Lithium Barbier reaction

Sonochemical techniques have been used predominantely in the lithium Barbier reaction [142-145]. 

In the last 10 years, the Barbier reaction method has been utilized more with other metals than with magnesium. The number of papers published on the lithium-Barbier reaction is three to four times that of magnesium [149-157]. Reactions can be carried out at lower temperatures than possible with Mg-Barbier reactions and yields are often very high with fewer by-products. Other metals of note are samarium, in the form of its diiodide [158-165], and zine [166-169], the metal of choice for the pre-Barbier one-step reaction, and the classic Reformatsky reaction. In situ reactions have been reported for A1 [170], Ce [171], Cd [172,173], Ga [174], Hg [175], In [176], Mn [177], Pb [178-180], Sb [181-183], Sn [184,185], and Ti [186]. An excellent paper by Li reviews the Barbier reactions of many metals in aqueous media [187]. 

This lithium process is the analogue of the magnesium-based Barbier reaction [135],... 

An extension of the Barbier reaction to carboxylates salts [90] affords a simple access to furanyl ketones [91]. By sonication of a mixture of a lithium carboxylate, an alkyl chloride and lithium in THE at room temperature, the intermediate organolithium reagent forms rapidly, then generates the 2-furanyl lithium which adds to the carboxylate group in high yields. The method constitutes an example of a reaction cascade , in which several intermediates are generated sequentially (Scheme 3.13). 

The reaction with alkyl- and aryllithium reagents has also been carried out without preliminary formation of RLi a mixture of RX and the carbonyl compound was added to a suspension of lithium pieces in THF.364 Yields were generally satisfactory. The magnesium analog of this process is called the Barbier reaction,365 Lithium dimethylcopper Me2CuLi... 

An intramolecular 2-alkylation was also observed in a sulfonyl free radical induced addition-cyclization <95SL763>. A key intermediate in a new synthesis of pallescensin A (a biologically active labdane diterpene) was prepared by a cationic cyclization reaction with a furan <95SYN1141>. The sonochemical Barbier reaction was extended to carboxylate salts. 2-Furanylketones 10 can be obtained by sonication of a mixture of furan, lithium carboxylate, an alkylchloride, and lithium in THF <95JOC8>. 

Fig. 17.47. Reductive lithiation of a carbamoyl chloride to the (dialkylamino)carbonyl lithium compound A and its immediately following reaction with a carbonyl compound (Barbier reaction) leading to alcohol B.

There are very few studies of the Barbier reaction mechanism with magnesium as the metallic source. However, with the discovery that the reaction will often proceed to a greater extent with other metals such as lithium, some good mechanistic studies have been conducted. The focus of most of these studies has been the reaction of an alkyl or aryl halide with a ketone. The conclusions drawn from these studies are considered to be valid for magnesium as well, and they will be referenced in this section. 

The Barbier reaction discussed in Sect. 3.3.2 was not accelerated by addition of LiCl. In the literature there are only a few examples where lithium salts are ben-... 

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. 

The Barbier reaction, extensively studied by Luche and co-workers (see Luche et al., 1990), is similar to the Grignard synthesis except that it proceeds in one step. In a recent variation that has now become common practice, lithium is used instead of magnesium. The scope of the reaction, rather restricted so far, can be widened by conducting it in an ultrasonic bath. No special precautions or equipment are needed, and even impure solvents can be used. 

Lithium in Barbier-Type Reactions 91 Table 3. Yields of Li-Barbier reactions under ultrasonic irradiation [29]... 

A quite different version of the Li-Barbier reaction, which was recently published [38], has already been referred to on p. 86 n-Butyllithium was used to generate the intermediate lithium compound from iV-(2-iodobenzyl) phenacyla-mine, achieving the first ever reported intramolecular Barbier reaction, with an aryl halide. As was the case with the iodonitrile (p. 86 of this Section), the metal-halogen exchange reaction of the n-butyllithium proved to be much faster than the carbonyl addition reaction. 

The Barbier reaction is generally formulated in terms of formation of an organo-metallic intermediate, followed by addition of this species to the carbonyl compound in the usual manner. However there is little mechanistic evidence to bolster this point of view, and in one instance of an analogous reaction using lithium instead of magnesium, evidence against such a process has been reported. 

Effects of the Activation of the Metals. In the last decade several reports on the mechanism of the Barbier reaction have appeared in which not magnesium but lithium and zinc were the metals applied. 

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. 

In the following, attention will be focussed on the metals magnesium, zinc and lithium respectively in their reactions with organohalides. Unfortunately only in a limited number of the reports on the reactions of those metals, are Barbier reactions involved. 

The use of lithium in Barbier reactions was successfully introduced at the end of the 1960s. A considerable number of such reactions have been published since then (see Sect. 3.3). 

This Section will cover these new developments as well as the older, more traditional, ones. As was the case with magnesium and lithium in the previous Sections, it should be mentioned that also not all the examples of zinc-activation presented here have been applied in Zn-Barbier reactions. Several of them come from other organic synthetic procedures such as the Reformatsky or the Simmons-Smith reaction. 

In general, in the reaction of benzyl halide with lithium, the yield of benzyl-lithium is low since the Wurts coupling reaction proceeds. How ever, with the addition of ketones to this reaction system and ultrasound irradiation, Barbier reaction then proceeds. It is believed that this reaction yields benzyllithium as an intermediate and the benzyllithium reacts with ketone [23]. 

Lithium or zinc, besides magnesium as the metal atom, can be used as shown in eq. (3.36). The Barbier reaction with lithium is usually carried out under an inert gas atmosphere, at room temperature or below, for about two hours. The yield is usually 80% or less. However, in the reactions under ultrasonic irradiation, the yields are improved as shown in eq. (3.36). For example, benzaldehyde reacts with -heptylbromide under ultrasonic irradiation for only ten minutes to give an alcohol in 94% yield as shown in eq. (3.37) [84]. 

Recently, different a-lithioenamines 75 have been prepared by chlorine-lithium exchange from the corresponding chloroenamines 74 and reacted with electrophiles to give functionalized enamines 76. A mixture of lithium and a catalytic amount of DTBB was used as the lithiating reagent (Scheme 2.12) [67]. The process can be performed either step-by-step (lithiation-reaction with the electrophile) at -90 °C or under Barbier-reaction conditions at -40 °C. In the case of using carbonyl compounds as electrophiles, after acidic hydrolysis, a-hydroxyketones were obtained, intermediates 74 acting in this case as acyl anion equivalents [41]. 

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