Quinazolines amines

The much-used sulfonylation by aromatic sulfonyl chlorides is illustrated by the conversion of quinazolin-4-amine into the sulfonamide (247) using p- nitrobenzenesulfonyl chloride at 60 °C (56JCS3509). 

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... 

Alkaloids containing a quinazoline nucleus form a small but important group of natural products and have been isolated from a number of different families in the plant kingdom. The quinazoline alkaloids are of the four types (48), (49), (50), and (51). The structures of arborine, peganine, febrifugine, rutaecarpine, and evodi-amine have been elucidated by degradation and synthesis and are described in recent reviews on quinazoline alkaloids. ... 

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. 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

Alkaline hydrolysis of 6-methoxy- 4-methoxycarbonyl-2-methyl-tbiopyrimidine leaves unaffected only the methylthio group which can then be hydrolyzed in acid. 9-Alkylthioacridines are hydrolyzed by acid less readily than the corresponding alkoxy compounds and more readily than alkylamino derivatives. Peculiarly, a better yield of the amine results from 4-thioxo than from 4-methylthio-quinazoline on heating with primary amines. Displacement in 2-methylthio-quinolinium and 3-methylthiopyridazinium compounds (137) proceeds readily with the carbanion of diethylmalonate or the zwitterion of 2-methylbenzothiazolinium derivatives. 

A-Substituted 11-oxo-l l//-pyrido[2,l-6]quinazoline-6-carboxamides were prepared from 11-oxo-l l//-pyrido[2,l-6]quinazoline-6-carboxylic acids and amines in the presence of (/-Pr)2EtN and benzotriazol-l-yloxytris(dimethy-lamino)phosphonium hexafluorophosphate in CH2CI2 (98MIP1, 98MIP2, 99USP5908840, 99USP5914327). 

Chloromethyl)quinazoline 3-oxides, c.g. 8, react with ammonia and primary amines to yield 3//-1,4-benzodiazepine 4-oxides 10, sometimes accompanied by the simple substitution products 9.219 Dimethylamine220 and pyrrolidine221 react analogously, but other secondary amines afford only products of type 9. 

It has been proposed that the ring-expansion reaction is initiated by attack of the base at position 2 of the quinazoline oxide, which is rendered electron deficient by the inductive effect of the (V-oxide group. In fact, 2-(Chloromethyl)quinazolines, compounds that lack this feature, react with amines to give only simple substitution products.1133... 

Quinazolin-4(3/7)-one was converted into 4-chloroquinazoIine on heating with a mixture of phosphoryl chloride and phosphorus pentachlo-ride [80IJC(B)775], Phosphoryl chloride in the presence of triethylamine, however, transformed quinazolin-2,4(lf/,3//)-dione into 2-chloro-4-diethylaminoquinazoline. More bulky amines allowed formation of the 2,4-dichloro derivative (82CPB1947). 

Hydrates of acids such as Ts0H-H20 can probably also be dehydrated by treatment with silyl esters such as TsOSiMe3 (Scheme 13.1). Likewise, Ts0H-H20 is dehydrated in situ during aminations of hydroxy-N-heterocycles such as purines 242 (Scheme 4.24) or (lH,3H)-quinazoline-2,4-dione 250 (Scheme 4.27) by HMDS 2, in the presence of higher-boiling primary or secondary amines, to give the ami-... 

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>. 

The [l,3]oxazino[2,3- ]quinazolin-6-one 305 reacted with cyclic secondary amines (e.g., as in Equation 33) to afford the quinazolin-2,4-diones 306 <2002EPP1178048>. 

A simple, efficient, and high-yielding synthesis of quinazolin-4-ylamines and thieno[3,2-d]pyridin-4-ylamines based on the condensation of appropriately functionalized N -(2-cyanophenyl)-N,N-dimethylformamidines and primary amines has been reported by Han and coworkers (Scheme 6.253) [440]. Optimization of the reaction parameters resulted in the use of acetonitrile/acetic acid as a solvent mixture and of 1.2 equivalents of the requisite amine. In general, microwave heating at 160 °C for 10 min provided excellent product yields. 

The same research group has shown that the 5-fluorophenyl-l,2,4-oxadiazoles 73 (Scheme 6) form the triazoles 74 as the major products in the presence of amine nucleophiles, together with varying amounts of side products 75-77, with product 76, for example, being formed by the competitive addition of the methanol solvent to the N-O-cleaved photolytic product <2005H(65)387>. The formation of quinazolin-4-ones 75 has been studied separately, and has been optimized to allow good yields as shown by the example in Equation (6) <1999JOC7028>. 

In analogous fashion to isocyanate chemistry, isothiocyanates like 125 can be utilized to produce the corresponding quinazoline-2-thioxo-4-ones. Makino and co-workers reported the solid phase synthesis of quinazoline derivatives 126 through the reaction of polymer-bound primary amines 124 with isothiocyanates 125 <00TL8333>. 

Treatment of quinazoline 3-oxide with amines gives the rearrangement product, 1,4-benzodiazepine. 

The sensitivity of position 2 in 4-chloroquinazoline for nucleophilic addition was also demonstrated in the reaction with lithium piperidide (73RTC460). Whereas in the amination with potassium amide/liquid ammonia no open-chain intermediate could be isolated, with lithium piperi-dide/piperidine the open-chain compound ort/z6>-(piperidinomethy-leneamino)benzonitrile (78,60%) was obtained, in addition to 4-piperidino-quinazoline (80,19%) (Scheme 11.35). The formation of 80 from 78 involves... 

The application of the Chichibabin amination to effect a direct amination of quinazoline has been reported. It gives 4-aminoquinazoline (60MII) as well as 2,4-diaminoquinazoline (59GEP958197). No mechanistic details were discussed, but it can be expected (based on the experience with the amination with 4-phenyl- and 5-phenylpyrimidine) that amination of quinazoline would also involve, at least partly, participation of the Sn(ANRORC) mechanism. Amination with N-labeled potassium amide/liquid ammonia will certainly shed some light on the mechanism operative in this Chichibabin amination. 

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