Synthesis of substituted dibenz[b,f]oxepines from 2,4,6-trinitrotoluene

Article abstract of DOI:10.1007/s11172-010-0014-6

1,3-Dinitro[b,f]dibenzoxepine undergoes nucleophilic substitution with O-and S-nucleophiles, the nitro group at position 1 (peri-nitro group) being selectively replaced. The factors responsible for the selectivity of the reaction are discussed.

Full text of DOI:10.1007/s11172-010-0014-6

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 347—350, February, 2009
347
Synthesis of substituted dibenz[b,f]oxepines from 2,4,6ꢀtrinitrotoluene*
A. V. Samet,a V. N. Marshalkin,a K. A. Lyssenko,b and V. V. Semenova
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: sametav@server.ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: kostya@xray.ineos.ac.ru
1,3ꢀDinitro[b,f]dibenzoxepine undergoes nucleophilic substitution with Oꢀ and Sꢀnucleoꢀ
philes, the nitro group at position 1 (periꢀnitro group) being selectively replaced. The factors
responsible for the selectivity of the reaction are discussed.
Key words: 1,3ꢀdinitrodibenz[b,f]oxepine, phenolate anions, thiophenolate anions, SNAr
substitution reaction, aromatic nitro compounds.
volves the condensation followed by the intramolecular
nucleophilic substitution of the nitro group to form
1,3ꢀdinitrodibenz[b,f]oxepine.6 As was shown earlier,2,7—9
such benzannulated dinitro compounds can further be
functionalized by replacing one or both nitro groups with
nucleophiles.
We showed that one nitro group in 1,3ꢀdinitrodibenzꢀ
[b,f]oxepine (1) is replaced with Oꢀ and Sꢀnucleophiles
(phenolate and thiophenolate anions) (Scheme 1, Table 1).
In the course of investigation on the utilization of
aromatic polynitro compounds, we turned our attention
to the use of these compounds for the synthesis of
benzannulated sevenꢀmembered heterocycles,1—4 because
some classes of these compounds (in particular, 1,4ꢀbenꢀ
zodiazepines, dibenz[b,f]azepines, and dibenz[b,f]oxazeꢀ
pines) are widely used in medicine as agents having an
action on the central nervous system.
Scheme 1
Sintamil
Tricyclic
(antidepressant)
antidepressants
Reagents and conditions: RXH, K2CO3, DMF, 100 °C.
The reaction is regioselective and results in the substiꢀ
tution of the nitro group at position 1, i.e., of the nitro
group nearest to the bridgehead position. The selectivity
of substitution was confirmed by the Xꢀray diffraction
study of compound 2а (Fig. 1).
In the case of Sꢀnucleophiles, the structures of the
replacement products were confirmed by the indepenꢀ
dent synthesis of compound 2m from 2ꢀ[(4ꢀmethylꢀ
phenyl)sulfanyl]ꢀ4,6ꢀdinitrotoluene 3 (see Ref. 10) and
salicylaldehyde (Scheme 2).
Nitrazepam
(insomnia medication)
The aim of the present study was to synthesize related
systems, viz., substituted dibenz[b,f]oxepines, some of
which were also found to have biological activity.5 The
reaction of 2,4,6ꢀtrinitrotoluene with salicylaldehyde inꢀ
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
The result of the present study was unexpected. It is
known that the nitro group nearest to the bridgehead
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 344—346, February, 2009.
1066ꢀ5285/09/5802ꢀ0347 © 2009 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Samet et al.
