Catalytic enantioselective one-pot approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines

Article abstract of DOI:10.1039/C8OB01988F

The first enantioselective catalytic approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines has been conveniently developed in a one-pot fashion, starting from α,β-unsaturated acyl pyrazoles and 2-aminothiophenol. The organocatalytic two-s

Full text of DOI:10.1039/C8OB01988F

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Catalytic enantioselective one‐pot approach to cis‐ and trans‐2,3‐
diaryl substituted 1,5‐benzothiazepines
Sara Meninno,a* Ilaria Quaratesi,a Chiara Volpe,a Andrea Mazzanti,b and Alessandra Lattanzia*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The first enantioselective catalytic approach to cis‐ and trans‐2,3‐diaryl substituted 1,5‐benzothiazepines has been
conveniently developed in a one‐pot fashion, starting from α,β‐unsaturated acyl pyrazoles and ortho‐amino‐thiophenols.
The organocatalytic two‐step sulfa‐Michael/lactamization sequence is promoted by a readily available bifunctional
thiourea and p‐toluensulfonic acid, respectively. The protocol enables the access to both N‐unprotected cis‐ and trans‐
diastereoisomers in moderate to satisfactory overall yields (up to 84%) and good to excellent ee values (up to 99%).
Mechanistic investigations helped to shed light on the regio‐ and stereoselective outcome of the process.
www.rsc.org/
metal‐catalysed4 and organocatalytic protocols5 to access
either N‐protected or N‐H free 2‐substituted 1,5‐
benzothiazepines with high level of enantioselectivity (Scheme
Introduction
1,5‐Benzothiazepines are a class of privileged heterocyclic
scaffolds in medicinal chemistry, showing important biological
activities in the central nervous system, or used for the
treatment of cardiovascular and gastrointestinal disorders.1
The most renowned examples include the antidepressant
agent Thiazesim, the blood‐pressure regulator Diltiazem, also
employed to treat angina and the potent antiulcer agent BTM‐
1086 (Fig. 1).
1a).
Over the last decades, 1,5‐benzothiazepines have been the
subject of intensive investigations focused on the development
of efficient and environment friendly methodologies for their
synthesis, in view of their potential applications in the
pharmaceutical industry.2
A
good number of 1,5‐
benzothiazepines are chiral compounds. Consequently, the
first methodologies reported to prepare both enantioenriched
forms, useful for separate testing of their bioactivities, relied
on optical resolution of the racemates.3 Recent efforts in this
field have resulted in the development of a few
Scheme 1 Catalytic stereoselective routes to 2,3‐substituted 1,5‐benzothiazepines.
The preparation of 2,3‐disubstituted 1,5‐benzothiazepines as
both enantioenriched cis‐ and trans‐diastereoisomers is a
more ambitious goal. A classical solution to this challenge, has
been the elaboration of starting enantiopure building blocks,
as demonstrated for the synthesis of diltiazem from the
enantiomerically enriched epoxide (Fig. 1).6 No general
methods exist to prepare this class of benzothiazepines in a
truly catalytic manner. Within this context, only recently, the
group of Asano and Matsubara succeeded in developing an
effective organocatalytic method to trans‐2,3‐disubstituted
Fig.
1 Most renowned drugs and bioactive compounds showing the 1,5‐
benzothiazepine scaffold bearing one or two stereogenic centers.
1,5‐benzothiazepines (Scheme 1b).7
A
formal [4+3]
a. Dipartimento di Chimica e Biologia “A. Zambelli”, Università di Salerno, Via
Giovanni Paolo II 132, I‐84084, Fisciano, Italy [Fax: (+39)‐089‐969603; phone: cycloaddition reaction was devised from activated α,β‐
(+39)‐089‐969563; E‐mail: lattanzi@unisa.it; smeninno@unisa.it
unsaturated anhydrides and N‐protected 2‐aminothiophenols
b. Dipartimento di Chimica Industriale “Toso Montanari”, Università di Bologna, V.
Risorgimento 4, I‐40136 Bologna, Italy
Electronic Supplementary Information (ESI) available: Preparations of substrates
and new catalyst XI, optimization studies, characterization of adducts 3a and 7,
mechanistic data. NMR spectra of new compounds, HPLC profiles, ECD spectra and
computational data for compound 4e. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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under chiral isothiourea catalysis. The process turned out to be at 5 mol% loading (Table 1). Cinchona derived amine‐
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DOI: 10.1039/C8OB01988F
highly diastereoselective, leading to trans‐isomers, bearing a 3‐ squaramide I, being selected as the optimal promoter in our
carboethoxy group, in good yield and good to high ee values.
In 2017, we disclosed a convenient and efficient method to
prepare N‐unprotected 2‐substituted 1,5‐benzothiazepines by
conceiving an one‐pot sulfa‐Michael/lactamization sequence using
trans‐3‐substituted α,β‐unsaturated acylpyrazoles and 2‐
aminothiophenols.8 The first step was catalysed by 1 mol% loading
of a readily available Cinchona alkaloid derived squaramide,
followed by silica gel mediated cyclization to give the products in
good to excellent yield and enantioselectivity (up to 96% ee). The
protocol was successfully applied in a concise preparation of (R)‐
thiazesim. Encouraged by these results and considering as highly
desirable the development of catalytic methods for the synthesis of
2,3‐disubstituted 1,5‐benzothiazepines, we undertook an
investigation exploiting the sulfa‐Michael/lactamization route.
Herein, we present our study on a first enantioselective approach to
novel cis‐ and trans‐N‐unprotected 2,3‐diaryl substituted‐1,5‐
benzothiazepines based on the reaction of trans‐2,3‐disubstituted
α,β‐unsaturated acyl pyrazoles and 2‐aminothiophenols promoted
by common bifunctional organocatalysts followed by p‐
toluensulfonic acid (TsOH) catalysed lactamization (Scheme 1c).
This one‐pot catalytic method expands and complements the
sole catalytic approach reported up to now to access this
previous study, was checked in the sulfa‐Michael reaction
followed by the one‐pot acid catalysed lactamization sequence
(entry 1).
Table 1 Screening of catalysts.a
medicinally important heterocyclic scaffold 7
.
Entry
Cat.
t [h]
Yield
[%]b
56
50
43
25
35
24
32
33
68
83
70
cis/trans
[%]c
ee 4a
[%]d
Results and Discussion
1
2e
3
4
5
6
7
8
9
I
I
II
5
7
5
6
4
4
4
7
8
6
6
7
83/17
72/28
80/20
72/28
73/27
83/17
64/36
70/30
82/18
65/35
54/46
56/44
75 (70)
76 (65)
‐73 (‐59)
‐53 (‐42)
66 (53)
74 (68)
‐57 (‐50)
73 (78)
81 (62)
‐79 (‐94)
80 (93)
74 (95)
Model alkene 1a and 2‐amino thiophenol 2a were initially
treated with silica gel in toluene at room temperature, under
our previously reported conditions, without success.8 Further
optimization of reaction conditions9 enabled the identification
of the most effective catalyst to provide both cis‐ and trans‐
diastereoisomers of compound 4a (Scheme 2).10 Readily
available basic alumina promoted the formation of adduct 3a
in good yield and 82/18 diastereoisomeric ratio, when working
at room temperature. After silica gel filtration, the crude
reaction mixture was reacted in toluene at 80°C in the
presence of TsOH to give product 4a in 64% overall isolated
yield and comparable diastereoselective ratio. We next turned
our attention to develop an asymmetric procedure by using a
variety of bifunctional organocatalysts.
III
IV
V
VI
VII
VIII
IX
X
10
11
12
XI
55
a Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol, added in two portions),
cat. (0.005 mmol) in toluene (500 µL) under N2 atmosphere. After completion,
p‐toluenesulfonic acid monohydrate (0.02 mmol) was added. b Determined by
1H NMR analysis with 1,3,5‐(MeO)3C6H3 as an internal standard. c Determined
by 1H NMR analysis of the crude reaction mixture d Determined by chiral HPLC
analysis on cis‐4a and trans‐4a (in parenthesis). e Reaction performed in Et2O.
Compound 4a was obtained in acceptable conversion,
satisfactory level of enantioselectivity and 83/17 cis/trans
ratio. Performing the first step in diethyl ether did not improve
the outcome (entry 2). Quinidine‐derived squaramide II proved
to be only slightly less efficient than pseudo‐enantiomeric
catalyst
I (entry 3). Common amine‐thioureas such as
Takemoto’s catalyst III and Cinchona derived promoters IV‐VI
were significantly less active and similar level of
stereoselectivities were observed (entries 4‐7). Between
quinine and hydroquinine‐derived ureas VII and VIII (entries 8
and 9) a good conversion, diastereo‐ and enantioselectivity
were achieved when using catalyst VIII. In particular, cis‐4a
was recovered preferentially with up to 81% ee (entry 9).
Scheme 2 Optimized reaction sequence to racemic cis/trans‐4a.
The screening was carried out in toluene at room temperature,
starting from reagents 1a and 2a and using the organocatalysts
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Finally, amine‐thioureas derived from 1,2‐diaryl substituted corresponding alkene was found to significantly reduce the
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diamines, successfully employed by our group in domino level of enantioselectivity for both diasteDreOoI:is1o0.m10e3r9s/C(8OB01988F
4g).
reactions,11 were evaluated in the process (entries 10‐12).
Interestingly, they proved to be more effective than other
thioureas and both cis‐ and trans‐diastereoisomers of 4a were
obtained in similar ratio, satisfactory combined yield and
significantly improved enantioselectivity (up to 95% ee for the
trans‐isomer). Given the practical absence of any protocols to
access enantiomerically enriched trans‐ and cis‐2,3‐
substituted‐1,5‐benzothiazepines, we considered of high
interest the development of a straightforward method that
would enable their preparation under mild conditions.
