Larock indole synthesis

What is Larock indole synthesis?

The Larock heteroannulation, also known as Larock indole synthesis, is a palladium-catalyzed reaction that was first reported by Larock and colleagues in 1991. This reaction involves the chemoselective and “ligandless” heteroannulation of ortho-iodoanilines and disubstituted alkynes to produce substituted indole derivatives.

Larock indole synthesis - general reaction scheme
Larock indole synthesis
  • (if R2 > R3)
  • R1 = H, Me, CH3CO, Tosyl (see list of acronyms)
  • R2, R3 = alkyl, aryl, alkenyl, hydroxyalkyl, trialkylsilyl

The reaction’s outcome is influenced by various factors, such as the addition of a base, lithium halide, and its stoichiometry, the presence or absence of the ligand PPh3, and the reaction temperature.

For example, when using 5 mol % of Pd(OAc)2 as the catalyst and 5 eq. of base in 10 mL DMF, it is unnecessary to have a ligand present in the reaction of 0.25 mmol ortho-iodoaniline with 0.75 mmol alkyne (3 eq.). The bases tested for this reaction include KOAc, NaOAc, K2CO3, and Na2CO3, with potassium salts demonstrating better results than sodium salts. KOAc is always superior to K2CO3 except when no other reagent is added, such as LiCl. The best conditions for the Larock indole synthesis involve using 5 mol % Pd(OAc)2 and either KOAc or K2CO3 as the base, with 1 eq. LiCl and 2–5 eq. alkynes. The reaction must be carried out at a temperature > 120 ºC, and the addition of 5 mol % of ligand will lower the yield.

The Larock heteroannulation tolerates diversified substituents on the alkynes and nitrogen atom of anilines. For instance, the substituents on the nitrogen atom of anilines can be methyl, acetyl, tosyl, etc., and the alkynes can bear alkyl, aryl, alkenyl, hydroxyl, and silyl groups. This reaction is highly regioselective, with the more sterically bulky group ending up at the 2-position. However, for the case of diethyl acetal of 2-butynal, no regioselectivity was observed, possibly due to an electronic effect.

Furthermore, for the reaction between o-iodoacetylaniline and alkynes with a hindered or unhindered hydroxyalkyl group, the migration of the N-acetyl group from nitrogen to the alcohol group sometimes occurs, possibly arising from the base-catalyzed intramolecular transfer of the acetyl group.

The application of Larock indole synthesis extends to the synthesis of diverse heterocycles. These heterocycles include 5-azaindoles, 5-, 6-, and 7-aza-indoles, pyrrolo[3,2-c]quinolines, 12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline.


Synthesis of indoles via palladium-catalyzed heteroannulation of internal alkynes
Richard C. Larock and Eul Kgun Yum
Journal of the American Chemical Society 1991 113 (17), 6689-6690
DOI: 10.1021/ja00017a059