P. Beier et al. / Tetrahedron 64 (2008) 10977–10985
10983
3
4
(13), 155 (25), 174 (100), 176 (30); HRMS (ESIþ) calculated for
C19H21Cl2F2NaO5P: 491.0364, found: 491.0363.
(400 MHz, CDCl3)
d
1.09 (dt, 3H0, JHH¼6.0 Hz, JHP¼1.1 Hz, CH3),
3
4
1.30 (dt, 3H0, JHH¼7.1 Hz, JHP¼1.1 Hz, CH3), 1.35–1.41 (m, 6H,
2ꢃCH3), 1.53–2.55 (m, 10H, 10H0, 10ꢃCH2), 2.81 (s, 1H0, OH), 3.76–
3.86 (m, 2H0, CH2CH3), 4.05–4.22 (m, 4H, 2H0, CH2CH3), 5.12–5.21
(m, 2H, CH, OH), 5.64–5.72 (m, 1H0, CH), 7.31–7.42 (m, 4H, 4H0,
4.4.5. 1-(4-Chlorophenyl)-2,2-difluoro-3-hydroxy-3-(4-
methoxyphenyl)propyl diethyl phosphate (6bl); 3-(4-chlorophenyl)-
2,2-difluoro-3-hydroxy-1-(4-methoxyphenyl)propyl diethyl
phosphate (60bl)
C
ArH); 13C NMR (100.6 MHz, CDCl3)
d 15.7–16.0 (m), 16.0–16.1 (m),
20.6–20.7 (m), 20.8–20.9 (m), 24.6, 25.2, 29.6, 30.4–30.7 (m), 64.2–
64.6 (m), 71.7–72.3 (m), 74.2–74.7 (m), 75.3–75.9 (m), 87.6 (dt,
Ratio (8:1); colorless liquid (225 mg, 83%). Chromatography 20–
70% EtOAc/hexanes; Rf (30% EtOAc/hexanes) 0.10. 1H NMR
2JCF¼27.3, JCP¼9.1 Hz, COP), 117.0–122.1 (m), 128.0, 128.4, 129.6,
2
(400 MHz, CDCl3)
d
1.05 (dt, 3H, 3JHH¼7.1 Hz, 4JHP¼1.0 Hz, CH3), 1.12
130.0, 133.0, 134.0, 135.2, 135.9; 19F NMR (470 MHz, CDCl3)
d
ꢀ125.6
3
4
3
(dt, 3H, JHH¼7.1 Hz, JHP¼1.0 Hz, CH3), 1.25 (dt, 3H, JHH¼7.1 Hz,
4JHP¼1.0 Hz, CH3), 1.38 (dt, 3H, 3JHH¼7.1 Hz, 4JHP¼1.0 Hz, CH3), 3.71–
4.25 (m, 14H, 4ꢃCH2, 2ꢃOMe), 4.44–4.51 (m, 1H), 4.56–4.59 (m,
1H), 5.10–5.17 (m, 1H, CH), 5.49 (d, 1H, 3JHH¼5.8 Hz, OH), 5.67–5.76
(m, 1H, CH), 5.87–5.96 (m, 1H, CH), 6.87–6.94 (m, 4H, CArH), 7.28–
(dd, 1F0, 2JFF¼264.5 Hz, 3JFH¼16.9 Hz), ꢀ124.0 (dd, 1F, 2JFF¼268.4 Hz,
3JFH¼22.2 Hz), ꢀ116.0. (d, 1F0, JFF¼264.5 Hz), ꢀ109.5 (d, 1F,
2
2JFF¼268.4 Hz); 31P NMR (162 MHz, CDCl3)
d
ꢀ5.58 (s, P), ꢀ1.29 (s,
P0); FTIR (film, nmax cmꢀ1) 3339 (s), 2984 (m), 2939 (s), 2867 (m),
1599 (w), 1581 (w), 1493 (m), 1452 (m), 1265 (s), 1250 (s), 1090 (s),
1028 (s), 807 (m); GC–MS (EI) m/z 81 (15%), 99 (15), 141 (25), 155
(20), 174 (100), 176 (30), 149 (40), 151 (12), 277 (10), 308 (7); HRMS
(ESIþ) calculated for C18H26ClF2O5PNa: 449.1067, found: 449.1068.
