Nickel-Catalyzed Asymmetric Friedel-Crafts Propargylation of 3-Substituted Indoles with Propargylic Carbonates Bearing an Internal Alkyne Group

Article abstract of DOI:10.1021/acs.orglett.0c00465

The nickel-catalyzed highly enantioselective Friedel-Crafts propargylation of 3-substituted indoles with propargylic carbonates bearing an internal alkyne group was developed. A wide array of the propargylic carbonates as well as 3-substituted indoles can be applicable to the asymmetric nickel catalysis, providing the corresponding chiral C-3 propargylated indolenine derivatives bearing two vicinal chiral centers in up to 89% yield with up to >99% ee and 94:6 dr (24 examples).

Full text of DOI:10.1021/acs.orglett.0c00465

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Letter
Nickel-Catalyzed Asymmetric Friedel−Crafts Propargylation of
3‑Substituted Indoles with Propargylic Carbonates Bearing an
Internal Alkyne Group
Yusuke Miyazaki, Biao Zhou, Hiroaki Tsuji,* and Motoi Kawatsura*
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ABSTRACT: The nickel-catalyzed highly enantioselective Friedel−
Crafts propargylation of 3-substituted indoles with propargylic
carbonates bearing an internal alkyne group was developed. A wide
array of the propargylic carbonates as well as 3-substituted indoles
can be applicable to the asymmetric nickel catalysis, providing the
corresponding chiral C-3 propargylated indolenine derivatives
bearing two vicinal chiral centers in up to 89% yield with up to
>99% ee and 94:6 dr (24 examples).
Scheme 1. Catalytic Asymmetric Friedel−Crafts
he catalytic asymmetric Friedel−Crafts alkylation is one
Tof the fundamental and efficient methods for the
construction of carbon−carbon bonds in an enantioselective
manner.1 In particular, the catalytic asymmetric Friedel−Crafts
alkylation of indoles has attracted a lot of attention2 because
the indole skeleton is prevalent in a wide variety of natural
products3 and pharmaceutical compounds.4 Thus, the catalytic
asymmetric Friedel−Crafts alkylation of indoles has been well-
explored in the past two decades, and various catalyst systems
using transition-metal catalysts and organocatalysts have been
established, enabling the straightforward access to a wide array
of enantioenriched indole derivatives. While various electro-
philes such as activated alkenes,5 activated ketones,6 N-
protected imines,7 nitrones,8 strained ring systems,9 allylic
alcohol derivatives,10 and others1,2 have been employed in the
catalytic asymmetric Friedel−Crafts alkylation of indoles, the
use of propargylic alcohol derivatives remains rare despite that
an alkyne group can be utilized for further derivatization in
organic synthesis.11 In 2007, Nishibayashi and coworkers
reported the first catalytic asymmetric Friedel−Crafts prop-
argylation of indoles with propargylic alcohols as the
electrophile using a chiral thiolate-bridged diruthenium
complex, providing the corresponding β-propargylated indoles
in good yields with high enantioselectivity (Scheme 1, eq 1).12
After this seminal report, Nishibayashi’s group and others
disclosed the catalytic asymmetric propargylation of indoles
with propargylic alcohol derivatives.13 However, these catalyst
systems could not work in the reaction of propargylic alcohol
derivatives bearing an internal alkyne group because a terminal
alkyne group is essential to form a metal-allenylidene
intermediate that plays a pivotal role in the catalysis.14
Propargylation of Indoles
ing chiral propargylic amines in high yields with excellent
enantioselectivity.15 Based on the previous work, we attempted
to extend our asymmetric nickel catalysis to other trans-
formations. During the course of the study, we found that the
nickel/chiral bisphosphine catalyst system promoted the
asymmetric Friedel−Crafts propargylation of 3-substituted
indoles with propargylic carbonates having an internal alkyne
group to produce the chiral indolenine derivatives (Scheme 1,
eq 2). Herein, we report the details in this communication.
