Catalyst-free and selective synthesis of 2-aminothiophenes and 2-amino-4,5-dihydrothiophenes from 4-thiazolidinones in water

Article abstract of DOI:10.1039/c6ra11151c

2-Aminothiophenes and 2-amino-4,5-dihydrothiophenes were selectively and conveniently synthesized from 4-thiazolidinone derivatives. The meaningful product 10m was efficiently synthesized, which is a commonly-used intermediate for preparing olanzapine. The present method holds many advantages, such as easy operation, high yields, is catalyst-free and uses water as the solvent.

Full text of DOI:10.1039/c6ra11151c

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Catalyst-Free and Selective Synthesis of 2-Aminothiophenes and
2-Amino-4,5-dihydrothiophenes from 4-Thiazolidinones in Water
a
a
a
a, b
a, b
Fanxun Zeng , Pengjian Liu Xusheng Shao , Zhong Li , Xiaoyong Xu *
,
a
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China
b
Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong
Road, Shanghai 200237, China
Abstract
2
ꢀAminothiophenes and 2ꢀaminoꢀ4,5ꢀdihydrothiophenes were selectively and conveniently
synthesized from 4ꢀthiazolidinone derivatives. The meaningful product 10m was efficiently
synthesized, which is a commonlyꢀused intermediate for preparing Olanzapine. The present
method holds many advantages, such as easy operation, high yields, catalystꢀfree and using of
water as the solvent.
Introduction
[1]
Thiophenes are widely used in drug design and can be found in a number of marketed drugs
[2]
such as Olanzapine 1, Plavix 2 and Cymbalta 3 (Figure 1). Continuous studies on thiophenes are
[3]
[4]
[5]
also involved in dye chemistry, materials science, electronic and optoelectronic devices,
[6]
biodiagnostics, block copolymer selfꢀassembled superstructures, and conductivityꢀbased sensory
[7]
devices. As derivatives of thiophenes, dihydrothiophenes are also privileged scaffolds which
[8]
present in natural products, bioactive molecules and synthetic intermediates. For example,
[9]
4
,5ꢀdihydrothiopheneꢀ3ꢀcarbonitrile 4 (Figure 1) exhibit antibacterial and antifungal properties
and 2ꢀaminoꢀ4,5ꢀdihydrothiophenes (ADHTs) are used as starting materials for the synthesis of
[10]
[11]
partially hydrogenated thieno[2,3ꢀb]pyridines and pyrimidines.
Figure 1. Examples of bioactive thiophenes and dihydrothiophenes.
A variety of synthetic methods have been developed for the preparation of 2ꢀaminothiophenes
ATs), of which the most attractive route is Dieckmann or Thorpe–Ziegler cyclization of
(
[12]
thioacetals in basic medium (Scheme 1).
In addition, Brandsma explored a oneꢀpot
methodology using acetylenes and isothiocyanates for constructions of 5ꢀsubstituted

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[
13]
2
3
ꢀaminothiophenes.
Wang and coꢀworkers disclosed the efficient synthesis of
[14]
ꢀsubstitutedꢀ2ꢀaminothiophenes from substituted allyl benzotriazoles and isothiocyanates.
Then, ATs obtained by treatment of arylaminothienoꢀoxobutanamides with Lawesson’s reagent
[
15]
were reported.
Recently, isothiocyanates were reported to react with electronꢀdeficient
[
16]
[17]
allenes
or Morita–Baylis–Hillman adducts
to prepare ATs. In general, these synthetic
methods have inherent drawbacks such as narrow substrate scope and the use of strong base
nꢀbutyllithium. Therefore, the development of concise and efficient methods for the access of ATs
is still in high demand.
Scheme 1. Synthesis of ATs via Dieckmann or Thorpe–Ziegler cyclization of thioacetals.
Although ADHTs have great synthetic value, there are fewer publications on their synthesis in
comparison with the detailed study on synthesis of thiophenes. Dotsenko and coꢀworkers reported
the synthesis of ADHTs by baseꢀcatalyzed condensation of phenacyl thiocyanate with substituted
[18]
thioamides.
Shestopalov et al. disclosed a threeꢀcomponent condensation reaction involving
aldehydes, cyanothioacetamide and pyridinium or sulfonium ylides for synthesis of ADHTs
[
19]
(
Scheme 2, eq 1 and 2). ADHTs could also be synthesized by a domino reaction involving
[8g]
1
,3ꢀthiazolidinedione, malononitrile and aromatic aldehydes (Scheme 2, eq 3). More recently,
ADHTs were synthesized by Chandrasekaran from doubly activated cyclopropanes using
[20]
tetrathiomolybdate as the sulfur transfer reagent (Scheme 2, eq 4). However, these protocols
suffer from one or more drawbacks, such as low yields and the narrow scope of substrates.
Scheme 2. Previous strategies for the preparation of ADHTs.
Here, the synthesis of ATs and ADHTs from 4ꢀthiazolidinone derivatives was reported. At the
beginning, we intended to selectively reduce the carboxyl group of 4ꢀthiazolidinone derivatives 9

