[Omim]Cl/FeCl3-catalyzed cross-dehydrogenative-coupling of 1,4-benzoxazinones with various indoles

Article abstract of DOI:10.1007/s13738-020-01941-y

A novel C(sp³)–C(sp²) cross-dehydrogenative-coupling procedure was developed for the reaction of benzoxazin-2-ones with indole derivatives. Thus, ionic liquid-mediated coupling of 1,4-benzoxazinone derivatives with indoles were observed in which [Omim]Cl/FeCl₃ acted as both the solvent and the catalyst. Under [Omim]Cl/FeCl₃-TBHP conditions, derivatives of 1 coupled at room temperature with indoles bearing various substituents to give the target products in good yields and within 0.5–2?h time period. The procedure is relatively environmentally friendly and is applicable to several derivatives of both reactants to access the desired products.

Full text of DOI:10.1007/s13738-020-01941-y

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01941-y
ORIGINAL PAPER
[Omim]Cl/FeCl3‑catalyzed cross‑dehydrogenative‑coupling
of 1,4‑benzoxazinones with various indoles
Ali Sharif1 · Maryam Moazami1 · M. Saeed Abaee1 · Mojtaba Mirzaei1
Received: 30 October 2019 / Accepted: 22 April 2020
© Iranian Chemical Society 2020
Abstract
A novel C(sp3)–C(sp2) cross-dehydrogenative-coupling procedure was developed for the reaction of benzoxazin-2-ones
with indole derivatives. Thus, ionic liquid-mediated coupling of 1,4-benzoxazinone derivatives with indoles were observed
in which [Omim]Cl/FeCl3 acted as both the solvent and the catalyst. Under [Omim]Cl/FeCl3-TBHP conditions, derivatives
of 1 coupled at room temperature with indoles bearing various substituents to give the target products in good yields and
within 0.5–2 h time period. The procedure is relatively environmentally friendly and is applicable to several derivatives of
both reactants to access the desired products.
Keywords Ionic liquids · CDC reactions · Benzoxazinones · Heterocycles
Introduction
the desired fnal structures is facilitated [15–17]. As a conse-
quence of this strategy, several natural products and biologi-
cally active compounds have been synthesized so far [18].
Many biologically active compounds are known which
have 1,4-benzoxazinone skeleton in their structure [19–22].
1,4-Benzoxazinone are also synthetically manipulated to
access more complex molecules with desired pharmaceuti-
cal properties [18, 23]. Some related illustrative examples
are presented in Fig. 1. These chemical transformations are
usually performed through derivatization of the carbon atom
next to the amine functional group in the benzoxazinone
ring. Despite the efciency of this method, only a few related
studies are carried out so far. Two recent investigations are
the oxidative cross-dehydrogenative-coupling by Zhang
[24] and the iron-catalyzed oxidative carbon–hydrogen
bond functionalization by Huo [18]. Although these stud-
ies provided new methods for the synthesis of 3,4-dihydro-
1,4-benzoxazin-2-one derivatives, there is still demands for
the development of sustainable methods capable of function-
alizing C–H bonds of benzoxazinone rings.
Carbon–carbon (C–C) and carbon–heteroatom (C–X) bond
formations are of fundamental reactions and are among the
most important processes in synthetic organic chemistry to
quickly build up complex molecules from simpler reactants
[1]. In this context, direct coupling of C–H bonds with other
C–H or X–H bonds via cross-dehydrogenative-coupling
(CDC) reactions provides a useful route to form C–C or
C–X bonds to construct various target molecules, where X
would be heteroatoms such as oxygen, sulfur or nitrogen
[2–6]. A major advantage achieved by direct CDC reactions
is that the introductory steps for the preparation of reactants
containing carbon-leaving groups and carbon–metal bonds
are avoided [7–10]. In addition, CDC reactions are very use-
ful methods for oxidation of amines [11–14]. This is because
the undesired in situ oxidation of the starting amines to their
respective iminium ions is avoided. Therefore, addition of
nucleophiles of choice to the intermediate iminium to access
In the framework of increasing worldwide demands for
more severe environmental protection, ionic liquids (IL’s)
have been introduced in recent decades as useful surrogates
for traditional solvents in various chemical processes. This is
because IL’s have higher thermal stability, much low vapor
pressure, increased tendency to dissolve various reactants
and reagents and higher shelf lives [25–29]. One particular
application is furnished by altering the cationic or anionic
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-01941-y) contains
supplementary material, which is available to authorized users.
