Ketones Barbier-type reactions

Barbier-type reactions of alkyl iodides with ketones can be performed with Sml2 when Fe(III) compounds are used as catalysts [22]. Particularly efficient for the intramolecular reaction of co-iodo ketones such as compound 16 turned out to be Fe(dbm)3 (dbm = l,3-diphenyl-l,3-propanedionato). The latter is an air-stable, THF-soluble, non-hygroscopic complex that can be very easily prepared from... 

In analogy with iron-catalyzed Barbier-type reactions with Sml2 (cf. Scheme 8.5), intramolecular nucleophilic acyl substitutions (SNt) can be used to prepare cyclic ketones from esters [50]. An illustrative example is shown in Scheme 8.13 [51], Again, tris(l,3-diphenyl-l,3-propanedionato)iron(III) [Fe(dbm)3] is used as the catalyst. Compound 40 is obtained as one racemic diastereoisomer. 

Organopalladium complexes do usually not transfer a formal carbanion to aldehydes or ketones, but intramolecular Barbier-type reactions of this kind have been observed (Scheme8.2). 

Another important metal for Barbier-type reaction is samarium. Allyl bromide reacts with a ketone and Sm to give the homoallylic alcohol. Samarium compounds, such as Sml2, can also be used with allylic halides. 

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). 

The indium-mediated Barbier reaction has certainly become one of the most popular reactions for creating a carbon-carbon bond under aqueous conditions and has led to spectacular developments in recent years. Compared to other metals, indium is resistant to oxidation, hydrolysis, and has a very low first ionization potential (5.79 eV, in contrast to the second one which is quite normal) which confers on it a remarkable reactivity in Barbier-type reactions. In 1991, Li and co-workers reported the first allylation of aldehydes and ketones mediated by indium in water without any additives or special activation [133]. In particular, the use of indium allowed reactions with acid-sensitive compounds [134] or the preparation of complex carbohydrates such as deaminated... 

Of interest also is the aqueous Reformatsky cross-coupling reaction between a-halo ketones or aldehydes and carbonyl compounds in the presence of zinc, tin and indium. Like the Barbier-type reactions, indium was found to be the most efficient metal and it strongly reduced undesirable side reactions such as the reduction of the halide [134]. As usual in aqueous reactions implicating carbonyl compounds, lanthanum(III) triflate promoted the reaction [146]. 

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... 

In the presence of HMPA, allylic sulfones react with Sml2 and ketones to give a Barbier-type reaction (Scheme 26). Much lower yields are obtained if the reagents are not thoroughly degassed, and in the absence of HMPA [63]. 

This Barbier-type reaction with CH2Ii can be used to obtain iodohydrins and cyclopropanols. Highest yields of iodohydrins obtain when the ratio of ketone/ CH7.l1/Sml2 = 1 3 2. 

Alkylation. Zinc-mediated reaction of cinnamyl chloride with aldehydes and ketones in aqueous THE" and Barbier-type reactions involving perfluoroalkyl... 

Samarium(n) iodide-promoted intramolecular Barbier-type reactions have also been employed to produce a multitude of cyclic and bicyclic systems. Molander and McKie have enployed an intramolecular Barbier-type reductive coupling reaction to promote the formation of bicyclo[/n.n. l]alkan-l-ols from the corresponding iodo ketone substrates in good yield (eq 15). ... 

A very convenient hydroxymethylation process has been developed based on the Smiz-mediated Barbier-type reaction. Treatment of aldehydes or ketones with benzyl chloromethyl ether in the presence of SmIz provides the alkoxymethylated products in good to excellent yields. Subsequent reductive cleavage of the benzyl ether provides hydroxymethylated products. Even ketones with a high propensity for enolization can be alkylated by this process in reasonable yields. The method was utilized by White and Somers as a key step in the synthesis of ( )-deoxystemodinone (equation 27). ° This particular ketone substrate resisted attack by many other nucleophilic reagents (such as methyllithium) owing to competitive enolate formation. 

