Denitrocyclisation in the synthesis of dibenzothiazepinones

Article abstract of DOI:10.1070/MC2006v016n05ABEH002393

A new method has been elaborated for the synthesis of new compounds of the dibenzothiazepine series by intramolecular aromatic substitution of the nitro group.

Full text of DOI:10.1070/MC2006v016n05ABEH002393

Mendeleev
Communications
Mendeleev Commun., 2006, 16(5), 262–264
Denitrocyclisation in the synthesis of dibenzothiazepinones
Alexey V. Smirnov, Levan S. Kalandadze, Vladimir N. Sakharov and Mikhail V. Dorogov*
K. D. Ushinsky Yaroslavl State Pedagogical University, 150000 Yaroslavl, Russian Federation. E-mail: Michael_Dorogov@list.ru
DOI: 10.1070/MC2006v016n05ABEH002393
A new method has been elaborated for the synthesis of new compounds of the dibenzothiazepine series by intramolecular aromatic
substitution of the nitro group.
Dibenzothiazepines are of interest as potential antivirals, in
particular, for AIDS prevention and treatment.1–3 However, the
methods of their synthesis are usually limited to the reaction of
ortho-aminothiophenols with the derivatives of ortho-halobenzoic
acids, which does not offer a wide variety of these compounds
(Scheme 1).1–3
We have developed a new method to synthesise the specified
compounds based on the intramolecular aromatic substitution of
the nitro group (denitrocyclisation).4 Unlike the known methods,
our method makes it possible to introduce a required substituent
at the nitrogen atom even before the ring has formed, using
almost any primary amine for this purpose.1–2
serves as the main reagent in the synthesis. We used 2,4-di-
nitrochlorobenzene 1 to obtain dibenzothiazepines containing a
nitro group, which was then converted into an amino group.
Intermediate 2-(2,4-dinitrophenylthio)benzoic acid 3 can be
obtained in a high yield by heating equimolar amounts of the
specified reagents and triethylamine (acceptor of hydrogen
chloride) at 80 °C for 3 h (Scheme 2).†
At the next stage of the synthesis of dibenzothiazepines, a
solution of 2-(2,4-dinitrophenylthio)benzoyl chloride 4 in dioxane
was obtained. Product 4 is used without isolation from solution
in the subsequent reaction with primary amines to give corre-
sponding amides 5a–e (Scheme 3).‡
Thiosalicylic acid 2, which readily participates in nucleo-
philic substitution with various activated aromatic substrates,
†
1H NMR spectra of 5% solutions in [2H6]DMSO with TMS as an
internal standard were recorded on a Bruker DPX-300 instrument.
2-(2,4-Dinitrophenylthio)benzoic acid 3. A mixture of 2,4-dinitro-
chlorobenzene 1 (20.26 g, 0.1 mol), thiosalicylic acid 2 (15.42 g, 0.1 mol),
triethylamine (20.24 g, 0.2 mol) and isopropanol (150 ml) was stirred at
80 °C for 3 h; the reaction mixture was then cooled and neutralised with
hydrochloric acid. The precipitate that formed was filtered off, washed
with water and dried. Yield 90%, mp 220–223 °C. 1H NMR, d: 8.92
(s, 1H), 8.20 (d, 1H, J 8 Hz), 8.00 (d, 1H, J 8.1 Hz), 7.65 (m, 3H), 7.06
(d, 1H, J 7.9 Hz). Found (%): C, 48.65; H, 2.52; N, 8.70; S, 10.02. Calc.
for C13H8N2O6S (%): C, 48.75; H, 2.52; N, 8.73; S, 10.01.
R'
R'
O
Y
X
N
NH
O
+
R
R''
R
R''
SH
S
X = F, Cl, Br, I
Y = Cl, OH, OAlk
Scheme 1
262 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(5), 262–264
O
O
N
O
N
O
N
OH
N
O
R
N
O
O
O
O
O
N
+
O
Base, DMF
23–90%
S
O
Cl
HS
O
1
2
NH
S
O
O
N
R
5a–e
6a–e
N
O
O
Scheme 4 Reagents and conditions: i, 0–20 °C, 2 h, R = Me, Base = NaH
(80%), NaNH2 (23%), KOBut (88%); ii, 120 °C, 5 h, R = Me, Base = K2CO3
(90%).
