Synthesis of annulated γ-carbolines and heteropolycycles by the palladium-catalyzed intramolecular annulation of alkynes

Article abstract of DOI:10.1021/jo0343228

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 imin

Full text of DOI:10.1021/jo0343228

Syn th esis of An n u la ted γ-Ca r bolin es a n d Heter op olycycles by th e
P a lla d iu m -Ca ta lyzed In tr a m olecu la r An n u la tion of Alk yn es
Haiming Zhang and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received March 11, 2003
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
γ-carboline derivatives with an additional ring fused across the 4- and 5-positions in good to excellent
yields. When the tethered carbon-carbon triple bond is terminal or substituted with a triethylsilyl
group, the iminoannulation generates a tert-butyl-γ-carbolinium salt as the major product. The
palladium-catalyzed intramolecular annulations of N-substituted 2-bromo-1H-indole-3-carboxal-
dehyde, methyl 2-iodo-1H-indole-3-carboxylate, and 2-iodo-3-phenyl-1H-indole containing a phen-
ylpentynyl tether produce the corresponding heteropolycycles in moderate to good yields.
In tr od u ction
Pyrido[4,3-b]-5H-indoles, commonly known as γ-car-
bolines, which are condensed analogues of the ellipticine/
olivacine anticancer agents, have been studied exten-
sively because of their potential pharmaceutical impor-
tance.12 However, there are relatively few synthetic
studies of γ-carboline derivatives having wide scope and
generality,12,13 and the synthesis of new alkaloid deriva-
tives of γ-carboline with an additional ring fused across
the 4- and 5-positions is rare.14 Two closely related
examples of this type of heteropolycyclic system having
interesting biological activity are the pentacyclic γ-car-
boline 1, which is a cardiovascular agent,15 and the
Annulation processes have proven to be very useful in
organic synthesis due to the ease with which a wide
variety of complex carbocycles and heterocycles can be
rapidly constructed. In our own laboratories, it has been
demonstrated that palladium-catalyzed annulation meth-
odology1 can be effectively employed for the synthesis of
indoles,2 isoindolo[2,1-a]indoles,3 benzofurans,4 benzo-
pyrans,4 isocoumarins,4,5 R-pyrones,5,6 indenones,7 py-
ridines,8 isoquinolines,8 naphthalenes,9 and polycyclic
aromatic hydrocarbons.10 However, intramolecular pal-
ladium-catalyzed annulation has not been well-explored
mainly because of the difficulty of assembling a halide,
a carbon-carbon triple bond, and other necessary ele-
ments into the appropriate positions into a single starting
material.11
(11) For palladium-catalyzed intramolecular benzoannulations,
see: (a) Kawasaki, T.; Saito, S.; Yamamoto, 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 annu-
lations, see: (d) Hu, Y.; Yang, Z. Org. Lett. 2001, 3, 1387. (e) Piers, E.;
Marais, P. C. J . Org. Chem. 1990, 55, 3454.
(1) 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.
(2) (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.
(3) (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.
(4) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org.
Chem. 1995, 60, 3270.
(5) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(6) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett. 1998, 39,
5713.
(7) Larock, R. C.; Doty, M. J .; Cacchi, S. J . Org. Chem. 1993, 58,
4579.
(8) (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.
(9) (a) Huang, Q.; Larock, R. C. Org. Lett. 2002, 4, 2505. (b) Tian,
Q.; Pletnev, A. A.; Larock, R. C. J . Org. Chem. 2003, 68, 339.
(10) (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.
(12) (a) Saxton, J . E. In The Chemistry of Heterocyclic Compounds;
Taylor, E. D., Ed.; Wiley-Intersciences Publication: New York, 1994;
Vol. 25. (b) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic
Press: San Diego, CA, 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.
(13) (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. J . Acad. Sci. USSR, Org. Chem. 1984, 11, 2383.
(14) (a) Snyder, S. A.; Vosburg, D. A.; J arvis, 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.
(15) Yanagisawa, H.; Shimoji, Y.; Hashimoto, T. J pn. Kokai Tokkyo
Koho J P 05310738, 1993, Heisei; Chem. Abstr. 1994, 120, 245056.
