Denitrocyclization in synthesis of dibenzo[b,f][1,4]thiazepin-11(10H)-ones and their derivatives

Article abstract of DOI:10.1002/jhet.5570440604

(Chemical Equation Presented) A convenient synthesis of the novel dibenzo[b,f][1,4]thiazepin-11(10H)-ones is reported. As a key step, the synthetic route includes intramolecular aromatic denitrocyclization of 2-(2,4-dinitro-phenylsulfanyl)-benzoic acid am

Full text of DOI:10.1002/jhet.5570440604

Nov-Dec 2007
1247
Denitrocyclization in Synthesis of Dibenzo[b,f][1,4]thiazepin-
11(10H)-ones and Their Derivatives
Alexey V. Smirnova, Levan S. Kalandadze a, Vladimir N. Sakharova,
Mikhail V. Dorogova, Alexander V. Ivachtchenkob*
aThe Ushinsky Yaroslavl State Pedagogical University, 150000 Respublikanskaya 108, Yaroslavl, Russian Federation
bChemical Diversity, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, California, 92121 USA, e-mail: av@chemdiv.com
Received July 19, 2006
O-
O
N+
N+
O-
N+
R
O
O-
O
Base
N
O
S
O
DMF
S
NH
R
A convenient synthesis of the novel dibenzo[b,f][1,4]thiazepin-11(10H)-ones is reported. As a key step,
the synthetic route includes intramolecular aromatic denitrocyclization of 2-(2,4-dinitro-phenylsulfanyl)-
benzoic acid amides. Efficient procedures for denitrocyclization in the presence of different bases are
developed. Reduction of the nitro group in the obtained heterocycles resulted in formation of primary
amines, which were transformed into amides by acylation with different carboxylic acids. The synthesized
compounds have a great potential of bioactivity and are useful objects for biomedicinal screening.
J. Heterocyclic Chem., 44, 1247 (2007).
Scheme 1
INTRODUCTION
R'
O
R'
Y
X
Benzo-fused seven-membered lactams (benzoazepine-
2-ones) and their heterocyclic analogues represent well-
known pharmacophoric scaffolds with a wide portfolio of
interesting physiological activities. For example, they
were reported as potential Ca-channel blockers [1],
NMDA glycine-site antagonists [2], anticoagulants [3],
inhibitors of proteases [4,5] and antihypertensive agents
[6-8]. Dibenzo[b,f][1,4]thiazepin-11-ones and some of
their analogues were documented as novel non-nucleoside
inhibitors of HIV-1 reverse transcriptase [9,10]. These
recent examples reflect the ongoing interest in new benzo-
fused seven-membered lactams and their heterocyclic
analogues.
N
NH
O
R
R''
+
R
R''
SH
S
X = F, Cl, Br, I;
Y = Cl, OH, OAlk
We have developed a novel synthetic approach to
dibenzo[b,f][1,4]thiazepin-11(10H)-ones based on intra-
molecular nucleophilic substitution of nitro group
(denitrocyclization) as a key step.
Reaction of equimolar amounts of 1-chloro-2,4-
dinitrobenzene (1) and 2-mercapto-benzoic acid (2) in the
presence of TEA (2 equiv.) afforded 2-(2,4-dinitro-
phenylsulfanyl)-benzoic acid (3) (Scheme 2). The reaction
proceeded in 2-propanol at 80 ºC. The pure resulting
product was precipitated from the reaction mixture after
neutralization with hydrochloric acid.
In this work we have developed an efficient strategy for
synthesis of the novel dibenzo[b,f][1,4]thiazepin-
11(10H)-ones and their 10-substituted derivatives which
have a great potential of bioactivity and are useful objects
for biomedicinal screening.
RESULTS AND DISCUSSION
Scheme 2
Denitrocyclization is a well-documented synthetic
approach for the synthesis of heterocyclic compounds
[11]. However, this method has never been used for
preparation of the dibenzo[b,f][1,4]thiazepin-11(10H)-
ones, which were usually obtained by interaction of the
substituted ortho-aminothiophenols with ortho-halogeno-
benzoic acids derivatives (Scheme 1) In particular, this
method was used for the synthesis of 8-nitro-10H-
dibenzo[b,f][1,4]thiazepin-11-one [12], but in general this
approach is rather limited.
