Copper-catalyzed aerobic oxidative intramolecular amidation of 2-aminophenylacetylenes: A domino process for the synthesis of isatin

Article abstract of DOI:10.1039/c7nj02441j

A novel CuI-catalyzed oxidative amidation of 2-aminophenylacetylenes leading to the formation of isatins by using open air as an oxygen source has been developed. The reaction proceeded smoothly and provided a variety of isatin derivatives in good yields. The advantages of this one-pot reaction protocol include the use of a green oxidant, low-price catalyst and facile conditions, and easy handling.

Full text of DOI:10.1039/c7nj02441j

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Copper-catalyzed aerobic oxidative intramolecular amidation of 2-
aminophenylacetylenes: A domino process for the synthesis of
isatin
†
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
c
b
DOI: 10.1039/x0xx00000x
N. Salvanna *, Perla Ramesh , K. Santosh Kumar , Biswanath Das *
www.rsc.org/
A
novel
CuI-catalyzed
oxidative
amidation
of
2- oxidizing agents among which molecular oxygen is most
aminophenylacetylenes leading to the formation of isatins by preferable due to its inexhaustible and environmentally benign
5
using open air as an oxygen source has been developed. The features as well as it is inexpensive. From the viewpoint of
2
reaction proceeded smoothly and provided a variety of isatin sustainable and green chemistry, copper/O catalytic system is
derivatives in good yields. The advantages of this one-pot reaction considered as an ideal choice for many synthetic
protocol include the green oxidant, low-price catalyst, facile transformations since molecular oxygen act as a source of
conditions and easy handling.
oxygen atoms for the construction of oxygen containing
6
bioactive molecules. Therefore, the synthesis of bioactive
heterocyclic systems under aerobic conditions using copper
salts as catalysts is an emerging field of synthetic organic
chemistry in respect of ecological as well as economical points
of view.
Introduction
Heterocyclic compounds are of great importance as
pharmaceuticals,natural products, agrochemicals,materials
1
and as building blocks in organic synthesis. In fact, these
Isatin (Indoline-2,3-dione) is a privileged core structural motif
found in numerous bioactive natural products, synthetic
compounds have occupied central stage of organic
chemistry.Among the myriad of metal-catalyzed synthetic
transformations, domino reaction is defined as a powerful
synthetic tool for the preparation of heterocyclic systems,
since they can directly construct complex molecules in a one-
7
molecules and pharmaceutical drugs (Figure 1) that display a
8
wide range of pharmaceutical properties such as anti-HIV,
9
antimalarial, antibacterial, anticancer, antifungal, anti-
10
11
12
1
3
14
2
inflammatory and anticonvulsant. Isatins have been widely
used as powerful building blocks for the construction of
biologically active heterocyclic systems and spirocyclic
pot operation from readily available precursors. Particularly,
the domino reactions catalyzed by transition-metal have
become a hotspot of the research during the last few decades,
for their ability to milder the reaction conditions, shorten
15
compounds.
3
reaction procedures, and reduce wastes. Among transition
metals, copper-catalyzed reactions have indisputable
advantages as they are of great catalytic potential in
numerous synthetic transformations and are inexpensive, low
O
O
HO
N
S
H
OH
O
Cl
Cl
HO
O
4
N
toxic, easy to handle and environmentally benign. On the
N
other hand, several reagents such as peroxides (TBHP, DTBP,
N
OMe
N
HO
H
2 2 2 2
H O , mCPBA), PhI(OAc) , O , etc. are used as common
O
H2N
YK-4-279
HO
Arundaphine
HO
Tenidap
O
O
Br
S
HO
O
O
O
N
N
N
H
Br
H
Me
Anti-HIV
Convolutamydine A
Anticonvulsant agent
Fig. 1Representative biologically active isatin molecules.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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COMMUNICATION
Journal Name
Previously, several reports have been documented for the conditions, providing the desired product 5-methoxy-1-
1
6
synthesis of isatins, however, most of these existing methods methylindoline-2,3-dione (2a) in 82% yield (Table 1, entry 9).
are still inadequate due to some flaws, such as use of
peroxides as oxidants, harsh reaction conditions, poor atom-
efficiency, longer reaction time, use of hazardous reagents,
and generation of a waste that not only reduce process
efficiency but also raises problems to the environment.