7.32 (m, 6H, CArH), 7.36–7.42 (m, 4H, CArH), 7.53–7.56 (m, 2H, CArH);
3
13C NMR (100.6 MHz, CDCl3)
d
15.7 (d, JCP¼7.0 Hz, CH3), 15.7 (d,
3JCP¼6.7 Hz, CH3), 15.8 (d, JCP¼7.0 Hz, CH3), 16.0 (d, JCP¼6.7 Hz,
3
3
2
2
CH3), 55.2, 55.2, 63.8 (d, JCP¼5.7 Hz, CH2), 64.2, (d, JCP¼6.0 Hz,
CH2), 64.9 (d, 2JCP¼6.4 Hz, CH2), 65.0 (d, 2JCP¼6.2 Hz, CH2), 70.3 (dd,
4.5. General procedure for the preparation of difluoromethyl
diols 7 from phosphates 6
2JCF¼28.1, 27.6 Hz, CH), 71.8 (dd, JCF¼23.7, 30.3 Hz, CH), 74.7–75.4
2
(m), 77.1–77.8 (m), 113.7, 113.9, 116.6–122.2 (m), 128.0, 128.1, 129.3,
129.4, 129.7, 130.0, 134.0, 134.3, 134.9, 160.3, 160.4; 19F NMR
A solution sodium methoxide (0.125 mL, 4 M, 0.5 mmol) in
methanol was added to a solution of phosphate 6 (0.5 mmol) in THF
(4 mL). The mixture was stirred at room temperature for 1 h and
then aqueous solution of NH4Cl (4 mL) was added, the product was
extracted into ethyl acetate or dichloromethane (4ꢃ15 mL). The
combined organic extract was washed with saturated NaCl solution
(6 mL), dried (MgSO4), filtered, concentrated under reduced pres-
sure, and purified on silica gel to yield difluoromethyl diols 7.
2
3
(470 MHz, CDCl3)
d
ꢀ124.0 (ddd, 1F, JFF¼251.0 Hz, JFH¼19.5,
2 3
6.0 Hz, syn), ꢀ122.8 (dd, 1F, JFF¼251.0 Hz, JFH¼19.5 Hz, syn),
ꢀ122.3 (dd, 2F, 3JFH¼12.4, 11.5 Hz, anti); 31P NMR (162 MHz, CDCl3)
d
ꢀ1.49 (s, P0, syn), ꢀ1.41 (s, P, syn), ꢀ0.02 (s, P0, anti), 0.20 (s, P, anti);
FTIR (film, nmax cmꢀ1) 3320 (s), 2840 (m), 1614 (s), 1587 (m), 1516
(s), 1492 (m), 1253 (s), 1178 (m), 1164 (m), 1031 (s), 808 (m); GC–MS
(EI) m/z 77 (10%), 111 (10), 119 (10), 127 (20), 135 (40), 136 (40), 139
(20), 155 (25), 170 (25), 174 (100), 175 (10), 176 (40); HRMS (ESIþ)
calculated for C20H24ClF2O6PNa: 487.0865, found: 487.0873.
