Construction of Dibenzazocine Skeleton by Regiocontrolled Ring-Expansion Reaction of Cyclic Oxime with DIBAL-H: Facile Synthesis of 17β-Hydroxy­steroid Dehydrogenase Type 3 Inhibitor

Abstract

Synthetic studies on a 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) inhibitor are described. The unsymmetrical dibenzazocine skeleton was constructed by a regiocontrolled ring-expansion reaction of a cyclic oxime with DIBAL-H.

Key words

reduction - ring expansion - rearrangement - hetero­cycles - regioselectivity

• References and Notes

• 1 Fink BE, Gavai AV, Tokarski JS, Goyal B, Misra R, Xiao H.-Y, Kimball SD, Han W.-C, Norris D, Spires TE, You D, Gottardis MM, Lorenzi MV, Vite GD. Bioorg. Med. Chem. Lett. 2006; 16: 1532
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• 5b We prepared 3-iodo-1-methylthiobenzene from 3-(methylthio)aniline by Sandmeyer reaction. This procedure is described in ref. 6.
• 6 Procedure for the Sandmeyer Reaction for the Synthesis of 3-Iodo-1-methylthiobenzene A 300 mL round-bottomed flask equipped with a magnetic stirring bar was charged with 3-(methylthio)aniline (4.00 mL, 32.5 mmol), crushed ice (24 g), and MeCN (24 mL). To the stirred solution was added concd H₂SO₄ (24 mL) at 0 °C over 30 min. To the slurry was added aq NaNO₂ (4.04 g, 58.6 mmol) in cold H₂O (8 mL) at 0 °C dropwise over 30 min to maintain an internal temperature below 5 °C. After the mixture was stirred at 0 °C for 30 min, the mixture was poured into a solution of KI (18.9 g, 114 mmol) in H₂O (24 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 5 min, and then the mixture was allowed to warm to r.t. and the solution was stirred for 1 h, after which time TLC (hexanes–EtOAc, 3:1) indicated complete consumption of the starting aniline. The reaction was quenched with H₂O, and the mixture was extracted with CHCl₃ three times. The combined organic extracts were washed with sat. aq NaHCO₃, sat. aq Na₂S₂O₃, and brine, dried over anhyd Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes) to afford 3-iodo-1-methylthiobenzene (7.71 g, 30.8 mmol, 95%) as a pale yellow oil. The spectral data of 3-iodo-1-methylthiobenzene was identical with those reported in ref. 5a.
• 7a Eaton PE, Carlson GR, Lee JT. J. Org. Chem. 1973; 38: 4071
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• 8 Procedure for the DIBAL-H-Mediated Reductive Ring-Expansion Reaction of 5b A two-necked 30 mL round-bottomed flask equipped with a magnetic stirring bar was charged with oxime 5b (175 mg, 0.503 mmol) and dry CH₂Cl₂ (5.0 mL). To the solution was added DIBAL-H (1.03 M in hexane, 3.0 mL, 3.09 mmol) dropwise at r.t. in a water bath for 10 min. The solution was stirred for 12 h, after which time TLC (hexanes–EtOAc, 3:1) indicated complete consumption of 5b. The reaction mixture was cooled to 0 °C, and diluted with Et₂O. The reaction was then quenched with MeOH and 2 M aq NaOH, and the mixture was extracted with Et₂O three times. The combined organic extracts were washed with brine, dried over anhyd Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes–EtOAc, 9:1) to afford an inseparable mixture of 4b and 11b (113 mg, 0.337 mmol, 67%) as a yellow solid. Analytical Data IR (neat): 3376 (br), 2919, 2891, 1592, 1484, 