Synthesis and Formation Mechanism of a Compound with an Unprecedented Skeleton: Dodecahydro-4,10:5,9-diepoxydipyrrolo[3,4-b:3′,4′-f][1,5]diazocine

Abstract

The reaction of N-(2-{[(tert-butyldimethylsilyl)oxy]imino}ethyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (6b) with BF₃·OEt₂ afforded a compound with an unprecedented dodecahydro-4,10 : 5,9-diepoxydipyrrolo[3,4-b:3′,4′-f][1,5]diazocine skeleton (7) after aqueous work-up. The formation mechanism of meso-7 appears to involve dimerization of the hydrated forms (6aS)-C and (6aR)-C of the initial racemic product 9 via cation B generated by facile protonation at the C3a position of 9. Extensive computational studies revealed that the driving force of the facile hydration of 9 is probably release of the ring strain of 9, which arises in part from the bent sp²-hybridized C3a carbon.

Introduction

Intramolecular cycloaddition of nitrones containing an alkene moiety is well known,¹⁾ and is frequently employed for the synthesis of nitrogen-containing natural products.^2–7) In contrast, the corresponding cycloaddition of nitrones having an alkyne moiety is much less well studied, and the products are often labile and undergo further transformation or rearrangement.^8–15) In particular, 2,3-dihydroisoxazoles fused with a five-membered ring at the 3,4 positions 1 are unstable due to ring strain, and to our knowledge, have never been isolated.^10–15) We have developed many intramolecular and intermolecular cycloadditions of N-borano-nitrones generated from O-silyl oxime and BF₃·OEt₂, which generally take place under mild conditions (room temperature to 50 °C),^16–20) and we considered that it might be possible to isolate a compound of type 1 formed from ω-alkynyl O-silyl oximes and BF₃·OEt₂. We report herein compound 7 having an unprecedented skeleton formed by the dimerization of 3-phenyl-5-tosyl-4,5,6,6a-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (9) generated from ω-alkynyl O-silyl oxime 6b and BF₃·OEt₂. The mechanism of formation of 7 was explored by computational methods.

First, we prepared O-silyloximes 6a and 6b from N-tosyl glycine derivative 2 (Chart 1). Compound 2 was propargylated with 3a and 3b in the presence of cesium carbonate in acetone to give 4a and 4b in 51 and 62% yields, respectively. Reduction of the esters of 4a and 4b with sodium borohydride afforded 5a and 5b in 54 and 71% yields, respectively. Oxidation of alcohol 5a with pyridinium chlorochromate (PCC) followed by condensation with O-(tert-butyldimethylsilyl)hydroxylamine yielded O-(tert-butyldimethylsilyl)oxyme 6a as a mixture of (E) and (Z)-isomers in 58% yield. O-(tert-Butyldimethylsilyl)oxyme 6b [(E) and (Z)-isomers, 22%] was obtained by three-step sequence; oxidation with PCC, condensation with hydroxylamine, and O-silylation with tert-butyldimethylchlorosilane.

Chart 1

With 6a and 6b in hand, we next examined their cycloaddition. O-Silyloxime 6a, on treatment with of BF₃·OEt₂ (3.3 equivalent (equiv.)) followed by extractive work-up with a saturated aqueous solution of NaHCO₃, afforded a complex mixture from which no product was isolable. In sharp contrast, similar treatment of 6b afforded a crystalline compound in a moderate yield.²¹⁾ However, the spectral data were not consistent with the expected product, 3-phenyl-5-tosyl-4,5,6,6a-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (9). Finally, the structure of the product was unambiguously established by X-ray diffraction analysis as 7²²⁾ (Chart 2 and Fig. 1).

Chart 2

Fig. 1. ORTEP Drawings of 7

(a) Top view. (b) Side view. (Color figure can be accessed in the online version.)

ORTEP drawings of the top and side views revealed that 7 has a highly symmetric, ladder-shaped structure, probably formed by dimerization of the intramolecular cycloaddition product 9 of N-boranonitrone A generated from oxime 6b and BF₃. The six-membered ring in the middle of 7 has a chair conformation that connects two isoxazolidine rings derived from 9. Detailed examination showed that product 7 is a meso-compound constituted from both enantiomers of racemic 9.

