Supporting Information
Diversity-Oriented Synthesis of Diazapenones.
Anil Vasudevan,* Clara I. Villamil and Stevan W. Djuric
Enabling Chemistry Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Il 60064
Supporting Information Page # I. General Experimental Procedures
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II. Spectroscopic and Analytical Data
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I.
Spectroscopic and Analytical Data
General Experimental
Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. All reagent solutions unless otherwise noted were handled under an inert nitrogen atmosphere using syringe and cannula techniques. All reactions unless otherwise noted were carried out in flame or oven-dried glassware under an inert nitrogen atmosphere. Reactions were monitored by TLC and LC/MS. Unless otherwise noted, all 1H and
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C spectra were recorded in deuterated pyridine. 1HNMR
was recorded on a Varian Unity-500 (500 MHz), Varian Unity-400 (400 MHz) or Varian Unity-300 (300 MHz). Chemical shifts are reported in parts per million (ppm) downfield from TMS which was added as an internal standard. Data are reported as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration and coupling constant. 13C-NMR was recorded on a Varian Unity500 (125 MHz), Varian Unity-400 (100 MHz) or Varian Unity-300 (75 MHz) spectrometer, using broadband proton decoupling. Chemical shifts are reported in parts per million (ppm) downfield from TMS which was added as an internal standard. Analytical LC/MS was performed on a Waters Alliance HPLC ZMD mass spectrometer system running MassLynx 3.4 and Openlynx 3.4 software. The ZMD mass spectrometer was operated under positive APCI ionization conditions. The HPLC system was composed of a Waters 2795 autosampler, a Waters 996 diode-array detector, and a Sedere Sedex-75 evaporative light-scattering detector (ELSD). The column used was a Phenomenex Luna Combi-HTS C8(2), 5 µm, 2.1 x 30 mm. A gradient of 10-100% acetonitrile (A)/0.1% trifluoroacetic acid in water (B) was used at a flow rate of 1.5 mL/min (0-0.1 min 10% A, 0.1-3.1 min 10-100% A, 3.1-3.9 min 100-10% A, 3.9-4.0 min 100-10% A). Unless otherwise specified, extracts were dried over MgSO4 and solvents were removed under reduced pressure. Microwave reactions were performed in a singlemode microwave cavity using either a Smith Synthesizer (www.biotage.com) or a CEM Explorer (www.cem.com) in a septa capped reaction vessel with stirring, at 300W. The maximum temperature attained by the sample is reported, and the time reported includes 2
the time required to reach the target temperature. Samples were cooled using 25 psi compressed air. Flash column chromatography was carried out using Merck 60 230-400 mesh silica gel according to the procedure reported by Still et al.1 Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, NJ.
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Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
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General procedure for the synthesis of β-lactam intermediates:
To a solution of the boc-protected amine (1 mmol) in 15 mL anhydrous CH2Cl2 was added the aldehyde (1.1 mmol) and the reaction stirred at room temperature for 18 hours. The solvent was evaporated, and the resulting product was purified using ethyl acetate:hexanes to afford the desired imine. A solution of the imine (1.0 mmol) in anhydrous CH2Cl2 was cooled to 0°C. Triethylamine (2 mmol) was added, followed by drop-wise addition of the appropriate acid chloride (1.1 mmol). The reaction was stirred at room temperature for 14 hours, following which 50 mL saturated NaHCO3 was added. The organic layer was extracted, dried and chromatographed on silica gel using ethyl acetate:hexanes to afford the desired β-lactam precursors as separated diastereomers.
General procedure for the synthesis of [1,4]-diazepin-5-ones: The boc-protected β-lactam (0.2 mmol) was stirred in 10 mL of 4N HCl/dioxane for 6 hours. The dioxane was evaporated under reduced pressure and 15 mL saturated NaHCO3 added, following which the desired amine was extracted. A solution of the amine in 2 mL anhydrous N, N-DMF was heated at 200 °C for 40 minutes (two times for 20 minutes each) in a single-mode microwave cavity. Once the samples had been cooled to ambient temperature using compressed air, the solvent was evaporated, and the residue chromatographed using ethyl acetate:hexanes to afford the desired products as a white solid.
3-(4-Chloro-phenyl)-4-methoxy-octahydro-pyrido[1,2-a][1,4]diazepin-5-one, 15. 1
H NMR (400 MHz): δ 7.64 (d, 2 H), 7.30 (d, 2 H), 4.78 (d, 1 H), 4.40 (d, 1 H), 3.85-3.90
(m, 2 H), 3.52 (m, 1 H), 3.34 (s, 3 H), 3.22 (dd, 1 H), 2.79 (dd, 1 H), 1.57 (m, 1 H), 1.371.52 (m, 5 H). MS (DCI) m/e: 309 (M+ H)+. Anal. Calcd for C16H21ClN2O2: C, 62.23; H, 6.85; N, 9.07. Found: C, 61.94; H, 6.82; N, 8.78. 4
2-(3-Naphthalen-2-yl-5-oxo-decahydro-pyrido[1,2-a][1,4]diazepin-4-yl)-isoindole1,3-dione, 16. 1
H NMR (400 MHz): δ 8.64 (s, 1 H), 8.14 (d, 2 H), 7.60-7.64 (m, 5 H), 7.31 (m, 2 H),
7.15 (d, 1 H), 6.38 (d, 1 H), 5.54 (d, 1 H), 4.04 (m, 2 H), 3.61 (m, 1 H), 3.44 (m, 2 H), 1.59 (m, 1 H), 1.41-1.58 (m, 5 H). MS (DCI) m/e: 440 (M+ H)+. Anal. Calcd for C27H25N3O3: C, 73.78; H, 5.73; N, 9.56. Found: C, 73.50; H, 5.35; N, 9.26.
