Alkylation of Ketones with Alcohols

The a-alkylation of enolates derived from ketones with alkyl halides is a very important and frequently used method for forming new carbon-carbon bonds in organic synthesis [40]. Yet, if the a-alkylation of enolates derived from ketones with alkyl halides can be replaced by the direct reaction of ketones with alcohols, this method would provide a very useful waste-free, green route to a-alkylation, producing no side products other than water. 

This method provides a very convenient route to aliphatic ketones, to which a carbonyl function can be introduced in the desired position by selecting the ketones and alcohols employed. 

The iridium catalytic system can also be applied to the a-alkylation of active methylene compounds. The alkylation of cyanoacetates 93 with primary alcohols 94 was achieved by using [lrCl(coe)2]2 and PPhs to afford saturated a-alkylated products 95 (Equation 10.20) [42]. Here, the alkylation reaction was efficiently accomplished, without the need for any base. 

The [Cp lrCl2]2-catalyzed alkylation of arylacetonitrile 96 with primary alcohols has also been reported (Equation 10.21) [43]. Here, KOH proved to be the most successful base and the reaction proceeded in the absence of any solvent. 

The [Cp IrCl2]2 and [IrCl(cod)]2 catalysts have also been used in the alkylation of barbituric acid [43] and nitroalkanes [44] with primary alcohols. 

---

IrCl(cod)]2, in the presence of PPh3 and KOH, catalyzed the a-alkylation of ketones with alcohols [41]. As an example, the reaction of 2-octanone 87 with 1-butanol 88 was catalyzed by the iridium complex to give 6-dodecanone 89 in 80% yield (Equa-hon 10.19). The alkylation proceeded with complete regioselectivity at the less-hindered side of 2-octanone, and the reaction was promoted by a catalytic quantity of KOH (10mol%) in the absence of both a hydrogen acceptor and a solvent. 

Xu Q, Chen J, Tian H et al (2014) Catalyst-free dehydrative a-alkylation of ketones with alcohols green and selective autocatalyzed synthesis of alcohols and ketones. Angew Chem Int Ed 53(l) 225-229... 

Scheme 32 Electroenzymatic reduction of ketones with alcohol dehydrogenase Rh aryl, R alkyl, CHO, CO2H, yields 92-100%, 0 - 100% ee.

Complexation of [Cp IrCl2]2 with iV-heterocyclic carbenes has led to complexes such as 25, developed by Peris and coworkers [107, 108], and 133, developed by Crabtree and coworkers [12]. Complex 24 is activated by the addition of silver triflate and is effective for the iV-alkylation of amines with alcohols and for the iV-alkylation of anilines with primary amines. Complex 25 has also been shown to couple benzyl alcohol 15 with a range of alcohols, including ethanol 134, to give ether products such as ether 135 (Scheme 31). Complex 133 was an active hydrogen transfer catalyst for the reduction of ketones and imines, using 2-propanol as the hydrogen source. It was also an effective catalyst for the iV-alkylation of amines... 

A related process, from this conceptual point of view (Eq. 16), the use of the aldehyde generated in situ for further reactions, has allowed the a-alkylation of ketones with primary alcohols [62], Several ketones have been condensed with 1-butanol or benzyl alcohol affording the corresponding a-alkylated ketones in good yields (up to 96%) in the presence of [ lr(/z-Cl)(cod) 2] andKOH. 

The N-alkylation of amines with alcohols [63] can also be carried out with Ir catalysts through a similar domino sequence reaction. In this case, the aldehyde/ketone resulting from oxidation is condensed with an amine to the corresponding imine, which is hydrogenated to the alkylated amine [63]. By way of example, the reaction of benzyl alcohol with aniline in toluene afforded benzylaniline in a 88% isolated yield by using catalytic amounts of [ lr(/z-Cl)Cp Cl 2]/K2C03. 

Asymmetric induction occurs during the alkylation of ketones with the a-sulfinyl carbanion derived from optically active 1-chloroalkyl-p-tolyl sulfoxides (equation 18). The resulting chloro alcohol may be converted to an optically active epoxide under alk ine conditions and the sulfinyl group is removed with n-butyllithium. While the process benefits from high asymmetric induction in the alkylatitm reaction, it must be recognized that, when either R 91H and/or R R diasteretHnerk compounds are formed and require separation. 

In addition, transition-metal-free dehydrogenative a-alkylation of ketones with primary alcohols involving the Meerwein-Ponndorf-Verley-Oppenauer redox cycle has recently been developed by using LiOrBu or NaOH as base [237, 238]. 

Yamada YM, Uozumi Y (2006) A solid-phase self-organized catalyst of nanopalladium with main-chain viologen polymers a-alkylation of ketones with primary alcohols. Org Lett 8(7) 1375-1378 Yamada YM, Uozumi Y (2007) Development of a convoluted polymeric nanopalladium catalyst oi-alkylation of ketones and ring-opening alkylation of cyclic 1, 3-diketones with primary alcohols. Tetrahedron 63(35) 8492-8498... 

