Enantioselective Organocatalytic Michael Addition to Unsaturated Indolyl Ketones

Article abstract of DOI:10.1021/acs.orglett.1c00222

An efficient enantioselective organocatalytic method for the synthesis of N-alkylated indoles with α-branched alkyl substituents from the corresponding unsaturated indolyl ketones via a Michael addition has been developed. The resulting products were obtained in high enantioselectivities and in good yields. Various nucleophiles (nitroalkanes, malononitrile, malonic esters) can be used. The substitution pattern of the indole ring had no significant impact on the reaction outcome. Both electron-withdrawing and electron-donating substituents in any position of the heteroaromatic ring were well-tolerated.

Full text of DOI:10.1021/acs.orglett.1c00222

pubs.acs.org/OrgLett
Letter
Enantioselective Organocatalytic Michael Addition to Unsaturated
Indolyl Ketones
̌
̃
̃
̈
Dmitri Trubitson, Jevgenija Martonova, Marina Kudrjasova, Kristin Erkman, Ivar Jarving,
̃
and Tonis Kanger*
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ABSTRACT: An efficient enantioselective organocatalytic method for the synthesis of N-alkylated indoles with α-branched alkyl
substituents from the corresponding unsaturated indolyl ketones via a Michael addition has been developed. The resulting products
were obtained in high enantioselectivities and in good yields. Various nucleophiles (nitroalkanes, malononitrile, malonic esters) can
be used. The substitution pattern of the indole ring had no significant impact on the reaction outcome. Both electron-withdrawing
and electron-donating substituents in any position of the heteroaromatic ring were well-tolerated.
reactions have been used. Since Trost et al. demonstrated the
first enantioselective synthesis of chiral indolocarbazole
derivatives (Scheme 1, I),9 several other strategies have been
exploited. These methods generally consider indole to be a
nucleophilic coupling fragment reacting with different electro-
philic partners. However, difficulty in controlling regioselec-
tivity is often a problem.
Recently, Buchwald et al. reported the first polarity reversal
strategy where an indole derivative was used as an electrophile
in the enantioselective ligand-controlled metal-catalyzed
reaction to achieve N-alkylated products (Scheme 1, II).10
The method is based on the CuH-catalyzed N-alkylation of N-
(2,4,6-trimethylbenzoyloxy)indole with alkenes.
olecules bearing indole scaffolds can be found in a wide
Mrange of natural products, pharmaceutical compounds,
and agrochemicals.1 Some biologically active indoles contain a
stereogenic center at the α-position of the N-atom (Figure 1).
Therefore, such compounds have recently gained wide interest
in synthetic chemistry2−4 and in medicinal chemistry.5
The stereoselective derivatization of indole at the nitrogen
atom with electrophilic reagents is still challenging because the
most reactive nucleophilic center of the indole core is at C3.6
To avoid C3-alkylation and to achieve high N-selectivity, the
third position of the ring can be protected by substitution or,
alternatively, the N−H acidity and nucleophilicity of the
nitrogen atom can be increased by substituents in different
positions of the indole core. The application of these two
additional conditions provides high regioselectivity of the
nucleophilic attack but also changes electronic and steric
properties of indole core and limits the scope of the synthetic
methodologies.7
Based on the approach where an indole derivative was
applied as a non-nucleophile,11 we decided to employ the
electrophilic activation mode of the α-carbon of the nitrogen
atom by converting an indole to a Michael acceptor (Scheme
During the past two decades, the interest in new
enantioselective methodologies for the synthesis of chiral N-
substituted indoles with a branched alkyl substituent has
increased considerably.8 Both direct methods of the derivatiza-
tion of the indole core and indirect methods starting from
other nitrogen-containing heterocycles (isatin, indoline,
dihydroindole, etc.) via metal-catalyzed or organocatalytic
Received: January 20, 2021
Published: February 24, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00222
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1820−1824
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Scheme 2. Hydroamination of Indoles
reaction center in the indole ring is the N-atom. The simple
synthetic route provides easy access to enaminones possessing
indole core and Michael acceptor moiety. An asymmetric 1,4-
conjugate addition to the acceptor provides a direct entry to
the enantioselective synthesis N-substituted indoles with a
branched alkyl substituents. This two-step sequence totally
excludes the formation of C3-side product due to the
application of indole N-adducts as electrophiles.
Here, we describe the first enantioselective organocatalytic
formal N-alkylation of indoles using an indole derivative as a
Michael acceptor. To test our hypothesis, compound 1 was
synthesized and used as a model compound in a reaction with
nitromethane 2 in the presence of organocatalysts (Table 1).
For the stereoselective conjugate addition of nitroalkanes to
electron-deficient alkenes, various catalysts have been used.13
The screening of the catalyst was started with hydrogen
Figure 1. Selected biologically active enantiomeric N-substituted
indoles.
