Gold-catalyzed formation of aryl-fused pyrazolooxazepines via intramolecular regioselective 7-exo-dig cyclization

Article abstract of DOI:10.1039/C8OB03157F

An efficient method was developed for the synthesis of substituted aryl-fused pyrazolooxazepines from ortho-O-propargyl aryl pyrazoles by gold catalysis. In this organic transformation a new C-N bond was formed regioselectively via 7-exo-dig cyclization.

Full text of DOI:10.1039/C8OB03157F

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Gold-catalyzed formation of aryl-fused
pyrazolooxazepines via intramolecular regioselective 7-
exo-dig cyclization†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Ravinder Guduru,a,b,c N. S. V. M. Rao Mangina,a,b,c Balasubramanian Sridhar,d and
Galla V. Karunakar*a,b
www.rsc.org/
An efficient method was developed for synthesis of substituted aryl-fused pyrazolooxazepines from
ortho-O-propargyl aryl pyrazoles by gold-catalysis. In this organic transformation a new C-N bond was
formed regioselectively via 7-exo-dig cyclization. Moderate to good yields of aryl-fused
pyrazolooxazepine derivatives were obtained with significant molecular complexity in one-pot.
Introduction
For instance, substituted benzooxazepine derivatives such as
Medium-sized heterocyclic molecules are important building blocks
in medicinal chemistry.1 Nitrogen containing seven-membered
heterocyclic molecules2 have gained much attention in recent years
due to their potential applications in medicinal chemistry and
material sciences.3 The recent literature evidencing that
benzooxazepines exhibit a wide range of biological activities such
as anticancer,4a anti-HIV,4b antitumor,5 anti-inflammatory activities,6
and also useful for the treatment of Alzheimer’s disease.7
Sintamil is a antidepressant drug.8 Loxapine is antipsychotic drug9
and SC-19220 acts as prostaglandin E2 receptor agonist as well as
antihistaminic (Figure 1).10 Further, oxazepine derivatives were
used as precursors for synthesis of secoiridoids and monoterpenoid
alkaloids.11
The gold-catalyzed organic reactions are occupying an
important place in synthetic organic chemistry, due to their
selectivity and substrate tolerance.12 Distinctive synthetic methods
were discovered by selectively tuning the gold-catalysts,13 which
resulted in the generation of diversified molecular scaffolds.14
Regioselective metal-catalyzed organic transformations
gained much focus in recent years to construct medium-sized
heterocyclic molecules due to their applications in medicinal
chemistry. Our current research efforts led to the development
of gold-catalyzed regioselective organic transformations.15 We
initiated our investigations for intramolecular synthesis of
substituted benzopyrazolooxazepines under gold-catalysis.
Recently, gold-catalyzed seven-membered ring formation
reactions have been reported by the research groups of
Hashmi,16a Echavarren16b and Sawamura.16c Intermolecular
synthesis of benzopyrazolooxazepines were reported through
Smiles rearrangement,17a,b and copper-catalyzed cross coupling
reactions.17c
Me
N
O
Me
Me
NH
N
HN
NMe2
Cl
HN
O
N
O
NH
N
N
O2N
O2N
Cl
O
O
O
O
SC-19220
Prostaglandin E2
receptor agonist
Sintamil
Antidepressant drug
Loxapine
Antipsychotic drug
Antihistaminic
agent
O
NHOH
O
N
O
N
NH
O
O
O
OMe
N
H
O
NH2
NH2
p38 MAP
kinase inhibitor
TRPA 1 channel
activator
HDAC inhibitor
Fig. 1 Selected examples of important molecules containing
benzooxazepine core skeleton.
Results and discussion
a Division of Fluoro and Agrochemicals, CSIR-Indian Institute of Chemical
Technology, Hyderabad, 500007, India.
bAcademy of Scientific and Innovative Research, Ghaziabad- 201002, India.
cAuthors contributed equally
We visualized that 5-phenyl-3-(2-(prop-2-yn-1-yloxy)phenyl)-1H-
pyrazole 1a can be converted to the corresponding 5-methylene-2-
phenyl-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine 2a via 7-
exo-dig cyclization (path a, Scheme 1) or 2-phenyl-7H-
dCenter for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Hyderabad, 500007, India.
†Electronic Supplementary Information (ESI) available: Experimental details, 1H, 13
C
NMR spectra, mass for the compounds and crystallographic data of compound 2u
in CIF. (CCDC 1574971) See DOI: 10.1039/x0xx00000x
benzo[b]pyrazolo[5,1-d][1,5]oxazocine
3a
via
8-endo-dig
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cyclization (path b, Scheme 1) through intramolecular
hydroamination under gold-catalysis (Scheme 1).
observed that 64% yield of product 2a was isolaVteiedw A(rTticalebOlenlin1e,
DOI: 10.1039/C8OB03157F
entry 25). The substrate 1a was tested in the presence of
different copper catalysts (entries 26-29). Under these reaction
conditions, moderate yields of product 2a was observed.18
Table 1. Optimization of reaction conditionsa
Ph
Ph
N
Ph
NH
N
N
N
Gold cat.
path-a
Gold cat.
path-b
N
Ph
Ph
a
O
b
O
O
N
2a
1a
NH
3a
Benzopyrazolooxazocine
catalyst
N
Benzopyrazolooxazepine
N
solvent, time
O
1a
Scheme 1. Synthetic strategy for the formation of
benzopyrazolooxazepine (2a) or benzopyrazolooxazocine (3a) from
1a.
O
2a
Entry
Catalyst (mol %)
Solvent
Time (h)
Yield(%)c
1
2
3
4
5
6
Au(PPh3)Cl (10)
No Catalyst
AuCN (10)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
12
18
12
12
12
48
nrb
10
12
41
Based on the above synthetic approach, a reaction was performed by
taking 1a and 10 mol% of Au(PPh3)Cl in acetonitrile, which
produced 48% yield of product 2a (Scheme 2).
AuCl (10)
IPrAuCl (10)
[Au(JhonPhos)
(MeCN)[SbF6] (10)
KAuCl4 (10)
AuCl3 (10)
AuBr3 (10)
AgSbF6(10)
AgBF4 (10)
AgOTf (10)
Ph
Ph
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
12
12
12
12
24
24
24
24
43
11
30
26
32
43
46
44
N
7
8
9
10
11
12
13
14
NH
Au(PPh3)Cl (10 mol%)
N
N
CH3CN, 60 oC, 12 h
O
1a
O
2a
(48%)
Scheme
2
Conversion
of
5-phenyl-3-(2-(prop-2-yn-1-
AgNTf2(10)
Au(PPh3)Cl (10)/
AgSbF6 (15)
Au(PPh3)Cl (10)/
AgBF4 (15)
Au(PPh3)Cl (10)/
AgOTf (15)
yloxy)phenyl)-1H-pyrazole (1a) to benzopyrazolooxazepine (2a).
