S. Kobayashi et al. / Tetrahedron 59 (2003) 1547–1552
1551
(679 mg, 5.5 mmol) was added a mixture of N-phenyl-
benzaldimine (977 mg, 5.5 mmol) and difluoroenol silyl
ether 29 (1.02 g, 5.0 mmol) in dry CH2Cl2 (2 mL) at 2788C
under an argon atmosphere. After stirring for additional
15 min at 08C, the reaction was quenched with water. The
mixture was extracted with ether, and the organic phase was
washed with brine, dried over MgSO4. Removal of the
solvent under reduced pressure followed by column
chromatography on silica gel (hexane/ethyl acetate, 10/1)
afforded 1.27 g (70%) of the b-amino ketone 31 (R¼H) as
colorless crystals: IR (KBr) colorless crystals; mp 968C; IR
MgSO4, filtered, and concentrated under reduced pressure.
Yields were calculated by 19F NMR integration of products
relative to the 1,3-bis(trifluoromethyl)benzene internal
standard.
3.3.1. 4-Methoxyphenyl 2,2-difluoro-3-hydroxy-3-
phenylpropanoate (20). Colorless crystals; mp 98–998C;
;
IR (KBr) 3452, 1784, 1508 cm21 1H NMR d 2.72 (d,
J¼4.2 Hz, 1H), 3.80 (s, 3H), 5.30 (ddd, J¼15, 8.3, 4.2 Hz,
1H), 6.86–6.99 (m, 4H), 7.40–7.55 (m, 5H); 19F NMR d
42.2 (dd, J¼260, 15 Hz, 1F), 47.6 (dd, J¼260, 8.3 Hz, 1F);
MS m/z (%) 308 (Mþ, 25), 204 (3), 124 (100), 109 (46), 77
(16). Anal. calcd for C16H14O4F2: C, 62.33; H, 4.58. Found:
C, 62.29; H, 4.77.
1
(KBr) 3408, 1698 cm21; H NMR (500 MHz, CDCl3) d
3.87 (s, 3H), 4.59 (d, J¼9.0 Hz, 1H), 5.28 (ddd, J¼17, 9.0,
8.5 Hz, 1H), 6.60 (d, J¼8.5 Hz, 2H), 6.70 (t, J¼7.5 Hz, 1H),
6.92 (d, J¼8.5 Hz, 2H), 7.10 (t, J¼7.5 Hz, 2H), 7.3–7.4 (m,
3H), 7.45 (d, J¼7.5 Hz, 2H), 7.98 (d, J¼8.5 Hz, 2H); 19F
NMR (282 MHz, CDCl3) d 50.7 (dd, J¼269, 17 Hz, 1F),
58.5 (dd, J¼269, 8.5 Hz 1F); MS m/z (%) 367 (Mþ, 3), 182
(100), 135 (8), 104 (15), 92 (6), 77 (31). Anal. calcd for
C22H19NO2F2: C, 71.92; H, 5.21; N, 3.81. Found: C, 71.94;
H, 4.93; N, 3.66. Upon treatment with trifluoroacetic
anhydride (56 mL, 0.4 mmol) and pyridine (31 mL,
0.4 mmol) in Et2O (1 mL), b-amino ketone 31 (146 mg,
0.4 mmol) was readily converted into the title compound 24
(R¼CF3CO). After evaporation of the solvent, the residue
was filtered through a short pad of silica gel to give 439 mg
(95%) of crude 24, suitable for use in the next step without
further purification.
3.3.2. 4-Methoxyphenyl 2,2-difluoro-2-(1-hydroxycyclo-
hexyl)ethanoate (21). Colorless crystals; mp 54–558C; IR
(KBr) 3496, 2944, 1778, 1506 cm21; 1H NMR d 1.65–1.95
(m, 10H), 2.27 (s, 1H), 3.81 (s, 3H), 6.89–7.12 (m, 4H); 19F
NMR d 42.1 (s, 2F); MS m/z (%) 300 (Mþ, 18), 202 (2), 124
(100), 109 (53), 81 (48). Anal. calcd for C15H18O4F2: C,
59.99; H, 6.04. Found: C, 59.81; H, 6.09.
