Heterocycle annulation of enolizable vinyl quinone imides. Dihydroquinolines and quinolines from thermal 6π-electrocyclizations and indoles from photochemical cyclizations

Article abstract of DOI:10.1021/ol026849x

(equation presented) Enolizable vinyl quinone mono-and diimide substrates yield protected 6-hydroxy and 6-amino dihydroquinolines by thermal electrocyclization. Aromatization provides the corresponding quinolines in quantitative yields. The quinone monoimide substrates undergo clean photochemical conversion to 5-hydroxy indoles.

Full text of DOI:10.1021/ol026849x

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4265-4268
Heterocycle Annulation of Enolizable
Vinyl Quinone Imides. Dihydroquinolines
and Quinolines from Thermal
6π-Electrocyclizations and Indoles from
Photochemical Cyclizations
,†
Kathlyn A. Parker* and Thomas L. Mindt‡
Department of Chemistry, SUNY Stony Brook, Stony Brook, New York 11794-3400,
and Department of Chemistry, Brown UniVersity, ProVidence, Rhode Island 02912
kparker@notes.cc.sunysb.edu
Received September 4, 2002
ABSTRACT
Enolizable vinyl quinone mono- and diimide substrates yield protected 6-hydroxy and 6-amino dihydroquinolines by thermal electrocyclization.
Aromatization provides the corresponding quinolines in quantitative yields. The quinone monoimide substrates undergo clean photochemical
conversion to 5-hydroxy indoles.
Quinoline-containing natural products have attracted the
attention of synthetic and medicinal chemists for many
decades. The parent bicyclic substructure is found in natural
products that exhibit a wide spectrum of biological activities
and the quinoline, di- and tetrahydroquinoline, and oxo-
quinoline moieties are found in a large number of medicinally
interesting compounds.1,2
Numerous synthetic methods have been developed for the
preparation of this class of heterocycles.1,3 Most of the
classical preparations lead directly to aromatized quinolines
or proceed through dihydroquinolines without the isolation
of these sensitive intermediates. However, there is some
interest in the preparation of stable dihydroquinoline deriva-
tives.3,4 We now wish to report a new synthetic approach
that gives rise to protected 2-carboxy 6-amino and 6-hydroxy
dihydroquinolines and the facile elaboration of these products
to the corresponding 2-substituted quinolines. In addition,
we wish to describe a variation of our sequence that
efficiently gives rise to indoles.
Generalization of the electrocyclization-based annulation
recently discovered in our laboratories5 could provide access
to a variety of heterocycles. In the previously established
applications of this approach, enolization of vinyl quinones
1 followed by thermal 6π-electrocyclic ring closure of the
resulting quinone methides 2 provided benzopyran products
† SUNY Stony Brook.
‡ Brown University.
(1) See, e.g.: Jones, G. In Chemistry of Heterocyclic Compounds
“Quinolines”; John Wiley & Sons: New York, 1977 (part 1), 1982 (part
2), 1990 (part 3); Vol. 32.
(2) Michael, J. P. Nat. Prod. Rep. 2001, 17, 603-620 and previous
reviews in this series.
(3) (a) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. J. Heterocycl.
Chem. 1998, 35, 761-785. (b) Evans, P. A.; Robinson, J. E.; Moffett, K.
K. Org. Lett. 2001, 3, 3269-3271.
(4) See, e.g.: Altamura, M.; Meini, S.; Quartara, L.; Maggi, C. A. Regul.
Pept. 1999, 80, 13-26.
(5) Parker, K. A., Mindt, T. L. Org. Lett. 2001, 24, 3875-3878.
10.1021/ol026849x CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/07/2002

