Alkylation of -ketoesters

The familiar alkylation of -ketoesters followed by decarboxylation is still a useful route to a-alkyl ketones, although the alkylation of enamines is frequently the preferred route. Given below are two examples of alkylation of 2-carbethoxycycloalkanones (prepared in Chapter 10, Section I). In the first case, sodium ethoxide is the base employed to generate the enolate ion of 2-carbethoxycyclohexanone. In the second case, the less acidic 2-carbethoxycyclooctanone requires sodium hydride for the generation of the enolate ion. 

Significant progress has been made on the asymmetric Pd-catalyzed aliylic alkylation of prochiral enolates, with a number of ligands now available that provide products with high ee. Trost was the first to demonstrate that high enantiomeric excesses were capable with ketoester substrates [29] now asymmetric aliylic alkylation of ketoesters and simple ketone substrates has been achieved in several more cases. Table 4 summarizes the ligands, substrates, and ee for recent examples. 

Alkylation of / -ketoesters with a-haloketones has been used as an efficient synthesis of 1,4-diketones containing a /tester functionality (equation 78)558. 

Alkylation of / -ketoesters with ( -substituted alkyl halides is an efficient method for the synthesis of cyclic products577-580. In one such reaction sequence, the dianion of a / -ketoester was reacted with 2-(2-bromoethyl)-l,3-dioxolane, the co-substituent in this case being a masked aldehyde. Upon regeneration of the aldehyde functionality, a condensation reaction occurred to give the cyclohexanone as shown in equation 88577. 

Pyridine and related aromatic (quinoline, quinazoline) P,N derivatives (11, 12) have been created for Rh-catalyzed hydroboration-oxidation [44] or -amination [45]. Other pyridine-related auxiliaries have been synthesized for Pd-assisted allylic alkylation [46] in test conditions furnishing the substitution product in up to 93 % ee. The QUIPHOS ligand 13 has been tested in Pd-assisted allylic amination (up to 94 % ee) [47], allylic alkylation of -ketoesters (up to 95 % ee) [48], and Cu-catalyzed Diels-Alder reaction between an acryloyl derivative and cyclopentadiene [49]. 

Carbon is alkylated ia the form of enolates or as carbanions. The enolates are ambident ia activity and can react at an oxygen or a carbon. For example, refluxing equimolar amounts of dimethyl sulfate and ethyl acetoacetate with potassium carbonate gives a 36% yield of the 0-methylation product, ie, ethyl 3-methoxy-2-butenoate, and 30% of the C-methylation product, ie, ethyl 2-methyl-3-oxobutanoate (26). Generally, only one alkyl group of the sulfate reacts with beta-diketones, beta-ketoesters, or malonates (27). Factors affecting the 0 C alkylation ratio have been extensively studied (28). Reaction ia the presence of soHd Al O results mosdy ia C-alkylation of ethyl acetoacetate (29). 

A change in the pK of the molecule by elimination of the acidic enol function and inclusion of basic nitrogen leads to a marked change in biologic activity. That agent, chromonar (13) shows activity as a coronary vasodilator. Alkylation of ethyl acetoacetate with 2-chlorotriethylamine affords the substituted ketoester (10). Condensation with resorcinol in the presence of sulfuric acid affords directly the substituted coumarin (11). 

C-Alkylation of ethyl l,3-dithiane-2-carboxylate (for preparation, see 4.1.6) under mild soliddiquid phase-transfer catalytic conditions [32, 33] provides a potentially useful route to a-ketoesters. 

Alkylation of enolate is an important synthetic method.27 The alkylation of relatively acidic compounds such as /i-dikctoncs, /i-ketoesters, and esters of malonic acid can be carried out in alcohols as solvents using metal alkoxides as bases. The presence of two electron-withdrawing substituents facilitates formation of the enolate resulting from removal of a proton from the carbon situated between them. Alkylation then occurs by an Sn2 process. Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.5. These reactions are all mechanistically similar in that a... 

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... 

In the aliphatic series, the C-alkylation of enolates 17 is achieved through their O-silylated derivatives 66. In the presence of a catalytic amount of ZnBr2, the silyl enol ether 66 reacted with CICH2OCH3 to give only the C-alkylated a-ketoester 67. The alkylation is regiospecific but the ketoesters (67a, c) are obtained with modest yields (about 50% yield). 

The replacement of alanine residue by a lysine moiety leads to lisinopril (13-2) administered in this case as a free dicarboxylic acid this compound that is quite active orally in spite of its polarity. The synthesis is quite analogous to that above, involving reductive alkylation of tert-butoxycarbonyl protected lysilprohne (13-1) with ketoester (12-1). Separation of the desired diastereomer followed by the removal of the BOC group with triiluoroacetic acid and then saponification gives lisinopril (13-2) [14]. 

