An efficient synthetic route towards novel thienobenzothiazoles, thienobenzothiazepines, and thienobenzothiazines

Article abstract of DOI:10.1016/j.tet.2013.04.001

Efficient methods for the synthesis of novel nitrogen- and sulfur-containing heterocycles, annulated in the 4,5-position of benzothiophene, are described. Applying the Herz reaction, 3H-thienobenzodithiazole 2-oxide was prepared. This compound served as o-aminothiophenol precursor in the synthesis of a variety of thienobenzothiazoles, thienobenzothiazepines, thienobenzothiazines, and thienothiadiazole.

Full text of DOI:10.1016/j.tet.2013.04.001

Tetrahedron 69 (2013) 4176e4184
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthetic route towards novel thienobenzothiazoles,
thienobenzothiazepines, and thienobenzothiazines
*
Wim Van Snick, Yelaman K. Aibuldinov, Wim Dehaen
Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient methods for the synthesis of novel nitrogen- and sulfur-containing heterocycles, annulated in
the 4,5-position of benzothiophene, are described. Applying the Herz reaction, 3H-thienobenzodithiazole
2-oxide was prepared. This compound served as o-aminothiophenol precursor in the synthesis of a va-
riety of thienobenzothiazoles, thienobenzothiazepines, thienobenzothiazines, and thienothiadiazole.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 February 2013
Received in revised form 29 March 2013
Accepted 1 April 2013
Available online 6 April 2013
Keywords:
Benzothiophene
Nitrogen heterocycles
Herz reaction
Thia-Michael addition
Cyclization
1. Introduction
Sulfur-containing heterocyclic ring systems, such as benzothia-
zoles, benzothiazepines, and benzothiazines, have shown a great
potential in pharmaceutical research and serve as versatile scaf-
folds in experimental drug design.1e4 These heterocycles are gen-
erally synthesized via condensation of an o-aminothiophenol with
substituted aromatic aldehydes, acid chlorides, acetophenones,
a,
b
-unsaturated ketones or substituted
a-bromoacetophenones.
Our general point of interest goes to the synthesis of 4,5-
annulated benzothiophenes with N-containing heterocycles, thus
providing easy strategies towards the synthesis of novel benzothio-
phene fused structures. Therefore, we use the 5-aminobenzothio
phene scaffold as starting material. In our preceding work we de-
scribed the synthesis of ethyl 5-aminobenzothiophene-2-carboxy
late (1),5 the latter conveniently prepared by the condensation of
2-chloro-4-nitrobenzaldehyde with ethyl-2-mercaptoacetate, fol-
lowed by reduction of the nitro group.
In this manuscript, we wish to report the synthesis of novel
thienobenzothiazoles, thienobenzothiazepines, thienobenzothia-
zines, and thienobenzothiadiazole in moderate to high yields, all
based on our 5-aminobenzothiophene scaffold 1 (Scheme 1). It was
therefore necessary to introduce an extra sulfur atom into the
4-position of this 5-aminobenzothiophene 1, in order to obtain an
o-aminothiophenol derivative.
Scheme 1. Synthesis of novel thienobenzothiazoles, thienobenzothiazepines, thieno-
benzothiazines, and thienobenzothiadiazole.
One of the most commonly used pathways for the synthesis of
o-aminothiophenol derivatives takes place via the synthesis of
a
2-aminobenzothiazole. This 2-aminobenzothiazole is easily
* Corresponding author. Tel.: þ32 16 3 27439; fax: þ32 16 3 27990; e-mail
address: wim.dehaen@chem.kuleuven.be (W. Dehaen).
formed by reaction of the corresponding aniline with potassium
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.001

W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
4177
thiocyanate (or ammonium thiocyanate), followed by the oxidative
cyclization of the formed thiourea with bromine.6,7 The next step
involves the hydrolytic cleavage of the formed benzothiazole, to
yield the expected 2-aminothiophenol. However, the necessity of
hydroxide base under refluxing conditions forms an obstacle, as the
benzothiophene ester function, present in the starting material 1,
will be hydrolyzed too.
Another pathway towards our 2-aminothiophenol precursor is
the Herz reaction.8,9 This reaction involves the condensation of
a primary aniline with sulfur monochloride to give the corre-
sponding, benzodithiazolium chloride (Herz salt). Since the dis-
covery of Herz salts, a number of reports have appeared using this
method.10e16 This method was found very popular for the synthesis
of substituted o-aminothiophenols, as the salt can be easily hydro-
lyzed with sodium hydroxide. In his review, W.K. Warburton11 de-
scribed this Herz reaction and the subsequent hydrolysis of the
condensation product towards o-aminothiophenols. Of course, 2-
aminothiophenols readily undergo oxidation, forming the more
stable and in this case synthetically less useful disulfides. On the
other hand, the Herz salt can readily be hydrolyzed in water to give
the fairly stable 3H-benzodithiazole 2-oxide derivative. This was
reported by Herz,9 Warburton,11 Blomquist et al.,12 Huestis et al.,13
and Belica et al.14
literature procedures. The crude reaction product needed to be
dissolved in a large amount of methanol (about 150 mL per gram of
product), followed by precipitation of the product on addition of
water.13,15 In larger scale reactions (more than 10 g of product), the
workup of compound 3 seemed to become problematic. The exo-
thermic reaction, upon mixing both liquids, was difficult to control
and led to a drastic decrease of the yield with about 50%. Moreover,
this purification method turned out to be less efficient on large
scale, as the compound still contained impurities, which was in-
dicated by 1H NMR spectral analysis. We finally found that simply
washing the compound 3 with toluene removed these impurities.
Using this optimized procedure, we were able to synthesize 3 in an
overall yield of 78%.
The synthesized 3H-thienobenzodithiazole 2-oxide 3 serves as
a more stable and convenient alternative for the corresponding
oxidation-sensitive o-aminothiophenol, as we have noticed before.
Sawhney et al.16 have reported that 3H-benzodithiazole 2-oxide
can be reacted with benzaldehyde to afford 2-phenylbenzothia
zole. We applied this reaction procedure, using benzaldehyde and
triethylamine as base, at room temperature and in refluxing etha-
nol (Scheme 3 and Table 1, entry 1e2). In both cases we obtained
the expected 2-phenylthienobenzothiazole 5a in low to fair yields
(27% and 44% resp.).
We thus report herein the synthesis of a 5-amino-4-mercapto
benzothiophene precursor, being the corresponding 3H-thieno-
benzodithiazole 2-oxide 3, using the Herz reaction, and optimized
methods for the synthesis of five-, six-, and seven-membered
heterocyclic rings, starting from this benzodithiazole 2-oxide
precursor.
O
RCHO
R
S
S
piperidine
ot TEA
S
HN
N
COOEt
COOEt
solvent
S
S
5 a-k
3
2. Results and discussion
Scheme 3. Thienobenzothiazole synthesis from 3 and aromatic aldehydes.
Conforming these literature procedures, we synthesized the
corresponding Herz salt 2 by reaction of the starting compound 5-
aminobenzothiophene 1 with S2Cl2 in acetic acid. This Herz com-
pound 2 was readily hydrolyzed in water to give the 3H-thieno-
benzodithiazole 2-oxide 3 (Scheme 2). We have also tried to
hydrolyze compound 3, by treatment with a 1 M sodium hydroxide
solution (Scheme 2).11 Although the smell of sulfide was readily
observed, we were not able to isolate the desired 5-amino-4-
mercaptobenzothiophene derivative 4, due to the quick oxidation
of the free thiophenol function to disulfides. Moreover, 1H NMR
analysis also indicated hydrolysis of the ester function, as the
specific signals (a quartet at 4.45 ppm and a triplet at 1.45 ppm)
were no longer present in the 1H NMR spectrum.
Table 1
Optimization of thienobenzothiazole synthesis (R¼phenyl)
Entry
Benzaldehyde
Solvent
Temperature
25 ꢀC
Yield 5a [%]b
1
2
3
4
1.2 equiv
1.2 equiv
1.2 equiv
2.2 equiv
EtOHa
EtOHa
DMSO
DMSO
27
44
48
77
Reflux
25 ꢀCþ120 ꢀC
25 ꢀCþ120 ꢀC
a
Et3N is used as base.
Yields refer to isolated products.
b
The mechanism of the general benzothiazole synthesis starting
It is worth noting that brief heating of this dithiazole-oxide 3
causes decomposition, which is observed by the presence of sulfur
dioxide.15 In order to purify the compound, we generally followed
from 2-aminothiophenol is described in literature to go via for-
mation of a benzothiazoline intermediate,17 which is then oxidized
to the benzothiazole. We therefore used DMSO as solvent (Table 1,
entry 3). After completion of the reaction at room temperature, as
indicated by TLC, we increased the reaction temperature to 120 ꢀC
and observed the formation of the final benzothiazole 5a. We as-
sume that the solvent DMSO acts as oxidant, because of the strong
odor of dimethylsulfide, which was observed after reaction. Besides
the oxidation by DMSO, it is also possible that part of the aldehyde
present in the reaction is used as oxidant or hydride acceptor. In
support of this the yield strikingly increased (77%) on adding more
benzaldehyde to the reaction mixture (Table 1, entry 4).
We next explored this benzothiazole synthesis using a variety of
aldehydes to establish optimized reaction conditions, being an ex-
cess of aldehyde in DMSO with piperidine as base (Scheme 3 &
Table 2). We obtained moderate to good yields (39e77%). No specific
influence from the electronic effects of the substituents was ob-
served, except in one case, 5e (Table 2, entry 5). Thus, an electron-
donating substituent, such as the dimethylamino group, has a neg-
ative effect on the reaction, by making the aldehyde and the imine
Scheme 2. Synthesis of 3H-thienobenzodithiazole 2-oxide 3.

