Pyrimidine 5- chloro-2-methyl-> amination

Polystyrene-bound isothiuronium chloride, which is readily prepared from chloro-methyl polystyrene and thiourea, has been used as a starting material for the preparation of various substituted pyrimidines (Entries 9-11, Table 15.28). After oxidation to the corresponding sulfones, nucleophilic cleavage with amines proceeds smoothly to yield substituted 2-aminopyrimidine derivatives (see Section 3.8). 

These pyridazines are subject to direct deactivation of the leaving group. It would appear from the conditions used in its reactions with ammonia (115°) and methylamine (50°) that 4-chloro-2-ethylthiopyrimidine (225) is somewhat deactivated (indirect). In various aminations of pyrimidines, the effect of an alkylthio group seems to be very mildly deactivating, like that of methyl groups. However, these surmises from the conditions used are not as reliable as the direct qualitative comparison described above and the kinetic data. 

Chloropyrimidine is aminated with alcoholic ammonia at 130° while 4-chloro-2-methyl- and 4-chloro-6-methyl-pyrimidine yield the corresponding 4-amino derivatives at 100°. 4-Aminopyrimi-dine is not prepared from the chloro analog because of facile self-quatemization (see Section III, B, 2 for comments on factors involved) of the latter. 

Reaction of 4-chloro-6-fluoropyrido[3,4- pyrimidine 59 with [3-methyl-4-(pyridin-3-yloxy)phenyl]amine 60, followed by coupling the formed amine 61 with (3-azabicyclo[3.1.0]hex-6-yl)carbamic acid fi r7-butyl ester, afforded the substituted derivative 62 <2002EPP1249451>. Compound 59 was also reacted with 3-bromoaniline to give the 4-anilino derivative 63 that upon treatment with either methyl- or dimethylamine gave the corresponding 4,6-diamino derivatives 64 (Scheme 2) <1997W09726259, 1995W09519774>. 

Methyl-5-oxo-l,5-dihydro-8-carbamoyl-l,2,4-triazolo[4,3-c]pyrimidines 577 and 578 were prepared by the cyclization of 576 with acetic anhydride and ethyl oxalate, respectively (89PHA604).The 4-methyl-l,2-dihydropyra-zolo[3,4-d]pyrimidine-3,6-dione 579 also was obtained in the latter case, as a consequence of breaking the amide bond and releasing the amine moiety. Coupling ethyl dithioacetate and 5-chloro-4-hydrazinopyrimidine (580) afforded the triazolo[4,3-c]pyrimidine 581 (89H239) (Scheme 114). 

POCI3 chlorinations (Eq. (8)) are acid-catalyzed reactions of such reaction products]. The hydrogen bonding of azinones is related to that of iV-oxides, discussed below, and to that of ketones (with water and alcohols) and has been demonstrated by infrared measurements on pjn-idinethione in alcohols and by the electronic absorption spectra of azinones in water. 6-Chloro-l,3-dimethyl-pyrimidine-2,4-dione is rapidly aminated at 20° (with heat evolution) by methyl- or ethyl-amines, etc., in protic media (water or alcohols). 

As already mentioned in Section IV,A, 2-methyl-4-hydroxypyrido-[3,4-i/]pyrimidine (48) on silylation-amination with benzylamine, affords 97% of the corresponding N-benzyl derivative 50, whereas the conventional two-step procedure via the 4-chloro compound 49 gives 50 (86ABC495) in only 40% yield. 

Aminopurines are generally synthesized by the nucleophilic displacement of chloro or methyl-sulfanyl substituents by ammonia or amines (Section 7.1.1.3.4.1.). However, the Traube cyclization is also a useful method. Thus, adenine is prepared by the condensation of pyrimidine-4,5,6-triaminc with formamide under reflux.The same method can also be employed for the preparation of purine-2,6-diaminc (1) (Table 20). 

Extensive investigation of amide-induced amination of purine and its derivatives has shown that the parent compound (purine) as well as its 2-methyl and 8-methyl derivatives react with potassium [ - Njamide in ammonia to undergo exclusive amination at C6 without incorporation of the N label into the ring (Chichibabin reaction). Amination of 2-fluoro-, 2-chloro-, and 2-(methylsulfanyl)purine 7, and 2-chloro-6-phenylpurine with potassium [ N]amide in ammonia, however, gives purin-2-amines with complete incorporation of the N label in the pyrimidine ring. 

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