4- Chloro-2-phenylquinazoline

Quinazolines take part in the same types of reactions as pyrimidines, but because of their additional benzene ring, the products of these reactions may have the added feature of hindered rotation. An example of this is the synthesis of 2-phenyl-Quinazolinap by Guiry and co-workers <99TA2797>. Suzuki coupling of 4-chloro-2-phenylquinazoline (115) with boronic acids 116 led to 117 (R = OMe). These intermediates were parlayed into phosphinamines 117 (R = PPh2) and then subjected to chiral resolution to produce new chiral phosphinamine ligands for asymmetric catalysis. 

ChIoro-5a-cholestane, 332 3/3-Chlorocholest-5-ene, 453 4-Chlorocyclohexanone, 72 3 /3-Chloro-5,6a-difluoro-5a-cholestane, 453 4-Chloro-17a-hydroxy-5/3-pregnane-3,11, 20-trione, 86 Chloroiridic acid, 101 4-Chloro-2-phenylquinazoline, 450 Choice of protecting groups, 375 A/B-cfs-cholanic acid, 228 Cholan-12-one, 36 Cholesta-3,5-diene, 207, 331, 336... 

There are few reports of the nitration of phenylbenzodiazines. The nitration of 3-methyl-4-phenylcinnoline-l-oxide (77) with mixed acid at -10°C is stated to yield four mononitro products with no evidence for dinitration. However, the structures of these products were not established (47JCS1649). 2-Phenylquinoxaline (78) is reported to give the 4-nitrophenyl product (51G451). 4-Chloro-2-phenylquinazoline reacts with mixed acid at 0°C to yield the 3-nitrophenyl derivative with concomitant loss of the chloro group so that the product that is isolated is compound (79) (91UP1). 

Pheuob -> aniliiies A new general method for conversion of phenols into anilines has been described by Scherrer and Beatty. A sodium phenoxide (prepared conveniently with sodium hydride) is condensed with 4-chloro-2-phenylquinazoline (I) at about 100° for 10 min. to give a 4-aryloxy-2-phenylquinazoline (2) in 70-85% yield. 

The copper acetate-catalyzed aerial oxidation of 4-substituted-amino-6-hydroxy-2-phenylquinazolines in methanolic solution containing piperidine or dimethylamine gave the 5,6-quinones (17) in 64-79% yields. Some of these were also formed when 6-acetoxy-4-chloro-2-phenylquinazoline was oxidized under similar conditions. The 5,6-quinones (17) can be hydrolyzed by base to the 6-hydroxy-5,8-quinones (18) in high yields. They dimerize to the intermediate 6,6 -biquinazolinyl-5,8-quinones on prolonged heating at 80°-90°C, and these cyclize to form benzofuran derivatives. ... 

Nitration of quinazoline is in the 6-position in the benzene ring. 2- and 4-Substituted quinazolines are likewise nitrated in the 6-position <49JCS1354), but 4-chloro-2-phenylquinazoline reacts with mixed nitrating acid at 0°C to yield the w-nitrophenyl derivative with concomitant loss of the chloro substituent, the product isolated being 2-w-nitrophenyl-4(3/f)-quinazolinone <91UP 602-01). 

The S At reactivity of the quinazoline system offers synthetic applications for this heterocycle. For instance, 4-chloro-2-phenylquinazoline 30, by reaction with phenolates, is converted into the 4-(aryloxy)quinazoline 31. This undergoes a Chapman rearrangement at 300°C with a 1,3-migration of the aryl residue to N-3 forming the 3-arylquinazolin-4(3//)-one 32. The latter hydrolyses with aqueous acid to form benzoxazinone 33 and a primary arylamine ... 

The reaction of p-bu -calix[4]arene with 4-chloro-2-phenylquinazoline gave a mixture of the syn- and, 3-diether derivative 64. In solution, the syn form adopted predominantly the cone conformation, whereas in its crystals an energetically unfavorable 1,3-altemate conformation was present (2003NJC236). 

Selective nitrogen labell ing experiments may also provide a good means of elucidating certain reaction mechanisms. The reaction of 4-chloro-2-phenylquinazoline with labelled potassium azide was shown to lead to tautomer species. A, B, in which the position of the label is easily identified. Thus, in trifluoroacetic acid solution, the azide tautomers of type B... 

