Synthetic utilization of polynitroaromatic compounds. 3. Preparation of substituted dibenz[b,f][1,4]oxazepine-11(10H)-ones from 2,4,6-trinitrobenzoic acid via nucleophilic displacement of nitro groups

Article abstract of DOI:10.1021/jo051425c

1,3-Dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one, prepared by intramolecular displacement of nitro group in N-(2-hydroxyphenyl)-2,4,6-trinitrobenzamide, reacts with O- and S-nucleophiles to yield the products of mono- or bis-substitution of the nitro group

Full text of DOI:10.1021/jo051425c

Synthetic Utilization of Polynitroaromatic Compounds. 3.
Preparation of Substituted Dibenz[b,f][1,4]oxazepine-11(10H)-ones
from 2,4,6-Trinitrobenzoic Acid via Nucleophilic Displacement of
Nitro Groups
Alexander V. Samet, Victor N. Marshalkin, Konstantine A. Kislyi, Natalya B. Chernysheva,
Yuri A. Strelenko, and Victor V. Semenov*
N. D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Pr., 47 Moscow, 119991, Russia
vs@chemical-block.com
Received July 11, 2005
1,3-Dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one, prepared by intramolecular displacement of nitro
group in N-(2-hydroxyphenyl)-2,4,6-trinitrobenzamide, reacts with O- and S-nucleophiles to yield
the products of mono- or bis-substitution of the nitro groups. The nitro group in position 3 is displaced
first. This observation is in contrast with earlier results for the nitro-substituted benzoannulated
five-membered heterocycles. This difference in reactivity is likely due to the increased steric
hindrance for peri-nitro group displacement in the case of the benzoannulated seven-membered
heterocycle. N-Alkylation of the nitro-substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones yields
analogues of a known antidepressant drug Sintamil. The structure of the products is confirmed by
NOE experiments and alternative synthesis.
Introduction
cycles drew our attention as attractive synthetic targets.
Dibenz[b,f][1,4]oxazepin-11(10H)-ones could be accessed
by an intramolecular cyclization of 2-hydroxyanilides of
ortho-substituted benzoic acids (X ) Cl, F)8-10 (usually,
the presence of an additional electron-withdrawing sub-
Dibenz[b,f][1,4]oxazepin-11(10H)-ones are known to
display various kinds of biological activity.1,2 In particu-
lar, 10-[3-(dimethylamino)propyl]-2-nitrodibenz[b,f][1,4]-
oxazepin-11(10H)-one (Sintamil) is an efficient antide-
pressant.3,4
(3) Nagarajan, K.; Venkateswarlu, A.; Kulkarni, C. L.; Nagana, G.
A.; Shah, R. K. Indian J. Chem. 1974, 12, 236.
(4) Nagarajan, K.; David, J.; Kulkarni, Y. S.; Hendi, S. B.; Shenoy,
S. J.; Upadhyaya P. Eur. J. Med. Chem. 1986, 21, 21.
(5) Zlotin, S. G.; Kislitsin, P. G.; Podgursky, A. I.; Samet, A. V.;
Semenov, V. V.; Buchanan, A. C., III; Gakh, A. A. J. Org. Chem. 2000,
65, 8439.
(6) Zlotin, S. G.; Kislitsin, P. G.; Samet, A. V.; Serebryakov, E. A.;
Konyushkin, L. D.; Semenov, V. V.; Buchanan, A. C., III; Gakh, A. A.
J. Org. Chem. 2000, 65, 8430.
(7) Samet, A. V.; Zakharov, E. P.; Semenov, V. V.; Gakh, A. A.;
Buchanan, A. C., III. Synth. Commun. 2001, 31, 1441.
(8) Ku¨nzle F.; Schmutz, J. Helv. Chim. Acta 1969, 52, 622.
(9) Nagarajan K.; Venkateswarlu A.; Kulkarni C. L.; Shah R. K.
Indian J. Chem. 1974, 12, 227.
(10) Konstantinova, A. V.; Gerasimova, T. N.; Kozlova, M. M.;
Petrenko, N. I. Chem. Heterocycl. Compd. (Engl. Transl.) 1989, 25,
451.
Therefore, in the process of our work aimed at utiliza-
tion of aromatic polynitrocompounds,5-7 these hetero-
(1) Ouyang, X.; Tamayo, N.; Kiselyov, A. Tetrahedron 1999, 55, 2827.
(2) Okafor, C. O. Heterocycles 1977, 7, 391.
10.1021/jo051425c CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/18/2005
J. Org. Chem. 2005, 70, 9371-9376
9371

Samet et al.
