The Diels-Alder reactions of quinone imine ketals: A versatile synthesis of highly substituted 5-methoxyindoles

Article abstract of DOI:10.1021/ol016562k

Equation presented 32-71% overall N-Benzoylated quinone imine ketals undergo smooth cycloadditions in a [4 + 2] sense to yield the expected cycloadducts. The crude cycloadducts, when subjected to a short series of simple transformations, produce synthetic

Full text of DOI:10.1021/ol016562k

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3325-3327
The Diels−Alder Reactions of Quinone
Imine Ketals: A Versatile Synthesis of
Highly Substituted 5-Methoxyindoles
Scott C. Banfield, Dylan B. England, and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, Canada N6A 5B7
makerr@uwo.ca
Received August 10, 2001
ABSTRACT
N-Benzoylated quinone imine ketals undergo smooth cycloadditions in a [4 + 2] sense to yield the expected cycloadducts. The crude
cycloadducts, when subjected to a short series of simple transformations, produce synthetically useful quantities of 5-methoxyindoles in
excellent overall yields.
Recently we reported that quinone mono ketals (QMK) 1
and quinone imine ketals (QIK) 2 undergo smooth cycload-
dition at 13 kbar with 1,3-butadienes to yield the expected
endo cycloadducts 3 and 4 in excellent yields with extremely
high regiochemical and diastereofacial control (Scheme 1).1
to the synthesis of the seco-ergoline skeleton.2 Although
QMK’s have received some attention as dienophiles in the
Diels-Alder reaction,3 we are aware of only one report other
than ours of similar chemistry involving QIK’s.4 The
preparation and rich chemistry of QIK’s has been explored
by Swenton and co-workers.5
Our interest in the synthesis and reactivity of the indole
moiety, stemming from its position at the forefront of
medicinal and alkaloid chemistry,6 is ongoing. A strategy
occurred to us, which envisioned 5-methoxyindoles being
expeditiously accessible via the Diels-Alder reaction of
QIK’s. Scheme 2 illustrates such a strategy. Dihydronaph-
Scheme 1. The Diels-Alder Reactions of Quinoid Mono
Ketals
Scheme 2. Strategy for the Formation of 5-Methoxyindoles
The source of the regiocontrol is the ketal moiety since it
both sterically biases the dienophilic double bond and
removes a carbonyl from conjugation with it. A steric model
for this selectivity has been proposed by us previously.1b
Although isolable and stable, the adducts undergo facile acid-
catalyzed aromatization to produce the corresponding di-
hydronaphthalenes 5 and 6. We have applied this chemistry
10.1021/ol016562k CCC: $20.00 © 2001 American Chemical Society
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Table 1. The Synthesis of 5-Methoxyindoles from Quinone Imine Ketals
thalenes 7 (available via the reaction sequence shown in
Scheme 1) are subjected to oxidative cleavage of the olefinic
moiety producing dicarbonyl compound 8, which when
treated with acid would produce indole 9.7 Judicious choice
of the reactants allows access to a wide variety of 5-meth-
oxyindoles. Herein we report our success in this regard and
the development of an indole synthesis that complements
the methods which exist for the formation of the benzopyrrole
system.8
(1) (a) Kerr, M. A.; Jarvo, E. R.; Boothroyd, S. R. Synlett 1996, 897-
899. (b) Kerr, M. A. Synlett 1995, 1165-1167.
(2) Banfield, S. C.; Kerr, M. A. Synlett 2001, 436-438.
Table 1 shows the results of the high-pressure9 Diels-
Alder reactions of several QIK’s (10-12) with a variety of
dienes10 and subsequent conversion to indoles by the strategy
outlined in Scheme 2. QIK’s 11 and 12 were chosen simply
to illustrate the tolerability of substitution at the 2 and 3
(3) (a) Breuning, M.; Corey, E. J. Org. Lett. 2001, 1559-1562. (b)
Gerstenberger, I.; Hansen, M.; Mauvais, A.; Wartchow, R.; Winterfeldt, E.
Eur. J. Org. Chem. 1998, 643-650. (c) Russel, R. A.; Evans, D. A. C.;
Warrener, R. N. Aust. J. Chem. 1984, 37, 1699-1707. (d) Carren˜o, M. C.;
Farin˜a, F.; Ruano, J. L. C.; Puebla, L. J. Chem. Res., Synop. 1984, 288-
289. (e) Carren˜o, M. C.; Farin˜a, F.; Galan, A.; Ruano, J. L. C. J. Chem.
Res., Synop. 1979, 296-297.
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Org. Lett., Vol. 3, No. 21, 2001

