Switching Regioselectivity in the Asymmetric Bromocyclization of Difluoroalkenes Catalyzed by a Chiral Bisphosphine Oxide

Dedicated to Professor Hisashi Yamamoto on the occasion of his 80^th birthday

Abstract

We present an efficient approach for the enantioselective synthesis of difluoromethylene-containing oxazine compounds through 6-endo-selective bromocyclization of difluoroalkenes by using a chiral proton-bridged bisphosphine oxide complex as a catalyst precursor. The regioselectivity is significantly influenced by the solvent and the catalyst structure, and 6-endo cyclization products can be obtained preferentially with moderate to high enantioselectivity. This protocol offers complementary regioselectivity to our previously reported 5-exo-selective reaction, permitting the synthesis of diverse medicinally interesting compounds.

Key words

asymmetric catalysis - Brønsted bases - cyclization - organocatalysis - Lewis bases - oxazines

Publication History

Received: 21 April 2023

Accepted after revision: 26 June 2023

Accepted Manuscript online:
26 June 2023

Article published online:
09 August 2023

• References and Notes

• 1a Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 1b Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 1c Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
• 1d Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 1e Inoue M, Sumii Y, Shibata N. ACS Omega 2020; 5: 10633
• 2a Lapierre J, Ahmed V, Chen M.-J, Ispahany M, Guillemette JG, Taylor SD. Bioorg. Med. Chem. Lett. 2004; 14: 151
• 2b Meanwell NA. J. Med. Chem. 2011; 54: 2529
• 2c Zhou Q, Ruffoni A, Gianatassio R, Fujiwara Y, Sella E, Shabat D, Baran PS. Angew. Chem. Int. Ed. 2013; 52: 3949
• 2d Ivanova MV, Bayle A, Besset T, Pannecoucke X, Poisson T. Chem. Eur. J. 2016; 22: 10284
• 2e Meanwell NA. J. Med. Chem. 2018; 61: 5822
• 3 Ambizas EM, Ginzburg R. Ann. Pharmacother. 2007; 41: 957
• 4 Toschi L, Finocchiaro G, Bartolini S, Gioia V, Cappuzzo F. Future Oncol. 2005; 1: 7
• 5 Frampton JE, Moen MD. Drugs 2010; 70: 1283
• 6a Liu Y.-L, Yu J.-S, Zhou J. Asian J. Org. Chem. 2013; 2: 194
• 6b Yu J.-S, Liao F.-M, Gao W.-M, Liao K, Zuo R.-L, Zhou J. Angew. Chem. Int. Ed. 2015; 54: 7381
• 6c Rong M.-Y, Li J.-S, Zhou Y, Zhang F.-G, Ma J.-A. Org. Lett. 2020; 22: 9010
• 6d Liu J, Yu L, Zheng C, Zhao G. Angew. Chem. Int. Ed. 2021; 60: 23641
• 6e Uno H, Kawai K, Araki T, Shiro M, Shibata N. Angew. Chem. Int. Ed. 2022; 61: e202117635
• 7a Miller E, Kim S, Gibson K, Derrick JS, Toste FD. J. Am. Chem. Soc. 2020; 142: 8946
• 7b Miller E, Mai BK, Read JA, Bell WC, Derrick JS, Liu P, Toste FD. ACS Catal. 2022; 12: 12369
• 8 Yamashita K, Hirokawa R, Ichikawa M, Hisanaga T, Nagao Y, Takita R, Watanabe K, Kawato Y, Hamashima Y. J. Am. Chem. Soc. 2022; 144: 3913
• 9 Hirokawa R, Nakahara Y, Uchida S, Yamashita K, Hamashima Y. Chem. Asian J. 2023; e202300141
• 10 (5S)-5-Bromo-6,6-difluoro-2-phenyl-5-(p-tolyl)-5,6-dihydro-4H-1,3-oxazine (4a):Typical ProcedurePrecatalyst 1e (12.9 mg, 0.010 mmol, 10 mol%) and difluoroalkene 2a (28.7 mg, 0.10 mmol, 1.0 equiv) were placed in a well-dried Schlenk test tube under an argon atmosphere and dissolved in anhyd toluene (1.8 mL) and CH₂Cl₂ (0.2 mL). The mixture was cooled to –50 °C, and NBP (33.9 mg, 0.15 mmol, 1.5 equiv) was added. The mixture was stirred for 48 h at –50 °C, and then the reaction was quenched by adding a 1.5 M solution of butyl vinyl ether in MeOH (1.0 mL, precooled to –78 °C) through a cannula. The mixture was then gradually warmed to rt and diluted with brine (5.0 mL). The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined extracts were dried (MgSO₄) and concentrated under reduced pressure, and the residue was subjected to ¹H NMR analysis to determine the regioisomeric ratio. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (100:0 to 9:1)] to give a white solid; yield: 32.4 mg (88%, 3a/4a = 1:7.2, 86% ee); mp 103–104 °C; [α]_D ²⁰ = –0.8 [c 1.00, CHCl₃, 86% ee, (S)].HPLC (Method 1) [IJ-3, hexane–i-PrOH (99:1), flow rate 1.0 mL/min, column temp. 40 °C, λ = 254 nm]: t _R = 13.2 min (minor, R), 14.5 min (major, S); (Method 2) [OD-H, hexane/i-PrOH (99.5:0.5), flow rate 1.0 mL/min, column temp. 40 °C, λ = 254 nm]: t _R = 6.5 min (major, S), 6.9 min (minor, R). IR (neat): 2919, 1674, 1448, 1353, 1234, 1149, 1084, 1054 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.99–7.98 (m, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.44–7.41 (m, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 4.61 (dt, J = 17.8, 3.3 Hz, 1 H), 4.52 (dt, J = 17.8, 3.8 Hz, 1 H), 2.36 (s, 3 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 150.8, 139.7, 132.2, 131.9, 130.1, 129.3 (2 C), 128.4 (2 C), 127.8 (2 C), 127.6 (2 C), 120.9 (t, J = 261.7 Hz), 56.7 (t, J = 26.9 Hz), 56.1, 21.1. ¹⁹F NMR (470 MHz, CDCl₃): δ = –74.9 (br, 2 F).The spectral data for 4a were consistent with those reported in ref. 7a