The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline to 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl]2-(S)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1–2 equiv of H3PO4, 60 °C, 20 bar H2, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).

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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

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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.