10.1021/jo0343228 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003
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J . Org. Chem. 2003, 68, 5132-5138

Annulated γ-Carbolines and Heteropolycycles
SCHEME 2
indolonaphthyridone 2, which acts as a conformationally
restricted 5-HT3 receptor antagonist.16
Syntheses of annulated γ-carboline alkaloids have
typically employed electrocyclic ring closures of 1-aza-
trienes,14c,d or intramolecular Diels-Alder reactions.14a,b,e
However, both methods afford the desired γ-carbolines
in relatively low yields. Recently, we have developed a
general synthesis of 3,4-disubstituted â- and γ-carbolines
by the palladium-catalyzed iminoannulation of acetylenes
(Scheme 1).17 While certain â- and γ-carbolines could be
palladium-catalyzed annulations to synthesize various
complex heteropolycycles.
Resu lts a n d Discu ssion
In the early stage of our investigation, we were focused
on finding a general, high-yielding method to prepare
N-substituted 2-bromo-1H-indole-3-carboxaldehydes bear-
ing a tether with a carbon-carbon triple bond for the
palladium-catalyzed intramolecular iminoannulation. The
alkylation and acylation of 1H-indole-3-carboxaldehyde
to prepare alkyne-tethered indole-3-carboxaldehydes have
been reported previously.14a,b We anticipated that 2-bromo-
1H-indole-3-carboxaldehyde17 would undergo a similar
process and were delighted to observe that 2-bromo-1H-
indole-3-carboxaldehyde reacts readily with the appropri-
ate chlorides or bromides bearing a carbon-carbon triple
bond in the presence of NaI and K2CO3 in acetone,
affording the desired tethered indoles 3 in excellent yields
in most cases (Method A in Scheme 2, see Table 1 and
the Supporting Information for details). Relatively low
yields were obtained only when the halide contains a
conjugated enyne, which might be unstable under the
reaction conditions (compare 3c, 3p , and 3q with others).
An alternative method employing the Mitsunobu reac-
tion19 of 2-bromo-1H-indole-3-carboxaldehyde with steri-
cally unhindered alcohols containing a carbon-carbon
triple bond has also generated good to excellent yields of
the corresponding tethered indoles (Method B in Scheme
2, also see Table 1 and the Supporting Information for
details). However, when relatively sterically hindered
alcohols were employed, the corresponding Mitsunobu
reaction only produced moderate yields of the desired
tethered indoles (compare 3n -p with the others). The
acylation of 2-bromo-1H-indole-3-carboxaldehyde has
proven more difficult. After several unsuccessful at-
tempts, we finally managed to couple 2-bromo-1H-indole-
3-carboxaldehyde with 2-(phenylethynyl)benzoic acid in
SCHEME 1
prepared in good to excellent yields, the regioselectivity
of the reaction was too sensitive to the nature of the
alkynes to be of broad applicability.17 Alternatively, by
readily incorporating an alkyne-containing tether onto
the indole nitrogen, subsequent palladium-catalyzed
intramolecular iminoannulation would enable regio-
selective construction of two rings in a single step, and
provide a well-recognized entropic advantage (eq 1). Our
own interest in carboline synthesis therefore prompted
us to examine the synthesis of a variety of annulated
γ-carbolines. A brief communication of this study has
been reported previously.18 Herein, we wish to report the
full details of the palladium-catalyzed intramolecular
iminoannulation to synthesize annulated γ-carbolines,
and extension of this “intramolecular” concept to other
(16) 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.
(17) (a) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083. (b) Zhang,
H.; Larock, R. C. J . Org. Chem. 2002, 67, 9318.
(18) Zhang, H.; Larock. R. C. Org. Lett. 2002, 4, 3035.
J . Org. Chem, Vol. 68, No. 13, 2003 5133

Zhang and Larock
TABLE 1. Syn th esis of An n u la ted γ-Ca r bolin es by P a lla d iu m -Ca ta lyzed In tr a m olecu la r Im in oa n n u la tion (eq 3)a
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 % of Pd(OAc)2, 10 mol % of PPh3, and Na2CO3 (0.25 mmol). The mixture was then flushed with Ar and heated at 100 °C for the
b
indicated time. n-Bu3N (0.25 mmol) instead of Na2CO3 was used as the base. c The amide bond was dissociated during the imine
preparation.
