Ethyl a-bromoacetoacetate

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

Cyclocondensation of 2-amino-6-bromopyridine and 4-chloroacetoace-tate in PPA at 100 °C for 4h afforded a mixture of 2-chloromethyl-, 2-bromomethyl-6-bromo-, and 2-chloromethyl-, 2-bromomethyl-6-chloro-4//-pyrido[l,2-n]pyrimidin-4-ones in 84% yield (99JHC1065). The pyrido-[l, 2-a]pyrimidin-4-ones were separated by preparative reversed phase HPFC. The pure 2-bromomethyl-6-bromo-4//-pyrido[l,2-n]pyrimi-din-4-one was prepared from 2-amino-6-bromopyridine with ethyl 4-bromoacetoacetate in 63% yield. Reaction of 2-aminomethylpyridines and ethyl 4-chloroacetoacetate in PPA at 110°C gave 2-chloromethyl-4//-pyrido[l,2-n]pyrimidin-4-ones (95FFS69, 01H(55)535). 

Ethyl 2-bromoacetoacetate reacts with triethyl phosphite to give a mixture of diethyl l-(ethox-ycarbonyl)-2-oxopropylphosphonate (29%, Michaelis-Arbuzov product) aud diethyl l-methyl-2-(ethoxycarbonyl)vinyl phosphate (31%, Perkow product). By contrast, the reaction of diethyl bromomalonate with trialkyl phosphites takes only one course, and the products formed at either temperature are the enol phosphates (Perkow product) ... 

A series of carbapenams have been generated using the sulfide-contraction reaction to construct the constituent -amino acid segment. The thiopyroglutamate derivative (143) was condensed with ethyl 2-bromoacetoacetate in the presence of sodium bicarbonate to afford the a-acyl vinylogous carbamate (144 Scheme 31). The use of sodium bicarbonate in the sulfide contraction was critical in this particular... 

The Paal-Knorr cyclization was employed to produce highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads. Therefore, l,4-diketone-2,3-diester was assembled from an Sn2 displacement of ethyl 2-bromoacetoacetate with the anion of the ketoester. Condensation with an aniline then provided a library of fully substituted pyrroles. 

In the domino Michael/alkylation reaction applied to the synthesis of 3-(2H)-furanones, the ethyl 4-bromoacetoacetate 203 and nitrostyrene 204 were first trialed with a range of catalysts. In this instance, the so-called modified Feist Binary reaction was completed with an I-threonine bifunctional tertiary amine/thiourea catalyst 205 to produce the furanone 206 in excellent yield and high enantioselec-tivity (Scheme 7.42) [107]. In another report, the furan ring as part of other bicyclic or tricyclic systems was also prepared through an enantioselective Michael addi-tion/nucleophilic substitution reaction (Scheme 7.43) [108]. When diketones and ( )-P,P-bromonitrostyrenes 207 were stirred, again with a bifunctional thiourea... 

Experiment.—About 0-5 c.c. of ethyl acetoacetate is dissolved with shaking in the necessary amount of water, a few drops of ferric chloride solution are added, and to the cold solution dilute (1 10) bromine water is added, drop by drop, but rather quickly from a tap funnel, until the red colour of the ferric enolate has disappeared. The enol has now been completely used up by the bromine, but since, in order to restore the equilibrium, more enol is formed, the colour reappears after a short time and can at once be destroyed again by the addition of a few drops of bromine. The procedure can be repeated until the whole of the ethyl acetoacetate is converted into ethyl bromoacetoacetate. By means of this experiment the keto-... 

To 1170 g ethyl acetoacetate at 100-110°C was added a little at time 1605 g bromosuccinimide. After cooling to the mixture was added 300 ml of carbon tetrachloride. From the mixture was isolated ethyl ester of bromoacetoacetic acid which was distilled at 105-125°C/18 mm yield 67%. 

Bromacil may be prepared from bromoacetoacetic acid ethyl ester and icc-butyl urea in a two-step reaction according to the following scheme (Loux, 1962a,b) ... 

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