Direct N-alkylation of isatin by halomethyl ketones

Article abstract of DOI:10.1007/s10593-005-0289-y

Solid-phase syntheses are reported for 1-(2-oxoalkyl)indoline-2,3-diones. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0289-y

Chemistry of Heterocyclic Compounds, Vol. 41, No. 9, 2005
DIRECT N-ALKYLATION OF ISATIN
BY HALOMETHYL KETONES
M. A. Rekhter
Solid-phase syntheses are reported for 1-(2-oxoalkyl)indoline-2,3-diones.
Keywords: halomethyl ketones, 1-(2-oxoalkyl)indoline-2,3-diones.
Isatins may react with halomethyl ketones at the β-CO or NH group. If the reaction begins with
N-alkylation, the products formed smoothly isomerize to give 2-acylindole-3-carboxylic acids under mild
conditions as a result of the facile opening of the five-membered isatin ring in aqueous alkali and alcoholic
sodium alcoholates [1].
COOH
COR
O
O
O
RCOCH2I
+
–
N
N
H
N
O
1a,b
+
M
CH2COR
3a,b
4a,b
2a,b
1, 3, 4, a R = Ph, b R = Me; 2 a M = Na, b M = Li
Epoxy ketones are formed in the reaction at the β-CO group as a result of the Darzin condensation. The
five-membered ring of these epoxy ketones is cleaved at high temperature in solutions with high alkali
concentration and the products of their decarboxylation are mainly isolated instead of the acids [2]. Thus, as
indicated in our previous review [1], the direct alkylation of isatins by halomethyl ketones appears to be a good
approach for such syntheses. Radul et al. [3] have described the N-alkylation of isatin by α-bromo ketones in
aprotic solvents such as benzene and toluene in the presence of weakly basic condensing reagents such as
pyridine, triethylamine, and potassium carbonate. We should note that the solubility of isatin in these solvents is
very limited.
In the present work, we demonstrate the feasibility of carrying out this reaction in DMF, which is a polar
solvent, and in the solid phase. In the former case, phenacyl iodide (1a) was used as the N-alkylating reagent due
to the reduced tendency of 1a to generate the RCOC–HX carbanion (X = halogen) in comparison with its
chloride and bromide analogs. The RCOC–HX carbanion rapidly reacts with the β-CO group. The addition of
isatinsodium (2a) or isatinlithium (2b) (obtained from equimolar amounts of isatin and the hydride of the
corresponding metal) in DMF to a solution of ketone 1a in DMF at from -10 to -15°C led to N-phenacylisatin 3a
in 46% and 38% yield, respectively. In the latter case, mixing iodoacetone (1b) with salt 2a
__________________________________________________________________________________________
Institute for the Biological Protection of Plants, Academy of Sciences of the Republic of Moldova,
MD-2060 Kishinev, Moldova. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1320-1322,
September, 2005. Original article submitted May 19, 2003; revision submitted March 23, 2005.
0009-3122/05/4109-1119©2005 Springer Science+Business Media, Inc.
1119

(the 1b:2a mole ratio was 1:1.5) at 20°C over 120 h gave N-acetonylisatin (3b) in 40% yield. Further studies
may lead to higher yields for this reaction. The structures of products 3a and 3b were supported by the
conversion of these compounds into 2-acylindole-3-carboxylic acids 4a and 4b, respectively.
EXPERIMENTAL
Phenacyl Iodide (1a). A sample of phenacyl bromide (25-30 mmol) or phenacyl chloride and then KI or
anhydrous NaI (50 mmol) were added to absolute DMF (25-30 ml) at -10°C and the mixture was maintained for
~16 h at this temperature. The reaction mixture was used for the N-alkylation of isatin without isolation of iodide
1a.
N-Phenacylisatin (3a). A sample of salt 2a or 2b obtained according to Tacconi et al. [4] from isatin (30
mmol) and NaH or LiH (30 mmol) in anhydrous DMF (75 ml) was added in portions to the solution of phenacyl
iodide maintained at from -10 to -15°C such that each portion was reacted before addition of the next portion.
The reaction was monitored by thin-layer chromatography on Silufol plates using 4:1 benzene–acetone as the
eluent. After completing the addition of salt 2, the reaction mixture was stirred for 1 h at the same temperature.
Cooling was discontinued. The mixture was poured into a 10-fold volume of water at room temperature and
brought to pH 1. The precipitate formed was separated. Chromatography on a silica gel column using 4:1
benzene–acetone as the eluent gave 3.66 g (46%) 3a (in the case of salt 2a) or 3.02 g (38%) 3a (in the case of
salt 2b). The melting point of 3a was 144-145°C (145-146°C [5]).
N-Acetonylisatin (3b). A sample of 2a (3.38 g, 20 mmol) was thoroughly mixed with freshly distilled
iodoacetone (5.52 g, 30 mmol). The mixture obtained was maintained for 120 h in a flask protected with a
calcium chloride tube at room temperature and then extracted with dry benzene. The extract was evaporated.
Chromatography of the residue on a silica gel column with benzene as the eluent gave 1.62 g (40%) 3b;
mp 154-156°C (156-157°C [6]).
2-Benzoylindole-3-carboxylic Acid (4a). A sample of 3a (2.65 g, 10 mmol) was dissolved in 80% aq.
ethanol containing NaOH (5 g) and maintained for 3 h at ~20°C. Hydrochloric acid was added to bring the
mixture to pH 1. The precipitate of 4a was filtered off, washed with water, and dried to give 4a in 87% yield; mp
218-219°C (218-219°C [7]).
2-Acetylindole-3-carboxylic Acid (4b) was obtained according to our previous procedure [6] in
73% yield; mp 217-218°C (217-218°C [6]).
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