OH
N
O
N
OH
O
OH
N
O
N
OH
TEA, 2-propanol
80 oC, 3h, 90%
S
O
O
OH
O
+
OH
Cl
HS
1
2
3
The resulting acid was transformed into the acid
chloride (4) by treatment of (3) with thionyl chloride in

1248
A. Smirnov, L. Kalandadze, V. Sakharov, M. Dorogov, A. Ivachtchenko
Vol 44
dry dioxane. The reaction proceeded smoothly at 50 ºC.
The resulting solution of (4) was used for synthesis of
amides in parallel without isolation of the acid chloride
(Scheme 3). Treatment of (4) with primary amines in
dioxane in the presence of TEA afforded the desired
amides (5a-e) which were used for the following
denitrocyclization.
Scheme 4
O-
N+
O
N+
R1
O-
N+
O
O
O-
N
Base, DMF
O
S
O
a, b
S
NH
R1
5a-e
6a-e
Scheme 3
a - 0-20 oC, 2h, R1 = CH3, Base = NaH (80%), NaNH2 (23%), KO(CH3)3 (88%)
b - 120 oC, 5h, R1 = CH3, Base = K2CO3 (90%)
O-
N+
O
N+
O
N+
O-
N+
O-
O
O
O-
SOCl2
Scheme 5
O
S
S
O
a
O-
N+
R
R
O
O
OH
Cl
N
N
H2N
SnCl2
O
a
3
4
S
S
R1
NH2
6a-e
7a-e
b
R1COOH
CDI
O-
N+
O
N+
R1
HN
O
b
O
O-
R
N
O
S
O
S
NH
R1
8a-e
a - HCl, 80 oC, 2 h
b - dioxane, 50-100 oC, 5 h
5a-e
R
1 = a - CH3, b - C2H5, c - n-C3H7, d - cyclo-C5H9, e - cyclo-C3H5
a - dioxane, 50 oC, 2 h; b - TEA, dioxane, 20 oC, 2 h
The resulting compounds (6a-e) were transformed to the
corresponding amines (7a-e) via reduction of the nitro
group by treatment with tin (II) chloride in the presence of
hydrochloric acid at 80 ºC followed by neutralization of the
mixture with NaOH (Scheme 5). The desired amines (7a-e)
precipitated from the reaction mixture and then were
purified by reprecipitating from DMF in 80-90% yields.
The synthesized amines (7a-e) were used as building-
blocks for synthesis of amides in parallel. Reaction of
equimolar amounts of the corresponding acid with N,N'-
carbonyldiimidazole (CDI) afforded the corresponding
imidazolides which were transformed into the desired
amides (8a-e) (Table 1) by addition of the amines (7a-e)
in situ.
The obtained amides (5a-e) were considered as objects
for intramolecular nucleophilic substitution of nitro group
with amide nitrogen (Scheme 4). This reaction proceeded
only in the presence of a base. Thus, the reaction
proceeded even at room temperature in the presence of
such strong bases as sodium hydride, sodium amide or
potassium tert-butoxide in dry DMF. The reaction
products afforded in good yields only when sodium
hydride or potassium tert-butoxide were used. It can be
suggested that, under the described conditions, sodium
amide initiated Chichibabin amination [13].
We have found that denitrocylcization of (5a-e) can
also proceed in the presence of potassium carbonate as
deprotonating agent in a solution of wet DMF at 120 ºC.
This procedure allows one to obtain the desired products
in 80-90% yields.
The assignment of these structures was made on the
1
basis of elemental analysis and H NMR spectroscopy
1
data. H NMR spectra of the resulting compounds were
Table 1
Structure of compounds (8a-e)
Entry
R1
8a
Me
8b
Et
8c
Pr
8d
Cyclo-C5H9
8e
Cyclo-C3H5
Structure
R1
O
R
N
O
O
H3C
H
O
HN
N
S
R2
O
N+
NH
O
N
S
O
S
O

Nov-Dec 2007
Denitrocyclization in Synthesis of Dibenzo[b,f][1,4]thiazepin-11(10H)-ones
1249
and Their Derivatives
3
J= 8.5Hz, NH), 8.95 (d, 1H, Jo=1.1 Hz, CH), 1H). Anal. Calcd.
for C18H17N3O5S: C, 55.80; H, 4.42; N, 10.85; S, 8.28. Found: C,
55.09; H, 4.43; N, 10.82; S, 8.29.
clean and showed characteristic signals from protons of
two benzene rings and corresponding substituents at both
nitrogen atoms.
