Synthesis of Uracil and its Derivatives’ for Anticancer and Antiviral Drugs PREPARED BY ME \ ALI Yo

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halosuccinimides

This reaction can be achieved by a number of reagents, including

fluoromethyl hypofluorite (FCH2OF) cesium fluoroxysulfat (CsSO4F)

fluoroxytrifluoromethane (CF3OF) and acetyl hypofluorite

(CH3COOF).

5-Nitrouracil is most often synthesized by the direct C5-nitration

of uracil. This can be accomplished using reagents such as nitric acid

and sulfuric acid palladium(II) acetate and sodium nitrite copper(II)

nitrate and acetic anhydride and nitronium tetrafluoroborate

(NO2BF4).

Lastly, 5-(trifluoromethyl)uracil can be prepared by several methods,

including the direct C5-trifluoromethylation of uracil with aqueous

bis(trifluoromethyl) mercury in the presence of azoisobutyronitril

(AIBN). Unfortunately, this synthesis suffers from multiple

disadvantages such as low yields and the use of highly toxic

reagents. The superior synthesis of 5-(trifluoromethyl)uracil involves

the chlorination of thymine, first with phosphorus oxychloride in the

presence of a tertiary amine and then with elemental chlorine,

followed by fluorination with hydrogen fluoride and subsequent

hydrolysis using aqueous potassium or sodium fluoride. This method

is quite high yielding and used prominently in industry:

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The Synthesis of N-Substituted Uracils

The synthesis of N-substituted uracil analogues can also be

carried out through various methods of uracil ring formation if

appropriate starting materials, such as N-substituted urea or thiourea,

are used. However, it is difficult to achieve regioselectivity in this

fashion.

A more practical approach to N-substituted uracil analogue synthesis

is the direct N1 and/or N3-alkylation of uracils. It is believed that N1-H

of uracil is more acidic than N3-H, indicating that substitutions

involving the use of base and various alkyl halides should proceed

more readily at N1. While this is true in some cases, a mixture of N1

and N3 mono- and di substituted uracil products is often obtained.

The ratio between these three products is highly dependent on the

reaction conditions, the #####alents of substituting reagents used,

and the substituents already present on the starting uracil N1- or N3-

specific substitutions can be made more favorable by employing

uracil protecting groups (UPGs). An ideal UPG would be one that

directs alkylation completely to either N1 or N3, is stable enough to

withstand the substitution reaction conditions, and is labile enough to

be removed without difficulty after reaction completion. Many existing

UPGs are limited due to poor N-selectivity or harsh deprotection

steps, but an acceptable level of success has been achieved through

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the methods reviewed below.

N1-Directed Uracil Substitution:

The substitution of uracils at N1 can be facilitated by the direct

protection of N3, although UPGs that exclusively react with N3 are

uncommon. However, the N3- protection of some uracils can be

achieved indirectly. For example, when uracil is reacted with excess

benzoyl chloride, the N1,N3-dibenzoylated products initially obtained

can be quickly decomposed to their monosubstituted 3-benzoyl

derivatives via mildly basic conditions or chromatography on alumina

Alternatively, N1-substitution can be made more favorable through

the steric hindrance of N3-substitution. This can be accomplished by

protecting the uracil oxygen with bulky functionalities, such as the

trimethylsilyl group (figure 15). Bis(trimethylsilyl) acetamide (BSA) or

hexamethyldisilazane (HMDS) and trimethylsilyl chloride (TMSCl) can

be used for the trimethylsilylation of uracils.

N3-Directed Uracil Substitution:

N3-substitution is primarily facilitated through the direct

protection of N1, A number of UPGs have been successfully used for

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the N1-protection of uracils, including the benzhydryl, 2-(trimethylsilyl)

ethoxymethyl (SEM), benzyl, benzyloxymethyl (BOM),

methylthiomethyl (MTM), and p-methoxybenzyl (PMB)

groups

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