* Ali Sharif
sharif@ccerci.ac.ir
1
Faculty of Organic Chemistry and Natural Products,
Chemistry and Chemical Engineering Research Center
of Iran, Pajohesh Blvrd., Tehran 1496813151, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Fig. 1 Examples of important 1,4-benzoxazinone structures
components of IL’s to access improved selectivity and reac-
tivity in various synthetic transformations [30–33]. This is
practically feasible by tailoring IL’s with desired physical
and chemical characteristics [34, 35].
spectrometer, and absorptions are reported as wave num-
bers (cm−1). 1H NMR (500 MHz) and 13C NMR (125 MHz)
spectra were obtained on a FT-NMR Bruker Ultra Shield™
instrument as CDCl3 solutions, and the chemical shifts are
expressed as δ units with Me4Si as the internal standard.
Mass spectra were obtained on a Finnigan Mat 8430 appa-
ratus at ionization potential of 70 eV. Elemental analyses
were performed using a Thermo Finnigan Flash EA 1112
instrument. Reagents and starting materials were purchased
from commercial sources and were freshly used after being
purifed by standard procedures. The identities of the known
products were confrmed by the comparison of their melting
Based on our previous studies on the development of
environmentally friendly procedures [36–39], here we report
a convenient procedure for IL-mediated coupling of 1,4-ben-
zoxazinone 1 with 1H-indole derivatives 2 in the presence
of [Omim]Cl/FeCl3. The ionic liquid acts as both the solvent
and the catalyst of the process (Scheme 1). The procedure
presents a one-pot reaction which is mild and takes place at
room temperature and incorporates various derivatives of
the reactants.
1
points and their H NMR data with those reported in the
literature [18]. New products were characterized by their 1H
NMR, 13C NMR, IR, and mass spectra, and their purity were
confrmed by elemental analyses.
Experimental
General
Typical procedure for the synthesis of derivatives
of 1 [40]
Reactions were monitored by TLC using silica gel-coated
plates and EtOAc/hexanes solutions as the mobile phase.
Melting points are uncorrected. FT-IR spectra were
recorded using KBr disks on a Bruker Vector-22 infrared
2-Aminophenol (2.2 gr, 20 mmol) and KF (2.9 gr, 50 mmol)
were dissolved in dry DMF (100 mL). To this mixture was
added ethyl 2-bromoacetate (2.2 mL, 20 mmol), and the
Scheme 1 General reaction for the synthesis of 1,4-benzoxazinones
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Journal of the Iranian Chemical Society
mixture was stirred for 6 h at 60 °C. Then, the volatiles
of the mixture were removed under reduced pressure and
the residue was extracted by EtOAc (100 mL). The extract
was washed by water (40 mL), dried over Na2SO4 and the
volatile portion was removed under reduced pressure. The
intermediate was fractionated by column chromatography
using EtOAc/hexanes (1/10) as the eluent. Next, a mixture
of the intermediate (1.95 gr, 10 mmol), glacial MeCO2H
(0.9 mL, 15 mmol), and benzaldehyde (1.2 mL, 12 mmol)
in CH2Cl2 (50 mL) was cooled in an ice bath for 30 min. To
this mixture was added NaBH(OAc)3 (3.18 gr, 15 mmol) and
the mixture was stirred for 24 h. The mixture was washed
with water (40 mL) and extracted with CH2Cl2 (60 mL). The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was fractionated by column
chromatography using EtOAc/hexanes (1/10) as the eluent
to obtain 1a (1.56 gr, 65%).
