Synthesis of 4-methoxybenzylamino derivatives of dibenzothiadiazepinedioxide

Article abstract of DOI:10.3987/COM-04-10095

This article reports the synthesis of new dibenzothiadiazepinedioxides bearing a 4-methoxybenzylamino group at 8- or 9-C position of the tricyclic heterocycle. Construction of the 8- or 9-aminodibenzothiadiazepinedioxide is achieved via Weber's method and

Full text of DOI:10.3987/COM-04-10095

HETEROCYCLES, Vol. 63, No. 11, 2004, pp. 2457 - 2463
Received, 5th April, 2004, Accepted, 1st October, 2004, Published online, 1st October, 2004
SYNTHESIS OF 4-METHOXYBENZYLAMINO DERIVATIVES OF
DIBENZOTHIADIAZEPINEDIOXIDE
a
a
aNicolas Lebegue,* aSebastien Gallet, Nathalie Flouquet, Pascal Carato,
bStéphanie Giraudet, and aPascal Berthelot
aLaboratoire de Chimie Thérapeutique EA1043, Faculté des Sciences
Pharmaceutiques et Biologiques de Lille, 3 rue du Professeur Laguesse, B.P. 83
59006 LILLE Cedex, France. Fax: +33 03 20 96 49 13. e-mail:
nlebegue@pharma.univ-lille2.fr.
bInstitut de Recherche Servier, Division Recherche Cancérologie, 125 Chemin de
Ronde, 78290 Croissy sur Seine, France
Abstract- This article reports the synthesis of new dibenzothiadiazepinedioxides
bearing a 4-methoxybenzylamino group at 8- or 9-C position of the tricyclic
heterocycle. Construction of the 8- or 9-aminodibenzothiadiazepinedioxide is
achieved via Weber’s method and the 4-methoxybenzyl analogues are realized by
reductive amination using 4-anisaldehyde.
INTRODUCTION
Substituted thiadiazepinedioxides are known to possess a wide range of pharmaceutical activities. Several
derivatives of dibenzothiadiazepinedioxides are found to be active as antidepressant1-3 or psychotropic
agents as well as muscle relaxants.4,5 A number of triazolothiadiazepines are also found to have
antimicrobial,6
antibacterial,7 antifungal8 and analgesic9 activities. Some benzo- or
naphthothiadiazepine derivatives have been reported to possess anti-inflammatory10 properties. In
previous works, we have synthesized pyridobenzoxazepinedioxides with methoxyphenylalkyl moiety at
N-11 position of the tricyclic core (1) which displayed potent cytotoxic activity11 (Figure 1). Herein and
in continuation of our work, we synthesized dibenzothiadiazepinedioxyde derivatives bearing
4-methoxybenzylamino chain (8a-b) hoping they may have biological interest as cytotoxic compounds.

O
O
CH3
S N
O
O
S O
4
7
8
3
N
N
H
N
9
N
2
10
H
1
(CH2)n
OCH3
1 n = 1-3
8a-b
a: 8-substituted
b: 9-substituted
OCH3
Figure 1
RESULTS AND DISCUSSION
Synthesis of substituted dibenzothiadiazepine heterocycles is well known,12-14 but no 8- or 9-amino
derivatives were described in the litterature. We used Weber’s method for synthesis of amino derivatives
(7) and (8) which involves intramolecular SNAr reaction1,15 for the construction of the
1,2,5-dibenzothiadiazepine 1,1-dioxide framework (Scheme 1).
Scheme 1: Synthesis of 8- and 9-(4-methoxybenzylamino)dibenzothiadiazepines (8a-b)
SO2Cl
H2N
NO2
+
NO2
Br
2
3a-b
a
CH3
CH3
H
SO2
SO2
NO2
N
N
SO2
NO2
N
b
c
NO2
NH
O
NO2
CH3
NH
O
Br
Br
Br
6a-b
4a-b
5a-b
CH3
d
O
O
CH3
N
CH3
N
O
O
S
S
e
N
NH2
7a-b
N
N
H
H
H
OCH3
8a-b
a: 8-substituted
b: 9-substituted
Reagents : (a) DMF, pyridine, 75°C, 68-91%; (b) DMF, NaH, CH3I, rt, 86-88%; (c) i: Fe, AcOH, reflux;
ii: Ac2O, 60°C, 76-89%; (d) i: DMF, Cu, K2CO3, reflux; ii: 12N HCl, EtOH, reflux, 45-72%; (e) THF,
AcOH, 4-anisaldehyde, 55°C; ii: THF, NaBH3CN, 50°C, 64-70%.
Compounds (4a-b) were prepared from condensation between 2-nitrobenzenesulfonyl chloride (2) and
commercial available (3a) or synthesized bromonitroaniline (3b) in DMF in the presence of pyridine as
hydrochloric acid trap. 2-Bromo-4-nitroaniline16 (3b) was prepared in 89% yield from reaction of
pyridinium tribromide and 4-nitroaniline in a solution of THF and 10% aqueous hydrochloric acid.
Methylation of the sulfonamide nitrogen occured with sodium hydride and methyl iodide in DMF.
Reduction of the nitro group of derivatives (5a-b) with boiling Fe/AcOH followed by acetylation with

