Quinazolines 4-amino- from

The trichloromethyl group of 4-(trichloromethyl)quinazoline can be replaced by methoxy, hydroxy, aliphatic amino, and pyrrolidino groups to give quinazolines 1. From a preparative point of view, these nucleophilic aromatic substitution reactions are similar to the replacement of other more common leaving groups. In the reaction of 4-(trichloromethyl)quinazoline with a methoxide ion, in contrast to the usual aromatic substitution mechanism, a covalent solvation adduct was isolated as intermediate. Whereas 4-(trichloromethyl)quinazoline prefers to undergo aromatic substitution, 4-(tribromomethyl)quinazoline prefers aliphatic substitution. 2-Methyl-4-(tribromomcthyl)quinazoline affords 2-methylquinazolin-4(3/f)-one in 74% yield on treatment with sodium hypobromite in dioxane, probably via an aromatic substitution reaction of a tribromomethyl group. 

Compounds in which other heterocyclic rings (pyrazoles, isoxazoles, imidazoles ) are fused to thiopyrans have been described. The interesting thiazolium salts (56) were prepared by allowing the betaines (55) to react with 4-thioxothiazolidin-2-ones. Application of the Fischer indole synthesis and the Friedlander reaction to tetrahydrothiopyran-3-one led to the exported indolo-and quinolino-derivatives. Ring closure of (57) under acidic conditions afforded the rearranged product (58). Syntheses of benzothiopyrano[4,3,2-flfe]-quinazolines (59) from 1-amino-thioxanthones and of their S- and 7V-oxides have been described. ... 

Aminoquinazolines have been the subject of considerable investigation and a large number of derivatives have been prepared as potential antimalarials. The secondary and tertiary amino compounds can be prepared from the corresponding chloroquinazolines and the required primary or secondary amines. The reaction depends on the reactivity of the halogen atom, e.g, the 4-chloro atom reacts more readily than the 2-chloro atom in quinazolines and also on the basic strength of the amine used (see 6a). The reaction is... 

Fusion of 4-hydroxyquinazoIine with phosphorus pentasulfide yields 4-mercaptoquinazoline and, similarly, substituted 2,4-dimercapto-quinazolines have been obtained from the corresponding dihydroxy compounds. The greater reactivity of the 4-mercapto as compared with the 2-mercapto group has permitted the preparation of 4-amino-2-mercaptoquinazolines (see 7a). 

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, ... 

This method has been applied to a large-scale preparation of 6-bromoindole, which reacts with various arylboronic acids via the Suzuki reaction to afford 6-arylindoles (Eq. 10.50).64 6-Bromo-5-methoxyindole for use in the synthesis of marine bromoindole65 and 5-amino-7-ethoxycarbonylindole for use in synthesis of l//-pyrrolo[3,2-g]quinazoline ring system (Eq. 10.51)66 have been prepared from the appropriate o-nitrotoluene. 

The pyridazine ring of 111 is formed from [4+2] atom fragments in the cyclization of 3-amino-2-chloromethyl-quinazolin-4-one with activated acrylthioamides. The saturated pyridazine ring of 111 aromatized spontaneously to give 112 (Equation 12). Reaction with io-nitrostyrene yielded the 3-nitro analogue of 112 <2003MOL401>. 

The linearly fused benzologues, pyrimido[2,l-A]quinazolines, are most frequently synthesized from a 2-amino- or 2-iminoquinazoline. Synthesis from [6+0] atom fragments by bond formation 7 to the ring junction nitrogen takes place when the 2-aminoquinazoline bearing a suitable substituent at N-3 is cyclized. The 2-iminoquinazoline-3-propionates 197 cyclized on treatment with alkali to give 198 (Scheme 31) <1997EPP0778258>. 

Besson and coworkers reported an original approach for the synthesis of the rare thiazolo-[5,4-/]-quinazoline 29 in six steps [15] from commercially available 2-amino-5-nitrobenzonitrile 22 (Scheme 8.11). The authors studied the transposition of four steps (ii, iii, vi, and vii) of the synthesis of thiazoloquinazoline 29 to microwave irradiation of solutions, with the same concentration of starting material and volume of solvent, and found that yields of the desired compounds were better than those obtained by conventional heating (Tab. 8.3). The overall time for the synthesis of 29 was considerably reduced and the overall yield was enhanced. 

Quinazolines, the benzo derivatives of pyrimidines, were prepared in a variety of ways, from methods analogous to those for synthesizing pyrimidines to vastly different condensation schemes. In analogous fashion to many pyrimidine preparations, Yang and coworkers reported the condensation of polymer-tethered amidines 109 with cyclic anhydrides 110 to yield a library of 2-amino-4(3//)-quinazoIinones 111 after cleavage from the resin <00TL7005>. 

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. 

A series of 6- and 7-aciylamide derivatives of 4-(phenylamino)-quinazoline and 4-(phenylainino)-pyridopyrimidine, classes of epidermal growth factor receptor (EGER) inhibitors, have been prepared from the corresponding amino compounds by reaction with actoyl chloride/base <99JMC1803>. Reaction of thionyl chloride with hexahydro-7-methyl-pyrimido[l,6-a]-pyrimidine-6,8-dione yields the corresponding 9,9 -thiobispyriiiudopyrimidine derivative <99JHC453>. 

---