5134 J . Org. Chem., Vol. 68, No. 13, 2003

Annulated γ-Carbolines and Heteropolycycles
SCHEME 3
ene tether from the indole nitrogen to the carbon-carbon
triple bond, the parent isocanthine skeleton14a can be
readily constructed (entries 1-6). This route allows easy
access to a variety of substituted isocanthine derivatives
and tolerates various functional groups. For example,
tethered indoles 3a -f containing aryl, alkyl, alkenyl,
hydroxy, ester, and pyrimidyl functionalities all afforded
the desired annulation products 4a -f in excellent yields
(entries 1-6). Unfortunately, indole 3g containing a
triethylsilyl group did not generate the desired silyl-
substituted isocanthine derivative. Instead, a desilylated
γ-carbolinium salt with a tert-butyl group on the nitrogen
(4g) was isolated in a 53% yield, along with a 40% yield
of the desilylated isocanthine 4h (entry 7). Tethered
indole 3h with a terminal carbon-carbon triple bond also
afforded the same γ-carbolinium salt 4g as in the silyl
case in a 72% yield, as well as a 10% yield of isocanthine
(4h ) as the minor product (entry 8, also see the later
discussion). As we expected, tethered indole 3i readily
underwent a double intramolecular iminoannulation,
generating a complex isocanthine derivative 4i in an
excellent 91% yield (entry 9).
the presence of DCC and DMAP,20 which only afforded a
50% yield of the desired product 3r (eq 2). Unfortunately,
2-(1-octynyl)benzoic acid and 5-phenylpent-4-ynoic acid
failed to give any significant amount of the products
under the same reaction conditions.
Similarly, a phenylpentynyl tether has also been
successfully incorporated onto the nitrogen of methyl
2-iodo-1H-indole-3-carboxylate, 2-iodo-3-phenyl-1H-in-
dole,21 2-bromo-1H-indole-3-acetonitrile,22 and 2-iodo-1H-
indole-3-acetonitrile by employing the corresponding
2-haloindoles and 5-chloro-1-phenyl-1-pentyne in the
presence of NaI and K2CO3 or Cs2CO3 in acetone (Scheme
3).
The tert-butylimine of indole 3a was first prepared and
employed in the intramolecular palladium-catalyzed imi-
noannulation under the reaction conditions used in our
earlier intermolecular γ-carboline synthesis.17 Consider-
ing that an intramolecular reaction might provide an
entropic advantage, we lowered the reaction temperature
from 125 °C to 100 °C. We were pleased to see that under
these reaction conditions, the palladium-catalyzed in-
tramolecular iminoannulation produced a 93% yield of
the desired γ-carboline 4a in only 10 h (Table 1, entry
1). It is noteworthy that the preparation of the tert-
butylimines from the corresponding aldehydes is es-
sentially 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.17,23 Thus, by employing a
two-step protocol, namely imine formation, followed by
palladium-catalyzed intramolecular iminoannulation with-
out isolation of the intermediate imine, we have been able
to prepare a variety of annulated γ-carbolines and
investigate the scope and limitations of this process (eq
3). The results of this investigation are summarized in
Table 1.
Interestingly, by employing indole 3j with a tetra-
methylene tether, we have been able to isolate an
annulated γ-carboline 4j with a seven-membered ring
fused to the 4- and 5-positions in a 90% yield (entry 10).
We have also been able to obtain annulated γ-carbolines
4k and 4l with a five-membered ring fused across the 4-
and 5-positions in 84% and 91% yields, by employing
indoles 3k and 3l with a dimethylene tether, respectively
(entries 11 and 12). It is worth noting that ring systems
similar to carbolines 4j,k ,l have never been efficiently
prepared by either an intramolecular Diels-Alder reac-
tion24 or the electrocyclization of a 1-azatriene,14c since
those reactions require significant strain of the tether to
achieve the necessary transition-state geometry, espe-
cially for the case of a five-five ring juncture. Unfortu-
nately, our attempt to achieve a 12-membered ring fused
γ-carboline by employing tethered indole 4m failed to give
any significant amount of the desired product (entry 13).
A messy reaction with inseparable multiple products
occurred. Presumably because of the entropic disadvan-
tage of forming a 12-membered ring, the competitive
intermolecular annulation in this case is significant
enough to produce multiple byproducts.
