A novel way to tricyclic heteroaromatics; Thiazolo[5,4- b ]thieno[3,2- e ]pyridine derivatives

Article abstract of DOI:10.1055/s-0033-1339138

Thiazolo[5,4-b]thieno[3,2-e]pyridine derivatives, novel tricyclic heteroaromatics, have been designed and synthesized by a one-pot reaction of diazepinethiones and aldehydes. This reaction is based on a novel rearrangement reaction of seven-membered 1,4-diazepine-2-thiones to six-membered 3-aminopyridine-2-thiols catalyzed by scandium(III) triflate. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339138

PAPER
▌2317
paper
A Novel Way to Tricyclic Heteroaromatics; Thiazolo[5,4-b]thieno[3,2-e]pyri-
dine Derivatives
Thiazolo[5,4-b]thieno[3,2-e]pyridine Derivatives
Liye Huang,a,1 Ruina Yu,a,1 Ling Leng,b Feng Gong,b Xinhai Zhu,*a Yiqian Wan*a
a
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. of China
Fax +86(20)84113610; E-mail: ceswyq@mail.sysu.edu.cn
b
Institute of Blood Transfusion, Department of Molecular Biology, Beijing 100850, P. R. of China
Received: 15.03.2014; Accepted after revision: 27.04.2014
11a is readily obtained by a three-component reaction of
Abstract: Thiazolo[5,4-b]thieno[3,2-e]pyridine derivatives, novel
sulfur, 3-methylbutanal, and 3-(2-chlorophenyl)-3-oxo-
tricyclic heteroaromatics, have been designed and synthesized by a
propanenitrile.
one-pot reaction of diazepinethiones and aldehydes. This reaction is
based on a novel rearrangement reaction of seven-membered 1,4-di-
azepine-2-thiones to six-membered 3-aminopyridine-2-thiols cata-
lyzed by scandium(III) triflate.
N
S
isosteric substitution
N
1
N
2
Key words: rearrangement, cyclization, heterocycles, Lewis acid,
catalysis
acridine
thiazolo[5,4-b]quinoline
N
S
N
S
Heterocycles are an important class of molecular space
and constitute >50% of organic compounds.2 The remark-
able ability of heterocyclic nuclei to serve as both biomi-
metics and pharmacophores has largely contributed to
their unique value as traditional key elements of numerous
drugs.3 However, our ability to predict the usefulness of
new compounds before they are synthesized is still rudi-
mentary, therefore, research directed toward the discovery
of novel types of organic compounds continues at an un-
abated pace both in academia and pharmaceutical compa-
nies. Isosterism has often been an effective strategy and
tactic to provide novel compounds to address stability, se-
lectivity, toxicity, pharmacokinetics, and efficacy issues
in drug discovery and development.4
N
3
already known
isosteric substitution
N
S
S
N
4
unknown
Scheme 1 The design of novel hetero tricycles
At first glance, path B appears to be a reliable shortcut to
our key intermediate 6a. We reasoned that 6a could be ac-
cessed from compound 11a, because aminoquinones have
been readily prepared from 2-aminobenzophenones,9 and
a protocol for preparing 3-aminoquinoline-2-thiol from
aminoquinones has been successfully established,9c which
provide similar transformations for the preparation of 6a
from 11a.
It is well known that acridines 1 (Scheme 1), from isoster-
ism of anthracenes, are significant as raw materials for the
production of dyes and antitumor, antiparasitic, antibacte-
rial, antifungal, antiviral agents, and multi-drug resistance
modulators.5
On the other hand, path A should be an alternative way
from 11a to 6a. As is well known, a great number of meth-
ods for the synthesis of thienodiazepinones 8a have been
established.10 Moreover, Kovač et al.11a obtained 3-ami-
no-6-bromo-4-(2-pyridyl)quinolin-2-one from the rear-
rangement of corresponding bromazepam with
manganese(III) acetate as a catalyst in glacial acetic acid.
Hence, we reasoned that 12a could be accessed from com-
pound 8a. The conversion of 7a to 6a would be more prac-
tical, because thienodiazepinethione derivatives such as
7a would be more reactive than 8a to perform a rearrange-
ment to form 6a with Lewis acids as catalysts. The rule of
‘hard-soft acid-base’ should provide a good answer, as it
is well known that the donor atom, S, is of lower electro-
negativity and higher polarizability than the donor atom,
O. Hence, the thiol group will bound more tightly to the
soft metal ions of the common used Lewis acids, which
will facilitate the rearrangement of 7a. Moreover, thieno-
Moreover, thiazolo[5,4-b]quinolines 2 (Scheme 1), which
can be considered as isosterically substituted acridines,
are also very useful as raw materials for the production of
dyes6 and bioactive agents.5,7 However, very few com-
pounds from further isosterism, with the exception of bis-
thiazolo[5,4-b:4′,5′-e]pyridines 3 that are useful for the
treatment of diseases characterized by inhibiting exces-
sive or anomalous cell proliferation,8 have been reported.
Accordingly, our aim was to synthesize novel tricyclic he-
teroaromatics analogous to compound 3, but containing a
thiazolo[5,4-b]thieno[3,2-e]pyridine moiety 4.
As shown in Scheme 2, the key intermediate 6a might be
obtained from compound 11a via two routes; compound
SYNTHESIS 2014, 46, 2317–2326
Advanced online publication: 12.06.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339138; Art ID: ss-2014-f0184-op
© Georg Thieme Verlag Stuttgart · New York

2318
L. Huang et al.
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N
S
N
S
S
N
SH
Cl
NH2
Cl
Cl
H
O
N
5a
S
6a
path B
path A
H
S
N
S
N
N
S
OH
S
N
OH
Cl
Cl–
N
NH2
N
Cl
8a
Cl
Cl
H
NH2
N
S
12a
7a
13a
O
O
O
O
Cl
Cl
S
NH2
S
NH
Cl
N
O
O
9a
HN
S
O
Cl
O
O
Cl
14a
11a
10a
Scheme 2 Two routes of retrosynthesis of representative compound 5a
diazepinethione 7a could be easily provided from the re- and we found that scandium(III) triflate was the best
action of the corresponding thienodiazepinone 8a with choice because of its efficacy and water tolerance;14 we
phosphorus pentasulfide12 or Lawesson’s reagent.13 Ac- obtained 5a in 60% isolated yield at 150 °C in N,N-di-
cordingly, 6a could react with various aldehydes to pro- methylformamide. In addition to 5a, we also obtained an
vide the desired thiazolo[5,4-b]thieno[3,2-e]pyridine interesting byproduct 5b, which thought to arise from the
derivatives.
reaction of 6a with N,N-dimethylformamide, although the
mechanism is not clear. To overcome this drawback, the
use of other solvents was examined and finally N-meth-
ylpyrrolidin-2-one was identified as the best choice. As
shown in Table 1, using N-methylpyrrolidin-2-one as the
solvent gave a faster reaction rate and the isolated yield
was up to 80%.
To overcome the obvious drawback of path B (that is,
largely using anhydrous pyridine at reflux) and to chal-
lenge a novel type of rearrangement, we carried out the re-
action according to the path A (Scheme 3).
As expected, 8a was readily prepared according to the re-
ported method with slight modification (using morpholine
as base instead of triethylamine) from 3-(2-chlorophe-
nyl)-3-oxopropanenitrile in four steps with a total yield of
23%.12c It is intriguing that a rearrangement similar to that
in literature11 did not take place on treatment of 8a with
manganese(III) acetate in glacial acetic acid. After sulfu-
ration of 8a with phosphorus pentasulfide, compound 7a
was obtained in 90% isolated yield. Unfortunately, only a
small amount of 5-amino-4-(2-chlorophenyl)-2-isoprop-
ylthieno[2,3-b]pyridine-6-thiol (6a) was obtained when
7a was treated with manganese(III) acetate in glacial ace-
tic acid. Otherwise, some byproducts (e.g., 15a) appeared,
which encouraged us to pursue a more concise and
straightforward route (i.e., a one-pot route with treatment
by 4-chlorobenzaldehyde) directly toward our target com-
pound 5a. In this case, 5a was successfully obtained from
7a on reaction with 4-chlorobenzaldehyde in 39% isolated
To explore the scope of the one-pot reaction, a variety of
aldehydes were tested under the optimized reaction condi-
tions [i.e., thienodiazepinethione (0.3 mmol), aldehyde
(0.6 mmol), Sc(OTf)3 (1 mol%), NMP (2 mL), 150 °C].
