Atropisomerism in the 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine Nucleus: Effects of Central Chirality at C3 on the N-Mesylation Reaction

Hidetsugu Tabata; Yuka Tsuji; Tetsuya Yoneda; Tomohiko Tasaka; Tetsuta Oshitari; Hideyo Takahashi; Hideaki Natsugari

doi:10.1055/s-0037-1609868

Synlett, Table of Contents

Synlett 2018; 29(16): 2141-2146
DOI: 10.1055/s-0037-1609868

cluster

Atropisomerism in the 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine Nucleus: Effects of Central Chirality at C3 on the N-Mesylation Reaction

Hidetsugu Tabata*

^aFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Email: h-tabata@pharm.teikyo-u.ac.jp Email: natsu@pharm.teikyo-u.ac.jp

,

Yuka Tsuji

^aFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Email: h-tabata@pharm.teikyo-u.ac.jp Email: natsu@pharm.teikyo-u.ac.jp

,

Tetsuya Yoneda

^aFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Email: h-tabata@pharm.teikyo-u.ac.jp Email: natsu@pharm.teikyo-u.ac.jp

,

Tomohiko Tasaka

^bAffinity Science Corporation, 1-11-1 Nishigotanda, Shinagawa-ku, Tokyo 141-0031, Japan

,

Tetsuta Oshitari

^aFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Email: h-tabata@pharm.teikyo-u.ac.jp Email: natsu@pharm.teikyo-u.ac.jp

,

Hideyo Takahashi*

^cFaculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan Email: hide-tak@rs.tus.ac.jp

,

Hideaki Natsugari*

^aFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Email: h-tabata@pharm.teikyo-u.ac.jp Email: natsu@pharm.teikyo-u.ac.jp

^bAffinity Science Corporation, 1-11-1 Nishigotanda, Shinagawa-ku, Tokyo 141-0031, Japan

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Abstract

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Published as part of the Cluster Atropisomerism

Abstract

The mesylation reaction of the 1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine nucleus was investigated in detail. Two diastereomers (A and B) of 5-mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines, originating from chirality at C3 and at the Ar–N(SO₂) axis were formed, among which isomers of the derivative with a methyl group at C6 (R = CH₃) were separable at room temperature. A and B had chair-like and boat-like conformations, respectively, in which the C3-methyl group adopts a pseudoequatorial arrangement. Furthermore, A and B were shown to be the thermodynamically and kinetically controlled products, respectively.

Key words

benzodiazepines - mesylation - atropisomerism - conformation - chirality

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References

References and Notes
1 New address: H. Natsugari, Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 112-0033, Japan.

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9 Note that, according to nomenclature rules, the atom numbering for 5–7 differs from for 1 and 2.
10 Estimated from the Boltzmann equation.
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12 Although compound 2B is the major product in the mesylation reaction at r.t. for 6 h in pyridine, the ratio of 2A/2B (1:2.6) might not reflect the exact product ratio of the reaction because, presumably, 2B was partially converted into 2A during the reaction.
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14 For detailed computational studies on 2A/2B, see the Supporting Information.

