(R)-(−)-2-[(5-Oxido-5-phenyl-5λ⁴-isoquino[4,3-c][2,1]benzothiazin-12-yl)amino]benzonitrile

Abstract

Copper-catalyzed cross-coupling between (S)-S-methyl-S-phenylsulfoximine (1) and 2-iodobenzonitrile (2) resulted in the discovery of an unprecedented one-pot triple arylation sequence to give (R)-(−)-2-[(5-oxido-5-phenyl-5λ⁴-isoquino[4,3-c][2,1]benzothiazin-12-yl)amino]benzonitrile (4). Here, we describe the synthesis of the title compound (R)-4 and the elucidation of its structure by means of various techniques.

Introduction

Functionalized sulfoximines derived from (S)-S-methyl-S-phenylsulfoximine (1) are efficient chiral ligands in asymmetric metal catalysis [1,2,3,4,5,6]. Key step to access these compounds is the transition-metal catalyzed N-arylation reaction of (S)-1 with a suitable aryl halide. For an ongoing project towards novel sulfonimidoyl-based ligands we required (S)-N-(2-cyanophenyl)-S-methyl-S-phenylsulfoximine (3) in larger quantities. Originally, syntheses of (S)- and (R)-3 had only been achieved by palladium-catalyzed cross-couplings of the corresponding enantiopure sulfoximine 1 with 2-bromo- or 2-chlorobenzonitrile, respectively, [7,8,9]. Now it was envisaged to utilize a copper-catalyzed protocol [10] for the preparation of (S)-3 starting from 2-iodobenzonitrile (2). To our surprise, application of this copper-based system also furnished a novel compound [(R)-(−)-2-[(5-oxido-5-phenyl-5λ⁴-isoquino[4,3-c][2,1]benzothiazin-12-yl)amino]benzonitrile (4)], which was formed by an unexpected triple arylation cascade with aryl iodide 2 under these conditions.

Results and Discussion

Following the reported procedure [10], the N-arylation of sulfoximine (S)-1 was carried out with 2-iodobenzonitrile (2), cesium carbonate, and catalytic quantities of copper(I) iodide and N,N'-dimethylethylenediamine (DMEDA) in toluene (Scheme 1). However, arylation product (S)-3 was only obtained in 61% yield and a considerable amount (23%) of an unknown second compound was isolated. By diligent examination of all analytical data this product was identified as title compound (R)-4.

The unknown second compound was optically active which evidenced the retention of a stereogenic center at sulfur whose full stereochemical integrity could be confirmed by CSP-HPLC analysis. The IR spectrum unambiguously demonstrated the presence of a sulfonimidoyl moiety by displaying classificatory absorption bands at 1241 and 1149 cm⁻¹ for the S=O and S=N vibration, respectively [11]. Absorption bands at 3258 and 2221 cm⁻¹ were attributed to an amino and a nitrile group, respectively. Furthermore, three typical absorption bands at 1601, 1572 and 1515 cm⁻¹ showed vibrations of aromatic C=C bonds with diagnostic bands at 754 and 681 cm⁻¹ indicating both mono-substitution and 1,2-disubstitution of aromatic rings. The ¹H NMR spectrum taken in CDCl₃ consisted of 18 largely coupled sharp signals in the region of 7.11–8.81 ppm for carbon- and nitrogen-bound protons (the latter resonating at 10.51 ppm in d₆-DMSO). Importantly, the S-CH₃ singlet, typically around 3.20 ppm, was not present anymore, indicating a full substitution of the corresponding carbon atom. The ¹³C NMR spectrum recorded in CDCl₃ showed 11 quaternary carbons (with the nitrile carbon at 117.5 ppm) and 17 aromatic C-H groups. Consequently, the NMR data suggested a notably asymmetric molecular structure. All available mass spectrometric techniques provided a molar mass of 458 g mol⁻¹ for the unknown compound. From a combustion analysis an elemental composition of C₂₈H₁₈N₄OS was deduced which also supported the result of the MS experiments. Based on all these individual findings, the unknown compound was proposed to be (R)-(−)-2-[(5-oxido-5-phenyl-5λ⁴-isoquino[4,3-c][2,1]benzothiazin-12-yl)amino]benzonitrile (4). Finally, this assumption was unequivocally confirmed by X-ray crystal structure analysis of (R)-4 after recrystallization from acetonitrile (Figure 1).

Experimental

A large, flame-dried Schlenk tube under argon was charged with sulfoximine (S)-1 (0.897 g, 5.78 mmol), 2-iodobenzonitrile (2, 2.730 g, 11.56 mmol, 2.0 equiv.), Cs₂CO₃ (4.710 g, 14.45 mmol, 2.5 equiv.), CuI (0.110 g, 0.578 mmol, 10 mol%), dry toluene (12 mL) and DMEDA (126 µL, 1.16 mmol, 20 mol%) in the order given. After the Schlenk tube was tightly sealed with a stopper, the reaction mixture was stirred at 110 °C for 24 h and then cooled down to room temperature. DCM and aqueous HCl (c = 2 mol/L) were added. The organic phase was separated and the product was extracted from the aqueous layer with DCM three times. The combined organic phases were dried with MgSO₄ and filtered. After evaporation of solvents, the oily residue was subjected to column chromatography (SiO₂, n-pentane/EtOAc = 2/1). Product (R)-4 was isolated as a yellow solid. Additionally, sulfoximine (S)-3 was separately obtained as a yellow oil (61% yield, 0.899 g, 3.51 mmol).

