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Organic Process Research & Development
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MTBE (72 g). The layers were separated, and the aqueous layer extracted with MTBE (144 g).
The combined organic layer was washed with 4% aqueous NaHCO solution (200 g),
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concentrated under reduced pressure at below 40 °C to remove all solvents. Crude compound 6
was obtained as a thick oil (51.0 g), which was used directly in the next step without purification.
A pure sample was obtained by silica gel column purification with ethyl acetate/heptanes as
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eluent, which yielded a white solid with mp 70.7 C. H NMR (400 MHz, CDCl ) δ = 7.39ꢀ7.31
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(m, 4H), 7.29ꢀ7.23 (m, 1H), 4.36ꢀ4.25 (m, 1H), 3.82 (s, 2H), 3.11ꢀ3.04 (m, 2H), 2.46ꢀ2.36 (m,
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H), 2.31ꢀ2.17 (m, 1H), 2.03ꢀ1.87 (m, 3H), 1.60ꢀ1.52 (m, 1H), 1.42ꢀ1.34 (m, 2H), 1.18ꢀ1.11 (m,
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H); C NMR (101 MHz, CDCl ) δ = 140.45, 128.14, 128.09, 126.60, 64.13, 55.85, 49.60,
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5.49, 25.00, 14.53. HRMS (ESI) m/z: [M+H] Calcd for C H NO 232.1696; Found
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32.1696.
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-Benzyl-9-azabicyclo[3.3.1]non-3-ene (8) A solution of crude 6 from the previous step (50 g,
theoretical 0.21 mol, 1.0 eq.) in 70% aq. H SO (500 g, 3.6 mol, 17 eq.) was heated to 100 °C
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and stirred for 20 h until >99% conversion by HPLC. The batch was slowly quenched into a
solution of NaOH (288 g in 1200 g water) while maintaining the quench batch temperature at or
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below 30 C (The end pH was 7ꢀ8). The batch was then extracted with 3x1L ethyl acetate, and
the combined organic layer was washed with 300 mL water. The organic layer was concentrated
to remove all solvents to give 52.7 g oil residue which contained 43.8 g 8 by HPLC assay and
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6.8% LCAP in 97.3% overall yield for two steps. Pure 8 was obtained as a light yellow oil via
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silica gel column purification with ethyl acetate/heptanes as eluent. H NMR (400 MHz, CDCl )
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δ = 7.35ꢀ7.28 (m, 2H), 7.27ꢀ7.19 (m, 2H), 7.19ꢀ7.12 (m, 1H), 5.95 (td, J = 3.5, 10.1 Hz, 1H),
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.56ꢀ5.39 (m, 1H), 3.66ꢀ3.54 (m, 2H), 3.07 (br. s, 1H), 2.91ꢀ2.84 (m, 1H), 2.37 (ddd, J = 3.0, 4.3,
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8.8 Hz, 1H), 1.82ꢀ1.57 (m, 4H), 1.45ꢀ1.29 (m, 3H). C NMR (101 MHz, CDCl ) δ = 140.16,
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28.69, 128.04, 127.86, 127.12, 126.57, 57.79, 52.48, 50.55, 33.38, 28.37, 25.70, 16.09. HRMS
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ESI) m/z: [M+H] Calcd for C H N 214.1590; Found 214.1588.
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-Azabicyclo[3.3.1]nonane (5) A solution of 8 (10.0 g x 93.16 wt%, 44 mmol) in 50 mL
isopropanol was purged with argon three times and mixed with Pd(OH) on carbon (20 wt%)
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(2.0 g). The vessel was then purged with argon and pressurized with hydrogen at 40ꢀ50 psi and
agitated at 40ꢀ50 °C for 48 h until complete reaction by GC. The catalyst was filtered off through
Solka Floc, and the cake washed with 50 ml IPA. The filtrate contained 5.37 g (62.9 g x 8.53
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