SCHEME 1
SCHEME 3
SCHEME 2
TABLE 1. Reaction Conditions and Yields of
1-Nitro-3-RX-dibenz[b,f][1,4]oxazepine-11(10H)-ones 3a-r
product
RX
T, h
T, °C
yield, %
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
MeO
EtO
PrO
15 (1a)
65 (100a)
75
84 (81a)
20
24
30
30
10
60
3
75
90
19
i-PrO
80
80
no reaction
cyclo-C6H11
HOC2H4O
C6H5CH2O
PhO
3-MeC6H4O
4-MeC6H4O
2-MeOC6H4O
4-MeOC6H4O
2-BrC6H4O
4-BrC6H4O
PhCH2S
O
no reaction
100
80
87
63
stituent in the A ring is needed; Scheme 1). In this
respect, we were interested in utilization of an SNAr of
the nitro group for the construction of the targeted seven-
membered ring systems. This reaction has been success-
fully applied to the synthesis of several heterocyclic
systems.11,12
80
88
3
80
94
3
80
96
3
80
94 (96b)
100
71
3
80
3
80
3
80
96
3
80
90
BuS
PhS
4-CH3C6H4S
3
80
93
Results and Discussion
3
70
74
3
70
60
In this article we report the synthesis of dibenz[b,f]-
[1,4]oxazepin-11(10H)-ones containing various substitu-
ents in positions 1 and 3 from 2,4,6-trinitrobenzoic acid
(prepared, in turn, by oxidation of TNT with dilute
a Using NaOMe instead of MeOH and K2CO3. b With 2 equiv of
guaiacol.
6
HNO3 ). The acid was converted to the corresponding acid
TABLE 2. Reaction Conditions and Yields of
1-R′Y-3-RX-Dibenz[b,f][1,4]oxazepine-11(10H)-ones 4a-h
chloride, followed by its conversion to o-hydroxyanilide
1. Compound 1 underwent an intramolecular nucleophilic
displacement of the nitro group in mild conditions upon
treatment with base (aqueous NH3) to yield 1,3-dinitro-
dibenz[b,f][1,4]oxazepin-11(10H)-one 2 (Scheme 2).13Sub-
sequently, we found that the nitro groups in compound
2 (one or both) could undergo nucleophilic displace-
ment to afford products 3 and 4 (Scheme 3). A series of
O- and S-nucleophiles including alcohols, phenols, thiols,
and thiophenols were found to be reactive. The first nitro
group is displaced under relatively mild conditions
(65-100 °C). The substitution of the second function
required higher temperatures, specifically, 100-120 °C
for thiols and thiophenols and 140-150 °C for phenols
(Tables 1 and 2). For instance, reaction of compound 2
with 2 equiv of guaiacol at 120 °C resulted exclusively
in a product of monosubstitution 3k (Table 1). For
alcohols, the corresponding products of bis-substitution
4 were not detected.
starting
t
T
yield
%
product compd
R′Y
RX
h
°C
4a
4b
4c
4d
4e
4f
2
2
PhO
PhO
8
8
8
5
5
5
5
5
150
150
150
100
100
120
120
100
67
48
55
31
34
52
58
49
3-CH3C6H4O 3-CH3C6H4O
3p
3a
3a
3h
2
PhO
BuS
BuS
MeO
MeO
PhCH2S
4-CH3C6H4S PhO
4g
4h
4-CH3C6H4S 4-CH3C6H4S
2
BuS
BuS
not afford the expected 3 and 4. Phenols with both
electron-donating and electron-withdrawing substituents
reacted smoothly.
Regioselectivity of the nucleophilic substitution in 1,3-
dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one 2 was further
studied by NOE experiments (Scheme 4). For example,
irradiation of the methoxy group signal (δ 3.80) in 4e
caused an increase of intensity for the H(2) and H(4)
signals (δ 6.82 and 6.72, respectively), whereas upon
irradiation of SCH2 group signal (δ 4.18) intensities of
H(2) (δ 6.82) and ortho-phenyl (δ 7.38) proton signals
were increased. In the 2D NOESY spectrum of 4c, we
observed two cross-peaks between the signals of SCH2
(δ 2.94) and aromatic protons H(2) and H(4) (δ 6.60 and
7.08, respectively). In addition, a cross-peak between the
A number of primary alcohols ROH yielded the sub-
stitution products (R ) Me, Et, Pr, Bn, HO(CH2)2),
whereas secondary alcohols (i-PrOH, cyclohexanol) did
(11) Radl, S. Adv. Heterocycl. Chem. 2002, 83, 189.
