Silylating trimethylsilyl triflate

Direct 3-silylation of A -substituted indoles has been ellected by reaction of the indoles with trimethylsilyl triflate in the presence of triethylamine[12]. The trimethylsilyl group has also been introduced via 3-lithio-l-(phenylsulfonyl)-indole[13]. 

Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate) is the most synthetically useful representative of the family of trialkylsilyl perfluoroalkane-sulfonates (for a review, see reference 101) This reagent is commercially available or can be prepared easily by the reaction of chlorotrimethylsilane and triflic acid [101] It has wide application in organic synthesis as an excellent silylating reagent... 

The diastereomeric ratio of the trimethylsilyl triflate catalyzed amidoalkylation of a number of silyl enol ethers at — 40 CC appears to be dependent on the substituents in the substrate87. At — 40 °C the diastereomeric ratio is shown to be kinetically controlled. On allowing the reaction mixture to warm to 20 "C slow epimerization, increasing the amount of the minor isomer, is observed. In the case of the naphthalene derivative, sodium methoxide catalyzed epimerization of the kinetic mixture [(antijsyn) 88 12] produces the thermodynamic mixture [(antijsyn) 9 91]. 

The use of the enolsilyl ether of 1-menthone [16, 19, 21-23] and of some free triflic acid favors the formation of the thermodynamically controlled products as with free 2,2 -dihydroxydiphenyl [22] and only subsequently added HMDS 2 [22]. On reacting silylated alcohols and carbonyl compounds with pure trimethylsilyl triflate 20 under strictly anhydrous conditions no conversion to acetals is observed [24]. Apparently, only addition of minor amounts of humidity to hydrolyze TMSOTf 20 to the much stronger free triflic acid and hexamethyldisiloxane 7 or addition of traces of free triflic acid [18-21, 24, 26] or HCIO4 [25] leads to formation of acetals. 

Trialkylsilyl cations may play a key role in other Lewis acid-catalyzed reactions.59 For example, trimethylsilyl triflate can be formed by intermolecular transfer of the silyl group. When this occurs, the trimethylsilyl triflate can initiate a catalytic cycle that does not directly involve the Lewis acid. 

Trimethylsilyl triflate is also a powerful catalyst for acylation by anhydrides. Reactions of alcohols with a modest excess (1.5 equival) of anhydride proceed in inert solvents at 0°C. Even tertiary alcohols react rapidly.114 The active acylation reagent is presumably generated by O-silylation of the anhydride. 

Benzyloxybenzylamine (BOBA) 48 is a new class of an amine support and was prepared from Merrifield resin in two steps [56]. BOBA resin was treated with an aldehyde in the presence of an acid to give an imine that subsequently reacted with Yb(OTf)3-catalyzed silyl enolates (Scheme 18). Cleavage with trimethylsilyl triflate (TMSOTf) or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) gave either phenols or amines, respectively. 

Mukaiyama aldol reactions of aldehydes with silyl enol ethers are amongst the most widely used Lewis-acid-mediated or -catalyzed reactions. However, trimethylsilyl triflate is not active enough to promote these reactions,66 and more active silicon-based Lewis acids have been developed. One example is the species generated by mixing trimethylsilyl triflate (or chloride) and B(OTf)3,319,320 for which the formulation R3Si + [B(OTf)4] is suggested by NMR experiments. Only a catalytic amount of this was needed to complete Mukaiyama aldol reactions of... 

Using trimethylsilyl triflate, a one-pot reaction of acetoxyallylation and O-silylation of nitrones, gave silylated hydroxylamines (673). Enantiomers of the naturally occurring alkaloid dihydropinidine, potential antifeedants against the pine weevil Hylobius abietis, were prepared by diastereoselective, dimethylzinc mediated addition of pinacolyl 2-propenylboronate to (/ )- and to (S )-2-methyl tetrahydropyridine-A-oxide, obtained from D-alanine and L-alanine, respectively (Scheme 2.190) (674). 

The influence of catalytic C,C-coupling of six-membered cyclic nitronates can be used, under more drastic conditions, for the constmction of nitrogen-containing heterocycles via cascade chemical transformations (see, e.g., the coupling reaction of nitronate (368) with silyl enolates (369a-d) in the presence of trimethylsilyl triflate (154) (Scheme 3.211)). 

