Access to Fluorinated Quaternary Stereogenic Centers via Palladium-Catalyzed Asymmetric Allylic C–H Alkylation

Abstract

A Pd-catalyzed branch- and enantioselective allylic C–H alkylation reaction has been developed for the rapid assembly of fluorinated quaternary stereogenic centers from allylarenes and prochiral α-fluorinated esters. Using chiral phosphoramidite as ligand and 2,5-diphenylquinone as oxidant, the reaction proceeds smoothly under mild conditions and tolerates a broad scope of substrates, resulting in α-quaternary fluorinated ester products with high levels of yields, enantioselectivities, and regioselectivities.

Key words

palladium catalysis - allylic C–H alkylation - phosphoramidite - quaternary stereogenic center - fluorinated carbon

Publication History

Received: 20 April 2023

Accepted after revision: 07 June 2023

Accepted Manuscript online:
07 June 2023

Article published online:
13 July 2023

• References and Notes

• 1 Zhu Y, Han J, Wang J, Shibata N, Sodeoka M, Soloshonok VA, Coelho JA. S, Toste FD. Chem. Rev. 2018; 118: 3887
• 2 O’Hagan D. J. Fluorine Chem. 2010; 131: 1071
• 3 Mikami K, Itoh Y, Yamanaka M. Chem. Rev. 2004; 104: 1
• 4 Ma J.-A, Cahard D. Chem. Rev. 2004; 104: 6119
• 5a Trost BM, Crawley ML. Chem. Rev. 2003; 103: 2921
• 5b Pamies O, Margalef J, Canellas S, James J, Judge E, Guiry PJ, Moberg C, Backvall JE, Pfaltz A, Pericas MA, Dieguez M. Chem. Rev. 2021; 121: 4373
• 5c Susse L, Stoltz BM. Chem. Rev. 2021; 121: 4084
• 6 He ZT, Jiang X, Hartwig JF. J. Am. Chem. Soc. 2019; 141: 13066
• 7 Liu XJ, Jin S, Zhang WY, Liu QQ, Zheng C, You SL. Angew. Chem. Int. Ed. 2020; 59: 2039
• 8a Sripada A, Wolf C. J. Org. Chem. 2022; 87: 11880
• 8b Balaraman K, Wolf C. Angew. Chem. Int. Ed. 2017; 56: 1390
• 9a Trost BM. J. Org. Chem. 2004; 69: 5813
• 9b Lu Z, Ma S. Angew. Chem. Int. Ed. 2008; 47: 258
• 10a Wang P.-S, Gong L.-Z. Acc. Chem. Res. 2020; 53: 2841
• 10b Wang P.-S, Gong L.-Z. Chin. J. Chem. 2023; 41: 1841
• 11a Lin H.-C, Wang P.-S, Tao Z.-L, Chen Y.-G, Han Z.-Y, Gong L.-Z. J. Am. Chem. Soc. 2016; 138: 14354
• 11b Fan L.-F, Luo S.-W, Chen S.-S, Wang T.-C, Wang P.-S, Gong L.-Z. Angew. Chem. Int. Ed. 2019; 58: 16806
• 11c Lin HC, Xie PP, Dai ZY, Zhang SQ, Wang PS, Chen YG, Wang TC, Hong X, Gong LZ. J. Am. Chem. Soc. 2019; 141: 5824
• 11d Wang TC, Wang PS, Gong LZ. Sci. China Chem. 2020; 63: 454
• 11e Dai ZY, Wang PS, Gong LZ. Chem. Commun. 2021; 57: 6748
• 11f Liu R, Shen ML, Fan LF, Zhou XL, Wang PS, Gong LZ. Angew. Chem. Int. Ed. 2023; 62: e202211631
• 12a Wang TC, Fan LF, Shen Y, Wang PS, Gong LZ. J. Am. Chem. Soc. 2019; 141: 10616
• 12b Wang TC, Zhu L, Luo S, Nong ZS, Wang PS, Gong LZ. J. Am. Chem. Soc. 2021; 143: 20454
• 13 Nong Z.-S, Zhu L, Wang T.-C, Fan L.-F, Wang P.-S, Gong L.-Z. Nat. Synth. 2022; 1: 487
• 14a Teichert JF, Feringa BL. Angew. Chem. Int. Ed. 2010; 49: 2486
• 14b Zhang Z.-F, Xie F, Yang B, Yu H, Zhang W.-B. Chin. J. Org. Chem. 2011; 31: 429
• 15 Hamada Y, Shibata M, Sugiura T, Kato S, Shioiri T. J. Org. Chem. 2002; 52: 1252
• 16a Fan L.-F, Wang P.-S, Gong L.-Z. Org. Lett. 2019; 21: 6720
• 16b Fan L.-F, Xie P.-P, Wang P.-S, Hong X, Gong L.-Z. CCS Chem. 2022; 4: 1366
