Quinazoline-A-Oxides

The first starting material for building benzodiazepines was prepared inadvertently in a synthesis aimed at the benzodiazoxepine (6-1). The oxime acetamide (6-2) from 2-aminobenzophenone was thus treated with hydrogen chloride in the expectation that the new heterocycle would form by the elimination of water between the oxime and the enol form of the amide. The product mrned out in fact to be the quinazoline A-oxide (6-3), the product from the addition of the nucleophilic oxime nitrogen to the amide carbonyl group. 

Addition of methylamine to the 2-position of the quinazoline A-oxide 366 results in a ring-expansion to give the 1,4-benzodiazepine A-oxide 367, which can be further reduced with Raney nickel to afford the HIV Tat antagonist 368 (Scheme 201) <1995BMC391, CHEC-III(13.06.10.2)224>. 

Related 1,3-oxazepines have been obtained from irradiation of many other heterocyclic A-oxides including pyridine A-oxides, isoquinoline A-oxides, quinoxaline A-oxides, quinazoline A-oxides, phenanthridine A-oxides, benzophenazine A-oxides, and acridine A-oxides.4 However, the reported yields are variable and have generally been higher for phenyl and other aryl-substituted derivatives. 

Heating the oxime of 2-aminobenzophenone with ethyl orthoformate gives quinazoline A -oxide. A pyrazolopyrimidine Af-oxide has been similarly synthesized the chemistry of pyrazolopyrimidines has been reviewed [33601. 

An unusual reaction sequence, which also falls into category of NCCCN+C approaches, was described in 1980 [399]. In particular, oxime 662 reacted with chlorofluoroacetyl chloride to give acyl derivative 663, which underwent cycUza-tion to quinazoline A-oxide 664 upon action of BFg EtgO (Scheme 137). 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Unsubstituted quinazoline 3-oxide was prepared in an attempt to react quinazoline with hydroxylamine. This reaction gave a product of variable composition, but when an acetone solution was heated in a sealed tube it gave quinazoline 3-oxide. The oxide is more conveniently prepared, in excellent yield, from o-aminobenzaldehyde oxime and ethyl orthoformate. This method appears to be of general use and has been used for the preparation of 4-methylquinazoline... 

In addition to having typical A -oxide reactions, quinazoline 3-oxide also shows the same reactivity as quinazoline toward nucleophilic reagents, but the reaction goes a step further by eliminating water as shown in reaction 2d. Oxidation with hydrogen peroxide... 

The A -oxide reactions in quinazoline 3-oxide are, however, modified to a certain extent by the aforementioned properties. Thus, whereas it can be reduced to quinazoline with phosphorus trichloride or iron and ferrous sulfate in ethanol, reactions with alkali, acetic anhydride, and benzoyl chloride in the presence of cyanide result in ring fission (Scheme 4). 

Heterocyclic compounds that have water bound covalently across a C=N bond behave as secondary alcohols. When subjected to very gentle oxidative conditions, they are converted into the corresponding 0x0 compounds. Potassium permanganate in 0. IN sodium hydroxide at room temperature has been used to oxidize 2- and 6-hydroxypteri-dine to 2,4- and 6,7-dihydroxypteridine, respectively. In contrast, 4-hydroxypteridine was not attacked by this reagent even at 100°. Hydrogen peroxide in acid solution was used to oxidize quinazoline quinazoline 3-oxide 1,3,5-, 1,3,7-, and 1,3,8-triazanaphthalene and pteridine (which hydrate across the 3,4-double bond in the... 

A more detailed study of the reaction with malonitrile revealed that the yields are dependent of the molar ratio malonitrile/quinazoline. The yield increases from 29 (ratio 1.0) to 81% (ratio 2.0), suggesting that the mechanism of the ring transformation involves the contribution of 2 mol of malonitrile. Reaction of quinazoline 3-oxide with the above-mentioned active methylene compounds gives about the same results, although the yields are poor (Scheme 12) (73CPB1943, 75CPB746). 

Another dihydro derivative has been described in connection with medicinal chemical studies. Thus, reaction of 2-(chloromethyl)quinazoline-3-oxide (3) with hydrazine gives hydr-oxytriazocinamine 4 (and not a diazepine derivative as originally assigned), vigorous acetylation of which results in a rearrangement to give oxazolotriazocine 5.10... 

Oxidation of 2,3,4,4a-tetrahydro-l//-pyrido[l,2-a]quinazoline-iV-oxide (53) with the Hg(OAc)2-EDTA reagent in water afforded a ring-opened product (54) in quantitative yield [90AP(323)405]. 

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