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Synfacts 2013; 9(1): 0026
DOI: 10.1055/s-0032-1317869
Synthesis of Heterocycles
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed C–N/C–C Coupling Route to Substituted Indoles

Contributor(s):
Victor Snieckus
,
Suneel P. Singh
Knapp JM, Zhu JS, Tantillo DJ, Kurth MJ * University of California Davis, USA
Multicomponent Assembly of Highly Substituted Indoles by Dual Palladium-Catalyzed Coupling Reactions.

Angew. Chem. Int. Ed. 2012;
51: 10588-10591
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Further Information

Publication History

Publication Date:
17 December 2012 (online)

 
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Key words

indoles - azaindoles - Heck coupling - Buchwald–Hartwig cross-coupling - palladium catalysis

Significance

Reported is the one-pot synthesis of highly substituted indoles 4 via a sequential palladium-catalyzed C–N and C–C coupling reaction of o-bromoiodo arenes 1, carbonyl derivatives 3, and amines 2. The reaction is proposed to proceed by C–N coupling to generate aryleneamine intermediate 5 which undergoes an intramolecular arene–alkene coupling reaction (eq 1). This sequence of events is supported by an adequate number of experiments. The authors also suggest that the mechanism of the final step differs from a traditional Heck reaction. Among several ligands, bases and solvents tested, 1,1′-bis(diphenylphosphanyl)ferrocene (dppf) in combination with a weak base (Cs2CO3) in toluene was suited best. The addition of MgSO4 proved beneficial, presumably by favoring eneamine formation. The reaction failed when Pd(OAc)2 was used in place of Pd2dba3. Both aldehydes and cyclic/acyclic ketones gave moderate yields of indoles. Two examples of azaindoles (Y = N) were also reported. A pyridine derivative (R3 = 4-py) was also tolerated.


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Comment

The synthesis and functionalization of indoles has been a major area of focus for organic chemists due to its importance in the pharmaceutical field (see Book below). Numerous synthetic methods for indoles including Fischer indole synthesis and its modifications have been reported (see Review below). The current one-pot three-step method provides highly functionalized indoles in moderate yield using readily available starting materials. Although it was indicated that the reaction failed with a carbomethoxy derivative of 3, the reaction scope and limitations were not well investigated.


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Book

Heterocyclic Scaffolds II: Reactions and Applications of Indoles, Vol. 26.; G. W. Gribble, Volume Ed.; In Topics in Heterocyclic Chemistry; B. U. W. Maes, Series Ed.; Springer: New York, 2010.


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Review

G. R. Humphrey, J. T. Kuethe Chem. Rev. 2006, 106, 2875–2911.


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