Quinazoline-2,4-dione, reaction with

There has been little systematic study of the chemistry of 1,4-oxazepines. Vigorous acid hydrolysis cleaves the amide linkage in (369 R1=Ph, R2 = H) and recyclization gives 2-o-hydroxyphenyl-5-phenyloxazoline and l,2,3,4-tetrahydro-l,8-dihydroxy-3-phenyl-isoquinoline. The l,4-benzoxazepin-5-one (353) can be alkylated at N but on treatment with triethyloxonium fluoroborate it is converted to 5-ethoxy-3-phenyl-l,4-benzoxazepine — one of the very few examples of a fully unsaturated 1,4-oxazepine ring. This product is isomerized to l-ethoxy-4-hydroxy-3-phenylisoquinoline when boiled in methanol. The 4,l-benzoxazepine-2,5-diones (348) are converted to quinazolines by reaction with ammonia. The dihydro-l,4-oxazepin-5-one (343) can be acetylated at nitrogen and bromi-nated at the 6-position. 

Reaction of 1 -methylene-1,2,3,4-tetrahydro-5//-pyrazino[2,1 -Z)]quina-zoline-3,6-diones (435) with PhLi and MeMgBr in THE at —78°C gave a mixture of 1 l//-pyrido[2,l-Z)]-quinazolin-l 1-ones 435-439 (01T1987). 

The oxazino ring of the [l,4]oxazino[3,4-3]quinazoline-3,6-dione 303 opened on reaction with aniline, between the 0(2)-C(3) bond to give 304 (Equation 32) <1998H(48)1851>. 

The reaction of 3-isonitrosopyrazolo[5,l-6]quinazolin-2,9-dione 453 with the Vilsmeier reagent gave the expected o-cyanoamidine derivative, which was cyclized [77IJC(B)335] by hydroxylamine to [l,2,4]triazino[6,l-b]quinazolin-10-one 454. 

Thiation of [l,2,4]triazino[3,2-h]quinazoline-3,10-dione 782 with phosphorus pentasulfide in pyridine proceeded selectively to give the 3-thioxo analogue 783. The latter was converted to the corresponding 3-methylthio derivative 784 by reaction with methyl iodide. Treatment of 784 with hydrazine gave 785, which was converted to 786 and 787 by cyclization with formic acid or carbon disulfide (90JHC591). Cyclization of 785 with sodium nitrite in hydrochloric acid gave 788 (90JHC591). 

A series of 6- and 7-aciylamide derivatives of 4-(phenylamino)-quinazoline and 4-(phenylainino)-pyridopyrimidine, classes of epidermal growth factor receptor (EGER) inhibitors, have been prepared from the corresponding amino compounds by reaction with actoyl chloride/base <99JMC1803>. Reaction of thionyl chloride with hexahydro-7-methyl-pyrimido[l,6-a]-pyrimidine-6,8-dione yields the corresponding 9,9 -thiobispyriiiudopyrimidine derivative <99JHC453>. 

The reaction of immobilized /3-amino acids with isocyanates provides ureas that can be cyclatively cleaved26 to dihydropyrimidinediones, while the analogous reaction27 with anthranilic acids affords 2,4-quinazoline-diones (Fig. 8). A similar process is the cyclization28 of /3-keto esters derived from substituted anthranilates to furnish 4-hydroxyquinolinones, while the hydrazones of immobilized 7-keto esters are cyclatively cleaved29 to dihydropyridazinones. 

Isatoic anhydrides 11 are transformed with ammonia into quinazoline-2,4(li/,3i/)-diones 12 with concomitant formation of the corresponding anthranilic acids -or anthranil-amides. The reaction lacks generality and has seldom been used for the synthesis of quin-azoline-2.4(177,37f)-diones. 

A -[(Methanesulfonyl)oxy]phthalimide undergoes a ring-expansion reaction with aqueous ammonia at room temperature to afford quinazoline-2,4(l//,3/f)-dione via a Lossen rearrangement. 2-Ureidobenzamide can be isolated as an intermediate when the reaction is performed under mild conditions and further cyclized to quinazoline-2,4(l//,3//)-dione by heating (cf. p 12). 

The cyclization of o-ureidobenzoic esters to quinazoline-2,4-diones and 4-one-2-thiones, respectively, in aqueous alkali proceeded equally well with the N-hydroxy urea (X = O) and thiourea (X = S) esters 28. If the reagents were altered to triethylamine in pyridine the 2,l-benzisoxazol-3-ones were formed. Ethyl o-hydroxyaminobenzoate reacted with two molecular equivalents of methylisocyanate in ethanolic alkali and gave 3-methyl-l-methyl-aminocarbonyloxyquinazoline-2,4-dione. When three molecular equivalents were used the tricyclic quinazoline 29 was obtained. A similar reaction with methylisothiocyanate did not behave in the same way, and 3-methylquina-zolin-4-one-2-thione was formed. It was shown that the intermediate 1-hydroxy derivative (30) gave 3-methylquinazolin-4-one-2-thione, i.e., loss of the 1-oxygen atom, on further treatment with methylisothiocyanate in the presence of triethylamine. The preparation of quinazoline-2,4-diones by... 

The reaction with ammonia or primary amines in aqueous systems has been investigated repeatedly. Generally, two types of products are obtained during the reaction. The primary product is the ring-opened isatoic amide 42, which reacts with loss of C02, favored by a low ratio of amine, to the anthranilic acid amide (43),2 6 10,86 88 while a high ratio of amine or bulky amines leads to isatoic diamides (45), which undergo facile cyclization to the quinazoline diones 36 by heating.86,89 93 The kinetics of the reaction of IA with n-butylamine show that the rate law for formation of 43 is zero order... 

The reaction of the benzylidene derivative of 5-methyl-6-thioxo-5,6,ll,12-tetrahydrodibenzo[fe,/]azocin-12-one (63) with hydroxylamine has been found to initiate a novel rearrangement to yield the hydroximinoisothiochromene (64), while the mechanism shown in Scheme 24 has been invoked " to explain the formation of 2,3,4,4a-tetrahydropyrrolo[2,l-fc]quinazolin-9(l//)-one-l-carboxylic acids from the treatment of 1,10,11,11 a-tetrahydropyrrolo [2,1 -c] [ 1,4]benzodiazepin-5,11 -diones (65) with concentrated hydrochloric acid. De Lucca has discovered that hexahydro-... 

Primary amines behave in a similar way and, in the case of reactions with 2-cyanomethyl-3,l-benzoxazin-4-one (106), the final products are quinazoline-2,4-diones (107) (Equation (3)) <9iMl 605-01 >. With hydrazine at room temperature the 2-phenyl analogue (108) affords the corresponding... 

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>. 

The Diels-Alder reaction of azadiene 106 prepared from l-methyl-2,4-dihydro-lH-pyrazino[2,l-fo]quinazoline-3,6-dione [255] with 3-methyleneoxindole 107 proceeds smoothly in chloroform at rt to afford exo- (108) and endo-isomer (109) in 55 and 18% yields, respectively. Mild hydrolysis of... 

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