4178
W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
Table 2
catalytic systems have been reported to promote this reaction, such
as HCl,19 piperidine/acetic acid,22 amino acids,23 SiO2,24 Ga(OTf)3,25
HBF4/SiO2,26 NH4Cl,27 or sodium dodecyl sulfate in water.28 Mecha-
nistically, this method has been reported to proceed via a thia-
Michael addition of the sulfhydryl group of the 2-aminothiophenol
Benzothiazole synthesis by reaction of 3 with different aldehydes
Entry
Substituent Ra
Yield [%]b
1
2
3
4
5
6
7
8
9
Phenyl
2-Thienyl
5a, 77
5b, 64
5c, 62
5d, 69
5e, 39
5f, 76
5g, 60
5h, 55
5i, 65
5k, 55
4-Fluorophenyl
2-Methoxyphenyl
4-Dimethylaminophenyl
4-Cyanophenyl
4-(4-Fluorobenzyloxy)phenyl
o-Tolyl
on the
a,b-unsaturated ketone ([1,4]-addition), followed by an
intramolecular nucleophilic attack of the NH2 group on the carbonyl
carbon with subsequent dehydration ([1,2]-addition).26,29 An alter-
native pathway was also described, primarily forming an imine (or
azadiene) followed by intramolecular conjugate addition by the
sulfhydryl.26
2-Hydroxyphenyl
2-Chloro-4-fluorophenyl
10
Inspired by the previously reported benzothiazepine syntheses
using o-aminothiophenols, we herein report a method for the
synthesis of novel thienobenzothiazepines. This method comprises
the reaction of the 3H-thienobenzodithiazole 2-oxide 3 with
chalcones (Scheme 6). While optimizing this reaction, we found
that initially the thia-Michael adduct 8a was formed under basic
a
Procedure: 3 (1 equiv), aldehyde (2.2 equiv), DMSO, piperidine (1 equiv) stirred
overnight at 25 ꢀC, then 2e3 h at 120 ꢀC.
b
Yields refer to isolated products.
intermediate electron rich and thus less activated for a nucleophilic
attack. This results in a slower reaction with decreased yield.
In contrast, while performing the described reaction of 3H-thie-
nobenzodithiazole 2-oxide 3 with 2,6-dichlorobenzaldehyde, we
obtained a different compound, namely the thienobenzothiazepine
derivative 6 (Scheme 4), instead of the desired benzothiazole. In this
case, an intramolecular nucleophilic aromatic substitution reaction
of the sulfur atom to the 2-position of the intermediate imine has
occurred. On the contrary, this intramolecular substitution reaction
was not observed in the reaction with 2-chloro-4-fluorobenzal
dehyde (Table 2, entry 10). Here, the 2-(2-chloro-4-fluorophenyl)
thienobenzothiazole 5j was formed as the sole compound. Such an
intramolecular nucleophilic aromatic substitution has been reported
for the reaction of 2-aminothiophenol with 2-chloro-5-nitrobenzal
dehyde.18
Scheme 6. Synthesis of thia-Michael adducts 8 and benzothiazepines 9, from 3H-
thienobenzodithiazole 2-oxide 3 and chalcones.
conditions (Table 3). In a next step, this compound 8a was annu-
lated using acetic acid, resulting in the expected dihydrothienoben
zothiazepine 9a (Scheme 6 & Table 4). The formation of this thia-
Michael adduct shows evidence for the first mechanistic pathway.
Moreover, we were able to form the benzothiazepine 9a in one step,
by altering the reaction conditions. Thus, by adding an excess of
acetic acid to the reaction mixture, after formation of 8a, we ob-
tained the desired benzothiazepine 9a in an one-pot reaction
(Scheme 6). The yield of this one-pot reaction (44%) was lower than
Scheme 4. Synthesis of thienobenzothiazepine 6, via an intramolecular nucleophilic
aromatic substitution reaction.
As a last part in the synthesis of nitrogen- and sulfur-containing
five-membered ring structures, we finally synthesized the thieno-
benzothiadiazole-7 (Scheme 5). This thiadiazole derivative was
obtained in a yield of 66%, by treatment of the sulfoxide 3 with
sodium nitrite.
Table 3
Optimization of the reaction of 3 with chalcone (R1¼R2¼Ph)
O
AcOH
N
N
S
S
S
Entry
Basea/acid
Solvent
Temp
Time
Yield 8a [%]
HCl conc
NaNO2
HN
1
2
3
4
5
6
7
8
Piperidine
HCl (2dr)
Et3N
NH4Cl
Et3N
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
PiperidineþPPh3
EtOH/H2O
MeOH
EtOH
Reflux
Reflux
60 ꢀC
RT
20 h
16 h
16 h
19 h
19 h
18 h
19 h
17 h
3 h
d
d
d
d
38
49
76
d
57
32
d
47
76
COOEt
COOEt
O°C 4h
S
S
H2O
ꢀC
3
7 (66%)
MeOH
MeOH
EtOH
EtOH/H2O
Toluene
MeCN
MeCN
MeCN
EtOH
0
0
0
0
0
0
0
ꢀC to RT
ꢀC to RT
ꢀC to RT
ꢀC
Scheme 5. Synthesis of thienobenzothiadiazole-7.
9
10
11
12
13
ꢀC
1 h
The synthesis of 1,5-benzothiazepines has been extensively de-
scribed in literature, due to the broad applicability of the benzo-
thiazepine scaffold as pharmacophore.3,19 Generally,1,5-benzothiaze
pines are synthesized via condensation of 2-aminothiophenols with
ꢀC to RT
ꢁ15 ꢀC
17 h
20 min
17 h
b
0
ꢀC to RT
a
Excess of base used.
0.5 equiv of PPh3 used.
a,b
-unsaturated ketones (chalcones).20,21 In literature, several
b

W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
4179
Table 4
Thia-Michael addition in the presence of PPh3 and subsequent annulation reaction
Entry
a
,
b
-unsaturated ketone
Yield [%]
R1
R2
1
2
3
4
5
6
7
Phenyl
Phenyl
8a, 76
8b, 45
8c, 59
8d, 53
8e, da
8f, d
4-Methoxyphenyl
4-Chlorophenyl
2-Hydroxyphenyl
4-Methoxyphenyl
4-Nitrophenyl
4-Chlorophenyl
4-Fluorophenyl
4-Fluorophenyl
2-Chlorophenyl
4-Cyanophenyl
2,6-Dichlorophenyl
2-Methoxyphenyl
8g, d
8
9
10
11
Phenyl
Phenyl
9a, 86 (44b)
9b, 90
9c, 90
4-Methoxyphenyl
4-Chlorophenyl
2-Hydroxyphenyl
4-Fluorophenyl
4-Fluorophenyl
2-Chlorophenyl
Scheme 7. Synthesis of pyrazole fused thienobenzothiazepine 11.
9d, 85
a
The corresponding thienobenzothiazepine 9e was formed (16% yield).
Tandem reaction: (1) piperidine; (2) excess AcOH.
Other methods have been reported using different precursors. For
instance, benzothiazines are also synthesized by reaction of bis(o-
b
nitrophenyl)disulfide with
a-bromoacetophenones promoted by
SmI2,33 or by ring expansion of benzothiazolines or benzothia-
zoles.35,36 In 1994, Sawhney et al.37 also reported the synthesis of
benzothiazine, by use of a dithiazole 2-oxide precursor. The benzo-
dithiazole 2-oxide precursor was also reported in the synthesis of
benzothiazinones.38
the overall yield in two steps (66%). The compounds 9 were easily
purified by filtration, as the products precipitated from the reaction
solvent.
The results in Table 3 clearly show the need for low temperature
(0 ꢀC) in the reaction. Heating the reaction mixture from the start is
detrimental for the 3H-benzodithiazole 2-oxide moiety. Piperidine,
instead of triethylamine as base, was found to give slightly better
results (Table 3, entry 5e6). Furthermore, addition of water to the
reaction mixture breaks down the formed product, when left for
a longer period of time (entry 8). The same remark holds for the use
of acetonitrile as solvent (entry 10e12). The addition of PPh3 to the
reaction mixture seemed to have no effect on the formation of 8a
(entry 13). However, while applying the highest yielding reaction
condition (Table 3, entry 7: compound 3, chalcone and piperidine in
EtOH at 0 ꢀC in an overnight reaction) on a small series of
substituted chalcones, we observed a drastic decrease in the ob-
tained yields (7e15%). In these cases, we found that the addition of
PPh3 to the reaction mixture resulted in higher and acceptable
yields (Table 4, entry 8e11).
In agreement with the previously introduced methods for the
synthesis of thienobenzothiazoles, -benzothiazepines, and -ben-
zothiadiazole, we have developed a method for the synthesis of
thienobenzothiazines, starting from our precursor, 3H-thieno-
benzodithiazole 2-oxide 3. We have focused on the reaction of 3
with different a-bromoacetophenones. In analogy with the thia-
zepine synthesis, we have obtained compounds 12aed in good
yields (52e75%), using piperidine in ethanol at 0 ꢀC with slow
warming up to room temperature overnight (Scheme 8 & Table 5).
All reaction products were easily obtained by filtration of the pre-
cipitated product and purified by recrystallization from ethanol.
