J. W. Lim et al. / Tetrahedron Letters 57 (2016) 784–787
785
low yield (22%) for 36 h (entry 1). The yield of 2a was improved grad-
ually by increasing the amount of K-10 (entries 2–4). An optimum
yield (88%) of 2a was obtained using 500% (w/w) K-10 in refluxing
ODCB for 14 h (entry 4). The use of a large excess amount of K-10
(1000%, w/w) did not increase the yield although reaction time could
be shortened slightly (12 h) for the completion. The reactions at
lower temperature (130 °C) and the use of p-xylene as solvent were
less effective (entries 5 and 6). As expected, the reaction under N2
atmosphere showed almost no reaction (entry 7). It is interesting
to note that the use of montmorillonite KSF (entry 8) and H2SO4
(entry 9) was completely ineffective.
AcO
OAc
O
O
OH
N
N
H
H
laxatives
anticancer activity
HO
HO
OH
OH
Encouraged by the result various 2,2,N-triarylacetamides 1b–1o
were prepared,11 and the syntheses of 3,3-diaryl-2-oxindoles 2b–
2o were examined.16 As shown in Table 2, N-phenyl derivative
2b was obtained in good yield (89%). The reaction of N-unsubsti-
tuted amide 1c was somewhat sluggish, and 2c was obtained in
moderate yield (57%) for a long time (140 h). The enol content of
N-unsubstituted amide 1c would be small compared to N-substi-
tuted substrates due to the presence of amide–imidic acid tau-
tomerization,12b and this would be the reason for sluggish
reactivity of 1c. The nature of N-aryl moiety did not affect the
reactivity, and compounds 2d–2h were synthesized in good
yields (78–92%). Variation of diarylmethyl moiety also did not
affect the reactivity, and the corresponding oxindoles 2i–2k were
obtained in good yields (80–91%). Spirooxindole derivative 2l
could also be synthesized in good yield (84%). However, the
reaction of 1m gave 2m in very low yield (14%) while the
reaction of 1n failed completely, presumably due to the steric
hindrance. In addition, the pyridine derivative 1o also failed to
produce 2o presumably due to preferential acid–base interaction
between the pyridine moiety of 1o and K-10.
The reaction of N-benzyl derivative 1p showed a somewhat dif-
ferent reaction pathway under the standard condition, as shown in
Scheme 2. N-Debenzylation proceeds to afford 1c in moderate yield
(47%) along with a low yield of oxindole 2c (4%). It is interesting to
note that an appreciable amount of 3 (37%) was formed presumably
via C–N bond cleavage and recombination to the ortho-position of
aniline moiety.9g,17
The reaction of N-allyl derivative 1q produced 2-azacyclopenta
[a]inden-3-one derivative 4 (21%), N-deallylation amide 1c (17%),
and many intractable side products, as shown in Scheme 3.
Compound 4 could be formed via radical formation at the benzylic
position and a cascade cyclization process, as observed by Li and
co-workers in 5-exo-trig cyclization of 1,6-dienes with alkyl
chlorides.18 Unwanted N-deallylation to 1c might occur through
the migration of double bond to enamine intermediate and the
cleavage by moisture under acidic reaction conditions.19
O
O
N
H
N
H
F
Cl
F
Me
anticancer activity
anticancer activity
Figure 1. Biologically active 3,3-diaryl-2-oxindoles.
Table 1
Optimization for the synthesis of 2a from 1a
Entry
Conditionsa
2ab (%)
1
2
3
4
5
6
7
8
9
K-10 (100%, w/w), ODCB, reflux, 36 h
K-10 (200%, w/w), ODCB, reflux, 36 h
K-10 (300%, w/w), ODCB, reflux, 36 h
K-10 (500%, w/w), ODCB, reflux, 14 h
K-10 (500%, w/w), ODCB, 130 °C, 60 h
K-10 (500%, w/w), p-xylene, reflux, 60 h
K-10 (500%, w/w), N2 balloon, ODCB, reflux, 14 h
KSF (500%, w/w), ODCB, reflux, 14 h
H2SO4 (1.0 equiv), ODCB, 130 °C, 5 h
22
41
60
88c
37
24
<5
0
0d
a
All reactions were carried out with 1a (0.5 mmol) under O2 balloon atmosphere
except for entry 7.
b
Isolated yield (%) and variable amounts of 1a was remained except for entry 9.
c
Starting material was completely consumed.
Severe decomposition was observed.
d
I. K-10-assisted homolysis of I produced O-centered radical II
and hydroxyl radical.10,13 The reaction of II and 1a gave III and
C-centered radical IV. Otherwise, IV could be formed via the
reaction of hydroxyl radical and 1a.10 The radical IV was converted
to 2a via radical cyclization and a following loss of hydrogen
radical.14
a-Hydroxyamide III could also be converted to 2a via
intramolecular Friedel–Crafts reaction.8h,i,15
In order to optimize the reaction conditions, we examined the
synthesis of 2a under selected conditions (Table 1). The reaction of
1a in ODCB in the presence of K-10 (100%, w/w) produced 2a in
Ph
Ph
montmorillonite K-10
H
H
Ph
Ph
Ph
N
Ph
ODCB, O2 balloon, reflux
- H
O
O
no metal ! no base !!
N
N
O
Me
2a Me
K
Me 1a
-
10
Fr
i
e
as
d
e
s
i
l
st
-C
e
K-10
rafts
d
OH
O
O
OH
Ph
N
Ph
O
Ph
N
Ph
Ph
N
Ph
O
Ph
N
Ph
Ph
N
Ph
OH
O2
1a
- HO
+
O
O
Me
C-centered radical IV
Me
hydroperoxide I
Me
O-centered radical II
Me
III
Me
1a
- H2O
Scheme 1. Proposed mechanism for the conversion of 1a to 2a.