A convenient approach towards 2- and 3-aminobenzo[b]thiophenes

Article abstract of DOI:10.1016/j.tet.2010.01.069

Reaction of 1-(2-chloro-5-nitrophenyl)ethanone via Willgerodt-Kindler route with primary or secondary amines and sulfur allows a simple, efficient one-pot synthesis of 3-aminobenzo[b]thiophenes. Base-catalyzed transformation of 4-(2-chloro-5-nitrophenyl)-

Full text of DOI:10.1016/j.tet.2010.01.069

Tetrahedron 66 (2010) 2474–2485
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A convenient approach towards 2- and 3-aminobenzo[b]thiophenes
,
b
,
b
a
c
d
Dmitry A. Androsova , Andrey Y. Solovyev , Mikhail L. Petrov , Ray J. Butcher , Jerry P. Jasinski
*
a Department of Organic Chemistry, Saint-Petersburg State Institute of Technology, Moskovskii prospekt 26, Saint-Petersburg 190013, Russian Federation
b Center for Photochemical Sciences, Bowling Green State University, Bowling Green, OH 43403, USA
c Department of Chemistry, Howard University, Washington, DC 20059, USA
d Department of Chemistry, Keene State College, Keene, NH 03435, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 1-(2-chloro-5-nitrophenyl)ethanone via Willgerodt–Kindler route with primary or secondary
amines and sulfur allows a simple, efficient one-pot synthesis of 3-aminobenzo[b]thiophenes. Base-
catalyzed transformation of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole in the presence of primary
and secondary amines offers a convenient approach towards 2-aminobenzo[b]thiophenes.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 October 2009
Received in revised form 10 December 2009
Accepted 18 January 2010
Available online 1 February 2010
1. Introduction
3-bromobenzo[b]thiophene and piperidine in a sealed tube at
250–260 ꢀC for 46 h,9 and hydrogenation of 2-(phenylazo)-3,4,6-
Though derivatives of 2-dimethylamino-6-hydroxybenzo[b]thi
ophene are important intermediates in the synthesis of the selec-
tive estrogen receptor modulatorsdraloxifene and its analogs,1–4
2-aminobenzo[b]thiophenes in general belong to an elusive
group of benzo[b]thiophenes.
It was found that some 3-aminobenzo[b]thiophenes exhibit
high antifungal activity against clinically relevant Candida, Asper-
gillus, and dermatophyte species. The most active compound
N-(benzo[b]thiophen-3-yl)pyridin-3-amine showed a broad spec-
trum of activity against all tested fungal strains, including
fluconazole-resistant yeasts and Aspergillus fumigatus, especially
important organisms from the clinical point of view.5 In vitro
antimicrobial activity of some 3-arylaminobenzo[b]thiophenes was
evaluated. Selectivity against Bacillus cereus was observed, with low
minimal inhibitory concentrations.6
2-Aminobenzo[b]thiophene itself can be obtained in five steps
(overall yield 48%) from thiosalicylic acid. The key reaction involves
thio-ether cleavage of ortho-benzylmercaptophenylacetonitrile. In
contrast to 2-hydroxybenzo[b]thiophene, which exists mainly as
the tautomeric keto form, 2-aminobenzo[b]thiophene exists
preferably in the amino form.7 Other 2-aminobenzo[b]thiophenes,
synthesized classically, include 2-morpholinobenzo[b]thiophene,
which was obtained by the addition of morpholine and its alkali
metal salt to the C2–C3 double bond of benzo[b]thiophene (yield
45%) followed by aromatization with sulfur at 250 ꢀC (yield 60%),8
2-piperidino benzo[b]thiophene prepared in 85% yield by heating
a mixture of 2-bromobenzo[b]thiophene and piperidine in a sealed
tube at 220 ꢀC for 28 h and in 20% yield by heating a mixture of
trimethylbenzo[b]thiophene in the presence of acetic anhydride,
which afforded 2-acetamido-3,4,6-trimethylbenzo[b]thiophene
(yield 18%).10 2-Dimethylamino-6-benzyloxybenzo[b]thiophene
was prepared in two steps by the treatment of a mixture of
4-benzyloxybenzaldehyde and N,N-dimethylthioformamide with
LDA at ꢁ78 ꢀC and following cyclization–aromatization with
MeSO3H.4
3-Dialkylaminobenzo[b]thiophenes were synthesized by the
reaction of 3-bromobenzo[b]thiophene-1-oxide with secondary
amines followed by reduction of 3-aminobenzo[b]thiophene-1-
oxide with Dibal-H in a 60–80% yield.11 A number of 3-alkyl- and 3-
arylaminobenzo[b]thiophenes were synthesized by palladium- or
copper-catalyzed amination of 3-bromobenzo[b]thiophene.12–15
3-Aminobenzo[b]thiophene itself was previously prepared by:
(1) reduction of 3-nitrobenzo[b]thiophene using ethanolic ammo-
nium sulfide (75% yield). 3-Nitrobenzo[b]thiophene was obtained
from benzo[b]thiophene through the sequence of reactions in-
volving sulfonation, nitration and desulfonation (8% overall yield),16
(2) thermal decomposition of 3-azidobenzo[b]thiophene in
diethyl- or dimethylamine in a sealed tube at 90 ꢀC (6–10% yield).17
3-Aminobenzo[b]thiophenes-2-carboxylates were prepared by
(a) the reaction of 3-chloro-1,2-benzothiazole with diethyl sodium
18
malonate (70% yield),
(b) condensation of 2-cyanothiophenol
with ethyl bromomalonate in aqueous sodium hydroxide (82%
yield),18 (c) by the reaction of 2-fluorobenzonitrile with ethyl thi-
oglycolate and excess of triethylamine in DMSO at 100 ꢀC (62–70%
yield).19,20
In previous papers we have reported that 1-(2-chloro-5-nitro-
phenyl)ethanone can serve as
a
precursor for 2-amino-
benzo[b]thiophenes,21 while 4-(2-chloro-5-nitrophenyl)-1,2,3-
* Corresponding author. Tel.: þ7 812 463 6477; fax: þ7 812 460 8146.
E-mail address: da_androsov@hotmail.com (D.A. Androsov).
thiadiazole, prepared from 1-(2-chloro-5-nitrophenyl)ethanone,
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.069

D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
2475
was a convenient precursor for indole-2-thiols.22,23 Recently we
Table 1
Synthesis of 3-aminobenzo[b]thiophenes
discovered that structures reported in our original papers were
incorrectly assigned. In this paper we want to summarize our
previous results and to report the revised structures supported by
additional spectroscopic evidences and X-ray crystallographic data.
Entry
Amine
Product
Yield (%)
1
46
47
36
30
14
40
19
4
2. Results and discussion
2.1. 3-Aminobenzo[b]thiophenes
2
3
4
5
6
7
8
9
The reaction of 1-(2-chloro-5-nitrophenyl)ethanone 1 with
primary and secondary amines 2 under Willgerodt–Kindler con-
ditions afforded 3-aminobenzo[b]thiophenes 3 (Scheme 1, Table 1).
Scheme 1.
According to the general procedure, the substrate 1 was heated
in DMF at 35–100 ꢀC in the presence of amine 2 (1.2–3.7 equiv),
sulfur (1.5–5 equiv), and NaOAc (0–3 equiv) for 6–20 min. The
solvent was removed under reduced pressure and the desired
product was isolated by column chromatography.
A plausible mechanism of the reaction is shown below
(Scheme 2). The first stage of the reaction is enamine 5 forma-
tion by the ketone group of acetophenone 1 and the amine
group of alkylamine. The intermediate 5 reacts with sulfur to
give the sulfide 6. Subsequent formation of enthiolate 8, fol-
lowed by cyclization, leads to final product 3. As for conven-
tional Willgerodt–Kindler reaction, the rearrangement reaction
takes place when the amine group attacks thiocarbonyl 7 in
a nucleophilic addition forming an aziridine ring 9 and the
amine group moving along the central C–C bond rearranging to
10, further proton exchange and tautomerization affords thio-
acetamide 4.24
31
Generally, we found that a nitro group para to the chlorine atom
promotes the reaction. Reaction did not occur in the absence of
nitro group. For example, 1-(2-chlorophenyl)ethanone yielded
a
complex mixture of products instead of corresponding
10
10
benzo[b]thiophene.
The nature of base is not important. K3PO4, NaOAc or an excess
of amine can serve as a base. Primary amines gave better yields of
3-aminobenzo[b]thiophenes than secondary amines.
The reaction crucially depends on the concentration of the
amine. A 1.5–3 fold excess was preferable for secondary amines
and a 1.5–2 fold excess was preferable for primary amines. The
content of by-products depends on the nature of amine. In case of
primary amines, the major by-product was 3-methyl-5-nitro-
benzo[d]isothiazole, becoming dominant in the presence of 8–10
fold excess of amine. In contrast, in the case of secondary amines
the main by-product was the product of nucleophilic substitution
on the benzene ring.
11
12
We also found that the optimal ratio of acetophenone/sulfur is
1:5. The better yields of primary amines were observed at lower
temperature (35–60 ꢀC) while higher temperature (60–100 ꢀC)
worked better for secondary amines (Table 2). DMF was found to be
the most favorable solvent. Whereas primary amines are usually
more reactive than secondary amines in the classical Willgerodt–
Kindler reaction.25
Steric effects play an important role. The yield of 2-cyclo-
pentylaminobenzo[b]thiophene 3f (40%, entry 6) was higher than

