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.

Enaminones as building blocks in organic syntheses: on the reaction of 3-dimethylamino-2-propenones with malononitrile

“…Anal. Calcd for C 12 Synthesis of 2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxamide (6). A mixture of compound 4a (2.41 g, 0.01 mol) in acetic acid (15 mL) as a solvent was treated with hydrochloric acid (10 mL), was refluxed for 1 h. The reaction mixture was cooled to room temperature and then poured onto ice-water.…”

“…[2][3][4][5][6][7][8][9][10] Our synthetic approaches have attracted attention. [11][12][13][14][15] Sometime ago we reported that enaminones 1 react with malononitrile in refluxing ethanolic sodium ethoxide solution to yield alkoxypyridines 2. 16 However, it was subsequently noted that in ethanolic piperidine solution compound 3 was produced.…”

Synthesis of 2-substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidin-4(3H)-ones

“…In the last decade, the synthesis of aminoethyl functionalized heterocycles has represented an important part of our research studies. Within this context, we have been so far focused on the synthesis of two types of 2-(heteroaryl) ethylamines: a) the open-chain analogues of histamine, 1, [10][11][12][13] and bicyclic conformationally constrained analogues of histamine, 2-4, [14][15][16] and b) 2-substituted 6-(5-oxo-1phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides, 5, as 2aminoethyl-functionalized pyrimidines [17]. In continuation, we have focused our attention on 2-substituted 6-(5-oxo-1phenylpyrrolidin-3-yl)pyrimidin-4(3H)-ones, 6, as novel type of 2-aminoethyl-functionalized pyrimidines (Scheme 1).…”

Parallel Synthesis of 2-Substituted 6-(5-Oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides

“…In this context, we first reported the synthesis of non-racemic 1-heteroaryl-2-phenylethylamines 1 – 3 from α-amino acid derived enaminoketones [16]. Further, the syntheses of the pyrazole analogues of histamine were developed: 2-aminoethyl substituted 1 H -pyrazole derivatives 4 – 6 as the open-chain analogues [17,18,19,20] and 6,7-dihydro-1 H -pyrazolo[4,3- c ]pyridin-4(5 H )-one derivatives 7 [21], 5-(2-aminophenyl)pyrazole derivatives 8 [22], and 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1 H -pyrazole-4-carboxamides 9 [23] as the conformationally constrained analogues of histamine. In continuation, we have focused our attention on 2-substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10 (Figure 1).…”