Asymmetric Synthesis of 3-Methyleneindolines via Rhodium(I)-Catalyzed Alkynylative Cyclization of N-(o-Alkynylaryl)imines

Article abstract of DOI:10.1021/acs.orglett.1c01518

The first asymmetric synthesis of 3-methyleneindolines from alkynyl imines has been developed via a rhodium-catalyzed tandem process: regioselective alkynylation of the internal alkynes and subsequent intramolecular addition to the imines. The reaction pr

Full text of DOI:10.1021/acs.orglett.1c01518

pubs.acs.org/OrgLett
Letter
Asymmetric Synthesis of 3‑Methyleneindolines via Rhodium(I)-
Catalyzed Alkynylative Cyclization of N‑(o‑Alkynylaryl)imines
Shi-Yi Yuan, Qi-Qi Yan, Dan Wang, Ting-Ting Dan, Long He, Cheng-Yu He,* Wen-Dao Chu,*
and Quan-Zhong Liu*
Cite This: Org. Lett. 2021, 23, 4823−4827
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ABSTRACT: The first asymmetric synthesis of 3-methyleneindo-
lines from alkynyl imines has been developed via a rhodium-
catalyzed tandem process: regioselective alkynylation of the
internal alkynes and subsequent intramolecular addition to the
imines. The reaction proceeded with unconventional chemo-
selectivity and provided 3-methyleneindolines with good yields (up
to 82% yield) and high enantioselectivities (up to 97% ee).
Moreover, this transformation also features mild reaction
conditions, perfect atom economy, and a broad substrate scope.
hiral indoline scaffolds are found in numerous bio-
logically active molecules and have a broad application in
Scheme 1. Previous Works and Reaction Design
C
pharmaceutical chemistry. As a result, many asymmetric
synthetic approaches have been developed to generate such
ring systems.1 Among them, transition-metal-catalyzed intra-
molecular tandem cyclization of unsaturated hydrocarbons and
imines is an efficient way to access the substituted chiral
indoline. In 2015, Buchwald et al. reported the first copper-
catalyzed asymmetric cyclization of alkenyl imines to construct
2,3-disubstituted indolines via enantioselective Cu−H addition
to aryl olefins and subsequent nucleophilic addition of in situ
generated organocopper to imines (Scheme 1a).2 In 2018, Yun
and Xiong reported independently the copper-catalyzed
intramolecular borylative cyclization of alkenyl imines for the
synthesis of enantioenriched boron-containing 2,3-disubsti-
tuted indolines (Scheme 1a).3 However, a study in which
alkynyl imines were applied to catalytically synthesize chiral
indolines has not been disclosed so far.4 There are mainly two
types of reactions in the metal-catalyzed cyclization of alkynyl
imines (Scheme 1b): (1) the nucleophilic endo-attack of
nitrogen of N-(o-alkynylaryl)imines to an o-alkynyl group to
form the metal-bound azomethine ylides and then cyclo-
addition with electron-rich alkenes or N-allenamides to give
the corresponding polycyclic indole derivatives;5 (2) the
nucleophilic endo-attack of nitrogen of aryl aldimines to an
o-alkynyl group to form electropositive imine intermediates
that were subsequently tripped by nucleophiles to afford
dihydroisoquinolines or the imine group undergoes nucleo-
philic addition first to form electronegative amino intermedi-
ates, which were then trapped by alkynyl.6 Under both of the
reaction platforms of metal-catalyzed cyclization of alkynyl
imines, the electrons all transferred from imines to alkynes in
the tandem process, and the reaction in which the electrons
flow from alkynes to imines is rare (Scheme 1c).7 As a part of
Received: May 6, 2021
Published: June 3, 2021
https://doi.org/10.1021/acs.orglett.1c01518
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4823−4827
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our continuous efforts on the addition reactions of imines and
unsaturated imines,8 we envisioned that the opposite chemo-
selectivity, i.e., the organometal species reacted with alkynes
first rather than imines, might be realized under a carefully
optimized asymmetric reaction system.
