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. 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, PPh3, and 1 equivalent of LiCl or n-Bu4NCl. 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-Bu4N are used depending on the reaction conditions, but LiCl appears to be the more effective base in Larock indole annulation. The stoichiometry of LiCl is also considerably important, as more than 1 equivalent of LiCl will slow the rate of reaction and lower the overall yield. Bases Bases other than sodium or potassium carbonate have been used to produce a good overall yield of the annulation reaction. For example, KOAc can be used with 1 equivalent of LiCl. However, the reaction using KOAc must be used at 120 °C to reach completion of the reaction at a reasonable time. In contrast K2CO3 can be used at 100 °C. Alkynes The Larock indole synthesis is a flexible reaction partly due to the variety of substituted alkynes that can be used in the annulation reaction. In particular, alkynes with substituents including alkyls, aryls, alkenyls, hydroxyls, and silyls have been successfully used. However, bulkier tertiary alkyl or trimethylsilyl groups have been shown to provide a higher yield. The annulation reaction will also proceed more efficiently when 2–5 equivalents of an alkyne is used. Less than two equivalents appear to create suboptimal conditions for the reaction. PPh3 as a catalyst 5% mol of PPh3 was initially used in the reaction as a catalyst. However, later experiments have shown that PPh3 does not significantly improve the overall yield and is not necessary. Reaction mechanism 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