Other types of tethers have also proven to be successful
in this intramolecular annulation chemistry. For ex-
ample, indoles 3n and 3o with a tether containing an
aryl moiety afforded the desired annulated γ-carbolines
4n and 4o in 88% and 75% yields, respectively (entries
14 and 15). Indoles 3p and 3q with a tether incorporating
an alkene moiety also afforded the desired annulated
γ-carbolines 4p and 4q in 57% and 94% yields, respec-
tively. The relatively low yield of γ-carboline 4p may be
attributable to the fact that the (Z)-enyne moiety in
As seen from Table 1, by employing N-substituted
2-bromo-1H-indole-3-carboxaldehydes with a trimethyl-
(19) For recent reviews of the Mitsunobu reaction, see: (a) Dodge,
J . A.; J ones, S. A. Recent Res. Dev. Org. Chem. 1997, 1, 273. (b) Simon,
C.; Hosztafi, S.; Makleit, S. J . Heterocycl. Chem. 1997, 34, 349. (c)
Hughes, D. L. Org. Prep. Proced. Inter. 1996, 28, 127. (d) Hughes, D.
L. Org. React. 1992, 42, 335.
(20) For a similar acylation of 1H-indole-3-carboxaldehyde, see:
Kraus, G. A.; Kim. H. Synth. Commun. 1993, 23, 55.
(22) Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett. 1986,
27, 1051.
(23) (a) Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359.
(b) Zhang, H.; Larock, R. C. J . Org. Chem. 2002, 67, 7048.
(24) Benson, S. C.; Li, J .-H.; Snyder, J . K. J . Org. Chem. 1992, 57,
5285.
(21) Campo, M. A.; Larock, R. C. J . Org. Chem. 2002, 67, 5616.
J . Org. Chem, Vol. 68, No. 13, 2003 5135

Zhang and Larock
SCHEME 4
Now it is easy to understand why tethered indole 3h
containing a terminal carbon-carbon produced the tert-
butylcarbolinium salt 4g as the major product. In this
case, the tert-butylcarbolinium salt is unable to fragment
the tert-butyl group due to the lack of strain between the
tert-butyl group and the neighboring hydrogen. The
observed small amount (10%) of product 4h , absent of a
tert-butyl group, presumably arises from thermal frag-
mentation of the tert-butyl group.
It is also understandable that tethered indole 3g
bearing a triethylsilyl-substituted carbon-carbon triple
bond generated a mixture of the desilylated tert-butyl-
carbolinium salt and isocanthine 4h . In this case, the tert-
butylcarbolinium intermediate with a tert-butyl and a
triethylsilyl group on adjacent atoms might undergo
either protodesilylation to give the tert-butylcarbolinium
salt 4g (53%) without the silyl group or fragmentation
of the tert-butyl group to give a silyl-substituted isocan-
thine derivative, which finally protodesilylates under the
reaction conditions to give isocanthine 4h (40%).
Encouraged by the success of our palladium-catalyzed
intramolecular iminoannulation, we have also examined
several other types of palladium-catalyzed intramolecular
annulation. To our disappointment, the intramolecular
annulation of aldehydes 3a and 3n under the conditions
of our earlier indenone synthesis7 did not generate
significant amounts of the desired heterocycles (eq 4),
indole 3p can isomerize25 or undergo side reactions11a-c
in the presence of a palladium catalyst. Consistent with
this hypothesis is the fact that the more highly substi-
tuted enyne 3q gives an excellent yield.
Unfortunately, indole 3r having an amide linkage
underwent transamidation during imine preparation.
Therefore, this palladium-catalyzed intramolecular
iminoannulation methodology is limited to those tethered
indoles with a CH2-N bond linkage. Our attempts to
oxidize isocanthine 4a to the corresponding isocanthin-
6-one using benzyltriethylammonium permanganate26
(BTAP), which has been used to oxidize amines to
amides26 and employed to oxidize canthine derivatives
to their corresponding canthin-6-ones,27 also failed to give
any significant amount of the desired product.
