Acid and Solvent Effects on the Regioselectivity of Minisci-Type Addition to Quinolines Using Amino Acid Derived Redox Active Esters

Published as part of the Cluster Modern Heterocycle Synthesis and Functionalization

Abstract

Minisci-type reactions comprise an important class of reactions for the direct functionalization of basic heterocyclic compounds. On certain heterocycles, such as quinolines, Minisci-type reactions face a regioselectivity choice which often results in mixtures of regioisomers at the C2 and C4 positions, limiting utility. We present a study of the effect of solvent and Brønsted acid catalyst on regioselectivity in the addition of N-acetyl-substituted, α-amino alkyl radicals to quinolines. By tuning the solvent and acid combination we identify conditions that strongly favour C2 and strongly favour C4 and present a small scope of compatible substrates.

Key words

Minisci reaction - regioselectivity - Brønsted acid - heterocycles - radicals

• References and Notes

• 1a Duncton MA. J. MedChemComm 2011; 2: 1135
• 1b Minisci F, Vismara E, Fontana F. Heterocycles 1989; 28: 489
• 1c Minisci F, Fontana F, Vismara E. J. Heterocycl. Chem. 1990; 27: 79
• 2a Proctor RS. J, Phipps RJ. Angew. Chem. Int. Ed. 2019; 58: 13666
• 2b Sun AC, McAtee RC, McClain EJ, Stephenson CR. J. Synthesis 2019; 51: 1063
• 3a Proctor RS. J, Davis HJ, Phipps RJ. Science 2018; 360: 419
• 3b Reid JP, Proctor RS. J, Sigman MS, Phipps RJ. J. Am. Chem. Soc. 2019; 141: 19178
• 4a Liu X, Liu Y, Chai G, Qiao B, Zhao X, Jiang Z. Org. Lett. 2018; 20: 6298
• 4b Zheng D, Studer A. Angew. Chem. Int. Ed. 2019; 58: 15803
• 5 Tauber J, Imbri D, Opatz T. Molecules 2014; 19: 16190
• 6 Dou HJ. M, Lynch BM. Tetrahedron Lett. 1965; 6: 897
• 7a Minisci F, Vismara E, Morini G, Fontana F, Levi S, Serravalle M, Giordano C. J. Org. Chem. 1986; 51: 476
• 7b Minisci F, Vismara E, Fontana F, Morini G, Serravalle M, Giordano C. J. Org. Chem. 1986; 51: 4411
• 7c Minisci F, Vismara E, Fontana F, Morini G, Serravalle M, Giordano C. J. Org. Chem. 1987; 52: 730
• 8 O’Hara F, Blackmond DG, Baran PS. J. Am. Chem. Soc. 2013; 135: 12122
• 9 Cheng W.-M, Shang R, Fu Y. ACS Catal. 2017; 7: 907
• 10a Luo J, Zhang J. ACS Catal. 2016; 6: 873
• 10b Sherwood TC, Li N, Yazdani AN, Dhar TG. M. J. Org. Chem. 2018; 83: 3000
• 10c Shang T.-Y, Lu L.-H, Cao Z, Liu Y, He W.-M, Yu B. Chem. Commun. 2019; 55: 5408
• 11 C4-Addition Products – General Procedure Sequentially, N-heteroarene (0.20 mmol, 2.0 equiv.), redox-active ester (0.10 mmol, 1.0 equiv.), 4CzIPN (1.6 mg, 0.002 mmol, 2 mol%), and pTsOH (1.9 mg, 0.01 mmol, 10 mol%) were added to a 4 mL crimp top vial containing a stirrer bar. The vial was sealed with a crimp seal, evacuated, and refilled with argon three times. Anhydrous, freshly argon-sparged solvent (2.0 mL) was then added via syringe and the top wrapped with Parafilm. The reaction mixture was stirred under irradiation with blue LEDs for 14 h. The apparatus was maintained at approximately room temperature by use of a desk fan close to the vials. The solvent was removed under a stream of compressed air, and the crude residue was purified via flash column chromatography on silica gel. N-[2-Methyl-1-(quinolin-4-yl)propyl]acetamide (3b) DMA was used as a solvent. The crude mixture was purified via flash column chromatography (100% 40–60 PE to 3% MeOH in EtOAc) to give product 3b as a major regioisomer (19 mg, 32%). ¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 4.54 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 8.5 Hz, 1 H,), 7.74–7.70 (m, 1 H), 7.61–7.57 (m, 1 H), 7.27–7.25 (m, 1 H), 6.01 (br d, J = 8.9 Hz, 1 H), 5.65 (dd, J = 8.4, 8.4 Hz, 1 H), 2.27 (sept, J = 6.7 Hz, 1 H), 2.02 (s, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 0.94 (d,J = 6.9 Hz, 3 H).¹³C NMR (400 MHz, CDCl₃): δ = 169.5, 149.8, 148.6, 147.8, 130.2, 129.4, 126.9, 126.7, 123.4, 117.7, 53.7, 32.6, 23.3, 20.2, 18.2. FTIR: ν_max = 3750, 3296, 2966, 1647, 1548, 1371, 756 cm^–1. HRMS: m/z [M + H]⁺ calcd for [C₁₅H₁₉N₂O]⁺: 243.1492; found: 243.1483.
• 12 C2-Addition Products – General Procedure Sequentially, N-heteroarene (0.20 mmol, 2.0 equiv.), redox-active ester (0.10 mmol, 1.0 equiv.), 3DPAFIPN (1.3 mg, 0.002 mmol, 2 mol%), and 2,4,6-triisopropylsulfonic acid (1.3 mg, 0.01 mmol, 10 mol%) were added to a 4 mL crimp top vial containing a stirrer bar. The vial was sealed with a crimp seal, evacuated, and refilled with argon three times. Anhydrous, freshly argon-sparged solvent (2.0 mL) was then added via syringe and the top wrapped with Parafilm. The reaction mixture was stirred under irradiation with blue LEDs for 14 h. The apparatus was maintained at approximately room temperature by use of a desk fan close to the vials. The solvent was removed under a stream of compressed air, and the crude residue was purified via flash column chromatography on silica gel. N-[2-Methyl-1-(quinolin-2-yl)propyl]acetamide (4b) Dioxane was used as a solvent. The crude mixture was purified via flash column chromatography (100% 40–60 PE to 3% MeOH in EtOAc) to give product 4b as a major regioisomer (7.8 mg, 32%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.81 (d, J = 7.7 Hz, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.53 (t, J = 6.9 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 5.11 (dd, J = 6.3, 8.5 Hz, 1 H), 2.24 (sept, J = 6.7 Hz, 1 H), 2.10 (s, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H).¹³C NMR (400 MHz, CDCl₃): δ = 169.7, 159.7, 147.4, 136.2, 129.5, 128.9, 127.7, 127.3, 126.3, 121.3, 59.0, 34.3, 23.6, 19.3, 18.4. FTIR: ν_max = 3290, 2961, 2925, 2367, 1648, 1503, 1429, 1372, 823, 754 cm^–1. HRMS: m/z [M + H]⁺ calcd for [C₁₅H₁₉N₂O]⁺: 243.1492; found: 243.1484.