Ac2O led to compounds (6a-b). Intramolecular SNAr reaction is realized according to the Goldberg’s
method17 using K2CO3 and Cu powder in DMF at reflux. The resulting acetamidothiadiazepines
intermediates were refluxed in 12N aqueous hydrochloric acid and ethanol in order to release the primary
amino derivatives (7a-b). N-Alkylation at N-8 or N-9 nitrogen using 4-methoxybenzyl chloride or
methanesulfonate in basic conditions (K2CO3 or Et3N) did not provide compounds (8) but formation of
some N-11 alkylated products. 4-Methoxybenzylamino derivatives (8a-b) were synthesized by reductive
amination of compounds (7a-b) with 4-anisaldehyde, in the presence of NaBH3CN which allowed
reduction of the imino function, in 64-70% yield.
Compounds (8a-b) were tested for their antiproliferative activity against the L1210 leukemia cell line.
Both compounds (8a) and (8b) displayed low cytotoxicity, with IC50 values of respectively 12.7 µM and
29.9 µM compared to IC50 in the submicromolar range for analogues (1) bearing the methoxyphenylalkyl
moiety at N-11 position. Further studies are in progress to improve the potential cytotoxic activity of
these compounds.
EXPERIMENTAL
Melting points were determined on a BÜCHI B-540 apparatus and were uncorrected. IR spectra were
recorded as thin films on potassium bromide disks on a BECKMAN ACCULAB IV spectrophotometer.
MS spectra were performed on a APPLIED BIOSYSTEMS API 3000 LC/MS/MS (electrospray-ionspray
method, Laboratoire d’Application de Spectrométrie de Masse, Faculté de Medecine Henri Warembourg
de Lille). 1H NMR spectra were recorded on a BRUKER AC 300 P and 2D NMR spectra on a BRUKER
DPX 300 (LARMN, Universite de Lille 2), using tetramethylsilane as internal standard. Elemental
analyses were performed by C.N.R.S. – Vernaison.
2-Bromo-4-nitroaniline (3b). A solution of pyridinium tribromide (6.95 g, 22 mmol) in THF (50 mL) is
added dropwise to a solution of 4-nitroaniline (3 g, 22 mmol) in THF (25 mL) with 10% HCl (10 mL)
and stirred at rt for 12 h. The reaction mixture is filtered and the filtrate concentrated in vacuo. The
residue is dissolved in CH2Cl2, washed with 10% sodium bisulfite, dried over sodium sulfate, filtered and
evaporated under reduce pressure. The resulting yellow oil is purified by chromatography (petroleum
ether/ ethyl acetate 85/15) to afford a yellow powder in 89% yield, mp 105-106°C (isopropyl ether), lit.,16
106-107°C
General method for synthesis of sulfonamides (4a-b). 2-Nitrobenzenesulfonyl chloride (4.05 g, 18
mmol) is added portionwise to a solution of bromonitroaniline (3a-b) (15 mmol) in DMF (5 mL) and
pyridine (1.5 mL, 18 mmol). The reaction mixture is heated at 75°C for 5 h and evaporated under reduce
pressure. The oily product precipitated by addition of water (10 mL) and collected by filtration.
Recrystallization from ethanol 95% furnished the desired sulfonamides (4a-b).