CH3CN
CH3CN
CH3CN
CH3CN
Toulene
DCE
2
2
2
2
2
2
2
2
2
2
2
72
50
56
60
40
45
62
50
25
45
66
15
16
17
18
19
20
21
22
23
24
25
This positive result driven us to test this reaction for the yield
improvement of product 2a by utilizing different catalysts, catalyst
combinations and reaction conditions. Then, the starting material 1a
was tested without catalyst in acetonitrile; it was observed that the
1a remained intact (Table 1, entry 2). The substrate 1a was tested by
utilizing various gold-catalysts such as AuCN, AuCl, IPrAuCl,
[Au(JohnPhos)(MeCN)][SbF6], KAuCl4, AuCl3 and AuBr3. Under
these reaction conditions the product 2a was obtained in poor yields
(Table 1, entries 3-9). We have conducted experiments by
utilizing the substrate 1a in the presence of different silver
catalysts such as AgSbF6, AgBF4, AgOTf and AgNTf2.
Moderate yields of product 2a was observed under these
reaction conditions (Table 1, entries 10-13).
Good yield (72%) of product 2a was obtained when 1a was
treated in the presence of Au(PPh3)Cl (10 mol %) and AgSbF6
(15 mol %) in acetonitrile (Table 1, entry 14). Then we have
conducted experiments by using Au(PPh3)Cl with silver
catalysts such as AgBF4, AgOTf and AgNTf2. It was observed
that these reactions gave moderate yields of product 2a (Table
1, entries 15-17). Solvent effect on this reaction was tested by
utilising different solvents; moderate to good yields of product
2a was observed (Table 1, entries 18-21). To check the
catalytic effectiveness, we have conducted two experiments by
using lower loading of catalysts Au(PPh3)Cl/AgSbF6 in 2/3
mol % and 5/7.5 mol %. In these cases lower yields of product
2a was observed (Table 1, entries 22 and 23). Further we have
conducted another experiment to check the efficiency of the
catalytic combination of Au(PPh3)Cl/AgSbF6 (10/10 mol %),
Au(PPh3)Cl (10)/
AgNTf2 (15)
Au(PPh3)Cl (10)/
AgSbF6 (15)
Au(PPh3)Cl (10)/
AgSbF6 (15)
Au(PPh3)Cl (10)/
AgSbF6 (15)
Au(PPh3)Cl (10)/
AgSbF6 (15)
Au(PPh3)Cl (2)/
AgSbF6 (3)
Au(PPh3)Cl (5)/
AgSbF6 (7.5)
Au(PPh3)Cl (10)/
AgSbF6 (10)
Au(PPh3)Cl (10)/
AgSbF6 (15)
CuCl (10)
THF
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
12
30
30
30
30
64d
53
51
42
39
26
27
28
29
30
CuBr (10)
CuI (10)
Cu(OAc)2 (10)
IPrAuCl (10)/
AgNTf2(15)
IPrAuCl (5)/
AgNTf2 (7.5)
HCl (10)
CH3CN
12
64
31
CH3CN
CH3CN
CH3CN
12
12
12
57
32
33
cme
cme
HNTf2 (10)
aReaction conditions: all reactions were carried out at 60 C under nitrogen
o
atmosphere with 1a (0.364 mmol), and solvent (3 mL); bnr: no reaction;
cyields are for isolated products; Reaction was conducted without nitrogen
d
atmosphere; eComplex mixture was observed.
product 2a was observed in 66% yield (Table 1, entry 24). A Reactions were performed by utilizing IPrAuCl in combination
reaction was performed without nitrogen atmosphere, it was of AgNTf2 (entries 30 and 31), good yields of product 2a were
2 | J. Name., 2012, 00, 1-3
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isolated. Then the substrate 1a was tested in the presence of The above experimental results reveal that the catalyst
View Article Online
DOI: 10.1039/C8OB03157F
HCl and HNTf2 (entries 32 and 33), both the cases complex combination of Au(PPh3)Cl/AgSbF6 (10/15 mol%) in
mixture was observed.
acetonitrile is the best condition for the synthesis of substituted
aryl-fused pyrazolooxazepines (Table 1, entry 14). The scope
of substrates was studied by utilizing different substituted
ortho-O-propargyl aryl pyrazoles 1a-1m (Table 2).
Table 2 Scope of substituted benzopyrazolooxazepine (2)a
R1
R1
The substrate 1b which is having electron donating group at R1
position and 1c which is containing electron withdrawing group at
R1 position undergoes 7-exo-dig cyclization via intramolecular
hydroamination gave 64% and 61% yield of cyclized products 2b
and 2c, respectively (Table 2). Substrate 1d gave 58% yield of
desired product 2d. The substrates having aliphatic functional
groups at R1 position such as 1e, 1f and 1g and 1h gave the
corresponding products 2e, 2f, 2g and 2h in 78%, 70%, 68% and
81% yields, respectively (Table 2). Naphthyl substituted substrates
such as 1i, 1j, 1k, 1l and 1m produced good yields of the
corresponding products 2i, 2j, 2k, 2l and 2m, respectively (Table 2).
The substrate scope was further tested by utilizing different
substituted ortho-O-propargyl aryl pyrazoles (1n-1z) and these
results are incorporated in Table 3. Electron donating
functional group like di-tert-butyl containing substrates such as
1n, 1o and 1p gave 62%, 67% and 65% yields of cyclized
products 2n, 2o and 2p, respectively (Table 3). Bromo
substituted substrates such as 1q, 1r and 1s gave the
corresponding products 2q, 2r and 2s, in 76%, 64% and 71%
yields, respectively (Table 3). Electron withdrawing functional
group like nitro substituted substrates such as 1t, 1u, 1v and 1w
produced the corresponding products 2t, 2u, 2v and 2w, in
good yields. Further, the structure of the product 5-methylene-
10-nitro-2-(p-tolyl)-5,6-dihydrobenzo[f]pyrazolo[1,5-
N
Au(PPh3)Cl/AgSbF6
(10/15 mol%)
NH
N
N
CH3CN, 60 oC, 2 h
O
O
2a-m
1a-m
F
CH3
N
N
N
N
N
N
O
O
O
2a
(72%)
2c
(61%)
2b
(64%)
C4H9
C5H11
N
N
N
N
N
N
O
O
O
2d
(58%)
2e
2f
(70%)
(78%)
C8H17
C6H13
N
d][1,4]oxazepine 2u was confirmed by single crystal X-ray
analysis (Figure 2).19
N
N
N
N
N
O
O
O
2g
(68%)
2h
(81%)
2i
(64%)
CH3
CH3
F
C6H13
N
N
N
N
O2N
N
N
N
N
O
O
O
O
2u
2j
(62%)
2l
2k
(65%)
(63%)
Fig. 2 An ORTEP diagram of compound 2u (CCDC 1574971).
C8H17
N
N
Two electron withdrawing groups like 3,5-dichloro substitutions
containing substrates like 1x (R1 = C6H5), 1y (R1 = n-C4H9) and 1z
(R1 = n-C8H17) gave the corresponding product 2x, 2y and 2z in
72%, 74% and 85% yields, respectively (Table 3).
