Regio- and stereocontrolled synthesis of novel 3-sulfonamido-2,3,4,5- tetrahydro-1,5-benzothiazepines from 2-(bromomethyl)- or 2-(sulfonyloxymethyl) aziridines

Article abstract of DOI:10.1039/b804246m

2-(Bromomethyl)-1-sulfonylaziridines were converted into novel 3-sulfonamido-2,3,4,5-tetrahydro-1,5-benzothiazepines upon treatment with 2-aminothiophenol in THF in the presence of K₂CO₃. Starting from 3-substituted 2-(sulfonyloxymet

Full text of DOI:10.1039/b804246m

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Regio- and stereocontrolled synthesis of novel
3-sulfonamido-2,3,4,5-tetrahydro-1,5-benzothiazepines from
2-(bromomethyl)- or 2-(sulfonyloxymethyl)aziridines†
Michinori Karikomi,‡ Matthias D’hooghe, Guido Verniest and Norbert De Kimpe*
Received 11th March 2008, Accepted 12th March 2008
First published as an Advance Article on the web 16th April 2008
DOI: 10.1039/b804246m
2-(Bromomethyl)-1-sulfonylaziridines were converted into
novel 3-sulfonamido-2,3,4,5-tetrahydro-1,5-benzothiazepi-
nes upon treatment with 2-aminothiophenol in THF in
the presence of K2CO3. Starting from 3-substituted 2-
(sulfonyloxymethyl)aziridines, a regio- and stereocontrolled
synthesis of trans-2-phenyl- and trans-4-(phenyl or propyl)-
3-sulfonamido-2,3,4,5-tetrahydro-1,5-benzothiazepines was
developed in good yields via two different reaction pathways,
depending on the nature of the sulfonyloxy group.
Also trans-3-substituted 2-(sulfonyloxymethyl)aziridines were
prepared as substrates for the synthesis of 3-amino-1,5-
benzothiazepines. Aziridination of allylic alcohols 3 by treatment
with 1.1 equiv of chloramine-T trihydrate9 in acetonitrile in
the presence of 0.1 equiv of phenyltrimethylammonium bro-
mide (PTAB) afforded the corresponding 2-(hydroxymethyl)-1-
tosylaziridines, which were subsequently sulfonylated upon reac-
tion with 1 equiv of tosyl or mesyl chloride in dichloromethane
in the presence of Et3N at room temperature towards 2-
(sulfonyloxymethyl)aziridines 4a–c (Scheme 2).
1,5-Benzothiazepines1 comprise an important class of heterocycles
due to the existence of several biologically active representa-
tives such as Diltiazem2 and Thiazesim.3 Also their 3-amino
derivatives have received considerable interest, especially from
a medicinal point of view.4 Whereas several approaches are
available towards the synthesis of 1,5-benzothiazepines,5 the
preparation of the 3-amino-1,5-benzothiazepine skeleton remains
an unexplored field of chemistry.4a In continuation of our interest
in 2-(halomethyl)aziridines6 and 2-(halomethyl)oxiranes7 as three-
carbon building blocks in organic synthesis, their reactivity with
regard to 2-aminothiophenol was investigated in the present
report.
2-(Bromomethyl)aziridines 2a–c were prepared in high yields
starting from allylsulfonamides 1 upon treatment with 1 equiv
of bromine in dichloromethane, followed by ring closure of the
resulting intermediate 2,3-dihalopropylsulfonamides by means of
aqueous sodium hydroxide in ethanol at room temperature for 0.3
to 15 hours (Scheme 1).8
Scheme 2
Treatment of 2-(bromomethyl)aziridines 2 with 1.2 equiv of 2-
aminothiophenol in THF in the presence of potassium carbonate
provided an easy access to 3-sulfonamido-2,3,4,5-tetrahydro-
1,5-benzothiazepines 6 after reflux for 5 hours (Scheme 3).
Starting from 1-arenesulfonylaziridines 2a–b, the presence of the
corresponding acyclic intermediates 5 could be confirmed by
1
means of H NMR spectroscopy, implying that the formation
of benzothiazepines 6 proceeds through initial attack of the
sulfur atom of 2-aminothiophenol onto the less hindered aziridine
carbon atom in substrates 2, followed by nucleophilic displacement
of bromide by the amino group (Scheme 3). Benzothiazepine
6a was obtained as a 5 : 2 mixed crystal with toluene upon
recrystallization from toluene.10
Scheme 1
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
University, Belgium. E-mail: norbert.dekimpe@UGent.be; Fax: +32 9 264
6243; Tel: +32 9 264 5951
† Electronic supplementary information (ESI) available: Experimen-
tal details and characterisation data for compounds 6–8. See DOI:
10.1039/b804246m
‡ On leave from Utsunomiya University, Department of Applied Chem-
istry, Faculty of Engineering, Japan.
Scheme 3
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Scheme 4
This approach was further elaborated towards trans-
disubstituted 2,3,4,5-tetrahydro-1,5-benzothiazepines 7 and 8
starting from trans-2,3-disubstituted aziridines 4. Surprisingly,
