Dibenzo[ b, f ]pyrazolo[1,5-d ][1,4]oxazepines: Facile construction of a rare heterocyclic system via tandem aromatic nucleophilic substitution-smiles rearrangement-denitrocyclization

Article abstract of DOI:10.1055/s-0031-1289789

Condensation of 2-(1H-pyrazol-5-yl)phenols with 1-chloro-2-nitrobenzenes under basic conditions in N,N-dimethylformamide results in a tandem, atom-economical, aromatic nucleophilic substitution-Smiles rearrangement- denitrocyclization process to provide pyrazolo-fused dibenzo[b,f][1,4]oxazepines as a single regioisomer. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289789

PAPER
▌2401
Paper
Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines: Facile Construction of a Rare
Heterocyclic System via Tandem Aromatic Nucleophilic Substitution–Smiles
Rearrangement–Denitrocyclization
Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines
Alexander V. Sapegin,a Stanislav A. Kalinin,a Alexey V. Smirnov,a Mikhail V. Dorogov,a Mikhail Krasavin*b
a
The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
b
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia
Fax +61(7)37356001; E-mail: m.krasavin@griffith.edu.au
Received: 15.03.2012; Accepted after revision: 11.05.2012
vides ample evidence for the privileged character of this
Abstract: Condensation of 2-(1H-pyrazol-5-yl)phenols with 1-
scaffold (as defined by Evans7) and makes the develop-
chloro-2-nitrobenzenes under basic conditions in N,N-dimethyl-
ment of novel synthetic methodologies toward this and re-
lated heterocyclic systems particularly worthwhile.
formamide results in a tandem, atom-economical, aromatic nucleo-
philic
substitution–Smiles
rearrangement–denitrocyclization
process to provide pyrazolo-fused dibenzo[b,f][1,4]oxazepines as a
single regioisomer.
Of special value are tandem synthetic strategies, these are
atom-economical,8 generally more efficient, and less
time-consuming than linear multistep strategies. Earlier,
we reported a practically simple and streamlined entry to
dibenzo[b,f][1,4]oxazepin-11(10H)-ones 7 and their 9-
aza analogues 8 via condensation of 1-chloro-2-nitro de-
rivatives of benzene 9 and pyridine 10, respectively, with
secondary salicylamides 11 under basic conditions.9 The
reaction proceeded, as anticipated, via a denitrocycliza-
tion step,10 but was accompanied by an unexpected
(though not unprecedented11) Smiles rearrangement of the
initial diaryl ether adduct 12. Encouraged by this finding,
we became curious to see if NH-acidic azoles, such as pyr-
azole, could be effective participants in a similar tandem
process in lieu of the secondary amide functionality. This
would lead to the formation of a rare pyrazole-including
framework 13 (Scheme 1). Such tetracyclic scaffolds are
Key words: tetracyclic scaffolds, privileged structures, atom-
economical syntheses, dibenzo[b,f][1,4]oxazepines, Smiles rear-
rangement, nucleophilic aromatic substitution, denitrocyclization,
regiospecific reaction
The range of biological activity displayed by compounds
containing the dibenzo[b,f][1,4]oxazepine scaffold is
strikingly vast. From early applications of such com-
pounds as psychotropic drugs [e.g., Loxapine (1)1] and,
even more prominently, as prostaglandin receptors antag-
onists [e.g., Searle’s SC-19220 (2)2], the utility of diben-
zo[b,f][1,4]oxazepines has recently extended to the design
of potent progesterone receptor antagonists 3,3 p38 MAP
kinase inhibitors 4,4 TRPA1 ion channel modulators 5,5
and histone deacetylase inhibitors 66 (Figure 1). This pro-
Me
N
O
O
F3C
HN
NH
HN
N
O
H
Cl
N
N
N
Cl
O
O
O
1, Loxapine
psychotropic agent
2, SC-19220
PGE2 antagonist
3
progesterone receptor
antagonist
O
O
HOHN
N
HN
O
N
O
MeO
O
N
O
H
NH2
O
NH2
4
5
6
p38 MAP kinase inhibitor
TRPA1 channel activator
HDAC inhibitor
Figure 1 Examples of pharmacologically active dibenzo[b,f][1,4]oxazepines
SYNTHESIS 2012, 44, 2401–2407
Advanced online publication: 20.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289789; Art ID: SS-2012-N0274-OP
© Georg Thieme Verlag Stuttgart · New York

2402
A. V. Sapegin et al.
PAPER
R2
HN
HO
R1
O
N
K2CO3
R1
NO2
Cl
(2.5 equiv)
O
+
DMF, 75–80 °C
4 h
X
X
O
R2
65–90%
11
9, X = CH
10, X = N
7, X = CH
8, X = N
(a)
O–
N+
O–
O
R1
NO2
R1
NO2
R1
R2
O
R2
X
O
HN
X
N
OH
X
N
R2
O
O
12
?