Because of the ubiquitous presence of the isatins in
biologically active synthetic and natural compounds and of
their extensive applications as important synthetic
a
Table 1. Optimization of Reaction Conditions
intermediates, development of
a
simple, efficient,
Entry Catalyst
Base
Solvent Yield
b
environment friendly and promising method to access isatins is
highly desirable and in great demand. In this context,herein,
we report a domino process for the preparation of isatins from
(%)
1
2
3
4
5
6
7
8
CuI (20 mol%)
CS CO
2
DMF
NR
35
NR
25
20
55
50
65
3
3
3
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CS CO
2
DMSO
Xylene
DMSO
DMSO
DMSO
DMSO
DMSO
2-aminophenylacetylenes using a CuI as the catalyst under
CS CO
2
aerobic conditions via oxidative amidation.
t
LiO Bu
t
KO Bu
DIPEA
Results and discussion
TEA
At the outset, 2-ethynyl-4-methoxy-N-methylaniline (1a) was
selected as the model substrate to optimize the reaction
conditions using differentcatalysts, reaction solvents,
additives, and the loadings of the catalyst. The results are
summarized in Table 1. Initially, we started our investigations
by testing various solvents with 20 mol% CuI as a catalyst and
2,6
Lutidine
Pyridine
Pyridine
Pyridine
Pyridine
9
CuI (20 mol%)
CuI (10 mol%)
CuI (5 mol%)
DMSO
DMSO
DMSO
82
60
50
1
0
1
2
1
1
Cu(CH
3
CN)
4
.BF
4
DMSO 57
3
1.5 equiv. CsCO as a base at 120 °C under an air atmosphere
(
20 mol%)
for 16 h. We have obtained the desired product 2a in 35%
yield using dimethyl sulfoxide (DMSO) as the most suitable
solvent (Table 1, entry 2). A series of additives (bases) were
then investigated, which revealed that pyridine was the best
1
1
1
1
3
4
5
6
CuCl (20 mol%)
CuO (20 mol%)
Pyridine
Pyridine
Pyridine
Pyridine
DMSO
DMSO
DMSO
NR
NR
NR
Cu
Cu(OTf)
20 mol%)
2
O (20 mol%)
2
DMSO Trace
t
t
for the yield of 2a (82% yield) as compared to LiO Bu, KO Bu,
DIPEA, TEA and 2,6 Lutidine (Table1, entries 4-9). When the
copper catalyst loading was reduced to 10 mol% or 5 mol%,
the yield of the product 2a decreased (Table1, entries 10, 11).
In addition, when the reaction was carried out in the presence
(
17
18
19
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
CuI (20 mol%)
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
DMF
NR
Xylene
Trace
Toluene NR
Toluene 36
Toluene NR
Toluene 42
Toluene 82
c
2
0
d
e
f
Cu(CH
0% yield (Table 1, entry 12). Other copper salts, including
CuCl, CuO, Cu O and Cu(OTf) (Table 1, entries 13-16) were
3 4 4
CN) .BF catalyst the desired product 2a was obtained in
2
2
1
2
5
2
2
2
3
a
probed as catalysts, and showed no catalytic activity in this
reaction. Similarly, in the absence of Cu-catalyst, no product
was observed and the starting material was recovered.
Notably, by fixing CuI (20 mol%) as catalyst and pyridine (1.5
equiv.) as an additive, different solvents like DMF, xylene and
toluene were also screened, and no product was observed
Reaction conditions: Unless otherwise mentioned, all
reactions were carried out using 2-ethynyl-4-methoxy-N-
methylaniline 1a(0.5 mmol), base (1.5 equiv) and copper
catalyst (20 mol %) in 3 mL solvent at 120 °C for 16 h under
open atmosphere.
b
Isolated yields.
c
(Table 1, entries 17-19). When the reaction was carried out
O
2
balloon.
d
using O as oxidative agent instead of open air condition, the
2
Under N atmosphere.
2
o
Reaction at 40 C.
e
f
isolated yield of the product 2a decreased to 36% (Table 1,
entry 20). Moreover, switching to nitrogen atmosphere led to
the no formation of product (Table 1, entry 21). Finally, the
reaction period and the temperature effect on the reaction
were also examined. The experimental results indicated that
longer reaction time and raising of the temperature (150 °C) or
lowering of the temperature (40 °C) were not beneficial to
improve the yield of the desired product 2a (Table 1, entries
o
Reaction at 150 C.
