Synthesis of Heterocycles Based on Rhodium-Catalyzed C–H Amination

Abstract

A new stereoselective approach to substituted pyrrolidines and piperidines is described that involves Du Bois’ C–H ­amination reaction, Boc-activation of a cyclic sulfamate group, and base-promoted intramolecular cyclization. This methodology can be utilized for the synthesis of tetrahydrofuran and tetrahydrothiophene derivatives.

Key word

C–H amination - heterocycle synthesis - rhodium-catalyzed reaction - cyclization

• References and Notes


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• 8 Preparation of 8a from 4 via 5, 6a, and 7a; Sulfamate 5: Formic acid (0.69 mL, 15 mmol) was added to neat chlorosulfonyl isocyanate (1.3 mL, 15 mmol) at 0 °C and the mixture was stirred for 5 min. MeCN (10 mL) was added and the mixture was stirred at r.t. for 8 h to generate sulfamoyl chloride (1.5 M in MeCN). To an ice-cooled solution of 4 (1.40 g, 4.28 mmol) in DMA (10 mL) and MeCN (10 mL) was added sulfamoyl chloride (1.5 M in MeCN, 5.7 mL, 8.56 mmol). The mixture was stirred at r.t. for 1 h and saturated NaHCO₃ (5 mL) was added at 0 °C. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification of the residue by column chromatography (SiO₂ 30 g; hexane–EtOAc, 4:1 to 1:1) gave 5 (1.70 g, 97%) as a colorless amorphous solid. Cyclic Sulfamate 6a: To a solution of 5 (411 mg, 1.08 mmol) in CH₂Cl₂ (10 mL) at r.t. were added MgO (100 mg, 2.50 mmol), PhI(OAc)₂ (BAIB; 354 mg, 1.12 mmol), and Rh₂(OAc)₄ (9 mg, 0.02 mmol). After stirring at r.t. for 2 h, the mixture was filtered through cotton and concentrated in vacuo. Purification of the residue by column chromatography (SiO₂ 30 g; hexane–EtOAc, 3.5:1 to 1.5:1) gave 6a (371 mg, 84%) as a colorless amorphous solid. N-Boc Sulfamate 7a: To a stirred solution of 6a (1.10 g, 0.75 mol) in CH₂Cl₂ (20 mL) at r.t. were added Et₃N (0.59 mL, 4.08 mmol), Boc₂O (712 mg, 0.98 mmol), and DMAP (33 mg, 0.27 mmol). After stirring at r.t. for 5 h, the mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification of the residue by column chromatography (SiO₂ 15 g; hexane–EtOAc, 4:1) gave 7a (1.10 g, 80%) as a colorless amorphous solid. Pyrrolidine 8a: To an ice-cooled solution of 7a (100 mg, 0.20 mmol) in DMF (2 mL) was added NaH (60% in mineral oil, 16 mg, 0.40 mmol). The mixture was stirred at 0 °C for 5 min, then H₂O (36 μL, 2.0 mmol) was added and the mixture was stirred at r.t. for 5 min. The mixture was neutralized with 1 M HCl, extracted with EtOAc, washed with sat. NaHCO₃ and brine, dried over MgSO₄, and concentrated in vacuo. Purification of the residue by column chromatography (SiO₂ 5 g; hexane–EtOAc, 5:1) gave 8a (83 mg, 99%) as a colorless solid.

For related water-promoted displacement reactions, see:
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• 11 Representative One-Pot Preparation (Method B): Et₃N (0.05 mL, 0.38 mmol), DMAP (3 mg, 0.025 mmol), and Boc₂O (72 mg, 0.33 mmol) were added to a solution of 6a (100 mg, 0.25 mol) in DMF (2 mL) at r.t. The mixture was stirred at r.t. for 5 h, then NaH (60% in mineral oil, 30 mg, 0.75 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 5 min, then H₂O (45 μL, 2.5 mmol) was added, and the mixture was stirred at r.t. for 5 min. The mixture was neutralized with 1 M HCl, extracted with EtOAc, washed with saturated NaHCO₃ and brine, dried over MgSO₄, and concentrated in vacuo. Purification of the residue by column chromatography (SiO₂ 5 g; hexane–EtOAc, 5:1) gave 8a (85 mg, 81%) as a colorless solid.
• 12 The crystallographic data (CCDC 943270) can be obtained free of charge from the Cambridge Crystallographic Data centre via www.ccdc.cam.ac.uk/data_request/cif.
• 13 The crystallographic data (CCDC 943271) can be obtained free of charge from the Cambridge Crystallographic Data centre via www.ccdc.cam.ac.uk/data_request/cif.