N-Cyclopropyl-2-(2,4-dinitro-phenylsulfanyl)-benzamide
(5e). This compound was obtained as yellow solid in 60% yield,
mp 131-133˚; H nmr (DMSO-d6): ꢀ 1.58 (m, 4H, 2CH2). 4.08
1
EXPERIMENTAL
6
(m, 1H, NCH), 7.05 (d, 1H, J= 8.1 Hz, CH), 7.64 (m, 4H,
5
Melting points were measured with a Buchi B-520 melting
1
point apparatus and were not corrected. H NMR spectra were
4ArH), 8.23 (dd, 1H, Jo=8.1 Hz, Jo=1.1 Hz, CH), 8.36 (d, 1H,
3
J= 8.5Hz, NH), 8.96 (d, 1H, Jo=1.1 Hz, CH), 1H). Anal. Calcd.
recorded on Bruker DRX-500 spectrometers in DMSO-d6 or
CDCl3 using TMS as an internal standard.
for C16H13N3O5S: C, 53.48; H, 3.65; N, 11.69; S, 8.92. Found: C,
53.43; H, 3.65; N, 11.67; S, 8.93.
2-(2,4-Dinitro-phenylsulfanyl)-benzoic acid (3). A mixture
of 20.26 g (0.1 mol) of 1-chloro-2,4-dinitrobenzene (1), 15.42 g
(0.1 mol) of 2-mercapto-benzoic acid (2), 20.24 g (0.2 mol) of
TEA and 150 ml of 2-propanol was stirred at 80 ºC for 3 h. Then
the mixture was cooled down to a room temperature and poured
into 300 ml of 15% hydrochloric acid. The formed precipitate
was collected by filtration, washed with water and dried to
afford pure reaction product (3) as yellow crystals, 28.8 g (90%),
General Procedure for Synthesis of 10-substituted 8-nitro-
dibenzo[b,f][1,4]thiazepin-11-ones (6a-e). Potassium carbonate
(27.64 g, 0.2 mol) was added to a solution of 0.1 mol (5a-e) in
DMF (100 ml). The mixture was stirred at 120 ºC for 5 h. Then
the mixture was cooled down to room temperature and poured into
water. The formed precipitate was collected by filtration, washed
with water, dried and purified by crystallization from a mixture of
ethanol and DMF to afford pure reaction product (6a-e).
1
mp 220-223º; H nmr (DMSO-d6): ꢀ 7.06 (d, 1H, J= 7.9 Hz,
10-Methyl-8-nitro-10H-dibenzo[b,f][1,4]thiazepin-11-one
(6a). This compound was obtained as yellow solid in 90% yield,
mp 187-189˚; 1H nmr (DMSO-d6): ꢀ 3.60 (s, 3H, NCH3), 7.36 (m,
6
ArH), 7.65 (m, 3H, 3ArH), 8.00 (d, 1H, Jo= 8.1 Hz, CH), 8.20
(dd, 1H, Jo= 8.1 Hz, Jm=1.1 Hz, 5CH), 8.92 (d, Jm= 1.1 Hz, 3CH).
Anal. Calcd. for C13H8N2O6S: C, 48.75; H, 2.52; N, 8.73; S,
10.01. Found: C, 48.65; H, 2.52; N, 8.70, S, 10.02.
6
2H), 7.47 (m, 1H), 7.58(m, 1H), 7.66 (d, 1H, Jo= 8.0 Hz, CH),
7
8.22 (dd, 1H, Jo= 8.0 Hz, Jm= 1.1 Hz, CH), 8.38 (d, 1H, Jm= 1.1
9
Hz, CH). Anal. Calcd. for C14H10N2O3S: C, 58.73; H, 3.52; N,
General Procedure for Synthesis of 2-(2,4-dinitro-
phenylsulfanyl)-benzamides (5a-e). Thionyl chloride (13.09 g,
0.11 mol) was added to a suspension of 32.03 g (0.1 mol) of
compound (3) in 100 ml of dry dioxane. The mixture was treated
at 50 ºC for 2 h. Then the mixture was cooled down to a room
temperature and added dropwise to a solution of 0.11 mol of a
primary amine and 11.13 g (0.11 mol) of TEA in 200 ml of
dioxane. The mixture was stirred at room temperature for 2 h
and then poured into water. The formed precipitate was
collected by filtration, washed with water and dried to afford
pure reaction product (5a-e).
