Selective Tolyl Carbon Alkylation Mediated by Imidazoline‐Directed Lithiation (2004)

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 lithiationImidazolineSelective 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.