Divergent 2‐Chloroquinazolin‐4(3 H )‐one Rearrangement: Twisted‐Cyclic Guanidine Formation or Ring‐Fused N ‐Acylguanidines via a Domino Process

A highly efficient 2‐chloroquinazolin‐4(3 H )‐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).