The Barbier-type reaction of aldehydes and ketones with allyl halides (485) in the presence of Smh, leading to homoallyl alcohols (486), has received recent interest as a one-step alternative to the Grignard reaction. However, the reactions require the use of stoichiometric amounts of the reducing Sm(III) species. Recently, the electroreductive Barbier-type allylation of carbonyl compounds in an Sml2-mediated reaction has been developed [569]. The electrolysis of (485) is carried out in a DMF-SmCl3-(Mg/Ni) system in an undivided cell to give the adduct (486) in 50 85% yields (Scheme 168) [569]. Electrosynthesis of y-butyrolactones has been achieved by the reductive coupling of ethyl 3-chloropropionate with carbonyl compounds in the presence of a catalytic amoxmt of SmCfi [570]. 

Table 2.4. Results of Barbier-type reactions of allyl bromide or 3-methylallyl bromide with aldehydes and ketones as patented by Knorr [42]. The branch-chained structures of products, obtained with 3-methylallyl bromide (with an asterisk (x)), have been corrected (see page 25). (n.r. no yields reported)...

Lithium in Barbier-Type Reactions 87 Table 3.5. Yields of ketones from reaction of various nitriles with organobromides and lithium [23]... 

The preparation of tri-l-adamantylmethanol, which failed via the one-step Barbier-type reaction with Br-Ad and (Ad) (Ad) ketone (vide supra) was brought about by the one-step reaction of 2.8 equivalents of Br-Ad with one equivalent of the methyl ester of 1-adamantylcarboxylic acid yield 27%. 

These authors used a commercial coarse-ground manganese, which is easily available and cheap. The solvent of choice for Barbier-type reactions with this metal was ethyl ethanoate. Yields of reactions with aliphatic ketones were excellent. In order to get such good yields with aliphatic aldehydes 10% ZnCl2, CdCl2, or HgCl2 had to be added. 

Such problems may be found to be even more serious in Barbier-type reactions where the ketone is present in the reaction mixture from the very beginning. 

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. 

Kitazume and Ishikawa have published a number of communications on the regiospecific zinc mediated perfluoroalkylation of a variety of substrates [148-151]. A compilation of these results appeared in 1985 [152] (Scheme 71). Secondary alcohols are available in moderate yield by reaction of perfluoro-alkyl halides (RpX) with aldehydes as the result of a modified Barbier-type reaction [148-152]. However, reaction with ketones gave low yields of the expected tertiary alcohols, although the yields could be doubled by reaction in the presence of a bis[7i-cyclopentadienyl]titanium(II) catalyst, which was prepared in situ by reduction of the dichloride with zinc in the presence of ultrasound. 

Lithium bromide and lithium chloride can also enhance the reactivity of Sml2 in THF (Fuchs et ah, 1997 Miller et ah, 2000). Addition of anhydrous LiCl and LiBr to Sml2 resulted in rate enhancement and better yields in pinacol coupling of cyclohexanone. In the Barbier type reaction of 1-iodobutane with 2-octanone, the presence of LiBr and LiCl resulted in the formation of pinacol coupling product (diol from 2 moles of 2-octanone) as the major product rather than the nucleophilic addition of halide to ketone (eq. (52), table 8). 

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. 

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 reaction of r/cm-dihaloalkanes with alkyl or aryl aldehydes and ketones under Barbier conditions with Mg/Hg can be used to prepare unsaturated derivatives in a Wittig-type reaction. Some Japanese researchers [71] show that styrene and substituted styrenes, as well as octenes, can be prepared in yields as high as 75% using diiodomethane and the corresponding aldehydes [Eqs. (32) and (33)]. 

Nitriles and esters are also unreactive in Smh-promoted Barbier reactions. A very useful procedure for lactone synthesis has been developed making use of this fact. Treatment of 7-bromobutyrates or 8-bro-movalerates with Smh in THF/HMPA in the presence of aldehydes or ketones results in generation of lactones through a Barbier-type process (equations 25 and 26). This nicely complements the -metaUo ester or homoenolate chemistry of organosamarium(III) reagents described above (Section 1.9.2.1), and also the Reformatsky-type chemistry promoted by Sml2 (Section 1.9.2.3.2). Further, it provides perhaps the most convenient route to 7- and 8-carbanionic ester equivalents yet devised. 

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