Communications
stability of the intermediate benzylic radical (e.g., 7).[11]
A
radical mechanism for the copper-catalyzed oxyamination
would therefore result in the formation of regioisomer 8.
Our investigation began with an examination of the
reaction between oxaziridine 3 and indoles in the presence of
copper(II) catalysts. Under these strongly oxidizing condi-
tions, we found that electron-rich N-alkyl indoles underwent
rapid and exothermic decomposition to an intractable mix-
ture of products. On the other hand, the reaction of
N-acetylindole (4) proceeded smoothly within 1.5 h in 85%
yield and with 2:1 diastereoselectivity. Importantly, both
diastereomers of the oxyaminated product 8 corresponded to
the benzylic amine regioisomer that would be predicted on
the basis of a radical mechanism.[12] This outcome provides
further evidence against the cationic mechanism we originally
proposed.
Exclusive formation of the C3 aminated regioisomer was
observed in the oxyamination of all indole substrates that we
have examined to date. A range of structurally varied N-acyl
indoles were suitable substrates for oxyamination, including
substrates with electron-donating and electron-withdrawing
substituents at various positions on the indole (products 10–
13) and more complex N-acyl groups (product 14; Scheme 3).
The reaction of tryptamines and other indoles substituted at
C3 afforded the corresponding products in somewhat lower
yields under these conditions (e.g., product 15), which we
speculate might be attributable to unproductive side oxida-
tions of these more electron-rich substrates. After some
optimization, we found that the yield could be improved by
performing the reaction in acetone with a higher loading of
the copper(II) catalyst and with the less reactive
3,3-dimethyloxaziridine 9 as the terminal oxidant (product
16). This modification enabled the oxyamination of a variety
of more electron-rich indoles with alkyl substituents on the
indole olefin (products 17–21). The functional group compat-
ibility of this process is quite good: aryl halides, ethers, esters,
amides, and carbamates are all tolerated well under both sets
of reaction conditions.
Although the initial impetus for this study was to provide
additional evidence for a radical mechanism, we quickly
recognized that the aminal products could serve as syntheti-
cally valuable precursors to a variety of heterocyclic systems
found in bioactive compounds, including pyrroloindoline
natural products such as 1 and 2. Indeed, treatment of the
tryptamine-derived aminal 18 with NaOH resulted in facile
cleavage of the N-acetyl group with concomitant elimination
of acetone; under the basic conditions of this hydrolysis, the
N-Moc carbamate underwent spontaneous cyclization onto
the imine intermediate to produce pyrroloindoline 22 in 85%
yield (Table 1, entry 1). The cyclization of the homotrypt-
amine-derived aminal 19 to a-carboline 23 also proceeded in
good yield (Table 1, entry 2). This cyclization cascade can also
be terminated with oxygen nucleophiles; the latent alcohol of
O-acyl tryptophol derived aminal 20 was revealed under the
basic reaction conditions, and furoindoline 24 was obtained in
excellent yield (Table 1, entry 3). Substrates without an
internal nucleophile were also subjected to these reaction
conditions. The imine intermediate resulting from the hydrol-
ysis of 8 undergoes rearomatization to afford 3-aminoindole
Scheme 3. Scope of the indole oxyamination. The average yield of the
isolated product from two experiments is given in each case. [a] Reac-
tion conditions: CuCl2 (2 mol%), Bu4N+ClÀ (2 mol%), oxaziridine
(2 equiv), CH2Cl2, 238C. [b] Reaction conditions: CuCl2 (10 mol%),
Bu4N+ClÀ (10 mol%), oxaziridine (2 equiv), acetone, 238C. Boc=tert-
butoxycarbonyl, Moc=methoxycarbonyl.
25 (Table 1, entry 4).[13] The rearomatization of substituted
indolines was also successful (Table 1, entries 5 and 6).
The challenge of the enantioselective synthesis of pyrro-
loindolines has been addressed by several methods, including
asymmetric Heck cyclizations,[14] organocatalytic cascade
cyclizations of tryptamines,[15] and electrophilic cyclizations
of enantiomerically pure tryptophan derivatives.[16] We won-
dered if an asymmetric version of this copper-catalyzed
oxyamination might also serve as a platform for the enantio-
selective synthesis of pyrroloindolines with an amino sub-
stituent at C3, as exemplified by psychotrimine (1). Our
strategy took advantage of two key observations. First, we
found that a variety of acyl groups are tolerated on the indole
nitrogen atom, including amino acid derivatives (e.g., in 14).
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Angew. Chem. Int. Ed. 2010, 49, 9153 –9157