O
HO
Cl
(b)
+
N
N
13
NO2
HN
N
Scheme 1 Strategies for construction of the dibenzo[b,f][1,4]oxazepine scaffold: (a) described earlier9 and (b) investigated in this work
R2
O
of much interest considering that fusion of five-membered
cycles onto a dibenzo[b,f][1,4]oxazepine core has been
shown to attenuate the pharmacological properties of the
OH
R1
R1
R2
OEt
resulting compounds.12 Moreover, dibenzo[b,f]pyrazo-
lo[1,5-d][1,4]oxazepines 13 have recently found applica-
tion in the design of organic light-emitting devices
(OLEDs).13 Herein, we would like to report on a success-
ful realization of a new synthetic strategy toward 13.
Na
O
+
neat
reflux, 2 h
O
OH
ONa
17a–e
15
16
R2
N
N2H4•H2O
AcOH
The starting 2-(1H-pyrazol-5-yl)phenols 14a–e were pre-
pared via Claisen condensation of o-hydroxyacetophe-
nones 15 with aliphatic esters 16 followed by treatment of
the isolated sodium phenolates 17a–e with hydrazine hy-
drate (Scheme 2). Both steps involved only filtration as
the means of solid product isolation and provided good to
excellent yields of the desired material (Table 1).
R1
EtOH, reflux
5 h
N
H
OH
14a–e
Scheme 2 Preparation of 2-(1H-pyrazol-5-yl)phenols 14a–c
To our delight, compounds 14a–e underwent facile con-
densation with a number of 1-chloro-2-nitrobenzenes 18,
on heating with three equivalents of anhydrous potassium
carbonate in N,N-dimethylformamide. Moreover, 1H
NMR analyses of the crude reaction mixtures confirmed
the disappearance of the characteristic broad singlets cor-
responding to both the pyrazole moiety (NH, δ = 13.55–
12.70) and the phenol functionality (OH, δ = 11.40–
10.03), clearly indicating that the former participated in
Table 1 2-(1H-Pyrazol-5-yl)phenols 14a–e and Their Precursors
17a–e Synthesized
Compd
R1
R2
Yield of 17 Yield of 14
(%)
(%)
14a, 17a
14b, 17b
14c, 17c
14d, 17d
14e, 17e
H
H
75
60
58
67
72
84
76
65
74
63
H
Me
Et
H
1
the reaction. Additionally, the H NMR signals corre-
sponding to the aromatic portions of 14 and 18 exhibited
pronounced (~0.3 ppm) downfield and upfield shifts, re-
spectively. This, according to our previous denitrocycli-
zation experience,9 strongly attested to the formation of
Cl
Me
Me
Me
Synthesis 2012, 44, 2401–2407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines
2403
R2
R2
N
K2CO3
O2N
Cl
R3
N
R1
R1
(3 equiv)
N
N
+
H
DMF, 75 °C
7 h
OH
14a–e
O
18
R3
19a–o
Scheme 3 Preparation of dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines 19a–o
the previously undescribed tetracyclic compounds 19a–o
(Scheme 3).
Table 2 Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines 19a–o Synthe-
sized
R1
R2
R3
Yield (%)
The isolated yields of compounds 19a–o were good to ex-
Compd
cellent (Table 2) and their analytical data (1H and 13C
NMR and elemental analyses) were consistent with the 19a
H
H
CO2Me
CN
66
79
81
77
81
68
60
73
85
74
83
85
76
69
80
anticipated dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine
structure. However, establishing the regiochemical identi-
19b
H
H
ty of the products obtained presented a significant chal- 19c
H
H
NO2
lenge, although it was evident from the NMR data that
compounds 19a–o belonged to the same isomeric series.
19d
H
Me
Me
Me
Et
CO2Me
CN
Presumably, the regiochemistry of 19 would be deter- 19e
H
mined (Scheme 4) by the ability of the pyrazole moiety to
participate in the initial chlorine displacement event (path
19f
H
NO2
19g
19h
19i
H
CO2Me
CN
a) or in the subsequent Smiles rearrangement (path b) of
the initially formed diphenyl ether adduct 20.9 In both
cases regioisomer A would be formed in contrast to regio-
isomer B that might result from two sequential nucleo-
philic displacements (of the chlorine atom and the nitro
group), not accompanied by the Smiles rearrangement
(path c), a possibility that also should be considered.
