Gold-Catalyzed Regioselective Synthesis of Pyrazolo[1,4]oxazepines via Intramolecular 7-endo-dig Cyclization

Article abstract of DOI:10.1002/ejoc.201901852

An efficient gold-catalyzed intramolecular regioselective synthesis of pyrazolo[1,4]oxazepines were developed from alkynyl-substituted pyrazoles via 7-endo dig cyclization. In this reaction a new C–N bond was formed and substituted pyrazolo[1,4]oxazepines

Full text of DOI:10.1002/ejoc.201901852

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Gold-catalyzed regioselective synthesis of
pyrazolo[1,4]oxazepines via intramolecular 7-endo-dig cyclization
Authors: Yadagiri Thummala, Dalovai Purnachandar, Venkata Ramana
Doddi, Galla V Karunakar, Emmaniel Raju Chittala, and
Gottam Sreenivasulu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901852
Link to VoR: https://doi.org/10.1002/ejoc.201901852
01/2020

10.1002/ejoc.201901852
European Journal of Organic Chemistry
FULL PAPER
Gold-catalyzed
regioselective
synthesis
of
pyrazolo[1,4]oxazepines via intramolecular 7-endo-dig cyclization
Yadagiri Thummala,[a,b] Chittala Emmaniel Raju,[a,b] Dalovai Purnachandar,[a,b] Gottam Sreenivasulu,[a,b]
Venkata Ramana Doddi,[c] Galla V. Karunakar*[a,b]
Abstract:
An
efficient
gold-catalyzed
intramolecular
Hence, the development of new synthetic methods to generate
substitited 1,4-oxazepines are gaining attention in recent
years.14 Recently, Balci and co-workers reported that synthesis
of pyrazolo-pyrrolo-pyrazines from substituted N-propargyl
pyrazoles in the presence of gold-catalyst.15
Some of the disadvantages of the previously reported
procedures involved by utilization of harsh reaction conditions as
well as following of number of synthetic steps.16 The broad
applications of 1,4-oxazepine derivatives in medicinal chemistry
demanding to design versatile building blocks for the
development of new synthetic methods to access these
molecules.
regioselective synthesis of pyrazolo[1,4]oxazepines were
developed from alkynyl substituted pyrazoles via 7-endo dig
cyclization. In this reaction a new C-N bond was formed and
substituted pyrazolo[1,4]oxazepines were obtained in moderate
to very good yields. Whereas alkynyl substituted pyrazoles
treated with sodium hydride produced the corresponding
pyrazolo[1,4]oxazines regioselectively, via 6-exo dig cyclization
in one-pot synthesis.
Introduction
Gold-catalyzed17 organic transformations are increasing
interest in synthetic chemistry due to their selective reactions for
generation of valuable molecular scaffolds.18 Our current
research program focused on exploration of gold-catalyzed
regioselective organic transformations on substituted alkynes.19
We are interested to check the reactivity of alkynyl substituted
pyrazoles (1) in the presence of gold-catalyst. Initially, it was
anticipated that alkynyl substituted pyrazoles (1) can be
converted in the presence of gold-catalyst to the corresponding
pyrazolo[1,4]oxazepines 2 via 7-endo-dig cyclization (path a,
Scheme 1) or pyrazolo[1,4]oxazines 3 via 6-exo-dig cyclization
(path b, Scheme 1)
Nitrogen- and oxygen-containing heterocyclic molecules are
privileged scaffolds in medicinal chemistry.1 1,4-Distance
between the seven-membered heterocycles substituted by two
hetero atoms in 1,4-positions, are gaining much attention in
medicinal chemistry and pharmaceuticals.2 Among them,
nitrogen- and oxygen- bearing seven-membered heterocyclic
molecules such as substituted 1,4-oxazepines are used as
handy precursor for synthesis of monoterpenoids and
secoiridoids.3
Some of the [1,4]oxazepine core containing molecules
such as amoxapine,4 sintamil,5 and loxapine,6 are using as drugs
(Figure 1). Substituted oxazepines display biological properties
like antibacterial,7 antifungal,8 antitumor activity,9 antagonistic,10
antiinflammatory,11 telomerase inhibitors,12 and histone
deacetylase inhibitions.13
Scheme 1. Strategy for synthesis of pyrazolo[1,4]oxazepines (2) or
pyrazolo[1,4]oxazines (3) from alkynyl substituted pyrazoles (1)
Results and Discussion
By visualizing above synthetic strategy, an experiment was
conducted
by
utilizing
5-(((1,3-diphenylprop-2-yn-1-
yl)oxy)methyl)-3-phenyl-1H-pyrazole 1a and AuClPEt3 (10
mol%) in acetonitrile (Scheme 2).
Figure 1. Selected important [1,4]oxazepine core containing molecules
.
[a] Mr. Yadagiri Thummala, Mr. Chittala Emmaniel Raju, Dr. Dalovai
Purnachandar, Mr. Gottam Sreenivasulu and Dr. Galla V. Karunakar
Fluoro and Agrochemicals Department, CSIR-Indian Institute of
Chemical Technology, Hyderabad, 500007, India.
[b] Mr. Yadagiri Thummala, Mr. Chittala Emmaniel Raju, Dr. Dalovai
Purnachandar, Mr. Gottam Sreenivasulu and Dr. Galla V. Karunakar
Academy of Scientific and Innovative Research, Ghaziabad 201002,
India.
Scheme 2. Conversion of 5-(((1,3-diphenylprop-2-yn-1-yl) oxy) methyl)-
3-phenyl-1H-pyrazole (1a) to 2,6,8-triphenyl-4H, 6H-pyrazolo [5,1-c][1,4]
oxazepine( 2a).
[c] Dr. Venkata Ramana Doddi, Department of Chemistry and Chemical
Sciences, Central University of Jammu, Jammu, 180011, India.
1
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10.1002/ejoc.201901852
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the corresponding cyclized products 2k and 2l in very good
Very
interestingly,
2,6,8-triphenyl-4H,6H-pyrazolo[5,1-
yields, respectively (Table 2, entries 11 and 12).
c][1,4]oxazepine 2a was obtained exclusively in 52% yield.
It is notable that, in this reaction a new C-N bond was
formed regioselectively via 7-endo dig cyclization.
Table 1.Optimization of the reaction conditions.[a]
Then we have tested this reaction by utilizing different
catalysts and catalyst combinations to improve the yields of
product 2a. The substrate 1a was screened in the presence
of different gold-catalysts like AuCl3, KAuCl4 and AuCN
gave poor yields of product 2a (Table 1, entries 1-3).
