A practical synthesis of 2,3-dihydro-1,5-benzothiazepines

Article abstract of DOI:10.1039/c7gc02097j

2,3-Dihydro-1,5-benzothiazepines have been obtained through a domino process involving a Michael addition of 2-aminothiophenols to chalcones, followed by in situ cyclization. Up to 98% chemical yields have been obtained at room temperature under essential

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A practical synthesis of 2,3-dihydro-1,5-benzothiazepines
Domenico, C. M. Albanese,a Nicoletta Gaggerob,*and Meng Feib
Received 00th January 20xx,
Accepted 00th January 20xx
2,3-Dihydro-1,5-benzothiazepines have been obtained through a domino process involving a Michael addition of 2-
aminothiophenols to chalcones, followed by in situ cyclization. Up to 98% chemical yields have been obtained at room
temperature under essentially neutral conditions by using hexafluoro 2-propanol as an efficient medium.
DOI: 10.1039/x0xx00000x
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involve Lewis acids such as Er(OTf)3 in CH3CN,2 cerium(IV)
ammonium nitrate in ethanol at 60-65 °C under ultrasonic
irradiation,3 Mg(ClO4)2 in DCE under reflux,4 Ga(OTf)3 in CH3CN
at 60 °C,5 Brønsted acids such as glacial acetic acid in toluene
under reflux6 or in DMF by a microwave promoted process.7
Two papers deal with the use of ionic liquids, 1-octyl-3-methyl
imidazolium isothiocyanate ([omim]SCN) at 60 °C for 18 h8 and
N-methylimidazolium nitrate ([hmim]NO3) at 80 °C9 for the
synthesis of a series of 1,5-benzothiazepines.9
Introduction
The synthesis of heterocyclic compounds has received a great
deal of attention, most notably for the construction of the 1,5-
benzothiazepine scaffolds owing to their multiple
pharmacological and biological activities, such as calcium
antagonist, antihypertensive, antiarrhythmic, antibacterial,
and antidepressant.1
The commonly adopted strategy to construct the ring skeleton
As an alternative to homogeneous catalysis, several methods
take advantage of strong acids adsorbed on solid supports
such as fluoroboric acid10 or perchloric acid11 adsorbed on
silica-gel (HBF4-SiO2/HClO4-SiO2) in methanol. Mesoporous
materials such as MCM-41 in refluxing toluene12 or Pd
nanoparticle decorated nanocrystalline ZSM-5 catalyst in
toluene at 85 °C13 were also employed. However, a general
drawback of these methods is the high catalyst loading in
order to obtain good results.
of 2,3-dihydro-1,5-benzothiazepine
4 is the reaction of ortho-
aminothiophenols with α,β-unsaturated ketones
2
1
(chalcones) in a two steps domino process. The most generally
accepted mechanism entails the 1,4-conjugate addition by the
thiol group of
2 on chalcones 1 leading to a thia-Michael
adduct 3, followed by the intramolecular nucleophilic attack of
the amino group on the carbonyl to install the imino group
(Scheme 1).
Despite several procedures available for the synthesis of
benzothiazepines 4, we decided to explore the possibility to
R
NH2
Ar1
develop a more practical approach avoiding the use of any
promoting agent.
N
O
S
O
HS
Ar1
NH2 R
Here we report the results of a study on the use of hexafluoro-
2-propanol (HFIP) as an efficient medium for this two-
component domino process.
2
S
Ar
Ar1
Ar
R
Ar
1
3
4
In recent years, fluorous solvents have attracted increasing
interest as catalysts, solvents or co-solvents in organic
synthesis owing to their unique features.
Scheme 1. Thia-Michael addition/imine cyclization domino approach to 2,3-dihydro-
1,5-benzothiazepines 4.
