Aldehydes reductive dimerization

Metal-induced reductive dimerization of carbonyl compounds is a useful synthetic method for the formation of vicinally functionalized carbon-carbon bonds. For stoichiometric reductive dimerizations, low-valent metals such as aluminum amalgam, titanium, vanadium, zinc, and samarium have been employed. Alternatively, ternary systems consisting of catalytic amounts of a metal salt or metal complex, a chlorosilane, and a stoichiometric co-reductant provide a catalytic method for the formation of pinacols based on reversible redox couples.2 The homocoupling of aldehydes is effected by vanadium or titanium catalysts in the presence of Me3SiCl and Zn or A1 to give the 1,2-diol derivatives high selectivity for the /-isomer is observed in the case of secondary aliphatic or aromatic aldehydes. 

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. ... 

A vanadium catalyst is essential although the combination of Zn and MejSiCl is capable of reductive dimerization of aldehydes [20]. A reversible redox cycle for the in situ generated low-valent vanadium species mediating the electron transfer is achieved in the presence of Zn as the stoichiometric co-reductant (Scheme 4). 

Another method for reductive dimerization has been developed in hy-drosilylation. NiCl2-SEt2 is an effective catalyst in silylative dimerization of aromatic aldehydes with a hydrosilane (Scheme 12) [40]. A catalytic thiolate-bridged diruthenium complex [Cp RuCl(/ 2-SPrI)2RuCp ][OTf] also induces the conversion to 1,2-diaryl-1,2-disiloxyethane [41]. A dinuclear (siloxyben-zyl)ruthenium complex is considered to be formed, and the homolytic Ru - C bond fission leads to the siloxybenzyl radicals, which couple to the coupling product 14. 

Researchers have found that the reduction of a variety of aziridine esters yields the corresponding aziridine aldehyde which dimerizes diastereoselectively <06JA14772>. The reduction of 112 with excess DIBAL yields the dimer 113, which is in equilibrium with the monomer 114. This molecule reacts as the monomer and both reduction to 115 or reductive amination to 117 proceed in quantitative yields. In a very interesting reaction, treatment of 113 with /V-benzyl tryptamine provides the pentacyclic 116 in excellent yield. 

Increasing junction potential also increased carbinol yield as was seen with aldehyde reductions. In basic electrolytes or in nonaqueous media, the dimer 50 was the major product. 

The yields from aldehyde alkylidenation is somewhat lower due to the reductive dimerization of aldehydes with low-valent Ti. Alkylidenation of esters is possible by the reaction of 1,1 -dibromoalkane. TiCU and Zn in the presence of TMEDA to give (Z) vinyl ethers [60], Cyclic vinyl ethers are prepared from unsaturated esters in two steps. The first step is formation of the acyclic enol ethers using a stoichiometric amount of the Ti reagent, and the second step is ring-closing alkene metathesis catalysed by Mo complex 19. Thus the benzofiiran moiety of sophora compound I (199, R = H) was synthesized by the carbonyl alkenation of ester in 197 with the Ti reagent prepared in situ, and the subsequent catalytic RCM of the resulting enol ether 198 catalysed by 19 [61]. 

In conclusion, nitriles may be reduced electrochemically or with dissolving metal to produce amines. Nonetheless, such reactions must be used with caution. In addition to competitive decyanation, aldehyde or 2,4,6-trialkyIhexahydro-l,3,5-triazine formation and reductive dimerization are waiting to overwhelm the unwary. 

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. ... 

Kinetic studies have revealed that aliphatic ketyl radical anions are very shortlived compared with aromatic (half life of acetone " in aqueous 2-propanol is 72 ps, whereas that for acetophenone " is 1.5 ms) [253]. The reductive dimerization of simple aromatic aldehydes has been studied in aprotic solvents, with the second order rate constant being larger in acetonitrile than in DMF, because of ion-pair effects [254]. Electron-withdrawing substituents reduce the speed of dimerization (benzaldehyde " k = 2.4x 10 m" s", p-cyanobenzaldehyde k = 5 M s" ) [255], whereas protic solvents lead to protonation before dimerization [256]. 

In the reductive dimerization of methyl cinnamate to a cyclopentanone [Eq. (5)], similar yields are found at the cathode [42] and with metals (sodium, THE, and TBAI, —78°C) [40]. Because of the potential selective conversion at the electrode, halides can be reduced at the cathode to carbanions in the presence of carbonyl compounds, which are reduced at more cathodic potentials. This way labile carbanions can be obtained and reacted under conditions in which the same species generated by a metalorganic route would decompose. Eor example, trichlorobromoalkane can be cathodically converted in the presence of aldehydes to a dichloromethyl anion 0°C [route a, Eq. (6)] and be trapped to form a dichlorotetrahydrofuran, but for the metallorganic route [route b, Eq. (6)] a reaction temperature of — 110°C is necessary [43]. 