Table 3 Substrate scope and limitations.a
R2
R1
1) X (5 mol%)
m-xylene, rt
R3
O
R3
S
NH2
N
R2
N
+
R1
2) TsOH, 80°C
overnight
N
H
SH
O
1
2
4
CH3
Cl
OCH3
Ph
Ph
S
S
S
S
Ph
Ph
Ph
N
H
N
H
N
H
4d
O
N
O
O
O
H
Further optimization of the model reaction was then carried
4a
4b
4c
6 h, 73%,
7 h, 70%,
8 h, 71%,
4 h, 46%,
out using catalyst
X able to furnish both diastereoisomers with
cis/trans 48/52
59% ee (cis)
92% ee (trans)
cis/trans 53/47
79% ee (cis)
cis/trans 54/46
74% ee (cis)
cis/trans 35/65
75% ee (cis)
a view to improve the enantioselectivity (Table 2). The reaction
performed in toluene at 0°C led to a lower level of
enantioselectivity for cis‐4a (entry 1). Dilution or concentration
of the reaction mixture, when working at room temperature,
negatively affected either the conversion to the product and
level of enantioselectivity (entries 2 and 3). Solvent screening
showed that neither ethereal or halogenated solvents
outperformed the result achieved in toluene (entries 4 and 5).
94% ee (trans)
93% ee (trans)
82% ee (trans)
OCH3
F
O
Ph
S
N
S
S
S
N
Ph
Ph
O
Ph
NH
N
O
H
O
H
O
H
4f
4g
4e
4h
24 h, 47%,
3 h, 78%,
6 h, 72%,
30 h, 80%,
cis/trans 46/54 cis/trans 45/55
cis/trans 62/38
67% ee (cis)
cis/trans 54/46
80% ee (cis)
94% ee (trans)
45% ee (cis)
55% ee (cis)
99% ee (trans)
55% ee (trans) 99% ee (trans)
Table 2 Optimization of the reaction conditions.a
Cl
NO2
Ph
F
Ph
CH3
Entry
Solvent
t [h]
Yield
[%]b
72
37
52
54
25
58
61
cis/trans
[%]c
ee 4a
[%]d
S
S
S
S
O
Ph
O
H3C
Ph
1e
2f
3g
4
5
6
7
8
9
10
toluene
toluene
toluene
Et2O
CH2Cl2
C6H5Cl
mesitylene
xylenes
m‐xylene
benzene
7
70
5
5
26
7
7
5
7
7
55/45
55/45
65/35
48/52
64/36
57/43
51/49
51/49
51/49
65/35
70 (94)
76 (92)
54 (86)
60 (95)
54 (88)
66 (90)
80 (95)
75 (94)
79 (95)
75 (90)
NH
NH
4j
N
H
H3C
N
O
O
H
4i
4k
4l
4 h, 72%,
4 h, 51%,
26 h, 43%,
24 h, 48%,
cis/trans 41/59
58% ee (cis)
cis/trans 66/34
73% ee (cis)
cis/trans 65/35
70% ee (cis)
cis/trans 50/50
66% ee (cis)
95% ee (trans)
77% ee (trans)
95% ee (trans)
94% ee (trans)
Cl
Ph
S
S
Cl
Br
N
Ph
H3C
47
75
60
HN
O
23 h, 49%,
48 h, 67%,
H
cis/trans 63/37
73% ee (cis)
cis/trans 53/47
72% ee (cis)
4m
4n
O
95% ee (trans)
99% ee (trans)
a
a Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol, added in two portions),
X (0.005 mmol) in solvent (500 µL) under inert atmosphere. After completion,
p‐toluenesulfonic acid monohydrate (0.02 mmol) was added. b Determined by
1H NMR analysis with 1,3,5‐(MeO)3C6H3 as an internal standard. c Determined
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol, added in two portions), X
(0.010 mmol) in toluene (1 mL) under inert atmosphere. Yield of isolated
products are given.
d
by 1H NMR analysis of the crude reaction mixture. Determined by chiral
Starting alkenes bearing α‐aryl substituted moieties were also
converted to the desired products in high ee values for the
trans‐isomer and moderate for the cis‐isomer (4h,i), with the
exception of product 4j, whose diastereoisomers were
obtained with 73% and 77% ee (4j). Unfortunately, the process
e
HPLC analysis on analysis on cis‐4a and trans‐4a (in parenthesis). Reaction
performed at 0°C. f Reaction performed at C = 0.05 M. g Reaction performed
at C = 0.5 M.
Among the aromatic solvents furtherly checked (entries 6‐10)
m‐xylene afforded both cis‐ and trans‐4a with the highest yield
and ee values. The scope and limitation of the methodology
was then investigated working under conditions in Table 2,
entry 9 (Table 3). 2‐Amino thiophenol was first used as the
nucleophile. 1,5‐Benzothiazepines bearing electron‐donating
groups in the aryl ring at 2‐position (4b and 4c) were isolated
was incompatible with ,‐unsaturated acyl pyrazoles bearing
alkyl substitutents, which provided low conversion to the final
product after prolonged reaction time.12 Substituted 2‐
aminothiophenols were then reacted with different alkenes to
give both cis‐ and trans‐2,3‐disubstituted 1,5‐benzothiazepines
4k‐n
in comparable ratio, moderate to satisfactory yield,13
consistently high to excellent ee values for the trans‐isomer,
also when using an ortho‐substitution on the β‐aromatic ring in
the starting alkene (4l).
According to previously optimized conditions (Table 1, entry
9), the feasibility of obtaining cis‐2,3‐substituted 1,5‐
benzothiazepines with improved level of enantioselectivity has
with
enantioselectivity was observed with the less reactive alkene
1c Both diastereoisomers of benzothiazepines bearing
electron‐withdrawing group in the aromatic ring at 2‐position
or heteroaromatic residues (4d ) were isolated in good to
similar
diastereoselectivity,
although
lower
.
‐
f
acceptable yield and good to high ee values. A more sterically
demanding 2‐naphthyl moiety at the β‐position of the
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NH2
S
been shortly investigated using catalyst VIII in m‐xylene at
room temperature (Table 4).
View Article Online
DOI: 10.1039/C8OB01988F
O
Ph
O
NH2
SH
S
N
N
Ph
N
+
Ph
Table 4 Reaction sequence mediated by catalyst VIII.a
+
Ph
N
Ph
1a
toluene- d8
Ph
3a
N
H
rt
O
2a
4a
R2
R1
O
1) VIII (5 mol%)
S
NH2
Fig. 3 Reaction progress profile over time in the presence of 1,2‐dichloroethane as
-xylene, rt
N
m
R2
N
S
+
R1
2) TsOH, 80°C
overnight
N
H
100
90
80
70
60
50
40
30
20
10
0
SH
O
1
2a
4
F
Ph
O
Ph
Ph
S
S
Cl
Ph
O
N
H
N
H
N
H
O
4i
4e
4a
22 h, 84%,
cis/trans 70/30
81% ee (cis)
8 h, 68%,
20 h, 81%,
cis/trans 78/22
81% ee (cis)
/
82/18
cis trans
81% ee (
)
cis
a Reaction conditions as reported in Table 3. Yields of isolated products are given.
0
4
8
12
16
20
time (h)
1a 3a cis-
pyrazole
cis-4a
internal standard without catalyst in toluene‐d8 at rt.
Pleasingly, the prevalent cis‐
4 diastereoisomer was always
recovered in good yield and ee value, attesting that it is
possible to obtain good to high enantiocontrol for both
diastereoisomers of 1,5‐benzothiazepines, by proper choice of
two organocatalysts. Unfortunately, it was not possible to
obtain good crystals for any compound. For this reason a
hybrid approach based on NMR spectroscopy and Electronic
Circular Dichroism (ECD), supported by DFT conformational
analysis and TD‐DFT calculation of ECD spectra was employed
to assign the relative and absolute configuration of
compounds trans‐4e and cis‐4e. The relative configuration was
determined by the analysis of the coupling constants between
the two CH in position 2 and 3 of 1,5‐benzothiazepine, and the
ECD spectra were successfully simulated considering the 2R,3R
The absolute configuration of the other compounds
assigned by analogy.
At this point, mechanistic investigations were carried out to
shed light on the regio‐ and stereochemical outcome of the
model process. The uncatalysed model reaction was
4
was
1
monitored by H NMR in toluene‐d8 over time (Fig. 3). It is
interesting to note that in absence of any catalyst, low
amounts (< 10%) of the adduct 3a and compound 4a were
formed after 5 h.
Moreover, the amount of free pyrazole is always higher than
the amount of cis‐4a
, which was the only detected
absolute configuration for trans‐4e
,
and the 2S,3R
diastereoisomer besides Michael adduct 3a. In particular, after
7 h 12% of adduct 3a in 87/13 dr ratio, 10 % of cis‐4a, 62% of
1a and 27% of pyrazole were detected. Hence, the uncatalysed
parallel reaction might contribute to lower the final ee value
for the cis‐diastereoisomer. This experiment points out that a
competitive 1,2‐addition/elimination reaction would occur on
the starting alkene 1a to give the corresponding α,β‐
unsaturated thioester.14 The same study was then carried out
configuration of cis‐4e (Fig. 2).9
in C6D615 in the presence of 5 mol% of catalyst
X (Fig. 4).
The adduct 3a was gradually formed with a constant level of
the diastereoselectivity over time (65/35 dr). Compound 4a
was not observed in the reaction mixture, thus attesting that
the uncatalysed reaction is likely to be a negligible process,
when compared to a faster conversion of alkene 1a to 3a
,
promoted by the organocatalyst. The estimated conversion to
the adduct is in agreement with the final isolated yield of
compound 4a reported in Tables 2 and 3. Moreover, the
organocatalyst
promoted
the
competitive
1,2‐
addition/elimination reaction as attested by detection of 30%
of free pyrazole at the end of reaction.16 The presence of
either the adduct 3a and the ,‐unsaturated thioester 5a was
also confirmed by high resolution mass spectrometry analysis
(HRMS) of the crude reaction mixture.17
Fig. 2 TD‐DFT simulations of the ECD spectra of trans‐4e and cis‐4e. Simulations were
run at the TDDFT‐CAM‐B3LYP/6‐311++G(2d,p) level. Geometry optimization was
obtained at the PCM‐B3LYP/6‐311 +G(d,p) level.
