The Journal of Organic Chemistry
Article
1
2
1
.34 (d, J = 14.2 Hz, 1H), 2.03 (m, 1H), 2.88 (m, 1H), 1.44 (s, 9H),
.43 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).
H NMR (400 MHz, DMSO-d , 25 °C): δ 9.34 (s, 1H), 8.33 (s,
6
1H), 7.96 (d, J = 7.4 Hz, 1H), 7.10 (m, 2H), 6.88 (d, J = 7.4 Hz, 1H),
6.82 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.76 (br. m, 2H), 3.64 (s,
3H), 2.93 (br. s, 2H), 2.63 (br. m, 2H), 1.95 (m, 2H), 1.39 (m, 2H),
1.35 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H).
13
1
C{ H} NMR (75 MHz, CDCl , 50 °C): δ 184.6, 174.4, 163.4,
3
1
4
54.7, 149.9, 132.5, 130.4, 130.0, 114.1, 105.5, 79.6, 75.3, 62.0, 51.6,
7.3, 41.3 (br.), 34.4, 32.5, 32.3, 28.4, 14.1.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C H N O
19
1
4
8
61
4
15
F{ H} NMR (282 MHz, DMSO-d , 25 °C): δ −116.43.
6
1
3
1
9
33.4134; found: 933.4130.
Synthesis of 3-(Arylsulfanyl)-2-alkyl-1-hydroxyindolizines
C{ H} NMR (75 MHz, DMSO-d , 25 °C): δ 174.2, 164.9, 160.7
6
(d, 1J
= 240.7 Hz), 153.8, 137.9, 130.4, 127.7 (d, J
3
= 8.1 Hz),
C−F
C−F
2
General Procedure. 3,3-Difluorocyclopropene 1a or 1b (1 equiv),
substituted pyridine (or isoquinoline) (1 equiv), and aromatic thiol
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1
21.9, 121.4, 120.4, 118.5, 116.6 (d, J
08.1, 78.6, 60.4, 51.9, 46.8, 41.0 (br.), 33.4, 32.7, 28.0, 14.3.
HRMS (ESI-TOF) m/z: [M + H] calcd for C H FN O S
= 22.7 Hz), 116.3, 109.1,
C−F
(1.2−1.5 equiv) were dissolved in EtOH (14 mL/mmol). Water (10
+
3
0
36
2
7
equiv) was added, and the flask was equipped with a Liebig
condenser. The reaction mixture was heated at 70−80 °C for 18−36
h in air with periodic LC-MS monitoring. Then, the mixture was
concentrated under reduced pressure, and the crude product was
purified by HPLC. Solvents from the appropriate HPLC fractions
were removed in vacuo to afford 3-(arylsulfanyl)-2-alkyl-indolizin-1-
ols 6a−l.
5
87.2228; found: 587.2222.
3
-(4-Fluorophenylsulfanyl)-1-hydroxy-2-(2-hydroxyethyl)-indoli-
zine-7-carboxylic Acid Ethyl Ester (6d). The product was obtained
from tert-butyl-[2-(3,3-difluorocycloprop-1-enyl)-ethoxy]-dimethylsi-
lane 1b (0.5 mmol, 117 mg), ethylisonicotinate (75 mg, 1 equiv), and
4
6
-fluorothiophenol (96 mg, 1.5 equiv) and isolated by HPLC (30−
5% MeCN for 20 min; t ∼ 17 min) as a yellow amorphous solid.
R
4
-[7-Ethoxycarbonyl-1-hydroxy-3-(2-hydroxyphenylsulfanyl)-in-
Yield: 50%, 94 mg.
dolizin-2-ylmethyl]-N-Boc-4-methoxycarbonylpiperidine (6a). The
product was obtained from 4-(3,3-difluorocycloprop-1-enylmethyl)-
N-Boc-4-methoxycarbonylpiperidine 1a (166 mg, 0.5 mmol), ethyl-
isonicotinate (75 mg, 1 equiv), and 2-mercaptophenol (95 mg, 1.5
TLC: R = 0.61 (EtOAc; UV (254 nm), aq KMnO ). LC-MS: t ∼
f
4
R
2.6 min.
1
H NMR (300 MHz, DMSO-d , 25 °C): 9.39 (s, 1H [−OH]), 8.28
6
(dd, J = 1.9, 0.9 Hz, 1H), 7.98 (dd, J = 7.5, 0.8 Hz, 1H), 6.86 (dd, J =
equiv) and isolated by HPLC (30−70% MeCN for 20 min; t ∼ 17
R
7
3
3
.4, 1.8 Hz, 1H), 4.67 (br. s, 1H [−OH]), 4.26 (q, J = 7.1 Hz, 2H),
min) as yellow-green crystals (m.p. 212−214 °C). Yield: 25%, 73 mg.