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D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
procedure was applied to the synthesis of earlier unknown 4-(2-
chloro-5-nitrophenyl)-1,2,3-thiadiazole 13 from 1-(2-chloro-5-
nitrophenyl)-ethanone 1 in 89% overall yield (Scheme 4).
Scheme 4.
We next conducted the base-catalyzed (K2CO3) alkylamination
of 13 with a variety of primary and secondary amines 2a–x in DMF
at moderate temperature (50–90 ꢀC). The products of the reaction
were unexpected 2-aminobenzo[b]thiophenes 14a–x (Scheme 5,
Tables 3 and 4). In addition, we found that the reaction is tolerant to
the medium and MeCN, Me2CO, MeOH, EtOH can be used as the
solvents. The use of DMF allows the reaction even at room
temperature (20–25 ꢀC).
Scheme 2.
Table 2
Conditions for preparation of 3-aminobenzo[b]thiophenes
Entry
Product
Ratio
Amine/S/Base
Temperature
(ꢀC)
Time
(min)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3/5/3
2.17/5/0
3.2/3/2
3.8/5/0
2.3/5/0
2.15/5/0
1.95/5/0
1.5/1.5/1.5
3.7/3/2
1.2/1.5/1.5
1.4/5/1.5
60
45
60
60
60
60
35
100
60
100
100
10
10
8
10
10
10
6
180
15
20
12
9
10
11
3j
3k
Scheme 5.
Generally, we did not optimize the reaction conditions (ratio of
reagents, choice of solvent, temperature) in each particular case.
But according to our observations the yield of 2-amino-
benzo[b]thiophene can be increased at lower reaction temperature
(92%, 22 h; 25 ꢀC) vs (44%d3 h; 50 ꢀC) for product 14c. Reaction of
13 with aniline and N-phenylhydrazine under the same conditions
gave none of the desired 2-aminobenzo[b]thiophene.
the yield of 2-cyclohexylaminobenzo[b]thiophene 3g (19%, entry
7). Sterically hindered (dibutylamine, diallylamine, di-iso-propyl-
amine), aromatic (aniline) and heterocyclic (benzotriazole) amines
failed to react. An attempt to obtain N-unsubstituted benzothio-
phene using NH4Cl in the presence of NaOAc afforded 3-methyl-5-
nitro-benzo[d]isothiazole 11, yield 78% (Scheme 3). The synthesis of
11 under harsh conditions is reported in literature.26
The mechanism of this reaction was studied by 1H NMR moni-
toring of a reaction mixture containing 13, 2c, and K2CO3 in DMF at
25 ꢀC (Scheme 6). Initially, the thiadiazole ring-opening was
indicated by the disappearance of the thiadiazole H5 at dH 9.19.
Decomposition of the electron-withdrawing thiadiazole ring was
accompanied by nitrogen evolution and formation of thioamide 20.
The appearance of NH at dH 7.44 and an upfield shift of phenyl
protons at the 3, 4, and 6 positions moved by 0.30, 0.16, and
0.89 ppm, respectively, were observed. We also followed the
progress of the reaction by GC–MS. This supports formation of
intermediate 20 (m/z 286). After 22 h the transformation was
complete and the NMR spectrum showed a clean absorption
pattern of N-butyl-5-nitrobenzo[b]thiophen-2-amine 14c with dH
0.97 (CH3CH2CH2CH2–NH), 1.46 (CH3CH2CH2CH2–NH), 1.67
Scheme 3.
Whereas the classical Willgerodt–Kindler reaction requires high
temperature and prolonged heating,27,28 microwave assis-
tance25,29–31 or special reagents,32 surprisingly, our reaction
proceeded under mild conditions (Table 2).
(CH3CH2CH2CH2–NH),
3.24
(CH3CH2CH2CH2–NH),
4.28
2.2. 2-Aminobenzo[b]thiophenes
(CH3CH2CH2CH2–NH), 6.12 (H3), 7.59 (H7), 7.87 (H6), 8.21 (H4).
There were no detectable impurities present. The supposed
intermediates 16, 17, 18, 19, 21 were not detected by 1H NMR but
their formation is not in conflict with our observations and data
documented in literature.35–37
The Hurd–Mori reaction allows synthesis of 4-substituted 1,2,3-
thiadiazoles from methyl ketones by the action of thionyl chloride
on the corresponding ethylcarbazones or tosylhydrazones.33,34 This

D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
2477
Table 3
Table 3 (continued )
Synthesis of 2-aminobenzo[b]thiophenes
Entry
Amine
Product
Yield (%)
Entry
Amine
Product
Yield (%)
16
25
38
1
2
6
42
17
3
44
33
29
33
38
75
7
18
19
41
39
4
5
20
9
6
7
21
23
8
NH4OAc
9
22
23
63
20
10
11
17
49
24
74
12
13
26
Compound 14i (entry 9) was obtained in a low yield (7%) due to
the relatively high nucleophilicity of the pyrrolidine, which dis-
places the chlorine atom on the benzene ring faster than cyclization
to 14i occurs, affording thioamide 22 (62%) as a major product
(Scheme 7).
It is noteworthy that the best result in the synthesis of com-
pound 14h (entry 8) was achieved using the combination NH4OAc/
K2CO3/DMF that made it possible to generate dimethylamine in situ
(Scheme 8).
In order to understand how the electron-withdrawing nitro
group affects the reaction we prepared 4-(2-chlorophenyl)-1,2,3-
thiadiazole 25 (overall yield 37%) from 1-(2-chlorophenyl)-etha-
none 23 according to the Hurd–Mori procedure.34 Compound 25
was heated in the presence of n-BuNH2 and K2CO3 at 70 ꢀC for 24 h
but only starting material 25 and thioamide 26 were detected in the
reaction mixture. Complete conversion of 25 to 26 was achieved at
elevated temperature (130 ꢀC), but no traces of cyclic product 27
were found. Thus, the presence of the activating nitro group on the
61
55
14
15
33
(continued on next page)

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D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
Table 4
Conditions for preparation of 2-aminobenzo[6]thiophenes
Entry
Product
Ratio 13/2/K2CO3
Temperature
(ꢀC)
Time
(h)
1
2
3
4
5
6
7
8
14a
14b
14c
14d
14e
14f
14g
14h
141
14j
1/3/2
1/3/2
1/3/2
1/3/2
1/4/2
1/3/2
1/3/2
1/5/7
1/5/5
1/5/5
1/5/5
1/3/2
1/3/2
1/5/3
1/5/3
1/5/5
1/5/5
1/3/3
1/3/2
1/1.05/3
1/2/2
1/3/3
1/3/3
1/3/3
60
70
50
70
60
70
70
90
90
90
90
80
80
90
90
90
90
90
70
80
70
90
90
90
6
3
3
3
6
Scheme 8.
3
3
phenyl ring makes 1,2,3-thiadiazole ring susceptible to proton
abstraction facilitating anionic ring-opening. In addition, cycliza-
tion of 26 to 27 does not occur since the chlorine atom is insensitive
to intramolecular nucleophilic attack by sulfur under the reaction
conditions (Scheme 9).
12
12
12
12
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
14k
14l
14m
14n
14o
14p
14q
14r
14s
14t
14u
14v
14w
14x
3
12
12
12
12
12
3
3
3
12
12
12
Scheme 9.
Treatment of 13 with MeONa in MeOH under an inert atmo-
sphere led to 2-methoxy-5-nitrobenzo[b]thiophene 29 (yield 23%).
Formation of 29 can be explained relying on already known data on
the reactivity of 5-unsubstituded 1,2,3-thiadiazoles.35–37 By anal-
ogy with Scheme 6, an addition of MeONa to thioketene 19 results
in enthiol anion 28 cyclizing to benzothiophene 29 (Scheme 10).
Scheme 6.
Scheme 10.
An attempt to introduce the sulfur-containing nucleophile by
reaction of 13 with potassium thioacetate resulted in the product of
nucleophilic substitution on the benzene ring. This gave thio-
phenolate 30 without decomposition of the heterocyclic ring. An-
ion 30 can be trapped as thiol 31 (yield 80%) after addition of
diluted HCl (Scheme 11).
Scheme 11.
Scheme 7.

D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
2479
Decomposition of 13 under influence of base (K2CO3, MeCN;
80 ꢀC, 6 h) in the absence of nucleophiles afforded alkynethiolate
17, which reacted with water forming alkyne thiol 18. Tautomeri-
zation of 18 to 19 and subsequent dimerization afforded dithia-
fulvene 32 (Scheme 12).
explained by the less efficient delocalization of the amino group
lone-pair electrons into the benzene ring in the second case (Fig. 1,
Table 6).
Figure 1. nN–pAr Delocalization in 2- and 3-aminobenzo[b]thiophenes.
Scheme 12.
The H2 proton in N-methyl-5-nitrobenzo[b]thiophen-3-amine 3a
is shielded better (DdH2¼þ1.49 ppm) than H3 proton in isomeric N-
methyl-5-nitrobenzo[b]thiophen-2-amine 14a (DdH3¼þ1.36 ppm).
Whereas H3 protons in tertiary 2-N,N-dimethylamino-, 2-pyrroli-
dino- and 2-piperidinobenzo[b]thiophenes 14h–j (DdH3¼þ1.52, 1.60,
1.31 ppm) are shielded better than H2 proton in isomeric 3-N,N-
dimethylamino-, 3-pyrrolidino- and 3-piperidino-derivatives 3h–j
2.3. Effect of substitution pattern on 1H NMR chemical shifts
in 2- and 3-aminobenzo[b]thiophenes
In the 1H NMR spectra of 2- and 3-aminobenzo[b]thiophenes
the position of H3 and H2 protons is an indicative of the degree of
overlap between electron pair on the amino group nitrogen atom
and the endo-cyclic C2–C3 double bond. In contrast to electron-
deficient 5-nitrobenzo[b]thiophene,38 the heterocyclic ring in 2-
and 3-aminobenzo[b]thiophenes is electron-rich due to the
donating nature of the amino group. This results in a significant
shielding of proton in ortho-position to the amino group (Table 5).
(
DdH2¼þ0.97, 1.45, 0.91 ppm), see Table 6.
The difference in shieldings between tertiary 2- and 3-amino-
benzo[b]thiophenes reflects the partial deconjugation of the amino
group of the latter. This effect, pronounced for sterically bulky
piperidine substituent vs more compact pyrrolidine substituent,
indicates the twisting of the bulky group out of conjugation due to
the additional steric repulsion provoked by H4 atom in peri-
position of the benzene ring. The similar substituent influence can
be seen in 13C NMR spectra of 3-aminobenzo[b]thiophenes: C2-
atom of 3-pyrrolidino-derivative 3i bears the larger negative
charge (dC2¼99.9 ppm) vs relatively positively charged C2-atom of
3-piperidino-derivative 3j (dC3¼109.7 ppm), see Table 7.
Table 5
Chemical shifts (
(CDC13)
d, ppm) of ring protons in 2- and 3-aminobenzo[b]thiophenes
The values of the substituent-induced upfield chemical shifts of
H2 and H3 atoms in aminobenzo[b]thiophenes are closer to those
of the enamines of cyclopentanone than to the related chemical
shifts in anilines (Fig. 2).39,40
In spite of close similarity between the NMR spectra of 2- and
3-aminobenzo[b]thiophenes these isomers can easily be distin-
guished by NOE experiment. Thus, irradiation of H3 proton in
2-amino-derivative results in a significant NOE on benzene ring H4
proton, whereas irradiation of H2 proton does not lead to percep-
tible NOE on H4 proton (Fig. 3).
Entry Compd R2
R3
dH2
dH3
dH4
dH6
dH7
1
2
3
d
H
H
H
H
7.65 7.49 8.71 8.18 7.98
3a
3h
NHMe
N(Me)2
6.16
6.68
d
d
8.48 8.16 7.84
8.73 8.19 7.88
4
5
3i
3j
H
H
6.20
6.74
d
d
8.87 8.12 7.82
8.62 8.17 7.87
2.4. Molecular structures of representative compounds
6
7
14a
14h
NHMe
N(Me)2
H
H
d
d
6.13 8.24 7.89 7.60
5.97 8.20 7.82 7.59
Biaryl system of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole 13
has a propeller-like shape
4
(C1–C6–C7–C8)¼39.5ꢀ (Fig. 4).
8
14i
H
d
5.89 8.21 7.81 7.60
Piperidine ring in 1-(5-nitrobenzo[b]thiophen-2-yl)piperidine
14j has a shape of chair with the aromatic fragment in an equatorial
position. This relatively rigid conformation prevents N-atom from
9
14j
29
H
H
d
d
6.18 8.23 7.87 7.62
6.46 8.40 8.04 7.70
adopting favorable sp2 hybridization:
4
(C2–C1–N2–C13)¼16.5ꢀ,
10
OMe
4
(C2–C1–N2–C9)¼158.2ꢀ, and C1–N2 bond is slightly bent beyond
the aromatic ring plane
4
(C3–C2–C1–N2)¼174.2ꢀ. The nitro group
is twisted out of the benzene ring plane to a certain extent
(C6–C5–N1–O1)¼10.1ꢀ (Fig. 5).
4
The protons on the benzene ring in 2-amino-substituted
derivatives are shifted upfield comparing to the corresponding
protons in isomeric 3-amino-substituted derivatives. This can be
The state of hybridization of the N-atom can be roughly
estimated following trimethylamine example: the C–N–C angle in
tetrahedral sp3 hybridized N(CH3)3 is 108ꢀ and the total sum of

