REFERENCES
- Mitsunobu , O. 1991 . Comprehensive Organic Synthesis Edited by: Trost , B.M. , Fleming , I. and Winterfeldt , E. Vol. 6 , 65 – 101 . Pergamon Press .
- Salvatore , R.N. , Nagle , A.S. , Schmidt , S.E. and Jung , K.W. Thirty-Sixth National Organic Chemistry Symposium Abstract No. 234.
- Two buffer systems, i.e., potassium carbonate (pKa 10.25) and a mixture of di- and tri-sodium borate (pKa's 12.74, 13.80) were also tested to provide pH control. Of these, the borate buffer worked best and gave comparable selectivity (3.3) to the NaOH/pH 12.5 result.
- A typical reaction was carried out as follows: 0.01 mol each of amine and chloroacetamide were stirred in 8 mL of MeCN and 2 mL of water at 23°C (for reactions using 2 : 1 stoichiometry, 0.02 mol of amine was used). NaI was added (0.01 mol) and the reaction was kept at the desired pH by adding 40% (w/w) aqueous NaOH as needed. The reaction was judged complete when the pH became constant and by disappearance of chloroacetamide as determined by HPLC. After standard workup, the final composition of the reaction mixture was determined by 1H-NMR and HPLC.[6] In the case of compound 8, isolation of the product was carried out as follows: For a 1 : 1 stoichiometry reaction, the oil obtained after aqueous workup was dissolved in i-PrOH and 1 eq of 48% HBr was added. The solvent was stripped under vacuum and the residue was distilled again with i-PrOAc to remove traces of water during which white solids precipitated. The solids were slurried in 4 : 1 (v/v) i-PrOAc/i-PrOH at 50°C, then cooled slowly to room temperature, filtered, and washed with i-PrOAc to obtain the HBr salt of 8 in 45% yield and >96% purity. For a 2 : 1 stoichiometry reaction, after aqueous workup the resulting oil was dissolved in i-PrOH and 1 eq HCl was added. The solvent was stripped under vacuum during which white solids precipitated. i-PrOAc was added and the mixture distilled again to remove traces of water, then the solids were slurried in i-PrOAc at 50°C. The mixture was cooled slowly to room temperature, and the solids (a mixture containing about 90% of the HCl salt of 1 and 10% of the HCl salt of 8) were filtered off. To the mother liquor containing most of the product 8 was added i-PrOH and 1 eq of 48% HBr, then the solvents are stripped under vacuum to obtain white solids. After distilling again with i-PrOAc to remove traces of water, the solids were slurried in 4 : 1 (v/v) i-PrOAc/i-PrOH at 50°C, slowly cooled to room temperature, filtered, and washed with i-PrOAc to obtain the HBr salt of 8 in >97% purity and 75% yield.
- The recovered HCl salt of amine 1 could be used for additional reactions with chloroacetamide 6 by stirring in the MeCN/H2O solvent mixture and adding 1 eq NaOH to regenerate the free base of 1 prior to adding 6 and the NaI catalyst.
- For reactions with electrophile 5, the 1H-NMR signals from the N-CH2-CO group (singlets) were used for determining the ratio of products.[7] For reactions with electrophiles 6 and 7, the ratio of products was determined by HPLC analysis. [Column, Waters Symmetry C-18, 4.6 × 150 mm; eluent, initial 95 : 5 (v/v) 0.5% H3PO4/MeCN to 95 : 5 (v/v) MeCN/water over 13 min; flow rate, 1.6 mL/min; detection, UV 254 nm]. In all cases the retention time was greater for the dialkyl product relative to the corresponding monoalkyl product.
