Workers at Merck have recently published a new synthesis of 3-methylindoles. N-Boc-allyl amine and an ortho-chloroaryl triflate are coupled together in a 3-step one pot approach. The first step is a Heck reaction catalysed by Pd(OAc)2 with dppf as ligand and NaOAc in acetonitrile. A solvent switch from acetonitrile to DMF is carried out and then Pd(OAc)2 and the X-Phos ligand are added to cyclise to the indole with an exocyclic double bond.. Addition of camphorsulphonic acid at the end of the cyclisation isomerises the double bond to give the indole. This chemistry allows 4-, 5-, 6-, and 7-substituted indoles to be prepared in yields of 54-80% for the 3-step sequence.
Presumably alternative 3-substituted or even 2,3-disubstituted indoles could be prepared using this method by employing more substituted allyl amines.
C.A. Baxter,* E. Cleator,* M. Alam, A.J. Davies, A. Goodyear, and M. O'Hagan (Merck Sharp and Dohme), Org. Lett., 2010, 12(4), 668-671.