9.78; S, 11.20. Found: C, 58.66; H, 3.52; N, 9.80; S, 11.22.
10-Ethyl-8-nitro-10H-dibenzo[b,f][1,4]thiazepin-11-one (6b).
This compound was obtained as yellow solid in 85% yield, mp
1
119-121˚; H nmr (DMSO-d6): ꢀ 1.21 (t, 3H, J=7.1 Hz, CH3),
4.57 (q, 2H, J=7.1 Hz, NCH2), 7.34 (m, 2H, 2ArH), 7.45 (m, 1H,
6
ArH), 7.56 (m, 1H, ArH), 7.63 (d, 1H, Jo=8.0 Hz, CH), 8.20
7
(dd, 1H, Jo=8.0 Hz, Jm=1.1 Hz, CH), 8.37 (d, 1H, Jm=1.1 Hz,
9CH). Anal. Calcd. for C15H12N2O3S: C, 59.99; H, 4.03; N, 9.33;
S, 10.67. Found: C, 59.89; H, 4.03; N, 9.37; S, 10.69.
8-Nitro-10-propyl-10H-dibenzo[b,f][1,4]thiazepin-11-one
(6c). This compound was obtained as yellow solid in 80% yield,
2-(2,4-Dinitro-phenylsulfanyl)-N-methyl-benzamide (5a).
This compound was obtained as yellow solid in 79% yield, mp
174-176˚; 1H nmr (DMSO-d6): ꢀ 2.70 (d, 3H, J=5.3 Hz, NCH3),
1
mp 117-119˚; H nmr (DMSO-d6): ꢀ 0.90 (t, 3H, J=6.8 Hz,
CH3), 1.60 (m, 2H, CH2), 3.70 (m, 1H, CH), 4.60 (m, 1H, CH),
7.42 (m, 2H, 2ArH), 7.52 (m, 1H, ArH), 7.60 (m, 1H, ArH),
5
7.00 (d, 1H, Jo=8.1Hz, CH), 7.60 (m, 4H, 4ArH), 8.20 (m, 2H,
3,5CH), 8.95 (q, 1H, J=5.3 Hz, NH). Anal. Calcd. for
C14H11N3O5S: C, 50.45; H, 3.33; N, 12.61; S, 9.62. Found: C,
50.37; H, 3.33; N, 12.65; S, 9.63.
7.86 (d, 1H, Jo=8.0 Hz, CH), 8.22 (dd, 1H, Jo=8.0 Hz, Jo=1.1
6
Hz, 7CH), 8.40 (d, 1H, Jo=1.1 Hz, 9CH). Anal. Calcd. for
C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91; S, 10.20. Found: C,
61.05; H, 4.49; N, 8.88; S, 10.21.
2-(2,4-Dinitro-phenylsulfanyl)-N-ethyl-benzamide (5b).
This compound was obtained as yellow solid in 82% yield, mp
10-Cyclopentyl-8-nitro-10H-dibenzo[b,f][1,4]thiazepin-11-
one (6d). This compound was obtained as yellow solid in 87%
1
143-145˚; H nmr (DMSO-d6): ꢀ 1.02 (t, 3H, J=7.1 Hz, CH3),
5
1
3.21 (m, 2H, NCH2), 7.02 (d, 1H, Jo=8.1Hz, CH), 7.63 (m, 4H,
yield, mp 157-159˚; H nmr (DMSO-d6): ꢀ 1.75 (m, 8H, 4CH2),
4.50 (m, 1H, NCH), 7.41 (m, 2H, 2ArH), 7.51 (m, 1H, ArH),
4ArH), 8.20 (m, 2H, 3,5CH), 8.97 (t, 1H, J=5.2 Hz, NH). Anal.
Calcd. for C15H13N3O5S: C, 51.87; H, 3.77; N, 12.1; S, 9.23.
Found: C, 51.78; H, 3.78; N, 12.09; S, 9.24.