O
2m
(61%)
o
aReaction conditions: all reactions were carried out at 60 C under nitrogen
atmosphere with 1a-1m (0.364 mmol), Au(PPh3)Cl (10 mol%)/AgSbF6 (15
mol%) and CH3CN (3 mL) at 60 °C; yields are for isolated products.
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under the optimized conditions resulted the corresponding products
2aa and 2ab in 61% and 65% yields, respectiDvOeIl:y10(S.1c0h3e9m/Ce8O3)B.03157F
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Table 3 Scope of substituted benzopyrazolooxazepine (2)a
R1
R1
N
NH
Au(PPh3)Cl/AgSbF6
(10/15 mol%)
N
N
F
R1
CH3CN, 60 oC, 2 h
O
O
Au(PPh3)Cl/AgSbF6
(10/15 mol %)
NH
1n-z
2n-z
N
N
N
CH3
CH3CN, 60 oC, 2h
N
O
N
R2
: R1 = R2 = Ph
: R1 = 4-F-C6H4;
1aa
1ab
O
O
C8H17
R2 = 4-OMe-C6H4
2aa
(61%)
2ab
(65%)
O
N
N
N
N
N
N
Scheme 3. Conversion of alkyne disubstituted substrates 1aa,
and 1ab) to benzopyrazolooxazepine 2aa and 2ab.
O
O
O
2o
2n
(67%)
A tentative reaction mechanism can be proposed for the generation
of aryl-pyrazolooxazepines 2 from ortho-O-propargyl substituted
aryl pyrazoles 1 via gold-catalysis (Scheme 4). Substrate 1 would
give intermediate-I (IM-I) by reacting with gold-catalyst. Then IM-
I might generate vinyl-gold intermediate-II (IM-II) via 7-exo-dig
cyclization.13 7-Exo-dig preference would be assumed when gold(I)
forms a complex with a terminal carbon- carbon triple bond, the
internal carbon atom is more positively charged than the external
carbon atom, so the nucleophilic attack would driven by this path
way.13f Subsequently, IM-II might produce intermediate-III (IM-
(62%)
2p
(65%)
CH3
C5H11
N
Br
N
N
N
Br
Br
N
N
O
O
O
2q
(76%)
2r
2s
(71%)
(64%)
CH3
III),
which
would
produce
substituted
aryl-fused
pyrazolooxazepines 2 via protodeauration.
C4H9
N
R1
R1
R1
N
N
H
N
O2N
O2N
O2N
N
N
N
NH
NH
R2
N
7-
-
exo dig
N
N
Gold cat.
R2
cyclization
R2
O
[Au]
O
O
O
O
O
IM-I
IM-II
1
Au
2u
2t
(76%)
(62%)
2v
(80%)
R1
R1
N
N
protodeauration
C8H17
N
R2
N
C4H9
N
2
[Au]
O
R2
N
N
O
IM-III
O2N
Cl
Cl
N
N
N
Scheme 4. A plausible reaction mechanism.
O
O
O
Cl
2x
Cl
(72%)
2w
2y (74%)
(71%)
C8H17
Conclusions
In conclusion, we have established an efficient synthetic protocol for
the formation of substituted pyrazolo benzooxazepines and pyrazolo
naphthoxazepines from substituted ortho-O-propargyl aryl
pyrazoles. Significantly, this gold-catalyzed regioselective organic
transformation takes place via 7-exo-dig cyclization. The title
compounds were obtained in moderate to good yields.
N
Cl
N
O
Cl
2z
(85%)
aReaction conditions: all reactions were carried out at 60 C under nitrogen
atmosphere with 1n-1z (0.364 mmol), Au(PPh3)Cl (10 mol%)/AgSbF6 (15
mol%) and CH3CN (3 mL); yields are for isolated products.
o
Experimental Section
General information
Reactions were carried out in oven dried reaction flasks under nitrogen
atmosphere and also solvents, reagents were transferred by oven-dried
syringes. TLC was performed on Merck silica gel aluminium sheets using
Two more experiments were conducted with substrates which are
bearing substitutions at R1 and R2 position such as 1aa and 1ab
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UV as a visualizing agent and a 0.5% aqueous potassium permanganate
solution and heat as developing agents. Solvents were removed under
reduced pressure. Columns were packed as slurry of silica gel in hexane and
ethyl acetate solvent mixture. The elution was assisted by applying pressure
with an air pump. 13C NMR spectra were recorded on 100 MHz and 125
hexane and ethyl acetate as eluent (10:1.2) to give productV5ie-wmAertthicyleleOnnel-in2e-
DOI: 10.1039/C8OB03157F
phenyl-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine 2a (72%).
A
similar procedure was followed for the synthesis of all substituted pyrazolo
fused benzooxazepine and naphthoxazepine derivatives (2b-2ab).
5-Methylene-2-phenyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
1
MHz spectrometers. HNMR spectra were recorded on 300 MHz, 400 MHz
d][1,4]oxazepine: 2a. Rf: 0.65; Hexane: Ethyl acetate mixture (10 : 0.5);
and 500 MHz spectrometers in appropriate solvents using TMS as internal
standard. The following abbreviations were used to explain multiplicities: s =
singlet, d = doublet, dd = double doublet, t = triplet, m = multiplet. All
reactions were performed under nitrogen atmosphere with freshly distilled
and dried solvents. All solvents were distilled using standard procedures.
Unless otherwise noted, reagents were obtained from Aldrich, Alfa Aesar,
and TCI used without further purification. Synthesis of aryl-fused
pyrazolooxazepines (1a-1ab) were prepared by following reported
procedures.20
1
Yield: 72%, white solid; Melting Point: 106-108 °C; H NMR (CDCl3, 400
MHz): δ 7.94-7.90 (m, 2H), 7.83 (dd, J = 1.5, 7.9 z, 1H), 7.46-7.41 (m, 2H),
7.38-7.33 (m, 1H), 7.30-7.26 (m, 1H), 7.17-7.12 (m, 1H), 7.09 (dd, J = 1.3,
8.1 Hz, 1H), 7.02 (s, 1H), 6.05 (s, 1H), 4.94 (s, 1H), 4.80 (s, 2H) ppm; 13C
NMR (CDCl3, 125 MHz): δ 157.3, 152.1, 141.4, 132.5, 129.8, 128.8, 128.6,
128.3, 125.9, 123.6, 120.6, 119.4, 103.8, 103.0, 72.4 ppm; IR(CH2Cl2): ΰ =
3063, 1649, 1464, 1372, 1344, 1210, 1018, 756, 690 cm-1; HRMS (ESI+)
calculated for C18H15ON2 [M+H]+ 275.1178, found 275.1175.
5-Methylene-2-(p-tolyl)-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2b. Rf: 0.55; Hexane: Ethyl acetate mixture (10 : 0.3);
X-ray data for the compound KA263 was collected at 100 K on a Bruker
D8 QUEST instrument with an IμS Mo microsource (λ = 0.7107 A) and a
PHOTON-100 detector. The raw data frames were reduced and corrected for
absorption effects using the Bruker Apex 3 software suite programs.21 The
structure was solved using intrinsic phasing method3 and further refined with
the SHELXL program and expanded using Fourier techniques.22 Anisotropic
displacement parameters were included for all non-hydrogen atoms. All C
bound H atoms were positioned geometrically and treated as riding on their
parent C atoms [C-H = 0.93-0.97 Å, and Uiso(H) = 1.5Ueq(C) for methyl H or
1.2Ueq(C) for other H atoms].
