An efficient one-pot procedure for the synthesis of 1,5-benzothiazepinones catalyzed by tetrabutylammonium fluoride (TBAF)

Article abstract of DOI:10.1016/j.tetlet.2016.07.012

A practical and efficient method for the preparation of 1,5-benzothiazepinone derivatives in good yields has been developed using tetrabutylammonium fluoride (TBAF) as a catalyst. This study not only expands the previous work on the substrate scope and al

Full text of DOI:10.1016/j.tetlet.2016.07.012

Accepted Manuscript
An efficient one-pot procedure for the synthesis of 1,5-benzothiazepinones cat-
alyzed by tetrabutylammonium fluoride (TBAF)
Peng Zhang, Deyong Ye, Yong Chu
PII:
S0040-4039(16)30834-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.012
TETL 47874
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 May 2016
2 July 2016
5 July 2016
Please cite this article as: Zhang, P., Ye, D., Chu, Y., An efficient one-pot procedure for the synthesis of 1,5-
benzothiazepinones catalyzed by tetrabutylammonium fluoride (TBAF), Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.07.012
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An efficient one-pot procedure for the synthesis of
1,5-benzothiazepinones catalyzed by tetrabutylammonium
fluoride (TBAF)
Peng Zhang, Deyong Ye, Yong Chu*
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, P.R.
China
Received; Accepted; Published:
Abstract
A practical and efficient method for the preparation of 1,5-benzothiazepinone derivatives in good yields
has been developed by using tetrabutylammonium fluoride (TBAF) as a catalyst. This study not only
expands the previous work on the substrate scope and also provides more understanding of the chemistry
of such drug scaffold.
Key words： Benzothiazepine, Heterocyclic Chemistry, Cyclization, TBAF
1,5-benzothiazepine is a ubiquitous unit found in various drug molecules and functional organic
materials. Derivatives of it exhibit diverse biological properties depending on the nature and position of
the substituents on the bicyclic scaffold. To the best of our knowledge, some compounds bearing the
1,5-benzothiazepine moiety have already been introduced into the pharmaceutical market (Figure 1), such
as angina-relieving calcium channel blocker Diltiazem (1)1, antihypertensive agent Clentiazem (2)2,
anti-depressant GABBAA blocker Thiazesim (3)3, antipsychotic Quetiapine (4)4 and anti-platelet
aggregation agent TA-993 (5)5. The synthesis of them has aroused great interest of organic and medicinal
chemists. The most widely applicable approach for construction of the framework of 1,5-benzothiazepine
employs the condensation of 2-aminothiophenol and cinnamic acid derivatives. However, these reactions
require high-temperature conditions, leading to unsatisfactory product yields, or use of expensive
catalysts or toxic organic solvents nearly in all of the cases3,8. Moreover, it is disappointing that
electron-deficient cinnamic acid could not undergo these reactions in many cases.
*Corresponding author. Yong Chu Tel.: +86 21 51980125; Fax: +86 21 51980125. E-mail address: cy110@fudan.edu.cn

Recently, we developed a series of novel 1,5-benzothiazepinone derivatives typically shown as
compound (6). In general, these compounds exhibit good potency and highly selective to an important
kinase GSK-3β, which plays key roles in the regulation of many physiological responses in human beings.
According to that line, these novel inhibitors might provide an alternative choice for the treatment of
some severe human diseases, such as Alzheimer’s diseases, type 2 diabetes, chronic inflammatory
diseases, bipolar disorders and cancer6. More interesting, such type of compounds especially acted in a
non-ATP competitive manner7, by which it is expected to be better for reducing adverse effects of drugs.
The results attracted our great interest to explore an effective method towards the construction of a
1,5-benzothiazepine unit for the synthesis of more novel GSK-3β inhibitors. Herein, we report an efficient
and practical one-pot procedure for the preparation of 1,5-benzothiozepinone in good yields by
employing tetrabutylammonium fluoride (TBAF) as a catalyst (Scheme 1, 2). This method complements
in part the reported work on the substrate scope, for which there are reported only a few electron-rich
cinnamic acids with limited electron-donating groups, such as chlorine atom, methyl and methoxyl
groups were suitable. However, in our reaction, cinnamic acids with either moderate electron-donating or
moderate electron-withdrawing groups can smoothly undergo the mild cyclization in one-step with
2-aminothiophenol.
Figure 1. Therapeutics and biological agents bearing a 1,5-benzothiazepine core.
2