NR: No Reaction
After having established the optimum reaction conditions, we
next explored the substrate scope of the CuI-catalyzed aerobic
oxidative amidation reaction of 2-aminophenylacetylenes
(
Scheme 1). In general, different substituent groups such as
22-23). Therefore, the combination of substrate 1a (0.5 mmol),
OMe, F, Cl, and Br, on the aromatic ring, and various alkyl
CuI (20 mol %) and pyridine (1.5 equiv.) in DMSO under an air
atmosphere at 120 °C was chosen as the optimal reaction
substituent
groups
on
amine
group
of
2-
2
| J. Name., 2012, 00, 1-3
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NP lee wa s eJ od uo r nn oa tl aod fj uC s ht em ma ri sg it nr sy
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DOI: 10.1039/C7NJ02441J
Journal Name
COMMUNICATION
1
7
aminophenylacetylenewere well tolerated in the reactions and Based on the previous Cu-catalyzed reports
and the
provided corresponding isatin derivatives in good to excellent formation of isatin as the product, a plausible reaction
yields.
pathway for this domino reaction is proposed, as shown in
II
Scehem 2. Initially, Cu complex A was formed from the
substrate (1) through a radical addition of superoxide radical–
II
18
Cu intermediate,
oxidation of CuI by molecular oxygen. Further rearrangement
leads to the formation of intermediate . The O–O bond
cleavage of dioxetane intermediate could provide aryl
glyoxal , which further oxidized to final product through the
which intern could be generated via
Scheme 1.Copper-Catalyzed Aerobic Oxidative Amidation of 2-
a,b
Aminophenylacetylenes
B
B
C
2
formation of possible intermediate D.
O
R
O
H2O +
N
O2
2
R1
CuI
CuII
O
O
I
Cu / 1/2O2
R
NH
R1
O
1
R
OH
O
N
O
CuII
R1
D
O
Pyridine
R
A
O
NH
R1
R
NH
R1
O
C
O
CuI
R
NH
R1
B
Scheme 2. A Plausible Mechanism for the Copper-Catalyzed
Aerobic Oxidative Synthesis of Isatin.
Conclusions
In conclusion, we have successfully developed a facial one pot,
open air promoted oxidative amidation domino process for the
preparation of biologically important isatin derivatives in good
yields. The proposed method preceded using catalytic
amounts of an inexpensive CuI and atmospheric air as the
oxidizing agent, making this transformation practical and
sustainable.
Experimental Section:
General experimental procedure for the synthesis of isatins
from 2-aminophenylacetylenes: In a 10 mL round bottom
flask2-aminophenylacetylene
1 (0.5 mmol), pyridine (1.5
equiv), CuI (20 mol %), DMSO (3 mL)were taken. The reaction
mixture was stirred under refluxing conditions in open air for
a
Reaction conditions: 1 (0.5 mmol), pyridine (1.5 equiv), CuI
o
20 mol %), DMSO (3 mL), open air, 120 C, 16 h.
1
6 h. The progress of the reaction was monitored by TLC. After
(
b
the consumption of the starting materials, the reaction
mixture was allowed to cool, and subsequently extracted with
EtOAc (2x10 mL). The combined organic extracts were dried
Isolated yield.
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1
6g
over anhydrous Na
2 4
SO
. Concentration of the material in vacuo 1-Propylindoline-2,3-dione (2g): Red Solid, Yield: 81%, 77 mg;
o
followed by flash chromatography on silica gel column mp: 125-127 C; H NMR (400 MHz, CDCl
1
3
) δ 7.71 – 7.48 (m, 2H),
afforded isatin derivatives 2 in good yield.
7.18 – 7.05 (m, 1H), 6.91 (d, J = 7.9 Hz, 1H), 3.71 – 3.68 (m, 2H), 1.79
1
3
–
1.71 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl ) δ
3
Spectral Data:
183.68, 158.21, 151.10, 138.40, 125.38, 123.62, 117.53, 110.26,
+
4
1.80, 20.64, 11.36; ESIMS: m/z 212 [M+Na] ; Anal. Calcd for
1
6k
5-Methoxy-1-methylindoline-2,3-dione (2a): Red Solid, Yield:
C H NO : C, 69.83; H, 5.86; N, 7.40. Found: C, 69.68; H, 5.81; N,
1
1
11
2
o
1
3
82%, 78 mg; mp: 172-174 C; H NMR (400 MHz, CDCl ) δ 7.20 – 7.09
7
1
1
.37.