We propose a mechanism for this palladium-catalyzed
intramolecular iminoannulation chemistry, which is simi-
lar to our earlier intermolecular annulation (Scheme
4).8,17 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 through an exo-dig addition,
producing a vinylic palladium intermediate, which then
reacts with the neighboring imine substituent to form a
seven-membered palladacyclic immonium ion salt. Sub-
sequent reductive elimination produces a tert-butylcar-
bolinium salt and regenerates Pd(0). As previously
suggested by Heck,28 the tert-butyl group apparently
fragments to relieve the strain resulting from the inter-
action with the substituent present on the neighboring
carbon.
presumably because the desired products having a five-
five-six ring juncture are too strained to form or too
unstable under the reaction conditions. Interestingly, by
simply increasing the length of the linkage, the pal-
ladium-catalyzed intramolecular annulation of aldehyde
3j has generated a 48% yield of heterocycle 5a with a
five-five-seven ring juncture, which apparently arises
from tautomerization of the anticipated less stable
heterocycle 5b (Scheme 5). Similar tautomerization has
also been previously observed in our indenone synthesis.7
Unfortunately, the palladium-catalyzed intramolecular
annulation of aldehyde 3j under the conditions of Yama-
SCHEME 5
(25) For a recent review on the palladium-catalyzed isomerization
of double bonds, see: Negishi, E.-I. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; J ohn Wiley &
Sons: New York, 2002; Vol. 2, pp 2783-2788.
(26) (a) Schmidt, H.-J .; Schaefer, H. J . Angew. Chem., Int. Ed. Engl.
1979, 18, 68. (b) Schmidt, H.-J .; Schaefer, H. J . Angew. Chem., Int.
Ed. Engl. 1981, 20, 109.
(27) Li, J .-H.; Snyder, J . K. Tetrahedron Lett. 1994, 35, 1485.
(28) (a) Wu, G.; Rheingold, A. L.; Geib, S. J .; Heck, R. F. Organo-
metallics 1987, 6, 1941. (b) Wu, G.; Geib, S. J .; Rheingold, A. L.; Heck,
R. F. J . Org. Chem. 1988, 53, 3238.
5136 J . Org. Chem., Vol. 68, No. 13, 2003

Annulated γ-Carbolines and Heteropolycycles
SCHEME 6
3-carboxylate, and 2-iodo-3-phenyl-1H-indole containing
an alkyne tether have undergone palladium-catalyzed
intramolecular annulation, producing the corresponding
heteropolycycles in moderate to good yields. However,
none of the desired products were observed in the
palladium-catalyzed intramolecular annulation of an
alkyne-tethered 2-bromo-1H-indole-3-acetonitrile or 2-iodo-
1H-indole-3-acetonitrile.
Exp er im en ta l Section
Compounds 3a ,b,d -f,j,l,n ,q, 4a ,b,d -f,j,l,n ,q, and 5a have
been previously reported.18 2-Iodo-3-phenyl-1H-indole was
prepared according to a literature procedure.21 The preparation
and characterization of the starting materials and methyl
2-iodo-1H-indole-3-carboxylate and 2-iodo-1H-indole-3-aceto-
nitrile can be found in the Supporting Information.
Gen er a l P r oced u r e for th e Syn th esis of N-Su bstitu ted
2-Br om o-1H-in d ole-3-ca r boxa ld eh yd es. Meth od A: 2-Bro-
mo-1H-indole-3-carboxaldehyde17 (0.5 mmol), the alkynyl ha-
lide (0.6 mmol), NaI (0.75 mmol), and K2CO3 (0.75 mmol) were
placed in a 4-dram vial and acetone (3 mL) was added. The
vial was flushed with Ar and heated in an oil bath at 75 °C
for 24 h. The mixture was cooled and diluted with ether (5
mL). The precipitate was removed by filtration and the solvent
was evaporated. The residue was purified by chromatography
on a silica gel column. Meth od B: To a mixture of 2-bromo-
1H-indole-3-carboxaldehyde (0.5 mmol), the alkynyl alcohol
(0.6 mmol), and PPh3 (0.75 mmol) in CH2Cl2 (8 mL) was added
diethyl azodicarboxylate (0.75 mmol) at 0 °C. The resulting
mixture was flushed with Ar and stirred at room temperature
for 24 h. The mixture was concentrated and the residue was
purified by chromatography on a silica gel column.