Without utilizing catalyst, substrate 1a was tested and it
was found intact (Table 1, entry 4). A reaction was
conducted in the presence of AuClPPh3, which gave
product 2a in 32% yield (Table 1, entry 5). When a reaction
was tested in the presence of AuClPPh3/AgSbF6 produced
2a in 74% yield (Table 1, entry 6). Impressive yield (86%) of
product 2a was achieved when 1a was examined by
utilizing AuPEt3Cl (10 mol %) and AgSbF6 (15 mol %)
(Table 1, entry 7). Poor yields of product 2a observed when
the substrate 1a was examined with various silver catalysts
(Table 1, entries 8-11). A moderate yield of product 2a was
obtained when experiments were conducted by using
AuPEt3Cl with different silver catalysts (Table 1, entries 12-
14). Then different solvents were used to increase the
yields of 2a, all these cases moderate yields of products
were observed (Table 1, entries 15-20). Three experiments
were conducted by reducing catalytic amounts of
AuPEt3Cl/AgSbF6. These cases the product 2a yield was
Entry [a]
Catalyst
(mol %)
Solvent
Temp. ( oC)
/Time (h)
Yield[c] (%)
1
2
3
4
5
6
AuCl3 (10)
KAuCl4(10
AuCN (10)
No catalyst
AuClPPh3(10) CH3CN
AuClPPh3(10) CH3CN
AgSbF6 (15)
AuClPEt3(10)
AgSbF6 (15)
AgSbF6 (15)
AgBF4 (15)
AgOTf(15)
AgNTf(15)
AuClPEt3(10)
AgBF4(15)
AuClPEt3(10)
AgOTf(15)
CH3CN
CH3CN
CH3CN
CH3CN
70/8
70/8
70/6
28/24
28/24
70/4
22
26
15
nrb
32
74
86
7
CH3CN
70/4
22
18
11
13
8
9
10
11
12
CH3CN
CH3CN
CH3CN
CH3CN
70/8
70/8
70/8
70/8
54
50
56
40
51
36
44
48
21
61
48
CH3CN
CH3CN
CH3CN
Toulene
MeOH
DCM
70/6
70/6
70/6
70/7
60/6
40/8
40/8
40/6
40/6
70/12
70/18
13
14
15
16
17
18
19
20
21
22
23
AuClPEt3(10)
AgNTf(15)
AuClPEt3(10)
AgSbF6 (15)
AuClPEt3(10)
AgSbF6 (15)
AuClPEt3(10)
AgSbF6 (15)
AuClPEt3(10)
AgSbF6 (15)
AuClPEt3(10)
AgSbF6 (15)
AuClPEt3(10)
AgSbF6 (15)
AuClPEt3(5)
AgSbF6 (7.5)
AuClPEt3(2.5)
AgSbF6 (5)
not improved much (Table 1, entries 21-23). The substrate
1a was screened in the presence of Lewis acids like AlCl3
and FeCl3 which produced poor yields of product 2a (Table
1, entries 24-25).
The optimization results conclude that the combination of
AuPEt3Cl/AgSbF6 (10/15 mol %) in acetonitrile at 70 °C is the
best reaction condition for the formation of substituted
pyrazolo[1,4]oxazepines (Table 1, entry 7). Then the reactions
were planned to check the scope of this synthetic transformation
by utilizing different alkynyl substituted pyrazoles (1a-1u) and
these results are incorporated in Table 2.
DCE
THF
DMF
CH3CN
CH3CN
AuClPEt3(10)
AgSbF6 (10)
AlCl3(15)
71
24
33
The substrates which are containing aromatic
substitutions at R1, R2 and R3 positions such as 1a (R1 = R2
= R3 = Ph), 1b (R1 = R2 = Ph, R3 = 2-Napthyl), 1c (R1 = 1-
Napthyl, R2 = R3 = Ph) and 1d (R1 = Biphenyl, R2 = R3 = Ph)
gave very good yields of corresponding cyclized products
CH3CN
CH3CN
CH3CN
70/8
70/8
70/6
24
25
FeCl3 (15)
aReaction conditions: all reactions were carried out under nitrogen atmosphere
with 1a (0.137 mmol), solvent (2 mL); bnr: no reaction; cyields are for isolated
products.
2a, 2b, 2c and 2d, respectively (Table 2, entries 1-4). The
substrates which are bearing electron-donating functional
groups such as 1e (R3 = 4-Me-C6H4), 1f (R1 = 4-Me-C6H4,
R2 = R3 = Ph), 1g (R1 = 4-Me-C6H4, R2 = Ph R3 = 2-Napthyl),
1h (R3 = 4-ter-Butyl-C6H4, R1 = R2 = Ph) and 1i (R1 = 4-OMe-
C6H4, R2 = R3 = Ph) produced the corresponding products
The substrates which are substituted by electron-
withdrawing functional groups like 1m (R2 = 4-F-C6H4,) and
1n (R1 = 2,3-di-Cl-C6H3) under optimised reaction conditions
produced good yields of corresponding products 2m and
2n, respectively (Table 2, entries 13 and 14). The
substrates which are bearing both electron-donating and
electron-withdrawing functional groups like 1o (R2 = 4-F-
C6H4, R1 = 4-OMe-C6H4) and 1p (R2 = 4-F-C6H4, R2 = 4-
OMe-C6H4) gave the corresponding products 2o and 2p in
68% and 65% yields, respectively (Table 2, entries 15 and
16). The scope of this reaction was tested by utilizing alkyl
substitution at R2 position containing substrates such as 1q
(R2 = C6H13), 1r (R1 = 4-Cl-C6H4, R2 = C6H13) and 1s (R1 =
3,4,5-(OMe)3-C6H2, R2 = C4H9, R3 = 4-Me-C6H4). The
2e, 2f, 2g, 2h and 2i in very good yields, respectively
(Table 2, entries 5-9). Trimethoxy functional groups at R1
position containing substrate such as 1j (R1 = 3,4,5-(OMe)3-
C6H2) gave the corresponding pyrazolo[1,4]oxazepine 2j in
72% yield (Table 2, entry 10).
Electron-donating functional groups at R1 and R3
position containing substrates such as 1k (R1 = R3 = 4-Me-
C6H4) and 1l (R1 = 4-Me-C6H4, R3 = 4-OMe-C6H4) produced
2
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10.1002/ejoc.201901852
European Journal of Organic Chemistry
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corresponding products 2q, 2r and 2s were obtained in very
good yields, respectively (Table 2, entries 17-19).
a
Table 2 Scope of substituted pyrazolo[1,4]oxazepines (2)
Table 2(contd.)
