New method for the synthesis of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones derivatives

Article abstract of DOI:10.1007/s10593-011-0872-3

A new method has been developed for the synthesis of 4,5-dihydro-1,4- benzothazepin-3(2H)ones derivatives by the acylation of N-substituted 2-chloro-5-nitrobenzylamines with acetylmercaptoacetyl chloride and α-acetylmercaptopropionyl chloride with subsequent removal of the S-acetyl protecting group and intramolecular nucleophilic substitution. The oxidation of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones to the corresponding 1,1-dioxides has been investigated.

Full text of DOI:10.1007/s10593-011-0872-3

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
NEW METHOD FOR THE SYNTHESIS OF 4,5-DIHYDRO-
1,4-BENZOTHIAZEPIN-3(2H)-ONES DERIVATIVES
T. A. Volovnenko1*, T. N. Tarasiuk1, Yu. M. Volovenko1, and T. M. Tkachuk1
A new method has been developed for the synthesis of 4,5-dihydro-1,4-benzothazepin-3(2H)ones
derivatives by the acylation of N-substituted 2-chloro-5-nitrobenzylamines with acetylmercaptoacetyl
chloride and α-acetylmercaptopropionyl chloride with subsequent removal of the S-acetyl protecting
group and intramolecular nucleophilic substitution. The oxidation of 4,5-dihydro-1,4-benzothiazepin-
3(2H)-ones to the corresponding 1,1-dioxides has been investigated.
Keywords: 4,5-dihydro-1,4-benzothiazepin-3(2H)-one 1,1-dioxides, 4,5-dihydro-1,4-benzothiazepin-
3(2H)-ones, acylation, intramolecular nucleophilic substitution.
Interest in thiazepins is explained by their high biological activity [1-4]. Since the 1990s, it has been
known that 4,5-dihydro-1,4-benzothiazepin-3(2H)-one derivatives can be used for treatment of neurological
dysfunctions, such as epilepsy [5, 6] and also as neuroprotective agents against stroke [6]. However in recent
times, the isomers of thiazepines derivatives of 4,5-dihydro-1,4-benzothiazepin-3(2H)-one have been little
studied, which is connected with the definite difficulty of their synthesis.
Review of the literature shows that several routes are available for the synthesis of 4,5-dihydro-
1,4-benzothiazepin-3(2H)-one derivatives. The first method is based on the multicomponent Ugi reaction [7].
Interaction of carbonyl compounds, amines, isonitriles, and chloracetic acids lead to products of the Ugi
reaction, which are alkylated with thiourea with subsequent treatment of the reaction mixture with potassium
hydroxide. A second route is based on alkylation of thiophenyl derivatives containing in the ortho position the
groups –CH2NH2, –C(R)NH–, –CONH2, α-halocarboxylic acids [8] and their esters [9, 10] with subsequent
intramolecular acylation. When α-halocarboxyl chlorides are used [11], acylation at the nitrogen atom first
occurs, and then intramolecular S-alkylation.
We proposed earlier [12] a method for the synthesis of 4,5-dihydro-1,4-benzothiazepin-3(2H)-one
derivatives based on nucleophilic substitution of the chlorine atom in N-alkyl-N-(2-chloro-5-nitro-
benzyl)amines with thioglycolic acid or its ethyl ester with subsequent intramolecular acylation.
In this paper an alternative method for the synthesis of 4,5-dihydro-1,4-benzothiazepin-3(2H)-one
derivatives is proposed. It is based on acylation of N-alkyl- and N-aryl-N-(2-chloro-5-nitrobenzyl)amines with
acetylmercaptoacetyl and α-acetylmercaptopropionyl chlorides with subsequent removal of the S-acetyl
protective group and intramolecular nucleophilic substitution of the chlorine atom.
_______
*To whom correspondence should be addressed, e-mail: tavolov@univ.kiev.ua.
1Taras Shevchenko Kyiv National University, 64 Volodymyrska St., Kyiv 01601, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1264-1269, August, 2001. Original
article submitted March 2, 2011.
0009-3122/11/4708-1043©2011 Springer Science+Business Media, Inc.