-Butylindoline-2,3-dione (2h): Red Solid, Yield: 72%, 77 mg; mp:
13
(m, 2H), 6.83 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H), 3.22 (s, 3H); C NMR
16g
(
100 MHz, CDCl ) δ 183.77, 158.34, 156.60, 145.33, 124.58, 117.83,
o
1
3
3
33-135 C; H NMR (400 MHz, CDCl ) δ 7.65 – 7.53 (m, 2H), 7.11 (t,
+
110.97, 109.68, 56.02, 26.28; ESIMS: m/z 214 [M+Na] ; Anal. Calcd
J = 7.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 7.4 Hz, 2H), 1.69
9 3
for C10H NO : C, 62.82; H, 4.75; N, 7.33. Found: C, 62.56; H, 4.69; N,
(
(
ddd, J = 15.1, 11.2, 7.6 Hz, 2H), 1.42 (dq, J = 14.8, 7.4 Hz, 2H), 0.97
7
5
8
2
1
.21.
13
t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ 183.79, 158.25,
-Methoxy-1-propylindoline-2,3-dione (2b): Red Solid,Yield: 78%,
1
1
51.05, 138.63, 125.36, 123.71, 117.46, 110.44, 40.04, 29.26, 20.12,
o
1
5 mg; mp: 178-181 C; H NMR (400 MHz, CDCl
3
) δ 7.19 – 7.08 (m,
+
3.68; ESIMS: m/z 204 [M+H] ; Anal. Calcd for C12
H13NO
2
: C, 70.92;
H), 6.89 – 6.73 (m, 1H), 3.81 (s, 3H), 3.65 (dd, J = 15.3, 7.9 Hz, 2H),
H, 6.45; N, 6.89. Found: C, 70.80; H, 6.48; N, 6.86.
1
3
.79 – 1.65 (m, 2H), 0.99 (dd, J = 9.5, 5.3 Hz, 3H); C NMR (100
1
-Pentylindoline-2,3-dione (2i): Red Solid, Yield: 70%, 76 mg;mp:
MHz, CDCl
11.26, 109.66, 55.94, 41.74, 20.62, 11.32; ESIMS: m/z 220 [M+H] ;
Anal. Calcd for C12 : C, 65.74; H, 5.98; N, 6.39. Found: C,
3
) δ 184.00, 158.23, 156.33, 144.87, 124.50, 117.90,
o
1
1
3
41-143 C; H NMR (400 MHz, CDCl ) δ 7.59 (ddd, J = 9.1, 5.8, 2.0
+
1
Hz, 2H), 7.18 – 7.05 (m, 1H), 6.90 (d, J = 7.9 Hz, 1H), 3.78 – 3.62 (m,
H), 1.76 – 1.65 (m, 2H), 1.41 – 1.33 (m, 4H), 0.94 – 0.86 (m, 3H);
H13NO
3
2
13
65.88; H, 6.01; N, 6.44.
3
C NMR (100 MHz, CDCl ) δ 183.68, 158.12, 151.04, 138.43, 125.31,
1
-Butyl-5-methoxyindoline-2,3-dione (2c): Red Solid, Yield: 80%, 93
1
23.60, 117.51, 110.26, 40.21, 28.95, 26.92, 22.27, 13.90; ESIMS:
o
1
mg; mp: 180-182 C; H NMR (400 MHz, CDCl ) δ 7.20 – 7.08 (m,
+
3
m/z 218 [M+H] ; Anal. Calcd for C H NO : C, 71.87; H, 6.96; N,
1
3
15
2
2
H), 6.84 (dd, J = 8.1, 0.7 Hz, 1H), 3.80 (d, J = 5.3 Hz, 3H), 3.69 (t, J =
.3 Hz, 2H), 1.72 – 1.62 (m, 2H), 1.40 (dt, J = 14.7, 7.4 Hz, 2H), 0.97
6
1
1
.45. Found: C, 71.95; H, 6.92; N, 6.47.
-Heptylindoline-2,3-dione (2j): Red Solid, Yield: 74%, 91 mg; mp:
7
13
(t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl ) δ 184.14, 158.24,
o
1
3
50-151 C; H NMR (400 MHz, CDCl ) δ 7.62 – 7.56 (m, 2H), 7.11
3
1
2
6
5
56.35, 144.75, 124.49, 117.87, 111.48, 109.87, 56.04, 40.00, 29.25,
(
tt, J = 4.8, 2.4 Hz, 1H), 6.89 (t, J = 9.5 Hz, 1H), 3.72 (dd, J = 13.6, 6.3
+
3
0.09, 13.68; ESIMS: m/z 234 [M+H] ; Anal. Calcd for C13H15NO : C,
Hz, 2H), 1.70 (dt, J = 14.8, 7.4 Hz, 2H), 1.40 – 1.32 (m, 4H), 1.28 (td, J
6.94; H, 6.48; N, 6.00. Found: C, 66.83; H, 6.45; N, 6.03.
