Ethyl cyanoacetate synthesis

Ethyl cyanoacetate (Section 111,131) is sometimes preferable to diethyl malonate for the synthesis of acids. It forms a sodio derivative with sodium ethoxide ... 

The preparation of ethyl cyanoacetate proceeds via ethyl chloroacetate and begins with acetic acid Wnte a sequence of reactions descnbmg this synthesis... 

D A R A P S K I Amino Acid Synthesis (see Curtius) Amino acid synthesis from ethyl cyanoacetates... 

Thus, the condensation product of cyclohexanone and ethyl cyanoacetate (125) affords the intermediate (126) for the synthesis of cyclobarbital (112) on alkylation with ethyl bromide. The condensation product of cycloheptanone (127) affords the starting... 

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). 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

The lH-l,2,4-triazole compounds possess important pharmacological activities such as antifimgal and antiviral activities [18-20]. In the present study, the reactive intermediates 45a-c, prepared in situ from the dichlorides 44a-c, were reacted via the cycloaddition reaction with ethyl cyanoacetate 40 to give, after spontaneous rearrangement, the triazole hydrazides 41a-c. These compoimds were used as starting materials for the synthesis of the... 

An alternative cyclopropane synthesis via an active methylene compound can also be enhanced by sonication [110]. The number of examples quoted in the literature is low but in the case of ethyl cyanoacetate and dibromoethane sonicated with potassium carbonate and polyethylene glycol in ethylene dichloride the expected cyclopropane is generated in 85 % yield (Eq. 3.19). 

An example of commercial interest is the synthesis of citronitrile (Scheme 17), a compound with a citrus-like odor, which is used in the cosmetics and fragrance industries. The first step in the synthesis of citronitrile is the Knoevenagel condensation of benzyl acetone and ethyl cyanoacetate. This condensation has been carried out with MgO and Al-Mg calcined hydrotalcites as catalysts (148). Similar results were obtained with the two solid catalysts, with yields of 75% of the Knoevenagel adduct. 

The application of the Gewald thiophene synthesis to the preparation of selenophenes has so far met with only very limited success. The reaction of cyclohexanone with ethyl cyanoacetate and selenium to provide the selenophene (213) gave only an 8% yield (73KGS326). 

Catalytic reduction of the 2-nitrophenyIhydrazones (745) and subsequent air oxidation of the tetrahydro-l,2,4-benzotriazines (746) which are formed is used for the synthesis of 3,4-dihydro-1,2,4-benzotriazines (747) (80FES715). In another cyclization of an o-nitro group, which somewhat resembles others (e.g. 736 —> 737) described earlier, treatment of l,l-dialkyl-2-(2-nitrophenyl)hydrazines (748) with acids affords 2-alkyl-1,2,4-benzotriazinium salts (749) (77JCS(P1)478). The 2-nitrophenylbromohydrazone (750) with sodium ethoxide and ethyl cyanoacetate forms 6-bromo-3-phenyl-l,2,4-benzotriazine (751) a mechanism for this interesting transformation, in which the cyanoacetate plays no part, has been proposed (79JHC33). 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

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,... 

Scheme 2 Rapoport s Synthesis a Et2S04, tris(2-hydroxypropyl)amine, acetone, A, 1.5 h, 88% b Na, Ethyl cyanoacetate, EtOH, 93% c Pt02, H2 (33-49 psi), 12N HCl/EtOH, 7h d toluene, reflux, 1 h, 100% for steps c and d e trimethyloxonium fluoroborate, CH2CI2, rt, 43 h f NaBH4, EtOH, 5-10 °C - rt, 24 h, 61% for steps e and f g 10% Pd/C, CH20 aq,...

---