Cyclic sulfenamide: Versatile template for the synthesis of 1,4-benzothiazepines

Article abstract of DOI:10.1016/j.tetlet.2011.07.148

Two efficient syntheses of 1,4-benzothiazepines, substituted in the positions 2 and 5, have been achieved either by a ring expansion reaction of cyclic sulfenamides with methylpropiolate or tosylacetylene catalyzed by pyridine, via a postulated allenolate

Full text of DOI:10.1016/j.tetlet.2011.07.148

Tetrahedron Letters 52 (2011) 6321–6324
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Tetrahedron Letters
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Cyclic sulfenamide: versatile template for the synthesis of 1,4-benzothiazepines
⇑
Cédric Spitz, Vincent Reboul , Patrick Metzner
Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038, ENSICAEN & Université de Caen, 14050 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2011
Revised 22 July 2011
Accepted 27 July 2011
Available online 21 September 2011
Two efficient syntheses of 1,4-benzothiazepines, substituted in the positions 2 and 5, have been achieved
either by a ring expansion reaction of cyclic sulfenamides with methylpropiolate or tosylacetylene cata-
lyzed by pyridine, via a postulated allenolate intermediate; or by an
a-sulfenylation reaction promoted
by diethylamine and a subsequent acid catalyzed condensation reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sulfenamide
Pyridine
Methylpropiolate
Sulfenylation
1,4-Benzothiazepine
Among N,S-heterocycles, 2,3-dihydro-1,4-benzothiazepines
have emerged as privileged structures with cardioprotective effect.
For instance, two compounds, S107 and K201, are currently in a
phase II human clinical trial for the treatment of sudden cardiac
death and myocardial infarction (Scheme 1).1
Substitutions in the positions 2, 3, or 5 in these heterocycles
provide new opportunities for drug discoveries. In this context,
the development of novel synthetic strategies, which fulfill the
criteria of efficiency, selectivity, and atom economy, is highly
desirable.
Our initial tests began with phosphines9 as nucleophilic
catalysts (Table 1, entries 2 and 3). Unfortunately, in acetonitrile,
1,3-benzothiazines 4a were formed as the major products. A
4NH
S1
O
1,4-benzothiazepine
O
N
O
N
N
Bn
We report here two distinct but complementary approaches to
synthesize 1,4-benzothiazepines2 2 or 3, respectively, substituted
by an ester or an alkyl group (Scheme 2). The first synthesis con-
sists in reacting, in a single step, allenolate A (derived from the
Michael addition of neutral organic nucleophiles to methyl propi-
S
S
K201or JTV519
S107
Scheme 1. Structure of 1,4-benzothiazepines.
olate) with sulfenamide3 1. In the second pathway, an
a-sulfenyla-
tion reaction involving the trapping of enamine B (derived from an
amine and an aldehyde) by sulfenamide 1, followed by an acid
catalyzed condensation reaction is used.
CO2Me
+
Nu
H
In the first approach, we initiated the project by screening for a
suitable nucleophile4 to catalyze the reaction between methylpro-
piolate5 and sulfenamide 1a (Table 1).
The main challenge in this reaction was to avoid as a side
reaction, the generation of acetylide C6 from the allenolate
intermediate A, which after reaction with sulfenamide 1 led to
1,3-benzothiazines7 4 via a domino process8 (Scheme 3 and Table
1,9d entry 1).
O
R1
EWG
OMe
allenolate (A)
Nu
N
2
3
R1
S
EWG
N
S
CO2Me
Ts
R2
NR2
R1
1)
N
1
enamine (B)
2) H+ (cat)
(R2 = alkyl)
R2
S
⇑
Corresponding author.
E-mail address: vincent.reboul@ensicaen.fr (V. Reboul).
Scheme 2. Two Strategies for the Synthesis of 1,4-benzothiazepines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.148

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C. Spitz et al. / Tetrahedron Letters 52 (2011) 6321–6324
Table 1
Optimization of reaction conditions for the benzothiazepine synthesis
Ts
R
Ts
R
N
cat.