They allow to carry out reactions, which usually require strong
Lewis or Brønsted acids and high temperatures, under mild,
neutral conditions at moderate temperature. Compared to
other fluorinated solvents, HFIP is unique due to its high
ionization power, strong hydrogen bond ability, low
nucleophilicity and mild acidic character.14 The fields of
application of HFIP range from oxidations, nucleophilic oxirane
ring openings, cycloaddition reactions of imines,15 electrophilic
Traditional methods are carried out under harsh reaction
conditions including high temperature, the use of toxic,
difficult to recover organic solvents (DMF, toluene, DCE),
corrosive acids (AcOH, TFA, HCl), bases (pyridine, piperidine),
or electrophilic activation by Lewis acids. Moreover, the use of
both Brønsted and Lewis acids releases polluting waste or
poisonous metals.
Some of the more recent procedures reported in the literature
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Table 1. Optimization of the synthesis of 2,3-dihydro-1,5-diphenylbenzothiazepine 4a.a
aromatic substitution reactions,16 aza- and sulfa-Michael
reactions,17,18 to cite only a few. Also, in some cases, the
selectivity of the reaction can be modified and finely tuned by
HFIP in comparison to other solvents.18,19 Recently the critical
role of HFIP in a number of enantioselective processes has
been widely recognized.17,20 Although HFIP cannot be
described as a cheap solvent, it can be easily recovered during
Entry
2
(eq)
1.2
1.5
1.2
2
Solvent
t (h)
Yield 3a
Yield 4a (%)
(%)
-
1
HFIP
HFIP
3
72
70
71
86
84
45
56
45
-
2
3c
3
-
HFIP
3
-
4
HFIP
3
-
work-up and recycled owing to its low boiling point. As 5c
2
HFIP
3
-
6
1.2
2
HFIP/DCM 1-4
HFIP/DCM 1-4
HFIP/DCM 1-9
DCM
24
24
24
24
24
24
24
24
24
24
24
15
29
15
59
-
reported in ESI of the manuscript, the amount of consumed
HFIP is very low and does not have a significant impact on
process economy.16
7
8d
1.2
1.2
1.2
2
9
In particular, the acidity of HFIP (pKa = 9.2) seemed to be
tailored to activate both the Michael acceptor during the
conjugate addition and the carbonyl group in the cyclization
step. On the other hand, it cannot deactivate the amino group
by protonation.
10c
11c
12
13
14
15
16
HFIP/DCM 1-4
HFIP/DCM 1-4
HFIP/acetone 1-4
HFIP/CH3CN 1-4
HFIP/AcOEt 1-4
HFIP/dioxane 1-4
HFIP/DMF 1-4
50
80
< 5
< 5
< 5
3
-
1.2
1.2
1.2
1.2
1.2
77
88
87
2
Thus, the property of this solvent was exploited to carry out
the synthesis of 2,3-dihydro-1,5-benzothiazepines
absence of catalysts.
4 in the
13
15
a
b
Reaction conditions: 1a (0.125 mmol), HFIP (0.15 mL, 11 eq), 28 °C. Unless
otherwise noted the yields were determined by 1H NMR in the presence of
internal standard. c In the presence of 4Å molecular sieves. d HFIP (1.1 eq).
Results and discussion
In order to ascertain if HFIP could be employed as a co-solvent,
we used different 1:4 V/V mixtures HFIP/organic solvent as
reaction medium.
At the onset of the study equimolar amounts of trans-chalcone
1a and ortho-aminothiophenol (2a) were stirred at 28 °C in
HFIP without any catalyst. After 2 hours the chromatographic
purification of the crude mixture gave the 2,4-diphenyl-2,3-
dihydro-1,5-benzothiazepine (4a) in a 55% yield along with
Among the solvents examined, only the combination
HFIP/DCM led to the formation of benzothiazepine 4a
,
although in lower yield and longer reaction time compared to
our previous conditions (Table 1, entry 6). The amount of HFIP
in the mixture can be decreased without affecting the reaction
outcome (Table 1, entry 8).
minor amounts of the Michael adduct 3a
,
the starting
chalcone 1a, and 2,2′-diaminodiphenyl disulfide (
5
) (Scheme
2).