NEt3, PriOH
80 °C, 3 h, 90%
S
O
OH
e.g., the Chichibabin amination. The use of potassium carbonate
as the deprotonating agent also resulted in denitrocyclisation,
but only at temperatures no lower than 120 °C. The use of
potassium carbonate is beneficial as it becomes unnecessary to
use anhydrous DMF, whereas the yields of products 6a–e remain
high (80–90%).§
3
Scheme 2
The formation of a thiazepine ring occurs via the nucleophilic
replacement of the nitro group with the amide nucleophilic centre
that is formed on treatment with deprotonating agents (Scheme 4).
If strong bases, such as sodium hydride, sodium amide or potas-
sium tert-butylate were used, the reaction occurred even at room
temperature. The reaction product was formed in a low yield
only if sodium amide was used, perhaps due to a side reaction,
Another goal of this study was the functionalisation of 8-nitro-
dibenzothiazepines 6a–e to corresponding amino 7a–e¶ and
R
N
R
N
O
N
O
O
H2N
SnCl2
O
80–90%
O
N
O
N
O
N
O
N
S
S
6a–e
7a–e
O
O
O
O
R1
HN
O
SOCl2
R
N
S
O
S
O
O
R1COOH, CDI
OH
Cl
dioxane, 50–80 °C
S
3
4
8a–e
O
O
N
O
N
O
N
O
O
a R = Me
b R = Et
c R = Pr
b R1 =
a R1 =
O
NH
RNH2, NEt3
60–90%
S
S
O
Me
e R1 =
d R = cyclopentyl
e R = cyclopropyl
NH
R
O
N
c R1 =
d R1 =
S
O
N
5a–e
Scheme 3
O
H
Scheme 5
‡
§
Thionyl chloride (13.09 g, 0.11 mol) was added to a suspension of
Compound 5a–e (0.1 mol) and potassium carbonate (27.64 g, 0.2 mol)
compound 3 (32.03 g, 0.1 mol) in anhydrous dioxane (100 ml). The
mixture was stirred for 2 h at 50 °C and cooled, and a solution of a
primary amine (0.11 mol) and triethylamine (11.13 g, 0.11 mol) in
dioxane (200 ml) was then added dropwise. The reaction mixture was
stirred for 2 h, cooled and poured into water. The precipitate that formed
was filtered off and dried.
were added to DMF (100 ml). The reaction mixture was stirred for 5 h at
120 °C, cooled and poured into water. The precipitate was filtered off,
washed with water and recrystallised from an ethanol–DMF mixture.
6a: yield 90%, mp 187–189 °C. 1H NMR, d: 8.38 (s, 1H), 8.22 (d, 1H,
J 8.0 Hz), 7.66 (d, 1H, J 8.0 Hz), 7.58 (m, 1H), 7.47 (m, 1H), 7.36 (m,
2H), 3.60 (s, 3H). Found (%): C, 58.66; H, 3.52; N, 9.80; S, 11.22. Calc.
for C14H10N2O3S (%): C, 58.73; H, 3.52; N, 9.78; S, 11.20.
6b: yield 85%, mp 119–121 °C. 1H NMR, d: 8.37 (s, 1H), 8.20 (d, 1H,
J 8.0 Hz), 7.63 (d, 1H, J 8.0 Hz), 7.56 (m, 1H), 7.45 (m, 1H), 7.34 (m,
2H), 4.57 (dd, 1H), 3.51 (dd, 1H), 1.21 (t, 3H). Found (%): C, 59.89; H,
4.03; N, 9.37; S, 10.69. Calc. for C15H12N2O3S (%): C, 59.99; H, 4.03; N,
9.33; S, 10.67.
5a: yield 79%, mp 174–176 °C. 1H NMR, d: 8.95 (s, 1H), 8.20 (m,
2H), 7.60 (m, 4H), 7.00 (d, 1H, J 8.1 Hz), 2.70 (s, 3H). Found (%): C,
50.37; H, 3.33; N, 12.65; S, 9.63. Calc. for C14H11N3O5S (%): C, 50.45;
H, 3.33; N, 12.61; S, 9.62.