As shown in Table 1, arylaldehydes with electron-donat-
ing (entries 5–8) or also electron-withdrawing substitu-
ents (entries 9–11) afforded the desired products 5e–k in
very good yields. Furthermore, an ortho-substituted aryl-
aldehyde (entry 12) resulting in a good outcome indicated
no obvious stereohindrance effect. More importantly, he-
teroarylaldehydes performed the reaction very well (en-
tries 13 and 14), which would lead to important bioactive
molecules. In the example of an alkylaldehyde, interest-
ingly, the desired product 5c was also obtained in very
good yield comparable to their aromatic counterparts (en-
try 3).
yield. This encouraging result led us to screen other Lewis To understand further the one-pot reaction, especially to
acids [e.g., CuSO4, Bi(OTf)3, Sc(OTf)3, AlCl3 and TiCl4] confirm the intermediate 6a, we ran the model reaction
Synthesis 2014, 46, 2317–2326
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Thiazolo[5,4-b]thieno[3,2-e]pyridine Derivatives
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O
H
NH2
H
O
N
O
N
S
N
S
NH2
O
S
Cl
O
O
N
O
O
O
Cl
O
1) H2NNH2⋅H2O, EtOH
Cl
Cl
Et3N, CH2Cl2
2) HCl
11a
9a
10a
H
N
H
O
S
N
S
S
N
S
S
O
Cl
Cl
N
P2S5
toluene
AcOH
N
N
H
Cl
i-PrOH
Sc(OTf)3, NMP
Cl
Cl
5a
8a
7a
Cl
Sc(OTf)3
NMP
O
Sc(OTf)3
NMP
H
N
S
S
N
S
N
S
S
SH
H2N
NH2
NH2
Cl
Cl
Cl
15a
6a
Scheme 3 One-pot and stepwise synthesis of 5a
without the addition of 4-chlorobenzaldehyde under the enough information could be drawn from NMR spectra.
optimized conditions. After the complete consumption of Hence, the structure of 5a was determined by using X-ray
7a as shown by TLC, 6a was isolated and identified (EI, single crystal diffraction (Figure 1), MS, and NMR tech-
1H NMR and HRMS). It is hardly surprising that 13C niques, while the structures of its analogues were identi-
NMR analysis indicated some level of conversion of 6a to fied only by MS and NMR techniques.
15a, which was also found in the reaction mixture as a by-
product; it is well known that its analogues, 2-aminoben-
zenethiols, are readily transformed into diaryl disulfide.15
Considering its HRMS analysis result {HRMS (EI): m/z
[M+] calcd for C32H28Cl2N4S4: 666.0568; found:
666.0570}, the byproduct was thought to be 15a. Further,
tandem mass analysis was applied to unequivocally iden-
tify the structure of 15a. Moreover, 6a reacted with 4-
chlorobenzaldehyde to afford 5a in 70% isolated yield.
Hence, all evidence pointed to 6a as the product of this re-
arrangement, which was readily oxidized to 15a.
It should be noted that we have successfully synthesized
two other thiazolo[5,4-b]thieno[3,2-e]pyridine deriva-
tives 5o,p (entries 15 and 16) using this novel protocol, re-
Figure 1 Single crystal structure of 5a16
placing the isopropyl group by a phenyl group and also the
Considering these compounds containing a linear polycy-
clic aromatic moiety, which might be a toxicophore due to
its potent cytotoxicity, we selected compound 5a and 5b
for cytotoxicity assay with the MTT method on the
HEK293 cell line. The preliminary tests indicated that
2-chlorophenyl group by a phenyl group in good yields
from readily available starting materials. This result par-
tially confirmed our protocol to be useful for the prepara-
tion of a variety of thiazolothienopyridine derivatives.
We confirmed the structure of the target products by X-
ray single crystal diffraction techniques because not
© Georg Thieme Verlag Stuttgart · New York
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2320
L. Huang et al.
PAPER
spectra were recorded on an EQUINOX 55 Fourier transformation
infrared spectrophotometer coupled with an infrared microscope.
Single-crystal X-ray diffraction data was collected at 150(2) K on
an Agilent Technologies Gemini a Ultra system, with Cu-Kα radia-
tion (λ = 1.54178 Å). Melting points were determined on a WRS-
1B digital melting point apparatus and are uncorrected.
Table 1 The Reactions and Isolate Yields of Thienodiazepinethiones
with Different Aldehydes
N
S
S
S
H
R1
R3
N
S
N
Sc(OTf)3 (1 mol%)
R1
R3CHO
R2
N
+
(2-Aminothiophen-3-yl)(phenyl)methanone Derivatives 11;
General Procedure 1 (GP-1)
NMP, 150 °C, 12 h
R2
To a 30-mL vial was added nitrile (1.0 equiv), sulfur (1.0 equiv), al-
dehyde (1.0 equiv), morpholine (1.0 equiv), and EtOH (1.0 M) and
the vial was sealed. The reaction was stirred in an oil bath at 100 °C
for 6 h. The mixture was cooled to r.t., and then it was diluted by
EtOAc (200 mL). The organic phase was washed with H2O (3 × 40
mL) and brine, dried (anhyd Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel) to afford the desired compound.
7
5
Entry
R1
R2
R3
Product Yield (%)
1
2
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
4-ClC6H4
H
5a
5b
5c
5d
5e
5f
79
58
67
66
83
74
91
74
67
70
70
66
72
77
70
52
(2-Amino-5-isopropylthiophen-3-yl)(2-chlorophenyl)methan-
one (11a)
According to GP-1 using 3-(2-chlorophenyl)-3-oxopropanenitrile
(1.8 g, 10 mmol), sulfur (320 mg, 10 mmol), 3-methylbutanal (860
mg, 10 mmol), and morpholine (870 mg, 10 mmol) in EtOH (10
mL) gave 11a (2.2 g, 78%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.24 (m, 6 H, HAr, NH2), 6.05
(s, 1 H, HAr), 2.81 (sept, J = 6.8 Hz, 1 H, CH), 1.15 (d, J = 6.8 Hz,
6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 188.6, 166.1, 140.6, 133.7, 130.7,
130.4, 130.1, 128.6, 126.8, 120.2, 114.9, 29.9, 24.4.
3
i-Bu
4
Ph
5
4-MeC6H4
4-MeOC6H4
4-HOC6H4
4-i-PrC6H4
4-F3CC6H4
4-NCC6H4
4-AcC6H4
2-ClC6H4
2-furyl
6
7
5g
5h
5i
8
9
MS (EI): m/z (%) = 279 (55) [M+], 281 (20) [M + 2]+, 264 (100).
10
11
12
13
14
15
16
5j
(2-Amino-5-isopropylthiophen-3-yl)(phenyl)methanone (11b)
According to GP-1 using 3-oxo-3-phenylpropanenitrile (1.45 g, 10
mmol), sulfur (320 mg, 10 mmol), 3-methylbutanal (860 mg, 10
mmol), and morpholine (870 mg, 10 mmol) in EtOH (10 mL) gave
11b (1.8 g, 75%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.67–7.64 (m, 2 H, HAr), 7.50–
7.40 (m, 3 H, HAr), 6.93 (br s, 2 H, NH2), 6.51 (s, 1 H, HAr), 2.92
(sept, J = 6.8 Hz, 1 H, CH), 1.23 (d, J = 6.8 Hz, 6 H, 2 CH3).