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Different Approaches to the Enantioselective
Synthesis of N-Substituted Indoles with Branched
Substituents
b
c
time
(h)
temp
conv
ee
entry catalyst
(°C)
solvent
DCM
DCE
DCE
DCE
DCE
DCE
1.4-dioxane
toluene
toluene
toluene
(%)
(%)
1
2
3
4
5
6
7
8
9
I
I
48
48
48
48
1
24
48
48
48
48
rt
80
80
80
rt
nr
71
nd
92
II
III
IV
V
I
I
I
I
traces
12
nd
−88
rac
rac
94
94
94
92
d
99
31
69
82
85
93
rt
80
80
100
100
e
10
a
Reaction conditions: 0.1 mmol scale, 1 equiv of 1, 10 equiv of 2, 20
b
1, III). An appropriate starting material can be prepared by the
hydroamination of the corresponding silyl alkynes with an
indole (Scheme 2).12 It is a specific reaction where the only
mol % of catalyst, solvent (0.5 mL). Conversion was determined by
c
1H NMR from the crude mixture. Determined by chiral HPLC
d
e
analysis. 1 equiv of Rb2CO3 was added. Toluene (0.2 mL).
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bonding catalysts. Bifunctional cinchona alkaloid-based squar-
amides I, II, and thiourea III are widely used with nitro-group
containing Michael donors.14,15 The reaction did not take
place in the presence of catalyst I at room temperature in
DCM, although increasing the temperature to 80 °C led to
moderate conversion (71%) and afforded product in high ee
(92%) in DCE in 2 days (Table 1, entries 1 and 2). Only traces
of the product were detected in the presence of the catalyst II
under the same conditions (Table 1, entry 3). The reaction in
the presence of quinine-based thiourea III afforded product in
high enantioselectivity but the conversion was unreasonably
low (Table 1, entry 4). According to our previous experience
with indole chemistry with phase-transfer catalysis,7a PTC IV
was used (Table 1, entry 5). Full conversion was achieved at
room temperature but the formed product was racemic. Next,
cyclopropenimines as enantioselective Brønsted base catalysts
were applied.16 With the catalyst V, low conversion of the
starting material and obtained racemic product were character-
istic (Table 1, entry 6). Next, a brief screening of the solvents
with the most selective catalyst I revealed that toluene was the
best solvent in terms of both yield and enantioselectivity
(Table 1, entry 8). A slightly higher reactivity was achieved
when the temperature was raised to 100 °C (Table 1, entry 9).
Moreover, almost full conversion was reached by increasing the
concentration from 0.2 to 0.5 M without a significant impact
on the stereoselectivity (Table 1, entry 10).
Scheme 3. Scope and Limitations of the Reaction with
Nitromethane
a
Additionally, the influence of the catalyst amount on the
reaction rate was examined (see, Figure S1). There was no
significant difference when 10 or 20 mol % of the catalyst was
used. However, the experiment with 5 mol % of the catalyst
was inefficient demonstrating a considerable decline in reaction
rate and the conversion was only 78% in 26 h. Notably, the
catalyst amount did not affect the enantioselectivity of the
reaction, and the ee value remained constant and high during
the entire experiment.
Under optimized reaction conditions (toluene, 100 °C, 10
mol % of catalyst I, and reaction time 24 h), the substrate
scope of the reaction was investigated. Initially, variations on
the indolyl scaffold were evaluated (Scheme 3, I). The reaction
was run with monosubstituted indole derivatives that differ-
entiated from each other in the position and nature of the
substituent. The incorporation of the methyl group into the
C2- or C3-position did not have a significant impact on the
reaction yield or on the enantioselectivity. Substrates with
electron-withdrawing substituents at the C3- or C4-positions
tolerated the reaction well, providing the products 3c and 3d in
good yields (88 and 81%) and high ee-s (92% and 94%). A
drastic decline in the reaction yield was detected (most
probably a retro-Michael reaction occurred) when the 7-nitro-
substituted Michael acceptor 1e was used (yield 12%).
However, the ee value of the product 3e remained high
(93%). The tolerance toward electron-donating groups (and
also the substituent at the seventh position) on the indolyl ring
was well represented by 4- and 7-metoxy-substituted N-
functionalized indoles. The electron-donating groups did not
affect the reactivity, and the desired products 3f and 3g were
isolated in good yields (83% and 68%) and excellent
enantioselectivities (94% and 95%). Halogen-substituted C5-
and C6-unsaturated N-indolyl ketones reacted smoothly,
affording N-alkylated indoles 3h and 3i in good yields (71%
and 78%) and high ee’s (93% and 91%). Thus, the substitution
pattern of the indole ring is not essential and the method is
applicable to the monosubstituted indole derivatives possessing
a
Reaction conditions: 0.2 mmol scale, 1 equiv of 1−1o, 10 equiv of
nitromethane, 10 mol % of catalyst I, in 0.4 mL of toluene (0.5 M), 24
b
c
d
h. ee was determined by chiral HPLC analysis. 0.2 M. 0.1 mmol
scale. Reaction time 7 days.
e
substituents in any position. The absolute stereochemistry of
product 3g was unambiguously assigned by single-crystal X-ray
diffraction (see the SI), and other compounds in the series
were assigned based on the analogy.
