Synthesis of quinazolinones

One example of a successful application of solid-phase chemistry constitutes the highly versatile synthesis of quinazolinones 300/301 which efficiently combines an aza.-Wittig reaction with a multidirectional cyclisation cleavage. Iminophosphoranes were shown to be useful intermediates in organic synthesis, particularly for the preparation of different heterocyclic systems containing an endocyclic C,N double bond. In these cases, an aza-Mfrig-mediated anellation reaction was involved as the key step. 27-i29 

Reagents and conditions i) Merrifieid resin (3.4 mnrtol/g), CSjCOj, DMF, Kl. 80°C, 8h  

Alkylative esterification of 296 via the corresponding cesium salt with highly loaded Merrifield resin (3.4 mmol/g) resulted in polymer-bound o-azido ester 297. 31.132 Treatment of 297 with a fivefold excess of PPhj in THF at room temperature produced the corresponding 

The formation of the polymer-bound compounds was routinely monitored by FT-IR of the resin beads. The product composition 300 301 was strongly influenced by differences in nucleophilicity and/or steric hindrance. When those differences were minimal, both possible compounds 300 and 301 were generally formed in 1 1 ratio.i i 32 

Multicomponent assembly strategy with cyclisation-assisted cleavage 

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A number of new conditions and catalysts have been used for the synthesis of quinazolinones 50 from anthranilic acids, amines and ortho esters, including bismuth trifluoroacetate with an ionic liquid <06TL3561>, lanthanum nitrate or tosic acid under solvent-free conditions at room temperature <06TL4381> and Nafion-H <06SL2507>. 

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>. 

Another key strategy in solid-phase organic synthesis is to cleave molecules from the resin by means of intramolecular cyclization as the last step. This strategy normally leads to very pure compounds since only those molecules will be cleaved from the resin that have gone through the whole reaction sequence. This concept was used for a versatile synthesis of quinazolinones of type 151 and 152 as shown in Scheme 9.215... 

Chakraborty et al. (26) synthesized 1 by cyclization of the < -acyl-aminobenzamide 13 with diphosphorus pentoxide. Kametani et al. have developed a one-step synthesis of quinazolinone derivatives by condensation of sul-phinamide anhydrides generated from anthranilic acids and thionyl chloride with amides (27,28), imines (29,30), or thioamides (31). This reaction was applied to the synthesis of 1 (28,31,32), glycosminine (6) (28,31), glomerin (2) (27,31), homoglomerin (27), glycerine (3) (27), chrysogine (7) (27), and other quinazoline alkaloids (Scheme 1). 

Kametani, T., C. V. Loc, T. Higa, T. Ohsawa, M. Koizumi, M. Ihara, and K. Fukumoto The Synthesis of Quinazolinone Alkaloids Through Potential Iminoketene Intermediate. Heterocycles 12, 208 (1979). 

Scheme 9.26 Synthesis of quinazolinone derivatives from 2-halobenzamides.

The synthesis of quinazolinones under microwave irradiation was carried out by Mishra et al. [110] (Scheme 11.52). 

Microwave-assisted synthesis of quinazolinone using different bases was carried outbyPatil etal. [112] (Scheme 11.54). 

R. Cheng, T. Guo, D. Zhang-Negrerie, Y. Du, K. Zhao, One-pot synthesis of quinazolinones from anthranilamides and aldehydes via p-toluenesulfonic acid catalyzed cyclocondensation and phenyliodine diacetate mediated oxidative dehydrogenation. Synthesis 45 (2013) 2998-3006. 

More examples for the cascade process involving transfer hydrogenation include the Ir-catalyzed synthesis of quinazolinones from primary alcohols and aminobenza-mides (Scheme 5.31) [31], and the Ir-catalyzed three-component reaction of secondary amines, aldehydes, and alkynes (Scheme 5.32) [32],... 

SCHEME 5.31 Ir-catalyzed synthesis of quinazolinones from primary alcohols and... 

The clinical acceptance of the dihydrochlorothiazide diuretics led to the synthesis of a quinazolinone bioisostere, fenquizone (54). The synthesis follows the usual pattern of heating... 

The same methodology can be applied to the synthesis of pharmaceutically relevant quinazolines and quinazolinones containing a fused alicyclic ring [45,46]. 

The synthesis of oxaziridine-fused quinazolinones 277 follows a different route. Quinazolinones 274 (R = Et, nPr, n-hexyl) can readily be prepared by reacting 2-oxo-l-cyclohexanecarboxamide with aldehydes in the presence of ammonia solution. In the reaction of 274 and monoperoxyphthalic acid, the hydroxyoxaziridines 277 were formed via the presumed intermediates 275 and 276. No spectroscopic evidence was given for 277, nor was its relative configuration investigated [76JPR(318)895]. 

Beckmann rearrangements are useful to produce cycloalkylamines from ketoximes. This strategy was applied to produce cyclobutylamine derivatives 328 from the corresponding acyl derivatives during the synthesis of 4(3//)-quinazolinones " (equation 121). 

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 above two quinazolinones were prepared as intermediates in the synthesis of the chiral nonnucleoside reverse transcriptase inhibitor DPC 961 441, although compounds of this type can also be formed directly by the addition of lithium cyclopropylacetylide to the N-unsubstituted 2(l//)-quinazolinone 440, in the presence of a chiral alkoxide moderator <20000L3119, 2004JA5427>. 

Alkenyl quinazolinone derivatives can also be prepared under Lewis acid conditions, as demonstrated by the synthesis of analogs of the anticonvulsant piriqualone 574, where aldehyde condensation and elimination of water was conveniently effected with zinc chloride and acetic anhydride <2001BML177>. 

This contruction can be accomplished using an intramolecular aza-Wittig approach, as demonstrated by the synthesis of 2,3-dimethyl-4(3//)-quinazolinone 744 <1989T6375>, although the method has not been exploited greatly. 

The amide ring-closure method has also been used in a solid-phase combinatorial synthesis of inhibitors of poly(ADP-ribose)polymerase (PARP-1). The penultimate intermediates 770 were cleaved from the resin with trifluoroacetic acid, and this was followed by ring closure with sodium hydroxide, at room temperature, to give the quinazolinone products 771 <2004JME4151>. 

However, perhaps the simplest route to quinazoline derivatives involves the heating of 2-aminobenzamides with formic acid to give 4(3//)-quinazolinones, where the formic acid provides the solvent, the C-2 synthon, and the acid catalysis of the ring-closure step. For example, in the synthesis of the imidazoquinazolinone 798, both the imidazo and pyrimidine rings were formed simply by heating the triamino amide 797 in formic acid for 2h <1996JME918>. 

Similar results can be achieved by using cyanothioformamides <2002HAC291, 2002HAC611> or dithiocarbamates 861 <2005BML1877> instead of isothiocyanates, as shown by the synthesis of 2-phenyl-2-thioxo-4-quinazolinone 863 <2005BML1877>. Once again the intermediate thiourea 862 is not isolated. 

Synthesis of the title compounds from isoindole precursors was also reported (85KGS1368). According to this route, 1-aminoisoindole was cyclocondensed with 2-ethoxycarbonylcyclohexanone to give a 2 1 mixture of the isoindolofl, 2-b]- and -[2,l-a]quinazolinones (83 and 84), respectively. 

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. 

An improved modification of the Ganesan synthesis of Luotonin A has been developed under microwave heating for the synthesis ofvarious annulated [ 1,2-b ] quinazolinones. 

Hazarkhani, H. and Kamiri, B., A facile synthesis of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-quinazolinones under microwave irradiation, Tetrahedron, 2003, 59, 4757-4760. 

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