5k
5l
5m
5n
5o
5p
2-thienyl
4-ClC6H4
4-ClC6H4
13C NMR (75 MHz, CDCl3): δ = 191.0, 165.1, 141.3, 133.4, 130.7,
128.3, 128.2, 121.0, 114.6, 30.0, 24.5.
Cl
MS (EI): m/z (%) = 245 (55) [M+], 230 (100).
these compounds do not show obvious cytotoxicity even
at the concentration of 250 μg/mL.
(2-Amino-5-phenylthiophen-3-yl)(2-chlorophenyl)methanone
(11c)
According to GP-1 using 3-(2-chlorophenyl)-3-oxopropanenitrile
(1.8 g, 10 mmol), sulfur (320 mg, 10 mmol), 2-phenylacetaldehyde
(1.2 g, 10 mmol), and morpholine (870 mg, 10 mmol) in EtOH (10
mL) gave 11c (2.0 g, 65%) as a yellow solid; mp 165–166 °C.
We have developed an effective one-pot method based on
a novel rearrangement reaction for the construction of
novel thiazolo[5,4-b]thieno[3,2-e]pyridine derivatives.
Their structure was confirmed by using X-ray single crys-
tal diffraction, MS, and NMR techniques. This novel tri-
cyclic heteroaromatic family is expected to be attractive to
medicinal chemists and material scientists.
IR (KBr): 3393, 3283, 3059, 1578, 1551, 1454, 1427, 1273, 1200,
1155, 1053, 1028, 941, 759, 692, 646, 611, 491, 454 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.49–7.44 (m, 1 H, HAr), 7.42–
7.37 (m, 2 H, HAr), 7.37–7.33 (m, 2 H, HAr), 7.33–7.30 (m, 2 H,
HAr), 7.29–7.27 (m, 1 H, HAr), 7.23–7.15 (m, 3 H, HAr, NH2), 6.68
(s, 1 H, HAr).
13C NMR (75 MHz, CDCl3): δ = 189.3, 166.1, 140.2, 133.8, 130.8,
130.7, 130.2, 129.0, 128.6, 127.1, 126.9, 125.0, 124.6, 122.3, 116.9.
MS (EI): m/z (%) = 313 (100) [M+], 315 (40) [M + 2]+, 278 (85).
All reagents were purchased from commercial sources and used
without further treatment, unless otherwise indicated. Toluene was
treated with metal Na; CH2Cl2 was dried with molecular sieves
(4 Å) and the others reagents were used as received. Flash column
chromatography was performed on silica gel (200–300 mesh). TLC
HRMS (EI): m/z [M+] calcd for C17H12ONClS: 313.0323; found:
313.0324.
was carried out with Merck silica gel GF254 plates. 1H NMR and 13
C
NMR spectra were recorded at r.t. on a Mercury-Plus 300, a Bruker
Avance 400 and a Bruker Avance 500 instrument with TMS as an
internal reference. LC/MS was run on a LCMS-2010A or a LCQ
DECA XP instrument. MS/MS was run on a LCQ DECA XP instru-
ment. EI mass spectra were recorded on the Thermo DSQ mass
spectrometer. HRMS were performed on a Thermo MAT95XP
mass spectrometer or a Bruck APEX IV mass spectrometer. IR
N-[3-(2-Chlorobenzoyl)-5-isopropylthiophen-2-yl]-2-(1,3-di-
hydro-1,3-dioxo-2H-isoindol-2-yl)acetamide (10a); Typical
Procedure
To a 30-mL vial was added N-phthaloylglycine (2.05 g, 10 mmol)
and SOCl2 (8 mL) and the vial was sealed. The reaction was stirred
in an oil bath at 60 °C for 8 h. The mixture was cooled to r.t., the
Synthesis 2014, 46, 2317–2326
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Thiazolo[5,4-b]thieno[3,2-e]pyridine Derivatives
2321
SOCl2 was removed in vacuo, hexane (10 mL) was added, and the
mixture was stirred for 10 min resulting in white solid. After filtra-
tion, the solid (2.0 g, 90%) was washed with hexane and used direct-
ly in the next reaction. Phthaloylglycyl chloride (2.0 g, 9.0 mmol)
in CH2Cl2 (8 mL) was added dropwise to the solution of 11a (2.2 g,
7.9 mmol) and Et3N (3.0 mL) in CH2Cl2 (50 mL). The mixture was
stirred at r.t. until completion of the reaction, then diluted with
CH2Cl2 (150 mL). The organic phase was washed with H2O (3 × 40
mL) and brine, dried (anhyd Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel) to afford 10a (3.2 g, 89%) as a yellowish solid.
1H NMR (300 MHz, CDCl3): δ = 12.19 (br s, 1 H, NH), 7.92–7.84
(m, 2 H, HAr), 7.76–7.69 (m, 2 H, HAr), 7.45–7.30 (m, 4 H, HAr),
6.34 (s, 1 H, HAr), 4.70 (s, 2 H, CH2), 2.96 (sept, J = 6.8 Hz, 1 H,
CH), 1.21 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 191.4, 167.6, 164.3, 149.1, 143.4,
139.3, 134.5, 132.2, 131.2, 130.8, 130.3, 128.6, 126.9, 123.9, 121.1,
119.8, 41.2, 29.9, 24.6.
vent, CH2Cl2 (200 mL) was added to the residue and the organic
phase was washed with H2O (3 × 40 mL) and brine, dried (anhyd
Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel) to afford 9a (1.4 g, 61%)
as a yellow solid.
IR (KBr): 3400, 3340, 3230, 3060, 2970, 2910, 1680, 1640, 1510,
1430, 1310, 1230, 1160, 1080, 1030, 945, 810, 762, 696, 644, 590,
434 cm–1.
1H NMR (300 MHz, CDCl3): δ = 12.84 (br s, 1 H, NH), 7.47–7.32
(m, 4 H, HAr,), 6.36 (s, 1 H, HAr), 3.66 (s, 2 H, CH2), 3.00 (sept, J =
6.8 Hz, 1 H, CH), 1.80 (br s, 2 H, NH2), 1.26 (d, J = 6.8 Hz, 6 H, 2
CH3).
13C NMR (75 MHz, CDCl3): δ = 190.7, 171.5, 148.9, 142.5, 139.7,
130.8, 130.7, 130.8, 128.5, 126.7, 120.9, 119.8, 45.0, 29.8, 24.5.
MS (EI): m/z (%) = 336 (10) [M+], 338 (3) [M + 2]+, 264 (100).
2-Amino-N-(3-benzoyl-5-isopropylthiophen-2-yl)acetamide
(9b)
Following the typical procedure for 9a gave 9b (1.2 g, 60%) as a
yellow solid; mp 88–89 °C.
MS (ESI+): m/z: 489 (80) [M + Na]+, 491 (30) [M + 2 + Na]+, 521
(100) [M + MeOH + Na]+.
IR (KBr): 3411, 3194, 2964, 1677, 1608, 1522, 1450, 1411, 1363,
1307, 1273, 1241, 1162, 1061, 1020, 803, 736, 710, 662 cm–1.
N-(3-Benzoyl-5-isopropylthiophen-2-yl)-2-(1,3-dihydro-1,3-di-
oxo-2H-isoindol-2-yl)acetamide (10b)
1H NMR (300 MHz, CDCl3): δ = 12.87 (br s, 1 H, NH), 7.74–7.71
(m, 2 H, HAr), 7.57–7.44 (m, 3 H, HAr), 6.77 (s, 1 H, HAr), 3.67 (s, 2
H, CH2), 3.07 (sept, J = 6.8 Hz, 1 H, CH), 1.97 (br s, 2 H, NH2), 1.31
(d, J = 6.8 Hz, 6 H, 2 CH3).
