Carbonyl reduction proton donors

Selective reduction of a benzene ring (W. Grimme, 1970) or a C C double bond (J.E. Cole, 1962) in the presence of protected carbonyl groups (acetals or enol ethers) has been achieved by Birch reduction. Selective reduction of the C—C double bond of an a,ft-unsaturated ketone in the presence of a benzene ring is also possible in aprotic solution, because the benzene ring is redueed only very slowly in the absence of a proton donor (D. Caine, 1976). 

When saturated steroidal ketones are reduced in ammonia, an alcohol is usually present to act as a proton donor and high yields of steroidal alcohols are obtained. Under these conditions, reduction probably proceeds by protonation of the radical-anion (or ketyl) (61), which results from a one electron addition to the carbonyl group, followed by addition of a second electron and proton. Barton has proposed that reduction proceeds via protonation of the dianion (62) arising from addition of two electrons to the carbonyl group. This proposal implies that the ketyl (61) undergoes addition of a second electron in preference to undergoing protonation by the... 

Another fundamental reaction of >C=0 involves its reactivity as a base. In the Brpnsted sense, >C=0 - may react with a proton donor to produce a neutral ketyl radical (>C(.)OH, Figure 2, reaction 2). This is an important process when the reduction of a carbonyl compound is carried out under acidic conditions or in a protic media (e.g. elec-trochemically, with less reactive reducing reagents such as Mg or Zn, or when >C=0"-is produced via PIET and R3N"+ has available a-protons). The follow-up chemistry of >C(.)OH is that of a neutral free radical (dimerization to form pinacols, addition to unsaturated compounds, fragmentations/ring-openings, etc.), and thus beyond the scope of this chapter. 

Tetradentate chiral proton donors have been used for the asymmetric protonation of samarium enolates formed by the Sml2 reduction of a-heteroatom-substituted carbonyl compounds. For example, Takeuchi examined the reduction of a-heterosubstituted cyclohexanone 12 using Sml2 and the BINOL-derived chiral proton source 13.41 Ketone 14 was obtained in good yield and high enantiomeric excess (Scheme 2.11). Coordination of the proton source to samarium is key to the success of the transformation.41... 

As proton donor coordination has an impact on the rate of carbonyl reduction, it is reasonable to expect that glycols should significantly accelerate the rate of carbonyl reduction. Seminal work by Hilmersson examined the correlation between the number of ethereal oxygens in a series of ethylene glycol-based proton donors and the rate of reduction of ketones.13 His work showed that coordinating alcohols enhance the rate of ketone reduction substantially and that the rate increase is proportional to the number of ethereal oxygens in the proton donor source.13 The mechanistic basis for this... 

The mechanism of cathodic hydrogenation, which requires a proton donor, is most probably that given in Scheme 1 the reduction potentials are in the order E cathodic hydrogenation of carbonyls and polycyclic hydrocarbons , and activated... 

The contemporary view of these reductions recognizes that the reactions of carbonyl compounds with dissolving metals follow one of two general reaction paths. One of these prevails in reductions carried out in the absence of proton donors, the other in reductions in the presence of an alcohol or other proton source, frequently NH4CI. Two recent reviews present rather different mechanistic explanations for these reactions, particularly those in liquid NH3 in the absence of added proton donors. ... 

In terms of synthetic utility, the reduction of carbonyl compounds by a dissolving metal in liquid NH3 in the presence of an alcohol, water or NH4CI is far more common and usually far more efficient than reduction in the absence of a proton donor. Historically these reductions were carried out using active metals, usually Na, in alcohols and the experimental results are similar in both systems. - ... 

It must be emphasized that reduction of carbonyl compounds by dissolving metals, either in the presence or absence of an added proton donor is a kinetically controlled process. This was tacitly stated in 1972," and has been repeated or implied in more recent reviews of this topic. A recent study of the reduction of several bicyclo[2.2.1]heptanones using alkali metal-NH3-NH4Cl systems emphasizes that these reductions are kinetically controlled. ... 

Both disubstituted alkynes (Chapter 3.3, this volume) and isolated terminal double bonds may be reduced by alkali metals in NH3, but isolated double bonds are usually stable to these conditions. However, 16,17-secopregnanes (10 equation 8) afford mixtures of cyclization products (11) and (12) in 61% to 80% yield with Na naphthalenide-THF, Na-NHs-THF, Na-THF or Li-NHs-THF. With Na-NHa-THF-r-butyl alcohol, a 91% yield of a 72 28 mixture of (11) (12) (R = Me) is obtained. This type of radical cyclization of alkenes and alkynes under dissolving metal reduction conditions to form cyclopentanols in the absence of added proton donors is a general reaction, and in other cases it competes with reduction of the carbonyl group. Under the conditions of these reactions which involve brief reaction times, neither competitive reduction of a terminal double bond nor an alkyne was observed. However, al-lenic aldehydes and ketones (13) with Li-NHs-r-butyl alcohol afford no reduction products in which the diene system survives. ... 