N
Ts
and/or
and/or
N
+
R
N Ts
solvent
S
S
R
(2 eq)
S
S
R = CO2Me or Ts
2a (R = CO2Me)
5a (R = Ts)
(Z)-4a (R = CO2Me)
(Z)-6a (R = Ts)
(E)-4a (R = CO2Me)
(E)-6a (R = Ts)
1a
Entry
R
Catalyst (mol %)
Solvent (0.1 M)
Temp (°C)
Time (h)
0.5
% Conversiona(% yield)b
Ratioa 2a/Z-4a/E-4a
Ratioa 5a/Z-6a/E-6a
1
2
3
4
5
6
7
8
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CsF (10)
DPPP (10)
PPh3 (20)
DABCO (20)
DMAP (20)
Pyridine (20)
Pyridine (20)
Pyridine (20)
Pyridine (30)
Pyridine (50)
Pyridine (50)
Pyridine (100)
Pyridine (50)
Pyridine (50)
Pyridine (25+25)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DME
DME
DME
DME
rt
80
rt
rt
rt
100 (4, 86)
0/87/13
15/65/20
0/84/16
18/71/11
17/72/11
22/58/20
55/37/8
51/39/10
100/0/0
100/0/0
100/0/0
100/0/0
—
—
—
—
—
—
—
—
—
—
—
—
—
2
0.5
1
0.5
24
24
18
24
72
100
100
100
100
78
90
91
67
24
rt
60
60
60
60
60
60
60
80
80
9
10
11
12
13
14
15
CO2Mec
CO2Me
CO2Me
Ts
Ts
Ts
40
24
93 (2a, 69)
100 (2a, 80)
78
DME
DME
DME
2
1
50/0/50
81/0/19
100/0/0
75
—
—
30 + 30d
86 (5a, 61)
a
b
c
Determined by 1H NMR on the crude product.
Isolated yields.
Slow addition of methyl propiolate for 2 h.
In minutes.
d
CO2Me
MeO2C
O
(2 eq)
Ts
R1
R1
MeO2C
acetylide (C)
pyridine
OMe
N
Nu
Ts
(50 mol %)
N
S
allenolate (A)
1
CO2Me
DME
60 °C, 24 h
Our Previous
Work (Ref 9d)
S
R1
2b: R1 = Ph, 78%
EWG
1b-d
N
2c: R1 = Cyclohexyl, 82%
2d: R1 = m-BrC6H4, 71%
S
CO2Me
4
Scheme 4. Synthesis of 1,4-benzothiazepines 2b–d.
Scheme 3. Synthesis of 1,3-benzothiazines.
(Table 1, entry 13). It is worth mentioning that the reaction was
much faster as before (2 h instead of 40 h). On the other hand,
when the reaction was performed at 80 °C (entry 14), the amount
of the expected 1,4-benzothiazepine 5a increased to 81% (with 75%
of conversion). The best ratio in favor of 5a was obtained by two
sequential additions of 0.25 equiv of pyridine and 1 equiv of
tosylacetylene, after 30 min of reaction (entry 15). Using these
conditions, 1,3-benzothiazine 6a was not detected in the crude
mixture and 1,4-benzothiazepine 5a was isolated in 61% yield.
Reactions between various sulfenamides 1b–d and tosylacety-
lene were next examined (Scheme 5) and the corresponding
benzothiazepines 5b–d were obtained in each case in moderate
to good yields (51–75%).14
similar result was obtained using DABCO10 and DMAP11 (entries 4
and 5) as catalysts. At room temperature, it was found that pyri-
dine (20 mol %) catalyzed the desired ring expansion although with
low efficiency (22/58/20 ratio, entry 6). The formation of 1,4-ben-
zothiazepine 2a was enhanced by heating at 60 °C (entries 7 and
8). Furthermore, a great improvement was observed when the
reaction was performed in 1,2-dimethoxyethane (DME) instead
of acetonitrile since only the expected compound 2a was obtained
(entry 9). After some non benefit experiments (entry 10: slow
addition of methyl propiolate), variation of the amount of pyridine
was tested. The best compromise between the yield and catalyst
loading was established at 50% loading of catalyst for 69% yield
(entry 11). It is however, worth mentioning that a total conversion
and 80% isolated yield could be obtained with 1 equiv of pyridine
(entry 12).