(12) Buncel, E.; Dust, J.; Terrier, F. Chem. Rev. 1995, 95, 2261.
(13) Chernysheva, N. B.; Samet, A. V.; Marshalkin, V. N.; Polukeev,
V. A.; Semenov, V. V. Mendeleev Commun. 2001, 109.
9372 J. Org. Chem., Vol. 70, No. 23, 2005

Synthetic Utilization of Polynitroaromatic Compounds
SCHEME 4
SCHEME 6
o-hydroxyanilide 8. The intramolecular cyclization of the
latter with K2CO3 in DMF afforded compound 3a, which
was identical to the product prepared from 1,3-dinitro-
dibenz[b,f][1,4]oxazepine-11(10H)-one 2 via displacement
of the nitro group with methoxide anion.
Notably, this selectivity of nucleophilic substitution
was unexpected. To the best of our knowledge, a nucleo-
philic displacement of a peri-nitro group (that is, the one
adjacent to ring fusion point) in related heterocyclic
systems including phthalimides,15 benzo[b]thiophenes,16
benz[d]isoxazoles,17 and indazoles18 occurred first19
(Scheme 6).
In general, for both 1-X-2,4-dinitro- and 1-X-2,4,6-
trinitrobenzenes nitro groups in ortho-position to the
substituent X usually are substituted first20 (a heterocycle
annulated to benzene ring could be viewed as a special
case of substituent). Nevertheless, bulky substituents
(e.g., X ) t-Bu,20a COOMe14) could direct the nucleophilic
attack into para-position by hindering ortho-regions.
Moreover, with tertiary amides of 2,4,6-trinitrobenzoic
acid (X ) CONR2) ortho-substitution product is not
formed at all.6 Considering this evidence, we speculated
that for the seven-membered heterocycle annulated to
benzene ring, sterical hindrance for the nucleophilic
attack at peri-position could be more significant when
compared to a previously studied heterocyclic systems
with benzoannulated five-membered heterocycle. This
could be due to the different geometry of the molecule.
At least semiempirical calculation (method AM1, CS
MOPAC application) demonstrated that the distance
between peri-carbon atom and oxygen atom of the car-
bonyl group is noticeably shorter in 1,3-dinitrodibenz-
[b,f][1,4]oxazepine-11(10H)-one 2 than that in 3,5-
dinitrophthalimide15b (2.95 Å versus 3.20 Å, respectively)
(Scheme 7).
SCHEME 5
signals of ortho-phenyl (δ 6.92) protons and H(2) (δ 6.60)
was observed. These facts suggest that the BuS substitu-
ent is located in position 3, and the PhO group occupies
position 1.
On the basis of this evidence, we concluded that the
3-NO2 group (remote from the ring fusion point) was
substituted first upon the attack of 2 with both O-
nucleophiles (MeO-, preparation of 4e) and S-nucleo-
philes (BuS-, preparation of 4c). We further confirmed
the regiochemistry of substitution by an alternative
synthetic approach to 3a (Scheme 5).
Nucleophilic displacement of the nitro group in methyl
2,4,6-trinitrobenzoate 5 with methoxide anion proceeded
with low selectivity to yield a mixture of regioisomeric
esters 6a and 6b. The ratio of para- to ortho-substitution
product was 63:37 (lit.14 data 5:4). The mixture was
further subjected to an alkaline hydrolysis, and the
resulting regioisomeric acids 7a and 7b were easily
separated due to their different solubility in the media.
2,6-Dinitro-4-methoxybenzoic acid 7a was converted to
It must be mentioned, however, that primary and
secondary amides of 2,4-dinitro- and 2,4,6-trinitrobenzoic
acids (X ) CONH2, CONHR) provide for high ortho-
selectivity of the nucleophilic substitution.6,21,22 This fact
(15) (a) Williams, F.; Donahue, P. J. Org. Chem. 1978, 43, 250. (b)
Fischer, W.; Kvita, V. Helv. Chim. Acta 1985, 68, 846.
(16) Shevelev, S. A.; Dalinger, I. L.; Cherkasova, T. I. Tetrahedron
Lett. 2001, 42, 8539.
(17) Vinogradov, V. M.; Dalinger, I. L.; Starosotnikov, A. M.;
Shevelev, S. A. Russ. Chem. Bull. 2001, 50, 464.