H
Et
H
Et
NO2
19j
Cl
Cl
Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
CO2Me
CN
19k
19l
Intermolecular displacement of the chlorine atom in 18 by
the pyrazole moiety in 14 (path a) can be easily ruled out
based on the results of a model experiment. Under the
same reaction conditions, 3-methyl-5-phenyl-1H-pyr-
azole (21) failed to react with 4-chloro-3-nitrobenzonitrile
(22), even on prolonged (3 days) heating at 110 °C
(Scheme 5). Additionally, the absence in the reaction mix-
NO2
19m
19n
19o
CO2Me
CN
NO2
R2
N
R1
O2N
Cl
R3
N
+
H
OH
a
14
18
R2
N
R2
N
R2
R2
R1
OH
R1
N
H
N
N
N
R1
b
R1
c
N
N
O
NO2
NO2
Smiles
de-NO2
de-NO2
R3
O
O
R3
R3
R3
19, isomer A
19, isomer B
20'
20
Scheme 4 Possible reaction pathways determining the regiochemistry of dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines 19a–o
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2401–2407

2404
A. V. Sapegin et al.
PAPER
ture of pyrazole N-arylation products regioisomeric to in- All reactions were run in oven-dried glassware in an atmosphere of
N2. Melting points were measured with a Buchi В-520 melting point
apparatus and were not corrected. Analytical TLC was carried out
on Silufol UV-254 silica gel plates using appropriate EtOAc–hex-
termediate 20′ (which cannot be expected to participate in
subsequent cyclization events due to steric reasons) also
speak against the reaction proceeding via path a.
ane mixtures. Compounds were visualized with short-wavelength
UV light. 1H and 13C NMR spectra were recorded on Bruker MSL-
300 spectrometers in DMSO-d6 using TMS as an internal standard.
K2CO3
O2N
Cl
CN
Elemental analyses were obtained at Research Institute for Chemi-
cal Crop Protection (Moscow, Russia) using Carlo Erba Strumen-
tazione 1106 analyzer. The IR spectra were recorded using Specord
M-80 spectrophotometer on compound samples prepared as KBr
tablets. All and reagents were obtained from commercial sources
and used without purification. DMF was dried according to the stan-
dard procedure15 and K2CO3 was dried at 200 °C for 5 h prior to use.
(3 equiv)
N
no reaction
+
N
DMF, 90–110 °C
3 d
H
21
22
Scheme 5 Attempted reaction of a model pyrazole 21 with 3-chloro-
4-nitrobenzonitrile (22)
4-Chloro-2-(3-methyl-1H-pyrazol-5-yl)phenol (14d); Typical
Procedure for the Synthesis of Compounds 14a–e
Na metal (6.44 g, 0.280 mol) was carefully added to a soln of 5′-
chloro-2′-hydroxyacetophenone (11.9 g, 0.070 mol) in ethyl acetate
(100 mL) over 1 h. The resulting mixture was heated at reflux for 2
h, cooled to r.t., and poured over crushed ice–H2O mixture (1 L total
volume). The resulting precipitate was filtered off, washed with
cold i-PrOH (50 mL), air dried, and further dried in vacuo (60 °C,
Unfortunately, correlational NMR spectroscopy (NOESY,
HSQC, HMBC) provided insufficient information for an
unequivocal regiochemistry assignment of products 19a–o
and, thus, did not allow us to distinguish between reaction
paths b and c. To our relief, we were able to obtain a sin-
gle-crystal X-ray structure of a representative compound, overnight) to provide sodium 4-chloro-2-(3-hydroxybut-2-eno-
19h (Figure 2).14 It clearly showed that the compounds be-
yl)phenolate (17d) (10.9 g, 67%) as a light-yellow solid.
1H NMR (DMSO-d6, 300 K): δ = 16.87–17.11 (br s, 1 H, OH), 7.44
(s, 1 H, HAr), 7.11 (d, J = 8.2 Hz, 1 H, HAr), 6.61 (d, J = 8.5 Hz, 1 H,
HAr), 5.35–5.50 (br s, 1 H, -CH=), 2.04 (s, 3 H, CH3).
longed to the isomeric series A and thus confirmed that
the compounds 19 formed as a result of tandem aromatic
nucleophilic substitution–Smiles rearrangement–denitro-
cyclization.
A 65% aq soln of N2H4·H2O (5 mL) and glacial AcOH (0.021 mol)
were added to a soln of 17d (3.65 g, 0.016 mol) in EtOH (30 mL).
The resulting mixture was heated at reflux for 5 h, cooled to r.t., and
the volatiles were removed in vacuo. The resulting precipitate was
suspended in H2O (100 mL), filtered off, washed with more H2O, air
dried, and further dried in vacuo (60 °C, overnight) to provide 14d
(2.4 g, 74%) as an off-white solid; mp 95–97 °C.
IR (KBr): 3442, 3153, 1610 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 12.70–13.06 (br s, 1 H, NHpyrazole),
10.03–11.40 (br s, 1 H, Ar-OH), 7.64 (s, 1 H, HAr), 7.10 (d, J = 8.5
Hz, 1 H, HAr), 6.87 (d, J = 8.5 Hz, 1 H, HAr), 6.63 (s, 1 H, Hpyrazole),
2.31 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 K): δ = 154.1, 158.0, 128.0, 125.9, 122.9,
119.1, 118.1, 100.7, 10.7.