In contrast, the synthetic pathway using trimethylsilyl triflate and trimethylsilyl, azide followed by hydrogenation, de-O-silylation, condensation with thiocarbonyl diimidazole and spontaneous cyclization of an intermediate isothiocyanate, afforded a (3-anomer in good yield (Scheme 32). 

Methyl- and 2-phenyl-triazole 1-oxide (207) are silylated selectively at the 5-position with trimethylsilyl triflate to afford stable 5-trimethylsilyl derivatives (208) (Scheme 35). If the 5-position is blocked with a substituent, the 4-position is silylated. Thus, 5-chlorotriazole 1-oxide is converted to 5-chloro-4-trimethylsilyl-l,2,3-triazole 1-oxide in the presence of lithium tetramethylpiperidine. 

Phenyl-1,2,3-triazole 1-oxide (209) is selectively silylated at C(5) to afford (210) by treatment with trimethylsilyl triflate and diisopropylethylamine. If the C(5) position is blocked, electrophilic attack occurs at the C(4) position <93JCS(PI)625>. 

There are also several variations on this procedure. The use of trimethylsilyl triflate (TMSOTQ provides the silyl nitronate of methyl nitroacetate in good yield. However, for primary nitroalkanes, a second silylation occurs at the a-position of the nitronate (Eq. 2.5) (102). The use of TMSCl in the presence of lithium sulfide provides good yields of silyl nitronates from secondary nitroalkanes (103,104). Unfortunately, the number of examples is limited and this procedure is not applicable to primary nitroalkanes. 

Trimethylsilylpyrimidinium triflate, derived from pyrimidine and trimethylsilyl triflate, adds silylated enol ethers to form 1,4-dihydropyrimidines. /V-Acylpyrimidinium tetrafluoroborates undergo analogous reactions (85H(23)207). 

For some condensations with silylated substrates as starting compounds, trimethylsilyl triflate can be used as a catalyst [103, 104, 705] A typical example of such a reaction is the aldol type condensation of silyl enol ethers and acetals catalyzed by 1-5 mol% of trimethylsilyl triflate [705] (equation 53)... 

In 1991, Marko and Mekhalfia [23] employed the readily available trimethylsilyl-triflate (TMSOTf) as the catalyst and decided to call this reaction SMS for silyl-modified Sakurai condensation. Carbon tetrachloride appeared to be the best solvent and the presence of two chlorine atoms at the ortho,ortho positions of the aromatic ring provided good selectivity (Scheme 13.21). 

Spirocycles.1 In the presence of trimethylsilyl triflate, the silyl enol ether of an aldehyde reacts selectively with the acetal function of 1 to form an intermediate with a carbonyl group that can then react with the initially inert allylsilane group of 1 to form a spirocyclic system. This methodology permits synthesis of spirocyclic sys-... 

A new, direct route to 0,S-acetals is based in part on the ability of trimethylsilyl triflate to mediate synthesis of 0,0-acetals from carbonyl compounds and silyl ethers (10, 439). Thus reaction of 1 1 mixtures of a silyl ether and phenylthiotrimethylsilane with an aldehyde in the presence of catalytic to stoichiometric amounts of trimethylsilyl triflate can give 0,S-acetals in 37-93% yield. Acetone is amenable to this 0,S-ketalization, but reactions with cyclohexanone result mainly in 0,0-ketals. 

Another analogue of HTI which was used with either ketones or silyl enol ethers was [hydroxy(mesyloxy)iodo]benzene, PhI(OH)OS02Me [25]. A related reagent formed in situ from iodosylbenzene and trimethylsilyl triflate, probably PhI(OSiMe3)OTf, reacted similarly with silyl enol ethers to afford a-ketotriflates (see Table 5.3). /1-Diketones and /1-ketoesters underwent tosyloxylation by HTI the reaction was very effective in substrates with a perfluoroalkyl moiety and gave their hydrates [26] ... 

Cationic cyclization with vinylcyclopropyl silyl ethers.1 These ethers can serve as terminators in a cationic cyclization involving acetals. Thus reaction of the keto acetal 2 with 1 and then with a base and ClSi(CH3)3 provides a vinylcyclopropyl silyl ether 3, which undergoes facile cyclization to an eight-membered ring (4) in the presence of trimethylsilyl triflate. 

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