6
7.61 (m, 1H, ArH), 7.85 (d, 1H, Jo=8.0 Hz, CH), 8.21 (dd, 1H,
Jo=8.0 Hz, Jm=1.1 Hz, 7CH), 8.40 (d, 1H, Jm=1.1 Hz, 9CH). Anal.
Calcd. for C18H16N2O3S: C, 63.51; H, 4.74; N, 8.23; S, 9.42.
Found: C, 63.46; H, 4.74; N, 8.20; S, 9.43.
2-(2,4-Dinitro-phenylsulfanyl)-N-propyl-benzamide (5c).
This compound was obtained as yellow solid in 86% yield, mp
93-95˚; 1H nmr (DMSO-d6): ꢀ 0.80 (t, 3H, J=7.0 Hz, CH3), 1.40
(m, 2H, CH2), 3.08 (m, 2H, NCH2), 7.00 (d, 1H, Jo=8.1Hz, 6CH),
10-Cyclopropyl-8-nitro-10H-dibenzo[b,f][1,4]thiazepin-11-
one (6e). This compound was obtained as yellow solid in 82%
5
1
7.58 (m, 4H, 4ArH), 8.20 (dd, 1H, Jo=8.1Hz, Jm=1.1 Hz, CH),
yield, mp 153-155˚; H nmr (DMSO-d6): ꢀ 1.71 (m, 4H, 2CH2),
4.52 (m, 1H, NCH), 7.40 (m, 2H, 2ArH), 7.53 (m, 1H, ArH),
3
8.32 (m, 1H, NH), 8.94 (d, 1H, Jm=1.1 Hz, CH). Anal. Calcd.
6
for C16H15N3O5S: C, 53.18; H, 4.18; N, 11.63; S, 8.87. Found: C,
53.14; H, 4.19; N, 11.60; S, 8.88.
7.60 (m, 1H, ArH), 7.82 (d, 1H, Jo=8.0 Hz, CH), 8.22 (dd, 1H,
Jo=8.0 Hz, Jm=1.1 Hz, 7CH), 8.42 (d, 1H, Jm=1.1 Hz, 9CH). Anal.
Calcd. for C16H12N2O3S: C, 61.53; H, 3.87; N, 8.97; S, 10.26.
Found: C, 61.47; H, 3.88; N, 8.95; S, 10.27.
N-Cyclopentyl-2-(2,4-dinitro-phenylsulfanyl)-benzamide
(5d). This compound was obtained as yellow solid in 90% yield,
1
mp 140-142˚; H nmr (DMSO-d6): ꢀ 1.60 (m, 8H, 4CH2). 4.05
General Procedure for Synthesis of 10-substituted 8-
aminodibenzo[b,f][1,4]thiazepin-11-one (7a-e). Tin (II)
chloride dihydrate (78.96 g, 0.35 mol) and 85 ml (0.7 mol) of
6
(m, 1H, NCH), 7.01 (d, 1H, J= 8.1 Hz, CH), 7.61 (m, 4H,
5
4ArH), 8.21 (dd, 1H, Jo=8.1 Hz, Jo=1.1 Hz, CH), 8.37 (d, 1H,

1250
A. Smirnov, L. Kalandadze, V. Sakharov, M. Dorogov, A. Ivachtchenko
Vol 44
1
30% hydrochloric acid were added to a solution of 0.1 mol (6a-
e) in 100 ml of ethanol. The mixture was stirred at 80 ºC for 2 h.
Then the mixture was cooled down to room temperature and
added to a solution of 40 g (1 mol) of NaOH in 300 ml of water.
The formed precipitate was collected by filtration, washed with
water, dried, reprecipitated from DMF and dried to afford pure
reaction product (7a-e).
yield, mp 171-173˚; H nmr (DMSO-d6): ꢀ 3.48 (s, 3H, NCH3),
4.00 (d, 2H, J=6.5 Hz, NCH2), 7.05 (t, 1H, J=6.5 Hz, NH), 7.30
(m, 3H, Th), 7.42 (m, 1H, ArH), 7.49 (m, 1H, ArH), 7.60 (d, 1H,
6
Jo= 8.1 Hz, CH), 7.75 (m, 2H, 2ArH), 7.92 (dd, 1H, Jo=8.1 Hz,
7
9
Jm=1.0 Hz, CH), 8.65 (d, 1H, Jo=1.0 Hz, CH), 10.05 (s, 1H,
NH). Anal. Calcd. for C21H17N3O3S2: C, 59.56; H, 4.05; N, 9.92;
S, 15.14. Found: C, 59.48; H, 4.05; N, 9.96; S, 15.16.
