Triethylsilane alcohols

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)... 

Carboxamides and esters of arenecarboxylic acids are obtainable directly by reacting arenediazosulfones (Ar — N2 —S02 —Ar ) with CO and amines or alcohols, respectively, in the presence of Pd catalysts (Kamigata et al., 1989). Aromatic aldehydes are formed if the reaction is carried out in the presence of triethylsilane (Kikukawa et al., 1984). In an analogous way, arenediazonium salts can be transformed into ketones (ArCO —R R = CH3, C2H5, or C6H5) in the presence of stan-nanes, R4Sn (Kikukawa et al., 1982). 

Although catalytic hydrogenation is the method most often used, double bonds can be reduced by other reagents, as well. Among these are sodium in ethanol, sodium and rerr-butyl alcohol in HMPA, lithium and aliphatic amines (see also 15-14), " zinc and acids, sodium hypophosphate and Pd-C, (EtO)3SiH—Pd(OAc)2, trifluoroacetic acid and triethylsilane (EtsSiH), and hydroxylamine and ethyl acetate.However, metallic hydrides, such as lithium aluminum hydride and sodium borohydride, do not in general reduce carbon-carbon double bonds, although this can be done in special cases where the double bond is polar, as in 1,1-diarylethenes and in enamines. " °... 

Aldehydes and ketones can be converted to ethers by treatment with an alcohol and triethylsilane in the presence of a strong acid or by hydrogenation in alcoholic acid in the presence of platinum oxide. The process can formally be regarded as addition of ROH to give a hemiacetal RR C(OH)OR", followed by reduction of the OH. In this respect, it is similar to 16-14. In a similar reaction, ketones can be converted to carboxylic esters (reductive acylation of ketones) by treatment with an acyl chloride and triphenyltin hydride. " ... 

Additions of silylated ketene acetals to lactones such as valerolactone in the presence of triphenylmethyl perchlorate in combination with either allyltrimethylsilane 82, trimethylsilyl cyanide 18, or triethylsilane 84b, to afford substituted cyclic ethers in high yields have already been discussed in Section 4.8. Aldehydes or ketones such as cyclohexanone condense in a modified Sakurai-cyclization with the silylated homoallylic alcohol 640 in the presence of TMSOTf 20, via 641, to give unsaturated cyclic spiro ethers 642 and HMDSO 7, whereas the 0,0-diethyllactone acetal 643 gives, with 640, the spiroacetal 644 and ethoxytrimethylsilane 13b [176-181]... 

On reacting aldehydes such as benzaldehyde or cyclohexanecarboxaldehyde 720 with silylated alcohols such as 718 or 721, or with triethylsilane 84b in the presence of TMSOTf 20 at low temperatures, acetal formation and reduction is achieved in one step to afford ethers 719 and 722 in high yields [215] (Scheme 5.74). 

Oriyama and coworkers reported an iron-catalyzed reductive etherification of carbonyl compounds with triethylsilane and alkoxytriaUcylsilane [149, 150] and alcohols (Scheme 48) [151]. 

Aliphatic ketones can be reduced to hydrocarbons by triethylsilane and gaseous BF3.178 The BF3 is a sufficiently strong Lewis acid to promote formation of a carbocation from the intermediate alcohol. 

Normally, only a small stoichiometric excess (2-30 mol%) of silane is necessary to obtain good preparative yields of hydrocarbon products. However, because the capture of carbocation intermediates by silanes is a bimolecular occurrence, in cases where the intermediate may rearrange or undergo other unwanted side reactions such as cationic polymerization, it is sometimes necessary to use a large excess of silane in order to force the reduction to be competitive with alternative reaction pathways. An extreme case that illustrates this is the need for eight equivalents of triethylsilane in the reduction of benzyl alcohol to produce only a 40% yield of toluene the mass of the remainder of the starting alcohol is found to be consumed in the formation of oligomers by bimolecular Friedel-Crafts-type side reactions that compete with the capture of the carbocations by the silane.129... 

Aluminum chloride, used either as a stoichiometric reagent or as a catalyst with gaseous hydrogen chloride, may be used to promote silane reductions of secondary alkyl alcohols that otherwise resist reduction by the action of weaker acids.136 For example, cyclohexanol is not reduced by organosilicon hydrides in the presence of trifluoroacetic acid in dichloromethane, presumably because of the relative instability and difficult formation of the secondary cyclohexyl carbocation. By contrast, treatment of cyclohexanol with an excess of hydrogen chloride gas in the presence of a three-to-four-fold excess of triethylsilane and 1.5 equivalents of aluminum chloride in anhydrous dichloromethane produces 70% of cyclohexane and 7% of methylcyclopentane after a reaction time of 3.5 hours at... 

