Solid-Phase Synthesis of 2-Aminoquinazolinone Derivatives with Two- and Three-Point Diversity

Abstract

A versatile solid-phase method for the synthesis of various substituted 2-amino-4(3H)-quinazolinones with two- and three-point diversity is described. The synthesis commenced with the generation of polymer-bound S-methylisothiourea followed by N-acylation with different substituted o-nitrobenzoic acid. Finally, reduction of the nitro group triggered intramolecular cyclization via formation of guanidine to afford 2-amino-4(3H)-quinazolinone and its derivatives in high yields and purities.

ChemInform Abstract: Synthesis of 2‐Amino 3‐Substituted Quinazolin‐4(3H)‐one Derivatives via Iodine‐Mediated Guanidinylation of Pbf‐Activated Thiourea.

“…It is also noteworthy that the cyclization procedures are different between the guanidine heterocyclic skeletons of 1 and six-membered 2-(N-alkylamino)-pyrimidin-4-one derivatives [12]. The spectral data of compounds 1a and 1g is identical to that reported earlier [7,8]. With the reaction conditions described above, we screened a range of different primary amines to explore the scope and limitations of the synthetic methodology.…”

“…According to this mechanism, from thiourea 4 to heterocycles 5, prolonged reaction time and elevated reaction temperature helped product formation in high yield. Aromatic amines with electron-donating substituents promote the guanidinylation reaction (entries [8][9][10][11], at the same time electron-withdrawing substituents such as a nitro or a chloro group failed to afford compounds 5l and 5m (entries 12 and 13). It is also noteworthy that the cyclization procedures are different between the guanidine heterocyclic skeletons of 1 and six-membered 2-(N-alkylamino)-pyrimidin-4-one derivatives [12].…”

“…Furthermore, novel synthesis method involving Friedel-Craft's type substitution from aniline was reported recently [5]. Among them, the representative pathways involved one-carbon compounds as synthetic intermediate [7] and the guanidine conversion of S-methyl isothiourea, respectively [8]. Among them, the representative pathways involved one-carbon compounds as synthetic intermediate [7] and the guanidine conversion of S-methyl isothiourea, respectively [8].…”

“…However, despite the simple skeleton of 2-amino 3-substituted-quinazolin-4(3H)-ones with a free amino group at position 2, to date, only a limited number of synthesis strategies have been disclosed [6a,6b,7,8]. Among them, the representative pathways involved one-carbon compounds as synthetic intermediate [7] and the guanidine conversion of S-methyl isothiourea, respectively [8]. The major limitations of the methods mentioned above to 2-amino 3-substituted-quinazolin-4 (3H)-ones are the harsh reaction conditions and the difficulties in introducing substitutions at the 3-position.…”

Efficient Room‐Temperature One‐Pot Synthesis of 2‐Amino‐3‐alkyl(3‐aryl)quinazolin‐4(3H)‐ones

“…Solid-phase approaches to their synthesis have been reported using multistep procedures, and the cleavage from the resin most often requires strongly acidic conditions. [24] Moreover, in these methods, the ringclosure reaction, mainly from guanidine intermediates, may be nonregioselective depending on the nucleophilicity of both the nitrogen atoms.…”