Synthesis of Annulated γ-Carbolines by Palladium-Catalyzed Intramolecular Iminoannulation

Article abstract of DOI:10.1021/ol026255u

(Equation Presented) A variety of N-substituted 2-bromo-1H-indole-3-carboxaldehydes incorporating an alkyne-containing tether on the indole nitrogen have been converted to the corresponding tert-butylimines, which have been subjected to palladium-catalyze

Full text of DOI:10.1021/ol026255u

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3035-3038
Synthesis of Annulated γ-Carbolines by
Palladium-Catalyzed Intramolecular
Iminoannulation
Haiming Zhang and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received May 29, 2002
ABSTRACT
A variety of N-substituted 2-bromo-1H-indole-3-carboxaldehydes incorporating an alkyne-containing tether on the indole nitrogen have been
converted to the corresponding tert-butylimines, which have been subjected to palladium-catalyzed intramolecular iminoannulation, affording
various annulated γ-carbolines in excellent yields.
Pyrido[4,3-b]-5H-indoles, commonly known as γ-carbolines,
which are condensed analogues of the ellipticine/olivacine
anticancer agents, have been studied extensively because of
their potential biological and pharmaceutical importance.1
However, there are relatively few synthetic studies of
γ-carboline derivatives having wide scope and generality,2
and the synthesis of new alkaloid derivatives of γ-carboline
with an additional ring fused across the 4- and 5-positions
is rare.3 Two closely related examples of this type of
heteropolycyclic system having interesting biological activity
are the pentacyclic γ-carboline 1, which is a cardiovascular
agent,4 and the indolonaphthyridone 2, which acts as a
conformationally restricted 5-HT3 receptor antagonist.5
Annulation processes have proven to be very useful in
organic synthesis due to the ease with which a wide variety
of complicated carbocycles and heterocarbocycles can be
rapidly constructed. In our own laboratories, it has been
demonstrated that palladium-catalyzed annulation methods6
can be effectively employed for the synthesis of indoles,7
isoindolo[2,1-a]indoles,8 benzofurans,9 benzopyrans,9 iso-
coumarins,9,10 R-pyrones,10,11 indenones,12 pyridines,13 iso-
quinolines,13 and polycyclic aromatic hydrocarbons.14 How-
(1) (a) Saxton, J. E. In The Chemistry of Heterocyclic Compounds;
Taylor, E. D., Ed.; Wiley-Interscience: New York, 1994; Vol. 25. (b)
Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic Press: San
Diego, 1990; Vol. 39, Chapter 7. (c) Tan, G. T.; Pezzuto, J. M. In Chemistry
and Toxicology of DiVerse Classes of Alkaloids; Blum, M. S., Ed.; Alaken,
Inc.: Fort Collins, CO, 1996; pp 1-119.
(2) (a) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444. (b)
Sakamoto, T.; Numata, A.; Saitoh, H.; Kondo, Y. Chem. Pharm. Bull. 1999,
47, 1740. (c) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla,
J.; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J.
Org. Chem. 1996, 61, 5587. (d) Hibino, S.; Sugino, E.; Kuwada, T.; Ogura,
N.; Sato, K.; Choshi, T. J. Org. Chem. 1992, 57, 5917. (e) Hibino, S.; Kano,
S.; Mochizuki, N.; Sugino, E. J. Org. Chem. 1984, 49, 5006. (f) Prikhod’ko,
T. A.; Vasilevskii, S. F.; Shvartsberg, M. S. Bull. Acad. Sci. USSR, DiV.
Chem. Sci. 1984, 33, 2383.
(3) (a) Snyder, S. A.; Vosburg, D. A.; Jarvis, M. G.; Markgraf, J. H.
Tetrahedron 2000, 56, 5329. (b) Markgraf, J. H.; Snyder, S. A.; Vosburg,
D. A. Tetrahedron Lett. 1998, 39, 1111. (c) Gilchrist, T. L.; Kemmitt, P.
D.; Germain, A. L. Tetrahedron 1997, 53, 4447. (d) Gilchrist, T. L.;
Kemmitt, P. D.; Germain, A. L. Heterocycles 1994, 37, 697. (e) Shimoji,
Y.; Hashimoto, T.; Furukawa, Y.; Yanagisawa, H. Heterocycles 1993, 36,
123.
(4) Yanagisawa, H.; Shimoji, Y.; Hashimoto, T. Jpn. Kokai Tokkyo Koho
JP 05310738, 1993, Heisei; Chem. Abstr. 1994, 120, 245056.
(5) Clark, R. D.; Miller, A. B.; Berger, J.; Repke, D. B.; Weinhardt, K.
K.; Kowalczyk, B. A.; Eglen, R. M.; Bonhaus, D. W.; Lee, C.-H.; Michel,
A. D.; Smith, W. L.; Wong, E. H. F. J. Med. Chem. 1993, 36, 2645.
(6) For reviews, see: (a) Larock, R. C. J. Organomet. Chem. 1999, 576,
111. (b) Larock, R. C. Palladium-Catalyzed Annulation. In PerspectiVes in
Organopalladium Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier
Press: Lausanne, Switzerland, 1999; pp 111-124. (c) Larock, R. C. Pure
Appl. Chem. 1999, 71, 1435.
10.1021/ol026255u CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/15/2002