NH2
Notably, when the reaction has been carried out in DCM only,
59% yield of the Michael adduct 3a was isolated without
formation of benzothiazepine 4a (Table 1, entry 9). On the
other hand, when the Michael adduct 3a was stirred in
HFIP/DCM mixture under the usual conditions (28 °C, 24 h) the
benzothiazepine 4a could be recovered in quantitative yield.
A significant amount of starting chalcone 1a was recovered
both in neat HFIP and in the mixture HFIP/DCM due to the
Ph
N
O
2a
S
O
Ph
Ph
HFIP,
28 °C
S
Ph
4a
1a
Ph
Ph
3a
Scheme 2. Domino approach to 2,4-diphenyl-2,3-dihydro-1,5-benzothiazepine (4a).
formation of 2,2′-diaminodiphenyl disulfide (5) (Table 1, entry
The formation of disulfide
5 was not surprising in view of the
known HFIP ability to promote the oxidation of thiols.21 Also, in
our case, the oxidation process was meaningfully accelerated
by the presence of the electro-donating ortho amino group on
the aromatic ring of the thiol.22 When a small excess of 2a (1.2
eq) was employed in order to minimize the effect of the
competitive oxidation, the yield of the desired
benzothiazepine 4a could be increased to 72% (Table 1, entry
1).§ The addition of sodium sulfite or sodium
hydroxymethanesulfinate (rongalite) or ascorbic acid in order
to reduce in situ the disulfide, did not work, likely owing to
their negligible solubility in the reaction medium.
1,6). These results show that the competitive oxidation plays
an important role. It is interesting to note that the
intermediate Michael adduct 3a was completely converted to
benzothiazepine 4a only in neat HFIP (Table 1, entry 1),
whereas in neat DCM 4a is not formed at all (Table 1, entry 9).
An intermediate situation is obtained in the mixture HFIP/DCM
(Table 1, entry 6).
When a larger excess (2 eq) of thiol 2a was used in neat HFIP,
chalcone 1a was almost completely converted affording 86%
of benzothiazepine 4a after HFIP removal by distillation and
chromatographic purification (Table 1, entry 4). The excess of
thiol 2a was mostly recovered as the corresponding disulfide.
The latter can also be reduced by treatment with LiCl/NaBH4 in
order to recycle 2a 23
.
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A similar chalcone conversion was also observed in the up to 98% yield (Table 2). The reaction was found to be
DCM/HFIP mixture although a lower yield of 4a was obtained tolerant to a number of electron withdrawing or electron
due to the presence of uncyclized Michael adduct 3a (Table 1, donating substituents such as NO2, OH, OCH3, OCOCH3, Cl, Br.
entry 7).
Heteroaromatic chalcones 1l-n were also shown to be good
When the reaction was carried out by using 2 equivalents of 2a substrates for the reaction although the yield was moderate in
in DCM (24 h), followed by addition of HFIP (3 h), 36% of 3a the case of benzothiazepine 4l (Table 2, entries 12-14).
was obtained along with 33% of 4a. In addition, the reaction The 2-aminothiophenol scope was investigated by using as
performed in HFIP at 4 °C for 3 h furnished a 1.65/1 mixture of nucleophilic partners substituted 2-aminothiophenols bearing
3a/
4a.
electron-withdrawing or electron-releasing substituents in the
These evidences highlight that in the first step the amount of reaction with chalcone 1a under the optimized conditions
thiol is the most important parameter, whereas HFIP is (Scheme 4).
essential in accelerating the cyclization step that require
carbonyl activation, thus behaving as a hydrogen bond
donor.24 Notwithstanding, HFIP is also capable to accelerate
the first step of the process by a dual interaction with both
aminothiophenol
2 and chalcones 1. In fact, as previously
reported, HFIP might behave as a proton shuttle promoting
the proton shift from the thiol to the first anionic Michael
adduct (Scheme 3).17
Scheme 4. Use of substituted 2-aminothiophenols.