13
=
7.0, 3.7 Hz, 4H), 0.88 (t, J = 6.9 Hz, 3H); C NMR (100 MHz, CDCl
δ 183.67, 158.11, 151.04, 138.44, 125.29, 123.59, 117.50, 110.28,
0.24, 31.64, 28.86, 27.24, 26.83, 22.52, 14.02; ESIMS: m/z 246
3
)
-Methoxy-1-(penta-1,3-diyn-1-yl)indoline-2,3-dione (2d): Red
o
1
Solid,Yield: 76%, 93 mg; mp: 188-190 C; H NMR (400 MHz, CDCl
3
) δ
.14 (dt, J = 5.7, 2.8 Hz, 2H), 6.85 – 6.80 (m, 1H), 3.81 (s, 3H), 3.72 –
.66 (m, 2H), 1.70 (dd, J = 14.1, 7.0 Hz, 2H), 1.42 – 1.32 (m, 4H), 0.94
4
7
3
–
1
2
6
1
1
+
[
M+H] ; Anal. Calcd for C15
H
19NO
2
: C, 73.44; H, 7.81; N, 5.71. Found:
C, 73.58; H, 7.87; N, 5.75.
1
3
0.87 (t, 3H); C NMR (100 MHz, CDCl
3
) δ 184.04, 158.18, 156.36,
16k
5
7
2
1
2
-Chloro-1-methylindoline-2,3-dione (2k): Red Solid, Yield: 74%,
44.89, 124.56, 117.97, 111.21, 109.67, 55.96, 40.21, 28.96, 26.93,
o
1
3
1 mg; mp: 157-159 C; H NMR (400 MHz, CDCl ) δ 7.65 – 7.50 (m,
+
2.29, 13.91; ESIMS: m/z 270 [M+Na] ; Anal. Calcd for C14
H17NO
3
: C,
13
H), 6.89 (d, J = 8.3 Hz, 1H), 3.26 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
8.00; H, 6.93; N, 5.66. Found: C, 68.21; H, 6.89; N, 5.70.
82.56, 157.87, 149.75, 137.98, 129.72, 125.20, 118.19, 111.58,
-Heptyl-5-methoxyindoline-2,3-dione (2e): Red Solid, Yield: 76%,
+
6.60; ESIMS: m/z 218 [M+Na] ; Anal. Calcd for C
9
H
6
ClNO
2
: C, 55.26;
o
1
04 mg; mp: 194-196 C; H NMR (400 MHz, CDCl
3
) δ 7.19 – 7.08
H, 3.09; N, 7.16. Found: C, 55.36; H, 3.11; N, 7.11.
(
m, 2H), 6.88 – 6.74 (m, 1H), 3.81 (s, 3H), 3.68 (t, J = 7.3 Hz, 2H),
5
-Chloro-1-propylindoline-2,3-dione (2l): Red Solid, Yield: 70%, 78
1
3
1
2
.68 (dt, J = 14.6, 7.4 Hz, 2H), 1.41 – 1.20 (m, 8H), 0.88 (t, J = 6.8 Hz,
o
1
mg; mp: 163-165 C; H NMR (400 MHz, CDCl
3
) δ 7.55 (dd, J = 7.2,
1
3
H); C NMR (100 MHz, CDCl ) δ 184.04, 158.18, 156.37, 144.90,
3
2
2
1
2
.0 Hz, 2H), 6.93 – 6.83 (m, 1H), 3.77 – 3.60 (m, 2H), 1.82 – 1.63 (m,
24.56, 117.98, 111.21, 109.67, 55.97, 40.25, 31.65, 28.88, 27.26,
13
3
H), 1.08 – 0.93 (m, 3H); C NMR (100 MHz, CDCl ) δ 182.66,
+
6.84, 22.53, 14.02; ESIMS: m/z 276 [M+H] ; Anal. Calcd for
57.65, 149.37, 137.74, 129.32, 125.15, 118.31, 111.66, 41.94,
C H NO : C, 69.79; H, 7.69; N, 5.09. Found: C, 69.92; H, 7.65; N,
+
1
6
21
3
0.56, 11.31; ESIMS: m/z 224 [M+H] ; Anal. Calcd for C H ClNO :
1
1
10
2
5
.11.
C, 59.07; H, 4.51; N, 6.26. Found: C, 59.22; H, 4.48; N, 6.21.