4.5.1. anti-2,2-Difluoro-1,3-diphenylpropane-1,3-diol (anti-7a)12
White solid (102 mg, 80%). Chromatography 20–60% EtOAc/
hexanes; Rf (40% EtOAc/hexanes) 0.57; mp 129–131 ꢂC. 1H NMR
4.4.6. 4-(4-Chlorophenyl)-3,3-difluoro-4-hydroxy-2-methylbutan-
2-yl diethyl phosphate (6gb); 1-(4-chlorophenyl)-2,2-difluoro-3-
hydroxy-3-methylbutyl diethyl phosphate (60gb)
(400 MHz, CD3OD)
d
4.88 (br s, 2H, 2ꢃOH), 5.16 (t, 2H, 3JHF¼12.5 Hz,
2ꢃCH), 7.27–7.35 (m, 6H, Ph), 7.43–7.46 (m, 4H, Ph); 13C NMR
2
Ratio (10:1); colorless oil (96 mg, 42%). Chromatography 25–60%
(100.6 MHz, CD3OD)
d
72.9 (t, JCF¼28.1 Hz, CH), 121.9 (t,
EtOAc/hexanes; Rf (30% EtOAc/hexanes) 0.40. 1H NMR (400 MHz,
1JCF¼250.7 Hz, CF2), 128.9, 129.1, 129.4, 139.2; 19F NMR (470 MHz,
3
4
3
CDCl3)
d
1.08 (dt, 3H0, JHH¼7.1 Hz, JHP¼1.1 Hz, CH3CH2), 1.30 (dt,
CD3OD)
d
ꢀ121.5 (t, JFH¼12.5 Hz); FTIR (KBr, nmax cmꢀ1) 3460 (s),
3
4
3
3H0, JHH¼7.1 Hz, JHP¼1.2 Hz, CH3CH2), 1.35 (dt, 3H, JHH¼7.1 Hz,
3318 (s), 1495 (m), 1456 (m), 1160 (m), 1153 (m), 1042 (s), 1025 (m),
745 (m), 728 (m), 695 (m); GC–MS (EI) m/z 51 (10%), 77 (30), 79
(30), 105 (15), 107 (30), 140 (100), 141 (15); HRMS (ESIꢀ) calculated
for C15H13F2O2: 263.0884, found: 263.0872.
4JHP¼1.1 Hz, CH3CH2), 1.36 (dt, 3H, JHH¼7.1 Hz, JHP¼1.1 Hz,
CH3CH2), 1.42 (s, 3H0, CH3), 1.60 (d, 3H, J¼1.2 Hz, CH3), 1.77 (s, 3H,
CH3), 1.87 (s, 3H0, CH3), 3.19 (br s, 1H0, OH), 3.76–3.86 (m, 2H0, CH2),
4.04–4.19 (m, 4H, 2H0, CH2), 4.40 (d, 1H, 3JHH¼5.1 Hz, OH), 5.11–5.18
3
4
(m, 1H, CH), 5.63–5.72 (m,1H0, CH), 7.31–7.44 (m, 4H, 4H0, CArH); 13
C
4.5.2. syn-2,2-Difluoro-1,3-diphenylpropane-1,3-diol (syn-7a)
White solid (105 mg, 80%). Chromatography 20–60% EtOAc/
hexanes; Rf (40% EtOAc/hexanes) 0.41; mp 143–145 ꢂC. 1H NMR
3
NMR (100.6 MHz, CDCl3)
d
15.7 (d, JCP¼6.9 Hz, CH3CH2), 16.0 (d,
3JCP¼7.1 Hz, CH3CH2), 22.7, 23.4, 24.4, 64.1 (d, JCP¼6.3 Hz, CH2),
2
2
2
64.2 (d, JCP¼5.9 Hz, CH2), 64.3 (d, JCP¼5.9 Hz, CH2), 64.6 (d,
(400 MHz, CD3OD)
d
4.82 (dd, 2H, 3JHF¼14.1,11.4 Hz, 2ꢃCH), 4.87 (br
2JCP¼5.9 Hz, CH2), 71.8 (dd, JCF¼33.5, 23.8 Hz, CH), 84.0–84.7 (m),