Tertiary Alkyl Alcohols. Tertiary alkyl alcohols generally undergo facile reduction when treated with acids in the presence of organosilicon hydrides.127,136 This comparative ease of reduction reflects the enhanced stability and ease of formation of tertiary alkyl carbenium ions compared with primary and secondary carbenium ions. Thus, treatment of 1-methylcyclohexanol with mixtures of triethylsilane and aluminum chloride in dichloromethane produces near quantitative yields of methylcyclohexane with or without added hydrogen chloride in as little as 30 minutes at room temperature, in contrast to the more vigorous conditions needed for the reduction of the secondary alcohol cyclohex-anol.136... 

The tertiary alcohol m,m,/ra ,v-perhydro-9h-phcnalcnol (7) is converted stereospecifically and in high yield (92%) to /ran.v,/ran.v,/ran.v-pcrhydrophcnalcnc (10) when treated with either triethylsilane or triphenylsilane and trifluoroacetic acid in dichloromethane (Eq. 15). Studies indicate that the reaction path follows the cation rearrangement 8 9 and that the trans trifluoroacetate ester related to... 

In a similar fashion, 2-cumyladamantane (12, R = Ph) is formed in nearly quantitative yield upon treatment of the easily synthesized 2-cumyl-2-adaman-tanol (11, R = Ph)154 with triethylsilane and methanesulfonic acid in dichloromethane at —78°.155 The high yield of a single very strained hydrocarbon product in each reaction is quite surprising in view of the very complex interconversions of carbocations known to take place from the alcohol precursors.140,151 152 156... 

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... 

Intramolecular Friedel-Crafts reactions can sometimes compete with organosil-icon hydride reductions of benzylic-type alcohols to cause formation of undesired products. An example is the attempted reduction of alcohol 26 to the corresponding hydrocarbon. When 26 is treated with triethylsilane in trifluoroacetic acid at room temperature for 15 hours, a mixture of the two fluorene isomers 27 and 28 is obtained in a combined yield of 45%. None of the hydrocarbon structurally related to the substrate alcohol 26 is obtained.171 Whether this problem could be circumvented by running the reduction at a lower temperature or with a different acid remains subject to experimentation. 

Highly diasteroselective and chemoselective reductions may be performed on the hydroxy functions of (r/6-arene)-tricarbonylchromium complexes. Treatment of the chromium-complexed benzylic alcohol 29 with triethylsilane and boron trifluoride etherate in dichloromethane at —78° to 0° gives only diastereomer 30 in 75% yield (Eq. 40).181 In a similar fashion, treatment of the complexed exo-allyl-endo-benzylic alcohol 31 with an excess of Et3SiH/TFA in dichloromethane at room temperature under nitrogen produces only the endo-aflyl product 32 in 92% yield after 1.5 hours (Eq. 41). It is noteworthy that no reduction of the isolated double bond occurs.182... 

Aromatic and aliphatic carboxylic acids are reduced to the trifluoroacetates of the alcohol with Et3SiH/TFA.277 Use of an excess of the triethylsilane can give... 

The combination Et3SiH/(C6F5)3B reduces acid chlorides to methyl groups (Eq. 138).281,282 If a smaller amount of triethylsilane is used, the same combination reduces aryl acid chlorides to the trimethylsilyl ethers of the benzyl alcohols.281,282... 

The reduction of aldehydes with the combination Et3SiH/BF3 OEt2 gives both the alcohol and the symmetrical ether,70 as do the Et3SiH/TFA (and other acids) combinations.313 Addition of boron trifluoride etherate to a mixture of 1-octanal and triethylsilane leads to the formation of di-n-octyl ether in 66% yield and //-octyl alcohol in 34% yield (Eq. 155).74... 

The addition of water and a non-hydrogen-bonding solvent to the reduction medium causes the reactions to shift toward the formation of alcohol products.313 For example, triethylsilane in a mixture of concentrated hydrochloric acid and acetonitrile (5 4) reduces 1-heptanal to 1-heptanol in quantitative yield after 3 hours at room temperature. In a mixture of triethylsilane in sulfuric acid, water, and acetonitrile (2 2 5), //-hep(anal gives a 97% yield of the same alcohol after 1.25 hours (Eq. 156).313... 

Triethylsilane reduces benzaldehyde to benzyl alcohol in 98% yield after 32 hours in a reaction medium containing sulfuric acid, water, and sulfolane (1 2 5) (Eq. 157). Neither benzene nor dimethylformamide is effective as an interfacing solvent for producing alcohol products under these conditions.313... 