When an alkenic bond is conjugated with the carbonyl group, the carbonyl carbon and the p-carbon become the two reactive centers and a variety of products can be obtained depending on the medium. Presence of water in the reduction of 4-methyl-2-cyclohexenones results in a mixture of products. However, when the p-position is substituted such as in retinal (11), pinacolization takes place to form the pinacol (12) in 89% yield, provided that the electroreduction is carried out in an aprotic medium in the presence of a mild proton donor, such as diethyl malonate (equation 6). ... 

The electrochemical reduction of a,p-unsaturated ketones and related compounds in aprotic media in the absence of metal cations can, in some cases, lead to relatively stable anion radicals.However, in the presence of proton donors the latter are protonated to form hydroxyallyl radicals, which tend to dimerize more rapidly than they diffuse back to the electrode to undergo further reduction (Scheme 17). Although these allyl radicals prefer to dimerize by coupling at the -position, if this position is sterically hindered, as in the case of cholest-4-en-3-one, coupling at the carbonyl carbon may be observed, yielding pinacols. ... 

Addition of an electron to the LUMO of the carbonyl group to form a radical anion is the first step in the reduction process. Radical anions can be characterized in aprotic solvents by electron spin resonance (esr) spectroscopy. Those derived from unconjugated carbonyl compounds are highly reactive and can only be detected in a matrix at low temperatures [3]. Decay is rapid because the excess carbonyl compound acts as a proton donor toward the basic oxygen center in the radical anion. Aromatic carbonyl compounds give less reactive radical anions in which the free electron is delocalized over the whole... 

The reaction is most probably initiated by radical attack of a reduced carbonyl function on the aromatic ring in the adjacent system. The product is formed as the radical anion but reoxidized by air during work-up. In the presence of proton donors, or in alcoholic solvents, reduction of 98 gives a mixture of acyclic and partly hydrogenated cyclic products [288]. Substituted 98, such as the 4,4, 5,5 -tetracarboxylic acid, gives coupling in basic alcoholic medium but not in DMF [289]. 

Deprotection of ally I or ally loxy carbonyl derivatives of amino acids. This combination of reagents effects rapid reductive cleavage of allyl or allyloxycarbonyl derivatives of amino acids in CH2CI2 containing a proton donor (/7-NO2C6H5OH, acetic add, H2O). The actual catalyst is probably bis(triphenylphosphine)palladium(0). Benzyl, Boc, and Cbo groups are stable to these conditions. This cleavage does not induce racemization. 

Selective reduction of a benzene ring in the presence of another reducible group is possible if the other group is first protected in some way. Ketones, for example, may be converted to acetals or enol ethers to protect them from reduction. Conversely, reduction of benzene rings takes place only slowly in the absence of a proton donor, and selective reduction of an a,(3-unsaturated carbonyl system can be effected. 

A possible alternative pathway for the transformation of III to a saturated ketone, one that circumvents the formation of silyl enol ether IV, involves the protonolysis of the palladium enolate in via oxidative addition of a proton donor ZH (Z = OH or Cl). The resultant Pd(IV) intermediate, V, undergoes double reductive eliminadon to produce the saturated carbonyl and RsSiZ, along with regeneration the Pd(0) catalyst... 

Carbonyl reduction occurs by a typical nucleophilic addition mechanism under basic conditions, as shown previously in Figure 19.4a. Although the details of carbonyl-group reductions are complex, LiAlH4 and NaBH4 act as if they were donors of hydride ion nucleophile, H , and the initially formed alkoxide ion intermediate is then protonated by addition of aqueous acid. The reaction is effectively irreversible because the reverse process would require expulsion of a very poor leaving group. 

Just as addition of a Grignard reagent to an aldehyde or ketone yields an alcohol, so does addition of hydride ion, H (Section 17.4). Although the details of carbonyl-group reductions arc complex, LiAll-14 and N aBH4 act as if they were donors of hydride ion in a nucleophilic addition reaction (Figure 19.7).. Addition of water or aqueous acid after the hydride addition step protonates the tetrahedral alkoxide intermediate and gives the alcohol product. 

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