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M. S. Shmidt et al. / Tetrahedron Letters 53 (2012) 2514–2517
with respect to 4-NO2C6H4 and therefore the greater carbanionic
character that would be acquired by the migratory carbon.
Unlike the behavior of halides 2c, d in the reactions of alkylation
in the presence of alkoxide, using the haloester 2b, it was not pos-
sible to isolate the corresponding epoxide. The reaction at 0–5 °C
for 24 h leads to dioxindole 7 (2,3-dihydro-3-hydroxy-2-oxo-1H-
indole, 15%), isatide 8 (2,20,3,30-tetrahydro-3,30-dihydroxy-2,20-di-
oxo-[3,30-bi-1H-indole], 22%) and decomposition products (entry
5) (Scheme 3). The presence of dioxindole 7 can be explained by
the carbonyl reductive ability of sodium alkoxides.9 On the other
hand, the presence of isatide 8 is probably the result of the conden-
sation of isatin 1 with dioxindole 7 in the reaction medium.1a
Considering that the lability of the isatin nucleus against bases
was one of the factors that hindered the reaction, we used N-meth-
ylisatin (3e) as substrate. The reaction of this compound with the
haloester 2b under similar conditions led to the corresponding
epoxyester 5e in good yield (77%) (Scheme 3). This result is similar
to that obtained by Baiocchi, thus confirming that the N-substi-
tuted isatins are excellent substrates for the Darzens
condensation.11
In order to promote the formation of the O-alkyl regioisomers 4,
we used Ag2CO3 as base, an agent that showed high regioselectivity
in the alkylation of 2-quinolones.12 When the alkylation of isatin
(1) was attempted with halides 2a–d at room temperature in ben-
zene or chloroform, unreacted starting material was recovered in
all cases. On the other hand, the reaction with ethyl iodide (2a)
at 50 °C led to a mixture of derivatives N- and O-substituted 3a
and 4a together with a third product (entries 2, 3, and Scheme
5). The HRMS of this compound corresponds to the molecular for-
mula C18H14N2O4 and coincides with that of the ‘ethyl isatoide’ de-
scribed by Heller and Benade.13 Finally, the structure was
established on the basis of the 1H and 13C NMR correlation exper-
iments and the compound was identified as 2-ethoxy-3-(2,3-dihy-
dro-2,3-dioxo-1H-indolyl)-3-hydroxy-3H-indole (9).
The formation of 9 can be interpreted as the result of obtaining
the O-ethyl derivative 4a and subsequent addition of the anion of
isatin to the b-keto carbonyl (Scheme 5). Monitoring this reaction
by TLC, using CH2Cl2 as eluent, initial formation of 4a (25% after
6 h of reaction) together with significant amounts of unreacted
isatin 1 was observed. At longer reaction times, there is a decrease
of 4a and the appearance of 3a and 9, which are the main products
after 24 h of reaction (entry 2). By prolonging the heating, com-
pound 4a disappears, and a complex mixture of colored products
is obtained from which compound 10 (2,3-diethoxy-3-(2,3-dihy-
dro-2,3-dioxo-1H-indolyl)-3H-indole), along with 3a and 9, was
isolated. Compound 10 may be considered the result of the O-ethy-
lation of 9 in the basic medium of the reaction (Scheme 5).
During storing or chromatographic isolation of 4a, its partial
transformation into 9, among other products, was observed. These
results are consistent with the instability described for the O-alkyl
isatins 4 against hydrolysis14 generating the isatin anion (1ꢀ) and
the subsequent formation of 9 as described above.
5, whereas with the most reactive one, phenacyl iodide (2d), the
yields were generally high (entries 19, 20, 22).
