3-(Triflyloxy)benzynes Enable the Regiocontrolled Cycloaddition of Cyclic Ureas to Synthesize 1,4-Benzodiazepine Derivatives

Abstract

A versatile synthesis of 1,4-benzodiazepine derivatives through the reaction of various 3-(trifluoromethanesulfonyloxy)benzynes with N-(p-toluenesulfonyl)imidazolidin-2-ones is reported. This reaction system provides a 1,4-benzodiazepine bearing a trifluoromethanesulfonyloxy group as a single regioisomer among the four possible regioisomers.

Keywords

benzodiazepines - benzynes - triflyloxy group - imidazolidinones - regioselectivity - directing group

• References and Notes


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• 12 1,4-Benzodiazepines 4; General ProcedureCsF (3.0 equiv) was flame-dried under reduced pressure in a flask equipped with a three-way stopcock, and the flask was backfilled with argon. Cyclic urea 2 (3.0 equiv) and a magnetic stirrer bar were loaded into the flask, which was subject to three cycles of evacuation and backfilling with argon. 1,4-Dioxane (one-fifth of the total volume of the solvent) was added to the flask from a syringe. A solution of the appropriate precursor 1a–f (1.0 equiv) in anhyd 1,4-dioxane (one-fifth of total volume) was added to the flask through a cannula, which was washed with 1,4-dioxane (three-fifth of total volume). The mixture was then stirred at 80 °C for 30–60 min until the benzyne reaction was complete (TLC). The reaction was then quenched by addition of H₂O. The aqueous phase was extracted with EtOAc (×3), and the organic phases were combined, washed with sat. brine, and dried (MgSO₄). The solvent was removed under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, hexane–EtOAc).
• 13 1-Methyl-5-oxo-4-tosyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-6-yl Triflate (4e; Table 1, Entry 5)By following the general procedure, a mixture of CsF (46 mg, 0.30 mmol), 1-methyl-3-tosyl-2-imidazolidone (2b; 76 mg, 0.30 mmol), and 2-(tert-butyldimethylsilyl)-1,3-bis(trifluoromethanesulfonyloxy)benzene (1a; 50 mg, 0.10 mmol) was stirred in 1,4-dioxane (1.0 mL) for 40 min at 80 °C. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:2)] to give a colorless solid; yield: 33 mg (69%); mp 47–50 °C. IR (neat): 1697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.44 (s, 3 H), 2.87 (s, 3 H), 3.36 (t, J = 5.5 Hz, 2 H), 4.11 (t, J = 5.5 Hz, 2 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.42 (dd, J = 8.0, 8.0 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.7, 40.5, 44.1, 58.6, 115.6, 118.4 (q, J = 319 Hz), 118.6, 122.7, 128.8, 129.3, 133.1, 135.3, 145.1, 147.3, 149.4, 164.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –73.0. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₁₈H₁₇F₃N₂NaO₆S₂: 501.0372; found: 501.0371. The regiochemistry of 4e was determined by NOE experiments.
• 14 (3aR)-6-Oxo-5-tosyl-2,3,3a,4,5,6-hexahydro-1H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-7-yl Triflate [(R)-4o; Table 3, Entry 1]By following the general procedure, a mixture of CsF (46 mg, 0.30 mmol), (R)-2-tosylhexahydro-3H-pyrrolo[1,2-c]imidazole-3-one [(R)-2k] (84 mg, 0.30 mmol), and 2-(tert-butyldimethylsilyl)-1,3-bis(trifluoromethanesulfonyloxy)benzene (1a; 50 mg, 0.10 mmol) in 1,4-dioxane (1.0 mL) was stirred for 40 min at 80 °C. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (2:3)] to give a yellow solid; yield: 35 mg (70%); mp 141–143 °C; [α]_D ²⁰ +5.5 (c 0.15, CHCl₃). IR (neat): 1699, 1684 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.86–1.98 (m, 2 H), 2.05–2.16 (m, 2 H), 2.43 (s, 3 H), 3.24–3.35 (m, 2 H), 3.48–3.52 (m, 1 H), 4.07 (dd, J = 4.5, 16.0 Hz, 1 H), 4.24 (dd, J = 3.0, 16.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 7.29–7.34 (m, 3 H), 7.95 (d, J = 8.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.6, 22.1, 29.5, 45.1, 48.9, 65.8, 112.6, 116.0, 117.3, 118.4 (q, J = 319 Hz), 129.1, 129.2, 132.7, 135.2, 145.0, 146.4, 148.6, 164.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –73.1. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₀H₁₉F₃N₂NaO₆S₂: 527.0529; found: 527.0519.The enantiomeric excess of the product (R)-4o was determined to be 88% by HPLC on CHIRALCEL AD-3 [hexane–i-PrOH (90:10), flowrate: 1.0 mL/min]; t_R [(R)-isomer] = 30.0 min, t_R [(S)-isomer] = 33.0 min. The absolute configuration was assigned on the basis of that of (R)-2k, synthesized from d-proline.