Anal. Calcd for C10H9ClN2O: C, 57.57; H, 4.35; N, 13.43. Found:
C, 57.41; H, 4.35; N, 13.49.
2-(1H-Pyrazol-5-yl)phenol (14a)
White solid; yield: 1.78 g (84%); mp 128–131 °C.
IR (KBr): 3435, 3140, 1620 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 13.00–13.49 (br s, 1 H, NHpyrazole),
10.73–11.08 (br s, 1 H, Ar-OH), 7.86 (s, 1 H, Hpyrazole), 7.72 (d, J =
7.9 Hz, 1 H, HAr), 7.17 (t, J = 7.5 Hz, 1 H, HAr), 6.79–6.95 (m, 3 H,
HAr, Hpyrazole).
Figure 2 Single-crystal X-ray structure of compound 19h
13C NMR (DMSO-d6, 300 K): δ = 155.3, 139.1, 128.6, 128.6, 126.7,
119.2, 119.1, 117.2, 116.4, 101.0.
In summary, we have developed a streamlined synthetic
methodology towards the previously undescribed diben-
zo[b,f][1,4]oxazepines from readily available precursors.
The compounds were obtained in high yields as a single
regioisomer as a result of three chemical events occurring
in tandem. This represents a remarkable example of atom
economy and efficiency in constructing polycyclic het-
erocycles. Similar strategies involving other potentially
nucleophilic azoles are under investigated in our laborato-
ries and will be reported in due course.
Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N, 17.49. Found: C,
67.31; H, 5.04; N, 17.58.
2-(3-Methyl-1H-pyrazol-5-yl)phenol (14b)
White solid; yield: 1.4 g (76%); mp 128–131 °C.
IR (KBr): 3430, 3143, 1628 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 12.80–13.09 (br s, 1 H, NHpyrazole),
10.97–11.21 (br s, 1 H, Ar-OH), 7.63 (d, J = 7.9 Hz, 1 H, HAr), 7.15
(t, J = 7.9 Hz, 1 H, HAr), 6.82–6.94 (m, 2 H, HAr), 6.59 (s, 1 H,
Hpyrazole), 2.30 (s, 3 H, CH3).
Synthesis 2012, 44, 2401–2407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines
2405
13C NMR (DMSO-d6, 300 K): δ = 155.3, 128.6, 128.6, 126.6, 119.2,
119.1, 117.2, 116.4, 101.3, 10.6.
Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-carbonitrile
(19b)
Light-yellow solid; yield: 1.3 g (79%); mp 196–196 °C (EtOH–
DMF).
IR (KBr): 2239, 1615 cm–1.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.76; H, 5.79; N, 16.15.
2-(3-Ethyl-1H-pyrazol-5-yl)phenol (14c)
1H NMR (DMSO-d6, 300 K): δ = 8.34 (s, 1 H, HAr), 8.21 (d, J = 8.5
Hz, 1 H, HAr), 7.98–8.03 (m, 2 H, HAr, Hpyrazole), 7.63 (d, J = 7.4 Hz,
1 H, HAr), 7.42–7.60 (m, 2 H, HAr), 7.34 (t, J = 7.5 Hz, 1 H, HAr),
6.11 (s, 1 H, Hpyrazole).
13C NMR (DMSO-d6, 300 K): δ = 155.0, 151.6, 149.3, 141.3, 140.2,
136.8, 131.5, 130.3, 129.2, 126.5, 126.2, 124.1, 117.5, 110.2, 107.6.
White solid; yield: 2.31 g (65%); mp 50–52 °C.
IR (KBr): 3431, 3140, 1620 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 13.04–13.55 (br s, 1 H, NHpyrazole),
10.86–11.18 (br s, 1 H, Ar-OH), 7.60 (d, J = 7.5 Hz, 1 H, HAr), 7.12
(t, J = 7.0 Hz, 1 H, HAr), 6.84 (m, 2 H, HAr), 6.53 (s, 1 H, Hpyrazole),
2.70 (m, 2 H, CH2CH3), 1.28 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (DMSO-d6, 300 K): δ = 155.3, 128.6, 128.5, 126.6, 119.2,
119.1, 117.3, 116.4, 99.9, 18.5, 13.4.
Anal. Calcd for C16H9N3O: C, 74.12; H, 3.50; N, 16.21. Found: C,
73.90; H, 3.51; N, 16.29.
10-Nitrodibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine (19c)
Dark-yellow solid; yield: 0.67 g (81%); mp 217–219 °C (EtOH–
DMF).
Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.01; H, 6.44; N, 14.95.
