Synthesis of Trifluoromethylated Compounds
J . Org. Chem., Vol. 64, No. 24, 1999 8853
an argon atmosphere. The mixture was stirred at room
temperature until TLC (1:6 Et2O-PE) indicated total con-
sumption of the starting material (ca. 1 h 30 min). A solution
of MeONa (1 M in dry MeOH, 1.5 mL) was added, and the
suspension was stirred for 15 min. The mixture was then
diluted with Et2O and washed with a saturated solution of
NH4Cl and H2O. The organic layer was dried (Na2SO4) and
concentrated, and the residue was purified by flash chroma-
tography. Representative spectral and analytical data for
compounds 16a and (S,S)-18d are as follows.
Syn th esis of r-Ben zyloxy-r-tr iflu or om eth yl Nitr iles
21. Gen er a l P r oced u r e. To a cooled (0 °C) solution of the
benzyloxy hydrazone 16,17 (1 mmol) in MeOH (3 mL) was
added dropwise a cooled (0 °C) solution of magnesium mono-
peroxyphthalate hexahydrate (2.5 mmol) in MeOH (6 mL). The
mixture was stirred at 0 °C until TLC (Et2O-PE) indicated
total consumption of the starting hydrazone. CH2Cl2 and H2O
were added, and the organic layer was washed with brine and
H2O, dried (Na2SO4), and concentrated. The resulting residue
was purified by flash chromatography. Representative spectral
and analytical data for compound 21d are as follows.
2-Ben zyloxy-3,3,3-tr iflu or o-2-ph en ylpr opion itr ile (21d).
From 16d ; flash chromatography (1:20 Et2O-PE) gave 265 mg
(91%) of 21d as an oil: 1H NMR (CDCl3, 500 MHz) δ 4.54 (d,
1H, J ) 10.5 Hz), 4.81 (d, 1H, J ) 10.5 Hz), 7.36-7.44 (m,
5H), 7.59-7.63 (m, 3H), 7.74-7.75 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 69.8, 80.7 (q, J ) 32.5 Hz), 113.3, 121.2 (q, J )
284.2 Hz), 127.6, 127.8, 128.5, 128.6, 128.8, 129.1, 131.2, 135.0.
IR (film, cm-1) 1972, 1495; MS (rel intensity) m/z 291 M+ (4),
185 (100). Anal. Calc for C16H12F3NO: C, 65.98; H; 4.15; N,
4.81. Found: C, 66.08; H, 4.42; N, 4.96.
Syn th esis of r-Ben zyloxy-r-tr iflu or om eth yla ld eh yd es
22. Dry ozone was bubbled through a cooled (-78 °C) solution
of the R-benzyloxy-R-trifluoromethylhydrazone 16 or (S,S)-18
(1 mmol) in CH2Cl2 (3 mL) until the appearance of a perma-
nent blue-green color (ca. 5-10 min). After addition of Me2S
(0.37 mL, 5 mmol), the mixture was allowed to warm to room
temperature and concentrated, and the residue was purified
by flash chromatography. Representative spectral and analyti-
cal data for compounds rac-22b and (S)-22a are as follows.
2-Ben zyl-2-ben zyloxy-3,3,3-tr iflu or opr opan al (r a c-22b).
From 16b; flash chromatography (1:20 Et2O-PE) gave 253 mg
(82%) of rac-22b as an oil: 1H NMR (CDCl3, 300 MHz) δ 3.29-
3.40 (m, 2H), 4.76-4,84 (m, 2H), 7.22-7.38 (m, 10H), 9.58-
9.61 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 36.5, 68.9, 84.1 (q,
J ) 24.6 Hz), 123.8 (q, J ) 288.8 Hz), 127.3, 127.4, 127.9,
128.3, 130.6, 131.9, 136.8, 196.6; IR (film, cm-1) 1696, 1458;
MS (rel intensity) m/z 212 M+ (5), 91 (100); m/z calcd for
1-[2′-Ben zyloxy-2′-(tr iflu or om eth yl)p r op ylen ea m in o]-
p yr r olid in e (16a ). From rac-5a ; flash chromatography (1:30
Et2O-PE) gave 243 mg (81%) of 16a as an oil: 1H NMR
(CDCl3, 300 MHz) δ 1.57-1.59 (m, 3H), 1.88-1.92 (m, 4H),
3.15-3.23 (m, 4H), 4.53 (m, 2H), 6.26 (s, 1H), 7.25-7.33 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 15.1, 23.4, 50.4, 64.9, 79.2
(q, J ) 27.7 Hz), 127.1 (q, J ) 284.1 Hz), 127.2, 128.2, 138.6;
IR (film, cm-1) 1580; MS m/z (rel intensity) 300 M+ (29), 194
(56), 174 (14), 91 (100), 70 (41). Anal. Calcd for C15H19F3N2O:
C, 59.99; H, 6.38; N, 9.33. Found: C, 59.52; H, 6.32; N, 9.29.