5b: yield 82%, mp 143–145 °C. 1H NMR, d: 8.94 (s, 1H), 8.40 (t, 1H),
8.19 (d, 1H, J 8.1 Hz), 7.59 (m, 4H), 6.97 (d, 1H, J 8.0 Hz), 3.21 (dd,
2H), 1.02 (t, 3H). Found (%): C, 51.78; H, 3.78; N, 12.09; S, 9.24. Calc.
for C15H13N3O5S (%): C, 51.87; H, 3.77; N, 12.10; S, 9.23.
6c: yield 80%, mp 117–119 °C. 1H NMR, d: 8.40 (s, 1H), 8.22 (d, 1H,
J 8.0 Hz), 7.86 (d, 1H, J 8.0 Hz), 7.60 (t, 1H), 7.52 (d, 1H, J 8.1 Hz),
7.42 (m, 2H), 4.60 (m, 1H), 3.70 (m, 1H), 1.60 (m, 2H), 0.90 (t, 3H).
Found (%): C, 61.05; H, 4.49; N, 8.88; S, 10.21. Calc. for C16H14N2O3S
(%): C, 61.13; H, 4.49; N, 8.91; S, 10.20.
1
5c: yield 86%, mp 93–95 °C. H NMR, d: 8.94 (s, 1H), 8.32 (t, 1H),
8.20 (d, 1H, J 8.0 Hz), 7.58 (m, 4H), 7.00 (d, 1H, J 8.1 Hz), 3.08 (dd,
2H), 1.40 (m, 2H), 0.80 (t, 3H). Found (%): C, 53.14; H, 4.19; N, 11.60;
S, 8.88. Calc. for C16H15N3O5S (%): C, 53.18; H, 4.18; N, 11.63; S, 8.87.
5d: yield 90%, mp 140–142 °C. 1H NMR, d: 8.95 (s, 1H), 8.37 (d, 1H,
J 8.5 Hz), 8.21 (d, 1H, J 8.0 Hz), 7.61 (m, 4H), 7.01 (d, 1H, J 8.0 Hz),
4.05 (m, 1H), 1.60 (m, 8H). Found (%): C, 55.79; H, 4.43; N, 10.82;
S, 8.29. Calc. for C18H17N3O5S (%): C, 55.80; H, 4.42; N, 10.85; S, 8.28.
5e: yield 60%, mp 131–133 °C. 1H NMR, d: 8.94 (s, 1H), 8.38 (d, 1H,
J 8.5 Hz), 8.19 (d, 1H, J 8.1 Hz), 7.60 (m, 4H), 7.00 (d, 1H, J 8.0 Hz),
2.70 (m, 1H), 0.62 (m, 2H), 0.40 (m, 2H). Found (%): C, 53.43; H, 3.65;
N, 11.67; S, 8.93. Calc. for C16H13N3O5S (%): C, 53.48; H, 3.65; N, 11.69;
S, 8.92.
6d: yield 87%, mp 157–159 °C. 1H NMR, d: 8.40 (s, 1H), 8.21 (d, 1H,
J 8.0 Hz), 7.85 (d, 1H, J 8.0 Hz), 7.61 (t, 1H), 7.51 (d, 1H, J 8.1 Hz),
7.41 (m, 2H), 4.50 (m, 1H), 2.00–1.50 (m, 8H). Found (%): C, 63.46; H,
4.74; N, 8.20; S, 9.43. Calc. for C18H16N2O3S (%): C, 63.51; H, 4.74; N,
8.23; S, 9.42.
6e: yield 82%, mp 153–155 °C. 1H NMR, d: 8.37 (s, 1H), 8.27 (d, 1H,
J 8.0 Hz), 7.83 (d, 1H, J 8.0 Hz), 7.70 (m, 1H), 7.52 (m, 1H), 7.42 (m,
2H), 3.50 (m, 1H), 1.22 (m, 1H), 0.80 (m, 2H), 0.05 (m, 1H). Found
(%): C, 61.47; H, 3.88; N, 8.95; S, 10.27. Calc. for C16H12N2O3S (%):
C, 61.53; H, 3.87; N, 8.97; S, 10.26.
