Approaches towards the synthesis of 5-aminopyrazoles

The biological and medicinal properties of 5-aminopyrazoles have prompted enormous research aimed at developing synthetic routes to these heterocyles. This review focuses on the biological properties associated with this system. Various synthetic methods developed up to 2010 for these compounds are described, particularly those that involve the reactions of β-ketonitriles, malononitrile, alkylidenemalononitriles and their derivatives with hydrazines, as well as some novel miscellaneous methods.


Review
The 5-aminopyrazole system represents an important heterocyclic template that has attracted considerable interest because of its long history of application in the pharmaceutical and agrochemical industries [1][2][3][4]. These compounds have been extensively investigated over the past one hundred years and their chemistry has been reviewed in two books published in 1964 [5] and in 1967 [6].
In view of significant interest in the synthesis of these heterocyclics, we herein report a detailed account of the synthetic methods available for 5-aminopyrazoles.
As pyrazole derivatives do not exist in nature, probably, due to the difficulty in the construction of N-N bond by living organisms, their availability depends on the synthetic methods. A large number of synthetic methods have recently appeared. Some of the important methods are outlined below.
Recently, Kordik et al [36] treated α-cyano-4-nitroacetophenone (10) with aryl hydrazines in the presence of triethylamine Scheme 3: Condensation of cyanoacetaldehyde (7) with hydrazines. and obtained the corresponding 5-aminopyrazoles 11 in excellent yields. The latter were further converted into their sulfonamide derivatives 12 by reducing the nitro group to an amino group by catalytic hydrogenation followed by treatment with an arylsulfonyl chloride (Scheme 4).
Alternatively, 5-aminopyrazoles 17 containing a cyclohexylmethyl-or phenylmethyl-sulfonamido group at position-3 were prepared by treating β-ketonitriles 16 with a substituted hydrazine in the presence of Et 3 N in ethanol under reflux conditions. The intermediate 16 was obtained from β-ketoester 15 on treatment with TFA, which in turn was synthesized by condensing 4-(phenylsulfonamidomethyl)cyclohexane carboxylic acid or benzoic acid 13, respectively, with tert-butyl cyanoacetate (14), as illustrated in Scheme 5 [36].
Another solid phase synthesis of 5-aminopyrazoles has been reported [39] by utilizing enamine nitrile 25 as the starting material (Scheme 8). In this reaction, compound 25 was readily hydrolyzed to afford the β-ketonitrile derivative, i.e., 4-(1cyano-2-oxoethyl)benzamide 26 which reacted efficiently with hydrazines to give the corresponding 5-aminopyrazoles 27. Subsequent cleavage from the resin afforded 5-aminopyrazoles 28. This new 5-aminopyrazole synthesis is more versatile and efficient than its predecessor as it avoids the use of troublesome β-ketonitrile functionality. This new route is also ideally suited for the synthesis of combinatorial libraries for drug target screening.