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[21]
[22]
using NaBH
4
,
because 4ꢀthiazolidinones possess broad biological activities. Unfortunately,
no target product was obtained after many attempts. To our delight, interesting products ATs and
ADHTs were detected. Then, the optimized reaction conditions and the scope of substrates were
explored and the possible mechanism was also proposed.
Results and discussions
[23]
Starting materials aryl isothiocyanates 5 and key intermediates 4ꢀthiazolidinone derivatives
[21e]
8
were easily obtained according to reported procedures. The corresponding carboxylic acids
derivatives 9 were prepared by cleavage of tertꢀbutyl with TFA in DCM (Scheme 3).
Scheme 3. Preparation of 4ꢀthiazolidinone derivatives 9 from aryl isothiocyanates 5.
Initially, the reaction conditions were optimized (Table 1) for the direct synthesis of AT using
Nꢀphenyl 4ꢀthiazolidinone (9a) as a model substrate. Various reductants and solvents were
screened at room temperature, and the results are presented in Table 1. Among the various
4
reductants tested, NaBH was found to be superior in terms of yield of 10a (Table 1, Entry 1–4).
Among the solvents screened, water was found to give the best result (Table 1, Entry 6). Other
organic solvents, such as THF, MeOH and EtOH, afforded the product in relatively lower yields
(
Table 1, Entries 1, 2 and 5). The influence of the amount of reductants was then investigated, and
.0 equiv. of NaBH was the most effective. Moreover, it was found that the yield of AT decreased
and ADHT would occur when 3.0 equiv of NaBH was used (Table 1, Entry 10). The effect of
2
4
4
temperature was also studied. The yield of 10a increased to a remarkable 87% when the
temperature was decreased to 15 °C (Table 1, Entry 11). Further decreasing the temperature to
5
°C led to significant reduction of the yield and extended reaction time (48 h) (Table 1, Entry 12).
Therefore, Entry 11 was selected for the optimal reaction conditions. In order to investigate the
relationship between the amount of NaBH
4
and the products ratio, the amount of NaBH
4
was
was
further increased. Gratifyingly, the yield of 11a increased to 54% when 10.0 equiv. of NaBH
4
employed (Table 1, Entry 15). We next examined the effect of base in water on the reaction.
Saturated aqueous NaHCO , saturated aqueous KHCO , 1M Na CO , 1M K CO , 1M NaOH and
M KOH were tried, but the yield of 11a was not improved with AT as the main product (Table 1,
Entry 15 vs. Entries 17–22). At 10.0 equiv. of NaBH , MeOH was investigated again and the
3
3
2
3
2
3
1
4
result was similar with that of Entry 2. Obvious improved yield and ratio were observed upon
using EtOH as solvent (Table 1, Entries 15 vs. Entry 24). The similar yield was obtained when
4
KBH was used in water (Table 1, Entry 27), but the ratio is unsatisfied. To further increase the
yield of 11a, the reactions were carried out at different temperatures (Table 1, Entry 26–31). The

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yield of 11a increased to 85% when the temperature was increased to 60 °C and 2 mL H
2
O was
used (Table 1, Entry 30). Further increasing the temperature to 80 °C did not give better results
(
Table 1, Entry 31). The yield of 11a decrease to 70% when 5.0 equiv. of KBH
4
was employed
(Table 1, Entry 32). Based on the above observation, Entry 30 was selected for the optimal
reaction conditions.

