Quinazolinones diones

Benzoxazine-2,4-diones (43) (isatoic anhydrides) have proved useful synthons for various new heterocycles. For example, a base-catalyzed condensation with the oxindole (44) affords tetracycles (45) (80JHC1785), whereas the parent compound (43 R = H) and 3-hydroxyisothiazole give the quinazolinone (46) (69AJC2497). 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

Allylation of the pyrido[l,2-a]quinazoline-l,5-dione 136 (R = Ph, Ar = Ph) with allyl bromide afforded the corresponding 3-allyloxy derivatives. The hydroxymethylene group of the azepino[l,2-a]quinazolinone 142 was acetylated with acetyl chloride. When the cyclopenta[e]pyrido[l,2-a]py-rimidine-4-thione 160 (n = 0) was treated with methyl io de, a quaternary salt (177) was obtained. ... 

By the action of alcohol or amine, the pyrrolo[2,l-i>]quinazoline-l,9-dione 241 underwent a facile ring opening to give the corresponding 2-sub-stituted quinazolinone 243. ... 

Acylation of the hexahydropyrrolo[2,1 -6]quinazoline-1,9-dione 84 and the hexahydropyrido[2,l-i>]quinazolinone 102 with acetic anhydride in pyridine yielded the N-acetylated products 368 and 369, respectively. 

A few imines have been prepared by special methods. The reaction between benzyl azide and 1-phenylcyclopropaneearbaldehyde yielded the corresponding V-benzylimine. Similarly, reaction of 2-azido-V-(cyclopropylcarbonyl)-V-methylbenzenecarboxamide with an equimolar amount of triphenylphosphane occurred spontaneously at room temperature to give a quinazolinone in essentially quantitative yield. Treatment of tricyclo[4.4.1.0 ]undeca-3,7,9-triene-2,5-dione with bis(trimethylsilyl)carbodiimide in the presence of titanium(IV) chloride afforded V,V -dicyanotricyclo[4.4.1.0 ]undeca-3,7,9-triene-2,5-diimine in excellent yield. ... 

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). 

Isothioureas (179) heated with lA in aqueous media give quinazoline-diones (180). Heating in dry solvents (e.g. DMF) leads to quinazolinones 181 212,218-222 jg2 211,223 pj. 1 3211.212.220 (Scheme 30). Cyclic isothioureas... 

Anthranilic acids and derivatives are often used as starting materials for the preparation of quinazolinones. For example, Drizin and co-workers applied this strategy to build a library of quinazolinones in the search for selective aiA subtype antagonists. Anlhranilate esters 65 reacted with isocyanates to generate quinazolin-2,4-diones 66 <01JMC1971>. Similarly, quinazolin-4-ones 69 were synthesized by first converting 67 to 68 followed by cyclization with an isocyanate under acidic conditions. 

In the synthesis of 2-alkylthio-3-quinazolin-4-ones 76 reported by Powers, treatment of isatoic anhydride (74), derived from anthranilic acid, with aminoacetonitrile followed by reaction with thiophosgene provided the quinazolinone 75 <01JHC419>. Alkylation of 75 led to the thioethers 76 in good to excellent yields. A very similar compound, quinazolin-2.4-dione 78, was synthesized from 77 and aminoacetonitrile bisulfate <01JOC4723>. 

To date, a number of solid-phase syntheses of 4(3H)-quinazolinones [171], quinazohne-2,4-diones including monothioxo analogs [172,173], quinazo-lines [174,175], and dihydroquinazolines [176-178] have been developed. As a recent example, synthesis of 2-arylamino-3,4-dihydroquinazolines (56) by... 

For synthesis of quinazoline derivatives, various coupling reactions have been utilized after synthesis of quinazoline-2,4(lH,3H)-diones via palladium-catalyzed oxidative coupling by Hirota et aL [187]. For example, synthesis of diarylquinazolines by iron-catalyzed cross-coupling reaction [188], and diamino quinazolinones by palladium-catalyzed amination [171] have been developed Synthetic applications to quinazoline alkaloids are given in Sect. 3. 

Anti-HIV activity 1 -Hydroxy-W-methylacridone, 2-(pent-1 -enyl)quinoline, 2-(pent-2-en) quinolin, 2-acetyl-4(3H)-quinazolinone, 2- -pentylquinoline, 3-prenyl-4-prenyloxyquinolin-2-one, 4-methoxy-l-methylquinolin-2-one, )V-methyl-3,3-diprenylquinoline-2,4-dione, buchapine, y-fagarine, haplopine, (-1-)-platydesmine, uranidine [28, 30, 34, 38,40,41],... 

Some of the quinazolinones obtained from this reaction are known to be versatile intermediates in the synthesis of quinazoline alkaloids. Reaction 26 can also be applied to the synthesis of indole[2,l-b]quinazoline-6,12-dione (52), which is the antibiotic tryptanthrine (Scheme 18) [90] (next page). 

Quinazoline-2,4-dione Quinazolinone Dihydro Quinoline Quinolone Quinone Selenide Selenoxide Silane Tetraalkyl Siloxy Ether Silyl Chloride Silyl Enol Ether Silyl Ether... 

---