Received: February 5, 2020
We recently reported the nickel-catalyzed asymmetric
propargylic amination of propargylic carbonates bearing an
internal alkyne group, which allowed access to the correspond-
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A

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We commenced our investigation from the optimization of
reaction conditions (Table 1). The reaction of 3-methylindole
8). When the reaction was performed in the presence of 5 mol
% of Ni(cod)2 and 10 mol % of (R)-BINAP, the desired
product 3aa was obtained in diminished yield with maintained
enantioselectivity (entry 9). We also evaluated the effects of
solvents and reaction temperature in the asymmetric
propargylation of 1a. However, the screening did not lead to
improvement of the diastereoselectivity (see the Supporting
Information for the detailed results of the optimization).
With the optimized reaction conditions in hand, we
examined the reaction of 3-methylindole (1a) with various
propargylic carbonates 2 bearing an internal alkyne group
(Scheme 2). The reaction of 3-methylindole (1a) with
propargylic carbonate 2a could be conducted on a 1 mmol
scale without significant loss of the catalytic performance,
providing the desired propargylated indolenine 3aa in 65%
yield with 99% ee and 87:13 dr. Propargylic carbonates 2b−g
a
Table 1. Optimization of Reaction Conditions
b
c
d
entry
L
yield (%)
dr
ee (%)
1
2
3
4
5
6
(R)-SEGPHOS
(R)-BINAP
59
88
82
43
N.R.
N.R.
70
62
37
83:17
86:14
87:13
81:19
93
98
98
90
(R)-Tol-BINAP
(R)-DM-BINAP
(R)-MeO-MOP
(S,S)-iPr-Pybox
(R)-BINAP
e
7
81:19
98:2
h
98
98
98
a
f
Scheme 2. Scope of Propargylic Carbonates
8
g
(R)-BINAP
(R)-BINAP
9
a
Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), Ni(cod)2
(0.02 mmol), ligand (0.04 mmol), and iPr2NEt (0.30 mmol) in
b
c
toluene (1 mL) at 40 °C for 24 h. Isolated yield. Determined by 1H
d
NMR analyses of the crude reaction mixture. Determined by chiral
HPLC analysis. With 1.2 equiv of 2a. Without the use of iPr2NEt.
e
f
g
h
With 5 mol % Ni(cod)2 and 10 mol % (R)-BINAP. The dr ratio
could not be determined by the 1H NMR analysis due to overlapping.
(1a) with 1.5 equiv of propargylic tert-butylcarbonate 2a was
performed in the presence of 10 mol % of Ni(cod)2, 20 mol %
of (R)-SEGPHOS, and 1.5 equiv of iPr2NEt in toluene at 40
°C for 24 h. We confirmed that the C-3 propargylation of 1a
took place to give indolenine derivative 3aa bearing two vicinal
chiral centers in 59% yield with 93% ee and 83:17 dr (Table 1,
entry 1). Motivated by this initial result, we next tested the
other chiral ligands. The use of (R)-BINAP as the chiral ligand
increased both the yield and enantioselectivity, affording 3aa in
88% yield with 98% ee and 86:14 dr (entry 2).16 Replacing
phenyl groups on the phosphorus atom of (R)-BINAP with p-
tolyl groups did not influence the catalytic performance (entry
3). On the other hand, changing the phenyl substituents to 3,5-
dimethylphenyl substituents decreased the yield of 3aa to 43%,
albeit with satisfactory stereoselectivity (entry 4). The reaction
did not take place using (R)-MeO-MOP and (S,S)-iPr-Pybox
as the chiral ligands (entries 5 and 6). These results indicated
that a chiral bisphosphine ligand is essential for the present
asymmetric nickel catalysis. Reducing the amount of
propargylic carbonate 2a led to a decrease in the yield (entry
7). The reaction proceeded in the absence of the iPr2NEt to
give 3aa in 62% yield with 98% ee, indicating that the use of
the base is necessary for the high reaction performance (entry
a
Reaction conditions: 1a (0.20 mmol), 2 (0.30 mmol), Ni(cod)2
(0.02 mmol), (R)-BINAP (0.04 mmol), and iPr2NEt (0.30 mmol) in
toluene (1 mL) at 40 °C for 24 h. The dr ratios were determined by
b
c
1H NMR analyses of the crude reaction mixture. 1 mmol scale. The
d
reaction was conducted at 60 °C. With a trace amount of impurity.