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step is regioselective with the sulfa‐Michael reaction being the
View Article Online
DOI: 10.1039/C8OB01988F
prevalent process with respect to 1,2‐addition/elimination
route, when using the amine thiourea catalyst.19
NH2
TsOH (20 mol%)
S
S
O
NH
O
m-xylene, 80°C, 20 h
N
Ph
Ph
N
Ph
Ph
3a
4a
dr 75/25
58% ee (major)
90% ee (minor)
95%, cis/trans 75/25
57%ee (cis)
91% ee (trans)
Scheme 4 Lactamization of the diastereo‐ and enantioenriched mixture of
adduct 3a
.
The uncatalysed Michael reaction and lactamization, as well as
catalyst promoted lactamization might affect the overall
outcome in terms of diastereo‐ and enantioselectivity.
However, they are predicted to be poorly effective processes
during the reaction times generally exploited in Table 3.20
In view of synthetic applications of the methodology
toward preparation of benzothiazepine libraries, N‐alkylation
of both enantioenriched cis‐4a and trans‐4a was carried out
under basic conditions in ethyl acetate at 80°C with o‐nitro‐
benzyl iodide (Scheme 5). Pleasingly, the corresponding N‐
Fig. 4 Reaction progress profile over time in the presence of 1,2‐dichloroethane as
internal standard with 5 mol% X in C6D6 at room temperature and HRMS analysis of the
crude reaction mixture.
Since we could not isolate compound 5a by silica gel
chromatography, the reaction of model compound 1a with
alkylated derivatives were isolated in good yield as pure cis‐
9
thiophenol
under standard conditions (Scheme 3).
The adduct was isolated in 35% yield and 70/30
diastereoisomeric ratio, with both diastereoisomers showing
6 was also investigated in the presence of catalyst
or trans‐ diastereoisomers, maintaining the level of
9
X
enantioselectivity.
7
NO2
Ph
O
good ee values. Moreover, the
,‐unsaturated thioester 8
S
N
Ph
S
I
was isolated in 33% yield.18
Ph
K2CO3
AcOEt , 80°C, 40 h
Ph
N
O
Ph
Ph
SH
H
O
S
O
O
N
X (5 mol%)
Ph
N
cis-9
73%, 74% ee
N
-4a
cis
74% ee
+
NO2
N
Ph
SPh
+
Ph
m-xylene
rt, 7 h
Ph
Ph
Ph
Ph
O
1a
NO2
6
7
8
S
35%
dr 70/30
33%
Ph
I
S
80% ee (major)
90% ee (minor)
N
K2CO3
Ph
N
H
Scheme 3 Asymmetric sulfa‐Michael reaction of 1a with thiophenol.
AcOEt , 80°C, 71 h
O
trans-9
74%, 91% ee
4b
trans-
NO2
91% ee
This experiment confirmed that competitive 1,2‐
addition/elimination process is partially promoted by the
organocatalyst, thus affecting the overall yield of compounds
Scheme 5 N‐Alkylation of enantioenriched cis‐4a and trans‐4a
.
4
. The lactamization step was next studied by reacting
Conclusion
diastereo‐ and enantiomerically enriched 3a in m‐xylene at
80°C with 20 mol% of TsOH, to control the stereochemical
integrity over the cyclization step (Scheme 4). The mixture of
cis/trans‐4a was recovered with the same level of diastereo‐
and enantioselectivity of the starting adduct 3a, running out
the possibility of a retro‐sulfa Michael/sulfa‐Michael process
that would lead to epimerization/racemization. In this regard,
a racemic mixture of the adduct 3a (dr 71/29) treated under
In conclusion, we developed a one‐pot organocatalytic sulfa‐
Michael/lactamization route from trans‐2,3‐disubstituted ,‐
unsaturated acyl pyrazoles and 2‐aminothiophenols. The
methodology, which proceeds at room temperature with
readily available chiral amine‐thiourea or urea and low cost
TsOH, represents a first catalytic route where both cis‐ and
trans‐2,3‐disubstituted 1,5‐benzothiazepines are obtainable in
optically enriched form. The N‐H free 2,3‐substituted 1,5‐
benzothiazepines are recovered in moderate to good yield and
good to excellent enantioselectivity. Mechanistic studies
usefully highlighted that the stereoselectivity is established in
the sulfa‐Michael reaction and it is maintained during the
usual conditions at room temperature with catalyst
X for two
days showed a poor amount of trans‐4a (<10%), attesting that
the organocatalysed lactamization is a negligible process
within the reaction times reported in Table 3.9 Overall,
mechanistic investigations enabled to observe that the first
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
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ARTICLE
Journal Name
1 were prepaVreiedw Afroticllloe wOnilninge
lactamization step. The process is of interest not only because according to the literature. Alkenes
both diastereoisomers can be produced with useful level of general procedures reported in the literaDtuOrIe: 1.204.1039/C8OB01988F
enantioselectivity, but it is also advantageous in view of the 1‐(3,5‐Bis(trifluoromethyl)phenyl)‐3‐((1S,2S)‐2
crucial elaboration of the seven‐membered ring scaffold. The (cycloheptylamino)‐1,2‐di(naphthalen‐1yl)ethyl) thiourea (XI)
N‐deprotection step is not required and the enantioenriched (1S,2S)‐N1‐cycloheptyl‐1,2‐di(naphthalen‐1‐yl)ethane‐1,2‐
1,5‐benzothiazepines are immediately suited for N‐alkylation diamine (86 mg, 0.21 mmol), synthesized according to
or acylation, which are typical derivatizations to create literature,11b was dissolved in anhydrous CH2Cl2 (1 mL) in a
libraries of compounds for bioassay testing.
flamed‐dried two‐necked round‐bottom flask under a positive
pressure of nitrogen. The solution was cooled to 0 °C and 3,5‐
bis(trifluoromethyl)phenylisothiocyanate (38 µL, 0.21 mmol)
was added via syringe dropwise in 10 min. After ca. 1 h at 0 °C,
the crude mixture was allowed to warm up gradually to room
temperature. After reaction completion, as monitored by TLC
(CHCl3/MeOH 98/2), the solvent was removed under reduced
pressure and the crude product was purified by flash
chromatography (PE/EtOAc 98/2 – 90/10) to give the catalyst
Experimental section
All reactions requiring dry or inert conditions were conducted
in flame‐dried glassware under a positive pressure of nitrogen.
Anhydrous THF, toluene, m‐xylene, methanol were purchased
from Aldrich and used as received, all other solvents were
dried over molecular sieves. Molecular sieves (Aldrich
Molecular Sieves, 4 Å, 1.6 mm pellets) were activated under
vacuum at 200 °C overnight. Reactions were monitored by thin
layer chromatography (TLC) on Macherey‐Nagel pre‐coated
silica gel plates (0.25 mm) and visualized by UV light,
potassium permanganate and cerium sulfate staining
solutions. Flash chromatography was performed on Merck
XI in 95% yield. Light yellow solid, 97.2 mg, 65% yield. mp 95.1‐
1
98.2 °C. [α]D = +39.81 (c 0.52, CHCl3). H NMR (CD3OD, 400
19
MHz): δ 8.29 (d, 2H, J = 7.9 Hz), 8.23 (s, 2H), 7.80‐7.73 (m, 3H),
7.67‐7.62 (m, 3H), 7.60 (d, 1H, J = 7.1 Hz), 7.48‐7.34 (m, 6H),
6.82 (bs, 1H), 5.23 (d, 1H, J = 4.4 Hz), 2.50‐2.43 (m, 1H), 1.72‐
1.63 (m, 1H), 1.62‐1.52 (m, 1H), 1.50‐1.41 (m, 1H), 1.40‐1.14
(m, 8H), 1.05‐0.95 (m, 1H). 13C NMR (CD3OD, 100 MHz): δ
silica gel (60, particle size: 0.040–0.063 mm). H NMR and 13C
1
2
182.6, 143.1, 138.2, 137.6, 135.3, 133.0, 132.6 (q, JCF = 33.1
NMR spectra were recorded on Bruker Avance III HD 600,
Bruker Avance‐400, Bruker Avance‐300 or Bruker Avance‐250
spectrometer in CDCl3 or CD3OD as solvents at room
temperature. Chemical shifts for protons are reported using
residual solvent protons (1H NMR: δ = 7.26 ppm for CDCl3, δ =
3.31 ppm for CD3OD) as internal standard. Carbon spectra
were referenced to the shift of the 13C signal of CDCl3 (δ = 77.0
ppm) or CD3OD (δ = 49.0 ppm). The following abbreviations
are used to indicate the multiplicity in NMR spectra: s ‐ singlet;
d ‐doublet; t ‐ triplet; q ‐ quartet; dd ‐ double doublet; m ‐
multiplet; bs ‐ broad signal. Optical rotation of compounds was
performed on a Jasco P‐2000 digital polarimeter using WI
(Tungsten‐Halogen) lamp (λ = 589 nm). High resolution mass
spectra (HRMS) were acquired using a Bruker solariX XR
Fourier transform ion cyclotron resonance mass spectrometer
(Bruker Daltonik GmbH, Bremen, Germany) equipped with a 7
T refrigerated actively‐shielded superconducting magnet. The
samples were ionized in positive ion mode using a MALDI
ionization source. Melting points were measured with a Stuart
Model SMP 30 melting point apparatus and are uncorrected.
Petrol ether (PE) refers to light petroleum ether (boiling point
40‐60 °C). All starting materials (unless otherwise noted) were
purchased from Aldrich and used as received. Enantiomeric
Hz), 132.2, 130.1, 129.8, 129.2, 129.0, 127.0, 126.9, 126.7,
126.3, 126.2, 126.0, 125.5, 124.7 (q, JCF = 271.0 Hz), 124.6,
1
123.8, 123.4, 117.8, 59.6, 57.0, 36.9, 34.0, 29.2, 29.0, 25.3,
24.7. HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+
calculated for C38H36F6N3S: 680.2529, found: 680.2524.
