishi, H.
Tetrahedron 2009, 65, 2430.
(2) (a) Svodoba, J.; Nic, M.; Palecek, J. Collect. Czech. Chem.
Commun. 1993, 58, 592. (b) Cabiddu, M. G.; Cabiddu, S.;
Cadoni, E.; Demontis, S.; Fattuoni, C.; Melis, S.
Tetrahedron 2002, 58, 4529.
(3) Moretto, A. F.; Kirincich, S. J.; Xu, W. X.; Smith, M. J.;
Wan, Z.-K.; Wilson, D. P.; Follows, B. C.; Binnun, E.;
Joseph-McCarthy, D.; Foreman, K.; Erbe, D. V.; Zhang, Y.
L.; Tam, S. K.; Tam, S. Y.; Lee, J. Bioorg. Med. Chem. 2006,
14, 2162; and pertinent references cited therein.
(4) (a) Boschelli, D. H.; Kramer, J. B.; Conner, D. T.; Lesch, M.
E.; Schrier, D. J.; Ferin, M. A.; Wright, C. D. J. Med. Chem.
1994, 37, 717. (b) Lee, J.; Kirincicch, S. J.; Smith, M. J.;
Wilson, D. P.; Follows, B. C.; Wan, Z.-K.; Joseph-
Mccarthy, D. M.; Erbe, D. V.; Zhang, Y.-L.; Xu, W.; Tam,
S. Y. Patent PCT Int. Appl. WO 2005081960, 2005; Chem.
Abstr. 2005, 143, 266909. (c) Knieps, S.; Dedio, J.; Heitsch,
H.; Czechtiaky, W.; Grueneberg, S.; Shimshock, S.; Kosley,
R.; Lanter, C.; Li, H.; Sher, R.; Weichsel, A. A. European
Patent Appl. EP 1676834, 2006; Chem. Abstr. 2006, 145,
124339. (d) Sasikumar, T. K.; Burnett, D. A.; Zhang, H.;
Smith-Torhan, A.; Fawzi, A.; Lachowicz, J. E. Bioorg. Med.
Chem. Lett. 2006, 16, 4543. (e) Hachtel, S.; Dedio, J.;
Defossa, E.; Gruneberg, S.; Heitsch, H.; Bock, W.; Chen, C.;
Kosely, R.; Kung, C.-Y.; Patek, M.; Sher, R.; Shimshock, S.;
Weichsel, A. Patent PCT Int. Appl. WO 2008000409, 2008;
Chem. Abstr. 2008, 148, 121477. (f) Bissantz, C.;
Grundschober, C.; Masciadn, R.; Ratni, H.; Rogers-Evans,
M.; Schnider, P. A. Patent PCT Int. Appl. WO 2008077811,
2008; Chem. Abstr. 2008, 149, 128741.
13C NMR: d = 14.3, 20.5, 39.5, 120.8, 123.8, 124.8, 126.7, 131.4,
133.2, 134.1, 137.9, 161.9, 167.9.
MS: m/z (%) = 325 (7.3, [M+]), 283 (100).
Anal. Calcd for C15H16ClNO3S: C, 55.30; H, 4.95; N, 4.30. Found:
C, 55.11; H, 5.03; N, 4.25.
5-Chloro-2-(pyrrolidin-1-ylcarbonyl)benzo[b]thiophen-3-yl
Acetate (6h)
Pale-yellow solid; mp 95–97 °C (hexane).
IR (KBr): 1778, 1626 cm–1.
1H NMR (500 MHz): d = 1.95 (br s, 4 H), 2.40 (s, 3 H), 3.61 (br s,
4 H), 7.39 (dd, J = 8.7, 1.8 Hz, 1 H), 7.61 (d, J = 1.8 Hz, 1 H), 7.69
(d, J = 8.7 Hz, 1 H).
13C NMR: d = 20.7, 26.2, 48.8, 121.0, 123.8, 124.9, 127.0, 131.4,
133.3, 134.2, 138.7, 161.0, 167.9.
MS: m/z (%) = 323 (10, [M+]), 281 (100).
Anal. Calcd for C15H14ClNO3S: C, 55.64; H, 4.36; N, 4.33. Found:
C, 55.59; H, 4.47; N, 7.18.
5-Chloro-2-(piperidin-1-ylcarbonyl)benzo[b]thiophen-3-yl
Acetate (6i)
Pale-yellow oil; Rf = 0.30 (EtOAc–C6H6, 1:10).
IR (neat): 1778, 1634 cm–1.
1H NMR (500 MHz): d = 1.62–1.70 (m, 6 H), 2.40 (s, 3 H), 3.58 (br
s, 4 H), 7.38 (dd, J = 8.7, 1.8 Hz, 1 H), 7.57 (d, J = 1.8 Hz, 1 H),
7.69 (d, J = 8.7 Hz, 1 H).
(5) Lau, C. K.; Bélanger, P. C.; Dufresne, C.; Scheigetz, J.
J. Org. Chem. 1987, 52, 1670.
(6) Sarker, M.; Shahrin, T.; Steinmetz, M. G. Org. Lett. 2011,
13, 872.
(7) Abe, H.; Fujii, H.; Masunari, C.; Itani, J.; Kashino, S.;
Shibaike, K.; Harayama, T. Chem. Pharm. Bull. 1997, 45,
778.
Synthesis 2011, No. 21, 3429–3434 © Thieme Stuttgart · New York