Similarly, condensation of 3 with an excess of benzoquinone led to
a good yield of the intensively red dibenzothiazinone 12e after
chromatographic separation.
The necessity for PPh3 in the thia-Michael addition reaction can
be explained by its reducing effect on disulfides. In literature, the
condensation reaction of chalcones with o-aminothiophenols, in
situ formed by reductive cleavage of disulfides using PPh3, was
reported.30 In our case, the PPh3 actually prevents the formation of
disulfides, making it possible for the sulfur nucleophile to attack the
33
chalcone. Other reported methods use Zn,31 SnCl2,32 or SmI2 as
reducing agents for the in situ cleavage of disulfides.
Furthermore, compounds 8eeg were not formed (Table 4, entry
5e7). Reasons can be found in the poor solubility of the cyano- and
nitro-substituted chalcones, the steric hindrance of the dichlor-
ophenyl group, and the electron-donating effect of the methoxy
group (Table 4, entry 7), which deactivates the
a,b-unsaturated
ketone towards nucleophilic attack. However, in the reaction of
precursor 3 with the cyano-substituted chalcone (Table 4, entry 5),
we observed the formation of the corresponding thienobenzo-
thiazepine 9e in a low yield (16%).
An alternative way for benzothiazepines is effected by the con-
densation of 2-aminothiophenols with o-chlorobenzaldehyde de-
rivatives. Inspired by the reaction of 3 with 2,6-dichlorobenzal
dehyde, yielding compound 6 (Scheme 4), we have performed an-
other reaction of this type, using the chloroformylpyrazole 10.
Employing a literature procedure,34 we performed the reaction of 3
with 10 in ethanol using piperidine as base (Scheme 8). We obtained
the pyrazole fused thiazepine 11 without the need for further puri-
fication in a yield of 37% (Scheme 7).
Scheme 8. General method for the synthesis of 2H-thienobenzothiazines 12aed and
12e.
Table 5
Fused thiazine formation from 3 and bromoacetophenones
Entry
a
-Bromoacetophenone
Yield [%]
Aryl
R
1
2
3
4
4-Bromophenyl
Phenyl
Phenyl
H
H
12a, 75
12b, 74
12c, 70
12d, 52
In the last part, we looked at the synthesis of 2H-thienobenzo-
thiazines. Generally, 1,4-benzothiazines are synthesized by conden-
CH3
Phenyl
Phenyl
sation of o-aminothiophenols with
a
-bromoacetophenones.35,36

4180
W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
Finally, we have tested the alternative route to thieno-
instruments (Bruker Avance 300 MHz and Bruker AMX 400 MHz)
and chemical shifts ( ) are reported in parts per million (ppm)
benzothiazoles, using the condensation reaction of amine 1 with
organic isothiocyanates, and bromine-mediated oxidative cycli-
zation of the intermediate thiourea derivatives 13aec. The 2-(R)
aminothienobenzothiazoles 14aec were thus obtained in good
overall yield (Scheme 9). This method is complementary to the
previously mentioned one, leading to 5aek (Table 6).
d
referenced to tetramethylsilane (TMS) (1H) or the carbon signal of
deuterated solvents (13C). Mass spectra were run using a HP5989A
apparatus (CI and EI, 70 eV ionization energy) with Apollo 300 data
system, and a Kratos MS50TC instrument for exact mass mea-
surements (performed in the EI mode at a resolution of 10,000). For
column chromatography 70e230 mesh silica 60 (E.M. Merck) was
used as the stationary phase. Chemicals received from commercial
sources were used without further purification. The synthetic
procedure for the preparation of ethyl 5-aminobenzo[b]thiophene-
2-carboxylate (1) is described in our previous work.5
4.1.1. Ethyl 3H-thieno[30,20:3,4]benzo[1,2-d][1,2,3]dithiazole-7-carbo
xylate 2-oxide (3). A solution of ethyl 5-aminobenzo[b]thiophene-
2-carboxylate 1 (2.21 g, 10.0 mmol) in acetic acid (25 mL) was
slowly added to S2Cl2 (6 mL) at 0 ꢀC, whereupon a thick red-orange
slurry formed. The reaction mixture was then stirred for 2 h at 40 ꢀC
and diluted with toluene and filtered. The precipitate was washed
with toluene and finally with diethyl ether, and dried to yield 7-
(ethoxycarbonyl)thieno[30,20:3,4]benzo[1,2-d][1,2,3]dithiazol-2-
ium chloride (2) as a dark orange solid. This dithiazolium chloride
(Herz salt) was next stirred in water (100 mL) overnight. The re-
action mixture was filtered and the residue was dissolved in MeOH
(400 mL) and precipitated by adding cold water (150 mL). The
precipitate was filtered and dried, triturated with toluene and fil-
tered off to yield ethyl 3H-thieno-[30,20:3,4]benzo[1,2-d][1,2,3]
dithiazole-7-carboxylate 2-oxide 3 as yellow solid (2.36 g, 78%). Mp
Scheme 9. General method for the synthesis of 5-aminothienobenzothiazoles.
Table 6
138e139 ꢀC; IR: 3129, 2971, 1706, 1086 cmꢁ1 1H NMR (300 MHz,
;
Thienobenzothiazoles formation from 1 and different isothiocyanates
CDCl3):
d
1.44 (t, J¼7.1 Hz, 3H, CH3), 4.43 (q, J¼7.1 Hz, 2H, CO2CH2),
7.18 (d, J¼8.6 Hz, 1H), 7.62 (m, 2H), 7.92 (s, 1H); 13C NMR (75 MHz,
Entry
Substituent R
Yield [%]
Yield [%]
1
2
3
Butyl
Phenyl
Benzyl
13a, 63
13b, 82
13c, 86
14a, 74
14b, 80
14c, 91
CDCl3):
d 14.5, 62.1, 114.0, 115.5, 121.2, 127.5, 133.6, 136.6, 137.7,
138.5, 162.5; HRMS (EI): m/z calcd for C11H9NO3S3 (Mþ): 298.9745;
found: 298.9761.
4.1.2. Preparation of thienobenzothiazoles (5). To a mixture of ethyl
3H-thieno[30,20:3,4]benzo[1,2-d][1,2,3]dithiazole-7-carboxylate 2-
oxide 3 (150 mg, 0.50 mmol) and aldehyde (1.10 mmol) in DMSO
(4 mL) was added piperidine (0.05 mL, 0.50 mmol). The reaction
mixture was first stirred overnight at room temperature, and then
for 1.5e3 h at 120 ꢀC. After cooling, water was added, the pre-
cipitate was filtered and dried. The product was purified by re-
crystallization from ethanol or by column chromatography on silica
gel using CH2Cl2 as eluent to afford pure 5.
3. Conclusions
We have synthesized sulfurand nitrogen containing heterocycles,
fused in the 4,5-position of the benzothiophene scaffold. Therefore,
we firstly needed to derive a stable 5-amino-4-mercaptobenzothio
phene precursor. Using the Herz reaction, we were able to in-
troduce a sulfur atom in the 4-position of the benzothiophene
scaffold. The Herz salt was readily hydrolyzed in water to the 3H-
thienobenzodithiazole 2-oxide derivative, which was used as
o-aminothiophenol precursor. We have optimized the reaction
conditions for the synthesis of thienobenzothiazoles, -thiazepines,
-thiazines, and thienobenzothiadiazole, all starting from this pre-
cursor. The reaction of the latter with 2,6-dichlorobenzaldehyde did
not result in the usual thienobenzothiazole, but gave rise to a thia-
zepine, due to an intramolecular nucleophilic substitution reaction.
We introduced a new reaction procedure for the synthesis of thie-
nobenzothiazepines. In the condensation reaction with substituted
chalcones, we found that low temperature and the addition of PPh3
to the reaction mixture were crucial for this thienobenzothiazepine
synthesis.
4.1.3. Ethyl 2-phenylthieno[30,20:3,4]benzo[1,2-d]thiazole-7-carboxy
late (5a). Mp 163e163.5 ꢀC; IR: 3075, 2972, 1703, 1259 cmꢁ1 1H
;
NMR (300 MHz, CDCl3):
J¼7.2 Hz, 2H, CO2CH2), 7.51 (m, 3H), 7.89 (d, J¼8.7 Hz, 1H), 8.11 (m,
3H), 8.20 (s,1H); 13C NMR (75 MHz, CDCl3):
14.5, 62.0, 121.0, 122.4,
d
1.45 (t, J¼7.2 Hz, 3H, CH3), 4.44 (q,
d
127.5, 128.5, 129.3, 130.8, 131.1, 132.1, 133.5, 135.6, 139.9, 152.5,
162.5, 167.1; HRMS (EI): m/z calcd for C18H13NO2S2 (Mþ): 339.0388;
found: 339.0396.
4.1.4. Ethyl 2-(thien-2-yl)thieno[30,20:3,4]benzo[1,2-d]thiazꢁo1le-7-
carboxylate (5b). Mp 177e178 ꢀC; IR: 3078, 1697, 1283 cm
;
1H
NMR (300 MHz, CDCl3):
d
1.45 (t, J¼7.2 Hz, 3H, CH3), 4.44 (q,
4. Experimental section
4.1. General methods
J¼7.2 Hz, 2H, CO2CH2), 7.16 (t, J¼4.5 Hz, 1H), 7.52 (d, J¼4.7 Hz, 1H),
7.68 (d, J¼3.2 Hz, 1H), 7.88 (d, J¼8.9 Hz, 1H), 8.06 (d, J¼8.6 Hz, 1H),
8.16 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 14.5, 62.0, 121.1, 122.1,
128.2, 128.3, 128.6, 129.5, 130.4, 132.0, 135.7, 137.1, 139.9, 152.0,
160.5, 162.5; HRMS (EI): m/z calcd for C16H11NO2S3 (Mþ): 344.9952;
found: 344.9962.