N-(2-Bromo-5-nitrophenyl)-2-nitrobenzenesulfonamide (4a). White powder; yield 91%; mp
192-193°C; IR: 3300, 1570, 1540, 1350, 1180; 1H NMR (CDCl3) δ 7.70 (d, 1H, J= 8.80 Hz), 7.75 (td, 1H,
J= 1.40, 7.85 Hz), 7.82 (td, 1H, J= 1.40, 7.85 Hz),7.91 (dd, 1H, J= 2.30, 8.80 Hz), 7.98 (dd, 1H, J= 1.40,
7.40 Hz), 8.08 (dd, 1H, J= 1.40, 7.40), 8.35 (s, 1H), 8.64 (d, 1H, J= 2.30 Hz). Anal. Calcd for
C12H8N3O6BrS: C, 35.84; H, 2.00; N, 10.45. Found: C, 35.78; H, 2.03; N, 10.37
N-(2-Bromo-4-nitrophenyl)-2-nitrobenzenesulfonamide (4b). Beige powder; yield 68%; mp
1
177-178°C; IR: 3280, 1570, 1340, 1180; H NMR (CDCl3): δ 7.76 (td, 1H, J= 1.30, 7.45 Hz), 7.83 (td,
1H, J= 1.30, 7.35 Hz), 7.98 (m, 2H), 8.07 (dd, 1H, J= 1.30, 7.35 Hz), 8.22 (dd, 1H, J= 2.60, 9.10 Hz),
8.33 (s, 1H), 8.41 (d, 1H, J= 2.60 Hz). Anal. Calcd for C12H8N3O6BrS: C, 35.84; H, 2.00; N, 10.45.
Found: C, 35.72; H, 1.98; N, 10.51
General method for synthesis of N-methylsulfonamides (5a-b). Substituted benzenesulfonamide
(4a-b) (5 mmol) dissolved in DMF (10 mL) is added dropwise to a suspension of 60% sodium hydride
(0.4 g, 10 mmol) in DMF (5 mL) and stirred for 3 h at rt. Iodomethane (1 mL, 15 mmol) in DMF (5 mL)
is added dropwise to the previous solution and stirred for 12 h at rt. The resulting solution is evaporated
under reduced pressure, precipitated from water and filtered. The resulting powder is then recrystallized
from 95% ethanol.
N-(2-Bromo-5-nitrophenyl)-N-methyl-2-nitrobenzenesulfonamide (5a). Light brown powder; yield
88%; mp 137-138°C; IR: 1580, 1550, 1450, 1350, 1180; 1H NMR (CDCl3): δ 3.47 (s, 3H), 7.63-7.69 (m,
2H), 7.75-7.84 (m, 3H), 8.12 (dd, 1H, J= 2.70, 8.55 Hz), 8.20 (d, 1H, J= 2.70 Hz). Anal. Calcd for
C13H10N3O6BrS: C, 37.52; H, 2.42; N, 10.10. Found: C, 37.45; H, 2.39; N, 10.02.
N-(2-Bromo-4-nitrophenyl)-N-methyl-2-nitrobenzenesulfonamide (5b). Light yellow powder; yield
86%; mp 143-145°C; IR: 1590, 1560, 1450, 1360, 1160; 1H NMR (CDCl3): δ 3.48 (s, 3H), 7.62-7.68 (m,
3H), 7.74-7.79 (m, 2H), 8.23 (dd, 1H, J= 2.80, 8.80 Hz), 8.47 (d, 1H, J= 2.80 Hz). Anal. Calcd for
C13H10N3O6BrS: C, 37.52; H, 2.42; N, 10.10. Found: C, 37.60; H, 2.36; N, 10.08.
General method for synthesis of diacetamides (6a-b). Substituted dinitrobenzenesulfonamide (5a-b) (5
mmol) in acetic acid (45 mL) with iron powder (2.95 g, 50 mmol) is refluxed for 1 h. The reaction
mixture is filtered, the filtrate is added to acetic anhydride (10 mL) and stirred for 12 h at 60°C. The
solution is concentrated in vacuo, diluted with water (20 mL) and extracted with dichloromethane. The
organic extracts are dried over sodium sulfate, filtered, evaporated under reduced pressure and
crystallized from the appropriate solvent.
2-Acetamido-N-(5-acetamido-2-bromophenyl)-N-methylbenzenesulfonamide (6a). Beige powder;
1
yield 76%; mp 122-126°C (isopropyl ether); IR: 3360, 3320, 1690, 1680, 1590, 1440, 1340, 1180; H
NMR (CDCl3): δ 1.80 (s, 3H), 2.16 (s, 3H), 3.16 (s, 3H), 6.87 (d, 1H, J= 2.60 Hz), 7.30 (td, 1H, J= 0.85,
8.15 Hz), 7.57-7.67 (m, 3H), 7.76 (dd, 1H, J= 2.60, 8.60 Hz), 7.93 (dd, 1H, J= 1.70, 8.15 Hz), 8.21 (dd,

