S. Fustero et al. / Journal of Fluorine Chemistry 128 (2007) 647–653
651
aspirator pressure followed by further evacuation with a two-
stage mechanical pump. Yields refer to chromatographically
and spectroscopically pure compounds. All new compounds
were determined to be at least 95% pure by means of NMR. All
melting points were determined with an open capillary.
Chemical shifts were reported in d values relative to
tetramethylsilane in 1H NMR standard, fluorotrichloromethane
in 19F NMR, and the solvent peak in 13C NMR. 1H NMR was
measured at 300 MHz, 19F NMR at 282.4 MHz, and 13C NMR
at 75.5 MHz. The units for coupling constants are Hertz (Hz).
Peak splitting patterns in NMR are reported as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
organic layer was separated and the aqueous phases extracted
with dichloromethane (3 Â 20 mL). The combined organic
extracts were washed with brine (3 Â 20 mL), dried (Na2SO4),
and concentrated in vacuo to furnish a yellowish solid
containing a mixture of diastereoisomers. Medium pressure
liquid chromatography (MPLC) [n-hexane/EtOAc (5:1)] on
deactivated silica gel (Rf = 0.2) provided the diastereomerically
pure syn-6 as a white crystalline solid (91%). m.p. 97–99 8C;
[a]D25: À251.88 (c 1.00; CHCl3). 1H NMR (CDCl3, 300 MHz)
d (ppm): 2.90 (dd, J1 = 13.7, J2 = 7.0, 1H), 3.45 (dd, J1 = 13.8,
J2 = 5.9, 1H), 3.64 (s, 3H), 4.36–4.47 (m, 1H), 6.37 (d, J = 8.9,
2H), 6.61 (d, J = 9.0, 2H), 7.29–7.50 (m, 8H), 7.76–7.93 (m,
4H); 13C NMR (CDCl3, 75.5 MHz) d (ppm): 54.5 (t,
2JCF = 30.2), 54.6 (c), 55.5 (t), 113.6 (d), 114.0 (d), 120.4
4.1.1. 2,2-Difluoro-N-(4-methoxyphenyl)-2-
phenylacetimidoyl chloride (3)
1
(d), 120.9 (t, JCF = 249), 122.1 (d), 124.6 (d), 124.8 (t,
This compound was prepared in accordance with the
protocol previously described [8], starting from the corre-
sponding acid. Purification by means of distillation under
reduced pressure (b.p. 102 8C at 6 Â 10À2 Torr) gave a yellow
oil (97%). 1H NMR (CDCl3, 300 MHz) d (ppm): 3.67 (s, 3H),
6.79 (d, J = 9.1, 2H), 7.01 (d, J = 9.0, 2H), 7.35–7.58 (m, 5H);
13C NMR (CDCl3, 75.5 MHz) d (ppm): 55.8 (c), 114.5 (d),
116.0 (t, 1JCF = 249), 123.3 (d), 126.4 (t, 3JCF = 5.7), 128.9 (d),
3JCF = 6.3), 125.7 (d), 126.4 (d), 127.4 (d), 127.5 (s), 128.0 (d),
129.4 (d), 130.3 (d), 132.4 (s), 132.9 (t, 2JCF = 25.9), 138.2 (s),
138.3 (s), 151.8 (s); 19F NMR (CDCl3, 282.4 MHz) d (ppm):
1
2
À100.8 (dd, JFF = 250, JFH = 8.2, 1F), À107.2 (dd,
1JFF = 249, 2JFH = 12.4, 1F). HRMS Calc. for C26H23F2NO2S:
451.1418, Found: 451.1410.
4.1.4. (À)-(2S,SS)-2-(N-Benzyloxycarbonyl)aminopropyl-
3,3-difluoro-3-phenyl-1-(1-naphtyl)sulfoxide (syn-7)
2
131.2 (d), 133.9 (t, JCF = 26.4), 137.5 (s), 137.9 (t,
2JCF = 37.0), 158.9 (s); 19F NMR (CDCl3, 282.4 MHz) d
(ppm): À97.0 (s, 2F). HRMS Calc. for C15H12ClF2NO:
295.0575, Found: 295.0586.
This compound was prepared in accordance with a
previously described protocol [13] with 6 as a starting
compound. Purification by means of flash chromatography
(n-hexane-EtOAc (2:1)) on deactivated silica gel (Rf = 0.4)
gave a white solid (72%): m.p. 137–139 8C; [a]D25: À181.48
4.1.2. (+)-(SS)-3,3-Difluoro-3-phenyl-N-( p-
1
methoxyphenyl)-2-iminopropyl-1-(1-naphtyl)sulfoxide (5)
This compound was prepared in accordance with the
protocol previously described [12], starting from 3 and 4.
