Substitutions reductive, triethylsilane

Cyclic diene ether 93 underwent oxidative acetalization to produce corresponding 3-substituted acetals 100 and 101 (Scheme 17) <1995TL8263>. Further Lewis acid-catalyzed reduction with triethylsilane afforded corresponding 3-bromo- and 3-hydroxy-oxonenes (102 R = Br (68%) 103 R = OH (49%), respectively) together with 1 1 diastereomeric mixture of acyclic methyl ethers 104 (R = Br (18%) R = OH (13%)). 

Reduction with Triethylsilane allows for the formation of enantiomerically pure 5-substituted pyrrolidinones and 2-substituted pyrrolidines in the same manner. ... 

Because of Us high polarity and low nucleophilicity, a trifluoroacetic acid medium is usually used for the investigation of such carbocationic processes as solvolysis, protonation of alkenes, skeletal rearrangements, and hydride shifts [22-24] It also has been used for several synthetically useful reachons, such as electrophilic aromatic substitution [25], reductions [26, 27], and oxidations [28] Trifluoroacetic acid is a good medium for the nitration of aromatic compounds Nitration of benzene or toluene with sodium nitrate in trifluoroacetic acid is almost quantitative after 4 h at room temperature [25] Under these conditions, toluene gives the usual mixture of mononitrotoluenes in an o m p ratio of 61 6 2 6 35 8 A trifluoroacetic acid medium can be used for the reduction of acids, ketones, and alcohols with sodium borohydnde [26] or triethylsilane [27] Diary Iketones are smoothly reduced by sodium borohydnde in trifluoroacetic acid to diarylmethanes (equation 13)... 

The reduction is general for a variety of substituted benzophenones Such substituents as CH3 OH, OCH3, F, Br. N(CH3)2, NO2. COOH, COOCH3, NHCOC Hreaction conditions and do not alter the course of the reduction Diarylmethanols are reduced to diarylmethanes under the same conditions and probably are the intermediates in the reduction of ketones [26] Triethylsilane also can be used as a reducing agent in trifluoroacetic acid medium [27J This reagent is used for the reduction of benzoic acid and some other carboxylic acids under mild condiUons (equation 14) Some acids (phthalic, sue cinic, and 4-nitrobenzoic) are not reduced under these conditions [27]... 

The reaction of thiyl radicals with silicon hydrides (Reaction 8) is the key step of the so-called polariiy-reversal catalysis in the radical chain reduction. The reaction is strongly endothermic and reversible with alkyl-substituted silanes (Reaction 8). For example, the rate constants fcsH arid fcgiH for the couple triethylsilane/ 1-adamantanethiol are 3.2 x 10 and 5.2xlO M s respectively. 

The low reactivity of alkyl and/or phenyl substituted organosilanes in reduction processes can be ameliorated in the presence of a catalytic amount of alkanethiols. The reaction mechanism is reported in Scheme 5 and shows that alkyl radicals abstract hydrogen from thiols and the resulting thiyl radical abstracts hydrogen from the silane. This procedure, which was coined polarity-reversal catalysis, has been applied to dehalogenation, deoxygenation, and desulfurization reactions.For example, 1-bromoadamantane is quantitatively reduced with 2 equiv of triethylsilane in the presence of a catalytic amount of ferf-dodecanethiol. 

Benzyl Alcohols. Benzyl alcohols of nearly all kinds undergo reduction when treated with acid in the presence of organosilicon hydrides. The most obvious exception to this is the behavior of benzyl alcohol itself. It resists reduction by the action of trifluoroacetic acid and triethylsilane, even after extended reaction times.26 Reducing systems consisting of triethylsilane and sulfuric acid/acetic acid or p-toluenesullonic acid/acetic acid mixtures also fail to reduce benzyl alcohol to toluene.134 As previously mentioned, substitution of boron trifluoride for trifluoroacetic acid results in the formation of modest yields of toluene, but only when a very large excess of the silane is used in order to capture the benzyl cation intermediate and suppress Friedel-Crafts oligomerization processes.129,143... 

Ring-substituted benzyl alcohols sometimes undergo such reduction more effectively than unsubstituted alcohols. For example, treatment of a dichloromethane solution of 2,4,6-trimethylbenzyl alcohol with trifluoroacetic acid and triphenylsilane produces a 41% isolated (89% by GLC) yield of isodurene.26 Treatment of 2-me(hyl-4,6-di-/m-buty I benzyl alcohol with a three-fold excess of triethylsilane and trifluoroacetic acid in dichloromethane at room temperature gives an 85% yield of 2-mclhyl-4,6-di-/m-butyltoluene together with 15% of 3,5-di-ferf-butyltoluene. The latter is presumably formed by loss of protonated formaldehyde from the Cl ring-protonated substrate.128 Similar treatment of 2,4,6-tri-ferf-butylbenzyl alcohol produces a 90% yield of 2,4,6-tri-tert-butyltoluene within one hour (Eq. 21).128... 