Table 2(contd.)
3
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10.1002/ejoc.201901852
European Journal of Organic Chemistry
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thiopene)
gave
the
corresponding
substituted
pyrazolo[1,4]oxazepine 2u in 63% yield (Table 2, entry 21).
Further, experiments were performed to convert the
alkynyl substituted pyrazoles
1 to the corresponding
pyrazolo[1,4]oxazines (Table 3). As assumed in the
3
synthetic scheme 1, the substrate 1a was tested in the
presence of different catalysts and Lewis acids to get the 6-
endo dig cyclised product pyrazolo-[1,4]oxazine 3a. But we
could not obtain the desired product. Hence, we have
planned to test the substrate 1a in the presence of NaH.
a
Table 3 Scope of substituted pyrazolo[1,4]oxazines (3)
aReaction conditions: all reactions were carried out at 0 oC under
nitrogen atmosphere with (0.27 mmol), NaH (1.2 equiv.) in DMF (3
mL); are for isolated products.
bYields
1
An experiment was performed by employing the substrate 1a in
the presence of sodium hydride in DMF at 0 C. To our delight,
o
aReaction conditions: all reactions carried out at 70 oC under nitrogen
atmosphere, 1 (0.27 mmol) in the presence of AuClPEt3 (10 mol %)/AgSbF6
(15 mol %) and solvent (3 mL); bYields are for isolated products.
the intramolecular cyclized product 7-benzyl-2,6-diphenyl-4H-
pyrazolo[5,1-c][1,4]oxazine 3a was obtained in 67% yield (Table
3, entry 1). Scope of this reaction was tested by utilizing alkynyl
substituted pyrazoles (Table 3). The substrate 1l gave the
corresponding product 3b in 64% yield (Table 3, entry 2). The
alkyl substitution at R2 position containing substrate 1s gave
product 3c in 56% yield (Table 3, entry 3). A reaction was
conducted with substarte 1r produced the corresponding product
3d in 59% yield (Table3, entry 4).
The substrate which is having alicyclic substitution at R2
position like 1t (R3 = C6H11) produced the corresponding
product 2t in 83% yield (Table 2, entry 20). Hetero aromatic
substitution at R3 position containing substrate 1u (R3 =
4
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A plausible reaction mechanism can be proposed for
formation of pyrazolo[1,4]oxazepines 2 by following (Scheme 3).
Initially, gold-catalyst coordinate with substrate 1 may give
intermediate-I (IM-I).15 This IM-I might produce vinyl-gold
intermediate-II (IM-II) via 7-endo-dig cyclization,20 which would
finally produce pyrazolo[1,4]oxazepines 2 via protodeauration.
(Scheme 3).
similar procedure was followed for the synthesis of remaining substituted
pyrazolo[1,4]oxazepine derivatives (2b-2u).
2,6,8-Triphenyl-4H,6H-pyrazolo[5,1-c][1,4]oxazepine (2a)
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.4); Yield: 86%, Colourless
Oil;1H NMR (500 MHz, CDCl3): δ= 7.82 (d, J = 7.2 Hz, 2H), 7.48-7.45 (m,
2H), 7.42 (d, J = 7.5 Hz, 2H), 7.40-7.34 (m, 7H), 7.34 – 7.30 (m, 2H),
6.78 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 5.20 (d, J = 6.5 Hz, 1H), 4.83 (dd, J
= 34.9, 14.1 Hz, 2H) ppm (purity ˃95%); 13C NMR (100 MHz, CDCl3): δ=
152.80, 144.46, 143.19, 140.77, 134.63, 132.81, 129.64, 128.70, 128.68,
128.40, 128.31, 128.24, 128.16, 127.04, 126.00, 120.02, 103.53, 75.76,
59.65 ppm; IR (KBr neat): ΰ = 3060, 1719, 1445, 1269, 1024, 955,
761cm-1; HRMS (ESI+) calculated for C25H21N2O [M+H]+ 365.1671, found
365.1654.
2-(Naphthalen-2-yl)-6,8-diphenyl-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2b)
Scheme 3. A plausible reaction mechanism.
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.5); Yield: 76%, white solid;
Melting Point: 88-90 °C; 1H NMR (400 MHz, CDCl3): δ= 8.28 (s, 1H), 7.98
(dd, J = 8.5, 1.7 Hz, 2H), 7.89-7.81 (m, 3H), 7.53-7.50 (m, 2H), 7.47 (d, J
= 3.7 Hz, 1H), 7.46-7.42 (m, 3H), 7.43-7.41 (m, 2H), 7.40-7.36 (m, 3H),
7.36-7.33 (m, 1H), 6.93 (s, 1H), 6.11 (d, J = 6.5 Hz, 1H), 5.24 (d, J = 6.5
Hz, 1H), 4.95 (dd, J = 36.6, 14.4 Hz, 2H) ppm (purity ˃95%); 13C NMR
(100 MHz, CDCl3): δ= 152.81, 144.59, 143.21, 140.74, 134.60, 133.53,
133.36, 130.22, 129.68, 128.71, 128.44, 128.33, 128.26, 128.16, 127.77,
127.03, 126.86, 126.28, 126.08, 124.77, 124.15, 120.13, 103.79, 75.73,
59.67 ppm; IR (KBr neat): ΰ = 3421, 1625, 1489, 1268, 1046, 818, 754
cm-1; HRMS (ESI+) calculated for C29H23N2O [M+H]+ 415.1829, found
415.1812.
Conclusion
In conclusion, an efficient gold-catalyzed synthetic protocol
was
developed
for
the
formation
of
substituted
pyrazolo[1,4]oxazepines from alkynyl substituted pyrazoles
regiosectively via 7-endo dig cyclization. Whereas alkynyl
substituted pyrazoles treated under sodium hydride produced
the corresponding pyrazolo[1,4]oxazines regioselectively via 6-
exo dig cyclization. Moderate to very good yields of substituted
pyrazolo[1,4]oxazepines and pyrazolo[1,4]oxazines were
achieved in one-pot synthesis.
