Niementowski condensation

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

Scheme 6.250 Formation of 8H-quinazolino[4,3-b]quinazolin-8-ones through double Niementowski condensation.

The same authors have described a related Niementowski condensation for the preparation of 3H-nitroquinazolin-4-ones. Subsequent manipulation of this structure led to 8H-thiazolo[5,4-/ quinazolin-9-ones through a series of open-vessel microwave-assisted transformations, as indicated in Scheme 6.251 [205, 438]. 

An efficient microwave-assisted multi-step synthesis of8//-quinazolino [4,3-b] quina-zolin-8-one has been investigated by Besson and co-workers77. The synthesis involved two Niementowski condensations starting from substituted anthranilic acids (Scheme 3.49). Both homogeneous and heterogeneous conditions were studied in an effort to develop a convenient synthesis of the desired compounds. The solventless procedure allowed easier access to the quinazolino[4,3-fi]quinazolin-8-ones and gave better yields than the method performed in the presence of solvents. However, the procedure with solvents would offer the possibility of investigating the microwave-assisted solid-phase synthesis of these quinazolinones, which would faciltate purification of the final products. 

Alexandre, F.R., Berecibar, A., Wrigglesworth, R. and Besson, T., Novel series of of 8H-quinazolino [4,3-fr]quinazolin-8-ones via two Niementowski condensation, Tetrahedron, 2003,59, 1413-1419. 

The Niementowski reaction involves condensation of an o-aminobenzoic acid (13) with 2 resulting in a quinolinol (14). 

Developing their work on the use of microwave-assisted Niementowski reactions, the same group published the synthesis of novel triaza- and tetraaza-benzo a -indeno[l,2-c]anthracen-5ones by the condensation of anthranilic acid with 2-(2-aminophenyl)indole or benzimidazole (Scheme 3.49)78,79. 

Path A involves N-formylation of anthranilic acid, condensation of the resultant 2-formaminobenzoic acid with the amine followed by intramolecular amidation of the intermediate amidine to form the product. On the other hand, the amine instead of anthranalic acid may be formylated and go through the known Niementowski reaction (path B). When the reaction of 2-formamidobenzoic acid with aniline and the condensation of formanilide with anthralic acid were conducted under microwave irradiation, the desired 3-phenylquinazolin-4(3 JT)-one was obtained in both cases in a few minutes in 68-87% yield. 

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). 

In 1895, Niementowski discovered the reaction that still bears his name the condensation of 2-aminobenzoic acid (anthranilic acid) with formamide to give quinazolin-4-one. He used two molecular equivalents of formamide and heated at 125°C for 3 hr.279 The yield is excellent, even on the 500 g scale.280 The reaction also goes well when the benzene ring is substituted, whether by electron-attracting or electron-releasing substituents.1 The course of the reaction is as follows.281,282 Ammonium-2-formamidobenzoic acid is first formed and can be isolated when the reaction is run at a lower temperature. At 130°C, this salt is dehydrated to 2-formamidobenzamide (163), which slowly cyclizes to quinazolin-4-one. 

Niementowski found that no other amide reacted so freely with o-amino-amides as did formamide and that the difficulty increased with each carbon atom added to the acyl group.279 To introduce a C-aryl substituent, it is preferable to heat an oacylamino acid with formamide. Thus, 2-benzamido-benzoic acid, in formamide at 160°C for 3 hr, gave a good yield of 2-phenyl-quinazolin-4-one.293 However, the use of formamide to condense 2-acetamidobenzoic acid resulted in a mixture of two products, one with... 

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]. 

Two related reactions of quinoline construction, the Pfitzinger and Niementowski reaction, can be considered as extensions of the Friedlander synthesis. Niementowski reaction uses anthranilic acid for the synthesis of 4-hydroxy quinolines, and Pfitzinger reaction applies substituted isatins as precursors for ort/io-aminophenylglyoxylic acid, which is used as the condensation component with carbonyl compounds to produce 4-carboxylic acid quinolines. 

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. 

This reaction is related to the Friedldnder Condensation and Niementowski Reaction. 

Since the Niementowski quinoline synthesis involves the condensation of an aldehyde or ketone (2) with an anthranilic acid (1), it is... 

A similar set of reaction conditions was reported wherein the Niementowski reaction was carried out in the presence of phosphorous oxychloride. " This phosphorous oxychloride-mediated condensation between 24 and 25 afforded a nearly 1 1 ratio of the two possible 4-hydroxyquinoline isomers 26 and 27. 

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. 

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. ... 

An extension of the Niementowski reaction that has been used for the condensation of anthranilic acids with lactams has been reported by Sastry et al. Addition of phosphorous oxychloride at room temperature to a solution of lactam 46 was followed by addition of anthranilic acid (1). Subsequent stirring at room temperature followed by heating at reflux furnished products 48 in 60-90% yield. The reaction presumably proceeds via formation of 47 followed by condensation with anthranilic acid (1) and cyclodehydration to give 48. Additional examples of phosphorous oxychloride mediated 4-quinazolone syntheses with either anthranilic acid or the corresponding... 

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). 

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