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Acylation of N-alkyl(aryl)-N-(2-chloro-5-nitrobenzyl)amines 1a-g with the acid chlorides 2a,b carried
out in mild conditions led to the formation of the S-acetyl-N-acyl derivatives 3a-l. Without isolation of the acyl
derivatives 3a-l, the reaction mixture was treated with a base which brought about deacetylation and formation
of the β-mercaptoamines 4a-l. It was not possible to isolate the latter because under the conditions of removing
the S-acetyl protecting group they underwent intramolecular nucleophilic substitution of the chlorine atom with
the mercapto group with formation of the 4,5-dihydro-1,4-benzothazepin-3(2H)-ones 5a-l.
O
R1
O
R1
O2N
O2N
Alk2NH
NHR
DMF, Et3N
50–60oC
Cl
N
R
+
S
Me
S
O
Cl
O
Cl
Me
1a–g
2a,b
3a–l
R
O
O2N
N
R1
O2N
O
N
S
R
SH
R1
Cl
4a–l
5a–l
1a, 3–5 a,h R = Me; 1b, 3–5 b,i R = Pr; 1c, 3–5 c,j R = MeOCH2CH2; 1d, 3–5 d,k R = Bn,
1e, 3–5 e,l R = PhCH2CH2; 1,3–5 f R = 3-MeOC6H4; g R = 4-MeC6H4;
2a, 3–5 a–g R1 = H; 2b, 3–5 h–l R1 = Me
The structures of the 4,5-dihydro-1,4-benzothazepin-3(2H)-ones 5a-g (R1 = H) were confirmed by
1
characteristic signals in their H NMR spectra: two singlets of the methylene protons at 4.04-4.16 (2-CH2) and
4.76-4.82 ppm (5-CH2) in compounds 5a-e, 4-25 (2-CH2) and 5.14-5.18 ppm (5-CH2) for compounds 5f,g, and
also the corresponding signals of the aromatic protons (Tables 1 and 2).
It is known [13] that the presence in a molecule of an asymmetric carbon atom can lead to the
disappearance of magnetic equivalence of neighboring protons or groups of protons. This occurs in compounds
5h-l (R = Me), in which atom C-2 is asymmetric and the protons of the methylene group 5-CH2 become
magnetically inequivalent and appear as two doublets in the regions of 4.9-4.28 and 5.23-5.37 ppm. In addition,
for compounds 5h-l there is a characteristic doublet at 1.32 ppm for the protons of the methyl group found at
position 2 of the ring, and a quartet of the protons of the methyne groups at 5.19-5.31 ppm.
1
A characteristic of the H NMR spectra of compounds 5d and 5k is the doublet of the H-6 proton at
7.87 ppm. The diamagnetic shift of this proton is explained by the magnetic-anisotropic phenyl ring of the
benzyl group in position 4 of the molecules. For the remaining compounds 5a-c and 5e-j,l, proton H-6 appears
at weaker field, 8.01-8.25 ppm.
The given method for the synthesis of the derivatives of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones
5a-l is a one-pot method, i.e., all stages of the reaction – acylation, removal of the S-acetyl protecting group,
intramolecular nucleophilic substitution – occur in a single flask. This permits the preparation of the required
products 5a-l in yields of 70-85%.
It is of particular interest to investigate the oxidation of the compounds synthesized, since 1,1-dioxide
derivatives of thiazepines (sulfones) are frequently used in the pharmacological industry [5, 6].
