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

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). Two distinct guanidine structural classes were generated selectively via a 2‐chloroquinazolinone rearrangement. The reaction either arrests at the twisted‐cyclic guanidine stage or gives ring‐fused N‐acylguanidines via a domino rearrangement/intramolecular cyclization, depending on diamine substitution.