Barbier additions alkyl halides

Recently, the iron-promoted Barbier-type addition of alkyl halides to aromatic aldehydes has been reported (Equation (26)).326 According to the proposed mechanism, the initial step is the formation of an alkyl radical, which can be reduced to the corresponding carbanion. This carbanion nucleophile can react, while coordinated to the iron pentacarbonyl complex, with the corresponding aldehyde. This stoichiometric method is limited with respect to substrate scope and yield. The same authors have also developed the Reformatsky-type addition of cr-halosub-stituted carbonitriles to aldehydes and ketones in the presence of iron pentacarbonyl.3... 

Inanaga showed that the presence of HMPA also accelerates the Barbier addition of alkyl halides to ketones and significantly improves the yield of the adducts.14 He also found that HMPA was a useful additive in the Sml2-mediated synthesis of lactones from bromo esters and ketones (Scheme 2.5). Since Inanaga s pioneering work, the Barbier reaction employing Sml2 HMPA... 

In 1980, Kagan reported the first detailed study of the Sml2-mediated Barbier reaction,98 and showed the clear difference in behaviour of primary, secondary and tertiary alkyl halides in such couplings (Scheme 5.64). It is important to note that the reaction of z -BuMgBr or. s-BuMgBr with ketones typically leads to reduction of the carbonyl group, so the use of Sml2 to mediate such additions is noteworthy. 

In 1993, Molander found that in the presence of catalytic Fe(III) salts, Sml2 mediates intramolecular Barbier additions to esters to give cyclic ketones (or cyclic hemiketals, if they prove to be stable).135 Double addition to the ester is not observed, nor is reduction of the cyclic ketone product. This suggests that the tetrahedral intermediate, a samarium alkoxide of a cyclic hemiketal, is partially stable to the reaction conditions and the ketone group is not revealed until work-up. Molander found that both alkyl and allyl halides could be used in the additions (Scheme 5.83).135... 

The sequential nucleophilic substitution Barbier additions are controlled by the diflerent rates of reduction of the alkyl halides or the tether length, if the... 

Molander has also studied the Sml2-mediated double Barbier additions of alkyl dihalides to ketoesters.22,23 These impressive anionic-anionic, inter-molecular-intramolecular sequences require the use of Nil2 as an additive and irradiation with visible light and allow access to a range of bicyclic and tricyclic systems. The reactions proceed by reduction of the more reactive alkyl halide, intermolecular Barbier addition to the ketone, lactonisation and a second Barbier addition to the lactone carbonyl (Scheme 6.18).22... 

One of the main issues with the use of magnesium and zinc as inexpensive co-reductants is their reactivity with alkyl halides. Also, additives such as TMSOTf are relatively expensive. In an attempt to address these limitations, Namy utilised mischmetal (La 33%, Ce 50%, Nd 12%, Pr 4%, Sm and other lanthanides 1%) as the stoichiometric reductant for the regeneration of the Sm(II).31,32 This reagent system provides an important alternative since it does not require the use of additives and mischmetal is relatively inexpensive. This system has been utilised successfully in Barbier and Reformatsky reactions, halide reductions and pinacol couplings (Scheme 7.7).31,32... 

Samarium diiodide is a one electron reductant that is capable of reducing both alkyl halides and carbonyl compounds. The rate of the reduction depends on the nature of the substrate and the reaction conditions. The mechanism of the addition of alkyl halides to carbonyls was extensively studied. In case of the samarium Grignard processes, it was concluded that the reaction proceeds through an organosamarium intermediate. However, the mechanism of the samarium Barbier processes is not fully understood and there is no unambiguous evidence in favor of any of the possible pathways. 

These examples again have some mechanistic implications in that they appear to rule out cyclization via 5n2 displacement of the halide by a samarium ketyl. However, one cannot distinguish between a mechanism based on allylsamarium addition to the carbonyl versus an electron transfer mechanism as outlined for the alkyl hdide substrates above. Both mechanisms allow for isomerization of the double bond (via 1,3-allylic transposition in the case of an allylmetallic, or configurational instability in an allylic radical in a diradical coupling mechanism) and also provide reasonable routes for generation of butadiene. Further mechanistic work is clearly required in order to provide a more detailed understanding of all of these intramolecular Barbier-type reactions. 

Barbier coupling reaction Metal-mediated addition of alkyl, allyl or benzyl halides to carbonyl compounds. 38... 

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