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With trifluoroacetic acid; sodium t-butanolate;Pd(dba)2; In tetrahydrofuran; methanol; dichloromethane; toluene; |
Example 10 This is an example of making a ligand on a solid support, in this case a resin bead having a tether. The tether, 2-(3-bromo-4-methoxyphenyl)ethanol, was first synthesised as follows: To <strong>[774-81-2]3-bromo-4-methoxyphenylacetic acid</strong> (12.26 g, 50.0 mmol) in 100 mL tetrahydrofuran (THF) was added borane dimethylsulfide complex (6.0 mL, 60.0 mmol) with cooling in an ice bath. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuuo. The residue was taken up in 100 mL methanol and concentrated in vacuuo to remove borate. Thie operation was repeated three times, affording analytically pure alcohol as a yellow oil (10.86 g, 94% yield). See N. M. Yoon, et al., J. Org. Chem., 38, 2786 (1973), herein incorporated by reference. Then, 2-(3-Bromo-4-methoxyphenyl)ethanol was immobilized onto Wang resin (100-200 mesh, 0.89 mmol/g loading) according to the procedure described by Hanessian and Xie (Tetrahedron Letters, 39, 1998, 733-736), herein incorporated by reference. The resulting resin (1.50g, 1.14 mmol), 2,6-diisopropylaniline (404mg, 2.28 mmol), sodium tert-butoxide (219mg, 2.28 mmol), Pd(dba)2 (13 mg, 23 mumol) and Ligand 2 (shown above in Example 2) (16 mg, 46 mumol) in 10 mL toluene were heated to 100 C. for 23 hr. The resin was drained, washed with three times with 10 mL of toluene (referred to as "10 mL*3"), and then 10 mL*5 THF, 10 mL*3 DMF, 10 mL*3 H2O, 10 mL*3 methanol, 10 mL*3 DMF, 10 mL*3 THF, and 10 mL CH2Cl2, and dried under vacuum, affording 1.61 g of tan color resin (100% based on the loading of the Wang resin). In order to characterize the resin, 144 mg of the resin was treated with 10 [v/v] % trifluoroacetic acid in CH2Cl2 for 30 min. at 21 C. The resin was filtered off and rinsed with 10 mL*5 CH2Cl2. The combined filtrates were washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and concentrated, affording 24.9 mg of a brown oil. The GC-MS analysis of the cleaved product revealed a mixture of the desired coupling product (70%) and its trifluoroacetic acid ester (30%) that was presumably formed during the acid cleavage, and it did not show unreacted 2-(3-bromo-4-methoxyphenyl)ethanol. The resin bound ligand is shown below as structure (8), and the cleaving reaction shows the unbound ligand as structure 9: Analysis of the cleaved product (9) showed: 1H-NMR (CDCl3, 300 MHz) delta 1.13 (d, J=6.9, 6H), 2.61 (t, J=6.6, 2H), 3.14 (sep, J=6.6, 2H), 3.66 (t, J=6.5, 2H), 3.94 (s, 3H), 5.62 (brs, 1H), 5.95 (d, J=2.1, 1H), 6.51 (dd, J=2.1, 8.1, 1H), 6.79 (d, J=8.1, 1H), 6.89 (dt, J=1.1, 7.9, 1H), 7.20-7.32 (m, 4H). MS (EI+) 327 (M+). |
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