2-Aminopyrazoles, methylation with

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. 

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

The importance of this ring-opening reaction is illustrated by the following. 5-Methyl-isoxazole (110) on treatment with ammonia was partly converted into cyanoacetoneimine (111), and when refluxed with phenylhydrazine it yielded the 5-aminopyrazole (113) through the intermediate cyanoacetone (112) (63AHC(2)365). 

The acetylene aminopyrazole 103 was capable of inhibiting the processes of lipid peroxidation both in the enzymatic and nonenzymatic peroxidation system (76MI2). Finally, 4-[3-(l-methyl-l//-pyrazol-3-yl)-prop-2-ynyl]morpholine hydrochloride 104 was patented as a compound with high hypoxic activity (93MIP1). 

Under more vigorous conditions such as prolonged heating, the degradation of these isoxazoles is also effected by weaker nucleophilic reagents. Thus, 5-methylisoxazole (113) on treatment with ammonia is partly converted into cyanoacetoneimine (112) and when refluxed with phenylhydrazine yields l-phenyl-3-methyl-5-aminopyrazole (115), in the latter case undoubtedly via the intermediate formation of cyanoacetone (114). ... 

A typical cyclization reaction starting from a 3-aminopyrazole is the transformation of 255 <2000BML821 >. This compound was treated first with ethoxycarbonyl isothiocyanate followed by sodium methoxide to yield a cyclic intermediate which was methylated by methyl iodide to give the stable product 256. In the cases of the synthesis of 257 <1995PHA675>, the dimeric 258 <2005JHC975>, the azo-substituted 259 <2001JCM439>, and the diaryl... 

Several syntheses of indiplon have been described and two routes are shown in Scheme 15.5 (Sorbera et al., 2003 Dusza et al., 2002). Treatment of acetophenone 26 with refluxing dimethylformamide dimethylacetal (DMF-DMA) provided enamide 27. Alkylation of the amide with methyl iodide using NaH in DMF afforded 28. 3-Ketonitrile 29 was treated with DMF-DMA to give enamide 30. Cychzation with aminoguanidine produced aminopyrazole 31. The condensation of enamide 28 with aminopyrazole 31 in acetic acid furnished indiplon (4). Alternatively, enamine 28... 

Diazo(trimethylsilyl)methyl lithium (3) was found to be the reagent of choice for the synthesis of azoles from heterocumulenes (Scheme 8.43). The reaction is typically carried out in ether at 0-20 °C. Thus, alkyl- (or aryl-)substituted keteni-mines are transformed into 1,2,3-triazoles 188 (246), while C-acceptor-substituted ketenimines yield either 4-aminopyrazoles 189 or 1,2,3-triazoles, depending on the substituents (247). Isocyanates are converted into 5-hydroxy-1,2,3-triazoles 190 (248). Reaction of 3 with isothiocyanates are strongly solvent dependent. 

The understanding and discussion of pK (AG°) values needs knowledge of the structure of the species involved in the equilibrium. The problem of the tautomerism of neutral species is well known [Section IV,G and reference (76MI3)]. However, it is often not recognized that a similar problem arises with charged species, e.g., in cations formed on protonation of neutral molecules having two or more basic sites. This tautomerism can be classified as annular, as in benzotriazole (10) protonated forms, or as functional, as in 1-methyl-4-aminopyrazole (529) cations. 

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. 

The phenyl derivative (173 R1 =Ph, R2 = H) has been obtained (66%) by N-amination of 1-phenacylpyrazole followed by base-catalyzed cyclodehydration. Using a different approach the l-acyl-2-methyl compound (173 R1 = Me, Rz = COMe) is formed (58%) by condensation of 1-aminopyrazole with 3-chloropentane-2,4-dione [CHCl(COMe)2]. Treatment of the derivative (173 R1 = Me, R2 = COMe) with hot concentrated hydrochloric acid gives the 2-methyl derivative (173 R1 = Me, R2 = H) (78TL1291). 

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. 

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>. 

Almost all N-aminopyrazoles were obtained by the amination of pyrazole or its derivatives with HOSA or MSH (Table 11). Only on formation of l-amino-3,5-dimethylpyrazole having the - N label was labeled chloroamine used. As a rule, yields of N-aminopyrazoles are rather high, but with an increase in the number and size of substituents on the ring, yields decrease. 3(5)-methyl- and 3(5)-aminopyrazolcs are aminated with the formation of a nearly inseparable mixture of I-NH2-3-R- and I-NH2-5-R-pyrazoles in a 1 1 ratio. However, if the substituent at position 3 is more bulky, the main or even the dominant component in the mixture is l-NH2-3-R-pyrazole (compare for, instance, data for 3-ethyl- and 3-phenylpyrazoles in Table II). No doubt, this is the result of steric interference by the substituent. 

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. 

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