5-Amino-3-substituted pyrazoles

Diels-Alder addition of TADs, especially PTAD, to various five-, six-, and seven-membered heterocyclic systems has been described. For example, amino-substituted pyrazoles 93 give the corresponding [4+2] adducts... 

Substituted pyrazoles are formylated (Vilsmeier-Haack reaetion) and aeetylated (Friedel-Crafts reaction) at C-4 (B-76MI40402). Both hydroxy and amino substituents in positions 3 and 5 facilitate the reaetion (80ACH(105)127,80CHE1), but the heteroatoms eompete with the C-substitution. For instanee, when the amino derivative (91 R = = Ph, R = H)... 

Studies on the potential of the electrochemical approach to pyrazolotriazoles 117 showed that under the conditions of bicycle synthesis from 3-amino-4-hydrazonopyrazoles the N-l-unsubstituted triazole ring of 117 was further oxidized in a one-electron peak, followed by proton removal to yield the bis-(l,l )-2-phenylpyrazolo[3,4-i/][l,2,3]triazoles 118. This observation is significant, since in spite of pronounced pharmaceutical applications of pyrazoles, the redox characteristics of substituted pyrazoles have received limited attention (Scheme 13) <2001MI1022>. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

Most syntheses of imidazo-fused systems involve cyclization of amino substituted heterocycles (or their tautomers), suitably substituted at an adjacent ring position. This provides a convenient route to imidazo[2,1 -ft]thiazoles, imidazo[1,2- ]imidazoles (Scheme 4), imidazo[l,2-6]pyrazoles, imidazo[l,5- Jimidazoles and imidazo[l,5-c]thiazoles. 

The aromatic 2-substituted pyrazole 1-oxides 74 are derived from pyrazoles 89 by appending an oxygen atom to the pyridine type ring nitrogen atom of the pyrazole nucleus. The second nitrogen atom of the pyrazole ring can be attached to an alkyl, aryl, hydroxy, or amino group. 

Sakya SM, Rast B (2003) EfBcient synthesis of 5-alkyl amino and thioether substituted pyrazoles. Tetrahedron Lett 44 7629-7632... 

The orientation of the substituent gtoups in 1,2,4-oxadiazole substituted pyrazoles 39, formed by reaction of benzonittile oxides with an unsymmetrically substituted hydrazine, has been determined by C NMR assignments <1998JHC161>. The scope and limitations in the regioselective synthesis of 1,3,5-trisubstituted pyrazoles from / -amino enones and hydrazine derivatives were investigated by C chemical-shift prediction mles for 1,3,5-trisubstituted pyrazoles <2001H(55)331>. 

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 mechanisms of the cascade reactions of amino-substituted imidazoles, pyrroles, and pyrazoles with 1,3,5-triazines have been studied using MP2/6-31 U-K //B3LYP/6-31G calculations in both the gas phase and in solution <05JOC998>. 

The introduction of a carbonyl carbamate group at position 4 of the pyrazol-3-one ring can be done directly by fusion of appropriately 2-substituted /i-keto ester with a hydrazine (04TJC659) (Scheme 16). The jS-keto ester 67 was synthesized in two steps from ethyl 4,5-dioxo-2-phenyl-4,5-dihydrofuran-3-carboxylate 65 by decarbonylation to ethoxy-carbonylbenzoylketene intermediate 66 in refluxing benzene and then nucleophilic addition by methyl carbamate. Ethyl 2-benzoyl-3-[(methoxy-carbonyl)amino]-3-oxopropanoate 67 with diphenylhydrazine on heating in benzene gave 4-substituted pyrazol-3-one 68 in 44% yield. 

The most commonly used strategy for the synthesis of this class of C-nucleosides was the annulation of the 1,3,5-triazine ring onto suitably substituted pyrazol-4-yl C-nucleosides. Thus, the C-nucleosides 836, related to adenosine and formycin, was prepared by reacting the 3-aminopyrazol-4-yl C-nucleoside 832 with ethoxy V-cyanoformimidate (76JHC1305 96MI2) or by reacting the 3-amino-2-carbamimidoylpyrazol-4-yl C-nucleoside 835 with triethyl orthoformate [84H(22)345] (Scheme 218). 

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