Table 1. Optimization of the Reaction Conditions
The carbon−carbon triple bond is a versatile functional
group that has abundant derivatization possibilities.9 The
transition-metal-catalyzed hydroalkynylation of internal al-
kynes with terminal alkynes has been extensively studied for
its perfect atom economy in the synthesis of functionalized
alkynes.10 Due to the wealth of carbo- and heterocycles in
natural products, it is of great importance to develop efficient
asymmetric annulation protocols; however, the synthesis of
enantioenriched heterocycles via transition-metal-catalyzed
alkynylative tandem reactions of alkynes is quite limited.11
Consequently, we proposed the rhodium-catalyzed enantiose-
lective alkynylative cyclization of N-(o-alkynylaryl)imines, even
though several challenges were encountered in this process
(Scheme 1d). The first issue is the unconventional chemo-
selectivity: the rhodium acetylide complex should undergo
cross addition with aryl alkynes rather than imines. The second
issue is the enantioselectivity: a suitable catalytic system should
be found to effectively distinguish the prochiral imines during
the intramolecular addition of alkenyl rhodium. If successful,
this could be an efficient path to the construction of
enantioenriched 3-methyleneindolines.12
With these considerations in mind, we initiated our
investigation by searching for a suitable chiral ligand for the
alkynylative cyclization reaction of alkynyl imine 1a and
(triisopropylsilyl)acetylene 2a using [Rh(COD)Cl]2 as the
catalyst and MgSO4 as the additive to prevent hydrolysis of the
imine substrates. A screening of frequently used ligands (L1−
L4) indicated that the efficiency was extremely low for our
desired reaction (Table 1, entries 1−4), and the major side
product was the N-substituted indole 3a′ derived from the
opposite chemoselectivity. (S)-SYNPHOS (L5) could pro-
mote this transition with a higher yield but showed almost no
enantioselectivity (entry 5). To our delight, the desired
product 3a was obtained with a much higher yield and
moderate enantioselectivity when (R,R)-Ph-BPE (L6) was
applied as the chiral ligand (entry 6). Then, we examined the
solvent effects and found that tetrahydrofuran was privileged in
the promotion of both reactivity and enantioselectivity (71%
yield, 77% ee, entry 7). After evaluation of a series of bases,
Cs2CO3 was proved to be vital to this transformation; other
bases such as its homologue K2CO3 only led to 14% yield and
27% ee (entry 8). This finding suggested that the cesium ion
may play a role in the enantioselective addition step via
coordination with imine. Decreasing the reaction temperature
resulted in an enhancement of enantioselectivities but a large
erosion of the yields (entries 9−11). Applying 1.5 equiv of
Cs2CO3 gave an improved yield to 60% (entry 12). Notably, in
the absence of MgSO4, the reaction was obviously inhibited to
give 8% yield (entry 13), and the addition of 4 Å molecular
sieve led no reaction as well (entry 14). These results indicated
that MgSO4 played an important role in the cascade reaction
indeed, but not the initially supposed role of dehydration. We
suspected that a trace amount of hydrate water in the MgSO4
may accelerate the reaction, so 20 equiv water was applied
instead of MgSO4. Gratifyingly, the addition of free water
significantly promoted the reactivity and afforded the product
3a with satisfactory yield and enantioselectivity (83% yield and
91% ee, entry 15). However, applying a stoichiometric amount
a
b
b
c
entry
L
solvent
T (°C) conv (%) yield (%) ee (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
THF
THF
THF
THF
60
60
60
60
60
60
60
60
40
30
25
30
30
30
30
30
76
56
35
55
77
100
100
45
92
87
53
85
18
<5
100
38
15
13
6
27
24
22
5
19
47
62
71
14
61
56
24
60
8
2
50
77
27
82
83
86
88
d
8
9
10
11
e
12
THF
THF
THF
THF
f
13
g
14
h
15
83
27
91
i
16
THF
a
b
Reactions were performed under an Ar atmosphere. Determined by
c
1H NMR analysis of unpurified mixtures. Determined by HPLC
d
e
analysis. K2CO3 was applied instead of Cs2CO3. 1.5 equiv of
Cs2CO3 was used. Mg2SO4 was not added. 50 mg of 4 Å MS was
applied instead of Mg2SO4. 20 equiv of H2O was applied instead of
Mg2SO4. 1 equiv of H2O was applied instead of Mg2SO4.
f
g
h
i
of water to the model reaction only led to 27% NMR yield,
which indicates that the equivalent of water has an important
influence on the reaction.
