Zirconocene catalyzed diastereoselective carbometalation of cyclobutenes

We functionalize cyclobutene species into polysubstituted metalated cyclobutanes through the Dzhemilev reaction.


Procedure for the synthesis of (3-hexylcyclobut-2-en-1-yl)methanol (1d):
Following the reported procedure 2 rhodium pre-catalyst was synthesized from the commercially available [Rh(OMe)(1,5-cod)] 2 . Butyl 3-hexylcyclobut-2-ene-1-carboxylate was synthesized following the reported procedure 3 using this synthesized rhodium pre-catalyst from the reaction of 1-octyne and butyl acrylate. This crude butyl 3-hexylcyclobut-2-ene-1-carboxylate (1 equiv, 10 mmol) was further reduced with LiAlH 4 (2 equiv, 20 mmol) in THF (40 mL) at 0 o C to synthesize title compound. R f = 0.53 (Hexane/EtOAc = 9:1); Yield: 51% (yellow oil) 1  General procedure for the synthesis of cyclobutene methylethers (1a/1c): To a flame dried 3-necked round bottom flask equipped with Teflon coated stirring bar, under argon atmosphere was added a suspension of NaH (1.5 equiv, 7.5 mmol) in THF (20 mL) at 0 o C. Then substituted cyclobutenol 1b/1d (5 mmol, dissolved in 10 mL of THF) was added dropwise over a period of 2 min and the reaction mixture was allowed to stir at this temperature for an additional hour before introduction of MeI (1.2 equiv, 6 mmol). The reaction mixture was warmed to room temperature and stirred overnight. After that the reaction was completed, observed with TLC, the reaction mixture was cooled in an ice bath and quenched with water, extracted with Et 2 O (3 times) and dried over MgSO 4 . Combined organic layer was filtered and concentrated under reduced pressure to give crude oils which was then purified by flash chromatography using hexane/ Et 2 O as eluent to get the desire 1a/1c almost quantitative yield.

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Typical procedure for the synthesis of 1-(((3-hexylcyclobut-2-en-1-yl)methoxy)methyl)-4methoxybenzene (1e):  To a flame dried 3-necked round bottom flask equipped with Teflon coated stirring bar, under argon atmosphere was added a suspension of NaH (1.5 equiv, 3 mmol) in THF (8 mL) at 0 o C. Then substituted cyclobutenol (2 mmol, dissolved in 4 mL of THF) was added dropwise over a period of 2 min and the reaction mixture was allowed to stir at this temperature for an additional hour before introduction of 4methoxy benzylbromide (1.2 equiv, 2.4 mmol) and tetra-n-butylammonium iodide (0.1 equiv, 0.2 mmol, dissolved in 2 mL of THF). The reaction mixture was warmed to room temperature and stirred overnight. After that the reaction was completed, observed by TLC, the reaction mixture was cooled in an ice bath and quenched with water, extracted with Et 2 O (3 times) and dried over MgSO 4 . Combined organic layer was filtered and concentrated under reduced pressure to give crude oils which was then purified by flash chromatography using hexane/ Et 2 O as eluent to get the desire 1e in 81% yield. General procedure for the synthesis of 2b and 2l: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (14.6 mg, 0.05 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (0.5 mL, 2.5 M in Et 2 O, 1.25 mmol) at rt (22 °C) under inert atmosphere and stirring for 30 min at rt. In a parallel separate flask containing a solution of substrate 1b/1d (0.25 mmol) in dry THF (2 ml) equipped with a magnetic stirrer, and a rubber septum was added a solution of EtMgBr (0.1 mL, 2.5 M in Et 2 O, 0.25 mmol) under inert atmosphere at 0 °C and stirring for 30 min at the same temperature. Then the resulting substrate solution was transferred to the 25-mL three-neck flask through a cannula and the resulting mixture was allowed to stir at rt for overnight (12 h). During the course of reaction, the color of reaction mixture changes from pale yellow to dark yellow/ orange. The reaction mixture was then hydrolyzed with an aqueous solution of 1N HCl. The layers were separated and the aqueous phase was extracted with Et 2 O (3 times). The combined organic fractions were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude oils. Finally, the crude mixtures were then purified by flash chromatography using hexane/ Et 2 O as eluent.
Typical procedure for the synthesis of 2d: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (14.6 mg, 0.05 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (0.5 mL, 2.5 M in Et 2 O, 1.25 mmol) at rt (22 °C) under inert atmosphere. After stirring for 30 min at rt, substrates 1a (0.25 mmol), diluted in 2 ml of dry THF were added dropwise to this solution. The resulting mixture was allowed to stir at rt for overnight (12 h). Then the electrophile, iodine (317 mg, 1.25 mmol) solubilized in dry THF (3 mL) was added at 0 °C and slowly warm-up to room temperature (over 2 h). Finally reaction mixture was hydrolyzed with an aqueous solution of 1N HCl. The layers were separated and the aqueous phase was extracted with Et 2 O (3 times). The combined organic fractions were washed with saturated solution of sodium thiosulfate, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude oil. Finally, the crude mixture was then purified by flash chromatography using hexane/ Et 2 O as eluent to get 2d in 67% yield.
Typical procedure for the synthesis of 2e: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (14.6 mg, 0.05 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (0.5 mL, 2.5 M in Et 2 O, 1.25 mmol) at rt (22 °C) under inert atmosphere. After stirring for 30 min at rt, substrates 1a (0.25 mmol), diluted in 2 ml of dry THF were added dropwise to this solution. The resulting mixture was allowed to stir at rt for overnight (12 h). Then for bromination, NBS (222 mg, 1.25 mmol) was solubilized in dry THF (4 mL) and added at 0 °C then slowly warm-up to room temperature (over 2 h). Finally reaction mixture was hydrolyzed with an aqueous solution of 1N HCl. The layers were separated and the aqueous phase was extracted with Et 2 O (3 times). The combined organic fractions were washed with brime, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude oil. Finally, the crude mixture was then purified by flash chromatography using hexane/ Et 2 O as eluent to get 2e in 58% yield.
Typical procedure for the synthesis of 2f: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (14.6 mg, 0.05 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (0.5 mL, 2.5 M in Et 2 O, 1.25 mmol) at rt (22 °C) under inert atmosphere. After stirring for 30 min at rt, substrates 1a (0.25 mmol), diluted in 2 ml of dry THF were added dropwise to this solution. The resulting mixture was allowed to stir at rt for overnight (12 h). Then CuI (4.8 mg, 0.025 mmol) and flame-dried LiCl (2.1 mg, 0.05 mmol) brought into solution in dry THF (3 mL) at 0 °C and wait for 15 min, followed by the addition of freshly distilled allyl bromide (108 μL,1.25 mmol) to the solution and stirred at rt for 3 h. Finally reaction mixture was hydrolyzed with an aqueous solution of 1N HCl. The layers were separated and the aqueous phase was extracted with Et 2 O (3 times). The combined organic fractions were washed with brime, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude oil which was then purified by flash chromatography using hexane/ Et 2 O as eluent to get 2f in 72% yield.

