An Efficient and Regioselective Difluoromethylation of 3-Iodoindazole with Chlorodifluoromethane

Abstract

A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluoromethane is described. The reaction was extensively optimized with regard to combinations of base, solvent, addition order as well as stoichiometry. A key reaction parameter was the generation of a 2-M stock solution of the gaseous reagent chlorodifluoromethane in acetonitrile. This allowed control of the quantity of carbene generated in the reaction mixture, providing good N1-regioselectivity between the two reactive indazole nitrogens. Upon optimization of this protocol 1-difluo­romethyl-3-iodoindazole was synthesized on a preparative scale providing 14.2 grams of product in 59% yield.

Key words

alkylations - fluorinated carbenes - indazoles - chlorodi­fluoromethane - regioselectivity

References and Notes

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9

All reactions were run under normal atmosphere. ^¹H NMR and ^¹9F NMR spectra were run on a Varian Inova 400 spectrometer. ^¹³C NMR spectra were run at 100 MHz on the same spectrometer. Structure determination of isomers 3-5 was determined by 2D NMR on a Varion Inova 500 instrument equipped with cryoprobe, gHSQC, gHMBC. All chemical shifts are reported as δ relative to trimethylsilane. GC-MS ratios were determined using a Hewlett Packard 6870 series GC system with a 5973 mass selective detector. LCMS was run on a Hewlett Packard Series 1100 instrument. Purification was done using a Biotage version 2.0 with a Biotage 40M silica column. All solvents and reagents were obtained and used without further purification from commercial sources.
3-Iodoindazole (2): Indazole 2 was synthesized in accordance with Rault^¹0 using indazole (10.0 g, 85.0 mmol, Aldrich), DMF (150 mL), KOH (14.2 g, 254.0 mmol), and iodine (43.0 g, 169.0 mmol) to produce 2 (21.0 g, 82.2 mmol, 97%) as a yellow solid; mp 142-144 ˚C. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.52 (1 H, d, J = 8.0 Hz), 7.36-7.44 (2 H, m), 7.16 (1 H, d, J = 8.0 Hz). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 140.42, 127.23, 126.79, 121.24, 120.40, 110.53, 93.50. ESI-MS: m/z = 245 [M⁺ + H]. HRMS: m/z
[M + H] calcd for C₇H₆N₂I: 244.9576; found: 244.957.
CHClF ₂ Solution in MeCN: To a flame-dried round-bottom flask equipped with a stir bar were added anhyd MeCN (60 mL) and the flask was capped with a septum. The flask was then weighed and recorded. CHClF₂ (Synquest Labs Inc.) was vigorously bubbled through the solution using a Teflon needle for 15 min with constant stirring at 25 ˚C. The flask was weighed again and the molarity was calculated by mass of solution.
1-(Difluoromethyl)-3-iodo-1 H -indazole (3): Indazole 2 (20.0 g, 82.0 mmol) in MeCN (320 mL) was cooled to 0 ˚C and KOH (8 N, 20 mL) was added slowly over 10 min. After stirring at 0 ˚C for 30 min, CHClF₂ in MeCN (44 mL, 1.9 M, 82.0 mmol) was added by addition funnel over 15 min. The reaction mixture was allowed to warm to 25 ˚C and was stirred overnight. NH₄Cl (sat. aq; 100 mL) was then added and the organics were extracted with EtOAc (3 × 100 mL), dried with MgSO₄ and concentrated. Purification by chromatography (silica gel; 0-5% EtOAc-hexane) produced 3 as an off-white solid (14.16 g, 48.16 mmol, 59%); mp 86-89 ˚C. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.22 (1 H, t, J = 58.0 Hz), 7.86 (1 H, d, J = 8.4 Hz), 7.69 (1 H, dd, J = 8.0 Hz), 7.59 (1 H, d, J = 8.2 Hz), 7.44 (1 H, t, J = 7.5 Hz). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 138.08, 129.70, 129.14, 124.00, 121.86, 110.76, 110.60, 101.46. ESI-MS: m/z = 294.1 [M⁺ + H]. HRMS: m/z [M + H] calcd for C₈H₆N₂F₂I: 294.9544; found: 294.9557.
2-(Difluoromethyl)-3-iodo-2 H -indazole (4): isolated as an off-white solid (35 mg, 0.11 mmol, 4%); mp 89-92 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.19 (1 H, t, J = 57.2 Hz), 7.70 (1 H, d, J = 8.1 Hz), 7.50 (1 H, d, J = 8.6 Hz), 7.59 (1 H, dd, J = 6.5 Hz), 7.21 (1 H, t, J = 6.6 Hz). ^¹³C NMR (500 MHz, DMSO-d ₆): δ = 149.09, 129.05, 127.80, 124.25, 121.22, 118.44, 112.21, 77.88. ^¹9F NMR (400 MHz, DMSO-d ₆): δ = -37.69, -31.52, 28.38. ESI-MS: m/z = 294.1 [M⁺ + H]. HRMS: m/z [M + H] calcd for C₈H₆N₂F₂I: 294.9544; found: 294.9558.
2-(Difluoromethyl)-2 H -indazole (5): isolated as a colorless oil (14 mg, 0.08 mmol, 1%). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.89 (1 H, s), 8.16 (1 H, t), 7.79 (1 H, d, J = 8.0 Hz), 7.71 (1 H, d, J = 8.0 Hz), 7.39 (1 H, t, J = 8.0 Hz), 7.16 (1 H, t, J = 8.0 Hz). ^¹³C NMR (400 MHz, DMSO-d ₆): δ = 149.7, 128.10, 123.11, 123.04, 121.55, 121.15, 117.92, 111.06. ESI-MS: m/z = 168.2 [M⁺ + H]. HRMS: m/z [M + H] calcd for C₈H₇N₂F₂: 169.0577; found: 169.0580.