P r ep a r a tion of N-Su bstitu ted 2-Br om o-1H-in d ole-3-
ca r boxa ld eh yd es: 2-Br om o-1-[(E)-7-p h en ylh ep t-6-en -4-
yn yl]-1H-in d ole-3-ca r boxa ld eh yd e (3c). This compound
was prepared with use of (E)-7-chloro-1-phenylhept-1-en-3-yne
according to Method A. The product was purified with 4:1
hexanes/EtOAc to afford 147 mg (75%) of the indicated
compound as a yellow oil: 1H NMR (CDCl3) δ 2.09 (quintet, J
) 7.2 Hz, 2H), 2.48 (dt, J ) 2.1, 7.2 Hz, 2H), 4.42 (t, J ) 7.2
Hz, 2H), 6.16 (dt, J ) 16.2, 2.1 Hz, 1H), 6.90 (d, J ) 16.2 Hz,
1H), 7.25-7.46 (m, 8H), 8.33 (m, 1H), 10.04 (s, 1H); 13C NMR
(CDCl3) δ 17.4, 28.7, 44.5, 81.5, 90.5, 108.4, 110.1, 115.7, 121.5,
123.6, 124.4, 125.6, 125.8, 126.4, 128.8, 129.0, 136.5, 137.1,
141.2, 185.6; IR (neat, cm-1) 3017, 2926, 1654; HRMS calcd
for C22H18BrNO 391.0572, found 391.0579.
moto’s indenol synthesis29 did not afford any significant
yield of the desired alcohol or the tautomeric ketone.
To our great satisfaction, the intramolecular annula-
tion of alkyne-tethered methyl 2-iodo-1H-indole-3-car-
boxylate 3s under the conditions of our earlier isocou-
marin synthesis4,5 smoothly produced a 52% yield of the
desired heterocycle 5c (Scheme 6). Equally exciting was
the fact that the intramolecular annulation of indole 3t
under the conditions of our earlier phenanthrene syn-
thesis10 also generated the desired annulation product
5d in a 68% yield (Scheme 6). However, neither the
2-bromoindole 3u nor 2-iodoindole 3v containing aceto-
nitrile functionality generated any of the desired carba-
zole 5e under the conditions of our earlier palladium-
catalyzed aminonaphthalene synthesis (Scheme 6).9b
Messy reactions were observed in both cases. One pos-
sible reason is that the 2-haloindoles might be reduced
to the corresponding indoles under the reaction condi-
tions, as previously observed in our own laboratory.30
2-Br om o-1-(4-p h en ylbu t-3-yn yl)-1H-in d ole-3-ca r boxa l-
d eh yd e (3k ). This compound was prepared with use of
4-phenylbut-3-yn-1-ol according to method B. The product was
purified with 3:1 hexanes/EtOAc to afford 161 mg (92%) of the
indicated compound as a yellow solid: mp 104-105 °C; 1H
NMR (CDCl3) δ 2.95 (t, J ) 7.2 Hz, 2H), 4.53 (t, J ) 7.2 Hz,
2H), 7.24-7.33 (m, 7H), 7.46 (m, 1H), 8.34 (m, 1H), 10.05 (s,
1H); 13C NMR (CDCl3) δ 20.6, 44.0, 83.6, 84.8, 110.0, 115.7,
121.4, 122.8, 123.5, 124.2, 125.4, 125.6, 128.2, 128.3, 131.5,
136.8, 185.6; IR (neat, cm-1) 3055, 3017, 2807, 2237, 1652;
HRMS calcd for C19H14BrNO 351.0259, found 351.0265.
The preparation and characterization of all other tethered
indoles can be found in the Supporting Information.
Gen er a l P r oced u r e for th e Syn th esis of An n u la ted
γ-Ca r b olin es b y P a lla d iu m -Ca t a lyzed In t r a m olecu la r
Im in oa n n u la tion . The N-substituted 2-bromo-1H-indole-3-
carboxaldehyde (0.25 mmol) was placed in a 2-dram vial and
tert-butylamine (1 mL) was added. The vial was flushed with
Ar and carefully sealed. The mixture was heated at 100 °C
for 8 h and cooled, diluted with ether, dried over anhydrous
Na2SO4, and filtered. The solvent was evaporated and the
residue was dissolved in DMF (5 mL) and transferred to a
4-dram vial containing Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
and Na2CO3 (0.25 mmol). The mixture was flushed with Ar
Con clu sion s
In conclusion, a number of N-substituted 2-bromo-1H-
indole-3-carboxaldehydes bearing a tether with a carbon-
carbon triple bond have been prepared, and an efficient
synthesis of various annulated γ-carbolines by imination
of these aldehydes, followed by palladium-catalyzed
intramolecular iminoannulation has been developed. A
wide variety of functionalized 2-bromo-1H-indole-3-car-
boxaldehydes participate in this process to afford the
desired γ-carbolines in good to excellent yields. When the
tethered carbon-carbon triple bond is terminal or sub-
stituted with a silyl group, the iminoannulation generates
a tert-butyl-γ-carbolinium salt as the major product. This
chemistry has also been extended to other palladium-
catalyzed intramolecular annulations. An N-substituted
2-bromo-1H-indole-3-carboxaldehyde, 2-iodo-1H-indole-
(29) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett.
