Ethyl Acetoacetate1

(1; R1 = Me, R2 = Et)

[141-97-9]  · C6H10O3  · Ethyl Acetoacetate  · (MW 130.16) (2; R1 = R2 = Me)

[105-45-3]  · C5H8O3  · Methyl Acetoacetate  · (MW 116.13) (3; R1 = Me, R2 = t-Bu)

[1694-31-1]  · C8H14O3  · t-Butyl Acetoacetate  · (MW 158.22) (4; R1 = Ph, R2 = Et)

[94-02-0]  · C13H16O3  · Ethyl Benzoylacetate  · (MW 192.29)

(three- or four-carbon nucleophile in alkylations,2 conjugate additions,3 and various condensation reactions4,5)

Physical Data: (1) bp 180-181 °C; d 1.025 g cm-3. (2) bp 169-170 °C; d 1.076 g cm-3. (3) bp 71-72 °C/11 mmHg; d 0.961 g cm-3. (4) bp 266-270 °C; d 1.113 g cm-3.

Preparative Methods: ethyl, methyl, and t-butyl acetoacetates and ethyl benzoyl acetate are commercially available. A wide variety of acetoacetic esters may be prepared via alcoholysis of diketene6 and ester exchange reaction of t-butyl acetoacetate.7

Handling, Storage, and Precautions: use in a fume hood.

Alkylations.

Alkylation at the a-carbon of ethyl acetoacetate via an alkali metal enolate and subsequent removal of the ester group by sequential hydrolysis and decarboxylation provides a classical synthesis of methyl ketones (eq 1).8 The ambident reactivity of the acetoacetate anion often causes competing C- and O-alkylations.9 The extent of C vs. O alkylation depends on the nature of the leaving group, metal counterion, and solvent.10,11 In general, heterogeneous reaction conditions, less electropositive metal cations, e.g. lithium, nonpolar or protic solvents, and polarizable alkylating agents such as alkyl iodides and allylic, propargylic, and benzylic halides favor C-alkylation. Highly dipolar aprotic solvents, e.g. HMPA, and highly reactive alkylating agents such as alkyl sulfonates and sulfates tend to favor O-alkylation. Use of phase-transfer catalysis,12 heating crystalline thallium(I) enolates with alkyl iodides,13 and alkylation in the presence of Tetra-n-butylammonium Fluoride base (eq 2)14 are among the methods that successfully avoid or minimize O-alkylation. While primary and unhindered secondary halides give good yields of C-alkylated products, tertiary halides undergo elimination under anionic alkylation conditions. In such cases, alkylation may be achieved via reaction of the enol with cationic species (eq 3).15

Metal coordinated alkenes react with acetoacetate anion, affording an alternative type of alkylation.16 p-Allyl palladium species, catalytically generated by reaction of Pd0 complexes with allylic acetates or halides, provide efficient C-allylation of the acetoacetate anion.17 Alkylations with vinyl epoxides, allylic carbonates, and allylic carbamates via Pd0 catalysis proceed without the need for an external base since the p-allylpalladium species in these systems are sufficiently basic to deprotonate acetoacetate in situ.17 The regio- and stereoselectivities in alkylations with cyclic vinyl epoxides (eq 4)18 are opposite to those observed under standard carbanion conditions.19 A highly efficient Pd0-catalyzed addition of methyl acetoacetate to 1,3-dienes can be achieved using 1,3-Bis(diphenylphosphino)propane ligand (eq 5).20

Manganese(III) Acetate promotes the radical addition of ethyl acetoacetate to enol ethers and subsequent oxidative cyclization to 1-alkoxy-1,2-dihydrofurans, which may be hydrolyzed to alkylated acetoacetate derivatives (eq 6).21 The corresponding reaction with simple alkenes is less general.22

a,g-Dianions of acetoacetates (see Methyl Dilithioacetoacetate) can be generated by treatment with 1 equiv of Sodium Hydride, followed by 1 equiv of n-Butyllithium, or 2 equiv of Lithium Diisopropylamide in THF.23 Reaction of the dianion with a variety of alkylating agents including alkyl halides (eq 7)23 and epoxides (eq 8)24 results in regioselective g-alkylation.

Acylations.

C-acylation at the a-carbon of ethyl acetoacetate may be achieved by reaction of the magnesio or sodio derivative with an acid chloride.25 Acylation may also be performed efficiently in the presence of MgCl2 and pyridine (eq 9).26

The dianions of acetoacetates undergo g-C-acylation with esters.27 Proton transfer occurs readily from product to the starting enolate. As a result, two equivalents of the dianion are needed to ensure complete conversion. This problem can be overcome by employing N-methoxy-N-methyl amides (see N-Methoxy-N-methylacetamide) as acylating agents.28 Addition of catalytic amounts of N,N,N,N-Tetramethylethylenediamine greatly improves the efficiency of acylation of dilithio ethyl acetoacetate (eq 10).29 N,N-Dimethyl carboxamides can also be used as acylating agents in the presence of Boron Trifluoride Etherate.30

Carbonyl Additions and Condensations.

