Coupling alkylative

Detergents are metal salts of organic acids used primarily in crankcase lubricants. Alkylbenzenesulfonic acids, alkylphenols, sulfur- and methjiene-coupled alkyl phenols, carboxyUc acids, and alkylphosphonic acids are commonly used as their calcium, sodium, and magnesium salts. Calcium sulfonates, overbased with excess calcium hydroxide or calcium carbonate to neutralize acidic combustion and oxidation products, constitute 65% of the total detergent market. These are followed by calcium phenates at 31% (22). 

Scheme 12.21. Synthesis of dehydrohomoancepsenolide using a three-component cross-coupling/alkylation, by Furstner and Dierkes [68]. THF — tetrahydrofuran, Cy — cyclohexyl.

One-electron oxidations can give stable ty -ff-metal-carbon bonds accompanied by loss of donor ligand. The reactions, which proceed according to Eq. (e), arc not presented here unless formation of an > -T-metal-carbon bond with the carbon of RX is established. One-electron oxidation can often compete with the two-electron oxidative addition with coupled alkyl cis coproducts. The reaction of an anionic transition-metal complex with an organic halide is an oxidative addition ... 

Monomeric Mo(0) complexes such as [(C6H5)2P(CH2)2P(C6H5)2]2MoL2 (L = CO, N2) give with alkyl halides only coupled alkyls and the 7-coordinated complexes (C H,)3P2CH2CH2[P(CsH5)3]2MoL2X X (X = Cl, Br) . 

Preparation of symmetrical and unsymmetfical aliphatic ethers can be accomplished by coupling alkyl halides and sodium alkoxides (H illiamson). The formation of the alkoxide may be slow and incomplete because the slow-dissolving alkoxide coats the sodium. This difficulty can be overcome by using a large excess of alcohol. After the sodium has dissolved, the alkyl halide is added to form the ether which is finally removed by fractional distillation. Sodium f-butoxide is not only formed slowly but also reacts very slowly with alkyl halides. The reaction of the f-alkyl halide with the sodium alcoholate is not any better, for the chief products are olefins. Consequently, another method must be considered for preparing f-alkyl ethers (method 118). Even in the conversion of s-alkyl halides, olefin formation occurs. 

Couplings. Alkyl cyanonickelates (also cyanocobaltates and cyanoferrates) prepared in sim from M(CN)j and RLi at -78° couple with organic halides. 

Due to concern about these issues, in combination with early interest and success in coupling aryl and vinyl electrophiles, progress toward the development of palladium- or nickel-based methods for cross-coupling alkyl halides/ sulfonates has been relatively slow. However, during the past decade (particularly the last few years), important advances have been described that clearly demonstrate that the aforementioned obstacles can be overcome and that the development of general catalysts for coupling alkyl electrophiles is a realistic objective. 

The attractiveness of organo-9-BBN derivatives as coupling partners is largely due to their accessibility via the hydroboration of alkenes and alkynes on the other hand, they suffer from the drawbacks of not being easily manipulated in air or commercially available. In contrast, boronic acids are air-stable, and a large number and variety are commercially available. Consequently, the development of methods for cross-coupling alkyl electrophiles with boronic acids is undoubtedly an important objective. 

Representative examples of the application of Pd/PCy3 to Kumada-Mura-hashi couplings of primary alkyl chlorides are illustrated in Table 8 (entries 1-5). In contrast to most other palladium-based methods for cross-coupling alkyl electrophiles, the reaction proceeds well even for a p-branched alkyl halide (entry 2). 

Many of the methods that have been reported for coupling alkyl electrophiles with terminal alkynes require a strong base and therefore have limited functional-group compatibility [35]. In contrast, the Sonogashira reaction, which is widely used to cross-couple aryl and vinyl electrophiles with terminal alkynes, employs a mild base (e.g., an amine). Expanding the scope of Sonogashira couplings to include alkyl electrophiles would be a welcome advance in alkyne chemistry. 

The required 2-(4-methoxybenzocyclobutenyl)-ethyl iodide 79 was prepared by a multistep process from 2-bromo-5-methoxybenzaldehyde via l-cyano-4-methoxybenzocyclobutene 77 as illustrated. 2-Methylcyclohexenone was then converted into 2-methyl-3-vinyl-6-n-butylthiomethylenecyclohexanone 80. Blocking C-6 was considered necessary to insure regiospecihc condensation of 79 at C-2. However, the condensation reaction afforded adduct 81 in only 16% yield. In subsequent work (with 2-methylcyclopentenone) 1 4 addition of a vinyl Grignard or lithium reagent and coupled alkylation of the intermediate enolate occurred at C-2 without the need to block C-6 (Scheme 1, Scheme 14 - ). 

Suzuki and colleagues described the first palladium-catalyzed oxidative carbonylation of alkenylboranes as early as 1981. They prepared 1-alkenylboranes by hydroboration of alkynes and subsequent oxidative carbonylation mediated by a catalytic amount of PdCL, in the presence of NaOAc and BQ in methanol, which provided unsaturated esters in good yields (Scheme 8.27a) [106]. Later, a stereoselective synthesis of ]S-mono- and / , / -disubstituted a, ]S-unsaturated esters was established by a stepwise cross-coupling alkylation followed by an oxidative carbonylation of 2-bromo-1-alkenylboranes (Scheme 8.27b) [107]. Good yield and excellent stereoselectivity was achieved. 

Dear, G.J. Mallett, D.N. Higton, D.M. Roberts, A.D. Bird, S.A. Young, H. Plumb, R.S. Ismail, I.M. The potential of serially coupled alkyl-bonded silica monolithic columns for high resolution separations of pharmaceutical compounds in biological fluids. Chromatographia 2002, 55, 177-184. 

Acylation and Coupling Reactions. Reagents used for the preparation of unsymmetrical ketones by coupling alkyl halides with acid chlorides include activated nickel, prepared by the action of lithium and naphthalene on nickel(II) chloride in glyrae (Vol,8,... 

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