General procedure for the synthesis of racemic 2,3‐
substituted‐1,5‐benzothiazepines (4)
To a suspension of (E)‐α,β‐unsaturated N‐acylpyrazole
1 (0.1
mmol) and aluminum oxide (aluminium oxide Fluka for
chromatography 17994 pH = 10 ± 0.5, 101.96 mg) in dry
diethyl ether (500 µL) 2‐aminothiophenol
2 (0.11 mmol) was
added under N2 atmosphere. The reaction mixture was stirred
at room temperature for 5‐24 h. After completion, the
reaction mixture was filtered through a short pad of flash
silica‐gel and the organic solvent was evaporated. Then, the
crude mixture was dissolved in dry toluene (500 µL), p‐
toluenesulfonic acid monohydrate (0.02 mmol) was added and
the suspension was stirred at 80 °C for 20 h. The crude product
was purified by flash chromatography (hexane/ EtOAc100/1 ‐
70/30) to afford racemic 1,5‐benzothiazepines 4.
General procedure for the enantioselective synthesis of cis‐ and
trans‐2,3‐substituted‐1,5‐benzothiazepine (4)
excess of 1,5‐benzothiazepines
4, 9, adduct 3a and 7 was
(E)‐α,β‐unsaturated N‐acylpyrazole
or VIII (0.01 mmol) were dissolved in dry m‐xylene (1 mL) and
2‐aminothiophenol (0.11 + 0.10 mmol) was added in two
portions (the second portion added after 2 hours) under
nitrogen atmosphere at room temperature. After completion,
p‐toluenesulfonic acid monohydrate (0.04 mmol) was added.
The suspension was stirred at 80°C until completion. The crude
mixture was analysed by 1H‐NMR to determine the
diastereoisomeric ratio. The crude product was purified by
1 (0.2 mmol) and catalyst X
determined by HPLC (Waters‐Breeze 2487, UV dual λ
absorbance detector and 1525 Binary HPLC Pump) using Daicel
chiral columns. The absolute configuration of 1,5‐
benzothiazepines was determined by a hybrid NMR/ECD
approach supported by DFT conformational analysis and TD‐
DFT calculation of ECD spectra of compound 4e. Other
configurations were assigned in analogy. Catalyst III was
2
purchased from Strem Chemicals and used as received.
Catalysts I‐II 21
,
IV‐VI 22
,
VII‐VIII 23
,
IX 11a
,
X
,
were prepared
11b
6 | J. Name., 2012, 00, 1‐3
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Organic & Biomolecular Chemistry
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ARTICLE
flash chromatography (hexane/EtOAc 100/1 ‐ 70/30) to afford (2
product
(2 ,3 )‐2,3‐Diphenyl‐2,3‐dihydrobenzo[b][1,4]thiazepin‐
S,3R)‐2‐(4‐Methoxyphenyl)‐3‐phenyl‐2,3‐
View Article Online
4.
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐onDeO(4I:c1)0.1039/C8OB01988F
19
S
R
Yellow solid, 11.6 mg, 16% yield. mp 68.7‐73.7 °C. [α]D
=
4(5H)‐one (4a)
+47.1 (c 0.44, CHCl3), 75% ee. 1H NMR (CDCl3, 400 MHz): δ 7.95
(bs, 1H), 7.72 (d, 1H, J = 7.2 Hz), 7.43 (t, 1H, J = 7.5 Hz), 7.29‐
17
White solid, 41.1 mg, 62% yield. mp 187.6‐189.7 °C. [α]D
=
+17.4 (c 0.66, CHCl3), 81% ee. 1H NMR (CDCl3, 400 MHz): δ 8.14 7.26 (m, 1H), 7.23 (d, 2H, J = 8.4 Hz), 7.15‐7.12 (m, 2H), 7.09‐
(bs, 1H), 7.73 (d, 1H, J = 7.6 Hz), 7.43 (t, 1H, J = 7.6 Hz), 7.32‐ 7.05 (m, 2H), 6.93 (d, 2H, J = 7.5 Hz), 6.77 (d, 2H, J = 8.1 Hz),
7.20 (m, 6H), 7.13‐7.11 (d, 2H, J = 7.6 Hz), 7.07‐7.03 (m, 2H), 4.94 (d, 1H, J = 6.0 Hz), 4.19 (d, 1H, J = 6.0 Hz), 3.80 (s, 3H). 13
C
6.92 (d, 2H, J = 7.5 Hz), 4.98 (d, 1H, J = 6.3 Hz), 4.22 (d, 1H, J = NMR (CDCl3, 100 MHz): δ 172.0, 159.8, 142.2, 134.9, 134.7,
6.3 Hz). 13C NMR (CDCl3, 100 MHz): δ 172.1, 142.3, 136.2, 131.2, 130.8, 130.1, 129.2, 128.1, 127.4, 127.3, 126.6, 123.1,
135.0, 134.6, 130.8, 130.2, 130.1, 128.9, 128.6, 128.0, 127.4, 113.4, 60.6, 55.2, 51.1. HRMS (MALDI‐FT ICR) exact mass
127.3, 126.6, 123.2, 61.3, 51.1. HRMS (MALDI‐FTICR) exact calculated [M+H]+ calculated for C22H20NO2S: 362.1209, found:
mass calculated [M+H]+ calculated for C21H18NOS: 332.1104, 362.1206. HPLC analysis with Chiralpak IC column, 70:30 n‐
found: 332.1110. HPLC analysis with Chiralpak IC column, 95:5 hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR =
n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR 17.8 min, major enantiomer tR = 7.4 min.
= 17.4 min, major enantiomer tR = 21.4 min.
(2 ,3 )‐2,3‐Diphenyl‐2,3‐dihydrobenzo[b][1,4]thiazepin‐
4(5H)‐one (4a)10b
(2
R,3R)‐2‐(4‐Methoxyphenyl)‐3‐phenyl‐2,3‐
R
R
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4c)
20
White solid, 21.7 mg, 30% yield. mp 142.2‐144.1 °C. [α]D = ‐
White solid, 21.9 mg, 33% yield. mp 190.2‐193.7 °C. [α]D = ‐ 165.0 (c 0.58, CHCl3), 82% ee. 1H NMR (CDCl3, 600 MHz): δ 7.64
17
1
318.54 (c 0.68, CHCl3), 94% ee. H NMR (CDCl3, 300 MHz): δ (dd, 1H, J = 7.6, 1.1 Hz), 7.62 (bs, 1H), 7.49 (td, 1H, J = 7.6, 1.4
7.65 (d, 1H, J = 7.9 Hz), 7.53‐7.48 (m, 2H), 7.30 (t, 1H, J = 7.7 Hz), 7.29 (td, 1H, J = 7.6, 1.1 Hz), 7.22 (d, 1H, J = 7.7 Hz), 7.19‐
Hz), 7.26‐7.07 (m, 9H), 6.96‐6.93 (m, 2H), 4.89 (d, 1H, J = 12.2 7.17 (m, 2H), 7.16‐7.14 (m, 2H), 7.12‐7.11 (m, 1H), 6.87 (d, 2H,
Hz), 4.17 (d, 1H, J = 12.2 Hz). 13C NMR (CDCl3, 75 MHz): δ J = 8.7 Hz), 6.62 (d, 2H, J = 8.7 Hz), 4.87 (d, 1H, J = 12.2 Hz),
172.6, 142.7, 141.5, 136.3, 135.4, 130.5, 129.9, 128.4, 128.0, 4.13 (d, 1H, J = 12.2 Hz), 3.68 (s, 3H). 13C NMR (CDCl3, 100
127.4, 127.0, 126.6, 126.4, 123.4, 58.3, 54.4. HRMS (MALDI‐ MHz): δ 172.7, 158.6, 141.5, 136.3, 135.6, 135.1, 130.5, 129.9,
FTICR) exact mass calculated [M+H]+ calculated for C21H18NOS: 128.0, 127.4, 127.3, 126.9, 126.5, 123.3, 113.7, 57.9, 55.1,
332.1104, found: 332.1110. HPLC analysis with Chiralpak IC 54.6. HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+
column, 80:20 n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor calculated for C22H20NO2S: 362.1209, found: 362.1206. HPLC
enantiomer tR = 9.6 min, major enantiomer tR = 14.2 min.
(2 ,3 )‐3‐Phenyl‐2‐( ‐tolyl)‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4b)
analysis with Chiralpak IC column, 70:30 n‐hexane:2‐propanol,
1 mL/min, 254 nm; minor enantiomer tR = 10.1 min, major
enantiomer tR = 14.7 min.
S
R
p
18
White solid, 26.2 mg, 38% yield. mp 189 °C (Decomp.). [α]D
=
(2S,3R)‐2‐(4‐Chlorophenyl)‐3‐phenyl‐2,3‐
+36.4 (c 0.54, CHCl3), 74% ee. 1H NMR (CDCl3, 400 MHz): δ 7.99 dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4d)
17
(bs, 1H), 7.72 (d, 1H, J = 7.2 Hz), 7.42 (t, 1H, J = 7.5 Hz), 7.29‐ Brown solid, 25.6 mg, 35% yield. mp 193 °C (Decomp.). [α]D
=
1
7.26 (m, 1H), 7.21‐7.19 (m, 2H), 7.16‐7.03 (m, 6H), 6.93‐6.91 +34.00 (c 0.50, CHCl3), 59% ee. H NMR (CDCl3, 400 MHz): δ
(m, 2H), 4.94 (d, 1H, J = 6.2 Hz), 4.20 (d, 1H, J = 6.2 Hz), 2.34 (s, 7.72 (d, 1H, J = 7.8 Hz), 7.52‐7.44 (m, 2H), 7.31‐7.27 (m, 1H),
3H). 13C NMR (CDCl3, 100 MHz): δ 172.0, 142.2, 138.4, 134.9, 7.26‐7.23 (m, 4H), 7.17‐7.13 (m, 2H), 7.10‐7.07 (m, 2H), 6.94
134.7, 133.1, 130.8, 130.1, 130.0, 129.0, 128.7, 127.4, 127.3, (d, 2H, J = 7.7 Hz), 4.93 (d, 1H, J = 6.3 Hz), 4.19 (d, 1H, J = 6.3
126.5, 123.1, 60.9, 51.0, 21.2. HRMS (MALDI‐FTICR) exact mass Hz). 13C NMR (CDCl3, 100 MHz): δ 171.7, 142.1, 135.1, 134.8,
calculated [M+H]+ calculated for C22H20NOS: 346.1260, found: 134.4, 134.3, 131.4, 130.7, 130.4, 128.6, 128.2, 127.6, 127.5,
346.1265. HPLC analysis with Chiralpak IC column, 95:5 n‐ 126.8, 123.2, 60.5, 50.8. HRMS (MALDI‐FTICR) exact mass
hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR = calculated [M+H]+ calculated for C21H17ClNOS: 366.0714,
31.0 min, major enantiomer tR = 25.1 min.