Mendeleev Commun. 2006 263

Mendeleev Commun., 2006, 16(5), 262–264
amido derivatives 8a–e.†† Nitro derivatives were reduced chemi-
cally using tin(II) chloride as a reducing agent. The final stage
involved acylation using acylimidazoles obtained in situ from
acids and carbonyldiimidazole as the reagents (Scheme 5).
3 R. Pauwls, Nature, 1990, 343, 470.
4 S. Radl, Adv. Heterocycl. Chem., 2002, 83, 189.
References
Received: 31st May 2006; Com. 06/2738
1 K. D. Hargrave, G. Schmidt, W. Engel and K. Schromm, European
Patent, 419861, 1991.
2 R. H. Nicol, M. J. Slater and S. T. Horgson, US Patent, 5607929, 1997.
†† A mixture of anhydrous dioxane (3 ml), a carboxylic acid (0.0011 mol)
and carbonyldiimidazole (CDI) (0.18 g, 0.0011 mol) was stirred for 1 h at
50 °C. After that, compound 7a–e (0.001 mol) was added, and the mix-
ture was stirred for 5 h at 100 °C. The mixture was cooled and poured
into a solution of sodium carbonate. The precipitate was filtered off,
washed with water and recrystallised from an ethanol–DMF mixture.
8a: yield 80%, mp 171–173 °C. 1H NMR, d: 10.05 (s, 1H), 8.65 (s, 1H),
7.92 (s, 1H), 7.75 (s, 1H), 7.60 (d, 2H, J 8.0 Hz), 7.49 (d, 1H, J 8.1 Hz),
7.42 (d, 1H, J 8.0 Hz), 7.30 (m, 3H), 7.05 (t, 1H), 4.00 (t, 2H), 3.48
(s, 3H). Found (%): C, 59.48; H, 4.05; N, 9.96; S, 15.16. Calc. for
C21H17N3O3S2 (%): C, 59.56; H, 4.05; N, 9.92; S, 15.14.
¶
Compound 6a–e, tin dichloride dihydrate (78.96 g, 0.35 mol) and 30%
hydrochloric acid (85 ml, 0.7 mol) were added to 100 ml of ethanol. The
mixture was stirred for 2 h at 80 °C, cooled and poured into a solution of
sodium hydroxide (40 g, 1 mol) in water (300 ml). The precipitate was
filtered off, washed with water and reprecipitated from DMF.
1
7a: yield 93%, mp 227–229 °C. H NMR, d: 7.50 (d, 1H, J 8.1 Hz),
7.41 (d, 1H, J 8.1 Hz), 7.29 (m, 2H), 7.11 (d, 1H, J 8.0 Hz), 6.72 (s, 1H),
6.50 (d, 1H, J 8.2 Hz), 5.26 (s, 2H), 3.52 (s, 3H). Found (%): C, 65.50;
H, 4.72; N, 10.95; S, 12.52. Calc. for C14H12N2OS (%): C, 65.60; H, 4.72;
N, 10.93; S, 12.51.
1
8b: yield 72%, mp 257–259 °C. H NMR, d: 10.22 (s, 1H), 8.10 (s,
1H), 8.00 (m, 3H), 7.88 (d, 1H, J 8.1 Hz), 7.57 (d, 1H, J 8.0 Hz), 7.40
(d, 1H, J 8.1 Hz), 7.32 (d, 1H, J 8.0 Hz), 7.25 (t, 2H), 4.52 (dd, 1H), 3.65
(dd, 1H), 1.25 (t, 3H). Found (%): C, 63.66; H, 4.42; N, 9.71; S, 7.41.
Calc. for C23H19N3O4S (%): C, 63.73; H, 4.42; N, 9.69; S, 7.40.
8c: yield 65%, mp 208–210 °C. 1H NMR, d: 9.80 (s, 1H), 7.85 (s, 1H),
7.80 (s, 3H), 7.52 (d, 1H, J 8.0 Hz), 7.45 (m, 5H), 7.26 (m, 3H), 4.50
(m, 1H), 3.54 (d, 2H, J 6.2 Hz), 3.42 (m, 1H), 1.55 (m, 2H), 0.90 (t, 3H).
Found (%): C, 59.81; H, 4.82; N, 8.75; S, 13.33. Calc. for C24H23N3O4S2
(%): C, 59.86; H, 4.81; N, 8.73; S, 13.32.