With these optimized conditions in hand (Table 1, entry 11),
various aryl and alkylsulfenamides were tested. Using sulfena-
mides 1b–d, expected 1,4-benzothiazepines 2b–d (Scheme 4) were
isolated in good yields (71-82%).13
We then explored the use of another electron-deficient alkyne,
that is, tosylacetylene. This compound should allow further trans-
formations and functionalization of the vinyl sulfone group.12
Using our previous optimized conditions, an equal amount of
1,4-benzothiazepine 5a and 1,3-benzothiazine (E)-6a was obtained
Ts
(1+1 eq)
pyridine
Ts
R1
R1
N
Ts
(25 + 25 mol %)
N
S
DME, 80 °C
30 min + 30 min
Ts
S
5b: R1 = Ph, 75%
1b-d
5c: R1 = Cyclohexyl, 51%
5d: R1 = m-BrC6H4, 65%
Scheme 5. Synthesis of 1,4-benzothiazepines 5b–d by reaction of tosylacetylene
with cyclic sulfenamides.

C. Spitz et al. / Tetrahedron Letters 52 (2011) 6321–6324
6323
As plausible mechanism, the zwitterion A,15 chelated by DME,
R1
S
R2
R1
TsOH.H2O
(10 mol%)
NHR2
S
could attack the electrophilic sulfur atom of sulfenamide 1 to lead
to the corresponding zwitterion D which in turn cyclizes after an
addition/elimination reaction (Scheme 6) into the final 1,4-
benzothiazepine.
O
N
H
toluene, 60 °C
2 h
i-Pr
7a-d or 9
i-Pr
13 (R1= i-Pr; R2= Boc): 84%
4a (R1= i-Pr; R2= Ts ): 94%
4b (R1= Ph; R2= Ts ): 83%
4c (R1= Cy; R2= Ts ): 75%
As the previous methodology cannot be applied to an acetylenic
species bearing an alkyl group instead of the EWG (COOEt, Tos), a
second pathway in two steps was envisioned to access
benzothiazepines substituted by an alkyl group in the 2-position.16
Instead of trapping the sulfenamide 1 by an allenolate, we chose an
enamine, formed in situ by the reaction between isovaleraldehyde
and an amine. This sulfenylation reaction17 was tested with com-
pound 1d and various secondary amines (Scheme 7). The best yield
in sulfide 7d18 (90%) was obtained with 30% M of diethylamine in
CH3CN at rt.
These conditions were next applied to other sulfenamides 1a–c/
8a (Table 2, entries 1–4) and in all cases the corresponding prod-
ucts were obtained in good yields. On the other hand, using prop-
anal instead of isovaleraldehyde (entries 5–8), afforded low yields,
while no reaction occurred using phenylacetaldehyde (entry 9) or
acetophenone (entry 10).
4d (R1= 3-Br-C6H4; R2= Ts ): 80%
Scheme 8. TsOH catalyzed condensation reactions.
H C
CHO
1)
3
R1
S
R1
N
Ts
HNEt2 (cat)
MeCN, rt, 22 h
N
Ts
2) TsOH.H2O (cat)
toluene
S
CH3
60 °C, 2 h
14a (R1= i-Pr): 25%
14b (R1= Ph): 30%
1a-d
14c (R1= Cy): 30%
2
14d (R1= 3-Br-C6H4): 32%
CO2Me
N
O
OMe
Scheme 9. One-pot reactions.
