Barbier type alkylation

Figure 2 Plausible mechanism of Barbier-type allylation and alkylation with Sm and iodine (cat.).

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... 

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... 

Barbier-type C-alkylation of imines can be carried out with alkylstrontium halides generated from strontium metal and alkyl halide.38 IV-Alkylation competes, and RSrI is strongly nucleophilic, as shown by a-alkylation of imines derived from enolizable... 

Aryl radical cyclization.10 Sml2 in HMPA/THF at 25° can effect cyclization of l-allyloxy-2-iodobenzene to a Sm(III) intermediate (a) that can be trapped by electrophiles, including aldehydes or ketones. The report suggests that a similar mechanism operates in the Barbier-type coupling generation of an alkyl radical followed by formation of RSml2, which adds to a carbonyl compound to form an adduct that is hydrolyzed to an alcohol. 

Reformatsky reactions have a bad reputation as being difficult to entrain. To the authors experience, however, the reactive donors such as alkyl bromo-acetates do not pose particular problems even under rather conventional conditions. Commercial zinc dust activated by pre-treatment with either iodine of preferentially with cuprous chloride (i.e. Zn(Cu)) readily inserts into these halocarbonyl compound with formation of the corresponding zinc enolates. Protocols 1 and 2 describe prototype examples for Reformatsky reaction in the conventional two-step or Barbier-type set-up, respectively. 

The coupling reaction of a-keto esters with allyl, propargyl, and allenyl halides using indium metal in aqueous solvents affords a-hydroxy-y,<5-unsaturated esters (Equation (28)).197,198 1,3-Dicarbonyl compounds undergo efficient carbonyl allylation reactions in an aqueous medium through a Barbier-type reaction (Equation (29)). The reaction is general and a variety of 1,3-dicarbonyls has been alkylated using allyl bromide or allyl chloride in conjunction with indium.199... 

These examples again have some mechanistic implications in that they appear to rule out cyclization via 5n2 displacement of the halide by a samarium ketyl. However, one cannot distinguish between a mechanism based on allylsamarium addition to the carbonyl versus an electron transfer mechanism as outlined for the alkyl hdide substrates above. Both mechanisms allow for isomerization of the double bond (via 1,3-allylic transposition in the case of an allylmetallic, or configurational instability in an allylic radical in a diradical coupling mechanism) and also provide reasonable routes for generation of butadiene. Further mechanistic work is clearly required in order to provide a more detailed understanding of all of these intramolecular Barbier-type reactions. 

Alkylation of carbonyl compounds. The Barbier-type reaction is mediated by Dyl2 in THE The reagent, possessing a reactivity pattern similar to that of (thfl Tmlj, must be prepared just before use. 

Organolithiums. Barbier-type condensation occurs when an alkyl nitrile and a carbonyl compound are treated with LDTBB. Trialkyl phosphates are converted to alkyllithiums in the same way. ... 

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

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. 

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. 

The Barbier reaction is that between an alkyl halide and a carbonyl compound in the presence of magnesium (Barbier, 1898). In Barbier-type reactions, an organometallic intermediate species is supposed to be produced in the presence of the substrate. As this organometallic intermediate is usually highly reactive with water, Barbier-type reactions were previously conducted after careful exclusion of water. 

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