4-Methyl-2-(3-methyl-1H-pyrazol-5-yl)phenol (14e)
IR (KBr): 1682, 1619, 1223, 1200 cm–1.
White solid; yield: 1.6 g (63%); mp 61–63 °C.
1H NMR (DMSO-d6, 300 K): δ = 8.46 (s, 1 H, HAr), 8.24 (d, J = 8.5
Hz, 1 H, HAr), 8.00–8.13 (m, 2 H, HAr, Hpyrazole), 7.77 (d, J = 7.5 Hz,
1 H, HAr), 7.66 (d, J = 7.9 Hz, 1 H, HAr), 7.55 (t, J = 7.2 Hz, 1 H,
HAr), 7.39 (t, J = 6.9 Hz, 1 H, HAr), 6.08 (s, 1 H, Hpyrazole).
13C NMR (DMSO-d6, 300 K): δ = 155.4, 153.0, 148.5, 145.9, 141.3,
140.2, 138.0, 131.7, 129.3, 126.7, 123.7, 121.9, 121.6, 121.4, 118.1,
108.2.
IR (KBr): 3426, 3139, 1618 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 12.85–13.12 (br s, 1 H, NHpyrazole),
10.71–11.22 (br s, 1 H, Ar-OH), 7.36 (s, 1 H, HAr), 6.91 (d, J = 6.6
Hz, 1 H, HAr), 6.73 (d, J = 7.5 Hz, 1 H, HAr), 6.47 (s, 1 H, Hpyrazole),
2.32 (s, 3 H, Ar-CH3), 2.27 (s, 3 H, pyrazole-CH3).
13C NMR (DMSO-d6, 300 K): δ = 153.3, 129.1, 129.1, 127.2, 126.9,
126.8, 116.9, 116.2, 101.1, 20.2, 10.7.
Anal. Calcd for C15H9N3O3: C, 64.52; H, 3.25; N, 15.05. Found: C,
64.32; H, 3.27; N, 15.12.
Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.98; H, 6.42; N, 14.91.
Methyl 2-Methyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-
carboxylate (19d)
White solid; yield: 1.64 g (77%); mp 146–148 °C (i-PrOH).
IR (KBr): 1741, 1622, 1220, 1205 cm–1.
Methyl 2-Ethyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-
carboxylate (19g); Typical Procedure for the Synthesis of Com-
pounds 19a–o
A mixture of 14c (1.88 g, 10 mmol), methyl 4-chloro-3-nitrobenzo-
ate (2.16 g, 10 mmol), and K2CO3 (1.15 g, 30 mmol) in anhyd DMF
(15 mL) was stirred at 75 °C for 7 h, then cooled to r.t. and poured
into H2O (100 mL). The resulting precipitate was filtered off and
crystallized (i-PrOH) to provide 19g (1.92 g, 60%) as a white solid;
mp 94–96 °C.
1H NMR (DMSO-d6, 300 K): δ = 8.01 (s, 1 H, HAr), 7.83–7.95 (m,
2 H, HAr), 7.67 (d, J = 7.2 Hz, 1 H, HAr), 7.55 (d, J = 7.9 Hz, 1 H,
HAr), 7.50 (t, J = 6.9 Hz, 1 H, HAr), 7.34 (t, J = 7.5 Hz, 1 H, HAr),
6.82 (s, 1 H, Hpyrazole), 3.88 (s, 3 H, CO2CH3), 2.35 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 K): δ = 165.0, 155.5, 151.4, 149.0, 141.1,
136.5, 131.5, 129.2, 128.9, 127.2, 126.4, 123.4, 122.9, 121.4, 107.4,
52.5, 13.5.
IR (KBr): 1744, 1623, 1219, 1201 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 8.01 (s, 1 H, HAr), 7.83–7.96 (m,
2 H, HAr), 7.69 (d, J = 7.9 Hz, 1 H, HAr), 7.57 (d, J = 8.2 Hz, 1 H,
HAr), 7.49 (t, J = 7.2 Hz, 1 H, HAr), 7.33 (t, J = 7.2 Hz, 1 H, HAr),
6.87 (s, 1 H, Hpyrazole), 3.88 (s, 3 H, CO2CH3), 2.71 (m, 2 H,
CH2CH3), 1.29 (t, J = 7.9 Hz, 3 H, CH2CH3).
13C NMR (DMSO-d6, 300 K): δ = 165.0, 157.1, 155.5, 149.1, 141.0,
136.5, 131.4, 129.2, 128.9, 127.2, 126.4, 123.4, 122.9, 121.6, 121.4,
106.1, 52.5, 21.1, 13.4.
Anal. Calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found: C,
70.41; H, 4.60; N, 9.19.
2-Methyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-carbo-
nitrile (19e)
Light-yellow solid; yield: 1.1 g (81%); mp 208–209 °C (EtOH–
DMF).