1
7b: yield 84%, mp 181–183 °C. H NMR, d: 7.52 (d, 1H, J 8.1 Hz),
7.38 (d, 1H, J 8.1 Hz), 7.29 (t, 2H), 7.00 (d, 1H, J 8.0 Hz), 6.73 (s, 1H),
6.50 (d, 1H, J 8.1 Hz), 4.90 (s, 2H), 4.50 (dd, 1H), 3.45 (dd, 1H), 1.18
(t, 3H). Found (%): C, 66.57; H, 5.22; N, 10.33; S, 11.88. Calc. for
C15H14N2OS (%): C, 66.64; H, 5.22; N, 10.36; S, 11.86.
1
7c: yield 82%, mp 172–174 °C. H NMR, d: 7.50 (d, 1H, J 8.1 Hz),
7.41 (d, 1H, J 8.1 Hz), 7.29 (m, 2H), 7.10 (d, 1H, J 8.0 Hz), 6.72 (s, 1H),
6.51 (d, 1H, J 8.2 Hz), 5.30 (s, 2H), 4.45 (m, 1H), 3.36 (m, 1H), 1.50
(m, 2H), 0.90 (t, 3H). Found (%): C, 67.53; H, 5.68; N, 9.82; S, 11.29.
Calc. for C16H16N2OS (%): C, 67.58; H, 5.67; N, 9.85; S, 11.27.
1
8d: yield 58%, mp 103–105 °C. H NMR, d: 10.00 (s, 1H), 8.10 (s,
1H), 7.80 (d, 1H, J 8.1 Hz), 7.65 (s, 1H), 7.60 (d, 1H, J 8.2 Hz), 7.40
(d, 1H, J 8.0 Hz), 7.20 (m, 4H), 6.50 (s, 1H), 4.50 (t, 1H), 2.10 (m, 2H),
1.95 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H). Found (%): C, 68.26; H, 4.99;
N, 6.89; S, 7.94. Calc. for C23H20N2O3S (%): C, 68.30; H, 4.98; N, 6.93;
S, 7.93.
1
7d: yield 92%, mp 248–250 °C. H NMR, d: 7.55 (d, 1H, J 8.0 Hz),
7.34 (d, 1H, J 8.0 Hz), 7.20 (m, 2H), 6.95 (d, 1H, J 8.0 Hz), 6.75 (s, 1H),
6.44 (d, 1H, J 8.1 Hz), 4.85 (s, 2H), 4.55 (t, 1H), 2.10 (m, 1H), 1.90–
1.40 (m, 7H). Found (%): C, 69.58; H, 5.84; N, 9.05; S, 10.34. Calc. for
C18H18N2OS (%): C, 69.65; H, 5.84; N, 9.02; S, 10.33.
1
8e: yield 50%, mp > 300 °C. H NMR, d: 10.30 (s, 1H), 8.70 (d, 2H,
1
7e: yield 78%, mp 215–217 °C. H NMR, d: 7.65 (d, 1H, J 8.0 Hz),
J 8.1 Hz), 8.05 (s, 1H), 7.81 (d, 1H, J 7.9 Hz), 7.75 (d, 2H, J 8.1 Hz),
7.70 (d, 1H, J 8.2 Hz), 7.45 (t, 1H), 7.38 (d, 1H, J 8.1 Hz), 7.30 (t, 2H),
3.35 (m, 1H), 1.20 (m, 1H), 0.80 (m, 2H), 0.20 (m, 1H). Found (%):
C, 68.12; H, 4.43; N, 10.72; S, 8.28. Calc. for C22H17N3O2S (%): C, 68.20;
H, 4.42; N, 10.85; S, 8.27.
7.40 (d, 1H, J 8.0 Hz), 7.35 (m, 2H), 7.10 (d, 1H, J 8.0 Hz), 6.70 (s, 1H),
6.55 (d, 1H, J 8.0 Hz), 5.20 (s, 2H), 3.30 (m, 1H), 1.20 (m, 1H), 0.70 (m,
2H), 0.05 (m, 1H). Found (%): C, 67.99; H, 5.00; N, 9.95; S, 11.37.
Calc. for C16H14N2OS (%): C, 68.06; H, 5.00; N, 9.92; S, 11.35.
264 Mendeleev Commun. 2006