[7439-95-4]  · Mg  · Magnesium  · (MW 24.31)

(formation of organomagnesium compounds; reduction of metal halides; reduction of organic functional groups)

Physical Data: mp 651 °C; bp 1107 °C; d 1.74 g cm-3.

Preparative Methods: widely commercially available in forms (most commonly turnings and powders) and in purity (98-99.95%) suitable for many applications in organic synthesis. For some applications magnesium powder or activated magnesium is freshly prepared via the reduction of a magnesium(II) salt or the evaporative deposition of magnesium metal. The commercially available magnesium-anthracene adduct [86901-19-1] also provides a highly reactive form of magnesium metal.

Handling, Storage, and Precautions: most freshly prepared magnesium powders and organomagnesium compounds are pyrophoric.

Formation and Reactions of Organomagnesium Compounds.

The carbon-carbon bond forming reactions of organomagnesium (Grignard) reagents via their reaction with carbon electrophiles constitute one of the cornerstones of organic synthesis (eq 1). Much is known about this most famous of organometallic reactions. The mechanisms of Grignard formation2-13 and reaction14,15 have been studied extensively. Structural16,17 and thermochemical18 data of the organomagnesium compounds have been reported.

Many novel organomagnesium compounds have been prepared. These include dimetallic species19,20 such as methylenedimagnesium dibromide (see also Magnesium Amalgam)21 and 1,n-(dimagnesio)alkanes such as 1,4-bis(bromomagnesio)pentane, an intermediate which has been used for the stereoselective conversion of esters to trans-1,2-disubstituted cyclopentanols (eq 2).22 Remarkably, even a soluble trimagnesium compound was recently prepared under relatively routine reaction conditions (eq 3).23

The form of the magnesium metal employed is often critical to the successful formation of the organomagnesium reagent. For simple primary or secondary alkyl bromides or iodides, and simple aryl or vinyl bromides or iodides, commercially available magnesium turnings or powders of modest purity (>98%) are often suitable. If necessary, activating the surface of the magnesium with iodine,1,24 dibromoethane,1,25 or ultrasound26 treatment, or employing ultrapure magnesium metal,27 is usually sufficient to facilitate Grignard reagent formation with such substrates. In the case of many organochlorine or organofluorine compounds, as well as unreactive bromides and iodides, a more reactive form of magnesium must be employed. Three practical methods have been developed for the preparation of highly reactive magnesium (active magnesium) for use in organic synthesis. A highly reactive magnesium slurry is prepared via the evaporative deposition of magnesium in THF using a relatively simple preparative apparatus.28-30 Magnesium halides are reduced by Potassium metal,31,32 or better Lithium Naphthalenide,33,34 to afford an active magnesium powder often referred to as Rieke magnesium. Magnesium metal can be activated by treatment with anthracene,35 or the magnesium-anthracene adduct,36 which is in equilibrium with the finely divided metal powder, can be used directly.

The formation of allyl or benzylic Grignard species is often accompanied by dimerization of the allylic or benzylic halide. Indeed, this reductive dimerization can be preparatively useful using the classical Grignard-forming reaction conditions,37 but to avoid it, an active magnesium is typically employed.38,39 Oppolzer40 reported a comparison of the three methods discussed above in a 1984 study of the metallo-ene reaction. The magnesium variant of the metallo-ene reaction41 features the formation and subsequent cycloisomerization of an allylmagnesium chloride from an allylic chloride. As shown in eq 4, magnesium-mediated cyclization and trapping with the electrophilic oxygen source Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (i.e. MoOPH) proceeds in 55% yield with magnesium slurry prepared by evaporative deposition, in 55% yield with Rieke magnesium, and in 56% yield with magnesium-anthracene.

The extent to which these activated forms of magnesium have expanded the range of substrates suitable for formation of organomagnesium species cannot be overemphasized. For example, alkyl fluorides are very poor substrates for the classical Grignard conditions. In contrast, treatment of octyl fluoride with Rieke magnesium32,34 affords the corresponding organomagnesium reagent which reacts with Carbon Dioxide in 89% yield (eq 5). The chloride shown in eq 6 is benzylic, thus prone to dimerization with classical magnesium sources, and requires formation of a dianionic intermediate. Magnesium powder is reported to afford the diorganomagnesium species in only 43% yield. In contrast, the dichloride reacts with magnesium-anthracene in 92% yield.36,42 Cyclopropylmethyl compounds are prone to rearrange via ring opening to the n-butenyl isomers. Formation of the Grignard reagent from cyclopropylmethyl bromide under classical conditions followed by trapping with carbon dioxide affords 4-pentenoic acid (eq 7). In contrast, treatment of cyclopropylmethyl bromide at -78 °C with the magnesium slurry prepared via evaporative deposition affords mostly cyclopropylacetic acid (92% of the product mixture, 78% yield) after trapping with carbon dioxide.28

The chemistry of organomagnesium compounds is extraordinarily rich and diverse. It is impossible to detail comprehensively their many reactions with classical organic electrophiles (e.g. aldehydes, ketones, carboxylic acid derivatives, carbon dioxide, C-N multiple bonds, epoxides, alkyl halides, etc.) within the space limitations here. Fortunately, several standard texts give a good account of these procedures.43,44 The following paragraphs highlight several of the many less routine uses of these reagents. For example, in addition to the reaction with traditional carbonyl electrophiles, organomagnesium reagents add efficiently to certain mixed orthoformates to afford acetals. For example (eq 8), n-butylmagnesium bromide adds to phenyl diethyl orthoformate in 90% yield.45

The one-pot combination of alkyl halide, magnesium metal, and carbon electrophile is often referred to as the Barbier reaction.46 This strategy is particularly appropriate for the cyclization of substrates containing both reacting partners within their structure. The intramolecular reaction of halo ketones can afford cyclized products, but often in only modest-to-good yield with magnesium.47 For example (eq 9), the cycloheptanone derivative cyclizes to the hydroazulene ring skeleton in 54% yield. Lithium/ultrasound,48,49 Lithium, Tin(II) Chloride,50 and Samarium(II) Iodide51 may offer suitable alternative reagents for such cyclizations.