Melting points (not corrected) were determined using a Reich-
ert Thermovar apparatus. IR spectra were recorded using a Bruker
ALPHA-P spectrometer. IR measurements were based the ATR
technique instead of the normal transmission method using KBr
pellets. 1H and 13C NMR spectra were measured on commercial
4.1.5. Ethyl 2-(4-fluorophenyl)thieno[30,20:3,4]benzo[1,2-d]thiazole-
7-carboxylate (5c). Mp 215e217 ꢀC; IR: 3076, 2983, 1706, 1263,

W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
4181
1223 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.45 (t, J¼7.2 Hz, 3H, CH3),
HRMS (EI): m/z calcd for C18H13NO3S2 (Mþ): 355.0337; found:
355.0341.
4.44 (q, J¼7.2 Hz, 2H, CO2CH2), 7.21 (t, J¼8.7 Hz, 2H), 7.90 (d,
J¼8.9 Hz, 1H), 8.10 (m, 3H), 8.20 (s, 1H); 13C NMR (75 MHz, CDCl3):
d
14.5, 62.0, 116.3, 116.6, 121.1, 122.3, 128.5, 129.5, 129.6, 129.8, 130.8,
4.1.12. Ethyl 2-(2-chloro-4-fluorophenyl)thieno[30,20:3,4]benzo[1,2-d]
thiazole-7-carboxylate (5j). Mp 215e216 ꢀC; IR: 3079, 2990, 1715,
132.1, 135.7, 139.9, 152.5, 162.5, 162.9, 165.8, 166.3; HRMS (EI): m/z
calcd for C18H12NO2S2F (Mþ): 357.0293; found: 357.0278.
1254, 1232 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d
1.44 (t, J¼7.1 Hz, 3H,
CH3), 4.44 (q, J¼7.1 Hz, 2H, CO2CH2), 7.15 (td, J¼2.6, 8.6 Hz, 1H), 7.30
(dd, J¼8.3, 2.6 Hz, 1H), 7.92 (d, J¼8.6 Hz, 1H), 8.14 (d, J¼9.0 Hz, 1H),
8.25 (s, 1H), 8.33 (dd, J¼8.6, 2.6 Hz, 1H); 13C NMR (150 MHz, CDCl3):
4.1.6. Ethyl 2-(2-methoxyphenyl)thieno[30,20:3,4]benzo[1,2-d]thiazole-
7-carboxylate (5d). Mp 185e186 ꢀC; IR: 3084, 2978, 1715, 1261,
1246 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.45 (t, J¼7.1 Hz, 3H, CH3), 4,
d 14.5, 62.0, 100.2, 115.0, 115.2, 118.2, 118.4, 121.2, 122.6, 128.4, 128.7,
12 (s, CH3O), 4.44 (q, J¼7.1 Hz, 2H, CO2CH2), 7.13 (m, 2H), 7.49 (t,
J¼8.1 Hz, 1H), 7.89 (d, J¼8.7 Hz, 1H), 8.13 (d, J¼8.9 Hz, 1H), 8.28 (s,
128.8, 132.0,132.1, 133.5,133.6,133.8,133.9, 136.1,140.3,151.0,161.9,
162.5, 162.7, 164.4; HRMS (EI): m/z calcd for C18H11NO2S2ClF (Mþ):
390.9904; found: 390.9896.
1H), 8.56 (d, J¼7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 14.5, 55.9,
61.9, 111.7, 120.5, 121.4, 122.1, 122.2, 128.6, 129.4, 131.9, 132.1, 135.1,
139.4, 150.5, 157.1, 161.9, 162.7; HRMS (EI): m/z calcd for C19H15NO3S2
(Mþ): 369.0493; found: 369.0487.
4.1.13. Ethyl 8-chlorobenzo[f]thieno[20,30:5,6]benzo[1,2-b][1,4]-thia-
zepine-2-carboxylate (6). To a mixture of ethyl 3H-thieno[30,20:3,4]
benzo[1,2-d][1,2,3]dithiazole-7-carboxylate 2-oxide 3 (150 mg,
0.50 mmol) and 2,6-dichlorobenzaldehyde (193 mg, 1.10 mmol) in
DMSO (4 mL) was added piperidine (0.05 mL, 0.50 mmol). The re-
action mixture was first stirred overnight at room temperature, and
then for 3 h at 120 ꢀC. After cooling, water was added, the precipitate
was filtered and dried. The product was purified by recrystallization
from ethanol to afford pure ethyl 8-chlorobenzo[f]thieno[20,30:5,6]
benzo[1,2-b][1,4]thiazepine-2-carboxylate 6 as bright yellow nee-
dles (135 mg, 72%). Mp 200e201 ꢀC; IR: 3085, 2979, 2912,1712,1251,
4.1.7. Ethyl 2-(4-(dimethylamino)phenyl)thieno[30,20:3,4]benzo[1,2-
d]thiazole-7-carboxylate (5e). Mp 214e216 ꢀC; IR: 2898, 1702,
1603, 1283, 1184, 1074 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.44 (t,
J¼7.2 Hz, 3H, CH3), 3.07 (s, 6H, N(CH3)2), 4.44 (q, J¼7.2 Hz, 2H,
CO2CH2), 6.75 (d, J¼8.9 Hz, 2H), 7.85 (d, J¼8.9 Hz, 1H), 7.96
(d, J¼8.9 Hz, 2H), 8.04 (d, J¼8.9 Hz, 1H), 8.18 (s, 1H); 13C NMR
(75 MHz, CDCl3):
d 14.5, 40.3, 61.9, 111.8, 120.5, 121.1, 121.8,
128.6, 128.8, 130.1, 132.2, 135.2, 139.0, 152.3, 152.7, 162.7, 168.0;
HRMS (EI): m/z calcd for C20H18N2O2S2 (Mþ): 382.0810; found:
382.0816.
1066 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.44 (t, J¼7.1 Hz, 3H, CH3),
4.44 (q, J¼7.1 Hz, 2H, CO2CH2), 7.34 (m, 2H), 7.42 (m, 2H), 7.78 (d,
J¼8.7 Hz, 1H), 8.46 (s, 1H), 9.13 (s, 1H); 13C NMR (75 MHz, CDCl3):
4.1.8. Ethyl 2-(4-cyanophenyl)thieno[30,20:3,4]benzo[1,2-d]thiazole-
d 14.5, 62.0,123.1, 123.4, 125.8, 130.1,130.2,130.5,132.4, 134.0, 134.9,
7-carboxylate (5f). Mp 268e270 ꢀC; IR: 3077, 2987, 2226, 1708,
135.1,140.5,142.4,146.3,160.6,160.6,162.7; HRMS (EI): m/z calcd for
1246 cmꢁ1
;
1H NMR (300 MHz, CD2Cl2):
d
1.44 (t, J¼7.2 Hz, 3H,
C18H12NO2S2Cl (Mþ): 372.9998; found: 373.0016.
CH3), 4.44 (q, J¼7.2 Hz, 2H, CO2CH2), 7.83 (d, J¼8.1 Hz, 2H), 7.99 (d,
J¼9.0 Hz, 1H), 8.14 (d, J¼9.0 Hz, 1H), 8.25 (m, 3H); 13C NMR
4.1.14. Ethyl thieno[30,20:3,4]benzo[1,2-d][1,2,3]thiadiazole-7-carboxy
late (7). A mixture of ethyl 3H-thieno[30,20:3,4]benzo[1,2-d][1,2,3]
dithiazole-7-carboxylate 2-oxide 3 (150 mg, 0.50 mmol), concen-
trated HCl (1 mL), and water (1 mL) in acetic acid (6.5 mL) was
stirred at room temperature for 30 min, and then cooled to 0 ꢀC. A
solution of NaNO2 (34.5 mg, 0.5 mmol) in water (1 mL) was slowly
added. The reaction mixture was stirred for 4 h, and then filtered.
The precipitate was washed with a NaHCO3 solution, and then with
water and dried to afford pure ethyl thieno[30,20:3,4]benzo[1,2-d]
[1,2,3]thiadiazole-7-carboxylate 7 (87.1 mg, 66%). Mp 156.5e
157.5 ꢀC; IR: 3078, 2979, 1714, 1288, 1244 cmꢁ1; 1H NMR (300 MHz,
(75 MHz, CD2Cl2):
d 14.2, 62.0, 114.2, 118.3, 121.5, 122.5, 127.8,
128.3, 131.3, 132.1, 133.0, 136.1, 137.3, 140.4, 152.5, 162.2, 164.4;
HRMS (EI): m/z calcd for C19H12N2O2S2 (Mþ): 364.0340; found:
364.0360.
