Synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one compounds based on o-nitrochloro derivatives of benzene and pyridine

Article abstract of DOI:10.1016/j.mencom.2008.09.019

A new approach to the construction of tricyclic dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one systems based on N-substituted salicylamides and o-nitrochloro derivatives of benzene and pyridine has been developed.

Full text of DOI:10.1016/j.mencom.2008.09.019

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 281–283
Synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one and
pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one compounds
based on o-nitrochloro derivatives of benzene and pyridine
Alexander V. Sapegin,*a Vladimir N. Sakharov,a Levan S. Kalandadze,b Alexey V. Smirnov,a
Tatyana A. Khristolyubova,a Vladimir V. Plakhtinskiic and Alexander V. Ivashchenkoa
a K. D. Ushinsky Yaroslavl State Pedagogical University, 150000 Yaroslavl, Russian Federation.
Fax: +7 485 230 5522; e-mail: Sapegin_yar@mail.ru
b LLC ‘Intellectual Dialogue’, 150000 Yaroslavl, Russian Federation. Fax: +7 485 230 5522
c Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation. Fax: +7 485 272 6112;
e-mail: plakhtinskiyvv@ystu.ru
DOI: 10.1016/j.mencom.2008.09.019
A new approach to the construction of tricyclic dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-
10(11H)-one systems based on N-substituted salicylamides and o-nitrochloro derivatives of benzene and pyridine has been
developed.
The pharmacological properties of dibenzo[b,f][1,4]oxazepin-
11(10H)-one derivatives and their use in medical practices have
been reported.1–6
11(10H)-ones 7a in good yields.17,22,23 Another less popular
method involves the heating of xanthen-9-one oximes 4 with
phosphorus pentachloride17 or polyphosphoric acid.24 This results
in a dibenzoxazepine system via Beckmann rearrangement.
Note that the synthesis of benzoxazepinones 7a,b based on the
reaction of 2-(2-halophenoxy)phenylamines 5a and 2-(2-halo-
phenoxy)pyridine-3-amines 5b with carbon monoxide under
pressure in the presence of palladium catalysts.25 This method
involves the oxidation of dibenzo[b,f][1,4]oxazepines 6. Sodium
dichromate in acetic acid as the oxidant gives derivatives 7a,18
whereas hydrogen peroxide gives a mixture of products including
target dibenzoxazepinone 7a.26
We found that the use of intramolecular nucleophilic aromatic
substitution of a nitro group (denitrocyclisation27) for constructing
a tricyclic system is a promising method for the synthesis of
dibenzo[b,f][1,4]thiazepin-11(10H)-one derivatives.28–30 A dis-
tinctive feature of this approach is that not only the phenol
nucleophilic centre but also the amide one are involved in the
reaction.
The synthesis of derivatives 7a was described in 1934; it
involved the thermal cyclisation of 2-(2-aminophenoxy)benzoic
acid 1a (Scheme 1).7–9 This synthesis can be performed using
different10–13 esters 1a,b, and the cyclisation can be carried out
in different solvents.14–16 Another method for constructing the
heterocyclic system of compounds 7a,b involves intramolecular
aromatic substitution in 2-(o-halobenzamido)phenols,2,4,17–19
2-(o-nitrobenzamido)phenols 2a20,21 or 2-halo-N-(2-hydroxy-
phenyl)nicotinamides 2b.4 Intramolecular acylation of 1-iso-
cyanato-2-phenoxybenzenes 3 gives dibenzo[b,f][1,4]oxazepin-
NH2
R
O
X
O
(OH, OAlk, OPh)
We used this approach to synthesise dibenzo[b,f][1,4]oxazepin-
11(10H)-one derivatives 13a–f and hitherto unknown pyrido[2,3-b]-
[1,4]benzoxazepin-10(11H)-one derivatives 13g–l (Scheme 2).
