Synthesis of N-arylisatins using different heterogeneous catalyst under microwave irradiations

Article abstract of DOI:10.14233/ajchem.2013.14146

N-Arylisatins having both biological and medical properties are synthesized by the reaction of methyl-2-oxo-2-(arylamino)acetates and arynes using NaHCO3 in presence of different heterogeneous catalyst under microwave irradiations in high yield in shorter

Full text of DOI:10.14233/ajchem.2013.14146

Asian Journal of Chemistry; Vol. 25, No. 9 (2013), 4935-4938
http://dx.doi.org/10.14233/ajchem.2013.14146
Synthesis of N-Arylisatins Using Different Heterogeneous Catalyst Under Microwave Irradiations
*
RAVINDER SINGH and RAMESH KUMAR
Department of Chemistry, Pt. N.R.S. Government College, Rohtak-124 001, India
*Corresponding author: E-mail: gahlawat.ravinder@gmail.com
(Received: 4 June 2012;
Accepted: 11 March 2013)
AJC-13107
N-Arylisatins having both biological and medical properties are synthesized by the reaction of methyl-2-oxo-2-(arylamino)acetates and
arynes using NaHCO3 in presence of different heterogeneous catalyst under microwave irradiations in high yield in shorter reaction time.
Key Words: Synthesis, N-Arylisatin, Microwave irradiation.
We started our work by reacting methyl-2-oxo(phenyl-
amino)acetate with 2-(trimethylsilyl) phenyltrifluoromethane-
sulphonate in presence of NaX zeolite catalyst under micro-
wave irradiation at 560 W for 4 to 10 min. The corresponding
N-phenylisatin is obtained in 65-94 % yield.
INTRODUCTION
Isatins have both biological and medical properties
including antifungal, antiviral, anti HIV, anti AIDS, antipro-
tozoal, anticancer and antileukema1-7. In recent years, isatins
have been synthesized by different methods but they require
tedious work up and long reaction time8-17. Microwave assisted
organic synthesis is currently gaining ground in synthetic
organic chemistry largely due to the dramatic reduction in time
Mechanistically, it is believed that in first step, the nucleo-
philic attack by nitrogen on the benzyne occurs, resulting in
the formation of an aryl carbanion. The aryl carbanion attacks
the distant ester carbonyl and displaces a methoxy group which
eventually lead to the desired isatin (Scheme-II).
(from days or hours to minutes or seconds)18,19
.
Here, we report a microwave assisted synthesis of N-
arylisatin by reaction of arynes with methyl-2-oxo-2-
(arylamino)acetate in excellent yield in shorter reaction time
(Scheme-I).
We further explored our work by reacting different methyl-
2-oxo(arylamino)acetate with 2-(trimethylsilyl)phenyl-
trifluoromethanesulphonate using NaX, NaY and NaZ zeolite
catalyst under microwave ireradiation at 560 W power. The
results are shown in Table-1. Here electron-rich substituent
seems to promote this reaction to a small extent, whereas
electron deficient group lower the yield of the reaction in same
way as in ordinary conditions.
H
N
COOCH3
OTf
+
NaHCO3(Base)
O
EXPERIMENTAL
Catalyst
TMS
R2
MW, 5-10 min.
1
The H and 13C NMR spectra were recorded at 300 and
R1
75.5 MHz or 400 and 100 MHz, respectively. Thin layer
chromatography was performed using commercially prepared
60-mesh silica gel plates and visualization was effected with
short wavelength UV light (254 nm).
O
O
Typical procedure for synthesis of the isatin derivatives
(1-17): To a dry s dram vial containing a solution of the amide
(0.5 mmol) and the aryl amino precursor (1.0 mmol) in MeCN
(5.0 mL, anhydrous) was added NaHCO3 (1.0 mmol) and CsF
(3.0 mmol). The vial was sealed and allowed to stir for 24 h.
The reaction mixture was then filtered through a lug of silica
gel using ethyl acetate, concentrated in vacuo and purified by
N
R1
R2
Scheme-I