4‑Benzyl‑3‑(5‑bromo‑1‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3c)
1
White solid in 75% yield; mp 192–194 °C; H NMR
(500 MHz, CDCl3) δ 7.53 (s, 1H), 7.32–7.42 (m, 3H),
7.32–7.25 (m, 3H), 7.15 (d, J = 8.0 Hz, 1H), 7.10 (t,
J=7.0 Hz, 2H), 6.96 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz,
1H), 6.58 (s, 1H), 6.30 (s, 1H), 4.62 (d, J = 14.5 Hz, 1H),
4.07 (d, J=14.5 Hz, 1H), 3.61 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 164.3, 141.8, 135.8, 135.3, 134.1, 128.9, 128.4,
128.3, 128.1, 127.9, 125.5, 125.3, 121.9, 120.1, 116.6,
114.1, 113.5, 110.9, 106.8, 55.3, 51.5, 33.1; MS (70 eV)
m/z (%) 446, 418, 327, 248, 221, 196, 91; IR (KBr, cm−1)
2859, 1756, 1371, 1239, 1198, 756. Anal. Calcd for
C24H19BrN2O2: C, 64.44; H, 4.28; N, 6.26. Found: C, 64.35;
H, 4.11; N, 6.05.
4‑Benzyl‑3‑(1‑benzyl‑5‑bromo‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3d)
Typical procedure for the synthesis of products 3
1
1H-Indole (2a, 0.14 gr, 1.2 mmol) was added to a mix-
ture of 1a (0.24 gr, 1.0 mmol) in [Omim]Cl/FeCl3 (0.4
gr, 1.0 mmol). tert-Butyl hydroperoxide (TBHP) (0.3 gr,
2.4 mmol) was added to this mixture, and it was stirred for
0.5 h at room temperature. The mixture was extracted with
EtOAc (10 mL), the extract was washed with water (15 mL)
and dried over Na2SO4, and the volatile portion was removed
under reduced pressure. The residue was fractionated by col-
umn chromatography using EtOAc/hexanes (1/10) as the
eluent to obtain 3a (0.32 gr, 93%).
White solid in 80% yield; mp 159–161 °C; H NMR
(500 MHz, CDCl3) δ 7.57 (d, J=1.5 Hz, 1H), 7.42–7.33 (m,
3H), 7.32–7.27 (m, 5H), 7.25 (dd, J=1.5, 9.0 Hz, 1H), 7.14
(dd, J=1.0, 7.9 Hz, 1H), 7.12–7.04 (m, 2H), 6.98–6.91 (m,
3H), 6.85 (d, J=8 Hz, 1H), 6.68 (s, 1H), 5.33 (s, 1H), 5.11
(s, 2H), 4.63 (d, J=14.5 Hz, 1H), 4.09 (d, J=14.5 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 164.4, 141.9, 136.2, 135.8,
134.9, 134.1, 128.9, 128.8, 128.6, 128.2, 128.1, 127.9,
127.8, 126.7, 125.5, 122.2, 120.3, 116.6, 114.2, 113.8,
111.6, 107.3, 55.4, 51.7, 50.4; MS (70 eV) m/z (%) 522,
496, 403, 325, 298, 196; IR (KBr, cm−1) 3062, 1760, 1499,
1452, 1203, 1160, 742. Anal. Calcd for C30H23BrN2O2: C,
68.84; H, 4.43; N, 5.35. Found: C, 68.98; H, 4.21; N, 5.30.
Structural data of products 3
4‑Benzyl‑3‑(1H‑indol‑3‑yl)‑3,4‑dihydro‑2H‑benzo[b][1,4]
oxazin‑2‑one (3a) [18]
4‑Benzyl‑3‑(6‑chloro‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3e) [18]
1
Yellow solids in 93% yield; mp 63–66 °C; H NMR
(500 MHz, CDCl3) δ 8.15 (s, 1H), 7.51 (d, J = 8.0 Hz,
1H), 7.39–7.25 (m, 6H), 7.21 (t, J = 7.0 Hz, 1H), 7.13 (t,
J=7.5 Hz, 2H), 7.08 (t, J=7.5 Hz, 1H), 6.92 (t, J=7.5 Hz,
1H), 6.83 (d, J=8.0 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 5.41
(s, 1H), 4.62 (d, J=15.0 Hz, 1H), 4.16 (d, J=15.0 Hz, 1H).
White solid in 78% yield; mp 40–42 °C; 1H NMR
(500 MHz, CDCl3) δ 8.28 (s, 1H), 7.45–7.32 (m, 4H),
7.29 (s, 3H), 7.18–7.04 (m, 3H), 6.95 (t, J = 7.5 Hz, 1H),
6.87 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 5.36 (s, 1H), 4.64 (d,
J=15.0 Hz, 1H), 4.11 (d, J=15.0 Hz, 1H).