1
Yield: 64%, white solid; Melting Point: 100-102 °C; H NMR (CDCl3, 400
MHz): δ 7.83-7.77 (m, 3H), 7.28-7.21 (m, 3H), 7.16-7.10 (m, 1H), 7.07 (dd,
J = 0.9, 8.0 Hz, 1H), 6.97 (s, 1H), 6.03 (s, 1H), 4.91 (s, 1H), 4.77 (s, 2H),
2.38 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 157.2, 152.1, 141.4,
141.2, 138.1, 129.7, 129.3, 128.7, 125.7, 123.5, 120.6, 119.4, 103.6, 102.7,
72.4, 21.3 ppm; IR(CH2Cl2): ΰ = 3019, 1648, 1460, 1213, 1019, 9856, 790,
758 cm-1; HRMS (ESI+) calculated for C19H17ON2 [M+H]+ 289.1335, found
289.1332.
2-(4-Fluorophenyl)-5-methylene-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2c. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.4);
Crystal Data for 2u:19 C19H15N3O3 (M =333.35 g/mol): monoclinic, space
group P21/c (no. 14), a = 7.021(9) Å, b = 20.14(3) Å, c = 21.54(3) Å, β =
95.79(2)°, V = 3030(7) Å3, Z = 8, T = 100.0 K, μ(Mo Kα) = 0.101 mm-1,
Dcalc = 1.4612 g/cm3, 38713 reflections measured (4.46° ≤ 2Θ ≤ 61.62°),
9422 unique (Rint = 0.0356, Rsigma = 0.0330) which were used in all
calculations. The final R1 was 0.0454 (I>2σ(I)) and wR2 was 0.1193 (all
data). CCDC 1574971 contains supplementary Crystallographic data for the
structure. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44(0) 1223 336 033; email: deposit@ccdc.cam.ac.uk].
1
Yield: 61%, white solid; Melting Point: 116-118 °C; H NMR (CDCl3, 400
MHz): δ 7.90-7.85 (m, 2H), 7.80 (dd, J = 1.5, 7.9 Hz, 1H), 7.30-7.24 (m,
1H), 7.16-7.06 (m, 4H), 6.95 (s, 1H), 6.02 (s, 1H), 4.93 (s, 1H), 4.78 (s, 2H)
ppm; 13C NMR (CDCl3, 125 MHz): δ 162.9 (d, J = 247.948 Hz, 1C), 157.3,
151.2, 141.5, 141.4, 129.9, 128.7, 127.6 (d, J = 8.174 Hz, 1C), 123.6, 120.7,
119.4, 115.6 (d, J = 20.889 Hz, 2C), 103.6, 103.0, 72.4 ppm; IR(CH2Cl2): ΰ =
2920, 1649, 1479, 1218, 1020, 840, 760 cm-1; HRMS (ESI+) calculated for
C18H14ON2F [M+H]+ 293.1084, found 293.1082.
5-Methylene-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine: 2d. Rf:
0.5; Hexane: Ethyl acetate mixture (10 : 1); Yield: 58%, white solid; Melting
Genaeral
procedure
for
synthesis
of
5-methylene-5,6-
1
Point: 72-74 °C; H NMR (CDCl3, 500 MHz): δ 7.76 (dd, J = 1.5, 7.9 Hz,
dihydrobenzo[f]pyrazolooxazepines 2a-2ab.
1H), 7.67 (d, J = 1.9 Hz, 1H), 7.28-7.24 (m, 1H), 7.14-7.10 (m, 1H), 7.08
(dd, J = 1.2, 8.0 Hz, 1H), 6.71 (s, 1H), 5.92 (s, 1H), 4.92 (s, 1H), 4.77 (s, 2H)
ppm; 13C NMR (CDCl3, 125 MHz): δ 157.1, 141.4, 140.8, 140.1, 129.8,
128.7, 123.6, 120.6, 119.3, 106.5, 103.1, 72.3 ppm; IR(CH2Cl2): ΰ = 2922,
1650, 1579, 1530, 1464, 1384, 1212, 1018, 922, 759 cm-1; HRMS (ESI+)
calculated for C12H11ON2 [M+H]+ 199.0865, found 199.0871.
To a 10 mL round-bottomed flask equipped with magnetic stir bar the
substrate 5-phenyl-3-(2-(prop-2-yn-1-yloxy)phenyl)-1H-pyrazole 1a (0.1 g,
0.364 mmol, 1 equiv.) was taken and dissolved in CH3CN (3 mL). To this
reaction mixture Au(PPh3)Cl (0.017 g, 0.0364 mmol, 10 mol %) and AgSbF6
(0.018 g, 0.0546 mmol, 15 mol %) was added and stirred at 60 °C for 2 hours
under nitrogen atmosphere. Progress of the reaction was monitored by using
TLC. After completion of the reaction, the reaction mixture was filtered
through celite plug and washed the celite plug with Ethyl acetate. The Ethyl
acetate layer was concentrated under reduced pressure to get crude residue
which was purified by column chromatography through silica gel using
2-Butyl-5-methylene-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine:
2e. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.7); Yield: 78%, Yellow
1
liquid; H NMR (CDCl3, 500 MHz): δ 7.73 (dd, J = 1.5, 7.9 Hz, 1H), 7.26-
7.22 (m, 1H), 7.12-7.08 (m, 1H), 7.06 (dd, J = 1.2, 8.0 Hz, 1H), 6.52 (s, 1H),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
5.84 (s, 1H), 4.84 (s, 1H), 4.74 (s, 2H), 2.68 (t, J = 7.7 Hz, 2H), 1.72-1.66
(m, 2H), 1.47-1.39 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (CDCl3,
100 MHz): δ 157.1, 154.9, 141.3, 140.5, 129.5, 128.7, 123.4, 120.5, 119.6,
105.5, 102.0, 72.5, 31.5, 27.9, 22.5, 13.9 ppm; IR(CH2Cl2): ΰ = 2956, 1649,
1463, 1382, 1217, 1022, 880, 761 cm-1; HRMS (ESI+) calculated for
C16H19ON2 [M+H]+ 255.1491, found 255.1494.
cm-1; HRMS (ESI+) calculated for C22H17ON2 [M+H]+ 325.1335, found
View Article Online
DOI: 10.1039/C8OB03157F
325.1334.
