indoles - rhodium catalysis - oxidative coupling
Significance
Reported here is the rapid synthesis of indoles 3 via
the rhodium-catalyzed oxidative coupling of acetanilides 1 and internal alkynes 2.
Extensive optimization with regard to the catalyst, additives and
solvent led to the preferred conditions detailed above. Both electron-rich
and -deficient acetanilides participate well in the reaction. Substrates
bearing an ortho-substituent are also
tolerated. When a meta-substituent is present,
cyclization is directed to the least sterically hindered position.
Experiments to probe the reaction mechanism using deuterated substrates and
solvents suggest that initial rhodation on the aniline occurs at
both ortho-positions, and that only the
least hindered regioisomer undergoes cyclization to give
the observed regioselectivity. Removal of the acetyl group was achieved
in >90% yield in all cases on standard treatment
with KOH or K2CO3 in MeOH-CH2Cl2.
Comment
Indoles are ubiquitous in nature and are present in many drug
compounds (see Book below). Aside from classical methods, transition-metal-catalyzed
reactions have, within the last decade, become recognized as powerful
tools for the synthesis of indoles (G. Zeni, R. C. Larock Chem. Rev. 2004, 104, 2285).
However, these methods typically rely on a preactivated substrate in
the form of an aryl halide, adding cost and reducing the number
of readily available starting materials. The current method takes
advantage of a C-H activation event to provide indoles
from simple and inexpensive anilines. The substrate scope with regard
to aryl substitution was adequately studied but the acetylene scope
is somewhat limited at this stage. Extension to functionalized acetylenes
would be advantageous for further synthetic manipulation.
Book: J. A. Joule, In Science
of Synthesis, Vol. 10; J. Thomas, Ed.; Georg Thieme Verlag:
Stuttgart, New York, 2000, 361-593.