3 (Scheme 1; X, Y ) O). Extension of this class of reactions
to the preparation of nitrogen heterocycles would rely on
the isomerization of enolizable vinyl quinone imides 16
(Scheme 1; X, Y ) NR or X ) NR, Y ) O).
Scheme 3. Annulation of Diimide Substrates and
Transformation of Dihydroquinolines to 6-Amino Quinolinesa
Scheme 1. Generalization of Two-Step Heterocycle
Annulation
The preparation of substrates for these investigations would
be based on the Stille coupling of vinyl tin reagents with
amide derivatives7 of bromo phenylenediamines or of bromo
amino phenols as shown in Schemes 2 and 4. The desired
a (a) 5 mM in toluene, 5% HMPA, rt (55% 9a, 60% 9b); (b) for
9b: TBAF or K2CO3, DMF, rt (quantitative); (c) 50% H2SO4, rt
(80%).
The synthesis of quinone diimide substrates 8 was based
on bromo phenylene diamine 4 (Scheme 2).9 We prepared
acetamide derivative 8a by this three-step scheme. Acetyl-
ation followed by palladium-catalyzed coupling of substrate
5a with vinyl stannane 610 and finally oxidation of Stille
product 7a completed the synthesis of quinone diimide 8a.
Addition of small amounts of HMPA12 to a dilute solution
of diimide 8a at room temperature afforded the desired
annulation product dihydroquinoline 9a in good yields
(Scheme 3). This conversion represents the first example of
a new synthesis of protected dihydroquinolines.
Scheme 2. Preparation of Vinyl Quinone Diimide Substratesa
Diacetamide 9a was unreactive under standard deprotec-
tion conditions13 and could not be carried forward efficiently.
Therefore, with the goal of obtaining annulation products
that could be deprotected under mild conditions, we tested
the utility of the SES group11 in the annulation scheme. Thus,
a (a) Ac2O, py, rt (96%); (b) SESCl,11 py, rt (64%); (c) (Ph3P)4Pd,
toluene, reflux (50% 5a, 58% 5b); (d) Pb(OAc)4, CHCl3, rt (92%
8a, 100% 8b).
Scheme 4. Preparation of Monoimide Substratesa
quinone di- and monoimides would then be accessible by
oxidation.8
(6) Ortho quinone methide imines (from the thermolytic dehydration of
o-(2-hydroxy-3-propenyl) anilines in refluxing xylene or o-dichlorobenzene
for several hours) have been reported to undergo electrocyclization to 1,2-
dihydroquinolines; see: Wiebe, J. M.; Caille, A. S.; Trimble, L.; Lau, C.
K. Tetrahedron 1996, 52, 11705-11724.
(7) Stille coupling is reported not to proceed with free arylamines; see:
Falcou, A.; Marsacq, D.; Hourquebie, P.; Ducheˆne, A. Tetrahedron 2000,
56, 225-231. Our own experience confirms this.
(8) The synthesis and physical and chemical properties of quinone di-
and monoimides are described in the pioneering papers of Roger Adams.
See, e.g.: Adams, R.; Reifschneider, W. Bull. Soc. Chim. Fr. 1958, 23-
65.
a (a) 6, (Ph3P)4Pd, toluene, reflux (76% 13a, 50% 13b); (b) 50%
AcOH, THF (94% 14a, 90% 14b); (c) Pb(OAc)4, CHCl3 (quantita-
tive for 15a and 15b).
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Org. Lett., Vol. 4, No. 24, 2002