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[a]
Table 1. Optimization of reaction conditions
[
c]
[c]
Entry
Reductant
equiv.)
NaBH (2.0)
Solvent
Temp
Time (h)
Yield (%)
Yield (%)
(
(°C)
25
25
25
25
25
25
25
25
25
25
15
5
10a
6
11a
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
21
1
2
3
4
5
6
7
8
9
THF
MeOH
MeOH
THF
24
24
24
0.5
8
4
NaBH
NaBH CN (2.0)
LiAlH
NaBH
4
(2.0)
20
Trace
8
3
4
(2.0)
(2.0)
4
EtOH
68
78
8
NaBH (2.0)
H O
2
8
4
NaBH
NaBH
NaBH
NaBH
4
4
4
4
(1.0)
(1.2)
(1.5)
(3.0)
H
H
H
H
2
2
2
2
O
O
O
O
24
24
18
6
68
70
62
10
[d]
11
NaBH (2.0)
H O
2
20
48
6
87(83 )
Trace
Trace
47
4
12
13
14
15
16
NaBH
NaBH
NaBH
NaBH
4
(2.0)
(5.0)
(7.5)
(10)
H
H
H
H
2
2
2
2
O
O
O
O
72
37
29
25
33
4
25
25
25
15
4
6
51
4
2
54
NaBH (10)
H O
2
3
52
4
satd. aqueous
1
7
8
NaBH
NaBH
4
(10)
(10)
25
25
3
3
69
56
5
NaHCO
satd. aqueous
KHCO
1M Na CO3
3
1
4
Trace
3
19
20
21
22
23
24
25
26
27
28
NaBH (10)
25
25
25
25
25
25
25
15
25
40
40
60
80
60
3
3
47
48
26
15
4
2
NaBH
NaBH
NaBH
NaBH
4
4
4
4
(10)
(10)
(10)
(10)
2 3
1M K CO
1M NaOH
1M KOH
MeOH
0.5
0.5
4
Trace
Trace
24
Trace
Trace
Trace
62
NaBH (10)
EtOH
4
5
4
KBH
KBH
4
4
(10)
(10)
(10)
(10)
EtOH
4
Trace
33
Trace
58
H
H
H
2
2
2
O
O
O
3
KBH
4
4
2
27
63
KBH
0.5
0.5
0.2
0.2
0.2
18
74
b
29
KBH (10)
H O
2
16
77
4
b
[d]
30
KBH
KBH
KBH
4
(10)
(10)
(5.0)
H
2
H
2
H
2
O
O
O
6
85(81 )
b
31
4
14
77
70
b
32
4
22
[
a] Reaction conditions: substrate 9a (0.2 mmol), water (1 mL). [b] Reaction conditions: substrate
a (0.2 mmol), water (2 mL). [c] Yield was determined by UPLC (ultra performance liquid
9

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chromatography). [d] Isolated yield.
With the optimal conditions established, we explored the substrates scope for synthesis of ATs.
The results were summarized in Table 2 and it demonstrated broad substrates scope. The reactions
of substrates bearing electronꢀdonating groups on the aromatic ring of 4ꢀthiazolidinones, such as
methyl (9b) and methoxy (9c) groups, afforded the corresponding products in good yields. But for
the substrate containing an 2,4ꢀdimethoxy group, the yield of 10d decreased rapidly. Meanwhile,
the reactions of substrates bearing electronꢀwithdrawing groups on the aromatic ring of
4
ꢀthiazolidinones, such as fluoro (9f), chloro (9e), cyano (9i) and nitro (9j) groups, also afforded
the corresponding products in good yields. In the case of substrate containing an orthoꢀnitro (9h)
group, only 39% yield was obtained. Heteroaromatic substrate (9k) provided a lower yield. Upon
the introducing methyl or phenyl into thiophene ring, the reactions also occurred smoothly to
generate corresponding products 10l-10n in moderate to good yields. Most important, the
meaningful product 10m could be provided conveniently, which is the commonlyꢀused
[24]
intermediate of typical antipsychotics Olanzapine.
[a]
Table 2. Synthesis of ATs.
[
4
a] Reaction conditions: 4ꢀthiazolidinone derivative 9 (0.5 mmol) and NaBH (1.0 mmol) were

