Methyl Dilithioacetoacetate

[30568-00-4] (M1 = M2 = Li+)

[53437-05-1]  · C5H6Li2O3  · Methyl Dilithioacetoacetate  · (MW 127.99) (M1 = Li+, M2 = Na+)

[64670-05-9]  · C5H6LiNaO3  · Methyl Lithiosodioacetoacetate  · (MW 144.04)

(four-carbon chain, all four carbons of which can be reacted regioselectively; versatile starting material in synthesis of complex molecules; undergoes g-alkylation and g-acylation)

Solubility: sol THF, ether, dimethoxyethane, and HMPA; slightly sol hydrocarbon solvents.

Form Supplied in: generated in situ.

Analysis of Reagent Purity: NMR spectroscopy or mass spectrometry of D2O quench.1

Preparative Methods: dianion (1) is prepared in a dry solvent, usually THF or diethyl ether, by adding the b-keto ester to 1.1 equiv of Sodium Hydride, which has been washed free of mineral oil, and then adding 1.05 equiv of n-Butyllithium at 0 °C (eq 1).1 It may also be prepared by treating the b-keto ester with 2.0 equiv of Lithium Diisopropylamide or Lithium 2,2,6,6-Tetramethylpiperidide at 0 °C.1 These methods may be used to generated the dianions of a wide range of b-keto esters. The dianion (1) may be quenched with D2O and the degree of dianion formation determined by integration of the 1H NMR methyl peak at d 2.2 relative to the ester signal or by mass spectrometry.1 Occasionally it is necessary to add HMPA to dissolve the dianions of more substituted b-keto esters.

Handling, Storage, and Precautions: generated in solution; stable for hours at 0 °C; reacts with moisture and oxygen.

Introduction.

Acetoacetate esters provide a four-carbon chain to homologate simpler molecules. The utility of this homologation is that all four carbons subsequently can be reacted regioselectively. Thus the acetoacetate unit is one of the most versatile starting materials available in the synthesis of complex natural and unnatural products.

Alkylation of Methyl Acetoacetate Dianion.

The dianion (1) reacts with primary and secondary halides and sulfonates to give the g-alkylated products (2) in good yield (eq 2 and Table 1). Halides are the most common alkylating agents. However, sulfonates will also react. The triflate is effective in the case of hindered alkylating agents.7 Primary halides react without difficulty. Secondary halides are less reactive and some do not react under these conditions. Tertiary halides do not undergo alkylation. The reaction is compatible with a number of other functional groups and protecting groups. It is not necessary to protect alcohol groups, provided excess dianion is used. Following monoalkylation of (1), addition of a second equiv of base will regenerate a dianion which can be alkylated a second time (eq 3).57 Highest yields in this one-pot bisalkylation required the addition of N,N-Dimethylpropyleneurea.57 Other esters of acetoacetate, such as ethyl, t-butyl, and 2-trimethylsilylethyl, have also been used in these reactions.

A recent example which exemplifies the complex carbon skeletons which can be assembled from acetoacetate dianions is taken from the synthesis of latrunculin A (eq 4).58 The dianion of the b-keto ester (3) reacts with the phosphonium salt (4) which is generated in situ. The resulting phosphorane is treated with an aldehyde to give the diene b-keto ester (5), all in one pot. The next higher vinylog of (4) yields (E,E,Z)-trienes in the same reaction.58c

Epoxides react with (1) to give alcohols (Table 1). In the case of simple epoxides the initially formed alcohols often could not be isolated, because they underwent cyclization to tetrahydrofuranylidene-2-acetates (6) (eq 5).16 In the case of more complex epoxides the alcohols usually could be isolated in good yield and in most cases the opening of the epoxide ring was regioselective.68-70

The dianion of methyl acetoacetate reacts with other simple electrophiles including benzenesulfenyl halides,62 alkyl nitrates,63 chlorophosphates,64 and carbon dioxide.65 Often the reaction is very clean, leading to the g-substituted product.

The dianion (1) undergoes aldol condensations with a variety of aldehydes (Table 2). The resulting d-hydroxy-b-keto esters (7) can be cyclized to the b-keto-d-lactones, oxidized or dehydrated (eq 6). The stereoselectivity in the addition to chiral aldehydes is low, although it can be improved with the addition of Lewis acids.77 In the case of a,b-unsaturated aldehydes and ketones, only 1,2-addition is observed.

Dianion (1) can be acylated. A limited amount of work has been carried out using nitriles as the acylating agent and the product was found to be the enamino b-keto ester (8) (eq 7).92

A much larger range of ester derivatives have been condensed with dianion (1) (Table 3). Because the monoanion of the initial product (9) is more acidic than the monoanion (10) of acetoacetate, the starting dianion (1) is quenched as the reaction proceeds. Initially this problem was overcome by adding an extra equiv of base during the reaction.92 However, the problem does limit the yield of (9) (eq 8). Now an excess of dianion (1) is usually used to optimize the yield of acylated product (9). It was also found that addition of Boron Trifluoride Etherate improves the yield of (9).93 Addition of TMEDA also leads to increased yields in these acylations.94

The acylated products have been used in the synthesis of many polyketide aromatic natural products.96 For example, condensation of (1) with the monoanion (10) of methyl acetoacetate yields the triketo ester (11), which can be cyclized to the orsellinate (12) (eq 9).92,97 The conversion of (1) to (12) can be carried out in one pot by refluxing the solution of the dianion (1) and the monoanion (10) (eq 9).98,99 These condensations could be applied to dicarboxylic acid derivatives to yield polyketo diesters which readily cyclized (eq 10).96,101 Acylations with amides in the presence of BF3.Et2O led to improved yields of the triketo esters (11).93 This was further refined with the use of N-methoxy-N-methylamides as acylating agents.96b,103

Dianion (1) undergoes 1,4-addition to certain Michael acceptors such as a,b-unsaturated thioamides,104 a,b-unsaturated sulfoxides,105 and a,b-unsaturated sulfones.106

Dianion (1) has proven to be so useful that several synthetic equivalents to it have been developed and these are listed in Table 4. Most of these reagents are generated under the strongly basic conditions that (1) is formed under. However, the bistrimethylsilyl ether (13) reacts with alkylating and acylating reagents in the presence of Lewis acids and provides a very useful complement to (1).

Related Reagents.

Acetoacetic Acid; Acetone; Acetone Cyclohexylimine; Acetone Hydrazone; Diketene; Dimethyl 1,3-Acetonedicarboxylate; Ethyl Acetoacetate; Ethyl 4-Chloroacetoacetate; Ethyl 4-(Triphenylphosphoranylidene)acetoacetate; 1-Methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene; N-Methoxy-N-methylacetamide; 2,4-Pentanedione; Trimethylsilylacetone; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.


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Larry Weiler

University of British Columbia, Vancouver, BC, Canada



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