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ether and combined organic layers were washed with aqueous solution of
NaHCO3 and dried over MgSO4. Solvents were evaporated under reduced
pressure and crude product was purified by flash column chromatography to
afford compound 3b as a yellow oil (155 mg, 0.59 mL, 77%). 1H NMR (400 MHz,
CDCl3) d 1.23 (d, 3JHH = 6.4 Hz, CH3, 3H), 1.29 (d, 3JHH = 6.2 Hz, CH3, 3H), 3.56 (s,
NH, 1H), 4.13 (m, 2H), 4.75 (m, 1H), 5.76 (ddd, 2JHP = 25.6 Hz,
5. Boutselis, I. G.; Yu, X.; Zhang, Z.; Borch, R. F. J. Med. Chem. 2007, 50, 856–864.
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12. Typical procedure: Isopropyl N-benzyl difluoromethylphosphonamidate 3b. To a
cold solution of t-butyllithium (1.3 M in THF, 0.76 mL, 0.99 mmol, 1.3 equiv), in
dried THF (5 mL) at À78 °C was added dropwise diisopropyl methylsulfanyl
difluoromethylphosphonate 6 (200 mg, 0.76 mmol, 1.0 equiv) and the solution
was stirred over 15 min. To this anion, benzylamine (0.108 mL, 0.99 mmol,
1.3 equiv) was slowly added, and after 30 min at À78 °C, the reaction mixture
was quenched by addition of aqueous solution of NH4Cl and then slowly
warmed to room temperature. The aqueous layer was extracted with diethyl
2JHF
=
2JHF = 49.4 Hz, CF2H, 1H), 7.17–7.27 (m, Ar, 5H); 13C NMR (100 MHz,
CDCl3) d 23.0 (d, 3JCP = 3.8 Hz), 23.1 (d, 3JCP = 4.2 Hz), 43.9, 71.8 (d, 2JCP = 6.7 Hz),
1
1
1
112.0 (ddd, JCF = 254.7 Hz, JCF = 259.8 Hz, JCP = 198.7 Hz, CF2), 126.2, 126.5,
127.6, 138.2; 19F NMR (376 MHz, CDCl3)
d
À135.6 (ddd, JFH = 49.4 Hz,
2
2JFP = 86.2 Hz, JFF = 347.2 Hz, 1F), –133.8 (ddd, JFH = 49.4 Hz, JFP = 86.3 Hz,
2
2
2
2JFF = 347.2 Hz, 1F); 31P NMR (162 MHz, CDCl3)
d
9.73 (dd, JPF = 86.2 Hz,
2
2JPF = 86.3 Hz, 1P); HRMS (ESI) m/z [M+H]+ calcd for C11H17F2NO2P 264.0965,
found 264.0973.
13. Isopropyl N-phenyl difluoromethylphosphonamidate 16. Following the typical
procedure from phosphonate 6 (200 mg, 0.76 mmol), and aniline (0.09 mL,
0.99 mmol), the reaction mixture was stirred from À78 °C to 20 °C over 1 h,
and phosphonamidate 16 was obtained as a yellow oil (141 mg, 74%). 1H NMR
3
3
(400 MHz, CDCl3) d 1.27 (d, JHH = 6.2 Hz, CH3, 3H), 1.37 (d, JHH = 6.2 Hz, CH3,
2
2
3H), 4.87 (m, 1H), 5.93 (ddd, JHP = 27.3 Hz, JHF
=
2JHF = 48.7 Hz, CF2H, 1H),
6.91–7.28 (m, Ar, 5H); 13C NMR (100 MHz, CDCl3) d 23.9 (d, 3JCP = 4.4 Hz), 24.1
(d, 3JCP = 4.3 Hz), 73.4 (d, 2JCP = 7.1 Hz), 112.2 (ddd, 1JCF = 259.7 Hz,
1JCF = 259.7 Hz, JCP = 195.7 Hz, CF2), 118.9 (d, JCP = 5.9 Hz), 122.8, 129.3,
1
3
138.6; 19F NMR (376 MHz, CDCl3)
d
À133.9 (ddd, 2JFH = 48.7 Hz,
2JFP = 87.7 Hz, JFF = 345.1 Hz, 1F), –135.5 (ddd, JFH = 48.7 Hz, JFP = 88.9 Hz,
2
2
2
2JFF = 345.1 Hz, 1F); 31P NMR (162 MHz, CDCl3)
d
5.51 (dd, JPF = 87.7 Hz,
2
2JPF = 88.9 Hz, 1P); HRMS (ESI) m/z [M+H]+ calcd for C10H15F2NO2P 250.0808,
found 250.0820.
14. The experiment realized with 6 and BnNHLi at 20 °C over 2 h afforded the
expected corresponding phosphonamidate, but this latter was accompanied
with other unidentified products.