5-Methylene-2-(p-tolyl)-5,6-dihydronaphtho[1,2-f]pyrazolo[1,5-
d][1,4]oxazepine: 2j. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.4);
1
Yield: 62%, Yellow liquid; H NMR (CDCl3, 400 MHz): δ 8.53 (d, J = 8.1
Hz, 1H), 7.87-7.81 (m, 3H), 7.77 (d, J = 8.6 Hz, 1H), 7.57-7.52 (m, 1H),
7.50-7.44 (m, 1H), 7.29-7.22 (m, 3H), 7.07 (s, 1H), 5.96 (s, 1H), 5.05 (s,
2H), 4.88 (s, 1H), 2.39 (s, 3H) pm; 13C NMR (CDCl3, 100 MHz): δ 157.4,
152.0, 141.7, 138.9, 138.1, 132.3, 131.4, 130.5, 129.9, 129.3, 128.4, 127.0,
125.9, 125.6, 125.0, 120.5, 116.5, 107.8, 101.5, 76.0, 21.3 ppm; IR(CH2Cl2):
ΰ = 2921, 1646, 1465, 1396, 1226, 1080, 819, 753 cm-1; HRMS (ESI+)
calculated for C23H19ON2[M+H]+ 339.1491, found 339.1490.
5-Methylene-2-pentyl-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine:
2f. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 70%, Yellow
1
liquid; H NMR (CDCl3, 400 MHz): δ 7.73 (dd, J = 1.5, 7.9 Hz, 1H), 7.25-
7.21 (m, 1H), 7.12-7.09 (m, 1H), 7.08-7.04 (m, 1H), 6.52 (s, 1H), 5.84 (s,
1H), 4.84 (s, 1H), 4.74 (s, 2H), 2.67 (t, J = 7.8 Hz, 2H), 1.75-1.67 (m, 2H),
1.43-1.33 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (CDCl3, 100
MHz): δ 157.1, 154.9, 141.3, 140.4, 129.5, 128.6, 123.4, 120.5, 119.5, 105.5,
102.0, 72.4, 31.6, 29.1, 28.1, 22.4, 14.0 ppm; IR(CH2Cl2): ΰ = 2954, 1649,
1462, 1379, 1216, 1020, 878, 757 cm-1; HRMS (ESI+) calculated for
C17H21ON2 [M+H]+ 269.1648, found 269.1644.
2-(4-Fluorophenyl)-5-methylene-5,6-dihydronaphtho[1,2-f]pyrazolo[1,5-
d][1,4]oxazepine: 2k. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.4);
1
Yield: 65%, white solid; Melting Point: 122-124 °C; H NMR (CDCl3, 400
MHz): δ 8.51 (d, J = 8.4 Hz, 1H), 7.94-7.89 (m, 2H), 7.86 (d, J = 8.0 Hz,
1H), 7.79 (d, J = 8.6 Hz, 1H), 7.58-7.53 (m, 1H), 7.51-7.45 (m, 1H), 7.29 (d,
J = 8.8 Hz, 1H), 7.13 (t, J = 8.8 Hz, 2H), 7.05 (s, 1H), 5.95 (s, 1H), 5.06 (s,
2H). 4.90 (s, 1H) ppm; 13C NMR (CDCl3, 100 MHz): δ 162.9 (d, J = 247.222
Hz, 1C), 157.5, 151.0, 141.7, 139.2, 132.3, 131.5, 130.6, 128.9, 128.5, 127.7
(d, J = 8.070 Hz, 1C), 127.1, 125.5, 125.1, 120.5, 116.3, 115.6 (d, J = 22.008
Hz, 2C), 107.7, 101.7, 76.0 ppm; IR(CH2Cl2): ΰ = 3058, 1647, 1507, 1438,
1370, 1225, 1097, 822, 753 cm-1; HRMS (ESI+) calculated for C22H16ON2F
[M+H]+ 343.1241, found 343.1252.
2-Hexyl-5-methylene-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine:
2g. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.8); Yield: 68%, Yellow
1
liquid; H NMR (CDCl3, 500 MHz): δ 7.73 (dd, J = 1.3, 8.0 Hz, 1H), 7.26-
7.21 (m, 1H), 7.10 (t, J = 7.0 Hz, 1H), 7.06 (dd, J = 1.3, 8.0 Hz, 1H), 6.52 (s,
1H), 5.84 (s, 1H), 4.84 (s, 1H), 4.74 (s, 2H), 2.67 (t, J = 7.9 Hz, 2H), 1.73-
1.66 (m, 2H), 1.44-1.37 (m, 2H), 1.35-1.30 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H)
ppm; 13C NMR (CDCl3, 100 MHz): δ 157.1, 155.0, 141.3, 140.5, 129.5,
128.7, 123.4, 120.5, 119.6, 105.5, 102.0, 72.5, 31.6, 29.4, 29.1, 28.2, 22.6,
14.1 ppm; IR(CH2Cl2): ΰ = 2926, 1650, 1463, 1382, 1218, 1022, 880, 760
cm-1; HRMS (ESI+) calculated for C18H23ON2 [M+H]+ 283.1804, found
283.1809.
2-Hexyl-5-methylene-5,6-dihydronaphtho[1,2-f]pyrazolo[1,5-
d][1,4]oxazepine: 2l. Rf: 0.75; Hexane: Ethyl acetate mixture (10 : 0.6);
1
Yield: 63%, Yellow liquid; H NMR (CDCl3, 400 MHz): δ 8.46 (d, J = 8.6
5-Methylene-2-octyl-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine:
2h. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 81%, Yellow
Hz, 1H), 7.84 (dd, J = 1.3, 8.0 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.56-7.49
(m, 1H), 7.48-7.42 (m, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 5.77 (d, J
= 0.6 Hz, 1H), 5.0 (s, 2H), 4.79 (s, 1H), 2.74 (t, J = 7.9 Hz, 2H), 1.78-1.68
(m, 2H), 1.49-1.39 (m, 2H), 1.38-1.30 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H) ppm;
13C NMR (CDCl3, 100 MHz): δ 157.3, 154.6, 141.7, 138.1, 132.3, 131.4,
130.2, 128.3, 126.9, 125.7, 124.9, 120.5, 116.6, 109.8, 100.4, 76.0, 31.7,
29.5, 29.2, 28.4, 22.6, 14.1 ppm; IR(CH2Cl2): ΰ = 2926, 1647, 1447, 1378,
1224, 1002, 818 cm-1; HRMS (ESI+) calculated for C22H25ON2 [M+H]+
333.1961, found 333.1968.
1
liquid; H NMR (CDCl3, 500 MHz): δ 7.73 (dd, J = 1.5, 7.9 Hz, 1H), 7.25-
7.22 (m, 1H), 7.12-7.08 (m, 1H), 7.06 (dd, J = 1.2, 8.0 Hz, 1H), 6.52 (s, 1H),
5.84 (s, 1H), 4.84 (s, 1H), 4.74 (s, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.73-1.66
(m, 2H), 1.44-1.36 (m, 2H), 1.36-1.22 (m, 8H), 0.88 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (CDCl3, 100 MHz): δ 157.1, 154.9, 141.3, 140.5, 129.5, 128.7,
123.4, 120.5, 119.6, 105.5, 102.0, 72.5, 31.8, 29.4, 29.2, 28.2, 22.6, 14.1
ppm; IR(CH2Cl2): ΰ = 2922, 1649, 1462, 1380, 1217, 1021, 878, 758 cm-1;
HRMS (ESI+) calculated for C20H27ON2 [M+H]+ 311.2117, found 311.2113.