Fluoride ion is effective in promoting the reduction of aldehydes by organosil-icon hydrides (Eq. 161). The source of fluoride ion is important to the efficiency of reduction. Triethylsilane reduces benzaldehyde to triethylbenzyloxysilane in 36% yield within 10-12 hours in anhydrous acetonitrile solvent at room temperature when tetraethylammonium fluoride (TEAF) is used as the fluoride ion source and in 96% yield when cesium fluoride is used.83 The carbonyl functions of both p-anisaldehyde and cinnamaldehyde are reduced under similar conditions. Potassium bromide or chloride, or tetramethylammonium bromide or chloride are not effective at promoting similar behavior under these reaction conditions.83 Moderate yields of alcohols are obtained by the KF-catalyzed PMHS, (EtO SiH, or Me(EtO)2SiH reduction of aldehydes.80,83,79... 

Unsymmetrical ethers may be produced from the acid-promoted reactions of aldehydes and organosilicon hydrides when alcohols are introduced into the reaction medium (Eq. 173).327,328 An orthoester can be used in place of the alcohol in this transformation.327 335 A cyclic version of this conversion is reported.336 Treatment of a mixture of benzaldehyde and a 10 mol% excess of triethylsilane with methanol and sulfuric, trifluoroacetic, or trichloroacetic acid produces benzyl methyl ether in 85-87% yields.328 Changing the alcohol to ethanol, 1-propanol, 2-propanol, or 1-heptanol gives the corresponding unsymmetrical benzyl alkyl ethers in 45-87% yield with little or no side products.328 A notable exception is the tertiary alcohol 2-methyl-2-propanol, which requires 24 hours.328 1-Heptanal gives an 87% yield of //-lie ply I methyl ether with added methanol and a 49% yield of benzyl n-heptyl ether with added benzyl alcohol under similar conditions.328... 

They offer the advantage that reductions can be effected under conditions that permit the conversion of substrates that may be adversely sensitive to the presence of strong Brpnsted acids. For example, in the presence of a 10% excess of triethylsilane, addition of one-half equivalent of boron trifluoride etherate to octanal results, within one hour, in the formation of a 66% yield of dioctyl ether after a basic hydrolytic workup. Benzaldehyde provides a 75% yield of dibenzyl ether under the same reaction conditions. The remainder of the mass is found as the respective alcohol.70 Zinc chloride is also capable of catalyzing this reaction. With its use, simple alkyl aldehydes are converted into the symmetrical ethers in about 50% yields.330... 

Under certain conditions, the trifluoroacetic acid catalyzed reduction of ketones can result in reductive esterification to form the trifluoroacetate of the alcohol. These reactions are usually accompanied by the formation of side products, which can include the alcohol, alkenes resulting from dehydration, ethers, and methylene compounds from over-reduction.68,70,207,208,313,386 These mixtures may be converted into alcohol products if hydrolysis is employed as part of the reaction workup. An example is the reduction of cyclohexanone to cyclohexanol in 74% yield when treated with a two-fold excess of both trifluoroacetic acid and triethylsilane for 24 hours at 55° and followed by hydrolytic workup (Eq. 205).203... 

Reduction of the ketone carbonyl of cis-1, 2,3,4,4a,9b-hexahydro-8-hydroxydi-benzofuran-3-one with trifluoroacetic acid and triethylsilane at 0° produces a mixture of the a- and /3-isomers of the C3 alcohol with an u / ratio of 1 4 (Eq. 211).394 This result can be compared with the isomer ratio of 100 1 that results when sodium borohydride is used as the reducing agent.394 The same cis pair of alcohol isomers is formed in 77% combined yield, but in a reversed ratio of a /3 = 4 1, when the less saturated tetrahydrodibenzofuran analog is used as the substrate (Eq. 212).394... 

Reduction of the keto group in naphtho derivative 115 with sodium borohydride results in 69% of the alcohol 116 (Scheme 23, Section 2.1.3.3 (1999PHA645)). Further triethylsilane reduction gives 117 in 67% yield. Synthesis of a series of pyrrolo-benzazepine and pyrrolo-benzothiazepine acetic acids (Scheme 77, Section 5.1.1 (1994MI385)) includes reduction of ketoesters 380 into corresponding hydroxyl esters, subsequent deoxygenation with iodine/PPhs and hydrolysis. 

In addition to the alkylation of benzyl alcohols with silyl enol ethers, the hydroxyl group could be removed in a reduction employing triethylsilane Et3SiH as the reductant. With 1 mol% of Bi(OTf)3 as the catalyst, the desired (5-arylester 34 could be isolated in 75% yield (Scheme 26). 

Scheme 26 Bi(OTf)3-catalyzed reduction of benzyl alcohols with triethylsilane...

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