B
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having a wide range of substituents such as methyl, methoxy,
trifluoromethyl, ethyl ester, and halogen groups at the para
position on their phenyl rings underwent the reaction to give
the corresponding indolenine derivatives 3ab−ag in 72−89%
yields with excellent enantioselectivity and high diastereose-
lectivity. The asymmetric propargylation of 1a with propargylic
carbonates 2h−k proceeded well without a significant
influence of the meta and ortho substituents on their phenyl
rings to afford the propargylated indolenine 3ah−ak in up to
84% yield with 99% ee and 87:13 dr. Indolenine derivatives 3al
and 3am bearing naphthalene rings were obtained in high
yields and stereoselectivity. Thiophene ring-containing sub-
strate 2n reacted with 1a at 60 °C to give the propargylated
product 3an in 78% yield with 97% ee and 87:13 dr. The nickel
catalyst system also promoted the reaction of 1a with
propargylic carbonates 2o and 2p bearing the hexyl and
cyclohexyl groups, furnishing the desired product 3ao and 3ap
in satisfactory yield and high stereoselectivity. In addition, the
replacement of the methyl group at the propargylic position to
propyl (2q) and phenethyl (2r) groups did not affect the
stereoselectivity. In the reaction of 2r, the desired product 3ar
was obtained in low yield probably due to the steric effect of
the phenethyl group at the propargylic position.
the propargylation product 3ea in good yield with excellent
enantioselectivity. 3-Phenylindole (1f) also participated in the
reaction, providing the desired product 3fa in 52% yield with
90% ee and 88:12 dr. When the reaction of 5-bromo-3-
methylindole (1b) with propargylic carbonate 2s was
performed under the reaction conditions, the indolenine 3bs
was obtained in 76% yield with 99% ee and 94:6 dr. The
absolute stereochemistry of two vicinal carbon centers of 3bs
was determined to be S and R by the single crystal X-ray
crystallographic analysis.
We also examined the reaction of 2-methylindole (1g),
indole (1h), and N-methyl-3-methylindole (1i) with prop-
argylic carbonate 2a under the optimized reaction conditions
(Scheme 4).17 Although the elevated reaction temperature and
Scheme 4. Reactions of 2-Methylindole, Indole, and N-
Methyl-3-methylindole
We next examined the scope of 3-substituted indole
derivatives 1, as shown in Scheme 3. The reaction of 5-
a
Scheme 3. Scope of 3-Substituted Indole Derivatives
prolonged reaction time were required, the catalytic asym-
metric propargylation of 2-methylindole (1g) took place at the
C-3 position of 1g to give the propargylation product 3ga in
41% yield with 77% ee (Scheme 4a). The reaction of indole
(1h) with 2a was carried out in the presence of 10 mol % of
Ni(cod)2 and 20 mol % of (R)-BINAP at 60 °C, providing the
3-propargylated indole 3ha in 44% yield with 91% ee (Scheme
4b). On the other hand, the reaction of N-methyl-3-
methylindole (1i) failed to give the propargylation product
3ia under the optimized reaction conditions (Scheme 4c).
