Silyl-N-heterocyclics

N-heterocyclics, hydroxy, N-condensed imines, cyclic N-macrocyclics oxo-heterocyclics silyl-N-heterocyclics... 

Synthesis of multisubstituted furan rings using silyl protection 99CSR209. Synthetic applications of furan Diels-Alder chemistry 97T14179. Transformation of furans to N-heterocycles by aza-Achmatovicz reaction 98SL105. 

Developments in the synthesis and characterization of stable silylenes (RiSi ) open a new route for the generation of silyl radicals. For example, dialkylsilylene 2 is monomeric and stable at 0 °C, whereas N-heterocyclic silylene 3 is stable at room temperature under anaerobic conditions. The reactions of silylene 3 with a variety of free radicals have been studied by product characterization, EPR spectroscopy, and DFT calculations (Reaction 3). EPR studies have shown the formation of several radical adducts 4, which represent a new type of neutral silyl radicals stabilized by delocalization. The products obtained by addition of 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO) to silylenes 2 and 3 has been studied in some detail. ... 

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]. 

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. 

Silylation-aminations of a variety of other hydroxy-N-heterocycles, for example 4(lH)-pyridinone, 2(lH)-pyrimidone, uracil, 2(lH)-quinoline, and 9(10H)-acridone are described in the full paper, which was published in English [27]. 

The advantages of the one-step silylation-amination of hydroxy-N-heterocycles are demonstrated by the amination of 2-methylpyrido[3,4-d]pyrimidin-4-one 261. Whereas silylation-amination of 261 with three equivalents of benzylamine-... 

In contrast with the hitherto described silylation-aminations of six-membered heterocycles, silylation-amination of five-membered hydroxy-N-heterocycles such as benzoxazol-2-one 289 with excess benzylamine and HMDS 2, to give 2-benzyla-minobenzoxazole, fails, because of the equilibrium between 2-trimethylsilyloxy-... 

Hydrates of acids such as Ts0H-H20 can probably also be dehydrated by treatment with silyl esters such as TsOSiMe3 (Scheme 13.1). Likewise, Ts0H-H20 is dehydrated in situ during aminations of hydroxy-N-heterocycles such as purines 242 (Scheme 4.24) or (lH,3H)-quinazoline-2,4-dione 250 (Scheme 4.27) by HMDS 2, in the presence of higher-boiling primary or secondary amines, to give the ami-... 

The formation of the activated intermediate for the AE with R -NH-R is accelerated by the addition of a proton or Lewis acid to the 2-carbonyl group in 151. This is necessary for aminations of uridine (150) or thymidine (162) with weakly basic amines such as aniline, e.g., to 161e (Section III, A). Silylated hydroxy-N-heterocycles lacking such an activating conjugated carbonyl group, however, usually react only with amines when a Lewis acid is present (Section III,A). 

To remove the water, which is formed on dimerization of trimethylsilanol, at least one additional equivalent of a silylating agent such as HMDS [boiling point = 126°C] must be used. Excess HMDS can then react with trimethylsilanol or water to give hexamethyidisiloxane and ammonia, but will also reconvert any hydrolyzed hydroxy-N-heterocycle into the corresponding activated 0-silylated intermediates. Thus, sufficient HMDS should be used to silylate the hydroxy-N-heterocycle and all the alcoholic, phenolic, or other acidic hydroxy groups present in the heterocyclic or amine moiety. It should also be used to convert trimethylsilanol and water (or intruded humidity) from the reaction into hexamethyidisiloxane and ammonia (Eqs. 1-3). 

At normal pressure, the ammonia formed on silylation with HMDS evolves so rapidly it does not react with any silylated hydroxy-N-heterocycle to give the corresponding aminoheterocycle. Trimethylsilanol and hexamethyidisiloxane both exhibit a boiling point of 99°C, but form an azeotropic mixture boiling at 70-90°C. Since HMDS has a boiling point of I26°C, it is advisable to remove trimethylsilanol and hexamethyidisiloxane continuously with a small Vigreux distillation column to accelerate the reaction and follow its progress. 

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