Following the typical procedure for 10a gave 10b (2.9 g, 90%) as a
yellow solid; mp 209–210 °C.
IR (KBr): 3432, 2961, 1778, 1720, 1617, 1531, 1422, 1395, 1325,
1241, 1171, 1114, 952, 814, 739, 707, 662 cm–1.
13C NMR (100 MHz, CDCl3): δ = 192.4, 171.2, 148.5, 142.3, 140.0,
131.6, 128.6, 128.3, 120.3, 120.3, 44.8, 29.6, 24.4.
MS (EI): m/z (%) = 302 (10) [M+], 230 (100).
HRMS (EI): m/z [M+] calcd for C16H18O2N2S: 302.1084; found:
302.1083.
1H NMR (300 MHz, CDCl3): δ = 12.33 (br s, 1 H, NH), 7.91–7.88
(m, 2 H, HAr), 7.75–7.72 (m, 2 H, HAr), 7.68–7.65 (m, 2 H, HAr),
7.56–7.44 (m, 3 H, HAr), 6.75 (s, 1 H, HAr), 4.68 (s, 2 H, CH2), 3.03
(sept, J = 6.8 Hz, 1 H, CH), 1.27 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 192.9, 167.6, 164.1, 148.8, 143.1,
139.9, 134.4, 132.2, 131.8, 128.7, 128.5, 123.9, 120.6, 120.4, 41.2,
30.0, 24.7.
2-Amino-N-[3-(2-chlorobenzoyl)-5-phenylthiophen-2-yl]acet-
amide (9c)
Following the typical procedure for 9a gave 9c (1.0 g, 50%) as a
yellow solid; mp 147–148 °C.
MS (EI): m/z (%) = 432 (55) [M+], 230 (100), 160 (70), 245 (65).
HRMS (EI): m/z [M+] calcd for C24H20O4N2S: 432.1138; found:
432.1139.
IR (KBr): 3412, 3171, 1718, 1679, 1620, 1539, 1506, 1428, 1409,
1290, 1238, 1161, 1080, 1036, 941, 799, 754, 692, 641, 478 cm–1.
1H NMR (300 MHz, CDCl3): δ = 12.99 (br s, 1 H, NH), 7.49–7.47
(m, 3 H, HAr), 7.42–7.36 (m, 3 H, HAr), 7.34–7.29 (m, 2 H, HAr),
7.23–7.21 (m, 1 H, HAr), 6.89 (s, 1 H, HAr), 3.70 (s, 2 H, CH2), 1.78
(br s, 2 H, NH2).
13C NMR (100 MHz, CDCl3): δ = 191.0, 171.9, 150.1, 139.5, 133.6,
133.5, 131.1, 130.7, 130.2, 128.9, 128.5, 127.6, 126.8, 125.60,
122.2, 121.1, 44.8.
MS (EI): m/z (%) = 370 (20) [M+], 372 (7) [M + 2]+, 337 (45), 313
(100), 139 (88).
HRMS (EI): m/z [M+] calcd for C19H15O2N2ClS: 370.0537; found:
370.0535.
N-[3-(2-Chlorobenzoyl)-5-phenylthiophen-2-yl]-2-(1,3-di-
hydro-1,3-dioxo-2H-isoindol-2-yl)acetamide (10c)
Following the typical procedure for 10a gave 10c (2.8 g, 90%) as a
yellow solid; mp 201–202 °C.
IR (KBr): 3430, 1777, 1722, 1616, 1546, 1526, 1470, 1416, 1392,
1319, 1271, 1234, 1197, 1157, 1110, 1086, 1037, 949, 848, 815,
756, 713, 693, 648 cm–1.
1H NMR (300 MHz, CDCl3): δ = 12.27 (br s, 1 H, NH), 7.94–7.91
(m, 2 H, HAr), 7.77–7.75 (m, 2 H, HAr), 7.50–7.38 (m, 6 H, HAr),
7.33–7.28 (m, 2 H, HAr), 7.24–7.21 (m, 1 H, HAr), 6.88 (s, 1 H, HAr),
4.75 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 191.6, 167.5, 164.4, 150.1, 138.9,
134.4, 134.4, 133.1, 132.0, 131.23, 130.7, 130.3, 129.0, 128.5,
127.8, 126.8, 125.6, 123.8, 122.3, 120.9, 40.9.
MS (EI): m/z (%) = 500 (45) [M+], 502 (15) [M + 2]+, 313 (70), 160
(100).
HRMS (EI): m/z [M+] calcd for C27H17O4N2ClS: 500.0592; found:
500.0591.
5-(2-Chlorophenyl)-7-isopropyl-1,3-dihydro-2H-thieno[2,3-
e][1,4]diazepin-2-one (8a); Typical Procedure
To a 30-mL vial was added 9a (1.4 g, 4.4 mmol), AcOH (800 mg),
and i-PrOH (6 mL) and the vial was sealed. The reaction was stirred
in an oil bath at 70 °C for 8 h. The mixture was cooled to r.t., CH2Cl2
(150 mL) was added, and the organic solvent was washed with sat.
aq NaHCO3 (3 × 40 mL) and H2O, brine, dried (anhyd Na2SO4), and
concentrated in vacuo. The residue was crystallized (EtOAc) to give
8a (0.85 g, 61%) as a yellowish solid.
2-Amino-N-[3-(2-chlorobenzoyl)-5-isopropylthiophen-2-
yl]acetamide (9a); Typical Procedure
In a 250-mL round bottom flask, 10a was dispersed in EtOH (150
mL) and cooled by an ice bath. Hydrazine hydrate (430 mg, 2 equiv)
was added dropwise and the reaction was stirred for 8 h then al-
lowed to warm to r.t. HCl (36%, 2.5 mL) was added and the mixture
stirred at r.t. for 2 h. The insoluble mass was filtered off and the fil-
trate was neutralized with sat. aq NaHCO3. After removal of sol-
IR (KBr): 3180, 3080, 2960, 1670, 1550, 1500, 1430, 1350, 1230,
1200, 1010, 982, 877, 833, 754, 631, 582, 523, 461 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.61 (br s, 1 H, NH), 7.45–7.27
(m, 4 H, HAr), 6.18 (s, 1 H, HAr), 4.49 (s, 2 H, CH2), 2.98 (sept, J =
6.8 Hz, 1 H, CH), 1.23 (d, J = 6.8 Hz, 6 H, 2 CH3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2317–2326

2322
L. Huang et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 168.2, 166.6, 145.1, 142.6, 138.3,
133.0, 130.7, 130.4, 129.9, 126.8, 126.3, 120.1, 57.6, 30.1, 24.5.
MS (EI): m/z (%) = 318 (85) [M+], 320 (30) [M + 2]+, 289 (100),
IR (KBr): 3436, 3130, 3094, 3033, 2963, 1592, 1557, 1519, 1482,
1448, 1355, 1314, 1285, 1234, 1193, 1166, 1077, 1054, 1028, 993,
875, 809, 763, 717, 697, 674, 599, 549 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.61–7.59 (m, 2 H, HAr), 7.46–
7.39 (m, 3 H, HAr), 6.52 (s, 1 H, HAr), 4.83 (s, 2 H, CH2), 3.06 (sept,
J = 6.9 Hz, 1 H, CH), 1.30 (d, J = 6.7 Hz, 6 H, 2 CH3).
13C NMR (100 MHz, DMSO-d6): δ = 195.7, 165.0, 145.7, 139.8,
133.7, 131.0, 130.8, 129.1, 128.3, 121.6, 65.2, 29.5, 24.5.
MS (EI): m/z (%) = 300 (75) [M+], 299 (100).
HRMS (EI): m/z [M+] calcd for C16H16N2S2: 300.0749; found:
275 (65).
7-Isopropyl-5-phenyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diaze-
pin-2-one (8b)
Following the typical procedure for 8a gave 8b (677 mg, 60%) as a
yellow solid; mp 188–189 °C.