(2 ,3 )‐3‐Phenyl‐2‐( ‐tolyl)‐2,3‐
found: 366.0718. HPLC analysis with Chiralpak IC column, 95:5
n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR
= 22.8 min, major enantiomer tR = 11.7 min.
R
R
p
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4b)
White solid, 22.8 mg, 33% yield. mp 146.0‐150.0 °C. [α]D18= ‐ (2
R
,3
R
)‐2‐(4‐Chlorophenyl)‐3‐phenyl‐2,3‐
1
233.72 (c 0.60, CHCl3), 93% ee. H NMR (CDCl3, 400 MHz): δ dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4d)
17
7.63 (d, 1H, J = 7.7 Hz), 7.49 (t, 1H, J = 7.6 Hz), 7.29 (t, 1H, J = Light brown solid, 27.8 mg, 38% yield. mp 76.1‐78.6 °C. [α]D
=
1
7.6 Hz), 7.24‐7.08 (m, 7H), 6.90 (d, 2H, J = 8.0 Hz), 6.84 (d, 2H, J ‐247.83 (c 0.46, CHCl3), 92% ee. H NMR (CDCl3, 400 MHz): δ
= 8.1 Hz), 4.88 (d, 1H, J = 12.2 Hz), 4.17 (d, 1H, J = 12.2 Hz), 7.63 (d, 1H, J = 7.4 Hz), 7.52 (td, 1H, J = 7.6, 1.3 Hz), 7.31 (t, 1H,
2.19 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 173.0, 141.6, 139.8, J = 7.8 Hz), 7.26‐7.23 (m, 2H), 7.18‐7.12 (m, 5H), 7.06 (d, 2H, J =
137.0, 136.2, 135.6, 130.4, 129.9, 129.1, 127.9, 127.3, 126.8, 8.0 Hz), 6.88 (d, 2H, J = 8.0 Hz), 4.86 (d, 1H, J = 12.2 Hz), 4.09
126.5, 126.1, 123.3, 58.0, 54.3, 21.0. HRMS (MALDI‐FTICR) (d, 1H, 12.2 Hz). 13C NMR (CDCl3, 100 MHz): δ 172.7, 141.6,
exact mass calculated [M+H]+calculated for C22H20NOS: 141.3, 136.1, 135.1, 133.0, 130.7, 129.9, 128.6, 128.2, 128.1,
346.1260, found: 346.1265. HPLC analysis with Chiralpak IC 127.7, 127.5, 127.0, 123.5, 57.6, 54.3. HRMS (MALDI‐FTICR)
column, 80:20 n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor exact mass calculated [M+H]+ calculated for C21H17ClNOS:
enantiomer tR = 10.6 min, major enantiomer tR = 15.8 min.
366.0714, found: 366.0717. HPLC analysis with Chiralpak IC
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 7
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Journal Name
column, 80:20 n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor HPLC analysis with Chiralpak IC column, 80:20Vienw‐hAertixclaenOen:li2ne‐
DOI: 10.1039/C8OB01988F
enantiomer tR = 9.8 min, major enantiomer tR = 13.9 min.
(2 ,3 )‐2‐(4‐Fluorophenyl)‐3‐phenyl‐2,3‐
propanol, 1 mL/min, 254 nm; minor enantiomer tR = 10.7 min,
major enantiomer tR = 17.4 min.
S
R
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4e)
(2
S,3R)‐2‐(Naphthalen‐2‐yl)‐3‐phenyl‐2,3‐
22
Brown solid, 28.0 mg, 40% yield. mp 174 °C (Decomp.). [α]D
=
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4g)
+37.9 (c 0.87, CHCl3), 81% ee. 1H NMR (CDCl3, 400 MHz): δ 8.03 Yellow solid, 25.9 mg, 34% yield. mp 205 °C (Decomp.). [α]D
=
17
(bs, 1H), 7.73 (d, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.7 Hz), 7.31‐ +36.1 (c 0.69, CHCl3), 45% ee. 1H NMR (CDCl3, 400 MHz): δ 7.84
7.25 (m, 3H), 7.17‐7.13 (m, 2H), 7.09‐7.06 (m, 2H), 6.94‐6.90 (d, 1H, J = 7.5 Hz), 7.79 (d, 1H, J = 8.4 Hz), 7.75 (t, 2H, J = 6.5
(m, 4H), 4.96 (d, 1H, J = 6.3 Hz), 4.20 (d, 1H, J = 6.3 Hz). 13C Hz), 7.69 (s, 1H), 7.60‐7.57 (m, 2H), 7.50‐7.44 (m, 3H), 7.30 (t,
1
NMR (CDCl3, 100 MHz): δ 172.4, 162.8 (d, JCF = 245.9 Hz), 1H, J = 7.6 Hz), 7.19 (d, 1H, J = 7.4 Hz), 7.11‐7.07 (m, 1H), 7.01‐
142.3, 134.9, 134.5, 132.0 (d, 4JCF = 3.0 Hz), 131.8 (d, 3JCF = 8.2 6.97 (m, 2H), 6.94‐6.92 (m, 2H), 5.15 (d, 1H, J = 6.4 Hz), 4.29 (d,
Hz), 130.7, 130.3, 128.6, 127.5, 127.4, 126.6, 123.3, 114.8 (d, 1H, J = 6.4 Hz). 13C NMR (CDCl3, 62.5 MHz): δ 171.9, 142.2,
2JCF = 21.3 Hz), 60.6, 50.9. HRMS (MALDI‐FT ICR) exact mass 135.0, 134.6, 133.8, 133.4, 132.8, 130.8, 130.3, 129.7, 128.9,
calculated [M+H]+ calculated for C21H17FNOS: 350.1009, found: 128.2, 127.7, 127.6, 127.5, 127.42, 127.39, 126.7, 126.3, 126.0,
350.1006. HPLC analysis with Chiralpak IC column, 95:5 n‐ 123.1, 61.4, 51.1. HRMS (MALDI‐FT ICR) exact mass calculated
hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR = [M+H]+ calculated for C25H20NOS: 382.1260, found: 382.1283.
13.6 min, major enantiomer tR = 12.6 min.
(2 ,3 )‐2‐(4‐Fluorophenyl)‐3‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4e)
HPLC analysis with Chiralpak IC column, 80:20 n‐hexane:2‐
propanol, 1 mL/min, 254 nm; minor enantiomer tR = 13.6 min,
major enantiomer tR = 7.9 min.
R
R
22
White solid, 26.6 mg, 38% yield. mp 182.0‐184.1 °C. [α]D = ‐ (2R,3R)‐2‐(Naphthalen‐2‐yl)‐3‐phenyl‐2,3‐
322.3 (c 0.99, CHCl3), 94% ee. 1H NMR (CDCl3, 300 MHz): δ 7.90 dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4g)
18
(bs, 1H), 7.65‐7.60 (m, 1H), 7.50 (td, 1H, J = 7.6, 1.3 Hz), 7.33‐ Yellow solid, 28.2 mg, 37% yield. mp 210 °C (Decomp.). [α]D
=
1
7.11 (m, 7H), 6.94‐6.89 (m, 2H), 6.80‐6.74 (m, 2H), 4.88 (d, 1H, ‐82.0 (c 0.42, CHCl3), 55% ee. H NMR (CDCl3, 400 MHz): δ
J = 12.2 Hz), 4.09 (d, 1H, J = 12.2 Hz). 13C NMR (CDCl3, 62.5 7.73‐7.61 (m, 5H), 7.53 (td, 1H, J = 7.6, 1.3 Hz), 7.39‐7.27 (m,
MHz): δ 172.7, 161.7 (d, 1JCF = 245.0 Hz), 141.6, 138.7 (d, 4JCF
=
5H), 7.26‐7.22 (m, 2H), 7.16‐7.05 (m, 4H), 5.09 (d, 1H, J = 12.2
3.1 Hz), 136.1, 135.3, 130.6, 129.9, 128.0, 127.9, 127.5, 126.9, Hz), 4.33 (d, 1H, J = 12.2 Hz). 13C NMR (CDCl3, 75 MHz): δ
2
126.0, 123.4, 115.3 (d, JCF = 21.4 Hz), 57.6, 54.7. HRMS 172.7, 141.5, 139.9, 136.4, 135.3, 133.0, 132.5, 130.6, 129.8,
(MALDI‐FT ICR) exact mass calculated [M+H]+ calculated for 128.7, 128.5, 128.0, 127.8, 127.5, 127.0, 126.5, 126.1, 125.9,
C21H17FNOS: 350.1009, found: 350.1006. HPLC analysis with 125.4, 123.9, 123.4, 58.3, 53.9. HRMS (MALDI‐FT ICR) exact
Chiralpak IC column, 80:20 n‐hexane:2‐propanol, 1 mL/min, mass calculated [M+H]+ calculated for C25H20NOS: 382.1260,
254 nm; minor enantiomer tR = 9.7 min, major enantiomer tR = found: 382.1263. HPLC analysis with Chiralpak IC column,
13.8 min.
