S. Akai et al. / Tetrahedron Letters 47 (2006) 1881–1884
1883
the generation of the cation intermediates (C) from the
5-sulfinylindoles (6) followed by the conjugate addition
of carbon nucleophiles to them.
try of Education, Culture, Sports, Science, and Technol-
ogy, Japan, and the Shorai Foundation for Science and
Technology.
To examine the feasibility of this plan, we preliminarily
investigated the Pummerer-type reaction of various N-
protected 5-sulfinylindoles (6) with the allylsilane (7a)
(2 equiv) in the presence of trifluoroacetic anhydride
(4 equiv). The N-p-toluenesulfonyl (Ts) indole (6a) gave
the expected 4-allylindole (8a) in 30% yield (Table 1,
entry 6) and the formation of other regioisomers was
not observed at all. The structure of 8a was determined
References and notes
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1
based on H NMR data and the nuclear Overhauser
effect (NOE) experiment. The use of the N-H, the N-
Me and the N-tert-butyldimethylsilyl (TBS) indoles gave
complex mixtures (entries 1–3), and the N-benzoyl (Bz)
and the N-benzyloxycarbonyl (Cbz) derivatives afforded
small amounts of 8 (entries 4 and 5). In the latter cases,
the corresponding sulfides (3) were isolated as the major
side product. After intensive studies by changing the
solvents, the reaction temperature and the activating
reagents, we discovered that the reaction of 6 with
trifluoroacetic anhydride in refluxing MeCN signifi-
cantly reduced the formation of 3 to give 8a in 60% yield
(entry 7).13
´
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Next, we examined various carbon nucleophiles (7)
(Table 2). The use of the vinylsulfide (7b) gave the
indole-4-acetaldehyde (8b) after aqueous workup (entry
1). The b-diketones (7c,d) were found to be good nucleo-
philes to afford the products (8c,d) in 68% and 90%
yields, respectively (entries 2 and 3). A similar reaction
using 7e gave the indole-4-acetate (8e) as a single prod-
uct (entry 5). Similar reactions of indoles (6b–e) having
substituents at the 2- and/or 3-position with some
nucleophiles (7a,c) gave the corresponding 4-substituted
indoles (8f–i) (entries 5–8). It is worth noting that the
nucleophilic substitution exclusively occurred at the
C4-position in all cases. Because 6b–e were prepared
by the aromatic Pummerer-type reaction of the aniline
derivatives (1) shown in Scheme 1 followed by the oxida-
tion,10a the iterative use of the aromatic Pummerer-type
reaction has been proved to open a new route to the
regioselective preparation of biologically important
3,4-di- and 2,3,4-tri-substituted indole derivatives.
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13. A typical experimental procedure: under a nitrogen
atmosphere, trifluoroacetic anhydride (92 lL, 0.65 mmol)
was added to a solution of 6a (65 mg, 0.16 mmol) and 7a
(110 mg, 0.33 mmol) in anhydrous MeCN at 80 °C. The
In conclusion, we have developed a novel regioselective,
carbon–carbon bond-forming reactions at the C4-posi-
tion of the indole skeleton. This method features nucleo-
philic substitution on electron sufficient indoles that was
attained via their umpolung initiated by the aromatic
Pummerer-type reaction. The iterative application of
the single sulfinyl group of the aniline derivatives (1)
to two types of the aromatic Pummerer-type reactions
has attained an efficient construction of the multi-substi-
tuted indoles (8). The application of this method is
under study in our laboratory.
Acknowledgements
This research was financially supported in part by a
Grant-in-Aid for Scientific Research (S) from the Minis-