Barbier approach

Grigg and coworkers developed bimetallic domino reactions such as the electro-chemically driven Pd/Cr Nozaki-Hiyama-Kishi reaction [69], the Pd/In Barbier-type allylation [70], Heck/Tsuji-Trost reaction/1,3 dipolar cycloaddition [71], the Heck reaction/metathesis [72], and several other processes [73-75]. A first example for an anion capture approach, which was performed on solid phase, is the reaction of 6/1-134 and 6/1-135 in the presence of CO and piperidine to give 6/1-136. Liberation from solid phase was achieved with HF, leading to 6/1-137 (Scheme 6/1.30) [76]. 

Madsen and Hyldtoft proposed a novel zinc-mediated domino reaction to give functionalized dienes.267 Using a Barbier reaction, different approaches of interesting compounds have been reported vitamin D3 analogs, 1 bicy-... 

A variety of functionalised organic halides have been found to be compatible with the Sml2-mediated Barbier and Grignard reactions. For example, ben-zyloxymethyl chloride can be used in conjunction with Sml2 for the alkoxy-methylation of ketones.120 This addition has been found to work well even for hindered ketones such as 101, an intermediate in White s 1987 approach to 2-desoxystemodinone (Scheme 5.70).121 It is important to note that, in contrast to analogous organometallics, decomposition via a-elimination is not observed. 

Williams used Sml2 to mediate the Barbier coupling of functionalised a-halo-2-methylazoles with aldehydes.127 For example, coupling of iodide 106 with aldehyde 107 proceeded in good yield to give 108, thus illustrating the value of the method for a future approach to phorboxazole A (Scheme 5.75). 

Curran described an efficient, approach to the BCD ring system of the penitrem indole alkaloids that exploits a Sml2-mediated radical-anionic sequence.11 Treatment of iodide 17 with Sml2 and HMPA gave 18, the product of radical cyclisation-intermolecular Barbier addition, in satisfactory yield (Scheme 6.6). 

Styrene is an important olefinic substrate in Heck reactions a styrene carrying an alkoxysilyl moiety should open up a more convergent approach to the synthesis of the title compounds. Silane 15 was prepared via Barbier-Grignard reaction of p-bromostyrene with triethoxymethyl silane [21]. 

In developing the method described here, many of the techniques used by others were considered, and some of them were incorporated into the final method. In the overall approach, this method most closely resembles that of Barbier etal. (5) in which hydrocarbons were measmed and partially characterized by compound classes. We should add, however, that the method discussed here includes different overall measurement techniques and is applicable to microgram quantities in contrast to the milligrams available to the above workers. 

Ketones. Sonochemical Barbier reaction allows direct access to ketones from the condensation of lithium carboxylates and organohalides in the presence of Li. An interesting approach to 2-furanyl ketones involves in situ deprotonation of furan with nascent t-BuLi (generated with the assistance of ultrasound) and subsequent reaction with RCOOLi. 

In many cases, sonochemical methods avoid a distinct preparation step of the organometallic, and one-step Barbier procedures find an improved efficiency. A complete analysis of many reactions is not easy, since the mechanical and chemical effects of sonication are superposed. In many cases, however, some confirmation of the sonochemistry rules can be found, and the reactions correspond to the third type. The discussions given in the descriptive part below are not limited to the sonochemical results, but relate, whenever possible, to the conventional parent reactions, to permit an easy comparison of the respective merits of each approach. 

Effects of Sonication. In a subsequent study [92] on the accelerating effect of ultrasonic waves on the Barbier reaction of benzaldehyde, 1-bromo-heptane and lithium, Luche and co-workers could not state that cavitation was the only important phenomenon. No information had been obtained on the effects of non-cavitational shock waves or the frequency. The authors came to the conclusion that the work published had to be considered as an approach for a better knowledge of the interaction of ultrasound with a heterogeneous system, but the problem in its generality could not be considered as fully understood. 

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