Nucleophiles complex hydrides

Reagents of choice for reduction of epoxides to alcohols are hydrides and complex hydrides. A general rule of regioselectivity is that the nucleophilic complex hydrides such as lithium aluminum hydride approach the oxide from the less hindered side [511, 653], thus giving more substituted alcohols. In contrast, hydrides of electrophilic nature such as alanes (prepared in situ from lithium aluminum hydride and aluminum halides) [653, 654, 655] or boranes, especially in the presence of boron trifluoride, open the ring in the opposite direction and give predominantly less substituted alcohols [656, 657,658]. As far as stereoselectivity is concerned, lithium aluminum hydride yields trans products [511] whereas electrophilic hydrides predominantly cis products... 

Only two topics are of importance for this section the reduction of pyrazolium salts and 3-pyrazolin-5-ones by complex hydrides, and the nucleophilic photosubstitution of pyrazoles and indazoles. 

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

Estradiol is formed by lithium aluminium hydride reduction of the ketone. We can formulate this simply as hydride acting as the nucleophile, though hydride delivery by LAH is strictly more complex than this. Unless you are specifically asked for details, treat LAH as a source of hydride ion. 

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... 

The mechanism of reduction by boranes and alanes differs somewhat from that of complex hydrides. The main difference is in the entirely different chemical nature of the two types. Whereas complex hydride anions are strong nucleophiles which attack the places of lowest electron density, boranes and alanes are electrophiles and combine with that part of the organic molecule which has a free electron pair [119]. By a hydride transfer alkoxyboranes or... 

The structure of the cyclic ketone is of utmost importance. Reduction of cyclic ketone by complex hydrides is started by a nucleophilic attack at the carbonyl function by a complex hydride anion. The approach of the nucleophile takes place from the less crowded side of the molecule (steric approach or steric strain control) leading usually to the less stable alcohol. In ketones with no steric hindrance (no substituents flanking the carbonyl group or bound in position 3 of the ring) usually the more stable (equatorial) hydroxyl is generated (product development or product stability control) [850, 851, 852, 555]. The contribution of the latter effect to the stereochemical outcome of... 

The effect of steric hindrance can be nicely demonstrated in the reduction of two bicyclic ketones, norcamphor and camphor. The relatively accessible norcamphor yielded on reduction with complex hydrides predominantly (the less stable) endo norborneol while sterically crowded camphor was reduced by the same reagents predominantly to the less stable exo compound, isobor-neol [837], From the numerous examples shown it can be deduced that the stereoselectivity increases with increasing bulkiness (with some exceptions), and that it is affected by the nucleophilicity of the reagent and by the solvent. 

A nucleophilic mechanism can be applied in reductions with complex hydrides of highly fluori-nated aliphatic and alicyclic fluoroalkenes with electron-deficient C = C bonds the hydride anion adds as a strong nucleophilic agent to the more electrophilic carbon atom the intermediate anion can then lose a fluoride ion either from the original C = C bond, or from the allylic position finishing an SN2 displacement of the fluorine. Thus, the reductions of vinylic C-F bonds with hydrides proceed by a nucleophilic addition-elimination mechanism. Displacement of fluorine in highly fluorinated aromatic compounds proceeds by the same mechanism ... 

Nucleophilic hydride ion replaces selectively the fluorine at the C4 position in perfluoropyridine to give 4//-perfluoropyridine as the sole product from the reaction with lithium aluminum hydride.147 The same position is attacked with this complex hydride in 3-chloro-2,4,5,6-tet-rafluoropyridinc resulting in 3-chloro-2,5,6-trifluoropyridine (9).148... 

It has been established that complex hydrides react via nucleophilic displacement of either vinylic or allylic halogen by hydrogen [121-124] (Scheme 57). 

Kinetic studies of the substitution reaction of 2-chloro-l-methylpyridinium iodide with phenoxides are consistent with the SnAt mechanism, with rate-determining nucleophilic attack.38 The effects of a variety of ring substituents on the reactivities of 2-fluoro- and 2-chloro-pyridines in reactions with sodium ethoxide in ethanol have been examined. The results were discussed in terms of the combination of steric, inductive, and repulsive interactions.39 Substitution in 2,4,6-trihalopyridines normally occurs preferentially at the 4-position. However, the presence of a trialkylsilyl group at the 3-position has been shown to suppress reaction at adjacent positions, allowing substitution at the 6-position.40 Methods have been reported for the introduction and removal of fluorine atoms for polyfluoropyridines. Additional fluorine atoms were introduced by metallation, chlorination, and then fluorodechlorination, while selective removal of fluorine was achieved by reduction with either metals or complex hydrides or alternatively by substitution by hydrazine followed by dehydrogena-tion-dediazotization.41... 

C. Nucleophilic Addition to Pyrrolium Complexes Hydride Addition... 

Bis(arene) ruthenium complexes (99) + are electrophilic and add various nucleophiles (see Nucleophile), including hydride, to form (100) (Scheme 24). Methyl groups of methylated arene rings are acidic and can be deprotonated, giving the corresponding exo-methylene complexes (101). This is similar to the chemistry developed for analogous iron complexes, and is reminiscent of the a-mthenocenyl carbonium ions (Section 4.5). 

Reduction by complex hydrides Phosphorus nucleophiles Nucleophilic Attack at Hydrogen Attached to Ring Carbon or Ring Nitrogen... 

Reduction by complex hydrides Azide ions and nitrite ions Nucleophilic Attack at Hydrogen. 6.1 Metalation at a ring carbon atom... 

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