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stirred in water (2.5 mL) at 15 °C for 0.5–24 h. [b] Reaction conditions: 4ꢀthiazolidinone
derivative 9 (0.5 mmol) and NaBH (0.5 mmol) were stirred in water (2.5 mL) at 15 °C for 0.5 h.
4
Then, the scope of substrates to give ADHTs was explored (Table 3). The reactions of
substrates bearing electronꢀdonating or electronꢀwithdrawing groups proceeded smoothly to give
the expected products 11a–11j in moderate to good yields. In case of the substrates containing
2
,4ꢀdimethoxy and 4ꢀnitro groups, the yields of products 11d and 11i decreased slightly, which
were different to the reactions of ATs. When benzene ring was replaced with biphenyl, the yield
of 11g was only 52%. The decreased water solubility of substrate 9g might cause the lower yield.
Heteroaromatic substrate (9k) also performed smoothly to afford product 11k in moderate yield.
The yield still remained high when the R
2 2
was the methyl group. But upon changing R to phenyl,
no desired product was obtained and the major product was the AT 10n in yield of 56%.
[a]
Table 3. Synthesis of ADHTs.
[
a] Reaction conditions: 4ꢀthiazolidinone derivative 9 (0.5 mmol) and KBH (5.0 mmol) were
4
stirred in water (5.0 mL) at 60 °C for 0.5 h. [b] The major product is 10n in yield of 56%.
1
13
19
Besides H, C and F NMR spectroscopy, the structures of 10g and 11a were confirmed by

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Xꢀray diffraction analysis (Figure 2). The results confirmed that the ADHTs were obtained instead
of 2ꢀaminoꢀ2,3ꢀdihydrothiophenes. In addition, ADHTs 11 exists amino–imino automerism due to
1
13
19
prototropic tautomerism (Scheme 4). This tautomerism can be seen in both H, C and F NMR
spectra. Xꢀray single crystal analysis of 11a revealed that it only exist amino form (Figure 2). The
[25]
similar tautomerism was previously studied in the 2ꢀaminoꢀ1,3ꢀthiazolidinꢀ4ꢀone derivatives.
Figure 2. Singleꢀcrystal Xꢀray diffraction structures of 10g and 11a.
Scheme 4. Tautomers of 11.
A possible reaction mechanism was proposed in Scheme 5. Initially, reduction and
deprotonation of 4ꢀthiazolidinone derivatives 9 led to formation of carboxylates A. The followed
C−N bond cleavage formed aldehydes B, which underwent intramolecular cyclization to form
tetrahydrothiophenes C. Subsequently, tetrahydrothiophenes C were consumed in two paths: a
and b. Tetrahydrothiophenes C released CO to give hydroxyl compounds D in path a. Finally,
2
hydroxyl compounds D underwent a dehydration process to give ATs 10. In path b, the C=N bond
was reduced first to form carboxylates E, the second step was decarboxylation of carboxylates
E with the followed release of hydroxyl ion, and 2,5ꢀdihydrothiophenes G were given.
2
,5ꢀdihydrothiophenes G can be easily converted to more stable 4,5ꢀdihydrothiophenes 11.