• 17 Synthesis of Allylation Products 3ab–am; General Procedure: To a flame-dried and N₂-purged Schlenk tube (10 mL) were added isopropyl 2-(benzo[d]thiazol-2-yl)-2-fluoroacetate (0.10 mmol, 25.3 mg, 1.0 equiv), Pd(dba)₂ (0.005 mmol, 2.8 mg, 5 mol%), phosphoramidite L5 (0.0075 mmol, 5.8 mg, 7.5 mol%), Li₂CO₃ (0.050 mmol, 3.7 mg, 0.5 equiv), 2,5-diphenylquinone (0.12 mmol, 31.2 mg, 1.2 equiv) and a stirring bar. The Schlenk tube was then evacuated and filled with nitrogen. This cycle was repeated three times and followed by the addition of anhydrous 1,4-dioxane (1 mL) and allylarene (0.2 mmol, 2.0 equiv) via a syringe, then the resulting mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (petroleum ether /ethyl acetate = 50:1) to provide the desired product. Isopropyl (2R,3R)-2-(Benzo[d]thiazol-2-yl)-2-fluoro-3-phenylpent-4-enoate (3aa): Compound 3aa was prepared according to the general procedure by using allylbenzene (23.6 mg). Eluent for column chromatography (petroleum ether/ethyl acetate = 50:1). Yield: 99% (36.6 mg); colorless oil; b/l > 20:1, dr = 6:1. Enantiomeric excess: 90%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 95:5, flow rate 1.0 mL/min, T = 30 °C, 254 nm): t_R = 4.743 (minor), 5.319 (major) min; [α]_D ²⁰ –11.4 (c 0.45, CHCl₃). ¹H NMR (400 MHz, CDCl₃ ): δ = 8.17 (d, J = 8.1 Hz, 1 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.53 (dd, J = 8.9, 7.7 Hz, 1 H), 7.50–7.41 (m, 3 H), 7.38–7.32 (m, 2 H), 7.31–7.27 (m, 1 H), 6.13–5.99 (m, 1 H), 5.08–4.98 (m, 2 H), 4.88–4.69 (m, 2 H), 1.00 (d, J = 6.3 Hz, 3 H), 0.93 (d, J = 6.3 Hz, 3 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –163.59. ¹³C NMR (101 MHz, CDCl₃): δ = 166.74 (d, J = 31.8 Hz), 165.77 (d, J = 26.0 Hz), 153.36, 137.49 (d, J = 1.3 Hz), 135.24 (d, J = 2.1 Hz), 133.90 (d, J = 5.4 Hz), 129.62 (d, J = 2.9 Hz), 128.64, 127.77, 126.43, 125.76, 123.97, 121.85, 119.93, 99.10 (d, J = 196.4 Hz), 70.87, 56.62 (d, J = 17.9 Hz), 21.30, 21.27. IR (KBr): 3064, 3031, 2982, 2854, 1754, 1637, 1602, 1511, 1455, 1264, 1103, 937, 819, 760, 730, 701 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for (C₂₁H₂₁FNO₂S)⁺: 370.1272; observed: 370.1271. Isopropyl (2R,3R)-2-(Benzo[d]thiazol-2-yl)-2-fluoro-3-(4-(trifluoromethyl)phenyl)pent-4-enoate (3ak): The compound 3ak was prepared according to the general procedure by using 1-allyl-4-(trifluoromethyl)benzene (37.2 mg). Eluent for column chromatography (petroleum ether/ethyl acetate = 50:1). Yield: 93% (40.7 mg); white solid; b/l > 20:1, dr = 5:1. Enantiomeric excess: 92%, determined by HPLC (CHIRALPAK IG, hexane/isopropanol = 95:5, flow rate 1.0 mL/min, T = 30 °C, 254 nm): t_R = 5.208 (major), 5.670 (minor) min; [α]_D ²⁰ –10.2 (c 0.77, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 8.58 (d, J = 8.2 Hz, 1 H), 8.36 (d, J = 8.0 Hz, 1 H), 8.07–8.01 (m, 4 H), 7.99–7.93 (m, 1 H), 7.91–7.84 (m, 1 H), 6.50–6.39 (m, 1 H), 5.52–5.41 (m, 2 H), 5.39–5.15 (m, 2 H), 1.43 (d, J = 6.3 Hz, 3 H), 1.35 (d, J = 6.3 Hz, 3 H). ¹⁹F NMR (471 MHz, CDCl₃): δ = –62.63, –163.68. ¹³C NMR (126 MHz, CDCl₃): δ = 166.19 (d, J = 31.8 Hz), 165.55 (d, J = 25.8 Hz), 153.35, 141.73, 135.25 (d, J = 2.1 Hz), 133.17 (d, J = 5.3 Hz), 130.07 (d, J = 2.9 Hz), 130.06 (q, J = 32.5 Hz), 126.55, 125.92, 125.57 (q, J = 3.8 Hz), 125.28 (q, J = 272.6 Hz), 124.03, 121.90, 120.70, 98.79 (d, J = 197.0 Hz), 71.17, 56.17 (d, J = 17.9 Hz), 21.29, 21.21. IR (KBr): 3055, 2989, 2964, 2933, 1747, 1510, 1329, 1266, 1193, 1118, 1071, 1015, 802, 761, 733 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for (C₂₂H₂₀F₄NO₂S)⁺: 438.1145; observed: 438.1140.