Ethyl 2- cyanoacetate hydrolysis

When acetone is condensed with ethyl cyanoacetate in the presence of a solution of anhydrous ammonia in absolute alcohol at —5°, the ammonium salt of the dicyano-imlde (I) is precipitated. Upon dissolving this salt in water and adding excess of concentrated hydrochloric acid, the crystalline dicyano-imide (II) is obtained. Hydrolysis of the last-named with strong sulphuric acid affords p p dimethylglutaric acid (III). 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, I21, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124). Hydrolysis affords vinbarbital (111). > ... 

Reaction of ethyl cyanoacetate with ethyl thiol acetate produces a and mixture of the dihydrothiazole derivative 80. This is ji-alkylated with methyl iodide and base (8 ), the active methylene group is brominated (82), and then a displacement with piperidine (83) is performed. Hydrolysis completes the synthesis of the diuretic agent, ozolinone (84). 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

The submitters prepared o-chlorohydrocinnamonitrile by the following procedure. Ethyl cyanoacetate (3040 g., 27 moles) was added to a solution of 140 g. (6.1 g. atoms) of sodium in 4 1. of absolute ethanol, followed by 970 g. (6 moles) of o.a-dichloro-toluene (Eastman Organic Chemicals), to afford 890 g. (63%) of ethyl 2-(o-chlorobenzyl)cyanoacetate,2 b.p. 117-123° (0.03 mm.). Hydrolysis of this material in 2 1. of 10% aqueous sodium hydroxide at room temperature gave a quantitative yield (790 g.) of 2-(o-chlorobenzyl)cyanoacetic acid, m.p. 129-132° without recrystallization. Decarboxylation of 750 g. of the acid in 750 ml. 

Methylsuccinic anhydride is prepared by condensation of ethyl 2-bromopropionate with ethyl cyanoacetate followed by hydrolysis of the nitrile, decarboxylation of the resultant p-ketoacid, and dehydration. 

Thus, with methyl and also ethyl cyanoacetate, the anilinomethylene chromonedione (220) (this form has been found94 to predominate in dimethylsulfoxide solution rather than the tautomeric structure of the formal SchifFs base from 3-formyl-4-hydroxycoumarin and aniline) yields, initially, with potassium hydroxide in DMF, following hydrolysis, the pyronocoumarin 221. 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

Dimethylglutaric acid has been prepared by heating di-methylpropanetricarboxylic acid above its melting point 3 by hydrolysis of the condensation product of ethyl cyanoacetate and ethyl /3,/3-dimethylacrylate 7 by the action of sulfuric acid on diethyl /3,/3-dimethyl-a,a -dicyanoglutarate 8 by hydrolysis of the nitrile obtained by the action of calcium cyanide on /3,/3-di-methylbutyrolactone 4 by the action of sulfuric acid on /3,/3-di-methyl-a,c/-dicyanoglutarimide 9 and by the action of sodium hypobromite on methone.5 The present procedure is essentially that of Walker and Wood.6... 

Several syntheses are on record which avoid the preparation of 5-benzyloxyindole in these procedures, the indole ring is usually formed after provision is made for the introduction of the ethanamine side chain. The first of these (107, 108) was an adaptation of Ewins original trypt-amine synthesis. A subsequent route (109) started from ethyl a-cyano-2,5-dimethoxycinnamate (VIII), which was prepared by condensation of 2,5-dimethoxybenzaldehyde with ethyl cyanoacetate. When this was boiled with potassium cyanide solution, addition of the elements of hydrogen cyanide was accompanied by hydrolysis of the ester function and decarboxylation, to give 2,5-dimethoxyphenylsuccinonitrile (IX). 

Excellent results were also obtained using activated hydrotalcite as a solid base catalyst in the Knoevenagel condensation of benzaldehyde with ethylcya-noacetate [110], ethylacetoacetate [111] or malononitrile [112] (see Fig. 2.34). Similarly, citronitrile, a perfumery compound with a citrus-like odor, was synthesized by hydrotalcite-catalyzed condensation of benzylacetone with ethyl-cyanoacetate, followed by hydrolysis and decarboxylation (Fig. 2.34) [113]. 

Tridecylic acid has been prepared by the malonic ester 33 1-thesisfrom imdecyl iodide, by the oxidation of a-hydroxymyristic add in acetone with potassium permanganate, by the action of dodecyl bromide on potassium cyanide and subsequent hydrolysis, and from imdecyl iodide and ethyl cyanoacetate. The present method is an adaptation of that of Ruzicka, Stoll, and Schinz. ... 

The amidine-functionalized cobalt(III) sarcophaginates with apical carboxylic acid and the complex resulting from its decarboxylation, as well as the [Co(MEazasar)]3+ azasarcophaginate (formed by capping with ammonia resulting from the hydrolysis of the ethyl cyanoacetate nitrile groups), are minor clathrochelate products of this reaction [134]. 

For purposes of classification the 4-aminopyrazoles are considered to be 4-imino-2-pyrazolines and analogs of 2-pyrazolin-4-ones. These compounds are listed in Table XL. Such compounds can be prepared by direct cyclization using ethyl diazoacetate and ethyl cyanoacetate.92 This is the same as eq. 243, except that the malonic ester is replaced by ethyl cyanoacetate. Purines can be hydrolyzed to 4-imino-2-pyrazolines by using strong acid.1210 1846 By far the most frequently used preparation is reduction of appropriately substituted pyrazoles, such as 4-nitro,368,812,819,1015,1019,1049 4-nitroso1165 or 4-aryl-azo.671 974,995 The hydrolysis of the carbethoxy 4-imino-2-pyrazolines derived from ethyl cyanoacetate and ethyl diazoacetate forms 4-imino-2-pyrazolin-3-carboxylic acid which is readily decarboxylated to the parent compound.92... 

In connection with a synthesis of the hydroazulenic sesquiterpene kessanol (304), Knoevenagel condensation of photocitral-A (302) with ethyl cyanoacetate was found to give (303) as a single isomer. The following sequence includes an intramolecular Prins reaction initiated with SnCU. In Isobe s synthesis of vemolepin (307) the two carbons of the -y-iactone are introduced by a Knoevenagei condensation. Reaction of ketone (305) with di-f-butyl maionate followed by treatment with DBU affords (306), which is transformed to the a,a -dihydroxy compound (308). Hydrolysis of the esters foliowed by decarboxy-iation, formation of the y-lactone, Mannich reaction and elimination yields vemolepin (307 Scheme 58).3"... 

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