Allylic halides 3-keto esters

Ahonen, M. Sjoholm, R. (1995) Zn-mediated chemoselective allylation of keto esters with allylic halides in aqueous medium, Chem. Lett., 341-2. 

Alkylation of P-dicarbonyl compounds and p-keto esters occurs preferentially on the carbon atom, whereas acylation produces the 0-acyl derivatives (see Chapter 3). There are indications that C- and 0-alkylated products are produced with simple haloalkanes and benzyl halides, but only C-alkylated derivatives are formed with propargyl and allyl halides [e.g. 90]. Di-C-alkylation frequently occurs and it has been reported that the use of tetra-alkylammonium 2-oxopyrrolidinyl salts are more effective catalysts (in place of aqueous sodium hydroxide and quaternary ammonium salt) for selective (-90%) mono-C-alkylation of p-dicarbonyl compounds [91]. 

The coupling reaction of a-keto esters with allyl, propargyl, and allenyl halides using indium metal in aqueous solvents affords a-hydroxy-y,<5-unsaturated esters (Equation (28)).197,198 1,3-Dicarbonyl compounds undergo efficient carbonyl allylation reactions in an aqueous medium through a Barbier-type reaction (Equation (29)). The reaction is general and a variety of 1,3-dicarbonyls has been alkylated using allyl bromide or allyl chloride in conjunction with indium.199... 

Palladium complexes also catalyze the carbonylation of halides. " Aryl (see 13-15), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex.Similar reactivity was reported with vinyl triflates. a-Halo ketones are converted to (3-keto esters with CO, an alcohol, NBU3 and a palladium catalyst at 110°C. Use of an amine instead of the alcohol or alkoxide leads to an amide. 

Allylic halide substrates in the P-keto ester series cyclize well, and convenient routes to five-, six- and seven-membered rings have been described (equations 50 and 51). Unfortunately, the dia-stereoselectivity in these examples again is highly dependent on the substitution patterns about the dicarbonyl substrate. 

The group of Tietze has described syntheses of variously substituted pyrazolones 20 starting from solid-phase-bound p-keto esters. Single or iterative alkylation of the dianion of immobilized acetoacetate with allyl-, benzyl- or alkyl halides produced a set of y-substituted ketoesters 18 that could be transformed to the phenyl-hydrazones 19. Treatment of these intermediates in toluene at 100 °C produced 1-phenylpyrazolone derivatives 20 in 40-75% yield (Scheme 6) [14]. 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

Enamine alkylations are S vi2 reactions therefore, when we choose our alkylating agents, we are usually restricted to the use of methyl, primary, allylic, and benzylic halides. a-Halo esters can also be used as the alkylating agents, and this reaction provides a convenient synthesis of j8-keto esters ... 

Among other reactions, the bis-metallated species (151) derived from nitroalkanes condense with dialkyl carbonates to give comp>ounds (152), in 60—80% yield, which can serve as precursors of both a-amino-acids and a-hydroxyamino-esters as well as a-keto-esters. Oxazolin-5-ones (153) can be alkylated at the 4-position by alkyl halides in hot DMF containing HMPA and ethyldi-isopropylamine. Yields are good (60—90%) for allylic, benzylic, and propargylic halides but otherwise poor (e.g. 32% with EtI) under these conditions acid hydrolysis of the products affords substituted a-amino-acids. Mesoionic l,3-oxazol-5-ones (154), obtained from imidoyl chlorides and acyl-tetracarbonylferrates, react with alcohols to give N-acyl-a-amino-acid esters. ... 

Malonic acid labeled with carbon-14 at C2 or at Cl,3 and the corresponding mono- and diesters have become important and highly versatile building blocks for the synthesis of a broad range of labeled compounds, such a,/3-unsaturated acids and esters, cycloalkanes, 8-keto esters, a-amino acids, phenols, dihydropyridines/pyridines, pyrimidines and quinolines. In addition, they are widely used as acetic acid synthons ( CH2COOR CHCOOR) for the extension of carbon chains of alkyl, allyl and benzyl halides as well as of saturated and a,)8-unsaturated carbonyl compounds. This Section discusses aU malonates, wherever labeled, and unlabeled malonates used with carbon-14-labeled reaction partners. However, it is the [2- " C]malonates that have been most often used in radiochemical synthesis. 

Active methylene compounds such as 1,3-diketones, 1,3-keto carboxylic esters, malononitrile, and ethyl cyanoacetate were alkylated by alkyl halides catalyzed by the ionic liquid [bmim][OH] under microwave irradiation. The alkyl halides included allyl, benzyl, methyl, and butyl bromides/iodides. The open-chain 1,3-ketones produced the monoalkylated products, whereas the cyclic diketones provided the dial-kylated products in one stroke. Malononitrile and ethyl cyanoacetate also furnished the dialkylated products (Fig. 12.24) [17]. 

Recent advances in organometallic chemistry have led to development of various novel methods in synthetic organic chemistry. A Pd-catalyzed reaction has been a particularly useful method. In these reactions, Pd-catalyzed carbonylation is a very attractive method because one carbon is elongated from various functional groups, such as aryl halide, alkyl halide, allyl acetates, allyl carbonates, and even the keto-carbonyl groups, to form esters, amides, and unsaturated ketones (Scheme 1). 

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