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D. G. Hingane, R. S. Kusurkar / Tetrahedron Letters 52 (2011) 3686–3688
thermal electrocyclization reaction for the synthesis of 11H-indo-
lo[3,2-c]quinoline 1, isocryptolepine 2 and 5-methyl-11H-indo-
lo[3,2-c]quinolin-5-inium iodide 3.The retro synthetic analysis is
shown in Scheme 1.
References and notes
1. Boye, G. L.; Ampofo, O. Proceedings of the First International Symposium on
Cryptolepine; University of Science and Technology: Kumasi, Ghana, 1983.
2. Oliver-Bever, B. Medicinal Plants in Tropical West Africa; Cambridge University
Press: Cambridge, 1986. p 41.
3. (a) Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C. H., Jr.; Martin, G. E.
J. Heterocycl. Chem. 1996, 33, 239; (b) Cimanga, K.; De Bruyne, T.; Pieters, L.;
Claeys, M.; Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703.
4. Dubovitskii, S. V.; Radchenko, O. S.; Novikov, V. L. Russ. Chem. Bull. 1996, 45, 2656.
5. Murray, P. E.; Mills, K.; Joule, J. A. J. Chem. Res. 1998, 377.
6. Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts, G.; Pieters, L.;
Haemers, A.; Dommisse, R. A. Synlett 2003, 615.
7. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron Lett. 2005, 46, 4509.
8. Miki, Y.; Kuromatsu, M.; Miyatake, H.; Hamamoto, H. Tetrahedron Lett. 2007, 48,
9093.
9. Agarwal, P. K.; Sawant, D.; Sharma, S.; Kundu, B. Eur. J. Org. Chem. 2009, 292.
10. Kraus, G. A.; Guo, H. Tetrahedron Lett. 2010, 51, 4137.
Thus, 1-phenylsulfonylindole 4 (Scheme 2) on treatment with
LDA and reaction with cyclohexanone furnished alcohol 5. Further
deprotection and dehydration was carried out using sodium
methoxide which gave a very poor yield of product 6. Tetrabutyl-
ammonium fluoride (TBAF) being a good reagent for similar depro-
tection11 reactions, it was thought to carry out first deprotection
using TBAF and then dehydration. Thus, compound 5 was treated
with TBAF, in THF under reflux for 2 h to get a solid product in
84% yield. It showed the absence of –OH in IR and 1H NMR and
the presence of one olefinic triplet at 6.04 in 1H NMR.
However, the spectral data were not consistent with the ex-
pected deprotected product, indicating structure 6 might be result-
ing from the tandem deprotection and dehydration reactions
during the treatment with TBAF. Similar one step deprotection
and dehydration is not reported earlier using TBAF. The yield in
this reaction was very high (84%) as compared to the yield using
sodium methoxide12 (48%, 14 h reflux). Thus TBAF was shown to
be a good reagent for this one-pot reaction. Vilsmeyer Haack
formylation of compound 6 produced 2-(l-cyclohexenyl)-3-formyl-
indole 7 in 88% yield.13
Further, oximination of 7 with hydroxylamine hydrochloride
and refluxing in dioxane furnished an unreported product 8 which
showed the absence of aldehydic proton and a downfield singlet at
11.50 in 1H NMR. Four alicyclic methylene carbons were identified
in 13C NMR spectrum and confirmed by DEPT experiment.14 For-
mation of 8 can be explained by initial formation of oxime and sub-
sequent thermal intramolecular electrocyclisation. Further
dehydrogenation of 8 using Pd/C in o-dichlorobenzene afforded
compound 1 in good yield.15 Naturally occurring isocryptolepine
2 was resulted in the overall yield of 37% by treatment of 1 with
methyl iodide and sodium carbonate.6 Compound 3 was obtained
by treatment of 1 with methyl iodide in acetonitrile for 24 h stir-
ring.16 Spectral data17,18 were consistent with those of the reported
compounds 2 and 3.
11. Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
12. Kano, S.; Sugino, E.; Shibuya, S.; Hibino, S. J. Org. Chem. 1981, 46, 3856.
13. Compound 7: White crystals; yield, 88%; mp 210–212 °C; 1H NMR (300 MHz,
CDCl3 + DMSO-d6): d 1.7 (m, 5H), 2.25 (m, 3H), 6.18 (br s, 1H), 7.15 (m, 2H),
7.35 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 9.91 (s, 1H), 11.66 (br s, 1H); 13
C
NMR (75 MHz, CDCl3 + DMSO-d6): d 19.90, 20.65, 24.04, 26.34, 109.98, 111.92,
119.49, 120.35, 121.59, 124.18, 126.26, 133.00, 133.96, 150.60, 183.80.; GC–MS
(DIP): 225(M+); calcd for C15H15NO: C, 80.0, H, 6.66, N, 6.22; Found: C, 80.10, H,
6.72, N, 6.44.
