LETTER
A Practical Parallel Synthesis of 2-Substituted Indolizines
2087
H3C
N
N
81%
OCH3
OCH3
99%
87%
N
30%
OCH3
4a (1a + 2a)
4b (1a + 2b)
4h (1e + 2a)
4n (1j + 2a)
4o (1a + 2e)
4p (1a + 2f)
N
N
OCH3
N
89%
30%
32%
NO2
OCH3
H3C
H2N
4i (1f + 2a)
N
O
N
85%
N
OCH3
80%
76%
H3CO
NO2
4c (1a + 2c)
CH3
4j (1g + 2a)
N
N
52%
96%
N
OCH3
OCH3
N
OCH3
~100%
~100%
4d (1b + 2a)
4q (1a + 2i)
H3C
N
4k (1h + 2a)
N
Br
N
OCH3
4e (1c + 2a)
CH3
4r (1a + 2h)
CH3
N
69%
41%
N
N
63%
66%
OCH3
OCH3
CH3
4s (1a + 2g)
CH3
78%
86%
4l (1i + 2a)
4f (1a + 2d)
CH3
N
N
OCH3
CH3
CH3
4m (1d + 2d)
Cl
4t (1k + 2g)
4g (1d + 2a)
Figure 3 Yields of 2-substituted indolizines 4a–t
The electron-withdrawing nature of substrates 2e and 2f purification. Reduction of the indolizines subsequently
may account for slower cyclization reactions leading to 4o gave an entry to the analogous indolizidines.
and 4p. The bicyclic nature of substrate 1j may make the
quinoline nitrogen less accessible to the N-alkylation,
thereby making the first step of the two-part process slow-
er, leading to low yields of 4n. Likewise the combination
of bulky substrates 1d and 2d may slow the N-alkylation
reaction to 4m.
Typical Experimental Procedures
4a: A solution of 2-picoline (0.10 mol, 23 g) and 2-bromo-4¢-meth-
oxyacetophenone (0.10 mol, 9.9 mL) in acetone (500 mL) was heat-
ed at reflux for 4 h. The quaternary salt was isolated via filtration
and re-dissolved in hot (60–80 ºC) water (500 mL). K2CO3 (0.100
mol, 13.8 g) was added and the mixture heated at 80 °C for 8 h. Af-
ter filtration and drying in vacuo, 4a (22 g, 98.7%) was obtained;
mp 184 ºC (dec., water), lit.7 mp 227–228 ºC (EtOAc). Parallel syn-
theses were run on a 10 mmol scale. 1H NMR (400 MHz, CDCl3):
d = 7.90 (br d, J = 5.9 Hz, 1 H), 7.62 (td, J = 8.8, 2.2 Hz, 2 H), 7.42
(br, 1 H), 7.35 (br d, J = 9.0 Hz, 1 H), 7.26 (s, 1 H), 6.96 (td, J = 8.8,
2.2 Hz, 2 H), 6.65 (br, 2 H), 6.46 (t, J = 6.2 Hz, 1 H), 3.86 (s, 3 H).
HRMS: m/z [M + H]+ calcd for C15H13NO: 223.0997; found:
224.1067. Anal. Calcd for C15H13NO: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.85; H, 5.78; N, 6.52.
H2 / PtO2
N
N
HOAc
R
R
H
H
4a (R = p-OCH3)
4b (R = m-OCH3)
5a 100%
(syn : anti = 3.67 :1.00)
5b 78%
(syn : anti > 25 :1)
Scheme 2
5: A suspension of 2-(4-methoxyphenyl)indolizine (4a) (231 mg,
1.00 mmol), and PtO2 (10 mg) in HOAc (20 mL) was hydrogenated
at 55 psi for 8 h. The catalyst was removed by filtration, and solvent
was evaporated. A quantitative yield of 5 was obtained (ratio of syn-
and anti-diastereomers: 3.67:1.00). The two isomers can be separat-
ed by silica PTLC (10% EtOAc–CH2Cl2) or alumina PTLC (5%
EtOAc–hexane). syn-5: 1H NMR (400 MHz, CDCl3): d = 7.30 (td,
J = 8.7, 2.1 Hz, 2 H), 6.86 (td, J = 8.7, 2.2 Hz, 2 H), 3.80 (s, 3 H),
3.40–3.00 (m, 3 H), 2.62 (t, J = 9.4 Hz, 1 H), 2.40–2.25 (m, 1 H),
2.10–1.95 (m, 2 H), 1.84 (bd d, J = 9.4 Hz, 2 H), 1.76–1.62 (m, 2
H), 1.60–1.45 (m, 1 H), 1.40–1.20 (m, 2 H). ESMS: m/z = 232
The corresponding indolizidines 5, which are also of bio-
logical interest,2,5,6 were obtained via catalytic hydrogena-
tion over platinum oxide in AcOH (Scheme 2).
In summary, through the appropriate choice of solvents
and reagents, a general method for the preparation of 2-
substituted indolizines has been developed. The method
was applied to a range of commercially available pi-
colines and a-bromoketones to afford the expected in-
dolizines in a parallel manner without the need for
Synlett 2003, No. 13, 2086–2088 © Thieme Stuttgart · New York