N-(10-Ethyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]thiaze-
pin-8-yl)-3-methyl-4-nitro-benzamide (8b). This compound
was obtained as yellow solid in 72% yield, mp 257-259˚; H
8-Amino-10-methyl-10H-dibenzo[b,f][1,4]thiazepin-11-one
(7a). This compound was obtained as white solid in 93% yield,
mp 227-229˚; H nmr (DMSO-d6): ꢀ 3.52 (s, 3H, CH3), 5.26 (s,
1
1
nmr (DMSO-d6): ꢀ 1.25 (t, 3H, J=7.1 Hz, CH3), 3.22 (s, 3H,
CH3), 3.65 (m, 1H, CH), 4.52 (m, 1H, CH), 7.25 (t, 2H), 7.42
(m, 1H, ArH), 7.49 (m, 1H, ArH), 7.60 (d, 1H, Jo= 8.1 Hz,
2H, NH2), 6.50 (m, 1H, ArH), 6.72 (m, 1H, ArH), 7.11 (d, 1H,
6
Jo= 8.1 Hz, CH), 7.29 (m, 2H, 2ArH), 7.41 (dd, 1H, Jo=8.1 Hz,
Jm=1.0 Hz, 7CH), 7.50 (d, 1H, Jo=1.0 Hz). Anal. Calcd. for
C14H12N2OS: C, 65.60; H, 4.72; N, 10.93; S, 12.51. Found: C,
65.50; H, 4.72; N, 10.95; S, 12.52.
5'
6CH), 7.63 (d, 1H, Jo=8.0 Hz, CH), 7.75 (m, 2H, 2ArH), 7.92
7
(dd, 1H, Jo=8.1 Hz, Jm=1.0 Hz, CH), 8.20 (dd, 1H, Jo=8.0 Hz,
ꢀ
6'
Jm=1.1 Hz, CH), 8.37 (d, 1H, Jm=1.1 Hz, 2 CH), 8.65 (d, 1H,
Jo=1.0 Hz), 10.22 (s, 1H, NH). Anal. Calcd. for C23H19N3O4S:
C, 63.73; H, 4.42; N, 9.69; S, 7.40. Found: C, 63.66; H, 4.42;
N, 9.71; S, 7.41.
8-Amino-10-ethyl-10H-dibenzo[b,f][1,4]thiazepin-11-one
(7b). This compound was obtained as white solid in 84% yield,
mp 181-183˚; 1H nmr (DMSO-d6): ꢀ 1.18 (t, 3H, J=7.1 Hz, CH3),
4.50 (q, 2H, J=7.1 Hz, CH2), 4.90 (s, 2H, NH2), 6.52 (m, 1H,
ArH), 6.72 (m, 1H, ArH), 7.13 (d, 1H, Jo= 8.1 Hz, 6CH), 7.28 (m,
2H, 2ArH), 7.42 (dd, 1H, Jo=8.1 Hz, Jm=1.0 Hz, 7CH), 7.51 (d, 1H,
Jo=1.0 Hz). Anal. Calcd. for C15H14N2OS: C, 66.64; H, 5.22; N,
10.36; S, 11.86. Found: C, 66.57; H, 5.22; N, 10.33; S, 11.88.
8-Amino-10-propyl-10H-dibenzo[b,f][1,4]thiazepin-11-one
(7c). This compound was obtained as white solid in 82% yield,
2-Benzenesulfonylamino-N-(11-oxo-10-propyl-10,11-dihydro-
dibenzo[b,f][1,4]thiazepin-8-yl)-acetamide (8c). This compound
was obtained as white solid in 65% yield, mp 208-210˚; 1H nmr
(DMSO-d6): ꢀ 0.90 (t, 3H, CH3), 1.55 (m, 2H, CH2), 3.42 (m,
1H, CH), 3.54 (d, 2H, J= 6.2Hz, NCH2), 4.50 (m, 1H, CH), 7.26
(m, 4H, 4ArH), 7.45 (m, 5H, Ph), 7.52 (t, 1H, J=6.2 Hz, NH),
6
1
7.62 (d, 1H, Jo= 8.1 Hz, CH), 7.94 (dd, 1H, Jo=8.1 Hz, Jm=1.0
mp 172-174˚; H nmr (DMSO-d6): ꢀ 0.90 (t, 3H, J=6.8 Hz,
7
9
Hz, CH), 8.65 (d, 1H, Jo=1.0 Hz, CH), 10.15 (s, 1H, NH).