positions of the dienophile. We have been unsuccessful in
promoting these reactions using ambient pressure conditions;
however, on the basis of literature precedent with quinone
mono ketals, the use of Lewis acids appears to hold some
promise3a and work is in progress to explore this method of
cycloaddition. Treatment of the crude isolated adduct in THF
with a drop of concentrated HCl results in the rapid (<5
min) and quantitative conversion to the dihydronaphthalenes
shown in Table 1. Previously1b we had used catalytic
p-toluenesulfonic acid in toluene to effect the aromatization
with yields of only 50-60%; the use of HCl in THF was a
simple but exceedingly important modification of our
protocol. Purification of the dihydronaphthalene is usually
accomplished by simple trituration with hexanes. Although
acid labile, the adducts (prior to aromatization) are otherwise
stable and can be chromatographically purified and stored
for extended periods of time in the freezer. It should be
emphasized that a single regioisomer of the Diels-Alder
adduct was formed in all cases.
to scission with NaIO4 supported on silica gel.12 The crude
dicarbonyl compound was treated with acid (p-TsOH/
toluene) to form the indoles shown in Table 1 in excellent
overall yields (32-71% over the five steps).13
As expected, the tetrasubstituted olefin in 14 was the most
difficult to cleave oxidatively. In the other cases this
transformation proceeded in yields typical of previous
literature examples. It should be noted that NaIO4 supported
on silica was key to the clean cleavage of the diol.
The dienes and dienophiles were selected to illustrate the
generality of this method for the formation of 5-methoxy-
indoles with virtually any substitution pattern. Compound
28, in fact, is a hexasubstituted indole. It is evident that by
employing the appropriate dienes and dienophiles a wide
variety of indoles may be prepared. Note that 23 and 25
represent the seco-ergoline system with the formyl group as
a handle for elaboration into the side chain present in the
ergot alkaloids.
In summary, we have reported a simple and high-yielding
preparation of densely substituted 5-methoxyindoles. The key
steps are the hyperbaric Diels-Alder reaction of the quinone
imine ketal and the subsequent oxidative cleavage of the
dihydronaphthalene. The overall synthesis of the indoles
requires only two purifications, one of which is a final
purification of the indole by flash column chromatography.
Efforts are underway to examine more electron withdrawing
nitrogen substituents as well as Lewis acids in order to make
this an ambient pressure and truly scalable process.
With the adducts in hand, the oxidative cleavage of the
olefin could be effected. While a variety of methods were
investigated (ozonolysis, Johnson-Lemieux oxidation), di-
hydroxylation with catalytic OsO4 in the presence of NMO11
proved to be the method of choice. The diol was typically
not isolated in pure form, the crude product being subjected
(4) Coutts, I. G. C.; Culbert, N. J.; Edwards, M.; Hadfield, J. A.; Musto,
D. R.; Pavlidis, V. H.; Richards, D. J. J. Chem. Soc., Perkin Trans. 1 1985,
9, 1829-1836.
(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.
(6) (a) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry, 2nd
ed.; Pergammon Press: New York, 1996; Vol. 2, pp 203-257. (b) Snieckus
V. A. In The Alkaloids; Academic Press: New York, 1968; Vol. 11, Chapter
1.
(7) Kraus and co-workers cleaved a 1,4-tosylamido dihydronaphthalene
in an elegant synthesis of the pyrroloindole subunit of CC-1065. See: Kraus,
G. A.; Yue, S.; Sy, J. J. Org. Chem. 1985, 50, 284-286.
(8) (a) Gribble, G. W. J. Chem. Soc., Perkin. Trans. 1 2000, 1045-
1075. (b) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996. (c)
Brown, R. K. In Heterocyclic Compounds, Vol. 25 Part 1; Wiley: New
York, 1972; Chapter 2.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC), the Ontario Min-
istry of Science and Technology, and MedMira Laboratories
for generous financial support of this research. D.B.E. is the
recipient of an OGSST scholarship.
Supporting Information Available: Complete experi-
1
mental procedures as well as H NMR, 13C NMR, IR, and
MS analysis data for compounds 13-28. This material is
(9) (a) Klarner, F.-G.; Diedrich, M. K.; Wigger, A. E. In Chemistry Under
Extreme or Non-Classical Conditions; van Eldik, R., Hubbard, C. D., Eds.;
Wiley: New York, 1997; Chapter 3. (b) Jurczak J.; Gryko, D. T. In
Chemistry Under Extreme or Non-Classical Conditions; van Eldik, R.,
Hubbard, C. D., Eds.; Wiley: New York, 1997; Chapter 4. (c) Isaacs, N.
S. In High-Pressure Techniques in Chemistry and Physics; Holzapfel, W.
B., Isaacs, N. S., Oxford: New York, 1997; Chapter 7.
(10) Diels-Alder reactions were typically performed on a 2 to 3 mmol
scale. See the Supporting Information for experimental details.
(11) Lemaire-Audoire, S.; Vogel, P. J. Org. Chem. 2000, 65, 3346-
3356.
available free of charge via the Internet at http://pubs.acs.org.
OL016562K
(12) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622-
2624.
(13) Although not isolated in practice, the crude diol resulting from
osmylation and the crude dicarbonyl resulting from oxidative cleavage were
characterized by NMR in one case to confirm that these were, in fact,
synthetic intermediates.
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