We used 4-chloro-3-nitrobenzonitrile 8a and 2-chloro-3-nitro-
pyridine 8b as the substrates and N-alkyl- and N-aryl-substituted
salycilamides 9 as the reagents. The reaction was carried out in
DMF in the presence of a base. If strong bases such as sodium
hydride, sodium amide or potassium tert-butoxide 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, e.g., Chichibabin amination.
The use of potassium carbonate as the deprotonating agent also
resulted in denitrocyclisation at temperatures of ³ 80 °C. The
use of potassium carbonate was beneficial as it became unnecessary
to use anhydrous DMF and the yields of the target products
were high.†
R"
1a,b
OH
O
N
(F, Cl, NO2)
X
R
R''
N
O
R'
6
R"
2a,b
R"
O
N
X
R
O
R'
R''
R"
7a,b
(Br, I)
O
X
O
OH
N
NH2
5a,b
NCO
Hypothetically, the first step of the reaction of compounds
8 and 9 is either replacement of the chlorine atom with the
phenol oxygen atom to give intermediate compounds 10 or
replacement of the chlorine atom with an amide reaction centre
to give intermediate compounds 12.
3
O
a X = C
b X = N
4
Scheme 1
– 281 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 281–283
It was found using 1H NMR spectroscopy‡ that, in the
reaction of compounds 8a and 9a, the signals of the phenol
proton (d 13.7 ppm) and amide proton (d 8.5 ppm) in com-
pound 9a were no longer observed even 30 s after the start of
the reaction. Simultaneously, the signal of the amide proton in
compound 10a§ was recorded in the region of d 9.5–10.0 ppm,
which then decreased to zero in the course of the reaction.
Obviously, this means that in this case, the reaction of com-
pounds 8a and 9a initially gives not amide 12a but diphenyl
ether 10a, whose amide reaction centre can subsequently be
involved in denitrocyclisation to yield 13a or 14a.
R1
O
N
X
K2CO3
O
R2
R1
NO2
R2
13a–l
R2
X
N
HN
R1
NO2
O
O
+
In the reaction with compound 8b as the substrate, the
course of the reaction was determined using model experiments
(Scheme 3). We had to do so because, unlike in the first
HO
X
8a,b
Cl
HO
9a–f
12a–l
K2CO3 DMF
NO2
†
1H NMR spectra and two-dimensional correlation spectra 1H–1H NOESY
of 5% solutions of the samples in [2H6]DMSO were recorded using a
Bruker MSL-300 spectrometer.
General procedure for the synthesis of 13a–l. A mixture of compound
8 (0.10 mol), compound 9 (0.10 mol) and anhydrous K2CO3 (34.5 g,
0.25 mol) in DMF (150 ml) was stirred for 4 h at 75–80 °C, cooled and
poured into water. The precipitate formed was filtered off and recrystal-
lised from ethanol. Yield, 65–80%.
O
R1
R1
N
O
K2CO3
O
X
O
10a–l
R1
O
X
N
NH
R2
R2
O
1
13a: yield 80%, mp 147–149 °C. H NMR, d: 7.86 (s, 1H), 7.76 (d,
11a–l
1H, J 8.8 Hz), 7.68 (d, 1H, J 8.8 Hz), 7.59 (t, 2H), 7.34 (m, 2H), 3.54
(s, 3H). Found (%): C, 71.93; H, 4.03; N, 11.16. Calc. for C15H10N2O2
(%): C, 71.99; H, 4.03; N, 11.19.
R2
N
1
13b: yield 79%, mp 155–158 °C. H NMR, d: 7.88 (s, 1H), 7.72 (d,
O
1H, J 8.1 Hz), 7.68 (m, 2H), 7.58 (t, 1H), 7.34 (m, 2H), 4.22 (dd, 2H),
1.60 (m, 3H). Found (%): C, 72.50; H, 4.59; N, 10.63. Calc. for
C16H12N2O2 (%): C, 72.71; H, 4.58; N, 10.60.