4936 Singh et al.
Asian J. Chem.
OTf
N
H
COOCH
3
O
TMS
R
1
R
2
catalyst
R
2
-
-
HCO3
(Base)
HCO3
(Base)
O
N
N
COOCH
3
OCH
3
O
O
R
1
R
1
R
2
catalyst
catalyst
R
2
R
2
O
O
N
N
OCH
3
R
1
O
R
1
O
catalyst
catalyst
Scheme-II: Possible mechanism for Scheme-I
flash chromatography using gradient solvent combinations of
ethyl acetate/hexanes or dichloromethane/hexanes.
CDCl3) δ 183.1, 157.5, 151.9, 138.5, 133.4, 130.2, 129.0,
126.2, 125.8, 124.5, 117.5; HRMS (EI) calcd. (%) for [M +
H]+ (M=C14H9NO2) 224.0706, found (%) 224.0707.
1-Phenylindoline-2,3-dione (1): The product was isolated
as an orange solid. 1H NMR (300 MHz,CDCl3) δ 7.70 (ddd,
J = 0.6, 1.3, 7.5Hz,1H), 7.60-7.41 (m, 6H), 7.18 (td,J = 0.8,
7.6 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 13C NMR (75 MHz,
1-p-Tolylindoline-2,3-dione (2): The product was
isolated as a red-orange solid. 1H NMR (400 MHz, CDCl3) δ
7.80 (d, J = 7.5 Hz,1 H), 7.66 (t, J = 7.3 Hz, 1H), 7.49 (d, J =
TABLE-1
REACTION OF VARIOUS METHYL-2-OXO-2(ARYLAMINO)ACETATES WITH
2-(TRIMETHYLALLYL)PHENYL TRIFLUOROMETHANESULFONATE
Yield (%)
S. No.
Substrate (R2)
Time (min)
m.p. (ºC)
Using NaX catalyst
Using NaY catalyst
Using NaZ catalyst
1
2
H
4-Me
7
6
5
6
7
7
7
7
4
10
8
9
8
8
5
5
5
89
85
86
92
72
75
79
88
78
80
65
68
90
84
82
74
94
91
95
95
97
81
83
87
94
86
88
71
75
94
89
91
82
98
85
83
84
91
68
72
74
85
75
78
61
64
84
81
78
71
90
136-139
137-139
145-148
235-237
194-197
178-180
198-201
173-176
282-284
127-129
177-181
124-127
109-113
157-162
114-117
164-168
130-133
3
4-Oph
4-F
4-Cl
4
5
6
4-Br
4-I
7
8
2-I
4-CN
9
10
11
12
13
14
15
16
17
4-CO2Et
4-CF3
3-CF3
2-t-Bu
2-Ph
2,5-(OMe)2
2,4,6-Me3
2,3-(CH)4