6-(Naphthalen-1-yl)-2,8-diphenyl-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2c)
Rf = 0.55; Hexane: Ethyl acetate mixture (10 : 0.3); Yield: 82%, white
solid; Melting Point: 100-102 °C; 1H NMR (400 MHz, CDCl3) δ= 8.13 –
8.03 (m, 1H), 7.93 – 7.80 (m, 4H), 7.65 (d, J = 7.0 Hz, 1H), 7.52 – 7.43
(m, 5H), 7.42 – 7.31 (m, 6H), 6.85 (s, 1H), 6.21 (d, J = 6.6 Hz, 1H), 5.75
(d, J = 6.7 Hz, 1H), 5.04 (dd, J = 19.3, 11.1 Hz, 2H). ppm; 13C NMR (101
MHz, CDCl3): δ= 152.97, 144.29, 143.35, 136.03, 134.49, 134.16,
132.80, 130.46, 129.96, 129.67, 128.95, 128.71, 128.39, 128.28, 127.36,
126.27, 126.05, 125.78, 125.39, 125.25, 124.43, 120.00, 103.72, 74.36,
59.46. ppm; IR (KBr neat): ΰ = 3019, 1648, 1460, 1213, 1019, 9856, 790,
758 cm-1; HRMS (ESI+) calculated for C29H23N2O [M+H]+ 415.1345,
found 415.1332.
Experimental Section
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 UV
as a visualizing agent and a 0.5% aqueous anisaldehyde 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 and 125 MHz spectrometers. 1HNMR spectra
were recorded on 300 MHz, 400 MHz 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 alkynyl substituted pyrazoles (1a-1u) were prepared by following
reported procedures.21
6-([1,1'-Biphenyl]-4-yl)-2,8-diphenyl-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2d)
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 76%, white solid;
1
Melting Point: 166-168 °C; H NMR (500 MHz, CDCl3): δ= 7.84 (dd, J =
5.2, 3.2 Hz, 2H), 7.62-7.57 (m, 5H), 7.51-7.47 (m, 4H), 7.46-7.41 (m, 3H),
7.41-7.37 (m, 4H), 7.35-7.32 (m, 1H), 6.80 (s, 1H), 6.12 (d, J = 6.5 Hz,
1H), 5.26 (d, J = 6.5 Hz, 1H), 4.87 (dd, J = 43.1, 14.0 Hz, 2H) ppm; 13
C
NMR (100 MHz, CDCl3): δ= 152.84, 144.47, 143.27, 141.12, 140.79,
139.74, 134.62, 132.79, 129.67, 128.84, 128.68, 128.58, 128.41, 128.33,
128.26, 127.49, 127.46, 127.18, 126.01, 119.89, 103.57, 75.56, 59.68
ppm; IR (KBr neat): ΰ = 2921, 1618, 1437, 1363, 1078, 828, 762 cm-1;
HRMS (ESI+) calculated for C31H25N2O [M+H]+ 441.1980, found
441.1967.
6,8-Diphenyl-2-(p-tolyl)-4H,6H-pyrazolo[5,1-c][1,4]oxazepine (2e)
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.5); Yield: 81%, white
solid; Melting Point: 96-98 °C; 1H NMR (400 MHz, CDCl3): δ= 7.71 (d, J =
8.0 Hz, 2H), 7.49-7.32 (m, 8H), 7.19 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 7.7
Hz, 2H), 6.75 (s, 1H), 6.01 (d, J = 6.5 Hz, 1H), 5.18 (d, J = 6.5 Hz, 1H),
4.88 (dd, J = 47.3, 9.9 Hz, 2H), 2.36 (s, 3H) ppm (purity ˃95%); 13C NMR
(100 MHz, CDCl3): δ= 152.97, 144.26, 143.36, 138.21, 134.52, 129.93,
129.70, 129.37, 128.76, 128.68, 128.41, 128.24, 125.90, 119.53, 115.64,
115.43, 103.44, 75.04, 59.62, 21.36 ppm; IR (KBr neat): ΰ = 2917, 1628,
1443, 1224, 1045, 822, 761 cm-1; HRMS (ESI+) calculated for C26H23N2O
[M+H]+ 379.1674, found 379.1654.
General procedure for synthesis of of 2,6,8-Triphenyl-
4H,6H-pyrazolo[5,1-c][1,4]oxazepines (2a-2u).
To a 10 mL round-bottomed flask equipped with magnetic stir bar the
substrate
5-(((1,3-diphenylprop-2-yn-1-yl)oxy)methyl)-3-phenyl-1H-
pyrazole 1a (100 mg, 2.7 mmol, 1 equiv.) was taken and dissolved in
CH3CN (3 mL). To this reaction mixture AuPEt3Cl (9.6 mg, 10 mol %) and
AgSbF6 (14 mg, 15 mol %) was added and stirred at 70 °C for 4 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 hexane and ethyl acetate as eluent (10:1.2) to give
product 2,6,8-triphenyl-4H,6H-pyrazolo[5,1-c][1,4]oxazepine 2a (86%). A
2,8-Diphenyl-6-(p-tolyl)-4H,6H-pyrazolo[5,1-c][1,4]oxazepine (2f)
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.4); Yield: 67%, Colourless
liquid; 1H NMR (400 MHz, CDCl3): δ= 7.84-7.81 (m, 2H), 7.46 (dd, J =
7.7, 1.6 Hz, 2H), 7.42-7.35 (m, 5H), 7.35-7.29 (m, 3H), 7.19 (d, J = 8.0
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901852
European Journal of Organic Chemistry
FULL PAPER
Hz, 2H), 6.78 (s, 1H), 6.08 (d, J = 6.4 Hz, 1H), 5.17 (d, J = 6.4 Hz, 1H),
4.82 (dd, J = 27.0, 14.0 Hz, 2H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ= 152.97, 144.26, 143.36, 138.21, 136.66, 134.52, 129.70,
129.37, 128.76, 128.68, 128.41, 128.24, 125.90, 119.53, 115.64, 115.43,
103.44, 75.04, 59.62, 21.36 ppm; IR (KBr neat): ΰ = 2923, 1715, 1446,
1270, 1099, 817, 761 cm-1; HRMS (ESI+) calculated for C26H23N2O
[M+H]+ 379.1830, found 379.1817.
2-(4-Methoxyphenyl)-8-phenyl-6-(p-tolyl)-4H,6H-pyrazolo
c][1,4]oxazepine (2l)
[5,
1-
Rf = 0.4; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 68%, white solid;
Melting Point: 153-155 °C; 1H NMR (400 MHz, CDCl3): δ= 7.75 (d, J =
8.7 Hz, 2H), 7.46 (dd, J = 8.8, 6.0 Hz, 2H), 7.41-7.29 (m, 5H), 7.18 (d, J =
7.8 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 6.05 (d, J = 6.4 Hz,
1H), 5.17 (d, J = 6.4 Hz, 1H), 4.80 (dd, J = 25.2, 14.0 Hz, 2H), 3.82 (s,
3H), 2.36 (s, 3H) ppm (purity ˃95%); 13C NMR (100 MHz, CDCl3): δ
159.80, 152.57, 144.45, 143.02, 137.89, 137.84, 134.74, 129.54, 129.35,
128.35, 128.24, 127.28, 127.03, 125.62, 120.01, 114.05, 103.06, 75.67,
59.62, 55.35, 21.25 ppm; IR (KBr neat): ΰ = 2955, 1609, 1438, 1246,
1030, 808, 756 cm-1; HRMS (ESI+) calculated for C27H25N2O2 [M+H]+
409.1936, found 409.1916.
