Ketones ketone -> ketyl reduction

Fig. 14.45. Chemistry of the drying of THF or ether with potassium and benzophenone featuring the ketone -> ketyl reduction and the trapping reaction of the ketyl with residual water.

Reduction of Ketones and Enones. Although the method has been supplanted for synthetic purposes by hydride donors, the reduction of ketones to alcohols in ammonia or alcohols provides mechanistic insight into dissolving-metal reductions. The outcome of the reaction of ketones with metal reductants is determined by the fate of the initial ketyl radical formed by a single-electron transfer. The radical intermediate, depending on its structure and the reaction medium, may be protonated, disproportionate, or dimerize.209 In hydroxylic solvents such as liquid ammonia or in the presence of an alcohol, the protonation process dominates over dimerization. Net reduction can also occur by a disproportionation process. As is discussed in Section 5.6.3, dimerization can become the dominant process under conditions in which protonation does not occur rapidly. 

Treatment of fluorene, xanthene, thioxanthene, phenyl-4-pyridyl-methane, phenyl-2-pyridylmethane, 4,5-methylenephenanthrene, tetra-phenylcyclopentadiene, or phenalene with base and a trace of oxygen in DMSO (80% )-tert-buty alcohol (20%) solution gave significant amounts of the ketyls—i.e., Figure 6. These reactions may involve the initial formation of the ketone followed by reduction by the carbanion to yield the ketyl. 

D — hydroxylated organosodium compound B — hemiacetal anion A. This sequence is completely analogous to the sequence ketone —> ketyl — hydroxylated radical A —> hydroxylated organosodium compound B —> sodium alkoxide that occurs in the reduction of a ketone with Na in /PrOH (Figure 17.53). 

A much more highly diastereoselective process results when alkenic 3-keto ester and 3-ketoamide substrates can be utilized in the ketone-alkene reductive coupling process. Both electron deficient and unactivated alkenes can be utilized in the reaction (equations 65 and 66). In such examples, one can take advantage of chelation to control the relative stereochemistry about the developing hydroxy and car-boxylate stereocenters. Favorable secondary orbital interactions between the developing methylene radical center and the alkyl group of the ketyl,and/or electrostatic interactions in the transition state account for stereochemical control at the third stereocenter. 

There is an inherent competition between simple reduction of the ketone and the reductive cyclization process with unsaturated carbonyl substrates. Cyclization processes that are slower than that of the ketyl-alkene cyclization forming a five-membered ring, suffer frtxn lower yields owing to this competition. For example, ketyl-alkyne coupling can also be achieved when mediated by Smb, but yields are lower than those achieved with analogous keto-alkenes (equation 68). This might have been expected on the basis that radical additions to alkynes are slower than corresponding additions to alkenes. Similarly, the rate... 

In the pinacol coupling, two ketones are reductively coupled to give a 1,2-diol. (Compare the photochemical pinacol coupling discussed in Section 5.3.1.) The two ketones are usually identical, but intramolecular dimerizations can give unsymmetrical 1,2-diols. The reaction proceeds by electron transfer to the ketone to give a ketyl radical anion. This compound dimerizes to give the 1,2-diol. 

Molander et al. studied the intramolecular coupling of unactivated olefinic ketones by a reductive ketyl-olefin radical cyclization, mediated by Sml2 in the presence of HMPA [47] (Scheme 18). 

Related to the epoxy ketones are cyclopropyl ketones, whose ketyls can also fragment under reductive conditions afforded by Smli [98]. Ring expansions have been developed based upon these observations [99], and yields and selectivities can be high when the cleavage is stereoelectronically favored (Eqs. 88, 89). As shown by the results depicted in Eq. (88), the ring expansion can be accompanied by y9-elimination of appropriately situated leaving groups. 

Samarium(ir) iodide in the presence of HMPA effectively promotes the intramolecular coupling of unactivated alkenic ketones by a reductive ketyl-alkene radical cyclization process (eq 25). This protocol provides a means to generate rather elaborate carbocycles through a sequencing process in which the resulting organosamarium species is trapped with various electrophiles to afford the cyclized product in high yield. ... 

Protonated ketyl radical anions are key intermediates in the complex process leading to the Clemmensen ketone-to-methylene reduction.i 1, 120 Since this reaction requires strongly acidic conditions, sonochemical activation was expected... 

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. 

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... 

The mechanism for the transformation of 5 to 4 was not addressed. However, it seems plausible that samarium diiodide accomplishes a reduction of the carbon-chlorine bond to give a transient, resonance-stabilized carbon radical which then adds to a Smni-activated ketone carbonyl or combines with a ketyl radical. Although some intramolecular samarium(n)-promoted Barbier reactions do appear to proceed through the intermediacy of an organo-samarium intermediate (i.e. a Smm carbanion),10 ibis probable that a -elimination pathway would lead to a rapid destruction of intermediate 5 if such a species were formed in this reaction. Nevertheless, the facile transformation of intermediate 5 to 4, attended by the formation of the strained four-membered ring of paeoniflorigenin, constitutes a very elegant example of an intramolecular samarium-mediated Barbier reaction. 

Diols (pinacols) can be synthesized by reduction of aldehydes and ketones with active metals such as sodium, magnesium, or aluminum. Aromatic ketones give better yields than aliphatic ones. The use of a Mg—Mgl2 mixture has been called the Gomberg-Bachmann pinacol synthesis. As with a number of other reactions involving sodium, there is a direct electron transfer here, converting the ketone or aldehyde to a ketyl, which dimerizes. 

The acetate function of 98 was then cleaved by treatment with samarium diiodide in methanol in high yield (81 %) [44], A potential mechanism for this transformation is shown in Scheme 3.18. Reduction of the ketone function forms a samarium ketyl radical (103). Transfer of a second electron forms a carbanion (104) which undergoes p-elimination of acetate to generate the samarium enolate 105. Protonation and tautomerization then affords the observed product 107. 

The bimolecular reduction of ketones to pinacols by magnesium may involve ketyls as intermediates, the bivalence of magnesium favoring the bimolecular reduction product. Ketyl formation with sodium in liquid ammonia eventually leads to the reduction of the ketone to the alcohol. The corresponding pinacol is also cleaved to the alcohol under the same conditions.128... 

Reductive Cross-Coupling of Nitrones Recently, reductive coupling of nitrones with various cyclic and acyclic ketones has been carried out electrochem-ically with a tin electrode in 2-propanol (527-529). The reaction mechanism is supposed to include the initial formation of a ketyl radical anion (294), resulting from a single electron transfer (SET) process, with its successive addition to the C=N nitrone bond (Scheme 2.112) (Table 2.9). 

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