4.1.9. Ethyl 2-(4-((4-fluorobenzyl)oxy)phenyl)thieno[30,20:3,4]-benzo-
[1,2-d]thiazole-7-carboxylate (5g). Mp 196e196.5 ꢀC; IR: 3057, 1704,
1264, 1219 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.44 (t, J¼7.0 Hz, 3H,
CH3), 4.44 (q, J¼7.0 Hz, 2H, CO2CH2), 5.12 (s, 2H, CH2O), 7.09 (m, 4H),
7.43 (m, 2H), 7.87 (d, J¼8.9 Hz, 1H), 8.05 (m, 3H), 8.18 (s, 1H); 13C
NMR (75 MHz, CDCl3):
d
14.5, 62.0, 69.6, 115.5, 115.6, 115.7, 115.9,
CDCl3):
d
1.45 (t, J¼7.1 Hz, 3H, CH3), 4.45 (q, J¼7.1 Hz, 2H, CO2CH2),
120.9, 122.2, 126.6, 128.5, 129.2, 129.5, 129.6, 130.6, 132.2, 135.5,
139.6, 145.4, 152.6, 161.0, 162.6, 166.8; HRMS (EI): m/z calcd for
C25H18NO3S2F (Mþ): 463.0712; found: 463.0719.
8.04 (d, J¼8.9 Hz, 1H), 8.31 (s, 1H), 8.61 (d, J¼9.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3):
d 14.4, 62.3, 121.6, 122.2, 129.1, 130.0, 136.9, 138.7,
143.3, 157.5, 162.0; HRMS (EI): m/z calcd for C11H8N2O2S2 (Mþ):
264.0027; found: 264.0029.
4.1.10. Ethyl 2-(o-tolyl)thieno[30,20:3,4]benzo[1,2-d]thiazole-7-carbo
xylate (5h). Mp 146e147 ꢀC; IR: 3076, 2977, 1704, 1258 cmꢁ1
;
1H
4.1.15. Thia-Michael addition: general procedure (8). A mixture of
ethyl 3H-thieno[30,20:3,4]benzo[1,2-d][1,2,3]dithiazole-7-carboxy
late-2-oxide 3 (150 mg, 0.50 mmol), PPh3 (65.6 mg, 0.25 mmol),
NMR (300 MHz, CDCl3):
d
1.45 (t, J¼7.2 Hz, 3H, CH3), 2.69 (s, 3H,
CH3), 4.44 (q, J¼7.1 Hz, 2H, CO2CH2), 7.37 (m, 3H), 7.80 (d, J¼7.3 Hz,
1H), 7.92 (d, J¼8.6 Hz, 1H), 8.15 (d, J¼8.9 Hz, 1H), 8.23 (s, 1H); 13C
and
a,b-unsaturated ketone (0.50 mmol) in EtOH (4 mL) was
NMR (75 MHz, CDCl3):
d
14.5, 21.6, 62.0, 120.8, 122.6, 126.4, 128.6,
cooled to 0 ꢀC and piperidine (0.1 mL, 1.00 mmol) was added. The
reaction mixture was stirred at 0 ꢀC, and allowed to slowly
warm up to room temperature overnight. The precipitated re-
action product was filtered and washed with cold ethanol. The
product was purified by recrystallization from ethanol to afford
pure 8.
130.2, 130.7, 131.4,131.8, 132.0, 132.8, 135.5,137.4, 139.8, 152.1, 162.6,
166.9; HRMS (EI): m/z calcd for C19H15NO2S2 (Mþ): 353.0544;
found: 353.0535.
4.1.11. Ethyl 2-(2-hydroxyphenyl)thieno[30,20:3,4]benzo[1,2-d]thiazole-
7-carboxylate (5i). Mp 184e185 ꢀC; IR: 2984, 1705, 1285 cmꢁ1 1H
;
NMR (300 MHz, CDCl3):
d
1.46 (t, J¼7.2 Hz, 3H, CH3), 4.44 (q,
4.1.16. Ethyl 5-amino-4-((3-oxo-1,3-diphenylpropyl)sulfanyl)ben-
J¼7.1 Hz, 2H, CO2CH2), 6.99 (t, J¼7.4 Hz, 3H), 7.12 (d, J¼8.3 Hz, 1H),
7.41 (t, J¼7.1 Hz, 1H), 7.73 (d, J¼7.0 Hz, 1H), 7.92 (d, J¼8.9 Hz, 1H),
8.04 (d, J¼8.7 Hz, 1H), 8.21 (s, 1H), 12.30 (s, 1H, OH); 13C NMR
zothiophene-2-carboxylate (8a). Mp 173e175 ꢀC; IR: 3468, 3365,
2977, 1716, 1675, 1595, 1245 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
1.41 (t, J¼7.1 Hz, 3H, CH3), 3.58 (dd, J¼6.2, 17.7 Hz, 1H, CH2), 3.76
(75 MHz, CDCl3):
d
14.5, 62.1, 116.7, 118.1, 119.8, 121.2, 121.4, 128.2,
(dd, J¼7.9, 17.5 Hz, 1H, CH2), 4.36 (q, J¼7.1 Hz, 2H, CO2CH2), 4.62 (s,
2H, NH2), 4.77 (dd, J¼6.2, 7.9 Hz, 1H, CH), 6.89 (d, J¼8.7 Hz, 1H),
128.3, 128.4, 131.9, 132.9, 136.1, 140.1, 150.2, 157.9, 162.4, 168.2;

4182
W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
7.15 (m, 5H), 7.44 (m, 2H), 7.55 (m, 2H), 7.83 (s, 1H), 7.88 (d,
169.6; HRMS (EI): m/z calcd for C26H21NO2S2 (Mþ): 443.1014;
found: 443.1013.
J¼7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
14.5, 38.2, 61.8, 63.1,
119.3, 123.5, 125.5, 126.2, 127.6, 127.7, 128.2, 128.5, 128.8, 129.0,
129.1, 130.3, 130.8, 131.6, 134.3, 135.1, 137.5, 139.1, 142.4, 144.0,
150.1, 162.8; HRMS (EI): m/z calcd for C26H23NO3S2 (Mþ): 461.1119;
4.1.20.2. Ethyl 2-(4-fluorophenyl)-4-(4-methoxyphenyl)-2,3-
dihydro-thieno[20,30:5,6]benzo[1,2-b][1,4]thiazepine-9-carboxylate
M
þ not found.
(9b). Mp 178e179 ꢀC; IR: 2903, 1702, 1286, 1179 cmꢁ1 1H NMR
;
(300 MHz, CDCl3):
d
1.40 (t, J¼7.1 Hz, 3H, CH3), 3.07 (t, J¼12.6 Hz,
4.1.17. Ethyl 5-amino-4-((1-(4-fluorophenyl)-3-(4-methoxyphenyl)-
3-oxopropyl)sulfanyl)benzo[b]thiophene-2-carboxylate (8b). Mp 128
1H, CH2), 3.29 (dd, J¼4.7, 13.0 Hz, 1H, CH2), 3.90 (s, 3H, CH3O), 4.40
(q, J¼7.1 Hz, 2H, CO2CH2), 5.15 (dd, J¼4.4, 12.2 Hz, 1H, CH), 6.98 (m,
4H), 7.21 (m, 2H), 7.42 (d, J¼8.6 Hz, 1H), 7.89 (d, J¼8.5 Hz, 1H), 8.03
e129 ꢀC; IR: 3476, 3370, 2990, 1712, 1665, 1596, 1248, 1226 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
1.41 (t, J¼7.2 Hz, 3H, CH3), 3.49 (dd,
(d, J¼8.8 Hz, 2H), 8.27 (s,1H); 13C NMR (75 MHz, CDCl3):
d 14.5, 37.8,
J¼6.4,17.5 Hz,1H, CH2), 3.69 (dd, J¼7.9,17.3 Hz,1H, CH2), 3.87 (s, 3H,
CH3O), 4.37 (q, J¼7.2 Hz, 2H, CO2CH2), 4.62 (br s, 2H, NH2), 4.74 (dd,
J¼6.4, 7.9 Hz, 1H, CH), 6.83 (m, 2H), 6.89 (d, J¼8.7 Hz, 1H), 6.91 (d,
J¼8.9 Hz, 2H), 7.11 (m, 2H), 7.33 (m, 4H), 7.54 (d, J¼8.7 Hz, 1H), 7.75
55.6, 61.8, 62.1, 114.3, 115.7, 116.0, 118.6, 123.5, 125.6, 127.8, 127.9,
129.4, 130.6, 135.0, 138.6, 139.9, 140.0, 142.4, 150.7, 160.7, 162.4,
162.8, 164.0, 168.6; HRMS (EI): m/z calcd for C27H22NO3S2F (Mþ):
491.1025; found: 491.1047.
(s,1H), 7.88 (d, J¼8.9 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 14.5, 43.4,
46.8, 55.7, 61.6, 109.1, 113.9, 114.3, 115.2, 115.4, 115.7, 117.2, 124.7,
128.6, 128.7, 129.1, 129.2, 129.4, 129.7, 130.1, 130.5, 131.9, 132.1, 132.1,
132.2, 132.3, 133.3, 134.3, 137.5, 137.5, 142.4, 144.5, 148.2, 162.9,
163.7, 163.9, 195.3; HRMS (EI): m/z calcd for C27H24NO4S2F (Mþ):
509.1131; found 509.1170.
