Ethylmagnesium Bromide

EtMgBr

[925-90-6]  · C2H5BrMg  · Ethylmagnesium Bromide  · (MW 133.28)

(ethyl group introduction; used for preparation of other Grignard reagents)

Solubility: sol diethyl ether (6.8 M L-1), dibutyl ether (5.4 M L-1), diisopropyl ether (1.0 M L-1), THF (1.5 M L-1), anisole (0.28 M L-1).

Form Supplied in: 3.0 M solutions in diethyl ether (d 1.020 g mL-1), 1.0 M solution in THF (d 1.010 g mL-1) and 1.0 M solution in t-butyl methyl ether (d 0.841 g mL-1).

Preparative Methods: details for preparation and determination of concentration are available.1

Handling, Storage, and Precautions: for preparation and use of EtMgBr the usual requirements for Grignard reagents must be considered (anhydrous Magnesium turnings and solvents, inert atmosphere). Reaction apparatus and bottles for storage of EtMgBr should be flushed with N2 and protected from moisture. At the end of the reaction the BrMg derivatives can be decomposed by adding dil acid. If the reaction product is sensitive to acid, hydrolysis can be done with a saturated NH4Cl solution.1

Reactions with Carbonyl Compounds.

EtMgBr with aldehydes produces secondary alcohols. Various aliphatic,2 aromatic,3 and allylic4 aldehydes are transformed into corresponding hydroxy derivatives in 50-100% yield. Stereoselectivity of EtMgBr addition to the terminal or secondary aldehyde group is low; the Cram and anti-Cram isomers are formed in ratio 2:1 to 4:1. Unexpected anti-Cram selectivity is achieved in the MAD- or MAT-mediated alkylation of nonchelating a-chiral aldehydes (MAD = Methylaluminum Bis(2,6-di-t-butyl-4-methylphenoxide); MAT = Methylaluminum Bis(2,4,6-tri-t-butylphenoxide)).5 The Cram selectivity is enhanced (9:1) with addition of crown reagents;6 nevertheless, Et2Mg gives Cram isomers with greater selectivity than EtMgBr.crown. Hexamethylphosphoric Triamide as cosolvent also affects the stereochemistry of addition.7

Addition of EtMgBr to ketones (including cyclobutanone and macrocyclic ketones8) produces tertiary alcohols. The addition of Cerium(III) Chloride suppresses side reactions of enolizable ketones.9 Stereoselectivity of the addition depends on ketone structure, solvent, temperature,10 and reagents for stereoselective activation (eqs 1-3).5,11

Highly stereoselective (92:8) addition to 2-acetyl-1,3-oxazine derivatives (eq 2)12 is controlled by chelation to the oxygen rather than the nitrogen atom of the ring. Addition opposite to the 2-substituent side with formation of cis-cyclohexanols is predominant for 2-substituted cyclohexanones (eq 3).13 3-Substituted N-alkylpiperidin-4-one derivatives14 react in a similar stereoselective manner. Addition to 4-t-butylcyclohexanones is nonselective: equal amounts of both equatorial and axial cyclohexanols are produced. The organoaluminum compound MAD5 can be used for stereoselective activation to produce equatorial cyclohexanols exclusively.

In general, esters with an excess of Grignard reagent produce tertiary alcohols15 (secondary alcohols from formic acid esters). In contrast, the one-pot synthesis of secondary alcohols from esters and EtMgBr/Lithium Borohydride results from a slow addition of EtMgBr to the ester to provide a ketone intermediate which is reduced rapidly with LiBH4 to form a secondary alcohol (eq 4).

EtMgBr can be used for ester O-acyl bond cleavage and removal of common acyl groups16 without affecting base-sensitive groups (silyl ether, halide, or phosphate) adjacent to the ester (eq 5). Debenzoylation of secondary alkyl esters requires excess of the reagent (up to 30 equiv). Interaction of alkyl esters with EtMgBr in the presence of Titanium Tetraisopropoxide results in hydroxy cyclopropane formation (eq 6). Ring opening produces an ethyl ketone.17

g-Butyrolactone treated with EtMgBr in excess generates 4-ethylhexane-1,4-diol (eq 7).18 a-Silylated derivatives of g-butyro- and g-valerolactone react with the Grignard reagent to give 2-substituted 4,5-dihydrofurans,19 useful for the production of g-keto acids (eq 8).

