Aminopyrimidines, formation

Formation of the amino-acrylate of aminopyrimidine intermediates was reported. In the absence of base, alkylation occurred on the carbon and not the nitrogen, followed by cyclization to give 125. In the presence of base (EtONa), condensation occurred on the nitrogen. Cyclization under thermal conditions afforded 128. °... 

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

A related agent, g1 icetanile sodium (42), is made b / a variant of this process. Methyl phenyl acetate is reacted with chlorosulfonic acid to give 38, which itself readily reacts with aminopyrimidine derivative 39 to give sulfonamide Saponification to acid 4 is followed by conversion to the acid chloride and amide formation with 5-chloro-2-methoxyaniline to complete the synthesis of the hypoglycemic agent glicetanile (42). ... 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

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>. 

A microwave-assisted, one-pot, two-step protocol was developed for the construction of polysubstituted 2-aminoimidazoles 101 via the sequential formation of imidazo[l,2-a]pyrimidinium salts from readily available 2-aminopyrimidines 99 and a-bromocarbonyl compounds 100, followed by opening of the pyrimidine ring with hydrazine <06OL5781>. A... 

As shown in Scheme 199, the 5-aminopyrimidine stmcture may be also incorporated into a more complex bicyclic system. Thus, diazotization of 3-amino-4-oxo-4//-pyrimido[ 1,23 lpyndazincs 1198 followed by treatment with 50% aqueous tetrafluoroboric acid results in precipitation of salts 1199. When heated with alcohols, nucleophilic attack on the carbonyl group opens the pyrimidine ring. The obtained species 1200 assume conformation 1201 that is more suitable for bond formation between the opposite charged nitrogen atoms. Alkyl l-(pyridazin-3-yl)-l//-l,2,3-triazole-4-carboxylates 1202 are obtained in 31-66% yield <2002ARK(viii)143>. 

Irradiation of tetrazolo[l,5- ]pyrimidine 1 in benzene in the presence of trifluoroacetic acid was investigated by Takeuchi and Watanabe <1998JP0478> (Scheme 10). Formation of 2-anilinopyrimidine 57, 2-aminopyrimidine 58, and biphenyl was observed. The authors assumed that 57 was formed via a singlet nitrene, whereas formation of the other products may result from the triplet nitrene intermediate. In contrast to this early assumption, Hill and Platz <2003PCP1051> exclude the formation of a triplet nitrene upon spectroscopic evidence as discussed in Section 11.18.5.1. 

In extension of this work, the amino-debromination reaction of 4-methoxy-, 4-phenyl-, 4-t-butyl-, and 4-(A-methylanilino)-5-bromopyrimi-dine was investigated. It was found that in all these reactions, good yields of the corresponding 6-aminopyrimidines are obtained no indication for the formation of a 4-substituted 5-aminopyrimidine was observed (Scheme II.3) (64TL2093 65TL555 68TL9). 

An interesting consequence of the mechanism presented in Scheme 11.26 is that, in principle, from the intermediary 45 by ring closure a double N-labeled 2-aminopyrimidine 42 can also be obtained These results suggest that the formation of the 2-amino-4-phenylpyrimidine can occur according to two routes by an initial addition at C-6 (the main process. Scheme 11.25) and by initial addition at C-4 (the minor process. Scheme 11.26) (74RTC111). Both routes involve a degenerate ring transformation. 

Sulfadiazine Sulfadiazine, Ari-2-pyrimidinylsulfanilamide (33.1.7), is synthesized by reacting 4-acetylaminobenzenesulfonyl chloride with 2-aminopyrimidine, which gives an acetanilide derivative (33.1.6). The subsequent hydrolysis of this product with a base leads to the formation of the desired sulfadiazine [5-8],... 

Having a cyano group and an amino group ortho to each other on a ring is another system that has led to the formation of fused pyrimidine ring systems. In this case, an aminopyrimidine is the result. Compound 42 in Scheme 5 is one such structure. Treatment of 42a with formamide leads to the amino derivative 43 <1999PS(155)175>. Alternatively 42b provides 44 after treatment with triethyl orthoformate followed by hydrazine <1999PS(155)175>. 

Microwave irradiation, for 15-20 min under solvent-free conditions, promoted the regiospecific three-component one-step cyclocondensation of benzoylacetonitrile, an aromatic aldehyde, and aminopyrimidinones 460 to give 6-cyano-5,8-dihydropyrido[2,3-, pyrimidin-4(3/7)-ones 461 rather than the isomers 462. The formation of 461 proceeds via a Michael-type addition of C-5 in aminopyrimidine 460 to the activated double bond of the arylidene-benzoylacetonitrile intermediate followed by cyclization with the removal of a water molecule. Compounds 461 were also prepared conventionally by refluxing the reactants in absolute ethanol for 40 8 h <2001TL5625>. 

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 analogous reaction to that described in Equation (42) using paraformaldehyde in equimolar amount to dimedone (instead of a large excess) was irradiated for 3 min to yield pyrimido[4,5- ]quinoline-4,6-dione 591 via formation of intermediate adduct 590 <2006TL27>. The 5-aryl-5,6,7,8,9,10-hexahydropyrimido[4,5-/ ]quinolines 592 were also prepared by the cyclocondensation reaction of 6-aminopyrimidine 460 with dimedone and 4-sub-stituted benzaldehydes by boiling in absolute ethanol for 30 min <1998JHC231>. 

One of the first so-called potassium sparing, nonthiazide diuretic agents contains a pterdine nucleus. This is reflected in the use of the pterdine staring material tetra-aminopyrimidine (38-2) in the synthesis. Thus, reaction of benzaldehyde with that polyamine and potassium cyanide leads to the formation of the cyanohydrinlike a-aminonitrile (63-2) from reaction of the most basic amino group. Treatment of the intermediate with a base leads to the addition of the amine to the nitrile to give the dihydropteridine (63-3). Simple exposure to air leads to dehydrogenation and the formation of triamterine (63-4) [65]. 

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