Cyclocondensation of 2-iodobenzaldehyde with benzamidines catalyzed by copper(I) iodide: a route to 2-arylquinazolines

Abstract

The reaction of benzamidines with 2-bromo-and 2-iodobenzaldehydes catalyzed by the CuI/L-proline system has been studied. Reaction with 2-iodobenzaldehyde leads to the formation of quinazolines in good yield. 2-Bromobenzaldehyde forms 2-arylquinazolines in low yield due to the competing reaction involving two molecules of amidine leading to a dihydrotriazine.Keywords: benzamidine, 2-iodobenzaldehyde, quinazoline, catalysis by copper(I).Up to the present many efficient methods have been developed for the N-arylation of various nitrogen nucleophiles with aryl bromides and iodides using the Cu(I)/ligand system as catalyst [1][2][3][4][5][6][7][8][9][10][11]. Intramolecular reactions of such type lead to benzo-condensed heterocycles [12][13][14][15], which broaden significantly the possibility of synthesizing many difficultly available compounds of this family. These methods are attractive from the availability and cheapness of reactants, simplicity of use, and frequent high yields.The aim of the present work was the involvement of benzamidines in cyclocondensation with o-halobenzaldehydes in the presence of a catalyst (CuI) and the development based on it of a new method of synthesis of 4-unsubstituted quinazolines, which are usually obtained in several stages and not always in good yield [16,17]. There was no information in the literature at the beginning of our investigation on such reactions. However, in the course of our work a report appeared from Chinese authors [18], which described the interaction of amidines with various aromatic aldehydes, ketones, and esters containing an atom of chlorine or bromine in the ortho position. In particular, 2-bromobenzaldehyde gives 2-substituted quinazolines in yields of 55-82% with amidines on catalysis with the CuI/L-proline system.In our experiments the reaction of 2-bromobenzaldehyde with amidines proceeded esentially by other route. We tested various conditions. The temperature regime, reaction time, solvent, and base were varied. The most characteristic experiments are given in Table 1. The yield of 2-phenylquinazoline 3a in the reaction with benzamidine did not exceed 32%. On carrying out the reaction with other ligands (N,N'-dimethylethylenediamine, ethylene glycol, 8-hydroxyquinoline) the target compound was formed in only trace amounts or was not formed at all. Variation of the reactant/catalyst ratio and the use of 4 Å molecular sieve did not affect the yield of quinazoline. Precise reproduction of the conditions of [18] also did not lead to the formation of quinazoline in satisfactory yield.

Six‐Membered Aromatic Nitrogen Heterocyclic Anti‐Tumor Agents: Synthesis and Applications

“…using o ‐iodobenzaldehydes 158 reacted with benzamidines 159 in this synthetic methodology can yield quinazoline 160 (Scheme 56). [204] …”

“…Lobanov et al using o-iodobenzaldehydes 158 reacted with benzamidines 159 in this synthetic methodology can yield quinazoline 160 (Scheme 56). [204] Beifuss et al effectively demonstrated the feasibility of utilizing 2-bromobenzyl bromides 161 as substrates through the inclusion of DMEDA as an additive (Scheme 57). [205] The use of water as a solvent in the reaction yielded satisfactory results, with Cu 2 O displaying exceptional catalytic efficiency under these circumstances.…”

Ultrasound‐Assisted Preparation of Copper(I) Oxide Nanocubes: High Catalytic Activity in the Synthesis of Quinazolines

“…Further,t hey are limited by 1) the use of toxic solvents such as DMF and DMSO,2 )the need for al ong reactiont ime, and 3) poor yields. [21,22] We chose 2-bromobenzaldehyde (1a)a nd benzamidine hydrochloride (2a)a sm odel substrates, and the reactionw as performed in the presence of the Cu 2 On anocatalyst, base, and solventb yu sing ad omestic microwave for 4min. The tandem cyclization of 1a with 2a in the presence of 5mol %C u 2 O nanocatalyst and 2.0 equivalents of Cs 2 CO 3 in EG at 160 W( domestic microwave) for 4min furnished 2-phenylquinazoline (3aa)in51% yield ( Table 1, entry 1).…”