Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

A successful enone version of an intramolecular aza-[3 + 3] annulation reaction is described here. Use of piperidinium trifluoroacetate salt as the catalyst and toluene as the solvent appears to be critical for a successful annulation. We also demonstrated for the first time that microwave irradiation can accelerate aza-[3 + 3] annulation reactions. An attempt to expand the scope of the enone aza-[3 + 3] annulation was made in the form of propyleine synthesis as a proof of concept. While synthesis of the enone annulation precursor was successfully accomplished, the annulation proved to be challenging and was only modestly successful.


Azido-alcohol 7.
In a 250 mL round bottom flask equipped with magnetic stir bar, bromide 6 (8.06 g, 27.87 mmol) was taken up in MeOH (75 mL) and p-TsOH (0.47 g, 2.4 mmol) was added in one portion. The solution was stirred at ambient temperature for 1.5 h, as TLC analysis [R f = 0.16 (15% EtOAc in petroleum ether)] indicated complete consumption of the starting material. The solution was neutralized by addition of solid NaHCO 3 (0.60 g). The excess solid was filtered off through a fritted funnel and MeOH was removed in vacuo to give an alcohol that was used in the next step without further purification.

Vinylogous amide 9.
In a 1 liter three-neck round bottom flask equipped with thermometer was made a suspension of LAH (7.54 g, 198.79 mmol) in anhydrous THF (290 mL). To this suspension was added slowly (dropwise) a solution of azido alcohol 7 (5.54 g, 33.13 mmol) in THF (100 mL) while maintaining the internal temperature below 30 °C. An additional portion of THF (10 mL) was used to ensure complete salvation of the azido alcohol. When the bubbling of the reaction mixture slowed, the cool bath was replaced with an oil bath and a water-cooled condenser was fitted to the flask. The mixture was heated under reflux for S4 40 h, at which point the flask was removed from the heat bath and allowed to cool. The excess LAH was destroyed by the addition of saturated aqueous Na 2 SO 4 (20 mL) added slowly due to a large exotherm. A white precipitate formed and the mixture was filtered, washing with MTBE (3 × 65 mL). The filtrate was then dried over Na 2 SO 4 , and concentrated to provide amino alcohol intermediate (4.27 g, 90%) as a pale yellow oil, which was used without further purification. 1 H NMR (500 MHz, CDCl 3 ) δ 1.25 (d, 3H, J = 10.5 Hz), 1.41-1.63 (br m, 7H), 2.04 (q, 2H, J = 10.5 Hz), 2.69 (t, 2H, J = 11.5 Hz), 4.26 (quint, 1H, J = 10.5 Hz), 5. 48-5.68 (m, 2H).
A solution of amino alcohol intermediate (3.31 g, 23.11 mmol) and 1,3-cyclohexanedione in EtOH (7.5 mL) and toluene (75 mL) was prepared in a 250 mL round bottom flask. A water-cooled condenser was placed on the flask and the mixture was heated at 80 °C for 6-7 h, and then allowed to cool to ambient temperature. The solvents were removed and the crude material was purified via silica gel flash column chromatography (neutralized SiO 2 with 2% Et 3 N in hexanes; 9-12% MeOH in CH 2 Cl 2 ) to afford vinylogous amide 9 (2.83 g, 11.92 mmol, 52%) as a pale yellow solid.

Enone 10.
Vinylogous amide 9 (0.340 g, 1.43 mmol) was taken up in acetone (15 mL), and activated MnO 2 (88%, 3.23 g, 37.25 mmol) was added. The reaction mixture was stirred for 2 h. Occasionally, the allyl alcohol was slow to oxidize, so additional amounts of oxidant were added to ensure complete consumption of the starting material. After the reaction was deemed complete, the solid was filtered off using a 3 inch bed of Celite TM and washed with acetone. The filtrate was concentrate in vacuo and was then purified by silica gel flash column chromatography (9% MeOH in EtOAc) to yield enone 10 (0.219 g, 65%) as a reddish-yellow oil.