KETENE, feef-butylcyano-, 55, 32 37, 38 Ketene 1 1-dimethylpropylcyano-, 55, 38 7-KETOESTERS, 58, 79, 81, 82 7-KETOESTERS TO PREPARE CYCLIC DIKETONES, 58, 83 KETONE terf-butyl phenyl, 55, 122 Ketone, methyl ethyl- 55, 25 Ketone, methyl vinyl, 56, 36 KETONES, acetylenic, 55, 52 Ketones, alkylation of, 56, 52 KETONFS aromatic, aromatic hydrocarbons from 55, 7... 

One of the most powerful strategies for asymmetric ring construction is to desymmelrize a preformed ring. Yasamusa Hamada of Chiba University in Japan has reported (J. Am. Chem. Soc. 2004, /26, 3690) that the inexpensive diaminophosphine oxide 2 nicely catalyzes the asymmetric alkylation of the cyclohexanone carboxylate 1 to give 3. Although no examples were given, this asymmetric alkylation would probably work as well with heterocyclic P-ketoesters. 

As described previously [63], P-ketoester 111 [Fig. (31)] was subjected to Baker s yeast reduction to afford the optically active P-hydroxyester 112 (60-80% yield). Dianion alkylation of 112 with (E)-3-methyl-4-(0-tert-butyldimehtylsilyl)-2-butene afforded the desired a-alkyl product 113 in 58-70% isolated yield. 

Ketoesters with alkyl substituents in the a-position give a blue-violet color with ferric chloride.3 Copper chelates of the a-alkyl-/3-ketoesters could not be isolated. The corresponding 5-pyrazolones, although often difficultly crystallizable, appear to be the most suitable derivatives. The 5-pyrazolone from sec-butyl a-w-caproylpropionate is prepared according to von Auwers and Dersch 4 and has melting point 80.4-82.9°. 

The procedure is essentially that of Horeau and Jacques 5 as modified by Cason, Rinehart, and Thornton.6 The reaction described is that discovered by Blaise 7 and is more extensively discussed in the second-named paper. Ethyl a-M-caproylpro-pionate has been prepared by the alkylation of ethyl -caproyl-acetate with methyl iodide in the presence of sodium ethoxide.8 This method would not be expected to yield a pure product owing to contamination with starting ketoester and disubstituted ketoester. 

With BINAPO as ligand, the alkylation of dibenzoate 92 with p-ketoester 101 provides the mono-alkylated product 102 in modest ee (Scheme 8E.13) [65], Subsequently, a simultaneous allylation-Heck annulation reaction provided the pentacycle 103, which was further function-... 

We discussed making 57 from the lactone 59 in chapter 25 and we have used the ketoester 60 in chapters 19 and 25. Alkylation of 60 gives 61, reaction with concentrated HC1 gives the acid corresponding to 55 and polyphosphoric acid (PPA) catalyses the cyclisation to 54. 

Manabe has prepared the chiral quaternary phosphonium salt 17 with a multiple hydrogen bonding site this salt accelerates the alkylation of the ketoester 18, giving products such as 19 with ca. 40% ee at room temperature (Scheme 6) [13]. 

Isopropyl anisole (171) was converted to bromide (172) by metalation, formylation and bromination. Alkylation with cyclopropyl ketoester produced (173) whose transformation to alcohol (174) was achieved by saponification, decarboxylation and reduction.. Its conversion to homoallylic bromide (175) was accomplished by the method of Julia et al. [56]. Alkylation of ethyl acetoacetate with bromide (175) furnished p-ketoester (176). It was subjected to cyclization with stannic chloride in dichloromethane. The resulting tricyclic alcohol provided the olefinic ester (177) by treatment with mesylchloride and triethylamine. Epoxidation followed by elimination led to the previously reported intermediate (146) whose conversion to triptolide (149) has already been described. 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

This next example shows the alkylation of a /3-diketone (pA a = 9). Because this compound is more acidic than a /3-ketoester or a /3-diester, the weaker base potassium carbonate was used. However, sodium ethoxide would also be satisfactory as the base for this reaction ... 

Let s try a synthesis. Suppose the target is ethyl 2-methyl-3-oxo-2-propylpentanoate. The presence of the /3-ketoester functionality suggests employing an alkylation reaction and/or an ester condensation. In one potential pathway, the propyl group can be attached by alkylation of a simpler /3-ketoester. Further retrosynthetic analysis suggests that the new target (ethyl 2-methyl-3-oxopentanoate) can be prepared from ethyl propanoate by a Claisen ester condensation. 

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