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TABLE 1. Characteristics of Compounds 5a-l, 6a,b
Found, %
——————
Com-
pound
Empirical
formula
mp, оС
Yield, %
Calculated, %
N
S
C10H10N2O3S
C12H14N2O3S
C12H14N2O4S
C16H14N2O3S
C17H16N2O3S
C16H14N2O4S
C16H14N2O3S
C11H12N2O3S
C13H16N2O3S
C13H16N2O4S
C17H16N2O3S
C18H18N2O3S
C10H10N2O5S
C16H14N2O5S
11.73
11.76
13.44
13.46
195 (о- xylene)
145 (2-PrOH)
110 (C6H6)
86
81
73
85
71
70
70
75
78
74
84
79
82
80
5а
5b
5с
5d
5e
5f
10.54
10.52
12.06
12.04
9.95
9.92
11.34
11.36
8.93
8.91
10.18
10.20
197 (2-PrOH)
142 (DMF/H2O)
110 (2-PrOH)
184 (MeСN)
197 (MeСN)
171 (dioxane)
110 (PhMe)
8.51
8.53
9.76
9.76
8.46
8.48
9.69
9.71
8.90
8.91
10.21
10.20
5g
5h
5i
11.12
11.10
12.69
12.71
10.01
9.99
11.43
11.44
9.46
9.45
10.80
10.82
5j
8.52
8.53
9.77
9.76
150 (n-BuOH)
110 (DMF/Н2О)
256 (2-PrOH)
185 (2-PrOH)
5k
5l
8.20
8.18
9.37
9.36
10.38
10.37
11.85
11.86
6a
6d
8.08
8.09
9.25
9.26
The oxidation of 7,8-dimethoxy-4,5-dihydro-1,4-benzothiazepin-3(2H)-one to the 1,1-dioxide in 38%
yield under the influence of potassium permanganate in acetic acid has been described [8]. Oxidation of
compounds 5a and 5d with m-perchloroacetic acid occurred in high yield and the products, the 1,1-dioxides of
4,5-dihydroxy-1,4-benzothiazepin-3(2H)one 6a,d were readily isolated in pure form.
Cl
R
R
O
O
O2N
N
O2N
N
OH
O
O
CH2Cl2
S
S
O
O
5a,d
6a,d
5, 6 a R = Me, d R = Bn
The structures of the 4,5-dihydroxy-1,4-benzothiazepin-3(2H)-one 1,1-dioxides 6a and 6d were
confirmed by elemental analysis and the presence in the IR spectra of intense bands in the position of the
1
stretching vibrations of the SO2 group at 1351 and 1164 cm-1. The H NMR spectra are characterized by the
signals of the aromatic protons and also the regular chemical shifts of the protons on C-2 at 5.08-5.09, the
1
signals on C-5 are found at 5.03 ppm. Analogously to compounds 5d and 5k, in the H NMR spectra of
compound 6d a diamagnetic shift of the signal of proton 6 under the influence of the benzyl group is observed.
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TABLE 2. 1H NMR Spectra of Compounds 5a-l, 6a,b
Com-
Chemical shifts, , ppm (J, Hz)
pound
2.94 (3H, s, СН3); 4.08 (2Н, s, 2-СН2); 4.76 (2H, s, 5-СН2);
5а
7.34 (1H, d, J = 8.8, Н-9); 7.99 (1H, dd, J = 8.8, J = 2.8, Н-8); 8.20 (1H, s, Н-6)
0.80 (3Н, t, J = 7.6, СН3); 1.48 (2Н, m, СН2СН3);
5b
3.33 (2Н, t, J = 6.8, СН2СН2СН3); 4.05 (2Н, s, 2-СН2); 4.78 (2H, s, 5-СН2);
7.31 (1Н, d, J = 8.8, Н-9); 7.97 (1Н, d, J = 8.8, Н-8); 8.23 (1H, s, Н-6)
3.16 (3Н, s, СН3); 3.37 (2Н, t, J = 5.4, СН2); 3.55 (2Н, t, J = 5.4, СН2);
4.08 (2Н, s, 2-СН2); 4.82 (2H, s, 5-СН2); 7.32 (1Н, d, J = 8.8, Н-9);
