Carbonyl Reduction with

Several theoretical studies have considered LiH addition as a model for the more computationally difficult L1A1H4 and NaBH4 [45]. However, reaction of aldehydes and ketones with LiH seldom if ever leads to reduction [46]. AIH3, while less commonly used than the complex boron and aluminium hydrides, is useful for reducing carbonyls [47] and therefore is a suitable model for computational study. Calculations [2, 5] show that gas-phase reduction of formaldehyde by AIH3 occurs by formation of complex 1, which rearranges via a four-centre transition state to form an aluminium methoxide product. Two conformational isomers of 

The rate-determining step for reduction is the formation of the four-centre cyclic transition state 2. The relatively short C-O and long H-C bond lengths indicate an early transition state consistent with the Hammond postulate. The obtuse H-C-0 angle of attack (92.4°) is greater than the value observed for addition of 

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Cope rearrangement 17, 213 f., 643 Corey catalysts 74 f., 80 -, aldol condensations with 74 -, carbonyl allylations with 74 -, carbonyl reductions with 74 f. 

FIGURE 12.7 Transition state for carbonyl reductions with JST 144. 

Generality and Scope of Carbonyl Reduction with Sml2... 

Reduction in the latter case occurs by means of a dialkylborane species, but the overall products are the same as in the bimolecular process. However, the stereochemical outcome of these two processes may be very different. In the two-step process, the first step is rate determining since carbonyl reductions with dialkylboranes are generally very fast. The rate of reduction should then be independent of the carbonyl compounds structure or concentration. 

One of the more important characteristics of carbonyl reduction with LiAlH4 is the diastereoselectivity of the reaction when reduction introduces a second stereogenic center. As a general rule, hydride is delivered to... 

Carbon monoxideliron carbonyl Reductions with carbon monoxide... 

Lithiated 71 (Ar = o-An, u-Tol and 1-Naphth) reacted with carbon dioxide affording the phosphinocarboxylic acid boranes 74 in 55-60% yields. Their deprotection using TFA, with retention of conflguration, and coupling with (S)-(—)-2-(diphenylphosphino)methylpyrrolidine furnished amidodiphosphines 81 (48-51% yield). Finally, carbonyl reduction with borane (and concomitant N-and P-protection) followed by a deboronation step gave access to P,N ligands 82. 

As noted previously, nicotinamide cofartor regeneration is based on coupling, for example, the desired enzymatic reduction process, for example, carbonyl reduction, with a second reaction in which a cosubstrate is oxidized, which reforms the reduced nicotinamide cofartor for reuse in the desired biotransformation. The general concept is shown in Scheme 2.2a, exemplified for asymmetric ketone reduction and reductive amination of a-keto adds as representative processes. These are particularly valuable for organic chemistry because they yield enantiomerically pure alcohols and ct-amino adds, respectively. Because the cosubstrate is required in stoichiometric amounts, it should be readily available and inexpensive and its oxidation product should be iimocuous. The most... 

SchifT s bases A -Arylimides, Ar-N = CR2, prepared by reaction of aromatic amines with aliphatic or aromatic aldehydes and ketones. They are crystalline, weakly basic compounds which give hydrochlorides in non-aqueous solvents. With dilute aqueous acids the parent amine and carbonyl compounds are regenerated. Reduction with sodium and alcohol gives... 

Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

There are, however, two useful alkylating-redudng methods. One is the methylenation of the ester carbonyl group with Tebbe s reagent, the other is the conversion of thionolactones to cyclic thioketals and subsequent reduction. 

Hydroxyall l Hydroperoxyall l Peroxides. There is evidence that hydroxyalkyl hydroperoxyalkyl peroxides (2, X = OH, Y = OOH) exist in equihbrium with their corresponding carbonyl compounds and other a-oxygen-substituted peroxides. For example, reaction with acyl haUdes yields diperoxyesters. Dilute acid hydrolysis yields the corresponding ketone (44). Reduction with phosphines yields di(hydroxyalkyl) peroxides and dehydration results in formation of cycHc diperoxides (4). 

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

Two classes of charged radicals derived from ketones have been well studied. Ketyls are radical anions formed by one-electron reduction of carbonyl compounds. The formation of the benzophenone radical anion by reduction with sodium metal is an example. This radical anion is deep blue in color and is veiy reactive toward both oxygen and protons. Many detailed studies on the structure and spectral properties of this and related radical anions have been carried out. A common chemical reaction of the ketyl radicals is coupling to form a diamagnetic dianion. This occurs reversibly for simple aromatic ketyls. The dimerization is promoted by protonation of one or both of the ketyls because the electrostatic repulsion is then removed. The coupling process leads to reductive dimerization of carbonyl compounds, a reaction that will be discussed in detail in Section 5.5.3 of Part B. 

Clemmensen reaction is the reduction of carbonyl compounds with amalgamated zinc and concentrated hydrochloric acid... 

Meerwein-Pondorff reduction is the synthesis of alcohols by heating carbonyl compounds with aluminium isopropoxide in isopropanol and distilling off acetone by-product... 

Reduction with metal deuteride complexes (section Ill-A) is undoubtedly the most convenient way to convert carbonyl compounds into the corresponding deuterated alcohols. For stereochemical reasons, however, it is sometimes necessary to resort to reductions with alkali metals in O-deuterated alcohols, or in liquid deuterioammonia-O-deuterioalcohol mixtures. 

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