A plausible mechanism for the formation of 7 would involve hydrated compound C (Chart 3). Here, for convenience, we begin with the protonation of (6aS)-9. Thus, boron fluorides are removed from the initial cycloadduct (6aS)-8 by extractive work-up, which frees up the lone pair of oxygen in the cycloadduct. Then, (6aS)-9 is protonated at the 3a-position to generate oxonium cation (6aS)-B, which is hydrated to give (6aS)-C. Cation (6aS)-B undergoes an equilibrium addition reaction with (6aR)-C leading to D, which undergoes ring closure via oxonium ion E to provide the product 7.²³⁾

Chart 3

The crucial step in this sequence should be facile hydration of racemic 9 to afford (6aS)-C and (6aR)-C via oxonium ion B.^24–27) To gain insight into the mechanism of formation of compound 7 from the initial cycloadduct 9, we turned our attention to a computational study of compound 9, which should be highly reactive, as well as 3,4-dimethyl-2,3-dihydroisoxazole (F) for comparison, because most monocyclic 2,3-dihydroisoxazoles are sufficiently stable to be isolated.^9,25–27) M06-2X/6-31G(d) calculation of (6aR)-9 revealed high strain arising from the restriction imposed by the pyrrolidine ring (Table 1). The bicyclic structure of (6aR)-9 seems clearly strained compared to the mono-cyclic compound F (runs 1 and 2). In fact, the C4–C6 distance in (6aR)-9 is much shorter than the C6–C7 distance in monocyclic F (runs 3), and likewise the C4–C3a–C6a angle is much smaller than the C3–C4–C7 angle in F (run 4). The C4 and C5 in F and C3 in (6aR)-9 take planar forms (the sum of the three valence angles^28,29) is 360°) and they are typical sp² hybrid carbons, whereas C3a of (6aR)-9 is slightly pyramidalized (runs 5 and 6). In monocyclic F, the dihedral angles O1–C5–C4–C3 (3.8°) and O1–C5–C4–C7 (177.5°) are normal values for an alkene (runs 7 and 8 for F). In bicyclic (6aR)-9, in contrast, the dihedral angle O₂⁻C3–C3a–C6a (1.2°) takes a normal value, whereas O₂⁻C3–C3a–C4 (160.3°) deviates from 180° by approx. 20° suggesting that the C3a–C4 bond is out of plane [runs 6 and 7 for (6aR)-9]. Accordingly, the high reactivity of 9 may derive mainly from the bent structure of C3a (Table 1).

Table 1. Comparison of Calculated Structures of (6aR)-9 and F at the M06-2X/6-31G(d) Level and Some Reactions of (6aR)-9 and F

(Color figure can be accessed in the online version.)

To obtain the strain energy due to the bicyclic system of (6aR)-9, heats of hydrogenation and hydration were calculated for (6aR)-9 and monocyclic 2,3-dihydroisoxazole F (runs 9 and 10). As a result, the strain energies associated with the bicyclic structure were estimated to be 10.4 kcal/mol from hydrogenation and 5.6 kcal/mol from hydration. These calculations are consistent with the experimental fact that bicyclic 2,3-dihydroisoxazoles 1 are highly reactive, whereas the monocyclic compounds are, in general, stable enough for isolation. Thus, the driving force for facile hydration of the initial cycloadduct (6aR)-9 to cation B would be release of the ring strain, partially arising from the bent sp² carbon, C3a.

In conclusion, we have found compound 7, which has an unprecedented skeleton, is formed by dimerization of (6aS)-9 and (6aR)-9 generated by intramolecular cycloaddition of ω-acetylenic O-silyloxime via N-boranonitrone. Computational analysis of compound 9 revealed that the driving force of the facile hydration of 9, which is the crucial step in the dimerization, is release of the high ring strain of 9.

Experimental

General

Melting points were determined with a Yanagimoto micro melting point apparatus and are uncorrected. IR spectra were recorded with a Shimadzu FTIR-8200A, and ¹H-NMR and ¹³C-NMR spectra were recorded on a Bruker-AV300 (300 MHz) or a Bruker-AV600 spectrometer. Measurements of MS and high-resolution MS (HRMS) were performed with a JEOL JMS-700 mass spectrometer. Column chromatography was carried out on silica gel (Silica Gel 60 N, Kanto Chemical Co., Inc. or Silica Gel BW-127ZH, Fuji Silysia Chemical, Ltd.). Merck precoated TLC plates (silica gel 60 F254, 0.25 mm, Art 5715) were used for the TLC analysis. All computations were carried out with the GAUSSIAN 09 series of programs.³⁰⁾ All compounds were calculated by M06-2X³¹⁾/6-31G(d), and an ultrafine grid was used for geometry optimization.

