Divergent 2‐Chloroquinazolin‐4(3<i>H</i>)‐one Rearrangement: Twisted‐Cyclic Guanidine Formation or Ring‐Fused <i>N</i>‐Acylguanidines via a Domino Process
Gang Yan, Bereket L. Zekarias, Xiaoyu Li, Victor A. Jaffett, Ilia A. Guzei, Jennifer E. Golden
Abstract
A highly efficient 2-chloroquinazolin-4(3H)-one rearrangement was developed that predictably generates either twisted-cyclic or ring-fused guanidines in a single operation, depending on the presence of a primary versus secondary amine in the accompanying diamine reagent. Exclusive formation of twisted-cyclic guanidines results from pairing 2-chloroquinazolinones with secondary diamines. Use of primary amine-containing diamines permits a domino quinazolinone rearrangement/intramolecular cyclization, gated through (E)-twisted-cyclic guanidines, to afford ring-fused N-acylguanidines. This scalable, structurally tolerant transformation generated 55 guanidines and delivered twisted-cyclic guanidines with robust plasma stability and an abbreviated total synthesis of an antitumor ring-fused guanidine (4 steps, 55 % yield).