A Bifurcated Multicomponent Synthesis Approach to Polycyclic Quinazolinones

Abstract

The rapid synthesis of diverse substituted polycyclic quinazolinones was achieved by two orthogonal Ugi four-component reaction (Ugi-4CR)-based protocols: the first two-step approach via an ammonia-Ugi-4CR followed by palladium-catalyzed annulation; in the second approach, cyanamide was used unprecedently as an amine component in Ugi-4CR followed by an AIBN/tributyltin hydride-induced radical reaction. Like no other method, MCR and cyclization could efficiently construct many biologically interesting compounds with tailored properties in very few steps.

Scheme 1. Representatives and Synthesis of Polycyclic Quinazolinones

Scheme 2. Substrate Scope in the [Pd]-Catalyzed Synthesis of Polycyclic Quinazolinones^–

Acid, isocyanide, aldehyde, and ammonia components are depicted with red, green, blue, and pink color, respectively. Ugi reaction was carried out using 6 (1 mmol), 7 (1 mmol), 8 (1 mmol), and 9c (1 mmol) in TFE (1 M) for 12 h at r.t. [Pd]-catalyzed reaction conditions: 10–34a (0.2 mmol), Pd(OAc)₂ (5 mol %), dppf (10 mol %), K₂CO₃ (1 mmol), 1,4 dioxane (2 mL), reflux, overnight. Yield refers to purified products.

Scheme 3. Scale-up Synthesis

Scheme 4. Synthesis of luotonin Derivatives

Scheme 5. Various Isocyanides in the Synthesis of Polycyclic Quinazolinones via Radical Cyclization^–

Acid, aldehyde, isocyanide, and cyanamide components are depicted with red, blue, green, and pink color, respectively. Ugi reaction was carried out using 36 (1 mmol), 37 (1 mmol), 8 (1 mmol), and 38 (1 mmol) in TFE (1 M) for 12 h at r.t. Radical cyclization conditions: 39–41a (0.15 mmol), tributyltin hydride (0.3 mmol), AIBN (0.15 mmol), benzene (7 mL), reflux, overnight. Yield refers to purified products.