The complementary magnesium-mediated cyclizations of cyanoiodoalkanes can be an efficient reaction. For example, the iodonitrile shown (eq 10) undergoes magnesium-mediated cyclization to form the relatively sterically congested 2,2-disubstituted cyclohexanone in 71% yield.52

Magnesium is an alternative to zinc metal for effecting the Reformatsky reaction and has been used in the synthesis of b-keto esters.53 For example (eq 11), t-butyl bromoacetate is condensed with cyclohexanone in 80% yield.54

Organomagnesium species can effect the carbometalation of alkenes and alkynes.55,56 The more common variants, however, are the copper-catalyzed reactions, a subject which has been comprehensively reviewed by Lipshutz and Sengupta.57 For example (eq 12), the Ethylmagnesium Bromide/Copper(I) Bromide combination effects net syn addition across 1-octyne. The resulting alkenyl metal species can be stereospecifically trapped by a variety of electrophiles, including Allyl Bromide (85%) and 1-heptene oxide (94%).58 This reaction constitutes a useful stereoselective alkene synthesis. Dichlorobis(cyclopentadienyl)titanium also catalyzes the net syn addition of organomagnesium reagent across alkynes.59 (See also the corresponding organolithium and organocopper compounds for alternative reagents.57)

Organomagnesium reagents undergo efficient copper-catalyzed conjugate addition reactions.57 For example (eq 13), n-butylmagnesium bromide undergoes CuBr-Me2S-catalyzed addition to acrolein in the presence of Chlorotrimethylsilane and Hexamethylphosphoric Triamide (HMPA) to afford the (E)-silyl enol ether in 89% yield (96% E).60

Organomagnesium reagents undergo copper-catalyzed reaction with alkyl, allyl, vinyl, and aryl halides or sulfonates, and with epoxides.57 For example (eq 14), n-butylmagnesium bromide undergoes copper-catalyzed substitution of the propargyl methyl ether to afford an allene.61 The substitution proceeds in high chemical yield and with good stereochemical control.

A number of other transition metals catalyze interesting reactions of organomagnesium reagents.59,62 Of particular novelty is the titanium-catalyzed hydromagnesiation of alkenes. For example (eq 15), vinylcyclohexanol transmetalates with ethylmagnesium bromide in the presence of catalytic Cp2TiCl2 to afford, after capture by carbon dioxide, the g-lactone shown in 58% yield.63-65

Reductions with Magnesium.

Magnesium is a common agent for reducing a variety of transition metal salts,66-68 for example the reduced titanium reagent (Titanium(IV) Chloride-Mg) used widely in carbonyl coupling reactions.69 Magnesium itself effects the reductive dimerization (pinacol coupling) of ketones70 and enones71 (see also Magnesium Amalgam and TiCl4-Mg). Magnesium effects the reductive dimerization of organotin oxides72 (eq 16) and dialkylantimony bromides (eq 17).73

Magnesium has been used for the reduction of 1,1-dibromoalkanes,74 although reductive dimerization has been found to compete in some cases,75,76 and in the formation of Ph3P=CCl2 from triphenylphosphine and carbon tetrachloride.77 Magnesium has been used as an alternative to n-Butyllithium or lithium amalgam for the conversion of 1,1-dibromoalkenes to alkynes (eq 18).78

Magnesium reacts with amines to form magnesium amides,79 and with alcohols to form magnesium alkoxides. In the latter context, magnesium has been used as a drying agent for alcohols,80 but the combination of magnesium-methanol has also found significant utility as a selective reducing agent for certain organic functional groups (e.g. conjugated ketones, esters, nitriles, amides).81 The combination of Cadmium Chloride-magnesium in aqueous THF also shows interesting selective functional group reductions, e.g. the selective 1,2-reduction of enones (eq 19) and the selective reduction of an epoxide in the presence of an allylic acetate (eq 20).82,83

The combination of magnesium-Chlorotrimethylsilane has been used for the reductive silylation of 1,1-dibromides,84 conjugated trienes,85 heterocycles,86 and, as shown in eq 21, certain chloro-substituted enynes.87 Magnesium has been also used as a reactive metal electrode in an electroreductive silylation of alkenes.88

1,3-Dienes form reactive complexes with magnesium.89 In this capacity, active magnesium has been used for the reductive silylation and dialkylation of certain conjugated 1,3-dienes. For example (eq 22), treatment of 1,4-diphenyl-1,3-butadiene with Rieke magnesium affords the magnesium-diene complex. Addition of Dichlorodimethylsilane affords the cis-diphenylsilacyclopentene in 66% yield.90

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James M. Takacs

University of Nebraska, Lincoln, NE, USA

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