Selective Tolyl Carbon Alkylation Mediated by Imidazoline‐Directed Lithiation

Abstract

Imidazoline‐directed lithiation of 2‐o‐tolyl‐4,5‐dihydro‐1H‐imidazole and its subsequent treatment with electrophiles yields C‐alkylated products, without the need for a nitrogen protecting group. A variety of electrophiles were used to install aromatic, heteroaromatic, and alkyl substituted moieties.

Keywords:

• Directed lithiation
• Imidazoline
• Selective alkylation

Notes

^aWhere X = H: Prepared in 60% yield from 2‐methyl benzonitrile, following the procedure described by Spychala, J. Tetrahedron Lett. 1999, 40 (14), 2841–2844. Where X = F: Prepared from 3‐fluoro‐2‐methylbenzonitrile, using a similar procedure.

^bSelected data for 4: ¹H NMR (300 MHz, CDCl₃): δ 7.38–7.16 (14 H, m), 3.99 (2 H, s) 3.99–3.93 (2 H, m), 3.38–3.32 (2 H, m), 3.08–2.91 (4 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 166.31, 141.93, 140.51, 137.56, 130.78, 129.50, 129.32, 128.72, 128.43, 128.30, 127.32, 127.26, 126.06, 125.85, 53.24, 51.92, 49.96, 37.41, 35.32. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₇H₁₈N₂, 341.2012; found, 341.2019.

^cSelected data for 5: ¹H NMR (300 MHz, CDCl₃): δ 7.41–7.09 (9 H, m), 3.69 (4 H, Br s), 3.19–3.14 (2 H, m), 2.93–2.88 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 165.43, 141.85, 140.44, 131.53, 129.95, 129.46, 128.59, 128.32, 128.14, 125.80, 125.76, 99.90, 50.33, 38.10, 35.20. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₇H₁₈N₂, 251.1542; found, 251.1535.

^dTypical procedure: To a solution of 1 (100 mg, 0.63 mmol) in THF (6 mL) at room temperature under N₂ atmosphere was added n‐BuLi soln dropwise (2.5 M in hexanes, 750 µL, 1.88 mmol). The mixture was stirred for 15 min then cooled to −78°C and a solution of benzyl bromide (74 µL, 0.63 mmol) in THF (200 µL) was added slowly. TLC analysis (10%MeOH/2%NH₄OH/88%DCM) and LCMS showed that the reaction was complete within 10 min. The reaction was quenched while still at −78°C by addition of saturated NH₄Cl solution, and then allowed to warm to room temperature. The mixture was extracted into EtOAc (3x), and the combined organic phases were washed with brine (1x), dried (Na₂SO₄), and evaporated. Purification by chromatography on silica eluting with 100% DCM→5% MeOH/2% NH₄OH/93% DCM (30‐min gradient) gave 5 in 63% yield.

^eDianion formation was carried out at −20°C.

^fThe major product from these reactions was N‐alkylated. Efforts to overcome this by employing additives such as HMPA, TMEDA, and DMPU, and adjusting the reaction temperature and time, have so far been unsuccessful.