s, 2H, 2ꢃOH), 7.30–7.37 (m, 6H, Ph), 7.44–7.46 (m, 4H, Ph); 13C NMR
2
1
3
2
119.3 (ddd, JCF¼260.3, 269.9 Hz, JCP¼9.1 Hz, CF2), 128.1, 128.5,
129.5, 130,0, 132.7, 134.2, 135.3, 135.5 (d, 3JCF¼1 Hz, CCH); 19F NMR
(100.6 MHz, CD3OD)
d
74.1 (dd, JCF¼26.6, 24.2 Hz, CH), 122.2 (dd,
1JCF¼255.2, 247.9 Hz, CF2), 129.0, 129.3, 129.3, 139.2; 19F NMR
2
3
2
3
(470 MHz, CDCl3)
d
2
ꢀ126.8 (dd, 1F, JFF¼263.9 Hz, JFH¼21.1 Hz),
(470 MHz, CD3OD)
d
ꢀ124.8 (dt, 1F, JFF¼250.9 Hz, JFH¼14.1 Hz),
3
3
2
ꢀ123.8 (dd, 1F0, JFF¼263.9 Hz, JFH¼16.9 Hz), ꢀ114.5 (d, 1F0,
ꢀ122.8 (dt, 1F, JFF¼250.9 Hz, JFH¼11.4 Hz); FTIR (KBr, nmax cmꢀ1
)
2JFF¼263.5 Hz), ꢀ113.0 (d, 1F, JFF¼263.9 Hz); 31P NMR (162 MHz,
3397 (s), 1496 (m), 1457 (m), 1199 (m), 1144 (m), 1060 (s), 1034 (m),
1023 (m), 759 (m), 730 (m), 704 (m); GC–MS (EI) m/z 77 (25%), 79
(30), 107 (30), 140 (100), 141 (15); HRMS (ESIꢀ) calculated for
C15H13F2O2: 263.0884, found: 263.0896.
2
CDCl3)
d
ꢀ5.17 (s, P), ꢀ1.20 (s, P0); FTIR (CHCl3, nmax cmꢀ1) 3595 (m),
3337 (m), 1600 (w), 1494 (m), 1152 (m), 1031 (s); GC–MS (EI) m/z 77
(25%), 99 (50), 126 (33), 141 (25), 155 (100), 174 (30) (major); 59
(25%), 77 (20), 92 (20), 109 (22), 141 (30), 155 (28), 174 (100), 176
(35), 277 (20) (minor); HRMS (ESIþ) calculated for C15H23F2O5PCl:
387.0940, found: 387.0937.
4.5.3. anti-1,3-Bis(4-chlorophenyl)-2,2-difluoropropane-1,3-diol
(anti-7b)32
White solid (69 mg, 79%). Chromatography 20–40% EtOAc/hex-
4.4.7. 1-(2-(4-Chlorophenyl)-1,1-difluoro-2-hydroxyethyl)-
cyclohexyl diethyl phosphate (6jb); 1-(4-chlorophenyl)2,2-difluoro-
2-(1-hydroxycyclohexyl)ethyl diethyl phosphate (60jb)
anes; Rf (33% EtOAc/hexanes) 0.26; mp 149–150 ꢂC. 1H NMR
(400 MHz, CD3OD)
d
4.88 (br s, 2H, 2ꢃOH), 5.19 (t, 2H, 3JHF¼12.4 Hz,
2ꢃCH), 7.32–7.34 (m, 4H, CArH), 7.41–7.43 (m, 4H, CArH); 13C NMR
2
Ratio (2.45:1); colorless oil (103 mg, 58%). Chromatography 20–
(100.6 MHz, CD3OD)
d
72.0 (t, JCF¼28.4 Hz, CH), 121.8 (dd,
40% EtOAc/hexanes; Rf (30% EtOAc/hexanes) 0.25. 1H NMR
1JCF¼250.8, 250.5 Hz, CF2), 129.0, 130.9, 135.0, 138.1; 19F NMR