With the optimal reaction conditions established, the scope
of the N-(o-alkynylaryl)imines 1 was examined (Scheme 2).
We found that substrates derived from various aryl aldehydes
worked well in this reaction. The para-substituted and meta-
substituted phenyl substrates, including those with electron-
deficient substituents (NO2, F, Cl, Br) as well as electron-rich
substituents (Me, CH2Cl, Ph), were all converted smoothly
into the corresponding chiral indolines with moderate to good
yields and high ee values (52−80% yield, 77−92% ee, 3a−3i).
Pyridine-substituted alkynyl imine also gave the desired
cyclization product 3j, albeit with slightly lower ee value
(76% ee). A variety of substrates bearing electron-withdrawing
and electron-donating groups at the 4/5-position of the aryl
nucleus of N-(o-alkynylaryl)imines underwent the reaction
with high efficiency (62−82% yield, 82−94% ee, 3k−3o). As
for the alkynyl motif in the alkynyl imines, the substrate with
an electron-donating group (Me) at the 4-position of
phenylacetylene reacted smoothly under the standard con-
ditions to afford the corresponding chiral indoline with 67%
yield and 86% ee (3r). However, substrate with an electron-
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Letter
a
Scheme 2. Substrate Scope of N-(o-Alkynylaryl)imines
Scheme 3. Gram-Scale Reaction and Synthetic
Transformations
aromatization proneness, 3-methyleneindoline 3a was readily
transformed into 3-propargyindole 5a with diminished ee value
(95% yield, 68% ee) in the presence of p-TsOH. The
unexpected 3-allylindole 6a could be obtained via selective
reduction and isomerization under Pd/C hydrogenation
conditions, but unfortunately, the enantioselectivity in the
process could not be maintained (68% yield, 34% ee). The
isomerization was likely via an allyl-Pd intermediate, which
corresponded to the presumption of the acidity of the proton
in the stereocenter.
Based on the investigation of the importance of water and
cesium carbonate (Table 1, entries 13−16) and literature
studies,11b a possible catalytic cycle of this protocol was
proposed (Scheme 4). First, the catalytic active Rh(I)−
a
Reaction conditions: 1 (0.10 mmol), 2a (1.5 equiv), [Rh(COD)Cl]2
(10 mol %), Cs2CO3 (1.5 equiv), H2O (20 equiv), and (R,R)-Ph-BPE
(12 mol %) in THF (2 mL) at 30 °C under Ar for 12 h. The yield
refers to isolated yield. The ee value was determined by HPLC.
withdrawing group such as CF3 at the 4-position of
phenylacetylene only led to the product with 54% yield and
71% ee (3r), presumably due to the decreased nucleophilic
reactivity of the alkenyl rhodium. In addition, the enyne
substrate was also suitable for this transition and gave the
cyclization product 3s in 63% yield and 68% ee. Alkyl alkyne
derived alkynyl imine substrate had enough reactivity in this
transformation, but the stereocontrol was somewhat inefficient
(65% yield, 52% ee, 3t). Next, we studied the alkynylation
reagent scope. Various silyl acetylenes such as (trimethylsilyl)-
acetylene, (triethylsilyl)acetylene, and (tert-butyldimethylsilyl)-
acetylene provided the corresponding products with high
yields and excellent ee values (63−80% yield, 95−97% ee, 3u−
3w). Phenylacetylene was not suitable for this reaction, and the
corresponding product was not detected at all. The absolute
configuration of the cyclization product 3a was unequivocally
established as (2S)-3a by X-ray crystallography analysis of its
derivative 3a-Ns.