Next, we turned our attention to the scope of Michael
acceptors with parent indolyl scaffolds (Scheme 3, II). Both
electron-withdrawing and electron-donating substituents at the
para-position of a phenyl ring did not have a significant impact
on the reaction yield (68% and 76%), but slightly better
enantioselectivity (95%) was achieved in the case of methoxy-
substituted substrate 1j. The p-bromo-substituted product 3l
was isolated in high yield (89%), and the achieved ee was
comparable with the model compound 3. The bulky 1-
naphthyl substituent of 1m led to a moderate yield (50%) and
slightly decreased the ee value (85%). Heteroaromatic furyl
derivative 3n was obtained in high yield and ee (77% and 94%,
respectively). Notably, the reaction rate and stereoselectivity
dropped drastically when the substrate 1o with the aliphatic
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butyl chain was used instead of a phenyl ring (Scheme 3, III).
The reaction was unacceptably slow, indicating the importance
of π−π interactions. The product 3o was isolated after 7 days
in only 6% yield.
Next, the scope of Michael donors and acceptors was
studied briefly (Scheme 4). The reaction with malononitrile
explored. It was converted to a 5-HT6 receptor modulator
analogue precursor 5.17 The treatment of compound 3 with
Raney nickel induced the reduction of the nitro group to an
amino group followed by intramolecular cyclization, affording
the corresponding chiral imine 4 without the loss of
enantioselectivity (Scheme 5, II). The imine 4 was later easily
hydrogenated in a flow reactor with Pd/C cartridge providing
chiral pyrrolidine derivative 5 in high dr ratio (14:1) and good
yield (62%). The cis-configuration of the substituents in the
pyrrolidine ring was determined by selective NOESY (details
in the SI). The diastereomeric ratio of the product 5 was
improved after the purification of the reaction (>25:1).
a
Scheme 4. Scope of Michael Donors and Acceptors
In summary, we have developed the first enantioselective
organocatalytic method for the synthesis of N-alkylated indoles
starting from unsaturated indolyl ketones. The main feature of
our method is exploiting an indole derivative as an electrophile
totally avoiding the regioselectivity problems common with
other N-alkylation methods. A wide range of electrophilic
indole N-adducts bearing various substituents provide
exclusively N-alkylated indoles with a branched substitutents
in good yields (up to 89%) and high to excellent ee values (up
to 95%). The enantioselectivity of the reaction does not
depend on the substitution pattern of the indole ring.
a
Reaction conditions: 0.2 mmol scale, 1 equiv of 1 or 1o, 10 equiv of
nucleophile, 10 mol % of catalyst I, in 0.4 mL of toluene (0.5 M), 24
h. Reaction time 1 h.
b
ASSOCIATED CONTENT
■
sı
* Supporting Information
was complete with 1h but the enantiomeric purity of the
product 3p was considerably lower. There was no reaction
with acetonitrile. Malonic ester reacted smoothly affording
product 3q in 67% yield and 93% ee. A 1:1 mixture
diastereomers 3r was obtained with nitroethane in high ee’s
(92%/92%). To our delight, the diastereomers of 3r were
chromatographically separable. The reaction with 2,4-penta-
nedione led to the mixture of products. The substitution of the
phenyl ring with an alkoxycarbonyl group in the indole-based
Michael acceptor (compound 1s) led to the substantial
decrease of the reactivity and no reaction was detected with
nitromethane.
To evaluate the synthetic potential of the current method-
ology, a gram-scale experiment was performed with substrate 1
(Scheme 5, I). The scale-up of the reaction did not affect either
the reaction yield or enantioselectivity (78% yield, 92% ee).
Furthermore, the synthetic transformation of compound 3 was
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00222.
Synthesis of starting compounds, copies of H and 13C
spectra, and HPLC chromatograms (PDF)
1
Accession Codes
CCDC 2054770 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Tonis Kanger − Department of Chemistry and Biotechnology,
̃
Tallinn University of Technology, 12618 Tallinn, Estonia;
orcid.org/0000-0001-5339-9682; Email: tonis.kanger@
taltech.ee
Scheme 5. Demonstration of Synthetic Utility
Authors
Dmitri Trubitso
̃
n − Department of Chemistry and
Biotechnology, Tallinn University of Technology, 12618
Tallinn, Estonia
Jevgenija Martonova − Department of Chemistry and
̃
Biotechnology, Tallinn University of Technology, 12618
Tallinn, Estonia
̌
Marina Kudrjasova − Department of Chemistry and
Biotechnology, Tallinn University of Technology, 12618
Tallinn, Estonia
Kristin Erkman − Department of Chemistry and
Biotechnology, Tallinn University of Technology, 12618
Tallinn, Estonia
̈
Ivar Jarving − Department of Chemistry and Biotechnology,
Tallinn University of Technology, 12618 Tallinn, Estonia
Complete contact information is available at:
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Strategies for the asymmetric functionalization of indoles: an update.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Estonian Ministry of Education and
Research (Grant Nos. PRG1031 and PRG399) and the Centre
of Excellence in Molecular Cell Engineering (2014-
2020.4.01.15-0013) for financial support. The authors thank
Dr. Aleksander-Mati Muurisepp (Tallinn University of
̈ ̈
Technology) for IR spectra.
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