X
O
1
13c: yield 70%, mp 134–137 °C. H NMR, d: 7.88 (s, 1H), 7.82 (d,
14a–l
1H, J 8.0 Hz), 7.68 (m, 2H), 7.58 (t, 1H), 7.34 (m, 2H), 4.22 (dd, 2H),
1.66 (m, 2H), 0.98 (m, 3H). Found (%): C, 73.20; H, 5.08; N, 10.09.
Calc. for C17H14N2O2 (%): C, 73.37; H, 5.07; N, 10.07.
8: a X = C, R1 = CN 10–14: a X = C, R1 = CN, R2 = Me
b X = N, R1 = H
b X = C, R1 = CN, R2 = Et
c X = C, R1 = CN, R2 = Pr
d X = C, R1 = CN, R2 = Ph
1
13d: yield 65%, mp 151–154 °C. H NMR, d: 8.58 (s, 1H), 8.18 (m,
9: a R2 = Me
b R2 = Et
2H), 7.92 (m, 2H), 7.72 (m, 2H), 7.52 (m, 4H), 7.30 (d, 1H, J 8.8 Hz).
Found (%): C, 76.71; H, 3.88; N, 9.01. Calc. for C20H12N2O2 (%): C,
76.91; H, 3.87; N, 8.97.
13e: yield 80%, mp 169–172 °C. 1H NMR, d: 7.91 (s, 1H), 7.73–7.85
(m, 4H), 7.60 (d, 1H, J 8.1 Hz), 7.52 (m, 2H), 70.31 (m, 2H), 7.24 (t,
1H), 2.54 (s, 3H). Found (%): C, 77.15; H, 4.33; N, 8.62. Calc. for
C21H14N2O2 (%): C, 77.29; H, 4.32; N, 8.58.
e X = C, R1 = CN, R2 = p-MeC6H4
f X = C, R1 = CN, R2 = p-ClC6H4
g X = N, R1 = H, R2 = Me
c R2 = Pr
d R2 = Ph
e R2 = p-MeC6H4
f R2 = p-ClC6H4
h X = N, R1 = H, R2 = Et
i X = N, R1 = H, R2 = Pr
j X = N, R1 = H, R2 = Ph
1
13f: yield 85%, mp 147–150 °C. H NMR, d: 7.95 (s, 1H), 7.80 (m,
k X = N, R1 = H, R2 = p-MeC6H4
l X = N, R1 = H, R2 = p-ClC6H4
2H), 7.54–7.71 (m, 7H), 7.32 (t, 1H). Found (%): C, 69.08; H, 3.20;
N, 8.12. Calc. for C20H11ClN2O2 (%): C, 69.27; H, 3.20; N, 8.08.
13g: yield 65%, mp 113–116 °C. 1H NMR, d: 8.29 (d, 1H, J 5.0 Hz),
7.76 (m, 2H), 7.57 (t, 1H), 7.23–7.34 (m, 3H), 3.56 (s, 3H). Found (%):
C, 68.81; H, 4.46; N, 12.44. Calc. for C13H10N2O2 (%): C, 69.02; H,
4.46; N, 12.38.
13h: yield 65%, mp 61–64 °C. 1H NMR, d: 8.28 (d, 1H, J 4.4 Hz), 7.5
(m, 2H), 7.56 (t, 1H), 7.21–7.32 (m, 3H), 4.23 (dd, 2H), 1.34 (t, 3H).
Found (%): C, 69.78; H, 5.04; N, 11.72. Calc. for C14H12N2O2 (%): C,
69.99; H, 5.03; N, 11.66.
13i: yield 75%, mp 83–86 °C. 1H NMR, d: 8.29 (d, 1H, J 3.7 Hz),
7.75 (m, 2H), 7.55 (t, 1H), 7.22–7.32 (m, 3H), 4.16 (t, 2H), 1.68 (m,
2H), 0.89 (t, 3H). Found (%): C, 70.64; H, 5.56; N, 11.07. Calc. for
C15H14N2O2 (%): C, 70.85; H, 5.55; N, 11.02.