Methyl 2-(Tosylamino)acetate (2)³²⁾

To a solution of glycine methyl ester hydrochloride (3.56 g, 28.3 mmol) and p-toluenesulfonyl chloride (8.10 g, 42.51 mmol) in CH₂Cl₂ (80 mL) was added dropwise a solution of Et₃N (9.60 mL, 70.9 mmol) and 4-dimethylaminopyridine (DMAP) (1.04 g, 8.50 mmol) in CH₂Cl₂ (30 mL) at 0 °C. The mixture was stirred at room temperature for 24 h, then diluted with a saturated aqueous solution of NH₄Cl, and extracted with CH₂Cl₂. The organic layer was dried (MgSO₄) and concentrated in vacuo. The residue was chromatographed on silica gel (hexane–Et₂O, 1/3) to give 2 (3.99 g, 58%) as a colorless solid. ¹H-NMR (300 MHz, CDCl₃) δ: 7.77–7.72 (2H, m), 7.34–7.29 (2H, m), 5.02 (1H, br s), 3.79 (2H, d, J = 5.5 Hz), 3.64 (3H, s), 2.43 (3H, s). The ¹H-NMR data were identical with those reported.³²⁾

Methyl N-(Prop-2-yn-1-yl)-N-tosylglycinate (4a)

To a mixture of 2 (3.00 g, 12.4 mmol) and Cs₂CO₃ (4.44 g, 13.6 mmol) in acetone (150 mL) was added propargyl bromide (3a, 1.00 mL, 13.6 mmol) at room temperature. The mixture was stirred at 60 °C for 3 h, then cooled and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (hexane–AcOEt, 2/1) to give 4a (1.77 g, 51%) as colorless crystals. mp 60–61 °C; IR (KBr) cm⁻¹: 3279, 2932, 2125, 1736, 1346, 1157; ¹H-NMR (300 MHz, CDCl₃) δ: 7.73 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 4.26 (2H, d, J = 2.4 Hz), 4.12 (2H, s), 3.70 (3H, s), 2.43 (3H, s), 2.14 (1H, t, J = 2.4 Hz); ¹³C-NMR (150 MHz, CDCl₃) δ: 168.9, 143.9, 135.9, 129.6, 127.5, 74.3, 52.3, 46.7, 37.4, 21.6 (one signal overlapped); electrospray ionization (ESI)-MS m/z: 304.0616 (Calcd for C₁₃H₁₅NNaO₄S [M + Na]⁺: 304.0620).

N-(2-Hydroxyethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (5a)

To a solution of 4a (0.10 g, 0.36 mmol) in MeOH (6 mL) was added NaBH₄ (0.082 g, 2.16 mmol) at 0 °C. The mixture was stirred at room temperature for 19 h, and then concentrated in vacuo. The residue was partioned between water and CH₂Cl₂, and the organic layer was dried (MgSO₄) and concentrated in vacuo. The residue was chromatographed on silica gel (hexane–AcOEt, 1/1) to give 5a (0.049 g, 54%) as colorless crystals. mp 57–58 °C; IR (KBr) cm⁻¹: 3516, 3260, 2951, 2116, 1344, 1167; ¹H-NMR (600 MHz, CDCl₃) δ: 7.75 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 4.21 (2H, d, J = 2.4 Hz), 3.80 (2H, q, J = 5.4 Hz), 3.36 (2H, t, J = 5.4 Hz), 2.43 (3H, s), 2.25 (1H, t, J = 5.4 Hz), 2.09 (1H, t, J = 2.4 Hz); ¹³C-NMR (150 MHz, CDCl₃) δ: 143.8, 135.4, 129.6, 127.7, 76.9, 60.5, 49.0, 37.9, 21.5 (one signal overlapped); ESI-MS m/z: 276.0678 (Calcd for C₁₂H₁₅NNaO₃S [M + Na]⁺: 276.0670).

