Niementowski quinazoline synthesis reactions

Niementowski quinazoline synthesis. Formation of 4-oxo-3,4-dihydroquinazolines by cycli-zation of the reaction products of anthranilic acid and amides. 

The Niementowski quinazoline synthesis is the condensation of an anthranilic acid (1) with an amide (2) to produce a 4-keto-3,4-dihydro-quinazoline product (3). The reaction occurs under thermal conditions, and reaction temperatures > 100 °C are generally required. This reaction is also often referred to as the Niementowski reaction, and occasionally as the Niementowski 4-quinazolone synthesis or von Niementowski synthesis. ... 

Reaction of carboxamides with isatoic anhydrides 7 in place of anthranilic acid as a source of the anthraniloyl group is an attractive extension of the Niementowski synthesis (cf. p 30). The reaction of isatoic anhydrides 7 with formamide or 2-hydroxybenzamides at elevated temperatures in a melt or in tbe presence of suitable solvents gives high yields of tbe respective quinazolin-4(3//)-oncs 8/ whereas with alkyl-, aralkyl-, or arylcarboxamides the yields of the corresponding 2-substituted quinazolin-4(3//)-oncs arc low Guanidine and ami-... 

Many reactions in heterocyclic multistep syntheses involve thermal condensations. Among these, the Niementowski reaction is the most common method for synthesis of the 31-f-quinazolin-4-one ring. It involves the fusion of anthranilic acid (or a derivative, e.g. 2-aminobenzonitrile) vith formamides or thioamides (or their S-methyl derivatives) and usually needs high temperatures and requires lengthy and tedious conditions. Recently, Besson and coworkers studied the possibilities offered by this reaction and explored the preparation of novel bioactive heterocycles (e.g. 38, 39, and 40 in Scheme 9.11) in which the quinazoline skeleton is fused with thiazole, indole or benzimidazole rings [50a-c]. 

The Niementowski synthesis of the 3H-quinazolin-4-one core was re-investigated by Besson and coworkers using microwave irradiation [96]. It enabled significant rate enhancements and good yields compared with conventional reaction conditions. 

The Bischler and Niementowski syntheses are the most important methods for the synthesis of quinazolines and quinazolinones, with the latter and more well-known reaction being m improvement on the Bischler synthesis. Additional methods for the synthesis of quinazoline and quinazolinone ring systems involve various rearrangement reactions and metal-mediated processes. Examples of these reactions are illustrated below. 

The Niementowski synthesis, first described in 1895, remains one of the most important methods for synthesizing quinazolines and quinazolinones. This reaction involves condensation of anthranilic acids with formamide or acetamide derivatives to form the intermediate quinazoline-4(3//)-ones under thermal conditions. 

The synthesis of quinolines and quinazolines via the Niementowski reaction has also been carried out using microwave conditions. Condensation of anthranilic acid 1 and ketones 32 and 33 under microwave irradiation gave products 34 and 35, respectively. 

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