K. Ninomiya et al. / Journal of Fluorine Chemistry 127 (2006) 651–656
655
yield. This was used to the next reaction without further
purification. To a THF (1.0 mL) solution of the amide (40 mg,
0.069 mmol) was added a 1.0 M THF solution of tetrabuty-
lammonium fluoride (TBAF) (0.1 mL, 0.103 mmol) at RT and
the mixture was stirred at RT for 6 h. To the reaction mixture
was added a water and ethyl acetate and was extracted with
ethyl acetate (5 mL, four times). The combined organic layers
were dried over MgSO4 and purified by silica gel TLC (hexane/
ethyl acetate = 1:3) to give (R,R)-4 (23 mg, 0.067 mmol) in
98% yield.
THF and water (THF/H2O = 10 mL/40 mg) (10 mL), and the
mixture was stirred at RT for 24 h and concentrated under
vacuum. To the resulting residure was added dioxane (10 mL)
solution of benzyloxycarbonyl chloride (CbzCl, 420 mg,
2.46 mmol) and pyridine (0.3 mL, 3.69 mmol) at RT, and the
mixture was stirred at 55 8C for 12 h. After being cooled to RT,
ethyl acetate (15 mL) and brine (10 mL) were added and
extracted with ethyl acetate (15 mL, four times). The combined
organic layers were dried over MgSO4, concentrated, and silica
gel flash column chromatography (hexane/ethyl acetate = 50:1
to 4:1) gave the corresponding amide (533 mg 1.05 mmol) in
85% yield (two steps). To a THF (5 mL) solution of the amide
(300 mg, 0.589 mmol) was added a THF solution of TBAF
(0.89 ml, 0.89 mmol) at RTand the mixture was stirred for 20 h.
The reaction mixture was diluted with ethyl acetate. The
organic layers were concentrated and subsequent silica gel flash
column chromatography (hexane/ethyl acetate = 10:1 to 0:1)
gave (R,R)-8 (160 mg, 0.589 mmol) in quantitative yield.
26
(R,R)-6: ½aꢀD +3.8 (ca. 1.6, CHCl3); rf 0.30 (hexane/ethyl
acetate = 2:1); bp 200 8C/2.4 Torr (Kugelrohr); 1H NMR
(270 MHz, ppm, CDCl3, J = Hz) d 1.04 (9H, s), 1.61–1.72
(2H, m), 3.64–3.79 (4H, m), 7.35–7.47 (6H, m), 7.64–7.67 (4H,
m); 13C NMR (125.8 MHz, ppm, CDCl3, J = Hz) d 19.01, 26.71,
28.54 (t, JC–F = 10.1), 28.70 (t, JC–F = 10.1), 59.51 (d, JC–
F = 4.8), 60.17 (d, JC–F = 3.9), 114.64 (t, JC–F = 286.5), 127.89,
129.96, 133.29, 133.39, 135.65; 19F NMR (470.6 MHz, ppm,
CDCl3, J = Hz) d 23.06 (1F, dd, JF–F = 162.4, JH–F = 11.1), 23.63
(1F, dd, JF–F = 164.1, JH–F = 11.5); IR n (cmꢁ1) 3366, 2932,
2858, 1472, 1261, 1184, 1113, 1013, 702. Anal. calcd. for
C21H26F2O2Si: C, 66.99; H, 6.96. Found: C, 66.89; H, 6.98.
27
(R,R)-8: ½aꢀD ꢁ12.6 (ca. 1.4, CHCl3); rf 0.20 (hexane/ethyl
acetate = 2:1); bp 140 8C/3.2 Torr (Kugelrohr); 1H NMR
(270 MHz, ppm, CDCl3, J = Hz) d 2.10 (2H, m), 3.18–3.71
(4H, m), 5.03 (2H, s), 7.28 (5H, s); 13C NMR (125.8 MHz, ppm,
CDCl3, J = Hz) d 26.41 (t, JC–F = 9.6), 29.01 (t, JC–F = 9.6),
37.94, 58.54, 66.81, 114.32 (t, JC–F = 278.0), 127.51, 127.95,
128.12, 136.10, 156.64; 19F NMR (470.6 MHz, ppm, CDCl3,
J = Hz) d 23.46 (2F, s); IR n (cmꢁ1) 3325, 2923, 1699, 1456,
1182, 1130, 1042, 1005. Anal. calcd. for C13H15F2NO3: C,
57.56; H, 5.57; N, 5.16. Found: C, 57.09; H, 5.58; N, 5.17.
