NIEMENTOWSKI Quinazolone synthesis

NIEMENTOWSKI Quinazolone synthesis 275 NOYORI Chiral homogeneous hydrogenation 276 277... 

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. 

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%. 

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. ... 

The Niementowski reaction and variations thereof have found widespread use in the pharmaceutical and agrochemical fields for the synthesis of compounds containing 4-quinazolones. This reaction was used by Xu et al. in the first step of the synthesis of a series of fluoroquinoline derivatives (51) that were evaluated for their antifungal activities. The... 

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