Construction of the Pyrimidine Ring

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]. 

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

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 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. 

Furans have occasionally been used as substrates for pyrimidine syntheses which involve acyclic intermediates as in most of the other ring structures used in the construction of the pyrimidine ring . In the furan example shown (Scheme 92), A(-butylisomaleimide was reacted with trimethylsilyl azide, when the A 3-butyluracil (579) was formed after simple removal of the A(l-silyl group <72JOC1738>. 

Extension of this work by studying the reaction of 3-methyl-5-nitro-pyrimidin-4(3//)-one with -X-arylketones in the presence of ammonium acetate surprisingly revealed the formation of a mixture of 4-arylpyrimidines and 6-arylpyridin-2(l//)-ones (00JCS(P1)27). The ratio between pyridine and pyrimidine formation is dependent on the substituent X. With electron-donating substituents the formation of the pyridin-2(l//)-ones is favored, with electron-attracting substituents the formation of the pyrimidine derivatives (Scheme 21) In the formation of the 6-arylpyridin-2(l//)-ones the C-4- C-5-C-6 part of the pyrimidone-4 is the building block in the construction of the pyridine ring. Therefore, the pyrimidone can be considered as an activated o -nitroformylacetic acid (Scheme 21). 

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... 

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>. 

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. 

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. 

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. 

Another interesting MW-assisted MCR for construction of the DHP ring as part of a more complex bicyclic scaffold was reported by Quiroga et al. They realized the MW-assisted synthesis of both pyrazolopyridines 7 and pyrido[2,3-d]pyrimidines 8 under solvent-free conditions (Scheme 17.8) [38]. 

Given the extensive presence of the pyrimidine ring in numerous compounds of medicinal value, this chapter will primarily focus on the contemporary methods to construct pyrimidine rings and pyrimidine-fused systems. In addition, the syntheses of a few commercial drugs are discussed to showcase the preparations of pyrimidines in industrial settings. 

Pyrimidines used to be prepared via the construction of the heterocyclic ring as shown in Fig. 35. A 4-substituted-cyano-benzene is subjected to treatment with hydrogen chloride gas in an ethanolic solution, after the reaction is complete ammonia is bubbled into the solution to yield the ami-no-imine, which in turn is reacted with a suitably substituted phenyl diethyl malo-nate to give the dihydroxypyrimidine. The hydroxyl groups are removed by chlorination with phosphorus oxychloride followed by hydrogenation over palladium. The first part of this synthetic pathway is relatively straightforward, but the latter stages can result in poor yields if not performed correctly. 

Palladium-catalyzed reaction of bis(o-trifluoroacetamidophenyl) acetylene 685 with various aryl and vinyl halides and triflates led to the formation of indolo[l,2-c] quinazolines 686 (Scheme 143) [406]. If the reaction was performed in presence of CO, the corresponding acyl derivatives 687 were obtained [407], In both cases, the indole heterocyclic system was formed first the subsequent pyrimidine ring closure resulted in construction of the tetracyclic ring system. 

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. 

There is another point about the thermodynamic stability of prebiotic compounds. This is the fact that a series of thermodynamically very stable molecules seem to have been ignored in the course of prebiotic molecular evolution as building blocks of living structures. Take sugars, for example six-membered rings have not been used for the construction of nucleic acids, where only o-ribose takes the stage. Furthermore, only two types of purine and only two of the pyrimidine bases have been utilized among the many possible nucleic acids. Actually one could make a... 

A variety of methods for the preparation of pyrimido[4,5-,7]pyridazines are discussed in CHEC(1984) < 1984CHEC(3)329> and CHEC-II(1996) <1996CHEC-II(7)737>, and most of the work that has appeared since describes adaptations of the earlier methods. Notable examples include the use of imide hydrazinolysis in a two-step construction of the ring system (Scheme 23) < 1996H(43)1597, 2002JHC571>. In addition, the reaction of 4-(halomethyl)pyrimidine-5-carboxylates with... 

The synthetic uses of pyrimidines in the construction of non-heterocycles appear to be relatively small. While the ring opening reaction of a pyrimidine N-oxide with phenylmag-nesium bromide has been reported to give benzaldehyde upon hydrolysis (it thus plays the same role as DMF) (67JOC3788) the Diels-Alder capabilities of the pyrimidines do, on the other hand, appear to hold considerable promise in organic chemistry. 

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-... 

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