Reaction of malononitrile and its derivatives with hydrazines
Malononitrile (60) and its derivatives have been shown to react smoothly with hydrazines to yield 3,5-diaminopyrazoles that possess a wide spectrum of biological activity. As early as in 1884, Rothenburg [46] reported the simplest reaction, i.e., the condensation of malononitrile with hydrazine to give 3,5diaminopyrazole (61) (Scheme 15). The work was subsequently reinvestigated by Sato [47] who found that instead of 3,5-diaminopyrazole, two other products were produced. These compounds were characterized as 5-amino-4-cyanopyrazole 64 and 5-amino-3-hydrazinopyrazole (65). It was suggested that the formation of 64 resulted when two moles of malononitrile condensed with one mole of hydrazine. In this reaction dimerization of malonitrile 62 occurs before the reaction with hydrazine to give 63. However, when one mole of malononitrile condenses with two moles of hydrazine, the formation of 65 takes place via the mechanistic pathway outlined in Scheme 16.
Reaction of ketenes, particularly those with a cyano group at one end and a leaving group such as alkoxy, alkylthio or halogen at the other, with hydrazine and its derivatives has assumed great importance in the synthesis of 5-aminopyrazoles [56,57]. The advantage of this procedure resides in the frequent possibility of forecasting the structure of the reaction product.
Cheng and Robins [58] have reported the synthesis of 5-amino-4-cyanopyrazoles 76 by the reaction of hydrazines with alkoxymethylenemalononitriles 74a (Y = OR', Scheme 20). Similar results were obtained when aminomethylenemalononitriles 74b (Y = NHR') were treated with hydrazine indicating that reaction is initiated on the vinyl ether (vinylamine) group of 74a/b to give 5-aminopyrazole-4-carbonitrile 76 through the intermediacy of 75 [59]. However, Elnagdi et al. [60] have reported that when ethyl hydrazinoacetate condenses with 74a or b, a change in regiochemistry occurs to yield 3-amino-4cyanopyrazoles 77 (Scheme 20). An interesting synthesis of 5(3)-aminopyrazoles 81 and 82 [63] has been developed using thioacetals 79 and 80 of malononitrile, which are conveniently obtained by the reaction of aniline and diethyl phosphite with bis(methylthio)methylenemalononitrile 74d, respectively. Reaction with hydrazine monohydrate was thought to occur with loss of the methylthio group by nucleophilic attack of hydrazine and subsequent cyclization by attack on the cyano group (Scheme 22).
Acylated hydrazine, as expected, reacts with ethoxymethylenemalononitrile 74a in a similar manner. However, the reaction proceeds only in refluxing phosphorus oxychloride to produce compound 85 with a vinylated amino group (Scheme 24) [66]. Ketene dithioacetals 86 were utilized for the synthesis of corresponding pyrazole carbodithioates 88 by cyclization with methyl-or benzylhydrazine carbodithioate 87 in ethanolic TEA at room temperature. As before, the reaction proceeds via the nucleophilic substitution of the alkylthio group by the unsubstituted nitrogen of the hydrazine. The reaction of bis(methylthio)methylenecyanoacetamide 86 (R = CH 3 , X = CONH 2 ) with aromatic amines gave the corresponding 3-N-substituted aminoacrylamides 89, which on further treatment with phenylhydrazine furnished the corresponding 5-amino-3-arylamino-1phenylpyrazole-4-carboxamides 90 (Scheme 25) [67]. Synthesis of 5-amino-1-heteroaryl-3-methyl/aryl-4-cyanopyrazoles 102 has been carried out by us by treating various heteroarylhydrazines with alkylidenemalononitriles 101 in refluxing ethanol (Scheme 28) [70]. The starting material 101a (R = C 2 H 5 , R 1 = CH 3 ) was obtained by the reaction of malononitrile with triethyl orthoacetate in acetic anhydride whilst methoxyarylmethylidenemalonitriles 101b,c were obtained via a two step procedure involving the aroylation of the malonitrile with aroyl chlorides in the presence of NaH, followed by the treatment of the resulting intermediate with dimethyl sulfate.

Miscellaneous
In addition to methods involving the reaction of hydrazine with β-ketonitriles, malononitrile and its derivatives, a number of other procedures have also been developed for the synthesis of 5-aminopyrazoles. These methods are summarized below.
Another interesting synthesis that affords tetrasubstituted 5-aminopyrazole derivatives 162 involves the reaction of N,Ndisubstituted hydrazines 160 with ketones [88]. The hydrazones 161 so formed undergo cyclization in the presence of base to yield the desired compounds 162 (Scheme 46). Abdelhamid et al. [89,90] have reported the synthesis of substituted 5-aminopyrazoles 164 by the treatment of active methylene compounds such as malononitrile, ethyl cyanoacetate etc. with hydrazonoyl halides 163 in ethanolic sodium ethoxide (Scheme 47). Ioannidou and Koutentis [91] investigated the conversion of isothiazoles into pyrazoles on treatment with hydrazine. The influence of various C-3, C-4 and C-5 isothiazole substituents and some limitations of this ring transformation were investigated. When a good nucleofugal group (e.g., Cl, Br and I) is present at C-3 in the isothiazole 165, it is replaced by an amino group and 5-aminopyrazoles 166 are obtained. However, when the 3-substituent is not a good leaving group it is retained in the pyrazole product 167. A series of 3-chloro-5-substituted isothiazole-4-carbonitriles 168 bearing steric and/or electronic constraints at C-5 were also treated with anhydrous hydrazine and the corresponding 3-aminopyrazoles 169 were obtained in varying yields. However, when the substituent at C-5 in isothiazole was a better nucleofuge (e.g., PhO, PhS and Cl), the 5-hydrazinoisothiazole 170 was rapidly produced in good yield. Several isothiazoles 171 with a variety of C-4 substituents were also reacted with anhydrous hydrazine to yield the corresponding 3-amino-5-phenylpyrazoles 172. Reaction time and the yield of the reaction was dependent on the substituents present (Scheme 48). Scheme 48: Synthesis of 3-amino-5-phenylpyrazoles from isothiazoles.
Conclusion 5-Aminopyrazole is an important heterocyclic system which has great significance in pharmaceutical industry as well as being a useful synthon for the synthesis of many bridgehead heterocycles. This review describes new strategies and the development of novel concepts along with conventional methods to synthesize a wide variety of substituted 5-aminopyrazoles. Conventional methods such as condensation of β-ketonitriles, malononitrile and its derivatives with hydrazines in addition to modern methods of resin supported solid-phase synthesis, multi-component synthesis and ring transformations provide useful synthetic routes to 5-aminopyrazoles.