R1
Ts
N
S
N
The cyclization reaction was next explored and first tested with
the N-Boc sulfide 9a in the presence of large excess of TFA. Com-
pound 13 was obtained in a moderate yield (63%) due to the pres-
ence of N-deprotected product. To avoid this side reaction, 10% M
of pTSA was chosen.20 Under these conditions, the expected ben-
zothiazepine 13 was isolated in 84% yield. This reaction was next
extended to other sulfides 7a–d (Scheme 8) to afford the corre-
sponding 1,4-benzothiazepines 4a–d in very good yields.21
As low yields were obtained in the case of aldehydes 10a–d, the
sequential one-pot reaction was investigated without the interme-
diate purification. 1,4-Benzothiazepines 14 were obtained in mod-
erate overall yields (Scheme 9).22
In summary, we have defined conditions, which allow to trap an
intermediate allenolate or enamine with a sulfenamide, respec-
tively, using a catalytic amount of pyridine or diethylamine. This
methodology provides a catalytic access to the original 2-substi-
tuted 1,4-benzothiazepines with high efficiency and atom economy.
N
1
allenolate (A)
MeO2C
D
Scheme 6. Proposed mechanism for the formation of 1,4-benzothiazepines 2.
Br
O
NHTs
S
Br
O
H
30 mol% amine
H
MeCN, rt, 16 h
N
Ts
S
Proline: 22%
1d
Piperidine: 73%
7d
Diethylamine: 90%
Scheme 7. Catalyst screening for the
a-sulfenylation reaction of isovaleraldehyde.
Acknowledgments
Table 2
Diethylamine catalyzed
a
-sulfenylation reactions of carbonyl compounds19
We thank the ‘‘Crunch’’ Network (‘‘Centre de Recherche Uni-
versitaire Normand de Chimie’’), the ‘‘Région Basse-Normandie’’,
the ‘‘Ministère de la Recherche’’, CNRS (Centre National de la
Recherche Scientifique), and the European Union (FEDER funding)
for financial support. We would also like to thank A.–C. Gaumont
for carefully reading the manuscript and for helpful comments.
O
R3
NHR2
S
R1
R1
R4
O
HNEt2 (30 mol%)
N R2
R4
S
MeCN, rt, 16 h
R3
1a-d or 8a
Entry
SM
R1
R2
R3
R4
Product
% Yielda
Supplementary data
1
1b
1a
1c
8a
1a
1c
1b
1d
1a
1a
Ph
Ts
Ts
Ts
Boc
Ts
Ts
Ts
Ts
Ts
Ts
i-Pr
i-Pr
i-Pr
i-Pr
CH3
CH3
CH3
CH3
Ph
H
H
H
H
H
H
H
H
H
Ph
7b
7a
7c
9a
10a
10c
10b
10d
11
73
77
65
64
45
32
34
37
0
2b
3b
4b
5
i-Pr
Supplementary data (1H and 13C spectra) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.148.
Cyc
i-Pr
i-Pr
6
7
8
9
Cyc
Ph
3-Br-C6H4
i-Pr
References and notes
1. (a) Kaneko, N.; Matsuda, R.; Hata, Y.; Shimamoto, K. Curr. Clin. Pharm. 2009, 4,
126; (b) Thevis, M.; Beuck, S.; Thomas, A.; Kohler, M.; Schlorer, N.; Vajiala, I.;
Schanzer, W. Drug Test Anal. 2009, 1, 32; (c) Toischer, K.; Lehnart, S. E.;
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Kaneko, N.; Loughrey, C. M.; Smith, G. L.; Hasenfuss, G.; Seider, T. Basic Res.
Cardiol. 2010, 105, 279.
10
i-Pr
H
12
0
a
b
c
Isolated yields.
Reaction performed at 60 °C.
Cy = cyclohexyl.

