Re-enter the syn-(Me,I)Bimane: A Gateway to Bimane Derivatives with Extended π-Systems

Abstract

syn-α-Diiodobimane (syn-(R²,I)B) is a key intermediate for the derivatization of the bimane core in the α-positions. Here we describe an expeditious method to prepare symmetric α-bimane derivatives, such as syn-(R²,I)B, as well as unsymmetric ones. Our strategy turns the synthesis of α derivatives with extended π-systems practical and affordable. We applied this approach to the synthesis of ethynylbenzaldehyde bearing bimanes as potential selective probes for aldolase class I enzymes.

Key words

bimane - fluorescence - intermediate - iodobimane - derivatives

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• 17 Experimental Procedures For materials, methods, and analysis see the Supporting Information. Preparation of syn-(Me,Br)B (13) 5-Methyl-4,4-dihydropyrazol-3-one (4, 250 mg, 2.55 mmol) and K₂CO₃ (1.76 g, 12.75 mmol, 5 equiv) were suspended in 80 mL of DCM, and the mixture was stirred for 15 min. NBS (1 g, 5.61 mmol, 2.2 equiv) was added in one portion, and the mixture was stirred for additional 24 h at rt in the dark. The resulting crude was then diluted with DCM and filtrated through a bed of Celite^®. The filtrate was concentrated under reduced pressure, and the resulting residue was chromatographed over silica gel (from 100% CHCl₃ to CHCl₃–acetone mixture, 9:1) yielding 51 mg of syn-(Me,Br)B in 12% yield. ¹H NMR (400 MHz, CDCl₃): δ = 2.47 (s, 6 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 13.39, 97.78, 147.82, 155.43 ppm. MS (ES-API): m/z [M + H]⁺ calcd for C₈H₆Br₂N₂O₂: 320.89; found: 320.9. Preparation of syn-(Me,I)B (9) 5-Methyl-4,4-dihydropyrazol-3-one (4, 250 mg, 2.55 mmol) and K₂CO₃ (1.76 g, 12.75 mmol, 5 equiv) were suspended in 80 mL of DCM. The mixture was cooled down to –19 °C in the freezer compartment of a regular fridge, followed by the addition of NIS (2.87 g, 12.75 mmol, 5 equiv) in the dark. After stirring for 45 min at –19 °C, the mixture was diluted with DCM and filtered. The extraction of all the fluorescent products from the reaction flask was corroborated by visual inspection using UV light (395 nm). The resulting filtrate was concentrated under reduced pressure and reacted without further purification with a solution of ICl (132 μL, 2.55 mmol) in DCM that was added dropwise to the mixture in the dark (NIS can be used instead of ICl but the reaction is slower). After stirring for 45 min at rt in the dark, the solvent together with the excess iodine were removed under reduced pressure (during the evaporation the sublimated iodine had to be removed with a spatula several times), and the resulting residue was washed three times with 10 mL of CHCl₃ and two times with 10 mL of a CHCl₃–acetone mixture (4:1) to remove the remaining iodine together with all the soluble byproducts of the reaction (after each washing the supernatant was carefully removed using a Pasteur pipette leaving the syn-(Me,I)B precipitate on the bottom of the round-bottom flask), yielding 161 mg of syn-(Me,I)B (over 99% pure) in 30% yield. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.45 (s, 6H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 15.01, 68.27, 152.29, 157.24 ppm. MS (ES-API): m/z [M + H]⁺ calcd for C₈H₆I₂N₂O₂: 416.86; found: 416.8. Preparation of syn-(Me,Cl)(Me,I)B (14) 5-Methyl-4,4-dihydropyrazol-3-one (4, 500 mg, 5.10 mmol) and K₂CO₃ (3.52 g, 25.50 mmol, 5 equiv) were suspended in 80 mL of DCM. The mixture was cooled down to –19 °C in the freezer compartment of a regular fridge, followed by the addition of NIS (5.74 g, 23.43 mmol, 5 equiv) and 3-methyl-4,4-dichloro-2-pyrazolin-5-one (5, 850 mg, 5.10 mmol) in the dark. After stirring for 45 min at –19 °C, the mixture was diluted with DCM. The excess iodine was removed under reduced pressure and then with further washings with a dichloromethane–acetone (1:1) mixture until no impurities were left. The residue was flash chromatographed over silica gel eluting with a gradient of dichloromethane to ethyl acetate. A yellow colored mixture of mainly 14 and 9 was isolated (210 mg). The actual yield for 14 (19%) was estimated from the integration of the ¹H NMR signals. ¹H NMR (400 MHz, CDCl₃): δ = 2.46 (s, 3 H, CH₃), 2.49 (s, 3 H, CH₃) ppm. HRMS (ES-TOF): m/z [M + H]⁺ calcd for C₈H₆ClIN₂O₂: 324.9241; found: 324.9264. Data from LC–MS: 9, m/z = 416.9 [M + H]⁺ and 14, m/z = 324.9 [M + H]⁺. Preparation of 3a Bis(triphenylphosphine)palladium(II)-chloride (5.0 mg) and cuprous iodide (2.0 mg) were added to 4-ethynylbenzaldehyde (40.1 mg, 3.15 mmol, 10 equiv), diisopropylethylamine (0.53 mL, 3.03 mmol), and syn-(Me,Cl)(Me,I)B (14, 100 mg, 0.31 mmol) in MeCN (200 mL). The mixture was stirred at 80 °C for 1 h under nitrogen. The solvent was evaporated, and the residue was flash chromatographed over silica gel eluting with EtOAc–DCM. The product was isolated as a yellow solid in 52% (53 mg) yield. ¹H NMR (400 MHz, CDCl₃): δ = 2.50 (s, 3 H, CH₃), 2.59 (s, 3 H, CH₃), 7.66 (d, J = 8.4 Hz, 2 H, ArH), 7.86 (d, J = 8.4 Hz, 2 H, ArH), 10.02 (s, 1 H, CH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 191.42, 156.73, 154.39, 150.88, 144.38, 136.00, 132.27, 129.72, 128.50, 110.86, 102.37, 97.44, 80.38, 13.19, 11.88 ppm. UV (CHCl₃): λ_max = 410 nm. Fluorescence (CHCl₃) λ_max = 475 nm (ϕF: 0.83). HRMS (ES-TOF) m/z: [M+H]⁺ calculated for C₁₇H₁₁ClN₂O₃: 327.0536; found: 327.0549.