2-substituted quinazolinone synthesis

The Bischler synthesis, first described in 1893, involves the fusion of A-acylanthranilic acid and ammonia to generate the corresponding 2-substituted quinazolinone, which exists in equilibrium with the 4-hydroxy quinazoline tautomer. Bischler s original synthesis, shown below, involved direct conversion of ammonium-A-acetylanthranilate to the corresponding 2-alkyl-2,3,4-dihydro-4-quinazolinone under thermal conditions. 

Zhou, Yin et al. disclosed an efficient CuCl-catalyzed synthesis of 2-hetarylquinazolin-4(3//)-ones through aerobic oxidative C(sp )-H amination of (2-azaaryl)methanes with 2-aminobenzamides using oxygen as the sole oxidant under mild conditions (Scheme 8.106). Three C(sp )-H and three N-H bonds are removed in one reaction to produce the highly valuable Af-heterocycles. This copper-catalyzed tandem oxidation-amination-cyclization transformation is easy to handle, and various prepared 2-hetaryl-substituted quinazolinones could be obtained in moderate to good yields [180]. 

Scheme 60 Synthesis of 2-substituted quinazolinones and quinazolines via Cul-catalyzed N-arylation of amidines...

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

The synthesis of substituted quinazolin-4(. 7/)-ones and quinazolines via directed lithiation has been reviewed <2000H(53)1839>, and the topic has also been briefly discussed in a more general review on the synthesis of quinazolinones and quinazolines <2005T10153>. For example, the lithiation of 4-methoxyquinazoline 312 with LiTMP followed by reaction with acetaldehyde gave only a minor amount of the 2-substituted product 313, with the major product 314 being the result of lithiation at the 8-position in the benzene ring <1997T2871>. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

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. 

Although the yield in this synthesis of 2-quinazolinone is low, it provides a route to a 4-substituted ring system it deserves further study of its scope [3105]. 

The condensation of appropriately substituted o-ketoanilines with cyanate also has been used to prepare quinazolinones. For example, in the synthesis of novel reverse transcriptase inhibitors, 3-trifluoromethylquinazo ine derivative 98 was synthesized by Corbett and coworkers <01BMCL211>. Treatment of trifluoromethyl ketone 96 with potassium cyanate yielded aminol 97, which was subsequently dehydrated in refluxing xylenes to give the quinazolinone 98. 

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

Palazzo, S., L. I. Giannola, and S. Caronna Reaction of Formation of 2-Substituted 4-Quinazolinones in Polyphosphoric Acid Synthesis of Glycosminine. Atti Accad. Sci. Lett. Arti Palermo, Parte 1, 34, 339 (1976) [Chem. Abstr. 89, 43309n (1978)]. 

The synthesis of 2- -propylthio and 2- -propylamino substituted 6-iodo-3-n-propylpyridopyrimidinones 2c and 2d, respectively, is outlined in Figure S. Alkylation of the benzo-fused thiouracil Ita with n-propyl iodide and sodium hydride afforded 2-n-propylthioquinazolinone 2c. Reaction of 2-methylthio-quinazolinone 2b-l with 2-n-propylamine resulted in mercaptan displacement to give 2-n-propylaminoquinazolinone 2d. 

M. Dabiri, M. Baghbanzadeh, A.S. Delbari, Novel and efficient one-pot tandem synthesis of 2-styryl-substituted 4(3fl)-quinazolinones, J. 

Scheme 8.105 Synthesis of 5-substituted imidazo/benzimidazo[2,1-6]quinazolinones.

A microwave-assisted method has been developed by Ighilahriz et al. (2008) for the synthesis of 4(3H)-quinazolinones by condensation of anthranilic acid, orthoesters (or formic acid) and substituted anilines, using Keggin-type heteropolyacids upw p p3Up, H SiMOjP o-nnp or... 

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