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D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
Table 6
Substituent effects on ring protons in 2- and 3-aminobenzo[b]thiophenes (CDCI3)
Entry
Compd
R2
R3
dH2
dH3
dH4
dH6
dH7
1
2
3
d
H
H
H
H
0
0
d
0
0
0
3a
3h
NHMe
N(Me)2
þ1.49
þ0.23
þ0.02
þ0.14
þ0.97
d
ꢁ0.02
ꢁ0.01
þ0.10
4
5
3i
3j
H
H
þ1.45
þ0.91
d
d
ꢁ0.06
þ0.09
þ0.06
þ0.01
þ0.16
þ0.11
6
7
14a
14h
NHMe
N(Me)2
H
H
d
d
þ1.36
þ1.52
þ0.47
þ0.51
þ0.29
þ0.36
þ0.38
þ0.39
8
14i
14j
29
H
H
H
d
d
d
þ1.60
þ1.31
þ1.03
þ0.50
þ0.48
þ0.31
þ0.37
þ0.31
þ0.14
þ0.38
þ0.36
þ0.28
9
10
OMe
Substituent-induced chemical shifts (Dd, ppm). Positive values denote an upfield shift with respect to the unsubstituted substance.
Table 7
Chemical shifts (
(CDC13)
d, ppm) of ring carbons in 2- and 3-aminobenzo[b]thiophenes
Entry
Compd
R2
R3
Dc2
97.0
Dc3
Dc3a
1
2
3a
3h
H
H
NHMe
N(Me)2
145.5
149.0
132.4
134.7
108.4
3
4
3i
3j
H
H
99.9
145.8
149.2
133.7
135.0
109.7
5
6
14a
14h
NHMe
N(Me)2
H
H
157.3
159.9
95.9
95.5
138.2
138.3
7
8
9
14i
14j
29
H
H
H
156.1
160.7
168.1
93.6
97.3
98.3
137.9
138.5
138.2
OMe
Figure 2. Chemical shifts of protons (d, ppm) in ortho-position to N-substituent in
selected 2- and 3-aminobenzo[b]thiophenes, enamines of cyclopentanone, dia-
lkylanilines and their parent compound (CDCl3).
C–N–C angles is 324ꢀ. The projection of the N(CH3)3 molecule on
the plane gives the planar sp2 hybridized structure and the sum of
C–N–C angles amounts to 360ꢀ. The other transition states of the
molecule have the sum of the C–N–C angles ranging from 324ꢀ to
360ꢀ. The sum of the Rx–N–Ry angles in the tertiary amine 14j is
348.5ꢀ, while the corresponding value for the secondary amine 3d
is 356.4ꢀ, indicating that N-atom of 3d is sp2 hybridized to a great
extent (Fig. 6).
studied the reactivity of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadia-
zole 13 with N,O,S-nucleophiles. The unusual base-induced trans-
formation of 13 in the presence of amines granted a simple and
practical route to potentially important2-aminobenzo[b]thiophenes
14. A similar transformation of 13 in the presence of methanol pro-
duced 2-methoxy-5-nitrobenzo[b]thiophene 29.
3. Conclusion
4. Experimental
4.1. General
In conclusion, we have found and developed simple, convenient
approach to potentially important 3-aminobenzo[b]thiophenes 3
starting from cheap, commercially available 1-(2-chloro-5-nitro-
phenyl)ethanone 1. The method allowed us to synthesize a number
of earlier unknown heterocycles. We have also synthesized and
Reagents. All chemicals were used as purchased. Solvents for
crystallization and chromatography were technical grade. When

D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
2481
columns or by direct introduction of the effluent into the ion source
using EI or ES technique. 1H and 13C NMR spectra (300 and 75 MHz,
respectively) were recorded on a Varian Mercury Plus-300 spec-
trometer using TMS or the signal of residual solvent protons as an
internal standard. GC analyses were performed on a Varian 3900 gas
chromatograph equipped with J&W capillary column (DB-1301,
30 mꢂ0.25 mm ID). An initial temperature of 70 ꢀC was maintained
for 3 min and then a heating rate of 20 ꢀC/min was applied until the
final temperature of 270 ꢀC was reached.
4.2. Synthesis of 3-aminobenzo[b]thiophenes
4.2.1. General procedure for the synthesis of 3-amino-
benzo[b]thiophenes (3a–k). 1-(2-Chloro-5-nitrophenyl)ethanone 1
(200 mg; 1.0 mmol), the corresponding amine 2a–k (1.2–
3.8 equiv), DMF (10 mL), elemental sulfur (1.5–5 equiv), and NaOAc
(0–3 equiv) (in that order; for molar ratios see Table 2) were
charged into 50 mL round bottom flask. The mixture was heated
and stirred for 6–180 min at 35–100 ꢀC. DMF was removed under
reduced pressure and the residue purified by column chromatog-
raphy (SiO2, hexane/ethyl acetate (8:1)) affording corresponding
3-aminobenzo[b]thiophene 3a–k (yields 4–47%, see Table 1).
Figure 3. Selected NOE correlations for compound 3a,h and 14a,h.
4.2.1.1. N-Methyl-5-nitrobenzo[b]thiophen-3-amine (3a). Yellow
solid, 96 mg (46%), mp 138–139 ꢀC. IR (neat): 3239, 3126, 1598,
1579, 1432, 1327, 1245, 1204, 1146, 1117, 1055, 888, 843, 796,
769 cmꢁ1. 1H NMR (CDCl3)
d: 3.01 (s, 3H), 4.10 (br s, 1H), 6.16 (s, 1H),
Figure 4. CHEM3D presentation of X-ray structure of 4-(2-chloro-5-nitrophenyl)-
1,2,3-thiadiazole (13).
7.84 (d, J¼9.0 Hz, 1H), 8.16 (dd, J¼9.0, 2.4 Hz, 1H), 8.48 (d, J¼2.4 Hz,
1H). 13C NMR (CDCl3)
d: 32.2, 97.0, 115.6, 118.8, 123.6, 132.4, 143.5,
144.7, 145.5. m/z (EI) 208 (Mþ, 49%), 162 (100), 134 (44), 89 (21), 63
(30). HRMS (EI) calcd for C9H8N2O2S [Mþ] 208.0307, found
208.0306.
4.2.1.2. N-Allyl-5-nitrobenzo[b]thiophen-3-amine (3b). Red solid,
111 mg (47%), mp 105–107 ꢀC. 1H NMR (CDCl3)
d
: 3.89 (d, J¼5.7 Hz,
2H), 4.19 (br s, 1H), 5.26 (dd, J¼10.2, 1.2 Hz, 1H), 5.38 (dd, J¼17.4,
1.5 Hz, 1H), 5.98–6.12 (m, 1H), 6.18 (s, 1H), 7.81 (d, J¼9.0 Hz, 1H), 8.13
(dd, J¼9.0, 2.1 Hz,1H), 8.48 (d, J¼2.1 Hz,1H). 13C NMR (CDCl3)
d: 48.2,
98.1, 115.6, 117.2, 118.8, 123.5, 132.54, 134.6, 141.8, 144.7, 145.2. m/z
(EIþ) 234 (Mþ, 81%), 193 (34), 173 (23), 161 (43), 147 (100), 120 (21),
89 (17), 63 (31). HRMS (EI) calcd for C11H10N2O2S [Mþ] 234.0463,
found 234.0461.
Figure 5. CHEM3D presentation of X-ray structure of 1-(5-nitrobenzo[b]thiophen-2-
yl)piperidine (14j).
4.2.1.3. N-Butyl-5-nitrobenzo[b]thiophen-3-amine (3c). Red solid,
90 mg (36%), mp 109–110 ꢀC. 1H NMR (CDCl3)
d
: 1.01 (t, J¼6.9 Hz,
3H), 1.45–1.57 (m, 2H), 1.69–1.79 (m, 2H), 3.23 (t, J¼7.2 Hz, 2H), 6.13
(s, 1H), 7.82 (d, J¼8.7 Hz, 1H), 8.14 (dd, J¼8.7, 2.1 Hz, 1H), 8.48 (d,
J¼2.1 Hz, 1H). 13C NMR (CDCl3)
d: 13.9, 20.4, 31.4, 45.4, 96.9, 115.6,
118.7, 123.5, 132.5, 142.5, 144.6, 145.4. m/z (EI) 250 (Mþ, 59%), 207
(88), 161 (100), 147 (26), 133 (15), 89 (19). HRMS (EI) calcd for
C12H14N2O2S [Mþ] 250.0776, found 250.0774.
4.2.1.4. N-Benzyl-5-nitrobenzo[b]thiophen-3-amine (3d). Red solid,
86 mg (30%), mp 123–126 ꢀC. 1H NMR (CDCl3)
d: 4.43 (br s, NH, CH2Ph,
3H), 6.16 (s, 1H), 7.29–7.45 (m, 5H), 7.82 (d, J¼8.7 Hz, 1H), 8.15 (dd,
J¼8.7, 2.1 Hz, 1H), 8.50 (d, J¼2.1 Hz, 1H). 13C NMR (CDCl3)
d: 50.0, 98.2,
Figure 6. CHEM3D presentation of X-ray structure of N-benzyl-5-nitro-
benzo[b]thiophen-3-amine (3d).
115.6, 118.8, 123.6, 127.7, 127.75, 128.8, 132.5, 138.2, 141.9, 144.7, 145.3.
m/z (EI) 284 (Mþ, 47%), 282 (11), 147 (18), 91 (100), 77 (8), 65 (44), 51
(20). HRMS (EI) calcd for C15H12N2O2S [Mþ] 284.0620, found
284.0624. Crystallographic data: CCDC 762351.
required, solvents were freshly distilled from appropriate drying
agents before use.
General Methods. Analytical TLC was performed using silica gel 60
F254 TLC plates. Flash chromatography was performed using Merck
silica gel 60 (230–400 mesh). Melting points were uncorrected. LR
and HR mass spectra were obtained on Micromass 70-VSE and
Micromass Q-Tof Ultima instruments equipped with GS, HPLC
4.2.1.5. N-iso-Propyl-5-nitrobenzo[b]thiophen-3-amine
(3e). Red-orange solid, 32 mg (14%), mp 148–150 ꢀC. 1H NMR
(CDCl3)
d
: 1.34 (d, J¼6.3 Hz, 6H), 3.62–3.69 (m, 1H), 3.87 (br s, 1H),
6.14 (s, 1H), 7.85 (d, J¼8.7 Hz, 1H), 8.18 (dd, J¼8.7, 2.1 Hz, 1H), 8.49
(d, J¼2.1 Hz, 1H). 13C NMR (CDCl3)
d: 22.8, 46.4, 97.2, 115.6, 118.8,

