Organic Process Research & Development
Article
(m, 2H) ppm; 19F NMR (376 MHz, DMSO-d6) δ −72.88 (s,
3F), −72.55 (s, 3F) ppm; 13C NMR (101 MHz, DMSO-d6) δ
173.62−176.95 (m, 2C), 128.60 (q, J = 274.53 Hz, 1C),
127.47 (q, J = 274.25 Hz, 1C), 34.23 (s, 1C), 33.45 (q, J =
29.80 Hz, 1C), 32.63 (s, 1C), 32.02 (q, J = 30.60 Hz, 1C),
24.36−24.75 (m, 1C), 24.01 (br d, J = 3.58 Hz, 1C) ppm;
HRMS calcd for C6H7F3O2 167.0398, found 167.0368.
120.98 (q, J = 542.98 Hz, 1C), 120.31 (q, J = 149.28 Hz, 1C),
83.75 (q, J = 34.72 Hz, 1C), 67.44 (s, 1C), 33.40 (br s, 2C),
29.73 (s, 1C) ppm; GCMS calcd for C14H12F6O5S 406.0,
found 406.0.
Benzyl 3-(Trifluoromethyl)bicyclo[1.1.0]butane-1-car-
boxylate (16). A solution of compound 15 (60 g, 148 mmol)
in DMAc (1.2 L) at 0 °C was added with tBuOK (24.8 g, 222
mmol). The solution was stirred for 1 h at 0−10 °C. TLC
(petroleum ether:ethyl acetate = 5:1) showed that the starting
material (Rf = 0.7) was consumed, and one main spot (Rf =
0.8) was detected. Water (1.2 L) was added, and the mixture
was extracted with MTBE (400 mL × 3). The organic layer
was washed with brine (300 mL) and concentrated in vacuum.
The crude product was purified by silica gel chromatography
(eluting with petroleum ether/ethyl acetate = 100/1 to 4/1) to
afford 16 as an oil (11.7 g, 46 mmol, 31% yield). Spectroscopic
Benzyl 3-Oxocyclobutane-1-carboxylate (13). The
solution of 3-oxocyclobutane-1-carboxylic acid 12 (100 g,
876 mmol), TsOH (10 g, 58.1 mmol), and BnOH (100 g, 920
mmol) in toluene (1.0 L) was stirred at 120 °C for 16 h. The
solution was cooled to ambient temperature and was washed
with water (300 mL × 3) and brine (200 mL × 1). The
organic phase was separated and was dried over Na2SO4,
filtered, and concentrated in vacuum (30 mmHg, 45 °C). The
crude product was purified by a silica gel column (petroleum
ether/ethyl acetate = 100/1 to 10/1) to afford an oil (114 g,
1
data of 16: H NMR (400 MHz, CDCl3) δ 7.30−7.54 (m,
1
558 mmol, 63.7% yield). Spectroscopic data of 13: H NMR
5H), 5.11−5.29 (m, 2H), 2.77 (s, 2H), 1.43−1.52 (m, 2H)
(400 MHz, CDCl3) δ 7.32−7.44 (m, 5H), 5.20 (s, 2H), 3.38−
3.52 (m, 2H), 3.22−3.36 (m, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ 203.48 (s, 1C), 173.81 (s, 1C), 135.42 (s, 1C),
127.60−129.14 (m, 5C), 67.09 (s, 1C), 51.62 (s, 2C), 27.41
(s, 1C) ppm; GCMS calcd for C12H12O3 204.1, found 204.1;
HRMS calcd for C12H12O3 203.0768, found 203.0648.
ppm; 19F NMR (376 MHz, CDCl3) δ −62.39 (s, 3F) ppm; 13
C
NMR (101 MHz, CDCl3) δ 167.37 (s, 1C), 135.43 (s, 1C),
128.32−128.58 (m, 5C), 120.55−128.58 (m, 1C), 67.39 (s,
2C), 35.15 (s, 1C), 23.43 (q, J = 46.46 Hz, 1C), 17.17 (s, 1C)
ppm; GCMS calcd for C13H11F3O2 256.0, found 256.0.
