138
J. Fetter, F. Bertha, L. Poszávácz, G. Simig
Vol. 42
form): δ 2.54 (s, 3H), 3.96-4.14 (m, 4H), 5.83 (s, 1H), 7.50 (d,
J=8.2 Hz, 1H), 7.54 (s, 1H), 7.99 (d, J=8.2 Hz, 1H).
procedure has been described in the patent literature for
the synthesis of 6-formylindole [7].
Anal. Calcd. for C H NO (209.20): C, 57.41; H, 5.30; N,
10 11
4
3-Methyl-4-nitrobenzaldehyde (4) is easily available by
chromic acid oxidation of 2,4-dimethyl-1-nitrobenzene [8]
(Scheme 2). Our strategy for the synthesis of 5-formylindole
(2) was to use compound 4, after protection of the aldehyde
function, in Batcho-Leimgruber indole synthesis. Therefore,
ethylene acetal 5 was prepared from aldehyde 4 by conven-
tional method [9]. Treatment of acetal 5 with dimethylfor-
mamide dimethyl acetal in DMF at 140° and subsequent cat-
alytic reduction of the nitro group of crude enamine 6 in
toluene afforded the ethylene acetal 7 of 5-formylindole in
65% yield. Acetal 7 was easily cleaved with hydrochloric
acid in aqueous THF to give the desired 5-formylindole (2).
The synthetic sequence starting from 3-methyl-4-nitroben-
zaldehyde gives 49% overall yield and represents, to our
knowledge, the best route to 5-formylindole (2).
6.70. Found: C, 57.25; H, 5.28; N, 6.58.
5-(1,3-Dioxolan-2-yl)-1H-indole (7).
A solution of acetal 5 (20.9 g, 0.1 mol), N,N-dimethylfor-
mamide dimethyl acetal (94%, 42.5 mL, 0.3 mol) and pyrrolidine
(5.4 mL, 7.8 g, 0.11 mol) in DMF (100 ml) was heated at 140° for
7 h under nitrogen atmosphere. After evaporation in vacuo (bath
temperature < 50°) the residue (6, 25.2 g) was dissolved in
toluene (220 mL). The solution was hydrogenated in the presence
5
of palladium on charcoal (10%, 3.5 g) under 7x10 Pa hydrogen
at room temperature. After removal of the catalyst, the solvent
was evaporated to dryness and the residue was triturated with
toluene (50 mL) to give 7 (12.3 g, 65%) as light yellow crystals,
mp 127-128° (toluene), IR (potassium bromide) 1400, 3330
-1
1
cm ; H NMR (DMSO-d ): δ 3.83-4.11 (m, 4H), 5.76 (s, 1H),
6
6.45 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.35 (d, J=2.7 Hz,
EXPERIMENTAL
1H), 7.38 (d, J=8.5 Hz, 1H), 7.61 (s, 1H), 11.15 (bs, 1H).
Anal. Calcd for C H NO (189.22): C, 69.83; H, 5.86; N,
11 11
2
7.40. Found: C, 69.51; H, 5.91; N, 7.34.
The melting points were determined on a Büchi 535 apparatus.
The IR spectra were recorded on an Aspect 2000 computer con-
trolled Bruker IFS-113ν vacuum optic FT spectrometer using
KBr pellets or films of liquids. The H NMR spectra were
recorded on a Bruker WM 250 FT, or a Varian Gemini-200, or a
Varian Unity Inova 400 spectrometer, in deuteriochloroform or
1H-Indole-5-carboxaldehyde (2).
To a solution of acetal 7 (9.5 g, 50 mmol) in tetrahydrofuran
(100 mL) was added aqueous hydrogen chloride solution (10%,
20 ml) at 0° and the mixture was stirred for 20 min. The reaction
mixture was neutralised with saturated aqueous sodium bicar-
bonate solution. The organic solvent was evaporated and the
aqueous residue was extracted with ethyl acetate (3x150 mL).
The organic phase was washed with water (2x30 mL), dried
1
dimethylsulfoxide-d . Chemical shifts were reported as δ values
6
(ppm) downfield from internal tetramethylsilane.
2-(3-Methyl-4-nitrophenyl)-1,3-dioxolane (5).
(MgSO ) and evaporated to give 2 (6.6 g, 91%), mp 99-101°
(diethyl ether-hexane) as light yellow crystals, lit. [10] mp 99-
101°.
A mixture of 3-methyl-4-nitrobenzaldehyde (4, 16.5 g, 0.1
mol), ethylene glycol (16.7 mL, 0.3 mol) and p-toluenesulfonic
acid (0.16 g, 1 mmol) was stirred at 130° for 2 h. After cooling to
room temperature dichloromethane (160 mL) was added and the
solution was extracted with saturated aqueous sodium bicarbon-
ate solution (2x50 mL). The organic phase was washed with
4
REFERENCES AND NOTES
water (2x30 mL), dried (MgSO ) and evaporated to afford 5
4
[1a] R. W. Oxford, D. Butina and M. R. Owen, Glaxo Group Ltd.,
EP 303.507 (1989); Chem. Abstr., 111, P57535t (1989); [b] P. Blatcher,
M. Carter, R. Hornby and M, R. Owen, Glaxo Group Ltd., WO 95.09166
(1995); Chem. Abstr., 123, P143646 (1995); [c] N. Mealy and J.
Castener, Drugs of the Future, 21, 476 (1996).
(17.2, 82%) as a light yellow oil, which can be used in the next
reaction step without further purification. After distillation (bp
113-114°, 0.05 mmHg) the product solidified, mp 34-35°; IR
-1 1
(potassium bromide) 1355, 1520 cm ; H NMR (deuteriochloro-