T. Przewloka et al. / Tetrahedron Letters 48 (2007) 5739–5742
5741
C13H8ClNOS: 261.00. Found: 262.0 (M+H)+ Anal.
Calcd for C13H8ClNOS: C, 59.66; H, 3.08; N, 5.35.
Found: C, 59.47; H, 2.90; N, 5.16.
O
O
Ar
a
N
N+
N
3
3-(4-Cyanobenzoyl)-indolizine (Table 1, entry 3): To a
stirred suspension of 1-[2-(4-cyanophenyl)-2-oxo-ethyl]-
2-methyl-pyridinium bromide (5 g, 12 mmol) in DMF
(50 mL) was added 40 mL DMF–Me2SO4 After the
addition, the reaction mixture was stirred at rt for
15 min. To it was then added Et3N (50 mL) while the in-
ner temperature was kept between 25 and 40 ꢁC. After
stirring at room temperature for 2 h, the reaction mix-
ture was added to ice water (200 mL) with stirring,
which led to the formation of slurry. The precipitates
were collected, washed with water, dried under vacuum,
and recrystallized from EtOAc to give 3.3 g (85%) of 3-
(4-cyanobenzoyl)-indolizine as a white solid. Analytical
data are identical to previously reported.20
O
N
N+
Br-
b
Ar
Ar
O
5
2
Scheme 3. Reagents and conditions: (a) Me2SO4, 130 ꢁC, 2 h; (b) 2,
TEA, rt, overnight.
under similar conditions. In this case, the ratio between
the desired product 5 and the intramolecular condensa-
tion 2-arylindolizene (3) is about 1:1, likely due to the in-
creased steric hindrance caused by the methyl group in
the DMA–Me2SO4 iminium adduct. After chromato-
graphic purifications, the isolated yield of 5 is low yield
(16%), indicating the reaction conditions need further
optimization in order to achieve optimal results.
References and notes
In summary, a variety of 3-acylated indolizines were
synthesized in good to excellent yields using the methyl-
sulfate salt of A (R = Me), the adduct formed from
DMF and Me2SO4 as the key reagent. The low cost of
DMF/Me2SO4, the short reaction time, the mild reac-
tion conditions, and the easy purification of the prod-
ucts make this an attractive new method for the
synthesis of indolizine compounds. The methodology
is amendable to large scale synthesis and was success-
fully applied to the kilogram manufacturing of STA-
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3-(5-Chlorothiophenecarbonyl)-indolizine (Table 1, entry
11): A mixture of equal mole equivalent of DMF and
Me2SO4 (2 mL) was stirred at 60–80 ꢁC for 3 h. After
cooled to room temperature, the DMF–Me2SO4 adduct
was added to a solution of 1-[2-(5-chlorothiophen)-2-
oxo-ethyl]-2-methyl-pyridinium bromide25 (0.168 g,
0.5 mmol) in DMF (1 mL) at room temperature. After
the reaction mixture was stirred for 15 min, Et3N
(3.5 mL) was then added. The reaction mixture was stir-
red for 1 h while keeping the temperature at ꢀ40 ꢁC.
The reaction was quenched with ice water (20 mL) and
extracted with ethyl acetate (10 mL · 3). The extracts
were dried (Na2SO4) and condensed (HPLC/ LC–MS
analysis of the crude product indicated >99% selectivity
of the desired product over the side reaction product).
Further purified by column chromatography (silica gel
and 20% ethyl acetate in hexanes) gave 120 mg (91%)
of 3-(5-chlorothiophene-2-carbonyl)-indolizine as
a
1
crystalline solid. Mp: 71.5–72 ꢁC; H NMR (CDCl3) d
(ppm), 9.79 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 4.5 Hz,
1H), 7.55–7.50 (m, 2H), 7.15(t, J = 7.5 Hz, 1H), 6.95
(d, J = 3.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.53 (d,
J = 4.8 Hz, 1H); 13C NMR (CDCl3) d (ppm), 174.9,
144.0, 140.0, 136.2, 130.5, 128.7, 127.0, 124.8, 124.6,
121.8, 118.8, 114.0, 103.2; ESMS Calcd for
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