IR (KBr): 2241, 1606 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 8.36 (s, 1 H, HAr), 8.20 (d, J = 8.8
Hz, 1 H, HAr), 7.99 (d, J = 9.0 Hz, 1 H, HAr), 7.67 (d, J = 7.5 Hz, 1
H, HAr), 7.43–7.60 (m, 2 H, HAr), 7.34 (t, J = 7.5 Hz, 1 H, HAr), 6.80
(s, 1 H, Hpyrazole), 2.38 (s, 3 H, CH3).
Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.03; H, 5.04; N, 8.79.
Methyl Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-carbox-
ylate (19a)
White solid; yield: 0.78 g (66%); mp 173–175 °C (EtOH).
13C NMR (DMSO-d6, 300 K): δ = 155.4, 151.8, 149.2, 141.3, 136.8,
131.5, 130.3, 129.2, 126.5, 126.2, 124.1, 117.5, 110.2, 107.7, 13.3.
IR (KBr): 1745, 1619, 1223, 1200 cm–1.
Anal. Calcd for C17H11N3O: C, 74.71; H, 4.06; N, 15.38. Found: C,
74.79; H, 4.07; N, 15.45.
1H NMR (DMSO-d6, 300 K): δ = 8.02–8.05 (m, 2 H, HAr, Hpyrazole),
7.83–7.94 (m, 2 H, HAr), 7.68 (d, J = 7.3 Hz, 1 H, HAr), 7.56 (d, J =
7.5 Hz, 1 H, HAr), 7.51 (t, J = 7.0 Hz, 1 H, HAr), 7.35 (t, J = 7.5 Hz,
1 H, HAr), 6.10 (s, 1 H, Hpyrazole), 3.87 (s, 3 H, CO2CH3).
13C NMR (DMSO-d6, 300 K): δ = 165.0, 155.6, 151.4, 149.0, 141.1,
140.2, 136.5, 131.5, 129.2, 128.9, 127.2, 126.4, 123.4, 122.9, 121.4,
107.4, 52.5.
2-Methyl-10-nitrodibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine
(19f)
Dark-yellow solid; yield: 0.88 g (68%); mp 237–239 °C (EtOH–
DMF).
IR (KBr): 1680, 1617, 1352 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 8.42 (s, 1 H, HAr), 8.21 (d, J = 8.9
Hz, 1 H, HAr), 7.99 (d, J = 9.2 Hz, 1 H, HAr), 7.71 (d, J = 7.9 Hz, 1
H, HAr), 7.63 (d, J = 8.2 Hz, 1 H, HAr), 7.53 (t, J = 7.5 Hz, 1 H, HAr),
Anal. Calcd for C17H12N2O3: C, 69.86; H, 4.14; N, 9.58. Found: C,
69.67; H, 4.16; N, 9.63.
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A. V. Sapegin et al.
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7.37 (t, J = 7.9 Hz, 1 H, HAr), 6.89 (s, 1 H, Hpyrazole), 2.37 (s, 3 H,
CH3).
13C NMR (DMSO-d6, 300 K): δ = 155.1, 152.2, 148.6, 145.9, 141.3,
138.0, 131.7, 129.3, 126.7, 123.7, 121.8, 121.6, 121.2, 118.1, 108.1,
13.5.
13C NMR (DMSO-d6, 300 K): δ = 153.7, 151.9, 148.7, 139.8, 136.5,
131.2, 130.8, 130.6, 128.5, 126.5, 124.1, 123.3, 123.1, 117.6, 110.1,
104.7, 13.5.
Anal. Calcd for C17H10ClN3O: C, 66.35; H, 3.28; N, 13.65. Found:
C, 66.14; H, 3.31; N, 13.72.
Anal. Calcd for C16H11N3O3: C, 65.53; H, 3.78; N, 14.33. Found: C,
65.38; H, 3.77; N, 14.40.
5-Chloro-2-methyl-10-nitrodibenzo[b,f]pyrazolo[1,5-d][1,4]ox-
azepine (19l)
Brown solid; yield: 1.06 g (85%); mp 224–226 °C (DMF).
2-Ethyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-carboni-
trile (19h)
IR (KBr): 1681, 1615, 1341 cm–1.
Light-yellow solid; yield: 1.07 g (73%); mp 178–181 °C (EtOH–
DMF).
IR (KBr): 2235, 1610 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 8.39 (s, 1 H, HAr), 8.21 (d, J = 8.5
Hz, 1 H, HAr), 7.99 (d, J = 9.2 Hz, 1 H, HAr), 7.73 (s, 1 H, HAr), 7.62
(d, J = 8.5 Hz, 1 H, HAr), 7.51 (d, J = 8.5 Hz, 1 H, HAr), 6.92 (s, 1 H,
H
pyrazole), 2.38 (s, 3 H, CH3).
