Nucleosides silylation-amination

All these steps proceed to afford free or N -substituted crystalline cytidines 6 in high yields [11] (cf. the preparation of N (tetramethylene)cytidine 6b in 95.4% yield in Section 1.1.). This simple one-pot reaction is also very easy to perform on a technical scale, as are the subsequently discussed analogous silylation-aminations of purine nucleosides and other hydroxy-N-heterocycles (cf. Sections 4.2.4 and 4.2.5). The concept of silylation-activation while simultaneously protecting hydroxyl groups in alcohols, phenols, or phosphoric acids by silylation was subsequently rediscovered and appropriately termed transient protection [16-18]. 

Polar functional groups such as alcohols or phenols 11 or trimethylsilanol 4 are transformed by monofunctional silylating reagents Me3SiX 12 into their hpophilic and often volatile trimethylsilyl ethers 13 whereas water is converted into persilyl-ated water (=Me3SiOSiMe3, hexamethyldisiloxane, HMDSO, 7, b.p. 100 °C). The persilylation of phenols and, in particular, catechol (or hydroquinone) systems (Scheme 2.1) protects them efficiently against air oxidation even at temperatures of up to 180 °C. (cf, e.g., the silylation-amination of purine nucleosides with dopamine hydrochloride in Section 4.2.4)... 

Unfortunately, the two fuU papers on the silylation-amination of pyrimidine [49] and purine nucleosides [64] as discussed in Sections 4.2.3 and 4.2.4, were pubhshed in German and are thus not readily accessible, although a few detailed procedures from Sections 4.2.3 and 4.2.4 were subsequently published in English [65]. The third paper on the silylation-amination of aromatic hydroxy-N-hetero-cycles, however, as discussed in Section 4.2.5 was, fortunately, pubhshed in English [27]. 

Because aromatic purines and purine nucleosides and free purines such as hypo-xanthine and guanine 242 are readily silylated-aminated [64] (cf Scheme 4.24), it is obvious that 6-membered hydroxy-N-heterocycles are analogously silylated-aminated, with reactivity in the order given in Scheme 4.25 [73] X=OTf is the best leaving group and X=NHSiMe3 (cf the transamination as discussed in Section 4.2.4) is the weakest. 

ZnCl2 and SnCU sometimes function well, but are not considered as practical. Mercuric chloride, which was used in some of our silylation-aminations of purine nucleosides (76LA745), oxidizes the primary or secondary amines used as well as the reaction products. Furthermore, the toxic mercury-containing side products formed are difficult to remove (62CCC902, 62CCC906). 

The available equipment might also influence the choice of the amination method. Thus, amination with volatile amines such as ammonia, methyl- or ethylamine via silylation-amination (cf. Section IV,D) on a laboratory scale demands the use of a small stainless-steel autoclave, whereas activation (e.g., of nucleosides by 0-sulfonylation or O-phosphorylation-1,2,4-triazolide formation) proceeds readily at room temperature and normal pressure (cf. Section 1V,G). The availability of high-pressure equipment will facilitate the difficult aminations of halopyridines (cf. reactions 86 111 and 112 113 in Section IV,B). 

In numerous synthetic studies it has been demonstrated that DMP can be used for a selective oxidation of alcohols containing sensitive functional groups, such as unsaturated alcohols [297,1215-1218], carbohydrates and polyhydroxy derivatives [1216, 1219-1221], silyl ethers [1222,1223], amines and amides [1224-1227], various nucleoside derivatives [1228-1231], selenides [1232], tellurides [1233], phosphine oxides [1234], homoallylic and homopropargylic alcohols [1235], fluoroalcohols [1236-1239] and boronate esters [1240]. Several representative examples of these oxidations are shown below in Schemes 3.349-3.354. Specifically, the functionalized allylic alcohols 870, the Baylis-Hillman adducts of aryl aldehydes and alkyl acrylates, are efficiently oxidized with DMP to the corresponding a-methylene-p-keto esters 871 (Scheme 3.349) [1217]. The attempted Swern oxidation of the same adducts 870 resulted in substitution of the allylic hydroxyl group by chloride. 

The introduction of a 2-fluoro substituent through reaction with an electrophilic fluorine source was achieved following the synthesis of 2-tributylstannyl derivatives of purine nucleosides [16] (Scheme 4). Xenon difluoiide was nsed as the fluorinat-ing reagent, and the method was compatible with the presence of alkenes in the substrate, as well as 6)-silyl and acetonide protecting groups, and with amine substitution of the purine [16-18],... 

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