A one-pot conversion of ortho-alkynyl benzaldehydes into indolo[2,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2013.07.162

The conversion of readily available 2-halobenzaldehydes into indolo[2,1-a]isoquinolines in two operations represents a very direct entry to this class of molecules.

Full text of DOI:10.1016/j.tetlet.2013.07.162

Accepted Manuscript
A one-pot conversion of ortho-alkynyl benzaldehydes into indolo[2,1-a]isoqui‐
nolines
George A. Kraus, Jonathan Beasley
PII:
S0040-4039(13)01354-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.162
TETL 43374
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 June 2013
28 July 2013
31 July 2013
Please cite this article as: Kraus, G.A., Beasley, J., A one-pot conversion of ortho-alkynyl benzaldehydes into
indolo[2,1-a]isoquinolines, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.162
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
A one-pot conversion of ortho-alkynyl benzaldehydes into indolo[2,1-a]isoquinolines
George A. Krausa  and Jonathan Beasleya
aDepartment of Chemistry, Iowa State University, Ames, IA 50011, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
The conversion of readily available 2-halobenzaldehydes into indolo[2,1-a]isoquinolines in two
operations represents a very direct entry to this class of molecules.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Indolo[2,1-a]isoquinoline
Indole
Sonogashira
Imine
Microwave-Assisted
2-Alkynyl benzaldehyde
1. Introduction
Indolo[2,1-a]isoquinolines and their dihydro analogs exhibit a
diverse array of activities. These compounds are components in
tubulin-binding drugs,1 estrogen receptor modulators,2 and
organic semiconductors3. Some members of this class are natural
products.4 Representative compounds are shown below in Figure
1.
Scheme 1. Indole synthesis of Kraus and Guo
2. Results and discussion
The reaction of 2-bromobenzaldehyde with the methyl ether
of propargyl alcohol under Sonogashira reaction conditions
developed by Shu12 afforded the 2-alkynylbenzaldehyde 4.
Formation of the imine using aniline 3 and treatment with
potassium tert-butoxide according to the conditions of Kraus and
Guo did not generate the expected indole 5.13 The major organic
product lacked the N-H as evidenced by NMR and the acetylenic
resonances were absent from the carbon NMR. The mass
spectrum and proton and carbon NMR supported the assignment
of structure 6. Presumably, compound 6 arose from the
cyclization of the anion of 5 under the basic conditions, as shown
in Scheme 2.
Figure 1. Representative indolo[2,1-a]isoquinolines
Because of their biological activity, a number of approaches to
this class of molecules have been reported. The most commonly
used approach involves organopalladium couplings of 2-aryl
indoles through both intermolecular5 and intramolecular6
pathways. However, some innovative routes involving rhodium-
based cyclizations,7 copper-mediated cyclizations,8 and platinum-
based cyclizations9 have recently been reported. Approaches
utilizing metalation10 have also been reported. We recently
reported an indole synthesis shown in Scheme 1 utilizing a two-
step approach in one pot involving imine formation and six-
electron ring closure, followed by a 1,5-hydrogen shift.11 In the
process of extending our indole synthesis, we have discovered a
novel tandem cyclization to indolo[2,1-a]isoquinolines.
———
 Corresponding author. Tel.: +1-515-294-7794; fax: +1-515-294-0105; e-mail: gakraus@iastate.edu

