Synthesis of β- and γ-carbolines by the palladium/copper-catalyzed coupling and copper-catalyzed or thermal cyclization of terminal acetylenes

Article abstract of DOI:10.1016/S0040-4039(02)00005-9

A variety of 3-substituted β- and γ-carbolines have been synthesized from N-substituted 3-iodoindole-2-carboxaldehydes and 2-bromoindole-3-carboxaldehydes, respectively. The coupling of these aldehydes with various terminal acetylenes using cat. PdCl

Full text of DOI:10.1016/S0040-4039(02)00005-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1359–1362
Synthesis of b- and g-carbolines by the
palladium/copper-catalyzed coupling and copper-catalyzed or
thermal cyclization of terminal acetylenes
Haiming Zhang and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 4 December 2001; accepted 21 December 2001
Abstract—A variety of 3-substituted b- and g-carbolines have been synthesized from N-substituted 3-iodoindole-2-carboxalde-
hydes and 2-bromoindole-3-carboxaldehydes, respectively. The coupling of these aldehydes with various terminal acetylenes using
cat. PdCl2(PPh3)2/CuI readily affords the corresponding alkynylindole carboxaldehydes, which have subsequently been converted
to the corresponding tert-butylimines, which have then been cyclized to b- and g-carbolines by either copper-catalyzed or thermal
processes. © 2002 Elsevier Science Ltd. All rights reserved.
The transition metal-mediated,1 base-promoted,2 elec-
trophile-induced3 and thermal cyclization4 of alkynes
which possess a nucleophile in close proximity to the
carbonꢀcarbon triple bond have been shown to be very
effective for the synthesis of a wide variety of hetero-
and carbocycles. In our own laboratory, a variety of
isoquinolines, pyridines and naphthyridines have been
successfully synthesized by the copper-catalyzed,5 palla-
dium-catalyzed6 and electrophile-induced7 cyclization
of alkynes having a tert-butylimine group in close
proximity to the triple bond.
Herein, we wish to report the successful synthesis of
various b- and g-carbolines by the palladium/copper-
catalyzed coupling and subsequent copper-catalyzed or
thermal cyclization of terminal acetylenes.
We have found that the palladium/copper-catalyzed
coupling of 3-iodo-1-methylindole-2-carboxaldehyde
(1a) with phenylacetylene gave a 100% yield of the
alkynylindole 2a, which was then converted to the
corresponding tert-butylimine in a quantitative yield
(Scheme 2 and Table 1). The tert-butylimine was then
subjected to copper-catalyzed (10 mol% CuI) cycliza-
tion, which afforded a 90% yield of the desired b-carbo-
line 3a after 20 h (Table 1, entry 1). As observed in our
previous carboline synthesis,10 transformation of the
aldehyde to the corresponding tert-butylimine is essen-
tially quantitative, requiring no further purification or
characterization. We thus employed this coupling–imi-
nation–cyclization sequence to synthesize a variety of
Pyrido[3,4-b]indoles and pyrido[4,3-b]indoles, com-
monly known as b- and g-carbolines, respectively, are
the key structural units for a variety of biologically
important alkaloids.8 Numerous b- and g-carbolines
have been studied extensively as antitumor agents.8 The
isolation and synthesis of naturally occurring carbolines
and the synthesis of b- and g-carboline derivatives have
received considerable attention in the literature,8,9
because of their biological and pharmaceutical
importance.
Recently, we have developed a general synthesis of
3,4-disubstituted b- and g-carbolines by the palladium-
catalyzed iminoannulation of internal alkynes (Scheme
1).10 Our interest in carboline synthesis has prompted
us to examine the synthesis of a variety of 3-substituted
b- and g-carboline derivatives from terminal alkynes.
* Corresponding author. Tel.: +1-515-294-4660; fax: +1-515-294-0105;
e-mail: larock@iastate.edu
Scheme 1. Iminoannulation of internal alkynes.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00005-9

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H. Zhang, R. C. Larock / Tetrahedron Letters 43 (2002) 1359–1362
tuted b-carbolines in excellent yields (entries 2–4).
R2
R2
I
Alkyl-substituted terminal acetylenes have proven quite
successful in this b-carboline synthesis. For example,
1-decyne gave 88 and 93% yields of the coupling
product 2b and b-carboline 3b, respectively (entry 2).
Moreover, hydroxy- and ester-substituted terminal
alkynes also afforded Sonogashira coupling products
and the corresponding b-carbolines in excellent yields
(entries 3 and 4). For example, 4-butyn-1-ol afforded an
87% yield of the coupling product 2c, which subse-
quently gave the desired b-carboline 3c in a 95% yield
(entry 3). Methyl 10-undecynoate produced 98 and 95%
yields of the coupling and cyclization products 2d and
3d, respectively (entry 4). Finally, N-methoxymethyl-
substituted iodoindole 1b was employed in the palla-
dium/copper-catalyzed coupling and copper-catalyzed
cyclization of phenylacetylene. The coupling afforded
the alkynylindole 2e in a 95% yield, and cyclization
generated the desired b-carboline 3e in a 100% yield
(entry 5).
N
CHO
cat. Pd/Cu
N
R1
2
CHO
N
R1
1
R2
1. t-BuNH2
2. cat. CuI
N
R1
3
Scheme 2. b-Carboline synthesis.
3-substituted b-carbolines using N-substituted 3-iodoin-
dole-2-carboxaldehydes and other terminal acetylenes
(Scheme 2).11 The results of this study are summarized
in Table 1, entries 2–5.
As summarized in Table 1, the palladium/copper-cata-
lyzed Sonogashira coupling12 of 3-iodo-1-methylindole-
2-carboxaldehyde (1a) with a variety of terminal
acetylenes afforded excellent yields of the correspond-
ing 3-alkynyl-1-methylindole-2-carboxaldehydes, which
were then converted to the corresponding tert-
butylimines. Subsequent copper-catalyzed cyclization
was also quite effective, generating the desired 3-substi-
Encouraged by our success with the b-carboline synthe-
sis, we have also investigated the palladium-catalyzed
coupling of terminal acetylenes using N-substituted 2-
bromoindole-3-carboxaldehydes in order to synthesize
various 3-substituted g-carbolines (Scheme 3). The pal-
ladium/copper-catalyzed coupling of phenylacetylene
and 2-bromo-1-methylindole-3-carboxaldehyde (4a)
Table 1. Synthesis of b- and g-carbolines by the palladium/copper-catalyzed coupling and copper-catalyzed or thermal
cyclization of terminal acetylenesa