Table 1. Synthesis of substituted dibenz[b,f]oxepines 2a—m*
Product
RХ
T/°C
Yield (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
РhO
100
100
100
100
100
100
100
100
100
100
100
70
76
75
79
81
64
67
68
76
58
69
72
72
67
4ꢀMeC6H4O
3ꢀMeC6H4O
4ꢀMeОC6H4O
3ꢀMeОC6H4O
2ꢀMeОC6H4O
4ꢀClC6H4O
3ꢀClC6H4O
2,4ꢀCl2C6H3O
4ꢀBrC6H4O
4ꢀAcNHC6H4O
PhS
membered systems (for example, in dibenzoxazepinone
A)2 or, at least, the substitution is nonselective.14
It was hypothesized2 that the selective substitution of
the nitro group remote from the bridgehead position in
dibenzoxazepinone A is due to substantial steric hindrance
caused by the C=O group to the attack on the peri posiꢀ
tion. From this standpoint, the difference in the regioselecꢀ
tivity between compound A and 1,3ꢀdinitrodibenz[b,f]ꢀ
oxepine 1 can be attributed to the fact that the C—H group
in the latter compound causes much less hindrance to the
periꢀattack than the carbonyl group in compound A.14,15
2j
2k
2l
2m
4ꢀMeC6H4S
70
* The reaction time is 3 h.
O(3)
O(2)
N(1)
C(4)
C(6)
Experimental
O(5)
C(4A)
C(3)
C(5A)
The 1H NMR spectra were recorded on Bruker AM 300 and
Bruker DRX 500 instruments operating at 300.13 and 500.13 MHz,
respectively, in DMSOꢀd6. The EI mass spectra (70 eV) were
obtained on a Kratos MSꢀ30 instrument. 2ꢀ[(4ꢀMethylphenyl)ꢀ
sulfanyl]ꢀ4,6ꢀdinitrotoluene 3 was synthesized from 2,4,6ꢀtriꢀ
nitrotoluene according to a known procedure.10
The Xꢀray diffraction data for compound 2a (C20H13NO4)
were measured at –173 °C on an automated threeꢀcircle Smart
APEX II CCD diffractometer (MoꢀKα, graphite monochroꢀ
mator, ωꢀscanning technique, 2θ < 60°). At –173 °C, the
crystals are monoclinic: a = 4.5725(6) Å, b = 31.849(4) Å,
C(7)
C(8)
C(9)
C(2)
C(1)
C(4B)
C(5B)
C(10)
C(13)
C(13´)
C(14´)
C(14)
C(15)
C(12)
C(11)
O(1)
C(17)
C(17´)
C(16)
C(16´)
3
c = 10.5834(14) Å, β = 93.539(3)°, V = 1538.3(3) Å , space
group Р21/c, Z = 4 (Z´ = 1), M = 331.31, dcalc = 1.431 g cm–3
,
Fig. 1. General view of compound 2a with displacement ellipꢀ
soids drawn at p = 50%. Two positions of the disordered phenyl
substituent are shown.
μ = 1.01 cm–1, F(000) = 688. A total of 20721 reflections were
measured (Rint = 0.0807), of which 4752 independent reflecꢀ
tions were used in calculations.
Scheme 2
The structure of 2a was solved by direct methods and refined
by the fullꢀmatrix leastꢀsquares method with anisotropic disꢀ
placement parameters. An analysis of difference Fourier maps
showed that the phenyl substituent is disordered over two equally
occupied sites. The atoms of the disordered phenyl substituent
were refined isotropically. The hydrogen atoms were positioned
geometrically and refined using a riding model. The final R
factors were R = 0.0551 based on 2737 reflections with I > 2σ(I),
wR2 = 0.1412, GOOF = 0.980 based on all measured reflections.
All calculations were carried out with the use of the SHELXTL
PLUS 5 program package.
Nucleophilic substitution in 1,3ꢀdinitro[b,f]dibenzoxepine
(general method). Anhydrous K2CO3 (0.83 g, 6 mmol) was added
to a solution of 1,3ꢀdinitrodibenz[b,f]oxepine 1 (1.42 g, 5 mmol)
and the corresponding phenol (thiophenol) (5.5 mmol) in anhyꢀ
drous DMF (10 mL). The reaction mixture was stirred at 100 °C
for 3 h, cooled to room temperature, and poured into water
(150 mL). Then concentrated HCl was added to pH 2. The
precipitate that formed was filtered off, dried, and recrystalꢀ
lized; MeCN was used as the solvent for crystallization (unless
otherwise stated).