4‑Benzyl‑3‑(5‑bromo‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3b) [18]
4‑Benzyl‑3‑(5‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3f) [18]
1
Yellow solid in 68% yield; mp 152–154 °C; H NMR
White solid in 75% yield; mp 69–71 °C; 1H NMR (500 MHz,
CDCl3) δ 8.04 (s, 1H), 7.42–7.28 (m, 5H), 7.27 (s, 1H),
7.22 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.10 (t,
J=7.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.95 (t, J=7.0 Hz,
1H), 6.85 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 5.4 (s, 1H), 4.63
(d, J=15.0 Hz, 1H), 4.15 (d, J=15.0 Hz, 1H), 2.43 (s, 3H).
(500 MHz, CDCl3) δ 8.21 (s, 1H), 7.56 (s, 1H), 7.41–7.24
(m, 6H), 7.18 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H),
7.10 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.86
(d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 5.31 (s, 1H), 4.63 (d,
J=14.5 Hz, 1H), 4.07 (d, J=14.5 Hz, 1H).
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Journal of the Iranian Chemical Society
4‑Benzyl‑3‑(2‑phenyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3 g) [18]
4‑Benzyl‑3‑(1‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3i) [18]
1
White solid in 70% yield; mp 86–87 °C; 1H NMR
(500 MHz, CDCl3) δ 8.2 (s, 1H), 7.52 (s, 2H), 7.44–7.32
(m, 4H), 7.25–7.16 (m, 3H), 7.15–7.07 (m, 3H), 7.07–6.99
(m, 2H), 6.99–6.93 (m, 2H), 6.92–6.85 (m, 1H), 6.72 (d,
J=8.0 Hz, 1H), 5.6 (s, 1H), 4.45 (d, J=16.0 Hz, 1H), 3.90
(d, J = 16.0 Hz, 1H).
White solid in 84% yield; mp 194–195 °C; H NMR
(500 MHz, CDCl3) δ 7.53 (d, J = 8 Hz, 1H), 7.42–7.32
(m, 5H), 7.32–7.26 (m, 2H), 7.21–7.14 (m, 2H), 7.11
(t, J = 8.0 Hz, 1H), 6.96 (t, J = 7.0 Hz, 1H), 6.86 (d,
J = 8.0 Hz, 1H), 6.63 (s, 1H), 5.45 (s, 1H), 4.65 (d,
J = 15.0 Hz, 1H), 4.19 (d, J = 15.0 Hz, 1H), 3.65 (s, 3H).
4‑Benzyl‑3‑(2‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3 h) [18]
4‑Benzyl‑3‑(1‑benzyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3j) [18]
1
1
Yellow solid in 85% yield; mp 194–197 °C; H NMR
Yellow solid in 93% yield; mp 146–148 °C; H NMR
(500 MHz, CDCl3) δ 8.07 (s, 1H), 7.33–7.24 (m, 3H),
7.18 (dd, J = 31.0, 8.0 Hz, 4H), 7.13–7.07 (m, 3H), 6.98
(t, J = 7.0 Hz, 1H), 6.92 (t, J = 7.0 Hz, 1H), 6.82 (d,
J = 8.0 Hz, 1H), 5.36 (s, 1H), 4.60 (d, J = 16.0 Hz, 1H),
3.98 (d, J = 16.0 Hz, 1H), 1.90 (s, 3H).
(500 MHz, CDCl3) δ 7.51 (d, J = 8.0, 1H), 7.40–7.33 (m,
3H), 7.33–7.26 (m, 5H), 7.26–7.18 (m, 2H), 7.14 (m,
2H), 7.07 (t, J = 8.0 Hz, 1H), 6.97–6.95 (m, 2H) 6.92 (t,
J=7.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 5.43
(s, 1H), 5.17 (s, 2H), 4.62 (d, J = 15.0 Hz, 1H), 4.18 (d,
J = 15.0 Hz, 1H).