TBAF has been widely used for most of the fluoride-assisted reactions in organic syntheses, such as
deprotection of silyl groups, desilyation, and fluorination. It has also been widely used as a powerful
catalyst for many types of base-catalyzed reactions such as elimination, alkylation, aldol condensation,
and Michael addition. Moreover, TBAF is stable enough in general conditions and easily prepared and
used. In 2008, Yao et al. reported that TBAF was applied as a catalyst for the synthesis of
3-sulfanylpropionic acid from thiols and α,β-unsaturated carboxylic acids9. Based on these work, we tried
to use fluorine-contained reagents as catalysts in our synthesis of 1,5-benzothiozepinones and
successfully presented a facile TBAF-catalyzed cyclization to form the bicycle system. In Table 1 and 2,
the isolated yields for a variety of different cinnamic acids as starting materials are depicted.
In the initial model reaction，we used 2-aminothiophenol 7 and cinnamic acid 8a as substrates to
study the catalytic efficiency of TBAF (Table 1). In consideration of the reactions involving TBAF being
o
usually carried out below 100 C due to its low thermal stability, we firstly mixed the two substrates
o
without solvent and heated them at 80 C for 24 hours, and the corresponding product 9a was isolated
only in 24% yield (Table 1, entry 1). However, 72% yield of product 9a was gratifyingly obtained when
an amount of 10 mol % of TBAF was applied in the same reaction (Table 1, entry 2). This result
highlights the role of TBAF as a promoter. The examination of other fluoride sources such as KF and CsF
showed that TBAF was the most effective reagent among of them (Table 1, entries 3, 12, 13). Adjustment
of the amount of TBAF indicated that the use of 0.1 equivalent of TBAF could get the best yield of 82%
(Table 1, entry 3), and a little more or less catalyst could decrease the yields slightly or greatly (Table 1,
entry 4-8). Besides, both the reaction temperature and reaction time are important for the yield. All of the
o
o
yields decreased either at higher (100 C) or lower (60 C) reaction temperature(Table 1, entries 10,11),
and a shorter reaction time resulted in a lower yield even the suitable amount of TBAF was used (Table 1,
entries 9). We also found that the condition of solvent-free is crucial in this reaction. All the yields were
poor (<20%) when various solvents were tested, such as DMF, EtOH, and MeCN (Table 1, entries 14–16).
By these experiments, we finally established an optimal reaction procedure: adding the amount of 10
mol % of TBAF into a mixture of 2-aminothiophenol and unsaturated acid without any solvents, and then
carrying out the reaction in solvent-free at 80 oC for 24 hours10.
3

Scheme 1. Synthesis of 1,5-benzothiozepinone 9a as the model reaction.
Table 1 Optimization of the reaction conditions
Entry 7:8a
Additive (eq.) Solvent
Temp (oC) Time (hours)
Yield (%)
1
1.5:1
1.5:1 TBAF (0.1)
TBAF (0.1)
—
Neat
Neat
Neat
80
80
80
80
80
80
80
80
80
60
100
80
80
80
80
80
24
24
24
24
24
24
24
24
12
24
24
24
24
24
24
24
24
72
82
64
63
36
5
2
3
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
4
TBAF (0.05) Neat
5
TBAF (0.2)
TBAF (0.4)
TBAF (0.8)
TBAF (1.0)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
KF (0.1)
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
DMF
EtOH
CH3CN
6
7
8
5
9
60
34
72
55
41
5
10
11
12
13
14
15
16
CsF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
0
20
Conditions: 2-aminothiophenol (3 mmol or 4 mmol), cinnamic acid (2 mmol), solvent (1 mL) or
solvent free.
With the optimized reaction condition in hand, we investigated the scope of cinnamic acids.
2-aminothiophenol was still selected as the partner to react with different cinnamic acids. The results
show that both aryl cinnamic acids and aliphatic cinnamic acids can undergo this cyclization to generate
the desired products 9b in moderate to excellent yields (40%-80%, Table 2). As R group was hydrogen,
the reaction gave the product only in 40% yield (Table 2, entries 1). However, higher yields were
4

