Communication
The methods available in the literature for the synthesis of
2-acyl-3-amino-substituted benzofurans and indoles include re-
actions between the corresponding 2-cyanophenol, 2-amino-
its potential usefulness. There are limited examples with dicar-
bonyl/imidoyl insertion for the synthesis of a-ketoamides/
esters and iminoimidates.[13a–c]
benzonitrile,[6a–c]
or
3-hydroxypyridine-2-carbonitrile
for
Based on these facts, we hypothesized that the concise syn-
thesis of 2-acyl-3-amino-substituted benzofurans/indoles could
be achieved by a palladium-catalyzed cascade process involv-
ing an oxidative addition, isonitrile insertion, a-Csp3ÀH cross-
coupling,[14] reductive elimination, and isomerization of o-iodo-
phenol/anilides, a-bromoketones, and isonitriles (Sche-
me 1c,d). In a similar way, o-iodoanilines could be transformed
to isatins by a cascade reaction consisting of an oxidative addi-
tion, double isonitrile insertion, amination, reductive elimina-
tion, and hydrolysis (Scheme 1e).
furo[3,2-b]pyridines, with a-bromoketones mediated by strong
base[6d–e] (Scheme 1a). In addition, recent methods to construct
isatins include a) intramolecular oxidative cyclization of formyl-
N-aryl-formamides;[7a] b) reaction of arynes with methyl 2-oxo-
2-(arylamino)acetates;[7b] c) intramolecular oxidative CÀH ami-
nation of 2-amino acetophenones;[7c–g] and d) reaction of ani-
lines with carbonyl precursors[7h] (Scheme 1b). Although these
methodologies provide useful access to oxygen or nitrogen
heterocycles, there are some limitations, for example, the mul-
tistep synthesis of starting materials, hazardous reagents, harsh
reaction conditions, low reaction yield, and poor substrate
scope.
The initial investigation began with 2-iodophenol (1a), phe-
nacyl bromide (2a), and tertiary butyl isonitrile (3a) as model
substrates by using 10 mol% of Pd(OAc)2 and K2CO3 (2.0 equiv)
in CH3CN for 16 h at 858C. To our delight, compound 6a was
isolated in 20% yield (Table 1, entry 1). Encouraged by this ini-
tial result, the reaction was screened with various solvents and
DMSO was found to be the best choice (entries 2–5). Changing
the catalyst from Pd(OAc)2 to other PdII and Pd0 sources failed
to improve the reaction yield (entries 6–11). The effect of base
was also examined and K2CO3 was found to be superior to
other bases (entries 12–15); compound 6a was prepared with
a yield of 70% (entry 5). Furthermore, it was observed that the
product yield was affected by increasing the amount of base
from 2.0 to 3.0 and 3.5 equivalents, affording 6a in 85 and
83% for 3.0 and 3.5 equivalents, respectively (entries 16–17).
The effect of temperature on the
In this context, we became interested in the development of
a facile approach for the synthesis of 2-acyl-3-amino-substitut-
ed benzofurans/indoles and isatins. Recently, palladium-cata-
lyzed cascade reactions have emerged as an attractive strategy
to avoid the need for elaborate precursors and enhance the ef-
ficiency of reaching target molecules.[8] Palladium-catalyzed mi-
gratory insertion of isonitrile[9] and carbon monoxide have
emerged as a powerful methods for the construction of carbo-
or heterocycles.[10–12] To the best of our knowledge, palladium-
catalyzed single isonitrile insertion followed by a-Csp3ÀH
cross-coupling, or double isonitrile insertion followed by ami-
nation, is not known for the synthesis of heterocycles despite
reaction was also examined and
it was found that the reaction
yield was diminished at 608C
(entry 18); at 1008C there was
no significant change (entry 19).
Finally, studies with 1.2 equiva-
lents phenacyl bromide (2a) and
1.1 equivalents tertiary butyl iso-
nitrile (3a) were conducted and
resulted in decreased reaction
yields (Table 1, entries 21 and
22). Thus, the reaction parame-
ters given in Table 1, entry 16
were the optimum reaction con-
ditions.
With the optimized reaction
conditions in hand, the scope of
phenols (1a–f), a-bromoketones
(2a–k), and isonitriles (3a–d)
were investigated, as shown in
Table 2. Pleasingly, the reaction
performed on a larger scale (five-
fold) underwent smooth conver-
sion to afford compound 6a in
83% yield. If the R1 position of
the
a-bromoketones
was
a phenyl ring, both electron-do-
nating and electron-withdrawing
Scheme 1. Synthetic approaches towards 2-acyl-3-amino benzofurans/indoles and isatins.
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Chem. Eur. J. 2014, 20, 1 – 7
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ÝÝ These are not the final page numbers!