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D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
123.5, 132.8, 141.0, 144.7, 145.3. m/z (EI) 236 (Mþ, 43%), 221 (100),
175 (37), 148 (29), 121 (15). HRMS (EI) calcd for C11H12N2O2S [Mþ]
236.0620, found 236.0618.
and DMF was removed under reduced pressure. The residue was
purified by column chromatography (SiO2, hexane/ethyl acetate
5:1) to afford 152 mg (78%) of the light orange product, mp 109–
110 ꢀC (Lit. Mp 114–115 ꢀC).26 1H NMR (CDCl3)
d
: 2.85 (s, 3H), 8.05
4.2.1.6. N-Cyclopentyl-5-nitrobenzo[b]thiophen-3-amine
(d, J¼8.7 Hz, 1H), 8.38 (dd, J¼8.7, 2.1 Hz, 1H), 8.84 (d, J¼2.1 Hz, 1H).
(3f). Red solid, 104 mg (40%), mp 142–145 ꢀC. 1H NMR (CDCl3)
d:
13C NMR (CDCl3)
d: 17.5, 119.6, 120.7, 121.7, 135.1, 145.6, 157.4, 164.1.
1.72–1.87 (m, 6H), 2.05–2.12 (m, 2H), 3.81–3.88 (m, 1H), 4.02 (br s,
m/z (EI) 194 (Mþ, 42%), 164 (46), 148 (17), 136 (35), 121 (25), 69 (27),
1H), 6.14 (s, 1H), 7.81 (d, J¼9.0 Hz, 1H), 8.17 (dd, J¼9.0, 2.1 Hz, 1H),
63 (100).
8.45 (d, J¼2.1 Hz,1H). 13C NMR (CDCl3)
d: 24.3, 33.4, 56.4, 97.6,115.6,
118.7, 123.5, 132.7, 141.7, 144.6, 145.3. m/z (EI) 262 (Mþ, 90%), 233
(68), 220 (29), 194 (100), 173 (32), 159 (18), 148 (55), 121 (21), 69
(34). HRMS (EI) calcd for C13H14N2O2S [Mþ] 262.0776, found
262.0774.
4.3. Synthesis of 2-aminobenzo[b]thiophenes
4.3.1. Ethyl 2-(1-(2-chloro-5-nitrophenyl)ethylidene)hydrazinecarbo
xylate (12). A mixture of 1-(2-chloro-5-nitrophenyl)ethanone 1
(28.1 g, 0.14 mol), ethyl carbazate (17.5 g, 0.17 mol), and 1 mL of
AcOH in 800 mL of EtOH/H2O (1:1) was refluxed for 3 h and left
overnight at rt. The precipitate was filtered, washed with EtOH/H2O
(1:1) and dried affording 37.8 g (94%) of 12 as a white solid, mp
4.2.1.7. N-Cyclohexyl-5-nitrobenzo[b]thiophen-3-amine
(3g). Orange solid, 52 mg (19%), mp 121–123 ꢀC. 1H NMR (CDCl3)
d:
1.44–1.49 (m, 5H), 1.68–1.72 (m, 1H), 1.81–1.86 (m, 2H), 2.15–2.19
(m, 2H), 3.29 (tt, J¼9.6, 3.6 Hz, 1H), 3.90 (br s, 1H), 6.13 (s, 1H), 7.82
(d, J¼8.7 Hz, 1H), 8.15 (dd, J¼8.7, 2.1 Hz, 1H), 8.49 (d, J¼2.1 Hz, 1H).
169–170 ꢀC. 1H NMR (CDCl3)
d
1.36 (t, J¼7.0 Hz, 3H), 2.26 (s, 3H),
4.34 (q, J¼7.0 Hz, 2H), 7.55 (d, J¼8.7 Hz, 1H), 7.98 (br s, 1H, NH), 8.16
13C NMR (CDCl3)
d: 25.0, 25.9, 33.1, 53.8, 96.9, 115.6, 118.7, 123.5,
(dd, J¼8.7, 2.7 Hz, 1H), 8.31 (d, J¼2.7 Hz, 1H); 13C NMR (75 MHz,
132.8, 140.9, 144.6, 145.3. m/z (EI) 276 (Mþ, 89%), 233 (55), 194 (58),
173 (31), 159 (18), 148 (46), 89 (14), 55 (100). HRMS (EI) calcd for
C14H16N2O2S [Mþ] 276.0933, found 276.0928.
CDCl3) d 14.5, 16.4, 62.5, 124.5, 125.8, 130.8, 139.3, 140.0, 146.6; m/z
(EI) 285 (Mþ, 20%), 250 (7), 195 (47), 178 (100), 166 (75), 151 (22),
137 (37), 102 (67); HRMS (EI) calcd for C11H12ClN3O4 [Mþ] 285.0516,
found 285.0514.
4.2.1.8. N,N-Dimethyl-5-nitrobenzo[b]thiophen-3-amine
(3h). Orange solid, 9 mg (4%), mp 130–132 ꢀC. IR (neat): 3124,
2953, 2832, 2787, 1598, 1568, 1501, 1473, 1422, 1265, 1245, 1196,
1172, 1145, 1098, 1086, 1038, 930, 890, 879, 848, 812, 778 cmꢁ1. 1H
4.3.2. 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole (13). A solution
of 12 (37.5 g, 0.13 mol) in 60 mL of SOCl2 was refluxed for 2 h,
cooled and poured into water. The precipitate was thoroughly
washed with water and dried affording 30.2 g (95%) of pure 13 as
light-yellow crystals. Product 13 can be crystallized from CHCl3/
NMR (CDCl3)
d
: 2.93 (s, 6H), 6.68 (s, 1H), 7.88 (d, J¼8.7 Hz, 1H), 8.19
(dd, J¼8.7, 2.4 Hz, 1H), 8.73 (d, J¼2.4 Hz, 1H). 13C NMR (CDCl3)
d:
44.4, 108.4, 118.3, 118.7, 123.7, 134.7, 144.9, 145.4, 149.0. m/z (EI) 222
(Mþ, 100%), 176 (86), 160 (62), 148 (21), 134 (42), 89 (40), 63 (33).
HRMS (EI) calcd for C10H10N2O2S [Mþ] 222.0463, found 222.0460.
MeOH, mp 121 ꢀC. 1H NMR (CDCl3)
d
7.75 (d, J¼9.0 Hz, 1H) 8.26 (dd,
J¼9.0, 2.7 Hz, 1H), 9.07 (d, J¼2.7 Hz, 1H), 9.19 (s, 1H); 13C NMR
(75 MHz, CDCl3)
d 124.6, 126.8, 131.0, 131.7, 135.9, 138.8, 146.9,
156.9; m/z (EI): 241 (Mþ, 2%), 213 (71), 167 (100), 155 (21), 132 (50),
123 (47); HRMS (EI) calcd for C8H4ClN3O2S [Mþ] 240.9713, found
240.9710. Crystallographic data: CCDC 762350.
4.2.1.9. 1-(5-Nitrobenzo[b]thiophen-3-yl)pyrrolidine
(3i). Red
solid, 78 mg (31%), mp 134–137 ꢀC. 1H NMR (CDCl3)
d: 2.04–2.12 (m,
4H), 3.49–3.52 (m, 4H), 6.20 (s, 1H), 7.82 (d, J¼9.0 Hz, 1H), 8.12 (dd,
J¼9.0, 2.1 Hz, 1H), 8.87 (d, J¼2.1 Hz, 1H). 13C NMR (CDCl3)
d: 25.3,
4.4. General procedure for the synthesis of 2-amino-
benzo[b]thiophenes (14a–x)
51.5, 99.9, 118.2, 119.1, 123.6, 133.7, 144.4, 145.6, 145.8. m/z (EI) 248
(Mþ, 100%), 201 (37), 192 (24), 173 (34), 160 (43), 146 (36), 133 (20),
89 (46). HRMS (EI) calcd for C12H12N2O2S [Mþ] 248.0620, found
248.0615.
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole 13 (0.5 g, 2.07 mmol),
K2CO3 (0.57 g, 4.13 mmol), the corresponding amine 2a–x
(1.05–5.0 equiv), and 10 mL DMF (in that order; for molar ratios see
Table 4) were charged into a 50 mL round bottom flask. The mixture
was stirred for 3–22 h at 25–90 ꢀC. DMF was removed under reduced
pressure and the residue purified by column chromatography (SiO2,
CHCl3/hexane (1:3), (1:2), (1:1) (2:1), or CHCl3/MeOH (40:1), (100:1))
affording the corresponding 2-aminobenzo[b]thiophene 14a–x (yields
6–92%, see Table 3).
4.2.1.10. 1-(5-Nitrobenzo[b]thiophen-3-yl)piperidine
(3j). Yellow-orange solid, 27 mg (10%), mp 143–145 ꢀC. 1H NMR
(CDCl3) d: 1.61–1.69 (m, 2H), 1.81–1.88 (m, 4H), 3.04–3.11 (m, 4H),
6.74 (s, 1H), 7.87 (d, J¼9.0 Hz, 1H), 8.17 (dd, J¼9.0, 2.1 Hz, 1H), 8.62
(d, J¼2.1 Hz, 1H). 13C NMR (CDCl3)
d: 24.3, 26.2, 54.1, 109.7, 118.0,
118.7, 123.7, 135.0, 145.0, 145.2, 149.3. m/z (EI) 262 (Mþ, 100%), 215
(24), 206 (12), 160 (41), 146 (14), 133 (36), 89 (49). HRMS (EI) calcd
for C13H14N2O2S [Mþ] 262.0776, found 262.0776.
4.4.1. N-Methyl-5-nitrobenzo[b]thiophen-2-amine (14a). Purified
by column chromatography (SiO2, CHCl3/Hexane (1:1)). Red crys-
tals, 0.026 g (6%), mp 163–164 ꢀC. IR (neat): 3393, 1559, 1503, 1327,
1295, 1249, 1218, 1058, 880, 829, 809, 758, 721, 657 cmꢁ1. 1H NMR
4.2.1.11. 4-(5-Nitrobenzo[b]thiophen-3-yl)morpholine
(3k). Orange solid, 31 mg (12%), mp 183–184 ꢀC. 1H NMR (CDCl3)
d:
3.14–3.17 (m, 4H), 3.96–3.99 (m, 4H), 6.83 (s, 1H), 7.90 (d, J¼9.0 Hz,
(CDCl3)
d
3.00 (d, J¼5.1 Hz, 3H), 4.31 (br s, 1H), 6.13 (s, 1H), 7.60 (d,
1H), 8.20 (dd, J¼9.0, 2.1 Hz, 1H), 8.62 (d, J¼2.1 Hz, 1H). 13C NMR
J¼8.7 Hz, 1H), 7.89 (dd, J¼8.7, 2.1 Hz, 1H), 8.24 (d, J¼2.1 Hz, 1H); 13C
(CDCl3)
d
: 53.0, 67.0, 110.8, 117.7, 119.0, 123.9, 134.5, 145.0, 145.3,
NMR (CDCl3) d 33.2, 95.9, 115.0, 115.3, 121.6, 138.2, 141.5, 145.9,
147.8. m/z (EI) 264 (Mþ, 96%), 206 (96), 160 (100), 146 (14), 133 (32),
89 (48). HRMS (EI) calcd for C12H12N2O3S [Mþ] 264.0569, found
264.0571.
157.3; m/z (EI): 208 (Mþ, 100%), 178 (10), 162 (64), 146 (14), 128 (12),
69 (13); HRMS (EI) calcd for C9H8N2O2S [Mþ] 208.0307, found
208.0307.
4.2.1.12. 3-Methyl-5-nitro-benzo[d]isothiazole (11). A mixture of
1-(2-chloro-5-nitrophenyl)ethanone 1 (200 mg, 1.0 mmol), NH4Cl
(160 mg, 3.0 mmol), NaOAc (246 mg, 3.0 mmol), and sulfur
(160 mg, 5.0 mmol) was added to 10 mL of DMF and stirred for
10 min. at 55–60 ꢀC. The resulting dark solution was cooled to rt
4.4.2. N-Allyl-5-nitrobenzo[b]thiophen-2-amine (14b). Purified by
column chromatography (SiO2, CHCl3/Hexane (1:1)). Dark-red
crystals, 0.20 g (42%), mp 67–68 ꢀC. 1H NMR (CDCl3)
d 3.87 (br s,
2H), 4.50 (br s, 1H), 5.25 (dd, J¼10.2, 1.2 Hz, 1H), 5.34 (dd, J¼17.4,
1.5 Hz, 1H), 5.89–6.01 (m, 1H), 6.13 (s, 1H), 7.57 (d, J¼8.7 Hz, 1H),