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16 For general experimental methods, see the Supporting Information.
17 5-Mesyl-1,3-Dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1) DMAP (21 mg, 0.17 mmol) and MsCl (0.13 mL, 1.72 mmol) were added to a stirred solution of 7a (61 mg, 0.35 mmol) in pyridine (3.5 mL) at 0 °C under argon. The mixture was stirred at 25 °C for 18 h and then the solvent was evaporated at 25 °C. H₂O (6.0 mL) and EtOAc (10 mL) were added to the residue, and the mixture was extracted with EtOAc (10 × 3 mL). The extracts were t washed with water, dried, and concentrated. The concentrate was purified by column chromatography [silica gel, EtOAc–hexane (1:5)] to give colorless crystals; yield: 68 mg (78%); mp 92–94 °C. IR (ATR): 2897, 1327 cm^–1. ¹H NMR (600 MHz, CD₂Cl₂): δ = 0.86 (d, J = 6.6 Hz, 3 H), 2.15 (br s, 1 H), 2.51 (br s, 1 H), 2.74–2.90 (m, 1 H), 2.85 (s, 3 H), 2.88 (s, 3 H), 2.97–2.99 (m, 1 H), 4.08 (br s, 1 H), 6.98–7.02 (m, 2 H), 7.26–7.30 (m, 1 H), 7.41 (dd, J = 1.0, 7.7 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 15.6, 32.9, 40.0, 42.5, 54.0, 62.1, 117.9, 122.2, 129.2, 131.3, 131.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₉N₂O₂S: 255.1162; found: 255.1164. 5-Mesyl-1,3,6-trimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (2) In a similar manner to the synthesis of 1 from 7a described above, compound 2 was prepared from 7b, except that the reaction was conducted for 6 h at 25 °C instead of 18 h at 25 °C and gave separable diastereomers of 2 (2A and 2B) in a ratio of 1:2.6 in 66% yield. These diastereomers were separated by column chromatography [silica gel, EtOAc–hexane (1:5)]. (aS*,3S*)-5-Mesyl-1,3,6-trimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (2A) Colorless crystals; yield: 24.5 mg (47.7%); mp 133–135 °C; TLC: R_f = 0.38 (silica gel, 25% EtOAc–hexane). IR (ATR): 2892, 1322 cm^–1. ¹H NMR (600 MHz, CD₂Cl₂): δ = 0.77 (d, J = 6.3 Hz, 3 H), 2.25 (dd, J = 10.9, 13.3 Hz, 1 H), 2.35–2.40 (m, 1 H), 2.37 (s, 3 H), 2.41 (dd, J = 12.1, 14.0 Hz, 1 H), 2.86 (s, 3 H), 2.92 (s, 3 H), 3.04 (ddd, J = 1.6, 3.6, 13.3 Hz, 1 H), 4.25 (ddd, J = 1.6, 3.5, 14.0 Hz, 1 H), 6.92 (d, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 7.18 (dd, J = 7.8, 7.8 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 19.0, 34.3, 34.9, 39.3, 50.3, 120.5, 129.1, 129.4, 130.1, 142.0, 143.2, 170.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₂₁N₂O₂S: 269.1318; found: 269.1319.(aR*,3S*)-5-Mesyl-1,3,6-trimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (2B) Colorless crystals; yield: 9.4 mg (18.3%); mp 127–130 °C; TLC: R_f = 0.31 [silica gel, 25% EtOAc–hexane]. IR (ATR): 2876, 1324 cm^–1. ¹H NMR (600 MHz, CD₂Cl₂): δ = 0.92 (d, J = 6.7 Hz, 3 H), 1.59–1.66 (m, 1 H), 2.34 (s, 3 H), 2.65 (ddd, J = 1.5, 4.0, 10.9 Hz, 1 H), 2.75 (s, 3 H), 2.89 (s, 3 H), 2.91 (dd, J = 10.9, 12.4 Hz, 1 H), 3.40 (dd, J = 11.9, 12.4 Hz, 1 H), 3.47 (ddd, J = 1.5, 4.2, 12.4 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.89 (d, J = 7.7 Hz, 1 H), 7.18 (dd, J = 7.7, 7.8 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 15.3, 18.3, 30.0, 37.8, 39.8, 52.1, 60.6, 123.7, 128.5, 140.5, 147.5, 155.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₂₁N₂O₂S: 269.1318; found: 269.1319.
18 Crystal Data for 1, 2A, and 2B All measurements were made on a RIGAKU RAXIS RAPID imaging-plate area detector with graphite monochromated Cu Kα radiation. The data were collected at a temperature of –100 °C. The structure was solved by the SIR92 direct method and expanded by using Fourier techniques. The nonhydrogen atoms were refined anisotropically. All calculations were performed by using the CrystalStructure crystallographic software package except for the refinement, which was performed by using SHELXL97 (See Ref. 19). Crystal data of 1 (see Ref. 20): C₁₂H₁₈N₂O₂S; mp 92–94 °C, M _r = 254.35, Cu Kα (λ = 1.54187 Å), monoclinic, P2₁/n, colorless prism: 0.25 × 0.20 × 0.05 mm, crystal dimensions: a = 7.83330(14) Å, b = 9.04486(16) Å, c = 18.1712(3) Å, β = 91.5053(10)°, T = 173 K, Z = 4, V = 1287.01(4) Å³, D _calc = 1.313 g/cm³, μCu Kα = 21.802 cm^–1, F₀₀₀ = 544.00, GOF = 1.063, R _int = 0.0376, R₁ = 0.0389, wR₂ = 0.1016. Crystal data of 2A (see Ref. 20): C₁₃H₂₀N₂O₂S: mp 133–135 °C, M _r = 268.37, Cu Kα (λ = 1.54187 Å), monoclinic, P2₁/n, colorless prism: 0.40 × 0.35 × 0.20 mm, crystal dimensions: a = 8.38672(15) Å, b = 8.82991(16) Å, c = 18.4671(4) Å, β = 92.8791(13)°, T = 173 K, Z = 4, V = 1365.84(4) Å³, D _calc = 1.305 g/cm³, μCu Kα = 20.811 cm^–1, F₀₀₀ = 576.00, GOF = 1.014, R _int = 0.0410, R₁ = 0.0348, wR₂ = 0.0906. Crystal data of 2B (see Ref. 20): C₁₃H₂₀N₂O₂S: mp 127–130 °C, M _r = 268.37, Cu Kα (λ = 1.54187 Å), triclinic, P-1, colorless prism: 0.35 × 0.20 × 0.08 mm, crystal dimensions a = 8.33(4) Å, b = 8.71(6) Å, c = 9.82(5) Å, α = 96.87(11)°, β = 106.76(8)°, γ = 94.85(14)°, T = 173 K, Z = 4, V = 672(7) Å³, D _calc = 1.325 g/cm³, μCu Kα = 21.137 cm^–1, F₀₀₀ = 288.00, GOF = 0.950, R _int = 0.1560, R₁ = 0.0719, wR₂ = 0.1790.
19 Sheldrick GM. SHELX97 [Includes SHELXS97, SHELXL97 and CIFTAB]: Programs for Crystal Structure Analysis (Release 97-2) . Institüt für Anorganische Chemie der Universität; Göttingen: 1998
20 CCDC 1837601, 1837602 and 1837601 contain the supplementary crystallographic data for compounds 1, 2A, and 2B, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Supplementary Material

Supporting Information