Vol. 25, No. 9 (2013)
Synthesis of N-Arylisatins Using Different Heterogeneous Catalyst Under Microwave Irradiations 4937
8.2 Hz, 2H), 7.42 (d, J = 8.3H z, 2H), 7.30 (d, J = 7.5 Hz, 1H)
7.00 (d, J = 8.1 Hz, 1H) 2.56 (s, 3H), 13C NMR (100 MHz,
CDCl3) δ 183.2, 157.6, 152.0, 139.1, 138.5, 130.7, 130.3,
126.0, 125.6, 124.3, 117.6, 111.4, 21.4; HRMS(EI) calcd. (%)
for C18H11NO2 237.0790, found (%) 237.0791.
Ethyl-4-(2,3-dioxoindolin-1-yl)benzoate (10): The
product was isolated as a light orange solid. 1H NMR (400MHz,
CDCl3) δ 8.21 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.59-
7.52 (m, 3H), 7.20 (t, J = 7.51 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H),
4.40 (d, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H) 13C NMR (100
MHz, CDCl3) δ 182.3, 165.6, 157.1, 150.9, 138.6, 136.9, 131.3,
130.6, 126.0, 125.5, 124.8, 117.7, 111.4, 61.5, 14.5; HRMS(EI)
calcd. (%) for C17H13NO4 295.0839, found (%) 295.0845.
1-[4-(Trifluoromethyl)phenyl]indolin-2,3-dione (11):
1-(4-Phenoxyphenyl)indoline-2,3-dione (3): The prod-
uct was isolated as a yellow-orange solid. 1H NMR (400 MHz,
CDCl3) δ 7.66 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H),
7.40-7.34 (m, 4H), 7.18-7.11 (m, 4H), 7.07 (d, J = 8.2 Hz,
2H), 6.88 (d, J = 7.97 Hz, 1H), 13C NMR (100 MHz, CDCl3)
δ 183.0, 157.9, 157.6, 156.2, 151.8, 138.5, 130.1, 127.7, 127.4,
125.6, 124.4, 124.3, 119.8, 119.5, 117.5, 111.3, HRMS (EI)
calcd for C20H13NO3 315.0895, found (%) 315.0899.
1
The product was isolated as a bright orange solid. H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 6.9
Hz, 1H), 7.62-7.59 (m, 3H), 7.23 (t, J = 7.5 Hz, 1H), 6.98 (d,
J = 8.1Hz, 1H); 13C NMR (100 MHz, CDCl3, extra peaks due
to C-F coupling) δ 182.2, 157.2, 150.8, 138.7, 136.2, 131.0,
130.6, 128.9, 127.33, 127.29, 127.26, 127.22, 126.3, 126.1,
125.1, 125.0, 122.4, 117.7, 111.3, HRMS(EI) calcd. (%) for
C15H8F3NO2 291.0507, found (%) 291.0509.
1-(4-Fluorophenyl)indoline-2,3-dione (4): The product
1
was isolated as a bright orange solid. H NMR (400
MHz,CDCl3) δ 7.72(d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.8 Hz,
1H), 7.44-7.40 (m, 2H), 7.29-7.24 (m, 2H), 7.20 (t, J = 7.6
Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 13C NMR (100 MHz, CDCl3
extra peaks due to C-F coupling) δ 182.8, 163.7, 161.2, 157.6,
151.7, 138.6, 129.0, 128.9, 128.3, 128.2, 125.9, 124.7, 117.7,
117.4, 117.2, 111.3, HRMS(EI) calcd. (%) for C14H8FNO2
241.0539, found. (%) 241.0539.
1-[3-(Trifluoromethyl)phenyl]indolin-2,3-dione (12):
The product was isolated as a yellow orange solid. 1H NMR
(400 MHz, CDCl3) δ 7.74-7.65 (m, 5H), 7.60 (td, J = 1.2, 8.0
Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H); 13C
NMR (100 MHz, CDCl3, extra peaks due to C-F coupling) δ
182.3, 157.3, 150.9, 138.7, 133.7, 130.9, 129.6, 126.1, 125.74,
125.70, 125.0, 123.04, 123.00, 117.7, 111.2; HRMS(EI) calcd.
(%) for C15H8F3NO2 291.0507, found (%) 291.0507.
1-(4-Chlorophenyl)indoline-2,3-dione (5): The product
was isolated as an orange solid. 1H NMR (400 MHz, CDCl3) δ
7.71(d, J = 7.5 Hz, 1H), 7.59-7.53 (m, 3H), 7.39 (d, J = 8.6
Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 6.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 128.6, 157.4, 151.3, 138.6, 134.7,
131.5, 134.4, 137.5, 126.0, 124.7, 117.7, 111.3 HRMS(EI)
calcd. (%) for C14H8NO2Cl 257.0244, found (%) 257.0248.
1-(4-Bromophenyl)indoline-2,3-dione (6): The product
1-(2-tert-Butylphenyl)indolin-2,3-dione (13): The product
1
was isolated as a light orange solid. H NMR (400 MHz,
CDCl3) δ 7.66 (t, J = 7.9 Hz, 2H), 7.51 (td, J = 1.1, 7.8 Hz,
1H), 7.44 (t, J = 7.7 Hz, 1H), 7.34 (td, J = 1.3,7.5 Hz, 1H),
7.14 (t, J = 7.5 Hz, 1H), 7.05 (dd, J = 1.4, 7.8 Hz, 1H), 6.42
(d, J = 8.0 Hz, 1H), 1.32(s, 9H); 13C NMR (100 MHz, CDCl3,
δ 183.4, 159.2, 154.1, 149.6, 138.7, 131.7, 130.5, 130.2, 129.4,