Yield: 23% (0.616 g, 1.34 mmol); mp = 211–212 °C (racemate: 263–265 °C); [α] = −57.7 (c = 0.6 g, 100 mL⁻¹, CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ = 7.11 (ddd, J = 8.2 Hz, 7.1 Hz, 1.2 Hz, 1H, Ar-H), 7.25 (dd, J = 8.0 Hz, 1.1 Hz, 1H, Ar-H), 7.27 (td, J = 7.6 Hz, 1.0 Hz, 1H, Ar-H), 7.42–7.50 (m, 3H, Ar-H), 7.50–7.58 (m, 3H, Ar-H), 7.70 (dd, J = 7.8 Hz, 1.5 Hz, 1H, Ar-H), 7.78 (ddd, J = 8.8 Hz, 7.5 Hz, 1.6 Hz, 1H, Ar-H), 7.87–7.90 (m, 2H, Ar-H), 8.07 (dd, J = 7.6 Hz, 1.6 Hz, 1H, Ar-H), 8.19–8.24 (m, 2H, Ar-H and NH), 8.50 (dd, J = 8.1 Hz, 1.5 Hz, 1H, Ar-H), 8.81 (d, J = 8.4 Hz, 1H, Ar-H) ppm; ¹³C NMR (150 MHz, CDCl₃): δ = 103.4 (C), 105.5 (Ar-C), 116.9 (Ar-C), 117.5 (C), 118.4 (Ar-C), 120.3 (Ar-CH), 121.8 (Ar-CH), 122.3 (Ar-CH), 123.6 (Ar-CH), 123.8 (Ar-CH), 124.8 (Ar-CH), 125.9 (Ar-CH), 127.6 (Ar-CH), 127.7 (2 Ar-CH), 129.0 (2 Ar-CH), 132.0 (2 Ar-CH), 132.4 (Ar-CH), 132.5 (Ar-C), 132.8 (Ar-CH), 133.9 (Ar-CH), 141.7 (Ar-C), 144.0 (Ar-C), 144.2 (Ar-C), 148.0 (C), 153.2 (C) ppm; ¹H NMR [600 MHz, (CD₃)₂SO]: δ = 6.98 (ddd, J = 8.2 Hz, 7.2 Hz, 1.1 Hz, 1H, Ar-H), 7.11 (dd, J = 8.1 Hz, 0.8 Hz, 1H, Ar-H), 7.40 (ddd, J = 8.6 Hz, 7.2 Hz, 1.6 Hz, 1H, Ar-H), 7.53 (td, J = 7.7 Hz, 1.0 Hz, 1H, Ar-H), 7.56–7.60 (m, 2H, Ar-H), 7.60–7.64 (m, 1H, Ar-H), 7.67–7.73 (m, 2H, Ar-H), 7.80 (d, J = 8.0 Hz, 1H, Ar-H), 7.84–7.88 (m, 3H, Ar-H), 8.04 (dd, J = 7.8 Hz, 1.4 Hz, 1H, Ar-H), 8.12 (dd, J = 7.7 Hz, 1.8 Hz, 1H, Ar-H), 8.18 (dd, J = 8.1 Hz, 1.5 Hz, 1H, Ar-H), 8.68 (dd, J = 7.5 Hz, 1.7 Hz, 1H, Ar-H), 10.51 (s, 1H, NH) ppm; ¹³C NMR [150 MHz, (CD₃)₂SO]: δ = 103.5 (C), 110.2 (Ar-C), 117.0 (Ar-C), 117.4 (C), 118.0 (Ar-C), 119.7 (Ar-CH), 122.6 (Ar-CH), 123.6 (Ar-CH), 124.5 (Ar-CH), 125.6 (Ar-CH), 126.2 (Ar-CH), 127.1 (2 Ar-CH), 127.3 (Ar-CH), 127.4 (Ar-CH), 129.3 (2 Ar-CH), 131.7 (Ar-C), 131.8 (Ar-CH), 132.2 (Ar-CH), 133.0 (Ar-CH), 133.1 (Ar-CH), 133.9 (Ar-CH), 141.9 (Ar-C), 143.7 (Ar-C), 144.0 (Ar-C), 147.4 (C), 155.6 (C) ppm; IR (ATR): ν = 3640, 3258, 2324, 2221, 2020, 1980, 1936, 1601, 1572, 1546, 1515, 1484, 1459, 1422, 1376, 1333, 1277, 1241, 1206, 1149, 1092, 1038, 1009, 976, 844, 794, 754, 720, 681 cm⁻¹; EI-MS: m/z (%) = 458 (100) [M]⁺, 410 (15), 381 (22), 357 (9), 333 (62), 102 (6), 77 (12), 51 (10); CI-MS: m/z (%) = 499 (3) [M+C₃H₅]⁺, 487 (16) [M+C₂H₅]⁺, 459 (100) [M+H]⁺, 358 (7); ESI-MS: m/z (%) = 939 (9) [2M+Na]⁺, 497 (8) [M+K]⁺, 481 (24) [M+Na]⁺, 459 (42) [M+H]⁺, 358 (100); ESI-HRMS: m/z calcd for C₂₈H₁₉N₄OS: 459.12741; found 459.12793 with ∆ = 1.14 ppm; anal. calcd for C₂₈H₁₈N₄OS (458.54): C, 73.34; H, 3.96; N, 12.22; found C, 73.44; H, 4.09; N, 12.30; HPLC: t_r = 16.8 min [major], t_r = 25.2 min [minor] (Chiralpak AD-H, 0.6 mL min⁻¹, n-heptane/isopropanol = 60/40, λ = 230 nm, 20 °C); >99% ee.

Crystallographic data were collected with a Bruker Kappa APEX II CCD-diffractometer with monochromatic Mo–Kα radiation (λ = 0.71073 Å) and a CCD detector. The structure was solved by direct methods using SHELXS-97 and refined against F2 on all data by full-matrix least-squares methods using SHELXL-97 [13,14].