Alcohols reaction with complex hydrides

With 2,4-substituted, bispidones of lower symmetry and analoguous 1,5-dicarboxylic acid esters (e.g., compounds 10-48 in Table 1) the reduction under Wolff-Kishner conditions fails, but reaction with complex hydrides leads to the corresponding bispidoles. The treatment with LiAUTj yields a 1 1 mixture of the epimeric tris alcohols, whereas reduction with NaBELj at ambient temperature in various solvents leads to the epimeric mono-alcohols in different ratios up to epimerically pure compounds (see Scheme 9) (116, 117), which can be further reduced to the tris alcohols with LiAlH4. For example, the reduction of 14 with NaBH4 in dry methanol yields 65% syn- (84b) and 35% anri-product (84a), while the reaction in a mixture of dioxane-water leads exclusively to the anti-configuration of alcohol 84a (117). 

By studying the NMR spectra of the products, Jensen and co-workers were able to establish that the alkylation of (the presumed) [Co (DMG)2py] in methanol by cyclohexene oxide and by various substituted cyclohexyl bromides and tosylates occurred primarily with inversion of configuration at carbon i.e., by an 8 2 mechanism. A small amount of a second isomer, which must have been formed by another minor pathway, was observed in one case (95). Both the alkylation of [Co (DMG)2py] by asymmetric epoxides 129, 142) and the reduction of epoxides to alcohols by cobalt cyanide complexes 105, 103) show preferential formation of one isomer. In addition, the ratio of ketone to alcohol obtained in the reaction of epoxides with [Co(CN)5H] increases with pH and this has been ascribed to differing reactions with the hydride (reduction to alcohol) and Co(I) (isomerization to ketone) 103) (see also Section VII,C). 

The reaction of complex hydrides with carbonyl compounds can be exemplified by the reduction of an aldehyde with lithium aluminum hydride. The reduction is assumed to involve a hydride transfer from a nucleophile -tetrahydroaluminate ion onto the carbonyl carbon as a place of the lowest electron density. The alkoxide ion thus generated complexes the remaining aluminum hydride and forms an alkoxytrihydroaluminate ion. This intermediate reacts with a second molecule of the aldehyde and forms a dialkoxy-dihydroaluminate ion which reacts with the third molecule of the aldehyde and forms a trialkoxyhydroaluminate ion. Finally the fourth molecule of the aldehyde converts the aluminate to the ultimate stage of tetraalkoxyaluminate ion that on contact with water liberates four molecules of an alcohol, aluminum hydroxide and lithium hydroxide. Four molecules of water are needed to hydrolyze the tetraalkoxyaluminate. The individual intermediates really exist and can also be prepared by a reaction of lithium aluminum hydride... 

Disadvantages of the Rosenmund reduction are high temperature, sometimes necessary to complete the reaction, and long reaction times. In this respect, reduction with complex hydrides offers considerable improvement. Again special, not too efficient reagents must be used otherwise the reduction proceeds further and gives alcohols (p. 145). One of the most suitable complex... 

There are several ways to cleave the auxiliary from the product 7. Typical reactions include reduction with complex hydrides such as LiBH4 to obtain the alcohol 18 or transamination to the Weinreb amide and subsequent reduction with DIBAL to give the aldehyde 19 that would have been obtained from direct aldol reaction. ... 

The reduction of epoxides withborane is noteworthy as it gives rise to the less substituted alcohol as the major product (7.96), in contrast to reduction with complex hydrides (compare with Scheme 7.71). The reaction is catalysed by small amounts of sodium or lithium borohydride and high yields of the alcohol are obtained. With 1-alkylcycloalkene epoxides, the 2-alkylcycloalkanols produced are entirely cis, and this reaction thus complements the hydroboration-oxidation of cycloalkenes described in Section 5.1, which leads to trans products. Reaction with borane in the presence of boron trifluoride has also been used for the reduction of epoxides and for the conversion of lactones and some esters into ethers. 