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C. Spitz et al. / Tetrahedron Letters 52 (2011) 6321–6324
2. For recent report on the synthesis of 1,4-benzothiazepines ring: (a) Zeng, F.;
Alper, H. Org. Lett. 2010, 12, 5567; (b) Rujirawanich, J.; Gallagher, T. Org. Lett.
2009, 11, 5494.
3. Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem.
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toluenesulfonyl-acetylene (21.6 lL, 0.12 mmol, 1 equiv) were added. After
30 min, the solvent was evaporated under reduced pressure. The crude product
was purified by column chromatography on silica gel using dichloromethane
as the eluent to afford the corresponding benzothiazepine 5b as a white solid
(49 mg, 75%).
4. The Michael addition of neutral organic nucleophiles to electron-deficient
acetylenes generates zwitterions, which can be trapped by electrophiles to
afford a large variety of structures: (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu,
S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899; (b)
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15. (a) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Heidary, M.; Ng, S. W. Tetrahedron
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Kaneko, N.; Oosawa, T.; Sakai, T.; Oota, H. WO 9212148 1992.; (c) Corey, E. J.
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5. Among the activated
p
systems, dimethylacetylene-dicarboxylate (DMAD) is
17. (a) Kumamoto, T.; Kobayashi, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1972, 45,
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18. 7d was obtained as a 1:1 mixture of two diastereoisomers.
19. Typical procedure for the preparation of aldehyde 7 (7a as example): A mixture of
isovaleraldehyde (2 equiv) and diethylamine (0.3 equiv) in CH3CN (1 mL for
0.10 mmol of isovaleraldehyde) was stirred for 5 min at room temperature. A
solution of sulfenamide 1a (100 mg, 0.3 mmol, 1 equiv) in CH3CN (1 mL) was
added and the mixture was stirred overnight at room temperature. After
evaporation of the solvent under reduced pressure, the crude aldehyde was
purified by column chromatography on silica gel using pentane/Et2O (6/4) as
the eluent to afford benzothiazepine 7a as a yellow oil (97 mg, 77%) as a 50/50
mixture of two diastereoisomers.
the most employed. On the other hand, only a few examples rely on the use of
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G.; García-Tellado, F. Angew. Chem., Int. Ed. 2009, 48, 2090; (c) Liu, W.; Jiang, H.;
Zhu, S. Synlett 2009, 3295; (d) Tejedor, D.; Santos-Expósito, A.; Méndez-Abt, G.;
Ruiz-Pérez, C.; García-Tellado, F. Synlett 2009, 1223; (e) Liu, H.; Zhang, Q.;
Wang, L.; Tong, X. Chem. Commun. 2010, 312; (f) Liu, H.; Zhang, Q.; Wang, L.;
Tong, X. Chem. Eur. J. 2010, 16, 1968.
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Gonzalez-Platas, J. Org. Lett. 2001, 3, 1905.
7. Spitz, C.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Reboul, V.; Metzner, P. J.
Org. Chem. 2009, 74, 3936.
8. Tejedor, D.; López-Tosco, S.; Méndez-Abt, G.; García-Tellado, F. Eur. J. Org. Chem.
2010, 33.
9. Phosphines as catalyst: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535;
(b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035; (c) Ye, L.-W.;
Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 1140; (d) Spitz, C.; Lohier, J.-F.; Reboul,
V.; Metzner, P. Org. Lett. 2009, 11, 2776.
20. Davies, S. G.; Key, M.-S.; Rodriguez-Solla, H.; Sanganee, H. J.; Savory, E. D.;
Smith, A. D. Synlett 2003, 1659.
10. Tertiary amines as catalyst: (a) Tejedor, D.; García-Tellado, F.; Marrero-Tellado,
J. J.; Armas, P. Chem. Eur. J. 2003, 3122; (b) Zhao, G.-L.; Shi, M. J. Org. Chem.
2005, 9975; (c) Tejedor, D.; Santos-Expósito, A.; García-Tellado, F. Chem. Comm.
