Pyrimidine ring construction

Move 3] This work surveys complementary routes for the synthesis of pyrazolo[f,5-a] pyrimidine-7-ones 1 and pyrazolo[l,5-a]pyrimidin-5-ones 2. The use of 1,3-dimeth-yluracil 3 as an electrophile for pyrimidine ring construction affords pyrazolo[f,5-a] pyrimidin-5-ones 2, contrary to literature reports. Novel use of trans-3-ethoxyacrylate 4 as an electrophile also afforded 2, and the isolated intermediates from this reaction support our proposed mechanism. (55 words)... 

The H mode of the pyrimidine ring construction assuming the stepwise formation of the N(l)-C(2) and C(2)-N(3) bonds as a result of the insertion of a component serving as the source of the C(2) atom is more often used in practice. The simplest modification involves intramolecular condensation of 3-(acylamino)thienopyri-dines produced by acylation of 3-amino-2-carbamoylthieno[2,3-Z>]pyridines or their structural analogs (1995PS83). An example is the synthesis of pyrimidothienobenzo-quinoline 98 from chloroacetamide 99. 

Construction of Isoxazole, Pyrazole and Pyrimidine Rings from Aminopropenones... 

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... 

All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often one pot , ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. 

The major intermediates in the biosynthesis of nucleic acid components are the mononucleotides uridine monophosphate (UMP) in the pyrimidine series and inosine monophosphate (IMP, base hypoxanthine) in the purines. The synthetic pathways for pyrimidines and purines are fundamentally different. For the pyrimidines, the pyrimidine ring is first constructed and then linked to ribose 5 -phosphate to form a nucleotide. By contrast, synthesis of the purines starts directly from ribose 5 -phosphate. The ring is then built up step by step on this carrier molecule. 

Pyrazole 1131 was prepared from the mesylate 1130, which proved to be an excellent precursor for this type of nucleoside as in 1132. The construction of the pyrimidine ring was achieved through the steps shown in Scheme 220 to give 1133 and 1134 [85JCS(P1)1425 89JCS(P1)925]. 

Pyrido[2,3- pyrimidine bicyclic systems represent interesting fused heterocyclic compounds having pharmacological and biological properties. Their syntheses are well documented in the literature. The pyridine or pyrimidine rings have been used as precursors for constructing the second heterocyclic ring. 

A final approach to pyrimido[4,5-( ]pyridazines involves construction of a pyrimidine ring from a 3-aminopyridazine -carboxylic acid derivative as described in both CHEC(1984) and CHEC-II(1996) <1984CHEC(3)329, 1996CHEC-II(7)737>. Further examples of this approach have appeared since the publication of CHEC-II(1996) <2000JCCS951, 2006JHC243> and the approach has been used to prepare peri-fused systems (Scheme 20) <1993JRM1239>. 

Korbonits et al. (91CB111) employed acyl-substituted 4-amino- 1-azabu-tadienes for the construction of the pyrimidine ring (Scheme 10). Thus,... 

Several purine derivatives are found in nature, e.g. xanthine, hypoxanthine and uric acid. The pharmacologically important (CNS-stimulant) xanthine alkaloids, e.g. caffeine, theobromine and theophylline, are found in tea leaves, coffee beans and coco. The actual biosynthesis of purines involves construction of a pyrimidine ring onto a pre-formed imidazole system. 

FIGURE 22-36 De novo synthesis of pyrimidine nucleotides biosynthesis of UTP and CTP via orotidylate. The pyrimidine is constructed from carbamoyl phosphate and aspartate. The ribose 5-phosphate is then added to the completed pyrimidine ring by orotate phosphori-bosyltransferase. The first step in this pathway (not shown here see Fig. 18-11a) is the synthesis of carbamoyl phosphate from C02 and NH), catalyzed in eukaryotes by carbamoyl phosphate synthetase II. 

Synthesis of this ring may be achieved by the construction of one of the heterocycles followed by using it as a basis to build the other ring onto it or by the Dimroth rearrangement of l,2,4-triazolo[4,3-a]pyrimidines. 1,2-Diaminopyrimidines are general precursors, and they can be generated from 1-amino or 2-aminopyrimidines. The 3- and 5-amino-l,2,4-triazoles are alternative precursors that can act as a source of three carbons to complete the pyrimidine ring. 

Triazolopyrimidine rings may also be formed by constructing the pyrimidine ring onto a preformed triazole. Reaction of ethyl acetoacetate with 3-amino-5-substituted-l,2,4-triazoles in glacial acetic acid led to the for-... 

The biosynthetic pathway to pyrimidine nucleotides is simpler than that for purine nucleotides, reflecting the simpler structure of the base. In contrast to the biosynthetic pathway for purine nucleotides, in the pyrimidine pathway the pyrimidine ring is constructed before ribose-5-phosphate is incorporated into the nucleotide. The first pyrimidine mononucleotide to be synthesized is orotidine-5 -monophosphate (OMP), and from this compound, pathways lead to nucleotides of uracil, cytosine, and thymine. OMP thus occupies a central role in pyrimidine nucleotide biosynthesis, somewhat analogous to the position of IMP in purine nucleotide biosynthesis. Like IMP, OMP is found only in low concentrations in cells and is not a constituent of RNA. 

There is a large body of data on the synthesis and properties of pyrido [S rd thienoP -dlpyrimidine derivatives (81). All methods used for the construction of the pyrimidine ring can be classified into several types (F-t). 

The actual biosynthesis of purines (illustrated below in abbreviated form for the nucleotide adenosine monophosphate AMP 10.9) involves construction of a pyrimidine ring onto a pre-formed imidazole. 

Two strategies have been used to construct the pyrimidine ring onto a triazole structure in order to produce l,2,4-triazolo[l,5-c]pyrimidines ... 

Synthetic approaches to the construction of thienopyrimidines are sufficiently well developed. Three possible types of annulation of thiophene to the pyrimidine ring and, correspondingly, three isomeric thienopyrimidines are known thieno[2,3-<7]pyrimidine (1), thieno[3,2-J]pyrimidine (2), and thieno[3,4-c]-pyrimidine (3). The structures and the conventional numbering of these heterocyclic systems are shown below. 

The known approaches to the synthesis of thienopyrimidines can be divided into two main groups construction of the pyrimidine ring by intramolecular cyclization of thiophene derivatives and thiophene ring closure in pyrimidine derivatives. 

Most compounds of this group are accessible only by an indirect route involving thienopyrimidinones, preparation of chlorothienopyrimidines from these compounds, and the replacement of the chlorine atom with OR, SR, or other groups. However, procedures for the direct construction of the target pyrimidine ring were described for the preparation of specific compounds. 

A number of 9-deazaadenosine acyclo C-nucleosides carrying different polyhydroxyalkyl chains (e.g., 351) were prepared by Buchanan and his group from 3 amino-2-cyanopyrrol-4-yl acyclo C-nucleosides (e.g., 349) through construction of their fused pyrimidine rings. Unfortunately, none of these compounds was found active against representative RNA and DNA viruses in cell cultures [91JCS(P1)195] (Scheme 102). 

Oxoformycin B (388), the catabolite of formycin and formycin B, was synthesized before the parent nucleosides in 1970 from the 2,5-anhydro-l-ureido-D-allitol derivative 416. Compound 416 was used to build the 4,5-dimethoxycarbonylpyrazol-3-yl C-nucleoside 419, followed by construction of the fused pyrimidine ring as shown in Scheme 117. Selective amidation of the ester function at C5, rather than that at C4, is a key step during this... 

---