128.4, 125.4, 124.2, 11.8, 112.7, 35.8, 31.9; HRMS(EI) calcd.
(%) for C18H17NO2 279.1259, found (%) 279.1259.
1
was isolated as a light orange solid. H NMR (400 MHz,
CDCl3) δ 7.69-7.66 (m, 3H) 7.56 (t, J = 7.8 Hz, 1H), 7.32 (d,
J = 8.5 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 182.5, 157.2, 151.1, 138.6,
133.3, 132.0, 127.7, 125.9, 124.7, 122.6, 117.6, 111.3, HRMS
(EI) calcd. (%) for C14H8NO2Br 300.9738, found (%) 300.9742.
1-(4-Iodophenyl)indoline-2,3-dione (7): The product
was isolated as an orange solid. 1H NMR (400 MHz, CDCl3) δ
7.88 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 7.51 Hz, 1H), 7.56 (t, J
= 7.8 Hz, 1H), 7.21-7.17 (m, 3H), 6.90 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 182.5, 157.2, 151.1, 139.3,
138.6, 132.7, 127.8, 126.0, 124.8, 117.6, 11.3, 94.1; HRMS
(EI) calcd. (%) for C14H8NO2I 348.9600, found (%) 348.9601.
1-(2-Iodophenyl)indoline-2,3-dione (8): The product
was isolated as a ruby red solid. 1H NMR (400 MHz, CDCl3)
δ 8.01(d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.53-7.51
(m, 2H), 7.36 (d, J = 7.6 Hz, iH), 7.26-7.15 (m, 2H), 6.49 (d,J
= 8.0 Hz, 1H); 13C NMR (100 MHz,CDCl3) δ 182.6, 157.0,
151.3, 140.8, 138.7, 136.2, 131.5, 130.2, 129.7, 125.8, 124.5,
117.2, 111.8, 98.1; HRMS(EI) calcd. (%) for [M + Na]+
(M=C14H8INO2) 371.9492, found (%) 371.9497.
1-((1,1/-Biphenyl)-2-Yl]indoline-2,3-dione (14): The
product was isolated as a red solid. 1H NMR (400 MHz, CDCl3)
δ 7.56-7.53 (m, 4H), 7.40-7.36 (m, 2H), 7.26-7.23 (m, 5H),
7.03 (t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 13C NMR
(100 MHz, CDCl3) δ 182.8, 158.0, 152.2, 141.1, 138.3, 138.2,
131.7, 130.6, 130.1, 129.3, 128.74, 128.69, 128.2, 128.1,
125.4, 124.1, 117.2, 111.6, HRMS(EI) calcd. (%) for
C30H11NO2 299.0946, found (%) 299.0946.
1-(2,4-Dimethoxyphenyl)indoline-2,3-dione (15): The
product was isolated as a orange solid. 1H NMR (400 MHz,
CDCl3) δ 7.64 (dd, J = 7, 7.5 Hz, 1H), 7.49 (t, J = 1.4, 7.9 Hz,
1H), 7.11 (td, J = 0.73, 7.5 Hz, iH), 7.02-6.96 (m, 2H), 6.86
(d, J = 2.6Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.73
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.1, 157.7, 154.0,
152.2, 149.3, 138.4, 125.3, 124.0, 121.6, 117.6, 116.0, 114.7,
113.7, 111.8, 56.4, 56.0; HRMS(EI) calcd. (%) for C16H13NO4
283.0845, found (%) 283.0839.
4-(2,3-Dioxoindolin-1-yl)benzonitrile (9): The product
1
was isolated as a light orange solid. H NMR (400 MHz,
1-Mesitylindoline-2,3-dione (16):The product was isolated
as a yellow orange solid. 1H NMR (400 MHz, CDCl3) δ 7.70
(d, J = 7.2 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5
Hz, iH), 7.03 (s, 2H), 6.4 (d, J = 7.8 Hz, 1H), 2.35 (s, 3H),
2.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 13.2, 157.5, 151.7,
139.8, 138.8, 136.3, 129.9, 128.0, 125.8, 124.3, 117.7, 111.2,
21.3, 18.1; HRMS(EI) calcd. (%) for C17H15NO2 265.1100
found (%) 265.1103.
CDCl3) δ 8.08 (d, J = 8.3 Hz, 2H), 7.714-7.705 (m, 3H), 7.64
(t, J = 7.8Hz, 1H), 7.23 (t, J = 7.51 Hz, 1H), 6.99 (d, J = 7.9
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 181.9, 157.2, 150.0,
137.9, 137.6, 133.8, 127.0, 124.9, 124.1, 118.4, 117.9, 110.9,
110.5, HRMS(EI) calcd. (%) for [M + H]+ (M=C15H8N2O2)
249.0659, found (%) 249.0656.

4938 Singh et al.
Asian J. Chem.
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1-(Naphthalen-1-yl)indoline-2,3-dione (17): The prod-
uct was isolated as an orange solid. 1H NMR(400 MHz, CDCl3)
δ 8.02 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.75 (d,
J = 7.3 Hz, iH), 7.70 (t, J = 8.4 Hz, 1H), 7.64-7.49 (3, 4H),
7.45 (td, J = 1.1, 7.9 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.44 (d,
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158.2, 152.8, 138.8, 135.0, 130.4, 129.5, 129.0, 127.6, 127.1,
126.0,. 125.7, 124.4, 122.6, 117.6, 112.0; HRMS(EI) calcd.
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