Alkylquinazolines are catalytically reduced to the corresponding 3,4-dihydro derivatives/ The only example of a 4-substituted quin-azoline which was reduced to its 3,4-dihydro derivative is 2-chloro-4-phenylquinazoline which gave 4-phenyl-3,4-dihydroquinazoline/ 4-Methylquinazolines are susceptible to oxidation, as is shown by the attempted nitration of 2,4-diraethylquinazoline which causes the removal of the methyl group with formation of 4-hydroxy-2-methyl-6-nitroquinazoline/ When the 4-substituent is —C(Et) (C02Et)2 recrystallization of the picrate from ethanol is sufficient to convert it to 4-hydroxyquinazoline/ Similar hydrolyses occur in acid solution and the mechanism undoubtedly involves a hydrated intermediate/... 

Ninety-eight grams of 6-chloro-2-chloromethyl-4-phenylquinazoline 3-oxide hydrochloride were introduced into 600 cc of ice cold 25% methanolic methylamine. The mixture was initially cooled to about 30°C and then stirred at room temperature. After 15 hours the reaction product which precipitated was filtered off. The mother liquor was concentrated in vacuo to dryness. The residue was dissolved in methylene chloride, washed with water and dried with sodium sulfate. The methylene chloride solution was concentrated in vacuo and the crystalline residue was boiled with a small amount of acetone to dissolve the more soluble impurities. The mixture was then cooled at 5°C for 10 hours and filtered. The crystalline product, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, was recrystallized from ethanol forming light yellow plates, MP 236° to 236.5°C. 

It has been established that the conversion of 2-chloro-4-phenylquinazo-line into 2-amino-4-phenylquinazoline by treatment with potassium amide/liquid ammonia also occurs with ring opening (74RTC227).This was proved by the experimental result that in the 2-amino compound obtained from 2-chloro-4-phenyl[3- N]quinazoline, about 70% of the label is present in the amino group, i.e., formation of 2-[ N-amino]-4-phenylquina-zoline (83) see Scheme 11.36. 

Comparison of the percentage Sn(ANRORC) participation of 2-chloro-4-phenylquinazoline (70%) with that of 2-chloro-4,6-diphenylpyrimidine (70%) shows that the reactivity of C-4 in the quinazoline ring is somewhat higher than at C-4,6 in the pyrimidine ring, taking into account that the probability for attack at C-4 in 2-chloro-4-phenylquinazoline is only half of that at C-4,6 in 2-chloro-4,6-diphenylpyrimidine. 

Fluoro-2-phenylquinazoline has been prepared by fluoride displacement of chlorine from 4-chloro-2-phenylqui-nazoline <2002JOC8991>. 

A mixture of 5-chloro-2-(trichloroacetamido)diphenyl ketone (1.89 g, 5 mmol), NH4OAC (1.93 g, 25 mmol), and DMSO (25 mL) was allowed to stir at rt for 24 h. The solution was then poured into ice water (150 g). The precipitate formed was collected by filtration, washed with H O, and dried to give 6-chloro-4-phenylquinazolin-2(1 ff)-one as colorless crystals yield 1.27 g (99%) mp 321 -323 C. 

Acetamido-7-chloro-5-phenyl-3//-1,4-benzodiazepin-3-one (3) undergoes ring contraction and hydrolysis in cold dilute alkali to form 6-chloro-4-phenylquinazoline-2-carboxylic acid (4). In refluxing ethanolic hydrogen chloride, 3 affords the ethyl ester of 4. When heated with acetic acid, rearrangement and ring contraction of 3 to the isomeric A -acetyl-6-chloro-4-phenylquin-azoline-2-carboxamide take place. ... 

Chloro-2,5-epoxy-2-methyl-5-phenyl-l,2,4,5-tetrahydro-3//-l,4-benzodiazepin-3-one undergoes ring contraction to afford 2-acetyl-6-chloro-4-phenylquinazoline on treatment with ethanolic hydrogen chloride. ... 

Chloro-4,5-epoxy-5-phenyl-l,3,4,5-tetrahydro-2//-l,4-benzodiazepin-2-one undergoes ring contraction to give 6-chloro-4-phenylquinazolin-2(iy/)-one in aqueous tetrahydrofuran.- ... 

Catalytic hydrogenation of 8-chloro-6-phenyl-l,3-dihydro-2//-4,1,5-benzoxadiazocin-2-one oxime in the presence of Raney nickel affords 6-chloro-2-(hydroxymethyl)-4-phenylquinazoline in 49% yield. 

