LETTER
The Diels-Alder Reactions of Quinone Imine Ketals
437
Academic Press: San Diego, CA, 1975; V 15, Ch 1. c) Stoll,
A; Hofmann, A. In The Alkaloids; Manske, R.H.F., Ed.;
Academic Press: New York, NY, 1965; V 8, Ch 21.
(2) Kerr, M.A.; Jarvo, E.R.; Boothroyd, S.R. Synlett 1996, 897-
899.
THF and treated with a drop of concentrated HCl to yield
the aromatized compound 12 in 85% overall yield.6 Hy-
drogenation followed by treatment with fluoride yielded
the alcohol 137 which when treated under Swern8 con-
ditions produced a mixture of aldehyde 14 and indole
15. Typically the crude material isolated from the Swern
oxidation was treated with p-toluenesulfonic acid in tolu-
ene to effect complete conversion to 15 in 87% overall
yield.9 The overall yield of 15 from 5 was 57% over the six
steps.
(3) Kerr, M.A. Synlett 1995, 1165-1167.
(4) a) Lipshutz, B.H.; Buzard, D.J.; Vivian, R.W. Tetrahedron
Lett. 1999, 6871-6874. b) Peterson, G.A.; Kunng, F.A.;
McCallum, J.S.; Wulff, W.A. Tetrahedron Lett. 1987, 1381-
1384. c) Cacchi, S.; Ciattini, P.G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1986, 5541-5544.
(5) a) Swenton, J.S.; Bonke, B.R.; Chen, C.-P.; Chou, C.-T. J.
Org. Chem. 1989, 54, 51-58. b) Swenton, J.S.; Shih, C.; Chen,
C.-P.; Chou, C.-Y.; J. Org. Chem. 1990, 55, 2019-2026. c)
Swenton, J.S.; Bonke, B.R.; Clarke, W.M.; Chen, C.-P.;
Martin, K.V. J. Org. Chem. 1990, 55, 2027-2034.
If the double bond was left intact prior to desilylation the
alcohol 16 was produced, which when oxidized with PCC
gave, not unexpectedly the fully oxidized compound 17
(Scheme 3).10 If, instead, the oxidation was performed us-
ing Swern conditions, the reaction yielded a complicated
mixture and not the expected product 18. Interestingly,
structures such as 17 have been shown to reduce rectal
temperatures in rats and have stimulated interest for their
potential as fever reducing agents.11
(6) Procedure for the preparation of Diels-Alder adduct 12: The
quinone imine ketal 5 (0.259 g, 1.0 mmol) and the diene 10
(0.609 g, 3.1 mmol) were taken up in dry methylene chloride
(0.5 mL) in a dry 10 mL pear shaped flask. This solution was
transferred with the aid of an additional 0.5 mL CH2Cl2, to a
~7 cm length of heat shrinkable Teflon tubing which was
pinched and sealed at one end with a brass screw clamp.
Excess air was squeezed from the tube and it was sealed with
a brass screw clamp. The vessel was then pressurized in a
LECO Tempres HPC 200 system at 13 kbar for a period of 7
days, after which time the reaction mixture was concentrated
and taken up in THF (20 mL). Concentrated HCl (1 drop) was
added and the mixture was stirred for 5 min and diluted with
water. Extractive workup with diethyl ether yielded crude 12,
which was purified by column chromatography on silica gel
(elution with 25% EtOAc/hexane). The yield was 0.360 g
(85%) as a white gum. 1H NMR (400 MHz, CDCl3) = 9.53
(s, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H),
7.54-7.45 (m, 3H), 6.83 (d, J = 8.8 Hz, 1H), 6.11-6.01 (m,
1H), 5.86-5.81 (m, 1H), 3.96 (AB of ABX, 2H), 3.85 (s, 3H),
3.55 (dd, J = 21.9, 5.1 Hz, 1H), 3.35 (t, J = 11.1 Hz, 1H), 3.04
(d, J = 21.9 Hz, 1H), 0.73 (s, 9H), -0.10 (s, 3H), -0.14 (s, 3H);
13C NMR (100 MHz, CDCl3) = 165.4, 154.0, 135.1, 131.6,
131.3, 128.9, 128.4, 127.9, 127.3, 124.6, 123.6, 123.4, 108.0,
69.1, 55.5, 38.3, 25.8, 24.3, 18.6, -5.6, -5.7; IR (thin film)
= 3337, 1672 cm-1; HRMS (EI 70 eV) - calcd for
Scheme 3
C25H33NO3Si: 423.2230, found: 423.2211.
(7) Physical data for 13: 1H NMR (400 MHz, DMSO) = 10.23
(s, 1H), 8.03 (d, J = 7.4 Hz, 2H), 7.67-7.58 (m, 3H), 7.36 (d,
J = 8.6 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.42-5.40 (m, 1H),
3.85 (s, 3H), 3.68-3.63 (m, 1H), 3.58-3.52 (m, 1H), 3.21-3.19
(m, 1H), 2.83 (dd, J = 18.0, 5.1 Hz, 1H), 2.10 (d, J = 13.0 Hz,
1H), 1.79-1.75 (m, 2H), 1.57-1.51 (m, 1H); 13C NMR (100
MHz, DMSO) = 165.2, 154.7, 134.9, 134.5, 131.4, 129.2,
128.5, 127.3, 125.4, 124.4, 107.5, 65.0, 55.3, 35.5, 23.7, 22.8,
16.6; IR (thin film) = 3275, 1645 cm-1; HRMS (EI 70 eV) -
calcd for C19H21NO3: 311.1521, found: 311.1519.
(8) The insoluble nature of the alcohol 13 required the use of
DMSO as a co-solvent. See: Swern, D.; Mancuso, A.J.
Synthesis 1981, 165-185.
(9) Procedure for the formation of indole 15: The crude product
from the Swern reaction was purified by column
In summary, we have shown that the tricyclic subunit
present in most of the ergot alkaloids can be prepared in
high overall yield by the cycloaddition of a quinone mono
ketal with an appropriate diene, followed by several sim-
ple transformations. In future reports we intend to show
the generality of this method for the formation of more so-
phisticated compounds related to the natural products and
unusually substituted indoles in general.
Acknowledgement
We thank the Natural Sciences and Engineering Research Council
(NSERC), the Ontario Ministry of Science and Technology and
MedMira Laboratories for generous financial support of this re-
serch.
chromatography on silica gel (elution with 30% EtOAc/
hexane to yield a mixture of the aldehyde 14 (25 mg) and the
indole 15 (16 mg). The aldehyde was taken up in dry toluene
(5 mL) and treated with 1 crystal of p-toluenesulfonic acid
monohydrate. After 10 min the mixture was diluted with
EtOAc and washed successively with H2O, saturated
NaHCO3, and brine before drying over MgSO4. Evaporation
of the solvent yielded pure indole 15 (24 mg). m.p. = 111-
113 °C; 1H NMR (400 MHz, CDCl3) = 7.97 (br d, 1H), 7.71
References and Notes
(1) a) Ninomiya, I; Kiguchi, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, CA, 1990; V 38, Ch 1. b)
Ninomiya, I; Kiguchi, T. In The Alkaloids; Brossi, A., Ed.;
Synlett 2001, No. 3, 436–438 ISSN 0936-5214 © Thieme Stuttgart · New York