5-Methylene-2-octyl-5,6-dihydronaphtho[1,2-f]pyrazolo[1,5-d][1,4]
oxazepine: 2m. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.4); Yield:
61%, Yellow liquid; 1H NMR (CDCl3, 400 MHz): δ 8.46 (d, J = 8.4 Hz, 1H),
7.84 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.53 (t, J = 7.0 Hz, 1H),
7.46 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 5.78 (s, 1H),
5.01 (s, 2H), 4.80 (s, 1H), 2.74 (t, J = 7.7 Hz, 2H), 1.79-1.69 (m, 2H), 1.48-
1.39 (m, 2H), 1.37-1.28 (m, 8H), 0.88 (t, J = 6.7 Hz, 3H) ppm; 13C NMR
(CDCl3, 125 MHz): δ 157.3, 154.6, 141.7, 138.0, 132.3, 131.4, 130.2, 128.3,
126.8, 125.6, 124.9, 120.5, 116.6, 109.8, 100.4, 76.0, 31.8, 29.5, 29.4, 29.2,
28.3, 22.6, 14.1 ppm; IR(CH2Cl2): ΰ = 2922, 1647, 1509, 1377, 1223, 1096,
5-Methylene-2-phenyl-5,6-dihydronaphtho[1,2-f]pyrazolo[1,5-
d][1,4]oxazepine: 2i. Rf: 0.5; Hexane: Ethyl acetate mixture (10 : 0.6);
1
Yield: 64%, Yellow liquid; H NMR (CDCl3, 400 MHz): δ 8.53 (d, J = 8.3
Hz, 1H), 7.96-7.92 (m, 2H), 7.86 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.6 Hz,
1H), 7.58-7.53 (m, 1H), 7.50-7.42 (m, 3H), 7.39-7.33 (m, 1H), 7.28 (d, J =
8.8 Hz, 1H), 7.10 (s, 1H), 5.97 (s, 1H), 5.06 (s, 2H), 4.90 (s, 1H) ppm; 13C
NMR (CDCl3, 125 MHz): δ 157.4, 151.9, 141.8, 139.1, 132.7, 132.3, 131.5,
130.6, 128.6, 128.4, 128.3, 127.1, 125.9, 125.6, 125.0, 120.5, 116.4, 107.9,
101.8, 76.1 ppm; IR(CH2Cl2): ΰ = 3056, 1648, 1462, 1372, 1227, 822, 753
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
1002, 821, 751 cm-1; HRMS (ESI+) calculated for C24H29ON2 [M+H]+
361.2274, found 361.2273.
8.0 Hz, 2H), 6.98 (s, 1H), 6.96 (d, J = 9.6 Hz, 1H), 6.05 (s, 1H), 4.94 (s, 1H),
View Article Online
4.77 (s, 2H), 2.40 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 156.2, 152.2,
DOI: 10.1039/C8OB03157F
140.9, 139.8, 138.3, 132.3, 131.0, 129.4, 129.3, 125.8, 122.4, 121.3, 115.9,
104.1, 103.5, 72.5, 21.3 ppm; IR(CH2Cl2): ΰ = 2917, 1649, 1475, 1342, 1116,
1019, 824, 669 cm-1; HRMS (ESI+) calculated for C19H16ON2Br [M+H]+
367.0440, found 367.0453.
8,10-Di-tert-butyl-5-methylene-2-phenyl-5,6-dihydrobenzo[f]pyrazolo
[1,5-d][1,4]oxazepine: 2n. Rf: 0.7; Hexane: Ethyl acetate mixture (10 : 0.7);
1
Yield: 62%, white solid; Melting Point: 168-170 °C; H NMR (CDCl3, 400
MHz): δ 7.94 (d, J = 7.0 Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.44 (t, J = 7.7
Hz, 2H), 7.39-7.32 (m, 2H), 6.91 (s, 1H), 6.01 (s, 1H), 4.84 (s, 1H), 4.80 (s,
2H), 1.42 (s, 9H), 1.37 (s, 9H) ppm; 13C NMR (CDCl3, 100 MHz): δ 155.4,
15.9, 145.7, 142.8, 141.9, 140.5, 132.7, 128.6, 128.2, 125.9, 124.7, 123.8,
121.2, 104.6, 100.3, 73.0, 35.2, 34.6, 31.5, 30.3 ppm; IR(CH2Cl2): ΰ = 2966,
1648, 1467, 1380, 1021, 869, 763, 693 cm-1; HRMS (ESI+) calculated for
C26H31ON2 [M+H]+ 387.2430, found 387.2443.
10-Bromo-5-methylene-2-pentyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2s. Rf: 0.5; Hexane: Ethyl acetate mixture (10 : 0.7);
1
Yield: 71%, Yellow liquid; H NMR (CDCl3, 400 MHz): δ 7.83 (d, J = 2.4
Hz, 1H), 7.31 (dd, J = 2.4, 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.52 (s,
1H), 5.86 (s, 1H), 4.86 (s, 1H), 4.71 (s, 2H), 2.66 (t, J = 7.9 Hz, 2H), 1.75-
1.66 (m, 2H), 1.42-1.34 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H) ppm; 13C NMR
(CDCl3, 100 MHz): δ 156.1, 155.1, 140.9, 139.0, 132.1, 131.0, 122.4, 121.4,
115.9, 106.1, 102.7, 72.5, 31.6, 29.1, 28.2, 22.5, 14.0 ppm; IR(CH2Cl2): ΰ =
2954, 1649, 1482, 1379, 1218, 1018, 876, 791, 726 cm-1; HRMS (ESI+)
calculated for C17H20ON2Br79 347.0753, found 347.0764 and C17H20ON2Br81
[M+2] 349.0733, found 349.0740.
8,10-Di-tert-butyl-5-methylene-2-(p-tolyl)-5,6-dihydrobenzo[f]pyrazolo
[1,5-d][1,4]oxazepine: 2o. Rf: 0.65; Hexane: Ethyl acetate mixture (10 : 0.4);
1
Yield: 67%, white solid; Melting Point: 162-164 °C; H NMR (CDCl3, 400
MHz): δ 7.83 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 2.4
Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 6.0 (s, 1H), 4.83 (s, 1H), 4.79
(s, 2H), 2.39 (s, 3H), 1.42 (s, 9H), 1.37 (s, 9H) ppm; 13C NMR (CDCl3, 125
MHz): δ 155.4, 152.0, 145.6, 142.7, 141.9, 140.4, 138.1, 129.9, 129.3, 125.9,
124.7, 123.8, 121.3, 104.4, 100.1, 73.0, 35.2, 34.6, 31.5, 30.3, 21.3 ppm;
IR(CH2Cl2): ΰ = 2961, 1648, 1446, 1370, 1019, 877, 756 cm-1; HRMS (ESI+)
calculated for C27H33ON2 [M+H]+ 401.2587, found 401.2586.