treatment of 2-(sulfonyloxymethyl)aziridines 4a and 4b with 1.1
equiv of 2-aminothiophenol in THF in the presence of 1.1
equiv of K2CO3 afforded 4-substituted 3-aminobenzothiazepines
7a,b, whereas aziridine 4c was transformed into 2-phenyl-3-
aminobenzothiazepine 8 applying the same reaction conditions
(Scheme 4). In both cases, no traces of the other regioisomers
were identified in the reaction mixtures.
Fig. 1
compounds 7 and of 9.2 Hz between H-2 and H-3 for compound
8.
Apparently, tosylates 4a and 4b are more reactive as com-
pared to mesylate 4c. Indeed, 2-(tosyloxymethyl)aziridines 4a,b
undergo initial nucleophilic displacement of the tosyloxy group
by means of 2-aminothiophenol towards intermediate aziridines
9, which cyclise spontaneously to afford 4-substituted 3-
aminobenzothiazepines 7 (pathway a, Scheme 5). On the other
hand, 2-(mesyloxymethyl)aziridine 4c suffers from initial ring
opening by 2-aminothiophenol at the benzylic position towards
acyclic intermediate 10, followed by cyclization upon nucleophilic
substitution of the mesyloxy moiety (pathway b, Scheme 5).
In conclusion, a highly efficient synthesis of 3-sulfonamido-
2,3,4,5-tetrahydro-1,5-benzothiazepines has been accomplished
starting from easily accessible aziridine substrates. Furthermore,
this approach can be applied successfully for the regio- and
stereocontrolled synthesis of trans-2- or trans-4-substituted 3-
sulfonamido-2,3,4,5-tetrahydro-1,5-benzothiazepines by choice of
the appropriate leaving group.
Notes and references
1 For reviews on 1,5-benzothiazepines, see: (a) A. Levai, J. Heterocycl.
Chem., 2000, 37, 199; (b) A. Levai, Pharmazie, 1999, 54, 719.
2 M. Chaffman and R. N. Brogden, Drugs, 1985, 29, 387.
3 S. Y. Dike, D. H. Ner and A. Kumar, Bioorg. Med. Chem. Lett., 1991,
1, 383.
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Chem., 1985, 28, 1517; (b) K. Bajaj, V. K. Srivastava, S. Lata, R.
Chandra and A. Kumar, Indian J. Chem., Sect. B, 2003, 42, 1723.
5 (a) M. M. Baag, M. K. Sahoo, V. G. Puranik and N. P. Argade,
Synthesis, 2007, 457; (b) O. Prakash, A. Kumar, A. Sadana, R. Prakash,
S. P. Singh, R. M. Claramunt, D. Sanz, I. Alkorta and J. Elguero,
Tetrahedron, 2005, 61, 6642; (c) M. Sindler-Kulyk and D. C. Neckers,
J. Org. Chem., 1982, 47, 4914.
6 (a) M. Karikomi and N. De Kimpe, Tetrahedron Lett., 2000, 41, 10295;
(b) M. D’hooghe, A. Waterinckx and N. De Kimpe, J. Org. Chem.,
2005, 70, 227; (c) M. D’hooghe, T. Vanlangendonck, K. W. To¨rnroos
and N. De Kimpe, J. Org. Chem., 2006, 71, 4678; (d) M. D’hooghe and
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7 M. Karikomi, S. Yamori and T. Toda, Heterocycles, 1993, 35, 619.
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Scheme 5
The structural identity of benzothiazepines 7 and 8 was
confirmed by means of detailed one- and two-dimensional NMR
spectroscopic analysis. For example, the presence of cross-peaks
in the COSY-spectrum of 4-phenylbenzothiazepine 7a between
the NH and the C-4 benzylic proton supported the assigned
substitution pattern (Fig. 1). A NOE-effect of 3.8% between the
same two protons proved this assignment to be correct. Similarly,
cross-peaks between the NH proton and the adjacent methylene
protons supported the structure of benzothiazepine 8 bearing a
phenyl group at the 2-position. For both benzothiazepines 7 and
8, the relative configuration was assigned as trans based on the
large vicinal coupling constants of 9.6 Hz between H-3 and H-4 for
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Catal. Commun., 2005, 6, 221; (j) S. L. Jain, J. K. Joseph and B. Sain,
J. Mol. Catal. A, 2006, 256, 16; (k) S. L. Jain and B. Sain, Green Chem.,
2006, 8, 943.
1.0 Hz); 6.85 (1H, td, J = 7.9, 1.0 Hz); 7.10 (1H, td, J = 7.9, 1.0 Hz);
7.36 (1H, dd, J = 7.6, 1.3 Hz); 7.56 (3H, m); 7.96 (2H, m). 13C NMR
(68 MHz, CDCl3): d 37.0, 51.4, 52.0, 120.6, 122.1, 125.1, 126.9, 128.5,
129.3, 132.8, 132.9, 141.6, 151.3. IR (neat, cm−1): m = 3320, 1588, 1475,
1323. MS (70 eV): m/z (%): 320 (M+, 5); 243 (39); 203 (100). Anal.
Calcd for C15H16N2O2S2·0.4C7H8: C 59.84, H 5.42, N 7.84. Found: C
58.86, H 5.65, N 7.76%.
10 Spectroscopic data for 3-aminobenzothiazepine 6a. 1H NMR
(270 MHz, CDCl3): d 2.60 (1H, ddd, J = 14.5, 4.9, 1.3 Hz); 2.75 (1H,
dd, J = 14.5, 2.6 Hz); 2.93 (1H, dd, J = 13.9, 1.6 Hz); 3.31 (1H, m); 3.64
(1H, m); 3.91 (1H, m); 6.00 (1H, d, J = 10.2 Hz); 6.77 (1H, dd, J = 7.9,
1904 | Org. Biomol. Chem., 2008, 6, 1902–1904
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