Ethyl 2-(Bromomethyl)acrylate

(R = Et)

[17435-72-2]  · C6H9BrO2  · Ethyl 2-(Bromomethyl)acrylate  · (MW 193.04) (R = t-Bu)

[53913-96-5]  · C8H13BrO2  · t-Butyl 2-(Bromomethyl)acrylate  · (MW 221.09)

(powerful allylic alkylating reagent1-3 employed as its organozinc derivative to prepare a-methylene lactones4 and lactams;5 important source of functional acrylic monomers for polymerization6,7)

Alternate Name: ethyl 2-(bromomethyl)propenoate.

Physical Data: R = Et, bp 40-41 °C/0.1 mmHg; R = t-Bu, bp 60-61 °C/0.1 mmHg.

Solubility: insol H2O; sol ether, acetone, alcohol, THF, chloroform.

Form Supplied in: colorless liquid.

Preparative Methods: many preparations of these compounds have been described,8 for example dehydrobromination of b,b-dibromoisobutyric esters9-11 or acid, or bromination of t-butyl or Ethyl a-(Hydroxymethyl)acrylate with Phosphorus(III) Bromide.12

Handling, Storage, and Precautions: reputed to be lachrymatory, vesicatory, and toxic. Usual precautions of storage in darkness between 0 and 5 °C and handling with gloves under a well ventilated hood are recommended.

Electrophilic Alkylating Reagent.

The electrophilic reactivity of the allylic bromide moiety is increased by the presence of the carboxylate group (Michael acceptor) and the reagent can thus act as a powerful allylic electrophile. It can be coupled with various organometallic reagents, gem-dimetallic reagents2,3 or O-,13,14, S-,15-17, N-, and P-nucleophiles (eq 1).18,19

The alkylation with Cyanomethylcopper1 gave 89% yield of the corresponding 1-(3-cyanoethyl)acrylic ester, while p-2-(methoxyallyl)nickel bromide was tested as a source of 5-ethoxycarbonyl-5-hexen-2-one.20 Palladium-catalyzed cross-coupling with vinyl- and aryltin21 and vinylzirconium reagents22 allowed the preparation of the corresponding 2-allyl- and 2-benzylacrylates. Coupling with functional zinc or zinc-copper organometallic derivatives23-25 gives rise to various polyfunctional acrylic derivatives (eq 2).26

The allylation of other nucleophiles such as the enolates of cyclic 1,3-diketones27 (or their enol ethers28), b-keto esters,29 b-dimethylaminopropionates,30 and bicyclic enolates31 has been reported. Tandem alkylation-Michael addition with dienolates gives rise to cyclic or bicyclic compounds,32 while tandem alkylation-Claisen condensations leads to the formation of functional a-methylenecyclopentanones (eq 3).33

Alkylation of enamines34 has been proposed as the first step in the synthesis of potential antitumor a-methylene d-valerolactones.

Unsymmetrical organic sulfides containing the methacrylic ester group are produced under nonbasic reaction conditions.35 Thio-Claisen rearrangement36 took place via S-allylation with ethyl 2-(bromomethyl)acrylate (eq 4).

N-Allylation by ethyl 2-(bromomethyl)acrylate has been developed as key steps in the synthesis of bioactive molecules such as a-methylene-b-alanine,37 or analogs of Iboga alkaloids.38

Synthesis of a-Methylene Lactones and Lactams.

One of the most important applications of ethyl 2-(bromomethyl)acrylate was found in a pseudo-Reformatsky reaction. First described by Ohler et al.,4 this reaction leads to the formation of potential antitumor a-methylene-g-lactones,39,40 via an organozinc intermediate (eq 5).

This reaction was extensively applied to various carbonyl compounds. 5-Mono- or 5,5-disubstituted a-methylene-g-lactones bearing a steroidal moiety,41 nucleic acid bases,42 furanose systems,43 six-membered44 or five-membered45 heterocyclic groups, adamantyl groups,46 and bornyl groups47 have been prepared and evaluated as antineoplasic and allergenic48,49 compounds. Bis-a-methylene-g-lactones have been produced from dicarbonyl compounds.50

The Reformatsky reaction with imines leads to the corresponding less toxic a-methylene-g-lactams.5 Bis addition of the organozinc intermediate to acyl chlorides or nitriles before cyclization leads to the formation of new a-methylene-g-lactones and lactams (eq 6).51

Attempts to improve the yield of the Reformatsky reaction included the use of Tin,52 tin-aluminum alloy,53 Zinc dust in aqueous ammonium chloride solution,54 or electrogenerated zinc.55 Low valent metal halides (Lithium Aluminum Hydride-Chromium(III) Chloride)56 and Tin(II) Chloride57 were found to undergo insertion into the carbon-bromine bond of 2-(bromomethyl)acrylates. Asymmetric induction from complex reagents made with SnCl2, tartaric ester, and allylic bromides has been described.58

The preparation of intermediate organozinc derivatives of 2-(bromomethyl)acrylates59 by direct action of zinc dust in THF (or DME) at controlled temperature allowed regio- and stereoselective condensations with polyfunctional electrophilic compounds without side reactions (eq 7).60

Their coupling with chiral imines, derived from a-amino esters61 or b-amino alcohols,62 leads to the formation of the corresponding a-methylene-g-lactams (R,R) or (S,S) via a diastereoselective set of reactions (de > 95%).

Other organometallic reagents derived from ethyl 2-(bromomethyl)acrylate are known, such as organotin,63 which allows palladium-promoted arylation, and organomercury,64 for acylation reactions. Ethyl 2-(bromomethyl)acrylate/p-(allyl)nickel in DMF is a powerful selective nucleophilic reagent for haloaromatics65 and iodoalkanes66 (eq 8).

Polymer Chemistry.

Ethyl 2-(bromomethyl)acrylate also has an important place in polymer chemistry as a monomer6 or as a source of functional monomers such as sulfur-containing acrylic compounds67 or 6-O-methylallylgalactose intermediates for the preparation of poly(vinyl)saccharides.7 It also has been employed as a chain-transfer agent.68

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Jean Villiéras & Monique Villiéras

Université de Nantes, France

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