Quinazolines, 4-chloro-, reaction with

The 3-OH substituent of the 3-hydroxy tautomer of the pyridazino[6,l-A]quinazoline 22 was exchanged for a Cl group on treatment with POCI3 and the chloro group was replaced on reaction with secondary and primary amines and with alkoxides <2000HC0147>. 

Whereas the reaction of small primary amines with 2-(chloromethyl)quinazoline 3-oxides 1 leads to ring-enlarging rearrangement to 1,4-benzodiazepines (cf. p 159), weak primary amines.secondary amines, hydroxylamine, thiolates, " thiocyanate. cyanide, and the carbanions of nitroethane and nitropropane lead only to products 2 derived from substitution of the halogen. In a few cases, also in the reaction of 2-(chloro-methyl)quinazoline 3-oxides with methylamine, the unrearranged 2-[(methylamino)methyl]-quinazoline 3-oxide products are isolated. " ... 

Other synthons for 1,3-dicarbonyl compounds that have been successfully applied include p-chloro-a,P-unsaturated ketones and aldehydes, P-dimethylamino-a,P-unsaturated ketones (easily obtained from ketones by reaction with DMFDMA), P-alkoxy-enones"" and vinyl-amidinium salts."" Alkynyl-ketones react with 5-alkyl-isothioureas, giving 2-alkylthio-pyrimidines" and propiolic acid reacts with urea to give uracil directly in about 50% yield. "" 1,3-Keto-esters with formamidine produce 4-pyrimidinones"" and C-substituted formamidines with ethyl cyanoacetate give 2-substituted-6-amino -pyrimidinones. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ortho-aminonitriles " and in general, from P-enamino esters. ... 

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 ... 

Condensation of 2-azido-P-phenethylamine with 4-chloro- or 4-nitrobenzaldehyde followed by reaction with diphenylketene in refluxing toluene gives the ketenimine 59 which undergoes an intramolecular [2tc + 27t] cyclisation to the azeto[2,l-6][l,3]benzodiazepines 60 <97T13449>. The method may be used also to synthesise azeto[2,l- )]quinazolines, the main thrust of the publication, but the tether cannot be increased further as the respective 8- and 9-membered ring systems could not be formed. UV irradiation of 4,6-diazido-3-methylisoxazolo[4,5-c]pyridine gives two products which have been identified and isoxazolo-... 

Of greater versatility is an extension of Albert and Royer s acridine synthesis. The first successful use of this in the quinazoline series was for the removal of the chlorine atom in 2-chloro-4-phenylquin-azoline, although it had been used previously to prepare 8-nitro-6-methoxyquinazoline in very poor yield. The 4-chloroquinazoline is converted to its 4-(A -toluene-p-sulfonylhydrazino) quinazoline hydrochloride derivative which is decomposed with alkali in aqueous ethylene glycol at lOO C (Scheme 13). The yields are high (60-70%) when R is Me, Cl, OMe but low when R is NO2, and in the latter case it is preferable to use dilute sodium carbonate as the base. This reaction is unsatisfactory if the unsubstituted pyrimidine ring is unstable towards alkali, as in 1,3,8-triazanaphthalene where the pyrimi-... 

Kinetic studies have been carried out on the displacement reactions of various chloroazanaphthalenes with ethoxide ions and piperi-dine. - 2-Chloroquinoxaline is even more reactive than 2-chloro-quinazoline, thus demonstrating the powerfully electrophilic nature of the -carbon atoms in the quinoxaline nucleus. The ease of displacement of a-chlorine in the quinoxaline series is of preparative value thus, 2-alkoxy-, 2-amino-, - 2-raethylamino-, 2-dimethyl-amino-,2-benzylamino-, 2-mercapto-quinoxalines are all readily prepared from 2-chloroquinoxaline. The anions derived from substituted acetonitriles have also been used to displace chloride ion from 2-chloroquinoxaline, ... 

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

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>. 

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. 

As we have already seen in several examples, the electron withdrawing nature of the nitrogen atoms in heterocyclic systems leads to a marked increase in their ability to participate in cross-coupling reactions. The triazolo[l,5-a]quinazoline system in 8.23. is a nice example, since not only the 5-chloro, but also its 5-tosyloxy derivative was shown to couple readily with 2-tributylstannyl-thiophene in 78% and 91% yield respectively.32 Interestingly, in case of the chloro derivative the addition of copper... 

Similar to their 1,3,4-thiadiazolo analogues, l,3,4-selenadiazolo[2,3-a]quinazolines (380) were synthesized by the reaction of diazotized anth-ranilic acid or its esters with either 2-selenocyano-1,3-diketones or 2-chloro-1,3-diketones, followed by treatment with potassium seleno-cyanate (82G545 83JHC719). 

Chloro-3,4,7-l 1 b-tetrahydro-2//,6//, 1 lb-phenyl-1, 3-oxazino[3,2-c]-quinazolines (574) were obtained by the reaction of 2-acylamino-5-chlorobenzophenones (573) with 3-aminopropanoI [70YZ629 72GEP-(0)2141616 80PHA256 81CPB2135]. 

Cyclocondensation of 2-aminopyridines and methyl 2-chloro-3,5-dinitrobenzoate in boiling ethanol in the presence of sodium acetate for 12 h gave 8,10-dinitro-6//-pyrido[l,2-a]quinazolin-6-ones (312) [96JAP(K)96/157476]. 6//-Pyrido[l,2-a]quinazoline derivatives were prepared in the reaction of 2-aminopyridine and salicylaldehydes followed by treatment with NaBH4 (93MI7). 

Amino-3-chloro-5-trifluoromethylpyridine with electron-rich alkenes and formaldehyde in the presence of trifluoroacetic acid in boiling acetonitrile for 1 h yielded 6a,7,8,9,10,10a-hexahydro-6//-pyrido[l,2-a]-quinazolines (326) (96TL2615). The regiochemistry is dictated by the reaction of formaldehyde at the primary amino group. 

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