14. Experimental procedure for the preparation of compound 8: A mixture of 2-(1-
cyclohexenyl)-3-formylindole
7
(0.225 g,
1 mmol),
hydroxylamine
hydrochloride (0.139 g, 2 mmol), and sodium acetate (0.164 g, 2 mmol) in
10 mL dioxane was refluxed under stirring for 24 h and the reaction was
quenched by the 20 mL of water. The product was extracted with ethyl acetate
(20 mL Â 3) and the combined organic layers were washed with brine.
Evaporation of the solvent, followed by column chromatography(CHCl3/
MeOH 9.8:0.2), gave compound 8 as a yellow solid, Yield, 78%; mp 280–
282 °C (decomp.); 1H NMR (300 MHz, DMSO-d6): d 1.88 (m, 4H), 2.92 (m, 4H),
7.21 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 8.14(d,
J = 7.6 Hz, 1H), 9.04 (s, 1H), 11.50 (s, 1H, exchangeable with D2O); 13C NMR
(75 MHz, DMSO-d6): d 21.90, 22.90, 23.49, 32.02, 111.34, 114.08, 119.74,
120.24, 121.28, 125.75, 139.46, 139.72, 143.24, 151.08.; GC–MS (DIP) 222(M+);
calcd for C15H14N2 C, 81.08, H, 6.30, N, 12.62; Found C, 81.10, H, 6.42, N, 12.50.
15. Compound 1: 11H-Indolo [3,2-c] quinoline; yield, 88%; mp 280 °C; 1H NMR
(300 MHz, DMSO-d6): d 7.36 (t, J = 8 Hz, 1H), 7.50 (m, 1H), 7.74 (m, 3H), 8.12 (d,
J = 8.2 Hz, 1H), 8.32(d, J = . 7.6 Hz, 1H), 8.52(d, J = 8.2 Hz,1H), 9.6 (s, 1H),
12.75(s, 1H); IR (Nujol): v 1427, 3422 cmÀ1; GC–MS (DIP) = 218(M+); calcd for
C
15H10N2: C, 82.56, H, 4.58, N, 12.84; Found C, 82.14, H, 4.72, N, 12.76.
16. Molina, A.; Vaquero, J. J.; Garcia-Navio, J.; Alvarez-Builla, J.; Pascual-Teresa, B.;
Gago, F.; Rodrigo, M.; Ballesteros, M. J. Org. Chem. 1996, 61, 5587.
17. Compound 2: Isocryptolepine (5-methyl-5H-indolo[3,2-c] quinoline); yellow
solid; yield, 85%; mp 192–193 °C; 1H NMR (300 MHz, DMSO-d6): d 4.22 (s, 3H),
7.24 (t, J = 7.1 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.77–7.82
(m, 2H), 8.02 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 7.4 Hz, 1H), 8.76 (d, J = 7.6 Hz, 1H),
9.28 (s, 1H); 13C NMR (75 MHz, DMSO-d6): 42.70, 116.16, 118.0, 118.18, 120.0,
120.52, 120.69, 124.36, 125.38, 125.92, 126.09, 130.04, 135.78, 139.04, 152.14,
In summary, a new method having a key step of thermal intra-
molecular electrocyclisation was established for the synthesis of
11H-indolo[3,2-c]quinoline 1, isocryptolepine 2 and its biologically
active derivative, 5-methyl-11H-indolo[3,2-c]quinolin-5-inium
iodide 3.
153.20; IR (Nujol):
v ; GC–MS
2940, 3047, 1616, 1636, 1596 cmÀ1
(DIP) = 232(M+); calcd for C16H12N2: C, 82.73, H, 5.21, N, 12.06; Found C,
82.83, H, 5.34, N, 12.16.
18. Compound 3: 5-methyl-11H-indolo[3,2-c]quinolin-5-inium iodide; cream
colour solid; yield, 92%; mp 298–299 °C; 1H NMR (300 MHz, DMSO-d6): d
4.58 (s, 3H), 7.58 (t, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz,
1H), 8.09 (t, J = 7.8 Hz, 1H), 8.19 (t, J = 8.5 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H),
8.49(d, J = 8.5 Hz, 1H), 8.84(d, J = 7.8 Hz, 1H), 10.24 (s, 1H), 14.08 (br s, 1H); IR
(Nujol): v 3450 cmÀ1; calcd for C16H13IN2: C, 53.35, H, 3.64, N, 7.78; Found C,
53.62, H, 3.52, N, 7.90.
Acknowledgements
We are grateful to, Mrs. J. P. Chaudhari for NMR spectra and Mr.
Shishupal for GC–MS and IR spectra. D.G.H. is thankful to UGC for
FIP.