Benzyl 3-(Trifluoromethyl)cyclobut-1-ene-1-carboxy-
late (19a). The solution of compound 15 (20.0 g, 46.8 mmol)
and TMEDA (10.9 g, 94.0 mmol) in DMF (120 mL) was
stirred at 80 °C for 16 h. TLC (petroleum ether:ethyl acetate =
5:1) showed that the SM (Rf = 0.5) was consumed, and one
main spot (Rf = 0.6) was detected. The solution was poured
into water (600 mL). The solution was extracted with MTBE
(500 mL × 3). The combined organic phase was washed with
brine (100 × 2 mL), dried over Na2SO4, filtered, and
concentrated in vacuum (30 mmHg, 45 °C). The crude
product was purified by a column (SiO2, petroleum ether/ethyl
acetate = 100/1 to 10/1) to afford 19a (9.1 g, 35.4 mmol,
Benzyl 3-Hydroxy-3-(trifluoromethyl)cyclobutane-1-
carboxylate (14). TMSCF3 (87 g, 614 mmol) was added
dropwise into the solution of compound 13 (114 g, 558 mmol)
and CsF (102 g, 670 mmol) in THF (1.14 L) at 0 °C during
30 min. The solution was then stirred at 25 °C for 16 h. TLC
(petroleum ether:ethyl acetate = 5:1) showed that the SM (Rf
= 0.56) was consumed, and one main spot (Rf = 0.2) was
detected. The solution was filtered and concentrated in
vacuum at 30 mmHg, 45 °C. The crude product was purified
by a silica gel column (eluent: petroleum ether/ethyl acetate =
100/1 to 10/1) to afford an oil 14 (96.0 g, 350 mmol, 62.7%
yield). Spectroscopic data of 14: 1H NMR (400 MHz, CDCl3)
δ 7.31−7.44 (m, 5H), 5.17 (s, 2H), 3.30 (br s, 1H), 2.92−3.07
(m, 1H), 2.74−2.84 (m, 2H), 2.41−2.55 (m, 2H) ppm; 19F
NMR (376 MHz, CDCl3) δ −84.90 (s, 3F) ppm; 13C NMR
(100 MHz, CDCl3) δ 174.67 (br d, J = 16.87 Hz, 1C), 135.43
(s, 1C), 128.03−128.93 (m, 5C), 125.31 (q, J = 279.63 Hz,
1C), 70.87 (br dd, J = 31.91, 13.57 Hz, 1C), 67.04 (d, J = 2.93
Hz, 1C), 34.15 (br s, 2C), 28.85 (d, J = 2.93 Hz, 1C) ppm;
GCMS calcd for C13H13F3O3 274.1, found 274.1; HRMS calcd
for C13H13F3O3 273.0817, found 273.0728.
Benzyl 3-(Trifluoromethyl)-3-((trifluoromethyl)-
sulfonyl)oxy)cyclobutane-1-carboxylate (15). A solution
of compound 14 (96.0 g, 350 mmol) and pyridine (55.4 g, 700
mmol) in CH2Cl2 (960 mL) at 0 °C was added dropwise with
Tf2O (119 g, 420 mmol). The solution was stirred at 25 °C for
2 h. TLC (petroleum ether:ethyl acetate = 5:1, SM Rf = 0.2)
showed that the SM was consumed, and one main spot was
detected. The solution was poured into ice water (200 mL)
and extracted with EtOAc (300 mL × 3). The combined
organic phase was washed with brine (200 mL × 1), dried over
Na2SO4, filtered, and concentrated. The crude product was
purified by a silica gel column (eluent: petroleum ether/ethyl
acetate = 100/1 to 10/1) to yield 15 as a light yellow oil (110
g, 271 mmol, 77.0% yield). Spectroscopic data of 15: 1H NMR
(400 MHz, CDCl3) δ 7.31−7.64 (m, 5H), 5.19 (s, 2H), 2.89−
3.27 (m, 5H) ppm; 19F NMR (376 MHz, CDCl3) δ −82.55 (s,
3F), −75.30 (s, 3F) ppm; 13C NMR (101 MHz, CDCl3) δ
171.83 (s, 1C), 135.09 (s, 1C), 128.11−129.74 (m, 5C),
1
75.0% yield) as a yellow oil. Spectroscopic data of 19a: H
NMR (400 MHz, CDCl3) δ 7.31−7.43 (m, 5H), 6.63 (d, J =
1.13 Hz, 1H), 5.22 (s, 2H), 3.41 (qdt, J = 8.53, 8.53, 8.53, 4.85,
1.66, 1.66 Hz, 1H), 2.91−2.99 (m, 1H), 2.79−2.87 (m, 1H)
ppm; 19F NMR (376 MHz, CDCl3) δ −71.78 (s, 3F) ppm; 13
C
NMR (101 MHz, CDCl3) δ 161.11 (s, 1C), 141.84 (s, 1C),
139.04 (q, J = 3.67 Hz, 1C), 135.40 (s, 1C), 128.31−128.79
(m, 5C), 125.51 (q, J = 274.88 Hz, 1C), 121.26−127.02 (m,
1C), 66.48 (s, 1C), 40.85 (q, J = 32.28 Hz, 1C), 29.80 (q, J =
3.67 Hz, 1C) ppm; GCMS calcd for C13H11F3O2 256.1, found
256.1; HRMS calcd for C13H11F3O2 255.0711, found
255.2368.
(cis)-3-(Trifluoromethyl)cyclobutane-1-carboxylic
Acid 1 (cis). A solution of compound 19a (8.45 g, 33.0 mmol)
in ethyl acetate (169 mL) was added with Pd-C (10%, 1.7 g)
under N2. The resulting suspension was degassed under
vacuum and purged with H2 three times. The mixture was
stirred under H2 (15 Psi) at 25 °C for 4 h. TLC showed
(petroleum ether:ethyl acetate = 5:1) that the SM (Rf = 0.6)
was consumed. The reaction slurry was filtered through a pad
Celite to obtain a filtrate. The organic phase was washed with
brine (20 mL × 2), dried over Na2SO4, filtered, and
concentrated in vacuum (30 mm Hg, 45 °C). The crude
product was purified by a column (SiO2, DCM/MeOH = 100/
1 to 30/1) to afford 1 (cis) (5.5 g, 32.7 mmol, 99.0% yield) as a
1
yellow oil. Spectroscopic data of 1 (cis): H NMR (400 MHz,
DMSO-d6) δ 12.35 (br s, 1H), 2.98−3.22 (m, 2H), 2.26−2.41
(m, 2H), 2.11−2.25 (m, 2H) ppm; 19F NMR (376 MHz,
E
Org. Process Res. Dev. XXXX, XXX, XXX−XXX