D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
2483
7.85 (dd, J¼8.7, 2.1 Hz, 1H), 8.19 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
159.9; m/z (EI) 222 (Mþ, 100%), 207 (3), 192 (6), 176 (60), 146 (27);
d
49.2, 96.8, 115.0, 115.3, 117.5, 121.6, 133.7, 138.2, 141.4, 145.8, 156.0;
HRMS (EI) calcd for C10H10N2O2S [Mþ] 222.0463, found 222.0464.
m/z (EI) 234 (Mþ, 100%), 207 (23), 188 (13), 161 (20); HRMS (EI)
calcd for C11H10N2O2S [Mþ] 234.0463, found 234.0463.
4.4.9. 1-(5-Nitrobenzo[b]thiophen-2-yl)pyrrolidine (14i) and 2-(5-
nitro-2-(pyrrolidin-1-yl)phenyl)-1-(pyrrolidin-1-yl)ethanethione
(22). After completion of the reaction 100 mL of water was added
and precipitate was filtered and washed with water. Crystallization
from CHCl3/EtOH afforded 0.41 g (62%) 22 as yellow needles, mp
4.4.3. N-Butyl-5-nitrobenzo[b]thiophen-2-amine (14c). Purified by
column chromatography (SiO2, CHCl3/Hexane (1:1)). Red crystals,
0.52 g (92%), mp 74–75 ꢀC. 1H NMR (CDCl3)
1.40–1.52 (m, 2H), 1.63–1.72 (m, 2H), 3.21–3.28 (m, 2H), 4.27 (br t,
d
1.00 (t, J¼7.4 Hz, 3H),
224–225 ꢀC. 1H NMR (CDCl3)
d
1.96–2.03 (m, 8H), 3.42–3.46 (m,
6H), 3.93 (t, J¼6.0 Hz, 2H), 4.17 (s, 2H), 6.75 (d, J¼8.7 Hz, 1H), 7.98–
8.04 (m, 2H); 13C NMR (CDCl3)
24.4, 25.8, 26.5, 48.5, 50.8, 51.5,
1H), 6.12 (s, 1H), 7.59 (d, J¼8.7 Hz, 1H), 7.87 (dd, J¼8.7, 2.4 Hz, 1H),
8.21 (d, J¼2.4 Hz, 1H); 13C NMR (CDCl3)
d
13.8, 20.2, 31.4, 46.7, 96.0,
d
114.9, 115.1, 121.6, 138.0, 141.6, 145.9, 156.5; m/z (EI) 250 (Mþ, 75%),
207 (100), 194 (15), 161 (65), 148 (22), 134 (16), 120 (9); HRMS (EI)
calcd for C12H14N2O2S [Mþ] 250.0776, found 250.0776.
54.2, 114.2, 123.3, 124.0, 127.0, 139.2, 154.2, 197.1; calcd for
C16H21N3O2S: C 60.16; H 6.63; N 13.15; O 10.02; S 10.04; found: C
59.94; H 6.51; N 12.83.
The solution was filtered, concentrated, and the solid residue
was chromatographed (SiO2, CHCl3/Hexane (1:2)) to afford 0.036 g
4.4.4. N-Benzyl-5-nitrobenzo[b]thiophen-2-amine
(14d). Purified
by column chromatography (SiO2, CHCl3/Hexane (1:1)). Red crys-
tals, 0.194 g (33%), mp 99–100 ꢀC. IR (neat): 3385, 1548, 1506, 1450,
1331, 1249, 1217, 1185, 1058, 1026, 884, 828, 809, 752, 696 cmꢁ1. 1H
(7%) of 14i as red crystals, mp 124–125 ꢀC. 1H NMR (CDCl3)
d 2.07–
2.12 (m, 4H), 3.37–3.41 (m, 4H), 5.89 (s, 1H), 7.60 (d, J¼8.7 Hz, 1H),
7.81 (dd, J¼8.7, 2.4 Hz, 1H), 8.21 (d, J¼2.4 Hz, 1H); 13C NMR (CDCl3)
NMR (CDCl3)
d
4.39 (d, J¼5.1 Hz, 2H), 4.72 (br t, 1H), 6.10 (s, 1H),
d 25.9, 50.5, 93.6, 113.9, 114.3, 121.5, 137.9, 142.0, 146.0, 156.1; m/z
7.26–7.40 (m, 5H), 7.52 (d, J¼8.7 Hz, 1H), 7.82 (dd, J¼8.7, 2.1 Hz, 1H),
(EI) 248 (Mþ, 100%), 202 (78); HRMS (ESI) calcd for C12H13N2O2S
8.13 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
d
50.9, 96.9, 115.0, 115.3,
[MþH]þ 249.0691, found 249.0698.
121.5, 127.6, 127.9, 128.8, 137.5, 138.2, 141.3, 145.8, 155.9; m/z (EI)
284 (Mþ, 22%), 91 (100), 65 (20); HRMS (EI) calcd for C15H12N2O2S
[Mþ] 284.0620, found 284.0619.
4.4.10. 1-(5-Nitrobenzo[b]thiophen-2-yl)piperidine (14j). Purified
by column chromatography (SiO2, CHCl3/Hexane (1:2)). Red crys-
tals, 0.092 g (17%), mp 139–140 ꢀC. 1H NMR (CDCl3)
d 1.58–1.76 (m,
4.4.5. N-iso-Propyl-5-nitrobenzo[b]thiophen-2-amine
(14e). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:1)). Brown crystals, 0.142 g (29%), mp 84–85 ꢀC. 1H NMR
6H), 3.28–3.31 (m, 4H), 6.18 (s, 1H), 7.62 (d, J¼8.7 Hz, 1H), 7.87 (dd,
J¼8.7, 2.4 Hz, 1H), 8.23 (d, J¼2.4 Hz, 1H); 13C NMR (CDCl3)
d 23.7,
25.1, 51.5, 97.3, 115.0, 115.1, 121.5, 138.5, 141.3, 145.8, 160.7; m/z (EI):
262 (Mþ, 100%), 247 (13), 216 (42), 133 (16), 89 (27), 69 (24); HRMS
(ESI) calcd for C13H15N2O2S [MþH]þ 263.0858, found 263.0854.
Crystallographic data: CCDC 762349.
(CDCl3)
d
1.32 (d, J¼6.6 Hz, 6H), 3.62–3.69 (br m, 1H), 4.15 (br d,
1H), 6.14 (s, 1H), 7.61 (d, J¼8.7 Hz, 1H), 7.88 (dd, J¼8.7, 2.1 Hz, 1H),
8.23 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
d: 22.8, 48.5, 96.4, 114.8,
115.1, 121.5, 138.1, 141.6, 145.9, 155.4; m/z (EI) 236 (Mþ, 97%), 221
(100), 194 (27), 175 (18), 166 (10), 148 (63), 136 (10), 121 (19), 69
(8); HRMS (EI): calcd for C11H12N2O2S [Mþ] 236.0620, found
236.0619.
4.4.11. 4-(5-Nitrobenzo[b]thiophen-2-yl)morpholine (14k). Purified
by column chromatography (SiO2, CHCl3/Hexane (1:2), (1:1), (2:1),
CHCl3). Dark-yellow crystals, 0.27 g (49%), mp 153–154 ꢀC. 1H NMR
(CDCl3) d 3.28–3.31 (m, 4H), 3.87–3.90 (m, 4H), 6.28 (s, 1H), 7.67 (d,
4.4.6. N-Cyclopentyl-5-nitrobenzo[b]thiophen-2-amine
(14f). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:1)). Dark-green crystals, 0.179 g (33%), mp 124–125 ꢀC. 1H NMR
J¼9.0 Hz, 1H), 7.94 (dd, J¼9.0, 2.1 Hz, 1H), 8.30 (d, J¼2.1 Hz, 1H); 13C
NMR (CDCl3)
d 50.4, 66.1, 98.5, 115.76, 115.80, 121.8, 138.6, 140.7,
145.9, 160.2; m/z (EI) 264 (Mþ, 100%), 218 (20), 206 (48), 160 (25),
133 (23); HRMS (ESI) calcd for C12H13N2O3S [MþH]þ 265.0636,
found 265.0647.
(CDCl3)
d 1.64–1.82 (m, 5H), 2.02–2.12 (m, 2H), 3.78–3.88 (m, 1H),
4.31 (br d, J¼5.1 Hz, 1H), 6.11 (s, 1H), 7.57 (d, J¼8.7 Hz, 1H), 7.86 (dd,
J¼8.7, 2.4 Hz, 1H), 8.20 (d, J¼2.4 Hz, 1H); 13C NMR (CDCl3)
d 24.0,
33.2, 58.1, 96.6, 114.8, 115.1, 121.5, 138.2, 141.6, 145.9, 155.8; m/z (EI)
262 (Mþ, 65%), 233 (14), 194 (100), 166 (8), 148 (58), 136 (10), 121
(16), 69 (21); HRMS (EI): calcd for C13H14N2O2S [Mþ] 262.0776,
found 262.0778.
4.4.12. N-(1-Adamantyl)-5-nitrobenzo[b]thiophen-2-amine
(14l). Purified by column chromatography (SiO2, CHCl3/Hexane
(2:1)). Dark-yellow crystals, 0.177 g (26%), mp 126–127 ꢀC. 1H NMR
(CDCl3)
d
1.65–1.75 (m, 6H), 1.95 (d, J¼2.7 Hz, 6H), 2.16 (br s, 3H),
4.11 (br s, 1H), 6.34 (s, 1H), 7.58 (d, J¼8.7 Hz, 1H), 7.88 (dd, J¼8.7,
4.4.7. N-Cyclohexyl-5-nitrobenzo[b]thiophen-2-amine
(14g). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:1)). Red crystals, 0.217 g (38%), mp 130–131 ꢀC. 1H NMR (CDCl3)
2.1 Hz, 1H), 8.24 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
d 29.6, 36.3,
42.6, 53.9, 102.4, 115.2, 115.5, 121.4, 139.2, 140.8, 145.7, 153.2; m/z
(EI) 328 (Mþ, 46%), 193 (6), 166 (17), 135 (100), 107 (35); HRMS (EI)
calcd for C18H20N2O2S [Mþ] 328.1246, found 328.1244.
d
1.17–1.48 (m, 5H), 1.60–1.66 (m, 1H), 1.76–1.83 (m, 2H), 2.10–2.15
(m, 2H), 3.22–3.33 (m, 1H), 4.23 (br d, J¼6.9 Hz, 1H), 6.11 (s, 1H),
7.57 (d, J¼8.7 Hz, 1H), 7.85 (dd, J¼8.7, 2.1 Hz, 1H), 8.19 (d, J¼2.1 Hz,
4.4.13. N-(2-Morpholinoethyl)-5-nitrobenzo[b]thiophen-2-amine
(14m). Purified by column chromatography (SiO2, CHCl3/MeOH
(100:1)). Orange crystals, 0.388 g (61%), mp 159–160 ꢀC. 1H NMR
1H); 13C NMR (CDCl3)
d 24.8, 25.6, 33.0, 55.7, 96.0,114.6,114.8,121.4,
138.0,141.6, 145.8, 155.6; m/z (EI) 276 (Mþ, 52%), 233 (17), 194 (100),
166 (10), 148 (47), 136 (8), 121 (12), 83 (9), 55 (87); HRMS (EI): calcd
for C14H16N2O2S [Mþ] 276.0933, found 276.0932.
(CDCl3)
d 2.50–2.53 (m, 4H), 2.67–2.70 (m, 2H), 3.27–3.32 (m, 2H),
3.73–3.76 (m, 4H), 5.03 (br t, 1H), 6.13 (s, 1H), 7.61 (d, J¼8.7 Hz, 1H),
7.88 (dd, J¼8.7, 2.1 Hz, 1H), 8.23 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
4.4.8. N,N-Dimethyl-5-nitrobenzo[b]thiophen-2-amine
(14h). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:2)). Red crystals, 0.35 g (75%), mp 133–134 ꢀC. IR (neat): 3083,
2905, 2810, 1555, 1502, 1425, 1332, 1246, 1184, 1058, 908, 880,
d 42.6, 53.3, 56.6, 67.0, 96.3, 115.0, 115.3, 121.6, 138.2, 141.5, 146.0,
156.3; m/z (EI): 307 (Mþ, 30%), 207 (7), 161 (31), 100 (100); HRMS
(EI) calcd for C14H17N3O3S [Mþ] 307.0991, found 307.0992.
700 cmꢁ1
.
1H NMR (CDCl3)
d
3.04 (s, 6H), 5.97 (s, 1H), 7.59 (d,
4.4.14. N,N-Diethyl-5-nitrobenzo[b]thiophen-2-amine
(14n). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:3), (1:2), (1:1)). Red crystals, 0.29 g (55%), mp 41–42 ꢀC. 1H NMR
J¼8.4 Hz, 1H), 7.82 (dd, J¼8.4, 2.4 Hz, 1H), 8.20 (d, J¼2.4 Hz, 1H); 13C
NMR (CDCl3)
d 42.2, 95.5, 114.4, 114.7, 121.5, 138.3, 141.8, 145.9,

