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.
center|380px|thumb|The Larock indole synthesis
Overall reaction
The reaction usually occurs with an o-iodianiline or its derivatives, 2–5 equivalents of an alkyne, palladium(II) (PdII), an excess of sodium or potassium carbonate base, PPh<sub>3</sub>, and 1 equivalent of LiCl or n-Bu<sub>4</sub>NCl. N-methyl, N-acetyl, and N-tosyl derivatives of ortho-iodoanilines have been shown to be the most successful anilines that can be used to produce good to excellent yields.
Reagents and optimal conditions
Chlorides
Either LiCl or n-Bu<sub>4</sub>N are used depending on the reaction conditions, but LiCl appears to be the more effective base in Larock indole annulation. O-bromoanilines and o-chloroanilines are more readily available and cost-effective over using o-iodianiline in Larock indole synthesis. The optimized Indole reaction uses 10% Pd/C (3.0 mol%) with 1.1 equivalent of NaOAc, and NMP at 110–130 °C. Monguchi et al. state that their optimized condition of the Larock indole synthesis without LiCl is a more mild, environmentally benign, and efficient strategy for producing indoles.
Applications
Indoles are one of the most prevalent heterocyclic structures found in biological processes, so the production of indole derivatives are important in a diversity of fields.
Nishikawa et al. derived iso-tryptophan by using Larock indole synthesis with pre-synthesized α-C-glucosylpropargyl glycine and o-iodo-tosylanilide. This reaction produced the product which had the reverse regioselectivity of normal Larock indole synthesis. The larger substituent was placed adjacent to the forming carbon-carbon bond, rather than the carbon-palladium bond. The explanation for the reverse regioselectivity which produced the iso-tryptophan is unknown.
[[File:Larock Indole Synthesis of alpha-C-Glycosylamino Acid to Iso-Tryptophan.jpg|center|500px|thumb|Larock indole synthesis of iso-tryptophan using α-C-glycosylamino acid
[[File:A reaction using Larock Indole Synthesis to produce chirally active tryptophan.jpg|center|450px|thumb|Chirally active tryptophan by Larock indole synthesis