P. Sai Prathima et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
tion was carried under nitrogen atmosphere, the product forma-
Table 2
Oxidation of indoles
a
tion was observed (83%, 12 h) with slight effect on the rate of reac-
tion. Further it is also noteworthy that no product formation was
observed either in the absence of TEMPO or PIDA. This clearly
demonstrates that this reaction requires the interplay of both the
PIDA/TEMPO and also atmospheric oxygen for completion of the
cycle. Thus in conclusion PIDA/TEMPO together with atmospheric
oxygen acts as the best protocol for the C–H oxidation of oxindole
Entry
Indole 3
Product 2
Time (h)
Yieldb (%)
R = H, R1 = H (3a)
1
2
3
4
5
6
7
2a
2e
2b
2h
2f
12
18
18
11
11
8
72
68
71
82
84
80
81
R = H, R1 = F (3b)
R = H, R1 = C1 (3c)
R = H, R1 = Me (3d)
1
R = H, R = OMe (3e)
R = H, R1 = NO
2
(3f)
2m
2g
1
a.
R = Me, R1 = H (3g)
15
With optimal reaction conditions in hand, we next examined
the generality of this method using different oxindole derivatives
bearing both electron-donating (methyl, methoxy) and electron-
withdrawing groups (chloro, bromo, iodo, fluoro, and trifluo-
romethoxy) at C-5, chloro at C-7 and substituents (methyl, benzyl,
ethyl) at N-1 position. All the reactions of the substituted oxindole
derivatives proceeded well to furnish the desired products in mod-
erate to good yields as shown in Figure 2. It was observed that the
unsubstituted oxindole derivative 1a was more reactive compared
to the substituted derivatives, which furnished the desired isatin
8
(3h)
—
24
24
NR
N
H
9
(3i)
—
NR
N
H
a
Reaction conditions: 3 (0.5 mmol), PIDA (0.25 mmol) and TEMPO (0.5 mmol) in
3
CN (4 mL), at room temperature.
CH
b
Isolated yields.
2
a in 94% yield under shorter reaction times.
Compounds with electron donating substituents in the oxindole
As expected no desired product was obtained in case of 2-
methyl indole 3h and 3-methyl indole 3i as the methyl substituent
showed significant influence on the reaction yield (Table 2, entries
and 9).
On the basis of the above observations and the catalytic oxida-
tions available on the literature, a tentative mechanism to rational-
ize this transformation is illustrated in Scheme 3.
ring (2f and 2h) gave better yields 72%, 74% than the withdrawing
substituents. However, the compounds with electron withdrawing
substituents in the indolinone ring (2b, 2c, 2d, 2e, and 2k) gave
8
6
2%, 68%, 71%, 61%, and 62%, respectively. However, there is con-
siderable influence for C-7 substitution (2j) with respect to reac-
tion rate. In case of substitution at N-1 position the yields were
moderate for compounds (2g, 2i, and 2l).
The hydrogen bonding of polar solvent facilitates the formation
Further we extended the scope of the reaction for C–H oxidation
of indole derivatives in the presence of air (Scheme 2).7a A series of
functional groups, including methyl, methoxy, fluoro, chloro, nitro,
and N-methyl were well tolerated under the optimal reaction
conditions (Table 2). Isatin 2a could be obtained in 72% yield by
direct oxidation of indole 3a under optimized conditions. It
should be noted that the reaction of 3d, 3e, 3g could lead to
desired products in 82%, 84%, and 81% respectively (entries 4, 5,
and 7). The 5-nitroindole 3f gave the desired product without
any undesired oxidative side reaction (entry 6). However, for the
electron-withdrawing substituents fluoro and chloro afforded the
product in 68% and 71% yields (entries 2 and 3).
15
of enol tautomer A. This formation is supported by the data
(
(
(
Table 1) from the solvent screening, in which low polar solvent
DCM) resulted in no reaction, whereas increasing solvent polarity
MeCN) facilitated the reaction. The increased concentration of the
enol tautomer A likely may be due to the hydrogen bonding nature
of the polar solvent. The catalytic cycle is initiated by the formation
of acetic acid by phenyl iodine diacetate. The TEMPO B undergoes
dismutation in the presence of AcOH to oxoammonium salt D and
16
intermediate C. This oxoammonium salt D is responsible for the
selective oxidation of 1a to 2a. The main role of PIDA is to regener-
ate TEMPO, and subsequently it gets reoxidized to its initial state
17
with molecular oxygen to complete the catalytic cycle. The
oxoammonium cation, which is oxidized from TEMPO, oxidizes
oxindole 1a to isatin 2a and further it gets converted to intermedi-
ate C. The rearrangement of enol tautomer A to 2a is clearly repre-
sented in Scheme 3.
O
R1
PIDA
TEMPO, CH CN, rt
R1
O
In conclusion, we have successfully developed a convenient,
simple, metal-free efficient protocol for direct synthesis of indo-
N
R
3
N
R
1
8
3
lin-2, 3-diones in moderate to good yields by using TEMPO in
air as an oxidant under mild conditions. This represents a signifi-
cant advancement in the area of organocatalytic C–H bond activa-
2
Scheme 2. C–H oxidation of indoles by hypervalent iodine(III)/TEMPO.
O2
N
H
I(OAc)2
O
O
P
h
H
I
+
D
2
A
NR
N
O
-H
c
O
N
O
H
H
O
PIDA
PhI + 2AcOH
O
O
O
O
H
N
R
N
R
N
R
N
R
A
1
a
2a
N
O
N
H
C
B
Scheme 3. Possible reaction mechanism.