10.1002/ejoc.202000519
European Journal of Organic Chemistry
FULL PAPER
J = 267 Hz), 117.3 (q, J = 4.5 Hz), 116.9, 87.06, 51.6, 27.6. 19F NMR
(376 MHz, CDCl3) δ –59.5. LC/MS (CI): m/z = 238 [M–H2C=C(CH3)2+H]+,
294 [M+H]+. Anal. Calcd. for C12H14F3NO4: C 49.15; H 4.81; N 4.78.
Found: C 49.49; H 4.80; N 4.94.
[M+H]+. Anal. Calcd. for C12H14F3NO4: C 49.15; H 4.81; N 4.78. Found: C
49.09; H 4.96; N 4.68.
cis-1-(tert-Butoxycarbonyl)-5-(trifluoromethyl)pyrrolidine-2-carboxy-
lic acid (25). 10% Pd–C (5.0 g) was added to a solution of 24 (25.0 g,
89.5 mmol) and in MeOH (250 mL), which was then hydrogenated at
50 °C for 48 h under H2 (70 bar) in an autoclave. The resulting mixture
was filtered, and the filtrate was evaporated in vacuo. Yield 25.1 g (99%);
Methyl 5-(trifluoromethyl)-1H-pyrrole-3-carboxylate (21). A solution of
carboxylic acid 11 (10.0 g, 55.8 mmol) in MeOH (100 mL) was cooled to
0 °C, and SOCl2 (5.28 mL, 8.64 g, 72.6 mmol) was added dropwise at
0 °C. The resulting solution was warmed up to rt and stirred for 18 h.
Then, the solvent was evaporated in vacuo, and H2O (200 mL) was
added to the residue. Aqueous mixture was extracted with t-BuOMe
(3200 mL), combined organic layers were washed with H2O (2200
mL), saturated aq K2CO3 (100 mL), brine (100 mL), dried over Na2SO4,
filtered through a pad of silica gel (100 mL) and evaporated in vacuo.
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colorless solid; mp 135–137 °C. H NMR (400 MHz, CDCl3) δ 7.72 (br s,
1H), 4.50 – 4.25 (m, 2H), 2.49 – 2.20 (m, 2H), 2.19 – 2.01 (m, 2H), 1.45
(s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 173.5, 154.0, 126.2 (q, J = 279
Hz), 80.5, 60.8, 58.6 (q, J = 34.0 Hz), 29.1, 28.2, 25.5. 19F NMR (376
MHz, CDCl3) δ –75.5. LC/MS (CI): m/z = 282 [M–H]–. Anal. Calcd. for
C11H16F3NO4: C 46.65; H 5.69; N 4.95. Found: C 46.86; H 6.09; N 4.67.
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Yield 9.16 g (85%); colorless solid; mp 124–127 °C. H NMR (500 MHz,
cis-5-(Trifluoromethyl)pyrrolidine-2-carboxylic acid hydrochloride
(26).[91,99,100] N-Boc F3C-proline 25 (25.0 g, 88.3 mmol) was added to 4 M
HCl –1,4-dioxane (250 mL). The reaction mixture was stirred at rt for 18
h, then evaporated in vacuo at 60 °C. Yield 19.4 g (100%); yellowish
DMSO-d6) δ 12.77 (s, 1H), 7.66 (s, 1H), 6.90 (s, 1H), 3.71 (s, 3H). 13C
NMR (126 MHz, DMSO-d6) δ 164.0, 127.4, 121.2 (q, J = 266 Hz), 120.7
(q, J = 39.6 Hz), 115.9, 110.9 (q, J = 3.2 Hz), 51.3. 19F NMR (470 MHz,
DMSO-d6) δ –58.6. LC/MS (CI): m/z = 192 [M–H]–. Anal. Calcd. for
C7H6F3NO2: C 43.54; H 3.13; N 7.25. Found: C 43.75; H 2.81; N 6.94.
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crystals; mp 131–132 °C. H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 3H),
4.39 – 4.28 (m, 1H), 4.26 (t, J = 7.3 Hz, 1H), 2.29 – 2.12 (m, 2H), 2.12 –
2.01 (m, 1H), 2.00 – 1.90 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ
171.2, 125.0 (q, J = 280 Hz), 60.3, 58.5 (q, J = 31.9 Hz), 27.6, 24.7. 19F
NMR (376 MHz, DMSO-d6) δ –72.1. LC/MS (CI): m/z = 182 [M–H–HCl]–.
Anal. Calcd. for C6H9ClF3NO2: C 32.82; H 4.13; N 6.38; Cl 16.14. Found:
C 32.92; H 3.79; N 6.62; Cl 15.92.