Anal. Calcd. for C24H23N3O4S2: C, 59.86; H, 4.81; N, 8.73; S,
13.32. Found: C, 59.81; H, 4.82; N, 8.75; S, 13.33.
CH3), 1.50 (m, 2H, CH2), 3.36 (m, 1H, CH), 4.45 (m, 1H, CH),
5.30 (s, 2H, NH2), 6.50 (m, 1H, ArH), 6.72 (m, 1H, ArH), 7.11
6
(d, 1H, Jo= 8.1 Hz, CH), 7.29 (m, 2H, 2ArH), 7.41 (dd, 1H,
Jo=8.1 Hz, Jm=1.0 Hz, 7CH), 7.50 (d, 1H, Jo=1.0 Hz). Anal.
Calcd. for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85; S, 11.27.
Found: C, 67.53; H, 5.68; N, 9.82; S, 11.29.
Furan-2-carboxylic acid (10-cyclopentyl-11-oxo-10,11-
dihydro-dibenzo[b,f][1,4]thiazepin-8-yl)-amide (8d). This
compound was obtained as white solid in 58% yield, mp 103-
1
105˚; H nmr (DMSO-d6): ꢀ 1.60 (m, 2H, CH2), 1.80 (m, 2H,
8-Amino-10-cyclopentyl-10H-dibenzo[b,f][1,4]thiazepin-
11-one (7d). This compound was obtained as white solid in 92%
CH2), 1.95 (m, 2H, CH2), 2.10 (m, 2H, CH2), 4.50 (m, 1H, CH),
6.80 (m, 3H, Fu), 7.26 (m, 4H, 4ArH), 7.60 (d, 1H, Jo= 8.1 Hz,
1
yield, mp 248-250˚; H nmr (DMSO-d6): ꢀ 1.6 (m, 8H, 4CH2),
7
6CH), 7.92 (dd, 1H, Jo=8.1 Hz, Jm=1.0 Hz, CH), 8.66 (d, 1H,
4.55 (m, 1H, NCH), 4.85 (s, 2H, NH2), 6.52 (m, 1H, ArH), 6.72
Jo=1.0 Hz, 9CH), 10.10 (s, 1H, NH). Anal. Calcd. for
C23H20N2O3S: C, 68.30; H, 4.98; N, 6.93; S, 7.93. Found: C,
68.26; H, 4.99; N, 6.89; S, 7.94.
6
(m, 1H, ArH), 7.13 (d, 1H, Jo= 8.1 Hz, CH), 7.28 (m, 2H,
7
2ArH), 7.42 (dd, 1H, Jo=8.1 Hz, Jm=1.0 Hz, CH), 7.51 (d, 1H,
Jo=1.0 Hz). Anal. Calcd. for C18H18N2OS: C, 69.65; H, 5.84; N,
9.02; S, 10.33. Found: C, 69.58; H, 4.85; N, 9.05; S, 10.34.
8-Amino-10-cyclopropyl-10H-dibenzo[b,f][1,4]thiazepin-
11-one (7e). This compound was obtained as white solid in 78%
N-(10-Cyclopropyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]-
thiazepin-8-yl)-isonicotinamide (8e). This compound was
obtained as white solid in 50% yield, mp >300˚; 1H nmr
(DMSO-d6): ꢀ 0.20 (m, 1H, CH), 0.80 (m, 2H, CH2), 1.20 (m,
1H, CH), 3.35 (m, 1H, CH), 7.26 (m, 4H, 4ArH), 7.62 (d, 1H,
1
yield, mp 215-217˚; H nmr (DMSO-d6): ꢀ 1.6 (m, 4H, 2CH2),
4.56 (m, 1H, NCH), 4.84 (s, 2H, NH2), 6.53 (m, 1H, ArH), 6.74
6
6
Jo= 8.1 Hz, CH), 7.75 (d, 2H, J=7.9 Hz, 2PyH), 7.94 (dd, 1H,
(m, 1H, ArH), 7.12 (d, 1H, Jo= 8.1 Hz, CH), 7.29 (m, 2H,
7
9
7
Jo=8.1 Hz, Jm=1.0 Hz, CH), 8.65 (d, 1H, Jo=1.0 Hz, CH), 8.70
(d, 2H, J=7.9 Hz, 2PyH), 10.31 (s, 1H, NH). Anal. Calcd. for
C22H17N3O2S: C, 68.20; H, 4.42; N, 10.85; S, 8.27. Found: C,
68.12; H, 4.43; N, 10.72; S, 8.28.
