An Ethynyl-Substituted 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-one as a Versatile Precursor for Chiral Templates and Chiral Photocatalysts

Abstract

The title compound was synthesized and separated into its enantiomers. The enantiomerically pure alkyne was ligated to several aryl azides and aryl halides. The resulting 7-substituted 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-ones were used either as chiral templates in the intramolecular [2+2] photocycloaddition of 4-allyloxyquinolone (up to 72% ee) or as a chiral photocatalyst for the intramolecular [2+2] photocycloaddition of 4-(3-butenyl­oxy)quinolone (up to 79% ee with 10 mol% catalyst).

Key words

cycloadditions - cyclobutanes - enantioselectivity - heterocycles - organocatalysis - photochemistry

References and Notes

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16

Representative Procedure for the Synthesis of 10c
An oven-dried Schlenk tube was charged with alkyne 5 (20.0 mg, 97.4 µmol), triflate 8c (34.0 mg, 106 µmol) Pd(PPh₃)₄ (11.0 mg, 9.74 µmol), CuI (1.9 mg, 9.74 µmol), and LiCl (24.7 mg, 584 µmol) and was 5 times evacuated and purged with argon. A mixture of DMF (2.3 mL) and Et₃N (770 µL, 1.95 mmol) was degassed by 3 freeze-pump-thaw cycles, added to the Schlenk tube, and the resulting suspension was heated to 60 ˚C for 71 h. The reaction mixture was cooled to r.t. and diluted with EtOAc (20 mL) and H₂O (15 mL). After separation of the layers the aqueous phase was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, pentane-EtOAc = 5:1 to 1:1) yielded compound 10c (33.7 mg, 89.7 µmol, 92%) as a colorless grease.
^¹H NMR (360 MHz, CDCl₃): δ = 1.02 (s, 3 H), 1.15 (d, ^² J = 13.4 Hz, 1 H), 1.19 (s, 3 H), 1.22-1.27 (m, 2 H), 1.29-1.34 (m, 5 H), 1.71-1.96 (m, 8 H), 2.20 (dt, ^² J = 13.4 Hz, ⁴ J = 2.1 Hz, 1 H), 2.52 (tt, ^³ J = 10.3 Hz, ^³ J = 5.5 Hz, 1 H), 2.71-2.77 (m, 4 H), 3.12 (d, ^² J = 11.6 Hz, 1 H), 3.43 (ddd, ^² J = 11.6 Hz, ⁴ J = 3.2 Hz, ⁴ J = 1.5 Hz, 1 H), 5.42 (s, 1 H), 6.96 (s, 2 H) ppm. ^¹³C NMR (90.6 MHz, CDCl₃): δ = 22.6, 25.6, 29.2, 29.9, 30.4, 30.6, 30.8, 33.8, 36.3, 38.4, 44.3, 48.5, 51.7, 52.4, 79.9, 94.1, 120.6, 128.8, 136.6, 137.7, 176.4 ppm. HRMS: m/z calcd for C₂₆H₃₃NO: 375.2562; found: 375.2564.

19

Representative Procedure for the Synthesis of 11c
A round-bottom flask was charged with alkyne 5 (19.6 mg, 95.5 µmol), azide 9c (45.0 mg, 188 µmol), and CuI (1.8 mg, 9.56 µmol) in THF (2.0 mL). Et₃N (192 µL, 191 µmol) was added, and the flask was closed with a rubber septum and heated to 50 ˚C for 3 h. The reaction mixture was cooled to r.t. and diluted with EtOAc (15 mL) and H₂O (10 mL). After separation of the layers the aqueous phase was extracted with EtOAc (3 × 15 mL), and the combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, EtOAc) yielded compound 11c (42.0 mg, 94.9 µmol, 99%) as a yellow solid.
^¹H NMR: (360 MHz, CDCl₃): δ = 1.12 (s, 3 H), 1.29 (s, 3 H), 1.33 (s, 3 H), 1.38-1.44 (m, 2 H), 1.52 (d, ^² J = 14.2 Hz, 1 H), 1.80 (d, ^² J = 13.5 Hz, 1 H), 2.71 (d, ^² J = 14.2 Hz, 1 H), 3.02 (d, ^² J = 12.2 Hz, 1 H), 3.17-3.28 (m, 2 H), 5.81 (s, 1 H), 7.10 (d, ^³ J = 9.1 Hz, 1 H), 7.45 (ddd, ^³ J = 8.0 Hz, ^³ J = 7.1 Hz, ⁴ J = 1.0 Hz, 1 H), 7.55 (ddd, ^³ J = 8.5 Hz, ⁴ J = 1.0 Hz, ⁴ J = 0.5 Hz, 1 H), 7.76-7.81 (m, 1 H), 8.04 (dd, ^³ J = 9.1 Hz, ⁴ J = 2.7 Hz, 1 H), 8.30 (dd, ^³ J = 8.0 Hz, ⁴ J = 1.3 Hz, 1 H), 8.47 (s, 1 H), 8.63 (d, ⁴ J = 2.7 Hz, 1 H) ppm. ^¹³C NMR (90.6 MHz, CDCl₃): δ = 25.7, 29.8, 30.5, 34.6, 37.1, 38.3, 45.2, 47.6, 47.8, 51.9, 116.5, 117.8, 118.5, 118.9, 121.3, 121.6, 124.4, 126.4, 126.9, 133.7, 135.3, 154.6, 154.6, 155.8, 176.2, 176.3 ppm. HRMS: m/z calcd for C₂₆H₂₆N₄O₃: 442.2005; found: 442.2002.

22

Representative Irradiation Procedure (Table 1, Entry 3)
An oven-dried Duran tube was charged with 4-allyloxy-quinolone (12, 7.6 mg, 37.9 µmol) and template 10c (35.6 mg, 94.8 µmol) in dry toluene (7.6 mL), and the solution was degassed by three freeze-pump-thaw cycles. The reaction mixture was irradiated under argon at -70 ˚C (λ = 300 nm, light source: Rayonet RPR-3000 Å) for 3 h, and the solvent was removed in vacuo. Purification of the crude product by flash chromatography (silica gel, pentane-EtOAc = 1:1 to EtOAc) yielded the recovered template 10c (25.6 mg, 68.3 µmol, 72%) and product 13 (6.9 mg, 34.3 µmol, 91%, 72% ee) as colorless solids. The analytical data of product 13 were in agreement with the values previously reported.^³b,²0,²¹