Ketone-amide coupling

Fig. 14.50. Crossed McMurry reactions ketone/ester coupling (top) and ketone/amide coupling (bottom).

Analogous intramolecular chelation-controlled ketone/olefin couplings with Sml2, in which Sm+3 was complexed in a cyclic manner to the ketyl anion and a /1-carbonyl of an ester or amide functionalilty, were reported as early as 1987 (Scheme 31)86. The cyclized samarium intermediate 49 could be further reacted with added electrophiles such... 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

When multiple labelling in any of the primed or unprimed positions 8, 9, 12, 13, 19 and 20 is required, the route is slightly modified (Scheme 5). First the ketone is coupled with the anion of triethyl phosphonoacetate (11), as described above (Scheme 3). The ester product 12 is converted into the A -methoxy-A -methylamide (16) by reacting it with the anion prepared by deprotonation of A, 0-dimethylhydroxylamine with BuLi. The amide 16 can now be reacted with methyl magnesium iodide (17) as described above, thus giving access to carotenoids with multiple labelling in the required positions via the multiply labelled ketone 7 [38]. 

The reaction has been extended to ketones, carboxylic acids and esters (all of which couple a to the C=0 group), and amides (which couple a to the nitrogen) by running it in the presence of H2. ° Under these eonditions it is likely that the excited Hg abstracts H from H2, and that the remaining H- abstracts H from the substrate. 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

Trost et alJ2 also explored the compatibility of di-, tri-, and tetrasubstituted allenes with their intermolecular Alder-ene protocol. Multiple substituents present the opportunity for a mixture of products to arise from differing regio- and chemoselectivity. 1,1-Disubstituted allenes were coupled to methyl vinyl ketone with excellent chemo-selectivity only when one set of /3-hydrogens was activated by an cy-ester or amide (Equation (69)). If the /3-hydrogens were of similar acidity, a mixture of products was obtained, as in the coupling of allenol 103 with methyl vinyl ketone dienes 104 and 105 are produced in a 1.3 1 mixture (Equation (70)). 

Electroreduction of aliphatic amides in the presence of chlorotrimethylsilane gives coupling products and this reaction is useful for the synthesis of a-amino ketones (Scheme 22) [41]. In this reaction, the formation of an Mg salt promotes the coupling of two anion radical centers. 

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