obtained when substituent groups were introduced to β-carbon in cinnamic acids. The cinnamic acids
with electron-withdrawing small substituents, such as halogen or trifluoromethyl at the ortho position
gave the corresponding products in a higher yield (70%-80%) than that at the meta or para position
(30%-71%). The results indicated that the reaction would be affected a little by electronic effect (Table 2,
entries 4-9, 12-14). In all, cinnamic acids with either moderate electron-donating or moderate
electron-withdrawing groups in the benzene ring could smoothly undergo this kind of cyclization to
generate 1,5-benzothiazepinone derivatives 9b in moderate to good yields (Table 2, entries 3-13, 15-17).
It should be noted that the yields were reasonably unsatisfactory (25%-38%) when the acids had strong
electron-donating groups in the benzene ring (Table 2, entries 18-19).
Scheme 2. Synthesis of various 1,5-benzothiozepinones 9b.
Table 2 Synthesis of various 1,5-benzothiozepinone in the presence of 10 mol % TBAF
Entry
R
Yield
40
Entry
11
R
Yield
65
H
4-Me-phenyl
2-CF3-phenyl
3-CF3-phenyl
4-CF3-phenyl
4-MeO-phenyl
4-MeOCH2-phenyl
4-COOMe-phenyl
4-CN-phenyl
4-Morpholino-phenyl
1
2
3
4
5
6
7
8
9
10
Me
75
80
12
2-Thiophenyl
2-F-phenyl
3-F-phenyl
4-F-phenyl
2-Cl-phenyl
3-Cl-phenyl
4-Cl-phenyl
4-Br-phenyl
70
57
13
70
30
14
62
70
15
55
51
16
74
57
17
64
25
18
71
38
19
68
Conditions: 2-aminothiophenol (4 mmol), unsaturated acid 8b (2 mmol), TBAF (10 mol %), solvent free,
80 oC.
Based on the results of experiments, a reasonable mechanism is proposed and illustrated in Scheme 3.
Initially，2-aminothiophenol 7 is catalyzed by fluoride ion and makes a stronger nucleophilic attack of
unsaturated acid 8 to form intermediate 10 in a typical Michael addition, and then the acid group of 10 is
5

in situ activated by n-Bu4N+ to perform an intramolecular amidation to produce the 1,5-benzothiozepinone
derivatives 9.
Scheme 3. Proposed mechanism for the formation of 1,5-benzothiozepinones 9.
In summary, we have developed an efficient method for the construction of 1,5-benzothiozepinone
framework, which is characterized in many biologically active molecules. The approach relies on a
TBAF-catalyzed Michael addition and the subsequent cation-accelerated intramolecular amidation under
mild condition. This study expands the previous work on the substrate scope. In this reaction, cinnamic
acids with either moderate electron-donating or electron-withdrawing groups can smoothly undergo the
cyclization. Furthermore, this reaction is also environmentally friendly due to its solvent-free condition. A
variety of 1,5-benzothiozepinone derivatives were successfully synthesized according to this approach in
good yields, and further investigation of these derivatives on their biological activities is ongoing in our
laboratory.
Acknowledgment
We gratefully acknowledge the financial support by the National Natural Science Foundation of
China (Grant No. 81373275 to Yong Chu).
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10. General procedure for the preparation of 1,5-benzothiozepinone derivatives 9 using TBAF as a catalyst: A mixture
of 2-aminothiophenol 7 (4 mmol), unsaturated acid 8 (2 mmoL), and TBAF (0.2 mmol, 10 mol %) was heated to 80
oC under stirring for 24 hours. After cooling, 30 mL of dichloromethane was added. The mixture was washed with
aq HCl (2N), aq Na2CO3 (saturated), and brine. Then, the organic layer was dried over MgSO4 and concentrated.
The crude product residue was purified by chromatography on silica to give pure product 9.
7

An efficient one-pot procedure for the synthesis of
1,5-benzothiazepinones catalyzed by tetrabutylammonium
fluoride (TBAF)
Peng Zhang, Deyong Ye, Yong Chu*
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, P.R.
China
Graphical abstract
8

An efficient one-pot procedure for the synthesis of
1,5-benzothiazepinones catalyzed by tetrabutylammonium
fluoride (TBAF)
Peng Zhang, Deyong Ye, Yong Chu*
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, P.R.
China
Highlights
► An efficient method was established for the construction of 1,5-benzothiozepinone framework. ►
TBAF-catalyzed Michael addition and the subsequent cation-accelerated intramolecular amidation was
performed under mild condition. ► Either moderate electron-donating or electron-withdrawing groups
could smoothly undergo the cyclization. ► This reaction was environmentally friendly due to its
solvent-free condition.
9