Reagents and conditions:
, C6H6, piperidine, 80 °C.
position (periꢀnitro group) is selectively replaced with
nucleophiles in dinitroꢀsubstituted benzannulated fiveꢀ
membered heterocycles.11—13 However, the reverse selecꢀ
tivity of substitution is observed in analogous fused sevenꢀ

Substituted dibenz[b,f]oxepines from trinitrotoluene
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
349
1
3ꢀNitroꢀ1ꢀphenoxydibenz[b,f]oxepine (2a). M.p. 135—137 °C.
Found (%): C, 72.28; H, 4.15; N, 3.97. C20H13NO4. Calcuꢀ
lated (%): C, 72.50; H, 3.95; N, 4.23. 1H NMR, δ: 7.03 (d, 1 H,
J = 11.6 Hz); 7.10 (m, 3 H); 7.26 (m, 2 H); 7.33 (s, 1 H); 7.36
(d, 1 H, J = 7.8 Hz); 7.40 (d, 1 H, J = 8.0 Hz); 7.46 (m, 3 H);
7.90 (s, 1 H). MS, m/z (Irel (%)): 331 [M]+ (100), 179 (80),
163 (58), 77 (78).
N, 3.50; Cl, 17.72. H NMR, δ: 7.03 (s, 2 H); 7.18 (d, 1 H,
J = 8.3 Hz); 7.22 (m, 2 H); 7.30 (m, 2 H); 7.40 (m, 2 H); 7.61
(d, 1 H, J = 2.1 Hz); 7.84 (d, 1 H, J = 1.8 Hz). MS, m/z
(Irel (%)): 401 [M]+ (57), 399 [M]+ (100), 192 (50), 179 (80),
163 (78).
1ꢀ(4ꢀBromophenoxy)ꢀ3ꢀnitrodibenz[b,f]oxepine
M.p. 160—162 °C. Found (%): C, 58.78; H, 3.12; N, 3.23;
(2j).
1ꢀ(4ꢀMethylphenoxy)ꢀ3ꢀnitrodibenz[b,f]oxepine
(2b).
Br, 19.15. C20H12BrNO4. Calculated (%): C, 58.56; H, 2.95;
N, 3.41; Br, 19.48. H NMR, δ: 6.99 (m, 4 H); 7.21 (t, 1 H,
J = 7.7 Hz); 7.29 (m, 2 H); 7.40 (m, 2 H); 7.54 (d, 2 H,
J = 8.3 Hz); 7.84 (s, 1 H). MS, m/z (Irel (%)): 411 [M]+ (47),
409 [M]+ (52), 255 (48), 192 (49), 179 (100), 163 (87).
1
M.p. 149—151 °C. Found (%): C, 72.70; H, 4.51; N, 3.89.
C21H15NO4. Calculated (%): C, 73.03; H, 4.38; N, 4.06.
1H NMR, δ: 2.35 (s, 3 H); 7.01 (d, 2 H, J = 8.0 Hz); 7.05 (d,
1 H, J = 11.5 Hz); 7.09 (d, 1 H, J = 11.5 Hz); 7.26 (m, 4 H);
7.36 (d, 1 H, J = 7.8 Hz); 7.38 (d, 1 H, J = 8.0 Hz); 7.44 (t, 1 H,
J = 7.9 Hz); 7.85 (s, 1 H). MS, m/z (Irel (%)): 345 [M]+ (100),
179 (65), 163 (43).
1ꢀ[(4ꢀAcetylamino)phenoxy]ꢀ3ꢀnitrodibenz[b,f]oxepine (2k).
M.p. 242—244 °C. Found (%): C, 67.69; H, 4.15; N, 7.40.
C22H16N2O5. Calculated (%): C, 68.04; H, 4.15; N, 7.21.