(2 ,3 )‐2‐(Furan‐3‐yl)‐3‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4f)
70:20 n‐hexane:2‐propanol,
enantiomer tR = 8.1 min, major enantiomer tR = 10.7 min.
(2 ,3 )‐3‐(4‐Methoxyphenyl)‐2‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4h)
1 mL/min, 254 nm; minor
S
R
S R
21
Ochre yellow solid, 19.3 mg, 30% yield. mp 76.4‐79.6 °C. [α]D
1
= +1.1 (c 0.60, CHCl3), 67% ee. H NMR (CDCl3, 250 MHz): δ Ochre yellow solid, 28.9 mg, 40% yield. mp 167.4‐172.0 °C.
19
1
7.72‐7.69 (dd, 1H, J = 7.5, 1.2 Hz), 7.54 (bs, 2H), 7.45‐7.41 (dd, [α]D = +57.4 (c 0.51, CHCl3), 55% ee. H NMR (CDCl3, 400
1H, J = 7.4, 1.7), 7.20‐7.13 (m, 8H), 6.62 (s, 1H), 4.95 (d, 1H, J = MHz): δ 8.18 (bs, 1H), 7.72 (d, 1H, J = 7.7 Hz), 7.44‐7.40 (m,
6.3 Hz), 4.17 (d, 1H, J = 6.1 Hz). 13C NMR (CDCl3, 100 MHz): δ 1H), 7.33‐7.22 (m, 6H), 7.12 (d, 1H, J = 7.8 Hz), 6.80 (d, 2H, J =
171.9, 143.1, 142.2, 142.0, 135.0, 134.7, 130.6, 130.3, 128.6, 8.7 Hz), 6.60 (d, 2H, J = 8.8 Hz), 4.94 (d, 1H, J = 6.3 Hz), 4.17 (d,
127.6, 127.5, 126.7, 123.1, 121.0, 111.0, 51.7, 50.3. HRMS 1H, J = 6.3 Hz), 3.70 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
(MALDI‐FT ICR) exact mass calculated [M+H]+ calculated for 172.3, 158.8, 142.3, 136.3, 135.0, 131.9, 130.2, 130.1, 128.9,
C19H16NO2S: 322.0896, found: 322.0892. HPLC analysis with 128.6, 128.0, 126.6, 126.5, 123.1, 112.8, 61.3, 55.1, 50.3.
Chiralpak IC column, 90:10 n‐hexane:2‐propanol, 1 mL/min, HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+ calculated
254 nm; minor enantiomer tR = 15.0 min, major enantiomer tR for C22H20NO2S: 362.1209, found: 362.1206. HPLC analysis with
= 11.8 min.
(2 ,3 )‐2‐(Furan‐3‐yl)‐3‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4f)
Chiralpak IC column, 80:20 n‐hexane:2‐propanol, 1 mL/min,
254 nm; minor enantiomer tR = 13.8 min, major enantiomer tR
= 10.0 min.
R
R
19
Brown solid, 10.9 mg, 17% yield. mp 151.8 °C (Decomp.). [α]D
(2R,3R)‐3‐(4‐Methoxyphenyl)‐2‐phenyl‐2,3‐
1
= ‐175.9 (c 0.51, CHCl3), 99% ee. H NMR (CDCl3, 400 MHz): δ dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4h)
7.92 (s, 1H), 7.67 (d, 1H, J = 7.6 Hz), 7.48 (t, 1H, J = 7.2 Hz), Ochre yellow solid, 28.9 mg, 40% yield. mp 157.8 °C
19
1
7.30‐7.28 (m, 1H), 7.23‐7.19 (m, 6H), 7.15 (s, 1H), 6.97 (s, 1H), (Decomp.). [α]D = ‐245.3 (c 0.54, CHCl3), 99% ee. H NMR
6.00 (s, 1H), 4.84 (d, 1H, J = 11.9 Hz), 3.88 (d, 1H, J = 11.8 Hz). (CDCl3, 400 MHz): δ 7.65‐7.62 (dd, 1H, J = 7.7, 1.1 Hz), 7.55 (bs,
13C NMR (CDCl3, 100 MHz): δ 172.7, 143.1, 141.6, 138.8, 136.3, 1H), 7.52‐7.48 (td, 1H, J = 7.7, 1.3 Hz), 7.32‐7.28 (td, 1H, J = 7.5,
135.8, 130.6, 129.8, 128.1, 127.7, 126.89, 126.80, 126.0, 123.3, 1.1 Hz), 7.23 (d, 1H, J = 7.8 Hz), 7.11‐7.09 (m, 5H), 6.95‐6.93
108.5, 54.5, 50.0. HRMS (MALDI‐FT ICR) exact mass calculated (m, 2H), 6.67 (d, 2H, J = 8.7 Hz), 4.83 (d, 1H, J = 12.2 Hz), 4.12
[M+H]+ calculated for C19H16NO2S: 322.0896, found: 322.0892. (d, 1H, J = 12.2 Hz), 3.69 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
8 | J. Name., 2012, 00, 1‐3
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173.3, 158.6, 142.9, 141.7, 136.2, 130.9, 130.4, 128.4, 127.5, (CDCl3, 100 MHz): δ 171.4, 147.0, 142.9, 142.0, 141.1, 136.3,
View Article Online
DOI: 10.1039/C8OB01988F
127.3, 126.8, 126.42, 126.35, 123.3, 113.4, 58.4, 55.0, 53.5. 131.0, 130.8, 128.7, 127.9, 127.4, 126.2, 126.1, 123.6. 123.0,
HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+ calculated 58.2, 54.1. HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+
for C22H20NO2S: 362.1209, found: 362.1206. HPLC analysis with calculated for C21H17N2O3S: 377.0954, found: 377.0951. HPLC
Chiralpak IC column, 70:30 n‐hexane:2‐propanol, 1 mL/min, analysis with Chiralpak IC column, 90:10 n‐hexane:2‐propanol,
220 nm; minor enantiomer tR = 14.1 min, major enantiomer tR 1 mL/min, 254 nm; minor enantiomer tR = 31.0 min, major
= 25.1 min.
(2 ,3 )‐3‐(4‐Chlorophenyl)‐2‐phenyl‐2,3‐
enantiomer tR = 25.1 min.
(2 ,3 )‐7‐Methyl‐3‐phenyl‐2‐(m‐tolyl)‐2,3‐
S
R
S
R
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4i)
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4k)
White solid, 18.7 mg, 26% yield. mp 181.5‐183.8 °C. [α]D
20
19
Yellow solid, 22.0 mg, 30% yield. mp 158 °C (Decomp.). [α]D
=
=
1
+63.07 (c 0.56, CHCl3), 81% ee. H NMR (CDCl3, 250 MHz): δ +17.3 (c 0.54, CHCl3), 70% ee. 1H NMR (CDCl3, 400 MHz): δ 7.70
7.75‐7.72 (dd, 1H, J = 7.2, 0.7 Hz), 7.51 (bs, 1H), 7.47‐7.43 (dd, (s, 1H), 7.58 (d, 1H, J = 7.7 Hz), 7.11‐7.04 (m, 8H), 6.93‐6.90 (m,
1H, J = 7.7, 1.3 Hz), 7.32‐7.30 (m, 6H), 7.18‐7.15 (m, 1H), 7.02 3H), 4.89 (d, 1H, J = 6.2 Hz), 4.81 (d, 1H, J = 6.2 Hz), 2.39 (s,
(d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J = 8.7 Hz), 4.92 (d, 1H, J = 6.4 3H), 2.29 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 172.0, 142.0,
Hz), 4.17 (d, 1H, J = 6.3 Hz). 13C NMR (CDCl3, 100 MHz): δ 140.7, 137.5, 136.2, 134.7, 130.8, 130.7, 129.3, 127.8, 127.34,
171.5, 141.9, 135.8, 135.1, 133.4, 133.0, 132.1, 130.3, 130.1, 127.28, 127.2, 125.4, 123.7, 61.1, 51.1, 21.4, 21.2. HRMS
128.8, 128.7, 128.1, 127.6, 126.8, 123.2, 61.0, 50.4. HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+ calculated for
(MALDI‐FT ICR) exact mass calculated [M+H]+ calculated for C23H22NOS: 360.1417, found: 360.1413. HPLC analysis with
C21H17ClNOS: 366.0714, found: 366.0711. HPLC analysis with Chiralpak IE‐3 column, 70:30 n‐hexane:2‐propanol, 0.6
Chiralpak IC column, 95:5 n‐hexane:2‐propanol, 1 mL/min, 254 mL/min, 254 nm; minor enantiomer tR = 30.6 min, major
nm; minor enantiomer tR = 17.4 min, major enantiomer tR = enantiomer tR = 15.2 min.
15.7 min.
