Reformatsky-type additions

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... 

The Reformatsky-type addition of organozinc reagents to imines is a well-known process for / -aminoester synthesis. However, this transformation often affords... 

A substoichiometric protocol for Reformatsky-type addition of a-halo esters, a-halo ketones, a-halonitriles, and a-halophosphonates to carbonyl compounds has been developed via samarium-mediated reaction.150 p-Hydroxy esters and P-hydroxynitriles have been obtained in good to excellent yields. 

Sml2 Reformatsky methodology is now sufficiently robust that Linhardt employed Reformatsky-type addition to carbon electrophiles in a solid-phase synthesis of C-sialosides (see Chapter 7, Section 7.3).146 The use of a-halo ketones in intermolecular Reformatsky reactions is less common and is typically restricted to simple coupling partners. For example, Ohta showed that... 

Linhardt employed Reformatsky-type additions to carbon electrophiles (see Chapter 5, Section 5.5) in a solid-phase synthesis of C-sialosides.43 Immobilised sialyl donor 9 was treated with Sml2 in the presence of ketone and aldehyde... 

Metallic nickel was found to react with halo-acetonitriles to form cyanomethyInickel halides, which underwent Reformatsky-type additions to aldehydes which afforded -hydroxynitriles. 

In a series of studies [97-99] the one-step - Reformatsky type - addition reaction to carbon-carbon double and triple bonds was investigated with ultrasound irradiation in which zinc was used together with activated allylic bromides such as... 

Reformatsky-Type Additions of Haloacetonitriles to Aldehydes Mediated by Metallic Nickei... 

Scheme 4-318. Reformatsky-type addition of ester enolates to carbonyl compounds catalyzed by iron(II).

Additions of the Reformatsky-type reagents to aldehydes can also proceed in ionic solvents (Scheme 108).287 Three ionic liquids have been tested 8-ethyl-l,8-diazbicyclo[5,4,0]-7-undecenium trifluoromethanesulfonate ([EtDBU][OTf]), [bmim][BF4], and [bmim][PF6]. The reactions in the first solvent provided higher yields of alcohols 194 (up to 93%), although results obtained for two other ionic liquids were also comparable with those reported for conventional solvents. 

Asymmetric additions of Reformatsky-type reagents to nitrones 258a and 258b have also been reported (Scheme 139). The reagents were prepared in situ from ZnEt2 and the corresponding iodoacetic acid ester. Diisopropyl (R,R)-tartrate 262 was employed as a chiral inductor. Enantioselectivities varied significantly the best results were obtained at 0 °C when a nitrone was added to the reaction mixture over a 2 h period. 

Reformatsky-type reactions. This Ni(0) can effect selective addition of halo-acetonitriles to aldehydes. 

E Aidol-Type Additions of Ester Anions and the Reformatsky Reaction... 

In addition to aldehydes and ketones, a variety of other functional groups can be used as electrophiles in Reformatsky-type reactions.1-3 Among them, nitriles play a prominent role since they lead to p-oxoesters after hydrolytic work-up (the primary enamines initially formed can only be isolated when stabilized by extended conjugation or by conformational means, cf. Table 14.1, entry 4). 

Particularly challenging is the use of chiral ligands in order to impose enan-tiocontrol on a Reformatsky reaction. Although preparatively useful levels of asymmetric induction have been described in the recent literature by using enantiomerically pure amino alcohol ligands43 this reaction has not yet reached a similar level of perfection as the enantioselective addition of other organozinc reagents to aldehydes in the presence of the same type of additives. Some selected examples of stereoselective Reformatsky type reactions which delineate the present state of the art are summarized in Scheme 14.6. 

Apart from the role of mischmetal as a co-reductant in SmL-catalysed reactions such as pinacolization (Section 8.3.3) mischmetal has been found to be a useful reactant in its own right. Thus a combination of mischmetal and additives (1,2-diiodoethane or iodine) has been active in Reformatsky-type reactions. Though giving slightly lower yields than Sml2, they are less air-sensitive there is the further handicap of requiring slow (dropwise) addition of reactants. 

In addition to serving as a useful replacement for lithium or magnesium in Barbier-type coupling reactions, SmI also provides advantages over zinc as a reductant in Reformatsky-type coupling reactions (equation 54).The latter only performs well when an activated form of zinc is utilized, and thus the homogeneous conditions afforded by SmI provide the advantage of enhanced reactivity under milder conditions. 

Two particular reactions are characteristic of the (3-functional alkyltin compounds. First, conjugative electron attraction by the functional group makes C-C=X a good leaving group, and the Sn-C bond has an enhanced reactivity in substitution (e.g. hydrolysis) and addition where C=X is a nitrile, ketone, ester, or amino group, the compounds add across the N=C bond in isocyanates, and undergo Reformatsky-type reactions with carbonyl compounds.91-92... 

Treatment of a-iodo ketone and aldehyde with an equimolar amount of Et3B yielded the Reformatsky type adduct in the absence of PhaSnH (Scheme 21), unlike ot-bromo ketone as shown in Scheme 15 [22], Ethyl radical abstracts iodine to pro-duee carbonylmethyl radical, which would be trapped by EtsB to give the corresponding boron enolate and regenerate an ethyl radical. The boron enolate reacts with aldehyde to afford the adduct. The three-component coupling reaction of tert-butyl iodide, methyl vinyl ketone and benzaldehyde proceeded to give the corresponding adduct 38, with contamination by the ethyl radical addition product 39. The order of stability of carbon-centered radical is carbonylmethyl radical > Bu > Pr > Ef > Me . 

The starting reagent is the Reformatsky-type. In this case, instead of adding to a carbonyl group, addition is to the nitrile. See Reformatskv Reaction for a discussion of reagent. 

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