2-(Naphthalen-2-yl)-8-phenyl-6-(p-tolyl)-4H, 6H-pyrazolo [5, 1-
c][1,4]oxazepine: (2g)
Rf = 0.7; Hexane: Ethyl acetate mixture (10 : 0.3); Yield: 74%, white solid;
Melting Point: 95-97 °C; 1H NMR (500 MHz, CDCl3): δ= 8.27 (s, 1H), 7.98
(dd, J = 10.0, 7.0 Hz, 1H), 7.89-7.77 (m, 4H), 7.52-7.44 (m, 5H), 7.41 (dd,
J = 6.5, 4.5 Hz, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H),
6.92 (s, 1H), 6.11 (d, J = 6.4 Hz, 1H), 5.21 (d, J = 6.4 Hz, 1H), 4.94 (dd, J
= 44.2, 13.6 Hz, 2H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=
144.64, 143.00, 137.95, 137.74, 134.68, 133.53, 133.34, 130.24, 129.98,
129.61, 129.37, 128.42, 128.24, 128.08, 127.76, 127.42, 127.03, 126.27,
126.07, 124.75, 124.16, 120.36, 103.75, 75.70, 59.64, 21.24 ppm; IR
(KBr neat): ΰ = 3449, 1620, 1439, 1272, 1042, 815, 757 cm-1; HRMS
(ESI+) calculated for C30H25N2O [M+H]+ 429.1977, found 429.1967.
2-(4-(Tert-butyl)phenyl)-6,8-diphenyl-4H,6H-pyrazolo[5,1-
8-(4-Fluorophenyl)-2,6-diphenyl-4H,6H-pyrazolo[5,1-c][1,4]oxazepine
(2m)
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.4); Yield: 62%, Yellow
solid; Melting Point: 87-89 °C; 1H NMR (400 MHz, CDCl3): δ 7.73-7.70
(m, 2H), 7.37-7.33 (m, 2H), 7.31-7.23 (m, 6H), 7.22-7.08 (m, 2H), 6.97-
6.91 (m, 2H), 6.67 (s, 1H), 5.90 (d, J = 6.5 Hz, 1H), 5.07 (d, J = 6.4 Hz,
1H), δ 4.69 (dd, J = 26.4, 14.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3):
δ= 152.90, 144.39, 143.32, 136.64, 134.52, 132.75, 129.77, 128.82,
128.73, 128.47, 128.40, 128.27, 126.02, 119.71, 115.69, 115.48, 103.64,
75.11, 59.63 ppm; IR (KBr neat): ΰ = 2922, 1602, 1439, 1221, 1077, 828,
761 cm-1; HRMS (ESI+) calculated for C25H20FN2O [M+H] +383.1581,
found 383.1563.
c][1,4]oxazepine (2h)
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.5); Yield: 64%, Colourless
Oil; 1H NMR (400 MHz, CDCl3): δ= 7.77-7.75 (m, 2H), 7.49-7.43 (m, 3H),
7.43-7.41 (m, 2H), 7.40-7.37 (m, 4H), 7.37-7.34 (m, 2H), 7.35-7.31 (m,
1H), 6.76 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 5.20 (d, J = 6.5 Hz, 1H), 4.91
(dd, J = 36.1, 14.0 Hz, 2H), 1.33 (s, 9H) ppm (purity ˃95%); 13C NMR
(100 MHz, CDCl3): δ= 152.79, 151.39, 144.30, 143.24, 140.82, 134.63,
130.01, 129.59, 128.68, 128.35, 128.23, 128.12, 127.03, 125.72, 125.58,
119.82, 103.39, 75.69, 59.66, 34.70, 31.35 ppm; IR (KBr neat): ΰ = 2959,
1721, 1448, 1269, 1070, 838, 764 cm-1; HRMS (ESI+) calculated for
C29H29N2O [M+H]+ 421.2296, found 421.2281.
6-(2,3-Dichlorophenyl)-2,8-diphenyl-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2n)
Rf = 0.7; Hexane: Ethyl acetate mixture (10 : 0.4); Yield: 68%, white solid;
1
Melting Point: 145-147 °C; H NMR (400 MHz, CDCl3): δ= 7.84-7.81 (m,
2H), 7.58 (dd, J = 7.8, 1.0 Hz, 1H), 7.49-7.43 (m, 3H), 7.42-7.36 (m, 5H),
7.35-7.30 (m, 1H), 7.27-7.23 (m, 1H), 6.81 (s, 1H), 5.89 (d, J = 3.3 Hz,
1H), 5.53 (d, J = 6.5 Hz, 1H), 4.92 (dd, J = 69.9, 12.8 Hz, 2H) ppm; 13
C
6-(4-Methoxyphenyl)-2,8-diphenyl-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2i)
NMR (100 MHz, CDCl3): δ= 152.88, 143.92, 143.87, 140.96, 134.55,
133.36, 132.72, 130.66, 129.84, 129.74, 128.67, 128.34, 127.52, 126.32,
126.04, 118.06, 103.66, 73.24, 59.63 ppm; IR (KBr neat): ΰ = 3417,
1692, 1438, 1281, 1075, 821, 759 cm-1; HRMS (ESI+) calculated for
C25H19Cl2N2O [M+H]+ 433.0875, found 433.0872.
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 70%, white solid;
Melting Point: 157-159 °C; 1H NMR (400 MHz, CDCl3): δ= 7.82 (d, J =
5.2 Hz, 2H), 7.48-7.44 (m, 2H), 7.41-7.35 (m, 5H), 7.35-7.28 (m, 3H),
6.91 (d, J = 4.5 Hz, 2H), 6.78 (s, 1H), 6.08 (d, J = 6.4 Hz, 1H), 5.16 (d, J
8-(4-Fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-4H,6H-pyrazolo [5,
1-c][1,4]oxazepine (2o)
= 6.4 Hz, 1H), 4.82 (dd, J = 28.1, 14.0 Hz, 2H), 3.81 (s, 3H) ppm; 13
C
NMR (100 MHz, CDCl3): δ= 159.50, 152.72, 144.49, 142.84, 134.68,
132.80, 129.94, 129.58, 128.66, 128.46, 128.38, 128.22, 127.38, 125.98,
120.22, 114.08, 103.49, 75.57, 59.59, 55.38 ppm; IR (KBr neat): ΰ =
2923, 1608, 1437, 1247, 1024, 826, 758 cm-1; HRMS (ESI+) calculated
for C26H23N2O2 [M+H]+ 395.1777, found 395.1768.