Scheme 2
reaction, we failed to isolate intermediate compounds 10g–l or
12g–l from the reaction mixture, or obtain them in a pure form,
for the identification and assignment of signals. The reaction of
compound 8b with 2-hydroxy-N,N-dimethylbenzamide 15 in
DMF in the presence of potassium carbonate gave N,N-dimethyl-
2-(3-nitropyridin-2-yloxy)benzamide 16 in a high yield.¶ On
the other hand, we did not detect a reaction of compound 8b
with 2-methoxy-N-methylbenzamide 17 even at 110 °C. Data
of model experiments suggest that the reaction of 8b with
compounds 9 occurs by the same pathway as in the case of 8a.
1
13j: yield 80%, mp 145–148 °C. H NMR, d: 8.10 (d, 1H, J 4.5 Hz),
7.83 (m, 2H), 7.60 (t, 1H), 7.20–7.42 (m, 8H). Found (%): C, 74.76; H,
4.20; N, 9.77. Calc. for C18H12N2O2 (%): C, 74.99; H, 4.20; N, 9.72.
§
Synthesis of model compound 10a for identification and assignment of
1
13k: yield 85%, mp 151–154 °C. H NMR, d: 8.11 (d, 1H, J 4.8 Hz),
signals. A mixture of compound 8a (0.05 mol), methyl salicylate (0.05 mol)
and anhydrous K2CO3 (0.10 mol) in DMF (150 ml) was stirred for 3 h at
80 °C, then the reaction mixture was cooled and poured into water. The
precipitate formed was filtered off and recrystallised from ethanol. The
resulting ester was hydrolysed at 20 °C for 3 h in water–ethanol using
an equimolar amount of sodium hydroxide. Acidification of the reaction
mixture with concentrated hydrochloric acid to pH 1 gave the pure acid.
Amide 10a was synthesised by heating a mixture of phenoxysalicylic
acid (0.10 mol), methylamine (0.10 mol) and N,N-carbonyldiimidazole
(0.10 mol) in dioxane at 50 °C for 3 h. Yield, 53%, mp 128–131 °C.
1H NMR, d: 9.43 (s, 1H), 8.54 (m, 2H), 7.45 (m, 5H), 2.64 (d, 3H).
7.84 (m, 2H), 7.65 (t, 1H), 7.37 (m, 2H), 7.27 (m, 5H), 2.40 (s, 3H).
Found (%): C, 75.25; H, 4.67; N, 9.29. Calc. for C19H14N2O2 (%): C,
75.48; H, 4.67; N, 9.27.
13l: yield 90%, mp 132–135 °C. 1H NMR, d: 8.11 (d, 1H, J 4 Hz),
7.85 (m, 2H), 7.66 (t, 1H), 7.20–7.78 (m, 7H). Found (%): C, 66.85; H,
3.44; N, 8.71. Calc. for C18H11ClN2O2 (%): C, 66.99; H, 3.44; N, 8.68.
‡
1
Analytical control technique using H NMR spectroscopy. Compounds
8a,b (0.02 mol) and 9a (0.02 mol) and anhydrous K2CO3 (0.06 mol)
were added to [2H6]DMSO (5 ml); the reaction mixture was stirred at
75 °C and samples were taken at a specified time.
– 282 –

Mendeleev Commun., 2008, 18, 281–283
Obviously, the amide group in salicylamides 9 cannot serve as
This study was supported by the Federal Agency for Science
and Innovations (state contract no. 02.527.11.9002).
the nucleophilic reaction centre at the first stage of the process
in question, and compounds 10a–l are intermediate products on
the pathway that leads to the target tricyclic systems.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2008.09.019.
NMe2
NO2
O
O
HO
References
N
O
15
1
D. W. Zaharevitz, R. Gussio, A. Wiegand, R. Jalluri, N. Pattabiraman,
G. E. Kellogg, L. A. Pallansch, S. S. Yang and R. W. Buckheit, Med.
Chem. Res., 1999, 9, 551.
