Niementowski reaction

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. 

Independently, Zhou and co-workers used the same approach in their synthesis of highly functionalized quinazolines as potential anti-cancer therapeutics. In one example, fusion of 2-amino-3,4,5-trimethoxybenzoic acid with formamide under thermal conditions gave the desired quinazolinone in 25% yield. A dibenzofliran quinazoline derivative produced using this process exhibited anti-proliferative properties against several tumor types, including Bcap-37, PC3, A431, and BGC823 cell lines. 

Hattori and co-workers used a Niementowski approach to synthesize a series of orally active 2-substituted-4(3//)quinazolinones as inhibitors of poly(ADP-ribose) polymerase. Treatment of a substituted 4-fluoro amide (which was readily synthesized in three steps from commercially available 2-amino-6-fluoro-benzoic acid) with aqueous sodium hydroxide, produced the desired quinazolinone, which showed significant inhibitory activity. 

A significant niunber of variations on the Niementowski reaction have been developed over the years in an effort to improve reaction yields and product purity. The most common modifications involve the use of imidates, imidoylchlorides, dithiazoles, benzonitriles, or amidines. Select examples of these modifications are highlighted below. 

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

Microwave irradiation of a mixture of substituted anthranilic acid 224 with formamide (5 equiv) at 150 °C for 5 min gave quinazoUnones 225 in good yields (Scheme 82). This microwave version of the Niementowski reaction [ 143] showed significantly improved yields compared to the conventional reaction conditions [144]. 

A more elaborate example is the Niementowski reaction to give access to quinazo-linones and quinolines [62], The determining step consists in the reaction of anthra-nilic acid with some amides or ketones (Eq. 11). 

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. 

Alexandre, F.R., Berecibar, A. and Besson, T., Microwave-assisted Niementowski reaction. Back to the roots, Tetrahedron Lett., 2002,43, 3911-3913. 

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. 

The most common synthetic method towards quinazolin-4-ones is the Niementowski reaction, a cyclocondensation of anthranilic acid with for-mamide which requires high temperatures (130-150 °C) and long reaction times (6 hours). It is noteworthy that a remarkable reduction of the reaction time (20 min) was achieved under microwave heating conditions (150 °C) [123]. Moreover, microwave-accelerated reactions were cleaner and afforded higher yields than those under conventional thermal conditions (Scheme 48). 

SCHEME 25.4 (a) Microwave-assisted Niementowski reaction (Reference 51). (b) Neat microwave reaction... 

The Niementowski reaction has not been widely used for heterocyclic host molecules. The following examples comprise most of what has been done, mainly at 170°C for 2 hr (good yields) pyrido[2,3-d]pyrimidin-4-one (see 3) from 2-aminopyridine-3-carboxylic acid285,286 pyrido[3,2-d]-pyrimidin-4-one (see 6) from 3-aminopyridine-2-carboxylic acid216,287 and pyrido[3,4-d ]pyrimidin-4-one (see 4) from 3-aminopyridine-4-carboxylic acid.288 289... 

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]. 

Pursuing their efforts on the Niementowski reaction and its possibilities, Besson and coworkers have recently extended the family of fused quinazolinones which can be obtained via the microwave-assisted Niementowski reaction from the starting amidines (43). The authors described rapid and convenient access to pentacy-clic 6,7-dihydro-5a,7a,13,14-tetraazapentaphene-5,8-diones (44) structurally related to well studied terrestrial alkaloids (e.g. rutaecarpine and luotonine A) [50e]. The strong thermal effect, because of graphite-microwaves interaction, was particularly efficient in these reactions, in which the quinazolinone and the piperazine rings are fused. Only 10% by weight of graphite was used, in pressurized monomode reactors (Scheme 9.13). 

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. 

This reaction is related to the Camps Reaction, Conrad-Limpach Quinoline Synthesis, Doebner-Miller Reaction, Gould-Jacobs Quinoline Synthesis, Niementowski Reaction, and Skraup Reaction. 

Other references related to the Niementowski reaction are cited in the literature."... 

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

Stefan Niementowski (1866-1925), professor of general and analytical chemistry at the Lemberg Polytechnic Institute, twice elected president of the Polytechnic Institute, member of the Polish Academy of Skills, discovered methods of synthesis of y-hydroxyquinolines and 4-oxoquinazo-lines, later called Niementowski reactions. 

The scope of the Niementowski reaction has been somewhat limited due to the reaction conditions required to effect this transformation. Traditionally, the reaction is carried out by simply heating the two reaction components at sufficiently high temperatures to enable the reaction to proceed. In addition to heating, sometimes an acid such as polyphosphoric acid is added to the reaction mixture. ... 

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. 

In another variant of the Niementowski reaction, it was found that this transformation can be carried out under relatively mild, base-catalyzed conditions. Since a variety of substituted anthranilamides (29) can be prepared by a regiospecific ortho metalation-amination sequence, this method appears to be a very versatile modification of the Niementowski quinoline synthesis. Lithiation of 28 with 5-butyllithium was followed by treatment with tosyl azide. Reduction of the azide with sodium borohydride under phase transfer conditions furnished 29. After conversion of 29 into the corresponding imine 30, treatment of 30 with LDA afforded 31 in good yield. 

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 reaction has been used to synthesize a series of 4-substituted-2,3-polymethylenequinolines that were then studied for their CNS effects—namely for local anesthetic activity, analaleptic activity, and antihistaminic activity. The initial 4-hydroxyquinoline product 47 was converted to the chloride, which could then be displaced by various alkylamines to give 48. 

Aminoquinolines have been synthesized in a manner analogous to the Niementowski reaction, wherein the carboxylic acid in 1 was replaced with a nitrile (49). This transformation has been carried out under either acidic or basic conditions. Under the former conditions, a variety of Lewis acids have been employed to effect this transformation, including zinc chloride, aluminum trichloride, boron trifluoride diethyl etherate, and titanium tetrachloride. In a representative example, 49 was combined with 50 and heated at reflux in the presence of boron trifluoride diethyl etherate to furnish 51, which contains an embedded 4-aminoquinoline ring system. ... 

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 Niementowski reaction has also been carried out using DMF as a catalyst. For example, heating 24 with formamide (6 equiv) in the presence of a catalytic amount of DMF afforded 25, which served as an intermediate in the synthesis of Src kinase inhibitors. ... 

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. 

A modification of the Niementowski reaction involving the use of N-acylanthranilic acids facilitated the synthesis of 4-quinazolones 28, which have a variety of groups at the 2-position, including Me, Et, Pr, Ph, and substituted phenyl. A -Acylanthranilic acids 27 were heated in the presence 1.5 equiv of formamide at temperatures ranging from 150-180 °C, depending on the substrate. Yields ranged from 65-83%. 

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