Ruthenium-Catalyzed Cascade Annulation of Indole with Propargyl Alcohols

Article abstract of DOI:10.1002/anie.201801846

Cascade transformations forming multiple bonds and one-pot procedures provide rapid access to natural-product-like scaffolds from simple precursors. These atom-economic processes are valuable tools in organic synthesis and drug discovery. Herein, we report on ruthenium-catalyzed cascade annulations of indole with readily available propargyl alcohols. These provide rapid access to diverse carbazoles, cyclohepta[b]indoles, and further fused polycycles with high selectivity. A bifunctional ruthenium complex featuring a redox-coupled cyclopentadienone ligand acts as a common catalyst for the different cascade processes.

Full text of DOI:10.1002/anie.201801846

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Title: Ruthenium Catalyzed Cascade Annulation of Indole with
Propargyl Alcohols
Authors: Edgar Haak, Julia Kaufmann, and Elisabeth Jäckel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801846
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10.1002/anie.201801846
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Ruthenium Catalyzed Cascade Annulation of Indole with
Propargyl Alcohols
Julia Kaufmann, Elisabeth Jäckel and Edgar Haak*[a]
Abstract: Multiple bond-forming cascade transformations and one-
pot procedures provide rapid access to natural product-like scaffolds
from simple precursors. These atom-economical processes are
valuable tools in organic synthesis and drug discovery. Herein, we
report on ruthenium-catalyzed cascade annulations of indole with
readily available propargyl alcohols. Thereby, diverse carbazoles,
cyclohepta[b]indoles and further fused polycycles are rapidly
accessible with high selectivity. A bifunctional ruthenium complex
containing a redox-coupled cyclopentadienone ligand acts as a
common catalyst for the different cascade conversions that take place.
The rapid production of molecular complexity by transition-metal
catalyzed cascade reactions facilitates the preparation of natural
product inspired frameworks and drug-like molecules, important
lead structures in the development of bioactive compounds.[1]
This atom-economical approach to the one-pot synthesis of
complex molecular scaffolds from readily available starting
materials improves practical efficiency in synthesis and provides
rapid access to intricate molecular structures.[2] Annulated indole
Scheme 1. Ruthenium-catalyzed conversion of indole with propargyl alcohols.
derivatives
like
cyclopenta[b]indoles,
carbazoles
or
cyclohepta[b]indoles occupy
a
prominent position among
bioactive natural products and pharmaceutically important
compounds.[3] Various methods to access these privileged motifs
have been reported.[4-6] However, many steps are required to
generate the multiply functionalized cyclization precursors in most
cases and more efficient procedures would be beneficial.
First we focused on the optimization and the scope of the
carbazole forming cascade annulation. Best results are obtained
by using 3 equivalents of the volatile alcohol 1a, larger 1-alkenyl
propargyl alcohols are applied stöchiometrically. The catalyst load
was raised to 4 mol-%. The substrates are directly generated from
the corresponding enones and ethynyl magnesium bromide. Most
Bifunctional (cyclopentadienone)ruthenium(0) complexes of type
A catalyze various cascade conversions of propargyl alcohols
with diverse nucleophiles.[7] Usually, these reactions are initiated
by the formation of organometallic alkynyl, vinylidene or
allenylidene intermediates. We previously reported on the
conversion of 1-alkenyl propargyl alcohol 1a with indole to yield
carbazole 2a (scheme 1a).[7f] The allylation / cycloisomerization
cascade reaction proceeds presumably via alkynyl intermediate
B. On the other hand, alkylated indole derivatives 4a-c are
generated from secondary propargyl alcohols 3a-c (scheme
alkylated substrates form carbazoles
2
regioselectively.
Conversion of the sterically more hindered substrates 1c and 1e
occur slowly and low yields are obtained. The latter forms traces
of the regioisomeric byproduct 5e. Arylated substrates generate
the byproducts 5 in higher amounts. Only alcohol 2d yields the
regioisomeric carbazole 5d as the sole product. Small amounts of
5d are also obtained in absence of catalyst A, whereas formation
of the other carbazoles is not observed under these conditions
(scheme 2).
1b).[7f] This redox-isomerization
/ Michael-addition cascade
reaction is initiated by formation of alkynyl species C. Herein, we
report on the extensive expansion of these and further cascade
processes to obtain various annulated heterocycles from indole
and readily available propargyl alcohols.
[a]
J. Kaufmann, E. Jäckel, Dr. E. Haak
Institute of Chemistry
Otto von Guericke University Magdeburg
Universitätsplatz 2, 39106 Magdeburg, Germany
E-mail: edgar.haak@ovgu.de
Supporting information for this article is given via a link at the end of
the document.
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Scheme 3. Redox-isomerization / Michael-addition cascade. [a] 0.5 Equiv. of
indole were used; yield based on indole; [b] 2 equiv. of indole were used; yield
based on 3g; [c] analogues reaction conditions as for the preparation of 4; yields
of 7 determined from the crude products by NMR spectroscopic analysis with
an internal standard.
Scheme 2. Carbazole formation via cascade annulation of indole. [a] 3 Equiv.