ever, palladium-catalyzed intramolecular annulation has not
been well explored mainly because of the difficulty of
assembling a halide, a carbon-carbon triple bond, and other
necessary elements into the appropriate positions into a single
molecule.15
We were excited to see that under these reaction conditions,
the palladium-catalyzed intramolecular iminoannulation pro-
duced a 93% yield of the desired γ-carboline 4a in only 10
h (Table 1, entry 1). It is noteworthy that transformation of
the aldehydes to the corresponding tert-butylimines is
essentially quantitative, requiring no further purification and
characterization of the starting imines used for the subsequent
palladium-catalyzed annulation, as we have observed in our
previous work.16,17 Thus, by employing a one-pot protocol,
namely imine formation, followed by a palladium-catalyzed
intramolecular iminoannulation, we have been able to
synthesize a variety of annulated γ-carbolines (Scheme 1).
The results of this investigation are summarized in Table 1.
As seen in Table 1, by employing 2-bromo-1H-indole-3-
carboxaldehydes with a trimethylene tether from the indole
nitrogen to the carbon-carbon triple bond, the parent
isocanthine skeleton3a,b can be readily constructed (entries
1-5). This route allows easy access to a variety of substituted
isocanthine derivatives and tolerates various functional
groups. For example, tethered indoles 3a-e containing aryl,
alkyl, hydroxy, ether, ester, and pyrimidyl functionalities all
afforded the desired annulation products 4a-e in excellent
yields (entries 1-5).
Recently, we have developed a general synthesis of 3,4-
disubstituted â- and γ-carbolines by the palladium-catalyzed
iminoannulation of internal acetylenes.16 While certain â-
and γ-carbolines could be prepared in good to excellent
yields, the regioselectivity of the reaction was too sensitive
to the nature of the internal acetylenes to be of broad
applicability.16 Alternatively, by readily incorporating an
alkyne-containing tether onto the indole nitrogen, subsequent
palladium-catalyzed intramolecular iminoannulation should
enable regioselective construction of two rings in a single
step and provide the well-recognized entropic advantage of
promoting stubborn reactions. Our own interest in carboline
synthesis therefore prompted us to examine the synthesis of
a variety of annulated γ-carbolines. Herein, we report the
successful synthesis of various annulated γ-carbolines by
palladium-catalyzed intramolecular iminoannulation (Scheme
1).
Interestingly, by employing indole 3f with a tetramethylene
tether, we have been able to isolate an annulated γ-carboline
4f with a seven-membered ring fused to the 4- and 5-posi-
tions in a 90% yield (entry 6). We have also been able to
obtain an annulated γ-carboline 4g with a five-membered
ring in a 91% yield, by employing indole 3g with a
dimethylene tether (entry 7). It is worth noting that ring
systems similar to carbolines 4f and 4g have never been
efficiently prepared by either an intramolecular Diels-Alder
reaction18 or electrocyclization of a 1-azatriene,3c since those
reactions require significant straining of the tether to achieve
the necessary transition-state geometry, especially in the case
of a five-five ring juncture.
Furthermore, other types of tethers have also proven to
be successful in this intramolecular annulation chemistry.
For example, both indole 3h with a tether containing an aryl
moiety and indole 3i with a tether incorporating a cyclo-
pentenyl group afforded the desired annulated γ-carbolines
4h and 4i in 88 and 94% yields, respectively (entries 8 and
9).
Scheme 1
The tert-butylimine of indole 3a was first prepared and
employed in the palladium-catalyzed intramolecular imi-
noannulation under the reaction conditions used in our earlier
intermolecular γ-carboline synthesis.16 Considering that an
intramolecular reaction might provide an entropic advantage,
we decreased the reaction temperature from 125 to 100 °C.
(7) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(8) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551. (b) Roesch,
K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412.
(9) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270.
(10) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
(11) Larock, R. C.; Han, X.; Doty, M. J. Tetrahedron Lett. 1998, 39,
5713.
Unfortunately, all efforts to prepare N-substituted 2-bromo-
1H-indole-3-carboxaldehydes with an amide linkage have
been unsuccessful so far. Therefore, annulated γ-carbolines
bearing an amide linkage have yet to be prepared by this
protocol.
(12) Larock, R. C.; Doty, M. J.; Cacchi, S. J. J. Org. Chem. 1993, 58,
4579.
Interestingly, the palladium-catalyzed intramolecular an-
nulation of aldehyde 3f itself under the conditions of our
earlier indenone synthesis12 has generated a 48% yield of
heterocycle 5a, which apparently arises from tautomerization
of the anticipated less stable heterocycle 5b (Scheme 2).
Similar tautomerization has also been observed in our
intermolecular indenone synthesis.12 Unfortunately, the pal-
(13) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. (b)
Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042.
(14) (a) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org. Chem.
1997, 62, 7536. (b) Larock, R. C.; Tian, Q. J. Org. Chem. 1998, 63, 2002.
(15) To the best of our knowledge, this is the first example of palladium-
catalyzed intramolecular annulation involving a halide, a carbon-carbon
triple bond, and a nucleophile in the same molecule. For palladium-catalyzed
intramolecular benzoannulations, see: (a) Kawasaki, T.; Saito, S.; Yama-
moto, Y. J. Org. Chem. 2002, 67, 2653. (b) Weibel, D.; Gevorgyan, V.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 1217. (c) Saito, S.; Tsuboya, N.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 5042. For other palladium-catalyzed
intramolecular annulations, see: (d) Hu, Y.; Yang, Z. Org. Lett. 2001, 3,
1387. (e) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454.
(16) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083.
(17) Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359.
(18) Benson, S. C.; Li, J.-H.; Snyder, J. K. J. Org. Chem. 1992, 57,
5285.
3036
Org. Lett., Vol. 4, No. 18, 2002