-Chloro-1-heptylindoline-2,3-dione (2m): Red Solid, Yield: 70%, 98
1
6k
1-Methylindoline-2,3-dione (2f): Red Solid, Yield: 80%, 64 mg;
5
o
1
mp: 119-121 C; H NMR (400 MHz, CDCl ) δ 7.66 – 7.50 (m, 2H),
o
1
3
mg; mp: 174-176 C; H NMR (400 MHz, CDCl ) δ 7.59 – 7.51 (m, 2H),
3
13
7.19 – 7.09 (m, 1H), 6.98 – 6.85 (m, 1H), 3.30 – 3.18 (s, 3H); C NMR
6
–
.86 (d, J = 8.2 Hz, 1H), 3.79 – 3.63 (m, 2H), 1.77 – 1.63 (m, 2H), 1.41
(100 MHz, CDCl ) δ 183.53, 158.30, 151.36, 138.79, 125.11, 123.94,
3
13
1.32 (m, 4H), 1.31 – 1.22 (m, 4H), 0.94 – 0.81 (m, 3H); C NMR
+
1
17.17, 110.31, 26.32; ESIMS: m/z 184 [M+Na] ; Anal. Calcd for
NO : C, 67.08; H, 4.38; N, 8.69. Found: C, 67.22; H, 4.40; N,
.64.
(
100 MHz, CDCl
3
) δ 182.67, 157.60, 149.35, 137.68, 129.41, 125.32,
C
9
H
7
2
1
18.41, 111.49, 40.46, 31.65, 28.87, 27.20, 26.84, 22.55, 14.04;
8
+
2
ESIMS: m/z 280 [M+H] ; Anal. Calcd for C15H18ClNO : C, 64.40; H,
6
.49; N, 5.01. Found: C, 64.32; H, 6.52; N, 4.97.
4
| J. Name., 2012, 00, 1-3
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NP lee wa s eJ od uo r nn oa tl aod fj uC s ht em ma ri sg it nr sy
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DOI: 10.1039/C7NJ02441J
Journal Name
COMMUNICATION
+
2
8.93, 26.84, 22.27, 13.91; ESIMS: m/z 297, 295 [M+H] ; Anal. Calcd
5
2
-Chloro-1-nonylindoline-2,3-dione (2n): Red Solid, Yield: 68%, 104 for C13H14BrNO : C, 52.72; H, 4.76; N, 4.73. Found: C, 52.56; H, 4.80
o
1
mg; mp: 175-177 C; H NMR (400 MHz, CDCl
H), 6.87 (dd, J = 7.9, 1.0 Hz, 1H), 3.71 (t, J = 7.4 Hz, 2H), 3.45 – 3.36
m, 2H), 1.90 – 1.80 (m, 2H), 1.75 – 1.65 (m, 2H), 1.48 – 1.40 (m,
3
) δ 7.63 – 7.48 (m, N, 4.75.
2
(
13
Acknowledgements
2H), 1.33 (d, J = 8.6 Hz, 2H), 0.92 – 0.81 (m, 7H); C NMR (100 MHz,
CDCl ) δ 182.1, 157.30, 148.90, 137.92, 129.0, 124.6, 118.06, 111.8, The authorsare thankful to CSIR andUGC – New Delhi(for
3
4
0.80, 33.59, 32.47, 29.08, 28.83, 26.82, 26.82, 22.3, 13.7;ESIMS: awarding research fellowship) and the Department of
+
m/z 308 [M+H] ; Anal. Calcd for C17
H
22ClNO
.55. Found: C, 66.52; H, 7.25; N, 4.52.
-Butyl-5-fluoroindoline-2,3-dione (2o): Red Solid, Yield: 76%, 83
2
: C, 66.33; H, 7.20; N, Chemistry, OU, PG College, Narsapur, Telangana.
4
1
o
1
Notes and references
mg; mp: 155-157 C; H NMR (400 MHz, CDCl
3
) δ 7.37 – 7.25 (m,
2
H), 6.93 (dd, J = 8.6, 3.6 Hz, 1H), 3.74 (t, J = 7.3 Hz, 2H), 1.75 – 1.62
†
Part 241 in the series, “Studies on novel synthetic
1
3
(
m, 2H), 1.48 – 1.34 (m, 2H), 0.98 (t, J = 7.3, 3.2 Hz, 3H); C NMR
100 MHz, CDCl ) δ 183.24, 160.39, 158.01, 147.12, 125.04, 124.80,
18.04, 111.82, 40.16, 29.13, 20.07, 13.62; ESIMS: m/z 222 [M+H] ;
Anal. Calcd for C H FNO : C, 65.15; H, 5.47; N, 6.33. Found: C,
methodologies”
(
3
+
1
(a) D. M. DSouza andT. J.Muller, Chem. Soc. Rev.2007, 36,
095. (b) P. Ramesh, R. Anjibabu, Y. N. Reddy, M.
