A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring

Abstract

We report herein a new methodology for synthesizing quinazoline derivatives bearing an heteroarylamino moiety at position 4 of the quinazoline ring. As an alternative to the Buchwald-Hartwig cross-coupling reaction which appears, until now, as the only efficient way to react 4chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol% of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2substitued-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest.

Acid catalyzed synthesis of 2-(2-aminophenyl)quinazoline-4-amine and reaction with aromatic aldehydes

“…In an attempt to understand if the nature and position of the substituent on the aromatic ring of the aldehyde influenced the relative amounts of the species in solution at 80 °C and 20 °C we used the Hammett-Brown parameter (σ*), calculated for the aryl group using the "ACD Lab Sigma Predictor" program. The relationship of this parameter with log K, defined as the ratio K = [5] / [2a], is depicted in scheme 1. A linear relationship was observed between these values, either at 80 °C or at 20 °C, confirming that the polar effect of the aromatic substituent influences this equilibrium.…”

2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

“…Key substrate (1) was obtained from a condensation reaction of o-phenylenediamine with ethyl pyruvate to provide the corresponding lactam followed by a chlorination reaction using POCl 3 [8] (Scheme 1). Next, chlorimine (1) was reacted by a nucleophilic aromatic substitution reaction (S N Ar) with various phenol derivatives using cesium carbonate in DMF at 70 • C. The desired intermediates (2a-2t) were obtained in moderate to quantitative yields (45 to 99%).…”

Looking for new antiplasmodial quinazolines: DMAP-catalyzed synthesis of 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines and their in vitro evaluation toward Plasmodium falciparum

“…Nevertheless, because of the expensive costs of both palladium catalysts and ligands, in order to set up a cheap and simple operating procedure, we decided to study the one pot S N Ar reaction between 4-chloro-2-trichloromethylquinazoline 1and benzyl alcohol. To facilitate the S N Ar reaction between 1 and poorly nucleophilic species like amino- substituted heterocycles, our group recently reported a synthetic procedure usingN-Ndimethylaminopyridine (DMAP) as an efficient catalyst, involving the formation of a highly reactive quinazoline intermediate which we isolated and characterized by X-ray diffraction [25]. Then, benefiting from our experience in the use of microwave irradiation for introducing substituents at position 4 of the quinazoline ring [26], and considering that a successful microwave-assisted S N Ar reaction between a 4-chloroquinazoline derivative and ethylene glycol had been reported [27], we focused on a S N Ar reaction protocol combining a DMAP catalysis with microwave irradiation.For that purpose, we first prepared substrate 1 (Figure 1), from commercial 2-methylquinazolin-4(3H)-one, according to a previously reported microwave synthesis using PCl 5 in POCl 3 [28].…”

“…This last was first chlorinated at position 4, by using POCl 3 , according to a previously microwaveassisted reported procedure [25], leading to 4-chloro-2-methylquinazoline in 73% yield. Then, the general DMAP-catalyzed operating procedure described in § 3.…”