TLC: R = 0.60 (EtOAc; UV (365 nm)). LC-MS: t ∼ 2.6 min.
.57 (t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H), 1.29 (t, J = 7.1 Hz,
f
R
H).
1
H NMR (400 MHz, DMSO-d , 25 °C): δ 10.15 (s, 1H), 9.29 (s,
19
6
F NMR (282 MHz, DMSO-d , 25 °C): δ −116.52 (tt, J = 8.8, 5.1
6
1H), 8.32 (dd, J = 1.9, 0.9 Hz, 1H), 7.86 (dd, J = 7.4, 0.9 Hz, 1H),
6.94 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 6.86 (dd, J = 7.5, 1.8 Hz, 1H),
6.83 (dd, J = 8.0, 1.3 Hz, 1H), 6.54 (td, J = 7.5, 1.3 Hz, 1H), 5.81 (dd,
Hz).
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1
C{ H} NMR (75 MHz, DMSO-d , 25 °C): δ 165.1, 160.8 (d,
6
1J
4
3
= 243.2 Hz), 137.5, 131.2 (d, J
= 3.1 Hz), 127.8 (d, J
=
C−F
C−F
C−F
J = 7.8, 1.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3,76 (br. m, 2H), 3.64
s, 3H), 2.90 (s, 2H), 2.63 (br. m, 2H), 1.96 (br. m, 2H), 1.38 (m,
2
8.0 Hz), 121.8, 121.7, 121.0, 120.2, 116.6 (d, J
= 22.4 Hz), 116.3,
C−F
(
2
1
08.8, 107.4, 60.9, 60.5, 27.8, 14.3.
HRMS (ESI-TOF) m/z: [M + H] calcd for C19
H), 1.35 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H).
+
13
1
H
19FNO
4
S
C{ H} NMR (75 MHz, DMSO-d , 25 °C): δ 174.3, 165.1, 153.8,
6
376.1019; found: 376.1026.
1
1
2
53.8, 137.9, 126.7, 125.3, 122.1, 121.3, 120.9, 120.4, 119.8, 118.7,
15.8, 115.3, 108.8, 107.9, 78.6, 60.4, 51.9, 46.8, 41.2 (br.), 33.4, 32.7,
4
-[3-(4-Carboxyphenylsulfanyl)-7-ethoxycarbonyl-1-hydroxyin-
dolizin-2-ylmethyl]-N-Boc-4-methoxycarbonylpiperidine (6e). The
product was obtained from 4-(3,3-difluorocycloprop-1-enylmethyl)-
N-Boc-4-methoxycarbonylpiperidine 1a (166 mg, 0.5 mmol), ethyl-
isonicotinate (75 mg, 1 equiv), and 4-mercaptobenzoic acid (100 mg,
8.0, 14.3.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C H N O S
3
0
37
2
8
5
85.2271; found: 585.2265.
4
-(7-Ethoxycarbonyl-1-hydroxy-3-o-tolylsulfanylindolizin-2-yl-
1
1
mg.
.3 equiv) and isolated by HPLC (25−75% MeCN for 20 min; t ∼
R
methyl)-N-Boc-4-methoxycarbonylpiperidine (6b). The product was
obtained from 4-(3,3-difluorocycloprop-1-enylmethyl)-N-Boc-4-me-
thoxycarbonylpiperidine 1a (166 mg, 0.5 mmol), ethylisonicotinate
7 min) as yellow-green crystals (m.p. 226−228 °C). Yield: 45%, 137
TLC: R = 0.45 ((EtOAc/AcOH, 100:1); UV (365 nm), aq
(
75 mg, 1 equiv), and 2-thiocresol (93 mg, 1.5 equiv) and isolated by
f
KMnO ). LC-MS: t ∼ 2.6 min.
HPLC (30−70% MeCN for 20 min; t ∼ 17 min) as yellow crystals
4
R
R
1
H NMR (400 MHz, DMSO-d , 25 °C): δ 12.72 (s, 1H
(m.p. 173−175 °C). Yield: 45%, 130 mg.
6
[
−COOH]), 9.28 (s, 1H [−OH]), 8.36 (br. s, 1H), 7.90 (d, J =
.5 Hz, 1H), 7.78 (m, 2H), 6.89 (dd, J = 7.4, 1.8 Hz, 1H), 6.82 (m,
2H), 4.29 (q, J = 7.1 Hz, 2H), 3.74 (m, 2H), 3.64 (s, 3H), 2.93 (s,
H), 2.66 (m, 2H), 1.97 (m, 2H), 1.39 (m, 2H), 1.35 (s, 9H), 1.32 (t,
J = 7.1 Hz, 3H).