1
1
1
2
12
2
Yedukondalu, T. N. Reddy, B. Kummari, A. Raju, N. Srinivasu,
Asian J. Org. Chem., 2017, 6, 984.
65.01; H, 5.50; N, 6.37.
5-Fluoro-1-pentylindoline-2,3-dione (2p): Red Solid, Yield: 72%, 85
o
1
2
(a) K. C. Nicolaou, D. J. Edmonds, P. G.Bulger, Angew. Chem.
Int. Ed. 2006, 45, 7134. (b) L. F.Tietze, G.Brasche, K.Gericke,
Domino Reactions in Organic Synthesis; Wiley-VCH:
mg; mp: 160-162 C; H NMR (400 MHz, CDCl ) δ 7.36 – 7.28 (m,
3
2H), 6.91 (dd, J = 8.6, 3.6 Hz, 1H), 3.77 – 3.68 (m, 2H), 1.77 – 1.63
1
3
(m, 2H), 1.46 – 1.33 (m, 4H), 0.96 – 0.85 (t, 3H); C NMR (100 MHz,
Weinheim, 2006. (c) A. Padwa, S. K.Bur, Tetrahedron 2007
63, 5341. (d) F. Wang, P. Zhao, C.Xi, Heterocycles 2012, 84,
09.(e) X.Zeng, Chem. Rev. 2013, 113, 6864.
,
CDCl ) δ 183.09, 160.34, 157.85, 147.09, 124.83, 124.59, 118.00,
3
+
111.55, 40.28, 28.87, 26.77, 22.20, 13.83; ESIMS: m/z 236 [M+H] ;
2
2
Anal. Calcd for C13H14FNO : C, 66.37; H, 6.00; N, 5.95. Found: C,
3
4
A. V.Gulevich, A. S.Dudnik, N.Chernyak, V.Gevorgyan, Chem.
Rev. 2013, 113, 3084.
66.50; H, 6.04; N, 5.98.
5-Fluoro-1-heptylindoline-2,3-dione (2q): Red Solid, Yield: 70%, 95
o
1
(a) E. S. Sherman, S. R. Chemler, T.B. Tan, O. Gerlits, Org.
Lett.2004, 6, 1573. (b) T. P. Zabawa, D. Kasi, S. R. Chemler, J.
Am. Chem. Soc.2005, 127, 11250. (c) Y. Ohta, S. Oishi, N.
Fujii, H. Ohno, Chem. Commun. 2008, 835. (d) L. A. Adrio, K.
K. Hii, Chem. Commun.2008, 2325.(e) A.Dandia, J.Joshi,
S.Kumari, S. L.Gupta, Chem. Biol. Interface 2013, 3, 61.
(a) R. A.Sheldon, Chem. Ind.1992, 903. (b) D. J. C. Constable,
P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L. Jr. Leazer, R. J.
Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A.
Zaks, T. Y.Zhang, Green Chem.2007, 9, 411.
mg; mp: 165-168 C; H NMR (400 MHz, CDCl
3
) δ 7.37 – 7.24 (m,
2
1
1
3
H), 6.93 – 6.85 (m, 1H), 3.72 (t, J = 7.4 Hz, 2H), 1.75 – 1.65 (m, 2H),
13
3
.40 – 1.19 (m, 8H), 0.92 – 0.83 (t, 3H); C NMR (100 MHz, CDCl ) δ
83.10, 160.18, 157.89, 147.11, 124.77, 118.12, 112.31, 111.44,
+
1.63, 27.14, 22.51, 14.00; ESIMS: m/z 264 [M+H] ; Anal. Calcd for
15 2
C H18FNO : C, 68.42; H, 6.89; N, 5.32. Found: C, 68.21; H, 6.85; N,
5
5.34.
5-Bromo-1-propylindoline-2,3-dione (2r): Red Solid, Yield: 72%, 95
o
1
mg;mp: 161-163 C; H NMR (400 MHz, CDCl ) δ 7.70 (td, J = 4.4, 2.1
3
Hz, 2H), 6.89 – 6.78 (m, 1H), 3.77 – 3.63 (t, 2H), 1.79 – 1.66 (m, 2H),
13
6
7
(a) A. Campbell, S. Stahl, Acc. Chem. Res. 2012, 45, 851. (b) X.