(2 ,3 )‐3‐(4‐Chlorophenyl)‐2‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4i)
(2
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4k)
White solid, 12.2 mg, 17% yield. mp 199.6‐201.9 °C. [α]D = ‐
R,3R)‐7‐Methyl‐3‐phenyl‐2‐(m‐tolyl)‐2,3‐
R
R
20
White solid, 30.7 mg, 42% yield. mp 182.8‐185.2 °C. [α]D = ‐ 333.2 (c 0.60, CHCl3), 95% ee. 1H NMR (CDCl3, 600 MHz): δ 7.50
282.2 (c 0.60, CHCl3), 95% ee. 1H NMR (CDCl3, 600 MHz): δ 7.86 (d, 1H, J = 7.8 Hz), 7.20‐7.18 (m, 2H), 7.14 (t, 2H, J = 7.4 Hz),
(s, 1H), 7.64 (d, 1H, J = 7.3 Hz), 7.50 (t, 1H, J = 7.3 Hz), 7.31 (t, 7.11‐7.10 (m, 2H), 7.04 (s, 1H), 6.97 (t, 1H, J = 7.9 Hz), 6.87 (d,
1H, J = 7.5 Hz), 7.21 (d, 1H, J = 7.8 Hz), 7.14‐7.10 (m, 7H), 6.93‐ 1H, J = 7.3 Hz), 6.75‐6.74 (m, 2H), 4.82 (d, 1H, J = 12.2 Hz), 4.17
6.92 (m, 2H), 4.81 (d, 1H, J = 12.2 Hz), 4.14 (d, 1H, J = 12.2 Hz). (d, 1H, J = 12.2 Hz), 2.45 (s, 3H), 2.17 (s, 3H). 13C NMR (CDCl3,
13C NMR (CDCl3, 150 MHz): δ 172.3, 142.5, 141.4, 136.3, 134.1, 150 MHz): δ 172.8, 142.7, 141.4, 141.1, 138.0, 136.1, 135.6,
133.3, 131.3, 130.6, 128.6, 128.2, 127.6, 127.1, 126.4, 126.3, 129.9, 128.2, 128.1, 127.9, 127.8, 127.30, 127.27, 124.0, 123.2,
123.4, 58.3, 53.8. HRMS (MADI‐FT ICR) exact mass calculated 123.1, 58.1, 54.3, 21.32, 21.28. HRMS (MALDI‐FT ICR) exact
[M+H]+ calculated for C21H17ClNOS: 366.0714, found: mass calculated [M+H]+ calculated for C23H22NOS: 360.1417,
366.0711. HPLC analysis with Chiralpak IC column, 80:20 n‐ found: 360.1413. HPLC analysis with Chiralpak IE‐3 column,
hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR = 70:30 n‐hexane:2‐propanol, 0.6 mL/min, 254 nm; minor
19
7.6 min, major enantiomer tR = 10.7 min.
(2 ,3 )‐3‐(4‐Nitrophenyl)‐2‐phenyl‐2,3‐
enantiomer tR = 24.3 min, major enantiomer tR = 22.9 min.
(2 ,3 )‐2‐(2‐Fluorophenyl)‐3‐phenyl‐2,3‐
S
R
S R
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4j)
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4l)
White solid, 16.7 mg, 23% yield. mp 214.6‐218.4 °C. [α]D
19
18
Pale yellow solid, 23.3 mg, 31% yield. mp 207.4‐211.8 °C. [α]D
=
1
= +71.3 (c 0.58, CHCl3), 73% ee. H NMR (CDCl3, 300 MHz): δ +5.4 (0.59, CHCl3), 66% ee. 1H NMR (CDCl3, 400 MHz): δ 8.20 (s,
8.02 (bs, 1H), 7.90 (d, 2H, J = 8.0 Hz), 7.75 (d, 1H, J = 7.5 Hz), 1H), 8.08‐8.04 (td, 1H, J = 7.5, 1.3 Hz), 7.61 (d, 1H, J = 7.8 Hz),
7.49 (t, 1H, J = 7.7 Hz), 7.35‐7.24 (m, 6H), 7.16 (d, 1H, J = 7.7 7.26‐7.25 (m, 1H), 7.17‐7.13 (m, 2H), 7.10‐7.06 (m, 3H), 6.99
Hz), 7.13 (d, 2H, J = 8.7 Hz), 4.96 (d, 1H, J = 6.5 Hz), 4.31 (d, 1H, (d, 2H, J = 7.5 Hz), 6.91 (s, 1H), 6.80 (t, 1H, J = 8.9), 5.48 (d, 1H,
J = 6.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 170.9, 147.0, 142.0, J = 6.6 Hz), 4.21 (d, 1H, J = 6.6 Hz), 2.38 (s, 3H). 13C NMR (CDCl3,
1
141.8, 135.2, 131.7, 130.6, 129.9, 129.1, 128.5, 128.3, 127.0, 100 MHz): δ 172.3, 160.8 (d, JCF = 245.8 Hz), 142.0, 141.0,
2
123.4, 122.4, 60.9, 50.7. HRMS (MALDI‐FT ICR) exact mass 135.0, 134.4, 131.1, 130.4, 129.9 (d, JCF = 8.4 Hz), 127.5,
calculated [M+H]+ calculated for C21H17N2O3S: 377.0954, 127.4, 124.9, 124.1 (d, 4JCF = 2.9 Hz), 123.9, 123.7, 123.6, 114.6
found: 377.0951. HPLC analysis with Chiralpak IC column, (d, 3JCF = 22.8 Hz), 51.0, 50.6, 21.2. HRMS (MALDI‐FT ICR) exact
90:10 n‐hexane:2‐propanol,
enantiomer tR = 31.0 min, major enantiomer tR = 24.7 min.
(2 ,3 )‐3‐(4‐Nitrophenyl)‐2‐phenyl‐2,3‐
1
mL/min, 254 nm; minor mass calculated [M+H]+ calculated for C22H19FNOS: 364.1166,
found: 364.1163. HPLC analysis with Chiralpak IC column, 95:5
n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR
= 16.4 min, major enantiomer tR = 12.1 min.
R
R
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4j)
Ochre yellow solid, 15.1 mg, 20% yield. mp 175.5‐177.5 °C. (2R,3R)‐2‐(2‐Fluorophenyl)‐3‐phenyl‐2,3‐
19
1
[α]D = ‐132.7 (c 0.42, CHCl3), 77% ee. H NMR (CDCl3, 400 dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4l)
MHz): δ 8.01‐7.99 (m, 3H), 7.68 (d, 1H, J = 8.0 Hz), 7.54 (t, 1H, J Cream coloured solid, 18.2 mg, 25% yield. mp 201.0‐205.9 °C.
18
1
= 7.4 Hz), 7.40‐7.33 (m, 3H), 7.11‐7.10 (m, 3H), 6.92‐6.91 (m, [α]D = ‐369.0 (c 0.62, CHCl3), 94% ee. H NMR (CDCl3, 400
2H), 4.86 (d, 1H, J = 12.2 Hz), 4.28 (d, 1H, J = 12.3 Hz). 13C NMR MHz): δ 7.89 (bs, 1H), 7.46 (d, 1H, J = 7.8 Hz), 7.24‐7.22 (m,
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2H), 7.17‐7.13 (m, 3H), 7.11‐7.05 (m, 2H), 7.03‐6.98 (m, 2H), (2
Journal Name
R,3R)‐7‐Bromo‐3‐(4‐chlorophenyl)‐2‐phenyl‐2,3‐
View Article Online
6.89 (t, 1H, J = 7.5 Hz), 6.82 (t, 1H, J = 9.3 Hz), 5.30 (d, 1H, J = dihydrobenzo[b][1,4]thiazepin‐4(5H)‐onDeO(4I:n10).1039/C8OB01988F
12.5 Hz), 4.24 (d, 1H, J = 12.4 Hz), 2.43 (s, 3H). 13C NMR (CDCl3, White solid, 26.7 mg, 30% yield. mp 206.2‐210.7 °C. [α]D = ‐
18
1
1
100 MHz): δ 172.8, 158.9 (d, JCF = 245.4 Hz), 141.23, 141.20, 405.1 (c 0.77, CHCl3), 99 % ee. H NMR (CDCl3, 400 MHz): δ
135.9, 135.2, 129.7, 128.7 (d, 3JCF = 8.3 Hz), 128.0, 127.6 (d, 2JCF 8.26 (bs, 1H), 7.47‐7.41 (m, 2H), 7.385‐7.381 (m, 1H), 7.18‐7.13
4
= 23.9 Hz), 127.18, 127.15, 124.1 (d, JCF = 3.4 Hz), 124.0, (m, 5H), 7.07 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J = 8.4 Hz), 4.86 (d,
122.6, 115.5 (d, 2JCF = 22.4 Hz), 52.9, 50.0, 21.3. HRMS (MALDI‐ 1H, J = 12.2 Hz), 4.07 (d, 1H, J = 12.2 Hz). 13C NMR (CDCl3, 100
FT ICR) exact mass calculated [M+H]+ calculated for MHz): δ 172.6, 142.9, 140.9, 137.1, 134.7, 133.2, 130.0, 129.8,
C22H19FNOS: 364.1166, found: 364.1163. HPLC analysis with 128.7, 128.2, 127.7, 127.6, 126.4, 124.9, 124.3, 57.6, 54.3.
Chiralpak IC column, 90:10 n‐hexane:2‐propanol, 1 mL/min, HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+ calculated
254 nm; minor enantiomer tR = 17.8 min, major enantiomer tR for C21H16BrClNOS: 442.9640, found: 442.9637. HPLC analysis
= 18.9 min.
(2 ,3 )‐3‐(4‐Chlorophenyl)‐7‐methyl‐2‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4m)
with Chiralpak IC column, 70:30 n‐hexane:2‐propanol, 1
mL/min, 254 nm; minor enantiomer tR = 10.5 min, major
enantiomer tR = 7.9 min.
S
R
17
White solid, 20.5 mg, 27% yield. mp 192.8‐194.0 °C. [α]D
=
Synthesis of N‐o‐nitrobenzyl‐1,5‐benzothiazepines (9)
+47.0 (c 0.52, CHCl3), 73% ee. 1H NMR (CDCl3, 600 MHz): δ 7.78 trans‐ or cis‐ 1,5‐Benzothiazepine 4a (33.1 mg, 0.1 mmol) was
(s, 1H), 7.59 (d, 1H, J = 7.8 Hz), 7.32‐7.25 (m, 5H), 7.09 (d, 1H, J dissolved in ethyl acetate (770 µL), then 1‐(iodomethyl)‐2‐
= 7.1 Hz), 7.02 (d, 2H, J = 8.5 Hz), 6.94 (s, 1H), 6.85 (d, 2H, J = nitrobenzene (52.6 mg, 0.2 mmol) and potassium carbonate
8.5 Hz), 4.89 (d, 1H, J = 6.5 Hz), 4.16 (d, 1H, J = 6.4 Hz), 2.40 (s, (27.6 mg, 0.2 mmol) were added and the mixture was stirred
3H). 13C NMR (CDCl3, 150 MHz): δ 171.6, 141.8, 140.9, 136.0, at 85°C for 48 hours. After completion, the mixture was cooled
134.8, 133.4, 133.2, 132.1, 130.1, 128.7, 128.1, 127.59, 127.57, to room temperature and diluted with ethyl acetate. The
125.3, 123.8, 61.0, 50.5, 21.2. HRMS (MALDI‐FT ICR) exact aqueous phase was extracted with ethyl acetate (50 mL x 3),
mass calculated [M+H]+ calculated for C22H19ClNOS: 380.0870, then the combined organic phases were washed with
found: 380.0866. HPLC analysis with Chiralpak IC column, 95:5 saturated aqueous NaCl and dried over anhydrous Na2SO4.
n‐hexane:2‐propanol, 1 mL/min, 254 nm; minor enantiomer tR After concentration under reduced pressure, the crude
= 21.6 min, major enantiomer tR = 13.8 min.