3.3.3. 4-Methoxyphenyl 2-fluoro-3-hydroxy-3-phenyl-
propanoate (22). Colorless crystals, as a mixture of
diastereomers. A diastereomer ratio of 2:1 was determined
by comparing the intensities of the indicated 19F NMR
peaks ( p ¼major isomer; p p ¼minor isomer); mp 718C
(decomposition); IR (KBr) 3452, 1780, 1754, 1506 cm21
;
3.2.5. 2,2-Difluoro-1-(4-methoxyphenyl)-4-penten-1-one
(26). To a stirred suspension of anhydrous powder KF
(finely ground and activated by heating with a heat gun
under vacuum) (696 mg, 1.2 mmol) and CuI (274 mg,
1.44 mmol) in 1 mL of anhydrous DMF was added a
solution of the difluoroenol silyl ether 29 (310 mg,
1.2 mmol) in dry DMF (1 mL). The reaction mixture was
allowed to warm to 408C, followed by addition of 0.42 mL
(4.8 mmol) of allyl bromide. After stirring for 3 h, the
reaction was quenched with water. The mixture was
extracted with ether, and the organic phase was washed
with brine, dried over MgSO4. Removal of the solvent under
reduced pressure followed by column chromatography on
silica gel (hexane/ethyl acetate, 10/1) afforded 141 mg
1H NMR d 2.7–2.8 (m, 1H), p3.78 (s, 3H), p p 3.79 (s, 3H),
5.1–5.5 (m, 2H), 6.8–6.9 (m, 4H), 7.3–7.6 (m, 5H); 19F
NMR d p p 239.6 (dd, J¼49, 21 Hz, 1F), p236.1 (dd, J¼49,
17 Hz, 1F); MS m/z (%) 290 (Mþ, 10), 184 (2), 124 (100),
109 (41), 77 (17). Anal. calcd for C16H15O4F: C, 66.20; H,
5.21. Found: C, 66.12; H, 5.13.
3.3.4. Bis(4-methoxyphenyl) 2,2,3,3-tetrafluorosuccinate
(23). Colorless crystals; mp 61–628C; IR (KBr) 1790,
1
1600 cm21; H NMR d 3.81 (s, 6H), 6.87–6.95 (m, 4H),
7.07–7.15 (m, 4H); 19F NMR d 41.9 (s, 4F); MS m/z (%)
402 (Mþ, 51), 279 (2), 251 (11), 223 (35), 123 (100), 107
(25), 95 (32). Anal. calcd for C18H14O6F4: C, 53.74; H, 3.51.
Found: C, 53.64; H, 3.76.
1
(52%) of 26 as a colorless oil: IR 1692, 1610 cm21; H
NMR d 2.95 (dt, J¼7.0, 17.6 Hz, 2H), 3.89 (s, 3H), 5.25 (d,
J¼11.2 Hz, 1H), 5.26 (d, J¼14.4 Hz, 1H), 5.85 (ddt,
J¼14.4, 11.2 Hz, 7.0, 1H), 6.96 (d, J¼9.1 Hz, 2H), 8.10
(d, J¼9.1 Hz, 2H); 19F NMR d 62.8 (t, J¼17.6 Hz, 2F); MS
m/z (%) 226 (Mþ, 4), 135 (100), 107 (11), 92 (14), 77 (21).
Anal. calcd for C12H12O2F2: C, 63.71; H, 5.35. Found: C,
63.64; H, 5.20.
3.3.5. 4-Methoxyphenyl 2,2-difluoro-3-[N-phenyl-N-(tri-
fluoroacetyl)amino]-3-phenylpropanoate (25). The crude
product was purified by silica gel column chromatography
(hexane/Et2O¼10:1) to afford 25 as a colorless oil; IR
1
(NaCl) 1784, 1714 cm21; H NMR (500 MHz, CDCl3) d
3.78 (s, 3H), 6.19 (d, J¼8.0 Hz, 1H), 6.80 (dd, J¼13.8,
16.4 Hz, 1H), 6.86 (d, J¼9.0 Hz, 2H), 6.89 (d, J¼9.0 Hz,
2H), 7.01 (t, J¼8.0 Hz, 1H), 7.16 (d, J¼7.5 Hz, 2H), 7.28
(dd, J¼7.5, 8.0 Hz, 2H), 7.36 (t, J¼7.5 Hz, 1H), 7.38 (t,
J¼7.5 Hz, 1H), 7.44 (t, J¼7.5 Hz, 1H), 7.66 (d, J¼8.0 Hz,
1H); 19F NMR (282 MHz, CDCl3) d 53.5 (dd, J¼256,
13.8 Hz, 1F), 54.9 (dd, J¼256, 16.4 Hz, 1F), 94.3 (s, 3F);
MS m/z (%) 479 (Mþ, 3), 356 (100), 328 (29), 172 (48), 167
(36), 77 (71). Anal. calcd for C24H18NO4F5: C, 60.13; H,
3.78; N, 2.92. Found: C, 60.10; H, 3.99; N, 2.77.
3.3. Typical procedure for the synthesis of esters by the
Baeyer–Villiger oxidation
To a mixture of ketone (0.2 mmol) and m-CPBA
(0.25 mmol) in CH2Cl2/HFIP (1 mL/1 mL) was added
phosphate buffer (0.2 mL) at ambient temperature. After
stirring for additional 10 min, the reaction mixture was
concentrated under reduced pressure. The residue was
dissolved with Et2O/THF¼10:1. The solution was washed
with ice-cooled 2% aqueous Na2SO3, ice-cooled 1%
aqueous NaHCO3, and ice-cooled brine, dried over
3.3.6. 4-Methoxyphenyl 2,2-difluoro-4-pentenoate (27).
Colorless oil; bp 908C (1.0 mm Hg); IR (NaCl) 1788, 1602,
1508 cm21; 1H NMR d 2.98 (dt, J¼7.1, 15.6 Hz, 2H), 3.81