N-(2-{[(tert-Butyldimethylsilyl)oxy]imino}ethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (6a)

To a stirred mixture of MS 4A (2 g) and pyridinium chlorochromate (0.64 g, 2.96 mmol) in 1,2-dichloroethane (60 mL) was added a solution of alcohol 5a (0.50 g, 1.96 mmol) in 1,2-dichloroethane (20 mL) at 0 °C over 10 min. The mixture was stirred at room temperature for 3 h, diluted with ether, and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was partitioned between water and ether. The organic layer was washed with brine, dried (MgSO₄), and concentrated in vacuo, and the residue was dissolved in CH₂Cl₂ (2.5 mL). To this solution were added MS 4A (1 g), O-tert-butyldimethylsilylhydroxylamine (0.29 g, 1.97 mmol) and PPTS (0.050 g, 0.20 mmol). The mixture was stirred at room temperature for 16 h, then filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (hexane-AcOEt, 6/1) to give 6a (0.28 g, 37%) as a mixture of (E)-isomer and (Z)-isomer (5/4). IR (NaCl) cm⁻¹: 3281, 2930, 2122, 1472, 1354, 1163; ¹H-NMR (300 MHz, CDCl₃) δ: 7.73 (2H, d, J = 8.1 Hz), 7.43 (1H × 5/9, t, J = 6.0 Hz, E-isomer), 7.25–7.35 (2H, m), 6.94 (1H × 4/9, t, J = 4.2 Hz, Z-isomer), 4.18 (2H × 4/9, d, J = 4.2 Hz, Z-isomer), 4.12 (2H × 4/9, d, J = 2.4 Hz, Z-isomer), 4.09 (2H × 5/9, d, J = 2.4 Hz, E-isomer), 3.97 (2H × 5/9, d, J = 6.0 Hz, E-isomer), 2.43 (3H × 4/9, s, Z-isomer), 2.43 (3H × 5/9, s, E-isomer), 2.10 (1H × 4/9, t, J = 2.4 Hz, Z-isomer), 2.05 (1H × 5/9, t, J = 2.4 Hz, E-isomer), 0.92 (9H × 4/9, s, Z-isomer), 0.91 (9H × 5/9, s, E-isomer), 0.16 (6H × 4/9, s, Z-isomer), 0.14 (6H × 5/9, s, E-isomer); ¹³C-NMR (75 MHz, CDCl₃) δ: 151.6, 149.5, 143.9, 143.8, 135.7, 135.5, 129.7, 129.6, 127.7, 127.6, 74.1, 74.0, 45.6, 42.6, 38.2, 36.8, 26.0, 25.9, 21.5, 18.1, −5.4 (several signals overlapped); ESI-MS m/z: 403.1485 (Calcd for C₁₈H₂₈N₂NaO₃SSi [M + Na]⁺: 403.1488).

Methyl N-(3-Phenylprop-2-yn-1-yl)-N-tosylglycinate (4b)

To a mixture of 2 (1.00 g, 4.10 mmol) and Cs₂CO₃ (1.47 g, 4.50 mmol) in acetone (50 mL) was added 3-chloro-1-phenyl-1-propyne (3b, 0.60 mL, 4.50 mmol) at room temperature. The mixture was stirred at 60 °C for 3 h, then cooled and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (hexane–AcOEt, 2/1) to give 4b (0.91 g, 62%) as colorless crystals. mp 80–81 °C; IR (KBr) cm⁻¹: 2959, 2239, 1759, 1348, 1163; ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (2H, d, J = 8.1 Hz), 7.30–7.24 (5H, m), 7.15 (2H, d, J = 8.1 Hz), 4.48 (2H, s), 4.16 (2H, s), 3.72 (3H, s), 2.37 (3H, s); ¹³C-NMR (75 MHz, CDCl₃) δ: 168.9, 143.8, 136.0, 131.6, 129.6, 128.6, 128.2, 127.6, 121.9, 86.1, 81.4, 52.3, 47.1, 38.4, 21.5; ESI-MS m/z: 380.0927 (Calcd for C₁₉H₁₉NNaO₄S [M + H]⁺: 380.0933).