^gSelected data for compound 6: ¹H NMR (300 MHz, CDCl₃): δ 7.41–7.30 (3 H, m), 7.23–7.20 (1 H, m), 7.02 (2 H, d, J = 8.7 Hz), 6.80 (2 H, d, J = 8.7 Hz), 3.78 (3 H, s), 3.71 (4 H, Br s), 3.15–3.10 (2 H, m), 2.87–2.82 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 165.48, 157.71, 140.52, 136.84, 133.89, 131.31, 129.98, 129.51, 129.45, 128.33, 125.78, 116.59, 113.53, 55.19, 47.93, 37.12, 35.44. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₈H₂₀N₂O, 281.1648; found, 281.1657. 7: ¹H NMR (300 MHz, CDCl₃): δ 7.41–7.14 (5 H, m), 6.75–6.65 (3 H, m), 3.75 (3 H, m), 3.69 (4 H, Br s), 3.18–3.13 (2 H, m), 2.90–2.85 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 165.42, 159.40, 143.49, 140.45, 131.52, 129.95, 129.46, 129.07, 128.32, 125.81, 120.94, 114.14, 111.24, 55.02, 49.62, 38.14, 35.12. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₈H₂₀N₂O, 281.1648; found, 281.1653. 8: ¹H NMR (300 MHz, CDCl₃): δ 7.41–7.29 (3 H, m), 7.23–7.18 (1 H, m), 6.83 (1 H, s), 6.74 (1 H, s), 3.70 (4 H, Br s), 3.15–3.09 (2 H, m), 2.85–2.79 (2 H, m), 2.27 (6 H, s). ¹³C NMR (300 MHz, CDCl₃): δ 165.50, 141.79, 140.64, 137.62, 131.52, 129.87, 129.45, 128.29, 127.38, 126.38, 125.76, 50.50, 37.96, 35.31, 21.18. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₉H₂₂N₂, 279.1855; found, 279.1868. 9: ¹H NMR (300 MHz, CDCl₃): δ 7.35–7.07 (12 H, m), 6.85–6.82 (1 H, m), 3.58 (4 H, Br s), 3.02–2.96 (2 H, m), 2.85–2.79 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 165.46, 141.92, 141.79, 140.25, 139.02, 131.19, 130.09, 129.92, 129.60, 129.35, 129.21, 128.29, 127.89, 127.22, 126.60, 125.72, 125.69, 50.27, 35.00, 34.70. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₂₃H₂₂N₂, 327.1855; found, 327.1847. 10: ¹H NMR (300 MHz, CDCl₃): δ 7.35–7.13 (7 H, m), 7.08–7.06 (2 H, m) 3.67 (4 H, Br s), 3.28–3.20 (1 H, m), 3.06–2.98 (2 H, m), 1.29 (3 H, d, J = 6.6 Hz). ¹³C NMR (300 MHz, CDCl₃): δ 165.62, 146.61, 139.61, 131.58, 130.70, 129.71, 129.14, 128.24, 128.00, 127.49, 127.09, 125.82, 125.72, 50.20, 42.11, 41.95, 20.91. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₈H₂₀N₂, 265.1699; found, 265.1713. 13: ¹H NMR (300 MHz, MeOD): δ 7.95 (1 H, d, J = 7.7 Hz), 7.80 (1 H, d, J = 7.7 Hz), 7.52–7.40 (4 H, m), 7.22–7.19 (1 H, m), 6.88 (1 H, s), 3.40 (4 H, s), 3.34–3.28 (2 H, m overlaid with MeOD), 3.20–3.16 (2 H, m). ¹³C NMR (300 MHz, MeOD): δ 167.31, 163.21 (d, J = 246.4 Hz), 142.67, 140.35, 135.76, 127.21, 126.27, 126.21, 125.82, 125.38, 124.62, 123.06, 121.74, 121.45, 116.80, 47.02, 34.88, 27.30. LCMS: ES⁺ m/z 265 (M + 1). Anal. Calcd for C₁₉H₁₇ClFN₂S.HCl: C, 63.24%; H, 5.03%; N, 7.76%; S, 8.89%. Found: C, 63.03%; H, 4.86%; N, 8.03%; S, 8.49%. 