IR (KBr): 3430, 3095, 2964, 1677, 1592, 1546, 1495, 1368, 1226,
1058, 1007, 873, 773, 723, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.53 (br s, 1 H, NH), 7.62–7.59
(m, 2 H, HAr), 7.42–7.34 (m, 3 H, HAr), 6.47 (s, 1 H, HAr), 4.42 (s, 2
H, CH2), 3.03 (sept, J = 6.7 Hz, 1 H, CH), 1.27 (d, J = 6.8 Hz, 6 H,
2 CH3).
13C NMR (75 MHz, CDCl3): δ = 169.4, 167.4, 144.9, 143.4, 138.8,
130.5, 129.5, 128.4, 126.3, 121.4, 57.8, 30.3, 24.7.
300.0748.
5-(2-Chlorophenyl)-7-phenyl-1,3-dihydro-2H-thieno[2,3-
e][1,4]diazepine-2-thione (7c)
Following the typical procedure for 7a gave 7c (492 mg, 90%) as a
brown solid; mp 199–200 °C.
IR (KBr): 3397, 1608, 1567, 1493, 1473, 1434, 1380, 1352, 1317,
1164, 1076, 1037, 999, 948, 843, 809, 757, 710, 691, 655 cm–1.
MS (EI): m/z (%) = 284 (95) [M+], 255 (100), 241 (50), 149 (60).
HRMS (EI): m/z [M+] calcd for C16H16ON2S: 284.0978; found:
284.0977.
1H NMR (300 MHz, DMSO-d6): δ = 12.45 (br s, 1 H, NH), 7.58–
7.57 (m, 1 H, HAr), 7.42–7.35 (m, 6 H, HAr), 7.24–7.13 (m, 3 H,
HAr), 4.56 (s, 2 H, CH2).
13C NMR (75 MHz, DMSO-d6): δ = 200.6, 171.0, 169.8, 140.6,
140.2, 139.7, 139.3, 132.2, 131.5, 131.3, 131.0, 129.9, 128.9, 128.4,
125.0, 122.1, 64.7.
MS (EI): m/z (%) = 368 (100) [M+], 370 (40) [M + 2]+, 333 (85).
HRMS (EI): m/z [M+] calcd for C19H13N2ClS2: 368.0203; found:
5-(2-Chlorophenyl)-7-phenyl-1,3-dihydro-2H-thieno[2,3-
e][1,4]diazepin-2-one (8c)
Following the typical procedure for 8a gave 8c (523 mg, 55%) as a
yellow solid; mp 219–220 °C.
IR (KBr): 3180, 3097, 2925, 1677, 1596, 1550, 1504, 1478, 1434,
1374, 1339, 1253, 1219, 1076, 1045, 1006, 948, 908, 875, 841, 795,
757, 735, 692, 520 cm–1.
368.0202.
1H NMR (300 MHz, CDCl3): δ = 10.22 (br s, 1 H, NH), 7.53–7.20
(m, 9 H, HAr), 7.13–7.08 (m, 1 H, HAr), 4.33 (s, 2 H, CH2).
13C NMR (75 MHz, CDCl3): δ = 172.7, 171.3, 139.6, 139.1, 131.9,
131.5, 130.5, 129.9, 128.4, 127.4, 123.5, 121.5, 57.1.
MS (EI): m/z (%) = 352 (60) [M+], 354 (20) [M + 2]+, 323 (100).
HRMS (EI): m/z [M+] calcd for C19H13ON2ClS: 352.0432; found:
5-Amino-4-(2-chlorophenyl)-2-isopropylthieno[2,3-b]pyridine-
6-thiol (6a)
To a 10-mL vial was added 7a (100 mg, 0.3 mmol), Sc(OTf)3 (1.5
mg, 0.003 mmol), and NMP (2.0 mL) and the vial was sealed. The
reaction was stirred in an oil bath preheated to 150 °C for 12 h. The
mixture was cooled to r.t., and it was dilute with EtOAc (120 mL).
The organic phase was washed with sat. aq NH4Cl (3 × 30 mL),
H2O, and brine, dried (anhyd Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel) to afford crude 6a (36 mg, 36%) as a yellow solid; mp 143–144
°C.
352.0430.
5-(2-Chlorophenyl)-7-isopropyl-1,3-dihydro-2H-thieno[2,3-
e][1,4]diazepine-2-thione (7a);10e,12c Typical Procedure
Compound 8a (300 mg), P2S5 (1.5 g), and toluene (30 mL) were
added to a three-necked round-bottom flask under a N2 atmosphere.
The mixture was stirred under reflux for 16 h. After removal of the
solvent, sat. aq NaHCO3 (30 mL) was added to the residue and the
mixture was stirred for 3 h. Filtration and washing with H2O gave
7a (270 mg, 90%) as a yellow solid; mp 175–176 °C.
IR (KBr): 3450, 3350, 3190, 3050, 2960, 2920, 2850, 1720, 1600,
1510, 1430, 1350, 1290, 1120, 1050, 827, 750, 698, 638, 594, 451
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.59–7.56 (m, 1 H, HAr), 7.43–
7.40 (m, 2 H, HAr), 7.32–7.28 (m, 1 H, HAr), 6.26 (s, 1 H, HAr), 3.12
(sept, J = 6.9 Hz, 1 H, CH), 1.31 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (125 MHz, CDCl3): δ = 156.9, 156.8, 150.4, 138.6, 138.5,
133.7, 131.5, 131.4, 130.4, 130.2, 127.7, 127.6, 114.4, 31.3, 24.1,
24.0.
IR (KBr): 3442, 3129, 3064, 2960, 2925, 2867, 1924, 1594, 1562,
1483, 1434, 1348, 1315, 1168, 1078, 1037, 991, 808, 781, 738, 655,
603, 460 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.53–7.29 (m, 4 H, HAr), 6.23 (s,
1 H, HAr), 4.91 (s, 2 H, CH2), 3.02 (sept, J = 6.6 Hz, 1 H, CH), 1.25
(d, J = 6.8 Hz, 6 H, 2 CH3).
MS (EI): m/z (%) = 334 (90) [M+], 336 (40) [M + 2]+, 319 (100).
HRMS (EI): m/z [M+] calcd for C16H15N2ClS2: 334.0360; found:
13C NMR (75 MHz, CDCl3): δ = 194.7, 166.7, 146.7, 144.4, 137.5,
133.3, 131.2, 131.1, 130.2, 128.5, 127.1, 120.9, 64.3, 30.3, 24.6.
334.0361.
MS (EI): m/z (%) = 334 (80) [M+], 336 (30) [M + 2]+, 319 (100).
HRMS (EI): m/z [M+] calcd for C16H15N2ClS2: 334.0360; found:
Thiazolo[5,4-b]thieno[3,2-e]pyridine Derivatives 5a–n; General
Procedure 2 (GP-2)
To a 10-mL vial was added compound 7a (100 mg, 0.3 mmol),
Sc(OTf)3 (1.5 mg, 0.003 mmol), aldehyde (0.6 mmol), and NMP
(2.0 mL) and the vial was sealed. The reaction was stirred in an oil
bath preheated to 150 °C for 12 h. The mixture was cooled to r.t.,
and it was dilute with EtOAc (120 mL). The organic phase was
washed with sat. aq NH4Cl (3 × 30 mL), water, and brine, dried (an-
hyd Na2SO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel) to afford the desired
compound.
334.0361.
7-Isopropyl-5-phenyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diaze-
pine-2-thione (7b)
Following the typical procedure for 7a gave 7b (657 mg, 92%) as a
yellow solid; mp 162–163 °C.
