Quinazolines alkylation

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. 

A. Quinazolines Substituted in the Pyrimidine Ring 1. Alkyl- and Aryl-quinazolines... 

Decarboxylation of a-(4-quinazolinyl) acetic esters in alkaline solution is useful for the preparation of less readily accessible 4-alkyl quinazolines (see 4c). This method is limited to derivatives where... 

Pyrimidine-2-thiones (e.g., 206) have been shown to exist as such by comparison of their ultraviolet spectra with those of both alkylated forms.The ultraviolet spectra of pyrimidine-4-thiones are different from those of 4-alkylthiopyrimidines, therefore the former compounds exist as 207 and/or 208, the predominant form not having been determined. Infrared spectral evidence suggests that quinazoline-4-thione exists as 209 and/or 210 and has been used recently to demonstrate the thione formulation for pyrimidine-2- and -4-thione, pyrazine-2-thione, and quinoxaline-2-thione. In view of this work, the report that X-ray crystallographic evidence supports the mer-... 

The mesomeric effect of the C=S linkage is very pronounced and is responsible for the facile quaternization of heterocyclic N-alkylated thiones (159) this effect is operative even when such a shift does not increase the aromaticity of the ring. Thione derivatives of pyridazine, benzothiazole, quinazoline, 1,3-thiazine, triazole,and isoindole are examples of compounds which readily form quaternary salts. 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

Arylthio but not 2-arylthio groups in quinazolines can be replaced with hydroxide ion or alkylamines. 4-Alkylthio-2-alkyl (or aryl)-quinazolines are readily alkoxylated (65°, 1 hr, 80-90% yield) at the 4-position. Arylthio and alkylthio groups have been found to be poorer leaving groups than chloro in several azines. 

Treatment of 3-amino-4-oxoquinazolines (9) with cyanamide gave the 2-amino-l,2,4-triazolo [l,5-c]quinazolines 11 as a result of cyclodehydration of the intermediate 3-guanidino-4-oxoquinazolines 10 (68CB2106) (Scheme 9). Similarly, reaction of the 3-amino-4-thioxoquinazoline 12 with alkyl or aryl isothiocyanates yielded the mesoionic l,2,4-triazolo[l,5-cjquinazolines 14 (84S881) (Scheme 10). 

Treatment of 2-[(4-methoxyphenyl)methyl] derivative of 2,3,6,7-tetra-hydro-l//,5//-pyrido[3,2,l-//]quinazoline-l,3-diones with (NH4)2Ce(N03)g afforded 2-unsubstituted derivatives. A 2-unsubstituted derivative was N-alkylated with 4-methoxybenzyl chloride in DMF in the presence of K2CO3 at 50 °C (01MIP22). 

Lee, C.-H. Skibo, E. B. Active site directed reductive alkylation of xanthine oxidase by imidazo[4,5-g]quinazoline-4,9-diones functionalized with a leaving group. Biochemistry 1987, 26, 7355-7362. 

Lemus, R. L. Skibo, E. B. Studies of extended quinone methides. Design of reductive alkylating agents based on the quinazoline ring system, j. Org. Chem. 1988, 53, 6099-6105. 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Alkylation of the 3-lactim ether, (4A)-3-ethoxy-4-isopropyl-l,4-dihydropyrazino[2,l-3]quinazolin-6-one with BnBr gave pure l,4-/ra r-diastereomer. The higher diastereoselectivity - as compared to the lactams - was explained by the fully boat conformation of the piperazine ring in the lactim ethers <2005TA3160>. 

Alkylation of 31 with dibromomethane and 1,2-dibromoethane was performed under solvent-PTC conditions with good yields and short irradiation times (15 min) [16]. The synthesis of original benzimidazo-[l,2-c]-quinazoline dimers 32(a,b) was successfully achieved by use of potassium carbonate in the microwave active DMF solvent (Scheme 8.13). 

The triazine ring could be formed by reaction [82S853 83BSF(2)226] of alkyl (2-aryl-4-thioxo-3,4-dihydro-2//-quinazolin-3-yl)acetates 477, prepared from 476, with hydrazine to yield 6-aryl-2,4-dihydro[l,2,4]tria-zino[4,3-c]quinazolin-3-ones 478. 

Quinazolines undergo many of the same reactions as pyrimidines, such as the modification of an amino group. Gangjee and co-workers reported the reductive alkylation of diaminoquinazolinones 141 with various aryl carbonyl compounds 142, which regioselectively produced quinazolinones 143 <00JHC1097>. 

Antibacterial activity has also been observed with a variety of sulphameth-oxypyridazine derivatives like the imine obtained upon reaction of (95, R1 = MeO R2 = H) with 5-nitrofurfural [312], 2-aryl-3-nitrofurylacrylamides (105) [313], quinazoline-2,4-diones (106) [314], thiazolin-4-ones of type (107) [315] and with aldol condensation products of the latter [316], Sulpnonylpyridazmones (108, R1, R3 = alkyl, Ph R2 = substituted NH2, HO, RO) [273,274], trichloromethylchloropyridazines (109) [317] and 3-mer-captopyridazine 2-oxide derivatives [318, 319] have been claimed as antibacterial agents. 

---