of 1a were used.
Next, the scope of the redox-isomerization / Michael-addition
cascade was investigated. Conveniently, the process can be
accelerated by using microwave irradiation instead of
conventional heating. Various alkylated indoles 4 are selectively
obtained in high yield. Propargyl alcohols derived from readily
available terpene aldehydes ((S)-perillaldehyde, (R)-myrtenal,
citral) lead to complex indole enones 4d-f that are versatile
building blocks. These conversions can be performed on a gram
scale. Alcohol 3g derived from acrolein adds two equivalents of
indole after redox-isomerization to yield compound 6. Mono-
adduct 4g is selectively obtained if two equivalents of the alcohol
are used. The proposed mechanism is supported by the formation
of the redox-isomerization products 7 in absence of indole
(scheme 3).
The
cascade
process
was
extended
to
produce
cyclohepta(b)indoles
8
from secondary 1-alkenyl propargyl
alcohols 3c-f in one pot by adding a half-stöchiometric amount of
pTsOH to the crude reaction mixture and reheating. The final
rearomatization causes preferential product formation via 7-endo-
trig cyclization. Annulation of intermediate 4f occurs slowly, due
to the formation of a quaternary center (scheme 4).
Scheme 4. Cyclohepta[b]indole formation via cascade annulation. [a] Byproduct
9 (24%); [b] accompanied by 4f (19%).
The perilla derivative 3d forms enone 8d by migration of the
terminal double bond. This migration process also causes the
formation of the polycyclic byproduct 9. After the first migration
step nucleophilic attack of C-2 of the indole core leads to a 6-
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10.1002/anie.201801846
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endo-trig Michael-addition / ene cyclization cascade to generate
complex indole derivative 9 as a single diastereomer (scheme 5).
1
The structure of 9 was assigned based on H-1H COSY, HSQC,
HMBC and 1H-1H NOESY spectra.
Scheme 7. Acid-catalyzed conversion of 11a and 10a.
The ruthenium-catalyzed cyclization of the indolyl propargyl
alcohols 10 can be extended by a silica mediated cycloaddition of
cyclic 1,3-dicarbonyl compounds (e.g. 1,3-cyclohexanedione) to
yield pentacyclic annulated indole derivatives 14 with high syn-
selectivity in a one-pot process (scheme 9). Assignments are
based on 1H-1H COSY, HSQC, HMBC and 1H-1H NOESY spectra.
Scheme 5. Plausible mechanism for the formation of 9.
Having a convenient process to obtain indolyl ketones 4 in hand
we decided to generate the corresponding propargyl alcohols in
order to investigate subsequent cyclizations. Conversion of 4 to
the corresponding propargyl alcohols 10 requires transmetallation
to cerium. The addition occurs highly selective and in very good
yields. Subsequent ruthenium-catalyzed cyclization applying
catalyst A occurs in a 6-exo-dig fashion to yield exo-methylene-
tetrahydrocarbazoles 11 in good purity (scheme 6). Presumably,
this reaction is initiated by the formation of a ruthenium-alkynyl-
complex.
Scheme 8. Annulation/cycloaddition cascade to yield pentacyclic indole
derivatives 14. [a] see scheme 6.
In agreement with our previously reported studies,[7c-f] we assume
that the initially formed -complex 15 is in equilibrium with the
alkynyl species 16-18. Alkynyl complex 16, formed from substrate
1 is attacked by indole and generates enynol compound 19. This
conversion may possibly proceed via an allenylidene intermediate.
Subsequent cycloisomerization leads to alkyl complex 23 that
liberates the carbazole 2. Redox-isomerization of alkynyl complex
17, formed from substrate 3, results in alkenyl species 20 that
adds indole at the metalated carbon. The resulting alkyl
compound 21 liberates indolyl ketone 4. Alternatively, enone 7 is
liberated from complex 20 and subsequent Michael-addition of
indole leads to 4. Acid-mediated cyclization occurs with ,-
unsaturated ketones 4 to yield cyclohepta[b]indoles 8. Finally, 6-
exo-dig cyclization of alkynyl complex 18, formed from substrate
Scheme 6. Cylization of indolyl propargyl alcohols 10. Yields determined from
the crude products by NMR spectroscopic analysis with an internal standard. [a]
Reaction time 15 minutes. [b] Reaction time 30 minutes. [c] Reaction time 60
minutes; 4 mol-% catalyst A used.
Chromatography of the sensitive compounds 11 is difficult due to
their easy conversion to the corresponding carbazoles by acid
catalysis as it is shown for derivative 11a (scheme 7a). In contrast
to the ruthenium-catalyzed reaction, the acid-mediated cyclization
of the initial indolyl propargyl alcohol 10a proceeds in a 5-exo-tet
fashion yielding cyclopenta(b)indole 13 (scheme 7b).
10,
generates
alkenyl
species
22
that
liberates
tetrahydrocarbazole 11 (scheme 9).
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Keywords: annulation • cascade reactions • homogeneous
catalysis • propargyl alcohols • ruthenium
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Julia Kaufmann, Elisabeth Jäckel, Edgar
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Ruthenium-Catalyzed Cascade
Annulation of Indole with Propargyl
Alcohols
One catalyst, divers cascade reactions: Various annulations of indole with
propargyl alcohols yielding carbazoles, cyclohepta[b]indoles and further fused
polycyles are catalyzed by a common ruthenium catalyst. Thereby different
cascade reactions take place.
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