If the double bond is conjugated with the carbonyl (i.e., an a,P-unsaturated aldehyde, or ketone), reduction of the double bond only, yielding the saturated carbonyl compound, can also be effected by the same metal catalysts with continuous careful monitoring so that only one equivalent of hydrogen is consumed before the reaction is stopped. In contrast, with complex hydrides, it is only the reduction of the carbonyl that occurs and the corresponding alcohol, with the double bond remaining intact, is generally isolated from the reaction mixture. 

Although reduction of ketones with alkali metals, for example, sodium (Na°) in ethanol (CH3CH2OH), to the corresponding alcohol, as already noted, has been replaced with complex hydrides, a minor product in the original reaction, the result of coupling two ketones at their respective carbonyl carbons, was occasionally found on workup of the reaction mixture. The diol (a pinacol) thus formed could be made the major product if the reaction was carried out with magnesium (Mg°) or amalgamated aluminum (Al-Hg) instead of sodium (Na°). The process, which doubtlessly involves a series of one-electron transfer reactions, is shown in Equation 9.21. 

Extensive studies on the Wacker process have been carried out in industrial laboratories. Also, many papers on mechanistic and kinetic studies have been published[17-22]. Several interesting observations have been made in the oxidation of ethylene. Most important, it has been established that no incorporation of deuterium takes place by the reaction carried out in D2O, indicating that the hydride shift takes place and vinyl alcohol is not an intermediate[l,17]. The reaction is explained by oxypailadation of ethylene, / -elimination to give the vinyl alcohol 6, which complexes to H-PdCl, reinsertion of the coordinated vinyl alcohol with opposite regiochemistry to give 7, and aldehyde formation by the elimination of Pd—H. 

A synthetically useful diastereoselectivity (90% dc) was observed with the addition of methyl-magnesium bromide to a-epoxy aldehyde 25 in the presence of titanium(IV) chloride60. After treatment of the crude product with sodium hydride, the yy -epoxy alcohol 26 was obtained in 40% yield. The yyn-product corresponds to a chelation-controlled attack of 25 by the nucleophile. Isolation of compound 28, however, reveals that the addition reaction proceeds via a regioselective ring-opening of the epoxide, which affords the titanium-complexed chloro-hydrin 27. Chelation-controlled attack of 27 by the nucleophile leads to the -syn-diastereomer 28, which is converted to the epoxy alcohol 26 by treatment with sodium hydride. 

The reaction of these complexes with metal hydrides of the type [CoF1(CO)4], [MnFl(CO)3], [MoFlCp(CO)3], [WHCp(CO)3], or [WFlCp(CO)2(PMe3)l progresses with the liberation of alcohol, ethane, and the corresponding gold(I) derivatives/ 87... 

The complex OsH(OH)(CO)(P Pr3)2 also reacts with methyl acrylate, methyl vinyl ketone, and allyl alcohol.91 Reaction with methyl acrylate leads to OsH(OH) (COXrf-CH2=CHC02MeXP Pr3)2 containing the olefin trans to the hydride ligand. In solution, this complex releases the olefin to generate the starting complex. The thermodynamic magnitudes involved in the equilibrium have been determined in toluene-t/a by 31P 1H NMR spectroscopy. The values reported are AH° = 17.0 0.5 kcal-mor1 and AS° = 54.0 1.2 cal-K 1-mol 1. In the presence of the methyl vinyl ketone complex OsH(OH)(CO)(P Pr3)2 affords 0sH CHCHC(0) Me (CO)(P Pr3)2 and water, whereas in the presence of allyl alcohol the loss of... 

Reduction to Alcohols. The organosilane-mediated reduction of ketones to secondary alcohols has been shown to occur under a wide variety of conditions. Only those reactions that are of high yield and of a more practical nature are mentioned here. As with aldehydes, ketones do not normally react spontaneously with organosilicon hydrides to form alcohols. The exceptional behavior of some organocobalt cluster complex carbonyl compounds was noted previously. Introduction of acids or other electrophilic species that are capable of coordination with the carbonyl oxygen enables reduction to occur by transfer of silyl hydride to the polarized carbonyl carbon (Eq. 2). This permits facile, chemoselective reduction of many ketones to alcohols. 

