Organic Chemistry Portal
Organic Chemistry Highlights

Monday, June 28, 2004
Douglass Taber
University of Delaware

Preparation of Cyclic Amines

As cyclic amines are at the heart of medicinal chemistry, there is always interest in new methods for their preparation. Marco Ciufolini of the Université Claude Bernard in Lyon reports (Org. Lett. 2003, 5, 4943. DOI: 10.1021/ol0358049) the preparation of a series of dihydro indole derivatives, exemplified here by 3, 6, and 9, by free radical cyclization of an N-O precursor. The N-O precursor can be prepared from the corresponding bromide, as illustrated by the conversion of 1 to 2 and of 4 to 5. Alternatively, a radical precursor such as 8 can be prepared separately. The generated radical is then trapped by 7 to make a new radical, that cyclizes to 9.

Heteroaromatics such as 10 are inexpensive compared to enantiomerically-pure cyclic amines such as 11. Yong-Gui Zhou of the Dalian Institute of Chemical Physics reports (J. Am. Chem. Soc. 2003, 125, 10536. DOI: 10.1021/ja0353762) the development of a chiral Ir catalyst that effects hydrogenation of 10 to 11 (700 psi H2, RT, 18 h) in 93% ee. The process is compatible with esters, alcohols and ethers on the sidechain.

The Fischer indole synthesis has been a workhorse of medicinal chemistry. What has been needed is a procedure of comparable ease and efficiency for converting a ketone or aldehyde such as 12 to the corresponding pyridine, such as 13. Antonio Arcadi of the University of Milan has now developed (J. Org. Chem. 2003, 68, 6959. DOI: 10.1021/jo0347260) just such a procedure, based on a gold-catalyzed condensation with propargylamine. The gold catalyst is commercially available. The regioselectivity of this procedure is noteworthy.

D. F. Taber, Org. Chem. Highlights 2004, June 28.