Oxidative Cyclization of Naphtholic Sulfonamides Mediated by a Chiral Hypervalent Iodine Reagent: Asymmetric Synthesis versus Resolution

^§ Author to whom correspondence regarding coupled preferential crystallization technology should be addressed.

Abstract

A chiral aryl iodide promotes the enantioselective oxidative cyclization of 1-naphtholic sulfonamides, albeit in moderate ee and low yield. The products tend to crystallize as conglomerates. Recrystallization thus increases their ee to > 99% ee. This highly enantioenriched material provides seed crystals for the resolution of the racemate (prepared in high yield by oxidative cyclization with (diacetoxyiodo)benzene in trifluoroacetic acid) by coupled preferential crystallization. This enables the production of significant quantities of highly enantioenriched products, despite the low efficiency of the enantioselective reaction.

Key words

asymmetric catalysis - coupled preferential crystallization - hypervalent iodine - sulfonamides - resolution

• References


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• 11 Experimental protocols: Most commercial reagents and solvents were used as received, except CH₂Cl₂, which was freshly distilled from CaH₂ under Ar. All reactions were performed under Ar in flame- or oven-dried flasks equipped with Teflon™ stirring bars and fitted with rubber septa for the introduction of materials via syringe. Reactions were monitored by thin-layer chromatography (TLC) using silica gel 60 F₂₅₄ pre-coated plates. Spots were visualized by UV or with KMnO₄ or vanillin stains. Flash chromatography utilized Silicycle^® 230–400 mesh silica gel. Unless otherwise stated, ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra were recorded from CDCl₃ solutions at r.t. Chemical shifts are reported in parts per million (ppm) on the δ scale and coupling constants, J, in hertz (Hz). Multiplicities are reported as ‘s’ (singlet), ‘d’ (doublet), ‘t’ (triplet), ‘q’ (quartet), ‘dd’ (doublet of doublets), ‘ddd’ (doublet of doublet of doublets), ‘m’ (multiplet), and further qualified as ‘br’ (broad), ‘app’ (apparent). Infrared (IR) spectra (cm^–1) were recorded from films (Perkin Elmer^® Universal ATR Sampling Accessories). Low- and high-resolution mass spectra (m/z) were obtained in the electron impact (EI) or electrospray (ESI; MeOH solutions) mode, as specified. Optical rotations were measured at the Na D line (589 nm) with a Perkin Elmer^® 241 polarimeter. Enantiomeric excesses reported in this experimental section were determined with a Thar SFC station (Model 840) equipped with chiral columns OD-H (0.46 cm × 25 cm × 5 μm), AD-H (0.46 cm × 25 cm × 5 μm), AS-H (0.46 cm × 25 cm × 5 μm), OJ-H (0.46 cm × 25 cm × 5 μm) and Lux 3u Cellulose 2 (50 × 4.60 mm). The operating pressure was 120 bar and the column temperature was 33–34 °C. Enantiomeric excesses of some of the compounds were determined by high-performance liquid chromatography (HPLC), which was performed with an Agilent 1100 HPLC, equipped with a variable wavelength UV/Vis detector and Chiralcel OD-H chiral column (0.46 cm × 25 cm × 5 μm), Chiralcel AD-H chiral column (0.46 cm × 25 cm × 5 μm), Chiralcel OJ-RH (0.46 cm × 15 cm × 5 μm). The intensities of the signals of each enantiomer in enantioenriched products were corrected on the basis the ratios of the signal intensities observed for the racemates. More detailed experimental protocols are provided in the Supporting Information. Enantioselective oxidative cyclization of sulfonamides 1: Typical procedure for (R)-(+)-2a: A solution of MCPBA (150 mg of commercial, 70% pure reagent, corresponding to 105 mg of MCPBA, 470 μmol, 1.3 equiv) in CH₂Cl₂ (8 mL) was added over 5 min (syringe) to a cold (–20 °C) solution of 1a (100 mg, 360 μmol, 1.0 equiv) and iodide 3 (50 mg, 72 μmol, 0.2 equiv) in CH₂Cl₂ (12 mL). The mixture was stirred at –20 °C and monitored for completion by TLC. After 13 h, the reaction was quenched with aq. sat. NaHCO₃ (10.0 mL) and aq. sat. Na₂S₂O₃ (5.0 mL), and extracted with CH₂Cl₂ (5 × 15 mL). The combined extracts were dried (Na₂SO₄) and evaporated. The residue was purified by flash column chromatography (EtOAc/hexanes, 2:3) to afford 2a (20 mg, 20%); [α] _d ²⁴ = +36.5° (c 0.59, CHCl₃). SFC analysis [Column: OD-H; 5:95:0.1 iPrOH/liq CO₂/diethylamine, flow rate = 1.0 mL/min; t_R (1) = 44.53 min (minor), t_R (2) = 52.79 (major)] indicated an ee of 67%. Spectral properties of the racemic compound are provided in ref. 5b. Compound (S)-(–)-2a: The same procedure described above was used, except that iodide 4 was employed instead of 3, to give (S)-(–)-2a (20 mg, 20%); [α] _d ²⁴ = –24.2° (c 0.58, CHCl₃). SFC analysis under the same conditions detailed above indicated an ee of 46% [t_R (1) = 44.50 min (major), t_R (2) = 53.15 (minor)]. (+)-2-(3-(Methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthal-en-2-yl 3-Chlorobenzoate [(+)-18]: Yield: 38 mg (25%) from 100 mg of 1a and catalyst 3; yellow oil; eluent: 2:3 Et₂O/pentane; [α] _d ²³ = +16.8° (c 0.06, CHCl₃). SFC analysis [Column: OD-H; 10:90:0.1 (iPrOH/liq CO₂/diethylamine), flow rate = 1.0 mL/min; t_R (1) = 44.10 min (minor), t_R (2) = 48.87 (major)] indicated an ee of 80%. IR (film): 3390–3156 (broad), 1721, 1690 cm^–1. ¹H NMR (CDCl₃, 300 MHz): δ = 8.09 (d, J = 7.8 Hz, 1 H), 8.00 (s, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H), 7.45–7.37 (m, 2 H), 7.32 (d, J = 7.7 Hz, 1 H), 6.78 (d, J = 10.0 Hz, 1 H), 6.13 (d, J = 9.9 Hz, 1 H), 4.33 (t, J = 5.9 Hz, 1 H), 3.15 (app q, J = 6.7 Hz, 2 H), 2.93 (s, 3 H), 2.20–2.10 (m, 1 H), 2.06–1.96 (m, 1 H), 1.91–1.75 (m, 1 H), 1.68–1.57 (m, 1 H). ¹³C NMR (CDCl₃, 75 MHz): δ = 195.7, 164.0, 136.8, 135.0, 134.6, 133.5, 132.6, 130.9, 129.9, 129.8, 129.4, 128.8, 128.2, 128.1, 127.7, 127.3, 80.6, 43.1, 40.4, 35.0, 23.5. HRMS: m/z [M – H]^– calcd for C₂₁H₁₉NO₅S³⁵Cl: 432.0672; found: 432.0670.