22
(R,R)-7: ½aꢀD ꢁ14.1 (ca. 1.5, CHCl3); rf 0.70 (hexane/ethyl
acetate = 7:1); bp 130 8C/1.6 Torr (Kugelrohr); 1H NMR
(270 MHz, ppm, CDCl3, J = Hz) d 1.05 (9H, s), 1.55–1.74
(2H, m), 3.30 (2H, d, JC–F = 6.0), 3.73–3.79 (2H, m), 7.25–7.47
(6H, m), 7.64–7.67 (4H, m); 13C NMR (125.8 MHz, ppm,
CDCl3, J = Hz) d 19.27, 25.22 (t, JC–F = 10.6), 28.86, 29.72 (t,
J
C–F = 10.1), 48.18 (d, JC–F = 4.8), 59.87 (d, JC–F = 5.0), 113.77
(dd, JC–F = 286.1, 288.9), 127.94, 130.02, 133.22, 133.31,
135.68; 19F NMR (470.6 MHz, ppm, CDCl3, J = Hz) d 22.82
(1F, dd, JF–F = 160.0, JH–F = 11.5), 24.74 (1F, dd, JF–F = 164.4,
4.4. (1R,3R)-3-(aminomethyl)-2,2-
difluorocyclopropylmethyl anthracene-9-carboxylate (10)
J
H–F = 14.4); IR n (cmꢁ1) 2932, 2858, 2098 (N3), 1458, 1429,
To a CH2Cl2 (5 mL) solution of (R,R)-8 (65 mg, 0.24 mmol)
was added EDC (75 mg, 0.39 mmol), 9-anthracenecarboxylic
acid (59 mg, 0.26 mmol), and DMAP (8 mg, 0.072 mmol) at
RT, then Et3N (0.05 mL, 0.39 mmol) was added to the mixture
at 0 8C. The mixture was stirred for 4 h at 60 8C in a dark place.
After being cooled to RT, the reaction mixture was diluted with
ethyl acetate (6 mL) and extracted with ethyl acetate six times
(10 mL of each). The combined organic layers were washed
with NaHCO3 and brine, and dried over MgSO4. Silica gel TLC
(hexane/ethyl acetate = 2:1) give (R,R)-9 (20 mg, 0.042 mmol)
in 18% yield, while starting (R,R)-8 (42 mg, 0.156 mmol) was
recovered in 65% yield. A methanol (1.0 mL) solution of (R,R)-
9 (18 mg, 0.038 mmol) was stirred at RT in the presence of Pd/
C (5.4 mg, 30 wt.%) under H2 (1 atom) for 5 days and filtrated
though a glass sintered glass filter with a Celite pad. The filtrate
was evaporated under reduced pressure to give (R,R)-10
(9.0 mg, 0.039 mmol). This compound was gradually decom-
posed to form unidentical products when it was stored as a
methanol or CHCl3 solution at RT. Therefore, it should keep
under argon atmosphere in a dark place. Due to the unstable
nature of 10, we gave up to subject it to the elemental analysis.
1261, 1186, 1113, 1007, 834, 702. Anal. calcd. for
C21H25F2N3OSi: C, 62.82; H, 6.28; N, 10.47. Found: C,
62.91; H, 6.31; N, 10.46.
27
(R,R)-4: ½aꢀD +8.0 (ca. 0.2, CHCl3); rf 0.35 (hexane/ethyl
acetate = 1:3); mp 186–193 8C (recrystallization from hexane–
ether); 1H NMR (270 MHz, ppm, CDCl3, J = Hz) d 1.89–2.07
(2H, m), 3.67–3.77 (4H, m), 7.48–7.55 (4H, m), 8.05–8.08 (4H,
m), 8.57 (1H, s); 13C NMR (125.8 MHz, ppm, CDCl3, J = Hz) d
26.57 (t, JC–F = 10.6), 30.23 (t, JC–F = 10.1), 37.37 (d, JC–
F = 5.8), 58.70 (d, JC–F = 4.8), 115.64 (t, JC–F = 286.0), 125.35,
125.98, 127.12, 128.60, 128.64, 129.00, 131.95, 132.20,
171.81; 19F NMR (470.6 MHz, ppm, CDCl3, J = Hz) d 24.70
(2F, dd, JF–F = 364.2, JH–F = 15.8); IR n (cmꢁ1) 3260, 2926,
2855, 1628, 1549, 1248, 1178, 1115, 1003, 733. Anal. calcd. for
C20H17F2NO2: C, 70.37; H, 5.02; N, 4.10. Found: C, 70.46; H,
5.03; N, 4.09.
27
(S,S)-4 (½aꢀD ꢁ7.2 (ca. 0.6, CHCl3)) was prepared in the
same method from (S,S)-1 in 16% overall yield.
4.3. (R,R)-[3-(tert-Butyldiphenylsilanyloxymethyl)-2,2-
difluorocyclopropylmethyl]carbamic acid benzyl ester (8)
27
(R,R)-9: ½aꢀD ꢁ29.5 (ca. 1.20, CHCl3); rf 0.60 (hexane/ethyl
1
acetate = 2:1); H NMR (270 MHz, ppm, CDCl3, J = Hz) d
(R,R)-7 (494 mg, 1.23 mmol) and triphenylphosphine
(354 mg, 1.35 mmol) was dissolved in a mixed solvent of
1.88–2.04 (2H, m), 3.12–3.23 (1H, m), 3.49–3.56 (1H, m),
4.48–4.63 (2H, m) 4.94 (2H, s), 7.20–7.27 (5H, m), 7.38–7.51