Niementowski synthesis

Friedlander synthesis, 2, 444 Benzacridinones, dihydro-von Niementowski synthesis, 2, 447 Benz[6]acridinones, tetrahydro-von Niementowski synthesis, 2, 447 Benzaldehyde... 

Domon, L., Le Coeur, C., Grelard, A., Thiery, V. and Besson, T., Efficient modified von Niementowski synthesis of novel derivatives of 5a, 14b, 15-triazabenzo [a ]indeno[ 1,2-c]anthracen-5-one from indolo [l,2-c]quinazoline, Tetrahedron Lett., 2001, 42, 6671-6674. 

It was reported that the Niementowski synthesis of 4-hydroxy-3-nitro-7-phenyl-l,8-naphthyridin-2(lH)-one (25) from ethyl 2-amino-6-phenylni-cotinate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315], It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

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-... 

Quinazolines can be prepared by several methods. AT-Acylanthranilic acids undergo cyclization with ammonia or primary amines via amides 14 forming quinazolin-4(3ii0-ones 15 (Niementowski synthesis). Alternatively o-(acylamino)benzaldehydes or -acetophenones react with ammonia producing quinazolines 16 (Bischler synthesis) ... 

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 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 Niementowski synthesis is still used today to prepare a host of quinazolines and quinazolinones of biological significance. For example, the original Niementowski synthesis was used as a key step in the synthesis of gefitinib (Iressa) by Richards and co-workers. ° Fusion of 4,5-dimethyoxyanthranilic acid and formamide fiimished the desired quinazolinone in 20% yield. This yield was significantly improved in later work by Orfi and co-workers using formadine acetate and formamide under microwave conditions to provide the product in quantitative yield. 

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. ... 

The use of methyl anthranilate (26) in the Niementowski reaction was reported by Meyer and Wagner in 1943. One of the factors limiting the usefulness of the Niementowski synthesis under conventional conditions is the propensity of anthranilic acid to undergo thermal decarboxylation at sustained heating of 150 °C or above. Methyl anthranilate, however, is stable at temperatures approaching its boiling point of 260 °C. Moreover, it was found to react with formamide at about 200 °C to form the expected 4-quinazolone product in 49% yield. Extension of this procedure to amides larger than acetamide, however, did not result in improved yields compared to the use of anthranilic acid. 

In an extension of the Niementowski synthesis, it was found that 4-quinazolones could be also be synthesized via an isatoic anhydride intermediate/ Isatoic anhydride has been prepared from anthranilic acid using either phosgene or ethyl chlorocarbonate. Clark and Wagner reported that when isotoic anhydride 38 was heated with a primary amine and triethyl orthoformate, 39 was formed. The reaction likely proceeds by way of initial attack of the amine on the carbonyl group at the 4-position of 38 to form the corresponding anthranilamide followed by ring closure with triethyl orthoformate. If triethyl orthoformate is not added to the reaction mixture, the anthranilamide that is formed can be isolated and used as an intermediate for the synthesis of quinazolones by various methods. ... 

Naphthyridines have been prepared by means of a Niementowski synthesis from ethyl 2-amino-6-phenylnicotinate and by means of Friedlander synthesis from 2-aminonicotinaldehydes. Ethyl 2-amino-6-phenylnicotinate (IX lll), which is readily prepared from ethyl a-ethoxycarbonyl acetimidate and benzoylacetaldehyde, condenses with the simple esters (DC-122 R = H, CH3, CfiHs) in the presence of sodium to give good yields of 1,8-naphthyridinones (IX-113). 

Overall, the heterocyde serves as vehide for the conversion of phenols into the corresponding primary arylamines (transformation Ar-OH —Ar-NH2) [314]. The chloroquinazoline 49 is obtained from anthranilic acid and benzamide in an application of the Niementowski synthesis (c p. 495). 

Neber rearrangement 31 Nenitzescu synthesis (indole) 144 Niementowski synthesis (quinazoline) 495... 

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