Organic Letters
Letter
amount of n-tetrabutylammonium iodide (Bu NI) in the
found that a clean reaction proceeded with the use of 3 equiv
of TBHP in toluene at room temperature to give the desired
peroxyindolenine 5a in 96% yield (Scheme 2a). When 2 equiv
of TBHP was used, tetrahydropyridoindole 7a was obtained in
45% yield along with 5a. The structure of 7a was confirmed by
X-ray analysis (Scheme 2c). A reaction kinetic profile analysis
4
presence of TBHP as an oxidant and coupling reagent
1
1
(
Scheme 1b). The reaction required high temperatures to
proceed, and the authors proposed an intermolecular radical
coupling mechanism to give peroxyindolenine intermediates 3
before the oxidative cyclization to 2. On the other hand, the
authors also investigated the biological activities, which
revealed a promising antitumor activity of these adducts, in
which, importantly, both the indolenine and the peroxy units
1
using in situ H NMR monitoring of the reaction progress
revealed the rapid consumption of 4a to give 7a as an
intermediate, which was then converted to 5a via intermo-
lecular oxidative coupling with TBHP (Scheme 2b). The
intermediacy of 7a was also confirmed by a control experiment
using isolated 7a, which was reacted with 2 equiv of TBHP
under identical conditions to give 5a in 89% yield (Scheme
2d). These results indicated that, in contrast to Zhong’s
oxidative 5-membered peroxycyclization under high-temper-
11a
were found to be crucial for the antiproliferative activities.
Here, we report the hypoiodite-catalyzed tandem oxidative
dearomative peroxycyclization of homotryptamine derivatives
4
to the corresponding peroxytetrahydropyridoindolenines 5
(Scheme 1c). We found that, in contrast to 5-membered
11
peroxycyclization (Scheme 1b), 6-membered intramolecular
cyclization proceeded to give a tetrahydropyridoindole
1
1
ature conditions, our 6-membered oxidative cyclization
proceeded preferentially before intermolecular coupling with
TBHP. In addition, no reactions were observed in the absence
1
2
intermediates 7 before intermolecular oxidative coupling
with a peroxide to give peroxyindolenines 5. In addition, we
obtained epoxytetrahydropyridoindolenines 6 as unexpected
products during the course of mechanistic studies by using
TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) as an additive.
This serendipitous finding prompted us to develop a
chemoselective divergent synthesis of peroxy- and epoxyindo-
lenines 5 and 6 by simple modification of the reaction
conditions. Moreover, we demonstrated the synthetic utility of
epoxyindolenines 6 to provide synthetically useful structures
such as oxindoles, iminoester, and 2-methyleneindolenine
derivative.
of Bu NI for either the aminocyclization of 4a to 7a or the
4
oxidative peroxidation of 7a to 5a.
Because our initial findings suggested that our reaction
11
mechanism might differ from that of Zhong et al., we further
investigated the reaction mechanism of oxidative 6-membered
peroxycyclization in detail. As in our previous oxidative
4a,b,5,6
coupling reactions,
control experiments revealed that
hypoiodite might be a catalytic active species for both the
oxidative cyclization of 4a to 7a and the peroxidation of 7a to
1
3
5
a. In addition, to evaluate the roles of indole and
sulfonamide N-H groups for the oxidation reactions, N-Me
indole 8a and N-Me sulfonamide 8b were prepared and
examined under the standard conditions (Scheme 2e). While,
the reaction of 8a gave no detectable products and most of the
starting material 8a was recovered, the reaction of N-Me
sulfonamide 8b proceeded to consuming starting materials
completely, albeit to give a complex mixture of unidentified
products. Therefore, similar to the previous oxidative coupling
We began our investigation by examining the oxidative
coupling of homotryptamine derivative 4a using TBHP as an
oxidant and coupling partner in the presence of 10 mol % of
13
Bu NI (Scheme 2). After an investigation of the reaction
4
13
parameters (i.e., solvents, amount of oxidant used, etc.), we
Scheme 2. Tandem Oxidative Cyclization/Peroxidation of
5
,6
of arenols in which umpolung of arenols proceeded,
umpolung of the indole moiety through the generation of N-
I indole intermediate might be crucial for the oxidation
reaction process.
Next, we questioned whether our 6-membered peroxycyc-
lization proceeded via a radical mechanism, as in Zhong’s 5-
11
membered radical peroxycyclization. Oxidative cyclization of
a proceeded to give 7a in similar yields in the presence of
4
either 1,1-diphenylethylene (DPE) or TEMPO as a radical
scavenger (Scheme 3a). On the other hand, while the use of
DPE did not influence the outcome of the oxidative
peroxidation of 7a to 5a, the use of TEMPO suppressed
peroxidation but gave an unexpected product, which was
determined to be epoxyindolenine 6a (Scheme 3b). Notably,
epoxyindolenine 6a was not obtained from peroxyindolenine
5
a under identical conditions in the presence of TEMPO
(
Scheme 3c), suggesting that a different route may be followed
from common intermediate 7a to epoxide 6a.
We were interested in this unexpected new reaction, and
especially investigated the role of TEMPO for the epoxidation
of tetrahydropyridoindole 7a (Scheme 3d). Again, no reaction
proceeded in the absence of iodide or TBHP, suggesting that
both are required for oxidative epoxidation, as in peroxidation
(
entries 3 and 4 versus entries 1 and 2). Given the results in
Scheme 3b that another radical scavenger (i.e., DPE) did not
suppress the peroxidation reaction, we speculated that
TEMPO might not suppress peroxidation by the scavenging
B
Org. Lett. XXXX, XXX, XXX−XXX