A facile one-pot method for the preparation of N-Alkyl isatins under microwave irradiation

Article abstract of DOI:10.1081/SCC-120016324

N-Alkyl isatins have been prepared by reaction of the isatin and 5-bromoisatin with K₂CO₃ and convenient alkyl halides in DMF under microwave irradiation with the high yield, simple work-up and short time.

Full text of DOI:10.1081/SCC-120016324

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A Facile One-Pot Method for the Preparation of N -
Alkyl Isatins Under Microwave Irradiation
a
b
c
Javad Azizian , Hossain Fallah-Bagher-Shaidaei & Hassan Kefayati
a
Department of Chemistry, Shahid Beheshty University, Evin, Tehran, Iran
Department of Chemistry, Islamic Azad University, Rasht, Iran
b
c
Department of Chemistry, Science and Research Campus, Islamic Azad University, Tehran,
Iran
Published online: 17 Aug 2006.
To cite this article: Javad Azizian , Hossain Fallah-Bagher-Shaidaei & Hassan Kefayati (2003) A Facile One-Pot Method for the
Preparation of N -Alkyl Isatins Under Microwave Irradiation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:5, 789-793, DOI: 10.1081/SCC-120016324
To link to this article: http://dx.doi.org/10.1081/SCC-120016324
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 5, pp. 789–793, 2003
A Facile One-Pot Method for the Preparation of
N-Alkyl Isatins Under Microwave Irradiation
1
,
2
Javad Azizian, * Hossain Fallah-Bagher-Shaidaei,
3
and Hassan Kefayati
1
Department of Chemistry, Shahid Beheshty University,
Evin, Tehran, Iran
2
Department of Chemistry,
Islamic Azad University, Rasht, Iran
3
Department of Chemistry, Science and Research
Campus, Islamic Azad University, Tehran, Iran
ABSTRACT
N-Alkyl isatins have been prepared by reaction of the isatin and
5
-bromoisatin with K CO and convenient alkyl halides in DMF
2 3
under microwave irradiation with the high yield, simple work-up
and short time.
*
Correspondence: Javad Azizian, Department of Chemistry, Shahid Beheshty
University, P.O. Box 19395-4716, Evin, Tehran, Iran; E-mail: j-azizian@cc.
sbu.ac.ir.
7
89
DOI: 10.1081/SCC-120016324
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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7
90
Azizian, Fallah-Bagher-Shaidaei, and Kefayati
Nowadays there is considerable interest in the rapid synthesis of a
variety heterocyclic compounds under microwave irradiation in domestic
[
1–3]
microwave ovens.
utilized forthe highly accele ra ted synthesis of N-alkylisatins.
We wish to report now that such irradiation can be
The methods which have been developed for the preparation of
[
4–6]
N-alkylisatins are based on the preparation from N-alkylanilines or
Preparation from
N-alkylanilines is tedious multistep processes which usually give N-alkyl-
[
7–9]
on the alkylation of isatin with alkyl halides.
isatins in low-to-moderate yield. Alkylation of isatin with the different
[9]
reagent is a difficult procedure or require a long time.
[8]
We wish to report a facile one-pot synthesis of N-alkylisatins (3a–f )
from the isatin and 5-bromoisatin with alkyl halides in the presence
of a convenient base in a short time and with the high yield and simple
work-up using an unmodified commerical domestic microwave oven.
It was found that when a mixture of isatin, K CO and alkyl halide in
2
3
N,N-dimethylformamide (DMF), an excelent energy transfer medium,
was irradiated in a microwave oven for 2–5 min, N-alkylisatins (3a–f )
were isolated in 72–98% yield. The reaction was performed in a beaker
covered with a stemless funnel. Using this condition the various
N-substituted isatins were prepared with the yield shown in Table 1. In
all cases, the products were identified by their spectroscopic properties
and by comparison with authentic samples.
N-Alkylation of a mixture of isatins (1a–f ) with alkyl halides, by
using of sodium ethoxide (EtONa) as a strong base in ethanol is carried
out and the product of 3a, 3b, 3e and 3f isolated with a good yield but 3c
and 3d were produced in a lower amounts (Sch. 1) (see Table 1).
Table 1. Products of the reaction of isatin and 5-bromoisatin with alkyl halides.
Irradiation condition
0
c
P (W ) t (min) P (W) t (min) Yield (%) Yield (%)
a
b
Product
R
R
3a
3b
3c
3d
3e
3f
H
CH3
80
80
80
2
2
3
–
–
1
2
87
76
82
76
57
32
BrCH
Et
BrEt
PhCH
BrPhCH
3
150
150
H
80
3
150
2
72
24
H
2
2
80
80
3
3
150
150
1
2
98
94
81
66
a
By using K CO in DMF.
2
3
b
By using EtONa in EtOH.
Irradiation power in watt.
c

