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Scheme 2 The proposed mechanism for C3-formylation of indole.
free radical process. When N-((1H-indol-3-yl)methyl)aniline 5
(Scheme 2) was subjected to the optimized conditions, the
formylation product 3a was obtained in 70% yield (see ESIw).
The cross dehydrogenative coupling product 5 may be involved
as an intermediate in the present reaction. Based on our
observations and studies from other groups,14,19 a plausible
catalytic cycle has been proposed as shown in Scheme 2.
Initially, a reaction between an iodide (Iꢀ) ion and TBPB
provides a benzoyloxy radical (or tert-butyloxy radical) and
iodine (I2). The thus-generated radical abstracts a hydrogen
atom from the C–H bond adjacent to a nitrogen atom to
afford radical 6, followed by oxidation to afford the iminium
ion 7. Subsequently, nucleophilic attack of indole 1a to 7
affords intermediate 5. Intermediate 5 undergoes a similar
process to give the second iminium ion 8, followed by hydro-
lysis to give the corresponding 3-formylindole 3a. We think
that the I2/Iꢀ redox process accelerates the formation of
iminium ions 7 and 8. Investigations that provide a more
detailed mechanism are underway in our laboratory.
6 Another plausible mechanism involving free radicals has also been
suggested for this catalyst system, see ref. 5a and c.
7 R. J. Sundberg, in Indoles, Academic Press, London, 1996, p. 105.
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¨
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In summary, the first nBu4NI-catalyzed C3-formylation of
indoles with N-methylaniline is presented. The method can be
applied to N–H and N-substituted indoles without using toxic
phosphorus oxychloride and transition metal.
14 W. Wu and W. Su, J. Am. Chem. Soc., 2011, 133, 11924.
15 (a) W. Wu, J. Xu, S. Huang and W. Su, Chem. Commun., 2011,
47, 9660; (b) E. M. Ferreira and B. M. Stoltz, J. Am. Chem. Soc.,
2003, 125, 9578.
16 Other oxidants were also investigated, see ESIw.
17 The reaction gave poor yields catalyzed by nBu4NCl or nBu4NBr
under standard conditions, see ESIw.
18 (a) S. Murata, M. Miura and M. Nomura, J. Chem. Soc., Chem.
Commun., 1989, 116; (b) S. Murata, M. Miura and M. Nomura,
J. Org. Chem., 1989, 54, 4700.
Financial support from the National Natural Science
Foundation of China (No. 21172120, 20902050) is gratefully
acknowledged.
Notes and references
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1955, 591, 53; (b) L. Horner and W. Kirmse, Justus Liebigs Ann.
Chem., 1955, 597, 48; (c) C. M. R. Volla and P. Vogel, Org. Lett.,
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1 For books and reviews, see: (a) A. Varvoglis, Hypervalent Iodine in
Organic Synthesis, Academic Press, London, 1997, p. 1; (b) T. Wirth
and Y. Kita, Hypervalent Iodine Chemistry, Springer Verlag, 2003;
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5187–5189 5189