H. Zhang, R. C. Larock / Tetrahedron Letters 43 (2002) 1359–1362
1361
to its close proximity. The cyclization, either catalyzed
by CuI (b-carboline synthesis) or promoted by heat
(g-carboline synthesis), forms an aromatic carbolinium
salt with a tert-butyl group on the nitrogen. As previ-
ously suggested by Heck,14 the tert-butyl group appar-
ently fragments to isobutene, relieving the strain
resulting from interaction with the substituent present
on the neighboring carbon.
CHO
R2
CHO
Br
N
N
cat. Pd/Cu
R1
R2
R1
4
5
t-BuNH2
N
R2
∆
N
In conclusion, an efficient synthesis of b- and g-carboli-
nes by the palladium/copper-catalyzed coupling and
copper-catalyzed or thermal cyclization of terminal
acetylenes has been developed. A variety of functional-
ized terminal acetylenes participate in this process to
afford the desired nitrogen heterocycles in good to
excellent yields. Further investigation into the scope
and limitations of this b- and g-carboline synthesis is
under way.
R1
6
Scheme 3. g-Carboline synthesis.
was first examined. The coupling reaction proceeded
smoothly, producing the desired alkynylindole 5a in a
93% yield (Table 1, entry 6). The alkynylindole 5a was
then heated with tert-butylamine at 100°C, with the
expectation of forming the corresponding tert-
butylimine. To our pleasant surprise, instead of the
tert-butylimine, the g-carboline product 6a was
detected by TLC analysis after 20 h and subsequently
isolated in a 92% yield. This preliminary result
prompted us to investigate the synthesis of 3-substi-
tuted g-carbolines by the palladium/copper-catalyzed
coupling and thermal cyclization of other terminal
acetylenes.13 The results of this study are summarized in
Table 1, entries 7–10.
Acknowledgements
We gratefully acknowledge the donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society, for partial support of this research, and
Johnson Matthey, Inc., and Kawaken Fine Chemicals
Co., Ltd. for donations of palladium catalyst.
References
As shown in Table 1, the palladium-catalyzed Sono-
gashira coupling of 2-bromo-1-methylindole-3-carbox-
aldehyde (4a) with a variety of terminal acetylenes
afforded good to excellent yields of the corresponding
2-alkynyl-1-methylindole-3-carboxaldehydes. The tert-
butylimines, generated in situ by heating the corre-
sponding aldehydes with tert-butylamine, underwent
spontaneous thermal cyclization to produce the desired
3-substituted g-carbolines in good to excellent yields.
As we expected, alkyl-substituted terminal acetylenes
have again proven successful in this g-carboline synthe-
sis. For example, 1-decyne gave 82 and 87% yields of
the coupling product 5b and g-carboline 6b, respectively
(entry 7). Unfortunately, 3-butyn-1-ol, which is quite
successful in the b-carboline synthesis, did not give any
significant yield of the coupling product. However,
another hydroxy-containing acetylene, 10-undecyn-1-ol
afforded the coupling product 5c and the corresponding
g-carboline 6c in 61 and 72% yields, respectively (entry
8). Moreover, methyl 10-undecynoate also underwent
coupling and cyclization successfully, affording an 86%
yield of the coupling product 5d and an 88% yield of
the g-carboline 6d (entry 9). Finally, the N-
methoxymethyl-substituted bromoindole 4b was
employed in the palladium-catalyzed coupling and ther-
mal cyclization of phenylacetylene. The coupling
afforded the alkynylindole 5e in a 97% yield, and the
cyclization generated the desired g-carboline 6e in an
80% yield (entry 10).
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1362
H. Zhang, R. C. Larock / Tetrahedron Letters 43 (2002) 1359–1362
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coupling product was isolated by column chromatogra-
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for characterization, the remaining material was trans-
ferred to a 2-dram vial, and tert-butylamine (5 mL/
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heated at 100°C for 24 h and then cooled, diluted with
ether, dried (Na2SO4), and filtered. The solvent was evap-
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which was then transferred to a 2-dram vial, and CuI (10
mol%) and DMF (10 mL/mmol) were added. The mix-
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moindole-3-carboxaldehydes. The rest of the procedure is
similar to that used in the b-carboline synthesis. The
coupling product was transferred to a 2-dram vial and
tert-butylamine (5 mL/mmol) was added. The mixture
was flushed with Ar and heated at 100°C for the indi-
cated period of time. The solvent was evaporated and the
residue was purified by column chromatography.
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