Synthesis of Quinazolines and Tetrahydroquinazolines: Copper‐Catalyzed Tandem Reactions of 2‐Bromobenzyl Bromides with Aldehydes and Aqueous Ammonia or Amines

Abstract

An efficient synthesis of diversely substituted quinazolines and 1,2,3,4-tetrahydroquinazolines through copper-catalyzed tandem reactions of the readily available 2-bromobenzyl bromides, aldehydes, and aqueous ammonia or amines has been developed. By using ammonia and simple aliphatic amines as the nitrogen source, the present method provides a versatile and practical protocol for the synthesis of quinazolines and 1,2,3,4-tetrahydroquinazolines.

Chemical Insights Into the Synthetic Chemistry of Quinazolines: Recent Advances

“…Fan et al documented an effective one-pot method for the formation of diversely functionalized quinazolines 70 via copper-catalyzed tandem reaction among 2-bromobenzyl bromide derivatives 67, aldehyde derivatives 68, and ammonium hydroxide 69 (Fan et al, 2014). The reaction proceeds through cupric acetate-catalyzed amination of 2-bromobenzyl bromides 67 to 2-aminobenzyl amines, followed by condensation with aldehydes and subsequent intramolecular nucleophilic cyclization and aromatization, furnishing quinazoline derivatives (Scheme 22A).…”

Synthesis of Quinazolines and Dihydroquinazolines: o-Iodoxybenzoic Acid Mediated Tandem Reaction of o-Aminobenzylamine with Aldehydes

“…Compounds 1-3, 6, 7, 10, 12, 14, 20-25 and 29-33 have been reported previously. 3,5,8,10,14,[21][22][23][24][25][26] Quinazolines 1-15 and 29-33 via the IBX-Mediated Tandem Reaction between o-Aminobenzylamine and Aldehydes; General Procedure o-Aminobenzylamine (98 mg, 0.8 mmol) and the appropriate aldehyde (0.8 mmol) were dissolved in MeCN (10 mL), followed by the addition of IBX (448 mg, 1.6 mmol). The resulting solution was stirred at r.t. and was monitored by TLC.…”

“…[6][7][8][9] Very recently, Fan and co-workers disclosed a copper-catalyzed tandem reaction of o-bromobenzyl bromides with aldehydes and aqueous ammonia or amines. 10 Interestingly, there are not very many syntheses of dihydroquinazolines. A few of the noteworthy examples include the copper acetate, acetic acid and potassium iodide catalyzed selective oxidation of ring-fused aminals, copper-catalyzed activation of α-amino peroxy-and hydroxydihydroquinazoline intermediates which, in turn, were synthesized from o-aminobenzylamines via oxidative cross-dehydrogenative coupling in the presence of potassium iodide and tert-butyl hydroperoxide, TEMPO-mediated iron-catalyzed oxidative tandem reaction of N-alkylanilines, and coppercatalyzed intermolecular cyclization of nitriles and o-aminobenzylamines via cascade coupling and aerobic oxidation (Scheme 1, b).…”

Experimental and theoretical investigations into the stability of cyclic aminals

“…These methods allow the synthesis of the partially unsaturated alkaloids vasicine or deoxyvasicine in good yields [22,28] (Scheme 2). Furthermore, copper-catalysed reactions or oxidation with sodium hypochlorite were also described to yield the aromatic quinazoline core [26,29–30] (Scheme 2). Besides all the oxidation reactions described, also reductive conditions applying NaBH 4 onto the tetrahydroquinazoline-based aminal systems were investigated, thereby providing the possibility to “open” the rigid aminal core gaining access to sterically more flexible compounds [31–33] (Scheme 2).…”