4.1.20.3. Ethyl 4-(4-chlorophenyl)-2-(4-fluorophenyl)-2,3-dihydro-
thieno-[20,30:5,6]benzo[1,2-b][1,4]thiazepine-9-carboxylate (9c). Mp
197e198 ꢀC; IR: 2983, 1703, 1286 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.40 (t, J¼7.1 Hz, 3H, CH3), 3.08 (t, J¼12.5 Hz, 1H, CH2), 3.27 (dd,
J¼4.7, 13.0 Hz, 1H, CH2), 4.40 (q, J¼7.1 Hz, 2H, CO2CH2), 5.15 (dd,
J¼4.7, 12.1 Hz, 1H, CH), 6.97 (t, J¼8.5 Hz, 2H), 7.21 (m, 2H), 7.42 (d,
J¼8.6 Hz, 1H), 7.47 (d, J¼8.5 Hz, 2H), 7.90 (d, J¼8.6 Hz, 1H), 7.99 (d,
4.1.18. Ethyl 5-amino-4-((3-(4-chlorophenyl)-1-(4-fluorophenyl)-3-
oxopropyl)sulfanyl)benzo[b]thiophene-2-carboxylate (8c). Mp 149
e150 ꢀC; IR: 3476, 3371, 2974, 1710, 1679,1590, 1249, 1226 cmꢁ1; 1H
J¼8.5 Hz, 2H), 8.27 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 14.5, 37.9,
61.9, 62.3, 115.8, 116.0, 118.7, 123.6, 125.4, 127.8, 127.9, 128.9, 129.2,
130.5, 135.3, 136.0, 137.7, 139.0, 139.6, 139.7, 142.4, 150.2, 160.8,
162.7, 164.1, 168.2; HRMS (EI): m/z calcd for C26H19NO2S2ClF (Mþ):
495.0530; found: 495.0555.
NMR (300 MHz, CDCl3):
d
1.42 (t, J¼7.2 Hz, 3H, CH3), 3.49 (dd, J¼6.0,
17.7 Hz, 1H, CH2), 3.70 (dd, J¼7.5, 17.3 Hz, 1H, CH2), 4.38 (q, J¼7.2 Hz,
2H, CO2CH2), 4.62 (s, 2H, NH2), 4.75 (t, J¼6.4 Hz, 1H, CH), 6.87 (m,
3H), 7.12 (m, 2H), 7.41 (d, J¼7.5 Hz, 2H), 7.55 (d, J¼8.5 Hz, 1H), 7.80
(m, 3H); 13C NMR (75 MHz, CDCl3):
d
14.5, 43.8, 46.5, 61.6, 108.9,
4.1.20.4. Ethyl 2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-
thieno[20,30:5,6]benzo[1,2-b][1,4]thiazepine-9-carboxylate (9d). Mp
226e227 ꢀC; IR: 2976, 1712, 1251 cmꢁ1; 1H NMR (300 MHz, CDCl3):
115.3,115.6,117.2,124.9,129.1,129.2,129.6,130.0,132.4,134.5,134.9,
137.2, 140.0, 144.5, 148.2, 160.5, 162.9, 163.8, 195.6; HRMS (EI): m/z
calcd for C26H21NO3S2ClF (Mþ): 513.0635; found: 495.0529
[MþꢁH2O].
d
1.41 (t, J¼7.0 Hz, 3H, CH3), 2.97 (t, J¼12.8 Hz, 1H, CH2), 3.49 (m, 1H,
CH2), 4.41 (q, J¼7.1 Hz, 2H, CO2CH2), 5.84 (m, 1H, CH), 6.96 (m, 1H),
7.08 (d, J¼8.1 Hz, 1H), 7.20 (m, 2H), 7.42 (m, 4H), 7.81 (d, J¼7.3 Hz,
1H), 7.93 (d, J¼8.5 Hz, 1H), 8.38 (s, 1H), 14.3 (s, 1H, OH); 13C NMR
4.1.19. Ethyl 5-amino-4-((1-(2-chlorophenyl)-3-(2-hydroxyphenyl)-
3-oxopropyl)sulfanyl)benzo[b]thiophene-2-carboxylate (8d). Mp 145
(75 MHz, CDCl3): d 14.5, 36.3, 58.1, 62.0, 118.5, 118.7, 119.0, 120.4,
e146 ꢀC; IR: 3470, 3368, 2980, 1702, 1638, 1289 cmꢁ1
;
1H NMR
123.9, 125.4, 127.9, 128.3, 128.8, 129.4, 129.7, 130.3, 131.2, 134.0,
135.8, 139.8, 140.7, 142.3, 147.0, 162.6, 162.7, 173.5; HRMS (EI): m/z
calcd for C26H20NO3S2Cl (Mþ): 493.0573; found: 493.0550.
(300 MHz, CDCl3):
d
1.42 (t, J¼7.1 Hz, 3H, CH3), 3.59 (dd, J¼6.5,
17.5 Hz, 1H, CH2), 3.80 (dd, J¼7.5, 17.5 Hz, 1H, CH2), 4.38 (q, J¼7.2 Hz,
2H, CO2CH2), 4.67 (s, 2H, NH2), 5.41 (t, J¼7.0 Hz, 1H, CH), 6.83 (t,
J¼7.7 Hz, 1H), 6.90 (m, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.44 (t,
J¼7.7 Hz, 1H), 7.55 (d, J¼8.6 Hz, 1H), 7.60 (d, J¼8.1 Hz, 1H), 7.98 (s,
4.1.20.5. Ethyl 2-(4-cyanophenyl)-4-(2-methoxyphenyl)-2,3-dihydro-
thieno[20,30:5,6]benzo[1,2-b][1,4]thiazepine-9-carboxylate (9e). This
compound was obtained as sole product in the thia-Michael addi-
tion reaction, conforming the general procedure for the synthesis of
1H), 11.92 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d 14.5, 43.2, 43.4,
61.6, 108.3, 117.2, 118.7, 119.0, 119.1, 125.1, 127.2, 128.6, 128.8, 129.7,
130.0, 132.5, 133.9, 134.6, 136.7, 138.1, 144.6, 148.5, 162.5, 162.9,
202.3; HRMS (EI): m/z calcd for C26H22NO4S2Cl (Mþ): 511.0679;
found: 511.0680.
compounds (8). IR: 2978, 2226, 1705, 1241, 1173 cmꢁ1
;
1H NMR
(600 MHz, DMSO-d6):
d
1.33 (t, J¼7.0 Hz, 3H, CH3), 3.05 (t,
J¼12.8 Hz, 1H, CH2), 3.48 (dd, J¼4.8, 12.8 Hz, 1H, CH2), 3.88 (s, 3H,
CH3O), 4.35 (q, J¼7.0 Hz, 2H, CO2CH2), 5.53 (dd, J¼4.8, 12.8 Hz, 1H,
CH), 7.10 (d, J¼8.8 Hz, 2H), 7.47 (d, J¼8.8 Hz, 1H), 7.49 (d, J¼8.5 Hz,
2H), 7.79 (d, J¼8.0 Hz, 2H), 7.95 (s, 1H), 8.15 (d, J¼8.8 Hz, 2H), 8.21
4.1.20. Preparation of thienobenzothiazepines 9. General procedure:
To the 3-oxopropylsulfanylbenzo[b]thiophene derivative (thia-Mi-
chael adduct) 8 (0.50 mmol) in MeOH (6 mL) was added 2e3 drops
of acetic acid. This reaction mixture was refluxed until TLC-analysis
(eluent: CH2Cl2) indicated completion of the reaction (5e24 h).
After cooling, the precipitated product was filtered, washed with
MeOH, and dried to afford pure thienobenzothiazepine 9.
(d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d 14.1, 35.6, 55.5,
60.9, 61.6, 110.3, 114.1, 116.9, 118.6, 124.3, 125.4, 127.1, 129.3, 129.4,
129.5, 132.7, 134.5, 137.5, 141.6, 149.0, 150.8, 161.7, 162.0, 173.5;
HRMS (EI): m/z calcd for C28H22N2O3S2 (Mþ): 498.1072; found:
498.1089.
4.1.20.1. Ethyl 2,4-diphenyl-2,3-dihydrothieno[20,30:5,6]benzo[1,2-
4.1.21. Ethyl 8-methyl-10-phenyl-10H-pyrazolo[4,3-f]thieno[20,30:5,6]-
benzo[1,2-b][1,4]thiazepine-2-carboxylate (11). A mixture of ethyl
3H-thieno[30,20:3,4]benzo[1,2-d][1,2,3]dithiazole-7-carboxylate 2-
oxide 3 (150 mg, 0.50 mmol) and 5-chloro-3-methyl-1-phenyl-1H-
pyrazole-4-carbaldehyde (121 mg, 0.55 mmol) in EtOH (4 mL) was
cooled to 0 ꢀC and piperidine (0.1 mL, 1.00 mmol) was added. The
reaction mixture was stirred at 0 ꢀC, and allowed to slowly warm
up to room temperature overnight. The precipitated reaction
product was filtered and washed with cold ethanol to afford pure
b][1,4]thiazepine-9-carboxylate (9a). Mp 206e207 ꢀC; IR: 2974,
1709, 1245 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
1.40 (t, J¼7.1 Hz,
3H, CH3), 3.14 (t, J¼12.6 Hz, 1H, CH2), 3.36 (dd, J¼4.5, 12.8 Hz, 1H,
CH2), 4.39 (q, J¼7.1 Hz, 2H, CO2CH2), 5.19 (dd, J¼4.5, 12.4 Hz, 1H,
CH), 7.26 (m, 4H), 7.44 (d, J¼8.5 Hz, 1H), 7.52 (m, 4H), 7.89 (d,
J¼8.7 Hz, 1H), 8.08 (m, 2H), 8.31 (s, 1H); 13C NMR (75 MHz, CDCl3):
d
14.5, 38.1, 61.8, 63.1, 119.1, 123.4, 125.5, 126.2, 127.6, 128.2, 128.9,
129.0, 130.7, 131.4, 135.0, 137.6, 138.8, 142.4, 144.0, 150.4, 162.8,

W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
4183
ethyl 8-methyl-10-phenyl-10H-pyrazolo[4,3-f]thieno[20,30:5,6]ben
zo[1,2-b]-[1,4]thiazepine-2-carboxylate 11 (77 mg, 37%). Mp
145.5e146.5 ꢀC; IR: 3089, 2972,1714,1247 cmꢁ1; 1H NMR (300 MHz,
stirring the resulting mixture for another 12 h, the reaction mixture
was added to a 1:1 mixture of water and methanol (10 mL) and the
precipitate formed was filtered off and dried in vacuum. Purifica-
tion by column chromatography (silica, eluent CH2Cl2/EtOAc 95:5)
afforded pure 12e (70 mg, 63%) as a deep red solid. Mp 159e160 ꢀC;
CDCl3):
d
1.42 (t, J¼7.1 Hz, 3H, CH3), 2.40 (s, 1H, CH3), 4.41 (q,
J¼7.1 Hz, 2H, CO2CH2), 7.40 (d, J¼8.7 Hz, 1H), 7.54 (m, 5H), 7.82 (d,
J¼8.6 Hz, 1H), 8.28 (s, 1H), 8.72 (s, 1H); 13C NMR (75 MHz, CDCl3):
IR: 3062, 1700, 1622, 756 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.45 (t,
d
12.4, 14.4, 62.0, 119.7, 120.0, 123.7, 124.9, 125.3, 128.2, 128.7, 129.2,
J¼7.15 Hz, 3H, CH3), 4.46 (q, J¼7.10 Hz, 2H, CO2CH2), 6.86 (s, 1H),
129.3,129.4,135.2, 137.3,137.9, 140.6,141.0,148.7, 149.0,155.4,162.5;
HRMS (EI): m/z calcd for C22H17N3O2S2 (Mþ): 419.0762; found:
419.0760.