Scheme 26.5 Alkylation of ketones with the benzhydrilic alcohol 10.

Aldehydes and ketones react with aniline derivatives in the presence of hydrogen and a catalyst to yield N-alkylanilines (Fache et al., 1996 Freifelder, 1971). N-Alkylation of aliphatic amines under microwave irradiation is a well-documented process (Caddick, 1995 Loupy et al., 1998 Varma, 1999 Lidstrom et al., 2001 Wathey et al., 2002). Jiang et al. (1996) reported the N-alkylation of anilines with alcohols over Raney nickel under microwave irradiation. More recently, Khadilkar and Jaizinghani (1999) carried out the direct monobenzylation of aniline with ben-zylchloride on alumina supported potassium carbonate. They reported a fast and efficient metal-free method for the N-alkylation of anilines under microwave irradiation. Romera et al. (2004) reported potassium iodide catalyzed monoalkylation of anilines, where they obtained 54-98% yield. 

They are colourless liquids with characteristic odours, and are prepared by the condensation of ketones with alkyl orthoformates in the presence of alcohols, or by the reaction of acetylenes with alcohols in presence of HgO and BF3. In some cases trichloroethanoic acid is used as the catalyst. They lose alcohol when heated and form vinyl ethers. Exchange of alcohol groups occurs when the ketals of the lower alcohols are boiled with alcohols of greater molecular weight. See acetals. 

By studying the NMR spectra of the products, Jensen and co-workers were able to establish that the alkylation of (the presumed) [Co (DMG)2py] in methanol by cyclohexene oxide and by various substituted cyclohexyl bromides and tosylates occurred primarily with inversion of configuration at carbon i.e., by an 8 2 mechanism. A small amount of a second isomer, which must have been formed by another minor pathway, was observed in one case (95). Both the alkylation of [Co (DMG)2py] by asymmetric epoxides 129, 142) and the reduction of epoxides to alcohols by cobalt cyanide complexes 105, 103) show preferential formation of one isomer. In addition, the ratio of ketone to alcohol obtained in the reaction of epoxides with [Co(CN)5H] increases with pH and this has been ascribed to differing reactions with the hydride (reduction to alcohol) and Co(I) (isomerization to ketone) 103) (see also Section VII,C). 

Certain catalysts promote the reduction of ketones with organosilanes. The reduction of acetophenone with Et3SiH is catalyzed by the diphosphine 65 and gives only a small amount of overreduction to ethylbenzene.377 Aryl alkyl enones and ynones are reduced to the corresponding alcohols with triethoxysilane and the titanium-based catalyst 66.378 Trichlorosilane reduces acetophenone in 90% yield with /V-formylpyrrolidinc catalysis.379... 

It is well accepted that the asymmetric reduction of simple dialkyl ketones generally proceeds with low enantioselectivity.68 Ohkuma et al.69 reported that hydrogenation of simple ketones can be achieved using Ru(II) catalysts in the presence of diamine and alcoholic KOH in 2-propanol. Promising results have been achieved in the asymmetric hydrogenation of alkyl aryl ketones with a mixture of an Ru-BINAP complex, chiral diamine, and KOH (Scheme 6-33). 

Scheme 40 Cathodic intermolecular coupling of ketones with vinyl trimethylsilane R R alkyl, R prim. sec. alcohol, yields 35-96%.

Furthermore, the N-alkylation of 2-aminobenzyl alcohol 114 with ketones 115 in the presence of [IrCl(cod)]2 and KOH gave quinoline derivatives 116 (Equation 10.28) [52]. The reaction may be initiated by the formation of ketimine from 114 and 115, and the ketimine thus formed is oxidized by Ir catalyst and the 114 which serves as a hydrogen acceptor giving the corresponding aldehyde, which is eventually converted into quinoline 116 through intramolecular aldol-type condensation. 

Analogously, alkanes have been oxidized with anhydrous hydrogen peroxide and catalytic amounts of MTO in CHsCN . With these substrates, the main products are alkyl hydroperoxides together with alcohols and ketones. 

Asymmetric reduction of a,fi-enon s. This combination of reagents (1 1) in conjunction with N-cthylaniline (2 equivalents) reduces alkyl aryl ketones to alcohols with high stereoselectivity.1 Under these conditions 2,/1-unsaturated ketones arc reduced to optically active (S)-allylic alcohols. Optical yields of 80 98% have been reported for open-chain enones. Reduction of cyclic enones is somewhat less efficient. The method was used to reduce 1 to 2, which has been used as an intermediate in an anthracyclinone synthesis.2... 

Ferles et al. have studied the crossed hydrocoupling of acetone and cyclopentanone with pyridinium salts.167 The products were similar to those found for hydrocoupling of ketones with the pyridine free bases except for the Af-alkyl group. In the case of cyclopentanone, the tertiary alcohol product eliminated water in some cases to form an olefin. 

---