4‑Benzyl‑3‑(1,2‑dimethyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3 k) [18]
Table 1 Optimization of the conditions for the synthesis of 3a
Entry Solvent
Conditions
Time (h) Yield (%)a,b
1
Brown solid in 79% yield; mp 197–199 °C; H NMR
1
2
3
4
[Omim]Cl/FeCl3 TBHP
0.5
0.5
0.5
0.5
93
0
45
50
(500 MHz, CDCl3) δ 7.34–7.24 (m, 4H), 7.23–7.15 (m,
4H), 7.14 (d, J = 8.0 Hz, 1H), 7.11–7.05 (m, 1H), 7 (t,
J = 7.0 Hz, 1H), 6.94–6.88 (m, 1H), 6.81 (d, J = 8.0 Hz,
1H), 5.42 (s, 1H), 4.6 (d, J = 16.0 Hz, 1H), 4.02 (d,
J = 16.0 Hz, 1H), 3.66 (s, 3H), 2.15 (s, 3H).
–
TBHP
TBHP/FeCl3
MeCN
MeCN
TBHP/
FeCl2.4H2O
5
6
7
8
MeCN
TBHP
0.5
0.5
0.5
0.5
0
55
0
[Omim]Cl/FeCl2 TBHP
4‑Benzyl‑3‑(1‑benzyl‑2‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3l)
–
–
TBHP/FeCl3
TBHP/
0
FeCl2.4H2O
1
White solid in 85% yield; mp 167–169 °C; H NMR
9
10
[Omim]PF6
[Omim]PF6
TBHP
0.5
0.5
0
65
(500 MHz, CDCl3) 7.43–7.19 (m, 9H), δ 7.19–7.08 (m,
4H), 7.07–7.01 (m, 1H), 7.01–6.92 (m, 3H), 6.89 (d,
J = 8.0 Hz, 1H), 5.43 (s, 1H), 5.34 (d, J = 17.0 Hz, 1H),
5.23 (d, J=17.0 Hz, 1H), 4.69 (d, J=16.0 Hz, 1H), 4.04 (d,
J=16.0 Hz, 1H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 166.1, 140.8, 137.5, 137.2, 136.9, 136.7, 134.9, 128.9,
128.8, 127.6, 127.4, 126.1, 125.7, 121.8, 120.4, 119.2,
118.9, 117.2, 113.4, 109.6, 106.3, 56.1, 50.1, 46.7, 10.3;
MS (70 eV) m/z (%) 458, 430, 339, 261, 237, 221, 91, 65;
IR (KBr, cm−1) 3498, 3031, 1762, 1603, 1494, 1021, 747.
Anal. Calcd for C31H26N2O2: C, 81.20; H, 5.72; N, 6.11.
Found: C, 81.39; H, 5.57; N, 6.22.
TBHP/
FeCl2.4H2O
11
12
13
14
15
16
[Omim]PF6
TBHP/FeCl3
0.5
0.5
0.5
0.5
0.5
0.5
70
15
50
60
62
70
[Omim]Cl/CuCl2 TBHP
[Omim]Cl/AlCl3 TBHP
[Emim]Cl/FeCl3 TBHP
[Bmim]Cl/FeCl3 TBHP
[C10mim]Cl/
TBHP
FeCl3
17
[C12mim]Cl/
FeCl3
TBHP
0.5
72
18
19
20
[Omim]Cl/FeCl3 O2
[Omim]Cl/FeCl3 H2O2
[Omim]Cl/FeCl3 (NH4)2S2O8
0.5
0.5
0.5
5
35
5
aIsolated yields
bRoom temperature
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Journal of the Iranian Chemical Society
Fig. 2 Efect of the concentra-
tion of the IL (dotted bar) and
the oxidant (solid bar) on the
synthesis of 3a (after 0.5 h reac-
tion time)
4‑Benzyl‑3‑(1H‑indol‑3‑yl)‑7‑methyl‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3m) [18]
4‑Benzyl‑7‑methyl‑3‑(2‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3o)
1
1
Orang solid in 70% yield; mp 174–175 °C; H NMR
(500 MHz, CDCl3) δ 8.12 (s, 1H), 7.54 (d, J=8.0 Hz, 1H),
7.38–7.30 (m, 6H), 7.16 (t, J = 7.0 Hz, 1H), 6.96 (s, 1H),
6.89 (d, J=8.0 Hz, 1H), 6.76–6.71 (m, 2H), 5.40 (s, 1H),
4.58 (d, J = 15.0 Hz, 1H), 4.15 (d, J = 15.0 Hz, 1H), 2.35
(s, 3H).