(18) Starosotnikov, A. M.; Kachala, V. V.; Lobach, A. V.; Vinogradov,
V. M.; Shevelev, S. A. Russ. Chem. Bull. 2003, 52, 1782.
(19) Similar selectivity is observed for 1,3-dinitronaphthalene: (a)
Hanker, J.; Katzoff, L.; Aronson, L.; Seligman, M.; Rosen, H.; Seligman,
A. J. Org. Chem. 1965, 30, 1779. (b) Novi, M.; Dell’erba, C.; Sancassan,
F. J. Chem. Soc., Perkin Trans. 1 1983, 1145. For polynitrofluorenes,
the selectivity depends on the nature of the nucleophile and temper-
ature: (c) Perepichka, I.; Popov, A.; Orekhova, T.; Bryce, M.; Vdov-
ichenko, A.; Batsanov, A.; Goldenberg, L.; Howard, J.; Sokolov, N.;
Megson, J. J. Chem. Soc., Perkin Trans. 2 1996, 2453 and references
therein.
(20) For a discussion of selectivity of nucleophilic nitro group
substitution and some examples, see refs 6, 15, and also (a) Benedetti,
F.; Marshall, D.; Stirling, C.; Leng, J. J. Chem. Soc., Chem. Commun.
1982, 918. (b) Serushkina, O. V.; Dutov, M. D.; Solkan, V. N.; Shevelev,
S. A. Russ. Chem. Bull. 2001, 50, 2406 and references therein.
(14) Segura, P.; Bunnett, J.; Villanova, L. J. Org. Chem. 1985, 50,
1041.
J. Org. Chem, Vol. 70, No. 23, 2005 9373

Samet et al.
SCHEME 7
SCHEME 8
presence of a base (Scheme 9). In particular, with
3-(dimethylamino)propyl chloride as alkylating agent (R1
) Me2N(CH2)3) product 9b (Sintamil analog3) is prepared
from 3a.
Experimental Section
N-(2-Hydroxyphenyl)-2,4,6-trinitrobenzamide (1). In a
10-L flask, to a suspension of 2,4,6-trinitrobenzoyl chloride
(485 g, 1.76 mol) in dry benzene (9 L), 2-aminophenol (385 g,
3.53 mol) was added portionwise, and the mixture was refluxed
for 8 h. The resulting precipitate was filtered off, washed with
benzene (3 × 800 mL) and hot water (15 × 1.5 L), and dried.
Yield: 505 g (82%), mp 201-203 °C. 1H NMR (DMSO-d6,
δ): 6.8-7.0 (m, 3H), 8.05 (d, J ) 8.3 Hz, 1H), 9.10 (s, 2H),
9.70 (br s, 1H), 10.35 (br s, 1H). EI-MS (70 eV) (m/z, I, %):
348 [M+, 5], 153 [69], 108 [99], 79 [100]. Anal. Calcd for
C13H8N4O8: C, 44.84; H, 2.32; N, 16.09. Found: C, 45.20; H,
2.15; N, 15.91.
1,3-Dinitrodibenz[b,f][1,4]oxazepine-11(10H)-one (2).
In a 5-L jar, to a solution of the anilide 1 (505 g, 1.45 mol) in
a mixture of MeOH (1.9 L) and MeCN (1.9 L), 25% aqueous
NH3 (400 mL) was added. The lid was tightly closed, and the
mixture was heated at 50 °C for 120 h (stirring was not
needed). Then the resulting precipitate was filtered off, washed
with MeOH (1 L), and dried. Yield: 376 g (86%), black needles.
This product was sufficiently pure for synthetic purposes (and
pure by NMR). An analytical sample could be prepared by
column chromatography on silica gel (eluent benzene/EtOAc
1:1). Orange needles, mp 289-290 °C. 1H NMR (DMSO-d6,
δ): 7.15-7.30 (m, 3H), 7.48 (d, J ) 8.2 Hz, 1H), 8.49 (s, 1H),
8.51 (s, 1H), 11.20 (br s, 1H). EI-MS (70 eV) (m/z, I, %): 301
[M+, 49], 211 [32], 126 [94], 74 [100]. Anal. Calcd for
C13H7N3O6: C, 51.84; H, 2.34; N, 13.95. Found: C, 52.15; H,
2.52; N, 13.60.
Preparation of 1-Nitro-3-RX-dibenz[b,f][1,4]oxazepine-
11(10H)-ones 3a-r (General Procedure). To prepare com-
pounds 3h-r, to a suspension of 1,3-dinitrodibenz[b,f][1,4]-
oxazepine-11(10H)-one 2 (1.50 g, 5 mmol) and anhydrous
K2CO3 (0.76 g, 5.5 mmol) in DMF (20 mL), a corresponding
reagent RXH (5.5 mmol) was added upon stirring. Tempera-
tures and reaction times are given in Table 1. Upon cooling,
the reaction mixture was poured in water (200 mL) and
neutralized with HCl. The precipitate was filtered off, succes-
sively washed with hot water (20 mL) and MeOH (5 mL), and
dried. Compound 3q was additionally crystallized from ben-
zene, while 3r was washed with hot benzene to remove
disulfides formed as side products.
