Esters Barbier additions

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 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... 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

There seems, however, to-day, to be overwhelming evidence that the French chemists were correct and that citronellol and rhodinol are two very similar, but chemically different, compounds, citronellol being represented by the formula (1) and rhodinol by formula (2). Considerable evidence of this is to be found in the work of Barbier and Locquin. Starting from the acetic esters of ordinary d-citronellol and rhodinol from oil of geranium or rose, they attached hydrogen chloride to the double bond, and obtained the same additive product according to the equations — ... 

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. 

Although organosamariums can react with esters and lactones, they preferentially undergo addition to aldehydes or ketones. This allows organosamariums bearing an ester functionality to be generated and used in intermolecular Barbier couplings (Scheme 5.74).98,99... 

Intramolecular Sml2-mediated Barbier Reactions Involving Addition to Esters and Amides... 

The Sml2-mediated Reformatsky reaction provides a useful alternative to traditional versions of the reaction as it proceeds under mild, homogeneous conditions, with high chemo- and diastereoselectivity. Although a-halo esters are the most common substrates for the reaction, in principle any a-halo carbonyl compound can be employed in the reaction. The reactions are most often carried out by the addition of Sml2 to a 1 1 mixture of the a-halocarbonyl compound and the coupling partner. These are often referred to as Barbier conditions (see Section 5.4). 

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. 

Evidence for a radical coupling mechanism (as opposed to a carbanionic carbonyl addition mechanism) in the intramolecular Smh-promoted Barbier reactions has come from studies on appropriately functionalized substrates in the 3-keto ester series. It is well known that heterosubstituents are rapidly eliminated when they are adjacent to a carbanionic center. Indeed, treatment of a 3-methoxy organic halide (suitably functionalized for cyclization ) with an organolithium reagent leads only to alkene (equation 48). No cyclized material can be detected. On the other hand, treatment of the same substrate with Sml2 provides cyclized product and a small amount of reduced alcohol, with none of the alkene detected by gas chromatographic analysis (equation 49). ... 

The first enantiospecific total synthesis of (+)-ajmaline [(+)-17] was developed by Cook et al. 161). D-(+)-Tiyptophan methyl ester (126) was converted enantiospecifically, via intermediate 127, to the optically active )-N -benayltetracyclic ketone (-) 107, which was then transformed into the ot,P-unsaturated aldehyde (-)-128. When compound (-)-128 was stirred with 3-bromo-4-hq>tene in die Barbier Grignard process conditions the 1,4-addition products 129a,b... 

Simple esters did not lead to addition products. However, the Barbier procedure was effective, even at atmospheric pressure, when the ester was activated by an electron-withdrawing group ethyl trifluoropyruvate and hexafluoroacetone were respectively obtained from diethyl oxalate and ethyl trifluoroacetate (Fig. 9). 

As mentioned in Sect. 2.3, Inanaga and co-workers have demonstrated that Barbier-type reactions of organic halides with carbonyl compounds are promoted by addition of HMPA [16]. They reported a mild convenient method for the direct synthesis of lactones from bromo esters and ketones or aldehydes by using a HMPA-promoted Barbier-type reaction with Sml2 (Scheme 13). They also found that the SmI2/THF-HMPA system was highly useful for the generation of... 

With Iodine. As is the case with magnesium (see Sect. 5.3.1) iodine has been applied [58] in a Barbier-type reaction with propargyl bromide and cyclohexanone. More recently, in a Reformatsky reaction under sonication [59], use was made of iodine-activated zinc. In the absence of iodine the sonicated mixture of zinc, ethyl 2-bromo-ethanoate and acetophenone reacted slowly and gave no addition product recovery of the ester and the ketone were quantitative. 

Manganese metal (commercial quality) without any special preparation allows Barbier or Reformatsky reactions, respectively, to be performed from allylic bromides and a-halogenoesters. The use of manganese is of real preparative interest since these reactions have a large scope of application and occur under mild conditions to give high yields of 1,2-addition products (16]. It should be noted that numerous functional ketones (keto-esters, keto-acetals, w-chloro-ketones) were converted into the corresponding functional alcohols very efficiently (Schemes 13.13 and 13.15). 

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