Purification by means of flash chromatography (n-hexane-
EtOAc (2:1)) on deactivated silica gel (Rf = 0.3) afforded a
white solid (89% yield): m.p. 124–126 8C; [a]D25: +29.48 (c
(c 1.00; CHCl3). H NMR (CDCl3, 300 MHz) d (ppm): 1.17
(s, 1H), 2.97 (dd, J1 = 14.1, J2 = 9.6, 1H), 3.45 (dd, J1 = 14.1,
J2 = 3.4, 1H), 4.78–4.91 (m, 3H), 7.08 (m, 13H), 7.78–8.01
(m, 4H); 13C NMR (CDCl3, 75.5 MHz) d (ppm): 50.8
(t, 2JCF = 30.6), 53.7 (t), 66.0 (t), 119.9 (t, 1JCF = 249), 120.3
(d), 122.7 (d), 124.5 (d), 124.5 (d), 124.6 (d), 124.7 (d), 125.7
(d), 126.5 (d), 126.9 (d), 127.1 (d), 127.4 (d), 128.1 (d), 129.4
(s), 130.5 (s), 132.4 (s), 134.9 (s), 137.1 (s), 154.1 (s); 19F
1
1.05; CHCl3). H NMR (CDCl3, 300 MHz) d (ppm): 3.73 (s,
3H), 3.92 (d, J = 12.8, 1H), 3.97 (d, J = 12.7, 1H), 6.78 (s, 4H),
7.41–7.99 (m, 12H); 13C NMR (CDCl3, 75.5 MHz) d (ppm):
1
NMR (CDCl3, 282.4 MHz) d (ppm): À104.3 (dd, JFF = 249,
1
1
2
54.8 (t), 55.8 (c), 114.6 (d), 114.6 (d), 118.8 (t, JCF = 246),
2JFH = 9.3, 1F), À107.4 (dd, JFF = 247, JFH = 14.4, 1F).
HRMS Calc. for C27H23NO3F2S: 479.1367, Found:
479.1350.
121.4 (d), 121.8 (d), 123.2 (d), 126.1 (d), 126.7 (t, 3JCF = 6.0),
127.3 (d), 128.0 (d), 128.2 (d), 128.9 (d), 129.0 (d), 129.4 (d),
130.9 (s), 132.2 (d), 133.8 (s), 134.5 (t, 2JCF = 25.9), 140.3 (s),
2
140.8 (s), 157.8 (s), 158.1 (t, JCF = 33.0); 19F NMR (CDCl3,
4.1.5. (À)-(2R)-2-(N-Benzyloxycarbonyl)amino-3,3-
282.4 MHz) d (ppm): À95.92 (d, J = 283, 1F), À97.07 (d,
J = 283, 1F). HRMS Calc. for C26H21F2NO2S: 450.1339,
Found: 450.1349.
difluoro-3-phenylpropanol (8)
This compound was prepared in accordance with a
previously described protocol [13], starting from 7. Purification
by flash chromatography (n-hexane-EtOAc (3:1)) on deacti-
vated silica gel (Rf = 0.25) gave a white solid (79%): m.p. 93–
95 8C; [a]D25: À20.18 (c 1.03; CHCl3). 1H NMR (CDCl3,
300 MHz) d (ppm): 2.49 (t, J = 6.4, 1H), 3.53–3.58 (m, 2H),
4.18–4.21 (m, 1H), 4.77 (d, J = 12.2, 1H), 4.86 (d, J = 12.2,
1H), 5.40 (d, J = 9.8, 1H),7.10–7.29 (m, 10H); 13C NMR
(CDCl3, 75.5 MHz) d (ppm): 58.0 (t, 2JCF = 27.6), 60.6 (t), 67.6
(t), 121.8 (t, 1JCF = 248), 125.8 (t, 3JCF = 6.3), 128.4 (d), 128.6
(d), 128.9 (d), 130.7 (d), 134.8 (t, 2JCF = 25.6), 136.4 (s), 156.9
(s); 19F NMR (CDCl3, 282.4 MHz) d (ppm): À103.9 (dd,
4.1.3. (À)-(2S,SS)-3,3-Difluoro-3-phenyl-N-( p-
methoxyphenyl)-2-aminopropyl-1-(1-naphtyl)sulfoxide
(syn-6)
To a stirred solution of b-imino sulfoxide 5 (6.7 mmol) in
50 mL of THF/MeOH (2:1) at À40 8C, an excess of NaBH4
(1.1 g, 26.8 mmol) was added portion-wise, after which the
temperature was allowed to rise to À20 8C. The mixture was
then stirred for 5 h until the starting material 5 totally
disappeared, as determined through TLC analysis. After
quenching the reaction with saturated aqueous NH4Cl, the
2
1
1JFF = 249, JFH = 14.4, 1F), À105.2 (dd, JFF = 251,