The influence of the base is observed in the reactions with the
nitrobenzyl halide 2c, a compound with intermediate methylene
acidity. In this case, using K2CO3 at different temperatures in differ-
ent solvents, mainly N-alkyl derivative 3c was obtained (entries 7–
12).ꢀIn contrast, when the reaction was carried out at 5–10 °C in
EtO /EtOH, a considerably stronger base, epoxide 5c (30-(4-nitro-
phenyl)spiro[2-oxoindoline-3,20-oxirane]) was obtained in excel-
lent yields (95%) (Scheme 3) (entry 13). As the temperature or
the reaction time increased, the yield of 5c decreased (entries 14
and 15) with the simultaneous appearance and increase in the
yield of
a compound of mp 370–372 °C. By bi-dimensional
heteronuclear correlation spectra, the structure of the product
was established as 1,4-dihydro-3-hydroxy-2-(4-nitrophenyl)-4-
oxoquinoline (6c). The best yields of 6c were obtained after 24 h
at 20–25 °C (entry 15).
The origin of compound 6c could be interpreted as the result of
the N-substitution of isatin generating 3c and its subsequent alk-
oxide induced ring open-ring closing rearrangement.9 However,
by monitoring the reaction at room temperature (TLC,
Cl2CH2:MeOH (4.7:0.3), we observed the appearance of the epoxide
5c (Rf: 0.55) after 2 h of reaction.
At 5 h, we began detecting 6c (Rf: 0.30), which increased in
intensity as isatin (1) and epoxide 5c decreased. At 24 h, 6c was
the main product together with traces of epoxide 5c. Neither 3c
nor any other intermediate product was detected at any time. On
the other hand, the reaction of 5c with EtOꢀ/EtOH under similar
conditions slowly led to 6c only, whereas 3c under the same con-
ditions led to a complex mixture of products. These results indicate
that, under our working conditions, 5c is a precursor of hydroxy-
quinolinone 6c (Scheme 3).
The reaction of isatin (1) with phenacyl halide 2d in EtOꢀ/EtOH
showed a behavior similar to that of the previous case, producing
epoxide 5d and hydroxyquinolinone 6d according to the condi-
tions, although in this case, the rearrangement 5d?6d was even
faster. Thus, at 0–5 °C in 2 h, the yield of epoxide 5d was practically
quantitative (entry 24), whereas at 20 °C in 4 h or at 70 °C in 1 h,
good yields of 6d were obtained (entries 25 and 26).
A possible mechanism for the alkoxide-promoted rearrange-
ment 5?6 is shown in Scheme 4. This mechanism involves the ini-
tial attack of the alkoxide with cleavage of the lactam and
generation of an anionic nitrogen. This, in turn, induces the open-
ing of the oxirane ring. Finally, the expansion of the pentagonal
ring would result from a 1,2-intramolecular migration of a carbon
of the ring to the ester carbonyl, with displacement of ROꢀ.
The 5d?6d rearrangement would be favored by the carbanionic
character that can be acquired by the migratory carbon due to the
stability conferred by the electron acceptor group (COC6H5 or 4-
NO2C6H4). The 5d?6d rearrangement would be faster than
5c?6c due to the greater acceptor effect of the electrons of COC6H5
In general, alkylation of isatin (1) in the presence of Ag2CO3
with iodides 2b–d led to complex mixtures of compounds that
probably result from reactions such as those indicated in Scheme
5 (entries 6, 16, 17, 26, 27). The expected O-alkyl derivative 4c
was isolated only in low yields using HCCl3 as solvent (entry 17).
In other cases the corresponding N-substituted compounds 3 were
the main products. Several attempts to increase the yields of O-al-
kyl derivatives 4 failed. Shorter reaction times and a lower reaction
temperature allowed recovering abundant unreacted isatin (1).
Increasing the temperature or using MW, the yield of the corre-
sponding N-alkyl derivatives 3 and the formation of dimerization
products increased.
O
R
O
O
R'O2C
R
H
NaOR'
R'OH
-
N
NH
H
5c,d
O
RO-
-O CO2R'
H
OH
R
N
H
6c,d
R
N
H
R=COC6H5, 4-NO2C6H4
In summary, herein we have presented the results of alkylation
reactions of isatin in basic media. These reactions allow obtaining
Scheme 4.
Shmidt, María S.