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O
O
O
OH
O
O
NC
NC
H
OH
NC
R1 NH
O
S
S
S
R1
N
R1
N
R2
R2
R2
O
O
9
H
A
B
OH
S
H
NC
NC
R2
-
H O
2
-CO2
R2
S
R1 NH
R1 NH
O
OH
path a
path a
a
O
R2
D
10
a
NC
S
R1
N
O
OH
S
HO
b
H
O
R2
C
R2
NC
R1 NH
-CO2
path b
NC
S
path b
R1 NH
E
F
path b
NC
-
OH
R2
NC
OH
R2
H
S
S
R1 NH
R1 NH
path b
11
G
Scheme 5. Proposed mechanism for the formation of 10 and 11.
Conclusions
A new and efficient method for the synthesis of ATs and ADHTs derivatives was developed
using inexpensive and readily available starting materials and reagents. Many advantages, such as
easy operation, high yields, using of water as a solvent, catalystꢀfree and broad substrates scope,
make this method absorb more attention.
Experimental Section
General Procedure for the Synthesis of tert-butyl
2-cyano-2-(4-oxo-3-arylthiazolidin-2-ylidene)acetates (8a–8n)
Tertꢀbutyl cyanoacetate (10 mmol) followed by a solution of aryl isothiocyanate 5 (10 mmol) in
anhydrous DMF (10 mL) were added to a cold suspension of powdered KOH (20 mmol) in dry
DMF (10 mL). The mixture was stirred at room temperature for 0.5 h, then cooled again to 0°C,
treated with a solution of appropriate 2ꢀhalogen acyl chloride 7 (15 mmol) in anhydrous DMF (10
mL) and stirred at room temperature overnight. The mixture was poured into iceꢀcold water, and
the resulting precipitate was filtered off, dried, and crystallized from DCMꢀEtOH to give
compounds 8a–8n in yield of 68%–80%.
General Procedure for the Synthesis of 2-cyano-2-(4-oxo-3-arylthiazolidin-2-ylidene)acetic
acid (9a–9n)

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To a solution of tertꢀbutyl acetate derivative 8 (5 mmol) in DCM (50 mL) was added a mixture
of TFA (7.5 mL) and DCM (75 mL). The mixture was stirred at room temperature until the
reaction was complete as indicated by TLC (typically 24 h). The solvent was evaporated under
reduced pressure. The residual solid was further crystallized from DCMꢀMeOH to afford the
compounds 9a–9n in yield of 84%–91%.
General Procedure for the Synthesis of ATs (10a–10n)
Carboxylic acid compound 9 (0.5 mmol) was added to a solution of NaBH (1 mmol) in water
4
(2.5 mL) at 15 °C. The reaction mixture was stirred at 15 °C until the reaction was complete as
determined by TLC analysis (typically 0.5–24 h). The reaction mixture was quenched with 1 M
HCl, and the product precipitated was filtered. The solid was purified by silica gel column
chromatography (PE : EA = 5:1) to afford the compounds 10a–10n.
General Procedure for the Synthesis of ADHTs (11a–11m)
4
Carboxylic acid compound 9 (0.5 mmol) was added to a solution of KBH (5 mmol) in water (5
mL) at 60 °C. The reaction mixture was stirred at 60 °C for 0.5 h. The reaction mixture was cooled
to room temperature and quenched with 1 M HCl. The aqueous layer was extracted with EtOAc
(3×2 mL). The combined organic phases were washed once with brine, dried with anhydrous
Na SO , vacuumꢀfiltered, and concentrated under reduced pressure. The residue was purified by
2
4
silica gel column chromatography (PE : EA = 3:1) to afford the corresponding ADHTs 11a–11m.
Acknowledgements
This work was financial supported by Shanghai Foundation of Science and Technology
(15431902100) and National Natural Science Foundation of China (21272071).
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DOI: 10.1039/C6RA11151C
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Table of contents entry
COOH
NC
NaBH4 (1.0 or 2.0 equiv)
R2
R2 KBH4 (10 equiv)
NC
NC
S
R1
N
S
S
H2O, 60 o
H2O, 15 o
C
C
R2
R1 NH
R1 NH
O
1
3 examples
14 examples
up to 85% yield
up to 83% yield
The image of selectively synthesis of 2ꢀaminothiophenes and 2ꢀaminoꢀ4,5ꢀdihydrothiophenes
from 4ꢀthiazolidinones in water.