14: ¹H NMR (300 MHz, MeOD): δ 8.74–8.71 (1 H, m), 8.50 (1 H, ddd, J = 1.5 Hz, 7.9 Hz, 7.9 Hz), 7.95–7.87 (2 H, m), 7.53–7.46 (1 H, m), 7.42–7.35 (2 H, m), 4.14 (4 H, s), 3.39–3.31 (4 H, m). ¹³C NMR (300 MHz, MeOD): δ 168.98, 163.20 (d, J = 246.4), 157.05, 148.78, 143.08, 131.73 (d, J = 9.3 Hz), 129.44, 127.28, 127.30 (d, J = 8.2 Hz), 127.24 (d, J = 18.1 Hz), 127.01, 121.60 (J = 23.1 Hz), 47.02, 34.88, 27.30. LCMS: ES⁺ m/z 270 (M + 1). Anal. Calcd for C₁₆H₁₆FN₃.2HCl. 1.3 H₂O: C, 53.08%; H, 5.71%; N, 11.61%; Cl, 18.61%. Found: C, 53.33%; H, 5.34%; N, 11.51%; Cl, 18.92%. 15: ¹H NMR (300 MHz, MeOD): δ 8.80 (1 H, s), 8.77 (1 H, d, J = 5.6 Hz), 8.52 (1 H, d, J = 8.2 Hz), 8.05 (1 H, dd, J = 5.6 Hz, 7.9 Hz), 7.56–7.49 (1 H, m), 7.45–7.39 (2 H, m), 4.18 (4 H, s), 3.20 (4 H, Br s). ¹³C NMR (300 MHz, MeOD): δ 163.08 (d, J = 247.0 Hz), 157.22, 148.90, 143.12, 138.93, 137.73, 133.91 (d, J = 4.9 Hz), 129.04, 128.18, 127.28 (d, J = 4.9 Hz), 125.74 (d, J = 22.5 Hz), 121.56 (d, J = 22.5 Hz), 47.03, 36.45, 28.50. LCMS: ES⁺ m/z 270 (M + 1). Anal. Calcd for C₁₆H₁₆FN₃.2HCl. 0.5 H₂O: C, 54.71%; H, 5.45%; N, 11.96%; Cl, 20.19%. Found: C, 54.74%; H, 5.45%; N, 11.72%; Cl, 20.02%. 16: ¹H NMR (300 MHz, MeOD): δ 8.78 (2 H, d, J = 6.9 Hz), 7.98 (2 H, d, J = 6.6 Hz), 7.57–7.40 (3 H, m), 4.18 (4 H, s), 3.26 (4 H, Br s). ¹³C NMR (300 MHz, MeOD): δ 164.50, 163.12 (d, J = 247.0 Hz), 142.93, 141.01, 131.47 (d, J = 9.3 Hz), 129.25, 127.96 (d, J = 18.1 Hz), 127.25, 127.22 (d, J = 7.7 Hz), 121.60 (d, J = 23.1 Hz), 46.97, 37.38, 27.91. LCMS: ES⁺ m/z 270 (M + 1). Anal. Calcd for C₁₆H₁₆FN₃.2HCl: C, 56.15%; H, 5.30%; N, 12.28%; Cl, 20.72%. Found: C, 56.00%; H, 5.33%; N, 12.16%; Cl, 20.56%. 17: ¹H NMR (300 MHz, MeOD): δ 7.52–7.35 (3 H, m), 6.02 (1 H, s), 4.14 (4 H, s), 3.19 (2 H, t, J = 7.3 Hz), 2.94 (2 H, t, J = 7.3 Hz), 2.37 (3 H, s). ¹³C NMR (300 MHz, MeOD): δ 171.98, 168.50, 164.52, 163.30 (d, J = 246.4 Hz), 130.99 (d, J = 9.3 Hz), 129.12 (d, J = 18.1 Hz), 127.31 (d, J = 5.5 Hz), 126.60, 121.52 (d, J = 23.1 Hz), 103.29, 46.84, 27.61, 26.23, 12.46. LCMS: ES⁺ m/z 274 (M + 1). Anal. Calcd for C₁₅H₁₆FN₃O.HCl. 0.2 H₂O: C, 57.49%; H, 5.60%; N, 13.41%; Cl, 11.31%. Found: C, 57.31%; H, 5.52%; N, 13.22%; Cl, 11.27%. 18: ¹H NMR (300 MHz, MeOD): δ 7.49–7.44 (3 H, m), 6.46 (1 H, s), 4.17 (4 H, s), 3.91 (3 H, s), 3.20–3.05 (4 H, m), 2.41 (3 H, s). ¹³C NMR (300 MHz, MeOD): δ 168.09, 163.24 (d, J = 246.4 Hz), 150.11, 147.10, 127.73, 127.27, 127.08 (d, J = 18.1 Hz), 123.63, 121.60 (d, J = 23.1 Hz), 108.53, 46.99, 26.58, 26.06, 11.58. LCMS: ES⁺ m/z 287 (M + 1). Anal. Calcd for C₁₆H₁₉FN₄. 3.1 HCl. 0.1 H₂O: C, 47.90%; H, 5.60%; N, 13.97%; Cl, 27.39%. Found: C, 48.25%; H, 5.61%; N, 13.61%; Cl, 27.11%.