A variety of para-substituted 2-phenyl-2-butanols undergo quick and efficient reductions to the corresponding 2-phenylbutanes when they are dissolved in dichloromethane and a 2-10% excess of phenylmethylneopentylsilane and boron trifluoride is introduced at 0° (Eq. 30).126 Several reactions deserve mention. For example, when R = CF3, use of trifluoroacetic acid produces no hydrocarbon product, even after two hours of reaction time. In contrast, addition of boron trifluoride catalyst provides an 80% yield of product after only two minutes. When R = MeO, both trifluoroacetic acid and boron trifluoride produce a quantitative yield of the hydrocarbon within two minutes. However, when R = NO2, attempts to promote the reduction with either trifluoroacetic acid or even methanesulfonic acid fail even after reaction periods of up to eight hours, only recovered starting alcohol is obtained. Use of boron trifluoride provides a quantitative conversion into 2-(/ -nitrophenyl)butane after only ten minutes. It is significant that the normally easily reducible nitro group survives these conditions entirely intact.126129 Triethylsilane may be used as the silane.143... 

It is clear that the ionizing power of the solvent used is important in many of these reductions. When 2,4,6-trimethylbenzyl chloride is heated with diphenylsi-lane in nitrobenzene at temperatures as high as 130°, no isodurene is formed.193 Not unexpectedly, the same lack of reactivity is reported for a series of benzyl fluorides, chlorides, and bromides substituted in the para position with nitro or methyl groups or hydrogen when they are heated in nitrobenzene solutions with triethylsilane, triethoxy silane, or diphenylsilane.193... 

The triethylsilane/trifluoroacetic acid reagent system reduces alkenes to alkanes in poor to excellent yields depending largely on the ability of the alkene to form carbocations upon protonation. Under these conditions the more substituted olefins are reduced in better yields and styrene double bonds are reduced in high yields.127,202,207,221-228 The reduction of 1,2-dimethylcyclohexene with this reagent gives a mixture of cis- and trans- 1,2-dimethylcyclohexane.229 The formation of the trifluoroacetate esters is a side reaction.205,230... 

The TFA-catalyzed triethylsilane reductive condensation of an aldehyde with indoles provides a convenient route to 3-substituted indoles in modest to good yields (Eq. 197).355... 

For benzo[Z ]thiophene the heterocycle is rather more resistant to ring opening and oxidation with hydrogen peroxide in acetic acid at 95 C, for example, gives the 1,1-dioxide (Scheme 7.22) reduction with either sodium and ethanol or triethylsilane in trifluoroacetic acid affords 2,3-dihydrobenzo[Z)]thiophene. Electrophiles give mainly 3-substituted benzo[Z ]thiophenes, although these products are often accompanied by smaller amounts of the 2-isomers. 

A reduction of symmetrically substituted dihydropyridines 358 to the corresponding hexahydro derivatives 359 can be executed at 50 °C under the action of a mild reducing agent —triethylsilane [307]. At room temperature, on the other hand, the reaction stops at the formation of tetrahydro derivatives 360 (Scheme 3.95). Both processes are stereoselective. 

The highly substituted indole, ecopladib (82), which shares many structural elements with the phospholipase inhibitor varespladib (37), shows similar biological activity. Alkylation of hydroxy benzoate (72) with the dimethyl acetal from bromoacetaldehyde (73) affords the ether (74). Acid-catalyzed reaction of this intermediate with 2-methyl-5-chloroindole (75) in the presence of triethylsilane leads in effect to condensation of the acetal with the activated 3 position on the indole ring to afford 76. The nature of the reduction of the aldehyde carbon is not immediately apparent. Alkylation of the anion on nitrogen from reaction of the indole with sodium hydride and bromodiphenylmethane then adds the third... 

Again, no reaction was observed in the absence of mercaptoethanol. The mechanistic steps for the transformation were elucidated by the Chatgilialoglu et ah and are represented in Scheme 4.13, in analogy with the pathway reported for the radical reduction of aromatic azides with triethylsilane in toluene, with the addition of silyl radicals to the azide function, liberation of nitrogen and formation of silyl-substituted aminyl radical. The thiol is the hydrogen atom donor to this intermediate and it can be regenerated by its interaction with the silane, thus propagating the chain. The hydrolysis of the silylamine occurred... 

The acid-catalyzed alkylation of indoles by carbonyl compounds is complicated by the fact that the resulting indol-3-yl carbinols are usually reactive under these conditions. The most common outcome is the formation of W -indolylmethanes, as is discussed in the next section. In some cases, the carbinol intermediates can be diverted to alkylation by reductive trapping using triethylsilane-TFA. This reaction gives good yields of 3-benzyl indoles and there are a few examples of 3-alkylatiOTi using N-substituted indoles [120]. 

A new method of D-glucan analysis involves reductive cleavage of permethylated compounds with triethylsilane and trimethylsilyl triflate or boron trifluoride-etherate as catalyst, followed by acetylation, which yields a series of acetylated, methylated 1,5-anhydro-glucitols. A number of isomeric substituted 1,5-anhydro-glucitols were synthesized as references. /3-Glycosyl-... 

The stereoselective intramolecular reductive etherification of 5-trialkylsiloxy substituted ketones with catalytic bismuth tribromide and triethylsilane provides a convenient method for the construction of cis-2,6-disubstituted tetrahydropyrans (Equation 28) [46]. This method was highlighted in the key step of an expeditious total synthesis of the antibiotic (—)-centrolobine. 

---