7.97 (1Н, dd, J = 8.8, J = 2.0, Н-8); 8.14 (1H, d, J = 2.0, Н-6)
5с
5d
5e
5f
4.16 (2Н, s, 2-СН2); 4.57 (2Н, s, СН2); 4.76 (2H, s, СН2);
7.20–7.24 (5Н, m, Н Ph); 7.29 (1Н, d, J = 8.8, Н-9); 7.87 (1Н, d, J = 2.4, Н-6);
7.90 (1H, d, J = 2.4, Н-8)
2.75 (2Н, t, J = 7.6, СН2Ph); 3.61 (2Н, t, J = 7.6, СН2СН2Ph);
4.04 (2Н, s, 2-СН2); 4.77 (2H, s, 5-СН2); 7.12–7.17 (5Н, m, Н Ph);
7.26 (1Н, m, J = 8.4, Н-9); 7.93 (1Н, d, J = 8.8, Н-8); 8.08 (1H, s, Н-6)
3.74 (3Н, s, ОСН3); 4.26 (2Н, s, 2-СН2); 5.18 (2Н, s, 5-СН2);
6.66 (1Н, d, J = 5.2, H-6'); 6.7 (1Н, s, H-2'); 6.80 (1Н, d, J = 8.0, H-4');
7.23 (1Н, t, J = 8.0, H-5'); 7.41 (1Н, d, J = 8.8, Н-9); 8.02 (1Н, d, J = 8.0, Н-8);
8.09 (1Н, s, Н-6)
2.32 (3Н, s, СН3); 4.25 (2Н, s, 2-СН2); 5.14 (2Н, s, 5-СН2); 6.97 (2Н, d, J = 7.6, H Ph);
7.13 (2Н, d, J = 7.6, H Ph); 7.40 (1Н, d, J = 8.0, Н-9); 8.01–8.06 (2Н, m, Н-6,8)
5g
5h
1.32 (3Н, d, J = 6.4, СН3); 2.95 (3H, s, NСН3);
4.20 (1Н, d, J = 16.4) and 5.35 (1H, d, J = 16.8, 5-СН2); 5.23 (1Н, q, J = 5.8, Н-2);
7.28 (1H, d, J = 8.8, Н-9); 7.98 (1H, d, J = 8.4, Н-8); 8.21 (1H, s, Н-6)
0.80 (3Н, t, J = 7.2, СН2СН3,); 1.32 (3Н, d, J = 6.8, СН3); 1.47 (2Н, m, СН2СН3);
3.36 (2Н, m, СН2СН2СН3); 4.28 (1Н, d, J = 16.8) и 5.33 (1H, d, J = 16.8, 5-СН2);
5.22 (1Н, q, J = 6.8, Н-2); 7.27 (1Н, d, J = 8.8, Н-9); 7.97 (1Н, d, J = 8.8, Н-8);
8.25 (1H, s, Н-6)
5i
5j
1.31 (3Н, d, J = 6.4, СН3); 3.16 (3Н, s, ОСН3); 3.37 (2Н, t, J = 5.4, СН2);
3.55 (2Н, t, J = 5.4, СН2); 4.29 (1Н, d, J = 16.8) и 5.35 (1H, d, J = 16.4, 5-СН2);
5.23 (1Н, q, J = 6.8, Н-2); 7.27 (1Н, d, J = 8.4, Н-9); 7.95 (1Н, d, J = 8.8, Н-8),
8.16 (1H, s, Н-6)
1.38 (3Н, d, J = 6.4, СН3); 4.19 (1Н, d, J = 16.8) и 5.37 (1Н, d, J = 16.4, 5-СН2);
4.60 (2Н, s, СН2Ph); 5.31 (1Н, q, J = 6.4, Н-2); 7.15–7.19 (5Н, m, Н Ph);
7.24 (1Н, d, J = 8.8, H-9); 7.88 (2H, m, Н-6,8)
5k
5l
1.32 (3Н, d, J = 6.4, СН3); 2.75 (2Н, t, J = 7.6, СН2Ph); 3.63 (2Н, t, J = 7.6, СН2СН2Ph);
4.28 (1Н, d, J = 16.4) и 5.30 (1H, d, J = 17.2, СН2); 5.19 (1Н, q, J = 6.8, Н-2);
7.12–7.17 (5Н, m, Н Ph); 7.24 (1Н, d, J = 8.4, Н-9); 7.93 (1Н, d, J = 8.8, Н-8);
8.08 (1H, s, Н-6)
2.99 (3H, s, СН3); 5.01 (2Н, s, СН2); 5.08 (2H, s, СН2);
8.17 (1H, d, J = 8.8, H-9); 8.41 (1H, d, J = 8.4, Н-8); 8.52 (1H, s, Н-6)
6a
6d
4.61 (2Н, s, СН2); 5.03 (2Н, s, СН2); 5.09 (2H, s, СН2); 7.11–7.20 (5Н, m, Н Ph);
8.06 (1Н, d, J = 1.6, Н-6); 8.10 (1Н, d, J = 8.8, Н-9);
8.29 (1H, dd, 1J = 8.4, 2J = 2.0, Н-8)
So a new method for the synthesis of 4,5-dihydro-1,4-benzothazepin-3(2H)-ones has been developed,
and their oxidation by m-chloroperbenzoic acid to the corresponding 1,1-dioxides has been studied.
