Ketones Barbier syntheses with

The Sml2-mediated Barbier cyclisation of alkyl halides bearing cyclic ketones has been used extensively to form bicyclic systems.103 When the alkyl halide tether is attached a to the cyclic ketone carbonyl, cyclisation typically proceeds to give syn products. For example, Cook used such a cyclisation in a two-directional strategy for the synthesis of tetracyclic polyquinines treatment of bis-bromide 111 with Sml2 in THF-HMPA gave diol 112 in 68% yield (Scheme 5.80).133... 

Najera s methyl BTFP sulfone 319 has been applied in the synthesis of terminal olefins [106] (Scheme 103, cf Scheme 78 and the relevant text). Reaction of 319 (1 molar equivalent) with aldehydes or ketones (1.1 molar equivalent) could be conveniently carried out using P4-f-Bu (1.2 molar equivalent) or KOH-TBAB (9 molar equivalent) imder Barbier conditions. Some examples are shown in Table 25. 

The Barbier reaction has been used for the synthesis of alcohols that were difficult to prepare by normal Grignard reagent techniques. This is particularly true for the preparation of cyclic alcohols from halogenated ketones. Several researchers [49-51] have shown that cyclobutanols and cyclopentanols can be prepared in good yields from <5- and y-iodo- and bromoketones in either solvents with Mg or Mg/HgCl2 [Eq. (17)]. 

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. 

The achiral allylation of aldehydes has also been achieved in recyclable ionic liquids" and in water." Greener still is the corresponding Barbier allylation" of aldehydes and ketones with allylic bromides in water mediated by tin metal. The atom efficiency of this reaction is actually less than the corresponding tetraallyltin allylation of (say) benzaldehyde (65% and 83%, respectively) because of the loss of the heavy bromine atom, but this neglects the synthesis of tetraallyltin, which is prepared from allyl bromide or chloride. A particularly intriguing recent advance with this thoroughly studied reaction is the use of nano-tin " (Scheme 5.8.17). 

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... 

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... 

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. 

A soln. of benzaldehyde and tetra- -butylammonium bromide in DMF cooled to — 10° in a cell fitted with a foamy Ni cathode surrounding a sacrificial Zn rod anode, and electrolyzed at a constant current of 0.3 A with bromotrifluoromethane bubbling through the soln. for ca. 4-5 h 2,2,2-trifluoro-l-phenylethanol. Y 95%. The dissolving (sacrificial) zinc anode is essential in what is effectively an electro-assisted Barbier-type synthesis. The reaction is general with aldehydes, and reasonable yields are obtained with easily reducible ketones (preferably with added TMEDA). F.e.s. S. Si-bille et al.. Tetrahedron 45, 1423-8 (1989). 

As shown in a model study (Fig. 60), extension of the Barbier procedure to carboxylic acids is unsatisfactory for ketone synthesis. On the other hand, lithium carboxylates and lithium and alkyl chlorides lead to good to excellent yields when sonicated in THF. An application of such a procedure to the preparation of long chain alkyl ketones is given in Ch. 9, p. 361. The use of chlorides is required. The reason seems to be the necessity of a rapid formation of the organometallic (p. 217). When this formation is slow, with bromides or iodides, complex electron transfers take place and imexpected couplings result. 

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