TLC: R = 0.63 (EtOAc; UV (365 nm), aq KMnO ). LC-MS: t ∼
f
4
R
7
3
.0 min.
1
H NMR (400 MHz, DMSO-d , 25 °C): δ 9.35 (s, 1H [−OH]),
6
2
8
1
.35 (br. s, 1H), 7.85 (br. d, J = 7.4 Hz, 1H), 7.22 (br. d, J = 7.6 Hz,
H), 7.03 (br. t, J = 7.4 Hz, 1H), 6.92 (br. t, J = 7.6 Hz, 1H), 6.86 (br.
1
3
1
C{ H} NMR (100 MHz, DMSO-d , 25 °C): δ 174.2, 166.7,
d, J = 7.4 Hz, 1H), 5.84 (br. d, J = 7.9 Hz, 1H), 4.28 (q, J = 7.1 Hz,
6
1
1
2
64.9, 153.8, 141.4, 138.0, 130.3, 128.2, 124.7, 122.0, 121.8, 120.5,
18.8, 116.5, 109.2, 106.3, 78.6, 60.4, 51.9, 46.8, 41.0 (br.), 33.4, 32.7,
8.0, 14.3.
2
2
7
H), 3.75 (br. m, 2H), 3.65 (s, 3H), 2.88 (s, 2H), 2.63 (br. m, 2H),
.41 (s, 3H), 1.96 (br. m, 2H), 1.39 (m, 2H), 1.35 (s, 9H), 1.31 (t, J =
.1 Hz, 3H).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C H N O S
13
1
C{ H} NMR (75 MHz, DMSO-d , 25 °C): δ 174.3, 165.0, 153.9,
31 37
2
9
6
613.2220; found: 613.2215.
1
1
1
38.0, 134.2, 134.2, 130.7, 126.9, 125.6, 123.7, 122.0, 121.5, 120.5,
18.8, 116.1, 109.0, 107.1, 78.6, 60.5, 51.9, 46.9, 41.1, 33.4, 32.7, 28.0,
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-[3-(2-Carboxyphenylsulfanyl)-1-hydroxy-7-trifluoromethylin-
dolizin-2-ylmethyl]-N-Boc-4-methoxycarbonylpiperidine (6f). The
product was obtained from 4-(3,3-difluorocycloprop-1-enylmethyl)-
N-Boc-4-methoxycarbonylpiperidine 1a (166 mg, 0.5 mmol), 4-
trifluoromethylpyridine (74 mg, 1 equiv), and thiosalicylic acid (100
mg, 1.3 equiv) and isolated by HPLC (25−75% MeCN for 20 min; t
∼ 17 min) as yellow-green crystals. Yield: 45%, 137 mg.
9.4, 14.3.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C H N O S
3
1
39
2
7
5
83.2478; found: 583.2481.
4
-[7-Ethoxycarbonyl-3-(4-fluorophenylsulfanyl)-1-hydroxyindo-
lizin-2-ylmethyl]-N-Boc-4-methoxycarbonylpiperidine (6c). The
product was obtained from 4-(3,3-difluorocycloprop-1-enylmethyl)-
N-Boc-4-methoxycarbonylpiperidine 1a (166 mg, 0.5 mmol), ethyl-
isonicotinate (75 mg, 1 equiv), and 4-fluorothiophenol (96 mg, 1.5
R
TLC: R = 0.45 ((EtOAc/AcOH, 100:1); UV (254 nm)). LC-MS:
f
t
∼ 2.6 min.
R
1
equiv) and isolated by HPLC (35−85% MeCN for 20 min; t ∼ 17
H NMR (400 MHz, DMSO-d
6
, 25 °C): δ 13.36 (s, 1H
R
min) as light yellow crystals (m.p. 175−177 °C). Yield: 50%, 147 mg.
TLC: R = 0.67 (EtOAc; UV (365 nm), aq KMnO ). LC-MS: t ∼
[−COOH]), 9.25 (s, 1H [−OH]), 7.99 (m, 1H + 1H), 7.89 (d, J
= 7.4 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.60
(dd, J = 7.4, 1.8 Hz, 1H), 5.81 (d, J = 8.0 Hz, 1H), 3.75 (br. m, 2H),
f
4
R
2.9 min.
7
695
J. Org. Chem. 2021, 86, 7687−7700