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. Modifications and variations o-bromoanilines or o-chloroanilines do not undergo Larock indole synthesis. However, researchers from Boehringer-Ingelheim were able to successfully use both o-bromoanilines and o-chloroanilines to form indoles by using N-methyl-2-pyrrolidone (NMP) as the solvent with 1,1'bis(di-tert-butylphosphino)ferrocene as the palladium ligand. O-bromoanilines and o-chloroanilines are more readily available and cost-effective over using o-iodianiline in Larock indole synthesis. Monguchi et al. also derived 2- and 2,3-substituted indoles without using LiCl. 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. Optically active tryptophan which adheres to the regioselectivity of the Larock indole synthesis can also be synthesized using o-iodoaniline with propargyl substituted bislactim ethyl ether.