^hAs determined by LCMS analysis.

ⁱSelected data for 19: ¹H NMR (300 MHz, CDCl₃): δ 7.43–7.40 (1 H, m), 7.33–7.28 (1 H, m), 7.24–7.15 (2 H, m), 3.76 (4 H, Br s), 2.86–2.81 (2 H, m), 1.59 (1 H, ddd, J = 6.6, 13.4, 20.0 Hz), 1.48–1.41 (2 H, m), 0.92 (6 H, d, J = 6.4 Hz). ¹³C NMR (300 MHz, CDCl₃): δ 165.47, 141.98, 131.10, 129.71, 129.39, 128.35, 125.44, 50.36, 41.13, 31.12, 28.00, 22.45. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₄H₂₀N₂, 217.1699; found, 217.1694. 20: ¹H NMR (300 MHz, CDCl₃): δ 7.43–7.40 (1 H, m), 7.33–7.28 (1 H, m), 7.24–7.15 (2 H, m), 3.76 (4 H, Br s), 2.86–2.81 (2 H, m), 1.77–1.62 (5 H, m), 1.48–1.41 (2 H, m), 1.31–1.12 (4 H, m), 0.78–0.86 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 165.51, 142.10, 131.03, 129.72, 129.44, 128.36, 125.43, 50.24, 39.70, 37.59, 33.20, 30.64, 26.59, 26.25. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₇H₂₄N₂, 257.2012; found, 257.2009. 21: ¹H NMR (300 MHz, CDCl₃): δ 7.43–7.40 (1 H, m), 7.32–7.26 (1 H, m), 7.20–7.16 (2 H, m), 3.74 (4 H, Br s), 2.74 (2 H, d, J = 7.2 Hz), 1.84 (1 H, ddd, J = 6.8, 13.7, 20.5 Hz), 0.87 (6 H, d, J = 6.6 Hz). ¹³C NMR (300 MHz, CDCl₃): δ 165.63, 140.51, 131.52, 130.56, 129.11, 128.36, 125.55, 50.31, 42.23, 30.06, 22.39. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₃H₁₈N₂, 203.1542; found, 203.1541. 22: ¹H NMR (300 MHz, CDCl₃): δ 7.43–7.40 (1 H, m), 7.32–7.26 (1 H, m), 7.20–7.15 (2 H, m), 3.74 (4 H, Br s), 2.74 (2 H, d, J = 7.2 Hz), 1.71–1.55 (5 H, m), 1.55–1.42 (1 H, m), 1.19–1.10 (3 H, m), 0.99–0.86 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 165.71, 140.16, 131.63, 130.54, 129.03, 128.32, 125.47, 40.29, 40.72, 39.66, 33.08, 26.43, 26.25. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₆H₂₂N₂, 243.1855; found, 243.1846.

^jSelected data for 23: ¹H NMR (300 MHz, CDCl₃): δ 7.40–7.04 (9 H, m), 3.72 (4 H, Br s), 3.38–3.21 (3 H, m), 2.63–2.58 (2 H, m). ¹³C NMR (300 MHz, CDCl₃): δ 164.81, 141.53, 137.72, 131.46, 130.77, 129.53, 128.56, 128.47, 127.26, 126.56, 118.75, 50.71, 43.82, 38.96, 23.40. HRMS‐TOF (m/z): [M + H]⁺ calcd for C₁₉H₁₉N₃, 290.1651; found, 290.1641.