Nickel-Catalyzed Oxidative Cyclotrimerization of α-Amino Ketones: Selective Synthesis of Pyrazoles

Abstract

A new strategy for the synthesis of 3-methylene-2,3-dihydro-1H-pyrazoles is presented by Ni-catalyzed oxidative cyclotrimerization of α-amino ketones. This unprecedented method allows three α-amino ketones to undergo sequential multiple deprotonations and deamination through two C–C bonds and one N–N bond formation cascade.

Key words

nickel - oxidation - cyclotrimerization - α-amino ­ketones - pyrazoles

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• 10 Typical Experimental Procedure for the Ni-Catalyzed Cyclotrimerization of α-Amino Arylketones: To a Schlenk tube were added α-amino arylketones 1 (0.3 mmol), (C₅H₅)Ni(II)Cl(PPh₃) (5 mol%), PhCOOH (1 equiv) and DCE (CH₂ClCH₂Cl, 2 mL). Then the tube was sealed under air and stirred at 80 °C (the temperature of the heating bath) for the indicated time until complete consumption of the starting material as monitored by TLC and GC–MS analysis. After the reaction was finished, the reaction mixture was diluted with Et₂O, filtered by a short crude silica gel column and concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography (hexane–EtOAc) to afford the desired product 2. (Z)-(5-Benzylidene-1,2-diphenyl-2,5-dihydro-1H-pyrazole-3,4-diyl)bis(phenylmethanone) (2a): Yellow solid: 38.9 mg, 75% yield; mp 190.2–191.5 °C (uncorrected). ¹H NMR (500 MHz, CDCl₃): δ = 8.11 (d, J = 7.4 Hz, 1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.21–7.32 (m, 13 H), 7.09 (td, J = 7.3, 4.0 Hz, 7 H), 6.92–6.95 (m, 2 H), 6.59–6.62 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 191.9, 186.3, 144.0, 139.1, 138.7, 136.8, 132.6, 132.5, 131.4, 131.2, 130.9, 129.2, 128.7, 128.1, 127.9, 127.7, 127.5, 127.4, 127.0, 126.9, 126.8, 126.6, 125.3, 122.8, 120.0, 114.2. IR (neat): 1715, 1593, 1448, 1363, 1223, 958, 804, 736, 690 cm^–1. LRMS (EI, 70 eV): m/z (%) = 518 [M⁺] (100), 295 (94). HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₂₆N₂O₂: 519.2067; found: 519.2089.
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• 12 See the data in detail in Supporting Information (Figures S1 and S2 and Schemes S1 and S2).

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