Halogenated 2-oxocoumarins react like g-lactones, affording the ring-opening products and 4-ethyldihydrocoumarin derivatives (eq 9).20 Lactone ring opening can be effected by EtMgBr in benzene, whereas in ether or THF the addition reaction is predominant.

The reaction of Diketene21 with EtMgBr in the presence of the NiCl2{bis(diphenylphosphino)propane} complex gives 3-methylenepentanoic acid (eq 10).

Acyl chlorides react with EtMgBr, affording ethyl ketones (eq 11). The reaction is applicable to acyl chlorides of high CH acidity.22,23

Cyclic anhydride reactions with EtMgBr can give products of anhydride ring opening24 (eq 12), or the hydroxy acid formed may lactonize (eq 13).25

Interaction with C=C, C=N, and C&tbond;N Bonds.

The regioselectivity of EtMgBr addition to double bonds is determined by substrate structure. Regioselective 1,4-addition of EtMgBr to 2H-benzopyrans and 2-oxobenzopyran26 is observed. Allenic27 bonds and double bonds conjugated with azomethines28 undergo 1,2-addition. Reactions with conjugated enynes29 lead to both g-alkynic (1,2-addition) and b-allenic (1,4-addition) compounds. Chiral zinc(II) complexes30 catalyze the asymmetric 1,4-addition to a,b-unsaturated ketones. High stereoselectivity can be achieved in conjugate additions of g-hydroxy enones31 (eq 14). Preliminary complexation of EtMgBr with the alkoxide, followed by Et group transfer, results in formation of the syn product (anti:syn = 0:100).

Several removable chiral auxiliaries have been used to achieve diastereoselective conjugate addition (eq 15).32,33

Interaction of a,b-unsaturated ketones34 with EtMgBr followed by addition of Chlorotrimethylsilane forms b-ethyl enol silyl ethers.

Reaction with 2-substituted methyl acrylates35 results in dimerization by conjugate addition (eq 16). Successive addition of EtMgBr and aldehydes to a-alkyl acrylates affords d-lactones.36 The diastereoselectivity of the product increases with the bulkiness of aldehyde employed (eq 17).

The copper-catalyzed reaction of EtMgBr with cyclic carbonates of vicinal diols37 proceeds in SN2 fashion and results in (E)-allylic alcohol formation with high diastereoselectivity (de >99%) (eq 18).

The interaction of EtMgBr with chiral N-enoylsultams38 proceeds with Et group addition on the b-carbon in stereocontrolled fashion. Cross aldol condensation with the thioamide enolates forms predominantly the threo isomer (eq 19).39

Reaction of EtMgBr with the endocyclic C=N bond of benzothiazine40 or BF3-complexed thiazolines41 proceeds by 1,2-addition.42 1,4-Addition of EtMgBr to chiral a,b-unsaturated aldimines provides an asymmetric synthesis of aldehydes (eq 20).43

Crotonaldehyde oxime44 with EtMgBr gives threo aziridines. Diazadienes45 with EtMgBr give enediamines and/or tautomeric b-aminoimines in polar solvents; in nonpolar solvents, C-alkylation products can also be isolated.

Reaction of pyridinium salts with EtMgBr produces 4-ethyl-1,4-dihydro- and 2-ethyl-1,2-dihydropyridines in variable ratios (eq 21).46 The presence of Copper(I) Iodide (5 mol %) favors 4-addition. When the 4-position is blocked, a regiospecific synthesis of 1,2-dihydropyridine may be feasible. The similar addition to the unsubstituted electrophilic position of the quinoline47 ring is observed.

Addition of EtMgBr to nitriles forms ketimine-magnesium derivatives; hydrolytic workup gives ethyl ketones. Ketones are obtained from p-substituted benzonitrile,48 4-cyanomethylisoxazole, and isothiazole derivatives.49 Treatment of cyanohydrin OTMS derivatives50 with EtMgBr followed by hydrolysis affords a-hydroxy ketones. For sterically hindered cyano compounds,51 forcing conditions are required (5 kbar).

Ketimine anions, generated by the reaction of nitriles with EtMgBr, are dimerized to form symmetrical azines52 by Copper(I) Iodide and t-butyl peroxybenzoate (eq 22).

Reaction with Lactols, Acetals, and Aminals.