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a Varian
Mercury 400 (400 MHz) spectrometer. Elemental analyses were determined on a vario MICRO cube elemental
1046

analyzer. Melting points were measured with a small Boetius apparatus equipped with a VEB Analytic RNMK
apparatus. Purity of the compounds synthesized was monitored by TLC on Silufol UV-254 plates with 9:1
chloroform–ethanol as eluent.
2-R'-4-R-7-Nitro-4,5-dihydro-1,4-benzothiazepin-3(2H)-ones 5a-l (General Method). The
corresponding acid chloride 2 (0.05 mol) was added dropwise to a solution of amine 1 (0.05 mol) and Et3N
(0.1 mol) in dry DMF (50 ml). The mixture was heated for 5 h at 50-60°C, cooled to room temperature, and a
base (0.1 mol) was added (40% aqueous dimethylamine 5a,b, diethylamine 5c-g, or piperidine 5h,i). The
mixture was heated for 3 h more at 50-60°C, cooled, water (250 ml) added; the precipitate was filtered off and
dried, and crystallized from the corresponding solvent.
4-R-7-Nitro-4,5-dihydro-1,4-benzothazepin-3(2H)-one 1,1-Dioxides 6a,d (General Method).
m-Perchloroacetic acid (0.05 mol) was added dropwise with stirring to a solution 4,5-dihydro-1,4-benzo-
thiazepin-3(2H)-one 5c or 5d (0.02 mol) in CH2Cl2 (100 ml). The reaction mixture was stirred for 3 h. The
solvent was evaporated, water (100 ml) added and sodium hydroxide to pH 9. The reaction mixture was stirred
for a further 5 h, the precipitate was filtered off, washed with water, dried, and crystallized.
REFERENCES
1.
2.
3.
H. Narita, M. Gaino, T. Suzuki, H. Kurosawa, H. Inoue, and T. Nagao, Chem. Pharm. Bull., 38, 407
(1990).
M. Amblard, I. Daffix, P. Bedos, G. Bergé, D. Pruneau, J.-L. Paquet, J.-M. Luccarini, P. Bélichard,
P. Dodey, and J. Martinez, J. Med, Chem., 42, 4185 (1999).
P. Huang, G. H. Loew, H. Funamizu, M. Mimura, N. Ishiyama, M. Hayashida, T. Okuno, O. Shimada,
A. Okuyama, S. Ikegami, J. Nakano, and K. Inoguchi, J. Med. Chem., 44, 4082 (2001).
R. Malli, M. Frieden, M. Trenker, and W. E. Graier, J. Biol. Chem., 280, 12114 (2005).
W. R. Buckett, P. J. Harris, J. R. Housley, J. E. Jeffery, and K. J. Nichol, WO Pat. Appl. 1992/021668.
J. R. Housley, J. E. Jeffery, K. J. Nichol, and B. J. Sargent, US Pat. Appl. 1996/5580866
A. G. Neo, C. F. Marcos, S. Marcaccini, and R. Pepino, Tetrahedron Lett., 46, 7977 (2005).
J. Szabo, L. Fodor, Á. Katocs, G. Bernath, and P. Sohar, Chem. Ber., 119, 2904 (1986).
H. Hagen and H. Fleig, Liebigs Ann. Chem., 1994 (1975).
4.
5.
6.
7.
8.
9.
10.
K. Kamei, N. Maeda, K. Nomura, M. Shibata, R. Katsuragi-Ogino, M. Koyama, M. Nakajima, T. Inoue,
and T. Ohno Tatsuoka, Bioorg. Med. Chem., 14, 1978 (2006).
11.
12.
13.
W. Reid and A. Eltz, Liebigs Ann. Chem., 599 (1988).
T. A. Volovnenko, T. N. Tarasyuk, and Yu. M. Volovenko, Zh. Org. Farm. Khim., 9, No. 2, 60 (2011).
H. Hunter, Introductory Course in NMR Spectroscopy [Russian translation], Mir, Moscow (1984), 217.
1047