Barbier-reaction condition

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]. 

Masked lithium homoenolates of type XII are of interest in synthetic organic chemistry and can be considered as three-carbon homologating reagents with umpolung reactivity [122]. The lithiation of the jS-chloro orthoester 147 with lithium in the presence of a catalytic amount of DTBB, under Barbier-reaction conditions, and using carbonyl compounds as electrophiles, followed by acidic hydrolysis, led to lactones 149 as reaction products, the masked lithium homoenolate 148 bang proposed as a reaction intermediate (Scheme 2.20) [123]. 

In 1991, Whitesides etal. reported the first application of aqueous medium Barbier-Grignard reaction to carbohydrate synthesis through the use of tin in an aqueous/organic solvent mixture (Eq. 8.48).106 These adducts were converted to higher carbon aldoses by ozonolysis of the deprotected polyols followed by suitable derivatization. The reaction showed a higher diastereoselectivity when there was a hydroxyl group present at C-2. However, no reaction was observed under the reaction conditions when there was an /V-acctyl group present at the C-2 position. 

In 1991, Li and Chan reported the use of indium to mediate Barbier-Grignard-type reactions in water (Eq. 8.49).108 When the allylation was mediated by indium in water, the reaction went smoothly at room temperature without any promoter, whereas the use of zinc and tin usually requires acid catalysis, heat, or sonication. The mildness of the reaction conditions makes it possible to use the indium method to allylate a methyl ketone in the presence of an acid-sensitive acetal functional group (Eq. 8.50). Furthermore, the coupling of ethyl 2-(bromomethyl)acrylate with carbonyl compounds proceeds equally well under the same reaction conditions, giving ready access to various hydroxyl acids including, for example, sialic acids. 

The use of substoichiometric amounts of an arene (naphthalene or biphenyl) was first studied in the reaction of bromobenzene and benzaldehyde with sodium, under Barbier-type reaction conditions The possibility of using a substoichiometric amount of DTBB... 

Barbier-type reaction conditions ) in THF at —30°C (—78°C for phenylacetonitrile) yielding, after hydrolysis, the expected compounds 20 (Scheme 8) . ... 

Thus, chloro enamines 113, either under Barbier-type reaction conditions (—40 °C) or in a two-step process (hthiation at —90 °C and Sg reaction at —90 to —40 °C), were lithiated with DTBB (5%) and finally hydrolyzed, after condensation with different electrophiles, giving the expected functionalized enamines 114 (Scheme 44) °. ... 

Functionalized propargyUc organolithium compounds are probably involved in the transformation of chlorinated ethers or amines 211 into polyfunctionalized products 212, which were achieved through a DTBB-catalyzed lithiation under Barbier-type reaction conditions (Scheme 73). The reaction failed for the corresponding thioethers (Y =... 

Barbier-type reaction conditions) to yield, after hydrolysis with phosphate buffer and final esterification with methanol under PTSA catalysis, the corresponding functionalized methyl esters 229 (Scheme 77) . 

A special case of functionalized aryllithium reagents appears when the corresponding aryl group bears a ketal moiety at the benzylic position due to the lability of the benzyUc carbon-oxygen bonds. However, working under Barbier-type conditions and using naphthalene (10%) as the electron carrier catalyst, the reaction of chlorinated materials 242 afforded, after hydrolysis with water, the corresponding polyfunctionalized products 243 (Scheme 81). ... 

In the case of chlorobenzyl chlorides 504, the same process had to be performed under Barbier-type reaction conditions. These dichlorinated materials 504 were lithiated with DTBB in a catalytic amount (4%) in the presence of different electrophiles to give, after final hydrolysis with water, the corresponding difunctionalized products 505 (Scheme 141) ". ... 

Benzamides 565 without any substituent at the para position reacted with lithium and a catalytic amount of naphthalene under Barbier-type reaction conditions (in the presence of a carbonyl compound) in THF at —78 °C to give, after hydrolysis, the corresponding dearomatized products 566 (Scheme 151). When 567 was used as starting material with a 4-ferf-butyl group in p-position, and using 3-pentanone as electrophile and under the same reaction conditions, the fraw -product 568 was the only one isolated . 

The allylic alcohol 176, prepared by the hydrolysis of allylic bromide 173 <2004JME1423>, was oxidized with MnOz to the corresponding aldehyde 177, which reacted easily with allyl bromide in the presence of zinc under Barbier s conditions to give the adduct 178 (Scheme 25). Of particular note is the fact that the peroxide bridge was not sensitive to Zn under these reaction conditions <20050L5219>. 

Although organomagnesium compounds are among the earliest reported organometallic compounds they were regarded as curiosities until 1900. At that time Victor Grignard, then a graduate student, worked in the laboratory of Professor Barbier at the University of Lyon in France. His task was to optimize conditions for what is now known as the Barbier reaction (equation 1). ... 

Since the reaction with the aldehyde occurs faster, it is best to carry out this reaction under Barbier-like conditions in general, the base is added to a mixture of the aldehyde and sulfone. 

In some cases, such as with the allylic bromosulfone 17, the best reaction conditions to add to imines are obtained under Barbier conditions, reaction in this manner gives the unsaturated aminosulfone 18. Treatment with catalytic potassium hydride, results in a 5-endo-trig cyclization to form the pyrrolidine 19 in 65% yield (Scheme 1.8).25,26... 

Barbier reactions can be highly regioselective depending on the conditions of allylation, they could proceed via Sg2 - or SEZ-pathway.256 270 272 Good diastereoselectivity can also be obtained by using a chiral electrophile (Equations (158)-( 160)).258 273-275... 

Table 5.1 Conditions employed in Sml2-mediated Barbier reactions for alkyl halides.

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... 

E = H) resulting from a lithium—hydrogen exchange in intermediate 198. This hydrogen abstraction from the reaction medium, probably from THF at the a-position, has already been observed in other cases for very reactive organolithium intermediates. The use of Barbier-type reaction conditions did not improve the obtained results124. 

When (Z)-6-chloro-l-phenylhex-l-ene 200 was lithiated under DTBB catalysis, the cyclized product 202 was always obtained either at —78 or at —30 °C. After the first chlorine-lithium exchange a carbolithiation took place to yield the intermediate 201, which by reaction with electrophiles, E, and final hydrolysis gave products 202 (Scheme 60). At —78 °C the reaction under Barbier-type conditions did not work. Also in this case, the corresponding reduced product (202 with E = H) was the main by-product detected. 

Functionally substituted benzylic, allylic, and vinylic compounds containing alkoxides, esters, ethers, nitriles, or amides can be reacted with halosilanes under Barbier conditions using HMPT to yield C- and O-silylated products, 1,2- or 1,4-addition products, as well as reductive dimers. Radical and anionic intermediates are postulated, based on SET reactions from the metal, and multiple silated species can be obtained. The use of the TMSCl-Mg-HMPT system has been extensively investigated by Galas group [85] at the University of Bordeaux, and their work has greatly advanced the science of the Barbier reaction with silanes. 

Much milder reaction conditions in the Barbier-type reaction can be employed by utilizing iron(III) salts as catalysts. For example, when 2 mol % FeCb is added to Smh, the Barbier reaction between a primary organic iodide and a ketone is complete within 3 h at room temperature (equation 19). The iron(III) is probably reduced by Smh to a low-valent species which serves as an efficient electron transfer catalyst, thus lowering the activation energy for the coupling process vide infra). 

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