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.4); Yield: 68%, white solid;
Melting Point: 119-121 °C; 1H NMR (400 MHz, CDCl3): δ= 7.83-7.80
(m,2), 7.47-7.41 (m, 2H), 7.40-7.34 (m, 3H), 7.35-7.30 (m, 2H), 7.09-7.03
(m, 2H), 6.93-6.89 (m, 2H), 6.78 (s, 1H), 6.01 (d, J = 6.3 Hz, 1H), 5.16 (d,
J = 6.3 Hz, 1H), δ 4.82 (dd, J = 30.4, 14.0 Hz, 2H), 3.81 (s, 3H) ppm; 13
C
2,8-Diphenyl-6-(3,4,5-trimethoxyphenyl)-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2j)
NMR (100 MHz, CDCl3): δ= 159.56, 152.80, 144.57, 141.75, 132.71,
130.20, 130.12, 129.41, 128.69, 128.43, 128.36, 125.95, 119.87, 115.52,
115.30, 114.11, 103.62, 75.76, 59.62, 55.37 ppm; IR (KBr neat): ΰ =
2924, 1604, 1440, 1249, 1027, 832, 765 cm-1; HRMS (ESI+) calculated
for C26H22FN2O2 [M+H]+ 413.1687, found 413.1665.
Rf = 0.5; Hexane: Ethyl acetate mixture (20 : 0.8); Yield: 72%, white solid;
1
Melting Point: 176-178 °C; H NMR (500 MHz, CDCl3): δ= 7.85-7.82 (m,
2H), 7.49 (dd, J = 8.0, 1.5 Hz, 2H), 7.43-7.40 (m, 2H), 7.39 (d, J= 1.7 Hz,
2H), 7.38 (s, 1H), 7.35 – 7.32 (m, 1H), 6.81 (s, 1H), 6.65 (s, 2H), 6.10 (d,
J = 6.6 Hz, 1H), 5.11 (d, J = 6.6 Hz, 1H), 4.87 (dd, J = 72.3, 12.4 Hz, 2H),
3.87 (s, 6H), 3.85 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ= 153.43,
152.91, 144.34, 143.20, 137.69, 136.34, 134.39, 132.71, 129.73, 128.68,
128.43, 128.35, 128.17, 125.96, 119.93, 103.90, 103.56, 75.79, 60.88,
59.62, 56.16 ppm; IR (KBr neat): ΰ = 3449, 1633, 1459, 1236, 1129, 836,
767 cm-1; HRMS (ESI+) calculated for C28H27N2O4 [M+H]+ 455.2136,
found 455.2111.
8-Phenyl-2, 6-di-p-tolyl-4H, 6H-pyrazolo [5, 1-c][1,4]oxazepine: (2k)
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.8); Yield: 71%, white solid;
Melting Point: 129-131 °C; 1H NMR (500 MHz, CDCl3): δ= 7.71 (d, J =
8.1 Hz, 2H), 7.46 (dd, J = 9.5, 6.5 Hz, 2H), 7.41-7.35 (m, 3H), 7.31 (d, J =
8.1 Hz, 2H), 7.19 (d, J = 7.6 Hz, 4H), 6.75 (s, 1H), 6.07 (d, J = 6.5 Hz,
1H), 5.17 (d, J = 6.5 Hz, 1H), 4.81 (dd, J = 34.9, 14.1 Hz, 2H), 2.36 (s,
6H) ppm (purity ˃95%); 13C NMR (100 MHz, CDCl3): δ= 152.81, 144.40,
143.02, 138.11, 137.89, 137.81, 134.70, 130.01, 129.54, 129.34, 128.34,
128.22, 127.02, 125.88, 125.66, 120.09, 103.31, 75.64, 59.61, 21.34,
21.23 ppm; IR (KBr neat): ΰ = 2924, 1720, 1451, 1268, 1104, 1024, 759
cm-1; HRMS (ESI+) calculated for C27H25N2O [M+H]+ 393.2093, found
393.2089.
8-(4-Fluorophenyl)-2-(4-methoxyphenyl)-6-phenyl-4H,6H-
pyrazolo[5,1-c][1,4]oxazepine (2p)
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.5); Yield: 65%, Yellow
solid; Melting Point: 142-144 °C; 1H NMR (400 MHz, CDCl3): δ= 7.76-
7.74 (m, 2H), 7.48-7.45 (m, 2H), 7.42-7.35 (m, 5H), 7.09-7.03 (m, 2H),
6.93-6.91 (m, 2H), 6.72 (s, 1H), 6.00 (d, J = 3.4 Hz, 1H), 5.18 (d, J = 6.5
Hz, 1H), 4.89 (dd, J = 36.4, 14.4 Hz, 2H), 3.83 (s, 3H) ppm (purity ˃95%);
13C NMR (100 MHz, CDCl3): δ= 159.84, 152.72, 144.28, 143.34, 134.53,
129.68, 128.75, 128.67, 128.39, 128.23, 127.28, 125.50, 119.42, 115.63,
115.42, 114.06, 103.16, 75.04, 59.62, 55.35 ppm; IR (KBr neat): ΰ =
2921, 1605, 1440, 1244, 1031, 831, 754 cm-1; HRMS (ESI+) calculated
for C26H22N2O2F [M+H]+ 413.1693, found 413.1665.
8-Hexyl-2,6-diphenyl-4H,6H-pyrazolo[5,1-c][1,4]oxazepine (2q)
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 75%, Colourless
liquid; 1H NMR (500 MHz, CDCl3): δ= 7.87-7.84 (m, 2H), 7.42-7.39 (m,
2H), 7.38-7.31 (m, 5H), 7.30-7.23 (m, 1H), 6.63 (s, 1H), 5.48 (d, J = 4.1
Hz, 1H), 5.23 (d, J = 4.9 Hz, 1H), 4.73 (dd, J = 62.1, 13.3 Hz, 2H), 2.92-
2.73 (m, 2H), 1.58-1.54 (m, 2H), 1.38-1.22 (m, 6H), 0.89-0.85 (m, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ= 151.62, 143.52, 142.68, 140.98,
133.12, 128.71, 128.60, 128.10, 128.06, 127.16, 125.80, 116.51, 103.24,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901852
European Journal of Organic Chemistry
FULL PAPER
76.78, 60.23, 33.61, 31.57, 28.84, 27.60, 22.63, 14.13 ppm; IR (KBr
neat): ΰ = 2927, 1721, 1447, 1268, 1071, 765, 695 cm-1; HRMS (ESI+)
calculated for C25H29N2O [M+H]+ 373.2281, found 373.2275.