(2 ,3 )‐3‐(4‐Chlorophenyl)‐7‐methyl‐2‐phenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4m)
mixture was purified by flash chromatography (hexane/ethyl
acetate 100/0 ‐ 90/10) to give pure trans‐ or cis‐
(2 ,3 )‐5‐(2‐Nitrobenzyl)‐2,3‐diphenyl‐2,3‐
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (trans‐9)
R
R
9
9.
R R
20
White solid, 16.7 mg, 22% yield. mp 180.6 °C (Decomp.). [α]D
1
22
= ‐518.8 (c 0.98, CHCl3), 95% ee. H NMR (CDCl3, 400 MHz): δ White solid, 34.5 mg, 74% yield. mp 188.8‐191.5 °C. [α]D = ‐
7.71 (s, 1H), 7.51 (d, 1H, J = 7.8 Hz), 7.12‐7.09 (m, 8H), 7.03 (s, 466.5 (c 0.78, CHCl3), 91% ee. 1H NMR (CDCl3, 400 MHz): δ 7.96
1H), 6.94‐6.91 (m, 2H), 4.77 (d, 1H, J = 12.2 Hz), 4.13 (d, 1H, J = (d, 1H, J = 8.2 Hz), 7.90 (d, 1H, J = 7.8 Hz), 7.62‐7.51 (m, 3H),
12.2 Hz), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 172.4, 7.42 (d, 1H, J = 8.0 Hz), 7.37 (t, 1H, J = 7.8 Hz), 7.31 (t, 1H, J =
142.6, 141.3, 141.1, 136.0, 134.1, 133.2, 131.2, 128.5, 128.1, 7.5 Hz), 7.23‐7.21 (m, 2H), 7.16‐7.08 (m, 6H), 6.91‐6.88 (m,
128.0, 127.5, 126.3, 124.1, 122.8, 58.2, 53.8, 21.3. HRMS 2H), 5.54 and 5.50 (ABq, 2H, J = 17.2 Hz), 4.95 (d, 1H, J = 12.2
(MALDI‐FT ICR) exact mass calculated [M+H]+ calculated for Hz), 4.28 (d, 1H, J = 12.2 Hz). 13C NMR (CDCl3, 100 MHz): δ
C22H19ClNOS: 380.0870, found: 380.0866. HPLC analysis with 172.3, 148.0, 145.9, 142.2, 137.0, 135.5, 133.6, 132.6, 131.0,
Chiralpak IC column, 80:20 n‐hexane:2‐propanol, 1 mL/min, 129.9, 129.7, 128.4, 127.99, 127.95, 127.5, 127.4, 127.0, 126.3,
254 nm; minor enantiomer tR = 8.4 min, major enantiomer tR = 124.8, 123.5, 57.9, 54.8, 49.9. HRMS (MALDI‐FT ICR) exact
10.9 min.
(2 ,3 )‐7‐Bromo‐3‐(4‐chlorophenyl)‐2‐phenyl‐2,3‐
mass calculated [M+H]+ calculated for C28H22N2KO3S: 505.0983,
found: 505.0978. HPLC analysis with Chiralpak AD column,
S
R
dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (4n)
70:30 n‐hexane:2‐propanol,
enantiomer tR = 22.6 min, major enantiomer tR = 27.7 min.
,3 )‐5‐(2‐Nitrobenzyl)‐2,3‐diphenyl‐2,3‐
1 mL/min, 254 nm; minor
25
White solid, 32.9 mg, 37% yield. mp 60.4‐65.4 °C. [α]D
=
1
+23.38 (c 0.61, CHCl3), 72% ee. H NMR (CDCl3, 400 MHz): δ (2
S R
8.32 (bs, 1H), 7.57 (d, 1H, J = 8.2 Hz), 7.42‐7.39 (dd, 1H, J = 8.3, dihydrobenzo[b][1,4]thiazepin‐4(5H)‐one (cis‐9)
24
1.9), 7.314‐7.309 (m, 1H), 7.22‐7.21 (m, 4H), 7.15 (d, 1H, J = 7.4 White solid, 34.1 mg, 73% yield. mp 142.8‐146.4 °C. [α]D = ‐
1
Hz), 7.10 (m, 2H), 6.93 (d, 2H, J = 7.5 Hz), 4.92 (d, 1H, J = 6.3 118.1 (c 0.74, CHCl3), 74% ee. H NMR (CDCl3, 400 MHz): δ
Hz), 4.16 (d, 1H, J = 6.3 Hz). 13C NMR (CDCl3, 75 MHz): δ 172.0, 8.04‐8.00 (m, 2H), 7.78‐7.75 (dd, 1H, J = 7.6, 1.5 Hz), 7.63‐7.59
136.0, 134.6, 134.4, 134.0, 131.4, 130.6, 129.6, 129.4, 128.9, (td, 1H, J = 7.6, 1.2 Hz), 7.50‐7.46 (m, 1H), 7.44‐7.39 (m, 1H),
128.3, 127.7, 127.4, 126.2, 123.9, 60.6, 50.9. HRMS (MALDI‐FT 7.37‐7.29 (m, 3H), 7.25‐7.22 (m, 2H), 7.17‐7.15 (m, 2H), 7.13‐
ICR) exact mass calculated [M+H]+ calculated for 7.10 (m, 1H), 7.05‐7.01 (m, 2H), 6.92‐6.90 (m, 2H), 5.61 and
C21H16BrClNOS: 442.9640, found: 442.9637. HPLC analysis with 5.57 (ABq, 2H, J = 17.3 Hz), 4.87 (d, 1H, J = 6.8 Hz) 4.29 (d, 1H, J
Chiralpak IE3 column, 70:30 n‐hexane:2‐propanol, 0.6 mL/min, = 6.8 Hz). 13C NMR (CDCl3, 100 MHz): δ 171.1, 148.1, 146.8,
220 nm; minor enantiomer tR = 17.1 min, major enantiomer tR 135.8, 134.6, 133.6, 133.0, 130.8, 130.7, 130.1, 129.83, 129.79,
= 10.7 min.
128.6, 128.0, 127.5, 127.41, 127.39, 125.0, 123.6, 61.1, 51.6,
50.5. HRMS (MALDI‐FT ICR) exact mass calculated [M+H]+
calculated for C28H22N2KO3S: 505.0983, found: 505.0978. HPLC
10 | J. Name., 2012, 00, 1‐3
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Organic & Biomolecular Chemistry
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Journal Name
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8
9
S. Meninno, C. Volpe and A. Lattanzi, Chem. Eur. J., 2017, 23,
View Article Online
analysis with Chiralpak IC column, 95:5 n‐hexane:2‐propanol, 1
mL/min, 220 nm; minor enantiomer tR = 39.8 min, major
enantiomer tR = 25.5 min.
4547.
DOI: 10.1039/C8OB01988F
See the Electronic Supporting Information for details.
10 (a) H. Duddeck, M. Kaiser and A. Lévai, Liebigs Ann. Chem.,
1985, 869; b) G. Kaupp and E. Ringer, Chem. Ber., 1986, 119
1525.
,
Conflicts of interest
There are no conflicts to declare.
11 For selected examples, see: (a) S. Meninno, G. Croce and A.
Lattanzi, Org. Lett., 2013, 15, 3436; (b) S. Meninno, J.
Overgaard and A. Lattanzi, Synthesis, 2017, 49, 1509; (c) S.
Meninno, A. Roselli, A. Capobianco, J. Overgaard and A.
Lattanzi, Org. Lett, 2017, 19, 5030.
12 The reaction carried out on aliphatic substituted
,‐
Acknowledgements
unsaturated acyl pyrazole (R1 = Me, R2 = n‐propyl), followed
by treatment with TsOH, gave the expected product in less
than 30% yield after 7 days.
We thank MIUR, the Regione Campania (POR CAMPANIA FESR
2007/2013 O.O. 2 .1, CUP B46D14002660009) for the FT‐ICR
mass spectrometer facilities and Farma‐BioNet (CUP
B25C13000230007) and the “Centro di Tecnologie Integrate
per la Salute” (CITIS, Project PONa3‐00138), Università di
Salerno, for the 600 MHz NMR facilities, for financial support.
We thank Dr. P. Iannece and Dr. P. Oliva for assistance with
mass spectra and NMR analyses.
13 2‐Aminothiophenols undergo easy oxidation by molecular
oxygen to the corresponding disulfides. The degree of
oxidation is expected to be higher for electron‐rich aryl
thiols, which in turn affects the yield of compounds 4. See: A.
Lattanzi In Comprehensive Organic Synthesis II; P. Knochel, G.
A. Molander, Eds.; Elsevier: Oxford, 2014; Vol. 7, pp 837. See
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14 B.‐L. Zhao and D.‐M. Du, Org. Biomol. Chem., 2014, 12, 1585.
15 The choice of C6D6 as the solvent instead of toluene‐d8 was
dictated by the necessity to have an aromatic solvent
Notes and references
showing the 69 ppm region as free as possible of solvent
signals to facilitate the analysis.
1
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