page_title: Larock indole synthesis
section_title: Reaction mechanism
hierarchical_section_title: Larock indole synthesis / Reaction mechanism
caption_attribution_description: English: The mechanism shows that Larock Indole Synthesis is regioselective and favors the larger R group to bind the Palladium.
context_page_description: The Larock indole synthesis is a heteroannulation reaction that uses palladium as a catalyst to synthesize indoles from an ortho-iodoaniline and a disubstituted alkyne. It is also known as Larock heteroannulation. The reaction is extremely versatile and can be used to produce varying types of indoles. Larock indole synthesis was first proposed by Richard C. Larock in 1991 at Iowa State University.
context_section_description: The Larock indole synthesis proceeds via the following intermediate steps:
  Pd(OAc)2 is reduced to Pd(0).
  A coordination of the chloride occurs to form a chloride-ligated zerovalent palladium.
  The o-iodoaniline undergoes oxidative addition to Pd(II).
  The alkyne coordinates to the Pd(II) by ligand exchange.
  A migratory insertion causes the alkyne to undergo regioselective syn-insertion into arylpalladium bond. Regioselectivity is determined during this step.
  The nitrogen displaces the halide in the resulting vinylic palladium intermediate to form the six-membered palladium-containing heteroatom.
  The Pd(II) center undergoes a reductive elimination to form the indole and regenerate Pd(0) which can then be recycled into the catalytic indole process.
  The carbopalladation step is regioselective when unsymmetrical alkynes are used. Although it was previously believed that the alkyne is inserted with the less sterically-hindering R-group adjacent to the arylpalladium, Larock et al. observed that the larger more sterically-hindering R-group is inserted next to the arylpalladium. They suggest that the driving force of the alkyne insertion may be the steric hindrance present in the developing carbon-carbon bond and the orientation of the alkyne prior to syn-insertion of the alkyne into the aryl palladium bond. Alkyne insertion occurs so that the large substituent on the alkyne avoids steric strain from the short developing carbon-carbon bond by interacting with the longer carbon-palladium bond.
caption: Regioselectivity of the alkyne insertion in Larock indole synthesis[3]
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