Esters direct alkylation

Backbone Connection Ester, Direct (Alkyl), Ether, Amide... 

Direct alkylation of esters can be carried out by forming the enolate with LDA fol lowed by addition of an alkyl halide Tetrahydrofuran (THF) is the solvent most often used m these reactions... 

Direct alkylation or acylation of the oxygen of THF by exchange or addition occurs with the use of trialkyl oxonium salts, carboxonium salts, super-acid esters or anhydrides, acyhum salts, and sometimes carbenium salts. 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Theoretically, even the direct alkylation of carbenium ions with isobutane is feasible. The reaction of isobutane with a r-butyl cation would lead to 2,2,3,3-tetramethylbutane as the primary product. With liquid superacids under controlled conditions, this has been observed (52), but under typical alkylation conditions 2,2,3,3-TMB is not produced. Kazansky et al. (26,27) proposed the direct alkylation of isopentane with propene in a two-step alkylation process. In this process, the alkene first forms the ester, which in the second step reacts with the isoalkane. Isopentane was found to add directly to the isopropyl ester via intermediate formation of (non-classical) carbonium ions. In this way, the carbenium ions are freed as the corresponding alkanes without hydride transfer (see Section II.D). This conclusion was inferred from the virtual absence of propane in the product mixture. Whether this reaction path is of significance in conventional alkylation processes is unclear at present. HF produces substantial amounts of propane in isobutane/propene alkylation. The lack of 2,2,4-TMP in the product, which is formed in almost all alkylates regardless of the feed (55), implies that the mechanism in the two-step alkylation process is different from that of conventional alkylation. 

Methyl esters undergo trans-esterification with the quaternary ammonium salts at high temperature and the reaction has been used with some effect for the preparation of, for example, n-butyl esters by heating the methyl ester with tetra-n-butylammo-nium chloride at 140°C [31]. Optimum yields (>75%) are obtained in HMPA or in the absence of a solvent. A two-step (one-pot) trans-esterification under phase-transfer catalysed conditions in which the carboxylate anion generated by initially hydrolysis of the ester is alkylated has been reported for Schiff s bases of a-amino acids [32] and for A-alkoxycarbonylmethyl [1-lactams [33]. Direct trans-esterification of methyl and ethyl esters with alcohols under basic catalytic conditions occurs in good yield in the presence of Aliquat [34, 35]. 

Alkylation of trifluoro- and trichloroacetamides with a-bromoacetic esters has been utilized for the synthesis of a wide range of a-aminoacetic acids [11-13] (Table 5.13). Hydrolysis of the intermediate a-trihaloacetamidoacetic esters with methanolic potassium hydroxide converts the methyl and ethyl esters directly into the amino carboxylic acids. /-Butyl a-aminoacetates are more stable, but they are hydrolysed under phase-transfer catalytic conditions (see Chapter 9.2). Reaction of the trihaloacetamides with 1,4-dibromobutane and 1,5-dibromopentane and subsequent hydrolysis provides a simple route to pyrrolidine-2-carboxylic acid (75%) and piperidine-2-carboxylic acid (58%) [11, 12],... 

Simple aliphatic nitriles, aldehydes, ketones and esters are not readily alkylated under liquiddiquid phase-transfer conditions. Direct alkylation of aldehydes under even mildly basic phase-transfer conditions has to compete with aldol and Cannizzaro reactions and yields are low and variable [e.g. 6], a,a-Disubstituted aldehydes are C-alkylated, e.g. formylcyclohexane has been alkylated (>70%) with a range of reagents using benzyltrimethylammonium isopropoxide as the basic catalyst [7], whereas a-unsubstituted alkanals tend to undergo aldol condensation under basic liquid liquid two-phase conditions [8]. 

The preparation of 2-benzylcyclopentanone from 2-benzyl-2-carbomethoxycyclopentanone has not been previously reported. Starting with the ethyl ester, however, the compound has been prepared by heating the ester for many hours with concentrated hydrochloric acid. - The direct alkylation of cyclopentanone with benzyl chloride in the presence of sodium amide in liquid ammonia goes only in a poor yield. ... 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

Af-Unsubstituted 1,2,4-diazaarsoles are directly alkylated by diphenyl diazomethane, diazo esters, sulfur ylides, and alkyl vinyl ethers <90TL7607, 95HAC403). 1-Alkyl-1,2,4-diazo-arsoles (12) (R = Me, CHPhj) react with dimethylsulfoxonium yhde to give bicyclic arsiranes (13) (Equation (1))... 

Lipo-amino acid derivatives are readily obtained in good yields by direct alkylation of amino acids esters with the related alkyl halides, e.g. farnesyl bromide, under careful control of the reaction conditions to avoid exhaustive alkylation of the amino group. 128 Alternatively, peptoid chemistry is applied for N-alkylation of glycine ester via reaction of alkyl amines, e.g. hexadecylamine, with ethyl bromoacetate. 36,98 ... 

Friedel-Crafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation in the pyrimidine 5-position can be carried out on pyrimidines with at least two strongly donating groups, and more readily with three such groups. Thus, a-haloketones and a-bromocarboxylic esters can be used for direct alkylation of 6-aminouracils (118), for example in the formation of (119). The 5-position can also act as the nucleophile for Michael additions (e.g. 118 — 120, where a subsequent elimination occurs) (92AHC(55)129). For similar reactions in barbituric acids see (85AHC(38)229). 

Kleinman and co-workers 20 synthesized a lactone precursor to the (2/ ,46, 56 )- -hydroxy-ethylene dipeptide stereoselectively in four steps using the lithium salt of ethyl propiolate as a homoenolate equivalent. As summarized in Scheme 11, addition of ethyl lithiopropiolate to a protected a-amino aldehyde affords hydroxy acetylenic esters as a mixture of dia-stereomers. Reduction of the acetylene group and subsequent lactonization gives a readily separable (4S)-lactone-enriched mixture. Direct alkylation with alkyl halide and lithium hexamethyldisilanazide yields the tram-lactone as the major stereoisomer. 

Although the present procedure attaches the isoxazole via alkylation of a /9-keto ester, there are several different methods by which attachment could have been effected. Both alkylation of a cyclohexanone enamine6 and direct alkylation of an enone anion followed by hydrogenation of the enone double bond have been used successfully.2,3... 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

A chiral triether (syn-syn) with two different ether residues (Y1 = CH2C02Et Y2 = CH2C02CH2-pyrene, type AABH) has been obtained (55%) by direct alkylation of the corresponding monoether (K2C03/THF),120 and resolved by enantioselective HPLC (Chiracel OD). The excimer fluorescence of 58 increased up to twofold by addition of e.g. L-alanine methyl ester or L-phenylglycinol but no chiral discrimination was observed. 

Direct alkylation is used to introduce substituents a to an ester, ketone or nitrile. Look at the target molecule to identify these substituents. Alkylation is achieved by treating the starting material with LDA, followed by a primary halide. 

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