Ketones reductive dimerization

Aliphatic ketones reductively dimerize upon treatment with TiCl3 (reported as TiCla in the literature (vide supra)) and zinc in the presence of pivalonitrile in dichloromethane (Equation (14)). In the reaction, addition of pivaloni-trile produces a dramatic accelerating effect. 

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. 

Ethers have also been prepared by the reductive dimerization of two molecules of an aldehyde or ketone (e.g., cyclohexanone dicyclohexyl ether). This was accomplished by treatment of the substrate with a trialkylsilane and a catalyst. ... 

Stereospecific ketone reduction was also observed (Giordano et al. 1985) with potassium, rubidium, and cesium (but not with sodium) in tertiary alcohols (but not in secondary or primary alcohols). The undesirable dimerization probably proceeds more readily in the case of sodium. Tertiary alcohols are simply more acidic than primary or secondary alcohols. It is reasonable to point out that the ketone-to-alcohol reduction of 3a-hydroxy-7-oxo-5p-cholic acid by alkali metals is a key step in the industrial synthesis of 3a,7p-dihydroxy-5p-cholic acid. 

The bimolecular reduction of aliphatic nitroso compounds is complex and somewhat unreliable. With careful control of reaction conditions, a-nitroso ketones (in dimeric form) may be reduced with stannous chloride in an acidic medium at room temperature to the azoxy compounds, while dimeric a-nitroso acid derivatives may be reduced at about 50°C [10, 35, 36]. Nitrosoalkanes, on the other hand, are decomposed at room temperature to alcohols and nitrogen, and are reduced to amines at 50°-60°C. It has been postulated that only the dimeric nitroso compounds can be reduced to azoxy compounds and, in fact, that the dimer has a covalent nitrogen-nitrogen bond. Equations (31)—(34) summarize these data [10]. 

An important preparation of pyrazines (303) is from a-amino ketones RCOCH2NH2 or their monooximes which spontaneously condense to give 2,5-dihydropyrazines (302). The a-amino ketones are often prepared in situ by reduction of isonitroso ketones, and the dihydropyrazines are usually oxidized to pyrazines before isolation icf Section 3.2.2.3.3). Catalytic reduction of a-azido ketones also leads to 2,5-dihydropyrazines (80OPP265). Similarly, a-nitro ketones may be reduced to the a-amino ketones which dimerize spontaneously (69USP3453278). 

The samarium-lV-bromosuccinimide combination reductively dimerizes carbonyl compounds.163 This pinacol-type coupling gives diols in 60-80% yield, with some diastereoselectivity the by-product from simple reduction (i.e. alcohol) is typically 5-10%. The conditions suggest a single electron transfer to give carbonyl radical anion, which then self-couples. Even congested ketones such as benzophenone and fluorenone worked well. 

Samarium metal, in the presence of various additives such as ammonium chloride or bromide, induces reductive dimerizations of aromatic ketones to give 1,2-diols, with some diastereoselectivity, and with some alcohol (i.e. reduced ketone) by-product.164 The syn-selectivity observed in many cases may be due to samarium chelation of the... 

Since the introduction of the titanocene chloride dimer 67a to radical chemistry, much attention has been paid to render these reactions catalytic. This field was reviewed especially thoroughly for epoxides as substrates [123, 124, 142-145] so only catalyzed reactions using non-epoxide precursors and a few very recent examples of titanium-catalyzed epoxide-based cyclization reactions, which illustrate the principle, will be discussed here. A very useful feature of these reactions is that their rate constants were determined very recently [146], The reductive catalytic radical generation using 67a is not limited to epoxides. Oxetanes can also act as suitable precursors as demonstrated by pinacol couplings and reductive dimerizations [147]. Moreover, 5 mol% of 67a can serve as a catalyst for the 1,4-reduction of a, p-un saturated carbonyl compounds to ketones using zinc in the presence of triethylamine hydrochloride to regenerate the catalyst [148]. 

Reductive dimerization of ketones Aromatic -unsaturated ketones are reduced and dimerized to 1,5-hexadienes by sequential reaction with LiAIH4, Fe3(CO)i2, and HCl. The effectiveness of iron carbonyls shows the order Fe3(CO), 2 > Fe2(CO)y > FeiCO). ... 

All five Group I metals (Li, Na, K, Rb and Cs) and three Group II metals (Ca, Sr, Ba) have been used in NH3 to effect the reduction of ketones to secondary alcohols. " In addition, it has been reported that Yb-NH3 reduction of a,p-unsaturated ketones affords the saturated alcohol as the major product, which presumably arises via reduction of the intermediate saturated ketone.Reduction of (+)-camphor with Yb-NH3 both in the absence and presence of NH4CI affords the same 86 14 ratio of bomeol (2) to iso-bomeol (3). In the presence of NH4CI, the ketone is completely consumed and dimeric reduction products are not observed. Excess Yb-THF-HMPA effects bimolecular reduction of aromatic ketones, but aliphatic ketones are apparently inert to Yb-THF. - ... 

The reduction of imines to amines (equation 21) by dissolving metals is usually carried out using active metals in a protic solvent, typically Na-alcohol, Zn-NaOH and A1 or Mg in alcohols. - ""- Although the mechanism of these reductions has not been investigated in detail it is almost certainly analogous to that of the reduction of ketones (Section 1.4.2). It has been established that radical anions are intermediates in these reductions and in the absence of a proton donor reductive dimerization is the principal reaction path. ... 

Reductive dimerization of a,p-unsaturated ketones is effected by either Cr" or V" chloride to give 1,6-diketones, but aliphatic a, -unsaturated aldehydes are dimerized to the allylic glycals. Interestingly, nonconjugated aldehydes are stable towards these reagents. Similar pinacolic couplings of aldehydes and ketones with Ti" reagents were developed by Corey. ... 

Stereoselective radical addition on the exo-face of levoglucosenone 250 leads to the C-linked dimer 251 in a modest 26% yield. The expected competing reaction is the direct hydrogen abstraction by the initial radical species. Stereoselective hemiketal and ketone reductions afford the 1,6-anhydro derivative 252, which is deprotected and opened to give the final C-ana-log of a /3-(1 4) disaccharide 253. 

Dicarboxylic esters in the presence of Na in ether or in benzene (carcinogen) cyclize to furnish not (3-keto esters but instead a-hydroxy ketones (acyloins). This acyloin condensation involves reductive dimerization of a ketyl radical anion (see Chapter 9). ... 

Both ring expansions and contractions are well documented. Ring size can strongly influence the course of the reaction. For example, Vogel found that the diol (20), obtained by reductive dimerization of cyclobutanone, cleanly rearranged to the ketone (21) on warming in dilute sulfuric acid (21) was subsequently used to prepare the novel pentalene (22 equation 14). 

Samarium. In 1996, Endo determined that, in the presence of Mg/Me SiCl, carbonyl compounds can be reductively dimerized by a catalytic quantity of Sml2 (Eq. 3.30) [51, 52]. Aliphatic and aromatic aldehydes and ketones can be coupled with this system. This catalytic process has recently been applied to the synthesis of hydroxyl-functionalized polymers [53]. 

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