- Analytical data: HBr salt of 8: Mp 178–185°C (dec). 1H NMR (300 MHz, D2O) δ 7.46–7.55 (5H, m), 4.16 (2H, s), 3.51 (2H, t, J = 7.4 Hz), 3.49 (2H, q, J = 7.2 Hz), 3.39 (2H, q, J = 7.2 Hz), 3.20 (2H, t, J = 7.4 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.22 (3H, t, J = 7.2 Hz); 13C NMR (75.5 MHz, D2O) δ 164.8, 136.7, 129.5, 129.2, 127.8, 49.0, 47.9, 42.0, 41.3, 32.1, 13.1, 12.2. Anal. Calcd for C14H23N2OBr: C, 53.33; H, 7.35; N, 8.89; Br, 25.35. Found: C, 53.41; H, 7.22; N, 8.91; Br, 25.74. HBr salt of 9: Mp 187–189°C (dec). 1H NMR (300 MHz, D2O) δ 7.43–7.58 (5H, m), 4.44 (4H, s), 3.77 (2H, t, J = 7.3 Hz), 3.50 (4H, q, J = 7.3 Hz), 3.37 (4H, q, J = 7.3 Hz), 3.26 (2H, t, J = 7.3 Hz), 1.27 (6H, t, J = 7.3 Hz), 1.24 (6H, t, J = 7.3 Hz); 13C NMR (75.5 MHz, D2O) δ 163.8, 135.7, 129.6, 129.2, 128.1, 58.0, 56.4, 42.1, 41.6, 31.0, 13.2, 12.2. Anal. Calcd for C20H34N3O2Br: C, 56.07; H, 8.00; N, 9.80; Br, 18.65. Found: C, 55.83; H, 8.00; N, 9.87; Br, 18.43. Monoalkylated product (1 + 6): 1H NMR (300 MHz, CDCl3) δ 7.14–7.32 (5H, m), 3.29–3.56 (6H, m), 2.79–2.94 (4H, m), 2.06 (1H, br.s), 1.77–2.00 (4H, m). Dialkylated product (1 + 6) was not isolated in pure form. The identity of the compound was confirmed by HPLC-MS; 344(MH+). Monoalkylated product (1 + 7): 1H NMR (300 MHz, CDCl3) δ 7.16–7.34 (5H, m), 4.67–4.75 (1H, m), 3.30–3.70 (4H, m), 2.78–2.96 (4H, m), 1.96–2.37 (4H, m), 1.90 (1H, br.s). Dialkylated product (1 + 7); 1H NMR (300 MHz, CDCl3) δ 7.13–7.34 (5H, m), 4.63–5.51 (2H, m), 3.26–4.05 (8H, m), 2.77–3.22 (4H, m), 1.69–2.43 (8H, m). Monoalkylated product (2 + 5); 1H NMR (300 MHz, CDCl3) δ 7.20–7.38 (5H, m), 3.87 (2H, s), 3.40 (2H, q, J = 7.2 Hz), 3.38 (2H, s), 3.20 (2H, q, J = 7.2 Hz), 2.50 (1H, br.s), 1.13 (6H, t, J = 7.2 Hz). Dialkylated product (2 + 5); 1H NMR (300 MHz, CDCl3) δ 7.22–7.38 (5H, m), 3.89 (2H, s), 3.48 (4H, s), 3.35 (4H, q, J = 7.7 Hz), 3.28 (4H, q, J = 7.7 Hz), 1.23 (6H, t, J = 7.7 Hz), 1.17 (6H, t, J = 7.7 Hz). Monoalkylated product (3 + 5); 1H NMR (300 MHz, CDCl3) δ 7.19 (2H, t, J = 7.7 Hz), 6.72 (1H, t, J = 7.7 Hz), 6.64 (2H, d, J = 7.7 Hz), 4.20 (1H, br.s), 3.86 (2H, s), 3.45 (2H, q, J = 7.4 Hz), 3.22 (2H, q, J = 7.4 Hz), 1.25 (3H, t, J = 7.4 Hz), 1.17 (3H, t, J = 7.4 Hz). Dialkylated product (3 + 5); 1H NMR (300 MHz, CDCl3) δ 7.16 (2H, t, J = 7.7 Hz), 6.70 (1H, t, J = 7.7 Hz), 6.51 (2H, d, J = 7.7 Hz), 4.24 (4H, s), 3.42 (4H, q, J = 7.4 Hz), 3.36 (4H, q, J = 7.4 Hz), 1.25 (6H, t, J = 7.4 Hz), 1.17 (6H, t, J = 7.4 Hz). Monoalkylated product (4 + 5); 1H NMR (300 MHz, D2O + DCl) δ 7.27 (2H, d, J = 9.2 Hz), 6.85 (2H, d, J = 9.2 Hz), 4.31 (2H, s), 3.24 (2H, q, J = 7.1 Hz), 3.18 (2H, q, J = 7.1 Hz), 0.99 (3H, t, J = 7.1 Hz), 0.95 (3H, t, J = 7.1 Hz). Dialkylated product (4 + 5); 1H NMR (300 MHz, D2O + DCl) δ 7.45 (2H, d, J = 9.2 Hz), 6.86 (2H, d, J = 9.2 Hz), 4.68 (4H, s), 3.20 (4H, q, J = 7.1 Hz), 3.17 (4H, q, J = 7.1 Hz), 0.99 (6H, t, J = 7.1 Hz), 0.92 (6H, t, J = 7.1 Hz).