The intermolecular McMurry reaction has proven a particularly valuable route to alkenic hydrocarbons. This is especially true for polyenes and sterically hindered kenes. For example, -carotene (37 equation 78) can be prepared in 85% yield by reductive dimerization of retinal. Isorenieratene (38 equation 78) is similarly synthesized in 96% yield, and the aldehyde (39 equation 79) has been ela-... 

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]. 

In 1999, Cozzi and Umani-Ronchi described a diastereoselective intermolecular pinacol coupling of aromatic and aliphatic aldehydes in the presence of a catalytic quantity of TiCl4(THF)2/Schiff base (Eq. 3.38) [60]. Manganese is employed as the stoichiometric reductant with the Cozzi/Umani-Ronchi system, zinc generally affords a lower yield of the diol. The reaction is believed to proceed via a pathway analogous to that illustrated in Fig. 3-5. The observations of Cozzi and Umani-Ronchi that the Schiff base affects reaction diastereoselectivity and increases the reaction rate bode well for studies of asymmetric variants. In an initial investigation, these workers obtained 10% ee in a reductive dimerization of benzaldehyde (Eq. 3.39). 

Reductive couplings. Aliphatic and aromatic aldehydes undergo reductive dimerization on exposure to TiBr2-Cu. 

Reductions. Chemoselective reduction of sulfoxides to sulfides and a-diketones to a-ketols employs the title reagent in MeCN at 0°. Aldehydes are dimerized to give 1,2-diols (dl- meso-) on exposure to Tifi, with or without adding Cu. ... 

Aldehydes usually undergo reductive dimerization upon electrolysis, as in the formation of 4,5-octanediol in 55% yield from butanal. Small chain aldehydes (such as acetaldehyde) give significant amounts of reduction to the alcohol but the proportion of dimer increases as the chain length increases, which is probably due to increased hydration of the small aldehydes and the alcohol products. 

Pinacolization. In dichloromethane, aromatic aldehydes undergo reductive dimerization under the influence of TiClj. The reaction is highly stereoselective, giving the iy/j-l,2-diols predominantly syn anti 200 1). A cross-coupling is the major reaction when methyl phenylglyoxylate and pyridine are present, and p-amino-a-hydroxy esters are obtained with the further introduction of an amine. ... 

Reduction of ethylenic carboxylic acids, esters, and amides on low H2 overvoltage cathodes gives rise to high yields of the respective dihydro compounds, as in the catalytic process, although on metals of high H2 overvoltage reductive dimerization occurs. a,/3-Unsaturated aldehydes and ketones are reduced to a number of products due to the mechanism of reduction. ... 

Alkenes can be obtained from aldehydes or ketones on reductive dimerization by treatment with a reagent prepared from titanium(III) chloride and zinc-copper couple (or L1A1H4), or with a species of active titanium metal formed by reduction of titanium(III) chloride with potassium or lithium metal. This McMurry coupling reaction is of wide application, but in intermolecular reactions generally affords a mixture of the E- and Z-alkenes (2.99). 

Reductions. Sm(II) has been developed as a versatile one-electron reductant of broad utility in organic synthesis. Sm(II) can be prepared and regenerated in situ by reduction of Sm(III) in DMF with a consumable magnesium anode (52-54), Under these conditions aromatic esters are reductively dimerized to 1,2-diJketones with only 10% Sm(III) (52). Similarly, allylic chlorides can be added to ketones to give homoallylic alcohols (55). SmCl3-catalyzed electrosynthesis of y-butyrolactones from 3-chloro esters and ketones or aldehydes proceeds in 25-76% yield (54). 

Additionally, several low-valent cerium reagents transform aldehydes and ketones into pinacols via reductive dimerization (Imamoto et al., 1982a) ... 

A synthetic sequence has been discovered in which aldehydes which are not branched at the a-position undergo formal reductive dimerization to give symmetrical olefins (e.g. Scheme 14). At the key step, a-stannylalkyl halides, which are stable and easily handled, smoothly couple on treatment with n-butyl-lithium under very mild conditions (-78 to 0 °C). Furthermore, the difference in reactivity between a-stannylalkyl iodides and chlorides enabled a moderate yield of a cross-coupled olefin from two different aldehydes to be obtained, a-Branched aldehydes exhibit a different pattern of reactivity, furnishing terminal olefins instead of coupled products (Scheme 15), probably for steric reasons. 

This process is similar to the Mcmurry reaction [167] the reductive dimerization of aldehydes and ketones by [Ti] forming oleftnic C=C bonds. The mechanism of the Furstner synthesis presumably involves single-electron transfer to the carbonyl groups (78 -> 80) and intramolecular radical combination in 80 (supported by Ti-chelation) to... 

Such a mechanism would relate metathesis to the Fleming and MacMurry [53, 54] reaction for the reductive dimerization of aldehydes or ketones to alkenes. 

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