5-Methylene-10-nitro-2-phenyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2t. Rf: 0.45; Hexane: Ethyl acetate mixture (10 : 0.7);
1
Yield: 62%, white solid; Melting Point: 148-150 °C; H NMR (CDCl3, 500
MHz): δ 8.75 (d, J = 2.5 Hz, 1H), 8.12 (dd, J = 2.7, 9.0 Hz 1H), 7.94-7.91
(m, 2H), 7.48-7.43 (m, 2H), 7.41-7.36 (m, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.17
(s, 1H), 6.12 (s, 1H), 5.07 (s, 1H), 4.85 (s, 2H) ppm; 13C NMR (CDCl3, 100
MHz): δ 161.2, 152.5, 143.5, 140.0, 139.1, 131.9, 128.7, 125.9, 124.8, 124.5,
121.8, 119.4, 105.3, 104.8, 72.2 ppm; IR(CH2Cl2): ΰ = 2927, 1653, 1520,
1344, 1085, 764, 693 cm-1; HRMS (ESI+) calculated for C18H14O3N3 [M+H]+
320.1029, found 320.1028.
8,10-Di-tert-butyl-5-methylene-2-octyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2p. Rf: 0.7; Hexane: Ethyl acetate mixture (10 : 0.3);
1
Yield: 65%, Yellow liquid; H NMR (CDCl3, 400 MHz): δ 7.54 (d, J = 2.4
Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 5.79 (s, 1H), 4.74 (s, 1H),
4.73 (s, 2H), 2.67 (t, J = 7.9 Hz, 2H), 1.75-1.66 (m, 2H), 1.48-1.41 (m, 2H),
1.40 (s, 9H), 1.34 (s, 9H), 1.33-1.21 (m, 10 H), 0.88 (t, J = 6.9 Hz, 3H) ppm;
13C NMR (CDCl3, 100 MHz): δ 155.3, 154.9, 145.5, 141.9, 141.8, 140.3,
124.4, 123.7, 121.3, 106.3, 99.2, 73.1, 35.1, 34.5, 31.9, 31.4, 30.3, 29.7, 29.5,
29.49, 29.4, 29.2, 28.3, 22.6, 14.1 ppm; IR(CH2Cl2): ΰ = 2954, 1650, 1540,
1380, 1224, 1022, 877, 792, 722 cm-1; HRMS (ESI+) calculated for
C28H43ON2 [M+H]+ 423.3369, found 423.3375.
5-Methylene-10-nitro-2-(p-tolyl)-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2u. Rf: 0.45; Hexane: Ethyl acetate mixture (10 : 0.8);
1
Yield: 76%, white solid; Melting Point: 162-164 °C; H NMR (CDCl3, 500
MHz): δ 8.53 (d, J = 2.7 Hz, 1H), 8.11 (dd, J = 2.7, 9.0 Hz, 1H), 7.81 (d, J =
8.0 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H),
6.10 (s, 1H), 5.06 (s, 1H), 4.84 (s, 2H), 2.40 (s, 3H) ppm; 13C NMR (CDCl3,
125 MHz): δ 161.2, 152.5, 143.4, 140.0, 138.9, 138.6, 129.4, 129.0, 125.8,
124.5, 121.8, 119.6, 105.1, 104.7, 72.2 ppm; IR(CH2Cl2): ΰ = 2921, 1651,
1512, 1343, 1079, 896, 791 cm-1; HRMS (ESI+) calculated for C19H16O3N3
[M+H]+ 334.1186, found 334.1183.
10-Bromo-5-methylene-2-phenyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2q. Rf: 0.7; Hexane: Ethyl acetate mixture (10 : 0.3);
1
Yield: 76%, white solid; Melting Point: 128-130 °C; H NMR (CDCl3, 400
MHz): δ 7.95-7.89 (m, 3H), 7.44 (t, J = 7.5 Hz, 2H), 7.39-7.33 (m, 2H), 7.01
(s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.06 (s, 1H), 4.96 (s, 1H), 4.77 (s, 2H) ppm;
13C NMR (CDCl3, 100 MHz): δ 156.3, 152.2, 141.0, 139.9, 132.4, 132.2,
131.1, 128.6, 128.5, 125.9, 122.5, 121.3, 116.0, 104.3, 103.7, 72.5 ppm;
IR(CH2Cl2): ΰ = 3062, 1649, 1440, 1372, 1210, 1018, 765, 690 cm-1; HRMS
(ESI+) calculated for C18H14ON2 [M+H]+ 353.0284, found 353.0283.
2-Butyl-5-methylene-10-nitro-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2v. Rf: 0.65; Hexane: Ethyl acetate mixture (10 : 0.6);
Yield: 80%, white solid; Melting Point: 69-71 °C; 1H NMR (CDCl3, 300
MHz): δ 8.66 (d, J = 2.7 Hz, 1H), 8.09 (dd, J = 2.7, 9.0 Hz, 1H), 7.17 (d, J =
9.0 Hz, 1H), 6.69 (s, 1H), 5.93 (s, 1H), 4.99 (s, 1H), 4.79 (s, 2H), 2.69 (t, J =
7.7 Hz, 2H), 1.77-1.63 (m, 2H), 1.52-1.36 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H)
ppm; 13C NMR (CDCl3, 100 MHz): δ 161.1, 155.3, 143.4, 139.9, 138.2,
124.7, 124.3, 121.7, 119.6, 106.7, 104.4, 72.3, 31.4, 27.8, 22.4, 13.8 ppm;
IR(CH2Cl2): ΰ = 2956, 1651, 1546, 1344, 1126, 1017, 927, 804 cm-1; HRMS
(ESI+) calculated for C16H18O3N3 [M+H]+ 300.1342, found 300.1338.
10-Bromo-5-methylene-2-(p-tolyl)-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2r. Rf: 0.65; Hexane: Ethyl acetate mixture (10 : 0.4);
1
Yield: 64%, Yellow liquid; H NMR (CDCl3, 500 MHz): δ 7.93 (d, J = 2.4
Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.34 (dd, J = 2.2, 8.6 Hz, 1H), 7.25 (d, J =
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Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
5-Methylene-10-nitro-2-octyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
ppm; IR(CH2Cl2): ΰ = 2924, 1603, 1469, 1211, 1046, 760, 6V8i9ewcAmrt-i1c;leHORnMlinSe
+
+
DOI: 10.1039/C8OB03157F
d][1,4]oxazepine: 2w. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.6);
Yield: 71%, white solid; Melting Point: 76-78 °C; 1H NMR (CDCl3, 500
MHz): δ 8.66 (d, J = 2.6 Hz, 1H), 8.09 (dd, J = 2.7, 9.0 Hz, 1H), 7.16 (d, J =
9.0 Hz, 1H), 6.68 (s, 1H), 4.98 (s, 1H), 4.79 (s, 2H), 2.68 (t, J = 7.6 Hz, 2H),
1.75-1.68 (m, 2H), 1.44-1.38 (m, 2H), 1.36-1.27 (m, 8H), 0.88 (t, J = 7.1 Hz,
3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 161.1, 155.4, 139.9, 138.2, 124.8,
124.3, 121.7, 119.6, 106.7, 104.4, 72.3, 31.8, 29.3, 29.2, 28.1, 22.6, 14.1
ppm; IR(CH2Cl2): ΰ = 2924, 1652, 1520, 1344, 1256, 1092, 882 cm-1; HRMS
(ESI+) calculated for C20H26O3N3[M+H]+ 356.1968, found 356.1967.