2484
D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
(CDCl3)
d
1.26 (t, J¼7.2 Hz, 6H), 3.40 (q, J¼7.2 Hz, 4H), 5.97 (s, 1H),
(dd, J¼8.7, 2.4 Hz, 1H), 8.25 (d, J¼2.4 Hz, 1H); 13C NMR (CDCl3)
7.58 (d, J¼8.4 Hz, 1H), 7.81 (dd, J¼8.4, 2.1 Hz, 1H), 8.18 (d, J¼2.1 Hz,
d
14.2, 47.8, 61.9, 97.4, 115.5, 115.8, 121.7, 138.4, 141.1, 145.9, 154.7,
169.7; m/z (EI) 280 (Mþ, 30%), 207 (100), 161 (34), 134 (10); HRMS
(EI) calcd for C12H12N2O4S [Mþ] 280.0519, found 280.0519.
1H); 13C NMR (CDCl3)
d 12.4, 47.0, 94.2, 114.08, 114.13, 121.3, 137.7,
142.1, 145.9, 157.9; m/z (EI) 250 (Mþ, 66%), 235 (100), 207 (25), 189
(23), 161 (20); HRMS (ESI) calcd for C12H15N2O2S [MþH]þ 251.0850,
found 251.0854.
4.4.21. N-(2-(1H-Indol-3-yl)ethyl)-5-nitrobenzo[b]thiophen-2-amine
(14u). Purified by column chromatography (SiO2, CHCl3/MeOH
(100:1)). Yellow crystals, 0.20 g (23%), mp 160–161 ꢀC. 1H NMR
4.4.15. N,N-Dibutyl-5-nitrobenzo[b]thiophen-2-amine
(14o). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:2)). Red crystals, 0.21 g (33%), mp 45–46 ꢀC. 1H NMR (CDCl3)
(CDCl3)
d
3.15 (t, J¼6.5 Hz, 2H), 3.57 (q, J¼6.5 Hz, 2H), 4.35 (br t,
J¼5.3 Hz, 1H), 6.13 (s, 1H), 7.08 (d, J¼2.4 Hz, 1H), 7.13–7.18 (m, 1H),
7.21–7.27 (m, 1H), 7.40 (d, J¼7.8 Hz, 1H), 7.57 (d, J¼8.7, Hz, 1H), 7.62
(d, J¼7.8 Hz, 1H), 7.86 (dd, J¼8.7, 2.4 Hz, 1H), 8.09 (br s, 1H), 8.20 (d,
d
1.00 (t, J¼7.4 Hz, 6H), 1.35–1.47 (m, 4H), 1.63–1.73 (m, 4H), 3.34 (t,
J¼7.5 Hz, 4H), 5.95 (s, 1H), 7.59 (d, J¼8.4 Hz, 1H), 7.82 (dd, J¼8.4,
2.1 Hz, 1H), 8.20 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
d
13.9, 20.2,
J¼2.4 Hz, 1H); 13C NMR (CDCl3)
d 25.0, 46.9, 96.5, 111.4, 112.5, 115.0,
29.3, 53.2, 94.0, 114.0, 114.1, 121.3, 137.6, 142.2, 145.9, 158.6; m/z (EI)
306 (Mþ, 46%), 263 (44), 221 (100), 207 (22), 191 (7), 175 (16), 161
(27), 57 (47); HRMS (ESI) calcd for C16H23N2O2S [MþH]þ 307.1473,
found 307.1480.
115.2, 121.6, 122.3, 122.5, 127.2, 136.5, 138.2, 141.5, 145.9, 156.3; m/z
(EI) 337 (Mþ, 8%), 207 (7), 143 (8), 130 (100); HRMS (EI) calcd for
C18H15N3O2S [Mþ] 337.0885, found 337.0882.
4.4.22. 2,6-Dimethyl-1-(5-nitrobenzo[b]thiophen-2-yl)piperidine
(14v). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:2), (1:1)). Orange crystals, 0.38 g (63%), mp 98–99 ꢀC. 1H NMR
4.4.16. N,N-Di-iso-propyl-5-nitrobenzo[b]thiophen-2-amine
(14p). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:2)). Red crystals, 0.15 g (33%), mp 85–86 ꢀC. 1H NMR (CDCl3)
(CDCl3)
d
1.19 (d, J¼6.9 Hz, 6H),1.58–1.62 (m, 3H),1.82–1.85 (m, 3H),
d
1.35 (d, J¼7.5 Hz, 12H), 3.85 (heptet, J¼6.9 Hz, 2H), 6.17 (s, 1H),
3.50–3.54 (m, 2H), 6.35 (s,1H), 7.66 (d, J¼8.7 Hz,1H), 7.91 (dd, J¼8.7,
7.58 (d, J¼8.7 Hz, 1H), 7.82 (dd, J¼8.7, 2.1 Hz, 1H), 8.21 (d, J¼2.1 Hz,
2.4 Hz, 1H), 8.30 (d, J¼2.4 Hz, 1H); 13C NMR (CDCl3)
d 17.0, 19.5, 31.8,
1H); 13C NMR (CDCl3)
d
20.5, 51.2, 98.3, 114.4, 121.1, 137.7, 141.4,
54.5, 102.3, 115.5, 115.7, 121.9, 139.8, 140.4, 145.7, 159.4; m/z (EI) 290
(Mþ, 33%), 275 (100), 81 (15), 55 (65); HRMS (ESI) calcd for
C15H19N2O2S [MþH]þ 291.1164, found 291.1167.
145.8, 156.2; m/z (EI) 278 (Mþ, 56%), 263 (70), 221 (100), 194 (20),
175 (26), 148(20), 121 (11); HRMS (ESI) calcd for C14H19N2O2S
[MþH]þ 279.1162, found 279.1167.
4.4.23. 2-(1-(5-Nitrobenzo[b]thiophen-2-yl)piperidin-2-yl)ethanol
(14w). Purified by column chromatography (SiO2, CHCl3/MeOH
(100:1)). Red-orange crystals, 0.127 g (20%), mp 114–115 ꢀC. 1H
4.4.17. N-(Cyclopropylmethyl)-5-nitro-N-propylbenzo[b]thiophen-2-
amine (14q). Purified by column chromatography (SiO2, CHCl3/
Hexane (1:2)). Red crystals, 0.23 g (38%), mp 48–49 ꢀC. 1H NMR
NMR (CDCl3)
d 1.53–1.75 (m, 5H), 1.80–1.92 (m, 2H), 2.01–2.08 (m,
(CDCl3)
d
0.29 (q, J¼4.8 Hz, 2H), 0.58–0.64 (m, 2H), 0.97 (t, J¼7.4 Hz,
1H), 3.12–3.27 (m, 1H), 3.47–3.51 (m, 1H), 3.71–3.76 (m, 2H), 3.97–
3H), 1.07–1.19 (m, 1H), 1.73 (heptet, J¼7.5 Hz, 2H), 3.23 (d, J¼6.6 Hz,
4.03 (m, 1H), 6.18 (s, 1H), 7.59 (d, J¼8.4 Hz, 1H), 7.84 (dd, J¼8.4,