SCHEME 9
could not be explained by steric or electronic reasons (cf.
ortho-/para- ratio of ca. 10:16 for X ) CONHMe and
CONHBut and 37:63 for X ) COOMe). Involvement of
an amide NH in stabilization of a transition state could
be an additional powerful factor facilitating ortho-attack6
(Scheme 8a). Alternatively, participation of the amide
nitrogen in intramolecular nucleophilic substitution reac-
tion leading to a benzazetidine intermediate A (Scheme
8b) could be envisaged.
The exact mechanism remains to be clarified, but the
putative “NH-proton effect” cannot affect the nucleophilic
substitution in dibenz[b,f][1,4]oxazepinone 2 anyway. In
this molecule, the amide nitrogen is distanced from the
peri-carbon atom, as CONH fragment is a part of the
seven-membered ring. The reaction regiochemistry is
driven by a steric hindrance for peri-attack caused by the
carbonyl group.
Interestingly, this change in regioselectivity between
benzoannulated five-membered heterocycles and dibenz-
[b,f][1,4]oxazepinone-10(11H)-ones is observed not only
for the substitution of the nitro group. Thus, a reaction
of fluorine displacement for N-substituted 3-fluorophthal-
imides (F atom in peri-position) proceeds more rapidly
than for their 4-fluoro isomers.15a In contrast, in 1,2,3,4-
tetrafluorodibenz[b,f][1,4]oxazepine-11(10H)-one fluorine
atom in remote position 3 is displaced first.23
In reaction with alcohols (preparation of compounds
3a-g), 50 mmol of the corresponding alcohol and 12 mmol of
K2CO3 were used for 5 mmol of 2.
Product 3a was also prepared according to the above
procedure for 3h-r using MeONa instead of MeOH and
K2CO3.
3-Methoxy-1-nitrodibenz[b,f][1,4]oxazepin-11(10H)-
one (3a): mp 268-270 °C (MeCN). 1H NMR (DMSO-d6, δ):
3.90 (s, 3H), 7.15-7.25 (m, 4H), 7.28 (d, J ) 8.0 Hz, 1H), 7.33
(d, J ) 7.9 Hz, 1H), 10.65 (br s, 1H). EI-MS (70 eV) (m/z, I,
%): 286 [M+, 100], 241 [35]. Anal. Calcd for C14H10N2O5: C,
58.74; H, 3.52; N, 9.79. Found: C, 58.60; H, 3.64; N, 9.69.
1-Nitro-3-phenoxydibenz[b,f][1,4]oxazepine-11(10H)-
1
one (3h): mp 223-224 °C (MeCN). H NMR (DMSO-d6, δ):
7.13 (s, 1H), 7.15 (d, J ) 8.1 Hz, 1H), 7.20-7.28 (m, 5H), 7.30
(t, J ) 8.1 Hz, 2H), 7.48-7.53 (m, 2H), 10.77 (br s, NH). EI-
MS (70 eV) (m/z, I, %): 348 [M+, 80], 303 [43], 211 [12], 77
[100]. Anal. Calcd for C19H12N2O5: C, 65.52; H, 3.47; N, 8.04.
Found: C, 65.40; H, 3.56; N, 7.98.
Further, dibenz[b,f][1,4]oxazepine-11(10H)-ones 3 un-
derwent N-alkylation with different alkyl halides in the
(21) Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A.
Tetrahedron Lett. 2000, 41, 4973.
3-Butylsulfanyl-1-nitrodibenz[b,f][1,4]oxazepin-11(10H)-
one (3p): mp 199-202 °C (MeCN). 1H NMR (DMSO-d6, δ):
0.90 (t, J ) 7.2 Hz, 3H), 1.44 (m, 2H), 1.63 (m, 2H), 3.15 (t, J
) 7.1 Hz, 2H), 7.2-7.3 (m, 3H), 7.41 (d, J ) 7.8 Hz, 1H), 7.56
(d, J ) 2.1 Hz, 1H), 7.63 (d, J ) 2.1 Hz, 1H), 10.80 (br s, 1H).
(22) Serebryakov, E. A.; Kislitsin, P. G.; Semenov, V. V.; Zlotin, S.
G. Synthesis 2001, 1659.
(23) Konstantinova, A. V.; Yakovleva, O. D.; Gerasimova, T. N.
Chem. Heterocycl. Compd. (Engl. Transl.) 1991, 27, 1016.
