10//- quinazoline-6,9-dione

Quinazoline-2,4-dione (108) has been assigned the dioxo formulation on the basis of its infrared spectrum. A dioxo structure has also been demonstrated for the derivative 108a by ultraviolet spectral comparisons and infrared data. ... 

Hydrates of acids such as Ts0H-H20 can probably also be dehydrated by treatment with silyl esters such as TsOSiMe3 (Scheme 13.1). Likewise, Ts0H-H20 is dehydrated in situ during aminations of hydroxy-N-heterocycles such as purines 242 (Scheme 4.24) or (lH,3H)-quinazoline-2,4-dione 250 (Scheme 4.27) by HMDS 2, in the presence of higher-boiling primary or secondary amines, to give the ami-... 

The [l,3]oxazino[2,3- ]quinazolin-6-one 305 reacted with cyclic secondary amines (e.g., as in Equation 33) to afford the quinazolin-2,4-diones 306 <2002EPP1178048>. 

The dicobalt octacarbonyl-catalyzed transformation of azoarenes into 2-arylindazolin-3-ones by carbonylation has been known for many years157 high pressures of carbon monoxide are required and under more forcing conditions the products are quinazoline-2,4-diones (Scheme 92). Reactions... 

Antibacterial activity has also been observed with a variety of sulphameth-oxypyridazine derivatives like the imine obtained upon reaction of (95, R1 = MeO R2 = H) with 5-nitrofurfural [312], 2-aryl-3-nitrofurylacrylamides (105) [313], quinazoline-2,4-diones (106) [314], thiazolin-4-ones of type (107) [315] and with aldol condensation products of the latter [316], Sulpnonylpyridazmones (108, R1, R3 = alkyl, Ph R2 = substituted NH2, HO, RO) [273,274], trichloromethylchloropyridazines (109) [317] and 3-mer-captopyridazine 2-oxide derivatives [318, 319] have been claimed as antibacterial agents. 

While the examples outlined in the previous section all pertain to attack by a basic N-atom, another possibility is intramolecular attack by an acidic N-atom, i.e., a deprotonated amide. For example, in AT-(2-carbamoylphe-nyljcarbamalcs of model phenols (8.135, X = H, Cl, or MeO, Fig. 8.11), the deprotonated carboxamido group attacks the carbamate carbonyl C-atom to form a quinazoline-2,4-dione with release of the phenol [173]. In acidic media, formation of the quinazoline-2,4-dione is decreased by competitive breakdown of the intermediate to an anthranilate and C02 in addition to the phenol (not shown). 

Ozonation of the antiepileptic drug carbamazepine resulted in the formation of three main DBFs l-(2-benzaldehyde)-4-hydro-(7//,i//)-quinazoline-2-one, l-(2-benzaldehyde)-(7/7,5/7)-quinazoline-2,4-dione, and l-(2-benzoic... 

The constitutionally isomeric 3-substituted (l//,3//)-quinazoline-2,4-diones and 2-phenylimino-4//-3,l-benzoxazin-4-ones are easy to distinguish via their El mass spectra (93RCM374). For quinazolinediones, the most striking feature is the loss of CO2, proving that a rearrangement due to anilino migration must occur. 

The products obtained in the reaction of A -cyclopropyl-4,5-difluoroanthranilic acid hydrazides 429 with triphosgene were dependent on the steric hindrance imposed by substituent R at position 3, and not the electronic effect of this group. While the unsubstituted compound 429 (R = H) gave exclusively the 4-hydrazono-3,l-benzoxazin-2-one-type product 430, the similar reactions of the chloro-, methyl-, and methoxy-substituted analogs 429 (R = Cl, Me, OMe) resulted in formation of the corresponding quinazoline-2,4-diones 431 as the sole products. For the fluoro-substituted compound 429 (R = F), a 20 80 mixture of the products 430 and 431 was obtained (Equation 46) <2005JHC669>. 

The Schmidt reaction of isatin and hydrazoic acid in sulfuric acid gave anthranilamide (81), quinazoline-2,4-dione (79), and 2-(o-amino-phenyl)-quinazolin-4-one (82).297 A similar reaction has been reported... 

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. 