White solid in 69% yield; mp 185–187 °C; H NMR
(500 MHz, CDCl3) δ 7.96 (s, 1H), 7.30–7.22 (m, 4H),
7.17–7.08 (m, 4H), 7.03–6.96 (m, 2H), 6.8 (d, J =8.0 Hz,
1H), 6.7 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 4.57 (d,
J = 16.0 Hz, 1H), 3.97 (d, J = 16.0 Hz, 1H), 2.35 (s, 3H),
2.06(s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.3, 140.6,
136.9, 135.4, 135.2, 132.3, 129.1, 128.6, 127.2, 126.7, 125.9,
121.7, 120.2, 118.8, 117.5, 117.4, 113.3, 110.5, 106.1, 55.9,
50.1, 20.5, 11.7; MS (70 eV) m/z (%) 382, 354, 263, 171,
130, 91; IR (KBr, cm−1) 3386, 3058, 1741, 1254, 737. Anal.
Calcd for C25H22N2O2: C, 78.51; H, 5.80; N, 7.32. Found:
C, 78.52; H, 5.75; N, 7.49.
4‑Benzyl‑7‑methyl‑3‑(1‑methyl‑1H‑indol‑3‑yl)‑3,4‑dihy‑
dro‑2H‑benzo[b][1,4]oxazin‑2‑one (3n)
1
White solid in 90% yield; mp 214–216 °C; H NMR
(500 MHz, CDCl3) 7.52 (d, J = 8.0 Hz, 1H), δ 7.38–7.24
(m, 7H), 7.17–7.12 (m, 1H), 6.97 (s, 1H), 6.89 (d, J=8.0 Hz,
1H), 6.71 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 5.39 (s, 1H), 4.57
(d, J=15.0 Hz, 1H), 4.1 (d, J=15.0 Hz, 1H), 3.64 (s, 3H),
2.35 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.7, 140.9,
135.7, 135.5, 130.7, 128.8, 127.8, 126.8, 126.7, 126.2,
125.9, 124.7, 121.3, 118.9, 118.3, 116.1, 112.9, 108.4,
106.2, 55.1, 50.8, 31.9, 19.6; MS (70 eV) m/z (%) 382, 354,
263, 171, 143, 91; IR (KBr, cm−1) 3046, 1757, 1513, 1448,
1227, 1153, 739. Anal. Calcd for C25H22N2O2: C, 78.51; H,
5.80; N, 7.32. Found: C, 78.48; H, 5.70; N, 7.43.
Results and discussion
We first optimized the reaction of 1a (R1 = H) with 2a
(R2 =R3 =R4 =H) under various conditions (Table 1). The
best results were obtained when a 1.0:1.2:2.4 mixture of
1a, 2a and TBHP was dissolved in [Omim]Cl/FeCl3 and
stirred at room temperature to obtain 3a in 93% yield after
0.5 h (entry 1). Conducting the reaction in the absence of
an IL and a catalyst (entry 2) gave no product and reactants
remained intact. Lower yields of 3a were obtained when
the conditions reported by Huo et al. [18] were simulated
(entries 3–4). Moreover, catalyst-free reaction in MeCN
(entry 5) gave no product proving the need for either a
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Journal of the Iranian Chemical Society
Table 2 Synthesis of various derivatives of 3
Entry
1
Reactants
Product
T (oC)
25
Time (h)
0.5
Yield (%)a
93
1a (R1 =H)
2a (R2 =R3 =R4 =H)
2
3
1a (R1 =H)
25
25
1.5
1.5
68
75
2b (R2 =R4 =H, R3 =Br)
1a (R1 =H)
2c (R2 =Me. R3 =Br, R4 =H)
4
1a (R1 =H)
25
1
80
2d (R2 =CH2Ph, R3 =Br, R4 =H)
5
6
7
1a (R1 =H)
25
25
25
1
78
75
70
2e (R2 =R4 =H, R3 =Cl)
1a (R1 =H)
0.5
1.5
2f (R2 =R4 =H, R3 =Me)
1a (R1 =H)
2 g (R2 =R3 =H, R4 =Ph)
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Journal of the Iranian Chemical Society
Table 2 (continued)
Entry
8
Reactants
Product
T (oC)
25
Time (h)
1
Yield (%)a
85
1a (R1 =H)
2 h (R2 =R3 =H, R4 =Me)
9
1a (R1 =H)
25
25
1
1
84
93
2i (R3 =R4 =H, R2 =Me)
10
1a (R1 =H)
2j (R3 =R4 =H, R2 =CH2Ph)
11
12
13
14
1a (R1 =H)
25
25
25
25
1.5
79
85
70
90
2 k (R2 =R4 =Me, R3 =H)
1a (R1 =H)
1
2 l (R2 =CH2Ph, R3 =H, R4 =Me)
1b (R1 =Me)
2
2a (R2 =R3 =R4 =H)
1b (R1 =Me)
1.5
2i (R3 =R4 =H, R2 =Me)
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Journal of the Iranian Chemical Society
Table 2 (continued)
Entry
15
Reactants
Product
T (oC)