These results indicate that the present nickel catalyst system
works well for the enantioselective Friedel−Crafts propargy-
lation of 3-substituted indoles, even though the exact reason is
unclear at this stage.
a
Reaction conditions: 1 (0.20 mmol), 2a or 2s (0.30 mmol),
Ni(cod)2 (0.02 mmol), (R)-BINAP (0.04 mmol), and iPr2NEt (0.30
mmol) in toluene (1 mL) at 40 °C for 24 h. The dr ratios were
determined by H NMR analyses of the crude reaction mixture. 15
mol % of Ni(cod)2 and 30 mol % of (R)-BINAP were used. With a
trace amount of impurity.
b
1
c
To explain the stereoselectivity of the nickel-catalyzed
enantioselective Friedel−Crafts propargylation of 3-substituted
indoles, we propose the plausible transition state models as
shown in Scheme 5 based on the reaction mechanism of the
nickel-catalyzed asymmetric propargylic amination15 and the
stereochemical outcome of the products. The 3-methylindole
would attack the γ carbon atom of the η1-allenylnickel species
via favored transition state (TS1) to produce the major
stereoisomer (3S,4R)-3aa. In contrast, changing the orienta-
tion of the 3-methylindole seems to cause a steric repulsion
between the aromatic rings of 3-methylindole and the η1-
bromo-3-methylindole (1b) with propargylic carbonate 2a
smoothly proceeded using the nickel catalyst system to give the
desired product 3ba in 82% yield with 98% ee and 90:10 dr.
Three-substituted indole derivatives 1c and 1d bearing methyl
ester groups with different chain length underwent the reaction
in the presence of 15 mol % of Ni(cod)2 and 30 mol % of (R)-
BINAP to afford the propargylated indolenines 3ca and 3da in
59 and 64% yield with 98 and 96% ee, respectively. A ketone
group was also compatible with the reaction system, providing
C
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Letter
Scheme 5. Plausible Transition State Model
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of
Science (17K05794). We thank Mr. Kohei Oshimoto (Nihon
University) for his experimental support.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00465.
Experimental details and procedures; X-ray crystal
structure of 3bs; NMR spectra; HPLC chromatograms
(PDF)
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H.; Verma, A. K.; Choi, E. H. Biomedical Importance of Indoles.
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Accession Codes
CCDC 1969975 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.
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AUTHOR INFORMATION
Corresponding Authors
■
Hiroaki Tsuji − Department of Chemistry, College of
Humanities & Sciences, Nihon University, Tokyo 156-8550,
Japan; orcid.org/0000-0002-8899-3435; Email: tsuji@
chs.nihon-u.ac.jp
Motoi Kawatsura − Department of Chemistry, College of
Humanities & Sciences, Nihon University, Tokyo 156-8550,
Japan; orcid.org/0000-0002-8341-6866;
Email: kawatsur@chs.nihon-u.ac.jp
Authors
Yusuke Miyazaki − Department of Chemistry, College of
Humanities & Sciences, Nihon University, Tokyo 156-8550,
Japan
Biao Zhou − Department of Chemistry, College of Humanities &
Sciences, Nihon University, Tokyo 156-8550, Japan;
orcid.org/0000-0002-4138-9425
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00465
Notes
The authors declare no competing financial interest.
D
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Quaternary Carbon Centers: Copper-Catalyzed Enantioselective
Propargylation of Indoles with Propargylic Esters. Angew. Chem., Int.
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(14) For examples, see: (a) Nishibayashi, Y.; Wakiji, I.; Hidai, M.
Novel Propargylic Substitution Reactions Catalyzed by Thiolate-
Bridged Diruthenium Complexes via Allenylidene Intermediates. J.
Am. Chem. Soc. 2000, 122, 11019−11020. (b) Nishibayashi, Y.;
Wakiji, I.; Ishii, Y.; Uemura, S.; Hidai, M. Ruthenium-Catalyzed
Propargylic Alkylation of Propargylic Alcohols with Ketones:
Straightforward Synthesis of γ-Keto Acetylenes. J. Am. Chem. Soc.
2001, 123, 3393−3394. (c) Nishibayashi, Y.; Yoshikawa, M.; Inada,
Y.; Hidai, M.; Uemura, S. Ruthenium-Catalyzed Propargylation of
Aromatic Compounds with Propargylic Alcohols. J. Am. Chem. Soc.
