Ketones 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... 

Molander has also studied the Sml2-mediated double Barbier additions of alkyl dihalides to ketoesters.22,23 These impressive anionic-anionic, inter-molecular-intramolecular sequences require the use of Nil2 as an additive and irradiation with visible light and allow access to a range of bicyclic and tricyclic systems. The reactions proceed by reduction of the more reactive alkyl halide, intermolecular Barbier addition to the ketone, lactonisation and a second Barbier addition to the lactone carbonyl (Scheme 6.18).22... 

The Barbier reaction will be defined in the classic sense and will include any one of the following reaction sequences (1) addition of an organic halide to a mixture of magnesium and an electrophilic coreactant such as a ketone, (2) addition of a mixture of an organic halide and coreactant, over time, to magnesium, or (3) the combination of all three reagents at once. 

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... 

Compounds with carbon-nitrogen multiple bonds were also successfully used in the Barbier procedure. Allylic groups add to imines in high yields (> 77% in the examples published), even enolizable substrates, possibly due to the low basicity of the medium.37 Additions to nitriles occur in THF in the presence of the zinc-silver couple.38 Terpenic ketones were prepared by this method. 

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... 

In 1980, Kagan reported the first detailed study of the Sml2-mediated Barbier reaction,98 and showed the clear difference in behaviour of primary, secondary and tertiary alkyl halides in such couplings (Scheme 5.64). It is important to note that the reaction of z -BuMgBr or. s-BuMgBr with ketones typically leads to reduction of the carbonyl group, so the use of Sml2 to mediate such additions is noteworthy. 

A variety of functionalised organic halides have been found to be compatible with the Sml2-mediated Barbier and Grignard reactions. For example, ben-zyloxymethyl chloride can be used in conjunction with Sml2 for the alkoxy-methylation of ketones.120 This addition has been found to work well even for hindered ketones such as 101, an intermediate in White s 1987 approach to 2-desoxystemodinone (Scheme 5.70).121 It is important to note that, in contrast to analogous organometallics, decomposition via a-elimination is not observed. 

Dihaloalkanes have also been used in Sml2-mediated Barbier reactions. For example, Sml2 mediates the addition of diiodomethane to a range of aldehydes and ketones (Scheme 5.71).122 In the case of additions to aldehyde 102, high diastereocontrol is observed. 

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 Aldehydes and Ketones... 

An interesting addition of a methylene moiety across a double bond of an unsaturated ketone under Barbier conditions has been reported by some French chemists [Eq. (16) 48]. 

The addition reactions of TMSCl to ketones under Barbier conditions, with HMPT as solvent, yield a variety of products, depending on the eqivalents of TMSCl used and the type of groups on the ketone. Table 3 illustrates the addition reactions for acetophenone and some of its analogues. 

Another plausible mechanism fa- the Sml2-mediated Barbier reaction involves coupling of ketyl and alkyl radictds in a diradical coupling mechanism. Alternatively, addition of an alkyl radical to a Sm -activated ketone carbonyl may be invoked. ... 

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... 

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... 

Addition of allylic halides to ketones or aldehydes in the presence of Zn in aqueous media, analogous to Barbier reaction or in the absence of solvents (see Toda). 

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... 

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