Support-bound quinazolin-2,4-diones can be N-alkylated, either with alkyl halides under basic conditions or with aliphatic alcohols by means of the Mitsunobu reaction (Entries 12-14, Table 15.29). The methyl group of a 2-methylquinazolin-4-one is sufficiently acidic to undergo aldol condensations with aldehydes [343]. Aminations of chloroquinazolines are discussed in Section 10.1.2. 

Scheme 8. Stepwise assembly of quinazoline-2,4-dione oligomers.

Gordeev MF, Hui HC, Gordon EM, Patel DV, A general and efficient solid phase synthesis of quinazoline-2,4-diones, Tetrahedron Lett., 38 1729-1732, 1997. 

The chemical fixation of C02 in the presence of DBU or DBN led to l//-quinazoline-2,4-diones 115 <02T3155>, 5-acylated thiouracils 116a,b were obtained from pyridin-3- and 4-yl thioureas <02AJC287>, and dihydropyrimidines were obtained by an improved Biginelli reaction protocol... 

Pyridyl quinolone carboxylic acids, (V), and 7-piperazine quinazolin-2,4-dione derivatives, (VI), prepared by Park (5) and Domagala (6), respectively, exhibited broad-spectrum antibacterial activity with reduced cytotoxicity. 

Benzo[f]quinazoline-l,3-diones, 55, 207 Benzo(/]quinazoline-1,3-dione, 2,4-dimethyl-6-phenyl-, 55, 226 Benzo[/i]quinazoline-2,4-diones, 55, 200 Benzo[g]quinoline-5,10-dione, 3-methyl-, 57, 14... 

Dibenzofuran, I- and 2-hydroxy-chlorination, 59, 251 chloro-dehydroxylation, 59, 251 Dibenzofuran, methoxy-, dimethoxy-, bromination, 59, 252 Dibenzo[/, /i]quinazoline-2,4-dione, 1,3-dimethyl-, 55, 226... 

Cyclic tertiary amines, such as A -methylpyrrolidine, react with (l//,3//)-quinazoline-2,4-dione (18) in the presence of POCI3 to give 2-(/V-methyl-4-chlorobutylamino)-4-chloroquinazoline (19) in 67% yield (82CPB347I, 82H7, 82HI5, 82H1879). 

Since the full paper on applications of the silylation-amination method to a representative series of hydroxy-N-heterocycles was published in English in 1984 (84CBI523), only a few examples from this paper will be discussed here. (I H,3H)-Quinazoline-2,4-dione (18) can be monoaminated at I30°C with equivalents of l-(2-hydroxyethyl)-piperazine in 68% yield, to 179 whereas with five equivalents of amine and OMCTS (157) at I80°C, 56% of the desired 2,4-bis-aminated product 180 is obtained along with 24% of 181 as a side product. Since this reaction and most of the other reactions described were not optimized, these yields can probably be improved considerably. 

A series of chloro-, fluoro- and nitro-protected nucleoside phosphoramidite derivatives of quinazoline-2,4-dione (201) has been prepared and their ability to form DNA triplexes has been assessed. 

A recent example of the parallel synthesis of different quinazoline-2,4-dione derivatives (46) demonstrates how to combine the advantages of fluorous synthesis with those of solid-phase chemistry without using expensive perfluorinated solvents [22] (Scheme 3.22). In the beginning, a fluorous benzyl alcohol (47) is adsorbed on fluorous reversed-phase silica gel (FRPSG). Then, in a sequence of splits and reactions, the linker group, which remains bound to the FRPSG by fluorophilic interactions, is converted into a library of differently substituted carboxamido-urethanes (48). These are cyclized and the liberated quinazoline-2,4-diones (46) are eluted from the support with the fluorophobic solvents water and CHjCN/... 

Scheme 3.22 Fluorous synthesis of a library of substituted quinazoline-2,4-diones (46) [22]. The key to this approach is a fluorous benzyloxycarbonyl group on which the target molecules are stepwise constructed and which keeps the different synthetic intermediates bound to fluorous reversed-phase silica gel (FRPSG) during the purification cycles. The structural diversity of the target compound library (46) is introduced by the different anthranilic acid derivatives and primary amines in boxes) (TBTU = 0-(benzotriazol-1-yl)-N,/ /,N, N -tetramethyluronium tetrafluoroborate).

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