2006, 2667.
11. Pyridine as catalyst: (a) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3,
3495; (b) Li, C.-Q.; Shi, M. Org. Lett. 2003, 5, 4273; (f) Nair, V.; Devi, B. R.; Vidya,
N.; Menon, R. S.; Abhilash, N.; Rath, N. P. Tetrahedron Lett. 2004, 45, 3203; (c)
Nair, V.; Pillai, A. N.; Menon, R. S.; Suresh, E. Org. Lett. 2005, 7, 1189; (d) Nair, V.;
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21. Typical procedure for the preparation of benzothiazepine 4 (4a as example): To a
solution of aldehyde 7a (1 equiv) in toluene (1 mL for 0.10 mmol of 7a) was
added p-toluenesulfonic acid (0.1 equiv) and the mixture was stirred at 60 °C
for 2 h. Water (5 mL) was added and the aqueous layer was extracted with
diethyl ether (3 Â 10 mL). The combined organic layer was washed with brine,
dried over MgSO4, filtered, and the solvent removed under reduced pressure.
The crude product was purified by column chromatography on silica gel using
pentane/Et2O (9/1) as the eluent to afford the benzothiazepine 4a a colorless
oil (45 mg, 94%).
12. (a) Pandey, G.; Tiwari, K. N.; Puranik, V. G. Org. Lett. 2008, 10, 3611; (b)
Desrosiers, J. N.; Charette, A. B. Angew. Chem., Int. Ed. 2007, 46, 5955; (c) Noshi,
M. N.; El-Awa, A.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2007, 129, 11242.
13. Typical procedure for the preparation of benzothiazepine 2 (2c as example): To a
22. Typical procedure for the preparation of benzothiazepine 14 (14b as example): A
mixture of propionaldehyde (2 equiv) and diethylamine (0.3 equiv) in
acetonitrile (1 mL for 0.10 mmol of propionaldehyde) was stirred for 5 min
at room temperature. A solution of sulfenamide 1 (45 mg, 0.12 mmol, 1 equiv)
in acetonitrile (1 mL for 0.30 mmol of sulfenamide) was added and the mixture
was stirred at room temperature for 22 h. The solvent was evaporated under
reduced pressure to afford the crude aldehyde 10b, which was directly
dissolved (1 equiv) in toluene (1 mL for 0.10 mmol of 10b) and p-
toluenesulfonic acid (0.5 equiv) was added. The mixture was stirred at 60 °C
for 5 h. Water was added and the aqueous layer was extracted with diethyl
ether. The combined organic layer was washed with brine, dried over MgSO4,
filtered, and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography on silica gel using pentane/
Et2O (9/1) as the eluent to yield the corresponding benzothiazepine 14b as a
colorless oil (15 mg, 30%).
solution of sulfenamide 1c (45 mg, 0.12 mmol) and pyridine (4.8
0.06 mmol, 0.5 equiv) in DME (1.0 mL) was added methyl propiolate
(21.4 L, 0.24 mmol, 2 equiv) at 60 °C and the reaction mixture was stirred
lL,
l
at 60 °C for 24 h. The solvent was evaporated under reduced pressure. The
crude product was purified by column chromatography on silica gel using
dichloromethane/pentane (6/4) as the eluent to afford the corresponding
benzothiazepine 2c as a white solid (45 mg, 82%).
14. Typical procedure for the preparation of benzothiazepine 5 (5b as example): To
a
solution of sulfenamide 1b (44 mg, 0.12 mmol) and pyridine (2.4
0.06 mmol, 0.25 equiv) in DME (1 mL) was added p-toluenesulfonylacetylene
(21.6 L, 0.12 mmol, 1 equiv) at 80 °C. The reaction mixture was stirred at
80 °C for 30 min, then pyridine (2.4 L, 0.06 mmol, 0.25 equiv) and p-
lL,
l
l