1H NMR (DMSO-d6, 300 K): δ = 8.01 (s, 1 H, HAr), 7.93 (d, J = 8.5
Hz, 1 H, HAr), 7.76 (d, J = 8.5 Hz, 1 H, HAr), 7.67 (d, J = 7.9 Hz, 1
H, HAr), 7.43–7.51 (m, 2 H, HAr), 7.33 (t, J = 7.0 Hz, 1 H, HAr), 6.81
(s, 1 H, Hpyrazole), 2.74 (m, 2 H, CH2CH3), 1.32 (t, J = 7.4 Hz, 3 H,
CH2CH3).
13C NMR (DMSO-d6, 300 K): δ = 155.0, 151.7, 149.2, 141.1, 136.8,
131.5, 130.3, 129.2, 126.5, 126.2, 124.1, 117.51 110.2, 107.7, 20.9,
13.3.
13C NMR (DMSO-d6, 300 K): δ = 153.8, 152.3, 148.4, 146.2, 140.0,
137.9, 131.0, 130.7, 128.3, 123.7, 123.3, 123.1, 121.7, 117.9, 108.7,
13.3.
Anal. Calcd for C16H10ClN3O3: C, 58.64; H, 3.08; N, 12.82. Found:
C, 58.64; H, 3.10; N, 12.89.
Methyl 2,5-Dimethyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-
10-carboxylate (19m)
White solid; yield: 1.44 g (76%); mp 131–133 °C (i-PrOH).
IR (KBr): 1741, 1622, 1221, 1200 cm–1.
Anal. Calcd for C18H13N3O: C, 75.25; H, 4.56; N, 14.63. Found: C,
75.03; H, 4.57; N, 14.70.
1H NMR (DMSO-d6, 300 K): δ = 7.97 (s, 1 H, HAr), 7.89 (d, J = 8.4
Hz, 1 H, HAr), 7.65 (d, J = 7.0 Hz, 1 H, HAr), 7.49 (s, 1 H, HAr), 7.27–
7.42 (m, 2 H, HAr), 6.79 (s, 1 H, Hpyrazole), 3.88 (s, 3 H, CO2CH3),
2.35 (s, 3 H, Ar-CH3), 2.32 (s, 3 H, pyrazole-CH3).
2-Ethyl-10-nitrodibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine (19i)
Dark-yellow solid; yield: 0.92 g (85%); mp 221–223 °C (EtOH–
DMF).
IR (KBr): 1689, 1620, 1347 cm–1.
13C NMR (DMSO-d6, 300 K): δ = 165.0, 153.1, 151.7, 149.2, 141.3,
136.7, 135.9, 131.9, 130.5, 129.3, 127.5, 126.3, 124.1, 121.0, 120.9,
117.7, 52.3, 20.3, 13.5.
1H NMR (DMSO-d6, 300 K): δ = 8.42 (s, 1 H, HAr), 8.22 (d, J = 8.9
Hz, 1 H, HAr), 7.99 (d, J = 9.2 Hz, 1 H, HAr), 7.72 (d, J = 7.2 Hz, 1
H, HAr), 7.63 (d, J = 7.5 Hz, 1 H, HAr), 7.53 (t, J = 7.5 Hz, 1 H, HAr),
7.37 (t, J = 7.2 Hz, 1 H, HAr), 6.94 (s, 1 H, Hpyrazole), 2.74 (m, 2 H,
CH2CH3), 1.30 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (DMSO-d6, 300 K): δ = 155.8, 155.1, 148.6, 145.8, 141.2,
138.1, 131.6, 129.2, 126.7, 123.7, 121.8, 121.5, 121.3, 118.1, 106.7,
21.1, 13.2.
Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.12; H, 5.05; N, 8.71.
2,5-Dimethyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-10-car-
bonitrile (19n)
Light-yellow solid; yield: 0.63 g (69%); mp 182–185 °C (EtOH–
DMF).
Anal. Calcd for C17H13N3O3: C, 66.24; H, 4.26; N, 13.67. Found: C,
66.28; H, 4.27; N, 13.74.
IR (KBr): 2241, 1608 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 8.08 (s, 1 H, HAr), 7.90 (d, J = 8.5
Hz, 1 H, HAr), 7.79 (d, J = 7.9 Hz, 1 H, HAr), 7.50 (s, 1 H, HAr), 7.27–
7.42 (m, 2 H, HAr), 6.83 (s, 1 H, Hpyrazole), 2.35 (s, 3 H, Ar-CH3), 2.32
(s, 3 H, pyrazole-CH3).
Methyl 5-Chloro-2-methyldibenzo[b,f]pyrazolo[1,5-d][1,4]ox-
azepine-10-carboxylate (19j)
Grey solid; yield: 0.73 g (74%); mp 192–195 °C (DMF).