Ethylmagnesium bromide reacts with lactols to form secondary and tertiary alcohols, or the products formed from them (eq 23).53 Such reaction can show interesting solvent effects, and can be highly diastereoselective (eq 24).54

Reaction between EtMgBr and a mixed orthoester results in preferential substitution of a phenoxy group (eq 25).55 The methoxy groups of N-dialkylformamide dimethyl acetal56 can be easily substituted in a similar manner.

Dialkyl acetals derived from a,b-unsaturated aldehydes57 afford the cross-coupling product with EtMgBr in the presence of Titanium(IV) Chloride (eq 26). The TiCl4-catalyzed coupling of EtMgBr with cyclic chiral acetals58 provide a convenient route for the preparation of chiral alcohols of high optical purity (eq 27).

Reaction of dithiolane59 derived from benzophenone with EtMgBr in the presence of a Ni catalyst proceeds in an unusual manner, with ethylidene coupling product formation (eq 28).

EtMgBr reacts with perhydrobenzooxazine derivatives60 to provide primary amines in good chemical yield and with high enantiomeric excess. Diastereoselective ring opening of oxazoline61 or oxadiazine62 derivatives by EtMgBr is also observed.

Reaction with Epoxides.

Interaction of EtMgBr with (S)-(+)-Epichlorohydrin63 and trans-1,2-epoxy-1,3-bis(trimethylsilyl)propane64 proceeds with stereoselective opening of the oxirane ring.

Substitution at the sp2 Carbon Atom.

The substitution of halogens in vinyl iodides and 2-bromo-1,4-benzodioxin, and the substitution of alkoxy groups of enol ethers,65 are catalyzed by NiCl2(dppp) or Tetrakis(triphenylphosphine)palladium(0) and proceed with retention of configuration when alkene derivatives are used. During reaction of (E)-(1-halo-1-alkenyl)boron esters66 with EtMgBr the halogen substituent is replaced by the Et group with complete inversion of configuration at the vinylic center.

Substitution of the R1R2N group67 is observed in the reactions of EtMgBr with diethylaminodinitrobutadienes or (3-dimethylamino-2-propenoyl)ketene dithioacetals (eq 29).

Ethylmagnesium bromide can give ipso substitution products with arenes and azines. When EtMgBr reacts with 2-methylsulfonyl-6-chloropyridine68 the SO2Me group is replaced; the chlorine atom is unaffected. An SET mechanism is probably involved, since 4-phenylsulfonylpyridine under the same conditions gives 4,4-bipyridine. The replacement of pyrimidine 4-chloro substituents69 by EtMgBr occurs in the presence of NiCl2(dppp). The same types of catalysts, PdCl2(dppf) and PdCl2(dppb), are effective in the preparation of selectively monoalkylated benzenes.70

Substitution at Heteroatoms.

Nucleophilic cleavage of the 1,2-dithiolane S-S bond71 by EtMgBr is a facile and selective route to mono-5-substituted 1,3-propanedithiols (eq 30). In the reaction of (1-chlorovinyl)diphenylphosphine oxide72 with EtMgBr the chlorovinyl moiety is the leaving group.

Ring opening of 1,2-propanediol cyclic sulfite73 by EtMgBr affords a chiral sulfinate with high regio- and stereoselectivities (eq 31).

Ephedrine sulfinamides from oxathiazolidine derivatives74 can be obtained in a similar way using Grignard reagents, but EtMgBr gives lower diastereoselectivity in the production of sulfinamides. Asymmetric synthesis of silicon compounds75 is achieved by an EtMgBr substitution reaction at the Si atom.

Miscellaneous.

EtMgBr is used for the preparation of alkynic Grignard reagents76 including g-functional Grignard reagents77 generated from propargylic alcohols (see Ethynylmagnesium Bromide). Addition of EtMgBr in the presence of CuI to alkynic Grignard reagents affords vinylic magnesium reagents.78

EtMgBr is used for the preparation of 2-pyridylmagnesium bromide79 and as a base80 for carbanion generation. Highly regio- and stereoselective cycloaddition of reactive nitrones to magnesium alkoxides of allyl alcohols81 is realized by use of EtMgBr (eq 32).

Trifluoroacetyltriphenylsilane reacts with EtMgBr to produce 2,2-difluoroenol silyl ether (eq 33).82

EtMgBr is also used for thione reduction83 and preparation of alkyl isothiocyanates84 and organozinc85 compounds.

Related Reagents.

t-Butylmagnesium Chloride; Methylmagnesium Bromide.


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Dzintra Muceniece

Latvian Institute of Organic Synthesis, Riga, Latvia



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