9374 J. Org. Chem., Vol. 70, No. 23, 2005

Synthetic Utilization of Polynitroaromatic Compounds
TABLE 3. Yields of Dibenz[b,f][1,4]oxazepine-
Anal. Calcd for C17H16N2O4S: C, 59.29; H, 4.68; N, 8.13; S,
9.31. Found: C, 59.55; H, 4.80; N, 7.95; S, 9.49.
11(10H)-ones 9a-f (N-Alkylation of Compounds 3a,h)
1-Nitro-3-phenylsulfanyldibenz[b,f][1,4]oxazepin-11-
(10H)-one (3q): mp 240-241 °C (benzene). 1H NMR (DMSO-
d6, δ): 7.08 (t, J ) 7.8 Hz, 1H), 7.14-7.20 (m, 4H), 7.23 (d, J
) 7.9 Hz, 1H), 7.52 (m, 3H), 7.57 (m, 2H), 10.71 (br s, 1H).
EI-MS (70 eV) (m/z, I, %): 364 [M+, 100], 319 [47]. Anal. Calcd
for C19H12N2O4S: C, 62.63; H, 3.32; N, 7.69; S, 8.80. Found:
C, 62.57; H, 3.38; N, 7.60; S, 8.85.
3-(4-Methylphenyl)sulfanyl-1-nitrodibenz[b,f][1,4]-
oxazepin-11(10H)-one (3r): mp 269-270 °C (MeCN) (dec).
1H NMR (DMSO-d6, δ): 2.44 (s, 3H), 7.07-7.24 (m, 6H), 7.34
(d, J ) 8.0 Hz, 2H), 7.46 (d, J ) 8.0 Hz, 2H), 10.71 (br s, 1H).
EI-MS (70 eV) (m/z, I, %): 378 [M+, 100], 333 [52], 123 [51].
Anal. Calcd for C20H14N2O4S: C, 63.48; H, 3.73; N, 7.40; S,
8.47. Found: C, 63.22; H, 3.81; N, 7.50; S, 8.39.
Preparation of 1-R′Y-3-RX-dibenz[b,f][1,4]oxazepine-
11(10H)-ones 4a-h (General Procedure). To prepare com-
pounds 4c-f, to a suspension of the corresponding compound
3 (5 mmol) and anhydrous K2CO3 (0.76 g, 5.5 mmol) in DMF
(20 mL), a corresponding reagent R′YH (5.5 mmol) was added
upon stirring. Temperatures and reaction times are given in
Table 2. Upon cooling, the reaction mixture was poured in
water (200 mL) and neutralized with HCl. The precipitate was
filtered off, successively washed with hot water (20 mL) and
MeOH (5 mL), and crystallized from benzene.
To prepare the products 4a,b,g,h, dibenz[b,f][1,4]oxazepine-
11(10H)-one 2 (1.50 g, 5 mmol) was used as a starting
compound, and 11 mmol of both K2CO3 and corresponding
reagent was taken.
1,3-Diphenoxydibenz[b,f][1,4]oxazepin-11(10H)-one (4a):
mp 227-230 °C. 1H NMR (DMSO-d6, δ): 6.28 (s, 1H), 6.69 (s,
1H), 6.94 (d, J ) 8.1 Hz, 2H), 7.10 (m, 5H), 7.20 (m, 2H), 7.32
(m, 3H), 7.40 (t, J ) 8.1 Hz, 2H), 10.25 (br s, 1H). Anal. Calcd
for C25H17NO4: C, 75.94; H, 4.33; N, 3.54. Found: C, 75.77;
H, 4.39; N, 3.67.
3-Butylsulfanyl-1-phenoxydibenz[b,f][1,4]oxazepin-11-
(10H)-one (4c): mp 128-129 °C. 1H NMR (DMSO-d6, δ): 0.82
(t, J ) 7.2 Hz, 3H), 1.33 (m, 2H), 1.52 (m, 2H), 2.94 (t, J ) 7.1
Hz, 2H, SCH2), 6.60 (s, 1H, H(2)), 6.92 (d, J ) 8.1 Hz, 2H,
o-Ph), 7.08 (s, 1H, H(4)), 7.13 (m, 3H), 7.20 (t, J ) 8.1 Hz,
1H), 7.35 (m, 3H), 10.31 (br s, 1H). EI-MS (70 eV) (m/z, I, %):
391 [M+, 92], 335 [100], 302 [48]. Anal. Calcd for C23H21NO3S:
C, 70.56; H, 5.41; N, 3.58; S, 8.19. Found: C, 70.82; H, 5.54;
N, 3.33; S, 8.06.
