Gold-catalyzed cyclization of allenyl acetal derivatives

The gold-catalyzed transformation of allenyl acetals into 5-alkylidenecyclopent-2-en-1-ones is described. The outcome of our deuterium labeling experiments supports a 1,4-hydride shift of the resulting allyl cationic intermediates because a complete deuterium transfer is observed. We tested the reaction on various acetal substrates bearing a propargyl acetate, giving 4-methoxy-5-alkylidenecyclopent-2-en-1-ones 4 via a degradation of the acetate group at the allyl cation intermediate.


(I) Representative synthetic procedures:
(a) General procedure: Unless otherwise noted, all the reactions were performed in oven-dried glassware under nitrogen atmosphere with freshly distilled solvents. The THF was dried with sodium/benzophenone and distilled before use. N,N-dimethylformamide (DMF) and dichloromethane (DCM) were distilled from CaH 2 under nitrogen. DMF and triethylamine (Et 3 N) were stored over 4 Å molecular sieves prior to use. All other commercial reagents were used without further purification. 1 H NMR and 13 C NMR spectra were recorded on a Varian 400, Bruker 400 and a Bruker 600 MHz spectrometer using chloroform-d (CDCl 3 ) and benzene-d 6 (C 6 D 6 ) as internal standard.

(b-1) Synthesis of 1-bromo-2-(dimethoxymethyl)cyclohex-1-ene (s-1). [1]
To dry DMF (11.8 mL, 152.9 mmol) in DCM (100 mL) was slowly added PBr 3 (12.0 mL, 127.5 mmol) at 0 °C and the mixture was stirred for 1 h at this temperature before the addition of cyclohexanone (5 g, 51.0 mmol) in dry DCM. The resulting solution was stirred for 8 h at room temperature. After completion of the reaction, the residue was carefully and slowly added to crushed ice and neutralized with saturated NaHCO 3 solution and extracted with EtOAc (3 × 50 S2 mL). The combined organic extracts were initially washed with saturated aqueous NaHCO 3 , followed by water and brine. The organic phase was dried over MgSO 4 , filtered, and concentrated in vacuo to afford the crude bromocyclohex-1-enecarbaldehyde (5.30 g, 28.0 mmol, 55%) as yellow oil. To this yellow oil, 15.3 mL (140.2 mmol) of trimethyl orthoformate and PTSA (0.48 g, 2.80 mmol) were added and stirred at 25-30 °C until complete consumption of the aldehyde (8 h, TLC). After completion of the reaction, the mixture was diluted with hexane and neutralized by using saturated aqueous NaHCO 3 solution. The resulting mixture was then extracted with hexane (2 × 20 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the crude product (s-1) (6.06 g, 25.8 mmol, 92%) as pale yellow oil that was used for the next step without further purification.
The reaction was quenched by adding dried DMF (2.99 mL, 38.7 mmol), and the resulting mixture was allowed to reach room temperature for another 30 min. The resulting solution was partitioned between 50 mL hexane and saturated Na 2 CO 3 (aq) (1:1, v/v), and the aqueous layer was extracted with hexane (2 × 30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was eluted through a triethylamine-pretreated silica gel column to give compound (s-2) (3.89 g, 21.1 mmol, 82%) as pale yellow oil.

(b-3) Synthesis of 1-(2-(dimethoxymethyl)cyclohex-1-enyl)but-2-ynyl acetate (s-3).
A THF (100 mL) solution of 1-bromo-1-propene (2.71 mL, 31.7 mmol) was cooled to −78 °C before addition of n-butyllithium (17.7 mL, 44.4 mmol, 2.5 M). The reaction was kept at −78 °C for 30 min, and to this solution was added a THF (5 mL) solution of compound (s-2) (3.89 g, 21.1 mmol) and the reaction was allowed to reach room temperature for 30 min, followed by addition of acetic anhydride (2.99 mL, 31.7 mmol) at 0 °C. The resulting mixture was stirred at room temperature for another 1 h before it was quenched with saturated aqueous Na 2 CO 3 . The aqueous solution was extracted with hexane (30 mL × 3). The combined organic layer was dried S3 over anhydrous Na2SO4 and concentrated in vacuo. The crude product s-3 (4.89 g, 18.4 mmol, 87%) was obtained as pale yellow oil and used for next step without further purification. To a well stirred mixture of lithium bromide (3.19 g, 36.8 mmol) and copper iodide (6.98 g, 36.8 mmol) in THF (100 mL) at 0 °C was added methylmagnesium chloride (12.3 mL, 36.8 mmol, 3 M), and the solution was stirred for 20 min at 0 °C. The propargylic ester (s-3) (4.89 g, 18.4 mmol) in THF (5 mL) was added dropwise and the resulting mixture was slowly warmed to rt and stirred for an additional 5 h. At the completion of the reaction indicated by TLC, the mixture was poured into a saturated aqueous solution of ammonium chloride and partitioned between hexane/saturated Na 2 CO 3 (aq) (1:2, v/v). The aqueous layer was extracted with hexane (2 × 100 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The crude product was purified on a triethylamine-pretreated silica column to afford desired vinylallenyl acetal (1a) (3.35 g, 14.1 mmol, 76.6%) as a yellow oil.

(b) General procedure for the gold(I)-catalyzed carbocyclization of propargylic ester acetals:
Chloro(triphenylphosphine)gold (I) (8.0 mg, 0.016 mmol) and silver triflate (4.2 mg, 0.016 mmol) was added to a dried Schlenk tube under an N 2 atmosphere, and then freshly distilled DCM (1.0 mL) was introduced by a syringe. The resulting mixture was stirred at room temperature for 10 minutes before the addition of propargylic ester acetal (5a) (100 mg, 0.32 mmol) in DCM (2.2 mL). The reaction mixture was stirred for another 5 minutes at 25 ºC (reaction monitored by TLC). After completion of the reaction, the brown suspension was filtered through a short bed of silica gel and the solvent was removed under reduced pressure.
The crude product was purified by flash chromatography to afford the desired ketone 6a (58 mg, 0.25 mmol, 76%) as dark yellow oil.