25
Time (h)
2
Yield (%)a
69
1b (R1 =Me)
2 h (R2 =R3 =H, R4 =Me)
aIsolated yields
Fig. 3 A plausible mechanism for the reaction
Table 3 Comparison of the
Catalyst
Additive
Solvent
Oxidant Conditions
T (h) Yield %
10 75 [41]
present work (synthesis of 3a)
with recent related procedures
Zn(OTf)2
9,10-Phenan- MeCN
threnequi-
–
White LED
none
Ru(bpy)3Cl2
FeCl2
–
–
–
–
MeCN
MeCN
[Omim]Cl/FeCl3 TBHP
–
Fluorescent bulb 10
5024
6518
93 (This work)
TBHP
–
–
1
0.5
catalyst or an IL so that the reaction can proceed. Conduct-
ing the reaction in [Omim]Cl/FeCl2 led to 55% formation
of 3a, implying that the Fe(III)-containing IL has a better
catalytic efect on the process (entry 6). Alternatively, when
either FeCl3 (entry 7) or FeCl2∙4H2O (entry 8) was used
instead of an IL, no 3a was formed to further illustrate the
catalytic efect of the IL on the process.
(entry 11). Alternatively, [Omim]Cl/CuCl2 (entry 12) or
[Omim]Cl/AlCl3 (entry 13) gave 3a in lower yields, support-
ing that FeCl4− ([Cl/FeCl3]−) ion causes better conversion of
the reactants to the product. Finally, change of the cationic
part of the IL proved that [Omim] has a better performance
on the progress of the reaction (entries 14–17). In addition,
the role of the oxidizing agent was studied, where TBHP
showed by far a much better efect on the coupling process
(entries 18–20).
These results convinced us that [Omim]Cl/FeCl3 behaves
as both a dissolving medium and a catalyst for the reaction.
Therefore, we decided to use other catalytic systems to fur-
ther evaluate the role of counter ions. While [Omim]PF6
alone caused no reaction (entry 9), [Omim]PF6-FeCl2∙4H2O
(entry 10) or [Omim]PF6-FeCl3 improved the outcome
Next, we investigated the efect of the concentration of
both the IL and the oxidant on the progress of the model
reaction (Fig. 2). For the IL, the yield of 3a increased as the
amount of the IL reached to 1.00 equivalent and remained
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Journal of the Iranian Chemical Society
unchanged at a higher concentration (dotted bar). Simi-
lar trend was observed for the amount of TBHP until 2.4
equivalents of the oxidant were used and the yield dropped
to lower amounts for higher concentrations of TBHP (solid
bar). It should be noted that the reaction can be performed
with equimolar amounts of TBHP as well. However, it takes
longer time (more than 3 h) to reach to about 80% yield.
We then evaluated the generality of the reaction by
coupling various derivatives of the two reactants 1 and 2
under the optimized conditions (Table 2). Therefore, reac-
tion of 1a with the parent 1H-indole derivative 2a (entry
1) or other derivatives of 2 bearing electron withdrawing
or electron donating groups with diferent substitution pat-
terns gave the desired products 3a–3l in high yields within
0.5–2 h mixing at room temperature (entries 1–12). Similar
results were observed when a methyl substituted derivative
of 1 was reacted with derivatives of 2 to get products 3m–o
(entries 13–15). The structure of the products was elucidated
comparison of the present work with other recent related
studies is summarized in Table 3.
Acknowledgements CCERCI is gratefully acknowledged for fnancial
support of this work.
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