Knoevenagel condensation of acetoacetates with carbonyl compounds may be carried out using a wide range of catalysts and reaction conditions.4 A particularly mild and efficient procedure involves the use of Titanium(IV) Chloride and pyridine in THF at low temperatures, which allows the condensation of ethyl acetoacetate with aliphatic, aromatic, and heteroaromatic aldehydes to produce a-alkylideneacetoacetates (eq 11).31 The condensation of t-butyl acetoacetate with aldehydes and subsequent cleavage of the t-butyl ester by heating with catalytic p-Toluenesulfonic Acid provides a convenient synthesis of a,b-unsaturated methyl ketones.32 a-Alkyl-substituted acetoacetates can add to aldehydes; however, the adducts often undergo acyl cleavage under the reaction conditions to give a,b-unsaturated esters (eq 12).33 The dianion of methyl acetoacetate reacts with aldehydes and ketones in the g-position to give aldol adducts (eq 13).34

Conjugate Additions and Annulation Reactions.

A wide variety of activated alkenes, alkynes, and allenes participate in conjugate additions or Michael reactions with acetoacetates. a,b-Unsaturated ketones, esters, nitriles, aldehydes, lactones, sulfoxides, sulfones, and nitro compounds are among the more commonly used alkene acceptors.3 Although conventional procedures employ strongly basic catalysts, neutral reaction conditions (eq 14)35,36 are often used to overcome side reactions such as bis additions and self condensations.

1,5-Diketones produced by the conjugate addition of acetoacetates to a,b-unsaturated ketones are useful in the synthesis of cyclohexenones via intramolecular aldol condensation.37 A sequence of Knoevenagel condensation, Michael addition, aldol cyclization, and dealkoxycarbonylation may be carried in one pot using ethyl acetoacetate, an aliphatic aldehyde, and Piperidine catalyst (eq 15).38 In general, however, annulation reactions of acetoacetates involve the Michael addition and the aldol cyclization as two separate steps (eq 16).39

Trimethylsilyl Enol Ethers.

Successive silylation of methyl acetoacetate with Chlorotrimethylsilane gives the mono- and the bis(trimethylsilyl) enol ethers (eq 17),40 which are useful as synthetic equivalents of acetoacetate in reactions with a variety of electrophiles. Lewis acid-catalyzed reaction of the mono(trimethylsilyl) enol ether with N-acylimines,41 oxonium ions,42 thianium ions43 and vinyl iminium ions (eq 18)44 gives a-C-alkylated acetoacetate derivatives.

TiCl4-catalyzed aldol addition of the bis(trimethylsilyl) enol ether of methyl acetoacetate to carbonyl compounds occurs exclusively in the g-position.45 Highly diastereoselective aldol additions can be achieved in reactions with a-alkoxy aldehydes (eq 19).46 The bis(trimethylsilyl) enol ether may also be used as a 1,3-dianionic synthon for annulation with dicarbonyl electrophiles. Lewis acid-catalyzed annulation with a,a-dialkoxy ketones,47 b,b-dialkoxy ketones,40 and 1,4-keto aldehydes (eq 20)48 allows the construction of five-, six-, and seven-membered ring systems, respectively.

Asymmetric Reduction.

Highly enantioselective asymmetric hydrogenation of acetoacetates can be achieved using 2,2-Bis(diphenylphosphino)-1,1-binaphthyl-ruthenium complexes (eq 21).49 The resulting 3-hydroxybutanoates (see Ethyl 3-Hydroxybutanoate) are versatile auxiliaries and building blocks for the synthesis of enantiomerically pure products. Racemic a-substituted acetoacetates may also be hydrogenated in high stereoselectivity via dynamic kinetic resolution.50

Heterocyclic Synthesis.

A wide variety of five- and six-membered heterocyclic systems may be derived by the cyclocondensation of acetoacetates with 1,2- and 1,3-bifunctional reagents wherein one or both of the functionalities are heteroatomic (Table 1). The regioselectivity in these cyclizations can often be altered by replacing acetoacetates with their enol ether or enamine derivatives.

The classical synthesis of coumarins via the von Pechmann reaction58 involves the condensation of acetoacetates with phenols under acid catalysis (eq 22).59 Chromones are produced when the phenol contains a deactivating group or the acetoacetates are a-substituted. The condensation of acetoacetates with anilines can give either 2-hydroxy- or 4-hydroxyquinolines, depending upon the reaction temperature.60 In the Hantzch synthesis of symmetrical dihydropyridines, two equivalents of acetoacetates are condensed with aldehydes in the presence of Ammonia (eq 23).61 A variation of the Hantzch synthesis for the preparation of unsymmetrical dihydropyridines involves the condensation of a-(alkylidene)acetoacetates with 3-aminocrotonate.62

Related Reagents.

Acetoacetic Acid; Acetone; Acetone Cyclohexylimine; Acetone Hydrazone; N,O-Dimethylhydroxylamine; Ethyl 4-Chloroacetoacetate; Ethyl 4-(Triphenylphosphoranylidene)acetoacetate; 1-Methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene; N-Methoxy-N-methylacetamide; Methyl Dilithioacetoacetate.


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Shridhar G. Hegde

Monsanto Company, St. Louis, MO, USA



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