1H, J= 1.90, 8.60 Hz), 9.07 (s, 1H). Anal. Calcd for C17H18N3O4BrS: C, 46.37; H, 4.12; N, 9.54. Found:
C, 46.31; H, 4.02; N, 9.60.
2-Acetamido-N-(4-acetamido-2-bromophenyl)-N-methylbenzenesulfonamide (6b). Beige powder;
yield 89%; mp 190-192°C (95% ethanol); IR: 3340, 3320, 1690, 1670, 1580, 1430, 1340, 1140; 1H NMR
(CDCl3): δ 1.87 (s, 3H), 2.18 (s, 3H), 3.21 (s, 3H), 7.10 (d, 1H, J= 8.70 Hz), 7.21 (td, 1H, J= 0.90, 7.80
Hz), 7.45 (dd, 1H, J= 2.30, 8.70 Hz), 7.58 (td, 1H, J= 1.40, 8.25 Hz), 7.85 (dd, 1H, J= 1.40, 7.80 Hz),
7.90 (d, 1H, J= 2.30 Hz), 8.00 (s, 1H), 8.39 (dd, 1H, J= 1.75, 8.30 Hz), 9.22 (s, 1H). Anal. Calcd for
C17H18N3O4BrS: C, 46.37; H, 4.12; N, 9.54. Found: C, 46.28; H, 4.05; N, 9.51.
General method for syntesis of aminodibenzothiadiazepines (7a-b). A solution of substituted
diacetamidobenzenesulfonamide (6a-b) (5 mmol) in DMF (20 mL) is treated with potassium carbonate
(1.5 g, 10 mmol), copper powder (0.17 g, 3 mmol), stirred and heated under reflux for 8 h. After this time,
the mixture is filtered and the solution evaporated under reduced pressure. The residue is precipitated in
water and collected by filtration. The resulting powder is heated under reflux for 2,5 h in a solution of
ethanol 95% (20 mL) with 12N HCl (4 mL). The reaction mixture is diluted with water and 10% aqueous
ammoniac solution is added untill precipitation. The precipitate is collected by filtration and recrystallized
from 95% ethanol.
8-Amino-6,11-dihydro-6-methyldibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (7a). Light purple
powder; yield 45%; mp 235-238°C; IR: 3460, 3360, 1600, 1440, 1300, 1150; 1H NMR (CDCl3): δ 2.86 (s,
3H), 4.99 (s, 2H), 6.17 (d, 1H, J= 2.75 Hz), 6.55 (dd, 1H, J= 2.75, 8.80 Hz), 6.79 (td, 1H, J= 7.15, 8.80
Hz), 6.88 (d, 1H, J= 8.80 Hz), 7.17 (dd, 1H, J= 1.65, 8.25 Hz), 7.38 (td, 1H, J= 1.65, 8.25 Hz), 7.60 (dd,
1H, J= 1.65, 8.25 Hz), 8.90 (s, 1H). Anal. Calcd for C13H13N3O2S: C, 56.71; H, 4.76; N, 15.26. Found: C,
56.59; H, 4.69; N, 15.20.
9-Amino-6,11-dihydro-6-methyldibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (7b). Light purple
powder; yield 72%; mp 208-213°C; IR: 3460, 3340, 1600, 1580, 1320, 1150; 1H NMR (CDCl3): δ 2.79 (s,
3H), 5.30 (s, 2H), 6.21 (dd, 1H, J= 2.10, 8.50 Hz), 6.30 (d, 1H, J= 2.10 Hz), 6.88 (m, 2H), 7.28 (d, 1H, J=
8.50 Hz), 7.38 (dd, 1H, J= 6.90, 7.45 Hz), 7.64 (d, 1H, J= 6.90 Hz), 9.04 (s, 1H). Anal. Calcd for
C13H13N3O2S: C, 56.71; H, 4.76; N, 15.26. Found: C, 56.62; H, 4.63; N, 15.18 .
General method for syntesis of 4-methoxybenzylaminodibenzothiadiazepines (8a-b). A solution of
7a or 7b (2 mmol), 4-anisaldehyde (2.2 mL, 20 mmol) and acetic acid (0.2 mL, 4 mmol) in THF (40 mL)
is heated at 55°C untill TLC indicates starting aminodibenzothiadiazepine is consumed. After
concentration, ether (30 mL) is added and the precipitate is collected by filtration. The resulting solid is
dissolved in THF (30 mL) and NaBH3CN (0.18 g, 3 mmol) is slowly added. The suspension is stirred at rt
for 1 h and at 50°C for 5 days. After cooling, aqueous 1N NaOH is added and the solution is extracted