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N-Alkyl Isatins
791
Scheme 1. Reaction of isatins (1a–f) with alkyl halides.
In order to control the reaction and also for a little vaporisation, the
irradiation period was interrupted with a cooling time and in some cases,
to optimize the yields for each sequence of irradiation, a different power
was used (see Table 1).
Attempted to preparation of 1-tert-butylisatin and 1-iso-propylisatin
from the reaction of isatin with tert-butyl bromide and iso-propyl iodide,
respectively, but no product could be obtained from the both procedures.
Therefore, this procedure is proper for the preparation of N-alkylisatin
from the reaction of isatin with a primary alkyl halide.
In conclusion, this procedure for the synthesis of N-substituted
isatins is rapid and convenient and provides products in high yields
with simple work-up of the reaction mixtures.
EXPERIMENTAL
Melting points were measured on an Electrothermal IA9100
apparatus and are uncorrected. IR spectra were recorded as KBr pellets
1
13
on a Bomem FT-IR MB-100 spectrometer. H and C NMR spectra were
measured with BRUKER DRX-300 AVANCE spectrometer. Microwave
irradiation were carried out in a SANYO oven model EM-5641.
General Procedure for the Synthesis of N-alkylisatins (3a–f )
(
K CO (1 g), an appropriate alkyl halide (15 mmol) and DMF (3 mL)
a) By using K CO in DMF: A mixture of isatin (0.735 g, 5 mmol),
2 3
2
3
contained in a 100 mL beakerwas placed in the mic or wave oven, the
beaker was covered with a stemless funnel and subjected to irradiation
in condition as shown in Table 1. Then it was allowed to cool to room
temperature and 5 mL cool water is added. The precipitate thus obtained

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7
92
Azizian, Fallah-Bagher-Shaidaei, and Kefayati
was filtered off and washed with water. The crude product recrystallized
from ethanol to give orange-red needles of 3a–f.
(b) By using EtONa in EtOH: A suspension of isatin (0.735 g,
mmol) in absolute ethanol (3 mL) with an alcoholic solution of
5
sodium ethoxide and an appropriate alkyl halide (15 mmol) contained
in a 100 mL beaker was placed in the microwave oven. Treatment with
the same methods that used in part a produce orange–red needles of 3a–f.
ꢀ ꢀ
[8]
ꢁ1
3a: M.p. 132–133 C (Lit. 133 C). IR (KBr) (ꢀmax, cm ): 1727 and
606 (CO); H NMR (CDCl ) ꢁ: 3.20 (3H, s, CH ), 6.87 (1H, m, CH),
1
1
7
1
3 3
1
.07 (1H, m, CH), 7.55 (2H, m, 2CH); C NMR (CDCl ) ꢁ: 26.59 (CH ),
3
3
3
10.47 (CH), 117.69 (C), 124.22 (CH), 125.48 (CH), 138.94 (CH), 151.80
(
C), 158.59 (CO), 183.77 (CO).
3b: M.p. 162–163 C (Lit. 162 C). IR (KBr) (ꢀmax, cm ): 1732 and
607 (CO); H NMR (CDCl ) ꢁ: 3.26 (3H, s, CH ), 6.83 (1H, d, CH), 7.72
[8]
ꢀ ꢀ
ꢁ1
1
1
3
3
1
3
(
1H, brd, CH), 7.75 (1H, d, CH);
C NMR (CDCl ) ꢁ: 26.77 (CH ),
3
3
112.01 (CH), 117.08 (C), 118.98 (C), 128.49 (CH), 141.00 (CH), 150.53
(
C), 157.90 (CO), 182.55 (CO).
ꢀ
[10]
c: M.p. 90–91 C (Lit. ). IR (KBr) (ꢀmax, cm ): 1739 and 1609
ꢁ1
3
CO); H NMR (CDCl ) ꢁ: 1.24 (3H, t, CH ), 3.72 (2H, q, CH ), 6.88 (1H,
1
(
d, CH), 7.05 (1H, dd, CH), 7.49 (1H, d, CH), 7.55 (1H, dd, CH); C NMR
3
3
2
1
3
(
(
CDCl ) ꢁ: 12.88 (CH ), 35.30 (CH ), 110.56 (CH), 117.85 (C), 124.02
3 3 2
CH), 125.69 (CH), 138.89 (CH), 150.98 (C), 158.21 (CO), 184.11 (CO).
ꢀ
[10]
d: M.p. 147–148 C (Lit. ). IR (KBr) (ꢀmax, cm ): 1734 and 1603
ꢁ1
3
1
(
(
CO); H NMR (CDCl ) ꢁ: 1.30 (3H, t, CH ), 3.78 (2H, q, CH ), 6.84
3 3 2
1
1H, d, CH), 7.68 (1H, dd, CH), 7.72 (1H, d, CH); C NMR (CDCl ) ꢁ:
3
3
12.83 (CH ), 35.53 (CH ), 112.18 (CH), 116.82 (C), 119.16 (C), 128.61
3 2
(
CH), 140.96 (CH), 149.76 (C), 157.53 (CO), 182.92 (CO).
[8]
ꢀ ꢀ
ꢁ1
3e: M.p. 132–133 C (Lit. 132 C). IR (KBr) (ꢀmax, cm ): 1732 and
612 (CO); H NMR (CDCl ) ꢁ: 4.93 (2H, s, CH ), 6.80 (1H, d, CH), 7.09
1
1
3 2
(
1
1H, dd, CH), 7.35 (5H, m, 5CH), 7.49 (1H, dd, CH), 7.61 (1H, d, CH);
3
C NMR (CDCl ) ꢁ: 44.42 (CH ), 111.45 (CH), 118.04 (C), 124.28
3
2
(
(
2CH), 125.78 (2CH), 127.84 (CH), 128.56 (CH), 129.45 (CH), 134.92
C), 138.79 (CH), 151.11 (C), 158.68 (CO), 183.68 (CO).
3
601 (CO).
ꢀ
[8]
f: M.p. 152–153 C (Lit. 152 C). IR (KBr) (ꢀmax, cm ): 1731 and
ꢀ
ꢁ1
1
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N-Alkyl Isatins
793
3
4
5
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Received in Japan May 23, 2001

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