Abstract
The sequential N-functionalization of 2-aminobenzylamine (2-ABA) followed by cyclodehydration allowed for a straightforward and efficient synthesis of 3,4-dihydroquinazolines with N-aryl substituents bearing electron-withdrawing groups. The sequence involves an initial SNAr displacement, N-acylation and MW-assisted ring closure. Remarkably, the uncatalyzed N-arylation of 2-ABA led to the monosubstitution product using equimolar amounts of both reagents. The individual steps were optimized achieving good to excellent overall yields of the desired heterocycles, avoiding additional protection and deprotection steps. A mechanistic interpretation for the cyclodehydration reaction promoted by trimethylsilyl polyphosphate (PPSE) is also proposed on the basis of literature data and our experimental observations.
Highlights
Dihydroquinazolines (DHQs) represent heterocyclic cores of pharmacological interest
Our synthetic approach represents the first method for the preparation of 2-substituted-3-aryl-3,4-dihydroquinazolines with electron-withdrawing groups (EWGs) in the aryl moiety
A careful optimization of the individual steps allowed for the selective functionalization of 2-ABA, avoiding the use of protecting groups, and affording the desired heterocycles in good to excellent overall yields
Summary
Dihydroquinazolines (DHQs) represent heterocyclic cores of pharmacological interest. For example, vasicine is a 3,4-dihydroquinazoline alkaloid isolated from natural sources with antitumor activity [1]. The already described methods for the synthesis of 4-unsustituted N-aryl-3,4-DHQs are either limited to symmetrical substitution patterns, lead to byproducts and afford low yields, require the use of complex catalysts and ionic liquids or involve reductive conditions that are incompatible with nitro or cyano groups. Selective SNAr reactions were reported for polyhaloaryl substrates [73,74], while alkanediamines require in most cases either a large excess of the nucleophile [75,76,77] or Boc protection [78,79] in order to obtain the monoarylated product in acceptable yields.
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