(2S,2′S)-1-[2′-Ben zyloxy-2′-p h en yl-3′,3′,3′-(t r iflu or o)-
p r op ylen ea m in o]-2-(1′′-m eth oxy-1′′,1′′-d ip h en yl)p yr r oli-
d in e [(S,S)-18d ]. From (S,S)-14d ; flash chromatography (1:
20 Et2O-PE) gave 458 mg (82%) of (S,S)-18d as an oil: [R]24
D
1
-106.7° (c 1.15, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.09-
0.19 (m, 1H), 1.32-1.42 (m, 1H), 1.86-1.95. (m, 1H), 1.98-
2.07 (m, 1H), 2.37-2.48 (m, 1H), 2.67-2.81 (m, 1H), 2.88 (s,
3H), 4.67-4.76 (m, 2H), 4.81 (dd, 1H, J ) 1.2, 9.2 Hz), 6.39 (s,
1H), 7.18-7.69 (m, 20H); 13C NMR (CDCl3, 75 MHz) δ 21.5,
26.1, 49.1, 51.2, 65.8, 66.4, 82.4 (q, J ) 26.5 Hz), 85.5, 124.4
(q, J ) 262.0 Hz), 124.8, 126.6, 126.8, 127.0, 127.1, 127.3,
127.5, 127.8, 128.2, 128.4, 129.9, 129.5, 129.6, 135.8, 139.4,
141.0, 141.9; IR (film, cm-1) 1458; MS m/z (rel intensity) 361
(100). Anal. Calcd for C34H33F3N2O2: C, 73.10; H, 5.95; N, 5.01.
Found: C, 73.11; H, 6.00; N, 5.01.
Syn th esis of r-Meth oxy-r-tr iflu or om eth ylh yd r a zon es
19 a n d (S,S)-20. Gen er a l P r oced u r e. To a cooled (0 °C)
solution of the R-hydroxy-R-trifluoromethylhydrazone 5 or
(S,S)-14 (1 mmol) in dry THF (5 mL) was added NaH (60% in
parafine, 120 mg, 3 mmol) and methyl iodide (0.19 mL, 3
mmol) dropwise under an argon atmosphere. The mixture was
stirred at room temperature until TLC (1:6 Et2O-PE) indi-
cated total consumption of the starting material. A solution
of MeONa (1 M in dry MeOH, 1.5 mL) was added, and the
suspension was stirred for 15 min. The mixture was then
diluted with Et2O and washed with saturated NH4Cl solution
and H2O. The organic layer was dried (Na2SO4) and concen-
trated, and the residue was purified by flash chromatography.
Representative spectral and analytical data for compounds 19d
and (S,S)-20c are as follows.
C
17H15F3O2 308.1024, found 308.1044.
(2S)-2-Ben zyloxy-3,3,3-tr iflu or o-2-m eth ylpr opan al ((S)-
22a ). From (S,S)-18a ; flash chromatography (1:20 Et2O-PE)
gave 146 mg (63%) of (S)-22a as an oil: [R]25 -38.5° (c 1.2,
D
CHCl3);1H RMN (CDCl3, 300 MHz) δ 1.58 (s, 3H), 4.64 (d, 1H,
J ) 11.1 Hz), 4.73 (d, 1H, J ) 11.0 Hz), 7.36-7.40 (m, 5H),
9.65-9.66 (m, 1H); 13C RMN (CDCl3, 75 MHz) δ 13.3, 67.6,
81.7 (q, J ) 27.2 Hz), 123.7 (q, J ) 287.4 Hz), 127.5, 128.1,
128.5, 136.6, 195.4; IR (film, cm-1) 1748, 1456; MS (rel
intensity) m/z 232 M+ (2), 91 (100). Anal. Calcd for
C
11H11F3O2: C, 56.90; H, 4.77. Found: C, 56.61; H, 5.05.
1-Nitr oso-2-(1′-m eth oxy-1′,1′-d ip h en yl)pyr r olid in e (23).
