F
D. S. Belov et al.
Paper
Synthesis
2,2,2-Trifluoro-1-[5-(3-fluorophenyl)-1H-pyrrol-2-yl]ethanone
(2g)
13C NMR (100 MHz, DMSO-d6): δ = 55.6, 55.8, 109.7, 110.3, 111.9,
117.4 (q, J = 290.5 Hz), 119.6, 122.4, 123.7 (q, J = 3.7 Hz), 125.5, 144.3,
149.1, 149.8, 167.0 (q, J = 34.4 Hz).
Compound 2g was obtained following the general procedure for
arylpyrrole trifluoroacetylation from 1g (5.50 g, 34.2 mmol).
Pyrrole-2-carboxylic Acids 3 by a Haloform Reaction; General Pro-
cedure
Yield: 6.50 g (74%); white solid; mp 150–155 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.00 (dd, J = 4.3, 2.5 Hz, 1 H), 7.21
(td, J = 8.5, 2.1 Hz, 1 H), 7.27 (dd, J = 4.1, 2.0 Hz, 1 H), 7.48 (td, J = 7.9,
6.4 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 10.5 Hz, 1 H), 12.95 (s,
1 H).
13C NMR (100 MHz, DMSO-d6): δ = 111.4, 112.9 (d, J = 24.1 Hz), 115.7
(d, J = 20.9 Hz), 117.1 (q, J = 289.9 Hz), 122.5 (d, J = 2.41 Hz), 123.2 (q,
J = 3.2 Hz), 126.2, 130.9 (d, J = 8.8 Hz), 132.0 (d, J = 8.8 Hz), 142.0 (d, J =
2.4 Hz), 162.6 (d, J = 243.3 Hz), 168.0 (q, J = 34.5 Hz).
The appropriate trifluoroethanone 2 (1 equiv) was added to a solu-
tion of NaOH (3 equiv) in a H2O–EtOH mixture (1:1, 0.33 M). The re-
sulting reaction mixture was refluxed for 12 h and cooled to r.t. A
concentrated aqueous HCl solution (~12 M, 3 equiv) was added drop-
wise. The resulting precipitate was filtered off and washed with H2O.
If no precipitation occurred, the reaction mixture was extracted with
Et2O or EtOAc (3 × 100 mL). The combined organic layer was washed
with brine, dried over MgSO4, filtered, and evaporated. If necessary,
the acids could be purified by chromatography (hexanes–EtOAc, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C12H8F4NO: 258.0537; found:
258.0536.
5-(4-Chlorophenyl)-1H-pyrrole-2-carboxylic Acid (3a)3
2,2,2-Trifluoro-1-[5-(2-fluorophenyl)-1H-pyrrol-2-yl]ethanone
(2h)
Compound 3a was obtained following the general procedure for halo-
form reaction from 2a (9.79 g, 35.7 mmol).
Compound 2g was obtained following the general procedure for
arylpyrrole trifluoroacetylation from 1g (650 mg, 4.0 mmol).
Yield: 6.90 g (87%); gray solid; mp 171−172 °C.
IR (KBr): 3426, 1659, 1517, 1474, 1439, 1285, 1236, 1096, 786, 757
Yield: 701 mg (68%); gray solid; mp 115–120 °C.
cm–1
.
IR (KBr): 3336, 1661, 1652, 1476, 1252, 1228, 1220, 1198, 1139, 1113,
1H NMR (400 MHz, DMSO-d6): δ = 6.60 (d, J = 3.5 Hz, 1 H), 6.71 (d, J =
3.7 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 2 H), 7.86 (d, J = 8.6 Hz, 2 H), 11.87 (br
s, 1 H); COOH missing due to broadening.
13C NMR (100 MHz, DMSO-d6): δ = 107.8, 115.3, 126.5 (2 С), 126.9,
128.6 (2 С), 130.8, 131.1, 134.0, 162.8.
885, 801, 760 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 6.79 (s, 1 H), 7.27–7.38 (m, 3 H),
7.42–7.50 (m, 1 H), 7.98 (td, J = 7.9, 1.5 Hz, 1 H), 12.87 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 113.6 (d, J = 8.8 Hz), 116.4 (d, J =
21.7 Hz), 117.0 (q, J = 289.9 Hz), 118.0 (d, J = 12.0 Hz), 122.9 (q, J = 3.2
Hz), 124.9 (d, J = 3.2 Hz), 125.7, 129.3 (d, J = 2.4 Hz), 131.1 (d, J = 8.8
Hz), 137.4, 159.2 (d, J = 249.8 Hz), 168.0 (q, J = 35.3 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C11H9ClNO2: 222.0316; found:
222.0316.