1999, 40, 4089.
(30) (a) Pletnev, A. A.; Larock, R. C. J . Org. Chem. 2002, 67, 9428.
(b) Pletnev, A. A.; Tian, Q.; Larock, R. C. J . Org. Chem. 2002, 67, 9276.
J . Org. Chem, Vol. 68, No. 13, 2003 5137

Zhang and Larock
and heated at 100 °C for the indicated time. The completion
of the reaction was established by the observation of palladium
black. The mixture (except for entries 4 and 6-8 in Table 1,
which produce reasonably water soluble products) was diluted
with EtOAc, washed with satd aq NH4Cl, and dried over
anhydrous Na2SO4. The solvent was evaporated and the
residue was purified by chromatography on a silica gel column.
The solvent from the reaction mixtures of entries 4 and 6-8
was directly evaporated and the residue was purified by
chromatography on a silica gel column.
hexanes/EtOAc to afford 39 mg (52%) of the indicated com-
pound as a white solid: mp 209-210 °C; H NMR (CDCl3) δ
1
2.16 (m, 2H), 2.95 (t, J ) 6.0 Hz, 2H), 4.10 (t, J ) 6.0 Hz, 2H),
7.27-7.31 (m, 3H), 7.31-7.46 (m, 3H), 7.65 (m, 2H), 8.15 (m,
1H); 13C NMR (CDCl3) δ 22.1, 22.8, 40.9, 98.2, 103.8, 109.1,
121.4, 122.4, 124.0, 124.3, 128.3 (2), 129.4, 132.3, 138.2, 144.7,
153.4, 159.4; IR (neat, cm-1) 3056, 2923, 1702; HRMS calcd
for C20H15NO2 301.1103, found 301.1108. Anal. Calcd for
C
20H15NO2: C, 79.73; H, 5.02; N, 4.65. Found: C, 79.43; H,
4.81; N, 4.41.
P r ep a r a t ion of An n u la t ed γ-Ca r b olin es: 3-[(E)-â-
St yr yl]-5,6-d ih yd r o-4H -in d olo[3,2,1-ij]-1,6-n a p h t h yr -
id in e (4c). The mixture was chromatographed with 12:1
CHCl3/MeOH to afford 73 mg (94%) of the indicated compound
as a yellow solid: mp 131-132 °C; 1H NMR (CDCl3) δ 2.35
(quintet, J ) 7.2 Hz, 2H), 3.15 (t, J ) 7.2 Hz, 2H), 4.16 (t, J )
7.2 Hz, 2H), 7.24-7.31 (m, 2H), 7.34-7.50 (m, 5H), 7.63 (d, J
) 8.0 Hz, 2H), 7.86 (d, J ) 15.6 Hz, 1H), 8.12 (d, J ) 8.0 Hz,
1H), 9.14 (s, 1H); 13C NMR (CDCl3) δ 21.3, 22.2, 40.5, 108.8,
114.0, 116.6, 120.4, 121.2, 121.7, 123.9, 126.2, 127.1, 127.9,
9-P h en yl-7,8-d ih yd r o-6H-ben zo[c]p yr id o[1,2,3-lm ]ca r -
ba zole (5d ). To a 4-dram vial were added 2-iodo-3-phenyl-1-
(5-phenylpent-4-ynyl)-1H-indole (3t, 0.25 mmol), Pd(OAc)2 (5
mol %), NaOAc (0.50 mmol), LiCl (0.25 mmol), and DMF (5
mL). The mixture was flushed with Ar and heated at 100 °C
for 8 h. The mixture was diluted with EtOAc, washed with
satd aq NH4Cl, and dried over anhydrous Na2SO4. The solvent
was evaporated and the residue was purified by chromatog-
raphy on a silica gel column with 10:1 hexanes/EtOAc to afford
56 mg (68%) of the indicated compound as a yellow solid: mp
239-241 °C; 1H NMR (CDCl3) δ 2.27 (quintet, J ) 6.0 Hz, 2H),
2.89 (t, J ) 6.0 Hz, 2H), 4.34 (t, J ) 6.0 Hz, 2H), 7.31 (m, 1H),
7.39 (m, 3H), 7.44-7.56 (m, 5H), 7.64 (m, 2H), 8.58 (d, J ) 8.0
Hz, 1H), 8.76 (d, J ) 8.0 Hz, 1H); 13C NMR (CDCl3) δ 22.6,
24.6, 41.1, 108.9, 112.2, 119.7, 120.9, 122.1, 122.4, 123.0, 123.5,
123.7, 125.7, 127.1, 127.7, 128.3, 128.9, 129.0, 130.6, 135.1,
135.5, 138.9, 139.0; IR (neat, cm-1) 3050, 2944; HRMS calcd
128.7, 132.2, 137.5, 140.3, 140.4, 142.9, 146.0; IR (neat, cm-1
)
3054, 2947, 2865; HRMS calcd for C22H18N2 310.1470, found
310.1476.