IR (KBr): 1745, 1620, 1224, 1205 cm–1.
13C NMR (DMSO-d6, 300 K): δ = 153.2, 151.7, 149.2, 141.3, 136.7,
135.9, 132.0, 130.4, 129.3, 126.3, 124.1, 121.0, 120.9, 117.7, 109.9,
107.6, 20.3, 13.5.
1H NMR (DMSO-d6, 300 K): δ = 8.00 (s, 1 H, HAr), 7.85–7.93 (m,
2 H, HAr), 7.70 (s, 1 H, HAr), 7.55 (d, J = 9.5 Hz, 1 H, HAr), 7.48 (d,
J = 9.4 Hz, 1 H, HAr), 6.85 (s, 1 H, Hpyrazole), 3.89 (s, 3 H, CO2CH3),
2.37 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 K): δ = 165.0, 154.3, 151.5, 148.8, 139.8,
136.3, 130.8, 130.4, 129.4, 128.3, 127.2, 123.4, 123.2, 122.8, 108.1,
52.3, 13.3.
Anal. Calcd for C18H13N3O: C, 75.25; H, 4.56; N, 14.63. Found: C,
75.11; H, 4.56; N, 14.68.
2,5-Dimethyl-10-nitrodibenzo[b,f]pyrazolo[1,5-d][1,4]oxaze-
pine (19o)
Dark-grey solid; yield: 1.38 g (80%); mp 207–209 °C (EtOH–
DMF).
Anal. Calcd for C18H13ClN2O3: C, 63.44; H, 3.85; N, 8.22. Found:
C, 63.27; H, 3.87; N, 8.26.
IR (KBr): 1685, 1619, 1354 cm–1.
5-Chloro-2-methyldibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepine-
10-carbonitrile (19k)
1H NMR (DMSO-d6, 300 K): δ = 8.39 (s, 1 H, HAr), 8.21 (d, J = 8.9
Hz, 1 H, HAr), 7.99 (d, J = 8.9 Hz, 1 H, HAr), 7.47–7.56 (m, 2 H,
HAr), 7.33 (d, J = 8.5 Hz, 1 H, HAr), 6.87 (s, 1 H, Hpyrazole), 2.36 (s, 3
H, Ar-CH3), 2.33 (s, 3 H, pyrazole-CH3).
13C NMR (DMSO-d6, 300 K): δ = 153.1, 152.1, 148.8, 145.8, 141.4,
138.1, 136.1, 132.1, 129.3, 123.7, 121.7, 121.2, 120.8, 118.0, 107.9,
20.3, 13.5.
Light-yellow solid; yield: 1.52 g (83%); mp 215–217 °C (DMF).
IR (KBr): 2241, 1604 cm–1.
1H NMR (DMSO-d6, 300 K): δ = 8.02 (s, 1 H, HAr), 7.91 (d, J = 8.5
Hz, 1 H, HAr), 7.77 (d, J = 8.5 Hz, 1 H, HAr), 7.71 (s, 1 H, HAr), 7.44–
7.55 (m, 2 H, HAr), 6.88 (s, 1 H, Hpyrazole), 2.37 (s, 3 H, CH3).
Anal. Calcd for C17H13N3O3: C, 66.44; H, 4.26; N, 13.67. Found: C,
66.25; H, 4.23; N, 13.71.
Synthesis 2012, 44, 2401–2407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines
2407
(6) Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.;
Acknowledgment
Gensini, M.; Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli,
M.; Valli, C.; Terao, M.; Garattini, E. ACS Med. Chem. Lett.
2010, 1, 411.
This research was supported by the Russian Federation Ministry of
Science and Education (Contract 13.G25.31.0079 ‘Development of
Cooperation of Higher Education Institutions and Organizations
Implementing Complex High-Technology Production’, in accor-
dance with Government Act 218, 09.04.2010). Mikhail Krasavin
acknowledges a 2012 Griffith University New Researcher Grant.
(7) Evans, B. E. J. Med. Chem. 1988, 31, 2235.
(8) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(9) Sapegin, A. V.; Sakharov, V. N.; Kalandadze, L. S.;
Smirnov, A. V.; Khristolyubova, T. A.; Plakhtinskii, V. V.;
Ivashchenko, A. V. Mendeleev Commun. 2008, 18, 281.
(10) Radl, S. Adv. Heterocycl. Chem. 2002, 83, 189.
(11) Rotas, G.; Kimbaris, A.; Varvounis, G. Tetrahedron 2004,
60, 10825.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
(12) Walther, G.; Daniel, H.; Bechtel, W. D.; Brandt, K. Arzneim.
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(14) Crystallographic data (excluding structure factors) for the
structure 19h have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 871488. Copies of the data can be obtained
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or e-mail:
deposit@ccdc.cam.ac.uk].
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2401–2407