Novel method for synthesis of isatins [3]

Full text of DOI:10.1023/A:1017575504084

Chemistry of Heterocyclic Compounds, Vol. 37, No. 3, 2001
NOVEL METHOD FOR
SYNTHESIS OF ISATINS
M. A. Mironov, M. I. Kleban, and V. S. Mokrushin
Keywords: aromatic isocyanides, 2,3-disubstituted indoles, isatins.
Isatins, which are a basis for obtaining antiviral drugs, pesticides, dyes, and analytical reagents, have
attracted the attention of researchers for many decades [1]. We propose a novel method for synthesis of
difficultly accessible isatins containing electron-acceptor groups NO2, Cl, CF3. The method is based on the
reaction we have found out between aromatic isocyanides and tertiary amines [2], and includes two steps. In the
first step, we obtain 2-triethylammonio-3-arylaminoindolates 3 from the corresponding aromatic formamide 1
without isolation of the intermediate isocyanides 2. Heating compounds 3 with excess SOCl2 followed by
hydrolysis of the reaction products leads to the target isatins 4. The total yield of isatins, calculated on the basis
of the formamide, is 40%-55%. The mechanism of this reaction will be the subject of further studies.
R3
R3
R2
R1
R2
R1
POCl3
NEt3
R1
O
KOH
R3
R2
R3
N
H
H
N
C
1a–d
HN
R2
R1
2a–d
+
NEt3
–
N
R3
3a–d
O
1. SOCl2
2. H2O, H+
R2
R1
a R1 = R3 = H, R2 = NO2
b R1 = R3 = CF3, R2 = H
c R1 = CF3, R2 = Cl, R3 = H
d R1 = R2 = R3 = Cl
3
O
N
H
4a–d
5-Nitroisatin (4a). 4-Nitroformylaniline (0.83 g, 5 mmol) was added to a mixture of dry benzene
(20 ml), triethylamine (2 ml), and phosphorus oxychloride (0.56 ml, 6 mmol). This was stirred for 1 h at 10°C,
then with cooling the reaction mixture was washed with a 10% KOH solution (12 ml). The organic layer was
removed and it was dried over Na2SO4, and boiled for 4 h. Hexane (10 ml) was added, and the precipitate of
compound 3a [2] was filtered off. SOCl2 (8 ml) was added to the precipitate (0.84 g) and boiled for 5 h, the
excess thionyl chloride was driven off, and then water (1 ml) and concentrated hydrochloric acid (15 ml) was
____________________________________________________________________________________________
The Urals State Technical University, Ekaterinburg 620002, Russia; e-mail: mir@htf.ustu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 397-398, March, 2001. Original article submitted
December 8, 2000.
368
0009-3122/01/3703-0368$25.00©2001 Plenum Publishing Corporation

added and it was boiled for another 2 h. The excess acid was driven off, the residue was washed with water
(2 × 20 ml), and extracted with hot ethanol, from which on evaporation yellow crystals of the product
precipitated. Yield 0.2 g (42%); mp 245°C. Lit. mp 245°C [1].
The following compounds were obtained similarly.
4,6-Ditrifluoromethylisatin (4b). Yield 57%; mp 193-194°C (benzene). 1H NMR spectrum
(DMSO-d6), , ppm: 11.52 (1H, s, NH); 7.60 (1H, s, 5-H); 7.42 (1H, s, 7-H). Mass spectrum, m/z: 283 [M]+,
δ
255 [M - CO]+. Found, %: C 42.33; H 1.07; N 5.04. C10H3F6NO2. Calculated, %: C 42.42; H 1.06; N 4.95.
1
5-Chloro-6-trifluoromethylisatin (4c). Yield 48%; mp 210-211°C (benzene). H NMR spectrum
(DMSO-d6), , ppm: 11.31 (1H, s, NH); 7.68 (1H, s, 4-H); 7.23 (1H, s, 7-H). Mass spectrum, m/z: 249 [M]+,
δ
221 [M - CO]+. Found, %: C 43.41; H 1.16; N 5.57. C9H3ClF3NO2. Calculated, %: C 43.32; H 1.20; N 5.61.
1
4,5,6-Trichloroisatin (4d). Yield 46%; mp 112-113°C (1:1 benzene–hexane). H NMR spectrum
(DMSO-d6), , ppm: 11.39 (1H, s, NH); 7.12 (1H, s, 7-H). Mass spectrum, m/z: 249 [M]+, 221 [M - CO]+.
δ
Found, %: C 38.29; H 0.76; N 5.44. C8H2Cl3NO2. Calculated, %: C 38.37; H 0.80; N 5.59.
This research was done with the support of the CRDF foundation (grant REC-005).
REFERENCES
1.
2.
G. I. Zhungietu and M. A. Rekhter, Isatin and Isatin Derivatives, Shtiintsa, Kishinev (1977), p. 210.
M. A. Mironov and V. S. Mokrushin, Mendeleev Commun., 242 (1998).
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