Methyl 1H-pyrrole-3-carboxylate (22).[97,98] A solution of 1H-pyrrole-3-
carboxylic acid (75.0 g, 0.675 mmol) in MeOH (750 mL) was cooled to
0 °C, and SOCl2 (58.9 mL, 96.5 g, 811 mmol) was added dropwise at
0 °C. The resulting solution was warmed up to rt and stirred for 18 h.
Then, the solvent was evaporated in vacuo, and H2O (1000 mL) was
added to the residue. Aqueous mixture was extracted with t-BuOMe
(3500 mL), combined organic layers were washed with H2O (2500
mL), saturated aq K2CO3 (250 mL), brine (250 mL), dried over Na2SO4,
filtered through a pad of silica gel (250 mL) and evaporated in vacuo.
Yield 69.2 g (82%); colorless solid; 87–90 °С. 1H NMR (400 MHz,
DMSO-d6) δ 11.41 (br s, 1H), 7.46 – 7.31 (m, 1H), 6.80 (dd, J = 2.4, 2.1
Hz, 1H), 6.42 (dd, J = 2.4, 1.3 Hz, 1H), 3.68 (s, 3H). LC/MS (CI): m/z =
94 [M–OMe]+, 126 [M+H]+. Anal. Calcd. for C6H7NO2: C 57.59; H 5.64; N
11.19. Found: C 57.99; H 5.44; N 11.21.
cis-(5-(Trifluoromethyl)pyrrolidin-2-yl)methanol hydrochloride (27).
A solution of N-Boc F3C-proline 25 (18.4 g, 65.1 mmol) in THF (250 mL)
was cooled to 0 °С under argon atmosphere. Then, 10 M BH3SMe2 in
THF (13.2 mL, 0.132 mol) was added dropwise, and the reaction mixture
was warmed to rt and stirred for 18 h. Next, the mixture was cooled to
0 °С and MeOH (26.3 mL, 20.9 g, 0.651 mmol) was slowly added at
10 °С. Most of solvents was evaporated in vacuo and the residue was
diluted with in H2O (300 mL). Aqueous solution was the extracted with
EtOAc (3100 mL), combined organic phases were washed with H2O
(2100 mL) and brine (2100 mL), dried over Na2SO4, filtered through a
pad of silica gel (100 mL) and evaporated in vacuo. Then, the residue
was added to 4 M HCl –1,4-dioxane (250 mL) and the reaction mixture
was stirred at rt for 18 h. The solvent was evaporated in vacuo, and
crystals thus obtained were dried over P2O5 in vacuo. Yield 12.7 g (95%);
Methyl 2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (23). H2SO4
(96%, 30.2 mL, 55.5 g, 0.543 mol) and FeSO47H2O (45.3 g, 0.163 mol)
were added to DMSO (750 mL) at rt. Then, CF3I (117 g, 0.598 mol) was
blown into the reaction mixture, and methyl 1H-pyrrole-3-carboxylate (22,
67.9 g, 0.543 mol) was added at rt. Next, 9 M aq H2O2 (108 mL, 1.36
mol) was slowly added dropwise at 45 °С. The resulting mixture was
stirred at 45 °С for 30 min, then cooled to rt and poured into H2O – ice
(1500 g; 1:1, v/m). Aqueous mixture was extracted with t-BuOMe (3500
mL), combined organic layers were washed with H2O (2500 mL),
saturated aq K2CO3 (2250 mL) and brine (250 mL), dried over Na2SO4,
filtered through a pad of silica gel (100 mL) and evaporated in vacuo. The
crude compound was purified by recrystallization from hexanes – t-
BuOMe (4:1, v/v). Yield 37.8 g (36%); colorless crystals; mp 123–124 °C.
1H NMR (400 MHz, CDCl3) δ 9.02 (br s, 1H), 6.80 (s, 1H), 6.74 (s, 1H),
3.84 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.4, 122.6 (q, J = 40.3 Hz),
120.3 (q, J = 268.0 Hz), 119.0, 116.2 (q, J = 2.1 Hz), 113.0, 51.7. 19F
NMR (376 MHz, CDCl3) δ –59.9. LC/MS (CI): m/z = 192 [M–H]–. Anal.
Calcd. for C7H6F3NO2: C 43.54; H 3.13; N 7.25. Found: C 43.31; H 3.42;
N 7.14.
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yellowish powder; mp 71–72 °C. H NMR (400 MHz, D2O) δ 4.37 (h, J =
7.4 Hz, 1H), 3.84 – 3.76 (m, 2H), 3.64 (dd, J = 12.9, 8.5 Hz, 1H), 2.35 –
2.24 (m, 1H), 2.13 (tdd, J = 12.9, 7.4, 5.0 Hz, 2H), 1.85 – 1.72 (m, 1H).