1H NMR, δ: 2.05 (s, 3 H); 6.97 (m, 3 H); 7.06 (d, 1 H,
J = 11.7 Hz); 7.20 (t, 1 H, J = 7.7 Hz); 7.28 (m, 3 H); 7.38 (t,
1 H, J = 7.9 Hz); 7.68 (d, 1 H, J = 8.0 Hz); 7.74 (s, 1 H). MS,
m/z (Irel (%)): 388 [M]+ (100), 346 (67), 255 (20), 179 (15).
3ꢀNitroꢀ1ꢀ(phenylsulfanyl)dibenz[b,f]oxepine (2l). M.p. 199—
200 °C (benzene). Found (%): C, 68.88; H, 3.95; N, 4.16, S, 8.90.
C20H13NO3S. Calculated (%): C, 69.15; H, 3.77; N, 4.03;
1ꢀ(3ꢀMethylphenoxy)ꢀ3ꢀnitrodibenz[b,f]oxepine
(2c).
M.p. 152—154 °C. Found (%): C, 72.68; H, 4.62; N, 4.00.
C21H15NO4. Calculated (%): C, 73.03; H, 4.38; N, 4.06.
1H NMR, δ: 2.37 (s, 3 H); 6.83 (d, 1 H, J = 7.9 Hz); 6.88 (s,
1 H); 7.00 (m, 2 H); 7.04 (d, 1 H, J = 8.1 Hz); 7.21 (t, 1 H,
J = 7.9 Hz); 7.31 (m, 4 H); 7.40 (t, 1 H, J = 8.0 Hz); 7.80 (s,
1 H). MS, m/z (Irel (%)): 345 [M]+ (85), 179 (80), 163 (64),
65 (100).
1
S, 9.23. H NMR, δ: 7.03 (d, 1 H, J = 11.4 Hz); 7.10 (d, 1 H,
1ꢀ[(4ꢀMethoxy)phenoxy]ꢀ3ꢀnitrodibenz[b,f]oxepine (2d).
M.p. 177—179 °C. Found (%): C, 69.93; H, 4.02; N, 3.61.
C21H15NO5. Calculated (%): C, 69.80; H, 4.18; N, 3.88.
1H NMR, δ: 3.78 (s, 3 H); 7.03 (d, 2 H, J = 8.0 Hz); 7.11 (m,
4 H); 7.22 (s, 1 H); 7.27 (t, 1 H, J = 7.8 Hz); 7.29 (d, 1 H,
J = 7.8 Hz); 7.45 (m, 2 H); 7.87 (s, 1 H). MS, m/z (Irel (%)): 361
[M]+ (100), 179 (60), 163 (33).
J = 11.4 Hz); 7.20 (t, 1 H, J = 7.7 Hz); 7.28 (m, 2 H); 7.42 (m,
6 H); 7.60 (s, 1 H); 7.88 (s, 1 H). MS, m/z (Irel (%)): 347 [M]+
(100), 346 (41), 271 (37), 163 (30).
1ꢀ[(4ꢀMethylphenyl)sulfanyl]ꢀ3ꢀnitrodibenz[b,f]oxepine
(2m). M.p. 207—209 °C (benzene). Found (%): C, 70.16;
H, 3.90; N, 4.04; S, 8.81. C21H15NO3S. Calculated (%):
1
C, 69.79; H, 4.18; N, 3.88; S, 8.87. H NMR, δ: 2.42 (s, 3 H);
1ꢀ[(3ꢀMethoxy)phenoxy]ꢀ3ꢀnitrodibenz[b,f]oxepine (2e).
M.p. 113—116 °C. Found (%): C, 70.04; H, 3.98; N, 4.10.
C21H15NO5. Calculated (%): C, 69.80; H, 4.18; N, 3.88.
