Acidity hydridization effects

The mechanism by which the Group III hydrides effect reduction involves activation of the carbonyl group by coordination with a metal cation and nucleophilic transfer of hydride to the carbonyl group. Hydroxylic solvents also participate in the reaction,59 and as reduction proceeds and hydride is transferred, the Lewis acid character of boron and aluminum becomes a factor. 

Reduction of 10 with lithium aluminum hydride (LAH) in ether furnished19 an intermediate, presumably the phosphine derivative 11, which was treated with acid to effect ring enlargement, giving the 5-phosphino-D-xylopyranose derivative 14. This compound was immediately converted by air oxidation19 into the stable crystalline compounds, 5-deoxy-3-0-methyl-5-C-(phosphinyl)-D-xylopyranose (15) and the 5-C-(hydroxyphosphinyl) derivative 16 in overall yields of 15 and 3.5%, respectively, from 10. Compound 16 was obtained in 90% yield from 15 by oxidation with bromine.19 No mutarotation was observed19 for compounds 15 and 16 in water during 48 h. 

The rate enhancements observed when using inorganic iodide salts can be similarly rationalized, the methyl iodide being effectively generated, in these cases, by a combination of the acidic hydride and the salt [these equilibria are essentially equivalent with those in Eqs. (24) and (26)] ... 

Lithium aluminum hydride, effect of solvents on reduction of carbohydrate sulfonic esters, 269 Lutease, 380 Luteic acid, fungal, 378 Lyxitol, 1-acetamido-l-deoxy-L-, 170 Lyxofuranose, 5 - acetamido - 5 - deoxy-D-, 171... 

The rate-determining step in the ionic hydrogenation reaction of carbon-carbon double bonds involves protonation of the C==C to form a carbocation intermediate, followed by the rapid abstraction of hydride from the hydride source (equation 45). ° There is a very sensitive balance between several factors in order for this reaction to be successful. The proton source must be sufficiently acidic to protonate the C—C to form the intermediate carbocation, yet not so acidic or electrophilic as to react with the hydride source to produce hydrogen. In addition, the carbocation must be sufficiently electrophilic to abstract the hydride from the hydride source, yet not react with any other nucleophile source present, i.e. the conjugate anion of the proton source. This balance is accomplished by the use of trifluoroacetic acid as the proton source, and an alkylsilane as the hydride source. The alkene must be capable of undergoing protonation by trifluoroacetic acid, which effectively limits the reaction to those alkenes capable of forming a tertiary or aryl-substituted carbocation. This essentially limits the application of this reaction to the reduction of tri- and tetra-substituted alkenes, and aryl-substituted alkenes. 

A variety of enzymes catalyze the oxidative decarboxylation of jS-hydroxy acids. Isotope effect studies of malic enzyme (29), isocitrate dehydrogenase (63), and 6-phosphogluconate dehydrogenase (64) indicate that all three of these oxidative decarboxylations occur by stepwise mechanisms in which hydride transfer occurs first, forming a j3-keto acid that then undergoes decarboxylation. Hydride transfer and decarboxylation are both partially rate determining. 

However they illustrate the effect of charge of the complex on acidity. The replacement on Os(II) of the chloride in trans-[Os(ri2-H2)(Cl)(dppe)2]PFg by the acetonitrile in trans-[Os(Ti2-H2)(NCMe)(dppe)2](BF4)2 results in a change of about 9 pKg units. Methylene chloride is an excellent solvent for very acidic hydride complexes but it tends to react with nucleophilic hydrides. 

Oxidative addition of C-CN bonds to nickel(0) can be followed by transmetalation with various main-group organometaUic reagents, and subsequent reductive elimination can result in the functionalization of C-CN bonds of nitriles (Scheme 5). As the simplest case, C-CN bonds can be transformed to C-H bonds via transmetalation with metal hydrides. Indeed, nickel-catalyzed hydrodecyanation of various aromatic and aliphatic nitriles proceeds with tetramethyldisUoxane as a hydride donor (Scheme 6) [44]. While a wide range of nitriles can be decyanated by this protocol, a relatively high amount of catalyst is required in this process, presumably because of the formation of catalyticaUy inactive (PCy3)2Ni(CN)2. The use of AlMe3 as a Lewis acid is effective in some cases to promote the C-CN bond activation. Under these reaction conditions, the relative reactivity order of different aryl electrophiles is estimated Ar-SMe>Ar-CN>Ar-OAr>Ar-OMe. 

Jen et al. (1973) obtained amine ester 380 by reaction of the benzylidene Schiff base with sodium hydride in DMF, followed by methyl methane-thiolsulfonate, and finally p-toluenesulfonic acid to effect imine cleavage. Treatment of 380 in anhydrous methanol-pyridine with mercuric chloride stereospecifically produced crystalline methoxyamine 381, which was converted to 382 by standard means. Exposure of 380 to mercuric chloride In DMF-water led to 6-oxopenicillanic acid benzyl ester (383), a material that had been prepared in another manner by Lo and Sheehan (1972). Finally, Taylor and Burton (1977) have studied the 6-methylthio-lation of keteniminopenams (see p. 249). 

S,6S)-isomer (9%). Reaction of 571 with lithium aluminum hydride effected reduction of both the lactone and the N-methoxylactam, leading to the diol (—)-572. The primary alcohol was brominated by Appel reaction with carbon tetrabromide and triphenylphosphine, the bromide then cycliz-ing spontaneously to give the oft-synthesized swainsonine acetonide (-)-488 in 88% yield. Finally, hydrolysis with aqueous hydrochloric acid followed by purification by ion-exchange chromatography provided the target alkaloid, (—)-378. 

A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1), Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBHjCN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH -HOAc and NaBHjCN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBHjCN with temperature control. At 20"C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes cun also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,l2]. 

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

Unequivocal syntheses of cis- and mns-(i -decahydroquinoxalincs have been achieved by lithium aluminum hydride reduction of the corresponding cis- and trans-decahydroquinoxaIin-2-ones. The latter compounds were prepared by condensation of chloroacetic acid and cis- and trans-1,2-diaminocyclohexane, respectively. The resolution of frans-dUdecahydroquinoxaline was effected by use of first dibenzoyl-cZ-tartaric acid and then of dibenzoyl- -tartaric acid. "" (C/. p. 215.)... 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Manx- different reducing agents are effective, but the most common choice in the laboratory is sodium cyanoborohydride, NaBH3CN. Sodium cyanoboro-hydride is similar in reactivity to sodium borohydride (NaBH4) but is more stable in weak acid solution. 

---