As expected, excellent result was obtained by using 4-methyl-
2-aminothiophenol (2c), bearing the electron-releasing methyl
group, whereas a lower yield was obtained with 4-chloro-2-
aminothiophenol
(2b), bearing the electron-withdrawing
chlorine substituent (Scheme 4).
Less nucleophilic ortho-aminophenol and ortho-phenylene
diamine failed to give the corresponding cyclized products also
after longer reaction times (66 h) at 45 °C.
We never observed imine intermediates by 1H-NMR analysis of
the crude reaction mixtures. These results represent a strong
evidence in favor of a reaction pathway consisting of a 1,4
conjugate addition followed by ring closure, according to the
mechanism generally reported in the literature.6,8,15,25
In order to access the feasibility of the procedure on larger
scale a few experiments have been carried out by recovering
and recycling HFIP in subsequent runs using chalcone 1a. The
yield of 2,3-dihydro-1,5-benzothiazepine 4a remained
unchanged and only less than 10% of HFIP was added in order
to restore identical initial conditions.&
Scheme 3. Proton shuttle strategy in the Michael addition step.
Solvents different from DCM gave unsatisfactory results. In
particular, when acetone, acetonitrile or ethyl acetate have
been used, the Michael adduct 3a has been recovered with
yields of 77%, 88% and 87%, respectively, whereas the
benzothiazepine 4a was formed in less than 5% yield (Table 1,
entries 12-14). On the other hand, the use of dioxane or DMF
provided only low yields of almost equimolar mixtures of 3a
and 4a (Table 1, entries 15,16). In order to investigate the
influence of water on the reaction outcome, 4Å molecular
sieves were added. When the reaction was carried out in neat
HFIP, no improvement had been observed (Table 1, entries
1,3). However, when the mixture HFIP/DCM was used in the
presence of molecular sieves, the Michael adduct had been
completely converted to benzothiazepine (Table 1, entries
6,10 and 7,11).
The method was successfully applied to the synthesis of 2-(4-
methylphenyl)-4-(4-bromophenyl)-2,3-dihydro-1,5-benzothia
zepine (4o) which has recently been used to modulate the
activity of store-operated calcium channels (SOCs).26 The
regulation of SOCs enables to treat diverse disorders including
autoimmune, liver and kidney diseases.
Benzothiazepine 4n has been investigated for antioxidant
activity.27
Conclusion
In summary, we have used for the first time hexafluoro-2-
propanol as an efficient medium for the synthesis of 2,3-
The reaction scope was shown by reacting ortho-
aminothiophenol (2a) with a series of substituted chalcones
1a-p generating the corresponding benzothiazepines 4a-p in
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Table 2. Benzothiazepine 4a-p.a
Entry
1
t (h)
3
Benzothiazepine
Yieldb (%)
Entry
9
t (h)
Benzothiazepine
Yieldb (%)
86
6
75
2
3
3
6
98
81
10
11
4
5
91
70
4
6
72
12
6
41
5
3.5
87
13
11
60
6
4
90
73
14
12
63
7
8
3
3
15
16
6
4
65
69
74
a Reaction conditions: 2 (2 eq), 28 °C, HFIP (11 eq). b Isolated yields.
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We have demonstrated that our novel protocol allows to
employ a variety of chalcones and 2-aminothiophenols bearing
both electron-donor or electron-withdrawing substituents to
provide a simple access to benzothiazepines.
We anticipate that the mild conditions employed in the new
procedure will allow it to be used for the large-scale synthesis
of a large number of benzothiazepines.
In addition, hexafluoro-2-propanol can be easily recovered by
distillation and recycled in further reactions.
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Conflicts of Interest
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25 T. S. Saleh, N. M. A. El-Rahman and R. S. A. Assaker
There are no conflicts of interest to declare.
Green Chem. Lett. Rev., 2012, 5, 1-6.
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Patent 2011/0269743 A1.
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owing to its cumbersome separation from benzothiazepine 4a
by chromatography.
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