6.99 (d, J¼9.79 Hz 1H), 7.66 (d, J¼9.88 Hz, 1H); 7.89 (s, 2H), 8.21 (s,
1H); 13C NMR (75 MHz, CDCl3):
d 14.5, 29.8, 120.5, 120.9, 122.0,
126.6,131.7,133.5,133.6,135.4,136.9,137.0,139.7,144.5,145.9,161.9,
182.5; HRMS (EI): m/z calcd for C17H12NO3S2 (MþH): 342.0258;
found: 342.0252.
4.1.22. Preparation of 2H-thienobenzothiazines 12. General pro-
cedure: A mixture of ethyl 3H-thieno[30,20:3,4]benzo[1,2-d][1,2,3]
dithiazole-7-carboxylate-2-oxide 3 (150 mg, 0.50 mmol) and
a
-bro-
4.1.23. Ethyl 5-(3-butylthioureido)benzo[b]thiophene-2-carboxylate
(13a). To a solution of ethyl 5-aminobenzo[b]thiophene-2-carboxy
late 1 (208 mg, 0.941 mmol) in acetonitrile (3 mL) was added butyl
isothiocyanate (400 mg, 3.5 mmol). After stirring the resulting
mixture for another 12 h, the reaction mixture was added to a 1:1
mixture of water and methanol (10 mL) and the precipitate formed
was filtered off and dried in vacuum to afford analytically pure
product 13a as an off-white solid (198 mg, 63%). Mp 152e153 ꢀC; IR:
moketone (0.50 mmol) in EtOH (4 mL) was cooled to 0 ꢀC and pi-
peridine (0.05 mL, 0.50 mmol) was added. The reaction mixture was
stirred at 0 ꢀC, and allowed to slowly warm up to room temperature
overnight. The precipitated reactionproduct was filtered and washed
with cold ethanol. The product was purified by recrystallization from
ethanol to afford pure 2H-thienobenzothiazine 12.
4.1.22.1. Ethyl 3-(4-bromophenyl)-2H-thieno[20,30:5,6]benzo[1,2-
2958, 1712, 1542, 1249 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 0.92 (t,
b][1,4]-thiazine-8-carboxylate (12a). Mp 155e156 ꢀC; IR: 2993,
J¼7.09 Hz, 3H, CH3), 1.33 (q, J¼7.36 Hz, 2H, CH2), 1.43 (t, J¼7.10 Hz,
3H, CH3), 1.56 (t, J¼7.06 Hz, 2H, CH2), 3.64 (d, J¼6.17 Hz, 2H, CH2),
4.42 (q, J¼7.10 Hz, 2H, CH2), 5.99 (s, 1H), 7.31 (d, J¼8.58 Hz, 1H), 7.72
(s, 1H), 7.91 (d, J¼8.50 Hz, 1H), 7.97 (br s, 1H), 8.03 (s, 1H); 13C NMR
2903, 1706, 1244 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 1.43 (t,
J¼7.0 Hz, 3H, CH3), 3.67 (s, 2H, CH2), 4.42 (q, J¼7.0 Hz, 2H, CO2CH2),
7.64 (m, 4H), 7.92 (d, J¼8.3 Hz, 2H), 8.14 (s, 1H); 13C NMR (75 MHz,
CDCl3):
d
14.4, 23.0, 61.9, 119.5, 120.1, 125.8, 127.7, 129.0, 129.2, 132.1,
(75 MHz, CDCl3): d 13.9,14.4, 20.2, 31.2, 45.5, 62.1,122.1,124.7,124.8,
132.2, 135.0, 136.2, 136.3, 141.1, 153.5, 162.7; HRMS (EI): m/z calcd
129.9, 133.5, 136.4, 139.9, 140.9, 162.4, 180.9; HRMS (EI): m/z calcd
for C16H21N2O2S2 (MþH); 337.1044; found: 337.1037.
for C19H14NO2S2Br (Mþ): 432.9629; found: 432.9669.
4.1.22.2. Ethyl 3-phenyl-2H-thieno[20,30:5,6]benzo[1,2-b][1,4]thi-
4.1.24. Ethyl 5-(3-phenylthioureido)benzo[b]thiophene-2-carboxy
late (13b). Similarly, starting from ethyl 5-aminobenzo[b]-thio-
phene-2-carboxylate 1 (214 mg, 0.967 mmol) and phenyl iso-
thiocyanate (261 mg, 1.9 mmol), product 13b was obtained as an
off-white solid (279 mg, 82%). Mp 183e184 ꢀC; IR: 3307, 1701, 1245,
azine-8-carboxylate (12b). Mp 143e144 ꢀC; IR: 3068, 2979, 2903,
1708,1258 cmꢁ1; 1H NMR (300 MHz, CD2Cl2):
d
1.40 (t, J¼7.0 Hz, 3H,
CH3), 3.71 (s, 2H, CH2), 4.38 (q, J¼7.0 Hz, 2H, CO2CH2), 7.50 (m, 3H),
7.57 (d, J¼8.5 Hz, 1H), 7.69 (d, J¼8.5 Hz, 1H), 8.04 (m, 2H), 8.12 (s,
1H); 13C NMR (75 MHz, CD2Cl2):
d
14.2, 23.1, 61.8, 119.7, 119.9, 127.6,
692 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.42 (t, J¼7.12 Hz, 3H, CH3),
4.41 (q, J¼7.23 Hz, 2H, CO2CH2), 7.43 (m, 5H), 7.85 (m, 2H), 7.92 (s,
1H), 8.02 (s, 1H); 13C NMR
14.4, 31.1,121.9,123.7,125.1, 125.5, 127.7,
127.7, 128.4, 128.9, 131.0, 135.0, 136.2, 137.3, 140.6, 141.3, 155.0,
162.4; HRMS (EI): m/z calcd for C19H15NO2S2 (Mþ): 353.0544;
found: 353.0553.
d
130.1, 134.8, 135.9, 136.7, 139.4, 140.7, 162.6, 180.5; HRMS (EI): m/z
calcd for C18H17N2O2S2 (MþH): 357.0731; found 357.0722.
4.1.22.3. Ethyl 2-methyl-3-phenyl-2H-thieno[20,30:5,6]benzo[1,2-
b]-[1,4]thiazine-8-carboxylate (12c). Mp 110e111 ꢀC; IR: 3048,
4.1.25. Ethyl 5-(3-benzylthioureido)benzo[b]thiophene-2-carboxylate
(13c). Similarly, starting from ethyl 5-aminobenzo[b]thio-phene-2-
carboxylate 1 (199 mg, 0.9 mmol) and benzylisothiocyanate
(201 mg,1.35 mmol), product 13c was obtained as an off-white soꢁli1d
2974, 2923, 1703, 1259 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.33 (d,
J¼6.8 Hz, 3H, CH3), 1.43 (t, J¼7.1 Hz, 3H, CH3), 4.30 (q, J¼6.8 Hz,
1H, CH), 4.42 (q, J¼7.1 Hz, 2H, CO2CH2), 7.51 (m, 3H), 7.64 (d,
J¼8.5 Hz, 1H), 7.71 (d, J¼8.7 Hz, 1H), 8.07 (m, 2H), 8.18 (s, 1H); 13C
(285 mg, 86%). Mp 164e165 ꢀC; IR: 3328,1693,1512,1269, 751 cm
;
NMR (75 MHz, CDCl3):
d
14.4, 17.6, 29.8, 61.8, 116.3, 119.8, 127.4,
1H NMR (300 MHz, CDCl3):
d
1.41 (t, J¼7.12 Hz, 3H, CH3), 4.39 (q,
127.6, 128.9, 129.0, 131.0, 134.7, 137.0, 139.8, 141.1, 158.3, 162.7;
HRMS (EI): m/z calcd for C20H17NO2S2 (Mþ): 367.0701; found:
367.0702.