Synthesis 2014, 46, 2317–2326
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolo[5,4-b]thieno[3,2-e]pyridine Derivatives
2323
8-(2-Chlorophenyl)-2-(4-chlorophenyl)-6-isopropylthiazo-
lo[5,4-b]thieno[3,2-e]pyridine (5a)
From 7a: According to GP-2 using 7a and 4-chlorobenzaldehyde
(84 mg, 0.6 mmol) gave 5a (108 mg, 79%) as a white solid; mp
152–153 °C.
HRMS (EI): m/z [M+] calcd for C21H21N2ClS2: 400.0829; found:
400.0828.
8-(2-Chlorophenyl)-6-isopropyl-2-phenylthiazolo[5,4-b]thie-
no[3,2-e]pyridine (5d)
According to GP-2 using 7a and benzaldehyde (64 mg, 0.6 mmol)
gave 5d (83 mg, 66%) as a yellow solid; mp 175–176 °C (CHCl3–
hexane).
From 6a: To 10-mL vial was added 6a (36 mg, 0.108 mmol),
Sc(OTf)3 (0.5 mg, 0.001 mmol), 4-chlorobenzaldehyde (30 mg,
0.216 mmol), and NMP (2.0 mL) and the vial was sealed. The reac-
tion was stirred in an oil bath preheated to 150 °C for 12 h. The mix-
ture was cooled to r.t., it was dilute with EtOAc (50 mL). The
organic phase was washed with sat. aq NH4Cl (3 × 15 mL), H2O,
and brine, dried (anhyd Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel) to
afford 5a (34 mg, 70%) as a white solid.
IR (KBr): 2961, 2925, 2872, 1607, 1519, 1472, 1311, 1278, 1169,
1051, 960, 836, 803, 754, 699, 679 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.05–7.98 (m, 2 H, HAr), 7.66–
7.58 (m, 1 H, HAr), 7.56–7.34 (m, 6 H, HAr), 6.74 (s, 1 H, HAr), 3.24
(sept, J = 6.8 Hz, 1 H, CH), 1.40 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 166.6, 159.3, 155.7, 154.7, 143.3,
134.8, 134.6, 134.0, 133.8, 132.2, 131.6, 131.4, 130.1, 130.1, 129.1,
127.9, 126.8, 115.6, 31.7, 24.5, 24.4.
IR (KBr): 3053, 3021, 2965, 2894, 2869, 1552, 1519, 1477, 1315,
1283, 1211, 1179, 1038, 958, 948, 811, 734, 706 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 8.6 Hz, 2 H, HAr),
7.65–7.59 (m, 1 H, HAr), 7.54–7.43 (m, 3 H, HAr), 7.38 (d, J = 8.6
Hz, 2 H, HAr), 6.73 (s, 1 H, HAr), 3.24 (sept, J = 6.8 Hz, 1 H, CH),
1.40 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 165.2, 159.5, 155.6, 154.9, 143.2,
137.5, 134.7, 133.8, 132.5, 132.1, 131.7, 130.1, 129.3, 129.0, 126.7,
115.5, 31.7, 24.4, 24.4.
MS (EI): m/z (%) = 454 (75) [M+], 456 (50) [M + 2]+, 439 (100),
419 (95), 202 (70).
HRMS (EI): m/z [M+] calcd for C23H16N2Cl2S2: 454.0126; found:
454.0127.
MS (EI): m/z (%) = 420 (80) [M+], 422 (35) [M + 2]+, 405 (95), 385
(100), 185 (85).
HRMS (EI): m/z [M+] calcd for C23H17N2ClS2: 420.0516; found:
420.0514.
8-(2-Chlorophenyl)-6-isopropyl-2-(p-tolyl)thiazolo[5,4-b]thie-
no[3,2-e]pyridine (5e)
According to GP-2 using 7a and 4-tolualdehyde (72 mg, 0.6 mmol)
gave 5e (108 mg, 83%) as a yellow solid; mp 160–161 °C (CHCl3–
hexane).
IR (KBr): 2962, 2927, 2869, 1594, 1556, 1516, 1471, 1385, 1302,
1276, 1085, 1049, 827, 754 cm–1.
8-(2-Chlorophenyl)-6-isopropylthiazolo[5,4-b]thieno[3,2-e]pyr-
idine (5b)
From 7a in NMP: According to GP-2 using 7a and paraformalde-
hyde (54 mg, 0.6 mmol) in NMP (2 mL) gave 5b (60 mg, 58%) as
a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 8.1 Hz, 2 H, HAr),
7.66–7.59 (m, 1 H, HAr), 7.57–7.42 (m, 3 H, HAr), 7.23 (d, J = 8.0
Hz, 2 H, HAr), 6.73 (s, 1 H, HAr), 3.24 (sept, J = 6.8 Hz, 1 H, CH),
2.40 (s, 3 H, CH3), 1.40 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 166.7, 159.0, 155.8, 154.5, 143.3,
141.9, 134.8, 134.3, 133.8, 132.2, 131.5, 131.3, 130.1, 130.0, 129.8,
127.8, 126.7, 115.6, 31.7, 24.5, 24.4, 22.0.
MS (EI): m/z (%) = 434 (55) [M+], 436 (25) [M + 2]+, 419 (70), 399
(100), 192 (60).
HRMS (EI): m/z [M+] calcd for C24H19N2ClS2: 434.0673; found:
434.0674.
From 7a in DMF: According to GP-2 using 7a and 4-chlorobenzal-
dehyde (84 mg, 0.6 mmol) in DMF (2 mL) gave 5b (31 mg, 30%)
as a byproduct as a yellow oil.
IR (KBr): 3063, 2963, 2926, 2869, 1720, 1671, 1549, 1452, 1303,
1281, 1052, 871, 835, 749, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.03 (s, 1 H, CH), 7.67–7.56 (m,
1 H, HAr), 7.52–7.42 (m, 3 H, HAr), 6.73 (s, 1 H, HAr), 3.25 (sept,
J = 6.8 Hz, 1 H, CH), 1.40 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 160.3, 155.4, 154.3, 154.0, 141.8,
135.2, 134.5, 133.6, 131.6, 131.5, 130.4, 130.3, 127.0, 115.3, 31.7,
24.4, 24.3.
MS (EI): m/z (%) = 344 (55) [M+], 346 (25) [M + 2]+, 329 (100),
309 (65).
HRMS (EI): m/z [M+] calcd for C17H13N2ClS2: 344.0203; found:
8-(2-Chlorophenyl)-6-isopropyl-2-(4-methoxyphenyl)thiazo-
lo[5,4-b]thieno[3,2-e]pyridine (5f)
According to GP-2 using 7a and 4-methoxybenzaldehyde (81 mg,
0.6 mmol) gave 5f (100 mg, 74%) as a yellow solid; mp 132–133
°C.
IR (KBr): 3056, 2960, 2923, 2852, 1604, 1551, 1518, 1474, 1308,
1281, 1210, 1173, 1050, 1021, 958, 829, 811, 757, 733, 698, 678
cm–1.
344.0202.
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.9 Hz, 2 H, HAr),
7.64–7.60 (m, 1 H, HAr), 7.55–7.42 (m, 3 H, HAr), 6.94 (d, J = 8.9
Hz, 2 H, HAr), 6.72 (s, 1 H, HAr), 3.85 (s, 3 H, CH3), 3.23 (sept, J =
6.8 Hz, 1 H, CH), 1.39 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (100 MHz, CDCl3): δ = 166.3, 162.3, 158.8, 155.8, 154.5,
143.4, 134.9, 134.0, 133.8, 132.2, 131.4, 130.1, 129.9, 129.5, 126.9,
126.7, 115.5, 114.4, 55.6, 31.4, 24.3, 24.2.
MS (EI): m/z (%) = 450 (45) [M+], 452 (20) [M + 2]+, 435 (55), 415
(100), 200 (55).
HRMS (EI): m/z [M+] calcd for C24H19ON2ClS2: 450.0622; found:
450.0623.