K2CO3
NMe2
DMF
2
3
4
R. A. Smits, H. D. Lim, B. Stegink, R. A. Bakker, I. J. Esch and R. Leurs,
J. Med. Chem., 2006, 49, 4512.
K. Nagarajan, J. David and G. A. Bhat, Indian J. Chem., Sect. B, 1985,
24, 840.
J. M. Klunder, K. D. Hargrave, M. West, E. Cullen and K. Pal, J. Med.
NO2
Cl
16
NHMe
NO2
N
O
MeO
Chem., 1992, 35, 1887.
8b
Me
5
6
K. Nagarajan, J. Indian Chem. Soc., 1997, 11, 831.
J. K. Chakrabarti and T. A. Hicks, Eur. J. Med. Chem. Chim. Ther.,
1987, 22, 161.
N
N
17
O
7
8
R. Q. Brewster and F. Strain, J. Am. Chem. Soc., 1934, 56, 117.
K. Brewster, R. J. Clarke, J. M. Harrison, T. D. Inch and D. Utley,
J. Chem. Soc., Perkin Trans. 1, 1976, 1286.
MeO
18
9
L. K. Ottesen, F. Ek and R. Olsson, Org. Lett., 2006, 9, 1771.
Scheme 3
10 A. M. Allen and R. Y. Moir, Can. J. Chem., 1959, 37, 1799.
11 K. Nagarajan, Indian J. Chem., 1974, 12, 236.
1H–1H NOESY spectrum of the end product obtained from
compound 8a†† contains a cross-peak that characterises the
interaction of NMe protons (d 3.5 ppm) with one aromatic
proton (the proton at C9, d 7.68 ppm). The signal of this proton
is a doublet with J 8.8 Hz, which characterises its ortho-interac-
tion with another proton (the proton at C8, d 7.76 ppm); this is
also observed as a cross peak in the NOESY spectrum.
1H–1H NOESY spectrum of the end product obtained from
compound 8b†† contains a cross-peak in the region characterising
the interaction of the protons in the NMe group (d 3.56 ppm)
with an aromatic proton in the pyridinium ring (the proton at
C3, d 7.76 ppm).
12 L. Wang, G. M. Sullivan, L. A. Hexamer, L. A. Hasvold, R. Thalji,
M. Przytulinska, Z. Tao, G. Li, Z. Chen, Z. Xiao, W. Gu, J. Xue, M. Bui,
P. Merta, P. Kovar, J. J. Bouska, H. Zhang, C. Park, K. D. Stewart,
H. L. Sham, T. J. Sowin, S. H. Rosenberg and N. Lin, J. Med. Chem.,
2007, 50, 4162.
13 J. F. Liegeois, F. A. Rogister, J. Bruhwyler, J. Damas, T. P. Nguyen,
M. O. Inarejos, E. Chleide, M. Mercier and J. E. Delarge, J. Med. Chem.,
1994, 37, 519.
14 R. A. Bunce and J. E. Schammerhorn, J. Heterocycl. Chem., 2006, 43,
1031.
15 M. Tomita and T. Kitamura, Yakugaku Zasshi, 1955, 75, 1138.
16 K. Nagarajan, J. David, Y. S. Kulkarni, S. B. Hendi, S. J. Shenoy and
P. Upadhyaya, Eur. J. Med. Chem. Chim. Ther., 1986, 21, 21.
17 K. Nagarajan, Indian J. Chem., 1974, 12, 252.
18 A. V. Konstantinova, T. N. Gerasimova, M. M. Kozlova and N. I. Petrenko,
Khim. Geterotsikl. Soedin., 1989, 539 [Chem. Heterocycl. Compd. (Engl.
Transl.), 1989, 25, 451].
19 X. Xing, J. Wu, J. Luo and W. Dai, Synlett., 2006, 13, 2099.
20 A. V. Samet, V. N. Marshalkin, K. A. Kislyi, N. B. Chernysheva, Yu. A.
Strelenko and V. V. Semenov, J. Org. Chem., 2005, 70, 9371.
