Pyrimidine modifications

Tetrafluoro phenoxazine dC Figure 5.4. Selected pyrimidine modifications. 

Despite considerable localization of tt-electrons at the nitrogen atoms of pyrimidine, the ring system is still sufficiently aromatic to possess substantial stability. This is a great advantage in the primary synthesis of pyrimidines, in the synthesis of pyrimidines from the breakdown or modification of other heterocyclic systems and in the myriad of metatheses required to synthesize specifically substituted pyrimidines. 

The analogs of pyrimidine and purine bases can be derived by purely formal structural modifications or, more rationally, from the results of biochemical investigation. 

An X-ray crystallographic study of 2-hydroxy-4,6-dimethylpyrimi-dine led to no conclusions regarding its structure. Because of the rapid exchange of the NH protons of pyrimidin-2-one both in dimethyl sulfoxide and in water, nuclear magnetic resonance spectroscopy does not afford positive evidence for either the oxo or the hydroxy formulation. The statement that 4,6-dimethylpyrimidin-2-one had been isolated in two modifications, 94 and 95, was soon disproved. ... 

The present one-step procedure for making 4-methylpyrimidine is simpler and easier than the three-step method used in the past. The present procedure and modifications of it have been used to make a variety of 4- and 4,6-substituted pyrimidines.2 8... 

FapyGua from isolated DNA, no further chemical modifications to the purine and pyrimidine bases have been observed (Halliwell and Aruoma, 1992). 

Zgierski MZ, Fujiwara T, Kofron WG, Lim EC (2007) Highly effective quanching of the ultrafast radiationless decay of photoexcited pyrimidine bases by covalent modification photophysics of 5,6-trimethylenecytosine and 5,6-trimethyleneuracil. Phys Chem Chem Phys 9 3206-3209... 

DNA at the sites where the restriction enzymes will act. Modification of host DNA is brought about by methylation of purine or pyrimidine bases. 

Figure 1.43 indicates major sites of reactivity within the ring structures for nucleophilic displacement reactions. Cytosine, thymine, and uracil all react toward nucleophilic attack at the same two sites, the C-4 and C-6 positions. The presence of powerful nucleophiles, even at neutral pH, can lead to significant base modification or cleavage with pyrimidine residues (Debye, 1947). For instance, hydrazine spontaneously adds to the 5,6-double bond, initiating further ring reactions,... 

As in the case of pyrimidine bases discussed previously, adenine and guanine are subject to nucleophilic displacement reactions at particular sites on their ring structures (Figure 1.50). Both compounds are reactive with nucleophiles at C-2, C-6, and C-8, with C-8 being the most common target for modification. However, the purines are much less reactive to nucleophiles than the pyrimidines. Hydrazine, hydroxylamine, and bisulfite—all important reactive species with cytosine, thymine, and uracil—are almost unreactive with guanine and adenine. 

One of the most important reactions of purines is the bromination of guanine or adenine at the C-8 position. It is this site that is the most common point of modification for bioconjugate techniques using purine bases (Figure 1.53). Either an aqueous solution of bromine or the compound N-bromosuccinimide can be used for this reaction. The brominated derivatives then can be used to couple amine-containing compounds to the pyrimidine ring structure by nucleophilic substitution (Chapter 27, Section 2.1). 

Figure 27.1 Three common nucleoside triphosphate derivatives that can be incorporated into oligonucleotides by enzymatic means. The first two are biotin derivatives of pyrimidine and purine bases, respectively, that can be added to an existing DNA strand using either polymerase or terminal transferase enzymes. Modification of DNA with these nucleosides results in a probe detectable with labeled avidin or streptavidin conjugates. The third nucleoside triphosphate derivative contains an amine group that can be added to DNA using terminal transferase. The modified oligonucleotide then can be labeled with amine-reactive bioconjugation reagents to create a detectable probe.

In a recent study, this so-called SPOT synthesis was applied for the preparation of pyrimidines [45]. The group of Blackwell described primarily the appropriate support modification of commercially available cellulose sheets (Scheme 7.28). The initial introduction of the amine spacer was achieved within 15 min utilizing micro-wave irradiation, as compared to 6 h by conventional heating. The acid-cleavable Wang-type linker was attached by classical methods at ambient temperature. 

Scheme 7.28 Support modification for SPOT synthesis of pyrimidines.

Quinazolines undergo many of the same reactions as pyrimidines, such as the modification of an amino group. Gangjee and co-workers reported the reductive alkylation of diaminoquinazolinones 141 with various aryl carbonyl compounds 142, which regioselectively produced quinazolinones 143 <00JHC1097>. 

The synthetic pathway to tetrazolo[l,5-tf]pyrimidines starting from 5-amino-tetrazoles has already been discussed in CHEC-II(1996) <1996CHEC-II(8)465>. During the recent period of time, several modifications of this approach have been described. The obtained products - among them some partly saturated derivatives - and the applied reagents as well as yields and references are summarized in Table 9. 

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