2-ter t-Bu t yl-5,6-d ih yd r o-4H -in d olo[3,2,1-ij]-1,6-n a p h -
th yr id in iu m Br om id e (4g). The mixture was chromato-
graphed with 4:1 CHCl3/MeOH to afford 46 mg (53%) of the
1
indicated compound as a yellow solid: mp >300 °C; H NMR
(CDCl3) δ 2.01 (s, 9H), 2.42 (quintet, J ) 6.0 Hz, 2H), 3.44 (t,
J ) 6.0 Hz, 2H), 4.38 (t, J ) 6.0 Hz, 2H), 7.44 (t, J ) 7.8 Hz,
1H), 7.57 (d, J ) 8.0 Hz, 1H), 7.64 (t, J ) 7.8 Hz, 1H), 8.78 (d,
J ) 8.0 Hz, 1H), 9.15 (s, 1H), 10.06 (s, 1H); 13C NMR (CDCl3)
δ 21.2, 22.2, 31.1, 41.6, 68.0, 110.2, 118.1, 119.8, 120.9, 123.3,
124.4, 129.4, 132.3, 134.1, 141.7, 143.6; IR (neat, cm-1) 3016,
for
25H19N: C, 90.06; H, 5.74; N, 4.20. Found: C, 90.27; H, 5.44;
N, 4.17.
C25H18N 333.1518, found 333.1523. Anal. Calcd for
C
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research and J ohnson Matthey, Inc. and Kawak-
en Fine Chemicals Co., Ltd. for donations of palladium
acetate.
2980; MS m/z (rel intensity) 345 (21, M+), 209 (100, MH+
t-Bu - Br). Anal. Calcd for C18H21BrN2: C, 62.62; H, 6.13; N,
8.11. Found: C, 62.16; H, 6.22; N, 8.01.
-
The preparation and characterization of all other annulated
γ-carbolines can be found in the Supporting Information.
3-P h en yl-5,6-d ih yd r o-1H,4H-ben zo[b]p yr a n o[3,4,5-h i]-
in d olizin -1-on e (5c). To a 4-dram vial were added methyl
2-iodo-1-(5-phenylpent-4-ynyl)-1H-indole-3-carboxylate (3s, 0.25
mmol), Pd(OAc)2 (5 mol %), Na2CO3 (0.25 mmol), LiCl (0.25
mmol), and DMF (5 mL). The mixture was flushed with Ar
and heated at 100 °C for 24 h. The mixture was diluted with
EtOAc, washed with satd aq NH4Cl, and dried over anhydrous
Na2SO4. The solvent was evaporated and the residue was
purified by chromatography on a silica gel column with 1:1
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of starting materials; characterization data
for compounds 3g-i,m ,o,p ,r -v and 4h ,i,k ,o,p ; 1H and 13C
NMR spectra for compounds 3c,g-i,k ,m ,o,p ,r -v and
1
4c,g,k ,o,p , and 5c,d , and H NMR spectrum for compound 4i.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0343228
5138 J . Org. Chem., Vol. 68, No. 13, 2003