2H), 3.38 (t, J¼7.7 Hz, 2H), 6.00 (s, 1H), 7.57 (d, J¼8.7 Hz, 1H), 7.81
2.4 Hz, 1H), 8.20 (d, J¼2.4 Hz,1H); 13C NMR (CDCl3)
d 18.7, 24.7, 27.4,
(dd, J¼8.7, 2.1 Hz, 1H), 8.18 (d, J¼2.1 Hz, 1H); 13C NMR (CDCl3)
d
3.9,
31.1, 45.7 55.5, 60.2, 96.5, 114.76, 114.79, 116.7, 121.5, 124.9, 138.9,
141.6, 145.8, 159.9; m/z (EI) 306 (Mþ, 22%), 289 (14), 261 (100), 215
(23); HRMS (ESI) calcd for C15H19N2O3S [MþH]þ 307.1108, found
307.1116.
9.3, 11.4, 20.3, 54.7, 57.7, 94.4, 114.17, 114.20, 121.3, 137.6, 142.1, 145.9,
158.7; m/z (EI) 290 (Mþ, 11%), 261 (9), 207 (10), 55 (100); HRMS
(ESI) calcd for C15H19N2O2S [MþH]þ 291.1157, found 291.1167.
4.4.18. N-Benzyl-N-methyl-5-nitrobenzo[b]thiophen-2-amine
(14r). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:2), (1:1), (2:1)). Red crystals, 0.25 g (41%), mp 82 ꢀC. IR (neat):
3085, 3022, 2918, 1598, 1535, 1494, 1443, 1417, 1328, 1306, 1246,
1193, 1165, 1137, 1092, 1058, 1030, 1002, 987, 942, 917, 874, 823, 807,
4.4.24. 1-Methyl-4-(5-nitrobenzo[b]thiophen-2-yl)piperazine
(14x). Purified by column chromatography (SiO2, CHCl3/MeOH
(40:1)). Yellow crystals, 0.43 g (74%), mp 139–140 ꢀC. 1H NMR
(CDCl3) d 2.38 (s, 3H), 2.58–2.62 (m, 4H), 3.33–3.36 (m, 4H), 6.23 (s,
1H), 7.65 (d, J¼8.7 Hz, 1H), 7.91 (dd, J¼8.7, 2.4 Hz, 1H), 8.27 (d,
793, 747, 694 cmꢁ1. 1H NMR (CDCl3)
d
3.06 (s, 3H), 4.56 (s, 2H), 6.07
J¼2.4 Hz, 1H); 13C NMR (CDCl3)
d 46.1, 50.3, 54.2, 98.4, 115.56,
(s, 1H), 7.26–7.36 (m, 5H), 7.61 (d, J¼8.7 Hz, 1H), 7.85 (dd, J¼8.7,
115.59, 121.7, 138.7, 141.0, 145.9, 160.1; m/z (EI): 277 (Mþ, 100%), 220
(14), 206, (13), 192 (34), 160 (14), 146 (9), 133 (16); HRMS (ESI) calcd
for C13H16N3O2S [MþH]þ 278.0959, found 278.0963.
2.1 Hz,1H), 8.21 (d, J¼2.1 Hz,1H); 13C NMR (CDCl3)
d 39.7, 59.0, 95.6,
114.58, 114.66, 121.4, 127.2, 127.8, 128.8, 136.5, 138.0, 141.8, 145.9,
159.3; m/z (EI) 298 (Mþ, 20%), 91 (100); HRMS (ESI) calcd for
C16H15N2O2S [MþH]þ 299.0843, found 299.0854.
4.4.25. Ethyl 2-(1-(2-chlorophenyl)ethylidene)hydrazinecarboxylate
(24). A mixture of 1-(2-chlorophenyl)ethanone 23 (3 g,
19.4 mmol), ethyl carbazate (2.42 g, 23.3 mmol), and one drop of
AcOH in 40 mL of EtOH/H2O (1:1) was refluxed for 3 h and left
overnight at rt. The precipitate was filtered, washed with EtOH/H2O
(1:1) and dried affording 2.19 g (47%) of 24 as white crystals, mp
4.4.19. N-tert-Butyl-5-nitrobenzo[b]thiophen-2-amine
(14s). Purified by column chromatography (SiO2, CHCl3/Hexane
(1:1)). Yellow crystals, 0.20 g (39%), mp 114–115 ꢀC. IR (neat): 3347,
3109, 2970, 1508, 1469, 1335, 1204, 1060, 903, 827, 796 cmꢁ1 1H
.
NMR (CDCl3)
d
1.42 (s, 9H), 4.18 (br s, 1H), 6.31 (s, 1H), 7.61 (d,
130–131 ꢀC. 1H NMR (CDCl3)
4.33 (q, J¼7.1 Hz, 2H), 7.26–7.30 (m, 2H), 7.35–7.38 (m, 1H), 7.41–
d
1.34 (t, J¼7.1 Hz, 3H), 2.22 (s, 3H),
J¼8.7 Hz, 1H), 7.90 (dd, J¼8.7, 2.1 Hz, 1H), 8.26 (d, J¼2.1 Hz, 1H); 13C
NMR (CDCl3)
d
29.3, 53.6, 101.2,115.3,115.6, 121.4, 138.9, 141.1, 145.8,
7.44 (m, 1H), 7.93 (br s, 1H, NH); 13C NMR (CDCl3)
d 14.6, 16.8, 62.2,
153.8; m/z (EI) 250 (Mþ, 37%), 194 (100), 148 (46), 121 (12), 57 (69);
126.9, 129.7, 129.9, 130.5, 132.3, 138.8, 149.5; m/z (EI) 240 (Mþ, 13%),
205 (33), 161 (30), 152 (26), 133 (100), 126 (25), 111 (7); HRMS (EI)
calcd for C11H13ClN2O2 [Mþ] 240.0666, found 240.0664.
HRMS (EI) calcd for C12H14N2O2S [Mþ] 250.0776, found 250.0775.
4.4.20. Ethyl
2-(5-nitrobenzo[b]thiophen-2-ylamino)acetate
(14t). Purified by column chromatography (SiO2, CHCl3/Hexane
4.4.26. 4-(2-Chlorophenyl)-1,2,3-thiadiazole (25). A solution of 24
(2.0 g, 8.32 mmol) in 6 mL of SOCl2 was refluxed for 2 h, cooled and
poured into water. The precipitate was thoroughly washed with
water and dried affording 1.3 g (79%) of pure 25 as light-brown
(2:1)). Yellow crystals, 0.052 g (9%), mp 163–164 ꢀC. 1H NMR
(CDCl3)
d
1.33 (t, J¼7.2 Hz, 3H), 4.01 (d, J¼5.1 Hz, 2H), 4.29 (q,
J¼7.2 Hz, 2H), 4.95 (br t, 1H), 6.13 (s, 1H), 7.62 (d, J¼8.7 Hz, 1H), 7.91

