Isoquinolines by Manganese-Catalyzed Annulation of Aryl Imines with Alkynes

Significance

Reported is a [MnBr(CO)₅]-catalyzed [4+2] annulation of aryl ketimines and alkynes to produce diversely substituted isoquinoline derivatives 3 (variation of the Povarov reaction, see Review below). The reactions of differently ring substituted diaryl and aryl alkyl ketimines with substituted or terminal aromatic and aliphatic acetylenes to produce derivatives 3 with good yields are reported. A C–H bond activation mechanism is proposed as a major route based on ¹H NMR data of X, Y, and 3 and detection of H₂ as well as CO by GC. The five-membered manganacycle intermediate X is formed from the reaction of imines 1a with [MnBr(CO)₅], which upon subsequent addition to acetylene 2a affords the isoquinoline derivative 3 through another intermediate, the seven-membered manganacycle Y. The regio­selectivity appears to depend on the electronegativity and secondary directing effect of the substituent and its position in the aromatic ring.

Comment

Aryl-substituted isoquinolines are of great pharmaceutical importance due to their wide range of biological activities. Methods for isoquinoline synthesis involving [4+2] annulation or cycloaddition are well known. Pd(OAc)₂-catalyzed annulation of ortho-alkynyl-arylaldehyde and -imines affords isoquinolines (K. R. Roesch, H. Zhang, R. C. Larock J. Org. Chem. 2001, 66, 8042). The reported method provides another general route to differently substituted isoquinoline derivatives with functional-group tolerance and conditional regioselectivity, with moderate to good yields. Further investigations of the mechanism and of applications of the manganese-catalyzed C(sp²)–H bond-activation process are encouraged.

Review

L. S. Povarov Russian Chem. Rev. 1967, 36, 656–670.