Trimethylaluminum1

Me3Al

[75-24-1]  · C3H9Al  · Trimethylaluminum  · (MW 72.10)

(Lewis acid with methylation ability;2-8 can effect useful C-C bond forming reactions including carboalumination,14 methylenation,15,16 and cyclopropanation;17 can serve as a precursor to various sophisticated Lewis acids27 or chiral catalysts28,29)

Physical Data: mp 15 °C; bp 127 °C; d 0.743 g cm-3 (30 °C).

Solubility: freely miscible with saturated and aromatic hydrocarbons; reacts violently with H2O and protic solvents.

Form Supplied in: clear colorless liquid; widely available as a neat liquid in a stainless container or 1-2 M solution in hydrocarbon solvents (hexane, heptane, toluene).

Analysis of Reagent Purity: brochures from manufacturers describe an apparatus and method for assay.

Handling, Storage, and Precautions: indefinitely stable under an inert atmosphere. Neat trimethylaluminum or concentrated solutions are highly pyrophoric. Solutions that are more dilute are not pyrophoric and are safer to handle. The nonpyrophoric limits are 11 wt % in hexane and 14 wt % in heptane. Halogenated hydrocarbons should be avoided because of possible explosive reactions sometimes observed for mixtures of CCl4 and organoaluminums.

Methylation.

The Lewis acidity of Me3Al has been used to activate electronegative atoms, such as oxygens, halogens, and other functional groups. It also methylates the resulting electrophilic species. Bridgehead methylation of bicyclo[2.2.2]octyl bromide (eq 1)2a and regioselective methylation of terpene derivatives3a are early examples that show these features. More recent examples include methylation of bromododecahedrane2b and unusual aromatic substitutions of N-hydroxyaniline derivatives (eq 2).3b Substitution reactions of glycosyl fluorides,4 benzyl or glycal acetates,5a,b and sulfonyl groups6 at activated positions can be effected with Me3Al (eqs 3-6).

Boron Trifluoride Etherate alters the reactivity of g- or d-lactols toward Me3Al (eq 7).7 Me3Al traps isocyanates generated from certain sigmatropic rearrangements (eq 8).8

In connection with the asymmetric Sharpless epoxidation, the regioselective cleavage of 2,3-epoxy alcohols and their derivatives has been well studied. In contrast to organocuprates, which provide 1,3-diols via C-2 attack, trialkylaluminiums give 1,2-diols via C-3 attack (eq 9).9a,b It should be noted that substrates with a phenyl group at C-3 undergo the methylation largely in retentive manner.9c,d n-Butyllithium catalyzes the regioselective b-addition to a- and b-alkoxy epoxides (eq 10).10a,b This regioselectivity also holds for epoxy acids (eq 11).9d A mixed reagent, Me3Al and water (5:3), effects the regioselective and stereospecific methylation of g,d-epoxy acrylates (eq 12).10c,d

Asymmetric reactions via regioselective ring cleavage of chiral unsaturated acetals have been reported. The regioselectivity is sensitive to the solvent employed (eq 13).11a,b Recent developments have been described by Ishihara et al.11c,d

Cross couplings of organoaluminums with vinyl halides,13b enol phosphates,12a carboxylic acid chlorides, and thioesters12b,c are achieved by employing Pd or Cu catalysts (eqs 14 and 15). Unsaturated N-acylsulfoximines13a or C-alkylated purine nucleosides are thus prepared (eq 16).13b

Other useful C-C bond formations using Me3Al include the carboalumination of 1-alkynes. The procedure with Trimethylaluminum-Dichlorobis(h5-cyclopentadienyl)zirconium (eq 17) has broad applicability,14a-c and has been used in many natural product syntheses (eq 18).14d Direct manipulation of the alkenylalanes provides a stereoselective route to trisubstituted alkenes (eq 19).14e,f

The Tebbe reagent (see m-Chlorobis(cyclopentadienyl)(dimethylaluminum)-m-methylenetitanium) is conveniently generated in situ by the reaction of Dichlorobis(cyclopentadienyl)titanium and Me3Al, which, in contrast to the Wittig reaction, methylenates ester carbonyls to provide enol ethers (eq 20).15 See also Trimethylaluminum-Dichlorobis(h5-cyclopentadienyl)titanium. A triad reagent, Diiodomethane-Zinc-Me3Al, effects chemoselective methylenation of aldehydes (eq 21),16 while the combination of CH2I2 and Me3Al (or other organoaluminums) leads to cyclopropanation of alkenes (eq 22).17 The regiochemical course of the latter reaction is markedly different from the Simmons-Smith reaction. Regioselective addition of polyhalomethanes to alkenes is induced by Me3Al (eq 23).18

Carbon-heteroatom bond formation is often facilitated by the co-addition of Me3Al. Aminolysis of esters is achieved by the action of amines or their hydrochlorides in the presence of Me3Al (eq 24),19a-c the latter procedure being particularly useful when volatile amines are concerned (see Dimethylaluminum Amide). The technique is also applicable to the synthesis of acid hydrazides.19d Selenoformamides are available from the corresponding formamides by reaction with (Me2Al)2Se, generated in situ from (Bu3Sn)2Se (eq 25).20 The corresponding tellurium chemistry works also. Me3Al-LiSPh offers a tandem Michael-aldol approach to the oxahydrindene subunit of avermectins (eq 26).21a

The steric course of reduction of cyclic imines is impressively reversed by a mixed reagent, Lithium Aluminum Hydride-Me3Al (eq 27).21b

Rearrangements.

Allyl vinyl ethers undergo [3,3]-sigmatropic rearrangements in the presence of Me3Al, which also captures the resulting aldehyde (eq 28).22 In contrast, use of Triisobutylaluminum results in a primary alcohol.

Me3Al effects sequential Beckmann rearrangement-methylation of oxime sulfonates. The rearranged imines can be stereoselectively reduced with Diisobutylaluminum Hydride to give amines (eq 29, cf. eq 27).23a-c Related alkylative ring enlargement24 or alkylative Beckmann fragmentation23d reactions are also known (eqs 30 and 31).

b-Hydroxy methanesulfonates or N-nitrosulfoximines have been activated by Me3Al to induce asymmetric pinacol-type rearrangement (eq 32)25 or carbocyclization reactions (eq 33).26

Lewis Acid.

Me3Al serves as the precursor to various sophisticated Lewis acids with different acidities, such as MeAl(OTf)226 and MeAl(OC6F5)2,11c,d or other acids with unique spatial environments (eq 34).27 Chiral Lewis acids, such as (1)28 and (2),29 serve as catalyst for asymmetric Diels-Alder reactions. The catalyst generated from (3) and Me3Al has been used for asymmetric cyanohydrin synthesis.30


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Keisuke Suzuki & Tetsuya Nagasawa

Keio University, Yokohama, Japan



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