Methyl acetate, acetoacetate synthesis

For retrosynthetic analysis, a methyl ketone is a characteristic product of the aceto-acetic ester synthesis starting with ethyl acetoacetate, and other complex ketones can be derived from other j8-ketoester starting materials. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The final variation of the Feist-Benary furan synthesis encompasses reactions of 1,3-dicarbonyls with 1,2-dibromoethyl acetate (52). For example, treatment of ethyl acetoacetate (9) with sodium hydride followed by addition of 52 at 50°C yields dihydrofuran 53. The product can be easily converted into the corresponding 2-methyl-3-furoate upon acid catalyzed elimination of the acetate, thus providing another strategy for the synthesis of 2,3-disubstituted furans. 

The Michael addition to nitroalkenes followed by cyclization provides a general method for the synthesis of various pyrroles. The reaction of nitroalkenes with acetoacetate followed by reduction with Zn in acetic acid provides another route to 2-methyl-3-pyrrolecarboxylates (Eq. 10.8).10... 

Synthesis of northern half building block 53 (Scheme 9) commenced with the acetoxylation of commercially available tert-hutyl acetoacetate to 54 by bromination and in situ displacement of the bromide by acetate. Deprotonation with NaH and alkylation with neryl bromide (55) afforded 58 in excellent yield. Catalytic Se02 oxidation led to selective oxidation of the terminal E-methyl group and gave 59 in 45% yield. Since the remainder is mainly unreacted starting material, this can be re-used. Reduction of the C8-C9 double... 

Our synthesis started with ethyl 5-methyl-4-isoxazole carboxylate (50), prepared from ethyl acetoacetate and DMF dimethyl acetal (Scheme 5.4).14 Ester 50 was reduced with LiAlH4 and the resulting alcohol was oxidized to afford aldehyde 51. Enone 52 was obtained from aldehyde 51 using conditions developed by McCurry and Singh.15 The next step was the aromatization of the cyclohexane ring of 52 to produce the aromatic "A" ring of the monomer. Treatment of enone 52 with iodine in the presence of sodium ethoxide produced phenol 53.16... 

A solution of 50-mCi portions of [3H3]-130 in 9 1 EtOH/H20 mixture have been stored at — 20 °C at a radioactive concentration of 4.5 mCi ml -1 and the radiochemical purity of the sample was 95-96% after one year. No labile tritium was found after refluxing a portion of the sample for 1 h in a methanolic solution of NaOH. The intermediate 131, 5-(4-chlorobenzoyl)-4-methyl-l//-pyrrole-2-acetic acid, has been obtained in an eight-step synthesis starting with tert-buiyX acetoacetate (equation 52). 

Variations of the above procedures are sometimes employed. /S-Keto esters may be obtained by alcoholysis of the intermediate diacyl esters by sodium methoxide in methanol, as in the preparation of methyl /3-oxocaprylate (88%). The starting /S-keto ester can be converted to the new /S-keto ester in a single step. Thus, in the synthesis of ethyl ben- > zoylacetate (55%)> ethyl acetoacetate and ethyl benzoate are converted directly to this keto ester by distilling the lower-boiling product, ethyl acetate, thereby forcing the reaction to completion. ... 

Z)-2-butenylene dicarbonate with dimethyl malonate gives a low yield (20—40%) of 2-vinylcyclopropane-l,l-dicarboxylate with up to 70% ee (Scheme 2-38) [54], Reaction with methyl acetoacetate or acetylacetone takes place in a different manner to give a dihydrofuran derivative (59% ee), which results from nucleophilic attack of enolate oxygen at the cyclization step, (c) Asymmetric elimination of an acetyl-acetate ester gives (R)-4-rerr-butyl-l-vinylcyclohexene of up to 44% ee (Scheme 2-39) [55]. (d) Palladium-catalyzed allylic silylation is also applied to asymmetric synthesis... 

The synthesis of a variety of substituted 1,4-dihydropyridines has been achieved by reaction of aldehydes, ethyl/methyl acetoacetates, and ammonium acetate in water using a phase-transfer catalyst under the action of MW irradiation. Compared with classical Hantzsch s reaction conditions, this new method consistently has the ad-... 

The Pd-catalysed allylation of carbon nucleophiles with allylic compounds via Jt-aUylpaUadium complexes is called the Tsuji-Trost reaction [32]. Typically, an allyl acetate or carbonate (54) reacts with a Pd-catalyst resulting in displacement of the leaving group to generate a Jt-allylpalladium complex (55) that can undergo substitution by a nucleophile (56) (Scheme 4.14). In 1965, Tsuji reported the reaction of ti-aUylpaUadium chloride with nucleophiles such as enamines and anions of diethyl malonate and ethyl acetoacetate. A catalytic variant was soon reported thereafter in the synthesis of allylic amines [33]. In 1973, Trost described the alkylation of alkyl-substituted 7i-aUylpalladium complexes with methyl methylsulfonylacetate... 

N-Benzyloxyamino acids have also been esterified (203) to give O-protected substrates (275-277) for the synthesis of N-hydroxypeptides (Scheme 56). To obtain methyl (275), tert-hutyl (276) and benzyl (277) esters diazomethane, tert-huiy acetate with perchloric acid and benzyl chloride with acetoacetate were used, respectively. N-Isopropoxyamino acid esters (291) have also been prepared (203). 

Lee used baker s yeast in his enzymatic approach to the synthesis of 1,4-dihydropyridines. The traditional Hantzsch synthesis was explored whereby 2 equiv of methyl acetoacetate 180 and ammonium acetate were treated with baker s yeast in a phosphate buffer to produce the corresponding dihydropyridine 179 in 67% yield. A modified Hantzsch was also employed in the synthesis of asymmetrical derivative 277. Treatment of 1 equiv of methyl acetoacetate 180 with 1 equiv of crotonitrile 217 gave the corresponding dihydropyridine derivative 277 in 46% yields. The traditional and modified approaches were also conducted using ethyl acetoacetate with similar yields for the reported reaction products. 

Vigante and co-workers used the Hantzsch synthesis to prepare a series of novel symmetrical and unsymmetrical 1,4-dihydropyridine analogs to evaluate their antioxidant ability and therapeutic potential for the treatment of cancer. Reaction of P-unsaturated ketone 278 with p-aminocrotonate derivatives 214 and 210 in refluxing acetic acid gave the corresponding 1,4-dihydropyridine derivatives 279 and 280 in 70% and 65% yield, respectively. This method proved more effective than traditional Hantzsch syntheses involving phenothiazine and either 2 equiv methyl acetoacetate (37%) or P-... 

Zolfigol et al. [66] reported the synthesis of 1,4-DHP derivatives 46 and 47 under mild and solvent-free conditions using a mixture of ethanolamine, aldehydes, and methyl acetoacetate in the presence of acetic acid and iodine as a catalyst for the synthesis of 1,4-DHPs (Schemes 10.30 and 10.31). 

Acetoacetic ester synthesis (Section 22.7) The synthesis of a methyl ketone by alkylation of an alkyl halide with ethyl aceto-acetate, followed by hydrolysis and decarboxylation. 

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