2-Aminopyrazol-3-ones, methylation with

A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-l//-pyrazoles by reaction of a-chloro-/ -arylacrylonitriles with hydrazine hydrate <2004RJ01518>. Reaction of 2-(3,3-dicyano-2-propenylidene)-4,4,5,5-tetra-methyl-l,3-dioxolane 641 with hydrazine afforded 3-(2-hydroxy-l,l,2-trimethylpropoxy)pyrazole 642 (Equation 134) <2003RJ01016>. Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic, and sulfonyl hydrazines led to the synthesis of N-l-substituted 3-acyM-cyano-5-aminopyrazoles, which are versatile intermediates for the synthesis of many biologically active scaffolds <2006TL5797>. 2-Hydrazinothiazol-4(5//)-one reacted with a variety of cinnamonitrile derivatives and activated acrylonitriles to yield annelated pyrazolopyrano[2,3-rf thiazole <1998JCM730>. 

The amino group of 2-aminopyrazol-3-one 16 was even more difficult to alkylate with methyl iodide (81JHC957) (Scheme 4). The reaction proceeded slowly under a variety of conditions and it was necessary to operate at higher temperatures, which lead to deamination of starting material. Thus, reaction of 5-aminopyrazol-3-one 16 with methyl iodide in ethanol at 100 °C in a sealed tube gave a mixture containing pyrazol-3-ones 17a,b, 18a,b and 19a,b. 

The second example of an acylation during which the acid chloride is generated in situ (67BCF88) (Scheme 12) involves the reaction of 4-aminopyrazol-3-one 30 with 2-hydroxy-5-(methoxycarbonyl)benzoic acids 47a c where phosphorus trichloride is used and gives methyl 3- [(3-oxopyrazol-4-yl)amino]carbonyl -4-hydroxybenzoates 48a c. 

Adembri et al. (72JHC1219) (Scheme 15) demonstrated the existence of a tautomeric mixture of 2-aminopyrazol-3-ones 47a-c/2-aminopyrazoles 48a-c in diethyl ether by methylation with diazomethane. The products were 2-amino-1-methylpyrazol-3-one 49a-c and 2-amino-3-methoxypyrazole 50a-c, respectively. 

Several specialized cyclization strategies should not be dismissed. A novel rhodium acetate-mediated cyclization was employed for the first synthesis of 3-methyl-4,6-diphenylfuro[3,4-tf]is-oxazole (9) from the 5-(a-diazobenzyl)isoxazole (185) (Equation (56)). The reactive intermediate is believed to be a carbenoid species <9iCB248i>. Another strategy exploits the reactivity of 4-halo-pyrazol-5-ones (e.g., 186) with stabilized anions (e.g., cyanoacetate esters and nitriles) to afford the 4-cyanofuro[2,3-c]pyrazol-5-ones (187) and 5-aminofuro[2,3-c]pyrazoles (188) (Scheme 30) <84H(22)2523>. Also of interest is the trichloroacetonitrile cyclization of aminopyrazole ketones (189) to the pyrrolo[2,3-c]pyrazoles (190) (Equation (57)) <86S74>. The generality of this cyclization is not known. 

Polyfluorinated aliphatic aldehydes reacted with 1-phenyl-3-methylpyrazol-5-one, l-phenyl-3-methyl-5-amino (N,N-dimethylaminomethylenamino)pyrazole, and l-phenyl-3-aminopyrazol-5-one at room temperature in the absence of catalyst with formation of 4-(l-hydroxypolyfluoroalkyl)pyrazoles <2000JFC(101)111>. Dehydration of the 4-(l-hydroxypolyfluoroalkyOpyrazoles with morpholinosulfur trifluoride generated 4-polyfluoroalkylidenepyrazoles, which were active dienophiles and reacted with 2,3-dimethylbutadiene and cyclopentadiene forming spirocyclic pyrazole derivatives. 

Bridged Sulfonamides. The most convenient syntheses of 3-bridged pyrazole sulfonamides utilizes either a mercapto group or amine functionality as a handle to prepare the requisite sulfonamide. For example, one can prepare a pyrazole sulfonamide with many of the required substituents by the scheme depicted below. Condensation of methyl hydrazine with chloroacrylonitrile yields N-methyl-3-aminopyrazole 58 (12-13). The amine is protected by acylation. Chlorination at the 4 position with sulfuryl chloride, followed by deprotection provides 3-amino-4-chloropyrazole 59. The sulfonamide 60 is prepared by decomposition of the diazonium salt of 59 in SO2/CUCI followed by amination of the resulting sulfonyl chloride. 

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