1-[2′-Met h oxy-2′-p h en yl-3′,3′,3′-(t r iflu or o)p r op ylen e-
a m in o]p yr r olid in e (19d ). From 5d ; flash chromatography
(1:30 Et2O-PE) gave 229 mg (80%) of 19d as an oil: 1H NMR
(CDCl3, 300 MHz) δ 1.87-1.99 (m, 4H), 3.24-3.34 (m, 4H),
3.36 (s, 3H), 6.47 (s, 1H), 7.34-7.61 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 23.4, 50.5, 52.3, 82.1 (q, J ) 26.8 Hz), 124.4 (q, J
After complete elution of the products (S)-22 obtained by
ozonolysis, the column was further eluted (1:3 Et2O-PE) to
obtain compound 23 (65-85%) as an oil: [R]27D -190.5° (c 1.5,
CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 0.27-0.44 (m, 1H),
1.34-1.57 (m, 1H), 2.10-2.21 (m, 1H), 2.26-2.41 (m, 1H),
2.77-2.86 (m, 1H), 3.07 (s, 3H), 3.42-3.53 (m, 1H), 5.80 (d,
1H, J 8.9 Hz), 7.21-7.39 (m, 10H); 13C NMR (CDCl3, 75 MHz)
δ 19.4, 26.5, 46.6, 51.2, 63.0, 84.8, 126.3, 127.5, 127.8, 127.9,
129.1, 139.5, 140.6; IR (film, cm-1) 1664; MS (CI) m/z (rel
intensity) 297 M+ + 1 (60), 197 (100); m/z calcd for C18H21N2O2
297.1603, found 297.1590.
) 285.0 Hz), 124.6, 127.7, 128.4, 129.1, 134.3; IR (film, cm-1
)
1585; MS m/z 286 M+ (42), 217 (100). Anal. Calcd for
14H17F3N2O: C, 58.73; H, 5.99; N, 9.79. Found: C, 58.30; H,
C
6.10; N, 9.67.
(2S,2′S)-1-[2′-Met h oxy-2′-(t r iflu or om et h yl)n on ylen e-
a m in o]-2-(1′′-m eth oxy-1′′,1′′-d ip h en yl)p yr r olid in e [(S,S)-
20c]. From (S,S)-14c; flash chromatography (1:30 Et2O-PE)
Syn th esis of r-Meth oxy-r-tr iflu or om eth ylca r boxylic
Acid s 24. Gen er a l P r oced u r e. Dry ozone was bubbled
through a cooled (-78 °C) solution of the R-methoxy-R-
gave 419 mg (83%) of (S,S)-20c as an oil: [R]22 -118.1° (c 1,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 0.21-0.29 (m, 1H), 0.91-
0.94 (m, 3H), 1.27-1.41 (m, 10H), 1.44-1.49 (m, 1H), 1.65-
1.71 (m, 1H), 1.79-1.98 (m, 1H), 1.98-2.11 (m, 2H), 2.66-
2.71 (m, 1H), 2.78-2.82 (m, 1H), 3.01 (s, 3H), 3.30 (s, 3H), 4.86
trifluoromethylhydrazone 19 or (S,S)-20 (1 mmol) in CH2Cl2
(15 mL) until appearance of a permanent green color (ca. 5-10
min). After addition of Me2S (0.075 mL, 1 mmol), the mixture
was allowed to reach room temperature. To the resulting
(dd, 1H, J ) 1.9, 9.0 Hz), 6.09 (s, 1H), 7.26-7.44 (m, 10H); 13
C
solution was added BuOH (12 mL) and 2-methyl-2-butene (10
t
NMR (CDCl3, 75 MHz) δ 14.0, 21.3, 22.2, 22.6, 25.8, 29.0, 30.1,
31.8, 48.9, 51.1, 51.3, 66.7, 72.8 (q, J ) 25.9 Hz), 85.6, 124.4,
125.5 (q, J ) 285.7 Hz), 127.0, 127.1, 127.3, 129.4, 129.8, 140.1,
141.3; IR (film, cm-1) 1593; MS m/z (rel intensity) 307 (100).
Anal. Calcd for C29H39F3N2O2: C, 69.02; H, 7.79; N, 5.55.
Found: C, 68.91; H, 7.69; N, 5.61.
mL). After the mixture cooled to 0 °C, a solution of NaClO2
(10 mmol) and KH2PO4 (9 mmol) in H2O (12 mL) was added
dropwise, and the mixture was stirred for 16 h at room
temperature. The solvent was removed, and the residue was
treated with 1 M NaOH and extracted with Et2O. The aqueous
layer was acidified to pH 1 (HCl) and extracted with ethyl