product starting compd
RX
R1
yield, %
9a
9b
9c
9d
9e
9f
3a
3a
3h
3h
3h
3h
MeO Bu
MeO Me2N(CH2)3
PhO
PhO
PhO
PhO
51
32a
56
58
43
48
Me
CH2dCHCH2
4-O2NC6H4CH2
PhCOCH2
a Isolated as a hydrochloride.
and the precipitate of 4-methoxy-2,6-dinitrobenzoic acid 7a was
filtered off. Yield: 31.3 g (47% with respect to methyl 2,4,6-
trinitrobenzoate 5). mp 181 °C (lit.14 mp 179-180 °C). 1H NMR
(DMSO-d6, δ): 3.99 (s, 3H), 7.98 (s, 2H); 14.0-14.5 (br s, 1H).
The mother liquor remaining after precipitation of 7a was
evaporated to dryness, and the residue was extracted with hot
benzene (3 × 500 mL). The combined extracts were cooled to
room temperature, and the precipitated 2-methoxy-4,6-dini-
trobenzoic acid 7b was filtered off. Yield: 24.0 g (36% with
respect to 5).25 mp 150-152 °C (lit.14 mp 150-151 °C). 1H NMR
(DMSO-d6, δ): 4.02 (s, 3H), 8.24 (d, J ) 2.0 Hz, 1H), 8.43 (d,
J ) 2.0 Hz, 1H), 14.0-14.5 (br s, 1H).
N-(2-Hydroxyphenyl)-2,6-dinitro-4-methoxybenza-
mide (8). A suspension of 2,6-dinitro-4-methoxybenzoic acid
7a in SOCl2 (5-fold molar excess) was refluxed for 30 min (until
the gas evolution ceased), and excess SOCl2 was removed in
vacuo. The resulting oil soon solidified. 2,6-Dinitro-4-meth-
oxybenzoyl chloride thus obtained (mp 100-101 °C after
crystallization from benzene) was converted to anilide 8 under
the action of 2-aminophenol as described for the compound 1.
Yield: 72%, mp 232-234 °C. 1H NMR (DMSO-d6, δ): 4.00 (s,
3H), 6.82 (t, J ) 8.1 Hz, 1H), 6.89 (d, J ) 8.2 Hz, 1H), 6.98 (t,
J ) 8.2 Hz, 1H), 7.93 (d, J ) 8.1 Hz, 1H), 8.00 (s, 2H), 9.63 (br
s, 1H), 10.12 (br s, 1H). Anal. Calcd for C14H11N3O7: C, 50.46;
H, 3.33; N, 12.61. Found: C, 50.58; H, 3.22; N, 13.00.
Cyclization of N-(2-Hydroxyphenyl)-2,6-dinitro-4-meth-
oxybenzamide 8 (Alternative Synthesis of 3a). A suspen-
sion of the anilide 8 (1.67 g, 5 mmol) and anhydrous K2CO3
(0.76 g, 5.5 mmol) in DMF (20 mL) was stirred at 120 °C for
3 h, whereupon the reaction mixture was worked up as
described above in the general procedure for compounds
3a-r. Yield of 3a was 68%.
Preparation of Dibenz[b,f][1,4]oxazepine-11(10H)-
ones 9a-f by N-Alkylation of 3a,h (General Procedure).
To a stirred suspension of dibenz[b,f][1,4]oxazepin-11(10H)-
one 3a (3h) (3 mmol) in acetone (10 mL), 2.5 M aqueous
solution of NaOH (1.3 mL) was added, the temperature was
raised to ∼60 °C, and the corresponding alkyl halide (5 mmol)
was introduced. The reaction mixture was refluxed with
stirring for 2 h, then additional portions of 2.5 M aqueous
NaOH (0.6 mL) and alkyl halide (2 mmol) were added. In 2 h
the addition of aqueous alkali and alkyl halide was repeated
again, and stirring was continued for 5 h more. Then acetone
was removed from the reaction mixture in vacuo, the residue
was extracted with ether (3 × 10 mL), and the combined
extracts were dried with MgSO4 and evaporated to dryness.
The residue was crystallized from i-PrOH. Yields of the
products 9a-f are given in Table 3.