2ArH), 7.43 (dd, 1H, Jo=8.1 Hz, Jm=1.0 Hz, CH), 7.52 (d, 1H,
Jo=1.0 Hz). Anal. Calcd. for C16H14N2OS: C, 68.06; H, 5.00; N,
9.92; S, 11.35. Found: C, 67.99; H, 5.00; N, 9.95; S, 11.37.
General Procedure for Synthesis of 10-substituted N-(11-
oxo-11H-dibenzo[b,f][1,4]thiazepin-8-yl-amides (8a-e). A
mixture of 0.0011 mol of the corresponding carboxylic acid,
0.0011 mol of CDI and 3 ml of dry dioxane was stirred at 50
ºC for 1 h. Then 0.001 mol of (7a-e) was added to the reaction
mixture; it was refluxed for 5 h, then cooled down to a room
temperature and poured into 5% water solution of sodium
bicarbonate. The formed precipitate was collected by
filtration, washed with water, dried and purified by crystal-
lization from a mixture of ethanol and DMF to afford pure
reaction product (8a-e).
REFERENCES
[1] Floyd, D.M., Kimball, S.D., Krapcho, J., Das, J., Turk, C.F.,
Moquin, R.V., Lago, M.W., Duff, K.J., Lee, V.G., White, R.E., J. Med.
Chem. 1992, 35, 756-772.
[2] Donati, D.; Fabio, R.D., Pharm. Acta Helv. 2000, 74,
239-246.
[3] Tamura, S.Y., Goldman, E.A., Bergum, P.W., Semple J.E.,
Bioorg. Med. Chem. Lett. 1999, 9, 2573-2578.
Thiophene-2-carboxylic acid [(10-methyl-11-oxo-10,11-
dihydrodibenzo[b,f][1,4]thiazepin-8-ylcarbamoyl)-methyl]-
amide (8a). This compound was obtained as white solid in 80%
[4] Tabrizchi, R., Curr. Opin. Investig. Drugs. 2003, 4, 329-332.
[5] Robl, J.A., Simpkins, L.M., Stevenson, J., Sun, C.Q.,
Murugesan, N., Barrish, J.C., Asaad, M.M., Bird, J.E., Schaeffer, T.R.,

Nov-Dec 2007
Denitrocyclization in Synthesis of Dibenzo[b,f][1,4]thiazepin-11(10H)-ones
1251
and Their Derivatives
Trippodo, N.R., Petrillo, E.W., Karanewsky, D.S., Bioorg. Med. Chem.
Lett. 1994, 4, 1789-1794.
[8] Inoue, H., Konda, M., Hashiyama, T., Otsuka, H., Watanabe,
A., Gaino, M., Takahashi, K., Date, T., Okamura, K., Takeda, M.,
Narita, H., Murata, S., Odawara, A., Sasaki, H., Nagao, T. J. Med.
Chem., 34, 675-687 (1991).
[9] Klunder, J.M., Hargrave, K.D., West, M., Cullen, E., Pal, K.,
Behnke, M.L., Kapadia, S.R., McNeil, D.W., Wu, C., Chow, G.C.,
Adams, J., J. Med. Chem. 1992, 35, 1887-1897.
[6] Murakami, Y., Hara, H., Okada, T., Hashizume, H., Kii, M.,
Ishihara, Y., Ishikawa, M., Shimamura, M., Mihara, S., Kato, G., Hanasaki,
K., Hagishita, S., Fujimoto, M., J. Med. Chem. 1999, 42, 2621-2632.
[7] Robl, J.A., Simpkins, L.M., Asaad, M.M., Bioorg. Med.
Chem. Lett. 2000,10, 257-260.