Synthesis of Azacycles Based on Iridium-Catalyzed Sequential Allylic Amination

Abstract

The iridium-catalyzed sequential allylic amination of substrates having two allylic carbonate moieties proceeded smoothly, providing the novel method for synthesis of azacycles.

amination - iridium - cyclizations - azacycles

References

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Preparation of 4a and 5-7: To a solution of a corres-ponding dialdehyde (1 equiv) in THF was added vinyl-magnesium bromide (2.6 equiv) under an argon atmosphere at 0 °C. After being stirred at same tempareture for 3 h, the reaction mixture was quenched with 1 M HCl, and then extracted with Et₂O. The organic phase was washed with H₂O, aq NaHCO₃ and brine, dried over MgSO₄, and concentrated at reduced pressure. Purification of the residue by flash chromatography (hexane:EtOAc = 3:1) afforded diol. To a solution of diol (1 equiv) in pyridine or pyridine-CH₂Cl₂ were added DMAP (0.06 equiv) and MeOCOCl (5 equiv) under an argon atmosphere at 0 °C. After being stirred at same tempareture for 1-24 h, the reaction mixture was diluted with H₂O, and then extracted with Et₂O. The organic phase was washed with H₂O and brine, dried over MgSO₄, and concentrated at reduced pressure. Purification of the residue by flash chromatography (hexane:EtOAc = 10:1) afforded 4a or 5-7.

The configuration of cis- and trans-isomers was assigned since ¹H NMR data showed similarity with the related 2,6-disubstituted piperidines. In general, the signals due to the N-benzylic hydrogen of cis-2,6-disubstituted piperidines give singlet, while that of trans-isomers give the AB quartet. See:

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<A NAME="RU04803ST-10">10</A>

Representative Experimental Procedure: A mixture of 4a (100 mg, 0.387 mmol), benzylamine 2A (41.5 mg, 0.387 mmol), and [IrCl(cod)]₂ (10.4 mg, 0.0155 mmol) in MeCN (1.0 mL) was stirred under argon atmosphere at 20 °C for 2 h. The reaction mixture was concentrated at reduced pressure. Purification of the residue by preparative TLC (hexane:EtOAc = 10:1) afforded cis-9A (43 mg, 52%) and trans-9A (26 mg, 32%). cis-9A: ¹H NMR (500 MHz, CDCl₃): δ = 7.28-7.19 (5 H, m), 5.70 (2 H, m), 5.13 (2 H, d, J = 17.1 Hz), 5.02 (2 H, d, J = 10.1 Hz), 3.74 (2 H, s), 3.06 (2 H, br m), 1.81 (2 H, br m), 1.58 (2 H, br m). ¹³C NMR (125 MHz, CDCl₃): δ = 141.7, 137.7, 130.0, 127.7, 126.6, 115.6, 66.4, 53.8, 30.4. HRMS: Calcd for C₁₅H₁₉N (M⁺): 213.1517. Found: 213.1525. trans-9A: ¹H NMR (500 MHz, CDCl₃):
δ = 7.44-7.10 (5 H, m), 5.78 (2 H, ddd, J = 8.9, 10.1, 17.1 Hz), 5.08 (2 H, d, J = 10.1 Hz), 5.00 (2 H, d, J = 17.1 Hz), 3.80, 3.39 (2 H, AB q, J = 13.7 Hz), 3.39 (2 H, br m), 2.10 (2 H, br m), 1.61 (2 H, br m). ¹³C NMR (125 MHz, CDCl₃): δ = 140.4, 139.7, 128.6, 127.9, 126.3, 116.2, 63.8, 51.2, 30.0. HRMS: Calcd for C₁₅H₁₉N (M⁺): 213.1517. Found: 213.1510.