Purine and Pyrimidine

7/30/2019 Purine and Pyrimidine

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Pyrimidine The family of compounds based on the pyrimidine ring is one of the most important in the fieldof heterocyclic chemistry. Pyrimidines are found among the “bases” of nucleic acids Thepyrimidine ring is stable, with resonance energy of 26 kcal/mol. Its numerous resonance forms

Rings where one or more nitrogen atom replaces carbon of pyridine exhibit the usual benzene-

type of electron delocalization and have additional resonance forms arising from the electron-accepting character of each nitrogen atom. Thus, the carbons of pyrimidine are even lessreactive to electrophilic substitution than are those of pyridine. However, the placement oncarbon of electron-releasing substituents such as amino restores reactivity to the ring. Otherproperties studied for pyridine are found in pyrimidines, such as the easy nucleophilicdisplacement of halogen, formation and reactions of Noxides, stabilization of carbanions formedfrom C-methyl substituents, The pyrimidine ring has properties of a typical strongly pi-deficientsystem. Thus, it is but weakly basic, with K b10−13. This basicity is less than that of pyridine (K b 2 ×10−9), which can be explained by the added electron-withdrawing effect of the second C=N unit.As expected, pyrimidine is even less reactive to electrophiles than pyridine.When successful, an electrophilic agent will attack the 5-position, which has same character asthe 3-position of pyridine. The explanation based on resonance theory can be applied topyrimidine substitution. An example of a successful substitution by bromine is shown in Scheme9.58.

If common electron-releasing groups, these substituents greatly activate the ring. Thus, 2aminopyrimidine can be brominated in water at 80◦C and can react with diazonium ions in coldmedia (Scheme 9.59). This order of reactivity is phenol. Because amino and hydroxyl derivativesare easily prepared directly by ring synthesis and are found in natural products.



As a typical pi-deficient system, hydroxyl groups on the pyrimidine are involved in tautomeric

equilibrium with the oxo form, and it is this form that greatly dominates in the equilibrium.

Nevertheless, electrophilic substitution is easily effected on the oxopyrimidine structure. For

example, the diketo pyrimidine uracil (9.120) reacts readily with nitric acid to give the 5-nitro

product 9.121. This suggests that the reactive species may be the hydroxyl form, albeit in a low

concentration (Scheme 9.60).

The stabilization effect of pyrimidine resonance is not lost in the oxo form, because it can bewritten with a cyclic resonance form (Scheme 9.61).

When OH is placed at the 5-position, tautomerism is not important, and the normal phenol-likeacidity is present. Thus, the pK a of 5- hydroxypyridine is 6.78. This compound is therefore astronger acid than 3-hydroxypyrimidine with pK a 8.72, the result of the second C=N unit addingto the electron-withdrawing anion stabilizing effect. Barbituric acid, nominally 2,4,6-trihydroxypyrimidine, is entirely in the tri-oxo form in the solid state, but in solution the 4-hydroxy makes a contribution and is the source of the considerable acidity with pK a 3.9(Scheme9.62).

They are highly important pyrimidine “bases” of nucleic acids. The structures of the bases are



All the bases except adenine have carbonyl groups from the tautomeric shift of an OH group,and another chemical property has to be considered: the capability for carbonyl oxygen toaccept a proton in the phenomenon of hydrogen bonding. Hydrogen bonds are weak (typically 3–5 kcal/mol) but are of great importance in biological structures e.g. nucleic acids.

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Nitrogen in a C=N unit serve as an acceptor. The bases all have NH or NH 2 groups that serve ashydrogen donors. The H-bonding takes place specifically between certain pairs of bases, and thisis the source of binding between the two strands of the nucleic acid DNA in the well-knowndouble helix structure. Two of the bases involved are pyrimidines (C and T) and two are purineswhere an imidazole ring is fused to the pyrimidine (G and A). The H-bonding in the double helixof DNA occurs between G of one chain and C of the other, and between A and T, as diagrammedin Figure 9.1. The sequence of the bases on the DNA strands is the basis for the genetic code.RNA is single stranded but involved in base-pairing with one of the strands of DNA after thedouble helix is opened. The RNA-DNA pairing involves G-C, but adenine is paired with U ratherthan T. All the bases are planar, and the H-bonded pairs together lie in a plane.Many useful transformations are possible with pyrimidine derivatives, and these play a role in

the synthesis of particular compounds.1. Pyridones, reaction of the oxo derivatives with PCl5 or POCl3 gives the chloro derivatives,

which can be used to attach various nucleophiles to the ring. Chlorine can be removed bycatalytic hydrogenation.

