Notes and references
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Scheme 3 The preparation of bioactive compounds. Reaction con-
ditions: PdCl2(PhCN)2 (5 mol%), Xantphos (10 mol%) and other
conditions are the same as the standard conditions given in Table 1.
3 (a) C. Zhang, Z. Xu, L. Zhang and N. Jiao, Angew. Chem., Int. Ed.,
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Interestingly, N-methyl-7-azaindole and N-benzyl pyrrole
could also undergo the reaction efficiently (4s and 4t).
As for the investigation of the amines, both primary and
secondary amines could be the appropriate partners (4u–4y),
and stronger electron-donating N-methylbenzylamine could
generate the target product 4u with a yield as high as 86%.
Surprisingly, t-BuNH2 performed slightly better than n-BuNH2
(4w and 4x), indicating that the hindrance of amines may not be
the key factor for the monocarbonylation, while the nucleo-
philicity played a more important role, and that hypothesis
could possibly be further clarified when only a trace amount of
product 4z was achieved. To further verify the structure of
indole-3-amide, the single crystal structure of 4v was analyzed
(CCDC 895173, ESIw).
Indole-3-ketoamide has been proved to be the nucleus
skeleton of a large number of molecules with biological
activity such as 3w (Scheme 3), which belongs to a group of
HIV-1 inhibitors targeting the glycoprotein gp120 situated in
the viral envelope.2 To further extend the practical application
of the present carbonylation method, we focused our efforts to
synthesize compounds 3w and 3x from indoles and N-benzoyl-
piperazine. Unfortunately, using the above double carbonyla-
tion procedure, only 29% yield of 3x was obtained, thus
reoptimization of the Pd-catalyst is necessary to obtain high
yield of the pharmaceutically interesting product. We finally
found that 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos) could be a more favorable assisting ligand with
the presence of PdCl2(PhCN)2 to replace PdCl2(dppf), and
moderate yields of 3w and 3x could be obtained (for experi-
mental details, see ESIw). Thus, this methodology would be of
importance to the facile synthesis of these bioactive HIV-1
inhibitors from readily available starting substrates.
5 For reviews on C–X carbonylation, see: (a) A. Brennfuhrer,
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In conclusion, we have developed an efficient carbonylative
synthesis of indole-3-a-ketoamides and indole-3-amides with
good tolerance of both secondary and primary amines as
nucleophiles. Complete control of product selectivity in the
carbonylation of unfunctionalized (hetero)aromatics was
proved to be possible through slight modification of reaction
conditions. Further investigations to understand the reaction
mechanism and the synthetic applications to other hetero-
aromatic C–H bonds are ongoing in our laboratory.
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We thank the Chinese Academy of Sciences and National
Natural Science Foundation of China (21002106 and 21133011)
for financial support.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11023–11025 11025