A Simple Synthesis of 5‐(2‐Aminophenyl)‐1H‐pyrazoles

Abstract

A four-step synthesis of 1-substituted 5-(2-aminophenyl)-1H-pyrazoles 5 as a novel type of histamine analogs and versatile building blocks for further transformations was developed. The synthesis starts from commercially available 2-nitroacetophenone (12), which is converted into the enamino ketone 13 as the key intermediate. Cyclization of the key intermediate 13 with monosubstituted hydrazines 14a -14l afforded the 5-(2-nitrophenyl)-1H-pyrazoles 17a -17l. Finally, catalytic hydrogenation of the nitro compounds 17a, 17c -17e, and 17g -17j furnished the title compounds 5a, 5c -5e, and 5g -5j, respectively, in good yields. As demonstrated by some further transformations, additional functionalization of compounds 17 and 5 is feasible, either by electrophilic substitution at C(4) of the pyrazole ring, or at the NH 2 group.Introduction. -In biological processes, histamine, tyramine, dopamine, tryptamine, serotonin, and melatonin play a crucial role as chemical messengers. Therefore, preparation of their novel synthetic analogs based on the 2-(heteroaryl)ethylamine scaffold is an important target in medicinal and synthetic organic chemistry [1].Pyrazoles are an important class of heterocyclic compounds. Despite their rare occurrence in nature, numerous pyrazole derivatives have found use in various applications, and a general interest in their chemistry is still continuing (for a review, see [2]). Among numerous synthetic options for the construction of the pyrazole ring, two classical approaches are most frequently employed: a) cyclocondensation of a 1,3-dicarbonyl compound with a hydrazine derivative and b) 1,3-dipolar cycloaddition of a CÀNÀN type 1,3-dipole (diazoalkane, nitrile imine, or azomethine imine) to a C,C multiple bond [2].Recently, a part of our research has been focused on the synthesis of functionalized pyrazoles utilizing the

2-(Azolyl)anilines: methods of synthesis, cyclocondensations, and biological properties

“…The resulting (2-nitrophenyl)-azoles 18 and 19 were converted into the corresponding heterylanilines 20 and 21 via palladium-catalyzed reduction with quantitative yields. Janjic et al 4 obtained (2E)-3-(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one (16) by interaction of 2'-nitroacetophenone (14) with N,N'-dimethylformamide dimethyl acetal (DMFDMA). Compound 16 interacting with alkylor arylhydrazines formed 1-substituted 5-(2-nitrophenyl)-1H-pyrazoles 22 in 53-97% yield.…”

“…The first report, which described the hydrolytic cleavage of the pyrimidine ring of 2-alkyl [1,2,4] New potential inhibitors of vascular endothelial receptors of type 1 and 2 have been found among 2-(1-aryl-1H-1,2,4-triazol-3-yl)-N-(hetarylmethyl)aniline derivatives 70 synthesized using a four-step method by Kiselyov 32 (Scheme 24). It was shown, that interaction of 4-chloroquinazoline (67) with arylhydrazides 68 in anisole could be regarded as a nucleophilic substitution followed by nucleophilic opening of pyrimidine ring and formation of 2-(1-phenyl-1H-1,2,4-triazol-3-yl)anilines 69.…”

“…41 An effective copper-catalyzed synthesis of N-substituted heterocycles using ligands for the formation of the C-N bond was discussed in the work of Subramanian and Kaliappan 42 (Scheme 38). It was shown, that 2-(1H-imidazol-1-yl)-aniline (112a), 2-(1H-benzimidazol-1-yl)aniline (112b), or 2-(1H-1,2,4-triazol-1-yl)aniline (112c) reacted with 2-bromopyridines 113 in DMF in the presence of copper(II) acetate, potassium phosphate, and ligands (phenanthroline monohydrate or tetrabutylammonium iodide) affording 9-phenyl-9H-imidazo[1,2-a]benzimidazole (114a), 5-phenyl-5H-benzimidazo[1,2-a]benzimidazole (114b), or 4-phenyl-4H- [1,2,4]triazolo[1,5-a]benzimidazole (114c), respectively.…”

“…41 It was shown that compounds 62 in reaction with isocyanides in different solvents formed a mixture of two isomeric heterocycles, namely, 2-substituted 5-amino [1,2,4] The structure of key compounds was proven by X-ray diffraction analysis. 41 An effective copper-catalyzed synthesis of N-substituted heterocycles using ligands for the formation of the C-N bond was discussed in the work of Subramanian and Kaliappan 42 (Scheme 38).…”

Synthesis of 3-(2-aminoethyl)-5-hydroxy-1H-pyrazole derivatives

“…2 Recently, a part of our research has been focused on the synthesis of histamine analogues 2-5 based on aminoethyl functionalized pyrazole scaffold. [4][5][6][7] Within this context, syntheses of analogues 2 4 and 3 5 have been developed first, followed by synthesis of conformationally constrained histamine analogues 4 6 and 5 7 . Next, we focused our attention on 3-(2- We found pyrazolols 6 interesting because they are structurally closer analogues of histamine 1 than their known regioisomers 2.…”