Table 1. Synthesis of Annulated γ-Carbolines by Palladium-Catalyzed Intramolecular Iminoannulationa
a Representative procedure: the aldehyde (0.25 mmol) and tert-butylamine (1 mL) were placed in a 2 dram vial. The vial was flushed with Ar and
carefully sealed, and the mixture was heated at 100 °C for 8 h. The mixture was cooled, diluted with ether, and dried over anhydrous Na2SO4, and the solvent
was evaporated. The residue was dissolved in 5 mL of DMF and transferred to a 4 dram vial containing 5 mol % Pd(OAc)2, 10 mol % PPh3, and Na2CO3
(0.25 mmol). The mixture was then flushed with Ar and heated at 100 °C for the indicated time.
ladium-catalyzed intramolecular annulation of aldehyde 3f
under the conditions of Yamamoto’s indenol synthesis19 did
not afford any significant yield of the desired alcohol or the
tautomeric ketone.
We proposed a mechanism for this palladium-catalyzed
intramolecular iminoannulation chemistry that is similar to
that of our earlier intermolecular iminoannulations.13,16
Specifically, oxidative addition of the indole bromide to Pd-
(0) produces an organopalladium intermediate, which then
intramolecularly adds across the tethered carbon-carbon
triple bond by an exo-dig addition, producing a vinylic
palladium intermediate, which then reacts with the neighbor-
ing imine substituent to form a seven-membered palladacy-
clic immonium ion salt. Subsequent reductive elimination
produces a tert-butylcarbolinium salt and regenerates Pd(0).
As previously suggested by Heck,20 the tert-butyl group
apparently fragments to relieve the strain resulting from
interaction with the substituent present on the neighboring
carbon.
(20) (a) Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organome-
tallics 1987, 6, 1941. (b) Wu, G.; Geib, S. J.; Rheingold, A. L.; Heck, R.
F. J. Org. Chem. 1988, 53, 3238.
(19) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999,
40, 4089.
Org. Lett., Vol. 4, No. 18, 2002
3037

yields. This chemistry has also been extended to palladium-
catalyzed intramolecular carboannulation, which produces
the desired heterocycle in a moderate yield. Further inves-
tigation into the scope and limitations of this palladium-
catalyzed intramolecular iminoannulation and extensions to
other intramolecular annulation chemistry are under way.
Scheme 2
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research and Johnson Matthey, Inc., and Kawaken Fine
Chemicals Co., Ltd., for donations of palladium acetate.
Supporting Information Available: General experimen-
tal procedures and spectral data for ketone 5a and the
compounds listed in Table 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, an efficient synthesis of various annulated
γ-carbolines by palladium-catalyzed intramolecular imino-
annulation has been developed. A wide variety of function-
alized 2-bromo-1H-indole-3-carboxaldehydes participate in
this process to afford the desired γ-carbolines in excellent
OL026255U
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Org. Lett., Vol. 4, No. 18, 2002