Pyrimidines precursors

Pyrimido[4,5- f]pyrimidines may be used as pyrimidine precursors. Thus, the dihydro derivative (736) undergoes alkaline hydrolysis to the amide (737 R = PrCO) which may be deacylated in ethanolic hydrogen chloride to give 5-aminomethyl-2-propylpyrimidin-4-amine (737 R = H) (64CPB393) rather similarly, the pyrimidopyrimidinedione (738) reacts with amines to give, for example, 6-amino-5-benzyliminomethyl-l,3-dimethylpyrimidine-2,4(lFf,3Ff)-dione (739 R = CH2Ph) or the hydrazone (739 R = NH2) (74JCS(Pl)1812). 

Biosynthesis of Thiamine Diphosphate from Thiazole and Pyrimidine Precursors... 

Thiamine diphosphate, biosynthesis, from thiazole and pyrimidine precursors, 269-271... 

Since pyrimidine catabolites are water-soluble, their overproduction does not result in clinical abnormalities. Excretion of pyrimidine precursors can, however, result from a deficiency of ornithine transcar-bamoylase because excess carbamoyl phosphate is available for pyrimidine biosynthesis. 

Amongst other fused seven-membered ring systems, the synthesis of novel [l,2,5]selena (and [l,2,5]thia)diazolo[3,4-e][l,4]oxazepines from fused pyrimidine precursors has been described by Ueda and co-workers <00JHC1269>. 

Pyrimidine ort o-quinodimethanes can also be produced from 5,6-dihydrocyclobuta[,y pyrimidine precursors <1997TL4873, 2002MOL507, 2006LOC703>, and in the case of the 2,4-diphenyl example 905, trapping of the intermediate 906 with dimethyl acetylenedicarboxylate was accompanied by aromatization to give dimethyl 2,4-diphenylquinazoline-6,7-dicarboxylate 907 in 50% yield <2002MOL507>. 

The investigations that describe the syntheses of pyrrolo[2,3-,7 pyrimidines from pyrimidines, with very few exceptions, have nitrogen functionality at the 4/6-position of the pyrimidine ring. Primarily this nitrogen-containing group is an amine moiety. Even within these limits, the major type of pyrimidine precursor has no substituent at position 5. 

A hydrazine or substituted hydrazine in lieu of the amino group on the pyrimidine precursor is also an effective species. In what may be described as a Fischer indole-type reaction, 2-amino-6-hydrazino-4(3//)-oxopyrimidine 129 undergoes thermolytic cyclization when heated with compounds 130 (Scheme 12). The resultant product 131 is obtained in modest yield <1996H(43)323, B-2002MI439>. 

Although only a relatively few examples of thieno[3,2-r/ pyrimidines were described in CHEC-II(1996) <1996CHEC-II(7)229>, there has been a significant interest shown in this series since then. While the vast majority of syntheses originate with a suitably substituted thiophene, some approaches involving pyrimidine precursors have also been reported. 

The use of a pyrimidine precursor continues to be the more popular approach to furo pyrimidines. The one-pot three-component condensation reactions of alkyl or aryl isocyanides with A[A -dimethylbarbituric acid in the presence of terephthaldialdehyde proceeded spontaneously at room temperature in DMF to give good yields of the corresponding l,4-bis(6-alkyl or arylamino-1,3-dimethylfurano[2,3-4]pyrimidin-2,4(l//,3//)-dione-5-yl)benzenes <2006BMCL3697>. 

A useful pyrimidine precursor is 2,4-diamino-6-oxo-pyrimidine. Heating a mixture of this pyrimidine and l-bromo-2-butanone in DMF afforded 2-amino-6-ethyl-3,4-dihydro-4-oxo-7(7/)-pyrrolo[2,3-,y pyrimidine in modest yield <2006JMC1055>. 

One example of the synthesis of a thienopyrimidine commencing with a pyrimidine precursor appeared in 2006. Thus, 4-chloro-5-cyano-6-aryl-2-methylthiopyrimidines react with either ethyl (or f-butyl) 2-mercaptoacetate to afford 5-amino-4-aryl-2-methylthiothieno[2,3-,y]pyrimidine-6-carboxylic acids <2006JMC3888>. 

Type B syntheses starting from HPs require a Dimroth rearrangement. By contrast, in the following reaction paths, the 1,3 orientation of two nitrogen atoms needed to form the triazole ring of the TP is preformed in the pyrimidine precursor. 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