6-(2-Chlorophenyl)-8-hexyl-2-phenyl-4H,6H-pyrazolo[5,1-c][1,
4]oxazepine (2r)
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.5); Yield: 73%, Colourless
Oil; 1H NMR (500 MHz, CDCl3): δ= 7.85 (d, J = 7.1 Hz, 2H), 7.53 (d, J =
7.0 Hz, 1H), 7.38 (t, J = 7.1 Hz, 2H), 7.34-7.27 (m, 2H), 7.23-7.16 (m,
2H), 6.59 (s, 1H), 5.63 (s, 1H), 5.34 (d, J = 3.8 Hz, 1H), 4.73 (dd, J =
32.5, 13.4 Hz, 2H), 2.84-2.77 (m, 2H), 1.68-1.47 (m, 2H), 1.68-1.24 (m,
6H), 0.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 151.55, 143.43,
142.59, 138.52, 133.18, 132.69, 129.73, 129.21, 128.76, 128.76, 128.15,
127.11, 125.86, 114.98, 103.30, 75.47, 60.59, 33.87, 31.64, 28.90,
27.77, 22.71, 14.23 ppm; IR (KBr neat): ΰ = 2925, 1659, 1438, 1239,
1041, 865, 759 cm-1; HRMS (ESI+) calculated for C25H28ClN2O [M+H]+
407.1911, found 407.1904.
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.5); Yield: 67%, white solid;
Melting Point: 190-192 °C; 1H NMR (400 MHz, CDCl3): δ= 7.80 (d, J =
7.2 Hz, 2H), 7.53 (dd, J = 7.9, 1.6 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.33-
7.26 (m, 3H), 7.24-7.20 (m, 4H), 7.19 (d, J = 7.7 Hz, 2H), 7.13 (t, J = 6.9
Hz, 1H), 6.40 (s, 1H), 5.30 (s, 2H), 4.00 (s, 2H) ppm; 13C NMR (125 MHz,
CDCl3): δ= 151.63, 138.52, 138.33, 134.26, 134.02, 133.98, 133.29,
133.17, 131.64, 130.47, 128.71, 128.65, 128.29, 127.92, 127.39, 126.38,
125.68, 121.15, 99.06, 63.47, 31.75 ppm; IR (KBr neat): ΰ = 2921, 1660,
1447, 1321, 1072, 967, 771 cm-1; HRMS (ESI+) calculated for C25H21N2O
[M+H]+ 365.1653, found 365.1626.
7-Benzyl-2-(4-methoxyphenyl)-6-(p-tolyl)-4H-pyrazolo[5,1-
c][1,4]oxazine (3b)
Rf = 0.6; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 64%, white solid;
Melting Point: 138-140 °C; 1H NMR (500 MHz, CDCl3): δ= 7.75 (d, J =
8.5 Hz, 2H), 7.50 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.33-7.22
(m, 3H), 7.18 (d, J = 7.9 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.72 (q, J =
15.9 Hz, 2H), 6.28 (s, 1H), 5.11 (dd, J = 29.9, 11.9 Hz, 2H), 3.82 (s, 3H),
2.34 (s, 3H) ppm (purity ˃95%); 13C NMR (100 MHz, CDCl3): δ= 159.46,
157.54, 142.47, 138.87, 136.04, 135.70, 132.55, 129.12, 128.57, 128.37,
127.64, 127.18, 127.16, 126.82, 126.49, 113.99, 96.60, 93.79, 64.63,
55.36, 21.25 ppm; IR (KBr neat): ΰ = 2926, 1665, 1445, 1248, 1028, 828,
758 cm-1; HRMS (ESI+) calculated for C27H25N2O2 [M+H]+ 409.1946,
found 409.1927.
8-Butyl-2-(p-tolyl)-6-(3,4,5-trimethoxyphenyl)-4H,6H-pyrazolo[5,1-
c][1,4]oxazepine (2s)
Rf = 0.5; Hexane: Ethyl acetate mixture (20 : 0.8); Yield: 81%, Colourless
Oil; 1H NMR (400 MHz, CDCl3): δ= 7.75 (d, J = 8.0 Hz, 2H), 7.22 (d, J =
8.0 Hz, 2H), 6.61 (d, J = 3.8 Hz, 2H), 5.47 (d, J = 5.3 Hz, 1H), 5.13 (d, J =
5.2 Hz, 1H), 4.73 (dd, J = 56.2, 13.2 Hz, 2H), 3.84 (s, 6H), 3.83 (s, 3H),
2.98-2.71 (m, 2H), 2.37 (s, 3H), 1.64-1.52 (m, 2H), 1.47-1.34 (m, 2H),
0.93 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 153.33,
151.81, 143.32, 142.95, 137.93, 137.62, 136.70, 130.25, 129.40, 125.68,
116.34, 104.06, 103.16, 77.82, 60.83, 60.23, 56.13, 33.23, 29.83, 22.29,
21.35, 13.95 ppm; IR (KBr neat): ΰ = 2927, 1716, 1458, 1227, 1126, 818,
759 cm-1; HRMS (ESI+) calculated for C27H33N2O4 [M+H]+ 449.2446,
found 449.2442.
2-Cyclohexyl-6,8-diphenyl-4H,6H-pyrazolo[5,1-c][1,4]oxazepine (2t).
Rf = 0.4; Hexane: Ethyl acetate mixture (10 : 0.7); Yield: 83%, Yellow
liquid; 1H NMR (300 MHz, CDCl3): δ= 7.46-7.29 (m, 10H), 6.28 (s, 1H),
6.00 (d, J = 6.5 Hz, 1H), 5.11 (d, J = 6.5 Hz, 1H), 4.77 (dd, J = 33.2, 12.6
Hz, 2H), 2.81 – 2.58 (m, 1H), 1.99 (d, J = 11.1 Hz, 1H), 1.89-1.55 (m,
3H), 1.54-1.23 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ= 160.16,
143.40, 143.33, 141.02, 134.74, 129.58, 128.40, 128.15, 128.02, 126.98,
119.37, 103.29, 75.42, 59.64, 37.73, 33.43, 33.15, 26.36, 26.14 ppm; IR
(KBr neat): ΰ = 2926, 1722, 1450, 1269, 1037, 756, 699 cm-1; HRMS
(ESI+) calculated for C25H27N2O [M+H]+ 371.2123, found 371.2117.