Scheme 4. Proposed Catalytic Cycle
To demonstrate the synthetic applicability of this method, a
gram-scale reaction of 1a was carried out with only 5.0 mol %
catalyst loading, and the enantioenriched 3-methyleneindoline
3a was isolated with 72% yield and 88% ee (Scheme 3). Under
general desilication conditions, the desired terminal-alkyne-
contained indoline could not be obtained, and 3-allenylindole
4a was afforded with 86% yield instead, probably due to the
acidity of the proton in the stereocenter and the intense
tendency of aromatization.10b Taking advantage of the
acetylide complex M1 was obtained from Rh precatalyst and
2a under basic reaction conditions. Subsequently, M1 reacted
with internal alkyne of the substrate via syn-insertion to afford
vinyl rhodium intermediate M2, which could be trapped by the
prochiral imine through asymmetric addition to provide the
N−Rh(I) complex M3. The cesium ion might act as a Lewis
acid to coordinate with imine to accelerate the cyclization
reaction and take part in the stereocontrol.13 Finally, the M3
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reacted with water to give the indoline product 3a and the
intermediate hydroxy rhodium, which could regenerate the
active Rh(I)−acetylide complex M1 via σ-metathesis with
terminal alkyne 2a. Two points need to be noted in the
transition: On one hand, applying other chiral ligands such as
L1−L4, the Rh(I)-acetylide complex M1 may reacted with
imine first to afford the intermediate M2′, which led to the side
product 3a′. On the other hand, the water might play two roles
in the reaction: (1) it reacted with N-metalated intermediates
to give the indoline products and hydroxy rhodium (2) it
reacted as cosolvent to make Cs2CO3 dissolved to accelerate
the reaction.
In conclusion, we have developed the first Rh-catalyzed
asymmetric alkynylative cyclization of N-(o-alkynylaryl)imines
and enabled highly enantioselective synthesis of 3-methyl-
eneindolines. Compared with previous metal-catalyzed annu-
lation reactions of alkynyl imines, this reaction was accelerated
by free water and proceeded with an unconventional
chemoselectivity. In addition, this tandem process featured
100% atom economy, broad functional group tolerance, and
versatile derivation of product. Further mechanism study and
investigation of metal-catalyzed asymmetric cyclization of
alkynyl imines are underway in our laboratory and will be
reported in due course.
Chemical Engineering, China West Normal University,
Nanchong 637002, China
Qi-Qi Yan − Chemical Synthesis and Pollution Control Key
Laboratory of Sichuan Province, College of Chemistry and
Chemical Engineering, China West Normal University,
Nanchong 637002, China
Dan Wang − Chengdu Institute of Product Quality Inspection
Co., Ltd., Chengdu 610000, China
Ting-Ting Dan − Chemical Synthesis and Pollution Control
Key Laboratory of Sichuan Province, College of Chemistry
and Chemical Engineering, China West Normal University,
Nanchong 637002, China
Long He − College of Chemistry and Materials Engineering,
Guiyang University, Guiyang 550005, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01518
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We express our gratitude to the National Natural Science
Foundation of China (Nos. 21772158, 21801208, and
21572183), The Science & Technology Department of
Sichuan Province (Nos. 2019YJ0339 and 2020YJ0394), and
The Fundamental Research Funds of China West Normal
University for generous financial support.
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REFERENCES
Experimental procedures; 1H NMR and 13C NMR
spectra; HPLC spectra; X-ray crystallographic data
(PDF)
■
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Accession Codes
CCDC 2077763 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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AUTHOR INFORMATION
Corresponding Authors
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Cheng-Yu He − Chemical Synthesis and Pollution Control
Key Laboratory of Sichuan Province, College of Chemistry
and Chemical Engineering, China West Normal University,
Nanchong 637002, China; orcid.org/0000-0003-3426-
279X; Email: hecy@cwnu.edu.cn
Wen-Dao Chu − Chemical Synthesis and Pollution Control
Key Laboratory of Sichuan Province, College of Chemistry
and Chemical Engineering, China West Normal University,
Nanchong 637002, China; orcid.org/0000-0003-0058-
2461; Email: chuwendaonpo@126.com
Quan-Zhong Liu − Chemical Synthesis and Pollution Control
Key Laboratory of Sichuan Province, College of Chemistry
and Chemical Engineering, China West Normal University,
Nanchong 637002, China; Email: quanzhongliu@
cwnu.edu.cn
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