phenylene diamine 4 was converted to the di-SES derivative
5b and the same coupling/oxidation sequence was applied,
providing diimide substrate 8b. Employment of the annula-
tion conditions as described above cleanly provided di-
hydroquinoline 9b. Treatment of the SES-protected di-
hydroquinoline 9b with TBAF or with potassium carbonate
resulted in aromatization with regiospecific loss of one of
the two SES groups and quantitative formation of quinoline
10. Liberation of the second amino group to afford p-amino
quinoline 11 was achieved by stirring intermediate 10 in 50%
sulfuric acid for 20 h.
Testing the scope of the new annulation methodology with
vinyl quinone monoimide substrates was of particular interest
because it would provide 6-hydroxy quinolines. 6-Oxygen-
ated quinoline systems appear in the structures of a number
of medicinally interesting and synthetically challenging
natural products, including those of quinine, streptonigrin,
and the luzopeptins.14
Resorting again to the use of the SES protecting group,
we prepared monoimide 15b (Scheme 4) and subjected it to
the cyclization conditions. This substrate proved to be stable
at room temperature in the toluene/HMPA medium. How-
ever, when the solution was stirred at reflux in the dark,
reaction was complete in 1 h and SES-protected dihydro-
quinoline 16b was isolated in satisfying yields. Treatment
of this compound with either base or a fluoride source
effected both deprotection and aromatization, affording
6-hydroxyquinoline 17 in quantitative yields.
Remarkably, exposure of the same annulation reaction
mixtures (monoimide 15a or 15b in toluene containing 0.5%
HMPA)16 to light at room temperature resulted in total
conversion of the substrate to the protected indole (18a and
18b) rather than to the protected dihydroquinoline system
(Scheme 6).17 Deprotection of each of these products
The synthesis of vinyl quinone monoimides is outlined in
Scheme 4. The protected aminophenol 12a15 underwent Stille
coupling with stannane 6, and the resulting TES-ether 13a
was deprotected to give phenol 14a. Oxidation afforded the
desired annulation substrate 15a.
Scheme 6. Photochemical Reaction Conditions Yield Indole
Productsa
As anticipated, addition of HMPA to a toluene solution
of monoacetimide substrate 15a at room temperature in the
dark effected clean conversion to dihydroquinoline 16a,
successfully extending the methodology to 6-hydroxy quino-
line systems (Scheme 5). However, attempts to remove the
a (a) For 15a: 5 mM in toluene, 0.5% HMPA, hV, rt (69%). For
15b: 2 mM in toluene, 0.5% HMPA, hV, rt (59%); (b) NaOMe,
MeOH, rt (quantitative); (c) CsF, DMF, rt (quantitative).
Scheme 5. Annulation of Monoimide Substrates and
Conversion of Dihydroquinolines to 6-Hydroxy Quinolinesa
provided the corresponding 5-hydroxy indoleacetic acid ester
1918 in quantitative yield.
Although the photochemical isomerization of vinyl qui-
nones to benzofurans is known,19 the corresponding conver-
sion of vinyl quinone imides to indoles is a new reaction. In
the systems examined so far, the mild conditions required
and the simplicity of the procedure were dazzling.
The synthesis of quinolines and indoles by a short
sequence based on Stille coupling of protected bromo
diamines and amino phenols followed by electrocyclization
a (a) For 15a: 5 mM in toluene, 5% HMPA, rt, dark (71%). For
15b: 2 mM in toluene, 2.5% HMPA, reflux, dark (58%); (b) for
16b: K2CO3, DMF, 50 °C or CsF, DMF, rt (quantitative).
(14) Total syntheses of each of these targets have been reported. For
quinine, see: Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J.
M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239-3242. For
streptonigrin, see: Boger, D. L.; Panek, J. S.; Duff, S. R. J. Am. Chem.
Soc. 1985, 107, 5745-54. For luzopeptins, see: Boger, D. L.; Ledeboer,
M. W.; Kume, M.; Searcey, M.; Jin, Q. J. Am. Chm. Soc. 1999, 121, 11375-
11383. Valognes, D.; Belmont, P.; Xi, N.; Ciufolini, M. A. Tetrahedron
Lett. 2001, 42, 1907-1909.
acetyl group from this cyclization product, under conditions
such as those applied to diacetamide 9a, provided neither
dihydroquinoline nor quinoline.13
(9) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797-
11810.
(15) For the preparation of protected amino phenols 12a and 12b, see
Supporting Information.
(10) Collins, P. W.; Kramer, S. W.; Gasiecki, A. F.; Weier, R. M.; Jones,
P. H.; Gullikson, G. W.; Bianchi, R. G. J. Med. Chem. 1987, 30, 193-
197.
(11) SES ) trimethylsilylethanesulfonyl (Weinreb, S. M.; Demko, D.
M.; Lessen, T. A. Tetrahedron Lett. 1986, 27, 2099-2102).
(12) With the diimides, the rate of reaction accelerated with the amount
of HMPA added up to approximately 5 vol %.
(13) Basic reaction conditions (NaOMe, MeOH) left dihydroquinoline
9a unchanged, whereas acidic conditions (AcOH or up to 37% HCl) resulted
in the formation of decomposition products.
(16) Employment of higher concentrations of HMPA resulted in the
formation of mixtures of dihydroquinoline and indole products.
(17) The formation of indole products from diimide substrates 8a and
8b was not observed even after prolonged exposure to light or upon
irradiation in a photochemical reactor in toluene containing HMPA.
(18) Related indoles have been used in nonpeptidic neurotensin mimetics;
see: Dodd, D. S.; Kozikowski, A. P.; Cusack, B.; Richelson, E. Bioorg.
Med. Chem. Lett. 1994, 4, 1241-1246.
(19) Iwamoto, H.; Takuwa, A.; Hamada, K.; Fujiwara, R. J. Chem. Soc.,
Perkin Trans. 1 1999, 575-581.
Org. Lett., Vol. 4, No. 24, 2002
4267

of quinone imides provides the chemist with a new and
attractive “disconnect” for retrosynthetic analysis. The mech-
anism of the photochemical indole synthesis and possible
applications of the new methodologies for the preparation
of nitrogen-containing heterocyclic natural products are
currently under investigation.
was a Fellow of the Graduate Assistance in Areas of National
Need program of the U.S. Department of Education. We
thank Dr. Tun-Li Shen for the mass spectroscopic measure-
ments.
Supporting Information Available: Detailed descrip-
tions of the experimental procedures and complete analytical
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The work described in this com-
munication was supported by the National Institutes of Health
(CA-87503). For a part of his graduate school career, T.L.M.
OL026849X
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Org. Lett., Vol. 4, No. 24, 2002