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Tanabe, Y.; Miyake, Y.; Nishibayashi, Y. Copper-Catalyzed
Enantioselective Propargylic Amination of Propargylic Esters with
Amines: Copper−Allenylidene Complexes as Key Intermediates. J.
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(15) Watanabe, K.; Miyazaki, Y.; Okubo, M.; Zhou, B.; Tsuji, H.;
Kawatsura, M. Nickel-Catalyzed Asymmetric Propargylic Amination
of Propargylic Carbonates Bearing an Internal Alkyne Group. Org.
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́
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(e) Rueping, M.; Raja, S.; Nunez, A. Asymmetric Brønsted Acid-
Catalyzed Friedel-Crafts Reactions of Indoles with Cyclic Imines-
Efficient Generation of Nitrogen-Substituted Quaternary Carbon
Centers. Adv. Synth. Catal. 2011, 353, 563−568. (f) Feng, J.; Yan, W.;
Wang, D.; Li, P.; Sun, Q.; Wang, R. The Highly Enantioselective
Addition of Indoles and Pyrroles to Isatins-Derived N-Boc Ketimines
Catalyzed by Chiral Phosphoric Acids. Chem. Commun. 2012, 48,
8003−8005. (g) Kano, T.; Takechi, R.; Kobayashi, R.; Maruoka, K.
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(9) Selected examples, see: (a) Bandini, M.; Cozzi, P. G.;
Melchiorre, P.; Umani-Ronchi, A. Kinetic Resolution of Epoxides
by a C-C Bond−Forming Reaction: Highly Enantioselective Addition
of Indoles to cis, trans, and meso Aromatic Epoxides Catalyzed by
[Cr(salen)] Complexes. Angew. Chem., Int. Ed. 2004, 43, 84−87.
(b) Lin, S.; Jacobsen, E. N. Thiourea-Catalysed Ring Opening of
Episulfonium Ions with Indole Derivatives by Means of Stabilizing
Non-Covalent Interactions. Nat. Chem. 2012, 4, 817−824. (c) Xiong,
H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. Copper-Catalyzed Highly
Enantioselective Cyclopentannulation of Indoles with Donor−
Acceptor Cyclopropanes. J. Am. Chem. Soc. 2013, 135, 7851−7854.
(d) Wales, S. M.; Walker, M. M.; Johnson, J. S. Asymmetric Synthesis
of Indole Homo-Michael Adducts via Dynamic Kinetic Friedel−
Crafts Alkylation with Cyclopropanes. Org. Lett. 2013, 15, 2558−
2561. (e) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Cao, Y.; Ma,
Y.; Kong, W.; Sun, Q.; Wang, R. Highly Enantioselective Ring-
Opening Reactions of Aziridines with Indole and Its Application in
the Building of C3-Halogenated Pyrroloindolines. Chem. - Eur. J.
2014, 20, 16478−16483. (f) Ge, C.; Liu, R.-R.; Gao, J.-R.; Jia, Y.-X.
Cu(I)-Catalyzed Enantioselective Friedel−Crafts Alkylation of
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(16) For the formation of 3aa, the reactivity of propargylic esters
bearing methyl carbonate and pivalate as the leaving groups was
inferior to that of propargylic tert-butyl carbonate 2a under the
optimized reaction conditions (For propargylic methyl carbonate:
29% NMR yield, 83:17 dr. For propargylic pivalate: trace).
(17) We confirmed that the propargylation of 2,3-dimethylindole
with 2a proceeded at the C-3 position under the optimized reaction
conditions to give the propargylation product in 25% yield with 91%
ee and 46:54 dr.
(10) Selected examples, see: (a) Trost, B. M.; Quancard, J.
Palladium-Catalyzed Enantioselective C-3 Allylation of 3-Substi-
tuted-1H-Indoles Using Trialkylboranes. J. Am. Chem. Soc. 2006,
E
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Org. Lett. XXXX, XXX, XXX−XXX