【麻省理工Rick L. Danheiser副教授】连续流光化学Danheiser苯环化反应

he yellow solution is poured into a 500-mL separatory funnel containing 120 mL of diethyl etherand 120 mL of 5% aqueous HClsolution. The aqueous layer is separated and extracted with two 60-mL portions of diethyl ether. The combined organic layers are washed with 120 mL of saturated NaClsolution, dried over 10 g of anhydrous MgSO 4 , and filtered through a 30-mL sintered glass Büchner funnel (medium porosity, 30 mm diameter). The MgSO 4 is washed with diethyl ether(3 x 10 mL) and the combined filtrate is concentrated by rotary evaporation (20 °C, 20 mmHg) to afford 4 g of a yellow oil. This material is immediately dissolved in 15 mL of acetonitrileand transferred via glass funnel (9 cm diameter) to a 250-mL single-necked, round-bottomed flask equipped with a 25 x 10 mm, Teflon-coated, octagonal magnetic stir bar ( Note 7). The original flask is rinsed with acetonitrile(2 x 5 mL), which is transferred via glass funnel (9 cm diameter) to the 250-mL flask. water(0.22 mL, 12.2 mmol, 1.0 equiv) and triethylamine(2.56 mL, 1.86 g, 18.4 mmol, 1.5 equiv) ( Note 8) are added via syringe. A 50-mL pressure-equalizing addition funnel is attached. A solution of 4-acetamidobenzenesulfonyl azide(4.41 g, 18.4 mmol, 1.5 equiv) ( Note 9) in 25 mL of acetonitrileis then added via the addition funnel over 15 min. The addition funnel is rinsed with 5 mL of acetonitrileand the reaction flask is wrapped with aluminum foil. The resulting dark yellow solution is stirred at room temperature for 2 h, during which time a white precipitate appears (Figure 1).

The solution is then concentrated by rotary evaporation (40 °C, 20 mmHg) to provide 10.7-16.6 g of a thick yellow suspension. This material is diluted with 1:1 diethyl ether-hexanes (100 mL) and filtered through 5 g of Celite in a 30-mL sintered glass funnel (medium porosity, 30 mm diameter) into a 250-mL, round-bottomed flask. The solid material is washed with 1:1 diethyl ether-hexanes (3 x 15 mL), and the filtrate is then concentrated by rotary evaporation (20 °C, 20 mmHg) to yield 2.8-4.7 g of a dark yellow oil.

This material is dissolved in a minimum amount of 1:7 ethyl acetate-hexanes (ca. 6 mL) and loaded onto a column (64 mm diameter) of 200 g of silica gel (Note 10) prepared as a slurry in 1:7 ethyl acetate-hexanes. Elution with 1:7 ethyl acetate-hexanes (35 mL fractions collected in 20 x 150 mm test tubes) affords the product in fractions 21-57. These fractions are combined and the solvent is removed by rotary evaporation (20 °C, 20 mmHg). Further concentration at room temperature, 0.05 mmHg for 1 h provides 1.77 g (83%) of diazo ketone 1as a yellow crystalline solid (Notes 11and 12).

B. Diethyl benzyl(3-hexyl-4-hydroxy-6,8-dimethylnaphthalen-2-yl)phos-phoramidate (2).

Figure shows the continuous flow photochemical reactor employed for this reaction. Fluorinated ethylene propylene (FEP) tubing, o.d. = 1.59 mm, i.d. = 0.76 mm, length = 1520 cm (Note 13), is wrapped around a quartz immersion well in tightly packed coils leaving 90 cm of tubing free at each end. The length of tubing wrapped around the well is 1340 cm (internal volume = 6.1 mL). The ends of the tubing are secured to the well with Teflon tape. The top end of the tubing is fitted with a nut, ferrule, and a thread to a female Luer adapter for attachment to a syringe as shown in Figure 2. The bottom end of the tubing is connected through a rubber septum to a 100-mL, round-bottomed flask equipped with an argon inlet needle and a needle vent.

The receiving flask is wrapped in aluminum foil (Figure 3). The immersion well is connected to recirculating tap water via PVC tubing. A Pyrex filter and a Hanovia 450 W medium-pressure mercury lamp are placed inside the immersion well (Note 14).

A 100-mL pear flask equipped with a rubber septum and argon inlet needle is charged with 2-diazo-1-(2,4-dimethylphenyl)ethan-1-one (1) (1.56 g, 8.90 mmol, 1.2 equiv), diethyl benzyl(oct-1-yn-1-yl)phosphoramidate2(2.63 g, 7.48 mmol, 1.0 equiv), and CH2Cl2 (30 mL) (Notes 15 and 16). The yellow solution is degassed via three freeze-pump-thaw (-196 °C, 0.05 mmHg) cycles. A 20-mL plastic syringe is charged with 5 mL of CH2Cl2, the syringe is connected to the Luer adapter, the lamp is turned on (Note 17), and the 5 mL of CH2Cl2 is pumped through the system at a rate of 0.58 mL/min (Note 18). Approximately one-half of the reaction mixture is transferred to a 20-mL plastic syringe and pumped through the system at a rate of 0.58 mL/min (calculated residence time = 10.4 min). The syringe is charged with the other half of the reaction solution which is then pumped through the system. The total time required for the injection of the 30-mL reaction solution is 50 min. The 100-mL pear flask is then rinsed with two 0.6-mL portions and one 9 mL portion of CH2Cl2 with each portion pumped through the tubing at a rate of 0.58 mL/min. The lamp is turned off, the aluminum foil on the 100-mL collection flask is removed, and the orange solution is concentrated by rotary evaporation (20 °C, 20 mmHg) to afford 3.97 g of dark orange oil (Note 19). This material is dissolved in 50 mL of toluene (Note 20) and the flask is equipped with a 20 x 10 mm, Teflon-coated, oval magnetic stir bar and an 11-cm Liebig condenser fitted with an argon inlet adapter. The orange solution is heated at reflux in an oil bath for 5 h and then concentrated to afford 3.70 g of orange solid (Note 21). This material is dissolved in 15 mL of CH2Cl2 and concentrated onto 10 g of silica gel. The resulting free-flowing powder is deposited onto a column (80 mm diameter) of 300 g of silica gel prepared as a slurry in 1:2 ethyl acetate-hexanes. Elution is carried out with a gradient of 1:2 to 4:1 ethyl acetate-hexanes, with a ratio of 1:2 EtOAc-hexanes used for fractions 1-81, 1:1 for fractions 82-121, 2:1 for fractions 122-151, and 4:1 for the remaining fractions. Fractions (35 mL) are collected in 20 x 150 mm test tubes. The desired product is obtained in fractions 70-164. These fractions are combined and the solvent is removed by rotary evaporation (20 °C, 20 mmHg). Further concentration at room temperature, 0.1 mmHg for 10 h provides 3.15 g (88%) of 2 as a pale yellow solid.

参考资料

一、Org. Synth. 2016, 93 , 127-145，DOI: 10.15227/orgsyn.093.0127

二、 Strategic Applications of Named Reactions in Organic Synthesis, László Kürti and BarbaraCzakó, Danheiser benzannulation, page 122-123.

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