In related studies, Cp2ZrCl2 has been found to catalyze at room temperature an aluminum hydride (i-Bu2AlH) reduction of CO to linear Ci-C5 alcohols (430). The system involves reaction of complex 55 with CO, which precipitates the starting zirconium(IV) complex and leaves a yellow solution, that on hydrolysis yields the alcohols. Toluene solutions of Cp2Ti(CO)2 complex under H2/CO effect Eq.(69), i.e., a homogeneous stoichiometric hydrogenation of carbon monoxide to methane (426). 

This finding is the consequence of the distribution of various ruthenium(II) hydrides in aqueous solutions as a function of pH [RuHCl(mtppms)3] is stable in acidic solutions, while under basic conditions the dominant species is [RuH2(mtppms)4] [10, 11]. A similar distribution of the Ru(II) hydrido-species as a function of the pH was observed with complexes of the related p-monosulfo-nated triphenylphosphine, ptpprns, too [116]. Nevertheless, the picture is even more complicated, since the unsaturated alcohol saturated aldehyde ratio depends also on the hydrogen pressure, and selective formation of the allylic alcohol product can be observed in acidic solutions (e.g., at pH 3) at elevated pressures of H2 (10-40 bar [117, 120]). (The effects of pH on the reaction rate of C = 0 hydrogenation were also studied in detail with the [IrCp (H20)3]2+ and [RuCpH(pta)2] catalyst precursors [118, 128].)... 

We then studied group 5 metals, especially tantalum-for which the laboratory already had great experience. Because of the studied reaction, alkyl or hydride-type compounds such as those developed in the laboratory could not be employed. Consequently, we became interested in alkoxo-type derivatives, either synthesized by reaction of the grafted complex with an alcohol or obtained by direct synthesis starting from an alkoxy-tantalum compound grafted on silica. In all cases, resulting complexes have been characterized by surface organometallic chemistry techniques, especially EXAFS and solid-state NMR (ID and 2D with C-labeled compounds). Indeed various compounds bonded by one, two or three surface bonds have been prepared and characterized. 

A plausible mechanism involves the reaction of the dihydride precursor with t-butylethylene to the 14-e complex [Ir(C6H3-2,6 CH2P-f-Bu2 2)]> which undergoes the oxidative-addition reaction of the alcohol to afford a hydride alkoxide complex. Further /i-hydride ehmination gives the alde-hyde/ketone and regenerates the dihydride active species [55]. In the particular case of 2,5-hexanediol as the substrate, the product is the cycHc ketone 3-methyl-2-cyclopenten-l-one. The formation of this ketone involves the oxidation of both OH groups to 2,5-hexanedione followed by an internal aldol reaction and further oxidation as in the final step of a Robinson annotation reaction [56]. 

Reaction Pathway. The simplest pathway is illustrated by the /3-keto ester substrate in Scheme 50. As suggested by reaction with RuCl2[P(C6H5)3]3 as the catalyst precursor (40c, 96), this hydrogenation seems to occur by the monohydride mechanism. The catalyst precursor has a polymeric structure but perhaps is dissociated to the monomer by alcoholic solvents. Upon exposure to hydrogen, RuC12 loses chloride to form RuHCl species A, which, in turn, reversibly forms the keto ester complex B. The hydride transfer in B, from die Ru center to the coordinated ketone to form C, would be the stereochemistry-determining step. Liberation of the hydroxy ester is facilitated by the al-... 

The chemistry of flavins is complex, a fact that is reflected in the uncertainity that has accompanied efforts to understand mechanisms. For flavoproteins at least four mechanistic possibilities must be considered.1533 233 (a) A reasonable hydride-transfer mechanism can be written for flavoprotein dehydrogenases (Eq. 15-23). The hydride ion is donated at N-5 and a proton is accepted at N-l. The oxidation of alcohols, amines, ketones, and reduced pyridine nucleotides can all be visualized in this way. Support for such a mechanism came from study of the nonenzymatic oxidation of NADH by flavins, a reaction that occurs at moderate speed in water at room temperature. A variety of flavins and dihydropyridine derivatives have been studied, and the electronic effects observed for the reaction are compatible with the hydride ion mecha-nism.234 236... 

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