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Typical procedure for the synthesis of 2g: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (14.6 mg, 0.05 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (0. Typical procedure for the synthesis of 2m: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (87.6 mg, 0.3 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (1.0 mL, 2.5 M in Et 2 O, 2.5 mmol) at rt (22 °C) under inert atmosphere. After stirring for 30 min at rt, substrates 1d (0.25 mmol), diluted in 2 ml of dry THF were added dropwise to this solution. The resulting mixture was allowed to stir at rt for overnight (12 h). Then CuI (4.8 mg, 0.025 mmol) and flame-dried LiCl (2.1 mg, 0.05 mmol) brought into solution in dry THF (3 mL) at 0 °C and wait for 15 min, followed by the addition of freshly distilled allyl bromide (216 μL, 2.5 mmol) to the solution and stirred at rt for 3 h. Finally reaction mixture was hydrolyzed with an aqueous solution of 1N HCl. The layers were separated and the aqueous phase was extracted with Et 2 O (3 times). The combined organic fractions were washed with brime, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude oil which was then purified by flash chromatography using hexane/ Et 2 O as eluent to get 2m in 50% yield.
Typical procedure for the synthesis of 2q: Into a flame-dried, 25-mL three-neck flask, containing a solution of bis(cyclopentadienyl)zirconium dichloride (14.6 mg, 0.05 mmol) in dry THF (5 ml) and equipped with a magnetic stirrer, a glass stopper, a rubber septum and an inert gas inlet, was added a solution of EtMgBr (0.5 mL, 2.5 M in Et 2 O, 1.25 mmol) at rt (22 °C) under inert atmosphere. After stirring for 30 min at rt, substrates 1c (0.25 mmol), diluted in 2 ml of dry THF were added dropwise to this solution. The resulting mixture was allowed to stir at rt for overnight (12 h). Then CuI (4.8 mg, 0.025 mmol) and flame-dried LiCl (2.1 mg, 0.05 mmol) brought into solution in dry THF (3 mL) at 0 °C and wait for 15 min, followed by the addition of 4iodoanisole (293 mg, 1.25 mmol) and Pd(PPh 3 ) 4 (28.9 mg, 0.025 mmol) solubilized in dry THF (3 mL) respectively at rt. Then resulting mixture was allowed to stir at 50 °C for 4 hours at which time it was quenched with an aqueous solution of 1N HCl. The layers were separated and the aqueous phase was extracted with Et 2 O (3 times). The combined organic fractions were washed with brime, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude oil. Finally, the crude mixture was then purified by flash chromatography using hexane/ Et 2 O as eluent to get 2q in 61% yield.