1H NMR, δ: 3.76 (s, 3 H); 6.68 (d, 1 H, J = 8.1 Hz); 6.75 (m,
1 H); 6.84 (d, 1 H, J = 8.3 Hz); 7.02 (d, 1 H, J = 11.6 Hz); 7.12
(d, 1 H, J = 11.6 Hz); 7.27 (t, 1 H, J = 8.0 Hz); 7.35 (d, 1 H,
J = 8.0 Hz); 7.38 (m, 2 H); 7.45 (m, 2 H); 7.93 (s, 1 H). MS,
m/z (Irel (%)): 361 [M]+ (100), 179 (30), 163 (29), 120 (38).
1ꢀ[(2ꢀMethoxy)phenoxy]ꢀ3ꢀnitrodibenz[b,f]oxepine (2f).
M.p. 153—155 °C. Found (%): C, 69.75; H, 4.29; N, 3.55.
C21H15NO5. Calculated (%): C, 69.80; H, 4.18; N, 3.88.
1H NMR, δ: 3.78 (s, 3 H); 7.03 (d, 2 H, J = 8.0 Hz); 7.11 (m,
4 H); 7.22 (s, 1 H); 7.27 (t, 1 H, J = 7.8 Hz); 7.29 (d, 1 H,
J = 7.8 Hz); 7.45 (m, 2 H); 7.87 (s, 1 H). MS, m/z (Irel (%)): 361
[M]+ (100), 179 (60), 163 (33).
7.04 (d, 1 H, J = 11.0 Hz); 7.09 (d, 1 H, J = 11.0 Hz); 7.20 (t,
1 H, J = 7.7 Hz); 7.28 (m, 4 H); 7.35 (d, 2 H, J = 8.0 Hz); 7.38
(t, 1 H, J = 7.9 Hz); 7.59 (s, 1 H); 7.83 (s, 1 H). MS, m/z
(Irel (%)): 361 [M]+ (100), 271 (30), 163 (41).
Independent synthesis of compound 2m. A solution of
2ꢀ[(4ꢀmethylphenyl)sulfanyl]ꢀ4,6ꢀdinitrotoluene 3 (1.52 g,
5 mmol), salicylaldehyde (0.61 g, 5 mmol), and piperidine
(0.51 g, 6 mmol) in benzene (5 mL) was refluxed for 5 h, cooled,
and diluted with MеOH (10 mL). The precipitate was filtered
off, washed with ethanol (1 mL), and dried. The yield was 73%.
1
The melting point and the H NMR spectrum of the reaction
product are identical to those of the aboveꢀdescribed comꢀ
pound 2m.
References
1ꢀ(4ꢀChlorophenoxy)ꢀ3ꢀnitrodibenz[b,f]oxepine
(2g).
M.p. 158—160 °C. Found (%): C, 65.90; H, 3.15; N, 4.22;
Cl, 10.03. C20H12ClNO4. Calculated (%): C, 65.67; H, 3.31;
N, 3.83; Cl, 9.69. 1H NMR, δ: 6.98 (s, 2 H); 7.06 (d, 2 H,
J = 8.2 Hz); 7.20 (t, 1 H, J = 7.8 Hz); 7.28 (m, 2 H); 7.40 (m,
4 H); 7.83 (s, 1 H). MS, m/z (Irel (%)): 367 [M]+ (29), 365 [M]+
(100), 179 (57), 163 (35).
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(2h).
M.p. 156—158 °C. Found (%): C, 65.79; H, 3.84; N, 4.11;
Cl, 9.52. C20H12ClNO4. Calculated (%): C, 65.67; H, 3.31;
N, 3.83; Cl, 9.69. 1H NMR, δ: 6.96 (m, 3 H); 7.08 (s, 1 H); 7.21
(m, 2 H); 7.28 (m, 2 H); 7.40 (m, 2 H); 7.45 (s, 1 H); 7.85 (s,
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Cl, 18.10. C20H11Cl2NO4. Calculated (%): C, 60.02; H, 2.77;
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Received October 30, 2008;
in revised form February 3, 2009