Phosphorylation of dCDP to dCTP (step k, Fig. 25-14) completes the biosynthesis of the first of the pyrimidine precursors of DNA. The uridine nucleotides arise in two ways. Reduction of UDP yields dUDP (step), Fig. 25-14). However, the deoxycytidine nucleotides are more often hydrolytically deaminated (reactions / and / ) 274 Methylation of dUMP to form thymidylate, dTMP (step n, Fig. 25-14), is catalyzed by thymidylate synthase. The reaction involves transfer of a 1-carbon unit from methylene tetrahydrofolic acid with subsequent reduction using THF as the electron donor. A probable mechanism is shown in Fig. 15-21. See also Box 15-E. Some bacterial transfer RNAs contain 4-thiouridine (Fig. 5-33). The sulfur atom is introduced by a sulfurtransferase (the Thil gene product in E. coli). The same protein is essential for thiamin biosynthesis (Fig. 25-21)274a... 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Most derivatives of this ring system are prepared from 2-aminopyrimidines. Ethoxy-methylenemalonic ester (220) is a versatile synthon which can be reacted with 2-aminopyrimidines to give pyrimido[l,2-a]pyrimidine precursors. Reaction of 2-aminopyrimidine (219) with this ester gives the aminomethylenemalonic ester (221), which can be thermally cyclized to the heterocyclic ester (222). The enamine analogous to (221) which is derived from 2-amino-4,6-dimethylpyrimidine cannot be cyclized under these conditions. Presumably this cyclization fails due to steric hindrance of the methyl groups (72JMC1203). 

Pyrimido[l,6-tf]pyrimidines are conveniently prepared from functionally 4-substituted pyrimidine precursors. Specifically, 4-chloro-, 4-amino- and 4-methylthio-pyrimidines serve as useful intermediates for the synthesis of derivatives of this ring system. 

The application of Gabriel-Coleman synthesis to the synthesis of biopterin (30) is reliable, however, it has a serious problem in that the condensation of the pyrimidine precursor with asymmetrically substituted sugar derivatives is sometimes less regioselective or even nonregioselective. For example,... 

Although a large number of thieno[2,3-af]pyrimidines have been synthesized from pyrimidine precursors, most have evolved from pyrimidines bearing a carbonyl moiety at C-5 and an alkylated sulfur at C-6. Either 6-thiol- or 6-chloropyrimidines may be used. In the latter case, displacement of the chlorine by a sulfur anion is commonly used. In general, pyrimidines of the type (264) are the immediate precursors or are formed in situ. For most of the investigations the derivatives (264 R = R3 = Me R2 = aryl) have been used. The cyclization to the products (265) can be effected by... 

A related synthesis of 3-substituted fervenulins (394) uses an azo group at the 5-position of the pyrimidine precursor (393) instead of a nitroso group <81H(16)559>. Finally, yet another type of nitrogen functionality at the pyrimidine 5-position is that shown in (396), introduced by treatment of a pyrimidine (395) with diethyl azodicarboxylate. Cyclization of (396) using nitrobenzene or lead tetraacetate affords fervenulin (394) or toxoflavin (397) derivatives <76JCS(Pl)2398>. All these reactions are shown in Scheme 31. 

Syntheses of pyrimido[4,5-e]-1,2,4-triazines (6-azapteridines) by [6 + 0] component cyclization of pyrimidine precursors are uncommon. Two examples, however, are the preparation of compounds (410) and (414) (Equations (69) and (70)). Formation of the latter is interesting in that it involves an intramolecular acyl transfer of the ester group from one nitrogen atom to an adjacent one <65JA1976, 75JOC2329). 

Bicyclic 6-6 Systems Five or More Heteroatoms Table 1 Synthesis of 7-azapteridines (8) from pyrimidine precursors. 

The preparation of purines via an appropriate pyrimidine dominated the synthetic chemistry of purine especially in the early pre Second World War literature. The reason for this is undoubtedly connected with the difficulty of obtaining suitable imidazole, compared with pyrimidine, precursors and additionally by the tendency of imidazole precursors to be rather labile and prone to aerial oxidation. To some extent these disadvantages have been overcome in recent years and this particular route to purines including nucleosides and nucleotides has been used increasingly. The method of course is of special significance in that it is the route adopted in living systems for the de novo biosynthesis of purine nucleotides, and interestingly it also appears to be the route favoured in the so-called abiotic syntheses from simple acyclic precursors (see Section 4.09.8.1). 

In bacteria, the pyrimidine precursor 38 is derived from 5-aminoimidazole ribotide (37), an intermediate of the basic branch of purine biosynthesis, which supplies all carbon atoms for 38 by a complex rearrangement reaction (the fate of the individual carbon atoms is indicated by Greek letters in Fig. 4). In yeasts, a totally unrelated reaction sequence uses carbon atoms from vitamin Be (39) that are indicated by roman letters in Fig. 4 for the assembly of the thiamine precursor 38,... 

Pteridine is pyrazino[2,3-r/]pyrimidine, and the two principal synthetic routes are therefore the construction of the pyrazine on suitable pyrimidine precursors, or the annulation of a pyrimidine ring to a suitably substituted pyrazine. Minor synthetic routes involve the transformation of other ring systems into the pteridine system which can be achieved from purines and oxadiazolopyrimidines. or from tricyclic ring systems by degradation of a third ring. By far the most important route to pteridines involves starting from a suitable pyrimidine pyrimidine-4,5-diamines are the most widely used starting materials. 

From Pyrimidine Precursors From Pyrimidine-4-hydrazines... 

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