The 3-azido-3/f-indoles 3 undergo thermal rearrangement, upon refluxing in dimethylformamide, giving variable yields and ratios of quinazolines 4 and quinoxalines 5, along with the formation of the parent indoles 6. Thus, heating of 3-azido-5-chloro-3-methyl-2-phenyl-3//-indolc for 16 hours in dimethylformamide affords 6-chloro-4-methyl-2-phenylquinazoline (30%), 6-chloro-3-methyl-2-phenylquinoxaline (20%), and a trace of 5-chloro-3-methyl-2-phenyl-l//-indole. ... 

Chloro-2-methyl-4-phenylquinazoline 1-Oxide (2, R = Me = Ph R = Cl) Typical Procedure ... 

A solution of 6-chloro-2-methyl-4-phenylquinazoline (1, R = Me = Ph R = Cl 2.5 g, 10 mmol) and 30% aq II2O2 (1.2 mL, 10 mmol) in HOAc (15 mL) was heated on a steam bath for 10 h. After the third and seventh hour, an additional portion of 30% aq HjOj (0.6 mL, 5 mmol) was added. After 10 h, the mixture was concentrated in vacuo to a small volume, diluted with CHjClj, and washed with an excess of ice-cold aq NUjCOj. The organic layer was dried, concentrated in vacuo, and the residue recrystallized from acetone yield 1.4 g (52%) mp 156 °C. 

Chloro-2-methyl-4-phenylquinazoline 1-oxide gives l-acetyl-5-chloro-3-phenyl-l//-indazole on irradiation. This transformation is believed to proceed by rearrangement of the oxaziridines formed as primary isomerization products. ... 

Sternbach and coworkers pointed out that the reactions of the 6-chloro-2-chloromethyl-l,2-dihydro-4-phenylquinazoline 3-oxides 11 with a base gives either the 1,3-dihydro-2//-azirino[ 1,2-fl]quinazoline 4-oxides 13 or the 3H-1,4-benzodiazepine 4-oxide 15. In the first step of the reaction the anion 12 is formed by abstraction of a proton from the 1-nitrogen. The intermediate anion 12 can rearrange to the ring-chain tautomer 14. The relative stabilities of the two anions 12 and 14 are assumed to determine whether product 13 or 15 is formed. Thus when R is hydrogen or chloromethyl, the anion 12 is relatively sufficiently stable to allow the formation of the azirino-quinazoline 13. If, however, R is the electron-releasing methyl group, the anion 12 is destabilized and is converted to anion 14, which leads to benzodiazepine 15. The solvent polarity also influences the stability of the anions 12 and 14. In a nonpolar solvent (ether), the 5//-benzodiazepine 16 (R = Me) was obtained, which can be derived from anion 12 (R = Me) via the azirinoquinazoline 13 (R = Me). In a polar solvent (aqueous ethanol), however, the 3H-benzodiazepine 15 derived from anion 14 (R = Me) was the major product. As bases, potassium /er/-butoxide and sodium hydride were used. ... 

Haloquinazolines also react with amide ion in ammonia to give amino substitution products by an ANRORC process. Nitrogen labelling studies indicate that about half of the 4-aminoquinazoline resulting from 4-chloroquinazoline forms by an Sn(ANRORC) route. Amide ion must add to the unsubstituted 2 position prior to ring opening, Eq. (11).50 Similarly, 2-chloro-4-phenylquinazoline gives 2-amino-4-... 

Using ethanolic ammonia at 160 °C it was shown that, depending on the ammonia concentration, 34—67% of the 2-amino-4-phenylquinazoline produced from the chloro compound arises by a ring opening process. 2-Chloro- and 4-chloroquinazo-lines also undergo a ring opening substitution pathway in ethanol-ammonia.47 Thus, the Sn(ANRORC) mechanism is not limited to amide ion in ammonia. 

The fluorescence and phosphorescence of quinazoline, 6-chloro-4-phenyl-and 6-chloro-l-methyl-4-phenylquinazolin-2(lH)-one were recorded in ethanol containing 1% of concentrated sulfuric acid. The luminescence of these compounds on thin-layer chromatography (TLC) plates saturated with ethanol was reported. 4-Morpholino- and 4-piperidino-6-methoxy-2-phenyl-quinazoline also have luminescent properties, and the ultraviolet fluorescence in the crystals and in hexane or benzene solution was discussed. The time and wavelength resolved emission from quinazoline vapor at low pressures was studied with a pulsed frequency double-dye laser and were compared with those of quinoxaline and cinnoline. ... 

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