N-(2-Hydroxyethyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (5b)

To a solution of 4b (0.10 g, 0.28 mmol) in MeOH (7 mL) was added NaBH₄ (0.042 g, 1.12 mmol) at 0 °C. The mixture was stirred at room temperature for 19 h, and then concentrated in vacuo. The residue was partioned between water and CH₂Cl₂, and the organic layer was dried (MgSO₄) and concentrated in vacuo. The residue was chromatographed on silica gel (hexane–AcOEt, 2/1) to give 5b (0.065 g, 71%) as colorless crystals.

mp 85–86 °C; IR (KBr) cm⁻¹: 3547, 2918, 2239, 1321, 1163; ¹H-NMR (300 MHz, CDCl₃) δ: 7.80 (2H, d, J = 8.4 Hz), 7.31–7.20 (5H, m), 7.10 (2H, dd, J = 8.4, 1.5 Hz), 4.42 (2H, s), 3.84 (2H, q, J = 5.7 Hz), 3.42 (2H, t, J = 5.7 Hz), 2.36 (3H, s), 2.16 (1H, t, J = 5.7 Hz); ¹³C-NMR (75 MHz, CDCl₃) δ: 143.6, 135.3, 131.3, 129.4, 128.3, 128.0, 127.6, 121.8, 85.5, 81.8, 60.3, 48.8, 38.5, 21.2; ESI-MS m/z: 352.0983 (Calcd for C₁₈H₁₉NNaO₃S [M + Na]⁺: 352.0983).

N-[2-(Hydroxyimino)ethyl]-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide

To a stirred mixture of MS 4A (0.5 g) and pyridinium chlorochromate (0.078 g, 0.36 mmol) in 1,2-dichloroethane (6 mL) was added a solution of alcohol 5b (0.079 g, 0.24 mmol) in 1,2-dichloroethane (2 mL) at 0 °C over 10 min. The mixture was stirred at room temperature for 2 h, then diluted with ether, and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was partitioned between water and ether. The organic layer was washed with brine, dried (MgSO₄), and concentrated in vacuo, and the residue was dissolved in EtOH–H₂O (1/1, 8 mL). To the solution were added NH₂OH·HCl (0.046 g, 0.66 mmol) and AcONa (0.055 g, 0.66 mmol). The mixture was stirred at room temperature for 21 h, then concentrated in vacuo, and the residue was partitioned between AcOEt and H₂O. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was chromatographed on silica gel (hexane–AcOEt, 3/1) to give the title oxime (0.023 g, 31%) as a mixture of (E)-isomer and (Z)-isomer (7/3) as a colorless solid. IR (KBr) cm⁻¹: 3547, 2918, 2239, 1491, 1344, 1163; ¹H-NMR (300 MHz, CDCl₃) δ: 8.4–8.2 (1H × 3/10, br), 8.0–7.75 (1H × 7/10, br), 7.77 (2H, d, J = 8.4 Hz), 7.43 (1H × 7/10, t, J = 5.7 Hz, E-isomer), 7.32–7.19 (5H, m), 7.17 (2H × 3/10, d, J = 8.4 Hz), 7.11 (2H × 7/10, t, J = 8.4 Hz, E-isomer), 6.91 (1H × 3/10, t, J = 4.2 Hz, Z-isomer), 4.34 (2H × 3/10, s, Z-isomer), 4.31 (2H × 7/10, s, E-isomer), 4.23 (2H × 3/10, d, J = 4.2 Hz, Z-isomer), 4.02 (2H × 7/10, d, J = 5.7 Hz, E-isomer), 2.35 (3H × 3/10, s, Z-isomer), 2.33 (3H × 7/10, s, E-isomer); ¹³C-NMR (75 MHz, CDCl₃) δ: 148.8, 146.7, 143.9, 135.6, 135.3, 131.5, 129.72, 129.66, 128.6, 128.5, 128.13, 128.09, 127.8, 122.0, 86.1, 81.4, 45.7, 42.6, 39.3, 37.9, 21.4 (several signals overlapped); ESI-MS m/z: 365.0940 (Calcd for C₁₈H₁₈N₂NaO₃S [M + Na]⁺: 365.0936).

