pentan-3-yl 2,2,2-trichloroethanimidate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-pentanol (1 mmol) in anhydrous Et2O (0.2 mL) was added dropwise to NaH (0.1 mmol; 60% in mineral oil) suspended in Et2O (1 mL) under nitrogen. The mixture was stirred for 10 min at room temperature and then added dropwise over a period of 20 min to a solution of trichloroacetonitrile (1.5 mmol) in Et2O (1 mL) at −5° C. under nitrogen. The reaction mixture was warmed to room temperature, and stirred for 2 h. After removal of solvent, the residue was triturated with MeOH/hexane with vigorous stirring to give precipitates, which were filtered off and washed with cold hexane. The filtrate was evaporated under reduced pressure to give 3-pentyl trichloroacetimidate. The freshly prepared 3-pentyl trichloroacetimidate (0.75 mmol) and CF3SO3H (0.075 mmol) were added to a solution of azido carboxylate ester (2A) (0.6 mmol) in CH2Cl2 (5 mL) under nitrogen. The reaction mixture was stirred at room temperature for 24 h, during which more imidate and CF3SO3H (0.075 mmol) were added 5 times every 4 h period. The reaction was quenched with 5% aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane) to afford the product (14B). Azide (14B) can then be converted to amine (1) as described above. The reaction mixture was warmed to room temperature stirred for 2 h After removal of solvent the residue was triturated with MeOH/hexane with vigorous stirring to give precipitates which were filtered off washed with cold hexane The filtrate was evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By a procedure similar to that for 11a, the reaction of alcohol 10b (498 mg, 1.5 mmol) with 3-pentyl trichloroacetimidate (420 mg, 1.8 mmol) in the presence of CF3SO3H (15.6 μL, 0.18 mmol), followed by another batches of the imidate and CF3SO3H, gave the alkylation product 11b (495 mg, 82% yield). Colorless oil; TLC (EtOAc/hexane, 1:1) Rf=0.2; [α]D20=−61.3 (c=0.65, CDCl3); IR (neat) 2100, 1756, 1634, 1246 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.56 (1 H, d, JP-2=21.6 Hz), 5.71 (1 H, d, J=6.9 Hz), 4.52 (1 H, d, J=7.8 Hz), 4.34-4.30 (1 H, m), 4.11-4.01 (4 H, m), 3.31-3.23 (2 H, m), 2.69-2.64 (1 H, m), 2.12-2.08 (1 H, m), 2.01 (3 H, s), 1.51-1.43 (4 H, m), 1.39-1.31 (6 H, m), 0.90-0.81 (6 H, m); 13C NMR (150 MHz, CDCl3) δ 171.0, 141.7, 126.3 (C-1, d, JP-1=182 Hz), 810.9, 73.7, 62.14, 62.10, 54.3, 57.1, 31.0, 26.2, 25.4, 23.6, 16.4, 16.3, 9.6, 9.2; 31P NMR (162 MHz, CDCl3) δ 16.99; HRMS calcd for C17H32N4O5P (M++H): 403.2110, found: m/z 403.2111.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Pentyl trichloroacetimidate was prepared as follows. Under an atmosphere of nitrogen, a solution of 3-pentanol (8.815 g, 100 mmol) in anhydrous Et2O (14 mL) was added dropwise to NaH (0.4 g, 10 mmol, 60% oil dispersion prewashed with hexane) suspended in Et2O (10 mL). The mixture was stirred for 10 min at room temperature, and added dropwise over a period of 20 min to a cold (−5° C.) solution of trichloroacetonitrile (15 mL, 150 mmol) in Et2O (20 mL) under an atmosphere of nitrogen. The reaction mixture was warmed to room temperature, and stirred for 2 h. After removal of solvent, the residue was triturated with MeOH/hexane (1:19, 10 mL) with vigorous stirring for 1 min to give precipitates, which were filtered off and washed with cold hexane. The filtrate was evaporated under reduced pressure to dryness, giving 3-pentyl trichloroacetimidate (16 g, 70% yield) as light brown oil. TLC (EtOAc/hexane, 1:4) Rf=0.3; 1H NMR (600 MHz, CDCl3) δ 8.17 (1 H, br s, NH), 4.89 (1 H, m, J=6.0 Hz), 1.69 (4 H, qd, J=7.4, 6.0 Hz), 0.94 (6 H, t, J=7.4 Hz); 13C NMR (150 MHz, CDCl3) δ 162.7, 92.2, 81.9, 25.7 (2×), 9.4 (2×); HRMS calcd for C7H13Cl3NO (M++H): 232.0063, found: m/z 232.0067. Under an atmosphere of nitrogen, the freshly prepared 3-pentyl trichloroacetimidate (350 mg, 1.5 mmol) and CF3SO3H (13 μL, 0.15 mmol) were added to a solution of alcohol 10a (321 mg, 1.2 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature for 24 h, during which more imidate and CF3SO3H (350 mg and 13 μL mmol) were added 5 times every 4 h period. The reaction was quenched with aqueous NaHCO3 solution (5%). The aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 3:7) to afford the alkylation product 11a (317 mg, 78% yield). Colorless solid, mp 115-117° C.; TLC (EtOAc/hexane, 1:1) Rf=0.4; [α]D20=−48.9 (c=1.1, CHCl3); IR (neat) 2101, 1712, 1655 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.75 (1 H, s), 5.98 (1 H, d, J=7.4 Hz), 4.53 (1 H, d, J=5.0 Hz), 4.51-4.16 (3 H, m), 3.33-3.28 (2 H, m), 2.82 (1 H, dd, J=17.6, 5.6 Hz), 2.22-2.16 (1 H, m), 2.00 (3 H, s), 1.49-1.45 (4 H, m), 1.25 (3 H, t, J=7.1 Hz), 0.95-0.80 (6 H, m); 13C NMR (150 MHz, CDCl3) δ 171.1, 165.8, 137.9, 128.1, 82.0, 73.4, 61.0, 58.0, 57.2, 30.5, 26.2, 25.6, 23.5, 14.1, 9.5, 9.3; HRMS calcd for C16H27N4O4(M++H): 3390.2032, found: m/z 339.2035. 3-Pentyl trichloroacetimidate was prepared The reaction mixture was warmed to room temperature stirred for 2 h After removal of solvent the residue was triturated with MeOH/hexane (1:19, 10 mL) with vigorous stirring for 1 min to give precipitates which were filtered off washed with cold hexane The filtrate was evaporated under reduced pressure to dryness