10-Butyl-3-methoxy-1-nitrodibenz[b,f][1,4]oxazepin-
11(10H)-one (9a). BuBr is used as alkylating agent. mp 132-
133 °C. 1H NMR (DMSO-d6, δ): 0.91 (t, J ) 7.5 Hz, 3H), 1.36
(m, 2H), 1.62 (t, J ) 7.5 Hz, 2H), 3.6-4.4 (br s, 2H), 3.91 (s,
3H), 7.09 (br s, 1H), 7.21 (m, 2H), 7.31 (m, 2H), 7.52 (d, J )
8.0 Hz, 1H). EI-MS (70 eV) (m/z, I, %): 342 [M+, 81], 286 [99],
182 [82], 106 [100]. Anal. Calcd for C18H18N2O5: C, 63.15; H,
5.30; N, 8.18. Found: C, 62.89; H, 5.21; N, 8.44.
1-Benzylsulfanyl-3-methoxydibenz[b,f][1,4]oxazepin-
11(10H)-one (4e): mp 179-181 °C.1H NMR (DMSO-d6, δ):
3.80 (s, 3H, OCH3), 4.18 (s, 2H, SCH2), 6.72 (d, J ) 1.9
Hz, 1H, H(2)), 6.82 (d, J ) 1.9 Hz, 1H, H(4)), 7.11 (m, 2H),
7.17 (t, J ) 8.0 Hz, 1H), 7.23 (t, J ) 8.1 Hz, 1H), 7.30 (m, 3H),
7.38 (d, J ) 8.0 Hz, 1H), 10.31 (br s, 1H). Anal. Calcd for
C21H17NO3S: C, 69.40; H, 4.71; N, 3.85; S, 8.82. Found: C,
69.52; H, 4.79; N, 3.58; S, 8.99.
4-Methoxy-2,6-dinitrobenzoic Acid (7a) and 2-Meth-
oxy-4,6-dinitrobenzoic Acid (7b). To a suspension of methyl
2,4,6-trinitrobenzoate 524 (80.0 g, 0.295 mmol) in MeOH (460
mL), a solution of NaOMe (16.8 g, 0.311 mol) in MeOH (150
mL) was added. The mixture was refluxed for 40 min, then
1
MeOH was evaporated to
/
of the initial volume, and the
10
precipitate was filtered off and washed with water (3 × 200
mL). The product is a mixture of methyl 4-methoxy-2,6-dinitro-
and methyl 2-methoxy-4,6-dinitrobenzoates in 63:37 ratio
(according to NMR data). Yield: 65.0 g (86%).
To a solution of NaOH (11.4 g, 0.285 mol) in water (500 mL)
and MeOH (50 mL), the mixture of methyl 4-methoxy-2,6-
dinitro- and methyl 2-methoxy-4,6-dinitrobenzoates (65.0 g,
0.254 mol) was added. The reaction mixture was stirred at 80
°C for ca. 3 h (the reaction progress was monitored by TLC;
eluent EtOAc/heptane 1:3). The hot clear solution was acidified
until it became turbid and then cooled to room temperature,
(25) Earlier (see ref 14), 2-methoxy-4,6-dinitrobenzoic acid was
prepared in 5% yield from 2-methoxy-4,6-dinitrotoluene. The procedure
described here is by far preferable.
(24) Laskowski, D.; Adams, O. Anal. Chem. 1959, 31, 148.
J. Org. Chem, Vol. 70, No. 23, 2005 9375

Samet et al.
10-(3-(Dimethylamino)propyl)-3-methoxy-1-nitrodibenz-
[b,f][1,4]oxazepin-11(10H)-one Hydrochloride (9b). 3-(Di-
methylamino)propyl chloride hydrochloride was used as alky-
lating agent. To the dried ethereal extract, concentrated HCl
(0.5 mL) was added with stirring, and the resulting precipitate
Acknowledgment. We are grateful to Chemical
Block Ltd. Company (www.chemblock.com) for financial
support of this research.
Supporting Information Available: Characterization
data for compounds 3b,c,f,g,i-o, 4b,d,f-h, and 9c-f, 1H NMR
spectrum for 7b, and NOE measurements for 4c,e (2D NOESY
spectrum for 4c and NOE difference spectrum for 4e). This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
was filtered off and washed with ether. mp 242-245 °C. H
NMR (DMSO-d6, δ): 2.02 (m, 2H), 2.70 (s, 6H), 3.06 (m, 2H),
3.90 (s, 3H), 4.1 (br s, 2H), 7.3-7.4 (m, 4H), 7.47 (d, J ) 8.0
Hz, 1H), 7.69 (d, J ) 8.0 Hz, 1H), 10.35 (br s, 1H). Anal. Calcd
for C19H21N3O5‚HCl: C, 55.95; H, 5.44; Cl, 8.69; N, 10.30.
Found: C, 55.82; H, 5.48; Cl, 8.65; N, 10.37.
JO051425C
9376 J. Org. Chem., Vol. 70, No. 23, 2005