6-Aminopyrimidin-4 -ones

The unexpected 8-hydroxymethylhexahydropyrido[2,3-, pyrimidine-6-spiro-l -cyclohexane-2, 4,6 -triones 520 were obtained from microwave-assisted cyclocondensation of equimolar amounts of 6-aminopyrimidin-4-ones 460 and dime-done with a large excess of formaldehyde (37% in water) in the presence of EtsN as a catalyst <2006TL27>. The reaction proceeded via an initial formation of the 2 1 dimedone/formaldehyde adduct 521 that gave intermediate 522 and 523 which could undergo cyclocondensation with excess formaldehyde to give 520 (Equation 42) <2006TL27>. 

The synthesis of purines from monoacyl pyrimidine-4,5-diamines is a commonly used method (for example, [2252]). Similarly, 8-hydroxymethylpurin-6-one is synthesized from S-acylamino-6-aminopyrimidin-4-one and ethyl glycoiate but... 

Tliree-bond formation through consecutive (3 + 1 + 1) atoms heterocy-clization of 4(6)-aminopyrimidines with one carbon followed by one nitrogen (Scheme 1). 

Ring B of pyrimido[l,6-tf]pyrimidines has been most frequently synthesized from [3+3] atom fragments. The 6-aminopyrimidin-2-one derivative, cytidine 211, on reaction with acrylic acid under thermal conditions gave the pyrimido[l,6- ]pyrimidin-4,6-dione 212 <1996MI301> while reaction with 3-chloropropionaldehyde under base catalysis resulted in the pyrimido[l,6- ]pyrimidine-6-one 213 (Scheme 33) <1996MI501, 1996BAP209>. 

Hie cyclic anhydride (80.4) reacts with trimethylsilyi azide under anhydrous conditions to give a mixture of I,3-oxazine-2,6-dione isomers, which was used without further purification to synthesis several extended purines. Reaction with formamidine acetate in DMF in effect replaced the furandione ring by a pyrimidinone. Cyanamide produced a new fiued 2-aminopyrimidin-4-one [in (80.5, R = NH )], while urea led to a pyrimidinedione. Isatoic anhydride similarly yields 2-aminoquinazolin-4-one on treatment with cyanamide-DMF. 

Besides formyl, other acyl groups such as acetyl or benzoyl in the 5-position of the pyrimidine nucleus have been used for cyclizations. Thus, 5-acyl-6-aminopyrimidin-4(3//)-ones condense with malononitrile in refluxing pyridine to give the corresponding 7-amino-4-oxo-3,4-dihydropyrido[2,3-(7]pyrimidine-6-carbonitriles 21.171... 

Reaction of 3-formyM/7-pyrido[ 1,2- ]pyrimidin-l-ones with hydroxylamine O-sulfonic acid at 5 °C, then 50 °C yielded 3-nitriles <2003T4113>. Treatment of 2-hydroxy-3-(dimethylamono)methyF4//-pyrido[l,2- ]pyrimidin-4-one with Mel, then with KCN gave the 3-cyanomethyl derivative <2004MI215>. A condensation product was obtained from 5-amino-l-ethyl-6-hydroxy-l,3-dihydrobenzimidazol-2-one and 3-lbrmyl-2-hydroxyA//-pyndo[ 1,2- ]pynmidin-l-one <2002W002/38549>. l-(2-Aminopyrimidin-4-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-ones were prepared from l-(2-methylthiopyrimidin l-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-one by treatment with MCPBA, and then with aralkylamines <2005W005/070932>. 

Several studies deal with the reactivity of 2,4-disubstituted-6-aminopyrimidines, which have competing sites for ring formation with 1,3-biselectrophiles. Treatment of 2,4,6-triaminopyrimidine with ethyl acetoacetate in acetic acid formed the pyrimido[l,6-tf]pyrimidin-4-one 216, while the expected pyrido[2,3-r/]pyrimidin-7-one 217 was obtained under thermal conditions (Scheme 34) <1999JOC634>. 

Dehydration of the aminopyrimidin-6-yl-benzamide 288 with polyphosphoric acid gives rise to the purin-4-one angular tricyclic system 289 in moderate yield (Equation 78) <1995JHC1725>. 

Pyrimidinyl halides are not only precursors for Pd-catalyzed reactions, but also important pharmaceuticals in their own right. One of the most frequently employed approaches for halopyrimidine synthesis is direct halogenation. When pyrimidinium hydrochloride and 2-aminopyrimidine were treated with bromine, 5-bromopyrimidine and 2-amino-5-bromopyrimidine were obtained, respectively, via an addition-elimination process instead of an aromatic electrophilic substitution [4, 5], Analogously, 2-chloro-5-bromopyrimidine (1) was generated from direct halogenation of 2-hydroxypyrimidine [6], Treating 1 with HI then gave to 2-iodo-5-bromopyrimidine (2). In the preparation of 5-bromo-4,6-dimethoxypyrimidine (4), N-bromosuccinimide was found to be superior to bromine for the bromination of 4,6-dimethoxypyrimidine (3) [7]. 

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