2. Amino groups can be created by the reduction of the diazo group from coupling with

diazonium ions.3. Pyrimidines also form N-oxides, which have reactivity of pyridine N-oxides.

An extensively used synthesis of pyrimidines involves the combination of two 3-atom units. Allthe pyrimidine bases of the nucleic acids can be made this way, and this and other processesare of much importance in the synthesisof new bases for modification of the natural nucleoside units in the nucleic acids.A common reaction is that of beta-dicarbonyl compounds with 1,3-diamino groups as found in

urea, thiourea, andguanidine (Scheme 9.63).

With urea and thiourea, the C=O and C=S groups, are retained at the 2-position of thepyrimidine product, but tautomerism occurs with the guanidine product to yield a 2-

aminopyrimidine.



Diesters also react smoothly with the urea derivatives, which undergo displacement of thealkoxy groups to create amide bonds. Barbituric acid can be made this way by reaction of diethylmalonate (9.122, R=R’=H) with urea (Scheme 9.64). An important family of pharmaceuticalagents results from the use of substituted malonic esters. Thus, with a phenyl and an ethylsubstituent the important hypnotic agent, phenobarbital (9.123) is produced. Veronal, which isanother important hypnotic, is prepared from diethyl-substituted malonates.

A valuable synthesis of 4-alkylpyrimidines consists of the use of beta-ketoesters in reactions withthe urea derivatives (Scheme 9.65).



The bases uracil and thymine can be made by this route (Scheme 9.66).

2-Alkylpyrimidones can be made by using amidines (9.124) instead of urea derivatives incondensations with carbonyl compounds and diesters (Scheme 9.67).

Another combination is that of nitrile group or groups with the urea or amidine derivatives. Fromthe nitrile group will originate an amino group. In Scheme 9.68, the synthesis of cytosine isshown by this approach.

Some of the useful transformations that can be performed with the pyrimidones are shown inScheme 9.69, using uracil as the starting material.



Other types of ring closures are possible that are useful for pyrimidine synthesis, such as a 5 + 1condensation. Thus, the condensation of a 1,3-diamino derivative with a one-carbon acylatingreagent can be used effectively. An example is shown as Scheme 9.71 where the product isbarbituric acid.

As shown in Scheme 9.72, the starting materials are guanidine and ethyl cyanoacetate. Thiscombination

will give a 2,4-diaminopyrimidine (9.125). The oxo group reacts with POCl3 to give the chloroderivative 9.126. Peroxide oxidation occurs selectively at N-3 to give the N-oxide 9.127. As inpyridines, ring halogen is made reactive by being alpha to nitrogen and gamma to the N-oxidefunction. In 9.127, the chlorine is easilydisplaced by amines, here with piperidine, to give the drug minoxidil (9.128).



The synthesis of nucleosides is accomplished by converting a pyrimidine to a metallic derivativeat the NH group of the cyclic amide moiety and then employing the anion so produced in asubstitution reaction at a 1-chloro derivative of an aldose, usually ribose or desoxyribose. Thisreaction is of the SN2 type, because inversion of the configuration at the 1-position of the aldosetakes place. The process is illustrated in Scheme 9.74 for the synthesis of the nucleosidecytidine, starting from the pyrimidine cytosine. An early reagent for making the anion wasmercuric chloride as shown in the scheme, but other variations, such as making the N-trimethylsilyl derivative, rather

than a metallic derivative, for the alkylation are also employed. The acetyl protecting groups areremoved from N and O to obtain cytidine.

FUSED PYRIMIDINES: PURINES AND PTERIDINES

Purine and pteridine compounds are of great importance as medicinal and in other biochemicalstudies. The compounds of natural and synthetic interest have amino groups, or carbonyl groupsfrom OH tautomerism. Hydrogen bonding is especially strong in the carbonyl containingstructures and causes them to have high melting points and low water solubility.

Tautomerism makes it difficult to predict the position of the proton in this component of thepurine structure.In adenine, the proton is largely found at the 9-position, whereas in guanine a mixture of the twoforms is present in solution. In nucleosides, it is the 9-position that is attached to the sugar

moiety as notedin section 3.2.3. The numbering in purines is exceptional to the rules of nomenclature but isaccepted by the International Union of Pure and Applied Chemistry (IUPAC). It is illustrated inFigure 9.2.

