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Preparation of H,4 PyrrolidineQuin-BAM (PBAM)
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A 100 mL, round-bottomed flask (24/40 joint) equipped with a Teflon-coated oval stir bar (32 × 15 mm), rubber septum and an inlet needle connected to an argon/vacuum manifold (Note 16) was first charged with (R,R)-1,2-diaminocyclohexane (1.63 g, 14.3 mmol, 1 equiv, Notes 17 and 18). Then, Pd(dba)2 (164 mg, 285 ?mol, 0.02 equiv), rac-BINAP (356 mg, 572 ?mol, 0.04 equiv), 2,4-dichloroquinoline (1) (5.66 g, 28.6 mmol, 2 equiv) and sodium tert-butoxide (4.12 g, 42.9 mmol, 3 equiv, Note 19) were added. The reaction vessel was evacuated and backfilled with argon three times, then left under a positive pressure of 5Within the first 10 minutes of heating, vigorous gas evolution is observed as the mixture becomes homogeneous. Within 20 min, the color of the solution transitions from yellow to red to dark brown/black. Over approximately 90 min, the gas evolution subsides, and a gentle reflux is observed. 6If the solution is cooled for longer than 5 minutes, the reaction mixture may thicken to an extent that renders it difficult to transfer the entire contents of the flask to the quench beaker. 7This served to break up the largest fragments of material and to increase the surface area of the solid for efficient quenching in the following step. 8This workup procedure should fully hydrolyze all P-Cl bonds leaving sodium phosphate as the byproduct of POCl3 quenching.4 9This served to fully quench the suspension and to produce a finer crude solid with fewer chunks. This facilitated transfer into the Soxhlet thimble and allowed for a more efficient extraction due to increased surface area of the solid. 10It may be necessary to filter the hexanes extract if red solid precipitates from the solution: The combined extracts were filtered through Celite? (21 g) in a coarse sintered glass funnel (46 mm diameter). The filter cake was washed with hexanes (2 × 50 mL) 11The crude 2,4-dichloroquinoline (1) exhibited the following: mp 62.0–64.2 (uncorrected); Rf = 0.42 (10% EtOAc/hexanes); IR (film) 3062, 1572, 1553 cm?1; 1H NMR (500 MHz, CDCl3) δ: 7.53 (s, 1 H), 7.67 (ddd, J = 8.3, 6.9, 1.2 Hz, 1 H), 7.81 (ddd, J = 8.5, 6.9, 1.4 Hz, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 8.21 (dd, J = 8.4, 1.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ: 122.2, 124.4, 125.4, 128.1, 129.2, 131.8, 144.6, 148.3, 150.0; HRMS (APCI-ESI) calcd for C9H6Cl2N [M+H]+ 197.9872; found 197.9870. This data matched the values given in the literature.2 The checkers observed the development of a brown discoloration during prolonged storage at ambient temperature in air. This does not affect its use in subsequent reactions. 12The submitters obtained yields between 33–36% using a smaller Soxhlet apparatus, which may have contributed to a greater extraction efficiency, with thimble dimensions: 33 mm × 94 mm (int. diam. × ext. length). 13The crude material can be further purified by recrystallization. The crude solid (5.0 g) was dispensed into a 50 mL Erlenmeyer flask and dissolved in 20 mL of a 3:1 mixture of hexanes and toluene with heating in a ~70 °C water bath. The solution was allowed to slowly cool to room temperature (Note 14) before it was placed in an ice-water bath. After 2 hours, the mother liquor was decanted. The recrystallization flask was kept in the ice-water bath while the crystals were rinsed with ice-cold hexanes (5 mL). The hexanes were decanted and residual solvent was removed by vacuum (0.2 mmHg) to leave yellow crystalline solid (2.99–3.17 g, 60–63% recovery, Note 15). 16The apparatus was flame-dried under reduced pressure (1–2 mmHg) and then maintained under a positive pressure of argon during the course of reaction. Davis et al. Page 2 Organic Synth. Author manuscript; available in PMC 2012 November 23. argon.3 Toluene (35 mL) was dispensed into the flask, and the resulting red-brown solution was placed into an oil bath heated to 80 °C with stirring (Notes 20 and 21, Caution: possible exotherm!). The reaction was monitored by TLC (Note 22); after 1.5 h, nearly complete conversion was observed. The reaction was cooled to 25 °C, and saturated NH4Cl (10 mL) and water (10 mL) were added to the flask. The suspension was stirred for 5 min and cooled to 0 °C for 10 min. The reaction mixture was filtered through a Büchner funnel (9 cm diameter) and washed with water (50 mL) and hexanes (150 mL) to afford a light yellow solid. This crude solid was transferred to a pre-weighed 100 mL round-bottomed flask with a 24/40 joint and dried under vacuum (1–2 mmHg) for at least 10 h to leave 4.57–4.80 g of a light beige-yellow solid (73–77%) (Note 23), which was used in step C without further purification. 发自小木虫Android客户端 |
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