(ESI ) calculated for C24H19ON2 [M+H] 351.1491, found 351.1501.
(E)-2-(4-Fluorophenyl)-5-(4-methoxybenzylidene)-5,6-
dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepine: 2ab. Rf: 0.45; Hexane:
Ethyl acetate mixture (10 : 0.7); Yield: 65%, white solid; Melting Point: 164-
166 °C; 1H NMR (CDCl3, 400 MHz): δ 7.84-7.78 (m, 2H), 7.32-7.24 (m,
4H), 7.07 (t, J = 8.8 Hz, 2H), 7.01-6.94 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H),
6.65 (s, 1H), 6.20 (t, J = 8.1 Hz, 1H), 4.81-4.73 (m, 1H), 4.67-4.60 (m, 1H),
3.80 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 162.8 (d, J = 246.481 Hz,
1C), 160.8, 154.5, 153.1, 146.6, 145.9, 133.6, 130.8, 129.1, 129.0, 128.5,
127.5 (d, J = 8.069 Hz, 1C), 127.2, 121.1, 120.4, 116.9, 115.5 (d, J = 22.007
Hz, 2C), 115.2, 113.9, 104.7, 64.9, 55.3 ppm; IR(CH2Cl2): ΰ = 2924, 1604,
1512, 1448, 1252, 1020, 837, 754 cm-1; HRMS (ESI+) calculated for
C25H20FN2O2 [M+H]+ 399.1503, found 399.1513.
8,10-Dichloro-5-methylene-2-phenyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2x. Rf: 0.65; Hexane: Ethyl acetate mixture (10 : 0.7);
1
Yield: 72%, white solid; Melting Point: 139-141 °C; H NMR (CDCl3, 400
MHz): δ 7.91 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 2.4
Hz, 1H), 7.47-7.42 (m, 2H), 7.40-7.35 (m, 2H), 7.01 (s, 1H), 6.09 (s, 1H),
5.0 (s, 1H), 4.87 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz): δ 152.2, 151.8,
140.4, 139.3, 132.0, 129.6, 128.7, 128.6, 128.5, 126.9, 126.7, 125.9, 122.3,
105.0, 104.0, 73.1 ppm; IR(CH2Cl2): ΰ = 2923, 1648, 1540, 1444, 1370, 993,
878, 761, 686 cm-1; HRMS (ESI+) calculated for C18H13ON2Cl2 [M+H]+
343.0399, found 343.0409.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the Department of Science and Technology (DST) India grant no:
DST-SB/EMEQ-257/2014. We also thank Dr. S. Chandrasekhar, director
CSIR-IICT for his support. We thank Dr. S. Suresh, Dr. B. V. Subbareddy,
Dr. K. Srinivas and Dr. Rajesh for their help. G. R thanks to CSIR for his
senior research feloowship and NSVMRM thanks UGC for his senior
research feloowship and AcSIR. Manuscript communication number:
IICT/Pubs./2018/077.
2-Butyl-8,10-dichloro-5-methylene-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2y. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.4);
Yield: 74%, white solid; Melting Point: 76-78 °C; 1H NMR (CDCl3, 500
MHz): δ 7.60 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 6.52 (s, 1H), 5.90
(s, 1H), 4.90 (s, 1H), 4.81 (s, 2H), 2.67 (t, J = 7.6 Hz, 2H), 1.72-1.65 (m,
2H), 1.47-1.38 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (CDCl3, 125
MHz): δ 155.1, 151.7, 140.3, 138.4, 129.3, 128.3, 126.8, 126.7, 122.4, 106.9,
103.1, 73.2, 31.4, 27.8, 22.4, 13.9 ppm; IR(CH2Cl2): ΰ = 2956, 1650, 1382,
1231, 999, 848 cm-1; HRMS (ESI+) calculated for C26H17ON2Cl2 [M+H]+
323.0712, found 323.0711.
Notes and references
1
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Gerwick, O. Taglialatela-Scafati, Eds.: Springer: Dordrecht, 2012;
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Ress, E. F. V. Scriven, Eds.: Pergamon, Oxford, U.K., 1996; Vol. 1-
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Eicher, S. Hauptmann, S. The Chemistry of Heterocycles: Structure,
Reactions, Syntheses, and Applications, 2nd ed., Wiley-VCH:
Weinheim, Germany, 2003.
8,10-Dichloro-5-methylene-2-octyl-5,6-dihydrobenzo[f]pyrazolo[1,5-
d][1,4]oxazepine: 2z. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.8);
Yield: 85%, white solid; Melting Point: 59-61 °C; 1H NMR (CDCl3, 400
MHz): δ 7.60 (d, J = 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.52 (s, 1H), 5.89
(s, 1H), 4.90 (s, 1H), 4.80 (s, 2H), 2.66 (t, J = 7.9 Hz, 2H), 1.73-1.65 (m,
2
3
(a) G. M. Cragg, D. J. Newman, Expert Opin. Invest. Drugs 2000, 9,
2783; (b) J. W. Blunt, B. R. Copp, R.A. Keyzers, M. H. G. Munro,
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2H), 1.42-1.36 (m, 2H), 1.33-1.25 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13
C
NMR (CDCl3, 100 MHz): δ 155.1, 151.7, 140.3, 138.4, 129.3, 128.3, 126.8,
126.7, 122.4, 106.9, 103.1, 73.2, 31.8, 29.4, 29.3, 29.2, 28.1, 22.6, 14.1 ppm;
IR(CH2Cl2): ΰ = 2924, 1652, 1382, 1231, 1017, 848, 793 cm-1; HRMS (ESI+)
calculated for C20H25ON2Cl2[M+H]+ 379.1338, found 379.1341.
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4
(a) M. S. Alsaid, M. G. El-Gazzar, M. M. Ghorab, Drug Res., 2013,
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d][1,4]oxazepine: 2aa. Rf: 0.6; Hexane: Ethyl acetate mixture (10 : 0.7);
Yield: 61%, Yellow liquid; 1H NMR (CDCl3, 400 MHz): δ 7.88-7.80 (m,
2H), 7.42-7.21 (m, 10H), 6.99 (d, J = 7.5 Hz, 2H), 6.72 (s, 1H), 6.31 (t, J =
8.0 Hz, 1H), 4.87-4.75 (m, 1H), 4.70-4.60 (m, 1H) ppm; 13C NMR (CDCl3,
100 MHz): δ 154.4, 154.1, 146.6, 146.2, 134.8, 133.6, 132.8, 130.8, 129.7,
128.6, 128.4, 128.2, 127.0, 125.8, 121.2, 120.4, 117.3, 117.1, 104.9, 64.9
8 | J. Name., 2012, 00, 1-3
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