HRMS (ESI): m/z [M + H]+ calcd for C12H9F3NO: 240.0631; found:
240.0631.
5-(4-Chloro-3-fluorophenyl)-1H-pyrrole-2-carboxylic Acid (3b)
Compound 3b was obtained following the general procedure for halo-
form reaction from 2b (5.15 g, 17.7 mmol).
2,2,2-Trifluoro-1-(5-phenyl-1H-pyrrol-2-yl)ethanone (2i)
Yield: 4.10 g (97%); gray-yellowish solid; mp 205–210 °C.
Compound 2i was obtained following the general procedure for
arylpyrrole trifluoroacetylation from 1i (1.57 g, 11.0 mmol).
IR (KBr): 3459, 3235, 1719, 1669, 1475, 1217, 1204, 757 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 6.75 (s, 1 H), 6.82 (s, 1 H), 7.55 (t,
J = 8.1 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 7.98 (d, J = 11.2 Hz, 1 H), 12.13
(s, 1 H), 12.44 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 109.0, 112.9 (d, J = 22.7 Hz), 116.3,
117.4 (d, J = 17.6 Hz), 122.1 (d, J = 2.9 Hz), 125.1, 130.7, 132.6 (d, J =
8.1 Hz), 134.1, 157.5 (d, J = 244.4 Hz), 161.7.
Yield: 1.10 g (42%); white solid; mp 155–160 °C.
IR (KBr): 3313, 1652, 1642, 1639, 1521, 1475, 1252, 1227, 1199, 1190,
1164, 1143, 1133, 1080, 1061, 882, 797, 763, 755, 735 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 6.88 (dd, J = 4.0, 2.4 Hz, 1 H), 7.21–
7.27 (m, 1 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.43 (t, J = 7.4 Hz, 2 H), 7.97 (d,
J = 7.5 Hz, 2 H), 12.91 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 110.8, 117.2 (q, J = 290.7 Hz), 123.4
(q, J = 3.2 Hz), 126.0, 126.4 (2 C), 128.9 (2 C), 129.1, 129.9, 143.7, 167.7
(q, J = 34.5 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C11H8ClFNO2: 240.0222; found:
240.0223.
5-(3-Fluoro-4-methylphenyl)-1H-pyrrole-2-carboxylic Acid (3c)
Compound 3c was obtained following the general procedure for halo-
form reaction from 2c (9.77 g, 36.1 mmol).
1-[5-(3,4-Dimethoxyphenyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-
ethanone (2j)
Yield: 6.60 g (84%); gray solid; mp 180–185 °C
Compound 2j was obtained following the general procedure for
arylpyrrole trifluoroacetylation from 1j (9.66 g, 47.6 mmol) as a gray
solid (to facilitate precipitation, hexane was added to the reaction
mixture).
IR (KBr): 3349 (br), 3234 (br), 1675, 1479, 1441, 1261, 1253, 1183 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.22 (s, 3 H), 6.65 (dd, J = 3.6, 2.6
Hz, 1 H), 6.81 (dd, J = 3.6, 2.3 Hz, 1 H), 7.25 (t, J = 8.1 Hz, 1 H), 7.58 (dd,
J = 7.9, 1.2 Hz, 1 H), 7.71 (d, J = 11.7 Hz, 1 H), 12.02 (br s, 1 H), 12.14–
12.72 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 14.0 (d, J = 2.9 Hz), 108.0, 111.3 (d,
J = 24.2 Hz), 116.4, 120.8 (d, J = 2.9 Hz), 122.8 (d, J = 16.8 Hz), 124.5,
131.4 (d, J = 8.8 Hz), 131.9 (d, J = 5.9 Hz), 135.4 (d, J = 2.2 Hz), 161.0 (d,
J = 241.5 Hz), 161.9.
Yield: 12.00 g (85%).
1H NMR (400 MHz, DMSO-d6): δ = 3.78 (s, 3 H), 3.84 (s, 3 H), 6.86 (dd,
J = 4.2, 2.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 7.22–7.27 (m, 1 H), 7.49
(dd, J = 8.4, 2.0 Hz, 1 H), 7.65 (d, J = 1.7 Hz, 1 H), 12.75 (br s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H