N-(2-{[(tert-Butyldimethylsilyl)oxy]imino}ethyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (6b)

To a solution of the above oxime (0.023 g, 0.064 mmol) in DMF (0.5 mL) were added tert-butyldimethylsilyl chloride (0.013 g, 0.083 mmol) and DMAP (0.039 g, 0.32 mmol) at room temperature. The mixture was stirred 15 h, then diluted with H₂O and extracted with ether. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was chromatographed on silica gel (hexane–AcOEt, 6/1) to give 6b (0.022 g, 71%) as a 1 : 1 mixture of (E)- and (Z)-isomers as a colorless solid. IR (KBr) cm⁻¹: 3649, 2932, 2301, 1439, 1348, 1169; ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (2H, d, J = 8.4 Hz), 7.50 (1H × 1/2, t, J = 6.0 Hz), 7.32–7.19 (5H, m), 7.11 (2H × 1/2, br d, J = 8.4 Hz), 7.10 (2H × 1/2, br d, J = 8.4 Hz), 7.01 (1H × 1/2, t, J = 4.5 Hz), 4.33 (2H × 1/2, s), 4.30 (2H × 1/2, s), 4.25 (2H × 1/2, d, J = 4.5 Hz), 4.03 (2H × 1/2, d, J = 6.0 Hz), 2.35 (3H × 1/2, s), 2.34 (3H × 1/2, s), 0.91 (9H × 1/2, s), 0.89 (9H × 1/2, s), 0.15 (6H × 1/2, s), 0.14 (6H × 1/2, s); ¹³C-NMR (75 MHz, CDCl₃) δ: 151.8, 149.8, 143.9, 143.8, 135.7, 131.54, 131.50, 129.7, 129.6, 128.10, 128.06, 127.8, 127.7, 122.1, 86.0, 81.5, 81.4, 45.9, 42.8, 39.2, 37.8, 26.0, 25.9, 21.4, 18.1, −5.4 (several signals overlapped); ESI-MS m/z: 479.1785 (Calcd for C₂₄H₃₂N₂NaO₃SSi [M + Na]⁺: 479.1801).

(3aR*,4S*,5R*,5aS*,8aS*,9R*,10S*,10aR*)-5,10-Diphenyl-2,7-ditosyldodecahydro-4,10:5,9-diepoxydipyrrolo[3,4-b:3′,4′-f][1,5]diazocine (7)

To a stirred solution of O-TBS oxime 6b (0.10 g, 0.20 mmol) in 1,2-dichloroethane (2.0 mL) was added BF₃·OEt₂ (0.083 mL, 0.66 mmol) at 0 °C, and the mixture was stirred at room temperature. After 22 h, a saturated aqueous solution of NaHCO₃ (0.2 mL) was further added, and the mixture was stirred for 30 min. The mixture was diluted with H₂O (20 mL) and extracted with CHCl₃ (30 mL x 3). The organic layer was dried (MgSO₄) and concentrated in vacuo to give crystalline solid. Trituration of the solid with hexane-CHCl₃ afforded colorless crystals of 7 (26 mg) after filtration. The filtrate was concentrated and chromatographed on silica gel (hexane–CH₂Cl₂–ether, 5/5/1) to give 7 (8 mg, total 52%) as colorless crystals. mp >300 °C (CHCl₃–hexane); IR (KBr) cm⁻¹: 2859, 1597, 1474, 1342, 1167; ¹H-NMR (300 MHz, CDCl₃) δ: 7.48 (4H, d, J = 8.4 Hz), 7.40–7.20 (12H, m), 7.16 (2H, br d, J = 8.4 Hz), 3.99 (2H, td, J = 8.1, 6.3 Hz), 3.74 (2H, td, J = 8.1, 6.3 Hz), 3.36 (2H, dd, J = 10.2, 8.1 Hz), 3.03 (2H, dd, J = 10.2, 8.1 Hz), 2.82 (2H, dd, J = 10.2, 6.3 Hz), 2.43 (6H, s), 2.29 (2H, dd, J = 10.2, 6.3 Hz); ¹³C-NMR (75 MHz, CDCl₃) δ: 143.8, 133.6, 131.4, 129.5, 129.3, 129.0, 128.4, 128.0, 126.8, 126.0, 102.2, 66.0, 53.4, 52.3, 50.0, 21.6; ESI-MS m/z: 707.1963 (Calcd for C₃₆H₃₆N₄NaO₆S [M + Na]⁺: 707.1974).

X-Ray Diffraction Analysis²²⁾

Crystallographic data of compound 7 are given in Supplementary Materials.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

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