J¼7.02 Hz, 2H, CO2CH2), 4.88 (d, J¼4.76 Hz, 2H, CH2), 6.29 (s, 1H),
7.30 (br s, 6H), 7.72 (s,1H), 7.86 (d, J¼8.56 Hz,1H) 7.97 (s,1H), 8.17 (s,
1H); 13C NMR
d 14.4, 49.6, 62.0,122.1,124.7,127.8, 127.9,128.9, 129.1,
129.8, 133.3, 136.4, 137.2, 139.8, 141.0, 162.4, 181.3; HRMS (EI): m/z
4.1.22.4. Ethyl 2,3-diphenyl-2H-thieno[20,30:5,6]benzo[1,2-b][1,4]-
calcd for C19H19N2O2S2 (MþþH): 371.0888; found: 371.0881.
thiazine-8-carboxylate (12d). Mp 147e148 ꢀC; IR: 2982, 1697,
1252 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.39 (t, J¼7.0 Hz, 3H, CH3),
4.1.26. Ethyl-2-butylaminothieno[30,20:3,4]benzo[1,2-d]thiazole-7-
carboxylate (14a). A solution of Br2 (51 mg, 0.321 mmol) in acetic
acid (1 mL) was added to precursor 13a (108 mg, 0.321 mmol) in
acetic acid (3 mL) at rt After stirring the resulting mixture for an-
other 20 min, the reaction mixture was added to a 1:1 mixture of
water and methanol (15 mL) and the precipitate formed was fil-
tered off and dried in vacuum to afford analytically pure product
14a as an off-white solid (79 mg, 74%). Mp 158e159 ꢀC; IR: 3359,
4.38 (q, J¼7.0 Hz, 2H, CO2CH2), 7.20 (m, 5H), 7.46 (m, 3H), 7.64 (d,
J¼8.7 Hz, 1H), 7.70 (d, J¼8.7 Hz, 1H), 8.02 (m, 2H), 8.07 (s, 1H); 13C
NMR (75 MHz, CDCl3):
d 14.5, 38.5, 62.0, 116.3, 120.1, 127.6, 127.7,
128.6, 128.9, 129.0, 129.3, 130.3, 133.5, 134.7, 135.6, 136.6, 137.1,
138.1, 141.3, 155.6, 162.7; HRMS (EI): m/z calcd for C25H19NO2S2
(Mþ): 429.0857; found: 429.0858.
4.1.22.5. Ethyl 9-oxo-9H-thieno[2,3-c]phenothiazine-2-carboxy
late (12e). A solution of benzoquinone (105 mg, 0.975 mmol) in
MeOH (2 mL) was added slowly to a solution of ethyl 3H-thieno-
2929, 1691, 1511, 1265, 751 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 0.98
(t, J¼7.26 Hz, 3H, CH3), 1.47 (m, 5H), 1.71 (m, 2H), 3.44 (t, J¼6.93 Hz,
2H, CH2), 4.42 (q, J¼7.08 Hz, 2H, CH2), 5.67 (s, 1H), 7.65 (d,
[30,20:3,4]benzo[1,2-d][1,2,3]dithiazole-7-carboxylate 2-oxide
3
J¼8.69 Hz, 1H), 7.74 (d, J¼8.78 Hz, 1H), 7.99 (s, 1H); 13C NMR
d 13.9,
(100 mg, 0.325 mmol) in MeOH (2 mL) at room temperature. After
14.5, 20.2, 31.7, 45.8, 61.8, 119.3, 120.4, 127.7, 132.1, 135.1, 136.5,

4184
W. Van Snick et al. / Tetrahedron 69 (2013) 4176e4184
2. Priyanka; Sharma, N. K.; Jha, K. K. Int. J. Curr. Pharm. Res. 2010, 2, 1.
3. Bariwal, J. B.; Upadhyay, K. D.; Manvar, A. T.; Trivedi, J. C.; Singh, J. S.; Jain, K. S.;
Shah, A. K. Eur. J. Med. Chem. 2008, 43, 2279.
150.3, 162.8, 167.6; HRMS (EI): m/z calcd for C16H19N2O2S2 (MþH):
335.0888; found: 335.0869.
4. Fringuelli, R.; Milanese, L.; Schiaffella, F. Mini-Rev. Med. Chem. 2005, 5, 1061.
5. (a) Van Snick, W.; Nulens, W.; Jambon, S.; Dehaen, W. Synthesis 2009, 767; (b)
Van Snick, W.; Dehaen, W. Tetrahedron 2009, 65, 8497; (c) Van Snick, W.;
Parchina, A.; Dehaen, W. Tetrahedron 2011, 67, 4179.
4.1.27. Ethyl-2-phenylaminothieno[30,20:3,4]benzo[1,2-d]thiazole-7-
carboxylate (14b). Similarly, from Br2 (76 mg, 0.477 mmol) and
precursor 13b (170 mg, 0.477 mmol) was prepared product 14b as
an off-white solid (134 mg, 80%). Mp 164e165 ꢀC; IR: 3330, 1691,
6. Gupta, A.; Rawat, S. J. Curr. Pharm. Res. 2010, 3, 13.
7. Rathore, B. S.; Kumar, M. Bioorg. Med. Chem. 2006, 14, 5678.
8. Herz, R. (to Cassella & Co.) German Patent 360690, 1922.
9. Herz, R.; Balhorn, H. U.S. Patent 1,452,805, 1923.
10. Chenard, B. L. J. Org. Chem. 1984, 49, 1224.
11. Warburton, W. K. Chem. Rev. 1957, 57, 1011.
12. Blomquist, A. T.; Diuguid, L. I. J. Org. Chem. 1947, 12, 718.
13. Huestis, L. D.; Walsh, M. L.; Hahn, N. J. Org. Chem. 1965, 30, 2763.
14. Belica, P. S.; Manchand, P. S. Synthesis 1990, 6, 539.
15. Leawood, W. C. D., Jr. U.S. Patent 3,808,222, 1974.
16. Sawhney, S. N.; Sharma, P.; Bajaj, K.; Gupta, A. Synth. Commun. 1993, 23, 263.
17. Praveen, C.; Kumar, K. H.; Muralidharan, D.; Perumal, P. T. Tetrahedron 2008, 64,
2369.
1514, 1268 cmꢁ1
;
1H NMR (300 MHz, DMSO):
d
1.36 (t, J¼6.71 Hz,
3H, CH3), 4.38 (q, J¼6.56 Hz, 2H, CH2), 7.04 (t, J¼7.05 Hz, 1H), 7.38 (t,
J¼7.39 Hz, 2H), 7.82 (d, J¼8.49 Hz, 3H), 8.00 (d, J¼8.62, 1H), 8.29 (s,
1H), 10.65 (s, 1H); 13C NMR
d 14.2, 30.7, 41.7, 61.6, 104.7, 117.7, 119.8,
120.5, 122.1, 128.5, 129.1,131.5, 134.4, 136.1,140.6, 150.2, 161.5, 161.8;
HRMS (EI): m/z calcd for C18H15N2O2S2 (MþH): 355.0574; found:
355.0562.
4.1.28. Ethyl-2-benzylthieno[30,20:3,4]benzo[1,2-d]thiazole-7-carbox-
ylate (14c). Similarly, from Br2 (88 mg, 0.55 mmol) and precursor
13c (204 mg, 0.55 mmol) was prepared product 14c as an off-white
solid (183 mg, 91%). Mp 175e176 ꢀC; IR: 3328, 1693, 1512, 1269,
18. Mahmoud, M. R.; Guirgius, D. B. Phosphorus, Sulfur Silicon Relat. Elem. 1995,
102, 279.
19. Ansari, F. L.; Umbreen, S.; Hussain, L.; Makhmoor, T.; Nawaz, S. A.; Lodhi, M. A.;
Khan, S. N.; Shaheen, F.; Choudhary, M. I.; Rahman, A.-u. Chem. Biol. 2005, 2,
487.
751 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.41 (t, J¼7.06 Hz, 3H, CH3),
4.39 (q, J¼7.06 Hz, 2H, CO2CH2), 4.63 (s, 2H), 7.37 (m, 5H), 7.55 (d,
1H), 7.70 (d, 1H), 7.96 (s, 1H); 13C NMR
14.5, 49.8, 61.8, 119.1, 120.4,
ꢀ
20. Levai, A. J. Heterocycl. Chem. 2000, 37, 199.
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pp 255e298.
d
22. Rao, V. R.; Reddy, M. M. M. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181, 461.
23. Kumar, A.; Akanksha. Tetrahedron 2007, 63, 11086.
24. Kodomari, M.; Noguchi, T.; Aoyama, T. Synth. Commun. 2004, 34, 1783.
25. Pan, X.-Q.; Zou, J.-P.; Huang, Z.-H.; Zhang, W. Tetrahedron Lett. 2008, 49, 5302.
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1200.
124.5,126.9,127.6,127.8,128.1,128.9,129.1,132.0,135.2,136.6,137.2,
149.7, 162.7, 167.8; HRMS (EI): m/z calcd for C19H16N2O2S2 (MþH):
369.0731; found: 369.0721.
Acknowledgements
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The authors are grateful to the IWT [Institute for the Promotion
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voor Wetenschappelijk Onderzoek’ (FWO), the ‘Ministerie voor
Wetenschapsbeleid’ and the K.U. Leuven for continuing financial
support. The authors also thank BELSPO through IAP VI/27.
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