Organic Letters
Letter
diphenylamine was suppressed. Control experiments to
support the proposed mechanism revealed that (1) ethylene
behaved as a hydrogen acceptor, (2) cyclohexenone was not a
key intermediate, and (3) phenol did not participate in the
AUTHOR INFORMATION
Corresponding Author
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Masahiko Hayashi − Department of Chemistry, Graduate
School of Science, Kobe University, Kobe 657-8501, Japan;
The result in entry 18 of Table 1, inspired us to employ the
Pd/C−ethylene system for the synthesis of indoles. Indoles are
biologically important heteroaromatic moieties found in nature
in compounds such as tryptophan and some alkaloids.17
Indoles have been reported to exhibit antioxidant activity,
anticonvulsant activity, and other biological activities. Many
synthetic methods for indole derivatives have been reported so
far. After the first indole synthesis by Baeyer in 1869,18 more
than 20 representative named reactions such as Fischer indole
synthesis,19 Reissert indole synthesis,20 Madelung indole
synthesis,21 Nenitzescu indole synthesis,22 Cadogan−Sundberg
indole synthesis,23 Hemetsberger indole synthesis,24 Gassman
indole synthesis,25 Mori−Ban indole synthesis,26 Sugasawa
indole synthesis,27 Saegusa−Ito indole synthesis,28 Leimgrub-
er−Batcho indole synthesis,29 Bartoli indole synthesis,30
Larock indole synthesis,31 and Fukuyama indole synthesis32
have been developed. The starting materials in all these
reactions, except the Nenitzescu indole synthesis,22 are
substituted benzenes, which are not always easy to prepare
tive previous synthetic methods of indoles). In contrast to the
reported methods, our method uses substituted cyclo-
hexanones as the starting material. Scheme 3 shows the entire
synthetic route from cyclohexanone to indole via 1,3-
diketones.
As shown in Table 3, a variety of substituted indoles were
synthesized in high and to excellent yield. In the case of indole
synthesis, addition of K2CO3 was not necessary. This may be
because of the high reactivity for aromatization of intermediate
enamine. Noteworthy is compound 7; only Bartoli indole
synthesis28 can introduce substituent at the 7 position so far.
Our method has enables the introduction of substituents at any
position of the indole by incorporating the substituents on the
cyclohexanones, pyrrolidine, and α-bromo ketones in advance.
Therefore, providing a valuable approach to prepare function-
alized indoles.
Authors
Katsumi Maeda − Department of Chemistry, Graduate School
of Science, Kobe University, Kobe 657-8501, Japan
Ryosuke Matsubara − Department of Chemistry, Graduate
School of Science, Kobe University, Kobe 657-8501, Japan;
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Financial support for this project was partially provided
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT), Japan.
REFERENCES
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(1) Arpe, H.-J. Benzene derivatives. In Industrial Organic Chemistry,
5th edition; WIELEY-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2010.
(2) Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry, 8th ed.;
Freeman, W. H. and Co.: New York, 2018; Chapters 15 and 16.
2006, 128, 10028−100029.
10354−10355.
(7) (a) Hayashi, M.; Yamada, K.; Nakayama, S.; Hayashi, H.;
Soc., Perkin Trans.1 2000, 1501−1503.
In conclusion, we have achieved the practical synthesis of
anilines and indoles from cyclohexanones using a Pd/C−
ethylene system under nonaerobic condition. The reaction
proceeds in good yields and affords a new approach to the
syntheses of these substrates which are important building
blocks in industry and academia.
2011, 333, 209−213. (b) Diao, T.; Pun, D.; Stahl, S. S. Aerobic
Pd(DMSO)2(TFA)2: Evidence for ligand-controlled chemoselectivity.
J. Am. Chem. Soc. 2013, 135, 8205−8212. (c) Pun, D.; Diao, T.; Stahl,
by Pd(TFA)2/2-dimethylpyridine: Evidence for the role of Pd
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
Solvent effect, effect of the nature of additives and their
amounts, control experiments to support proposed
mechanism, previous synthetic methods of indoles,
general procedure for the synthesis of substituted
anilines, general procedure for the synthesis of
substituted indoles, characterization of products 1H
and 13C NMR of products, references (PDF)
economy__A challenge for organic synthesis: homogeneous catalysis
(10) El-Deeb, I. Y.; Tian, M.; Funakoshi, T.; Matsubara, R.; Hayashi,
1533
Org. Lett. 2021, 23, 1530−1534