A rapid and efficient method for the reduction of nitrogen heterocycles

ORGN 147

Daniel C. Poppy, ralph.salvatore@umb.edu1, Andrew McKinney1, Kevin R. Jackson1, Aaron M. Smith1, Ralph N. Salvatore, ralph.salvatore@umb.edu1, Elena-Maria Savarides, tgavin@iona.edu2, Mary Jane Eddattel, tgavin@iona.edu2, and Terrence Gavin, tgavin@iona.edu2. (1) Department of Chemistry, University of Massachusetts-Boston, Boston, MA 02125, (2) Department of Chemistry, Iona College, Iona College, 715 North Avenue, New Rochelle, NY 10801
The selective reduction of heterocyclic rings in benzo-fused nitrogen compounds such as quinoxalines, quinolines and isoquinolines is important in organic synthesis, since the corresponding tetrahydro products serve as key intermediates in the preparation of drugs, agrochemicals, dyes, higher alkaloids etc. Numerous methods have been used for this transformation; however, conventional procedures often require extended reaction times, substantial purifications, and result in mixtures of stereoisomers. We wish to report herein a rapid, easy, and efficient method for the selective reduction of various substituted N-heterocycles. At the outset of this work, mono and di-substituted alkyl and aryl quinoxalines were rapidly reduced in high yield to their respective 1,2,3,4-tetrahydro-derivatives by in-situ generated borane in THF solution. Solutions of borane-THF were efficiently generated from the addition of iodomethane to lithium borohydride and this technique, produced products that are indistinguishable from those obtained from commercially available borane-THF solutions. In the case of the 2,3-di-substituted compounds, reduction was stereoselective yielding exclusively the corresponding cis-isomers. Therefore, high yields and fast reaction times render borane-THF a superior reagent for the transformation of quinoxalines to 1,2,3,4-tetrahydroquinoxalines. Likewise, sodium borohydride in acetic acid also reduces alkyl and aryl quinoxalines, but proceeds with lower yields and often produces side products. Sodium borohydride in ethanol reduces quinoxaline and 2-methylquinoxaline in high yield, however, the reaction is very slow, whereas 2,3-dialkyl and 2-aryl quinoxalines were not efficiently reduced by sodium borohydride in ethanol. Currently, we are extending this procedure to the reduction of various substituted isoquinolines and quinolines, respectively.