D.A. Androsov et al. / Tetrahedron 66 (2010) 2474–2485
2485
crystals, mp 30–31 ꢀC. 1H NMR (CDCl3)
7.57 (m, 1H), 8.12–8.16 (m, 1H), 9.05 (s, 1H); 13C NMR (CDCl3)
d
7.37–7.47 (m, 2H), 7.53–
J¼9.0 Hz, 1H), 8.02 (dd, J¼8.7, 2.7 Hz, 1H), 8.24 (d, J¼2.7 Hz, 1H),
8.27 (dd, J¼9.0, 2.7 Hz, 1H), 8.34 (d, J¼2.7 Hz, 1H). m/z (EI) 426 (Mþ,
100%), 390 (18), 298 (8), 264 (13), 199 (58), 164 (19), 155 (43), 132
(28), 123 (19); HRMS (EI) calcd for C16H8Cl2N2O4S2 [Mþ] 425.9303,
found 425.9305.
d
127.4, 129.6, 130.4, 130.6, 131.9, 132.3, 134.6, 159.1; m/z (EI) 196
(Mþ, 5%), 168 (100), 133 (49), 89 (48); HRMS (EI) calcd for
C8H5ClN2S [Mþ] 195.9862, found 195.9862.
4.4.27. N-Butyl-2-(2-chlorophenyl)ethanethioamide (26). A mixture
of 25 (0.086 g, 0.43 mmol), K2CO3 (0.18 g, 1.3 mmol), and n-butyl-
amine (0.16 g, 2.19 mmol) in 10 mL DMF was heated and stirred at
130 ꢀC for 24 h. After cooling to rt, the solvent was evaporated
under vacuum. The residue was dissolved in CHCl3 and thoroughly
washed with water. Evaporation of the CHCl3 afforded 0.088 g (97%)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.069.
of pure 26 as a brown oil. 1H NMR (CDCl3)
1.25–1.35 (m, 2H), 1.49–1.58 (m, 2H), 3.61 (t, J¼7.5 Hz, 2H), 4.22 (s,
2H), 7.27–7.33 (m, 2H), 7.38–7.46 (m, 2H); 13C NMR (CDCl3)
13.7,
d
0.90 (t, J¼7.5 Hz, 3H),
References and notes
1. Grese, T. A.; Pennington, L. D.; Sluka, J. P.; Adrian, M. D.; Cole, H. W.; Fuson, T. R.;
Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler, P. K.; Short, L. L.; Venugopalan,
M.; Yang, N. N.; Sato, M.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1998, 41,
1272–1283.
2. Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; Jones, C. D.; Lugar, C. W.;
Martin, M. J.; Matsumoto, K.; Pennington, L. D.; Winter, M. A.; Adrian, M. D.;
Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Short, L. L.; Glasebrook, A.
L.; Bryant, H. U. J. Med. Chem. 1997, 40, 146–167.
d
20.0, 29.8, 45.9, 50.2, 127.5, 129.3, 129.8, 131.9, 133.3, 134.3, 200.2;
m/z (EI) 206 (Mþ, 100%), 164 (7), 150 (27), 134 (9), 125 (15), 89 (15),
57 (16).
4.4.28. 2-Methoxy-5-nitrobenzo[b]thiophene
(29). Na
(0.29 g,
3. Lee, K. C.; Moon, B. C.; Lee, J. H.; Chung, K.-H.; Katzenellenbogen, J. A.; Chi, D. Y.
Bioorg. Med. Chem. 2003, 11, 3649–3658.
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Gifford-Moore, D. S. Bioorg. Med. Chem. 1999, 9, 759–764.
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J.-M.; Kirsch, G. Bioorg. Med. Chem. 2008, 16, 8172–8177.
12.42 mmol) was dissolved in 50 mL of dry MeOH. Compound 13
(1.0 g, 4.14 mmol) was added to the resulting solution and the
mixture was stirred and refluxed for 24 h under an atmosphere of
argon. After cooling, several drops of AcOH were added to neu-
tralize the mixture. The solvent was evaporated under reduced
pressure and the residue was chromatographed (SiO2, EtOAc/Hex-
ane (1:8)) affording 0.2 g (23%) of 29, as yellow crystals, mp 118 ꢀC.
IR (neat): 3087, 3021, 2943, 1601, 1550, 1507, 1443, 1336, 1296, 1250,
1208, 1193, 1163, 1138, 1056, 977, 939, 900, 828, 812, 792, 723,
6. Queiroz, M.-J. R. P.; Begouin, A.; Ferreira, I. C. F. R.; Kirsch, G.; Calhelha, R. C.;
Barbosa, S.; Estevinho, L. M. Eur. J. Org. Chem. 2004, 3679–3685.
7. Stacy, G. W.; Villaescusa, F. W.; Wollner, T. E. J. Org. Chem. 1965, 30, 4074–4078.
8. Grandclaudon, P.; Lablache-Combier, A. J. Org. Chem. 1978, 43, 4379–4381.
9. Brower, K. R.; Amstutz, E. D. J. Org. Chem. 1954, 19, 411–414.
10. Benincori, T.; Sannicolo, F. J. Org. Chem. 1988, 53, 1309–1312.
11. David, E.; Perrin, J.; Pellet-Rostaing, S.; Fournier dit Chabert, J.; Lemaire, M.
J. Org. Chem. 2005, 70, 3569–3573.
12. Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965–3968.
13. Ferreira, I. C. F. R.; Queiroza, M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59,
3737–3743.
14. Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, 2861–2873.
15. Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793–796.
16. Boswell, D. E.; Brennan, J. A.; Landis, P. S.; Rodewald, P. G. J. Heterocycl. Chem.
1968, 5, 69–75.
17. Toselli, M.; Spagnolo, P.; Zanirato, P. Gazz. Chim. Ital. 1989, 119, 411–413.
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19. Hallas, G.; Towns, A. D. Dyes Pigm. 1997, 35, 219–237.
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21. Solovyev, A. Y.; Androsov, D. A.; Neckers, D. C. J. Org. Chem. 2007, 72, 3122–3124.
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Organic Synthesis, 2nd ed.; Wiley-Interscience: Hoboken, 2005.
25. Zbruev, O. I.; Stiasni, N.; Kappe, C. O. J. Comb. Chem. 2003, 5, 145–148.
26. Kameswaran, V. US Patent 6,355,796 B1, 2002.
27. Schwenk, E.; Bloch, E. J. Am. Chem. Soc. 1942, 64, 3051–3052.
28. Klingele, M. H.; Brooker, S. Eur. J. Org. Chem. 2004, 3422–3434.
29. Poupaert, J. H.; Duarte, S.; Colacino, E.; Depreux, P.; McCurdy, C. M.; Lambert, D. L.
Phosphorus Sulfur Silicon Relat. Elem. 2004, 179, 1959–1973.
653 cmꢁ1 1H NMR (CDCl3)
. d 4.04 (s, 3H), 6.46 (s, 1H), 7.70 (d,
J¼8.7 Hz, 1H), 8.04 (dd, J¼8.7, 2.4 Hz, 1H), 8.40 (d, J¼2.4 Hz, 1H); 13C
NMR (CDCl3)
d 60.0, 98.3, 116.9, 117.0, 122.3, 138.2, 138.7, 145.7,
168.1; m/z (EI) 209 (Mþ, 100%), 194 (15), 166 (55), 136 (22), 120 (85);
HRMS (EI); calcd for C9H7NO3S [Mþ] 209.0147, found 209.0148.
4.4.29. 4-Nitro-2-(1,2,3-thiadiazol-4-yl)benzenethiol (31). A mix-
ture of 13 (0.3 g, 1.24 mmol), K2CO3, (0.52 g, 3.73 mmol), and
potassium thioacetate (0.42 g, 3.73 mmol) in DMF (10 mL) was
stirred and heated at 70 ꢀC for 12 h. The solvent was evaporated
under reduced pressure. The residue was dissolved in 200 mL of
water and stirred with charcoal for 10 min at rt. The charcoal was
filtered and the resulting solution was acidified with aqueous HCl
(3 M) to form a yellow precipitate. The precipitate was filtered and
thoroughly washed with water to yield 1.9 g (80%) of 31 as yellow
powder, mp 116–117 ꢀC. 1H NMR (CDCl3)
J¼8.7 Hz,1H), 8.15 (dd, J¼8.7, 2.7 Hz,1H), 8.58 (d, J¼2.7 Hz,1H), 8.92
d 4.77 (s, 1H), 7.60 (d,
(s, 1H); 13C NMR (CDCl3)
d 123.9, 125.8, 116.9, 129.4, 131.1, 135.1,
142.2, 159.4; m/z (EI) 237 ([Mꢁ2]þ, 52%), 209 (74), 165 (84), 153
(24), 132 (17), 121 (100); HRMS (EI) calcd for C8H5N3O2S2 [Mþ]
238.9823, found 238.9825.
30. Aghapoor, K.; Darabi, H.-R.; Tabar-Heydar, K. Phosphorus Sulfur Silicon Relat.
Elem. 2002, 177, 1183–1187.
31. Aghapoor, K.; Darabi, H.-R.; Tabar-Heydar, K. Phosphorus Sulfur Silicon Relat.
Elem. 2002, 177, 1189–1192.
32. Schroth, W.; Andersch, J. Synthesis 1989, 202–204.
4.4.30. (E)-2-(2-Chloro-5-nitrobenzylidene)-4-(2-chloro-5-nitro-
phenyl)-1,3-dithiole (32). A mixture of compound 13 (0.5 g,
2.07 mmol) and K2CO3, (0.86 g, 6.21 mmol) in MeCN (20 mL) was
stirred and refluxed for 6 h. After cooling to rt, the mixture was
poured into water (200 mL) and refluxed for an additional 1 h. The
precipitate was filtered and thoroughly washed with water to yield
0.42 g (95%) of 32 as orange powder, mp 220–223 ꢀC. 1H NMR
33. Butler, R. N.; O’Donoghue, D. A. J. Chem. Soc., Perkin Trans. 1 1982, 1223–1227.
34. Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359–5364.
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38. Caddy, B.; Martin-Smith, M.; Norris, R. K.; Reid, S. T.; Sternhell, S. Aust. J. Chem.
1968, 21, 1853–1866.
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(DMSO-d6)
d
6.92 (s, 1H), 7.36 (s, 1H), 7.79 (d, J¼8.7 Hz, 1H), 7.89 (d,