Z. Xia et al. / Tetrahedron Letters 47 (2006) 8817–8820
Table 2. Synthesis of 3-acylindolizines from DMF di-t-butyl acetal
CH3
8819
R2
R2
R2
DMF
+
R1
+
(tBuO)2CHNMe2
(10-12 eq.)
N
N+
N
130 oC
10 min.
O
O
R1
R1
2
1
3
Entry
R2
R1
1 (%) (isolated yield)
1:3 ratio (1H NMR)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Et
OH
Methyl
Ethyl
Phenyl
62
83
58
68
55
64
75
67
80
65
54
80
36
65
73
30
75
65/35
90/10
75/25
80/20
75/25
80/20
95/5
95/5
92/8
95/5
85/15
95/5
4-Methoxyphenyl
3-Methoxyphenyl
4-Chlorophenyl
4-Nitrophenyl
3-Cyanophenyl
4-Cyanophenyl
3,4-Dichlorophenyl
5-Chlorothien-2-yl
5-Cyanothien-2-yl
2-Furanyl
60/40
90/10
90/10
95/5
4-Cyanophenyl
4-Cyanophenyl
4-Cyanophenyl
4-Cyanophenyl
MeOCH2O
90/10
gave a better selectivity. In most cases, the reaction pro-
ceeded cleanly and the desired product 1 was obtained in
a good to excellent yield after flash column (silica gel)
separation. One exception was observed with para-
line. Mp 156–157 ꢁC (recrystallized from ethyl acetate);
1H NMR (300 MHz, CDCl3) d (ppm), 9.98 (d,
J = 6.6 Hz, 1H), 7.89–7.77 (m, 4H), 7.60 (d, J = 11 Hz,
1H), 7.30–7.22 (m, 2H), 7.01 (m, 1H), 6.57 (d,
J = 6.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d (ppm),
181.75, 144.91, 140.17, 132.12, 129.41, 129.23, 126.92,
125.43, 122.09, 118.88, 118.42, 114.60, 114.12, 103.61;
ESMS calcd for C16H10N2O: 246.1. Found: 247.1
(M+H)+. Anal. Calcd for C16H10N2O: C, 78.03; H,
4.09; N, 11.38. Found: C, 77.82; H, 3.92; N, 11.11.
1
hydroxy-picolinium salt (entry 16). Although H NMR
analysis of crude reaction mixture indicated an excellent
selectivity (95/5), the desired product was isolated in
only a 30% yield due to decomposition during the reac-
tion. When the OH was protected with methoxymethyl
group (entry 17), much higher yield (75%) of the desired
3-substituted indolizine was obtained.
In summary, DMF di-t-butyl acetal is found to be a
highly useful reagent for the synthesis of a variety of
3-acylated indolizines, which in other ways are not read-
ily accessible. The short reaction time and easiness of
handling should render this new method applicable to
the synthesis of 3-substituted indolizines, which could
be further functionalized regioseletively at other posi-
tions. In our laboratory, we have successfully applied
this method for the synthesis of a variety of indolizine
derivatives that ultimately led to the discovery STA-
References and notes
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5312,
a novel microtubule inhibitor selected for
development.20
General procedure: A mixture of 1-[2-(4-cyanophenyl)-2-
oxo-ethyl]-2-methyl-pyridinium bromide21 (1 mmol)
and DMF di-t-butyl acetal (10 mmol) in DMF (7 ml)
was heated at 130 ꢁC for 10 min. The reaction was
quenched with ice water (20 ml) and extracted with ethyl
acetate (15 ml · 3). The extracts were dried (Na2SO4)
and the solvent was evaporated. Proton NMR measure-
ment of the crude product mixture indicated a ratio of
92:8 of the major and the minor products. The residue
was subjected to silica gel column chromatography
(30–50% ethyl acetate in hexanes) to give 197 mg
(80%) 3-(4-cyanobenzoyl) indolizine as a white crystal-
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