4 -quinazolinone derivatives reaction

Due to the electron-withdrawing nature of the pyrimidine ring, alkenylpyrimidines can undergo addition reactions at the /3-carbon, and while this is a well-established route to substituted pyrimidine derivatives <1994HC(52)1, 1996CHEC-II(6)93>, it has also been used to prepare quinazolinone derivatives 578 from 2-alkenyM(3//)-quinazo-linones 577 <2000T7245>. 

The cyanomethyl-substituted pyrido[2,l-i ]quinazolinones 211 (R = CH2CN) can be transformed by chain elongation into the propionic acid and propionic acid ester derivatives. Reactions were effected by heating the cyanomethyl derivatives for 2 hr in diethyl carbonate in the presence of sodium hydride, followed by evaporation and treatment with methyl iodide and sodium hydride in dimethylformamide at 0°C, and finally by stirring of the evaporated oily residue in a mixture of isopropanol and coned, sodium hydroxide to obtain the acids,and in 0.5 N aqueous acetic acid to obtain the esters. ... 

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). 

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. 

Microwave-assisted synthesis of 4(3H)-quinazolinone derivatives has been developed by Dabiri et al. (2004) via a one pot condensation reaction of isatoic anhydride, primary amines, and ortho esters in the presence of catalytic amounts of p-toluenesulfonic acid. 

Pyrido[2, l-6]quinazolinone (analogous to 204) and its 2,8-dinitro derivative were brominated by bromine in acetic acid, but the products are of unknown structure. Reaction with a mixture of phosphoryl chloride and... 

It has since transpired that the active aziridinating species in these reactions are the N-acetoxylated hydrazine derivatives, rather than nitrenes exposure of ethyl-quinazolinone ( Q1-NH2 ) to lead tetraacetate at low temperature generates N-(acetoxyamino)-quinazolinone ( Q -NHOAc ), which is a relatively stable sub-... 

The 2-aminoquinazolines 259 were prepared in two independent ways. The 2-quinazolinone 258 was transformed to 2-aminoquinazoline 259 by treatment with phosphorus oxychloride and subsequently with sodium amide in liquid ammonia, or with phosphorus pentachloride under carefully controlled conditions [75JCS(P1)1471]. Attempts to prepare the N-substituted derivatives failed, but the reaction was successful with the unsubstituted cis cyclopentane-fused homolog [76JCS(P1)1415]. 

Thioquinazolincs can also be prepared by the reaction of lithiated quinazoline derivatives with disulfides. For example, reaction of the lithio species derived from 6-bromo-4(3//)-quinazolinone 74 with tetra-iso-propylthiuram disulfide gave the 6-dithiocarbamate 75 in 81% yield <2004M323>. 

A -Aminopyrimidinones and quinazolinones can be acylated and sulfonylated to give amide and sulfonamide derivatives, and also reacted with isocyanates to give ureas, and with aldehydes and ketones to give imines. They can also participate in cyclization reactions to form fused pyrimidine heterocycles. 

Carboxylic acids can also be used as a source of the C-4 atom, and the reaction of a diphenylurea derivative 835 with carboxylic acids in polyphosphoric acid (PPA), followed by treatment of the intermediates 836 with sodium borohydride has been used as a source of 3,4-dihydro-2-quinazolinones 837 <2006H(68)1443>. 

A reaction of particular interest is the photochemical rearrangement of compound 243 to 3-methyl-4(3//)-quinazolinone (246). This transformation (243 -> 246) (Scheme 10), which takes place in high yield in ethanol, has been applied to several other derivatives and is clearly analogous to the photorearrangement of pyridazinium-5-olates to 4-pyrimidones (Section in,A,6). The mechanism of the reaction is not clear. 

Benzoxazin-4-ones (39) react with amines to give quinazolinones (40) (77JOC656), but this typical reaction is replaced in 1,3-benzoxazine-2-thiones (41) by the formation of imino derivatives (42) since now the oxygen ring atom is joined directly to the aryl nucleus (76MI22700). 

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. 

Apart from early reports on the bromination of quinazolinones which gave undefined products, reports dealing with the direct introduction of a halogen into a quinazoline nucleus via the electrophilic reaction are scarce, probably because these derivatives are more easily accessible by cyclization of appropriate halogen-substituted precursors (cf. Section 6.3.1.1.1.). Quinazolin-4(3//)-one can be brominated by bromine in aqueous potassium bromide solution... 

Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4-dihydroquinazolines (191) and quinazolines (192), quinazoline derivatives (e.g. 193),pyrrolo( 1,2-a)quinoxalines (194), indolo[3,2-clquinolines (195), and indolo[l,2-c]quinazolines (196),"8 imidazolinones (197),"9 quinazolinones (198),"9, 120 pyrido[2,3-d]pyrimidine derivatives (199), 21 and 4,5-dihydropyrazolo(3,4-d]pyrimidine derivatives (200). 22 Tributyl(cyclohepta-1,3,5-trienylimino)phosphorane (201), prepared by thermal isomerization of the 2,4,6-derivative, reacts with a,p-unsaturated ketones to give 9H-cyclohepta[b]pyridine derivatives (202). 23 a synthesis of (2,4)pyridinophanes (204) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported. 24... 

Further reaction of the spiro compound 298 with pyridine and triethyl phosphite produced an additional amount of the benzoxazine 297, its N-dianthraniloyl derivative, poly(anthraniloyl)benzoxazinone and the pyr-ido[2,l-i)]quinazolinone 286. 

The reaction of the tetrahydropyrrolo[2, l-6]quinazolinone 95 with chlo-rosulfonic acid at 0"C gave the chlorosulfonyl derivative 373, which was then converted to the sulfonamides 374 by the action of amines. ... 

When the tetrahydropyrrolo[2,1 -6]quinazolinone 95 or its hydrochloride salt was heated in benzoyl chloride, the product of the reaction was the a-chlorobenzylidine derivative 403. ... 

Thionation of quinazolinones and then reaction with anthranilic acid derivatives gave 57 A regioselective reaction of isatoic anhydride with isatin-3-imines gave 58". Selfpolymerization of isatoic anhydride, doped over montmorillonite yielded... 

Simple tertiary amines can be grafted to a carbon skeleton, either by exchange reactions or by Mannich reactions. The hydrochloride salt of the camptothecin derivative (a) (Figure 38.15) is soluble in water at concentrations up to 1 mg/mL the comparable value for camptothecin itself is 0.0025 mg/mL. Similar results were obtained in solubilizing the benzodiazepine (b) and the quinazolinone (c). The adenosine Ai antagonist KW-3902 (d) was solubilized in an original manner by converting it to an amidinic and cyclized bioisostere (e). ... 

THF models transfer their C-2 fragment in between 1,4- or 1,5-binucleophilic sites to generate five- or six-membered rings. The acid-catalyzed reactions of 2-aryloxazolidines and oxazinanes with o-aminobenzamide, o-aminothiophenol, and o-phenylenediamine give 2-aryl-4( 1 //)-quinazolinones 69, 2-arylthiazoles, and a mixture of 2-arylbenzimidazole and l-benzyl-2-arylbenzimidazole 68, respectively. Whereas benzothiazole and benzimidazole could be formed by air oxidation of their initially formed dihydro derivatives, l-benzyl-2-phenylbenzimidazole, as formulated below, could arise from initially formed diimine, its cyclization, and subsequent 1,3-hydride shift (88JCR(S)322, 89IJC(B)802). It is the sole product when o-phenyl-enediamine and the model are used in 1 2 stoichiometry. 

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