with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered, evaporated under reduce
pressure and purified by chromatography (ethyl acetate/ petroleum ether 7/3).
6,11-Dihydro-9-(4-methoxybenzylamino)-6-methyldibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (8a).
Light brown powder; yield 64%; mp 185-186°C (80% ethanol); IR: 3360, 1590, 1510, 1440, 1320, 1160;
1H-NMR (DMSO-d6): δ 2.78 (s, 3H), 3.73 (s, 3H), 4.19 (d, 2H, J= 6.05 Hz), 6.23-6.29 (m, 2H), 6.44 (t,
1H, J= 6.05 Hz), 6.84-6.92 (m, 4H), 7.27-7.31 (m, 3H), 7.42 (td, 1H, J= 1.65, 7.65 Hz), 7.64 (dd, 1H, J=
1.65, 8.25 Hz), 9.05 (s, 1H). MS (EI) m/z 395 (M+). Anal. Calcd for C21H21N3O3S: C, 63.78; H, 5.35; N,
10.63. Found: C, 63.72; H, 5.39; N, 10.68.
6,11-Dihydro-8-(4-methoxybenzylamino)-6-methyldibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (8b).
Light yellow powder; yield 70%; mp 202-203°C (95% ethanol); IR: 3340, 1580, 1500, 1450, 1310, 1160;
1H-NMR (DMSO-d6): δ 2.84 (s, 3H), 3.73 (s, 3H), 4.15 (s, 2H), 6.05 (s, 1H), 6.50 (d, 1H, J= 2.80 Hz),
6.59 (dd, 1H, J= 2.80, 8.80 Hz), 6.79 (td, 1H, J= 1.80, 8.30 Hz); 6.91 (m, 3H), 7.27 (d, 1H, J= 8.80 Hz),
7.29-7.41 (m, 3H), 7.61 (dd, 1H, J= 1.40, 7.85 Hz), 8.93 (s, 1H). MS (EI) m/z 395 (M+). Anal. Calcd for
C21H21N3O3S: C, 63.78; H, 5.35; N, 10.63. Found: C, 63.81; H, 5.29; N, 10.65.
REFERENCES
1. D. Giannotti, G. Viti, P. Sbraci, V. Pestellini, G. Volterra, F. Borsini, A. Lecci, A. Meli, P. Dapporto,
and P. Paoli, J. Med. Chem., 1991, 34, 1356.
2. F. Borsini, G. Volterra, A. Lecci, S. Evangelista, A. Mancinelli, C. Cutrufo, M. Parlani, T. Mennini,
D. Barone, and A. Meli, Arzneim.-Forsch., 1991, 41, 573.
3. F. Borsini, A. Meli, G. Volterra, D. Giannotti, and V. Pestellini, Ital. Patent, 1998, 9466.
4. A. Weber and J. Frossard, Ann. Pharm. Fr., 1966, 6, 445.
5. W. E. Kreighbaum, Patent, 3,322,789, 1967 (Chem. Abst., 1967, 67, 100161).
6. M. Kidwai, P. Sapra, P. Misra, R. K. Saxena, and M. Singh, Bioorg. Med. Chem., 2001, 9, 217.
7. B. Kalluraya, P. Vishwanatha, C. H. Jyothi, V. F. Priya, and G. Rai, Indian J. Heterocycl. Chem.,
2003, 12, 355.
8. B. Kalluraya, R. Gururaja, and G. Rai, Indian J. Chem. Sect. B, 2003, 42, 211.
9. B. Kalluraya, M. Abdul Rahiman, and D. Banji, Indian J. Chem. Sect. B, 2002, 41, 1712.
10. R. J. Cherney, J. J.-W. Duan, M. E. Voss, L. Chen, L. Wang, D. T. Meyer, Z. R. Wasserman, K. D.
Hardman, R-Q. Liu, M. B. Covington, M. Qian, S. Mandlekar, D. D. Christ, J. M. Trzaskos, R. C.
Newton, R. L. Magolda, R. R. Wexler, and C. P. Decicco, J. Med. Chem., 2003, 46, 1811.
11. Patent application PCT/FR04/00235 filed february 3rd 2004.
12. A. Weber, U. S. Patent, 3,274,058, 1966 (Chem. Abst., 1967, 66, 95092).
13. A. Weber, U. S. Patent, 3,268,557, 1966 (Chem. Abst., 1966, 65, 15406).

14. F. Borsini, A. Meli, G. Volterra, D. Giannotti, and V. Pestellini, U. S. Patent, 5,011,833, 1991.
15. D. Giannotti, G. Viti, R. Nannicini, V. Pestellini, and D. Bellarosa, Bioorg. Med. Chem. Lett., 1995, 5,
1461.
16. W. P. Reeves and R. M. King, Synth. Comm., 1993, 23, 855.
17. (a) I. Goldberg, Ber., 1906, 39, 1691. (b) I. Goldberg, Ber., 1907, 40, 4541.