6,8-Diphenyl-2-(thiophen-2-yl)-4H,6H-pyrazolo[5,1-c][1,4]oxazepine
(2u).
Rf = 0.5; Hexane: Ethyl acetate mixture (10 : 0.7); Yield: 63%, Yellow
liquid; 1H NMR (500 MHz, CDCl3): δ= 7.46-7.44 (m, 2H), 7.43-7.40 (m,
2H), 7.40-7.38 (m, 4H), 7.37-7.32 (m, 3H), 7.26 (dd, J = 5.1, 1.1 Hz, 1H),
7.05 (dd, J = 5.0, 3.6 Hz, 1H), 6.69 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 5.18
(d, J = 6.5 Hz, 1H), 4.78 (dd, J = 20.1, 11.6 Hz, 2H) ppm; 13C NMR (100
MHz, CDCl3): δ= 148.16, 144.44, 143.06, 140.69, 136.02, 134.40,
130.02, 129.66, 128.70, 128.39, 128.17, 127.53, 126.99, 125.28, 124.64,
120.16, 103.59, 75.65, 59.49 ppm; IR (KBr neat): ΰ = 2923, 1625, 1441,
1222, 1049, 846, 756 cm-1; HRMS (ESI+) calculated for C23H19N2OS
[M+H]+ 371.1237, found 371.1218.
7-Pentyl-2-(p-tolyl)-6-(3,4,5-trimethoxyphenyl)-4H-pyrazolo[5,1-
c][1,4]oxazine (3c)
Rf = 0.7; Hexane: Ethyl acetate mixture (20 : 0.8); Yield: 56%, Colourless
liquid; 1H NMR (500 MHz, CDCl3): δ= 7.21 (s, 3H), 6.76-6.74 (m, 2H),
6.33-6.30 (m, 2H), 3.93 (d, J = 0.8 Hz, 2H), 3.92 (s, 6H), 3.92 (s, 3H),
2.63-2.58 (m, 3H), 1.62 (s, 1H), 1.50-1.43 (m, 3H), 1.41-1.34 (m, 3H),
1.25 (s, 1H), 0.93-0.90 (m, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ=
153.09, 149.96, 149.38, 146.05, 142.36, 133.80, 126.59, 125.48, 124.19,
106.35, 106.15, 105.91, 84.97, 60.96, 56.38, 56.29, 34.39, 31.40, 29.65,
22.48, 18.53, 13.92 ppm; IR (KBr neat): ΰ = 2958, 1671, 1459, 1232,
1127, 832, 764 cm-1; HRMS (ESI+) calculated for C27H33N2O4 [M+H]+
449.2456, found 449.2439.
6-(2-Chlorophenyl)-7-heptyl-2-phenyl-4H-pyrazolo[5,1-c][1,4]oxazine
(3d)
Rf: 0.5; Hexane: Ethyl acetate mixture (10 : 0.6); Yield: 59%, Yellow
liquid; 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 7.3, 1.8 Hz, 1H), 7.70
(d, J = 7.2 Hz, 2H), 7.43 – 7.36 (m, 2H), 7.29 (m, 4H), 6.58 (s, 1H), 4.79
(q, J = 12.3 Hz, 2H), 2.34 – 2.20 (m, 2H), 1.65 – 1.48 (m, 2H), 1.39 (m,
2H), 1.28 (m, 3.7 Hz, 6H), 0.88 (t, J = 6.7 Hz, 3H) ppm; 13C NMR (101
MHz, CDCl3) δ 149.01, 144.63, 136.38, 133.50, 131.87, 129.75, 129.64,
129.38, 128.81, 128.06, 127.07, 125.67, 102.33, 89.52, 68.35, 31.33,
28.63, 28.57, 22.60, 18.93, 14.10 ppm; IR (KBr neat): ΰ = 2925, 1699,
1463, 1195, 1064, 811, 759 cm-1; HRMS (ESI+) calculated for
C25H28ClN2O [M+H]+ 407.1907, found 407.1887.
Acknowledgements
We thank the Department of Science and Technology (DST)
India grant no: DST-SB/EMEQ-257/2014 and CSIR, New Delhi
for financial support. We also thank Dr. S. Chandrasekhar,
Director CSIR-IICT for his support. Y. T. thanks to CSIR for his
senior research fellowship. D. P and G. S thanks to UGC for
their senior research fellowship and AcSIR. C. E. R thanks to
DST-Inspire fellowship and AcSIR. Manuscript communication
number: IICT/pubs.2019/320.
Genaeral procedure for synthesis of 7-Benzyl-2, 6-diphenyl-4H-
pyrazolo [5,1-c][1,4]oxazines: (3a-3d).
To a 10 mL round-bottomed flask equipped with magnetic stir bar the
substrate
5-(((1,3-Diphenylprop-2-yn-1-yl)oxy)methyl)-3-phenyl-1H-
pyrazole 1a (100 mg, 0.27 mmol, 1 equiv.) was taken and dissolved in
DMF (3 mL). To this reaction mixture sodium hydride (29 mg, 1.2 equiv.)
was added and stirred at 0 °C for 1 hour under nitrogen atmosphere.
Progress of the reaction was monitored by 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 silicagel using hexane and
ethyl acetate as eluent (10:1.2) to give product 7-benzyl-2,6-diphenyl-4H-
pyrazolo[5,1-c][1,4]oxazines 3a (67%). A similar procedure was followed
for the synthesis of all substituted pyrazolo-oxazine derivatives (3b-3d).
Keywords:
gold-catalysis,
7-endo
dig
cyclization,
pyrazolo[1,4]oxazepines, C-N bond formation.
Notes and references
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7-Benzyl-2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]oxazine (3a)
7
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Entry for the Table of Contents
Table of Contents
Key Topic* gold-catalysis, 7-endo dig cyclization,
pyrazolo[1,4]oxazepines, C-N bond formation.
Yadagiri Thummala,[a,b] Chittala Emmaniel
[a,b]
Raju,
Dalovai Purnachander,[a,b] Gottam
[a,b]
Sreenivasulu,
Venkata Ramana Doddi,[c]
and Galla V. Karunakar*[a,b]
Page No. – Page No.
Title: Gold-catalyzed regioselective
synthesis of pyrazolo[1,4]oxazepines
via
intramolecular
7-endo-dig
cyclization.
9
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