Barbier-type additions

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... 

Barbier-type additions are attractive methods because the required allylic halide precursors are often commercially available, and are more stable than a preformed organometallic reagent (Equation 5). The required 2-alkoxycarbonyl allylic zinc reagents can be prepared from zinc powder. Lactonization tends to occur under the reaction conditions however, the diastereoselectivity of the reactions tends to be poor with 3-substituted reagents. Zinc-mediated Barbier-type allylations are mild enough for use with functionalized substrates and can utilize both aldehydes and ketones as substrates. 

The one-pot Barbier-type addition of alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, or allenylchromium compounds to aldehydes or ketones is known as the Nozaki-Hiyama-Kishi (NHK) reaction. An excellent review by Furstner published in 1999 detailed the exhaustive literature on the carbon-carbon bond formations involving organochromium(III) reagents. This chapter will present major developments and examples of recent carbon-carbon bond formation methodology and improvements as well as their use in natural products synthesis since 1999. 

In a separate report, preparation of the lithium enolate of 31 in the presence of indium trichloride and benzaldehyde provided a 77% yield of 32 with complete trans selectivity however, sequential addition of indium trichloride and benzaldehyde provided Barbier-type products. Organotin enolates have also been used in a Darzens-type... 

Usually, in situ preparation in Barbier-type carbonyl additions are carried out with the bromides or chlorides even sterically blocked carboxylates, such as 2,4,6-trimethylbenzoic acid esters, can be used successfully15. The reactions are accelerated by ultrasound16,17. 

Cleghorn LAT, Cooper IR, Grigg R, MacLachlan WS, Sridharan V (2003b) Additive effects in palladium-indium mediated Barbier type allylations. Tetrahedron Lett 44 7969-7973... 

Additionally, various intra- and intermolecular iron-catalyzed Barbier-type reactions of organosamarium com-pounds and carbonyl electrophiles have been reported by Molander and co-workers. 

An electroreductive Barbier-type allyla-tion of imines (434) with allyl bromide (429) also occurs inaTHF-PbBr2/Bu4NBr-(Al/Pt) system to give homoallyl amine (436) (Scheme 151) [533]. The combination of Pb(II)/Pb(0) redox and a sacrificial metal anode in the electrolysis system plays a role as a mediator for both cathodic and anodic electron-transfer processes. The metals used in the anode must have a less positive anodic dissolution potential than the oxidation potentials of the organic materials in order to be present or to be formed in situ. In addition, the metal ion plays the role of a Lewis acid to form the iminium ion (437) by associating with imine (435) (Scheme 151). 

The same polymeric arenes that served as metallation catalysts in equation 119 can also be used for silylation in Barbier-type reactions (equation 131). The polymer is presumably converted to a lithium arene adduct that activates metallic lithium for metallation of the halogenated substrates, before addition of an electrophile to achieve the synthetic goal. Equations 132-135 illustrate some of the cases investigated. The products can be characterized by the usual spectroscopic methods . 

The Reformatsky reactions are run following two basic procedures (i) a two-step Grignard-type protocol which first involves the formation of an organometallic zinc eno-late derivative followed by addition of the electrophile, and (ii) a Barbier-type protocol where the bromoester and the electrophile are simultaneously exposed to the action of zinc metal. 

An interesting aspect of the Bi-mediated Barbier-type allylation is that the reaction can be conducted in aqueous media. When the reaction is carried out using metallic bismuth powder in water, addition of an equimolar amount of potassium fluoride improves the yield of homoallyl alcohol (Equation (40)).74 The reaction is also compatible with hydroxyl and carboxyl groups of the carbonyl substrates. When succinaldehydic acid, 4-oxopentanoic acid,... 

Indium trichloride promotes catalytically the addition of alkynylstannanes to aldehydes (Table 25).42 Metallic indium also mediates the same Barbier-type coupling between alkynyl halides and aldehydes or ketones to give secondary or tertiary propargyl alcohols (Table 26). Secondary alcohols can be oxidized in situ according an Oppenauer process.395 Thus, alkynyl ketones have been prepared from aldehydes via an indium-mediated alkynylation reaction followed by an indium-mediated Oppenauer oxidation. They are also obtained via an indium-mediated alkynylation of the relevant acyl chlorides (Table 27).396... 

The intramolecular variant of the chrDmium(II) ion mediated Barbier-(jiignard-type addition reaction was first described by Still and Mobilio in an elegant synthesis of ( )-Aspeidiol (122 R = H). Chro-mium(II)-mediated cyclization of (121 R = Bn) provided a 4 1 mixture of (122) and (123) in 64% yield (equation 50). The relative topicity of the process is Ik. This result is in acco with a syncliiud chair transition structure (124) in which both hydrocarbon chains diverge from the reacting centers pseudo-... 

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