2
Tetrahedron
Scheme 2. Synthesis of 6 from 4.
The conversion of readily available halo benzaldehydes into
Figure 3. Indolo[2,1-a]isoquinolines
indolo[2,1-a]isoquinolines in two operations represents a very
direct and potentially very flexible entry to this class of
molecules. Interestingly, database searches for this type of
transformation yielded only one precedent for the formation of an
indolo[2,1-a]isoquinoline from an alkynyl indole. Fürstner and
coworkers reported that 2-(2-ethynylphenyl)indole reacted with
platinum chloride to generate a mixture of two products where
the indolo[2,1-a]isoquinoline was a minor product as shown in
Scheme 3.9
Acetal 15 was synthesized from 2-bromobenzaldehyde in 30%
yield using the diethyl acetal of propionaldehyde.16 As shown in
Scheme 5, the reaction of 15 with 3 provided indolo[2,1-
a]isoquinoline aldehyde 16 upon reaction with potassium tert-
butoxide. The yield, albeit only 22%, is the result of imine
formation, cyclization to the indole, closure onto the alkyne, and
hydrolysis.
Scheme 3. Platinum chloride-mediated cyclization
Scheme 5. Cyclization of 15.
In order to evaluate the scope and limitations of this approach,
we synthesized a series of ortho-alkynyl aldehydes. Aldehyde 7
was prepared by the method of Shu.12 Interestingly, the reaction
of 7 using the reaction conditions that produced 6 afforded only
indole 8 in 45% yield as shown in Scheme 4. The rationale for
the different outcomes is not clear. We suggest that there may be
equilibrium between the anion of indole 5 and the vinylic anion
produced by cyclization to 6 and that the methoxymethyl group
stabilizes the vinylic anion so that protonation by tert-butanol
generates 6.
3. Conclusion
The conversion of 2-halobenzaldehydes into indolo[2,1-
a]isoquinolines by a Sonogashira reaction followed by an indole
forming reaction represents a convenient route to this useful class
of molecules. The indole forming reaction proceeds at room
temperature and is compatible with several functional groups.
Acknowledgment
We thank the Institute for Physical Research and Technology
and the Iowa State University Department of Chemistry for
partial support of JB.
Supplementary data
Full reaction conditions and product spectra for ortho-alkynyl
aldehydes and indolo[2,1-a]isoquinolines can be found in the
supplementary data associated with this article.
Scheme 4. Synthesis of indole 8.
To determine if this effect is extendable, aldehydes 9 – 11,
References
shown in Figure 2, were prepared by literature procedures.
15
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Figure 2. Substrates for cyclization.
The reaction of 9 – 11 with 3 produced indolo[2,1-
a]isoquinolines 12, 13, and 14 in 65%, 36% and 28% yields,
respectively, as shown in Figure 3. Although some yields are
modest, the products are the only fluorescent spots on TLC and
are readily purified. The substitution patterns on the ring systems
of 12 and 13 are closer to those of the biologically active
molecules.
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3
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13. Representative synthesis of indolo[2,1-a]isoquinolines: In a 10 ml
microwave reaction vial (CEM Discover System) equipped with a
magnetic stir bar, aniline 3 (0.5 mmol), aldehyde 4 (0.5 mmol), and
glacial acetic acid (0.01 ml, 0.17 mmol) were added to dry methanol
(3.0 ml). The vial was capped and placed into the microwave, which
was then run at 300 Watts, to 80 °C for 10 minutes. After cooling to
room temperature the solution was transferred to a round bottom flask
and the methanol was removed under vacuum. Tetrahydrofuran (10.0
ml) was added to the mixture, followed by a 1M solution of t-BuOK in
THF (0.8 ml, 0.8 mmol) slowly at room temperature. The resulting
mixture was stirred for 2 hours at room temperature. The reaction was
quenched with a saturated solution of NH4Cl and extracted three times
with ethyl acetate. The combined organic layers were dried over
anhydrous MgSO4 and filtered. The filtrate was concentrated under
vacuum, and the crude residue was purified by silica gel column
chromatography using a mixture of ethyl acetate and hexanes as eluent
to give indolo[2,1-a]isoquinoline 6 as a brown solid in 31% yield. 1H
NMR (300 MHz, CDCl3): 8.14 (d, J = 7.8 Hz, 1H), 8.06 (dd, J = 7.2,
2.1 Hz, 1H), 7.81 (dd, J = 6.6, 2.1 Hz, 1H), 7.46 (m, 3H), 7.32 (m, 3H),
6.67 (s, 1H), 4.94 (s, 2H), 3.51 (s, 3H). 13C NMR (75 MHz, CDCl3):
136.7, 134.6, 132.5, 130.0, 128.7, 128.0, 127.0, 126.4, 123.8, 122.4,
121.7, 120.9, 115.3, 112.0, 95.3, 72.8, 58.1. HRMS ACPI (m/z): calcd
for C18H16NO [M+ + H], 262.1226; found, 262.1228.
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Graphical Abstract
A one-pot conversion of ortho-alkynyl
benzaldehydes into indolo[2,1-
a]isoquinolines
Leave this area blank for abstract info.
George A. Kraus* and Jonathan Beasley
Department of Chemistry, Iowa State University, Ames, IA 50011, United States