4,5-Diaminopyrimidines are frequently the starting framework for the construction of the secondring in both cyclic systems. To obtain the requisite diaminopyrimidines, a monoaminopyrimidineis first prepared by the conventional routes and the second amino group added by the sequenceof coupling with benzenediazonium ion followed by reduction, or by nitrosation with HNO 2 andreduction. The former method is illustrated in Scheme 9.75.



To add the fused ring (a pyrazine) of a pteridine, the diamino compound is condensed with analpha-dicarbonyl compound. Thus, using compound 9.132 would give pteridine 9.133 (Scheme9.76).

A well-known purine is the central nervous stimulant (CNS) caffeine (9.134), which is found incoffee and chocolate. Its synthesis (Scheme 9.77) illustrates the technique of forming the fusedimidazole ring of purines. Diaminobenzenes reacted with carboxylic acids or esters to formbenzimidazoles; this process is known as the Phillips synthesis. It is this reaction that is used tofuse imidazoles to pyrimidines. Here, the process is known as the

Traube purine synthesis. The initially formed purine is tri-methylated with methyl chloride and

base to form caffeine (9.134). Note that under these conditions it is the 7-nitrogen that ismethylated.

Many biologically active purines have been prepared by the Traube synthesis,in which variouscarboxylic acids provide novelty at imidazole carbon. Alkylation of the imidazole NH also leads tonovel structures. This methods is used for synthesis of the effective CNS stimulant bamiphylline(Scheme 9.78). The alkylation takes place preferentially on the imidazole tautomer shown inScheme 9.78.



The Bases of Nucleic Acids, Nucleosides, and Nucleotides

Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are composed of long chains (polymers)of repeating pentose and phosphate groups. Attached to the 1-position of each pentose is aheterocyclic compound known as a base, they are weak. It is the sequence of the bases on thepolymer chain that gives rise to the all-importantgenetic code.Monomeric building blocks for the nucleic acids also are found in living systems; these are thenucleosides (3.30), which are composed of the pentose (shown here is deoxyribose) and thebase, and the nucleotides (3.31), which are phosphate derivatives of the nucleosides.

The bases of the nucleic acids are derivatives of pyrimidine or purine Their structures are shownin Figure 3.3. In genetic code studies, they are denoted by the first letter of their names, asshown in the figure.



The bases are attached at a ring nitrogen atom to carbon-1 of the pentoses. The nitrogen of attachment is indicated by an arrow on the structures. DNA and RNA differ in the basesincorporated on the polymeric chain: DNA makes use of A, G, C, and T, whereas RNA uses A, G,C, and U. Four of the bases possess carbonyl groups. In early studies, the oxygen was written inthe tautomeric hydroxyl form, and this confused the structural assignment of their bonding tothe pentose. The tautomerism is expressed in Scheme 3.10 for cytosine as an example, wherethe enol

form can be viewed as a hydroxypyrimidine. In the solid state, only the keto form is observed,but in an aqueous solution, a small amount of the enol form is present in the tautomericequilibrium (e.g., for cytosine, 0.2% enol and 99.8% keto). Recognition of the keto form asdominant played a significant role in the unraveling of the structure of the nucleic acids and led

J. D. Watson and F. Crick to propose the famous double helix held together by H-bonds to thecarbonyl oxygens. An interesting account of the discovery of the double helix and clarification of the structure of the pyrimidine bases has been given by Watson.

Some of the nucleosides and nucleotides that are found in nature are generally derivatives of thesame bases that are present in the nucleic acids. Of great biological importance is the

nucleoside adenosine (3.32), which is formed from adenine. As found with the phosphorus groupin Some of the nucleosides and nucleotides that are found in nature are generally derivatives of the same bases that are present in the nucleic acids. Of great biological importance is thenucleoside adenosine (3.32), is formed from adenine. As found with the phosphorus group in thetriphosphate form (ATP, 3.33), it is involved in many fundamental processes.



Adenine is also found in the coenzyme nicotinamide adenine dinucleotide (NAD) (3.34); here,dinucleotide refers to the presence of the diphosphate group to distinguish it from themonophosphate of the nucleotide. Another feature of NAD is the presence of a quaternizedpyridine ring.

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Purine and Pyrimidine