8-(2-Chlorophenyl)-2-isobutyl-6-isopropylthiazolo[5,4-b]thie-
no[3,2-e]pyridine (5c)
According to GP-2 using 7a and 3-methylbutanal (52 mg, 0.6
mmol) gave 5c (80 mg, 67%) as a yellow oil.
IR (KBr): 2964, 2927, 2869, 1556, 1471, 1302, 1276, 1170, 1086,
1049, 879, 827, 754, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.62–7.55 (m, 1 H, HAr), 7.50–
7.38 (m, 3 H, HAr), 6.68 (s, 1 H, HAr), 3.22 (sept, J = 6.8 Hz, 1 H,
CH), 2.95 (d, J = 7.2 Hz, 2 H, CH2), 2.26–2.17 (m, 1 H, CH), 1.38
(d, J = 6.8 Hz, 6 H, 2 CH3), 1.02 (d, J = 6.6 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 170.6, 158.8, 156.0, 154.4, 142.3,
134.9, 134.0, 133.8, 131.8, 131.2, 130.2, 130.1, 126.8, 115.4, 44.4,
31.7, 29.9, 24.5, 24.4, 22.7, 22.7.
4-[8-(2-Chlorophenyl)-6-isopropylthiazolo[5,4-b]thieno[3,2-
e]pyridin-2-yl]phenol (5g)
According to GP-2 using 7a and 4-hydroxybenzaldehyde (73 mg,
0.6 mmol) gave 5g (119 mg, 91%) as a white solid; mp 154–155 °C.
MS (EI): m/z (%) = 400 (25) [M+], 402 (10) [M + 2]+, 385 (30), 358
(100), 343 (25), 307 (25).
© Georg Thieme Verlag Stuttgart · New York
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IR (KBr): 3060, 2961, 2929, 2869, 1607, 1474, 1278, 1168, 1051,
960, 835, 754, 700 cm–1.
H, HAr), 6.74 (s, 1 H, HAr), 3.25 (sept, J = 6.6 Hz, 1 H, CH), 1.40 (d,
J = 6.7 Hz, 6 H, 2 CH3).
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 8.5 Hz, 2 H, HAr),
7.64–7.55 (m, 1 H, HAr), 7.52–7.38 (m, 3 H, HAr), 6.82 (d, J = 8.5
Hz, 2 H, HAr), 6.70 (s, 1 H, HAr), 3.23 (sept, J = 6.7 Hz, 1 H, CH),
1.38 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (100 MHz, CDCl3): δ = 167.0, 159.4, 158.6, 155.4, 154.7,
143.5, 134.7, 134.3, 133.8, 132.0, 131.7, 130.1, 129.7, 126.8, 126.3,
116.2, 115.5, 31.4, 24.4, 24.2.
MS (EI): m/z (%) = 436 (85) [M+], 438 (40) [M + 2]+, 421 (100),
401 (95), 193 (90).
HRMS (EI): m/z [M+] calcd for C23H17ON2ClS2: 436.0465; found:
436.0464.
13C NMR (75 MHz, CDCl3): δ = 163.9, 160.3, 155.4, 143.1, 137.7,
135.2, 134.5, 133.7, 132.8, 132.0, 130.3, 130.2, 128.2, 126.8, 118.4,
115.5, 114.5, 31.7, 24.4, 24.4.
MS (EI): m/z (%) = 445 (65) [M+], 447 (27) [M + 2]+, 430 (100),
410 (60), 198 (55).
HRMS (EI): m/z [M+] calcd for C24H16N3ClS2: 445.0469; found:
445.0469.
1-{4-[8-(2-Chlorophenyl)-6-isopropylthiazolo[5,4-b]thieno[3,2-
e]pyridin-2-yl]phenyl}ethanone (5k)
According to GP-2 using 7a and 4-acetylbenzaldehyde (88 mg, 0.6
mmol) gave 5k (97 mg, 70%) as a white solid; mp 173–174 °C.
IR (KBr): 2973, 2929, 2897, 1455, 1406, 1381, 1084, 1045, 879 cm–1.
8-(2-Chlorophenyl)-6-isopropyl-2-(4-isopropylphenyl)thiazo-
lo[5,4-b]thieno[3,2-e]pyridine (5h)
According to GP-2 using 7a and 4-isopropylbenzaldehyde (89 mg,
0.6 mmol) gave 5h (102 mg, 74%) as a white solid; mp 108–109 °C.
1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 8.5 Hz, 2 H, HAr), 8.00
(d, J = 8.6 Hz, 2 H, HAr), 7.66–7.60 (m, 1 H, HAr), 7.55–7.43 (m, 3
H, HAr), 6.74 (s, 1 H, HAr), 3.25 (sept, J = 6.8 Hz, 1 H, CH), 2.64 (s,
3 H, CH3), 1.40 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 197.4, 165.0, 156.0, 155.6, 155.1,
143.3, 138.9, 137.8, 135.0, 134.6, 133.8, 132.1, 131.8, 130.2, 129.0,
128.0, 126.8, 115.5, 31.7, 27.2, 24.5, 24.4.
MS (EI): m/z (%) = 462 (40) [M+], 464 (15) [M + 2]+, 447 (70), 427
(100).
HRMS (EI): m/z [M+] calcd for C25H19ON2ClS2: 462.0622; found:
462.0621.
IR (KBr): 3063, 3021, 2959, 2929, 2869, 1608, 1549, 1517, 1472,
1309, 1278, 1183, 1151, 961, 836, 754, 732, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 7.2 Hz, 2 H, HAr),
7.67–7.56 (m, 1 H, HAr), 7.55–7.38 (m, 3 H, HAr), 7.29 (d, J = 7.6
Hz, 2 H, HAr), 6.72 (s, 1 H, HAr), 3.23 (sept, J = 6.1 Hz, 1 H, CH),
2.95 (sept, J = 6.1 Hz, 1 H, CH), 1.40 (d, J = 6.1 Hz, 6 H, 2 CH3),
1.27 (d, J = 6.1 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 166.7, 159.0, 155.8, 154.5, 152.8,
143.4, 134.9, 134.3, 133.8, 132.2, 131.7, 131.5, 130.1, 130.0, 128.0,
127.2, 126.7, 115.6, 34.5, 31.7, 24.5, 24.4, 24.1.
MS (EI): m/z (%) = 462 (30) [M+], 464 (10) [M + 2]+, 447 (45), 427
(100).
HRMS (EI): m/z [M+] calcd for C26H23N2ClS2: 462.0986; found:
462.0985.
2,8-Bis(2-chlorophenyl)-6-isopropylthiazolo[5,4-b]thieno[3,2-
e]pyridine (5l)
According to GP-2 using 7a and 2-chlorobenzaldehyde (84 mg, 0.6
mmol) gave 5l (90 mg, 66%) as a yellow solid; mp 146–147 °C.
IR (KBr): 3053, 2965, 2922, 2869, 1552, 1520, 1478, 1316, 1211,
1180, 1038, 958, 812, 706 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.17–8.09 (m, 1 H, HAr), 7.66–
7.59 (m, 1 H, HAr), 7.56–7.42 (m, 4 H, HAr), 7.39–7.29 (m, 2 H,
HAr), 6.76 (s, 1 H, HAr), 3.25 (sept, J = 6.8 Hz, 1 H, CH), 1.41 (d,
J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 163.0, 159.9, 156.4, 154.9, 141.5,
134.8, 134.7, 133.8, 133.0, 132.5, 132.1, 131.6, 131.6, 131.0, 130.2,
130.2, 127.3, 126.8, 115.5, 31.7, 24.5, 24.4.
MS (EI): m/z (%) = 454 (60) [M+], 456 (45) [M + 2]+, 439 (85), 419
(100), 202 (55).
HRMS (EI): m/z [M+] calcd for C23H16N2Cl2S2: 454.0126; found:
454.0124.