3-Benzo[1,3]dioxol-5-yl-4-phenoxy-octahydro-pyrido[1,2-a][1,4]diazepin-5-one, 17. 1
H NMR (400 MHz): δ 7.24 (m, 5 H), 7.14 (d, 1 H), 6.92 (m, 2 H), 5.90 (d, 2 H), 4.91 (d,
1 H), 4.58 (d, 1 H), 4.08 (m, 1 H), 3.98 (m, 1 H), 3.42 (m, 1 H), 3.28 (m, 1 H), 2.92 (m, 1 H), 1.50 (m, 1 H), 1.44-1.62 (m, 5 H). MS (DCI) m/e: 381 (M+ H)+. Anal. Calcd for C22H24N2O4; C, 69.46; H, 6.36; N, 7.36; O, 16.82. Found: C, 69.36; H, 6.42; N, 7.25.
4-Benzyloxy-3-(4-chloro-phenyl)-octahydro-pyrido[1,2-a][1,4]diazepin-5-one, 18. 1
H NMR (400 MHz): δ 7.65 (d, 2 H), 7.34 (d, 2 H), 7.28 (m, 5 H), 4.96 (d, 1 H), 4.93 (d,
1 H), 4.45 (m, 2 H), 3.6-3.8 (m, 3 H), 3.25 (dd, 1 H), 2.81 (dd, 2 H), 1.4-1.5 (m, 5 H). MS (DCI) m/e: 385 (M+ H)+. Anal. Calcd for C22H25ClN2O2.0.25 H2O: C, 67.86; H, 6.60; N, 7.19; Found: C, 67.60; H, 6.21; N, 7.23.
6-Benzyloxy-7-(4-methoxy-phenyl)-hexahydro-thiazolo[3,4-a][1,4]diazepin-5-one, 19. 1H NMR (400 MHz): δ 8.05 (d, 2 H), 7.25-7.35 (m, 5 H), 6.95 (d, 2 H), 5.22 (d, 1 H), 5.15 (d, 1 H), 4.95 (d, 1 H), 4.75 (d, 1 H), 4.61 (d, 1 H), 4.48 (d, 1 H), 4.24 (m, 1 H), 3.61 (s, 3 H), 3.19 (m, 1 H), 2.97 (m, 2 H), 2.77 (m, 1 H). MS (DCI) m/e: 385 (M+ H)+. Anal. Calcd for C21H24N2O3S: C, 65.60; H, 6.29; N, 7.29. Found: C, 65.36; H, 6.32; N, 7.03.
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7-Benzo[1,3]dioxol-5-yl-6-methoxy-hexahydro-thiazolo[3,4-a][1,4]diazepin-5-one, 20. 1
H NMR (400 MHz): δ 7.24 (d, 1 H), 7.04 (dd, 1 H), 6.87 (d, 1 H), 5.96 (s, 2 H), 5.05 (d,
1 H), 4.75 (d, 1 H), 4.45 (q, 1 H), 4.28 (s, 1 H), 4.14 (s, 1 H), 3.35 (s, 3 H), 3.17-3.25 (m, 2 H), 2.72-2.85 (m, 2 H). MS (DCI) m/e: 323 (M+ H)+. Anal. Calcd for C15H18N2O4S: C, 55.88; H, 5.63; N, 8.69. Found: C, 55.74; H, 5.51; N, 8.45.
4-Benzyloxy-3-(4-chloro-phenyl)-octahydro-pyrrolo[1,2-a][1,4]diazepin-5-one, 21 1
H NMR (400 MHz): δ 7.45 (d, 2 H), 7.25-7.40 (m, 7 H), 4.75 (d, 1 H), 4.58 (d, 1 H),
4.44 (s, 1 H), 4.28 (q, 1 H), 4.18 (s, 1 H), 3.81 (m, 1 H), 3.54 (m, 1 H), 3.15 (d, 1 H), 2.65 (m, 1 H)1.88 (m, 1 H), 1.65 (m, 1 H), 1.48 (m, 1 H), 1.31 (m, 1 H). MS (DCI) m/e: 371 (M+ H)+. Anal. Calcd for C21H23ClN2O2.0.15 H2O: C, 68.01; H, 6.25; Cl, 9.56; N, 7.55. Found: C, 67.76; H, 6.46; N, 7.22.
4-Methoxy-3-naphthalen-2-yl-octahydro-pyrrolo[1,2-a][1,4]diazepin-5-one, 22. 1
H NMR (400 MHz): δ 8.66 (s, 1 H), 8.25 (d, 1 H), 7.80-7.92 (m, 3 H), 7.36 (m, 2 H),
4.86 (d, 1 H), 4.71 (d, 1 H), 3.75-3.90 (m, 2 H), 3.68 (s, 3 H), 3.15 (m, 1 H), 2.91 (m, 1 H), 2.75 (dd, 1 H), 1.86 (m, 1 H), 1.22-1.44 (m, 3 H). MS (DCI) m/e: 311 (M+ H)+. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03. Found: C, 73.32; H, 7.10; N, 8.93.
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