title: One-pot parallel solution-phase synthesis of 1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols.
abstract: Two variations of enaminone-based parallel solution-phase synthesis of 1-substituted 4-(2-aminoethyl)-1 H-pyrazol-5-ols 8 and their NH-tautomers 8' were developed. The synthetic strategy comprises a two step preparation of the N-protected alpha-enamino lactams 3a and 3b from 2-pyrrolidinone (1), "ring switching" transformation of 3a, b with monosubstituted hydrazines 4a-u, and acidolytic removal of the N-protecting group. In order to ensure a clean and fast conversion, reactions of Cbz-enaminone 3a with hydrazines 4a-k were carried out under microwave irradiation to afford the "ring-switched" intermediates 7a-k. Deprotection of 7a-k with HBr-AcOH at 50 degrees C gave a library of 11 analytically pure 4-(2-aminoethyl)-1 H-pyrazol-5-ols (di)hydrobromides 8/ 8'a-k in 16-75% yields over two steps. The other reagent, Boc-enaminone 3b, was more reactive and ring switching transformations with hydrazines 4b, d, k proceeded smoothly and cleanly under conventional heating. Finally, a parallel one-pot transformation of the Boc-enaminone 3b with hydrazines 4a-u followed by subsequent deprotection of the intermediates 9a-u with HCl-EtOAc furnished a library of 21 analytically pure 4-(2-aminoethyl)-1 H-pyrazol-5-ols (di)hydrochlorides 8/ 8'a-u in 40-100% yields.
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, 1000 Ljubljana, Slovenia.
authors.forename: David
authors.initials: D
authors.lastname: Kralj
authors.forename: Ana
authors.initials: A
authors.lastname: Novak
authors.forename: Georg
authors.initials: G
authors.lastname: Dahmann
authors.forename: Uros
authors.initials: U
authors.lastname: Groselj
authors.forename: Anton
authors.initials: A
authors.lastname: Meden
authors.forename: Jurij
authors.initials: J
authors.lastname: Svete
mesh_terms: D000085:Acetates / Q000737:chemistry; D019342:Acetic Acid / Q000737:chemistry; D000588:Amines / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D006834:Hydrazines / Q000737:chemistry; D018054:Hydrobromic Acid / Q000737:chemistry; D006842:Hydrocarbons, Brominated / Q000737:chemistry; D006851:Hydrochloric Acid / Q000737:chemistry; D007769:Lactams / Q000737:chemistry; D008872:Microwaves; D008956:Models, Chemical; D011720:Pyrazoles / Q000138:chemical synthesis*; D011760:Pyrrolidinones / Q000737:chemistry; D012996:Solutions / Q000737:chemistry; D013696:Temperature
chemical_list: D000085:Acetates; D000588:Amines; D006834:Hydrazines; D006842:Hydrocarbons, Brominated; D007769:Lactams; D011720:Pyrazoles; D011760:Pyrrolidinones; D012996:Solutions; D018054:Hydrobromic Acid; C007650:ethyl acetate; C028537:2-pyrrolidone; D019342:Acetic Acid; D006851:Hydrochloric Acid