Palladium -quinazolinone

A mixture of 2.0 g (0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-qulnazolinone, Oi g of 5% palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of this reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, the mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silica gel column is eluted with ethyl acetate-benzene (1 1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropylether and recrystallized from isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone Is obtained. Yield 52.5% MP 195°-196°C. 

The reduction of quinazolinone 242 with hydrogen at 3 atm in the presence of a palladium-on-calcium-carbonate catalyst furnished perhydroquin-azolinone 243. The stereochemistry of 243, with four chiral centers, was not investigated (70M1767). 

The hydrogenation of 3-substituted 4(377)-quinazolinones 402 has been performed with both palladium and platinum oxide to give the 1,2-dihydro derivatives 403 <2001JME1971, 2004H(63)2019>, while the reduction of 2(1//)-quinazolinones 404 is readily performed with sodium borohydride in methanol <1990H (30)493 >. 

Palladium-catalyzed carbonylation of 2-iodoanilines 898 gives a 2-acylpalladium species that can be reacted with ketenimines to give 2,3-disubstituted (3//)-quinazolinones 899 <2000JOC2773>. When carbodiimides are used in place of the ketenimines under the same conditions, 2-amino-4(3//)-quinazolinones 900 are produced, and when isocyanates are employed, 2,4(l//,3//)-quinazolinediones 901 are obtained <2000JOC2773>. 

Suschitzky and co-workers hydrogenated the lactam 305 over palladium on charcoal under pressure in the presence of 1 molar equivalent of hydrochloric acid in ethanol at room temperature and observed the formation of the azepino[2, l- )]quinazolinone 306 and its iV-oxide 307 in yields of 12 and 69%, respectively. 

Spath and KuflFner °° obtained the tetrahydropyrido[2, l- )]quinazolinone 203 when the pyrido[2,1 - >]quinazolinone 286 was hydrogenated over palladium on carbon in acetic acid. By means of hydrogenation in ethanol for 4 days, Paterson et prepared the hexahydropyrido[2,l- )]quinazolinone 102. 

Dehydrogenation of the tetrahydropyrido[2,l-/i]quinazolinone 203 over palladium sponge at 275°C afforded the pyrido[2,l-6]quinazolinone 286. ° Dehydrogenation of compounds 332 (R = R = H, = 0, 1) with the mercuric acetate-EDTA complex yielded compounds 99 ( = 0,1) in high yields. ... 

Harayma and co-workers used a palladium-assisted cyclization to synthesize rutaecarpine, a compound that has been shown to induce hypotension and vasorelaxation. Treatment of an iV-acyl-2-bromo-indole tethered quinazolinone with palladium (II) acetate in the presence of PCys and potassium acetate furnished the desired product in 89% yield. 

Larksarp and Alper used a palladium(II) catalyzed cyclocarbonylation reaction to generate a series of more complex and biologically relevant 4(3 0-Penicillium chrysogenum), have been shown to exhibit PTK inhibition and cholecystokinin inhibition as well as antimicrobial, anti-convulsant, anti-depressant and anti-inflammatory properties. Reaction of o-iodoaniline, a substituted ketenimine, and carbon monoxide with palladium(II) acetate and l,l -bis-diphenylphosphino-ferrocene (dppf) under thermal conditions gave the desired quinazolinone in near quantitative yield. In the same report, the authors showed that similar reactions could also be conducted with isocyanates and carbodiimides (not shown). 

Since Watanabe s synthesis of 4(3H)-quinazolinones in 1993 via transition-metal catalyzed reductive N-heterocychzation [ 181 ], several catalytic methods for quinazoline synthesis have been developed [182-186]. For example, palladium-catalyzed cyclocarbonylations of halides with appropriate reactants provided regioselective synthesis of 4(3H)-quinazolinone derivatives [182] and indoloquinazolines [184]. Also selenium-catalyzed reductive N-heterocyclization to quinazolinones has been developed by Sonoda et al. [183]. Copper-catalyzed heteroannulation with alkynes has been developed as highly region- and stereoselective route to 2-(2-arylvinyl)-l,2,3,4-tetrahydroquinazolin-4-ones 64 by Kimdu et al. [ 185] (Scheme 12). Recently, condensation of anthranylamide with various aldehydes to 4-quinazotinones has been found to give excellent yields in the presence of cupric chloride [186]. 

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. 

Mori and Shibasaki s group described the use of a special titanium-isocyanate complex for a novel one-step synthesis of isoindolinones and quinazolinones starting from o-halophenyl alkyl ketones [260]. As shown in Scheme 2.35, this reaction proceeds through the oxidative addition of the enol lactone, generated by palladium-catalyzed carbonylation of o-halophenyl alkyl ketones, to the titanium-isocyanate complex A. 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

The reaction of heterocumulenes or alkynes with ortho-iodoanilines under a carbon monoxide atmosphere has been shown to give4(3ff)-quinazolinones or 2-quinolones, respectively. A related cyclocarbonylation reaction has been used to synthesize new cardanol and cardol derivatives in a regioselective manner. Versatile and efficient routes to various spirocyclic compounds, including [5,5]-, [5,6]- and [5,7]-spiroindolines, have been established by exploiting a sequence of palladium-catalyzed cyclization processes (eq 105). ... 

Alper and coworkers successfully exploited the cydocarbonylation reactions of o-iodophenols 1, 2-hydroxy-3-iodopyridine 2, and o-iodoanilines 3 with heterocumu-lenes, giving rise to benzo(e]-l,3-oxazin-4-one 4, pyrido[3,2-e]-l,3-oxazin-4-one 5, 4 (3H)-quinazolinone 6, and 4(3H)-quinazolindione 7 derivatives (Scheme 13.2) (21,22]. The reactions proceed in the presence of equimolar amount of palladium acetate and a bidentate phosphine ligand (dppb or dppf) and a base (i-Pr2NEt or K2CO3), in benzene or THF at 80-100 °C under a pressure of 20 atm of carbon monoxide. Carbodumides, isocyanate, and ketenimines were used as cumulenes, and good regioselectivities were achieved with unsymmetrical reactants. The reaction mechanism is beheved to involve in situ formation of a carbamate ester or urea-type intermediate followed by palladium-catalyzed carbonylation and cyclization to yield the products. 

Larksarp,C.andAlper,H. (2000) Palladium-catalyzed cydocaibonylation of o-iodoanilines with heterocumulenes regioselective preparation of 4 (3H)-quinazolinone derivatives. The Journal of Organic Chemistry, 65,... 

An efficient route to quinazolinones was reported by Willis et al. They described the palladium-catalyzed coupling of o-bromobenzoate esters such as 50 with monosubsti-tuted ureas (Scheme 24.25) [100]. The reactions proceeded via initial intermolecular C—N bond formation followed by intramolecular base-promoted cyclization to yield the 3-alkylated quinazolinedione products in good yields. Complete regiocontrol was observed, which originates from the initial aryl C—Nbond formation occurring at the least hindered N-atom of the urea nucleophile. 

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