Intramolecular Barbier Reactions

An alternative, low-yielding route to the tetrahydro-l/7-3-benzazepines 223 from the amides 222 via an intramolecular Barbier reaction has been reported (Equation 29) <2005H(65)2925>. The other significant products from this reaction were the deiodinated noncyclized compounds. 

Although Curran s rate data for the reduction of radicals to organosamar-iums allow for an element of predictablity,2 problems can arise when multifunctional substrates are involved. For example, in the attempted intramolecular Barbier reaction of alkyl iodide 13, treatment with Sml2 results in the formation of side product 15 in addition to the expected product cyclohexanol 14 (Scheme 3.7).8 In this case, the p-keto amide motif in 13 is reduced at a rate competitive with alkyl iodide reduction, indicating that there are likely two mechanistic pathways through which the reaction proceeds a thermodynamic pathway initiated by reduction of the R I bond providing the... 

Exceptionally clean cyclization can be accomplished by utilizing conjugated enones as precursors for the Barbier reaction (equation 43). High diastereoselectivity is achieved in these reactions, and under the mild conditions required for cyclization the TMS ether protecting group remains intact. It is also interesting that a neopentyl halide is effective in the cyclization. This result would appear to exclude an 5N2-type displacement of an organic halide by a samarium ketyl as a possible mechanism for the Smh-promoted intramolecular Barbier reaction. 

Curiously, the relative stereochemistry between the carboxylate and the adjacent hydroxy group in the Sml2-mediated intramolecular pinacolic coupling reaction is opposite to that observed in the intramolecular Barbier reactions and ketone-alkene reductive coupling reactions discussed previously (compare... 

Tetraglyme (2,5,8,11,14-pentaoxapentadecane) has been used in the hy-droxymethylation of aldehydes via addition of benzyl chloromethyl ether in the presence of Sml2. Addition of tetraglyme suppresses the competitive pinacol formation, presumably by a complex formation with Sml2 as evidenced by a purple color [25]. Tetraglyme has also been used as a cosolvent in an intramolecular Barbier reaction involving an iodoaldehyde and a THF solution of diiodosamar-ium [26]. 

Diiodosamarium induced an intramolecular Barbier reaction, under mild conditions (room temperature), in the presence of a catalytic amount of iron tris(dibenzoylomethane [Fe(DBM)3]. In this way many bicyclic tertiary alcohols were prepared. These conditions were also convenient for the cyclization... 

One of the limitations of the intramolecular Barbier reaction of a>-haloalkyl p-keto ester substrates, as developed in our laboratory, was the inability to utilize secondary alkyl halides. Under the aprotic conditions utilized, a retroaldol reaction transpired that led to undesired transformations of the intermediate generated (Eq. 2). 

The little-used Kihara indole synthesis is an example of an intramolecular Barbier reaction applied to the synthesis of 3-phenyl- and 3-aIkyl-3-hydroxyindolines, which can be dehydrated to the corresponding indoles (Scheme 1) [1], In some cases, the dehydration of indoline to indole was spontaneous. The major byproduct in the Kihara indole synthesis is deiodination of the starting ortho-io6o aniline. Some examples are shown in Scheme 1 (equations 2-5). 

The following paragraphs discuss intramolecular Barbier reactions with different recipient functional groups ... 

It may be of interest here to report that attempts to prepare patchouli-alcohol via an intramolecular Barbier reaction of a haloketone with magnesium were unsuccessful [76], [77] but that executing this reaction in a sealed tube with sodium in THF at 100 °C gave the required product (see Sect 3.2 for Na-Barbier reactions) ... 

Studies on the stereochemistry of these intramolecular Barbier reactions in which mono- and tetra-substituted cyclohexanones and several other cycloal-kanones were involved revealed a preference for the cis ring closure. Some preliminary conclusions were drawn regarding the mechanism of the Barbier reaction (see also Sect. 4.4). 

Haloacetals in Barbier Reactions. An interesting variation of the intramolecular Barbier reaction as discussed in the previous paragraph was the use of haloacetals. 

An intramolecular Barbier reaction which might shed more light on the mechanism of this type of reactions is the following one in which aromatic halo-phosphinates are involved [85] ... 

Acetals can be used as the solvent for organometallic compounds but in certain cases a Barbier-type reaction may take place (see Sect. 2.4.2 for intramolecular Barbier reactions with haloacetals). 

A quite different version of the Li-Barbier reaction, which was recently published [38], has already been referred to on p. 86 n-Butyllithium was used to generate the intermediate lithium compound from iV-(2-iodobenzyl) phenacyla-mine, achieving the first ever reported intramolecular Barbier reaction, with an aryl halide. As was the case with the iodonitrile (p. 86 of this Section), the metal-halogen exchange reaction of the n-butyllithium proved to be much faster than the carbonyl addition reaction. 

Intermediacy of Organometallics. It is illustrative to quote some of the final words of a rather recent paper [68] on the magnesium-induced cyclization of 2-(3-iodopropyl)-cycloalkanones, an intramolecular Barbier reaction (see also Sect. 2.4.2, p, 46 in chap. 2) ... 

Almost twenty years earlier mechanically activated magnesium had been used [22] in an intramolecular Barbier reaction of diethyl 5-bromo-3-bromo-methylpentylphosphonate in THF, leading to 1-phosphabicyclo [2,2.1] heptane 1-oxide in 11% yield ... 

Recently reactions of dienemagnesium reagents with l,n-dibromoalkanes and bromocyanoalkanes were published [43] which led to the formation of spiroalkanes and -ketones in an intramolecular Barbier reaction through an intermediately formed halo- or cyano-substituted Grignard reagent ... 

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