21 A. V. Samet, K. A. Kislyi, V. N. Marshalkin and V. V. Semenov, Izv.
Akad. Nauk, Ser. Khim., 2006, 529 (Russ. Chem. Bull., Int. Ed., 2006,
55, 549).
2D correlation spectra 1H–1H NOESY provide more detailed
information on denitrocyclisation products. They do not match
structures 14 that can result from direct denitrocyclisation of
compounds 10. The spectral data are in full agreement with
structures 13, which are presumably formed due to the Smiles
rearrangement31–33 preceding the intramolecular aromatic sub-
stitution of the nitro group and occurring via intermediates 11
and 12 (Scheme 2).
Thus, this study has shown that the first stage of the process
of interest involves the hydroxy group as the nucleophilic reaction
centre in salicylamides. The formation of the target tricyclic
systems involves binuclear diphenyl ethers or phenoxypyridines
as intermediates. The intramolecular aromatic substitution of
the nitro group is preceded by a Smiles rearrangement. An
undeniable advantage of the approach to the construction of
dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]-
benzoxazepin-10(11H)-one systems is that diverse substituents
can be introduced at the nitrogen atom before the tricyclic system
is formed and that a wide range of compounds belonging to
these classes can be obtained in high yields.
22 Y. Nagai, A. Irie, H. Nakamura, K. Hino, H. Uno and H. Nishimura,
J. Med. Chem., 1982, 25, 1065.
23 B. S. Wagh, B. P. Patil, M. S. Jam, S. S. Harak and S. B. Wagh, Heterocycl.
Commun., 2007, 13, 165.
24 A. T. Troshchenko and T. P. Lobanova, Zh. Org. Khim., 1967, 3, 501
[J. Org. Chem. USSR (Engl. Transl.), 1967, 3, 480].
25 S. Lu and H. Alper, J. Am. Chem. Soc., 2005, 42, 1477.
26 K. Brewster, R. A. Chittenden, J. M. Harrison, T. D. Inch and C. Brown,
J. Chem. Soc., Perkin Trans. 1, 1976, 1291.
27 S. Radl, Adv. Heterocycl. Chem., 2002, 83, 189.
28 A. V. Smirnov, L. S. Kalandadze, V. N. Sakharov and M. V. Dorogov,
Mendeleev Commun., 2006, 262.
29 L. S. Kalandadze, A. V. Smirnov and M. V. Dorogov, Izv. Vyssh. Uchebn.
Zaved., Khim. Khim. Tekhnol., 2007, no. 1, 78 (in Russian).
30 L. S. Kalandadze, A. V. Smirnov and M. V. Dorogov, Izv. Vyssh. Uchebn.
Zaved., Khim. Khim. Tekhnol., 2007, no. 8, 51 (in Russian).
31 S. Smiles and W. J. Evansan, J. Chem. Soc., 1935, 1, 181.
32 M. Mizuno and M. Yamano, Org. Lett., 2005, 7, 3629.
33 H. Zuo, L. Meng, M. Ghate, K. Hwang, Y. K. Cho, S. Chandrasekhar,
C. R. Reddy and D. Shin, Tetrahedron Lett., 2008, 49, 3827.
¶
A mixture of compound 8b (0.05 mol), compound 14 (0.05 mol) and
anhydrous K2CO3 (0.12 mol) in DMF (150 ml) was stirred for 4 h at
75–80 °C, then the reaction mixture was cooled and poured into water.
The precipitate formed was filtered off and recrystallised from ethanol to
give compound 16. Yield 85%; mp 110–113 °C. 1H NMR, d: 7.81 (s,
1H), 7.65 (d, 1H, J 8.8 Hz), 7.54 (d, 1H, J 8.8 Hz), 7.49 (t, 2H), 7.34 (m,
2H), 3.45 (s, 6H).
1
†† For H–1H NOESY spectra of the end products obtained from com-
pounds 8a and 8b, see Online Supplementary Materials.
Received: 28th February 2008; Com. 08/3089
– 283 –