Primary alkyl reactions with alkenyl halides

Transition metal-catalyzed cross-coupling reactions between vinyl organometallic compounds and unactivated alkyl halides that can be usually performed with palladium, nickel and cobalt are of particular synthetic interest [37-39]. Recently, the groups of Cahiez [48] and Cossy [49] concurrently reported the first iron-catalyzed reaction of alkenyl Grignard compounds with primary and secondary alkyl halides (X=Br, I) (Scheme 5.15). The two protocols basically differ in the iron source... 

Alkyl halides are readily reduced to the corresponding hydrocarbon by Sml2 in the presence of a proton source. The ease with which halides are reduced by Sml2 follows the order I > Br > Cl. The reduction is highly solvent dependent. In THE solvent, only primary alkyl iodides and bromides are effectively reduced however, addition of HMPA effects the reduction of aryl, alkenyl, primary, secondary, and tertiary halides (eq 1). Tosylates are also reduced to hydrocarbons by Sml2. Presumably, under these reaction conditions the tosylate is converted to the corresponding iodide which is subsequently reduced. ... 

Carbanions are classified as soft nucleophiles. It would be expected that they would be good nucleophiles in Sn2 reactions, and this is generally true. The reactions of aryl-, alkenyl-, and alkyllithium reagents with primary alkyl halides and tosylates appear to proceed by Sn2 mechanisms. Similar reactions occur between arylmag-nesium halides (Grignard reagents) and alkyl sulfates and sulfonates. Some examples of these reactions are given in Scheme 7.2. 

The alkylation reactions proceed with moderate to good yields with primary iodides (Entries 1,3,6, and 7) or bromides (Entries 2,4, and 5) in the absence of additives or polar solvents. The only byproducts detected were small amounts of ( )-a- and P-A -phthaloyl alanines and ( )-A -phthaloyl aspartic acid. In a few instances, small amounts of A Vinylphthalimide, resulting from double decarboxylation, were also detected. Shorter reaction times were required when the reaction was performed at 40 °C. Secondary iodides also gave alkylated derivatives (Entries 8 and 9). However, no alkylation was observed when more hindered substrates, such as a-cholestanyl iodide and menthyl iodide or bromide were used. These halides were recovered unchanged or suffered elimination to afford mixtures of alkenes after several days at room temperature. On the other hand, no alkylation took place with methyl p-toluenesulfonate, ethyl triflate, and propylene oxide under the same reaction conditions. Similarly, alkenyl and aiyl halides were unreactive with nickelacycles. 

Cook reported the iron/diphosphine-catalyzed alkylation of arene-, heteroarene-, and alkeneamides with primary alkyl halides (Eq. 19) [53] and, shortly after, the alkylation of aromatic amides with benzyl chlorides and secondary alkyl bromides (Eq. 20) [54]. The reaction with primary alkyl bromides proceeded well for aromatic, heteroaromatic, and alkenyl amides despite using phenylmagnesium bromide as a base, the reaction with benzyl chlorides proceeded well under air. As previously observed by Nakamura [28, 34], the slow addition of the Grignard reagent was crucial in order to achieve high yields, presumably because of the competing homocoupling [29]. Secondary alkyl bromides and iodides could be employed in the reaction with benzamides, but acyclic secondary alkyls underwent partial isomerization to the linear alkyl. 

Primary alkyl chlorides and bromides can be distinguished from aryl and alkenyl halides by reaction with sodium iodide in acetone (Finkelstein reaction) ... 

The reaction of amides with alkyl or alkenyl halides leads to the elimination of hydrogen halide and formation of (more highly) unsaturated compounds in mixtures with primary and secondary amides the composition depends on the structure of the organic moiety... 

Alkyl and Alkenyl Bromides. LiBr has been extensively used as a source of bromide in nucleophilic substitution and addition reactions. Interconversion of halides and transformation of alcohols to alkyl bromides via the corresponding sulfonate or trifluoroacetate have been widely used in organic synthesis. Primary and secondary alcohols have been directly converted to alkyl bromides upon treatment with a mixture of Triphenylphosphine, Diethyl Azodicarboxylate, and LiBr. ... 

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