Intramolecular Aza-[3 + 3] annulation of enone 10.
Procedure with conventional heating. In a flame-dried sealed tube was made a solution of enone 10 (23.5 mg, 0.100 mmol) in toluene (3.0 mL). To this solution was added piperidinium trifluoroacetate salt (9.9 mg, 0.05 mmol) and Na 2 SO 4 (72 mg) and the reaction was capped with a rubber septum. The headspace was flushed then flushed with a stream of N 2 . The rubber septum was removed and the tube was quickly capped and then heated at 150 °C for 3 h. The reaction mixture was allowed to cool to room temperature, and it was diluted with EtOAc (5 mL), then washed with H 2 O (5 mL), and saturated aqueous NaHCO 3 (5 mL). The aqueous washes were back-extracted with EtOAc (2 × 5 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated to a crude semisolid, which was purified by silica gel flash column chromatography (9-12% MeOH in CH 2 Cl 2 ) to afford aza-tricycle 11 (19 mg, 87%) as a yellow oil, which solidified upon placement under high-vacuum.

Lactam 22.
Preparation of 20. To a solution of glutarimide (2.85 g, 25.20 mmol) in THF (80 mL) was added CH 3 MgCl (3 M in THF, 9.0 mL, 27.0 mmol) dropwise at 0 °C. The reaction mixture was allowed to warm up to rt and was stirred for 30 min and then cooled back down to 0 °C.
The resulting reaction mixture was stirred for 12 h at rt before NaBH 3 CN (1.74 g, 27.69 mmol) and HOAc (7.5 mL) were added successively. After stirring at ambient temperature for 45 min, reaction was quenched with sat aq NaHCO 3 solution (80 mL). After layer separation, the organic phase was washed with an additional portion of NaHCO 3 solution (80 mL). Aqueous washes were back-extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with sat aq NaCl (2 × 50 mL) and dried over Na 2 SO 4 . After solvent removal under reduced pressure, the crude residue was purified through two silica gel columns (1 st : 0-50% acetone in EtOAc; 2 nd : 7-10% MeOH in CH 2 Cl 2 ) to afford lactam 22 (8.70 g, 77%) as a thick colorless oil. To a solution of lactam 22 (1.10 g, 2.45 mmol) in CH 2 Cl 2 (15 mL) was added freshly distilled MeOTf (0.35 mL, 3.09 mmol). The reaction mixture was stirred at ambient temperature for 8 h before the reaction mixture was treated with cold 5% aq Na 2 CO 3 (20 mL). After separation of the layers, the aqueous phase was extracted with CH 2 Cl 2 (2 × 10 mL). Combined organics were washed with sat aq NaCl (15 mL), and dried over Na 2 SO 4 . Removal of the excess solvent gave the desired O-methyl lactim ether as a colorless oil, which was used for the next step without further purification.

Alcohol 25.
To a solution of MeONa prepared by dissolving Na metal (0.640 g, 27.82 mmol) in anhydrous MeOH (35 mL) was added a solution of compound 23 (3.22 g, 5.59 mmol) in MeOH (35 mL). The reaction mixture was heated under reflux overnight. After cooling the reaction mixture to rt, MeOH was evaporated and H 2 O (60 mL) was added to the crude residue, and subsequently, aq HCl (1 M) was also added dropwise to adjust the pH to 5-6. The resulting mixture was extracted with CH 2 Cl 3 (3 × 70 mL), the combined organic layers were washed with sat aq NaCl (2 × 25 mL) and dried over Na 2 SO 4 . Upon removal of excess solvents under reduced pressure, the crude vinylogous urethane 24 was submitted to the next step without further purification.

Cycloadduct 16.
To a solution of freshly prepared enone 17-cis (193.8 mg, 0.730 mmol) in dry degassed toluene (7 mL) under N 2 atmosphere were added powdered Na 2 SO 4 (~100.0 mg) and piperidinium trifluoroacetate (150.0 mg, 0.750 mmol). The reaction mixture was heated at 100 °C for 5 h before the excess solvent was evaporated under reduced pressure. The crude residue was submitted to flash column chromatography using silica gel deactivated with NEt 3 (2% in EtOAc:hexanes 9:1) eluted with 10% EtOAc in hexanes). Cycloadduct 16 (60.3 mg, 34% yield) was obtained as a very air-sensitive yellow oil with significant contamination according to 1 H NMR analysis.