Guo, D. Gu, Z. Wu, W. Zhang, Chem. Rev. 2014, 115, 1622.
(a) Y. Zhang, Z. J. Li, H. S. Xu, Y. Zhang, W.Wang, RSC
Adv.2011, 1, 389. (b) D. Anshu, P. Vijay, J. Anuj Kumar, S.
R.Kuldeep, Green Chem.2011, 13, 2135. (c) A. Anand Kumar,
M.Kumar, Green Chem.2011, 13, 1332. (d) W. T. Wei, C. X.
Chen, R. J.Lu, J. J. Wang, X. J. Zhang, M.Yan, Org. Biomol.
Chem.2012, 10, 5245. (e) T. Rajasekaran, G. Karthik, B.
Sridhar, B. V.Subba Reddy, Org. Lett.2013, 15, 1512. (f) B.
Jiang, X. Wang, H. W. Xu, M. S. Tu, S. J. Tu, G.Li, Org.
Lett.2013, 15, 1540. (g) P. Pakravan, S. Kashanian, M. M.
Khodaei, F. J.Harding, Pharmacol. Rep.2013, 65, 313. (h) D. K.
1.06 – 0.91 (t, 3H); C NMR (100 MHz, CDCl
3
) δ 182.49, 157.48,
149.81, 140.58, 128.06, 118.68, 116.37, 112.05, 41.95, 20.57, 11.33;
+
ESIMS: m/z 268, 266 [M+H] ; Anal. Calcd for C11
H, 3.76; N, 5.22. Found: C, 49.44; H, 3.80 N, 5.25.
-Bromo-1-butylindoline-2,3-dione (2s): Red Solid, Yield: 70%, 98
2
H10BrNO : C, 49.28;
5
o
1
mg; mp: 172-174 C; H NMR (400 MHz, CDCl
3
) δ 7.73 – 7.68 (m, 2H),
6
1
.83 (t, J = 5.8 Hz, 1H), 3.72 (t, J = 7.3 Hz, 2H), 1.71 – 1.62 (m, 2H),
1
3
.39 (dt, J = 14.6, 7.4 Hz, 2H), 1.00 – 0.93 (t, 3H); C NMR (100 MHz,
CDCl
12.42, 40.29, 29.15, 20.12, 13.71; ESIMS: m/z 284, 282 [M+H] ;
Anal. Calcd for C H BrNO : C, 51.09; H, 4.29; N, 4.96. Found: C,
3
) δ 182.81, 157.65, 149.79, 140.90, 128.12, 118.59, 116.51,
+
1
12
12
2
49.91; H, 4.27; N, 4.94.
Chaudhary, S. Ahmad, S. Maity, M. S.Alam,Pharm. Lett.2013
,
5-Bromo-1-pentylindoline-2,3-dione (2t): Red Solid, Yield: 68%, 100
o
1
5, 285.
mg; mp: 180-182 C; H NMR (400 MHz, CDCl
3
) δ 7.78 – 7.67 (m, 2H),
8
(a) T. Jiang, K. L. Kuhen, K. Wolff, H. Yin, K. Bieza, J. Caldwell,
B. Bursulaya, T. Y.-H.Wu, Y.He, Bioorg. Med. Chem.
Lett.2006, 16, 2105. (b) V. S. Pawar, D. K. Lokwani, S. V.
6
1
1
.83 (d, J = 9.0 Hz, 1H), 3.71 (t, J = 7.1 Hz, 2H), 1.74 – 1.61 (m, 2H),
13
.36 (m, 4H), 0.90 (t, 3H); C NMR (100 MHz, CDCl
3
) δ 182.50,
57.40, 149.78, 140.58, 128.03, 118.70, 116.35, 112.05, 40.39,
This journal is © The Royal Society of Chemistry 20xx
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COMMUNICATION
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DOI: 10.1039/C7NJ02441J
GRAPHICAL ABSTRACT
Copper-catalyzed aerobic oxidative intramolecular amidation of 2-
aminophenylacetylenes: A domino process for the synthesis of isatin
a
b
c
b
N. Salvanna * Perla Ramesh , K. Santosh Kumar , Biswanath Das *
A novel CuI-catalyzed oxidative amidation of 2-aminophenylacetylenes leading to the
formation of isatins by using open air as an oxygen source has been developed. The reaction
proceeded smoothly and provided a variety of isatin derivatives in good yields. The
advantages of this one-pot reaction protocol include green oxidant, low-price catalyst, facile
conditions and easy handling.