Utility of cyanoacetic acid hydrazide in heterocyclic synthesis

This review describes the synthesis and reactions of cyanoacetic acid hydrazide as building block for the synthesis of polyfunctionalized heterocyclic compounds with pharmacological interest.


Introduction
Cyanoacetic acid hydrazide is a versatile and convenient intermediate for the synthesis of wide variety of heterocyclic compounds.The β-functional nitrile 1-4 moiety of the molecule is a favorable unit for addition followed by cyclization or via cycloaddition with numerous reagents providing heterocyclic compounds of different ring sizes with one or several heteroatoms that are interesting as pharmaceuticals, 5,6 as herbicides, 7 as antibacterial agents, 8 and as dyes. 9,10Their reactions with dinucleophiles usually result in the formation of polycyclic ring systems which may be the skeleton of important heterocylic compounds.In previous publications, novel synthesis of azoles, 11,12 azines, 13 and azoloazines, 14 had been reported utilizing β-functional nitriles as starting components.Among the β-functional nitriles, cyanoacetic acid hydrazide and their analogues are especially important starting materials or intermediates for the synthesis of various nitrogen-containing heterocyclic compounds.Our research deals with the effective use of cyanoacetic acid hydrazide in the synthesis of a variety of polyfunctional heterocyclic compounds with biological interest.

Synthesis of Cyanoacetic Acid Hydrazide
Cyanoacetic acid hydrazide was obtained by careful addition of hydrazine hydrate to ethyl cyanoacetate in ethanol with stirring at 0°C. 15

Scheme 1
Cyanoacetic acid hydrazide can act as an ambident nucleophile, that is, as both an N-and a Cnucleophile.On treatment of cyanoacetic acid hydrazide with various reagents, the attack can take place at five possible sites: the nucleophile is able to attack the carbon of the carbonyl function (position 3) and the carbon atom of the nitrile function (position 5).While the active methylene group (position 4) and amino groups (positions 1 and 2) are able to attack electrophiles.

Reactions of Cyanoacetic Acid Hydrazide
The reactions of cyanoacetic acid hydrazide with numerous reagents are classified separately in one category due to the huge number of references.We have arranged this huge volume of data in terms of the type of the heterocycles formed, starting with five and six membered rings in order of increasing number of heteroatoms.Such systematic treatment provides a clear idea about the synthetic possibilities of the method and may be useful in selecting the direction of further research.

Thiophenes and their fused derivatives
Reaction of compound 2 with cyclic ketones and sulfur in the presence of morpholine under Gewald reaction conditions afforded thiophene derivatives 3 and 4. 16

Scheme 3
The reaction of 2 with alkylisocyanate yields alkylcarbamoyl derivative 6 that cyclized into pyrazole derivative 7 up on treatment with 2N sodium hydroxide. 17

Scheme 14
Compound 2 reacts with hydrazone derivatives in refluxing dioxane containing a catalytic amount of triethylamine to yield pyrazoloazine derivatives 30. 28

Thiazoles and their fused derivatives
Reaction of 2 with carbon disulfide in DMF and potassium hydroxide had been reported to afford nonisolable intermediate 31 that transformed into thiazole derivative 32 by the action of phenacyl bromide.On the other hand treatment of compound 32 with salicylaldehyde gave the 2H-chromen-2-one derivative 34 via the nonisolable arylidene 33 followed by intramolecular addition of hydroxy group to the nitrile function.

Scheme 28
Refluxing of 2 with benzylidenemalononitrile in ethanol in presence of piperidine gave pyridone derivative 54. 41tOH/piperidine

Scheme 29
On heating 2 and arylidene of ethyl cyanoacetate in ethanol containing triethyl amine under reflux afforded diaminopyridine derivative 58 rather than aminopyridine derivative 56. 42

Scheme 36
Refluxing of cyanoaceto-N-arylsulfonylhydrazide 15 with arylidenecyanoacetate in presence of pyridine 51,52 afforded pyridone derivative 73, while in the presence of ethanol containing a catalytic amount of piperidine 51

Scheme 37
Substituted N-benzoylaminopyridone 76 was prepared by cyclocondensation of Nbenzoylcyanoacetohydrazide 6c with ethyl acetoacetate in presence of sodium methoxide.

Scheme 41
The reaction of N-cyanoacetylhydrazone of epiandrosterone 81 with malononitrile in ethanol in the presence of a catalytic amount of piperidine afforded pyridine-2-one derivative 82. 57

Scheme 56
When anthranilonitrile was fused on an oil bath at 170 °C with different N-arylidenes of cyanoacetohydrazide 96 in presence of triethyl amine, it afforded triazolo[4,3-a]quinoline derivatives 106.Compounds 106 are assumed to be formed by the initial Thorpe-Ziegler addition 65 of the methylene group 96 to the CN group of anthranilonitrile to afford the acyclic intermediates 104, followed by loss of a water molecule to afford the acyclic intermediates 105, which in turn undergo a further cyclization via addition of the NH to the activated C=N to give the final products 106. 704-Amino-5-arylidenehydrazinocarbonylthiazole-2(3H)-thiones 131 were prepared by the reaction of N-arylidene cyanoacetic acid hydrazides 96 with sulphur and phenyl isothiocyanate in the presence of triethyl amine.These compounds were cyclized by acetic anhydride to give the corresponding thiazolo [4,5-d]pyrimidines 132. 86

Conclusions
The data considered in this review clearly demonstrate the high synthetic potential of cyanoacetic acid hydrazide.Many biologically active heterocyclic compounds have been

Scheme 9 The reaction of 2 10
Scheme 9