1258, 813, 756 cm^–1. ¹H NMR [400 MHz, CDCl₃, isomeric mixture (6:1)]: δ (major isomer) = 7.22–7.15 (m, 2 H), 6.96 (d, 1 H, J = 2.0 Hz), 6.90 (dd, 1 H, J = 8.0, 2.0 Hz), 6.89 (d, 1 H, J = 7.6 Hz), 6.46 (d, 1 H, J = 8.0 Hz), 4.35 (s, 2 H), 3.27–3.18 (m, 2 H), 3.16–3.08 (m, 2 H), 2.37 (s, 3 H); δ (minor isomer) = 7.02–7.15 (m, 3 H), 6.81 (d, 1 H, J = 8.0 Hz), 6.77 (dd, 1 H, J = 7.6, 2.0 Hz), 6.61 (d, 1 H, J = 2.0 Hz), 4.37 (s, 2 H), 3.27–3.18 (m, 2 H), 3.16–3.08 (m, 2 H), 2.41 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.5, 145.3, 140.7, 139.3, 137.3, 133.7, 132.5, 132.2, 132.1, 131.9, 131.8, 131.2, 130.22, 130.19, 129.7, 128.3, 127.7, 127.6, 125.8, 124.6, 122.5, 121.2, 119.9, 119.8, 51.1, 50.8, 35.4, 34.8, 32.1, 31.6, 17.9, 15.6. HRMS (ESI⁺): m/z calcd for C₁₆H₁₇BrNS [M + H⁺]: 334.0260; found: 334.0249.
• 9 5-Acetyl-5,6,11,12-tetrahydro-8-bromo-dibenz[b,f]-azocine (12a) Colorless plates. IR (neat): 2944, 1651, 1496, 1386, 1282, 724 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.12 (m, 4 H), 7.10–7.00 (m, 2 H), 6.96–6.88 (m, 1 H), 5.75 (d, 1 H, J = 14.8 Hz), 4.02 (d, 1 H, J = 14.8 Hz), 3.26–3.12 (m, 2 H), 2.94–2.72 (m, 2 H), 1.80 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.2, 140.5, 139.3, 139.0, 137.3, 132.7, 131.2, 131.1, 130.8, 128.7, 128.5, 128.0, 119.7, 52.0, 34.6, 30.9, 22.7. HRMS (ESI⁺): m/z calcd for C₁₇H₁₇BrNO [M + H⁺]: 330.0488; found: 330.0489.
• 10 Crystal Data for 12a C₁₇H₁₆BrNO; MW = 330.22, triclinic, a = 8.647(4) Å, b = 8.985(4) Å, c = 9.396(5) Å, α = 90.802(5)°, β = 96.809(6)°, γ = 102.040(6)°, V = 708.4(6) ų, T = 173(2) K, space group P1, Z = 2. The final residuals were R = 0.0663 and wR2 = 0.1682. Crystallographic data of 12a have been deposited with the Cambridge Crystallographic Data Centre (CCDC) as supplementary publication no. CCDC 903314. Copies of the data can be obtained free of charge from the CCDC via http://beta-www.ccdc.cam.ac.uk/pages/Home.aspx.
• 11 5-Acetyl-5,6,11,12-tetrahydro-8-bromo-2-methylthio-dibenz[b,f]azocine (12b) Colorless oil. IR (neat): 3002, 2921, 1657, 1491, 1386, 1286, 754 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.20 (m, 2 H), 7.03 (dd, 1 H, J = 8.0, 2.0 Hz), 6.97 (dd, 1 H, J = 8.0 Hz), 6.91 (d, 1 H, J = 8.0 Hz), 6.89 (d, 1 H, J = 2.0 Hz), 5.73 (d, 1 H, J = 14.8 Hz), 3.99 (d, 1 H, J = 14.8 Hz), 3.24–3.10 (m, 2 H), 2.88–2.70 (m, 2 H), 2.42 (s, 3 H), 1.80 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.3, 139.4, 139.3, 139.1, 137.3, 137.2, 132.7, 131.1, 130.8, 128.8, 128.4, 125.1, 119.8, 52.0, 34.7, 30.7, 22.7, 15.3. HRMS (ESI⁺): m/z calcd for C₁₈H₁₉BrNOS [M + H⁺]: 376.0365; found: 376.0381.
• 12 5-Acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azocine (1) Colorless oil. IR (neat): 3027, 2930, 1658, 1494, 1389, 765 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.49 (d, 2 H, J = 7.2 Hz), 7.45–7.27 (m, 5 H), 7.21–7.00 (m, 5 H), 5.83 (d, 1 H, J = 14.8 Hz), 4.16 (d, 1 H, J = 14.8 Hz), 3.38–3.15 (m, 2 H), 3.00–2.81 (m, 2 H), 1.82 (s, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 170.3, 140.5, 139.43, 139.37, 139.1, 135.4, 131.2, 129.9, 128.8, 128.7, 128.6, 128.54, 128.46, 127.8, 127.1, 126.9, 126.3, 52.8, 34.8, 31.2, 22.8. HRMS (ESI⁺): m/z calcd for C₂₃H₂₂NO [M + H⁺]: 328.1696; found: 328.1699.