8-(2-Chlorophenyl)-6-isopropyl-2-[4-(trifluoromethyl)phe-
nyl]thiazolo[5,4-b]thieno[3,2-e]pyridine (5i)
According to GP-2 using 7a and 4-(trifluoromethyl)benzaldehyde
(104 mg, 0.6 mmol) gave 5i (98 mg, 67%) as a white solid; mp 125–
126 °C.
IR (KBr): 2974, 2932, 2879, 1657, 1459, 1427, 1381, 1325, 1089,
1046, 876 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 2 H, HAr), 7.69
(d, J = 8.0 Hz, 2 H, HAr), 7.66–7.60 (m, 1 H, HAr), 7.56–7.42 (m, 3
H, HAr), 6.75 (s, 1 H, HAr), 3.25 (sept, J = 6.8 Hz, 1 H, CH), 1.41 (d,
J = 6.7 Hz, 6 H, 2 CH3).
13C NMR (100 MHz, CDCl3): δ = 164.6, 159.9, 155.4, 155.1, 143.1,
136.9, 134.9, 134.4, 133.7, 132.7 (q, J = 32.7 Hz), 131.9, 131.7,
130.1, 128.0, 126.7, 125.9, 123.8 (q, J = 271.5 Hz), 115.4, 31.4,
24.1, 24.0.
8-(2-Chlorophenyl)-2-(furan-2-yl)-6-isopropylthiazolo[5,4-
b]thieno[3,2-e]pyridine (5m)
According to GP-2 using 7a and furan-2-carbaldehyde (58 mg, 0.6
mmol) gave 5m (88 mg, 72%) as a beige solid; mp 167–168 °C.
MS (EI): m/z (%) = 488 (40) [M+], 490 (18) [M + 2]+, 473 (85), 453
(100), 437 (45), 423 (30), 219 (45).
HRMS (EI): m/z [M+] calcd for C24H16N2ClF3S2: 488.0390; found:
488.0391.
IR (KBr): 2973, 2929, 2883, 1452, 1420, 1381, 1332, 1275, 1088,
1046, 880 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.65–7.39 (m, 5 H, HAr), 7.18–
7.03 (m, 1 H, HAr), 6.70 (s, 1 H, HAr), 6.58–6.45 (m, 1 H, HAr), 3.23
(sept, J = 6.9 Hz, 1 H, CH), 1.39 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 159.0, 156.1, 155.1, 154.6, 148.9,
145.0, 142.9, 134.5, 134.2, 133.6, 132.0, 131.5, 130.0, 129.9, 126.7,
115.4, 112.6, 112.3, 31.5, 24.3, 24.2.
MS (EI): m/z (%) = 410 (70) [M+], 412 (25) [M + 2]+, 395 (80), 375
(100).
HRMS (EI): m/z [M+] calcd for C21H15ON2ClS2: 410.0309; found:
410.0307.
4-[8-(2-Chlorophenyl)-6-isopropylthiazolo[5,4-b]thieno[3,2-
e]pyridin-2-yl]benzonitrile (5j)
According to GP-2 using 7a and 4-cyanobenzaldehyde (78 mg, 0.6
mmol) gave 5j (93 mg, 70%) as a white solid; mp 224–225 °C.
IR (KBr): 3067, 2966, 2932, 2869, 1552, 1469, 1449, 1312, 1210,
1063, 1038, 961, 827, 733, 721, 699, 678 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.08 (d, J = 8.0 Hz, 2 H, HAr), 7.69
(d, J = 8.0 Hz, 2 H, HAr), 7.66–7.60 (m, 1 H, HAr), 7.55–7.39 (m, 3
Synthesis 2014, 46, 2317–2326
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolo[5,4-b]thieno[3,2-e]pyridine Derivatives
2325
8-(2-Chlorophenyl)-6-isopropyl-2-(thiophen-2-yl)thiazolo[5,4-
b]thieno[3,2-e]pyridine (5n)
According to GP-2 using 7a and thiophene-2-carbaldehyde (67 mg,
0.6 mmol) gave 5n (98 mg, 77%) as a beige solid; mp 163–164 °C.
Acknowledgment
This work was supported financially by grants from the National
Natural Science Foundation of China 21272287.
IR (KBr): 2961, 2922, 2869, 1604, 1551, 1472, 1278, 1051, 754 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.39 (m, 6 H, HAr), 7.15–
7.04 (m, 1 H, HAr), 6.72 (s, 1 H, HAr), 3.24 (sept, J = 6.7 Hz, 1 H,
CH), 1.40 (d, J = 6.8 Hz, 6 H, 2 CH3).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
13C NMR (75 MHz, CDCl3): δ = 159.8, 159.0, 155.4, 154.5, 142.8,
137.8, 134.5, 134.0, 133.6, 132.0, 131.5, 129.9, 129.8, 129.0, 128.0,
126.6, 115.5, 31.5, 24.3, 24.2.
References
MS (EI): m/z (%) = 426 (65) [M+], 428 (30) [M + 2]+, 411 (90), 391
(1) These authors contributed equally.
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HRMS (EI): m/z [M+] calcd for C21H15N2ClS3: 426.0080; found:
426.0083.
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2-(4-Chlorophenyl)-6-isopropyl-8-phenylthiazolo[5,4-b]thie-
no[3,2-e]pyridine (5o)
According to GP-2 using 7b and 4-chlorobenzaldehyde (84 mg, 0.6
mmol) gave 5o (98 mg, 70%) as a white solid; mp 181–182 °C.
IR (KBr): 3433, 2961, 2924, 1594, 1546, 1496, 1468, 1402, 1311,
1280, 1090, 964, 880, 830, 730, 707 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 8.3 Hz, 2 H, HAr),
7.85–7.78 (m, 2 H, HAr), 7.64–7.50 (m, 3 H, HAr), 7.41 (d, J = 8.3
Hz, 2 H, HAr), 7.09 (s, 1 H, HAr), 3.25 (sept, J = 6.8 Hz, 1 H, CH),
1.42 (d, J = 6.8 Hz, 6 H, 2 CH3).
13C NMR (125 MHz, CDCl3): δ =164.6, 160.0, 155.9, 154.4, 142.6,
137.3, 137.1, 135.3, 132.3, 130.9, 130.7, 129.2, 128.7, 128.3, 115.4,
31.4, 24.1.
MS (EI): m/z (%) = 420 (50) [M+], 422 (20) [M + 2]+, 405 (100).
HRMS (EI): m/z [M+] calcd for C23H17N2ClS2: 420.0516; found:
420.0510.
8-(2-Chlorophenyl)-2-(4-chlorophenyl)-6-phenylthiazolo[5,4-
b]thieno[3,2-e]pyridine (5p)
According to GP-2 using 7c and 4-chlorobenzaldehyde (84 mg, 0.6
mmol) gave 5p (69 mg, 52%) as a yellow solid; mp >250 °C.
IR (KBr): 3060, 2962, 2925, 2872, 1471, 1278, 1049, 960, 835, 755,
704 cm–1.
1H NMR (300 MHz, CDCl3–TFA): δ = 7.99–7.92 (m, 1 H, HAr),
7.82–7.39 (m, 12 H, HAr), 7.34 (s, 1 H, HAr).
13C NMR (75 MHz, CDCl3–TFA): δ = 161.9 (q, J = 43.3 Hz), 133.4,
132.7, 132.6, 132.4, 132.0, 131.9, 131.8, 131.4, 131.1, 130.8, 130.5,
130.0, 129.6, 127.8, 127.5, 127.1, 115.7, 114.4 (q, J = 284.1 Hz).
MS (EI): m/z (%) = 488 (50) [M+], 490 (40) [M + 2]+, 453 (100),
226 (90).
HRMS (EI): m/z [M+] calcd for C26H14N2Cl2S2: 487.9970; found:
487.9969.
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melittin added were used as a positive control group.
© Georg Thieme Verlag Stuttgart · New York
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Synthesis 2014, 46, 2317–2326
© Georg Thieme Verlag Stuttgart · New York