1H NMR (400 MHz, DMSO-d6) δ 10.01 (br s, 2H), 4.47 (h, J = 8.1 Hz,
1H), 3.94 – 3.25 (m, 4H), 2.31 – 2.19 (m, 1H), 2.12 – 1.96 (m, 2H), 1.85 –
1.71 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 124.3 (q, J = 279 Hz),
63.2, 59.9, 58.3 (q, J = 32.4 Hz), 25.8, 24.4. 19F NMR (376 MHz, DMSO-
d6) δ –71.1. LC/MS (CI): m/z = 170 [M–HCl+H]+. Anal. Calcd. for
C6H11ClF3NO: C 35.05; H 5.39; N 6.81; Cl 17.24. Found: C 34.93; H
5.65; N 6.85; Cl 16.93.
cis-1-(tert-Butyl)
3-methyl
5-(trifluoromethyl)pyrrolidine-1,3-
dicarboxylate (28). Pd-C (10%, 5.0 g) was added to a solution of pyrrole
20 (5.00. g, 17.0 mmol) in MeOH (100 mL), which was then
hydrogenated at 80°C for 48 h under H2 atmosphere (100 bar) in
autoclave. Then, the resulting mixture was filtered, and the filtrate was
evaporated in vacuo. The crude compound was purified by flash
chromatography using gradient hexanes – t-BuOMe as eluent. The
compound existed as a ca. 5:4 mixture of rotamers. Yield 3.84 g (76%);
colorless crystals; mp 79–81 °C. 1H NMR (400 MHz, CDCl3) δ 4.60 –
4.32 (m, 1H), 4.07 – 3.91 (m, 1H), 3.66 (s, 3H), 3.43 (t, J = 9.6 Hz, 1H),
2.99 (p, J = 8.5 Hz, 1H), 2.44 – 2.32 (m, 2H), 1.40 (s, 9H). 13C NMR (151
MHz, CDCl3) δ 171.9, 153.9 and 153.5, 125.5 (q, J = 282 Hz), 81.0, 57.1
(q, J = 22.6 Hz), 52.2, 48.7 and 48.3, 42.0 and 41.4, 29.0, 28.1. 19F NMR
1-tert-Butyl 3-methyl 2-(trifluoromethyl)-1H-pyrrole-1,3-dicarboxylate
(24). A mixture of NaH (60%, 6.96 g, 0.174 mol) in DMF (500 mL) was
cooled to –10 °С under argon atmosphere. Then, a solutiom of pyrrole 23
(28.0 g, 0.145 mol) in DMF (50 mL) was added dropwise. The resulting
mixture was stirred at rt for 2 h, then cooled to –10 °С and Boc2O (43.2
mL, 41.0 g, 0.188 mol) was added dropwise. The solution was stirred for
at –10 °С for 1 h, then warmed up to rt and stirred for another 18 h. The
resulting mixture was poured into ice – H2O (1000 g, 1:1, m/v), aqueous
mixture was extracted with t-BuOMe (3500 mL). Combined organic
extracts were washed with H2O (500 mL), brine (2250 mL), dried over
Na2SO4 and evaporated in vacuo. Yield 38.7 (91%); yellowsih oil. 1H
NMR (400 MHz, CDCl3) δ 7.25 (d, J = 3.3 Hz, 1H), 6.38 (d, J = 3.3 Hz,
1H), 3.76 (s, 3H), 1.51 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 163.6,
147.0, 124.9 (q, J = 1.6 Hz), 124.1 (q, J = 2.6 Hz), 120.5 (q, J = 40.5 Hz),
119.7 (q, J = 269 Hz), 111.0, 86.8, 52.2, 27.3. 19F NMR (376 MHz,
CDCl3) δ –56.1. LC/MS (CI): m/z = 238 [M–H2C=C(CH3)2+H]+, 294
(376 MHz, CDCl3)
δ –76.0. LC/MS (CI): m/z = 198 [M–CO2–
H2C=C(CH3)2+H]+, 244 [M–Ot-Bu]+, 242 [M–H2C=C(CH3)2+H]+. Anal.
Calcd. for C12H18F3NO4: C 48.48; H 6.10; N 4.71. Found: C 48.10; H
6.50; N 4.97.
cis-4-(Methoxycarbonyl)-2-(trifluoromethyl)pyrrolidin-1-ium chloride
(29). N-Boc pyrrolidine 28 (2.50 g, 8.41 mmol) was added to 4 M HCl –
1,4-dioxane (20 mL). The reaction mixture was stirred at rt for 18 h and
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